Copper-Catalyzed Aerobic Oxidative Cyclization of Ketoxime Acetates with Pyridines for the Synthesis of Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1055/s-0035-1561950

A copper(I)-catalyzed aerobic oxidative coupling of ketoxime acetates with simple pyridines for the synthesis of imidazo[1,2-a]pyridines has been developed. This reaction tolerates a wide range of functional groups and it affords a series of valuable imidazo[1,2-a]pyridines in high yields under mild conditions.

Full text of DOI:10.1055/s-0035-1561950

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
A
special topic
Z.-H. Ren et al.
Special Topic
Synthesis
Copper-Catalyzed Aerobic Oxidative Cyclization of Ketoxime Ace-
tates with Pyridines for the Synthesis of Imidazo[1,2-a]pyridines
Zhi-Hui Ren*
Mi-Na Zhao
N
OAc
H
N
CuI (10 mol %)
Yukun Yi
+
H
H
N
R1
N
NMP, air, 100 °C
R1
Yao-Yu Wang
Zheng-Hui Guan*
R2
R3
R3
R2
R1 = alkyl, OMe, 1,3-dioxole, F, Cl, Br, styryl
30 examples
66–95% yield
R
R
2 = H, alkyl
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710127,
P. R. of China
3 = alkyl, OMe, F, Cl, Br
guanzhh@nwu.edu.cn
Received: 24.01.2016
Accepted after revision: 23.02.2016
Published online: 29.03.2016
H
N
OAc
N
N
CuI, air
H
H
N
DOI: 10.1055/s-0035-1561950; Art ID: ss-2016-c0058-st
Abstract A copper(I)-catalyzed aerobic oxidative coupling of ketoxime
acetates with simple pyridines for the synthesis of imidazo[1,2-a]pyri-
dines has been developed. This reaction tolerates a wide range of func-
tional groups and it affords a series of valuable imidazo[1,2-a]pyridines
in high yields under mild conditions.
Scheme 1 Copper-catalyzed aerobic oxidative coupling of acetophe-
none oxime acetate with pyridine
Imidazo[1,2-a]pyridines are among the most important
fused heterocycles, and they are present in many pharma-
ceuticals and biologically active compounds, such as zolp-
idem, alpidem, and zolimidine.10 Conventional methods for
the synthesis of imidazo[1,2-a]pyridines are generally
based on condensations of 2-aminopyridines with α-halo
ketones.11 These methods usually have limited substrate
scopes and they lack atom economy. Recently, copper-cata-
lyzed dehydrogenative cyclizations of 2-aminopyridines
with simple ketones or of pyridine with ketoxime acetates
have been developed for the synthesis of imidazo[1,2-
a]pyridines.12 However, these methods generally give low
yields, especially with substituted pyridines or propiophe-
none oxime acetate as substrates. Consequently, simple and
practical methods for the synthesis of imidazo[1,2-a]pyri-
dines remain highly desirable.
We commenced our investigation with the CuI-cata-
lyzed coupling of acetophenone oxime acetate [1a; N-(1-
phenylethylidene)acetamide] with pyridine (2a) in MeCN at
120 °C. 2-Phenylimidazo[1,2-a]pyridine (3aa) was obtained
in 21% yield (Table 1, entry 1). Screening of various copper
catalysts [CuI, CuBr, CuCl, Cu(OAc)2, CuBr2, and CuCl2]
showed that CuI is the most effective catalyst and that
Cu(II) salts are inactive as catalysts (entries 2–6). Subse-
quently, we screened a series of solvents in an attempt to
improve the reaction efficiency, and we found that DMF,
N,N-dimethylacetamide (DMA), and NMP are better sol-
vents than DCE, toluene, or DMSO for this reaction (entries
7–13). The highest yield was obtained in NMP (entry 13).
Key words copper, catalysis, pyridines, ketoxime esters, coupling, im-
idazopyridines
Ketoximes and their derivatives are a class of valuable
chemicals1 that are readily accessible through condensation
of ketones with hydroxylammonium salts in nearly quanti-
tative yields under mild conditions. However, in conven-
tional synthetic chemistry, chemical transformations of ke-
toximes are mainly limited to Beckmann rearrangements to
give amides.2 In modern organic chemistry, transition-met-
al-catalyzed cross-coupling has achieved great successes, as
recognized by the award of the Nobel Prize in Chemistry in
2010.3 In this context, coupling reactions initiated by Pd(0)-
catalyzed oxidative addition of ketoxime carboxylates have
been developed by the groups of Abell,4 Zhu,5 Hartwig,6 and
Bower.7 Cu(I)-catalyzed reductive cleavages of ketoxime
carboxylates for the synthesis of various valuable com-
pounds, such as enamides or azaheterocycles, have also
been developed by us and by other groups.8,9
An active iminium radical and an α-carbon radical are
often generated in the Cu(I)-catalyzed reductive cleavage of
ketoxime carboxylates.8,9 We therefore hypothesized that a
radical-scavenger reagent might trap the iminium radical or
α-carbon radical to afford valuable organic compounds.
