Post on 02-Apr-2021
Selective synthesis and reactivity of indolizines
María José González Soria
Instituto de Síntesis Orgánica
Facultad de Ciencias
SELECTIVE SYNTHESIS AND REACTIVITY OF
INDOLIZINES
MARÍA JOSÉ GONZÁLEZ SORIA
Alicante, 26/07/2018
Manuscript submitted for a PhD in Organic Synthesis, University of Alicante
Mention of International PhD
Scientific advisor:
FRANCISCO ALONSO VALDÉS
Agradecimientos
Quiero agradecer en especial a Luis y a mi madre, a mis hermanas y hermanos y a
Juan por todo el apoyo recibido durante este tiempo.
Asimismo, agradezco a Francisco Alonso por su ayuda y por darme la oportunidad
de trabajar en su grupo de investigación, al Instituto de Síntesis Orgánica y a la
Generalitat Valenciana por el apoyo económico. También a mi familia orgánica,
Juani, Iris y Xavi, por estar siempre a mi lado cuando más lo he necesitado tanto en
lo profesional como en lo personal. A Nieves, Manu, María y Edgar, y a todos los
compañeros del laboratorio y, en general, a todos los miembros del Departamento de
Química Orgánica e Instituto de Síntesis Orgánica de la Universidad de Alicante,
muchas gracias por todo.
Y gracias a mi padre, sin su sacrificio no habría podido llegar hasta aquí.
Index
7
PROLOGUE 7
SUMMARY 11
GENERAL INTRODUCTION 15
A. Introduction to nanoparticles 17
A.1. Properties of metallic nanoparticles 17
A.2. Synthesis of metallic nanoparticles 18
A.3. Metallic nanoparticles in catalysis 21
A.4. Copper nanoparticles (CuNPs) 23
B. Introduction to indolizines 27
B.1. Structure and applications 27
B.2. Synthetic methods 29
GENERAL OBJECTIVES 37
CHAPTER I. Multicomponent synthesis of 1-
aminoindolizines
41
1. Introduction 43
1.1.1. Multicomponent reactions in heterocyclic
synthesis
43
1.1.2. Multicomponent synthesis of indolizines 44
2. Results and discussion 48
1.2.1. Previous study 48
1.2.2. Substrate scope 49
1.2.3. Reutilization of the catalyst 54
1.2.4. Comparison with commercial catalysts 54
1.2.5. Reaction mechanism 57
1.2.6. Biological activity 59
CHAPTER II. Catalytic hydrogenation of indolizines:
synthesis of indolizidines
65
1. Introduction 67
2. Results and discussion 72
2.2.1. Optimization of the reaction 72
2.2.2. Reutilization of the catalysts 76
Index
8
2.2.3. Substrate scope 77
2.2.4. Stereochemistry and mechanism 80
2.2.5. Debenzylation of indolizidines 82
2.2.6. Biological activity 86
CHAPTER III. Reactivity of indolizines: synthesis of dyes 87
1. Introduction 89
2. Results and discussion 95
3.2.1. Substrate scope 95
3.2.2. Structural analysis 100
3.2.3. Reaction mechanism 107
3.2.4. Optical properties 110
3.2.5. Metal detection 115
CHAPTER IV. Reactivity of indolizines with
nitrosocompounds: synthesis of β-enaminones
and pyrroles
119
1. Introduction 121
4.1.1. β-Enaminones 121
4.1.2. Pyrroles 123
2. Results and disussion 127
4.2.1. Synthesis of β-enaminones 127
4.2.2. Selectivity in the synthesis of β-enaminones 133
4.2.3. Synthesis of pyrroles 135
4.2.4. Reaction mechanism 139
Conclusions 157
Resumen
Conclusiones 161
Experimental part 165
General 167
Experimental part of chapter I 168
Experimental part of chapter II 187
Index
9
Experimental part of chapter III 199
Experimental part of chapter IV 210
Selected NMR spectra 229
Abbreviations 239
Prologue
13
Part of the results reported in this thesis have already been published:†
- “Synthetic and mechanistic studies on the solvent-dependent copper-
catalyzed formation of indolizines and chalcones” Albaladejo, M. J.; Gonzalez-Soria,
M. J.; Alonso, F. ACS Catalysis 2015, 5, 3446.
- “Synthesis of aminoindolizidines through the chemoselective and
diastereoselective catalytic hydrogenation of indolizines” Albaladejo, M. J.;
Gonzalez-Soria, M. J.; Alonso, F. J. Org. Chem. 2016, 81, 9707.
- “Catalyst-free remote-site C-H alkenylation: regio- and diastereoselective
synthesis of solvatochromic dyes” Albaladejo, M. J.; Gonzalez-Soria, M. J.; Alonso,
F. Green Chemistry 2018, 20, 701.
- “Substrate-controlled divergent synthesis of enaminones or pyrroles from
indolizines and nitrosocompounds” Gonzalez-Soria, M. J.; Alonso, F. Manuscript in
preparation.
† This research has been generously supported by the Spanish Ministerio de Economía y
Competitividad, the Generalitat Valenciana, the Instituto de Síntesis Orgánica and the University of
Alicante.
Summary
17
SUMMARY
The present doctoral thesis report describes the synthesis and reactivity
of indolizines.
In chapter I, the multicomponent synthesis of 1-aminoindolizines is
presented using CuNPs/C as catalyst in dichloromethane. A reaction
mechanism is proposed based on the participation of propargylamines as
intermediates.
In chapter II, the catalytic hydrogenation of indolizines is studied,
introducing a new straightforward methodology to obtain indolizidines with a
high diastereoselectivity.
In chapter III, the reactivity of indolizines in acidic media is
investigated. A new series of indolizine dyes is reported, the optical and
structural properties of which are extensively studied.
In chapter IV, a new synthesis of β-enaminones and pyrroles is
developed from the metal-free reaction of indolizines with nitrosocompounds.
General introduction
21
GENERAL INTRODUCTION
A. INTRODUCTION TO NANOPARTICLES
A.1. Properties of metallic nanoparticles
The particles with a size between 1 and 100 nm are considered
nanoparticles (NPs).1 The Greek word “nano” refers to the variation of a
property in a magnitude of 10–9
. The nanometer is the length unit equivalent to
one billionth of a meter (1 nm = 10–9
m). Commonly, it is a unit used to
measure the wavelength of ultraviolet and infrared radiation and visible light.
In order to give an idea about how small a nanometer is, different examples
can be compared: the diameter of human hair is between 10.000 and 50.000
nm, the viruses have a diameter of about 80 nm, and the molecule of fullerene
C60 has an icosahedron structure with a diameter of ca. 1 nm (Figure 1).
Figure 1. Comparison of the size of atoms, NPs and some other biological entities.
1a
The properties of metal nanoparticles (MNPs) differ from those of the
bulk solid. Changes in the physical form also result in changes in the optical,
electronic, magnetic and catalytic properties of the metal. A very peculiar
feature of MNPs is their high surface-to-volume ratio, what confers greater
chemical reactivity on them when compared with the equivalent bulk solid.
1 Reviews and monographs: (a) Gu, H.; Xu, K.; Xu, C.; Xu, B. Chem. Commun. 2006, 941. (b)
Nanoparticles: From Theory to Application, 2nd
Edn.; Schmid, G., Ed.; Wiley-VCH: Weinheim, 2010. (c)
Goesmann, H.; Feldmann, C. Angew. Chem. Int. Ed. 2010, 49, 1362. (d) Vollath, D. Nanomaterials: An
Introduction to Synthesis, Properties and Applications, 2nd Edn.; Wiley-VCH: Weinheim, 2013.
General Introduction
22
A.2. Synthesis of metallic nanoparticles
MNPs can be obtained through physical and chemical methods. Within
these two types of methods, different techniques can be mentioned as can be
seen in Scheme 1. It should be noted that the chemical methods are the most
used ones because of the simplicity to implement and, in addition, the higher
control of the size of the particle attained.2 The chemical reduction of salts of
transition metals is the most widely used method to generate MNPs in
suspension, commonly called metallic colloids.
Scheme 1. Classification of the methods of preparation of NPs.
Turkevich was the one who proposed a mechanism for the formation of
nanoclusters based on the nucleation, growth and agglomeration of metallic
2 Reviews and monographs: (a) Roucoux, A.; Schulz, J.; Patin, H. Chem. Rev. 2002, 102, 3757. (b)
Cushing, B. L.; Kolesnichenko, V. L.; O’Connor, C. J. Chem. Rev. 2004, 104, 3893. (c) Dahl, J. A.; Maddux,
B. L. S.; Hutchison, J. E. Chem. Rev. 2007, 107, 2228. (c) Inorganic Nanoparticles: Synthesis, Applications,
and Perspectives; Altavilla, C., Ciliberto, E., Eds.; CRC Press: London, 2010. (d) An, K.; Alayoglu, S.;
Somorjai, G. A. J. Colloid Interface Sci. 2012, 373, 1. (e) Xu, C.; De, S.; Balu, A. M.; Ojeda, M.; Luque, R.
Chem. Commun. 2015, 51, 6698.
Chemical
Methods
- Chemical reduction of metal salts
- Thermal, photochemical or sonochemical
decomposition
- Reduction and displacement of ligands from
organometallic compounds
- Microemulsion techniques
- Electrochemical reduction
- Microwaves
- Solvothermal methods
- Biologic methods
Physical
Methods
- Condensation of metal atomic vapors
- Laser ablation
- Pulse wire discharge (PWD)
- Mechanical grinding
-
General introduction
23
atoms until the formation of the particle.3 This mechanism, which still remains
valid, is first based on the reduction of the metal salt to the corresponding
zero-valent metal atoms. Then, these metallic atoms act as centers of
nucleation, giving rise to clusters whose growth will continue as long as the
supply of atoms is maintained, thus forming the particle (Figure 2).
Figure 2. Mechanism for the formation of MNPs proposed by Turkevich.
NPs have a large surface area compared to their mass, which generates
an excess of free energy on their surface making them thermodynamically
unstable. Therefore, a crucial aspect in the formation of NPs is their
stabilization. Two NPs may be attracted to one another by van der Waals
forces and, in the absence of repulsive forces counteracting this attraction,
agglomeration may occur. There are different methods to counteract this
attraction. Depending on the type of protection used, the stabilization of
metallic NPs in solution can be classified in:4
a) Electrostatic: double layer of anions and cations is formed that
interacts with the surface of the metallic NP avoiding the agglomeration.
b) Steric: stabilization occurs by adsorption of molecules on the surface,
such as polymers, surfactants, dendrimers or ligands.
c) Electrosteric: a combination of the above two effects; the
nanoparticles can be stabilized in micelles or microemulsions.
d) Solvents: THF, THF/MeOH or long-chain alcohols.
3 (a) Turkevich, J.; Stevenson, P. C.; Hillier, J. Discuss. Faraday Soc. 1951, 11, 55. (b) Turkevich, J. Gold
Bull. 1985, 18, 86. (c) Review: Wu, Y.; Wang, D.; Li, Y. Chem. Soc. Rev. 2014, 43, 2112. 4 Metal Nanoclusters in Catalysis and Materials Science. The Issue of Size Control; Corain, B., Schmid, G.,
Toshima, N., Eds.; Elsevier: Amsterdam, 2008.
General Introduction
24
The synthesis of metal nanoparticles by chemical reduction of metal
salts can be carried out using different reducing agents. The most commonly
used reducing agents are oxidizable solvents (usually alcohols),5 H2,
6 CO,
7
hydrides,8 some salts such as sodium citrate or activated alkali metals, among
others.
The synthesis of MNPs based on the use of activated alkali metals has
been extensively developed in the last decade in our research group. Metal
lithium and an arene as an electron transfer agent are used in this
methodology, in which highly reactive metals commonly known as Rieke
metals are generated.9
The process involves a first electron transfer from the alkali metal to the
arene, generating a radical anion (Ar•–
). The radical anion can be further
reduced giving rise to a dianionic species (Ar2–
). Both, the anions and dianions
mentioned can act as electron transfer agents and reduce different metal salts
to generate nanoparticles of transition metals in low-valence state (Scheme 2).
Scheme 2. Generation of MNPs by reduction with the alkali metal-arene system.
A widely used electron carrier is 4,4'-di-tert-butylbiphenyl (DTBB),
because its radical anion is a very potent reducing agent (reduction potential:
5 Shiraishi, Y.; Arakawa, D.; Toshima, N. Eur. Phys. J. E: Soft Matter Biol. Phys. 2002, 8, 377.
6 Boutonnet, M.; Kizling, J.; Touroude, R.; Maire, G.; Stenius, P. Appl. Catal. 1986, 20, 163.
7 Kopple, K.; Meyerstein, D.; Meisel, D. J. Phys. Chem. 1980, 84, 870.
8 (a) Mayer, A. B. R.; Johnson, R. W.; Hausner, S. H.; Mark, J. E. J. Macromol. Sci., Pure Appl. Chem. 1999,
A36, 1427. (b) Crooks, R. M.; Zhao, M.; Sun, L.; Chechik, V.; Yeung, L. K. Acc. Chem. Res. 2001, 34, 181. 9 Reviews: (a) Rieke, R. D. Crit. Rev. Surf. Chem. 1991, 1, 131. (b) Rieke, R. D.; Hanson, M. V. Tetrahedron
1997, 53, 1925. (c) Rieke, R. D. Aldrichimica Acta 2000, 33, 52. (d) See, also: Schöttle, C.; Bockstaller, P.;
Popescu, R.; Gerthsen, D.; Feldmann, C. Angew. Chem. Int. Ed. 2015, 54, 9866.
General introduction
25
E1/2 = –2.14 eV). In addition, it favors the transfer of electrons against other
possible secondary reactions (protonation or homocoupling of the arene), due
to the steric contribution of the two tert-butyl groups present in its structure.
This method has allowed to obtain MNPs, such as Ni,10
Cu,11
and Fe,12
with uniform size and high reactivity against different functional groups. An
advantage of this methodology is that the synthesis of MNPs occurs at ambient
temperature and in short reaction times, without the need for nucleating agents
or stabilizers.
A.3. Metallic nanoparticles in catalysis13
Transition metals represent a fundamental tool in organic synthesis,
since they are capable of promoting a large number of reactions, both in the
transformation of different functional groups and in the coupling reactions for
the formation of carbon-carbon bonds.14
However, many of these metals do
not exhibit a natural or spontaneous reactivity to organic molecules and, in
many cases, may not be due to the chemical properties inherent in the metal
but they are in an inadequate physical form. It is the case of metals with a low
surface area or with a surface deactivated by the existence of oxide films or
salts.
10
Reviews: (a) Alonso, F.; Yus, M. Chem. Soc. Rev. 2004, 33, 284. (b) Alonso, F.; Yus, M. Pure Appl.
Chem. 2008, 80, 1005. (c) Alonso, F.; Riente, P.; Yus, M. Acc. Chem. Res. 2011, 44, 379. (d) Yus, M.;
Alonso, F. e-EROS Encyclopedia of Reagents for Organic Synthesis [Online], 27 May 2014. 11
(a) Alonso, F.; Vitale, C.; Radivoy, G.; Yus, M. Synthesis 2003, 443. (b) Alonso, F.; Moglie, Y.; Radivoy,
G.; Vitale, C.; Yus, M. Appl. Catal. A: Gen. 2004, 271, 171. (c) Radivoy, G.; Alonso, F.; Moglie, Y.; Vitale,
C.; Yus, M. Tetrahedron 2005, 61, 3859. (d) Moglie, Y.; Mascaró, E.; Nador, F.; Vitale, C.; Radivoy, R.
Synth. Commun. 2008, 38, 3861. 12
(a) Alonso, F.; Moglie, Y.; Radivoy, G.; Vitale, C.; Yus, M. Tetrahedron 2006, 62, 2812. (b) Moglie, Y.;
Alonso, F.; Vitale, C.; Yus, M.; Radivoy, G. Appl. Catal. A: Gen. 2006, 313, 94. (c) Moglie, Y.; Radivoy, G.;
Vitale, C. Tetrahedron Lett. 2008, 49, 1828. 13
Monographs: (a) Nanoparticles and Catalysis; Astruc, D., Eds.; Wiley-VCH: Weinheim, 2008. (b)
Selective Nanocatalysts and Nanoscience: Concepts for Heterogeneous and Homogeneous Catalysis;
Zecchina, A.; Bordiga, S.; Groppo, E., Eds.; Wiley-VCH: Weinheim, 2011. (c) Nanocatalysis: Synthesis and
Applications; Polshettiwar, V., Asefa, T., Eds.; John Wiley & Sons: Hoboken (NJ), 2013. (d)
Nanomaterials in Catalysis; Serp, P.; Philippot K., Eds.; Wiley-VCH: Weinheim, 2013. 14
Transition Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004.
General Introduction
26
These problems can be attenuated, or even eliminated, if metals are
subjected to any of the various activation techniques available. These
activation processes lead to the generation of what we know as activated
metals, which are characterized by a high reactivity and large surface area.15
Transition MNPs have emerged in recent years as a new family of
catalysts capable of efficiently promoting a wide variety of reactions of
interest in organic synthesis.16
In particular, MNPs are an important tool in
organic synthesis due to their high efficiency, selectivity and high capacity for
the transformation of functional groups. In addition, they meet in many cases
the requirements demanded for the so-called Green Catalysis,17
that is to say,
the synthesis of catalysts of low environmental impact, of easy preparation and
with the possibility of being reused without loss of the efficiency.
Metal NPs have been widely used as catalysts in different reactions of
hydrogenation, oxidation, hydrosilylation, amination, carbonylation,
cycloaddition and coupling (formation of C-C and C-heteroatom bonds),
among others. In addition, they have been defined as semi-heterogeneous
catalysts,18
i.e., they are at the interface between heterogeneous and
homogeneous catalysts.
15
Fürstner, A. Active Metals; VCH: Weinheim, 1996. 16
Reviews: (a) Corma, A.; García, H. Chem. Soc. Rev. 2008, 37, 2096. (b) Ranu, B. C.; Chattopadhyay, K.;
Adak, L.; Saha, A.; Bhadra, S.; Dey, R.; Saha, D. Pure Appl. Chem. 2009, 81, 2337. (c) Somorjai, G. A.; Li, Y.
Top. Catal. 2010, 53, 832. (d) Polshettiwar, V.; Luque, R.; Fihri, A.; Zhu, H.; Bouhara, M.; Basset, J.-M.
Chem. Rev. 2011, 111, 3036. (e) Balanta, A.; Godard, C.; Claver, C. Chem. Soc. Rev. 2011, 40, 4973. (f)
Cong, H.; Porco, Jr., J. A. ACS Catal. 2012, 2, 65. (g) Wu, L.; Zhang, Y.; Ji, Y.-G. Curr. Org. Chem. 2013, 17,
1288. (h) Wang, Y.; Xiao, Z.; Wu, L. Curr. Org. Chem. 2013, 17, 1325. (i) Geukens, I.; De Vos, D. E.
Langmuir 2013, 29, 3170. (j) For a special issue on nanocatalysis, see: Acc. Chem. Res. 2013, 46, issue nº
8. (k) Zaera, F. Chem. Soc. Rev. 2013, 42, 2746. 17
Reviews: (a) Kidwai, M. In Handbook of Green Chemistry; Anastas, P. T., Crabtree, R. H., Eds.; Wiley-
VCH: Weinheim, 2009, Vol. 2, pp. 81–92. (b) Yan, N.; Xiao, C.; Kou, Y. Coord. Chem. Rev. 2010, 254,
1179. (c) Polshettiwar, V.; Varma, R. S. Green Chem. 2010, 12, 743. (d) Gilbertson, L. M.; Zimmerman, J.
B.; Plata, D. L.; Hutchinson, J. E.; Anastas, P. T. Chem. Soc. Rev. 2015, 44, 5758. (e) Duan, H.; Wang, D.;
Li, Y. Chem. Soc. Rev. 2015, 44, 5778. 18
Reviews: (a) Widegren, J. A.; Finke, R. G. J. Mol. Catal. A: Chem. 2003, 198, 317. (b) Astruc, D.; Lu, F.;
Aranzaes, J. R. Angew. Chem. Int. Ed. 2005, 44, 7852. (c) Durán Pachón, L.; Rothenberg, G. Appl.
Organomet. Chem. 2008, 22, 288. (d) Narayanan, R.; Tabor, C. Top. Catal. 2008, 48, 60. (e) Shylesh, S.;
Schünemann, V.; Thiel, W. R. Angew. Chem. Int. Ed. 2010, 49, 3428.
General introduction
27
However, most of the reactions mentioned above are catalyzed by noble
transition metals, such as Pd, Pt, Ru, Rh, Ir, etc. In general, these transition
metals have some disadvantages such as the high cost, the need for the use of
additives or ligands to avoid the agglomeration of the particles, as well as the
use of complex methods of synthesis of the catalysts.
The synthesis of less noble transition metal nanoparticles, such as Cu or
Fe, represents an interesting alternative in organic synthesis due to their low
cost and low or no environmental impact compared to other transition metals.
On the other hand, the immobilization of metallic nanoparticles on high
surface area inorganic supports allows a greater stability and dispersion of the
particles, as well as an advantage of the special activity and reuse of the
catalyst.19
A.4. Copper nanoparticles (CuNPs)20
In recent years, our research group has been especially interested in the
study of CuNPs catalysts. This metal was chosen because of its low cost and
easy availability, in addition to its properties, some due to its electronic
configuration of "noble" metal. A very important fact that can be highlighted
is its low toxicity compared to other transition metals; the oral toxicity in
humans (LDLO) is 100 mg/kg.21
In addition, copper is an essential nutrient
needed to prevent anemia and keep the skeletal, reproductive and nervous
systems healthy.
19
Reviews: (a) Sun, J.; Bao, X. Chem. Eur. J. 2008, 14, 7478. (b) White, R. J.; Luque, R.; Budarin, V. L.;
Clark, J. H.; Macquarrie, D. J. Chem. Soc. Rev. 2009, 38, 481. (c) Campelo, J. M.; Luna, D.; Luque, F.;
Marinas, J. M.; Romero, A. A. ChemSusChem 2009, 2, 18. (d) De Rogatis, L.; Cargnello, M.; Gombac, V.;
Lorenzut, B.; Montini, T.; Fornasiero, P. ChemSusChem 2010, 3, 24. (e) Cao, A.; Lu, R.; Veser, G. Phys.
Chem. Chem. Phys. 2010, 12, 13499. (f) Munnik, P.; de Jongh, P. E.; de Jong, K. P. Chem. Rev. 2015, 115,
6687. 20
Review on the synthesis and applications of CuNPs: Gawande, M. B.; Goswami, A.; Felpin, F.-X.; Asefa,
T.; Huang, X.; Silva, R.; Zou, X.; Zboril, R.; Varma, R. S. Chem. Rev. 2016, 116, 3722. 21
.Concise Encyclopedia of Chemical Technology, 5th Edn.; Kirk-Othmer, Ed.; John Wiley & Sons:
Hoboken, 2007; Vol. 1, pp. 672–685.
General Introduction
28
Different physical, chemical and biological techniques have been studied
for the synthesis of copper nanoparticles.20,22
According to the method chosen
for the synthesis of the nanoparticles, different oxidation states, sizes and
particle shapes will be achieved, which will confer some properties or other to
the nanoparticles.
The CuNPs used in the present work were prepared by reduction of
anhydrous CuCl2 with metal lithium powder and a catalytic amount of an
arene (DTBB), used as an electron carrier. The reaction was carried out in dry
tetrahydrofuran (THF) as a solvent, under an argon atmosphere and at room
temperature.
The generation of the CuNPs from the CuCl2-Li-DTBB system could be
described as shown in Scheme 3. First, the formation of the radical anion or
dianion takes place through an electron transfer from lithium to the arene,
which has an intense green coloration. Electron transfer from these species to a
receptor in the medium is a very quick process. In this case, the receptor is
CuCl2, which rapid reduction leads to the formation of CuNPs of spherical
morphology and a size of 1–5 nm, approximately.11d
This method has been
proved to be more convenient than the one originally developed by Rieke et
al., which involved the reduction of copper(I) iodide with potassium metal and
a catalytic amount of naphthalene (10 mol%) in 1,2-dimethoxyethane.23
In this
case, the required long stirring times (8-12 h at room temperature) led to a
grey-black granular solid suspended in a clear solution.
Once the CuNPs are formed, what can be determined visually since the
reaction mixture acquires a black coloration, they can be used in suspension or
supported on different inorganic materials.
22
Reviews: (a) Umer, A.; Naveed, S.; Ramzan, N.; Rafique, M. NANO 2012, 7, 1230005. (b) Benavente,
E.; Lozano, H.; González, G. Recent. Pat. Nanotechnol. 2013, 7, 108. 11
(d) Moglie, Y.; Mascaró, E.; Nador, F.; Vitale, C.; Radivoy, R. Synth. Commun. 2008, 38, 3861. 23
(a) Rieke, R. D.; Rhyne, L. D. J. Org. Chem. 1979, 44, 3445. (b) Rieke, R. D.; Sell, M. S.; Klein, W. R.;
Chen,T.; Brown, J. D.; Hanson, M. V. En Active Metals; Fürstner, A.; VCH: Weinheim, 1996; p. 33.
General introduction
29
Scheme 3. Synthesis of CuNPs with the Li-arene system.
In the last years, our research group has developed several catalysts
based on the immobilization of CuNPs on different supports. Some of our
recent applications of supported CuNPs in organic synthesis follow:
Scheme 4. Cross-dehydrogenative coupling of amines and alkynes.
24
24
Alonso, F.; Arroyo, A.; Martín-García, I.; Moglie, Y. Adv. Synth. Catal. 2015, 357, 3549.
General Introduction
30
Scheme 5. Multicomponent synthesis of 1,2,3-triazoles (Click Chemistry).25
Scheme 6. Cross-coupling reactions.26
25
Alonso, F.; Moglie, Y.; Radivoy, G. Acc. Chem. Res. 2015, 48, 2516. 26
Mitrofanov, A. Y.; Murashkina, A. V.; Martín-García, I.; Alonso, F.; Beletskaya, I. P. Catal. Sci. Technol.
2017, 7, 4401.
General introduction
31
B. INTRODUCTION TO INDOLIZINES
B.1. Structure and applications
Indolizines are fused bicyclic systems with a nitrogen atom in the bridge
linking the two rings (Figure 3). One of the cycles is an electron rich pyrrole
and the other one is a π-deficient pyridine. In general, these compounds are
light and air sensitive, and act as weak bases, having the simplest indolizines a
pKa of 3.94.27
They also tend to be protonated at C3 when the ring is
unsubstituted.
Figure 3. Common structure of indolizines.
The indolizine system is an important scaffold in natural product
synthesis.28
They also have a large variety of pharmacological activities,29
including anticancer, anti-inflammatory, antioxidant, antibacterial, antifungal,
anti-tubercular30
or analgesic activity, among others (Figure 4).
27
Armarego, W. L. F. J. Chem. Soc. 1964, 4226. 28
Bronner, S. M.; Im, G.-Y. J.; Garg, N. K. In Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp. 221–265. 29
Reviews: (a) Vemula, V. R.; Vurukonda, S.; Bairi, C. K. Int. J. Pharm. Sci. Rev. Res. 2011, 11, 159. (b)
Sing, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237. (c) Sharma, V.; Kumar, V. Med. Chem. Res.
2014, 23, 3593. (d) Sadowski, B.; Klajn, J.; Gryko, D. T. Org. Biomol. Chem. 2016, 14, 7804. 30
Gundersen, L-L.; Charnock, C.; Negussie, A.H.; Rise, F.; Teklu, S. Eur. J. Pharm. Sci. 2007, 30, 26.
General Introduction
32
Figure 4. Structure and biological activity of some indolizines.
Some indolizines have been reported to be HIV-1 viron infectivity factor
(VIF) inhibitors, with those derived from VEC-5 (VIF-ElonginC), with the
modification of the three substituents improving the inhibition activity (Fig.).31
Figure 5. Structure of VEC-5 and derivatives.
31
Huang, W.; Zuo, T.; Luo, X.; Jin, H.; Liu, Z.; Yang, Z.; Yu, X.; Zhang, L.; Zhang, L. Chem. Biol. Drug Des.
2013, 81, 730.
General introduction
33
In the lasts years, new synthetic strategies have been developed not only
to obtain new biologically more active indolizines but also to exploit their
important fluorescence-related applications. For instance, some indolizines are
organic fluorophores with tunable emission wavelength covering the full range
of visible color, only by changing the substituents, which can be applied as
fluorescent probes (Figure 6).32
Figure 6. Structure of indolizines with fluorescent properties.
B.2. Synthetic methods
The two more common classical methods to obtain indolizines are the
Scholtz reaction33
and the Tshitschibabin34
reaction (Scheme 7) but, in the last
years, new methodologies have been developed in order to obtain a large
variety of different substitution patterns. Indolizines have been synthesized
following different methods,29b,d,35
which can be classified according to the
type of bond being formed during the synthesis of the indolizine, such as: one
C-N and other C-C bonds, two C-C bonds, or the transformation of a ring, for
example, the ring contraction of 4H-quinolizine. The indolizine syntheses can
32
(a) Kim,E.;Koh,M.; Lim, B.J.;Park, S.B. J. Am. Chem. Soc. 2011, 133, 6642. (b) Liu, B.; Wang, Z.; Wu, N.;
Li, M.; You, J.; Lan, J. Chem. Eur. J. 2012, 18, 1599. (c) Park, S.; Kwon, D. I.; Lee, J.; Kim, I. ACS Comb. Sci.
2015, 17, 459. 33
Scholtz, M. Ber. Dtsch. Chem. Ges. 1912, 45, 1718. 34
Kostik, E. I.; Abiko, A.; Oku, A. J. Org. Chem. 2001, 66, 2618. 29
(b) Sing, G. S.; Mmatli, E. E. Eur. J. Med. Chem. 2011, 46, 5237. (d) Sadowski, B.; Klajn, J.; Gryko, D. T.
Org. Biomol. Chem. 2016, 14, 7804. 35
Shipman, M. In Science of Synthesis; Thomas, E. J., Ed.; Georg Thieme: Stuttgart, 2001; Vol. 10, pp.
745–787.
General Introduction
34
be also classified by the type of the reaction, with the most common reactions
used being the condensation, 1,3-dipolar cycloaddition and 1,5-dipolar
cycloaddition, among others.36
Scheme 7. Classical methods for the synthesis of indolizines.
The synthetic principle of the 1,3-dipolar cycloaddition applied to the
synthesis of indolizines is advantageous with respect to the classical methods,
because of the use of more simple procedures; however, the substituents at the
positions 1, 2 and 3 are restricted to electron-withdrawing groups. There are
different types of starting materials for that reaction: the pyridinium ylides and
their derivatives are the most common ones (Scheme 8).37
36
(a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209. (b) Review: Cernaks, D. Chem. Heterocycl. Compd.
2016, 52, 524. (c) Sandeep, C.; Mohammed, A. K.; Attimarad, M.; Padmashali, B.; Kulkarni, R. S.;
Venugopala, R.; Odhav, B.; Katharigatta, N. V. J Basic Clin. Pharm. 2017, 8, 49. 37
(a) Yang, Y.; Kuang, C.; Jin, H.; Yang, Q. Synthesis 2011, 21, 3447. (b) Hu, H.; Feng, J.; Zhu, Y.; Gu, N.;
Kan, Y. RSC Adv. 2012, 2, 8637.
General introduction
35
Scheme 8. 1,3-Dipolar cycloaddition-based synthesis of indolizines.
Some cyclization reactions forming a new C3-N4 bond to obtain
indolizines are carried out by iodine-mediated38
and transition-metal
catalyzed39
cycloisomerization of pyridines bearing alkynyl, propargyl, allenyl
or cyclopropenyl substituents at the 2 position (Scheme 9). Some methods
based on two-component intermolecular annulations catalyzed by copper have
also been reported (Scheme 10).40
38
(a) Kim, I.; Choi, J.; Won, H. K.; Lee, G. H. Tetrahedron Lett. 2007, 48, 6863. (b) Kim, I.; Kim, S. G.; Kim,
J. Y.; Lee, G. H. Tetrahedron Lett. 2007, 48, 8976. 39
For reviews, see: (a) Majumdar, K. C.; Debnath, P.; De, N.; Roy, B. Curr. Org. Chem. 2011, 15, 1760. (b)
Dudnik, A. S.; Gevorgyan V. In Catalyzed Carbon-Heteroatom Bond Formation; Yudin, A. K., Ed.; Wiley-
VCH: Weinheim, 2011, pp 317–410. (c) Wang, L.; Tang, Y. Eur. J. Org. Chem. 2017, 2207. (d) For a
leading reference, see: Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (e)
See also: Yan, B.; Zhou, Y.; Zhang, H.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783. (f) Li, Z.; Chernyak,
D.; Gevorgyan, V. Org. Lett. 2012, 14, 6056 and the references cited therein. (g) Zhang, C.; Zhang, H.;
Zhang, L.; Wen, T. B.; He, X.; Xia, H. Organometallics 2013, 32, 3738. 40
(a) Barluenga, J.; Lonzi, G.; Riesgo, L.; López, L. A.; Tomás, M. J. Am. Chem. Soc. 2010, 132, 13200. (b)
Yang, Y.; Xie, C.; Xie, Y.; Zhang, Y. Org. Lett. 2012, 14, 957. (c) Hu, H.; Feng, J.; Zhu, Y.; Gu, N.; Kan, Y. RSC
Adv. 2012, 2, 8637. (d) Oh, K.H.; Kim, S.M.; Park, S.Y.; Park, J.K. Org. Lett. 2016, 18, 2204.
General Introduction
36
Scheme 9. Synthesis of indolizines by cycloisomerization.
Scheme 10. Synthesis of indolizines via intermolecular annulation.
General introduction
37
Pyrroles can be also used as starting materials for the synthesis of
indolizines by formation of a C8-C9 bond. There are a few examples of this
type of synthesis because of the less number of commercially available
pyrroles, their lower oxidation potential and their less stability compared with
the pyridines. One example starting from a N-H free pyrrole and using a
cyclopentadiene-phosphine/Pd catalyst is the reaction of pyrroles with 1,4-
dibromo-1,3-dibutadienes.41
The use of allyl bromides to N-alkylate a 2-
formylpyrrole has been also reported (Scheme 11).42
Other routes, starting
from N-substituted pyrroles, include the transition-metal free one-pot synthesis
of fully-substituted pyridine-ring indolizines43
or the intramolecular
aromatization of dicarbonyl compounds (Scheme 12).44
Scheme 11. Synthesis of indolizines from N-H free pyrroles.
41
Hao, W.; Wang, H.; Ye, Q.; Zhang, W.-X.; Xi, Z. Org. Lett. 2015, 17, 5674. 42
Park, S.; Kim, I. Tetrahedron 2015, 71, 1982. 43
Kucukdisli, M.; Opatz, T. J. Org. Chem. 2013, 78, 6670. 44
Lee, J. H.; Kim, I. J. Org. Chem. 2013, 78, 1283.
General Introduction
38
Scheme 12. Synthesis of indolizines from N-substituted pyrroles.
The indolizines can act as nucleophiles, so that they rarely suffer
nucleophilic attacks. The C1 and C3 are the most preferred positions to react
with electrophiles because of the resonance stability of the pyridine ring as
show in Scheme 13. 45
Scheme 13. Resonance stability of indolizines.
The reactivity of the indolizines has not been studied as much as new
syntheses, though there are some typical reactions for this type of heterocycles
(Scheme 14).36,46
45
De Souza, C. R.; Gonçalves, A. C.; Amaral, M. F. Z. J.; Dos Santos, A. A.; Clososki, G. C. Targets
Heterocycl. Syst. 2016, 20, 365. 36
(a) Uchida, T.; Matsumoto, K. Synthesis 1976, 209. (b) Review: Cernaks, D. Chem. Heterocycl. Compd.
2016, 52, 524. (c) Sandeep, C.; Mohammed, A. K.; Attimarad, M.; Padmashali, B.; Kulkarni, R. S.;
Venugopala, R.; Odhav, B.; Katharigatta, N. V. J Basic Clin. Pharm. 2017, 8, 49. 46
Elattar, K. M.; Youssef, I.; Fadda, A. A. Synth. Commun. 2016, 46, 719.
General objectives
43
Taking into account what aforementioned, the main objectives of this
thesis are:
1. To develop an efficient multicomponent synthesis of 1-
aminoindolizines based on the use of copper nanoparticles as the
catalyst.
2. To transform the indolizines into indolizidines by catalytic
hydrogenation.
3. To explore the reactivity of the indolizines in acid medium.
4. To study the reactivity of the indolizines against nitrosocompounds.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
47
1. MULTICOMPONENT SYNTHESIS OF 1-AMINOINDOLIZINES
1.1. INTRODUCTION
1.1.1. Multicomponent reactions in heterocyclic synthesis
Multicomponent Reactions (MCRs) are those which involve three or
more starting materials to synthesize a product and all, or at least most of the
atoms, contribute to the final compound. MCRs offer many advantages
compared with the traditional methodologies, such as selectivity, efficiency,
time saving, atom-economy and simplicity. It should be also noted that one-
pot reactions only involve one synthetic procedure and one work-up procedure
compared with multi-step reactions, thus being a greener chemistry (less use
of solvents, energy consumption and waste). Another advantage is the easier
scale-up of this type of reactions; in that way, most of the new procedures can
be carried out on an industrial scale. These are some of the reasons whereby
MCRs have been very studied in the last years.47,48
The types of MCRs for the synthesis of heterocycles can be classified
according to the size of the new formed heterocycle or the number of
heteroatoms in the cycle.49
They can be also classified according to the type of
reaction being used to form the heterocycle.1c
On the other hand, the synthesis of nitrogen heterocycles can be
challenging50
due to the necessity of using protecting groups in many cases,
hence needing additional steps. Some of them are very important because are
present in many different drugs. Therefore, it is important to develop new
47
For general reviews, see: (a) Orru, R. V. A.; Ruijter, E. Synthesis of Heterocycles via Multicomponent
Reactions I and II. Top. Heterocycl. Chem.; Springer: Berlin, 2010; Vol. 25, pp. 231–288. (b) Dömling, A.;
Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (c) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K.
Chem. Rev. 2014, 114, 8323. 48
For reviews on MCRs using metals see: (a) Arndtsen, B. A. Chem. Eur. J. 2009, 15, 302. (b) Maji, P. K.;
Islam, R. U.; Bera, S. K. Heterocycles 2014, 89, 869. (c) Guo, X.-X.; Gu, D.-W.; Wu, Z.; Zhang, W. Chem.
Rev. 2015, 115, 1622. (d) Das, D. ChemistrySelect 2016, 1, 1959. 49
Jiang, B.; Rajale, T.; Wever, W.; Tu, S.-J.; Li, G. Chem. Asian J. 2010, 5, 2318. 50
Blakemore, D. C.; Castro, L.; Churcher, I.; Rees, D. C.; Thomas, A. W.; Wilson, D. M.; Wood, A. Nat.
Chem. 2018, 10, 383.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
48
strategies that enable the synthesis of rather inaccessible nitrogen-containing
heterocycles in a more efficient and environmentally friendly manner and with
a high compatibility with different functional groups in order to have a broad
scope.
1.1.2. Multicomponent synthesis of indolizines
One of the first multicomponent synthesis of indolizines was developed
starting from 2-propargylpyridines, aryl iodides, and CO, all of which are
incorporated into the final indolizine (Scheme 1.1).51
Scheme 1.1. Multicomponent synthesis of indolizines from 2-propargylpyridines.
Another palladium-catalyzed multicomponent synthesis of indolizines
has been reported by Liu and co-workers and consists on a three-component
cascade reaction of 2-(2-enynyl)pyridines with nucleophiles and allyl halides,
enabling the synthesis of densely functionalized indolizines using Pd as
catalyst in the presence of a base in MeCN (Scheme 1.2).52
Scheme 1.2. Synthesis of 1,2,3-substituted indolizines.
51
Li, Z.; Chernyak, D.; Gevorgyan, V. Org. Lett. 2012, 14, 6056. 52
Liu, R.-R.; Lu, C.-J.; Zhang, M.-D.; Gao, J.-R.; Jia, Y.-J. Chem. Eur. J. 2015, 21, 7057.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
49
More recently, Liu and coworkers have developed a multicomponent
reaction using pyridines, methyl ketones and alkenoic acids in neat conditions
under an O2 atmosphere. This synthesis involves a cascade of processes
starting with a copper-catalyzed bromination of the methyl ketone, pyridine N-
alkylation, 1,3-dipolar cycloaddition of the pyridinium ylide with the alkenoic
acid, followed by an oxidative decarboxylation and dehydrogenative
aromatization of the primary cycloadduct (Scheme 1.3).53
Scheme 1.3. Synthesis of indolizines through a 1,3-dipolar cycloaddition.
Another example of multicomponent synthesis of indolizines through a
1,3-dipolar cycloaddition starts from pyridine derivatives, benzyl bromides
and electron-deficient alkenes or alkynes in the presence of a base and the
ionic liquid [OMIM]Br (Scheme 1.4).54
Scheme 1.4. Synthesis of indolizines through a 1,3-dipolar cycloaddition in an ionic
liquid.
Introducing an amino group in the skeleton of the indolizine opens many
possibilities for a further functionalization. In this context, the synthesis of 3-
aminoindolizines was developed via Pd/Cu-catalyzed sequential Sonogashira
cross-coupling/cycloisomerization55
or via a multistep sequence using
53
Wang, W.; Han, J.; Sun, J.; Liu, Y. J. Org. Chem. 2017, 82, 2835. 54
Zhang, X.; Lu, G.; Xu, Z.; Cai, C. ACS Sustainable Chem. Eng. 2017, 5, 9279. 55
Lange, P. P.; James, K. ACS Comb. Sci. 2012, 14, 570.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
50
Hantzsch ester as a hydride transfer agent starting from
pyridinecarboxaldehydes and malononitrile (Scheme 1.5).56
Scheme 1.5. Two synthetic approaches to 3-aminoindolizines.
A new protocol emerged in order to synthesize 1-aminoindolizines in a
single-step reaction and high atom economy starting from 2-
pyridinecarbaldehyde derivatives, secondary amines and terminal alkynes
(Scheme 1.6). Indeed, Liu and Yan were the first to report that kind of
multicomponent synthesis using a gold catalyst.57
Other catalytic processes
with different metals such as silver,58
iron,59
copper60
and zinc61
were
described for the same purpose.
56
Li, L.; Chua, W. K. S. Tetrahedron Lett. 2011, 52, 1392. 57
Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. 58
Bai, Y.; Zeng, J.; Ma, J.; Gorityala, B. K.; Liu, X.-W. J. Comb. Chem. 2010, 12, 696. 59
Patil, S. S.; Patil, S. V.; Bobade, V. D. Synlett 2011, 16, 2379. 60
(a) Dighe, S. U.; Hutait, S.; Batra, S. ACS Comb. Sci. 2012, 14, 665. (b) Pan, C.; Zou, J.; Zeng, R. Chin. J.
Chem. 2013, 31, 799. 61
Mishra, S.; Bagdi, A. K.; Ghosh, M.; Sinha, S.; Hajra, A. RSC Adv. 2014, 4, 6672.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
51
Scheme 1.6. Multicomponent syntheses of 1-aminoindolizines.
More recently, several related methods have been developed to obtain
indolizines with the same substitution based on copper nanocatalysts, such as
CuNPs-decorated mesoporous ZSM-5 in DCM62
or CuI/CSP nanocomposites
in EG.63
A Copper Organic Framework decorated with CuNPs has been also
reported for the multicomponent synthesis of 1-aminoindolizines; in this case,
the catalyst could be recycled over 5 cycles without losing conversion.64
62
Sharma, B.; Satpati, B.; Srivastava, R. RSC Adv. 2016, 6, 87066. 63
Rajesh, U. C.; Purohit, G.; Rawat, D. S. ACS Sustainable Chem. Eng. 2015, 3, 2397. 64
Rani, P.; Siril, P. F.; Srivastava, R. Mol. Catal., 2017, 433, 100.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
52
1.2. RESULTS AND DISCUSSION
1.2.1. Previous study
Recently, in our research group, the multicomponent synthesis of
indolizines and pyrrolo[1,2-a]quinolines has been effectively accomplished
from pyridine-2-carbaldehyde derivatives, secondary amines and alkynes
using CuNPs/C as catalyst in dichloromethane. Interestingly, the same
procedure, when applied in the absence of solvent using piperidine as the
secondary amine, has led to heterocyclic chalcones as major products and
exclusive E stereochemistry (Scheme 1.7).65
Scheme 1.7. Synthesis of indolizines and chalcones catalyzed by CuNPs/C.
In this chapter, we are going to focus, mainly, in the synthesis of 1-
aminoindolizines. For this reaction, the metal support, solvent and conditions
were previously optimized using pyridine-2-carbaldehyde (1a), piperidine (2a)
and phenylacetylene (3a) as model compounds;66
copper nanoparticles on
activated carbon (CuNPs/C) was found to be the catalyst of choice in
dichloromethane at 70 ºC.
65
Albaladejo, M. J.; Alonso, F.; Yus, M. Chem. Eur. J. 2013, 19, 5242. 66
Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por
Nanopartículas de Cobre Soportadas, Tesis Doctoral, Universidad de Alicante, 2014.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
53
The copper-on-activated-carbon catalyst was previously characterized67
by different techniques. The copper content, 1.6 wt%, was determined by
Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Analysis by TEM
revealed the presence of spherical nanoparticles dispersed on the active carbon
with diameters of ca 4-8 nm (Figure 1.1). Energy-dispersive X-ray (EDX)
analysis on various regions confirmed the presence of copper, with energy
bands of 8.04, 8.90 keV (K lines) and 0.92 keV (L line). X-Ray Photoelectron
Spectroscopy (XPS) analysis showed two O (1s) peaks at 532.2 and 534.2 eV,
and three Cu (2p3/2) peaks at 934.1, 936.4, and 945.7 eV. From these results it
was inferred that the surface of the copper nanocatalyst was mainly oxidized
and it was a mixture of oxidized copper nanoparticles (Cu2O and CuO).
0
5
10
15
20
25
30
35
40
45
dis
trib
uti
on
(%
)
diameter (nm)diameter (nm)
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0
Figure 1.1. TEM image and size distribution of CuNPs/C.
1.2.2. Substrate scope
With the optimized conditions in hand, a wide range of indolizines was
synthesized in modest-to-high isolated yields using a low catalyst loading (0.5
mol%) (Table 1.1). Pyridine-2-carbaldehyde (1a) was successfully combined
with nine different secondary amines (Table 1.1, 2a–i) and five aryl acetylenes
containing electron-neutral, -withdrawing or -releasing substituents (Table 1.1,
3a–e). Aliphatic alkynes (Table 1.1, 3f and 3g) were found to be more
67 Alonso, F.; Moglie, Y.; Radivoy, G.; Yus, M. Adv. Synth. Catal. 2010, 352, 3208.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
54
reluctant to react, leading to the expected indolizines (Table 1.1, 4agf and
4agg) in relatively lower yields (55% and 42%, respectively) due to partial
decomposition during chromatographic purification. In contrast, the alkyne
derived form phthalimide was obtained in a good yield (Table 1.1, 4agh).
Reactions with pyridine-2-carbaldehydes substituted at the 6 position
(1b–d) required prolonged heating, probably because of steric reasons (Table
1.2). Poor yield was noted for the 5-bromoindolizine 4bga due to the major
formation of the A3 coupling product. However, we could make use of this
result to prove the reaction mechanism (see below). Indolizines derived from
6-methylpyridine-2-carbaldehyde (1c) and dibenzylamine (2g) with different
electronic substituents in the aromatic alkyne were synthesized with moderate-
to-good yields (Table 1.2, 4cga–4cge). N-Methylaniline (1f) was also tested
with 6-methylpyridine-2-carbaldehyde, to form the expected indolizine in a
moderate yield (Table 1.2, 4cfa). The best yield was attained for the sulfone-
functionalized indolizine 4dga. The methodology was found to be also
effectual when applied to quinoline-2-carbaldehyde (1e), giving the
corresponding pyrrolo[1,2-a]quinolines 4eaa–ega in good-to-high isolated
yields (Table 1.2).
Our method was not as good for aliphatic alkynes, that is why we
decided to use a commercial catalyst which a good performance according to
the literature.14b
We tested CuI, in the absence of solvent and with a higher
metal loading (10 mol%), in the multicomponent synthesis of indolizines from
pyridine-2-carbaldehyde, secondary amines and aliphatic alkynes. Five
different amines were tested with 1-hexyne leading to the corresponding
indolizines in moderate-to-good yields (Table 1.3, 4aai, 4aci, 4adi, 4afi, and
4agi). The conversion was worse for shorter or longer aliphatic-chain alkynes
(Table 1.3, 4agj–4agm). Finally, 6-methylpyridine-2-carbaldehyde was tested
with dibenzylamine and 1-hexyne, giving the expected indolizine in good
conversion (85% by GC) but with a moderate isolated yield (Table 1.3, 4cgi).
Although the use of CuI generally increases the conversion for this type of
indolizines, the isolated yields are low or moderate because of the instability
of these indolizines in column chromatography and the additional work-up
required removing CuI from the reaction crude.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
55
Table 1.1. Synthesis of 1,3-disubstituted indolizines catalyzed by CuNPs/C. a
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C [20 mg, ca. 0.5 mol%,
determined from the Cu content (1.4 wt%) and the Cu2O/CuO area from XPS (ca. 1:1)], CH2Cl2 (1 mL),
70 ºC; reaction time and isolated yield in parentheses.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
56
Table 1.2. Multicomponent synthesis of indolizines substituted at C5 catalyzed by
CuNPs/C. a
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.5 mmol), CuNPs/C (20 mg, ca. 0.5 mol%),
CH2Cl2 (1 mL), 70 ºC; reaction time and isolated yield in parentheses. b The propargylamine 6bfa (see
below) was the major product (72%).
