Michaelis-Arbuzov reaction acids

The Arbuzov reaction,also called the Michaelis-Arbuzov reaction, allows for the synthesis of pentavalent alkyl phosphoric acid esters 4 from trivalent phosphoric acid esters 1 (Z,Z = R,OR) by treatment with alkyl halides 2. 

Preparation of tris(trimethylsilyl) phosphite — Preparation of a silyl ester of a trivalent phosphorus acid for Michaelis-Arbuzov reaction... 

In the instances of phosphorous and phosphonous acid systems, the generation of a new C-P bond via the classical Michaelis-Arbuzov reactions as noted above leads to products that are esters themselves. Isolation of the free acid product requires cleavage of the ester linkage in a separate reaction step, generally after isolation and purification of the initial product. The advent of silyl phosphorus reagents for the Michaelis-Arbuzov reaction allowed free acid products to be isolated simply by water workup of the reaction system. Further, since the byproduct was a silyl-halide, the general concern that the by-product halide would participate in an extraneous Michaelis-Arbuzov reaction was obviated. 

A useful approach for the preparation of chiral (3-aminophospho-nic acids from the naturally occurring a-amino acids has been reported.139 The overall scheme (Equation 3.4) involves formation of the phthalimide-acid halide from the starting a-amino acid followed by a Michaelis-Arbuzov reaction with triethyl phosphite to give the acylphosphonate. Complete reduction of the carbonyl group in three steps followed by hydrolysis of the ester and amide linkages provides the target material in very high yield without racemization (>99% ee). 

The Michaelis-Arbuzov reaction of methyl 5-deoxy-5-iodo-2,3-0-isopropylidene-/ -D-ribofuranoside38 (43) with diethyl ethylphosphonite gave,35 in 80% yield, the 5-C-[(ethoxy)ethylphosphinyl] derivative which, on treatment with SDMA and then mineral acid, yielded (30%) 5-deoxy-5-C-[(RS)-ethylphosphinyl]-D-ribopyranose (44) as a mixture of diastereoisomers. These compounds showed no mutarotation in methanol during 24 h. Upon treatment with acetic anhydride-pyridine, the product, 44, was converted (90% yield) into a syrup, presumably consisting of four diastereoisomers of the peracetate 45, separation of which was not attempted. Treatment of 45 with sodium methoxide in methanol regenerated 44 quantitatively. 

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... 

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 nucleophihc 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 Michaehs Becker reaction. ... 

The formation of the diaryl ester of the phosphonic acid as shown in equation (23) requires stronger heating than for other Michaelis-Arbuzov reactions using alkyl esters. This is the result of difficulty in accomplishing the nucleophilic displacement reaction on the aromatic ring. More will be noted later (see Section 5.2) concerning the Michaelis-Arbuzov reaction of aryl esters of phosphorous acid. 

Quasiphosphonium ions involving oxygen directly bound to the positive phosphorus site are generated as intermediates in numerous other reactions. For example, the Michaelis-Arbuzov reaction (see Section 3.5) produces a quasiphosphonium ion as an intermediate that undergoes attack by the associated amon at the carbon end of the C T P linkage. The reaction follows a different course when aryl ester linkages are present on the starting trivalent phosphorus acid derivative. In such instances, a quasiphosphomum ion is... 

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). 

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. " ... 

Triethyl phosphite does not react with aldimines in EtOH. However, the addition of HCOgH (1 eq) to the (EtO)3P/aldimine mixture in EtOH induces an exothermic reaction resulting in the exclusive formation of the iminoalkylphosphonate. Undoubtedly, the 1,4-addition of triethyl phosphite is promoted by initial protonation at the nitrogen atom, which activates the double bond toward Michael addition and generates the formate anion for the dealkylation step (Michaelis-Arbuzov reaction). The dialkyl-substituted formylphosphonates are obtained by hydrolysis of the imine function with an appropriate hydrolytic procedure using either 6 M HCl or 1 M oxalic acid. The method provides a simple and convenient access to a broad range of substituted diethyl 2-formyl-alkylphosphonates in satisfactory overall yields (45-80%). ... 

