Isatin drivatives : Synthesis, Reactivity and anti corrosion properties

DOCTORAL THESIS

Khalil .A. Al Maamari

Speciality : Organic chemistry / Pharmaceutical chemistry

ISATIN DERIVATIVES : SYNTHESIS, REACTIVITY AND ANTI

CORROSION PROPERTIES

Defended in : 25 July 2013, before the jury :

President :

El Mokhtar ESSASSI Professor at the Faculty of Science, University of

Mohammed- V-Agdal, Rabat

Examiners :

Youssef KANDRI RODI Professor at the Faculty of Science and Technology Fes, University of Sidi Mohamed Ben Abdllah

Noureddine Hamou AHABCHANE Professor at the Faculty of Science, University of Mohammed- V-Agdal, Rabat

Abddelfettah ZERZOUF Professor at the High school teachers, Takadoum, Rabat

Invited :

Youssef RAMLI Doctor in laboratory of control of drugs, Rabat

UNIVERSITY OF MOHAMMED- V-AGDAL

Faculty of Science

Rabat

Faculté des Sciences, 4 Avenue Ibn Battouta B.P. 1014 RP, Rabat – Maroc Tel +212 (0) 37 77 18 34/35/38, Fax : +212 (0) 37 77 42 61, http://www.fsr.ac.ma

To :

my dear parents ,

my wife,

my children ( Marwan , Mostafa , Mortada , Maram )

my brothers,

my sisters,

the pure spirit of my brother ( Nabeel ),

my whole family,

My friends,

Every dear to my heart,

For their presence at all times,

For the support they have given me,

With all my affection and gratitude .

ACKNOWLEDGEMENTS

This work was carried out at the Laboratory of Organic Heterocyclic Chemistry, Faculty of Science, University Mohammed V-Agdal, under the supervision of Professor . Dr. El Mokhtar ESSASSI.

The grace of the almighty and sincere hard work has made the presentation of this dissertation possible.

It is an exciting and memorable moment of my life to express my deep sense of gratitude and humble thanks to my beloved guide, Mr. Prof. Dr. El Mokhtar ESSASSI, Professor, Department of Chemistry, College of science, Rabat, Morocco, for his invaluable guidance and constant encouragement that framed foundation of this project. I am proud to say that it has been a most fruitful and enjoyable experience to work under his untiring guidance. His discipline, principle, simplicity and provision of fearless work environment will be cherished in my life.

I take this opportunity to express my deep sense of gratitude to my esteemed Mr. Prof .Dr .Abdelfettah ZERZOUF, Professor organic chemistry, normale superieur school, Rabat ,takdoum. Under whose advice this work has materialized. I am highly indebted to him for his valuable guidance, suggestions and keen interest throughout the course of this research work and has spared no effort to serve on the jury of this thesis .

I would also like to express my sincere thanks to Mr. Noureddine AHABCHANE Professor at the Faculty of Sciences of Rabat, for the honor he has done me by agreeing to serve on the jury and for his encouragement.

I wish to extend my thanks to Mr. Youssef KANDRI RODI Professor at the Faculty of Science and Technology of Fes , for brought considerable interest in this work and has spared no effort to serve on the jury of this thesis .

I want to thank Mr. Youssef RAMLI, National laboratory of drug control, agreeing to be part of the jury, and to him I extend my warmest thanks

I offer my deep thanks to Dr. Rachid BOUHFID , insitiute of nanomaterials and technology, MAScIR, Rabat ,Morocco ,for his great help and encouragement .

I would like to extend my thanks and deep appreciation to the center of doctoral studies at the Faculty of Science, University of Mohammed V, and I thank Prof. Dr. Mohammad LFERDE, my sincere thanks to Miss Karima ECHTIOUI a doctoral center secretary for cooperation and overcome all the difficulties during the study period.

Many thanks also go to many of my lab mates and friends. We have shared many happiness and some times, sadness during the past three years of study. At difficult times, they offered great help and encouragement. At good times, they shared the happiness with me. ( Hamid ENNAJIH ,Asmaa ZANZOUL ,Nada SEBBAR , NABIL , ALI , IBRAHIM , SARAH , CALEB, BALLO, HICHAM , NAJIB , ABDULRAHMAN, Mohamed FAL , ABDULSALAM ,IMAN,ELHAFI Mohamed ,Ebrahim LOKMAN ) .

My special thanks go to my colleague MONA Shaui for the permanent cooperation with me.

I would also like to give thanks to all the Chemistry Department members at Faculty of science as well as supporting staff, and visitors.

I am particularly grateful to Mr MANSOURI Mohammed preparer to the Chemistry Department for legal aid. I express my sincere thanks .

I wish to express my sincere thanks to my Foundation Academy in Yemen, Hodeidah University for its ongoing quest for the rehabilitation of faculty members .

Finally, I am deeply indebted to all members of family who have encouraged me for as long as I can remember .

I extend my thanks and appreciation to the Hodeidah University to provide an opportunity to complete a PhD.

Last but not least: my brother Prof . Dr .AHMED, thank you very much for you support and love and for standing at my side all the time. Without you, I would not have made it .

ABBREVIATIONS AND SYMBOLS

DMSO-d6 Dimethylsulfoxyde deuterated

DMF Dimethylformamide DMA Dimethylamine AcOH Acetic acid

DCM Dichloromethane dd Doublet of doublets

DEPT Destortion enhancement by polarisation transfer

Et3N Triethylamine

H Hour

TBAB Tetrabutylamoniumbromide R . T Room temperature

TLC Thin layer chromatography NMR Nuclear magnetic resonance

FVP Flash vaccum pyrrolysis J Coupling constant ppm Part per million

δ Chemical shift IE Electron impact S ingletS m multiplet t triplet d Doublet q Quadruplet F° Melting point

