Microwave-assisted one-pot synthesis of substituted 3-bromoimidazo[1,2 -A]pyridines and imidazoheterocycles

Article abstract of DOI:10.1002/jhet.1764

Herein, an efficient, one-pot microwave-assisted synthesis of a diverse set of 3-bromoimidazo[1,2-a]pyridines is being reported with good yields (40-85%). The method involves electrophilic aromatic bromination using bromodimethylsulfonium ion generated in situ via oxidation of HBr salt by DMSO. This methodology was also applied to the synthesis of related imidazoheterocycles.

Full text of DOI:10.1002/jhet.1764

Month 2014
Microwave-Assisted One-Pot Synthesis of Substituted 3-Bromoimidazo
[1,2-a]pyridines and Imidazoheterocycles
Shashikant M. Patil, Malcolm Mascarenhas, Rajiv Sharma, S. Mohana Roopan, and Abhijit Roychowdhury
a
a
a
b
a
*
aDepartment of Medicinal Chemistry, Piramal Healthcare Ltd., 1-Nirlon Complex, Goregaon (East), Mumbai
400063, India
bOrganic Chemistry Division, School of Advanced Sciences, VIT University, Vellore-632014, Tamil Nadu, India
*
E-mail: abhijit.roychowdhury@piramal.com
Received March 12, 2012
DOI 10.1002/jhet.1764
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
Herein, an efficient, one-pot microwave-assisted synthesis of a diverse set of 3-bromoimidazo[1,2-a]pyr-
idines is being reported with good yields (40–85%). The method involves electrophilic aromatic bromination
using bromodimethylsulfonium ion generated in situ via oxidation of HBr salt by DMSO. This methodology
was also applied to the synthesis of related imidazoheterocycles. Copyright © 2014 HeteroCorporation
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
reagent economics along with reaction duration drove us to
focus on microwave conditions for the one-pot ring construc-
tion and bromination. In brief, treatment of 2-aminopyridines
in DMSO at 80ꢀC with one equivalent a-bromocarbonyl
compounds yielded 3-bromoimidazo[1,2-a]pyridine deriva-
tives in good yields under microwave conditions.
The imidazo[1,2-a]pyridine scaffold when functionalized
appropriately is a starting point for preparation of a plethora
of biologically active molecules [1]. Appropriately functio-
nalized imidazo[1,2-a]pyridine is also an attractive building
block for the synthesis of tricyclic heterocycles [2,3]. Many
of the recently reported biologically active imidazo[1,2-a]
pyridine scaffolds possess a key functional group in the
3-position. There are a number of synthesis of derivatized
imidazo[1,2-a]pyridine in the literature, but an imidazo[1,2-a]
pyridine functionalized with a reactive functionality in 3-posi-
tion to enable further functionalization has a scope for further
development. Herein, we report an efficient one-pot micro-
wave-assisted synthesis of multifunctional 3-bromoimidazo
[1,2-a]pyridine scaffold amenable for further functionalization.
As a part of a medicinal chemistry program to synthesize
new chemical entities around a 3-functionalized imidazo
[1,2-a]pyridine scaffold, it was imperative to have an
efficient and easy synthesis of 3-bromoimidazo[1,2-a]pyri-
dine scaffold. All reported literature procedures for the
synthesis of 3-bromoimidazo[1,2-a]pyridine are at least two
steps. Typically, the imidazo[1,2-a]pyridine ring is con-
structed in solvents such as ethanol [4], THF [5], and acetone
[6] and a subsequent bromination step by using bromine
[7], NBS [8], pyridinium hydrobromide perbromide [9],
1,2-dibromo-1,1,2,2-tetrafluoroethane [10], and so on and
yields 3-bromoimidazo[1,2-a]pyridine scaffold.
RESULTS AND DISCUSSION
In our initial attempts, concentrated HNO3 was used as an
oxidant for the one-pot bromination. However, this method
was not amenable to microwave conditions because the
HNO3 was added after 1 h of reaction at room temperature.
Besides, HNO3 is a harsh oxidizing agent, and thus, we
decided to explore DMSO as an in situ mild oxidant. As an
initial attempt, 2-aminopyridine and ethyl bromopyruvate in
DMSO were stirred at 80ꢀC for 6 h to yield the desired com-
pound (Table 1, entry 1) in 62% yield. The job in hand was to
further reduce the reaction time, and thus, we subjected the
same substrates to microwave conditions and could achieve
similar yields in 10 min. We extended this methodology to
substituted pyridines (Table 1). As evident from the table,
the cyclization reaction is dependent on the electronic nature
of the substituted pyridine. The yields are good for electron
donating groups (Table 1, entries 2–5) and poor for electron
withdrawing groups such as cyano substituted pyridine
(Table 1, entry 8). In case of a 5-nitro substituted substrate,
we observed no cyclization to the imidazo[1,2-a]pyridine
scaffold (Table 1, entry 9). In general, the yield of these
reactions primarily depends on the cyclization step.
