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Catalytic S-H Bond Activation

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The chemical synthesis of medicinal agents, advanced materials and fine chemicals requires the availability of structurally diverse chemical building blocks. The goal of my research program is to develop new transition metal catalyzed reactions beyond what is currently considered synthetically feasible as a means to expand the structural and functional diversity of synthetically accessible compounds. The ability to combine a series of stoichiometric transformations to achieve a new catalytic reaction is a powerful approach to reaction design. An improved understanding of fundamental transition metal reactivity, coupled with the discovery of novel reactivity, would provide the foundation for this approach to be of widespread use. My group uses a comprehensive approach to methodology development, by combining organic and organometallic synthesis with fundamental physical organic/mechanistic studies.

We have discovered the first metal catalyst [Tp*Rh(PPh3)2] capable of alkyne hydrothiolation using alkyl thiols. These reactions generate the branched isomer in high isolated yields and with high regioselectivity, both of which are critical to synthetic utility. A preliminary communication has recently been published [Cao, C.; Fraser, L. R; Love, J. A. “Rhodium-catalyzed Alkyne Hydrothiolation with Aromatic and Aliphatic Thiols,” J. Am. Chem. Soc. 2005, 127, 17614-17615] and a full paper will be submitted shortly [Yang, J.; Sabarre, A.; Shoai, S.; Fraser, L. R.; Cao, C.; Love, J. A. “Scope and Limitations of Alkyne Hydrothiolation using Rhodium Pyrazolylborate Catalysts,” J. Org. Chem., to be submitted]. The branched alkyl vinyl sulfides readily undergo Kumada-type cross-coupling to provide convenient access to 1,1-disubsituted olefins in two steps from readily available alkynes [Sabarre, A.; Love, J. A. “Synthesis of 1,1-Disubstituted Olefins Via Catalytic Alkyne Hydrothiolation/Kumada Cross Coupling,” Org. Lett. 2008, submitted].

We subsequently sought to evaluate a series of rhodium pyrazolylborate complexes for their activity in alkyne hydrothiolation. The conformation of the pyrazolylborate ligand was investigated in both solution (multinuclear VT-NMR and IR spectroscopy) and the solid state (X-Ray crystallography) and was found to depend heavily on the position and degree of substitution of the pyrazolyl rings. In catalytic hydrothiolation, complexes that readily adopt k3-coordination gave the best yields and selectivities [Fraser, L. R.; Bird, J.; Wu, Q.; Cao, C.; Patrick, B. O.; Love, J. A. “Effect of Anionic Ligands on the Regioselectivity of Rhodium-Catalyzed Alkyne Hydrothiolation,” Organometallics 2007, 26, 5602-5611].

We have also discovered that [ClRh(PPh3)3] catalyzes regioselective alkyne hydrothiolation using alkyl thiols, producing linear alkyl vinyl sulfides. [Shoai, S.; Bichler, P.; Kang, B.; Buckley, H. L.; Love, J. A. “Catalytic Alkyne Hydrothiolation of Alkyl Thiols using Wilkinson’s Catalyst,” Organometallics 2007, 26, 5778-5781]. Thus, convenient access to both branched and linear vinyl sulfides can be obtained by appropriate selection of anionic ligand. Mechanistic studies have indicated that both [Tp*Rh(PPh3)2] and [ClRh(PPh3)3] catalyze hydrothiolation by the following general mechanism: thiol oxidative addition, alkyne migratory insertion, vinyl sulfide reductive elimination. The regioselectivity arises in the migratory insertion step: with [ClRh(PPh3)3], insertion into the Rh-H bond occurs preferentially to give rise to the linear vinyl sulfide product, whereas with [Tp*Rh(PPh3)2], insertion into the Rh-S bond is favored. This is an unusual example of preferential insertion of a pi-bond into an M-X bond in the presence of a hydride ligand. Shoai, S.; Kang, B.; Love, J. A., manuscript in preparation.