Health Articles

Developments towards regioselective synthesis of 1,2disubstituted benzimidazoles

Developments Towards Regioselective Synthesis of 1,2-Disubstituted Lusa C. R. Carvalho,[a] Eduarda Fernandes,[b] and M. Manuel B. Marques*[a]  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 tine), a histamine H1 receptor antagonist for the oral treat- Abstract: 1,2-Disubstituted benzimidazoles play an im- ment of allergic rhinitis and chronic idiopathic urticaria.
portant role in several areas and particularly as drugdiscovery targets. Herein, several methods to assemblethese structures are reviewed, from the classical ap-proaches to the more recently developed metal-cata-lyzed intramolecular amination process, the cascadearylACHTUNGREamination/condensation reaction and polymer-sup-ported benzimidazole assembly under microwave condi-tions.
Keywords: amination · cross-coupling · nitrogen hetero-cycles · regioselectivity · synthetic methods Heterocyclic compounds are known to play an importantrole in drug discovery, since the majority of therapeuticdrugs contain a heterocyclic unit. Within the vast range ofheterocycles, benzimidazoles were found to be trendy struc-tures employed in several areas such as materials science,for example, in fuel cells,[1] or in the pharmaceutical indus-try. A successful example is Nexium (esomeprazole), aproton pump inhibitor used to treat peptic ulcers and gastro- Moreover, 1,2-disubstituted benzimidazoles were also de- esophageal reflux disease, which became one of the most scribed as intermediates for dyes and polymers,[13] and have widely prescribed drugs, with sales of about $5 billion in frequently been used as ligands.[14] In addition, there have 2009.[2] In 1872, when Hobrecker reported the first benzimi- also been reports of their use as possible precursors for ami- dazole synthesis, of 2,5- and 2,6-dimethylbenzimidazole, he noboronic acids with an interest as bifunctional organic cat- never suspected that benzimidazole scaffold would become such a preeminent structure.[3] Undoubtedly, benzimidazoles are important scaffolds, 1,2-Disubstituted benzimidazoles and their derivatives thus substantial efforts have been made to the search for represent an important branch of this family. These struc- new synthetic strategies to assemble this structure, both in tures were reported as valuable bioactive structures, such as solution[16] and in the solid phase.[17] Solid-phase synthesis is specific angiotensin II receptor type 1 selective antagonists,[4] extremely useful for combinatorial approaches towards or hepatitis C virus NS5B polymerase inhibitors.[5] Further- novel benzimidazole libraries with increased structural com- more, they exhibit several other pharmacological activities including antidiabetic,[6] antihistamine,[7] analgesic,[8] antivi- While methods to prepare 1- or 2-substituted benzimida- ral,[9] chemotherapeutic,[10] antifungal,[11] and antiparasitic[12] zoles have highly increased during the last years,[18] the as- applications. The relevance of these compounds can be dem- sembly of 1,2-disubstutitued benzimidazoles remains an in- onstrated by the profusion of pharmaceutical products in tricate task (Scheme 1).[19] the market, for example, the antihypertensives Micardis (tel- The classical and most common methods to assemble misartan) and Atacand (candesartan), or Bilaxten (bilas- benzACHTUNGREimidazoles involve the condensation of o-phenyleneACHTUNGREdi- ACHTUNGREamine with aldehydes, carboxylic acids, or their derivatives(nitriles, amidates, orthoesters; Scheme 2, route a).[20] N-Al-kyltion or N-arylation of benzimidazoles are frequent alter- [a] L. C. R. Carvalho, Dr. M. M. B. Marques natives (Scheme 2, route b).[6] However, these methods are Departamento de Qumica usually not suitable for the regioselective synthesis of the Faculdade de CiÞncias e TecnologiaUniversidade Nova de Lisboa 1,2-disubstitutued benzimidazoles and are limited to the Campus de Caparica 2829-516 Caparica (Portugal) available starting materials. Consequently, improvements Fax: (+ 351) 21-294-8550 were made towards the development of new strategies, such as the metal-catalyzed arylamination chemistry (Scheme 2, [b] Dr. E. Fernandes route d)[16a] and the cascade arylamination/condensation Departamento de CiÞncias Qumicas method (Scheme 2, route e).[16b,c] The development of solid- Faculdade de Farmcia, Universidade do PortoRua Anibal Cunha 164, 4099-030 Porto (Portugal) phase synthesis (Scheme 2, route c),[17] allied with the opti- Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. M. B. Marques et al.
tives with 1,2-diaminoarenes followed by cyclization.[20] Dueto the lack of differentiation between the two nitrogenatoms, usually leading to a mixture of regioisomers, thismethod is not suitable to assemble 1,2-disubstituted benz-ACHTUNGREimidazoles. Additionally, this method is restricted to theavailable starting materials, which is the main limitation forthe construction of more complex molecules.
