ONE-POT SUFEX–HWE REACTION: A THREE-COMPONENT ENTRY TO ALKENYL SULFONAMIDES IN BATCH AND PARALLEL SYNTHESIS
- 1Enamine Ltd., Winston Churchill Street 78, Kyiv, Ukraine, 02094
- 2Taras Shevchenko National University of Kyiv, Volodymyrska Street 60, Kyїv, Ukraine, 01601
- 3Enamine Scientific Research Institute, Winston Churchill Street 67, Kyiv, Ukraine, 02094
Abstract
A robust one-pot sulfur(VI) fluoride exchange – Horner-Wadsworth-Emmons (SuFEx–HWE) reaction was developed as a direct three-component entry to α,β-unsaturated (alkenyl) sulfonamides, an electrophilic warhead class of growing importance in covalent drug discovery. The key reagent, diethyl [(fluorosulfonyl)methyl]phosphonate, was prepared in four steps and obtained on a 70 g scale in a single run. Control experiments established that the amine reacted first at the sulfonyl fluoride (SuFEx), and the resulting α-phosphonyl sulfonamide then underwent condensation with the aldehyde, so that a single operation at rt converted an aldehyde, an amine, and the phosphonate into the alkenyl sulfonamide with complete Eselectivity. Optimization identified DBU (3 equiv.) – LiCl (2 equiv.) in MeCN as the batch conditions (up to 94% yield), whereas iPr2NEt proved to be more general for the compound library synthesis. In a uniform 520reaction parallel set-up, the two protocols gave synthesis success rates of 52% and 65%, respectively. Aliphatic amines and (hetero)aromatic aldehydes were the most productive reaction partners. Heteroaromatic amines demonstrated poor performance that could be somewhat improved by changing the base. In the case of aliphatic aldehydes, the results were also modest, and they could not be altered by the base variation. A homologous reagent bearing an α-methyl group extended the method to trisubstituted alkenyl sulfonamides (88 library members, 79% success rate on the optimal substrate set), albeit with moderate E/Z selectivity.
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BibTeX
@misc{drozd2026onepot,
title = {{ONE-POT SUFEX–HWE REACTION: A THREE-COMPONENT ENTRY TO ALKENYL SULFONAMIDES IN BATCH AND PARALLEL SYNTHESIS}},
author = {Iryna P. Drozd and Maksym V. Kovalov and Vasyl Naumchyk and Illia O. Doroshenko and Bohdan V. Vashchenko and Dmytro S. Radchenko and Serhii Zhersh and Yulian M. Volovenko and Oleksandr O. Grygorenko},
howpublished = {ChemRxiv},
year = {2026},
month = sep,
doi = {10.26434/chemrxiv.15008621/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008621/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - ONE-POT SUFEX–HWE REACTION: A THREE-COMPONENT ENTRY TO ALKENYL SULFONAMIDES IN BATCH AND PARALLEL SYNTHESIS
AU - Iryna P. Drozd
AU - Maksym V. Kovalov
AU - Vasyl Naumchyk
AU - Illia O. Doroshenko
AU - Bohdan V. Vashchenko
AU - Dmytro S. Radchenko
AU - Serhii Zhersh
AU - Yulian M. Volovenko
AU - Oleksandr O. Grygorenko
PY - 2026
DA - 2026/09/10
PB - ChemRxiv
DO - 10.26434/chemrxiv.15008621/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008621/v1
AB - A robust one-pot sulfur(VI) fluoride exchange – Horner-Wadsworth-Emmons (SuFEx–HWE) reaction was developed as a direct three-component entry to α,β-unsaturated (alkenyl) sulfonamides, an electrophilic warhead class of growing importance in covalent drug discovery. The key reagent, diethyl [(fluorosulfonyl)methyl]phosphonate, was prepared in four steps and obtained on a 70 g scale in a single run. Control experiments established that the amine reacted first at the sulfonyl fluoride (SuFEx), and the resulting α-phosphonyl sulfonamide then underwent condensation with the aldehyde, so that a single operation at rt converted an aldehyde, an amine, and the phosphonate into the alkenyl sulfonamide with complete Eselectivity. Optimization identified DBU (3 equiv.) – LiCl (2 equiv.) in MeCN as the batch conditions (up to 94% yield), whereas iPr2NEt proved to be more general for the compound library synthesis. In a uniform 520reaction parallel set-up, the two protocols gave synthesis success rates of 52% and 65%, respectively. Aliphatic amines and (hetero)aromatic aldehydes were the most productive reaction partners. Heteroaromatic amines demonstrated poor performance that could be somewhat improved by changing the base. In the case of aliphatic aldehydes, the results were also modest, and they could not be altered by the base variation. A homologous reagent bearing an α-methyl group extended the method to trisubstituted alkenyl sulfonamides (88 library members, 79% success rate on the optimal substrate set), albeit with moderate E/Z selectivity.
ER -