Copper-catalyzed synthesis of 2-unsubstituted, N-substituted benzimidazoles

Article abstract of DOI:10.1021/jo902160y

(Chemical Equation Presented) An efficient copper-catalyzed intramolecular arylation of formamidines forming 2-unsubstituted benzimidazoles in excellent yields is reported. Sixteen examples bearing sterically demanding substituents on nitrogen like Mes, 2,6-diisopropylphenyl, or 2-tert-butylphenyl and tolerating various functional groups demonstrate the utility of this method.

Full text of DOI:10.1021/jo902160y

pubs.acs.org/joc
modular, highly efficient methods5 for the synthesis of
Copper-Catalyzed Synthesis of 2-Unsubstituted,
N-Substituted Benzimidazoles
NHC-precursors is of great interest. Benzimidazolylidenes,
most often prepared by deprotonation of 2-unsubstituted
benzimidazolium salts, are an important class of NHCs
and have been successfully utilized in organocatalytic pro-
cesses6,7 as well as in transition metal catalysis.8 The required
2-unsubstituted benzimidazolium salts can be prepared either
by cyclization of substituted 1,2-diaminoarenes with ortho-
formate as the C1-building block (method A, Scheme 1)9 or,
much more common,10 by quaternization of the nitrogen
atom of N-substituted benzimidazoles with alkyl electro-
philes (method B).11,12
Keiichi Hirano, Akkattu T. Biju, and Frank Glorius*
€
Organisch-Chemisches Institut der Westfalischen
Wilhelms-Universita€t Mu€nster, Corrensstrasse 40,
48149 Mu€nster, Germany
glorius@uni-muenster.de
Received October 7, 2009
SCHEME 1. Representative Methods for the Synthesis of Ben-
zimidazolium Salts
An efficient copper-catalyzed intramolecular arylation of
formamidines forming 2-unsubstituted benzimidazoles in
excellent yields is reported. Sixteen examples bearing
sterically demanding substituents on nitrogen like Mes,
2,6-diisopropylphenyl, or 2-tert-butylphenyl and tolerat-
ing various functional groups demonstrate the utility of
this method.
(5) For some recent reports, see: (a) Prasad, B. A. B.; Gilbertson, S. R.
€
Org. Lett. 2009, 11, 3710. (b) Urban, S.; Tursky, M.; Frohlich, R.; Glorius, F.
Dalton Trans. 2009, 6934. (c) Hirano, K.; Urban, S.; Wang, C.; Glorius, F.
Org. Lett. 2009, 11, 1019. (d) Ogle, J. W.; Zhang, J.; Reibenspies, J. H.;
Abboud, K. A.; Miller, S. A. Org. Lett. 2008, 10, 3677. (e) Kuhn, K. M.;
N-Heterocyclic carbenes (NHCs) have found widespread
applications as organocatalysts1,2 and as ligands in transi-
tion metal catalysis.3,4 The success of NHCs is based on
many attractive properties like extraordinary electron-rich-
ness, stability of metal-NHC complexes, and on their often
large steric demand.3 Consequently, the development of
€
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S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (b) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606. (c) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534.
(2) For some of our key papers on NHC-organocatalysis, see: (a) Lebeuf,
R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243. (b) Hirano, K.; Piel, I.;
Glorius, F. Adv. Synth. Catal. 2008, 350, 984. (c) Schrader, W.; Handayani,
P. P.; Burstein, C.; Glorius, F. Chem. Commun. 2007, 716. (d) Burstein, C.;
Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418. (e) Burstein, C.;
Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
Pharm. Bull. 1990, 38, 1147. See also ref 2d
.
(7) For the successful application of N-mesityl-N0-methylbenzimidazo-
lium iodide as NHC precursor in organocatalytic umpolung reactions, see:
Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334.
