Section 1 - INFLIBNET Centreshodhganga.inflibnet.ac.in/bitstream/10603/40077/10/10... · 2018. 7....
Transcript of Section 1 - INFLIBNET Centreshodhganga.inflibnet.ac.in/bitstream/10603/40077/10/10... · 2018. 7....
Section 1Synthesis of Indole and Benzo[b]furan
via Sonogashira cross coupling
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4.1
Introduction
This chapter deals with the synthesis and characterisation of various indole
and benzo[b]furan derivatives via Sonogashira cross coupling reaction.
4.1.a
Indole
Indoles1 are colourless crystalline solids with a range of odours like
naphthalene. Most indoles are quite stable in air with the exception of those
which carry a simple alkyl group at C-2. 2-methylindole autoxidises easily,
even in a dark brown bottle. The word indole is derived from the word India:
a blue dye imported from India was known as indigo in the sixteenth century.
Chemical degradation of the dye gave rise to oxygenated indoles, which were
named indoxyl and oxindole. For all practical purposes, indole exists entirely
in the 1H-form, 3H-indole (indolenine) being present to the extent of only ca.
1 ppm. 3H-Indole can be generated in solution but tautomerises to 1H-indole
within about 100 seconds at room temperature.3
Indoles represent an essential class of heterocyclic compounds in nature.
Based on the various biological actions, this ring system has become a
privileged building block for the pharmaceutical products. Nowadays, a
variety of drugs with significant structural diversity and different biological
activity belong to the indole family.1 In Figure 4.2 few selected examples of
known pharmaceutical agents based on the indole scaffold are shown. The
corresponding medical indications are listed in Table 4.1.
4| Synthesis of Indole and Benzo[b]furan via
Table 4.1
Selected indole drugs and their medical indication.
Entry Name
a Sumatriptan
b Melatonin
c Tryptophan
d Pergolid
e Lisurid
f Reserpin
g Vincristine
h Ergotamin
i Ajmalin
j Yohimbin
In general, indole derivatives
nervous systems (CNS),
lisurid e, and ergrotamin
Obviously, the development
stimulated by their widespread
the preparation and functionalization of indoles continued to be an important
Figure 4.2 Selected biologically active compounds with ind
Synthesis of Indole and Benzo[b]furan via Sonogashira cross coupling
drugs and their medical indication.
Disease
Sumatriptan migraine headaches, hypertonia
primary insomnia
Tryptophan epilepsy, depression
Parkinson’s disease
migraine headaches
hypertension
cancer chemotherapy
migraine headaches
cardiac arrhythmia
hypertension, aphrodisiac
derivatives are used for diseases related
(CNS), e.g. against migraine headaches like
ergrotamin h, or vincristine g against Parkinson’s
development of novel methods for the synthesis
their widespread utility in life sciences.4 Over
the preparation and functionalization of indoles continued to be an important
Selected biologically active compounds with ind
Sonogashira cross coupling
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Drug
Imigran
Circadin
Ardeydorm
Parkotil
Dopergin
Briserin
Oncovin
Ergo-Kranit
Gilurytmal
Yocon
related to the central
like sumatriptan a,
Parkinson’s disease.
synthesis of indoles is
Over the last century
the preparation and functionalization of indoles continued to be an important
Selected biologically active compounds with indole skeleton.
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object of research. Today, a range of well-established “classical” methods are
available. Typical examples include the Fischer indole synthesis, the Gassman
synthesis, the Madelung cyclization, the Bischler indole synthesis and the
Batcho-Leimgruber synthesis.5
In addition, a variety of most modern transition metal-based syntheses and
domino reactions have been developed.6 In general, the availability of starting
materials and the functional group tolerance define the suitability of the
respective indole synthesis.7 In the last two decades transition metal-catalyzed
coupling reactions have dramatically improved the synthesis of biologically
active molecules.8
Especially palladium catalyzed carbon-carbon, carbon-nitrogen, and carbon-
oxygen bond forming reactions have become powerful tools for synthesis.9
Striking features of these methods are their tolerance towards a wide range of
functional groups on both coupling partners and their ability to efficiently
construct complex organic building blocks in few steps. In Figure 4.3 several
palladium catalyzed coupling reactions of indoles are illustrated. In a
published review,10 the more recent developments from 2003 to 2011 in
palladium-catalyzed coupling reactions of indoles are highlighted and
summarized. Emphasis is given on those reactions leading to new substituted
indole derivatives and less on coupling reactions of azaindoles, carbazoles,
and oxindoles.
