Efficient and green microwave-assisted one-pot synthesis of azaindolizines in PEG-400 and water

Article abstract of DOI:10.1080/00397911.2016.1223314

A facile, convenient, environmentally benign, and one-pot synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines and in-situ generated phenacyl bromides under microwave irradiation in polyethylene glycol (PEG-400) and water (1:2) has been developed. The protocol provides a better alternative to the existing method as it involves utilization of in-situ-generated α-bromoacetophenones, avoids the use of lachrymatric α-haloketones as well as volatile toxic organic solvents, and reduces the reaction time to obtain excellent yield.

Full text of DOI:10.1080/00397911.2016.1223314

Synthetic Communications
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
An Efficient and Green Microwave Assisted One
Pot Synthesis of Azaindolizines in PEG-400 and
Water
Devendra S. Wagare, Mazhar Farooqui, Tushar D. Keche & Ayesha Durrani
To cite this article: Devendra S. Wagare, Mazhar Farooqui, Tushar D. Keche & Ayesha Durrani
(2016): An Efficient and Green Microwave Assisted One Pot Synthesis of Azaindolizines in
PEG-400 and Water, Synthetic Communications, DOI: 10.1080/00397911.2016.1223314
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Date: 25 August 2016, At: 02:51

An Efficient and Green Microwave Assisted One Pot Synthesis of Azaindolizines in
PEG-400 and Water
Devendra S. Wagare1, Mazhar Farooqui2, Tushar D. Keche1, Ayesha Durrani2
1Department of chemistry, Vivekanand college, Aurangabad. India, 2Department of
chemistry, Dr. Rafique Zakaria College for women, Aurangabad, India
Abstract
A facile, convenient, environmentally benign and one pot synthesis of Imidazo[1,2-
a]pyridines from 2-aminopyridines and in-situ generated phenacyl bromides under
microwave irradiation in PEG-400 and water (1:2) has been developed. The developed
protocol provides the better alternative to the existing method as it involves utilization of
in-situ generated α-bromoacetophenones and avoids the use of lachrymatric α-
haloketones as well as volatile toxic organic solvents and to reduced reaction time to
obtained excellent yield.
GRAPHICAL ABSTRACT
KEYWORDS: Imidazo[1,2-a]pyridines; 2-aminopyridines; PEG-400-water, Microwave
irradiation; NBS.
1. INTRODUCTION
Theazaindolizines (bridgehead azaheterocycles)containing imidazole ring systems have
several valuable diversified pharmaceutical activity and are used as hypotensive,[1]
1

antiulcer[2] andanxiolytic agents[3] in addition to bradycardic,[4] antiasthmatic,[5]
antimicrobial,[6] as HIF-1αprolyl hydroxylase inhibitors,[7] cytoprotective[8]. Imidazo[1,2-
a]pyridines that directly Interact with Hepatitis CNS4B[9] and imidazo[1,2-a]pyridine ring
can be considered a biosimilar “aza-indole” analogue. Functionalized imidazo[1,2-
a]pyridines and other imidazo-fused heterocycles are prevalent structural motifs in
biologically active and pharmaceutically important compounds[10-14]. Inrecent years, N-
bromosuccinimide (NBS) emerged as a brominating agents gaining popularity in organic
synthesis due to user friendly and easy to handle.[15] Microwave irradiation has emerged
as a powerful and well controlled heating source for various organic reactionsduetoits
reduced reaction times and enhanced yields.[16]
Water acts as an environmentally benign, readilyavailable, non-toxic, non-flammable and
economically affordable solvents in organic chemistry. PEG-400 is non-toxic, easily
available, inexpensive, non-ionic liquid medium of low volatility, thermally stable,
reusable and also are phase transfer catalyst.[17]A number of methods have been reported
for the synthesis of this important framework; the most exploited one involves 2-
aminopyridine and as starting material. The main part of the protocols involves initial
coupling reactions between endocyclic nitrogen of 2-aminopyridine and various reagents,
such as α-halo carbonyl compounds,[18]diazoketones,[19]oxothioamide,[20]1,2-
diols,[21]imidazo[1,2-a]pyridines. But these methodshavelacuna as difficulty to obtain
starting materials, lowyields, use of lachrymatric α-halo ketones and tedious workup
procedures. Herein,we have developed a versatile,environmentally benign, convenient
protocol for theone-pot synthesis of different derivatives of imidazo[1,2-a]pyridines from
2