Chapter I. Multicomponent synthesis of 1-aminoindolizines
57
Table 1.3. Multicomponent synthesis of indolizines catalyzed by CuI. a
a Reaction conditions: 1 (2 mmol), 2 (2 mmol), 3 (2 mmol), CuI (38.1 mg, 10 mol%), neat, 70 ºC;
reaction time and isolated yield in parentheses.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
58
1.2.3. Reutilization of the catalyst
The CuNPs/C catalyst, which could be reused in other multicomponent
reactions, could not be efficiently recycled in this case (only 40% of
conversion was obtained in the second cycle). The possible poisoning of the
catalyst and the observed leaching of the metal could be the reasons that
account for this behavior. This fact is not so important because of the low
charge of copper used in the formation of the indolizines.
In the case of the synthesis of chalcones, 66
the catalyst could be recycled
in 4 cycles using low loading (0.13 mol%) with a decrease in the catalytic
activity (Scheme 1.8).
Scheme 1.8. Reutilization of the catalyst in the synthesis of the chalcone (E)-3-
phenyl-1-(pyridin-2-yl)prop-2-en-1-one (5aa) using 0.13 mol% CuNPs/C.
1.2.4. Comparison with commercial catalysts
In principle, any laboratory-made catalyst should be more efficient
than commercially available catalysts used for the same purpose. Otherwise, it
is difficult to economically justify the time, materials and human resources
employed during its preparation. Taking into account this premise, we
undertook a comparative study on the reactivity of CuNPs/C with that of some
commercial copper catalysts. The standard conditions were applied to the
Chapter I. Multicomponent synthesis of 1-aminoindolizines
59
model reaction of pyridine-2-carbaldehyde (1a), piperidine (2a) and
phenylacetylene (3a). As shown in Scheme 1.9, the best performance was
attained with CuNPs/C in terms of catalyst loading, reaction time and
conversion.
Scheme 1.9. Synthesis of indolizine 4aaa catalyzed by CuNPs/C and commercial
catalysts. Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), catalyst
(10 mol%, unless otherwise stated), CH2Cl2 (1 mL), 70 ºC. Conversion into 4aaa
determined by GC.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
60
A similar study was done by comparing the catalytic activity of
CuNPs/C with that of the same commercial copper catalysts as above in the
synthesis of chalcones (Scheme 1.10). Chalcone 5aa was used as the model
target, which was obtained in less than 50% conversion in all cases with the
exception of CuI; moderate conversion was obtained with the latter, though
larger amount of this non-recyclable catalyst and longer reaction time than
with CuNPs/C were required. Moreover, an increase in the amount of CuI had
a detrimental effect on the conversion.
Scheme 1.10. Synthesis of chalcone 5aa catalyzed by CuNPs/C and commercial
catalysts. Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), Cu
catalyst (10 mol%), neat, 70 ºC. Conversion into 5aa was determined by GC.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
61
1.2.5. Reaction mechanism
The kinetic profile for the synthesis of the indolizine 4aaa shows almost
a linear increase of the conversion within the first 3 h (up to 92%), being
nearly quantitative after 4 h (98%) (Figure 1.2). For this particular reaction,
TON and TOF of up to 200 and 65 h–1
, respectively, were recorded.
0
20
40
60
80
100
0 5 10 15 20
Co
nve
rsio
n (
%)
t (h) Figure 1.2. Plot showing the evolution of the synthesis of the indolizine 4aaa
catalyzed by CuNPs/C.
Based on our previous mechanistic studies on the aldehyde-amine-
alkyne coupling (A3 coupling), as well as on other methodologies, we can
propose a reaction mechanism for this multicomponent synthesis of
indolizines including: (a) CuNPs-mediated enhancement of the alkyne acidity
by coordination to the carbon-carbon triple bond, so that enables the formation
of the corresponding copper(I) acetylide; (b) addition of the latter to the in-situ
generated iminium ion derived from the aldehyde and the secondary amine; (c)
copper-promoted cycloisomerization of the resulting propargylamine (A3
product) through a 5-endo-dig and aromatization processes; and (d)
protonolysis of the intermediate copper indolizide (Scheme 1.11). The
participation of propargyl amines as indolizine precursors has been often
postulated10–14
but, to the best of our knowledge, never demonstrated. These
pyridinyl propargyl amines must be rather elusive intermediates, which once
generated in the reaction medium, rapidly cyclize to the corresponding
indolizines. It is noteworthy that tiny peaks attributable to propargylamines
Chapter I. Multicomponent synthesis of 1-aminoindolizines
62
were detected by GC-MS (the same m/z as that of indolizines) in some of the
reaction crudes derived from pyridine-2-carbaldehyde (1a). Notwithstanding
the limitations to isolate a pyridinyl propargylamine and transform it into the
corresponding indolizine, we turned our attention to the 6-substituted pyridine-
2-carbaldehyde derivatives.
Scheme 1.11. Reaction mechanism proposed for the three-component synthesis of
indolizines catalyzed by CuNPs/C.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
63
The steric hindrance arisen between the 6-substituent of the pyridine and
the alkyne substituent prior to ring closure, could be a chance to isolate the
pursued propargylamine. We capitalized on the low indolizine conversion
recorded for some 6-bromopyridin-2-carbaldehyde derivatives and managed to
isolate propargylamine 6bga. Subsequent treatment of 6bga with CuNPs/C in
dichloromethane furnished the expected indolizine 4bga after prolonged
heating (Scheme 1.12). These results distinctly unveil that 2-pyridinyl
propargyl amines are the precursor intermediates of indolizines.
Scheme 1.12. Transformation of propargylamine 6bga into the indolizine 4bga.
1.2.6. Biological activity
Indolizines have diverse biological activities, as aforementioned in the
general introduction, that is why we decided to study the possible activity of
the new synthesized 1-aminoindolizines (indolizines 4a'-4h' were previously
synthesized in our research group66
but their biological activity had not been
assessed yet). Both, in-silico and in vitro screening, were performed through
the Lilly Open Innovation Drug Discovery (OIDD) program.68
There are four main therapeutic areas for testing the compounds:
Neuroscience, Endocrine/Cardiovascular, Oncology, and Neurodegeneration
and pain. Within these, the indolizines were tested in different target cell lines.
66
Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por
Nanopartículas de Cobre Soportadas, Tesis Doctoral, Universidad de Alicante, 2014. 68
https://openinnovation.lilly.com
Chapter I. Multicomponent synthesis of 1-aminoindolizines
64
Neuroscience
Calcitonin Gene-Related Peptide (CGRP) Receptor Antagonist: the
CGRP plays an important role in the patho-physiology of migraine. The
CGRP level has been reported to be elevated during a migraine attack.
m-Glu2R Receptor Allosteric Antagonist: glutamate is the major
excitatory neurotransmitter acting as G-protein coupled receptors. Antagonist
of glutamate receptors have been postulated to be useful in neurological and
psychiatric indications.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
65
Nav1.7 Antagonist: Nav1.7 is a sodium ion channel involved in
generation, propagation and neurotransmitter release. Many nonselective
sodium channels inhibitors are used clinically as analgesics and anesthesics,
however, their efficacy is limited by their lack of selectivity over the other
sodium channel anti-targets. That is why selective Nav1.7 inhibitors may
provide a novel therapeutic approach to chronic pain of different etiologies
without significant safety side-effects.
Endocrine/Cardiovascular
GLP-1 Secretion: Glucagon-like peptide 1 is a potent anti-
hyperglycemic hormone which induces glucose-dependant insulin secretion
and supresses glucagon secretion. There are two assays where indolizines have
shown some activity.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
66
PCSK9 Synthesis inhibition: the proprotein convertase subtilisin kesin
(PCSK) belongs to the proteinase K family, this plays a major role regulating
the cholesterol homeostasis. The PCSK9 regulates LDL level reducing its
accumulation.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
67
RXFP1 Antagonist: relaxin is a reproductive hormone involved in the
remodelation of the tract during the pregnancy. Some clinical trials have been
reported to use relaxin as a treatment of scleroderma, fibromyalgia or
preeclampsia.
Oncology
SETD8 Inhibitor: SET domain containing lysine methyltransferase 8 is
an essential enzyme which catalysed the cell cycle stages. SETD8 interacts
directly with several proteins for the regulation of transcription, DNA
replication and DNA damage repair. The SETD8 depletion results in a large
scale chromatin decondensation/less compact chromatin in vivo, decreasing
the proliferation of carcinogenic cells.
Chapter I. Multicomponent synthesis of 1-aminoindolizines
68
K-Ras/Wnt Synthetic Lethal: most colorectal cancers are developed from
benign lesions, then an activating KRAS mutation is required for the
progression to colorectal cancer. The reason for the co-mutational requirement
is due to undefined interactions between the WNT and KRAS signalling
pathways. It is important to develop small molecules selectively lethal to
tumor cells that depend on this WNT-KRAS synergy.
Neurodegeneration and pain
Protein Translation Inhibition for Alzheimer’s disease (Tau): the
Alzheimer’s disease is characterized by the accumulation of amyloid plaques
and intracellular formation of neurofibrillary tangles, composed by Aβ protein
and tau protein respectively. A therapeutic strategy is the inhibition of those
proteins.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
71
2. CATALYTIC HYDROGENATION OF INDOLIZINES: SYNTHESIS
OF INDOLIZIDINES
2.1. INTRODUCTION
There is a general upsurge of interest in developing new strategies to
effectively obtain saturated N-heterocycles from readily accessible starting
materials. This demand is supported by the potential development of new
pharmaceuticals related to this type of heterocycles and their natural
abundance.69
Among them, indolizidine alkaloids are widespread in nature and
have attracted a great deal of attention because of their structural diversity and
varied biological activity.70
Indolizidine alkaloids are bicyclic compounds, which have one basic
nitrogen in their structure. Many of them present biological activity such as
fitotoxic, antibacterial, antifungal or neurological activities, and they can be
extracted from diverse natural sources: poisonous frogs, ants, fungi, plants,
etc.
Figure 2.1. Common structure of indolizidines.
For instance, indolizidine 167B was originally found as a trace
component in the skin secretions of a frog belonging to the genus
Dendrobates,71
whereas (+)-monomorine I was isolated from both Pharaoh’s
ant Monomorium pharaonis and from bufonid toads of the Melanopbryniscus
69
(a) Synthesis of Heterocycles via Metal-Catalyzed Reactions that Generate One or More Carbon-
Heteroatom Bonds; Top. Heterocycl. Chem.; Wolfe, J. P., Ed.; Springer-Verlag: Berlin, 2013; Vol. 32. (b)
Synopsis: Vo, C.-V. T.; Bode, J. W. J. Org. Chem. 2014, 79, 2809. 70
Reviews: (a) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24,
191. (c) Michael, J. P. Beilstein J. Org. Chem. 2007, 3, No. 27, doi:10.1186/1860-5397-3-27. (d) Michael,
J. P. Nat. Prod. Rep. 2008, 25, 139. 71
Edwardsj, M. W.; Daly, J. W. J. Nat. Prod. 1988, 51, 1188.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
72
genus.72
(–)-Tashiromine was first isolated from the stems of Maackia
Tashiroi (Leguminosae),73
a bush from subtropical Asia, and later on from
leaves and seeds of the Poecilanthe74
genus and from Ethiopian Crotalaria
species.75
Swainsonine was first identified in the Australian legume Swainsona
canescens76
and, subsequently, as the toxin in Astragalus and Oxytropis
species that cause locoism in livestock.77
In contrast, the potential importance
of swainsonine in the therapy for cancer and immunology has been reported.78
(+)-Lentiginosine was first isolated from the leaves of Astragalus lentiginosus
in 1990,79
which is a potent glycosidase-inhibitor, also the synthetic (–)-
lentiginosine80
is so effectual against different cell lines. Indolizidines have
also played an important role in the synthesis of other natural products.81
Due
to the insignificant isolated amounts of these alkaloids from their natural
sources, new synthetic methods to obtain them have been developed.
72
(a) Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E. J.; Stein, F. Experientia 1973, 29, 530. (b)
Garrafo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.; Gross, E. G. J. Nat. Prod. 1993, 56, 357. 73
Ohmiya, S.; Kubo, H.; Otomasu, H.; Saito, K.; Murakoshi, I. Heterocycles 1990, 30, 537. 74
Greinwald, R.; Bachmann, P.; Lewis, G.; Witte, L.; Czygan, F.-C. Biochem. Syst. Ecol. 1995, 23, 547. 75
Asres, K.; Sporer, F.; Wink, M. Biochem. Syst. Ecol. 2004, 32, 915. 76
Collegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem. 1979, 32, 2257. 77
Molyneux, R. J.; James, L. F. Science 1982, 216, 190. 78
Olden, K.; Breton, P.; Grzegorzewski, K.; Yasuda, Y.; Gause, B. L.; Oredipe, O. A.; Newton, S. A.; White,
S. L. Pharmacol. Ther. 1991, 50, 285. 79
Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D. Biochemistry 1990, 29, 1886. 80
Cordero, F. M.; Vurchio, C.; Brandi, A. J. Org. Chem. 2016, 81, 1661. 81
Bronner, S. M.; Im, G.-Y. J.; Garg, N. K. In Heterocycles in Natural Product Synthesis; Majumdar, K. C.,
Chattopadhyay, S. K., Eds.; Wiley-VCH: Weinheim, 2011; pp. 221–265.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
73
Figure 2.2. Structure of some naturally-occuring indolizidines.
The synthetic strategies developed to construct the indolizidine skeleton
according to the substitution pattern pursued (Scheme 2.1),82
include: (a) the
use of pyrroles as building blocks,83
(b) from α-aminoacids via
stereocontrolled rhodium-catalyzed hydroformylation of N-allylpyrroles84
or
via a decarboxylative annulation with γ-nitroaldehydes,85
(c) based on
organosulfur and selenium chemistry (i.e., conjugate addition of nitrogen
nucleophiles containing ester or chloroalkyl substituents to acetylenic
sulfones, followed by base-mediated intramolecular alkylation or acylation),86
(d) by stereocontrolled cyclic nitrone cycloaddition,87
(e) by addition of
allylsilanes to N-acyliminium ions,88
(f) by stereoselective conjugate addition
reactions,89
(g) through radical azidation reactions,90
(h) through chiral
82
Pansare, S. V.; Thorat, R. G. In Targets in Heterocyclic Systems. Chemistry and Properties; Attanasi, O.
A.; Spinelli, D., Eds.; Società Chimica Italiana: Roma, 2013; Vol. 17, pp 57–86. 83
Review: Jefford, C. W. Curr. Org. Chem. 2000, 4, 205. 84
Review: Lazzaroni, R.; Settambolo, R. Chirality 2011, 23, 730. 85
Kang, Y.; Seidel, D. Org. Lett. 2016, 18, 4277. 86
Review: Back, T. G. Can. J. Chem. 2009, 87, 1657. 87
Review: Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15, 7808. 88
Review: Remuson, R. Beilstein J. Org. Chem. 2007, 3, No. 32, doi:10.1186/1860-5397-3-32. 89
Review: Toyooka, N.; Tsuneki, H.; Kobayashi, S.; Zhou, D.; Kawasaki, M.; Kimura, I.; Sasaoka, T.;
Nemoto, H. Curr. Chem. Biol. 2007, 1, 97. 90
Review: Lapointe, G.; Kapat, A.; Weidner, K.; Renaud, P. Pure Appl. Chem. 2012, 84, 1633.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
74
oxazolopiperidone lactams,91
(i) via enaminone intermediates,92
(j)
enantioselective Brönsted-acid catalyzed vinylogous Mannich reaction,93
or
(k) the sequential double addition to N-protected piperidine through the α-
lithio-derivatives followed by an intramolecular reductive amination.94
However, despite the synthesis of indolizidines by the reduction of indolizines
seems to be a direct approach, it has been barely documented and limited to
some isolated examples.95
Just a few reports describe the synthesis of
indolizidines by heterogeneous catalytic hydrogenation of the pyrrole ring of
5,6,7,8-tetrahydroindolizines.96
To the best of our knowledge, there is only one
systematic study on the synthesis of indolizidines by full hydrogenation of
indolizines, recently reported by Coelho et al.97
At any rate, partial reduction is
a common problem encountered, which together with a desirable higher
diastereoselectivity,98
make the selective hydrogenation of indolizines a
challenging objective.
91
Review: Escolano, C.; Amat, M.; Bosch, J. Chem. Eur. J. 2006, 12, 8198. 92
Riley, D. L.; Michael, J. P.; de Koning, C. B. Beilstein J. Org. Chem. 2016, 12, 2609. 93
Abels, F.; Lindemann, C.; Koch, E.; Schneider, C. Org. Lett. 2012, 14, 5972. 94
Nebe, M. M.; Zinn, S.; Opatz, T. Org. Biomol. Chem. 2016, 14, 7084. 95
(a) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 2074. (b) Chai, W.; Kwok,
A.; Wong, V.; Carruthers, N. I.; Wu, J. Synlett 2003, 13, 2086. (c) Zhang, L.; Li, X.; Liu, Y.; Zhang, D. Chem.
Commun. 2015, 51, 6633. 96
(a) Castaño, A. M.; Cuerva, J. M.; Echavarren, A. M. Tetrahedron Lett. 1994, 35, 7435. (b) Gracia, S.;
Jerpan, R.; Pellet-Rostaing, S.; Popowycz, F.; Lemaire, M. Tetrahedron Lett. 2010, 51, 6290. (c) Jiang, C.;
Frontier, A. J. Org. Lett. 2007, 9, 4939. (d) Ortega, N.; Tang, D.-T. D.; Urban, S.; Zhao, D.; Glorius, F.
Angew. Chem. Int. Ed. 2013, 52, 9500. 97
Teodoro, B. V. M.; Correia, J. T. M.; Coelho, F. J. Org. Chem. 2015, 80, 2529. 98
See, ref. 95a (79:12:9 dr), ref. 95b (3.67:1.00 dr), ref. 96a (2:2:1 dr), ref. 96b (85–88% de), ref. 96d
(91:5:2:1 dr).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
75
Scheme 2.1. Different approaches to the synthesis of indolizidines.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
76
2.2. RESULTS AND DISCUSSION
2.2.1. Optimization of the reaction
First, the catalyst and reaction conditions were optimized for the
catalytic hydrogenation of indolizines. N,N-Dibenzyl-3-phenylindolizin-1-
amine (4aga) was chosen as the model substrate because its hydrogenation
was considered more challenging due to the presence of three carbon-nitrogen
bonds prone to undergo hydrogenolysis. In addition, the different
hydrogenation degree for the five and six- membered rings of the indolizine
nucleus made the desired transformation more difficult to achieve. In
principle, all reactions were carried out at room temperature with 10 mol% of
a platinum catalyst in different solvents or mixtures of solvents at various
hydrogen pressures (Table 2.1); MeOH-CH2Cl2 or MeOH-HOAc mixtures
favored solubilization of the starting indolizine with respect to the use of only
MeOH. As regards the use of PtO2 as catalyst (Table 2.1, entries 1–14), higher
pressure (3.7 atm) and shorter reaction time (2 h) increased the conversion into
the desired indolizidine 7aga, particularly in the presence of HOAc as solvent
(Table 2.1, entry 8); variable amounts of the mono-debenzylated indolizidine
8aga and a semihydrogenation product (at this stage postulated to be 10aga)
were also formed.
Longer reaction time (8 h) at the same pressure had a detrimental effect
on the conversion due to additional by-product formation (Table 2.1, compare
entries 8 and 9). The combination of HOAc with either MeOH or CH2Cl2 gave
quite good results but did not improve those reached with HOAc (Table 2.1,
entries 13 and 14). Then, we explored the behaviour of different platinum-
based supported catalysts. The highest conversions were achieved with Pt(5
wt%)/CaCO3 and Pt(5 wt%)/C (Table 2.1, entries 18 and 24, respectively), as
above, when pressure (3.7 atm) and short reactions time (3 h) were applied in
HOAc, with the concomitant formation of 8aga and 10aga. As in the case of
PtO2 (Table 2.1, entry 11), lower catalyst loading (5 mol%) in the supported
catalysts led to a decrease in the conversion though of a lower magnitude
compared to the former (Table 2.1, entries 19 and 25).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
77
Table 2.1. Hydrogenation of indolizine 4aga using platinum catalysts.a
Entry Catalyst Solvent P (H2, atm) t (h) 7/8/9/10 (%)b
1 PtO2 MeOH-CH2Cl2c 1.0 72 47/-/-/-
2 PtO2 MeOH-CH2Cl2c 3.7 2 44/7/-/6
3 PtO2 EtOH 3.7 8 8/2/-/-
4 PtO2 CH2Cl2 3.7 2 8/-/-/-
5 PtO2 EtOAc 3.7 2 23/-/-/-
6 PtO2 EtOAc 3.7 9 26/-/-/-
7 PtO2 HOAc 1.0 24 39/-/-/-
8 PtO2 HOAc 3.7 2 65/2/-/21
9 PtO2 HOAc 3.7 8 26/10/-/5
10 PtO2 HOAc 5.1 1 48/-/-/-
11 PtO2d HOAc 3.7 2 40/-/-/12
12 PtO2 HOAc 1.0e 23 19/24/-/25
13 PtO2 MeOH-HOAcf 3.7 2 53/-/-/20
14 PtO2 CH2Cl2-HOAcf 3.7 2 65/13/-/10
15 Pt(1 wt%)/Al2O3 MeOH-CH2Cl2c 3.7 2 31/-/-/-
16 Pt(1 wt%)/Al2O3 HOAc 3.7 2 55/-/-/-
17 Pt(5 wt%)/Al2O3 HOAc 1.0e 20 -/-/-/-
18 Pt(5 wt%)/CaCO3 HOAc 3.7 3 62/14/-/14
19 Pt(5 wt%)/CaCO3d HOAc 3.7 3 57/7/-/30
20 Pt(5 wt%)/CaCO3 HOAc 1.0e 20 10/23/-/36
21 Pt(5 wt%)/SiO2 HOAc 3.7 3 -/-/-/-
22 Pt(10 wt%)/C MeOH-CH2Cl2c 3.7 4 24/-/-/-
23 Pt(10 wt%)/C HOAc 3.7 2 56/-/-/-
24 Pt(5 wt%)/C
HOAc 3.7 3 68/6/-/8
25 Pt(5 wt%)/Cd HOAc 3.7 3 52/7/-/15
26 Pt(5 wt%)/C HOAc 1.0e 23 16/19/-/9
27 Pt(5 wt%)/C HOAc 1.0e 7g 30/14/-/26
28 Pt(5 wt%)/C HOAc 1.0e 48g 22/46/-/-
29 Pt(5 wt%)/C MeOH-HOAcc 3.7 3 9/5/-/- a Reaction conditions: 4aga (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. b Conversion
determined by GC. c 3:1 v/v. d 5 mol%. e In balloon. f 1:1 v/v. g Reaction at 50 ºC.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
78
Other metal catalysts were also tested with the aim to minimize by-
product formation (Table 2.2). Pd(10 wt%)/C provided a moderate conversion
into 7aga at ambient pressure and prolonged stirring in MeOH, together with a
substantial amount of mono-debenzylated 8aga (Table 2.2, entry 1); higher
hydrogen pressure shortened the reaction time but did not improve the
conversion (Table 2.2, entry 2). An interesting effect of the pressure was
noticed with Pd(20 wt%)/C in HOAc, leading to 8aga at 3.7 atm or 9aga at
ambient pressure with some selectivity (Table 2.2, entries 4 and 5).
Unfortunately, any possibility for directly transforming the starting indolizine
4aga into 8aga or 9aga by the choice of the pressure vanished because of the
low diastereoselectivity attained in both cases (Table 2.2, footnotes d and g).
This lack of diastereoselectivity was also manifested with the deployment of
Pd(5 wt%)/CaCO3 which, conversely, was highly chemoselective towards the
formation of 8aga (Table 2.2, entry 7). Other catalysts, either heterogeneous
[Pd(OH)2/C, Rh(5 wt%)/C and Ru(5 wt%)/C] or homogeneous
{[Rh(COD)Cl]2, [RuCl2(p-cymene)]2 and [Ir(COD)Cl]2}, and/or reaction
conditions furnished complex reaction mixtures (Table 2.2, entries 6, 8, 9 and
11), no product (Table 2.2, entries 12–14) or a certain amount of N-
benzylidene-3-phenylindolizin-1-amine, i.e., the imine of mono-debenzylated
8aga (Table 2.2, entries 3, 16 and 17).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
79
Table 2.2. Hydrogenation of indolizine 4aga using other metal catalysts.a
Entry Catalyst Solvent
P (H2, atm) t (h) 7/8/9/10 (%)b
1 Pd(10 wt%)/C MeOH 1.0 48 64/19/-/-
2 Pd(10 wt%)/C MeOH 3.7 7 48/4/-/-
3 Pd(10 wt%)/C HOAc 3.7 2 -c
4 Pd(20 wt%)/C HOAc 3.7 3 -/92d/8/-
5 Pd(20 wt%)/C HOAc 1.0e
23 -/16f/64
g/-
6 Pd(5 wt%)/CaCO3 HOAc 3.7 3 -h
7 Pd(5 wt%)/CaCO3 HOAc 1.0e
20 -/81i/-/-
8 Pd(OH)2/C MeOH 1.0 22 -h
9 Pd(OH)2/C MeOH-CH2Cl2j
1.0 13 -h
10 Pd(OH)2/C MeOH-CH2Cl2j
3.7 6 -/27/-/-
11 Pd(OH)2/C MeOH-
CH2Cl2k 1.0 15 -
h
12 Rh(5 wt%)/C HOAc 1.0e
20 -
13 Rh(5 wt%)/C HOAc 3.7 3.5 -
14 Ru(5 wt%)/C HOAc 3.7 4 -
15 [Rh(COD)Cl]2 MeOH-CH2Cl2j
3.7 10 -l
16 [RuCl2(p-cymene)]2 i-PrOH 3.7 8 -m
17 [Ir(COD)Cl]2 HOAc 3.7 8 -n
a Reaction conditions: 4aga (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. b Conversion
determined by GC. c Monodebenzylated 4aga (25%) and its imine (35%). d 55:45 dr. e In balloon. f
62:38dr. g 64:19:17 dr. h Complex mixture. i 47:44:9 dr. j MeOH-CH2Cl2 (3:1 v/v). k MeOH-CH2Cl2 (1:1
v/v). l Unidentified product (29%). m Imine of monodebenzylated 4aga (12%). n Imine of
monodebenzylated 4aga (4%).
From this optimization study it can be concluded that PtO2 and Pt (5
wt%)/C are the best catalysts in terms of conversion and selectivity (Table 2.1,
entries 8 and 24, respectively).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
80
2.2.2. Reutilization of the catalysts
Given the heterogeneous nature of both catalysts, they are potentially
recoverable and recyclable. PtO2 could be easily reused by decantation,
supernatant removal and catalyst washing in the same hydrogenation flask. In
contrast, further manipulation and centrifugation were required for Pt(5
wt%)/C. For comparative purposes, all recycling experiments were conducted
at 3.7 atm for 2 h (Figure 2.3). Catalyst reutilization was found to be more
efficient with PtO2 than with Pt(5 wt%)/C (60% versus 36% in the second
cycle). The catalytic activity of both catalysts decreased in subsequent cycles:
35 and 30% for PtO2 and <10% for Pt(5 wt%)/C, albeit better conversions
would be expected for longer reaction times. In addition to this, we also
observed that the catalytic performance of Pt(5 wt%)/C with substrates other
than 4aga was lower than with PtO2. In view of the aforementioned results, the
catalytic system of choice was that composed of PtO2 (10 mol%) in HOAc at
3.7 atm H2 (Table 2.1, entry 8).
0
10
20
30
40
50
60
70
1 2 3 4
Pt(IV) oxide Pt(5 wt%)/C
cycles
co
nvers
ion
(%)
Figure 2.3. Catalyst recycling experiments in the hydrogenation of 4aga (3.7 atm H2,
2 h).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
81
2.2.3. Substrate scope
In order to study the substrate scope, the optimized catalyst and
reaction conditions were applied to a variety of indolizines 4, derived from
pyridine-2-carbaldehyde (1a), secondary amines (2) and terminal alkynes (3),
producing the expected indolizidines 6 in modest-to-high yields and with high-
to-excellent diastereoselectivity (Table 2.3). The yield and diastereoselectivity
were found to be dependent on the substituents at the 1 and 3 positions, with
the amino group at the 1 position apparently exerting a stronger effect. For
instance, the indolizines derived from piperidine and arylacetylenes were
isolated in lower yields, with the lowest diastereoselectivity been recorded for
the phenylacetylene derivative (7aaa). The diastereomeric ratio was improved
when a para substituent was present in the arylacetylene-derived moiety while
at the same time maintaining the 1-piperidinyl group (Table 2.3, compare 7aaa
with 7aab and 7aac). Fortunately, purification by column chromatography
allowed the isolation of 7aaa and 7aab as single diastereoisomers. Better yield
and excellent diastereoselectivity were observed when changing the 1-
piperidinyl into a 1-morpholino group (Table 2.3, compare 7aaa with 7aba).
In general, the results with acyclic amines were better than those with the
cyclic counterparts concerning all, the yield, the diastereoselectivity and the
reaction time. The diastereoselectivity increased when increasing the steric
hindrance of the secondary amine (Table 2.3, compare 7ada and 7aea with
7aca and 7aga). The indolizidines derived from dibenzylamine followed a
similar trend to that of dibutylamine (7aca), being generally obtained in
relatively short hydrogenation reaction times and as single diastereoisomers
(Table 2.3, 7aga-7agf). This remarkable behavior was displayed irrespective
of the substituent at the 3 position of the indolizidine nucleus, including aryl
substituents with electron-neutral (Table 2.3, 7aga and 7agb), -releasing
(Table 2.3, 7agc) and -withdrawing groups (Table 2.3, 7agd and 7age), as well
as aliphatic substituents (Table 2.3, 7agf).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
82
Table 2.3. Synthesis of the indolizidines 7.a
a Reaction conditions: 4 (0.5 mmol), PtO2 (10 mol%), HOAc (3 mL), H2 (3.7 atm), rt; reaction time and
isolated yield in parentheses; diastereomeric ratio in brackets determined by GC-MS from the reaction
crude. b Diastereomeric ratio after purification by column chromatography. c Reaction at 4.1 atm.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
83
We endeavored to extend this method to more demanding indolizines
in order to validate its applicability. Such is the case of N,N-dibutyl-1-
phenylpyrrolo[1,2-a]quinolin-3-amine (4eca), a benzo-fused indolizine
coming from the coupling of quinoline-2-carbaldehyde (1e), dibutylamine (2c)
and phenylacetylene (3a). We also applied the same conditions to 1-phenyl-3-
(piperidin-1-yl)pyrrolo[1,2-a]quinoline (4eaa), but the chemoselectivity was
very low. It is worthy of note that the catalytic hydrogenation failed under the
standard pressure and that a slightly higher pressure was necessary to initiate
the reaction. Consequently, the latter was found to be more chemoselective at
lower than at higher conversions, with an increase of byproduct formation in
the second case. The scant yield of the expected hexahydropyrrolo[1,2-
a]quinolin-3-amine 7eca was compensated for the high diastereomeric ratio
reached; the presence of the fused benzene in the tricyclic indolizine core did
not vary the stereochemical outcome with respect to the bicyclic counterparts.
We went one step further by dealing with the hydrogenation of the
trisubstituted indolizine 4cga, the precursors of which were 6-methylpyridine-
2-carbaldehyde (1c), dibenzylamine (2g) and phenylacetylene (3a). In this
case, a short reaction time was more convenient to minimize byproduct
formation. It was gratifying to know that, though in modest isolated yield, the
four-stereocenter indolizidine 7cga could be obtained with very high
diastereoselectivity.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
84
2.2.4. Stereochemistry and mechanism
First, the stereochemistry of the indolizidines 7 was proposed on the
basis of 2D-NMR experiments conducted for 7aba, 7aga, 7eca and 7bga
(Figure 2.4) and, later on, unequivocally established by X-ray crystallographic
analysis of compound 7aaa (Figure 2.5). In view of these data, the major
diastereoisomer obtained in the catalytic hydrogenation of the indolizines is
that resulting from the addition of hydrogen to the same face of the indolizine
nucleus.
Figure 2.4. Selected
1H-
1H correlations from NOESY experiments.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
85
Figure 2.5. X-ray structure of compound 7aaa.
Finally, we wanted to know about the hydrogenation pathway and the
structure of any possible semihydrogenated intermediate. With this purpose in
mind, indolizine 4aaa was hydrogenated under the standard conditions but for
a shorter reaction time. These intermediates were found to be rather elusive
because of their minor formation and high tendency to over-hydrogenation.
Notwithstanding these added difficulties, we managed to isolate a certain
amount of the 5,6,7,8-tetrahydroindolizine 10aaa, which confirmed the
preferential hydrogenation of the six-membered ring of the indolizine nucleus.
Further hydrogenation of 10aaa gave rise to the fully reduced indolizidine
7aaa with the same stereoselectivity as above. These results lend weight to the
argument that the stereochemistry of the indolizidines is fixed in a second
stage, where all hydrogen atoms are delivered from the catalyst to the same
face of the pyrrole ring in 10aaa (Scheme 2.2).
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
86
Scheme 2.2. Sequential hydrogenation of the indolizine 4aaa and hydrogenation
model of 10aaa.
2.2.5. Debenzylation of indolizidines
Secondary amines are versatile nitrogenated compounds with multiple
applications in organic chemistry as, for example, as organocatalysts, as Lewis
bases (e.g., for the activation of electron-deficient olefins) or as building
scaffolds for multicomponent reactions, among many others. On the other
hand, in organic chemistry, it is desirable that the selective conversion of a
single starting material into two or more different products can be
accomplished by the selection of the catalyst. In this vein, attempts to directly
transform indolizine 4aga into the mono-benzylated secondary amine 8aga
were found to be successful in terms of conversion under palladium catalysis;
regretfully, the diastereoselectivity of these reactions was too low (Table 2.2,
entries 4 and 7, footnotes d and i). Then, we decided to take advantage of the
presence of two benzyl groups in the indolizidines 7aga-7agf and 7cga to
investigate the possibilities of effecting selective hydrogenolysis, leading to
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
87
secondary amines 8 or primary amines 9, through mono- and di-debenzylation
processes, respectively.
Taking into account the information in tables 2.1 and 2.2, four catalysts
were considered for this study, including platinum and palladium catalysts,
using indolizidine 7aga as the starting material (Table 2.4). As a general trend,
platinum catalysts provided the mono-debenzylated product 8aga whereas the
palladium catalyst favoured the full debenzylated product 9aga. A significant
effect of the hydrogen pressure was also discerned, with ambient pressure
resulting in higher conversions and less formation of side products. Prolonged
stirring was recommended in both cases because did not alter the high
selectivity attained with the platinum catalysts [Pt(5 wt%)/C and PtO2] (Table
3.4, entries 3 and 4) and guaranteed the full hydrogenolysis with Pd(20
wt%)/C (Table 2.4, compare entries 7 and 8).
Table 2.4. Optimization of the hydrogenolysis of 7aga. a
Entry Catalyst P
(H2, atm) t (h)
8aga/9aga
(%)b
1 Pt(5 wt%)/C 3.7 2 15/-
2 Pt(5 wt%)/C 3.7 6 31/-
3 Pt(5 wt%)/C 1.0c
22 61/-
4 PtO2 1.0c
17 83/-
5 Pt(5 wt%)/CaCO3 1.0c
16 59/-
6 Pd(20 wt%)/C 3.7
2 31/-
7 Pd(20 wt%)/C 1.0c
7 6/77
8 Pd(20 wt%)/C 1.0c
23 -/82 a Reaction conditions: 7aga (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL)
and H2 at rt. b Conversion determined by GC. c In balloon.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
88
The optimized conditions were first applied to the selective mono-
debenzylation of some of the indolizidines 7aga-7agf. As representative
examples, indolizidines derived from aromatic alkynes of diverse electronic
nature (neutral, rich and deficient ones), as well as from aliphatic alkynes,
were converted into the monobenzylated counterparts 7 in moderate-to-high
yields (Table 2.5). Although both catalysts, PtO2 and Pt(5 wt%)/C selectively
catalyzed the mono-debenzylation reaction at ambient hydrogen pressure and
temperature, the yields were slightly higher when the former was utilized for
7aga and 7agc, and the latter for 7agd and 7agf.
Table 2.5. Mono-debenzylation of indolizidines 7.a
a Reaction conditions: 7 (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL) and H2 (1 atm) at rt;
isolated yield after purification by preparative TLC (hexane/EtOAc 6:4); conversions into 8
were in the range 82->99%); diastereomeric ratio determined by GC-MS from the reaction
crude. b Reaction catalyzed by PtO2. c Reaction catalyzed by Pt(5 wt%)/C.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
89
When the same substrates, as above, were submitted to hydrogenolysis
catalyzed by Pd(20 wt%)/C at ambient hydrogen pressure and temperature, the
corresponding free amino indolizidines 8 were produced in high yields as a
result of a di-debenzylation process (Table 2.6). It is noteworthy that the
original stereochemical integrity of the indolizidines was unaffected during the
hydrogenolyses leading to the desired products as single diastereomers.
Table 2.6. Di-debenzylation of indolizidines 7.a
a Reaction conditions: 7 (0.3 mmol), Pd(20 wt%)/C (10 mol%), HOAc (3.0 mL) and
H2 (1 atm) at rt; conversions into 9 were in the range 73->99%. Compounds 9aga and
9agd were purified by preparative TLC (EtOAc). Compounds 9agc and 9agf did not
require any further purification. Diastereomeric ratio determined by GC-MS from the
reaction crude.
Chapter II. Catalytic hydrogenation of indolizines: synthesis of indolizidines
90
2.2.6. Biological activity
Endocrine/Cardiovascular
GLP-1 Secretion: Glucagon-like peptide 1 is a potent anti-
hyperglycemic hormone which induces glucose-dependant insulin secretion
and supresses glucagon secretion. There are two primary assays where
indolizines have activity.
Chapter III. Reactivity of indolizines: synthesis of dyes
93
3. REACTIVITY OF INDOLIZINES: SYNTHESIS OF DYES
3.1. INTRODUCTION
There is a general upsurge of interest in developing more efficient and
sustainable processes for the alkenylation of aromatic and heteroaromatic
compounds based on C-H activation. Among them, the transition-metal free
cross-coupling of aryl halides with alkenes is praiseworthy but requires the
action of strong bases that curtail the substrate scope of the method.99
The
cross-dehydrogenative coupling (CDC) of arenes and alkenes (oxidative Heck-
type or Fujiwara-Moritani reaction) represents a much more advantageous and
resourceful strategy because skips the pre-installation of the halide on the
aromatic unit and produces hydrogen as the only byproduct (i.e., high atom
economy).100
At any rate, the presence of a noble transition metal is necessary,
normally accompanied by a stoichiometric oxidant under thermal treatment;
rhodium,101
ruthenium102
and, especially, palladium103
catalysts are the most
common metals in this field. The control of the regio- and stereoselectivity are
major issues in this type of reactions; the former is commonly addressed by
activation of HetCsp2-H bonds (e.g., NCsp2-H bonds) or by the introduction of a
directing group (e.g., ortho alkenylation). Remote site-selective Csp2-H
olefination is, yet, a much more challenging hot topic.104
99
Sun, C.-L.; Shi, Z.-J. Chem. Rev. 2014, 114, 9219. 100
Reviews: (a) Li, B.; Dixneuf, P. H. Chem. Soc. Rev. 2013, 42, 5744. (b) Wu, Y.; Wang, J.; Mao, F.;
Kwong, F. Y. Chem. Asian J. 2014, 9, 26. (c) Zhou, L.; Lu, W. Chem. Eur. J. 2014, 20, 634. (d) Kitamura, T.;
Fujiwara, Y. In From C-H to C-C Bonds. Cross-Dehydrogenative Coupling; Li, C.-J., Ed.; The Royal Society
of Chemistry: Cambridge (UK), 2015. 101
(a) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichim. Acta 2012, 45, 31. (b) Ye, B.; Cramer, N.
Acc. Chem. Res. 2015, 48, 1308. (c) Satoh, T.; Miura, M. In Catalytic Transformations via C-H Activation
1, Science of Synthesis; Thieme: Stuttgart, 2016; Chapter 1.1.6. 102
Arockiam, P. B.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. 103
(a) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. (b) Doman, P. K.; Dong, V. M. In Catalytic
Transformations via C-H Activation 1, Science of Synthesis; Thieme: Stuttgart, 2016; Chapter 1.1.5. 104
(a) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518. (b) Deng, Y.; Yu, J.-Q. Angew. Chem.
Int. Ed. 2015, 54, 888. (c) Bera, M.; Maji, A.; Sahoo, S. K.; Maiti, D. Angew. Chem. Int. Ed. 2015, 54, 8515.
(d) Zhang, Z.; Tanaka, K.; Yu, J.-Q. Nature 2017, 543, 538.
Chapter III. Reactivity of indolizines: synthesis of dyes
94
In recent years, the selective alkenylation of nitrogen heterocycles
making use of the CDC tool has been paid a great deal of attention;105
this
additional introduction of functionality can be ultimately used for further
synthetic purposes or to enhance the inherent biological activity of the
compounds. Pyridines,106
uracils,107
indole derivatives,108
imidazo[1,2-
a]pyridines109
and indolizines110
are some of the substrates successfully
subjected to this reaction (Scheme 3.1). However, the corresponding methods
implemented are far from being sustainable and green, and conditional on
close site-selective C-H activation. Furthermore, it seems rather unviable to
scale up the procedures from the economic (expensive catalysts), safety (high
temperatures in O2 atmosphere) and environmental point of view (use of non-
recommended solvents111
). Therefore, there is a justification to explore new
routes toward heterocycle alkenylation. Moreover, the alkenylation of
aromatic compounds by C-H activation also elongates the π-system, producing
conjugated organic materials with new and potential photophysical
characteristics (e.g., as organic electronic materials).112
105
Nakao, Y. In Catalytic Transformations via C-H Activation 1, Science of Synthesis; Thieme: Stuttgart,
2016; Chapter 1.2. 106
Wen, P.; Li, Y.; Zhou, K.; Ma, C.; Lan, X.; Ma, C.; Huang, G. Adv. Synth. Catal. 2012, 354, 2135. 107
(a) Huang, Y.; Song, F.; Wang, Z.; Xi, P.; Wu, N.; Wang, Z.; Lan, J.; You, J. Chem. Commun. 2012, 48,
2864. (b) Yu, Y.-Y.; Georg, G. I. Chem. Commun. 2013, 49, 3694. 108
(a) Zhang, L.-Q.; Yang, S.; Huang, X.; You, J.; Song, F. Chem. Commun. 2013, 49, 8830. (b) Yang, X.-F.;
Hu, X.-H; Feng, C.; Loh, T.-P. Chem. Commun. 2015, 51, 2532. (c) Kannaboina, P.; Kumar, K. A.; Das, P.
Org. Lett. 2016, 18, 900. (d) Gorsline, B. J.; Wang, L.; Ren, P.; Carrow, B. P. J. Am. Chem. Soc. 2017, 139,
9605. 109
(a) Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271. (b) Zhan, H.;
Zhao, L.; Li, N.; Chen, L.; Liu, J.; Liao, J.; Cao, H. RSC Adv. 2014, 4, 32013. 110
Hu, H.; Liu, Y.; Zhong, H.; Zhu, Y.; Wang, C.; Ji, M. Chem. Asian J. 2012, 7, 884. 111
Reviews: (a) Eastman, H. E.; Jamieson, C.; Watson, A. J. B. Aldrichim. Acta 2015, 48, 51. (b) Prat, D.;
Wells, A.; Hayler, J.; Sneddon, H.; McElroy, R.; Abou-Shehadad, S.; Dunne, P. J. Green Chem. 2016, 18,
288. 112
Review: Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem. Int. Ed. 2015, 54, 66.
Chapter III. Reactivity of indolizines: synthesis of dyes
95
Scheme 3.1. Transition-metal catalyzed alkenylation of some N-heterocycles.
Chapter III. Reactivity of indolizines: synthesis of dyes
96
On the other hand, natural dyes and pigments have been used for
millennia, mainly, as coloring agents.113
However, synthetic dyes show greater
stability, which has allowed to introduce new applications and open new
markets in such varied fields. Dyes derived from indolizines (Figure 3.1) have
been relatively poorly studied compared to the more common types of
triphenylmethane, azo compound, or anthraquinone (Figure 3.2).
Figure 3.1. Examples of indolizine dyes.
Figure 3.2. Classical types of dyes.
113
Handbook of Natural Colorants; Bechtold, T., Mussak, R., Eds.; John Wiley & Sons: Chichester (UK),
2009.
Chapter III. Reactivity of indolizines: synthesis of dyes
97
Organic dyes with a D-π-A configuration contain both electron-donating
(D) and electron-withdrawing groups (A) connected by a π-conjugated section;
alternatively, a D-A-π-A configuration can be molecularly designed where the
additional intercalated A is a heterocyclic component (Figure 3.3). The
particular light absorption of these compounds makes them ideal candidates
for chemosensors114
and dye-sensitized solar cells.115
The construction of the
alkenyl linker usually relies on a Wittig reaction, for which a proper
functionalization of the starting materials is required.
Figure 3.3. Dyes with D-π-A and D-A-π-A configurations.
Moreover, both the pyridinyl chalcone and indolizine systems are very
useful scaffolds in synthetic organic chemistry as well as in materials science.
In the latter respect, indolizine dyes have found practical applications as
materials in laser-based recording and reading devices, electrochromic
devices,116
thermography and fotothermography, optical filters,117
as well as
114
Selected reviews: (a) Zhou, Y.; Yoon, J. Chem. Soc. Rev. 2012, 41, 52. (b) Jung, H. S.; Chen, X.; Kim, J.
S.; Yoon, J. Chem. Soc. Rev. 2013, 42, 6019. (c) Uglov, A. N.; Bessmertnykh-Lemeune, A.; Guillard, R.;
Averin, A. D.; Beletskaya, I. P. Russ. Chem. Rev. 2014, 83, 196. 115
Reviews: (a) Ooyama, Y.; Harima, Y. Eur. J. Org. Chem. 2009, 2903. (b) Wu, Y.; Zhu, W. Chem. Soc.
Rev. 2013, 42, 2039. (c) Viewpoint: Kloo, L. Chem. Commun. 2013, 49, 6580. 116
Jung, Y.-S.; Jaung, J.-Y Dyes Pigments 2005, 65, 205. 117
Inagaki, Y.; Kubo T. (Fuji Photo Film Co., Ltd.). JP 03074471A, 1991; Chem. Abstr. 1991, 115, 138212.
Chapter III. Reactivity of indolizines: synthesis of dyes
98
photoelectric converters.118
. Within the most recent literature, several articles
covering the photophysical behavior (e.g., halochromism, fluorescence, etc.)
of indolizine119
and heterocyclic chalcone dyes120
have been reported (Figure
3.4). It is worth noting that the more specific 2-pyridinyl chalcones can
additionally behave as probes for sensing of metal ions by coordination
through the 2-pyridinylcarbonyl fragment.22b
Figure 3.4. Examples of indolizines and chalcones with photophysical properties.
As part of our interest in studying the reactivity of indolizines, we
explored their reactivity under acidic conditions, leading to indolizine dyes
through a singular remote alkenylation process.
118
Tanabe, J.; Shinkai, M.; Tsuchiya, M. (TDK Electronics Co., Ltd.). JP 2008101064A, 2008; Chem. Abstr.
2008, 148, 520703. 119
(a) Rotaru, A.; Druta, I.; Avram, E.; Danac, R. ARKIVOC 2009, xiii, 287. (b) Amaral, M. F. Z. J.;
Deliberto, L. A.; de Souza, C. R.; Naal, R. M. Z. G.; Naal, Z.; Clososki, G. C. Tetrahedron 2014, 70, 3249. (c)
Kim, E.; Lee, Y.; Lee, S.; Park, S. B. Acc. Chem. Res. 2015, 48, 538. (d) Song, Y. R.; Limb, C. V.; Kima, T. W.
Luminescence 2016, 31, 364. (e) Zhang, Y.; Garcia-Amorós, J.; Captain, B.; Raymo, F. M. J. Mater. Chem.
C 2016, 4, 2744. (f) Outlaw, V. K.; Zhou, J.; Bragg, A. E.; Townsend, C. A. RSC Adv. 2016, 6, 61249. 120
(a) Rurack, K.; Bricks, J. L.; Reck, G.; Radeglia, R.; Resch-Genger, U. J. Phys. Chem. A 2000, 104, 3087.
(b) Mashraqui, S. H.; Khan, T.; Sundaram, S.; Ghadigaonkar, S. Tetrahedron Lett. 2008, 49, 3739. (c) El-
Daly, S. A.; Gaber, M.; Al-Shihry, S. S.; El Sayed, Y. S. J. Photochem. Photobiol. A: Chem. 2008, 195, 89.
(d) Gaber, M.; El-Daly, S. A.; El-Sayed, Y. S. Y. J. Mol. Struct. 2009, 922, 51. (e) El-Sayed, Y. S. Opt. Laser
Technol. 2013, 45, 89. (f) El-Sayed, Y. S.; Gaber, M. Spectrochim. Acta, Part A 2015, 137, 423–431. (g)
Shinozaki, Y.; Arai, T. Heterocycles 2017, 95, 972.
Chapter III. Reactivity of indolizines: synthesis of dyes
99
3.2. RESULTS AND DISCUSSION
The reactivity of indolizines in acidic medium was formerly optimized
for the indolizine 4aga,66
with the highest conversion to the corresponding dye
being obtained with HOAc at room temperature.
3.2.1. Substrate scope
With the optimized conditions in hand, a wide range of dyes were
synthesized from different indolizines in low-to-high isolated yields (Table
3.1). We first studied the effect of the substitution on the 3-aryl group for a
series of 1-dibenzylamino indolizine derivatives. The presence of electron-
donating groups at the para position (4agb and 4agc) was found to be
somewhat beneficial with respect to the unsubstituted indolizine (4aga),
obtaining the corresponding dyes (11agb and 11agc) in good isolated yields.
