Oxindoles from isatins

Syntheses of symmetrical 3,3-diindolyl or 3,3-dipyrrolyl oxindoles from isatins have also been reported [51, 52]. 

The heterogeneous catalyst kaolin, preloaded with KOH, was used for the synthesis of 3-hydroxy-3-indolyl oxindoles from isatins and indoles in good to excellent yields by Srihari and Murthy (2011) (Scheme 2.15). The feasibility of the reaction was studied in various organic solvents such as CH2CI2, CH3CN, DMF, MeOH, and DMSO and found that the reaction did not proceed in CH2CI2, DMF, and DMSO, whereas the... 

Dipolar cycloadditions of the unusual dipolarophiles 9-arylidenefluorenes 446 with the dipoles generated from isatin 432a and cyclic amino acid proline 433a were carried out under four different conditions to yield a series of novel dispiro oxindole derivatives 50a-f via [3+2] cycloaddition (Scheme 100) <2002T8981>. 

Indoles from isatins or oxindoles via diborane Synthesis 2,84 (1972)... 

Isoindigo, obtained from isatin and oxindole, is converted diastereoselectively into diazacrisenodiones by reduction with Zn/AcOH, and subsequent acid-catalyzed rearrangement148 (Scheme 37). 

Isatin-2,3-thiosemicarbazone is said to be produced only from isatin-2-thiosemicarbazone and thiosemicarbazine direct reaction of isatin with an excess of thiosemicarbazine gives only the C-3 substituted oxindole. The isatin-2,3-thiosemicarbazone cyclizes to a thiotriazinoindole derivative when heated280 (Scheme 59). 

The literature contains many transformations of compounds of the type 184 and the 2-isatylidene analogs of 184 such compounds are frequently prepared from oxindoles and indoxyls, " rather than from isatins. 

G. A. Russell, C. L. Myers, P. Bruni, F. A. Neugebauer, and R. Blankespoor, Semidiones. X. Semidione radical anions derived from indan-2.3-dione, coumaran-2.3-dione, thianaphthalenequi-none, isatin, and IV-hydroxy isatin. Nitroxide radicals derived from isatin, dioxindole, oxindole, and other indole derivatives, /. Am. Chem. Soc. 92, 2762-2768 (1970). 

Wierenga discovered that borane-dimethyl sulfide reduced 3-(alkylthio)oxindole 5 to the desired indole (Scheme 3, equation 1), because LAH was sluggish or completely ineffective [15]. Subsequently, Wierenga generalized this smooth reduction of 3-(alkylthio)oxindoles (equation 2) [16]. Also reduced to 3-alkylindoles with BH -SMe were 3-hydroxyoxindoles (88-93%), which were prepared from isatins by selective C-3 addition of Grignards. Sano and coworkers used aluminum hydride to reduce 3-(phenylthio)oxindole 6 to the desired indole (equation 3)... 

Its striking total synthesis was however accompUshed by Overman et al. by following a different route (Scheme 7.27) [76]. meso-Chimonantine (123), a natural product by itself, was chosen as a starting point as it aheady contains two of the pyrroUdinoindoline units of target compound 121. Starting from commercially available oxindole and isatin, mexo-chimonantine had been synthesized previously in the Overman laboratories in a stereocontrolled 13-step procedure [77]. Now, four additional steps were necessary to access the central intermediate for the... 

From 1913 to 1930, R. Stolle published several manuscripts describing the synthesis of oxindoles from anilines and a-chloroacyl chlorides. His typical substrates were chloroacetanilides or the corresponding MA -diphenylamide. The manuscripts also described the synthesis of isatines (2,3-dioxindoles) from arylamines and oxalyl chloride. The reactions require high temperatures (typically > 150 °C) to complete the cyclization step. 

Khorshidi and Tabatabaeian (2010) used Ru(III)-exchanged FAU-Y zeolite as an efficient reusable heterogeneous catalyst for preparation of oxindoles from condensation reaction of indoles with isatins nnder very mild reaction conditions (Scheme 2.11). In evaluating the reusability of the solid catalyst, only 8% loss of efficiency in terms of the product yield was observed after five runs, which promises minimization of waste. 

The three-component reaction between isatin 432a, a-aminoacids 433 (proline and thioproline) and dipolarophiles in methanol/water medium was carried out by heating at 90 °C to afford the pyrrolidine-2-spiro-3 -(2-oxindoles) 51. The first step of the reaction is the formation of oxazlidinones 448. Loss of carbon dioxide from oxazolidinone proceeds via a stereospecific 1,3-cycloreversion to produce the formation of oxazolidinones almost exclusively with /razw-stereoselectivity. This /f-azomethine ylide undergo 1,3-dipolar cycloaddition with dipolarophiles to yield the pyrrohdinc-2-r/ V -3-(2-oxindolcs) 51. (Scheme 101) <2004EJ0413>. 

This method was also effective for the preparation of ferf-butyloxycarbonyl (Boc)-protected bis-indolyloxindole from the corresponding Boc-protected 2-methylindole without cleavage of the Boc group. Furthermore, pyrrole and /V-me thy I pyrrole also react efficiently with isatin, under similar conditions, to afford 3,3-di(2-pyrrolyl) oxindole derivatives (Fig. 13). 

The following exemplify reactions of the aldol type. 3-Hydroxythiophene with benzaldehyde forms (269). Anions derived from oxindole (270 Z = NH) and indoxyl (271) react with isatin (272) to give isoindigo (273) and indirubin (274). 

Heating of iV-methyloxindole and 35 in toluene gives 36 and N-methylisatin.142 In a similar manner isatin was obtained from oxindole.142 The mechanism of these transformations has been discussed. The o ... 

The Martinet procedure for the synthesis of indole-2,3-diones involves the reaction of an aminoaromatic compound and either an oxomalonate ester or its hydrate in the presence of an acid to yield a 3-(3-hydroxy-2-oxindole)carboxylic acid derivative which after oxidative decarboxylation yields the respective isatin. This method was applied with success for the synthesis of 5,6-dimethoxyisatin from 4-aminoveratrole whereas the use of 2,4-dimethoxyaniline was less successful40 (Scheme 9). 

In an alternative methodology, 4- and 6-substituted-2-oxindoles, obtained from o-nitroarylmalonates, were converted to 3,3-dibromooxindoles by reaction with pyridinium perbromide. These intermediates were hydrolyzed to the corresponding isatins. This method, although limited to substrates with moderate to strongly electron withdrawing groups... 

The condensation products from the reactions of isatins with cyanoacetates can be reduced at the carbon-carbon double bond with Zn dust in HC1 or by hydrogenation with Pd/C. Subsequent decarboxylation can be achieved by refluxing in 2-ethoxy ethanol. Further reduction of the nitrile yields an ethylamine oxindole (Scheme 98). 

An important issue with respect to the Knovenagel condensation is that a mixture of isomeric disubstituted 3-methyleneoxindoles can be obtained. NMR measurements, including nOe experiments, and quantum chemical calculations have also shown that 3-[cyano(ethoxycarbonyl)methylene]-2-oxindoles, which are obtained from the reaction of isatin or from 1-methylisatin with ethyl cyanoacetate, exist as a mixture of the E and Z isomers, and that the E isomer exists in an equilibrium between two conformers, trans-s-cis and (rans-s-/ram431 (Scheme 100). 

In the same year [17] Baeyer prepared isatin from oxindol. The nitroso-compound of oxindol yields the amido-compound on reduction, and this is converted into isatin by oxidation or by nitrous acid. 

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