Study On The Synthetic Methods Of N-heterocycles From α-aminoamides

In the past century,N-heterocycles have become an important class of organic compounds that have attracted much attention and been studied by many researchers.This is mainly due to their widespread presence not only in natural products,but also as core units of plenty of drugs.So far,N-heterocycles have been widely used in medicine,pesticides,materials as well as other fields,and have had a profound and long-lasting impact on our life.Therefore,the research of N-heterocycles is no longer limited to extraction and separation from organisms or performance testing.It has developed into a new stage of complex molecular designation,chemical synthesis,and structure-activity research.Based on the viewpoints of organic synthetic methodologies,there are two main protocols for the synthesis of N-heterocycles.One of them can be achieved by modifying the N-heterocyclic rings through organic conversion,and another one can be realized by construction of the skeleton of N-heterocycles from acyclic precursors.However,some of the established synthetic methods still have problems such as difficulty in obtaining raw materials,multiple steps,harsh reaction conditions,poor selectivity,low yield,and so on.Therefore,in order to overcome the limitations and shortcomings of various methods,it is of great significance to develop facile and efficient synthetic methods of N-heterocycles.Among them,the development of simple,efficient,and mild condition reactions for the synthesis of N-heterocycles based on acyclic precursors is still an active research field in organic synthetic chemistry.In summary,we have conducted investigations on the synthetic methods of N-heterocycles based onα-aminoamides,and achieved the following research results:1.A series of α-bromo-1,3-dicarbonyl compounds had been prepared from N-bromosuccinimide(NBS)and 1,3-dicarbonyl compounds.In the presence of NaOEt,α-bromo-β-oxoamides underwent nucleophilic substitution reactions with various amines.The products were α-amino-β-hydroxy-2-enamides,α-amino-βoxo-amides or their enol-keto tautomeric mixture.This transformation featured commercially available starting materials,mild reaction conditions,simple execution and good yields.Through the above work,we had developed a facile and efficient method to the synthesis of α-aminoamides.In addition,the synthesizedα-aminoamides with flexible substituents provided a wealth of precursors for the following investigations.2.We had achieved a facile and efficient synthesis of pyrrolin-4-ones via tandem[2+1+2]annulation and 1,2-alkyl migration reactions of α-bromo-βoxoamides and primary amines in the presence of NaOEt.It was found that the intramolecular hydrogen bonding activation was crucial for this transformation,and the novel protocol could be successfully expanded to tandem[2+3]annulation and 1,2-alkyl migration of α-bromo-β-oxoamides with α-arylamino-β-oxo-amides and their enol-keto tautomeric mixture for the synthesis of pyrrolin-4-ones with more flexible substituent patterns.The simple execution and commercially available starting materials made this protocol an attractive synthetic route to pyrroline-4-ones.3.We had developed a highly chemoselective method for divergent synthesis of polysubstituted 2-acyl-lH-indoles and 2-carbomyl-1H-indoles from a series ofα-arylamino-β-hydroxy-2-enamides via two different electrophilic activation strategies,which had been successfully expanded to α-arylamino-β-oxo-amides and their enol-keto tautomeric mixture.The salient feature of this protocol was the use of either Hendrickson reagent in combination with triflic anhydride or triflic acid to control chemoselectivity in the intramolecular cyclodehydration.Detailed NMR studies revealed that α-arylamino-β-hydroxy-2-enamides preferentially reacted with Hendrickson reagent and the electrophilic activation occurred in a chemoselective manner on the site of enol moeity rather than amide group of the substrate in the presence of Hendrickson reagent combined with triflic anhydride.In addition,it had been proven that triflic acid played dual roles as a protonating reagent and an inducing reagent for the enol-keto tautomerization reaction of α-aryl amino-β-hydroxy-2-enamides.These findings provided direct evidences for the mechanisms of the chemoselective cyclo-dehydration reactions by which an efficient and predictable approach for the synthesis of indoles with flexible substituent patterns was achieved.The mild reaction conditions,simple execution,excellent yields,high chemoselectivity,and wide range of synthetic potential of the products made this protocol much attractive for academic research and practical applications.