Copper-catalyzed synthesis of 2-aminobenzimidazoles from carbonimidoyl dichlorides and amines

Article abstract of DOI:10.1016/j.tetlet.2012.07.072

A new protocol for the synthesis of a variety of 2-aminobenzimidazole derivatives has been developed. O-haloaryl carbonimidoyl dichloride reacted with anilines to generate an o-haloaryl guanidine intermediate, which underwent copper catalyzed ring closure to afford 2-aminobenzimidazole derivative in moderate yields.

Full text of DOI:10.1016/j.tetlet.2012.07.072

Tetrahedron Letters 53 (2012) 5253–5256
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Tetrahedron Letters
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Copper-catalyzed synthesis of 2-aminobenzimidazoles from carbonimidoyl
dichlorides and amines
⇑
Hui Yu , Qiong Liu, Yuzhe Li, Chongzhi Ni
Department of Chemistry, Tongji University, Shanghai 200092, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new protocol for the synthesis of a variety of 2-aminobenzimidazole derivatives has been developed.
O-haloaryl carbonimidoyl dichloride reacted with anilines to generate an o-haloaryl guanidine interme-
diate, which underwent copper catalyzed ring closure to afford 2-aminobenzimidazole derivative in
moderate yields
Received 4 May 2012
Revised 10 July 2012
Accepted 17 July 2012
Available online 31 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminobenzimidazole
Copper-catalyzed
O-Haloaryl carbonimidoyl dichloride
Introduction
products. Herein, as a part of our efforts on copper-catalyzed syn-
thesis of heterocycles, we wish to report a new protocol for the
2-Aminobenzoimidazoles play an important role in biological
and pharmaceutical areas for their significant and potential biolog-
ical activities.1 2-Aminobenzoimidazoles’ core structure can be
widely found in commercial drugs such as Vermox, Fenbendazole,
oncodazole, and mizolastine. Chiral 2-aminobenzoimidazoles can
serve as efficient organocatalyst in asymmetric chemistry, espe-
cially for enantioselective Michael addition.2 Therefore, 2-amino-
benzimidazole has been a target molecule of medicinal chemistry
and organic chemistry. The conventional methods for the prepara-
tion of 2-aminobenzimidazoles involved the nucleophilic aromatic
substitution reaction (SNAr) of 2-halobenzimidazole.3 Though this
transformation was widely used in the construction of 2-amino-
benzimidazole motif, there still remained some drawbacks such
as harsh reaction conditions and low yields.
Over the past ten years, copper-catalyzed Ullmann type C–N
bond formation provided new choices for the assembly of
2-aminobenzimidazoles, such as intramolecular N-arylation of
ortho-halophenyl guanidines (path a),4 or intermolecular coupling
of 1,2-dihalobenzene and guanidines (path b).5 Anyway, these
methods suffered from the multi-step synthesis of the requisite
guanidines precursor. Recently, more convenient approach to
2-aminobenzimidazoles was developed by Bao and Xi indepen-
dently. 2-Haloaryl guanidines’ intermediate was generated in situ
by amination of 2-haloaryl carbodiimides6 (path c) or addition of
2-haloanilines to carbodiimides7 (path d, R3 = H), and then under-
went condensation cyclization catalyzed by copper to give the
preparation of 2-aminobenzimidazoles from carbonimidoyl dichlo-
rides and amines (Fig. 1).
Results and discussion
In our previous work, we reported the synthesis of substituted
guanidines from carbonimidoyl dihalides and amines.8 By the com-
bination of this guanylation process and copper-catalyzed cycliza-
tion, we envisioned that 2-aminobenzimidazoles could be obtained
from N-(2-halophenyl) carbonimidoyl dihalides and amines.
N-(2-bromophenyl) carbonimidoyl dichloride 1a, easily pre-
pared from N-(2-bromophenyl) formamide 2 by treatment with
SOCl2 and SO2Cl2,9 was selected as the model substrate to react
with aniline 3a for this copper-catalyzed process. To optimize the
reaction conditions, we examined different solvents, bases, and
ligands. The results are listed in Table 1. Firstly the reaction was
carried out in DMF with CuI (5 mol%), 1,10-phenthroline (10
mol%) as the catalyst, Cs2CO3 (3.5 equiv) as the base at 100 °C
under N2. To our delight, 16 h later, the desired product 4a was
X1
+
X2
N
NR2R3
NHR1
NH
NR2R3
NHR1
a
b
N
Br
NR2R3
N
c
d
R1
N
NH2
C
R1
R1
+
N
+
N
C N
HNR2R3
Br
R2
Br
⇑
Corresponding author.
E-mail address: yuhui@mail.tongji.edu.cn (H. Yu).
Figure 1. Reported copper-catalyzed synthesis of 2-aminobenzimidazoles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.072

