Mendeleev Commun., 2011, 21, 106–107 – 106 – © 2011 Mendeleev Communications. All rights reserved. Mendeleev Communications Alkyl hydrogen (1-aminoalkyl)phosphonates 1 are important organophosphorus analogues of amino acids and can inhibit enzymes of amino acid metabolism. Usually they are prepared from the corresponding phosphonic acids by their conversion into chlorides or activated esters, or by using dicyclohexylcarbodiimide (DCC). 1 Reported synthesis of alkyl hydrogen phosphonates from phos- phinic acids in case of amino derivatives 2 involves amino group protection, esterification with DCC, oxidation with sodium per- iodate and removal of protection. 2 Here we report a convenient method for the preparation of (1-aminoalkyl)phosphinic acids 2 from oximes, their monoesteri- fication as well as synthesis of a dipeptide phosphorus analogues 3, 4 (Scheme 1, cf. refs. 2–4). Acids of type 2 are usually accessed through addition of H 3 PO 2 5,6 or bis(trimethylsilyl)phosphonite 7 to N-substituted imines. The use of benzhydryl protection was reported in a three-stage preparation of phosphinic analogues of protein amino acids. 8 Recently we have invented one-step synthesis of acids 2 by a reaction of oximes with anhydrous H 3 PO 2 9 that involved the addition of this acid to the C=N bond and reduction of the N–O bond. This approach is further investigated in the present study. The possible intermediate, [1-(N-hydroxyamino)ethyl]phosphinic acid, on the pathway to acid 2a was independently obtained by reduction of acetophosphinic acid oxime. However, this com- pound was not converted to acid 2 on treatment with H 3 PO 2 . Similarly, reduction of the N–O bond and formation of an addi- tion product were not observed in the case of O-alkylaldoxime. These observations suggested that the addition of H 3 PO 2 at the C=N bond is preceded by the reduction of the N–O bond. It is known that O-dialkylphosphite esters of ketoxime and ethyl ester of acetohydroxamic acid can undergo a phosphite-phosphate re- arrangement by a radical mechanism to give N-phosphorylated imines. 10,11 This mechanism of N–O bond reduction followed by H 3 PO 2 addition to the imine double bond is likely to occur in the formation of acids 2. We have found the conditions providing to control the reaction between oximes and H 3 PO 2 . Phosphinic analogues of alanine 2a, valine 2b and leucine 2c were obtained in yields of about 50% upon regulated addition of oximes to H 3 PO 2 and HCl solutions to heated lower alcohols. † In our one-step procedure for the preparation of monoesters, the amino group protection, activation and esterification of the phosphorus acid moiety were achieved by the action of bromine on solutions of hydrochlorides of amino phosphinic acids 2 in appropriate alcohols. ‡ Here, (1-aminoalkyl)phosphonic acid bromide is initially formed, whose alcoholysis in the presence of pyridine as an HBr scavenger results in monoesters 1. Previously, 8 oxidation of Synthesis of alkyl hydrogen (1-aminoalkyl)phosphonates Radii M. Khomutov,* Elena N. Khurs and Tatyana I. Osipova V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation. Fax: +7 499 135 1405; e-mail: khomutov@genome.eimb.relarn.ru 03.017 DOI: 10.1016/j.mencom.2011. Addition of hypophosphorous acid to aldoximes affords (1-aminoalkyl)phosphinic acids which on treatment with bromine in alkanols are transformed into alkyl hydrogen (1-aminoalkyl)phosphonates. R' NH 2 O H N Me P 3 O OH H R' NH 2 O H N Me P O OH OAlk i, Br 2 /AlkOH ii, AlkOH/Py R NOH R P NH 2 O H OH R P NH 2 O OAlk OH 2a R = Me 2b R = Pr i 2c R = Pr i CH 2 1a R = Alk = Me 1b R = Me, Alk = Et i, Br 2 /AlkOH ii, AlkOH/Py H 3 PO 2 Z-Ala-OSu or Z-Leu-OSu HBr/AcOH 4a R' = Alk = Me 4b R' = Pr i CH 2 , Alk = Et Scheme 1 † A solution of acetaldoxime (29.5 g, 0.5 mol) in MeOH (40 ml) was added with stirring over 1 h under N 2 to a boiling solution of 95% H 3 PO 2 (70 g, 1 mol) in 125 ml of 3% HCl in MeOH. The mixture was refluxed for 4 h, kept for 12 h at 20 °C and evaporated in vacuo at < 45 °C; the residue was dissolved in a minimum amount of water, neutralized with 25% NH 4 OH with stirring and cooling, and chromatographed on a Dowex 50x8 resin (H + form, elution with 0.5 N NH 4 OH). Ninhydrin positive fractions were evaporated in vacuo; the residue was dried in vacuo over P 2 O 5 and KOH to give 30 g (55%) of acid 2a. 6 A TLC-homogeneous product was obtained by chromatography on a Dowex 50x8 resin (H + form, elution with 15% aqueous Pr i OH), followed by evaporation of the appropriate fractions in vacuo and drying of the residue in vacuo over P 4 O 10 and KOH. Ascending TLC was performed on Silufol UV 254 plates (Kavalier, Czechoslovakia), system: Pr i OH–25% NH 4 OH–H 2 O, 7:1:2 (A); the compounds were detected by colour reactions with ninhydrin and ammonium molybdate. Known acids 2b, 6 yield 53%, and 2c, 6 yield 49%, were obtained by a similar manner. ‡ A solution of Br 2 (650 mg, 4.06 mmol) in CHCl 3 (1 ml) was added at 4 °C with stirring to a solution of acid 2a (436 mg, 4 mmol) in 5 ml of dry MeOH containing 1 equiv. of HCl. After discoloration, the mixture was gradually added at 4 °C with stirring to dry MeOH (10 ml) containing pyridine (1.2 g, 14 mmol). The mixture was kept for 12 h at 20 °C and evaporated in vacuo; the residue was dissolved in H 2 O (3 ml) and the product was isolated on a Dowex 50x8 resin (H + form, elution with 15% aqueous Pr i OH). The fractions containing monoester 1a according to TLC (system A) were evaporated in vacuo; the residue was dried in vacuo over P 4 O 10 and KOH to give 450 mg (80%) of monoester 1a, mp 232–234 °C (decomp.), R f 0.53 (A). 1 H NMR (400 MHz, D 2 O) d: 1.34 (dd, 3H, 3 J HH 7.3 Hz, 3 J HP 14.9 Hz), 3.34 (dq, 1H, 3 J HH 7.3 Hz, 2 J HP 12.5 Hz), 3.53 (d, 3H, 3 J HP 10.4 Hz). 31 P NMR (162 MHz, D 2 O) d: 17.7 (dqq, 1P, 3 J 1,PH 14.9 Hz, 3 J 2,PH 10.4 Hz, 2 J PH 12.5 Hz).