Electrochemical S-vinylation of sulfinamides with β-bromostyrenes

Abstract

We present an electrochemical method for sulfoximine synthesis via radical cross-coupling of sulfonimidoyl and styryl radicals, generated from sulfinamides and bromostyrenes. This approach enables the efficient synthesis of vinyl sulfoximines, including bioactive-tethered derivatives, in moderate to good yields.

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Sulfoximine-containing molecules have gained significant attention in medicinal chemistry due to their unique structural features, including a stereogenic center at the sulfur atom and a small, hydrophilic core.¹ These compounds exhibit diverse biological properties; for example as a proline-rich tyrosine kinase inhibitor (A),² cyclin-dependent kinases (CDK) inhibitors (B),³ or CYP24 hydroxylase inhibitor (C).⁴ Beyond their pharmaceutical applications, sulfoximines have also been employed as pesticides in crop protection.⁵ Given their widespread importance in drug discovery and agrochemicals, the development of efficient and sustainable synthetic methodologies to access sulfoximines remains a crucial research goal. Several strategies have been explored for sulfoximine synthesis. One of the most common approaches involves the amination of sulfoxides using aminating reagents.^6–9 However, such approach is often limited by the need for stoichiometric oxidants and low substrate tolerance, restricting its broader applicability.⁷ More recently, radical methodologies have emerged as promising alternatives for sulfoximine synthesis.^10–13 Bolm¹¹ and Gau¹² reported methods using sulfonimidoyl radicals, generated from sulfonimidoyl chloride or fluoride.

Electrochemical synthesis—the use of electric current to mediate redox transformations in organic synthesis—has witnessed a renaissance in recent years and is developing as an inherently green and sustainable method to access radical intermediates under precise reaction conditions.^13,14 In this context, Ling and co-workers developed an electrochemical approach that generates sulfonimidoyl radicals in situ via paired electrolysis, enabling vinyl sulfoximine synthesis.¹⁵ Against the background of recent developments in sulfoximine synthesis and our interest in this research area,¹⁶ we herein present a modified electrochemical approach that circumvents the need for DBU and triethylamine salts. Our protocol employs carbonate salts as the sole additive, enabling the efficient synthesis of vinyl sulfoximines under ambient conditions (Scheme 1).

Scheme 1 Biologically relevance sulfoximines bearing molecules and strategies for the generation of sulfonimidoyl radicals.

Initially, we investigated the reaction of sulfinamide 1a with β-bromostyrene (2a) under electrochemical conditions, using a graphite electrode and K₂CO₃ as the base. To our delight, the desired product 3a was formed in 41% yield (Table 1, entry 1). With this positive result we then proceeded to screen other solvents, yet both THF or methanol gave inferior results. On increasing the ratio of water, a sharp decrease in the yield of 3a was observed (Table 1, entry 4). We next went for evaluation of organic and inorganic bases; using pyridine and KOH as base the product 3a was formed only in traces while Na₂CO₃ or K₃PO₄ gave 3a in 39% and 33%, respectively (Table 1, entries 5–8). When the reaction was performed in presence of electrolytes in acetonitrile, the product 3a was not detected (Table 1, entry 9); similarly, a significant decrease in the yield of 3a was observed under aerobic conditions (Table 1, entry 10). Changing the cathode to Ni plate resulted in a significant increase in the yield of the desired product 3a, which could be isolated in 77% yield (Table 1, entry 11). The reaction failed to deliver the product in absence of electric current indicating the necessity of electricity. Further, on increasing or decreasing the reaction current does not provide a better than at 3 mA (Table 1, entry 12).

Table 1 Optimization of reaction conditions^a

Entry	Variation from condition	Yield [%] of 3a
a Reaction conditions: 1a (0.1 mmol), 2a (3.0 equiv.) and K2CO3 in MeCN : H2O (10 : 1, 2.0 mL) under argon. ^1H NMR yields were calculated using mesitylene as internal standard. b Isolated yield. c Nickel as cathode.
1	None	41
2	THF : H2O	39
3	MeOH : H2O	Traces
4	MeCN : H2O (1 : 5)	13
5	Pyridine instead of K2CO3	Traces
6	KOH instead of K2CO3	Traces
7	Na2CO3 instead of K2CO3	39
8	K3PO4 instead of K2CO3	33
9	TBAI, TBClO4, TBABF4 in MeCN	—
10	Under air	14
11	Ni as cathode	84 (77)^b
12	No current	NR
13^c	At 5 mA/1 mA current	75/63

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We first investigated the substrate scope (Scheme 2) by varying the sulfinamide (1). Both pivolyl and benzoyl protecting groups were well tolerated in this transformation; however, the benzoyl-protected sulfinamide yielded product 3c in only 22%, whereas the Boc- and pivolyl-protected variants afforded products 3a and 3b in significantly higher yields of 77% and 67%, respectively.

