The Michaelis-Becker reaction

The range of suitable participants in the Michaelis-Becker reaction is essentially the same as for the Michaelis-Arbuzov reaction. Halo-aldehyde and -ketone substrates suffer the competing reaction of direct attack at the carbonyl group leading to Perkow reaction products (with a-halocarbonyl compounds) or Pudovik reaction products, which often cyclize (cf. Sections 4 and 6). 

For reviews of the Michaelis-Becker reaction, see Refs 6,13,14, and 59 the latter is one of a series of five reviews by Troev on the structure and reactions of dialkyl phosphites.59-63 

This protocol is representative of the Michaelis-Becker reaction in its simplest form, using sodium ethoxide as the base. It gives triethyl 3-phosphonopropionate 26 in better yield than the corresponding Michaelis-Arbuzov reaction (circa 60%), which suffers side reactions (substrates with -electron withdrawing groups are susceptible to dehydrohalogenation during the Michaelis-Arbuzov reaction).65 

Caution Carry out all protocols in an efficient hood and wear disposable vinyl or latex gloves and chemical-resistant safety goggles at all times. 

To a three-necked round-bottomed flask (2 L) equipped with a magnetic stirrer bar, fitted with an efficient water condenser and an addition funnel (250 mL) and protected by a calcium chloride guard tube, add sodium ethoxide (68 g, 1 mol) and anhydrous xylene (500 mL). 

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Virtually simultaneously with the development of the Michae-lis-Arbuzov reaction, another closely related approach toward C-P bond formation was introduced. This involved the reaction of the salts of trivalent phosphorus-centered oxyacids with the same haloal-kanes as used in the Michaelis-Arbuzov reaction. First reported by Michaelis and Becker,142 this approach is commonly known as the "Becker reaction" or the "Michaelis-Becker reaction." Fundamental aspects of this reaction system have been reviewed previously.1 2 143... 

Dialkyl hydrogen phosphites are alkylated in high yield under basic liquiddiquid phase-transfer catalytic conditions via the Michaelis-Becker reaction to yield dialkyl alkylphosphonates without serious side reactions [16, 17]. 

Since the duration of the process is limited by the environment of the phosphorus atom, completion of the reaction in the case of dipropoxyphenylphosphonite required 2.5 h (160-170°C), while in the case of tripropyl phosphite it required 6 h. N-Acetyl(phosphoryl)indole 158 is also produced in the Michaelis-Becker reaction from N-chloroacetylindole and sodium diethyl phosphite [160]. 

The Michaelis-Becker reaction is generally lower yielding than the corresponding Michaelis-Arbuzov reaction, however, it is frequently successful when the Michaelis-Arbuzov reaction fails, for example, the Michaelis-Becker synthesis of the useful reagent 24 is successful, whereas the Michaelis-Arbuzov approach resulted in dehalogenation (Scheme 14).57,58... 

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... 

Formation of Fluorinated Phosphorus Compounds by the Michaelis-Becker Reaction... 

Tertiary phosphine oxides and sulfides are also produced by way of the Michaelis-Arbuzov reaction beginning with phosphonous esters [R2POR ] and thiophosphonous esters [R2PSR ], when used in reaction with haloalkanes (see Section 3.5). Similarly, phosphine oxides are formed from trivalent phosphorus reagents in the Michaelis-Becker reaction as well as the conjugate addition reactions of phosphinous acid derivatives with a, -unsaturated compounds (see Section 3.5). 

The competing halogen-metal and proton-metal exchange reactions mean that the Michaelis-Becker reaction has only limited use for the synthesis of a-halogenomethylphosphonates. 

Nylen successfully used the Michaelis-Becker reaction for the preparation of phosphonoacetic esters. 56 Thus, diethyl l-(ethoxycarbonyl)methylphosphonate can be obtained in satisfactory yield (50%) by the reaction of sodium diethyl phosphite with ethyl chloroacetate in refluxing Et20 (Scheme The choice of the reaction solvent is crucial to the success of the reaction.For... 

The Michaelis-Becker reaction has been investigated with a-chloro-, a-bromo-, and a-iodoac-etates. In contrast to a-chloroacetates, on treatment with sodium diethyl phosphite, a-bromo- and a-iodoacetates undergo reduction to the corresponding acetates. Low yields (18-30%) of unsubstituted and a-alkyl substituted / w(2,2,2-trilluorocthyl) l-(ethoxycarbonyl)methylphosphonates, prepared from sodium bE(2,2,2-trifluoroethyl) phosphite and the corresponding a-bromo esters, have recently been reported. ... 

The Michaelis-Becker reaction can, by its nature, be carried out at lower temperatures than are required for the Arbuzov reaction and thus its use can provide some compounds that cannot be prepared by the latter method for example, 2-chloro-A,A-diethylethylamine affords the required phosphonate on reaction with sodium diethyl phosphite but not with triethyl phosphite.298 However, side reactions often lead to lower yields than those from the Arbuzov reaction for instance, the halide ion produced can readily dealkylate the resulting phosphonate to the monoester,299 so that it is essential to remove the sodium halide before working the product up by distillation. 

