Aryl acetoacetates

Diketene is of course a masked form of acetoacetic ester, and as such reacts in much the expected manner with a variety of mono- and di-nucleophiles. Aromatic and heteroaromatic amines, and phenols, for example, give acetoacetanilides and aryl acetoacetates the latter can be cyclized in excellent yield to coumarins while reaction of the former with excess of diketene followed by cyclization gives dioxopyridines (e.g. equation 164). Amidines, ureas, thioureas, S- alkylthioureas and carbodiimides also react with diketene to give pyrimidines e.g. equation 165), although in the case of amidines, S- alkylthioureas and carbodiimides the initially formed products are 1,3-oxazines which are converted into pyrimidines on subsequent treatment with acid or base. 

Aryl acetoacetates, which may be obtained by the reaction of phenols with diketene, are cyclized on treatment with sulfuric acid (54JCS854). The yields of coumarins are similar to those obtained by a Pechmann reaction on the phenol. 

The use of preformed aryl acetoacetates seems to offer no advantage over the usual method, giving chromones or coumarins under the influence of the normal catalysts (54JCS854). 

Phenols react with diketene under basic catalysis to give aryl acetoacetates. These are generally substances which on attempted distillation decompose to the parent phenol, but on treatment with coned, sulfuric acid afford coumarins in 75-90% yield. ... 

The hydrolysis of alkyl and aryl acetoacetates (HS) possesses pH-independent rate constants (Table 1) corresponding to the decomposition of the conjugate base of the ester (CH3CO-CH"-CO2Ar). Comment on the hydrolysis mechanism considering that the value of PLg for the alkaline hydrolysis of aryl acetates is -0.26. 

The reverse of the reaction of aryloxide ions with acetylketene is the alkaline hydrolysis of aryl acetoacetates which has the mechanism given in Scheme 32. 

Two mechanisms can be envisioned for the Pechmann condensation (1) acid-catalyzed transesterification of the P-keto ester followed by acid-catalyzed cyclodehydration of the resulting aryl acetoacetate (4), or (2) acid-catalyzed Friedel-Crafts-like phenol alkylation ortho to the phenolic hydroxyl group) followed by intramolecular transesterification/cyclization of the resulting o-hydroxycinnamic acid ester (5). 

In 1954, Lacey demonstrated that aryl acetoacetates 4 prepared from the condensation of a range of phenols with diketene could be cyclized in warm sulfuric acid to the corresponding coumarins (3) in yields comparable to those obtained from the corresponding phenols under conventional Pechmann condensation conditions, thereby establishing 4 as a viable intermediate in the Pechmann condensation. ... 

The intermediacy of o-hydroxycinnamic acid esters (5) in the Pechmann condensation was first proposed by Pechmann in 1884. In 1932, Robertson and co-workers provided support for this proposal through their examination of the reactions of w-methylanisole and dimethylresorcinol with ethyl acetoacetate under the conditions of the Pechmann condensation. Allowing these anisoles to stand with ethyl acetoacetate in sulfuric acid resulted in the formation of 4,7-dimethylcoumarin and 7-methoxy-4-methylcoumarin, respectively. 3 -(2-Methoxy-4-methylphenyl)-2-butenoic acid could likewise be converted to 4,7-dimethylcoumarin under similar conditions. These observations revealed cinnamate intermediates such as 5 to be viable intermediates in the Pechmann condensation and demonstrated that the formation of aryl acetoacetate intermediates such as 4 is not required for coumarin formation. 

It follows therefore that ethyl malonate can be used (just as ethyl aceto- acetate) to prepare any mono or di-substituted acetic acid the limitations are identical, namely the substituents must necessarily be alkyl groups (or aryl-alkyl groups such as CjHjCHj), and tri-substituted acetic acids cannot be prepared. Ethyl malonate undergoes no reaction equivalent to the ketonic hydrolysis of ethyl acetoacetate, and the concentration of the alkali used for the hydrolysis is therefore not important. 

Since Grignard reagents can easily be obtained from aryl halides, they are of special value in the s nthesis of many aromatic compounds, particularly as, for reasons already stated (pp. 270, 276), aromatic compounds cannot generally be prepared by means of ethyl acetoacetate and ethyl malonate. 

The most important synthesis of pyrazolones involves the condensation of a hydrazine with a P-ketoester such as ethyl acetoacetate. Commercially important pyrazolones carry an aryl substituent at the 1-position, mainly because the hydrazine precursors are prepared from readily available and comparatively inexpensive diazonium salts by reduction. In the first step of the synthesis the hydrazine is condensed with the P-ketoester to give a hydrazone heating with sodium carbonate then effects cyclization to the pyrazolone. In practice the condensation and cyclization reactions are usually done in one pot without isolating the hydrazone intermediate. 

In 1893 Pietro Biginelli reported the first synthesis of 4-aryl-3,4-dihydropyrimidin-2(l//)-ones (DHPMs) via an one-pot process using three components. Thus, DHPM 7 was synthesized by mixing benzaldehyde (5), ethyl acetoacetate (6), and urea (3a) in ethanol at reflux in the presence of a catalytic amount of HCl. 

Acetoacetic Ester Synthesis The formation of a substituted acetone through the base-catalyzed alkylation or arylation of a (3-keto ester. 

Carbazole-1- and carbazole-3-amino groups have been diazo-and the diazonium salts coupled with 1,3-dike-tones and ethyl acetoacetate, used in Sandmeyer reactions, reduced to the hydrazines and made to effect intramolecular arylation of a 9-aryl group, such as in the transformation of 215 (R = Me or C02Me) into 216 (R = Me or C02Me). It is worth repeating the earlier observation... 

Although amidoximes are indifferent towards non-activated esters they react on heating with an excess of ethyl acetoacetate. Water and ethanol are eliminated and a 5-aryl-3-acetonyloxadiazole is formed (83. 95,107,117). 

Tetrahydropyrrolo[4,3-. ]pyridines can be synthesized from 5,5-dimethyltetramic acid, 84, in a sequence of steps that begins with aryl aldehydes to generate arylmethylene-substituted tetramic acids. A Michael reaction with methyl acetoacetate followed by treatment with ammonium acetate yields the tetrahydropyrrolopyridine derivatives (Scheme 20) <2005H(65)377>. A similar reaction can be carried out with aroyl-substituted butenolides to give substituted furopyridine derivatives. 

Anomalous Fischer cyclizations are observed with certain o-substituted aryl-hydrazones, especially 2-alkoxy derivatives[l]. The products which are formed can generally be accounted for by an intermediate which would be formed by ( p.s o-substitution during the sigmatropic rearrangement step. Nucleophiles from the reaction medium, e.g. Cl or the solvent, are introduced at the 5-and/or 6-position of the indole ring. Even carbon nucleophiles, e.g. ethyl acetoacetate, can be incorporated if added to the reaction solution[2]. The use of 2-tosyloxy or 2-trifluoromethanesulfonyloxy derivatives has been found to avoid this complication and has proved useful in the preparation of 7-oxygen-ated indoles[3]. 

Reaction XLIV. (b) Condensation of Alkyl and Aryl Halogen Compounds with the Sodio- and other Metallo-derivatives of Ethyl Aceto-acetate and its Homolognes. (A., 186, 214 201, 143 213, 143.)—Like malonic ester, acetoacetic ester contains two 1 3-carbonyl groups with a methylene group in position 2. It is only to be expected then that it yields with metallic sodium or sodium alcoholate sodio-derivatives from which mono- and di-, alkyl and aryl homologues can be obtained by treatment with a suitable halide, including halogen esters. Acetoacetic acid... 

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