Copper and Zinc Catalyzed Additions of Alkynes and Ynamides to Carbonyl Electrophiles

Abstract

Fluorine-containing pharmaceuticals are of increasing interest which is at least partly due to the favorable stability to biodegradation, increasing bioavailability and lipophilicity and other desirable pharmacological and physicochemical effects. The catalytic enantioselective alkynylation of trifluoromethyl ketones is of particular interest with respect to Efavirenz, a commonly prescribed reverse transcriptase inhibitor. The possibility of an asymmetric formation of the important trifluoromethyl-derived propargylic alcohol pharmacophore was investigated. Addition of phenylacetylene to 3,3,3-trifluoroacetophenone was achieved in moderate to high yield and enantioselectivity using catalytic zinc(II) triflate and the chiral ligand cinchonine in triethylamine and acetonitrile as solvent. While more investigation is required to develop a reproducible procedure, the results indicate that excellent yields and ee are possible under mild conditions.

Ynamides derived from alkynes and electron-deficient amines have received increasing interest due to their huge synthetic potential, including utilization in the total synthesis of natural compounds. The addition of ynamides to acyl chlorides has been accomplished at room temperature using copper iodide as catalyst. This economical and practical carbon-carbon bond formation provides convenient access to a variety of 3-aminoynones from aliphatic and aromatic acyl chlorides in up to 99% yield. Steric hindrance does not seem to affect the reaction and the ynamide addition to pivaloyl chloride gave was achieved in 90% yield.

The first catalytic asymmetric addition of ynamides to aliphatic and aromatic aldehydes is described. This reaction provides unprecedented access to a diverse family of N-substituted propargylic alcohols that are obtained in high yield and ee in the presence of 10 mol% of zinc triflate and N-methylephedrine The use of apolar solvent mixtures is essential to avoid product racemization and to optimize ee’s without compromising conversion. Furthermore, asymmetric addition of terminal ynamides to trifluoromethyl ketones with a readily available chiral zinc catalyst is accomplished and gives CF3-substituted tertiary propargylic alcohols in up to 99% yield and 96% ee. The exclusion of organozinc additives and base as well as the general synthetic utility of the products are key features of this reaction. The value of the β-hydroxy-β-trifluoromethyl ynamides is exemplified by selective transformations to chiral Z- and E-enamides, an amide, and N,O-ketene acetals. The highly regioselective hydration, stereoselective reduction, and hydroacyloxylation reactions proceed with high yields and without erosion of the ee value of the parent β-hydroxy ynamides.