Intermolecular cycloaddition of nonstabilized azomethine ylides generated from 1,3-thiazolidine-4-carboxylic acids: synthesis of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles Ana L. Cardoso, a Agnieszka Kaczor, a,c Artur M. S. Silva, b Rui Fausto, a Teresa M. V. D. Pinho e Melo a, * and Ant onio M. d’A. Rocha Gonsalves a a Department of Chemistry, Coimbra University, 3004-535 Coimbra, Portugal b Department ofChemistry, University of Aveiro, P-3810-193 Aveiro, Portugal c Faculty of Chemistry, Jagiellonian University,Ingardena 3, 30-060 Krakow, Poland Received 12 July 2006; accepted 9 August 2006 Available online 1 September 2006 Abstract—The 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate with nonstabilized azomethine ylides, generated via the decar- boxylative condensation of 1,3-thiazolidine-4-carboxylic acids with aldehydes, afforded 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazole deriva- tives. 2-Substituted-1,3-thiazolidine-4-carboxylic acids led to the stereoselective formation of 5,7a-dihydro-1H,3H-pyrrolo[1,2-c]thiazoles. Quantum-chemistry calculations were carried out allowing the rationalization of the observed stereoselective formation of the anti-dipole. Ó 2006 Elsevier Ltd. All rights reserved. 1. Introduction The observation made by Rizzi that the rate of thermal decar- boxylation of a-amino acids is accelerated in the presence of carbonyl compounds led to the proposal that azomethine ylide intermediates were involved. 1 This type of 1,3-dipole generation has been further explored and became an interest- ing route to nonstabilized azomethine ylides. The work reported by Tsuge and co-workers has shown that the decarboxylative approach to azomethine ylides occurs via the formation of an oxazolidinone intermediate, rather than the direct decarboxylation, followed by carbon dioxide elimination. In fact, N-phenylaminoacetic acid 1 undergoes condensation with paraformaldehyde, under reflux, to give 3-phenyloxazolidin-5-one 2, isolated in quantitative yield. This compound readily eliminates carbon dioxide to give the corresponding azomethine ylide 3, which can be trapped by reacting with dipolarophiles (Scheme 1). 2a Isolation of other N-substituted-oxazolidin-5-ones from the condensa- tion of formaldehyde with a-amino acids has also been reported. 2b Based on the cycloadducts’ stereochemistry, it is possible to conclude that the formation of the 1,3-dipole is stereospecific in many instances, which is in agreement with a process via 1,3-dipolar cycloreversion of the oxazoli- din-5-one intermediate. Cyclic a-amino acids such as 1,3-thiazolidine-4-carboxylic acids can be used for the generation of nonstabilized azo- methine ylides by decarboxylative condensation with carbonyl compounds. The reaction with aldehydes is reported to in- volve the highly stereoselective formation of the anti-dipole, although the subsequent cycloaddition shows little exo/endo selectivity. The nonstabilized ylides can participate in both inter- and intramolecular cycloaddition processes, originat- ing a range of nitrogen heterocycles, including bridgehead NHPh CO 2 H (CH 2 O) n O N O Ph N Ph N Ph - CO 2 1 2 3 4 Δ Scheme 1. Keywords: Azomethine ylides; 1,3-Dipolar cycloaddition; 1,3-Thiazolidine-4-carboxylic acids; 5,7a-Dihydro-1H,3H-pyrrolo[1,2-c]thiazoles. * Corresponding author. Tel.: +351 239 854475; fax: +351 239 826068; e-mail: tmelo@ci.uc.pt 0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2006.08.029 Tetrahedron 62 (2006) 9861–9871