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4.1.b
Benzo[b]furans
Benzofuran (I) is the generic name of 2, 3-benzofuran or benzo[b]furan, which
is a heterocyclic compound consisting of fused benzene and furan (II) rings.
In earlier literature, it was named as coumarone. This colourless solid is a
component of coal tar. Numbering begins with the hetero atom and proceeds
around the nucleus as shown in (I) (Figure 4.4).
Benzofuran is a planar heteroaromatic molecule and its electronic structure is
similar to that of furan. Additional stabilization was provided by the fused
benzene ring. The 10 π electron system was formed by two 2p electrons
provided by the oxygen hetero atom.
Natural products play an important role in both drug discovery and chemical
biology. Indeed, many approved therapeutics as well as drug candidates are
derived from natural sources.11, 12 5-Methoxybenzofuran is the simplest form
of naturally occurring benzofuran which is found as a result of fungal
contamination of oak beer barrels.13 Benzofuran is the "parent" of many
related compounds with more complex structures. Some representative
examples are shown in Table 4.1 with their pharmacodynamic activity.
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Table 4.1
Biological activities of Benzofuran derivatives
Compound Activity Compound Activity
Toxic to goldfish14, 15
Toxic to gold fish14,
15
Uricosuricagent16
Antiarrhythmicactivity16, 17
O
O
CH3
DihydroTremetone
HO
Bacteriostaticactivity14, 15
O
H3CO
H3CO O
O
Amidarone
Antianginalactivty16
Antitumoractivity14, 15
CoronaryVasodilator
16, 17
4.2
Recent literature survey related to indoles
Yamanaka et al18 observed that treatment of 1-alkynes with o-iodo-N-
mesylanilides 1 under Sonogashira conditions9, 19 directly afforded indole
products 4 in a single operative step through a domino coupling cyclization
process with palladium and copper catalysts involved both in the coupling
and in the cyclization reaction (Scheme 4.1).
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Interestingly, treatment of the crude o-(phenylethynyl)-N-ethoxycarbonyl
anilide 1, prepared through a Sonogashira coupling, with a strong base such
as sodium ethoxide was found to give 2-phenylindole 2 in good yield.18 This
suggested that the cyclization of o-alkynylanilides can be performed through
base-mediated reactions as well (Scheme 4.2).
Mahanty J. S. et al20 converted o-[(3-Hydroxy-3,3-dimethyl)prop-1-yl)trifluoro
acetanilide 1 into o-(1-methylethenyl)indole 2. In this case, the palladium
catalyzed cyclization was followed by the hydrolysis of the amide bond and a
dehydration process leading to the formation of the olefinic double bond
(Scheme 4.3)
Synthesis of Indole derivatives via Sonogashira coupling were also attempted
using various energy sources.
Srinivasan K. V. and his co-workers21 described general one-pot synthesis of
2-substituted indoles 3 via a palladium acetate-catalyzed tandem Sonogashira
coupling at room temperature under ultrasonic (US) irradiation and standard
stirred conditions employing Bu4NOAc as the base in acetonitrile. Electron
donating and withdrawing groups present in both coupling partners 1 and 2
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were well tolerated under these mild conditions. The reaction was attempted
in the absence of any ligand, copper and amine.
Stevens et al22 showed that Sonogashira coupling chemistry can be employed
to construct a new series of indolyl quinols. Sulfonamides 1 undergo
Sonogashira coupling under thermal or microwave (MW) conditions with the
alkyne, 4-ethynyl-4-hydroxycyclohexa-2,5-diene-1-one 2 followed by
cyclization to yield 4-[1-(arylsulfonyl-1H-indol-2-yl)]-4-hydroxycyclo-hexa-
2,5-diene-1-ones 3 (Scheme 4.5).
An efficient and novel route for the synthesis of 1H-indol-2-yl-(4-aryl)-
quinolin-2(1H)-ones 4 via a palladium catalyzed site selective cross-coupling
reaction and cyclization process was described by Wu et al.23 3-Bromo-4-aryl-
quinolin-2(1H)-ones1 reacted with 2-ethynylaniline 2 via Pd-catalyzed
Sonogashira coupling (to 3) and CuI-mediated cyclization, lead to the desired
1H-indol-2-yl-(4-aryl)-quinolin-2(1H)-ones 4 in good yields (Scheme 4.6).
