C(sp3)-H sulfinylation of light hydrocarbons with sulfur dioxide via hydrogen atom transfer photocatalysis in flow

Abstract

Sulfur-containing scaffolds originating from small alkyl fragments play a crucial role in various pharmaceuticals, agrochemicals, and materials. Nonetheless, their synthesis using conventional methods presents significant challenges. In this study, we introduce a practical and efficient approach that harnesses hydrogen atom transfer photocatalysis to activate volatile alkanes, such as isobutane, butane, propane, ethane, and methane. Subsequently, these nucleophilic radicals react with SO₂ to yield the corresponding sulfinates. These sulfinates then serve as versatile building blocks for the synthesis of diverse sulfur-containing organic compounds, including sulfones, sulfonamides, and sulfonate esters. Our use of flow technology offers a robust, safe and scalable platform for effectively activating these challenging gaseous alkanes, facilitating their transformation into valuable sulfinates.

Fig. 1. C(sp³)–H sulfinylation of light alkanes as a strategy for the direct valorization of abundant gaseous feedstocks.

A Challenges of light alkane functionalization. B Industrial routes towards alkyl sulfinates in comparison with our approach C Examples of alkyl sulfonyl-containing drugs. BDE: bond dissociation energy, FG: functional group.

Fig. 2. Reaction scope for the photocatalytic sulfinylation of light alkanes with sulfur dioxide and trapping with electrophiles.

Photocatalytic reactions are performed in flow at 0.2 M concentration (SO₂, 0.6 mmol scale), with 5 equiv. of light alkane and 1 mol% of NaDT photocatalyst, under irradiation of UV-A light (365 nm, 144 W optical output power). Residence time of 1 h for isobutane, n-butane and propane, 2 h for ethane and methane. Pressure of 34 bar for isobutane, n-butane and propane, 52 bar for ethane and methane. The outflow is collected in a flask containing NaHCO₃ and alkyl bromide (0.2 mmol) and is stirred for 1 h at 60 °C. For reactions with methane, the photocatalytic step is performed at 4 mmol scale (SO₂), 6 mmol scale for entry 23 and 24. Diastereomeric ratio of the major isomer of compound 10 is 1:1. See Supplementary Information for further experimental details.

Fig. 3. Functionalization of ethyl sulfinic acid into diverse ethyl sulfonyl compounds.

See SI for further experimental details. TT = thianthrene.

Fig. 4. Telescoped reaction sequence in flow of the photocatalytic sulfinylation of propane with SO₂ and subsequent trapping with benzyl bromide.

See Supplementary Information for further experimental details.