To the best of our knowledge, no extensive study has been undertaken on the regioselectivity achieved with thesemethodologies, which are frequently applied to simple un-substituted diaminoarenes. The reported works are typicallylimited to the optimization of the reaction conditions. Anexample is the condensation of o-phenylenediamine with al- Scheme 1. Examples of the intricate task of assembling 1,2-disubstutitued dehydes, one of the most studied approaches for the prepa- Eduarda Fernandes was born in Vinhais(Portugal). She obtained a degree in phar-maceutical sciences in 1991 and a Ph.D. inpharmaceutical chemistry in 1996. In 1997she joined the department of chemical sci-ences of the Faculty of Pharmacy, Univer-sity of Porto, and was made an AssistantProfessor in 2008. Her research interestsfocus on the development of in vitro andin vivo methodologies for the developmentand screening of antioxidant and anti-in-flammatory drugs, as well as the underly-ing mechanisms of pro-oxidant and pro-in-flammatory xenobiotics.
Lusa C. R. Carvalho was born in Lisbon(Portugal), and she received her degree inchemistry in 2006 from the Instituto Supe-rior Tcnico. In 2007, she joined the re-search group of Dr. M. Manuel B. Mar- Scheme 2. Available methods to assemble 1,2-disubstituted benzimida- ques in the Faculdade de CiÞncias e Tecno- logia, focusing her research interests in car-bohydrate solid-phase synthesis. She obtained herM.Sc.in 2008 and currently she is under- mization of microwave conditions[21] allowed a more rapid, taking her Ph.D. research on heterocyclic efficient and sustainable route to achieve this relevant class chemistry, mainly focused on the synthesis of benzimidazoles.
of novel indole and benzimidazole deriva- The pursuance of simple and regioselective synthetic tives with anti-inflammatory properties.
methods for these compounds remains an emerging research Maria Manuel Marques was born in area. This Minireview highlights the developments made Lisbon (Portugal). She studied chemistry over the last few years on the synthesis of 1,2-disubstituted at the new University of Lisbon from benzimidazoles, not only in regard of the optimization of where she also received her Ph.D. in 2001 the reaction conditions, but also towards novel regioselec- in organic chemistry under the supervisionof Prof. Dr. Sundaresan Prabhakar. From tive methods that could lead to more complex molecules in September 2001 to May 2003 she worked a straightforward way.
as a postdoctoral research fellow at the In-stitute of Organic Chemistry at the Univer-sity of Vienna with Prof. Dr. J. Mulzer. In The Classical Methods Struggle 2003, she joined the Faculty of Science andTechnology, New University of Lisbon(Requimte) as an assistant research fellow.
The classical synthetic methods to assemble the benzimida- Her research encompasses the develop- zole ring are still widely used owing to their inherent sim- ment of new methodologies towards bioactive compounds, in particular small heterocyclic molecules with anti-inflammatory activity. Since 2004she has also been involved in the organic chemistry teaching at the same One of the most traditionally used methods relies on the department, and supervises several Ph.D. and master students.
condensation of aldehydes, carboxylic acids or their deriva-  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 Regioselective Synthesis of Disubstituted Benzimidazoles ration of simple 1,2-disubstituted structures. The employ-ment of several catalysts under mild conditions such aspoly(N,N'-dibromo-N-ethylbenzene-1,3-disulfonamide)(PBBS) or N,N,N,N-tetrabromobenzene-1,3-disulfonamide(TBBDA),[22] l-proline[23] or SiO2/ZnCl2 under solvent-freeconditions[24] usually provides the products in good yields(Scheme 3).
Scheme 5. Reduction and cyclization from o-nitroanilines[25] (PPA = poly-phosphoric acid).
Scheme 3. Synthesis of simple 1,2-disubstituted benzimidazoles using a to elicit substitution on the sterically less-hindered nitrogen.
SiO2/ZnCl2 system[24] (MW = microwave).
In the first reported synthesis of Telmisartan (10), the alky-lation of 8 with the 4-(bromomethyl)-2-biphenylcarboxylicacid tert-butyl ester (9) afforded a mixture of two dibenzimi- In 2010, Erion and co-workers prepared some phosphonic dazoles (Scheme 6).[26] acid containing benzimidazoles by the cyclization of 3-nitro- The same was observed by Kool and Taniguchi that ob- 1,2-phenylenediamine(1) with the aldehyde 2, using FeCl3/ tained mixtures of N1- and N3-isomers of toluoyl nucleoside SiO2 system as catalyst (Scheme 4).[6] (12 and 13, respectively) in a 1:19 ratio (Scheme 7).[27] In their pursuit towards purine-based FBPase inhibitors, Erion and co-workers have recently synthesized severalbenzACHTUNGREimidazole-based compounds that mimic the previousones. The adopted synthetic strategy for N-alkylation ofbenzimiACHTUNGREdaACHTUNGREzole consisted on a Mitsunobu approach or reac-tion with alkyl bromides (Scheme 8).[6] Recently, Kayalgil and co-workers reported the synthesis Scheme 4. Preparation of phosphonic acid containing benzimidazoles.[6] of 1,3-diarylpyrazinoACHTUNGRE[1,2-a]benzimidazole derivatives. The When the two nitrogen atoms need to be differentiated, thereduction and cyclization fromo-nitroanilines is a commonlyused method. First the freeamine group undergoes reac-tion, such as acylation, followedby the nitro group reductionand subsequent reaction with asuitable substrate to give thebenzACHTUNGREimidaACHTUNGREzole scaffold.[5,25] o- Scheme 6. First reported Telmisartan synthesis[26] (TFA = trifluoroacetic acid).
