Enols from 1,3-dicarbonyl compounds

When ethoxide is used as a base to abstract a-proton, it could react with the alkyl halide (Sn2) to form ether. However, the acid-base equilibrium with the diketone prefers the more stable, less basic enolate over the ethoxide, essentially consuming the ethoxide. Thus, the very stable enolates from 1,3-dicarbonyl compounds are able to undergo Sn2 reactions with alkyl halides without competition from the alkoxide catalyst. 

This sequence illustrates the use of enolates from 1,3-dicarbonyl compounds in Michael reactions they are useful too in alkylations, aldol condensations (Knoevenagel conditions), and reactions with epoxides, as in the synthesis3 of 20. Nowadays they tend to be used if they are readily available, or if the disconnections suggest their use, as in the building of 11 into 18. Examples include the diketone 11 and the six-membered equivalent both used in steroid synthesis, acetoacetates 16 and 19 and the keto-lactones 20, malonic acid 21 and its esters, "Meldrum s acid 22, a very enolisable malonate derivative,4 and the keto-ester 25 formed via its stable enolate 24, by the cyclisation of the diester 23, an intermediate in nylon manufacture. The compounds 11,16, 19, 20 R=H, 21, 22, and 25 are all available commercially. 

Indium(III) chloride catalyzes the microwave-assisted reaction of a-azidochalcones 34 with 1,3-dicarbonyl compounds 35 in water to form polysubstituted pyrroles 36 (Scheme 11) [42]. The reaction has been explained through the formation of an azirine interm iate. Addition of enols from 1,3-dicarbonyl compounds on azirines forms aziridines, which undergo ring opening to form a,(5-unsaturated amines. The amines cyclize via dihydropyrroles to form pyrroles. 

The best-known reactions belonging to this class are based either on the photo-NOCAS process [32] or on the photochemistry of Barton esters [69]. In the first case, a three-component reaction involving a cyanoarene, an olefin, and a nucleophile (usually the solvent) occurs. The reaction is generally initiated by a PET process between the aromatic and the olefin. The examples presented below are chosen from among the most representative and most recent. A typical reaction is illustrated in Scheme 3.26, where an enolized P-dicarbonyl compound acts as an added nucleophile. 

More complex carbonyl compounds can be much more strongly enolized. P-Dicarbonyl compounds (1,3-dicarbonyl compounds) exist largely in their enol forms, for example (Fig. 19.21). In the enol forms of these compounds, it is possible to form an intramolecular hydrogen bond, thus forcing the equilibrium position away from the diketo forms. There is also conjugation between the carbon—carbon... 

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... 

The procedure described illustrates a general method for the preparation of o ,j3-unsaturated aldehydes and ketones from the enol ethers of 3-dicarbonyl compounds. 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The enolate anion 1 may in principle be generated from any enolizable carbonyl compound 4 by treatment with base the reaction works especially well with /3-dicarbonyl compounds. The enolate 1 adds to the a ,/3-unsaturated compound 2 to give an intermediate new enolate 5, which yields the 1,5-dicarbonyl compound 3 upon hydrolytic workup ... 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

The enolized form of 2-acetyl-2-cyclohexen-l-one has been synthesized in low yield by dehydrochlorination of 2-acetyl-2-chlorocyclohexanone in collidine at 180° and by elimination of acetamide from 3-acetamido-2-acetylcyclohexanone at 120-140°. The preparation of other a,/3-unsaturated /3-dicarbonyl compounds has been attempted with varying degrees of success. The... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Nickel-based Ziegler catalysts can be prepared using halogen-free or-ganoaluminum compounds of low Lewis acidity, e.g., dialkylaluminum alkoxides. However, the catalytic properties of these systems differ remarkably from those described above. The nickel components in such a case may be nickel acetylacetonate, or the nickel enolates of various other /3-dicarbonyl compounds (44, 45), in particular such halogenated /3-dicarbonyl compounds as hexafluoroacetylacetone (44, 46). 

Aside from alcohols, other oxygen nucleophiles have also participated in hydroalkoxylation reactions with alkynes. The most common of these are 1,3-dicarbonyl compounds, whose enol oxygens are readily available to add to alkynes. Cyclization reactions of this type have been carried out under Pd(0) catalysis with various aryl or vinyl iodides or triflates, often in the presence of CO, affording the corresponding furan derivatives (Equation (95)).337-340 A similar approach employing cyclic 1,3-diketones has also been reported to prepare THFs and dihydropyrans under Pd, Pt, or W catalysis.341 Simple l-alkyn-5-ones have also been isomerized to furans under the influence of Hg(OTf)2.342... 