For the existence of para electron-withdrawing groups, the opposite effect was
noted, with lower yields around 50% for 11agd and 11age. The substitution of
the 3-aryl group into a 3-alkyl substituent in 4 exerted a certain detrimental
effect (11agi). Next, we tested the influence of the amino substituents:
replacing a benzyl with a methyl group had a considerable decrease in the
yield (compare 11ada with 11aga). That decrease was more pronounced in the
case of N-methyl-N-phenethyl- (11aea), N-piperidinyl- (11aaa) or N,N-
dibutylamino (11aca) substituents; in the last two cases, the reaction was
especially slow. Dyes bearing a N-methyl-N-phenyl moiety could be also
synthesized, either containing the normal indolizine/pyridinyl (11afa) or the 5-
methylindolizine/6-methylpyridinyl (11cfa) nuclei, the second one in very
modest yield. Pleasantly, the yield was boosted above 70% when two strong
electron-donating groups (i.e., 4-methoxyphenyl) were bonded to nitrogen
(11aha). The methodology was also effective for the construction of chiral
dyes, such in the case of the (R)-N-benzyl-N-α-methyl)benzylamino derivative
66 Albaladejo, M. J. Síntesis de Aminas Propargílicas, Indolizinas y Chalconas Catalizadas por
Nanopartículas de Cobre Soportadas, Tesis doctoral, Universidad de Alicante, 2014.
Chapter III. Reactivity of indolizines: synthesis of dyes
100
Table 3.1. Transformation of indolizines 4 into dyes 11.a,b
a Reaction conditions: indolizine 4 (0.5 mmol) and HOAc (3 mL) at rt for the specified time; then sat.
NaHCO3 until neutralization. b Yield of the isolated product 11 based on 2 equiv. of 4. c NMR yield
based on 2 equiv. of 4.
Chapter III. Reactivity of indolizines: synthesis of dyes
101
11aia. It can be concluded that the existence of the 1-dibenzylamino and 3-
aryl groups is essential to obtain good yields.
Scale up is a hurdle generally encountered in organic synthesis, more
markedly in multi-step procedures and in catalysis, which often curtails the
transfer of laboratory basic research into the productive sector. In this vein, we
tried to adapt the preceding one-pot method to a multi-gram scale. For this
purpose, several parameters were readjusted: (a) 5 mol% CuI was used instead
of 0.5 mol% CuNPs/C; (b) CH2Cl2 was removed, making the reaction greener
under solvent-free conditions; (c) the neutralization step was executed with
NaOH solution instead of sat. NaHCO3 to avoid excessive bubbling; and (d)
the purification of the dye was accomplished by recrystallization in lieu of
column chromatography, with the former being always preferred by the
chemical industry. We must underline that the use of CuNPs/C is
advantageous because it enables an adequate metal separation from the
reaction medium by filtration; in contrast, with CuI, washing with ammonia
solution is suggested during the work-up for copper removal. Nevertheless, in
this manner, 187 mmol (20 g) of pyridine-2-carbaldehyde were converted to
40 g of the pure dye 11aga (Scheme 3.2). The yield achieved (72%) is
concordant with that of the small-scale synthesis and denotes a highly robust
and reproducible method.
Scheme 3.2. Multigram scale one-pot synthesis of the dye 11aga.
Chapter III. Reactivity of indolizines: synthesis of dyes
102
Attempts to prepare mixed dyes from two different indolizines by
varying either the 1-dialkylamino and/or the 3-aryl substituent were unfruitful.
The formation of the homoadducts was preferred to that of the heteroadducts
[Scheme 3.3, eq. (1) and (2)]. In the case of 4aga and 4agc, three spots were
observed by TLC, two of them corresponding to the homoadducts 11aga and
11agc [Scheme 3.3, eq. (2)]. The third one, after isolation by column
chromatography, showed a mixture of two heteroadduct dyes in a 1:1 ratio
(Figure 3.5), hence demonstrating a low reaction selectivity.
As a general trend, indolizine 4aga reacted faster as the nucleophilic
partner leading to the indolizine dye 10aga preferentially over others bearing
other 1-alkyl- or arylamino groups (Schemes 3.3 and 3.4).
Scheme 3.3. Some attempts to synthesize mixed dyes.
Chapter III. Reactivity of indolizines: synthesis of dyes
103
Figure 3.5.
1H NMR spectrum of a 1:1 mixture of 11AB and 11BA.
Scheme 3.4. Competing experiments in the synthesis of dyes.
Chapter III. Reactivity of indolizines: synthesis of dyes
104
3.2.2. Structural analysis
From the structural viewpoint, we were delighted to find out that the
resulting trisubstituted indolizine dyes 11 maintained the original structure of
the starting material 4, but had grown up selectively through the 7-position of
the indolizine nucleus by the incorporation of a heterocyclic chalcone
fragment from another indolizine molecule. In this sense, the dyes 11 can be
considered as indolizine-chalcone hybrids selectively bonded through a Csp2-
Csp2 bond. Certainly, this is a very singular Csp2-Csp2 bond formation with the
following salient features: (a) the conversion of 4 into 11 can be formally
considered as a remote-site C–H self-alkenylation reaction; (b) transition-
metal catalysis is dispensable; (c) contrary to the published alkenylation
strategies which result in quaternaryCsp2-tertiaryCsp2 bond formation, the more
challenging quaternaryCsp2-quaternaryCsp2 bonds are made now (i.e., with a
1,1-disubstituted alkenyl fragment); (d) it is worthwhile mentioning the
extraordinary selectivity achieved in this reaction, with the dyes 11 being
obtained with absolute control of both the regioselectivity and the
stereoselectivity. Thus, out of the ten potential isomers which can be drawn as
products (five possible regioisomers at the indolizine positions 2, 5, 6, 7, and
8, each as two possible Z/E diastereoisomers), only one was formed, the 7-
substituted E isomer.
The structure of the dyes 11 was unequivocally established by X-ray
crystallography of 11aga and 11agc (Figure 3.6). The X-ray plot of 11aga
brings into view a quasi-flat arrangement of the chalcone-indolizine backbone.
Conversely, the phenyl group at the β-position of the C=O (C15–C16) lays
near perpendicular to that backbone (C17–C16–C15–C22 torsion angle 80º) in
order to reduce the steric interaction of the ortho Hs with the C=O and the C5–
H. The phenyl ring on the indolizine nucleus also appears deviated from co-
planarity (C2–C1–C9–C14 torsion angle 31º) to prevent C2–H/C14–H and
C8–H/C10–H interactions. Finally, the carbonyl group and the C–N of the
pyridinyl group are exposed to view in an anti-periplanar conformation (O1–
C23–C24–N2) to minimize dipole-dipole interactions. The structural X-ray
patterns displayed by the dyes 11aga and 11agc were alike.
Chapter III. Reactivity of indolizines: synthesis of dyes
105
Figure 3.6. Plot showing the X-ray structure and atom numbering of the dyes 11aga
and 11agc.
Surprisingly, the response of the dyes in solution was very different from
that in the solid state: duplicity of some NMR signals was observed for all
compounds 11 except 11agi. For instance, compound 11aga exhibited a ca.
1:5 signal ratio in CDCl3 which was constant irrespective of the reaction
conditions or purification method (chromatography or recrystallization).
Apparently, compounds 11 exist as a mixture of two distinguishable rotamers
in solution; the fact that the above ratio varies with the NMR solvent used
would bolster this hypothesis (Table 3.2). In general, the major rotamer seems
to be more favored in the more polar solvents (Table 3.2, compare entry 2 with
5, 7 and 8); this fact entails important consequences in the optical performance
of the dyes (see below). The trend to signal coalescence and to equal the
population species, noticed by heating, is also typical of rotamers (Table 3.2,
entries 5 and 6).
Chapter III. Reactivity of indolizines: synthesis of dyes
106
Table 3.2. Chemical shifts and ratio of the two rotamers A (major) and B (minor).
pyridine-D5
C6D6
CDCl3
acetone-D6
DMSO-D6
r.t.
DMSO-D6
110 ºC
ethanol-
D6
CD3CN
Entry Solvent δA/δB (ppm) A/B εa
1 pyridine-D5 4.31/4.24 3.52:1 13.26
2 C6D6 4.21/4.05 3.65:1 2.28
3 CDCl3 4.19/4.15 4.97:1 4.81
4 acetone-D6 4.23/4.15 5.41:1 21.01
5 DMSO-D6 4.15/4.09 5.60:1 47.24
6 DMSO-D6 4.24/4.20b 3.00:1
b 47.24
7 ethanol-D6 4.16/4.10 6.00:1c 25.30
8 CD3CN 4.14/4.09 12.00:1c 36.64
a Dielectric constant. b Data obtained at 110 ºC. c Ratio estimated from other spectrum signals.
The coexistence of the two rotamers could be ascribed to the
circumstance that compounds 11 are push-pull highly conjugated systems,
possessing the electron-releasing and -withdrawing amino and acyl groups,
respectively. Therefore, resonant forms with a partial double bond connecting
the chalcone and indolizine nucleus could be drawn (Scheme 3.5a). The
restricted rotation around that bond would lead to two highly conjugated and
conformationally stable η-enaminoketones. NOESY experiments are in
agreement with the rotamer A being the major one which, in turn, coincides
with the structure of 11aga in the solid state (Scheme 3.5b). The conformation
suggested for rotamer B is more dubious, albeit it is evident that Hd' and Hk'
are far each other now (Scheme 3.5b).
Chapter III. Reactivity of indolizines: synthesis of dyes
107
Scheme 3.5. (a) Proposed structures for the rotamers A and B of 11aga in solution
and their resonant forms. (b) Selected NOEs.
Chapter III. Reactivity of indolizines: synthesis of dyes
108
In fact, these two protons experienced the most pronounced variation in
the chemical shift (ca. 0.40 and 0.55 ppm, respectively) with a displacement to
a higher field (Figure 3.7). Due to the relative spatial proximity of the β-
phenyl and Hk', the former might exert a shielding impact on the latter by
polarization and field effects.121
The calculated dipolar moments122
for the
rotamer A (3.17 D) and rotamer B (1.32 D) marry up with their abundance as a
function of the solvent polarity; i.e., the rotamer A prevails in polar solvents.
Figure 3.7. Partial assignment of the
1H NMR signals of 11aga (CDCl3). Letters with
a prime denote hydrogens of the minor rotamer.
We managed to get a 1H NMR spectrum of the pure rotamer A by
dissolving the solid 11aga in CDCl3 just before running the NMR experiment
(Figure 3.8). In-situ 1H NMR analysis of this sample at room temperature
disclosed that complete rotamer equilibration was attained after 2 h (Figure
3.9).
121
Anson, C. W.; Thamattoor, D. M. J. Org. Chem. 2012, 77, 1693. 122
The dipolar moments were determined by calculation with the PM3 semiempirical method: Stewart,
J. J. P. J. Comput. Chem. 1991, 12, 320.
Chapter III. Reactivity of indolizines: synthesis of dyes
109
Figure 3.8.
1H NMR spectrum of the pure rotamer A of dye 11aga (solid 11aga was
dissolved in CDCl3 just before running the NMR experiment).
Figure 3.9. In-situ
1H NMR analysis of the rotamer A of dye 11aga in CDCl3.
Chapter III. Reactivity of indolizines: synthesis of dyes
110
Rotamers were also observed for dyes of the 3-aryl-1-dibenzylamino
series (Table 3.3, entries 1–5 and 14): the presence of electron-withdrawing
groups at the para position of the phenyl group displaced the equilibrium
towards the rotamer A (Table 3.3, entries 4 and 5) and vice versa (Table 3.3,
entry 3). A quite homogeneous A/B ratio was measured for the N-alkylated
(non-benzylic) dyes 11ada–11aca (Table 3.3, entries 7–10). The most
pronounced effect in favor of the minor rotamer B was noted for the N-phenyl
substituted dyes 11aca and 11afa (Table 3.3, entries 11 and 12), probably due
to electron delocalization of the N lone pair though the phenyl ring. This effect
was of less magnitude in dye 11aha because the p-OMe groups work in the
opposite direction (Table 3.3, entry 13). Startlingly, the dye 11agi, bearing two
alkyl chains in the chalcone-indolizine skeleton, was held up to view as a
single set of NMR signals in solution; the broad signals plotted might be
linked to the existence of unresolved rotamers during the time-scale of the
Table 3.3. 1H NMR chemical shifts of dyes 11 and ratio of the two rotamers A
(major) and B (minor).
Entry Dye δA/δB (ppm)a A/B
1 11aga 6.86/6.35 83:17
2 11agb 6.84/6.34 83:17
3 11agc 6.81/6.34 78:22
4 11agd 6.90/6.36 91:9
5 11age 6.95/6.38 88:12
6 11agi 6.85b >99:1
7 11ada 6.93/6.38 83:17
8 11aea 6.86/6.38 81:19
9 11aaa 6.84/6.33 85:15
10 11aca 6.88/6.40 84:16
11 11afa 6.84/6.45 70:30
12 11cfa 2.62/2.58c 68:32
c
13 11aha 3.78/3.73d 79:21
d
14 11aia 6.97/6.41 86:14 a Chemical shift of Hk/Hk' unless otherwise stated.
b Only one rotamer was detected
by NMR. c
Ratio determined from the MeAr group. d Ratio determined from the
OMe group.
Chapter III. Reactivity of indolizines: synthesis of dyes
111
NMR experiment at room temperature. The larger conformational freedom of
the butyl group, compared to that of the phenyl group, could account for this
abnormality. As a general tendency, all the δB data for N-C-H were at higher
field than the δA counterparts.
3.2.3. Reaction mechanism
The dyes 11 are trisubstituted indolizines which keep the original
structure of the starting indolizine 4 but have selectively grown up through the
7-position. The reactivity at this position might be supported, in part, by the
deuteration studies by Engewald et al. to determine the exchange rate of the
indolizine hydrogens in D2O/dioxane at 50 ºC123
and in 0.02 M D2SO4/dioxane
at 200 ºC.124
These studies established the following relative order of reactivity
of the positions against electrophiles: 3 > 1 > > 2 > 7 ~ 5 > 6 > 8. In our case,
the positions 1 and 3 are already substituted and the position 2 is more
sterically encumbered than the position 7. Nevertheless, the amino group at the
position 1 seems to play a paramount role in this selectivity.
When the transformation of 4aga into 11aga was carried out following
the standard procedure but in CD3CO2D instead of CH3CO2H, no
incorporation of D was observed in 11aga; this result supports the activating
character of acetic acid and rules out any structural role. In-situ NMR analysis
of the reaction of 4aga with CD3CO2D in CDCl3 brought forth a major
depletion of the signal intensity for the indolizine hydrogen atoms (e.g., NC5-
H, ca. 8.2 ppm) and the benzylic methylene groups (NCH2, ca. 4.2 ppm). This
outcome could indicate a first deuteration/protonation stage involving the
nitrogen atoms. However, signals corresponding to the dye 11aga were not
present in the spectra. We observed that some dye 11aga was formed after
prolonged exposure of indolizine 4aga to HOAc but the reaction was much
slower compared to that subjected to posterior neutralization with sat.
NaHCO3, evidencing the necessity of water and/or base for the onward
progress of the reaction.
123
Engewald, W.; Mühlstädt, M.; Weiss, C. Tetrahedron 1971, 27, 4171. 124
Engewald, W.; Mühlstädt, M.; Weiss, C. Tetrahedron 1971, 27, 851.
Chapter III. Reactivity of indolizines: synthesis of dyes
112
Figure 3.10. In-situ
1H RMN analysis of indolizine 4aga in CDCl3 after the addition
of 20 equiv. of CD3CO2D.
On the basis of the above results, the following reaction mechanism was
put forward, exemplified for the substrate 4aga (Scheme 3.6): two molecules
of the indolizine 4aga are involved in the process, one acting as an
electrophile (after proper activation) and the other one as a nucleophile. On
one hand, it is our belief that 4aga possesses an enamine character and,
therefore, it might experience hydrolysis prior protonation to give the
corresponding ketone, with the concomitant loss of dibenzylamine (detected in
the reaction crude by GC/MS and 1H NMR). On the other hand, another
molecule of 4aga would act as a nucleophile through the dienamine subunit,
selectively reacting at its less hindered γ position (7 position of the indolizine
nucleus), by conjugate addition to an intermediate of the type 12. Ring
opening by C–N bond cleavage in 13 would furnish 14 which would,
eventually, undergo re-aromatization of the indolizine nucleus and oxidation
of the dihydropyridine ring, giving rise to the dye 11aga.
0 s
2 s
5 min
10 min
15 min
30 min
1 h
2 h
4 h
6 h
Chapter III. Reactivity of indolizines: synthesis of dyes
113
Scheme 3.6. Proposed reaction mechanism for the formation of the dyes 11.
We got some evidence on the formation of an intermediate of the type
13 by reacting indolizine 4aga with acetic acid, followed by acid evaporation
(in air). IR analysis of a sample, exposed to view the absence of acetic acid
[typical bands at 3500-2500 cm–1
(O-H); 1758 and 1714 cm–1
(C=O)] but the
presence of a peak at 1709 cm–1
, typical of a five-membered α,β-unsaturated
ketone [cyclopent-2-one, 1707 cm–1
(C=O)]. The stretching frequency of the
N-H bond in trisubstituted ammonium salts is manifested in the form of a
medium-intensity wide band of pronounced structure, with the maximum
interval being located at 2700-2250 cm–1
. We observed that type of shape in
the spectrum of the sample, but it is less conclusive due to its low intensity.
Chapter III. Reactivity of indolizines: synthesis of dyes
114
Unfortunately, dissolution of this sample for NMR analysis mainly gave
11aga [1662 cm–1
(C=O)].
The amino group can be considered as both a leaving (enamine hydrolysis)
and a nucleophilic group (dienamine), contributing largely to the optical and
structural properties of 11 in solution. It is noteworthy the relatively good
isolated yields recorded for a process which implies the reaction of a
nucleophile and an in-situ generated electrophile, both derived from the same
molecule. On the other hand, this process entails a change in the intrinsic
electronic properties of the indolizine nucleus because the pyridine ring (π-
deficient) acts as a nucleophile and the pyrrol (π-exceeding) ring as an
electrophile.
3.2.4. Optical properties
The heterocyclic chalcone moiety, selectively grafted to the 7-position of
the indolizines 4, notably enlarges the π-conjugation system of the indolizine
nucleus generating a new chromophoric assembly which confers dye attributes
to them. For instance, compound 11aga in the solid state exhibits a nice
reddish orange color that resembles that of Congo Red. In acetonitrile solution
(2 × 10–3
M), however, the pale yellow color of the starting indolizine 4aga
(λmax 340 nm), changes into reddish purple for the corresponding dye 11aga
(λmax 493 nm), a color similar to that of a young red wine (reach in
anthocyanins) (Figure 3.11).
Figure 3.11. The starting indolizine 4aga and the dye 11aga in acetonitrile solution
(2.0 × 10–3
M).
Chapter III. Reactivity of indolizines: synthesis of dyes
115
Analysis of the color of other dyes could be nicely rationalized as a
function of the substitution pattern. The following remarks could be made
taking dye 11aga as a reference compound with λmax = 493 nm: (a) the
influence of the p-substituent in the 3-aryl-1-dibenzylamino series of dyes is
scanty (Figure 3.12a), with a slight batochromic effect for those with electron-
donating substituents (Table 3.4, compare entries 1, 4 and 5 with 2 and 3); (b)
the contribution to color of the aryl units at the β-position of the carbonyl
group and 3-position of the indolizine seem to be negligible (Table 3.4,
compare entries 6, 7 and 14) (Figure 3.12b); (c) the batochromic shift for dyes
with a 1-alkylamino (non-benzylic) group was noticeable (Table 3.4, entries
8–10) (Figure 3.12c); (d) on the contrary, the 1-arylamino group lead to a
hypsochromic shift with the highest λ (Table 3.4, entries 11 and 12) (Figure
3.12d); (e) the highest λmax was recorded for the N,N-di-(4-
methoxyphenyl)amino derivative 11aha (Table 3.4, entry 13) (Figure 3.12d).
In summary, the chalcone-indolizine framework seems to be the chromophoric
component of the dyes, whereas the amino groups are auxochromic
components that modulate the color according as the electronic character of
their substituents.
Table 3.4. Vis radiation absorption data of dyes 11.
Entry Dye λmax (nm) (M–1
cm–1
)
1 11aga 493 7150
2 11agb 498 11450
3 11agc 504 6000
4 11agd 492 12400
5 11age 493 13850
6 11agi 486 13450
7 11ada 515 7100
8 11aea 522 9700
9 11aaa 521 15600
10 11aca 506 5350
11 11afa 480 26600
12 11cfa 482 23000
13 11aha 532 13400
14 11aia 486 20250
Chapter III. Reactivity of indolizines: synthesis of dyes
116
Figure 3.12. UV-Vis spectra for the different dyes 11.
A significant singularity of dyes 11 is that their color in the solid state
varies with their particle size. We briefly evaluated the influence of the
particle size on the color of 11aga by spectrophotometry and SEM. A
relatively wide maximum absorbance range of 420–520 nm was recorded for a
sample of crystalline 11aga (Figure 3.13). For a mortar ground sample, a
variation from reddish orange to almost black was observed; this result is
consonant with the decrease in the particle size observed by SEM and the
linear constant absorption in all the visible spectrum (Figure 3.14).
Figure 3.13. Color of dye 11aga in solid state, its TEM image and UV-Vis spectrum.
a) b)
c) d)
Chapter III. Reactivity of indolizines: synthesis of dyes
117
Figure 3.14. Dye 11aga after being ground in a mortar, its TEM image and UV-Vis
spectrum.
Another remarkable attribute to be highlighted is that the dyes 11 are
solvatochromic, that means that in solution they bring into view a different
color depending on the solvent utilized; different sheds of pink, violet, and
orange have been observed for 11aga (Table 3.5, Figure 3.15). A correlation
between the rotamer population, solvent polarity and visible absorbance can be
established: the proportion of the rotamer A generally increases with the
solvent polarity while the wavelength decreases. This hypsochromic (blue)
shift of λmax while increasing the solvent polarity is a clear case of negative
solvatochromism.
Table 3.5. Solvatochromic behavior of dye 11aga (2.0 × 10–5
M).
Entry Solvent λmax (nm) Abs Color
1 CHCl3 526 0.352 violet
2 hexane 520 0.072 light pinkish
3 EtOH 519 0.288 violet
4 CH2Cl2 511 0.350 purple
5 DMF 505 0.354 red
6 dioxane 504 0.297 pinkish
7 acetone 495 0.393 orange
8 MeCN 493 0.322 orange
Chapter III. Reactivity of indolizines: synthesis of dyes
118
Figure 3.15. Vis spectra and color of the dye 11aga in different solvents (2.0 × 10
–5
M).
In spite of the fact that the research on functional dyes is a very active
research field, its application as a practical technology is often hampered
because of reasons such as: (a) the expensive materials and catalysts required;
(b) the multi-step sequences that decrease the efficiency of the process
increasing the waste; (c) the non-green conditions and reaction media used; (d)
the experimental procedures are implemented at a laboratory scale but are
troublesome when scaled up. We took advantage of the optical characteristics
of dyes 11 to analyze their colouration power when injected into plastics. The
experiments were carried out at Colortech Química S.L. and IQAP
Masterbatch Group S.L. A preliminary examination revealed that migration of
the dye 11aga occurred in poly(vinyl chloride) (PVC) and polyamides but
Chapter III. Reactivity of indolizines: synthesis of dyes
119
high compatibility was found with polyolefins [e.g., polypropylene (PP) or
polystyrene (PS)]. Three plates were prepared (Figure 3.16): two with 11aga
and HIPS (high-impact polystyrene SB), with or without TiO2, and a third one
with 11aga and PP. The first conclusion is that the dye 11aga possesses a
strong colouration power at a very low concentration. We were delightfully
astonished to check that the solvatochromic character of the dye was also
demonstrated in plastic materials transparent to the visible radiation, such as
PS and PP. Indeed, three differently coloured plastic plates could be obtained
with a single dye. The effect was particularly dramatic when changing the
polymeric material from HIPS to PP.
Figure 3.16. Plates of 11aga injected into plastics: (a) 0.2 wt% 11aga + 0.5 wt%
TiO2 in HIPS (high-impact polystyrene SB); (b) 0.2 wt% 11aga in HIPS; (c) 0.05
wt% 11aga in PP (polypropylene).
3.2.5. Metal detection
In the lasts years, the photochemical properties of organic π-conjugated
molecules have been widely studied due to their interesting utility as
fluorescent probes or sensors.114
Developing new chemosensors for transition
metal ions or toxic anions has a huge importance for environmental and
biological applications. Recently, some examples of indolizines and chalcones
with some optical properties have been reported to be Cu(II)125
and pH126
sensors.
114
Selected reviews: (a) Zhou, Y.; Yoon, J. Chem. Soc. Rev. 2012, 41, 52. (b) Jung, H. S.; Chen, X.; Kim, J.
S.; Yoon, J. Chem. Soc. Rev. 2013, 42, 6019. (c) Uglov, A. N.; Bessmertnykh-Lemeune, A.; Guillard, R.;
Averin, A. D.; Beletskaya, I. P. Russ. Chem. Rev. 2014, 83, 196. 125
(a) Mashraqui, S. H.; Khan, T.; Sundaram, S.; Ghadigaonkar, S. Tetrahedron Lett. 2008, 49, 3739. (b)
Gaber, M.; El-Daly, S. A.; El-Sayed, Y. S. Y. J. Mol. Struct. 2009, 922, 51. (c) El-Sayed, Y. S.; Gaber, M.
Spectrochim. Acta Part A 2015, 137, 423.
Chapter III. Reactivity of indolizines: synthesis of dyes
120
In this context, the standard dye 11aga, with a chalcone and indolizine
moiety, was tested as a potential metal sensor with different metals in solution.
The dye was dissolved in a EtOH:H2O (8:2) solvent mixture (λmax 521 nm) at
10–5
M concentration. Then, the metal salt was added at 10–3
M concentration in
the same mixture of solvents and the absorbance was measured with a UV-Vis
spectrophotometer. Apparently, the dye did not form any complex with
alkaline and alkaline-earth metals (Table 3.6, entries 1-5) as no variation in the
absorbance was observed. Regarding transition metal ions, some of them did
not vary the solution color (Table 3.6, entries 6, 9, 13, 17 and 18), but a
significant change in the absorbance of the solution was observed in others
(Table 3.6, entries 7, 8, 10-12, 14-16, 19-20).
Table 3.6. Vis absorbance of a solution of the dye 11aga in the presence of different
metal ions.a
Entry Metal λmax
(nm)
Color
change Entry Metal
λmax
(nm)
Color
change
1 Li+ 521 No 12 Cu
+ 491 Yes
2 Na+ 521 No 13 Zn
2+ 521 No
3 K+ 521 No 14 Rh
2+ –
b Yes
4 Mg2+
521 No 15 Ir4+
–b Yes
5 Ca2+
521 No 16 Pd2+
535 Yes
6 Mn2+
521 No 17 Pt2+
521 No
7 Fe2+
504 Yes 18 Hg2+
521 No
8 Fe3+
–b Yes 19 Ag
+ 431 Yes
9 Co2+
521 No 20 Au3+
430 Yes
10 Ni2+
517 Yes 21 Al3+
430 Yes
11 Cu2+
428 Yes a A 1:1 mixture of dye 11aga (10–5M) and metal ion (10–3M) in EtOH:H2O (8:2). b No max was
observed.
126
(a) Zhang, Y.; Garcia-Amorós, J.; Captain B.; Raymo, F. M. J. Mat. Chem. 2016, 4, 2744. (b) Outlaw, V.
K.; Zhou, J.; Bragg, A. E.; Townsend, C. A. RSC Adv. 2016, 6, 61249.
Chapter III. Reactivity of indolizines: synthesis of dyes
121
The variation experienced by λmax can be explained in terms of
complexation of the metal ions to the pyridinoyl moiety as shown in Figure
3.17. However, no selectivity towards any particular ion was observed.
Figure 3.17. Proposed complexation model of dye 11aga to metal ions.
Some organic compounds with chromogenic properties have been
reported to be able to complex toxic anions in solution such as CN– 127
or NO2
in air.128
We also tested different anions under the same conditions as in the
case of the cations, but, unfortunately, no interaction anion-dye was observed.
Table 3.7. Vis absorbance of a solution of the dye 11aga in the presence of different
anions.a
Entry Anion λmax
(nm)
Color
change Entry Metal
λmax
(nm)
Color
change
1 Cl– 521 No 5 ClO
– 521 No
2 I– 521 No 6 IO3
– 521 No
3 AcO– 521 No 7 CN
– 521 No
4 SO42–
521 No 8 NO3– 521 No
a A 1:1 mixture of dye 11aga (10–5M) and anion (10–3M) in EtOH:H2O (8:2).
127
Gotor, R.; Costero, A. M.; Gil, S.; Parra, M.; Martínez-Máñez, R.; Sancenón, F.; Gaviña, P. Chem.
Commun. 2013, 49, 5669. 128
Juárez, L. A.; Costero, A. M.; Parra, M.; Gil, S.; Sancenón, F.; Martínez-Máñez, R. Chem. Commun.
2015, 51, 1725.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
125
4. REACTIVITY OF INDOLIZINES WITH NITROSOCOMPOUNDS:
SYNTHESIS OF -ENAMINONES AND PYRROLES
4.1. INTRODUCTION
Continuing the study on the reactivity of indolizines, we explored the
reaction versus different electrophiles, focusing our attention on
nitrosocompounds. Interestingly, we found out that the course of the reaction
was driven by the aromatic or aliphatic nature of the substituent at the 3-
position of the indolizine ring.
Scheme 4.1. Synthesis of β-enaminones and pyrroles from indolizines and
nitrosocompounds.
4.1.1. β-Enaminones
Enaminones can be considered as push-pull olefins which merge the
nucleophilic character of the enamines with the electrophilic one of the
enones.129
The enaminone moiety can be found as part of the structure of
different natural products, such as the glucose-lowering (–)-multiflorin (I),130
and also of some synthetic compounds, such as the anticonvulsant II131
(with
129
Reviews: (a) Kuckländer, U. In The Chemistry of Enamines, Part 1; Rappoport, Z., Ed.; Wiley:
Chichester, 1994; Chapter 10. (b) Elassar, A.-Z. A.; El-Kahir, A. A. Tetrahedron 2003, 59, 8463. (c) Negri,
G.; Kascheres, C.; Kascheres, A. J. J. Heterocycl. Chem. 2004, 41, 461. (d) Stanovnik, B.; Svete, J. Chem.
Rev. 2004, 104, 2433. (e) Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015, 51, 16437. (f)
Chattopadhyay, A. K.; Hanessian, S. Chem. Commun. 2015, 51, 16450. 130
Kubo, H.; Kobayashi, J.; Higashiyama, K.; Kamei, J.; Fujii, Y.; Ohmiya, S. Biol. Pharm. Bull. 2000, 23,
1114. 131
Scott, K. R.; Rankin, G. O.; Stables, J. P.; Alexander, M. S.; Edafiogho, I. O.; Farrar, V. A.; Kolen K. R.;
Moore, J. A.; Sims, L. D.; Tonnut, A. D. J. Med. Chem. 1996, 38, 4033.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
126
comparable potency to that of diazepam) or the fluorinated quinolone
antibacterials (e.g., ciprofloxacin, III) (Figure 4.1).132
In addition, enaminones
are highly versatile scaffolds in heterocyclic chemistry133,134
and, particularly,
in the total synthesis of alkaloids.
Figure 4.1. Examples of natural and synthetic enaminones.
Different synthetic strategies have been developed to construct
enaminones, the most common ones being condensation reactions, addition
reactions, cleavage of heterocycles and acylation of enamines (Scheme
4.2).135,1a–c
Among them, the condensation of primary or secondary amines
with 1,3-dicarbonyl compounds is the most used methodology. However, the
less nucleophilic aromatic amines are more reluctant to react and azeotropic
removal of water is mandatory in order to shift the equilibrium towards the
enaminone. Some alternative procedures mostly based on transition-metal
catalysis have emerged in the last years,136
with those involving the
transmutation of heterocycles into enaminones being uncommon.136b
132
Kaushik, A.; Ogbaghebriel, A.; Sharma, A. AAA’s Quinolones & Fluoroquinolones: Man-made
Antibiotics; LAP Lambert: Düsseldorf, 2011. 133
Reviews: (a) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277. (b) Kuckländer, U. In The Chemistry of
Enamines, Part 1; Rappoport, Z. Ed.; Wiley: Chichester, 1994. (c) Kascheres, C. M. J. Braz. Chem. Soc.
2003, 14, 945. 134
Recent examples: (a) Zhang, Q.; Liu, X.; Xin, X.; Zhang, R.; Liang, Y.; Dong, D. Chem. Commun. 2014,
50, 15378. (b) Yan, R.; Li, X.; Yang, X.; Kang, X.; Xiang, L.; Huang, G. Chem. Commun. 2015, 51, 2573. (c)
Wan, J.-P.; Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034. (d) Wang, F.; Jin, L.; Kong, L.; Li, X. Org. Lett. 2017,
19, 1812. 135
Review: Ferraz, H. M. C.; Pereira, F. L. C. Quim. Nova 2004, 27, 89. 136
(a) Bhatte, K. D.; Tambade, P. J.; Dhake, K. P.; Bhanage, B. M. Catal. Commun. 2010, 11, 1233. (b)
Seki, H.; Georg, G. I. J. Am. Chem. Soc. 2010, 132, 15512. (c) Miura, T.; Funakoshi, Y.; Morimoto, M.;
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
127
Scheme 4.2. Typical procedures for the synthesis of β-enaminones.
4.1.2. Pyrroles
The pyrrole ring can be found in numerous natural products (e.g.,
lamellarin O, IV)137
as well as in the small-molecule drug list of the FDA
Orange Book,138
albeit it is relatively less frequent in drugs. Nevertheless, the
Biyajima, T.; Murakami, M. J. Am. Chem. Soc. 2012, 134, 17440. (d) Shi, L.; Xue, L.; Lang, R.; Xia, C.; Li, F.
ChemCatChem 2014, 6, 2560. (e) Xu, K.; Zhang, Z.; Qian, P.; Zha, Z.; Wang, Z. Chem. Commun. 2015, 51,
11108. 137
Huang, X.-C.; Xiao, X.; Zhang, Y.-K.; Talele, T. T.; Salim, A. A.; Chen, Z.-S.; Capon, R. J. Mar. Drugs
2014, 12, 3818. 138
Miniperspective: Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, 57, 5845.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
128
best-selling pharmaceutical within the recent past, atorvastatin (V, a
cholesterol-lowering agent), consists of a polysubstituted pyrrole ring. The
latter ring is represented in other best-selling drugs, such as sunitib (anticancer
agent),139
or in agrochemicals, such as the fungicides fenpiclonil (VI, Beret®)
and fludioxonil (Celest®).140
The N-arylated pyrroles VII141
and TDR37250
(VIII)142
have been identified as powerful substances for the treatment of
leishmaniasis and malaria, respectively (Figure 4.2).
Figure 4.2. Examples of biologically active pyrroles.
139
Review: Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442. 140
Lamberth, C. In Bioactive Heterocyclic Compound Classes: Agrochemicals; Lamberth, C., Dinges, J.,
Eds.; Wiley-VCH: Weinheim, 2012; Chapter 13. 141
Baiocco, P.; Poce, G.; Alfonso, S.; Cocozza, M.; Porretta, G. C.; Colotti, G.; Biava, M.; Moraca, F.;
Botta, M.; Yardley, V.; Fiorillo, A.; Lantella, A.; Malatesta, F.; Ilari, A. ChemMedChem 2013, 8, 1175. 142
Murugesan, D.; Mital, A.; Kaiser, M.; Shackleford, D. M.; Morizzi, J.; Katneni, K.; Campbell, M.;
Hudson, A.; Charman, S. A.; Yeates, C.; Gilbert, I. H. J. Med. Chem. 2013, 56, 2975.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
129
Pyrroles are usually synthesized using the Hantzsch procedure,143
the
Knorr synthesis,144
and the Paal-Knorr synthesis (Scheme 4.3).
Scheme 4.3. Classical methods for the synthesis of pyrroles.
Multitude of efficient approaches to the synthesis of pyrroles have been
devised,145
mostly relying on transition-metal catalysis and multicomponent
reactions. Palladium,146
rhodium, gold and copper147
catalysts have been the
143
Wang, Y.; Jiang, C.-M.; Li, H.-L.; He, F.-S.; Luo, X.; Deng, W.-P.; J.Org. Chem. 2016, 81, 8653. 144
Li, T.; Yan, H.; Li, X.; Wang, C.; Wan, B. J.Org. Chem. 2016, 81, 12031. 145
Reviews: (a) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084.
(b) Yoshikai, N.; Wei, Y. Asian J. Org. Chem. 2013, 2, 466. (c) Estévez, V.; Villacampa, M.; Menéndez, J. C.
Chem. Soc. Rev. 2014, 43, 4633. (d) Vessally, S. RSC Adv. 2016, 6, 18619. (e) Anuradha, S.; Piplani, P. J.
Heterocycl. Chem. 2017, 54, 27. (f) Fujita, T.; Ichikawa, J. Heterocycles 2017, 95, 694. 146
Senadi, G. C.; Hu, W.-P.; Garkhedkar, A. M.; Boominathan, S. S. K.; Wang, J.-J. Chem. Commun. 2015,
51, 13795.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
130
most applied transition metals for this purpose, not only in MCRs but in
intramolecular cyclizations148
or intermolecular annulations involving
alkynes149
or other substrates;150
organocatalyzed procedures are also
known.151
As occurred in the case of the enaminones, the transformation of
other heterocycles into pyrroles is barely documented.152
Due to the type of
starting materials normally deployed for pyrrole synthesis (such as enamino
amides,153
enamino esters or ketones154
), the majority of the products end with
a carboxylate/carbonyl moiety attached to the pyrrole ring.
147
(a) Liu, P.; Liu, J.-L.; Wang, H.-S.; Pan, Y.-M.; Liang, H.; Chen, Z.-F. Chem. Commun. 2014, 50, 4795. (b)
Zhou, C.; Ma, D. Chem. Commun. 2014, 50, 3085. 148
(a) Jiang, Y.; Chan, W. C.; Park, C.-M. J. Am. Chem. Soc. 2012, 134, 4104. (b) Du, W.; Zhao, M.-N.; Ren,
Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Chem. Commun. 2014, 50, 7437. (c) Tiwari, D. K.; Pogula, J.; Sridhar, B.;
Tiwari, D. K.; Likhar, P. R. Chem. Commun. 2015, 51, 13646. 149
(a) Rakshit, S.; Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585. (b) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (c) Zheng, J.; Huang, L.; Li, Z.; Wu,
W.; Li, J.; Jiang, H. Chem. Commun. 2015, 51, 5894. (d) Undeela, S.; Thadkapally, S.; Nanubolu, J. B.;
Singarapu, K. K.; Menon, R. S. Chem. Commun. 2015, 51, 13748. 150
(a) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem. Soc. 2012, 134, 20230. (b) Tan, W. W.;
Yoshikai, N. Chem. Sci. 2015, 6, 6448. (c) Chen, X.; Xie, Y.; Xiao, X.; Li, G.; Deng, Y.; Jiang, H.; Zeng, W.
Chem Commun. 2015, 51, 15328. (d) Siddiki, S. M. A. H.; Touchy, A. S.; Caudhari, C.; Kon, K.; Toyao, T.;
Shimizu, K. Org. Chem. Front. 2016, 3, 846. 151
(a) Cyr, D. J. St.; Arndtsen, B. A. J. Am. Chem. Soc. 2007, 129, 12366. (b) Liao, J.-Y.; Shao, P.-L.; Zhao,
Y. J. Am. Chem. Soc. 2015, 137, 628. 152
(a) Kelly, A. R.; Kerrigan, M. H.; Walsh, P. J. J. Am. Chem. Soc. 2008, 130, 4097. (b) Parr, B. T.; Green,
S. A.; Davies, H. M. L. J. Am. Chem. Soc. 2013, 135, 4716. (c) Zhou, A.-H.; He, Q.; Shu, C.; Yu, Y.-F.; Liu, S.;
Zhao, T.; Zhang, W.; Lu, X.; Ye, L.-W. Chem. Sci. 2015, 6, 1265. 153
Zhang, Z.-J.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Org. Lett. 2013, 15, 4822. 154
(a) Li, Y.; Xu, H.; Xing, M.; Huang, F.; Jia, J.; Gao, J. Org. Lett. 2015, 17, 3690. (b) Zhao, M.; Wang, F.;
Li, X. Org. Lett. 2012, 14, 1412. (c) Attanasi, O. A.; Favi, G.; Mantellini, F.; Moscatelli, G.; Santeusanio, S.
J. Org. Chem. 2011, 76, 2860. (d) Palmieri, A.; Gabrielli, S.; Cimarelli, C.; Ballini, R. Green Chem. 2011, 13,
3333. (e) Xu, H.; Li, Y.; Xing, M.; Jia, J.; Han, L.; Ye, Q.; Gao, J. Chem. Lett. 2015, 44, 574. (f) Dhara, D.;
Gayen, K. S.; Khamarui, S.; Pandit, P.; Ghosh, S.; Maiti, D. K. J. Org. Chem. 2012, 77, 10441.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
131
4.2 RESULTS AND DISCUSSION
4.2.1 Synthesis of β-enaminones
We first assessed the effect of the amino substituent at the 1-position of
the indolizine. For this purpose, indolizine 4 (derived from pyridine-2-
carbaldehyde, a secondary amine and phenylacetylene) and nitrosobenzene
(15a) were deployed as the model substrates and allowed to react at room
temperature in ethanol (Table 4.1, entries 1–5). The dibenzylamino substituted
indolizine 4aga gave the highest conversion (Table 4.1, entry 3). A range of
solvents was tested for this indolizine derivative, concluding that acetonitrile
was the best choice (Table 4.1, entry 7). The absence of solvent or presence of
CuNPs/C (utilized for the synthesis of the indolizines) were detrimental to the
conversion (Table 4.1, entries 6 and 13, respectively).
With the optimized conditions in hand (Table 4.1, entry 7), we tried and
expand the procedure to other substrates (Table 4.2). Nitrosobenzene (15a)
was combined with indolizines bearing all sort of substituents on the aryl ring
at the 3-position (R1), i.e., electron-neutral, electron-donating and electron-
withdrawing ones; the corresponding β-enaminones 16agaa–16agea were
formed in good isolated yields. The outcome for indolizines with additional
substitution was uneven. For instance, the 5-methyl-substituted indolizine
4cga performed much better that the (methylsulfonyl)phenyl counterpart
(4dga), which was more reluctant to react and required warming at 50 ºC for
improving the yield. The product for that indolizine brought into view two sets
of signals by NMR in the crude, what was attributed to the obtention of the
two possible β-enaminones in a ratio 1.5/1, being the major one the product
16dgaa. The procedure was also successfully applied to the more complex dye
of indolizine 11aga, furnishing the expected product 16agaa’ with a double
pyridinyl chalcone motif. Nitrosoarenes other than nitrosobenzene were also
tested (15b–15h); para-substituted representative examples with electron-
donating, electron-withdrawing and halogen groups gave rise the enaminones
16agab–16agae in moderate yields. Ortho-substituted nitrosobenzenes
behaved similarly (16agaf–16agah), though some by-product formation was
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
132
observed in the case of the cyano derivative 16agag. As an exception, a β-
alkyl-β-enaminone could be also synthesized (16agid), albeit only with the
presence of the strong electron-releasing dimethylaminophenyl group.
Table 4.1. Optimization of the enaminone synthesis.a
Entry R1 R
2 Solvent Conv. (%)
b
1 (CH2)5 EtOH 71
2 Bu
Bu EtOH 32
3 Bn Bn EtOH 80
4 Bn Me EtOH 76
5 Ph Me EtOH 49
6 Bn Bn -
25c
7 Bn Bn MeCN 90
8 Bn Bn THF 36
9 Bn Bn PhMe 49
10 Bn Bn CH2Cl2 42
11 Bn Bn H2O 15
12 Bn Bn CH3COCH3 24
13 Bn Bn MeCNd 45
a Reaction conditions: 4 (0.1 mmol), 15a (0.1 mmol), solvent (1 mL), rt,
overnight. b Conversion into 16agaa determined by GC. c Reaction at 50
ºC.d In the presence of CuNPs/C (5 mol%).
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
133
Table 4.2. Synthesis of the enaminones 16.a
a Reaction conditions: 4 (0.3 mmol), 15 (0.3 mmol), MeCN (1 mL), rt, overnight; isolated yield in
parentheses. b Reaction at 50 ºC.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
134
The kinetic profile corresponding to the reaction of the indolizine 4aga
with nitrosobenzene (15a) displays the highest conversion variation in the
interval 4–8 h (Figure 4.3); the progress of the reaction is much slower at the
outset of the reaction and after 8 h.
Figure 4.3. Plot displaying the evolution of the synthesis of the enaminone 16agaa
from the indolizine 4aga and nitrosobenzene 15a.
We also attempted to reach the enaminone in one pot from the
commercial starting materials, pyridine-2-carbaldehyde (1a), dibenzylamine
(2g) and phenylacetylene (3a), without the need to isolate the intermediate
indolizine (Scheme 4.4); the moderate success of this approach could be due to
the interference of CuNPs/C in the second step of the sequence (see, Table 4.1,
entry 13). It was, however, gratifying to demonstrate that the enaminone
16agaa could be synthesized with equal efficiency at a gram scale (Scheme
4.5).
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
135
Scheme 4.4. One-pot synthesis of the enaminone 16agaa.
Scheme 4.5. Gram-scale synthesis of the enaminone 16agaa.
It is noteworthy that all the β-enaminones were obtained as single
stereoisomers. The Z stereochemistry was unequivocally assigned by X-ray
crystallographic analysis of enaminone 16agaa (Figure 4.4). The formation of
an intramolecular hydrogen bond with the participation of the oxygen carbonyl
group and the N–H of the arylamino moiety is a common feature to all the
enaminones, also observable by 1H NMR.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
136
Figure 4.4. X-ray structure of the enaminone 16agaa.
Regarding the atom economy of this reaction, after completing the
reaction, we treated the crude with HClaq. in order to protonate the
dibenzylamine formed during the reaction; in this way, it could be extracted
from the organic phase into the aqueous phase. After the separation of the two
phases, the aqueous phase was treated with NaHCO3 until neutral pH, what
allowed to recover dibenzylamine in the organic phase.
The usefulness of the obtained enaminones as building blocks for
heterocyclic synthesis was exemplified by transforming 16agaa into the
pyridinyl-containing oxazole155
18, pyrazoles156
19 and 20, and indole157
21
(Scheme 4.6).
155
Domínguez, E.; Ibeas, E.; Martínez de Marigorta, E.; Palacios, J. K.; San Martín, R. J. Org. Chem. 1996,
61, 5435. 156
Kovács, S.; Novák, Z. Tetrahedron 2013, 69, 8987. 157
He, Z.; Liu, W.; Li, Z. Chem. Asian J. 2011, 6, 1340.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
137
Scheme 4.6. Transformation of the enaminone 16agaa into different
heterocyclic compounds.
4.2.2. Selectivity in the synthesis of β-enaminones
As said in the introduction, -enaminones are readily accesible by the
condensation of primary or secondary amines with 1,3-dicarbonyl compounds;
this path is particularly effective for symmetrically substituted diketones.
However, for unsymmetrical substrates and when coordinating fragments are
present, other factors go into play which might condition both the conversion
and regioselectivity of the reaction. In this context and, in order to validate our
procedure, the unsymmetrical 1,3-dione 22 was synthesized and subjected to
some of the available literature methods for enaminone synthesis (Table 4.3).
For instance, Cu(OTf)2, which proved to be a good catalyst for the
condensation of acetylacetone with aniline (78% yield), completely failed in
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
138
the test reaction (Table 4.3, entry 1); this behavior could be explained in terms
of copper complexation with the pyridinylcarbonyl unit of 22.19
In contrast,
good conversion was attained with Yb(OTf)2 albeit towards the opposite
regioisomer 23 (Table 4.3, entry 2). The reaction was unproductive in the
absence of catalyst (Table 4.3, entries 3 and 4), whereas montmorillonite K-10
under ultrasounds18c
also formed the product 23 in moderate conversion (Table
4.3, entry 5). It is clear that the condensation route is not valid for the target
enaminone 16agaa because of the larger electrophilicity of the carbonyl
bonded to the pyridine ring and, therefore, this fact reinforces the utility of our
strategy.
Table 4.3. Reaction of the 1,3-dione 22 with aniline under different conditions.a
Entry Catalyst Conditions 16agaa, 23 (%)b
Ref.
1 Cu(OTf)2 (5 mol%) neat, rt, 16 h - 158
2 Yb(OTf)2 (5 mol%) neat, rt, 60 min 0, 85 158
3 - neat, 70 ºC, 16 h - 158
4 - H2O, rt, 16 h - 159
5 MK-10c
ultrasounds, 16 h 0, 65 160
a
1,3-Dione 22 (0.2 mmol), aniline (0.4 mmol). b
Conversion into 16agaa or 23
determined by GC. c Montmorillonite K-10 (60 mg).
158
Chen, J.; Yang, X.; Liu, M.; Wu, H.; Ding, J.; Su, W. Synth. Commun. 2009, 39, 4180. 159
Stefani, H. A.; Costa, I. M.; Silva, D. de O. Synthesis 2000, 1526. 160
Valduga, C. J.; Squizani, A.; Braibante, H. S.; Braibante, M. E. F. Synthesis 1998, 1019.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
139
4.2.3 Synthesis of pyrroles
Indolizine 4agi and nitrosobenzene (15a) were used as the model
substrates to optimize the reaction conditions (Table 4.4). Practically, every
organic solvent tested was adequate to accomplish this transformation,
providing conversions above 85% for 17agia (Table 4.4, entries 2–7). On the
contrary, the absence of solvent or presence of water had an adverse effect,
decreasing the conversion or impeding the reaction, respectively (Table 4.4,
entries 1 and 8). Ethanol was considered the solvent of choice because of
being a recommended solvent161
and achieving the highest conversion (Table
4.4, entry 2). To our delight, the reaction proceeded under ambient conditions
and, as occurred in the case of the β-enaminones, the presence of CuNPs/C
exerted a negative effect on the conversion (Table 4.4, entry 9).
