Michael-terminated tandem reactions for the synthesis of nitrogen and sulfur heterocycles and substituted spiranes

Scope and method of study. The synthesis of 5- and 6-ring nitrogen and sulfur heterocycles from ethyl {dollar}omega{dollar}-halo-2-alkenoates employing a tandem S{dollar}sb{lcub}rm N{rcub}{dollar}2-Michael addition sequence is described. In addition, a tandem nucleophilic decarboxylation-Michael addition route allowing for the preparation of functionalized spiranes from methyl 2-oxocycloalkanecarboxylates having alkyl chains incorporating a terminal acrylate Michael acceptor is reported.; Findings and conclusions. A tandem S{dollar}sb{lcub}rm N{rcub}{dollar}2-Michael addition sequence has been developed for the preparation of 5- and 6-ring nitrogen and sulfur heterocycles from ethyl {dollar}omega{dollar}-halo-2-alkenoates. The preparation of nitrogen heterocycles involves reaction of the haloester with a primary amine and triethylamine in methanol or ethanol solvent. This initially affords a secondary amine intermediate which then cyclizes onto the acrylate acceptor to form the heterocyclic product. The formation of sulfur heterocycles involves reaction of the haloester with thiourea to initially yield the isothiuronium halide adduct which is then hydrolyzed in aqueous base to afford the sulfur heterocyclic product proceeding through a thiolate intermediate. The process is useful for the preparation of mono-, fused- and spirocyclic rings having an acetate residue at C-2 relative to the heteroatom. The reactions proceed in 60-80% yields and can be carried out in a single reaction flask. The mechanism, stereochemistry, and scope of these reactions are discussed.; A one-pot tandem decarboxylation-Michael addition sequence has also been developed for the construction of functionalized spiranes. Starting substrates were readily prepared by alkylation of methyl 2-oxocycloalkanecarboxylates with a side chain group incorporating a terminal acrylate Michael acceptor. The process is initiated by nucleophilic ester cleavage-decarboxylation of the cyclic {dollar}beta{dollar}-ketoester with lithium chloride in hexamethylphosphoramide (HMPA) solvent at 95-130{dollar}spcirc{dollar}C and the resulting anion is trapped by subsequent Michael addition to the side-chain acrylate acceptor. Both 5- and 6-rings can be prepared by this procedure. Yields range from 50-70% and closure occurs such that the two carbonyl groups are oriented trans to one another in the major product.