Copper-mediated three-component synthesis of 3-cyanoimidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c5cc05821j

A copper-mediated three-component approach towards the synthesis of 3-cyanoimidazo[1,2-a]pyridines from 2-aminopyridines, acetophenones and benzyl cyanide was developed. This cascade reaction proceeds through a copper-mediated oxidative release of cyanide

Full text of DOI:10.1039/c5cc05821j

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Copper-Mediated Three-Component Synthesis of 3-
Cyanoimidazo[1,2-a]pyridines
Qiaodong Wen,a Ping Lu*a and Yanguang Wang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
would like to describe the results of our efforts.
A
copper-mediated three-component approach towards 3-
cyanoimidazo[1,2-a]pyridines from 2-aminopyridines,
acetophenones and benzyl cyanide was developed. This cascade
reaction proceeds through a copper-mediated oxidative releasing
of cyanide from benzyl cyanide, a copper-mediated Ortoleva−King
reaction, and a copper-catalyzed cyanation.
O
S
O
N
N
N
Cl
N
N
N
Cl
O
O
N
Zolimidine
N
n-Pr
n-Pr
Imidazo[1,2-a]pyridines are an important class of organic
compounds in medicinal chemistry due to their pharmaceutical
activities.1 A number of clinically used drugs and clinical candidates,
such as zolimidine, alpidem, zolpidem, saripidem, necopidem, and
GSK812397, compose of an imidazo[1,2-a]pyridine scaffold (Scheme
1).2 The imidazo[1,2-a]pyridines provide many organic material
molecules with optoelectronic properties.3,4 Consequently, a variety
of synthetic methods to construct imidazo[1,2-a]pyridines have
been developed. Essential approaches include: (i) the isocyanide-
based multi-component reactions (IMCR),5 (ii) the condensation of
2-aminopyridines with α-halocarbonyl compounds,2a,4c,6 (iii) the
copper-catalyzed three-component coupling of 2-aminopyridines
with aldehydes and alkynes,7 and (iv) other intramolecular and
intermolecular cyclizations.8-10 More recently, It was reported that
the copper-catalyzed aerobic oxidative cyclizations of 2-
aminopyridines with methyl ketones in the presence of Lewis acid
could directly furnish imidazo[1,2-a]pyridines from more easily
available starting materials.11
On the other hand, the copper-catalyzed cyanation reactions
have emerged as powerful tools to synthesize aryl nitriles with a
variety of cyanating agents.12 In this aspect, we developed the
copper-catalyzed cyanation of 2-arylpyridines, aryl halides, indoles,
and aryl boric acids using benzyl cyanide as an environmentally
benign and operational safe cyanating reagent.13 These results
encouraged us to investigate the copper-mediated three-
component reaction of 2-aminopyridines, acetophenones and
benzyl cyanide for the preparation of 3-cyanoimidazo[1,2-
a]pyridines, which have rarely been reported before.14 Herein, we
Alpidem
Zolpidem
N
N
N
N
N
N
N
Cl
N
OH
N
N
N
N
O
n-Pr
i-Bu
O
Saripidem
Necopidem
GSK812397
Scheme 1. Structures of several commercial drugs containing
imidazo[1,2-a]pyridine skeletons.
Our model reaction was carried out with 2-aminopyridine (1a),
acetophenone (2a), benzyl cyanide (3a), and equivalent amount of
CuI in N,N-dimethylformamide (DMF) at 120°C under ambient air
conditions. 2-Phenylimidazo[1,2-a]pyridine-3-carbonitrile (4a) was
obtained in 36% isolation yield (Table 1, entry 1). However, only
trace amount of 4a was detected when CuBr, CuCl, Cu2O, or
Cu(OAc)2 was used as copper catalyst (Table 1, entries 2–5). By
screening the solvents, N-methyl-2-pyrrolidone (NMP) was the
optimal with the formation of 4a in 73% yield (Table 1, entries 6–
10). By virtue of the aerobic oxidative process involved, we
conducted the reaction in O2 atmosphere. As a result, only 44%
yield of 4a was isolated (Table 1, entry 11). Subsequently, we
attempted to add some additives to increase the yield.
