Perkow reaction

In the Perkow reaction, [8] a trialkyl phosphite combines with a halo carbonyl compound to give an enol phosphate ester and an alkyl halide. 

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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. 

Winkler, T. and Bencze, W.L., Perkow reaction induced C,C-bond formation, Helv. Chim. Acta, 63, 402, 1980. 

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... 

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). 

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... 

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... 

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. 

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... 

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

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... 

Perkow reaction. Formation of enol phosphates on treatment of a-halocarbonyl compounds with trialkyl phosphites. 

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. 

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. " ... 

Trimethyl phosphite does not react with chloroacetyl chloride through a Michaelis-Arbu-zov/Perkow reaction sequence. It gives an acylpseudophosphonium salt, which, in turn, reacts readily with trimethyl phosphite to give a new adduct. Subsequent warming affords dealkylation to give the final dimethyl l-(dimethoxyphosphinyloxy)vinylphosphonate (Scheme 7.3). More interesting from the mechanistic standpoint is the use of diethyl trimethylsilyl phosphite. In reaction with chloroacetyl chloride at 30°C, the initial adduct loses MejSiCl rapidly to give diethyl 2-chloroacetylphosphonate in 37% yield." ... 

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 ... 

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