Mechanism of Acylative Oxidation–Reduction–Condensation Reactions Using Benzoisothiazolones as Oxidant and Triethylphosphite as Stoichiometric Reductant

We previously described a new organocatalytic
oxidation–reduction–condensation
for amide/peptide construction. The reaction system relies on triethylphosphite
as the stoichiometric reductant and organocatalytic benzo­isothiazolone/O2 in air as the oxidant. The reaction was assumed to generate
catalytic quantities of S-acylthio­salicylamides
as electrophiles, which are rapidly intercepted by amine reactants
to generate amides/peptides and o-mercapto­benzamides.
The latter are then gently reoxidized to the benzo­isothiazolones
under Cu-catalyzed aerobic conditions to complete the catalytic cycle.
To gain a mechanistic understanding, we describe herein our studies
of the stoichiometric generation of S-acylthio­salicyl­amides
under oxidation–reduction–condensation conditions from
a variety of benzoisothiazolones and carboxylic acids using triethylphosphite
as the terminal reductant. These studies have revealed the presence
of more than one reaction pathway when benzo­isothiazolones react
with triethylphosphite (including a rapid, direct deoxygenation of
certain classes of benzo­isothiazolones by triethyl­phosphite)
and allow the identification of optimal reaction characteristics (benzo­isothiazolone
structure and solvent) for the generation of thioesters. These explorations
will inform our efforts to develop highly effective and robust organocatalytic
oxidation–reduction–condensation reactions that are
based on the benzoisothiazolone and related motifs.