Nickel‐Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO₂ Surrogate

Abstract

The development and mechanistic investigation of a nickel‐catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench‐free, inorganic sulfur salt (K2S2O5) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X‐ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2, likely released upon thermal decomposition of K2S2O5. Key to the success of the reaction is the role of K2S2O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 2─Development of a Scalable Nickel-Catalyzed Sulfonylation

“…In the search for a better understanding of the reaction, we turned our attention to the study of the catalytic cycle. Earlier work established the feasibility of SO 2 insertion as well as reduction by formate . Attempts to prepare the proposed active catalyst by reduction of NiCl 2 (dppe) with HCO 2 K revealed the production of a Ni(0)-bis-dppe complex 17 (Figure A).…”

“…Development continued from our initial discovery where we first observed methylsulfone formation with dppe and NiCl 2 in combination with K 2 S 2 O 5 and HCO 2 Na. We found both methyl iodide and dimethyl sulfate to be suitable methylating reagents but less desirable to use as part of commercial manufacturing due to toxicity.…”

“…Furthermore, we anticipated improved control of the hydro-dehalogenation pathway as the formate concentration could be maintained at a consistent minimum via a slow continuous charge. Earlier studies had shown that water was detrimental to the reaction; however, the high solubility of HCO 2 K in water (3.3 g/mL at 25 °C) would mitigate the impact.…”

“…To guide our continued optimization, we formulated and investigated a mechanistic proposal for the sulfonylation (Scheme ). The proposed catalytic cycle commences from the formation of an active Ni catalyst by reduction with HCO 2 K. Oxidative addition to aryl bromide 1 provides complex 9 (confirmed by single-crystal X-ray analysis).…”

“…With full control of the reaction established by means of the slow addition of a HCO 2 K/ethylene glycol solution, we proceeded to demonstrate the scalability of this process. Experiments established that SO 2 poisons the catalyst; thus, decreasing K 2 S 2 O 5 (1.5–1.2 equiv) enabled lower catalyst loading (10–5 mol %). Incorporation of the new conditions from 6 g to 3 kg scale batches delivered fantastic results (Table ).…”