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The chemistry of isatins: a review from 1975 to 1999 Joaquim Fernando M. da Silva,* Simon J. Garden and Angelo da C. Pinto Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, RJ, 21945-970, Brazil Isatina (1H-indol-2,3-diona) é um composto de grande versatilidade sintética, podendo ser utilizado na obtenção de diversos sistemas heterocíclicos, como derivados indólicos e quinolínicos, o que a torna uma importante matéria-prima na síntese de fármacos. Isatina também tem sido detectada em tecidos de mamíferos, o que tem despertado o interesse em seu est...
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The chemistry of isatins: a review from 1975 to 1999 Joaquim Fernando M. da Silva,* Simon J. Garden and Angelo da C. Pinto Departamento de Química Orgânica, Instituto de Química, Universidade Federal do Rio de Janeiro, RJ, 21945-970, Brazil Isatina (1H-indol-2,3-diona) é um composto de grande versatilidade sintética, podendo ser utilizado na obtenção de diversos sistemas heterocíclicos, como derivados indólicos e quinolínicos, o que a torna uma importante matéria-prima na síntese de fármacos. Isatina também tem sido detectada em tecidos de mamíferos, o que tem despertado o interesse em seu estudo como modulador em diversos processos bioquímicos. Os avanços na aplicação de isatinas em síntese orgânica, bem como na compreensão de seus efeitos biológicos e farmacológicos, nos últimos vinte e cinco anos encontram-se relatados nesta revisão e seus respectivos materiais suplementares. Isatin (1H-indole-2,3-dione) is a synthetically versatile substrate, where it can be used for the synthesis of a large variety of heterocyclic compounds, such as indoles and quinolines, and as a raw material for drug synthesis. Isatin has also been found in mammalian tissues, and its function as a modulator of biochemical processes has been the subject of several discussions. The advances in the use of isatin for organic synthesis during the last twenty-five years, as well as a survey of its biological and pharmacological properties are reported in this review and in the accompanying supplementary information. Keywords: isatin, heterocyclic synthesis, drug synthesis, metal complexes 1. Introduction, 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.

O

532O6N1

H

Figure 1 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 foundas 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, Supplementary Material 1. A graphical survey of the application of isatin in the synthesis of other heterocyclic systems is presented in Supplementary Material 2 and Supplementary Material 3 is a summary of metal complexes and some organometallic derivatives of isatin. These supplementary materials are available at www.sbq.org.br. 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 isatins 2.1 The Sandmeyer methodology 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).

NOH O

Cl3CCH(OH)2 O 1) H2SO4 NH2OH.HCl N 2) H2O

O NH2 Na2SO4 N H H H

S NH2SN

O

O O

O

, 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 derivatives22,23 The Sandmeyer synthesis has been described as being unapplicable to ortho-hydroxy or ortho-alkoxyanilines. Therefore an alternative procedure for the synthesis of the isonitrosoacetanilides was reported24,25 (Scheme 2)., OMe O OMe H NH Cl2 Cl N Cl 1. Pyridine 2. NMeO2RR

NO

NMe OMeH2OMeHN1. H + 3ONNNOH2. H2NOHOOORRScheme 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%) e 6-bromo-5-methoxyisatin (63%). These isomers can be separated by conversion to the corresponding sodium isatinates using 0.5N 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)., Br BrOOMeO MeO MeO O + O

N

NH Br

N

2HHNaOH 0,5N O O-Na+ O O-Na+Br MeO + MeOO O NH2 Br NH2 4,5 < pH < 8,0 pH < 4,0 BrOOMeO MeOOONBrNHHScheme 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)., OH NOH Cl H2NOH Cl - + OH - 2 Cl3C +H O HC=NOH2 Cl Cl Cl Cl H3O+ HO- Cl3CH HCN + H2O2 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 clhoraloxime 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 glyoxalic acid oxime and the isonitrosoacetanilide respectively. Under the conditions of the reaction, refluxing aqueous Na2SO4, it could be expected that the glyoxalic acid oxime would decarboxylatively decompose with the concomitant formation of water and HCN (Scheme 5). Na2SO Cl NO H OCl CCHNOH 4 23 HO2CCHNOH Cl NaCl NaHSO4 ArNH2 H NOH N CO2, H2O, HCN Ar O, Scheme5Afuther possibility exists. It has been shown that nitrosoalkenes decompose, with formation of HCN, via the formation of an oxazete and retro-cyclisation31 (Scheme 6). Cl NOONCOCl2 + RCN Cl R Cl Cl R Scheme 6 Whatever the mechanism for formation of HCN during the Sandmeyer isonitrosoacetanilide synthesis, it is resasonable to recommend that appropriate precautions be taken during the preparation of these compounds. 2.2 Use of nitroacetanilides Nitroacetanilides, obtained by alkaline hydrolysis of 1-arylamino-1-methylthio-2- nitroethenes, are readily cyclised 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). HOOOHΦNNON2HANNOH MeS NO2HH

HO

N OH NOH HA -H2OOONNHH, Scheme 7 2.3 The Stolle procedure The 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 BF .Et O333 2 , although TiCl 344 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 case of dimethoxyanilines, spontaneous cyclization to yield dimethoxyisatins in the absence of a Lewis acid has been observed, as exemplified in the synthesis of melosatin A12, albeit in very low yield (Scheme 8).

O

(COCl)2

O MeO NH2 MeO N OMe OMe H

Melosatin A Scheme 8 Methoxyisatins can be converted to the corresponding phenolic compounds by the action of pyridinium hydrobromide perbromide. This seems to be the best method for obtaining these derivatives, as aminophenols are not useful substrates for the synthesis of isatins39. 2.4 The Martinet isatin synthesis, 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).

HO

O O CO2R

O

O NH N2 O

H O O O

O N

H

Scheme 9 The Martinet procedure is readily applied to napthylamines, thus yielding benzoisatin derivatives41. 2.5 The Gassman procedure A fundamentally different and general procedure developed by Gassman is another option for the synthesis of isatins42,43. This methodology consists in the formation and subsequent oxidation of an intermediate 3-methylthio-2-oxindole44-46 to give the corresponding substituted isatins in 40-81% yield. Two complementary methods for the synthesis of the 3-methylthio-2-oxindoles were developed, and the methodology of choice is dependent upon the eletronic effect of substituents bonded to the aromatic ring. When electron withdrawing groups are present, the, oxindole derivative can be synthesized via a N-chloroaniline intermediate, which further reacts with a methylthioacetate ester to furnish an azasulfonium salt (Method 1, Scheme 10). In the case of electron donating groups that destabilize the N-chloro intermediate, and thus give diminished yields of the azasulfonium salt, a second method of generetion of this salt, by reaction of the chlorosulfonium salt with an appropriate aniline (Method 2, Scheme 10), gives better yields of the 3-methylthio-2-oxindoles. Various methodologies have been devised for the conversion of these oxindoles to isatins. Reaction with N-chlorosuccinimide generates the unstable 3-chloro-3-methylthio-2- oxindoles, which were hydrolysed to isatins in the presence of red mercuric oxide and BF3.Et2O in aqueous THF. Hydrolysis in the absence of these reagents gave a mixture of the isatn and the 3,3-dimethylthio-2-oxindole ketal42. Air oxidation of methylthio-oxindoles in the presence of a base in aqueous methanol also resulted in formation of the respective isatin, although over oxidation, generating anthranilic acid derivatives, was a problem and generated anthranilic acid derivatives 47 (Scheme 10). Method 1 SMe Cl SMe 1) tBuOCl N-Chlorosuccinimide NH 2) MeSCH2CO2EtOOX23) Et3N; 4) H3O+ N NXXHHMethod 2 CO2Et 1) S HgO/BF3 or Cl Cl H2O/THF/∆ 2) Et3N; 3) H3O+

O O N

X H Scheme 10, Recently Wright and co-workers have described a modified Gassman oxindole synthesis. They point out the problem associated with the preparation of the chlorosulfonium salt (reagent for Method 2) from chlorine gas and ethyl methylthioacetate, and demonstrated a modified procedure that makes use of a sulfoxide as a synthetic equivalent of a sulfenyl halide48 (Scheme 11). The Gassman procedure can also be applied to N-alkylanilines43. SMe CO2Et Cl2, CH Cl CO2Et22SS

O

-78 oC Cl N

R

CO2Et (COCl)2, CH2Cl2

S

-78 oC

O

Scheme 11 2.6 Metalation of anilide derivatives A more recent method for the synthesis of isatins is based upon the directed ortho- metalation (DoM) of N-pivaloyl- and N-(t-butoxycarbonyl)-anilines. The corresponding dianions are treated with diethyl oxalate and the isatins are obtained after deprotection and cyclisation of the intermediate α-ketoesters. This method has the advantage of being regioselective for the synthesis of 4-substituted isatins from meta-substituted anilines where the substituent is a metalation directing group (e.g. OMe) 49 (Scheme 12).,

R R O O

1) n-BuLi, THF; N O

N O 2) diethyl oxalate O H H O OEt R O

HCl 12N/THF/∆ (79-89%) O

N H

Scheme 12 The synthesis of 5-azaisatin was realized by ortho-lithiation of the 4-aminopyridine t- butylcarbamate followed by reaction with an excess of diethyl oxalate. Heating the glyoxylic ester under vaccum gave 5-azaisatin50 (Scheme 13). O OEtNONOBuLi H (CO Et) NNO2HOO

O

∆ N O

N H

Scheme 13, Recently, a metal-halogen exchange method was described for the synthesis of isatins by lithiation of ortho-bromophenylureas, carbonylation and subsequent intramolecular cyclisation to give the desired products in 71-79% yield51 (Scheme 14).

O

R BrROO1) MeLi, 0 oC Li R 2) t-BuLi, 0 oCNN3) CO

O N

4) H3O+ Li N

H

ONHScheme 14 2.7 Miscellaneous procedures These previously discussed methodologies are the most general and/or most commonly employed procedures for the synthesis of isatins. Other methodologies have been employed, but they are less general and some of them lead to the desired product in low yield. Parrick and co-workers developed a synthetic methodology for isatins from indoles, using N-bromosuccinimide to promote their oxidation to yield 3,3-dibromooxindoles which were subsequently hydrolysed to the desired isatins52,53. By using this method it was possible to obtain 7-azaisatin from 7-azaindole, although in low yield. This isatin is more readily obtained by oxidation of the indolic compound using chromic anhydride in acetic acid54 and this methodology can also be applied to the oxidation of 5-azaindole to yield 5-azaisatin55. 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, (otherwise bromination of the aromatic ring occurs), suits well for the regioselective synthesis of 4- and 6-substituted isatins, such as 6-benzoylisatin56 (Scheme 15). R1 R1 CO2Et R2 Cl (EtO2C)2CH2 R2 CO Sn, HCl2Et NaH R3 NO2 R3 NO2 R1 R1 Br R1 O R2 R Br R2 Py.HBr.Br 22 H2O/MeOHOOOR3NRNR3 N3HHH26-75% Scheme 15 Nitrones and dichloroketene react to furnish 3,3-dichlorooxindoles, which upon hydrolysis, lead to the desired isatins57. N-Aryl-benzoisatins can also be obtained from napthoquinones and anilines as a result of oxidation of the cyclic anils 58 (Scheme 16).

