J8-ketoester

The enedione (283) is a useful starting material for a two-step synthesis of 2,3,4,5-tetrasubstituted furans which are not otherwise readily accessible (81JCS(P1)2398). Michael addition of an active methylene compound, e.g. (284), to the enedione (283) led to the two regioisomeric adducts (285) and (286) which could then be cyclized to furans (287) and (288) under mild conditions (Scheme 75). The formation of Michael adducts was successful with both j8-ketoesters (284) and cyclic 1,3-diones. Normal routes to furans require much more drastic conditions the Michael addition allowed the preparation of 1,4-diones particularly activated by the presence of an easily enolizable group. This is a useful synthetic pathway because alternative routes for the preparation of complex furans are not at present available. 

Examples are known where intermolecular carbenoid transformations between diazomalonates or certain diazoketones and appropriate olefins result in competition between formation of cyclopropane and products derived from allylic C—H insertion2-4. For example, catalytic decomposition of ethyl diazopyruvate in the presence of cyclohexene gave the 7-ejco-substituted norcarane 93 together with a small amount of the allylic C—H insertion product 94 (equation 95)142 143. In some cases, e.g. rhodium(II) decomposition of a-diazo-j8-ketoester 95, the major pathway afforded C—H insertion products 96 and 97 with only a small amount of the cyclopropane derivative 98. In contrast, however, when a copper catalyst was employed for this carbenoid transformation, cyclopropane 98 was the dominant product (equation 96)144. The choice of the rhodium(II) catalyst s ligand can also markedly influence the chemoselectivity between cyclopropanation and C—H... 

Scheme 12 shows a series of reactions between 2-bromomethyl-pyridine and compounds containing active methylene groups the sequence 12(a) may be varied by using derivatives of acetylacetone or malonic ester instead of a j8-ketoester.40 Reactions 12(b) and 12(c) provide useful routes to 3-hydroxy and 3-amino compounds, which are noted for their instability in air (although 62 was stable in air for several weeks).30... 

Acetylisothiazoles have also been obtained from 5-cyanoisothiazoles and methylmagnesium iodide and by hydrolysis of j8-ketoesters derived from isothiazole-5-carboxylic esters.70... 

In this experiment proton NMR spectroscopy is nsed in evalnating the equilibrium composition of various keto-enol mixtures. Chemical shifts and spin-spin splitting patterns are employed to assign the spectral features to specific protons, and the integrated intensities are used to yield a quantitative measure of the relative amounts of the keto and enol forms. Solvent effects on the chemical shifts and on the equilibrium constant are investigated for one or more j8-diketones and j8-ketoesters. 

For acetone and the majority of cases in which this keto-enol tautomerism is possible, the keto form is far more stable and little if any enol can be detected. However, with j8-diketones and j8-ketoesters, such factors as intramolecular hydrogen bonding and conjugation increase the stability of the enol form and the equilibrium can be shifted significantly to the right. 

CpFe(CO)2(THF)](BF4) gives ds-epoxides as minor product and ketones as major product with phenyldiazomethane (Sch. 30) [140], Evidence presented suggests that a Fe-Lewis acid-catalyzed process is operative rather than a metal carbene mechanism. The use of ethyldiazoacetate in this reaction gives, besides the expected j8-ketoester (minor product), the 3-hydroxy-2-phenylacrylic acid ethyl ester [141],... 

The mercaptals obtained by the acid catalyzed reaction of j8-ketoesters, e.g., ethyl acetoacetate, with methyl thioglycolate (73) undergo the Dieckmann cyclization with alcoholic potassium hydroxide at lower temperatures to give ethyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (74) in 75% yield. Besides ethyl acetoacetate, ethyl a-ethylacetoacetate, ethyl benzoyl acetate, and ethyl cyclopentanonecarboxylate were also used in this reaction/ It is claimed that /3-diketones, hydroxy- or alkoxy-methyleneketones, or )8-ketoaldehyde acetals also can be used in this reaction. From acetylacetone and thioglycolic acid, 3,5-dimethyl-2-thiophenecarboxyl-ic acid is obtained/ ... 

Monocyclic l,4-diazepin-5-ones and fused l,5-benzodiazepin-2-ones, e.g. (169) and (170), can be readily prepared by the reactions of 1,2-diamines with j8-ketoesters <67AHC(8)2l, p. 57, 68CRV747, p. 776, 71JHC797). Similarly reactions with malonic acids and esters give l,4-diazepine-5,7-diones (171) (67AHC(8)21, pp. 55, 69, 68CRV747, p. 78l). 