Here, we report a simple and efficient copper-catalyzed
aerobic oxidative coupling of ketoxime acetates with pyri-
dines to give imidazo[1,2-a]pyridines (Scheme 1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Z.-H. Ren et al.
Special Topic
Synthesis
When the reaction temperature was changed to 100 °C, the
yield of 3aa increased to 95% (entry 14), whereas a 62%
yield was obtained at 80 °C (entry 15).
Having established the optimal conditions for the reac-
tion, we next examined its scope (Scheme 2). The copper-
catalyzed aerobic oxidative coupling reaction displayed a
broad functional-group tolerance and proved to be a quite
general method. Aryl methyl ketoxime acetates substituted
on the aromatic ring with methyl, alkyl, methoxy, 1,3-diox-
ole, fluoro, or chloro groups, or with sensitive functional
groups, such as bromo or iodo, all gave the corresponding
substituted imidazo[1,2-a]pyridines 3aa–na in 81–95%
yield. Both electron-rich and electron-deficient ketoxime
acetates reacted smoothly to give the desired products in
high to excellent yields, implying that electronic effects of
the substrates have little effect on the oxidative coupling re-
action. In addition, 1-(2-naphthyl)ethanone oxime acetate
(1o) and benzalacetone oxime acetate (1p) showed similar
reactivities to aryl methyl ketoxime acetates, giving the cor-
responding 2-naphthyl- or 2-phenylethenyl-substituted
imidazo[1,2-a]pyridines 3oa and 3pa in 78% and 72% yield,
respectively.
3-Substituted imidazo[1,2-a]pyridines, which are ob-
tained in low yields by other methods,12 were easily synthe-
sized in high yields by our reaction. Aryl alkyl ketoxime ace-
tates, such as the aryl ethyl and aryl butyl ketoxime acetates
1q–u, were well tolerated in the reaction system, and gave
the corresponding 3-methyl- or 3-propyl-substituted imid-
azo[1,2-a]pyridines 3qa–ua in 71–78% yield. Additionally,
the antiulcer drug zolimidine (3va) was synthesized in 81%
yield on a 10 mmol scale under the standard conditions,
demonstrating the synthetic utility of our method.
Table 1 Optimization of the Reaction Conditionsa
OAc
N
N
[Cu]
N
solvent
N
3aa
1a
2a
Entry
Catalyst
Solvent
Temp (°C)
Yieldb (%)
1
CuI
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DCE
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
21
18
13
–
2
CuBr
CuCl
Cu(OAc)2
CuBr2
CuCl2
CuI
3
4
5
–
6
–
7
15
22
5
8
CuI
toluene
1,4-dioxane
DMF
9
CuI
10
11
12
13
14
15
CuI
67
17
48
71
95
62
CuI
DMSO
DMA
CuI
CuI
NMP
CuI
NMP
CuI
NMP
Next, we synthesized the substituted pyridines 2b–h,
which have been reported to give only low yields of the cor-
responding products,12 and we used them to explore the
scope of the reaction (Scheme 3). 4-Methyl-, 4-methoxy-,
a Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), catalyst (10 mol%),
solvent (1 mL), air
b Isolated yield.
N
N
N
N
N
N
N
N
N
N
N
N
3aa, 95%
3ba, 86%
3ca, 87%
OMe
3da, 83%
3ea, 81%
3fa, 82%
OMe
O
N
N
N
N
N
N
O
OMe
OMe
F
N
N
N
N
3ga, 95%
3ha, 89%
3ia, 81%
3ja, 84%
3ka, 88%
N
N
N
N
N
N
N
Cl
Br
I
N
N
N
N
N
3la, 84%
3ma, 86%
3na, 85%
3oa, 78%
3pa, 72%
3qa, 78%
N
N
N
N
N
N
O
N
N
t-Bu
N
N
S
O
C3H7
3ua, 71%
3ra, 73%
3sa, 75%
3ta, 73%
3va, 88% Zolimidine
Scheme 2 Synthesis of imidazo[1,2-a]pyridines by coupling of ketoxime acetates 1 with pyridine (2a). Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol,
1.2 equiv), CuI (10 mol%), NMP (1.5 mL), 100 °C, air. The isolated yields are reported.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Z.-H. Ren et al.
