Section 1 - INFLIBNET Centreshodhganga.inflibnet.ac.in/bitstream/10603/40077/10/10... · 2018. 7. 2. · Scheme 4.10 Synthesis of benzo[b]furan via Domino process Arias L. et al28

Section 1Synthesis of Indole and Benzo[b]furan

via Sonogashira cross coupling

4| Synthesis 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


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


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



Mol. wt. 193.09


Calcd. 87.01 5.74 7.25

Obs 87.32 5.48 7.10


6.86 (s, 1H), 7.16-7.69 (m, 9H), 8.39 (brs, 1H)


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


Melting Point Yellowish oil

Mol. wt. 157.21


Calcd. 84.04 7.05 8.91

Obs 84.30 7.34 8.84


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)


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


Melting Point Yellow oil65

Mol. wt. 201.33


Calcd. 83.53 9.51 6.96

Obs 83.68 9.22 7.14


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)


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


Melting Point Yellowish oil66

Mol. wt. 173.25


Calcd. 83.19 8.73 8.08

Obs 83.42 8.34 8.22


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


Mol. wt. 194.23


Calcd. 80.39 5.19 14.42

Obs 80.56 5.02 14.12


7.2-8.1 (m, 9H), 8.5 (brs, 1H)


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


Melting Point Yellow oil67

Mol. wt. 159.23


Calcd. 82.97 8.23 8.80

Obs 82.84 8.34 8.64


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)


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


Mol. wt. 194.23

Elemental Analysis C H

Calcd. 86.57 5.19

Obs 86.34 5.39


7.33 (s, 1H), 7.34-7.90 (m, 9H)


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


Melting Point Yellowish oil

Mol. wt. 158.20


Calcd. 83.51 6.37

Obs 83.84 6.12


0.99-1.04 (m, 4H), 2.01-2.08 (m, 1H), 6.37 (s, 1H)

7.15-7.47 (m, 4H)


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


Melting Point Colourless oil68

Mol. wt. 200.12


Calcd. 83.96 8.05

Obs 83.56 8.22


1.20-2.90 (m, 11H), 6.42 (s, 1H), 7.20-7.56 (m, 4H)


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


Mol. wt. 195.22


Calcd. 79.98 4.65 7.17

Obs 79.76 4.84 7.38


6.85 (s, 1H), 7.13-8.58 (m, 8H)


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


Melting Point Colourless liquid37

Mol. wt. 202.29


Calcd. 83.12 8.97

Obs 83.25 8.68


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)


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


145 | P a g e

3m 2-butylbenzofuran



Mol. wt. 174.24


Calcd. 82.72 8.10

Obs 82.56 8.32


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



Mol. wt. 160.21


Calcd. 82.46 7.55

Obs 82.23 7.72


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)


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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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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Figure 4.11 1H NMR spectra of 2-cyclopropylbenzofuran (3i)

Figure 4.12 Mass spectra of 2-cyclopropylbenzofuran (3i)


149 | P a g e

4.10

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