The 2 + 2 + 1 synthesis of 2,3,5-trisubstituted thiophenes

Thiophene skeleton is present in alkaloids tinoridine, sitaxentan and motapizone, used as anti-inflammatory drugs, anti-hypertensive drugs, and PDE3 inhibitors. Modifications of this skeleton are highly desired. Under the promotion of alkali, 1,4-dicarbonyls and thiocyanato aryl ketone could undergo 2 + 2 + 1 reaction to construct thiophene skeleton. Simultaneously, bisaroylation at C-2 and C-5 positions and arylation at C-3 position were realized. Infrared, nuclear magnetic, mass spectrometry and single crystal all confirmed structure of the product. The reaction should involve 3 + 2 cycloaddition, in situ ring opening, tautomerization, S_N2 reaction and other processes.