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Benoit J. and his co-workers24 developed Sonogashira/copper(I)-catalyzed
heteroannulation sequence to convert 3,5-diamino-6-chloro-1,2,4-triazines 1
and alkynes or arynes 2 in to the corresponding 3-amino-5H-pyrrolo[2,3-e]-
1,2,4-triazine derivatives 4 in good yields via 3 (Scheme 4.7).
4.3
Recent literature survey related to benzo[b]furans
Recently Karimi B. et al25 reported one-pot, three-component reaction of
arylglyoxals 1, benzamide 2 and phenols 3 using catalytic amounts of
zirconiumoxychloride octahydrate 4 under solvent-free conditions to produce
new amido-substituted benzo[b]furans 5. The reactions showed
chemoselectivity towards benzofuran 5 instead of oxazols 6 (Scheme 4.8).
Protti S. et al26 synthesized 2-Substituted benzo[b]furans 3 by a one-step
metal-free photochemical reaction between 2-chlorophenol derivatives 1 and
terminal alkynes 2 by tandem formation of an aryl-C and a C–O bond via an
aryl cation intermediate (Scheme 4.9).
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Rafael Cano and his co-workers27 synthesized benzo[b]furan derivatives by
using impregnated copper or palladium–copper on magnetite as catalysts for
the domino and stepwise Sonogashira-cyclization processes (Scheme 4.10).
Scheme 4.10 Synthesis of benzo[b]furan via Domino process
Arias L. et al28 investigated fully regiocontrolled synthesis of 2- and 3-
substituted benzo[b]furans. Direct reaction between phenols 1 and α-
bromoacetophenones 2 in the presence of neutral alumina yielded 2-
substituted benzo[b]furans 3 with complete regiocontrol. When a basic salt
such as potassium carbonate was used, the corresponding 2-oxoether 4 was
obtained. Cyclization of these latter compounds promoted by neutral alumina
yielded the corresponding 3-substituted benzo[b]furans 5 (Scheme 4.11).
Liang Y. M. and his co-workers29 synthesized a variety of 2-aroyl (acyl, or
carboxyl)-3-vinyl benzo[b]furans 2 via C–C bond formation in good to
excellent yields by Pd/C-catalyzed cyclization/isomerization of propargylic
compounds 1 (Scheme 4.12).
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Various catalysts are reported for the sonogashira cyclisation. Such as
Iodine,30 CuI/[bmim]OAc in [bmim]PF6,31 FeCl3-CuCl2,32 PdCl2(CH3CN),33
Na2PdCl4,34 palladium-NHC,35 Pd2(dba)3,36 TiCl4,37 NaIO3-pyridine,38 Pd-
MCM-41,39 Pd(PhCN)2Cl2/P(t-Bu)3,40 and Cu(OTf)2.2
Up till now various basic catalysts have been also employed for Sonogashira
coupling, such as piperidine,41 DBU,42 Et3N,43 Bu4NOAc,21 TBAF,44 and
Cs2CO3.45
A variety of 3-functionalized benzo[b]furans 2 were achieved by FeCl3-
mediated intramolecular cyclization of electron-rich α-aryl ketones 1 (Scheme
4.13).46
Mukkanti K. and his co-workers47 coupled phenyl 2-propynyl ethers 1 with
aryl iodides under Sonogashira reaction conditions to give 3-phenoxy-1-aryl-
1-propyne derivatives 2. The latter compounds underwent an initial Claisen
rearrangement followed by ring closure to give functionalized benzo[b]furans
3 (Scheme 4.14).
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Kabalka G. W. and his co-workers48 developed microwave-enhanced,
solventless Mannich condensation–cyclization sequence involving the
reaction of o-ethynylphenol 1 with secondary amines 3 and para-
formaldehyde 2 on cuprous iodide doped alumina in the absence of solvent.
The procedure generated 2-(dialkylaminomethyl)benzo[b]furans in good
yields (Scheme 4.15).