The most important kinds of conjugate addition reactions are Michael reactions, which involve the addition of C nucleophiles to C=C 7r bonds. The nucleophiles are often 1,3-dicarbonyl compounds such as malonates, cyanoacetates, j8-ketoesters, and 1,3-diketones, but simple carbonyl compounds may also be used. Only catalytic amounts of base are usually required. 

As shown in eq. 3 (p. 9) the reaction of acyl arylhydrazines with jS-ketoesters forms 2-aryl-3-pyrazolin-5-ones.679,849,984,988,1001 The aeyl group is lost in the cyclization and these products have no N-l substituent. Formyl-, acetyl- and benzoylhydrazines may be used. This is a very frequently employed method for preparation of 2-aryl-3-pyrazoIin-5-ones. The condensing agents generally used have been phosphorus trichloride, phosphorus oxychloride and phosphorus penta-chloride. A modification of this, also mentioned earlier, has been the condensation of a symmetrically substituted hydrazine with a j8-ketoester to give l,2-disubstituted-3-pyrazolin-5-ones.54,370 The sub-... 

The standard /3-ketoester-hydrazine reaction for preparation of 2-pyrazolin-5-ones has been used for direct synthesis of the 4-oximino derivatives by starting with an a-oximino-jS-ketoester.269,1125,1534,1536 In a modification of this by Biilow and Bozenhardt258 a hydrazone of the a-oximino-j8-ketoester was used. Ponzio and Ruggeri1125 have used a-oximino-j8-hydrazonohydroxamic acids and hydrazines, and other oximino compounds, as illustrated in eq. 209. 

Scheme 2.95 Asymmetric electrophilic fluorination of j8-ketoesters, catalyzed by chiral titanium TADDOL complexes (Np = 1-naphthyl, R = Et, R = 2,4,6-(/Pr)3C6H2-CH2) pH].

Xanthone derivatives can be obtained by oxidation of the hydroxyxanthanes prepared by the Paquette method or by employing the same method on derivatives of salicylic acid ° or j8-ketoesters ° . With the latter procedure compounds 349 and 350, respectively, were prepared. 

The reaction of a-hydrazino-j8 -ketoesters (509) with hydroxylamine produced 4-hydrazinoisoxazolin-5-ones (510) (71GEP2024393, 70JMC1250). 

The condensation of monosaccharides with j8-ketoesters and related compounds ... 

A major route to 2-amino-6/f-l,3,4-thiadiazines is by the condensation of a-haloketones with thiosemicarbazides (Section 6.17.7.2.2(ii)). Replacement of the thiosemicarbazide by a thiocarbamic acid or by a thiocarbazide results in formation of 3,6-dihydro-2//-l,3,4-thiadiazin-2-ones. Likewise, replacement with an A -arylthiohydrazide yields a 4//-l,3,4-thiadiazin-5(6/f)-one (Section 6.17.7.2.2(ii)). 3,6-Dihydro-27/-thiadiazin-2-ones are also available by the condensation of alkyl-hydrazines with a-(methoxycarbonylsulfenyl)alkylaryl ketones (Section 6.17.7.2.2(vi)), while the ring closure of (arylhydrazonoalkylthio)acetic acids with dicyclohexylcarbodiimide provides an alternative route to 4 -l,3,4-thiadiazin-5(677)-ones (Section 6.17.7.1.2). 2-Phenylimino-3-aryl-2,3-dihydro-l,3,5-thiadiazin-6-ones result from treatment of a-hydrazono-j8-ketoesters with aryl-isothiocyanates (Section 6.17.7.2.2(iv)). 

A dedicated combinatorial approach for rapid parallel synthesis of polymer-bound enones has been reported [30]. The two-step procedure combines initial high-speed acetoacetylation of Wang resin with a selection of common j8-ketoesters (Scheme 16.6) with subsequent microwave-mediated Knoevenagel condensations with a set of 13 different aldehydes (Section 16.1.8). Acetoacetylations were performed successfully in parallel within 10 min in open PEA vessels, in 1,2 dichlorobenzene at 170 °C, using a multi-vessel rotor system. 

A method for microwave-assisted transesterifications has been published [74]. The microwave-mediated derivatization of poly(styrene-co-allyl alcohol) was investigated as key step in the polymer-assisted synthesis of heterocycles. The procedure was applied to several j8-ketoesters and multigram quantities of products were obtained when neat mixtures of the reagents in open vessels were exposed to micro-wave irradiation in a domestic microwave oven. The soluble supports obtained were used for preparation of a variety of bicyclic heterocycles, for example pyrazo-lopyridinediones or coumarins. 