OH O

1) PhNH2 2) H2O O

Br N O O O

Scheme 16 1,4-Dimethylisatin can be obtained from air oxidation and hydrolysis of the cyclocondensation product of aryliminoacylhydrazones59 (Scheme 17)., CHOONN1. BF3.Et2O N or PPANH2. Air N NHΦ

O

H2O (76%) O

N

Scheme 17 Meth-Cohn and co-workers have observed that the treatment of 1,2-bis (N- methylanilino)-1,2-dichloroethanes, obtained by the dimerisation of the Vilsmeier reagents prepared from N-methylformanilides in POCl3 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). X X

X

POCl3 Hünig's X base ClNNNN

CHO

Cl Cl Cl ON Ar 1) Br X2 X Br H2O 2) H2OONCl N Scheme 18, Isatin is formed from 2-nitrocinnamaldehyde through the sequence shown below61 (Scheme 19): CHOOOCOMe NH2OH.HCl COMe MeCN NO2 NO2

N

OOOCrO3ONNClHHScheme 19 1-Napthlylamine, when reacted with 1,2,4-triazin-5-ones in acetic acid, gives benzo[e]indole-2,3-dione in 71 to 81% yields, but both aniline and 1-methylaniline fail to furnish the corresponding isatins62. A de novo isatin synthesis based upon a palladium catalysed double carbonylation of ortho-haloacetanilides in the presence of Et2NH to yield the corresponding glyoxylic acid amide was reported by Yamamoto and co-workers63. Hydrolysis of this amide yielded the respective isatin (Scheme 20)., X COCONEt2 CONEt2

CO

Et NH +2 NHAc Pd NHAc NHAc X = Br, I (30-77%) (14-70%) 3N HCl

O O N H

(93%) Scheme 20 1-(Dialkylimino)isatins can be prepared from cyclohexanone in three steps, the last involving DDQ oxidative aromatization64 (Scheme 21).

N O

H2NNMe2 NH (COCl)2 OHOODDQONNNNScheme 21, Rigby has developed a different approach for the construction of the hydroindolone intermediates65. These compounds were prepared by [1+4] cycloaddition of vinyl isocyanates and isocyanides (Scheme 22). NHC6H11

DPPA

CO2H C6H11NC

O N H

(84%) Scheme 22 The resultant dienamides can be hydrolysed and subsequently oxidised by DDQ to yield isatin derivatives66 (Scheme 23). NHC6H11OOO

N

1) (CO N2H)2, MeOH 2) DDQOOOOScheme 23 The formation of isatins has been reported during decomposition studies of the structure or reactivity of natural products. In this manner, the attempted epoxidation of rutacridone led to N-methylisatin67 (Scheme 24)., O OHOOtBuOOH N +O Mo(CO)6 O OMeNNScheme 24 Isatins are also formed during the photo-oxidation of 5,6-dihydroindoles68, from the oxidation of indoles with thallium (III) trinitrate69 and by electrochemical oxidation of indigo carmine70. 1-Ethyl-5,6-methylenedioxyisatin is obtained in the electrochemical reduction of cinoxacin, an antibacterial agent, in 92% yield71 (Scheme 25). OOOCO2H O e- OONON2ONScheme 25 3. Reactivity of isatin and derivatives towards electrophiles 3.1 N-alkylation Many methods have been devised for the N-alkylation of isatins. These derivatives are commonly synthesized from the reaction of the sodium salt of isatin with alkyl halides or sulphates72,73. Various methods for the preparation of this salt have been reported, and include the reaction of isatin with sodium hydride, either in toluene under reflux74 or in DMF75. Other methods include the use of potassium carbonate in DMF76,77 or in acetone78. In the latter case an aldol reaction of the solvent also occurs with the C-3 carbonyl of the isatin derivative., Heating in ortho-dichlorobenzene results in a retro-aldol reaction and the obtention of the N- alkylated isatin. More recently the use of CaH2 in DMF has been reported79 and this method was used for the synthesis of both mono and bis-N-alkylisatins. These latter compounds have been previously prepared using dihaloalkanes and NaH in dioxane80 or DMF81 or by the use of LiH82. Some of these alkylation methodologies were evaluated for the synthesis of isatins bearing a glycosidic residue linked to the N-1 position 83. An alternative method for preparing 1-alkylisatins consists in the reaction of isatin and alkyl halides in a benzene-chloroform/50% aq. KOH biphasic system, employing tetrabutylammonium hydrogensulfate as the phase transfer catalyst84. N-Propargylisatins, obtained from isatin and propargyl halides79,85, can be converted to N-acetonylisatins through hydration with Hg(II) salts in acidic media86. The synthesis of 1-methylisatin by the method of Stolle, using tris(methylphenylamino) methane instead of N-methylaniline, leads to the desired product in low yields87. The reaction of isatin with vinyl acetate in the presence of Na2PdCl4 yields 1- vinylisatin88. On the other hand, O-alkylation at position 2 has been reported, along with the N-alkyl product, using γ-butyrolactone89 or allyl bromide90 as alkylating agents and the sodium salt of isatin. O-Methylisatin is described as the product of the reaction of methyl iodide with the silver salt of isatin, which can be prepared from isatin and silver acetate91. The alkoxy group has been reported to be displaced by nucleophiles such as hydrazines92. 3.2 N-arylation N-Arylisatin can be obtained from isatin in quantitative yields by reaction with Ph3Bi(OAc)2 and Cu0 under an inert atmosphere93 or from aryl bromides and cupric oxide94., 3.3 N-methyleneamino derivatives The Mannich reaction is readily applied to isatins. The products of this reaction, the N- aminomethylisatins (Mannich bases), can also be obtained from the N-hydroxymethyl derivatives by reaction with an amine95 or by reaction with acetyl chloride to yield N- chloromethylisatin which can be further treated with potassium phthalimide or alcohols to give the corresponding N-phthalimidomethyl or N-alkoxymethyl isatins96. The Mannich reaction can also be performed with isatin derivatives, such as isatin-3-hydrazones97 and isatin-3-thiosemicarbazones98. 3.4 N-acylation and N-sulfonylation The synthesis of N-acylisatins under a variety of conditions has been described using acyl chlorides or anhydrides under reflux, either alone99 or using perchloric acid in benzene, triethylamine in benzene100, pyridine in benzene101, or triethylamine in chloroform102,103 as catalysts; or by conversion of isatin to sodium isatide using NaH in toluene under reflux and subsequent reaction with acyl chlorides77. The use of diacyl chlorides, e.g. oxalyl chloride104, octanedioyl or nonanedioyl chlorides105, yields bis-acylisatins. Attempts to use 2,2-dimethylmalonyl chloride to furnish 2,2-dimethylmalonyl-bis-isatin failed, and led instead to an unusual tricyclic compound which was characterized by spectroscopic methods and by X-ray diffraction106 (Scheme 26).,

O

OOOOOOO Cl ClONONONNa

N

O O NaNOOCl

O

Scheme 26 Other complex products have been obtained from the reaction of isatin and acetic anhydride in the presence of pyridine107 (Scheme 27).

O

NNOO

O O

AcO2

O

+ CO PyO2

H N

H OONNOH

O

Scheme 27 Similarly, dimers may be formed in the acetylation of indolylglyoxalates with acetic anhydride in pyridine108 (Scheme 28). CO2R COCO2R AcOO2PyONNOHHN

H

, Scheme 28 N-Sulfonylisatins are obtained from the reaction of isatin and sulfonyl chlorides by applying the same methodologies as used for obtaining 1-acylisatins. For example, 1- tosylisatin is formed in 71-74% yield by mixing tosyl chloride with isatin in the presence of Et3N or with the sodium salt of isatin109. 3.5 N-Haloderivatives The treatment of isatin with sodium hypochlorite in acetic acid leads to 1-chloroisatin, an effective mild oxidizing agent for the conversion of alcohols to aldehydes and ketones110 and of indoles to 3-chloroindoles without formation of by-products111. N-[phenyliodine(III)] bisisatin can be obtained from the sodium salt of isatin and phenyliodine (III) bistrifluoroacetate in 85% yield. This compound is a member of a group of iodine(III)imides, which possess mild oxidizing properties112. 3.6 Reactivity of the aromatic nucleus Although isatins with substituents attached to the aromatic ring are usually obtained from the corresponding functionalized anilines, they can be synthesized by electrophilic aromatic substitution. Nitration of isatin using the sulfonitric mixture yields 5-nitroisatin113. Precise temperature control is needed114, otherwise a mixture of nitrated products are formed115. The bromination of isatin in alcohols gives 5,7-dibromo-3,3-dialkoxyoxindoles in an acid catalyzed ketalization of the halogenated isatin116. Monobromination at position 5 can be achieved, at least on a microscale, with the use of N-bromoacetamide in acetic acid medium117. 5-Bromoisatins can suffer arylation by the use of aryl or heteroarylboronic acids via a palladium-catalyzed Suzuki cross-coupling reaction118. Recently, 4,6-dibromoisatin, a, key intermediate in the synthesis of convolutamidine A, was prepared by bromination in ethanol of a 5-aminoisatin derivative119 (Scheme 29). Br O Br , EtOH OH2NO2H2NOOONBrNHHBr O 1. tBuONO, DMF 2. (CO2H)

O

2, H2O Br N

H

Scheme 29 4. Application of isatins in organic synthesis Many synthetic methodologies have been described for the conversion of isatins to other heterocyclic systems. This chemistry can be generalised as one of the following strategies: a. Partial or total reduction of the heterocyclic ring, leading to indoles and derivatives; b. Oxidation of the heterocyclic ring. For example, conversion of isatin to isatoic anhydride, with subsequent conversion to other heterocyclic systems (Scheme 30);, OOONu O Nu

O

N ENOENHHHIsatoic anhydride Scheme 30 c. Nucleophilic addition at position C-3, which may be further followed by a cyclization process, with or without N1-C2 bond cleavage (Scheme 31); O nXXnXYO+ OYNnYNNRRRScheme 31 or by a spiroannelation at position C-3 (Scheme 32): n O nHOXYYXX O + OONnYNNRRRScheme 32 d. Nucleophilic substitution at position C-2, leading to the opening of the heterocyclic ring. This process may be followed by an intramolecular or by an intermolecular exo-trig cyclization (Scheme 33)., O O CONu CONu O + Nu- Y N Y:N N Y: HHOOCONu Y: O + Nu- CONu

Y

EXNENHR N XHRRScheme 33 4.1 - Reduction of the heterocyclic ring 4.1.1- Synthesis of indoles The reduction of isatins with lithium aluminum hydride in pyridine gave indoles in moderate yields. However, the use of THF as a solvent under an inert atmosphere gave greater yields (86-92%) and this procedure was applied to the synthesis of substituted ellipticine derivatives120. Isatins can be chemoselectively alkylated at positions 1 or 3. Subsequent reduction of these compounds using metal hydrides leads to 1- or 3-alkylindoles121 (Scheme 34).,

HO R R

RLi O LiAlH4

N N O H H O N H O

1) NaH O BH3.THF2) RX N

N R R

Scheme 34 The analgesic drug pemedolac122-124, analogues of etodolac125,126 and the synthesis of the alkaloids hobartine and aristoteline127 were initiated by the C-3 alkylation of isatins to yield dioxindoles that were then reduced to the corresponding indoles by the use of lithium aluminum hydride (Scheme 34)., CO2Me

O O HO CO2Me LDA N O H N H

LiAlH4 H (72%) O

OH CO2H N N H H

PemedolacON

N

O + Piperidine, EtOH 1) KBH4HH(86%) 2) LiAlHN 4OHN

H H

N H

N

HCl, ∆

N H N H

Hobartine (25%) Aristoteline (62%) Scheme 34, In a similar manner, 1-acylisatins can be reduced to 1-alkylindoles by BH3.THF in high yields99 (Scheme 35).