4.4
Sonogashira Coupling Reaction
The Nobel Prize in Chemistry 2010 was awarded jointly to Richard F. Heck,
Ei-ichi Negishi and Akira Suzuki "for palladium-catalyzed cross couplings in
organic synthesis".49 The traditionally accepted mechanistic pathway of the
Sonogashira reaction is similar to that originally proposed by Sonogashira
and Hagihara in 1975.50 A search for the term "Sonogashira" in Web of
Science® provides over 3216 references for journal publications between 1999
to August, 2013. The Sonogashira reaction is the most frequently used method
to affect the alkynylation of an aryl halide. Typically palladium is used along
with generally twice this amount of CuI as co-catalyst. Alkynes undergo the
cross-coupling reaction with aryl and heteroaryl halides in the presence of
PdCl2(PPh3)2 as catalyst, CuI as cocatalyst and amine as the solvent. It is
believed that copper assists the reaction through formation of an acetylide
and then this group is transferred to palladium by a transmetalation step.
Nevertheless, modifications of the conditions have continued to be
investigated because copper acetylides can also lead to homocoupling
products. Although many researchers have established some flexibility in the
conditions, no general method is yet available for all substrates for this
reaction.51
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Bakherad et al43 successfully developed Pd/Cu-catalyzed heterocyclization
involving Sonogashira coupling for the synthesis of 2-aryl-substituted
imidazo[1,2-a]pyridines 3 from the reaction of 2-amino-1-(2-
propynyl)pyridinium bromide 1 with various iodobenzenes 2 (Scheme 4.16).
A convenient and general method for the synthesis of isoindoline fused with
triazoles3 from o-iodobenzyl azide 1 and acetylenes 2 through palladium–
copper catalysis was described by Chowdhury et al52 (Scheme 4.17).
Larock and Kevin53 described the use of tert-butylimine nucleophiles 1 in the
palladium-catalyzed annulation of terminal alkynes 2 to prepare
isoquinolines 3 (Scheme 4.18).
Cho, C. S.54 reacted 2-Iodoaniline 1 with terminal acetylenic carbinols 2 in
THF at 80°C in the presence of a catalytic amount of PdCl2(PPh3)2 and CuI
along with aqueous tetrabutyl ammonium hydroxide to afford the
corresponding 2-arylquinolines 3 in good yields (Scheme 4.19).
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An unprecedented microwave-assisted desulfitative Sonogashira-type cross-
coupling protocol for the efficient alkynylation of the C3-position of
phenylsulfanylated-2(1H)-pyrazinones 1 was reported by Van der Eycken
and co-workers55 (Scheme 4.20). It has been demonstrated that the –SPh or
–SMe group, as a surrogate for halides, underwent facile cross-coupling to
give alkynylated derivatives 3 which was further utilized for diverse
functionalization. Soheili A. et al56 have reported efficient and general
protocol for the copper-free sonogashira coupling of aryl bromides at room
temperature.
Heravi M. M. et al57 reported the reaction of 3-mercaptopropargyl-1,2,4-
triazoles 1 with various iodobenzenes 2 catalyzed by Pd–Cu. Mechanistically,
either thiazolo-1,2,4-triazines 4 or 5 were the possible products (via 3), as
illustrated in Scheme 4.21. The reaction led to the regioselective formation of
6-benzylthiazolo[3,2-b]1,2,4-triazoles 5.
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Carril M. et al58 developed a novel protocol on water chemistry. They reported
more sustainable protocol leading to 2-alkyl- or 2-aryl-substituted
benzo[b]furans. The reaction is accomplished using water as the solvent
without organic solvents.
4.4.1
General reaction mechanism
Typically, two catalysts are needed for this reaction: a zero valent palladium
complex and a halide salt of copper (I). Examples of such palladium catalysts
include compounds in which palladium is ligated to phosphines [Pd(PPh3)4].
A common derivative is Pd(PPh3)2Cl2, but bidentate ligand catalysts, such as
Pd(dppe)Cl, Pd(dppp)Cl2, and Pd(dppf)Cl2 have also been used.59 The
drawback of such catalysts is the need for high loadings of palladium (up to 5
mol %), along with a larger amount of a copper co-catalyst.59 Pd (II) is often
employed as a pre-catalyst since it exhibits greater stability than Pd (0) over
an extended period of time and can be stored under normal laboratory
conditions for months.60 The Pd (II) catalyst is reduced to Pd (0) in the
reaction mixture by either an amine, a phosphine ligand, or a reactant,
allowing the reaction to proceed.61 The oxidation of triphenylphosphine to
triphenylphosphine oxide can also lead to the formation of Pd (0) in situ when
catalyst such as bis(triphenylphosphine)palladium(II) chloride is used.
Copper (I) salts, such as copper iodide, react with the terminal alkyne and
produce a copper (I) acetylide, which acts as an activated species for the
coupling reactions. Cu (I) is a co-catalyst in the reaction, and is used to
increase the rate of the reaction.62
In general, this reaction is divided in two cycles.