Pyrroles are the core unit of a wide variety of natural products [76]. Although many methods are available for the synthesis of these species, most are multi-step procedures resulting in low yields [77, 78]. However, Hantzsch made another important contribution to the progress of multicomponent chemistry. In his procedure pyrroles were successfully prepared from primary amines, j8-ketoesters, and a-halo-genated j5-ketoesters [79]. Only a few other one-step procedures have been reported for pyrroles but, because of to long reaction times and insufficient scope of substitution at the ring, these are not very satisfactory [80, 81]. 

The base-catalyzed reaction of j8-ketoesters with a-halogenoketones (Feist-Benary reaction) <02CB 1545,11CB493 > yields 3-alkoxycarbonylfurans (23) (Scheme 16). Usually the reaction starts with an aldol condensation if in the first step an alkylation of the ) -carbonyl compound takes place, the reversed regiochemistry is observed <68JH05>. 

This reaction was first reported by Haddadin and Issodorides in 1965. It is the preparation of quinoxaline-1,4-dioxides from the cycloaddition between benzofuroxan (i.e., benzofu-razan A -oxide) and dienes, a.y -unsaturated ketones, enamines, or enolates. Unfortunately, this reaction is not named after the authors who discovered it instead it is known as the Beirut reaction after the city in which the inventors carried out is the initial work. In most cases, ketones," /3-diketones, j8-ketoesters, )8-ketonitrile, LS-dinitrile, and/8-ketoamides all are suitable for this reaction, and the corresponding enolates can be easily prepared in the presence of a weak base such as triethylamine. In addition, even phenolic enolates from phenol, resorcinol, hydroquinone, or benzoquinone undergo a similar dehydrative condensation with benzofuroxan under mild conditions (e.g., Na0H/H20, H2O, MeOH/RNH2, Si02/MeCN at room temperature), to give phenazine iV,iV -dioxide derivatives. ... 

The alkylation of substances such as )8-diketones, j8-ketoesters, and esters of malonic acid can be carried out in alcoholic solvents using metal alkoxides as bases. The presence of two electron-withdrawing substituents favors formation of a single enolate by abstraction of a hydrogen from the carbon situated between them. Alkylation then occurs by an Sn2 process. 

The same research group has also demonstrated a catalytic enantioselective tandem carbonyl yhde formation-cycloaddition of the a-diazo-j8-ketoester 91 using 0.5 mol% of Rh2(R-DDBNP)4 95, as catalyst to afford the cycloadduct 93 in good yields (Scheme 28) with up to 90% ee [ 109]. A detailed study on enantioselective reaction using a series of dirhodium tetrakiscar-boxylate and tetrakisbinaphtholphosphate catalysts under different solvent conditions has been described [56]. These studies indicate that dirhodium tetrakisbinaphtholphosphate catalysts are superior to the more commonly used carboxylates and carboxamidates in asymmetric transformations. Typically, the reaction [58] of the nitrophenyl-substituted diazodione 96 and phenyl acetylene in the presence of the binaphthyl catalyst 95 at 0 °C afforded the cycloadduct 97 with 76% ee (Scheme 29). 

The mechanism of a Dieckmann condensation is identical to the mechanism we described for the Claisen condensation. An anion formed at the a-carbon of one ester in Step 1 adds to the carbonyl of the other ester group in Step 2 to form a tetrahedral carbonyl addition intermediate. This intermediate ejects ethoxide ion in Step 3 to regenerate the carbonyl group. Cyclization is followed by formation of the conjugate base of the j8-ketoester in Step 4, just as in the Claisen condensation. The j8-ketoester is isolated after acidification with aqueous acid. 

In a crossed Claisen condensation (a Claisen condensation between two different esters, each with its own a-hydrogens), a mixture of four j8-ketoesters is possible therefore, crossed Claisen condensations of this type are generally not synthetically useful. Such condensations are useful, however, if appreciable differences in reactivity exist between the two esters, as, for example, when one of the esters has no a-hydrogens and can function only as an enolate anion acceptor. These esters have no a-hydrogens ... 

Claisen condensation A carbonyl condensation reaction between two esters to give a j8-ketoester. 

This review describes rearrangements of aUyUc esters bearing oxygen, amino and sulfur substituents in the a- or jS-position of the acid moiety. In principle, chelate formation can also be proposed in the rearrangement of j8-ketoesters, but this so-called Carrol rearrangement is described in Chapters. 

The activity of rhodium (and ruthenium) NHC complexes in hydrosilylation of ketones was already reported in 1977 by Hill and Nile (300). Recently, several new rhodium NHC complexes allowing enantioselective hydrosilylation of ketones and j8-ketoesters were developed (for review, see (220)). 

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