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CHAPTER-5
SYNTHESIS, CHARACTERIZATION OF SOME NEW
HOMOALLYLAMINES AND β-AMINO KETONES
153
5.1. Introduction
Multicomponents reactions (MCRs) are those reactions in which three or more reactants come
together in a single reaction vessel to form a new product which contains portions of all the components.
First 'officially' reported MCR was the Strecker synthesis (Sheme-5.1) of α-amino nitrile in 1850 [1].
During this one and a half century period, some notable achievements include the discovery of the
Biginelli [2], the Mannich [3], and the Passerini [4] reactions culminating in 1959 when Ugi published
probably the most versatile MCR based on the reactivity of isocyanides [5]. Multicomponent reactions
(MCRs) have recently emerged as valuable tools in the preparation of structurally diverse chemical
libraries of drug-like heterocyclic compounds. In view of the increasing interest for the preparation of
large heterocyclic compound libraries, the development of new and synthetically valuable
multicomponent reactions remains a challenge for both academic and industrial research teams.
R H
ONH3 HCN
R
NH2
CN
R = Aromatic, aliphatic, hetetocyclic substituents
264 265
Scheme-5.1: Strecker synthesis
The condensation of activated carbonyl compounds with in-situ formed iminium species, called
the Mannich reaction, provides β-amino carbonyl compounds. Using these multicomponent reactions
we have prepared two series of compounds i.e, homoallylamines and β-amino ketones in microwave and
studied their animicrobial activity.
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5.1.1 Biological importance of homoallylamines and β-amino ketones
Allylamines, (266) are fundamental building blocks in organic chemistry and their synthesis is
an important industrial and synthetic goal. The allylamine fragment can be encountered in natural
products, but often the allylamine is transformed to a range of products by fictionalization, reduction, or
oxidation of the double bond.
R
NR1 R2
R3
266
R, R1, R2, R3 = Aromatic, Aliphatic, Hetetocyclic
Fig. 5.1: Functionalised homoallylamines
Homoallylic amines are valuable intermediates in organic synthesis [6] as starting materials in
the preparation of biologically active substances [7] as resolving agents [8], and as chiral auxiliaries for
asymmetric synthesis [9]. They are used for the synthesis of β-amino acids [10], as well as β-lactams
[11] and HIV-protease inhibitors [12]. The homoallylic amine moiety is not widely present in natural
products, however, compounds like Eponemycin [13], which exhibits potent activity against B16
melanoma cells, or a depsipeptide cryptophycin 337 [14], which is an analog of a potent anti-tumor
compound Cryptophycin, contain this subunit.
On the other hand, homoallylic amines are excellent building blocks for the synthesis of
numerous nitrogen-containing natural products [15]. Chiral homoallylic amines were utilized as the key
intermediates in the preparation of many natural products, such as an amino-sugar vancosamine isolated
from Vancomycin [16], a spirocycle alkaloid alichlorine isolated from a Japanese sponge Halichondria
okadai Kadota [17], an alkaloid from Prosopis africana, desoxoprosopinine [18], and many others [19].
With the utilization of ring-closing metathesis methodology, numerous piperidine alkaloids can be
easily prepared from the corresponding aminodienes [20]. Preparation of β-amino acids is of particular
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interest to medicinal and bioorganic chemists as various β-amino acid moieties can be found in taxoids,
β-lactam antibiotics and other compounds.
A plethora of synthetic methods have been devised for the preparation of homoallylic amines.
All methods for their synthesis can be divided into four groups: a) nucleophilic addition to imines and
iminium ions. b) [3,3]-Sigmatropic rearrangement of N-protected amino acid allylic esters. c) [2,3]-
Sigmatropic rearrangements of N-allyl α-amino esters or allylic ammonium salts. d) Miscellaneous
synthesis.
Acid catalyzed alkylation of N-acyl-a-alkoxyamines with a variety of nucleophiles has
extensively studied and well demonstrated to be an excellent alternative method to alkylation of imines
by Naoki et al, (1994) [21]. This type of reaction provides a convenient method for the synthesis of
homoallyl- and homopropargyl amines and β-amino esters.
NHCO2Me
OMe
R1 R2-Br
NHCO2Me
R2
R1Zn
THF
267 268 269
Where R1 = Me, Ph, i-Pr, H: R2 = PhCH2, Allyl, Vinyl.
Scheme - 5.2: Preparation of homoallylamines
Lanthanide triflates are used as effective catalysts for the allylation of imines with
allyltributylstannane to afford homoallylamines (Scheme-5.3) in moderate to good yields by Cristina et
al, (1995) [22].
R NR1 Sn(Bu)3
Ln(OTf)3 R
HNR1
270 271272
Where R = Me, Ph,H: R1= 4-OCH3Ph, Benzyl
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Scheme-5.3: Preparation of homoallylamines using lanthanide catalysts.
Billet et al, (2001) have used crotylsilane in a three-component reaction for the synthesis of
homoallylamines (Scheme-5.4) from aldehydes. A moderate to good syn:anti 5:1 diastereoselectivity
was observed. The obtained homoallylamines were transformed into pyrrolidines or piperidines [23].
R H
O
H2N R1 SiMe3
Lewis acid
R
HNR1
R
HNR1
273 274 275276 277
Where R, R1 = Ph, PhCH2, PhCHCH2, -OMePh
Scheme - 5.4: Preparation of homoallylamines using crotylsilane.
A complete conformational analysis of 4-methyl-2-(3-pyridyl)quinoline (278)) and structurally
related compounds with known antifungal properties was carried out using ab initio and DFT
calculations by Villagra et al, (2003) [24].
R1
NH
R
278
Where R, R1 = Ph, PhCH2, PhCHCH2, -Cl, Br
Fig. 5.2: Cyclised derivatives of homoallylamines
Ella-Menye et al, (2005) have reported the three-component “aza Sakurai–Hosomi” reaction
performed on (±) O-protected mandelic aldehydes and observed the unexpected syn hydroxy
homoallylamines (280) and (281) as the major adducts [25].
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CHO
OR
OH
NHCBz
OH
NHCBz
SiMe3
CBzNH2, Lewis acid
280
281
279
Where R = Tributyldimethyl silane, Tributyl diphenyl silane, Teteraisopropyl silane
Scheme 5.5: Preparation of homoallylamines using “aza Sakurai–Hosomi” reaction
Fernando et al, (2006) studied the synthesis and in vitro evaluations and structural activity
relationship of homoallylamines and related derivatives as antifungal agents. Among them few
derivatives (282 and 283) showed excellent antifungal activity against dermatophytes [26].
Br
NH
O
282
Cl
NH
O
283
Fig. 5.3: N-(1-(Furan-2-yl) but-3-enyl)benzenamine derivatives
Vladmir et al, (2008) reported the synthesis of homoallylamines bearing furan ring and studied
their antifungal, cytotoxic activity against (MCF-7) and lung (H-460) activity. Compound N-(1-(furan-
2-yl)but-3-enyl)pyridin-4-amine (284) showed excellent activity [27].
N
NH
O
284
Fig. 5.4: N-(1-(Furan-2-yl)but-3-enyl)pyridin-4-amine
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Bismuth (III) nitrate pentahydrate catalyzes efficiently the three-component condensation of
aldehydes, amines, and allyltributylstannane at room temparature to afford the corresponding
homoallylic amines (Scheme-5.6) in excellent yield, Ponnaboina et al, (2009) [28].
R H
O
H3CO
NH2SnBu3
R
HN
OCH3
CH3CN
Bi(NO3)3.5H2O
285 286 287288
Where R = Ph, PhCH2, -OMePh
Scheme 5.6: Preparation of homoallylamines using Bismuth (III) nitrate catalyst
Gonzalez et al, (2010) used indium metal and titanium tetraethoxide for the synthesis of
homoallylamines (Scheme-5.7) similar homoallylamines are used in the synthesis of naturally occurring
ring alkaloids [29].
BrR H
O
t-BuSNH2
O
In, Ti(OEt)4
THF, 60oC R
NHS
O
t-Bu
289
290 291
292
Where R = Ph, Bn, 4-ClPh, 4-OMe- Ph
Scheme 5.7: Preparation of homoallylamines using Indium catalyst
Yamaguchi et al, (2011) have reported a nuclephilic allylation of 2- aminotetrahydrofuran and 2-
aminotetrahydropyran with allylic alcohols to provide α-hydroxyhomoallylamines (Scheme - 5.8) in
high yields using Pd/Et3B and Pd/Et2Zn [30].
159
Ph H
O
RNH2
Pd catalyst
Ph
NHR
OH
Et3B
293 294 295296
Where R = Ph, Bn, 4-ClPh, 4-OMe -Ph, 4-Me-Ph
Scheme 5.8: Preparation of homoallylamines using Pd/Et3B catalyst
Highly enantioselective asymmetric synthesis (Scheme-5.9) of highly optically pure 2-
substituted piperidines was developed by Piao et al, (2012) using aldehydes, amines and allyl bromides
[31].
NH
R NH
R NH2R
R O
InBr
NH3
Where R = Ph, 4-F-Ph, 4-NO2-Ph, 2-Br-Ph, 2-OMe- 3-ClPh, -OMePh.
298
299
300301302
Scheme 5.9: Retro synthetic pathway of 2- substituted piperidines
In general homoallylic amines are prepared either by the addition of organometallic reagents to
imines or by nucleophillic addition of allylsilanes, allyltin, allylboron or allyl germane reagents to
imines in the presence of different Lewis acid catalysts as discussed in the above examples. The
common drawback in the reported methods is generation of aldehyde sideproduct because of unstable
intermediate imine. Also in some processes the removal of catalyst is difficult. Moreover the reported
yields are less because of decomposition of some catalyst sensitive aldehydes. Most of the synthesis
protocols reported so far requires long reaction times, stringent conditions, and highly toxic
reagents/catalysts, the catalysts are often expensive and tedious to prepare. The reactions are often
characterized by low yields. Therefore, there is a need for the development of simple, convenient and
environmentally benign approaches for the synthesis of homoallylic amines.
