Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Chemistry

Major

Organic Chemistry

First Advisor

Levi M. Stanley

Abstract

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 °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.

Copyright Owner

James Alfonzo Walker Jr.

Language

en

File Format

application/pdf

File Size

199 pages

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