Arbuzov-Michaelis intermediates

AUcoxyaminophosphines react with alkyl halides in an Arbuzov Michaelis type reaction to form phosphonic acid diamides via thermally unstable phosphonium intermediates (equation 5). ... 

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. 

Hudson, H.R., Rees, R.G., and Weekes, J.E., Methyltrineopentyloxyphospho-nium iodide a crystalline Michaelis-Arbuzov intermediate and its mode of decomposition, Chem. Commun., 1297, 1971. 

Henrick, K., Hudson, H.R., and Kow, A., Michaelis-Arbuzov intermediates x-ray crystal structures of the methyl bromide adducts of neopentyl diphe-nylphosphinite and dineopentyl phenylphosphonite, Chem. Commun., 226, 1980. 

Brief consideration will be given to NMR investigation of intermediates, products and kinetics of reactions. Alkylation, arylation, metalation, reaction with organometallics, thermolysis and thermal rearrangements, isomerisation and many other reactions such as the Wittig, Michaelis and Arbuzov reactions, which are typical of organophosphorus... 

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 possibility that R-0 fission may occur in advance of attack by halide ion has been demonstrated in the reactions of dineopentyl phenyl phosphite or neopentyl diphenyl phosphite with alkyl halides. In these cases the Michaelis-Arbuzov intermediates cannot be isolated but the neopentyl halides which are formed are contaminated with varying amounts of rearrangement product (t-pentyl halide) (Table IV). These results may explain the formation of mixtures of isomeric halides (9,10,11) in certain applications of Rydon s method for alkyl halide preparation (12). S i fission of the R-0 bond appears to be encouraged by the electron-attracting effect of phenoxy-substituents (Figure 3). 

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 mechanism of the Perkow reaction has been a subject of some debate but is now generally thought to proceed by initial attack of phosphorus at the carbonyl carbon atom, not by rearrangement of a Michaelis-Arbuzov intermediate 5.77,78... 

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... 

Quasiphosphomum intermediate species are found to be involved in the transition metal-catalyzed reaction of haloaromatics and vinylic halides with trivalent phosphorus-containing esters. These reactions, while giving products that appear to be from a Michaelis-Arbuzov type reaction, actually involve addition-elimination reactions. 

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. 

The reaction is presumed to occur by initial formation of HjfMenO) PO], which then undergoes direct P-alkylation by nucleophilic attack of phosphorus on carbon with displacement of halide. An alternative alkylation mechanism involving nucleophilic attack of oxygen on carbon, followed by a Michaelis-Arbuzov rearrangement i) of a dialkyl phenylphosphonite (C6H5(MenO)POR) intermediate with the alkyl halide was effectively eliminated by the observation that reaction of methyl phenylphosphinate with a tenfold excess of methyl-c/3 iodide gave the product distribution shown in Eq. (2). 

Analogously, ethyl 4-fluoro-3-methylcrotonate is brominated with NBS in the presence of AIBN and then reacted with triethyl phosphite to produce good yields (72-78%) of a-fluorophosphonate, a key intermediate in the synthesis of fluorinated vitamin A esters (Scheme 3.3)7 Following a similar procedure (radical bromination and Michaelis-Arbuzov rearrangement), ( )-l-fluoro-3-(l-trityl-l,2,4-triazol-3-yl)-2-propenylphosphonate, a good inhibitor of imidazoleglycerol phosphate dehydratase, has been prepared in 25% overall yield. ... 

The reaction of trialkyl phosphites with perfluoroalkenes in an autoclave at l(X)-140°C results in the formation of dialkyl perfluoroalkenylphosphonates in low to good yields (21-81%, Scheme 3.7). " The mechanism involves the attack of the phosphite nucleophile at the polarized terminal CF2 position to form a perfluoroalkenyltrialkoxyfluorophosphorane, which is stable under the usual conditions. This fluorophosphorane, which may be regarded as an isolable Michaelis-Arbuzov intermediate, decomposes on heating with elimination of alkyl fluoride to give dialkyl perfluoroalkenylphosphonates (Scheme 3.7). ... 

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. 

Many different mechanisms have been proposed for the Perkow reaction.2-4 It involves nucleophilic attack of the phosphite at the carbonyl carbon and affords a zwitterionic intermediate 5 which rearranges to form a cationic species 6 that subsequently dealkylates to give the corresponding vinyl phosphate 7. The conversion proceeds via a Michaelis-Arbuzov cleavage of an alkoxy group by halide ion as shown. 

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