Phosphonous acids, 1-aminoalkyl

E. (Aminoalkyl)phosphonous Acids [(Aminoalkyl)phosphinic Acids]. 374... 

Phosphoric acid, monoalkyl phosphates, and phosphonic acids, but not dialkyl phosphates (107), can be aminoalkylated on the oxygen (108—110). 

Diaikanol aminoalkyl phenols as admixtures enhance the strength [675]. The additives are useful in very small amounts and do not affect the initial properties of the fluid. The strength additive does not cause set acceleration or early set strength enhancement but provides enhanced compressive strength of the cement in later stages. Addition of small amounts of potassium ferricyanide and nitrile-trimethyl phosphonic acid promotes the formation of complex compounds and thus increases the strength of cement rock [1771]. 

Scheme 21 summarizes further reactions leading to phosphonic acid analogues of amino acids. Treatment of the nitrone (138 R =Me or Pr ) with a dialkyl hydrogen phosphonate (best as the Li derivative which shows greater diastereoselectivity than the Na or K salts), and subsequent steps involving acidolysis of the oximino compound (139) lead to the free (ot-aminoalkyl)-phosphonic acids (140)(phosphonoalanine, phosphonova1ine). 

The addition of compounds of type 3 to C=N double bond systems leads to O-alkyl(aminoalkyl) O-silylphosphonates 9. Monoalkyl esters of aminoalkyl phosphonous acids 10 are formed in excellent yield by solvolysis of 9 [3]. 

The methodology of the catalytic asymmetric aldol reaction has been further extended to the aldol-type condensation of (isocyanomethyl)phosphonates (12) with aldehydes, providing a useful method for the synthesis of optically active (l-aminoalkyl)phosphonic acids, which are a class of biologically interesting phosphorous analogs of a-amino acids (Scheme 8B1.6) [21,22], Higher enantioselectivity and reactivity are obtained with diphenyl ester 12b than with diethyl ester 12a (Table 8B1.6). 

Isocyanomethyl)phosphonate 97 is also a beneficial pronucleophile leading to optically active (l-aminoalkyl)phosphonic acids, phosphonic acid analogs of a-amino acids via tra s-5-alkyl-2-oxazoline-4-phosphonates 98 (E = PO(OPh)2, Sch. 25) [50]. ... 

The gold-catalyzed aldol reaction has been successfully applied to the asymmetric synthesis of (l-aminoalkyl)phosphonic acids, phosphonic analogs of a-amino acids (Scheme 2-57) [80, 81]. The reaction of (isocyanomethyl)phosphonates 65 with... 

The use of phenylphosphonous dichloride in the preceding reactions leads to derivatives of the [(1-aminoalkyl)phenyl]phosphinic acids. Oximes of (1-oxoalkyl)phosphonic acids react with Ph2PCl/Et2N to give l-(diphenylphosphinoyliminoalkyl)phosphonates (166) by spontaneous... 

Optically active (1-aminoalkyl)phosphonic acids have also been obtained using a methodology based on the chemistry of 1,3,2-oxazaphospholidines (Scheme 9). The diastereoisomers (l73 a) and (l73 b) afe separated by column chromatography, then alkylated and hydrolysed to the (S) and (B) acids (174). ... 

Other (4-aminoalkyl)phosphonic acids (181) have been... 

In an investigation into the relative spatial requirements of phosphono and amino groups in (aminoalkyl)phosphonic acids and phosphinic acids vis-a-vis their behaviour towards NMDA, several q-. 

Aminoethyl)phosphonic acid (AEP) has been prepared, together with other (u-aminoalkyl)phosphonic acids, by the borane-Me2S reduction of oo-(dialkoxyphosphiny 1) carboxamides, and also via its N,0,0-tris(trimethylsilyl) derivative (248) obtained from an N-acylaziridine. 

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... 

In planning a general enantioselective route to (l-aminoalkyl)phosphonic acids, French workers originally considered the alkylation of (212) (R = H), but this procedure led to products of only moderate e.e.s. Newer work has now considered the preparation and use of the perhydro-l,4,2-oxazaphosphorine... 

The conversion of (l-aminoalkyl)phosphinic acids into the corresponding (1-guanidinoalkyl)phosphonic acids, e.g. (284), has been carried out as indicated, and the structures of (284) (R = Me, and R = Ph, monohydrate) have been confirmed by X-ray diffraction work. ... 

As an example of developments in the phosphorus-containing peptide field, the syntheses of (285), a tripeptidic (l-hydroxy-2-aminoalkyl)phosphonic acid, and some analogues, have been reported the compound (285) itself is a good inhibitor of human renin. ... 

Further esterification of monobenzyl benzylphosphonate may be carried through the Mitsunobu procedure, the best yields being achieved using the potassium salt of the substrate. Monoesters of iV-protected (1-aminoalkyl)phosphonic acids are further esterified by alcohols in the presence of BOP-type reagents [(l-aminoalkyl)alkylj- and [(l-aminoalkyl)aryl]-phosphinic acids, again as their potassium salts, have been converted into esters by reactive alkyl halides in the presence of 18-crown-6 ether (see also reference The... 