Unfortunately, lower yields were obtained by employing the
selected Brønsted acid and Lewis acid (Table 1, entries 12–15).
Pursuit to introduce 10 mol% of CuBr2 as a co-catalyst also resulted
in a decreased yield (Table 1, entry 16). Both increasing and
reducing the amount of CuI led to the diminution of yields (Table 1,
entries 17–19). Therefore, the optimized conditions were
established (Table 1, entry 6).
a.Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China;
E-mail: pinglu@zju.edu.cn; orgwyg@zju.edu.cn
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Screening of the reaction conditions a
N
O
[Cu], additive
Ph
+
+
N
Ph
CN
solvent , air
120 oC, 17 h
Ph
N
NH2
CN
4a
2a
3a
1a
Scheme 2. Screening of cyanation reagents.
Entry
[Cu] (equiv)
CuI (1.0)
CuBr (1.0)
CuCl (1.0)
Cu2O (1.0)
Cu(OAc)2 (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.2)
CuI (0.8)
CuI (0.6)
Additive (equiv)
Solvent
DMF
Yield (%)b
36
With the optimized reaction conditions in hand, we tested the
substrate diversity. Firstly, various methyl ketones were examined
with 2-aminopyridine and benzyl cyanide (Table 2). Electron-
donating group on acetophenones could afford the corresponding
products in moderate to good yields (4b-4i). Steric effect was
1
-
2
-
DMF
trace
trace
trace
trace
73
3
-
DMF
4
-
DMF
observed
when
using
1-(o-tolyl)ethanone
and
1-(2-
methoxyphenyl)ethanone as the substrates. Thus, 4c and 4h were
obtained in relatively lower yields in comparison with 4b and 4g,
respectively. With mild electron-withdrawing group on the phenyl
ring of acetophenone, 1-(4-chlorophenyl)ethanone afforded 4j in 81%
yield. However, when it came to stronger electron-withdrawing
groups (CN and F), the yields were obviously decreased (4k and 4l).
Besides, the fused aryl ketone 2-acetonaphthone afforded the
corresponding product 4m in 67% yield. Hetero-aryl methyl ketone
and α,β-unsaturated methyl ketone were also compatible for this
transformation, although in diminished yields (4n and 4o).
5
-
DMF
6
-
NMP
7
-
DMAc
DMSO
DMF/H2O
NMP/H2O
NMP
34
8
-
trace
46
9
-
10
11c
12
13
14
15
16
17
18
19
a
-
40
O2
44
Table 2. Substrate scopes of various ketones.a
TsOH (0.1)
NMP
21
O
HOAc (0.1)
NMP
52
R1
N
CuI (1.0 equiv)
Ph
+
CN
N
BF3•Et2O (0.1)
NMP
60
+
NH2
N
NMP, air
120 oC, 17 h
N
R1
CN
ZnI2 (0.1)
NMP
34
1a
2
3a
4
Me
N
CuBr2 (0.1)
NMP
51
N
Me
Et
N
N
N
-
-
-
NMP
55
CN
CN
CN
4c, 56%
4b, 80%
4a, 73%
NMP
59
Me
N
N
N
N
NMP
58
t-Bu
OMe
Cl
Me
N
N
CN
CN
Reaction conditions 1a (0.6 mmol), 2a (0.5 mmol), 3a (0.6 mmol), Cu
CN
b
catalyst (0.5 mmol), solvent (1 mL), air, 120°C, 17 h. Isolated yields of 4a
4e, 71%
4d, 64%
4f
, 60%
based on 2a. c The reaction was conducted with an oxygen balloon.
