7-Ketocarboxylic esters

In contrast to the results above, the reaction of a-ketocarboxylic esters follows a different course giving 26, the product of P-H addition of the tautomeric PH phosphazene form to the keto C=0 double bond [126] (Scheme 27). 

Highest yields are obtained when the reaction is carried out in boiling toluene until all water and ethanol are eliminated by azeotropic distillation. Other /S-ketocarboxylic esters such as ethyl benzoyl acetate, o-methoxybenzoyl acetate and ethyl acetonedicarboxylate react similarly with aromatic amidoximes (50). 

Variations of the synthesis of MOT derivatives from AT include the reactions of 3-ketocarboxylic esters with 1-formylaminoguanidine, which is an intermediate in the preparation of AT (82JAP57/175193), or with AT in situ (83JAP58/124787). 

Synthesis A also may lead to N-substituted TPs. 4-Alkyl-ATs and 5-alkylamino-1,2,4-triazoles are cyclized by 3-ketocarboxylic esters (and equivalents) forming 3- and 4-alky 1-oxo-TPs, respectively [67JCS(C)503 70GEP1946315 87T2497]. Similar reactions with 1,3-diketones afford the following 1,3,4-triazolo[ 1,5-a]pyrimidinium salts 3-methyl (74KGS565),... 

In general, 1,3-dicarbonyl compounds, which include y9-dialdehydes, y9-ketoaldehydes, y -diketones, and y -ketocarboxylic esters, can exist in solution or as the pure compound in three tautomeric forms the diketo form (4a), the cw-enoUc (4b), and the trans-enolic form (4c). 

Addition of aldehydes to activated double bonds. Aldehydes (1) react with a,f unsaturated carboxylic esters (2a), ketones (2b), or nitriles under the catalytic influence of sodium cyanide to give y-ketocarboxylic esters (3a), y-diketones (3b), or y-ketonitriles... 

Several further reports have appeared on the interaction of tervalent phosphorus isocyanates and a-ketocarboxylic esters, giving (22) (see Organophosphorus Chemistry Vol. 7, p. 126 Vol. 8, p. 107) in the case of ethyl benzoylformate, the isomeric compounds (23) and (24 R =Ph, R = C02Et) are also formed, and the... 

Ketocarboxylic esters condense with AT, as a rule, to give exclusively 7-oxo derivatives (see Scheme 1) an exception is that of a side reaction in a special case (93JHC1325). Esters having instead a 3-acetal or 3-enolether functionality, however, are known to tend to reverse reactivity (e.g., 99EUP947516, 04MI2). 2-Chlorocin-namic acid (15a, Scheme 6) or its ester remarkably also behave so (00CHE1329). 

Boehringer Ingelheim applied a chiral auxiliary for introduction of the trifluor-omethyl group in their synthesis of indole and azaindole trifluoropentanols (Figure 9.7). Under tetrabutylammonium fluoride catalysis the trifluoromethylation to the chiral a-ketocarboxylate ester results in a 84 16 diastereoselectivity. Further crystallization yields enantiopure material that is saponified to the acid under recovery of the chiral auxiliary. Transformation to the epoxide and construction of the azaindole from alkynyl pyridine [73] give access to the whole class of enantiopure pentanol indoles and azaindoles including BI 115. 

The standard synthesis for 2,4-dihydro-3//-pyrazol-3-ones is the cyclocondensation of hydrazine, alkyl-or arylhydrazines with y ketocarboxylic esters Knorr synthesis, 1883), e.g. ... 

Formal cycloaddition processes are particularly featured, especially using ketenes as substrates. Indeed, ketenes proved appropriate as reaction partners for asymmetric NHC-catalysed [4-1-2] cycloaddition processes (i) with / ,y-unsaturated a-ketocarboxylic esters and amides to give dihydropyranones (ISO) and (ii) with 3-aroylcoumarins (151) to give dihydrocoumarin-fused dihydropyranones (152). Significantly both 0... 

Constitution of the Esters of the (3-Ketocarboxylic Acids and of the P-Diketones.—Ethyl acetoacetate is taken as example. It reacts like a ketone with phenylhydrazine, bisulphite, and other ketone reagents on the other hand it shows an acid reaction, it dissolves in alkalis, and gives the colour reaction with ferric chloride characteristic of ends and also of phenols. From this double behaviour it was formerly concluded that it was either purely ketonic or purely enolic and that the reactions in the other form were to be attributed to a rearrangement caused by the reagents used. The true state of affairs was first disclosed by... 

Thermal degradation prior to ionization can cause decarbonylation or decarboxylation of the analyte. Decarbonylation, for example, is observed from a-ketocarboxylic acids and a-ketocarboxylic acid esters, whereas decarboxylation is typical behavior of P-oxocarboxylic acids such as malonic acid and its derivatives and di-, tri-, or polycarboxylic acids. 

Use of a /3-ketocarboxylic acid derivative may circumvent this problem (8-ketocarboxylic acid derivatives react with esters of a-amino carboxylic acids to give (Y) a-aminonitriles afford (Z) in a condensation step. 

Retrosynthetic Scheme 1 shows the general synthetic approach. Under certain conditions, the preparation of the /3-ketocarboxylic acids R4—CO—CH2—COOH or their esters might become the largest chal-... 

Allyl esters of acetoacetates7-8-9-11 react with Pd° catalysts to generate initially a bisphosphine allylpal-ladium cation, with the 3-ketocarboxylate serving as counterion. Under the reaction conditions the (3-ketocarboxylate decarboxylates, yielding a -Tr-allylpalladium ketone enolate complex. The required nucleophile is thus formed in situ and is capable of Pd-mediated alkylation. A wide spectrum of reactions have been based on this chemistry which will be discussed in later sections. 

Alkylation of cyclopropanecarboxylic acid esters,6 Deprotonation of methyl silyloxycyclopropanecarboxylates (1), prepared as shown, is possible with LDA in THF at — 78°. The resulting anions react with primary alkyl iodides and benzylic or allylic bromides to give 2 in high yield. These products are cleaved by F to methyl 4-ketocarboxylates 3. 

In aqueous-alcoholic sodium hydroxide, a-(l,2-dithiol-3-ylidene) /1-keto esters are hydrolyzed. The corresponding ketocarboxylic acid,... 

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). 

Fig. 13.29. Synthesis of complicated ketones in analogy to the acetoacetic ester synthesis II generation of a cyclic ketone. In the first step, the /3-ketoester is alkylated at its activated position. In the second step, the /3-ketoester is treated with Li I . SN2 reaction of the iodide at the methyl group generates the /3-ketocar-boxylate ion as the leaving group. The /3-ketocarboxylate decarboxylates immediately under the reaction conditions (temperature above 100 °C) and yields the enolate of a ketone.

The carbonyl group in aldehydes (RCHO) and ketones (RCOR ) is one of the frequently encountered functionalities in the composition of organic compounds. This group has no active hydrogen atoms, excluding the cases of high content of enols for /3-dicarbonyl compounds (/3-diketones, esters of /3-ketocarboxylic acids, etc.) ... 

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