160
Nitrogen containing molecules are significant synthetic targets owing to their wide range of
applications as pharmaceutical and bioactive compounds. Mannich reaction has been one of the classical
methods for the synthesis of nitrogenous compounds, especially β- amino carbonyl compounds that are
versatile intermediates for the synthesis of β- amino alcohols and β- amino acids, which have the great
deal of biological importance.
In 1987 Gennari et al, have reported the synthesis of enantio- and diastereo-controlled synthesis
of the β-lactums by the addition silyl ketene acetal derived from (lS,2R)-N-methylephedrine-0-
propionate to imines using TiCl4 as a catalyst (Scheme-5.10) [32].
NMe2
OH
H
Ph
Me
OSiMe3 N
Me H H
Ph
PhO
PhN
H Ph
303 304
Scheme-5.10: Asymmetric synthesis β-lactums
Manabe et al, (1999) reported the three-component Mannich-type reactions of aldehydes,
amines, and ketones were efficiently catalyzed by dodecylbenzenesulfonic acid at ambient temperature
in water to get various β-amino ketones in good yields [33].
RCHO R1NH2 R3
O
R2
Dodecylbenzenesulfonic acid
R
NH
R2R3
OR1
Where R = Ph, Furfuraldehyde, Isovaleraldehyde
R1 = Ph, -OMePh, 4-Cl-Ph
R2, R3 = H, Ph, Cyclohexanone
305 306 307308
Scheme 5.11: Synthesis of β-amino ketones
161
The synthesis of β-amino ketones from aldehydes has been achieved in water using indium
trichloride as catalyst (Scheme-5.12) by Loh et al, (2000). The catalyst was recovered after the reaction
was complete and reused for a repeat reaction without any significant drop in reactivity [34].
PhCHO
Ph
NH
Ph
OPh
PhNH2
OTMS
Ph
InCl3
309 310 311 312
Scheme-5.12: Synthesis of β-amino ketones using InCl3 catalyst
Chiral β -amino alcohol units are useful as chiral building blocks for various biologically active
compounds. Matsunaga et al, (2003) have reported a highly enantio- and diastereoselective direct
catalytic asymmetric Mannich-type reaction to provide anti-amino alcohols. The process worked well
with from as little as 0.25 to 1 mol % of catalyst loading [35].
NPPh2
O
OO
OH
NH
OH
OPh2P
O
Et2Zn/S,S-Binol
313 314315
Scheme-5.13: Synthesis of anti amino alcohols
The transition metal salt-catalyzed direct three component Mannich reactions of aryl aldehydes,
aryl ketones, and carbamates are described by Xu et al, (2004). The RuCl3.xH2O, AuCl3-PPh3, and
AuCl3-catalyzed direct Mannich reactions (Scheme-5.14) led to the synthesis of N-protected β -aryl- β -
amino ketones [36].
162
CHO
R
O
R1
NH O
CBz
R R1NH2CBz
AuCl3-PPh3
316 317 318
Where R, R1 = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 4-NO2
Scheme 5.14: Transition metal catalysed synthesis of β-amino ketones
Phukan et al, (2006) have reported the synthesis of Mannich reaction between an aryl aldehyde,
aryl ketone and benzyl carbamate using iodine as catalyst (Scheme 5.15). Even the less reactive amines,
also produced Cbz-protected β -aryl β -amino carbonyl compounds in high yields [37].
CHO
R
O
R1
NH O
CBz
R R1NH2CBz
Iodine, 10 mol%
319 320 321
Where R, R1 = H, 4-Cl, 4-Br, 4-Me, 4-OMe, 2-OCH3,
4-OCH3, 2,4-Dichloro
Scheme 5.15: Iodine catalysed synthesis of β-amino ketones
1-Aryl-3-phenethylamino-1-propanone hydrochlorides (Fig 5.5) which are potential potent
cytotoxic agents, were synthesized via Mannich reactions using paraformaldehyde, phenethylamine
hydrochloride as the amine component and substituted acetophenones, as the ketone component by
Mete et al, (2007) [38].
163
O
NH
RHCl
322
Where R = Ph, 4-F-Ph, 4-Me-Ph, 4-Nitro-Ph, 4-OHPh
Figure 5.5: β-Amino ketones
Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts
that direct reactions to yield predominantly one chiral product, complementing enzymes and metal
complexes. Yang et al, (2008) have synthesised β-amino aldehydes (Scheme-5.16) in extremely high
enantioselectivities and reasonable yields [39].
R H
NBoc
H
O
R
NHBoc
CHO
S-Proline
323 324 325
Where R = Ph, 4-CF3Ph, 4-MePh, 3-Nitro-Ph, Furyl, isopropyl
Scheme 5.16: Proline catalysed synthesis of β-amino aldehydes
A novel class of non-steroidal progesterone receptor antagonists with aromatic β-amino ketone
scaffold have been synthesized by Du et al, (2010).These compounds have shown high binding affinity
and great selectivity for the cognate receptor. Among all the synthesised compounds, 3-(3-
fluorophenyl)-3-(4-nitrophenylamino)-1-p-tolylpropan-1-one (Fig 5.6) found to be the most potent
progesterone receptor antagonist in contransfection assay and a model of ligand-induced decidualization
[40].
164
O
F
NH
NO2
326
Fig 5.6: 3-(3-Fluorophenyl)-3-(4-nitrophenylamino)-1-p-tolylpropan-1-one
Wang et al, (2012) have reported the synthesis and antidiabetic study of series of β-amino-
ketone containing nabumetone moiety. All the synthesised compounds are screened for antidiabetic
activity invitro, compound 4-(3-(4-hydroxyphenyl)-1-(3-methoxyphenyl)-3-oxopropylamino)-N-(5-
methylisoxazol-3-yl)benzenesulfonamide (Fig 5.7) has shown peroxisome proliferator-activated
receptor activation and α-glucosidase inhibition activity significantly [41].
O
HO
OMe
NH
SNH N
O
MeO
O
327
[PPAR activation 69.75]
Fig 5.7: 4-(3-(4-Hydroxyphenyl)-1-(3-methoxyphenyl)-3-oxopropylamino)-N-(5-methylisoxazol-3-
yl)benzenesulfonamide
Mannich bases have been widely applied as prodrugs of amine derivative drugs. The analogous
C-Mannich bases (β-aminoketones) have received rather less attention probably because, they are not
sufficiently susceptible to elimination at pH encountered in vivo. Compounds, in which there is a
thermodynamic advantage to elimination, may be an exception. Further from the literature, it was
observed that, β-aminoketones are biologically potent molecules such as, antibacterial, antifungal,
analgesic, anti-inflammatory, and as antivirals.
165
However, the drastic reaction conditions for the classical intermolecular Mannich reaction limit
its synthetic usefulness. Therefore, numerous modifications of this reaction have been developed to
overcome the drawbacks. Many metal complexes have been used as Lewis acid catalysts to promote the
reaction under anhydrous conditions as discussed earlier and few water-compatible Lewis acids were
reported. However, these catalysts suffer from some disadvantages such as requiring a large amount of
Lewis acid (usually more than 10 mol %), a long reaction time, and/or atmosphere sensitive reagents.
There is increasing interest in developing environmentally benign reactions and atom-economic
catalytic processes that employ unmodified ketones, amines, and aldehydes for Mannich-type reaction
in recent years. Cerium chloride is used in many organic reactions as a catalyst, as a reagent. Since it is
highly soluble in water can be easily removed from the reaction by water wash. These properties of
cerium chloride prompted us to try Mannich reaction using cerium chloride as a catalyst. In view of
these facts and in continuation of our research on pharmaceutically important heterocycles, we prepared
a rapid and efficient three-component synthesis of β-aminoketones via a CeCl3 (1 mol %) catalyzed one
pot reaction in microwave, in 3 minutes duration. The product formed can be easily isolated just by
pouring in to water.
5.2. Results and discussions
An efficient catalytic three-component reaction of aldehydes, amines and allyltributylstannate
has been successfully developed to produce homoallylic amines at 25oC, in excellent yields, in the
presence of 1 mol % of trifluoroacetic acid (Scheme 5.17). Newly synthesized compounds were
confirmed by spectral studies. This is a convenient and environmentally benign approach for the
synthesis of homoallylic amines.
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R CHO R1 NH2
SnBu3
TFA 1 mol%
RT R NH
R1
328(a-q) 329(a-q)
330331(a-q)
Scheme 5.17: CF3CO2H catalysed synthesis of Homoallylamines
R NR1
HOCF3
O
R NR1
SnBu3
RHN R1
SnBu3
NHR
R1
HSnBu3
OCF3
O
H
H
HO
CF3
O
Scheme 5.17a: Proposed mechanism for CF3CO2H catalysed synthesis of Homoallylamines
The reaction of benzaldehyde, 1-naphthylamine, and allyltributyl in the presence of 0.1
equivalents CF3COOH (TFA) in acetonitrile at 25˚C resulted in the formation of the homoallylic
amines in 68-98 % yield. The scope and generality of this process is illustrated with respect to different
substrates. Both Aromatic, aliphatic, cyclic and heterocyclic aldehydes reacted smoothly with different
amines to afford the corresponding homoallylic amines in high to excellent yields of the products within
25-60 min, whereas ketones did not yield any product even after long reaction times (15-29 hrs.)