O O BH3.THF N (72-86%) N R O R

Scheme 35 As part of the synthetic methodology for the synthesis of the cytotoxic marine alkaloid, dragmacidin, 6,7-dibromo-4-methoxyisatin was reduced to the corresponding indole in 33% yield using a commercial solution of 1M BH3.THF128. Wierenga and co-workers investigated the use of BH3.THF and the dimethylsulfide complex for the reduction of 3-methyl-3-thiomethyl-2-oxindoles and 3-alkyl-3-hydroxy-2- oxindoles. The resulting indoles were obtained in excellent yields129. Isatins are readily converted to 3-fluoroindoles in a two step process involving firstly the reaction of an isatin derivative with DAST (diethylaminosulfur trifluoride) to yield the 3,3-difluoro-2-oxindole derivative and secondly reduction of the difluorooxindole using BH3.THF to give the respective 3-fluoroindole. The reaction course was shown to proceed by formation of the 3,3-difluoroindolines, which subsequently eliminated HF. The presence of electron withdrawing groups on the aromatic nucleus retarded elimination of HF resulting in the obtention of 3,3-difluoroindolines as the major product130. Isatins have been used for the synthesis of fused indole derivatives. The reduction of 1-methylisatin-3-oximes, by Zn in acidic media, leads to an acetamidooxindole, which upon reaction with P4S10 gives indolothiazoles in moderate to good yields131 (Scheme 36)., NOH NHAc N Zn P4S10 O SAcOH/Ac 2O O (27-71%) NNNRRRScheme 36 4.1.2 - Synthesis of oxindoles and dioxindoles The products of partial reduction of isatin, dioxindole and oxindole, have been widely used in organic synthesis, especially in the development of new drugs. Some natural products also belong to these classes of compounds, for instance dioxibrassinin132. There is also a medical interest, as dioxindole has been isolated from the urine of a schizophrenic patient and from suspected drug abusers133. Dioxindoles can be obtained from isatins by reduction of, or by carbanion addition to the C-3 ketone functionality. Amongst the methods for the reduction of isatin to dioxindoles are the use of Zn/HgCl2 in refluxing benzene72 and Fe/HCl in aqueous ethanol134, as well as eletrochemical135 and photochemical75 reduction. N-Methylisatin can be reduced to the corresponding dioxindole in quantitative yield by reaction with potassium tetracarbonylhydridoferrate (KHFe(CO) 1364) . Oxindoles can be prepared by the reduction of dioxindoles or isatins: by using red phosphorous and iodic acid134; by reduction of isatin with H2S in a pyridine/co-solvent mixture1137; by reduction of the isatin-3-ethylene thioketal with Raney nickel138 or by the Wolf-Kishner reaction139-142, where the use of lower molecular weight alcohols as solvent, such as EtOH or iPrOH, lead to high yields of the desired product143. It has however been found that isatin could be reduced to the corresponding oxindoles in high yields (76-92%) by the use of hydrazine hydrate as the solvent in the absence of any additional base144,145., A chromatographic method for the quality control of oxindoles, frequently used as raw materials for pharmaceutical products, using normal phase HPLC has been developed146. Indigo, isoindigo and indirubin are natural pigments bearing the oxindole motif and have considerable economical importance. As a consequence synthetic methodologies have been developed for the obtention of these pigments and analogues: indigo and monothioindigo can be obtained from the reaction of isatin withPS1474 10 ; isoindigos have been prepared by an acid catalyzed reaction of isatin and oxindole derivatives148,149 and from the reaction of N- methylisatoic anhydride or N-methylisatin with sodium phosphonates150,151; isoindigos and thioisoindigos can be prepared from the condensation of isatin promoted by Lawesson’s reagent152; indirrubins, which are described as effective antileukemic agents, can be prepared from isatin and indican, a compound extracted in high yields from Baphicacanthus cusia153, or from isatin and N-methyl-O-acetylindoxyl149,154 and from isatin and 3-hydroxyindole155; pyrrolo-indigo compounds can be prepared by the condensation of isatin with pyrrolin-4- ones156; and thionaphthene indigo dyes (Thioindigo Scarlet) are obtained from hydroxythionaphthenes and isatin in acidic media157. In a reverse sense, isatin has been identified as one of the products of the oxidation of indigo by nitric acid and light. This process may be involved in the fading of indigo in museum collection objects158 and denim jeans159,160. The same conversion can be realized by ozonolysis161, acidic bromate162 or by a chemiluminescent autoxidation of indigo163. N- Methylisatin is also obtained in the photooxidation of N-methylindole-3-acetic acid164. Isoindigo, obtained from isatin and oxindole, is converted diastereoselectively into diazacrisenodiones by reduction with Zn/AcOH, and subsequent acid-catalyzed rearrangement148 (Scheme 37).,

H

O N

O O

O + AcOH, HCl, ∆N (100%) NHOHN

H

HHNNO

O H

Zn, HCl HCl 4N, ∆ (85%)

H O

NONHHScheme 37 Isatin oximes have also been reduced to 3-aminooxindoles by use of SnCl2/HCl165 or by electrochemical means166,167. 3-Aminooxindoles have also been obtained by reduction of isatin-3-imines and isatin-3-hydrazones by hydrogenation and converted into ureido derivatives for study as antiulcer agents168-171. 3-Formyloxindoles are prepared from the Vilsmeyer-Haack reaction of oxindole172, while 3-acyloxindoles, useful as analgesic and anti- inflammatory compounds, are obtained by reaction of oxindole with isocyanates160,173,174,175, acyl chlorides176, or with esters177. Oxindoles178 and 1-aryloxindoles179,180 can suffer nucleophilic heterocyclic ring opening with hydroxides, leading to phenylacetic acid derivatives which also possess anti-inflammatory activity. Phenylacetic acids are also reported to be formed during the Wolff-Kishner reduction of 1-naphthylisatins181. A unique procedure for the synthesis of these acids is also described in a French patent, where diclofenac is claimed to be obtained during the reduction of an isatin-3-sulfonylhydrazone by sodium borohydride at 60-70 oC182. Oxindoles have also been employed in the synthesis of polyimides for use in coatings and laminates for printed circuits183., 4.1.3 - Reduction involving free radicals Isatin and 1-methylisatin can be reduced by merostabilized free radicals to isatide and N,N’-dimethylisatide through the intermediate dioxindolyl radicals184 (Scheme 38): O OH HOOOO

O

NNNRORRN2

H H

O N

O O

N O

H

Scheme 38 4.2 - Oxidation of the heterocyclic ring The oxidation of isatin using either hydrogen peroxide185,186 or chromic anhydride yields isatoic anhydride187 (Scheme 39):

O O O CrO3 O N (72%) N O H H

Scheme 39 Isatoic anhydride can be condensed with proline in polar aprotic solvents at high temperature, or in a reaction catalyzed by the enzyme catalase, to yield a pyrrolo[1,4]benzodiazepine ring, a structural pattern found in some antineoplasic antibiotics188 (Scheme 40).,

O O R O CrO3OHN+ NNOHO H 2 C H O R

CatalaseNR= H 68% R = OH 76% N H

H O

Scheme 40 6-Chloroisatoic anhydride can also be converted into benzodiazepinones by cyclocondensation with 2-azetidinecarboxylic acid, which reacts with ethyl isocyanoacetate, to give imidazo[1,5-a]-[1,4]benzodiazepinones189- 192 (Scheme 41).

O Cl H O O H N

+ N

N O N Cl H HO2C O N Cl CO2Et N

CNCH2CO2Et

N O

Scheme 41, Isatin-2-iminooxides lead to isatoic acid derivatives and quinazolinediones by photolysis, while isatin-3-iminooxides are reported to furnish only quinazolinediones. In both cases some isatin is also obtained193 (Scheme 42). O O

O

NR1

N

ONOR2 R2

O

NR1 O

NR

O1NNOR2 R2 Scheme 42 In a related reaction, isatin-3-phenylhydrazone yields 1,3-benzazoxane-2-one-4- hydrazone upon treatment, under reflux, with an ethanolic solution of cupric chloride194 (Scheme 43).

NNHPh NNHPh O CuCl2 O N N O R2 R2

Scheme 43 Isatoic anhydrides can be converted to isatins by treatment with cyanide and further hydrolysis of the 2-imino derivatives in acidic media195 (Scheme 44)., OOOKCN DMF NHNON

O

HCl O

N

Scheme 44 Anthranilates can be prepared from isatins by reaction of hydrogen peroxide in an alkaline solution24,196, or by the use of chloroamine-T or dichloroamine-T197 or by hydrolysis of isatoic anhydride with an aqueous alkaline solution198 and may also be formed through oxidation of indigo carmine by hypohalides in alkaline medium199. Anthranilic acid is also formed in the photolysis of isatin to isatoic anhydride, which is subsequently hydrolysed200. Anthranilic acid hydrazides are synthesized from isatoic acid and hydrazines201. The economic importance of anthranilates resides in their well-estabilished anti- inflammatory activity. Thus, many derivatives have been synthesized with the objective of discovering new pharmacological agents such as immunosupressants202, fungicides203 and agents for the prevention of nerve cell damage204. Anthranilic acid has also been used in the synthesis of polycyclic aromatic hydrocarbons, such as dicyclooctabiphenylenes205, phenanthrenequinones206, fluorenones207, benzonorbornadienes208, toluenes209, naphthalenes and anthracenes210 and benzyne-furan adducts211. Most of these syntheses are based upon the formation of benzyne after diazotization of anthranilic acid and the subsequent addition to a diene. This methodology has been used in the synthesis of odorous compounds212 and for the synthesis of podocarpic acid213 (Scheme 45).,

O O CO2H iC5H11ONO NH2

(57%) Scheme 45 Anthranilate, as well as isatin, isatoic anhydride, dioxindole and oxindole have been found to be products of microbial oxidation of indoles, as shown in the sequence below214,215 (Scheme 46). Similar pathways are found in the degradation of indole-3-acetic acids216. CO2H O NH2

O

NNOHHNHOH

O N H

Scheme 46 The treatment of isatin-3-oximes or their O-sulfonates with bases, such as sodium methoxide in refluxing diethyleneglycol217 or NaOH and CuSO 2184 leads to 2-cyanoanilines. Under Beckmann rearrangement conditions, O-tosyl oximes furnish the cyanoanilines219, while the parent oxime gives the intermediate 2-cyanophenylisocyanate220. When the O-acetyl oximes are reacted with sodium azide, cyanoanilines are also produced221. Campbell217 proposed a mechanism where the E-isomer of the oxime suffers elimination, forming a 2- cyanoisocyanate, which upon hydrolysis and decarboxylation gives 2-cyanoaniline (Scheme 47).,

HO N

N O

H O

O N

N H H B

CN CN NCO NH2 Scheme 47 Isatin-3-oximes are also decomposed to benzonitrile derivatives under Vilsmeier- Haack conditions, furnishing formamidines222 (Scheme 48). R1 CN

DMF

N N R2

NOH

R1 POCl3

O N

R H2 R1 CNNNONR2 (27-50%) Scheme 48 These methods have been applied to the efficient synthesis of substituted cyanoanilines such as 2-cyano-4-nitroaniline223., The oxidation of isatin with metachloroperbenzoic acid yields 1,4-benzoxazine-2,3 (4H)-dione, which was subsequently converted to blepharin, a glycoside obtained from Blepharis edulis Pers. whose seeds are used in rejuvenescent therapy in Ayurvedic medicine224. This oxidation can also be performed with potassium persulfate in sulfuric acid225,226 (Scheme 49). OOOOMCPBA KBH4(80%) NNOHHOOH O HO

