New approaches to the preparation of halogenated methylenediphosphonates, phosphonoacetates, and malonates

Abstract

Smiles Rearrangement and O-Methylation of IIIc.-A solution of 160 mg of IIIc in 10 ml of Claisen alkali was allowed to stand for 10 min, acidified, and extracted with chloroform to give a partially rearranged product. The rearranged mixture was dissolved in 10 ml of tetrahydrofuran and stored for 24 hr at 5°with excess ethereal diazomethane. Evaporation of excess reagent and solvent gave a material which upon preparative thin layer chromatography in cyclohexane-ethyl acetate (1:1) gave 60 mg of a more polar compound identified as estra-l ,3,5(10)triene-2,3,11/3,17/3-tetrol 2-(2-benzoyl-4-nitro)phenyl ether 3methyl ether (IVa) [nmr 3.70 (s, 3-OCII3), 4.73 (m, H-lla)] and 28 mg of a less polar material identified as the isomeric 2methyl ether 3-(2-benzoyl-4-nitro)phenyl ether IVb [nmr 3.66 (s, 2-OCH3), 4.55 (m, H-lla)]. Neither of the two compounds could be obtained crystalline.2.3-Dihydroxyestra-l,3,5(10)-triene-l 1,17-dione 3-Methyl Ether (Vc).-To a solution of 30 mg of IVa in 10 ml of acetone Jones reagent was added dropwise until the orange-brown colorpersisted. The mixture was allowed to stand for 20 min at room temperature, poured into water, and extracted with chloroform. Following evaporation of the solvent, the noncrystalline product Va was homogenous according to thin layer chromatography in cyclohexane-ethyl acetate (1:1). A solution of the above oil in piperidine was refluxed for 2 hr and cooled, benzene was added, and the reaction mixture was washed well with 5% sulfuric acid. Drying and evaporation of solvent gave 8 mg of a semisolid Vc which crystallized from methanol: mp 135-140°; [a]n +129.7°; nmr 0.93 (s, C-18 CII3), 3.86 (s, 3-OCII3), 6.57 (s, H-l), and 6.62 (s, H-4).

Controlled monohalogenation of phosphonates

“…[10,11] There are several methods for the preparation of monohalogenomethylenediphosphonates. They include: a) the partial reduction of dihalogenated methylenediphosphonates [11][12][13][14][15][16][17] developped mainly for the chloro and bromo derivatives; b) the unselective electrophilic halogenation of metalated methylenediphosphonates [18][19][20][21] studied with all four halogens; c) the electrophilic phosphorylation (SNP(V)) of lithiated halogenomethylphosphonates [2,3,22,23] applied to fluoro-and chloro-derivatives; d) the self-condensation of lithiated dihalogenomethylphosphonates [7,22,[24][25][26] carried out with fluoro-and chloro-derivatives ; e) the Michaelis-Arbuzov reaction of trialkyl phosphites with diethyl dichloromethylphosphonate. [27] There are no known methods for the selective conversion of methylenediphosphonates to monohalogenated methylenediphosphonates by a common route to the four halides.…”

“…Diethyl bromomethylenediphosphonate (5b),[11,12] pale yellow oil; decomposes on distillation; crude yield 1.72 g (94 %); 31 P-NMR (CDCl3), δ: 13.4 (s); 1 H-NMR (CDCl3), δ:1.27 (t, 12H, 3 JHH=7.0, CH3CH2O), 3.81 (t, 1H, 2 JPH=17.0, CHBr), 3.91-4.35 (m, 8H, CH3CH2O);13 C-NMR (CDCl3), δ: 16.7 (d, 3 JPC=2.6, CH3CH2O), 29.9 (t, 1 JPC=142.2, CHBr), 64.7 (d, 2 JPC=11.9,…”

A Facile Approach for the Synthesis of Α -Halogenated Alkylidenediphosphonates by Reaction of Alkyllithium With Chlorophosphate and Halogen Reagent

“…5 Additionally, α-halogenated alkylidenediphosphonates result in more active compounds than the parent structure in organic synthesis 1,6-11 and particular biological systems. [12][13] Common methods for the preparation of α-monohalogenated methylenediphosphonates include the partial reduction of dihalogenated methylenediphosphonates, 14 [23][24][25][26] Developing general methods for the preparation of elaborated methylenediphosphonates, especially those tolerating substituents such as alkyl group or halogen atom on the α-carbon position is of great interest. The successful application of LDA process for the synthesis of α-lithiated alkylidenediphosphonates has confirmed its efficiency in the synthesis of alkylidenediphosphonates and (E)-vinylphosphonates with a considerable degree of stereoselectivity.…”

Synthetic Applications of Dialkyl (Chloromethyl)phosphonates and N,N,N‘,N‘-Tetraalkyl(chloromethyl)phosphonic Diamides

“…The same result can be achieved by reduction with NaSH at approximately 0 °C, although reductions are particularly sensitive to the nature of the phosphonate esters. Yields are also closely dependent on the reaction temperature used, for example, lower temperatures are required for ethyl esters (0 °C, 91% yield; 25 °C, 49% yield) than for isopropyl (0 °C, 84% yield; 25 °C, 94% yield) . This dehalogenation reaction was also performed by using Na 2 SO 3 as the reducing agent. 94c,d A recently introduced procedure is the selective electrochemical reduction of one chlorine atom of tetraethyl dichloromethylenebisphosphonate, which has been accomplished in 70% yield using a buffered medium…”