SHORT COMMUNICATION

DOI: 10.1002/ejoc.201001423

A Direct, Regioselective Palladium-Catalyzed Synthesis of N-SubstitutedBenzimidazoles and Imidazopyridines

Jorge Alonso,[a] Nis Halland,[a] Marc Nazaré,*[a] Omar R’kyek,[a] Matthias Urmann,[a] andAndreas Lindenschmidt*[a]

Keywords: Benzimidazoles / Nitrogen heterocycles / Palladium / Homogeneous catalysis / Regioselectivity

Unsymmetric, N-substituted benzimidazoles and imidazo-pyridines can be prepared directly from 2-halonitroarenesand amides through Pd(TFA)2/(R)-BINAP-catalyzed cross-coupling and subsequent reductive aminocyclization. This

Introduction

Benzimidazoles play a predominant role in drug discov-ery and can certainly be regarded as privileged structuresin medicinal chemistry.[1] The ability of this heterocyclicscaffold to solicit an interaction with a variety of biologicaltargets is well documented by the multitude of reports onthe observed biological activity, as well as by the fact thatseveral benzimidazole-based compounds are in develop-ment or marketed as drugs.[2–7] In many cases, the benz-imidazole is unsymmetrically substituted at one of the ni-trogen atoms of the imidazole moiety. In spite of the greatimportance of this scaffold, only a very few general regio-selective routes to N-substituted benzimidazoles have beenreported so far. Some of these methods described aremultistep processes that often require harsh reaction condi-tions and are thus limited in the substrate range.[8–10] Sur-prisingly, transition-metal-catalyzed reactions have rarelybeen successfully applied for the regioselective constructionof N-substituted benzimidazoles, until recently.[11] The lim-ited access to this structural motif often complicates theoptimization of a potential drug substance and conse-quently there is a continuous need for a direct, regioselec-tive and versatile process for the synthesis of N-substitutedbenzimidazoles.

Herein, we report a novel and general palladium-cata-lyzed method for the regioselective synthesis of unsymmet-rical, multifunctional N-substituted benzimidazoles and im-idazopyridines from 2-halonitroarenes and substitutedamides (Scheme 1).[12]

[a] Sanofi-Aventis Deutschland GmbH, Industriepark Höchst,Building G878, 65926 Frankfurt am Main, GermanyFax: +49-69-331-399E-mail: Marc.Nazare@sanofi-aventis.com

Andreas.Lindenschmidt@sanofi-aventis.comSupporting information for this article is available on theWWW under http://dx.doi.org/10.1002/ejoc.201001423.

© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2011, 234–237234

sequence can be conducted by a one-pot procedure. Themethod is versatile and allows the straightforward, regio-selective preparation of these important nitrogen heterocy-cles.

Scheme 1. Synthesis of benzimidazoles from 2-halonitroarenes andamides.

Results and DiscussionAlthough copper- and palladium-catalyzed protocols for

the C–N cross-coupling between aryl halides and amideshave been reported, very few examples employing 2-haloni-troarenes exist.[13] Therefore, we first directed our effortstowards a practical protocol for the synthesis of benzimid-azoles by developing an efficient and general amidation of2-halonitroarenes. Some representative results obtainedduring our optimization of the reaction are shown inTable 1 and Figure 1. An initial screen of catalyst systemscontaining highly active monodentate ligands did not pro-duce the desired coupling product in useful yields (Entries1–3). However, when bidentate ligands were used, adequateproduct formation could be observed, with exception in thecases when either palladium(0) sources or dppf as ligandwas used (Entries 4–8), where inferior yields were obtained.Pd(TFA)2/(R)-BINAP[14] was found to be very effective incatalyzing the reaction and provided excellent yields with a8 mol-% catalyst loading (Entry 9).[15] Significantly loweryields were obtained when the catalyst loading was de-creased (Entry 10). Studies directed towards the replace-ment of the base cesium carbonate resulted in a reducedyield as well (Entries 11–13).[16]

N-Substituted Benzimidazoles and Imidazopyridines

Table 1. Influence of the palladium source, the catalyst loading,ligand, and base on the arylation of N-phenylacetamide with 4-chloro-3-nitroanisol.

YieldEntry Pd-source (mol-%) Ligand (mol-%) Base (1.4 equiv.)

