Aminophosphonates reactions

Simple esters cannot be allylated with allyl acetates, but the Schiff base 109 derived from o -amino acid esters such as glycine or alanine is allylated with allyl acetate. In this way. the o-allyl-a-amino acid 110 can be prepared after hydrolysis[34]. The Q-allyl-o-aminophosphonate 112 is prepared by allylation of the Schiff base 111 of diethyl aminomethylphosphonates. [35,36]. Asymmetric synthesis in this reaction using the (+ )-A, jV-dicyclohex-ylsulfamoylisobornyl alcohol ester of glycine and DIOP as a chiral ligand achieved 99% ec[72]. 

Symmetrical cyclic triazines (masked imines) have been used in reaction with diethyl trimethylsilyl phosphite to provide phosphonates bearing silyl-substituted a-aminophosphonates.349... 

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. 

Scheme 8.4 RCM reaction leading to cyclic fluorinated aminophosphonates.

This three-component coupling of a carbonyl, an amine and a hydrophosphoryl compound leads to a-aminophosphonates. The Kabachnik-Fields Reaction is very important in drug discovery research for generating peptidomimetic compounds. 

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 ... 

A more detailed discussion of the mechanism of the Kabachnik-Fields reaction, its synthetic potential and the biological activity of the a-aminophosphonates. 

The reaction of functionalized iminium salts 4 derived from aziridines with trimethylphosphite gives aminophosphonates 11 by a Michaelis-Arbuzov rearrangement. This reaction is general(6 ). 

With those derived from U-oxazolines and orthoaminophenols, depending on the reaction conditions, linear or cyclic aminophosphonates of type 11 or 12 are obtained. 

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)... 

The proposed mechanism for this catalytic asymmetric hydrophosphonylation is shown in Figure 35. The first step of this reaction is the deprotonation of dimethyl phosphite by LPB to generate potassium dimethyl phosphite. This potassium phosphite immediately coordinates to a lanthanoid to give I due to the strong oxophilicity of lanthanoid metals. The complex I then reacts (in the stereochemistry-determining step) with an imine to give the potassium salt of the a-aminophosphonate. A proton-exchange reaction affords the product... 

Croft et al. [15] reported significant increases in kt when iron was chelated by DTPA, ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), and several aminophosphonic acids. Compared to aqueous Fe2+, increases in /cj from 1000-fold to 50,000-fold were indicated. They also note that DTPA inhibits reaction (3). Graf et al. [10] suggest that reaction (3) is completely inhibited by DTPA, EHPG, phytate, and desferal. These two studies are not entirely consistent in their findings, possibly due to the... 

Croft S, Gilbert BC, Smith JRL, Stell JL, Sanderson WR. Mechanisms of peroxide stabilization. An investigation of some reactions of hydrogen peroxide in the presence of aminophosphonic acids. J Chem Soc Perkin Trans 1992 2 153-160. 

The first three steps show that the reaction sequence in Figure 14.45 actually provides a widely applicable approach to such a-aminophosphonic acids. The step leading to the acyl azide F, i.e., the nitrite oxidation of an acyl hydrazide (Formula C in Figure 14.45), is as commonly used for the preparation of an acyl azide synthesis as that shown in Figure 14.44. 

The lanthanide triflate remains in the aqueous phase and can be re-used after concentration. From a green chemistry viewpoint it would be more attractive to perform the reactions in water as the only solvent. This was achieved by adding the surfactant sodium dodecyl sulfate (SDS 20 mol%) to the aqueous solution of e.g. Sc(OTf)3 (10 mol%) [145]. A further extension of this concept resulted in the development of lanthanide salts of dodecyl sulfate, so-called Lewis acid-surfactant combined catalysts (LASC) which combine the Lewis acidity of the cation with the surfactant properties of the anion [148]. These LASCs, e.g. Sc(DS)3, exhibited much higher activities in water than in organic solvents. They were shown to catalyze a variety of reactions, such as Michael additions and a three component a-aminophosphonate synthesis (see Fig. 2.44) in water [145]. 

The most successful asymmetric variants of the Abramov reaction employ chiral substrates, either chiral carbonyl compounds or aldimines, or chiral phosphorus(III) reagents.5,51,86,88 However, the Pudovik reaction using chiral catalysts is a superior route for the asymmetric synthesis of a-hydroxy- and a-aminophosphonates (Section 6). 

Chiral P-Hydroxy-a-Aminophosphonic Acids. An enan-tioselective synthesis of substituted dihydrooxazolin-4-yl phos-phonates was reported by the reaction of an aldehyde with a-isocyanomethylphosphonate ester catalyzed by (i )-(5)-(l) (eq 12). The enantiomeric purity of the product was determined by P H NMR spectroscopy using the chiral solvating reagent (.S)-(+)-2,2,2-trifluoro-l-(9-anthryl)ethanol. Independently, an asymmetric synthesis of ot-aminophosphonic acids was reported using the chiral ferrocenylamine catalyst (R)-(S)-(3) (eq 13). ... 

Aminoalkyl and Related Acids. - Further development of the classical three component approach to aminoalkylphosphonates (the Kabachnik-Fields reaction) has been reported. The reaction of aldehydes, hydroxylamines and dimethyltrimethylsilyl phosphite using lithium perchlorate/diethyl ether as a catalyst gives N-trimethylsilyloxy-a-aminophosphonate derivatives. The catalytic activities of various lanthanide triflates as well as indium trichloride have been examined for the Kabachnik-Fields type reactions of aldehydes, amines and the phosphorus nucleophiles HP(0)(0Et)2 and P(OEt)3 in ionic liquids. TaCb-Si02 has been utilized as an efficient Lewis acid catalyst for the coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce a-... 

A method for the stereoselective synthesis of a-aminophosphonates and their N-hydroxy derivatives by aminophosphonylation of carbohydrate and amino acid derivatives using nitrone- based chemistry has been reported (an example of reactions of N-monoprotected a-amino nitrones, whose progenitors were alanine, phenylalanine and leucine respectively, affording the corresponding N-hydroxy a-aminophosphonates, is given in Scheme 67). ... 

Conformationally constrained a-Boc-aminophosphonates (387), (388) (389), (390) and (391) were made via a transition metal catalysed Curtins rearrangement. The conformational constraint involved either a ring-closing metathesis reaction catalysed by the first generation Grubbs catalyst or intramolecular cyclopropanation mediated by Rh2(OAc)4 (Figure 66). ... 

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