Metal-free synthesis of γ-ketosulfones through Brønsted acid-promoted conjugate addition of sulfinamides

Abstract

A straightforward and general metal-free method has been developed to add sufinamide-derived sulfone units on Michael acceptors under mild conditions. This reaction enables the preparation of a large variety of original γ-ketosulfones, of which only a few synthetic methods have been reported. The mild reaction conditions used tolerate a wide diversity of functional groups and empower the implementation of a late-stage functionalisation strategy.

---

Introduction

Sulfur–carbon bond formation belongs to the fundamental transformations in synthetic organic chemistry. Indeed, organosulfur compounds are a relevant class of molecules with applications in various fields of chemistry, including natural products,¹ bioactive compounds,² and functional materials science.³ Among them, sulfones are important molecular frameworks and have drawn much attention for their synthesis.⁴ Although effective, most of the synthesis methods suffer from drawbacks such as the use of a toxic additive, a metal catalyst, some hazardous raw materials, and harsh reaction conditions, often generating undesired by-products that can pollute the final product and reduce the environmental attractiveness of these approaches.

Turning more specifically to the relevant subclasses of ketosulfones,⁵ while a wide variety of synthetic methods have been developed for the preparation of β-ketosulfones,⁶ the synthesis of their γ-ketosulfone isomers remains surprisingly underexplored and challenging. Usually, γ-ketosulfones are obtained in two steps by the conjugate addition of thiol derivatives onto various α,β-unsaturated ketones, followed by the oxidation of the corresponding sulfides into sulfones.⁷ The direct introduction of the sulfone moiety has also been investigated mainly using sulfinates⁸ or sulfinic acids⁹ as a source of sulfonyl derivatives. More specifically, complementary approaches have been devised from alternative sources of sulfone motif such as (i) the photoredox-catalyzed^10a,b or metal-catalyzed^10e hydrosulfonylation of enones with p-tolyl N-sulfonylimine or sulfur dioxide, (ii) a sulfonylation/migration process applied to arylallylic alcohols with arenesulfinic acid in the presence of hypervalent iodine (III) and concentrated sulfuric acid,^10c (iii) the direct sulfonylation of acrylates or acrylamides with arenesulfonyl hydrazides,^10d (iv) the asymmetric sulfonation of enones with arene sulfonylimines by cooperative organic multicatalysis,^10f or (v) the N-heterocyclic carbene-catalyzed Stetter reaction of aldehydes with α,β-unsaturated sulfones.^10g To our knowledge, no method has explored the use of sulfinamide as a source of sulfone moiety and there is still a strong demand to develop versatile and atom-economical approaches to produce γ-ketosulfones directly under mild conditions.

Our research group has long been interested in developing original environmentally friendly synthetic methods based on conjugate additions.¹¹ In this context, we have described the preparation of highly substituted sulfonated cyclopentanes via an acid-promoted Rauhut–Currier (RC) cascade¹² in the presence of simple and readily available sulfinamides.¹³ Mechanistically, the cascade is initiated by the nucleophilic addition of a S-nucleophile onto a Michael acceptor playing the role of RC donor. Interestingly, HBF₄ proved the best catalyst among a variety of Lewis and Brønsted acids explored, such as In(OTf)₃, Bi(OTf)₃, BF₃·OEt₂, TfOH, p-TsOH or Tf₂NH, to efficiently promote the conjugate addition of deactivated nucleophiles.^12c,13 In our continuing effort to develop eco-friendly synthetic methodologies, we have taken advantage of this unique sulfonamide capability to extend this approach to the synthesis γ-ketosulfones (Scheme 1). Indeed, there are several obvious advantages of the present method: (i) cheap and readily available aqueous HBF₄ proves to be an efficient promoter instead of a metal catalyst, which is usually expensive and complicated to remove completely from the target product; (ii) the reaction shows broad substrate scopes: cyclic, linear, aromatic, and heteroaromatic compounds are well tolerated at room temperature and in the open air; (iii) for aprotic polar solvent use, acetonitrile is recognised as a sustainable solvent by the Sanofi's Solvent Selection Guide;¹⁴ (iv) the by-product of the reaction is ammonium which is directly captured in situ by an acid–base interaction; (v) in general, reactions are clean, allowing the expected products to be easily purified and isolated in moderate to excellent yields.

Scheme 1 Acid-promoted synthesis of γ-ketosulfones.

Results and discussion

Based on the optimized conditions of our seminal work,¹³ the preliminary study was performed by reacting cyclohex-2-enone 1a with tert-butylsulfinamide 2a in the presence of one equivalent of aqueous HBF₄ at room temperature (Table 1). Pleasingly, in a CH₂Cl₂/CH₃CN 1 : 4 mixture, the desired γ-sulfone 3aa was isolated in a 41% yield (entry 1). A subsequent investigation on the solvent effect highlighted that an aprotic polar solvent was essential for the reaction, with CH₃CN giving the best results (entries 2–4). The reaction efficiency was not improved by adjusting the amount of HBF₄: a stoichiometric amount is required to reach full conversion of the starting material (entries 5–6). Conversely, the yield dropped to 73% starting from 2 equivalents of 2a, whereas the reaction concentration does not influence the reaction efficacy (entries 7–9).

Table 1 Optimisation of the reaction conditions^a

Entry	Solvent	HBF4 (equiv.)	tBuSONH2 2a (equiv.)	Yield^b (%)
a Reaction conditions: cyclohex-2-enone (0.20 mmol, 1 equiv.) under the appropriate reaction conditions (c = 0.4 mol L^−1) at room temperature for 24 h.b Isolated yield.c Starting material.d c = 0.8 mol L^−1.
1	CH2Cl2/CH3CN = 1/4	1	1.6	41
2	CH2Cl2	1	1.6	32
3	MeOH	1	1.6	s.m.^c
4	CH3CN	1	1.6	46
5	CH3CN	0.2	1.6	16
6	CH3CN	0.5	1.6	34
7	CH3CN	1	1.2	25
8	CH3CN	1	2	73
9^d	CH3CN	1	2	71

---

With the optimised reaction conditions established (Table 1, entry 8), the reaction scope was investigated, and Table 2 shows that cyclic enones efficiently participate in the reaction. Good to high yields were obtained for 3aa–3ac by reacting cyclohex-2-enone 1a with both alkyl- and aryl-sulfinamides. By starting from the inferior homolog cyclopent-2-enone 1b, the telescoped reduction of the ketone group was necessary to avoid degradation of the expected adduct. Indeed, during the purification by flash chromatography on silica gel, a retro-Michael reaction was observed restoring the starting material 1b. Notably, sulfinamides 2a–2c worked equally well, forming the desired γ-hydroxy sulfones 4ba, 4bb, and 4bc in high yields. Finally, the cis diastereoselectivity of the reduction turned out to be very satisfying (>10 : 1).

