A catalyst-free, efficient and selective synthesis of asymmetric diarylsulfones

The synthetic potential of the catalyst-free reaction of arylstannanes and sulfonyl chlorides, for the generation of asymmetric diarylsulfones, is described. Moreover, the efficiency of the reaction is improved using diarylstannanes as starting substrates. All the reactions studied went, exclusively, through an ipso-substitution and give acceptable yields of sulfones from aryl sulfonyl chlorides supporting either electronreleasing or electron-attracting substituents. A special work up is carried out in order to recover the diand trialkyltin chlorides generated as subproducts.


Introduction
Over the years, sulfones have emerged as interesting synthetic goals because they are valuable intermediates in organic synthesis 1 as well as important building blocks in biologically active compounds. Specially, aryl sulfones are found in several drugs, for example, in powerful inhibitors of enzymes 2 and for leprosy treatment. 3 The usual procedures for their preparation are the oxidation of the corresponding sulfides 4 and the sulfonylation of suitable arenes. 5 Nevertheless, their scope of application is limited by the availability of sulfides and by the substituent-directing effects and the reactivity substrate requirements, respectively. On the other hand, the metal-mediated crosscoupling reactions between sulfinic acid salts and aryl derivatives (halides and triflates) are milder alternatives for the synthesis of arylsulfones. 6 These reactions tolerate many functional groups but they imply the use of air or moisture sensitive reagents.
In recent years, we have been involved in searching new routes for the synthesis of arylstannanes 7 and we have focused on these substrates as valuable and easily accessible reagents in C-C bond forming reactions through catalyst-free processes.
Thus, we have performed new procedures for the regiospecific mono-, bi-and triaroylation as well as hindered alkanoylation of aromatic rings 8 based on the special reactivity of arylstannanes, a consequence of the exceptional leaving group ability of the trialkyltin group in electrophilic aromatic substitutions. 9 On the basis of our previous work and considering the importance of sulfones, we investigated the feasibility of the catalyst-free reaction of arylstannanes with sulfonyl chlorides as a synthetically useful route for the preparation of asymmetric diarylsulfones. Now, we are pleased to report the synthetic potential of this pair of reagents as well as the special work up carried out in order to recover the di-and trialkyltin chlorides generated (see experimental section).

Results and Discussion
We synthesized a series of electronically diverse starting trialkylarylstannanes (1a-f) and we studied their reactivity towards commercially available sulfonyl chlorides 2a and 2b ( Fig. 1), under the optimized reaction conditions we have previously established, that is, in ortho-dichlorobenzene (ODCB) as solvent, at 180ºC. 8b The reactions were followed by TLC until disappearance of starting stannane.  The results obtained (Table 1) show that the arylstannanes reacted efficiently with both sulfonyl chlorides providing the corresponding diaryl sulfones in good isolated yields (44% to 65%) after relatively short times (2 to 6 h). The reactions proceeded with arylstannanes supporting either electron releasing or electron withdrawing groups; they were regioselective and went, exclusively, through an ipso-sulfonyldestannylation independently whether the directing influences of the aryl substituents and the trialkylstannyl group are either matched (compound 1a) or mismatched (compounds 1b-f). Even the known high para-directing force of OMe group could be completely overcompensated (compound 1b). Also, experiment 1 shows that substrate 1a, where the influence of the substituent and the trialkyltin group are matched, reacted in a shorter reaction time (2 h). The high ipso-directing force shown by trialkylstannyl groups is probably due to the β-effect of the tin atom which makes easier the cleavage of an aryl group from the tin via an electrophilic ipso-substitution. 10 Experiment 6 shows that the more sterically hindered arylstannane 1f gave sulfone 3f in good yield (61%) after only 3 h, probable due to the fact that the electrophilic attack of arylstannanes is accelerated by the existence of neighboring groups on the arene system. 11 It should be mentioned that in all the experiments that we have carried out, it has been detected the presence of protodestannylation products, probably this being due to the presence of small amounts of HCl that could not be eliminated from the sulfonyl chloride. These protodestannylation products are irrelevant (3% to 9%) compared with the yields of the diarylsulfones obtained.
In order to improve the efficiency of these reactions we considered interesting to study the possibility of transferring more than one aryl group attached to tin. For this purpose, we applied the protocol to the reaction of sulfonyl chloride 2 with dibutyldi(mtolyl)stannane, as model system. After 4 h the starting stannane was consumed (TLC) and sulfone 3ca was obtained in a good isolated yield (68%, referred to the stoichiometric equation

Conclusions
In conclusion, the method provides a facile and specific access to a wide range of asymmetric diarylsulfones via arylstannanes. The method is attractive due to the availability, air-and moisture-stability of arylstannanes, as well as their compatibility with a variety of functional groups. Moreover, the transfer of two aryl groups from tin reduced the amount of non-benign organotin subproducts. The difficulties connected with organotin removal were largely solved in the workup and, in addition, these byproducts were recovered and not rejected.

General experimental methods
The reactions were carried out under dry nitrogen in heavy walled Schlenk tubes fitted with a teflon plug valve. Sulfonyl chlorides were commercially available and fractionally distilled under nitrogen before use. Aryltributylstannanes 1a-e and dibutyldi(m-tolyl)stannane were prepared by transmetallation of the appropiate Grignard reagents with tributyltin chloride in anhydrous THF. Aryltrimethylstannane 1f was obtained from the corresponding commercial aryl chloride by photostimulated reaction with Me 3 SnNa in liquid ammonia, according to the literature procedures. 13

Tributyltin chloride
After flash chromatographic procedure (10.0 g of 40-63 µm silica gel for 1.00-mmol scale reaction) the column was eluted with 100 mL of THF. The silica was dried using compressed air and poured into a 100-mL round-bottomed flask fitted with a condenser and a nitrogen T-joint. Sodium chloride (293 mg, 5.00 mmol) and 50 mL of dry THF were added and the mixture was heated at reflux with stirring for 4 days. It is then allowed to cool and poured into a chromatography column plugged with a small piece of cotton wool. All of the THF was drained with air pressure and then the column was eluted with ether (2 × 50 mL). The combined ethers were concentrated in vacuo giving tributyltin chloride in ca. 80 % with respect to the starting aryltributylstannane.

Dibutyltin dichloride
After workup of the reaction carried out with dibutyldi(m-tolyl)stannane, the resulting cloudy organic phase (∼5 mL for 1.0 mmol scale) was centrifuged. The amorphous offwhite sediment of (Bu 2 SnO) n was washed twice by centrifugation with DCM and reserved for its further conversion in Bu 2 SnCl 2 . 17