Copper Acetate Aerobic Oxidative Synthesis of Pyrido[1,2- a ]benzimidazoles from Aminopyridines and Phenylboronic Acids

Article abstract of DOI:10.1055/s-0037-1611847

Pyrido[1,2- a ]benzimidazoles, which show interesting and potentially useful biological activities, have drawn extensive attention from chemists. A straightforward copper acetate-oxidative one-pot synthesis of these compounds from 2-aminopyridines and phenylboronic acids through C-N bond formation and C-H bond activation was developed as a simple and convenient method.

Full text of DOI:10.1055/s-0037-1611847

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Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
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Synlett
H. Yan et al.
Letter
Copper Acetate Aerobic Oxidative Synthesis of Pyrido[1,2-a]benz-
imidazoles from Aminopyridines and Phenylboronic Acids
Hao Yan*a,b
Hui Guoa
H
N
B(OH)2
R2
Xiaoqiang Zhoub,c
Zhenyu Zuoa
Jingli Liua
Guanghui Zhanga
Shuan Zhanga
Cu(OAc)2
2
R1
R2
R1
N
N
NH2
DMSO, O , 120 °C
1
2
R
R
= H, Me, Cl, Br, F, OBn, COOEt, Ph
= Me, OMe, t-Bu, Cl, Br, COOMe, CN
22 examples
2
5–82% yield
a
College of Pharmacy, Shaanxi University of Chinese Medicine,
Xianyang 712046, P. R. of China
yanhao@sntcm.edu.cn
State Key Laboratory of Applied Organic Chemistry, College of
b
Chemistry and Chemical Engineering, Lanzhou University,
Lanzhou 730000, P. R. of China
College of Chemistry and Materials, Weinan Normal University,
c
Chaoyang Road, Weinan 714099, P. R. of China
Received: 06.04.2019
Accepted after revision: 13.05.2019
Published online: 06.06.2019
N
N
CN
Cl
DOI: 10.1055/s-0037-1611847; Art ID: st-2019-u0197-l
NC
N
Abstract Pyrido[1,2-a]benzimidazoles, which show interesting and
potentially useful biological activities, have drawn extensive attention
from chemists. A straightforward copper acetate-oxidative one-pot
synthesis of these compounds from 2-aminopyridines and phenyl-
boronic acids through C–N bond formation and C–H bond activation
was developed as a simple and convenient method.
N
N
N
N
N
F
F
HN
N
I
II
Key words oxidation, cyclization, N–H coupling, C–H activation,
pyridobenzimidazoles
N
N
CN
CF3
The imidazo[1,2-a]pyridine scaffold is a 5,6-fused nitro-
HN
NH
gen bridgehead heterocycle that is one of the most signifi-
1
cant structural units. It has a wide range of applications in
medicinal chemistry and in materials science.3 This
heterocycle can also be found embedded in numerous tri-
cyclic rings systems, such as pyrido[1,2-a]benzimidazole,
many of which have interesting and potentially useful bio-
logical activities (Figure 1). For example, compound I is
component of fungal cell walls that has been shown to have
2
III
Figure 1 Examples of pyrido[1,2-a]benzimidazoles with biological
activities
antifungal activity through inhibition of the synthesis of -
4
1
,6-glucan. Compound II has been found to possess poten-
idobenzimidazoles. For example, Yan et al. synthesized pyr-
ido[1,2-a]benzimidazoles by a multicomponent one-pot re-
action of chloroacetonitrile, malononitrile, an aromatic al-
dehyde, and a pyridine.10 Zhou and co-workers reported a
way of synthesizing pyrido[1,2-a]benzimidazoles by a cop-
per-catalyzed intermolecular and intramolecular C–N cou-
tial antitumor activity against a human breast adenocarci-
noma cell line. Compound III presents antimalarial proper-
ties through inhibition of the K1 strain of Plasmodium falci-
5
6
parum.
Numerous strategies have been used to synthesize pyri-
do[1,2-a]benzimidazoles, including a multicomponent cou-
pling reaction, a transition-metal-catalyzed intermolecu-
11
pling reaction of ortho-haloanilines and 2-halopyridines.