Scheme 2 Substrates scope; 1 (0.2 mmol), 2 (3.0 equiv.) and K₂CO₃ (4.0 equiv.) in MeCN : H₂O (10 : 1, 2.0 mL) were electrolyzed at 3 mA CCE using GF (anode) and Ni (cathode) under argon. FE = faradaic efficiency.

Next, we explored the effect of the aryl ring substitutions on the sulfinamide. A wide range of substituents, including electron-donating, electron-withdrawing groups, and halogens, were well-tolerated. Phenylsulfinamide yielded product 3d in 70%. Halogenated sulfinamides produced 3e and 3f gave slightly lower yields, whereas the methoxy-substituted sulfinamide gave product 3g in 56%. Notably, mono-CF₃-substituted arylsulfinamide provided product 3h in only 22% yield, while 3,5-CF₃ and CN-substituted sulfinamides failed to generate the corresponding sulfoximines (see ESI†). The presence of two CF₃ groups (see, ESI†) at the meta positions of the sulfinamide failed to provide the desired product, possibly due to their strong electron-withdrawing nature. Similarly, substitutions at the ortho position e.g. Cl or Me, (see ESI†) did not yield the corresponding sulfoximines, which may be attributed to steric hindrance. The thiophene-derived sulfinamide afforded product 3i in a good yield of 75%, whereas the naphthalene analogue provided 3j in 43%. We then assessed the influence of the substituents on the aryl ring of bromo styrene 2. The reaction tolerated diverse substitution patterns, including electron-donating, electron-withdrawing groups, and halogens, affording the respective products in moderate to good yields. Electron-donating groups positively influenced the yields (3k, 3l), while halogenated substrates led to moderate yields (3m, 46%; 3n, 55%). Strongly electron-withdrawing substituents such as CN and CO₂Me gave 3o and 3p in lower yields (30% and 32%, respectively), whereas CF₃-substituted styrene gave 3q in an excellent 73% yield. meta- and ortho-substituted bromostyrenes reacted efficiently, delivering products 3r (50%) and 3s (56%). The tri-methoxy-substituted bromostyrene provided 3t in 75% yield. Additionally, heterocyclic bromostyrenes were well tolerated; pyridine- and furan-containing derivatives gave products 3w and 3v in lower yields, while the thiophene analogue afforded 3u in 73%. Finally, bioactive tethered bromostyrene derivatives were also compatible, yielding products 3x–3z in moderate yields. The observed faradaic efficiencies (6.9–30.9%) are relatively low, which may be due to competitive hydrogen evolution resulting from water present in the reaction medium.

To demonstrate the applicability of the developed electrochemical protocol, a scale up reaction at 2 mmol scale were performed under the standard reaction condition to provide the desired product in 72% yield (Scheme 3A). Additionally, Michael addition reaction of 3a with thiol and pyrrolidine have been performed and the products 4 and 5 were isolated in 83% and 57% yield, respectively (Scheme 3B). Furthermore, the Boc-protecting group could be easily removed under acidic condition to deliver the free sulfoximine 6 (Scheme 3B).

Scheme 3 Scale up reaction and post-synthetic transformations.

We then performed several control experiments to get insight into the reaction mechanism (Scheme 4A). When the reaction was performed using TEMPO as radical quencher the reaction failed to provide the product 3a suggesting the radical nature of the reaction. Further, using 1,1-diphenyl ethene as radical trapping agent, we observed the formation of the adduct 7. Based on these control experiments and previous literature reports,¹⁷ we postulated that the sulfinamide anion 8 undergoes anodic oxidation to generate the N-centred radical intermediate which could undergo electronic rearrangement to generate the sulfonimidoyl radical 9 (Scheme 4B). At the cathode, the bromostyrene undergoes one-electron reduction to generate the styryl radical 10, which finally undergoes radical cross coupling with 9 to provide the sulfoximine 3a (Scheme 4B).

Scheme 4 Control experiment and possible reaction mechanism.

In conclusion, we have demonstrated the application of electrochemistry to access vinyl sulfoximines through a radical cross-coupling of the sulfonimidoyl and styryl radicals under metal- and additive-free conditions. The developed protocol successfully delivered a variety of sulfoximine derivatives in moderate to good yields. This strategy was further applied to synthesize bioactive tethered vinyl sulfoximines in moderate yields. Additionally, the synthetic applicability of the protocol was demonstrated through a scale-up reaction and subsequent post-synthetic modifications.

This publication is based upon work partially supported by King Abdullah University of Science and Technology (KAUST) under Award No. ORFS-CRG12-2024-6438.

Data availability

All experimental data, and detailed experimental procedures are available in the ESI.†

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d5cc02045j

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