Michaelis-Becker product

Biphasic conditions also circumvent the salt solubility problem but classic phase transfer conditions using aqueous sodium hydroxide suffer from competing hydrolysis of the phosphorus(III) esters. However, Kem and co-workers found that butyl esters (their substrate was dibutyl phosphonate) are sufficiently stable to provide Michaelis-Becker products in high yields dialkylphosphine oxides were also suitable substrates.67 Salvatore and co-workers have recently developed an efficient biphasic solid-liquid procedure utilising the cesium cation effect Protocol 7. 

The displacement reaction of mesylates by (EtO)2PONa has been investigated (18). Apart from the normal Michaelis-Becker products (P-alkylation), a substantial amount of olefins and 0-alkylation compounds are detected in polar solvents. The mesyloxy group is more readily displaced by the phosphonate oxyanion as it is harder than halides. The olefins arise from a hard-type process. 

While a "Perkow-route"71 81 for product formation generally ensues when a-halocarbonyl substrates are challenged with Michaelis-Becker reagents,173-175 ethyl 4-bromoacetylaceto-nate provides a simple substitution product.176 Simple substitution occurs also with a-haloesters and a-halophospho-nates.177/178... 

Reaction of the conjugate base of diethyl phosphite with 3-car-boxyethyl-substituted 2,5-halomethylfurans provided interesting products as alternatives to the normally anticipated Michaelis-Becker substitution-type products.452 Rather than simple substitution, overall reduction of the halomethyl linkage(s) to methyl(s) were observed with a Michael-type addition of phosphorus to the 4-position of the ring. 

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). 

Nevertheless, the Michaelis-Becker route does not always proceed cleanly, and dialkyl 1-alkynylphosphonates frequently contain undesired side products that are not easily removed. Because of the difficulties associated with the use of 1-bromoalkynes, it is unsurprising that this reaction is used infrequently, and the general synthetic utility of the procedure remains to be proven. Haloalkynes are triphilic, and the approach of anionic and neutral nucleophiles at the haloalkyne has been discussed and evaluated in terms of the three sites. ... 

Several innovations have significantly extended the scope and synthetic utility of the classical Michaelis-Becker phosphonoacetate preparation. Eor example, the coupling of the Michaelis-Becker and Homer-Wadsworth-Emmons reactions for the synthesis of a-substituted acrylic acids represents a useful modification. According to Scheme 8.10, Michaelis-Becker alkylation of a dialkyl phosphite with a haloacetic acid in the presence of 3 eq of a base (one to neutralize the carboxyl group, one to form the phosphite conjugate base, and one to deprotonate the initially formed alkylation product) leads to the phosphoryl-stabilized anion directly. Treatment of the anion... 

In the reactions of chloromethyl derivatives of furancarboxylic esters with sodium diethyl phosphite in CgHg at 80°C, the corresponding phosphonates are formed according to the Michaelis-Becker scheme. By contrast, when the bromo derivatives are used, the formation of both phosphonates and reduction products resulting from nucleophilic and halophilic attack by the phosphite anion takes place (Scheme... 

The Michaelis-Becker reaction can, by its nature, be carried out at lower temperatures than are required for the Arbuzov reaction and thus its use can provide some compounds that cannot be prepared by the latter method for example, 2-chloro-A,A-diethylethylamine affords the required phosphonate on reaction with sodium diethyl phosphite but not with triethyl phosphite.298 However, side reactions often lead to lower yields than those from the Arbuzov reaction for instance, the halide ion produced can readily dealkylate the resulting phosphonate to the monoester,299 so that it is essential to remove the sodium halide before working the product up by distillation. 

The dialkyl phosphite ion, however, can itself dealkylate the phosphonate product 300 and finally one may have to reckon with a competitive alkylation of the dialkyl phosphite ion by still unchanged phosphorous diester 301 and the use of allyl halides in the Michaelis-Becker reaction may lead also to diphosphonates owing to the ability of dialkyl phosphite ions to add to unsaturated systems (see Section 9.1).302... 

A related reaction that yields the same types of products as does the Michaelis-Arbuzov reaction begins with either a phosphinous acid or a monoester of a phosphonous acid. (The corresponding reaction may also be performed with a diester of phosphorous acid.) By treatment with an appropriate base, the conjugate base of the phosphorus-containing acid is generated that serves as the nucleophilic reagent for direct formation of the phosphonate or phosphine oxide product (or phosphonate product from a phosphorous acid diester). This procedure is commonly referred to as the Michaelis-Becker reaction. 

Other reported examples of the Michaelis-Becker reaction have been complicated by further reactions between product and reagent. A normal Michaelis-Becker reaction between a dialkyl sodium phosphite in thf and either Bu C=CCl or Bu CH=CCl2 is... 

Rare examples of normal Michaelis-Becker reactions which involve co-chloroalkanal diethyl acetals are to be found, and although the formation of dialkyl acylphosphonates from sodium dialkyl phosphites and, for example, benzoyl chloride, is to be observed at -85 °C, the system is further complicated, even at -10 °C, by further addition steps followed by rearrangements which would seem to render the process of little value for the synthesis of oxoalkyl phosphonic esters On the other hand, in a more detailed and systematic study of reactions between sodium dialkyl phosphites, (RO)2PONa(R = Et or Bu), and the ketones R CO(CH2) Cl, Sturtz and others have observed the formation of epoxides when n = 1 and (1-hydroxy alk-2-enyl)phosphonic diesters when n = 2(R = Me or Pr ), according to the displacement in 532, and of derivatives of tetrahydrofuran or tetrahy-dropyran, according to 533 n = 3 or 4) when R = Et, the formation of the cyclic ethers was accompanied by low yields of the expected (oxoalkyl)phosphonic diester, but otherwise the latter were isolated as a single product only for R = Me, n = 5, and R = Et or Pr when n = 2. 

Michaelis-Becker reaction between dialkyl thiophosphonates, (RO)2P(S)H, and alkyl halides, R X, in the presence of NaOR proceed satisfactorily at 70-80 °C in a few hours to give the diesters, (RO)2P(S)R Under such conditions, or during longer reaction periods or at higher reaction temperatures, the formation of the desired product may be... 

Anomalous Arbuzov reactions have been reported to occur between triethyl phosphite tmd unsaturated A-substituted derivatives of adenine and cytosine (225-231 B = adenin-N -yl or cytosin-N -yl). Thus, both ( ) and (Z) forms of (225) yield the corresponding (226). However, (227) yields the A-ethyl derivatives of the heterocycles, although in the presence of iodide anion the phosphonates (228) can be obtained. The chloroallene (229) yields (230) in the presence of iodide anion an additional product was ( , )-(231). In Michaelis-Becker reactions, (229) affords (231) with or without (230),... 

It was also established that alkylation of dialkyl H-phosphonates can be carried out also without phase-transfer catalysts in the presence of potassium carbonate [366]. In this case, the difficulties connected with the separation of the phase-transfer catalyst from the reaction product are avoided. This is one of the advantages of this method. This procedure is the only one so far that allows for Michaelis-Becker alkylation of dimethyl H-phospho-nate by alkyl halides. 

Sodium bis(trimethylsilyl)amide is another base that has been successfully used in a Michaelis-Becker synthesis of alkylphosphonates (Scheme 4.59) [110]. Similar to the other reactions described previously, the reaction proceeds through initial generation of a sodium diaUcylphosphonate followed by the addition of alkyl halide to generate the products. This base is attractive since it is relatively inexpensive and readily available as a solution. Overall, this type of base is significantly less hazardous to use than sodium metal or sodium hydride. The potassium salt of bis(trimethylsilyl)amide has also been used to promote the phosphonation of a benzyl bromide (Scheme 4.60) [111]. This chemistry was attractive as an aryl bromide was retained throughout the Michaelis-Becker chemistry and was available for further functionalization in subsequent reactions. 

By contrast, Michaelis-Arbuzov and Michaelis-Becker reactions of chlorobutynes 10c and lOe, as well as chloroadenallene 45, led to anomalous products. Compound 45 is readily accessible by chlorination S of adenallene (11c) with (C6H5)3P and CCI4 or methanesulfonyl chloride in pyridine (93 and 40% yield, respectively. Scheme 6). In-t estingly, attempted reaction of 11c with 4-toluenesulfonyl chloride and NEt3 in CH2CI2... 

Both the Michaelis-Arbuzov and the Michaelis-Becker reactions are often stereospecific, when compounds containing a chiral phosphorus center are used (retention of configuration), but this property has not been exploited in the synthesis of natural products or their analogs. This is probably a result of often harsh reaction conditions that make them incompatible with the synthesis of more complex, P-chiral molecules. Recently, however, a palladium-catalyzed version of the Michaelis-Becker reaction (a cross-coupling... 

The interaction of trimethyl boric ester and magnesium metliyi iodide in ether, followed by decomjiosition with acidified water, yields methyl boric acid, as white crystals, very volatile and unstable. It has never been isolated in the pure state, but Michaelis and Becker showed that it exerts a methylating action on magnesium phenyl bromide, the products consisting of phenyl boric acid and toluene. The esters of this acid are readily hydrolysed by cold water. 

The reactions belonging to this class of transformations, namely the Michaelis-Arbuzov (Arbuzov) and the Michae-lis-Becker reactions (Scheme 47.1), constitute classic methods for the C P bond formation and are widely used in the synthesis of organophosphorus natural products. ... 

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