An efficient and facile synthesis of benzimidazo[1,2-a]benzimidazoles via copper-catalyzed domino addition/double cyclization

Article abstract of DOI:10.1039/c4ra01181c

A copper-catalyzed synthesis of benzimidazo[1,2-a]benzimidazoles by domino addition/double cyclization of bis-(o-haloaryl)carbodiimides with primary amines was developed. A variety of the desired polycyclic benzimidazoles were efficiently and facilely assembled. Multibonds and polycyclic moieties were directly constructed in one pot. 2-Bromo-2′-iodo-diarylcarbodiimides gave good selectivity. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra01181c

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
An efficient and facile synthesis of benzimidazo
[1,2-a]benzimidazoles via copper-catalyzed
domino addition/double cyclization†
Cite this: RSC Adv., 2014, 4, 21904
Received 10th February 2014
Accepted 30th April 2014
Guodong Yuan,‡ Haiquan Liu,‡ Jilong Gao, Hongjuan Xu, Liu Jiang, Xiaoxia Wang
*
and Xin Lv
DOI: 10.1039/c4ra01181c
www.rsc.org/advances
A copper-catalyzed synthesis of benzimidazo[1,2-a]benzimidazoles by report about the copper-catalyzed one-pot multi-bond forming
domino addition/double cyclization of bis-(o-haloaryl)carbodiimides assembly of benzimidazo[1,2-a]benzimidazoles. In continua-
with primary amines was developed. A variety of the desired polycyclic tion of our efforts to synthesize heterocycles using domino
benzimidazoles were efficiently and facilely assembled. Multibonds methods,10 we investigated the Cu-catalyzed domino
and polycyclic moieties were directly constructed in one pot. 2- approaches to benzimidazo[1,2-a]benzimidazoles from bis-
Bromo-20-iodo-diarylcarbodiimides gave good selectivity.
(o-haloaryl)carbodiimides11,12 and primary amines.
Initially,
2-bromo-N-(((2-iodophenyl)imino)methylene)-
aniline 1a and benzylamine 2a were chosen as the model
substrates. In a typical experiment, substrate 1a (0.5 mmol,
1 equiv.) was treated with 2a (0.55 mmol, 1.1 equiv.) in the
presence of CuI (10 mol%), 1,10-phen (monohydrate, 20 mol%),
The benzimidazole skeleton is found in many biologically active
natural products and pharmaceuticals.1 Polycyclic benzimid-
azole derivatives are of signicance in medicinal chemistry2 and
materials science.3 As a subclass of imidazobenzimidazoles,2b,4
benzimidazo[1,2-a]benzimidazoles may exhibit interesting
pharmaceutical and biological activities. These polycyclic
molecules have also attracted great interest in the eld of
electroluminescent devices.5
Table 1 Optimization of the reaction conditionsa
The common approaches to imidazobenzimidazoles usually
suffer from the drawbacks such as the use of special reagents,
tedious procedures, low efficiency, and/or the narrow applica-
tion scopes.2a,b,5a,6 Recently, Fu et al. found that the Cu-catalyzed
oxidative intramolecular C–H amination lead to imidazobenzi-
midazoles.7 The method was efficient and economical.
However, substituted 2-(1H-imidazol-1-yl)-N-alkylbenzenamines
should be prepared beforehand and high reaction temperature
Entry Catalyst Base
Solvent Ligand
Yieldb
1
2
3
4
5
6
7
8
Cul
Cs2CO3 Dioxane 1,10-Phen$H2O
Cs2CO3 Dioxane 1,10-Phen$H2O
Cs2CO3 Dioxane 1,10-Phen$H2O
Cs2CO3 Dioxane 1,10-Phen$H2O
Cs2CO3 Dioxane 1,10-Phen$H2O
K3PO4 Dioxane 1,10-Phen$H2O
Na2CO3 Dioxane 1,10-Phen$H2O
K2CO3 Dioxane 1,10-Phen$H2O
K3PO4 DMF
K3PO4 Toluene 1,10-Phen$H2O
K3PO4 MeCN 1,10-Phen$H2O
K3PO4 Dioxane L-Proline
87%
70%
90%
81%
Trace
95%
60%
73%
91%
88%
39%
40%
CuBr
CuCl
Cu2O
—
ꢀ
(155 C) was required.
