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. 2014 Jul 3;16(13):3556-9.
doi: 10.1021/ol501509b. Epub 2014 Jun 13.

Redox-neutral α-sulfenylation of secondary amines: ring-fused N,S-acetals

Claire L Jarvis  1 , Matthew T Richers, Martin Breugst, K N Houk, Daniel Seidel
Affiliations

Redox-neutral α-sulfenylation of secondary amines: ring-fused N,S-acetals

Claire L Jarvis et al. Org Lett. .

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.

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Figures

Figure 1
Figure 1
Examples of bioactive N,S-acetals.
Scheme 1
Scheme 1. Selected Approaches to N,S-Acetals
Scheme 2
Scheme 2. Substrate Scope for the α-Sulfenylation
Reactions were performed on a 1 mmol scale. With 3 equiv of amine.
Scheme 3
Scheme 3. Regioselectivity of the α-Sulfenylation
Reactions were performed on a 1 mmol scale.
Figure 2
Figure 2
Free energy profile [in kcal·mol–1, M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM] for uncatalyzed transformations of 6-O (black) and 6-S (red) and THIQ in toluene.
Figure 3
Figure 3
Calculated transition-state structures [M06-2X-D3/def2-TZVPP/IEFPCM//TPSS-D2/6-31+G(d,p)/IEFPCM], relative free energies (in kcal·mol–1), and selected bond lengths (in Å) for the uncatalyzed and acetic-acid-catalyzed transformation of 6-S and THIQ.
See this image and copyright information in PMC

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