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. 2023 Feb 13;62(8):e202216296.
doi: 10.1002/anie.202216296. Epub 2023 Jan 13.

Transition-Metal-Free Difunctionalization of Sulfur Nucleophiles

Shobhan Mondal  1 , Ester Maria Di Tommaso  1 , Berit Olofsson  1
Affiliations

Transition-Metal-Free Difunctionalization of Sulfur Nucleophiles

Shobhan Mondal et al. Angew Chem Int Ed Engl. .

Abstract

Efficient protocols for accessing iodo-substituted diaryl and aryl(vinyl) sulfides have been developed using iodonium salts as reactive electrophilic arylation and vinylation reagents. The reactions take place under transition-metal-free conditions, employing odorless and convenient sulfur reagents. A wide variety of functional groups are tolerated in the S-diarylation, enabling the regioselective late-stage application of several heterocycles and drug molecules under mild reaction conditions. A novel S-difunctionalization pathway was discovered using vinyliodonium salts, which proceeds under additive-free reaction conditions and grants excellent stereoselectivity in the synthesis of aryl(vinyl) sulfides. A one-pot strategy combining transition-metal-free diarylation and subsequent reduction provided facile access to electron-rich thioanilines and a direct synthesis of a potential drug candidate derivative. The retained iodo group allows a wide array of further synthetic transformations. Mechanistic insights were elucidated by isolating the key intermediate, and the relevant energy profile was substantiated by DFT calculations.

Keywords: Aromatic Substitution; Difunctionalization; Hypervalent Compounds; Iodonium Salts; Sulfides.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Scheme 1
Scheme 1
Difunctionalization of sulfur nucleophiles.
Scheme 2
Scheme 2
Diarylation scope. [a] Reaction conditions: 1 (0.2 mmol), 2 d (0.28 mmol), DMF (0.2 M) under argon atmosphere for 18 h in the absence of light, isolated yields are reported. [b] BF4 salt was used. [c] OTs salt was used. [d] Reaction performed at rt for 12 h and 60 °C for 6 h.
Scheme 3
Scheme 3
Scope of aryl(vinyl) sulfides 7. [a] Reaction conditions: 6 (0.20 mmol), 2 c (0.40 mmol), DMF (0.2 M) under argon atmosphere for 18 h, isolated yields are reported. [b] OTs salt was used. [c] The diastereoselectivity was >20 : 1 in crude 1H NMR.
Scheme 4
Scheme 4
Mechanistic studies. Reaction conditions i) DMF, 40 °C, 12 h, ii) MeI, DMF, rt, 2 h. NMR yields are reported using TMB as internal standard.
Figure 1
Figure 1
Calculated free energy profile for diarylation of sulfur nucleophiles. [M06‐2X(SMD)/def2‐TZVP//M06‐2X(SMD)/def2‐SVP level in implicit DMF solvent].
Scheme 5
Scheme 5
Post synthetic applications of sulfide 3 a. Reaction conditions: i) B2(OH)4, 2,2′‐bipyridine, DMF, 40 °C, 4 h or Fe, NH4Cl, MeOH/THF/H2O, 70 °C, 5 h; ii) mCPBA, acetone, 16 h, 40 °C.; iii) phthalic anhydride, urea‐H2O2, EtOAc, 16 h, rt iv) PhCCH, PdCl2(PPh3)2, CuI, Et3N, 14 h, rt; iv) PhB(OH)2, Pd(PPh3)4, K2CO3, DMF, 15 h, 100 °C.
Scheme 6
Scheme 6
One pot synthesis of amino sulfides.
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