Synthesis of 2-fluoroalkylbenzimidazoles via copper(i)-catalyzed tandem reactions

Article abstract of DOI:10.1039/b900984a

Preparation of 2-fluoroalkylbenzimidazoles from N-aryl trifluoroacetimidoyl (or bromodifluoroacetimidoyl) chlorides and primary amines has been achieved via copper(i)-catalyzed tandem reactions. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b900984a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Synthesis of 2-fluoroalkylbenzimidazoles via copper(I)-catalyzed tandem
reactionsw
Jiangtao Zhu,a Haibo Xie,a Zixian Chen,ab Shan Lia and Yongming Wu*a
Received (in Cambridge, UK) 16th January 2009, Accepted 12th February 2009
First published as an Advance Article on the web 9th March 2009
DOI: 10.1039/b900984a
Preparation of 2-fluoroalkylbenzimidazoles from N-aryl
trifluoroacetimidoyl (or bromodifluoroacetimidoyl) chlorides
and primary amines has been achieved via copper(I)-catalyzed
tandem reactions.
Benzimidazoles are an important class of heterocyclic
compounds due to their wide range of biological properties
such as antiviral, antifungal, antibacterial, and anti-tumor
activities.1 Benzimidazoles have also served as important
synthetic intermediates for the preparation of dyes and
Scheme 1 A summary of the synthesis of N-benzimidazoles via
high temperature polymers.2 Among them, 2-fluoroalkyl
Ullmann reactions.
substituted molecules have already received considerable
attention due to their potential bioactivities.3
However to date, there are only a few methods reported for
the synthesis of 2-fluoroalkylbenzimidazoles compared to
non-fluorinated analogues.4 These compounds are commonly
prepared by the following methods: (1) condensation of
trifluoroacetic acid with ortho-aminoanilines,5 (2) reductive
cyclization of trifluoroacetic acid with ortho-nitroanilines,6 (3)
Scheme 2 Strategy for the synthesis of benzimidazoles.
synthesis from perfluoro (or polyfluoro) alkyl aldehydes with
ortho-aminoanilines,7 or (4) direct trifluoromethylation of
benzimidazoles with trifluoromethyl radicals.8 The drawbacks
of BrCF2-containing compounds from bromodifluoroacetimidoyl
halides.12 In our previous report, fluorinated amidines could
of these procedures lie in the limited diversity of the starting
be easily obtained from the reaction of imidoyl chlorides with
primary and secondary amines (Scheme 2).12d We expected
that if there is an iodine at the ortho position on the benzene
ring, the amidines may undergo Cu(I)-catalyzed cyclization to
afforded 1,2-disubstituted benzimidazoles.
materials, harsh reaction conditions and lack of regioselectivity.
Recently, the Ma group reported a new process for the
formation of 1,2-disubstituted benzimidazoles from 2-haloanilides
and primary amines at low temperature via the system of Cu(I)
and L-proline (route a, Scheme 1).9 Buchwald and co-workers
also developed a similar method from 2-haloanilines and amides
for the regiospecific synthesis of N-alkylbenzimidazoles (route b,
Scheme 1).10 Herein, we wish to report a new process for the
synthesis of N-substituted 2-fluoromethylbenzimidazoles from
imidoyl chlorides and amines by a Cu(I)-catalyzed cyclization
reaction without any ligands under mild conditions (route c,
Scheme 1).
At the beginning, iodoamidine 4a was used as the starting
material to investigate this reaction. It was found that when
CuI was used as the catalyst, DMF as the solvent and K2CO3
as the base, the cyclization product, benzimidazole 3a, could
be obtained in 79% yield after the mixture was stirred at 60 1C
for 3 h.
Because amidines 4 could be easily prepared from the
reaction of the corresponding fluorinated acetimidoyl halides
1 and amines 2, we presumed that in the presence of CuI,
benzimidazole 3a may be formed directly from fluorinated
acetimidoyl halides 1 and amines 2. Then we designed a
tandem reaction sequence using imidoyl chlorides and amines
as the starting materials to test this hypothesis. The reaction of
2-bromo-2,2-difluoro-N-(2-iodophenyl)acetimidoyl chloride
1a with butylamine was used as a model system to study this
transformation. When CuI was used as the catalyst in DMF at
60 1C, benzimidazole 3a was formed as the exclusive product
in 76% yield after 3 h. Then the effects of solvents, bases and
copper catalysts were investigated (Table 1). It was found that
in toluene or dioxane, amidine 4a was formed as the sole
product and it did not cyclize at all (entries 1, 2, Table 1). In
In recent years, trifluoromethyl imidoyl chlorides have been
successfully used as building blocks in synthetic organofluorine
chemistry by the Uneyama group.11 To construct new
CF2-containing reactive synthetic intermediates, our group
have focused on developing new methods for the synthesis
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 LingLing
Road, Shanghai 200032, P. R. China.
