Categories: Synthesis of N-Heterocycles > benzo-fused N-Heterocycles >
Synthesis of benzimidazoles
A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles employs formic acid, iron powder, and NH4Cl as additive to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functional groups demonstrates the general utility of this procedure.
E. J. Hanan, B. K. Chan, A. A. Estrada, D. G. Shore, J. P. Lyssikatos, Synlett, 2010, 2759-2764.
The use of various o-phenylenediamines and N-substituted formamides as C1 sources in a zinc-catalyzed cyclization in the presence of poly(methylhydrosiloxane) provides benzimidazoles in good yields. Benzoxazole and benzothiazole derivates can also be synthesized.
D. B. Nale, B. M. Bhanage, Synlett, 2015, 26, 2831-2834.
D-Glucose can be used as an efficient C1 synthon in the synthesis of benzimidazoles from o-phenylenediamines via an oxidative cyclization strategy. This method offers broad functional group tolerance, a biorenewable methine source, excellent reaction yields, a short reaction time, and water as an environmentally benign solvent.
D. Raja, A. Philips, P. Palani, W.-Y. Lin, S. Devikala, G. C. Senadi, J. Org. Chem., 2020, 85, 11531-11540.
A three-component reaction of o-iodoanilines or electron-rich aromatic amines with K2S and DMSO provides 2-unsubstituted benzothiazoles in good isolated yields with good functional group tolerance. A similar reaction of o-phenylenediamines provided 2-unsubstituted benzimidazoles without K2S. DMSO plays three vital roles: carbon source, solvent, and oxidant.
X. Zhu, F. Zhang, D. Kuang, G. Deng, Y. Yang, J. Yu, Y. Liang, Org. Lett., 2020, 22, 3789-3793.
A well-defined NHC-Pd(II)-Im complex enables a facile and alternative methodology for the direct C-H bond arylation of (benz)imidazoles with (hetero)aryl chlorides. Various activated, unactivated, and deactivated (hetero)aryl chlorides were used as arylating reagents to yield 2-(hetero)aryl (benz)imidazoles in good yields.
Z.-S. Gu, W.-X. Chen, L-X. Shao, J. Org. Chem., 2014, 79, 5806-5811.
A one-pot, multicomponent reaction enables the transformation of commercial aryl amines, aldehydes, and azides into valuable benzimidazole structural units with wide substrate scope and diversity via an efficient copper-catalyzed amination of N-aryl imines, in which imine acts as a directing group by chelating to the metal center.
D. Mahesh, P. Sadhu, T. Punniyamurthy, J. Org. Chem., 2015, 80, 1644-1650.
A copper(II)-catalyzed oxidative cross-coupling of anilines, primary alkyl amines, and sodium azide provides benzimidazoles in the presence of TBHP at moderate temperature via a domino C-H functionalization, transimination, ortho-selective amination, and a cyclization sequence. The reaction offers broad substrate scope and functional group compatibility.
D. Mahesh, P. Sadhu, T. Punniyamurthy, J. Org. Chem., 2016, 81, 3227-3234.
A highly recyclable nonnoble cobalt nanocomposite catalyzed the coupling of phenylenediamines and aldehydes to provide a wide range of biologically active benzimidazoles in high yields with good functional-group tolerance under additive- and oxidant-free conditions. The catalyst can be easily recycled for successive uses.
Z. Wang, T. Song, Y. Yang, Synlett, 2019, 30, 319-324.
Supramolecular nanoassemblies of an AIEE-ICT-active pyrazine derivative (TETPY) with strong absorption in the visible region catalyze the synthesis of a variety of a broad range of benzimidazoles, benzothiazoles and quinazolines in excellent yields under "metal-free" conditions in a mixed aqueous media.
S. Dadwal, M. Kumar, V. Bhalla, J. Org. Chem., 2020, 85, 13906-13919.
An acceptorless dehydrogenative coupling of aromatic diamine with primary alcohols enables a selective synthesis of 2-substituted and 1,2-disubstituted benzimidazoles. The reaction is catalyzed by a phosphine-free tridentate NNS ligand-derived manganese(I) complex.
