Perkow-Arbuzov reaction

Toke, L, Petnehazy, I., Keglevich, G., and Szakal, G., Reaction of trialkyl phosphites and a-halo-ketones in aprotic media (Perkow-Arbuzov reaction) and in protic solvents. Period. Polytech., Chem. Eng., 32, 101, 1988. 

In spite of many previous studies on the mechanisms by which trialkyl phosphites interact with a -halogenocarbonyl compounds, the reactive intermediates which lead to ketophosphonate (Arbuzov reaction) and to vinyl phosphate (Perkow reaction) have in no cases been clearly identified. It is generally believed (JL), however, that the Arbuzov product 4 results from initial attack by phosphorus at the cf-carbon atom, whereas the Perkow product 7 is formed by initial attack at the carbonyl carbon atom, followed by migration of phosphorus from carbon to oxygen (Scheme 1). 

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... 

The range of suitable participants in the Michaelis-Becker reaction is essentially the same as for the Michaelis-Arbuzov reaction. Halo-aldehyde and -ketone substrates suffer the competing reaction of direct attack at the carbonyl group leading to Perkow reaction products (with a-halocarbonyl compounds) or Pudovik reaction products, which often cyclize (cf. Sections 4 and 6). 

In the Perkow reaction, a trialkyl phosphite reacts with an a-halo-aldehyde or -ketone to yield an enol phosphate (i.e. [P—O] bond formation, e.g. Scheme 5).76 a-Haloaldehydes react cleanly but with a-haloketones the Michaelis-Arbuzov reaction usually competes with the product distribution depending on the reaction... 

Several interesting approaches to the synthesis of /I-ketophosphonates have recently been described. Typically, standard Arbuzov synthesis of /1-ketophospho-nates is unsatisfactory due to a competing Perkow reaction [51]. However, y,d-unsaturated /1-ketophosphonates are obtained in high yield via Arbuzov reaction of triethyl phosphite with a-iodoenones, readily available from tertiary allenic alcohols [52]. Another successful example of an Arbuzov-based approach involves reaction of bromoacetylated polystyrene with triethyl phosphite, which provided immobilized /J-ketophosphonate in excellent yield [53]. In another approach, the lithio derivative of dimethyl methylphosphonate was reacted with Weinreb amide to obtain the corresponding /J-ketophosphonate [54]. a,a-Diflu-oro-a-ketophosphonates have been synthesized via a cerium-mediated route... 

In contrast to the behavior of (chloroacyl)- and (bromoacyl)silanes, which react according to the Perkow rearrangement, the corresponding iodoacylsilane reacts ahnost completely with trimethyl phosphite in a Michael-Arbuzov reaction to afford dimethyl 2-(fcrt-butyldimethylsilyl)-2-oxoethylphosphonate in 96% yield. - ... 

Possibly the most frequently used and most widely known phosphonylated aldehyde is diethyl l-formylmethyIphosphonate. A vaiiety of methods for the preparation of this aldehyde are reported in the literature. The oldest employs tlie Michaelis-Arbuzov reaction between triethyl phosphite and bromoacetaldehyde diethyl acetal, which yields diethyl 2,2-diethoxyethylphosphonate on heating to 160°C (Scheme 5.5). Subsequent acid hydrolysis gives diethyl 1-formylmethylphosphonate. The aldehyde function requires protection because it is known that a-haloaldehydcs react with trialkyl phosphites in a Perkow reaction affording dialkyl vinylphosphates isomeric with the expected phosphonates. " ... 

In all cases mentioned at that time, the products were assumed to be phosphonates of the type expected from a normal Michaelis-Arbuzov reaction. - However, in light of the Perkow reaction, all the P-ketophosphonates described in numerous papers and patents have to be formulated as the isomeric vinyl phosphates. 

These contradictory results were elucidated later when, in 1952, Perkow showed for a-halogenoaldehydes and Pudovik and Allen and Johnson for oc-halogenoketones that both the Michaelis-Arbuzov reaction, with formation of 2-oxoalkylphosphonates, and the Perkow reaction, with formation of vinyl phosphates, can take place independently or simultaneously. It is important to mention that the formation of vinyl phosphates by an anomalous Michaelis-Arbuzov reaction ... 

Between 1948 and 1952 Morris and Van Winkle (1952), Arbuzov and Alimov (1951), and Perkow et al. (1952) investigated independently the reaction of polyhalogen aldehydes, primarily of chloral, with trialkyl phosphites. The conversion was assumed by some workers to be a true Michaelis-Arbuzov reaction and, accordingly, it was thought erroneously that the product formed in the reaction of chloral and trimethyl phosphite is the phosphonate of formula 66. Perkow et al. (1952) established that a-halogen carbonyl compounds give with trialkyl phosphites an anomalous Michaelis-Arbuzov reaction, so that the actual reaction product is 2,2-dichlorovinyl phosphate, 67. This reaction is known in the literature as Perkow s reaction. 

In 1952 Perkow discovered a new type of rearrangement in which trialkyl phosphites react with a-aldehyde.6,7 This anomalous Arbuzov reaction, which resulted in the formation of dialkylvinylphosphates, subsequently became known as the Perkow reaction. 1 The reaction of trialkyl phosphites with alkyl halides (Arbuzov reaction) proceeded to yield dialkoxy alkyl phosphonates.8 The alkyl halide undergoes a nucleophilic displacement to yield the nonisolable alkyl trialkoxy phophonium halide.8 The halide can then attack an alkoxy group to give phosphonate ester and RX. An increase in temperature favors the Arbuzov reaction leading to phosphonates (Sn2 displacement). 

