Synthesis and Decarboxylative Coupling of Sulfonyl Acetic Esters

The synthesis and palladium-catalyzed decarboxylative allylation (DCA) of α-sulfonyl allyl esters is the central focus of this dissertation. Specifically we describe the development of the racemic reaction in which the scope and mechanism are investigated. In addition, we demonstrate the superiority of Pd-catalyzed DCA to current methodology for the formation of tertiary sulfones. Furthermore, we demonstrate how the chemistry of the sulfone and the DCA, we developed, can be used in concert to obtain products that are not easily accessible. We next developed an asymmetric variant of the reaction in which the asymmetry comes from the substrate itself and not an outside source. Specifically, we observed high levels of conservation of enantioenrichment when the reaction proceeded in the presence of an achiral or racemic catalyst. We investigated this unusual behavior and propose a mechanism to explain the observation. Again, we compare the DCA to existing methodologies and demonstrate that it compares very favorably synthetically and in part answers unsolved challenges in asymmetric organic chemistry. In the course of this work it became apparent that the synthesis of our starting materials would also be a significant contribution to the field of organic chemistry. We have detailed the syntheses of both asymmetric and racemic sulfonyl acetic esters

Synthesis of Chiral Nonracemic Tertiary α-Thio and α-Sulfonyl Acetic Esters via SN2 Reactions of Tertiary Mesylates

Syntheses of enantioenriched sulfides and sulfones via substitution of tertiary mesylate with thiolate nucleophile were achieved with modest to excellent success

Transition Metal-Catalyzed Decarboxylative Allylation and Benzylation Reactions

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Chemical Reviews, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/cr1002744A review. Transition metal catalyzed decarboxylative allylations, benzylations, and interceptive allylations are reviewed

Stereospecific decarboylative allylation of sulfones

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of the American Chemical Society, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ja104196x.Allyl sulfonyl acetic esters undergo highly stereospecific, palladium-catalyzed decarboxylative allylation. The reaction allows the stereospecific formation of tertiary homoallylic sulfones in high yield. In contrast to related reactions that proceed at -100 °C and require highly basic preformed organometallics, the decarboxylative coupling described herein occurs under mild non-basic conditions and requires no stoichiometric additives. Allylation of the intermediate α-sulfonyl anion is more rapid than racemization, leading to a highly enantiospecific process. DFT calculations indicate that the barrier for racemization is 9.9 kcal/mol and thus the barrier of allylation must be <9.9 kcal/mol

Dual C–F, C–H Functionalization via Photocatalysis: Access to Multifluorinated Biaryls

Multifluorinated biaryls are challenging to synthesize and yet are an important class of molecules. Because of the difficulty associated with selective fluorination, this class of molecules represent a formidable synthetic challenge. An alternative approach to selective fluorination of biaryls is to couple an arene that already possesses C–F bonds in the desired location. This strategy has been regularly utilized and relies heavily on traditional cross-coupling strategies that employ organometallics and halides (or pseudohalides) in order to achieve the coupling. Herein we report conditions for the photocatalytic coupling via direct functionalization of the C–F bond of a perfluoroarene and C–H bond of the other arene to provide an expedient route to multifluorinated biaryls. The mild conditions and good functional group tolerance enable a broad scope, including access to the anti-Minisci product of basic heterocycles. Finally, we demonstrate the value of the C–F functionalization approach by utilizing the high fluorine content to systematically build complex biaryls containing between two and five C_aryl–F bonds via the synergistic use of photocatalysis and S_NAr chemistry

Photocatalytic Generation of 2‑Azolyl Radicals: Intermediates for the Azolylation of Arenes and Heteroarenes via C–H Functionalization

The 2-azolyl radical, generated from 2-bromoazoles via photocatalysis, is a powerful intermediate for the intermolecular arylation of unmodified (hetero)­arenes. The reaction is characterized by mild conditions, operational simplicity, tolerance toward functional and sterically demanding groups, broad scope, and anti-Minisci selectivity. A working mechanism is provided, and a low-solubility amine is essential for successful coupling. The utility of the reaction is demonstrated via late-stage functionalization of methyl estrone and application toward other bromoarenes

Selective Perfluoro- and Polyfluoroarylation of Meldrum’s Acid

This work describes the facile and mono-selective per- and polyfluoroarylation of Meldrum’s acid to generate a versatile synthon for highly fluorinated α-phenyl acetic acid derivatives, which provide straightforward access to fluorinated building blocks. The reaction takes place quickly, and most products were isolated without the need for chromatography. Importantly, this method provides an alternative strategy to access α-arylated Meldrum’s acids, which avoids the need for aryl-Pb­(IV) salts or diaryliodonium salts. Furthermore, we demonstrate the synthetic versatility and utility of the Meldrum’s acid products by subjecting our products to several derivatizations of the Meldrum’s acid products as well as photocatalytic hydrodefluorination

Selective and Scalable Perfluoroarylation of Nitroalkanes

Functionalized per- and polyfluoroarenes are important building blocks, with many industrially and medicinally important molecules containing them. Nucleophilic aromatic substitution can be employed as a quick and straightforward way to synthesize these building blocks. While many methods to derivatize fluoroarenes exist that use heteroatom centered nucleophiles, there are fewer methods that use carbon centered nucleophiles, and of those many are poorly defined. This work presents the SNAr reaction of nucleophiles generated from nitroalkanes with a variety of fluorinated arenes. Given that the products are versatile, accessing polyfluorinated arene building blocks in substantial scale is important. This method is highly regioselective, and produces good to moderate yields on a large scale, sans chromatography, and thus fulfills this need. In addition, the regioselectivity of the addition was probed using both DFT calculations and experimentally via halogen exchange