CONTENTS

General introduction ...1

References ...4

Part I

Introduction: ...7

A. bibliographic study of the synthesis and reactivity of isatin: ...7

I. Synthesis of Isatin : ...7

I.1. Sandmeyers method: ...7

I.2.Use of nitroacetanilides ...9

I.3.Method stolle ...9

I.4. Method Gassman ...11

I.5. Metalation of aniline derivatives...12

I.6. Another methods ...13

II. Study of the reactivity of isatin ...17

II.1. Alkylation and arylation ...18

II.2.Reactivity of the aromatic nucleus ...18

III. Application of Isatins in Organic Synthesis ...19

III.1.Reduction ...19

III.1.1.Synthesis of indoles ...19

III.1.2.Synthesis of oxindoles and dioxindoles ...21

III.2.Oxidation ...24

III.3. Nucleophilic attack at positions C-2 or C-3 ...26

III.3.1.Amine derivatives ...26

III.3.1.1.Ammonia, hydroxylamine ...26

III.3.1.2.Alkylamines ...27

III.3.1.3.Anilines and heterocyclic amines ...29

III.3.3.Reactive carbon nucleophiles ...32

Conclusion ...33

References: ...34

Chapter II:Study of the reactivity of isatin ...39

I . Literature review: ...40

I.1. Alkylation of isatin: ...40

II. Reactivity of isatin :...44

II.1. Synthesis of N-alkylisatins : ...44

II.2. Action of hydroxylamine on isatins ...50

II.3. Action of O- phenylenediamine on isatins ...53

II.4. Action of hydrazine on isatins ...57

Conclusion ...65

Experimental part ...66

General procedure : ...72

References...75

Chapter III:systhesis of novel poly heterocyclic systems via 1,3 – dipolar cycloaddition ...78

Introduction...79

I .Azomethine ylides ...80

I.1. geometric Shapes of ylides ...80

II.Generated Azomethine Ylides ...81

II.1 Ylides from Aldehydes ...82

II.1.2 With Secondary α-Amino Esters ...82

II.1.3 With Secondary α-Amino Acid ...84

II.4. Ylides from Imines ...87

II.4.1. By Prototropy ...87

II.4.2. By Metalation ...88

II.4.3. By Alkylation ...89

II.5.Ylides from Aziridines ...90

II. Condensation of isatin derivatives with L-proline ... 103

II.1.Action of L-proline on N-allylisatin ... 105

II.2. Action of L-proline on N-benzylisatin ... 112

Conclusion: ... 119

Experimental part ... 119

References... 126

Part II

Study of the corrosion inhibition of carbon steel by using N-alkyl isatin

1- Corrosion inhibitors : ... 131

2- Adsorption inhibitors ... 132

Methods for estimation the effectiveness of inhibitors : ... 133

1. Polarization curves ... 133

2. Gravimetric measurments ... 134

Organic inhibitors in aqueous media ... 134

1. Inhibition corrosion of Zinc ... 134

2. Inhibition corrosion of Copper ... 135

References... 136

Gravimetric and Electrochemical Evaluation of 1-allyl-1H-indole-2,3-dione of Carbon Steel Corrosion in Hydrochloric Acid ... 137

1. INTRODUCTION... 138

2. EXPERIMENTAL METHODS ... 139

2.1. Materials ... 139

2.2. Measurements ... 139

2.2.1. Weight loss measurements ... 139

2.2.2. Electrochemical measurements ... 139

3. RESULTS AND DISCUSSION ... 140

3.1. Polarization curves... 140

3.2. Electrochemical impedance spectroscopy ... 141

3.3.1. Effect of concentration inhibitor ... 145

3.3.2. Effect of temperature ... 146

3.3.3. Adsorption and thermodynamic considerations... 149

4. CONCLUSION... 153

References... 154

Anti-Corrosion Properties of Indole Derivative for Carbon Steel in HCl Solution ... 157

INTRODUCTION ... 158

EXPERIMENTAL ... 159

Materials ... 159

Solutions ... 159

Weight loss measurements ... 159

Polarization measurements ... 160

Electrochemical impedance spectroscopy ... 160

Potentiodynamic polarization ... 160

RESULTS AND DISCUSSION ... 161

Electrchemical Impedance Spectroscopy (EIS) ... 161

Potentiodynamic polarization curves ... 163

Weight loss studies ... 165

Adsorption isotherm studies ... 165

CONCLUSIONS ... 167

REFERENCES ... 168

RESUME DETAILLE

Le présent travail avait pour but, la synthèse de nouveaux systèmes hétérocycliques dérivés de l’indole, en utilisant comme matières premières l’isatine. Les propriétés biologiques et pharmacologiques ont été évaluées.

Dans la première partie, il nous a été possible de synthétiser de nouveaux systèmes hétérocycliques dérivés de l’isatine en évaluant leur inhibition de corrosion.

Le premier chapitre de cette partie, est un aperçu bibliographique sur la synthèse, la réactivité ainsi que sur l’aspect biologique de l’isatine. Les modifications structurales de la structure de base de l’isatine, ont permis l’apparition de nouveaux dérivés présentant un large spectre d’activité biologique.

Ainsi, dans le deuxième chapitre nous avons mis au point la synthèse de nouveaux dérivés de l’isatine via des réactions d’alkylation dans les conditions de la catalyse par transfert de phase liquide-solide avec différents agents alkylants à longues chaines. Dans tous les cas il nous a été possible d’isoler un seul type de composés N-alkylés avec de bons rendements.

Dans le troisième chapitre, il nous a été possible grâce à des réactions de cycloaddition dipolaire-1,3 sur les groupements dipolarophiles de l’isatine (carbonyle en position 3 pour préparer de nouveaux dispiro- hétérocycles contenant l’oxindole, la pyrrolidine et la pipérazine des ylures azométhine et la chaîne allyle et propargyle en position 1).

La condensation de L-proline avec des dérivés de 1-alkyl-5-haloisatine en donnant un intermédiaire d’iminium de carboxylate avec un intermédiaire cyclisé à oxazolodin-5-one. Cette décarboxylation thermale aboutie à l’azométhine.

Ce dipôle est présenté sous forme de deux mésomères A et B avec une dimérisation auto-condensation en donnant deux formes dispiro-oxindole.

Pour évaluer et caractériser l’efficacité inhibitrice de l’isatine, on a étudié dans la deuxième partie l’action inhibitrices de certains dérivés synthétisés dans la partie précédente.

En effet la gravimétrie et les études électrochimiques ont montré que tous les dérivés de N-allylisatine(Ind1) et N-acétylisatine(Ind2) sont des inhibiteurs efficaces de la corrosion de l’acier dans un milieu HCl 1M.

Les composés organiques contenant l’azote, le soufre et l’oxygène sont généralement utilisés comme inhibiteur de corrosion des plusieurs métaux dans le milieu acide.

La surface d'adsorption de l'inhibiteur utilisé conduit à une réduction de la capacité de double couche, ainsi que l’augmentation de la résistance de transfert de charge.

L'efficacité de l'inhibition obtenue à partir des mesures de perte de poids est comparable à celle obtenu à partir de la polarisation et des mesures d'impédance électrochimique.

La vitesse de corrosion de l'acier dans une solution de HCl en présence d'indoles diminue avec l'augmentation de la valeur de surface de couverture θ.