Enol adenosine 5 -phosphate derivatives (28, 29, 30) are formed by the Perkow reaction of a-chloromethyl ketone with an in situ-generated adenosine-5 -yl bis(trimethylsilyl)phosphite (27). Among these reactions, the use of a-chloro-2, 4 -difluoroacetophenone gave predominantly the enol phosphate derivative over the Arbuzov reaction product and the carbonyl adduct, which were formed as by-products.25... 

Sal keeva et al. studied the reactions of ethyl and /-butyl phosphorodiamidites with chloroacetone, bromoacetone, and a-chloroethyl acetate. The reaction pathway is determined by the structure of the intermediate quasiphosphonium compound responsible for the formation of the Arbuzov products as well as for the occurrence of the anomalous reaction yielding vinyl phosphate (Perkow product).26 The yield of the Arbuzov product increases from chloroacetone to bromoacetone, because the anions of low basicity are more rapidly ionized, which facilitates the formation of the ionic form of the intermediate. Also /-butyl phosphorodiamidite forms via Arbuzov reaction as the major product, because the second stage of the S l reaction is accelerated.26... 

Because the Arbuzov reaction can be carried out with an a-bromo ketone or an a-bromo ester (in which case it is called a Perkow reaction), it provides a way to S3uithesize a,/S-unsaturated ketones and esters. 

While a wide variety of alkyl halides have been employed successfully in the Michaelis-Arbuzov reaction, in certain instances the reaction may follow an abnormal course. The major example is the Perkow reaction (cf. Section III), which occurs with certain a-halo carbonyl compounds, and which has achieved commercial importance as a route to the biologically active enol phosphate esters [e.g., the insecticide Phosdrin (MeO)2-P(0)C(CH3)=CHC02Mel. 

In 1952, Perkow reported (242) that a-haloaldehydes did not react with trialkyl phosphites according to the Michaelis-Arbuzov reaction, although this had been repeatedly reported, but that a new type of reaction occurred, yielding dialkyl vinyl phosphates isomeric with the expected phosphonates. 

The Perkow reaction appears to have about the same limitations with respect to the phosphorus reagent as the Michaelis-Arbuzov reaction. Thus trialkylphosphines, triaryl phosphites, and phosphorotriamidites do not react, whereas all other P(III) derivatives of the general formula R R TOR, where R is a primary or secondary alkyl group, are able to undergo this transformation. 

We have now carried out crossover experiments in which the reaction of trimethyl phosphite with a mixture of differently substituted chloro- and bromoace-tophenones (e.g. C,H,.C0CH2C1 and p-MeC,H.C0CH2Br) affords a mixture ofproducts whose composition shows that halogen exchange has occurred. In other words,the ratio of Perkow to Arbuzov products is that which would be expected if C-H,-COCH2Br and p-MeCgH COCH l were also present in thereaction mixture 5 mol% in benzene, 8 mol% in chlorobenzene, 23 mol% in acetonitrile). ... 

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... 

The reaction of a silyl phosphite with an a-haloaldehyde or ketone generally leads to a 1 1 adduct (i.e. addition at the carbonyl carbon atom to yield a silyloxyphosphonate by the Abramov reaction, cf. Section 5). However, both the Perkow and the Michaelis-Arbuzov pathways are significant and frequently dominate, the outcome depending on the nature of the reactants and the reaction conditions.47... 

The chlorination process is extended to the preparation of 1-substimted-1-fonnyhnethylphos-phonates with comparable yields (53-92%). 5-3°8 Contrary to the previously reported results, the reaction of triethyl phosphite with trichloroacetaldehyde does not give diethyl 1,1-dichloro-1-formylmethylphosphonate (Michaelis-Arbuzov product) instead, the isomeric diethyl 2,2-dichlo-rovinylphosphate (Perkow product) is formed in 98% yield. However, protection of the formyl group before reaction with triethyl phosphite provides the expected diethyl 1,1-dichloro-l-formyl-methylphosphonate selectively in high yield (80%). ... 

The reaction of trimethyl phosphite with an allenic chloromethyl ketone proceeds with the formation of an oxaphospholene and not through the Michaelis-Arbuzov or Perkow rearrangements. ... 

Petnehazy, I., Szakal, G., Tdke, L., Hudson, H.R., Powroznyk, L., and Cooksey, C.J., Quasiphosphonium intermediates. Part 4. Isolation and identification of intermediates in the Arbuzov and Perkow reactions of neopentyl esters of phosphorus(III) acids with a-halogenoacetophenones. Tetrahedron, 39, 4229, 1983. 

Hudson, H.R., Matthews, R.W., McPartlin, M., Pryce, M.A., and Shode, O.O.. Quasiphosphonium intermediates. Part 7. The preparation of trinorborn-l-yl phosphite and its reactions with halogeno compounds. Stable intermediates of the Arbuzov and Perkow reactions and then sU uctural characterization by X-ray diffraction, NMR spectroscopy, and fast-atom-bombardment mass spectrometry, J. Chem. Soc., Perkin Trans. 2, 1433, 1993. 

Ethyl 2-bromoacetoacetate reacts with triethyl phosphite to give a mixture of diethyl l-(ethox-ycarbonyl)-2-oxopropylphosphonate (29%, Michaelis-Arbuzov product) aud diethyl l-methyl-2-(ethoxycarbonyl)vinyl phosphate (31%, Perkow product). By contrast, the reaction of diethyl bromomalonate with trialkyl phosphites takes only one course, and the products formed at either temperature are the enol phosphates (Perkow product) ... 

Arbuzov, B.A., Michaelis-Arbuzov and Perkow reactions. Pure Appl. Chem., 9, 307, 1964 Chem. Abstr, 62, 6353a. 1965. 

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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