Special Topic
Synthesis
and 3,5-dimethylpyridine gave the corresponding imid-
azo[1,2-a]pyridines 3ab–ad in 81–83% yield. When 3-
methylpyridine was used as the substrate, two regioiso-
mers 3ae and 3ae′ were isolated in a 2:1 ratio and a total
yield of 85%. Surprisingly, the reaction mainly occurred at
the more sterically hindered 2-position of 3-methylpyri-
dine to give 8-methyl-2-phenylimidazo[1,2-a]pyridine
(3ae) as the main product. We obtained similar results
when we used 3-fluoro-, 3-chloro-, or 3-bromo-substituted
pyridines as the substrates. In these cases, the correspond-
ing 8-haloimidazo[1,2-a]pyridines 3af–ah were isolated in
68–72% yield. Moreover, isoquinoline was also tolerated in
the reaction, giving 2-phenylimidazo[2,1-a]isoquinoline
(3ai) in 66% yield.
D
D
D
D
D
CuI (10 mol%)
NMP, air, 100 °C
1a +
+
N
N
2a-d5
2a
0.5 mmol
1.0 equiv
1.0 equiv
D
D
N
N
+
D
N
N
D
3aa/3aa-d4 = 1:1
KIE = 1
Equation 1 Kinetic isotope experiment
OAc
MeO
N
N
N
N
NH
N
Ph
Ph
Ph
N
N
N
Ph
Ph
Ph
1
A
B
3ab, 81%
3ad, 81%
3ac, 83%
CuI
CuII
N
F
2
N
N
N
N
N
H
N
Ph
Ph
Ph
[Cu]/O2
NH
N
N
N
N
O2
N
3ae'
Ph
3ae
3af, 68%
85% (2:1)
Ph
Ph
C
3
D
Scheme 4 Tentative mechanism for the CuI-catalyzed oxidative cou-
pling of a ketoxime acetate with pyridine for the synthesis of an imid-
azo[1,2-a]pyridine
Br
Cl
N
N
N
Ph
Ph
Ph
N
N
N
imidazo[1,2-a]pyridines. This copper-catalyzed, aerobic ox-
idative, coupling reaction tolerates a wide range of func-
tional groups and is a reliable method for the rapid synthe-
sis of a variety of valuable substituted imidazo[1,2-a]pyri-
dines in high yields under simple and mild conditions.
3ag, 70%
3ah, 72%
3ai, 66%
Scheme 3 Synthesis of imidazo[1,2-a]pyridines from ketoxime ester
1a and pyridines 2. Reaction conditions: 1a (0.5 mmol), 2 (1.2 equiv),
CuI (10 mol%), NMP (1.5 mL), 100 °C. Isolated yields are reported.
To gain insight into the mechanism of the reaction, we
studied the intermolecular kinetic isotope effect (KIE) of
the reaction (Equation 1). This experiment showed that
cleavage of the C–H bond of the pyridine might not be the
rate-determining step (KIE = 1).
Although the exact mechanism of the reaction remains
unclear, a tentative mechanism for this copper-catalyzed,
aerobic oxidative, coupling reaction is proposed in Scheme
4. First, reduction of ketoxime ester 1 by CuI gives the imin-
ium radical A, which rapidly isomerizes to the α-carbon
radical B.8,9 Subsequently, radical coupling of intermediate
B with pyridine (2) generates the intermediate C.8,9 Intra-
molecular cyclization of intermediate C and subsequent ox-
idation of intermediate D in the presence of Cu/O2 gives the
final product, the imidazo[1,2-a]pyridine 3.12
1
Column chromatography was carried out on silica gel. H NMR spec-
tra were recorded on a Bruker NMR at 400 MHz in CDCl3, and 13C NMR
spectra were recorded on Bruker NMR at 100 MHz in CDCl3. High-res-
olution mass spectra were recorded on a Bruker spectrometer in the
ESI mode. Unless otherwise stated, all reagents and solvents were
purchased from commercial suppliers and were used without further
purification. In all cases, the ketoximes were prepared from the corre-
sponding ketones by the reported methods.8
Imidazo[1,2-a]pyridines 3; General Procedure
The appropriate ketoxime acetate 1 (0.5 mmol), CuI (10 mol%, 9.5
mg), and pyridine derivative 2 (0.6 mmol) were added successively to
NMP (1.5 mL) in a 25 mL round-bottomed flask, and the mixture was
stirred at 100 °C under dry air for 4–6 h. When the reaction was com-
plete (TLC), the mixture was cooled to r.t., and the reaction was
quenched with 30% aq NH3 (5 mL). The mixture was extracted with
EtOAc (10 mL), and the extracts were washed with H2O (10 mL) and
brine (10 mL). The organic layer was removed under reduced pressure
to give a crude product that was further purified by chromatography
(silica gel, PE–EtOAc).
In summary, we have developed a simple and efficient
copper-catalyzed aerobic oxidative coupling of ketoxime
acetates with simple pyridines to give the corresponding
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Z.-H. Ren et al.