Les valeurs négatives de l'énergie libre d'adsorption, suggèrent qu’il y a une adsorption spontanée de “Ind2“ sur l'acier. Les études de polarisation révèlent que “Ind2“ agit comme un inhibiteur de type mixte.

Ces inhibiteurs de corrosion constituent un moyen de lutte contre des métaux et des alliages. L’originalité de cette méthode provient du fait que le traitement anticorrosion ne se fait pas sur le métal lui-même, mais par l’intermédiaire du milieu corrosif. Les molécules inhibitrices testés peuvent agir suivant différent mécanismes, leur confèrent ainsi des performances d’inhibition en fonction du milieu d’étude.

General introduction

1

General introduction

2

General introduction

The importance of the indole derivatives in different field and, in particular, chemistry, biology and pharmacology, has prompted researchers to develop many synthesis methods for their preparation and to find new fields of application.

The indole is among a wide variety of these heterocyclic systems studied to develop new active molecules. It should be noted that the excesses of indole have interesting pharmacological activities 1.

Isatin (indoline-2,3-dione), possessing an indole nucleus with two chemically distinct cyclic carbonyl groups, keto and lactam, has provoked tremendous interest due to its numerous biological and pharmacological activities. The growing importance of substituted isatins in the field of medicinal chemistry as potential chemotherapeutic agents and their implication for pro-drug design have been previously reported for example 2-10 figure 1 .

The indazoline A is an indole derivative used to treat alzheimer diseases (Inhibitors of acetylcholinesterase) .

The eletriptan B indole derivative containing anti migraine drug . A process route for the synthesis of eletriptan published by Pfizer starts from a preformed bromo-indole .

Fluvastatin C is a member of the drug class of statins, used to treat hypercholesterolemia and to prevent cardiovascular disease . It has also been shown to exhibit antiviral activity against Hepatitis C .

The ondansetron D is a indole derivative used mainly as an antiemetic . It is indicated for the prevention of acute nausea and vomiting associated with cancer chemotherapy .

N H O O O CH₃ CH3 O N CH₃ S O O N N CH₃ H A B

General introduction 3 N H₃C H₃C F COOH HO OH N O N N CH₃ CH₃ C _D Figure 1

Given the significant pharmacological activities associated with these heterocycles, and in order to contribute to the development of the chemistry of isatin, we are interested in the synthesis of new heterocyclic systems polyfunctional derivatives of isatin, calling for alkylation reactions under the conditions of phase transfer catalysis, the cyclo-condensation reactions and I, 3-dipolar cycloaddition .

The results that we obtained in this study are exposed in two parts :

The first part will be devoted to the synthesis of new molecules derived from the isatin . The first chapter of this part reports a bibliographic overview on synthesis and reactivity of the isatin .

The second chapter will discuss the reactivity of isatin. The N-alkyl derivatives, obtained by phase transfer catalysis, will subsequently subjected to condensation reactions with hydroxylamine to give the corresponding oxime , the ortho phenylenediamine in order to obtain indoloquinoxalines or with semicarbazide to yield corresponding hydraines .

The third chapter is devoted to the synthesis of precursors of 1,3-dipole used subsequently in 1,3-dipolar cycloaddition reactions , involving the azomethine ylides as dipoles, dipolarophiles the alkyl derivatives of isatin .

The second part of this work presented the study of inhibitors corrosion of some isatin derivatives .

General introduction

4

References

1. T. Nogrady, F. Donald, Chimie Thérapeutique; 3em édition, 2005, 527.

2. P. Mariappan , R. Srinivasan , K . Kumarasamy , S. Ganesan , T. Velayutham, S. Thangavel , K. Kandasamy , Indian J. Med . Res. 2012 . 136 . 822–826.

3. M.R. Islam , M. Mohsin , Bangladesh J . Pharmacol . 2007 . 2 . 7–12.

4. L. Matesic , J.M. Locke , J.B. Bremner, S.G. Pyne , D. Skropeta , M. Ranson ,K.L. Vine , Bioorg. Med . Chem . 2008 . 16 . 3118–3124.

5. N. Gao , L. Kramer, M. Rahmani , P. Dent , S. Grant , Mol. Pharmacol . 2006 . 70 . 645–655. 6. F. Wang ,Y. Fang , T. Zhu , M. Zhang , A. Lin , Q . Gu , W. Zhu ,Tetrahedron . 2008 . 64 .

7986–7991.

7. M.E. Lane , B. Yu , A. Rice , K.E Lipson , C. Liang , L. Sun ,C. Tang , G. McMahon , R.G. Pestell , S. A. Wadler , Cancer Res . 2001 . 61 . 6170–6177.

8. S. Patyna , A.D. Laird , D.B. Mendel , A.M. O’Farrell ,C. Liang , H. Guan , T. Vojkovsky , S. Vasile , X. Wang , J. Chen , Mol. Cancer Ther . 2006 . 5 . 1774–1782.

9. H.H. Li , X .H . Zheng , J.Z. Tan , L.L. Chen , H. Liu , X . M . Luo , X . Shen , L.P. Lin , K.X. Chen , J . Ding , Acta . Pharmacol . Sin . 2007 . 28 . 140–152.

10. Z. Juranić , F. Anastasova , I. Juranić , T. Stanojković , S. Radulović , N. Vuletić , Exp . Clin. Cancer Res . 1999 . 18 . 317–324.

Part I

5

Chapter I focus point on synthesis and reactivity of isatin

6

Chapter I

Chapter I focus point on synthesis and reactivity of isatin

7

Introduction:

Isatin (1-H-indole-2,3-dione), Figure1 and derivatives possess a broad range of biological and pharmacological properties and are widely used as starting materials for the synthesis of a broad range of heterocyclic compounds and as substrates for drug synthesis.

N H O O Figure 1

Formerly, the study of isatin derivatives was connected with dye synthesis, but more recently these heterocycles have been shown to demonstrate antiprotozoal, antibacterial, antifungal, antiviral, anti-HIV, anticonvulsant, antitumoral, anti-inflammatory, and antihelminthic activities; influence neurodegenerative diseases; participate in metabolism; acetylcholinesterase inhibitors; and stimulate the growth of plants 1.Drugs containing the isatin skeleton are used to treat diseases such as epilepsy2, tuberculosis3, and bulimia4.Therefore the need to create novel isatin derivatives for emerging drug targets is an active area of medicinal chemistry.

A. bibliographic study of the synthesis and reactivity of isatin:

I. Synthesis of Isatin :

I.1.

