Electrochemical Scaled-up Synthesis of Cyclic Enecarbamates as Starting Materials for Medicinal Chemistry Relevant Building Bocks
Advanced Synthesis and Catalysis 2020, 362 (15), 3229-3242
The electrochemical Shono oxidation of Boc-protected cyclic amines was revised. The conditions for scalable electrochemical synthesis of cyclic enecarbamates were found. The developed protocol included recycling of the full range of used reagents, favoring to E-factor reduction according to Green Chemistry requirements. The method opened the way for the convenient preparation of previously uncommon materials, which could become useful synthetic intermediates. Their synthetic potential was evaluated in [2+1] and [2+2] cycloadditions as well as electrophilic functionalization. Moreover, functionalized enecarbamates with carbonyl groups in β-position were used as latent 1,3-bielectrophiles in classical heterocyclizations. In a case of the hydrazine, the corresponding unusually decorated pyrazoles were prepared. The proposed methodology is a straightforward tool for the design and synthesis of Medicinal Chemistry relevant building blocks. As examples, 5-fluoro pipecolic and 3-fluoro isonipecotic acids were synthesized starting from Boc-protected esters of the pipecolic and the isonipecotic acids respectively; the 5-step approach to pyrazole containing α-aminoacids with different linkers between the aminoacidic and pyrazole moieties was elaborated based on the cheapest commercially available racemic and chiral cyclic α-aminoacids; the convenient approach to the functionalized tetrahydropyrido[3,4-d]pyridazines was proposed starting from Boc-protected ester of the isonipecotic acids.