Halonitrobenzenes like o-bro-monitrobenzene (4) can also beused in order to achieve the corresponding N-substituted o-nitroaniline (5; Scheme 5), which after hydrogenation af-fords the corresponding amine 6 that can undergo subse-quent acylation and cyclization to 7.[25] Functionalization of the Benzimidazole Ring Scheme 7. Synthesis of toluoyl nucleosides intermediates reported byKool and Taniguchi.[27] Another current method is the N-alkylation of 2-substitutedbenzimidazoles that is often achieved by reaction witheither an alkyl halide or an acyl chloride. Although com- reaction of a benzimidazole moiety with acyl chlorides gave monly used, this method is usually not regiospecific, tending the corresponding 2-aryloylbenzimidazole derivatives, which Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. M. B. Marques et al.
Scheme 8. N-Alkylation of benzimidazole by means of the Mitsunobu re-action or with alkyl bromides[6] (DEAD = diethylazodicarboxylate).
were then treated with 2-bromoacetophenones to give 1-(2-aryl-2-oxoethyl)-2-aryloylbenzimidazoles Scheme 11. N-Arylation of several 2-substituted 1H-benzimidazoles in a one-pot approach by Zhao and co-workers.[32] dine hydrochloride to form the 2-substituted 1H-benzimida-zoles, in the presence of CuBr and CsCO3, and sequentialaddition of the aryl iodide and ligand (3,4,7,8-tetramethyl-1,10-phenantroline) to afford the desired products in moder-ate yields.[32] When 2-bromo-4-methylacetaniline (14) wasemployed, a mixture of the two regioisomers (16 and 17)was obtained.
Functionalization of C-2 position is another possible Scheme 9. Kayalgil and co-workers approach to 1-(2-aryl-2-oxoethyl)-2- aryloylbenzimidazoles synthesis[28] (TEA = triethylamine).
During their recent work towards the synthesis of melaninhormone receptor 1 antagonists, Hçgberg and co-workersdescribed the synthesis of some benzimidazole intermediates Due to its limitations in scope, metal-catalyzed N-aryla- by acylation of the 2-position with the Weinreb amide in the tion of benzimidazoles has been scarcely used, and has only presence of LDA (lithium diisopropylamide) to afford the been applied to unsubstituted benzimidazoles.[29] Recently, desired compounds (Scheme 12).[33a] advances on Pd-based catalytic systems for efficient C Ncoupling reactions have been developed. Buchwald and co-workers have described the arylation of simple imidazole orbenzimidazole rings with aryl halides.[30] Bao et al. have developed a copper-catalyzed reaction (Scheme 10). The group has demonstrated that under theseconditions benzimidazole was less reactive towards aryl hal-ides than imidazole, requiring higher temperatures to give Scheme 12. C-2 acylation with the Weinreb amide.[33a] the product in moderate yields.[31] 2-Halo-substituted benzimidazoles, such as 2-chloro- or 2- bromobenzimidazoles, are important intermediates for func-tionalization of the benzimidazole scaffold at the 2-position(Scheme 13). These compounds are versatile intermediates Scheme 10. Metal-catalyzed N-arylation of benzimidazoles (TEAC = bis-ACHTUNGRE(tetraethylammonium)carbonate; dba =dibenzylideneacetone).
Recently, Zhao and co-workers developed the N-arylation of several 2-substituted 1H-benzimidazoles in a one-pot Scheme 13. Benzimidazole C-2 functionalization via 2-halobenzimida- manner (Scheme 11). The method relied on the use of ami-  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 Regioselective Synthesis of Disubstituted Benzimidazoles to prepare of 2-heterobenzimidazoles (Scheme 13, paths a, b ACHTUNGREimidazoles. Recently, the group developed a comprehensive and d) and 2-arylbenzimidazoles (Scheme 13, path c).
study of the regioselectivity of the reaction of 1,2-dihalo- In order to improve the regioselectivity of the synthesis of ACHTUNGREarenes with N-substituted amidines to obtain 1,2-disubstitut- N-substituted benzimidazoles, novel methods have been de- ed benzimidazoles (Scheme 16). Several factors and its influ- veloped, as explained below.
Metal-Catalyzed Intramolecular Amination/ The development of a metal-catalyzed intramolecular aryl-ACHTUNGREamination/cyclization approach was an elegant way to cir-cumvent the classical methods limitations, allowing the con-struction of complex benzimidazoles in a regioselective way.