Sandmeyers method:

The first method reported for the synthesis of isatin5,6 was developed by Sandmeyer, wherein the reaction of an aniline 1a-c with chloral hydrate and hydroxylamine hydrochloride in aqueous sodium sulfate forms an isonitrosoacetanilide 2a-c. Subsequent cyclization to the isatin 3a-c is accomplished after treating 2a-c with concentrated sulfuric acid . ( Scheme1) .

Chapter I focus point on synthesis and reactivity of isatin 8 NH₂ X Cl3CCH(OH)2 NH₂OH,HCl /∆ N H X NOH O H₂SO₄ 50°C- 80°C _N H X O O 1a:X=H 1b:X=Cl 1c:X=Br 2a:X=H 2b:X=Cl 2c:X=Br 3a:X=H 3b:X=Cl 3c:X=Br Scheme 1

Jnaneshwara7, found that the Sandmeyer method is limited. Despite its efficiency, because: a)-harsh reaction conditions, b)- fails if the isonitrosoacetanilides bear electron-donating groups, c)- the formation of a mixture of regioisomers,and d)- generally moderate yields. However, this latter shortcoming, can be improved under microwave conditions.

Kurkin et al 8. synthesized isatins 5a–c from optically active anilines 4a–c by Sandmeyer’s method. In addition they used ethanol as a solvent in order to increase the aniline solubility. Isatins 8a–c were purified by column chromatography and their enantiomeric purities that were achieved were 97–99% .Since Sandmeyer’s method has sufficiently harsh reaction conditions (concd H2SO4), they attempted to synthesize N-alkylated isatin by Stolle’s method

(oxalyl chloride/AlCl3 in CH2Cl2). However, they did not obtain the chiral isatin. This method

seems applicable for N-unsubstituted anilines, while Sandmeyer’s method makes it possible to prepare optically active isatins 5a–c in high yield with good enantioselectivity ( Scheme 2 ) .

NH C₂H₅O O H CH₃ 1- Cl_3CH(OH)2,Na2SO4 2- NH₂-OH.HCl and alcohol-water 3- H2SO4 N O O C₂H₅O H CH₃ O R R 4a R=H 4b R=Br 4c R=Me 5a R=H 5b R=Br 5c R=Me Scheme 2

Chapter I focus point on synthesis and reactivity of isatin

9

I.2.Use of nitroacetanilides

Kearney et al 9. obtained the nitroacetanilide 9 from 1-arylamino-1-methylsulfanyl-2-nitroethene 8 , by alkaline hydrolysis, readily cyclized isatin-3-oxime 12. The latter treated with sulfuric acid concentrated sulfuric acid or trifluoromethane, at room temperature, leads to the corresponding isatin ( Scheme 3 ) .

NH₂ R ₊ O2N MeS SMe NH R NO2 SMe _NaOH NH R NO₂ O NH R N O OH OH H₂SO4 N H N O OH HO R N H N O OH R _-H 2O N H O O R H₂SO4 6 7 8 9 10 11 12 13 Scheme 3

I.3.Method stolle

An important alternative to the Sandmeyer method is the method of Stolle. In this approach,N-substituted anilines 13 are reacted with oxalyl chloride to form an intermediate chlorooxalylanilide 14 which can be cyclized in the presence of Lewis acids such as anhydrous aluminum chlorid10, BF3·Et2O11 or TiCl412 has also been used to give the corresponding isatin 3a

(Scheme 4).This method has been used for the synthesis of 1-aryisatin13,14 and polycyclic isatins derived from phenoxazine, phenothiazine and dibenzoazepine15 as well as indoline16 .

Chapter I focus point on synthesis and reactivity of isatin 10 HN R (COCl)2 N Cl O O R N O O AlCl₃ 14 15 16 R Scheme 4

Raj et al17. described a new, one-pot procedure for the synthesis of isatins 16a-h starting from anilines 15a-h by using oxalyl chloride as the acylating agent and H-β zeoliteas a reusable catalyst in the presence 1,2-dichloroethane as solvent at 80 °C under heterogeneous conditions . The methodology thus demonstrates that H-β zeolite is superior catalyst as compared to homogeneous Lewis acid catalysts like SnCl4 and BF3.Et2O.The procedure requires simple

filtration of the catalyst and evaporation of the solvent to obtain good yields of isatins 48–79% ( Scheme 5 ) . R NH₂ H - zeolite 1,2-dichloroethane 80°C, 12-36h 15a R= H 15b R= Me 15c R= ipr 15d R= Cl 15e R= F 15f R= OMe 15g R= NO2 15h R= CO₂Me 16a R= H 16b R= Me 16c R= ipr 16d R= Cl 16e R= F 16f R= OMe 16g R= NO2 16h R= CO₂Me N O O R H 15a-h 16a-h Scheme 5

Klein et al18. reported,the treatment of benzyloximinoacetic acid 17 with oxalyl chloride to give (E)-2-((benzyloxy)imino)acetyl chloride 18 which reacting with aniline 1a and serves

Chapter I focus point on synthesis and reactivity of isatin

11

equally well to produce substituted anilines 19 in the presence of bases such as triethylamine or diisopropylethylamine in common organic solvents ( dichloromethane, tetrahydrofuran) then heated in methanesulfonic acid to produce isatin in good yield ( Scheme 6 ) .

Scheme 6

I.4. Method Gassman

Gassman 19,20 described two general methods for the synthesis of isatins involving conversion of substituted anilines 6 into 3-methylthiooxindoles 25 , which upon subsequent oxidation give the corresponding substituted isatins 13 ( Scheme 7) . The choice of methodology is dictated by the nature of the electronic effects of the substituents bonded to the aromatic ring.

Chapter I focus point on synthesis and reactivity of isatin

12

I.5. Metalation of aniline derivatives

However, the Sandmeyer, Stolle, and Gassman methodologies shown above, all suffer from a lack of regioselectivity, especially in the case of meta-substituted anilines , wherein a mixture of 4- and 6- substituted isatins are observed. More recently, a new method for the synthesis of isatins was developed by Hewawasam and Meanwell 21, which is insensitive to the electronic nature of substituents bound to the aromatic ring and is characterized by predictable regiochemical control.Since amino-protecting groups can direct metalation to the ortho-position of anilines, N-pivaloylanilines and N-(tert-butoxycarbonyl)anilines 27 were used to generate dianions 28 using an excess of a variety of butyllithium reagents (n-BuLi, s-BuLi, t-BuLi) in THF at -78ºC. The resulting dianions 28 were then treated with ethyl oxalate and the isatins 13 were obtained after deprotection and cyclisation of the intermediate α-ketoesters 29 using HCl.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 such as an amino protected group ( Scheme 8 ) .