Thus, an efficient one-pot synthesis of conveniently func-
tionalized 3-bromoimidazo[1,2-a]pyridine derivatives would
be an attractive addition to the synthetic methodologies
already available for such synthesis. Recently, Kawano and
Kato [11] reported a one-pot synthesis of 3-bromo-2-aryl
imidazo[1,2-a]pyridine scaffold, but the reaction conditions
used three equivalents of a-bromo ketones in DMSO and used
prolonged reaction duration. The method was also restricted to
very few simple examples. Thus, a need for improving the
This methodology was further extended to the synthesis of
2-aryl substituted-3-bromoimidazo[1,2-a]pyridine scaffolds.
Although an ester at 2-position is biologically significant,
other aromatic substituents will enhance the scope of the reac-
tion (Table 2). It was observed that these reactions resulted
in better yields at 100ꢀC as compared with 80ꢀC. Yields
© 2014 HeteroCorporation

S. M. Patil, M. Mascarenhas, R. Sharma, S. M. Roopan, and A. Roychowdhury
Vol 000
Table 1
One-pot synthesis of ethyl 3-bromoimidazo[1,2-a] pyridine-2-carboxylate scaffolds.
Entry
1
2-Aminopyridines
Product
Isolated yields (%)
62
85
2
3
4
82
70
5
80
6
7
8
9
70
72
16
No cyclisation
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave-Assisted One-Pot Synthesis of Substituted
3-Bromoimidazo[1,2-a]pyridines and Imidazoheterocycles
standard, and chemical shifts are reported in d units. High resolu-
tion mass spectra were recorded using a Bruker Daltonics Micro
TOF-Q spectrometer (ESI, N2) (Bremen, Germany). HPLC purity
was checked using Waters Alliance 2996 HPLC system. HPLC
conditions used for checking purity were Ascentis C18
(50 ꢁ 4.6 mm, 3.5 m) column; mobile phase: A: ACN, B: 0.01 M
NH4OAc + 0.5% TEA, pH 5.0 with AcOH (Time A/B%: 0/80, 6/20,
7/80, 10/80); flow rate: 1 mL/min. All chromatographic purifications
were performed with silica gel (60–120 mesh), whereas all TLC
(silica gel) development was performed on silica gel-coated (Merck
Kiesel 60F254, 0.2 mm thickness) sheets. All reagents and solvents
were of commercial quality and were used as supplied unless
otherwise stated. The microwave reactions were performed with a
CEM microwave synthesizer using 10mL sealed tube.
ranging from 30–80% have been observed for compounds
with different substitution. In cases of 2-aryl substituted
imidazo-pyridine core structure (Table 2), 3-methylthio deriv-
ative was observed in few cases as a minor side product. For ex-
ample, entries 4, 5, 6, 7 and 8 (Table 2) yielded less than 15% of
3-methylthio derivative. It should be noted that in case of 3-
bromoimidazo[1,2-a]pyridine-2-carboxylate scaffolds, no
3-methylthio product was observed (Table 1).
Upon successfully subjecting the one-pot microwave-
assisted synthesis to various substituted imidazo[1,2-a]
pyridine, we sought to extend this methodology to synthesize
more complex pharmaceutically important imidazoheterocyc-
lic scaffolds such as thiazolo-imidazoles (Table 3, entry 1),
thiadiazolo-imidazoles (Table 3, entry 2), benzthiazolo-
imidazoles (Table 3, entry 3), benzimidazolo-imidazoles
(Table 3, entry 4), and pyrimido-imidazoles (Table 3,
entry 5). In some cases (Table 3, entries 1 and 2), a nonbromi-
nated imidazoheterocycles was isolated (<20%). In case of
benzimidazolo-imidazole (Table 3, entry 4), a 3-methylthio
derivative was observed as a minor product (<10%). In this
endeavor, we were able to construct various diverse bromo
substituted imidazoheterocycles for further functionalization
with moderate to good yields.
