EMCA and DEEM as Michael Reagents Used in Organic Synthesis

This paper reviews on application of two Michael reagents - ethyl ethoxymethylenecyanoacetate (EMCA) and diethyl ethoxymethylenemalonate (DEEM, abbreviated also as DEMM, EMME or DEEMM) - in organic synthesis, especially in synthesis of biologically active compounds. The Michael reaction and its mechanism is tersely summarized, followed by examples of diversity of traditional and novel Michael donors and acceptors. Methods of synthesis of EMCA and DEEM are briefly described. Broad range of EMCA and DEEM use in synthesis of chain, cyclic, heterocyclic and fused heterocyclic structures is presented, focusing on the last ten years achievements. The chain derivatives are classified according to the type of atom (nitrogen, carbon, sulfur) which directly reacts with Michael reagent and adducts on the nitrogen atom are discussed with full particulars. Furthermore, possibilities of formation of cyclic compounds via cyanic or ester group are depicted and laboratory conditions for such reactions (especially for EMCA having both groups) are in each case given. Some attempts to generalize experimental results are made as they are supposed to facilitate prediction of the new processes products. The application of DEEM in preparation of registered drugs (quinolones, Rimazolium sulfate) is also recapitulated, because this reagent, as opposed to EMCA, is constantly used in contemporary pharmaceutical industry. Finally, our own results on reactions of 1-aryl-2-aminoimidazolines-2 with these two Michael reagents are reviewed with special emphasis on possibilities of isomeric enamine formation and ways of cyclization as well as on potential pharmacological activity of obtained compounds. Some computer modeling approaches to explain differentiated reactivity of DEEM and EMCA are also mentioned and critically discussed.