These mild and green conditions were extended to an array of
indolizines and nitrosocompounds (Table 4.5). First, the amino group at the 1-
position of the indolizine was varied: the expected pyrroles were produced in
good-to-excellent isolated yields for dibenzyl, dialkyl, cyclic, alkylaryl and
alkylbenzyl amino groups (17agia–17adia). Pyrroles with a substituted
pyridine, different alkyl chain length or functionalized alkyl chain were also
accessible by this way but with relatively lower yields (17cgia–17agma), in
the latter case because of some by-product formation. Finally, the N-aryl
substituent could be modified by the choice of the nitrosoarene, recording
moderate-to-good yields for the N-arylated pyrroles. It is worthwhile
mentioning that product 17agif was an atropoisomeric chiral pyrrole, with the
free rotation through the C–N bond at room temperature being suppressed by
the ortho-tolyl substituent.
The reaction profile for the pyrrole synthesis notably differed from that
of the enaminone synthesis: a high conversion (80%) was reached after only 1
h at room temperature, continuing to completeness after 6 h (Figure 4.5).
161
Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, R.; Abou-Shehadad, S.; Dunne, P. J. Green Chem.
2016, 18, 288.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
140
Table 4.4. Optimization of the pyrrole synthesis.a
Entry Solvent Conversion (%)b
1 neatc
57
2 EtOH
96
3 MeCN 93
4 THF 90
5 PhMe 95
6 CH2Cl2 91
7 CH3COCH3 85
8 H2Oc 0
9 EtOHd 59
a Reaction conditions: 4agi (0.1 mmol), 15a PhNO (0.1 mmol),
solvent (1.0 mL) at rt. b Conversion determined by GC. c Reaction
at 50°C. d CuNPs/C
Figure 4.5. Plot displaying the evolution of the synthesis of the pyrrole
17agia from the indolizine 4agi and nitrosobenzene 15a.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
141
Table 4.5. Synthesis of the pyrroles 17.a
a Reaction conditions: 1 (0.3 mmol), ArNO (0.3 mmol), EtOH (1.0 mL), rt, overnight; isolated yield in
parentheses.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
142
An effective one-pot synthesis of pyrrole 17agia was shown to be
plausible following a multicomponent synthesis of the indolizine and
nitrosocompound addition sequence (Scheme 4.7). CuI is recommended as
catalyst instead of CuNPs/C in order to improve the yield of the intermediate
3-alkylindolizine. Furthermore, the simplicity of the experimental operation
and satisfactory reproducibility allowed the gram scale synthesis of the pyrrol
17agia obtained by cristalization (Scheme 4.8).
Scheme 4.7. One-pot synthesis of the pyrrole 17agia.
Scheme 4.8. Gram-scale synthesis of the pyrrole 17agia.
The structure of the pyrroles 17 was confirmed by X-ray
crystallographic examination of the derivative 17agia (Figure 4.6). The
perpendicular arrangement of the N-phenyl group with respect to the pyrrole
ring accounts for the symmetry break when introducing an ortho-methyl group
and the consequent manifestation of atropoisomerism.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
143
Figure 4.6. X-ray structure for the pyrrole 17agia.
4.2.4 Reaction mechanism
Different studies were carried out in order to know the reaction
mechanism for the formation of the two products, the β-enaminones and the
pyrroles.
First, a series of labelling experiments was carried out. The starting
indolizines were synthesized from pyridine-2-carbaldehyde, deuterated
dibenzylamine and deuterated terminal alkyne. Then, they were subjected to
the standard conditions showing a total loss of D in the β-enaminone 16agaa.
In contrast, most of the original D was maintained in the case of the pyrrole
17agia (Scheme 4.9).
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
144
Scheme 4.9. Deuterium-labelling experiments in the synthesis of the β-enaminone
16agaa and pyrrole 17agia.
Another experiment consisted in the synthesis of 16agaa in a mixture of
deuterated solvents, CD3CN:D2O (1:0.4), observing the incorporation of D
into the final product (by 1H NMR of the reaction crude) but mainly at the
nitrogen atom of the amine with an incorporation of 83%.
Scheme 4.10. Incorporation of deuterium into the β-enaminone 16agaa.
In order to prove any participation of radicals in the reaction mechanism,
radical traps were added under the standard reactions (Scheme 4.11), but they
did not alter the outcome of the processes as the final compounds were
obtained in good conversions and the radical traps were recovered unchanged.
Those results are in concordance with an ionic reaction pathway.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
145
Scheme 4.11. Standard reactions carried out in the presence of radical traps.
In the case of β-enaminones, the reaction was performed under different
atmospheres. As it can be seen in Figure 4.7, neither the use molecular oxygen
nor an inert atmosphere (using dry MeCN) were beneficial for the reaction. In
contrast, the reaction was accelerated by under air or in the presence of water,
being almost complete after 2 h in the latter case.
Figure 4.7. Reaction profile for the synthesis of 16agaa under different atmospheres.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
146
With those results in hand, the following reaction mechanism
(exemplified for indolizine 4aga) was proposed for the formation of the β-
enaminones 16 from indolizines 4 (Scheme 4.12). As mentioned in the general
introduction, the position 3 of the indolizine nucleus is activated toward
electrophiles; therefore, first, nitrosobenzene could act as an electrophile to
form a C-N bond at the 3 position. Ring opening involving the resonance of
the dibenzylamino group followed by intramolecular 5-exo-dig cyclization
would furnish a dihydroisoxazole intermediate. Alternatively, the
intramolecular cyclization might occur prior to the ring opening, but involving
in this case a less favorable 5-endo-dig process. Dibenzylamine elimination
followed by isoxazole ring opening would provide the corresponding β-
enaminone. The fact that water accelerates the reaction could be related to
water acting as a proton source, as two new N-H bonds are formed.
Scheme 4.12. Proposed mechanism for the formation of β-enaminones.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
147
Comparing the structure of the starting indolizine with that of the final
pyrrole, it seems clear that the dibenzylamino substituent has migrated to the
vicinal carbon atom. Apparently, this substituent is lost during the reaction and
reincorporated again into the final structure. Indeed, when the reaction was
carried out in the presence of 3 eq. of an external secondary amine, such as N-
methylaniline, the corresponding amino substituent was integrated into the
pyrrole as also occurred with the dibenzylamino group, thus demonstrating
what postulated above (Scheme 4.13).
Scheme 4.13. Effect of the addition of an external amine in the synthesis of pyrroles.
Several reactions were also performed to explore the possibility of the
β-enaminone being the intermediate in the formation of the indolizines.
However, the reaction of the unique aliphatic β-enaminone we could obtain
(17agid) with dibenzylamine did not produce the expected pyrrole, either
under the standard conditions or higher reaction temperature (Scheme 4.14).
This behavior was somewhat expected as the precursor indolizine of 16agid
did not furnish the corresponding pyrrole at all.
Scheme 4.14. Reaction of the β-enaminone 16agid with dibenzylamine
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
148
Compound 25 was synthesized as a potential intermediate in the
formation of the pyrrole XXX by the addition of aniline to the ketoalkyne 24
in MeOH, followed by reaction with dibenzylamine. However, the reaction of
25 with nitrosobenzene did not provide the corresponding pyrrole (Scheme
4.15).
Scheme 4.15. Synthesis of 25 and its reaction with PhNO.
A retrosynthetic analysis of pyrrole 17agaa gave us two potential
precursors with their tautomeric forms (Scheme 4.16).
Scheme 4.16. Retrosynthetic analysis of pyrrole 17agaa.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
149
In-situ NMR analysis of the reaction of indolizine 4agi with
nitrosobenzene (15a) at room temperature in CD3CN for 1 h revealed the
presence of significant signal at 188.8 ppm in the 13
C NMR spectrum (Figure
4.8). This signal could be attributed to a doubly conjugated carbonyl group,
which might be bonded to a pyridinyl unit at to a carbon-carbon double bond.
Figure 4.8.
13C NMR for the synthesis of 17agia at 10 min.
The reaction between 4agi and 15a was also analyzed by GC-MS and
HRMS/Q-TOF after 10 min. In both cases, the presence of a peak of m/z 278
was confirmed; this peak dimished in intensity with the reaction course and
disappeared after completion of the reaction, thus evidencing its role as a
reaction intermediate (Figure 4.9).
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
150
Figure 4.9. HRMS/Q-TOF and low resolution MS spectra of the intermediate in the
synthesis of the pyrrole 17agia.
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
151
Several structures match the m/z 278 and some of the fragmentations
observed (Figure 4.10). However, taking into account the disconnection in
Scheme 4.16, the structure C can be practically ruled out as the intermediate.
This is a very important finding as demonstrates that the nitrosocompound
fragment is incorporated first and the dibenzylamine second, prior to the ring
closure. A wide peak at longer reaction time (27.5 min) was observed by GC-
MS. Although the molecular ion could not be detected, the average
fragmentation points to structures which are the immediate precursors of the
pyrroles (Figure 4.11).
Figure 4.10. Structures and MS fragmentation proposed for the pyrrole synthesis
intermediates.
Figure 4.11. Structures and MS fragmentation proposed for the pyrrole precursors.
On the basis of the above results, a tentative reaction mechanism has
been proposed including two variants (Figure 4.12). We have considered in
both variants that the source of oxygen in the nitrosocompound, given that the
reaction takes place nicely in solvents of different nature except in water. In
variant (a), two equivalents of nitrosobenzene are involved, one providing the
carbonyl oxygen and the other one providing the PhN moiety. Although it is
true that the reaction is faster with two equivalents of PhNO, this route entails
the sacrifice of one equivalent of PhNO that is transformed into
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
152
phenylhydroxylamine or O-ethyl-N-phenylhydroxylamine, depending on
whether water of ethanol are involved in the process. In this way, the pyrrole
precursor does not coincide with any of the structures proposed in Figure 4.11.
Scheme 4.16. Reaction mechanism proposed for the synthesis of pyrrole 17agia from
compound 4agg and nitrosobenzene (15a).
Chapter IV. Reactivity of indolizines with nitrosocompounds: synthesis of β-
enaminones and pyrroles
153
In the variant (b) one equivalent of PhNO participates but requires intra-
or intermolecular delivery of the anilino moiety (PhN) to provide one of the
pyrrole precursors in Figure 4.11, which could undergo intramolecular
condensation to give the pyrrole.
We believe that more experimentation is needed in order to propose a
more accurate reaction mechanism for the synthesis of pyrroles. We can,
however, establish the sequence of the process in which similar intermediates
to those shown might be involved (Scheme 4.17).
Scheme 4.17. Proposed reaction sequence in the synthesis of pyrroles from
indolizines and nitrosocompounds.
Conclusions
157
CONCLUSIONS
The multicomponent synthesis of a series of new 1-aminoindolizines and
pyrrolo[1,2-a]quinolines has been effectively accomplished using CuNPs/C as
catalyst in dichloromethane at 70 ºC. The methodology has been applicable to
a variety of amines and alkynes, with the latter including aryl alkynes (bearing
electron-neutral, -releasing, and -withdrawing groups) as well as aliphatic
alkynes with moderate-to-high isolated yields. Our catalyst has been shown to
be superior to some commercially available copper catalysts. A reaction
mechanism has been proposed based on the evidence of the participation of
propargylamines.
The synthesis of indolizidines through the heterogeneous catalytic
hydrogenation of indolizines has been accomplished using PtO2 as catalyst in
acetic acid as solvent and a pressure of 3.7 atm. The indolizidines have been
obtained with high diastereoselectivity, also in the case of forming four
stereocenters. Experimental evidence supports the indolizine hydrogenation
occurring through the pyrrolic intermediate 5,6,7,8-tetrahydroindolizine.
Furthermore, this indolizidines have been mono or didebenzylated by the
choice of the catalyst.
A number of new organic compounds have been synthesized by treating
the indolizines in acidic medium. These products are well-defined D-A-π-A
reddish-to-deep violet dyes derived from the condensation of two molecules of
indolizine. The structure of the indolizine dyes has been established by X-ray
analysis in the solid state, but it splits into two rotamers in solution. A reaction
mechanism has been proposed in which the same indolizine acts as both a
nucleophile and an electrophile. A preliminary study on the optical features of
these dyes has revealed a particle-size dependent color, high coloration power
and solvatochromic character, also in plastic materials.
The reactivity of the indolizines with nitrosocompounds has been also
studied, giving two different products depending on the substituent at the three
position of the indolizine. β-Enaminones have been formed for aromatic
substituents in good-to-high isolated yields, with this method providing
opposite regiochemistry to that of the reported procedures. For aliphatic
Conclusions
158
substituents, tetrasubstituted pyrroles have been obtained in moderate-to-good
yields. Many different experiments have been carried out in order to
understand the pathways for the formation of β-enaminones and pyrroles.
Resumen
161
RESUMEN
En la presente memoria se ha estudiado la síntesis multicomponente de
1-aminoindolizidinas y su reactividad.
En la introducción general se describe qué se considera una
nanopartícula y los diferentes medios que hay para sintetizarlas, además de los
métodos que se conocen para estabilizarlas. Se ha resaltado la importancia del
uso de nanopartículas metálicas en síntesis orgánica, destacando la
importancia de usar metales como el cobre, debido a su bajo coste y su baja
toxicidad frente a otros metales de transición como puede ser el caso del
platino, paladio, rutenio, rodio o iridio.
Nuestro grupo de investigación ha generado nanopartículas de cobre
mediante la reducción de cloruro de cobre (II) con litio metálico y DTBB, el
cual actúa como transportador de electrones. En el proceso tiene lugar una
transferencia electrónica del litio al areno, provocando la formación de un
anión radical y/o del dianión correspondiente, generando una suspensión verde
oscura. A continuación, se produce una transferencia electrónica por parte de
estas especies hacia la sal metálica. Esta transferencia, la cual es muy rápida,
provoca la reducción de la sal, y como consecuencia, la formación de
nanopartículas de cobre. La presencia de las nanopartículas hace que la
suspensión adquiera una coloración negra. Es en este momento en el que se
adiciona el soporte inorgánico a la mezcla, seguido de filtrado, lavado y
secado al aire para obtener el catalizador deseado, el cual, se usa en la síntesis
de derivados indolizidínicos.
También se introduce la estructura de indolizina, la cual se trata de un
biciclo de cinco y seis miembros, con un átomo de nitrógeno en el puente entre
ambos. Este tipo de estructuras han sido muy estudiadas debido a la
importancia de su actividad biológica. Se ha demostrado que las indolizinas
tienen diversas aplicaciones debido a su actividad anticancerígena,
antiinflamatoria, antioxidante, antibacteriana y antifúngica, entre otras. Cabe
destacar que en los últimos años se han desarrollado nuevas metodologías de
síntesis de indolizinas no solo por su importancia biológica, sino por sus
propiedades fotofísicas.
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Se ha incluido una revisión bibliográfica de las diferentes metodologías
clásicas que se usan para la síntesis de indolizinas como, por ejemplo, la
reacción de Tschitschibabin o la reacción de Scholtz. También se han descrito
otras síntesis de indolizinas a través de reacciones 1,3-dipolar o de
cicloisomerización de alquinos.
Las indolizinas pueden actuar como nucleófilos debido a la estabilidad
resonante que poseen dentro del anillo. Debido a la deslocalización electrónica
que poseen estas estructuras, las posiciones más reactivas son los carbonos
uno y tres. Sin embargo, a pesar de los numerosos estudios relacionados con la
síntesis de indolizinas, la reactividad de estos compuestos no se ha investigado
en profundidad, aunque hay descritos ejemplos de reacciones típicas como
nitración, acilación, etc.
Como se ha mencionado anteriormente, en nuestro grupo de
investigación se ha llevado a cabo la síntesis de indolizinas a través de una
reacción multicomponente. En el primer capítulo se describe en qué consiste
este tipo de reacciones y su uso para el desarrollo de nuevas metodologías para
la obtención de heterociclos; se comentan diversas síntesis multicomponentes
de indolizinas desarrolladas más recientemente. Considerando que la
introducción de un grupo amino en las estructuras de compuestos abre nuevas
funcionalizaciones dando lugar a una variedad más amplia de compuestos, se
presenta la síntesis multicomponente de 1-aminoindolizinas catalizada por
sales metálicas de oro, plata o hierro. En nuestro grupo de investigación se ha
logrado de manera efectiva la síntesis multicomponente de una serie de
indolizinas y pirrolo[1,2-a]quinolinas a partir de derivados de piridin-2-
carbaldehído, aminas secundarias y alquinos terminales usando NPsCu/C
como catalizador en diclorometano. Curiosamente, el mismo procedimiento,
cuando se aplica en ausencia de disolvente usando piperidina como amina
secundaria, ha conducido a chalconas heterocíclicas como productos
principales con rendimientos de moderados a buenos y estereoquímica E
exclusivamente (esta parte ha sido estudiada en detalle en una tesis anterior).
El catalizador ha sido caracterizado con anterioridad usando distintas técnicas
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para saber el contenido de Cu y el estado de oxidación de éste en el catalizador
de NPsCu/C.
La síntesis multicomponente de 1-aminoindolizinas se ha aplicado a una
gran variedad de aminas tanto alifáticas como bencílicas y aromáticas con
altos rendimientos (55-93%). También se han empleado alquinos de diferente
naturaleza electrónica, incluyendo alquinos aromáticos (con sustituyentes
electrónicamente neutros, electrón-atrayentes y electrón-donadores) y alquinos
alifáticos, aunque las indolizinas se obtienen con menores rendimientos (42-
77%). Además, se han probado piridin-2-carbaldehídos sustituidos en la
posición 6; cabe destacar el bajo rendimiento obtenido con el sustituyente de
bromo (20%), lo cual puede deberse a un mayor impedimento estérico. La
metodología ha aplicado a quinolin-2-carbaldehído obteniendo las pirrolo[1,2-
a]quinolinas con rendimientos de buenos a altos (66-92%). En los casos en los
que nuestro procedimiento no ha sido efectivo para la síntesis de indolizinas,
se ha probado un método alternativo, que consiste en el uso de CuI, en lugar
de nuestro catalizador, pero en este caso, en ausencia de disolvente. Se han
sintetizado varios ejemplos variando la amina de partida, la cadena alifática e
incluso con un metilo en la posición 6 del aldehído. Comparado con nuestro
método, se han obtenido las indolizinas con mayor conversión, aunque sigue
siendo baja y el rendimiento aislado, por consiguiente, también es bajo. Para la
obtención de indolizinas y chalconas se ha demostrado que el catalizador de
NPsCu/C es superior a un amplio número de catalizadores de cobre
comerciales, presentando la ventaja de poder reutilizarse en la síntesis de
chalconas durante cuatro ciclos con una leve disminución de la actividad
catalítica (conversión del 85-64%). En base a la pruebas mecanísticas
realizadas previamente en el grupo de investigación, se ha propuesto un
mecanismo de reacción para la formación de indolizinas, basado en la
concluyente evidencia experimental de la participación de aminas
propargílicas como intermedios: en primer lugar, la amina reacciona con el
aldehído formando la correspondiente sal de iminio, por otro lado, el
catalizador incrementa la acidez del protón del triple enlace del alquino,
formando un acetiluro de cobre. Ambos reaccionan formando la
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correspondiente amina propargílica; en este punto, se produce una ciclación y
posterior aromatización, obteniendo así la indolizina.
Finalmente, se expone la bioactividad que presentan estas estructuras,
comentando las líneas celulares en las cuales, algunas de ellas, han dado
actividad in-silico e in-vitro. Estas pruebas se llevaron a cabo a través del
programa Lilly Open Innovation Drug Discovery (OIDD).
En el segundo capítulo se ha desarrollado una nueva metodología para la
obtención de indolizidinas a partir de indolizinas. Existe un creciente interés
general en el desarrollo de nuevas estrategias para obtener de forma efectiva
N-heterociclos saturados a partir de materiales de partida fácilmente
accesibles. Esta demanda está respaldada por el desarrollo potencial de nuevos
productos farmacéuticos relacionados con este tipo de heterociclos y su
abundancia en compuestos naturales. Entre ellos, los alcaloides de indolizidina
han atraído una gran atención debido a su diversidad estructural y su variada
actividad biológica.
Los alcaloides indolizidínicos son compuestos bicíclicos que tienen un
nitrógeno básico en su estructura. Muchos de ellos presentan actividad
biológica del tipo fitotóxica, antibacteriana, antifúngica o neurológica, y se
pueden extraer de diversas fuentes de la naturaleza: hormigas, ranas
venenosas, hongos, plantas, etc. Se han desarrollado diferentes estrategias
sintéticas para construir el esqueleto de indolizidina según el patrón de
sustitución perseguido, pero sólo hay un estudio sistemático sobre la síntesis
de indolizidinas por hidrogenación completa de indolizinas, ya que la
reducción parcial es un problema común encontrado, que junto con una
diastereoselectividad deseable más alta, hacen que la hidrogenación selectiva
de indolizinas sea un objetivo desafiante.
Para conseguir la hidrogenación de indolizinas se ha hecho una
optimización exhaustiva, probando diferentes metales (aunque el más
estudiado ha sido el platino) y soportes, diferentes disolventes y distintas
presiones. Este estudio ha llevado a la conclusión de que el mejor catalizador
es el óxido de platino (IV), en ácido acético como disolvente y a una presión
de 3.7 atm (55 psi). Los catalizadores con mayor conversión (PtO2 y Pt/C) se
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han intentado reutilizar pero, desgraciadamente, tras el primer ciclo disminuyó
la conversión del producto deseado.
Estas condiciones óptimas de reacción se han aplicado a algunas
indolizinas ya descritas en el primer capítulo, obteniendo las correspondientes
indolizidinas con rendimientos de moderados a buenos. Se ha visto que el
rendimiento y la diastereoselectividad dependen de los sustituyentes en las
posiciones 1 y 3 de la indolizina, siendo el grupo amino en la posición 1 el
que, aparentemente, ejerce un efecto más fuerte. Las indolizinas derivadas de
piperidina y arilacetilenos se han aislado con rendimientos más bajos,
registrándose la diastereoselectividad más baja también en el crudo (92:8),
aunque tras la purificación aumentó esa diastereoselectividad (>99:1). Se ha
observado un mejor rendimiento y una excelente diastereoselectividad al
cambiar el 1-piperidinilo por un grupo 1-morfolino (68%, >99:1). La
diastereoselectividad ha aumentado al aumentar el impedimento estérico de la
amina secundaria. Las indolizidinas derivadas de dibencilamina se han
obtenido en tiempos de reacción de hidrogenación relativamente cortos y
como únicos diastereoisómeros. Este comportamiento se ha mostrado
independientemente del sustituyente que tuviera en la posición 3 la indolizina
de partida, incluidos los sustituyentes arilo con grupos electrónicamente
neutros, electrón-dadores y electrón-aceptores, y los sustituyentes alifáticos.
Las estructuras de este tipo de compuestos han sido comprobadas mediante
espectros 2D de RMN y por espectroscopía de rayos X, confirmando que
todos los sustituyentes se encuentran en la misma cara de la molécula. Se ha
podido aislar el intermedio, comprobando la secuencia de hidrogenación, la
cual comienza en el anillo de seis miembros y continúa con el de cinco.
El uso de dos catalizadores distintos para conseguir distintos compuestos
a partir del mismo producto de partida es muy interesante. En este sentido, se
ha estudiado la mono y doble desbencilación de las indolizidinas sintetizadas,
obteniendo estas estructuras con un grupo amina secundaria o primaria, la cual
podría funcionalizarse con posterioridad.
En el tercer capítulo, se expone la alquenilación C-H regio y
diastereoselectiva de indolizinas a través de una reacción sin metales en un
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medio ácido. El hecho más fascinante es la formación de enlaces Csp2-Csp2
utilizando un solo material de partida que sufre una autoalquilación para
formar una indolizina con una parte de chalcona, generando estructuras de alta
complejidad, las cuales se pueden emplear como colorantes. Los tintes
orgánicos con una configuración D-π-A contienen tanto grupos donadores de
electrones (D) como aceptores de electrones (A) conectados por una sección π
conjugada; alternativamente, una configuración D-A-π-A puede diseñarse
molecularmente donde la A intercalada adicionalmente es un componente
heterocíclico. Esta configuración permite aumentar la capacidad de absorción
de luz de estos compuestos haciéndolos candidatos ideales para ser empleados
como quimiosensores y ser aplicados en células solares sensibilizadas por
tintes. Se han obtenido hasta 14 tintes diferentes con rendimientos de bajos a
altos (23-83%). Las indolizinas sustituidas en la posición 3 con un grupo
aromático generan los correspondientes tintes con rendimientos buenos (50-
83%), disminuyendo el rendimiento aislado en el caso de tener un grupo
electrón-aceptor, ocurre lo mismo al poseer un grupo alifático en la misma
posición (54%). El mismo comportamiento se repite al cambiar la amina de
partida, observando que las aminas alifáticas reaccionan peor que las que
poseen una naturaleza electrónica diferente.
En este mismo capítulo, se ha descrito la reacción en dos pasos de un
tinte de indolizina a una escala de cuarenta gramos a partir de piridina-2-
carbaldehído, dibencilamina y fenilacetileno como materiales de partida. Para
esta escala, se ha decidido sustituir el catalizador, usando yoduro de cobre en
lugar de las nanopartículas de cobre, facilitando así la síntesis a escala
industrial. Además, de este modo se evita el uso de disolventes y la necesidad
de purificación de la indolizina. Seguidamente, se ha tratado el crudo con
ácido acético y a través de precipitación se ha obtenido el correspondiente
tinte, sin pérdida de rendimiento comparado con la menor escala. También se
ha intentado sintetizar tintes mixtos procedentes de dos indolizinas diferentes,
pero sin ningún resultado satisfactorio.
Los tintes muestran una única estructura en estado sólido pero en
cambio, se han observado dos estructuras estables en disolución (rotámeros),
de los cuales se ha hecho un estudio de resonancia magnética nuclear usando
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diferentes disolventes para ver la diferencia entre ellos. Este comportamiento
se ha repetido en todos los tintes, a excepción de uno de ellos, el cual posee
una cadena alifática en la posición 3 de la indolizina de partida. Se ha
propuesto un mecanismo de reacción basado en diferentes estudios realizados,
donde la indolizina tiene una doble funcionalidad actuando como nucleófila y
electrófila. En el primer paso la indolizina, en medio ácido, sufre una hidrólisis
para generar la correspondiente enamina, seguido por una adición Michael
debida al ataque de otra molécula de indolizina que favorece la apertura del
ciclo y, finalmente, se produce la rearomatización obteniendo el compuesto
deseado. Se ha hecho un extenso estudio de las propiedades ópticas de los
tintes, comparando las diferentes tonalidades de cada uno, la cual varía en
función de los sustituyentes que poseen. Los estudios preliminares sobre las
propiedades ópticas de los tintes han revelado que poseen propiedades
solvatocrómicas (es decir, se observan diferentes colores en solución para un
mismo tinte dependiendo de la polaridad del disolvente que se use). Además,
el color es dependiente del tamaño de partícula en estado sólido. Cuanto más
cristalina es la muestra, más grande es el tamaño de partícula, confiriendo al
sólido una tonalidad anaranjado-rojiza. Sin embargo, al disminuir el tamaño de
partícula, el color se vuelve más oscuro, pareciendo casi negro.
Sorprendentemente, el comportamiento solvatocrómico también se ha
mostrado tras injectar estos tintes a termoplásticos del tipo poliolefina
(poliestireno y polipropileno).
Debido a las propiedades ópticas de los tintes de indolizina, se ha
pensado que podrían utilizarse como detectores de metales, ya que hay varios
ejemplos donde los emplean para este fin. Debido a esto, se ha descrito el
estudio preliminar de la interacción del tinte de indolizina con varios cationes
metálicos, pudiendo observarse cambios de color en algunos casos pero sin
especial selectividad. Sin embargo, al probar diferentes aniones, no se ha
obtenido ninguna variación del color de la disolución.
En el cuarto capítulo, se estudia la reactividad nucleofílica de las
indolizinas frente a nitrosocompuestos como electrófilos. Esta reacción ha
resultado ser una útil herramienta sintética ya que se han obtenido distintos
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compuestos al cambiar los sustituyentes de las indolizinas. Estos compuestos
son β-enaminonas y pirroles, dependiendo de si el sustituyente en la posición 3
de la indolizina es un grupo aromático o alifático. La estructura de enaminona
se puede encontrar en diversos compuestos naturales o en compuestos
biológicamente activos. Existen varios métodos clásicos para la obtención de β
-enaminonas como son la reacción de condensación de aminas con
compuestos 1,3-dicarbonílicos, la reacción de adición a triples enlaces, la
apertura de heterociclos y la acilación de enaminas. En los últimos años se han
desarrollado nuevas metodologías que hacen uso de metales de transición para
catalizar estas reacciones. En el caso de los pirroles, éstos también son
compuestos que se encuentran formando parte de muchos medicamentos ya
comercializados, los cuales suelen sintetizarse comúnmente mediante la
síntesis de Hantzsch o la síntesis de Paal Knorr. Actualmente, se han
desarrollado numerosas metodologías efectivas para la síntesis de pirroles
polisustituidos usando metales de transición o la síntesis multicomponente.
En la reacción de indolizinas con nitrosocompuestos para la obtención
de β-enaminonas, se han optimizado las condiciones de reacción, estudiando,
en primer lugar, la mejor amina para su obtención seguida de la optimización
del disolvente. La mayor conversión se ha obtenido llevando a cabo la
reacción en acetonitrilo, sin el uso de metal y con la indolizina derivada de
dibencilamina a temperatura ambiente. Esta metodología se ha aplicado a
varias indolizinas sintetizadas en el primer capítulo, consiguiendo las
correspondientes β-enaminonas con rendimientos de moderados a buenos (35-
88%). Para las indolizinas con un grupo aromático sustituido en para, los
rendimientos obtenidos han sido altos (65-88%). Cabe destacar, que el menor
rendimiento se obtuvo para la indolizina con un grupo muy voluminoso en la
posición 5 de la indolizina debido, seguramente, al impedimento estérico que
ésta presenta. La metodología también ha sido efectiva empleando el tinte
derivado de indolizina con un buen rendimiento (64%). También se han
probado nitrosoderivados de diferente naturaleza electrónica y sustituidos
tanto en orto como en para, obteniendo los correspondientes compuestos con
rendimientos de moderados a buenos (40-74%). Sorprendentemente, se pudo
obtener la β-enaminona con una cadena alifática al usar la N,N-dimetil-4-
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nitrosoanilina (60%). Se ha podido escalar la reacción a 5 mmoles
consiguiendo el mismo rendimiento que a menor escala, obteniendo en este
caso el producto puro por precipitación. Se ha intentado llevar a cabo la
síntesis de β-enaminonas a través de la reacción multicomponente descrita en
el capítulo 1 en dos pasos en el mismo medio de reacción, es decir, generando
la correspondiente indolizina in situ, seguida de la adición del nitrosoderivado;
desgraciadamente la conversión ha sido menor. Para poder elucidar la
estereoquímica del compuesto se ha analizado la estructura por rayos X,
confirmando la estereoquímica Z, apoyado por la señal de resonancia
magnética nuclear de 1H que aparece a desplazamientos muy altos debido a la
formación de un enlace de hidrógeno entre el oxígeno carbonílico y el grupo
NH. También se han llevado a cabo algunas de las reacciones más comunes de
enaminonas, obteniendo los productos heterocíclicos deseados.
Después, se ha decidido estudiar la selectividad de nuestro método frente
a los métodos clásicos de obtención de β-enaminonas; para ello se ha
sintetizado un compuesto 1,3-dicarbonílico a partir de picolinato de etilo y
acetofenona. La mezcla de este compuesto y anilina se han sometido a las
condiciones de reacción descritas en la bibliografía. No todas las metodologías
descritas han funcionado, y en los casos que sí ha habido producto, se
comprobó que se obtiene mayormente el otro isómero. Por lo tanto, nuestra
metodología es selectiva y novedosa para obtener las β-enaminonas con esa
sustitución.
En segundo lugar, se ha optimizado la reacción para la obtención de
pirroles a partir de indolizinas con sustituyentes alifáticos en la posición 3. Se
ha observado que, en la mayoría de disolventes, se obtiene el pirrol con una
alta conversión, por lo que se decidió usar etanol, ya que es un disolvente
menos nocivo y más respetuoso con el medio ambiente. Al igual que en el
caso de la obtención de β-enaminonas, la reacción se ha llevado a cabo sin el
uso de ningún catalizador. Para comprobar que esta metodología es apta para
la síntesis de pirroles tetrasustituidos, las condiciones optimizadas de reacción
se han aplicado a diversas indolizinas obteniendo los correspondientes
compuestos finales con rendimientos de moderados a altos (33-96%). Todos
los pirroles obtenidos empleando diferentes aminas en la posición 1 de la
Resumen
170
indolizina se han obtenido con altos rendimientos (65-96%). Al tener un
sustituyente en la posición 6 de la indolizina, el rendimiento ha disminuido
considerablemente (33%). De igual manera, el rendimiento es menor cuando
se acorta o se alarga la cadena alifática (36-60%). En el caso de usar
nitrosocompuestos sustituidos en para o en orto, la conversión ha sido buena
(56-68%). En el perfil de reacción se puede apreciar cómo se obtiene una
conversión alta tan solo al cabo de una hora de reacción. Al igual que en el
caso de las β-enaminonas, se ha llevado a cabo la reacción a mayor escala,
obteniendo un buen rendimiento por precipitación del pirrol. En el caso de la
síntesis partiendo de piridin-2-carbaldehído, dibencilamina y 1-hexino, en
presencia de cobre y seguida de la adición de nitrosobenceno, se ha obtenido
una conversión buena, aunque es menor que aislando la indolizina
previamente. La estructura de los pirroles se ha confirmado por cristalografía
de rayos X.
El siguiente apartado del capítulo trata de explicar el mecanismo de la
reacción para la obtención de ambos compuestos. Para los dos casos, se han
sintetizado las indolizinas de partida deuteradas en la posición 2 y se han
sometido a las condiciones estándar de reacción, viendo que el deuterio se
pierde en el caso de las β-enaminonas, en cambio, se mantiene para la síntesis
de pirroles. La reacción de la β-enaminona en presencia de agua deuterada
demuestra que la incorporación de deuterio se produce en el protón
intercambiable del grupo NH.
Para verificar si hay presencia o no de radicales en el medio de reacción,
se han añadido trampas radicalarias en las reacciones estándar, pero los
compuestos finales se han obtenido con buena conversión, por lo que todo
indica que transcurre a través de un mecanismo iónico. Para el caso de las β-
enaminonas, se ha llevado a cabo la reacción bajo diferentes atmósferas, pero
se ha visto que la reacción bajo argón así como bajo oxígeno es mucho más
lenta. En cambio, la presencia de una cantidad catalítica de agua es beneficiosa
y aumenta la velocidad de reacción considerablemente. Considerando todos
los resultados obtenidos, se ha propuesto un mecanismo para la obtención de
β-enaminonas en el cual la indolizina actúa como nucleófilo reaccionando con
el nitrógeno del nitrosocompuesto, seguido de la pérdida de dibencilamina y
Resumen
171
siguiente ciclación dando una estructura intermedia de isooxazol, la cual se
abre y se protona dando lugar a la β-enaminona.
En el caso de la obtención de los pirroles se ha demostrado que se
produce una migración del sustituyente en la posición 1 a otro carbono en la
estructura final. Además, se ha intentado ver si la reacción procede de la
ciclación de la β-enaminona, usando la única enaminona alifática que se ha
obtenido, sin embargo, no se han obtenido resultados satisfactorios. Se ha
tratado de capturar el intermedio de la reacción usando hidracina,
hidroxilamina o el reactivo de Lawesson, pero ha sido imposible aislarlo. Se
ha realizado el seguimiento de la reacción por resonancia magnética y se ha
analizado por espectrometría de masas la reacción a los pocos minutos, antes
de la conversión completa. Con estos datos, se ha propuesto el que podría ser
el intermedio y el mecanismo de la reacción para obtener los pirroles.
Conclusiones
CONCLUSIONES
Se ha llevado a cabo la síntesis multicomponente de una serie de 1-
aminoindolizinas y pirrolo[1,2-a]quinolonas de manera efectiva a partir de
derivados de 2-piridincarbaldehído, aminas secundarias y alquinos terminales
utilizando CuNPs/C como catalizador en diclorometano a 70 ºC. La
metodología se ha aplicado a una variedad de aminas y alquinos, los últimos
incluyendo arilacetilenos así como alquilacetilenos, con rendimientos de
moderados a altos. Dicho catalizador ha demostrado ser superior a una serie de
catalizadores de cobre comerciales. Finalmente, se ha propuesto un
mecanismo de reacción basado en la probada participación de aminas
propargílicas como intermedios de reacción.
Se han sintetizado indolizidinas a través de la hidrogenación catalítica
heterogénea de indolizinas usando PtO2 como catalizador en ácido acético
como disolvente y a una presión de 3,7 atm. Las indolizidinas se han obtenido
con una elevada diastereoselectividad, incluso en el caso de poseer cuatro
estereocentros. Se ha demostrado experimentalmente que la hidrogenación de
la indolizina se produce a través del intermedio pirrólico 5,6,7,8-
tetrahidroindolizina. Además, estas indolizidinas se han podido mono- o di-
desbencilar usando un catalizador diferente.
Se ha sintetizado una nueva familia de compuestos orgánicos por
reacción de las indolizinas en medio ácido. Estos productos son tintes de
indolizina de color violeta-rojizos que tienen una estructura D-A-π-A bien
definida. La estructura de los tintes de indolizina se ha establecido mediante
análisis de rayos X en estado sólido, pero se pueden distinguir dos rotámeros
en disolución. Se ha propuesto un mecanismo de reacción en el que la propia
indolizina actúa como nucleófilo y electrófilo; en éste, una molécula sufre
hidrólisis en medio ácido y la adición Michael de la segunda molécula de
indolizina. Un estudio de las características ópticas de estos tintes ha revelado
un cambio de color dependiente del tamaño de partícula, un alto poder de
coloración y un carácter solvatocrómico (es decir, que el color de la disolución
del compuesto depende de la polaridad del disolvente usado), también en
materiales plásticos.
Conclusiones
176
Finalmente, se ha estudiado la reactividad de las indolizinas con
nitrosocompuestos, obteniendo dos productos diferentes según el sustituyente
en la posición tres de éstas. En el caso de poseer un sustituyente aromático se
obtienen β-enaminonas. Se ha realizado un estudio del alcance de esta
metodología cambiando los sustituyentes 1, 3 y 6 de las indolizinas y usando
compuestos nitrosoaromáticos con distintos sustituyentes en orto y para,
obteniendo las correspondientes β-enaminonas con rendimientos aislados de
moderados a buenos. El uso de esta metodología ha demostrado ser el más
apropiado para obtener ese tipo de regioisómero, comparado con las
metodologías clásicas de condensación de compuestos 1,3-dicarbonilos con
aminas que dan el regioisómero opuesto. Para sustituyentes alifáticos, se han
obtenido pirroles tetrasustituidos con rendimientos de moderados a buenos,
variando los cuatro sustituyentes en la estructura de pirrol. Se han llevado a
cabo varios experimentos para elucidar el mecanismo de reacción. Se ha
demostrado que proceden vía iónica, no radicalaria. La presencia de agua es
beneficiosa para la obtención de β-enaminonas, en cambio, una atmósfera de
oxígeno o de argón no lo son. Con todo ello, se ha propuesto un mecanismo
para la obtención de éstas en el que participa una estructura de isooxazol como
intermedio. En el caso de los pirroles, se ha demostrado que hay una
migración de la dibencilamina en la estructura. Tras varios experimentos,
enfocados en la obtención de un posible intermedio de reacción, se ha
propuesto la secuencia del mecanismo para la obtención de pirroles. En primer
lugar, se ha propuesto el ataque nucleófilo al nitrosocompuesto, abriendo la
estructura y perdiendo dibencilamina, formando así una cetona α,β-insaturada,
seguido del ataque de la dibencialamina y posterior ciclación para la obtención
del pirrol.
Experimental Part
179
EXPERIMENTAL PART
GENERAL
SOLVENTS AND REAGENTS
All the starting materials and other reagents were commercially
available of the best grade (Aldrich, Acros, Alfa Aesar, Fluorochem, Evonik)
and were used without further purification. THF was dried in a Sharlab PS-
400-3MD solvent purification system using an alumina column.
INSTRUMENTS AND CROMATOGRAPHY
Melting points were obtained with a Reichert Thermovar apparatus and
are uncorrected. NMR spectra were recorded on Bruker Avance 300 and 400
spectrometers (300 and 400 MHz for 1H NMR; 75 and 101 MHz for 13C
NMR); chemical shifts are given in (δ) parts per million and coupling
constants (J) in Hertz. Infrared analysis was performed with a Jasco 4100LE
(Pike MIRacle ATR) spectrophotometer; wavenumbers (υ) are given in cm–1.
Mass spectra (EI) were obtained at 70 eV on Agilent 5763 (GC) and Agilent
5973 (DIP) spectrometers; fragment ions in m/z with relative intensities (%) in
parentheses. HRMS analyses (EI) were also carried out at 70 eV on an Agilent
7200-QTOF spectrometer. Elemental analyses were performed on a Thermo
Finnigan Flash 1112 microanalyzer. The purity of volatile compounds and the
chromatographic analyses (GLC) were determined with an Agilent 6890N
instrument equipped with a flame ionization detector and an HP-5MS 30 m
capillary column (0.32 mm diameter, 0.25 µm film thickness), using nitrogen
(2 mL/min) as carrier gas, Tinjector = 270 ºC, Tcolumn = 60 ºC (3 min) and
60–270 ºC (15 ºC/min); retention times (tr) are given in min. Analytical thin-
layer chromatography (TLC) was carried out on ALUGRAM® Xtra SIL G
UV254 aluminium sheets. Column chromatography was performed using
silica gel 60 of 40–60 microns (hexane/EtOAc as eluent).X-ray data collection
was based on three -scan runs (starting = –34) at the values of = 0,
Experimental Part
180
120, 240 with the detector at 2 = –32. An additional run at = 0 of 100
frames was collected to improve redundancy. The diffraction frames were
integrated using the SAINT program and the integrated intensities were
corrected for Lorentz-polarization effects with SADABS.32
The purity of
volatile compounds and the chromatographic analyses (GLC) were determined
with a gas chromatograph equipped with a flame ionization detector and a 30
m capillary column (0.32 mm diameter, 0.25 m film thickness), using
nitrogen (2 mL/min) as carrier gas, Tinjector = 270 ºC, Tcolumn = 80 ºC (3 min)
and 80–270 ºC (20 ºC/min); retention times (tR) are given in min. Thin-layer
chromatography was carried out on TLC aluminium sheets covered with silica
gel. Column chromatography was performed using silica gel of 40–60 microns
(hexane/EtOAc as eluent). Preparative thin-layer chromatography was carried
on laboratory-made TLC glass plates with silica gel 60 PF254 (hexane/EtOAc).
Experimental Part
181
EXPERIMENTAL PART OF CHAPTER I
General procedure for the synthesis of indolizines catalyzed by CuNPs/C.
The aldehyde (1, 0.5 mmol), amine (2, 0.5 mmol), and alkyne (3, 0.5
mmol) were added to a reactor tube containing CuNPs/C (20 mg, ca. 0.5
mol%) and dichloromethane (1.0 mL). The reaction mixture was warmed to 70
ºC without the exclusion of air and monitored by TLC and/or GLC until total
or steady conversion of the starting materials. The solvent was removed under
vacuum; EtOAc (2 mL) was added to the resulting mixture followed by
filtration through Celite and washing with additional EtOAc (4 mL). The
reaction crude obtained after evaporation of the solvent was purified by
column chromatography (silica gel, hexane/EtOAc) or preparative TLC (silica
gel, hexane/EtOAc) to give the corresponding indolizine 4. Purification of the
5-substituted indolizines 4bga, 4cgc and 4dga was done by preparative TLC
(silica gel, hexane/EtOAc) with prior impregnation of the plate with Et3N in
order to minimize product decomposition. The reaction of 1b with 2g and 3a
furnished the corresponding propargylamine 5bga as the major product (72%).
General procedure for the synthesis of the indolizines catalyzed by CuI.
The aldehyde (1, 2 mmol), amine (2, 2 mmol), and alkyne (3, 2 mmol)
were added to a reactor tube containing CuI (38 mg, 10 mol%). The reaction
mixture was warmed to 70 ºC without the exclusion of air and monitored by
TLC and/or GLC until total or steady conversion of the starting materials.
EtOAc (2 mL) was added to the resulting mixture followed by filtration
through Celite and washing with additional EtOAc (4 mL). The reaction crude
obtained after evaporation of the solvent was purified by column
chromatography (silica gel, hexane/EtOAc) to give the corresponding
indolizines 4.
3-Phenyl-1-(piperidin-1-yl)indolizine (4aaa). Yellow oil; tr
18.51; Rf 0.38 (hexane/EtOAc, 9:1); IR (neat) υ 3055, 2927,
2848, 2789, 1597, 1509, 1425, 1301, 1014, 733, 697; 1H NMR
(400 MHz, C6D6) δ 1.38–1.51 (m, 2H; NCH2CH2CH2), 1.66–
Experimental Part
182
1.74 (m, 4H; 2 × NCH2CH2), 2.98 (t, J = 5.2, 4H; 2 × NCH2), 5.99–6.08 (m,
1H; ArH), 6.29–6.40 (m, 1H; ArH), 6.75 (s, 1H; ArH), 7.04–7.11 (m, 1H;
ArH), 7.14–7.24 (m, 2H; 2 × ArH), 7.33–7.41 (m, 2H; 2 × ArH), 7.55 (d, J =
9.2, 1H; ArH), 7.93 (d, J = 7.2, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ 24.9,
27.1, 55.7 (5 × CH2), 106.6, 111.0, 114.6, 118.5, 121.8, 126.8, 128.2, 129.2
(10 × ArCH), 122.8, 126.1, 132.1, 133.3 (4 × ArC); MS (70 eV) m/z (%) 277
(22) [M++1], 276 (100) [M
+], 234 (18), 233 (14), 220 (13), 219 (12), 207 (18),
206 (16), 78 (11); HRMS (EI) m/z calcd for C19H20N2 276.1626, found
276.1593.
4-(3-Phenylindolizin-1-yl)morpholine (4aba). Yellow oil; Rf
0.34 (hexane/EtOAc, 8:2); tr 18.68; IR (neat) υ 3060, 2951,
2851, 2811, 1509, 1426, 1301, 1259, 1112, 896, 734, 698; 1H
NMR (400 MHz, C6D6) δ 2.97 (t, J = 4.6, 4H; 2 × NCH2), 3.85
(t, J = 4.6, 4H; 2 × CH2O), 6.12–6.16 (m, 1H; ArH), 6.44 (ddd,
J = 9.0, J = 6.3 Hz, J = 0.9, 1H; ArH), 6.76 (s, 1H; ArH), 7.13–
7.23 (m, 1H; ArH), 7.25–7.32 (m, 2H; 2 × ArH), 7.45 (d, J = 7.2, 2H; 2 ×
ArH), 7.53 (dt, J = 9.0, J = 1.2, 1H; ArH), 8.01 (dd, J = 7.2, J = 0.9, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ 54.7 (2 × NCH2), 67.6 (2 × OCH2), 106.5,
111.1, 114.9, 118.2, 121.9, 127.0, 128.2, 129.2 (10 × ArCH), 123.0, 126.1,
130.6, 133.1 (4 × ArC); MS (70 eV) m/z (%) 279 (20) [M++1], 278 (100)
[M+], 221 (16), 220 (56), 219 (24), 192 (10), 96 (13), 78 (11); HRMS (EI) m/z
calcd for C18H18N2O 278.1419, found 278.1437.
N,N-Dibutyl-3-phenylindolizin-1-amine (4aca). Yellow oil;
Rf 0.80 (hexane/EtOAc, 8:2); tr 14.10; IR (neat) υ 3065, 3035,
2954, 2929, 2869, 2808, 1511, 1300, 1075, 770, 741, 722, 698; 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J = 7.2, 6H; 2 × CH3),
1.20–1.53 (m, 8H; 4 × CH2), 2.80–3.13 (t, J = 6.8, 4H; 2 × CH2), 6.31–6.43 (t,
J = 6.5, 1H; ArH), 6.45–6.59 (t, J = 7.5, 1H; ArH), 6.73 (s, 1H; ArH), 7.24–
7.32 (m, 1H; ArH), 7.34–7.50 (m, 3H; 3 × ArH), 7.51–7.61 (m, 2H; 2 × ArH),
8.17 (d, J = 7.2, 1H; ArH); 13
C NMR (75 MHz, CDCl3) δ 14.2 (2 × CH3), 20.7,
30.3, 56.9 (6 × CH2), 108.6, 110.7, 114.9, 118.2, 121.8, 126.8, 127.9, 129.0
Experimental Part
183
(10 × ArCH), 123.1, 128.1, 128.7, 132.9 (4 ×ArC); MS (70 eV) m/z (%) 321
(24) [M++1], 320 (100) [M
+], 278 (12), 277 (55), 263 (37), 235 (47), 221 (27),
220 (64), 219 (20), 194 (14), 193 (17), 192 (10), 105 (11); HRMS (EI) m/z
calcd for C22H28N2 320.2252, found 320.2280.
N-Benzyl-N-methyl-3-phenylindolizin-1-amine (4ada).
Yellow oil; Rf 0.60 (hexane/EtOAc, 8:2); tr 16.57; IR (neat)
ῦ 3060, 3030, 2932, 2784, 1598, 1510, 731, 696; 1H NMR
(400 MHz, C6D6) δ 3.08 (s, 3H; CH3), 4.49 (s, 2H; CH2),
6.39–6.45 (m, 1H; ArH), 7.72 (ddd, J = 9.2, 6.4, 0.8, 1H;
ArH), 7.45–7.63 (m, 7H; 7 × ArH), 7.72–7.78 (m, 2H; 2 × ArH), 7.80–7.86
(m, 2H; 2 × ArH), 7.97 (dt, J = 8.8, 1.2, 1H; ArH), 8.31 (dt, J = 7.2, 0.8 Hz,
1H; ArH); 13
C NMR (101 MHz, C6D6) δ 43.0 (CH3), 63.2 (CH2), 107.2, 111.0,
114.8, 118.4, 121.8, 126.9, 127.3, 128.2, 128.4, 128.6, 128.9, 129.1 (15 ×
ArCH), 122.9, 126.2, 131.1, 133.2, 140.0 (5 × ArC); MS (70 eV) m/z (%) 312
(34) [M+], 222 (17), 221 (100), 119 (35), 78 (17); HRMS (EI) m/z calcd for
C22H20N2 312.1626, found 312.1642.
