Palladium‐Catalyzed Selective Anti‐Markovnikov Oxidation of Allylic Esters

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The palladium(II)-catalyzed oxidation of alkenes to carbonyl compounds, usually referred to as the Wacker or Wacker– Tsuji reaction, is arguably one of the best-known reactions catalyzed by palladium. It is an important catalytic process industrially, for the production of ethanal, and synthetically, for the conversion of olefins to ketones. The oxidation of terminal alkenes typically proceeds with selective formation of methylketones. The anti-Markovnikov (AM) Wacker oxidation of terminal olefins to aldehydes remains, however, a major challenge. Under certain conditions, AM selectivity is obtained with styrenes, Michael-type acceptor alkenes and certain olefins, such as 2-vinyl-furanosides, bearing a directing functional group. Indeed, high aldehyde selectivity in the catalytic oxidation of phthalimide-protected allylic amines was reported by our group to yield a key intermediate in the preparation of b-amino acids. On the other hand, Sigman and co-workers have reported the regioselective oxidation of protected allylic amines controlled by various palladium catalysts to yield the corresponding methyl ketones. In 1986, Pd-catalyzed aldehyde selective oxidation of styrene with O2 and CuCl in tBuOH at 30 8C was reported by Feringa. Later, Wenzel reported good selectivity (6:1) for aldehyde formation from allyl acetate (56% combined yield of aldehyde and ketone), in tBuOHwith PdCl2/CH3CN/CuCl/ NaCl at 50 8C. More recently, the aldehyde-selective oxidation of styrenes was reported by Grubbs and co-workers using the catalyst [PdCl2(CH3CN)2], p-benzoquinone as oxidant, and tBuOH as solvent at 85 8C. However, a more general anti-Markovnikov alkene oxidation of non-aryl alkenes under mild conditions remains a challenge, despite the tremendous value in extending this reaction to other substrate classes, in particular allylic alcohols and esters. b-Hydroxy aldehydes are usually prepared by the crossaldol reaction between aldehydes or an aldehyde and a ketone. The direct catalytic formation of an aldehyde by selective attack at the terminal carbon of an a-olefin would be a highly valuable alternative. However, the selective antiMarkovnikov oxidation of allylic alcohols into b-hydroxy aldehydes has proven to be very difficult owing to formation of the ketone products and competing olefin isomerization. Herein, we demonstrate the aldehyde-selective catalytic oxidation of ester-protected allylic alcohols with as low as 0.5 mol% of [PdCl2(PhCN)2] and p-benzoquinone (BQ) as oxidant in tBuOH under ambient conditions. Importantly, the same anti-Markovnikov oxidation products were obtained selectively from both branched and linear allylic esters (Scheme 1), owing to rapid isomerization between allylic esters under the reaction conditions (see below).