Regioselective synthesis of 2- and 3-substituted imidazo[1,2-a]pyridines

Article abstract of DOI:10.3184/174751912X13499663832261

A range of 2- or 3-substituted imidazo[1,2-a]pyridines were prepared from 2-aminopyridine derivatives and gemdibromovinyl compounds by the tandem nucleophilic substitution (or nucleophilic addition)/cyclisation reaction.

Full text of DOI:10.3184/174751912X13499663832261

JOURNAL OF CHEMICAL RESEARCH 2012
RESEARCH PAPER 687
DECEMBER, 687–690
Regioselective synthesis of 2- and 3-substituted imidazo[1,2-a]pyridines
Guoping Liua, Xuefeng Congb, Jiaheng Hea, Shunzhong Luoa*, Di Wub and Jingbo Lanb
aInstitute of Nuclear Physics and Chemistry, China Academy of Engineering Physics, Mianyang 621900, P. R. China
bKey Laboratory of Green Chemistry andTechnology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang
Road, Chengdu 610064, P. R. China
A range of 2- or 3-substituted imidazo[1,2-a]pyridines were prepared from 2-aminopyridine derivatives and gem-
dibromovinyl compounds by the tandem nucleophilic substitution (or nucleophilic addition)/cyclisation reaction.
Keywords: imidazo[1,2-a]pyridine, 2-aminopyridine, gem-dibromovinylbenzene, regioselectivity, nucleophilic substitution
Imidazo[1,2-a]pyridines are a class of compounds that possess
a wide range of pharmacological properties including anti-
bacterial, antifungal, antiviral, anti-inflammatory activities.1,2
They can also be used for prophylactic and therapeutic treat-
ment of anxiety, diabetes, hyperglycaemia, hypertension,
and arteriosclerosis.3 Several drugs based on imidazo[1,2-a]
pyridine are already on the market including alpidem, necopi-
dem, saripidem, zolimidine and zolpidem.4–6 The common
approach for preparation of imidazo[1,2-a]pyridine ring
system mainly involves: (i) construction of the five-membered
imidazole ring by the two- or three-component coupling
of pyridine derivatives with a diversity of coupling partners or
intramolecular condensation of N-substituted-2-aminopyri-
dines prepared in advance;7–17 or (ii) construction of the
six-membered pyridine ring using substituted imidazoles as
starting materials.18,19
The pharmaceutical activity of imidazo[1,2-a]pyridines is
closely related to the substituted position and electronic prop-
erties of C-2 or C-3 substituents on the imidazole ring.20–22
Various 2-substituted and/or 3-substituted imidazo[1,2-a]
pyridines were prepared relying on the condensation or func-
tionalisation reactions of the skeleton of imidazo[1,2-a]
pyridine.7–19,23 However, there is no general methodology for
the selectively synthesis of 2- and 3-substituted imidazo[1,2-a]
pyridines. Recently, our laboratory reported the use of gem-
dihalovinyl substrates to achieve diverse heteroaromatics
via the tandem C-heteroatom coupling/C-H activation.24 In
continuation of our interest in the cyclisation reaction of
heteroaromatics, we now present the synthesis of 2- and 3-
substituted imidazo[1,2-a]pyridines using various gem-dibro-
movinyl substrates as starting materials (Scheme 1).
4–6). Subsequently, the amount of TBAF·3H2O necessary
was investigated. Increasing TBAF·3H2O loading resulted in a
negative effect (Table 1, entry 4), and reducing the amount of
TBAF·3H2O could improve the reaction efficiency (Table 1,
entries 5 and 6). Note that 3-substituted imidazo[1,2-a]pyridine
(3a) was obtained in 67% isolated yield together with 2-substi-
tuted imidazo[1,2-a]pyridine (4a) in 8% isolated yield while
3.0 equiv. of TBAF·3H2O was employed (Table 1, entry 5).
The two compounds 3a and 4a can be easily separated by
column chromatography due to their very different molecular
polarity. After screening other bases (e.g., KF, K2CO3, and
K3PO4), we found that KF gave the best result with 76% yield
of 3a together with 6% yield of 4a in DMF (Table 1, entry 8).
In addition, decreasing the reaction temperature could signifi-
cantly diminish yields (Table 1, entries 11 and 12). Thus, the
optimal reaction condition was obtained when KF (3.0 equiv.)
was employed as the base in DMF at 130 °C for 12 h under
nitrogen atmosphere.
