Zinc Catal Yzed Amide Dehydration And Selective Halogenation Of Aromatic Amines

Cyanogen are important functional groups in organic synthesis.Moreover,cyanated compounds frequently find applications in the synthesis of many products such as dyes,herbicides,drugs and materials.Cyanogen can be easily transformed into numerous functional groups（FGs）,such as amines,aldehydes,amides or other carboxylic acid derivatives.In addition,the cyano group can be used as a leaving group,with some conversion being achieved by cleavage of the C-CN bond.Therefore,the organic scientists have been paying attention to obtain nitrile compounds.Obviously,nitriles can be prepared in numerous ways,the dehydration of primary amides is one of the most fundamental methods for the synthesis of nitriles.Traditionally,this transformation has been performed in the presence of strongly acidic dehydrating reagents,such as P₂O₅,POCl₃,so that the compatibility of functional groups is limited,and a large amount of acidic or alkaline wastes are generated,which causing some pressure on environmental protection.Hence,the development of safer and cheaper dehydrating agents remains of interest.Aryl halides are broadly utilized to construct complex structures in organic syntheses,Moreover,they are important structural motifs in many natural products and synthetic drugs.However,previous halogenations of arenes,such as direct electrophilic halogenations and halogenations of aryldiazonium salts,which are generally bear some disadvantages,including low regioselectivity as well as tedious procedures.Thus,new methods that can selectively construct C-X groups are of importance.We mainly completed the synthesis of cyano groups by amide dehydration,and explored the selective chlorination of aromatic amines.The research contents are as follows:（1）Zinc catalyzed the dehydration of amidesOn the basis of previous work,this paper used non-precious metal Zn Br₂as catalyst,industrial waste polymethylhydrogensiloxane（PMHS）as dehydrating agent,and catalytic amount of propyl phosphoric anhydride（T3P）as additive.It was fortunate that the dehydration of amide compounds were achieved.The yield is as high as 93%.A variety of aromatic and aliphatic nitriles were synthesized in moderate to excellent yields straightforwardly.Notably,functional groups such as pyridyl,trifluoromethyl,nitro,alkenyl groups could be well tolerated.The systerm of Zn Br₂and T3P can be successfully applied to achieve the gram-scale reaction of cinnamamide.The key intermediates for the treatment of hypercalcemia drug Cinacalcet were synthesized by this method.To gain more insight in this process,preliminary mechanistic studies were performed for the reaction of benzamide based on³¹P NMR measurements.And,it was found that T3P interact with Zn Br₂.The cooperative effect of Zn salts and T3P enabled dehydration of silane molecules.（2）Selective halogenation of aromatic aminesOn the basis of previous work,we used N-chlorosuccinimide（NCS）as the halogen source and Zn（OTf）₂as the catalyst to achieve selective chlorination of a series of aromatic secondary amines.For the aromatic secondary amines with different substituents,used this method can be successfully obtain ortho-chlorinated products.The selectivity is good and the system is simple without additives,and the reaction can be completed in a very short time.This method not only avoids the use of expensive metals,but also avoids the use of metal chloride as a halogen source.