Deciphering substitution effects on reductive hydroalkoxylation of alkynyl aminols for stereoselective synthesis of morpholines and 1,4-oxazepanes: total synthesis of tridemorph and fenpropimorph.

Abstract

Acid catalysed reductive etherification of N-propargyl amino alcohols for the stereoselective synthesis of cis-2,5/2,6-disubstituted morpholines and cis-2,6/2,7-disubstituted oxazepanes has been developed. Mechanistic studies revealed that terminal alkynols gave morpholines via a 6-exo-dig hydroalkoxylation-isomerization-reduction cascade. Interestingly, an alkyne hydration-cyclization-reduction sequence is found to be involved in the formation of oxazepanes from alkyl substituted internal alkynols. The strategy was used as a key step in the total synthesis of fungicides tridemorph and fenpropimorph.