A New Method for Synthesis of Thioethers from Phenyl N-Sulfonamide

: A operationally simple, one-pot for regioselective synthesis of thioether route directly from phenyl N-sulfonamide by using inexpensive, easily handled trimethylsilyl iodide as reducing agent, acetonitrile as the solvent is described. Further no catalyst or additive are required, which avoids contamination from the transition metal catalysts in the products.


Present Work:
In continuation of our ongoing work for the synthesis of 7-Aminomethyl phthalides based fluorescent for the study of Cysteine-Specific Blue Fluorescence Probe 13 , we developed a novel method for the synthesis of thioether 4 by a one-pot reaction by using the commercial available, trimethylsilyl iodide as a reagent in acetonitrile under reflux conditions, where it undergo multiple functional group changes, varies with mole equivalent of TMS-I used in the reaction Scheme-1: When we treated substrate having trifunctional groups, 1 with 1.2 equivalent of TMS-I gives the Phthalimide-7-N-sulfonamide 2 by ester cleavage. In another reaction, the compound 1 on treatment with 2.4 eq of TMS-I, initially formed Phthalimide-7-N-sulfonamide 2 further undergoes desulfonation gives the phthalide-7-methylamine 3. As reported in the literature where TMS-I is used for reductive dimerization of phenyl sulfinic acid sodium salt or phenyl sulfonyl chloride to form the disulfide 11 which go through phenyl sulfenyl radical mechanism. To test whether it is possible to trap the in situ generated phenyl sulfenyl radical by phthalimide-7-methylamine 3 in one pot reaction, we carried a reaction by treating the substrate 1 with excess (8 eq) of TMSI, to generate phenyl sulfenyl radical after desulfonation.
Surprisingly, it gives regio selective product, thioether 4 by C-S bond formation in 30% yield.
The yield is low due to competitiveness between the phenyl sulfenyl radicals (to form dimer) and its reaction with phthalide-7-methylamine 3 to form thioether 4. Independently thioether 4 is obtained treating by 6 equivalents of TMS-I with phthalimide-7-N-sulfonamide 2 in 31% yield.

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To overcome the low yield of thioether 4, we used phenyl sulfonyl chloride as external source, as expected with 2 equivalents of it, the yield is increases to 52%.
In conclusion, this protocol offers a new, versatile, and novel approach for (a) phthalide (2 or Phenyl sulfonyl chloride were used as external source to generate in situ phenyl sulfenyl radicals, which was trapped by electron rich arenes. (d) No catalyst or additive or smelling thiol and exclusion of air are required, which avoided contamination by transition metal catalysts of the product, thioethers 4. We believe that this environmentally friendly method will find wide applications.
General Information: All reagents unless otherwise noted were obtained from commercial sources and used without further purification. The reactions were carried out under an argon atmosphere, and the products were isolated by column chromatography on silica gel (200-300 mesh) by using hexane and ethyl acetate as eluents. Melting points are uncorrected.
Compounds described in the literature was characterized by comparing their 1 H and 13 C NMR spectra and MS data to the reported data. 1 H and 13 C NMR spectra were recorded in CDCl3 and chemical shifts are reported in parts per million relatives to TMS. Low resolution (LR) and High-resolution (HR) mass spectrometry data were acquired on a Bruker Daltonics MicroTOF-Q-II Mass Spectrometer using CH3CN/H2O as solvent.    Wash the combined organic layer with water, 10% NaHCO3, brine, dried over MgSO4 and concentrated to get the residue. Column chromatography purification (elution with 20-30%  -N-(3-oxo-1,3-dihydro-isobenzofuran-4