Compounds containing an electron withdrawing group on the aldehydes reacted more efficiently
resulting with higher yields. Amines bearing an electron donating group also favoured the reaction
under the standard reaction conditions to give products less than 1 hour. Furthermore acid-sensitive
aldehyde, furfuraldehyde worked well without any decomposition under the reaction conditions because
of low concentration of acid and at ambient temperature. Enolizable aldehydes, such as
cyclohexanecarboxaldehyde also produced the corresponding homoallylamines in good yields. In all
cases, no homoallylic alcohol (the adduct of aldehyde and allyltributyltin) was obtained under these
167
reaction conditions due too rapid formation and activation of imines in the presence of catalytic amount
of CF3COOH. Results are summarized in Table-5.1.
Table-5.1: Newly synthesized homoallylic amines (331 a-q)
S. No R
R1 Reaction time(min)Yield (%)
331a Phenyl Napthyl 30 95
331b
2-Benzofuran
3,4-Diflurobenzyl
35
90
331c
Cyclopropyl 4-t-Butylphenyl
30
98
331d
2,4-Difluorophenyl 2,4,5-Trifluorophenyl 45
89
331e
2-Benzofuran
Napthyl
30
90
331f
2,4-Difluorophenyl 4-t-Butylaniine
45
95
331g 2-Fluoro-5-methoxyphenyl 3-Fluorophenyl 45
82
331h
Cyclopropane carboxaldehyde
4-Fluoro-3-trifluoromethyl-Phenyl
30
85
331i
Cyclohexane carboxaldehyde 4-Morpholinophenyl 60
78
331j
Cyclohexane carboxaldehyde 2,5-Dimemethylphenyl
30
88
331k 2-Allyloxyphenyl 4-(4-Chlorophenoxy) Phenyl45 75
331l
5-(2-Chlorophenyl)furan-2-carbaldehyde
4-(4-Chlorophenoxy) phenyl60
73
331m 1-Acetyl-1H-3-indolyl Benzo[d]thiazol-7-amine 60
68
331n
2,4-Difluorophenyl 2,4-Difluorophenyl 45
75
331o
2,6-Difluorophenyl 4-Chloro-3-fluorophenyl 30
78
331p
2-Thiophenyl 4-Cyanophenyl
45
68
331q 3-Ethoxyphenyl 4-Fluorophenyl 30 72
All aldehydes, amines, allyltributyltin, CF3CO2H and solvents are purchased from commercial
sources and all the aldehydes and solvents were distilled before use. Reactions were monitored on TLC
168
by comparison with the starting materials. Yields refer to the isolated yields of the products after
purification by flash chromatography.
All the reactions are monitored by mass analysis of crude reaction mixture and by TLC using
ethylacetate: hexane as eluent. An unambiguous structure proof of compound (331o) was achieved by
an examination of the crystal structure of compound (331o). In the molecule of the title homoallylic
amine, C16H13ClF3N, the dihedral angle between the two benzene rings is 84.63 (4)o. Weak
intramolecular N—H-----F hydrogen bonds generate S(6) and S(5) ring motifs. In the crystal structure,
weak intermolecuar N—H-----F hydrogen bonds link molecules into centrosymmetric dimers which are
arranged in molecular sheets parallel to the ac plane. Fig.-5.11 shows crystal structure of compound
(331o). In 1H NMR spectra, presence of triplet proton at 4.5-4.7 clearly confirmed the formation of
homoallylamine, and it is supported by 13 C NMR spectra where single peak at 48-50 indicates the
junction carbon of the homo allylamine. In case of compound (331a) LCMS of the compound shows
97.9% purity and also molecular ion peak 274, which confirms the molecular weight of the compound.
In 1H NMR peak at 4.55-4.61 (m, 1H, CH) indicates the junction –CH of homoallylamine. Also in the
aromatic region presence 4 set of multiplets indicates the presence of naphthalene and phenyl rings in
the compound.
Three-component Mannich reaction of ketones, aldehydes and different amines in microwave
irradiation afforded corresponding β-amino carbonyl compounds in good yields (Scheme 5.18).
Solvent Free, 83-95%
O O HN
R
R1
CeCl3/Microwave, 3 minR CHO R1 NH2
332 333(a-k) 334(a-k) 335(a-k)
Scheme 5.18: CeCl3 catalysed synthesis of β-amino ketones
169
The different substituent used and yield of the reactions are mentioned in Table-5.2.
Proposed mechanism for CeCl3 catalysed Synthesis of β-amino ketones
R1
NH2
NR1
R
CeCl3
O O
CeCl3
O
R
HNR1
CeCl3
R H
O
CeCl3
R NH2
OHR1
CeCl3
R NH
OH
R1
-H2O
Table-5.2: Newly synthesized β-aminoketones (335 a-k)
S.No R R1 Yield (%)a Anti/Synb
335a Phenyl t-Butylphenyl 87 100:0 335b 4-Fluorophenyl 2,4-Difluorophenyl 86 100:0 335c 2-Chlorophenyl 4-Cyanophenyl 95 100:0
335d 2-Fluoro-5-methoxy phenyl 2,4-Difluorophenyl 92 100:0 335e 2-Fluorophenyl 3,4-Difluorophenyl 88 100:0 335f 2-Allyloxyphenyl 3-Fluorophenyl 85 100:0 335g 2-Hydroxy-3-methyl phenyl 3-Methoxyphenyl 93 100:0 335h 4-Ethylphenyl 3,4,5-Trifluoro-methyl phenyl95 100:0 335i 4-Ethylphenyl 4-Methyl-3 nitro phenyl 90 60:40
335j 2-Benzofuran Napthyl 83 100:0 335k 4-Pyridyl 2-Methyl-5-aminoindole 88 100:0
170
In our initial experiments, substituted benzaldehyde (333a), substituted aniline (334), and
cyclohexanone (332) in acetonitrile were stirred for 4 hours in the presence of catalytic amount (1 mol
%) of CeCl3 at room temperature. Even after 4 hours, no product was observed in mass analysis; further
reaction mixture was heated to 80oC for 8 hours, which gave the corresponding β-aminoketones (335a)
in very low yield (25 %), with unreacted imine. Even after increasing the quantity of catalyst loading to
10 mol %, no any sign of improvement of the reaction. Further in our study we have used substituted
benzaldehyde (333a), aniline (334a), cyclohexanone (332), and 1 mol % of CeCl3 in microwave tube,
sonicated for 1 min, and irradiated in microwave for 3 min. Mass analysis of crude reaction mixture
showed formation of only product with no starting material or side product.
1H-NMR and 13C-NMR spectra were recorded on 400-MHz and 300-MHz Bruker
spectrometers, respectively. Elemental analysis was performed on a Thermo Finnigan FLASH EA 1112
CHN analyzer. Melting points were recorded (uncorrected) on a Buchi Melting Point B-545 apparatus.
All the compounds (335a-k) were synthesized in-house from the corresponding commercially available
aldehydes, amines and ketone. The products were characterized by1H-NMR, 13C-NMR, MS, and
elemental analysis. The structure of compound (335a) was further confirmed by single-crystal X-ray
analysis. In the molecule of the title compound, C23H29NO, the cyclohexanone ring has been distorted
from the standard chair conformation by the ketone group such that part of the ring is almost flat. The
remaining [(4-tert-butylanilino)(phenyl) methyl] portion of the molecule is in an equatorial position on
the cyclohexanone ring. The dihedral angle between the two benzene rings is 81.52 (8)o. In the crystal
packing, molecules are linked by N-H…O hydrogen bonds into infinite one-dimensional chains along
the axis and these chains are stacked down the c axis. The crystal structure is further stabilized by weak
C-H…O and C-H interactions. In this method major anti-isomer was formed except in the case of
compound (335i), where 1:1 mixture of syn and anti-isomers formed, confirmed by 13C-NMR, where
171
two distinct peaks for C=O is observed at 211 and 212. This may due to electron donating and electron
withdrawing groups present in the same molecule. The anti and syn isomers were identified by the
coupling constants (J) of the vicinal protons adjacent to C=O and NH in their 1H-NMR spectra. In
general, the coupling constants for anti-isomers are greater than that for syn isomers. The ratio of the
isomers was determined by integration of the corresponding peaks in 1H NMR spectra. For example in
case compound (335b) triplet peaks at 4.59 in 1H NMR indicates the junction –CH and the same carbon
is observed at 57.3 in 13C NMR, also C=O peak is seen at 211.8. LCMS of the compound shows 99.3%
purity and molecular ion peak at 336 which confirmed the molecular weight of the compound.
5.3. Synthesis
5.3.1. General procedures
5.3.1. General Procedure synthesis of Homoallylamines (331a-q)
To a mixture of aldehyde (10 mmol), amine (10 mmol) and allyltributyltin (10 mmol) in
acetonitrile (5 mL), CF3COOH (1 mmol) was added. The reaction mixture was stirred at 25˚C under
nitrogen atmosphere for an appropriate time. After completion of the reaction, as indicated by TLC and
mass analysis, the reaction mixture was extracted with diethyl ether (3×20 ml). The combined organic
layers were concentrated in vacuum and purified by flash chromatography to afford the pure
homoallylic amines (331a-q).
5.3.2. General procedure for synthesis of β-amino ketones (335a-k)
A mixture of aldehyde (1 mmol), amine (1 mmol), cyclohexanone (1 mmol) and cerium chloride
(1 mol %) were taken in a sealed pressure regulation 10-mL pressurized vials with“snap-on” cap and
sonicated for 2 min; resulting mixture was irradiated in the single-mode microwave synthesis system at
120W power and 100 ºC temperature for 3 minutes. Completion of reaction was confirmed by mass
172
analysis and TLC. Reaction mixture was diluted with water and the solid separated was filtered, dried
and recrystalised using ethyl acetate to yield pure product (335 a-k).
