Catalytic Functionalisation of Unactivated sp3 C−H Bonds via exo-Directing Groups: Synthesis of Chemically Differentiated 1,2-Diols

Zhi Ren, Fanyang Mo, and Guangbin Dong
J. Am. Chem. Soc.
DOI: 10.1021/ja3082186

Selective C-H oxidation of unactivated alkyl groups is a remarkably powerful way of installing new functionality in simple substrates. We’ve featured some developments in this area previously.

C-H oxidation at the β-carbon of an unactivated alcohol has, so far, been inaccessible due to the deactivating inductive effect of the proximal oxygen. Dong and co-workers have overcome this problem in a method that allows the selective preparation of orthogonally protected 1,2-diols from simple alcohol precursors.

Their method employs a neat oxime derivative of the alcohol to direct palladium C-H insertion β to oxygen. Oximes are known to direct palladation of C-H bonds on the ‘other side’ of the oxime moiety; by removing appropriate C-H bonds from the oxime directing group, palladation in this case occurs on the desired oxygen ‘side’.

The authors note that reaction concentration is critical to the success of the oxidation process. The optimised process uses a concentration of 0.2 M. At lower concentration (0.1 M) the reaction does not go to completion; at higher concentration (0.4 M) decomposition products are observed. Whether or not this narrow range of optimal conditions is variable by substrate is not discussed, but the scope of the reaction is exemplified in a number of substrates with consistently good conversion.

Selective preparation of 1,2 diol derivatives is critical to any application of this methodology in synthesis. The oxime directing group can be removed as a protecting group in the presence of the adjacent acetate. Similarly, the oxime is stable under conditions for acetate cleavage, allowing selective differentiation between the two masked hydroxyl groups.

Interestingly, the reaction gives better yields on larger scale. A test example showed an improvement from 61% yield on 0.1 mmol scale to 80% yield from a 5 mmol reaction.

In one example, a substrate derived from menthol was subjected to the reaction conditions. Instead of observing the expected 1,2 oxidation product, a postulated intermediate undergoes an interesting skeletal rearrangement to give an unusual substituted cyclopentane scaffold.

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