Dicarbonyl enolates, reactions with electrophiles

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

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. 

Other Electrophiles. In addition to carbonyl compounds, ester enolate (1) also reacts with other electrophiles. With nitrones, the product is dependent upon the structure of the nitrone a,N-dialkyl nitrones provide alkenes, while a-aryl-A-alkyl nitrones or aW-diaryl nitrones usually give aziridines. With the phenylhy-drazone of a 1,2-dicarbonyl compound, reaction with (1) provides a convenient preparation of 3(2f/)-P3 dazinones (eq 3). ... 

During the coverage period of this chapter, reviews have appeared on the following topics reactions of electrophiles with polyfluorinated alkenes, the mechanisms of intramolecular hydroacylation and hydrosilylation, Prins reaction (reviewed and redefined), synthesis of esters of /3-amino acids by Michael addition of amines and metal amides to esters of a,/3-unsaturated carboxylic acids," the 1,4-addition of benzotriazole-stabilized carbanions to Michael acceptors, control of asymmetry in Michael additions via the use of nucleophiles bearing chiral centres, a-unsaturated systems with the chirality at the y-position, and the presence of chiral ligands or other chiral mediators, syntheses of carbo- and hetero-cyclic compounds via Michael addition of enolates and activated phenols, respectively, to o ,jS-unsaturated nitriles, and transition metal catalysis of the Michael addition of 1,3-dicarbonyl compounds. ... 

Hydroxycoumarin can be considered as an enol tautomer of a 1,3-dicarbonyl compound conjugation with the aromatic ring favours the enol tautomer. This now exposes its potential as a nucleophile. Whilst we may begin to consider enolate anion chemistry, no strong base is required and we may formulate a mechanism in which the enol acts as the nucleophile, in a simple aldol reaction with formaldehyde. Dehydration follows and produces an unsaturated ketone, which then becomes the electrophile in a Michael reaction (see Section 10.10). The nucleophile is a second molecule of 4-hydroxycoumarin. 

The intramolecular interaction between an enolate and a carbonyl electrophile to form a six-membered ring is a well-known and general method (e.g. the Robinson annulation, see Section 2.3.3). This and related cyclization reactions involving interactions between 1,5-dicarbonyl moieties proceeds with high selectivity (A), and the alternative option, the formation of a four-membered ring (B), is much less favorable and rarely observed (Scheme 2.108). The usefulness of this method for the preparation of compounds containing the cyclohexenone moiety is abundantly documented in the literature. 

The enolate of a P-dicarbonyl compound is acidic. The resultant anion may be neutralized by reaction with an electrophile either on the central carbon (Scheme 3.38a) or on an oxygen atom (Scheme 3.38b). This reactivity of 3-dicarbonyl compounds makes them extremely useful in synthesis. 

Aldol reactions with dicarbonyl compounds can be used to make five- and six-membered rings. The enolate formed from one carbonyl group is the nucleophile, and the carbonyl carbon of the other carbonyl group is the electrophile. For example, treatment of 2,5-hexanedione with base forms a five-membered ring. 

Sakhibullina, V.G., Polezhaeva, N.A., and Arbuzov, B.A., Reactions of enolate anions of P-oxophos-phonates and P-dicarbonyl compounds with electrophiles, Zh. Obshch Khim., 56, 2479,1986 J. Gen. Chem. USSR (Engl. Transl.), 56, 2193, 1986. 

Dicarbonyl compounds may be converted into dianions, which react with electrophiles at the more basic site. Huckin and Weiler found that 3-keto ester dianions undergo aldol addition reactions at the more basic methyl position (equation 32). The lithium/sodium dianion shows surprisingly weak reactivity, giving the aldol in only 11% yield after 1 h at -78 °C In contrast, the lithium enolates of simple ketones and esters, which should be much less basic than the 3-keto ester dianion, react with aldehydes to give nearly quantitative yields of aldols in THF in seconds at -78 °C. ° Seebach and Meyer also studied this reaction, and obtained the oxolactone (equation 33). Simple diastereoselection in the reaction of 3-keto ester dianions has also been studied (vide infra). 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

We had to be careful in chapter 25 when we wanted to add bromoketones 4 to enolates 3 to make the 1,4-dicarbonyl compound 5. We could not use a lithium enolate because it would be too basic. No such difficulties exist in the reaction of enolates with allylic halides such as 2. Any enol(ate) equivalent will do as there are no acidic hydrogens and allylic halides are good electrophiles for the Sn2 reaction. 

When a normal carbonyl compound is treated with catalytic acid or base, we have a small proportion of reactive enol or enolate in the presence of large amounts of unenolized electrophile. Aldol reaction (self-condensation) occurs. With 1,3-dicarbonyl compounds we have a small proportion of not particularly reactive unenolized compound in the presence of large amounts of stable (and hence unreactive) enol. No aldol occurs. 

The cyclizations of 85 to 86 and of 87 to 88 represent the simple cases in which the internal nucleophile is the OH group of an alcohol [64,65]. An in situ generated hydroxy group, as in the addition of alcohols to carbonyl compounds, can also participate in phenylseleno-etherification reactions. This is examplified by the conversion of 89 into 90 in the presence of benzyl alcohol [66]. Another type of OH, which gives rise to these reactions is the enolic OH of /1-dicarbonyl compounds. Thus, Ley reported that compounds like 91 and 93 can be transformed into the cyclic derivatives 92 and 94 by treatment with N-PSP 11 in the presence of zinc iodide [67]. The cyclization of 95 to 96 represents a simple example of the selenolactonization process [68, 69]. It is interesting to note that the various cyclization reactions indicated in Scheme 14, which require different electrophilic selenenylating agents, can all be effected with phenyselenyl sulfate [70]. 

These allyl cation complexes 229 are electrophilic and react with a variety of nucleophiles, most notably with the stabilised enolates of P-dicarbonyl compounds such as malonates. The immediate product is again a Jt-complex of Pd(0) 230 but there is now no leaving group so the Pd(0) drops off and is available for a second cycle of reactions. Though the reaction strictly requires Pd(0), the more convenient Pd(II) compounds are often used with phosphine ligands. Reduction to Pd(0) occurs either because the phosphine is a reducing agent or by oxypalladation and p-elimination. 

Interesting heteroatom-substituted derivatives such as 67 have also been synthesized via the reaction of bis enol ether 66 with thiol-containing dicarbonyl electrophiles, Eq. 54 [81]. Compound 68 bearing a bridgehead silyl substituent was produced from the reaction of 65 with a ketoacylsilane [82], Subsequent decarboxylation and desilylation of 68 generates 69, Eq. 55. The overall sequence represents a method to obtain the product of a formal inversion of the usual reactivity of 65 with ketoaldehydes. Extensive studies failed to reverse the observed regio selectivity. 

Methoxy- and 2-acetoxy-furans are available from 2,5-dimethoxy- and 2,5-diacetoxy-2,5-dihydro-furans (18.1.1.4) via acid-catalysed elimination. They undergo Diels-Alder cycloadditions the adducts can be further transformed into benzenoid compounds by acid-catalysed opening. 3,4-Dihydroxyfuran is undetectable in tautomeric equilibria between mono-enol and dicarbonyl forms the dimethyl ether behaves as a normal furan, undergoing easy a-electrophilic substitution, mono- or dilithiation at the a-position(s), and Diels-Alder cycloadditions. 2,5-Bis(trimethylsilyloxy)furan is synthesised from succinic anhydride it too undergoes Diels-Alder additions readily. Both furan-2- and -3-thiols can be obtained by reaction of lithiated furans with sulfur in each case the predominant tautomer is the thiol form. ... 

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