Mechanistically, condensation of 2-aminopyridine with
ethyl bromopyruvate produces 3-bromoimidazo[1,2-a]pyri-
dine monohydrobromide (Scheme 1) [12]. Further reaction
of HBr (generated in situ) with DMSO leads to formation of
a bromodimethylsulfonium species [13]. This species probably
participates in the electrophilic bromination of the imidazo
[1,2-a]pyridine ring structure. As a proof of this hypothesis,
we isolated 3-bromoimidazo[1,2-a]pyridine monohydrobro-
mide and neutralized it thus removing HBr. As expected,
reaction of the neutralized species with DMSO did not yield
any bromo substituted product. Upon addition of one equiv-
alent of HBr to the isolated neutral species of imidazo[1,2-a]
pyridine in DMSO leads to 3-bromo substituted product in
good yields. This implies that the source of the bromine is
the HBr salt of the imidazo[1,2-a]pyridine moiety.
In summary, we have developed a microwave assisted one-pot,
atom-economical synthesis of 3-bromoimidazo[1,2-a]pyridine
scaffold using equimolar 2-aminopyridines and a-bromocarbonyl
compounds in the presence of DMSO as an oxidant. The reac-
tions are typically completed in less than 30 min with moderate
to excellent yields. The one-pot mild reaction condition has been
implemented on a variety of substituted imidazo[1,2-a]pyri-
dines. The methodology has also been extended to the formation
of other heterocyclic ring structures. This methodology is pres-
ently being applied to other classes of heterocycles.
Typical reaction condition and representative spectroscopic
data for compounds in Table 1
Ethyl-3,6-dibromo-8-methylimidazo[1,2-a]pyridine-2-carboxylate
(Table 1, 2). In a 10 mL pyrex tube containing a Teflon-coated
stir bar, a solution of 2-amino-5-bromo-3-methylpyridine (0.3 g,
1.6 mmol) in DMSO (3 mL) was added. Ethyl bromopyruvate, 90%
(0.22 mL, 1.76 mmol) was added to this solution, and the reaction
mixture was irradiated for 10 min in a CEM microwave synthesizer
at 300 W at 80ꢀC. Reaction mixture was diluted with water (20 mL),
and pH was adjusted to 8–9. The reaction mass was then filtered,
and it gave pure compound (0.49 g) (Table 1, 2).
Yield: 85%; pale yellow solid; mp 159–160ꢀC. 1H NMR
(300 MHz, DMSO-d6): d = 1.33 (t, J = 7.2 Hz, 3H), 2.51 (s, 3H),
4.35 (q, J = 7.2 Hz, 2H), 7.46 (s, 1H), 8.46 (s, 1H). 13C NMR
(75 MHz, CDCl3): d = 162.2, 144.2, 133.9, 130.4, 128.9, 122.4,
109.8, 100.7, 61.7, 16.6, 14.4. HRMS (ESI) m/z [M + H]+ Calcd
for C11H11Br2N2O2: 360.9182, found 360.9176; HPLC: 99.53%.
Ethyl 3-bromoimdazo[1,2-a]pyridine-2-carboxylate (Table 1,
1
1).
Yield: 76%; yellow solid; mp 68ꢀC. H NMR (300MHz,
CDCl3): d = 1.46 (t, J = 7.2 Hz, 3H), 4.50 (q, J = 7.2 Hz, 2H), 7.01
(t, J = 6.9Hz, 1H), 7.33 (t, J = 6.9Hz, 1H), 7.71 (d, J = 9.3 Hz,
1H), 8.22 (d, J = 6.9Hz, 1H); HRMS (ESI) m/z [M + H]+ Calcd
for C10H10Br1N2O2: 268.9920, found 268.9910; HPLC: 98.37%.
Ethyl 3,6-dibromo-7-methylimidazo [1,2-a]pyridine-2-carboxylate
1
(Table 1, 3). Yield: 82%; white solid; mp 176–178ꢀC. H NMR
(300 MHz, CDCl3): d =1.48 (t, J= 7.2 Hz, 3H), 2.51 (s, 3H), 4.51 (q,
J= 7.2 Hz, 2H), 7.55 (s, 1H), 8.39 (s, 1H). HRMS (ESI) m/z [M + H]+
Calcd for C11H11Br2N2O2: 360.9182, found 360.9177. HPLC: 99.53%.
Ethyl 3-bromo-8-methylimidazo [1,2-a]pyridine-2-carboxylate
(Table 1, 4). Yield: 70%; brown solid; mp 68–71ꢀC. 1H NMR
(300MHz, CDCl3): d = 1.48 (t, J = 7.2Hz, 3H), 2.69 (s, 3H), 4.53
(q, J = 7.2 Hz, 2H), 6.95 (t, J = 6.9Hz, 1H), 7.16 (d, J = 6.9Hz,
1H), 8.11 (d, J = 6.9Hz, 1H). HRMS (ESI+) m/z [M + H]+ Calcd
for C11H12Br1N2O2: 283.0077, found 283.0083. HPLC: 99.28%.
