Novel molecular transformations of amide based on neighboring functional group

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K05467
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 33020:Synthetic organic chemistry-related
• Research Institution: Kobe Pharmaceutical University
• Principal Investigator: Takeda Norihiko 神戸薬科大学, 薬学部, 講師 (30449871)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: アミド / 求核付加反応 / 環縮小反応 / ラクタム / 含窒素ヘテロ環化合物

Outline of Final Research Achievements

The novel transformations triggered by nucleophilic addition to amide carrying the neighboring functional group were developed. Sequential nucleophilic arylation/ring-contractive rearrangement of alpha-bromo-N-alkoxylactams with organometallic reagents provided 2-aroyl pyrrolidines incorporating various C(sp2) units such as aryl and heteroaryl groups. In the case of alpha-bromo-N-iminolactam with organometallic reagents, a wide range of C-nucleophiles including alkynyl, alkenyl and alkyl groups could be introduced. Moreover, conjugated N-alkoxylactam with Grignard reagent in the presence of silylating agent afforded 3-aroyl piperidines through sequential nucleophilic addition/ring recombination process. We also found that sequential nucleophilic addition/rearrangement of conjugated N-(arylamino)lactam with Grignard reagent gave alpha-arylated lactam with a quaternary carbon center.

Free Research Field

有機合成化学

Academic Significance and Societal Importance of the Research Achievements

アミドは優れた化学安定性を持つため、アミドを目的生成物とする合成戦略は多数存在するが、アミドを起点とした化学変換は現代有機化学を駆使しても容易ではない。本研究ではアミドカルボニル基への求核付加反応を基盤とした連続反応の開発に取り組んだ。アミド窒素原子上にヘテロ原子の導入、さらにα位へ隣接官能基を導入した環状アミドは、有機金属試薬による求核付加反応と続く第二の反応を可能とし、カルボニル基が再生する新たな分子変換法が開発できた。アミドから始まる分子変換法の開発は学術的独創性を備えているだけでなく、創薬研究や医薬品開発に役立つ合成法を提供する社会的意義を併せ持つ。