Concise copper-catalyzed one-pot tandem synthesis of benzimidazo[1,2-b] isoquinolin-11-one derivatives

Article abstract of DOI:10.1039/c0cc00185f

A simple and efficient copper-catalyzed one-pot tandem method has been developed for synthesis of benzimidazo[1,2-b]isoquinolin-11-one derivatives via reactions of substituted 2-halo-N-(2-halophenyl)benzamides with alkyl 2-cyanoacetates or malononitrile under mild conditions.

Full text of DOI:10.1039/c0cc00185f

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Concise copper-catalyzed one-pot tandem synthesis
of benzimidazo[1,2-b]isoquinolin-11-one derivativesw
Juyou Lu, Xiaoyu Gong, Haijun Yang and Hua Fu*
Received 2nd March 2010, Accepted 9th April 2010
First published as an Advance Article on the web 10th May 2010
DOI: 10.1039/c0cc00185f
A simple and efficient copper-catalyzed one-pot tandem method
has been developed for synthesis of benzimidazo[1,2-b]isoquinolin-
11-one derivatives via reactions of substituted 2-halo-N-(2-
halophenyl)benzamides with alkyl 2-cyanoacetates or malononitrile
under mild conditions.
Table 1 Copper-catalyzed one-pot tandem synthesis of ethyl benzi-
midazo[1,2-b]isoquinolin-11-one-6-carboxylate (3a) via coupling of
2-bromo-N-(2-bromophenyl)benzamide (1a) with ethyl 2-cyanoacetate
(2a): optimization of conditionsa
Nitrogen-containing heterocyclic compounds in the form of
biologically active drugs or agents play an important role in
the pharmaceutical and agrochemical industries.1 Benzimidazoles
have attracted much attention for their wide applications as
enzyme inhibitors,2 drugs,3 dyes,4 and polymers.5 Isoquinolin-
1(2H)-one derivatives are found in natural products,6 and they
are also versatile building blocks for the total synthesis of
natural alkaloids.7 Isoquinolin-1(2H)-ones exhibit various
biological and medicinal activities such as antihypertensive
activity,8a,b as NK3 antagonists,8c melatonin MT1 and MT2
receptor agonists,8d Rho-kinase inhibitors,8e and JNK inhibitors.8f
Some of them are also used as novel orally active 5-HT3
antagonists,9a thymidylate synthase (TS) inhibitors,9b or for
the treatment of stomach tumors and diseases of human
brain cells.6b The combined molecules of benzimidazole
and isoquinolinone frameworks, benzimidazoisoquinolinone
derivatives (Fig. 1), are valuable substrates for the synthesis of
biologically active compounds with structural features different
from those of existing drugs, and some of them are potent anti-
Trypanosoma cruzi agents.10 However, the methods for their
preparation remain rare, and some starting materials are not
readily available or difficult to prepare by the previous routes.10,11
Recently, great progress in copper-catalyzed cross couplings
has been made,12 and we have also developed some copper-
catalyst systems that were used in the coupling reactions.13 Some
N-heterocycles have been constructed via the copper-catalyzed
Entry
Cat.
Base
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
CuI
CuI
CuI
CuBr
CuCl
Cu2O
—
CuCl
CuCl
CuCl
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
K3PO4
Cs2CO3
DMF
65
70
Trace
41
85
DMSO
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
56
0c
90
82
84
a
Reaction conditions: 2-bromo-N-(2-bromophenyl)benzamide (1a)
(0.2 mmol), ethyl 2-cyanoacetate (2a) (0.24 mmol), catalyst (0.02 mmol),
base (0.4 mmol), solvent (2 mL) under nitrogen atmosphere, reaction
b
c
temperature (60 1C), reaction time (12 h). Isolated yield. No
addition of catalyst.
cross couplings by us14 and other research groups.15 Herein, we
report a concise copper-catalyzed one-pot tandem synthesis of
benzimidazo[1,2-b]isoquinolin-11-one derivatives from reactions
of substituted 2-halo-N-(2-halophenyl)benzamides with alkyl
2-cyanoacetates or malononitrile under mild conditions.
As shown in Table 1, 2-bromo-N-(2-bromophenyl)benzamide
(1a) and ethyl 2-cyanoacetate (2a) were chosen as the model
substrates to optimize reaction conditions including catalysts,
bases, solvents and temperature under nitrogen atmosphere.
First, solvents were investigated by using 0.1 equiv. of CuI as
the catalyst and 2 equiv. of K2CO3 as the base (relative to
amount of 1a) (entries 1–3), and DMSO provided the highest
yield (entry 2). Several copper catalysts were screened
(compare entries 2, 4–6), and CuCl was proven to be the most
effective catalyst for this tandem reaction (entry 5). No target
product was observed in the absence of catalyst (entry 7).
Other bases, Na2CO3, K3PO4, Cs2CO3, were tested at 60 1C
(entries 8–10), and the results showed that Na2CO3 provided
the highest yield (entry 8).
Fig. 1 Structure of benzimidazoisoquinolinone containing benzimi-
dazole and isoquinolinone framework.
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China.
E-mail: fuhua@mail.tsinghua.edu.cn; Fax: +86 10 62781695;
Tel: +86 10 62797186
The scope of copper-catalyzed one-pot tandem synthesis of