Ethyl 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine-2-carboxylate
1
(Table 1, 5). Yield: 80%; white solid; mp 144–145ꢀC. H NMR
(300 MHz, CDCl3): d =1.45 (t, J= 7.2 Hz, 3H), 4.49 (q, J=7.2Hz,
2H), 5.36 (s, 2H), 6.58 (d, J= 7.2 Hz, 1H), 6.83 (t, J= 7.2 Hz, 1H),
7.37 (m, 3H), 7.49 (bd, 2H), 7.84 (d, J= 7.2 Hz, 1H). HRMS (ESI)
m/z [M + H]+ Calcd for C17H16Br1N2O3: 375.0339, found 375.0326.
HPLC: 98.06%.
Ethyl 3-bromo-6-chloroimidazo[1,2-a]pyridine-2-carboxylate
(Table 1, 6). Yield: 70%; off white solid; mp 147–148ꢀC. 1H NMR
(300 MHz, CDCl3): d =1.48 (t, J= 7.2 Hz, 3H), 4.50 (q, J=7.2Hz,
2H), 7.30 (d, J= 9.6 Hz, 1H), 7.69 (d, J= 9.6 Hz, 1H), 8.28 (s, 1H).
HRMS (ESI) m/z [M + H] + Calcd for C10H9Br1Cl1N2O2 [M + H]+
302.9530, found 302.9530. HPLC: 98.21%.
EXPERIMENTAL
Melting points were recorded on Labindia visual melting point
1
apparatus (Mumbai, India). H NMR spectra were recorded on
300 MHz Bruker FT-NMR (Avance DPX300) spectrometer
(Faellandon, Switzerland) using tetramethylsilane as internal
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. Patil, M. Mascarenhas, R. Sharma, S. M. Roopan, and A. Roychowdhury
Vol 000
Table 2
One-pot synthesis of 3-bromo-2-aryl substituted imidazo[1,2-a]pyridine scaffold with various substitution on the aryl group.
Entry
1
Alphabromoacetophenones
Product
Isolated yields (%)
76a
72a
82a
55b
55b
40b
70b
2
3
4
5
6
7
8
9
63b
No reaction
aCorresponding 3-methylthio derivatives were observed in trace quantity on TLC (not isolated) and confirmed by LCMS.
bCorresponding 3-methylthio derivatives were isolated in yield of 10–20% (data included in experimental section).
Journal of Heterocyclic Chemistry
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Month 2014
Microwave-Assisted One-Pot Synthesis of Substituted
3-Bromoimidazo[1,2-a]pyridines and Imidazoheterocycles
Table 3
Synthesis of 3-bromo imidazoheteroaryl scaffolds.
Entry
1
Amino heterocyclics
a-Bromocarbonyls
Product
Isolated yields (%)
65a
2
55a
3
4
48
30b
5
30
Reaction condition: MW/DMSO/100ꢀC/20 min.
aCorresponding imidazoheterocyclic derivatives were isolated without bromination at 3-position (<20%).
bCorresponding 3-methylthio derivative was observed in trace quantity on TLC (not isolated) and confirmed by LCMS.
Ethyl 3,6-dibromoimidazo[1,2-a]pyridine-2-carboxylate (Table 1,
113.7, 93.6, 77.1, 40.1, 16.5. HRMS (ESI) m/z [M + H]+ Calcd for
7).
Yield: 72%; yellow solid; mp 166–168ꢀC. 1H NMR
C14H11Br1N3O2: 332.0029, found 332.0027. HPLC: 89.8%.
4-(3-Bromo-8-methylimidazo[1,2-a]pyridin-2-yl)benzonitrile
(300 MHz, CDCl3): d =1.48 (t, J= 7.2 Hz, 3H), 4.50 (q, J=7.2Hz,
2H), 7.43 (d, J= 9.6 Hz, 1H), 7.63 (d, J= 9.6 Hz, 1H), 8.38 (s, 1H).
HRMS (ESI) m/z [M + H]+ Calcd for C10H9Br2N2O2 : 346.9025,
found 346.9026. HPLC: 98.29%.