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H. Yu et al. / Tetrahedron Letters 53 (2012) 5253–5256
Table 1
isolated in 60% yield (Table 1, entry 1). Various solvents were
Optimization of the reaction conditionsa
screened and NMP (N-Methyl- 2-pirrolidone) was found to be the
best one (Table 1, entries 2–6). Different bases including t-BuONa,
DBU, K3PO4, and KOH were evaluated and Cs2CO3 remained as the
best one (Table 1, entries 7–11). The product cannot be obtained
without ligand, and other ligands gave lower yield compared to
1,10-Phenthroline (Table 1, entries 12–15). Some other copper
salts were also tested but lead to low yields (Table 1, entries 16–
17). On the basis of these results, the entry 6 undoubtedly repre-
sents the best conditions.
CuI(5%), L(10%)
N
Cl
N
Base(3.5eq), N2
+
PhNH2
NHPh
Cl
Solvent, 120ഒ, 12h
N
Br
Ph
3a
4a
1a
Entry
Base (3.5eq)
Solvent
Catalyst/Ligandb
Yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuONa
DBU
DMF
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/—
CuI/L2
CuI/L3
CuI/L4
CuBr/L1
Cu2O/L1
60
50
46
42
38
72
10
16
8
27
19
0
41
53
67
32
59
Dioxane
DMSO
DMA
toluene
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
Under the optimized conditions,10 we employed a variety of
carbonimidoyl dichlorides and substituted amines to examine
the scope of the reaction, and the results are summarized in Table
2. Here the reaction time was prolonged to 16 h to purchase higher
yields.
A family of anilines was used to react with 1a. The position of
the substituent group on the benzene ring had an influence on
the yields, for different MeO substituted anilines, the yields were
p > m > o, indicating the effect of steric hindrance in the reaction
(Table 2, entries 2–4). When sterically more hindered 2, 4, 6-tri-
methylaniline was applied under the optimized condition, no
product was obtained (Table 2, entry 5). Generally, the presence
of electron-withdrawing group on the phenyl ring of aniline gave
lower yields than ones containing electron-donating groups (Table
2, entries 6–9). For anilines with strong electron-withdrawing
group on the benzene ring such as NO2, no product could be found
and all the 4-nitroaniline was recovered (Table 2, entry 10). To our
delight, aliphatic amines such as BnNH2 and n-butyl amine could
K3PO4
KOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
a
The reactions were performed in a schlenk tube with 1a (0.5 mmol), aniline
(1.25 mmol), base (1.75 mmol), catalyst (5 mol%), and ligand (10 mol%) in solvent
(2 mL) for 12 h.
b
L1:1,10-Phenthroline; L2: 2-20dipirydine; L3: L-proline; L4: TMEDA.
Isolated yield after flash chromatography based on 1a.
c
Table 2
Synthesis of 2-aminobenzimidazoles from carbonimidoyl dichlorides and amines
CuI(5%), 1,10-Phen(10%)
N
X
Cl
N
Cs2CO3(3.5eq), N2
NR2
+
2 R2NH2
Cl
N
R1
R1
NMP, 120ഒ, 16h
R2
3
1
4
Entry
Substrate 1
Substrate 3
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
C6H5NH2
4a
4b
4c
4d
4e
4f
4g
4h
4i
73
42
56
64
—
75
62
54
38
—
2-MeOC6H4NH2
3-MeOC6H4NH2
4-MeOC6H4NH2
2,4,6-Me3C6H2NH2
4-MeC6H4NH2
4-FC6H4NH2
4-ClC6H4NH2
4-BrC6H4NH2
4-NO2C6H4NH2
BnNH2
4j
4k
4l
70
46
_
n -BuNH2
i-PrNH2
4m
N
Cl
14
15
16
C6H5NH2
C6H5NH2
C6H5NH2
4n
4o
4p
52
58
49
Cl
Br
N
1b
Cl
Cl
F
Br
1c
Cl
N
Cl
Cl
Br
Cl
1d
N
17
18
C6H5NH2
C6H5NH2
4a
4a
67
41
Cl
1e
Cl
I
N
Cl
Cl
1f
a
Isolated yield. Reaction conditions unless otherwise stated: CuI (5 mol%, 5 mg), 1, 10-phenanthroline (10 mol%, 9 mg), 1a (0.5 mmol), Cs2CO3 (1.5 mmol, 0.49 g), and
aniline (1.25 mmol) in NMP (2 mL).