Table 2 Reactivity of alicyclic conjugate enones with various sulfinamides^a,b,c

a Unless otherwise noted, reaction conditions: 1a or 1b (0.20 mmol, 1 equiv.), 2 (0.40 mmol, 2 equiv.), HBF₄ (0.20 mmol, 1 equiv.) in CH₃CN (c = 0.4 mol L⁻¹) at r.t. for 24 h. For the ketone reduction: NaBH₄ (0.24 mmol, 1.2 equiv.) in MeOH (c = 0.1 mol L⁻¹) at 0 °C to r.t. for 2 h.b Isolated yield.c Diastereomeric ratio and relative configuration were determined by ¹H NMR from the isolated product.

---

Next, we sought to expand this transformation to the reactivity of diverse acyclic α,β-unsaturated ketones. We were pleased to find that a range of scaffolds were efficiently converted in the presence of tert-butylsulfinamide 2a (Table 3). Either methyl, ethyl, or thien-2-ylmethyl vinyl ketone is compatible with our procedure, leading to 3ca, 3da or 3ea, respectively, in good to excellent yields. When the conjugate cyclohexenyl methyl ketone 1f was subjected to the procedure, the desired product 3fa was isolated in 67% yield with a complete cis selectivity. Next, we investigated the reactivity of acrolein 1g with 1 equivalent of the sulfinimine, and the targeted sulfonated scaffold 3ga was isolated. When the amount of 2a was increased up to 3 equivalents, we observed the major formation of the corresponding imine 5ga in a 3ga/5ga 36 : 64 ratio. Adding one more equivalent of acid reverses the reaction chemoselectivity, highlighting the key role of the acid in both the selectivity and the mechanism of the reaction.

Table 3 Reactivity of various open-chain α,β-unsaturated ketones with tert-butylsulfinamide 2a ^a,b

a Unless otherwise noted, reaction conditions: 1 (0.20 mmol, 1 equiv.), 2a (0.40 mmol, 2 equiv.), HBF₄ (0.20 mmol, 1 equiv.) in CH₃CN (c = 0.4 mol L⁻¹) at r.t. for 4–48 h.b Isolated yield.c Relative configuration determined by NMR from the isolated product.

---

Useful 4-chloro- and 4-fluoro-phenyl vinyl ketones were also accommodated, albeit in lower yields (3ha and 3ia). The reaction is more efficient by using electron-rich or -neutral arenes such as 1j and 1k, respectively giving 3ja and 3ka in good yields. Furthermore, as chalcones have historically received intensive attention from chemists because of their prominent drug activity,¹⁵ chalcone 1l was submitted to the reaction conditions affording the sulfone 3la in a 57% yield. Similarly, knowing the widespread presence of heteroarenes in many biologically active natural and synthetic products,¹⁶ heteroaryl vinyl ketones, such as 1m and 1n were also evaluated as substrates in our system. They provided access to the corresponding original heterocyclic γ-ketosulfones 3ma and 3na in satisfying yields. Given that this strategy promises to rapidly access sulfonyl compounds to explore structure–activity relationships,¹⁷ we speculated that our mild reaction conditions might be compatible with highly functionalised bioactive molecules. Therefore, we applied our approach to more complex structures derived from menthol and linoleic acid. The corresponding sulfonated 3oa and 3pa, respectively, were cleanly isolated, demonstrating the generality of this sulfonyl unit transfer method. Even if most of the synthesised γ-ketosulfones were isolated in good to high yields, 3ha, 3ia, 3ka, and 3ma were obtained in moderate yields. To evaluate the part of instability of the considered γ-ketosulfones in these unsatisfactory results, we studied the effect of telescoping a reduction step to the sulfonylation reaction (Table 4). Unfortunately, the newly formed γ-hydroxy sulfones 4ha, 4ia, 4ka, and 4ma were isolated in similar yields ruling out the involvement of a retro-Michael reaction to explain the yield erosion and questioning the stability of the starting vinyl ketones under acidic reaction conditions.

Table 4 Reactivity of various aryl vinyl ketones with tert-butylsulfinamide 2a.^a,b

a Unless otherwise noted, reaction conditions: 1 (0.20 mmol, 1 equiv.), 2a (0.40 mmol, 2 equiv.), HBF₄ (0.20 mmol, 1 equiv.) in the presence of CH₃CN (c = 0.4 mol L⁻¹) at r.t. for 4 h. Then, NaBH₄ (0.24 mmol, 1.2 equiv.) in MeOH (c = 0.1 mol L⁻¹) at 0 °C to r.t. for 2 h.b Isolated yield.

---

From a mechanistic point of view, in our early work, we showed that prior acid hydrolysis of sulfinamide to sulfinic acid could not be excluded and that the sulfone formation could result from the addition of both proton-activated sulfinamide or sulfinic acid (Scheme 3).¹³ To further decipher the reaction mechanism, we tried identifying some reaction intermediates by exploring the reactivity of N-octyl tert-butyl sulfinamide 2d with ethyl vinyl ketone 1d (Scheme 2). The sulfinamide 2d was chosen because the possibly expected N-alkylated sulfoximine intermediate should be less sensitive to hydrolytic conditions and thus, easier to characterise. After 5 h of reaction according to our procedure, an aliquot of the crude mixture was directly analysed by electrospray ionisation mass spectrometry analysis (ESI-MS). In positive ion mode, three major cationic intermediates were trapped: the hydrated sulfinyl adduct 6dd (m/z [M + H+ H₂O]⁺), the sulfonated sodium adduct 3da (m/z [M + Na]⁺) and the octylamine 7d (m/z [M + H]⁺) (Scheme 2).¹⁸ No sulfinic acid was detected in either positive or negative mode. Even if attempts to isolate the sulfinyl adduct 6dd were unsuccessful, these results support the fact that a highly hydrolysable sulfoximine might be a transient intermediate of the reaction. These observations enabled us to revisit our firstly proposed mechanism.¹³ Indeed, as we demonstrated in our previous work, the nucleophilic strength of the deactivated amine and the acidity of the proton source act as a Lewis pair and are key parameters to control the selectivity of the Michael reaction.^11c Thus, in acetonitrile, the protonation of the oxygen atom of the sulfinamide by aqueous HBF₄ is preferred due to its stronger basicity,²² which increases the nucleophilicity of the sulfur atom (Scheme 3). The corresponding protonated sulfinamide, acting as a proton shuttle, would favour the addition of the S-nucleophile by promoting enolization of the Michael acceptor. The resulting sulfoximine intermediate would then be rapidly hydrolyzed to sulfone 3 under the reaction conditions (Scheme 3).

