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, stenchfree, inorganic sulfur salt (K 2 S 2 O 5 ) as a uniquely effective SO 2 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 SO 2 insertion occurs via dissolved SO 2 , likely released upon thermal decomposition of K 2 S 2 O 5 . Key to the success of the reaction is the role of K 2 S 2 O 5 as a reservoir of SO 2 that is slowly released, thus preventing catalyst poisoning.

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy

“…With these intentions in mind, we successfully developed a one-pot catalytic synthesis of arylmethylsulfones using inexpensive NiCl 2 -dppe as a catalyst in the presence of K 2 S 2 O 5 and trimethyl phosphate (TMP) as a nontoxic methylating agent. 17,18 This new procedure allowed for the robust synthesis of arylsulfone 16 in good yield, most importantly avoiding the use of Pd or stoichiometric Cu and expensive SO 2 sources.…”

Copper‐Enabled Photo‐Sulfonylation of Aryl Halides Using Alkylsulfinates

“…We chose bromo‐fluoroindanone 1 a as a model substrate and sodium methanesulfinate ( 2 ) for developing our new photosulfonylation (Table 1) as this could map onto a potential synthetic intermediate to belzutifan (MK‐6482, Figure 1). [1c,d,h] Photoirradiation (365 nm) of mixtures of 1 a and 2 in DMSO provided product 3 a in only 11% yield, along with hydrodehalogenation [23] product 4 a as the major product (entry 1). We emphasize that attempts at applying literature conditions (NaSO 2 Me and Cs 2 CO 3 in DMSO with 365 nm irradiation) from reference 13 to compound 1 a (a substrate not in the original publication) provided very low yields (<10%) of the desired product 3 a , highlighting the synthetic challenge.…”

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

“…■ RESULTS AND DISCUSSION Initial Optimization. Development continued from our initial discovery 11 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.…”

“…Mechanistic Hypothesis. To guide our continued optimization, we formulated and investigated 11 a mechanistic proposal for the sulfonylation (Scheme 3). 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 Xray analysis).…”