Acylphosphonates with amines

An obvious synthetic application of amine addition to the a-keto group in acylphosphonates would be reductive amination. This has been demonstrated [42], and shown to be a useful route to 1-aminoalkylphosphonic acids. Thus, selected acylphosphonates were reacted with benzhydrylamine, giving after reduction of the resulting imine intermediate with triacetoxyborohydride and acid hydrolysis, satisfactory yields of the corresponding aminoalkylphosphonic acids. However, a limitation of this approach is unwanted cleavage of the phos-phonate P-C bond, which was observed with other amines such as benzylamine and a-benzylmethylamine [42]. 

One example of reductive amination of acylphosphonates has been reported. Thus, reaction of dimethyl 1-oxoalkylphosphonates with benzhydrylamine results in the formation of an imine reduced in situ with NalllKOAc),. The reaction is independent of the solvent, and THF, CIFCh and CHCI3 give similar results - After selective removal of the benzhydrylic group by catalytic hydrogenation and hydrolysis with concentrated HCl, the 1 -aminoalkylphosphonic acids are isolated in satisfactory yields (30-60%, Scheme 7.66) ... 

The facility with which the phosphorus-carbon bond in acylphosphonic derivatives is cleaved by the action of the more basic nucleophiles has already been commented upon. Those nucleophiles include alkoxides and amines, but it may be noted that thiols undergo normal addition to the carbonyl group. With regard to the latter, diethyl acetylphosphonate yields the monothioacetals 256 the derivatives may not be stable thermally but their decomposition occurs with cleavage of the phosphorus-carbon bond Reactions between the same substrate and simple carboxamides in the presence of an acid catalyst under dry conditions furnish the acylated enamides 257 ". ... 

Indeed, one of the main uses of j -phosphorylated ketones is the synthesis of C-phos-phorylated heterocyclic systems, and in this respect the reactions very often complement those of isomeric acylphosphonates. In the first of the examples chosen, the ketone 304 cannot be converted into 305 in a direct reaction with the appropriate amine instead, the carbonyl group must be protected as in 307, when a reaction with the amine then gives 308 hydrolysis of 308 with 3 M HCl yields 305. When treated with ZnCl2 under toluene, 305 yields the indolylphosphonic diester 310" In the same way, a direct reaction between 304 and ArONa fails to give 306, which must therefore be prepared via 307 and 309 with acid hydrolysis to 306 when the latter is treated with hot polyphosphoric acid, cyclization occurs to give the benzofuranylphosphonic diester In order to obtain the isomeric... 

Acylphosphonic acids react with pyridoxamine, which is a coenzyme of transaminases, with the formation of a-aminophosphonic acids (see also reductive amination. Section II. C. 4. c) The first step of the reaction is addition of the pyridoxamine to the carbonyl of the acylphosphonate, followed by prototropic rearrangement and hydrolysis to pyridoxal and an aminophosphonic acid (equation 59). This reaction is in contrast with the reverse... 

In contrast to most other nucleophiles (e.g. amines, alkoxides), hydroxylamine and hydrazine derivatives may also react with acylphosphonates as with ketones, and lead to the formation of imines, although these reactions are often accompanied with C—P bond cleavage. The extent of this side-reaction depends on the reagents, reaction conditions and/or the groups linked to the phosphorus. 

Bisphosphonates were prepared and from naturally occurring 1-amino acids [141], In this case, initial protection of the amino acid-amine moiety was required. Insertion of a phosphorus atom was divided into two steps initial reaction with a suitable phosphorus reagent to produce the acylphosphonate, and a second phosphorus attack to form the bis-phosphonate. Since conversion to acid chloride served as the acid activation process, the amine-protecting group had to be either Fmoc or phtaUmide, both of which are stable in acidic conditions. Prolonged reaction times always resulted in partial rearrangement and formation of by-products. 

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