Rh-Catalyzed Intermolecular Reactions of α‑Alkyl-α-Diazo Carbonyl Compounds with Selectivity over β‑Hydride Migration

Rh-carbenes derived from α-diazocarbonyl compounds have found broad utility across a remarkable range of reactivity, including cyclopropanation, cyclopropenation, C–H insertions, heteroatom–hydrogen insertions, and ylide forming reactions. However, in contrast to α-aryl or α-vinyl-α-diazocarbonyl compounds, the utility of α-alkyl-α-diazocarbonyl compounds had been moderated by the propensity of such compounds to undergo intramolecular β-hydride migration to give alkene products. Especially challenging had been intermolecular reactions involving α-alkyl-α-diazocarbonyl compounds. This Account discusses the historical context and prior limitations of Rh-catalyzed reactions involving α-alkyl-α-diazocarbonyl compounds. Early studies demonstrated that ligand and temperature effects could influence chemoselectivity over β-hydride migration. However, effects were modest and conflicting conclusions had been drawn about the influence of sterically demanding ligands on β-hydride migration. More recent advances have led to a more detailed understanding of the reaction conditions that can promote intermolecular reactivity in preference to β-hydride migration. In particular, the use of bulky carboxylate ligands and low reaction temperatures have been key to enabling intermolecular cyclopropenation, cyclopropanation, carbonyl ylide formation/dipolar cycloaddition, indole C–H functionalization, and intramolecular bicyclobutanation with high chemoselectivity over β-hydride migration. Cyclic α-diazocarbonyl compounds have been shown to be particularly resilient toward β-hydride migration and are the first class of compounds that can engage in intermolecular reactivity in the presence of tertiary β-hydrogens. DFT calculations were used to propose that for cyclic α-diazocarbonyl compounds, ring constraints relieve steric interaction for intermolecular reactions and thereby accelerate the rate of intermolecular reactivity relative to intramolecular β-hydride migration. Enantioselective reactions of α-alkyl-α-diazocarbonyl compounds have been developed using bimetallic N-imido-tert-leucinate-derived complexes. The most effective complexes were found by computation and X-ray crystallography to adopt a “chiral crown” conformation in which all of the imido groups are presented on one face of the paddlewheel complex in a chiral arrangement. Insight from computational studies guided the design and synthesis of a mixed ligand paddlewheel complex, Rh2(S-PTTL)3TPA, the structure of wh