Palladium(II) catalyzed allylic C-H alkylation reactions

The selective formation of new carbon-carbon bonds is a central challenge for organic synthesis; organic molecules are based on carbon scaffolds which must be assembled from simple building blocks. Since Kolbe performed the first organic C-C bond forming reaction in his synthesis of acetic acid in 1845, the growth of organic synthesis has witnessed the proliferation of methods to forge C-C bonds. A recurring theme among these methods is the use of pre-installed, oxidized “functional groups” to enable and control the bond forming reaction. For the past 50 years, however, C-H activation has beckoned to chemists as the synthetic “way of the future.” Rather than relying upon a functional group, C-H activation promises the direct conversion of the inert, ubiquitous C-H bond to the desired C-C bond. This strategy has inspired tremendous excitement and speculation, but only recently has it begun to be reduced to practice in synthetically useful reactions. This work describes the discovery of the first palladium(II)-catalyzed allylic C-H alkylation reaction. Allylic alkylation has long been performed by palladium(0) catalysis with allylic oxygenate starting materials. In contrast, this method proceeds directly from the readily accessible, chemically robust a-olefin moiety. The development of such a reaction was impeded by the inherent incompatibility of the various steps of the putative catalytic cycle. In order to achieve catalytic turnover, an electrophilic C-H cleavage, a nucleophilic functionalization, and an oxidative Pd(II) regeneration step would all have to operate simultaneously. This series of interlocking compatibility challenges was unraveled with the aid of stoichiometric model studies and mechanistic insights gleaned from previous allylic C-H functionalization reactions. Ultimately, a catalytic allylic C-H alkylation reaction was discovered. The original allylic C-H alkylation reaction had an olefin scope limited to allylarene substrates. These substrates could be described as “doubly activated” because the C-H bonds to be cleaved were both allylic and benzylic. Less reactive allylic C-H bonds displayed only very low reactivity under the reported conditions. This substrate limitation was investigated, and it was discovered that the catalytic cycle was inhibited by a necessary cosolvent, dimethylsulfoxide. This solvent was speculated to act as a ligand for palladium, competitively binding to the metal and displacing the ligand required for C-H cleavage. By identifying a more electron-rich C-H cleavage ligand which presumably could better compete with dimethylsulfoxide for binding to palladium, it was possible to overcome the inhibition and restore reactivity to the catalytic system. This allowed the development of an allylic C-H alkylation with a general substrate scope. The nucleophile scope of the allylic C-H alkylation was explored with the goal of expanding the diversity and complexity of both coupling partners. It was discovered that tertiary carbon nucleophiles, bearing two electron-withdrawing groups to stabilize a carbanion and one aliphatic side chain, could participate in the reaction. The addition of the aliphatic side chain allowed for additional functional groups or rings to be incorporated into the nucleophile, thereby enabling the coupling of two relatively valuable components. This work opened the door to future development of macrocyclization reactions and enantioselective alkylations.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemistry

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2013

Author dc:creator

• Young, Andrew

Contributors dc:contributor

• White, Maria C.
• Moore, Jeffrey S.
• Katzenellenbogen, John A.
• Rauchfuss, Thomas B.

• C-H activation
• Allylic alkylation
• Palladium catalysis
• Sulfoxide ligands
• Organometallic chemistry

Statement dc:rights

• Copyright 2012 Andrew Young

Language dc:language

en

Handle dc:identifier

http://hdl.handle.net/2142/42164

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/42164