Alkylation of p-dicarbonyl compounds

Although this looks complicated, if we start with what we are sure about, the later steps will become obvious. First, the ethyl acetoacetate is deprotonated, and the anion opens the epoxide at the less hindered site (although these anions do react with primary chlorides, this clearly has not 

FIGURE 17.39 Ethyl acetoacetate and diethyl malonate in synthesis. 

RC(=0)C1. The carbanion form of the enolate is a soft nucleophile (with some character of a carbon-carbon double bond) and reacts best with the soft electrophiles RBr and RI. 

5ilyl enol ethers are alkylated by 5 1-reactive electrophiles in the presence of Lewis acid 

While the greater nucleophilicity of azaenolates means that they will react with a wider range of electrophiles, their basicity, like that of lithium enolates, means that they will not react with SNl-reactive electrophiles like tertiary alkyl halides. The solution to this problem is to use silyl enol ethers, which are less reactive and so require a more potent electrophile to initiate reaction. Carbocations will do, and they can be generated in situ by abstraction of a halide or other leaving group from a saturated carbon atom. 

The best alkylating agents for silyl enol ethers are tertiary alkyl halides they form stable carbocations in the presence of Lewis acids such as TiCl4 or SnCl4. Most fortunately, this is just the type of compound that is unsuitable for reaction with lithium enolates or enamines, as elimination results rather than alkylation a nice piece of complementary selectivity. Below is an example the alkylation of cyclopentanone with 2-chloro-2-methylbutane. The ketone was converted to the trimethylsilyl enol ether with triethylamine and trimethylsilylchloride we discussed this step on p. 466 (Chapter 20). Titanium tetrachloride in dry dichloromethane promotes the alkylation step. 

The resulting anions are alkylated very efficiently. This diketone is enolized even by potassium carbonate, and reacts with methyl iodide in good yield. Carbonate is such a bad nucleophile that the base and the electrophile can be added in a single step. 

Enolates stabilized by two of the following electron-withdrawing groups may be formed with alkoxides COR, CO2R, CN, 

The presence of two, or even three, electron-withdrawing groups on a single carbon atom makes the remaining proton(s) appreciably acidic (pK 10-15), which means that even mild bases can lead to complete enolate formation. With bases of the strength of alkoxides or weaker, only the multiply stabilized anions form protons adjacent to just one carbonyl group generally have a pK 20. The most important enolates of this type are those of 1,3-dicarbonyl or p-dicarbonyl) compounds, 

Among the P-dicarbonyls, two compounds stand out in importance—diethyl (or dimethyl) mal-. A 

With these two esters, the choice of base is important nucleophilic addition can occur at the ester carbonyl, which could lead to transesterification (with alkoxides), hydrolysis (with hydroxide), or amide formation (with amide anions). The best choice is usually an alkoxide identical with the alkoxide component of the ester (th t is, ethoxide for diethyl malonate methoxide for dimethyl malonate). Alkoxides (pfC 16) are basic enough to deprotonate between two carbonyl groups but, should substitution occur at C=0, there is no overall reaction. 

In this example the electrophile is the allylic cyclopcntenyl chloride, and the base is ethoxide in ethanol—most conveniently made by adding one equivalent of sodium metal to dry ethanol. 

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Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

Alkylation of p-dicarbonyl compounds, cyano esters and malonodinitrile (Table 6.9)... 

The application of dianion chemistry in synthesis is not confined to 7-alkylation of p-dicarbonyl compounds. Dianions derived from p-keto sulfoxides can be alkylated at the 7 -carbon atom. Nitroalkanes can be deprotonated twice in the a-position to give dianions 7. In contrast to the monoanions, the dianions 7 give C-alkylated products in good yield (1.19). ... 

Moreno-Manas, M., Marquet, J., Vallribera, A. Synthetic and mechanistic aspects of a-alkylation and a-arylation of P-dicarbonyl compounds via their transition metal complexes. Russ. Chem. Buil. 1997, 46, 398-406. 

The a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

Alkylation of (3-dicarbonyl compounds is highly regioselective for the a carbon flanked by two carbonyl groups. A proton at this carbon in a P-ketone is relatively acidic (p a 9) and is removed by bases even as weak as carbonate. 

Two procedures called the acetoacetic ester synthesis and the malonic ester synthesis take advantage of the properties of p-dicarbonyl compounds and are standard methods for making carbon-carbon bonds. Both begin with alkylation of the enolate. Ethyl esters are normally used, with sodium ethoxide as the base. 

A hypervalent iodine-induced intramolecular cyclization of the a-(aryl)alkyl-P-dicarbonyl compound 482 furnishes the spirobenzannulated chroman 483 in good yield (Equation 197) <2001JOC59>. 

