Selectivity and Mechanism of Iridium-Catalyzed Cyclohexyl Methyl Ether Cleavage

Abstract

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 N 2 demethylation versus S N 1 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.

Light-Promoted Transfer of an Iridium Hydride in Alkyl Ether Cleavage

“…35 In total, the conformational factors that influence selectivity in cyclohexyl ether cleavage using 2/NaBAr F 4 are essentially identical with those observed for [(cod)Ir(PPh 3 ) 2 ]BAr F 4 . 35 The principal factors distinguishing 2/NaBAr F 4 from [(cod)Ir(PPh 3 ) 2 ]BAr F 4 are therefore the necessity of light and the requirement for a somewhat higher catalyst loading of 2 versus [(cod)Ir-(PPh 3 ) 2 ]BAr F 4 . 34,35 Reaction Mechanism.…”

“…In a previous report on iridium-catalyzed hydrosilylative ether cleavage, we interrogated the selectivity obtained for an array of cyclohexyl methyl ethers using [(cod)Ir(PPh 3 ) 2 ]BAr F 4 as a precatalyst. 35 In that case, we observed that the selectivity for demethylation versus 2°C−O cleavage depended on conformational factors and showed that selectivity was correlated with the computationally predicted conformational preferences of the substrate triethylsilyloxonium ions. Substrates with strong preferences for the silyloxonium group in the equatorial conformation (E ax − E eq > 4 kcal mol −1 ) underwent preferential demethylation, while substrates predicted to have greater populations in the axial conformation underwent selective demethoxylation, with the switch in reactivity being ascribed to the relative rates of S N 2 demethylation versus S N 1 demethoxylation.…”

“…This proposal is inspired by work on related systems that operate without light, [33][34][35][36][37]43,44 as well as the reported photochemical behavior of the bipyridine-supported iridium hydride reported by Miller. 24 Complex 2 likely reacts with NaBAr F 4 and triethylsilane to form the electrophilic σ-silane complex 4 that has been previously characterized by Djukic and co-workers under relevant alcohol dehydrosilylation conditions.…”

“…35 The principal factors distinguishing 2/NaBAr F 4 from [(cod)Ir(PPh 3 ) 2 ]BAr F 4 are therefore the necessity of light and the requirement for a somewhat higher catalyst loading of 2 versus [(cod)Ir-(PPh 3 ) 2 ]BAr F 4 . 34,35 Reaction Mechanism. The similar conformational influences on selectivity observed for light-promoted hydrosilylative alkyl ether cleavage with 2/NaBAr F 4 and the thermal bis(phosphine)iridium systems strongly imply mechanistic similarities between the two systems.…”

“…28 In the case of catalysis by 2/NaBAr F 4 , SET reduction of silyloxonium ion intermediates is very unlikely to give the selectivity observed for substrates in Tables 4 and 5, which has been previously rationalized in the context of competitive S N 1 and S N 2 processes. 35 The observation that 2/NaBAr F 4 catalyzes the hydrosilylation of carbonyl derivatives 39,40 and dehydrosilylation of alcohols 30 in the dark but does not catalyze hydrosilylative ether cleavage in the absence of light can be interpreted in the context of the relative reactivities of the plausible reaction intermediates. These three transformations share similar mechanisms, with heterolytic Si−H cleavage giving silyloxycarbenium 38,39 and mono- 30 and dialkylsilyloxonium 34,35,47 ions, respectively.…”