Preparation of Tetraethyl but-3-Enylidene-1,1-Bisphosphonate and Study of Its Reactivity as a Synthon of Tetraethyl 3,4-Diaminobutylidene-1,1-Bisphosphonate

Cyclisation of bisphosphonate substituted enynes

“…Reaction of diethyl but-3-enyl-1-phosphonate with lithium diisopropylamide (LDA) followed by diethyl chlorophosphate gave bisphosphonate 14 in quantitative yield according to a literature procedure (Scheme 3). 12 [It is of note that attempts to synthesise 14 by allylation of tetraethyl methylenebisphosphonate have been reported to give a modest yield (28%), which was attributed to competition between monoalkylation and dialkylation. 12 ] The required propargyl substituent was subsequently introduced as its trimethylsilyl derivative to give the novel enyne 15 in satisfactory yield, given the steric demands of creating a quaternary centre flanked by two phosphonate esters.…”

“…12 [It is of note that attempts to synthesise 14 by allylation of tetraethyl methylenebisphosphonate have been reported to give a modest yield (28%), which was attributed to competition between monoalkylation and dialkylation. 12 ] The required propargyl substituent was subsequently introduced as its trimethylsilyl derivative to give the novel enyne 15 in satisfactory yield, given the steric demands of creating a quaternary centre flanked by two phosphonate esters. Removal of the trimethylsilyl group using tetrabutylammonium fluoride proceeded smoothly to give the desired bisphosphonate enyne 9.…”

“…These gave the novel bisphosphonate alkene 17 and the novel silylated bisphosphonate alkene 18 in 78% and 67% yield, respectively. Finally, cyclisation accompanied by carbonylation (the catalytic Pauson-Khand (11), or under investigation (12,13), for the treatment of diseases characterised by abnormal calcium metabolism. reaction), which has been studied and applied extensively on the malonate substrates 1, the sulfonamide substrate 6 and the ether substrate 7, 16 was examined for the first time on the bisphosphonate substrate 9, leading to the isolation of the novel cyclopentenone 19 in 59% yield.…”

Optimization, Continuation and Lack of the One-Step Diphosphorylation Reaction. Assay of Modification of the Tetraethyl(pyrrolidine-2,2-diyl)bisphosphonate

“…8,16,37 Similarly, when the initial temperature is too low for the reaction to occur or when the amide is frozen, the consequent removal of the cold source induces an exothermic reaction and possibly brings it to boil. In these circumstances, the yield is somewhat low and the presence of polymers can be encountered as it was the case with N-benzylacetamide.…”

“…1 They are known for their various uses: dental (tooth pastes and mouthwashes) [2][3][4] and medical applications (against rheumatoid arthritis, 5,6 for the inhibition of bone resorptive processes such osteoporosis and Paget's disease, 2,[7][8][9] skeletal scintigraphy when combined with 99 Tc, [10][11][12] breast cancer therapy, 13 antiviral, 14,15 anti-inflammatory 16,17 and anti-rheumatismal agents, 18 pain-easing activities, 16 antimoebic 15 ), antibacterial agents, 19 plant growth regulators, 20 herbicides, [21][22][23] pesticides, 19 in the nuclear industry, [24][25][26] flame retardants 21 and 2 chelators in water treatment, 21 etc… Gem-bisphosphonates and gem-bisphosphonic acids can readily form complexes with calcium and magnesium and this behavior is one of the principles sustaining their use as drugs. 3,15 Recently, amino-gem-bisphosphonates have been involved in the conformational study of pyrrolinoxyl radicals 27 and they also work as spin trapping agents relevant to biology.…”