Benzylation of morphinandienes and new aspects of their acid-catalyzed rearrangement to new aporphines Attila Sipos * , Sa ´ ndor Bere ´ nyi Department of Organic Chemistry, University of Debrecen, PO Box 20, H-4010 Debrecen, Hungary article info Article history: Received 21 February 2008 Received in revised form 4 April 2008 Accepted 17 April 2008 Available online 22 April 2008 Keywords: Morphinan-5,8-dienes 5b-Substitution 6-Demethoxythebaine Acid-catalyzed rearrangement abstract The benzylation of thebaine and 6-demethoxythebaine resulted in different product mixtures. Expla- nations were given for both the observed differences in the ratio of 5b- versus 7-benzyl products and the deviation of the electronic structure of ring C of 7-benzyl products. The acid-catalyzed rearrangement of morphinan-5,8-dienes, 5,6- and 6,7-disubstituted morphinan-6,8-dienes was achieved and mechanistic interpretations for the formation of new, potentially dopamine-active aporphines were provided. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Thebaine (1) is the pharmaceutically most important, naturally occurring morphinan-6,8-diene, as it is used in the synthesis of a variety of opioid receptor agonist and antagonist compounds utilized as major alternatives in the treatment of severe pain and the management of drug dependence. 1 Besides this application, 1 is also an excellent starting compound to potent dopamine agonists such as N-propyl-2-fluoronorapomorphine via its acid-catalyzed rearrangement and further transformation. 2 The structure of thebaine (1) is frequently referred to as morphinandiene, as the chemically most interesting ring C of the morphinan backbone contains a conjugated diene motif, disregarding the fact that there is not only one type of morphinandiene. Maat et al. first reported the successful isolation and characterization of morphinan-5,8- diene structure. 3 It was the 7-methyl congener 2 that was formed in the 5-methylation reaction of 6-demethoxythebaine (3) under classic conditions elaborated by Gates and his colleagues (Fig. 1). 4 The methanesulfonic acid-mediated rearrangement of mor- phinan-6,8-dienes into apocodeines was investigated by Neu- meyer’s and Bere ´nyi’s groups (Scheme 1). 5 The 5b-substitution has remained one of the frequently applied and well-studied subjects of morphinan chemistry; recent appli- cation of 5b-substituted derivatives was reported for the prepara- tion of d-selective opioid agonists. 6 Coop and his co-workers 7 investigated the relationship between the spatial size of the elec- trophile partner and the change in the ratio of conventional 5b- substituted versus 7-substituted products. On the basis of their previous observations regarding the formation of 5b-trimethylsi- lylthebaine with the conventional procedure, they applied alkyl- arylsilyl chlorides with gradually increasing steric size to test the N O OCH 3 H 3 C 1, 3-8 X Y CH 3 SO 2 OH OH OCH 3 9-15 X Y N H 3 C H X Y 1, 9 OCH 3 H 3, 10 H H 4, 11 Cl H 5, 12 Br H 6, 13 F H 7, 14 H Cl 8, 15 H Br Scheme 1. Acid-catalyzed rearrangement of morphinan-6,8-dienes. N O OCH 3 OCH 3 H 3 C 1 morphinan-6,8-diene structure N O OCH 3 H 3 C 2 morphinan-5,8-diene structure H 3 C H 2 3 10 5 6 7 8 14 1 9 Figure 1. The structure of morphinandienes. * Corresponding author. Tel.: þ36 52 512900/22473; fax: þ36 52 512836. E-mail address: asipos@puma.unideb.hu (A. Sipos). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.04.069 Tetrahedron 64 (2008) 5851–5860