A J-ketoesters

One significant difference from the simple aldol reaction, however, is that the original adduct (113) now possesses a good leaving group (OEt) thus instead of adding a proton, as in the aldol reaction proper (p. 224), OEt is lost to yield a /J-ketoester, ethyl 3-ketobutanoate (ethyl acetoacetate, 114). This is finally convert by base ( OEt) into its stabilised (delocalised) carbanion, (115). 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

Fig. 13.4. Stereoselective deprotonation of a /J-ketoester to trialkylammonium or sodium enolates. The E- and Z-enolates are formed when NEt3 and NaH, respectively, are employed.

Functional group substituents on N-l of 2-pyrazolin-5-ones (Table XXXVII) are acyl, sulfonyl and various carboxyl derivatives, such as carbalkoxy, amides, thioamides, hydrazides, thiohydrazides and amidines. The usual synthesis of these compounds is by the classical 2-pyrazolin-5-one synthesis, reaction of a /J-ketoester with a hydrazine. In these cases the hydrazines are special types such as hydrazide,... 

When a catalytic amount of base is used, the most effective nucleophiles are enolates derived from relatively acidic compounds such as (J-ketoesters or malonate esters. The adduct anions are more basic than the nucleophile and are protonated under the... 

There have been a few reports recently of substantial MW rate enhancements of reactions of polar reactants in nonpolar solvents [53, 54], Soufiaoui et al. [53] have synthesized a series of l,5-aryldiazepin-2-ones 36 in high yield in only 10 min by the condensation of o-aryldiamines 34 with /J-ketoesters 35 in xylene under MW irradiation in open vessels (Scheme 4.18). The temperature at the end of these reactions was shown to be 136-139 °C. Surprisingly, they observed that no reaction occurred when the same reactions were heated conventionally for 10 min at the same temperature. These results could be taken as evidence for a specific MW effect. 

This type of reaction is usually best performed in DMSO solution. A simpler procedure has been proposed which uses anionic activation and microwave irradiation, with a metallic salt as the reagent and a PTC in the absence of solvent [75], This procedure was applied to the striking example of cyclic /J-ketoesters with considerable improvements (Eq. 53 and Tab. 5.25) which are readily apparent when the maximum yields obtained under classical Krapcho conditions (<20% when R-H) are considered [76],... 

Figure 16. Main features in enantioselective hydrogenation of a-ketoesters on cinchona alkaloid-modified metal catalysts [ 143]. [Reproduced with permission of Elsevier from Baiker, A. J. Mol. Catal. A 1997,115, 473-493.]...

The reaction of a, -unsaturated ketones 93, obtained from j -ketoesters 36 and chiral aldehydes 94 [derivatives of D-glyceral (92TL3809,93T7133), and D-mannitol (93T7133)], with MN have been used for the first time in the synthesis of optically pure 2-aminopyrans 95. Yields and diastereos-electivity were low however, recrystallization afforded one of the stereoisomers in a nearly pure state (d.e. 80-100%) (Scheme 27). 

Figure 1.41 a-Chloro-/J-ketoester using engineered Escherichia coli cells. 

Tautomerism, strictly defined, could be used to describe the reversible interconversion of isomers, in all cases and under all conditions. In practice, the term has increasingly been restricted to isomers that are fairly readily interconvertible, and that differ from each other only (a) in electron distribution, and (b) in the position of a relatively mobile atom or group. The mobile atom is, in the great majority of examples, hydrogen, and the phenomenon is then referred to as prototropy. Familiar examples are /J-ketoesters, e.g. ethyl 2-ketobutano-ate (ethyl acetoacetate, 23), and aliphatic nitro compounds, e.g. nitro-methane (24) ... 

Table 8.6 shows that the equilibrium mixture consists of almost entirely keto form in the case of simple aliphatic and aromatic ketones, whereas significant amounts of enol tautomer are present in /J-diketones and /J-ketoesters. In these latter cases, the enol contains a conjugated tt electron system and an intramolecular hydrogen bond (30). Phenol exists entirely in the enol form, as the alter-... 

Condensation of orf/zo-aryldiamines with /J-ketoesters by irradiation with microwaves in xylene gives very good yields of l,5-arylodiazepin-2-ones by a novel and simple route (equation 204)720. 

