Reformatsky-Claisen reaction

Ethyl chlorodifluoroacetate has been used in a silicon-induced Reformatsky-Claisen reaction of allyl chlorodifluoroacetates in the presence ot zinc as a route to 2,2-difluoro unsaturated acids [( S] (equahon 58) When this methodology is applied to chlorodifluoropropargylic esters, the corresponding allenic esters are formed [SS]... 

In the presence of a strong base, the ot carbon of a carboxylic ester can condense with the carbonyl carbon of an aldehyde or ketone to give a P-hydroxy ester, which may or may not be dehydrated to the a,P-unsaturated ester. This reaction is sometimes called the Claisen reaction,an unfortunate usage since that name is more firmly connected to 10-118. In a modem example of how the reaction is used, addition of tert-butyl acetate to LDA in hexane at -78°C gives the lithium salt of ferf-butyl acetate, " (12-21) an enolate anion. Subsequent reaction a ketone provides a simple rapid alternative to the Reformatsky reaction (16-31) as a means of preparing P-hydroxy erf-butyl esters. It is also possible for the a carbon of an aldehyde or ketone to add to the carbonyl carbon of a carboxylic ester, but this is a different reaction (10-119) involving nucleophilic substitution and not addition to a C=0 bond. It can, however, be a side reaction if the aldehyde or ketone has an a hydrogen. 

Reformatsky-type10 reaction into zinc enolates (2) by treatment with zinc dust in a refluxing aromatic hydrocarbon solvent. These undergo Claisen rearrangement to zinc carboxylates (3) of y,unsaturated acids. Yields are depressed by a-alkyl substitution of (1) thus (3) is obtained in 100% yield when R = R2 = CH3 and R3 = R4 = H. When R1 = CH3, R2 and R4 = H, and R3 = C6H5, the yield of (3) is only 16%. 

The Claisen rearrangement, discovered in 1912, has proven to be a powerful tool for the stereoselective generation of C—C bonds . It is widely employed in complex multistep syntheses (see, for example. References 86-89) and has inspired many variations, including the Carroll (1940), Eschenmoser (1964), Johnson (1970), Ireland (1972) and Reformatsky-Claisen (1973) reactions . 

In the Reformatsky-Claisen rearrangement, allylic alcohols arc cstcrificd with a-bromoaeyl bromides and converted to the zinc enolate by reaction with zinc dust in benzene or toluene at 100 110CC. Under these conditions, zinc enolates readily undergo rearrangement to yield ,<)-unsaturated zinc carboxylates99. 

The Reformatsky -Claisen variant is complicated by various side reactions, e.g., the condensation of the zinc enolate derived from acetic esters to yield 1,3-dicarbonyl compounds, known byproducts in the classical Reformatsky reaction. This side reaction is depressed by a-alkyl substitution of the ester. 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

Two further methods for the preparation of p-ketoesters consist of the Reformatsky reaction of pyrazolides[67] (a) and the magnesium bromide-induced Claisen condensation of pyrazolides[68] (b). 

In this reaction, the CH2C12/DMF solvent (9 1) suppresses the undesirable Claisen condensation and increases the yield of 2,2-difluoro-3-hydroxyesters. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which do not undergo the Reformatsky reaction. 

The oldest reaction involving a rearrangement of an organozinc compound is probably the Reformatsky reaction54 55. It took one hundred years until its key step could be classified as a [3,3)-sigmatropic shift ( metallo-Claisen rearrangement) on the basis of computational studies (equation 51)56. 

In the typical old-fashioned Reformatsky protocol12a d, a mixture of a-bromoester, carbonyl compound and zinc powder is heated in a solvent, generally benzene, for several hours. Under these conditions, the chemical yields often suffer from the concurrence of side-reactions, such as self-condensation of enolizable aldehydes, Claisen condensation of bromoesters or crotonization of the Reformatsky products. However, ever since the outset of Reformatsky studies, chemists have been aware about the need to activate the zinc surface in order to get higher reaction rates and shorter induction times before the process starts, with lower by-product formation. Thus, it became common practice to... 

Esters are rarely used as electrophiles in Reformatsky reactions. An example was reported by Atkins and coworkers the quinohne ester 89 failed to react with butanoic acid esters in classical Claisen condensation conditions, but was found to smoothly react with f-butyl ester 90 in the presence of zinc in good yield (equation 54)138. 

Furthermore, 2,2-difluoro-3-hydroxyesters are readily obtained from ClCFjCOOMe and carbonyl compounds by electrolysis in a one-compartment cell using a sacrificial zinc anode and a nickel complex as catalyst. The catalytic cycle for this reaction is shown in Scheme 9 with nickel zinc exchange being a key step. In this process, the CHjCyDMF solvent (9 1) system leads to suppression of undesired Claisen condensation and an increase in the yield of 2,2-difluoro-3-hydroxyester formation. It is notable that high yields are obtained even with ketones and enolizable aldehydes, which are not good participants in the Reformatsky reaction alternative for producing these substances. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

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