Todd-Atherton reaction

A synthesis of A-substituted a-aminobenzylphosphinic acids starts from ammonium hypophosphite this is allowed to react with primary amines together with aldehydes or ketones in the presence of HC1.60 The nature of the products and general success of the Atherton-Todd reaction for the preparation of dialkyl- and diaryl-phosphinic amides from secondary phosphine oxides depends on the order in which reactants are mixed and on the choice of polyhalogen reactant.61... 

Tertiary amines may be used as the base in the Michaelis-Becker reaction with highly reactive substrates. This approach has the advantage of overcoming the common problem of the low solubility of the metal dialkylphosphonate salts 22. However, amines are used as the base in the Atherton-Todd syntheses of phos-phorochloridates 27 and phosphoramidates 28 (Scheme 16), pathways which may thus compete with the Michaelis-Becker reaction of highly chlorinated substrates under such conditions the precise mechanism of the Atherton-Todd reaction is a subject of debate.61... 

There follows a series of four papers by Houalla et al. on further extensions of the Atherton-Todd reaction to the synthesis of pentacoordinated phosphorus compounds with the phosphorus as a heteratom within a wide variety of macrocyclic structures. The first paper22 describes the reaction of 1-hydridobicyclophosphoranes containing a secondary amine group (e.g. 56) with (57) which leads to a cyclic / /s(bicyclophosphorane)-(58), as well as the symmetrical bicyclophosphorane (59). The opportunity to exploit the reaction in the synthesis of novel macrocyclic structures was too good to miss and compounds such as (62) were prepared from the corresponding 6/s-phosphorane (60) and the Ws-phenol (61).23... 

PTC has been used efficiently for chlorination of dialkylphosphite and subsequent phosphorylation of secondary amines, O-alkylhydroxylamines, alcohols, etc. (Atherton-Todd reaction) via halophilic reaction with carbon tetrachloride ... 

This reaction was first reported by Atherton and Todd et al. in 1945T It is a transformation of dialkylphosphite into dialkyl chlorophosphate in the presence of carbon tetrachloride and a base (usually tertiary amine, secondary amine, or primary amine). Therefore, it is generally known as the Atherton-Todd reaction. In general, the formed dialkyl chlorophosphate is too reactive to be isolated, which further reacts with alcohol or amine to give phosphate or phosphoramidate. Only a few dialkyl chlorophosphates have been separated so far. ... 

The commonly known mechanism for the Atherton-Todd reaction is based primarily on the early kinetic investigations. It is believed that the initial step is the deportonation of the dialkyl phosphonate (RO)2P(0)H by a base to give a dialkyl phosphite anion that undergoes the halophilic substitution with CCI4, as illustrated here. 

Other references related to the Atherton-Todd reaction are cited in the literature. ... 

This reaction is related to the Atherton-Todd Reaction and Kabachnik-Fields Reaction. 

The Atherton-Todd reaction is an interaction of dialkyl phosphonates with chlorocarbons in the presence of a base (see Appendix) [80]. This is a route for the oxidation of dialkyl H-phosphonates to the highly reactive dialkyl chlorophosphates, which are usually not isolated, but rather used in situ under mild conditions [81]. 

Within this reaction cycle, dialkyl H-phosphonate and carbon tetrachloride react to form dialkyl chlorophosphate and chloroform as the final products of the Atherton-Todd reaction. A simple equilibrium shift (without salt formation) toward the dialkyl phosphite tautomer in step 1 [82] or formation of pentacoordinated phosphorane intermediates in step 2 [84,85] has also been discussed. It has been shown that the rate of this reaction depends on the strength of the applied base [86]. Amines are the most commonly used bases under Atherton-Todd conditions [80-85]. The validity of the deprotonation step in the above mechanism in the case of the base being an amine is, however, questionable, since it has been established that amines are alkylated and not protonated at the nitrogen by dialkyl phosphonates. It has been shown, however, [87] that in the case of basic activation with amines, which are the most commonly used bases, the phosphite intermediates are formed according to a different and more complex pathway (see Section 3.8.1). This pathway includes alkylation of the amine and formation of a monoalkyl H-phosphonate salt. 

