Polycyclic phosphonic acid derivatives obtained by a [4þ2] cycloaddition strategy using phosphonodienes Elise Villemin a , Koen Robeyns a , Raphael Robiette a , Marie-France Herent b , Jacqueline Marchand-Brynaert a, * a Universit e catholique de Louvain, Institute of Condensed Matter and Nanosciences (ICMN), Molecules, Solids and Reactivity (MOST), Place Louis Pasteur 1, Boîte L4.01.02, 1348 Louvain-la-Neuve, Belgium b Universit e catholique de Louvain, Louvain Drug Research Institute (LDRI), Avenue Mounier 73, B-1200 Bruxelles, Belgium article info Article history: Received 16 July 2012 Received in revised form 14 November 2012 Accepted 16 November 2012 Available online 23 November 2012 Keywords: 1-Phosphonodienes DielseAlder reaction Phosphonic acid HornereWadswortheEmmons reaction Benzyl deprotection abstract A practical route is described for the preparation of 1-phosphono-3(4-di)-substituted-1,3-butadienes based on the HornereWadswortheEmmons (HWE) reaction. Their reactivity in the DielseAlder (DA) reaction with three selected dienophiles is studied and compared to diethyl 1-phosphono-1,3-butadiene. A particular attention is given to the P-deprotection of cycloadducts from dibenzyl phosphonodienes. New phosphonated bicycles and tricycles have been obtained using this HWE/DA reaction sequence. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Our continuous interest in the DielseAlder (DA) reactions of 1- phosphono-1,3-butadiene (1a) leads us to consider 3(4)-alkyl- substituted derivatives to (i) possibly increase the diene reactivity by conformational and electron-donating effects, and (ii) provide an entry into cyclic dienes and consequently into unprecedented polycyclic phosphonated DA cycloadducts. Different methods are described in the literature for the prep- aration of 1-phosphono-3-alkyl-1,3-butadienes. Generally they use multistep synthesis giving low overall yields and/or mixtures of regioisomers. Phosphochloration reaction, 1 modification of phos- phonoepoxides, 2 transformations of phosphonocyclopropenes 3 are the major routes for the preparation of these dienes. Organome- tallic processes, such as selective reduction of conjugated alkynes by hydride in the presence of In(III), 4 and catalyzed Michae- liseArbuzov reaction on bromodienes 5 are other methods. Lastly, classical MichaeliseArbuzov reaction followed by acetate elimina- tion 6 and addition of dialkyl phosphite on propargyl alcohols and alkynes in the presence of Ni(0) or Pd(II) catalyst 7,8 lead to mixtures of 1-phosphonodienes and 2-phosphonodienes, which are not easily separable. 1-Phosphono-4-alkyl-1,3-butadienes are mainly obtained by isomerization of 1-phosphono-alkynes with Pd(0) catalyst 9 and HornereWadswortheEmmons (HWE) condensation of conjugated aldehydes with methylenediphosphonate. 10 All these methods are generally applied to dimethyl and diethyl phosphonates. The aim of this work is to propose the same strategy for the preparation of 3 and/or 4-substituted 1-phosphono-1,3-butadienes, and to illustrate the reactivity of these dienes in DielseAlder (DA) cycloadditions with three reactive dienophiles, previously identi- fied as good partners towards diethyl 1-phosphono-1,3-butadiene (1a). 11 The access to cycloadducts with a free phosphonic acid group by dibenzyl phosphonate deprotection is also reported. Lastly, the ability of some ethyl phosphonate cycloadducts to coordinate metal cations is illustrated. 2. Results and discussion 2.1. Synthesis of dienes 1aef A limited number of protecting groups of the phosphonate moiety is reported in the current literature for an easy access to free phosphonic acid derivatives. 12 The most common phosphonate ester is the diethyl phosphonate, because it is of practical handling and relative stability. The usual deprotection method 13 using * Corresponding author. Tel.: þ32 10 472746; fax: þ32 10 474168; e-mail address: Jacqueline.marchand@uclouvain.be (J. Marchand-Brynaert). Contents lists available at SciVerse ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tet.2012.11.059 Tetrahedron 69 (2013) 1138e1147