Aminoalkyl phosphonic derivatives examined include (2-amino-1-fluoroethyl)-phosphonic acid [(3-amino-2-hydroxypropyl)methyl]phosphinic acid (guanidinophenylmethyl)phosphonic acid (2-amino-2-phenylethyl)phosphonic acid and (—)-(aminocyclohexylmethyl)phosphonic acid and its Mosher derivative. ... 

With the possible exception of the (diazoalkyl)phosphonic acids, all other functionalized phosphonic acids have, at some stage, been employed as precursors in the synthesis of aminoalkyl phosphonic acids, with various degrees of success many such methods (in the context of Chapter 6, reactions of the precursors) will be considered as syntheses by modification , and reference should be made to the appropriate sections in this or the previous chapter for the preparation of those precursors. 

The situation with regard to the (aminoalkyl)phosphonic acids is, however, completely different. Not only have many (aminoalkyl)phosphonic acids, either in the free state or as derivatives, generally esters, been resolved, but also many synthetic procedures have been adapted for potential asymmetric preferment. The latter will be considered under each individual type of reaction, but it is convenient to consider the problem of resolution separately. 

The monoaminomonophosphonic acids, either in the free state or, very often, as their diethyl esters, have been resolved by the usual techniques of repeated crystallization of appropriate salts those of L-(+)-tartaric acid (2,3-dihydroxybutanedioic acid) or its mono-or di-benzoyl derivativesor of D-(-)-mandelic acid, have been widely employed the use of di-O-benzoylated L-tartaric anhydride, which is based on the separation of diastereoisomeric amides (111), has also been employed to a limited extent. In selected cases, such as the monoaminomonophosphonocarboxylic acids or A -acylated (aminoalkyl)phosphonic acids, resolution following salt formation with organic bases has also been carried out ephedrine, quinine and both enantiomers of l-phenylethylamine have all been used. In many cases, only one enantiomer of the (aminoalkyl)phosphonic acid (or diester) has been isolated in optically pure form. Sometimes, the acidity of the substrate, and hence choice of base for resolution, can be modified by using a mono- (as opposed to di-) ester or (or even in addition to) protection of the amino group as, for example, the phthalimido, benzyloxycarbonyl (cbz) or r r -butyloxycarbonyl (boc) derivative. Resolved di- and mono-esters can be hydrolysed to the free acids under acidic conditions, and A -protection can also be removed through the customary procedures. 

Currently, the most widely practised procedure for the quantitative estimation of diastereoisomeric purity (d.e.) and thus of enantiomeric purity (e.e.) consists in the derivatization of the aminoalkyl phosphonic acid as the A-(3,3,3-trifluoro-2-methoxy-2-phenylpropanoyl) derivative the latter is prepared from (R)-(+)-(3,3,3-trifluoro-2-methoxy-2-phenyl)propanoyl chloride (the so-called Mosher reagent) Although the diastereoisomeric derivatives 123 may also be separable by HPLC (e.g. on Zorbax-Sil) and which can be separately characterized [the derivative from (+)-Val was shown by X-ray... 

In principle, the interaction of a phosphorus(III) ester with an co-haloalkylamine should lead to an (co-aminoalkyl)phosphonic diester or a phosphinic acid analogue (Scheme 11). Such examples in the classical Michaelis-Arbuzov mould have been widely reported, but success in their outcome depends on the relative nucleophilicities of nitrogen and phos-phorus(III) centres towards the displacement of halogen. The interaction of triethyl phosphite and a halogen-substituted tertiary amine, such as 2-chloroethyldiethylamine, does not lead to a phosphonic diester, and in this particular case the product is a piperazinium diquaternary salt. However, successful Michaelis-Arbuzov reactions have been carried out between the bis(bromomethyl)phthalazines 130 (to both the mono- and di-phosphonic acid stages) and the series of [co-(2-cyano-4-pyridine)alkyl]phosphonic diesters 132 (n = 1-4) have been prepared from the 4-pyridinealkyl bromides 131 as precursors to the phosphonoalkylpiperidinecarboxylic acids 133 . ... 

Esters of (A -formylaminomethyl)phosphonic acid (159), important as precursors to the corresponding esters of (isocyanomethyl)phosphonic acid (160) [themselves useful in further syntheses of (aminoalkyl)phosphonic acids (Section IV.D.l)], have been made through the variation of the Michaelis-Arbuzov reaction which employs quaternary ammonium salts, e.g. 158 . The very few examples of this modification include its combination with the Gabriel reaction in a preparation of (phthalimidomethyl)phosphonic diesters ... 

Amongst additionally functionalized aminoalkyl phosphonic acids, of which the hydroxy- and oxo-derivatized compounds are the more important, (haloaminoalkyl)-phosphonic acids have been very seldom reported. In the reactions between trialkyl phosphites and the aminotetrachloroethanes 161, the integrity of the trichloromethyl group is, surprisinglv, retained, with the (l-amino-2,2,2-trichloroethyl)phosphonates 162 as the products, e.g. with R = Such compounds may be reduced by Bu3SnH, but the... 

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