DISSERTATION Erlangung des akademischen Grades eines ...

DISSERTATION

ZUR

Erlangung des akademischen Grades eines Doktors der Naturwissenschaften

der

Naturwissenschaftlichen Fakultät der Karl-Franzens-Universität Graz

Institut für Chemie, Organische und Bioorganische Chemie

Thema:

Synthesen und Reaktionen von Heterocyclen mit Fluoreszenz-optischen Eigenschaften

Vorgelegt von Mag. Guy Crépin ENOUA

Im November 2010

Graz-Österreich

DOCTORAL THESIS

SYNTHESES AND REACTIVITY OF

HETEROCYCLES WITH

FLUORESCENCE-OPTICAL PROPERTIES

ENOUA Guy Crépin, Mag.

Univ. Prof. Dr. Wolfgang STALDBAUER, Dissertation Supervisor

A Thesis presented for the degree of Doctorate in Natural Sciences, Option: Organic Chemistry Examiners committee Chairman : Univ. Pr. Dr. Georg URAY Examiners: Univ. Pr. Dr. Wolfgang KROUTIL Univ. Pr. Dr. Wolfgang STADLBAUER

Institute of Chemistry / Organic and Bioorganic Chemistry

Karl-Franzens University of Graz, Austria November, 2010

First of all, I would like to express my praises to God for His

guidance, protection and all the blessings He has bestowed upon

me. He granted me the strength to fulfill my doctoral studies

during these 3 years. To Him be the glory, honor and thanksgiving.

Dedications

I am dedicating this thesis to my mother KOBI Julienne, my father

ENOUANSOULOU Okira Felix, my grandmother NDIMI Catherine and am

thankful for their selfless sacrifices.

I am also writing this thesis in remembrance of my deceased brother Gaétan

Ndzila Okougou ENOUA, grandfathers Henri OKOU, Pierre NGOUMBA, and

uncles Isidore ANDA-MBELE and Firmin EFFENGUET.

This thesis is also dedicated to my brothers, my sisters, nephews, nieces,

cousins, and uncles who cannot partake in its defense because of the

geographical distance between the Republic of Congo and the Republic of

Austria.

Acknowledgements

The work presented in this thesis was conducted at the Institute of Chemistry,

Division of Organic and Bioorganic Chemistry, at the Karl-Franzens University

of Graz from December 2007 to November 2010.

I would like to express my deepest gratitude to Univ. Prof. Dr. Wolfgang

STADLBAUER for having accepted me in his laboratory and for his exceptional

supervision. As advisor he provided me with his full professional support in

dealing with this Ph.D research project. His constant encouragement helped

and challenged me throughout my studies.

I am also thankful to Univ. Prof. Dr. Georg URAY for his helpful contribution,

especially regarding the aspects of separation, purification, fluorescence

measurements of compounds and his invested time and valuable input to this

thesis. He greatly encouraged, advised and supported me during the writing of

this thesis. I feel much honored to have Professor URAY as second supervisor.

Both Professors STADLBAUER and URAY treated me like fathers would tutor a

son, they were very patient with my ``unforgivable mistakes`` in chemistry.

They are well respected due to their wide range of knowledge, good

interpersonal skills and humility which are worthy to emulate. What I learned

from both of them during these three years makes up a very important

foundation for my future research and teaching career.

I would also like to express my sincere thankfulness to Univ. Prof. Dr. Wolfgang

KROUTIL for examining this thesis and to Univ. Prof. Dr. Nadia Mösch-Zanetti,

head of Institute of Chemistry Karl-Franzens University, I am grateful to Univ.

Prof. Dr. Ulrike WAGNER, Institute of Biomolecular Sciences, Karl-Franzens

University of Graz for her help with the X-ray analyses. Univ. Prof. Dr. Klaus

ZANGGER was a helpful partner for various discussions about the

interpretation of NMR spectral analyses. His and Mr. Bernhard WERNER’s

assistance for recording numerous NMR and infrared spectra is greatly

appreciated as well as, Dr. Claudia REIDLINGER’s support for recording LC-

Mass spectral analyses.

My sincere thanks also go to Prof. Jean Boukari LEGMA, Prof. Adama SABA,

and Dr. Honorat Charles Roger NEBIE from University of Ouagadougou

(Burkina Faso) as well as Dr. Auguste BOUSSOUKOU from University Marien

NGOUBI of Brazzaville (Republic of Congo) for their teaching in

Electrochemistry and Organic Chemistry.

I am also thankful for Dr. Clement Bienvenu LOUBAKI’s efforts in talking with

Professor STADLBAUER for the provision of a place in Prof. STADLBAUER’s

laboratory for me.

I am grateful to Dr. Toma N. GLASNOV for reading my thesis. He and Dr.