MeO
N
N
N
N
OMe
OMe
N
N
CN
CN
CN
The influence of substituent groups on the phenyl ring of benzyl
cyanide was also investigated (Scheme 2). 4-Methoxybenzyl cyanide
(3b) afforded the desired product in a slightly higher yield. With
electron-withdrawing groups, 4-chlorobenzyl cyanide (3c) and 4-
fluorobenzyl cyanide (3d) provided 4a in significantly decreased
yields. These results were in accordance with our previous
conclusions13a due to the fact that the electron-donating group
could accelerate the oxidative release of cyanide anion from benzyl
cyanides.
4g, 83%
4h, 57%
4i, 78%
N
N
N
N
N
CN
F
N
CN
CN
CN
4j, 81%
4l
, 59%
4k, 52%
N
N
Ph
N
N
N
N
N
CN
4m, 67%
CN
4n, 40%
CN
4o, 45%
a Reaction conditions: 1a (0.6 mmol), 2 (0.5 mmol), 3a (0.6 mmol), CuI (0.5 mmol),
NMP (1 mL), air, 120 oC, 17 h. Isolated yield based on 2.
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The substrate scopes of 2-aminopyridines 1 were also studied.
As shown in Table 3, moderate to good yields (51%~82%) of the
desired products 4p-w were obtained with substituents at 4- and 5-
positions of 2-aminopyridines.
Table 3. Substrate scopes of 2-aminopyridines.a
Scheme 4. Mechanism studies.
A presumptive mechanism is proposed in Scheme 5. Firstly,
benzyl cyanide releases cyano anion in the presence of copper
catalyst under ambient air conditions,13 while CuI-mediated
generation of I2 or HOI occurs, which leads to the α-iodination of
acetophenone to form 2-iodo-1-phenylethan-1-one (A). Then, the
Ortoleva−King reacꢀon4c,15 of A with 1a to afford 8. Finally, 8
undergoes
cyanation18 to afford 4a.
a
copper-catalyzed iodination16,17 and subsequent
N
Ph
N
CN
As a synthetic application of this method, we successfully
converted our products 4j and 4t to the clinically used saripidem (5)
and necopidem (6) with 62% and 59% overall yields, respectively
(Scheme 3). Compared with previously reported procedures,7a,7b
our synthetic strategy is much facile and the starting materials are
easily available.
4a
[Cu]
[Cu], O2
N
CN-
Ph
CN
Ph
N
3a
I
7
I-
[Cu], O2
O
O
[Cu], O2
I
Ph
I-
Ph
N
A
Ph
2a
N
Ortoleva-King
reaction
8
N
1a
NH2
Scheme 5. Plausible mechanism of the cascade copper catalysis.
In conclusion, we have developed a novel synthesis of 3-
cyanoimidazo[1,2-a]pyridines by the copper-mediated three-
component reaction of 2-aminopyridines with acetophenones and
benzyl cyanide. The reaction performs under mild reaction
conditions in high conversion yields with two C–N bonds and one C–
CN bond formation in a single step. The cascade process is assumed
to include a copper-mediated Ortoleva−King reaction, a copper-
mediated oxidative releasing of cyanide from benzyl cyanide, and a
copper-catalyzed cyanation. Moreover, this approach was
successfully used for the synthesis of saripidem and necopidem,
which are sedative and anxiolytic drugs.
Scheme 3. Synthesis of saripidem (5) and necopidem (6).
In order to gain a good insight into the mechanism of reaction,
we captured the possible intermediates by operating the reaction in
the absence of benzyl cyanide (Scheme 4). In this case, 3-iodo-2-
phenylimidazo[1,2-a]pyridine
(7)
and 2-phenylimidazo[1,2-
a]pyridine (8) were isolated in 68% and 11% yield, respectively.
Then, 7 and 8 were individually subjected to the cyanation with
benzyl cyanide under standard reaction conditions. Both 7 and 8
could afford 4a in excellent yields, while 8 could be converted into 7
by treatment with equivalent amount of CuI.
The authors thank the National Nature Science Foundation of
China (Nos. 21272203; 21472173) for financial support.
This journal is © The Royal Society of Chemistry 20xx
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