title: Microwave-assisted intramolecular Huisgen cycloaddition of azido alkynes derived from alpha-amino acids.
abstract: The intramolecular version of the Huisgen cycloaddition is a potentially useful reaction for the stereocontrolled preparation of 1,5-disubstituted and 1,4,5-trisubstiututed triazoles. When alpha-azido propargyl esters derived from alpha-amino acids are submitted to [3 + 2] cycloaddition, the expected 4H-[1,2,3]triazolo[5,1-c][1,4]oxazin-6-ones are not formed; rather, an oligomeric cyclic polyester is obtained via a prevailing intermolecular cycloaddition. We have discovered that propargyl alpha-azido amides undergo metal-free intramolecular Huisgen cycloaddition in MeCN/H(2)O under microwave dielectric heating. This reaction provides access to new condensed triazoles that can be considered as conformationally constrained peptidomimetics. Moreover, the following microwave-assisted lactam ring opening provides 1,4-disubstituted and 1,4,5-trisubstituted triazole amino acids. The same kind of compounds are obtained from the ester cycloadduct by reaction with primary amines in the presence of AlMe(3). In order to interpretate this unpredictable behavior, an ab initio study of the reaction pathway was undertaken using GAMESS(US) at the B3LYP/6-31G** level of theory. Different relaxed potential energy profiles were obtained for esters and amides, suggesting that the cis-arrangement of the -CO=N- could account for the amide reactivity.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
authors.forename: Evita
authors.initials: E
authors.lastname: Balducci
authors.forename: Luca
authors.initials: L
authors.lastname: Bellucci
authors.forename: Elena
authors.initials: E
authors.lastname: Petricci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.forename: Andrea
authors.initials: A
authors.lastname: Tafi
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D001386:Azides / Q000737:chemistry; D003500:Cyclization; D008872:Microwaves; D013237:Stereoisomerism; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000480:Alkynes; D000577:Amides; D000596:Amino Acids; D001386:Azides; D014230:Triazoles