Under optimised conditions, the generality of the reaction
was examined (Table 2). It was found that the reaction of
a variety of gem-dibromovinyl substrates bearing electron-
neutral or electron-rich aryls (e.g., phenyl, p-methylphenyl,
p-methoxyphenyl, 3,4-dimethoxyphenyl and naphthyl), p-
halophenyls (e.g., p-fluorophenyl, p-chlorophenyl and p-bro-
mophenyl), heteroaryls (e.g., 2-thienyl and 2-pyridyl), vinyl
and alkyl with 2-aminopyridine mainly obtained 3-substituted
imidazo[1,2-a]pyridines (3), together with trace to small
amounts of 2-substituted imidazo[1,2-a]pyridines (4). Note
that 1,1-dibromodec-1-ene was able to react with 2-aminopyr-
idine, when CuI (10 mol%) was employed as a catalyst, and
3-octylimidazo[1,2-a]pyridine in 75% yield (Table 2, entry
3l). The reaction condition was also suitable for various substi-
tuted 2-aminopyridine substrates. 3-methyl-2-aminopyridine,
5-methyl-2-aminopyridine, 5-phenyl-2-aminopyridine and 3-
benzyloxy-2-aminopyridine could be efficiently converted into
the corresponding 3-substituted imidazo[1,2-a]pyridines in
synthetically useful yields (Table 2, entries 3m–p).
Result and discussion
As shown in Table 1, optimisation of the reaction conditions
was carried out first. According to our experience,24 the initial
investigation started with the coupling of gem-dibromovinyl-
benzene 1a and 2-aminopyridine 2a in the presence of CuI
using Cs2CO3 as the base in DMF for 24 h at 110 °C. 2-Pheny-
limidazo[1,2-a]pyridine (3a) was obtained in 20% yield
(Table 1, entry 1). When TBAF·3H2O (tetrabutylammonium
fluoride, 4.0 equiv.) was employed as the base, 3a was obtained
in 40% and 50% yield in DMF and DMSO, respectively
(Table 1, entries 2, 3). In controlled experiments, it was found
that CuI was not necessary for this reaction (Table 1, entries
Further studies showed that the reaction of gem-dibromovi-
nyl substrates bearing strongly electron-deficient aryls (e.g.,
p-nitrophenyl, m-nitrophenyl, o-nitrophenyl, and p-cyanophenyl)
and o-halophenyls (e.g., o-chlorophenyl, and o-bromophenyl)
with 2-aminopyridine under the same reaction condition
mainly obtained 2-substituted imidazo[1,2-a]pyridines (4),
together with trace to a moderate amount of 3-substituted
imidazo[1,2-a]pyridines (3).
Scheme 1 Synthesis of 2-substituted and 3-substituted imidazo[1,2-a]pyridines.
* Correspondent. E-mail: luoshzh@caep.ac.cn

688 JOURNAL OF CHEMICAL RESEARCH 2012
Table 1 Optimisation of the reaction of gem-dibromovinyl-
Table 3 Synthesis of 2-substituted imidazo[1,2-a]pyridinesa,b,c
benzene with 2-aminopyridinea
Entry Cat.
Base
(n equiv.)
Solvent Temp Time
Yieldb
(3a:4a)
/°C
/h
1
2
3
4
5
CuI
Cs2CO3 (4)
DMF
110
110
24
24
24
12
12
20% (3a)
40% (3a)
54% (3a)
23% (3a)
67% (3a)
8% (4a)
61% (3a)
8% (4a)
75% (3a)
6% (4a)
76% (3a)
6% (4a)
50% (3a)
52% (3a)
54% (3a)
17% (3a)
CuI TBAF·3H2O (4) DMF
a Reaction conditions: KF (3 equiv.), gem-dibromovinyl sub-
strate (0.5 mmol), 2-aminopyridine (0.6 mmol) and DMF
(1.0 mL) under nitrogen atmosphere.
CuI TBAF·3H2O (4) DMSO 110
-
-
TBAF·3H2O (5) DMSO 130
TBAF·3H2O (3) DMSO 130
b Isolated yield of 4.
c Together with trace to moderate amounts of 3.
6
7
8
-
-
-
TBAF·3H2O (2) DMSO 130
12
12
12
KF (3)
KF (3)
DMSO 130
attacked by the nucleophile (amino group), and then undergo
the nucleophile addition reaction of π-bond to give 2-substi-
tuted imidazo[1,2-a]pyridines. It is well known that the elec-
tron-withdrawing characteristics of o-halophenyls are stronger
than p-halophenyls because of the inductive effect of the
ortho-substituent. Therefore, gem-dibromovinyl substrates
bearing o-halophenyls would mainly undergo the nucleophilic
addition pathway (Path B) to provide 2-substituted imidazo
[1,2-a]pyridines, while gem-dibromovinyl-4-halobenzenes
would mainly undergo the nucleophilic substitution pathway
(Path A) to give 3-substituted imidazo[1,2-a]pyridines.
DMF
130
9
10
11
12
-
-
-
-
K2CO3 (3)
K3PO4 (3)
KF (3)
DMF
DMF
DMF
DMF
130
130
100
80
12
12
12
12
KF (3)
a Reaction conditions: CuI (10 mol%), base (2–5 equiv.), gem-
dibromovinylbenzene (0.5 mmol), 2-aminopyridine (0.6 mmol)
and solvent (1.0 mL) under nitrogen atmosphere.
b Yield of isolated product.
DMF, dimethyl formamide; DMSO, dimethyl sulfoxide; TBAF,
tetrabutylammonium fluoride.
