Journal
ACS CATALYSIS
Volume 6, Issue 4, Pages 2673-2680Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acscatal.6b00365
Keywords
alkene hydroacylation; ketone alpha-arylation; enantioselective catalysis; quaternary stereocenters; heterocycles
Categories
Funding
- NSF [CAREER 1353819]
- Iowa State University (ISU)
- ISU Institute for Physical Research
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1352080] Funding Source: National Science Foundation
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We report a strategy that combines alkene hydroacylation and enantioselective alpha-(hetero)arylation reactions to form a wide variety of nitrogen-containing heterocyclic ketones bearing alpha-chiral quaternary stereogenic centers. Exo-selective, intramolecular Ni-catalyzed hydroacylations of N-homoallylindole- and N-homoallylpyrrole-2-carboxaldehydes form alpha-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 alpha-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 alpha-chiral quaternary stereogenic center by enantioselective Ni-catalyzed alpha-arylation and alpha-heteroarylation reactions. The chiral, nonracemic products formed through a combination of alkene hydroacylation and alpha-(hetero)arylation reactions are formed in moderate to high yields (4499%) with excellent enantioselectivities (typically >95% ee). The identity of the precatalyst for Ni-catalyzed alpha-(hetero)arylation is dictated by the identity of the alpha-substituted heterocyclic ketone starting material. alpha-(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. alpha-(Hetero)arylation of five-membered heterocyclic ketones must be conducted at room temperature in the presence of an [((R)-BINAP)Ni(eta(2)-NC-Ph)] precatalyst or a catalyst generated in situ from Ni(COD)(2), (R)-DIFLUORPHOS, and benzonitrile.
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