Zinc Promoted Cross-Electrophile Sulfonylation to Access Alkyl-Alkyl Sulfones

Abstract

The transition metal-catalyzed multi-component cross-electrophile sulfonylation, which incorporates SO₂ as a linker within organic frameworks, has proven to be a powerful, efficient, and cost-effective means of synthesizing challenging alkyl-alkyl sulfones. Transition metal catalysts play a crucial role in this method by transferring electrons from reductants to electrophilic organohalides, thereby causing undesirable side reactions such as homocoupling, protodehalogenation, β-hydride elimination, etc. It is worth noting that tertiary alkyl halides have rarely been demonstrated to be compatible with current methods owing to various undesired side reactions. In this work, a zinc-promoted cross-electrophile sulfonylation is developed through a radical-polar crossover pathway. This approach enables the synthesis of various alkyl-alkyl sulfones, including 1°-1°, 2°-1°, 3°-1°, 2°-2°, and 3°-2° types, from inexpensive and readily available alkyl halides. Various functional groups are well tolerated in the work, resulting in yields of up to 93%. Additionally, this protocol has been successfully applied to intramolecular sulfonylation and homo-sulfonylation reactions. The insights gained from this work shall be useful for the further development of cross-electrophile sulfonylation to access alkyl-alkyl sulfones.

Keywords: alkyl–alkyl sulfone; catalyst‐free; cross‐electrophile coupling; organic halides; sulfonylation.

Figure 1

a) Important 1°/2°/3° alkyl–alkyl sulfones. b) Three‐component cross‐electrophile sulfonylation. c) Our design. d) Our reaction.

Scheme 1

Catalyst‐free cross‐electrophile sulfonylation of 1 and 2. The reaction conditions were 1 (0.4 mmol), Zn powder (2 equiv.), K₂S₂O₅ (2 equiv.), NaH₂PO₄ (50 mol%), DMSO (1.5 mL), 75 °C, 2 h, then add 2 (0.2 mmol), DMSO (0.5 mL), 75 °C, 22 h (General Procedure A). Isolated yields. ^a Variation: 1 (4 equiv.), Zn powder (4 equiv.), K₂S₂O₅ (4 equiv.), 48 h. ^b Variation: Add NaI (50 mol%), DMSO 4 mL, 48 h. ^c Variation: 1 (2 equiv.), Zn powder (2 equiv.), K₂S₂O₅ (2 equiv.), NaH₂PO₄ (50 mol%), DMSO (7.5 mL), 75 °C, 6 h, then add 2 (10 mmol), DMSO (2.5 mL), 75 °C, 48 h.

Scheme 2

Catalyst‐free cross‐electrophile sulfonylation of 1a and 2. The reaction conditions were 1a (0.2 mmol), 2 (2 equiv.), Zn powder (5 equiv.), K₂S₂O₅ (3 equiv.), NaH₂PO₄ (1.5 equiv.), DMSO (2 mL), 75 °C, 24 h (General Procedure B). Isolated yields. ^a Using General Procedure A.

Scheme 3

Catalyst‐free homo‐electrophile sulfonylation. The reaction conditions were 2 (0.4 mmol), Zn powder (1 equiv.), K₂S₂O₅ (1.5 equiv.), NaH₂PO₄ (75 mol%), NaI (25 mol%), DMSO (2 mL), 75 °C, 24 h (General Procedure C). Isolated yields.

Figure 2

Control experiments.

Figure 3

Free energy profiles of catalyst‐free cross‐electrophile sulfonylation process. Calculations were performed using Gaussian 16 at the M06‐L/6‐311 + G(d,p)‐SDD/SMD(DMSO)//B3LYP‐D3(BJ)/6‐31G(d)‐LANL2DZ level of theory. The bond lengths are shown in angstroms (Å). The Zn(II)I₂ used in DFT calculations is Zn(II)I₂‐complex.

Figure 4

Proposed mechanism.