By means of phosphites and other compounds containing P-H bonds

Dialkyl phosphites react with (hydroxymethyl)amines, giving a-amino phosphonic esters the same products can often be obtained by reaction of the phosphite with aminals, Schiff bases, or an aldehyde plus an amine321 (cf. page 708). Free phosphorous acid can itself be a-aminoalkylated in an acid medium, when according to the amine selected (ammonia can also be used) up to three methylenephosphonic acid groups can be attached to one nitrogen atom 322 

Nitrilotris(methylenephosphonic acid) (11 n = 3) 322 Ammonium chloride (17.8 g, 0.33 mole), crystalline phosphorous acid (82 g, 1 mole), water (100 ml), and concentrated hydrochloric acid (100 ml) are heated together to the boiling point in a flask fitted with a thermometer, stirrer, reflux condenser, and dropping funnel. 37% aqueous formaldehyde (160 ml, 2 moles, 100% excess) is added dropwise during 1 h and the whole is heated under reflux for a further hour. When the solution is then kept overnight most of the product crystallizes. Collection, washing with aqueous acetone, and drying at 120° affords it (74.9 g, 75%) with m.p. 210-215°. Concentration of the mother-liquor provides a second fraction. 

Hypophosphorous acid can also be aminoalkylated in the absence of mineral acid, (aminomethyl)phosphorous acids (12) are formed but in the presence of acid the second P-H group can also be substituted with formation of bis(aminomethyl)-phosphonic acids 323 

Secondary phosphine oxides324 and sulfides325 can be aminoalkylated to the tertiary compounds. 

The alkyl halides used in the Michaelis-Becker reaction (cf. page 728) may be replaced by other alkylating agents such as dialkyl sulfates326 or alkyl sulfonates 295,327 even the use of carboxylic esters for alkylation of sodium dialkyl phosphites is the subject of a patent.328 It is noteworthy that p-toluene-sulfonates often have advantages over alkyl halides in that alcohols are readily converted into these esters and, further, that the p-toluenesulfonate ion liberated, being a weak nucleophile, causes fewer side reactions. Alkyl p-toluene-sulfonates rank between alkyl chlorides and bromides in their reactivity towards sodium dialkyl phosphites.286 p-Toluenesulfonates of secondary alcohols give poor yields of phosphonate. 

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