A Practical and Convenient Method for the Synthesis of Some Benzimidazoles

Benzimidazole and its derivatives represent an important class of bioactive molecules.1 Some benzimidazoles are potent antiparasitic agents,2 topoisomerase I inhibitors,3 selective neuropeptide Y Y1 receptor antagonists,4 angiotensin II (AII) inhibitors,5 inhibitors of human cytomegalovirus (HCMV) replication,6 potential antitumour agents,7 antimicrobial agents,8 and inhibitors of the hepatitis C virus RNA polymerase.9 They have also shown significant activity against several viruses including HIV,10 herpes (HSV-1),11 RNA,12 and influenza.13 Benzimidazoles can also act as ligands to transition metals for modeling biological systems14 and have been widely used as carbon skeletons for N-heterocyclic carbenes.15 Many procedures have been reported for the synthesis of benzimidazoles16–20 and some of these methods involve: 1) reaction of the appropriate o-phenylenediamines with carboxylic acids in the presence of a strong protic acid21,22 or Lewis-acid catalysts,23–25 2) reaction of o-phenylenediamines with nitriles,26 3) the reaction between N-ethoxycarbonylthioamides [RC(S)NHCO2Et] and aromatic 1,2-diamines,27 and 4) palladium-catalyzed intramolecular arylamination of o-bromoarylamidines.28 Recently Wang and co-workers developed a new procedure for the preparation of these compounds by the reaction of o-phenylenediamines with orthoesters in the presence of Lewis acids.29 Although these methods are suitable for the synthesis of benzimidazoles, they have drawbacks, such as harsh reaction conditions, low yields, long reaction times, use of Lewis acids and formation of side-products; in some cases, more than one step is required. Therefore, the development of novel efficient, practical, economical, and environmentally benign methods for the synthesis of important and biologically active benzimidazoles remains an active research area.30–32 We now report a new method for the synthesis of some benzimidazoles by the reaction of o-phenylenediamines with orthoesters under solvent-free conditions without any additives such as base, acid or catalyst.

[1]  S. Khodabakhshi,et al.  A Rapid Access to Novel and Known Benzimidazole Derivatives Using Silica Chloride as a Reusable Catalyst , 2012 .

[2]  B. Kaboudin,et al.  Ammonium Phosphorodithioate:A Mild, Easily Handled, Efficient, and Air-Stable Reagentfor the Conversion of Amides into Thioamides , 2011 .

[3]  B. Kaboudin,et al.  Organic reactions in water: an efficient method for the synthesis of 1,2,4-oxadiazoles in water , 2011 .

[4]  B. Kaboudin,et al.  CuII–β‐Cyclodextrin Complex as a Nanocatalyst for the Homo‐ and Cross‐Coupling of Arylboronic Acids under Ligand‐ and Base‐Free Conditions in Air: Chemoselective Cross‐Coupling of Arylboronic Acids in Water , 2011 .

[5]  A. Heydari,et al.  Lewis acid catalyst free synthesis of benzimidazoles and formamidines in 1,1,1,3,3,3-hexafluoro-2-propanol , 2010 .

[6]  Yong-mei Wang,et al.  An expeditious synthesis of benzimidazole derivatives catalyzed by Lewis acids , 2007 .

[7]  P. Gogoi,et al.  An efficient and one-pot synthesis of imidazolines and benzimidazoles via anaerobic oxidation of carbon–nitrogen bonds in water , 2006 .

[8]  Yu. V. Koshchienko.  Novel benzimidazole dilithium compound , 2006 .

[9]  J. Scicinski,et al.  Rapid one-pot preparation of 2-substituted benzimidazoles from 2-nitroanilines using microwave conditions , 2005 .

[10]  H. Huynh,et al.  Solvent-controlled selective synthesis of a trans-configured benzimidazoline-2-ylidene palladium(II) complex and investigations of its Heck-type catalytic activity , 2005 .

[11]  H. Tian,et al.  An Efficient Procedure for the Synthesis of Benzimidazole Derivatives Using Yb(OTf)3 as Catalyst Under Solvent‐Free Conditions , 2004 .

[12]  S. LaPlante,et al.  Binding mode determination of benzimidazole inhibitors of the hepatitis C virus RNA polymerase by a structure and dynamics strategy. , 2004, Angewandte Chemie.

[13]  J. Gallucci,et al.  Ruffling-induced chirality: synthesis, metalation, and optical resolution of highly nonplanar, cyclic, benzimidazole-based ligands. , 2004, Journal of the American Chemical Society.

