Copper-catalyzed cascade synthesis of benzimidazoquinazoline derivatives under mild condition

Article abstract of DOI:10.1039/c1cc10383k

A convenient and efficient copper-catalyzed cascade method has been developed for the synthesis of benzimidazoquinazoline derivatives via reactions of readily available substituted 2-(2-halophenyl)benzoimidazoles with amidines or guanidine under mild conditions (even at room temperature).

Full text of DOI:10.1039/c1cc10383k

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COMMUNICATION
Copper-catalyzed cascade synthesis of benzimidazoquinazoline derivatives
under mild conditionw
Shan Xu, Juyou Lu and Hua Fu*
Received 20th January 2011, Accepted 7th March 2011
DOI: 10.1039/c1cc10383k
A convenient and efficient copper-catalyzed cascade method has
been developed for the synthesis of benzimidazoquinazoline
derivatives via reactions of readily available substituted
2-(2-halophenyl)benzoimidazoles with amidines or guanidine
under mild conditions (even at room temperature).
or difficult to prepare, which greatly impedes discovery of
more potent biologically active molecules.
Recently, there has been great progress in copper-catalyzed
cross couplings,17 and some N-heterocycles have been constructed
via copper-catalyzed cross couplings by other research
groups18 and us.19 Herein, we report a convenient and efficient
copper-catalyzed cascade synthesis of benzimidazoquinazoline
derivatives under mild conditions.
Nitrogen-containing heterocycles widely occur in natural
products and biologically active molecules.1 For example,
benzimidazoles are often used as enzyme inhibitors2 and
drugs.3 Quinazolines also show various biological and
medicinal properties, they act as potent tyrosine kinase
and cellular phosphorylation inhibitors,4 ligands for benzo-
diazepine and GABA receptors in the central nervous system5
or as DNA binders,6 and some of them show remarkable
activity as anticancer,7 antiviral,8 and antitubercular agents.9
The combined molecules of benzimidazole and quinazoline
frameworks, benzimidazoquinazoline derivatives (Fig. 1), are
valuable substrates with various biological activities, and they
exhibit a wide range of therapeutic activities, such as
anticancer,10 antiviral,11,12 antimicrobial,13 anti-inflammatory,11,14
and anticonvulsants.15 However, the methods for preparation
of benzimidazoquinazoline derivatives remain rare. In
previous routes,16 2-(2-aminophenyl)benzoimidazoles and
their precursors, 2-(2-nitrophenyl)benzoimidazoles, are often
used as the starting materials, and toxic isothiocyanates are
required for synthesis of benzimidazo[1,2-c]quinazolin-5-
amines.16c,d These methods show limited substrate scopes
because the used starting materials are not readily available
As shown in Table 1, 2-(2-bromophenyl)benzoimidazole
(1a) and benzamidine hydrochloride (2d) were used as the
model substrates to optimize reaction conditions including
catalysts, bases, solvents and temperature under nitrogen
Table
1 Copper-catalyzed cascade synthesis of 6-phenylbenzo-
[4,5]imidazo[1,2-c]quinazoline (3d) via reaction of 2-(2-bromophenyl)-
1H-benzo[d]imidazole (1a) with benzamidine hydrochloride (2d):
optimization of conditionsa
Temperature/ Yieldb/
Entry Catalyst
Base
Solvent
1C
%
1
2
3
4
5
6
7
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3 DMF
K2CO3 DMF
K3PO4 DMF
K3PO4 DMSO
K3PO4 DMSO
K3PO4 DMSO
K3PO4 DMSO :
60
60
60
60
40
25
25
54
64
71
81
84
68
83
CH2Cl2 = 2 : 1
K3PO4 DMSO :
CH2Cl2 = 3 : 1
K3PO4 DMSO :
CH2Cl2 = 3 : 1
K3PO4 DMSO :
CH2Cl2 = 3 : 1
Cu(OAc)2 K3PO4 DMSO :
CH2Cl2 = 3 : 1
K3PO4 DMSO :
CH2Cl2 = 3 : 1
K3PO4 DMSO :
CH2Cl2 = 3 : 1
8
CuI
25
25
25
25
25
25
86
42
13
54
65
0c
9
CuBr
Cu2O
10
11
12
13
Fig. 1 Structure of benzimidazoquinazoline containing quinazoline
and benzoimidazole framework.
Cu
—
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
w Electronic supplementary information (ESI) available: General
procedure for synthesis, characterization data and 1H and 13C NMR
spectra of compounds 3a–s. See DOI: 10.1039/c1cc10383k
a
Reaction condition: 2-(2-bromophenyl)-1H-benzo[d]imidazole (1a)
(0.5 mmol), benzamidine hydrochloride (2d) (0.75 mmol), catalyst
(0.05 mmol), base (1.5 mmol), solvent (2 mL) under nitrogen atmo-
b
c
sphere, reaction time (16 h). Isolated yield. No addition of catalyst.
c
5596 Chem. Commun., 2011, 47, 5596–5598
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atmosphere. First, bases (3 equiv) were investigated by using
0.1 equiv of CuI as the catalyst (relative to amount of 1a), and
DMF as the solvent at 60 1C (Table 1 entries 1–3), and K3PO4
produced the highest yield (Table 1 entry 3). A higher yield
(81%) was afforded when DMSO replaced DMF as the
solvent (Table 1 entry 4). The yield rose when temperature
decreased to 40 1C from 60 1C (Table 1 entry 5). However, a
68% yield was produced at room temperature (B25 1C)
(Table 1 entry 6), we observed that part of product 3d was
not dissolved in DMSO at this temperature, so small amount
of CH2Cl2 was added in order to improve dissolving power of
the product (Table 1 entries 7 and 8). We were pleased to find
that yields remarkably increased (compare Table 1 entries 6–8).
Other copper catalysts were screened (Table 1 entries 9–12), and
CuI was proven to be the most effective catalyst for this cascade
reaction (compare Table 1 entries 8–12). No target product was
observed in the absence of copper-catalyst (Table 1 entry 13).
The scope of copper-catalyzed cascade synthesis of benzi-
midazoquinazoline derivatives from reactions of substituted
2-(2-halophenyl)benzoimidazoles with amidines or guanidine
was investigated under the optimized conditions (10 mol%
CuI as the catalyst, 3 equiv of K3PO4 as the base under
nitrogen atmosphere). As shown in Table 2, most of the tested
substrates afforded good to excellent yields. For the
substituted 2-(2-halophenyl)benzoimidazoles, their relative
reactivity was in the order of aryl bromides 4 aryl chlorides
(compare Table 2 entries 1–17 and 18–22). Substituted
2-(2-bromophenyl)benzoimidazoles worked very well at room
temperature (Table 2 entries 1–17), and 2-(2-chlorophenyl)-
benzoimidazole also provided moderate to good yields when
the reaction temperature was raised to 100 1C (Table 2 entries
18–23), which showed ortho-substituent effect of benzoimid-
azole group during N-arylation (see Scheme 1) because aryl
chlorides were weak substrates in the previous copper-
catalyzed coupling reactions.17 The reactions above did not
need aid of any ligand or additive, and the result also showed
ortho-substituent effect of benzoimidazole group. For amidines
and guanidine, amidines exhibited better reactivity than
guanidine, and guanidine afforded benzimidazo[1,2-c]quinazolin-
5-amine derivatives in good yields when the temperature
rose (Table 2 entries 23–25). The method for synthesis of
benzimidazo[1,2-c]quinazolin-5-amine derivatives avoided use
of the toxic isothiocyanates used in previous routes.16c,d The
reactions above did not show an obvious difference for the
electronic effect in the substrates.
Table 2 Copper-catalyzed cascade synthesis of benzimidazoquin-
azoline derivativesa
3 (X, Yieldb)
3 (X, Yieldb)
In the cascade reactions above, no ligand or additive were
required, and the result showed the ortho-substituent effect20
of benzoimidazole group. Therefore, a possible mechanism for
synthesis of benzimidazoquinazoline derivatives is proposed in
Scheme 1. Firstly, coordination of substituted 2-(2-halophenyl)-
benzoimidazole with CuI gives I, and oxidative addition of I
leads to II. N-Arylation of II with amidine provides inter-
mediate III (see Supporting Information for the experimental
evidencew), and the intramolecular nucleophilic attack of NH
in benzoimidazole group to carbon in amidine or guanidine
affords the target product (3) releasing NH3.
In summary, we have developed an efficient copper-
catalyzed cascade method for the synthesis of benzimid-
azoquinazoline derivatives. The protocol uses inexpensive
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5596–5598 5597