Scheme 8

Smith22 at the University of Wales Swansea, used a metal-halogen exchange method for the synthesis of isatins and substituted isatins by lithiation of ortho-bromophenylureas, carbonylation and subsequent intramolecular cyclisation to give the desired products. The N-(2-bromophenyl)-N,N-dimethylurea 30 underwent lithiation on the nitrogen to form a monolithio

Chapter I focus point on synthesis and reactivity of isatin

13

intermediate using MeLi, followed by bromine-lithium exchange using t-BuLi to give the dilithio species 31. The intermediate 31 was then exposed to carbon monoxide to give 32 , which after cyclization forms the intermediate 33 followed by loss of LiNMe2 to give 34 and finally after

work up with dilute acid yielded the isatin product 35 in good yield ( Scheme 9 ) .

Scheme 9

I.6. Another methods

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-workers23,24, developed a synthetic methodology for isatins from indoles 36, using N-bromosuccinimide to promote their oxidation to yield 3,3-dibromooxindoles 37 that were subsequently hydrolyzed to the desired isatin 3a (Scheme 10) .

Chapter I focus point on synthesis and reactivity of isatin

14

By using this method, 1,4-Dimethylisatin 40 can be obtained from air oxidation of aryliminoacylhydrazone 38 in presence of BF3.Et2O to give intermediate 2-(2-phenylhydrazono)

indolin-3-one 39 which hydrolyzed to desired isatin in good yield 76% (Scheme 11) 25.

CH₃ N CHO N N H 1) BF3 .Et₂O or PPA 2) Air N O N N H CH₃ CH₃ N O O CH₃ CH₃ H₂O H₃C 38 39 40 Scheme 11

In a similar method, 4 and 6-substituted-2-oxindoles 43, obtained from ethyl O-nitroarylmalonate 42 were converted to 3,3-dibromo-oxindole 44 per share hydrobromide in the presence pyridinium perbromide. These intermediates were hydrolyzed to the corresponding26 isatin 45 ( Scheme 12 ) . R1 R₂ R₃ Cl NO2 (EtO2C)2CH2 NaH R1 R₂ R₃ NO2 CO2Et CO₂Et R₁ R2 R3 N O H Py,HBr,Br2 Sn,HCl R1 R₂ R₃ N O H Br Br R1 R₂ R₃ N O H O H₂O / MeOH 41 42 43 44 45 Scheme 12

Another route to isatins which also employs N-substituted formanilides was developed by Meth-Cohn and co-workers27, involves deprotonation of a Vilsmeier reagent or substituted chloroiminium ion, followed by dimerisation of the carbene formed upon treatment with base, and finally electrophilic cyclisation of the dimer by bromonium ion action. This route to isatins is said to be general for various ring substituents including electron-withdrawing groups such as the nitro group. Formation of isatin in a one pot synthesis takes place by reacting the N-substituted formanilides 46 with oxalyl chloride in THF to give the Vilsmeier reagent 47, followed by

Chapter I focus point on synthesis and reactivity of isatin

15

treatment with Hünig’s base to form a nucleophilic carbene 48. The unstable arylamino-dimers 49 have a limited shelf-life and react with electrophiles such as bromine to give intermediates such as 50, which upon cyclisation to 51, and hydrolysis yield the desire isatins 52 (Scheme 13) .

X N O H R COCl2 X N H Cl R Hünig's base NR₃ X N Cl R X N X N Cl R N Cl R R X Cl H X N N Cl R R X Cl Br2 Br cyclization N R Cl N R Br X X H₂O N O O R X 46 47 48 41 49 50 51 52 Scheme 13

A rather versatile and novel two step synthesis of isatins was presented by Mironov 28,29 in 2001 and allowed for the preparation of isatins containing electron withdrawing groups such as CF3ˉ, NO2ˉ, and Clˉ. The method is based on the reaction between aromatic isocyanides and

tertiary amines, where in the first step, 2-triethylammonio-3-arylaminoindolates 55a-d were obtained from the corresponding aromatic formamides 53a-d without isolation of the intermediate isocyanides 54a-d. Heating 55a-d in excess thionyl chloride followed by hydrolysis led to the target isatins 56a-d ( Scheme 14 ) .

Chapter I focus point on synthesis and reactivity of isatin 16 R₃ R₂ R₁ N C O Cl H POCl₃ NEt₃ R₃ R₂ R₁ N C KOH N HN NEt₃ R₃ R₂ R₁ R₁ R₂ R₃ SOCl₂ H₂O,H _N H R₃ R₂ R₁ O O 53a-d _54a-d 55a-d 56a-d a:R₁=R₃=H ,R2=NO2 b:R₁=R₃=CF3,R2=H c:R₁=CF₃ ,R₂=Cl ,R₃=H d:R₁=R₂=R₃=Cl Scheme 14

The formation of isatins has been reported during decomposition of some natural products. In this manner,the attempted epoxidation of rutacridone 57 in presence of 2-hydroperoxy-2-methylpropane led to N-methylisatin 58 ( Scheme 15)30.

N O HO O tBuOOH Mo(CO)6 _N O O 57 ₅₈ Scheme 15

Manley-King et al31 . developed the method to synthesis of C5 substituted isatin such as 5-(benzyloxy) indoline-2,3-dione 61 and C6 substituted isatin (E)-6-styrylindoline-2,3-dione 63 analogues , by treating of C3 substituted aniline such as (E)-3-(prop-1-en-1-yl)aniline 59 and C4 substituted aniline (4-(benzyloxy)aniline 62 with diethyl ketomalonate 2 in the presence of acetic acid and heating through air ,only single product was isolated from the reaction mixture in moderate yield ( Scheme 16 ,17 ) .

Chapter I focus point on synthesis and reactivity of isatin 17 O NH₂ O N H O O O O O O O H₃C O OH air, 120°C 4 59 60 61 Scheme 16 NH₂ NH O O O O O O O H₃C O OH air, 120°C 3 62 ₆₀ 63 Scheme 17

Söderberg et al32. developed a synthetic methodology for isatins 65a-c from 1-haloethynyl-2-nitrobenzene 64a-c. A clean product under milder reaction conditions were realized using (PdCl2(PPh3)2 in acetone at ambient temperature and 60°C. This case gave good

yield at different ratio,depending on the catalyst and solvent ( Scheme 18 ) .

X NO₂ N H O O (PdCl2(PPh3)2) Acetone 64a-c 65a-c 64a: X=Br 64b: X=Cl 64c: X=I 65a: X=Br 60°C 45% 65b: X=Cl rt 47% 65c: X=I rt 73% 60°C 83%

{

II. Study of the reactivity of isatin

Isatin will mainly react at three different sites, N-alkylation, namely aromatic substitution at C-5, and carbonyl reactions at C-3. If the system carry electron-withdrawing groups in the benzene ring or at the nitrogen attack at C-2 can also occur figure 2 .