Ethyl 3-bromo-6-cyanoimidazo[1,2-a]pyridine-2-carboxylate
(Table 2, 2). Yield: 65%; yellow solid; mp 187–188ꢀC. 1H NMR
(300 MHz, CDCl3): d = 2.66 (s, 3H), 6.89 (t, J = 6.9 Hz, 1H), 7.11
(d, J = 6.9 Hz, 1H), 7.77 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 6.9 Hz,
1H), 8.32 (d, J = 8.4 Hz, 2H). HRMS (ESI) m/z [M+ H]+ Calcd
for C15H11Br1N3: 312.0131, found 312.0135. HPLC: 95.50%.
3-Bromo-2-(3,4-dichlorophenyl)-8-methylimidazo[1,2-a]pyridine
(Table 1, 8). Yield: 16%; pale yellow; mp 195–197ꢀC. 1H NMR
(300 MHz, CDCl3): d =1.47 (t, J= 7.2 Hz, 3H), 4.52 (q, J=7.2Hz,
2H), 7.44 (dd, J= 9.3 Hz, 1.5 Hz, 1H), 7.81 (d, J=9.3Hz, 1H), 8.67
(d, J= 1.5 Hz, 1H). HRMS (ESI) m/z [M + H]+ Calcd for
C11H9BrN3O2: 293.9873, found 293.9852. HPLC: 99.10%.
Typical reaction condition and representative spectroscopic
data for compounds in Table 2 and 3
1
(Table 2, 3). Yield: 80%; off white solid; mp 149ꢀC. H NMR
(300 MHz, CDCl3): d = 2.66 (s, 3H), 6.87 (t, J= 6.9 Hz, 1H), 7.09
(d, J= 6.9 Hz, 1H), 7.55 (d, J= 6.9 Hz, 1H), 8.00 (dd, J=8.7Hz,
1.8 Hz, 1H), 8.05 (d, J= 8.7 Hz, 1H), 8.28 (d, J=1.8Hz, 1H).
HMRS (ESI) m/z [M + H]+ Calcd for C14H10Br1Cl2N2: 354.9399,
found 354.9389. HPLC: 98.21%.
3-Bromo-8-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (Table 2,
3-Bromo-2-(4-bromophenyl)-8-methylimidazo[1,2-a]pyridine
(Table 2, 4). Yield: 55%; yellow solid; mp 132–133ꢀC. 1H NMR
(300 MHz, CDCl3): d = 2.66 (s, 3H), 6.86 (t, J= 6.9Hz, 1H), 7.08 (d,
J=6.9Hz, 1H), 7.62 (d, J= 8.4Hz, 2H), 8.01 (d, J= 8.4 Hz, 2H), 8.05
(d, J= 6.9 Hz, 1H). HMRS (ESI) m/z [M + H]+ Calcd for
C14H11Br2N2: 364.9283, found 364.9267. HPLC: 98.48%.
2-(4-Bromophenyl)-8-methyl-3-(methylthio)imidazo[1,2-a]pyridine
(Table 2, 4b). Yield: 12%; off white solid; mp 104ꢀC. 1H
NMR (300 MHz, CDCl3): d = 2.26 (s, 3H), 2.68 (s, 3H),
6.88 (t, J = 6 Hz, 1H), 7.13 (d, J = 6 Hz, 1H), 7.63 (d,
J = 9 Hz, 2H), 8.23 (d, J = 9 Hz, 2H), 8.37 (d, J = 6 Hz, 1H).
1). In a 10 mL pyrex tube containing a Teflon-coated stirring bar, 2-
amino-3-methylpyridine (0.33 g, 3.05 mmol) and 2-bromo-40-
nitroacetophenone (0.75 g, 3.08 mmol) were mixed in DMSO (3 mL).
The mixture was irradiated for 20min in a CEM microwave system
at 300 W at 100ꢀC. Upon diluting the reaction mixture with ethanol
(5 mL), on filtration, it gave pure compound (0.75 g) (Table 2, 1).
Yield: 76%; light yellow solid; mp 201–202ꢀC. 1H NMR
(300 MHz, CDCl3): d = 2.69 (s, 3H), 6.93 (t, J= 6.9 Hz, 1H), 7.15 (d,
J= 6.9 Hz, 1H), 8.11 (d, J= 6.9 Hz, 1H), 8.36 (d, J= 9 Hz, 2H), 8.41
(d, J= 9 Hz, 2H). 13C NMR (75MHz, CDCl3 +drop DMSO-d6):
d = 147.1, 146.1, 139.7, 139.6, 128.3, 128.1, 124.6, 123.7, 121.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. Patil, M. Mascarenhas, R. Sharma, S. M. Roopan, and A. Roychowdhury
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Scheme 1. Plausible mechanism of 3-bromo imidazo[1,2-a]pyridine formation.