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Synthesis
2-Phenylimidazo[1,2-a]pyridine (3aa)
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 6.4 Hz, 1 H), 7.75 (s, 1 H),
7.68–7.65 (m, 2 H), 7.18–7.15 (m, 2 H), 7.07 (d, J = 7.2 Hz, 1 H), 6.78–
6.75 (m, 1 H), 2.49 (s, 3 H), 2.37 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.1, 144.6, 135.4, 132.8, 132.4,
130.7, 130.1, 128.5, 125.4, 124.5, 117.3, 112.2, 107.7, 21.1, 20.9.
Yellow solid; yield: 92.2 mg (95%).
1H NMR (400 MHz, CDCl3): δ = 8.07 (d, J = 6.4 Hz, 1 H), 7.96 (d, J = 7.6
Hz, 2 H), 7.82 (s, 1 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.45–7.41 (m, 2 H),
7.34–7.31 (m, 1 H), 7.16–7.12 (m, 1 H), 6.75–6.72 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 145.6, 133.7, 128.6, 127.9,
125.9, 125.5, 124.6, 117.4, 112.3, 108.1.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2: 223.1230; found:
223.1236.
HRMS (ESI): m/z [M + H]+ calcd for C13H11N2: 195.0917; found:
195.0922.
2-(4-Methoxyphenyl)imidazo[1,2-a]pyridine (3ga)
Yellow solid; yield: 106.4 mg (95%).
2-(4-Tolyl)imidazo[1,2-a]pyridine (3ba)
1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 6.8 Hz, 1 H), 7.86 (d, J = 8.4
Hz, 2 H), 7.74 (s, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.14–7.10 (m, 1 H), 6.95
(d, J = 8.0 Hz, 2 H), 6.74–6.71 (m, 1 H), 3.83 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 159.4, 145.5, 133.6, 127.2, 126.3,
125.4, 124.3, 117.1, 114.0, 112.1, 107.1, 55.2.
Yellow solid; yield: 89.4 mg (86%).
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 6.8 Hz, 1 H), 7.83 (d, J = 8.0
Hz, 2 H), 7.74 (s, 1 H), 7.59 (d, J = 8.8 Hz, 1 H), 7.22 (d, J = 7.6 Hz, 2 H),
7.12–7.08 (m, 1 H), 6.70–6.66 (m, 1 H), 2.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 145.4, 137.6, 130.8, 129.3,
125.8, 125.4, 124.4, 117.2, 112.1, 107.7, 21.2.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O: 225.1022; found:
225.1021.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2: 209.1073; found:
209.1083.
2-(3-Methoxyphenyl)imidazo[1,2-a]pyridine (3ha)
Yellow solid; yield: 34 mg (89%).
2-(3,4-Dimethylphenyl)imidazo[1,2-a]pyridine (3ca)
1H NMR (400 MHz, CDCl3): δ = 8.11 (d, J = 6.4 Hz, 1 H), 7.85 (s, 1 H),
7.66 (d, J = 8.8 Hz, 1 H), 7.55 (s, 1 H), 7.50 (d, J = 7.2 Hz, 1 H), 7.35–7.31
(m, 1 H), 7.19–7.15 (m, 1 H), 6.89 (d, J = 8.0 Hz, 1 H), 6.80–6.77 (m, 1
H), 3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 160.0, 145.6, 145.5, 135.1, 129.6,
125.5, 124.6, 118.4, 117.5, 114.1, 112.4, 110.9, 108.3, 55.3.
Yellow solid; yield: 96.6 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 6.4 Hz, 1 H), 7.75 (s, 2 H),
7.63–7.59 (m, 2 H), 7.16 (d, J = 7.6 Hz, 1 H), 7.12–7.08 (m, 1 H), 6.70–
6.67 (m, 1 H), 2.31 (s, 3 H), 2.27 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 145.8, 145.4, 136.8, 136.4, 131.1,
129.8, 127.1, 125.4, 124.3, 123.3, 117.2, 112.1, 107.6, 19.7, 19.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O: 225.1022; found:
225.1031.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2: 223.1230; found:
223.1232.
2-(3,4-Dimethoxyphenyl)imidazo[1,2-a]pyridine (3ia)
Yellow solid; yield: 102.9 mg (81%).
2-(5,6,7,8-Tetrahydronaphthalen-2-yl)imidazo[1,2-a]pyridine
(3da)
1H NMR (400 MHz, DMSO-d6): δ = 8.48 (d, J = 6.0 Hz, 1 H), 8.32 (s, 1
H), 7.57 (s, 2 H), 7.49 (d, J = 8.4 Hz, 1 H), 7.23–7.19 (m, 1 H), 7.01 (d,
J = 8.0 Hz, 1 H), 6.88–6.85 (m, 1 H), 3.85 (s, 3 H), 3.78 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 148.9, 148.6, 144.6, 144.5, 126.7,
126.7, 124.7, 118.0, 116.4, 112.1, 112.0, 109.1, 108.3, 55.5, 55.4.
Yellow solid; yield: 102.9 mg (83%).
