Aminophosphonates, formation

A. Aminophosphonic Acids.— The Michael addition of a dialkyl phosphite to acrylonitrile leads to C—P bond formation and the production in high yield of derivatives of 2-aminoethylphosphonic acid (45). This synthetic method appears to be preferable to those already described. ... 

Scheme 40 Formation of a-aminophosphonates by a three-component (a) or a two-component (b) route [97]...

Using the optimized system for the two-component reaction, the same group [89] tested the three-component reaction, starting from an aldehyde, an amine and a phosphite (Scheme 42). An orthoester (trialkyl orthoformate, methyl or ethyl) was added to remove the formed water and to promote the imine formation, which was beneficial for the reaction however, these trials afforded maximally 49% yield due to the low conversions and low selectivities towards the desired aminophosphonates. 

Keywords aldehyde, diethyl phosphite, alumina/ammonium formate, microwave irradiation, 1 -aminophosphonate... 

If additional catalysts are used, both acids and bases can have a positive influence on the reaction rate. Sometimes, the chemical yield and the diastereoselectivity of the formation of a-aminophosphonates are higher in two-component systems using preformed imines. In this case, due to the phosphonate <-> phosphite tautomerism, the addition to the imine could occur by either a four- or five-membered transition state ... 

As well as peptide formation the o -aminophosphonous acids undergo the typical amine reactions of amino acids. Further, they can be oxidised to the corresponding aminophosphonic acids without racemisation. For example, oxidation of the (S, R)... 

Electrophilic Azidation of (Chiral) Phosphorus-Stabilized Carbanions. Formation of Optically Active a-Aminophosphonic Acids... 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

A modification of the standard procedure for the formation of a-aminophosphonic acids from Schiff bases allows a one-pot procedure by employing a tertiary benzyl group for protection purposes, readily removable by treatment with acid the method (Scheme 9) is thus potentially useful for the preparation of aminophosphonic acids possessing reduction-sensitive groupings. 

The mechanism of this reaction is believed to involve formation of an activated imine by the ionic liquid so that addition of the phosphite is facilitated to give a phosphonium intermediate, which then undergoes reaction with the water generated during the formation of the imine to give the a-aminophosphonate and methanol (Fig. 12.45). 

Other derivatives of 1-phenylethylamines include the urea 10, which is used in the preparation of chiral aminophosphonic acid (Section D.8), and which is formed by the action of potassium isocyanate on the amine 1 and (S)-JV-phenylethylhydroxylamine 11, used for the formation of chiral nitrones for 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.)15. 

By the reaction of the camphor enolate with 1,2-di(chloromethyl)benzene, a borneol derivative 26 with a spiro substituent in position 3 was obtained21 25. It has been used in the form of a sulfonic ester for silylation of carbanions (Section D.9.) and for the enantioselective formation of aminophosphonic acids25. 

The additions of dialkyl phosphites and secondary phosphine sulphides to Schiff bases have been used to prepare a-aminophosphonates and tertiary phosphine sulphides, respectively. Trialkyl phosphites react readily with (AT-phenylbenzimidoyl)formic acid (25) to give the phosphonate (26) and the formate (27). Alternative mechanisms, both involving initial... 

In work aimed at elucidating the mode of pyridoxal mediated dephosphonylation of a-aminophosphonic acids, it was found that simple aminophosphonates reacted with pyridoxal to form Schiff bases, which complexed copper(II) ions, but did not react further. In contrast, o-hydroxyphenylphosphaglycine did react with pyridoxal at 40 °C with the formation of pyridoxamine, along with o-hydroxybenzoylphosphonic acid on the one hand (equation 45), and salicylaldehyde and H3PO4 (not shown) on the other. Apparently, the presence of the -hydroxy group is necessary for the success of the reaction, presumably by complexing the copper ion in the fashion indicated. The formation of 6>-hydroxybenzoylphosphonic acid illustrates the capability of a-aminophosphonic acids to participate in transamination (similarly to amino acids), while salicylaldehyde is the result of dephosphonylation (analogous to decarboxylation). 

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... 

The above-mentioned reactions give nearly quantitative yields of aminophosphonates and avoid the formation of water entirely. The analogous reaction of dialkyl H-phosphonates with... 

Amino-l-cyclohexylmethylphosphonic acid diethyl ester was utilized for the preparation of hapten 1, recently employed to induce the first monoclonal catalytic antibodies capable of catalyzing peptide bond formation[97]. The key steps of the synthesis of 1 include (a) preparation of scalemic a-aminophosphonate, (b) generation of the p-nitrobenzyl ester, (c) installation of a suitable second phosphonate ester linkage, (d) M-acylation with glutaric anhydride. 

Theoretical studies of the hydrolysis of methyl phosphate anion have found that the dissociative mechanism involving the formation of metaphosphate is favoured over the associative mechanism involving a pentacoordinated intermediate.Phytic acid, myo-inositol hexakis(dihydrogen phosphate) (127), was completely hydrolysed to inositol in an aqueous polybasic alcohol at 150 °C a reaction mechanism was proposed. The reactions of p-nitrophenyl diethyl phosphate (128) and ethyl p-niuophenyl ethylphosphonate (129) with a wide range of oximate ions (p/(a = 7-13) in 10% aqueous ethanol at 25 °C have been studied. For oximate ions with p a 9.0, the reactivity of the oximes tends towards that of alcoholate ions and their Q -effect disappears (as had been previously shown with / -niuophenyl acetate). The reason for this is the unfavourable solvation effects of the solvent. A review (253 references) has appeared on the synthesis and reaction of Q -aminophosphonates. ° ... 

Table 9-11. Inhibition of scale formation by different aminophosphonic acids.

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