Experimental
NMR spectra were obtained on a Bruker AMX-400 or a Bruker AMX-
600. The 1H NMR (400 MHz or 600 MHz) chemical shifts were mea-
sured relative to CDCl3 as the internal reference (CDCl3: δ 7.26 ppm).
The 13C NMR (100 MHz or 150 MHz) chemical shifts were given
using CDCl3 as the internal standard (CDCl3: δ 77.16 ppm). The
following abbreviations were used to designate the multiplicities: s,
singlet; d, doublet; t, triplet; bs, broad signal; m, multiplet. High-
resolution mass spectra (HR-MS) were obtained with a Waters-Q-
TOF-Premier (ESI). IR spectra were obtained on NEXUS 670 FTIR
using KBr disks. Melting points were determined with XRC-1 and are
uncorrected.
Unless otherwise noted, all reagents were obtained from commercial
suppliers and used without further purification. gem-Dibromovinyl
substrates were prepared according to the literature procedures.25–27
Solvents were dried over CaH2 (DMF or DMSO), and freshly distilled
prior to use. Unless otherwise indicated, all syntheses and manipula-
tions were carried out under N2 atmosphere.
A proposed mechanism for regioselective synthesis of
2- and 3-substituted imidazo[1,2-a]pyridines is shown in
Scheme 2. The reaction probably involves 1-bromoalkyne
in situ generated from dehydrohalogenation of gem-dibromov-
inyl substrates. Subsequently, the nucleophilic substitution
and nucleophilic addition of 1-bromoalkyne would take place
simultaneously and competitively. The nucleophilic substitu-
tion of 1-bromoalkyne bearing electron-rich, electron-neutral
and weakly electron-deficient aryls may be more prone to
occur, followed by isomerisation and intramolecular hydroam-
ination, and thus mainly give 3-substituted imidazo[1,2-a]
pyridines. When the alkynyl is adjacent to the strongly elec-
tron-deficient functional groups, it may be more likely to be
Table 2 Synthesis of 3-substituted imidazo[1,2-a]pyridinesa,b,c
Synthesis of 2-substituted and 3-substituted imidazo[1,2-a]pyridines;
general procedure
A flame-dried Schlenk test tube with a magnetic stirring bar was
charged with 1,1-dibromovinyl substrate (0.5 mmol), 2-aminopyri-
dine (0.6 mmol), KF (90 mg, 1.5 mmol), and DMF (1.0 mL) under N2.
A rubber septum was replaced with a glass stopper, and the system
was then evacuated twice and back filled with N2. The reaction
mixture was stirred for 10 min at room temperature, and then heated
at 130 ºC for 12 h. The reaction mixture was then cooled to ambient
temperature, DMF was removed under the reduce pressure, the resi-
due was dissolved with 5–10 mL of CH2Cl2, filtered through a plug of
silica gel, and washed with 10–20 mL of CH2Cl2. The combined
organic extracts were concentrated and the resulting residue was puri-
fied by column chromatography on silica gel to provide the desired
product.
3-Phenylimidazo[1,2-a]pyridine (3a)28: Colourless oil, 1H NMR
(400 MHz, CDCl3): δ 6.78 (t, J = 6.8 Hz, 1H), 7.16 (t, J = 7.8 Hz, 1H),
7.39 (t, J = 7.2 Hz, 1H), 7.49–7.56 (m, 4H), 7.65–7.69 (m, 2H), δ 8.32
(d, J = 7.2 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 112.6, 118.3,
123.4, 124.3, 125.8, 128.1, 128.2, 129.3, 129.3, 132.5, 146.1 ppm;
HRMS (ESI): m/z calcd for C13H10N2 [M+H]+ 195.0922, found
195.0924.
a Reaction conditions: KF (3 equiv.), gem-dibromovinyl substrate
(0.5 mmol), 2-aminopyridine or substituted 2-aminopyridine
(0.6 mmol) and DMF (1.0 mL) under nitrogen atmosphere.
b Isolated yield of 3.
2-Phenylimidazo[1,2-a]pyridine (4a)29: Grey solid, m.p. 131–133 °C,
1H NMR (400 MHz, CDCl3): δ 6.75 (t, J = 6.8 Hz, 1H), 7.14 (t, J =
8.0 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.62 (d,
c Together with trace to small amounts of 4.
d CuI (10 mol%) was added.

JOURNAL OF CHEMICAL RESEARCH 2012 689
Scheme 2 Proposed mechanism for synthesis of 2-substituted and 3-substituted imidazo[1,2-a]pyridines.
J = 9.2 Hz, 1H), 7.86 (s, 1H), 7.95 (d, J = 6.8 Hz, 2H), 8.10 (d, J =
6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 108.1, 112.6, 117.5,
124.8, 125.6, 126.1, 128.0, 128.8, 133.6, 145.6, 145.7 ppm; HRMS
(ESI): m/z calcd for C13H10N2 [M+H]+ 195.0922, found 195.0924.
