Michaelis-Arbuzov reaction intermediates

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. 

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. 

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. 

Quasiphosphonium ions involving oxygen directly bound to the positive phosphorus site are generated as intermediates in numerous other reactions. For example, the Michaelis-Arbuzov reaction (see Section 3.5) produces a quasiphosphonium ion as an intermediate that undergoes attack by the associated amon at the carbon end of the C T P linkage. The reaction follows a different course when aryl ester linkages are present on the starting trivalent phosphorus acid derivative. In such instances, a quasiphosphomum ion is... 

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... 

Hudson, H. R., Kow, A., Roberts, J. C. Quasiphosphonium intermediates. Part 3. Preparation, structure, and reactivity of alkoxyphosphonium halides in the reactions of neopentyl diphenylphosphinite, dineopentyl phenylphosphonite, and trineopentyl phosphite with halomethanes and the effect of phenoxy-substituents on the mechanism of alkyl-oxygen fission in Michaelis-Arbuzov reactions. J. Chem. Soc., Perkin Trans. 2 1983, 1363-1368. 

Because dialkyl 2-oxo-(0-(alkoxycarbonyl)alkylphosphonates are valuable synthetic intermediates that may be either converted to die corresponding amino compounds or treated with a variety of carbonyl compounds in a Homer-Wadsworth-Emmons reaction,procedures that effect their preparation are of special importance. The Michaelis-Arbuzov reaction, which furnishes low yields, does not appear to be an appropriate method for the preparation of dialkyl 2-oxo-(fl-(alkoxycarbonyl)alkylphosphonates. One of the most attractive synthetic methods involves the chemoselective reaction of a-metallated dialkyl alkylphosphonates with acylating reagents such as carboxylic acid chlorides, cyclic anhydrides, or esters. 

Since it is reasonably well established that the Michaelis-Arbuzov reaction occurs in two stages, via an ionic phosphonium intermediate which decomposes by a valency expansion of phosphorus, the overall process may be formulated more generally as ... 

Bicyclic phosphites (297) undergo the Michaelis-Arbuzov reaction when treated with alky] halides at somewhat higher temperatures than required for the simple esters of phosphorous acid. The boat conformation which is undoubtedly an intermediate is presumably converted to the thermodynamically stable chair form. 

Although alkoxyphosphonium intermediates are normally not isolated from the Michaelis-Arbuzov reaction, the available evidence supports the hypothesis of their transient existence. 

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. 

Structures to be considered for the intermediate in the normal Michaelis-Arbuzov reaction he between the extremes of purely ionic or purely covalent bonding. On the basis of present knowledge, decision between phosphorane (301,302) (9), ion pair (10), or phosphonium halide in-... 

The alkyl exchange reaction (207) differs from the Michaelis-Arbuzov reaction in that the phosphonium intermediate is generated by nucleophilic attack by a phosphoryl or thiophosphoryl group. 

Related reactions in the oxygen series were first observed only recently as complications in Michaelis-Arbuzov reactions. The 2-halo-alkyl phosphate and phosphonate esters which occur as intermediates in the Michaelis-Arbuzov reaction of certain cyclic phosphites and phos-phonites (cf. Section II-A-1) undergo an internal alkyl exchange reaction (eq. 4) (176). Although reaction of 8-bromoethyl acetate with triethyl phosphite is said to furnish the expected product, diethyl fi-acetoxyethylphosphonate, in 28% yield (220), reaction of this same alkyl halide with dimethyl phenylphosphonite (129) gave the expected methyl phenyl(/9-acetoxyethyl)phosphinate in not greater than 5% yield (eq. 6). Instead, the major products were d-acetoxyethyl phenyl-(methyl)phosphinate (60%) (12) and a mixture of ethylene bi [phenyl-(methyl)phosphinate], [CH20P(0)(Me)Ph]2, (13) and an, ester of... 

Following a comparison of the behaviours of trialkyl phosphites, mixed alkyl phenyl phosphites and triphenyl phosphite towards iodomethane and, in the last case, the breakdown of the phosphonium salt when treated with an alcohol, Landauer and Rydon considered that all the reactions involve a stage identical with that of the normal Michaelis-Arbuzov reaction. The absence of any rearrangement during the decomposition of complexes from neopentyl phosphites, and the configurational inversion which occurs when optically active 2-halooctanes are produced from optically active phosphite triesters (themselves obtained from optically active octan-2-ol), suggest that the mode of breakdown of the intermediate complexes is of S 2 character. 

In spite of the large volume of evidence for the participation of ionic intermediates in the Michaelis-Arbuzov reaction, there is also considerable evidence for the formation and breakdown of other species during the course of the same reaction such participation occurs together with, or in place of, that of ionic species. 

Variations in the types of reactants have been noted which are a reminder of those variations described in the previous chapter for the basic Michaelis-Arbuzov reaction. In this case, a a-haloketone reacts with a phosphorous chloride the reaction is envisaged as proceeding through a phosphonium intermediate which, when decomposed through alcoholysis, yields a (2-oxoalkyl)phosphonic derivative (Scheme 50). The usual pattern of... 

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... 

Carbon-phosphorus bonds are formed by the Pd-catlyzed allylation of various phosphorus compounds (Scheme 13). The reaction of l-acetoxy-2-cyclohexene with LiPPh2 in refluxing THF provides an allylic phosphine in low yield (<15%). The phosphine produced deactivates the catalyst by coordination, which lowers the yield. In contrast, the reaction of LiP(S)Ph2 with l-acetoxy-2-cyclohexene takes place at room temperature to give allylic diphenylphosphine sulfides in 85% yield. ° Pd-catalyzed Michaelis-Arbuzov reaction of cinnamyl acetate with trimethyl phosphite affords a dimethyl allylic phospho-nate. With the reaction conditions being rather severe, this method may not be applicable to an allylic acetate that can produce a conjugated diene via /3-hydride elimination from the intermediate 7r-allylpalladium complex. 

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