(8) (a) Ma, G.-N.; Zhang, T.; Shi, M. Org. Lett. 2009, 11, 875. (b) Zhang,
T.; Shi, M. Chem.;Eur. J. 2008, 14, 3759. (c) Chen, T.; Jiang, J.-J.; Xu, Q.;
(3) (a) Arduengo, A. J. III Acc. Chem. Res. 1999, 32, 913. (b) Bourissou,
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Ed. N-Heterocyclic Carbenes in Synthesis; Wiley-VCH: Weinheim, Germany,
2006. (e) Glorius, F., Ed. N-Heterocyclic Carbenes in Transition Metal
Catalysis; Springer: Berlin, Germany, 2007. (f) Kantchev, E. A. B.; O'Brien, C.
J.; Organ, M. J. Angew. Chem., Int. Ed. 2007, 46, 2768. (g) Hahn, F. E.; Jahnke,
M. C. Angew. Chem., Int. Ed. 2008, 47, 3122. (h) Diez-Gonzalez, S.; Marion, N.;
Nolan, S. P. Chem. Rev. 2009, 109, 3612.
Shi, M. Org. Lett. 2007, 9, 865. (d) Huynh, H. V.; Ho, J. H. H.; Neo, T. C.;
Koh, L. L. J. Organomet. Chem. 2005, 690, 3854. (e) O’Brien, C. J.; Assen, E.;
Kantchev, B.; Chass, G. A.; Hadei, N.; Hopkinson, A. C.; Organ, M. G.;
Setiadi, D. H.; Tang, T.-H.; Fan, D.-C. Tetrahedron 2005, 61, 9723.
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(f) Buisine, O.; Berthon-Gelloz, G.; Briere, J.-F.; Sterin, S.; Mignani, G.;
Branlard, P.; Tinant, B.; Declercq, J.-P.; Marko, I. E. Chem. Commun. 2005,
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(9) (a) Boydston, A. J.; Vu, P. D.; Dykhno, O. L.; Chang, V.; Wyatt,
A. R., II; Stockett, A. S.; Ritschdorff, E. T.; Shear, J. B.; Bielawski, C. W.
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(10) A Beilstein Crossfire search on the 30th of August 2009 revealed only
11 entries for the formation of benzimidazolium salts from substituted 1,2-
diamino arenes, whereas the alkylation (including activated alkyl groups like
benzyl or R-carbonyl) of benzimidazoles was found 322 times.
(4) For some of our key papers on the design and application of NHC-
€
€
ligands, see: (a) Wurtz, S.; Lohre, C.; Frohlich, R.; Bergander, K.; Glorius,
F. J. Am. Chem. Soc. 2009, 131, 8344. (b) Wurtz, S.; Glorius, F. Acc. Chem.
€
Res. 2008, 41, 1523. (c) Tewes, F.; Schlecker, A.; Harms, K.; Glorius, F.
€
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9570 J. Org. Chem. 2009, 74, 9570–9572
Published on Web 11/05/2009
DOI: 10.1021/jo902160y
r
2009 American Chemical Society

Hirano et al.
JOCNote
Several different methods for the synthesis of N-substituted
benzimidazoles exist. Besides the N-alkylation or N-arylation13
of benzimidazoles (method C), Pd- and Cu-catalyzed intra-
molecular cyclization reactions to 2-substituted benzimidazoles
as reported by Brain et al. (2-methyl and 2-phenylbenzimida-
zoles)14 and Batey and Evindar (2-aminobenzimidazoles)15 as
well as others16,17 represent an important alternative; however,
the latter methods were not described for 2-unsubstituted
substrates.