Scheme 16. Comprehensive study of the regioselectivity described by Firstly reported by Brain and co-workers,[34] this method Deng and Mani.[37] was readily adopted with high success by several groups thatused several metal salts such as palladium-, copper- orcobalt-based catalysts (Scheme 14).
ence on the regioselectivity were investigated, such as: thechemoselectivity of nitrogen atoms in the first aminationstep; the steric and electronic effect of the substituent onthe arene ring; the reactivity control between differentiatedhalides or even the reaction with different amidines.[37] A heretogeneous system for the synthesis of 1,2-disubsti- tuted benzimidazoles using copper(II) oxide nanoparticlesunder ligand-free conditions was described by Punniyamur-thy and co-workers (Scheme 17). The reactions revealed to Scheme 14. Brains approach using amidines.[34] In fact, the recent advances on metal-mediated coupling chemistry stimulated the development of these new method-ologies, allowing the easy assembly of heterocyclic com-pounds. Palladium-catalyzed arylamination chemistry hasbeen improved, mainly due to the development of newligand systems.[35] Concerning copper catalysis, the develop-ment of N,N-, N,O-, and O,O-bidentate ligands improved Scheme 17. Heterogeneous synthesis of benzimidazoles described by Ullmann-type coupling reactions.[36] In 2008, Buchwald and co-workers developed a copper- catalyzed amination for the synthesis of substituted 2-aryl-benzimidazoles in good yields from the corresponding ami- be efficient and general for the synthesis of 2-alkyl-, 2-aryl-, dines, also demonstrating that the procedure could be ex- and 2-aminobenzimidazoles. Moreover, the catalyst could be tended to the preparation of N-methylated benzimidazoles recovered and recycled without loss of activity and selectivi- (Scheme 15).[16a] More recently, the Punniyamurthy group described a cobalt-catalyzed intramolecular C N cross-coupling reactionby using (Z)-N-(2-halophenyl)-N-phenylamidines and N-(2-bromophenyl)benzamides as starting materials, and [Co-ACHTUNGRE(acac)2] as catalyst in the presence of K2CO3 (Scheme 18).
Scheme 15. Buchwald Cu-catalyzed amination.[16a] Mani and co-workers have previously reported on the CuI-catalyzed amination reaction of 1,2-dihaloarenes withguanidines and amidines, to achieve 2-substituted 1-H-benz- Scheme 18. Cobalt-catalyzed benzimidazole synthesis.[39] Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. M. B. Marques et al.
The corresponding substituted benzimidazoles were ob-tained in good to high yields.[39] The synthesis of benzimidazoles by a copper-catalyzed in- tramolecular amination in water (Scheme 19) was recentlyreported by Chen and co-workers.[40] Although successfullyapplied for the synthesis of 2-substituted 1H-benzimidazoles,it presented a limited scope for 1,2-disubstituted benzimida-zoles.
Scheme 21. Employment of o-haloarylcarbodiimides developed by Baoand co-workers.[43] Scheme 19. Copper-catalyzed (DMEDA = N,N'-dimethylethylenediamine).
The intramolecular amination method was also successful- ly applied in the synthesis of N-substituted 2-heterobenzimi- Scheme 22. Synthesis of benzimidazole derivatives from diphenylcarbo-diimides.[45] dazoles. Batey and co-workers reported a palladium orcopper-catalyzed intramolecular aryl guanidinylation for theformation of 2-aminobenzimidazoles in moderate to high The same approach was adopted by Cai and co-workers, yields (Scheme 20).[41] Other fused imidazole systems, like who synthesized a variety of 2-aminobenzimidazoles from o- purine or xanthine-based compounds, could also be readily haloanilines and carbodiimides by means of a copper-cata- obtained by this method.[42] lyzed reaction, in the presence of NaOtBu and by using N-methyl-2-pyrrolidinone (NMP) as solvent in a "ligand-free"manner (Scheme 23).[46] Scheme 23. Synthesis of 2-aminobenzimidazole from o-haloanilines and Scheme 20. Synthesis of 2-aminobenzimidazoles by a Cu-catalyzed guani- carbodiimides by means of a copper-catalyzed reaction.[46] dinylation method.[41] While by the usual method the precursors o-haloguani- Wang and co-workers, following a previous work from the dines needed to be previously synthesized, Bao and Lv dem- group,[47] developed a three-component reaction of sulACHTUNGREfonyl- onstrated that 2-heterobenzimidazoles like 2-amino, 2-imi- ACHTUNGREazides, terminal alkynes and 2-bromoaniline to achieve 2- dazoyl and 2-phenoxyl benzimidazoles could be easily pre- substituted 1-sulfonylbenzimidazoles. The proposed mecha- pared from o-haloarylcarbodiimides.[43] Thus, the group de- nism involves the copper-catalyzed azide/alkyne addition to veloped a one-pot copper-catalyzed addition/C N coupling form a ketenimine intermediate that is attacked by the method (Scheme 21), similar to previously described metal- amine to generate the corresponding N-sulfonylamidine.