For acylations with reactive esters, such as formate or oxalate (see Section 3.6.4.5), sodium alkoxides are still the bases of choice, but sodium hydride, dimsyl sodium, sodium or potassium amide or sodium metal have all been used for the in situ generation of the enolate anion. A typical example is shown in Scheme 47. Acylation by esters results in the production of 1 equiv. of the alkoxide ion, along with the p-dicarbonyl compound proton transfer then results in the production of the conjugate base of the dicarbonyl compound. This process normally leads to the more stable anion in the acylation of an unsymme-trical ketone. The acyl group thus becomes attached to the less-substituted a-position of the ketone. The less stable 0-acylated products are normally not observed in such reversible base-catalyzed reactions. Methyl alkyl ketones are normally acylated on the methyl group where both a-carbons are substituted to the same extent, acylation occurs at the less-hindered site. Acylation is observed only rarely at a methine carbon as the more stable p-diketone enolate cannot be formed. 

Rubottom oxidation reactions have been conducted on enolsilanes derived from a number of different carbonyl derivatives including carboxylic acids and esters.15 For example, the Rubottom oxidation of bis(trimethylsilyl)ketene acetal 30 provided a-hydroxy carboxylic acid 31 in 81% yield. Use of alkyl trimethylsilyl ketene acetal substrates generates a-hydroxy esters, as seen in the conversion of 32 to 33.16 The synthesis of 3-hydroxy-a-ketoesters (e.g., 36) has been accomplished via Rubottom oxidation of enolsilanes such as 35 that are prepared via Homer-Wadsworth-Emmons reactions of aldehydes and ketones with 2-silyloxy phosphonoacetate reagent 34.17 The a-hydroxylation of enolsilanes derived from P-dicarbonyl compounds has also been described, although in some cases direct oxidation of the P-dicarbonyl compound is feasible without enolsilane formation.18... 

The use of chelation to direct the stereochemical outcome of intramolecular additions of allylsilanes to P-dicarbonyl compounds can provide excellent levels of diasteieoselectivity. Cyclizations of this type proceed at low temperature under mild reaction conditions and are highly chemoselective, provit g routes to highly functionalized five-, six- and seven-membered rings (10 100b and 100c Scheme 47). For the cases examined, SnCU and FeQa proved to be less effective than TiCU in the cyclization of ethyl 2-alkyl-2-alkanoyl-4-(t ethyl8ilyl)methyl-4-pentenoale(99 = 1 Table 13). ... 

Catalytic reactions of allylic electrophiles with carbon or heteroatom nucleophiles to form the products of formal S 2 or S 2 substitutions (Equation 20.1) are called "catalytic allylic substitution reactions." Tliese reactions have become classic processes catalyzed by transition metal complexes and are often conducted in an asymmetric fashion. The aUylic electrophile is typically an allylic chloride, acetate, carbonate, or other t)q e of ester derived from an allylic alcohol. The nucleophile is most commonly a so-called soft nucleophile, such as the anion of a p-dicarbonyl compound, or it is a heteroatom nucleophile, such as an amine or the anion of an imide. The reactions with carbon nucleophiles are often called allylic alkylations. 

The synthesis of (polyhydroxy)alkyl-furan, -pyrrole, and -indole derivatives, etc., by condensation of aldoses and ketoses with P-dicarbonyl compounds has been reviewed. ... 

Use retrosynthetic analysis to choose the appropriate p-dicarbonyl compound and alkyl halide to prepare each of the following ... 

Additionally, unsubstituted and 6-substimted 2-(perfluoroalkyl)-4/f-pyran-4-ones 4 have been prepared using alkyl enolates derived from p-dicarbonyl compounds. The reaction of acetylacetone enol ether with ethyl perflnoroalkanoates in the presence of i-BuOK, followed by p-TsOH catalyzed cychzation in benzene afforded pyrones 4a,b in 57-75 % yields. Similarly, the parent compounds 4c,d were obtained from the for-mylacetone derivative in 40-64 % yields [4]. Analogue 4e was accessible in low yield from the corresponding triketone [5] (Scheme 2). 

In the previous section, synthesis of pyrimidine derivatives bearing fluorinated alkyl substituent at C-2 atom was discussed. Derivatives of fluorinated carboxylic acids and related compounds were used as the fluorine sources. The most important method for the preparation of other chain-fluorinated pyrimidines is the principal synthesis from fluoroalkyl-substituted three-carbon bis-electrophiles (e.g. p-dicarbonyl compounds). A huge number of fluorinated bis-electrophiles were introduced in the principal synthesis of pyrimidines bearing fluoroalkyl substituent at C-4 atom of the heterocyclic ring (Fig. 24), including fluorine-containing ... 

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