Clean and Economic Synthesis of Alkanesulfonyl Chlorides from S-Alkyl Isothiourea Salts via Bleach Oxidative Chlorosulfonation

A current eFirst paper by Jiaxi Xu et al. published in Synthesis DOI: 10.1055/s-0033-1338743 describes a simple and synthetically practical method to produce alkylsulfonyl chlorides from an alkyl chloride, bromide or mesylate.

Many of the previous methods for the formation of sulfonyl chlorides, such as the Reed reaction, have been referenced by Xu in his paper, but from these methods it is generally accepted that S-alkyl isothiourea salts are considered as easily accessible, inexpensive, and green starting materials.

The oxidative chlorosulfonation transformation of S-alkyl isothiourea salts into sulfonyl chlorides can be achieved by using many different reagents such as chlorine gas, H2O2–HCl, KMnO4/HCl, HCl-treated silica gel with PhIO and NaClO3/HCl. Xu has previously published the use of N-chlorosuccinimides and NaClO2  as the oxidative chlorinating reagents under acidic conditions but it was thought that the use of house-hold bleach would simplify product purification and be more atom efficient (scheme 1).



Table 1 describes some of the early optimisation of the oxidative chlorosulfonation step. Xu suggest that to achieve the best results the bleach should be titrated to know the actual concentration of NaClO.



S-alkyl isothiourea salt 2a was not entirely soluble in water and so would contaminate the product 3a when it was isolated by filtration.  By adding diethyl ether to the reaction highly pure 3a could be isolated and the amount of undesired hydrolysed product was reduced. With these newly optimised reaction conditions Xu synthesised a range of alkyl and benzyl sulfonyl chlorides in very good yields (Table 2).



To show that this chemistry was scalable Xu preformed a reaction on a 50 mmol scale and achieved a 96% yield over the 2 steps (scheme 2).

scheme 4


A mechanism similar to that proposed by Xu for his NCS/HCl oxidative chlorosulfonation has been postulated (scheme 3). In mild acidic aqueous solutions a chlorinium ion will be formed which is able to transform the S-alkyl

isothiourea salt into alkylsulfonyl methanimidamide salt 4 by 2 chlorination oxidation steps. 4 is then hydrolysed to sulfinic acid 5 which is subsequently oxidised to sulfonyl chloride 3.



This synthesis of alkylsulfonyl chlorides presented by Xu represents a cheap, simple and scalable method. With the use of bleach as the oxidant and without the need for any chromatography this method is one of the more environmentally friendly processes to produce alkylsulfonyl chlorides.



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