Selective Synthesis of Ortho-substituted 3-Cyclohexyl-2-phenyl-1,3-thiazolidin-4-one Sulfoxides and Sulfones by S-Oxidation with Oxone

Abstract

Abstract1,3-thiazolidin-4-ones, also known as thiazolidin-4-ones, are known to have a very wide range of biological activity. The corresponding S-oxides may show enhanced activity, and therefore viable synthetic routes to these S-oxides are required. S-oxidation of 3-cyclohexyl-2-phenyl-1,3-thiazolidin-4-ones with Oxone ® was investigated. For all compounds evaluated, selective oxidation to the sulfoxide was realized using 3 equivalents of Oxone ® at room temperature. Alternatively, the sulfone was prepared selectively at high temperature by increasing the equivalents of Oxone ® used; the extent of this selectivity was affected by the substituent of the aromatic ring. In those cases in which the reaction produced a mixture of the sulfoxide and sulfone, the ratio of the products was quantified by 1 H NMR.

Selective Synthesis of Substituted 3-Aryl-2-phenyl-1,3-thiazolidin-4-one Sulfoxides and Sulfones by S-Oxidation with Oxone

“…The effect of the substituents' electronic properties on yield somewhat mirrored previously reported oxidations of the 2-aryl-3-cyclohexyl-1,3-thiazolidin-4-ones with Oxone ® , which also showed the highest sulfone selectivity for OCH 3 and NO 2 substituents (Cannon et al, 2015). The highest sulfone selectivity was observed for p-OCH 3 substituted compound 1m (>12:1 sulfone:sulfoxide).…”

“…Results are summarized in Table 1. Oxidation of 1e at extended reaction times showed no sulfone formation by 1 H NMR at periods as long as 25 h. Clearly, low temperature oxidation with a reduced number of Oxone ® equivalents favors sulfoxide formation as was previously observed for the 3-cyclohexyl-thiazolidin-4-ones (Cannon et al, 2015). Scheme 3.…”

“…(Surrey, 1948) This method was applied to compounds 1a-1o to produce the corresponding sulfones (Scheme 6); results are summarized in Table 3. Although no measures were taken to optimize this reaction, the oxidation yields are overall significantly higher for the 3-aryl-2-phenyl-1,3-thiazolidin-4-ones (average yield=76%) versus 2-aryl-3-cyclohexyl-1,3-thiazolidin-4-ones (average yield =56%) previously synthesized by this method (Cannon et al, 2015).…”

“…Compounds 1a-o were oxidized according to the high temperature Oxone ® -based reaction conditions that had been previously optimized for 2-aryl-3-cyclohexyl-1,3-thiazolidin-4-ones (Cannon et al, 2015) to determine if selective formation of sulfones could be realized according to the substituted N3 aromatic ring (Scheme 5). Results are presented in Table 2.…”

“…We have previously reported the reaction of ortho-substituted 2-aryl-3-cyclohexyl-1,3-thiazolidin-4-ones with Oxone ® . (Cannon et al, 2015) For all ten compounds previously evaluated, selective oxidation to the sulfoxide was realized using 3 equivalents of Oxone ® at room temperature, and subsequent oxidation to the sulfone was not observed under these reaction conditions after 25 hours. Alternatively, the sulfones were prepared with variable selectively at higher temperature (refluxing aqueous methanol) by increasing the equivalents of Oxone ® used to 8.…”