3-p-Tolylimidazo[1,2-a]pyridine (3b): White solid, m.p. 68–70 °C;
1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H), 6.77 (t, J = 6.8 Hz, 1H),
7.15 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 7.8 Hz,
2H), 7.65–7.67 (m, 2H), 8.29 (d, J = 7.2 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 21.4, 112.4, 118.2, 123.4, 124.1, 125.8, 126.3,
128.1, 129.9, 132.2, 138.2, 146.0 ppm; HRMS (ESI): m/z calcd for
C14H12N2 [M+H]+ 209.1079, found 209.1079. IR (ATR): ν (cm−1):
3112, 2920, 2857, 1633, 1544, 1491, 1353, 759.
7.19 (t, J = 7.6 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.63–7.68 (m, 4H),
8.26 (d, J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 112.9,
118.4, 122.1, 123.2, 124.5, 124.6, 128.2, 129.5, 132.5, 132.8, 146.3
ppm; HRMS (ESI): m/z calcd for C13H9BrN2 [M+H]+ 273.0027, found
273.0021. IR (ATR): ν (cm−1): 3106, 2922, 1537, 1472, 1069, 838,
754.
3-(Thiophen-2-yl)imidazo[1,2-a]pyridine (3i):Yellow oil; 1H NMR
(400 MHz, CDCl3): δ 6.84 (t, J = 6.8 Hz, 1H), 7.18–7.21 (m, 2H), 7.27
(d, J = 3.6 Hz, 1H), 7.42 (d, J = 5.2 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H),
7.76 (s, 1H), 8.38 (d, J = 7.6 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 112.9, 118.1, 119.2, 123.8, 124.5, 126.0, 127.9, 129.9,
133.6, 146.3 ppm; HRMS (ESI): m/z calcd for C11H8N2S [M+H]+
201.0486, found 201.0484. IR (ATR): ν (cm−1): 3103, 2924, 1499,
1301, 844, 700.
3-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3c): Yellow solid, m.
1
p. 87–89 °C; H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 6.74 (t,
J = 6.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 7.44
(d, J = 8.4 Hz, 2H), 7.61–7.64 (m, 2H), 8.22 (d, J = 6.8 Hz, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ 55.4, 112.4, 114.7, 118.1, 121.5,
123.3, 124.0, 125.5, 129.6, 131.9, 145.8, 159.6 ppm; HRMS (ESI):
m/z calcd for C14H12N2O [M+H]+ 225.1028, found 225.1026. IR
(ATR): ν (cm−1): 3082, 2929, 2843, 1609, 1571, 1548, 1357, 1242,
751.
3-(Pyridin-2-yl)imidazo[1,2-a]pyridine (3j): White solid, m.p. 68–
70 °C; 1H NMR (400 MHz, CDCl3): δ 6.92 (t, J = 6.8 Hz, 1H), 7.14–
7.16 (m, 1H), 7.27 (t, J = 7.8 Hz, 1H), 7.67–7.72 (m, 3H), 8.14 (s, 1H),
8.65 (d, J = 4.8 Hz, 1H), 9.93 (d, J = 7.2 Hz, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 112.9, 117.6, 120.4, 120.9, 123.6, 125.5, 128.1,
134.6, 136.6, 147.5, 148.7, 150.6 ppm; HRMS (ESI): m/z calcd for
C12H9N3 [M+H]+ 196.0875, found 196.0876. IR (ATR): ν (cm−1):
3047, 2924, 1677, 1591, 1494, 1321, 748.
(E)-3-Styrylimidazo[1,2-a]pyridine (3k): Yellow solid, m.p. 128–
130 °C; 1H NMR (400 MHz, CDCl3): δ 6.88 (t, J = 6.8 Hz, 1H), 7.13
(d, J = 6.8 Hz, 2H), 7.18 (t, J = 7.8 Hz, 1H), 7.26 (t, J = 7.2 Hz, 1H),
7.36 (t, J = 7.2 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 9.2 Hz,
1H), 7.90 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 112.9, 113.1, 118.3, 123.3, 124.0, 124.2, 126.2, 127.8,
128.4, 128.8, 132.1, 137.0, 146.2 ppm; HRMS (ESI): m/z calcd for
C15H12N2 [M+H]+ 221.1079, found 221.1076. IR (ATR): ν (cm−1):
3103, 3034, 2928, 1629, 1493, 1350, 954, 753.
3-(3,4-Dimethoxyphenyl)imidazo[1,2-a]pyridine (3d): Yellow solid,
1
m.p. 68–70 °C; H NMR (400 MHz, CDCl3): δ 3.90–3.95 (m, 6H),
6.76 (t, J = 6.6 Hz, 1H), 6.98–7.00 (m, 2H), 7.08 (d, J = 8.0 Hz, 1H),
7.14 (t, J = 8.0 Hz, 1H), 7.62–7.65 (m, 2H), 8.25 (d, J = 7.2 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 56.04, 56.09, 108.6, 111.9,
112.4, 113.9, 118.2, 120.9, 121.9, 123.3, 123.9, 125.6, 132.1, 145.8,
147.9, 149.3, 149.6 ppm; HRMS (ESI): m/z calcd for C15H14N2O2
[M+H]+ 255.1134, found 255.1135. IR (ATR): ν (cm−1): 3080, 2924,
2851, 1634, 1501, 1252, 1225, 758.
