synthesis of b-hydroxysulfones from styrenes and sulfonylhydrazides : an electrochemical mechanistic study †

Copper(I) halides were used as mediators in the synthesis of b-hydroxysulfones via the oxysulfonylation of styrenes using sulfonylhydrazides. The feature of the developed process lies in the combination of a copper(I) salt with oxygen—the stoichiometric oxidant. Copper(II) species are responsible for the oxidation of sulfonylhydrazides, they are generated in small amounts in the O2/Cu(I)/Cu(II) redox system, which is formed during the reaction. The combination of these three components enables one to obtain in the case of a-methylstyrenes only b-hydroxysulfones and in the case of a-unsubstituted styrenes, bhydroxysulfones as the main products and b-ketosulfones as the by-products. With good yields bhydroxysulfones were prepared by reduction of the reaction mixture containing both products bhydroxysulfones and b-ketosulfones with NaBH4. An electrochemical study revealed that the Cu(I)/Cu(II) pair can serve as an effective mediator of b-hydroxysulfones formation via redox processes.


Introduction
b-Hydroxysulfones are of great interest as structural units of antifungal 1 and antitumor 2 compounds, they are known as intermediates in the synthesis of lactones 3 and unsymmetrical alkenes. 4Traditionally b-hydroxysulfones are obtained through the nucleophilic addition of sulnates to epoxides, [5][6][7][8] reduction of b-ketosulfones 9,10 and hydroxylation of a,b-unsaturated sulfones. 11Over the last few years, several oxidative strategies to prepare b-hydroxysulfones from olens have been established.In these reports air and low thermally stable sulnic acids [12][13][14] in combination with O 2 and PPh 3 (Scheme 1, eqn (1)) 15 or sulfonylhydrazides with O 2 and Fe(III) salts are required.
The latter method was applied for the synthesis of structures containing the b-hydroxysulfone moiety predominantly at a tertiary carbon atom, which cannot be further oxidized (Scheme 1, eqn (2)). 16or the sulfonylation of unsaturated compounds without additional insertion of oxygen into the molecule, a number of oxidants have been exploited: Cu(OAc) 2 , 17,18 CAN, 19 NBS, 20 K 2 S 2 O 8 , 21 peroxides, 22 I 2 /TBHP 23 and TBAI/TBHP 24,25 systems.It is well-known that oxygen is an ideal environmentally friendly oxidant, which offers fascinating industrial and academic prospects.][28][29] In this context, we have disclosed a process for the oxysulfonylation of styrenes utilizing sulfonylhydrazides in the presence of a O 2 /Cu(I) system, leading to b-hydroxysulfones.During the reaction the O 2 /Cu(I)/Cu(II) system is formed with a small amount of Cu(II) as conrmed by the near absence of the specic colour of Cu(II) species.As a result, b-hydroxysulfones 3 as main products and b-ketosulfones 4 as by-products are formed (Scheme 2).