Concentrated sulphuric acid is generally used as the condensing agent for simple monohydric phenols and /J-ketoesters, although phenol itself reacts better in the presence of aluminium chloride (Expt 8.45). The mechanism of the reaction is thought to involve the initial formation of a -hydroxy ester, which then cyclises and dehydrates to yield the coumarin. 

A couple of examples of /J-ketoester systems are given in Scheme 4.53. In each case, the second carbonyl gives rise to additional shielding. 

The common intermediate in two published biomimetic routes to Lythraceae alkaloids was substituted 4-phenylquinolizid-2-one. In one approach based on a biogenetic hypothesis of Ferris et al. (62), Wrobel and Gol biewski condensed pelletierine (126) with isovanillin (128) and obtained a transfused quinolizidine derivative (130, jS H-5) (64) in 75% yield. A model condensation of pelletierine (126) with benzaldehyde which resulted in a mixture of quinolizidones was reported earlier by Matsunaga et al. (65). In another approach Rosazza et al. (52) condensed A -pjperideine (132) with /J-ketoester 133 to get 134. The next stage in both approaches was reduction of the ketone and esterification or transesterification with derivatives of p-hydroxycinna-mic acid (135 or 136). Investigations into the oxidative coupling of 137 were unsuccessful. 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

If the enolization has enough time to proceed, the transformation in Figure 12.4 completely leads to a brominated /J-ketoester. Basically, the same method can be employed to also a-brominate ketones (Figure 12.5), alkylated malonic acids (Figure 12.6), acid bromides (Figure 12.7,12.8) and acid chlorides (not shown). The mechanistic details are detailed in the cited figures. Look at how similar they are. 

The butylated /J-ketoester C of Figure 13.26 is not the final synthetic target of the acetoacetic ester synthesis of methyl ketones. In that context, the /J-ketoester C is converted into the corresponding /J-ketocarhoxylic acid via acid-catalyzed hydrolysis (Figure 13.27 for the mechanism, see Figure 6.22). This /i-ketocarboxylic acid is then heated either in the same pot or after isolation to effect decarboxylation. The /f-ketocarboxylic acid decarboxylates via a cyclic six-membered transition state in which three valence electron pairs are shifted at the same time. The reaction product is an enol, which isomerizes immediately to a ketone (to phenyl methyl ketone in the specific example shown). 

The cyclic /J-ketoester E subsequently can be saponified in acidic medium. The acid obtained then decarboxylates via the mechanism of Figure 13.27 to provide the ester-free cycloalkanone D. Product D represents the product of a CH2 insertion into the starting ketone. 

Addition occurred in 2-trimethylsilyloxy-furan upon treatment with PhlO-BF3-Me3SiN3, with direct formation of 5-azidofuranone [99]. Some / -diketones and /j-ketoesters underwent a-azidation by PhIO-Me3SiN3 [100],... 

Reactions of unsymmetrical methylene 1,3-dicarbonyl compounds with enol ethers have been investigated by Yamauchi et al. [137]. As we have mentioned earlier, the a,/ -unsaturated ketone moiety in alkylidene-/ -ketoesters reacts exclusively as the oxabutadiene. However, high regioselectivity is also observed with mixed alkyl-phenyl-1,3-diketones with exclusive reaction of the aliphatic carbonyl group, whereas in alkylidene-1,3-dicarbonyl compounds bearing an aldehyde and a keto-moiety, the a,/J-unsaturated aldehyde reacts preferentially as oxabutadiene, but not exclusively [130a]. 

The synthesis of PYRUVOYL CHLORIDE from the corresponding acid not only represents the method of choice for the preparation of this substance, but can be applied to other acids as well. A one-pot procedure for the preparation of ETHYL 2-BUTYRYLACETATE illustrates another general method for the synthesis of /J-ketoesters. The synthesis of 4-PENTYLBENZOYL CHLORIDE by direct electrophilic substitution of 4-pentylbenzene with phosgene, derived in situ from oxalyl chloride, can likewise be applied to other aromatic substrates. 

A few natural products which contain the cyclopropyl ring have been synthesized through metal catalysed cyclopropanation using dicarbonyl diazomethanes. ( )-Cycloeudesmol 63, isolated from marine alga Chondria oppositiclada, was synthesized via a sequence involving a copper catalysed cyclopropanation of a-diazo-j -ketoester 61 to give the key intermediate 62 (equation 73) . Similarly, the bicyclo[3.1. OJhexane derivative 65 was synthesized from the corresponding a-diazo-j5-ketoester 64 via the catalytic method and was converted into ( )-trinoranastreptene 66 (equation 74). Intramolecular cyclopropanation of a-diazo-j -ketoesters 67 results in lactones 68 which are precursors to 1-aminocyclopropane-l-carboxylic acids 69 (equation 75) . 

