Regiospecific Suzuki coupling of 3,5-dichloroisothiazole-4-carbonitrile

Irene C. Christoforou, Panayiotis A. Koutentis, Charles W. Rees
2003 Organic and biomolecular chemistry  
3,5-Dichloroisothiazole-4-carbonitrile 1 reacts with aryl-and methylboronic acids to give in high yields the 3-chloro-5-(aryl and methyl)-isothiazole-4-carbonitrile 2 regiospecifically. The reaction was optimized with respect to base, phase transfer agent and palladium catalyst. Suzuki coupling at C-5 was also achieved in high yield using potassium phenyltrifluoroborate. The regiospecificity of either coupling method is maintained with 3,5-dibromoisothiazole-4carbonitrile 4 to give exclusively
more » ... o give exclusively 3-bromo-5-phenylisothiazole-4-carbonitrile 5. Suzuki cross-coupling conditions applied to 3-chloro-5-phenylisothiazole-4-carbonitrile 2a gave 3-phenoxy-5-phenylisothiazole-4-carbonitrile 6, which was prepared independently, and not the 3-phenyl derivative. All isothiazole products were fully characterized. A recent series of articles have described the broad antiviral activity of 3-methylthio-5-arylisothiazole-4-carbonitrile derivatives. 1-4 These isothiazoles were prepared by cyclisation of arylmethylene-malononitriles with disulfur dichloride and pyridine to afford the 3-chloro-5-arylisothiazole-4-carbonitriles 1,5 which were then converted into the 3-methylthio derivatives by treatment with sodium sulfide followed by iodomethane or alternatively by treating aryl thioesters with malononitrile followed by heating with elemental sulfur and treatment with iodomethane. 1 Both routes require the preparation of product specific intermediates; this could be overcome by starting from an appropriate halogenated isothiazole combined with modern aryl-aryl C-C bond forming techniques. 6 Whilst working on the synthesis and chemistry of 3-haloisothiazole-4,5-dicarbonitriles 7-9 3,5-dichloroisothiazole-4carbonitrile 1 was identified as a possible alternative synthetic precursor to 3-chloro-5-arylisothiazole-4-carbonitriles 2 (Scheme 1). O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 9 0 0 -2 9 0 7 T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
doi:10.1039/b306005e pmid:12968340 fatcat:qlq3j3pq6jc57nqiafpww7ttg4