Chapter I focus point on synthesis and reactivity of isatin 18

N

O

O

NU

R- X

H

Figure 2. Reactivity of isatin

II.1. Alkylation and arylation

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 sulphates 33,34. Various methods for the preparation of this salt have been reported, and include the reaction of isatin with sodium hydride, either in toluene under reflux 35 or in DMF 36. Other methods include the use of potassium carbonate in DMF 37,38 or in acetone 39. More recently the use of CaH2 in DMF has been reported 40 and this method was used for the synthesis of both

mono and bis-N-alkylisatins. the microwave promoted N-alkylation of isatins was done using various reaction conditions, however the best results were obtained using K2CO3 or Cs2CO3 and

a few drops of DMF or N-methyl-2-pyrrolidinone(NMP) 41.

On the other hand, O-alkylation at position 2 has been reported, along with the N-alkyl product, using γ-butyrolactone 42 or allyl bromide 43 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 acetate 44.

And afollow up to this topic, N-Arylisatin can be obtained from isatin in quantitative

yields by reaction with Ph3Bi(OAc)2 and Cu0 under an inert atmosphere 45 or from aryl bromides

and cupric oxide 46.

II.2.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-nitroisatin 47. Precise temperature control is needed 48, otherwise a mixture of nitrated products are formed 49.The

Chapter I focus point on synthesis and reactivity of isatin

19

bromination of isatin in alcohols gives 5,7-dibromo-3,3-dialkoxyoxindoles in an acid catalyzed ketalization of the halogenated isatin 50. Monobromination at position 5 can be achieved, at least on a microscale, with the use of N-bromoacetamide in acetic acid medium 51.

Recently, 4,6-dibromoisatin, a key intermediate in the synthesis of convolutamydine A, was prepared by bromination of a 5-aminoisatin derivative 52 in ethanol (Scheme 19) .

N O O O H H2N Br2 , EtOH N O O O H H2N Br Br N O H Br Br O tBuONO ,DMF (CO2H)2 , H2O 66 67 68 Scheme 19

III. 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 generalized as one of the following strategies:

- Partial or total reduction of the heterocyclic ring, leading to indoles and derivatives. - Oxydation reaction .

- Nucleophilic addition at position C-3, which may be further followed by a cyclization process.

- Nucleophilic substitution at position C-2, leading to the opening of the heterocyclic ring.

III.1.Reduction

III.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 derivatives 53.

Menicagli et al 54 . reported ,the isatins can be chemoselectively alkylated at positions N-1 or C-3. Subsequent reduction of these compounds using metal hydrides leads to N-1- or 3-alkylindoles 69 and 70 ( Scheme 20 ) .

Chapter I focus point on synthesis and reactivity of isatin 20 N O O H N N H R 1-RLi 2-LiAIH₄ 1-NaH 2-RX 3-BH₃,THF R 3a 69 70 Scheme 20

In 1994, Pinto et al 55. showed that N-acetylisatins 7156 were suitable substrates for the synthesis of alkylindoles 72 under mild reaction conditions ( Scheme 21) . In general, the N-alkylation of an indole produces a mixture of products due to side substitution reactions at C-3. This method uses BH3 as the reducing agent and is performed at room temperature ,to provided

pure products with good yields.

Indoles 74 have also been prepared from N-substituted-5-nitroisatin 73 using the ZrCl4/NaBH4 system in DME at room temperature, with a yield of 74% ( Scheme 22 ) .

But the direct reduction of 5-nitro-isatin produced the desired 5-nitroindole but with a yield of only 30% 57. N O O O R 2 R1 _BH 3 ,THF r.t N R2 R1 71 72 R1_=R2_{=Me ,R}1_{=H; R}2_=Et R1_{=H. R}2_{=n-Pr ; R}1_=Me.R2_=H R1_=H.R2_=C 6H4. R1=H. R2=CH2Cl R1_=H.R2_=(CH 2)10CH3 Scheme 21

Chapter I focus point on synthesis and reactivity of isatin 21 N O O O2N Cl ZnCl₄ / NaBH4 (1:4) DME N O₂N Cl 73 74 Scheme 22

On the other hand, Bastos et al 58. have described the synthesis of novel trifluoromethyl- indoles 76 from isatins 75a-e using (trifluoromethyl)trimethylsilane [ Me3SiCF3] as a

nucleophilic agent, producing 3-hydroxy-3-(trifluoromethyl)indolin-2-one 76a-e Subsequently, compounds 76 were reduced using [BH3.THF] complex yielding 3-(trifluoromethyl)indolin-3-ol

77a-e that, in turn, suffered dehydration generating 78a-e in 82-98% yields ( Scheme 23 ) . N O O R CH₃ Me₃SiCF₃ N O R CH₃ CF₃ HO THF /r.t ,24h BF₃ .THF N R CH₃ CF₃ HO SOCl₂ pyridine /24h,0°C-r.t N R CH₃ CF₃ 75a-e 76 77 78a-e 75a R=H 75b R=Br 75c R=Cl 75d R=CH₃ 75e R=NO₂ 78a R=H 78b R=Br 78c R=Cl 78d R=CH₃ 78e R=NO2 CsF, r.t /24h Scheme 23

III.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 dioxibrassinin 59. There is also a medical interest, as dioxindole has been isolated from the urine of a schizophrenic patient and from suspected drug abusers 60.

Dioxindoles can be obtained from isatins by reduction or by carbanion addition to the C-3 ketone functionality. Amongst the methods for the reduction of isatin to dioxindoles are the uses

Chapter I focus point on synthesis and reactivity of isatin

22

of Zn/HgCl2 in refluxing benzene 33 and Fe/HCl in aqueous ethanol 61, as well as eletrochemical 62

and photochemical 36 reduction. N-Methylisatin can be reduced to the corresponding dioxindole in quantitative yield by reaction with potassium tetracarbonylhydridoferrate [ KHFe(CO)4] 63.

Oxindoles can be prepared by the reduction of either dioxindoles or isatins. The reductions have been performed by using red phosphorous and iodic acid 61, by use of H2S in a

pyridine/co-solvent mixture 64 or by the Wolf-Kishner reaction 65-68 in presence of Ethanol or iso-propanol , lead to high yields of the desired product 69.

The first reported synthesis of oxindole was by Baeyer 70 and involved the reduction of isatin 3a in a two step process using sodium amalgam and base to initially form an intermediate 3-hydroxy-indolinone 79. This hydroxyl indolinone was then further reduced under acidic conditions in the presence of tin to afford oxindole 70 ( Scheme 24 ) .

