Isatins, condensation with

Under mildly basic conditions, such as with piperidine or diethylamine as catalyst, isatins condense with a wide variety of ketone to give compounds of the type 171.144,145,150,169,232,471-490 These compounds have frequently been used to prepare substituted tryptamines476,484,485,487 and also some 9//-pyridazino[3,4-6]indole... 

Isatins condense with benzene,541 alkylbenzenes,541 and phenols37,55,542 under acidic conditions to give 192. Hydroquinone and X-methylisatin with sulfuric-acetic acid gave 193.55 Pyrroles543 and indoles498,543 also condense with isatin under acidic543 or basic498 conditions. 

Under acidic catalysis, isatin condenses with thiophene or pyrrole to give indophenine dyes. These compounds are formed as a mixture of geometric isomers450, and may possess one or two thiophene units the latter being the major product451 (Scheme 108). 

Isatinates, obtained from the alkaline hydrolysis of isatin derivatives, are the precursors of the quinoline-4-carboxylic acids. These compounds are prepared by the Pfitzinger reaction from isatins in the presence of enolizable keto compounds in strongly alkaline medium, such as 8N KOH. In these solutions, isatinates condense with the keto compound and subsequently cyclize to the quinoline products. Recently, a modified procedure has been described, using acidic conditions. This methodology was subsequently applied to a concise manner for the preparation of derivatives of camptothecin, a topoisomerase I inhibitor23 (Scheme 115). 

Isatin (190) is a compound with interesting chemistry. It can be iV-acetylated with acetic anhydride, iV-methylated via its sodium or potassium salt and O-methylated via its silver salt. Oxidation of isatins with hydrogen peroxide in methanolic sodium methoxide yields methyl anthranilates (81AG(E)882>. In moist air, O-methylisatin (191) forms methylisatoid (192). Isatin forms normal carbonyl derivatives (193) with ketonic reagents such as hydroxylamine and phenylhydrazine and the reactive 3-carbonyl group also undergoes aldol condensation with active methylene compounds. Isatin forms a complex derivative, isamic acid (194), with ammonia (76JCS(P1)2004). 

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. ... 

A rate dependency was observed in the case of acid-promoted Pfitzinger condensation isatins substituted with electron-withdrawing groups reacted faster than the corresponding isatins with less electron-withdrawing substituents. ... 

Condensation of Isatin 3 with Ethyl Methyl Ketone 39/... 

Isatin is the inner anhydride (lactam) of a y-amino-a-ketocarboxylic acid, isatinic acid (A), and is converted into a salt of this acid by the action of alkali. The keto-group in position 3 can condense with many other substances, and for this reason isatin is manufactured on a technical scale and converted into valuable indigoid vat dyes. The magnificent thioindigo scarlet, which is obtained from isatin and a sulphur analogue of indoxyl (the so-called hydroxythionaphthene), may be taken as example qq... 

The reactive 3-carbonyl group in compounds of type (279) undergoes aldol condensation with active methylene compounds such reactions of isatin with indoxyl, oxindole (Section 3.3.2.5.4) and with thiophenes (Section 3.3.1.5.7.ii) have already been mentioned. These compounds also react with Grignard reagents and phosphorus halides as expected, e.g. isatin (279 Z = NH) with MeMgBr and PC13 yields (285) and (286), respectively. 

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-... 

Pfitzinger also studied the reaction of 5-methylisatin with acetone in the presence of a 5% aqueous solution of sodium hydroxide (boiling for several hours) and obtained 2,6-dimethyl-4-quinolinecarboxylic acid with a yield of 80% [6, 7], The acids 8 substituted in the benzene ring were synthesized by condensation of the appropriately substituted isatins 9 with acetone in the presence of a dilute aqueous solution of sodium hydroxide [12], a 33% alcohol solution of potassium hydroxide [13], a 3.2% aqueous solution of sodium hydroxide [14], a 10% aqueous solution of sodium hydroxide [15], an 18% alcohol solution of potassium hydroxide [16], and a 20% water-alcohol solution of potassium hydroxide [17],... 