[%][a]

1 Pd(TFA)2 (8) P(o-tol)3 (16) Cs2CO3 �102 Pd(TFA)2 (8) X-Phos (16) Cs2CO3 �103 Pd(TFA)2 (8) P(t-Bu)3HBF4 (16) Cs2CO3 �104 PdCl2(dppf) (8) – Cs2CO3 �105 Pd2(dba)3 (4) (R)-BINAP (8) Cs2CO3 �106 Pd(TFA)2 (8) Xantphos (8) Cs2CO3 687 PdCl2(BINAP) (8) – Cs2CO3 748 Pd(OAc)2 (8) (R)-BINAP (8) Cs2CO3 719 Pd(TFA)2 (8) (R)-BINAP (8) Cs2CO3 9310 Pd(TFA)2 (2) (R)-BINAP (2) Cs2CO3 1211 Pd(TFA)2 (8) (R)-BINAP (8) K3PO4 8412 Pd(TFA)2 (8) (R)-BINAP (8) K2CO3 2813 Pd(TFA)2 (8) (R)-BINAP (8) KOtBu �10

[a] Yield determined by 1H NMR spectroscopy vs. an internal stan-dard.

Figure 1. Structure of X-Phos, (R)-BINAP and Xantphos.

For the subsequent reductive aminocyclization, iron inglacial acetic acid was identified as the most-effective andreliable method.[17] With this novel reaction sequence, abroad spectrum of 2-halonitroarenes and amides can beemployed making the procedure generally applicable. Thisis illustrated by the preparation of a number of substitutedbenzimidazoles and imidazopyridines with a wide range ofelectronic and steric properties. (Table 2).

By reacting N-phenylacetamide with 2-chloro-, 2-bromo-,or 2-iodonitrobenzene, 2-methyl-1-phenyl-1H-benzimid-azole was produced in essentially identical yields (Entry 1).The corresponding imidazopyridines can be prepared bythe same process from the respective chloronitropyridinesin good to excellent yields as well (Entries 2–4). With sub-strates that contain more than one halogen substituent,such as 2,3-dichloronitrobenzene and 2,5-dichloronitroben-zene, an excellent regioselectivity is observed, as only thechlorine atom ortho to the nitro group reacts (Entries 5, 6).However, with 2,4-dichloronitrobenzene, no regioselectivityis detected, and a mixture of products is obtained regardlessof the amount of amide used. A number of different elec-tron-withdrawing and -donating substituents such asmethyl-, methoxy-, or ester groups in various positions onthe 2-halonitroarene substrate are tolerated (Entries 7–13).These results demonstrate the high versatility of this se-

Eur. J. Org. Chem. 2011, 234–237 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 235

Table 2. Preparation of benzimidazoles from 2-halonitrobenzenederivatives and N-phenyl-acetamide.[a]

[a] Reaction conditions: (i) 2-halonitrobenzene derivative (1 equiv.)or ortho-chloronitropyridine (1 equiv.), N-phenylacetamide(1.2 equiv.), Cs2CO3 (1.4 equiv.), Pd(TFA)2 (0.08 equiv.), and (R)-BINAP (0.08 equiv.) at 80 °C in toluene. (ii) Fe (10 equiv.) in glacialAcOH at reflux for 30 min. [b] Yield of isolated product with�95% purity (1H NMR and LC/MS). [c] Method B (one-pot reac-tion conditions) was used; see Experimental Section. [d] Preparedon a 5-g scale.

quence of reactions. Once more, a variety of substitutedimidazopyridines can be prepared in good to excellentyields as well (Entries 8–10, 12). It should be noted that inaddition to performing well on a 100-mg scale, the reaction

M. Nazaré, A. Lindenschmidt et al.SHORT COMMUNICATIONcan also be run on a multigram scale without any decreasein yield (Entry 13).[18] As expected, the very acid-sensitivedimethoxy-acetal protecting group is unstable under themildly acidic reaction conditions of the cyclization step.Nevertheless, the good yield (67%) of the obtained 2-methyl-1-phenyl-1H-benzoimidazole-5-carbaldehyde withthe unprotected, reactive aldehyde functionality underlinesthe relative mildness of the reaction conditions (Entry 14).Furthermore, the reaction sequence can be carried out as aone-pot procedure to give the final products in essentiallyequivalent yields relative to the standard procedure(Table 2, Entries 6, 12; Table 3, Entry 4). This represents animportant improvement over the currently available classi-cal regioselective routes to N-substituted benzimidazolesand imidazopyridines.