HRMS (ESI) m/z [M + H]+ Calcd for C15H14Br1N2S1:
333.0056, found 333.0048. HPLC: 99.83%.
6.87 (t, J =6 Hz, 1H), 7.04 (dd, J = 9 Hz, 3 Hz, 1H), 7.11
(d, J = 6 Hz, 1H), 7.35–7.44 (m, 4H), 7.50 (d, J = 6 Hz, 2H), 7.93
(d, J = 9 Hz, 1H), 8.00 (bs, 1H), 8.38 (d, J = 6 Hz, 1H). HRMS
(ESI) m/z [M + H]+ Calcd for C22H21N2O1S1: 361.1369, found
361.1356. HPLC: 99.06%.
3-Bromo-2-(4-chlorophenyl)-8-methylimidazo[1,2-a]pyridine
1
(Table 2, 5). Yield: 55%; off white solid; mp 139–140ꢀC. H
NMR (300 MHz, CDCl3): d = 2.68 (s, 3H), 6.88 (t, J = 6.9 Hz,
1H), 7.10 (d, J = 6.9 Hz, 1H), 7.47 (d, J = 8.7 Hz, 2H), 8.07
(d, J = 6.9 Hz, 1H), 8.12 (d, J = 8.7 Hz, 2H). HRMS (ESI) m/z
[M + H]+ Calcd for C14H11Br1Cl1N2: 320.9789, found
320.9798. HPLC: 97.77%.
2-(4-Chlorophenyl)-8-methyl-3-(methylthio)imidazo[1,2-a]pyridine
(Table 2, 5b). Yield: 15%; off white solid; mp 102ꢀC. 1H
NMR (300 MHz, CDCl3): d = 2.26 (s, 3H), 2.68 (s, 3H),
6.88 (t, J = 6 Hz, 1H), 7.12 (d, J = 6 Hz, 1H), 7.48 (d,
J = 9 Hz, 2H), 8.29 (d, J = 9 Hz, 2H), 8.37 (d, J = 6 Hz, 1H).
HRMS (ESI) m/z [M + H]+ Calcd for C15H14Cl1N2S1
289.0561, found 289.0534. HPLC: 99.28%.
3-Bromo-2-(4-methoxyphenyl)-8-methylimidazo[1,2-a]pyridine
(Table 2, 6). Yield: 40%; brown solid; mp 113–115ꢀC. 1H NMR
(300 MHz, CDCl3): d = 2.66 (s, 3H), 3.87 (s, 3H), 6.83 (t, J = 6.9 Hz,
1H), 6.99–7.48 (m, 3H), 8.02–8.09 (m, 3H). HRMS (ESI) m/z
[M + H]+ Calcd for C15H14Br1N2O1: 317.0284, found 317.0282.
HPLC: 99.56%.
3-Bromo-8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (Table 2,
8).
Yield: 70%; dark brown solid; mp 75–76ꢀC. 1H NMR
(300 MHz, CDCl3): d = 2.41 (s, 3H), 2.67 (s, 3H), 6.84
(t, J = 6.9 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 7.30 (d, J = 8.1 Hz,
2H), 8.02 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 6.9 Hz, 1H). HRMS
(ESI) m/z [M+ H]+ Calcd for C15H14Br1N2: 301.0335, found
301.0324. HPLC: 99.73%.
8-Methyl-3-(methylthio)-2-(p-tolyl)imidazo[1,2-a]pyridine (Table 2,
8b). Yield: 10%; semisolid. 1H NMR (300 MHz, CDCl3):
d = 2.26 (s, 3H), 2.44 (s, 3H), 2.69 (s, 3H), 6.84 (t, J = 6 Hz, 1H),
7.10 (d, J = 6 Hz, 1H), 7.30 (d, J = 9 Hz, 2H), 8.19 (d, J = 9 Hz,
2H), 8.37 (d, J = 6 Hz, 1H). HRMS (ESI) m/z [M+ H]+ Calcd for
C16H17N2S1: 269.1107, found 269.1119. HPLC: 99.82%.
Imidazoheterocycle sacaffold (Table 3)
5-Bromo-6-(3-methoxyphenyl)imidazo[2,1-b]thiazole (Table 3,
1). Yield: 65%; brown solid; mp 98ꢀC. 1H NMR (300 MHz,
CDCl3): d = 3.90 (s, 3H), 6.91 (dd, J = 8.1 Hz, 2.4 Hz, 1H), 6.95
(d, J = 4.5 Hz, 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.45 (d, J = 4.5 Hz,
1H), 7.60 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 8.1 Hz, 1H). HRMS
(ESI) m/z [M + H]+ Calcd for C12H10Br1N2O1S1: 308.9692,
found 308.9686. HPLC: 99.21%.
