Phenols, reaction with keto esters

The Pechmann Condensation ( or Coumarin Synthesis) allows the synthesis of coumarins by reaction of phenols with p-keto esters. 

Coumarin synthesis. The Pschorr coumarin synthesis involves the reaction of phenols with -keto esters in the presence of a condensing agent (usually sulfuric acid). In a synthesis of the coumarin mold metabolite aflatoxin M, (3), Biichi and Weinreb found that the usual conditions could not be employed because the phenol (I) is exceptionally sensitive to acidic reagents. However, they effected the desired condensation of... 

Acetals of a-bromo aldehydes are obtainable from <%,/ -dibromoalkyl acetates by an analogous procedure in which these esters are prepared from enol acetates and bromine and are then converted into acetals by means of alcohols.939 A simple synthesis of <%-keto aldehydes is to treat a-brominated phenacyl phenyl ethers with alkoxides or phenoxides.940 This method is particularly useful for the preparation of aryl acetals because it avoids the side reactions that can complicate reactions between phenols and aldehydes in an acidic medium. 

The course of this process corresponds to a S Ar reaction of phenol with the presumably protonated carbonyl group of the p-keto ester 10. This is followed by lactonization giving 11 and H2O elimination to produce the coumarin system. 

Polymer bound acrylic ester is reacted in a Baylis-Hillman reaction with aldehydes to form 3-hydroxy-2-methylidenepropionic acids or with aldehydes and sulfonamides in a three-component reaction to form 2-methylidene-3-[(arylsulfonyl)amino]propionic acids. In order to show the possibility of Michael additions, the synthesis of pyrazolones was chosen. The Michael addition was carried out with ethyl acetoacetate and BEMP as base to form the resin bound p-keto ester. This was then transformed into the hydrazone with phenylhydrazine hydrochloride in the presence of TMOF and DIPEA [28]. The polymer bound phenol was readily coupled to a variety of allyl halides by using the Pl- Bu to generate a reactive phenoxide [29]. 

In the absence of a catalytic amount of Lewis acids such as Mg(OTf)2, weak Bronsted acids, such as thioureas, BINOL, and BINOL-derived phosphoric acids, could not promote this reaction alone. The reaction could not proceed with phosphoric acid salts, suggesting that the use of free acid is essential for effective catalysis. The combination of chiral phosphoric acid 13e and Lewis acid Mgp2 (4 1 ratio) was identified to be the optimal catalyst for the AFC alkylation reactions of phenols with p,y-unsaturated a-keto esters, affording the alkylation product in good yields with up to 99% ee. Not only free phenols but also indoles could be successfully applied in AFC reactions with P,y-unsaturated a-keto esters under the binary-acid catalysis (82-94% ee). 

Scheme 6.31 AFC alkylation reactions of phenols with p,y-unsaturated a-keto esters catalyzed by binary acids reported by Luo.

Amides can also be obtained by AICI3 catalyzed ester amine exchange which proceeds primarily without racemization of chiral centers (eq 24). The reaction of phenols with /3-keto esters is known as the Pechmann condensation (eq 25). Aryl amines are used in the Riehm quinoline synthesis (eq 26) Aromatic systems may be coupled via the Scholl reaction (eq 27) and indole derivatives are prepared in the Stolle synthesis (eq 28). In the Zincke-Suhl reaction, phenols are converted to dienones (eq 29). 3 ... 

Malonic acid labeled with carbon-14 at C2 or at Cl,3 and the corresponding mono- and diesters have become important and highly versatile building blocks for the synthesis of a broad range of labeled compounds, such a,/3-unsaturated acids and esters, cycloalkanes, 8-keto esters, a-amino acids, phenols, dihydropyridines/pyridines, pyrimidines and quinolines. In addition, they are widely used as acetic acid synthons ( CH2COOR CHCOOR) for the extension of carbon chains of alkyl, allyl and benzyl halides as well as of saturated and a,)8-unsaturated carbonyl compounds. This Section discusses aU malonates, wherever labeled, and unlabeled malonates used with carbon-14-labeled reaction partners. However, it is the [2- " C]malonates that have been most often used in radiochemical synthesis. 

Aromatic halides react with crown ether-complexed K02 by an electron-transfer mechanism and not by nucleophilic attack, as was shown by Frimer and Rosenthal (1976) using esr spectroscopy. The corresponding phenol is the main reaction product (Yamaguchi and Van der Plas, 1977). Esters are saponified by the K02/18-crown-6 complex in benzene, presumably by an addition-elimination pathway (San Fillippo et al., 1976). The same complex has been used to cleave cr-keto-, or-hydroxy-, and or-halo-ketones, -esters, and -carboxylic acids into the corresponding carboxylic acids in synthetically useful quantities (San Fillippo et al., 1976). 

A range of 3,4-fused pyranobenzopyrandiones, e.g. (362), have been prepared from the reaction of 4-hydroxycoumarin with cyclic /3-keto esters (81JHC1655). In a similar vein, the use of ethyl 3-hydroxy-6,7-dimethoxychrom-3-ene-4-carboxylate (363) as the dicarbonyl component results in the formation of chromenocoumarins (364) from phenols (36JCS423). 

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