Rapid and Chemodivergent Synthesis of N‑Heterocyclic Sulfones and Sulfides: Mechanistic and Computational Details of the Persulfate-Initiated Catalysis

N-Heterocyclic sulfones
and sulfides are key functional motifs
in medicinal and agricultural chemistry and important building blocks
in organic synthesis. Currently available methods produce N-heterocyclic
sulfones in low yields and under harsh conditions. Here, we describe
a rapid sulfone synthesis under ambient conditions that is initiated
by persulfate with water as a cosolvent. The reaction has a broad
scope and is readily expanded to the chemodivergent synthesis of symmetrical
N-heterocyclic sulfones and sulfides. The products can be isolated
by simple filtration. Our combined experimental and computational
study suggests that the remarkable persulfate-initiated acceleration
of the sulfone formation in the biphasic system that enables the otherwise
sluggish reaction under ambient conditions is due to the combination
of the previously unknown rapid acidification of the persulfate–sulfinate
system, the self-catalysis of the reaction of sulfinic acid with halo-N-heterocycles,
and the substantial acceleration of the reaction in the aqueous phase.

氮杂环砜（N-Heterocyclic sulfones）与氮杂环硫化物是医药与农业化学领域的核心功能基序，同时也是有机合成中的重要合成砌块。当前已有的合成方法在制备氮杂环砜时存在产率偏低、反应条件严苛的问题。本文报道了一种以过硫酸盐为引发剂、水作为助溶剂的室温环境下快速砜类合成策略。该反应底物适用范围广泛，可便捷拓展至对称型氮杂环砜与硫化物的化学发散合成。目标产物仅通过简单过滤即可分离得到。我们结合实验与计算研究表明，在双相体系中，过硫酸盐引发的砜生成反应速率得到显著提升，使得原本在环境条件下难以进行的反应得以顺利进行，这一现象源于三方面的协同作用：此前未被报道的过硫酸盐-亚磺酸盐体系快速酸化、亚磺酸与卤代氮杂环反应的自催化效应，以及水相对反应的显著加速作用。