Lithiation-substitutions of N-Boc N-alkyl cyclopropylamines

Abstract

A series of lithiation-substitution reactions at the α and β positions of N-Boc N-alkyl cyclopropyl amines is reported. The cyclopropane ring is the preferred position for lithiation in the N-ethyl and N-methyl derivatives 6 and 7, but the N-allyl and N-benzyl derivatives 8 and 9 undergo lithiation at the methylene groups. Lithiations at β positions of the cyclopropylamine ring are observed if the α-position is blocked or the β-positions are activated by phenyl substitution as shown for the reactions of 10, 15 and 21. Both α and β lithiations can be used in lithiation-cyclization reactions to provide the bicyclic spiro or endo fused N-Boc amines 15, 16 and 25. Lithiations of N-Boc-4-tosyloxy piperidine 30 with s-BuLi/(−)-sparteine followed by trimethylsilyl chloride give the N-Boc azabicyclo[3.1.0] hexane 32 with enantiomeric excesses which range from 18–55%. Two β-carbomethoxy substituted N-Boc cyclopropylamines 18 and 26 can participate in a formal [3+2] cycloaddition with tetracyanoethylene to give highly substituted cyclopentanes.