Entry to γ-Amino-α-bromo-alkenylphosphonates by a Bromination-­Elimination Sequence

Abstract

g-Amino-a-bromo-1-alkenylphosphonates were prepared in a convenient way upon bromination of g-amino-a,b-unsaturated phosphonates followed by elimination of the b-bromine by basic treatment.a-Haloalkenylphosphorus derivatives are an important class of compounds and many research groups have been active in their synthesis, which has been reviewed in detail. 1 Also from a physiological point of view, these derivatives attract a lot of attention. a-Fluorovinylphosphonates have been prepared as intermediates for the synthesis of metabolically stable lysophosphatidic acid derivatives, 2 vinylphosphonates bearing various functional groups have been widely investigated, 3 and organophosphonates have been extensively used as mimics of the corresponding biologically active esters and acids. 4Even though a multitude of papers on a-halovinylphosphonates have been published, the corresponding amino substituted derivatives have not been described to the best of our knowledge. Apparently, this results from the reactivity of amino groups towards halogenated compounds, especially with brominated derivatives, which could lead to extensive self condensation reactions. However, this structural moiety seems interesting in view of the development of structural analogues of fosmidomycin, a promising anti-malarial agent. 5 Here, we want to present a straightforward methodology to prepare on a fairly large scale the g-amino-a-bromo-1-alkenylphosphonates.This paper extends the methodology of the easy and straightforward multigram synthesis of g-amino-a,b-unsaturated phosphonates 2 and 3, which has been published recently (Scheme 1). 6 Via a substitution-elimination sequence of dibromopropylphosphonates 1 with primary amines, the aminophosphonates 2 and 3 could be synthesized in a one-or two-step procedure, depending on the amine that was utilized. Furthermore, these aminophosphonates could be isolated and stored as oxalic acid salts. The aim of the further extension of the methodology was to evaluate the synthesis of azaheterocyclic phosphonates, which are being studied extensively in our laboratory. 7These g-amino-a,b-unsaturated phosphonates were considered to be possible precursors for the synthesis of phosphonylated aziridines or azetidines as they contain a nucleophilic nitrogen atom and a double bond that can provide a suitable leaving group after bromination. In a first attempt to brominate these g-amino-a,b-unsaturated phosphonates 2 and 3, the amino group was protected by treatment with aqueous hydrobromic acid in dichloromethane followed by addition of molecular bromine. Scheme 1After completion of the bromination, which could be monitored by 31 P NMR, the amino function was deprotected using triethylamine, leading to complex reaction mixtures. Several attempts were performed in order to develop a synthesis of phosphorylated aziridines, even in very diluted systems, but all attempts failed. Therefore, an alternative way of N-protection was needed. Since the aminophosphonates could easily be isolated and purified as oxalic acid s...