The formation of 2-unsubstituted, N-substituted benzi-
midazoles with sterically demanding nitrogen substituents
presents a severe present limitation, especially in the context
of NHC preparation. The synthesis of the N-mesityl benzi-
midazole requires a multistep synthesis containing two seq-
uential palladium-catalyzed amination steps.7,18 Moreover,
the installation of even more sterically hindered nitrogen
TABLE 1. Optimization of the Reaction Conditionsa
entry
CuX (mol %)
base
DBU
DBU
time [h]
yield [%]b
1
2
3
4
5
6
7
8
CuI (20)
CuI (10)
CuI (1)
1.3
2.3
6
99
99
98
97
DBU
DBU
DBU
NEt(i-Pr)2
KOt-Bu
K2CO3
CuBr (20)
CuCl (20)
CuI (20)
CuI (20)
CuI (20)
1.25
1.6
293
3.3
4.5
98
29c
57d
97
substituents;interesting for catalytic applications of the
corresponding benzimidazolylidenes
viously reported.
aGeneral procedure: formamidine 1a (0.5 mmol), CuX, and base
(2 equiv) were suspended in DMSO (2 mL). Base was added to the
mixture and the reaction was stirred in a preheated oil bath at
110 °C. bIsolated yield. cDecomposition to 2-bromoaniline was ob-
served. dCalculated based on the 1H NMR spectrum after chromato-
graphy due to the inseparable debrominated benzimidazole.
;has not been pre-
In the course of our studies on the development of the
copper-catalyzed heterocycle syntheses19 and the establish-
ment of general and modular methods rapidly providing
NHC-precursors using formamidines,5b,c we have discove-
red an extraordinarily efficient method to install various aryl
substituents on the nitrogen atom of benzimidazoles. Herein
we report a copper-catalyzed intramolecular amination of
formamidines, efficiently leading to 2-unsubstituted benzi-
midazoles (method D).
The cyclization of N,N0-bis(2-bromophenyl)formamidine
(1a)20 was selected for an optimization study (Table 1).
Gratifyingly, the reaction was smoothly catalyzed employing
20 mol % of CuI and 2 equiv of DBU, yielding the desired
benzimidazole quantitatively (entry 1). Reducing the catalyst
loading to 10 mol % still provided the product in quantita-
tive yield without significant loss of the reaction rate and
even 1 mol % of catalyst could keep this excellent yield, albeit
the reaction progress got slightly tardy (entries 2 and 3). The
use of other copper(I) salts, CuBr and CuCl, gave compar-
able results (entries 4 and 5). However, a weaker amine base,
diisopropylethylamine, was not capable of promoting the
reaction efficiently and decomposition of the formamidine
was observed (entry 6). On the other hand, a stronger base,
KOt-Bu, caused partial protodebromination either of the
starting material or of the product to give a normal benzi-
midazol (entry 7). A weaker inorganic base, K2CO3, gave the
desired benzimidazole in 97% yield, albeit after slightly
longer reaction time (entry 8). Obviously, this reaction does
not require any external ligand for copper, although the
formamidine might act as a ligand generating the active
catalyst in situ.
Under the best conditions discovered,21 the substrate
scope of this method was evaluated (Table 2). No proto-
debrominated products were obtained in any case. First,
symmetrical formamidines (1a-e,o,p) were employed.
A strongly electron-withdrawing CF3 group was perfectly
tolerated under these reaction conditions (2b). The sub-
strates bearing a methyl group ortho to the coupling site
reduced the reaction rate significantly, while the yields of the
desired products were still excellent in both cases (2c,d). In
addition, 2,6-disubstitution of the nucleophilic coupling
partner did not disturb the desired amination at all (2e).
Unsymmetrical formamidines (1f-n) were examined as well.
N-Mesityl benzimidazole, which was utilized by Scheidt7 as a
precursor of a NHC catalyst, was obtained in 85% yield (2f).
The variation on the annulated aromatic part was success-
fully accomplished and the N-mesityl benzimidazoles with
alkyl- as well as bromo-substituents were synthesized in
quantitative yields (2g,h). Other 2,6-disubstituted aromatic
rings such as a 2,6-diisopropylphenyl or a 9-anthracenyl
group were installed on the nitrogen atom in high yields
as well (2i,j). Surprisingly and gratifyingly, the 2-tert-butyl-
phenyl group could also be incorporated into the benzimida-
zole scaffold in 85% yield, albeit the reaction was slower (2k).