N-Methyl-N-phenethyl-3-phenylindolizin-1-amine
(4aea). Brown oil; Rf 0.66 (hexane/EtOAc, 8:2); tr 17.43;
IR (neat) ῦ 3059, 3024, 2931, 2784, 1599, 1510, 1348,
1300, 1051, 771, 734, 696; 1H NMR (300 MHz, C6D6) δ
2.83 (s, 3H; CH3), 2.86–2.94 (m, 2H; CH2CH2N), 3.23–
3.37 (m, 2H; CH2CH2N), 6.04–6.15 (m, 1H; ArH), 6.41 (ddd, J = 9.0, 6.3, 1.0,
1H; ArH), 6.84 (s, 1H; ArH), 7.12–7.30 (m, 8H; 8 × ArH), 7.41–7.48 (m, 2H;
2 × ArH), 7.55 (dt, J = 9.0, 1.0, 1H; ArH), 8.00 (dt, J = 7.2, 1.0, 1H; ArH); 13
C
NMR (75 MHz, C6D6) δ 34.8 (CH2CH2N), 44.5 (CH3), 60.5 (CH2CH2N),
107.6, 111.0, 115.0, 118.5, 121.8, 126.2, 127.0, 128.2, 128.6, 129.1, 129.2 (15
× ArCH), 123.2, 127.4, 130.1, 133.2, 141.1 (5 × ArC); MS (70 eV) m/z (%)
326 (36) [M+], 236 (18), 235 (100), 221 (11), 220 (40), 219 (13), 194 (27), 78
(12); HRMS (EI) m/z calcd for C23H23N2 [M + H]+ 327.1861, found 327.1877.
Experimental Part
184
N-Methyl-N,3-diphenylindolizin-1-amine (4afa). Yellow
oil; tR 18.43; Rf 0.71 (hexane/EtOAc, 8:2); IR (neat) ῦ 3056,
3032, 2877, 2808, 1597, 1497, 1432, 1310, 1211, 1114, 1037,
741, 692; 1H NMR (400 MHz, CDCl3) δ 3.33 (s, 3H; CH3),
6.41 (br, 1H; ArH), 6.55 (br, 1H; ArH), 6.69–6.76 (m, 4H; 4 ×
ArH), 7.13–7.18 (m, 3H; 3 × ArH), 7.27–7.30 (m, 1H; ArH), 7.41–7.44 (m,
2H; 2 × ArH), 7.54–7.55 (m, 2H; 2 × ArH), 8.24 (br, 1H; ArH); 13
C NMR
(101 MHz, CDCl3) δ 40.8 (CH3), 111.0, 112.1, 113.1, 116.8, 117.6, 122.3,
127.2, 128.0, 129.0, 129.1 (15 × CH), 122.9, 123.8, 128.5, 132.3, 150.3 (5 ×
ArC); MS (GC) m/z 299 (M++1, 24), 298 (M
+, 100), 284 (19), 283 (85), 181
(55), 149 (14), 141 (13), 78 (31), 77 (47), 51 (16). HRMS (EI) m/z calcd for
C21H18N2 298.1470, found 298.1469.
N,N-Dibenzyl-3-phenylindolizin-1-amine (4aga). Yellow oil;
Rf 0.69 (hexane/EtOAc, 8:2); tr 26.44; IR (neat) ῦ 3055, 3025,
2927, 2829, 1598, 1509, 1239, 730, 695; 1H NMR (300 MHz,
C6D6) δ 4.26 (s, 4H; 2 × CH2), 6.01–6.12 (m, 1H; ArH), 6.42
(ddd, J = 9.0, 6.3, 0.6 Hz, 1H; ArH), 6.81 (s, 1H; ArH), 7.10–7.17 (m, 2H; 2 ×
ArH), 7.18–7.30 (m, 7H; 7 × ArH), 7.31–7.37 (m, 2H; 2 × ArH), 7.50 (d, J =
7.2, 4H; 4 × ArH), 7.65 (d, J = 9.0, 1H; ArH), 7.91 (d, J = 7.2, 1H; ArH); 13
C
NMR (75 MHz, C6D6) δ 59.5 (2 × CH2), 108.8, 110.9, 115.2, 118.2, 121.8,
126.9, 127.2, 128.2, 128.5, 128.9, 129.1 (20 × ArCH), 123.1, 127.5, 133.0,
140.0 (6 × ArC); MS (70 eV) m/z (%) 388 (30) [M+], 298 (24), 297 (100), 193
(21), 91 (43); HRMS (EI) m/z calcd for C28H24N2 388.1939, found 388.1964.
N,N-Bis(4-methoxyphenyl)-3-phenylindolizin-
1-amine (4aha). Yellow solid; Rf 0.38
(hexane/EtOAc, 8:2); m.p. 46.5–47.1 ºC; IR
(neat) ῦ 3058, 3027, 2963, 2867, 1593, 1495,
1432, 1299, 1231, 1114, 738, 695; 1H NMR
(400 MHz, C6D6) δ 3.34 (s, 6H; 2 × CH3), 5.98–
6.02 (m, 1H; ArH), 6.25 (dd, J = 9.0, 6.4 Hz,
1H; ArH), 6.76 (d, J = 9.0 Hz, 2H; 2 × ArH), 6.84 (s, 1H; ArH), 7.05–7.09 (m,
Experimental Part
185
1H; ArH), 7.14–7.20 (m, 7H; 7 × ArH), 7.23 (d, J = 9.0 Hz, 1H; ArH) 7.32–
7.34 (m, 2H; 2 × ArH), 7.97 (d, J = 7.2 Hz, 1H; ArH); 13
C NMR (101 MHz,
C6D6) δ 55.1 (2 × CH3), 111.2, 112.9, 114.9, 116.5, 118.5, 122.3, 123.1, 127.2,
128.2, 129.2 (14 × CH), 123.3, 124.3, 132.6, 143.0, 155.0 (6 × ArC); MS
(DIP) m/z 421 (M++1, 31), 420 (M
+, 100), 405 (17), 210 (16), 205 (13);
HRMS (EI) m/z calcd for C28H24N2O2 420.1838, found 420.1839.
(R)-N-Benzyl-3-phenyl-N-(1-phenylethyl)indolizin-1-
amine (4aia). Yellow oil; Rf 0.67 (hexane/EtOAc, 6:4); IR
(neat) ῦ 3060, 3025, 2971, 2817, 1599, 1509, 1492, 1450,
1346, 1301, 1239, 1073, 1027, 737, 695; 1H NMR (400
MHz, CDCl3) δ 1.34 (d, J = 6.7, 3H; CH3), 3.96–4.14 (m,
2H; CH2), 4.30 (br s, 1H), 6.33 (br s, 1H; ArH), 6.50 (br s, 1H; ArH), 6.66 (s,
1H; ArH), 7.06–7.10 (m, 1H; ArH), 7.15 (t, J = 7.4, 2H; ArH), 7.23–7.28 (m,
4H; 4 × ArH), 7.35 (t, J = 7.5, 2H; 2 × ArH), 7.41–7.50 (m, 7H; 7 × ArH),
8.13 (br s, 1H; ArH); 13
C NMR (101 MHz, CDCl3) δ 19.8 (CH3), 56.7 (CH2),
63.4 (CH), 110.6, 111.1, 115.4, 118.2, 121.7, 126.4, 126.8, 127.0, 127.9,
128.0, 128.3, 128.6, 128.9 (20 × ArCH), 122.9, 125.0, 130.1, 132.8, 140.5,
144.6 (6 × ArC); MS (GC) m/z 403 (M++1, 4), 402 (M
+, 12), 298 (24), 297
(100), 193 (19), 91 (22). HRMS (EI) m/z calcd for C29H26N2 402.2096, found
402.2100.
1-(Piperidin-1-yl)-3-(p-tolyl)indolizine (4aab). Yellow oil;
Rf 0.60 (hexane/EtOAc, 8:2); tr 16.17; IR (neat) ῦ 3055, 3025,
2930, 2848, 2779, 1520, 1427, 1343, 1300, 1110, 1014, 810,
736; 1H NMR (300 MHz, CDCl3) δ 1.52–1.65 (m, 2H;
NCH2CH2CH2), 1.75–1.88 (m, 4H; 2 × NCH2CH2), 2.39 (s,
3H; CH3), 3.04 (m, 4H; 2 × NCH2), 6.37 (t, J = 6.5, 1H; ArH),
6.66 (s, 1H; ArH), 7.25, 7.43 (AA’XX’ system, 4H; 4 × ArH),
7.50 (d, J = 8.4, 1H; ArH), 8.14 (d, J = 7.2, 1H; ArH); 13
C
NMR (75 MHz, CDCl3) δ 21.4 (CH3), 24.4, 26.4, 55.6 (5 × CH2), 105.5,
110.8, 118.2, 121.8, 127.9, 129.7 (9 × ArCH, ArC), 114.5, 122.6, 124.9, 136.7
(4 × ArC); MS (70 eV) m/z (%) 291 (24) [M++1], 290 (100) [M
+], 248 (17),
Experimental Part
186
247 (14), 234 (12), 233 (11), 221 (17), 220 (15); HRMS (EI) m/z calcd for
C20H22N2 290.1783, found 290.1778.
3-(4-Methoxyphenyl)-1-(piperidin-1-yl)indolizine (4aac).
Yellow oil; Rf 0.57 (hexane/EtOAc, 8:2); tr 17.31; IR (neat)
ῦ 3035, 2931, 2848, 2789, 1519, 1281, 1242, 1175, 1032,
834, 736, 723; 1H NMR (400 MHz, C6D6) δ 1.55 (quintet, J
= 5.9, 2H; NCH2CH2CH2), 1.80 (quintet, J = 5.6, 4H; 2 ×
NCH2CH2), 3.12 (t, J = 5.4, 4H; 2 × NCH2), 3.44 (s, 3H;
OCH3), 6.22–6.12 (m, 1H; ArH), 6.45 (ddd, J = 9.0, 6.3, 0.9
Hz, 1H; ArH), 6.86 (s, 1H; ArH), 6.91, 7.40 (AA’BB’
system, 4H; 4 ×ArH), 7.68 (dt, J = 9.0, 1.2, 1H; ArH), 8.01 (dt, J = 7.2, 0.8,
1H; ArH); 13
C NMR (101 MHz, C6D6) δ 24.9, 27.1, 55.8 (5 × CH2), 54.9
(OCH3), 106.2, 110.8, 114.2, 114.7, 118.5, 121.7, 129.8 (9 × ArCH), 122.7,
125.6, 125.8, 131.9, 159.2 (5 × ArC); MS (70 eV) m/z (%) 307 (23) [M++1],
306 (100) [M+], 264 (14), 263 (12), 237 (16), 236 (14), 235 (11); HRMS (EI)
m/z calcd for C20H22N2O 306.1732, found 306.1749.
1-(Piperidin-1-yl)-3-[4-(trifluoromethyl)phenyl]indolizine
(4aad). Yellow oil; Rf 0.57 (hexane/EtOAc, 8:2); tr 14.73; IR
(neat) ῦ 3060, 2934, 2852, 2792, 1611, 1320, 1162, 1106,
1064, 1014, 845, 778; 1H NMR (300 MHz, CDCl3) δ 1.52–
1.67 (m, 2H; CH2), 1.83 (br s, 4H; 2 × CH2), 3.05 (br s, 4H; 2
× CH2), 6.47 (t, J = 6.6, 1H; ArH), 6.62 (t, J = 6.6, 1H; ArH),
6.75 (s, 1H; ArH), 7.48–7.61 (m, 1H; ArH), 7.63–7.70 (m,
4H; 4 × ArH), 8.21 (d, J = 6.9, 1H; ArH); 13
C NMR (75
MHz, CDCl3) δ 24.3, 26.3, 55.5 (5 × CH2), 106.6, 111.7,
118.5, 121.6, 126.0, 126.1, 127.4 (9 × ArCH), 121.1, 122.6, 123.4, 126.2,
136.1 (5 × ArC), 126.1 (q, JC-F = 15; 2 × ArCH); MS (70 eV) m/z (%) 345 (23)
[M++1], 344 (100) [M
+], 302 (17), 301 (13), 288 (13), 287 (11), 275 (16), 274
(15); HRMS (EI) m/z calcd for C20H19F3N2 344.1500, found 344.1572.
Experimental Part
187
N,N-Dibenzyl-3-(p-tolyl)indolizin-1-amine (4agb). Yellow
oil; Rf 0.83 (hexane/EtOAc, 8:2); tr 30.68; IR (neat) ῦ 3060,
3030, 2912, 1523, 1452, 1345, 1300, 817, 735, 726; 1H NMR
(400 MHz, C6D6) δ 2.52 (s, 3H; CH3), 4.58 (s, 4H; 2 × CH2),
6.33–6.42 (m, 1H; ArH), 7.72 (dd, J = 8.4, 6.4, 1H; 1 × ArH),
7.37, 7.45 (AA’XX’ system, 4H; 4 × ArH), 7.51–7.57 (m, 5H;
5 × ArH), 7.60 (d, J = 8.0, 2H; 2 × ArH), 7.80 (d, J = 7.6, 4H;
4 × ArH), 7.95 (d, J = 9.2, 1H; ArH), 8.26 (d, J = 7.2, 2H; 2 × ArH); 13
C NMR
(101 MHz, C6D6) δ 21.2 (CH3), 60.0 (2 × CH2), 108.6, 110.8, 115.0, 118.2,
121.9, 127.1, 128.4, 128.5, 129.0, 129.8 (19 × ArCH), 123.2, 127.3, 130.2,
136.5, 140.0 (ArC); MS (70 eV) m/z (%) 403 (9) [M++1], 402 (29) [M
+], 312
(26), 311 (100), 310 (12), 207 (17), 91 (58); HRMS (EI) m/z calcd for
C29H26N2 402.2096, found 402.2070.
N,N-Dibenzyl-3-(4-methoxyphenyl)indolizin-1-amine
(4agc). Yellow solid; m.p. 90.9–92.4 ºC; Rf 0.63
(hexane/EtOAc, 8:2); tr 33.52; IR (neat) ῦ 3065, 3035, 3006,
2917, 2819, 1521, 1478, 1282, 1240, 1034, 836, 820, 754,
735, 694; 1H NMR (400 MHz, CDCl3) δ 3.82 (s, 3H;
OCH3), 4.19 (br s, 4H; 2 × CH2), 6.06–6.83 (m, 3H; 3 ×
ArH), 6.96 (br s, 2H; 2 × ArH), 7.15–7.56 (m, 13H; 13 ×
ArH), 8.02 (s, 1H; ArH); 13
C NMR (101 MHz, CDCl3) δ 55.5 (CH3), 59.5 (2 ×
PhCH2), 107.9, 110.6, 114.4, 117.9, 121.6, 126.9, 128.2, 128.7, 129.4 (19 ×
ArCH), 122.5, 126.2, 128.0, 139.8, 158.7 (7 × ArC); MS (70 eV) m/z (%) 418
(29) [M+], 328 (25), 327 (100), 223 (15), 91 (76); elemental analysis calcd for
C29H26N2O: C 83.22, H 6.26, N 6.69, found: C 83.49, H 6.27, N 7.09.
N,N-Dibenzyl-3-[4-(trifluoromethyl)phenyl]indolizin-1-
amine (4agd). Yellow solid; m.p. 128.9–130.0 ºC; Rf 0.80
(hexane/EtOAc, 8:2); tr 23.86; IR (neat) ῦ 3065, 3025, 2927,
2819, 1613, 1321m 1165, 1105, 1065, 846, 754, 739, 727,
695; 1H NMR (400 MHz, CDCl3) δ 4.20 (s, 4H; 2 × CH2),
6.41 (t, J = 6.8, 1H; ArH), 6.56 (t, J = 7.4, 1H; ArH), 6.70 (s,
Experimental Part
188
1H; ArH), 7.18–7.40 (m, 10H; 10 × ArH), 7.49–7.66 (m, 5H; 5 × ArH), 8.15
(d, J = 6.8, 1H; ArH); 13
C NMR (101 MHz, CDCl3) δ 59.5 (2 × PhCH2),
109.3, 111.5, 115.9, 118.2, 121.6, 125.9, 126.0, 127.0, 127.4, 128.3, 128.7 (19
× ArCH), 121.2, 128.0, 136.2, 139.5 (6 × ArC); MS (70 eV) m/z (%) 456 (25)
[M+], 366 (25), 365 (100), 261 (26), 91 (43); elemental analysis calcd for
C29H23F3N2: C 76.30, H 5.08, N 6.14, found: C 76.85, H 5.16, N 6.61.
Methyl 4-[1-(dibenzylamino)indolizin-3-yl]benzoate
(4age). Yellow solid; Rf 0.60 (hexane/EtOAc, 8:2); m.p.
133.8–136.2 ºC; IR (neat) ῦ 3027, 2942, 2922, 2847,
1718, 1601, 1514, 1433, 1283, 1178, 1108, 859, 754, 737,
696; 1H NMR (400 MHz, C6D6) δ 3.54 (s, 3H; CH3), 4.15
(s, 4H; 2 × CH2), 5.95–5.99 (m, 1H; ArH), 6.33 (ddd, J =
9.0, 6.4, 0.8 Hz, 1H; ArH), 6.69 (s, 1H; ArH), 7.03–7.07
(m, 2H; 2 × ArH), 7.13–7.18 (m, 6H; 6 × ArH), 7.38–7.39 (m, 4H; 4 × ArH),
7.52 (dt, J = 9.0, 1.1 Hz, 1H; ArH), 7.74 (d, J = 7.2 Hz, 1H; ArH), 8.12 (d, J =
8.5 Hz, 2H; 2 × ArH); 13
C NMR (101 MHz, C6D6) δ 51.6 (CH3), 59.9 (2 ×
CH2), 109.8, 111.5, 116.1, 118.2, 122.0, 127.1, 127.3, 128.5, 128.9, 130.5 (19
× CH), 122.1, 128.2, 128.7, 129.0, 138.1, 139.8 (7 × ArC), 166.5 (C=O); MS
(DIP) m/z 447 (M++1, 8), 446 (M
+, 25), 356 (25), 355 (100), 251 (15), 91 (39).
HRMS (EI) m/z calcd for C30H26N2O2 446.1994, found 446.1978.
N,N-Dibenzyl-3-decylindolizin-1-amine (4agf). Yellow oil;
Rf 0.83 (hexane/EtOAc, 8:2); tr 26.00; IR (neat) ῦ 3050, 2955,
2923, 2854, 1529, 1462, 1375, 1341, 1089, 742, 720; 1H NMR
(300 MHz, C6D6) δ 0.81–0.96 (m, 9H; 3 × CH3), 1.22–1.65
(m, 24H; 12 × CH2), 2.51 (t, J = 7.7, 2H; CCH2), 3.04 (t, J =
7.2, 4H; 2 × NCH2), 6.13–6.20 (m, 1H; ArH), 6.42 (ddd, J = 9.0, 6.3, 0.9, 1H;
ArH), 6.63 (s; 1H; ArH), 7.24 (d, J = 7.2, 1H; ArH), 7.68 (dt, J = 9.0, 1.2, 1H;
ArH); 13
C NMR (75 MHz, C6D6) δ 14.3, 14.4 (3 × CH3), 21.0, 23.1, 26.4,
27.7, 29.8, 29.9, 30.0, 30.1, 31.0, 32.4, 57.7 (15 × CH2), 106.6, 110.1, 113.7,
118.3, 121.3 (5 × ArCH), 122.4, 126.5, 128.2 (3 × ArC); MS (70 eV) m/z (%)
Experimental Part
189
385 (29) [M++1], 384 (100) [M
+], 341 (24), 327 (21), 299 (19), 257 (15), 157
(36), 130 (10); HRMS (EI) m/z calcd for C26H44N2 384.3504, found 384.3474.
N,N-dibenzyl-3-cyclohexylindolizin-1-amine (4agg). Yellow
solid; m.p. 112.5–113.9 ºC; Rf 0.80 (hexane/EtOAc, 8:2); tr
23.51; IR (neat) ῦ 3089, 3060, 3030, 2919, 2848, 1534, 1494,
1450, 1420, 1363, 1356, 1339, 746, 738, 728, 695; 1H NMR
(400 MHz, CDCl3) δ 1.21–1.48, 1.70–2.10, 2.60–2.84 (3m,
11H; 5 × CH2, CH), 4.13 (s, 4H; 2 × NCH2), 6.28–6.40, 7.06–
7.61 (2m, 15H; 15 × ArH); 13
C NMR (101 MHz, CDCl3) δ 26.5, 26.7, 31.9,
59.5 (7 × CH2), 35.3 (CH), 104.1, 109.7, 113.0, 117.9, 121.1, 126.7, 128.1,
128.8 (15 × ArCH), 125.0, 127.3, 139.9 (5 × ArC); MS (70 eV) m/z (%) 394
(22) [M+], 304 (23), 303 (100), 91 (36); elemental analysis calcd for C28H30N2:
C 85.24, H 7.66, N 7.10, found: C 84.85, H 7.64, N 6.84.
2-((1-(dibenzylamino)indolizin-3-
yl)methyl)isoindoline-1,3-dione (4agh). Yellow
solid; m.p. 112.5–113.9 ºC; Rf 0.33 (hexane/EtOAc,
8:2); IR (neat) ῦ 3023, 2930, 2830, 1765, 1710,1421,
1388, 1330, 1303, 1104, 933, 737, 670; 1H NMR (300
MHz, CDCl3) δ 4.11 (s, 4H; 2 CH2), 4.99 (s, 2H;
CH2), 6.42–6.52 (m, 2H; 2 × ArH), 6.82 (s, 1H; ArH), 7.11–7.24 (m, 6H; 6 ×
ArH), 7.32–7.34 (m, 4H; 4 × ArH), 7.38–7.42 (m, 1H; 1 × ArH), 7.61–7.65
(m, 2H; 2 × ArH), 7.75–7.81 (m, 2H; 2 × ArH), 7.49 (dt, J = 6.8, 1.2 Hz, 1H;
ArH); 13
C NMR (75 MHz, CDCl3) δ 33.0, 59.6 (3 × CH2), 110.7, 110.9, 115.0,
117.4, 122.6, 123.4, 126.8, 128.1, 128.7, 134.1 (19 × ArCH), 115.4, 126.7,
126.9, 132.2, 139.7, 168.3 (7 × ArC); MS (70 eV) m/z (%) 471 (M+, 22), 381
(27), 380 (100), 235 (10), 233 (24), 130 (21), 91 (22); HRMS (EI) m/z calcd
for C31H25N3O2 471.1947, found 471.1903.
N,N-Dibenzyl-5-bromo-3-phenylindolizin-1-amine (4bga).
Yellow oil; Rf 0.54 (hexane/EtOAc, 8:2); IR (neat) ῦ 3081,
Experimental Part
190
3060, 3029, 2957, 2923, 2852, 1600, 1494, 1453, 1279, 1208, 1028, 749, 697; 1H NMR [300 MHz, (CD3)2CO] δ 4.21 (s, 4H; 2 × CH2), 6.45 (dd, J = 8.8, 6.8,
1H; ArH), 6.75 (dd, J= 6.8, 1.1, 1H; ArH) 6.76 (s, 1H; ArH); 7.17 (t, J= 7.2,
2H; 2 × ArH), 7.26 (t, J = 7.2, 4H; 4 × ArH), 7.29–7.38 (m, 5H; 5 × ArH),
7.42 (d, J= 7.2, 4H; 4 × ArH), 7.65 (dd, J= 8.8, 1.1, 1H; ArH); 13
C NMR [75
MHz, (CD3)2CO] δ 60.4 (2 × CH2), 112.6, 114.8, 116.9, 118.0, 126.8, 127.3,
128.0, 128.6, 130.8 (19 × ArCH), 112.2, 125.7, 128.2, 129.9, 134.2, 139.4 (7 ×
ArC); MS (70 eV) m/z (%) 469 (5) [M++1,
81Br], 468 (15) [M
+,
81Br], 467 (5)
[M++ 1,
79Br], 466 (15) [M
+,
79Br], 378 (11.5), 377 (49), 376 (13), 375 (48),
191 (17), 91 (100), 44 (13); HRMS (EI) m/z calcd for C28H2379
BrN2 466.1045,
found 466.1042; calcd for C28H2381
BrN2 468.1024, found 468.1022.
N,N-Dibenzyl-5-methyl-3-phenylindolizin-1-amine (4cga):
yellow oil (247 mg, 61%); tR 29.11; Rf 0.73 (hexane/EtOAc,
8:2); IR (neat) ῦ 3079, 3066, 3027, 2925, 2827, 1599, 1492,
1472, 1451, 1292, 1070, 748, 696; 1H NMR (300 MHz,
CDCl3) δ 2.01(s, 3H), 4.17 (s, 4H), 6.13 (d, J = 6.5 Hz, 1H), 6.48 (dd, J = 8.8,
6.5 Hz, 1H), 6.55 (s, 1H), 7.14–7.29 (m, 11H), 7.37 (d, J = 7.0 Hz, 1H), 7.49
(d, J = 8.9 Hz, 1H); 13
C NMR (75 MHz, CDCl3) δ 23.0, 59.4, 111.4, 111.9,
114.7, 115.6, 126.7, 126.8, 127.0, 128.0, 128.6, 130.9, 123.5, 127.2, 134.0,
136.0, 139.6; MS (EI) m/z 402 (M+, 0.3), 311 (23), 310 (99), 309 (39), 295
(10), 281 (18), 221 (10), 209 (13), 208 (24), 207 (100), 191 (17), 91 (26);
HRMS (ESI) m/z: [M]+ Calcd for C29H26N2 402.2096; Found 402.2093.
N,N-Dibenzyl-5-methyl-3-(p-tolyl)indolizin-1-amine (4cgb).
Yellow oil; Rf 0.76 (hexane/EtOAc, 8:2); IR (neat) ῦ 3024,
2973, 2919, 2821, 2796, 1453, 1292, 1146, 1119, 1070, 820,
754, 739, 694; 1H NMR (400 MHz, C6D6) δ 3.27(s, 3H; CH3),
4.20 (s, 4H; 2 × CH2), 5.92 (d, J = 6.4 Hz, 1H; ArH), 6.44 (dd,
J= 8.9, 6.4, 1H; ArH) 6.62, 6.99 (system AA’XX’, J = 8.7 Hz,
4H, 4 × ArH), 6.66 (s, 1H; ArH); 7.05 (t, J= 7.4, 2H; 2 ×
ArH), 7.14 – 7.18 (m, 4H; 4 × ArH), 7.45 (d, J= 6.4 Hz, 4H; 4 × ArH), 7.69
(d, J= 8.9 Hz, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ 22.9, 54.8 (2 × CH3),
Experimental Part
191
60.2 (2 × CH2), 111.6, 112.3, 112.4, 115.1, 116.2, 127.1, 128.5, 128.9, 132.6
(18 × ArCH), 123.9, 127.3, 128.6, 128.8, 134.3, 140.2, 159.4 (8 × ArC); MS
(70 eV) m/z (%) 416 (M+, 25), 326 (25), 325 (100), 91 (68); HRMS (EI) m/z
calcd for C30H28N2 416.2252, found 416.2262.
N,N-Dibenzyl-3-(4-methoxyphenyl)-5-methylindolizin-1-
amine (4cgc). Yellow oil; Rf 0.68 (hexane/EtOAc, 8:2); IR
(neat) ῦ 3030, 3001, 2934, 2837, 1605, 1506, 1291, 1245,
1149, 1029, 832, 743, 699; 1H NMR (400 MHz, C6D6) δ
1.79 (s, 3H, CH3), 2.10 (s, 3H, CH3), 4.20 (s, 4H; 2 × CH2),
5.93 (d, J = 6.4 Hz, 1H; ArH), 6.45 (dd, J= 8.9, 6.4 Hz, 1H;
ArH) 6.67 (s, 1H; ArH); 6.84 (d, J= 7.8, 2H; 2 × ArH), 6.99
(d, J = 8.0 Hz, 2H; 2 × ArH), 7.06 (t, J = 7.3 Hz, 2H; 2 × ArH), 7.14 – 7.18
(m, 4H; 4 × ArH), 7.45 (d, J= 7.2 H, 2H; 2 × ArH), 7.70 (d, J = 8.9 Hz, 1H;
ArH); 13
C NMR (101 MHz, C6D6) δ 21.2, 23.0 (2 × CH3), 60.2 (2 × CH2),
111.7, 112.4, 115.2, 116.1, 127.1, 127.7, 128.5, 129.0, 131.3 (18 × ArCH),
124.1, 127.5, 128.9, 133.6, 134.3, 136.7, 140.2 (8 × ArC); MS (70 eV) m/z (%)
433 (M++1, 10), 432 (M
+, 28), 342 (25), 341 (100), 91 (79); HRMS (EI) m/z
calcd for C30H28N2O 432.2202, found 432.2204
N,N-Dibenzyl-5-methyl-3-[4-
(trifluoromethyl)phenyl]indolizin-1-amine (4cgd). Brown
oil; Rf 0.54 (hexane/EtOAc, 8:2); IR (neat) ῦ 3085, 3061,
3029, 2925, 2850, 2802, 1614, 1453, 1432, 1321, 1164,
1120, 1064, 846, 741, 696; 1H NMR [300 MHz, (CD3)2CO] δ
2.04 (s, 3H; CH3), 4.19 (s, 4H; 2 × CH2), 6.32 (d, J= 6.4 Hz,
1H; ArH), 6.62 (dd, J= 8.8, 6.6 Hz, 1H; ArH), 6.79 (s, 1H;
ArH), 7.14–7.79 (m, 15H; 15 × ArH); 13
C NMR [75 MHz, (CD3)2CO] δ 23.4
(CH3) 60.5 (2 × CH2), 113.3, 113.6, 116.3, 116.8, 127.6, 128.9, 129.4, 131.5
(16 × ArCH), 124.7 (q, 3JC-F =3.6 Hz; 2 × HCCCF3), 129.2 (q,
2JC-F = 27.0 Hz;
CCF3), 122.7, 128.4, 129.2, 130.6, 134.7, 140.5 (6 × ArC); MS (70 eV) m/z
(%) 471 (8) [M+], 470 (23) [M], 380 (25), 379 (100), 275 (8), 91 (59); HRMS
(EI) m/z calcd for C30H25F3N2 470.1970, found 470.1982.
Experimental Part
192
Methyl 4-(1-(dibenzylamino)-5-methylindolizin-3-
yl)benzoate (4cge). Yellow oil; Rf 0.52 (hexane/EtOAc,
8:2); IR (neat) ῦ 3060, 3026, 2949, 2925, 1718, 1603,
1518, 1433, 1273, 1101, 748, 697; 1H NMR (300 MHz,
C6D6) δ 2.06 (s, 3H; CH3), 3.93 (s, 3H; CH3), 4.18 (s, 4H;
2 × CH2), 6.24 (d, J= 6.5 Hz, 1H; ArH),6.57 (dd, J= 8.7,
6.5 Hz, 1H; ArH), 6.61 (s, 1H; ArH), 7.16 – 7.22 (m, 2H;
ArH), 7.24 – 7.29 (m, 4H; ArH), 7.34, 7.99 (AA’BB’ system, J= 8.5 Hz, 4H;
4 ×ArH), 7.35 – 7.38 (m, 4H; ArH), 7.51 (d, J= 8.5 Hz, 1H; ArH); 13
C NMR
(101 MHz, CDCl3) δ 23.5, 52.3 (2 × CH3) 59.5 (2 × CH2), 112.3, 112.9, 115.7,
115.8, 126.9, 128.2, 128.3, 128.7, 130.0 (18 × ArCH), 122.4, 128.0, 128.1,
129.4, 134.0, 139.6, 140.4, 167.2 (9 × ArC); MS (70 eV) m/z (%) 461 (M+ + 1,
7), 460 (M+ , 21), 370 (26), 369 (100), 91 (62); HRMS (EI) m/z calcd for
C31H28N2O2 460.2151, found 460.2160.
N,5-Dimethyl-N,3-diphenylindolizin-1-amine (1l). Yellow
oil; tR 18.99; Rf 0.72 (hexane/EtOAc, 8:2); IR (neat) ῦ 3054,
3023, 2923, 2808, 1597, 1496, 1477, 1293, 1110, 762, 747,
691; 1H NMR (400 MHz, C6D6) δ 1.84 (s, 3H; CH3), 3.17 (s,
3H; CH3), 5.93 (d, J = 6.5 Hz, 1H; ArH), 6.37 (dd, J = 8.9, 6.5
Hz, 1H; ArH), 6.64 (s, 1H; ArH), 6.78–6.81 (m, 1H; ArH), 6.87–6.89 (m, 2H;
2 × ArH), 7.03–7.07 (m, 3H; 2 × ArH), 7.14–7.23 (m, 5H; 5 × ArH); 13
C NMR
(101 MHz, C6D6) δ 22.9, 40.7 (2 × CH3), 112.7, 113.7, 115.3, 115.9, 116.9,
117.4, 127.2, 127.4, 129.3, 131.3 (14 × CH), 122.9, 125.1, 130.4, 134.9, 136.0,
150.9 (6 × ArC); MS (70 eV) m/z 313 (M++1, 24), 312 (M
+, 100), 311 (32),
298 (12), 297 (49), 235 (12), 204 (11), 195 (44), 156 (15), 148 (13), 102 (10),
92 (31), 77 (39), 65 (17). HRMS (EI) m/z calcd for C22H20N2 312.1626, found
312.1618.
N,N-Dibenzyl-5-[4-(methylsulfonyl)phenyl]-3-
phenylindolizin-1-amine (4dga). Dark orange oil; Rf 0.54
(hexane/EtOAc, 6:4); IR (neat) ῦ 3028, 2954, 2919, 2849,
Experimental Part
193
1453, 1314, 1149, 768, 754, 698; 1H NMR [300 MHz, (CD3)2CO] δ 2.99 (s,
3H, CH3), 4.27 (s, 4H, 2 × CH2), 6.55 (dd, J = 6.6, 1.3, 1H; ArH); 6.72–6.84
(m, 4H, 4 × ArH), 6.92–6.97 (m, 3H; ArH), 7.16–7.52 (m, 14H; 14 × ArH),
7.74 (dd, J = 8.9, 1.3 Hz, 1H; ArH); 13
C NMR [75 MHz, (CD3)2CO] δ 44.8
(CH3), 60.4 (2 × CH2), 111.9, 115.8, 116.9, 118.5, 126.6, 127.3, 127.7, 128.1,
128.9, 129.2, 129.4 (23 × ArCH), 125.1, 129.8, 130.0, 135.0, 135.3, 140.5,
140.6, 142.2 (9 × ArC); MS (70 eV) m/z (%) 542 [M+] (16), 452 (18), 451
(68), 355 (15), 91 (100), 44 (55); HRMS (EI) m/z calcd for C35H30N2O2S
542.2028, found 542.2002
1-Phenyl-3-(piperidin-1-yl)pyrrolo[1,2-a]quinoline
(4eaa). Yellow solid; m.p. 107.1–110.2 ºC; Rf 0.66
(hexane/EtOAc, 8:2); tr 20.37; IR (neat) ῦ 3050, 2920,
2853, 2794, 1491, 1448, 1375, 1319, 1123, 781, 746,
696; 1H NMR (300 MHz, CDCl3) δ 1.58 (quintet, J = 5.7, 2H; NCH2CH2CH2),
1.81 (quintet, J = 5.7, 4H; 2 × NCH2CH2), 3.04 (t, J = 5.3, 4H; 2 × NCH2),
6.52 (s, 1H; ArH), 8.85 (d, J = 9.3, 1H; ArH), 6.99–7.08 (m, 1H; ArH), 7.16
(td, J = 7.4, 1.2, 1H; ArH), 7.33–7.57 (m, 8H; 8 × ArH); 13
C NMR (75 MHz,
CDCl3) δ 24.4, 26.5, 55.6 (5 × CH2), 108.5, 116.7, 117.7, 117.9, 123.3, 126.1,
127.5, 128.3, 128.6, 129.2 (10 × ArCH), 123.9, 127.7, 134.2, 135.8 (ArC); MS
(70 eV) m/z (%) 327 (25) [M++1], 326 (100) [M
+], 325 (11), 284 (10), 283
(11), 269 (12), 241 (11), 128 (14), 121 (17); HRMS (EI) m/z calcd for
C23H22N2 326.1783, found 326.1784.
N,N-Dibutyl-1-phenylpyrrolo[1,2-a]quinolin-3-amine
(4eca). Yellow oil; Rf 0.74 (hexane/EtOAc, 8:2); tr
18.45; IR (neat) ῦ 3060, 2954, 2929, 2858, 2803, 1490,
1447, 1361, 1315, 1111, 792, 746, 701; 1H NMR (300
MHz, CDCl3) δ 0.87 (t, J = 7.2, 6H; 2 × CH3), 1.20–1.58 (m, 8H; 4 × CH2),
2.79–3.16 (m, 4H; 2 × CH2), 6.56 (s, 1H; ArH), 6.78–6.94 (d, J = 8.7, 1H;
ArH), 7.05 (dt, J = 7.2, 0.9, 1H; ArH), 7.15 (dt, J = 7.4, 0.9, 1H; ArH), 7.31–
7.62 (m, 8H; 8 × ArH); 13
C NMR (75 MHz, CDCl3) δ 14.2 (2 × CH3), 20.6,
30.4, 56.9 (6 × CH2), 110.9, 117.8, 123.2, 126.1, 127.5, 128.4, 128.6, 129.3
Experimental Part
194
(12 × ArCH), 116.9, 133.4, 134.3, 135.9 (ArC); MS (70 eV) m/z (%) 371 (29)
[M++1], 370 (100) [M
+], 328 (13), 327 (48), 313 (19), 285 (41), 271 (23), 270
(57), 269 (20), 244 (13), 243 (14), 242 (12), 241 (17), 155 (12), 142 (13), 128
(22); HRMS (EI) m/z calcd for C26H30N2 370.2409, found 370.2423.
N,N-Dibenzyl-1-phenylpyrrolo[1,2-a]quinolin-3-
amine (4ega). Orange oil; Rf 0.64 (hexane/EtOAc, 8:2);
IR (neat) ῦ 3059, 3026, 2922, 2827, 1558, 1492, 1450,
1360, 1317, 1071, 1027, 962, 906, 739, 695; 1H NMR
(400 MHz, C6D6) δ 4.29 (s, 4H; 2 × CH2), 6.66 (s, 1H; ArH), 6.78 (d, J = 9.3,
1H; ArH), 6.83 (m, 1H; ArH), 6.99 (t, J = 7.5, 1H; ArH), 7.16 – 7.23 (m, 5H;
ArH), 7.25 – 7.29 (m, 4H; ArH), 7.35 (dd, J = 7.8, 1.6, 1H; ArH), 7.39 (dd, J =
7.8, 1.2, 1H; ArH), 7.51 (d, J = 7.3, 4H; ArH), 7.59 (d, J = 8.5, 1H; ArH), 7.65
(d, J = 9.3, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ 59.9 (2 × CH2), 111.2,
117.4, 117.9, 118.0, 123.4, 126.4, 127.3, 127.6, 128.6, 128.7, 128.9, 129.6 (22
× ArCH), 126.1, 126.5, 131.1, 134.7, 136.2, 139.8(8 × ArC); MS (70 eV) m/z
(%) 439 (M++1, 9) 438 (M
+, 27), 348 (26), 347 (100), 243 (13), 91 (44);
HRMS (EI) m/z calcd for C32H26N2 438.2096, found 438.2097.
3-Butyl-1-(piperidin-1-yl)indolizine (4aai): yellow oil (383
mg, 75%); tR 13.20; Rf 0.68 (hexane/EtOAc, 8:2); IR (neat) ῦ
2930, 2855, 2786, 1625, 1533, 1425, 1314, 1091, 733, 716; 1H
NMR (400 MHz, C6D6) δ 0.85 (t, J = 7.4 Hz, 3H; CH3), 1.23 –
1.32 (m, 2H; CH2), 1.46 – 1.54 (m, 4H; CH2), 1.67 – 1.73 (m,
4H; CH2), 2.43 – 2.47 (m, 2H; CH2), 2.99 – 3.02 (m, 4H; CH2),
6.15 – 6.18 (m, 1H; ArH), 6.35 (dd, J = 8.9, 6.4 Hz, 1H; ArH),
6.50 (s, 1H; ArH), 7.21 (d, J = 7.1 Hz, 1H; ArH), 7.57 (d, J = 9.0 Hz, 1H;
ArH); 13
C NMR (101 MHz, C6D6) δ 14.2 (CH3), 23.0, 24.9, 25.9, 27.2, 29.8,
56.0 (8 × CH2), 104.3, 110.1, 112.7, 118.4, 121.1 (5 × ArCH), 121.6, 124.3,
130.5 (3 × ArC); MS (EI) m/z 257 (M+ +1, 17), 256 (M
+, 86) 254 (17), 214
(19), 213 (100), 211 (11), 157 (36), 131 (10), 130 (26), 105 (10), 78 (19);
HRMS (ESI) m/z: [M + H]+ Calcd for C17H24N2 256.1939; Found 256.1935.
Experimental Part
195
N,N,3-Tributylindolizin-1-amine (4aci): yellow oil (214 mg,
37%); tR 12.94; Rf 0.80 (hexane/EtOAc, 8:2); IR (neat) ῦ 2955,
2929, 2870, 1527, 1457, 1375, 1339, 1314, 1088, 805, 740,
719; 1H NMR (400 MHz, C6D6) δ 0.82 – 0.87 (m, 9H; CH3).
1.22 – 1.31 (m, 2H; CH2), 1.34 – 1.43 (m, 4H; CH2), 149 –
1.56 (m, 6H; CH2), 2.44 – 2.48 (m, 2H; CH2), 3.02 – 3.05 (m, 4H; CH2), 6.13
– 6.17 (m, 1H; ArH), 6.41 (ddd, J = 9.0, 6.3, 0.8 Hz, 1H; ArH), 6.59 (s, 1H;
ArH), 7.20 (d, J = 7.1 Hz, 1H; ArH), 7.67 (dt, J = 9.0, 1.2 Hz; 1H; ArH); 13
C
NMR (101 MHz, C6D6) δ 14.1, 14.4 (2 × CH3), 21.0, 23.0, 26.0, 29.8, 31.0,
57.8 (9 × CH2), 106.6, 110.0, 113.7, 118.2, 121.3 (5 × ArCH), 122.4, 126.5,
128.2 (3 × ArC); MS (EI) m/z 301 (M+ + 1, 14), 300 (M
+, 73), 258 (12), 257
(45), 243 (33), 215 (36), 201 (25), 200 (13), 199 (11), 186 (11), 183 (10), 171
(12), 157 (100), 156 (12), 143 (12), 130 (28), 105 (19), 78 (10), 57 (17);
HRMS (ESI) m/z: [M + H]+ Calcd for C20H32N2 300.2565; Found 300.2568.
N-Benzyl-3-butyl-N-methylindolizin-1-amine (4adi):
yellow oil (258 mg, 44%); tR 14.67; Rf 0.68 (hexane/EtOAc,
8:2); IR (neat) ῦ 3060, 3028, 2955, 2929, 2868, 1529, 1454,
1406, 1061, 948, 798, 733, 698; 1H NMR (400 MHz, C6D6) δ
0.95 (t, J = 7.3 Hz, 3H; CH3), 1.36 (dq, J = 14.6, 7.3 Hz, 2H;
CH2), 1.57 – 1.63 (m, 2H; CH2), 2.50 – 2.54 (m, 2H; CH2), 2.83 (s, 3H; CH3),
4.23 (s, 2H; CH2), 6.24 – 6.28 (m, 1H; ArH), 6.45 (ddd, J = 9.0, 6.3, 0.8 Hz,
1H; ArH), 6.56 (s, 1H; ArH), 7.19 – 7.23 (m, 1H; ArH), 7.27 – 7.32 (m, 3H;
ArH), 7.53 – 7.55 (m, 2H; ArH), 7.70 (dt, J = 9.0, 1.2 Hz, 1H; ArH); 13
C NMR
(101 MHz, C6D6) δ 14.1 (CH3), 22.9, 25.9, 29.7 (3 × CH2), 43.3 (CH3), 63.5
(CH2), 105.0, 110.1, 112.9, 118.3, 121.2, 127.2, 128.5, 128.9 (10 × ArCH),
121.7, 124.5, 129.4, 140.2 (4 × ArC); MS (EI) m/z 292 (M+, 28), 202 (13), 201
(100), 158 (11), 157 (28), 119 (19), 92 (17), 91 (48), 78 (15), 65 (16); HRMS
(ESI) m/z: [M + H]+ Calcd for C20H24N2 292.1939; Found 292.1939.
3-Butyl-N-methyl-N-phenylindolizin-1-amine (4afi):
yellow oil (167 mg, 30%); tR 14.67; Rf 0.76 (hexane/EtOAc,
8:2); IR (neat) ῦ 3019, 2952, 2927, 2860, 1595, 1556, 1497,
Experimental Part
196
1314, 1148, 1081, 950, 739, 692; 1H NMR (400 MHz, C6D6) δ 0.95 (t, J = 7.3
Hz, 3H; CH3), 1.31 – 1.41 (m, 2H; CH2), 1.55 – 1.62 (m, 2H; CH2), 2.51 –
2.55 (m, 2H; CH2), 3.27 (s, 3H; CH3), 6.23 – 6.27 (m, 1H; ArH), 6.40 – 6.44
(m, 1H; ArH), 6.52 (s, 1H; ArH), 6.89 (t, J = 7.2 Hz, 1H; ArH), 6.93 – 6.95
(m, 2H; ArH), 7.23 – 7.34 (m, 4H; ArH); 13
C NMR (75 MHz, C6D6) δ 14.1
(CH3), 22.9, 25.8, 29.6 (3 × CH2), 40.8 (CH3), 110.0, 110.3, 113.6, 115.1,
117.2, 117.7, 121.7, 129.2 (10 × ArCH), 122.1, 123.1, 127.3, 151.1 (4 × ArC);
MS (EI) m/z 279 (M+ + 1, 16), 278 (M+, 72), 263 (17), 236 (19), 235 (100),
220 (29), 181 (15), 117 (11), 77 (12); HRMS (ESI) m/z: [M + H]+ Calcd for
C19H22N2 278.1783; Found 278.1782.
N,N-Dibenzyl-3-butylindolizin-1-amine (4agi): yellow solid;
(736 mg, 69%); tR 21.76; Rf 0.76 (hexane/EtOAc, 8:2); m.p.
55.8–57.6 ºC; IR (neat) ῦ 3023, 2952, 2921, 2823, 2796, 1623,
1551, 1450, 1427, 1344, 1316, 1244, 1148, 1027, 1001, 978,
809, 727, 696; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 7.3
Hz, 3H; CH3), 1.34 (dq, J = 14.5, 7.3 Hz, 2H; CH2), 1.28–1.41 (m, 2H; CH2),
2.68 (t, J = 7.3 Hz, 2H; CH2), 4.15 (s, 4H; 2 × CH2), 6.35–6.42 (m, 3H; 3 ×
ArH), 7.14–7.26 (m, 6H; 6 × ArH), 7.33 (d, J = 7.2 Hz, 4H; 4 × ArH), 7.40 (d,
J = 8.3 Hz, 1H; ArH), 7.51 (d, J = 6.6 Hz, 1H; ArH); 13
C NMR (75 MHz,
CDCl3) δ 14.1 (CH3) 22.6, 25.7, 29.4, 59.6 (5 × CH2), 106.3, 109.8, 112.9,
117.7, 121.1, 126.8, 128.1, 128.8 (15 × CH), 121.8, 125.1, 126.5, 139.9 (5 ×
ArC); MS (GC) m/z 369 (M++1, 8), 368 (M
+, 31), 278 (23), 277 (100), 233
(20), 130 (13), 91 (19). HRMS (EI) m/z calcd for C26H28N2 368.2252, found
368.2257.
N,N-Dibenzyl-3-propylindolizin-1-amine (4agj): yellow
solid (184 mg, 26%); tR 19.49; Rf 0.76 (hexane/EtOAc, 8:2);
IR (neat) ῦ 3074, 3024, 2958, 2924, 2870, 2796, 1624, 1542,
1492, 1452, 1424, 1341, 1315, 1235, 1138, 1065, 989, 938,
797, 731, 694; 1H NMR (400 MHz, C6D6) δ 0.79 (t, J = 7.4
Hz, 3H; CH3), 1.39 – 1.49 (m, 2H; CH2), 2.25 (t, J = 7.5 Hz, 2H; CH2), 4.19
(s, 4H; 2 CH2), 6.07 – 6.11 (m, 1H; ArH), 6.34 (ddd, J = 9.0, 6.3, 0.7 Hz,
Experimental Part
197
1H; ArH), 6.38 (s, 1H; ArH), 7.03 – 7.06 (m, 3H; 3 × ArH), 7.12 – 7.16 (m,
4H; ArH), 7.40 (d, J = 7.4 Hz, 1H; 4 ArH), 7.54 (dt, J = 9.0, 1.1 Hz, 1H;
ArH); 13
C NMR (101 MHz, C6D6) δ 14.0 (CH3), 20.7, 28.0, 60.2 (4 × CH2),
106.7, 109.9, 113.4, 118.0, 121.2, 127.1, 128.4, 129.0 (15 × ArCH), 121.2,
125.8, 126.6, 140.2 (5 × ArC); MS (EI) m/z 354 (M+, 29), 263 (100), 233 (41),
157 (16), 130 (23), 92 (11), 91 (99), 78 (14), 65 (20); HRMS (ESI) m/z: [M +
H]+ Calcd for C25H26N2 354.2096; Found 354.2097.
