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Construction of N ‐Boc‐2‐Alkylaminoquinazolin‐4(3 H )‐Ones via a Three‐Component, One‐Pot Protocol Mediated by Copper(II) Chloride that Spares Enantiomeric Purity
Author(s) -
Li Xiaoyu,
Golden Jennifer E.
Publication year - 2021
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.202001279
Subject(s) - chemistry , enantiomer , copper , chloride , enantiomeric excess , aminolysis , copper(ii) chloride , combinatorial chemistry , anthranilic acid , enantioselective synthesis , medicinal chemistry , stereochemistry , organic chemistry , catalysis
Chiral 2‐alkylquinazolinones are key synthetic intermediates, but their preparation in high optical purity is challenging. Thus, a multicomponent procedure integrating anthranilic acids, N ‐Boc‐amino acids, and amines in the presence of methanesulfonyl chloride, N ‐methylimidazole, and copper(II) chloride was developed to mildly afford N ‐Boc‐2‐alkylaminoquinazolin‐4(3 H )‐ones with excellent preservation of enantiomeric purity (>99% ee). Copper(II) chloride was essential to retaining enantiopurity, and reaction component structural changes were well tolerated, resulting in an efficient, all‐in‐one procedure that promotes sequential coupling, lactonization, aminolysis, and cyclization in good yields. The method was applied to the rapid assembly of four key intermediates used in the synthesis of high profile quinazolinones, including several PI3K inhibitor drugs.