5.4. Characterization
5.4.1. Experimental Data:
5.4.1.1. Naphthalene-1-y-(1-phenyl –but-3-enyl)- amine (331a)
Yield; 95%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC):δ = 2.72-2.83 (m, 2H, CH2), 4.55-4.61 (m, 1H, CH), 5.18-5.22 (d, 1H, J = 16 Hz), 5.31-5.36 (m,
1H, CH2), 5.80-5.90 (m, 1H, CH2), 6.36 (br. s, 1H, NH), 7.14-7.27 (m, 4H, Ar-H), 7.31-7.38 (m, 2H,
Ar-H), 7.41-7.78 (m, 4H, Ar-H), 7.93-7.7.95 (m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ =
43.4, 57.0, 106.3, 117, 118.6, 119.7, 123.4, 124.7, 125.6, 126.2, 127.0, 128.7, 128.9, 134.2, 134.7,
141.8, 143.0. LCMS (97.9%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm
5µm, RT = 3.4 min, m/z = 274 [M + H]+). Anal. Calc. for C20H19N: C 87.91, H 6.96, N 5.13. Found: C
87.9, H 6.95, N 5.11%.
5.4.1.2. (1-Benzofuran-2-yl-but-enyl)-(3,5-difluoro-benzyl)-amine (331b)
Yield; 90%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ= 2.59-2.75 (m, 2H, CH2), 3.71-3.75 (m, 1H,), 3.83-3.3.92 (m, 2H, CH2), 5.08- 5.17 (m, 2H,
CH2), 5.71-5.81 (m, 1H, CH), 6.64 (s, 1H, NH), 6.77-6.84 (m, 2H, Ar-H), 7.24-7.37 (m, 3H, Ar-H),
7.48-7.50 (m, 1H, Ar-H), 7.55-7.57 (m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 39.12, 44.3,
55.4, 103.4, 104, 110.9, 111, 118, 120.7, 122, 123, 128, 131.13, 134.2, 154.8, 158, 159.8, 162. LCMS
(96.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT=1.0 min,
m/z = 314 [M + H]+). Anal. Calc. for C19H17F2NO; C 72.84, H 5.43, N 4.47. Found: C 72.82, H 5.44, N
4.45%.
173
5.4.1.3. (4-Tert-butyl-phenyl)-(1-cyclopropyl-3-but-enyl)-amine (331c)
Yield; 90%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.6), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 0.330.35 (m, 2H, CH2), 0.50 (m, 2H, CH2), 1.09 (m, 1H, CH), 1.29 (s, 9H, t-butyl), 2.44-2.47
(m, 2H, CH2), 2.95-2.97 (m, 1H, CH), 3.5 (bs, 1H, NH), 5.12 (m, 2H, CH2), 5.97-5.99 (m, 1H, CH),
6.60-6.62 (d, 2H, J = 8 Hz, Ar-H), 7.237.24 (d, 2H, J = 8 Hz, Ar-H). 13C NMR (100 MHz,
CDCl3,24oC): δ= 2.6, 3.40, 16, 31.6, 39.7,56.8, 113, 117, 125.9, 135.2, 139.9, 145.4. LCMS (95%,
Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.1 min, m/z = 244
[M + H]+). Anal. Calc. for C17H25N;C 83.95, H 10.29, N 5.76. Found: C 83.97, H 10.26, N 5.75%
5.4.1.4. [1-(2, 4-Diflurophenyl)-but-3-enyl]- (2, 4, 5-trifluoro-phenyl)-amine (331d)
Yield; 90%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.47-2.2.63 (m ,2H, CH2), 4.13-4.26 (m, 2H, 2CH), 5.20-5.24 (m, 2H, CH2), 5.70-5.77 (m,
1H, CH), 6.11-6.5 (m, 1H, Ar-H), 6.84-6.88 (m, 1H, Ar-H), 7.09-7.73 (m, 3H, Ar-H). 13C NMR (100
MHz, CDCl3,24oC): δ = 42.9, 56.5, 101, 104, 115, 117, 119, 122, 132, 139, 139.7, 144, 147, 150. LCMS
(94.6%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT = 3.8 min,
m/z = 312 [M -H]). Anal. Calc. for C16H12F5N;C 61.34, H 3.83, N4.47. Found: C 61.33, H 3.84, N
4.45%.
5.4.1.5. (1-Benzofuran-2-yl-but-3-eny)-napthalen-1-yl-amine (331e)
Yield; 90%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.93 (t, 2H, J = 8 Hz, CH2), 4.90 (t, 1H, J = 4 Hz, CH), 5.35 (m, 2H, CH2), 5.94 (m, 1H, CH),
6.64 (m, 1H, Ar-H), 7.23-7.29 (m, 2H, Ar-H), 7.44-7.50 (m, 5H, Ar-H), 7.8(m, 1H, Ar-H), 7.90 (m, 1H,
Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 39.2, 51.69, 102, 106, 111, 118, 119, 120, 123, 124,
174
125.2, 126, 128, 133, 134, 154.3, 158. Anal.Calc. for C22H19NO; C 84.35, H 6.07, N 4.47. Found: C
84.32, H 6.06, N 4.46%.
5.4.1.6. (4-tert-Butyl-phenyl)- [1-(2, 4-difluoro-phenyl)-but-3-eny]-amine (331f)
Yield; 90%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.54), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 1.36 (s, 9H, t-butyl), 2.52 (m, 2H, CH2), 4.35 (q, 1H, J = 8 Hz, CH), 5.29 (m, 2H, CH2), 6.02
(m, 1H, Ar-H), 6.52 (d, 2H, J = 8 Hz, Ar-H), 7.18-7.23 (m, 4H, Ar-H), 7.32 (m, 1H, Ar-H). 13C NMR
(100 MHz, CDCl3,24oC): δ = 31.6, 33.7, 43.3, 56.77, 113, 115, 117, 118, 122, 125, 134, 140, 141, 144,
150. LCMS (90%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm,
RT=4.3min, m/z = 316 [M +H]+).Anal. Calc. for C20H23F2N; C 76.19, H 7.30, N 4.44. Found: C 76.16,
H 7.28, N 4.42%.
5.4.1.7. [1-(2-Fluoro-6-methoxy-phenyl)-but-3-enyl]- (3-fluorophenyl)-amine (331g)
Yield; 82%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.7), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.4 (m, 1H, CH2), 2.5 (m, 1H, CH2), 3.6 (s, 3H,-OCH3), 4.59 (t, 1H, J = 4 Hz, CH), 5.1 (m,
2H, CH2), 5.6 (m, 1H, CH), 6.1 (dd, 1H, J = 4 Hz, Ar-H), 6.39 (m, 2H, Ar-H), 6.6 (m, 1H, Ar-H), 6.7
(m, 1H, Ar-H), 6.9 (m, 2H, Ar-H). 13C NMR (100 MHz, CDCl3,24oC): δ = 40.9, 51.2, 55.8, 100.2,
104.4, 112.8, 113, 115, 116, 127, 128, 130, 133, 148, 152. LCMS (90%, Method; 0.1% HCOOH; ACN,
Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT = 3.5 min, m/z = 290 [M +H]+). Anal.Calc. for
C17H17F2NO; C 70.59, H 5.88, N 4.84. Found: C 70.60, H 5.85, N 4.83%.
5.4.1.8. (1-Cyclopropyl-but-3-enyl)-(4-fluoro-3-trifluoromethyl-phenyl)-amine (331h)
Yield; 85%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.8), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 0.330.35 (m, 2H, CH2), 0.50 (m, 2H, CH2), 2.4 (q, 2H, J = 8 Hz, CH), 2.9 (q, 1H, J = 8 Hz,
CH), 5.2 (m, 2H, CH2), 5.9 (m, 1H, CH), 6.68 (t, 1H, J = 4 Hz, Ar-H), 6.76 (t, 1H, J = 4 Hz, Ar-H), 7.0
175
(m, 1H, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ = 2.8, 3.1, 15.8, 39.3, 57, 110, 117.2, 118, 118.5,
121.5, 134, 144, 153. LCMS (93.5%, Method; 0.1% HCOOH; ACN, Flow 1.0mL/min, Column C 18
75X4.6mm 5µm, RT = 1.9 min, m/z = 272 [M -H]). Anal. Calc. for C14H15F4N; C 61.54, H 5.49,N 5.13.
Found: C 61.57, H 5.47, N 5.11%.
5.4.1.9. (1-Cyclohexyl-but-3-enyl)- (4-morpholin-4-yl-phenyl)-amine (331i)
Yield; 80%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.3), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 1.0-1.32 (m, 4H, 2CH2), 1.5 (m, 2H, CH2), 1.6-1.8 (m, 5H, CH2), 2.2 (m, 2H, CH2), 2.95-3.3
(bs, 4H, -NCH2), 3.75 (m, 4H, -OCH2), 5.2 (m, 2H, CH2), 5.75 (m, 1H, CH), 6.5-7.0 (bs, 4H, Ar-H). 13C
NMR (100 MHz, CDCl3, 24oC): δ = 26.8, 29.5, 35.6, 41.2, 51.0, 58.2, 68.9, 114.1,116, 118, 128, 129,
142. LCMS (96%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT
= 3.9 min, m/z = 315 [M + H]+). Anal.Calc. for C20H30N2O; C 76.43, H 9.55, N 8.92. Found: C76.41, H
9.54, N 8.91%.