N O O H Sodium amalgum base N OH O H H+, Sn N H 3a 79 70 Scheme 24

Noting that the hydrazones of α-dicarbonyl compounds may be decomposed under relatively mild conditions, Crestini 71 devised a one-pot Wolff-Kishner reduction of isatins by refluxing the isatins 3a in 98% hydrazine hydrate for 15-30 min without isolation of the intermediate hydrazones 80. The authors attribute the facility of this process in the absence of additional base to the possibility of the α-ketoamide to give anchimeric assistance in the stage of decomposition of the hydrazone, indole 70 afforded in good yield ( Scheme 25).

Chapter I focus point on synthesis and reactivity of isatin 23 N O O H 3a H₂NNH₂ N N O H NH₂ - N₂ N H 80 70 Scheme 25

Shanthi et al 72. developed a green approach to the synthesis of various 3-indolyl-3-hydroxy oxindoles. This method have some advantages such as (a) clean and simple reaction procedure (b) isolation of products without employing purification methods like column chromatography (c) use of eco-friendly catalyst.

The experiment was conducted with isatin 81 and indole 82 in the presence of catalytic amount of K2CO3 (20 mol %) in water. The reaction proceeded spontaneously at ambient

temperature and was completed within 1 h. The isolation of product 83 was straightforward as the solid precipitated on completion of the reaction ( Scheme 26 ) .

N R1 O O R + N R2 R3 H K₂CO₃ H₂O/ r.t ,1h N N HO R3 R2 H R R1 _O 81 82 83

R=H,allyl,benzyl R1_{=H,Cl R}2_{=H,Me R}3_=H,Br,MeO

Scheme 26

Meshram et al 73. demonstrated a practically, catalyst free synthesis of oxindoles in aqueous medium under microwav irradiation. The yields are high and the method is applicable for a variety of isatins as well as ketones like aromatic, heteroaromatic, aliphatic. The aqueous medium and rapid reaction makes the procedure more advantageous and eco-friendly.

They used this method to prepare 3-hydroxy-2-oxindole (aldole condensation) 86 by condensation acetophenone 85 with isatin 84 under microwaves conditions (Scheme 27 ) .

Chapter I focus point on synthesis and reactivity of isatin 24 N R2 O O R₁ + O R3 H2O MW N R₂ O R1 OH R₃ O R1_=H,Me,PhCH 2 R2_=H,NO 2,Br,I R3_=Ph,4-MeOC 6H4,4-NO2C6H4,3-NH2C6H4,2-thienyl,5-Me-2-furanyl,Me 84 85 86 Scheme 27

Garden et al 74. proposed a modification of the Sandmeyer’s method by the incorporation of ethanol as a co-solvent. This modification proved to be particularly useful in cases where the aniline derivative 87 was insoluble in the conventional reaction matrix. Application of the modified Sandmeyer methodology allowed the synthesis of 4,6-dibromoisatin 68 , a key intermediate for the synthesis of the marine natural product convolutamydine A (4,6-dibromo-3-hydroxy-3-(2-oxopropyl)indolin-2-one) 90 in 88% yield ( Scheme 28 ) .

NO₂ NH₂ 1-Acetic acid, Br2 2-EtOH,NaNO2,H2SO4 3-EtOH,Raney Ni,H2 4-Aqueous ethanolic HCl Br Br NH₂,HCl Cl_3CCH(OH)2 (NH2OH),H2SO4 Na₂SO4, H₂O/EtOH _N NOH H Br Br O H₂SO₄ N H O O Br Br N H O Br Br HO O Acetone , Et3NH 87 88 89 68 ₉₀ Scheme 28

III.2.Oxidation

In the oxidation of isatin 3a to isatoic anhydride 91 , the oxidizing agent selected should be able to introduce an oxygen atom between the two adjacent carbonyl groups without substantial decomposition of the ring system. In addition to chromium trioxide, several reagents have been successfully used in the process, mainly peracids, and have been reviewed in the oxidation of isatins 75 ,76 (Scheme 29 ) .

Chapter I focus point on synthesis and reactivity of isatin 25 N H O O N H O O O CrO₃ 72% 3a ₉₁ Scheme 29

Deligeorgiev et al 77.describe here a novel, cheap and environmentally friendly synthetic procedure for the oxidation of isatins 92a-f through the use of the urea–hydrogen peroxide complex 78 (percarbamide, H2NCONH2 . H2O2). The use of either a mixture of acetic acid/acetic

anhydride or formic acid and sulfuric acid catalysis led to the oxidation producing yields in the range 44–97% after 24 hours. Furthermore, the reactions were carried out at room temperature and gave isatoic anhydrides 93a-f with high purity. Irradiation of the mixture with ultrasound reduced the reaction time to 20 –135 min. ( Scheme 30 ) .

N H O O R NH₂ NH₂ O .H₂O₂ N H O R O O R=H,F,Cl,Br,CH₃,NO2 92a-f _93a-f Scheme 30

The oxidation of isatin 3a with metachloroperbenzoic acid yields 1,4-benzoxazine-2,3 (4H)-dione 94 , which was subsequently converted to blepharin 96 ,(glycoside obtained from Blepharis edulis Pers ) 79 ( Scheme 31 ) .

Chapter I focus point on synthesis and reactivity of isatin 26 N O O H N O O H MCPBA O KBH₄ N O O H OH N O O H O O HO OH OH OH 94 ₉₅ 96 3a H Scheme 31

III.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.

III.3.1.Amine derivatives

Treatment of isatin with ammonia gave rise to a mixture of products, there among isamic acid 99 and isamide 100. The structures of these two products were elucidated in 1976 80 . Isamic acid 99 can be regarded as a dimer formed by the addition/condensation of one equivalent of ammonia with two equivalents of isatin 3a . This intermediate 98 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 ( Scheme 32 ) .

Chapter I focus point on synthesis and reactivity of isatin 27 N H O O NH₃ N H N O HN O HO N H N O O NH₂ O HN N H N O RO O 3a _{97 98} 99 R=H 100 R=NH2 Scheme 32

Reacting isatin with hydroxylamine or hydrazine derivatives give rise to the expected condensed products. However when utilising amines a variety of products can be obtained 81.