Scheme 2 ESI-MS analysis for the crude reaction mixture of 1d with 2d.

Scheme 3 Plausible mechanism for the synthesis of γ-ketosulfone.

Conclusions

We have developed a metal-free, operationally simple, and environmentally friendly method for the synthesis of γ-ketosulfones at ambient temperature by using various readily available sulfinamides as the sulfur source. This easy-to-implement protocol represents not only new routes to the synthesis of original γ-ketosulfones but more importantly is tolerant to a wide range of substrates, including complex molecules. This chemistry should provide access to other sulfone-containing bioactive compound libraries which are difficult to synthesise via other methods.

Experimental section

General procedure for the synthesis of ketosulfones 3

To a solution of alkenone 1 (0.20 mmol) in CH₃CN (c = 0.4 mol L⁻¹) were successively added sulfinamide 2 (0.40 mmol) and aqueous HBF₄ 48% wt. (0.20 mmol). The resulting mixture was stirred at room temperature until the disappearance of the starting material (4 to 48 hours) before quenching with the addition of water (2 mL). The solution was then extracted with CH₂Cl₂ (3 × 10 mL). The organic phase was washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by flash chromatography with cyclohexane/ethyl acetate to yield the desired γ-ketosulfone 3.

3-(tert-Butylsulfonyl)cyclohexanone (3aa)

3aa was prepared following the general procedure by reacting 1a (19.4 μL, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. Flash chromatography (cyclohexane/ethyl acetate: 4/6) afforded the title compound 3aa as a white solid (32 mg, 73%). M.p.: 108–109 °C; IR (neat) ν_max/cm⁻¹ 2968, 1705, 1270, 1110, 664; ¹H NMR (300 MHz, CDCl₃) δ 3.57–3.47 (m, 1H), 2.75 (d, J = 9.1 Hz, 2H), 2.40–2.21 (m, 4H), 2.08–1.97 (m, 1H), 1.75–1.63 (m, 1H), 1.42 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 207.4, 61.4, 55.8, 42.4, 40.5, 25.3, 24.2 (3C), 23.8; HRMS (TOF-ESI) m/z: calcd for C₁₀H₁₈O₃NaS [M + Na]⁺ 241.0869, found 241.0875.

3-(Benzenesulfonyl)cyclohexanone (3ab)

3ab was prepared following the general procedure by reacting 1a (19.4 μL, 0.20 mmol), benzenesulfinamide 2b (56 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. Flash chromatography (cyclohexane/ethyl acetate: 7 : 3 to 6 : 4) afforded the title compound 3ab as a white solid (44 mg, 92%). M.p.: 87–88 °C; IR (neat) ν_max/cm⁻¹ 2965, 1706, 1260, 1137, 1084, 1019, 798; ¹H NMR (300 MHz, CDCl₃) δ 7.85 (br d, J = 7.2 Hz, 2H), 7.68 (br t, J = 7.7 Hz, 1H), 7.57 (br t, J = 7.2 Hz, 2H), 3.33–3.23 (m, 1H), 2.57 (m, 2H), 2.41–2.17 (m, 4H), 1.91 (qd, J = 12.7, 3.1 Hz, 1H), 1.71–1.57 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 206.6, 136.8, 134.4, 129.6 (2C), 129.1 (2C), 62.4, 40.6, 40.5, 23.8, 23.6; HRMS (TOF-ESI) m/z: calcd for C₁₂H₁₄O₃NaS [M + Na]⁺ 261.0556, found 261.0562. The data presented above agrees with that detailed in the literature.¹⁹

3-Tosyl cyclohexanone (3ac)

3ac was prepared following the general procedure by reacting 1a (19.4 μL, 0.20 mmol), p-toluenesulfinamide 2c (62 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. Flash chromatography (cyclohexane/ethyl acetate: 7 : 3 to 6 : 4) afforded the title compound 3ac as a yellow solid (38 mg, 75%). M.p.: 82–83 °C; IR (neat) ν_max/cm⁻¹ 2952, 1713, 1283, 1086, 1018, 664; ¹H NMR (300 MHz, CDCl₃) δ 7.72 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 3.30–3.20 (m, 1H), 2.53 (m, 2H), 2.44 (s, 3H), 2.41–2.18 (m, 4H), 1.95–1.73 (m, 1H), 1.67–1.58 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 206.7, 145.4, 133.6, 130.1 (2C), 129.0 (2C), 62.4, 40.6 (2C), 23.8, 23.6, 21.7; HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₆O₃NaS [M + Na]⁺ 275.0712, found 275.0721. The data presented above agree with that detailed in the literature.¹⁹

4-(tert-Butylsulfonyl)butan-2-one (3ca)

3ca was prepared following the general procedure by reacting 1c (16.7 μL, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 7 hours. Flash chromatography (cyclohexane/ethyl acetate 3 : 7 ratio) afforded the title compound 3ca as a white solid (26 mg, 68%). M.p.: 56–57 °C; IR (neat) ν_max/cm⁻¹ 2978, 1714, 1475, 1300, 1160, 1108 (CH); ¹H NMR (300 MHz, CDCl₃) δ 3.20 (t, J = 6.9 Hz, 2H), 3.02 (t, J = 7.7 Hz, 2H), 2.24 (s, 3H), 1.41 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 204.7, 59.2, 40.2, 34.1, 30.1, 23.4 (3C); HRMS (TOF-ESI) m/z: calcd for C₈H₁₆O₃NaS [M + Na]⁺ 215.0712, found 215.0719. The data presented above agree with that detailed in the literature.²⁰

1-(tert-Butylsulfonyl)pentan-3-one (3da)

3da was prepared following the general procedure by reacting 1d (19.9 μL, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 7 hours. Flash chromatography (cyclohexane/ethyl acetate: 5/5 to 4/6) afforded the title compound 3da as a white solid (39 mg, 95%). M.p.: 55–56 °C; IR (neat) ν_max/cm⁻¹ 2978, 1714, 1414, 1265, 1114, 976; ¹H NMR (300 MHz, CDCl₃) δ 3.21 (t, J = 6.9 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.51 (q, J = 7.3 Hz, 2H), 1.40 (s, 9H), 1.07 (t, J = 7.3 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 207.6, 59.1, 40.1, 36.2, 32.7, 23.4 (3C), 7.9; HRMS (TOF-ESI) m/z: calcd for C₉H₁₈O₃NaS [M + Na]⁺ 229.0869, found 229.0865.

