Thioamides Eschenmoser coupling reaction

A variety of thioamides possessing either mono- or di-alkyl substitution on the nitrogen can undergo the Eschenmoser coupling reaction. Primary thioamides are not acceptable substrates because of their ready conversion to nitriles under the condensation conditions. Although alkylation proceeds more readily on secondary rather than tertiary thioamides, use of the latter allows subsequent sulfur extrusion to... 

The mitomycins are a class of antitumor antibiotics that has been the target of numerous synthetic efforts. The Eschenmoser reaction was a key coupling step in the synthesis of a mitomycin intermediate, apomitomycin (153). Thiopyrrolidinone (149) was alkylated with the aryl bromoacetate (150), and the intermediate a-thioiminium salt was heated with DBU (Scheme 32). The desired condensation product (151) was obtained in excellent yield, although epimerization about the pyrrolidine ring had occurred to produce a 1 1 mixture of the cis and trans substituted diastereomers. Note that, in contrast to a-alkyl-substituted electrophiles, which require conversion to triflates for complete thioamide alkylation, the more reactive benzylic bromide in (150) gave efficient alkylation. The key intermediate (151) was cy-clized in the presence of sodium hydride and copper(I) bromide to yield a single product (152) in nearly quantitative yield. Epimerization to the more stable trans isomer occurred under the cyclization conditions. This intermediate was readily converted to the final product (153). 

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