Efficient pyrido[1,2-a]benzimidazole formation from 2-aminopyridines and cyclohexanones under metal-free conditions

Article abstract of DOI:10.1039/c5gc01978h

An efficient procedure for pyrido[1,2-a]benzimidazole preparation from 2-aminopyridines and cyclohexanones under metal-free conditions is described. Non-aromatic cyclohexanones were used as the aryl source via a dehydrogenation-aromatization process using molecular oxygen as the green oxidant.

Full text of DOI:10.1039/c5gc01978h

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DOI: 10.1039/C5GC01978H
Green Chemistry
COMMUNICATION
Efficient pyrido[1,2-a]benzimidazole formation from 2-
aminopyridines and cyclohexanones under metal-free conditions
Yanjun Xie,a Jun Wu,a Xingzong Che,a Ya Chen,a Huawen Huanga and Guo-Jun Deng*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient procedure for pyrido[1,2-a]benzimidazole prepara- manner of coupling partners (Scheme 2). The first route is mainly
tion from 2-aminopyridines and cyclohexanones under metal- based the transition-metal-catalyzed one-pot nucleophilic substitu-
free conditions is described. Non-aromatic cyclohexanones were tion of 2-aminopyridines with ortho-dihalo arenes (Scheme 2, eqn
used as aryl source via dehydrogenation-aromatization process 1).6 The copper-catalyzed cascade C–N coupling of 2-halo anilines
using molecular oxygen as the green oxidant.
with 2-halo pyridines provided an alternative synthetic route
(Scheme 2, eqn 2).7 The third approach mainly based on the in-
tramolecular cyclization of N-aryl-2-aminopyridines or N-benzyl-2-
aminopyridines (Scheme 2, eqn 3).8 Very recently, Antonchick and
co-worker developed a metal-free annulation of arenes with 2-
aminopyridine derivatives using PhI(OAc)2 as the effective promoter
(Scheme 2, eqn 4).9 This strategy provided a straightforward access
to pyrido[1,2- a]benzimizazole scaffold by avoiding functionaliza-
tion of the aromatic substrates. All of these methods which are
based on using two aromatic substrates have proven to be effective
for the preparation of various substituted pyrido[1,2-
a]benzimidazoles. However, as comparing with the extensively in-
vestigated imidazo[1,2-a]pyridines which have two aromatic rings,10
environmentally benign and efficient synthetic routes for pyrido[1,2-
a]benzimidazoles are still limited.
Nitrogen-containing heterocycles are frequently found in natu-
ral products, pharmaceutical drugs, agrochemicals and func-
tional materials.1 Among them, pyrido[1,2-
a]benzimidazoles
which consist of three aromatic rings showed great potential as
important drug candidates. For example, Rifaximin which
widely used as antibiotic drug contains
]benzimidazole moiety.2 Other pyrido[1,2-
derivatives such as compounds have been reported to pos-
a
pyrido[1,2-
a
a]benzimidazole
a-c
sess antifungal activity via inhibition of β-1,6-glucan synthe-
sis,3 anticancer properties,4 and antimalarial activity through
inhibition of Plasmodium species,5 respectively (Scheme 1).
Et2N
Me2N
Cl
NH
Cl
Previous work: from two aromatic coupling partners
N
N
N
N
N
N
R1
R2
CN
+
N
N
NH2
CF3
CN
a
c
b
(4)
R1
R2
H
N
Scheme 1 Selected important biologically active heterocycles contain-
ing pyrido[1,2- ]benzimidazole moiety.
N
+
NH2
R2
N
(1)
(3)
n
R1
a
X
Y
N
R2
R1
N
X
n = 0, 1
X = H, Cl, Br, I
(2)
+
Because of their important value in pharmaceuticals and ma-
terial chemistry, the synthesis of pyrido[1,2- ]benzimidazole
X = Cl, Br, I
Y = Cl, Br, I
X
Y
a
R2
R1
X = Br, I
Y = Br, I
and its derivatives has attracted considerable interest. In general,
four efficient synthetic routes were developed according to the
N
NH2
This work
N
O
I2
O2
R1
R2
+
N
R2
R1
a. Key Laboratory of Environmentally Friendly Chemistry and Application of Minis-
try of Education, College of Chemistry, Xiangtan University, Xiangtan 411105,
China; Fax: (+86)0731-5829-2251; Tel: (+86)0731-5829-8601; E-mail:
gjdeng@xtu.edu.cn
N
NH2
Metal fr ee!