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 6.4 Hz, 1 H), 7.68 (s, 1 H),
7.65 (s, 1 H), 7.63–7.59 (m, 2 H), 7.14–7.09 (m, 2 H), 6.72–6.69 (m, 1
H), 2.82 (s, 2 H), 2.78 (s, 2 H), 1.80 (s, 4 H).
13C NMR (100 MHz, CDCl3): δ = 145.7, 145.4, 137.4, 137.1, 130.5,
129.4, 126.6, 125.4, 124.5, 123.1, 117.1, 112.2, 107.7, 29.3, 29.2, 23.1
(2 C).
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2O2: 255.1128; found:
255.1135.
2-(1,3-Benzodioxol-5-yl)imidazo[1,2-a]pyridine (3ja)
HRMS (ESI): m/z [M + H]+ calcd for C17H17N2: 249.1386; found:
Yellow solid; yield: 100.0 mg (84%).
249.1399.
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 6.0 Hz, 1 H), 7.68 (s, 1 H),
7.56 (d, J = 8.8 Hz, 1 H), 7.44–7.41 (m, 2 H), 7.12–7.08 (m, 1 H), 6.85
(d, J = 7.6 Hz, 1 H), 6.71–6.68 (m, 1 H), 5.96 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 147.9, 147.4, 145.5, 145.4, 128.0,
125.4, 124.4, 119.6, 117.2, 112.2, 108.5, 107.3, 106.5, 101.0.
2-(2,4-Dimethylphenyl)imidazo[1,2-a]pyridine (3ea)
Yellow solid; yield: 89.9 mg (81%).
1H NMR (400 MHz, DMSO-d6): δ = 8.51 (d, J = 6.0 Hz, 1 H), 8.13 (s, 1
H), 7.80 (d, J = 7.2 Hz, 1 H), 7.55 (d, J = 8.8 Hz, 1 H), 7.25–7.21 (m, 1 H),
7.08 (d, J = 7.6 Hz, 2 H), 6.87–6.84 (m, 1 H), 2.48 (s, 3 H), 2.27 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C14H11N2O2: 239.0815; found:
13C NMR (100 MHz, DMSO-d6): δ = 144.9, 144.0, 136.5, 134.9, 131.5,
239.0823.
130.4, 128.9, 126.7, 126.5, 126.0, 124.7, 116.5, 111.9, 21.5, 20.7.
2-(4-Fluorophenyl)imidazo[1,2-a]pyridine (3ka)
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2: 223.1230; found:
Yellow solid; yield: 93.3 mg (88%).
223.1240.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 6.4 Hz, 1 H), 7.90–7.87 (m, 2
H), 7.74 (s, 1 H), 7.58 (d, J = 9.2 Hz, 1 H), 7.15–7.07 (m, 3 H), 6.74–6.71
(m, 1 H).
2-(2,5-Dimethylphenyl)imidazo[1,2-a]pyridine (3fa)
Yellow solid; yield: 91.0 mg (82%).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

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Synthesis
13C NMR (100 MHz, CDCl3): δ = 162.6 (d, JCF = 245.5 Hz), 145.6, 144.8,
129.9, 127.6 (d, JCF = 8.0 Hz), 125.5, 124.7, 117.3, 115.5 (d, JCF = 21.5
Hz), 112.4, 107.7.
HRMS (ESI): m/z [M + H]+ calcd for C13H10FN2: 213.0823; found:
213.0825.
3-Methyl-2-phenylimidazo[1,2-a]pyridine (3qa)
Yellow solid; yield: 81.1 mg (78%).
1H NMR (400 MHz, CDCl3): δ = 7.89 (d, J = 6.4 Hz, 1 H), 7.79 (d, J = 7.6
Hz, 2 H), 7.64 (d, J = 8.8 Hz, 1 H), 7.48–7.45 (m, 2 H), 7.36–7.33 (m, 1
H), 7.19–7.15 (m, 1 H), 6.85–6.82 (m, 1 H), 2.63 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.2, 142.3, 134.7, 128.4 (2 C), 128.2,
127.2, 123.4, 122.7, 117.3, 111.9, 9.5.
2-(4-Chlorophenyl)imidazo[1,2-a]pyridine (3la)
Yellow solid; yield: 95.8 mg (84%).
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2: 209.1073; found:
209.1082.
1H NMR (400 MHz, DMSO-d6): δ = 8.51 (d, J = 5.6 Hz, 1 H), 8.41 (s, 1
H), 7.98 (d, J = 7.2 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.48 (d, J = 7.2 Hz,
2 H), 7.25–7.23 (m, 1 H), 6.90–6.87 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 144.9, 143.2, 132.8, 132.1, 128.7,
127.2, 126.9, 125.2, 116.7, 112.4, 109.5.