Recently Gordeev et al. reported (140, 141) the synthesis and iterative deconvolution of a 300-member focused library of 1,4-dihydropyridines L5 as potential calcium channel blockers inspired by the strucmre of nifedipine and other known bioactive compounds. The library was built on SP as 30 pools of 10 individuals, following the synthetic scheme shown in Fig. 7.18. Rink amine resin was deprotected, split into 10 portions (steps a and b), and treated with P-ketoesters (step c. Mi, 10 representatives A-J, Fig. 7.19) to give 10 discrete N-supported P-enaminoesters 7.30. The resin aliquots were then mixed (step d) and split again into 30 identical, 10-member pools (step e). Each resin portion was treated with a different combination of 1,3-dicarbonyls (M2, three representatives K-M, Fig. 7.19) and aldehydes (M3, 10 representatives N-W, Fig. 7.19) to give 30 pools of 10 open-chain precursors 7.31 (step f), which were cyclatively cleaved to give the final hbrary L3 (step g. Fig. 7.18). Library QC was performed by off-bead MS, identifying all the expected molecular ions in several pools. 

Also used as a spectral comparison model for the elucidation of the B and G aflato-xinsss this compound was prepared in a multi-step synthesis. The von Pechmann condensation of phloroglucinol dimethyl ether (59)133 with diethyl cyclopentane-4,5-dione-l, 3-dicarboxylate (41) in acidic solution afforded the /J-ketoester (42), which readily underwent decarboalkoxylation, in a seperate step, to give the keto-coumarin (5). The beauty of this methodology is illustrated by the use of the symmetrical diketoester (41), which of course, only allows for the formation of a single coumarin (von Pechmann) product (42). The regiochemistry of the final product, however, was demonstrated to be the incorrect isomer insofar as the aflatoxin structures were concerned. 

A method frequently used and capable of a large number of variations is the cyclization of a-substituted-jS-ketoesters, apiides or hydra-zides with hydrazines to 4-arylazo-2-pyrazolin-5-ones. One variant of this is the treatment of an a,/J-diketoester with hydrazine (eq. 182).627,1573,1574,1576 Instead of the ester, hydrazides of a j8-diketoacids... 

Acyl-2-pyrazoIin-5-ones have been synthesized by three general methods. These are cyclization of aliphatic compounds, conversion of other 2-pyrazolin-5-ones and conversion of other heterocycles. As might be expected the reaction of /J-ketoesters with hydrazines has been utilized.124,1124,1532,1533 In this case the /J-ketoester has an a-acyl substituent (eq. 216). Both Borsche and Lewinsohn124 and Vila1533... 

A few bis(l-acyl-2-pyrazolin-5-ones) are known. Those linked through N-l have been prepared by reaction of carbazide with two equivalents of a /J-ketoester1037,1632 either with255 or without isolation of the intermediate hydrazone. The bis compounds linked at C-3 or C-4 are prepared by reaction of bis(/3-ketoesters) with semicarbazide.357,1222... 

The Dieckmann condensation is an intramolecular variant of the Claisen condensation where a diester is converted to a 3-ketoester. Typically, an alkoxide is used as the base to form the enolate which attacks the remaining ester to form the carbocycle. Five- and six-membered rings are formed readily with this method. Reviews (a) Davis, B. R. Garrett, P. J. In Comprehensive Organic Synthesis, Trost, B. M. Fleming, 1. Eds. Pergamon Press Oxford, 1991 Vol. 2, Chapter 3.6 Acylation of Esters, Ketones, and Nitriles, pp. 806-829. (b) Schaefer, J. P Bloomfield, J. J. Org. React. 1967,15, 1-203. 

An intramolecular variation of the ene/enone photocycloaddition is described by J. D. Winkler. As already described for the intermolecular transformation (see Demuth s enone cycloaddition reaction), a dioxenone is formed via cyclization of a 3-ketoester and subsequently irradiated. Intramolecular cycloaddition then leads to a strained tetracyclic photoproduct which can be ring-opened and decarboxylated to give the trans-fused bicyclo[5.3.1 ]undecan-11 -one. 

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