(i) The palladium cycle (ii) The copper cycle
Both cycles are briefly describe in Figure 4.5
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The palladium cycle The copper cycle
The active palladium catalyst is the 14 electron compound Pd0L2, complex A, which reacts with the aryl or vinyl halide in an oxidative addition to produce a Pd (II)intermediate, complex B. This step is believed to be the rate-limiting step of the reaction.
Complex B reacts in a transmetallation with the copper acetylide, complex F, which is produced in the copper cycle, to give complex C, expelling the copper halide, complex G.
Both organic ligands are trans oriented and convert to cis in a trans-cis isomerization to produce complex D.
In the final step, complex D undergoes reductive elimination to produce the alkyne, with regeneration of the palladium catalyst.
It is suggested that the presence of base results in the formation of a π-alkyne complex, complex E, which makes the terminal proton on the alkyne more acidic, leading to the formation of the copper acetylide, compound F.
Compound F continues to react with the palladium intermediate B, with regeneration of the copper halide, G.
Figure 4.5 Catalytic cycles for the Sonogashira reaction
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4.5
Objective
The aim of the present work is the development of indole and Benzofuran
derivatives via Sonogashira coupling and their catalytic functionalization via
palladium-copper catalysis in presence of basic ionic liquid [DBU]Ac as the
solvent and toluene as the cosolvent. Up till now various basic catalyst were
used for this transformation but this is the first report for the basic ionic liquid
mediated synthesis of title compound. The role of Pd-Cu and [DBU]Ac is
briefly discussed.
4.6
Result and discussion
We first selected o-iodo phenol 1 and phenyl acetylene 2 as the building block
for the model reaction. Our first objective was to optimize the mol ratio of the
[DBU]Ac in the model reaction. The results are summarized in table 4.2.
Table 4.2
The effect of different amounts of [DBU]Ac on the reaction of o-iodo
phenol and phenyl acetylene.a
Entry [DBU]Ac (mol %) Time (min)b Yieldc
1 20 90 652 30 80 703 40 75 724 50 60 805 60 60 80
ao-iodophenol (2.28 mmol), phenyl acetylene (2.96 mmol), Pd(OAc)2 (10 mg), CuI (10 mg) and toluene (5 mL). btime required to complete the reaction as indicated by TLC.cisolated yield.
As shown in table 4.2, best result was achieved when 50 mol % (entry 4) of IL was
taken for the synthesis. Reaction was completed in 60 min with 80 % yield. Pd(OAc)2
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and CuI were necessary to complete this transformation. We also tested the same
transformation in absence of CuI but reaction did not proceed to forward direction.
Jaseer, E. A et al2 investigated that when the reaction of o-iodo phenol 1 and phenyl
acetylene 2 was performed in polar solvent such as DMSO, DMF and Acetonitrile
provided poor yield and oxidative homo coupling of phenyl acetylene was produce
as the major product 4. While in non-polar solvents such as 1, 4-Dioxane and toluene,
the homo coupling product was found to be reduced to 2-5 %. Therefore all the
experiments were carried out in toluene as a co-solvent in the present syudy.
Above experimental results encouraged us to extend the scope of reaction
condition to apply on a range of variously substituted 2-iodo phenols/amines
and acetylenes (Scheme 4.23). Both aromatic and aliphatic acetylenes were
well-tolerated. All the reactions were completed in 60-120 min. Increase in the
equivalent of IL did not improve the conversion, use of 50 mol% IL is found
to be sufficient to accelerate the reaction forward. The percentage yield of all
the synthesized indoles/benzofurans using conventional technique is shown
in table 4.3.
Table 4.3
Characterisation data of all synthesized compound.
Entry X R Time (min) Yield
3a -NH -C6H5 90 85
3b -NH -C3H5 60 78
3c -NH -C6H11 105 84
3d -NH -C5H4N 120 82
3e -NH -C6H13 60 84
3f -NH -C4H9 60 78
3g -NH -C3H7 75 76
3h O -C6H5 60 80
3i O -C3H5 105 78
3j O -C6H11 75 82
3k O -C5H4N 105 75
3l O -C6H13 120 80
3m O -C4H9 75 78
3n O -C3H7 60 80
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4.6.1
Plausible reaction mechanism in [DBU]Ac
Oxidative addition of Pd (0) to 2-iodophenol/aniline 1 to produces
intermediate 2 in which Pd(0) oxidized to Pd (+2). Simultaneously terminal
proton of acetylene 3 gets abstracted by [DBU]Ac and insertion of Cu makes
terminal carbon of 4 more electrophilic. Then Palladium gets converted in its
original state affording intermediate 6. With the assistance of DBU[Ac] as a
base, the nitrogen atom or oxygen acts as a nucleophile and attacks the copper
coordinated alkyne 7 to give the indole-containing copper intermediate 8.
