The chemistry of isatins: a review from 1975 to 1999

Journal of the Brazilian Chemical Society

Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil¹  Garden, Simon J.¹  Pinto, Angelo C.¹  Silva, Joaquim F. M. da¹ 

关键词: isatin;    heterocyclic synthesis;    drug synthesis;    metal complexes;   

DOI  :  10.1590/S0103-50532001000300002

学科分类：化学（综合）

来源: SciELO

【 摘 要 】

Isatin (1H-indole-2,3-dione, Figure 1) was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo by nitric and chromic acids.  The synthetic versatility of isatin has led to the extensive use of this compound in organic synthesis. Three reviews have been published regarding the chemistry of this compound: the first by Sumpter, in 19541, a second by Popp in 19752, and the third on the utility of isatin as a precursor for the synthesis of other heterocyclic compounds3. The synthetic versatility of isatin has stemmed from the interest in the biological and pharmacological properties of its derivatives. These properties are more fully detailed in the supplementary material.In nature, isatin is found in plants of the genus Isatis4, in Calanthe discolor LINDL.5 and in Couroupita guianensis Aubl.6, and has also been found as a component of the secretion from the parotid gland of Bufo frogs7, and in humans as it is a metabolic derivative of adrenaline8-10. Substituted isatins are also found in plants, for example the melosatin alkaloids (methoxy phenylpentyl isatins) obtained from the Caribbean tumorigenic plant Melochia tomentosa11-13 as well as from fungi: 6-(3'-methylbuten-2'-yl)isatin was isolated from Streptomyces albus14 and 5-(3'-methylbuten-2'-yl)isatin from Chaetomium globosum15. Isatin has also been found to be a component of coal tar16.This review aims to document the publications concerning isatin, its synthesis, chemical reactivity and pharmacological properties during the period from 1975 to 1999. The biological and pharmacological data obtained from the scientific literature are summarized in Electronic Supplementary Information (ESI) 1. A graphical survey of the application of isatin in the synthesis of other heterocyclic systems is presented in ESI 2, and ESI 3 contains a summary of metal complexes and some organometallic derivatives of isatin. These ESI are available at http://www.sbq.org.br/jbcs/2001/vol12_n3/. The databases used for the preparation of this review were Chemical Abstracts, MEDLINE (www.healthgate.com), Beilstein (chemweb.com), Web of Science ISIS (webofscience.fapesp.br) and the IBM intellectual property network (www.patents.ibm.com). 2. Synthesis of Isatins2.1 The Sandmeyer methodologyThe 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).This method has some economic advantages, as the reagents are cheap and readily available, and the yields are usually high. Recently, the Sandmeyer methodology has been modified by the incorporation of ethanol as a co-solvent20. This modification proved to be particularly useful in cases where the aniline derivative was insoluble in the conventional reaction matrix. Application of the modified Sandmeyer methodology allowed the synthesis of 4,6-dibromoisatin, a key intermediate for the synthesis of the marine natural product convolutamydine A, in 85% yield, thus representing a greater than 700% improvement in yield over the existing published procedure. The use of microwave irradiation during both stages of the Sandmeyer procedure has been investigated, and this modified procedure was also employed for the synthesis of convolutamydine A21.In addition to the use of H2SO4 for the cyclization step, isonitrosoacetanilides can be heated in BF3.Et2O at 90 oC. After cooling the reaction mixture, addition of water allows isolation of the respective isatins. This methodology has proved to be particularly effective for the preparation of benzo-oxygenated isatin derivatives22,23The Sandmeyer synthesis has been described as being inapplicable to ortho-hydroxy or ortho-alkoxyanilines. Therefore an alternative procedure for the synthesis of the isonitrosoacetanilides was reported24,25 (Scheme 2).On the other hand, there are some disadvantages, for instance those listed below. a) The use of N-alkylanilines furnishes the corresponding N-alkylisatins in low yield. For example, N-methylisatin is obtained in 22% overall yield26.b) Meta-substituted anilines lead to two isomers (4-and 6-substituted isatins), e.g., 3-bromo-4-methoxyaniline yields 4-bromo-5-methoxyisatin (27%) and 6-bromo-5-methoxyisatin (63%). These isomers can be separated by conversion to the corresponding sodium isatinates using 0.5 mol L-1 NaOH. Subsequent controlled acidification of the reaction medium leads to cyclisation of the two isomers at different pH values, regenerating the corresponding isatins, which precipitate from the reaction medium27 (Scheme 3).c) The formation of HCN during the reaction has been detected by the formation of Prussian blue on addition of ferrous sulfate and NaOH28. The measured concentration of HCN in the mother liquors from the preparation of the isonitrosoacetanilides was found to be 100 to 200 ppm29. The mechanism informally proposed for the formation of HCN is described below (Scheme 4).An alternative explanation for the formation of HCN can be arrived at by consideration of the mechanism of formation of the intermediate isonitrosoacetanilides. It has been previously postulated, although never unambiguously demonstrated, that an intermediate dichloronitrosoalkene is initially formed by elimination of HCl from chloraloxime during the Sandmeyer isonitrosoacetanilide synthesis. This nitrosoalkene is subsequently attacked by the aniline to give an addition product that yields the isonitrosoacetanilide via a subsequent hydrolysis reaction30,31. However, competitive addition of water and aniline to the nitrosoalkene would lead to formation of the glyoxylic acid oxime and the isonitrosoacetanilide respectively. Under the conditions of the reaction, refluxing aqueous Na2SO4, it could be expected that the glyoxylic acid oxime would decarboxylatively decompose with the concomitant formation of water and HCN (Scheme 5).A further possibility exists. It has been shown that nitrosoalkenes decompose, with formation of HCN, via the formation of an oxazete and retro-cyclisation31 (Scheme 6).Whatever the mechanism for formation of HCN during the Sandmeyer isonitrosoacetanilide synthesis, it is reasonable to recommend that appropriate precautions be taken during the preparation of these compounds.2.2 Use of nitroacetanilidesNitroacetanilides, obtained by alkaline hydrolysis of 1-arylamino-1-methylthio-2-nitroethenes, are readily cyclized to isatin-3-oximes by the use of concentrated sulfuric acid or trifluoromethanesulfonic acid at room temperature; the latter giving somewhat higher yields32. Although this methodology is related to the Sandmeyer methodology, it has no obvious benefit over the latter (Scheme 7).2.3 The Stolle procedureThe most important alternative to Sandmeyer's procedure is the method of Stolle. In this method anilines are reacted with oxalyl chloride to form an intermediate chlorooxalylanilide which can be cyclized in the presence of a Lewis acid, usually aluminum chloride or BF3.Et2O33, although TiCl434 has also been used to give the corresponding isatin. This method has been used for the synthesis of 1-aryl35,36 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine37 as well as indoline38. In the

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