UNSYMMETRICAL KETONE SYNTHESIS VIA A 3-COMPONENT CONNECTION REACTION OF ORGANOZINCS, ALLYLATING AGENTS, AND CARBON-MONOXIDE

A wide variety of organozincs (diethylzinc, alkylzinc halides, and organozincs 2, 5, and 9a-e, functionalized with ester and nitrile groups) undergo a three-component connection reaction with carbon monoxide and allylic benzoates or phosphates 1a-h to furnish unsymmetrical ketones, e.g., 3, 6, and 10, in good yields under 1 atm of carbon monoxide at ambient temperature by the catalysis of tetrakis(triphenylphosphine)palladium in THF/HMPA. The regio- and stereoselectivities of the present carbonylation show marked contrast to those reported for the palladium-catalyzed carbonylation of unsymmetrical allylic substrates. For example, the reaction of crotyl benzoate with octylzinc iodide provides all the possible stereo- and regioisomers, i.e., cis- and trans-2-butenyl and 1-methyl-2-propenyl octyl ketones in comparable amounts. The carbonylative coupling of carvyl phosphates, trans- and cis-1h, and gamma-zincio ester 5 is stereospecific and proceeds with inversion of configuration at the allylic stereocenters to furnish cis- and trans-6h, respectively, as single diastereomers. In the absence of HMPA, the reaction feature changes dramatically and lactones 12 and 13 (composed of organozincs, carbon monoxide, and allylating agents in the ratios of 1:1:2 and 2:1:1, respectively) and symmetrical keto diesters 14 (composed of 2 mol of organozincs and 1 mol of carbon monoxide) are formed in varying ratios depending on the reaction conditions. Synthetic scope of the unsymmetrical ketones and mechanistic rationale for these unique and unprecedented reaction behaviors are discussed.