Protonolysis of 8 provides the corresponding indole (or benzo[b]furan)
product 9.
4.7
Experimental
All experiments were carried out under anhydrous conditions and an
atmosphere of dry nitrogen. All the chemicals were purchased from Sigma-
Aldrich and used without further purification. Melting points were
determined using μThermoCal10 (Analab scientific Pvt. Ltd.) melting point
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apparatus and are uncorrected. Progress of the reaction was monitored by
thin layer chromatography on Merck silica plates. Column chromatography
was performed using Merck silica gel (60-120 mesh size) and n-hexane as the
eluent. 1H and 13C NMR spectra were recorded on Bruker Avance 400 MHz
instruments using TMS as internal standard. Mass spectra were recorded on
Shimadzu LCMS 2010 mass spectrometer. Elemental analysis was performed
on the Perkin Elmer PE 2400 elemental analyzer.
4.7.1
General procedure for synthesis of indoles and benzo[b]furans
Under nitrogen, a mixture of 2-iodophenol/2-iodoaniline (2.28 mmol),
[DBU]Ac (50 mol%), CuI (10 mg), and Pd(OAc)2 (10 mg) was dissolved in
toluene (5 mL), and phenylacetylene (2.96 mmol) was added dropwise with
stirring into the reaction. The reaction system was stirred at reflux and
progress was monitored by TLC. Upon completion, the mixture was extracted
with EtOAc (3 x 15 mL). The extract was washed with brine (2 x 15 mL) and
dried over Na2SO4. After evaporation, the residue was purified via column
chromatography (n-Hexane as eluent) on silica gel to afford the pure product.
4.7.2
General procedure for the synthesis of [DBU]Ac ionic liquid
Aliquot of acetic acid (1 equiv.) was added over a period of 15 min to DBU (1
equiv.) by maintaining the temperature below 5 °C in an ice bath under
ultrasound. The reaction mixture was exposed to ultrasound for an additional
period of 15 min at ambient temperature. The oily residue obtained was dried
in vacuum at 60 °C for 1 h to afford [DBU][Ac] as a light yellow, viscous
liquid.
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4.8
Characterization
All spectroscopic characterization of representative compounds 3a and 3i are
shown in figure 4.7-4.9 and 4.10-4.12 respectively. The molecular structures
and characterization data for all synthesized compounds are given below in
tabular form.
4.9
Conclusion
In conclusion, we have demonstrated a concise and practical method for the
synthesis of indoles and benzo[b]furans. Both heterocycles could be obtained
in good to moderate yield by the reactions of 2-iodoanilines or 2-iodophenol
with terminal alkynes under mild conditions, namely in the presence of CuI,
Pd(OAc)2, and a basic ionic liquid [DBU]Ac in toluene as the cosolvent. It is
worth noting that simple aliphatic substituted terminal alkynes could be
tolerated to smoothly produce indole and benzo[b]furan derivatives.
Therefore, this method is complementary to those of the previously reported
Cu-catalyzed coupling/cyclizations.