4-(tert-Butylsulfonyl)-1-(thien-2-yl)butan-2-one (3ea)

3ea was prepared following the general procedure by reacting 1e (30 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 10 hours. Flash chromatography (cyclohexane/ethyl acetate: 75/25) afforded the title compound 3ea as a white solid (35 mg, 64%). M.p.: 84–85 °C; IR (neat) ν_max/cm⁻¹ 2962, 1717, 1473, 1265, 1108, 1007, 669; ¹H NMR (300 MHz, CDCl₃) δ 7.22 (dd, J = 5.1, 1.1 Hz, 1H), 6.98 (dd, J = 5.0, 3.6 Hz, 1H), 6.91 (m, 1H), 3.99 (s, 2H), 3.21 (t, J = 6.6 Hz, 2H), 3.08 (t, J = 6.8 Hz, 2H), 1.71 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 203.5, 134.4, 127.5, 127.4, 125.7, 59.3, 43.9, 40.4, 32.5, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₂H₁₈O₃NaS₂ [M + Na]⁺ 297.0590, found 297.0592.

1-Acetyl-2-tert-butylsulfonyl cyclohexane (3fa)

3fa was prepared following the general procedure by reacting 1f (25.7 μL, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 48 hours. Flash chromatography (cyclohexane/ethyl acetate: 5/5) afforded the title compound 3fa as a brown foam (33 mg, 67%). IR (neat) ν_max/cm⁻¹ 2944, 1711, 1271, 1110, 681; ¹H NMR (300 MHz, CDCl₃) δ 3.59 (m, 1H), 2.90 (m, 1H), 2.62–2.51 (m, 1H), 2.23 (s, 3H), 2.02 (m, 2H), 1.81–1.74 (m, 2H), 1.47–1.41 (m, 3H), 1.36 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 208.9, 61.1, 57.1, 48.3, 29.1, 27.6, 26.2, 24.6, 23.5 (3C), 21.9; HRMS (TOF-ESI) m/z: calcd for C₁₂H₂₂O₃SNa [M + Na]⁺ 269.1182, found 269.1180.

3-(tert-Butylsulfonyl)propanal (3ga)

3ga was prepared following the general procedure by reacting 1g (13.4 μL, 0.20 mmol), tert-butylsulfinamide 2a (24 mg, 0.20 mmol), HBF₄ (26 μL, 0.20 mmol) for 4 hours. Flash chromatography (cyclohexane/ethyl acetate: 3/7) afforded the title compound 3ga as a colourless oil (14 mg, 39%). IR (neat) ν_max/cm⁻¹ 2988, 1723, 1297, 1110; ¹H NMR (300 MHz, CDCl₃) δ 9.87 (s, 1H), 3.25 (t, J = 7.4 Hz, 2H), 3.10 (t, J = 7.0 Hz, 2H), 1.44 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 197.8, 59.4, 38.7, 34.8, 23.5 (3C); HRMS (TOF-ESI) m/z: calcd for C₇H₁₄O₃NaS [M + Na]⁺ 201.0556, found 201.0564.

(E)-N-[3-(tert-Butylsulfonyl)propyliden-1-yl]-tert-butylsulfinamide (5ga)

5ga was prepared following the general procedure by reacting 1g (13.4 μL, 0.20 mmol), tert-butylsulfinamide 2a (73 mg, 0.60 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. Flash chromatography (cyclohexane/ethyl acetate: 3/7) afforded the title compound 5ga as a white solid (14.5 mg, 26%). M.p.: 101–102 °C; IR (neat) ν_max/cm⁻¹ 2985, 1651, 1300, 1263, 1117, 1078; ¹H NMR (300 MHz, CDCl₃) δ 8.19 (t, J = 3.1 Hz, 1H), 3.34–3.28 (m, 2H), 3.15–3.09 (m, 2H), 1.45 (s, 9H), 1.20 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 165.6, 59.4, 57.2, 41.2, 27.5, 23.6 (3C), 22.5 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₁H₂₄NO₃S₂ [M + H]⁺ 282.1192, found 282.1205.

3-(tert-Butylsulfonyl)-1-(4-chlorophenyl)propan-1-one (3ha)

3ha was prepared following the general procedure by reacting 1h (33 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 5 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3) afforded the title compound 3ha as a white solid (16 mg, 28%). M.p.: 146–147 °C; IR (neat) ν_max/cm⁻¹ 2982, 1674, 1588, 1301, 1265, 1116; ¹H NMR (300 MHz, CDCl₃) δ 7.94 (d, J = 8.7 Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 3.55 (dd, J = 8.5, 6.4 Hz, 2H), 3.38 (dd, J = 8.5, 6.5 Hz, 2H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 195.3, 140.5, 134.4, 129.7 (2C), 129.3 (2C), 59.3, 40.5, 29.8, 23.5 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₇O₃NaSCl [M + Na]⁺ 311.0479, found 311.0476.

3-(tert-Butylsulfonyl)-1-(4-fluorophenyl)propan-1-one (3ia)

3ia was prepared following the general procedure by reacting 1i (30 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 5 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3 to 6/4) afforded the title compound 3ia as a white solid (16 mg, 29%). M.p.: 103–104 °C; IR (neat) ν_max/cm⁻¹ 2925, 1684, 1596, 1267, 1108, 979, 736; ¹H NMR (300 MHz, CDCl₃) δ 8.03 (m, 2H), 7.16 (br t, J = 8.7 Hz, 2H), 3.56 (dd, J = 8.4, 6.3 Hz, 1H), 3.38 (dd, J = 8.5, 6.4 Hz, 1H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 194.9, 166.3 (d, J = 254.4 Hz), 131.0 (d, J = 9.3 Hz, 2C), 116.1 (d, J = 21.9 Hz, 2C), 59.4, 40.7, 29.8, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₇O₃NaSF [M + Na]⁺ 295.0775, found 295.0779.

