Functional group oxidations and oxidative bond-forming reactions are ubiquitous in organic synthesis and vital to the construction of biologically active compounds. During the past several years, a number of important synthetic methods have been developed that proceed through an initial single electron oxidation. The mechanistic studies presented herein will focus on understanding and improving two important synthetic platforms that utilize single electron oxidation as a critical step in bond-forming reactions: 1) oxidative enolate heterocoupling, and 2) organo-SOMO activation. It is our hypothesis that the high distribution of heterocoupled products obtained in oxidative enolate heterocoupling reactions is in part a consequence of lithium enolate heteroaggregates formed from deprotonation of carbonyl precursors. To study this system in detail, the rates of oxidation of a series of enolates will be measured by stopped-flow spectrophotometry and ReactIR and compared to the thermodynamic ease of oxidation of these substrates as measured by cyclic voltammetry. In all of these studies, the impact of enolate countercation, oxidant, and solvent will be evaluated. NMR studies will be employed to determine the distribution of aggregates contained in solution that are derived from deprotonation of equimolar mixtures of carbonyl precursors. These data will be used to assess how both heteroaggregate distributions and kinetics of reaction impact product distribution in oxidative coupling reactions and provide an important guide in the rational design of high-yielding enolate heterocoupling reactions. In the second portion of the proposed work, initial studies of organo-SOMO activation show that the concentration of water not only impacts intermediate enamine formation, but also attenuates the solubility of Ce(IV). The interplay between these two factors is critical for reaction success. To examine this system, mechanistic studies including reaction progress kinetic analysis and spectrophotometry will be used to assess the impact of oxidant, solvent, and catalyst structure in two important organo-SOMO-activated processes: allylation and arylation. Additionally, the importance of oxidant phase-transfer and the relationship between reaction rate and enantioselectivity will be determined. The information acquired from these studies will be used to guide the development of more efficient organo-SOMO-activated processes. Overall, these rigorous mechanistic studies will catalogue the factors critical for concise reaction design enhancing the use of oxidative enolate heterocoupling and organo-SOMO-activated methods in the synthesis of medically important compounds.
The work described in this proposal will use our mechanistic understanding of Ce(IV)-based oxidants as a benchmark to understand and improve two important synthetic platforms that utilize single electron oxidation as a critical step in bond-forming reactions: 1) oxidative enolate heterocoupling, and 2) organo-SOMO activation. The proposed studies presented herein will provide synthetic chemists with mechanistic information crucial for the development of high yielding procedures valuable for the synthesis of complex molecules important in medicine.
|Patel, Niki R; Flowers 2nd, Robert A (2015) Mechanistic study of silver-catalyzed decarboxylative fluorination. J Org Chem 80:5834-41|
|Patel, Niki R; Flowers 2nd, Robert A (2013) Uncovering the mechanism of the Ag(I)/persulfate-catalyzed cross-coupling reaction of arylboronic acids and heteroarenes. J Am Chem Soc 135:4672-5|
|Casey, Brian M; Flowers 2nd, Robert A (2011) On the nature of the oxidative heterocoupling of lithium enolates. J Am Chem Soc 133:11492-5|
|Casey, Brian M; Eakin, Cynthia A; Jiao, Jingliang et al. (2010) Corrigendum to Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene. Tetrahedron 66:5720-5726|
|Devery 3rd, James J; Conrad, Jay C; MacMillan, David W C et al. (2010) Mechanistic complexity in organo-SOMO activation. Angew Chem Int Ed Engl 49:6106-10|
|Devery, James J; Mohanta, Pramod K; Casey, Brian M et al. (2009) Facile Route to Tetrasubstituted Pyrazoles Utilizing Ceric Ammonium Nitrate. Synlett :1490-1494|
|Casey, Brian M; Eakin, Cynthia A; Jiao, Jingliang et al. (2009) Solvent-dependent oxidative coupling of 1-aryl-1,3-dicarbonyls and styrene. Tetrahedron 65:10762-10768|
|Casey, Brian M; Eakin, Cynthia A; Flowers, Robert A (2009) Synthesis of gamma-halogenated ketones via the Ce(IV)-mediated oxidative coupling of cyclobutanols and inorganic halides. Tetrahedron Lett 50:1264-1266|
|Jiao, Jingliang; Nguyen, Larry X; Patterson, Dennis R et al. (2007) An efficient and general approach to beta-functionalized ketones. Org Lett 9:1323-6|
|Jiao, Jingliang; Zhang, Yang; Devery 3rd, James J et al. (2007) Mechanistic studies of Ce(IV)-mediated oxidation of beta-dicarbonyls: solvent-dependent behavior of radical cation intermediates. J Org Chem 72:5486-92|
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