Section 2
Characterization
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3c 2-cyclohexyl-1H-indole
Molecular Formula C14H17N
Melting Point 103-10564
Mol. wt. 199.14
Elemental Analysis C H N
Calcd. 84.37 8.60 7.03
Obs 84.60 8.35 6.89
1H NMR δ ppm(CDCl3)
1.25-3.05 (m, 11H), 6.48 (s, 1H), 7.26-7.62 (m, 4H),
8.02 (s, 1H)
13C NMR δ ppm(CDCl3)
24.3, 24.7, 26.1, 35.2, 104.2, 112.8, 119.7, 120.4, 120.8
127.8, 135.4, 137.8
3a 2-phenyl-1H-indole
Molecular Formula C14H11N
Melting Point 190-19263
Mol. wt. 193.09
Elemental Analysis C H N
Calcd. 87.01 5.74 7.25
Obs 87.32 5.48 7.10
1H NMR δ ppm(CDCl3)
6.86 (s, 1H), 7.16-7.69 (m, 9H), 8.39 (brs, 1H)
13C NMR δ ppm(CDCl3)
98.6, 111.2, 120.1, 120.6, 124.9, 127.8, 129.1,
132.3, 136.4, 137.8
3b 2-cyclopropyl-1H-indole
Molecular Formula C11H11N
Melting Point Yellowish oil
Mol. wt. 157.21
Elemental Analysis C H N
Calcd. 84.04 7.05 8.91
Obs 84.30 7.34 8.84
1H NMR δ ppm(CDCl3)
0.99-1.05 (m, 4H), 2.12-2.20 (m, 1H), 6.35 (s, 1H)
7.21-7.47 (m, 4H), 7.9 (brs, 1H)
13C NMR δ ppm(CDCl3)
10.1, 16.2, 102.3, 114.9, 121.3, 121.5, 122.1, 132.6,
136.8, 143.7
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3e 2-hexyl-1H-indole
Molecular Formula C14H19N
Melting Point Yellow oil65
Mol. wt. 201.33
Elemental Analysis C H N
Calcd. 83.53 9.51 6.96
Obs 83.68 9.22 7.14
1H NMR δ ppm(CDCl3)
0.89 (t, J = 6.8 Hz, 3H), 1.31-1.41 (m, 6H), 1.68-2.75 (m,
4H), 6.24 (s, 1H), 7.04-7.52 (m, 4H), 7.88 (br, 1H)
13C NMR δ ppm(CDCl3)
14.2, 21.8, 30.8, 31.2, 31.9, 99.8, 112.4, 119.7, 120.1,
121.2, 128.3, 135.8, 136.7
3f 2-butyl-1H-indole
Molecular Formula C12H15N
Melting Point Yellowish oil66
Mol. wt. 173.25
Elemental Analysis C H N
Calcd. 83.19 8.73 8.08
Obs 83.42 8.34 8.22
1H NMR δ ppm(CDCl3)
0.86 (t, J=7.5 Hz, 3H), 1.27-1.35 (m, 2H), 1.55-1.61(m,
2H), 2.60 (t, J=7.5 Hz, 2H), 6.15 (s, 1H),
6.97-7.43 (m, 4H), 7.61 (s, 1H)13C NMR δ ppm
(CDCl3)
13.2, 22.5, 27.6, 30.7, 101.6, 108.7, 119.6, 120.2, 121.3,
128.7, 135.8, 138.0
3d 2-(pyridin-2-yl)-1H-indole
Molecular Formula C13H10N2
Melting Point 157-15864
Mol. wt. 194.23
Elemental Analysis C H N
Calcd. 80.39 5.19 14.42
Obs 80.56 5.02 14.12
1H NMR δ ppm(CDCl3)
7.2-8.1 (m, 9H), 8.5 (brs, 1H)
13C NMR δ ppm(CDCl3)
106.5, 110.2, 117.3, 118.7, 119.5, 123.9, 125.1, 129.8,
133.6, 135.8, 136.7, 148.9, 150.8
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3g 2-propyl-1H-indole
Molecular Formula C11H13N
Melting Point Yellow oil67
Mol. wt. 159.23
Elemental Analysis C H N
Calcd. 82.97 8.23 8.80
Obs 82.84 8.34 8.64
1H NMR δ ppm(CDCl3)
0.89 (t, J = 7.6 Hz, 3H), 1.68-1.76 (m, 2H), 2.75 (t, J = 7.6
Hz, 2H), 6.24 (s, 1H), 7.13-7.70 (m, 4H), 7.86 (br, 1H)
13C NMR δ ppm(CDCl3)
13.8, 18.6, 29.8, 98.6, 111.3, 116.8, 119.8, 120.1, 120.9,
129.7, 137.6
3h 2-phenylbenzofuran
Molecular Formula C14H10O
Melting Point 118-1202
Mol. wt. 194.23
Elemental Analysis C H
Calcd. 86.57 5.19
Obs 86.34 5.39
1H NMR δ ppm(CDCl3)
7.33 (s, 1H), 7.34-7.90 (m, 9H)
13C NMR δ ppm(CDCl3)