5.4.1.10. (1-Cyclohexyl-but-3-enyl)- (2, 5-dimethyl-phenyl)-amine (331j)
Yield; 88%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 1.1-1.3 (m, 5H, CH2), 1.7 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.82 (m, 3H, CH2), 1.92 (d, 1H,
J = 12 Hz, CH2), 2.15 (s, 3H, Ar-CH3), 2.3 (m, 1H, CH2), 2.35 (s, 3H, Ar-CH3), 2.42 (m, 1H, CH2), 3.9
(q, 1H, J = 4 Hz, CH), 5.12(m, 2H, CH2), 5.8 (m, 1H, CH), 6.48 (d, 2H, J = 8Hz, Ar-H), 6.97 (d, 1H, J =
8 Hz, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ = 17.2, 21.7, 26.5, 26.7, 29.5, 35.8, 41.2, 57.0,
110.8, 116.4, 117.1, 117.5, 130.2, 135.2, 135.7, 136.6. LCMS (96%, Method; 0.1% HCOOH; ACN,
Flow 0.8mL/min, Column C 18 75X4.6mm 5µm, RT=3.9 min, m/z = 258 [M + H]+).Anal. Calc. for
C18H27N; C 84.05, H 10.51, N 5.45. Found: C 84.02, H 10.50, N 5.43%.
5.4.1.11. [1-(2-Allyloxy-phenyl)-but-3-enyl]-[4-(4-chloro-phenoxy)-phenyl]-amine (331k)
176
Yield; 75%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.55 (m, 1H, CH2), 2.75 (m, 1H, CH2), 4.3 (bs, 1H, NH), 4.68 (t, 2H, J = 4 Hz, -OCH2), 5.3
(m, 1H, CH), 5.36- 5.39 (m, 2H, CH2), 5.51 (d, 1H, J = 16 Hz, CH), 5.84 (d, 1H, J = 13.6 Hz, CH2), 5.9
(m, 1H, CH), 6.13-6.20 (m, 1H, Ar-H), 6.54 (d, 2H, J = 12 Hz, CH), 6.82-6.9 (m, 4H, Ar-H), 6.9 (m,
2H, Ar-H), 7.2 (m, 3H, Ar-H), 7.39 (d, 1H, J = 8 Hz, Ar-H). 13C NMR (100 MHz, CDCl3, 24oC): δ=
40.6, 52.0, 68.5, 11.6, 114.2, 117.0, 117.6, 118.2, 120.8, 123, 126.5, 127.1, 127.7, 130.2, 130, 133.2,
135.2, 144.2, 147.0, 155.6, 157.7. LCMS (98%, Method; 0.1% HCOOH; ACN, Flow 1.0mL/min,
Column C 18 75X4.6mm 5µm, RT = 2.6 min, m/z = 406 [M + H]+). Anal.Calc. for C25H24ClNO2; C
73.98, H 5.92, N 3.45. Found: C 73.97, H 5.90, N3.44%.
5.4.1.12. [4-(4-Chloro-phenoxy)-phenyl]-{1-[5-(2-chloro-phenyl)-furan-2-yl]-but-3-enyl}-amine
(331l)
Yield; 73%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ= 2.7 (bs, 2H, CH2), 4.50 (t, 1H, J = 4 Hz, CH), 5.0 (m, 2H, CH2), 5.6 (m, 1H, CH), 6.25 (s, 1H,
Ar-H), 6.76 (m, 2H, Ar-H), 7.16 (m, 4H, Ar-H), 7.18 (d, 1H, J = 4 Hz, Ar-H), 7.23 (m, 3H, Ar-H), 7.3
(m, 1H, Ar-H), 7.35 (d, 1H, J = 4 Hz, Ar-H), 773 (d, 1H, J = 4 Hz, Ar-H). 13C NMR (100 MHz, CDCl3,
24oC): δ = 40, 60, 100, 111.6, 118.5, 118.8, 120, 126, 127.6, 127.9, 129, 129.4, 130.7, 133.5, 144.5,
149, 150, 157. Anal.Calc. for C26H21Cl2NO2; C 69.33, H 4.67, N 3.11. Found: C 69.34, H 4.65, N
3.10%.
5.4.1.13. 1-{3-[1-(Benzothiazol-7-ylamino)-but-3-enyl]-indol-1-yl}-ethanone (331m)
Yield; 68%, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.5 (s, 1H, CH3), 2.72 (m, 1H, CH2), 2.88 (m, 1H, CH2), 4.78 (q, 1H, J = 4 Hz, CH), 5.26 (m,
2H, CH2), 5.85 (m, 1H, CH), 6.87 (d, 1H, J = 8 Hz, Ar-H), 7.0 (s, 1H, Ar-H), 7.27-7.41 (m, 3H, Ar-H),
7.7 (m, 1H, Ar-H), 7.89 (d, 2H, J = 8 Hz, Ar-H), 8.46 (bs, 1H, NH), 8.67 (s, 1H, Ar-H). 13C NMR (100
177
MHz, CDCl3, 24oC): δ= 26.9, 40.4, 50.4, 103.8, 105, 105.7, 115.1, 117.0, 118.9, 122.5, 123.6, 123.7,
123.8, 125.5, 128, 134, 135.7, 136.6, 145.6, 146.1, 168.6.LCMS (76%, Method; 0.1% HCOOH; ACN,
Flow 1.0mL/min, Column C 18 75X4.6mm 5µm, RT = 3.7 min, m/z = 362 [M + H]+).Anal. Calc. for
C21H19N3OS: C 69.81, H 5.26, N 11.63. Found: C 69.79, H 5.25, N 11.60%.
5.4.1.14. (2, 4-Difluoro-phenyl)- [1-(2, 4-difluoro-phenyl)-but-3-enyl]-amine (331n)
Yield; 75%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.6), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC), δ= 2.5-2.6 (m, 2H, CH2), 4.3 (bs, 1H, NH), 4.69 (m, 1H, CH), 5.24 (m, 2H, CH2), 5.74 (m, 1H,
CH), 6.34 (m, 1H, Ar-H), 6.59 (m, 1H, Ar-H), 6.64-6.87 (m, 3H, Ar-H), 7.3 (m, 1H, Ar-H). 13C NMR
(100 MHz, CDCl3, 24oC): δ = 41.2, 50.7, 103, 110, 11.4, 112.9, 119.0, 125.2, 128.5, 131.6, 133.4,
149.6, 152.1, 153.3, 155.6, 160.7 LCMS (94.7%, Method; 0.1% HCOOH; ACN, Flow 0.8mL/min,
Column C 18 75X4.6mm 5µm, RT = 3.9 min, m/z = 295.9 [M + H]+). Anal.Calc. for C16H13F4N; C
65.08, H 4.41, N4.75. Found: C 65.10, H 4.39, N 4.73%.
5.4.1.15. (4-Chloro-2-fluoro-phenyl)- [1-(2, 6-difluoro-phenyl)-but-3-enyl]-amine (331o)
Yield; 78%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.65), White solid; m.p. 126-127oC. 1H NMR (400
MHz, CDCl3, 24oC): δ = 2.72 (m, 1H, CH2), 2.87 (m, 1H, CH), 4.95 (m, 1H, CH), 5.28 (m, 1H, CH2),
5.71(m, 2H, CH2, NH), 5.81(m, 1H, CH), 6.68 (m, 1H, Ar-H), 6.8-6.9 (m, 4H, Ar-H), 7.2 (m, 1H, Ar-
H). 13C NMR (100 MHz, CDCl3): δ = 39.5, 48.3, 111.6, 113.0, 115.3, 117.5, 118.3, 121.2,124.4, 128.9,
129.0, 133.7, 152, 160, 162.5. LCMS (99.5%, Method; 0.1% HCOOH; ACN, Flow 0.8 mL/min,
Column C 18 75X4.6mm 5µm, RT = 4.2 min, m/z = 311.9 [M + H]+).Anal.Calc. for C16H13ClF3N: C
61.64, H 4.17, N 4.49. Found: C 61.61, H 4.14, N 4.47%.
5.4.1.16. 4-(1-Thiophen-2-yl-butylamino)-benzonitrile (331p)
178
Yield; 68%, (TLC, Pet-ether/EtOAc, 1:1, Rf =0.5), Thick liquid. 1H NMR (400 MHz, CDCl3,
24oC): δ = 2.7 (m, 2H, CH2), 4.77 (m, 1H, CH), 5.2 (m, 2H, CH2), 5.7 (m, 1H, CH), 6.56 (d, 2H, J =
8.Hz, Ar-H), 6.97 (d, 2H, J = 4 Hz, Ar-H), 7.20 (d, 1H, J = 4 Hz, Ar-H), 7.38 (d, 2H, J = 8 Hz, Ar-H).
