Isatin, reactions with ketones

During a systematic study of the reaction of isatin 7 with ketones of type 27 it was shown that either two products 28 and 29 (minor) or only one product 28 are formed depending on the structure of the initial ketone [28]. 

The direction of the reaction of the isatin 7 with ketones of the 35 type under the same conditions depends on the nature of the substituent Ar. Thus, if R = Ph, C6H40Me-4, OPh, or 0C6H40Me-4, a mixture of compounds 36 and 37 in ratios of 38 62, 40 60, 38 62, or 29 71 respectively was formed each time. On the other hand, with R = C6H4N02-4 or 0C6H4N02-4 only the acids 37 (Ar = C6H4N02-4 or 0C6H4N02-4) were obtained... 

Catalysts derived from readily available D-glucosamine catalyse asymmetric aldol reactions/ including amino alcohols derived from the sugar that catalyse reaction of isatin (58) with ketones in high yield and good delee ... 

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-... 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

Reaction of isatin or thioisatin 263 with (R)-(—)-thiaproline afforded thiazolo-oxazolidinones 264 as precursor of azomethine ylides, obtained by decarboxylation, for 1,3-dipolar cycloadditions (Equation 116) <2002SC435, 2004PS2549>. Condensation of 5-(alkylamino)methyl-2-pyrazolines 265 with ketones or aldehydes led to tetrahy-dro-imidazo[l,5-7]pyrazoles 266 (Equation 117) <1998JCCS375>. 

The word enamine was coined in 1927 by Wittig [27], However, at that time, enamines were usually not considered as reactive intermediates. An early example of enamine catalysis that was not explicitly recognized as enamine-based reaction was the reaction of isatin with ketone nucleophiles (acetone and acetophenone), first pnblished by Lindwall and coworkers in 1932 [28, 31]. Later, the interconversion of imininm ions and enamines in enzymatic reactions was recognized by Westheimer [32, 354]. The first person to propose a modem enamine-based... 

The reaction of isatins with ketones leading to 4-quinolinecarboxylic acids is carried out in the presence of strong nucleophiles (sodium hydroxide or potassium hydroxide). For this reason the generally accepted mechanism of the process is the following. The isatins 1 are converted by the action of alkalis into the salts of... 

As in the reactions with acetone, in the reaction of isatin 7 with symmetrical ketones in the presence of sodium hydroxide [20] or potassium hydroxide [21, 22] in a water-alcohol medium only one product of type 14 is formed each time. 

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],... 

Different regioselectivity was observed in the reaction of isatin 7 with the ketones 38 and 39, resulting in the synthesis of the acids 40 and 41 with yields of 35 and 41% respectively [22],... 

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. 

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],... 

On the other hand, in the reaction of the isatins 40 with the ketones 91, in which the Ar groups are condensed systems, the corresponding acids 92 are as a rule formed with high yields (Table 7) [19, 24, 29, 72, 81,91,98],... 

By the reaction of isatins with alkyl hetaryl ketones it is possible to obtain various 2-hetaryl-substituted 4-quinolinecarboxylic acids. Thus, in the presence of aqueous solutions of alkalis ketones of the furan series 103 react with isatins 59 with the formation of acids 104 containing a furyl substituent [12, 103, 104],... 

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 condensation of isatins 42 with cyclopentanone and its derivatives 128 has been investigated in a fair amount of detail [13, 19, 118-120], It was found that the size of the substituent adjacent to the carbonyl group of the ketones has a significant effect on the yield of the condensation products 129. Thus, in the case of 2-methylpentanone the yield of the acid 129 (R1 = Me, R = H) amounted to 78% in the case of 2-ethylcyclopentanone the yield was 1% (R = H, R1 = Et), and with 2-propylcyclopentanone the reaction did not occur [119],... 

The position and size of the substituent R2 in the cyclohexanone derivatives has a significant effect on their reaction with isatins. Thus, if R2 is at position 3 or 4, high yields of the products from condensation with isatins 42 are formed. On the other hand, from the ketones with various substituents R2 at position 2 under the same conditions good yields are only observed with R2 = Me [13, 19, 24, 119],... 

The reactions of isatins 7 [118, 126] and 42 [13, 82, 127-129] with ketones 134 containing seven and 7-17 CH2 units respectively in the ring have also been described. 

Among the ketones examined in this section it is also possible to include the di- and trihydroxy derivatives of benzene, which are capable under the reaction conditions of forming tautomers containing a keto group. Thus, 3-hydroxy-9-acridinecarboxylic acid 145 was obtained by heating isatin 7 with resorcinol in the presence of alkali in water [137], Other derivatives of 9-acridinecarboxylic acid 146 were synthesized with yields of 72-92% from phloroglucinol (used in the form of the dihydrate) and isatins 1. The reactions were conducted in the presence of sodium hydroxide [137, 138] or potassium hydroxide [139] in water. 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Lactim ethers and thioethers (300) furnish condensed quinazolones 301 when interacted with IA. ° Ring opening of lA s to the corresponding anthranilic acids and reaction of its potassium salts with chloroacetone yields 2-indolyl ketones 302. ° Potassium cyanide with iV-substituted lA s produces iminoindolinones 303, which were readily hydrolyzed to the corresponding isatins. Reaction of 303 to the spiroindoloquinazoline 304 takes place when KCN is treated with excess lA (Scheme 48). When... 

CHART 3.21. Bifunctional catalyst for the aldol reaction of isatins with ketones. 

Chen J-R, Liu X-P, Zhu X-Y, Qiao Y-F, Zhang J-M, Xiao W-J (2007) Organocatalytic Asymmetric Aldol Reaction of Ketones with Isatins Straightfmward Stereoselective Synthesis of 3-Alkyl-3-hydroxyindolin-2-ones. Tetrahedron 63 10437... 

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