E-mail: ymwu@mail.sioc.ac.cn; Fax: (+86) 21-54925192
b Department of Chemistry, Huazhong University of Science and
Technology, Wuhan, Hubei 430074, China
w Electronic supplementary information (ESI) available: General pro-
cedures for benzimidazole synthesis; characterization data and NMR
spectra for compounds 3a–3u. See DOI: 10.1039/b900984a
ꢀc
This journal is The Royal Society of Chemistry 2009
2338 | Chem. Commun., 2009, 2338–2340

View Article Online
Table 1 Optimization of the reaction conditions
Entry
CuX
Base
Solvent
3a (%)a
4a (%)a
1
2
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
Toluene
Dioxane
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
—
—
76
—
—
77
78
50
—
67
67
57
40
85
82
—
83
87
—
—
Trace
83
—
—
—
3
4b
5
K2CO3
K2CO3
K3PO4
NaH
6
7
8
9
10
11
12
13c
CuI
CuI
CuI
CuI
CuBr
CuCN
CuCl
CuI
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
60
a
b
c
2 equiv. n-butylamine. Addition of ligand
Isolated yield.
L-proline.
Scheme 3 Synthesis of fluorinated benzimidazoles.
Table 2 Synthesis of N-substituted 2-fluoromethylbenzimidazolesa
indicated that CuI was superior to CuBr, CuCN and CuCl
in this reaction (entries 3, 10–12, Table 1). Addition of ligands
such as L-proline was ineffective in improving the yields, under
this condition both the products, amidine 4a and benzimidazole
3a, were formed while amidine 4a was the major product
(entry 13, Table 1).
On the basis of the above studies, we reached the optimized
conditions for this reaction: CuI as the catalyst, DMF as the
solvent, and 4 equiv. of K2CO3 or K3PO4 as the base. The
scope of the reaction was then explored with different primary
amines and imidoyl chlorides and the results are listed in
Table 2.
Product/yield (%)b/
method/T (1C)
Entry
RF
R0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CF2Br1a
n-Bu
Allyl
HO(CH2)2
Cyclohexyl
Bn
p-Me-C6H4
p-Cl-C6H4
p-MeO-C6H4
p-NO2-C6H4
n-Bu
3a/76/A/60
3b/68/B/60
3c/68/A/60
3d/76/B/60
3e/82/B/60
3f/74/A/60
3g/31/A/80
3h/67/A/60
3i/58/A/80
3j/78/A/rt
3k/70/A/60
3l/87/A/40
3m/69/A/40
3n/93/A/60
3o/91/A/60
3p/62/A/80
3q/41/A/80
As summarized in Table 2, both aliphatic amines and aryl
amines could provide benzimidazoles 3 in good yields. This
reaction was compatible with a hydroxyl group (entries 3, 12,
Table 2). The yields of the reaction with 2,2,2-trifluoro-
N-(2-iodophenyl)acetimidoyl chloride 1b were higher than
that with 2-bromo-2,2-difluoro-N-(2-iodophenyl)acetimidoyl
chloride 1a. When 2,2,2-trifluoro-N-(2-iodophenyl)acetimidoyl
chloride 1b and butylamine were used as the two starting
materials, this transformation could go to completion at room
temperature (entry 10, Table 2).
CF31b
Allyl
HO(CH2)2
Cyclohexyl
p-Me-C6H4
p-MeO-C6H4
p-Cl-C6H4
p-NO2-C6H4
Next, imidoyl chlorides with an extra substituent on the
phenyl ring were investigated. We were pleased to observe
that substrates with either an electron-donating (Me) or an
electron-withdrawing (Cl, NO2) group in the para or meta
position to the iodo all worked well under the optimized
conditions. Especially a pair of regioisomeric benzimidazoles
bearing a nitro group were obtained in good yields by applying
the conditions described above without the need for further
optimization (Scheme 3, eqn (3) and (4)).
a
Reaction conditions: imidoyl chloride 1 (0.4 mmol), amine 2
(0.5 mmol), CuI (0.04 mmol), K2CO3 (1.6 mmol, method A) or
b
K3PO4 (1.6 mmol, method B), DMF (2 ml). Yields of isolated
products.
contrast, when DMF or DMSO was employed as the solvent,
benzimidazole 3a could be obtained in good yields (entries 3,
6, Table 1). Use of K2CO3 or K3PO4 (4 equiv.) was critical for
this reaction, other bases (such as NaH or Et3N) could not
effect the complete reaction sequence (entries 8, 9, Table 1).