3-Methyl-2-(4-tolyl)imidazo[1,2-a]pyridine (3ra)
Yellow solid; yield: 81.0 mg (73%).
1H NMR (400 MHz, DMSO-d6): δ = 8.30 (d, J = 6.4 Hz, 1 H), 7.69 (d,
J = 7.6 Hz, 2 H), 7.56 (d, J = 8.8 Hz, 1 H), 7.29–7.21 (m, 3 H), 6.95–6.92
(m, 1 H), 2.62 (s, 3 H), 2.35 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10ClN2: 229.0527; found:
229.0529.
13C NMR (100 MHz, DMSO-d6): δ = 143.4, 141.1, 136.3, 132.1, 129.1 (2
C), 127.7, 124.3, 123.7, 116.4, 111.8, 20.8, 9.4.
2-(4-Bromophenyl)imidazo[1,2-a]pyridine (3ma)
Yellow solid; yield: 117.0 mg (86%).
+
HRMS (ESI): m/z [M + H]+ calcd for C15H14N2Na: [M+Na] 245.1049;
found: 245.1061.
1H NMR (400 MHz, DMSO-d6): δ = 8.52 (d, J = 6.4 Hz, 1 H), 8.43 (s, 1
H), 7.92 (d, J = 8.0 Hz, 2 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.8 Hz,
1 H), 7.27–7.23 (m, 1 H), 6.92–6.88 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 144.9, 143.2, 133.2, 131.6, 127.5,
127.0, 125.2, 120.7, 116.7, 112.5, 109.5.
2-(4-tert-Butylphenyl)-3-methylimidazo[1,2-a]pyridine (3sa)
Yellow solid; yield: 99.0 mg (75%).
1H NMR (400 MHz, DMSO-d6): δ = 8.31 (d, J = 6.4 Hz, 1 H), 7.74 (d,
J = 7.6 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 7.25–
7.21 (m, 1 H), 6.95–6.92 (m, 1 H), 2.63 (s, 3 H), 1.32 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrN2: 273.0022; found:
273.0031.
13C NMR (100 MHz, DMSO-d6): δ = 149.5, 132.1, 127.5 (2 C), 125.2 (2
C), 124.3, 123.6, 116.5, 111.8, 34.3, 31.1, 9.4.
2-(4-Iodophenyl)imidazo[1,2-a]pyridine (3na)
Yellow solid; yield: 136.0 mg (85%).
HRMS (ESI): m/z [M + H]+ calcd for C18H21N2: 265.1699; found:
265.1712.
1H NMR (400 MHz, DMSO-d6): δ = 8.51 (d, J = 7.6 Hz, 1 H), 8.41 (s, 1
H), 7.78 (s, 4 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.24 (d, J = 7.6 Hz, 1 H), 6.91–
6.88 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 144.8, 143.3, 137.5, 133.5, 127.6,
127.0, 125.2, 116.7, 112.5, 109.5, 93.6.
2-(3,4-Dimethylphenyl)-3-methylimidazo[1,2-a]pyridine (3ta)
Yellow solid; yield: 86.1 mg (73%).
1H NMR (400 MHz, DMSO-d6): δ = 8.29 (d, J = 6.4 Hz, 1 H), 7.60 (s, 1
H), 7.55 (d, J = 8.8 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 7.21 (d, J = 7.6 Hz,
2 H), 6.94–6.91 (m, 1 H), 2.62 (s, 3 H), 2.29 (s, 3 H), 2.26 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10IN2: 320.9883; found:
320.9896.
13C NMR (100 MHz, DMSO-d6): δ = 143.3, 141.2, 136.2, 135.1, 132.4,
129.6, 128.9, 125.2, 124.2, 123.6, 116.4, 115.8, 111.7, 19.5, 19.2, 9.5.
2-(2-Naphthyl)imidazo[1,2-a]pyridine (3oa)
Yellow solid; yield: 95.2 mg (78%).
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2: 237.1386; found:
237.1389.
1H NMR (400 MHz, DMSO-d6): δ = 8.57–8.51 (m, 3 H), 8.11 (d, J = 8.4
Hz, 1 H), 7.98–7.95 (m, 2 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.63 (d, J = 8.8 Hz,
1 H), 7.54–7.46 (m, 2 H), 7.28–7.24 (m, 1 H), 6.91–6.88 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.0, 144.3, 133.3, 132.6, 131.4,
128.2, 128.1, 127.6, 126.9, 126.4, 125.9, 125.1, 124.1, 124.0, 116.6,
112.3, 109.7.
2-Phenyl-3-propylimidazo[1,2-a]pyridine (3ua)
Yellow solid; yield: 83.8 mg (71%).
