Michaelis reaction

In the Michaelis reaction (which usually gives lower yields than the corresponding Arbusov reaction), a metal dialkylphosphite (dialkylphosphonate - see below) is reacted with an alkyl halide to give a dialkyl ester of an alkyl phosphonate (6.272). Alkyl p-toluene sulphonates or dialkyl sulphates may be used in place of alkyl halides. Esters of unsaturated phosphonic acids, containing OH and CO groups can be obtained from an unsaturated aldehyde and a dialkyl phosphite (6.273). 

Vinylphosphonic acid and its ethyl ester can be obtained directly from the chloride (6.274). Diallyl phenylphosphonate is obtainable by (6.275). 

Diazoalkanes (6.276) and sodium dialkyl phosphites (6.277) can in some cases be used to obtain phosphonates. 

Alkylphosphonic acids and the majority of substituted alkylphosphonic acids are very stable and can be recrystallised from 6 N HCl or boiled for several hours with caustic soda without change. Arylphosphonic acids are often different, however. The aromatic ring in phenylphosphonic acid can be nitrated with nitric acid undergoing changes at 100°C and sulphonated with SO3 [22]. 

Dimethyl methylphosphonate can be used as a methylating agent (6.279). In aqueous alkaline solutions, p-halophosphonates are decomposed with rupture of the P-C bond (Conant-Swan fragmentation) (6.280) [23]. This reaction is believed to involve the monometaphosphate anion as an intermediate species (13.147). 

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The dibutyl ester of the phosphorous acid is usually employed because of the good solubility of its sodium derivative in light petroleum and aromatic hydrocarbons, which are satisfactory reaction media. The Michaelis reaction has been... 

In order to synthesize biologically relevant phosphonylimidazole 73, bromoimidazole 72 was derived from radical-initiated bromination of methyl l-p-methoxybenzyl-2-thiomethyl-5-imidazolylcarboxylate (71) [56]. The thiomethyl group served to block the C(2) position, which would otherwise undergo preferential halogenation under these conditions. As expected, a variety of Arbusov-Michaelis reaction conditions failed even under forcing conditions. On the other hand, Pd-catalyzed phosphorylation of 72 with diethyl phosphite led to methyl-4-diethylphosphonyl-l-p-methoxybenzyl-2-thiomethyl-5-imidazolylcarboxylate (73). After further manipulations, the desired phosphonic acid-linked aminoimidazoles, which resembled intermediates formed during purine biosynthesis, were accessed. 

Example 57 the synthesis of 2-chloro-iV -methyladenine-9-(2-methyl-propyl)bis phosphonate, analogous to the corresponding bisphosphate, has been performed by Jacobson and associates [93]. The key step in this synthesis is the Arbuzov-Michaelis reaction. 

The starting diol was transformed into the dibromide by elemental bromine with triphenyl phosphine adduct which undergoes the Arbuzov-Michaelis reaction under somewhat drastic conditions at 150 °C (step a). Catalytic removal of the benzyl group was performed by a Pd/C catalyst (step b) and the alcohol formed was allowed to react with dichloropurine in the presence of triphenylphosphine and diethylazodicarboxylate (Mit-sunobu reaction) (step c). Finally the desired product was obtained by reaction with methylamine (step d) and the removal of ethyl groups at the phosphorus centre was performed by transilylation using trimethyliodosilane (step e). 

Example 68 Salomonczyk et al. have performed the synthesis of ( )-my-oinositol 1,2-bis- and l,2,3-tris-(carboxymethylphosphonates) using the Ar-buzov-Michaelis reaction [108]. 

Phosphitylation of inositol 3,4,5,6-tetra-O-benzyl myo-inositol by diben-zyl-iV,Ar-diisopropylphosphoroamidite gave the corresponding bis-diben-zylphosphite (step a). After 12 h at 80 °C the Arbuzov-Michaelis reaction with the excess of benzyl bromoacetate at 80 °C gave after 12 h the fully protected bis-l,2-diphosphonate (step b), which was totally deprotected by catalytic hydrogenolysis to give the desired product (step c). 

Michaelis-Becker Reaction (Michaelis Reaction) The Reaction ... 

Most syntheses of phosphorus amino acid analogues involve the conversion of a nucleophilic, trivalent phosphorus species into a pentavalent adduct. The classical Arbuzov-Michaelis reaction is a well-known transformation that demonstrates this principle.1 In the case of a phosphite diester, the stable form of the reagent is the P-H derivative, depicted in Scheme 2 19 this tautomer is converted into a nucleophilic form by deprotonation or by silylation, which favors the trivalent P—O—Si isomer. 

The reaction of phosphorus(III) acid esters with a,co-dihaloalkanes at elevated temperature, proceeding via formation of co-haloalkylphosphonate or co-haloalkyl-phosphinate in the result of the Arbuzov-Michaelis reaction, is one of the first known synthetic approaches to 2-oxo-l,2-oxaphosphacyclanes 62 (Scheme 30) [1, 2, 51, 52],... 

The Michaelis-Arbuzov reaction is supplemented by a closely related reaction, variously referred to as the Michaelis reaction (86), the Michaelis-Becker reaction (185), or the Michaelis-Becker-Nylen reaction (115), which involves the use of the salts of dialkyl hydrogen phos-phonates. For example, diethyl 2-diethylaminoethylphosphonate was obtained by this method despite failure of the Michaelis-Arbuzov reac-... 

Syntheses for (carbamoylmethyl)phosphonates based upon the Aibusov and Michaelis reactions have been described briefly by Siddall." DHDECMP ( 60% purity) is available from a commercial source [Wateree Chemical]. The ligands are obtained typically with acidic phosphonate impurities, which have a deleterious effect on extraction selectivity. In order to overcome this problem, Mclsaac and coworkers designed a puriflcation procedure for DHDECMP that provides samples with 98-99% purity. ... 

Phosphonates can be prepared relatively easily via the Arbusov reaction, i.e. the alkylation of trialkyl phosphites with alkyl halides [58], or the Michaelis reaction, which is the reaction of alkali metal derivatives of dialkyl phosphites with alkyl halides [59,60]. 

Vinylphosphonates are not easily produced by the Arbuzov-Michaelis reaction, and are often obtained without control of the geometry. A new route to these compounds makes use of a palladium-catalysed coupling between vinyl bromides and dialkyl phosphites in a stereoselective manner and in correspondingly high yields. ... 

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