The Michaelis-Arbuzov reaction

The Michaelis-Arbuzov reaction is also known as the Michaelis-Arbuzov-Kaehne reaction or the Michaelis-Arbuzov rearrangement and is sometimes named after Arbuzov only. For reviews of the reaction see Refs 6, 12,17, and 18. 

The Michaelis-Arbuzov reaction is generally performed without solvent (as one or other, or both, of the reactants is usually a liquid), and the product phosphonate purified by distillation if a solvent is required THF, acetonitrile, benzene or toluene are suitable. Lawrence has collected details of the syntheses and Homer-Wadsworth-Emmons reactions of some common Michaelis-Arbuzov products 6 4 many such phosphonates are commercially available. 

This protocol is representative of the Michaelis-Arbuzov reaction in its simplest form, on a large scale. Protocol 1 may be used with minor modification to synthesize other simple dialkyl alkylphosphonates.20 The combination of triisopropyl phosphite 9 and a primary alkyl halide (methyl iodide) means that the formation of the potential by-product diisopropyl isopropylphosphonate is negligible because the product alkyl halide (isopropyl iodide) is a secondary alkyl halide and thus reacts much more slowly with triisopropyl phosphite 9 than does the desired reactant methyl iodide. 

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 two-necked round-bottomed flask (2 L) equipped with a magnetic stirrer bar and fitted with an efficient water condenser and an addition funnel (500 mL), add methyl iodide (113 mL, 284 g, 2 mol). 

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The Arbuzov reaction,also called the Michaelis-Arbuzov reaction, allows for the synthesis of pentavalent alkyl phosphoric acid esters 4 from trivalent phosphoric acid esters 1 (Z,Z = R,OR) by treatment with alkyl halides 2. 

The reaction with phosphite esters is known as the Michaelis-Arbuzov reaction and proceeds through an unstable trialkoxyphopsphonium intermediate. The second stage is another example of the great tendency of alkoxyphosphonium ions to react with nucleophiles to break the O—C bond, resulting in formation of a phosphoryl P—O bond. 

Figure 3.3 Adamanyl esters in the Michaelis-Arbuzov reaction. 

A wide variety of reagents have been found to undergo the Michaelis-Arbuzov reaction in a facile manner. Established approaches toward the generation of new C-P bonds using this variety of reagents are briefly summarized in the following ... 

In the instances of phosphorous and phosphonous acid systems, the generation of a new C-P bond via the classical Michaelis-Arbuzov reactions as noted above leads to products that are esters themselves. Isolation of the free acid product requires cleavage of the ester linkage in a separate reaction step, generally after isolation and purification of the initial product. The advent of silyl phosphorus reagents for the Michaelis-Arbuzov reaction allowed free acid products to be isolated simply by water workup of the reaction system. Further, since the byproduct was a silyl-halide, the general concern that the by-product halide would participate in an extraneous Michaelis-Arbuzov reaction was obviated. 

Additional advances have been made in the use of leaving groups other than halide for the nonphosphorus component of the Michaelis-Arbuzov reaction. The sensitive species 3,5-d i-t-b u ty I -4-hydroxybenzyl acetate has been noted to undergo efficient reaction (75-85% isolated yields) with a series of trialkyl phosphites upon heating at relatively low temperature (95°C) without the use of excess phosphite or additional catalyst.138 Chromatographic analysis of the reaction mixture indicates virtually quantitative conversion in the process. 

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... 

In contrast to the Michaelis-Arbuzov reaction, triaryl phosphites prove to be quite useful for addition to a,(3-unsaturated carbonyl compounds in this type of reaction. A wide variety of unsaturated compounds have been utilized successfully as substrates for such additions, including condensation products of the simple carbonyl compounds with urea,229 thiourea,230-233 N-substituted thioureas,232 234 235 ethyl carbamate,236 2-imidazolidinone,237 2-imidazoli-dinethione,237 and benzyl carbamate.238-240... 

Stamm, H. and Gerster, G., Reactions with aziridines. XXI. The (Michaelis-) Arbuzov reaction with N-acyl aziridines and other amidoethylations at phosphorus, Tetrahedron Lett., 1623, 1980. 