Unsaturated 3-fonnylphosphonates can be prepared by a Michaelis-Arbuzov reaction that employs l,l-diethoxy-4-bromo-2-butene as the masked formyl group. Reaction with triethyl phosphite at ISS C gives diethyl 4,4-diethoxy-2-butenylphosphonate in 50% yield. Deprotection is accomplished in 98% yield using a cold-saturated aqueous solution of tartaric acid. ... 

The Michaelis-Arbuzov reaction has been applied to t/7.v(trialkylsilyl) phosphites, which, on reaction with aliphatic or aromatic acyl halides in Et2O or CgHg at room temperature, undergo the rearrangement in mild conditions to produce the valuable fczXtrialkylsilyl) 1-oxoalkyl- or 1-oxoarylphosphonates in good yields (50-77%, Scheme 7.6). - Free acylphosphonic acids are obtained by treatment of the trimethylsilyl) esters with EtOH or by exposure to air for several hours. 

A relatively general procedure for the preparation of dialkyl 2-oxoalkylphosphonates by direct acylation of dialkyl 1-lithioalkylphosphonates has been introduced by Corey and Kwiatkowski in 1966. The use of phosphonate carbanions as nucleophiles in reaction with carboxylic esters avoids the problems associated with the Michaelis-Arbuzov reaction. The reaction sequence is initiated by the addition at low temperature of dimethyl 1-lithiomethylphosphonate (2 eq and frequently more) to a carboxylic ester (1 eq) to give the transient lithium phosphonoenolate. The dimethyl methylphosphonate, being readily available and easy to eliminate, is the most frequently used phosphonate, but other phosphonates such as diethyl and diisopropyl methylphosphonates can be used. When the resulting enolate is treated with acid, dimethyl 2-oxoalkylphosphonate is produced in moderate to good yields (45-95%, Scheme 7.20). The reaction has been achieved with... 

The dimethyl 2-methoxycarbonyl-2-(methoxyimino)ethylphosphonate used in the Homer-Wadsworth-Emmons reaction as an amino acid synthon is prepared by masking the carbonyl group of methyl bromopymvate with methoxyamine hydrochloride before submission to a Michaelis-Arbuzov reaction with trimethyl phosphite (Scheme 8.37).5 "5 By contrast, unprotected 3-benzoyl-... 

Because dialkyl 2-oxo-(0-(alkoxycarbonyl)alkylphosphonates are valuable synthetic intermediates that may be either converted to die corresponding amino compounds or treated with a variety of carbonyl compounds in a Homer-Wadsworth-Emmons reaction,procedures that effect their preparation are of special importance. The Michaelis-Arbuzov reaction, which furnishes low yields, does not appear to be an appropriate method for the preparation of dialkyl 2-oxo-(fl-(alkoxycarbonyl)alkylphosphonates. One of the most attractive synthetic methods involves the chemoselective reaction of a-metallated dialkyl alkylphosphonates with acylating reagents such as carboxylic acid chlorides, cyclic anhydrides, or esters. 

The 2-amino-4-phosphonobutanoic acid is available by a Michaelis-Arbuzov reaction from triethyl phosphite and ethyl 4-bromobutanoate followed by acid hydrolysis of the ester groups, bromination, and aimnonolysis. After treannent with ion-exchange resin (Dowex SOW), the pure acid is obtained in 48% yield - ... 

Alkyl, Cycloalkyl. Aralkyl and Related Acids. - Reports on Michaelis-Arbuzov reactions continue to be widely distributed throughout the literature. Phosphite-phosphonate isomerization occurs in the presence of copper(I)... 

From a synthetic viewpoint, the significant feature of the classical Michaelis-Arbuzov reaction of an alkyl halide with a P(III) ester is the formation of a carbon-phosphorus bond. Since its discovery by Michaelis and Kaehne (222) in 1898, it has been the principle synthetic route to the phosphonic acids, which, with their esters and amides, probably outnumber all other compounds containing the carbon-phosphorus bond (105). 

Bicyclic phosphites (297) undergo the Michaelis-Arbuzov reaction when treated with alky] halides at somewhat higher temperatures than required for the simple esters of phosphorous acid. The boat conformation which is undoubtedly an intermediate is presumably converted to the thermodynamically stable chair form. 

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