13C NMR (100 MHz, CDCl3): δ = 42.6, 52.7, 99.4, 113.1, 119.3, 120.3, 124.0, 124.4, 127.0, 133.3, 133.,
146.6, 150.1. LCMS (96.0%, Method; 0.1% HCOOH; ACN, Flow 0.8 mL/min, Column C 18
75X4.6mm 5µm, RT = 2.6 min, m/z = 355 [M + H]+). Anal.Calc. for C15H14N2S; C 70.87, H 5.51, N
11.02. Found: C 70.85, H 5.50, N 11.01%
5.4.2.1. 2-((4-Tert-butylphenylamino)(phenyl) methyl) cyclohexanone (335a)
Yield; 87%, Off white solid, M.p. 154-156oC (TLC, Pet-ether/EtOAc, 1:1, Rf= 0.3). 1H NMR
(400 MHz, CDCl3, 24oC):δ 7.41 (t, J = 8 Hz, 2H, Ar-H), 7.32 (m, 2H, Ar-H), 7.23 (m, 1H, Ar-H), 7.1 (t,
j = 8 Hz, 2H, Ar-H), 6.5 (t, J = 8.8 Hz, 2H, Ar-H), 4.63 (d, J = 7.2 Hz, 1H, CH), 2.8 (m, 1H, CH), 2.3-
2.5 (m, 2H,CH2), 1.8 (m, 4H,2CH2), 1.6 (m, 2H, CH2), 1.23 (s, 9H, 3CH3).13C-NMR (100 MHz, CDCl3,
24oC): δ 212.8, 144.8, 142.0, 140.1, 128.4, 127.3, 127.1, 125.8, 113.2, 58.1, 57.5, 41.7, 33.7, 31.5, 31.1,
27.8, 23.5. IR (neat): 1/λ = 3375, 3025, 1760, 1619 cm-1. LCMS (99.3%, Method; 0.1% HCOOH; ACN,
Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.4 min, m/z = 336.4 [M + H]+). Anal. Calcd for
C23H29NO (335.22): C, 82.34; H, 8.71; N, 4.18. Found: C, 82.30; H, 8.71; N, 4.20.
5.4.2.2. 2-((2,4-Fluorophenylamino) (4-fluorophenyl)methyl) cyclohexanone (335b)
Yield: 86%, Off white solid, M.p: 163-165ºC (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4), 1H-NMR
(400 MHz, CDCl3, 24oC): δ 7.33 (m, 2H, Ar-H), 7.02 (m, 3H, Ar-H), 6.78 (d, J = 8 Hz, 1H, Ar-H), 6.35
(t, J = 8.8 Hz, 1H, Ar-H), 4.89 (bs, 1H, NH), 4.59 (t, J = 6.8 Hz, 1H, CH), 2.78 (m, 1H, CH), 2.3-2.5
(m, 2H, CH2), 1.6-2.2 (m, 6H, 3CH2).13C-NMR (100 MHz, CDCl3, 24oC):δ 211.8, 163.1, 160.7, 152.5,
150.1, 136.5, 134.5, 128.9, 124.3, 121.2, 115.5, 113.6, 57.3, 42.3, 31.7, 28.5, 23.8. IR (neat): 1/λ =3375,
3025, 1760, 1619 cm-1. LCMS (98.0%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18
179
75X4.6mm 5µm, RT = 3.22 min, m/z = 334.0 [M + H]+). Anal. Calcd for C19H18F3NO (333.1) C, 68.46;
H, 5.44; N, 4.20.Found: C, 68.37; H, 5.35, N, 4.18.
5.4.2.3. 4- ((2-Chlorophenyl) (2-oxocyclohexyl) methylamino) benzonitrile (335c)
Yield: 95%, Off white solid, M.p. 225-227 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.5).1H-NMR
(400 MHz, CDCl3, 24oC): δ 7.19-7.37 (m, 6H, Ar-H), 6.6 (m, 1H, Ar-H), 6.57 (m, 1H, Ar-H), 5.7 (bs,
1H, NH), 5.36 (m, 1H, CH), 2.1-2.6 (m, 7H, 3CH2), 1.8 (m, 2H, CH2).13C NMR( 100 MHz, CDCl3,
24oC): δ 211.8, 149.9, 137.3, 136.7, 135.5, 134.9, 133.6, 130.2, 128.2, 127.3, 126.4, 113.8, 100.2, 60.3,
56.1, 53.5, 27.6, 26.8, 22.6. IR (neat): 1/λ = 3348, 3028, 2243, 1730, 1629 cm-1. LCMS (90.0%,
Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.10 min, m/z =
339.0 [M + H]+). Anal. Calcd for C20H19ClN2O (338.12) C, 70.90; H, 5.65; N, 8.27.Found: C, 70.80;
H, 5.68; N, 8.27.
5.4.2.4. 2-((2,4-Difluorophenylamino)(2-fluoro-methoxyphenyl)methyl)cyclohexanone (335d)
Yield: 92%, Off white solid, M.p.178-180ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.3). 1H-NMR
(400 MHz, CDCl3, 24oC): δ 6.97 (m, 2H, Ar-H), 6.76 (m, 2H, Ar-H), 6.69 (m, 1H, Ar-H), 6.48 (m, 1H,
Ar-H), 4.83 (bs, 2H, CH, NH), 3.72 (s, 3H, OCH3), 2.84 (m, 1H, CH), 2.43 (m, 2H, CH2), 1.74-1.95 (m,
6H, 3CH2). 13C-NMR (100 MHz, CDCl3, 24oC): δ 212.2, 156.4, 155.9, 155.7, 154.10, 153.4, 152.5,
150.1, 132.0, 128.9, 115.8, 113.1, 110.6, 103.4, 56.155.5, 52.4, 42.2, 32.0, 28.1, 24.2. IR (neat): 1/λ =
3364, 3019, 17410, 1614, 1474 cm-1. LCMS (99.8%, Method; 0.1% HCOOH; ACN, Flow 1mL/min,
Column C 18 75X4.6mm 5µm, RT = 3.43 min, m/z = 364.1 [M + H]+). Anal. Calcd for C20H20F3NO2
(363.14) C, 66.11; H, 5.55 N, 3.85.Found: C, 66.21; H, 5.45 N, 3.88.
5.4.2.5. 2- ( ( 3,4-Difluorophenylamino)(4- fluorophenyl)methyl)cyclohexanone (335e)
180
Yield: 88%, Off white solid, M.p: 235-238 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.4). 1H NMR
(400 MHz, CDCl3): δ 7.34 (m, 2H, Ar-H), 7.03 (m, 3H, Ar-H), 6.89 (m, 1H, Ar-H), 6.21 (m, 2H, Ar-
H), 4.76 (bs, 1H, NH), 4.46 (s, 1H, CH), 2.73 (m, 1H, CH), 2.3-2.44 (m, 2H, CH2), 1.6-1.92 (m, 6H,
3CH2).13C NMR (100 MHz, CDCl3, 24oC): δ 212.0, 162.7, 160.3, 151.5, 149.4, 143.8, 141.6, 136.4,
128.3, 116.9, 115.1, 108.5, 102.0, 57.8, 56.8, 41.8, 31.3, 27.5, 23.7. IR (neat): 1/λ = 3323, 3018, 1761,
1619, 1464 cm-1. LCMS (98.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18
75X4.6mm 5µm, RT = 3.22 min, m/z = 334.0 [M + H]+). Anal. Calcd for C19H18F3NO (333.13) C,
68.46; H, 5.44; N, 4.20.Found: C, 68.46; H, 5.48; N, 4.30.
5.4.2.6. 2-((3-Fluorophenylamino)(2-(allyloxy)phenyl)methyl)cyclohexanone (335f)
Yield: 85%, Brown solid, M.p. 175-177ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR
(400 MHz, CDCl3, 24oC): δ 7.37 (m, 1H, Ar-H), 7.20 (m, 1H, Ar-H), 6.8-6.96 (m, 3H, Ar-H), 6.12-6.35
(m, 4H, Ar-H, CH2=CH), 5.51 (d, J = 8 Hz, 1H, CH), 5.38 (m, 1H, CH), 5.11 (m, 1H, CH), 4.96 (bs,
1H, NH), 4.67 (s, 2H, OCH2), 2.94 (m, 1H, CH), 2.34 (m, 2H, CH2), 1.58-1.96 (m, 6H, 3CH2). 13C
NMR (100 MHz, CDCl3, 24oC): δ 213.0, 164.8, 162.4, 155.6, 148.9, 132.7, 129.6, 128.8, 127.7, 120.6,
117.1, 111.05, 109.0, 103.0, 99.6, 68.3, 55.3, 52.3, 41.6, 31.6, 27.7, 23.5. IR (neat): 1/λ =3326, 3017,
1758, 1634, 1484cm-1. MS-m/z = 354.1[M+1].. nal. Calcd for C22H24FNO2 (353.18) C, 74.76; H, 6.84;
N, 3.96.Found: C, 74.76; H, 6.88; N, 3.96.
5.4.2.7. 2-((3-Methoxyphenylamino)(2-hydroxy-3-methylphenyl)methyl) cyclohexanone (335g)
Yield: 93%, Off white solid, M.p. 185-187ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2).1H NMR
(400 MHz, CDCl3, 24oC): δ 7.36 (d, 1H, J = 12 Hz, Ar-H), 7.20 (m, 2H, Ar-H), 6.71 (m, 2H, Ar-H),
6.35 (m, 1H, Ar-H,), 6.02 (s, 1H, Ar-H), 4.42 (bs, 1H, NH), 4.01 (s, 1H, CH), 3.75 (s, 3H, -OCH3), 2.85
(m, 1H, CH), 2.11 (m, 4H, CH3, CH), 1.47-1.96 (m, 6H, 3CH2).13C NMR (100 MHz, CDCl3, 24oC): δ
211.0, 16.0, 151.5, 144.6, 129.8, 128.3, 126.2, 120.0, 119.1, 114.5, 105.2, 99.84, 74.27, 54.93, 51.27,
181
38.92, 34.81, 26.2, 25.5, 22.8, 16.22. IR (neat): 1/λ = 3356, 3037, 1757, 1636, 1464cm-1. LCMS (96.5%,
Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 4.0 min, m/z =
322.0 [M -18, -OH]). Anal. Calcd for C21H25NO3 (339.18) C, 74.31; H, 7.42; N, 4.13.Found: C, 74.34;
H, 7.52; N, 4.18.
