Pd-catalyzed C(sp3)-H oxygenation has emerged as an attractive strategy for organic synthesis. The most commonly proposed mechanism involves C(sp3)-H activation followed by oxidative addition of an oxygen electrophile to give an alkylpalladium(iv) species and further C(sp3)-O reductive elimination. In the present study of γ-C(sp3)-H acyloxylation of amine derivatives, we show a different mechanism when tert-butyl hydroperoxide (TBHP) is used as an oxidant-namely, a bimetallic oxidative addition-oxo-insertion process. This catalytic model results in an alkoxypalladium(ii) intermediate from which acyloxylation and alkoxylation products are formed. Experimental and computational studies, including isolation of the putative post-oxo-insertion alkoxypalladium(ii) intermediates, support this mechanistic model. Density functional theory reveals that the classical alkylpalladium(iv) oxidative addition pathway is higher in energy than the bimetallic oxo-insertion pathway. Further kinetic studies revealed second-order dependence on [Pd] and first-order on [TBHP], which is consistent with DFT analysis. This procedure is compatible with a wide range of acids and alcohols for γ-C(sp3)-H oxygenation. Preliminary functional group transformations of the products underscore the great potential of this protocol for structural manipulation.
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