An imino-Diels–Alder route to meso-2,6-disubstituted-4-piperidones Ana-Bel  en Garc  ıa, Carlos Vald es and Mar  ıa-Paz Cabal * Unidad asociada al CSIC, Instituto Universitario de Qu  ımica Organomet alica ‘Enrique Moles’, Universidad de Oviedo, 33071 Oviedo, Spain Received 23 January 2004; revised 15 March 2004; accepted 31 March 2004 Abstract—A convenient stereoselective preparation of meso-2,6-disubstituted-4-piperidones has been developed by imino-Diels– Alder reaction of 2-amino-1,3-butadienes with imines in the presence of catalytic amount of Cu(TfO) 2 . Ó 2004 Elsevier Ltd. All rights reserved. 1. Introduction meso-Compounds are attractive prochiral materials that can be readily transformed into enantiomerically pure compounds through various desymmetrization pro- cesses. 1 Among them, meso-2,6-disubstituted-4-piper- idones can be regarded a interesting frameworks as precursors of chiral biologically active and natural alkaloids. 2 A research theme in our laboratory for many years has been the study of the imino-Diels–Alder reaction of 2- amino-1,3-butadienes with nonactivated aldimines. This method generally furnishes 4-piperidones with high stereoselectivity. 3 It has been previously shown that this cycloaddition can also be carried out asymmetrically to give adducts in very high enantiomeric excess (Fig. 1). 4 Moreover, this methodology has been applied to the synthesis of alkaloids, 5 structurally diverse pipecolic acid derivatives, 6 and most recently, to solid-phase organic synthesis. 7 However, the requirement of specific substituents on the diene (R 1 ¼ CH 2 OR, R 2 ¼ alkyl) have been limiting the synthetic versatility of the reac- tion. 8 In relation with an ongoing research project in our laboratory, we were interested in synthesizing 4-piper- idones with different substituents at R 1 and R 2 ¼ H. For this reason, we set out to investigate the optimal con- ditions for the imino-Diels–Alder reaction of 2-amino- butadienes unsubstituted at C-3, and the application of this methodology to the synthesis of meso-2,6-disubsti- tuted-4-piperidones. The synthesis of 3-unsubstituted-2-aminodienes 1 and 2 were carried out from commercially available starting reagents as propargyltriphenylphosphonium bromide, morpholine, or N-methylaniline and aromatic aldehydes by a modification of a previous procedure (Fig. 2). 9 The synthetic sequence involves the preparation in situ of phosphorane II by reaction of b-enaminophospho- nium salt I with sodium hexamethyldisilazide followed by a Wittig reaction with aromatic aldehydes affording Keywords: Imino-Diels–Alder; Piperidones; meso-Compounds; Cu(TfO) 2 . *Corresponding author. Tel.: +34-985102990; fax: +34-985193446; e-mail: pcabal@fq.uniovi.es Figure 1. Imino-Diels–Alder reaction of 2-aminodienes. Figure 2. Synthesis of 2-aminodienes. 0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2004.03.195 Tetrahedron Letters 45 (2004) 4357–4360 Tetrahedron Letters