A new route to chiral sulfur compounds from sulfonylhydrazones
image: This schematic illustrates a chiral Rh(II)-catalyzed sulfonyl-retentive difunctionalization of sulfonylhydrazones, enabling the efficient construction of chiral sulfur-containing molecules through regio-, stereochemical-, and enantioselective C–N/C–S bond formation. The proposed mechanism highlights carbene-type Rh intermediates and intramolecular sulfur transfer processes leading to highly enantioenriched products. Key features of the transformation include:
view more
Credit: © Xihe Bi*, Genping Huang*, Xingwei Li*, et al. 2025.
In a significant advance in asymmetric sulfur chemistry, Xingwei Li, Genping Huang, Xihe Bi and co-workers report a highly enantioselective aza-Mislow-Evans rearrangement enabled by a chiral dirhodium-catalyzed cascade reaction between sulfenamides and alkynyl N-sulfonylhydrazones. Published in Chiral Chemistry, this work introduces an atom-economical strategy that merges carbene chemistry with sulfur migration to access enantioenriched allylic sulfenamides with excellent chemo-, E/Z-, and enantioselectivity.
Although the classical Mislow-Evans rearrangement of allylic sulfoxides has long served as a powerful stereoselective transformation, its nitrogen analogue has remained underdeveloped because of the difficulty in preparing enantioenriched allylic sulfilimines. To address this challenge, the authors employed readily available alkynyl triftosylhydrazones as in situ carbene precursors. Under the catalysis of the chiral dirhodium complex Rh2(R-p-CF3TPCP)₄, the reaction proceeds through highly chemoselective S-allenylation of sulfenamides, followed by hydrosulfonylation and a stereospecific aza-Mislow-Evans rearrangement. Notably, the sulfonyl group from the hydrazone precursor is retained and reincorporated into the product rather than discarded as waste, significantly improving atom economy.
The transformation operates under exceptionally mild conditions (0°C, 15 min) and accommodates a broad range of alkynyl hydrazones and sulfenamides. More than 50 examples were obtained in yields up to 89% and with enantioselectivities reaching 95% ee. The reaction tolerates aryl, heteroaryl, alkenyl, and cycloalkyl substituents and consistently furnishes chiral allylic sulfenamides with high stereocontrol.
The synthetic utility of the method was demonstrated through gram-scale synthesis and diverse downstream derivatizations. The products were readily converted into sulfinamides, sulfonamides, oxazolines, allylic amides, and enantioenriched carboxylic acids without erosion of stereochemical purity.
Mechanistic experiments, including crossover studies and isotopic labeling, together with DFT calculations, support a stepwise pathway involving Rh-carbene formation, sulfur ylide generation, protonation to a Rh-allene intermediate, hydrosulfonylation, and a final [2,3]-sigmatropic rearrangement. Protonation of an enolate intermediate was identified as the enantioselectivity-determining step. This work provides an efficient and sustainable route to valuable chiral allylic sulfenamides and expands the synthetic potential of sulfonylhydrazone-derived alkynyl carbenes.