Oxygen as oxidant!
Cy clohexanones as ar y sour ce!
b. Key Laboratory of Molecular Recognition and Function, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China.
Electronic Supplementary Information (ESI) available: [details of any supplemen-
tary information available should be included here]. See DOI: 10.1039/x0xx00000x
Scheme 2 Various procedures for pyrido[1,2-a]benzimidazole synthesis.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
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Cyclohexanones are commercially available, stable and the presence of KI (entry 2). Several iodide-containing chemi-
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widely used as raw materials to prepare many important bulk cals were then investigated, and I2 provedDOtoI: 1b0e.10th39e/Cm5oGsCt0e1f9f7e8cH-
chemicals including aromatic phenols.11 Recently, the Stahl tive for this kind of transformation (entry 3). The amount of
group developed a strategy to selective convert cyclohexanones iodide-containing chemical is crucial to the reaction yield, and
into phenols or cyclohexenones using Pd as the catalyst under the desired product could be obtained in 92% yield when 0.2
mild reaction conditions.12 We and others successfully trapped mmol of I2 was used (entry 6). Besides 1,1,2,2-
the dehydrogenation intermediates for further construction of tetrachloroethane, lower yield was obtained when the reaction
C-C,13 C-N,14 C-O,15 C-S16 bonds as well as heterocycles17 un- was carried out in other organic solvents such as toluene, di-
der oxidative conditions. In these transformations, cyclohexa- glyme, ortho-dichlorobenzene, 1,2-dichloroethane and NMP
nones were used as a versatile aryl source via a dehydrogena- (entries 8-12). The reaction yield was reduced to 76% when the
o
tion–tautomerization sequence.18 Based on our previous re- reaction temperature was decreased to 150 C (entry 14). Oxy-
search, we envision that it might be possible to prepare the bio- gen was necessary and much lower yield was obtained when
logically important nitrogen-containing imidazopyridines using the reaction was carried out in air (entry 15).
cyclohexanones as the aryl source. Herein, we report a novel
strategy for one-pot pyrido[1,2-a]benzimidazole formation Table 2 Reaction of 1a with various cyclohexanones (2)
a
from 2-aminopyridines and cyclohexanones under metal-free
conditions using oxygen as the oxidant.19
N
I
2 (1 equiv)
O
R1
+
N
Cl2CHCHCl2
160 oC, O2
R1
N
1a
NH2
Table 1 Optimization of the reaction conditionsa
2
3
N
O
additive
+
yieldb (%)
entry
product
cyclohexanone
O
N
solvent
N
NH2
N
1a
2a
3a
N
R1
R1
yield (%)b
entry
additive (equiv)
solvent
1
R1 = H
2a
3a
3b
88 (78)c
1
2
1,1,2,2- tetrachloroethane
1,1,2,2- tetrachloroethane
trace
31
R1 = Me
R1 = Et
89
87
84
2b
2
3
4
KI (0.5)
I2 (0.5)
2c
2d
3c
3d
3
1,1,2,2- tetrachloroethane
48
R1 = propyl
4
5
NaI (0.5)
I2 (0.2)
I2 (1.0)
1,1,2,2- tetrachloroethane
1,1,2,2- tetrachloroethane
27
23
R1 = isopropyl
R1 = tert-butyl
R1 = n-pentyl
5
6
7
2e
2f
3e
3f
83
83
86
6
7
8
1,1,2,2- tetrachloroethane
1,1,2,2- tetrachloroethane
toluene
92
88
49
I2 (1.5)
I2 (1.0)
2g
2h
3g
3h
R1 = tert-pentyl
8
68
88
83
I2 (1.0)
I2 (1.0)
I2 (1.0)
9
diglyme
25
R1 = Ph
R1 = CO2Et
O
9
2i
2j
3i
3j
N
10
11
o-DCB
70
79
10
DCE
12
I2 (1.0)
I2 (1.0)
NMP
54
73
76
64
11
12
2k
2l
3k
N
13c
14d
1,1,2,2- tetrachloroethane
1,1,2,2- tetrachloroethane
I2 (1.0)
I2 (1.0)
O
15e
1,1,2,2- tetrachloroethane
21
3a
76
Cl
a Conditions: 1a (0.2 mmol), 2a (0.3 mmol), solvent (0.9 mL), 160 oC,
N
c
24 h under oxygen unless otherwise noted. b GC yield based on 1a.
