The Synthesis Of Novel Methyl/Deuteromethyl Sulfonium Salt Reagents And Their Application

The "magic methyl effect" plays an important role in medicinal chemistry.The methyl group is one of the most important substrate groups found in organic compounds.Although often regarded as an inert group,it can effectively modulate the biological activity and physical property of the molecule,thereby altering the pharmacological effects of drug candidates.In case of d₃-methyl group,the kinetic isotope effect of deuterium makes the bond energy of C-D bonds stronger than that of C-H bonds.“Deuterium switch” in drug candidate molecules can improve biological properties,such as metabolic pathway,pharmacokinetics,and pharmacodynamics.In fact,traditional methylation reagents（such as methyl iodide and methyl trifluoromethanesulfonate）are often carcinogenic and volatile,which limited their application value to a certain degree.Therefore,developing new efficient methylation methods has been of great research value and scientific significance.Herein,we synthesized a series of novel methyl/deuteromethylsulfonium salt reagents by interrupted Pummerer reaction,and explored their application scopes.These reagents were prepared in one step,and the protocol features for easy separation and good scalability.Such sulfonium based reagents were bench-stable and displayed good thermal stability.A series of O-,N-,S-,Pnucleophilic substrates readily reacted with these regents under mild conditions to afford various alkylated products in good yields and selectivities.For d₃-methylation with same set of substrates,good D-incorporation level（95%-99%）were still observed.Moreover,this protocol could be successfully employed for late-stage modification of complex natural products and bioactive molecules,further demonstrating its potential application value.Mechanistic studies ruled out the possibility of dimethyl carbonate and methyl triflate as the active species in this methylation reaction.