K. Das, A. Mondal, D. Srimani, J. Org. Chem., 2018, 83, 9553-9560.
A practical intramolecular C-H amidation methodology using molecular iodine under basic conditions enables a transition-metal-free cyclization of crude imines for the sequential synthesis of N-protected benzimidazoles without purification of less stable condensation intermediates. The required imine substrates were readily obtained by condensation of simple o-phenylenediamine derivatives and a broad range of aldehydes.
Z. Hu, T. Zhao, M. Wang, J. Wu, W. Yu, J. Chang, J. Org. Chem., 2017, 82, 3152-3158.
Bioinspired ortho-quinone catalysts have been applied to oxidative synthesis of benzimidazoles, quinoxalines and benzoxazoles from primary amines in high yields under mild conditions with oxygen as the terminal oxidant.
R. Zhang, Y. Qin, L. Zhang, S. Luo, Org. Lett., 2017, 19, 5629-5632.
The use of elemental sulfur as traceless oxidizing agent enables a remarkably simple solvent-free and catalyst-free synthesis of benzazoles from alkylamines and o-hydroxy/amino/mercaptan anilines.
T. B. Nguyen, L. Ermolenko, W. A. Dean, A. Al-Mourabit, Org. Lett., 2012, 14, 5948-5951.
Reactions of ortho-substituted anilines and arylglyoxylic acids in DMSO at 40°C provide various benzo-fused five- to six-membered N-heterocycles in very good yields. The reaction proceeds via intramolecular Michael addition of α-iminocarboxylic acids, generated in situ, with an ortho-substituted nucleophile, followed by decarboxylation forms the N-heterocycles.
J. K. Laha, M. K. Hunjan, J. Org. Chem., 2022, 87, 2315-2323.
Sodium sulfide in combination with iron(III) chloride hexahydrate promote an unbalanced redox condensation reaction between o-nitroanilines and alcohols, leading to benzimidazole and quinoxaline heterocycles. Beside the role as a precursor for an iron-sulfur catalyst, hydrated sodium sulfide is also an excellent noncompetitive, multi-electron reducing agent.
T. B. Nguyen, L. Ermolenko, A. Al-Mourabit, Synthesis, 2015, 47, 1741-1748.
A broad range of functionalized 2-aryl benzimidazoles can be prepared by a solvent-free cobalt- or iron-catalyzed redox condensation of 2-nitroanilines and benzylamines via benzylamine oxidation, nitro reduction, condensation, and aromatization without any reducing or oxidizing agent. The method can be extended to afford various other diazaheterocycles.
T. B. Nguyen, J. Le Bescont, L. Ermolenko, A. Al-Mourabit, Org. Lett., 2013, 15, 6218-6221.
An efficient transition-metal-free transfer hydrogenative cascade reaction between ortho-nitroanilines and benzyl amines or alcohols provides benzimidazoles in good yields using a combination of KOtBu and Et3SiH as reagents. The reaction conditions tolerate diverse functional groups.
A. K. Kabi, R. Gujjarappa, A. Roy, A. Sahoo, D. Musib, N. Vodnala, V. Singh, C. C. Malakar, J. Org. Chem., 2021, 86, 14597-14607.
Brřnsted acid catalyzed cyclization reactions of 2-amino thiophenols and anilines with β-diketones under oxidant- and metal-free conditions give 2-substituted benzothiazoles and benzimidazoles in good yields, respectively. Various groups such as methyl, chloro, nitro, and methoxy linked on benzene rings were tolerated under the optimized reaction conditions.
M. S. Mayo, X. Yu, X. Zhou, X. Feng, Y. Yamamoto, M. Bao, Org. Lett., 2014, 16, 764-767.
The reaction of ortho-substituted anilines with functionalized orthoesters yields benzoxazole, benzothiazole, and benzimidazole derivatives in an efficient and connective methodology. The versatility of this approach enables the development of new libraries of heterocycles containing multifunctional sites.