Methyl and ethyl a-methoxyethyl ketones 19 and 20 condense with isatin 7 when heated in the presence of sodium hydroxide in water, and 2-(a-methoxyethyl)-substituted acids 21 and 22 are formed with yields of 74 or 60% respectively [26], Their analog isopentyl a-methoxyethyl ketone 23 with a bulky substituent does not react with isatin 7 under the same conditions, but under more severe conditions the corresponding derivative of 4-quinolinecarboxylic acid 24 is formed with a yield of 46% [27],... 

A probable mechanism for the formation of the two regioisomers as a result of the condensation of isatin 7 with unsymmetrical ketones of the MeCOCH2R type was presented in [31],... 

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],... 

In the search for antimalarial products and other biologically active compounds unsubstituted isatin 7 and its derivatives 59 were brought into condensation with pyruvic acid, resulting in the synthesis of the diacids 60 [7, 15, 45-47],... 

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. 

A series of dicarboxylic acids 73 were synthesized as a result of a systematic study of the condensation of isatin 7 with keto acids 72 in the presence of potassium hydroxide or sodium hydroxide (Table 1) [53-59],... 

Aryl-4-quinolinecarboxylic acids 78 (Table 3) were synthesized by the condensation of isatin 7 with monosubstituted acetophenones 77 [24, 63, 69, 71-80],... 

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],... 

Under similar conditions the condensation of isatin 7 with 1 l-propionyl[3,4]benzpyrene 93 leads to the acid 94 with a yield of 71% [19],... 

The thienyl-substituted acids 105 were synthesized by the condensation of isatins 9 with acylthiophenes 106 [104-106],... 

Compounds 109 and 110, containing two uncondensed or condensed thiophene rings, were synthesized with high yields from the corresponding ketones 111 and 112 and isatin 7 [77, 108], The bithiophene 117-119 [77, 108] or dibenzothiophene 120 [109] derivatives, containing two 4-quinolinecarboxylic acid residues as substituents, were easily obtained in the same way from the ketone 113 and the diketones 114-116 by condensation with isatin 7. 

The condensation of isatin 7 with 2-acetyl-4-phenylquinoline (sodium hydroxide or potassium hydroxide, water, boiling, 1 h) gave an 80% yield of 2-(4-phenyl-2-quinolinyl)quinoline-4-carboxylic acid [114, 115],... 

The reaction of isatin 7 with acylated dibenzothiophene [81, 109, 116], dibenzofuran [116], and dibenzopyran [72] with the general formula 124 and also the reaction of the isatins 59 with acetylphenothiazine [72] and acetylthianthrene [117] with the general formula 125 gave the corresponding quinolinecarboxylic acids 126 and 127, having a tricyclic condensed system with a heterocycle as substituent at position 2. 

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],... 

A compound of the triterpenoid series, ketomethyl glycyrrhetate 159, which contains seven condensed six-membered rings, is formed with a yield of 42% as a result of the condensation of isatin 7 with the diketone 160 [144], If the reaction is carried out in butanol instead of ethanol, the reaction takes place more quickly, but the yield of compound 159 is lower on account of resinification processes. 

However, the ketols 166 and 167, which are similar to compounds 164 and are the products from the condensation of isatin 7 with malononitrile or phenylacetic ester respectively, were transformed into 2-quinolone-4-carboxylic acid 168 or its 3-phenyl derivative 169 [146],... 

Papers in which the reactions of isatins with various reagents leading mainly to derivatives of 2-quinolone-4-carboxylic acid were studied are discussed below. The condensation of isatins 180 with diketene gave quinolonecarboxylic acids 181 acylated at position 3 [152],... 

The synthesis of derivatives of quinoline from isatins and carboxylic acid anhydrides can also be realized without isolating the intermediate N-acyl derivatives. Thus, unsubstituted 2-quinolonecarboxylic acid containing the 14C isotope at position 3 was synthesized by the condensation of isatin 7 with the anhydride (H314CC0)20 [172], The unsubstituted acid 168 [163] and its 3-aryl derivatives 195 [173, 174] were obtained by heating the isatin 7 directly with the respective anhydrides. 

The condensation of isatin 7 with the oximes of cyclic diketones 201 led to the dicarboxylic acids 202 (yields 22-23%) [178],... 

In the case of the condensation of the isatins 208 with the imidic esters 209 with a large excess of the latter it was found that the amides 210 are only formed with isatins not having substituents at position 4 (R = H). If R aH the process stops at the first stage, and compounds 211 are formed [180, 181],... 

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