5.4.2.8. 2-((3,4,5-Trifluorophenylamino)(4-ethylphenyl)methyl)cyclohexanone (335h)
Yield; 95%, Off white solid, M.p: 168-170 ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.6).1H NMR
(400 MHz, CDCl3, 24oC): δ 7.25 (m, 2H, Ar-H), 7.15 (m, 2H, Ar-H), 6.84 (m, 1H, Ar-H), 6.3 (m, 1H,
Ar-H), 4.84 (bs, 1H, NH), 4.46 (s, 1H, CH), 2.77 (m, 1H, CH), 2.64 (m, 2H, CH2), 2.36-2.46 (m, 2H,
CH2), 1.62-2.01 (m, 6H, 3CH2), 1.23 (t, J = 4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3, 24oC): δ
212.1, 143.57, 137.6, 128.17, 127.05, 104.5, 101.8, 58.2, 57.2, 42.2, 31.7, 28.1, 27.9, 24.2, 15.2. IR
(neat): 1/λ = 3275, 3063, 2925, 1724, 1630, 1544, 1461 cm-1. LCMS (95.9%, Method; 0.1% HCOOH;
ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 3.90 min, m/z = 362.1 [M + H]+). Anal.
Calcd for C21H22F3NO (361.17) C, 69.79; H, 6.14; N, 3.88.Found: C, 69.79; H, 6.14; N, 3.88.
5.4.2.9. 2-((4-Methyl-3-nitrophenylamino)(4-ethylphenyl)methyl)cyclohexanone (335i)
Yield; 90%, Yellow solid, M.p.178-180ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR
(400 MHz, CDCl3, 24oC): δ 7.22 (m, 2H, Ar-H), 7.17 (m, 3H, Ar-H), 6.96 (m, 1H, Ar-H), 6.6 (m, 1H,
Ar-H), 4.84 (bs, 1H, NH), 4.5-5.0 (m, 1H, CH, NH), 2.78 (m, 1H, CH), 2.6 (m, 2H ,CH2), 2.06-2.36 (m,
5H, CH2, CH3), 1.62-1.9 (m, 6H, 3CH2), 1.22 (t, J = 4Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3,
24oC): δ 212.9, 211.3, 149.4, 146.4, 146.2, 143.4, 137.5, 128.1, 121.6, 118.6, 109.2, 58.07, 57.08, 56.2,
28.5, 26.8, 24.8, 23.8, 19.4, 15.2. IR (neat): 1/λ = 3470, 3367, 2955, 1719, 1544, 1461 cm-1. LCMS
(94.3%, Method; 0.1% HCOOH; ACN, Flow 1mL/min, Column C 18 75X4.6mm 5µm, RT = 3.79 min,
182
m/z = 367.0 [M + H]+). Anal. Calcd for C22H26N2O3 (366.1) C, 72.11; H, 7.15; N, 7.64.Found: C, 71.99;
H, 7.18; N, 7.65.
5.4.2.10. 2-((Benzofuran-2-yl)(naphthalen-1-ylamino)methyl)cyclohexanone (335j)
Yield 83%, Brown solid, M.p. 218-220ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2).1H NMR (400
MHz, CDCl3, 24oC): δ 8.35 (m, 1H, Ar-H), 7.21-7.79 (m, 7H, Ar-H), 6.85 (m, 1H, Ar-H), 6.45 (m, 1H,
Ar-H), 4.60 (d, J = 8Hz, 1H, CH), 4.28 (bs, 1H, NH), 3.01 (m, 1H, CH), 1.5-2.59 (m, 8H, 4CH2). 13C
NMR (100 MHz, CDCl3, 24oC): δ 211.1, 158.0, 154.9, 140.0, 131.4, 128.7, 128.5, 124.2, 123.8, 122.5,
121.0, 120.9, 117.1, 113.7, 111.4, 104.5, 58.0, 53.10, 42.23, 35.01, 31.2, 26.3, 25.5, 21.10. IR (neat): 1/λ
= 3335, 3067, 1619, 1461, 1254 cm-1. Anal. Calcd for C25H23NO2 (369.17) C, 81.27; H, 6.27; N,
3.79.Found: C, 81.37; H, 6.27; N, 3.80.
5.4.2.11. 2-((2-Methyl-1H-indol-5-ylamino)(pyridin-4-yl)methyl)cyclohexanone (335k)
Yield 88%, Brown solid, M.p: 185-190ºC, (TLC, Pet-ether/EtOAc, 1:1, Rf = 0.2). 1H NMR (400
MHz, CDCl3, 24oC): δ = 8.59 (s, 1H, Ar-H), 8.52 (s, 1H, Ar-H), 7.94 (s, 1H, Ar-H), 7.8 (m, 1H, Ar-H),
7.34 (m, 1H, Ar-H), 7.01 (d, J = 12 Hz, 1H, Ar-H), 6.3-6.6 (m, 3H, Ar-H). 13C NMR (100 MHz, CDCl3,
24oC): δ = 211.3, 149.8, 149.3, 138.3, 137.8, 136.4, 135.5, 135.3, 134.0, 125.5, 122.6, 100.6, 62.2,
40.10, 27.1, 26.5, 21.4, 13.78. IR (neat): 1/λ = 3375, 3050, 2925, 1689, 1461, 1254 cm-1. MS, m/z
[M+1] 334. Anal. Calcd for C21H23N3O (333.18) C, 75.65; H, 6.95; N, 12.60.Found: C, 75.75; H, 6.98;
N, 12.6.
183
5.4.3. Spectral data
184
Fig. 5.8: 1 H NMR spectrum of compound 331p.
NH
CN
331p
S
185
Fig. 5.9: 13 C NMR spectrum of compound 331p.
NH
CN
331p
S
186
NH
CN
331p
S
187
Fig. 5.10: LCMS Data of compound 331p.
NH
CN
331p
S
Mol. Wt.: 254.35
188
Fig. 5.11: Single crystal X-ray structure of 331o
C16H13ClF3N, F000 = 640
Mr = 311.72 Dx = 1.450 Mg m−3
Monoclinic, P21/c Melting point = 399–400 K
Hall symbol: -P 2ybc Mo Kα radiation
λ = 0.71073 Å
a = 10.8980 (1) Å Cell parameters from 7434 reflections
b = 14.0073 (2) Å θ = 2.0–37.5º
c = 10.1651 (1) Å µ = 0.29 mm−1
β = 113.018 (1)ºT = 100 K
NH
F
F
F
Cl
189
Fig. 5.12: 1 H NMR spectrum of compound 331c.
NH
331c
190
Fig. 5.13: 13 C NMR spectrum of compound 331c
NH
331c
191
NH
331c
C17H25N
Mol. Wt.: 243.39
192
Fig. 5.14: LCMS Data of compound 331c
Fig. 5.15: 1 H NMR spectrum of compound 335a
O HN
335a
193
Fig. 5.16: 13 C NMR spectrum of compound 335a
O HN
335a
194
O HN
335a
C23H29NOMol. Wt.: 335.48
195
Fig. 5.17: LCMS data of compound 335a
Fig. 5.18: Crystal structure of compound 335a
Crystal data
C23H29NO Z = 2
Mr = 335.47 F000 = 364
Triclinic, P1 Dx = 1.204 Mg m−3
Hall symbol: -P 1 Melting point = 439–441 K
a = 6.5315 (2) Å Mo Kα radiation
λ = 0.71073 Å
b = 12.3946 (3) Å Cell parameters from 4449 reflections
c = 12.8853 (3) Å θ = 1.8–28.0º
α = 62.973 (1)º µ = 0.07 mm−1
β = 86.347 (2)º T = 100 K
γ = 85.103 (2)º Plate, colorless
NH
O
196
Fig. 5.19: 1 H NMR spectrum of compound 335k
HN
N
O NH
335K
197
Fig. 5.20: 13 C NMR spectrum of compound 335k
HN
N
O NH
335K
198
HN
N
O NH
335K
199
Fig. 5.21: LCMS data of compound 335k
5.5. Conclusion
HN
N
O NH
335K
Mol. Wt.: 333.43
200
This chapter describes a convenient and efficient process for the synthesis of two series of
compounds. Seventeen homoallylic amines are prepared though a three components coupling of various
aldehydes and amines with allyltributyltin in the presence of catalytic amount of CF3COOH. In addition
to its simplicity, efficiency and mild reaction conditions, this method provides high to excellent yields
of products in a short period which makes it a useful and attractive process for the synthesis of
homoallylic amines of synthetic importance. Newly synthesized compounds were characterized by 1H-
NMR, 13C-NMR, Mass spectrometry, X-ray study and elemental analyses. In another series eleven β-
amino ketone are prepared via CeCl3-catalyzed cascade reaction of anilines with various aromatic
aldehydes and carbonyl compounds. The significant features of this procedure include: facile operation,
cheap and readily available catalyst, high yields, and reasonably good diastereo selectivities, very less
reaction time. Antimicrobial activities of both the series are discussed in Chapter-6.
5.6. References
1. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27-51.
2. (a) Biginelli P. Gazz. Chim. Ital.1891, 24, 1317-1319. (b) Kappe, O. Acc. Chem. Res. 2000,
33,879-888.
3. (a) Mannich, C., Krosche, W. “Ueber ein Kondensationsprodukt aus Formaldehyd, Ammoniak
und Antipyrin” Arch. Pharm.1912, 250, 647-667. (b) Mannich, C. “Eine Synthese von β-
Ketonbasen” Arch. Pharm.1917, 255, 261-276.
4. Passerini, M. “Sopra gli isonitrili(II).Composticon aldeidi o con chetoni ed acidi organici
monobasici” Gazz. Chim. Ital. 1921,51, 181-188.