Trialkyl phosphites undergo reaction with molecular halogen via a mechanism reminiscent of the Michaelis-Arbuzov reaction to form the dialkyl phosphorochloridate in good yield (Equation 4.4).7 With cyclic esters, the halogen performing the displacement reaction at carbon remains attached within the molecule. 

The earliest developments in transition metal-assisted formation of aromatic C-P linkages were the result of the efforts of Tavs28 that were concerned with the use of Ni(II) halide salts for the reaction of aryl halides with trialkyl phosphites. These reactions involved conditions reminiscent of the Michaelis-Arbuzov reaction (heating at an elevated temperature) and produced arylphosphonate products in reasonable yield (Figure 6.8). 

King, R.B. and Diefenbach, S.P., Transition-metal cyanocarbon derivatives. 5. Reactions of (l-chloro-2,2-dicyanovinyl)manganese derivatives with trialkyl phosphites. A novel variant of the Michaelis-Arbuzov reaction leading to [2,2-dicyanovinylphosphonato]metal complexes, Inorg. Chem., 18, 63, 1979. 

The C—P bond formation of sp3 hybridized C—P bonds is readily achievable using the Michaelis-Arbuzov reaction. Such a method is not applicable to form heteroaryl Csp2—P bonds, but Pd-catalyzed reactions provide suitable approaches to such compounds. 

The formation of an s/Z-hybridized C—P bond is readily achievable using the Michaelis-Arbuzov reaction. Such an approach is not applicable to form heteroaryl C—P bonds in which the carbon atoms are sp2 hybridized, whereas palladium catalysis does provide a useful method for Csp2—P bond formation. The first report on Pd-catalyzed C—P bond formation was revealed by Hirao et al. [134-136]. Xu s group further expanded the scope of these reactions [137, 138], They coupled 2-bromothiophene with n-butyl benzenephosphite to form n-butyl arylphosphinate 161 [137]. In addition, the coupling of 2-bromothiophene and an alkylarylphosphinate was also successful [138], For the mechanism, see page 19-21. 

Sugars containing a carbon-phosphorus bond have been prepared by application of the Michaelis-Arbuzov reaction to bromodeoxy sugars. Thus, the reaction of 5-bromo-5-deoxy-l,2-0-isopropylidene-3-O-methyl-a-D-xylofuranose (131) with triethyl phosphite yields the corresponding diethyl phosphonate (132) compound 132 was employed for the synthesis of a sugar derivative having phosphorus as... 

Similarly, the Michaelis-Arbuzov reaction of the 5-bromo-3-0-methyl compound 8 with diethyl ethylphosphonite at 130-150° resulted29 in a quantitative yield of 5-deoxy-5-C-[(RS)-(ethoxy)ethylphos-phinyl]-1,2-0-isopropylidene-3-O-methyl-a-D-xylofuranose, which,... 

Likewise, the use of diethyl butylphosphonite in the Michaelis-Arbuzov reaction of 8 gave29 5-C-(butylphosphinyl)-D-xylopyranose 31 (50% yield) by way of intermediate 27 (R = Bu). The product was also characterized as the tri-O-acetyl derivative a single compound (m.p. 218.5-220°) was recovered,29 and structure 35, namely, 5-[(R)-butyl-phosphinyl]-/ -D-xylopyranose, could be assigned33 to this product from its n.m.r. spectrum. 

Compound 41 was obtained almost quantitatively by heating 42 in diethyl butylphosphonite, which provides, at least partly, the complicated reason for the lower yields from the Michaelis - Arbuzov reaction of 5-halogeno-l,2-0-isopropylidene-a-D-xylofuranose where the hydroxyl group on C-3 was not protected (see earlier). 

The Michaelis-Arbuzov reaction of methyl 5-deoxy-5-iodo-2,3-0-isopropylidene-/ -D-ribofuranoside38 (43) with diethyl ethylphosphonite gave,35 in 80% yield, the 5-C-[(ethoxy)ethylphosphinyl] derivative which, on treatment with SDMA and then mineral acid, yielded (30%) 5-deoxy-5-C-[(RS)-ethylphosphinyl]-D-ribopyranose (44) as a mixture of diastereoisomers. These compounds showed no mutarotation in methanol during 24 h. Upon treatment with acetic anhydride-pyridine, the product, 44, was converted (90% yield) into a syrup, presumably consisting of four diastereoisomers of the peracetate 45, separation of which was not attempted. Treatment of 45 with sodium methoxide in methanol regenerated 44 quantitatively. 