3-(tert-Butylsulfonyl)-1-phenylpropan-1-one (3ja)

3ja was prepared following the general procedure by reacting 1 h (26.4 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 5 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3 to 6/4) afforded the title compound 3ja as a white solid (31 mg, 61%). M.p.: 120–121 °C; IR (neat) ν_max/cm⁻¹ 2935, 2920, 1687, 1262, 1108, 1002, 740, 688; ¹H NMR (300 MHz, CDCl₃) δ 8.00 (br d, J = 7.3 Hz, 2H), 7.60 (br t, J = 7.6 Hz, 1H), 7.49 (br t, J = 7.7 Hz, 2H), 3.60 (dd, J = 8.5, 6.6 Hz, 1H), 3.39 (dd, J = 8.6, 6.7 Hz, 1H), 1.47 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 196.5, 136.1, 133.9, 128.9, 128.3, 59.3, 40.6, 29.8, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₈O₃NaS [M + Na]⁺ 277.0869, found 277.0887.

3-(tert-Butylsulfonyl)-1-(4-methoxyphenyl)propan-1-one (3ka)

3ka was prepared following the general procedure by reacting 1k (32 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 4 hours. Flash chromatography (cyclohexane/ethyl acetate: 5/5) afforded the title compound 3ka as a white solid (33 mg, 58%). M.p.: 75–76 °C; IR (neat) ν_max/cm⁻¹ 2926, 1674, 1601, 1573, 1251, 1112, 977; ¹H NMR (300 MHz, CDCl₃) δ 7.97 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 3.87 (s, 3H), 3.54 (dd, J = 8.5, 6.8 Hz, 2H), 3.37 (dd, J = 8.5, 6.6 Hz, 1H), 1.46 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 194.9, 164.1, 130.6 (2C), 129.2, 114.1 (2C), 59.3, 55.7, 40.7, 29.3, 23.5 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₄H₂₀O₄NaS [M + Na]⁺ 307.0975, found 307.0982.

3-(tert-Butylsulfonyl)-1,3-diphenyl propan-1-one (3la)

3la was prepared following the general procedure by reacting 1l (42 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 48 hours. Flash chromatography (cyclohexane/ethyl acetate: 9/1 to 8/2) afforded the title compound 3la as a white solid (38 mg, 57%) M.p.: 136–137 °C; IR (neat) ν_max/cm⁻¹ 2926, 1687, 1281, 1177, 1108; ¹H NMR (300 MHz, CDCl₃) δ 7.92 (d, J = 7.3 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.1 Hz, 1H), 7.43 (m, 2H), 7.40–7.29 (m, 3H), 5.19 (dd, J = 9.2 Hz, J = 3.5 Hz, 1H), 4.15 (dd, J = 17.9 Hz, J = 3.5 Hz, 1H), 3.72 (dd, J = 17.9 Hz, J = 9.2 Hz, 1H), 1.24 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 195.4, 136.4, 135.0, 133.7, 129.9 (2C), 129.0 (3C), 128.8 (2C), 128.3 (2C), 62.4, 60.1, 39.6, 24.4 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₉H₂₂O₃NaS [M + Na]⁺ 353.1182, found 353.1189.

3-(tert-Butylsulfonyl)-1-(thien-3-yl)propan-1-one (3ma)

3ma was prepared following the general procedure by reacting 1m (28 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 6 hours. Flash chromatography (cyclohexane/ethyl acetate: 6/4) afforded the title compound 3ma as a white solid (29 mg, 55%). M.p.: 133–134 °C; IR (neat) ν_max/cm⁻¹ 2952, 1669, 1416, 1264, 1106, 771; ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, J = 3.4 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.15 (t, J = 4.6 Hz, 1H), 3.52 (dd, J = 8.3, 6.2 Hz, 1H), 3.37 (dd, J = 8.5, 6.6 Hz, 1H), 1.45 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 189.1, 143.0, 134.6, 132.8, 128.5, 59.3, 40.5, 30.2, 23.5 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₁H₁₆O₃S₂Na [M + Na]⁺ 283.0433, found 283.0435.

3-(tert-Butylsulfonyl)-1-(1-tosyl-1H-indol-3-yl)propan-1-one (3na)

3na was prepared following the general procedure by reacting 1n (65 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3 to 6/4) afforded the title compound 3na as a brown solid (45 mg, 50%). M.p.: 143–144 °C; IR (neat) ν_max/cm⁻¹ 2971, 1666, 1539, 1266, 1116, 978; ¹H NMR (300 MHz, CDCl₃) δ 8.34 (s, 1H), 8.25 (dd, J = 7.3, 2.2 Hz, 1H), 7.96 (dd, J = 6.9, 1.3 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.40–7.26 (m, 4H), 3.54–3.50 (m, 2H), 3.44–3.38 (m, 2H), 2.36 (s, 3H, CH₃-Ar), 1.47 (s, 9H, tBu); ¹³C NMR (75 MHz, CDCl₃) δ 191.7, 146.2, 135.0, 134.5, 133.2, 132.5, 130.4 (2C), 127.4 (2C), 126.0, 125.1, 122.9, 120.4, 113.3, 59.4, 40.3, 30.7, 23.5 (3C), 21.8; HRMS (TOF-ESI) m/z: calcd for C₂₂H₂₅NO₅NaS₂ [M + Na]⁺ 470.1066, found 470.1073.