N,N-Dibenzyl-3-hexylindolizin-1-amine (4agk): yellow solid
(277 mg, 35%); tR 25.67; Rf 0.81 (hexane/EtOAc, 8:2); IR
(neat) ῦ 3026, 2953, 2925, 2854, 2798, 2782, 1622, 1545,
1493, 1455, 1423, 1312, 1237, 1143, 1075, 940, 792, 730, 695; 1H NMR (400 MHz, C6D6) δ 0.89 (t, J = 7.1 Hz, 3H; CH3),
1.16 – 1.26 (m, 6H; 3 CH2), 1.45 – 1.49 (m, 2H; CH2), 2.32 (t, J =7.6 Hz,
2H; CH2), 4.20 (s, 4H; 2 CH2), 6.09 – 6.12 (m, 1H; ArH), 6.34 (ddd, J = 9.0,
6.3, 0.8 Hz, 1H; ArH), 6.42 (s, 1H; ArH), 7.03 – 7.09 (m, 1H; ArH), 7.09 (d, J
= 7.2, 1H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.39 – 7.41 (m, 4H; ArH), 7.55
(dt, J = 9.0, 1.1 Hz, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ 14.4 (CH3), 23.1,
26.1, 27.4, 29.5, 32.0, 60.2 (7 × CH2), 106.6, 110.0, 113.4, 118.0, 121.2,
127.1, 128.4, 129.0 (15 × ArCH), 121.9, 125.7, 126.7, 140.2 (5 × ArC); MS
(EI) m/z 396 (M+, 10), 306 (22), 305 (100), 233 (26), 130 (13), 106 (13), 105
(23), 91 (78), 78 (13), 77 (23), 62 (22), 51 (14); HRMS (ESI) m/z: [M + H]+
Calcd for C28H32N2 396.2565; Found 396.2564.
N,N-Dibenzyl-3-(4-chlorobutyl)indolizin-1-amine (4agl):
yellow oil (161 mg, 20%); Rf 0.68 (hexane/EtOAc, 8:2); IR
(neat) ῦ 3066, 3027, 2925, 2827, 1599, 1492, 1472, 1451,
1292, 1070, 748, 696; 1H NMR (400 MHz, C6D6) δ 1.31 –
1.38 (m, 4H; CH2), 2.14 (t, J = 7.0 Hz, 2H; CH2), 3.01 (t, J =
6.4 Hz, 2H; CH2), 4.18 (s, 4H; 2 CH2), 6.08 – 6.12 (m, 1H; ArH), 6.30 (s,
1H; ArH), 6.34 (ddd, J = 9.0, 6.3, 0.7 Hz, 1H; ArH), 6.99 (d, J = 7.1 Hz, 1H;
ArH), 7.03 – 7.07 (m, 1H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.38 – 7.40 (m,
4H; ArH), 7.54 (dt, J = 9.0, 1.1 Hz, 1H; ArH); 13
C NMR (101 MHz, C6D6) δ
Experimental Part
198
24.4, 25.0, 32.3, 44.6, 60.2 (6 × CH2), 106.9, 110.1, 113.5. 118.0, 121.2,
127.1, 128.4, 129.0 (15 × ArCH), 120.8, 125.9, 126.6, 140.1 (5 × ArC); MS
(EI) m/z 404 (M+, 8), 402 (22), 313 (35), 312 (23), 311 (100), 233 (25), 130
(18), 91 (35), 43 (19); HRMS (ESI) m/z: [M + H]+ Calcd for C26H27ClN2
402.1863; Found 402.1864.
4-(1-(Dibenzylamino)indolizin-3-yl)butanenitrile (4agm):
yellow solid, m.p. 133.2 – 135.8 (265 mg, 35%); Rf 0.42
(hexane/EtOAc, 8:2); IR (neat) ῦ 3030, 2931, 2824, 1599,
1492, 1451, 1428, 1359, 1345, 1318, 1243, 1150, 979, 813,
732, 700; 1H NMR (400 MHz, C6D6) δ 1.09 – 1.16 (m, 2H;
CH2), 1.28 (t, J = 7.2 Hz, 2H; CH2), 2.13 (t, J = 7.2 Hz, 2H; CH2), 4.14 (s, 4H;
2 CH2), 6.04 – 6.07 (m, 1H; ArH), 6.19 (s, 1H; ArH), 6.30 – 6.34 (m, 1H;
ArH), 6.84 (d, J = 7.1 Hz, 1H; ArH), 7.03 – 7.05 (m, 2H; ArH), 7.11 – 7.16
(m, 4H; ArH), 7.37 (d, J = 7.1 Hz, 4H; ArH), 7.50 (dt, J = 9.0, 1.1 Hz, 1H;
ArH); 13
C NMR (101 MHz, C6D6) δ 15.9, 22.9, 24.3, 60.2 (5 × CH2), 107.4,
110.3, 113.8, 118.0, 121.0, 127.2, 128.4, 128.9 (15 × ArCH), 118.7, 119.2,
126.2, 126.5, 139.9 (6 × ArC); MS (EI) m/z 379 (M+, 29), 289 (22), 288 (100),
233 (17), 130 (21), 91 (26); HRMS (ESI) m/z: [M + H]+ Calcd for C26H25N3
379.2048; Found 379.2052.
N,N-Dibenzyl-3-butyl-5-methylindolizin-1-amine (4cgi):
yellow oil (382 mg, 50%); tR 23.99; Rf 0.71 (hexane/EtOAc,
8:2); IR (neat) ῦ 3064, 3025, 2956, 2930, 2870, 1538, 1452,
1428, 1359, 1029, 733, 698; 1H NMR (500 MHz, C6D6) δ 0.82
(t, J =7.4 Hz, 3H; CH3), 1.12 – 1.20 (m, 2H; CH2), 1.37 – 1.46
(m, 2H; CH2), 2.16 (s, 3H; CH3), 2.73 – 2.76 (m, 2H; CH2), 4.19 (s, 4H; 2
CH2), 5.83 (d, J = 6.4 Hz, 1H; ArH), 6.32 (dd, J = 8.9, 6.4 Hz, 1H; ArH), 6.41
(s, 1H; ArH), 7.03 – 7.06 (m, 2H; ArH), 7.13 – 7.16 (m, 4H; ArH), 7.42 – 7.43
(m, 4H; ArH), 7.57 (d, J = 8.9, 1H; ArH); 13
C NMR (126 MHz, C6D6) δ 14.2,
21.6 (2 CH3), 22.5, 29.7, 33.6, 60.2 (5 × CH2), 109.3, 112.2, 114.0, 116.2,
127.0, 128.4, 129.0 (14 × ArCH), 124.6, 126.5, 128.8, 133.8, 140.2 (6 × ArC);
MS (EI) m/z 382 (M+, 10), 292 (18), 291 (74), 106 (15), 92 (15), 91 (100), 77
Experimental Part
199
(14), 65 (16); HRMS (ESI) m/z: [M + H]+ Calcd for C27H30N2 382.2409;
Found 382.2404.
N,N-Dibenzyl-1-(6-bromopyridin-2-yl)-3-phenylprop-
2-yn-1-amine (5bga). Yellow solid; Rf 0.54
(hexane/EtOAc, 8:2); m.p. 92–96 ºC; IR (neat) ῦ 3081,
3060, 3024, 3002, 2926, 2893, 2840, 1597, 1579, 1552,
1121, 986, 795, 752, 732, 697, 687; 1H NMR (300 MHz,
CDCl3) δ 3.74, 3.85 (AB system, J = 13.5, 4H; 2 × CH2), 5.05 (s, 1H; NCH),
7.24–7.70 (m, 18H; 18 × ArH); 13
C NMR (75 MHz, CDCl3) δ 55.0 (2 × CH2),
58.1 (NCH), 84.3, 88.2 (C≡C), 121.5, 126.8, 127.1, 128.3, 128.8, 132.0, 138.5
(18 × ArCH), 123.1, 139.0, 141.5, 160.1 (5 × ArC); MS (70 eV) m/z (%)469
(5) [M++1,
81Br], 468 (17) [M
+,
81Br], 467 (5) [M
++1,
79Br], 466 (17) [M
+,
79Br], 375 (52), 295 (9), 191 (18), 91 (100); HRMS (EI) m/z calcd for
C28H2379
BrN2 466.1045, found 466.1039; calcd for C28H2381
BrN2 468.1024,
found 468.1028.
Experimental Part
200
EXPERIMENTAL PART OF CHAPTER II
General procedure for the hydrogenation of indolizines 4 catalyzed by
PtO2.
The indolizine 4 (0.5 mmol) was poured into the hydrogenation flask,
followed by the addition of PtO2 (11.4 mg, 10 mol%) and glacial HOAc (3
mL), with this mixture being subjected to hydrogenation at 3.74 atm (55 psi)
and ambient temperature. The reaction was monitored by TLC and/or GLC
until total or steady conversion of the starting material (see Table 3.1). The
catalyst was separated by filtration and the solvent was removed under
vacuum. Purification of the reaction crude by column chromatography (silica
gel, hexane/EtOAc) afforded the pure indolizidines 7 as single
diastereoisomers.
(1R*,3R
*,8aR
*)-3-Phenyl-1-(piperidin-1-
yl)octahydroindolizine (7aaa): yellow solid (83 mg, 58%); tR
12.62; Rf 0.40 (hexane/EtOAc, 4:6); mp 68.9–70.9 ºC (EtOH);
IR (neat) ῦ 3084, 3050, 3030, 2929, 2851, 2789, 2789, 1601,
1439, 1364, 1260, 1142, 1126, 1105, 863, 755, 698; 1H NMR
(400 MHz, CDCl3) δ 1.13–1.26, 1.34–1.66, 1.71–1.85, 1.98–
2.11, 2.29–2.40, 2.67–2.86, 3.11–3.32 (7m, 22H), 2.96 (t, J = 8.7 Hz, 1H),
7.19–7.25, 7.28–7.44 (2m, 5H); 13
C NMR (101 MHz, CDCl3) δ 24.7, 24.8,
25.6, 26.3, 26.6, 31.7, 51.7, 52.9, 65.3, 68.9, 70.2, 126.8, 127.4, 128.4, 143.8;
MS (EI) m/z 284 (M+, 9), 201 (13), 174 (10), 173 (76), 172 (100), 110 (44);
HRMS (ESI) m/z: [M + H]+ Calcd for C19H29N2 285.2341; Found 285.2331.
(1R*,3R
*,8aR
*)-1-(Piperidin-1-yl)-3-(p-
tolyl)octahydroindolizine (7aab): brown oil (52 mg, 35%); tR
13.14; Rf 0.40 (hexane/EtOAc, 1:1); IR (neat) ῦ 3046, 3009,
2927, 2851, 2786, 2747, 1512, 1439, 1260, 1143, 1126, 1105,
1036, 863, 813, 797, 735; 1H NMR (300 MHz, CDCl3) δ 1.15–
1.86 (m, 14H), 1.92–2.08 (m, 2H), 2.27–2.40 (m, 5H), 2.63–
2.86 (m, 3H), 2.92 (t, J = 8.7Hz, 1H), 3.16 (ddd, m, J = 9.0 Hz,
Experimental Part
201
7.4, 3.8, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H); 13
C NMR (75
MHz, CDCl3) δ 21.2, 24.8, 24.9, 25.6, 26.4, 26.6, 31.7, 51.8, 52.9, 65.4, 69.0,
70.0, 127.3, 129.1, 136.3, 140.9; MS (EI) m/z 298 (M+, 6), 215 (12), 188 (10),
187 (71), 186 (100), 110 (45); HRMS (ESI) m/z: [M + H]+ Calcd for C20H31N2
299.2487; Found 299.2500.
(1R*,3R
*,8aR
*)-3-(4-Methoxyphenyl)-1-(piperidin-1-
yl)octahydroindolizine (7aac): this compound was isolated
together with an inseparable impurity as a brown oil (71 mg,
aprox. 45%); tR 14.20; Rf 0.42 (hexane/EtOAc, 4:6); IR
(neat) ῦ 3060, 2991, 2930, 2852, 2785, 2749, 1611, 1509,
1439, 1300, 1242, 1179, 1170, 1143, 1126, 1101, 1036, 828,
798; Selected NMR data: 1H NMR (400 MHz, CDCl3) δ
1.06–1.91 (m, 15H), 1.94–2.09 (m, 2H), 2.26–2.49 (m, 2H),
2.73–2.81 (m, 2H), 2.91 (t, J = 8.7 Hz, 1H), 3.12–3.30 (m, 1H), 3.80 (s, 3H),
6.84–6.89 (m, 2H), 7.21–7.32 (m, 2H); 13
CNMR (101 MHz, CDCl3) δ 24.7,
24.8, 25.6, 26.2, 26.6, 31.7, 51.7, 52.8, 55.4, 65.2, 68.9, 69.7, 113.8, 128.4,
135.8, 158.6; MS (EI) m/z 314 (M+, 6), 231 (15), 204 (11), 203 (76), 202
(100), 110 (47); HRMS (ESI) m/z: [M + H]+ Calcd for C20H31N2O 315.2436;
Found 315.2435.
4-[(1R*,3R
*,8aR
*)-3-Phenyloctahydroindolizin-1-
yl]morpholine (7aba): yellow solid (97 mg, 68%); tR 12.69; Rf
0.34 (hexane/EtOAc, 8:2); mp 53.7–55.7 ºC (EtOH); IR (neat)
ῦ 3079, 3060, 3030, 2939, 2849, 2802, 2749, 1603, 1448, 1258,
1136, 1114, 998, 866, 755, 699; 1H NMR (300 MHz, CDCl3) δ
1.16–1.28, 1.34–1.38, 1.50–1.69, 1.71–1.88, 2.00–2.12, 2.31–
2.51, 2.73–2.91 (7m, 15H; 7 × CH2, CH), 2.30 (t, J = 8.7 Hz, 1H; CH), 3.06–
3.23 (m, 1H; CH), 3.66–3.77 (m, 4H; 2 × CH2), 7.21–7.36 (m, 5H; 5 × ArH); 13
C NMR (75 MHz, CDCl3) δ 24.6, 25.6, 26.7, 31.8, 51.1, 52.9, 67.4 (9 ×
CH2), 65.1, 68.9, 70.2 (3 × CH), 126.9, 127.3, 128.5 (5 × ArCH), 143.5 (ArC);
MS (EI) m/z 286 (M+, 3), 203 (14), 173 (71), 172 (100), 112 (41), 104 (10);
Experimental Part
202
Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78. Found: C, 75.88; H,
9.28; N 9.94.
(1R*,3R
*,8aR
*)-N,N-Dibutyl-3-phenyloctahydroindolizin-1-
amine (7aca): brown oil (108 mg, 66%); tR 12.74; Rf 0.54
(hexane/EtOAc, 8:2); IR (neat) ῦ 3060, 3025, 2936, 2852,
2792, 1601, 1492, 1451, 1363, 1263, 1145, 1027, 976, 755,
741, 731, 696; 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 6H), 1.14–
1.87, 2.01–2.15, 2.18–2.36, 2.75–2.86, (4m, 23H), 2.94 (t, J = 8.7 Hz, 1H),
3.29–3.45 (m, 1H), 7.19–7.25 (m, 1H), 7.28–7.38 (m, 4H); 13
C NMR (75
MHz, CDCl3) δ 14.4, 20.9, 25.0, 25.8, 27.1, 31.1, 34.1, 52.2, 52.8, 60.7, 69.5,
70.3, 126.8, 127.5, 128.4, 144.0; MS (EI) m/z 328 (M+, 4), 174 (10), 173 (84),
172 (100), 154 (40), 140 (10), 117 (10), 91 (11); HRMS (ESI) m/z: [M + H]+
Calcd for C22H37N2 329.2961; Found 329.2957.
(1R*,3R
*,8aR
*)-N-Benzyl-N-methyl-3-
phenyloctahydroindolizin-1-amine (7ada): brown oil; tR
14.14 (96 mg, 60%); Rf 0.57 (hexane/EtOAc, 8:2); IR (neat)
ῦ 3084, 3065, 3025, 2934, 2858, 2784, 1599, 1492, 1449,
1361, 1262, 1147, 1099, 1071, 1019, 867, 755, 731, 697; 1H
NMR (400 MHz, CDCl3) δ 1.14–1.27, 1.36–1.48, 1.49–1.61, 1.69–1.80, 1.81–
1.95, 2.10–2.19 (6m, 10H), 2.33 (s, 3H), 2.84 (d, J = 10.6 Hz, 1H), 3.02 (t, J =
8.7 Hz, 1H), 3.34–3.47 (d, m, J = 13.8 Hz, 2H), 4.10 (d, J = 13.8 Hz, 1H),
7.22–7.26, 7.28–7.40 (2m, 10H); 13
C NMR (101 MHz, CDCl3) δ 24.8, 25.5,
26.7, 32.1, 52.8, 59.0, 39.9, 63.1, 69.0, 70.1, 126.9, 127.0, 127.4, 128.4, 128.5,
128.9, 139.4, 143.5; MS (EI) m/z 320 (M+, 2), 237 (13), 173 (76), 172 (100),
146 (46), 91 (35); HRMS (ESI) m/z: [M + H]+ Calcd for C22H29N2 321.2335;
Found 321.2331.
(1R*,3R
*,8aR
*)-N-Methyl-N-phenethyl-3-
phenyloctahydroindolizin-1-amine (7aea): brown oil;
tR 15.50 (102 mg, 61%); Rf 0.66 (hexane/EtOAc, 4:6); IR
(neat) ῦ 3084, 3065, 3025, 2933, 2848, 2784, 2749, 1603,
Experimental Part
203
1493, 1451, 1362, 1262, 1144, 1100, 1029, 934, 867, 802, 755, 697; 1H NMR
(300 MHz, CDCl3) δ 1.19–1.89, 2.04–2.18 (2m, 10H), 2.42 (s, 3H), 2.44–2.63,
2.73–2.85, 2.94–3.11, 3.25–3.42 (4m, 7H), 7.15–7.36 (m, 10H); 13
C NMR
(101 MHz, CDCl3) δ 24.8, 25.7, 26.9, 32.8, 35.0, 52.8, 57.2, 40.1, 64.1, 69.2,
70.1, 125.9, 126.9, 127.4, 128.3, 128.4, 128.9, 141.1, 143.6; MS (EI) m/z 334
(M+, 1), 251 (11), 243 (39), 173 (70), 172 (100), 160 (42), 139 (10), 91 (11);
HRMS (ESI) m/z: [M + H]+ Calcd for C23H31N2 335.2487; Found 335.2490.
(1R*,3R
*,8aR
*)-N,N-Dibenzyl-3-
phenyloctahydroindolizin-1-amine (7aga): brown oil
(129 mg, 65%); tR 21.06; Rf 0.89 (hexane/EtOAc, 8:2);
IR ῦ 3060, 3025, 2936, 2852, 2792, 1601, 1492, 1451,
1363, 1263, 1145, 1027, 976, 755, 741, 731, 696; 1HNMR (300 MHz, CDCl3) δ 1.14–1.25 (m, 1H; Hf),
1.34–1.44 (m, 1H; He’), 1.46–1.59 (m, 2H; He, Hd’), 1.75–1.87 (m, 3H; Hb, Hf’,
Hg), 1.88–1.95 (m, 1H; Hg’), 1.99–2.08 (m, 1H; Hh), 2.08–2.19 (m, 1H; Hb’),
2.81 (d, J = 10.4 Hz, 1H; Hd), 2.98 (t, J = 8.8 Hz, 1H; Hc), 3.28 (d, J = 14.8
Hz, 2H; 2 × Hi), 3.36 (td, J = 8.8, 4.0 Hz, 1H; Ha), 4.20 (br s, 2H; 2 × Hi’),
7.19–7.27 (m, 3H; 3 × ArH), 7.28–7.40 (m, 8H; 8 × ArH), 7.41–7.51 (m, 4H;
4 × ArH); 13
C NMR (75 MHz, CDCl3) δ 24.8 (C-6), 25.6 (C-7), 27.0 (C-8),
32.4 (C-2), 52.9 (C-5), 56.1 (2 × C-9), 58.5 (C-1), 69.1 (C-8a), 70.2 (C-3),
126.7, 126.9, 127.4, 128.4, 128.5 (15 × ArCH), 140.8, 143.7 (3 × ArC); MS
(EI) m/z 396 (M+, 0.3), 306 (14), 305 (59), 222 (51), 174 (10), 173 (79), 172
(100), 117 (12), 91 (72); HRMS (ESI) m/z: [M + H]+ Calcd for C28H32N2
396.2565; Found 396.2585.
(1R*,3R
*,8aR
*)-N,N-Dibenzyl-3-(p-tolyl)octahydroindolizin-
1-amine (7agb): brown oil (119 mg, 58%); tR 22.80; Rf 0.86
(hexane/EtOAc, 8:2); IR (neat) ῦ 3079, 3060, 3030, 2935,
2858, 2794, 2754, 1603, 1493, 1451, 1362, 1263, 1145, 813,
770, 740, 728, 696; 1H NMR (400 MHz, CDCl3) δ 1.14–1.56,
1.75–1.96, 1.99–2.16 (3 m, 10H), 2.35 (s, 3H), 2.80 (d, J =
10.6 Hz, 1H), 2.94 (t, J = 8.7 Hz, 1H), 3.28 (d, J = 14.5 Hz,
Experimental Part
204
2H), 3.31–3.40 (m, 1H), 4.19 (br s, 2H), 7.12–7.16, 7.19–7.25, 7.25–7.34,
7.41–7.53 (4m, 14H); 13
C NMR (101 MHz, CDCl3) δ 21.3, 24.8, 25.6, 27.0,
32.4, 52.9, 56.1, 58.5, 69.1, 69.9, 126.7, 127.3, 128.3, 128.5, 129.2, 136.5,
140.7, 140.8; MS (EI) m/z 410 (M+, 0.2), 320 (10), 319 (41), 236 (31), 222
(10), 188 (11), 187 (77), 186 (97), 131 (12), 118 (14), 117 (11), 106 (10), 105
(27), 91 (100); HRMS (ESI) m/z: [M + H]+ Calcd for C29H35N2 411.2800;
Found 411.2813.
(1R*,3R
*,8aR
*)-N,N-Dibenzyl-3-(4-
methoxyphenyl)octahydroindolizin-1-amine (7agc):
brown oil (183 mg, 86%); tR 31.39; Rf 0.26 (hexane/EtOAc,
8:2); IR (neat) ῦ 3060, 3025, 2934, 2851, 2832, 2791, 2752,
1610, 1509, 1242, 1170, 1145, 1101, 1036, 828, 740, 728,
697; 1H NMR (300 MHz, CDCl3) δ 1.11–1.55, 1.76–2.15
(2m, 10H), 2.79 (d, J = 10.4 Hz, 1H), 2.91 (t, J = 8.7 Hz,
1H), 3.20–3.43 (d, m, J= 14.4 Hz, 3H), 3.81 (s, 3H), 3.93–4.45 (m, 2H), 6.86–
6.92, 7.18–7.26, 7.28–7.36, 7.42–7.54 (4m, 14H); 13
C NMR (75 MHz, CDCl3)
δ 24.9, 25.6, 27.0, 32.3, 52.8, 56.1, 55.4, 58.4, 69.1, 69.6, 113.9, 126.7, 128.3,
128.4, 128.5, 135.7, 140.8, 158.7; MS (EI) m/z 426 (M+, 0.3), 343 (10), 336
(18), 335 (74), 252 (35), 222 (23), 204 (13), 203 (91), 202 (100), 134 (10), 121
(47), 91 (75); HRMS (ESI) m/z: [M + H]+ Calcd for C29H35N2O 427.2749;
Found 427.2763.
(1R*,3R
*,8aR
*)-N,N-Dibenzyl-3-[4-
(trifluoromethyl)phenyl]octahydroindolizin-1-amine
(7agd): beige solid (128 mg, 55%); tR 19.28; Rf 0.80
(hexane/EtOAc, 7:3); mp 141.6–144.4 ºC; IR (neat) ῦ 3079,
3060, 3030, 2937, 2853, 2792, 2754, 1617, 1322, 1161,
1121, 1102, 1066, 1018, 834, 739, 729, 697; 1H NMR (300
MHz, CDCl3) δ 1.13–1.64, 1.74–1.99, 2.05–2.22 (3m, 10H),
2.79 (d, J = 10.5 Hz, 1H), 3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4 Hz, 2H),
3.32–3.49 (m, 1H), 3.97–4.42 (m, 2H), 7.20–7.26, 7.29–7.36, 7.43–7.52, 7.58–
7.63 (4m, 14H); 13
CNMR (75 MHz, CDCl3) δ 24.7, 25.5, 27.0, 32.3, 52.9,
Experimental Part
205
56.0, 58.6, 69.1, 69.7, 125.5 (q, 3JC-F = 3.8), 126.8, 127.6, 128.4, 128.5, 140.5,
148.0; MS (EI) m/z 464 (M+, 0.1), 373 (39), 291 (10), 290 (54), 242 (11), 241
(78), 240 (100), 172 (11), 91 (82); Anal. Calcd for C29H31F3N2: C, 74.98; H,
6.73; N, 6.03. Found: C, 74.95; H, 6.75; N, 5.90.
Methyl 4-[(1R*,3R
*,8aR
*)-1-(dibenzylamino)octa-
hydroindolizin-3-yl)]benzoate (7age): white solid (216
mg, 95%); Rf 0.60 (hexane/EtOAc, 8:2); mp 144.5–147.6;
IR (neat) ῦ 3058, 2945, 2792, 1719, 1274, 1110, 1097,
769, 733, 697; 1H NMR (300 MHz, CDCl3) δ 1.16–1.61
(m, 4H), 1.76–1.95 (m, 4H), 2.04–2.19 (m, 2H), 2.79 (d, J
= 10.7 Hz, 1H), 3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4
Hz, 2H), 3.39 (td, J = 8.7, 3.9 Hz, 1H), 3.92 (s, 3H), 4.17 (br s, 2H), 7.23 (t, J
= 7.3 Hz, 2H), 7.32 (t, J = 7.5 Hz, 4H), 7.45 (m, 6H), 8.02 (m, 2H); 13
C NMR
(75 MHz, CDCl3) δ 24.6, 25.4, 26.8, 32.1, 52.0, 52.8, 55.8, 58.5, 69.0, 69.6,
126.6, 127.1, 128.2, 128.3, 129.8, 128.7, 140.4, 149.2, 167.1; MS (EI) m/z 454
(M+, 0.4), 364 (18), 363 (72), 281 (13), 280 (65), 232 (14), 231 (100), 230
(96), 222 (10), 216 (20), 91 (70); Anal. Calcd for C30H34N2O2: C, 79.26; H,
7.54; N, 6.16. Found: C, 78.80; H, 7.48; N, 6.11.
(1R*,3S
*,8aR
*)-N,N-Dibenzyl-3-decyloctahydroindolizin-1-
amine (7agf): brown oil (166 mg, 72%); tR 25.57; Rf 0.83
(hexane/EtOAc, 7:3); IR ῦ 3079, 3060, 3020, 2922, 2852,
2791, 2754, 1603, 1493, 1452, 1364, 1263, 1148, 1027, 981,
938, 771, 733, 696; 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J =
6.7 Hz, 3H), 1.07–1.45, 1.47–1.89 (2m, 29H), 3.08–3.16, 3.17–3.25 (2m, 2H),
3.29 (d, J = 14.6 Hz, 2H), 3.84–4.29 (m, 2H), 7.17–7.23, 7.26–7.33, 7.39–7.50
(3m, 10H); 13
CNMR (75 MHz, CDCl3) δ 14.3, 22.9, 25.1, 25.7, 26.8, 27.0,
28.0, 29.5, 29.8, 29.9, 30.3, 32.1, 32.8, 53.0, 56.1, 58.0, 65.6, 69.8, 126.6,
128.3, 128.4, 140.9; MS (EI) m/z 460 (M+, 0.4), 370 (20), 369 (71), 238 (18),
237 (100), 236 (50), 166 (12), 138 (12), 124 (42), 122 (18), 111 (17), 110 (51),
98 (11), 97 (21), 96 (13), 91 (72), 84 (12); Anal. Calcd for C32H48N2: C, 83.42;
H, 10.50; N, 6.08. Found: C, 83.81; H, 10.23; N, 5.73.
Experimental Part
206
(1R*,3R
*,8aR
*)-N,N-Dibutyl-1-phenyl-1,2,3,3a,4,5-
hexahydropyrrolo[1,2-a]quinolin-3-amine (7eca):
yellow oil (85 mg, 45%), tR 21.37; Rf
0.75(hexane/EtOAc, 9:1); IR (neat) ῦ 3021, 2957, 2921,
2856, 2816, 1598, 1491, 1455, 1320, 1097, 1079, 1029, 803, 751, 703; 1H
NMR (300 MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H; 2 CH3), 1.14–1.43 (m,
8H; 4 × CH2), 1.94 (ddd, J = 14.0, 6.5, 3.6 Hz, 1H; CH), 2.06–2.19 (m, 4H; 2
× CH2), 2.52–2.65 (m, 3H), 2.92–3.00 (m, 2H), 3.36–3.52 (m, 2H), 4.35 (dd, J
= 9.8, 6.5 Hz, 1H; CH), 6.14 (dd, J = 8.1, 0.9 Hz, 1H; ArH), 6.64 (td, J = 7.3,
1.1 Hz, 1H; ArH), 6.79 (td, J = 8.2, 1.7 Hz, 1H; ArH), 7.05 (dd, J = 7.4, 1.2
Hz, 1H; ArH), 7.17–7.29 (m, 5H; ArH); 13
C NMR (75 MHz, CDCl3) δ 14.2 (2
× CH3), 20.6, 24.5, 27.9, 30.3, 36.1, 51.8 (9 × CH2), 60.7, 63.2, 64.2 (3 × CH),
114.9, 117.9, 125.9, 126.3, 128.1, 128.3, 128.7 (9 × ArCH), 125.6, 144.0,
146.9 (3 × ArC); MS (EI) m/z 376 (M+, 18), 329 (9), 247 (11), 246 (12), 245
(20), 244 (30), 221 (55), 220 (100), 202 (20), 155 (11), 154 (72), 117 (25), 115
(12), 91 (11); HRMS (ESI) m/z: [M+] Calcd for C26H36N2 376.2878; Found
376.2889.
(1R*,3R
*,5R*,8aR
*)-N,N-Dibenzyl-5-methyl-3-
phenyloctahydroindolizin-1-amine (7cga): yellow oil (82
mg, 40%), tR 28.22; Rf 0.83 (hexane/EtOAc, 8:2); IR (neat) ῦ
3027, 2926, 2849, 2797, 1492, 1452, 1140, 993, 732, 697, 617; 1H NMR (300 MHz, CDCl3) δ 0.54 (d, J = 6.4 Hz, 3H), 1.18–1.44 (m, 5H),
1.72–1.95 (m, 5H), 2.14–2.25 (m, 2H), 3.21 (d, J = 14.2 Hz, 2H; CH2), 3.23 (t,
J = 4.4 Hz, 1H), 3.28 (ddd, J = 9.5, 7.9, 3.6 Hz, 1H), 4.23 (d, J = 14.2 Hz, 2H;
CH2), 7.18–7.25 (m, 3H; 3 × ArH), 7.29–7.34 (m, J = 7.5 Hz, 8H; 8 × ArH),
7.46 (d, J = 7.5 Hz, 4H; 4 × ArH); 13
C NMR (75 MHz, CDCl3) δ 23.3 (CH3),
25.3, 27.3, 34.2, 35.6 (4 × CH2), 55.9 (2 × CH2N), 58.5, 62.9, 69.8, 70.8 (4 ×
CH), 126.2, 126.6, 126.7, 128.1, 128.4 (15 × ArCH), 140.1, 148.0 (3 × ArC);
MS (EI) m/z 319 (73), 222 (49), 207 (20), 187 (64), 186 (89), 117 (14), 106
(10), 104 (12), 92 (11), 91 (100); HRMS (ESI) m/z: [M+] Calcd for C29H34N2
410.2722, [M – Bn]+ 319.2174; Found 319.2195.
Experimental Part
207
General procedure for the hydrogenolysis of indolizidines 7 to
monobenzylated indolizidines 8.
The indolizidine 7 (0.3 mmol) was poured into the hydrogenation flask,
followed by the addition of Pt(5 wt%)/C (117 mg, 10 mol%) or PtO2 (11.4 mg,
10 mol%) and glacial HOAc (3 mL), with this mixture being subjected to
hydrogenation at ca. 1 atm (balloon) and ambient temperature. The reaction
was monitored by TLC and/or GLC until total or steady conversion of the
starting material. The catalyst was separated by filtration and the glacial
HOAc was neutralized with 2M NaOH, followed by extraction with EtOAc,
drying of the organic phase with Na2SO4 and solvent evaporation under
vacuum. Purification of the reaction crude by preparative TLC (silica gel,
hexane/EtOAc 6:4) afforded the pure indolizidines 8 as single
diastereoisomers.
(1R*,3R
*,8aR
*)-N-Benzyl-3-phenyloctahydroindolizin-1-
amine (8aga): brown oil (63 mg, 68%); tR 15.38; Rf 0.44
(hexane/EtOAc, 3:7); IR (neat) ῦ 3029, 2935, 2851, 2789, 1603,
1492, 1451, 1145, 1117, 754, 731, 609; 1H NMR (300 MHz,
CDCl3) δ 1.15–1.31 (m, 1H), 1.38–1.86 (m, 8H), 2.06–2.15 (m,
1H), 2.43 (dt, J = 13.5, 8.0 Hz, 1H), 2.83, (d, J = 10.7 Hz, 1H), 3.07 (t, J = 8.4
Hz, 1H), 3.14 (ddd, J = 7.9, 6.1, 3.1 Hz, 1H), 3.68, 3.86 (AB system, J = 13.4
Hz, 2H), 7.20–7.37 (m, 10H); 13
C NMR (75 MHz, CDCl3) δ 24.4, 25.4, 26.4,
41.7, 51.4, 52.1, 57.5, 68.8, 69.9, 126.8, 126.9, 127.6, 128.1, 128.3, 140.7,
143.3; MS (70 eV) m/z (%) 306 (M+, 3), 223 (20), 197 (21), 196 (20), 173
(61), 172 (100), 168 (11), 132 (29), 91 (25); HRMS (EI) m/z: Calcd for
C21H26N2 306.2096; Found 306.2092.
Experimental Part
208
(1R*,3R
*,8aR
*)-N-Benzyl-3-(4-
methoxyphenyl)octahydroindolizin-1-amine (8agc):
brown oil; (73 mg, 72%); tR 18.52; Rf 0.13 (hexane/EtOAc,
6:4); IR (neat) ῦ 3060, 2951, 2851, 1509, 1426, 1301, 1259,
1112, 896, 734, 698; 1H NMR (300 MHz, CDCl3) δ 1.19–
1.92 (m, 9H), 2.02–2.13 (m, 1H), 2.41 (dt, J = 13.5, 8.0 Hz,
1H), 2.81 (d, J = 10.7 Hz, 1H), 3.02 (t, J = 8.4 Hz, 1H), 3.14
(ddd, J = 7.8, 6.1, 3.1 Hz, 1H), 3.69, 3.87 (AB system, J =
13.4 Hz, 2H), 3.80 (s, 3H), 6.86 (d, J = 8.4 Hz, 2H), 7.21–7.36 (m, 7H); 13
C
NMR (75 MHz, CDCl3) δ 24.3, 25.3, 26.3, 41.6, 51.4, 52.0, 55.2, 57.4, 68.8,
69.4, 113.7, 126.8, 128.1, 128.3, 128.7, 135.0, 140.6, 158.6; MS (70 eV) m/z
(%) 336 (M+, 2), 253 (21), 252 (10), 231 (10), 227 (39), 226 (13), 212 (17),
207 (13), 203 (58), 202 (100), 162 (34), 135 (12), 134 (20), 132 (39), 106 (16),
92 (10), 91 (66), 84 (12), 77 (14), 65 (10); HRMS (EI) m/z: Calcd for
C22H28N2O 336.2202; Found 336.2185.
(1R*,3R
*,8aR
*)-N-Benzyl-3-[4-
(trifluoromethyl)phenyl]octahydroindolizin-1-amine
(8agd): brown oil (73 mg, 65%); tR 15.06; Rf 0.48
(hexane/EtOAc, 6:4); IR (neat) ῦ 3029, 2934, 2852, 2789,
2753, 1509, 1325, 1162, 1119, 1018, 837, 731, 697; 1H NMR
(300 MHz, CDCl3) δ 1.08–1.99 (m, 9H), 2.07–2.29 (m, 1H),
2.34–2.61 (m, 1H), 2.80 (d, J = 10.7 Hz, 1H), 3.08–3.21 (m,
2H), 3.67, 3.84 (AB system, J = 13.3 Hz, 2H), 7.20–7.35 (m,
5H), 7.47, 7.56 (AA’BB’system, J = 8.2 Hz, 4H); 13
C NMR (75 MHz, CDCl3)
δ 24.2, 25.3, 26.4, 41.8, 51.5, 52.1, 57.7, 68.7, 69.3, 124.3 (q, J = 271.8 Hz)
125.3 (q, J = 3.7 Hz), 126.8, 127.8, 128.1, 128.3, 129.1 (q, J = 32.2 Hz) 140.7,
147.9; MS (70 eV) m/z (%) 374 (M+, 2), 291 (8), 269 (11), 242 (10), 241 (62),
240 (100), 172 (11), 132 (20), 91 (38), 84 (27); HRMS (EI) m/z: Calcd for
C22H25F3N2 374.1970; Found 374.1967.
Experimental Part
209
(1R*,3R
*,8aR
*)-N-Benzyl-3-decyloctahydroindolizin-1-amine
(8agf): brown oil (90 mg, 81%); tR 19.19; Rf 0.20
(hexane/EtOAc, 3:7); IR (neat) ῦ 3029, 2922, 2852, 2817, 1566,
1454, 1145, 980, 743, 698; 1H NMR (300 MHz, CDCl3) δ 0.88
(t, J = 6.7 Hz, 3H), 1.09–1.40 (m, 20H), 1.43–2.04 (m, 9H), 2.2
(dt, J = 13.1, 7.8 Hz, 1H), 2.96–3.07 (m, 1H), 3.19 (d, J = 10.5
Hz, 1H), 3.65, 3.84 (AB system, J = 13.4 Hz, 2H), 7.17–7.35 (m, 5H); 13
C
NMR (75 MHz, CDCl3) δ 14.1, 22.7, 24.6, 25.2, 26.2, 26.6, 29.3, 29.6, 30.0,
31.9, 38.0, 51.6, 52.2, 56.9, 65.3, 69.4, 126.6, 128.1, 128.2, 140.7; MS (70 eV)
m/z (%) 370 (M+, 3), 261 (9), 238 (13), 237 (49), 236 (23), 229 (28), 135 (14),
134 (100), 132 (12), 124 (27), 111 (10), 110 (27), 97 (11), 91 (25); HRMS (EI)
m/z: Calcd for C25H42N2 370.3348; Found 370.3337.
General procedure for the hydrogenolysis of indolizidines 7 to
debenzylated indolizidines 9.
The indolizidine 7 (0.3 mmol) was poured into the hydrogenation flask,
followed by the addition of Pd(20 wt%)/C (16 mg, 10 mol%) and glacial
HOAc (3 mL), with this mixture being subjected to hydrogenation at ca. 1 atm
(balloon) and ambient temperature. The reaction was monitored by TLC
and/or GLC until total or steady conversion of the starting material. The
catalyst was separated by filtration and the glacial HOAc was neutralized with
2M NaOH, followed by extraction with EtOAc, drying of the organic phase
with Na2SO4 and solvent evaporation under vacuum. Compounds 9agc and
9agf did not require any further purification; compounds 9aga and 9agd were
purified by preparative TLC (EtOAc). In all cases, the pure indolizidines 7
were obtained as single diastereoisomers.
(1R*,3R
*,8aR
*)-3-Phenyloctahydroindolizin-1-amine (9aga):
yellow oil (55 mg, 85%); tR 11.11; Rf 0.20 (EtOAc/MeOH, 8:2);
IR (neat) ῦ 3038, 2932, 2854, 1555, 1455, 1388, 1311, 1145,
754, 698; 1H NMR (300 MHz, CDCl3) δ 1.21–1.62 (m, 6H),
1.63–1.88 (m, 3H), 2.02 (ddd, J = 7.5, 5.4, 2.7 Hz, 2H), 2.62 (ddd, J = 14.0,
8.8, 8.0 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 3.07 (t, J = 8.4 Hz, 1H), 3.27 (ddd,
Experimental Part
210
J = 7.7, 5.1, 2.4 Hz, 1H), 7.15–7.26 (m, 1H), 7.28–7.36 (m, 4H); 13
C NMR (75
MHz, CDCl3) δ 23.9, 25.2, 26.0, 43.9, 51.7, 52.3, 68.6, 69.4, 126.8, 127.4,
128.2, 143.2; MS (70 eV) m/z (%) 217 (M++1, 1), 216 (M
+, 8), 173 (51), 172
(100), 132 (8), 104 (7), 84 (15); HRMS (EI) m/z: Calcd for C14H20N2
216.1626, C14H17N [M+ – NH3] 199.1361; Found 199.1356.
(1R*,3R
*,8aR
*)-3-(4-Methoxyphenyl)octahydroindolizin-
1-amine (9agc): brown oil (57 mg, 77%); tR 12.59; Rf 0.17
(acetone); IR (neat) ῦ 2933, 2851, 1583, 1242, 1035, 828,
626; 1H NMR (300 MHz, CDCl3) δ 0.95–2.01 (m, 9H), 2.57
(dt, J = 13.9, 8.4 Hz, 1H), 2.73 (s, 2H), 2.8 (d, J = 10.8 Hz,
1H), 2.99 (t, J = 8.4 Hz, 1H), 3.27 (ddd, J = 7.9, 5.2, 2.5 Hz,
1H), 3.78 (s, 3H), 6.85, 7.24 (AA’XX’, J = 8.7 Hz, 4H); 13
C
NMR (75 MHz, CDCl3) δ 23.9, 25.2, 25.9, 43.7, 51.6, 52.1, 55.1, 68.6, 69.0,
113.6, 128.5, 134.9, 158.5; MS (70 eV) m/z (%) 247 (M++1, 3), 246 (M
+, 17),
203 (48), 202 (100), 162 (11), 134 (16), 132 (11), 84 (43); HRMS (EI) m/z:
Calcd for C15H22N2O 246.1732; Found 246.1723.
(1R*,3R
*,8aR
*)-3-[4-
(Trifluoromethyl)phenyl]octahydroindolizin-1-amine
(9agd): yellow oil (63 mg, 74%); tR 10.99; Rf 0.45
(EtOAc/MeOH, 8:2); IR (neat) ῦ 3024, 2939, 2851, 1553,
1457, 1322, 1162, 1117, 1066, 838; 1H NMR (300 MHz,
CDCl3) δ 1.29–1.60 (m, 4H), 1.73–1.89 (m, 3H), 2.12 (ddd, J
= 10.9, 4.9, 2.4 Hz, 1H), 2.60–2.83 (m, 5H), 3.19 (t, J = 8.5
Hz, 1H), 3.37–3.42 (m, 1H), 7.46, 7.57 (AA’XX’ system, J = 8.2 Hz, 4H); 13
C
NMR (75 MHz, CDCl3) δ 23.9, 25.2, 26.0, 44.2, 51.7, 52.5, 68.7, 68.9, 124.2
(q, J = 272.0 Hz), 125.3 (q, J = 3.6 Hz), 127.6, 129.0 (q, J = 32.0 Hz), 147.8;
MS (70 eV) m/z (%) 285 (M++1, 1), 284 (M
+, 5), 265 (7), 242 (8), 241 (62),
240 (100), 200 (6), 172 (9), 84 (12); HRMS (EI) m/z: Calcd for C15H19F3N2
284.1500, C15H16F3N [M+ – NH3] 267.1235; Found 267.1221.
Experimental Part
211
(1R*,3R
*,8aR
*)-3-Decyloctahydroindolizin-1-amine (9agf):
brown oil (77 mg, 92%); tR 15.44; Rf 0.20 (EtOAc/MeOH, 7:3);
IR (neat) ῦ 2921, 2851, 1560, 1467, 1458, 1387, 1147, 1121,
811, 721, 687; 1H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.7
Hz, 3H), 1.06 (ddd, J = 13.6, 8.1, 2.7 Hz, 1H), 1.20–1.85 (m,
27H), 2.04–2.19 (m, 2H), 2.35 (dt, J = 13.6, 8.3 Hz, 1H), 3.12–3.20 (m, 2H); 13
C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 24.2, 25.2, 25.9, 26.4, 29.3, 29.6,
29.9, 31.9, 33.5, 40.2, 52.1, 51.8, 65.0, 69.5; MS (70 eV) m/z (%) 280 (M++1,
1), 279 (M+, 1), 237 (16), 236 (11), 140 (10), 139 (100), 124 (17), 122 (15),
110 (25), 96 (11); Anal. Calcd for C18H36N2: C, 77.08; H, 12.94; N, 9.99.
Found: C, 76.72; H, 12.65; N, 9.50.
Experimental Part
212
EXPERIMENTAL PART OF CHAPTER III
General procedure for the synthesis of the dyes 11 from indolizines 4.
A solution of the starting indolizine 4 (0.5 mmol) in glacial acetic acid
(3.0 mL) was stirred for 6–14 h at room temperature (see Table 2). The
resulting mixture was neutralized with a saturated solution of sodium
bicarbonate and extracted with ethyl acetate (3 10 mL). The organic phase
was washed with a saturated solution of sodium bicarbonate (3 20 mL),
followed by decantation and drying with anhydrous magnesium sulfate. The
reaction crude obtained after solvent evaporation was purified by column
chromatography (silica gel, hexane/ethyl acetate) or submitted to
recrystallization in absolute ethanol to give the corresponding indolizine dyes
11.
(E)-3-[1-(Dibenzylamino)-3-
phenylindolizin-7-yl]-3-phenyl-1-(pyridin-2-
yl)prop-2-en-1-one (11aga). Orange solid; Rf
0.66 (hexane/EtOAc, 6:4); m.p. 138.9–140.4
ºC (EtOH); IR (neat) ῦ 3104, 3084, 3055, 3025,
2995, 2833, 1662 (C=O), 1560, 1541, 1490,
1469, 1360, 1207, 1139, 1049, 1026, 993, 873,
799, 747, 738, 695, 682, 661, 618; NMR data
of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 4.15 (s, 4H; 2 × CH2),
6.55 (s, 1H; ArH), 6.87 (dd, J = 7.8, 1.8, 1H; ArH), 7.17–7.51 (m, 22H; 22 ×
ArH), 7.76 (td, J = 7.8, 1.8, 1H; ArH), 7.99 (d, J = 8.1, 1H; ArH), 8.04 (d, J =
7.8, 1H; ArH), 8.12 (s, 1H; CHCO), 8.68 (d, J = 4.8, 1H; ArH); selected NMR
data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 4.19 (s, 4H; 2 ×
CH2), 6.35 (dd, J = 7.5, 1.8 Hz, 1H; ArH), 8.65 (d, J = 4.7 Hz, 1H; ArH);
NMR data of the mixture of rotamers: 13
C NMR (101 MHz, CDCl3) δ 58.8,
58.9 (CH2), 107.9, 108.1, 109.3, 113.8, 115.8, 120.2, 120.3, 121.3, 122.1,
122.5, 122.7, 122.8, 126.3, 126.4, 126.8, 126.9, 127.2, 127.5, 127.8, 127.9,
128.1, 128.2, 128.3, 128.4, 128.9, 129.0, 129.1, 129.2, 129.6, 129.9, 136.9,
148.6, 148.8 (CH), 125.7, 126.0, 126.7, 131.8, 133.4, 139.0, 139.2, 139.4,
Experimental Part
213
142.4, 155.6, 155.8, 156.1, 157.5 (ArC), 188.7, 189.5 (CO); MS (DIP) m/z 596
(M++1, 24), 595 (M
+, 53), 505 (28), 504 (100), 399 (21), 398 (67), 397 (21),
383 (13), 237 (18), 91 (66). Elemental analysis calcd. for C42H33N3O: C 84.68,
H 5.58, N 7.05, found: C 84.92, H 5.58, N 7.19.
(E)-3-[1-(Dibenzylamino)-3-(p-
tolyl)indolizin-7-yl]-1-(pyridin-2-yl)-3-(p-
tolyl)prop-2-en-1-one (11agb). Orange solid;
Rf 0.34 (hexane/EtOAc, 8:2); m.p. 174.3–175.4
ºC (EtOH); IR (neat) ῦ 3100, 3060, 3026, 2962,
2922, 2826, 1661 (C=O), 1559, 1544, 1507,
1470, 1377, 1361, 1205, 1138, 1047, 1029,
993, 874, 811, 800, 776, 746, 732, 697; NMR
data of the major rotamer: 1H NMR (400
MHz, CDCl3) δ 2.39, 2.42 (2s, 6H; 2 × CH3), 4.17 (s, 4H; 2 × CH2), 6.50 (s,
1H; ArH), 6.84 (dd, J = 7.8, 1.2, 1H; ArH), 7.10–7.26 (m, 16H; 16 × ArH),
7.32–7.40 (m, 4H; 4 × ArH), 7.74 (td, J = 7.8, 1.2, 1H; ArH), 7.95–8.03 (m,
2H; 2 × ArH), 8.08 (s, 1H; CHCO), 8.68 (d, J = 4.8, 1H; ArH); selected NMR
data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 2.38, 2.40 (2s, 6H; 2
× CH3), 4.19 (s, 4H; 2 × CH2), 6.34 (dd, J = 7.5, 1.6 Hz, 1H; ArH), 6.51 (s,
1H; ArH), 8.12 (s, 1H; ArH), 8.64 (d, J = 4.2 Hz, 1H; ArH); NMR data of the
mixture of rotamers: 13
C NMR (101 MHz, CDCl3) δ 21.4, 21.5, 21.7 (CH3),
58.7, 58.9 (CH2), 107.5, 107.8, 109.4, 113.8, 115.6, 119.3, 120.2, 121.3, 122.1,
122.5, 122.6, 122.7, 126.2, 126.8, 126.9, 127.8, 127.9, 128.2, 128.3, 128.4,
128.9, 129.1, 129.6, 129.7, 129.8, 136.9, 139.9, 148.6, 148.7 (CH), 125.2,
126.0, 126.7, 133.4, 136.3, 137.5, 139.0, 139.2, 155.9, 156.6 (ArC), 188.6,
189.4 (CO); MS (DIP) m/z 624 (M++1, 24), 623 (M
+, 48), 533 (41), 532 (100),
427 (20), 426 (58), 425 (17), 412 (10), 411 (12), 251 (12), 91 (83). Elemental
analysis calcd. for C44H37N3O: C 84.72, H 5.98, N 6.74; found: C 84.61, H
6.02, N 6.61.
