3-Aryl-2-azidopropanoic acids in cycloaddition reactions

Abstract

3-Aryl-2-azidopropanoic acids and their derivatives were studied in the [3+2] and [2+2] cycloaddition reactions. New heterocyclic scaffolds of 3-aryl-2-(1 H -1,2,3-triazol-1-yl)propanoic acids, [1,2,3]triazolo[1,5-a]pyrazin-6(7 H )-one and [1,2,3]triazolo[1,5-a]pyrazine-4,6(5 H ,7 H )-dione were obtained. α-Azidoacids and their derivatives are convenient precursors in the synthesis of drug-like compounds. The azido group can be used as a protected amino group or a precursor of the 1,2,3-triazole ring as a bioisostere to amide moiety. α-Azidoacids are synthetically available and can be easily obtained in diazotransfer reactions from the corresponding α-aminoacids or during the anionic Meerwein arylation of acrylates. In view of this, we decided to investigate them in 1,3-dipolar cycloaddition reactions in order to obtain new compounds for the study of their biological properties. 3-Aryl-2-azidopropanoic acids were investigated in 1,3-dipolar cycloaddition reactions to alkynes. The interaction of acids 1a,b with diethyl ester acetylenedicarboxylic acid 2 under Huisgen cycloaddition (metal free) resulted in the formation of 3-aryl-2-triazolylpropanoic acids 3a,b with good yields. The presence of compounds 3 of carboxyl and ester groups makes them convenient precursors for further heterocyclizations. On the example of 3-aryl-2-triazolylpropanoic acid 3b we have shown the possibility of obtaining [1,2,3]triazolo[1,5- a ] pyrazine rings. The acid 3b was converted by the action of oxalyl chloride to the corresponding acid chloride 4b , the latter in the reaction with isobutylamine under heating led to the formation of a bicyclic derivative 5b . Another synthetic approach to obtaining [1,2,3]triazolo[1,5- a ]pyrazines is the intramolecular cyclization of propargylamides of 2-azidoacids. To implement this approach, we obtained from 3-aryl-2-azidopropanoic acids 1c-f the corresponding propargyl amides 7c-f through intermediate chlorides 6c-f . Reflux of amides 7d,e in toluene for 24 h allowed to obtain the target [1,2,3]triazolo[1,5- a ]pyrazines 8d,e with low yields. We investigated 3-aryl-2-azidopropanoic acid chlorides 6c,f under the conditions of the [2+2]cycloaddition reaction with Schiff bases. However, in contrast to unsubstituted azidoacetic acid chloride, the interaction of acid chlorides 6c , f with Schiff bases 9a,b in the presence of triethylamine as a base at –20 o C did not lead to the formation of azetidinones 10 . The main reaction products were amides 11a,b . Thus, 3-aryl-2-azidopropanoic acids and their derivatives in cycloaddition reactions were investigated. A number of new functionalized 1,2,3-triazole and [1,2,3]triazolo[1,5- a ]pyrazine derivatives were synthesized. The obtained substances can be used for further modifications, and are of considerable interest for medical and pharmaceutical chemistry. Keywords: 3-aryl-2-azidopropanoic acids, alkynes, 1,3-dipolar cycloaddition, 1,2,3-triazoles, [1,2,3]triazolo[1,5- a ]pyrazines.