4-(tert-Butylsulfonyl)-1-{[(1R,2S,5R)-2-isopropyl-5-methyl cyclohex-1-yl]oxy} but-3-en-2-one (3oa)

3oa was prepared following the general procedure by reacting 1o (44 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) in a mixture of CH₂Cl₂/CH₃CN (8/2, 1 mL) for 17 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3) afforded the title compound 3oa as a yellow oil (41 mg, 59%). IR (neat) ν_max/cm⁻¹ 2955, 2920, 1722, 1301, 1116; ¹H NMR (300 MHz, CDCl₃) δ 4.20 (d, J = 16.8 Hz, 1H), 4.00 (d, J = 16.8 Hz, 1H), 3.26–6.09 (m, 4H), 2.22 (m, 1H), 2.03 (br d, J = 11.3 Hz, 1H), 1.64 (m, 2H), 1.43 (s, 9H), 1.35–1.18 (m, 4H), 0.91 (m, 8H), 0.78 (d, J = 6.9 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 206.6, 80.6, 73.9, 59.3, 48.2, 40.0, 39.9, 34.5, 31.6, 30.5, 25.8, 23.5 (3C), 23.4, 22.4, 21.1, 16.4; HRMS (TOF-ESI) m/z: calcd for C₁₈H₃₄O₄NaS [M + Na]⁺ 369.2070, found 369.2080.

(11Z,14Z)-1-(tert-butylsulfonyl)icosa-11,14-dien-3-one (3pa)

3pa was prepared following the general procedure by reacting 1p (58 mg, 0.20 mmol), tert-butylsulfinamide (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 6 hours. Flash chromatography (cyclohexane/ethyl acetate: 7/3) afforded the title compound 3pa as a yellow foam (42 mg, 51%). IR (neat) ν_max/cm⁻¹ 2982, 1712, 1268, 1102; ¹H NMR (300 MHz, CDCl₃) δ 5.35–5.27 (m, 4H), 3.21 (t, J = 7.8 Hz, 2H), 2.99 (t, J = 7.2 Hz, 2H), 2.76 (t, J = 5.8 Hz, 2H), 2.49 (t, J = 7.4 Hz, 2H), 2.03 (m, 4H), 1.60 (m, 2H), 1.42 (s, 9H), 1.30 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H, Me); ¹³C NMR (75 MHz, CDCl₃) δ 207.3, 130.3, 130.2, 128.2, 128.0, 59.2, 43.1, 40.2, 33.1, 31.7, 29.7, 29.5, 29.4, 29.2, 28.2, 27.3, 25.8, 24.9, 23.9, 23.5 (3C), 22.7, 14.2; HRMS (TOF-ESI) m/z: calcd for C₂₄H₄₄O₃NaS [M + Na]⁺ 435.2903, found 435.2915.

General procedure for the synthesis of hydroxysulfones (4)

The ketosulfone 3 (0.20 mmol) was dissolved in MeOH (c = 0.1 mol L⁻¹) at 0 °C and NaBH₄ (0.24 mmol) was then added. After stirring at room temperature for 2 hours, the reaction mixture was quenched by the addition of acetone (2 mL) before evaporation of the solvent. Water (2 mL) was then added, the aqueous layer was extracted with AcOEt (3 × 10 mL) and the combined organic extracts were washed with brine, dried over MgSO₄, filtered and concentrated. The crude product was purified by flash chromatography with cyclohexane/ethyl acetate to yield the desired hydroxysulfone 4.

3-(tert-Butylsulfonyl)cyclopentanol (4ba)

4ba was prepared following the general procedure by reacting 1b (32.8 μL, 0.40 mmol), tert-butylsulfinamide 2a (96 mg, 0.80 mmol), HBF₄ (52 μL, 0.40 mmol) for 24 hours. NaBH₄ (18 mg, 0.48 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 1/9) afforded the title compound 4ba as a white solid (73 mg, 88%, cis/trans = 10/1). M.p.: 79–80 °C; IR (neat) ν_max/cm⁻¹ 3499, 2993, 1282, 1143, 688; ¹H NMR (300 MHz, CDCl₃) δ 4.31 (br s, 1H), 3.72–3.62 (m, 1H), 2.47–2.20 (m, 4H), 2.13–2.06 (m, 1H), 2.02–1.91 (m, 1H), 1.79–1.72 (m, 1H), 1.44 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 72.4, 60.3, 55.7, 37.4, 35.6, 25.8, 24.3 (3C); HRMS (TOF-ESI) m/z: calcd for C₉H₁₈O₃NaS [M + Na]⁺ 229.0869, found 229.0868.

3-(Benzenesulfonyl)cyclopentanol (4bb)

4bb was prepared following the general procedure by reacting 1b (16.8 μL, 0.20 mmol), benzenesulfinamide 2b (56 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 3/7 to 2/8) afforded the title compound 4bb as a colourless oil (30 mg, 66%, cis/trans = 21/1). IR (neat) ν_max/cm⁻¹ 3480, 1446, 1284, 1142, 1085; 690; ¹H NMR (300 MHz, CDCl₃) δ 7.91 (br d, J = 7.4 Hz, 2H), 7.67 (br t, J = 7.8 Hz, 1H), 7.57 (br t, J = 6.9 Hz, 2H), 4.32 (br s, 1H), 3.61 (qt, J = 8.5 Hz, 1H), 2.35–2.10 (m, 4H), 1.96–1.85 (m, 2H), 1.83–1.73 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 138.2, 134.0, 129.5 (2C), 128.7 (2C), 72.7, 63.2, 36.3, 35.6, 24.8; HRMS (TOF-ESI) m/z: calcd for C₁₁H₁₄O₃NaS [M + Na]⁺ 249.0556, found 249.0560.

3-(p-Toluensulfonyl)-cyclopentan1-ol (4bc)

4bc was prepared following the general procedure by reacting 1b (16.8 μL, 0.20 mmol), p-toluenesulfinamide 2c (62 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 24 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 4/6) afforded the title compound 4bc as a colourless oil (36 mg, 75%, cis/trans = 17/1). IR (neat) ν_max/cm⁻¹ 3492, 1478, 1284, 1185; ¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 4.31 (br s, 1H), 3.58 (qt, J = 6.7 Hz, 1H), 2.45 (s, 3H), 2.28–2.13 (m, 4H), 1.95–1.84 (m, 2H), 1.79–1.74 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 144.9, 135.0, 130.0 (2C), 128.6 (2C), 72.6, 63.2, 36.2, 35.5, 24.6, 21.6; HRMS (TOF-ESI) m/z: calcd for C₁₂H₁₆O₃NaS [M + Na]⁺ 263.0712, found 263.0710. The data presented above are in agreement with that detailed in the literature.²¹

3-(tert-Butylsulfonyl)-1-(4-chlorophenyl)propan-1-ol (4ha)

4ha was prepared following the general procedure by reacting 1h (33 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 5 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 4/6) afforded the title compound 4ha as a colourless oil (11 mg, 18%). IR (neat) ν_max/cm⁻¹ 3469, 2924, 1282, 1110, 748; ¹H NMR (300 MHz, CDCl₃) δ 7.32 (m, 4H), 4.95 (dd, J = 8.5, 4.5 Hz, 1H), 3.07 (t, J = 7.3 Hz, 2H), 2.33–2.21 (m, 2H), 1.41 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 142.0, 133.8, 129.0 (2C), 127.2 (2C), 71.8, 59.3, 42.1, 30.2, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₉O₃NaSCl [M + Na]⁺ 313.0636, found 313.0638.