catalyzed intramolecular amination. Since diaza compounds The copper-catalyzed intramolecular C N coupling afforded have been previously described as ligands in copper-cata- the products in moderate to good yields (Scheme 24).[48] lyzed coupling reactions, the Bao group also investigated The intramolecular copper-catalyzed arylamination can the same approach in the absence of ligand.[44] also be applied to the synthesis of N-substituted 2-mercapto- Moreover, Bao and co-workers recently reported the use benzimidazoles. The preparation of these compounds was of CuACHTUNGRE(OAc)2/O2 system to prepare benzimidazole deriva- described by Muzart and co-workers, who attained the de- tives directly from the reaction of diarylcarbodiimides with sired products by the S-alkylation of thiourea derivatives, different nucleophiles, through addition/C H activation in a one-pot cascade procedure (Scheme 22).[45] (Scheme 25).[49] They also demonstrated that benzimidazole  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 Regioselective Synthesis of Disubstituted Benzimidazoles ACHTUNGREacetanilide followed by cyclization to afford the correspond-ing N-arylbenzimidazoles (Scheme 27).[16c] Scheme 24. Wangs three-component reaction.[48] When isomeric forms of aryl bromides were applied (19 and 21, respectively), the method provided access to the re- Scheme 25. Synthesis of N-substituted 2-mercapto benzimidazoles by gioselective synthesis of compounds 20 and 22 in high yields, Muzart and co-workers.[49] proving the advantage of the method (Scheme 28).
thiones could be obtained from 2-mercaptobenzimidazolessubstituted with a p-methoxybenzyl group.
Despite of the advantages of the method, it commonly re- quired a multistep synthesis to prepare the o-haloaryl or al-kylamidine precursors. Thus, cascade arylamination methodemerged as a suitable alternative.
Cascade Arylamination/Condensation Method Scheme 28. Regioselective synthesis of compounds 20 and 22.
Recently, Ma and Buchwald independently developed a re-gioselective benzimidazole synthesis based on a cascadearylACHTUNGREamination/condensation process.
As alternative to amination approach, Buchwald and In 2007, Ma and co-workers developed a mild process to Zheng reported a copper-catalyzed amidation method for achieve 1,2-disubstituted benzimidazoles.[16b] Encouraged by the preparation of N-alkylbenzimidazoles. The first amida- previous studies, the group investigated the o-NHCOR tion step was accomplished by using CuI as the catalyst and group effect on copper-catalyzed arylamination, producing trans-N,N-dimethyl-1,2-cyclohexanediamine as the ligand.
the corresponding o-aminoanilides. The 1,2-disubstituted Further dehydration conditions allowed the preparation of benzimidazoles were achieved in one-pot manner through (Scheme 29).[50] This method was also successfully applied (Scheme 26) in moderate to high yields.
by Legraverend and Ibrahim in the synthesis of substituted In a related report, Buchwald and co-workers developed a palladium-catalyzed amination of o-bromo- or o-chloro- Scheme 29. Copper-catalyzed amidation by Zheng and Buchwald.[50] In a recent report, Lindenschimdt and co-workers devel- Scheme 26. Intramolecular condensation/cyclization procedure developedby Ma and co-workers.[16b] oped a general palladium-catalyzed amidation of 2-haloni- Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

M. M. B. Marques et al.
troarenes with secondary amides using a [PdACHTUNGRE(tfa)2]/(R)-BINAP system (tfa = trifluoracetic acid; BINAP = 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl). After reductive ami-nocyclization with Fe/AcOH, the desired 1,2-disubstitutedbenzimidazoles were obtained with moderate to high yields(Scheme 30).[52] Scheme 32. N-Substituted 2-fluoromethyl benzimidazole assembly.[54,55] The Zhang group enlarged the scope using different (2- haloaryl)trifluoroacetimidoyl chlorides with Cl, Br, or I inthe ortho-position in the presence of a CuI/TMEDA system.
It was demonstrated that the presence of trifluoromethylgroup is essential for the amination reaction to proceed.
Scheme 30. Amidation Schmidt and co-workers[56] described the preparation of substituted benzimidazoles from 1,1-dibromoethenes and o-diaminobenzenes. The reaction proceeds in the presence of 1,4-diazabiclycoACHTUNGRE[2.2.2]octane (DABCO), using NMP as sol-vent at 100 8C (Scheme 33). The proposed mechanism, based Several other methods were reported to assemble 1,2-disub-stituted benzimidazoles.
Fluorinated heterocycles constitute a significant part of the benzimidazole family. Resembling the metal-catalyzedintramolecular amination process, Wu and co-workers re-ported the synthesis of N-alkyl and N-aryl 2-fluoroalkylben-zimidazoles by intramolecular cyclization reaction of severalamidines mediated by [bis(trifluoroacetoxy)iodo]benzene Scheme 33. Synthesis of substituted benzimidazoles from 1,2 dibromo- (BTI).[53] Interestingly, it was observed that when unsymmet- rical N,N-diarylfluoroethamidines were used, two possibleproducts could be formed due to the electronic effects ofsubstituent at the para-position of both benzene rings on experimental observations, involves the generation of an (Scheme 31).
alkynyl bromide intermediate upon treatment of dibromidewith base. Reaction of the generated intermediate with acorresponding diamine provides an alkynylamine com-pound, which subsequently cyclizes to give the desired sub-stituted benzimidazoles.
