Comparative Amine‐Catalyzed Thia‐Michael Reactions of Primary and Secondary Thiols with Maleic and Itaconic Anhydrides and Esters

Abstract

Experiments using two amine catalysts (triethylamine, TEA and triethylenediamine, DABCO®), two thiols (primary 1‐octanethiol, OctSH and secondary cyclohexanethiol, cHexSH) and four Michael acceptors (maleic anhydride, MA, itaconic anhydride, IA, dimethyl maleate, DMM and dimethyl itaconate, DMI) in thia‐Michael reactions were performed to gain mechanistic insight into these important carbon‐sulfur bond forming reactions. The TEA catalyst showed higher activity than DABCO®. IA gave a steady increase of product whereas MA initially displayed fast growth followed by decline of the product after 24 h. Both DMM and DMI displayed no product for the first three hours but significant amounts after 24 h. Among the thiols, OctSH gave more product than cHexSH in all cases. Overall, IA showed more final product than MA. In the opposite manner, DMM showed more product than DMI. Isomerization of the double bonds in IA, and to a lesser extent in DMM and DMI, was noticed. This led to formation of isomeric thia‐Michael products from IA. Density‐functional theory was used to calculate the ΔG of the reactions. It showed that the ΔG of the thia‐Michael reaction with MA to be 2.1±0.1 kcal/mol more favorable than the one with IA, and that ΔG of the reactions with primary thiol to be 1.1±1.0 kcal/mol less than with those using secondary thiols.