The dialkyl phosphite ion, however, can itself dealkylate the phosphonate product 300 and finally one may have to reckon with a competitive alkylation of the dialkyl phosphite ion by still unchanged phosphorous diester 301 and the use of allyl halides in the Michaelis-Becker reaction may lead also to diphosphonates owing to the ability of dialkyl phosphite ions to add to unsaturated systems (see Section 9.1).302... 

Dialkyl thiophosphites (RO)2P(S)H are also alkylated exclusively on the phosphorus in the Michaelis-Becker reaction, thus affording thiophosphonic esters.303... 

The alkyl halides used in the Michaelis-Becker reaction (cf. page 728) may be replaced by other alkylating agents such as dialkyl sulfates326 or alkyl sulfonates 295,327 even the use of carboxylic esters for alkylation of sodium dialkyl phosphites is the subject of a patent.328 It is noteworthy that p-toluene-sulfonates often have advantages over alkyl halides in that alcohols are readily converted into these esters and, further, that the p-toluenesulfonate ion liberated, being a weak nucleophile, causes fewer side reactions. Alkyl p-toluene-sulfonates rank between alkyl chlorides and bromides in their reactivity towards sodium dialkyl phosphites.286 p-Toluenesulfonates of secondary alcohols give poor yields of phosphonate. 

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-... 

A related reaction that yields the same types of products as does the Michaelis-Arbuzov reaction begins with either a phosphinous acid or a monoester of a phosphonous acid. (The corresponding reaction may also be performed with a diester of phosphorous acid.) By treatment with an appropriate base, the conjugate base of the phosphorus-containing acid is generated that serves as the nucleophilic reagent for direct formation of the phosphonate or phosphine oxide product (or phosphonate product from a phosphorous acid diester). This procedure is commonly referred to as the Michaelis-Becker reaction. 

Other reported examples of the Michaelis-Becker reaction have been complicated by further reactions between product and reagent. A normal Michaelis-Becker reaction between a dialkyl sodium phosphite in thf and either Bu C=CCl or Bu CH=CCl2 is... 

Both the Michaelis-Arbuzov and the Michaelis-Becker reactions have served to obtain thio ethers in the phosphonic and phosphinic acid series. 

The conditions required for the Michaelis-Becker reaction are generally mild, from the point of view of temperature, in contrast to the higher temperatures normally required in the Michaelis-Arbuzov procedure, and this important feature allows its use in the formation of peptides containing terminal (aminoalkyl)phosphonic ester groups. Even so, the alkalinity of the media in which the former reactions take place may result in secondary reactions when A-protection in a substrate is afforded by a phosphoryl substituent, as in a dialkyl A-(2-bromoethyl)phosphoramidate, loss of HBr may occur with the formation of dialkyl A-ethenylphosphoramidate and l-(dialkoxyphosphinyl)aziridine ... 

The reaction between alkyl halides and the anion of diethyl phosphonate, made by the ionization of the P-H bond by a very strong base, such as BuLi, to form a new carbon-phosphorus bond is known as the Michaelis-Becker reaction. 

Michaelis-Becker reaction. The Michaelis-Becker reaction is known as a synthetic route for alkylation of dialkyl H-phosphonates. Its standard procedure involves an interaction between alkali salts of dialkyl phosphites and alkyl halides [352]. 

Halides of some hydrocarbons, containing multiple carbon-carbon bonds as well as other functionalities, have also been phosphorylated via the Michaelis-Becker procedure [361-363]. The modem tendency in the application of the Michaelis-Becker synthesis is to carry out a one-pot synthesis without the necessity of intermediate isolation of the dialkyl phosphite salt. It has been shown that the Michaelis-Becker reaction can be carried out in the presence of potassium carbonate and a phase-transfer catalyst (tetrabutyl ammonium bromide— TBAB) [364]. 

The Michaelis-Becker reaction between the sodium diethyl phosphite and either of the halofluoro methanes, CF2CI2 or CFjBr, gives tetraethyl difluoromethylene bisphosphonate [370,371]. 

These conditions are also very convenient for the N-alkylation of N-arylformamides and P-alkylation of dialkyIphosphites. The latter process, known as the Michaelis-Becker reaction, is of particular practical value... 

Even more surprising is the Michaelis-Becker reaction of allene 45 with sodium diethyl phosphite in THF-HMPA mixture which gave , -4 -phosphonate 50 in 23% yield (Scheme 8). Dealkylation of 50 furnished phosphonic acid 51. The formation of 2 -phosphonate 47 by a rearrangment of intermediate 52 was expected according to the lite-... 

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