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.


Introduction
The chemical structure of sulfone, which has a profound impact on the stability, lipid solubility, and metabolism of molecules, serves as the foundation for numerous naturally occurring biologically active molecules and modern pharmaceutical compounds. [1]1°/2°/3°alkyl-alkyl sulfones are an important class of sulfones that occupy a pivotal position in pharmaceuticals because of their significant influence on the balance between lipid and water solubility. [2]Figure 1a depicts a selection of well-known drugs or pharmacological inhibitors that possess an alkyl-alkyl sulfone structure, including Tinidazole [3] (with 1°-1°sulfone), chlomezanone [4] (with intramolecular 2°-1°s ulfone), Remikiren [5] (with 3°-1°sulfone).Over this reason, organic chemists have dedicated considerable efforts over the past decades to developing highly selective, costeffective, and efficient synthetic methods for alkyl-alkyl sulfones. [6]Traditionally, sulfones are prepared from oxidizing corresponding thioethers and sulfoxides with strong oxidants, resulting in low functional-group compatibility. [7]Alternatively, strategies for sulfone construction from sulfonic, sulfinic, or their derivatives are hampered by the need for complex and multi-step substrate pre-synthesis. [8]An intensive effort has been made to identify mild and green alternatives for sulfone synthesis that begin with readily available substrate feedstocks.
In recent decades, transition metal-catalyzed crosselectrophile coupling (XEC) reactions have emerged as a reliable alternative to traditional cross-coupling methods for the construction of C─C or C─X bonds. [9]This approach involves the coupling of two electrophilic organohalides, facilitated by external reductants, thus circumventing the limitations associated with the use of preformed carbon nucleophiles. [10]Consequently, transition metal-catalyzed multi-component cross-electrophile sulfonylation, which incorporates sulfur dioxide as a linker into organic frameworks, has garnered significant interest among researchers due to its atom, step, and oxidation economy (Figure 1b). [11]Despite the progress in synthesizing alkyl-alkyl sulfones using this protocol, the reliance on a transition metal catalyst poses inherent limitations.Homocoupling remains a major competing pathway, even in the presence of a large excess of the coupling partner, which has been attributed to the similar reactivity of the catalyst toward different types of alkyl halides.Furthermore, tertiary alkyl halides have rarely been demonstrated to be compatible with current methods due to various undesired side reactions, such as protodehalogenation and elimination.To address these limitations, we hypothesized that a zinc-promoted radical-polar crossover pathway could significantly contribute to the synthesis of 1°/2°/3°alkyl-alkyl sulfones (Figure 1c). [12]This protocol involves selective singleelectron-reduction of a more substituted and reactive alkyl halide A (alkyl-I, alkyl-Br or activated alkyl-Cl), generating an alkyl radical C. Subsequently, the alkyl radical C attacks a SO 2 surrogate, leading to the formation of a sulfonyl radical D. Due to the slightly higher electronegativity of sulfur atoms The optimized reaction conditions were 1a (0.2 mmol), 2a (2 equiv.),Zn powder (5 equiv.),K 2 S 2 O 5 (3 equiv.),NaH 2 PO 4 (1.5 equiv.), and DMSO 2 mL, at 75 °C and under a nitrogen atmosphere, 24 h; b) Yields determined by GC using naphthalene as an internal standard; c) Isolated yield.
compared to carbon atoms, [13] sulfonyl radicals were apt to be reduced to sulfonyl anion E. This anion then undergoes chemoselective nucleophilic substitution on a less hindered and inert alkyl halide B (Alkyl-Cl), ultimately yielding the desired product.Herein, we have developed a catalyst-free, selective cross-electrophile sulfonylation protocol for the synthesis of alkyl-alkyl sulfones from cheap and readily available primary, secondary, and tertiary alkyl halides (Figure 1d).This method offers a straightforward and efficient approach to constructing a diverse range of sulfone-containing compounds.
ically active molecules like 4y, 4z and 4aa produced the desired products in 66%, 53% and 58% yields, respectively.The unactivated secondary chloride compounds are incompatible with this reaction system due to their low reactivity and significant steric hindrance.
By using only one alkyl halide as a coupling partner, the above method can be adapted for the synthesis of symmetric dialkyl sulfones (Scheme 3), which are less accessible using previously reported methods.Both alkyl chlorides and benzyl chlorides could be used (5a -5i).Various functional groups such as ether (5b), fluoro (5d and 5e), chloro (5f), trifluoromethyl (5g), ester (5h), and tert-butyl (5i) were well tolerated.