Results and discussion
The synthesis of b-hydroxysulfones 3aa-3fe and b-ketosulfones 4aa-4ab from styrenes 1a-1j with the use of sulfonylhydrazides Scheme 1 Recent works for the oxysulfonylation of styrenes.
2a-2e was conducted in CH 3 CN, CH 3 CN-H 2 O, THF and THF-H 2 O using a O 2 /Cu(I)/Cu(II) redox system.This system was a result of the transformation of CuCl, CuBr and CuI under aerobic conditions (Scheme 2).
Our preliminary studies were focused on the reaction of styrene 1a with sulfonylhydrazide 2a, leading to the formation of 1-phenyl-2-tosylethanol 3aa and 1-phenyl-2-tosylethanone 4aa.We examined the inuence of the Cu(I) salt counter-ion, oxygen source (air oxygen or 98% oxygen) and solvent type (Table 1) on the yield of 3aa.
Entries 1-3 indicated that among the copper(I) halides (CuBr, CuCl and CuI), the use of CuBr afforded the highest total yield of oxysulfonylation products and the yield of the desired product 3aa aer 7 h.When the reaction was performed for a more prolonged time (entry 4) the yield of 3aa reached 38%.Heating the reaction mixture for the rst 7 h to 80 C (entry 5) didn't increase the yield of 3aa.Decreasing (entry 6) or increasing (entry 7) the molar ratio of CuBr per mol of 1a in comparison with the previous entries resulted in a reduced yield of the desired product.Employing CH 3 CN, THF or THF-H 2 O (5 : 1) in place of CH 3 CN-H 2 O (5 : 1) negatively inuenced the reaction efficiency (entries 8-10).In entry 11, air oxygen was replaced with 98% oxygen and as a result the yield of 3aa was improved to 55%, the total yield of oxysulfonylation products in this case reached 91%.Attempts failed (entries 12-14) to increase the yield of desired product through modication of Scheme 2 The oxysulfonylation of styrenes 1a-1j using sulfonylhydrazides 2a-2e (in the codification of 3 and 4 the first letter index refers to the styrene 1 moiety, the second letter index to the hydrazide 2 moiety).the molar ratio of CuBr per mol of 1a, temperature and reaction time when compared to the conditions of entry 11, in which the best result was obtained; the total yield of 3aa and 4aa in these experiments didn't exceed 80%.
With the optimized reaction conditions in hand (entry 11, Table 1), the scope of the copper-mediated oxysulfonylation reaction was investigated.A number of b-hydroxysulfones 3aa-3ab were formed in 32-65% yield with b-ketosulfones 4aa-4ab observed as the by-products of the reaction in 18-33% yield (Table 2).
In all the examples, hydroxysulfone was predominantly formed independently of the properties of the substituents on the benzene ring.In most cases, the molar ratio of b-hydroxysulfone 3/ketosulfone 4 was 2 : 1.][32] That's why in order to transform the b-ketosulfones 4 byproducts into the desired b-hydroxysulfones 3 we ltered the reaction mixture from the CuBr aer the reaction was complete and then carried out the reduction of the ketosulfones using NaBH 4 (Scheme 3).As a result, the desired b-hydroxysulfones 3 were obtained in a 52-89% overall yield over two steps (Table 2 and entries 4, 11, 13, 14 in Table 1).
The oxysulfonylation reaction was also examined by applying of a-methylstyrenes (Table 3).A variety of a-methylstyrenes bearing either electron withdrawing or electron donating substituents on the aryl ring worked well under the conditions of entry 11 (Table 1) and the target b-hydroxysulfones were formed in most cases in good yield.It is important to note that in the reactions of methylsulfonylhydrazide with styrene 1a and octene-1 or cyclohexene with sulfonylhydrazide 2a the oxysulfonylation products were not observed in measurable yield.
The structures of all the synthesized hydroxysulfones 3 and ketosulfones 4 were conrmed by 1 H and 13 C NMR spectroscopy, elemental analysis, HRMS and IR spectroscopy.