G. Bastug, C. Eviolitte, I. E. Markó, Org. Lett., 2012, 14, 3502-3505.
An oxone mediated tandem transformation of 2-aminobenzylamines to 2-substituted benzimidazoles occurs at room temperature with aromatic, heteroaromatic, and aliphatic aldehydes. Initial condensation of 2-aminobenzylamine with appropriate aldehydes afforded a tetrahydroquinazoline intermediate which underwent oxone-mediated ring distortion to afford the desired compounds in good yields.
S. Hati, P. K. Dutta, S. Dutta, P. Munshi, S. Sen, Org. Lett., 2016, 18, 3090-3093.
The preparation of benzimidazoles and imidazopyridines proceeds smoothly under mild conditions in isopropyl alcohol at 70°C using 2,2,2-trichloroethyl imidates as the acylating agents. Addition of sodium acetate proved to be beneficial In cases where cyclization proceeded slowly. For substrates with poor nucleophilicity, using the more inert tert-amyl alcohol enabled superior reactions.
S. Caron, B. P. Jones, L. Wei, Synthesis, 2012, 44, 3049-3054.
A convenient method for the synthesis of 2-substituted benzimidazoles and benzothizoles offers short reaction times, large-scale synthesis, easy and quick isolation of the products, excellent chemoselectivity, and excellent yields as main advantages.
K. Bahrami, M. M. Khodaei, F. Naali, J. Org. Chem., 2008, 73, 6835-6837.
An efficient and convenient Ni-catalyzed C-N bond formation enables the synthesis of various benzimidazoles in excellent yields from various 2-haloanilines, aldehydes, and ammonia as nitrogen source.
F. Ke, P. Zhang, Y. Xu, X. Lin, J. Lin, C. Lin, J. Xu, Synlett, 2018, 29, 2722-2726.
A copper-catalyzed, one-pot, three-component reaction of 2-haloanilines, aldehydes, and NaN3 enabled the synthesis of benzimidazoles in good yields using catalytic amounds of CuCl and TMEDA in DMSO at 120°C for 12 h. The reaction tolarated many functional groups such as ester, nitro, and chloro.
Y. Kim, M. R. Kumar, N. Park, Y. Heo, S. Lee, J. Org. Chem., 2011, 76, 9577-9583.
Intramolecular N-arylations of amidines mediated by potassium hydroxide in DMSO at 120°C enable the preparation of diversely substituted benzimidazoles in good yields.
H. Baars, A. Beyer, S. V. Kohlhepp, C. Bolm, Org. Lett., 2014, 16, 536-539.
The use iodobenzene as a catalyst enables the synthesis of 1,2-disubstituted benzimidazoles by oxidative C-H amination of N″-aryl-N′-tosyl/N′-methylsulfonylamidines and N,N′-bis(aryl)amidines in the presence of mCPBA as terminal oxidant at room temperature. The reaction is general, and the target products can be obtained in good yields.
S. K. Alla, R. K. Kumar, P. Sadhu, T. Punniyamurthy, Org. Lett., 2013, 15, 1334-1337.
A mild, Ir-catalyzed annulation of imidamides with sulfonyl azides provides 1,2-disubstituted benzimidazoles in very good yield. This method offers high regioselectivity, efficiency, and good tolerance of functional groups.
L. Xu, L. Wang, Y. Feng, Y. Li, L. Yang, X. Cui, Org. Lett., 2017, 19, 4343-4346.
A fast and simple reaction of amidines gave benzimidazoles via iodine(III)-promoted oxidative C(sp3)-C(sp2) bond formation in nonpolar solvents, whereas the use of polar solvents favoured a C(sp2)-N bond formation to yield quinazolines. Further selective synthesis of quinazolines in polar solvent was realized using TEMPO as catalyst and K2S2O8 as the oxidant. No metal, base, or other additives were needed.
