Esters malonic, synthesis

Besides the direct method of enolate alkylation discussed in Section 23.8, a new alkyl group can also be introduced on the a carbon using the malonic ester synthesis and the acetoacetic ester synthesis. 

The acetoacetic ester synthesis prepares methyl ketones having two general structures  

The malonic ester synthesis is a stepwise method for converting diethyl malonate into a carboxylic acid having one or two alkyl groups on the a carbon. To simplify the structures, the CH3CH2 groups of the esters are abbreviated as Et. 

Before writing out the steps in the malonic ester synthesis, recall from Section 22.11 that esters are hydrolyzed by aqneons acid. Thus, heating diethyl malonate with acid and water hydrolyzes both esters to carboxy gronps, forming a 3-diacid (1,3-diacid). 

P-Diacids are unstable to heat. They decarboxylate (lose CO2), resnlting in cleavage of a carbon-carbon bond and formation of a carboxylic acid. Decarboxylation is not a general reaction of all carboxylic acids. It occurs with P-diacids, however, because CO2 can be eliminated through a cyclic, six-atom transition state. This forms an enol of a carboxylic acid, which in turn tautomerizes to the more stable keto form. 

Treatment of 2-methylcyclohexanone with NaOCH2CH3 in CH3CH2OH solution at room temperature forms the more substituted thermodynamic enolate, which then reacts with CH3I to form B. 

Problem 23.18 How can 2-pentanone be converted into each compound  

Tamoxifen has been commercially available since the 1970s, sold under the brand name of Nolvadex. 

Tamoxifen, the chapter-opening molecule, is a potent anticancer drug that has been used to treat certain forms of breast cancer for many years. One step in the synthesis of tamoxifen involves the treatment of ketone A with NaH as base to form an enolate. Alkylation of this enolate with CH3CH2I forms B in high yield. B is converted to tamoxifen in several steps, some of which are reactions you have already learned. 

Identify A, B, and C, intermediates in the synthesis of the five-membered ring called an a-methylene-7 butyrolactone. This heterocyclic ring system is present in some antitumor agents. 

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By the malonic ester synthesis (compare Section 111,165), for example ... 

The thermal decarboxylation of malonic acid derivatives is the last step m a multistep synthesis of carboxylic acids known as the malonic ester synthesis This synthetic method will be described m Section 21 7... 

The malonic ester synthesis is a method for the preparation of carboxylic acids and is represented by the general equation... 

The malonic ester synthesis is conceptually analogous to the acetoacetic ester synthesis The overall transformation is... 

The properties of diethyl malonate that make the malonic ester synthesis a useful procedure are the same as those responsible for the synthetic value of ethyl acetoacetate The hydrogens at C 2 of diethyl malonate are relatively acidic and one is readily removed on treatment with sodium ethoxide... 

Among the methods for preparing carboxylic acids carboxylation of a Grignard reagent and preparation and hydrolysis of a nitrile convert RBr to RCO2H The malonic ester synthesis converts RBr to RCH2CO2H... 

In a typical example of the malonic ester synthesis 6 heptenoic acid has been pre pared from 5 bromo 1 pentene... 

By performing two successive alkylation steps the malonic ester synthesis can be applied to the synthesis of a a disubstituted derivatives of acetic acid... 

The malonic ester synthesis has been adapted to the preparation of cyclo alkanecarboxyhc acids from dihaloalkanes... 

Section 21 7 The malonic ester synthesis is related to the acetoacetic ester synthesis Alkyl halides (RX) are converted to carboxylic acids of the type RCH2COOH by reaction with the enolate ion derived from diethyl mal onate followed by saponification and decarboxylation... 

The most widely used method for the laboratory synthesis of a ammo acids is a modification of the malonic ester synthesis (Section 21 7) The key reagent is diethyl acetamidomalonate a derivative of malonic ester that already has the critical nitrogen substituent m place at the a carbon atom The side chain is introduced by alkylating diethyl acetamidomalonate m the same way as diethyl malonate itself is alkylated... 

Malonic ester synthesis (Section 21 7) Synthetic method for the preparation of carboxylic acids involving alkylation of the enolate of diethyl malonate... 

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 ... 

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