[14]  F. Maddalena,et al.  In vivo synthesized proteins with monoexponential fluorescence decay kinetics. , 2004, Journal of the American Chemical Society.

[15]  C. Brain,et al.  An improved procedure for the synthesis of benzimidazoles, using palladium-catalyzed aryl-amination chemistry. , 2003, The Journal of organic chemistry.

[16]  M. Soufiaoui,et al.  Synthèse chimiosélective des benzimidazoles sur silice traitée par le chlorure du thionyle , 2003 .

[17]  R. Castillo,et al.  Synthesis and antiparasitic activity of 1H-benzimidazole derivatives. , 2002, Bioorganic & medicinal chemistry letters.

[18]  K. Janda,et al.  Traceless solid-phase synthesis of 5-benzoylbenzimidazoles , 2001 .

[19]  T. L. Gilchrist,et al.  A short synthesis of phenanthro[2,3-d]imidazoles from dehydroabietic acid. Application of the methodology as a convenient route to benzimidazoles , 2001 .

[20]  M. Ghassemzadeh,et al.  Zeolite-induced Heterocyclization: A Superior Method of Synthesis of Condensed Imidazoles† , 2000 .

[21]  P. Hipskind,et al.  Synthesis and evaluation of a series of novel 2-[(4-chlorophenoxy)methyl]benzimidazoles as selective neuropeptide Y Y1 receptor antagonists. , 1998, Journal of medicinal chemistry.

[22]  J. Girardet,et al.  Design, synthesis, and antiviral activity of alpha-nucleosides: D- and L-isomers of lyxofuranosyl- and (5-deoxylyxofuranosyl)benzimidazoles. , 1998, Journal of medicinal chemistry.

[23]  L. Kucera,et al.  Design, synthesis, and antiviral evaluations of 1-(substituted benzyl)-2-substituted-5,6-dichlorobenzimidazoles as nonnucleoside analogues of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole. , 1998, Journal of medicinal chemistry.

[24]  P. Boyer,et al.  Synthesis and biological activity of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-substituted benzimidazoles. , 1997, Journal of medicinal chemistry.

[25]  R. Partch,et al.  Synthesis of 2-Alkylbenzimidazoles via TiO2-Mediated Photocatalysis , 1997 .

[26]  Francisco Perandones,et al.  Synthesis of imidazo[4,5-b]pyridines from aminoimidazolecarbaldehydes , 1997 .

[27]  E. Imamiya,et al.  Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres. , 1996, Journal of medicinal chemistry.

[28]  B. Gatto,et al.  Substituted 2,5'-Bi-1H-benzimidazoles: topoisomerase I inhibition and cytotoxicity. , 1996, Journal of medicinal chemistry.

[29]  R. Perry,et al.  A novel palladium-catalyzed synthesis of 2-arylbenzimidazoles , 1993 .

[30]  B. Kratochvil,et al.  Determination of thermodynamic aqueous acid-base stability constants for several benzimidazole derivatives , 1993 .

[31]  W. Denny,et al.  Potential antitumor agents. 59. Structure-activity relationships for 2-phenylbenzimidazole-4-carboxamides, a new class of "minimal" DNA-intercalating agents which may not act via topoisomerase II. , 1990, Journal of medicinal chemistry.

[32]  P. Sehgal,et al.  Halobenzimidazole ribosides and RNA synthesis of cells and viruses. , 1978, Advances in virus research.

[33]  E. P. Papadopoulos,et al.  Heterocycles from N-ethoxycarbonylthioamides and dinucleophilic reagents. 2. Five-membered rings containing two heteroatoms at 1,3 positions , 1977 .

[34]  R. Lynn,et al.  Purine studies. Part XI. Condensation of tetraethoxymethane and similar orthocarbonates with ortho-diamines to give 8-ethoxypurines and related fused imidazoles , 1974 .

[35]  D. W. Hein,et al.  The Use of Polyphosphoric Acid in the Synthesis of 2-Aryl- and 2-Alkyl-substituted Benzimidazoles, Benzoxazoles and Benzothiazoles1 , 1957 .

[36]  A. Day,et al.  BENZIMIDAZOLE STUDIES. I. THE MECHANISM OF BENZIMIDAZOLE FORMATION FROM O-PHENYLENEDIAMINE , 1941 .

[37]  E. Wagner.  SOME REACTIONS OF AMIDINES AS AMMONO-CARBOXYLIC ACIDS OR ESTERS1 , 1940 .

[38]  K. Fries,et al.  Über tricyclische Verbindungen, in denen Naphtalin mit einem Heterocyclus anelliert ist , 1935 .