Cuny and co-workers synthesized pyrido[1,2-a]benzimid-
7
8
lar cyclization, and intramolecular cycloadditions promot-
azoles by photoinduced cyclization of 2-[(2-halophe-
ed photochemically or by halogen derivatives,9 some of
which have created new paradigms in the synthesis of pyr-
nyl)amino]pyridines in liquid ammonia. Junjappa and co-
12
workers developed a synthesis of pyrido[1,2-a]benzimidaz-
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
H. Yan et al.
Letter
oles through [3+3]-annulation of 2-methyl- or 2-(cyano-
Table 1 Optimization of the Reaction Conditionsa
methyl)benzimidazole dianions with -oxoketene dithioac-
13
B(OH)2
N
etals. The Zhu group constructed pyrido[1,2-a]benzimid-
azoles by demethylenation and cycloamination of N-
reaction conditions
N
N
NH2
14
benzyl-2-aminopyridines.
Ibrahim synthesized pyri-
do[1,2-a]benzimidazoles by condensation of (1H-benzimid-
azo-2-yl)acetonitrile with 3-substituted chromones.15 Di-
rect intramolecular C–H amination reactions to give pyri-
1a
2a
3a
Entry
Oxidant
Solvent
Temp (°C)
Time (h) Yield (%)b
16
do[1,2-a]benzimidazoles from N-aryl-2-aminopyridines
1
2
3
4
5
6
7
8
9
Cu(OAc)2
CuOAc
DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
150
100
120
120
120
120
120
8
8
28
28
–
were reported by Zhu group17 and the Maes group. Al-
though there is a rich literature on the synthesis of pyri-
do[1,2-a]benzimidazoles, most of methods are restricted by
the need for multistep preparations of the substrates or are
limited for economic or environmental reasons. Therefore,
an exploration of methods for constructing pyrido[1,2-
a]benzimidazoles from simple and readily accessible start-
ing material is still desirable.
18
DMF
CuBr
CuBr
CuI
2
DMF
8
DMF
8
–
DMF
8
–
Cu(OTf)
Cu(acac)
Cu
2
DMF
8
–
2
DMF
8
–
2
O
DMF
8
–
As part of our long-standing interest in the synthesis of
medicinally interesting heterocycle compounds,1 we de-
scribe an economical, easy, and rapid strategy for the
straightforward preparation of pyrido[1,2-a]benzimidazoles.
We began our study by treating pyridin-2-amine (1a)
with phenylboronic acid (2a) in the presence of Cu(OAc)2
PIDA
DMF
8
–
9
1
0
11
12
13
mCPBA
Oxone
H O
DMF
8
–
DMF
8
–
2
2
DMF
8
–
TBHP
–
DMF
8
–
(1.0 equiv) under air at 120 °C for eight hours in N,N-di-
1
4
5
DMF
8
–
methylformamide (DMF). The desired annulated product
1
Cu(OAc)
2
DMA
DMSO
NMP
8
30
60
–
pyrido[1,2-a]benzimidazole (3aa) was isolated in 28% yield
Table 1, entry 1) and characterized by 1H and C NMR
13
16
17
Cu(OAc)2
Cu(OAc)
8
(
spectroscopy, IR spectroscopy, and high-resolution mass
spectrometry. We then evaluated other oxidants, including
2
8
18
Cu(OAc)2
Cu(OAc)2
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
8
–
copper salts and other inorganic oxidants (Oxone, H O ), as
19c
2
2
8
20
75
75
55
72
85
85
80
30
trace
well as organic oxidants [diacetoxyiodobenzene (PIDA),
meta-chloroperbenzoic acid (mCPBA), or tert-butyl hydrop-
eroxide(TBHP)], but the yield of 3aa did not change signifi-
cantly (Table 1, entries 2–13).
In addition, in the absence of an oxidant, none of the
target product was obtained (Table 1, entry 14). On switch-
ing to DMA or DMSO as solvent (entries 15 and 16), DMSO
was shown to improve the yield of 3aa significantly to 60%
2
2
2
0d
1d
2d
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
8
8
8
23d
24
8
d
Cu(OAc)2
Cu(OAc)
Cu(OAc)
14
20
36
54
54
5d
2
2
2
2
6e
7f
2
(entry 16). The expected product was not formed when N-
Cu(OAc)
2
methyl-2-pyrrolidone (NMP) or toluene was used as the
solvent (entries 17 and 18). In an attempt to increase the
yield, the reaction was conducted under N or O (entries 19
2
8g
Cu(OAc)
2
a
Reaction conditions: 1a (0.32 mmol), 2a (0.38 mmol), oxidant (1.0 equiv),
solvent (2 mL), under air.
Isolated yield.
Under N2.