More recently Siddapa et al.[57] used dibromomethylarenes to access substituted benzimidazoles in the presence ofKOtBu as base followed by the addition of iodine and cata-lytic amount of benzoylperoxide under reflux conditions(Scheme 34). Cho and Kim reported the synthesis of 1,2-di- Scheme 31. Synthesis of N-substituted 2-fluoroalkylbenzimidazoles by ACHTUNGREsubstituted benzimidazoles from N-alkyl-1,2-diaminoarenes by means of alkyl group transfer, in the presence of a ruthe-nium catalyst and acetophenone as hydrogen acceptor(Scheme 35).[58] The Wu[54] and Zhang[55] groups have independently devel- oped similar procedures to assemble N-substituted 2-fluoACHTUNGREro- ACHTUNGREmethylbenzimidazoles. Both groups reported the doubleamination of fluorinated acetimidoyl halides with primaryamines catalyzed by CuI. While the Wu group applied aligand-free approach, Zhang and co-workers used a CuI/TMEDA (TMEDA = N,N,N',N'-tetramethyl-1,2-ethanedia- mine) system (Scheme 32). Wu approach consisted on a Cu-catalyzed coupling of imidoyl chlorides and primary amines Scheme 34. One-pot synthesis of benzimidazoles from gem-dibromo- under mild conditions.
ACHTUNGREmethylarenes using o-diaminoarenes.[57]  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 Regioselective Synthesis of Disubstituted Benzimidazoles Scheme 35. Ruthenium-catalyzed alkyl group transfer to prepare benz-ACHTUNGREimidazoles.[58] Scheme 36. Usual method for benzimidazole assembly by means of a solid-phase synthesis (DCC = N,N'-dicyclohexylcarbodiimide; DMAP = 4-dimethylaminopyridine).
Due to the imperative urgency to prepare new heterocyclicstructures with increased structural diversity, solid-phase or-ganic synthesis (SPOS) appeared as a valuable alternative NMR spectroscopy. Moreover, microwave-assisted accelera- over the synthesis in solution. This methodology simultane- tion can be utilized in the synthesis process.
ously allows the rapid construction of small libraries of com- During their work towards a triazafluorene library,[21] Sun plex derivatives and a high-throughput screening. Although and co-workers adopted a multidisciplinary approach in considerable work has been performed optimizing not only which a clear comparison between regular and microwave the SPOS reaction conditions, but also the polymeric sup- conditions was undertaken (Scheme 37). The group adopted ports and linkers, it still reveals limitations mainly due to a classical synthetic route to solid-phase conditions. It was the heterogeneous character of the reactions.
demonstrated that microwave-assisted synthesis is very ef- The polymer-supported synthesis of benzoannelated nitro- fective on speeding up the reaction, and that the reaction gen heterocycles, which includes benzimidazole derivatives, monitoring can be easily performed by 1H NMR spectrosco- is well established and several strategies have been de- scribed.[17] However, during thelast couple of years, no newstrategies to assemble benzimi-dazoles in SPOS have been re-ported.
best of our knowledge, no re-gioselective methods have beenperformed in the solid phase,opening room for improvementin this field.
The usual method to assem- ble benzimidazole scaffold onsolid support resembles one ofthe classical methods for benz-ACHTUNGREimidazole preparation: the re-duction and cyclization from o-nitroanilines. The process usual-ly involves the attachment of 4-fluoro-3-nitrobenzoic the solid support and subse-quent coupling of a primary Scheme 37. Solid-phase synthesis of triazafluorenes.[21] amine, by nucleophilic aromaticsubstitution, to provide the cor-responding nitroarene. Subse- Sustainable Methods quent reduction of nitro group to a primary amine followedby The pressure to explore new alternatives to perform chemi- (Scheme 36).[17,21] cal reactions with less environmental impact has forced or- The "re-discovery" of soluble polymer-supported chemis- ganic chemists to find new solutions, like the utilization of try provided an alternative to commonly insoluble SPOS.
water or ionic liquids (ILs) as solvents or to use solvent-free Polyethylene glycol (PEG) is one of the most successful conditions. Water is highly appreciated as a green solvent soluble supports that maintain all the advantages of poly- due to its inherent characteristics, such as nonflammability mer-supported synthesis, such as easy work-up and purifica- and easy handling, at same time being economical and avail- tion, while allowing an easy monitoring by regular proton able in large quantities.[59] Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim M. M. B. Marques et al.
There are already some examples in which water was suc- cessfully employed for the synthesis of 1,2-disubstituted ben-zimidazoles. In the last few years, several catalytic systems The author acknowledges Fundażo para a CiÞncia e Tecnologia for thePh.D. grant SFRH/BD/63407/2009, and for the project PTDC/QUI/ have been developed in water-mediated conditions: SiO/ H2SO4,[60] Zn/proline,[61] TMSCl (trimethylsilyl chloride),[62]metal hydrogen sulfates [MACHTUNGRE(HSO4)n],[63] or Dowex 50W.[64] Other examples involve the use of ILs either as solvent [1] a) J. A. Asensio, E. M. Sanchez, P. Gomez-Romero, medium[65] or as efficient catalysts in the reaction of o-phe- nylenediamine with aldehydes.[66] 1-(4-Sulfonic acid)butyl-3- [2] http://www.drugs.com/top200.html.