This monoalkyl H-phosphonate anion is the actual base, which then deprotonates the dialkyl H-phosphonate. It has been established that alkylanunonium or metal salts, containing monoalkyl H-phosphonate anions, promote the Atherton-Todd reaction [87], Taking into account the observation of Kong and Engel that the Atherton-Todd reaction does not take place in the absence of a base, these results indicate that the monoalkyl H-phosphonate anion is playing a key role as an intermediate in the amine-promoted Atherton-Todd reaction. A recent theoretical ab-initio study [88] of the mechanism of the Atherton-Todd reaction favors the following reaction scheme, which is based on energetic evaluation of alternative reaction pathways ... 

These results indicate that the energy gained in the formation of the early ion-dipole complex is sufficient to overcome the transition structure energy barrier. Since the energy of the transition structure is 8.6 kcal/mol lower than that of the separated reactants, a significant population of the late ion-dipole complex may be expected. These two ion-dipole complexes should be present on both sides of the transition structure along the reaction coordinate in the above scheme, but they do not exist for the simplified models. Preliminary AMI studies for the proton-transfer reaction of the fully methylated species reveal, however, two weakly bonded ion-dipole complexes. The early complex has an O-H distance of 2.11 A, and the late complex has a P-H distance of 1.90 A. The computafional study of the Atherton-Todd reaction (Table 3.4) is another indication supporting the... 

When the Atherton-Todd reaction is carried out in the presence of carboxylic acids, the formation of phosphate products is observed [89]. 

Amino acids were phosphorylated successfully using Atherton-Todd reaction conditions [89,90]. 

It was shown that the phosphorylation of amines by the Atherton-Todd reaction could be carried out conveniently and easily under phase-transfer conditions in the presence of catalytic amounts (about 5 mol %) of triethylbenzylammonium chloride (TEBA) [91]. 

It was shown that phosphoramides could also be obtained by the Atherton-Todd reaction between anilides and diaUcyl H-phosphonates under phase-transfer conditions [96]. 

Dialkyl chlorophosphates, except via the Atherton-Todd reaction, are also formed in the reaction between dialkyl H-phosphonates and copper dichloride in tetrachloromethane... 

Synthetic application. The synthetic applications of the Atherton-Todd reaction include preparation of diatkyl amidophosphates and di- or trialkyl phosphates by in situ condensation of the intermediately formed dialkyl chlorophosphates with N-H or 0-H containing substrates. Thus, when the reaction takes place in an excess of the basic compounds (primary or secondary amines), dialkyl phosphoramides are formed as final products [81],... 

N-phosphorylated proteins and amino acids play important roles in the regulation of enzyme activity and protein biosynthesis [107,108], The Atherton-Todd reaction is used for the convenient synthesis of A-phosphoryldipeptide acids. The dialkyl phosphonate group has been successfully used for direct phosphorylation and for protection of the amine group [109-112],... 

Pseudoephedrine reacts via the classical Atherton-Todd reaction with dimethyl H-phosphonate to give the corresponding amidophosphate, which undergoes stereoselective heterocyclization to give 2-methoxy-3,4-dimethyl-5-phenyl-2-oxo-l,3,2-oxazaphos-pholane 1 in 82% yield based on the amidophosphate [118]. 

The Atherton-Todd reaction is used for the phosphorylation of poly(A-vinylpyrrolidone-co-vinylamine) [119],... 

The Atherton-Todd reaction has been recently used to convert linear poly(alkylene H-phosphonate)s into the corresponding poly(alkylene phosphate)s [120]. 

General procedure for Atherton-Todd reaction (ref J. Chem. Soc., 1945,660j. 

General procedure for the phosphorylation of aminoalcohols using Atherton-Todd reaction (ref Zh. Obshch. Khim., 1974, 46, 21). 

Poly(alkylene H-phosphonate)s were converted into the poly(alkylene phosphorami-date) through the Atherton-Todd reaction with amines [298]. 

The Atherton-Todd reaction was used for the preparation of a new class of hydrophihc drug-carriers with an organic polyphosphate main chain. Pharmacologically active ethyl-4-aminobenzoate and phenethylamine were attached to poly(propylene H-phosphonate) and poly(3,6,9-trioxaundecamethylene H-phosphonate) [325]. 

Polyphosphoramidate with a spermidine side chain as a gene carrier was synthesized from poly (1,2-propylene H-phosphonate) by the Atherton-Todd reaction [341]. 

General procedure for the synthesis ofpolyialkylene phosphate)s (Atherton-Todd reaction conditions) ref. Mackromol. Chem., 1993,194, 3261). 

Phosphoramide, obtained by the Atherton-Todd reaction, is also applied as a flame retardant for rigid polyurethane foams [104],... 

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