Catalyzed Selective Direct α- and γ-Alkylation of Aldehydes with Cyclic Benzyl Ethers by Using T+BF4- in the Presence of an Inexpensive Organic Acid or Anhydride

The cross dehydrogenative coupling (CDC) of cyclic benzyl ethers with aliphatic and alpha,beta-unsaturated aldehydes has been developed. The mild reaction conditions, in which an N-oxoammonium salt derived from TEMPO (2,2,6,6-tetramethyl-1-piperidinoxyl) is employed as the oxidant in combination with a Cu catalyst, allow the use of relatively redox-unstable aldehydes under oxidative CDC conditions. The addition of a catalytic amount of trifluoroacetic acid (TFA) or Ac2O facilitates the reaction and increases the efficiency and selectivity. In contrast to the expected alpha-alkylation obtained with aliphatic aldehydes, alpha,beta-unsaturated aldehydes led preferentially to the more challenging g-alkylated products. The utility of the developed methodology was demonstrated by the synthesis of isochromane-derived bioactive compounds, such as the dopamine antagonist sonepiprazole.