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. 2022 Oct 24;61(43):e202210525.
doi: 10.1002/anie.202210525. Epub 2022 Sep 9.

Decarboxylative Sulfinylation Enables a Direct, Metal-Free Access to Sulfoxides from Carboxylic Acids

Viet D Nguyen  1 , Graham C Haug  1 , Samuel G Greco  1 , Ramon Trevino  1 , Guna B Karki  1 , Hadi D Arman  1 , Oleg V Larionov  1
Affiliations

Decarboxylative Sulfinylation Enables a Direct, Metal-Free Access to Sulfoxides from Carboxylic Acids

Viet D Nguyen et al. Angew Chem Int Ed Engl. .

Abstract

The intermediate oxidation state of sulfoxides is central to the plethora of their applications in chemistry and medicine, yet it presents challenges for an efficient synthetic access, limiting the structural diversity of currently available sulfoxides. Here, we report a data-guided development of direct decarboxylative sulfinylation that enables the previously inaccessible functional group interconversion of carboxylic acids to sulfoxides in a reaction with sulfinates. Given the broad availability of carboxylic acids and the growing synthetic potential of sulfinates, the direct decarboxylative sulfinylation is poised to improve the structural diversity of synthetically accessible sulfoxides. The reaction is facilitated by a kinetically favored sulfoxide formation from the intermediate sulfinyl sulfones, despite the strong thermodynamic preference for the sulfone formation, unveiling the previously unknown and chemoselective radicalophilic sulfinyl sulfone reactivity.

Keywords: Carboxylic Acids; Radical Reactions; Sulfinates; Sulfoxides; Visible Light.

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Figures

Figure 1.
Figure 1.
A. Applications of sulfoxides. B. Synthetic approaches to sulfoxides. C. Decarboxylative sulfinylation and the radicalophilc reactivity of sulfinyl sulfones.
Figure 2.
Figure 2.
Comparison of the chemical space of the currently available sulfoxides (blue) and the sulfoxides that may become accessible by the direct decarboxylative sulfinylation from known carboxylic acids and sulfinates (red/orange). A. The Cm/Fsp3/MW plot with the darker color representing higher population density (PDF). B. The population density plot for the known sulfoxides. C. The population density plot for the decarboxylative sulfinylation-accessible sulfoxides. D. Geometric diversity population analysis for the currently available and decarboxylative sulfinylation-accessible sulfoxides.
Figure 3.
Figure 3.
Direct decarboxylative sulfinylation. Reaction conditions: carboxylic acid 1 (0.3 mmol), sulfinate 2 (0.6 mmol), A1 (10 mol%), PBC (0.36 mmol), CH2Cl2 (3.3 mL), LED (400 nm), 12 h. Yields were determined by 1H NMR with 1,4-dimethoxybenzene as an internal standard.
Figure 4.
Figure 4.
Kinetic and computational studies of the sulfinyl sulfone role in decarboxylative sulfinylation and the sulfoxide/sulfone chemoselectivity.
Figure 5.
Figure 5.
The catalytic system for the direct decarboxylative sulfinylation.
Scheme 1.
Scheme 1.
Scope of carboxylic acids in the direct decarboxylative sulfinylation. Reaction conditions: see Figure 3, isolated yields.
Scheme 2.
Scheme 2.
Scope of sulfinates in the direct decarboxylative sulfinylation. Reaction conditions: see Figure 3, isolated yields.
Scheme 3.
Scheme 3.
Functionalization of natural products and drugs by the direct decarboxylative sulfinylation. Reaction conditions: see Figure 3, isolated yields. a 1 : 1 dr. b 4.4 : 1.8 : 1 dr. c Single diastereomer.
Scheme 4.
Scheme 4.
Conjunctive cross-decarboxylative sulfinylation. DABCO = 1,4-diaza-bicyclo[2.2.2]octane.
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