Under O
Cu(OAc)
Cu(OAc)
2
2
and 20). Gratifyingly, a pure oxygen atmosphere provided a
higher yield of 3aa (entry 20). Carrying out the reaction at
lower (100 °C) or higher (130 or 150 °C) temperatures did
not improve the yield (entries 21–23). Extending the reac-
tion time to 14 or 20 hours promoted the transformation,
affording 3aa in the highest yield of 85% (entries 24 and 25).
Product 3aa was obtained in 80% yield on decreasing the
b
c
d
e
f
2
.
2
2
(0.5 equiv) under O .
(0.2 equiv) under O
(0.1 equiv) under O .
2
2
.
2
g
Cu(OAc)
2
28). To save costs and in respect of green chemistry, the op-
timal conditions were selected as those shown in Entry 26.
By using these optimized reaction conditions,20 we next
examined the scope of the reaction with respect to the sub-
stituted 2-aminopyridine (Table 2). The reactions of various
Cu(OAc) load to 0.5 equivalents and prolonging the reac-
2
tion time to 36 hours (entry 26). Decreasing the amount of
Cu(OAc) to 0.2 or 0.1 equivalents provided 3aa in a lower
2
yield and in a trace amount, respectively (entries 27 and
2-aminopyridines 1 with phenylboronic acid (2a) generally
proceeded smoothly and led to the desired products 3;
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Synlett
H. Yan et al.
Letter
however, the position and nature of the substituents on the
pyridine ring had some influence on the yields. In general,
substrates with an electron-donating group (Me) provided
pyrido[1,2-a]benzimidazoles 3 in good yields (Table 2, en-
tries 2-4) than did those with electron-withdrawing groups
the transformation was general for a variety of phenylbo-
ronic acids. Reactions of 2-aminopyridine (1a) with m-tol-
ylboronic acid (2c) or (3-chlorophenyl)boronic acid (2j)
proceeded smoothly (Table 3, entries 2 and 9). Similarly,
treatment of 2-aminopyridine (1a) with phenylboronic ac-
ids containing a 4-methyl (2d), 4-methoxy (2f), 4-ethyl
(2g), 4-tert-butyl (2h), 4-choro (2k), 4-bromo(2l), 4-me-
thoxycarbonyl (2m), or 4-cyano (2n) group gave the desired
products 3ad, 3af, 3ag, 3ah, 3ak, 3al, 3am, and 3an in
yields of 57, 42, 64, 70, 52, 54, 65, and 33%, respectively (en-
tries 3, 5–7, and 10–13). Combinations of 2-aminopyridine
(1a) with phenylboronic acids bearing ortho-substituents
were problematic owing to steric hindrance; for example, o-
tolylboronic acid afforded the desired product in 36% yield
(entry 1). (2,3-Dimethylphenyl)boronic acid also gave the
corresponding product 3ae in 26% yield (Table 3, entry 4).
With (2-chlorophenyl)boronic acid, a trace amount of the
desired product was observed by TLC, but could not be iso-
lated (entry 8).
(
Cl, Br, F, or CO Et) on the pyridine ring (entries 6–8, 10, and
2
12), indicating that an electron-donating group on the pyri-
dine ring favors the reaction. The reactions of 2-aminopyri-
dines bearing bromo or methyl substituents on the C-6 po-
sition did not give the desired products (entries 5 and 9)
due to steric hindrance. Additionally, the substrate with a
benzyloxy group at the C-3 position of the pyridine ring re-
acted less efficiently to give product 3ka in 25% yield (entry
11). It is possible that steric hindrance by the benzyloxy
group hampers the progress of the reaction. Next, 2-amino-
pyrimidine and 2-aminobenzimidazole were employed as
substrates and, although these reacted with phenylboronic
acid under the standard conditions, none of the expected
cyclization products were obtained (entries 13 and 14). Fi-
nally, when a 2-aminoquinoline was used as the coupling
partner, a trace amount of the desired product was ob-
served by TLC but could not be isolated (entry 15).