H. Yu et al. / Tetrahedron Letters 53 (2012) 5253–5256
5255
N
X
CuI(5%), 1,10-Phen(10%)
HX
N
Cl
Cs2CO3 (3.5eq), N2
N
+
Cl
NMP, 120ഒ, 16h
H2N
Br
6a X = NH 0%
1a
1a
5a X = NH
5b X = O
6b X = O
24%
Scheme 1. Reaction between 1a and o-diaminobenzene 5a/o-hydroxyaniline 5b.
N
Cl
N
N
NHPh
Cs2CO3(3.5eq), N2
C
Ph
+
PhNH2
N
+
Cl
Cl
NHPh
NMP, 120ഒ
Br
Br
Br
2a
7
8
Time
1 h
12%
32%
76%
54%
3 h
Scheme 2. Reaction between 1a and aniline in the absence of copper.
N
X
N
X
N
X
NHR
NHR
RNH2
RNH2
C
R
CuI
N
4
Cl
Cs2CO3
1
9
10
Scheme 3. Proposed reaction mechanism.
also be successfully applied to the reaction, and the products were
obtained in 70% and 40% yields, respectively (Table 2, entries 11–
12). In case of isopropyl amine, the reaction lead to complex
mixture and no desired product was found (Table 2, entry 13).
When substituted N-(2-bromophenyl) carbonimidoyl dichloride
such as 1b, 1c, and 1d were used to react with aniline, the reaction
proceeded well and the products were isolated in moderate yields
(Table 2, entries 14-16). N-(2-iodophenyl) carbonimidoyl dichlo-
ride 1e gave the same product 4a in lower yield than its bromo
analogues possibly for its instability11 (Table 2, entry 17). As antic-
ipated, N-(2-chloroophenyl) carbonimidoyl dichloride 1f gave only
41% yield for its less reactivity (Table 2, entry 18).
Acknowledgments
This work was supported by the National Science Foundation of
China (No. 20802053).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.07.
072.
References and notes
The reaction between 1a and o-diaminobenzene 5a was also
tested, but no desired product bicyclic guanidine was detected.
Interestingly, when o-hydroxyaniline 5b was employed to the
reaction instead of o-diaminobenzene, a fused ring compound 6b
could be obtained in 24% yield12 (Scheme 1).
To disclose the details of the reaction process, 1a was heated
with 2 equiv aniline in the presence of 3.5 equiv Cs2CO3 at 120 °C
in NMP. 1 h later, TLC showed the consumption of 1a, then the
main product was carefully isolated and identified as 2-bromophe-
nyl carbodiimides 7 (76%), accompanied with a small amount of
1. (a) Huigens, R. W., III; Reyes, S.; Reed, C. S.; Bunders, C.; Rogers, S. A.;
Steinhauer, A. T.; Melander, C. Bioorg. Med. Chem. 2010, 18, 7260; (b) Rogers, S.
A.; Huigens, R. W. III; Melander,., C. A. J. Am. Chem. Soc. 2009, 131, 9868; (c)
Rivara, M.; Zuliani, V.; Cocconcelli, G.; Morini, G.; Comini, M.; Rivara, S.; Mor,
M.; Bordi, F.; Barocelli, E.; Ballabeni, V.; Bertoni, S.; Plazzi, P. V. Bioorg. Med.
Chem. 2006, 14, 1413; (d) Solominova, T. S.; Pilyugin, V. S.; Tyurin, A. A.; Kirlan,
A. V.; Tyurina, L. A. Pharm. Chem. J. 2004, 38, 425; (e) Mor, M.; Bordi, F.; Silva, C.;
Rivara, S.; Zuliani, V.; Vacondio, F.; Rivara, M.; Barocelli, E.; Bertoni, S.;
Ballabeni, V.; Magnanini, F.; Impicciatore, M.; Plazzi, P. Bioorg. Med. Chem. 2004,
12, 663; (f) Correa, R. G.; Khan, P. M.; Askari, N.; Zhai, D.; Gerlic, M.; Brown, B.;
Magnuson, G.; Spreafico, R.; Albani, S.; Sergienko, E.; Diaz, P. W.; Roth, G. P.;
Reed, J. C. Chem. Biol. 2011, 18, 825.
2. (a) Zhang, L.; Lee, M. M.; Lee, S. M.; Lee, J.; Cheng, M.; Jeong, B. S.; Park, H.; Jew,
S. Adv. Synth. Catal. 2009, 351, 3063; (b) Gomez-Torres, E.; Alonso, D. A.;
Gomez-Bengoa, E.; Najera, C. Org. Lett. 2011, 13, 6106; (c) Lin, J.; Tian, H.; Jiang,
Y.; Huang, W.; Zheng, L.; Zhang, S. Tetrahedron: Asymmetry 2011, 22, 1434; (d)
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3. (a) Deng, J.; Feng, E.; Ma, S.; Zhang, Y.; Liu, X.; Li, H.; Huang, H.; Zhu, J.; Zhu, W.;
Shen, X.; Miao, L.; Liu, H.; Jiang, H.; Li, J. J. Med. Chem. 2011, 54, 4508; (b)
Peterson, E. A.; Andrews, P. S.; Be, X.; Boezio, A. A.; Bush, T. L.; Cheng, A. C.;
Coats, J. R.; Colletti, A. E.; Copeland, K. W.; DuPont, M.; Graceffa, R.; Grubinska,
B.; Harmange, J. C.; Kim, J. L.; Mullady, E. L.; Olivieri, P.; Schenkel, L. B.; Stanton,
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2011, 21, 2064; (c) Oguro, Y.; Miyamoto, N.; Okada, K.; Takagi, T.; Iwata, H.;
Awazu, Y.; Miki, H.; Hori, A.; Kamiyama, K.; Imamura, S. Bioorg. Med. Chem.
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2-bromophenylguanidines
8 (12%). If the reaction time was
prolonged to 3 h, the yield of 7 decreased to 54% and the yield of
8 increased to 32% (Scheme 2). This result suggested that 8 was
not generated directly from 1a and aniline as expected, while 7
was involved as an intermediate. When 8 was subjected to the
standard condition, 4a was obtained in yield of 89%.
Based on the experimental results, a proposed reaction mecha-
nism is shown in Scheme 3. Reaction of N-(2-halophenyl) carbo-
nimidoyl dihalides 1 and amine formed 2-haloaryl carbodiimides
9, which was attacked by excess amine to create 2-haloaryl guani-
dine 10.13 10 was the key intermediate which could undergo ring
closure to product 4 under copper-catalyzed conditions.7,14
4. Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
5. (a) Deng, X.; McAllister, H.; Mani, N. S. J. Org. Chem. 2009, 74, 5742; (b) Deng, X.;
Mani, N. S. Eur. J. Org. Chem. 2010, 680.
6. Lv, X.; Bao, W. J. Org. Chem. 2009, 74, 5618.
7. (a) Wang, F.; Cai, S.; Liao, Q.; Xi, C. J. Org. Chem. 2011, 76, 3174; (b) Shen, G.; Bao,
W. Adv. Synth. Catal. 2010, 352, 981.
Conclusion
In summary, we have developed a one-pot method for the syn-
thesis of 2-aminobenzimidazoles from carbonimidoyl dichloride
and anilines under copper-catalyzed condition. The procedure
was easy to handle and various 2-aminobenzimidazoles have been
synthesized by such a strategy.
8. Yu, H.; Zhang, M.; Sun, W.; Li, Y.; Gao, R. Lett. in Org. Chem. 2010, 7, 566–570.
9. (a) Bruno, G. L.; Wermuth, C. G. J. Med. Chem. 1976, 1050, 19; (b) Wang, P.;
Zheng, G.; Wang, Y.; Wang, X.; Li, Y.; Xiang, W. Tetrahedron 2010, 66, 5402.
10. Typical experimental procedure for synthesis of 2-amino- benzimidazoles: Under
N2 atmosphere, a schlenk tube was filled with the mixture of 1a (0.5 mmol),
Cs2CO3 (1.5 mmol, 0.49 g), CuI (5 mol%, 5 mg), 1,10-phenanthroline (10 mol%,