5. (a) Ugi, I., Meyr, R., Fetzer, U. “Versuche mit Isonitrilen” Angew. Chem. 1959, 71, 386-388. (b)
Ugi, I., Steinbrückner, C. “Reaktion von Isonitrilen mit Carbonylverbindungen, Aminen und
Stickstoffwasserstoffsäure” Chem. Ber. 1961, 94, 734-742.
201
6. Yamaguchi, R., Masataka, M., Michihiko, Y., Mituyosi, K. “Highly regioselective .alpha.-
allylation of N-(alkoxycarbonyl) pyridinium salts by means of allyltin reagents” J. Org. Chem.
1985, 50, 287–288.
7. Moser, H., Rihs, G., Santer, H. “Der Einfluss von atropisomerie und chiralem Zentrum auf die
biologische Aktivität des Metolachlor” Z. Naturforsch. 1982, 87B, 451-462.
8. Whitesell, J. K. “C2 symmetry and asymmetric induction” Chem. Rev. 1989, 89, 1581-1590.
9. Sabine, L., Horst, K. “Carbohydrates as chiral templates diastereoselective synthesis of N-
glycosyl-N-homoallylamines and beta.-amino acids from imines” J. Org. Chem. 1991 56, 5883–
5889.
10. Xie, J., Soleilhac, J., Schmidt, C., Peyroux, J., Roques, B., Fournie-Zaluski M. “New kelatorphan-
related inhibitors of enkephalin metabolism: improved antinociceptive properties” J. Med. Chem.
1989, 32, 1497-1503.
11. Wright, D., Schulte II J. P., Page, M. “An Imine Addition/Ring-Closing Metathesis Approach to
the Spirocyclic Core of Halichlorine and Pinnaic Acid” Org. Lett. 2000, 2, 1847–1850.
12. Bloch, R. “Additions of Organometallic Reagents to C=N Bonds: Reactivity and Selectivity”
Chem. Rev. 1998, 98, 1407-1438.
13. Schmidt, U., Schmidt, J. “The Total Synthesis of Eponemycin” Synthesis. 1994, 3, 300-304.
14. Russell, A. B., Richard, E. M., Lian-Hai, Li., Marcus, A. Tius., “Synthesis of 1-Aza-cryptophycin
1, an Unstable Cryptophycin, An Unusual Skeletal Rearrangement” Tetrahydron. 2000, 56, 3339-
3351.
15. Puentes, C.O., Kouznetsov, V. “Recent advancements in the homoallylamine chemistry” J.
Heterocycl. Chem. 2002, 39:595-614.
202
16. Wright, D. L., Schulte, J. P., Page, M. A. “An Imine Addition/Ring-Closing Metathesis Approach
to the Spirocyclic Core of Halichlorine and Pinnaic Acid” Org. Lett. 2000, 2, 1847-1850.
17. Ciufolini, M.A., Hermann, C.W., Whitmire, K. H., Byrne N.E. “Chemoenzymatic preparation of
trans-2,6-dialkylpiperidines and of other azacycle building blocks.Total synthesis of (+)-
desoxoprosopinine” J. Am. Chem. Soc. 1989, 111, 3473-3475.
18. Felpin, F. X., Lebreton, J. “Recent Advances in the Total Synthesis of Piperidinic and Pyrrolidinic
Natural Alkaloids Using Ring Closing Metathesis as a Key Step” Eur. J. Org. Chem. 2003, 3693-
3712.
19. Leonor, Y., Vargas, M., Marı, V.,Castelli, Vladimir V. K., Juan, M. G., Silvia N. L.,
Maximiliano. S., Ricardo D. E., Juan C. R., Susana Z.“In Vitro Antifungal Activity of New Series
of Homoallylamines and Related Compounds with Inhibitory Properties of the Synthesis of Fungal
Cell Wall Polymers” Bioorg. Med. Chem. 2003, 11, 1531–1550.
20. Voigtmann, U., Blechert, S. “Enantioselective Synthesis of α,α′-Disubstituted Piperidines via
Ruthenium-Catalyzed Ring Rearrangement” Synthesis. 2000, 6, 893–898.
21. Naoki, K., Hiroki, Y., Tafhirou, M., Totsuya, S. “Reaction of ZV-Acyl-a-methoxyamines with
Organozinc Reagents.A Convenient Method for the Synthesis of Homoallylamines and P-Amino
Esters” Tetrahydron Letters. 1994. 35, (10)1561-1564.
22. Cristina, B., Pier, G. C., and Achille U. R. “Catalytic allylation of imines promoted by lanthanide
triflates” Tetrahedron Letters, 1995, 36(40), 7289-7292.
23. Billet, M., Philippe, K., Andre, M. “Syn diastereoselectivity in the synthesis of homoallylamine
using crotylsilane in the three-component reaction” Tetrahedron Letters 2001, 42, 631–634.
24. Villagraa, S. E., Maria C. B., Rodrı´gueza, A. M., Susana A. Z., Vladimir V. K., Ricardo D. E.
“Conformational and electronic study of homoallylamines with inhibitory properties against
203
polymers of fungal cell wall” Journal of Molecular Structure (Theochem). 2003, 666–667, 587–
598.
25. Ella-Menye, J. R., William, D., Billet, M., Philippe, K., Andre, M. “Unexpected 1,2 syn
diastereoselectivity in the three-component ‘aza Sakurai–Hosomi’ reaction” Tetrahedron Letters.
2005, 46, 1897–1900.
26. Fernando, D. S., Maxmiliano, S., Vladmir, V. K., Leonar, Y.V., Susan, A. Z, Uriel, M. C.,
Ricardo, D. E. “ Structural activity relationship study of homoallylamines and related derivatives
acting as antifungal agents” ” Bioorg. Med. Chem. 2006, 14, 1851–1862.
27. Vladmir, V. K., Leonor, Y., Vargas, M., Maxmiliano, S., Susan, A. Z, Uriel, M. C., Ricardo, D. E.
“Antifungal and cytotoxic activities of some N-substituted aniline derivatives bearing hetaryl
fragment” Bioorg. Med. Chem. 2008, 16, 794-809.
28. Ponnaboina, T., Kim, S. S. “Three components synthesis of homoallylic amines catalyzed by
bismuth (III) nitrate pentahydrate” Tetrahedron. 2009, 65, 5168–5173.
29. Gonzalez, G., Mohammed, M., Franscico, F., Miguel, Y. “Stereoselective α alkylation of
aldehydes with with chiral tert Butanesulfanamides and allylbromides” J. Org. Chem. 2010, 75,
6308-6311.
30. Yamaguchi, Y., Mariko, H., Katsumi, T., Masanar, K. “Nucleophilic allylation of N, O-acetals
with allylic alcohols promoted by Pd/Et3B and Pd/Et2Zn” Tetrahedron Letters. 2011, 52, 913-915.
31. Piao, F., Mithilesh, K. M., Jang, D. K. “Assymmetric synthesis of highly enantioriched 2-
substituted piperidine-2-ones by a combination enantioselective hydrazone allylation with ring
closing metathesis” Tetrahedron. 2012, 68, 7050-7055.
32. Gennari, C., Isabella, V., Gabriele, G., Giuliana, S.“Assymmetric synthesis of trans 6 –lactums
through TiC14-mediated addition to imines” Tetrahedron Letters.1987, 28(2), 227-230.
204
33. Manabe, K., Shu K. “Mannich-Type Reactions of Aldehydes, Amines, and Ketones in a Colloidal
Dispersion System Created by a Brønsted Acid-Surfactant-Combined Catalyst in Water” Org.
Lett. 1999, 1(12), 965-1967.
34. Loh, T. P., Sarah, B. K. W., Tan, K. L., Lin-Li W. “Three Component Synthesis of β-Amino
Carbonyl Compounds Using Indium Trichloride-Catalyzed One-pot Mannich-type Reaction in
Water” Tetrahedron. 2000, 56, 3227-3237.
35. Matsunaga, S., Naoya, K., Shinji H., Shibasaki, M. “Anti-Selective Direct Catalytic Asymmetric
Mannich-type Reaction of Hydroxyketone Providing β-Amino Alcohols” J. Am. Chem. Soc. 2003,
125, 4712-4713.
36. Xu, L. W., Xia, C. G., Lyi Li. “Transition Metal Salt-Catalyzed Direct Three-Component Mannich
Reactions of Aldehydes, Ketones, and Carbamates: Efficient Synthesis of N-Protected β-Aryl- β -
Amino Ketone Compounds” J. Org. Chem. 2004, 69, 8482-8484.
37. Phukan, P., Kataki, D., Pranita, C. “Direct synthesis of Cbz-protected b-amino ketones by iodine-
catalyzed three-component condensation of aldehydes, ketones and benzyl carbamate”
Tetrahedron Letters. 2006, 47, 5523–5525.
38. Mete, E., Gul, H. I., Cavit K. “Synthesis of 1-Aryl-3-phenethylamino-1-propanone Hydrochlorides
as Possible Potent Cytotoxic Agents” Molecules. 2007, 12, 2579-2588.
39. Yang, J. W., Carley, C., Michael, S., Daniela, K., Benjamin, L. “Proline-catalysed Mannich
reactions of acetaldehyde” Nature. 2008, 452—455.
40. Du, Y., Xiong, B., Hui, X., Wang, X., Feng, F., Meng, T., Hu, D., Zhang, D., Wang, M., Shen, J.
“Aromatic β-amino-ketone derivatives as novel selective non-steroidal progesterone receptor
antagonists” Bioorg. Med. Chem. 2010, 18, 4255-4268.
205
41. Wang, H., Yan, J., Song, X., Fan, L., Zhou, G., Jiang, L. “Synthesis and antidiabetic performance
of β-amino-ketone nabumetone moiety” Bioorg. Med. Chem. 2012, 20, 2119-2130.