The results for the syntheses of several benzimidazolesfrom 2-iodonitrobenzene and a variety of different amidesare summarized in Table 3. Cyclic as well as aliphatic alkyl,aryl and heteroaryl amides are successfully converted intothe respective benzimidazoles (Entries 1–4, 6–8). It shouldbe pointed out that the reaction sequence exhibits a signifi-cant substrate tolerance with respect to the amide compo-nent. For example, various functional groups such as a cy-ano-, ester- or amino group, a chloro substituent, or pyri-doarenes are compatible (Entries 5, 9–13). The amino aswell as the acid component of the employed amide can bevaried. The corresponding functionalized N-benzimidazolesare obtained in good to excellent yields in most cases. Eventhe annelated 1,2-cycloalkano-benzimidazoles are readilyaccessible in a direct, simple and regioselective fashion (En-tries 4 and 5).

Conclusions

In summary, we have developed a highly versatile, ef-ficient and mild method for the regioselective synthesis ofpolyfunctional benzimidazoles from commercially available2-halonitrobenzene derivatives and secondary amides. Thereadily applicable process allows the preparation of this im-portant class of heterocycles in good to excellent yields. Inaddition, starting from ortho-nitro-pyridines, the method isalso well suited for the synthesis of imidazopyridines. Be-cause of the wide scope of possible substrates and its intrin-sic regioselectivity, this process represents a valuable exten-sion of the classical synthetic methods towards benzimid-azoles and imidazopyridines.

Experimental SectionGeneral Procedure (Method A): The 2-halonitroarene (0.5 mmol),the amide (0.6 mmol), palladium trifluoroacetate (13 mg,0.04 mmol), (R)-BINAP (24 mg, 0.04 mmol), and cesium carbonate(212 mg, 0.7 mmol) were placed in a reaction tube, which was thenpurged with dry argon. Dry toluene (3 mL) was added, and themixture was heated at 80 °C for 18 h. The reaction mixture washydrolyzed with water (3 mL), and filtered through a pad of Celiteand rinsed with ethyl acetate. The crude product was dissolved inglacial acetic acid (10 mL) and was heated at reflux for 30 min in

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Table 3. Preparation of benzimidazoles from 2-iodonitrobenzene byusing various amides.[a]

[a] Reaction conditions (method A): (i) 2-iodonitrobenzene(1 equiv.), amide (1.2 equiv.), Cs2CO3 (1.4 equiv.), Pd(TFA)2

(0.08 equiv.) and (R)-BINAP (0.08 equiv.) at 80 °C in toluene. (ii)Fe (10 equiv.) in glacial AcOH at reflux for 30 min. [b] Yield ofisolated product with �95% purity (1H NMR and LC/MS). [c]Method B (one-pot reaction conditions) was used; see Experimen-tal Section.

N-Substituted Benzimidazoles and Imidazopyridines

the presence of iron powder (279 mg). The acid was removed undervacuum, and the residue was suspended in saturated sodium hydro-gen carbonate solution and extracted with ethyl acetate. The ob-tained crude product was purified by preparative HPLC (C18 re-verse-phase column, elution with a water/MeCN gradient with0.1% TFA). The fractions containing the product were evaporatedand lyophilized to yield a white solid.

Method B (One-Pot Procedure): The first reaction step was per-formed as described in Method A. After heating at 80 °C for 18 h,the iron powder and glacial acetic acid are directly added. The reac-tion mixture was then heated at reflux for 30 min. Work-up andproduct purification was conducted in the same manner as that inmethod A.

Supporting Information (see footnote on the first page of this arti-cle): General experimental methods and the characterization dataof the compounds are presented.

Acknowledgments

This work was supported by the European community by a MarieCurie Host fellowship for the transfer of knowledge (HCTMCR).

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[16] Though variations in the temperature only led to a moderatedecrease in yield, a switch from toluene to dioxane completelyinhibited product formation.

[17] A. Alberti, P. Carloni, P. Stipa, R. Andruzzi, G. Marrosu, A.Trazza, J. Chem. Soc. Perkin Trans. 2 1991, 1019–1023.

[18] 2-Methyl-1-phenyl-1H-benzoimidazol-5-carboxylic acid methylester was prepared on a 5-g scale from 4-chloro-3-nitrobenzoicacid methyl ester and phenylacetamide.

Received: October 19, 2010Published Online: December 9, 2010