(E)-3-[1-(Dibenzylamino)-3-(4-
methoxyphenyl)indolizin-7-yl]-3-(4-
Experimental Part
214
methoxyphenyl)-1-(pyridin-2-yl)prop-2-en-1-one (11agc). Orange solid; Rf
0.43 (hexane/EtOAc, 6:4); m.p. 157.1–158.8 ºC (EtOH); IR (neat) ῦ 3084,
3065, 3025, 2995, 2927, 2829, 1654 (C=O), 1608, 1556, 1540, 1506, 1469,
1362, 1286, 1249, 1234, 1206, 1175, 1138, 1026, 832, 808, 778, 750, 731,
700; NMR data of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 3.84 (s,
6H; 2 × OCH3), 4.19 (s, 4H; 2 × CH2), 6.47 (s, 1H; ArH), 6.81 (dd, J = 7.7,
1.8, 1H; ArH), 6.90 (d, 2H; J = 8.8, 2 × ArH), 6.97 (d, 2H; J = 8.8, 2 × ArH),
7.14–7.26 (m, 12H; 12 × ArH), 7.35–7.46 (m, 4H; 4 × ArH), 7.75 (td, J = 7.7,
1.7, 1H; ArH), 8.00 (dd, J = 8.0, 0.8, 1H; ArH), 8.02 (dd, J = 8.0, 0.8, 1H;
ArH), 8.03 (s, 1H, CHCO), 8.67–8.69 (m, 1H; ArH); selected NMR data of the
minor rotamer: 1H NMR (400 MHz, CDCl3) δ 3.85 (s, CH3), 4.20 (CH2), 6.34
(dd, J = 7.5, 1.8 Hz; ArH), 8.65 (d, J = 4.7 Hz; ArH); NMR data of the mixture
of rotamers: 13
C NMR (101 MHz, CDCl3) δ 55.2, 55.5 (CH3), 58.7, 58.9
(CH2), 107.2, 107.5, 109.6, 113.5, 113.7, 113.8, 114.4, 114.5, 115.5, 118.2,
120.1, 122.3, 121.1, 122.1, 122.7, 126.2, 126.8, 126.9, 128.1, 128.2, 128.3,
128.4, 129.3, 129.5, 130.8, 131.4, 136.9, 148.6, 148.7 (CH), 124.3, 124.9,
125.8, 126.7, 131.3, 131.9, 133.4, 134.8, 139.0, 139.2, 155.9, 156.1, 156.4,
157.7, 158.9, 159.1, 159.5, 161.1 (ArC), 188.7, 189.1 (CO); MS (DIP) m/z 656
(M++1, 20), 655 (M
+, 42), 565 (41), 564 (100), 459 (13), 458 (37), 443 (19),
91 (100). Elemental analysis calcd. for C44H37N3O3: C 80.59, H 5.69, N 6.41;
found: C 80.14, H 5.68, N 6.43.
Experimental Part
215
(E)-3-{1-(Dibenzylamino)-3-[4-
(trifluoromethyl)phenyl]indolizin-7-yl}-1-
(pyridin-2-yl)-3-[4-(trifluoromethyl)-
phenyl]prop-2-en-1-one (11agd). Orange
solid; Rf 0.37 (hexane/EtOAc, 8:2); m.p.
198.4–200.0 ºC (EtOH); IR (neat) ῦ 3084,
3065, 3025, 2937, 2829, 1662 (C=O), 1614,
1562, 1512, 1321, 1208, 1164, 1119, 1105,
1065, 1026, 993, 846, 752, 743, 733, 697;
NMR data of the major rotamer: 1H NMR
(400 MHz, CDCl3) δ 4.18 (s, 4H; 2 × CH2), 6.59 (s, 1H; ArH), 6.90 (dd, J =
7.8, 2.0, 1H; ArH), 7.12–7.34 (m, 13H; 13 × ArH), 7.44 (ddd, J = 7.5, 4.8, 1.2,
1H; ArH), 7.58–7.72 (m, 6H; 6 × ArH), 7.80 (td, J = 7.7, 1.7, 1H; ArH), 7.98
(d, J = 7.8, 1H; ArH), 8.07 (d, J = 7.5, 1H; ArH), 8.18 (s, 1H; CHCO), 8.70–
8.72 (m, 1H; ArH); selected NMR data of the minor rotamer: 1H NMR (400
MHz, CDCl3) δ 4.23 (s, 4H, 2 × CH2), 6.36 (dd, J = 7.5, 1.8 Hz, 1H; ArH),
8.21 (s, 1H; ArH), 8.75 (d, J = 4.7 Hz, 1H; ArH); NMR data of the mixture of
rotamers: 13
C NMR (101 MHz, CDCl3) δ 58.6, 58.8 (CH2), 108.2, 109.6,
116.9, 121.4, 122.5, 122.6, 123.2, 123.3, 124.8, 126.7, 127.0, 127.2, 127.3,
127.7, 127.9, 128.1, 128.3, 128.5, 128.7, 128.9, 129.4, 129.9, 137.1, 137.3,
148.7, 149.1 (CH), 124.8, 125.8, 126.5, 134.2, 135.2, 138.7, 138.9, 143.3,
153.9, 155.4 (ArC), 125.2 (q, 3JC-F = 3.3 Hz; CHCCF3), 125.9 (q,
3JC-F = 3.7
Hz; CHCCF3), 126.2 (q, 3JC-F = 3.3; CHCCF3), 188.6, 189.3 (CO); MS (DIP)
m/z 732 (M++1, 20), 731 (M
+, 42), 641 (39), 640 (93), 535 (26), 534 (79), 533
(25), 519 (16), 363 (10), 306 (31), 106 (15), 91 (100), 78 (26). Elemental
analysis calcd. for C44H31F6N3O: C 72.22, H 4.27, N 5.74; found: C 72.13, H
4.49, N 5.62.
Experimental Part
216
Methyl (E)-4-{1-[1-
(dibenzylamino)-3-(4-
(methoxycarbonyl)phenyl) indolizin-7-
yl]-3-oxo-3-(pyridin-2-yl)prop-1-en-1-
yl}benzoate (11age). Dark solid; Rf 0.12
(hexane/EtOAc, 8:2); m.p. 130.5-133.8 ºC
(EtOH); IR (neat) ῦ 3053, 3030, 2999,
2949, 2876, 1713 (C=O), 1654 (C=O),
1537, 1272, 1101, 1031, 766, 694; NMR
data of the major rotamer: 1H NMR (300
MHz, CDCl3) δ 3.94 (s, 3H; CH3), 3.99 (s, 3H; CH3), 4.18 (s, 4H; 2 × CH2),
6.59 (s, 1H; ArH), 6.95 (dd, J = 7.8, 1.9 Hz, 1H; ArH), 7.12–7.28 (m, 10H,
ArH), 7.43 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H; ArH), 7.55 (d, J = 8.5 Hz, 2H, ArH),
7.79 (td, J = 7.7, 1.7 Hz, 1H; ArH), 7.98 (d, J = 7.8 Hz, 1H; ArH), 8.05 (d, J =
8.5 Hz, 2H; ArH), 8.04–8.14 (m, 5H; 5 × ArH), 8.13 (d, J = 8.0 Hz, 1H; ArH),
8.20 (s, 1H; ArH), 8.70 (dd, J = 4.7, 0.7 Hz, 1H; ArH); selected NMR data of
the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 3.93, 3.97 (2s, 6 H; 2 ×
CH3), 4.21 (s, 4H; 2 × CH2), 6.38 (dd, J = 7.5, 1.9 Hz, 1H; ArH), 6.63 (s, 1H;
ArH); NMR data of the mixture of rotamers: 13
C NMR (75 MHz, CDCl3) δ
52.1, 52.2 (CH3), 58.4, 58.8 (CH2), 108.6, 109.5, 116.3, 121.6, 122.5, 122.6,
126.5, 127.0, 127.1, 127.9, 128.2, 128.3, 128.4, 128.9, 129.6, 130.3, 130.4,
137.1, 148.7 (CH), 125.2, 125.9, 126.6, 129.4, 134.3, 136.0, 138.6, 144.6,
154.4, 155.4, 166.7, 167.0, 188.3 (ArC); MS (DIP) m/z 732 (M++1, 20), 731
(M+, 42), 641 (39), 640 (93), 535 (26), 534 (79), 533 (25), 519 (16), 363 (10),
306 (31), 106 (15), 91 (100), 78 (26). Elemental analysis calcd. for
C44H31F6N3O: C 72.22, H 4.27, N 5.74; found: C 72.13, H 4.49, N 5.62.
(E)-3-[3-Butyl-1-
(dibenzylamino)indolizin-7-yl]-1-(pyridin-
2-yl)hept-2-en-1-one (11agi). Purple
semisolid; Rf 0.38 (hexane/EtOAc, 8:2); IR
(neat) ῦ 3027, 2956, 2928, 2870, 1644
(C=O), 1560, 1535, 1494, 1452, 1348, 1214,
Experimental Part
217
1062, 995, 740, 696; 1H NMR (300 MHz, CDCl3) δ 0.93 (t, J = 7.3 Hz, 3H;
CH3), 0.95 (t, J = 7.1 Hz, 3H; CH3), 1.25–1.69 (m, 8H; 4 × CH2), 2.71 (br s,
2H; CH2), 3.12 (br s, 2H; CH2), 4.30 (s, 4H; 2 × CH2), 6.31 (s, 1H; ArH), 6.85
(d, J = 7.4 Hz, 1H; ArH), 7.20–7.43 (m, 11H; ArH), 7.41 (ddd, J = 7.5, 4.8,
1.2 Hz, 1H; ArH), 7.78 (s, 1H; ArH), 7.83 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.00
(s, 1H; ArH), 8.14 (dd, J = 7.9, 0.9 Hz, 1H; ArH), 8.68 (ddd, J = 4.8, 1.7, 0.9
Hz, 1H; ArH); 13
C NMR (75 MHz, CDCl3) δ 13.9, 14.1 (CH3), 22.4, 23.3,
25.6, 29.3, 29.6, 32.5, 59.1 (CH2), 106.2, 108.3, 114.9, 118.2, 120.5, 122.3,
125.9, 126.9, 128.2, 136.8, 148.4 (CH), 124.2, 125.3, 139.2, 156.3, 160.4
(ArC), 189.1 (CO); MS (DIP) m/z 556 (M++1, 25), 555 (M
+, 59), 505 (40),
480 (18), 465 (37), 464 (100), 462 (10), 373 (27), 344 (10), 330 (27), 329 (1),
315 (19), 285 (16), 267 (36), 210 (20), 209 (12), 182 (12), 91 (67), 78 (17).
HRMS (EI) m/z calcd for C38H41N3O 555.3250, [M+–91] 464.2702, found
464.2688.
(E)-3-{1-[Benzyl(methyl)amino]-3-
phenylindolizin-7-yl}-3-phenyl-1-(pyridin-
2-yl)prop-2-en-1-one (11ada). Orange solid;
Rf 0.49 (hexane/EtOAc, 6:4); m.p. 125.6–
127.1 ºC (EtOH); IR (neat) ῦ 3084, 3055,
3025, 2986, 2946, 2808, 2779, 1661 (C=O), 1562, 1540, 1491, 1470, 1450,
1357, 1199, 1030, 770, 753, 697, 675; NMR data of the major rotamer: 1H
NMR (300 MHz, CDCl3) δ 2.67 (s, 3H; CH3), 4.04 (s, 2H; CH2), 6.56 (s, 1H;
ArH), 6.93 (dd, J = 7.8, 2.0, 1H; ArH), 7.10–7.60 (m, 17H; 17 × ArH), 7.76
(td, J = 7.7, 1.7, 1H; ArH), 7.99 (dt, J = 7.8, 1.1, 1H; ArH), 8.11 (dd, J = 7.7,
0.5, 1H; ArH), 8.16 (s, 1H; ArH), 8.69 (ddd, J = 4.8, 1.7, 0.9, 1H; ArH);
selected NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 2.71
(s, 2H; CH2), 4.14 (s, 3H; CH3), 6.38 (dd, J = 7.5, 1.9 Hz, 1H; ArH), 6.61 (s,
1H; ArH), 8.65 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH); NMR data of the mixture
of rotamers: 13
C NMR (75 MHz, CDCl3) δ 41.0, 42.2 (CH3), 62.5, 62.6 (CH2),
106.1, 109.4, 113.9, 115.7, 120.0, 120.2, 121.3, 122.2, 122.6, 122.7, 126.3,
126.4, 127.1, 127.2, 127.6, 127.9, 128.0, 128.2, 128.3, 128.4, 128.5, 129.0,
129.2, 129.9, 136.9, 148.6, 148.8 (CH), 124.2, 125.9, 126.3, 131.8, 135.6,
Experimental Part
218
138.6, 139.4, 155.6, 155.8, 156.0, 157.7 (ArC), 188.6, 189.3 (CO); MS (DIP)
m/z 520 (M++1, 17), 519 (M
+, 45), 429 (33), 428 (100), 322 (24), 78 (9);
Elemental analysis calcd. for C36H29N3O: C 83.21, H 5.63, N 8.09, found C
83.12, H 5.67, N 7.91.
(E)-3-{1-[Methyl(phenethyl)amino]-3-
phenylindolizin-7-yl}-3-phenyl-1-
(pyridin-2-yl)prop-2-en-1-one (11aea).
Violet semisolid; Rf 0.57 (hexane/EtOAc,
6:4); IR (neat) ῦ 3056, 3023, 2934, 2840,
2790, 1655 (C=O), 1599, 1534, 1509, 1489, 1472, 1358, 1205, 1048, 1025,
995, 940, 802, 748, 697, 674; NMR data of the major rotamer: 1H RMN (300
MHz, CDCl3) δ 2.68–2.74 (m, 2H; CH2CH2N), 2.79 (s, 3H; CH3), 3.13–3.24
(m, 2H; CH2N), 6.54 (s, 1H; ArH), 6.86 (dd, J =7.8, 1.9, 1H; ArH), 7.03–7.61
(m, 17H; 17 × ArH), 7.75 (td, J = 7.7, 1.7, 1H; ArH), 8.00 (d, J =7.8, 1H;
ArH), 8.09 (d, J = 7.7, 1H; ArH), 8.14 (s, 1H; ArH), 8.66–8.73 (m, 1H; ArH);
selected NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 2.84
(s, 3H; CH3), 6.38 (dd, J =7.5, 1.9 Hz, 1H; ArH), 6.65 (s, 1H; ArH); NMR data
of the mixture of rotamers: 13
C NMR (75 MHz, CDCl3) δ 33.9, 34.0, 59.4,
59.9 (CH2), 42.3, 43.4 (CH3), 106.0, 106.5, 109.5, 113.9, 115.9, 119.9, 120.2,
121.3, 122.0, 122.6, 122.7, 125.9, 126.1, 126.2, 126.4, 127.6, 127.8, 127.9,
128.2, 128.3, 128.4, 128.8, 129.0, 129.1, 129.2, 129.7, 129.8, 136.9, 148.6,
148.7, 148.9 (CH), 124.2, 126.0, 126.3, 131.8, 134.6, 139.4, 139.9, 140.2,
155.8, 156.1 (ArC), 188.6, 189.0 (CO); MS m/z 534 (M++1, 20), 533 (M
+, 51),
443 (35), 442 (100), 427 (11), 206 (11), 78 (7); Elemental analysis calcd. for
C37H31N3O: C 83.27, H 5.86, N 7.87, found C 83.75, H 5.56, N 7.79.
(E)-3-{1-[Methyl(phenethyl)amino]-3-
phenylindolizin-7-yl}-3-phenyl-1-(pyridin-2-
yl)prop-2-en-1-one (11aaa). Orange solid; Rf
0.60 (hexane/EtOAc, 6:4); m.p. 137.1–139.9 ºC
(EtOH); IR (neat) ῦ 3055, 2928, 2848, 2789,
1655 (C=O), 1557, 1536, 1472, 1464, 1378,
Experimental Part
219
1360, 1343, 1203, 1048, 1024, 994, 762, 697; NMR data of the major rotamer: 1H RMN (300 MHz, CDCl3) δ 1.46–1.56 (m, 2H; CH2CH2CH2N), 1.58–1.73
(m, 4H; 2 × CH2CH2N), 2.93 (s, 4H; 2 × CH2N), 6.56 (s, 1H; ArH), 6.84 (dd, J
= 7.7, 1.8, 1H; ArH), 7.25–7.60 (m, 12H; 12 × ArH), 7.78 (dd, J = 7.7, 1.7,
1H; ArH), 8.00 (dt, J = 7.9, 1.0, 1H; ArH), 8.06–8.13 (m, 1H; ArH), 8.16 (s,
1H; CHCO), 8.69 (ddd, J = 4.8, 1.7, 0.8, 1H; ArH); selected NMR data of the
minor rotamer: 1H RMN (300 MHz, CDCl3) δ 6.33 (dd, J = 7.8 Hz, 1H; ArH),
6.62 (s, 1H; ArH); NMR data of the mixture of rotamers: 13
C NMR (75 MHz,
CDCl3) δ 24.4, 26.1, 29.8, 54.7 (CH2), 106.0, 109.6, 115.9, 121.3, 122.2,
122.6, 122.7, 126.3, 126.4, 126.5, 127.5, 127.6, 127.8, 127.9, 128.1, 128.4,
128.7, 129.0, 129.1, 129.2, 129.6, 129.7, 136.9, 148.6, 148.8 (CH), 131.9,
136.1, 139.5, 155.6, 155.8, 156.2 (ArC), 188.7 (CO); MS m/z 484 (M++1, 40),
483 (M+, 100), 413 (5), 377 (7), 242 (6), 227 (5), 78 (5); Elemental analysis
calcd. for C33H29N3O: C 81.96, H 6.04, N 8.69, found C 81.66, H 6.15, N 8.80.
(E)-3-[1-(Dibutylamino)-3-phenylindolizin-
7-yl]-3-phenyl-1-(pyridin-2-yl)prop-2-en-1-
one (11aba). Violet semisolid; Rf 0.71
(hexane/EtOAc, 6:4); IR (neat) ῦ 3060, 2956,
2929, 2869, 1671 (C=O), 1625, 1596, 1561,
1516, 1489, 1466, 1363, 1298, 1272, 1241, 1206, 1048, 1025, 994, 921, 767,
697; NMR data of the major rotamer: 1H NMR (400 MHz, CDCl3) δ 0.84 (t, J
= 7.3, 6H; 2 × CH3), 1.11–1.24 (m, 4H; 2 × CH2CH2CH2N), 1.29–1.45 (m,
4H; 2 × CH2CH2N), 2.93 (t, J = 7.5, 4H; 2 × CH2N), 6.51 (s, 1H; ArH), 6.88
(dd, J = 7.8, 2.0, 1H; ArH), 7.19–7.63 (m, 12H; 12 × ArH), 7.73–7.80 (m, 1H;
ArH), 8.00 (dt, J = 7.9, 1.1, 1H; ArH), 8.07 (d, J = 7.8, 1H; ArH), 8.13 (s, 1H;
ArH), 8.69 (ddd, J = 4.8, 1.7, 0.9, 1H; ArH); NMR data of the minor rotamer: 1H NMR (400 MHz, CDCl3) δ 6.40 (d, J = 6.9 Hz, 1H; ArH), 6.62 (s, 1H;
ArH), 8.16 (dd, J = 7.9, 0.9 Hz, 1H; ArH); NMR data of the mixture of
rotamers: 13
C NMR (101 MHz, CDCl3) δ 14.2 (CH3), 20.4, 20.5, 30.3, 55.3,
56.1 (CH2), 93.7, 106.7, 109.2, 115.5, 121.3, 122.2, 122.6, 122.7, 123.3, 126.2,
126.4, 126.5, 126.6, 127.5, 127.6, 127.9, 128.2, 128.4, 128.7, 129.0, 129.1,
129.6, 129.7, 130.1, 132.8, 136.9, 137.2, 148.6, 148.8, 149.4 (CH), 125.4,
Experimental Part
220
126.1, 126.3, 131.9, 134.2, 139.6, 149.9, 155.9, 156.3 (ArC), 188.5 (CO); MS
(DIP) m/z 528 (M++1, 41), 527 (M
+, 100), 470 (14), 442 (11), 427 (11), 322
(11), 321 (12), 206 (10), 78 (7); Elemental analysis calcd. for C36H37N3O: C
81.94, H 7.07, N 7.96, found C 81.67, H 6.96, N 7.87.
(E)-3-{1-[Methyl(phenyl)amino]-3-
phenylindolizin-7-yl}-3-phenyl-1-
(pyridin-2-yl)prop-2-en-1-one (11afa).
Purple solid; Rf 0.28 (hexane/EtOAc, 3:7);
m.p. 125.6–128.8 ºC (EtOH); IR (neat) ῦ
3060, 3049, 2994, 2870, 1662 (C=O), 1596, 1492, 1212, 1025, 748, 693; NMR
data of the major rotamer: 1H NMR (300 MHz, CDCl3) δ 3.28 (s, 3H; CH3),
6.78 (d, J = 8.1 Hz, 2H; 2 × ArH), 6.81 (s, 1H; ArH), 6.86 (dd, J = 7.7, 2.0 Hz,
1H; ArH), 7.09–7.24 (m, 5H; 5 × ArH), 7.34–7.54 (m, 8H; 8 × ArH), 7.61 (m,
2H; 2× ArH), 7.78 (td, J = 7.8, 1.7 Hz, 1H; ArH), 8.00 (dt, J = 7.9, 1.0 Hz, 1H;
ArH), 8.11 (s, 1H; ArH), 8.24 (dd, J = 7.7, 0.6 Hz, 1H; ArH), 8.71 (ddd, J =
4.7, 1.7, 0.9 Hz, 1H; ArH); selected NMR data of the minor rotamer: 1H NMR
(300 MHz, CDCl3) δ 3.28 (s, 3H; CH3), 6.45 (dd, J = 7.4, 1.9 Hz, 1H; ArH),
8.03 (dt, J = 7.9, 1.1 Hz, 1H; ArH); NMR data of the mixture of rotamers: 13
C
NMR (75 MHz, CDCl3) δ 40.9 (CH3), 110.2, 112.5, 113.4, 113.9, 114.1,
117.1, 117.8, 118.1, 120.0, 120.5, 121.1, 121.9, 122.5, 122.7, 122.8, 126.5,
126.6, 127.5, 127.8, 128.0, 128.1, 128.2, 128.4, 128.8, 128.9, 129.1, 129.2,
129.5, 129.8, 136.9 (CH), 126.2, 127.7, 127.8, 129.1, 131.7, 132.1, 138.9,
141.8, 148.7, 148.8, 149.7, 155.6, 155.9 (ArC), 189.2, 189.7 (CO); MS (DIP)
m/z 506 (M++1, 39), 505 (M
+, 100), 491 (12), 490 (29), 252 (11), 230 (12), 78
(12), 77 (13); Elemental analysis calcd. for C35H27N3O: C 82.14, H 5.38, N
8.31, found C 82.31, H 5.49, N 8.08.
(E)-3-{5-Methyl-1-
[methyl(phenyl)amino]-3-
phenylindolizin-7-yl}-1-(6-
methylpyridin-2-yl)-3-phenylprop-2-en-
1-one (11cfa). Purple solid; Rf 0.22
Experimental Part
221
(hexane/EtOAc, 8:2); m.p. 127.1–134.9 ºC; IR (neat) ῦ 3050, 2915, 2869,
1652 (C=O), 1543, 1496, 1293, 1267, 1049, 772, 748, 694; NMR data of the
major rotamer: 1H NMR (300 MHz, CDCl3) δ 2.15 (s, 3H; CH3), 2.62 (s, 3H;
CH3), 3.26 (s, 3H; CH3), 6.56 (s, 1H; ArH), 6.65 (s, 1H; ArH), 6.73 (d, J = 8.7
Hz, 2H; 2 × ArH), 7.03–7.25 (m, 7H; 7 × ArH), 7.30–7.50 (m, 8H; 8 × ArH),
7.63 (t, J = 7.7 Hz, 1H; ArH), 7.66 (d, J = 7.0 Hz, 1H; ArH), 8.05 (s, 1H;
ArH); NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 2.08,
2.58, 3.26 (3s, 9H; 3 × CH3), 6.19 (s, 1H; ArH), 6.62 (s, 1H; ArH); NMR data
of the mixture of rotamers: 13
C NMR (75 MHz, CDCl3) δ 23.0, 23.2, 24.5,
24.6, 40.8, 40.9 (CH3), 111.4, 113.3, 113.9, 114.9, 115.2, 115.4, 116.7, 117.5,
117.9, 118.3, 118.4, 119.8, 119.9, 121.7, 126.1, 127.1, 127.3, 127.6, 127.9,
128.0, 128.1, 128.2, 128.8, 128.9, 129.3, 129.5, 129.6, 130.9, 131.1, 137.0
(CH), 124.7, 126.7, 127.2, 129.1, 129.2, 129.4, 134.3, 135.0, 135.4, 139.1,
149.8, 155.0, 155.1, 155.8, 156.4, 157.6 (ArC), 189.6 (CO); MS (DIP) m/z 534
(M++1, 40), 533 (M
+, 100), 518 (12), 416 (10), 397 (6), 266 (11), 251 (12), 92
(21); Elemental analysis calcd. for C37H31N3O: C 83.27, H 5.86, N 7.87, found
C 83.41, H 5.72, N 7.88.
(E)-3-{1-[Bis(4-
methoxyphenyl)amino]-3-
phenylindolizin-7-yl}-3-phenyl-1-
(pyridin-2-yl)prop-2-en-1-one
(11aha). Dark solid; Rf 0.58
(hexane/EtOAc, 6:4); m.p. 95.3–
96.7 ºC; IR (neat) ῦ 3054, 2953,
2927, 2854, 2833, 1656 (C=O), 1599, 1500, 1467, 1235, 1027, 823, 730, 697;
NMR data of the major rotamer: 1H NMR (300 MHz, CDCl3) δ 3.78 (s, 6H; 2
× CH3), 6.65–6.74 (m, 5H; 5 × ArH), 6.86–7.02 (m, 7H; 7 × ArH), 7.25–7.41
(m, 6H; 6 × ArH), 7.47 (t, J = 7.5 Hz, 2H; 2 × ArH), 7.55–7.60 (m, 2H; 2 ×
ArH), 7.71–7.83 (m, 1H; ArH), 7.95 (d, J = 7.9 Hz, 1H; ArH), 8.05 (s, 1H;
ArH), 8.17 (d, J = 7.7 Hz, 1H; ArH), 8.67 (dd, J = 4.7, 0.7 Hz, 1H; ArH);
selected NMR data of the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 3.73
(s, 3H; CH3), 6.42 (dd, J = 7.5, 1.6 Hz, 1H; ArH), 8.01 (d, J = 7.9 Hz, 1H;
Experimental Part
222
ArH); NMR data of the mixture of rotamers: 13
C NMR (75 MHz, CDCl3) δ
55.6 (CH3), 109.4, 111.7, 114.4, 114.5, 116.9, 121.8, 122.4, 122.7, 122.8,
123.3, 126.3, 126.5, 127.6, 127.7, 127.9, 128.1, 128.3, 128.8, 129.1, 129.2,
129.6, 136.9, 137.0, 148.6 (CH), 126.4, 127.8, 131.6, 138.8, 141.7, 154.7,
155.6, 155.7 (ArC), 188.9 (CO); MS (DIP) m/z 628 (M++1, 44), 627 (M
+,
100), 313 (30), 299 (9), 78 (6); Elemental analysis calcd. for C42H33N3O3: C
84.36, H 5.30, N 6.69, found C 84.61, H 5.69, N 6.79.
(E)-3-{5-Methyl-1-
[methyl(phenyl)amino]-3-phenylindolizin-
7-yl}-1-(6-methylpyridin-2-yl)-3-
phenylprop-2-en-1-one (11aia). Dark solid;
Rf 0.58 (hexane/EtOAc, 6:4); m.p. 95.3–96.7
ºC; IR (neat) ῦ 3054, 2953, 2927, 2854, 2833, 1656 (C=O), 1599, 1500, 1467,
1235, 1027, 823, 730, 697; NMR data of the major rotamer: 1H NMR (300
MHz, CDCl3) δ 1.33 (d, J = 6.8 Hz, 3H; CH3), 3.88, 4.03 (AB system, J = 14.2
Hz, 2H; CH2), 4.26 (q, J = 6.8 Hz, 1H; CHCH3), 6.64 (s, 1H; ArH), 6.91 (dd, J
= 7.7, 2.0 Hz, 1H; ArH), 7.07–7.53 (m, 21H; 21 × ArH), 7.80 (td, J = 7.7, 1.7
Hz, 1H; ArH), 8.04 (d, J = 7.8 Hz, 1H; ArH), 8.10 (d, J = 7.6 Hz, 1H; ArH),
8.16 (s, 1H; ArH), 8.71 (dd, J = 4.8, 0.8 Hz, 1H; ArH); selected NMR data of
the minor rotamer: 1H NMR (300 MHz, CDCl3) δ 3.73 (s, 3H; CH3), 6.35 (dd,
J = 7.3, 1.8 Hz, 1H; ArH), 6.60 (s, 1H; ArH), 8.01 (d, J = 7.9 Hz, 1H; ArH);
NMR data of the mixture of rotamers: 13
C NMR (75 MHz, CDCl3) δ 18.5
(CH3), 55.3 (CH2), 63.3, 109.2, 111.4, 116.3, 121.8, 122.4, 122.7, 126.4,
126.5, 127.5, 127.7, 127.8, 127.9, 128.1, 128.3, 128.4, 128.5, 129.0, 129.1,
137.0, 148.6 (CH), 126.0, 127.6, 129.4, 130.4, 132.0, 139.6, 140.0, 143.7,
155.7, 156.1 (ArC), 188.9 (CO); MS (DIP) m/z 628 (M++1, 44), 627 (M
+,
100), 313 (30), 299 (9), 78 (6); Elemental analysis calcd. for C43H35N3O: C
84.07, H 5.79, N 6.89, found C 84.17, H 5.92, N 6.79.
Experimental Part
223
EXPERIMENTAL PART OF CHAPTER IV
General procedure for the obtention of nitrosocompounds 15.
The corresponding amine (1 mmol) was dissolved in CH2Cl2 and added
to a solution of Oxone in H2O or to a solution of m-chloroperbonzoic acid in
CH2Cl2. After completion of the reaction, the crude was extracted with
CH2Cl2, dried with MgSO4 and evaporated under vacuum. The
nitrosocompounds were used without further purification in the next step.
General procedure for the synthesis of β-enaminones 16.
The indolizine 4 (0.3 mmol) was dissolved in MeCN in the reactor
tube, followed by the addition of ArNO 15 (0.3 mmol) and stirring at ambient
temperature overnight. The solvent was removed under vacuum. Purification
of the reaction crude by column chromatography (silica gel, hexane/EtOAc)
afforded the pure β-enaminones 16.
(Z)-3-Phenyl-3-(phenylamino)-1-(pyridin-2-yl)prop-2-
en-1-one (16agaa): yellow solid, m.p. 110.3–113.8 (74.6
mg, 83%); tR 19.26; Rf 0.46 (hexane/EtOAc, 8:2); IR
(neat) ν 3064, 3026, 2989, 2921, 1604, 1590, 1560, 1477,
1331, 1222, 1057, 766, 744; 1H NMR (300 MHz, CDCl3) δ 6.82 (d, J = 8.3
Hz, 1H; ArH), 6.86 (s, 1H; ArH), 6.97- 7.03 (m, 1H; ArH), 7.10-7.16 (m, 2H;
ArH), 7.28-7.45 (m, 6H; ArH), 7.83 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.18 (dt, J
= 7.9, 1.1 Hz, 1H; ArH), 8.64 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.93 (s ,
1H); 13
C NMR (75 MHz, CDCl3) δ 96.4, 121.7, 123.3, 124.3, 125.5, 128.4,
128.5, 128.7, 129.6, 136.8, 148.6 (15 × ArCH), 135.6, 139.4, 155.7, 162.5,
187.8 (5 × ArC); MS (EI) m/z 301 (M+
+ H, 11), 300 (M+, 50), 271 (44), 223
(19), 222 (100), 195 (34), 194 (86), 193 (18), 180 (41), 165 (10), 107 (11), 79
(42), 78 (29), 77 (32); HRMS (ESI) m/z: [M + H]+ Calcd for C20H16N2O
300.1263; Found 300.1257.
(Z)-3-(Phenylamino)-1-(pyridin-2-yl)-3-(p-
tolyl)prop-2-en-1-one (16agba): yellow solid, m.p.
Experimental Part
224
95.1 – 95.9 (94 mg, 88%); tR 21.31; Rf 0.40 (hexane/EtOAc, 8:2); IR (neat) ν
3052, 3027, 2973, 2919, 1560, 1517, 1482, 1330, 1220, 1057, 815, 746, 690; 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H; CH3), 6.84 (d, J = 7.4 Hz, 2H;
ArH), 6.84 (s, 1H; ArH), 7.01 (t, J = 7.4 Hz, 1H; ArH), 7.11- 7.18 (m, 3H,
ArH), 7.29-7.40 (m, 4H, ArH) 7.84 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.17 (dt, J
= 7.8 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.92 (s, 1H); 13
C NMR (75 MHz, CDCl3) δ 21.4 (CH3), 96.2, 121.7, 123.3, 124.2, 125.5,
128.4, 128.5, 128.7, 129.1, 136.9, 148.6 (15 × ArCH), 132.6, 135.6,
(139.6),139.9, 155.9, 162.9, 187.6 (5 × ArC); MS (EI) m/z 315 (M+ + H, 12),
314 (M+, 52), 313 (10), 285 (36), 237 (18), 236 (90), 222 (11), 209 (31), 208
(100), 207 (28), 194 (47), 79 (33), 78 (23), 77 (26); HRMS (ESI) m/z: [M +
H]+ Calcd for C21H18N2O 314.1419; Found 314.1418.
(Z)-3-(4-methoxyphenyl)-3-(phenylamino)-1-
(pyridin-2-yl)prop-2-en-1-one (16agca):
yellow solid, m.p. 135.2 – 136.7 (77 mg, 78%);
tR 25.88; Rf 0.27 (hexane/EtOAc, 8:2); IR (neat)
ν 3055, 3026, 2967, 2930, 1613, 1336, 1254, 1059, 1028, 745; 1H NMR (300
MHz, CDCl3) δ 3.82 (s, 3H; CH3), 6.81-6.87 (m, 5H; ArH), 6.99 – 7.04 (m,
1H; ArH), 7.14-7.19 (m, 2H; ArH), 7.36-7.41 (m, 3H; ArH), 7.84 (td, J = 7.7,
1.8 Hz, 1H; ArH), 8.17 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7,
0.9 Hz, 1H;ArH), 12.92 (s, 1H); 13
C NMR (100 MHz, CDCl3) δ 55.2 (CH3),
96.0, 113.8, 121.7, 123.3, 124.2, 125.4, 128.7, 130.1, 136.8, 148.6 (14 ×
ArCH), 127.7, 139.7, 155.9, 160.8, 162.4, 187.4 (6 × ArC); MS (EI) m/z 330
(M+, 24), 301 (15), 252 (44), 225 (26), 224 (100), 210 (41), 209 (34), 79 (38),
78 (35), 77 (44); HRMS (ESI) m/z: [M + H]+ Calcd for C21H18N2O2 330.1368;
Found 330.1355.
(Z)-3-(phenylamino)-1-(pyridin-2-yl)-3-(4-
(trifluoromethyl)phenyl)prop-2-en-1-one
(16agda): yellow solid, m.p. 133.8 – 136.4 (72
mg, 65%); tR 17.46; Rf 0.44 (hexane/EtOAc, 8:2);
IR (neat) ν 3060, 2943, 2923, 1598, 1560, 1322,
Experimental Part
225
1108, 1052, 831, 742, 698; 1H NMR (400 MHz, CDCl3) δ 6.81 (d, J = 7.6 Hz,
2H; ArH), 6.87 (s, 1H; ArH), 7.04 (t, J = 7.4 Hz, 1H; ArH), 7.15- 7.19 (m, 2H;
ArH), 7.40 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H; ArH), 7.55- 7.60 (m, 4H; ArH), 7.85
(td, J = 7.7, 1.7 Hz, 1H; ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J
= 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.81 (s, 1H); 13
C NMR (100 MHz, CDCl3) δ
96.9, 121.8, 123.4, 124.7, 125.4 (q, J =3.3 Hz), 125.8, 128.9, 129.0, 136.9,
148.7 (14 × ArCH), 123.7 (q, J = 272.2 Hz), 131.5 (q, J = 32.6 Hz), 138.9,
139.3, 155.3, 160.5, 188.2 (7 × ArC); MS (EI) m/z 368 (M+, 30), 349 (14), 340
(14), 339 (43), 291 (29), 290 (100), 263 (36), 262 (36), 261 (15), 248 (38), 208
(16), 207 (49), 191 (11), 107 (27), 79 (63), 78 (27), 77 (32); HRMS (ESI) m/z:
[M + H]+ Calcd for C21H15F3N2O 368.1136; Found 368.1140.
Methyl (Z)-4-(3-oxo-1-(phenylamino)-3-
(pyridin-2-yl)prop-1-en-1-yl)benzoate
(16agea): yellow solid, m.p. 112.8 – 113.1
(81.8 mg, 76%); Rf 0.29 (hexane/EtOAc, 8:2);
IR (neat) ν 3056, 2987, 2923, 1722, 1604,
1583, 1550, 1270, 1103, 1056, 746, 694; 1H NMR (300 MHz, CDCl3) δ 3.91
(s, 3H; CH3),6.80 (d, J = 7.6 Hz, 2H; ArH), 6.88 (s, 1H; ArH), 7.01 – 7.04 (m,
1H; ArH), 7.11- 7.16 (m, 2H; ArH), 7.39 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H; ArH),
7.51, 7.99 (AA’XX’ system, 4H; 4 × ArH), 7.84 (td, J = 7.7, 1.7 Hz, 1H;
ArH), 8.18 (dt, J = 7.9, 0.9 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.6, 0.8 Hz,
1H;ArH), 12.83 (s, 1H); 13
C NMR (75 MHz, CDCl3) δ 52.1 (CH3), 96.7,
121.8, 123.3, 124.5, 125.7, 128.5, 128.6, 128.8, 129.6, 136.9, 148.6 (14 ×
ArCH), 131.0, 139.0, 140.0, 155.4, 161.0, 166.3, 188.1 (7 × ArC); MS (EI)
m/z 359 (M+
+ H, 15), 358 (M+, 61), 330 (16), 329 (60), 281 (24), 280 (100),
266 (21), 253 (46), 252 (84), 251 (15), 239 (10), 238 (54), 221 (10), 220 (26),
193 (17), 192 (13), 191 (11), 169 (11), 165 (13), 107 (32), 106 (14), 79 (87),
78 (46), 77 (41); HRMS (ESI) m/z: [M + H]+ Calcd for C22H18N2O3 358.1317;
Found 358.1315.
(Z)-1-(6-methylpyridin-2-yl)-3-phenyl-3-
(phenylamino)prop-2-en-1-one (16cgaa): yellow solid,
Experimental Part
226
m.p. 126.5 – 127.8 (66 mg, 70%); tR 21.31; Rf 30.50 (hexane/EtOAc, 8:2); IR
(neat) ν 3057, 3026, 2921, 2852, 1606, 1560, 1479, 1328, 1218, 1063, 759,
696; 1H NMR (400 MHz, CDCl3) δ 2.60 (s, 3H; CH3), 6.81 (d, J = 7.5 Hz, 2H;
ArH),6.87 (s, 1H; ArH), 7.00 (t, J = 7.4 Hz, 1H; ArH), 7.11-7.15 (m, 2H;
ArH), 7.24 (d, J = 7.6 Hz, 1H; ArH), 7.31-7.41 (m, 3H; ArH), 7.43-7.45 (m,
2H; ArH), 7.71 (t, J = 7.7 Hz, 1H; ArH), 7.96 (d, J = 7.7 Hz, 1H; ArH), 12.93
(s, 1H); 13
C NMR (100 MHz, CDCl3) δ 24.6 (CH3), 96.5, 118.8, 123.2, 124.2,
125.2, 128.4, 128.5, 128.7, 129.6, 136.9 (14 × ArCH), 135.8, 139.5, 155.2,
157.5, 162.3, 188.3 (6 × ArC); MS (EI) m/z 314 (M+, 34), 286 (15), 285 (37),
223 (17), 222 (100), 209 (41), 207 (41), 194 (28), 193 (16), 180 (28), 165
(12),121 (14), 93 (59), 92 (26), 77 (39); HRMS (ESI) m/z: [M + H]+ Calcd for
C21H18N2O 314.1419; Found 314.1397.
(Z)-1-(6-(4-(methylsulfonyl)phenyl)pyridin-2-yl)-3-
phenyl-3-(phenylamino)prop-2-en-1-one (16dgaa):
yellow solid, m.p. 165.7 – 168.3 (38 mg, 28%); Rf 0.32
(hexane/EtOAc, 6:4); IR (neat) ν 3015, 2968, 2918, 2850,
1607, 1592, 1557, 1478, 1314, 1224, 1148, 1081, 950,
799, 763, 701; Seleted data for the major rotamer: 1H
NMR (400 MHz, CDCl3) δ 3.06 (s, 3H; CH3), 6.41 (s, 1H;
ArH), 6.82 – 6.86 (m, 2H; ArH), 7.01 – 7.05 (m,
1H,ArH), 7.13 – 7.19 (m, 3H; ArH), 7.35 – 7.53 (m, H; ArH), 7.75 – 7.84 (m,
2H; ArH), 7.88 – 7.91 (m, 2H; ArH), 7.95 – 8.01 (m, 4H; ArH), 8.04 – 8.06
(m, 1H; ArH), 8.25 – 8.28 (m, 1H; ArH), 12.73 (s, 1H); 13
C NMR (100 MHz,
CDCl3) δ 44.5 (CH3), 97.4, 121.3, 123.4, 124.4, 127.4, 127.8, 127.9, 128.5,
128.8, 131.6, 137.9 (18 × ArCH), 139.6, 139.9, 140.8, 143.7, 154.1, 155.0,
158.5, 190.4 (8 × ArC); Seleted data for the minor rotamer: 1H NMR (400
MHz, CDCl3) δ 3.08 (s; CH3), 6.99 (s; ArH), 8.22 (dd, J = 7.7; ArH), 12.99 (s,
1H); 13
C NMR (100 MHz, CDCl3) δ 44.6 (CH3), 96.3, 122.8, 123.3, 124.5,
127.9, 128.6, 129.9, 138.1 (ArCH), 133.7, 139.3, 140.6, 144.1, 153.9, 155.9,
162.8, 187.3 (ArC); MS (DIP) m/z 454 (M+, 22), 425 (17), 350 (18), 349 (74),
270 (10), 234 (16), 233 (100), 223 (12), 222 (78), 194 (45), 193 (12), 180 (28),
Experimental Part
227
154 (14), 153 (13), 77 (28); HRMS (ESI) m/z: [M + H]+ Calcd for
C27H22N2O3S 454.1351; Found 454.1344.
(Z)-1-(4-((E)-3-oxo-1-phenyl-3-(pyridin-
2-yl)prop-1-en-1-yl)pyridin-2-yl)-3-
phenyl-3-(phenylamino)prop-2-en-1-one
(16aga’): yellow solid (652 mg, 64%,
scale 2 mmol); Rf 0.56 (hexane/EtOAc, 6:4); IR (neat) ν 3057, 2973, 2895,
1667, 1562, 1482, 1327, 1217, 1047, 877, 805, 754, 691; Seleted data for the
major rotamer: 1H NMR (400 MHz, CDCl3) δ 6.78 – 6.82 (m, 2H; ArH), 6.91
(s, 1H; ArH), 6.95 – 7.02 (m, 2H; ArH), 7.07 – 7.13 (m, 4H; ArH), 7.19 – 7.26
(m, 2H; ArH), 7.28 – 7.48 (m, 8H; ArH), 7.81 (td, J = 7.7, 1.7 Hz, 1H; ArH),
7.99 (dt, J = 7.8, 1.0 Hz, 1H; ArH), 8.06 (d, J = 0.9 Hz, 1H; ArH), 8.25 (s, 1H;
ArH), 8.69 – 8.72 (m, 2H; ArH), 12.92 (s , 1H); Seleted data for the minor
rotamer: 1H NMR (400 MHz, CDCl3) δ 6.86 (s; ArH), 8.00 (dt, J = 7.8, 1.0
Hz; ArH), 8.18 (s, ArH) 8.29 (d, J = 1.2 Hz; ArH), 8.63 (dd, J = 5.1, 0.5 Hz;
ArH); NMR data for the mixture of rotamers:13
C NMR (101 MHz, CDCl3) δ
96.7, 96.8, 120.6, 120.7, 121.8, 112.2, 122.8, 123.3, 123.4, 124.3, 124.5,
124.6, 124.8, 125.9, 127.0, 127.1, 127.9, 128.5, 128.6, 128.7, 128.8, 128.9,
129.4, 129.8, 129.9, 130.1, 130.2, 137.1, 148.6, 148.9, 149.0, 149.1 (24 × CH),
135.6, 135.7, 137.9, 139.4, 139.5, 139.8, 149.4, 150.0, 153.7, 154.1, 154.5,
154.6, 155.8, 156.3, 162.6, 162.9, 187.4, 187.6, 189.1, 190.1 (10 × ArC); MS
(EI) m/z 507 (M+, 8), 415 (13), 402 (18), 401 (25), 287 (11), 286 (48), 222
(37), 194 (13), 193 (10), 180 (33), 78 (13), 77 (20), 44 (100); HRMS (ESI)
m/z: [M + H]+ Calcd for C34H25N3O2 507.1947; Found 507.2007.
(Z)-3-phenyl-1-(pyridin-2-yl)-3-(p-
tolylamino)prop-2-en-1-one (16agab): yellow
solid, m.p. 147.5 – 148.3 (43 mg, 46%); tR 21.26; Rf
0.44 (hexane/EtOAc, 8:2); IR (neat) ν 3041, 2997,
2913, 1593, 1558, 1477, 1332, 1223, 1061, 914, 744,
698; 1H NMR (300 MHz, CDCl3) δ 2.25 (s, 3H; CH3), 6.72 (d, J = 8.4 Hz, 2H;
ArH), 6.81 (s, 1H; ArH), 6.94 (d, J = 8.2 Hz, 2H; ArH), 7.29 – 7.45 (m, 6H;
Experimental Part
228
ArH), 7.87 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.19 (d, J = 7.9 Hz, 1H; ArH), 8.66
(d, J = 4.4 Hz, 1H;ArH), 12.95 (s, 1H); 13
C NMR (75 MHz, CDCl3) δ 20.8
(CH3), 95.9, 121.7, 123.2, 125.4, 127.4, 128.3, 128.4, 128.5, 128.6, 129.3,
129.5, 136.7, 148.6 (14 × ArCH), 134.0, 135.7, 136.8, 155.8, 162.8, 187.4 (6 ×
ArC); MS (EI) m/z 314 (M+, 30), 253 (24), 236 (100), 195 (36), 194 (66), 193
(29), 133 (19), 104 (41), 78 (49), 77 (19); HRMS (ESI) m/z: [M + H]+ Calcd
for C21H18N2O 314.1419; Found 314.1400.
(Z)-3-((4-acetylphenyl)amino)-3-phenyl-1-
(pyridin-2-yl)prop-2-en-1-one (16agac): yellow
solid, m.p. 146.8 – 151.1 (65 mg, 63%); tR 32.45;
Rf 0.17 (hexane/EtOAc, 8:2); IR (neat) ν 3062,
3001, 2923, 1670, 1587, 1547, 1475, 1336, 1269,
1059, 856, 796, 754, 694; 1H NMR (300 MHz,
CDCl3) δ 2.50 (s, 3H; CH3), 6.80 – 6.83 (m, 2H; ArH), 6.97 (s, 1H; ArH), 7.33
– 7.47 (m, 7H; ArH), 7.72 – 7.76 (m, 2H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H;
ArH), 8.18 (dd, J = 7.9, 0.9 Hz, 1H; ArH), 8.66 (ddd, J = 4.7, 1.6, 0.8 Hz,
1H;ArH), 12.86 (s , 1H); 13
C NMR (75 MHz, CDCl3) δ 26.3 (CH3), 98.3,
121.7, 121.9, 125.9, 128.2, 128.7, 129.3, 130.1, 136.9, 148.7 (14 × ArCH),
132.2, 135.2, 144.0, 155.2, 160.9, 188.6, 196.7 (7 × ArC); MS (EI) m/z 343
(M+, 10), 342 (28), 313 (36), 236 (43), 222 (100), 194 (61), 135 (26), 79 (35),
78 (45); HRMS (ESI) m/z: [M + H]+ Calcd for C22H18N2O2 342.1368; Found
342.1361.
(Z)-3-((4-(dimethylamino)phenyl)amino)-3-
phenyl-1-(pyridin-2-yl)prop-2-en-1-one
(16agad): brown oil (64 mg, 62%); Rf 0.25
(hexane/EtOAc, 8:2); IR (neat) ν 2989, 2919,
2859, 1601, 1519, 1361, 1331, 1226, 1114, 1062,
817, 727; 1H NMR (300 MHz, CDCl3) δ 2.87 (s,
6H; 2 x CH3), 6.48 – 6.52 (m, 2H; ArH), 6.75 (s, 1H; ArH), 6.72 – 6.75 (m,
2H; ArH), 7.25 – 7.44 (m, 6H; ArH), 7.83 (td, J = 7.7, 1.6 Hz, 1H; ArH), 8.18
(d, J = 7.9 Hz, 1H; ArH), 8.63 (d, J = 4.1 Hz, 1H;ArH), 13.05 (s , 1H); 13
C
Experimental Part
229
NMR (75 MHz, CDCl3) δ 40.6 (2 x CH3), 94.9, 112.5, 121.6, 124.7, 125.2,
128.3, 128.6, 129.4, 136.8, 148.6 (14 × ArCH), 128.5, 135.8, 147.8, 156.1,
163.2, 186.6 (6 × ArC); MS (DIP) m/z 344 (M+ + H, 25), 343 (M
+, 100), 265
(13), 249 (16), 237 (18), 224 (15), 223 (83), 222 (19), 208 (21), 195 (23), 193
(12), 135 (16), 134 (21), 105 (10), 78 (20); HRMS (ESI) m/z: [M + H]+ Calcd
for C22H21N3O 343.1685; Found 343.1681.