OH

O O OH H OHNO(40%) NOHHScheme 49 Isatin undergoes anodic methoxylation in acidic medium when using platinum electrodes in a unique fashion that results in the dimethoxylation of isatin at positions C-3a and C-7a227 (Scheme 50). O MeO O MeOH

O

- 2 e-

O

NNHMeO H 35% Scheme 50 4.3 - Nucleophilic attack at positions C-2 or C-3, Isatins and derivatives can suffer nucleophilic attack at positions C-2 and/or C-3. The chemoselectivity of these reactions depends on the nature of the nucleophile, on the nature of the substituents attached to the isatin nucleus, and especially of those bonded to the nitrogen atom, as well as upon the solvent and temperature employed. The initial products obtained can suffer further reaction in the presence of a second nucleophilic group to give cyclization products. For didactic reasons, these reactions have been sorted by the nature of the nucleophile. 4.3.1 - Amines and related compounds a) Ammonia, hydroxylamine and hydrazine Isatin reacts with ammonium hydroxide or ammonium acetate to furnish a mixture of compounds. Amongst them are isamic acid and its corresponding amide, isamide. Since 1877 there had been a discussion as to their structure, which in 1976 was finally elucidated, by Sir John Cornforth on the basis of chemical and spectroscopic data228. Isamic acid can be regarded as a dimer formed by the addition/condensation of one equivalent of ammonia with two equivalents of isatin. This intermediate suffers lactonization and subsequent conversion to isamic acid by an internal nucleophilic attack, where upon the acid is converted to isamide by reaction with a second equivalent of ammonia. 1-Methylisatin reacts similarly, furnishing N- methylisamic acid (Scheme 51).,

H N

O O

NH

O 3 HO N

N

R1 O

N

R1 O R2OCONNNH2NHOONNR1 R1 R = OH R1 = H or Me NH 3 R2 = NH2 Scheme 51 Isatin and 1-alkylisatins react with hydroxylamine or O-methyl hydroxylamine hydrochloride under aqueous alkaline conditions to furnish the corresponding 3-oximes, which have been studied as monoamine oxidase inhibitors229,230. Isatin oximes can be acylated simultaneously at the heterocyclic ring nitrogen and at the oxime oxygen by reaction with anhydrides or acid chlorides231. While these products are derived from the nucleophilic attack at the C-3 carbonyl, the reaction of N-acylisatins with the respective nucleophiles results in opening of the heterocyclic ring. The reaction of N-acetylisatin232 and N-chloroacetylisatin233 with ammonia yields products resulting from nucleophilic attack at the C-2 carbonyl that leads to, heterocyclic ring cleavage. The benzoylformamides obtained in these cases further react with a second equivalent of ammonia to produce quinazoline derivatives (Scheme 52). O O NH2 CONH2 O ONHN3NH3 N

NH N

OORRRScheme 52 Compounds bearing the 1,4-benzodiazepine moiety have potential use as anxiolytic agents. One of the methods for the synthesis of this heterocyclic system involves the reaction of 1-α-chloroacetylisatin with hexamethylenetetramine in methanol233, thus yielding the 1,4- benzodiazepine-5-carboxylic ester via solvolysis of the N-acylisatin and the in-situ nucleophilic substitution of chloride, generating the glycine amide that subsequently undergoes cyclo-condensation (Scheme 53).

N O N CO2Me N

N N

O N MeOH (51%) Cl N O H O

Scheme 53 In a similar fashion, 1-acetylisatin, when reacted with hydroxylamine hydrochloride furnishes quinazoline-3-oxide through cyclization of the intermediate hydroxamic acid234. This intermediate hydroxamic acid can be isolated by treatment of the quinazoline oxide with alkali235 (Scheme 54)., O NHOH

O

O NH2OH.HCl NHOH

N NH O

-H2O O

CONHOH O

N NaOH rt

N

Scheme 54 The reaction of oxalylbisisatin with O-methyl hydroxylamine hydrochloride yields the hydroxamic acid, with no further cyclization to a quinazoline occuring to yield quinazolines 104. Isatin and 1-alkylisatins furnish condensation products at the C-3 position when reacted with hydrazine236, alkyl and arylhydrazines237,238,239, heteroarylhydrazines derived from pyrimidine240, pyrazine241, thiazole242, 1,2,4-triazine243, quinazoline244,245, benzimidazole246,247, benzothiazole248,249, phthalazine250 and triazines251,252, acylhydrazides of oxalic253, benzoic254, phenoxyacetic255 and oxanilic acids256, arylsulfonylhydrazides257, guanylhydrazones258, semicarbazines259 and thiosemicarbazides260,261,262. The reaction of 1-methylisatin and semicarbazone yielded methisazone, a compound that found use in the treatment of variola, a viral disease that has now been eradicated 263 (Scheme 55).,

O NNHCSNH2 O H2NCSNHNH2 O N EtOH N

Methisazone Scheme 55 Isatin-3-imines also react with hydrazine derivatives such as heteroarylhydrazines264, thiosemicarbazides265 and acylhydrazides266, resulting in a substitution reaction at the C-3 position. Substitution reactions are also described to occur when O-methylisatin is treated with thiosemicarbazines, furnishing isatin-2-thiosemicarbazones91. The stereochemistry of isatin-3-thiosemicarbazone-5-sulfonate was studied in aqueous solution, and in acidic pH the Z isomer was determined to be the most stable, but after deprotonation, the corresponding anion slowly converts to the E isomeric anion267 (Scheme 56). CONH CONH CONH22 2

N

NNNNN- HO3S -O3S -O3SOOONNNHHHZisomer Z anion E anion Scheme 56 Isatin hydrazones and thiosemicarbazones can also be used as substrates for the Mannich reaction, leading to functionalization at N-1268,269. Isatin-3-hydrazone reacts with 1,1- dimethylamino-2-nitroethene to give a transamination product270 (Scheme 57)., NO2 NNH NO2 2 NHMe O MeNH NHMe N

N H N O

H N

H

Scheme 57 The reactions of 1-acyl or 1-arylsulfonylisatins with hydrazines, thiohydrazides and thiosemicarbazine derivatives are dependent on the nature of the nucleophile and on the reaction conditions. These reactions can lead to products of nucleophilic attack at C-2 and/or C-3. 2-Hydrazinopyridine and quinoline in aq. PrOH/AcOH271, bis-thiazolidinehydrazones in refluxing AcOH272 and thiocarbohydrazine in aqueous EtOH273,261 react with 1-acetylisatin to furnish solely the products of attack at the C-3 ketone group. The same occurs with the use of N-acetylhydrazide hydrochloride in dioxane, while the reaction of the free base in EtOH leads to the product resulting from attack at the C-2 position, giving a ring opened derivative, together with a small quantity of 1-acetylisatin-3-acetylhydrazone274. 1-(4-Nitrobenzoyl)- isatin reacts with guanidine in the presence of sodium ethoxide to yield the ring opened product275. The results described by Tomchin are far more complex than those described above. It has been stated that 1-acetylisatin reacts with thiosemicarbazide to furnish the corresponding isatin-3-thiosemicarbazone, together with a small portion of the ring opened product that results from attack at C-2. The yield of the latter product increases as the solvent is changed from ethanol to dimethylacetamide and to AcOH, whilst none of the ring opened product is obtained using dioxane. On the other hand, when the same solvents were used in the reaction of 1-butyrylisatin with thiosemicarbazides, the only product formed was the corresponding 3-, thiosemicarbazone. A further conflicting result is that of 1-tosylisatin which behaves similarly to 1-acetylisatin in its reaction with thiosemicarbazides, but when using dioxane as the solvent the major product is that due to ring opening109. The reaction of 1-acetyl-5-bromoisatin with thiosemicarbazine in EtOH yielded only the corresponding 3-thiosemicarbazone, while in acetic acid a mixture of products resulting from attack at C-2 and C-3 was observed, the former being favored276. Both products were also formed in the reaction of 1-acetylisatin with thioacylhydrazides in AcOH277. Tomchin and coworkers also described that O-methylisatin reacts with thiosemicarbazine to furnish isatin-2-thiosemicarbazone, which can undergo a cyclization reaction under acidic conditions to furnish a thiadiazanoindole derivative92; the kinetics of the reaction were subsequently determined278. Later, Tomchin also described that isatin-2- thiosemicarbazones suffer a cleavage reaction of the five member ring, and the intermediate formed recyclizes to a thiadiazole derivative279 (Scheme 58).

NH

O2OHO S H2NCSNHNH2 N NH

H

2 3 O+ NONNN

N

HHS

N H

H3O+ H2N

N

S N

O

NH2 Scheme 58, 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). NNHCSNH NNHCSNH22 NNHCSNH ∆2NNNNHH

S

Scheme 59 Isatin-3-thiosemicarbazones are useful substrates for the synthesis of other 3- substituted oxindoles. For example, they can be converted to thiohydantoin or thiazolidine derivatives by reaction with chloroacetic acid281 (Scheme 60). HSHClONNNNH2NN

OH

SOOONNHHScheme 60 b) Alkylamines The reaction of isatin and 1-alkylisatins with primary alkylamines yields the corresponding 3-imines, which upon reduction with sodium borohydride in hot ethanol yield phenylethanolamine derivatives282 (Scheme 61)., O OH

N

iPrNH2 NaBH4O O EtOH NHiPr N ∆ N NHCH3 Scheme 61 Secondary alkylamines react with isatin to give a 1:1 adduct, as a result of the nucleophilic attack of the amine at position C-3. In the case of dimethylamine a second equivalent of amine adds, leading to a 1:2 adduct as the kinetic product; upon heating the ring opened glyoxamide is formed. Diethylamine and higher non-cyclic amines only give the 1:1 adduct, probably due to steric hindrance, which decompose to dialkylamonium benzoylformates283 (Scheme 62). O HO NR2 R2N NR2 R NHO2OONNR= MeNHHHR= Et ∆ NEt2 CONMe2

OH

O O

N

H NH2 73% CO2 R2NH2

O

NH2 100% Scheme 62, On the other hand, the reaction of isatin with N,N-dimethylethylenediamine in water yields the spiro-diazolaneoxindole whereas the corresponding condensation reaction performed by azeotropic distillation in toluene yielded the unusual 2:1 adduct as the result of the addition of an unstable azomethine ylide to isatin283 (Scheme 63). OHHNNNHONNHOONNToluene, ∆ OOHNH2 NH2HHNNH2O

N

N N

N

O ONHN2HIsatin NH2 N

O N O O N H

Scheme 63 The decarboxylation of α-aminoacids catalyzed by isatin in aqueous media has been studied as a model for the enzymatic decarboxylation of these compounds. As a result, phenylglycine yields benzaldehyde and benzoic acid as products, but the efficiency of isatin is far lower than that of methoxatin (PQQ), the coenzyme of several alcohol and amine, dehydrogenases. The redox cycle for methoxatin is proposed to proceed as below284 (Scheme 64): OOOONHO Φ NH2HOHΦCO 2 B2H NH3 + H2O2 CO2 O2 + H2O OH OH NH N2 H Φ2O ΦCHO H ΦCO2H Scheme 64 Pipecolic acid, a cyclic aminoacid, when reacted with isatin, suffers decarboxylation, furnishing an azomethine ylide, which reacts with dipolarophiles, such as fumaronitrile, to yield a spiro derivative285 (Scheme 65).,

O

N CO2HNOHNOHCO2 N

H NC NC NC

CN N

O N H

Scheme 65 Proline and isatin also furnish an azomethine ylide, which reacts regio- and stereo- selectively with acrylates, such as (1R, 2S, 5R)-menthyl acrylate, to yield a mixture of diastereoisomers. The structure of the major diastereoisomer was determined by X-ray crystallography and the following transition state was proposed for its formation286 (Scheme 66):, OONCO H N2OOHNOHH2O