1H NMR (400 MHz, DMSO-d6): δ = 8.41 (d, J = 6.8 Hz, 1 H), 7.79 (d,
J = 7.2 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 1 H), 7.49–7.45 (m, 2 H), 7.36–7.33
(m, 1 H), 7.25–7.22 (m, 1 H), 6.94–6.91 (m, 1 H), 3.11–3.07 (m, 2 H),
1.69–1.63 (m, 2 H), 0.98–0.95 (m, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C17H13N2: 245.1073; found:
245.1071.
13C NMR (100 MHz, DMSO-d6): δ = 143.5, 140.9, 135.0, 128.6, 127.6,
127.2, 124.4, 123.9, 120.7, 116.8, 111.9, 24.9, 20.8, 13.8.
2-[(E)-2-Phenylvinyl]imidazo[1,2-a]pyridine (3pa)
Yellow solid; yield: 79.2 mg (72%).
HRMS (ESI): m/z [M + H]+ calcd for C16H17N2: 237.1386; found:
237.1395.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 6.4 Hz, 1 H), 7.56–7.52 (m, 5
H), 7.37–7.33 (m, 2 H), 7.26 (d, J = 7.2 Hz, 1 H), 7.16–7.12 (m, 2 H),
6.74–6.71 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.6, 144.0, 137.1, 130.5, 128.6,
127.6, 126.5, 125.4, 125.1, 119.8, 117.0, 112.2, 110.5.
2-[4-(Methylsulfonyl)phenyl]imidazo[1,2-a]pyridine (3va)
Yellow solid; 2.2 g (81%; 10 mmol scale).
1H NMR (400 MHz, DMSO-d6): δ = 8.59–8.55 (m, 2 H), 8.22 (d, J = 8.0
Hz, 2 H), 7.99 (d, J = 8.0 Hz, 2 H), 7.62 (d, J = 9.2 Hz, 1 H), 7.28 (d,
J = 7.6 Hz, 1 H), 6.95–6.92 (m, 1 H), 3.25 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C15H13N2: 221.1073; found:
221.1085.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
Z.-H. Ren et al.
Special Topic
Synthesis
13C NMR (100 MHz, DMSO-d6): δ = 145.1, 142.5, 139.4, 138.8, 127.6,
8-Fluoro-2-phenylimidazo[1,2-a]pyridine (3af)
127.2, 126.0, 125.7, 116.9, 112.8, 111.0, 43.6.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O2S: 273.0692; found:
273.0703.
Yellow solid; yield: 72.1 mg (68%).
1H NMR (400 MHz, DMSO-d6): δ = 8.54 (d, J = 6.8 Hz, 1 H), 8.40 (d,
J = 6.8 Hz, 1 H), 7.99 (d, J = 7.2 Hz, 2 H), 7.48–7.44 (m, 2 H), 7.36–7.33
(m, 1 H), 7.17–7.13 (m, 1 H), 6.90–6.85 (m, 1 H).
7-Methyl-2-phenylimidazo[1,2-a]pyridine (3ab)
13C NMR (100 MHz, DMSO-d6): δ = 150.4 (d, JCF = 247.4 Hz), 144.6,
133.3, 128.8, 128.0, 125.7, 123.6, 111.4 (d, JCF = 6.7 Hz), 110.9, 107.7
(d, JCF = 16.0 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C13H10FN2: 213.0823; found:
213.0831.
Yellow solid; yield: 84.2 mg (81%).
1H NMR (400 MHz, DMSO-d6): δ = 8.39 (d, J = 6.8 Hz, 1 H), 8.29 (s, 1
H), 7.94 (d, J = 7.6 Hz, 2 H), 7.44–7.40 (m, 2 H), 7.35–7.28 (m, 2 H),
6.72 (d, J = 6.8 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.2, 144.1, 135.3, 134.1, 128.6,
127.5, 126.0, 125.5, 114.9, 114.7, 108.5, 20.8.
8-Chloro-2-phenylimidazo[1,2-a]pyridine (3ag)
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2: 209.1073; found:
Yellow solid; yield: 79.8 mg (70%).
1H NMR (400 MHz, DMSO-d6): δ = 8.52 (s, 2 H), 7.98 (d, J = 7.2 Hz, 2
H), 7.47–7.43 (m, 3 H), 7.35 (d, J = 6.8 Hz, 1 H), 6.91–6.87 (m, 1 H).
209.1080.
7-Methoxy-2-phenylimidazo[1,2-a]pyridine (3ac)
13C NMR (100 MHz, DMSO-d6): δ = 144.7, 142.0, 133.3, 128.8, 128.0,
Yellow solid; yield: 93.0 mg (83%).
126.1, 125.7, 124.1, 121.1, 112.1, 111.1.
1H NMR (400 MHz, CDCl3): δ = 8.88 (d, J = 7.6 Hz, 2 H), 8.83 (d, J = 7.2
Hz, 1 H), 7.61 (s, 1 H), 7.40–7.37 (m, 2 H), 7.29–7.25 (m, 1 H), 6.87 (s, 1
H), 6.44 (d, J = 6.8 Hz, 1 H), 3.83 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10ClN2: 229.0527; found:
229.0530.
