Experimental and theoretical evidences of 2-aza-Cope rearrangement of nitrones Pedro Merino, * Toma ´s Tejero and Vanni Mannucci Laboratorio de Sintesis Asimetrica, Departamento de Quı ´mica Orga ´ nica, Instituto de Ciencia de Materiales de Aragon, Universidad de Zaragoza, Consejo Superior de Investigaciones Cientificas, E-50009 Zaragoza, Aragon, Spain Received 14 February 2007; revised 8 March 2007; accepted 12 March 2007 Available online 15 March 2007 Dedicated to professor Miguel Yus on occassion of his 60th birthday Abstract—Both the intramolecular cycloaddition of diastereomeric homochiral N-alkenyl nitrones and the corresponding theoret- ical calculations using DFT and ab initio methods provided evidences of a thermal [3,3] sigmatropic rearrangement of the nitrones with a complete chirality transfer. Ó 2007 Elsevier Ltd. All rights reserved. The aza-Cope rearrangement is a well-known [3,3] sig- matropic process which can take place with a variety of substrates containing a nitrogen atom in their struc- ture. 1 Depending on the position of the nitrogen the rearrangement is identified as a n-aza-Cope process (n = 1, 2 or 3), 2 the 3-aza-Cope reaction being the more studied. 3 The 2-aza-Cope rearrangement has been reported mainly taking place with iminium salts. 4 The synthetic utility of the reaction has been widely demonstrated. 4,5 In the case of nitrones, the possibility of a 2-aza-Cope rearrangement has only been suggested (see Scheme 1). 6 Although in one instance it was possible to isolate a rearranged nitrone as a side-product, 7 the actual inter- mediate was an iminium salt formed in situ. Up to now it has not been demonstrated the existence of a 2- aza-Cope rearrangement with nitrones. In this commu- nication, we report, for the first time, experimental evi- dences of a 2-aza-Cope rearrangement of nitrones based on the use of homochiral compounds. Also, a the- oretical study of the process has allowed to locate the corresponding transition structure for the [3,3] sigma- tropic rearrangement agreeing with the experimental findings. Readily available homoallylhydroxylamines 1 8 are use- ful building blocks for the construction of a variety of nitrogen-containing compounds. 9 In the course of our research directed to the synthesis of enantiomerically pure nitrogen-containing products 10 we envisaged com- pounds 1 as suitable starting materials for the prepara- tion of 6-substituted 4-hydroxy pipecolic acids. 11 The key step of the approach consisted of the intramolecular cycloaddition of N-alkenyl nitrone 2, obtained from the corresponding hydroxylamine 1a by MnO 2 -mediated oxidation. 12 The (Z)-configuration of nitrone 2 was assigned by 1D NOE experiments and unequivocally established by X-ray crystallography. Heating nitrone 2 in a sealed tube at 100 °C in toluene for 72 h afforded a mixture of compounds 4, 5 and 6 in a 75:5:20 ratio, respectively. 13 The configuration of all cycloadducts was unequivocally assigned by NMR including COSY, ROESY, and HSQC 2D experiments, and in the case of major adduct 4 an X-ray analysis confirmed its exo/ exo configuration. Whereas the obtention of compounds 4 and 5 from nit- rone 2 was expected according to the stereochemical 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.03.071 Keywords: Nitrones; Intramolecular dipolar cycloaddition; 2-Aza- Cope rearrangement; DFT methods. * Corresponding author. Tel./fax: +34 976 762075; e-mail: pmerino@ unizar.es Scheme 1. Tetrahedron Letters 48 (2007) 3385–3388