A Green Chemistry Comparative Analysis of the Syntheses of (<i>E</i>)-4-Cyclobutyl-2-[2-(3-nitrophenyl)ethenyl] Thiazole, Ro 24-5904

Abstract

The malonic acid, the Wittig−Horner, and Claisen syntheses for the preparation of Ro 24-5904 ( 1 ) are analyzed using the Andraos' reaction analysis metrics system. Although this analysis showed the direct coupling of 4-cyclobutyl-2-methylthiazole ( 19 ) with 3-nitrobenzaldehyde ( 5 ) is the most atom efficient route, the excess of 3-nitrobenzaldehyde ( 5 ) required for a reasonable reaction rate at the reported conditions significantly detracts from this chemistry. The malonic acid based synthesis to 3-nitrocinnamide ( 9 ) is atom efficient; however the thionation strategy and the use of Lawesson's reagent preclude its consideration. As demonstrated in the elegant Wittig−Horner route, the thionation with hydrogen sulfide is 100%, but the formation of a stoichiometric amount of potassium diethyl phosphate causes the waste mass efficiency to be similar to that for the process with Lawesson's reagent ( 10 ). A review of the literature has shown that there is a paucity of general environmentally benign thionating methods and focused R&D activities in a unified approach with different sectors of the chemical industry may serve to alleviate this situation.