3-(Naphthalen-2-yl)imidazo[1,2-a]pyridine (3e): Colourless oil;
1H NMR (400 MHz, CDCl3): δ 6.81 (t, J = 6.8 Hz, 1H), 7.19 (t, J =
8.0 Hz, 1H), 7.52–7.54 (m, 2H), 7.63 (d, J = 8.4 Hz, 1H), 7.69 (d, J =
9.2Hz, 1H), 7.80 (s, 1H), 7.87–7.89 (m, 2H), 7.95 (d, J = 8.4 Hz, 1H),
8.01 (s, 1H), 8.41 (d, J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 112.7, 118.3, 123.4, 124.4, 125.8, 126.5, 126.7, 126.7,
126.8, 127.9, 128.0, 129.0, 132.9, 133.0, 133.6, 146.3 ppm; HRMS
(ESI): m/z calcd for C17H12N2 [M+H]+ 245.1079, found 245.1077. IR
(ATR): ν (cm−1): 3053, 2921, 1630, 1499, 1356, 753.
3-Octylimidazo[1,2-a]pyridine (3l): Yellow oil; 1H NMR (400
MHz, CDCl3): δ 0.87–0.90 (m, 3H), 1.26–1.47 (m, 10H), 1.73–1.81
(m, 2H), 2.80–2.84 (m, 2H), 6.79 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 7.8
Hz, 1H), 7.41 (s, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.90 (d, J = 6.8 Hz, 2H)
ppm. 13C NMR (100 MHz, CDCl3): δ 14.2, 22.8, 24.0, 27.1, 29.4,
29.5, 29.6, 29.8, 32.0, 112.0, 118.1, 123.0, 123.2, 124.7, 130.8, 145.4
ppm; HRMS (ESI): m/z calcd for C15H22N2 [M+H]+ 231.1861, found
231.1863. IR (ATR): ν (cm−1): 3080, 2926, 2854, 1635, 1502, 1310,
752.
1
3-(4-fluorophenyl)imidazo[1,2-a]pyridine (3f): Colourless oil; H
NMR (400 MHz, CDCl3): δ 6.79 (t, J = 6.8 Hz, 1H), 7.18–7.22 (m,
3H), 7.49–7.52 (m, 2H), 7.65–7.67 (m, 2H), 8.22 (d, J = 6.8 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 112.7, 116.3, 116.5, 118.3,
123.1, 124.3, 124.7, 125.3, 125.4, 130.0, 130.1, 132.4, 146.1, 161.3,
163.8 ppm; HRMS (ESI): m/z calcd for C13H9FN2 [M+H]+ 213.0828,
found 213.0827. IR (ATR): ν (cm−1): 3155, 3049, 1716, 1553, 1449,
1409, 1140.
3-(4-Chlorophenyl)imidazo[1,2-a]pyridine (3g): White solid, m.p.
112–114 °C; 1H NMR (400 MHz, CDCl3): δ 6.80 (t, J = 6.8 Hz, 1H),
7.18 (t, J = 6.8 Hz, 1H), 7.48 (s, 4H), 7.66–7.68 (m, 2H), 8.26 (d,
J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 112.8, 118.4,
123.2, 124.5, 124.6, 127.8, 129.2, 129.6, 132.7, 134.1, 146.3 ppm;
HRMS (ESI): m/z calcd for C13H9ClN2 [M+H]+ 229.0533, found
229.0531. IR (ATR): ν (cm−1): 3092, 3021, 2923, 1537, 1482, 1090,
730.
8-Methyl-3-phenylimidazo[1,2-a]pyridine (3m): White solid, m.p.
110–111 °C; H NMR (400 MHz, CDCl3): δ 2.66 (s, 3H), 6.71 (t,
1
J = 7.2 Hz, 1H), 6.99 (d, J = 6.8 Hz, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.49
(t, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.69 (s, 1H), 8.20 (d,
J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 17.1, 112.6,
121.3, 123.1, 126.2, 128.0, 128.1, 129.2, 129.6, 131.8, 146.5 ppm;
HRMS (ESI): m/z calcd for C14H12N2 [M+H]+ 209.1079, found
209.1076. IR (ATR): ν (cm−1): 2955, 2922, 2852, 1604, 1492, 749.
1
6-Methyl-3-phenylimidazo[1,2-a]pyridine (3n): Colourless oil; H
NMR (400 MHz, CDCl3): δ 2.28 (s, 3H), 7.02 (d, J = 9.2 Hz, 1H), 7.38
(t, J = 7.2 Hz, 1H), 7.48–7.57 (m, 5H), 7.63 (s, 1H), 8.09 (s, 1H) ppm.