Moreover, the pentabromo benzimidazole 2l was formed in
93% yield without loss of any bromine atom. The formamidine
(11) For recent examples, see: (a) Ozdemir, I.; Demir, S.; Cetinkaya, B.;
Gourlaouen, C.; Maseras, F.; Bruneau, C.; Dixneuf, P. H. J. Am. Chem. Soc.
2008, 130, 1156. (b) Kamplain, J. W.; Lynch, V. M.; Bielawski, C. W. Org.
Lett. 2007, 9, 5401.
(12) For the direct synthesis of benzimidazolium salts from dihydropyr-
ꢀ
idines and isocyanides, see: Masdeu, C.; Gomez, E.; Williams, N. A. O.;
Lavilla, R. Angew. Chem., Int. Ed. 2007, 46, 3043.
(13) For selected examples, see: (a) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie,
R.; You, J. J. Org. Chem. 2007, 72, 8535. (b) Chen, W.; Zhang, Y.; Zhu, L.;
Lan, J.; Xie, R.; You, J. J. Am. Chem. Soc. 2007, 129, 13879. (c) Longbin, L.;
Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem.
2005, 70, 10135. (d) Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald,
S. L. J. Org. Chem. 2004, 69, 5578. (e) Lam, P. Y. S.; Deudon, S.; Averill,
K. M.; Li, R.; He, M. Y.; DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000,
122, 7600.
(14) (a) Brain, C. T.; Steer, J. T. J. Org. Chem. 2003, 68, 6814. (b) Brain,
C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893.
(15) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(16) Szczepankiewicz, B. G.; Rohde, J. J.; Kurukulasuriya, R. Org. Lett.
2005, 7, 1833.
(17) Murru, S.; Patel, B. K.; Le Bras, J.; Muzart, J. J. Org. Chem. 2009, 74
2217.
(18) For another synthetic route employing only one palladium-catalyzed
reaction, starting from 1-bromo-2-nitrobenzene, see: Duan, W.-L.; Shi, M.;
Rong, G.-B. Chem. Commun. 2003, 2916.
(19) (a) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346, 1661.
(b) Schuh, K.; Glorius, F. Synthesis 2007, 2297.
(20) Amidine 1a was formed in 75% yield from commercially available
substrates. See the Supporting Information for further details.
(21) For convenience, 20 mol % of CuI was used under standard
conditions. See the Supporting Information for further details.
J. Org. Chem. Vol. 74, No. 24, 2009 9571

Hirano et al.
JOCNote
TABLE 2. Substrate Scopea
SCHEME 2. Synthesis of Benzimidazolium Salts
atom and compares favorably with known procedures. The
application of these benzimidazole derivatives in catalysis is
ongoing in our laboratories.22
Experimental Section
Procedure for the Synthesis of 1-(2-Bromophenyl)-1H-benzo-
imidazole (2a). Formamidine 1a (177 mg, 0.50 mmol, 1 equiv)
was solvedin 2 mLof DMSO. CuI (19.0 mg, 0.1 mmol, 20 mol %)
and DBU (149.3 μL, 152 mg, 1.0 mmol, 2 equiv) were added and
the reaction was stirred for 1 h and 20 min at 110 °C. H2O (20
mL) and EtOAc (20 mL) were added and the layers were
separated. The aqueous layer was extracted with EtOAc (2 ꢀ
20 mL), and the combined organic layers were treated with brine
and dried over Na2SO4. The purification by column chro-
matography (i.d. 2 cm, SiO2: 14 cm, n-pentane/EtOAc 3:1)
yielded the benzimidazole 2a as a colorless oil (135 mg, 99%).