In a similar fashion, 1-acetylisatin 101, when reacted with hydroxylamine hydrochloride furnishes quinazoline-3-oxide 103 through cyclization of the intermediate hydroxamic acid 10282. ( Scheme 33 ) . N O O NH2OH,HCl -H₂O O NH O NHOH NHOH O N N CONHOH O 101 102 103 Scheme 33

On the other hand, the condensation of 1-methylisatin 58 with thiosemicarbazone which refluxed in ethanol to produce mehisazone 104 83 ( Scheme 34 ) .

N O O CH3 N NNHCSNH₂ O CH3 H₂NNHCSNH₂ EtOH 58 104 Scheme 34 III.3.1.2.Alkylamines

The condensation of the isatin or 1-alkylisatine with primary alkylamines, leads to the corresponding isatin-3-imines. If the reaction is carried out with secondary alkylamines, the

Chapter I focus point on synthesis and reactivity of isatin

28

reaction leads to a result of the two nucleophilic attack with the amine compound at position C-3 of isatin .On the other hand, the reaction of isatin 3a with N,N-dimethylethylenediamine in water yields the spiro-diazolaneoxindole 106 whereas the corresponding condensation reaction performed by azeotropic distillation in toluene yielded the compound 105 as the result of the addition of an unstable azomethine ylide to isatin 81 ( Scheme 35 ) .

N O O H N N N O H N O N O NH₂ N O H N N Toluene, H₂O ∆ 3a 105 106 Scheme 35

A more straightforward reaction is the condensation between isatin and aromatic amines that usually yield the anils, as outlined in ( Scheme 36 ) , where isatin 3a is condensed with p-anisidine 107 to yield the anil 108 . These anils can be used in synthesis of other oxindole containing systems. A recent example is the synthesis of 3-spiro β-lactam oxindole 110 via the 3,3-disubstituted oxindole 109 84 . Compound 109 was obtained when anil 108 was treated with ketene silyl acetal of ethyl acetate in the presence of a Lewis acid.

Chapter I focus point on synthesis and reactivity of isatin 29 H2N O CH3 N H O O N H N O O CH₃ EtOH N H O NH EtO2C OCH3 N H O NH O 3a 107 108 109 110 BF_3.OEt2,DCM H_{2C COEt(OTMS)} Scheme 36

III.3.1.3.Anilines and heterocyclic amines

The reaction of isatin 3a with ortho-phenylenediamine 111 gives indophenazine 114 , 3-iminoisatin 113 and/or spirobenzimidazoline 112 , 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 acid 85, 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 AcOH 86. These imines have been studied as hair dyes 87. The use of the polar aprotic solvent N,N-dimethylacetamide, and high temperatures yields spirobenzimidazoles in high yields 88. A summary of these reactions is depicted in ( Scheme 37 ) .

Chapter I focus point on synthesis and reactivity of isatin 30 N O O H N O H NH HN + NH₂ NH₂ N NH O H HO NH₂ N N O H NH₂ N H N N DMA, ∆ AcOH AcOH THF 3a 111 112 113 113 114 Scheme 37

The condensation of isatin 3a with o-phenylenediamine 111 in refluxing methanol has been reported 89 to produce a mixture of 114 in yield 39% , 116 in yield 30% and only traces of the spiro compound 115 ( Scheme 38 ) .

N H O O H₂N H₂N N H N N N H NH HN O N N H NH₂ O MeOH 114 115 116 3a 111 Scheme 38

In a similar experiment Bergman et al 90 , used 2-aminobenzylamineas 117 partner to isatin 3a , the spiro compound 118 ( which can be considered as a higher homologue of 115 ) was obtained as the sole product (Scheme 39 ) .

Chapter I focus point on synthesis and reactivity of isatin 31 H₂N N H O O N H NH HN O MeOH H₂N 3a 117 ₁₁₈ Scheme 39

III.3.2.Nucleophilic reagents, sulfur and phosphorous

The reactions of 1-alkylisatins 58 91 with thiols yield substitution products at position C-3, such as 1'-methylspiro[1,3]dithiolane-2,3'-indolin]-2'-one 119 in 80% yield ( Scheme 40 ) .

N O O CH₃ (CH2SH)2 N O CH₃ S S 58 ₁₁₉ Scheme 40

The addition of dialkylphosphites to isatin and N-substituted derivatives 16 at position C-3 generating dioxindolophosphonates92. The use of chlorophosphites generates 3-(3-chlorooxindolyl) phosphine oxides 120, 121 93 (Scheme 41) .

On the other hand, cyclic dioxaphospholanes 94, phosphites 95 and trialkyl phosphites 96 react with isatins to yield dimeric spiro phospholanes .

N O O R (PhO)2PX X=OH,Cl N R O POPh₂ X 16 120 X= OH 121 X= Cl Scheme 41

Chapter I focus point on synthesis and reactivity of isatin

32

III.3.3.Reactive 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.

α-Diazophosphorous derivatives attack at the C-3 position of the isatin 16 ring to give dioxindoles 12297,98 in presence diethylamine, which upon treatment with acid yield the ring expanded quinolones 123 ( Scheme 42 ) .

N O O R N O R N₂ POR1R2 HO P OH R R₁ R₂ O O N₂ POR1R2 Et₂NH HCl 16 _{122 123} Scheme 42

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 8 mol L-1 KOH.

In these solutions, isatins 13 condense with the keto compound 124 and subsequently cyclize to the quinoline products . Recently, a modified procedure has been described, using acidic conditions 99.

This methodology was subsequently applied to a concise manner for the preparation of derivatives of camptothecin, a topoisomerase I inhibitor 125100 ( Scheme 43 ) .

N O O H R ₊ N O O O _OHO 1-AcOH,HCl,r.t 2-AcOH, HCl R N N O O OH CO₂H O 13 _{124 125} Scheme 43

Chapter I focus point on synthesis and reactivity of isatin

33

The reaction of isatin 3a with phosphorous pentachloride led to 3,3-dichlorooxindole 126 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 thiols . 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 127 101 ( Scheme 44 ) . N O O H PCl₅ N O H Cl Cl _N O H benzene, ∆ Cl 3a 126 127 Scheme 44

Conclusion

Structural changes in the basic structure of isatin, allowed the emergence of new derivatives with a broad spectrum of biological activity.

Thus, the most important structural changes concern the substituents at positions 1, 3 and 5 of the bicyclic system.

Bibliographical studies have shown that the structural change on the different positions of the base molecule improves its pharmacological profile conferring sedative, anticonvulsant, anxiolytic, anti-microbial, anti-HIV and anti-cancer and inhibitor of corrosion.

Given the biological activities associated with these molecules, the goal of our work is devoted to the synthesis and reactivity of new compounds derived from isatin, and the study of their biological activities, as well as industrial uses.

Chapter I focus point on synthesis and reactivity of isatin

34

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