2-(4-Methoxyphenyl)-8-methyl-3-(methylthio)imidazo[1,2-a]
1
pyridine (Table 2, 6b).
Yield: 17%; colorless oil. H NMR
(300 MHz, CDCl3): d = 2.26 (s, 3H), 2.73 (s, 3H), ), 3.89 (s, 3H),
6.85 (t, J = 6 Hz, 1H), 7.05 (d, J = 9 Hz, 2H), 7.10 (d, J = 6 Hz,
1H), 8.25 (d, J = 9 Hz, 2H), 8.36 (d, J = 6 Hz, 1H). HRMS (ESI)
m/z [M+ H]+ Calcd for C16H17N2O1S1: 285.1056, found
285.1066. HPLC: 99.45%.
6-(3-Methoxyphenyl)imidazo[2,1-b]thiazole (Table 3, 1a). Yield:
15%; off white solid; mp 153ꢀC. 1H NMR (300 MHz,
CDCl3): d = 3.90 (s, 3H), 6.85 (bd, J = 6 Hz, 1H), 6.88
(dd, J = 9 Hz, 3 Hz, 1H), 7.32 (t, J = 9 Hz, 1H), 7.41 (d, J = 3 Hz,
1H), 7.44 (d, J = 6 Hz, 1H), 7.45 (d, J = 9 Hz, 1H), 7.76 (s, 1H).
2-(3-(Benzyloxy)phenyl)-3-bromo-8-methyl imidazo[1,2-a]
1
MS (ESI) m/z [M+ H]+ 231.0; HPLC: 99.55%.
pyridine (Table 2, 7). Yield: 30%; dark brown semisolid. H
NMR (300 MHz, CDCl3): d = 2.67 (s, 3H), 5.18 (s, 2H), 6.85 (t,
J = 6.9 Hz, 1H), 7.02 (dd, J = 7.8 Hz, 2.4 Hz, 1H), 7.07 (d,
J = 6.9 Hz, 1H), 7.30–7.42 (m, 4H), 7.48 (bs, 1H), 7.50 (d,
J = 6.9 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.77 (bs, 1H), 8.06 (d,
J = 6.9 Hz, 1H). HRMS (ESI) m/z [M + H]+ Calcd for
C21H18Br1N2O1: 393.0597, found 393.0590. HPLC: 99.13%.
2-(3-(Benzyloxy)phenyl)-8-methyl-3-(methylthio)imidazo[1,2-a]
5-Bromo-2-methyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-
b][1,3,4]thiadiazole (Table 3, 2).
Yield: 55%; white solid;
mp156–157ꢀC. 1H NMR (300 MHz, CDCl3): d = 2.80 (s, 3H),
7.72 (d, J = 8.4 Hz, 2H), 8.19 (d, J = 8.4 Hz, 2H). HRMS
(ESI) m/z [M + H]+ Calcd for C12H8Br1F3N3S1: 361.9569,
found 361.9554. HPLC: 97.5%.
2-Methyl-6-(4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazole
pyridine (Table 2, 7b). Yield: 11%; brown semisolid. 1H NMR
(300 MHz, CDCl3): d = 2.24 (s, 3H), 2.69 (s, 3H), 5.21 (s, 2H),
(Table 3, 2a).
1H NMR (300 MHz, CDCl3): d = 2.75 (s, 3H), 7.68 (d,
Yield: 18%; yellow solid; mp 218–220ꢀC.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
Microwave-Assisted One-Pot Synthesis of Substituted
3-Bromoimidazo[1,2-a]pyridines and Imidazoheterocycles
[2] Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.;
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D. A.; Tully, W. R.; Westwood, R. J Med Chem 1988, 31, 1098.
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mann, P. J.; Buhr, W.; Feth, M. P.; Simon, W. A.; Kromer, W. J Med
Chem 2007, 50, 6240; (b) Palmer, A. M.; Grobbel, B.; Brehm, C.;
Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Holst, H. C.; Simon,
W. A. Bioorg Med Chem 2007, 15, 7647.
[4] (a) Groselj, U.; Bezensek, J.; Meden, A.; Svete, J.; Stanovnik, B.;
Oblak, M.; Stefanic A. P.; Urleb, U. Heterocycles 2008, 75, 1355; (b) Xia,
G.; Li, J.; Peng, A.; Lai, S.; Zhang, S.; Shen, J.; Liu, Z.; Chen, X.; Ji, R.
