Advances in Directed Ortho Metalation: Copper- and Rhodium-Catalyzed Allylic Substitution and the DMG Dance

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Dalziel, Michael
Copper-Catalyzed Allylic Substitution , DMG Dance , 7-Azaindole , Directed Ortho Metalation , Rhodium-Catalyzed Allylic Substitution , Hard Nucleophiles
Chapter one of this thesis describes preliminary efforts towards the development of the rhodium-catalyzed allylic arylation reaction employing nucleophiles containing ortho-DMGs (directed metalation groups). Unfortunately, a variety of rhodium(I) catalysts and carbonate-based leaving groups screened during the optimization studies were not successful within this reaction, with poor regioselectivity being observed in all cases. Chapter two describes the optimization and scope of the copper-catalyzed SN2´ allylic arylation reaction using DoM (Directed ortho Metalation)-derived nucleophiles. An air stable and environmentally benign copper(I)-NHC catalyst has been found to facilitate this SN2´ allylic arylation process, forming C−C bonds in a highly regioselective manner. A variety of DMGs and acyclic allylic bromides were tolerated within this reaction, with a single example showcasing its application on the analogous cyclohexene derivative. Preliminary efforts towards the enantioselective variant of this reaction are also described. Chapter three describes the development and optimization of the DMG dance reaction on the 7-azaindole heterocycle, thus allowing its highly regioselective functionalization via sequential DoM reactions. Excellent C-6 anion formation of 7-azaindole was achieved, with a variety of carbon-based and heteroatom-based electrophiles being well tolerated. Preliminary application of the DoM reaction on L-745870, an antipsychotic agent containing the 7-azaindole skeleton, was successful. Studies towards the synthesis of other potentially bioactive analogues of L-745870 via this methodology are currently ongoing.
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