13C NMR (100 MHz, CDCl3): δ 117.5, 120.9, 122.2, 125.4, 127.5,
128.1, 129.2, 129.5, 132.3, 145.2 ppm, HRMS (ESI): m/z calcd for
C14H12N2 [M+H]+ 209.1079, found 209.1082. IR (ATR): ν (cm−1):
3071, 2924, 2854, 1603, 1507, 760.
3-(4-Bromophenyl)imidazo[1,2-a]pyridine (3h): White solid, m.p.
3,6-Diphenylimidazo[1,2-a]pyridine (3o): White solid, m.p. 58–
119–120 °C; 1H NMR (400 MHz, CDCl3): δ 6.81 (t, J = 6.8 Hz, 1H),
60 °C; 1H NMR (400 MHz, CDCl3): δ 7.36–7.48 (m, 5H), 7.52–7.61

690 JOURNAL OF CHEMICAL RESEARCH 2012
(m, 6H), 7.72–7.76 (m, 2H), 8.49 (s, 1H) ppm. 13C NMR (100 MHz,
CDCl3): δ 118.1, 120.7, 125.1, 126.2, 127.1, 127.2, 127.9, 128.1,
128.3, 129.1, 129.4, 133.1, 137.6, 145.5 ppm; HRMS (ESI): m/z calcd
for C19H14N2 [M+H]+ 271.1235, found 271.1234. IR (ATR): ν (cm−1):
3056, 2919, 1602, 1483, 1306, 760.
117.8, 125.0, 125.9, 127.2, 128.7, 130.5, 131.1, 131.8, 132.4, 142.0,
144.6 ppm; HRMS (ESI): m/z calcd for C13H9ClN2 [M+H]+ 229.0533,
found 229.0532. IR (ATR): ν (cm−1): 3068, 2927, 1634, 1498, 1300,
1059, 755.
2-(2-Bromophenyl)imidazo[1,2-a]pyridine (4v): Yellow oil; 1H
NMR (400 MHz, CDCl3): δ 6.76 (t, J = 5.2 Hz, 1H), 7.15–7.19 (m,
2H), 7.39 (t, J = 7.4 Hz, 1H), 7.62–7.68 (m, 2H), 8.12–8.16 (m, 2H),
8.28 (s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 112.0, 112.5, 117.6,
121.5, 124.9, 125.8, 127.6, 128.9, 131.7, 133.7, 134.4, 143.2, 144.5
ppm; HRMS (ESI): m/z calcd for C13H9BrN2 [M+H]+ 273.0027, found
273.0022. IR (ATR): ν (cm−1): 3168, 2922, 1676, 1585, 1310, 1028,
755.
1
8-Benzyloxy-3-phenylimidazo[1,2-a]pyridine (3p): Yellow oil; H
NMR (400 MHz, CDCl3): δ 5.35 (s, 2H), 6.49 (d, J = 7.6 Hz, 1H), 6.62
(t, J = 6.8 Hz, 1H), 7.30–7.42 (m, 4H), 7.48–7.56 (m, 6H), 7.66 (s,
1H), 7.94 (d, J = 7.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3):
δ 70.7, 102.6, 112.4, 116.6, 126.8, 127.4, 128.1, 128.2, 128.2, 128.6,
129.2, 129.4, 131.6, 136.2, 140.7, 148.3 ppm; HRMS (ESI): m/z calcd
for C20H16N2O [M+H]+ 301.1341, found 301.1342. IR (ATR): ν (cm−1):
3058, 2924, 2854, 1604, 1545, 1272, 698.
2-(4-Nitrophenyl)imidazo[1,2-a]pyridine (4q): Red solid, m.p.
202–204 °C; 1H NMR (400 MHz, CDCl3): δ 6.81 (t, J = 6.8 Hz, 1H),
7.18 (t, J = 7.8 Hz, 1H), 7.48 (m, 4H), 7.66–7.68 (m, 2H), 8.25 (d,
J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 110.1, 113.3,
118.1, 124.4, 125.8, 126.0, 126.6, 140.4, 143.5, 146.2, 147.4 ppm;
HRMS (ESI): m/z calcd for C13H9N3O2 [M+H]+ 240.0773, found
240.0776. IR (ATR): ν (cm−1): 3133, 2924, 1595, 1507, 1341, 748.
3-(4-Nitrophenyl)imidazo[1,2-a]pyridine (3q): Grey solid, m.p.
This work was supported by grants from the National NSF of
China (Nos 21172155 and 20901052), the Sichuan Provincial
Foundation (2012JQ0002) and the Basic Research Program
of National Defense of China (B1520110007). We thank the
Centre of Testing and Analysis, Sichuan University for NMR
measurements. G. L. and X.C. contributed equally to this work.
1
> 250 °C; H NMR (400 MHz, CDCl3): δ 6.93 (t, J = 6.8 Hz, 1H),
Received 24 July 2012; accepted 26 September 2012
Paper 1201429 doi: 10.3184/174751912X13499663832261
Published online: 5 December 2012
7.28–7.33 (m, 1H), 7.69–7.78 (m, 2H), 7.86 (s, 1H), 8.37–8.44 (m,
3H) ppm. 13C NMR (100 MHz, CDCl3): δ 113.6, 118.7, 123.2, 123.7,
124.7, 125.5, 127.5, 134.7, 135.9, 146.8, 147.3 ppm; HRMS (ESI):
m/z calcd for C13H9N3O2 [M+H]+ 240.0773, found 240.0772. IR
(ATR): ν (cm−1): 3137, 3081, 2925, 1598, 1510, 1336, 754.