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H. Yu et al. / Tetrahedron Letters 53 (2012) 5253–5256
9 mg) and aniline (1.25 mmol) then stirred in NMP (2 mL) at 120 °C for 16 h.
1H); 13C NMR (100 MHz, CDCl3): d 148.9, 142.3, 139.2, 134.6, 134.4, 130.7,
130.0, 129.3, 127.3, 122.6, 122.3, 121.0, 118.3, 117.6, 108.2.
11. Freshly distilled 1e is a yellow oil but turn to red and brown within 24 hours at
room temperature.
12. Martineau, A.; DeJongh, D. C. J. Anal. Appl. Pyrol. 1983, 5, 39.
13. (a) Li, Q.; Wang, S.; Zhou, S.; Yang, G.; Zhu, X.; Liu, Y. J. Org. Chem. 2007, 72,
6763; (b) Zhang, W.; Nishiura, M.; Hou, Z. Chem. Eur. J. 2007, 13, 4037.
14. Szczepankiewicz, B. G.; Rohde, J. J.; Kurukulasuriya, R. Org. Lett. 1833, 2005, 7.
After completion of the reaction, the mixture was cooled to room temperature,
then H2O (5 mL) was added. The mixture was extracted with EtOAc (3 ꢀ 5 mL)
and dried by anhydrous Na2SO4. Evaporation of the solvent followed by
purification on silica gel (petroleum ether/EtOAc = 4/1) provided the
corresponding product. N,1-Diphenyl-1H-2-aminobenzimidazole 4a: white
solid, m.p.164–166 °C, 1H NMR (400 MHz, CDCl3): d 7.65–7.62 (m, 6H), 7.55–
7.48 (m, 2H), 7.33–7.31 (m,2H), 7.22–7.19 (m, 1H), 7.10–7.01 (m, 3H), 6.32 (s,