Table 3 Substrate Scope of the Phenylboronic Acida
B(OH)2
N
Subsequently, the substrate scope of the phenylboronic
acid 2 was investigated by using 2-aminopyridine (1a) as
the reaction partner (Table 3). We were pleased to note that
R2
R2
Cu(OAc)2
2
N
N
NH2
DMSO, O , 120 °C
1a
2
3
Table 2 Substrates Scope of the Aminopyridinea
R2
Product
Yield (%)
b
Entry
n
B(OH)2
N
X
1
2
3
4
5
6
7
8
9
2-Me (2b)
3-Me (2c)
4-Me (2d)
3ab
3ac
3ad
3ae
3af
3ag
3ah
–
36
55
57
26
42
64
70
trace
50
52
54
65
33
R1
R1
Cu(OAc)2
N
N
NH2
DMSO, O2, 120 °C
X = C, N
n = 0, 1
1
2a
3
2,3-Me (2e)
2
4-OMe (2f)
b
Entry
n
X
R1
H
Product
Yield (%)
4-Et (2g)
4-t-Bu (2h)
2-Cl (2i)
3-Cl (2j)
4-Cl (2k)
4-Br (2l)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
1
1
1
C
3aa
3ba
3ca
3da
–
80
81
82
72
–
C
C
C
C
C
C
C
C
C
C
C
N
3-Me
4-Me
5-Me
6-Me
4-Cl
3aj
1
1
1
0
1
2
3
3ak
3al
3fa
3ga
3ha
–
34
45
35
–
4-CO
2
Me (2m)
3am
3an
5-Cl
1
4-CN (2n)
5-Br
a
2
Reaction conditions: 1a (0.32 mmol), 2 (0.38 mmol), Cu(OAc) (0.5
equiv), DMSO (2 mL), 120 °C, 36 h, under O
Isolated yield.
6-Br
2
.
b
1
1
1
1
1
0
1
2
3
4
5
5-F
3ja
3ka
3la
–
34
25
30
–
3-OBn
To gain insight into the mechanism of the amination
and cyclization, two sets of control experiments were per-
formed to identify the reaction steps and to explore the re-
action mechanism. First, when 2-aminopyridine (1a) and
phenylboronic acid (2a) were treated at a lower tempera-
ture (<50 °C) for a shorter time (1 h) under the standard
conditions, intermediate I was isolated [Scheme 1(a)]. On
increasing the temperature and prolonging the reaction
4-CO
H
2
Et
2-aminobenzimidazole
2-aminoquinoline
–
–
1
–
trace
a
2
Reaction conditions: 1 (0.32 mmol), 2a (0.38 mmol), Cu(OAc) (0.5
equiv), DMSO (2 mL), 120 °C, 36 h, under O
Isolated yield.
2
.
b
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Synlett
H. Yan et al.
Letter
time, intermediate I smoothly underwent oxidative cycliza-
tion to give 3aa [Scheme 1(b)]. When the reaction of 1a and
Cu(OAc) . Electrophilic substitution of the aromatic ring
2
gives C, which undergoes reversible protonation and elimi-
nation to give intermediate D. The reactive copper(III) in-
termediate E is then formed under the copper acetate/aero-
bic oxidative conditions. Reductive elimination of E finally
provides the product 3aa.1
2a was conducted in the presence of TEMPO under the
standard conditions, the desired product 3aa was isolated
in 80% [Scheme 1(c)], suggesting that the reaction is not a
radical process.
7,22
In conclusion, we have successfully developed a copper
acetate-induced oxidative, one-pot, straightforward syn-
thesis of pyrido[1,2-a]benzimidazole derivatives from 2-
aminopyridines and phenylboronic acids through C–N bond
formation and C–H bond activation. In the process, all the
starting substrates are commercially available without
preparation, and the procedure are carried out by using 0.5
equivalents of copper acetate in combination with oxygen
as the oxidative agent to activate the C–H bond, which is
simple and convenient. Most functional groups are tolerat-
ed and the reaction proceeds smoothly in their presence.
B(OH)2
H
standard conditions
50 °C, ~1 h
N
N
NH2
(a)
(b)
≤
N
1a
2a
Intermediate I
H
N
N
~120 °C
N
8
N
0%
3
aa
Intermediate I
Cu(OAc)2,
TEMPO(2.0 equiv)
N
N
B(OH)2
(c)
Funding Information
N
NH2
DMSO, O , 120 °C
2
8
0%
We acknowledge financial support from the Research Funds for the
Shaanxi University of Chinese Medicine (2016PY19), Youth Talent
Support Project of Shaanxi Association for Science and Technology
1a
2a
3aa
Scheme 1 Research on the reaction mechanism
(20170406). University Students’ Innovative Undertaking of Shaanxi
Province (201823033), University Students’ Innovative Undertaking
of Shaanxi University of Chinese Medicine (201807028), the Chinese
Medicine Project of Shaanxi Province (ZYMS005) and the National
Based on previous literature reports and on the results
of the above control experiments, a plausible mechanism
for the formation of pyrido[1,2-a]benzimidazole is depicted
in Scheme 2. The reaction is initiated by the Chan–Lam cou-
Natural Science Foundation of China (81001669).