Catalytic domino transformation is an efficient and conve-
nient strategy for the one-step assembly of molecular
complexity and diversity from readily available starting mate-
rials.8 Copper-catalyzed domino synthesis have received
considerable attention because of their low cost, high efficiency
and convenience.9 To the best of our knowledge, there is no
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
9
1,10-Phen$H2O
10
11
12
13
14
15
K3PO4 Dioxane 2-Piperidinecarboxylic acid 65%
K3PO4 Dioxane 2,20-Bipy
K3PO4 Dioxane
29%
75%
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College of
Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, People's
Republic of China. E-mail: lvxin@zjnu.cn
—
a
Reaction conditions: 2-bromo-N-(((2-iodophenyl)imino)methylene)-
aniline 1a (0.5 mmol, 1 equiv.), benzylamine 2a (0.55 mmol, 1.1
equiv.), Cu catalyst (0.05 mmol, 10 mol%), ligand (0.1 mmol, 20
mol%), and base (2 mmol, 4 equiv.), in solvent (3 mL), under nitrogen
atmosphere, at 100 ꢀC for 12 h. b Isolated yield.
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization and copies of NMR for all the key products. See DOI:
10.1039/c4ra01181c
‡ These authors contributed equally to this paper.
21904 | RSC Adv., 2014, 4, 21904–21908
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 2 Cu-catalyzed domino synthesis of benzimidazo[1,2-a]benzimidazolesa
Entry Carbodiimide 1
Amine 2
Product 3
Yieldb Entry Carbodiimide 1
Amine 2 Product 3
Yieldb
93%
1
95%
90%
11
12
2a
2
3
1a
1a
2d
2a
2a
84%c
55%c
87%c 13
4
5
1a
1a
90%c 14
96%
89%
88%c 15
1e
6
7
1a
1a
86%
88%
16
17
2a
2b
85%
83%
1f
8
9
1a
1a
1a
85%
86%
82%
18
19
20
2a
2a
2a
81%d
84%d
72%d
10
a
Reaction conditions: 1 (0.5 mmol, 1 equiv.), primary amine 2 (0.55 mmol, 1.1 equiv.), CuCl (0.05 mmol, 10 mol%), 1,10-phen$H2O (0.1 mmol, 20
mol%), and K3PO4 (2 mmol, 4 equiv.), in dioxane (3 mL), under nitrogen atmosphere, at 100 ꢀC for 12 h. Isolated yield. c For 24 h. For 18 h.
b
d
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 21904–21908 | 21905

View Article Online
RSC Advances
Communication
and K3PO4 (2 mmol, 4 equiv.) in dioxane at 100 ꢀC for 12 h. in Table 2, generally, both electron-donating and electron-
Encouragingly, the desired double-cyclized product 3a was withdrawing groups on the phenyl rings of bis-(o-haloaryl)car-
isolated in a good yield (Table 1, entry 1). Other copper catalysts bodiimides were well tolerated, and the desired double cyclized
such as CuBr, CuCl and Cu2O were then screened, and the best products were efficiently generated (Table 2, entries 1–12 and
result was obtained when CuCl was utilized as the catalyst 14–20). A range of the substrates including o-bromo-o0-iodo-
(Table 1, entries 2–4). Trace amount of the product was diphenylcarbodiimides (Table 2, entries 1–12), bis-(o-iodo-
observed in the absence of copper catalyst (Table 1, entry 5), phenyl)carbodiimides (Table 2, entries 14–17), and bis-(o-bro-
showing that the catalyst was indispensable for this reaction. mophenyl)carbodiimides (Table 2, entries 18–20) were
The effect of base was investigated (Table 1, entries 3 and 6–8), compatible with the reaction conditions, delivering the corre-
and K3PO4 turned out to be the optimal base (Table 1, entry 6). sponding benzimidazo[1,2-a]benzimidazoles in good to excel-
Different solvents were also examined for this domino trans- lent yields, though the reactions of the dibromides usually
formation (Table 1, entries 6 and 9–11). Dioxane, DMF and required a longer reaction time (Table 2, entries 18–20).