[3] J. B. Wright, methylimidazolium hydrogen sulfate ([(CH2)4SO3HMIM]- [4] a) P. Naik, P. Murumkar, R. Giridhar, M. Yadav, ; b) V. K. Vyas, M. Ghate, Mini-Rev.
([Hmim]TFA)[66b] (Scheme 38) were used to catalyze one- Med. Chem. 2010, 10, 1366 – 1384.
[5] T. Ishida, T. Suzuki, S. Hirashima, K. Mizutani, A. Yoshida, I. Ando, S. Ikeda, T. Adachi, H. Hashimoto, [6] Q. Dang, S. Kasibhatla, W. Xiao, Y. Liu, J. Dare, F. Taplin, K.
Reddy, G. Scarlato, T. Gibson, P. van Poelje, S. Potter, M. Erion, [7] L. Bielory, K. Lien, S. Bigelsen, [8] M. Gaba, D. Singh, S. Singh, V. Sharma, P. Gaba, Eur. J. Med.
Chem. 2010, 45, 2245 – 2249.
Scheme 38. Ionic liquids as catalysts in benzimidazole synthesis.[66a] [9] J. F. Miller, E. M. Turner, K. S. Gudmundsson, S. Jenkinson, A. Spal- tenstein, M. Thomson, P. Wheelan, pot condensations in water at room temperature. These pro- [10] M. Boiani, M. Gonzlez, Mini-Rev. Med. Chem. 2005, 5, 409 – 424.
[11] C. Chen, J. Yu, C. Bi, Y. Zhang, J. Q. Xu, J. X. Wang, M. G. Zhou, cedures seem to have advantages from the use of a water- soluble catalyst, allowing its easy recovery and re-utilization.
[12] J. Prez-Villanueva, R. Santos, A. Hernandez-Campos, M. A. Giulia- Other interesting example was reported by Bahrami and notti, R. Castillo, J. L. Medina-Franco, Med. Chem. Commun. 2011, co-workers, who synthesized 1,2-disubstituted benzimida- 2, 44 – 49.
[13] M. J. Plater, P. Barnes, L. K. McDonald, S. Wallace, N. Archer, T.
zoles by performing the reactions in aqueous micellar media Gelbrich, P. N. Horton, M. B. Hursthouse, by using sodium dodecylsulfate (SDS), which acts both as catalyst to promote the reaction and as a surfactant to solu- [14] S. Harkal, F. Rataboul, A. Zapf, C. Fuhrmann, T. Riermeier, A.
bilize the organic substrates.[67] Monsees, M. Beller, The Heravi group developed the synthesis of 2-aryl-1- [15] I. Georgiou, G. Ilyashenko, A. Whiting, arylmethyl-benzimidazoles in good yields by the reaction of [16] a) G. Brasche, S. L. Buchwald, ; o-phenylenediamine derivatives with various aromatic alde- ; b) B. Zou, Q. Yuan, D.
hydes in the presence of ferric perchlorate, without use of solvent at ambient temperature. The reported method toler- c) N. Zheng, K. W. Anderson, X. Huang, H.
Nguyen, S. Buchwald, ; ates several functional groups such as methyl, methoxy, nitro, and halogroups.[68] [17] C. Gil, S. Brse, [18] a) M. Shen, T. G. Driver, ; b) K.
Hirano, A. T. Biju, F. Gloriua, Summary and Outlook [19] P. Wang, G. Zheng, Y. Wang, X. Wang, Y. Li, W. Xiang, [20] a) R. Wang, X. Lu, X. Yu, L. Shi, Y. Sun, 1,2-Disubstituted benzimidazoles play an important role in b) Z. Zhang, J. Li, Y. Gao, Y. Liu, drug discovery. Indeed, these derivatives represent an excel- ; c) H. G. Richter, G. M. Benson, K. H.
lent scaffold for the development of novel pharmaceutical Bleicher, D. Blum, E. Chaput, N. Clemann, S. Feng, C. Gardes, U.
Grether, P. Hartman, B. Kuhn, R. E. Martin, J. M. Plancher, M. G.
drugs, dyes, polymers, ligands, and organic catalysts. The de- Rudolph, F. Schuler, S. Taylor, velopment of the novel approaches for benzimidazole syn- thesis offer alternatives to the restricted classical methods, [21] Y. Hsiao, G. Yellol, L. Chen, C. Sun, permitting the access to molecules with increased structural diversity in a straightforward way. However several chal- [22] R. Ghorbani-Vaghei, H. Veisi, [23] R. Varala, A. Nasreen, R. Enugala, S. R. Adapa, lenges remain, in particular concerning regioselectivity in solid-phase synthesis, for which recently developed solution- [24] R. G. Jacob, L. G. Dutra, C. S. Radatz, S. R. Mendes, G. Perin, E. J.
phase methods might be applied. Moreover, the ever new advances in metal-mediated C N couplings could open new [25] A. J. Blatch, O. V. Chetina, J. A. Howard, L. G. Patrick, C. A. Sme- thurst, A. Whiting, possibilities to the successful assembly of heterocyclic com- [26] U. J. Ries, G. Mihm, B. Narr, K. M Hasselbach, H. Wittneben, M.