cyclocondesation of in-situ generated α-bromoacetophenones and 2-aminopyridines in
PEG-400 and water(1:2) as a greener medium for getting high yield. In order to generate
α-bromo ketones in-situ we have carried out selective bromination of substituted
acetophenones with N-bromosuccinimide in PEG-400 and water(1:2) irradiated at
850c.[22] Main advantage of this protocol is no need to isolate in situ generated
lachrymatric α-bromo ketones and yields are relatively high.
2. RESULT AND DISCUSSION
The earlier reported methods for the synthesis of imidazo[1,2-a]pyridines involved
refluxing 2-amino pyridines and α-halo ketones in organic solvents. But α-halo ketones
are unstable and lachrymatric and difficult to handle it. Considering the hazardous effect
of α-halo ketones and volatile organic solvents prompted us to design new and green
methods for the synthesis of imidazo[1,2-a]pyridines. For the fate of proposal, we have
carried out reactions of acetophenones, NBS and 2-amino pyridines in water but reaction
not occurred without addition of PEG-400. In this protocol we used PEG-400 at a
catalytic amount and water as a solvent under microwave irradiationto obtained high
yield. We have optimized reaction condition under different proportion of PEG-400 and
water as a reaction medium and temperature was maintained at 80-85 throughout the
reaction. It was observed that when we used PEG-400/water in 1:2 proportion product
obtained with higher yield (entry 3 table 1) comparatively the yield obtained by using
PEG-400/water in 1;3 proportion and PEG-400 alone (entry 2&1 table 1). To establish
the generality and scope of the method given in this report, acetophenones carrying
different functional groups such as EDG and EWG were subjected to study their reaction
3

with 2-amino pyridine and NBS in PEG-400/water in 1:2 proportion and number of
(imidazo[1,2-a]pyridines) derivatives have been synthesized and The results are
presented in (Table 2),andIt was observed that electrons withdrawing group present on
the substrate increases the rate of reaction and yield of the imidazo[1,2-a]pyridines.(Table
2).Plausible mechanism for the reaction has been depicted in Figure 2. Initially NBS
released bromine as cation in the presence of water and enol form of acetophenones
attacked on bromine to generate α-bromoacetophenones and The main part of the
mechanism involves initial coupling reactions between endocyclic nitrogen of 2-
aminopyridine and α-bromoacetophenonesand followed by cyclisation to formed
imidazo[1,2-a]pyridines.
Plausible Mechanism of the Reactions
3. EXPERIMENTAL DETAILS
All the chemicals and solvents were of AR grade and used without further purification.
Melting points were determined in open capillary tubes and are uncorrected. Microwave
synthesizer (MAS-II) Sineo Technology Limited, China used for irradiation at 300 watt.
Formation of the compoundswere checked by TLC on aluminium sheets silica gel 60
F254 plates of 0.5 mm thickness. IR spectra were recorded on Shimadzu FT-IR-
8400Instrument using KBr pellet method. Mass spectra were recorded on Shimadzu GC-
MS-QP-2010 model using direct inlet probe technique.1H NMR and 13C NMR was
determined in DMSO-d6 solvent on a Bruker AC 400 MHz Spectrometer.
4

General Procedure for Preparation of Substituted Imidazo[1,2-A]Pyridines(4a-4j)
A mixture. of aromatic acetophenones (5 mmol), NBS (5.5 mmol), in PEG-400 and water
(1:2) 5 ml irradiated for 30 min.at 300 watt power at 80-85oC.The formation of α-
bromoacetophenone was monitored by TLC. Aftercompletion of bromination2-amino
pyridine (5mmol) was added to reaction mixture and reaction mass was further irradiated
for 3-5 min.at 300 watt powerat 80-85oC. The progress of reaction was monitored by
Thin layer chromatography (TLC). After completion of reaction 10ml of ethyl acetate
were added and stirred for 20 min. this process repeated twice. The combined Ethyl
acetate phase was removed under reduced pressure to obtain imidazo[1,2-a]pyridines(4a-
j).
Spectral Data of Some Selected 2-Phenyl Imidazo[1,2-A]Pyridines (4a-4d)
2-Phenylimidazo[1,2-A]Pyridine (4a)
M.P. 133OC; 134LIT.38MP (OC); 1H NMR (300 MHz, DMSO-d6): δ 6.83-6.89 (m, 1H),
7.11-7.24 (m, 1H), 7.29-7.33 (m, 1H), 7.41-7.44 (m, 2H), 7.57 (d, 1H, J 6.9 Hz), 7.94-
7.85 (m, 2H), 8.41 (s, 1H), 8.49-8.54 (m, 1H); 13C NMR (50 MHz, DMSO-d6): δ 107.32,
113.10, 115.89, 127.49, 128.13, 129.71, 129.92, 130.51, 134.12, 144.52; IR (KBr) cm-1:
1637, 769; ES-MS (m/z): 195 [M+H]+; HRMS-EI: found: 194.0837, calculated:
194.0843.spectra data was consistent with previous literature report. [38]
2-(4-Chlorophenyl)-Imidazo[1,2-A]Pyridine (4b)
M.P. 157OC 157-159;LIT. 38MP (OC);1H NMR (300 MHz, CDCl3): δ 6.79-6.91 (m, 1H),
7.25-7.31 (m, 1H), 7.35 (d, 2H, J 8.5 Hz), 7.59 (d, 1H, J 9.0 Hz), 7.74 (s, 1H), 7.79 (d,
5