N H N

CO2 O

N H O N O

O OH N CO2R*

N

H N

H

R*O2C

N O N H

Scheme 66 Similar processes can be found in the reactions of isatin with pyrrolidine or benzylamine and methyl acrylate287,288, with sarcosine or glycine and oxoindolin-3-ylidene, acetophenones289 and with phenylglycine and acenaphthylene290. The reaction of an unstable azomethine ylide and a chiral oxoindolin-3-ylidene acetate ester resulted in an asymmetric synthesis of the oxindole alkaloid Horsfiline291. This reaction has also been employed in the construction of a molecular library of spiro[pyrrolidine-2,3’-oxindoles] from isatin, aminoacids and chalcones292,293 (Scheme 67). R R4 O R3 R R4 3 4R2NRNPh 2 R3 H CO2H R

N

O COPhNOONOR1 NR1 R1 65-88% Scheme 67 Alkylamines and 1-acylisatins lead to 2’-acylamidobenzoylformamides due to opening of the heterocyclic ring294,295, which can be reduced to mandelic acid derivatives with NaBH4 or LiAlH 2964 . Under acidic conditions, the 2’-acylamidobenzoylformamides regenerate isatin63. Products arising from the opening of the heterocyclic ring are also obtained with 1- alkylsulfonylisatins297, 1,2-dioxo-1,2-dihydropyrrolophenothiazine298 and 1- iminobenzylideneisatin299 (Scheme 68). HSOON

N

O 6-Aminopenicillanic CO2H N acidOO

H

SNOROSOR

O

,

O NHR O O

RNH H O2

N (86-94%) N S S O O NHR O ORNH N 2(70-98%) NH N N Ph Ph

Scheme 68 In contrast the reaction of N-acetylisatin with diaminomaleonitrile has been reported to produce a pyrazinoindole300 (Scheme 69).

CN

O H2N CN

N CN

O H2N CN N

N N O O

Scheme 69 Isatin-1-ethylcarbamate and urea yield a ring-opened product, which after treatment with ammonia yields a spiro hydantoinquinazolone301 (Scheme 70). Similarly, 1- carboxamidoisatins furnish quinazolones upon treatment with thiourea derivatives302 (Scheme 71).,

H OONNH2 O H2NCONH2, THF OO N H N O OEt

O OEt

O HN O NH

NH3, EtOH (65%) NH

N O H

Scheme 70

NH

O N SEt HOOOH2NC(NH)SEt NMe

N

NOONHMe

H

O H

N

H N

O

[H+] NMeNO

H

Scheme 71 c)Anilines and heterocyclic amines As with alkylamines, isatin303,304, 1-alkylisatins305, 1-hydroxyisatin306 and 1,2-dioxo- 1,2-dihydropyrrolophenothiazine298 lead to the corresponding 3-imines when treated with, anilines or heteroarylamines307. These imines can be acylated308 or they may participate in the Mannich reaction and thus yielding N-1 substitution products309,310, although exchange of the imino group can also occur311. Upon reaction with N,N’-thionyldiimidazole, isatin and 1-methylisatin furnish the substitution product resulting from the addition of two imidazole groups at position C-3. These compounds where found to possess antimycotic activity312 (Scheme 72).

N

OONNNNSNNNOO42% NOHN

H

Scheme 72 Isatinyl-N-oxide, obtained from 1-hydroxyisatin, yields the corresponding 2-imino derivative when reacted with anilines or with aliphatic amines313 (Scheme 73). OOOΦNH2(70%) NΦNNOOScheme 73 The reaction of isatins with ortho-phenylenediamines gives indophenazines, 3- iminoisatins and/or spirobenzimidazolines, the proportion between them being affected mostly by the solvent polarity. Indophenazines were obtained in yields of 89% by treating isatins and ortho-phenylenediamines in acetic acid314-317; isatin-3-imines were obtained when using THF, benzene (90% yield) or MeOH (50% yield), together with indophenazines. Isatin- 3-imines are converted to the corresponding indophenazines by treatment with AcOH318., These imines have been studied as hair dyes319. The use of the polar aprotic solvent N,N- dimethylacetamide, and high temperatures yields spirobenzimidazoles in high yields320. A summary of these reactions is depicted in Scheme 74.

O

NH NH22

HO

O + NH

HN

DMA NH N ∆NH2OOHNNHHTHF AcOH NH2HNNN

NH

AcOH2NOONNNHHHScheme 74 These findings can be rationalised by consideration of a common intermediate. An intermediate carbinolamine could undergo either a nucleophilic substitution reaction, probably through an ionisation step facilitated by the high temperature and by assistance from the nitrogen lone pair to form the spiro compound in dimethylacetamide, or the intermediate may suffer dehydration in apolar solvents to form the corresponding isatin-3-imine. This imine can undergo facile syn-anti isomerisation upon protonation in acetic acid and thus yields the indoloquinoxaline derivative321. A number of indophenazines have been applied to the synthesis of photoconductor polymers322. Reaction of 5-azaisatin with o-phenylenediamine yielded a pyridopyrroloquinoxaline50 (Scheme 75).,

O

NH N2

N

O + 1. DMFNN2. POCl

N

NH 32NHHScheme 75 Other diamines, such as 2,3-diamino-4(3H)-quinazolone323 and 2,3-diaminobenzoic acid324, behave similarly to ortho-phenylenediamine when reacted with isatin. When the reaction is carried out with 1-acylisatins, ring opened products are formed using benzene, acetic acid or ethanol as the solvent325-329. However, it has been reported that with the latter two solvents a spiro benzimidazole derivative is also formed330. The formation of ring opened products has also been reported to occur when using alkyldiamines331 (Scheme 76). H NH2OONNH2 HN O + NHO

N

NH H + O2NN

O

O O Scheme 76 Likewise, the reactions of 1-acylisatins and anilines296 or N-methylanilines332 led to ring opened products, but one report states that 4-arylthio and 4-arylsulfonylanilines react with 1-acetylisatin to furnish 3-imines333. 1-Acetyl-3-dicyanomethyleneisatin undergoes a substitution reaction with aniline, in nonpolar solvents, leading to a cyanoenamine334 (Scheme 77).,

NC CN NC NHPh

PhNH

O 2 O N (68%) N

O O Scheme 77 The reactivity of isatin derivatives towards ortho-aminophenol and ortho- aminothiophenol has been the subject of a number of reports and some of the products obtained are quite intriguing. The first report attests that 1-acetylisatin reacts with o- aminophenol to furnish a ring opened product in ethanol as well as in AcOH. The same result occurred with o-aminothiophenol in acetic acid, whilst in ethanol two different products were formed in a disproportionation reaction, as can be inferred from the change of the oxidation state of what was the 1-acetylisatin C-3 ketone group. The structures were assigned based upon spectroscopic data and, for the benzothiazole derivative, on comparison with a sample obtained by a different route335 (Scheme 78)., O X

O

NH2 O + AcOH (X = O or S) N N or EtOH (X = O) XH NH

O

EtOH O (X = S) N SH O NH

S

+ NHNHSH O NH

O

Scheme 78 Subsequent reports336- 338 on the reactivity of isatins towards o-aminothiophenol reported that isatin furnishes a benzothiazinone (18%), due to attack at the C-2 position, and a spirobenzothiazole (10%), due to attack at C-3, when the reaction is carried out in dry xylene in the presence of anhydrous ZnCl2 at room temperature. If the same reaction is carried out under reflux, the products formed are the benzothiazinone (20%), the spiro benzothiazole (40%) and an indolobenzothiazide (15%). 1-Acetylisatin, under the same reaction conditions furnishes, at room temperature, the corresponding ring opened product (20%), which can suffer deacetylation (15%), whereas under reflux these products (40 and 30%, respectively) are accompanied with the spiro compound (5%). 1-Methylisatin reacts only at reflux furnishing solely the spiro compound (42%) (Scheme 79)., OSR= H HNNN+ S + O S NH2NN

H

(20%) (40%) (15%)

O

NHOSOS2 R = Ac HN O + + S N SH N + N O

R

NHCOCH N3 NH2

H

(20%) (15%) (5%) R = Me HN

S O N

Me (42%) Scheme 79 The reactions of these compounds with o-aminophenol occur only at reflux. In the case of isatin, the formation of a ring opened product (25%) occurs along with the 3-imino derivative (30%), whilst 1-acetylisatin furnishes solely a ring opened product (48%). Characterisation of the products was based upon their mass, IR, 1H and 13C NMR spectra (Scheme 80).,

OH

O O

N

R = H N +

O

NH2 N

H

(25%) (30%)

O

NH2 O + N OH

R

OOR= Ac N NHCOCH3 (48%) Scheme 80 The reaction of 5-fluoroisatin with o-aminophenol under the same conditions as the previous study was reported to result in the formation of a heterocyclic ring opened product and a nine membered ring compound. The isomeric 6-fluoroisatin was reported to furnish, apart from these two products, the corresponding 3-imine. The acetylated fluoroisatins behave similarly to 1-acetylisatin, giving rise to the ring opened product339 (Scheme 81)., OOFO5-F N + N R = H F NH2 N

N H O

NH2 O + N OHFR

OH

O O

O

N N 5-F or N + + 6-F R = Ac 6-F R = HNOFNH2FNFNHHOO

N

F NHCOCH3 Scheme 81 3.3.1.2 - Oxygen, sulfur and phosphorous nucleophiles Isatin340 and 1-arylisatins341,342,343 suffer hydrolysis in alkaline solutions, leading to isatinates. Kinetic studies have shown that this is a thermodynamically favored process, which also occurs under physiological conditions, implying that some, or all, of the biological and pharmacological activities described for isatins are indeed due to their isatinates344,345. The pH profile for the hydrolysis of isatin has shown that at pH < 3, isatin is the predominant species, and at pH > 6, the ring opened isatinate is the major component. At pH values between 5 and 6, the rate of hydrolysis is first-order in hydroxide concentration or inversely proportional to the concentration of the hydronium ion, but from pH 6.5 to 10.5 it is pH independent. This result reveals the existence of a complex behaviour for the hydrolysis of isatin, with different rate limiting steps depending upon the pH of the solution. 346. A similar profile has been observed for 1-methylisatin347 (Scheme 82).,

O

- 5 > pH > 6 O H3O+ N OHHHOOCO -2H CO - 2O O 6.5 > pH > 10.5 O OHHO

O

NN2HHNH2 NH2

O

CO - O- 10.5 > pH > 12 O HO- -NOHNH - Scheme 82 It was also observed that in the presence of ethanol and ethylene glycol the rate of hydrolysis decreases348. The effects of other solvents349, as well as the photophysics350 of the hydrolysis reaction of isatin have also been studied. Isatinates can be electrochemically reduced to mandelates at different pH values using mercury electrodes351. The isatinates can be converted to the corresponding oximes, which possess pharmacological interest as anti-inflammatory agents352. Isatin-3-imines are hydrolyzed to isatin and the corresponding amine. A ring opened intermediate is proposed to be involved in the process as it was detected by polarography353. The alkaline hydrolysis of isatin is the first step of a method for the construction of the indazolic ring system354. This method has been applied to the synthesis of serotonin antagonists355 (Scheme 83)., O O ONa NaOH 1. NaNOO 2O N 2. SnCl2 H NH2 O ONa CO2H O N(33%) N NHNH2 H Scheme 83 Isatin-3-ketals are obtained by reaction with diols under homogeneous356 or heterogeneous acid catalysis, employing the strongly acidic resin Dowex 50X-X2357 or by transacetalation with trimethyl orthoformate358. 1-Acetylisatin reacts with alcohols in neutral media to furnish ring opened products228 (Scheme 84).