88
(3m:3m'
=3:2)
N
N
0.2 mmol of 2a was used. d At 150 oC, e 24 h under air.
O
3m
13
2m
N
To get the optimized reaction conditions, we chose 2-
aminopyridine (1a) and cyclohexanone (2a) as the model reac-
tion in the absence of metal catalyst under an oxygen atmos-
phere (Table 1). When the reaction of 2-aminopyridine with 1.5
equiv. of cyclohexanone was performed in the absence of io-
3m'
a
Conditions: 1a (0.2 mmol), 2 (0.3 mmol), I2 (1.0 equiv.), 1,1,2,2-
tetrachloroethane (0.9 mL), 160 oC, 24 h under oxygen. b Isolated
yields based on 1a. c Ten mmol scale reaction yield in parenthesis.
o
dide-containing additive in 1,1,2,2-tetrachloroethane at 160 C,
no desired 3a was formed as determined by GC-MS and H
1
NMR methods (entry 1). Gratifyingly, the starting materials
were transformed into the desired product 3a in 31% yield in
2 | J. Name., 2012, 00, 1‐3
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Journal Name
With the optimized reaction conditions in hand, we then in-
COMMUNICATION
To further explore the scope of the reaction, VaiewnAurmticlbeeOrnlionef
DOI: 10.1039/C5GC01978H
vestigated the scope of the reaction with respect to 2- substituted 2-aminopyridine derivatives were employed to react
aminopyridine and various cyclohexanones (Table 2). The with cyclohexanone (Table 3). In general, good to excellent
model reaction of 1a with 1b gave the desired product 3a in yields were obtained under the standard reaction conditions.
88% isolated yield (Table 2, entry 1). When the same reaction Varying the position of the methyl substituent on 2-
was carried out on 10 mmol scale, 3a was obtained in 78% iso- aminopyridine had little effect on the outcome of the reaction
lated yield. Various 4-alkyl cyclohexanones smoothly reacted and the corresponding products 3n, 3o, 3p, and 3q were all
with 2-aminopyridine (1a) to give the corresponding products obtained in good yields. Halogen functional groups such as
in good yields (entries 2-8). The chain length of alky substitu- fluoro, chloro, bromo, and even iodo were well tolerated to give
ents did not make much difference on the reaction yields. The the corresponding products 3r-3v in good to high yields. Pyri-
desired product 3i was obtained in 88% yield when 4- dines bearing an electron-withdrawing trifluoromethyl group at
phenylcyclohexanone (2i) was treated with 2-aminopyridine different positions were smoothly reacted with 2a, affording the
(1a) under the optimized conditions (entry 9). To our delight, corresponding products 3w and 3x in 88% and 90% yields,
active ester group was well tolerated to afford the correspond- respectively. Finally, it was found that di-substituted 2-
ing product 3j in 83% yield (entry 10). A relatively lower yield aminopyridine with chloro and trifluoromethyl groups was
of 3k (64%) was obtained when a methyl group was located at good substrate for this kind of transformation to give the de-
the ortho position of cyclohexanone due to the steric effect (en- sired product 3y in 92% yield.
try 11). When 2-chlorocyclohexanone (2l) was employed as the
H
substrate, 3a was obtained in 76% yield and no chloro-
containing product (3l) could be observed (entry 12). When the
methyl group was located at the meta position, a mixture of two
isomers was isolated in a combined yield of 88% with a ratio of
3:2 (entry 13).
standard
conditions
N
N
(a)
N
N
3a
N-phenylpyridin-2-amine
not observed
N
standard
conditions
O
(b)
1a
+
a
N
Table 3 Reaction of 2a with various 2-aminopyridines (1)
Cl
3a,
76 %
N
I
2 (1 equiv)
O
R2
R2
O
N
I
+
N
path a
Cl2CHCHCl2
160 oC, O2
N
NH2
N
I2
O
2a
3a
[O]
A
1
2a
3
1a
path b
1a - I-
- H2O
N
N
N
N
N
+
N
N
N
N
- H2O, -H+
N
NH2
N
O
C
D
B
3n
3o
3p
, 80%
, 83%
N
, 85%
H+
- HI
H
N
N
N
N
N
N
N
I2
H+
NH
- HI
N
N
N
I
F
I
Cl
E
F
G
3q, 78%
3r, 80%
3s, 88%
Scheme 3 Control experiments and plausible reaction pathway.