13C NMR (100 MHz, CDCl3): δ = 157.8, 147.0, 145.2, 133.7, 128.6,
8-Bromo-2-phenylimidazo[1,2-a]pyridine (3ah)
127.6, 125.8, 125.7, 107.4, 106.8, 94.5, 55.4.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2O: 225.1022; found:
225.1033.
Yellow solid; yield: 97.9 mg (72%).
1H NMR (400 MHz, DMSO-d6): δ = 8.58–8.55 (m, 2 H), 7.99 (d, J = 7.6
Hz, 2 H), 7.60 (d, J = 7.2 Hz, 1 H), 7.48–7.44 (m, 2 H), 7.36 (d, J = 7.2 Hz,
1 H), 6.85–6.82 (m, 1 H).
6,8-Dimethyl-2-phenylimidazo[1,2-a]pyridine (3ad)
13C NMR (100 MHz, DMSO-d6): δ = 144.6, 142.6, 133.3, 128.8, 128.0,
Yellow solid; yield: 89.9 mg (81%).
127.5, 126.6, 125.7, 112.6, 111.2, 109.9.
1H NMR (400 MHz, DMSO-d6): δ = 8.23 (s, 1 H), 8.10 (s, 1 H), 7.96 (d,
J = 7.2 Hz, 2 H), 7.43–7.40 (m, 2 H), 7.31–7.29 (m, 1 H), 6.86 (s, 1 H),
2.48 (s, 3 H), 2.20 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C13H10BrN2: 273.0022; found:
273.0035.
13C NMR (100 MHz, DMSO-d6): δ = 144.3, 143.5, 134.2, 128.6, 127.4,
2-Phenylimidazo[2,1-a]isoquinoline (3ai)
126.4, 125.4, 121.9, 121.2, 109.2, 17.5, 16.5.
HRMS (ESI): m/z [M + H]+ calcd for C15H15N2: 223.1230; found:
223.1241.
Yellow solid; yield: 34 mg (66%).
1H NMR (400 MHz, DMSO-d6): δ = 8.56 (d, J = 7.6 Hz, 1 H), 8.40 (s, 1
H), 8.32 (d, J = 6.8 Hz, 1 H), 8.03 (d, J = 7.6 Hz, 2 H), 7.85 (d, J = 7.6 Hz,
1 H), 7.69–7.60 (m, 2 H), 7.48–7.44 (m, 2 H), 7.33–7.30 (m, 1 H), 7.24
(d, J = 7.2 Hz, 1 H).
8-Methyl-2-phenylimidazo[1,2-a]pyridine (3ae)
13C NMR (100 MHz, DMSO-d6): δ = 142.6, 142.1, 133.9, 129.3, 128.7,
Yellow solid; yield: 60.3 mg (58%).
1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 7.6 Hz, 2 H), 7.92 (d, J = 6.4
Hz, 1 H), 7.78 (s, 1 H), 7.43–7.40 (m, 2 H), 7.31 (d, J = 7.2 Hz, 1 H), 6.91
(d, J = 6.4 Hz, 1 H), 6.64–6.61 (m, 1 H), 2.65 (s, 3 H).
128.2, 128.1, 127.4, 127.3, 125.3, 124.2, 123.0, 122.6, 112.5, 111.2.
HRMS (ESI): m/z [M + H]+ calcd for C17H13N2: 245.1073; found:
245.1074.
13C NMR (100 MHz, CDCl3): δ = 146.1, 145.1, 134.0, 128.6, 127.7,
127.4, 126.1, 123.3, 123.2, 112.2, 108.5, 17.1.
Acknowledgment
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2: 209.1073; found:
209.1084.
We thank the National Natural Science Foundation of China (grant
numbers 21272183 and 21472147), the Fund of the Rising Stars of
Shanxi Province (2012KJXX-26), and the Fund of Shanxi Province
(2014JQ2078) for financial support.
6-Methyl-2-phenylimidazo[1,2-a]pyridine (3ae')
Yellow solid; yield: 28.1 mg (27%).
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.6 Hz, 2 H), 7.90 (s, 1 H),
7.77 (s, 1 H), 7.54 (d, J = 9.2 Hz, 1 H), 7.45–7.41 (m, 2 H), 7.34–7.30 (m,
1 H), 7.02 (d, J = 8.8 Hz, 1 H), 2.32 (s, 3 H).
Supporting Information
13C NMR (100 MHz, DMSO-d6): δ = 134.5, 134.0, 128.7, 127.9, 127.5,
124.2, 121.4, 116.1, 108.8, 17.5.
HRMS (ESI): m/z [M + H]+ calcd for C14H13N2: 209.1073; found:
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561950.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
Z.-H. Ren et al.
Special Topic
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G