O O O O Ethyleneglycol, O N p-TsOH N R H O O OR O ROH O N NH O O

Scheme 84, Bergman and Vallberg used the ethyl glyoxalate obtained by solvolysis of N- acetylisatin in refluxing ethanol to reinvestigate the reactions of N-acetylisatin with ethylenediamine and propane-1,3-diamine. The investigations were extended to a number of other diamines and the resulting dihydropyrazinones could be transformed to the corresponding pyrazidoindoles359 (Scheme 85).

O

CO2EtO N NH2 NH2NOOHNNHH

O

NH NN

H

O ONH

O

H2N NH2

H CONHCH

ON2

O

N +

NH NH O

O 2 Scheme 85 The reactions of isatins360,159 and 1-alkylisatins361 with thiols yield substitution products at position C-3, such as isatin-3-thioketals and 3-alkylthiooxindoles362 (Scheme 86).

O S S

(CH

O 2

SH)2

N (80%) O N H H

Scheme 86, Isatin-3-N-arylimines react with mercaptoacetic acid to yield spirothiazolinones363 (Scheme 87). These can be further acylated or submitted to a Mannich reaction, thus giving products substituted at the oxindole nitrogen atom364.

O NAr

HS O

S NAr O OH N (40-70%) O H N H

Scheme 87 The addition of thiols to isatin anils to yield the respective thioazoketals is general365. The reaction of isatin with P4S10 in pyridine resulted in the obtention of pentathiepino[6,7-b]indole136 (Scheme 88).

O

SSPS4S10OSNPySHN

H

Scheme 88 Dialkylphosphites add to isatin and 1-substituted derivatives at position C-3 generating dioxindolophosphonates366. Isatin-3-oximes react in a similar manner367. The use of chlorophosphines generates 3-(3-clorooxindolyl) phosphine oxides368 (Scheme 89)., O HO PO(OR)2 (RO) O 2

POH O

N (70-87%) NRRCl POΦ 2 (ΦO)2PCl O (30-71%) N

R

Scheme 89 On the other hand, cyclic dioxaphospholanes369, phosphites370 and trialkyl phosphites371,372 react with isatins to yield dimeric spiro phospholanes (Scheme 90). Cyclic indolic phosphates were obtained when 1-methylisatin was reduced with sodium in THF to yield a dianion that subsequently reacted with alkyl phosphorodichloridates373 (Scheme 91).

OR RO P OO N R R' O

(RO)

O 2

PR' O

N (35-80%) O R N R

Scheme 90,

O O O Na/THF O N N O O P

Cl2P(O)OR OR (52-64%) O

N

Scheme 91 Isatin-3-N,N-dimethylhydrazone when reacted with diethyl phosphonate, furnishes isatin-N-ethyl-N,N-dimethyl hydrazonium ethyl phosphonate374. The reaction of isatin with triphenylphosphine was believed to furnish indirrubin375, but a reinvestigation of this reaction has shown that the products formed are 3- triphenylphosphoranylideneoxindole and isoindigo376. 4.3.3 - Carbon nucleophiles Carbon nucleophiles add to isatin and derivatives at position C-3 in most cases, and the products formed have been submitted to further transformations giving rise to a variety of heterocyclic systems. Potassium cyanide and ammonium carbonate react with 1-alkyl377 or 1- alkenylisatins363 generating spirohydantoins. These compounds are inhibitors of the enzyme aldose reductase, and have potential use as hypoglycemic agents (Scheme 92).,

O O NH HN O OKCN N (NH4)2CO O3

(47%) N Scheme 92 Isatins can be used as the electrophilic component in the Wittig-Horner reaction with phosphonates and furnish products resulting from attack at position C-3378,379. Other α- carboxyphosphonates380 and α-carboxyphosphites381 have also been studied and yield 3- methyleneoxindoles in moderate yields (Scheme 93).

O O

(RO) P O2

O O

NOHN

H

Scheme 93 1-Alkyl and 1-acylisatin react with equimolar quantities of a succinyl triphenylphosphorylidene to give dimethyl 2-oxoindolin-3-ylidenesuccinate derivatives in low yields382 (Scheme 94). Dimers of this product are obtained from the reaction of isatin-3-(4- chlorophenyl)imine with DMAD in the presence of cupric acetate383. When the Wittig reaction is carried out with two equivalents of the Wittig reagent, 3-spiro-cyclopropanes are formed384 (Scheme 94)., CO2Me

CO O 2

Me CO Me Φ 3P CO2Me

O (13%) N O N R R

Ph3PCHR (2 eq.) (21-74%) O

N

Scheme 94 α-Diazophosphorous derivatives also attack at the C-3 position of the isatin ring to give dioxindoles385,386 which upon treatment with acid yield the ring expanded quinolones (Scheme 95).

O N2 HO

N2 POR1R2 POR1R2

O N Et2NH O N R R

(56-94%) O R2

P

R1 HCl OHNO

R

(59-99%) Scheme 95, 3-Alkyldioxindoles and their dehydration products, 3-methyleneoxindoles, are formed in the reactions of isatins with organoboron compounds, such as triallylboron387; organomagnesium reagents388,389; organozinc reagents390,391 ; organolithium reagents392,393, such as methyllithium154. These compounds are also obtained in aldolic and related condensations with acetone394 or its oxime395; aromatic396,397 and heteroaromatic methylketones398,399; cyclic alkylketones400; acetates401; propionates402; acetoacetates403; cyanoacetates404; nitroalkanes405; benzodiazepinones406; imidazolinones407; indoles408; 2- methylquinolines409; pyrazinones410; thiazolidinediones411-415 and xanthinones416 In the reaction of isatins with some cyclic ketones, such as 4-hydroxy-2H-benzopyran-2- one417, the initial dioxindole formed reacts with a second equivalent of the ketone yielding a 3,3-disubstituted oxindole. The addition of methyl lithium to isatin-3,3-dimethylketal (3,3-dimethoxyoxindole) at room temperature for 2.5 min lead to an indolenine derivative through addition at C-2 and substitution of one methoxy group at C-3. By extending the reaction time to 3 hours, the second methoxy group was also substituted, furnishing 2,3,3-trimethylindolenine. This same product was obtained when the reaction was carried out at 0 oC, together with 3,3- dimethyloxindole418 (Scheme 96)., MeO OMe OMe MeLi rt O 2.5 minNN

H

rt3h

N

0 oC OMe3h+ O

N N H

Scheme 96 Isatins fail to yield Knoevenagel condensation products with malonic acid419. However, malonic acid can be condensed with isatin in a mixture of ethanol and pyridine, in which the initial condensation product suffers decarboxylation, furnishing an acetic acid derivative. This can be converted to the acid chloride and submitted to a Friedel-Crafts acylation reaction, yielding acetophenone derivatives420. Alternatively the oxoindolinylidene acetic acid derivative can be treated with an arene in the presence of AlCl3 to yield spiro[indoline-3,3’- indan]-2,1-dione derivatives421. Microwave irradiation has been used for promoting the reaction of isatin with malononitrile to give 3-dicyanomethyleneoxindole and gives better results in comparison to the usual method422. The dielectric properties of this condensation product have been studied423. The dehydration of the dioxindoles can be achieved by treatment with a mixture of HCl and AcOH424,425. The 3-methyleneoxindoles can be selectively reduced at the carbon- carbon double bond using Na2S2O4 in aqueous ethanol426,427 (Scheme 97)., Ar

Ar O

Na O2S2O4

O EtOH, H2O O N (57-92%) N H H

Scheme 97 The condensation products from the reactions of isatins with cyanoacetates can be reduced at the carbon-carbon double bond with Zn dust in HCl or by hydrogenation with Pd/C. Subsequent decarboxylation can be achieved by refluxing in 2-ethoxyethanol. Further reduction of the nitrile yields an ethylamine oxindole428 (Scheme 98).

NC CN

CO2R 1) Zn/HCl or H2/Pd-C

O

O 2) 2-Ethoxy N ethanol, ∆

N

R' R' NH2 H2/Pt (46-87%) O

N

R' Scheme 98 The total synthesis of the marine natural products surugatoxin429-432 and neosurugatoxin435,436 began with a Knovenagel condensation employing 6-bromoisatin (Scheme 99)., O MeSOON

O O

Br N

O

H O

O

Br N

H

HOHNHO OH N NH HO O HONOOOHO OH OH

O

Br N

H

Surugatoxin Scheme 99 An important issue with respect to the Knovenagel condensation is that a mixture of isomeric disubstituted 3-methyleneoxindoles can be obtained. 1H 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 trans-s-trans437 (Scheme 100).,

NC

CO2Et

O N R

O Z NC CO2Et +

O N

ROO

O

O CN

CN

+

O

O N

N R R

E (trans-s-cis) E (trans-s-trans) Scheme 100 D.R. Long and co-workers have studied monosubstituted 3-methyleneoxindoles and for most of them only the E isomer could be detected. 2-Oxoindolin-3-ylideneacetonitrile exists as a separable E,Z-pair, but the Z-isomer slowly isomerises when dissolved in dimethylsulfoxide438. The Darzens reaction of isatin with ethyl chloroacetate yields glycidic esters. Alkaline hydrolysis of the glycidic esters yields indole-2,3-dicarboxylic and indole-3-carboxylic acids in a 6:1 proportion. The isolation of two isomeric glycidic esters, and the fact that both produce the indolecarboxylic acids in the same proportion led to a mechanistic proposal for the formation of the later through a common intermediate439 (Scheme 101)., HHOCOO2Et CO2EtO ClCH2CO2EtO + N NaOEtOONN

R

R R 1) NaOH 2) HCl H CO - -2 NHR CO - H CO22 OH CO -2 OH - - N CO2 CO2ONRRCO2 H2O H2O CO2H CO2H CO2HNNRRScheme 101 Masked carbanions, such as silanes, also react with isatins at position 3 and this methodology has been applied to the synthesis of 1,3-oxathiolanes440,441 (Scheme 102).

O Cl SO S

Me Si

O 3 O N CsF, MeCN N R R

(66-86%) Scheme 102, The reactions of some isatin derivatives with organometallic reagents follow reaction patterns that differ from those of isatin. Addition of phenylmagnesium bromide to isatin-3- acylhydrazones gave a product resulting from nucleophilic attack at C-2442 (Scheme 103).

OROR N N NH N H O PhMgBr N (30-50%) N H

Scheme 103 On the other hand, addition of Grignard or organolithium reagents to 1- (arylthio)isatins led to cleavage of the N-S bond and formation of the respective sulfides443 (Scheme 104).

O O O O PhSCl, Et3N N N (82%) S H O

R'MgBr (55-75%) O +

N SR' H

Scheme 104 2,2-Dimethoxy-1-methylpyrrolidine adds to isatin in a unique manner furnishing an α- diketone through an intermediate α-ketoester444 and the proposed mechanism is shown in, Scheme 105. When the reaction was performed with the lactam acetal, 2,2- dimethoxytetrahydroazepine, the product obtained was 1-methylisatin444,445.

O MeO O OMe

MeO N

O N O

+ H NH MeO2 N

N O O

(55%) O

NH

Scheme 105 Different reaction pathways can be observed in the reaction of isatins with carbanions under photochemical or thermal conditions. Thus, the reaction of isatin and isoxazolone under thermal conditions led to addition at position C-3, whilst under UV irradiation cleavage of the isatinic N1-C2 bond occured yielding isatic acid, which subsequently condensed with isoxazolone446 (Scheme 106)., O N

O

R Ph

O N H O R

O + N NO O

H O

O COR2HPh Ph +

N

NNONO

H

Scheme 106 The condensation of 1-methylisatin with 1-methylindole in an acidic medium led to a 3,3-bisindolyloxindole, which after reduction to an indoline and oxidative rearrangement with DDQ, furnished a tris-indolobenzene447 (Scheme 107).

