Sulfonium Ylide Mediated Benzylation Reaction Under Weak Acid Conditions For Drug Modification

Benzyl is one of the most commonly used protective groups in the synthesis of drug molecules and complex natural products,which has been widely used in organic synthesis because of its stability,mild deprotection conditions,and compatibility with most other groups.Benzyl groups are generally introduced through the synthesis of Williamson ether under strongly alkaline conditions,while benzylation under acidic conditions is rare.Meanwhile,due to the limitations of the current benzylation methods,such as poor functional group tolerance,inappropriate reaction conditions,low reaction yield and unnecessary byproducts,etc.,it is of great significance to develop an environmental and efficient benzylation method with wide applicability of substrates and mild reaction conditions for the synthesis of drug molecules and complex natural products.In this paper,a new benzylated reagent with Sulfur Ylide structure was developed:4-Nitrophenyl bis(carboethoxy)benzylylide,which was a kind of yellow crystal that can be stably stored at room temperature.The preparation process was efficient,economical and environmental friendly.The benzylating reagent could be used for the benzylation of a variety of substrates under weak acidic conditions,and had a wide range of applications in alkyl alcohols,mercaptans,thiophenols,acids,sugars,amines and even some drug molecules.The conditions of the benzylation were also very mild,and a number of acid or base sensitive perssads(silicyl,acyl,etc.)are well tolerated.The mechanism of the benzylated reaction was also described in detail.The presence of the active intermediate Bn OTf was clearly demonstrated by NMR monitoring of the activation process of thiophilide.Sulfur Ylide was first activated to form sulfur salts under acidic conditions,which were degraded to Bn OTf at room temperature due to its unstability,followed by the reaction of Bn OTf with substrates to achieve the corresponding benzylated functional groups.The reaction went through a process similar to S_N1 and was reversible.In summary,we have developed a benzylated method involving sulfur Ylide under weak acidic conditions,which had a broad range of substrates and could be used in the synthesis and modification of some drug molecules successfully.The development of this method will provide a powerful tool for the synthesis of drug molecules and complex natural products.