Regio- and stereochemistry of Na-mediated reductive cleavage of alkyl aryl ethers

We have investigated the regio- and stereochemistry of the reductive dealkoxylation of alkyl aryl ethers. Chiral non-racemic secondary alcohols were converted into the corresponding m-terphenyl or 2-biphenyl ethers either via inversion of configuration under Mitsunobu reaction conditions or with retention of configuration under SNAr conditions. The successive cleavage of the aromatic CO bond occurred in the presence of a stoichiometric amount of Na metal in dry tetrahydrofuran at rt with retention of configuration, thus highlighting that the overall inversion or retention of configuration for the whole two-step procedure is dictated by the stereochemistry of the first synthetic step.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide

(S)-2-Biphenyl 2-octyl etherC20H26Oer >95:5[α]D25 = +46.6 (c 1.0, EtOH)Absolute configuration (2S)Source of chirality: (2R)-(−)-2-octanol

(S)-2,6-Diphenylphenyl 2-octyl etherC26H30Oer >95:5[α]D25 = −10.2 (c 1.0, EtOH)Absolute configuration (2S)Source of chirality: (2R)-(−)-2-octanol

(R)-2-Biphenyl 3-octyl etherC20H26Oer >95:5[α]D25 = −26.0 (c 1.2, EtOH)Absolute configuration (2R)Source of chirality: (3S)-(+)-3-octanol

(R)-2,6-Diphenylphenyl 3-octyl etherC26H30Oer >95:5[α]D25 = +13.0 (c 1.2, EtOH)Absolute configuration (2S)Source of chirality: (2S)-(+)-3-octanol