Michaelis-Arbuzov reaction halide reagent

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. 

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... 

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 electron-withdrawing properhes of the phosphoryl group were explored and exploited in the very earliest studies. In 1927, A.E. Arbuzov and Dunin reported a study of the reacrion of diethyl l-(ethoxycarbonyl)methylphosphonate with sodium or potassium metal and showed that a-metallated phosphonate produets react with alkyl halides to form a-substituted phosphonoacetates. This approach not only complemented the Michaelis-Arbuzov reaction but also provided access to a more diversified range of phosphonates. The development of phosphonate carbaiuons became more sophisticated with the introduction of powerful bases such as NaH and NaNHj and hthium reagents. Subsequently, two major synthetic advances revolutionized phosphonate chemistry. 

One might expect that a phosphorus reagent having for R an aryl group activated for bimolecular nucleophilic substitution (68) by electron- withdrawing substituents might participate in a Michaelis-Arbuzov reaction. Kamai and Koshkina (159), who prepared a number of chloro-and nitro-substituted derivatives of triphenyl phosphite, found this to be the case for both ortho and para isomers of tris(monochlorophenyl) phosphite, which reacted with alkyl halides to furnish phosphonates. On the other hand, tris(2,4,6-trichlorophenyl) phosphite and tris(2,4-dichlorophenyl) phosphite (155) gave only complexes with methyl iodide however, lower reaction temperatures were employed. 

Isolation of alkoxyphosphonium intermediates has been achieved recently by the use of reagents which enter into the Michaelis-Arbuzov reaction at room temperature or below. Thus, Abramov et al. (3,4,8) obtained noncrystalline adducts from trialkyl phosphites and o ,iS-di-haloalkyl ethers. Razumov and Bankovskaya (278) found that reaction of alkyl dialkylphosphinite esters with alkyl halides carried cut at low temperature gave crystalline 1 1 adducts convertible to phosphine oxides on gentle warming. These latter adducts were sufficiently stable Tor measurement of their dipole moments and other properties. They should prove valuable for the study of valency expansion. Also of potential value for this purpose are the stable trialkoxyphosphonium fluoroborates (96,97), e.g., [EtP(OEt)s] BF4 , obtained by interaction of EtsO BF4" or Ph3C+ BF4 with phosphites at room temperature. 

Phosphorus reagents are an integral part of modern organic chemistry, so weTl devote the next few sections to discuss some of the most instructive aspects of organophosphoms chemistry. We ll begin with the Michaelis-Arbuzov reaction, which is a powerful means of creating a carbon-phosphorus bond and hence a key route to organophosphoms chemistry. The reaction involves the interaction of an alkyl halide and a trialkyl phosphite ... 

Michaelis and Kaehne isolated a product with saltlike properties from the reaction of triphenyl phosphite and methyl iodide. This observation has been confirmed by Arbuzov and Sazonova (30) and by Landauer and Rydon (206,284), who used this salt as a reagent for the preparation, in excellent yields, of alkyl halides, including neopentyl iodide, from the corresponding alcohols. The course of this reaction... 

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