Reactions Pfitzinger

The Doebner reaction can provide the 4-carboxyl quinoline when the Pfitzinger reaction does not." Pfiztinger reaction of pinnacolone with isatin did not provide the desired quinoline. Doebner reaction of aniline with acetaldehyde and pyruvic acid did furnish the quinoline, albeit in only 8% yield. 

The Pfitzinger reaction describes the condensation of an o-aminophenylglyoxylic acid 16 (which can be generated in situ from an isatin IS) with 2 results in a quinoline-4-carboxylic acid (17), which is the subject of its own chapter in this book. ... 

The Pfitzinger reaction entails the synthesis of quinoline-4-carboxylic acids 2 via condensation of isatic acids formed from isatins 1 and a-methylene carbonyl compounds in the presence of strong aqueous bases. Subsequent decarboxylation can afford the corresponding quinolines. " ... 

However the earliest example in the literature of a reaction that proceeds via the putative intermediates invoked in the Pfitzinger reaction can be traced to the formation of quindoline-5-carboxylic acid 10, a product of over-reduction of indigo. ... 

Deady and co-workers have employed the Pfitzinger reaction extensively as a means to access diverse indenoquinolinecarboxylates as a part of a study on the latter s cytotoxicity. " ... 

The Pfitzinger reaction consisting in the alkaline condensation of isatin or 6-bromoisatin with ketones has been applied extensively by Buu-Hoi et af.211.279.310.316,525,553 Cagniant, to acetylthio-... 

The Pfitzinger reaction of isatins with a-methylene carbonyl compounds is widely used for the synthesis of substituted quinoline-4-carboxylic acids. Ivachtchenko and colleagues have recently reported on the Pfitzinger reaction in a series of 5-sulfa-moylisatins (Scheme 6.239) [422]. Treatment of 5-sulfamoylisatins with diethyl mal-... 

Pfitzinger Reaction. Quinoline-4-carboxylic acids are easily prepared by the condensation of isatin with carbonyl compounds. The products may be decarboxylated to the corresponding quinolines. 

Tetrahydrobenzo[6]thiophene-2-carboxaldehyde condenses with compounds containing a CH2CN group.436 2-Acetyl- and 2-propionyl-4,5,6,7-tetrahydrobenzo[6]thiophene undergo the Pfitzinger reaction with isatins.436 Attempts to prepare 2-cyano-4,5,6,7-tetra-... 

Published data on the Pfitzinger reaction and its modifications, leading to quinoline-4-carboxylic acids, are reviewed, analyzed, and classified. 

Keywords isatin, isatin derivatives, ketones, 4-quinolinecarboxylic acid derivatives, condensation, cyclization, Pfitzinger reaction, recyclization. 

In spite of numerous papers in this field the literature does not contain any publications summarizing the enormous amount of data that has accumulated over more than a century. Individual and poor-quality data on the Pfitzinger reaction have only appeared in monographs [2-4] and in a review [5]. 

The present review covers all the available published data on the Pfitzinger reaction beginning from the time of its discovery. The investigated material has been classified on the basis of the structure of the initial ketones separate sections cover the reactions of isatins with dialkyl ketones, keto acids, alkyl aryl ketones, and alkyl hetaryl ketones and also with cyclic ketones. Papers describing the synthesis of 4-quinolinecarboxylic acids by methods related to the Pfitzinger reaction are discussed in a separated section. 

A single product is also formed in the case of unsymmetrical ketones of the MeCOCHR R2 or RCH2COCHR R2 type, since for the Pfitzinger reaction to occur the ketone must contain either a methyl group or a methylene group next to the carbonyl group. For example, only one appropriate cyclopropyl-substituted acid 16 is formed from methyl cyclopropyl ketone 15 and isatins 9 [23, 24],... 

If unsymmctrical ketones of the RCH2COCH2R1 type 27 are used in the Pfitzinger reaction, the process may be nonregioselective. Thus, careful study of the products from the reaction of isatin 7 with methyl ethyl ketone showed that 2,6-dimethyl-4-quinolinecarboxylic acid (mainly) and 2-ethyl-4-quinolinecarboxylic acid (and not only the former, as supposed earlier [8]) are obtained [22, 30],... 

Unsymmetrical ketones containing Ar and OAr substituents in the alkyl radicals behave differently in the Pfitzinger reaction. Thus, methyl p-phenylethyl ketone reacts with isatin 7 in the presence of potassium hydroxide in water and alcohol through the methyl group - a single product 2-(P-phenylethyl)-4-quinolinecarboxylic acid is formed with a yield of 79% [22, 32],... 

