Studies on Activities of N-H Imines: Nucleophilicity of N-H Imines and Utilities of Cyclic α,β-Unsaturated Imines

Abstract

N-Unsubstituted imines (N-H imines) are useful intermediates in the preparation of nitrogen-containing compounds that can be utilized in the synthesis of pharmaceutically relevant compounds. Due to its labile character, synthesis and utilization of N-H imines are rarely reported compared to N-substituted imines. Our group recently developed a novel ruthenium catalyst system which enabled generation of N-H imines from alkyl azides under mild and neutral conditions. Various catalysts were developed including chloride-bridged diruthenium catalyst and ruthenium bisammine complex to increase the efficiency of transformation of azides into N-H imines. N-H imines have been utilized in organic reactions as electrophiles, nucleophiles and directing groups. Allylic amines, oxime ethers and piperidones were prepared by the reaction of N-H imines with nucleophiles. N-H imines are used as a metal directing group to afford isoquinoline. Nitrogen atom of the N-H imine is utilized as a nucleophile in acylation reaction to synthesize N-acyl enamide. N-H imines have a great potential as a nucleophile in organic reaction for the synthesis of nitrogen containing compounds. In this thesis, the nucleophilicity of N-H imines was described for the synthesis of N-acylimines and cyclic α,β-unsaturated imines. In chapter 1, development of practical and simple synthetic method for the synthesis of α,β-unsaturated imines from allylic azides was described by a ruthenium catalysis. Various functional groups in the substrate azides are compatible with the transformation conditions. Particularly, electrophilic functionality such as ester group can be survived, which is not possible in the previous synthetic methods using strong nucleophiles. Cyclic 1H-azadienes can be synthesized, which cannot be afforded by the previous methods using nitriles as the starting substrates. Applications of the 1H-azadienes were demonstrated for the one-pot synthesis of N-benzyl-1-azadienes, hydrazones, tertiary carbinamines, dieneamide, and N-cyclohexenylacetamides. In chapter 2, a simple synthetic method for N-acylketimines labile to tautomerize to the corresponding enamides was described. Mild and neutral conditions provide a wide range of N-acylketimines, including aliphatic ones and those having various functional groups. Variation of acyl group is possible to give methacrylamide, propiolamide, t-butyl carbamates, and benzyl carbamates. In fact, to demonstrate a practical aspect of method, an aliphatic N-Boc ketimine was synthesized and isolated in gram-scale. Utilities of N-acylketimines are demonstrated by nucleophilic addition reactions to produce amides possessing a tertiary carbon-center.