Condensation, isatin

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, isatin, 5, 71 Condensation, phenylurea, 3, 93 Condensation, xanthone, 7, 84... 

PUtzing erReaction. Quinoline-4-carboxyhc acids are easily prepared by the condensation of isatin [91-56-5] (16) with carbonyl compounds (50). The products may be decarboxylated to the corresponding quinolines. The reaction of isatin with cycHc ketones has been reported, eg, the addition of cyclohexanone gives the tricycHc intermediate (17) [38186-54-8] which upon oxidation produces quinoline-2,3,4-tricarboxyhc acid [16880-83-4] (51). 

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. ... 

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. " ... 

Buu-Hoi has shown that n-alkyl methyl ketones excluding ethyl methyl ketone, yield primarily 2-monosubstituted cinchoninic acids. It has been demonstrated that the products of the condensation of isatin with aryloxyketones are the corresponding 3-aryloxy-4-quinoline carboxylic acids rather than the isomeric 2-aryloxymethylcinchoninic acids.In the case of simple a-alkoxyketones such as 1-alkoxyethyl methylketones, the preferred products are the 2-alkoxyalkylcinchoninic... 

Carboxylic acids with labile a-methylene protons react with isatin in the presence of strong aqueous base. In the total synthesis of methoxatin, the coenzyme of methanol dehydrogenase and glucose dehydrogenase, Weinreb employs a Pfitzinger condensation of an isatin 37 and pyruvic acid as a key step to provide the 4-quinolinic acid 38 in 50% yield under the standard basic conditions. ... 

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

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 regio- and stereochemical outcome of the intermolecular 1,3-dipolar cycloaddition of an azomethine ylide generated by the decarboxylative condensation of an isatin with an a-amino acid was unambiguously determined by a single-crystal X-ray study of the spirocyclic heterocycle 49 (R1 =4-Br, R2 = H, X = CH2) <1998TL2235>. 

When ethyl (3-methyleneoxindole)acetate was used as the dipolarophile in the decarboxylative condensation between isatin 432 and iV-benzylglycine, double spiro compounds 52 and 53 were obtained. These have the same configurations as some related molecules that were reported by Casaschi et al. <1994H(37)1673>. 

H(53)323> and 1,2,4-triazinoquinolines have been reported. The preparation of a novel heterocyclic ring system, the indazolotriazinopurine 107, by the condensation of 8-hydrazinotheophylline (103) with 5-substituted isatins 104, via the hemiaminal 105 and hydrazone 106 intermediates, has been described <00JHC373>. 

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>. 

Atophan can also be obtained by alkaline condensation of isatin with acetophenone. (Formulate.)... 

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... 

Interestingly enough, a closely related protocol was successfully proposed for the synthesis of spirooxindoles-containing tetrahydrochromene skeletons when aromatic aldehydes were switched for isatin derivatives. This high-yielded reaction was performed with dimedone, 4-hydroxycoumarin, or barbituric acids in water using triethylbenzylammonium chloride (TEBA) as catalyst (Scheme 36) [125]. A Knoevenagel condensation occurred first between isatin and malonitrile derivative, followed by Michael addition of 1,3-dicarbonyl substrates and cyclization to the cyano moiety. 

The probable pathway of the reaction is shown in Fig. 14 and it seems to be an addition of the indole to the carbonyl group of isatin, followed by the condensation of a second indole moiety on the same carbon, resulting in the formation of 3,3-di (3-indolyl)oxindole. 

Neurokinins comprise a group of peptides involved in nerve transmission. Specific members of this class of mediators control such diverse functions as visceral regulation and CNS function. The nonpeptide neurokinin antagonist talnetant (32-6), for example, has been evaluated for its effect on irritable bowel syndrome and urinary incontinence as well as depression and schizophrenia [36]. The quinoline portion of this compound is prepared by base-catalyzed Pfitzinger condensation of isatin (32-1) with the methoxy acetophenone (32-2). The methoxy ether in the product (32-3) is next cleaved by means of hydrogen bromide (32-4). Amide formation with the chiral a-phenylpropylamine (32-5) affords the neurokinin antagonist talnetant (32-6) [37]. 

The devastating mental deterioration that characterizes Alzheimer s disease has been attributed to a mishandling of the neurotransmitter acetylchohne. Inhibitors of acetylcholinesterase, the enzyme that catabolizes that substance, would be expected to help restore deficient acetylcholine levels. Several partly reduced acridines have shown some activity in treating Alzheimer s disease. At least one of these, tacrine (14-5), is now approved for use in patients. The initial step in the synthesis of the first of these consists of the sodium amide catalyzed condensation of isatin (14-1) with cyclohexanone. The reaction can be visualized by assuming the first step to involve an attack of amide on isatin to give an amido-amide such as (14-2) (note that no attempt has been made to account for charges). This can then react with... 

Laser irradiation of isatin (70) gave 71 as a result of bimolecular condensation (78TL3007). The diazine ring of 73 was formed during the cyclocondensation of anthranilic acids with the imidate esters derived from indolinone (72) (81AP271). 

Diphenyl-4,10-dicarboxy-6-methyl-l,7-phenanthroline (25) has been obtained179 along with the quinoline derivative (24) by the alkaline condensation of acetophenone with the substituted isatin (23). 

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. 

There are few dyes in this class but two derivatives are among the most important yellow disperse dyes. The simplest example is Cl Disperse Yellow 54 (62), which is marketed by several companies, as is its brominated derivative Cl Disperse Yellow 64, which has slightly superior fastness properties. The simple molecule may be prepared (B-70MI11203) by condensation between chloroacetone and isatin, followed by fusion of the resulting 3-hydroxy-2-methylquinoline-4-carboxylic acid with phthalic anhydride. 

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... 

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