Mechanistic Investigation
To get a better understanding about the mechanism of this multicomponent reductive cross-coupling reaction, several control experiments were carried out (Figure 2).When 2,2,6,6tetramethylpiperidine-1-oxyl (TEMPO) or 2,6-di-tert-butyl-4methylphenol (BHT) were added to the system, no desired sulfone product was detected (Figure 2; Equations S1 and S2, Supporting Information).Moreover, the sulfonyl radical and cyclohexyl radical was trapped by the addition of the radical trapping reagent 1,1-diphenylethylene to the reaction (Figure 2; Equation S3, Supporting Information).All these experiments indicates that cyclohexyl radical and sulfonyl radical might be involved in this mechanism.Subsequently, a radical clock experiment involving (chloromethyl)cyclopropane was conducted under the standard conditions (Figure 2; Equation S4, Supporting Information).Cyclopropane-opened product 6 was generated in 63% isolated yield, indicating that an alkyl radical intermediate might be generated from the alkyl iodide.No target product was detected with organic zinc reagent instead of alkyl iodine as the reactant (Figure 2; Equation S5, Supporting Information), excluding the intermediacy of organozinc reagents.In our standard reaction conditions, cyclohexyl sulfonate (7) can be isolated after the reaction with only 1a as the reactant (Figure 2; Equation S6, Supporting Information).When we employed cyclohexyl sulfonate (7) and 2a as the reactants in DMSO at 75 °C for 24 h, the corresponding sulfone product was obtained in 76% yield, showing that alkyl sulfonate might be the key intermediate (Figure 2; Equation S7, Supporting Information).
To gain a deeper understanding of the reaction mechanism, density functional theory (DFT) calculations were employed to the catalyst-free cross-electrophile sulfonylation.As shown in  Based on our previous work [12c] and the results described above, a plausible mechanism is proposed as shown in Figure 4. Initially, the steric hindered but active alkyl halide is reduced by Zn to generate alkyl radical I. Subsequently, the reaction of the alkyl radical with SO 2 , derived from metabisulfite with the help of NaH 2 PO 4 , yields the sulfonyl radical II, which is then reduced by Zn to produce the sulfonyl anion III.A subsequent bi-molecular substitution between less steric hindered alkyl chloride and sulfonyl anion gives the desired sulfone product.

Conclusion
In conclusion, we have developed a zinc-promoted crosselectrophile sulfonylation utilizing readily available alkyl halides and K 2 S 2 O 5 as reactants.1°−1°, 2°−1°, 3°−1°, 2°−2°, 3°−2°a lkyl-alkyl sulfones could be synthesized through this protocol.Additionally, this protocol has been applied to intramolecular sulfonylation and homo-sulfonylation reactions.High chemoselectivity can be achieved through regulating the steric hindrance and electron transfer between zinc and alkyl halide.A range of functional groups are well-tolerated in our system, enabling the synthesis of sulfones with up to 93% yields.Mechanistic investigation indicates that the electron transfer between alkyl halides and zinc generates an alkyl radical, followed by SO 2 insertion to form the sulfonyl radical.This method would significantly contribute to the development of easy and cost-effective synthetic approaches for sulfones, which are prevalent intermediates and bioactive compounds.

Experimental Section
General Procedure A for Cross-Electrophile Sulfonylation: An oven-dried 50 mL Schlenk tube equipped with a Teflon-coated magnetic stir bar was sequentially charged with Zn powder (0.4 mmol, 2 equiv.),K 2 S 2 O 5 (0.4 mmol, 2 equiv.),NaH 2 PO 4 (0.1 mmol, 50 mol%) in the glovebox.Then 1.5 mL DMSO, alkyl halides 1 (0.4 mmol, 2 equiv.)were added into the tube in turn.All these procedures were conducted in the glovebox.The vial was sealed with a rubber stopper and removed from the glove box.Then the vial was placed on the heating-base and reacted at 75 °C for 2 h.After which time the alkyl chloride 2 (0.2 mmol) was dissolved into 0.5 mL of DMSO and added to the Schlenk tube with a needle.Then the vial was placed on the heating-base and reacted at 75 °C for 22 h.After which time the vial was removed from the heating source, and the product was extracted from the crude reaction mixture with ethyl acetate (3 × 10 mL).The organic layers were combined and washed with brine (30 mL).Dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.The crude product residue was purified by preparative TLC using a solvent mixture (EtOAc, petroleum ether) as an eluent to afford the purified product.

Figure 3 ,
Figure 3, iodocyclohexane 1a was chosen as the starting point of the cycle, which was reduced by Zn to generate cyclohexyl radical 8 (see the Supporting Information for further details).This process is exergonic, with an energy release of 14.1 kcal mol −1 .The subsequent radical addition of 8 to sulfur dioxide gives cyclohexylsulfonyl radical intermediate 10 via transition state 9-ts, which is endergonic by 5.7 kcal mol −1 .The energy barrier for this step is only 1.4 kcal mol −1 , indicating that radical addition step can easily occur.Following this, 2 nd reduction of intermediate 10 by zinc irreversible generates bis(cyclohexylsulfonyl)zinc(II) intermediate 11, which releases 23.4 kcal mol −1 of energy.

Table 1 .
Summary of the effects of reaction parameters and conditions on the reaction efficiency.

Table 1 ,
entry 5).When replacing K 2 S 2 O 5 with Na 2 S 2 O 5 or Na 2 S 2 O 4 , yields were 88% and 36%, respectively (Table1, entries 6 and 7).The use of DMA instead of DMSO as a solvent led to 24% yield (Table1, entry 8).Other solvents like toluene, cyclohexane, and CH 2 Cl 2 were tested, and only a trace amount of product was found (Table1, entry 9 and SI).Lowering or increasing the reaction temperature reduced the yields slightly (Table1, entries 10 and 11).No desired product was observed at room temperature (Table1, entry 12).