toluene were found to be suitable solvents (Table 1, entries 6, 9 However, the 2-bromo-N-(((2-iodophenyl)imino)methylene)
and 10), whereas dioxane showed to be superior to others (Table aniline with a strong electron-withdrawing group (NO2) on the
1, entry 6). Among the ligands tested for the reaction, 1,10-phen aromatic ring showed less reactive and furnished the product
exhibited the highest activity (Table 1, compare entry 6 with only in a moderate yield (Table 2, entry 13). A variety of primary
entries 12–14). Notably, 75% yield of the desired product was amines were also employed. Either aliphatic (including the
obtained in a control experiment without the addition of ligand benzylamines; Table 2, entries 1–6 and 11–20) or aromatic
(Table 1, entry 15), indicating that the addition intermediate primary amines (Table 2, entries 7–10) efficiently reacted with
itself might act as a ligand.
bis-(o-haloaryl)carbodiimides to afford the corresponding
We next investigated the reaction scope by varying bis- polycyclic benzimidazole derivatives. The anilines bearing
(o-haloaryl)carbodiimides and N-nucleophiles. As summarized electron-poor aromatic rings (Table 2, entries 8 and 10)
Scheme 1 The selective domino reactions of unsymmetrical bis-(o-haloaryl)carbodiimides with primary aliphatic amines.
Scheme 2 The proposed mechanism for the domino reaction of bis-(o-haloaryl)carbodiimide with primary amine.
21906 | RSC Adv., 2014, 4, 21904–21908
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
performed as well as those with electron-rich phenyl rings
(Table 2, entry 9). Notably, a heteroaromatic aniline could also
be successfully employed as the N-nucleophile (Table 2,
entry 10).
2010, 45, 463–470; (c) R. G. Fu, Q. D. You, L. Yang,
W. T. Wu, C. Jiang and X. L. Xu, Bioorg. Med. Chem., 2010,
18, 8035–8043; (d) R. Rohini, K. Shanker, P. M. Reddy,
Y. P. Ho and V. Ravinder, Eur. J. Med. Chem., 2009, 44,
3330–3339; (e) M. Hranjec, I. Piantanida, M. Kralj,
L. Suman, K. Pavelic and G. Karminski-Zamola, J. Med.
Chem., 2008, 51, 4899–4910.
3 For selected examples, see: (a) M. Mamada, C. Perez-Bolivar
and P. Anzenbacher, Org. Lett., 2011, 13, 4882–4885; (b)
R. P. Ortiz, H. Herrera, R. Blanco, H. Huang, A. Facchetti,
T. J. Marks, Y. Zheng and J. L. Segura, J. Am. Chem. Soc.,
2010, 132, 8440–8452; (c) P. Dhagat, H. M. Haverinen,
R. J. Kline, Y. Jung, D. A. Fischer, D. M. Delongchamp and
G. E. Jabbour, Adv. Funct. Mater., 2009, 19, 2365–2372.
4 For selected examples, see: (a) V. A. Anisimova, A. A. Spasov,
I. E. Tolpygin, V. I. Minkin, M. V. Chernikov, D. S. Yakovlev,
A. Y. Stukovina, I. I. Goryagin, O. Yu. Grechko, N. V. Kirillova,
V. A. Kosolapov, E. V. Tibir'kova, O. A. Salaznikova,
L. V. Naumenko and N. A. Gurova, Pharm. Chem. J., 2010,
44, 345–351; (b) V. A. Anisimova, A. A. Spasov,
V. A. Kosolapov, I. E. Tolpygin, V. I. Porotikov,
A. F. Kucheryavenko, V. A. Sysoeva, E. V. Tibir'kova and
L. V. El'tsova, Pharm. Chem. J., 2009, 43, 491–494.
As shown in Scheme 1, excellent selectivity was achieved
during our research. It was noticeable that the reaction of
unsymmetrical 2-bromo-20-iodo-diphenylcarbodiimide gave the
polycyclic products with good to exclusive selectivity.
