Isatins with amines

Isatin reacts with secondary heterocyclic amines to give 3,3-diamino-oxindoles such as, for example, 164.460-462 Such compounds can also be prepared by reaction of secondary amines with isatin-3-anils.461 These secondary amines can also react with isatin with ring opening to give 165.461... 

Although reductive amination of isatin with dimethylamine did not succeed, reaction of N-substituted isatins with dimethylamine in the presence of palladium on carbon and hydrogen gave 170.170... 

Isatin reacts with formaldehyde and a variety of amines in the Mannich reaction to give compounds of type 42.i i-i93a similar reaction takes place with isatin-3-thiosemicarbazone, or 42 can react with thiosemicarbazide to give a similar product.In the absence of an amine, isatin and substituted isatins with form-... 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed and their modularly designed thioamide 0 derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones, reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor, and C( 1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones. Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-tra 5 -cf, -unsaturated methyl ketones has also been promoted... 

Solvent effects have been investigated in isatin (193) hydrolysis. Results from ethanol-water and acetonitrile-water mixtures revealed that for alkaline hydrolysis log k was correlated with the reciprocal of the dielectric constant. A tetrahedral intermediate (194) is involved, which breaks down to yield the ring-opened amino acid (195). A comparison has been made of the lability of isatin (193) towards diethyl-amine and hydroxide ion, the latter showing the greater effect. ... 

The reaction of isatin cr-chloride (160a) with electron-rich aryl compounds, in the presence of a Lewis acid, gives indolone salts (161) from which the indolones (162) can be liberated on treatment with base.49, 108, 109 The reaction of 160a with various amines, under these conditions, has been reported108 to give the unstable indolones (163) although later attempts to repeat the synthesis were unsuccessful.49... 

A wide variety of substituted isatins have reacted with hydroxyl-amine to give isatin-3-oximes (72).6,26,42,51,92,107,126,169 274 O-Substi-tuted hydroxylamines also give this reaction.275 5-Bromoisatin-3-oxime... 

A large variety of aromatic amines react with isatins to give anils (132).169,232,269,305,312,411 413 The imine from isatin and o-hydroxy-aniline forms complexes with copper acetate and zinc iodide.413 Reaction of these anils (132) with phenylhydrazine gives the isatin-3-phenylhydrazone.411 The imine 132 (R = 5-Me, R = H, Ar = p-tolyl)... 

Primary aliphatic amines are also reported to give imines of the type 132 (where Ar now is aliphatic) with isatin,92,170,431 433 although the... 

Isatin, and a number of derivatives, have been oxidized by lead dioxide to the radicals 210 and 211, which were not very stable but their ESR spectra were measured and analyzed (77G154). While isatin itself reacts with nucleophilic amines at position 3 (cf. 211), the corresponding radical... 

It has long been known16 that primary aromatic amines react with chloral hydrate and hydroxylamine hydrochloride (or preformed chloral oxime) in aqueous solution to give isonitrosoacetanilides (e.g, 40). The reaction is improved by addition of certain inorganic ions (e.g., sulfate16) and is of value as a route to isatins obtained by... 

The method developed by Sandmeyer is the oldest and the most frequently used for the synthesis of isatin. It consists in the reaction of aniline with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate to form an isonitrosoacetanilide, which after isolation, when treated with concentrated sulfuric acid, furnishes isatin in >75% overall yield17. The method applies well to anilines with electron-withdrawing substituents, such as 2-fluoroaniline18, and to some heterocyclic amines, such as 2-aminophenoxathine19 (Scheme 1). 

Meth-Cohn and co-workers have observed that the treatment of 1,2-bis (N-methylanilino)-l,2-dichloroethanes, obtained by the dimerisation of the Vilsmeier reagents prepared from iV-methylformanilides in POCI3 using a tertiary amine, with an eletrophilic species yielded isatins in 11 to 79% after hydrolysis. The best yields were observed when bromine was used as the electrophilic species60 (Scheme 18). 

Amines and hydroxylamine and hydrazine derivatives react with 36 at the lactim ether group and not at the keto group76 88 [Eq. (2)]. By contrast, in the reaction between the imidochloride of isatin and tosylhydrazine (or aniline) the keto group at position 3 was found to be attacked and at the same time the imidochloride was transformed into the lactam89 [Eq. (3)]. Thus it may be argued that, at least in the case of the isatin derivatives, the lactim ether function is more reactive than the imidochloride. 

A large variety of aromatic amines react with isatins to give anils... 

P. Meyer [52] prepared substituted indigo blues from the corresponding substituted isatins. This process depends on the fact that the final products of the action of dichloracetic acid on amines in which the para position is occupied are substituted isatins. The first product of the action of dichloracetic acid on paratoluidine is a paratolylimide derivative of paramethylisatin, CieHigNjO, which decomposes on boiling with acids into paratoluidine and methylisatin, C9H7NO2. 

Reaction of aromatic or heterocyclic amines with formaldehyde and urea or phenylthioureas gave 2-(oxo)thioxohexahydro-l,3,5-triazines 90. Regioselective cyclization and isomerization of propargylthio-l,2,4-triazinones were achieved to give the fused heterocycles 91-93. Cyclization of isatin 3-thiosemicarbazones gave 94 which can be alkylated to 95 . The imidazotriazepines 96 were obtained from heating a mixture of hydrazide and ortho-ester. 

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