3-(tert-Butylsulfonyl)-1-(4-fluorophenyl)propan-1-ol (4ia)

4ia was prepared following the general procedure by reacting 1i (30 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 5 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 4/6 to 3/7) afforded the title compound 4ia as a white solid (17 mg, 31%). M.p.: 61–62 °C; IR (neat) ν_max/cm⁻¹ 3479, 2990, 1509, 1260, 1109; ¹H NMR (300 MHz, CDCl₃) δ 7.34 (dd, J = 8.7 Hz, J = 5.4 Hz, 2H), 7.04 (t, J = 8.6 Hz, 2H), 4.91 (dd, J = 8.0, 4.6 Hz, 1H), 3.07 (t, J = 7.5 Hz, 2H), 2.52 (br s, 1H), 2.31–2.22 (m, 2H), 1.41 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 162.5 (d, J = 245 Hz), 139.3, 127.5 (d, J = 8.0 Hz, 2C), 115.6 (d, J = 21.3 Hz, 2C), 71.9, 59.3, 42.2, 30.2, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₃H₁₉O₃FNaS [M + Na]⁺ 297.0931, found 297.0937.

3-(tert-Butylsulfonyl)-1-(4-methoxyphenyl)propan-1-ol (4ka)

4ka was prepared following the general procedure by reacting 1k (32 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 4 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 4/6) afforded the title compound 4ka as a yellow oil (28 mg, 49%). IR (neat) ν_max/cm⁻¹ 3490, 2938, 1672, 1512, 1244, 1109, 1030; ¹H NMR (300 MHz, CDCl₃) δ 7.27 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.84 (t, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.11–2.98 (m, 2H), 2.27 (q, J = 7.5 Hz, 2H), 1.40 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 159.5, 135.6, 127.1 (2C), 114.2 (2C), 72.3, 59.2, 55.4, 42.5, 30.0, 23.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₄H₂₂O₄NaS [M + Na]⁺ 309.1131, found 309.1143.

3-(tert-Butylsulfonyl)-1-(thien-3-yl)propan-1-ol (4ma)

4ma was prepared following the general procedure by reacting 1m (28 mg, 0.20 mmol), tert-butylsulfinamide 2a (48 mg, 0.40 mmol), HBF₄ (26 μL, 0.20 mmol) for 6 hours. NaBH₄ (9.1 mg, 0.24 mmol) was next added. Flash chromatography (cyclohexane/ethyl acetate: 4/6) afforded the title compound 4ma as a white solid (24 mg, 47%). M.p.: 82–83 °C; IR (neat) ν_max/cm⁻¹ 3473, 2977, 1255, 1086, 777; ¹H NMR (300 MHz, CDCl₃) δ 7.25 (d, J = 4.7 Hz, 1H), 7.00–6.96 (m, 2H), 5.17 (dd, J = 7.3, 5.3 Hz, 1H), 3.11 (t, J = 7.4 Hz, 2H), 2.71 (br s, 1H), 2.45–2.35 (m, 2H), 1.41 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 147.2, 127.0, 125.0, 124.1, 68.6, 59.3, 42.2, 30.3, 25.6 (3C); HRMS (TOF-ESI) m/z: calcd for C₁₁H₁₈O₂NaS₂ [M + Na]⁺ 285.0590, found 285.0601.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank K. Leblanc for performing mass analyses. The Université Paris-Saclay, the French Ministry of Superior Education and Research, the CNRS, and the National Research Agency (ANR-17-CE11-0030-03) are gratefully acknowledged for financial support.