A possible pathway to the benzimidazo[1,2-a]benzimidazole
from the reaction of bis-(o-haloaryl)carbodiimide with primary
amine was shown in Scheme 2. The nucleophilic addition of
primary amine 2 to carbodiimide 1 initiated the reaction, and
addition intermediate 4 was generated; then 4 might give
intermediate 5 (or 50) through an intramolecular C–N coupling;
nally, product 3 (or 30) formed via another intramolecular C–N
coupling process. It was worthy noting that 3 was selectively
obtained when unsymmetrical substituted 2-bromo-20-iodo-
diphenylcarbodiimide and aliphatic primary amine were
utilized as the materials, probably due to the different reactivity
of the C–I bond and C–Br bond, as well as the NH-aryl group's
better activity than the NH-alkyl group's in the intramolecular
coupling process.
5 For selected examples, see: (a) T. Schaefer, U. Heinemeyer,
N. Langer, A. Wolleb, C. Lennartz, S. Watanabe,
T. M. Figueira Duarte, G. Wagenblast, D. Bauer, I. Muenster,
C. Schildknecht and H. Wolleb, World wide patent
2013068376, Chem. Abstr., 2013, 158, 721625; (b) T. Schaefer,
T. M. Figueira Duarte, C. Schildknecht, N. Langer,
U. Heinemeyer, H. Wolleb, S. Watanabe, C. Lennartz,
G. Wagenblast, A. Wolleb, K. Bardon and F. L. Benedito, US
patent 20120241681, Chem. Abstr., 2012, 157, 535109; (c)
T. Schaefer, T. M. Figueira Duarte, C. Schildknecht, N. Langer,
U. Heinemeyer, H. Wolleb, S. Watanabe, C. Lennartz,
G. Wagenblast, A. Wolleb, K. Bardon and F. L. Benedito,
Word wide patent 2012130709, 2011, Chem. Abstr., 2012, 157,
577352; (d) P. Stoessel, A. Buesing and D. Joosten, World wide
patent 2011160757, Chem. Abstr., 2011, 156, 112606.
6 For selected examples, see: (a) V. A. Anisimova, A. A. Spasov,
I. E. Tolpygin, V. A. Kosolapov, A. F. Kucheryavenko,
N. A. Gurova, O. Yu. Grechko, N. V. Kirillova, L. V. El'tsova,
L. V. Naumenko and V. D. Sysueva, Pharm. Chem. J., 2010,
44, 117–122; (b) P. Molina, M. J. Lidon and A. Tarraga,
Tetrahedron, 1994, 50, 10029–10036; (c) A. J. Hubert and
H. Reimlinger, Chem. Ber., 1970, 103, 2828–2835.
Conclusions
In conclusion, a novel, concise and efficient method for the
synthesis of benzimidazo[1,2-a]benzimidazoles has been
developed. A wide range of the polycyclic benzimidazole deriv-
atives, which might be useful in medicinal chemistry and
material elds, were facilely generated in good to excellent
yields through copper-catalyzed domino addition/double cycli-
zation process. The starting materials are readily available, the
application scope is broad, and the procedure is convenient.
Notably, multibonds and polycyclic moieties were directly con-
structed in one pot. Furthermore, good selectivity was observed
when unsymmetrical 2-bromo-20-iodo-diphenylcarbodiimides
were utilized. The domino transformation would be useful and
practical for the synthesis of various polycyclic N-heterocycles of
medicinal and material interests.