N O N

2 1. LAH, THFO AcOH 2. DDQNO

N N N

DDQ or N 1. BuLi 2. CuCl2

N

N N (40-53%) Scheme 107, The reactions of isatin and thiophene or 2,2’-bithiophene proceed similarly to those of indoles. However, in these cases mixtures of oligomeric products were obtained448. This reaction has been applied to the synthesis of electrically conducting polymers449. 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).

O HO

SSSNOSROONH2SO4NROR N

R

65% N R

S O O N R

20% Scheme 108 Isatin reacts with benzene and phenol under typical Friedel-Crafts conditions452,453. The corresponding 3,3-diaryloxindoles are obtained in high yields454 and their laxative properties have been studied455. Very high yields, up to 99%, are obtained when this reaction is performed using a combination of trifluromethanesulfonic and trifluoroacetic acids; this methodology enabled the preparation of libraries of 3,3-diaryloxindoles by using mixtures of aromatic compounds456., Dimethoxyisatins can be converted into 3,3-diaryloxindole quinones in two steps, by Friedel-Crafts reaction and subsequent oxidation with silver carbonate457 (Scheme 109). OMe O OHΦΦOΦHAlClON3NOMe H OHHOΦΦAg2CO3 Celite O

N

O H Scheme 109 When isatins are used in the Friedel-Crafts alkylation of m-cresol in an acidic medium at high temperature, the adduct formed suffers dehydration, furnishing a spiro dibenzopyran derivative458 (Scheme 110). O OH m-CresolOHN2SO4 100-150 oC O OHHN

H O

H2SO4 200-240 oC O

N H

, Scheme 110 3,3-Diaryloxindoles have been used as precursors for the synthesis of thermoplastic carbonates459. Diazoalkanes, such as diazomethane460 and diazoarylalkanes461,462 add to isatin at the C-3 position, leading to a carbinol that suffers a ring expansion to give the corresponding quinolone463 (Scheme 111).

O N2 OH OH

CH2NO 2

NONON H HH

Scheme 111 Oxindolylacrylates react with diazomethane in a regioselective manner, depending on the substituent attached to the carbon atom α to the ester carbonyl group. In non-substituted acrylates, the 1,3-dipolar cycloaddition occurs furnishing a pyrazoline which, upon heating, losses N2 to give a spiro cyclopropane derivative464,465. If α-cyanoacrylates are used, the cyano group reverses the polarization of the C-C double bond, and the diazomethane addition involves initial C-C bond formation β to the ester. The adduct loses N2, furnishing a quinolone465 (Scheme 112).,

N

N CO2EtNNCO2EtCO2Et

O O O N N N H H H

68%

N

N NCNNCN CO2Et CO2Et CO2Et CN

O ONNO N H H H 92%

Scheme 112 The same reaction when carried out in the presence of triethylamine gives a furoquinoline derivative466. The O-methylether of isatin reacts with diazomethane to furnish a quinoline derivative as the major product, together with a spirooxirane derivative467 (Scheme 113). O -O N2 OR OMe OMeNNNOMe R = H 3% R = Me 55%

O

OMe

N

15% Scheme 113, 2-Ethoxy-3-indolone suffers a thermal [2+2] cycloaddition with 1,1-dimethoxyethene, leading to an oxetane that is hydrolyzed to an indoleninylacetate in 40% yield468 (Scheme 114).

MeO O MeO OMe OMe CO2Me O HOH2O OEt N OEt OEt N N

Scheme 114 2-Oxoindolin-3-ylidene derivatives, which are prepared by Knoevenagel condensations of reactive methylene compounds with isatin, can readily undergo a variety of cyclization reactions with ethyl vinyl ether or with enamines giving rise to a variety of heterocyclic systems469,470. These compounds also readily undergo Diels-Alder reactions with cyclopentadiene giving a mixture of two diastereoisomers471 and with unsymmetrical butadienes472,473 or with isoprene474. 2-Oxoindolin-3-ylidene derivatives undergo cycloaddition with phenylnitrile oxide to yield the corresponding oxazoles464. 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 conditions22. This methodology was subsequently applied to a concise manner for the preparation of derivatives of camptothecin, a topoisomerase I inhibitor23 (Scheme 115).,

O

O O

O

NONOAcOHHNOHRO+ OH HCl, r.t. NOOO

H R

CO2H

O

R N AcOH HCl, 105 oC N

O

OH O Scheme 115 The Pftzinger reaction has been carried out with aliphatic ketones475, including acetone476, acetophenones and homologues477,478, chalcones479, and α-acyloxyacetophenones, leading in the last case to 3-hydroxyquinoline-4-carboxylic acids480; heteroaromatic ketones, such as 2- acetylphenothiazine481, acid chlorides482 and anhydrides483, furnishing 2-hydroxy-4-quinoline carboxylic acids; hydrazides484; enaminones, furnishing 4-carboxamido-quinoline-3- carboxylates, and with imidines, leading to 2-aminoquinoline-4-carboxamides485 (Scheme 116);, O CO2R2 CONH2HNRCO2R2O21

N

H N R1

R

HN NH2 CONH2

R

N NH2 Scheme 116 acylaminoacids and isocyanates to yield 3-acylamino-2-oxo-1,2-dihydroquinoline-4- carboxamides486 (Scheme 117); O CONHR NHCOAr ArCON H CO2H

O

N RNCONOHHScheme 117 lactam acetals to furnish dihydropyrroloquinolines444 (Scheme 118); O OM e CO2Me N OM e

O N

NNO46% Scheme 118, and diketene to yield 2-quinolones487 (Scheme 119).

O

O CO2H O COMe

O

N aq. alkaliNORR(8-47%) Scheme 119 The use of ammonium hydroxide as base furnishes 4-quinolinecarboxamides488, which when subjected to Hoffmann degradation conditions produce 4-aminoquinolines489. 4- Cyanoquinolines are produced when the corresponding acids are treated with 4- toluenesulfonamide and POCl 4903 . The Pfitzinger reaction has been used in the synthesis of methoxatine, a coenzyme of the bacterial enzyme alcohol dehydrogenase491,492 (Scheme 120) and of DuP 785, an anticancer agent493 (Scheme 121).

O O

O 1) KOH 30%+ O N CO H 2) AcOH2 3) MeOH, H2SO4, ∆. O H (50%) CO Me HO2C2 HN CO2HONCO2MeOONCO2H

O

Methoxatine Scheme 120,

O O F F O + N H CO2Na F

1) NaOH 30%

N F

DuP 785 Scheme 121 In a similar manner, the use of phenols494 or dihydronaphthalenones495 yield acridines, which are also obtained from the treatment of N-phenylisatin with aqueous sodium hydroxide496 (Scheme 122).,

OH O OH CO2H O 1) NaOH 2,5N+ N 2) AcOH (92%) HO OH N OH F H F O CO O 2 H N 1) NaOH 2N

2) AcOH (96%)

N

Scheme 122 1-Acylisatin, bearing at least one hydrogen atom at the α position of the acyl group, also furnishes an isatinate, but it reacts with a second equivalent of hydroxide, leading to 3,4- disubstituted -2-quinolones. This heterocyclic system is also formed by treatment of 1- acylisatins with alkoxide solutions497 (Scheme 123)., O COOK O KOH aq.R = H O

N

R NH2 KOH aq. R = Ac CO K COOK 2

O

N O NHCOCH3

H

Scheme 123 The use of N-acylisatins for the construction of quinolones has been applied to the synthesis of pyridoquinolines498 and pyrroloquinolines499 (Scheme 124). O CO2H ClNO1) NaOH, H2O N 2) AcOH (80%) NOOHNCl

CN

N N

H

Scheme 124 In a similar procedure, 1-iminobenzylideneisatins furnish cinnoline derivatives500 (Scheme 125):,

O O

N CO2H N Base

N N

Scheme 125 3-Dicyanomethyleneoxindoles undergo base catalysed alcoholysis to yield the respective 2-aminoquinolines501. 3-Methyleneoxindoles also suffer ring expansion to quinolones. Mechanistic studies, based on 1H NMR data, show that isomeric methyleneoxindoles lead to the same products through a nucleophilic ring opening step and a subsequent Z-E interconversion step of the benzylidene intermediates. Due to steric repulsions the Z isomer is more stable, but as the cyclization step from the E isomer is irreversible the equilibrium is shifted towards this isomer. The presence of electron-withdrawing groups bonded to the aromatic nucleus shifts the equilibrium in the direction of the Z isomer due to a decrease in the nucleophilicity of the carbamoyl nitrogen atom, and thus favors the cyclization product that results from the Z isomer502 (Scheme 126)., MeO2C NC CN CO2MeRROONNCO2Me CO2Me E isomer Z isomer CO2Me CO2Me CN CO2Me CO2Me CNNH NH CO2Me CO2Me E benzylidene Z benzylidene CO2Me CO2Me R CN R CO2MeNONNH CO2Me CO2Me R = H 81% R = H 0% R = NO2 <2% R = NO2 71% Scheme 126 When the alkaline hydrolysis is performed with N-phenacyl503 or N- acetonylisatins504,505, 2-substituted indoles are obtained after spontaneous decarboxylation of the resultant 2-acylindole-3-carboxylic acid . The mechanism of this reaction probably involves a ring opening reaction, followed by cyclization through a Knovenagel-like condensation506, but a very complex mechanism has also been proposed507. This methodology, has many advantages over others previously described for the obtention of these indolic derivatives, due to the readily available raw materials (Scheme 127).

O O ONa CO2Na O N NaOH, OH2O, ∆ COR O RN N R H O H

R = Phenyl or Alkyl

COR

(75-85%) N

H

Scheme 127 4.3. 4 - Halogen nucleophiles The reaction of isatin with phosphorous pentachloride led to 3,3-dichlorooxindole when the reaction was carried out in benzene at room temperature. This intermediate has been used in the synthesis of oxindoles substituted at position 3 by reaction with a diverse range of nucleophiles such as KSCN, amines and thiols508. When the reaction was performed with boiling benzene, a red crystalline product was obtained. This compound was originally characterized as 2-chloro-3H-indol-3-one based not on spectral data but on its reactivity. For example, 4-bromoisatin, after reaction with PCl5 in toluene under reflux for eight hours was treated with methanethiol to furnish the corresponding 2,2-thioketal, which was decomposed to 4-bromo-2-methylthio-indolin-3-one509 (Scheme 128)., Br O Br O 1. PCl5 SMe

O

2. MeSHNNSMeHHBr O ΦCH3 ∆ SMe

N

Scheme 128 The putative 2-chloro-3H-indol-3-one was also reacted with phenols510 and N,N- dimethylaniline511 to give dyestuffs (Scheme 129).

