Methylenebisphosphonates reactions

Phosphonates and related compounds, which can subsequently be used in the Wittig-Homer reaction (see Section 6.5), are readily alkylated in good yield (Table 6.8) [67-71], Mono-alkylation is observed with mildly basic conditions at 45°C [67] and dialkylation under stronger basic conditions at 60°C [70], Reaction of a,to-dihaloalkanes with phosphonocarboxylates leads to cycloalkylphosphonates [72], The methylenebisphosphonate reacts in a similar manner. 

The first examples of supercharged nucleotide analogues (85-87) have been described, in which methylenebisphosphonic acid containing an additional ioni-sable acidic function has been incorporated into p,y-bridged derivatives of adenosine triphosphate. The compounds and their protected precursors were obtained following acid-catalysed reaction of the respective precursors (88-90) with adenosine 5 -phosphoromorpholidate in pyridine in yields of 80,75 and 25%. 

As in all Michaelis-Arbuzov and Michaelis-Becker reactions, the usual order of decreasing reactivity at the carbon-halogen bond, I > Br > Cl > F, applies with carbon-fluorine bonds tending to be unreactive, other than in exceptional circumstances. Even for diiodomethane, the most reactive dihalomethane, reactions with trialkyl phosphites can be made to yield esters of (iodomethyl)phosphonic acid (11 R = O-alkyl, R = alkyl, n=, X = I or in the presence of more phosphite ester, the methylenebisphosphonic ester 12... 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

Reactions between amines and phosphonic dichlorides may not always proceed in the expected manner in spite of the (supposed) high reactivity of the latter phosphonic dichlorides can be expected to react in a stepwise fashion with amines (at least with secondary amines, but complications may arise with primary amines), but the displacement of only one chlorine atom occurs in a reaction between prop-2-enylphosphonic dichloride and diethylamine " . The methylenebisphosphonic tetrahalides 579 (Z = O or S, X -X = Cl Z = S, X -X" =F) react with Me2NH is a stepwise fashion with the replacement of the halogen atoms in a symmetrical, rather than an unsymmetrical, way but a similar reaction between 579 (X -X" = Cl, Z = O) and RNH2 (R = PR or Bu ) yield the 1,3,4-azadiphosphe-tidines 580 as mixtures of cis and trans isomers. ... 

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