The preferential -configuration of the enol esters, derived from p-dicarbonyl compounds under phase-transfer conditions, contrasts with the formation of the Z-enol esters when the reaction is carried out by classical procedures using alkali metal alkoxides. In the latter case, the U form of the intermediate enolate anion is stabilized by chelation with the alkali metal cation, thereby promoting the exclusive formation of the Z-enol ester (9) (Scheme 3.5), whereas the formation of the ion-pair with the quaternary ammonium cation allows the carbanion to adopt the thermodynamically more stable sickle or W forms, (7) and (8), which lead to the E-enol esters (10) [54],... 

Vitamin C, also known as L-ascorbic acid, clearly appears to be of carbohydrate nature. Its most obvious functional group is the lactone ring system, and, although termed ascorbic acid, it is certainly not a carboxylic acid. Nevertheless, it shows acidic properties, since it is an enol, in fact an enediol. It is easy to predict which enol hydroxyl group is going to ionize more readily. It must be the one P to the carbonyl, ionization of which produces a conjugate base that is nicely resonance stabilized (see Section 4.3.5). Indeed, note that these resonance forms correspond to those of an enolate anion derived from a 1,3-dicarbonyl compound (see Section 10.1). Ionization of the a-hydroxyl provides less favourable resonance, and the remaining hydroxyls are typical non-acidic alcohols (see Section 4.3.3). Thus, the of vitamin C is 4.0, and is comparable to that of a carboxylic acid. 

The asymmetric allylic C-H activation of cyclic and acyclic silyl enol ethers furnishes 1,5-dicarbonyl compounds and represents a surrogate of the Michael reaction [136]. When sufficient size discrimination is possible the C-H insertion is highly diastereoselective, as in the case of acyclic silyl enol ether 193 (Eq. 22). Reaction of aryldia-zoacetate 192 with 193 catalyzed by Rh2(S-DOSP)4 gives the C-H insertion product 194 (>90% de) in 84% enantiomeric excess. A second example is the reaction of the silyl enol ether 195 with 192 to form 196, a product that could not be formed from the usual Michael addition because the necessary enone would be in its tautomeric naphthol form (Eq. 23). 

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. 

It is not customary to attempt the isolation of ketone or aldehyde intermediates (121) the formula serves merely as a reminder that once hydrolysis of the protecting enol ether or acetal occurs, the same type of structure is formed from any given dicarbonyl compound. Cyclization has been carried out in refluxing ethanolic picric acid or acetic anhydride with a few drops of sulfuric acid, but Hansen and Amstutz (63JOC393) offered excellent theoretical reasons for avoiding an excess of acid, and reported that best results (Table 3) can be obtained by refluxing the dry hydrobromide in acetic anhydride containing no sulfuric acid. 

Magnesium enolates derived from /S-dicarbonyl compounds can be easily obtained by metallation with l-PrMgBr. A stable cyclic chelate is obtained. As example, the magnesium enolate of mixed malonate is shown in equation 48. 

The reaction with optically active hydrazones provided an access to optically active ketones. The butylzinc aza-enolate generated from the hydrazone 449 (derived from 4-heptanone and (,S )-1 -amino-2-(methoxymethyl)pyrrolidine (SAMP)) reacted with the cyclopropenone ketal 78 and led to 450 after hydrolysis. The reaction proceeded with 100% of 1,2-diastereoselectivity at the newly formed carbon—carbon bond (mutual diastereo-selection) and 78% of substrate-induced diastereoselectivity (with respect to the chiral induction from the SAMP hydrazone). The latter level of diastereoselection was improved to 87% by the use of the ZnCl enolate derived from 449, at the expense of a slight decrease in yield. Finally, the resulting cyclopropanone ketal 450 could be transformed to the polyfunctional open-chain dicarbonyl compound 451 by removal of the hydrazone moiety and oxymercuration of the three-membered ring (equation 192). 

The enolates from p-dicarbonyl compounds are so easily formed that they can be used in a very simple carbon-carbon bond forming reaction outside our general scheme. Consider what would happen if you made the enolate anion from the compound below and reacted it with methyl iodide. 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Numerous examples of the preparation of tetramic acids from N-acylated amino acid esters by a Dieckmann-type cyclocondensation have been reported (Entries 7-9, Table 15.4). Deprotonated 1,3-dicarbonyl compounds and unactivated amide enolates can be used as carbon nucleophiles. In most of these examples, the ester that acts as electrophile also links the substrate to the support, so that cyclization and cleavage from the support occur simultaneously. The preparation of five-membered cyclic imi-des is discussed in Section 13.8. 

Apart from their fundamental role in sulfur ylide chemistry, sulfonium salts have found applications as soft electrophiles. In alkylation of ambident nucleophiles such as the enolates of [3-dicarbonyl compounds they led to selective C-alkylation [205],... 

Dicarbonyl compounds.1 The reaction of enol silyl ethers with methyl vinyl ketone catalyzed by BF3 etherate results in 1,5-dicarbonyl compounds. Almost quantitative yields can be obtained, even from hindered ketones, by addition of an alcohol or even, to a less extent, of water. 

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