Unexpected rearrangement of gem-bisphosphonates as Michael-type acceptors.

SZAJNMAN, SERGIO HERNÁN; GARCÍA LIÑARES, GUADALUPE; MORO, PABLO; RODRIGUEZ, JUAN BAUTISTA

Canela, RS, Brasil

Congreso; 11th Brazilian Meeting on Organic Synhesis; 2005

The Brazilian Chemical Society

INTRODUCTION   Bisphosphonic acid derivatives exhibit a wide range of pharmacological actions. These compounds have been used in the treatment of bone disorders1 and also proved to be potent growth inhibitors of several pathogenic trypanosomatids.2 Bearing in mind the relevance of these drugs; it was decided to study the chemical behavior of tetraethyl ethenylidene bisphosphonate (1) and its epoxy derivative tetraethyl oxiranylidenebisphosphonate (2) as Michael-type acceptors.   RESULTS AND DISCUSSION   The reaction of 2 with a variety of Grignard reagents led to the unexpected rearranged product 3 regardless of the nature of the organometallic compound. The same results were obtained when either n-butylmagnesium bromide, allylmagnesium chloride, n-pentylmagnesium bromide or n-hexylmagnesium bromide were employed (Scheme). The reaction consists of a phosphonate-phosphate rearrangement that involves migration of a diethoxyphosphinyl group from a carbon atom to an oxygen atom.3   Scheme. Reaction of 2 with Grignard reagents.   Mechanistic studies were carried out and evidences that the reaction occurs through paramagnetic species are given. When the reaction mixture was reacted at room temperature for an extended period of time, the main products were identified as the diethyl alkyl phosphates derivatives, in which the source of the alkyl group was the Grignard reagent. Compound 1 behaved as a good Michael acceptor for sulfur- and oxygen-containing nucleophiles and the expected 1,4-addition products were obtained. In addition, 2 was reacted with alcoxides at room temperature, showing an unusual rearrangement that lead to diethyl 2-alkoxyethyl phosphonates. Moreover, the reaction of 2 with sulfur-containing nucleophiles was extremely encouraging. When 2 was treated with potassium thiocyanate the main isolated compound was once again the rearranged product 3 instead of the expected thiirane.   CONCLUSION   It can be concluded that while 1 has the ability to react as a typical Michael acceptor with a variety of nucleophiles, the epoxy derivative 2 suffers a very interesting and unusual phosphonate-phosphate rearrangement that leads to the enol phosphate 3 regardless of the nature of the nucleophile. Strong evidences to support a radical mechanism in the reaction of 2 with several Grignard reagents are given. This reaction is a significant novelty about a phosphonate-phosphate rearrangement reaction of an epoxy derivative of gem-bisphosphonates to produce an enol phosphate.   ACKNOWLEDGMENTS   We thank Fundación Antorchas, the National Research Council of Argentina, and the Universidad de Buenos Aires for financial support.       [1] G. A. Rodan, T. J. Martin, Science 2000, 289, 1508–1514. 2 S. H. Szajnman, B. N. Bailey, R. Docampo, J. B. Rodriguez, Bioorg. Med. Chem. Lett. 2001, 11, 789–792. 3 R. Gancarz, I. Gancarz, A. Deron, Phosphorus, Sulfur and Silicon 2000, 161, 61–69.