J.-P. Lin, F.-H. Zhang, Y.-Q. Long, Org. Lett., 2014, 16, 2822-2825.
CuI/l-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2-iodophenylcarbamates affords aryl amination products at room temperature, which undergo in situ additive cyclization under acidic conditions or heating to give substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones, respectively.
X. Diao, Y. Wang, Y. Jiang, D. Ma, J. Org. Chem., 2009, 74, 7974-7977.
An experimentally simple, general, efficient, and ligand-free synthesis of substituted benzimidazoles, 2-aminobenzimidazoles, 2-aminobenzothiazoles, and benzoxazoles via intramolecular cyclization of o-bromoaryl derivatives is catalyzed by copper(II) oxide nanoparticles in DMSO under air. The heterogeneous catalyst can be recovered and recycled without loss of activity.
P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy, J. Org. Chem., 2009, 74, 8719-8725.
An efficient method for the transformation of N-benzyl bisarylhydrazones and bisaryloxime ethers to functionalized 2-aryl-N-benzylbenzimidazoles and 2-arylbenzoxazoles involves a copper(II)-mediated cascade C-H functionalization/C-N/C-O bond formation under neutral conditions. Substrates having either electron-donating or -withdrawing substituents undergo the cyclization at moderate temperature.
M. M. Guru, M. A. Ali, T. Punniyamurthy, J. Org. Chem., 2011, 76, 5295-5308.
A set of benzimidazoles, 3H-imidazo[4,5-b]pyridines, purines, xanthines and benzothiazoles was readily prepared from (hetero)aromatic ortho-diamines or ortho-aminothiophenol and aldehydes using chlorotrimethylsilane in DMF as a promoter and water-acceptor agent, followed by oxidation with air oxygen.
S. V. Ryabukhin, A. S. Plaskon, D. M. Volochnyuk, A. A. Tolmachev, Synthesis, 2006, 3715-3726.
A simple and efficient procedure for the synthesis of substituted benzimidazoles through a one-pot condensation of o-phenylenediamines with aryl aldehydes in the presence of H2O2 and HCl in acetonitrile at room temperature features short reaction time, easy and quick isolation of the products, and excellent yields.
K. Bahrami, M. M. Khodaei, I. Kavianinia, Synthesis, 2007, 417-427.
Various 2-arylbenzimidazoles were synthesized from phenylenediamines and aldehydes via a one-step process using hypervalent iodine as oxidant. This method features mild conditions, short reaction times, high yields, and a simple procedure.
L-H. Du, Y.-G. Wang, Synthesis, 2007, 675-678.
Addition of oxone to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF results in rapid formation of benzimidazoles under very mild conditions. Products are isolated in high purity in most cases by simple aqueous precipitation. The reaction is applicable to a wide range of substrates but does not allow the conversion of aldehydes that are sensitive to oxone under acidic reaction conditions.
P. L. Beaulieu, B. Haché, E. von Moos, Synthesis, 2003, 1683-1692.
A mild and efficient one-pot synthesis enables the preparation of 2-substituted benzimidazoles from 1,2-phenylenediamines and triacyloxyborane intermediates generated in situ from carboxylic acids and borane-THF. This protocol tolerates acid-labile functional groups.
W. Cui, R. B. Kargbo, Z. Sajjadi-Hashemi, F. Ahmed, J. F. Gauuan, Synlett, 2012, 23, 247-250.
Efficient and general cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl azide allow a one-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines in good yields.
J. She, Z. Jiang, Y. Wang, Synlett, 2009, 2023-2027.
A NaH-mediated reaction of carbonitriles and N-methyl-1,2-phenylenediamine allows the formation of N-methylbenzimidazole and tolerates acid-labile acetal protective groups. Products were further converted in Suzuki, Sonogashira, Heck and Buchwald-Hartwig reactions.