O O

O 1. PCl5/∆ N 2. R R

N H

R = OH, NMe2 Scheme 129 On the other hand, the reaction of this chloride with anilines always led to isatin-3- imines. In an attempt to rationalize these contradictory results, it was proposed that 2-chloro- 3H-indol-3-one was the substrate but that this compound, which reacts with nucleophiles at the C-2 position, readily hydrolyzed in solvents containing water, thus yielding isatin and products resulting from attack at C-3512. Sir John Cornforth revisited the chemistry of this compound recently, and elucidated the structure as being 2-(2,2-dichloro-2,3-dihydro-3- oxoindol-1-yl)-3H-indol-3-one based upon 1H, 13C n.m.r. and X-ray crystallographic analysis. The same authors used this compound to synthesize an indoloquinazoline structurally related to the alkaloid tryptanthrin513 (Scheme 130).,

O

O Cl Cl O PCl

N

5 MeOH N ΦH/∆ ON

H

OONlightNNN(MeO)3C OH O Scheme 130 1-Methylisatin reacts with diethylaminosulfur trifluoride (DAST) to furnish 1-methyl- 3,3-difluorooxindol in 95% yield514. This methodology has been subsequently modified and extended to the synthesis of numerous other 3,3-difluorooxindole derivatives130,515 (Scheme 131). OFF

DAST

OONNScheme 131 5 - Metal complexes Isatin, due to its cis α-dicarbonyl moiety, is a potentially good substrate for the synthesis of metal complexes, either alone or with other ligands. Their derivatives, mostly those substituted at C-3, such as isatin-3-hydrazones and isatin-3-imines bearing an extra heteroaromatic ring are also generally employed as ligands. In this manner, Schiff bases, formed from isatin and amino silica gel are useful sorbents for divalent cations and for Fe (III)516 (Scheme 132). n

O MLn X Y N MLn O N O H N H

Scheme 131 Due to its ability to bind ferric ions, isatin-3-thiosemicarbazone can be used to form magneto-polymer composites with poly (vinyl chloride)517. An extensive list of metal complexes can be found in the Supplementary Material 3. 6. Crystallographic and spectral analysis 6.1 - Crystallographic data The crystallographic data for isatin reveals that it is almost planar, with a bond length between the two carbonyls of 1.55 Å. This large value was attributed to lone pair electron repulsion between the two oxygen atoms518,519, though this interpretation was subsequently refuted by comparison of bond lengths of cis and trans 1,2-diketones where no systematic or substantial difference between the bond lengths was observed520. A similar bond length was observed for 1-acetylisatin521, 1-α-chloroacetylisatin522, diethyl (2,3-dihydro-2-oxo-3- indolylidene)propanedioate523, 1,1’-oxalylbisisatin524 and 1-methylisatin525, as well as in derivatives where C-3 is tetrahedral, such as 3,3-dichloro-1H-indol-2(3H)-one526 and 5’- bromospiro-[1,3-dioxolano-2,3-indolin]-2’-one527, as well as in 3-methyleneoxindoles528 (Table 1) and in products obtained by nucleophilic ring opening of 1-acetylisatin, where the 1,2-dicarbonyl system assumes a s-trans conformation529. The crystal structure of 2- methoxyisonitrosoacetanilide, an intermediate in the Sandmeyer procedure for the synthesis of 7-methoxyisatin has also been determined530., Table 1

X R2 O N R1

X R1 R2 C2-C3OHH1.55 O Ac H 1.538 O Me H 1.545 Cl, ClHH1.556 OCH2CH2O H Br 1.539 CHCH=C(CH3)2HH1.508 6.2 - Infrared spectroscopy The infrared spectrum of isatin shows two strong bands at 1740 and 1620 cm-1 corresponding to the carbonyl stretching vibrations. A broad band occurs at 3190 cm-1 due to the N-H stretching, and it is accompanied by many sub-bands, all of which are moved to a lower frequency on deuteration, which also affects several bands in the region of 1400-1100 cm-1, associated with N-H in-plane bending531,532. Although the νC=O values are not modified by N-alkylation, N-acetylation leads to a hypsochromic shift of the lactam absorption of about 50-70 cm-1, while the ketone band shifts to 1750 cm-1, as a consequence of the extension of conjugation of the nitrogen lone pair with the acetyl group100. On the other hand, 3- methyleneoxindoles show a bathochromic shift for the lactam band of around 20 to 30 cm-1, this shift being greater when there are groups at the C-3 position, such as OH, which can form a hydrogen bond with the lactam carbonyl. In this case, νC=O appears at 1660 cm-1 438. 3,3- Difluorooxindoles reveal a hypsochromic shift of about 20 cm-1 in comparison to the respective isatin514., 6.3 - 1H NMR spectroscopy The 1H NMR spectrum of isatin shows the signals of the aromatic nucleus signals at 6.86 (doublet), 7.00 (triplet), 7.47 (doublet) and 7.53 (triplet) ppm (DMSO-d6), corresponding to H-7, H-5, H-4 and H-6 respectively. While N-alkylation does not alter this pattern, N- acetylation leads to a downfield shift of all the signals, but most significantly of H-7 due to the anisotropic effect of the carbonyl group. In a similar fashion, 3-methyleneoxindoles bearing cyano groups reveal a downfield shift of H-4 by about 0.6-1.0 ppm, with no significant effect over the other signals533,534 (Table 2). Table 2533

X O N R

X R H-4 H-5 H-6 H-7 CH3CO SolventOH7.50d 7.07t 7.60t 6.92d - DMSO-d6 O Me 7.59d 7.12t 7.61t 6.91t - DMSO-d6 O Ac 7.27d 7.33t 7.70t 8.38d 2.73s DMSO-d6 C(CN)2 H 7.87d 7.12t 7.59t 6.94d - DMSO-d6 6.4 - 13C NMR spectroscopy The 13C NMR spectrum of isatin was the object of controversy in the literature. Different proposals for assignment of the signals have been published42,535,536,537. This question was resolved by the obtention of the HETCOR spectrum, which revealed that the assignment proposed by Galasso, based on quantum mechanical calculations using the, CNDO/S wave functions, was correct536. This result allowed the correction of the assignments of the spectra of 1-acetylisatin538,539,540 and of 1-methylisatin and 3- dicyanomethyleneoxindole512,502. Again, acetylation of N-1 implies an important change in the pattern of the spectra, with a deshielding effect over C-7538 (Table 3). Table 3

X O N R

XOOOC(CN)2RHAc Me H C-2 159.6 157.8 158.1 163.6 C-3 184.6 180.1 183.2 146.4 C-3a 118.0 119.1 117.2 137.8 C-4 124.8 126.1 125.0 122.9 C-5 123.0 125.2 123.7 118.5 C-6 138.6 138.6 138.4 125.7 C-7 112.4 118.1 109.9 111.6 C-7a 150.9 148.5 151.3 150.4 Reference 536 538 512 512 6.5 - Mass spectrometry The electron-impact mass spectra of isatin542, 1-alkylisatins543 and derivatives, such as hydrazones544, usually show an intense molecular ion peak. In the case of 3,3-dissubstituted oxindoles545, the base peak corresponds to the loss of the substituents at C-3. A peak corresponding to the loss of CO (ion a) can also be observed, whose intensity decreases with, the increase in size of the alkyl chain of 1-alkylisatins546. Ion a usually looses HCN, leading to a fulvene ion (ion b). An arene aziridine is also observed (ion c), which arises from a second loss of CO547-549. The ions b and c are also observed in the gas-phase pyrolysis of isatin550. In a general manner, the mass spectra of 3-substituted isatins show a sequential loss of neutral molecules551 (Scheme 133).

X X R

O . X orNNRRion a ion b N+ ion c Scheme 133 A different pattern is observed in the mass spectra of isatin-3-oximes, where a peak corresponding to the loss of CO is not found; this is attributed to a Beckmann rearrangement of the molecular ion leading to a heterocyclic ring opened ion552. In the case of the acetylated derivatives, the molecular ion is usually of low intensity. The fragmentation pattern includes loss of ketene (ion d) and of CO (ion e) (Scheme 134).,

X

X X

O

N OHNNHOion d ion e + O+ N m/z = 43 Scheme 134 66 - 14N NQR The 14N nuclear quadrupole resonance of isatins and derivatives have been thoroughly studied as this method can furnish important information with respect to the electronic distribution around the nitrogen atom. The results obtained confirmed the existence of H bonds between isatin molecules in the solid state553, and showed a linear relationship between the depletion of charge of the C-N bonds and the electron withdrawing character of the substituents attached to the aromatic nucleus, as represented by the inductive Taft parameter554. The results also revealed that the lone pair of electrons of the nitrogen atom is involved in conjugation with the aromatic ring555. 6.7 - Further spectroscopic data The eletronic absoption spectra of isatin556,557,558, isatin-3-arylhydrazones559, isatin and 1-methylisatin anion radicals560 were studied and correlated with theoretical calculations with, good results. The electron spin resonance spectra of the isatin anion radical was also recorded and revealed that the monoanion radical exists in equilibrium with the dianion radical in the solvents employed560. DSC thermograms of some alkylisatins were also recorded561. 7. Technological applications 7.1 - Organic analytical chemistry Isatin is known to be a colour reagent for the aminoacid proline, forming a blue derivative562. This property has been exploited for the determination of the level of this aminoacid in pollens563,564,565,566 and other vegetal materials567 using paper chromatography, or for the detection of polymer bound compounds possessing proline residues568. It has also been used in a colourimetric screening test for human serum hyperprolinemia569, in a colourimetric assay of HIV-1 proteinase570 and for the estimation of the age of bones in crime investigations571. As isatin produces a fluorogenic derivative when reacted with tryptophan, it has been used for the detection of this aminoacid by thin layer chromatography572,573. It is also useful for the detection of 3,4-dehydroproline, which is oxidized by isatin and further reacted with p- dimethylaminobenzaldehyde to give a coloured derivative574. In a similar manner, isatin-3-hydrazone has been studied for the colourimetric determination of steroids575,576, including deoxycorticosterone577. A further application of isatin in steroid analysis is its use as a coloured marker in the Sephadex LH-20 chromatographic separation of steroidal blood components580,581. 1-Chloromethylisatin has been used as a derivatizing agent for alcohols582, small chain583 and fatty carboxylic acids584, amines, including indole585, and compounds containing acidic C-H bonds586 for their analysis by RP-HPLC or TLC., Isatin has been used in the determination of the enzymatic activity of ketopantoyl- lactone reductase587-590 and other fungal carbonyl reductases591-594, as it is a substrate of these enzymes that is reduced to a dioxindole in a reaction that can be monitored by colourimetry. Ketopantoyl-lactone reductase, also named as isatin hydrolase, can be used to remove unwanted isatin from the broth of the microbial production of indigo595,596. Isatin serves as a substrate for the biosynthesis of violacein, a trypanocide agent, by Chromobacterium violaceum597. 7.2 - Pigments and dyes Isatins, associated with other amino heterocycles, can be used for hair dyes598-616, while azobisisatins have been thoroughly studied as dyes for plastic materials617. 3- Methyleneoxindoles derived from isatins bearing a benzimidazole ring618, as well as thioindigoid thiazolidines619, have also been used for dyeing synthetic and natural fibers (Figure 2).

R O N R' N NC R' NNXNH O N O N R R R

Figure 2 7.3 - Miscellaneous applications, Isatins and derivatives have been used in the development of colour photographic recording materials620-622, of blood coagulation promoters623-626, of liquid crystal components for display devices627-629 and in the inhibition of corrosion of aluminum630 and Fe-Ni alloys631 and of iron632. Isatin can be used as a photosensitizer, together with a photoinitiator, for methacrylate633,634 and epoxysilicone635 polymerization. It is also used for the synthesis of branched polycarbonate resins, improving the moldability of this polymer636. The reaction of isatin with thiophene in an acidic medium, containing ferrous ion, gives rise to an intense violet color, due to the formation of indophenine dyes. Due to this phenomenon, it was proposed that isatin could be used as a revealing agent for the presence of thiophene in water-soluble organic solvents where it is used as a denaturating agent637. 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