Michaelis-Arbuzov phosphonate

Table 7.1 Representative Michaelis-Arbuzov phosphonate syntheses...

MICHAELIS-ARBUZOV Phosphonate Synthesis Ni catalyzed phosphonate synthesis from phosphites and aryl halides. Reaction of alkyl halides with phosphites proceeds without nickel salts (see 1st edition). 

An alkyl group can also migrate from oxygen to nitrogen or phosphorus [I, 72] (Michaelis-Arbuzov rearrangement) With this methodology, tetrafluoro-pyndine phosphonates and phosphmates can be obtained [75, 74], Chlorine fluoride... 

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. 

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... 

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. 

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. 

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. 

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 is the method of choice to prepare a-fluoromethyl phosphonates from trialkyl phosphites and fluorohalomethanes. For example, diethyl iododifluoromethyl phosphonate (2) is prepared in nearly quantitative yield from difluorodiiodoniethane and tricthyl phosphite (1). ... 

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 nucleophihc 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 Michaehs Becker reaction. ... 

The formation of the diaryl ester of the phosphonic acid as shown in equation (23) requires stronger heating than for other Michaelis-Arbuzov reactions using alkyl esters. This is the result of difficulty in accomplishing the nucleophilic displacement reaction on the aromatic ring. More will be noted later (see Section 5.2) concerning the Michaelis-Arbuzov reaction of aryl esters of phosphorous acid. 

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). 

Apart from their behaviour as ligands in metal catalyst systems, studies of the reactivity of phosphites towards a wide variety of other substrates have attracted attention. New aspects and applications of the classical Michaelis-Arbuzov reaction and its variants continue to appear. Evidence of the thermal disproportionation of methyltriaryloxyphosphonium halides formed in the reactions of triarylphosphites with alkyl halides, together with the formation of P-O-P intermediates, has been reported. The Michaelis-Arbuzov reaction has been used in the synthesis of phosphonate-based styrene-divinylbenzene resins and polyphosphonated chelation therapy ligands.Treatment of electron-rich benzylic alcohols dissolved in triethylphosphite with one equivalent of iodine affords a low-temperature one-pot route to the related benzylic phosphonates, compounds which are otherwise difficult to prepare. Upper-rim chloromethylated thiacalix[4]arenes have also been shown to undergo phosphonation on treatment with a phosphite ester in chloroform at room temperature. The nickel(II)-catalysed reaction of aryl halides with phosphite esters in high boiling solvents, e.g., diphenyl ether, (the Tavs reaction), has also... 

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