(Z)-3-((4-bromophenyl)amino)-3-phenyl-1-
(pyridin-2-yl)prop-2-en-1-one (16agae): yellow
solid, m.p. 149.7 – 152.1 (77 mg, 68%); tR 26.64;
Rf 0.52 (hexane/EtOAc, 8:2); IR (neat) ν 3042,
2995, 2918, 1596, 1552, 1475, 1330, 1279, 1221,
1057, 819, 746, 699; 1H NMR (300 MHz, CDCl3)
δ 6.68, 7.24 (system AA’XX’, J = 8.8 Hz, 4H; 4 × ArH), 6.88 (s, 1H; ArH),
7.34 – 7.43 (m, 6H; ArH), 7.85 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.17 (dt, J =
7.9, 1.0 Hz, 1H; ArH), 8.65 (ddd, J = 4.7, 1.7, 0.9 Hz, 1H;ArH), 12.83 (s, 1H); 13
C NMR (75 MHz, CDCl3) δ 97.1, 121.9, 124.7, 125.9, 128.6, 128.8, 130.1,
131.9, 137.1, 148.8 (14 × ArCH), 117.4, 135.3, 138.8, 155.6, 162.2, 188.3 (6 ×
ArC); MS (EI) m/z 378 (M+, 10), 299 (14), 281 (10), 271 (10), 260 (17), 257
(17), 221 (15), 208 (22), 207 (39), 195 (13), 193 (52), 192 (12), 191 (14), 165
(16), 156 (13), 154 (14), 107 (20), 102 (11), 79 (100), 78 (66), 77 (26), 76
(23); HRMS (ESI) m/z: [M + H]+ Calcd for C20H15BrN2O 378.0368; Found
378.0370.
(Z)-3-phenyl-1-(pyridin-2-yl)-3-(o-tolylamino)prop-
2-en-1-one (16agaf): yellow solid, m.p. 98.2 – 99.7
(58 mg, 62%); tR 19.97; Rf 0.4 (hexane/EtOAc, 8:2); IR
(neat) ν 3061, 3022, 2979, 2904, 1649, 1616, 1560,
1459, 1336, 1232, 1063, 831, 744, 698; 1H NMR (300
MHz, CDCl3) δ 2.48 (s, 3H; CH3), 6.53 (d, J = 7.8 Hz, 1H; ArH), 6.84 (td, J
=7.7, 1.2,1H;ArH), 6.88 (s, 1H; ArH), 6.95 (td, J = 7.4, 1.1 Hz, 1H; ArH),
7.18 (d, J = 7.2 Hz, 1H; ArH),7.26- 7.40 (m, 6H; ArH), 7.82 (td, J = 7.7, 1.7
Hz, 1H; ArH), 8.19 (d, J = 7.9 Hz, 1H; ArH), 8.64 (dd, J = 4.7, 0.8 Hz,
Experimental Part
230
1H;ArH), 12.90 (s , 1H); 13
C NMR (75 MHz, CDCl3) δ 18.3 (CH3), 96.1,
121.7, 124.8, 125.0, 125.4, 125.9, 128.2, 128.3, 129.6, 130.5, 136.8, 148.6 (14
× ArCH), 131.1, 135.7, 138.1, 155.8, 163.4, 187.7 (6 × ArC); MS (EI) m/z 314
(M+, 36), 236 (85), 209 (37), 208 (100), 194 (61), 193 (31), 79 (57), 78 (34);
HRMS (ESI) m/z: [M + H]+ Calcd for C21H18N2O 314.1419; Found 314.1414.
(Z)-3-((2-bromophenyl)amino)-3-phenyl-1-(pyridin-
2-yl)prop-2-en-1-one (16agag): yellow oil (84 mg,
74%); tR 23.42; Rf 0.28 (hexane/EtOAc, 8:2); IR (neat)
ν 3058, 3027, 2925, 2852, 1590, 1556, 1457, 1326,
1282, 1215, 1059, 994, 746, 697; 1H NMR (300 MHz,
CDCl3) δ 6.53 (dd, J = 7.6, 2.0 Hz, 1H; ArH), 6.90 (qd,
J = ¿?, 2H; ArH), 7.0 (s, 1H; ArH), 7.27 – 746 (m, 1H; ArH), 7.60 (dd, J =
7.6, 1.9 Hz, 1H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.25 (d, J = 7.9 Hz,
1H; ArH), 8.68 (ddd, J = 4.6, 1.6, 0.8 Hz, 1H;ArH), 12.77 (s , 1H); 13
C NMR
(75 MHz, CDCl3) 97.8, 117.4, 125.5, 125.9, 127.3, 128.6, 128.7, 130.1, 133.1,
135.6, 137.4, 148.3 (14 × ArCH), , 122.4, 135.6, 138.6, 161.8, 188.0 (6 ×
ArC); MS (EI) m/z 380 (M+ 81
Br, 23), 378 (M+ 79
Br, 26), 351 (11), 349 (19),
302 (40), 301 (13), 300 (47), 299 (100), 274 (25), 273 (12), 272 (28), 271 (27),
260 (35), 258 (28), 222 (12), 221 (59), 220 (16), 209 (13), 208 (39), 207 (32),
195 (70), 193 (72), 165 (28), 154 (13), 107 (33), 106 (17), 80 (12), 79 (79), 77
(13), 76 (13), 75 (12); HRMS (ESI) m/z: [M + H]+ Calcd for C20H15BrN2O
378.0368; Found 378.0371.
(Z)-2-((3-oxo-1-phenyl-3-(pyridin-2-yl)prop-1-en-1-
yl)amino)benzonitrile (16agah): yellow solid, m.p.
142.1 – 144.3 (34 mg, 35%); tR 19.31; Rf 0.44
(hexane/EtOAc, 8:2); IR (neat) ν 3064, 3026, 2989,
2921, 1604, 1590, 1560, 1477, 1330, 1211, 1056, 766,
744, 700; 1H NMR (300 MHz, CDCl3) δ 6.80 – 6.84
(m, 2H; ArH), 6.85 (s, 1H; ArH), 6.98 – 7.02 (m, 1H; ArH), 7.11 – 7.17(m,
2H; ArH), 7.29 – 7.46 (m, 6H; ArH), 7.86 (td, J = 7.7, 1.7 Hz, 1H; ArH), 8.19
(d, J = 7.9 Hz, 1H; ArH), 8.66 (d, J = 4.6 Hz, 1H;ArH), 12.94 (s , 1H); 13
C
Experimental Part
231
NMR (75 MHz, CDCl3) δ 96.4, 121.8, 123.3, 124.3, 125.6, 128.4, 128.5,
128.7, 129.7, 137.1, 148.4 (14 × ArCH), 115.1, 117.9, 135.5, 139.3, 155.5,
162.7, 187.4 (7 × ArC); MS (EI) m/z 326 (M+ + H, 0.6), 300 (46), 271 (41),
222 (100), 195 (36), 194 (91), 193 (24), 180 (48), 165 (12), 79 (49), 78 (35),
77 (42); HRMS (ESI) m/z: [M - CN]+ Calcd for C20H15N2O 299.1184; found
299.1182.
(Z)-3-((4-(dimethylamino)phenyl)amino)-1-
(pyridin-2-yl)hept-2-en-1-one (16agid): brown
oil (58 mg, 60%); tR 23.27; Rf 0.32
(hexane/EtOAc, 8:2); IR (neat) ν 3057, 2952,
2925, 2864, 1579, 1547, 1502, 1344, 1301, 1211,
1108, 829, 796, 761; 1H NMR (300 MHz, CDCl3)
δ 0.83 (t, J = 7.3 Hz, 3H; CH3), 1.23-1.35 (m, 2H; CH2), 1.51 – 1.61 (m, 2H;
CH2), 2.37 – 2.42 (m, 2H; CH2), 2.96 (s, 6H; CH3), 6.58 (s, 1H; ArH), 6.68 –
6.75 (m, 2H; ArH), 7.03 – 7.08 (m, 2H; ArH), 7.16 – 7.39 (m, 7H; ArH), 7.81
(td, J = 7.7, 1.7 Hz, 1H; ArH), 8.15 (d, J = 7.9 Hz, 1H; ArH), 8.65 (d, J = 4.0
Hz, 1H;ArH), 13.01 (s, 1H); 13
C NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.7,
30.7, 32.2 (3 x CH2), 40.7 (2 x CH3), 91.5, 112.7, 121.7, 125.1, 126.7, 136.9,
148.6 (9 × ArCH), 127.3, 149.2, 156.6, 169.9, 185.8 (5 × ArC); MS (EI) m/z
324 (M+ + H, 36), 323 (M
+, 100), 203 (72), 136 (43), 135 (91), 79 (18), 78
(40), 77 (19); HRMS (ESI) m/z: [M + H]+ Calcd for C20H25N3O 323.1998;
Found 323.1992.
Procedure for the synthesis of compound 18.
NH2-OH·HCl (0.33 mmol) and Na2CO3 (0.17 mmol) were added to a
stirred solution of 16agaa (0.3 mmol) in MeOH (3 mL) and water (1.5 mL) at
room temperature. Then, the reaction was acidified with acetic acid and
refluxed for 2 h. After cooling, the reaction was basified with NH4OH and
extracted with DCM. The organic phase was dried over MgSO4 and filtered.
The crude was purified by column chromatography.
Experimental Part
232
5-Phenyl-3-(pyridin-2-yl)isoxazole (18):162
white
solid (52 mg, 78 %); tR 13.08; Rf 0.13 (hexane/EtOAc,
8:2); 1H NMR (300 MHz, CDCl3) 7.29 (s, 1H; ArH),
7.36 (dd, J = 7.5, 4.8 Hz, 1H; ArH), 7.45 – 7.52 (m,
3H; ArH), 7.82 – 7.91 (m, 3H; ArH), 7.97 (d, J = 7.9 Hz, 1H; ArH), 8.71 (d, J
= 4.8 Hz, 1H; ArH); 13
C NMR (101 MHz, CDCl3) δ 100.6, 121.1, 124.7,
127.0, 129.1, 130.3, 137.4, 150.0 (10 × ArCH), 128.9, 146.5, 163.4, 169.6 (4 ×
ArC); MS (EI) m/z 223 (M+ + H, 14), 222 (M
+, 88), 194 (14), 193 (13), 144
(100), 116 (18), 78 (19), 77 (27).
General procedure for the synthesis of compound 19.
N2H4·H2O (1.5 mmol) was added to a stirred solution of 16agaa (0.3
mmol) in DMF and the reaction mixture was heated to 100°C during 2 h. After
that time, the reaction was diluted with EtOAc and the crude was purified by
column chromatography.
3-Phenyl-5-(2-pyridil)pyrazole (19):163
white solid
(56 mg, 85%); tR 14.41; Rf 0.21 (hexane/EtOAc, 6:4); 1H NMR (300 MHz, CDCl3) 7.10 (s, 1H; ArH),7.25 –
7.29 (m, 1H; ArH), 7.32 – 7.37 (m, 1H; ArH), 7.45 –
7.49 (m, 2H; ArH), 7.77 – 7.79 (m, 2H;ArH), 7.87 (d, J = 8.0, 2H; ArH), 8.69
(d, J = 3.7 Hz, 1H; ArH); 13
C NMR (75 MHz, CDCl3) δ 100.6, 120.3, 123.1,
125.8, 128.2, 128.9, 137.3, 149.5 (9 × ArCH), 132.7, 144.7, 148.7, 151.8 (4 ×
ArC); MS (EI) m/z 222 (M+ + H, 15), 221 (M
+, 100),192 (45), 165 (8), 115
(7).
General procedure for the synthesis of compound 20.
To a stirred solution of 16agaa (0.3 mmol) in EtOH, PhNHNH2·HCl
(1.5 mmol) was added, and the reaction mixture was heated to 70°C during 8
162
Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Comunn. 2011, 47, 3198. 163
Yu, W.-S.; Cheng, C.-C.; Cheng, Y.-M.; Wu, P.-C.; Song, Y.-H.; Chi, Y.; Chou, P.-T. J. Am. Chem. Soc.
2003, 125, 10800.
Experimental Part
233
hours. After that time, the reaction was concentrated under vacuum and the
crude was purified by column chromatography.
3-Phenyl-5-(2-pyridil)pyrazole (19): yellow oil (49 mg,
56%); tR 18.54; Rf 0.29 (hexane/EtOAc, 8:2); 1H NMR
(400 MHz, CDCl3) 7.15 – 7.17 (m, 2H; ArH), 7.21 – 7.24
(m, 1H; ArH), 7.29 – 7.45 (m, 10H; ArH), 7.61 (t, J = 7.8
1.8 Hz, 1H; ArH), 7.92 – 7.95 (m, 2H;ArH), 8.63 (ddd, J =
4.8 Hz, 1H; ArH); 13
C NMR (101 MHz, CDCl3) δ 106.6, 123.0, 123.8, 125.6,
126.0, 127.9, 128.2, 128.8, 129.1, 136.7, 149.6 (15 × ArCH), 132.9, 140.4,
143.4, 149.3, 152.3 (5 × ArC); MS (EI) m/z 298 (M+ + H, 16), 297 (M
+,
100),296 (90), 191 (15), 77 (15).
General procedure for the synthesis of the compound 21.
DMF was added to a mixture of compound 16agaa (0.3 mmol), N-
bromosuccinimide (0.33 mmol), iodine (0.015 mmol) and potassium carbonate
(0.35 mmol). The reaction was heated to 100°C for 1 h. Then, the reaction was
cooled to room temperature and was quenched with aqueous ammonia and
extracted with EtOAc. The combined organic layers were dried over MgSO4
and filtered. The crude was purified by column chromatography.
(2-Phenyl-1H-indol-3-yl)(pyridin-2-yl)methanone
(21): white solid (61 mg, 68%); tR 26.62; Rf 0.08
(hexane/EtOAc, 8:2); IR (neat) ν 3061, 3017, 2976,
2865, 1610, 1479, 1448, 1419, 1220, 1083, 1001, 883,
744, 698; 1H NMR (300 MHz, CDCl3) 7.08 – 7.18 (m,
4H; ArH), 7.26 – 7.29 (m, 4H; ArH), 7.43 – 7.47 (m, 1H;
ArH), 7.64 (td, J = 7.7, 1.6 Hz, 1H; ArH), 7.72 (d, J = 7.7 Hz, 1H; ArH), 8.11
– 8.14 (m, 1H; ArH), 8.21 (d, J = 4.4 Hz, 1H; ArH), 906 (br s, 1H; NH); 13
C
NMR (75 MHz, CDCl3) δ 111.2, 121.9, 122.7, 123.8, 1241, 125.3., 128.2,
128.6, 129.3, 137.1, 147.5 (13 × ArCH), 132.1, 135.7, 146.0, 146.8 (7 × ArC);
MS (EI) m/z 299 (M+ + H, 9), 298 (M
+, 46),269 (24), 221 (17), 220 (100), 191
(19), 165 (23), 134 (8).
Experimental Part
234
General procedure for the synthesis of the 1,3-dicarbonyl compound 22.
The compound 22 was prepared from acetophenone (10 mmol) and
ethyl picolinate (15 mmol) in the presence of K-t-BuO (30 mmol) as base and
t-BuOH as solvent, the mixture was stirred all night at ambient temperature.
The solvent was removed and the crude was extracted with EtOAc and a few
drops of HOAc. The organic layer was dried over MgSO4 and the crude was
purified by column chromatography.
1-Phenyl-3-(pyridin-2-yl)propane-1,3-dione (22): brown
solid (1128 mg, 50%); tR 16.45; Rf 0.38 (hexane/EtOAc,
8:2); IR (neat) ν 3059, 1599, 1535, 456, 1280, 1213, 1068,
993, 929, 771, 750, 707, 687; 1H NMR (300 MHz, CDCl3)
7.43 – 7.61 (m, 4H; ArH), 7.61 (s, 1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H;
ArH), 8.08 – 8.11 (m, 2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd,
J = 4.7, 1.7, 0.9 Hz, 1H; ArH), 16.49 (s , 1H); 13
C NMR (75 MHz, CDCl3) δ
93.6, 122.1, 126.3, 127.4, 128.6, 132.6, 137.1, 149.1 (10 × ArCH), 135.2,
152.4, 183.4, 186.3 (4 × ArC); MS (EI) m/z 225 (M+, 56), 197 (25), 196 (45),
148 (18), 147 (61), 106 (31), 105 (100), 102 (11), 96 (18), 79 (57), 78 (84), 77
(88), 69 (55), 51 (82); HRMS (ESI) m/z: [M + H]+ Calcd for C14H11NO2
225.0790; Found 225.0790.
(Z)-1-Phenyl-3-(phenylamino)-3-(pyridin-2-yl)prop-2-
en-1-one (23): yellow oil (35 mg, 59%); tR 19.47; Rf 0.28
(hexane/EtOAc, 8:2); IR (neat) ν 3050, 2923, 1592, 1553,
1515, 1455, 1422, 1321, 1287, 1213, 1054, 991; 1H NMR
(300 MHz, CDCl3) 6.38 (s, 1H; ArH), 6.67 – 6.69 (m, 2H; ArH), 6.98 – 7.02
(m, 1H; ArH), 7.11 – 7.16 (m, 2H; ArH), 7.28 – 7.33 (m, 2H; ArH), 7.42 –
7.51 (m, 3H; ArH), 7.61 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.00 – 8.02 (m,
2H;ArH), 8.67 (ddd, J = 4.8, 1.6, 0.9 Hz, 1H; ArH), 12.68 (s , 1H); 13
C NMR
(75 MHz, CDCl3) δ 97.7, 122.9, 124.1, 124.2, 124.3, 127.4, 128.3, 128.8,
131.5, 136.4, 149.7 (15 × ArCH), 139.5, 139.6, 153.9, 158.6, 190.4 (5 ×
ArC); MS (EI) m/z 300 (M+, 9), 196 (16), 195 (100), 181 (13), 105 (20), 78
Experimental Part
235
(7), 77 (21); HRMS (ESI) m/z: [M + H]+ Calcd for C20H16N2O 300.1263;
Found 300.1257.
General procedure for the reaction of pyrroles 17: The indolizine 4
(0.3 mmol) was dissolved in EtOH in the reactor tube, followed by the
addition of ArNO 15 (0.3 mmol) and stirring at ambient temperature
overnight. The solvent was removed under vacuum. Purification of the
reaction crude by column chromatography (silica gel, hexane/EtOAc) afforded
the pure pyrroles 7.
N,N-Dibenzyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-
1H-pyrrol-3-amine (17agia): yellow solid, m.p.
118.1–119.7 (132 mg, 96%); tR 38.74; Rf 0.48
(hexane/EtOAc, 8:2); IR (neat) ν 3062, 3054, 1595,
1493, 1328, 1205, 1027, 746, 694; 1H NMR (300 MHz, CDCl3) δ 0.64 (t, J =
7.3 Hz, 3H; CH3), 1.03 (m, 2H; CH2), 2.26 (m, 2H; CH2), 4.03 (s, 4H; CH2),
6.60 (d, J = 8.1 Hz, 1H; ArH), 6.85 (ddd, J = 7.4, 4.9, 1.1 Hz; ArH), 6.93 (s,
1H; ArH), 7.09 – 7.12 (m, 2H; ArH), 7.18 – 7.33 (m, 10H; ArH), 7.36 (d, J =
7.1 Hz, 4H; ArH), 8.40 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13
C NMR (75
MHz, CDCl3) δ 14.0 (CH3), 22.2, 25.9, 60.5 (CH2), 107.2, 119.6, 120.9,
126.6, 127.4, 127.9, 128.5, 128.8, 129.1, 135.4, 149.0 (17 × ArCH), 120.5,
131.1, 133.3, 134.7, 139.9, 151.5 (5 × ArC); MS (EI) m/z 458 (M+ + 1, 35),
457 (M+, 100), 428 (26), 367 (20), 366 (70), 338 (29), 337 (35), 336 (23), 275
(55), 274 (16), 260 (22), 231 (10), 91 (35), 77 (12); HRMS (ESI) m/z: [M +
H]+ Calcd for C32H31N3 457.2518; Found 457.2524.
2-(1-Phenyl-4-(piperidin-1-yl)-5-propyl-1H-pyrrol-
2-yl)pyridine (17aaia): yellow oil (67 mg, 65%); tR
17.63; Rf 0.46 (hexane/EtOAc, 8:2); IR (neat) ν 3054,
2931, 2867, 1712, 1589, 1494, 1438, 1382, 1151,
1049, 746, 694; 1H NMR (300 MHz, CDCl3) δ 0.74 (t,
J = 7.3 Hz, 3H; CH3), 1.20 – 1.32 (m, 2H; CH2), 1.5
(m, 2H; CH2), 1.71 (m, 4H; CH2), 2.53 (s, 2H; CH2), 2.91 (s, 4H; CH2), 6.57
Experimental Part
236
(dt, J = 8.1, 1.0 Hz, 1H; ArH), 6.79 (s, 1H; ArH), 6.87 (ddd, J = 7.3, 5.0, 0.8
Hz; ArH), 7.20 – 7.29 (m,3H; ArH), 7.35 – 7.40 (m, 3H; ArH), 8.41 (ddd, J =
4.9, 1.8, 0.9 Hz, 1H; ArH) 13
C NMR (75 MHz, CDCl3) δ 14.0 (CH3), 22.2,
25.9, 60.5 (CH2), 107.2, 119.6, 120.9, 126.6, 127.4, 127.9, 128.5, 128.8,
129.1, 135.4, 149.0 (17 × ArCH), 120.5, 131.1, 133.3, 134.7, 139.9, 151.5 (5 ×
ArC); MS (EI) m/z 346 (M+ + 1, 11), 345 (M
+, 43), 317 (24), 316 (100), 233
(4), 181 (4), 77 (4); HRMS (ESI) m/z: [M + H]+ Calcd for C23H27N3 345.2205;
Found 345.2216.
N,N-Dibenzyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-
1H-pyrrol-3-amine (17afia): yellow solid (88 mg,
80%); tR 21.15; Rf 0.42 (hexane/EtOAc, 8:2); IR (neat)
ν 3066, 3029, 2915, 2847, 1597, 1492, 1471, 1292,
1070, 752, 699; 1H NMR (300 MHz, CDCl3) δ 0.68 (t,
J = 7.4 Hz, 3H; CH3), 1.18 – 1.31 (m, 2H; CH2), 2.36 – 2.41 (m, 2H; CH2),
3.30 (s, 3H; CH3), 6.69 – 6.81 (m, 4H;ArH), 6.95 (ddd, J = 7.5, 4.9, 1.0 Hz;
ArH), 7.19 – 7.47 (m, 8H; ArH), 8.42 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H; ArH) 13
C
NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.2, 26.5 (CH2), 40.4 (CH3), 110.2,
112.8, 116.3, 120.1, 121.4, 127.7, 128.5, 128.8, 129.0, 135.7, 148.9 (15 ×
ArCH), 130.5, 131.7, 134.2, 150.0, 151.2 (6 × ArC); MS (EI) m/z 368 (M+ + 1,
30), 367 (M+, 100), 339 (21), 338 (77), 322 (13), 246 (17), 245 (57), 181 (21),
168 (11), 77 (12); HRMS (ESI) m/z: [M + H]+ Calcd for C25H25N3 367.2048;
Found 367.2059.
N-Benzyl-N-methyl-1-phenyl-2-propyl-5-(pyridin-2-
yl)-1H-pyrrol-3-amine (17adia): yellow oil (81 mg,
71%); tR 21.03; Rf 0.38 (hexane/EtOAc, 8:2); IR (neat) ν
3060, 3029, 2958, 2930, 2839, 1587, 1494, 1452, 1384,
1154, 992, 774, 740, 696; 1H NMR (300 MHz, CDCl3)
δ 0.74 (t, J = 7.3 Hz, 3H; CH3), 1.23 – 1.30 (m, 2H; CH2), 2.49 – 2.53 (m, 2H;
CH2), 2.62 (s, 3H; CH3), 4.01 (s, 2H; CH2), 6.60 (d, J = 8.1 Hz, 1H; ArH),
6.87 – 6.90 (m, 2H; ArH), 7.20 – 7.43 (m, 11H; ArH), 8.40 (ddd, J = 4.8, 1.5,
0.8 Hz, 1H; ArH) 13
C NMR (75 MHz, CDCl3) δ 14.2, 43.3 (2 × CH3), 22.7,
Experimental Part
237
26.4, 63.8 (3 × CH2), 105.9, 119.8, 121.1, 126.9, 127.7, 128.2, 128.5, 128.7,
128.9, 129.0, 135.4, 149.3 (15 × ArCH), 131.1, 131.2, 137.6, 139.9, 140.1,
151.7 (6 × ArC); MS (EI) m/z 382 (M+ + 1, 23), 381 (M
+, 72), 353 (19), 352
(64), 291 (19), 290 (82), 275 (16), 262 (32), 261 (25), 260 (37), 233 (10), 231
(12), 91 (100), 78 (12), 77 (24), 64 (17); HRMS (ESI) m/z: [M + H]+ Calcd for
C26H27N3 381.2205; Found 381.2199.
N,N-Dibutyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-
1H-pyrrol-3-amine (17acia): brown oil (51.6mg,
74%, scale 0.18mmol); tR 16.01; Rf 0.68
(hexane/EtOAc, 8:2); IR (neat) ν 3079, 2956, 2929,
2867, 1590, 1496, 1371, 1151, 742, 696; 1H NMR (300 MHz, CDCl3) δ 0.72
(t, J = 7.3 Hz, 3H; CH3), 0.89 (t, J = 7.2 Hz, 6H; 2 x CH3), 1.13 – 1.49 (m,
11?H; CH2), 2.47 – 2.52 (m, 2H; CH2), 2.81 – 2.86 (m, 4H; 2 x CH2), 6.61 (dt,
J = 8.1, 0.9 Hz, 1H; ArH), 6.80 (s, 1H; ArH), 6.87 (dd, J = 6.8, 5.1 Hz; ArH),
7.22 – 7.41 (m, 6H; ArH), 8.41 (dd, J = 4.8, 0.7 Hz, 1H; ArH) 13
C NMR (75
MHz, CDCl3) δ 14.1 (3 x CH3), 20.6, 22.6, 26.2, 30.4 (8 x CH2), 106.9, 119.6,
120.9, 127.4, 128.5, 128.9, 135.3, 149.2 (10 × ArCH), 120.6, 130.9, 133.5,
134.6, 139.8, 139.9, 151.5 (7 × ArC); MS (EI) m/z 390 (M+ + 1, 23), 389 (M
+,
77), 361 (16), 360 (56), 347 (28), 346 (100), 289 (16), 260 (16), 151 (10);
HRMS (ESI) m/z: [M + H]+ Calcd for C26H35N3 389.2831; Found 389.2834.
N,N-Dibenzyl-1-phenyl-2-propyl-5-(pyridin-2-yl)-
1H-pyrrol-3-amine (17cgia): yellow solid, m.p.
110.9–112.3 (47 mg, 33%); tR 39.04; Rf 0.64
(hexane/EtOAc, 8:2); IR (neat) ν 3029, 2953, 2922,
2871, 1597, 1571, 1492, 1451, 1360, 1201, 1161,
1028, 906, 782, 748, 698; 1H NMR (300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz,
3H; CH3), 0.99 – 1.11 (m, 2H; CH2), 2.27 – 2.32 (m, 2H; CH2), 2.35 (s, 3H;
CH3), 4.03 (s, 4H, CH2), 6.53 (d, J = 7.9 Hz, 1H; ArH), 6.73 (d, J = 7.5 Hz,
1H; ArH), 6.88 (s, 1H; ArH), 7.09-7.12 (m, 3H; ArH), 7.17-7.38 (m, 13H;
ArH); 13
C NMR (75 MHz, CDCl3) δ 14.0, 24.3 (CH3), 22.3, 25.9, 60.4 (CH2),
106.8, 118.1, 119.1, 126.6, 127.1, 127.9, 128.3, 128.5, 128.6, 129.1, 135.7 (19
Experimental Part
238
× ArCH), 132.9, 134.6, 137.7, 139.9, 140.2, 150.9, 157.3 (8 × ArC); MS (EI)
m/z 472 (M+ + 1, 36), 471 (M
+, 100), 442 (22), 381 (23), 380 (74), 352 (26),
351 (32), 350 (18), 289 (45), 274 (16), 207 (16), 91 (23), 77 (10); HRMS
(ESI) m/z: [M + H]+ Calcd for C33H33N3 471.2674; Found 471.2682
N,N-Dibenzyl-2-ethyl-1-phenyl-5-(pyridin-2-yl)-1H-
pyrrol-3-amine (17agja): yellow solid, m.p. 115.1–
118.1 (80 mg, 60%); tR 37.02; Rf 0.40 (hexane/EtOAc,
8:2); IR (neat) ν 3076, 3053, 3027, 2962, 2827, 1594,
1494, 1452, 1390, 1363, 773, 698; 1H NMR (400 MHz, CDCl3) δ 0.62 (t, J =
7.5 Hz, 3H; CH3), 2.34 (q, J = 7.5 Hz, 2H; CH2), 4.04 (s, 4H; CH2), 6.61 (d, J
= 8.1 Hz, 1H; ArH), 6.87 (ddd, J = 7.4, 4.9, 0.9 Hz, 1H; ArH), 6.94 (s, 1H;
ArH), 7.12 – 7.14 (m, 2H; ArH), 7.18 – 7.21 (m, 2H; ArH), 7.25 – 7.30 (m,
5H; ArH), 7.32 – 7.38 (m, 7H; ArH), 8.40 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13
C NMR (75 MHz, CDCl3) δ 138 (CH3), 17.1, 60.6 (CH2), 107.3, 119.6,
120.9, 126.7, 127.5, 127.9, 128.5, 128.8, 129.1, 135.5, 148.9 (17 × ArCH),
131.0, 134.2, 134.8, 139.8, 139.9, 151.4 (7 × ArC); MS (EI) m/z 444 (M+ + 1,
25), 443 (M+, 62), 353 (26), 352 (100), 261 (41), 260 (32), 91 (22), 77 (13);
HRMS (ESI) m/z: [M + H]+ Calcd for C31H29N3 443.2361; Found 443.2367.
N,N-Dibenzyl-2-pentyl-1-phenyl-5-(pyridin-2-
yl)-1H-pyrrol-3-amine (17agka): yellow oil (64
mg, 44%); tR 47.03; Rf 0.46 (hexane/EtOAc,
8:2); IR (neat) ν 3059, 3027, 2952, 2925, 2856,
1591, 1495, 1390, 1072, 904, 742, 696; 1H NMR (300 MHz, CDCl3) δ 0.75 (t,
J = 6.8 Hz, 3H; CH3), 1.03 – 1.08 (m, 6H; CH2), 2.30 (t, J = 7.2 Hz, 2H; CH2),
4.07 (s, 4H; CH2), 6.63 (d, J = 8.1 Hz, 1H; ArH), 6.91 (dd, J = 6.4, 4.9 Hz;
ArH), 6.98 (s, 1H; ArH), 7.13 – 7.41 (m, 16H; ArH), 8.45 (d, J = 4.2 Hz, 1H;
ArH) 13
C NMR (75 MHz, CDCl3) δ 13.9 (CH3), 22.1, 23.8, 29.7, 31.7, 60.5
(CH2), 107.3, 119.6, 120.9, 126.6, 127.4, 127.8, 128.5, 128.8, 129.1, 135.4,
148.9 (17 × ArCH), 120.6, 130.9, 133.5, 134.6, 139.8, 139.9, 151.5 (7 × ArC);
MS (EI) m/z 486 (M+ + 1, 38), 485 (M
+, 100), 429 (10), 428 (25), 394 (24),
Experimental Part
239
338 (63), 303 (21), 274 (31), 179 (11), 91 (36), 77 (19); HRMS (ESI) m/z: [M
+ H]+ Calcd for C34H35N3 485.2831; Found 485.2835.
N,N-Dibenzyl-2-(3-chloropropyl)-1-phenyl-5-
(pyridin-2-yl)-1H-pyrrol-3-amine (17agla):
yellow semisolid (59 mg, 40%); Rf 0.36
(hexane/EtOAc, 8:2); IR (neat) ν 3029, 2958, 2919,
2850, 1590, 1495, 1384, 1360, 1070, 779, 742, 698; 1H NMR (400 MHz,
CDCl3) δ 1.24 – 1.35 (m, 2H; CH2), 2.33 – 2.37 (m, 2H; CH2), 3.15 (t, J = 6.6
Hz, 2H; CH2), 4.03 (s, 4H; CH2), 6.63 (d, J = 8.1 Hz, 1H; ArH), 7.01 (s, 1H;
ArH), 7.08 – 7.13 (m, 2H; ArH), 7.20 – 7.23 (m, 2H; ArH), 7.25 – 7.30 (m,
4H; ArH), 7.32 – 7.36 (m, 7H; ArH), 8.43 (d, J = 4.2 Hz, 1H; ArH) 13
C NMR
(75 MHz, CDCl3) δ 21.5, 31.5, 44.6, 60.8 (4 × CH2), 107.5, 119.9, 121.1,
126.8, 127.7, 127.9, 128.4, 128.8, 129.0, 135.8, 148.8 (17 × ArCH), 131.8,
133.3, 135.0, 139.4, 139.7, 151.1 (7 × ArC); MS (EI) m/z 494 (9) [M+ + 1,
37Cl], 493 (27) [M
+,
37Cl], 492 (25) [M
+ + 1,
35Cl], 491 (70) [M
+,
35Cl], 428
(17), 402 (22), 401 (18), 400 (62), 366 (12), 365 (44), 339 (15), 338 (59), 337
(33), 336 (23), 275 (21), 274 (100), 273 (13), 272 (31), 260 (10), 233 (10), 232
(10), 231 (14), 182 (14), 181 (36), 91 (60), 78 (10), 77 (19); HRMS (ESI) m/z:
[M + H]+ Calcd for C32H30ClN3 491.2128; Found 491.2121.
3-(3-(Dibenzylamino)-1-phenyl-5-(pyridin-2-yl)-
1H-pyrrol-2-yl)propanenitrile (17agma): brown
oil (51 mg, 36%); Rf 0.25 (hexane/EtOAc, 8:2); IR
(neat) ν 3059, 3027, 2923, 1587, 1494, 1453, 1436,
1388, 1153, 1072, 909, 777, 739, 697; 1H NMR (400 MHz, CDCl3) δ 1.49 –
1.54 (m, 2H; CH2), 2.40 – 2.45 (m, 2H; CH2), 4.03 (s, 4H; 2 × CH2), 6.69 (dt,
J = 8.1, 1.0 Hz, 1H; ArH), 6.94 (ddd, J = 7.5, 4.9, 1.1 Hz, 1H; ArH), 7.00 (s,
1H; ArH), 7.08 – 7.13 (m, 2H; ArH), 7.20 – 7.23 (m, 2H; ArH), 7.25 – 7.30
(m, 4H; ArH), 7.04 – 7.07 (m, 2H; ArH), 7.20 – 7.38 (m, 14H; ArH), 8.43
(ddd, J = 4.8, 1.8, 0.9 Hz, 1H; ArH) 13
C NMR (75 MHz, CDCl3) δ 16.0, 20.5,
61.5 (4 × CH2), 107.3, 120.4, 121.2, 127.0, 128.1, 128.2, 129.3, 129.4, 135.6,
149.2 (20 × ArCH), 119.4, 129.3, 132.8, 135.1, 138.9, 139.4, 151.1 (8 × ArC);
Experimental Part
240
MS (EI) m/z 469 (M+ + H, 33), 468 (M
+, 92), 429 (31), 428 (92), 378 (27), 377
(97), 338 (25), 337 (100), 336 (62), 286 (13), 285 (24), 260 (13), 258 (11), 233
(17), 232 (14), 231 (17), 218 (10), 181 (11), 91 (61), 78 (10), 77 (18); HRMS
(ESI) m/z: [M + H]+ Calcd for C32H28N4 468.2314; Found 468.2323.
N,N-Dibenzyl-2-propyl-5-(pyridin-2-yl)-1-(p-tolyl)-
1H-pyrrol-3-amine (17agib): yellow oil (79 mg,
56%); tR 42.97; Rf 0.44 (hexane/EtOAc, 8:2); IR (neat)
ν 3027, 2957, 2926, 2868, 16698, 1587, 1512, 1436,
1354, 1151, 1100, 962, 826, 775, 739, 697; 1H NMR
(300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz, 3H; CH3),
0.98 – 1.08 (m, 2H; CH2), 2.21 – 2.26 (m, 2H; CH2),
2.37 (s, 3H; CH3), 4.03 (s, 4H; CH2), 6.57 (d, J = 8.1 Hz, 1H; ArH), 6.88 (ddd,
J = 7.4, 4.9, 0.9 Hz, 1H; ArH), 6.97 – 7.00 (m, 3H; ArH), 7.12 – 7.14 (m, 2H;
ArH), 7.17 – 7.22 (m, 2H; ArH), 7.25 – 7.32 (m, 5H; ArH), 7.35 – 7.38 (m,
4H; ArH), 8.43 (ddd, J = 4.9, 1.7, 0.8 Hz, 1H; ArH) 13
C NMR (75 MHz,
CDCl3) δ 14.1, 21.2 (2 × CH3), 22.3, 25.9, 60.5 (4 × CH2), 107.4, 119.6,
120.9, 126.6, 127.9, 128.2, 129.1, 129.5, 135.7, 148.7 (19 × ArCH), 130.7,
133.6, 134.7, 137.1, 137.3, 139.9, 151.3 (8 × ArC); MS (EI) m/z 471 (M+, 28),
380 (35), 351 (15), 289 (19), 207 (29), 91 (100), 78 (10), 77 (15), 65 (15);
HRMS (ESI) m/z: [M + H]+ Calcd for C33H33N3 471.2674; Found 471.2667.
1-(4-(3-(Dibenzylamino)-2-propyl-5-(pyridin-2-yl)-
1H-pyrrol-1-yl)phenyl)ethan-1-one (17agic): yellow
oil (90 mg, 60%); Rf 0.24 (hexane/EtOAc, 8:2); IR
(neat) ν 3060, 3027, 2958, 2927, 2869, 1736, 1683,
1598, 1496, 1358, 1261, 956, 777, 740, 698; 1H NMR
(300 MHz, CDCl3) δ 0.64 (t, J = 7.3 Hz, 3H; CH3),
0.98 – 1.03 (m, 2H; CH2), 2.28 – 2.33 (m, 2H; CH2),
2.28 (s, 3H, CH3), 4.03 (s, 4H; CH2), 6.86 (d, J = 8.0 Hz, 1H; ArH), 6.87 (s,
1H; ArH), 6.89 (ddd, J = 7.5, 4.9, 1.0 Hz; ArH), 7.7 – 7.38 (m, 13H; ArH),
7.91 (d, J = 8.5 Hz, 2H; ArH), 8.31 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13
C
NMR (75 MHz, CDCl3) δ 14.0 (CH3), 22.2, 25.9, 26.6 (CH2), 60.4 (CH3),
Experimental Part
241
107.7, 119.9, 121.3, 126.7, 127.9, 128.4, 128.8, 129.1, 135.6, 149.0 (19 ×
ArCH), 128.6, 131.2, 132.9, 135.1, 139.7, 144.5, 151.4, 197.2 (9 × ArC); MS
(EI) m/z 500 (M+ + H, 38), 499 (M
+, 100), 471 (10), 470 (28), 409 (30), 408
(96), 380 (32), 379 (41), 378 (26), 318 (15), 317 (63), 316 (17), 302 (19), 264
(16), 231 (11), 172 (11), 91 (65); HRMS (ESI) m/z: [M + H]+ Calcd for
C34H33N3O 499.2624; Found 499.2630.
N,N-Dibenzyl-1-(4-bromophenyl)-2-propyl-5-
(pyridin-2-yl)-1H-pyrrol-3-amine (17agie): yellow
oil (98 mg, 61%); Rf 0.48 (hexane/EtOAc, 8:2); IR
(neat) ν 3062, 3026, 2961, 2938, 2902, 2868, 1588,
1573, 1489, 1386, 1363; 1069, 959, 838, 775, 742,
695; 1H NMR (300 MHz, CDCl3) δ 0.66 (t, J = 7.3 Hz,
3H; CH3), 0.98 – 1.06 (m, 2H; CH2), 2.23 – 2.28 (m,
2H; CH2), 4.02 (s, 4H;2 × CH2), 6.76 (dd, J = 8.1, 0.9 Hz, 1H; ArH), 6.86 (s,
1H; ArH), 6.90 (ddd, J = 7.5, 4.9, 1.0 Hz; ArH), 6.97, 7.43 (system AA’BB’, J
= 8.6 Hz, 4H; ArH), 7.17 – 7.24 (m, 2H; ArH), 7.27 – 7.30 (m, 4H; ArH), 7.32
– 7.38 (m, 5H; ArH), 8.35 (ddd, J = 4.9, 1.7, 0.9 Hz, 1H; ArH) 13
C NMR (75
MHz, CDCl3) δ 14.0 (CH3), 22.3, 25.8, 60.4 (3 × CH2), 107.4, 119.8, 121.1,
126.7, 127.9, 129.3, 130.0, 131.9, 135.6, 148.9 (19 × ArCH), 121.0, 131.0,
133.1, 134.8, 139.1, 136.7, 151.3 (8 × ArC); MS (EI) m/z 538 (M+ + 1, 25),
537 (M+, 77), 536 (M
+ + 1, 26), 535 (M
+, 75), 508 (22), 506 (21), 447 (22),
446 (72), 445 (24), 444 (77), 418 (23), 417 (34), 416 (40), 415 (31), 414 (19),
356 (12), 355 (55), 354 (24), 353 (57), 352 (16), 340 (16), 338 (19), 261 (10),
260 (11), 259 (15), 258 (18), 232 (13), 231 (32), 172 (22), 157 (12), 155 (11),
91 (100), 78 (16); HRMS (ESI) m/z: [M + H]+ Calcd for C32H30BrN3
535.1623; Found 535.1621.
2-(1-Phenyl-4-(piperidin-1-yl)-5-propyl-1H-pyrrol-
2-yl)pyridine (17agif): yellow oil (96 mg, 68%); tR
38.06; Rf 0.56 (hexane/EtOAc, 8:2); IR (neat) ν 3026,
2957, 2928, 2868, 2823, 1698, 1646, 1587, 1492,
1454, 1435, 1386, 1150, 961, 775, 738, 697; 1H NMR
Experimental Part
242
(300 MHz, CDCl3) δ 0.65 (t, J = 7.3 Hz, 3H; CH3), 0.97 – 1.04 (m, 2H; CH2),
1.59 (s, 3H, CH3), 1.78 – 1.88 (m, 1H; CH2), 2.16 – 2.26 (m, 1H; CH2),3.99,
4.09 (AB system, J = 13.1, 4H; 2 × CH2), 6.51 (d, J = 8.2 Hz, 1H; ArH), 6.86
(ddd, J = 7.4, 4.9, 0.8 Hz; ArH), 7.01 (s, 1H; ArH), 7.13 – 7.29 (m, 11H;
ArH), 7.36 – 7.38 (m, 4H; ArH), 8.42 (ddd, J = 4.8, 1.7, 0.9 Hz, 1H; ArH) 13
C
NMR (75 MHz, CDCl3) δ 14.1, 16.9 (2 × CH3), 22.2, 25.9, 60.8 (3 × CH2),
107.0, 119.3, 119.6, 126.3, 126.6, 127.9, 128.3, 129.1, 129.2, 135.6, 148.8 (19
× ArCH), 133.4, 134.5, 135.9, 137.2, 138.8, 139.9, 151.1 (8 × ArC); MS (EI)
m/z 472 (M+ + 1, 31), 471 (M
+, 100), 442 (21), 381 (22), 380 (62), 352 (15),
351 (16), 289 (21), 274 (11), 260 (12), 207 (16), 91 (26); HRMS (ESI) m/z:
[M + H]+ Calcd for C33H33N3 471.2674; Found 471.2689.
General procedure for the synthesis of compound 24.
Ethylmagnesium bromide (3 mL) was added to a solution of 1-hexyne
(12 mmol) in dry THF at room temperature for 30 min. Then, pyridine-2-
carboxaldehyde (10 mmol) was added dropwise at 0 ºC. The reaction was
stirred for 2 h at 0 ºC and quenched with NH4Clsat and extracted wit EtOAc.
The organic layers were dried over MgSO4 and concentrated under vacuum.
The crude propargylic alcohol was used without further purification.
DMSO was added to a solution of oxalyl chloride in dichloromethane
at –78 ºC and the mixture was stirred for 45 min. The crude alcohol in
dichloromethane was added dropwise. After 45 min, Et3N was added and the
resulting mixture was allowed to warm to room temperature. After 4 h, the
reaction was quenched with NH4Clsat and extracted. The crude was purified by
column chromatography.
1-(Pyridin-2-yl)hept-2-yn-1-one (24): dark oil (539 mg,
29%); tR 16.45; Rf 0.38 (hexane/EtOAc, 8:2); 1H NMR
(300 MHz, CDCl3) 7.43 – 7.61 (m, 4H; ArH), 7.61 (s,
1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.08 – 8.11
(m, 2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd, J = 4.7, 1.7, 0.9
Hz, 1H; ArH), 16.49 (s , 1H); 13
C NMR (75 MHz, CDCl3) δ 13.5 (CH3), 19.3,
22.1, 29.8 (3 × CH2), 80.5, 99.5, 153.1, 178.2 (4 × ArCH), 80.5, 99.5, 153.1,
Experimental Part
243
178.2 (4 × ArC); MS (EI) m/z 187 (M+, 1), 186 (6), 159 (21), 158 (36), 146
(13), 145 (100), 144 (12), 130 (31), 117 (32), 106 (13), 79 (24), 78 (36).
General procedure for the synthesis of compound 26.
Dibenzylamine (1.1 mmol) was added to a solution of compound 24 (1
mmol) in MeOH and stirred until completion of the reaction (TLC). The
mixture was concentrated by rotatory evaporation and purified by column
chromatography to obtain compound 26.
(E)-3-(Dibenzylamino)-1-(pyridin-2-yl)hept-2-en-1-one
(25): yellow oil (230 mg, 60%); tR 31.37; Rf 0.20
(hexane/EtOAc, 8:2); IR (neat) ν 3025, 2957, 2933,
1512, 1470, 1450, 1353, 1189, 1081, 945, 745, 696,
687; 1H NMR (300 MHz, CDCl3) 7.43 – 7.61 (m, 4H;
ArH), 7.61 (s, 1H; ArH), 7.88 (td, J = 7.7, 1.8 Hz, 1H; ArH), 8.08 – 8.11 (m,
2H;ArH), 8.18 (dt, J = 7.9, 1.0 Hz, 1H; ArH), 8.74 (ddd, J = 4.7, 1.7, 0.9 Hz,
1H; ArH), 16.49 (s , 1H); 13
C NMR (75 MHz, CDCl3) δ 14.0 (CH3), 23.3,
29.6, 31.2, 52.5 (5 × CH2), 90.9, 121.8, 125.0, 126.9, 127.7, 129.0, 136.7,
148.1 (15 × ArCH), 136.6, 157.8, 169.1, 185.9 (5 × ArC); MS (EI) m/z 384
(M+, 5), 294 (19), 293 (86), 223 (13), 196 (25), 189 (48), 188 (22), 159 (15),
106 (24), 91 (100), 78 (31). HRMS (ESI) m/z: [M + H]+ Calcd for C26H28N2O2
384.2202; Found 384.1995.
Abbreviations
257
Abs Absorbance
aq. Aqueous
br broad
C Activated carbon
calcd. calculated
CDC Cross-dehydrogenative coupling
COSY Correlation spectroscopy
CSP Carbon spheres
d doublet
DIP Direct Inlet Probe
GC-MS Gas Chromatography-Mass Spectroscopy
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene,
DCM Dichloromethane
DIP Direct injection process
DMF dimethylformaldehyde
DMSO Dimethyl sulfoxide
d.r. Diastereomeric ratio
DTBB Di-tert-butylbiphenyl
ε Dielectric constant
E+ electrophile
EDX Energy-dispersive X-ray
EG Ethylene glycol
EI Electron impact
eq. equivalents
EWG Electronwithdrawing group
FDA Food and drug administration
HIPS High-impact polystyrene
HMBC Heteronuclear Multiple Bond Correlation
HPLC High Performance Liquid Chromatography
HSQC Heteronuclear Single Quantum Coherence
ICP-MS Inductively Coupled Plasma-Mass Spectrometry
IR Infrared radiation
L ligand
MCR Multicomponent reaction
m multiplet
max maximum
Abbreviations
258
MK Montmorillonite-K
MNPs Metallic nanoparticles
Ms mesylate
NMR Nuclear magnetic resonance
NOESY Nuclear Overhauser effect spectroscopy
NPs Nanoparticles
OIDD Open innovation drug discovery
OMIM 1-octyl-3-methylimidazolium
Pip Piperidinium
Piv Pivaloyl
PP Polpropylene
PS Polystyrene
PVC Poly(vinyl chloride)
rt Room temperature
s Singlet
SEM Scanning Electron Microscope
SB Styrene-butadiene
t triplet
TBS tert-butylsilyl
TEM Transmission Electron Microscopy
TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl
THF Tetrahydrofuran
Tf Triflate
TLC Thin layer chromatography
TMCl Trimethylsilyl chloride
TOF Turnover frequency
TON Turnover number
UV-Vis Ultraviolet-Visible
wt weight
XPS X-Ray Photoelectron Spectroscopy
XRD X-Ray Difraction
ZSM Zeolite Socony Mobil