1H NMR (400 MHz, CDCl3): δ 8.04 (s, 1H, NCHN), 7.89 (dd,
J = 7.2, 1.1 Hz, 1H, Ar-H), 7.81 (dd, J = 8.0, 1.3 Hz, 1H,
Ar-H), 7.54-7.48 (m, 1H, Ar-H), 7.45 (dd, J = 7.9, 1.8 Hz,
1H, Ar-H), 7.43-7.38 (m, 1H, Ar-H), 7.37-7.28 (m, 2H, 2 ꢀ
Ar-H), 7.21-7.17 (m, 1H, Ar-H). 13C NMR (100 MHz,
CDCl3): δ 143.2, 142.9, 135.1, 134.3, 134.2, 130.6, 129.1,
128.6, 123.7, 122.7, 121.4, 120.4, 110.5. IR (ATR): ν/cm-1
3061, 1731, 1614, 1587, 1493, 1454, 1306, 1288, 1260, 1230,
1203, 1158, 1142, 1056, 1030, 1007, 977, 889, 865, 786, 743, 716,
654, 634, 581, 553, 535. Rf (n-pentane/EtOAc 1:1): 0.29. MS
(GC-MS): m/z (%) 272 (100), 193 (86), 155 (5), 77 (5), 76 (18).
EM (ESI): m/z [M þ Hþ] calcd for C13H10BrN2 273.0022, found
273.0028. Elemental Anal. Calcd for C13H9BrN2 (273.13):
C 57.17, H 3.32, N 10.26. Found: C 57.27, H 3.26, N 10.04.
aGeneral procedure: formamidine (1 equiv) and Cul (20 mol %) were
suspended in DMSO (0.25 M). DBU (2 equiv) was added and the
mixture was stirred in a preheated oil bath at 110 °C. Isolated yields
are given. bOn a 20 mmol scale, the same yield was obtained. c140 °C.
with a 2-pyridyl substituent did not cause any catalyst
poisoning and afforded the desired benzimidazole 2m in high
yield. To prove the utility of this method an N-adamantyl-N0-
2-bromophenylformamidine was also examined in this reac-
tion. The formation of the N-adamantyl benzimidazole 2n was
realized by elevation of the reaction temperature to 140 °C.
Moreover, this method is applicable also to chlorinated forma-
midines, but distinctly longer reaction times were required and
partial decomposition of the starting materials was observed.21
Due to the synthetic versatility of the 2-unsubstituted
benzimidazoles, the simple manipulation of their structures
leads to valuable compounds for catalytic applications. In
the context of our general interest in the synthesis of new
NHC architectures, we have carried out the N-alkylation of
benzimidazoles 2 leading to the formation of the correspond-
ing benzimidazolium salt 3 in quantitative yield (Scheme 2).
The protocol presented herein represents an efficient and
straightforward method for the synthesis of benzimidazolium
salts in three steps from the corresponding aromatic amines.
In conclusion, a highly efficient copper-catalyzed synthesis of
N-substituted benzimidazoles is reported. This unprecedented
method provides rapid access especially to benzimidazoles
with sterically demanding aromatic groups on the nitrogen
Acknowledgment. We thank Mrs. Karin Gottschalk for
skillful technical assistance. Generous financial support by the
Deutsche Forschungsgemeinschaft, the Fonds der Chemischen
Industrie, the Deutsche Akademische Austauschdienst (fellow-
ship for K.H.), and the Alexander von Humboldt Foundation
(fellowship for A.T.B.) is gratefully acknowledged. The research
of F.G. has been supported by the Alfried Krupp Prize for
Young University Teachers of the Alfried Krupp von Bohlen
und Halbach Foundation.
Supporting Information Available: General experimental
methods and full characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(22) Very recently, a related paper on the ‘Synthesis of 1-Substituted
Benzimidazoles from o-Bromophenyl Isocyanide and Amines’ appeared:
Lygin, A. V.; de Meijere, A. Eur. J. Org. Chem. 2009, 5138-5141.
9572 J. Org. Chem. Vol. 74, No. 24, 2009