2H, J 8.5 Hz), 8.2(d, 1H, J 6.8 Hz); 13C NMR (50 MHz, CDCl3): δ 109.23 (CH), 111.51
(CH), 113.73 (CH), 125.12 (CH), 126.21 (CH), 128.61 (CH), 129.55 (CH), 131.76 (C),
134.37 (C), 142.46 (C), 145.19 (C); IR (KBr) cm-1: 1633, 760, 675; ES-MS (m/z): 229
[M+H]+; HRMS-EI: found: 228.0451, calculated: 228.0455. spectra data was consistent
with previous literature report. [38]
2-(4-Bromophenyl)-Imidazo[1,2-A]Pyridine (4c)
M.P. 214-215OC; 215-216;LIT.38MP (OC); 1H NMR (300 MHz, CDCl3): δ 6.38-6.48 (m,
1H), 6.63-6.71 (m, 2H), 7.41 (d, 1H, J 9.0 Hz), 7.53 (d, 2H, J 8.3 Hz), 7.63 (d, 2H, 7.5
Hz), 7.76 (s, 1H), 8.14 (d, 1H, J 6.3 Hz); 13C NMR (75 MHz, CDCl3+DMSO-d6): δ
108.53, 112.56, 116.34, 125.67, 127.63, 130.12, 133.21, 135.12, 135.45, 143.19, 146.42;
IR (KBr) cm-1: 1637, 760, ES-MS (m/z): 274(Br79), 275 Br80) [M+H]+; HRMS-EI:
found: 271.9947, calculated: 271.9950.spectra data was consistent with previous
literature report. [38]
2-(4-Methoxyphenyl)-Imidazo[1,2-A]Pyridine (4d)
M.P. 131OC; 132;LIT.38 MP (OC); 1H NMR (300 MHz, DMSO-d6): δ 3.73 (s, 3H), 6.51-
6.89 (m, 1H), 7.17 (d, 2H, J 8.2 Hz), 7.25-7.32 (m, 1H), 7.51 (m, 1H), 7.81(d, 2H, J 8.2
Hz), 8.24 (s, 1H), 8.49-8.51 (m, 1H); 13C NMR (75 MHz, CDCl3+DMSO-d6): δ 59.12,
109.11, 113.16, 115.22, 118.41, 119.11, 127.20, 129.43, 131.51, 134.32, 145.54, 161.32;
IR (KBr) cm-1: 1639, 765 ES-MS (m/z): 225 [M+H]+; HRMS-EI: found: 224.0947,
calculated:. 224.0950.spectra data was consistent with previous literature report. [38,37]
6

4. CONCLUSION
We have developed facile, one pot,environmentally benign convenient protocol for
thesynthesis of 2-phenylimidazo[1,2-a]pyridines from cyclocondesation of in-situ
generated α-bromoacetophenones and 2-aminopyridines in PEG-400 and water(1:2) as a
greener medium. Main advantage of this method over other prevailing methods is no
need to isolate lachrymatric α-bromoketones, low cost, environmentally benign and yield
relatively high.
ACKNOWLEDGEMENT
We are thankful to the Principal,Vivekanand college, Aurangabad forsupporting this
research work by providing the infrastructure at college central research facility.
SUPPORTING INFORMATION
Supplementary data (full experimental procedures and (1H and 13C NMR and HRMS
Spectral data) associated with this article can be found via the ‘‘Supplementary Content’’
section of this article’s webpage.
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Table 1. Optimization of reaction medium.
Solvent
Proportion
Temp. (OC)
80-85
Yield %
0
Water only
PEG-400
-
-
80-85
45
PEG+Water
PEG+Water
aisolated yield
1:2
1:3
80-85
80-89
60-65
80-85
11

Table 2. Evaluation of compounds (4a-4j)a
Product
R
R’
Reaction
Temp. (OC)
YIELD %
time in min.
4a
4b
4c
4d
4e
4f
H
H
32
31
31
32
33
31
32
32
35
31
80
80
80
80
85
85
85
80
85
85
84
84
84
86
84
86
86
85
89
84
H
4-Cl
4-Br
4-OCH3
4-CH3
H
H
H
H
6-Cl
6-Br
6-Cl
6-CH3
6-Br
4g
4h
4i
H
4-OCH3
4-CH3
4-Cl
4j
aReaction condition:1)acetophenones(0.5mmol),2-amino
pyridine(0.5mmol),NBS(0.5mmol), (PEG-400/water in (1:2) ratio.
2) aisolated yield
12

Figure 1. One pot Synthesis of Imidazo[1,2-a]pyridine
13

Figure 2. Mechanism of one-pot synthesis of imidazo[1,2-a]pyridines
14