Selectivity and Mechanism of Iridium-Catalyzed Cyclohexyl Methyl Ether Cleavage

Cationic bis­(phosphine)iridium complexes are found to catalyze the cleavage of cyclohexyl methyl ethers by triethylsilane. Selectivity for C–O cleavage is determined by the relative rates of S_N2 demethylation versus S_N1 demethoxylation, with the axial or equatorial disposition of the silyloxonium ion intermediate acting as an important contributing factor. Modulation of the electron-donor power of the supporting phosphine ligands enables a switch in selectivity from demethylation of equatorial methyl ethers to 2° demethoxylation. Applications of these accessible catalysts to the selective demethoxylation of the 3α-methoxy group of cholic acid derivatives is demonstrated, including a switch in observed selectivity controlled by 7α-substitution. The resting state of the catalyst has been characterized for two phosphine derivatives, demonstrating that the observed switch in C–O cleavage selectivity likely results from electronic factors rather than from a major perturbation of the catalyst structure.