For example, in triethylamine, only the amidine 4a could be
obtained (entry 9, Table 1). Testing different Cu(I) salts
In conclusion, we have demonstrated a convenient method
for the synthesis of 2-trifluoromethyl (or 2-bromodifluoromethyl)
benzimidazoles via the reaction of fluorinated imidoyl
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2338–2340 | 2339

View Article Online
chlorides with primary amines catalyzed by CuI in pure form.
Compared to the existing methods, our strategy can be
easily carried out at low temperatures without ligands.
Further investigations on this reaction are ongoing in this
laboratory.
5 (a) H. Bishop, A. S. Jones and J. C. Tatlow, J. Chem. Soc., 1964,
3076; (b) F. Ge, Z. Wang, W. Wan, W. Lu and J. Hao, Tetrahedron
Lett., 2007, 48, 3251.
6 D. S. VanVielt, P. Gillespie and J. J. Scicinski, Tetrahedron Lett.,
2005, 46, 6741.
7 Q. F. Wang, Y. Y. Mao, Z. S. Zhu and C. M. Hu, J. Fluorine
Chem., 1999, 95, 141.
8 (a) H. Kimoto, S. Fujii and L. Cohen, J. Org. Chem., 1982, 47,
This work was supported by the National Science Foundation
of China (Nos. 20532040 and 20772145).
2867; (b) M. Medebielle, J. Pinson and J. M. Saveant, J. Am.
´
Chem. Soc., 1991, 113, 6872; (c) J. Pinson and J. M. Saveant,
Tetrahedron Lett., 1990, 31, 1279; (d) Q. Chen and Z. Qui,
J. Fluorine Chem., 1987, 35, 343; (e) M. Kobayashi and
K. Uneyama, J. Org. Chem., 1995, 60, 6402; (f) K. Uneyama
and M. Kobayashi, J. Org. Chem., 1994, 59, 3003.
9 B. Zou, Q. Yuan and D. Ma, Angew. Chem., Int. Ed., 2007, 46,
2598.
Notes and references
1 (a) R. Morphy and Z. Rankovic, J. Med. Chem., 2005, 48, 6523;
(b) R. R. Wexler, W. J. Greenlee, J. D. Irvin, M. R. Goldberg,
K. Prendergast, R. P. Smith and P. B. M. W. M. Timmermans,
J. Med. Chem., 1996, 39, 625.
2 (a) G. Schwartz, K. Fehse, M. Pfeiffer, K. Walzer and K. Leo,
Appl. Phys. Lett., 2006, 89, 083509/1; (b) J. A. Asensio and
P. Gomez-Romero, Fuel Cells, 2005, 5, 336.
3 K. C. Joshi, R. Jain, A. Dandia and K. Sharma, J. Fluorine Chem.,
1992, 56, 1.
10 (a) N. Zheng, K. W. Anderson, X. Huang, N. Nguyen and
S. L. Buchwald, Angew. Chem., Int. Ed., 2007, 46, 7509;
(b) G. Brasche and S. L Buchwald, Angew. Chem., Int. Ed., 2008,
47, 1932; (c) N. Zheng and S. L Buchwald, Org. Lett., 2007, 9,
4749.
4 (a) M. R. Grimmett, in Imidazole and Benzimidazole Synthesis,
Best Synthetic Methods, ed. O. Meth-Cohn, Academic, London,
1997; (b) D. Yang, D. Fokas, J. Li, L. Yu and C. M. Baldino,
Synthesis, 2005, 47; (c) G. Evindar and R. A. Batey, Org. Lett.,
2003, 5, 133; (d) G. Evindar and R. A. Batey, J. Org. Chem., 2006,
71, 1802; (e) C. T. Brain and S. A. Brunton, Tetrahedron Lett.,
2002, 43, 1893; (f) C. T. Brain and J. T. Steer, J. Org. Chem., 2003,
68, 6814.
11 (a) K. Uneyama, J. Fluorine Chem., 1999, 97, 11; (b) K. Tamura,
H. Mizukami, K. Maeda, H. Watanabe and K. Uneyama, J. Org.
Chem., 1993, 58, 32.
12 (a) Y. M. Wu, Y. Li and J. Deng, J. Fluorine Chem., 2005, 126, 791;
(b) Y. M. Wu, Y. Li and J. Deng, Tetrahedron Lett., 2005, 126, 791;
(c) Y. M. Wu and Y. Li, J. Fluorine Chem., 2006, 127, 223;
(d) Y. M. Wu, M. Zhang and Y. Q. Li, J. Fluorine Chem., 2006,
127, 1168.
ꢀc
This journal is The Royal Society of Chemistry 2009
2340 | Chem. Commun., 2009, 2338–2340