Perkin reaction variations

An important variation of the Perkin reaction is the Erlenmeyer azalactone synthesis exemplified by equation (4), involving condensation of an aldehyde and an N-acylglycine derivative in the presence of acetic anhydride and sodium acetate. Although this reaction, analogous to the classical Perkin condensation, was initially limited to the use of aromatic aldehydes, Baltazzi and Robinson reported that the use of lead acetate and THF allowed the preparation of several azalactones derived from aliphatic aldehydes (equation 15). The results for the condensation of several aldehydes and ketones with hippuric acid (28) under these conditions are shown in Table 2. The reaction proceeds through the intermediate (26) (intramolecular condensation of 25), which reacts with the aldehyde in Perkin fashion to provide the so-called azalactone product (Scheme 8). It is the formation of such oxazolones from acylamino acids which is be-... 

A variation of this condensation involves reaction with aldehydes, and it is called the Perkin reaction. Condensation of an aldehyde (having no enolizable protons) with the enolate of an acid anhydride leads to an acetoxy ester such as 182.10 Internal acyl substitution by the alkoxide forms the 0-acetyl ester and liberates the carboxylate anion (183). Subsequent reaction with more acetic anhydride generates a new mixed... 

Fig. 6. Bronsted plot for the variation of rates of proton transfer (logi0 k, ) from disulphones (RCH) with ApK, the difference in acidity between the disulphone and base catalyst (B). Rates and equilibrium constants are statistically corrected and the numbers refer to the reactions in Table 5. Redrawn with permission from F. Hibbert, J. Chem. Soc., Perkin Trans. II, (1973) 1289.

The extensive studies of the reactions of pyrylium and pyridinium salts by Katritzky and his co-workers have led to an appreciation of the value of these salts in organic synthesis. Chromenylium salts, which are readily available from 1-tetralones, react with aqueous ammonia at room temperature to give 5,6-dihydrobenzo[h]quinolines in very high yield, providing an exceptionally good route to the nitrogen heterocycle. Considerable variation in the substituent pattern is possible and further rings may be annelated (A.R. Katritzky et al, J. chem. Soc. Perkin II, 1984, 857 and earlier papers). 

As exemplified by equation (2), the Perkin condensation of o-hydroxybenzaldehydes is an important method for the synthesis of substituted coumarins. An interesting variation on this procedure has been reported recently. Heating a mixture of o-fluorobenzaldehyde, 2-thiopheneacetic acid, acetic anhydride and triethylamine affords directly the coumarin (20 equation 13) instead of the expected cinnamic acid (21). The reaction proceeds similarly with several arylacetic acids. The reaction presumably proceeds through the cinnamic acids (21). The observed product can conceivably arise by direct nucleophilic displacement involving the carboxylate or by an elimination/addition (benzyne) mechanism. The authors note that when 2-fluorobenzaldehyde is replaced by its 2-bromo analog in this reaction, the substituted cinnamic acid (22) is the major product and the corresponding coumarin (20) is obtained only in low yield. It is suggested that since it is known that fluoride is displaced more rapidly in nucleophilic aromatic substitution reactions, while bromo aromatic compounds form benzynes more rapidly, this result is consistent with a nucleophilic displacement mechanism. 

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