Acknowledgements
This work was nancially supported by the National Natural
Science Foundation of China (no. 21202152) and the Zhejiang
Provincial Natural Science Foundation (no. Y4110044).
7 X. Q. Wang, Y. H. Jin, Y. F. Zhao, L. Zhu and H. Fu, Org. Lett.,
2012, 14, 452–455.
Notes and references
8 For selected reviews, see: (a) H. Pellissier, Chem. Rev., 2013,
113, 442–524; (b) L.-Q. Lu, J.-R. Chen and W.-J. Xiao, Acc.
Chem. Res., 2012, 45, 1278–1293; (c) L. F. Tietze, G. Brasche
and K. Gericke, Domino Reactions in Organic Synthesis,
Wiley-VCH, Weinheim, Germany, 2006.
9 For recent reviews, see: (a) H. Pellissier, Chem. Rev., 2013,
113, 442–524; (b) C. J. Ball and M. C. Willis, Eur. J. Org.
Chem., 2013, 425–441; (c) Y. Liu and J.-P. Wan, Chem. –
Asian J., 2012, 7, 1488–1501; (d) Y. Liu and J.-P. Wan, Org.
Biomol. Chem., 2011, 9, 6873–6894.
1 For selected recent reviews, see: (a) K. Shah, S. Chhabra,
S. K. Shrivastava and P. Mishra, Med. Chem. Res., 2013, 22,
5077–5104; (b) B. Narasimhan, D. Sharma and P. Kumar,
Med. Chem. Res., 2012, 21, 269–283; (c) S. Bhattacharya and
P. Chaudhuri, Curr. Med. Chem., 2008, 15, 1762–1777.
2 For selected examples, see: (a) S. Bonham, L. O'Donovan,
M. P. Carty and F. Aldabbagh, Org. Biomol. Chem., 2011, 9,
6700–6706; (b) N. A. Hamdya, A. M. Gamal-Eldeenb,
H. A. Abdel-Aziza and I. M. I. Fakhra, Eur. J. Med. Chem.,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 21904–21908 | 21907

View Article Online
RSC Advances
Communication
10 (a) G. Yuan, H. Liu, J. Gao, K. Yang, Q. Niu, H. Mao, 12 For previous reports about the Cu-catalyzed one-pot
X. Wang and X. Lv, J. Org. Chem., 2014, 79, 1749–1757;
(b) Q. Niu, H. Mao, G. Yuan, J. Gao, H. Liu, Y. Tu,
X. Wang and X. Lv, Adv. Synth. Catal., 2013, 355, 1185–
1192; (c) Z. Xia, K. Wang, J. Zheng, Z. Ma, Z. Jiang,
X. Wang and X. Lv, Org. Biomol. Chem., 2012, 10, 1602–
1611.
synthesis of benzimidazole derivatives from carbodiimides,
see: (a) Synthesis of 2-aminobenzimidazoles: F. Wang,
S. J. Cai, Q. Liao and C.-J. Xi, J. Org. Chem., 2011, 76, 3174–
3180; (b) Synthesis of 2-aminobenzimidazoles: H. F. He,
Z. J. Wang and W. L. Bao, Adv. Synth. Catal., 2010, 352,
2905–2912;
(c)
Synthesis
of
benzoxazoles
and
11 Bis-(o-haloaryl)carbodiimides could be efficiently prepared
from readily available materials according to a previous
literature: F. L. Zeng and H. Alper, Org. Lett., 2010, 12,
3642–3644.
benzimidazoles: G. D. Shen and W. L. Bao, Adv. Synth.
Catal., 2010, 352, 981–986; (d) Synthesis of 2-
heterobenzimidazoles: X. Lv and W. L. Bao, J. Org. Chem.,
2009, 74, 5618–5621.
21908 | RSC Adv., 2014, 4, 21904–21908
This journal is © The Royal Society of Chemistry 2014