Diethyl malonate enolate

The instructions for this problem point to a disconnection at the nucleophilic alpha carbon, thereby creating a four-carbon electrophile (RX) and a three-carbon nucleophile (enolate). However, the resulting enolate is not stable. Addition of an ester electron-withdrawing group leads to a starting material that can be further simplified. A second disconnection at the alpha carbon results in the familiar diethyl malonate enolate. Recognizing the TM as a derivative of acetic add can help you recognize the double disconnection that is possible. 

Stabilized anions exhibit a pronounced tendency to undergo conjugate addition to a p unsaturated carbonyl compounds This reaction called the Michael reaction has been described for anions derived from p diketones m Section 18 13 The enolates of ethyl acetoacetate and diethyl malonate also undergo Michael addition to the p carbon atom of a p unsaturated aldehydes ketones and esters For example... 

In this reaction the enolate of diethyl malonate adds to the p carbon of methyl vinyl ketone... 

Most of the reactions of ester enolates described so far have centered on stabilized eno lates derived from 1 3 dicarbonyl compounds such as diethyl malonate and ethyl ace toacetate Although the synthetic value of these and related stabilized enolates is clear chemists have long been interested m extending the usefulness of nonstabilized enolates derived from simple esters Consider the deprotonation of an ester as represented by the acid—base reaction... 

Section 21 9 Michael addition of the enolate ions derived from ethyl acetoacetate and diethyl malonate provides an alternative method for preparing their a alkyl derivatives... 

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

Stable enolates such as diethyl malonate anions react with allyl sulfones (or acetates) in the presence of nickel complexes to give a mixture of the a- and /-product83. The regioselectivity is generally poor in the nickel-catalyzed reaction, but the molybdenum-catalyzed reaction is selective for alkylation at the more substituted allylic site, thereby creating a quaternary carbon center84. 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

Free diethyl malonate has the constitution which corresponds to the usual formula there is no evidence for the existence of an enol-OR... 

Diethyl malonate can be converted into its enolate anion, which may then be used to participate in an Sn2 reaction with an alkyl halide (see Section 10.7). Ester hydrolysis and mild heating leads to production... 

The mechanistic steps can be deduced by inspection of structures and conditions. Enolate anion formation from diethyl malonate under basic conditions is indicated, and that this must attack the epoxide in an Sn2 reaction is implicated by the addition of the malonate moiety and disappearance of the epoxide. The subsequent ring formation follows logically from the addition anion, and is analogous to base hydrolysis of an ester. Ester hydrolysis followed by decarboxylation of the P-keto acid is then implicated by the acidic conditions and structural relationships. 

Diethyl malonate has been proposed for use as a proton source in these cyclization reactions [124], It is not a sufficiently strong acid to protonate the radical-anion rapidly. However it irreversibly protonates the enol intermediate generated after carbon-caibon bond formation. In one case, control of stereochemistry in favour of the traHS-sunstituted five membered ring 39 was achieved by the addition of cerium(Ill) ions [124],... 

In its original form, the Michael addition consisted on the addition of diethyl malonate across the double bond of ethyl cinnamate in the presence of sodium ethoxide to afford a substituted pentanedioic acid ester. Currently, all reactions that involve a 1,4-addition of stabilized carbon nucleophiles to activated 7i-systems are known as Michael additions. Among the various reactants, enolates derived from p-dicarbonyl compounds are substrates of choice due to their easy deprotonation under mild conditions. Recently, Michael addition-based MCRs emerged as highly potential methodologies for the synthesis of polysubstituted heterocycles in the five- to seven-membered series. 

Radhakrishna and coworkers showed that DPH Ih reacts with sodium enolates of substituted diethyl malonates to afford a-amino carboxylic acids in good yields (Scheme 13) ". ... 

Recently, Smulik and Vedejs have reported that amination of ester enolates and enim-inates with 0-(p-nitrobenzoyl)hydroxylamine 21 takes place with good yields . However, reaction of enolates derived from ethyl phenylacetate and phenylacetonitrile gave lower yields compared with stabilized enolates derived from diethyl malonate, diethyl 2-phenylmalonate and 2-phenyl-2-cyanopropionate (Scheme 23). 

As the last example of C-C bond-formation reactions catalyzed by alkaline earth hydroxides, we mention the recently reported a-arylation of diethyl malonate in the presence of a palladium catalyst and a base in a separate phase 299). The arylation of carbonyl compounds is a carbon-carbon coupling reaction between an aryl halide and an enolate, which is usually catalyzed by palladium salts in the presence of an appropriate base (300,301). The arylation of diethyl malonate with bromobenzene (Scheme 48) was performed with tetrachloropalladate as the... 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

Scheme 6.61 Mechanistic proposals of the 12-catalyzed asymmetric Michael addition of diethyl malonate to trans-P-nitrostyrene proposed by the Takemoto group (A, B, and C) and initial enolate complex (D) with the ammonium group as additional hydrogen-bond donor initiating an alternative mechanism suggested by Sods, Ptipai, and coworkers.

Deprotonation of methylene groups containing two electron-withdrawing alkoxycarbonyl groups with an appropriate base easily converts them into their corresponding enolate anions. These enolate anions are able to attack carbon electrophiles to form new C —C bonds. One of the important applications of this reaction is to construct small carbocyclic rings, in particular cyclobutanes. For example, intermolecular condensation of l,3-dibromo-2,2-dimethylpropane (1) and the dipotassium salt of diethyl malonate (2) gives diethyl 3,3-dimethylcyclobutane-l,l-dicarboxylate (3).18... 

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