References
2-(3-Nitrophenyl)imidazo[1,2-a]pyridine (4r): Grey solid, m.p.
187–189 °C; 1H NMR (400 MHz, CDCl3): δ 6.91 (t, J = 6.4 Hz, 1H),
7.28 (t, J = 7.2 Hz, 1H), 7.70–7.74 (m, 2H), 7.82 (s, 1H), 7.91 (d,
J = 7.6 Hz, 1H), 8.25 (d, J = 8.0 Hz, 2H), 8.32 (d, J = 7.6 Hz, 1H), 8.45
(s, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 109.1, 113.0, 117.8,
120.8, 122.5, 125.5, 125.8, 129.7, 131.8, 135.7, 143.5 ppm; HRMS
(ESI): m/z calcd for C13H9N3O2 [M+H]+ 240.0773, found 240.0770. IR
(ATR): ν (cm−1): 3136, 2923, 1634, 1521, 1342, 719.
3-(3-Nitrophenyl)imidazo[1,2-a]pyridine (3r): Yellow solid, m.p.
122–123 °C; 1H NMR (400 MHz, CDCl3): δ 6.83 (t, J = 6.8 Hz, 1H),
7.22 (t, J = 8.4 Hz, 2H), 7.70–7.74 (m, 2H), 7.99 (s, 1H), 8.16 (d,
J = 6.8 Hz, 2H), 8.32 (d, J = 7.6 Hz, 1H), 8.76 (s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 113.4, 118.6, 122.1, 122.7, 122.9, 123.4, 125.2,
130.4, 131.1, 133.5, 133.8, 146.8, 148.9 ppm; HRMS (ESI): m/z calcd
for C13H9N3O2 [M+H]+ 240.0773, found 240.0776. IR (ATR): ν (cm−1):
3095, 2923, 1635, 1545, 1348, 735.
2-(2-Nitrophenyl)imidazo[1,2-a]pyridine (4s): Grey solid, m.p.
138–139 °C; 1H NMR (400 MHz, CDCl3): δ 6.79 (t, J = 6.8 Hz, 1H),
7.18 (t, J = 7.8 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.60–7.64 (m, 2H),
7.70 (d, J = 7.6 Hz, 1H), 7.80 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 8.10
(d, J = 6.8 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 110.6, 112.8,
117.9, 123.5, 125.2, 125.8, 127.7, 128.5, 131.4, 131.8, 140.2, 145.3,
149.3 ppm; HRMS (ESI): m/z calcd for C13H9N3O2 [M+H]+ 240.0773,
found 240.0772. IR (ATR): ν (cm−1): 3149, 2921, 1525, 1362, 1279,
785, 753.
2-(4-Cyanophenyl)imidazo[1,2-a]pyridine (4t): Yellow solid, m.p.
198–200 °C; 1H NMR (400 MHz, CDCl3): δ 6.81 (t, J = 6.8 Hz, 1H),
7.20 (t, J = 8.8 Hz, 1H), 7.62 (d, J =9.2 Hz, 1H), 7.69 (d, J =8.0 Hz,
2H), 7.94 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 8.13 (d, J = 6.8 Hz, 1H)
ppm. 13C NMR (100 MHz, CDCl3): δ 111.3, 113.4, 118.5, 118.6,
123.2, 124.0, 125.3, 127.7, 133.1, 134.0, 134.1, 147.1 ppm; HRMS
(ESI): m/z calcd for C14H9N3 [M+H]+ 220.0875, found 220.0871. IR
(ATR): ν (cm−1): 3136, 3040, 2222, 1635, 1608, 1373, 757.
1
F. Couty, G. Evano in Comprehensive heterocyclic chemistry III, Vol. 11,
eds A.R. Katritzky, C.A. Ramsden, E.F.V. Scriven, R.J.K. Taylor, Elsevier,
Oxford, 2008, pp. 409–499.
K.S. Gudmundsson, J.D. Williams, J.C. Drach and L.B. Townsend, J. Med.
Chem., 2003, 46, 1449.
S.C. Goodacre, L.J. Street, D.J. Hallett, J.M. Crawforth, S. Kelly,
A.P. Owens, W.P. Blackaby, R.T. Lewis, J. Stanley, A.J. Smith, P. Ferris,
B. Sohal, S.M. Cook, A. Pike, N. Brown, K.A. Wafford, G. Marshall,
J.L. Castro and J.R. Atack, J. Med. Chem., 2006, 49, 35.
N. Hsua, S.K. Jha, T. Coleman and M.G. Frank, Behav. Brain Res., 2009,
201, 233.