To gain information on the kinetics and mechanism of the product-forming stage of the Michaelis-Arbuzov reaction, we have followed the decomposition of intermediates by H nmr spectroscopy. In CDCI3 the reactions follow excellent first-order kinetics (Table I) and are in accord with rate-determining collapse to products within the undissociated ion-pair (Figure 1). Synchronous... 

The Michaelis-Arbuzov reaction is the most used and well-known method for the synthesis of phosphonates and their derivatives and may also be used to synthesize phosphinates and tertiary phosphine oxides. The simplest form of the Michaelis-Arbuzov reaction is the reaction of a trialkyl phosphite, 3, with an alkyl halide, 4, to yield a dialkyl alkylphosphonate, 6, and new alkyl halide, 7 (Scheme 2). During this transformation the phosphorus atom of a ter-valent phosphorus(III) species (3) acts as a nucleophile resulting in the formation of an intermediate alkoxy phosphonium salt 5, containing a new [P—C] bond. The precise structure of the intermediates 5 is a subject of debate—as reflected by common reference to them as pseudophosphonium salts —with a penta-coordinate species (containing a [P—X] bond) being proposed and detected in some cases.18 Decomposition (usually rapid under the reaction conditions) of the intermediate 5 by nucleophilic attack of X- on one of the alkyl groups R1, with concomitant formation of a [1 =0] bond yields the product pentavalent phosphorus(V) compound (6) and the new alkyl halide, 7. 

Protocol 2 produces the protected fi-formylphosphonate 12 f)-ketophospho-nates may also be synthesized by other methods,23 however, they may not be prepared in unprotected form by the Michaelis-Arbuzov reaction because the Perkow reaction, in which an a-haloaldehyde or ketone and a trialkyl phosphite yield an enol phosphate (e.g. 13, Scheme 5,24 i.e. [P—O] bond formation), competes and frequently dominates (see Section 4). Conversely halocarboxylic acid derivatives (e.g. see Table 7.1, entry 3) and acyl halides (see Protocol 3) react well in the Michaelis-Arbuzov reaction to yield useful functionalized phosphonates. fi-Ketophosphonates are useful reagents for the synthesis of a,fi-unsaturated carbonyl compounds by the Horner-Wadsworth-Emmons reaction,3,4 25 and have other applications.23... 

Many other organic halides undergo the Michaelis-Arbuzov reaction Table 7.1 lists the Michaelis-Arbuzov syntheses of other phosphonates that are described in detail in the references given and for which the procedures differ little from Protocols 1-3. 

Allyl and propargyl halides participate in the Michaelis-Arbuzov reaction, though isomerization is sometimes observed. The Michaelis-Arbuzov reaction of alkynyl halides (15, Scheme 8) is synthetically useful when the alkyne is suitably substituted (e.g. Scheme 8, R2 = aryl, substituted ethenyl, Me3Si, Et3Sn, Cl, X = Cl, Br) and the area has been reviewed.37... 

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 Michaelis-Arbuzov reaction may be photoinitiated with appropriate sub- strates such as tetrahalomethanes and aryl iodides suitable phosphites undergo photo-Arbuzov rearrangement (see below). 

Substrates susceptible to Sn 1 attack and those bearing leaving groups other than halides have also been employed in the Michaelis-Arbuzov reaction, for example, dialkyl sulfates, alkyl mesylates, alkyl tosylates, quaternary ammonium species, activated acetates as have other electrophiles, for example, alkyl fluoroborates, lactones, lactams, aziridines, sulfones, iminium cations, and orf/io-quinonoids.6,13-15,18... 

R3 = F or Cl) and alkyl phosphorodifluoridites, -dichloridites and -dicyanidites (17, R1 = alkyl, R2 = R3 = F, Cl or CN) will undergo the Michaelis-Arbuzov reaction this area has been reviewed.45... 

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