Methods for alkene difunctionalizations: hydroacylation & carboacylation

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Walker Jr., James
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Levi M. Stanley
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The Department of Chemistry seeks to provide students with a foundation in the fundamentals and application of chemical theories and processes of the lab. Thus prepared they me pursue careers as teachers, industry supervisors, or research chemists in a variety of domains (governmental, academic, etc).

The Department of Chemistry was founded in 1880.

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This thesis presents the development of new catalyst for the coupling of alkene hydroacylation and enantioselective α-arylation to form heterocyclic ketones containing α-chiral quarternary stereocenters, the N-heterocyclic carbene-catalyzed intramolecular hydroacylation to form basic nitrogen-containing heterocycles, and the first examples of nickel-catalyzed alkene carboacylation triggered by amide C-N bond activation.

Chapter II discusses a strategy that combines alkene hydroacylation and enantioselective α-arylation to form a wide variety of nitrogen-containing heterocyclic ketones bearing α-chiral quarternary 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 quarternary stereogenic center by enantioselective Ni-catalyzed α-arylation and α-(hetero)arylation 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 à °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.

Chapter III describes the intramolecular hydroacylations of N-allylimidazole- 2-carboxaldehydes and N-allylbenzimidazole-2-carboxaldehydes. These exo-selective hydroacylations occur in the presence of a N-heterocyclic carbene catalyst to generate 5,6-dihydro- 7H-pyrrolo[1,2-α]imidazol-7-ones and 1,2-dihydro-3H-benzo[d] pyrrolo[1,2-α]imidazol-2-ones in high yields (66–99%). In addition, hydroacylations of N-allylimidazole-2-carboxaldehydes in the presence of a chiral, non-racemic NHC catalyst occur, forming 5,6- dihydro-7H-pyrrolo[1,2-α]imidazol-7-ones in moderate-to-high yields (39–98%) with modest enantioselectivities (56–79% ee).

Chapter IV discusses nickel-catalyzed formal carboacylation of ortho-allylbenzamides with arylboronic acid pinacol esters. These carboacylation reactions are triggered by the oxidative addition of an activated amide C-N bond to a nickel(0) catalyst and proceed via alkene insertion into a nickel(II)-acyl bond. The exo-selective carboacylation reactions generate 2-benzyl-2,3-dihydro-1H-inden-1-ones in moderate-to-high yields (46-99%) from a variety of arylboronic acid pinacol esters and substituted ortho-allylbenzamides. These results demonstrate that amides are practical substrates for alkene carboacylation via activation of an amide C-N bond, and this approach bypasses challenges associated with alkene carboacylation triggered by C-C bond activation.

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