Kabachnik-Medved’-Fields reaction

The reaction between ammonia (or a primary or secondary amine), formaldehyde and phosphorous acid is only one particular case of the Kabachnik-Medved -Fields reaction, consisting of the aminomethylation of a phosphorus species possessing a reactive P(0)H group, and so is of the Mannich type. The involvement of ammonia leads only to 226 and the intermediate aminomethylphosphonic 227 (R = H) and aminobis(methylene)bisphos-phonic acid 228 (R = H) are not isolable although they are detectable by NMR spectroscopy the sequence can be stopped at the earlier stages if a primary or secondary amine is used The use of a,co-diaminoalkanes leads to complexones of type 229 . Ethanolamine affords the related bis(phosphonic acid) 230 and diethanolamine yields 231 under similar conditions acidolysis of the linear compounds brings about their cyclization... 

Kabachnik-Medved -Fields reaction and further discussion has centred on the nature of unexpected products observed as a result of that reaction. It has been known for many years that aromatic ketones such as benzophenone and fluorenone do not participate in this reaction, or at best, do so very reluctantly in mixtures of these or similar ketones, primary amine, and dialkyl phosphonate, the formation of -hydroxy phosphonate takes place lOOx faster than fission of the latter in the reverse reaction meanwhile, the... 

The formation of dialkyl (a-aminoalkyl)phosphonothioates (33) through the Kabachnik-Medved -Fields interaction of dialkyl hydrogenphosphonothioates and carbonyl compounds in the presence of anmionia was established in the early days of the study of that reaction, as was the formation of dialkyl [a-(arylamino)arylmethyl]phos-phonothioates (34) by the addition of (RO)2P(S)H to anils (Scheme... 

The practical difficulties sometimes encountered in Kabachnik-Medved -Fields syntheses of (a-aminoalkyl)phosphonic acids from amines, aldehydes or ketones, and dialkyl hydrogenphosphonates, have been traced to the rearrangement of dialkyl (1-hydrox-yalkyl)phosphonates to isomeric phosphate esters under the essentially basic conditions the reactions involved are summarized in Scheme 17. The direct conversion of a (hydrox-yalkyl)phosphonic diester into the corresponding (aminoalkyl)phosphonate by the action of the amine is known, generally, not to take place, and it seems much more likely that successful Kabachnik-Medved -Fields syntheses proceed by the addition of the hydro-... 

The Kabachnik-Fields reaction is the three-component condensation of an aldehyde or ketone, an amine (secondary, primary, or ammonia) and a monobasic phosphorus(III) acid to yield an a-amino organophosphorus compound (a phos-phonate, phosphinate, or tertiary phosphine oxide) Scheme 28. It was discovered independently in 1952 by Kabachnik and Medved 120 and Fields,121 and may be regarded as a variant of the Pudovik reaction (Section 6), which was discovered contemporarily. The yields of the reaction tend to be only moderate (cf. Section 6), and are generally unsatisfactory with phosphinate reactants, but it is wide in scope and simple to perform. For a recent review of the Kabachnik-Fields reaction, including discussion of the mechanism (which usually proceeds via the imine), see Ref. 102. 

One of the very first methods for the preparation of a-aminophosphonic acids appears to be the one described by Kabachnik and Medved [8]. The Kabachnik-Fields reaction is still very useful, especially for the preparation of dialkyl 1-aminoalkanephosphonates. According to this method, a-aminophosphonates were obtained reacting ammonia, carbonyl compounds (aldehydes and ketones), and dialkyl H-phosphonate. A little later. Fields [9] presented a method of synthesis of 1-aminoalkylphosphonic acids by replacing ammonia with amine—reacting both (aldehydes and ketones) with ammonia, or amine and dialkyl H-phosphonate to give dialkyl esters of 1-aminoalkylphosphonic acid (see Appendix). Hydrolysis of the esters produced free aminoalkylphosphonic acids. Yields of aminophosphonates vary from 40 to 47%. 

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