The Perkow reaction

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 

Enol phosphates may be reduced to alkenes,79 eliminated to alkynes,80,81 employed as synthetic intermediates in organophosphorus chemistry and are useful in their own right, for example, as insecticides. For reviews covering enol phosphates and the Perkow reaction, see Refs 17, 82, and 83. 

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 

Dialkyl phosphites and their metal salts seldom undergo the Perkow reaction with a-halo-aldehydes or -ketones but usually yield a-hydroxy- and/or epoxy-phosphonate esters (i.e. Pudovik reaction products, cf. Section 6).78 

This protocol is Whitesides and co-workers modification of Clark and Kirby s procedure.84,85 Dimethyl phosphoenolpyruvate 38 is synthesized on a large scale by the Perkow reaction and hydrolysed to potassium phosphoenolpyruvate 39, which may be used as a phosphorylating agent for the 

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The reaction of aldehydes with carbon tetrachloride in the presence of excess tris(dimethylamino)phosphine has been used to prepare vinyl dihalides in yields of 50—70%. It is suggested that the reaction takes place via an intermediate salt (77), although the formation of this salt seems more likely to be analogous to the Perkow reaction than to involve attack on oxygen. 

Borowitz, I.J., Yee, K.C., and Crouch, R.K., Determination of stereochemistry in vinyl phosphorylated species by nuclear magnetic resonance shift reagents. Revised mechanistic pathways for the Perkow reaction, /. Org. Chem., 38,1713, 1973. 

Sekine, M., Okimoto, K., Yamada, K., and Hata, T., Silyl phosphites. 15. Reactions of silyl phosphites with a-halocarbonyl compounds. Elucidation of the mechanism of the Perkow reaction and related reactions with confirmed experiments, /. Org. Chem., 46, 2097, 1981. 

Because of the Perkow reaction, the above route for the production of ketophosphonates and phosphonopyruvates was abandoned. By coupling a-copperalkylphosphonates with acyl chlorides, we have been able to produce in one step ketophosphonate correctly functionalized as well as phosphonopyruvates in good yield and high purity (6). Rl... 

Both reactions involve nucleophilic attack of tricoordinated phosphorus on tetrahedral carbon and show all the characteristics of non-polar reactants combining through polar transition states although the solvent effects are sometimes quite modest.— Subsequent studies have demonstrated nucleophilic attack on activated alkenes,Z activated alkynes,Z the carbonyl groupZ-Z and halogen , whilst in the Perkow reaction (eqn. 1) all four possible sites in... 

Gramine - 3-(dimethylaminomethyl)indole (14) - is a readily obtainable derivative of indole and is produced with a quantitative yield by the Mannich reaction. In [19] it was phosphorylated with diethyl chlorophosphite. 3-(Dimethylaminomethyl)-l-(triethoxyphosphito)indole (15) was obtained also by the method in [20] using diethyl penten-3-on-2-yl phosphite. Compound 15 readily adds sulfur with the formation of the corresponding gramine 1-thiophosphate 16 and reacts with chloral according to the scheme of the Perkow reaction, forming phosphate 17 ... 

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... 

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... 

The phosphate is prepared by the Perkow reaction of ethyl trichloroacetate and triethyl phosphite (83% yield). 

As might be expected, keto-sugar acetates undergo the Perkow reaction with trimethyl phosphite to give a mixture of enol phosphates (27) and (28). In other cases the products appear to be dependent on the leaving group, and the Perkow products... 

Hoffmann, H. and Diehr, H.J., Reaction of tertiary phosphines on a-halocarbonyl compounds. Model experiment on the Perkow reaction. Tetrahedron Lett., 3, 583, 1962. 

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 ... 

With the presence of more than one halogen atom in the a-position of the halo ketone, the formation of 2-oxoalkylphosphonates becomes more difficult, and the reactions proceed exclusively according to the Perkow reaction. Thus, dichloromethyl, dibromomethyl, and tribromomethyl methyl ketones, in reaction with trialkyl phosphites, lead to the corresponding vinyl phosphates... 

Miller, J.A., Reactions of dimethyl phosphite with tetracyclone, Tetrahedmn Lett., 11, 3427, 1970. Borowitz, I.J., Firstenberg, S., Borowitz, G.B., and Schuessler, D., Organophosphorus chemistry. Part 17. Kinetics and mechanism of the Perkow reaction, 7. Am. Chem. Soc., 94, 1623, 1972. 

The Perkow reaction of triethyl phosphite with 2-chloroethyl trichloroacetate gives 0,0-diethyl-0-[l-(chloroethoxy)-2,2-dichlorovinyl] phosphate (69), introduced under the trade name Forstenon (Sallmann, 1952). 

Not only the a-polyhalogen aldehydes, but also the oc-polyhalogen ketones give the Perkow reaction with trialkyl phosphites, whereby vinyl phosphates are formed containing one chlorine atom less. In the reaction of triethyl phosphite with dichloromethyl-2,4-dichlorophenylketone, 0,0-diethyl-0-[l-(2,4-dichlorophenyl)-... 

Polish research workers prepared several analogues of chlorfenvinphos in order to develop a derivative with similar action but less toxic. The result of this work was 0,0-diethyl-0-[2-bromo-1 -(2,4-dichlorophenyl)vinyl] phosphate (bromfenvin-phos, 72). It is prepared by the Perkow reaction with triethyl phosphite and dibromoethyl-2,4-dichlorophenyl ketone (Fulde et al., 1974 Zwierzak, 1974). 

Based on the research work of Stiles (1952), one of the most important phosphorus ester insecticides, 0,0-dimethyl-0-[(l-methyl-2-carbomethoxy)vinyl] phosphate (mevinphos, 73) was introduced in 1957 under the trade name Phosdrin . It is prepared by the Perkow reaction from trimethyl phosphite and methyl a-chloroacetoacetate. 

The Perkow reaction has been used to generate a wide range of vinyl phosphates. Reaction of trialkyl phosphites with a-halogeno-ketones provide vinyl phosphates.1-5 Alkenes are produced via reduction of the dialkyl enol phosphate using either sodium or lithium in liquid ammonia. 

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). 

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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