Improving Alkyl–Alkyl Cross-Coupling Catalysis with Early Transition Metals through Mechanistic Understanding and Metal Tuning

Abstract

Alkyl-alkyl cross-coupling is a powerful C-C bond forming transformation typically catalyzed by late transition metals. Herein we report a mechanistic investigation into an early transition metal-catalyzed variant of this reaction. Through this mechanistic understanding, an ideal Y catalyst was determined through tuning of the metal in order to optimize for oxidation potential, the rate limiting step in this reaction. A wide substrate scope is revealed that includes a variety of functional groups as well as unactivated substrates.

Radical-Polar Crossover Catalysis with a d0 Metal Enabled by a Redox-Active Ligand

“…While mechanism 1 is also unlikely, because catalyst 1 is known to induce radical mechanisms, further studies were needed to rule it out. 19,40 The importance of an anionic intermediate in the synthesis of gem-difluoroalkenes is supported by a Hammett analysis of this reaction which revealed an overall increase in reaction rate with increasingly electron-deficient substrates (Figure 5). A linear relationship is observed for the p-t Bu, p-Me, p-H, m-Br, p-CF3 and p-CN substrates.…”

“…[14][15][16][17][18] In the mechanism that was previously disclosed, the redox-active ligand mediated the formation of an organic radical intermediate from the alkyl halide through single electron oxidation of the ligand. 19 We hypothesized that a reductive radical-polar crossover mechanism could be harnessed, despite using a d 0 metal, because the (tris)amido ligand can undergo multi electron transfer (Figure 1b). 17 Therefore, a test system was designed with an electron withdrawing group (EWG) and leaving group (LG) in the a-position to the radical.…”

“…27,[32][33][34][35][36] Based on previous studies, it was known that an electron rich, anionic complex was necessary for reduction of the electrophile to generate a carbon-based radical. 19 Therefore, we hypothesized that using 1 and 1 equivalent of transmetallation reagent BnZnBr, an anionic complex 2, would be electron rich enough to reduce the benzylic bromide substrate 3a (Figure 2). Excitingly, when in situ formed 2 was exposed to 1 equivalent of 3a, the expected elimination product 4a was formed in 98% yield based on an a 19 F NMR spectroscopy with an internal standard (see SI for isolated yields).…”

Radical-Polar Crossover Catalysis with a d0 Metal Enabled by a Redox-Active Ligand

“…While the fluoride leaving group is nonobvious, it gives a markedly different product than the cross-coupling product observed previously. The gem -difluorostyrene product that is formed is a valuable functional group that can be stoichiometrically prepared from specialized reagents. − It can be a bioisostere of a carbonyl group. − These motifs are also relevant to polymer chemistry. − Finally, these reagents are valuable linchpin reagents for further functionalization. ,− Based on previous studies, it was known that an electron-rich, anionic complex was necessary for reduction of the electrophile to generate a carbon-based radical . Therefore, we hypothesized that using 1 and 1 equiv of transmetalation reagent BnZnBr, an anionic complex 2 , would be electron-rich enough to reduce the benzylic bromide substrate 3a (Figure ).…”

“…Additionally, no competitive cross-coupling is observed between the organic fragments in the inner sphere mechanism of this coordinatively saturated complex further ruling out mechanism 3. While mechanism 1 is also unlikely, because catalyst 1 is known to induce radical mechanisms, further studies were needed to rule it out. , …”