Coupling Catalytic Alkene Hydroacylation and α‑Arylation: Enantioselective Synthesis of Heterocyclic Ketones with α‑Chiral Quaternary Stereocenters

We report a strategy that combines
alkene hydroacylation and enantioselective
α-(hetero)­arylation reactions to form a wide variety of nitrogen-containing
heterocyclic ketones bearing α-chiral quaternary stereogenic
centers. Exo-selective, intramolecular Ni-catalyzed hydroacylations
of N-homoallylindole- and N-homoallylpyrrole-2-carboxaldehydes
form α-substituted six-membered heterocyclic ketones in up to
95% yield, while N-heterocyclic carbene (NHC) catalyzed hydroacylations
of N-allylindole- and N-allylpyrrole-2-carboxaldehydes
form α-substituted five-membered heterocyclic ketones in up
to 99% yield. The racemic five- and six-membered products of Ni- and
NHC-catalyzed hydroacylation reactions are readily transformed into
heterocyclic ketones containing an α-chiral quaternary stereogenic
center by enantioselective Ni-catalyzed α-arylation and α-heteroarylation
reactions. The chiral, nonracemic products formed through a combination
of alkene hydroacylation and α-(hetero)­arylation reactions are
formed in moderate to high yields (44–99%) with excellent enantioselectivities
(typically >95% ee). The identity of the precatalyst for Ni-catalyzed
α-(hetero)­arylation is dictated by the identity of the α-substituted
heterocyclic ketone starting material. α-(Hetero)­arylations
of six-membered heterocyclic ketones occur at 65–85 °C
in the presence of a catalyst generated in situ from Ni­(COD)2 and (R)-BINAP or (R)-DIFLUORPHOS.
α-(Hetero)­arylation of five-membered heterocyclic ketones must
be conducted at room temperature in the presence of an [((R)-BINAP)­Ni­(η2-NC-Ph)] precatalyst or a
catalyst generated in situ from Ni­(COD)2, (R)-DIFLUORPHOS, and benzonitrile.

本研究报告了一种结合烯烃羟基酰化与手性选择性的α-(杂芳基)化反应的策略，以形成一类包含α-手性四级立体中心的氮杂环酮。通过外消旋选择性的Ni催化的N-亚甲基烯基吲哚和N-亚甲基烯基吡咯-2-羰基醛的分子内羟基酰化反应，可得到高达95%产率的α-取代六元杂环酮；而N-杂环卡宾(NHC)催化的N-烯基吲哚和N-烯基吡咯-2-羰基醛的羟基酰化反应，则可形成高达99%产率的α-取代五元杂环酮。Ni和NHC催化的羟基酰化反应的外消旋五元和六元产物，可通过手性选择性的Ni催化的α-芳基化和α-杂芳基化反应，迅速转化为含有α-手性四级立体中心的杂环酮。通过烯烃羟基酰化与α-(杂芳基)化反应的组合所形成的非外消旋手性产物，其产率适中至高（44–99%），并且具有优异的手性选择性（通常>95% ee）。Ni催化的α-(杂芳基)化的前催化剂的身份，取决于α-取代杂环酮起始原料的身份。六元杂环酮的α-(杂芳基)化反应在65–85 °C的温度下，在由Ni(COD)2和(R)-BINAP或(R)-DIFLUORPHOS原位生成的催化剂存在下进行。五元杂环酮的α-(杂芳基)化反应则需在室温下，在[((R)-BINAP)-Ni-(η2-NC-Ph)]前催化剂或由Ni(COD)2、(R)-DIFLUORPHOS和苯腈原位生成的催化剂存在下进行。