3,4,5-Triarylisothiazoles via C–C coupling chemistry

Abstract

The regiocontrolled preparation of triarylisothiazoles is presented. 3-Halo-5-phenylisothiazole-4-carbonitriles, 1 (hal = Cl) and 18 (hal = I), are converted into the corresponding 4-bromo derivatives 5 (3-hal = Cl) and 24 (3-hal = I) via a Hunsdiecker strategy while the 4-iodo analogues 7 (3-hal = Cl) and 22 (3-hal = I) are prepared via a Hoffmann and Sandmeyer strategy. Regioselective Suzuki, Stille and Negishi reactions occur at C-4 with both the 4-bromo- and 4-iodoisothiazoles 5 and 7, the latter being more reactive than the former. 3-Iodoisothiazoles 22 and 24 fail to give regiocontrolled Suzuki, Stille or Negishi couplings, however, 4-bromo-3-iodo-5-phenylisothiazole24 gives the regiospecific palladium catalysed Ullmann-type reaction product 3,3′-bi(4-bromo-5-phenylisothiazole)25. Alkali hydrolysis of 3-chloro-4,5-diphenylisothiazole8 gives the 3-hydroxy analogue 12 which is converted into 3-bromo-4,5-diphenylisothiazole13 with POBr₃. 3-Bromoisothiazole13 reacts with phenylzinc chloride to give 3,4,5-triphenylisothiazole17 but fails to undergo effective Suzuki or Stille couplings. 3,5-Diphenylisothiazole-4-carbonitrile26 is converted into the 4-bromo- and 4-iodo-3,5-diphenylisothiazoles 30 and 34 both of which are effective for Suzuki and Stille couplings. A series of triarylisothiazoles are prepared in this manner and fully characterised.