Bioorg Med Chem Lett 2005, 15, 2790; (c) Ismail, M. A.; Arafa, R. K.;
Wenzler, T.; Brun, R.; Tanious, F. A.; Wilson, W. D.; Boykin, D. W.
Bioorg Med Chem 2008, 16, 683.
[5] Kaizerman, J. A.; Gross, M. I.; Ge, Y.; White, S.; Hu, W.;
Duan, J. X.; Baird, E. E.; Johnson, K. W.; Tanaka, R. D.; Moser, H. E.;
Burli, R. W. J Med Chem 2003, 46, 3914.
[6] Sundberg, R. J.; Biswas, S.; Murthi, K. K.; Rowe, D.; McCall,
J. W.; Dzimianski, M. T. J Med Chem 1998, 41, 4317.
[7] (a) Moreau, E.; Chezal, J.; Dechambre, C.; Canitrot, D.; Blache, Y.;
Lartigue, C.; Chavignon, O.; Teulade, J. C. Heterocycles 2002, 57, 21; (b)
Gueiffier, A.; Blache, Y.; Viols, H.; Chapat, J. P.; Chavignon, O.; Teulade,
J. C.; Madesclaire, M.; Dauphin, G. J Heterocyclic Chem 1992, 29, 691;
(c) Sundberg, R. J.; Dahlhausen, D. J.; Manikumar, G.; Mavunkel, B.;
Biswas, A.; Srinivasan, V.; King F.; Waid, P. J Heterocylic Chem 1988, 25, 129.
[8] a) Bellingham, R.; Buswell, A. M.; Choudary, B. M.; Gordon,
A. H.; Moore, S. O.; Sasse, M.; Shamji, A.; Urquhart, M. W. J.; Peterson,
M. Org Process Res Dev 2010, 14, 1254; b) Rival, Y.; Grassy, G.; Taudou,
A.; Ecalle, R. Euro J Med Chem 1991, 26, 13.
J = 9 Hz, 2H), 7.95 (d, J = 9 Hz, 2H), 8.05 (s, 1H). MS (ESI)
m/z [M + H]+ 284.0; HPLC: 97.72%.
Ethyl 3-bromo-6-ethoxybenzo[d]imidazo[2,1-b]thiazole-2-
carboxylate (Table 3, 3).
Yield: 48%; brown solid; mp
208–210ꢀC. 1H NMR (300 MHz, CDCl3): d = 1.32 (m,
J = 7.2 Hz, 6H), 4.08 (q, J = 7.2 Hz, 2H), 4.28 (q, J = 7.2 Hz,
2H), 7.15 (dd, J = 9 Hz, 2.4 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H),
8.29 (d, J = 9 Hz, 1H). HRMS (ESI) m/z [M + H]+ Calcd
for C14H14Br1N2O3S1: 368.9903, found 368.9887. HPLC:
99.00%.
3-Bromo-9-methyl-2-(4-(trifluoromethyl)phenyl)-9H-benzo[d]
imidazo[1,2-a]imidazole (Table 3, 4). Yield: 30%; white solid;
mp 179ꢀC. 1H NMR (300MHz, CDCl3) d 3.83 (s, 3H), 7.24–7.34
(m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.4Hz, 2H), 8.07
(d, J = 8.1Hz, 1H), 8.23 (d, J = 8.4Hz, 2H). HRMS (ESI) m/z
[M + H]+ Calcd for C17H12Br1F3N3: 394.0161, found 394.0161.
HPLC: 98.83%.
Ethyl
(Table 3, 5).
3,6-dibromoimidazo[1,2-a]pyrimidine-2-carboxylate
Yield: 30%; pale yellow solid; mp 108ꢀC.
1H NMR (300 MHz, CDCl3): d =1.47 (t, J=7.2Hz, 3H), 4.50
(q, J= 7.2 Hz, 2H), 8.71 (d, J= 2.1 Hz, 1H), 9.78 (d, J= 2.1 Hz, 1H).
HRMS (ESI) m/z [M + H]+ Calcd for C9H8Br2N3O2: 347.8978,
found 347.8966. HPLC: 96.57%.
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39, 2937.
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Pelletier, J. C.; Chengalvala, M. V.; Cottom, J. E.; Feingold, I. B.; Shanno,
L. Bioorg Med Chem Lett 2010, 20, 2512.
Acknowledgments. The authors want to thank the analytical facility
at Piramal Healthcare Ltd., Mumbai, India for their support.
REFERENCES AND NOTES
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[1] Katritzky, A. R.; Xu, Y. J.; Tu, H. J Org Chem 2003, 68, 4935
and references cited therein.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet