Michaelis-Becker reaction acids

Tertiary phosphine oxides and sulfides are also produced by way of the Michaelis-Arbuzov reaction beginning with phosphonous esters [R2POR ] and thiophosphonous esters [R2PSR ], when used in reaction with haloalkanes (see Section 3.5). Similarly, phosphine oxides are formed from trivalent phosphorus reagents in the Michaelis-Becker reaction as well as the conjugate addition reactions of phosphinous acid derivatives with a, -unsaturated compounds (see Section 3.5). 

The synthesis of a number of phosphonate derivatives of methylenecyclo-propane nucleoside analogues (86a-l) has been reported by Zemlicka. Most were obtained by an alkylation-elimination approach. Starting from a meth-anesulfonate, methylenecyclopropane phosphonates were obtained by Michaelis-Becker reaction with alkyl phosphites and converted to vicinal dibromides, subsequently used for alkylation-elimination of nucleic acid type bases. All compounds were evaluated against herpes viruses, hepatitis B and HIV and were found to be inactive except for (86b), which was found to inhibit VZV proliferation. 

The more readily accessible diesters can replace the triesters of phosphorous acid in the preparation of phosphonic diesters. The alkylation of the diesters, which must be presented as anions, by primary alkyl halides occurs exclusively on the phosphorus atom (Michaelis-Becker reaction). 

Halogenoalkyl and Related Acids. - The synthesis of (2-chloroethyl)phos-phonic acid has been reviewed. Michaelis-Arbuzov and Michaelis-Becker reactions continue to be employed in the synthesis of polyhalogenated-alkyl... 

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. 

Michaelis-Becker reactions between sodium dialkyl phosphites and halogenated alkenes, seem to occur only with polyhalogenated alkenes, but the course of the reaction is then complicated by elimination and addition steps. Thus sodium dialkyl phosphites and 1,1,2-trichlorophenylethene react to give, ultimately, esters of (1-phenyl-1,2,2-ethane)trisphosphonic acid. Such reactions have been reviewed. ... 

As in all Michaelis-Arbuzov and Michaelis-Becker reactions, the usual order of decreasing reactivity at the carbon-halogen bond, I > Br > Cl > F, applies with carbon-fluorine bonds tending to be unreactive, other than in exceptional circumstances. Even for diiodomethane, the most reactive dihalomethane, reactions with trialkyl phosphites can be made to yield esters of (iodomethyl)phosphonic acid (11 R = O-alkyl, R = alkyl, n=, X = I or in the presence of more phosphite ester, the methylenebisphosphonic ester 12... 

Both the Michaelis-Arbuzov and the Michaelis-Becker reactions have served to obtain thio ethers in the phosphonic and phosphinic acid series. 

The more customary Michaelis-Becker reaction has not been widely adopted for the synthesis of oxoalkyl-phosphonic or -phosphinic esters, and only isolated examples are to be noted, sometimes in combination with a Michaelis-Arbuzov step. The steps in Scheme 51 were adopted to furnish acylphosphorus(V) derivatives of a carbohydrate nucleus (R = a carbohydrate moiety), and a similar sequence (Scheme 52) starts with bis(trimethylsilyl) hypophosphite and can provide novel bis(l-oxoalkyl)phosphinic acids, e.g.53r ... 

In complete contrast to the (l-oxoalkyl)phosphonic acids, for which essentially only one synthesis is available, based on the Michaelis-Arbuzov or Michaelis-Becker reactions, there are several procedures available for the synthesis of those acids with the 0x0 group at C(2) or at a carbon atom site even further from the phosphoryl centre. Historically, esters of (2-oxoalkyl)phosphonic acids were also obtained through application of the Michaelis-Arbuzov and Michaelis-Becker reactions, but it soon became apparent that complications occur, the major one being the concomitant formation, in many instances, of enol phosphates and, in some cases, this reaction became the main one, indeed, sometimes the only one. Several other procedures are now available for the preparation of oxoalkyl acids which place the 0x0 group accurately and with no side reactions of any importance, and these are therefore considered first in the following survey. 

Even more surprising is the Michaelis-Becker reaction of allene 45 with sodium diethyl phosphite in THF-HMPA mixture which gave , -4 -phosphonate 50 in 23% yield (Scheme 8). Dealkylation of 50 furnished phosphonic acid 51. The formation of 2 -phosphonate 47 by a rearrangment of intermediate 52 was expected according to the lite-... 

The phosphonylation, via a Michaelis-Becker-type reaction, and the phosphonomethylation, with lithiated phosphonate carbanions, " of protected ketones have been applied to the preparation of 4-oxoalkylphosphonates after acidic hydrolysis. 

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... 

The current intensified interests in the preparation of PEMs have prompted us to synthesize aromatic monomers such as trifluorovinyl ethers functionalized by acid groups. In particular, we reported the first preparation of 4-[(a,, -trifluorovinyl)oxy] benzene phosphonic acid (Fig. 2.21) [99]. [(a,, -Trifluorovinyl)oxy]benzene dialkyl phosphonate was prepared by several phosphonation methods, such as Michaehs-Arbuzov, Michaelis-Becker, or palladium-catalyzed arylation in the presence of various reactants. The reaction involving palladium triphenylphosphine as the catalyst led to the best yield [99]. 

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