102.6, 112.4, 121.8, 124.7, 125.8, 126.4, 128.0, 129.8,
131.4, 133.2, 155.1, 155.8
3i 2-cyclopropylbenzofuran
Molecular Formula C11H10O
Melting Point Yellowish oil
Mol. wt. 158.20
Elemental Analysis C H
Calcd. 83.51 6.37
Obs 83.84 6.12
1H NMR δ ppm(CDCl3)
0.99-1.04 (m, 4H), 2.01-2.08 (m, 1H), 6.37 (s, 1H)
7.15-7.47 (m, 4H)
13C NMR δ ppm(CDCl3)
5.2, 14.3, 98.6, 115.7, 124.4, 126.3, 127.8, 135.8,158.9, 162.7
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3j 2-cyclohexylbenzofuran
Molecular Formula C14H16O
Melting Point Colourless oil68
Mol. wt. 200.12
Elemental Analysis C H
Calcd. 83.96 8.05
Obs 83.56 8.22
1H NMR δ ppm(CDCl3)
1.20-2.90 (m, 11H), 6.42 (s, 1H), 7.20-7.56 (m, 4H)
13C NMR δ ppm(CDCl3)
24.4, 25.6, 29.6, 39.8, 102.5, 112.4, 122.2, 123.4, 124.4,
130.5, 153.9, 162.1
3k 2-(benzofuran-2-yl)pyridine
Molecular Formula C13H9NO
Melting Point 82-8469
Mol. wt. 195.22
Elemental Analysis C H N
Calcd. 79.98 4.65 7.17
Obs 79.76 4.84 7.38
1H NMR δ ppm(CDCl3)
6.85 (s, 1H), 7.13-8.58 (m, 8H)
13C NMR δ ppm(CDCl3)
106.3, 111.5, 117.8, 121.5, 123.6, 124.5, 125.9, 128.4,
138.6, 148.2, 149.1, 149.9, 156.8
3l 2-hexylbenzofuran
Molecular Formula C14H18O
Melting Point Colourless liquid37
Mol. wt. 202.29
Elemental Analysis C H
Calcd. 83.12 8.97
Obs 83.25 8.68
1H NMR δ ppm(CDCl3)
0.86-0.92 (m, 3H), 1.22-1.45 (m, 6H), 1.74-2.76 (m, 4H),
6.36 (s, 1H), 7.14-7.51 (m, 4H)
13C NMR δ ppm(CDCl3)
106.3, 111.5, 117.8, 121.5, 123.6, 124.5, 125.9, 128.4,
138.6, 148.2, 149.1, 149.9, 156.8
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3m 2-butylbenzofuran
Molecular Formula C12H14O
Melting Point Yellowish oil70
Mol. wt. 174.24
Elemental Analysis C H
Calcd. 82.72 8.10
Obs 82.56 8.32
1H NMR δ ppm(CDCl3)
0.85 (t, J=7.5 Hz, 3H), 1.25-1.35 (m, 2H), 1.55-1.61(m,
2H), 2.56 (t, J=7.5 Hz, 2H), 6.15 (s, 1H),
7.04-7.52 (m, 4H)13C NMR δ ppm
(CDCl3)
13.5, 21.7, 27.6, 32.1, 102.2, 111.3, 122.1, 123.6, 124.9,
130.1, 156.1, 160.2
3n 2-propylbenzofuran
Molecular Formula C11H12O
Melting Point Yellowish oil71
Mol. wt. 160.21
Elemental Analysis C H
Calcd. 82.46 7.55
Obs 82.23 7.72
1H NMR δ ppm(CDCl3)
1.12 (t, J = 7.6 Hz, 3H), 1.65-1.76 (m, 2H), 2.78 (t, J = 7.6
Hz, 2H), 6.24 (s, 1H), 7.28-7.85 (m, 4H)
13C NMR δ ppm(CDCl3)
13.8, 20.1, 23.4, 100.6, 110.4, 121.9, 122.5, 130.1,
129.4, 142.6, 156.8
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146 | P a g e
Figure 4.7 1H NMR spectra of 2-phenyl-1H-indole (3a)
Figure 4.8 13C NMR spectra of 2-phenyl-1H-indole (3a)
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Figure 4.9 Mass spectrum of 2-phenyl-1H-indole (3a)
Figure 4.10 1H NMR spectra of 2-cyclopropylbenzofuran (3i)
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148 | P a g e
Figure 4.11 1H NMR spectra of 2-cyclopropylbenzofuran (3i)
Figure 4.12 Mass spectra of 2-cyclopropylbenzofuran (3i)
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4.10
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