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

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journal contribution
posted on 18.05.2007, 00:00 by Michael A. Kuzemko, Susan D. Van Arnum, Henry J. Niemczyk
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.