Scope and limitations of HClO₄–SiO₂ as an extremely efficient, inexpensive, and reusable catalyst for chemoselective carbon–sulfur bond formation

Abstract

The scope and limitations of perchloric acid adsorbed on silica gel (HClO₄–SiO₂) as a highly efficient, inexpensive, and reusable catalyst for chemoselective carbon–sulfur bond formation by conjugate addition of thiols to α,β-unsaturated ketones under solvent-free conditions and at rt are reported. In the case of 1,3-diphenylpropenone, the reactions were best carried out either at 80 °C under solvent-free conditions or at rt in MeOH. The reaction of aryl, arylalkyl, alkyl thiols, and alkane dithiols with cyclic and acyclic α,β-unsaturated ketones afforded excellent yields of the corresponding β-sulfidocarbonyls after 2 min to 2 h. In the case of dithiols, the bis-thia-Michael adducts were formed. The rate of the reaction was found to be dependent on the electronic and steric factors of the α,β-unsaturated ketones and the thiols. A substituent at the β-carbon of the α,β-unsaturated ketone offered steric hindrance for conjugate addition and such substrates required longer times. In case of aromatic thiols, the presence of the nitro group reduced the nucleophilicity of the sulfhydryl sulfur atom resulting in slower rate of reaction for 4-nitrothiophenol compared to that of thiophenol and 4-methylthiophenol. For alkane thiol, the reaction rate was influenced by the steric crowding of the alkyl group attached to the sulfhydryl moiety. The rate of reaction for alkane thiols was sluggish compared to that of aryl thiols. The influence of the β-substituent on the rate of thia-Michael addition was utilized for selective reaction during inter-molecular competitions of cyclohexen-2-one versus 3-methyl-2-cyclohexenone, cyclohexen-2-one versus 4-methyl-3-penten-2-one, and 4-phenyl-3-buten-2-one versus 4-methyl-3-penten-2-one with thiophenol with 100:0, 91:9, and 70:30 selectivities, respectively. The difference in the rate of reaction of thiophenol and 4-nitrothiophenol was also reflected during the inter-molecular competition for the reaction with cyclohexen-2-one with an excellent selectivity of 100:0. The influence of the steric factor of the alkyl group in alkane thiol resulted in 62:38 selectivity during the inter-molecular competition of ethane thiol and tert-butanethiol with cyclohexen-2-one. During inter- and intra-molecular competitions of thia- versus aza- and thia- versus oxa-Michael addition reactions, chemoselective thia-Michael addition took place. The chemoselective thia-Michael addition over aza-Michael addition during intra-molecular competion reactions with 2-aminothiophenol was utilized for an efficient one-pot synthesis of benzothiazepines.