Redox-Neutral α-Sulfenylation of Secondary Amines: Ring-Fused N,S-Acetals

Abstract

Secondary amines react with thiosalicylaldehydes in the presence of catalytic amounts of acetic acid to generate ring-fused N,S-acetals in redox-neutral fashion. A broad range of amines undergo α-sulfenylation, including challenging substrates such morpholine, thiomorpholine, and piperazines. Computational studies employing density functional theory indicate that acetic acid reduces the energy barriers of two separate steps, both of which involve proton transfer.

Stronger Brønsted Acids: Recent Progress

“…150 Das and Seidel reported C−P bond formation at the α position of nitrogen by a three-component reaction of pyrrolidine, aldehyde, and diphenylphosphine oxide 137 in the presence of 20 mol % benzoic acid (Scheme 50). 151 This redox-neutral reaction affords an efficient route to α-amino phosphine oxides 138, which are not readily available by the classic Kabachnik− Fields reactions.…”

Sulfenylation of C–H Bonds for C–S Bond Formation under Metal‐Free Conditions

“…Seidel and co‐workers found that sulfenylation of secondary amines with thiosalicylaldehydes in the presence of catalytic amounts of acetic acid was possible. Various ring‐fused N,S‐acetals, found as key functional groups in pharmacologically active compounds, were obtained by this method . Computational studies employing density functional theory demonstrate that acetic acid could reduce the energy barriers of two separate steps (Scheme ).…”

Classical-Reaction-Driven Stereo- and Regioselective C(sp3)-H Functionalization of Aliphatic Amines

“…[39] This strategy was extended by the same group for the a-CAH sulfenylation of aliphatic amines. [40] Qu et al developed similar redox-neutral CAH oxygenation of pyrrolidine using 3,5-di-tert-butyl-o-benzoquinone. [41] During the optimization of the direct CAH oxygenation reaction, we observed that N-benzylated pyrrolidine 68 was formed in addition to the desired oxazine.…”