Michaelis-Arbusov reactions

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. 

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]. 

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). 

Trimethyl phosphite P(OMe)3 spontaneously iso-merizes to methyl dimethylphosphonate MePO-(OMe)2, whereas other trialkyl phosphites undergo the Michaelis-Arbusov reaction with alkyl halides via a phosphonium intermediate ... 

The Arbusov reaction is one of the best known methods for creating a carbon-phosphorus bond. In its simplest form (Michaelis-Arbusov) an alkyl halide reacts with a trialkyl phosphite to an alkanephosphonic acid diester as shown in Eq. (29) ... 

A Michaelis-Arbusov rearrangement followed by a Wittig-Horner reaction is involved in preparation of the distyrylbenzene derivative 11.37, as shown in Scheme 11.15. Precautions must be taken in the first stage to minimise formation of the carcinogenic by-product bis(chloromethyl) ether 11.16. The stilbene bis-ester 11.38 can be made by a similar procedure, or alternatively by the reaction of ethyl acrylate with 4,4 -dibromostilbene in the presence of a palladium-based catalyst (Scheme 11.16), a synthesis that yields the required trans form of the brightener. 

Michaelis-Arbusov reaction, 19 29, 53, 54 Michaelis constant, 10 255 14 626-627 Michaelis-Menten equation, in kinetic studies, 14 625-627 Michaelis-Menten kinetics, 10 254-255 Michael reaction, 14 570 Michaels addition, of PVA, 25 602 Michelson interferometer, 14 221, 225 Micrinite, 6 707t... 

A. K. Bhattacharya u. G. Thyagarajan, The Michaelis Arbusov Rearrangement, Chem. Rev. 81, 415 (1980). A.N. Pudovik u. M.G. Zimin, Addition Reactions of partially-esterified Phosphorus Acids. Rearrangements of a-Hydroxyalkyl Phosphorus Esters and their a-Mercapto- and a-Amino-Analoges, Pure Appl. Chem. 52,989... 

R. G. Harvey u. E. R. DeSombre, The Michaelis-Arbusov and related Reactions, Topics in Phosphorus Chemistry 1, 57 (1964). 

Primary phosphines are unpleasant and toxic reagents. They can be prepared from phosphonous halides, RPCI2, using LiAlILt. As is the case for secondary phosphines, easy access to pure phosphonous halides are required to make this route efficient. It has been found that compound 28 can be reduced to primary phosphine 29 using a mixture of UAIH4 and Me3SiCl (Scheme 13).31 This procedure appears useful, as phosphinates of type RP(0)(0Et)2 are often robust compounds that can be prepared in a number of ways. (e.g. Michaelis-Arbusov reaction, palladium-catalysed coupling of diethyl phosphite with aryl bromides, etc.)... 

Other trivalent phosphoms-containing nucleophiles, such as trialkyl phosphites [P(OR3)j, dialkyl alkylphosphonites [R P(OR)2], or alkyl dialkylphosphinites [R 2P(OR)J, can convert primary carbohydrate halides 177, 178, 179 to corresponding phosphorus derivatives 180, 181, 182 via the Michaelis-Arbusov reaction (O Scheme 78) [ 122,123]. 

Figure 6.51 Production of a non-fissile glycosyl phosphate analogue via the Michaelis-Arbusov reaction.

They also undergo the Michaelis-Arbusov reaction with alkyl halides, forming dialkyl phosphonates Q... 

The first example of a crystalline Michaelis-Arbusov intermediate (6) obtained from a trialkyl phosphite has been isolated from the reaction of... 

Scheme 7). Attempts at a similar Michaelis-Arbusov reaction using the butynyl chloride (55) unexpectedly gave 2-amino-6-chloro- -9-ethylpurine (56) as shown in Scheme 8. The photo-Arbusov rearrangement has been used as the key step in the syntiiesis of a series of acyclic... 

The synthesis of oligonucleotides contciining intemucleoside 3 -S-phosphorothiolate linkages using the Michaelis-Arbusov reaction, has been reported. 5 -0-monomethoxytrityl-3 -5-(2,4-dinitrophenyldisulphanyl)-3 -deoxythymidine (115) was prepared by reaction of 5 -... 

The key step in another synthesis is a Michaelis-Arbusov reaction of diethyl methylphosphonite with the JV-protected 2-amino-4-bromobutanoic acid. According to apaper from the Monsanto company [15], the latter may be obtained from bromobutyrolactone, which is first treated with phthalimide, and after ring-opening, esterified. [16]... 

Introduced concept of cc-enzymes NAD identified in yeast Michaelis-Arbusov reaction defined... 

Phosphonate esters can be made in the Michaelis-Arbusov reaction which entails substitution by trivalent phosphorus with displacement at the C atom (6.342). Alkoxyphosphonium compounds are sometimes produced, but these decompose at higher temperatures and should be regarded as intermediates in the Arbusov reaction (6.267, 3.108). One such intermediate which can be isolated is a crystalline salt-like compound formed as in (6.343)... 

B.A. Arbusov, The Michaelis-Arbusov and Perkow reactions, PureAppl. Chem., 9, 307, 1964. 

R. Harvey and E. De Sombre, Michaelis-Arbusov and related reactions. Topics Phos. Chem., 1,57, 1964. 

Phosphoramidate-linked dinucleotide analogues 79 have been obtained by the reaction of 5 -azido-nucleosides with the dimethyl sugar phosphite in a Staudinger-type reaction followed by in situ Michaelis-Arbusov reaction. Regioisomers with oxygen and nitrogen reversed were similarly obtained fiom an AZT derivative. ... 

The Michaelis-Arbusov and the Michaelis-Becker reactions are the methods of choice to access aliphatic phosphonates. Aromatic phosphonates are inaccessible in this way. They can be readily prepared by condensation of a (het)aryllithium with triethyl phosphite or diethyl chlorophosphite. Anilines or (thio)phenols can be orr/io-phosphorylated with particular ease by docking first the dialkoxyphosphoryl entity at the heteroatom before treating the 0,0-dialkyl... 

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