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Table 2 (continued )
3 (X, Yieldb)
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a
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DMSO and 0.5 mL of CH2Cl2 for entries 1–17; 2 mL of DMSO for
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´
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Scheme 1 Possible copper-catalyzed mechanism for synthesis of
benzimidazoquinazoline derivatives.
CuI as the catalyst, readily available substituted 2-(2-halophenyl)-
benzoimidazoles (from reactions of substituted benzene-1,2-
diamines with 2-haloobenzoic acids in acid medium21),
amidines and guanidine as the starting materials, reactions
of substituted 2-(2-bromophenyl)benzoimidazoles with amidines
worked very well at room temperature, and 2-(2-chlorophenyl)-
benzoimidazole and guanidine were also good substrates at
80 or 100 1C. Benzimidazoquinazoline and benzimidazo[1,2-c]-
quinazolin-5-amine derivatives were obtained in good to
excellent yields.
19 Selected papers (a) F. Wang, H. Liu, H. Fu, Y. Jiang and Y. Zhao,
Org. Lett., 2009, 11, 2469; (b) X. Liu, H. Fu, Y. Jiang and and
Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348.
The authors wish to thank the National Natural Science
Foundation of China (Grant No. 20972083), and the Ministry
of Science and Technology of China (2009ZX09501-004) for
financial support.
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¨
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Notes and references
1 (a) J. K. Landquist, in Comprehensive Heterocyclic Chemistry,
ed. A. R. Katritzky and C. W. Rees, Pergamon, New York,
c
5598 Chem. Commun., 2011, 47, 5596–5598
This journal is The Royal Society of Chemistry 2011