T. Okubo, R. Yoshikawa, S. Chaki, S. Okuyamac and A. Nakazato, Bioorg.
Med. Chem., 2004, 12, 423.
S.Z. Langer, S. Arbilla, J. Benavides and B. Scatton, Adv. Biochem.
Psychopharmacol., 1990, 46, 61.
H. Wang, Y. Wang, D. Liang, L. Liu, J. Zhang and Q. Zhu, Angew. Chem.
Int. Ed., 2011, 50, 5678.
T. Han, Z. Shi, Y. Peng and Z. Zhao, J. Chem. Res., 2011, 35, 243.
Z. Wu, Y. Pan and X. Zhou, Synthesis, 2011, 2255.
2
3
4
5
6
7
8
9
10 N. Chernyak and V. Gevorgyan, Angew. Chem. Int. Ed., 2010, 49, 2743.
11 E. Kianmehr, M. Ghanbari, M.N. Niri and R. Faramarzi, J. Comb. Chem.,
2010, 12, 41.
12 S.K. Guchhait and C. Madaan, Org. Biomol. Chem., 2010, 8, 3631.
13 J. Koubachi, S.E. Kazzouli, S. Berteina-Raboin, A. Mouaddib and
G. Guillaumet, J. Org. Chem., 2007, 72, 7650.
14 A.L. Rousseau, P. Matlaba and C.J. Parkinson, Tetrahedron Lett., 2007, 48,
4079.
15 S. Carballares, M.M. Cifuentes and G.A. Stephenson, Tetrahedron Lett.,
2007, 48, 2041.
16 A.R. Katritzky, Y.-J. Xu and H. Tu, J. Org. Chem., 2003, 68, 4935.
17 M.P. Groziak, S.R. Wilson, G.L. Clauson and N.J. Leonard, J. Am. Chem.
Soc., 1986, 108, 8002.
18 H.-J. Knölker, R. Boese and R. Hitzemann, Chem. Ber., 1990, 123, 327.
19 H. Galons, I. Bergerat, C. Combet Farnoux and M. Miocque, Synthesis,
1982, 1103.
20 K.S. Gudmundsson, J.C. Drach, L.B. Townsend, Tetrahedron Lett., 1996,
37, 6275.
3-(4-Cyanophenyl)imidazo[1,2-a]pyridine (3t): Yellow solid, m.p.
159–160 °C; 1H NMR (400 MHz, CDCl3): δ 6.90 (t, J = 6.8 Hz, 1H),
7.27 (t, J = 8.0 Hz, 1H), 7.70 (t, J = 6.0 Hz, 3H), 7.80–7.82 (m, 3H),
8.38 (d, J = 7.2 Hz, 1H) ppm. 13C NMR (100 MHz, CDCl3): δ 109.5,
111.1, 113.1, 117.8, 119.0, 120.2, 125.5, 125.8, 126.4, 130.2, 132.6,
138.3, 138.6, 143.7, 146.0 ppm; HRMS (ESI): m/z calcd for C14H9N3
[M+H]+ 220.0875, found 220.0873. IR (ATR): ν (cm−1): 3202, 3026,
2222, 1635, 1606, 1299, 732.
21 P.A. Bonnet, A.Michel, F. Laurent, C. Sablayrolles, E. Rechencq,
J.C. Mani, M. Boucard and J.P. Chapat, J. Med. Chem., 1992, 35, 3353.
22 M. Yamanaka, K. Miyake, S. Suda, H. Ohhara and T. Ogawa, Chem.
Pharm. Bull., 1991, 39, 1556.
23 D.S. Ermolat’ev, V.N. Giménez, E.V. Babaev and E. Van der Eycken,
J. Comb. Chem., 2006, 8, 659.
24 X. Qin, X. Cong, D. Zhao, J. You and J. Lan, Chem. Commun., 2011, 47,
5611.
25 M.L.N. Rao, D.N. Jadhav and P. Dasgupta, Org. Lett., 2010, 12, 2048.
26 A. Coste, F. Couty and G. Evano, Org. Lett., 2009, 11, 4454.
27 G. Chelucci, F. Capitta and S. Baldino, Tetrahedron, 2008, 64, 10250.
28 B.B. Touré, B.S. Lane, D. Sames, Org. Lett., 2006, 8, 1979.
29 M. Aginagalde, Y. Vara, A. Arrieta, R. Zangi, V.L. Cebolla, A.D. Camón,
F.P. Cossío, J. Org. Chem., 2010, 75, 2776.
2-(2-Chlorophenyl)imidazo[1,2-a]pyridine (4u): Yellow oil; 1H
NMR (400 MHz, CDCl3): δ 6.77 (t, J = 6.8 Hz, 1H), 7.16 (d, J = 8.2
Hz, 1H), 7.24 (t, J = 8.2 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.45 (d,
J = 8.0 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 8.13 (d, J = 6.8 Hz, 1H),
8.28–8.31 (m, 2H) ppm. 13C NMR (100 MHz, CDCl3): δ 112.6, 112.6,

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and its content may
not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written
permission. However, users may print, download, or email articles for individual use.