Studies On The Formation Of Acyl C-S/C-O Bonds Via Amide C-N Cleavage

Amide groups are widespread in both natural and synthetic world,and are the basic structural units in peptides and proteins.Many drug s are also amides.Amides are very stable;it is difficult to selectively break the amide C-N bonds.The key challenge associated with their transformations is the high stability originated from the n _N to?*_C=O conjugation.In recent years,the development of catalytic cross-coupling reactions of aromatic carboxylic acid derivative amides has attracted considerable attention,and many reliable methods for constructing C-C and C-heteroatom bonds have been developed.There are two main methods for activating amide bonds:the one is to instal strong electron-withdrawing groups(Ph,Ts,Boc,etc.)onto the nitrogen atom of the amides,which can weaken the strength of the C-N bond to activate the amide bond.This method generally requires transition metals such as Ni,Pd,Rh,etc.Howe ver,the high price of transition metal catalysts and the residue of the heavy metals in products greatly limit their application.Moreover,those methods are only applicable to the activated amides.Another one uses strong acids or bases to break amide bo nds.This method generally requires harsh reaction conditions and requires an excessive amount of nucleophiles to improve the yield.Therefore,it is very challenging to break the amide bonds,especially the unactivated ones under the mild and metal-free conditions.This article is devoted to the studies on the activation of amide bonds under the metal-free conditions.The specific research content and results are as follows:(1)A reaction of breaking activated amide C-N bonds to construct C-S bonds was developed.The reaction can be completed by using a catalytic amount of K₂CO₃(10 mol%),avoiding the use of expensive transition metals and excess amount of bases.Under the reaction conditions,both aromatic and aliphatic amides reacted readily with thiols to obtain thioesters.Aliphatic thiols with functional groups(such as cyclohexyl,Si(OEt)₃,NHC(O)t-Bu groups)can also react very well,providing corresponding products in high yields.It is worth mentioning it is easy to obtain acylthioesters with NH₂ groups,which could hardly be obtained by the old nucleosubstitution.This reaction can take place efficiently under metal-free and air-atmospheric conditions,and provides a facile and practically useful approach to the synthesis of valuable acyl thioest ers.(2)A reaction of breaking unactivated amide C-N bonds to construct C-O bonds was developed.Amide C-N bond is activated and split by acid and iodide co-catalysis,this reaction does not require the use of largely over-stoichiometric alcohols and enables esterification of a wide range of unactivated tertiary amides including the most inert N,N-dimethyl aliphatic ones with broad functional group tolerance.Scale-up experiments and modification of biologically active substrates also highlight the potential application of this strategy.This reaction not only solves the long-standing challenge in the catalytic activation of unactivated amide bonds,but also enables the further use of amides as valuable building blocks in organic synthesis.