Notes and references

1. For recent examples, see: (a) M. J. Tilby and M. C. Willis, Expert Opin. Drug Discovery, 2021, 16, 1227–1231; (b) F. L. Cherblanc, R. W. M. Davidson, P. Di Fruscia, N. Srimongkolpithak and M. J. Fuchter, Nat. Prod. Rep., 2013, 30, 605–624; (c) E. Iwasa, Y. Hamashima and M. Sodeoka, Isr. J. Chem., 2011, 51, 420–433.
2. For recent examples, see: (a) T. Neumann, L. Benajiba, S. Göring, K. Stegmaier and B. Schmidt, J. Med. Chem., 2015, 58, 8907–8919; (b) N. Boyer, K. C. Morrison, J. Kim, P. J. Hergenrother and M. Movassaghi, Chem. Sci., 2013, 4, 1646–1657; (c) H. Rueeger, R. Lueoend, O. Rogel, J.-M. Rondeau, H. Möbitz, R. Machauer, L. Jacobson, M. Staufenbiel, S. Desrayaud and U. Neumann, J. Med. Chem., 2012, 55, 3364–3386.
3. (a) S. Tamamuku and P. Jannasch, Macromolecules, 2012, 45, 6538–6546; (b) S.-M. Liu, Y. Yang, Z.-J. Jiang, Y.-H. Zhou, J. Zuo and J.-Q. Zhao, J. Appl. Polym. Sci., 2012, 124, 4502–4511.
4. For recent reviews, see: (a) Y. Fang, Z. Luo and X. Xua, RSC Adv., 2016, 6, 59661–59676; (b) N.-W. Liu, S. Liang and G. Manolikakes, Synthesis, 2016, 48, 1939–1976; (c) For selected examples of sulfones synthesis, see: E. J. Emmett and M. C. Willis, Asian J. Org. Chem., 2015, 4, 602–611; (d) Y. Xi, B. Dong, E. J. McClain, Q. Wang, T. L. Gregg, N. G. Akhmedov, J. L. Petersen and X. Shi, Angew. Chem., Int. Ed., 2014, 53, 4657–4661; (e) M. W. Johnson, S. W. Bagley, N. P. Mankad, R. G. Bergman, V. Mascitti and F. D. Toste, Angew. Chem., Int. Ed., 2014, 53, 4404–4407; (f) E. J. Emmett, B. R. Hayter and M. C. Willis, Angew. Chem., Int. Ed., 2013, 52, 12679–12683; (g) M. Jerek, Green Chem., 2012, 14, 3047–3052; (h) X. Zhao, E. Dimitrijević and V. M. Dong, J. Am. Chem. Soc., 2009, 131, 3466–3467.
5. (a) S. Trivedi, P. C. Patidar, P. K. Chaurasiya, R. S. Pawar, U. K. Patil and P. K. Singour, Pharma Chem., 2010, 2, 369–377; (b) J. Xiang, M. Ipek, V. Suri, M. Tam, Y. Xing, N. Huang, Y. Zhang, J. Tobin, T. S. Mansour and J. McKew, Bioorg. Med. Chem., 2007, 15, 4396–4405.
6. For a recent review, see: (a) R. J. Reddy and A. H. Kumari, J. Org. Biomol. Chem., 2021, 19, 3087–3118; (b) For recent and selected examples, see: B. Dam, A. K. Sahooa and B. K. Patel, Green Chem., 2022, 24, 7122–7130; (c) Y. Wang, Y. Zhao, C. Cai, L. Wang and H. Gong, Org. Lett., 2021, 23, 8296–8301; (d) X. Chen, S. Lu, Y. Zheng, J. Wang, L. Yang and P. Sun, Adv. Synth. Catal., 2022, 364, 1305–1312; (e) X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu and H. Jiang, Angew. Chem., Int. Ed., 2014, 53, 4205–4208.
7. For selected examples, see: (a) M. Winkler, Y. S. Raupp, L. A. M. Köhl, H. E. Wagner and M. A. R. Meier, Macromolecules, 2014, 47, 2842–2846; (b) W. Chen, Z. Jing, K. F. Chin, B. Qiao, Y. Zhao, L. Yan, C.-H. Tan and Z. Jiang, Adv. Synth. Catal., 2014, 356, 1292–1300.
8. (a) W. Keim, J. Herwig and G. Pelzer, J. Org. Chem., 1997, 62, 422–424; (b) B. Sreedhar, M. A. Reddy and P. S. Reddy, Synlett, 2008, 1949–1952.
9. (a) M. F. Browne and R. L. Shriner, J. Org. Chem., 1957, 22, 1320–1322; (b) I. H. Pitman, E. Shefter and M. Ziser, J. Am. Chem. Soc., 1970, 92, 3413–3417.
10. (a) M. J. Tilby, D. F. Dewez, L. R. E. Pantaine, A. Hall, C. Martínez-Lamenca and M. C. Willis, ACS Catal., 2022, 12, 6060–6067; (b) X. Wang, M. Yang, W. Xie, X. Fan and J. Wu, Chem. Commun., 2019, 55, 6010–6013; (c) X.-Q. Chu, H. Meng, X.-P. Xu and S.-J. Ji, Chem.–Eur. J., 2015, 21, 11359–11368; (d) Y. Yang, L. Tang, S. Zhang, X. Guo, Z. Zha and Z. Wang, Green Chem., 2014, 16, 4106–4109; (e) M. Fernández, U. Uria, L. Orbe, J. L. Vicario, E. Reyes and L. Carrillo, J. Org. Chem., 2014, 79, 441–445; (f) Z. Jin, J. Xu, S. Yang, B.-A. Song and Y. Robin Chi, Angew. Chem., Int. Ed., 2013, 52, 12354–12358; (g) A. Bhunia, S. R. Yetra, S. S. Bhojgude and A. T. Biju, Org. Lett., 2012, 14, 2830–2833.
11. (a) E. Drège, J. Oko, P.-E. Venot, N. Gigant and D. Joseph, RSC Adv., 2015, 5, 96720–96724; (b) Z. Amara, G. Bernadat, P.-E. Venot, P. Retailleau, C. Troufflard, E. Drège, F. Le Bideau and D. Joseph, Org. Biomol. Chem., 2014, 12, 9797–9810; (c) Z. Amara, E. Drège, C. Troufflard, P. Retailleau, M.-E. Tran Huu-Dau and D. Joseph, Chem.–Eur. J., 2014, 20, 15840–15848; (d) Z. Amara, E. Drège, C. Troufflard, P. Retailleau and D. Joseph, Org. Biomol. Chem., 2012, 10, 7148–7157.
12. For reviews, see: (a) K. C. Bharadwaj, RSC Adv., 2015, 5, 75923–75946; (b) P. Xie and Y. Huang, Eur. J. Org Chem., 2013, 6213–6226; (c) C. E. Aroyan, A. Dermenci and S. J. Miller, Tetrahedron, 2009, 65, 4069–4084.
13. N. Gigant, E. Drège, P. Retailleau and D. Joseph, Chem.–Eur. J., 2015, 21, 15544–15547.
14. D. Prat, O. Pardigon, H.-W. Flemming, S. Letestu, V. Ducandas, P. Isnard, E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani and P. Hosek, Org. Process Res. Dev., 2013, 17, 1517–1525.
15. For a review, see: P. Singh, A. Anand and V. Kumar, Eur. J. Med. Chem., 2014, 85, 758–777.
16. For a review, see: M.-Z. Zhang, Q. Chen and G.-F. Yang, Eur. J. Med. Chem., 2015, 89, 421–441.
17. For a review, see: T. Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal and S. W. Krska, Chem. Soc. Rev., 2016, 45, 546–576.
18. The sulfonated scaffold 3da was isolated in a 56% yield after purification by flash column chromatography.
19. N. K. Jana and J. G. Verkade, Org. Lett., 2003, 5, 3787–3790.
20. M. J. Tilby, D. F. Dewez, L. R. E. Pantaine, A. Hall, C. Martínez-Lamenca and M. C. Willis, ACS Catal., 2022, 12, 6060–6067.
21. M. Fernández, U. Uria, L. Orbe, J. L. Vicario, E. Reyes and L. Carrillo, J. Org. Chem., 2014, 79, 441–445.
22. A. Bagno, S. J. Eustace, L. Johansson and G. Scorrano, J. Org. Chem., 1994, 59, 232–233.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3ra08675e

---