Methylenebisphosphonates alkylation

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. 

Addition of alkyl and aryl amines to carbonylbisphosphonates, which could afford a new route to a-amino methylenebisphosphonates if the imine reduction proceeds normally and competing fragmentation chemistry does not pose severe problems, is currently under investigation in our laboratory. 

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... 

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