Reaction of Phosgeniminium Salts with Enolates Derived from Lewis Acid Complexes of 2'-Hydroxypropiophenones and Related β-Diketones

摘要

The 2-aminochromone ring system has proven to be a rich pharmacophore for use in the design of compounds with a diversity of biological effects that includes unique antiplatelet derivatives, antiproliferative agents, and phosphatidylinositol 3-kinase inhibitors. Our interest in the utilization of this template as well as the related 2-aminopyrone system as part of our medicinal chemistry efforts led us to explore a variety of new methods for their preparation. We recently reported a synthesis of 2-aminochromones (eg 4) that involves the thermal reaction of boron difluoride complexes of 2'-hydroxy-acetophenones (or 2'-hydroxypropiophenones) with phosgene iminium chloride. Hydrolysis of the readily isolated complex 3 with aqueous acetonitrile (or anhydrous methanol) affords the desired 2-aminochromone 4. This reaction is successfully performed either by preforming the boron difluoride complex 2 or through the generation of this complex in situ by the addition of boron trifluoride etherate to an ethylene dichloride solution of the starting 2'-hydroxyacetophenone prior to the introduction of the iminium chloride. As shown in Scheme 1, yields for the overall conversion of 1a to 4a in both instances are comparable (47 vs 56%). In contrast, attempts to utilize this methodology for the conversion of benzoylacetone (6, R' = H) to the 6-phenyl-2-aminopyrones 7a and 7b were unsuccessful, providing only small amounts of the desired products (Table 2).