Entzeroth, J. C. van Meel, W. Wienen, N. H. Hauel,  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 12544 – 12555 Regioselective Synthesis of Disubstituted Benzimidazoles [27] Y. Taniguchi, E. T. Kool, [46] F. Wang, S. Cai, Q. Liao, C. Xi, [28] S. Demirayak, I. Kayagil, L. Yurttas, [47] J. She, Z. Jiang, Y. Wang, Synlett 2009, 2023 – 2027.
[48] H. Jin, X. Xu, J. Gao, J. Zhong, Y. Wang, [29] L. Liu, M. Frohn, N. Xi, C. Dominguez, R. Hungate, P. Reider, [49] S. Murru, B. K. Patel, J. Bras, J. Muzart, [30] K. W. Anderson, R. E. Tundel, T. Ikawa, R. A. Altman, S. L. Buch- [50] N. Zheng, S. L. Buchwald, [51] N. Ibrahim, M. Lagraverend, [31] X. Lv, W. Bao, [52] J. Alonso, N. Halland, M. Nazar, O. R'kyek, M. Urmann, A. Lin- [32] D. Yang, H. Fu, L. Hu, Y. Jiang, Y. Zhao, [53] J. Zhu, H. Xie, Z. Chen, S. Li, Y. Wu, Synlett 2009, 3299 – 3303.
[33] a) P. K. Sasmal, S. Sasmal, C. Abbineni, B. Venkatesham, P. T. Rao, [54] J. Zhu, H. Xie, Z. Chen, S. Li, Y. Wu, M. Roshaiah, I. Khanna, V. J. Sebastian, J. Suresh, M. P. Singh, R.
Talwar, D. Shashikumar, K. H. Reddy, T. M. Frimurer, O. Rist, L.
[55] M.-W. Chen, X.-G. Zhang, P. Zhong, M.-L. Hu, Synthesis 2009, Elster, T. Hçgberg, ; b) T.
1431 – 1436.
Coon, W. Moree, B. Li, S. Zamani-Kord, S. Malany, M. A. Santos, [56] W. Shen, T. Kohn, Z. Fu, X. Jiao, S. Lai, M. Schmidt, L. M. Hernandez, R. E. Petroski, A. Sun, J. Wen, S. Sullivan, J. Hae- lewyn, M. Hedrick, S. J. Hoare, M. Bradbury, P. D. Crowe, G.
[57] C. Siddappa, V. Kambappa, A. C. Siddegowda, K. S. Rangappa, Beaton, ; c) X. Wang, P. Bhatia, J. Daanen, S. Latsaw, J. Rohde, T. Kolasa, A. Hakeem, M.
[58] C. S. Cho, J. U. Kim, Bull. Korean Chem. Soc. 2008, 29, 1097 – 1098.
Matulenko, M. Nakane, M. Uchic, L. Miller, R. Chang, R. More- [59] D. Dallinger, C. O. Kappe, land, J. Brioni, A. Stewart, [60] P. Salehi, M. Dabiri, M. Zolfigol, S. Otokesh, M. Baghbanzadeh, ; d) Y. Gong, W. He, ; e) S. Allin, W. R. Bowman, R. Karim, S. Rahman, [61] V. Ravi, E. Ramu, K. Vijay, A. Rao, [34] a) C. T. Brain, S. A. Brunton, ; [62] J. Wan, S. Gan, J. Wu, Y. Pan, b) C. T. Brain, J. T. Steer, [35] D. S. Surry, S. L. Buchwald, [63] K. Niknam, M. Zolfigol, N. Safikhan, [36] F. Monnier, M. Taillefer, ; [64] C. Mukhopadhyay, A. Datta, R. J. Butcher, B. Paul, N. Guchhait, R.
Singha, Arkivoc 2009, xiii, 1 – 22.
[37] X. Deng, N. S. Mani, [65] A. K. Yadav, M, Kumar, T. Yadav, R. Jain, [38] P. Saha, T. Ramana, N. Purkait, M. Ali, R. Paul, T. Punniyamurthy, [66] a) Y. S. Beheshtiha, M. M. Heravi, M. Saeedi, N. Karimi, M. Zakeri, [39] P. Saha, M. A. Ali, P. Ghosh, T. Punniyamurthy, N. Tavaroli-Hossieni, ; b) M.
[40] J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, C.
[67] K. Bahrami, M. M. Khodaei, A. Nejati, [41] G. Evindar, R. A. Batey, [42] B. G. Szczepankiewicz, J. J. Rohde, R. Kurukulasuriya, [68] H. A. Oskooie, M. M. Heravi, A. Sadnia, F. K. Behbahani, F. Jan- nati, Chin. Chem. Lett. 2007, 18, 1357 – 1360.
[43] X. Lv, W. Bao, [44] G. Shen, W. Bao, [45] H. He, Z. Wang, W. Bao, Published online: October 11, 2011 Chem. Eur. J. 2011, 17, 12544 – 12555  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Source: http://abs.mehmetakif.edu.tr/upload/0639_8612_yayinDosya.pdf