Substituted thiazolo benzimidazoles

A methodology for the synthesis of substituted thiazolo[3,2-rz]benzimidazoles 250 from 2-propargylmercapto benzimidazole 249 was developed based on a tandem Sonogashira cross-coupling with iodoaryls and a subsequent exocyclic heterocyclization (Equation 109) <2004TL5747>. 

The structural assignment of the two possible isomers of substituted thiazolo[3,2-a]benzimidazol-3(2 /) Ones (99) and (100) has been made, first based on NMR spectra <81CPB1876>. Furthermore, these derivatives were converted by desulfurization into the corresponding 1-acetylbenzimidazoles for structural determination <82CPB2714>. 

Although the mass spectra of thiazoles and imidazoles have been discussed previously in CHEC-1, no survey of thiazolobenzimidazoles has been made. A mass spectral study has been reported in which the fragmentation patterns of this type of compound were analysed and the structures of 2-or 3-substituted thiazolo[3,2-a]benzimidazoles (101)-(104) were confirmed <69JHC797>. 

The one-pot synthesis of thiazolo[3,4-a]benzimidazoles has been reported using a microwave-assisted condensation-cyclization (see Scheme 17) of a substituted 1,2-diamine, substituted benzaldehyde and mercaptoacetic acid [74]. Heating the mixture at reflux for 12 min using a single-mode microwave reactor for the most part gave the fused benzimidazoles in improved yield and dramatically shorter times, when compared to classical conditions of heating at reflux in benzene for 24-48 h (Scheme 29). 

The only case of this type reported in the literature concerns the preparation of the substituted hydroxy-thiazolo [3,2 -a -benzimidazole 408 from 2-aminothiazole 407 and 1,4-benzoquinone in glacial acetic acid (Equation 185)... 

Thiazolidines are also known to selectively intercept the biochemical processes of the pathogenic organisms such as bacteria, virus, and fungi, in the host species. Thiazolidines introduction into the HIV/AIDS (Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome) therapy is due to l-aryl-lff,3ff-thiazolo[3,4-a]benzimidazole (TBZ) analogues (Fig. 26). Barreca et al. have modified the TBZ by opening its B ring to explore the thiazolidines namely 2-(2,6-dihalo phenyl)-3-(substituted pyridin-2-yl)-thiazolidin-4-ones (Table 16) as potential anti-HIV-1 RT agents [173]. 

Rao A, Chimirri A, De Clercq E et al (2002) Synthesis and anti-HIV activity of l-(2, 6-difluorophenyl)-lH, 3H-thiazolo[3, 4-a]benzimidazole structurally-related 1, 2-substituted benzimidazoles. II Earmaco 57 819-823... 

Ohler, E., Kang, H.-S., and Zbiral, E., Regioselective cyclisation reactions of acyl-substituted epoxyphosphonates with 2-mercaptoazoles. Syntheses of thiazolo[3,2-fii]benzimidazole, imidazo[2,l-fc]thi-azole, and thiazolo[3,2-fc]-[l,2,4]triazole derivatives, Chem. Ber, 121, 977, 1988. 

Classical condensation-cyclization reactions using 1,2-diaminobenzenes 24, 2-mercaptoacetic acid 25 and appropriately substituted aromatic aldehydes 26 in dry benzene under reflux required a long reaction time to afford the thiazobenzimidazoles 27, which are potent anti-HIV agents, by Scheme 7. On the other hand, the microwave-assisted synthesis of lH,3H-thiazolo[3,4-a]benzimidazoles 27 was completed in toluene within 12 minutes [32]. 

Another route to merocyanine derivatives (308) proceeded via 2-ethoxymethylene-thiazolo[3,2-a]benzimidazol-3(2//)-one (307) with 1-methyl substituted nitrogen heterocycles (Scheme 7) <56JCS361, 55BRP730489, 56BRP743133, 56BRP749189, 57BRP785939). 

Cycloaddition and cyclization routes were used to access certain 1,3-diazines. The 4+2 cycloaddition reaction of 4-(N-allyl-N-aryl)amino-l,3-diaza-l,3-butadienes with vinyl-, isopropenyl-, and chloroketene led to pyrimidinone-fused pyrimidinones <97T13841>. Cis-cyclopenta[d]pyrimidines were derived from cis-2-amino-l-cyclopentanecarboxylates by cyclization with KOCN and KSCN <97JHC1211>. 2-Thioxopyrido[3, 2 4,5]thieno[3,2-r/]pyrimidin-4(3//)-ones 19 were prepared by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-/)]pyridines and isothiocyanates <97JHC937>. Thiazolyl-benzimidazoles derived from 2-cyanomethyl-l//-benzimidazole and 2,3-dihydrothiazole-2-(3//)-thiones were cyclized to the corresponding thiazolo[4,5-r/]pyrimidines <97PHA346>. Reductive cyclization of 6-cyanomethyl-5-nitropyrimidines afforded 7-alkyl-5//-pyrrolo[3,2-r/]pyrimidines and 6-amino-7,7-dialkyl-7//-pyrrolo[3,2-rf]pyrimidines <97T391>. 7-Methyl-5-alkyl-2-vinyl-pyrazolo[3,4-r/]pyrimidine-4,6(5//,7//)-diones arose from cyclization and alkylation of... 

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