Y
o
uth
T
a
l
e
nt
S
u
p
p
ortPro
j
e
ctof
S
h
a
a
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x
iAso
c
i
ati
o
n
for
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
(2
0
1
7
0
4
0
6)T
h
e
N
ati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
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of
C
h
i
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a
(8
1
0
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1
6
6
9)T
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e
C
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iPro
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(Z
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nts’
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erat
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of
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F
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dsforth
e
S
h
a
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ersity of
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P
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1
9)
16,21
Supporting Information
pling
of the 2-aminopyridine and the phenylboronic
acid to give the intermediate N-(pyridin-2-yl)aniline A. The
copper(II) adduct B is then formed in the presence of
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611847.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
R2
NH2
B(OH)2
R1
R2
Cu(OAc)2 + O2
N
N
R1
N
N
[
O]
H
N
R2
R1
R2
R1
N
N
Cu
Cu(OAc)2
OCOCH3
A
E
–
CH3COOH
CH3COOH
O2, H
– H2O
R2
N
N
N
CH COOH
N
3
R2
R1
R2
R1
R1
N
N
CuII
Cu
– CH3COOH
Cu
H
OCOCH3
3
CH COO
B
C
D
Scheme 2 A plausible reaction mechanism
©
2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

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H. Yan et al.
Letter
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(
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Takahashi, H.; Takemura, M.; Kitamura, A.; Someya, K.;
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(20) Pyrido[1,2-a]benzimidazole (3aa); Typical Procedure
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An oven-dried Schlenk tube was charged with 2-aminopyridine
(
6) Ndakala, A. J.; Gessner, R. K.; Gitari, P. W.; October, N.; White, K.
L.; Hudson, A.; Fakorede, F.; Shackleford, D. M.; Kaiser, M.;
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(
1a; 0.32 mmol), PhB(OH)2 (2a; 0.38 mmol), and Cu(OAc)2 (29
mg, 0.16 mmol). The Schlenk tube was sealed and then evacu-
ated and backfilled with O2 (three cycles). DMSO (2 mL) was
added, and the mixture was stirred at 120 °C for 36 h then
cooled to r.t. The solvent was diluted with EtOAc (10 mL), and
the mixture was washed with brine (5 mL) then dried (Na SO )
4581.
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2
4
(
(
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9) (a) Qian, G.; Liu, B.; Tan, Q.; Zhang, S.; Xu, B. Eur. J. Org. Chem.
and concentrated under vacuum. The residue was purified by
column chromatography (silica gel, PE–EtOAc) to give a yellow
solid; yield: 43 mg (80%); mp 174–176 °C.
2
014, 4837. (b) Rao, D. N.; Rasheed, S.; Vishwakarma, R. A.; Ras,
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IR (neat): 3057, 3018, 1641, 1502, 1466, 1356, 1258, 1226,
(
(
(
(
–1 1
1
6
7
144, 756, 723 cm . H NMR (400 MHz, CDCl ):  = 8.42 (dd, J =
3
7
.8, 1.2 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H), 7.86 (d, J = 8.0 Hz, 1 H),
.68 (dd, J = 9.2, 0.8 Hz, 1 H), 7.54–7.51 (m, 1 H), 7.42–7.34 (m, 2
H), 6.82 (t, J = 6.8 Hz, 1 H). C NMR (100 MHz, CDCl ):  = 148.4,
13
3
12) Barolo, S. M.; Wang, Y.; Rossi, R. A.; Cuny, G. D. Tetrahedron
1
44.5, 129.2, 128.6, 125.6, 125.1, 120.9, 119.9, 118.0, 110.3,
2
013, 69, 5487.
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8, 3498.
+
110.2. HRMS (ESI): m/z [M + H] calcd for C11H N : 169.0760;
9
2
found: 169.0757.
6
(
21) Han, Y.; Zhang, M.; Zhang, Y.-Q.; Zhang, Z.-H. Green Chem. 2018,
0, 4891.
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b) Zhang, M. Appl. Organomet. Chem. 2010, 24, 269. (c) King, A.
(
(
(
14) Liang, D.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2013, 15, 3476.
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dron Lett. 2015, 56, 4843.
2
(
(
E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S.
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2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E