To have a better understanding of the reaction, a control ex-
N
N
N
N
periment was performed. When
N-phenylpyridine-2-amine
N
N
Br
I
Br
which is a possible intermediate to give the final product via
intramolecular Csp2-H amination reaction was treated under the
standard reaction conditions, no desired product 3a could be
obtained (Scheme 3a). This means the biaryl intermediate was
not formed during the reaction process. As we previously men-
3t, 82%
3u, 78%
3v, 77%
CF3
Cl
N
N
N
N
tioned, 3a was obtained when 2-chlorocyclohexanone (2l
)
F3C
N
N
F3C
reacted with 1a (Scheme 3b). This means the cyclohexanones
may be iodinated firstly. Based on these observations and our
previous research, the plausible reaction pathway is illustrated
in Scheme 3. Cyclohexanone 2a is iodinated with iodine to give
3w, 88%
3x, 90%
3y, 92%
a
1
2a
(0.3 mmol), I2 (1.0 equiv.), 1,1,2,2-
Conditions: (0.2 mmol),
tetrachloroethane (0.9 mL), 160 oC, 24 h under oxygen, isolated
2-iodocyclohexanone (
aminopyridine (1a) with
quent tntramolecular cyclization of
tetrahydrobenzo[4,5]imidazo[1,2- ]pyridine (
A
).17b, 17e Nucleophilic substitution of 2-
affords an intermediate B 20
Subse-
provides 6,7,8,9-
). Alternatively,
1
.
yields based on
A
.
B
a
C
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condensation of 1a with 2a affords an imine intermediate D 21
which can be further converted into intermediate via isomeri-
sation reaction. Iodination of with iodine generates com-
pound F, which can further isomerize into intermediate . In-
tramolecular substitution of the iodo group with amine also
provides . Dehydrogenation-tautomerization of under oxi-
dative and acidic conditions affords the final product 3a 17, 22, 23
,
T. R. M. Rauws, A. K. Yadav, W. A. Herrebout, B. Van der
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Conclusions
10 For a selected review on imidazo[1,2-a]pyridine synthesis,
In summary, we have developed a novel approach for the
synthesis of nitrogen-containing pyrido[1,2-a]benzimidazoles
see: A. K. Bagdi, S. Santra, K. Monir and A. Hajra, Chem.
Commun., 2015, 51, 1555.
from 2-aminopyridines and cyclohexanones under metal-free
conditions. Iodine could smoothly mediate this kind of trans-
formation without the aid of metal catalyst. Oxygen was used
as an environmentally benign oxidant to give the corresponding
products in good to high yields. The reaction showed good sub-
strate scope and various functional groups such alkyl, ester, and
halogens were well tolerated under the optimized reaction con-
ditions. This method affords an efficient approach for biologi-
cally active nitrogen-containing heterocycles using non-
aromatic cyclohexanones as the aryl source. The mechanism
and synthetic applications of this reaction are under investiga-
tion.
11 (
mann’s Encyclopedia of Industrial Chemistry; Wiley-VCH:
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Acknowledgements
(d
This work was supported by the National Natural Science Founda-
tion of China (21572194, 21372187), the Research Fund for the
Doctoral Program of Higher Education of China, Ministry of Educa-
tion of China (20124301110005) and the Hunan Provincial Innova-
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19 There was only one report on studying the reaction of 2-
aminopyridine with 2-chlorocyclohexanone affording 6,7,8,9-
tetrahydrobenzo[4,5]imidazo[1,2-
high temperature (300 oC) was required to convert
pyrido[1,2- ]benzimidazole using Pd/C as the catalyst. N.
Campbell and E. B. McCall, J. Chem. Soc., 1951, 2411.
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C
). However,
C
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,
1999, 1501.
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8
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Green Chemistry
View Article Online
DOI: 10.1039/C5GC01978H
Efficient
pyrido[1,2-a]benzimidazole
formation
from
2-aminopyridines and cyclohexanones under metal-free conditions
Yanjun Xie,a Jun Wu,a Xingzong Che,a Ya Chen,a Huawen Huanga and Guo-Jun
Denga,b *
Pyrido[1,2-a]benzimidazole derivatives were selectively prepared from
2-aminopyridines and cyclohexanones under metal free conditions.