Under the conditions of the Pfitzinger reaction secondary alcohols are capable of being oxidized to ketones and entering into condensation with isatins with the formation of derivatives of 4-quinolinecarboxylic acid. Thus, the product 50 was obtained with a yield of 81% from the hydroxylactone 49 and isatin 7 [25],... 

There are also examples of the use of compounds that are converted into diketones under the conditions of the Pfitzinger reaction and then react with isatins. Thus, the diacid 56 (yield 58%) was obtained from 2-hydroxy-3-butanone and isatin 7 in the presence of potassium hydroxide in water [26], while the dicarboxylic acids 58 were synthesized from 3-chloro-2-butanone and isatins 57 [44], The initial chloro ketone is clearly saponified to 2-hydroxy-3-butanone under the reaction conditions. As in the reaction with isatin 7, the product is then oxidized to 2,3-butanedione, which reacts with two molecules of isatin. 

Structures 64 and 65 were proposed in [7] for the product from the condensation of isatin 7 with acetoacetic acid (a P-keto acid). The first must clearly be preferred, since the CH2 group must be more active than CH3 under the conditions of the Pfitzinger reaction. Actually in [21] the structure of the product 64 was proved by its oxidation to the tricarboxylic acid 66, which was also synthesized from the keto dicarboxylic acid 67 and isatin 7. 

Alkyl aryl ketones are most often used in the Pfitzinger reaction. In view of the large number of publications and the variety of the obtained compounds this material is examined in condensed form and is in a number of cases presented in tabular form. 

In one of the first papers [7] it was reported that when isatin 7 was heated (100°C, 6 h) with acetophenone 74 in the presence of potassium hydroxide in water and alcohol 2-phenyl-4-quinolinecarboxylic acid (cinchophen) was formed with a yield of 65%. Later on [60-69] the isatins 59, containing substituents in the benzene ring, were used in the Pfitzinger reaction with the same ketone, and the similarly substituted quinolinecarboxylic acids 75 were obtained (Table 2) [12, 14, 28, 31, 60-69],... 

It follows from the data in [101, 102] that the Pfitzinger reaction is sensitive to steric factors arising not only from the effect of substituents at the ortho positions of the benzene ring but to some degree also from the size of the substituent at the para position. 

During study of the behavior of alkyl 2,5-dimethylthienyl ketones 107 in the Pfitzinger reaction it was found that their reaction with isatin 7 under normal conditions, leading to compounds 108, only takes place with R = Me, Ph with R = Pr, Bu the corresponding products could not be isolated [107], This is clearly due to steric hindrances brought about by the groups 2-Me and R containing two or more carbon atoms. 

The Pfitzinger reaction provides a simple and convenient method for the synthesis of condensed polycyclic compounds containing a heterocycle from readily obtainable starting materials. Cyclic ketones and, more rarely, diketones are often used as starting compounds. 

The reaction of the isatins 9 with cyclohexanones 132 leads to the formation of derivatives of l,2,3,4-tetrahydro-9-acridinecarboxylic acid 133. If R = H the yields of the products 133 amount to 75-100% [19, 20, 65, 118, 123-125], However, it was noticed in [19] that cyclohexanone does not react with a-naphthisatin 10 under the conditions of the Pfitzinger reaction. 

In [135, 136] the behavior of ketones of the steroid series in the Pfitzinger reaction was also studied. From dehydroepiandrosterone 139 and isatin 7 compound 140 was synthesized with a yield of 20%, and the reaction was accompanied by isomerization of the double bond [135], The reaction of estrone 141 and isatin 7 leads to the acid 142 [136],... 

Heterocyclic ketones 147 [130, 140], 148 [52], 149 [141, 142], and 150 [143] have also been studied in the Pfitzinger reaction. Their structure, the structure of the obtained products 151-154, and the reaction conditions are given in the schemes (see below). Among the obtained the acids 153 (yields -70%), which inhibit the ignition of cotton induced by oils, should be mentioned. 

There are a few examples of the use of cyclic diketones in the Pfitzinger reaction. In all the described cases the products from reaction of only one carbonyl group in these compounds with the isatin were obtained. Thus, the keto acids 156 were formed as a result of the reaction of the salt 54 (previously obtained from the isatin 7) with the diketones 155 [42],... 

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