Microwave-assisted intramolecular Huisgen cycloaddition of azido alkynes derived from alpha-amino acids.
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.
Balducci
Evita
E
Dipartimento Farmaco Chimico Tecnologico, Universita degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.
Bellucci
Luca
L
Petricci
Elena
E
Taddei
Maurizio
M
Tafi
Andrea
A
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
D000480:Alkynes; D000577:Amides; D000596:Amino Acids; D001386:Azides; D014230:Triazoles