Thiazolo benzimidazoles

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 iodocyclization of 2-methallylmercapto benzimidazole 247 proceeded in a regioselective manner by treatment with iodine and aqueous KOH in chloroform to give the dihydro-thiazolo[3,2- ]benzimidazole 248 (Equation 108) <1999RJO730>. 

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>. 

With a-keto-N-arylhydrazidoylchlorides. The thiazolo[3,2-/z benzimidazole 373 was obtained by treating the 2-mercap-tobenzimidazole 371 with a-acetyl-iV-arylhydrazidoyl chloride 372 and NaOEt in refluxing ethanol (Equation 167)... 

With ketones. The 17/-imidazole-2(377)-thione 378 and 2-mercaptobenzoimidazole 380 reacted separately with cycloheptanone to form the tetrahydro-imidazo[2,l- ]thiazole 379 and the dihydro-thiazolo[3,2-tf]benzimidazole 381, respectively (Equations 170 and 171) <2000JHC943, 2001RJ0564>. 

A useful and simple preparation of the thiazolo[3,2-tf]benzoimidazol-3(2//)-one 391 is the reaction of 2-mercapto-benzimidazole 390 with chloroacetyl chloride (Equation 177) <1996MI442>. 

With dichloromaleimides. A similar cyclization of 2-mercaptobenzoimidazole with an appropriate dichloromaleimide as key reagent gave thiazolo[3,2- ]benzimidazole derivatives 406 (Equation 184) <2001H(55)2189>. 

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)... 

With S-vinylsulfilimines. A novel synthesis of the dihydro-thiazolo [3,2- ]benzimidazole 414 was achieved by the ring closure of 2-mercaptobenzoimidazole 412 using d -ethenylsulfilimine 413 and basic conditions (Equation 188)... 

Mercaptoacetic acid could be used as a versatile synthon for the synthesis of 17/,3//-thiazolo[3,4-tf]benzimidazole-type compounds <1996FA279, 1997FA673>. For instance, 2,3-diaminopyridine and 2-mercaptoacetic acid were reacted in a three-component reaction with a suitable carbonyl compound and provided the 17/,3//-thiazolo[3,4- ]-imidazo[4,5- ]pyridines 451 (Equation 212) <1994FA345>. 

C NMR data for condensed derivatives (thiazolo[3,2-a]benzimidazoles) have been reported (88CB977), but there does not seem to be a systematic investigation. NMR data are still lacking. 

Carboxy-methylthio)-NH-benzimidazole cyclisieren im allgemeinen in Acetanhydrid (iiber gemischte Anhydride) zu 3-Oxo-2,3-dihydro-[Pg.350]

Preparation of the prototype drug departs from the phenylenediamine strategy used in all of the previous examples. Condensation of thiazolo nitrile (53-2) with aniline catalyzed by aluminum chloride affords the amidine addition product (53-3). This is then converted to its reactive A -chloro derivative (53-4) by reaction with sodium hypochlorite. Treatment of that intermediate with a base such as potassium hydroxide leads directly to the cyclization product and thus the benzimidazole thiabendazole (53-6) [56]. The reaction can be rationalized by invoking as the first step the abstraction of chloride to leave behind a nitrene species such as (53-5) this would then readily insert in the CH bond at the ortho position. 

Cyclization between a ring nitrogen atom and the cyano group in 2-thiocyanatoalkylbenzimidazoles on heating yielded stable 1-imino-thiazolo[3,4-a]benzimidazoles (131) which can be written as a 1,3-dipolar tautomer possessing a 14- -electron system.134 The chemical reactivity of 131 has been investigated.134b... 

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]. 

Abdel-Aziz et al. [16] reported the regioselective 1,3-dipolar cycloaddition of nitrilimines with 2-(4-arylidene)-thiazolo-[3,2-a]-benzimidazole-3-(2H)-ones to afford the corresponding pyrazoylbenzimidazole (v). The pyrazolylbenzimidazoles were also examined for their anti-tumor activities against two tumor cell lines, Hep-2 and colon CaCo-2 and encouraging results were obtained. 

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... 

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