Michaelis-Becker reaction

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... 

Markovskii, L.N., Furing, G.G., Shermolovich, Y.G., and Yakobson, G.G., Phosphorylation of polyfluoroaromatic compounds. 3. Michaelis-Becker reaction in a series of polyfluoro-substituted benzene derivatives, Izv. Akad. Nauk S.S.S.R., 646, 1981. 

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]. 

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

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]. 

Vinylphosphonates are useful reagents but simple vinyl halides do not undergo the Michaelis-Arbuzov reaction except in the presence of a transition metal catalyst [Ni(II) or Cu(I), cf. Protocol 4] so vinylphosphonates are usually synthesized from other functionalized phosphonates or by the palladium-catalysed Michaelis-Becker reaction (cf. Protocol 8).38 Similarly, simple aryl halides undergo the Michaelis-Arbuzov reaction only under special conditions palladium or nickel species (Protocol 4) are suitable catalysts. Indeed these and other catalysts have been applied to the Michaelis-Arbuzov reaction of various substrates, though they are generally essential only with vinyl and aryl halides, as described herein.39... 

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). 

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... 

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... 

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... 

The so-called Michaelis-Becker reaction can be extended to the synthesis of several other halo-fluoromethyl phosphonates when the reaction temperature is varied. - ... 

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 Horner-Wadsworth-Emmons reagent 735 (Scheme 180) prepared through Michaelis-Becker reaction of 4-(chloromethyl)-l-tritylimidazole 734 with lithium diethyl phosphonate reacts with aldehydes or ketones to give 4-vinylimidazoles 736 <2002S1072>. 

The synthesis of a number of phosphonate derivatives of methylenecyclo-propane nucleoside analogues (86a-l) has been reported by Zemlicka. Most were obtained by an alkylation-elimination approach. Starting from a meth-anesulfonate, methylenecyclopropane phosphonates were obtained by Michaelis-Becker reaction with alkyl phosphites and converted to vicinal dibromides, subsequently used for alkylation-elimination of nucleic acid type bases. All compounds were evaluated against herpes viruses, hepatitis B and HIV and were found to be inactive except for (86b), which was found to inhibit VZV proliferation. 

Michaelis-Arbnzov Reactions Michaelis-Becker Reactions... 

The methods developed for the synthesis of 1-alkynylphosphonates use synthetic concepts such as charge affinity inversion and positive halogen abstraction. Four main reaction categories allow the preparation of 1-alkynylphosphonates the apparent Michaelis-Arbuzov and Michaelis-Becker reactions, the propargyl phosphite-allenylphosphonate rearrangement, carbanionic displacements at quinquevalent phosphorus centers SNPfV), and conversions of vinyl- to alkynylphosphonates by addition-elimination reactions. 1-Alkynylphosphonates possess remarkable potential, and cycloaddition reactions appear to offer very attractive synthetic procedures. ... 

The first attempt to prepare dialkyl 1-aIkynyIphosphonates by a Michaelis-Becker reaction was reported in 1965, " Only octyne is produced when 1-bromooctyne is allowed to react with sodium diethyl phosphite in liquid ammonia, the coproduct being diethyl phosphoramidate. It seems likely that reduction of the bromo compound occurs by a halogen-metal exchange, with the resulting diethyl bromophosphate being immediately converted into diethyl phosphoramidate by the hquid anunonia. ... 

Halogenomethyl)trimethylsilanes (X = Cl, Br) undergo the typical Michaelis-Becker reaction with a variety of dialkyl phosphites to give dialkyl l-(trimethylsilyl)methylphosphonates in modest yields (23-38%, Scheme This method, which is not economical in terms of yields, has only... 

The first synthesis of dialkyl fluoromethylphosphonates by a Michaelis-Becker reaction was described in 1967. The halogenofiuoromethane, which is no longer commercially available because of its mutagenic properties, is added to a refluxing toluene solution of sodium dialkyl phosphite. The corresponding fluoromethylphosphonate is obtained in modest yields (36 0%, Scheme 3.4). ... 

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. 

Tetraethyl methylenediphosphonate can be prepared from diethyl chloromethylphosphonate by reaction either with triethyl phosphite nnder drastic conditions (neat, 190°C, 27%, Michaelis-Arbuzov reaction)- or with sodium diethyl phosphite in refluxing CgHg (47%, Michaelis-Becker reaction).- - However, the yields are significantly lower than those obtained by SNP(V) reaction of diethyl 1-lithiomethylphosphonate with diethyl chlorophosphate (Scheme 3.54). 

Te aalkyl difluoromethylenediphosphonates can be also obtained in modest yields (34-47%) by the reaction of dialkyl 1-bromo-1,1-difluoromethylphosphonates with sodium dialkyl phosphites at 0°C in a formal Michaelis-Becker reaction. 126,282,303,525 mechanism probably involves an... 

Meisters, A., and Swan, J.M., Organophosphorus compounds. Part 6. Michaelis-Becker reaction. Diethyl 1-phenylepoxyethylphosphonate and diethyl 1-phenylvinyl phosphate from diethyl phosphonate and phenacyl chloride, Aust. J. Chem.. 18, 168, 1965. 

Phosphonylation of a -3-(9-isopropylidene-a -pyridoxyl chloride via a Michaelis-Becker reaction, followed by deprotection with 1 M HCl and oxidation of the resulting primary alcohol with MnOj, produces diethyl (4-fonnyl-3-hydroxy-2-methyl-5-pyridyl)methylphosphonate (Scheme 5.38), an analogue of pyridoxal 5 -phosphate whose 5-position side chain has been replaced by a phospho-nomethyl group. The alcohol oxidation step can be accomplished with a wide range of reagents, such as activated MnOj in CHCI3 at room temperature (53%), PCC in CH2CI2 (83-86%), or the Swem reaction (>95%). ... 

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