J. Sluiter, J. Christoffers, Synlett, 2009, 63-66.
An efficient oxidative protocol enables the synthesis of multisubstituted or fused tetracyclic benzimidazoles via a metal-free oxidative C-N coupling between the sp3 C-H and free N-H of readily available N1-benzyl/alkyl-1,2-phenylenediamines in the presence of oxygen and TEMPO.
D. Xue, Y.-Q. Long, J. Org. Chem., 2014, 79, 4727-4734.
A straightforward, efficient, and sustainable method for intramolecular N-arylation provides a library of benzimidazoles in high yields using Cu2O as the catalyst, DMEDA as the ligand, and K2CO3 as the base. Remarkably, the reaction was exclusively carried out in water, rendering the methodology highly valuable from both environmental and economical points of view.
J. Peng, M. Ye, C. Zong, F. Hu, L. Feng, X. Wang, Y. Wang, C. Chen, J. Org. Chem., 2011, 76, 716-719.
Various N-aryl-1H-indazoles and benzimidazoles were synthesized from common arylamino oximes in good to excellent yields depending upon the base used in the reaction. Triethylamine promoted the formation of benzimidazoles, whereas 2-aminopyridine promoted the formation of N-arylindazoles.
B. C. Wray, J. P. Stambuli, Org. Lett., 2010, 12, 4576-4579.
The reaction of N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) as nonhazardous electrophilic cyanating agent with various substituted 2-aminophenols and benzene-1,2-diamine enables a facile synthesis of 2-aminobenzoxazole and 2-aminobenzimidazole derivatives in the presence of lithium hexamethyldisilazide (LiHMDS). This protocol offers operational simplicity, short reaction time, and simple workup.
M. Kasthuri, H. S. Babu, K. S. Kumar, Ch. Sudhakar, P. V. N. Kumar, Synlett, 2015, 26, 897-900.
A metal-free and solvent-free C-N coupling of heteroaryl halides and amines provides numerous heteroaryl amines or their hydrochlorides without any external base. Further investigations elucidated that the basicity of amines played pivotal roles in the reactions. Moreover, this protocol was scalable to gram scales and applicable to drug molecules.
G.-G. Fan, B.-W. Jiang, W. Sang, H. Cheng, R. Zhang, B.-Y. Yu, Y. Yuan, C. Chen, F. Verpoort, J. Org. Chem., 2021, 86, 14627-14639.
The reaction of isothiocyanates with ortho-substituted anilines bearing N,N-, N,O-, and N,S-bis-nucleophiles, followed by an intramolecular, potassium periodate mediated oxidative cyclodesulfurization of the in situ generated monothioureas provides substituted 2-aminobenzazole derivatives in very good yields.
C. Duangkamol, W. Phakhodee, M. Pattarawarapan, Synthesis, 2020, 52, 1981-1990.
An efficient Cu(I)-catalyzed cascade intermolecular addition/intramolecular C-N coupling process enables the synthesis of a wide variety of 2-heterobenzimidazoles from o-haloarylcarbodiimides and N- or O-nucleophiles.
X. Lv, W. Bao, J. Org. Chem., 2009, 74, 5618-5621.
Condensation of N-aryl-2-nitrosoanilines with triphenylphosphine gives substituted aryliminophosphoranes which in a subsequent reaction with alkyl isocyanates furnish 2-alkylaminobenzimidazole derivatives in high yields.
E. Łukasik, Z. Wróbel, Synlett, 2014, 25, 217-220.
The condensation of (2-arylamino)iminophosphoranes with trifluoroacetyl esters or trifluoroacetic anhydride provides 2-(trifluoromethyl)benzimidazoles. (2-Arylamino)iminophosphoranes can be generated from simple 2-nitroarenes without the use of metallic reagents or expensive catalysts.
M. Walewska-Królikiewicz, B. Wilk, A. Kwast, Z. Wróbel, Synlett, 2022, 33, 1092-1096.