Proposed reaction mechanism
To study the plausible reaction mechanism, an investigation of the redox properties of oxygen, styrene 1a, p-toluenesulfonylhydrazide 2a and CuBr in CH 3 CN-H 2 O (5 : 1) with the use of cyclic voltammetry (CV) was carried out.Tetrabutylammonium perchlorate was chosen as a supporting electrolyte.The obtained CV curves are shown in Fig. 1.
Table 2 The structure and yield of b-hydroxysulfones 3 and b-ketosulfones 4 a a The yield was determined by 1 H NMR using 1,4-dinitrobenzene as an internal standard; the isolated yield aer reduction with NaBH 4 is reported in the parentheses.Table 3 The structure and yield of b-hydroxysulfones 3 a The oxidizing properties of oxygen are evidenced in reducing at the relatively early potentials, the peak on the CV curve with potential À1.10 V was responsible for its reduction.The chemically irreversible oxidation of styrene 1a takes place in the far region with a maximum at 1.90 V and runs into the discharge of the background.A chemically irreversible peak at 1.35 V was responsible for the oxidation of p-toluenesulfonylhydrazide 2a.Therefore, we can conclude that its oxidation goes rather more easily than the oxidation of styrene.
A chemically and electrochemically reversible peak at E 1/2 ¼ 0.55 V corresponds to the oxidation of Cu(I) into Cu(II), which takes place in the potential range between oxygen reduction and p-toluenesulfonylhydrazide 2a oxidation.This means that under experimental conditions the Cu(I)/Cu(II) couple can serve as an effective mediator of p-toluenesulfonylhydrazide 2a oxidation using oxygen.
On the basis of the obtained experimental data and previous studies of reactions proceeding through the generation of Scentered radicals from sulfonylhydrazides, [33][34][35] we proposed the pathway of the oxysulfonylation process (Scheme 4).2][43][44] An almost colourless solution during the reaction is evidence for a small amount of Cu(II).Aerwards, as a result of the successive oxidation of hydrazide 2a under the action of Cu(II), 16,33,34 oxygen or peroxyradical C, an S-centered tosyl radical A (Ts) is generated, which reacts with styrene 1a to form a C-centered benzyl radical B. 16 In the next step, radical B is trapped with oxygen forming peroxyradical C.][58] The fact that using of octene-1 and cyclohexene as starting reagents didn't lead to the formation of oxysulfonylation products can be explained by the low stability of the C-centered alkyl radical generated aer addition of tosyl radical A to their double bonds.

Conclusions
In summary, we have demonstrated a novel copper-mediated oxysulfonylation of styrenes using sulfonylhydrazides for the synthesis of b-hydroxysulfones in 32-93% yield.In the case of aunsubstituted styrenes, b-ketosulfones are formed as the byproducts.Applying a-methylstyrenes in this methodology gives b-hydroxysulfones as single products in high yield.Moreover, using cyclic voltammetry, experimental data and previous reports, a plausible reaction pathway was proposed.Coupling of two starting reagents proceeds under the action of the O 2 /Cu(I)/Cu(II) redox system.The distinguishing feature of the work lies in the combination of oxygen and a copper(I) salt, which is oxidized to copper(II) on a limited scale, which makes it possible to obtain b-hydroxysulfones as the main products.

Experimental
NMR spectra were recorded on a Bruker Avance II 300 MHz instrument.Chemical shis are measured relative to the residual solvent peaks as an internal standard set to d 7. 25  .IR spectra were recorded on a FT-IR spectrometer.High resolution mass spectra (HRMS) were measured using electrospray ionization (ESI). 59The measurements were carried out in positive ion mode (interface capillary voltage 4500 V); the mass ratio was from m/z 50 to 3000 Da; external/internal calibration was performed using an electrospray calibrant solution.Syringe injection was used for solutions in CH 3 CN (ow rate 3 mL min À1 ).

Treatment of the reaction mixture containing 3aa and 4aa
The solvent was removed under reduced pressure (10-20 Torr).The reaction residue was diluted with a mixture of solvents PE/ CHCl 3 /EA in a volume ratio of 1/2/2 (50 mL) and then ltered from the precipitate using SiO 2 (d ¼ 20 mm, h ¼ 80 mm).The precipitate was washed with a mixture of solvents PE/CHCl 3 /EA in a volume ratio of 1/2/2 (3 Â 30 mL).The combined organic phases were concentrated under reduced pressure (10-20 Torr).The yields of 3aa and 4aa were determined by 1 H NMR using 1,4-dinitrobenzene as an internal standard.

Table 1
Screening of the reaction conditionsThe yield was determined by 1 H NMR using 1,4-dinitrobenzene as an internal standard, the isolated yield aer reduction with NaBH 4 is reported in the parentheses.c 7 h at 40 C, then 12 h at 20-25 C. d 7 h at 80 C, then 12 h at 20-25 C.