benzimidazo[1,2-b]isoquinolin-11-one derivatives from reactions
of substituted 2-halo-N-(2-halophenyl)benzamides with alkyl
2-cyanoacetates or malononitrile was investigated under the
optimized conditions (10 mol% CuCl as the catalyst, 2 equiv.
of Na2CO3 as the base, DMSO as the solvent at 60–100 1C
w Electronic supplementary information (ESI) available: General
procedure for synthesis of compounds 3a–q, 5 and 7, characterization
1
data for compounds 3a–q, 5 and 7, and H and 13C NMR spectra of
compounds 3a–q, 5 and 7. See DOI: 10.1039/c0cc00185f
ꢀc
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Table 2 (continued)
Table 2 Copper-catalyzed one-pot tandem synthesis of benzimidazo-
[1,2-b]isoquinolin-11-one derivativesa
Entry
1
3
Yield (%)b
69
14
1d
15
16
17
72
81
70
Entry
1
1
3
Yield (%)b
1e
1e
90
2
1a
87
3
4
5
1a
1a
87
85
91
18
19
20
3a
3d
3a
3d
82
71
75
70
1f
21
1g
a
Reaction conditions: under nitrogen atmosphere, 1 (0.2 mmol),
2 (0.24 mmol), CuCl (0.02 mmol), Na2CO3 (0.4 mmol), DMSO
(2 mL), reaction temperature (60 1C for entries 1–8, 80 1C for entries
b
9–17; 100 1C for entries 18–21), reaction time (12 h). Isolated yield.
6
1b
89
under nitrogen atmosphere). As shown in Table 2, most of the
substrates examined provided good yields. For the substituted
2-halo-N-(2-halophenyl)benzamides, aryl bromides showed
higher reactivity than aryl chlorides (compare entries 1–4,
18–21). For N-(2-bromophenyl)-2-chlorobenzamide and
2-bromo-N-(2-chlorophenyl)benzamide, the target products
were also provided in good yields when reaction temperature
was raised to 100 1C (entries 18–21). In fact, the aryl chlorides
are weak substrates in the previous copper-catalyzed coupling
reactions,12 and the result above showed an ortho-substituent
effect of the amide group during C-arylations and N-arylations.
The reactions above did not need addition of any ligand or
additive, and the result also showed an ortho-substituent effect
of the amide group. In addition, the copper-catalyzed one-pot
tandem reactions could tolerate functional groups such as
ester, non-ortho-site C–Cl bond of the amides (entries 9–14).
In order to explore the copper-catalyzed one-pot tandem
synthetic mechanism of benzimidazo[1,2-b]isoquinolin-11-one
derivatives, the following control experiments were performed
under our standard conditions as shown in Scheme 1. Reaction
of 2-bromo-N-phenylbenzamide (4) with ethyl 2-cyanoacetate
(2a) provided product 5 in 87% yield (Scheme 1A). However,
treatment of N-(2-bromophenyl)benzamide (6) with 2-cyano-
acetate (2a) gave 2-phenylbenz[d]oxazole (7) in 81% yield
(Scheme 1B), and 2-cyanoacetate was not involved in the
coupling reaction. The result showed that the couplings of
substituted 2-halo-N-(2-halophenyl)benzamides with alkyl
7
8
9
1b
1b
63
80
81
10
11
12
1c
1c
65
65
78
13
1d
83
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1 Reactions of ethyl 2-cyanoacetate with 2-bromo-N-
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Scheme
2 Possible copper-catalyzed formation mechanism of
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2-cyanoacetates or malononitrile were initiated from the C–X
bond at the ortho-site of carbonyl of amide in 1. Therefore, a
possible formation mechanism of benzimidazo[1,2-b]isoquinolin-
11-one derivatives is proposed in Scheme 2 according to the
ortho-substituent effect of the Ullmann coupling reaction.14b–e,16
Firstly, copper-catalyzed Ullmann-type coupling of substituted
2-halo-N-(2-halophenyl)benzamide with alkyl 2-cyanoacetate
(C-arylation of alkyl 2-cyanoacetate) provides I in the
presence of base (Na2CO3), base-promoted nucleophilic attack
of the nitrogen in the amide of I yields II, and transfer of
double bond in II affords III. Finally, copper-catalyzed intra-
molecular N-arylation of III provides the target products 3.
In summary, we have developed a simple and efficient
copper-catalyzed one-pot tandem method for synthesis of
benzimidazo[1,2-b]isoquinolin-11-one derivatives. The couplings
of substituted 2-halo-N-(2-halophenyl)benzamides with alkyl
2-cyanoacetates or malononitrile were performed well under
mild conditions without addition of any ligand or additive.
The present method shows economical, practical and starting
material readily available advantages over the previous methods,
so it will provide a new strategy for construction of diverse and
useful nitrogen-containing heterocyclic compounds for organic
chemistry and medicinal chemistry.
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Financial support was provided by the National Natural
Science Foundation of China (Grant No. 20672065,
20972083), Chinese 863 Project (Grant No. 2007AA02Z160)
and the Key Subject Foundation from Beijing Department of
Education (XK100030514).
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This journal is The Royal Society of Chemistry 2010
4174 | Chem. Commun., 2010, 46, 4172–4174