Organic synthesis malonic ester

Obaza, J., Smith, F. X. A malonic ester synthesis with acid chlorides. The homologation of dioic acids. Synth. Common. 1982,12, 19-23. Sato, T., Otera, J. CsF in Organic Synthesis. Malonic Ester Synthesis Revisited for Stereoselective Carbon-Carbon Bond Formation. J. 

Extremely dry (or super-dry ) ethyl alcohol. The yields in several organic preparations e.g., malonic ester syntheses, reduction with sodium and ethyl alcohol, veronal synthesis) are considerably improved by the use of alcohol of 99-8 per cent, purity or higher. This very high grade ethyl alcohol may be prepared in several ways from commercial absolute alcohol or from the product of dehydration of rectified spirit with quicklime (see under 4). 

The synthetic importance of the malonic ester synthesis follows from the fact that the substituted malonic ester can easily be hydrolyzed, and subsequently decarboxylates to yield a substituted acetic acid 9. This route to substituted acetic acids is an important method in organic synthesis ... 

Application of 7r-allylpalladium chemistry to organic synthesis has made remarkable progress[l]. As described in Chapter 3, Section 3,7r-allylpalladium complexes react with soft carbon nucleophiles such as malonates, /3-keto esters, and enamines in DMSO to form carbon-carbon bonds[2, 3], The characteristic feature of this reaction is that whereas organometallic reagents are considered to be nucleophilic and react with electrophiles, typically carbonyl compounds, 7r-allylpalladium complexes are electrophilic and react with nucleophiles such as active methylene compounds, and Pd(0) is formed after the reaction. 

Needless to say, /i-keto esters are important compounds in organic synthesis. Their usefulness has been considerably expanded, based on Pd-catalysed reactions of allyl / -keto carboxylates 399. Cleavage of the allylic carbon-oxygen bond and subsequent facile decarboxylation by the treatment of allyl / -keto carboxylates with Pd(0) catalysts generate the 7i-allylpalladium enolates 400, 401. These intermediates undergo, depending on the reaction conditions, various transformations which are not possible by conventional methods. Thus new synthetic uses of / -keto esters and malonates based on Pd enolates have been expanded. These reactions proceed under... 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

Of the very many alkylation methods that have been developed, we can look at only a few first, two classics of organic synthesis, the malonic ester synthesis and the acetoacetic ester synthesis and then, several newer methods. In doing this we shall be concerned not only with learning a bit more about how to make new molecules from old ones, but also with seeing the variety of ways in which carbanion chemistry is involved. 

With only a few exceptions, the fatty acids are all straight-chain compounds, ranging from three to eighteen carbons except for the C3 and C5 compounds, only acids containing an even number of carbons are present in substantial amounts. As we shall see in Sec. 37.6, these even numbers are a natural result of the biosynthesis of fats the molecules are built up two carbons at a time from acetate units, in steps that closely resemble the malonic ester synthesis of the organic chemist (Sec. 26.2). 

Malonic acid undergoes all the characteristic reactions of dicarboxylic acids. Its esters are used in organic synthesis. 

A very useful reaction in organic synthesis is the so-called Michael addition of an organic compound RH to an a,/ -unsaturated system C=C—X, in which X may represent an electron-withdrawing group such as C=0, COOR, C=N, N02, S(=0)R. The addition, in which R attaches to the / -carbon atom to give R—C—CH—X, occurs in a protic medium with sufficiently acidic compounds, e.g., nitroalkanes, alcohols, thiols, malonic esters and requires a basic catalyst. 

There are two classical reaction sequences in organic chemistry that rely on enolate alkylation. One is the malonic ester synthesis.61 jjj synthetic example taken from the Clive and Hisaindee synthesis of brevioxime,62 diethyl malonate was treated with a base such as sodium ethoxide, under thermodynamic control conditions. The resulting enolate anion is treated with the indicated alkyl halide to give the alkylated product 81 (in 72% yield).Saponification of 81 to the dicarboxylic acid (82, in 99% yield), was followed by decarboxylation (sec. 2.9.D) and formation of the substituted acid 83, in 94% yield. ... 

Michael addition is one of the most efficient and effective routes to C-C bond formation[127]. This reaction is widely applied in organic synthesis and several new versions of it have been introduced recently. The commonly employed anionic alkyl synthons for Michael addition are those derived from nitroalkanes, ethyl cyanocarboxylates, and malonates, and their limitations have been largely overcome by newer methodologies. However, the newer approaches are by no means devoid of drawbacks such as long reaction times, modest product yields in many cases, and the requirement for excess nitroalkane. Michael addition reactions of Schiff s bases have long been known to constitute a convenient method for functionalizing a-amino esters at the a position and the ratio of Michael addition to cycloaddition product has been found to depend upon the metal ion employed to chelate the enolate produced upon deprotonation (see below). 

A very interesting development in this area is an application of crown chemistry to the malonic ester synthesis. A one-pot hydrolysis and decarboxylation procedure, using 18-crown-6 and potassium hydroxide in an organic solvent system, has been developed for esters with activating groups (Scheme 52). This procedure, which relies on the ability of 18-crown-6 both to catalyse ester hydrolysis and to facilitate decarboxylation under mild conditions, offers a simplification of what is often the yield-determining part of conventional malonate syntheses. 

The malonic ester synthesis might seem like an arcane technique that only an organic chemist would use. Still, it is much like the method that cells use to synthesize the long-chain fatty acids found in fats, oils, waxes, and cell membranes. Figure 22-4 outlines the steps that take place in the lengthening of a fatty acid chain by two carbon atoms at a time. The growing acid derivative (acyl-CoA) is activated as its thioester with coenzyme A (structure on page 1027). A malonic ester acylation adds two of the three carbons of malonic acid (as malonyl-CoA), with the third carbon lost in the decarboxylation. A )8-ketoester results. Reduction of the ketone, followed by dehydration and reduction of... 

Two specific j8-dicarbonyl compounds have had broad use in organic synthesis. These are acetoacetic ester (ethyl acetoacetate, ethyl 3-oxobutanoate), which can be used to make substituted acetone derivatives, and diethyl malonate (diethyl 1,3-propanedicarboxylic acid), which can be used to make substituted acetic acid derivatives. We shall consider syntheses involving ethyl acetoacetate and diethyl malonate in the upcoming sections of this chapter. 

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