Tahseen RAZZAQ accompanied me with their wisdom and encouragements.

The cooperation with them and also with my co-workers Ms. Nathalie

LACKNER and Mr. Günther LAHM made a real difference in my studies and

elaboration of this doctoral thesis.

My deep gratitude also goes to Mrs. Gritschi KERL and Mrs. Mag. Petra

RADESCHNIG in Vienna/Austria, both worked for OeAD in Burkina Faso, for

their generosity. Mrs. KERL especially played the role of a mother to me during

my stay in Austria. The friendship with M.Sc. Raymond OUEDRAOGO and

M.Sc. Albert SOUDRE also provided great comfort to me.

The “Church of Christ” in Graz/Austria became my Christian family while

staying in Austria. My special thanks go to Ms. Yasna VUČKOVIĆ from

Slovenia/Maribor, and GM Mag. Petra LANG and DI. Thomas LANG for their

generosity.

I gratefully acknowledge the financial support administered by the Austrian

Academic Exchange Service OeAD (Österreichischer Austauschdienst) through

a scholarship granted under the North-South-Dialog (Doctorate) scheme,

particularly Mrs Katharina ENGEL and Mrs. Mag. Christina DÜSS for their

generosity.

Finally, I feel deeply indebted to my fiancée Aicha Moussokoro BASSOLE for

being such a great source of encouragement to me. Her patience,

understanding and constant positive stimulation helped me to overcome the

stress related to my studies and the fact of being separated from for three

years, not to forget our baby.

PhD-Thesis-Karl-Franzens Universiy of Graz/Austria-2010 ENOUA Guy Crépin

LIST OF PRESENTATIONS AND CONFERENCE PROCEEDINGS List of Poster Presentations

1. Synthesis and Fluorescence Properties of 4-Cyano-6-methoxyquinolones

Enoua G. C., Uray G. and Stadlbauer W.

16th European Symposium on Organic Chemistry (16th ESOC), Prague (Czech

Republic), 12 - 16 July 2009 (Book of Abstracts p.197, poster P1.130).

2. 6-Methoxy- and 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile: syntheses and fluorescence properties


XXIVth European Colloquium on Heterocyclic Chemistry (24th ECHC), at the

Vienna University of Technology, Vienna (Austria), August 23 – 27, 2010 (Book

of Abstracts, PO-4)

List of Publications online

1. 4-Cyano-6-methoxyquinolones: Syntheses and Luminescence Properties


ECSOC-13, The Thirteenth International Electronic Conference on Synthetic

Organic Chemistry, http://www.usc.es/congresos/ecsoc/13/index.htm,

November 1-30, 2009 (a012)


2. Fluorescence Properties of 6-Methoxy- and 6,7-Dimethoxyquinoline-3,4-

dicarbonitriles

Enoua G. C., Uray G., Stadlbauer W.,

ECSOC-14, The Fourteenth International Electronic Conference on Synthetic

Organic Chemistry, http://www.usc.es/congresos/ecsoc/14/index.htm,

November 1-30, 2010 (a###); submitted.

List of Conference Proceedings

1. 4-Cyano-6-methoxyquinolones: Syntheses and Luminescence Properties

Enoua G. C., Uray G., Stadlbauer W.

In Proceedings of ECSOC-13, The Thirteenth International Electronic

Conference on Synthetic Organic Chemistry,

http://www.usc.es/congresos/ecsoc/13/index.htm, November 1-30, 2009

(a012); J. A. Seijas, Shu-Kun Lin, M. P. Vázquez Tato (Eds). CD-ROM edition,

ISBN 3-906980-23-5, Published in 2009 by MDPI, Basel, Switzerland.

2. Fluorescence Properties of 6-Methoxy- and 6,7-Dimethoxyquinoline-

dicarbonitriles

Enoua G. C., Uray G., Stadlbauer W.

In Proceedings of ECSOC-14, The Fourteenth International Electronic

Conference on Synthetic Organic Chemistry,

http://www.usc.es/congresos/ecsoc/14/index.htm, November 1-30, 2010; J.

A. Seijas, Shu-Kun Lin, M. P. Vázquez Tato (Eds). CD-ROM edition, ISBN 3-

906980-##-#, To be published in 2010 by MDPI, Basel, Switzerland; in

preparation.


CONTENTS

ABSTRACT……………………………………………………………………. 1

GENERAL INRODUCTION……………….…………………………………2

A. INTRODUCTION………………………………………………………..……………….2

B. METHODS FOR THE SYNTHESIS OF 4-HYDROXY-

QUINOLONE DERIVATIVES…………………………………………...................5

B.1. Cyclization of malondianilides with methane

sulfonic acid……………………………..…………………………………………..…5

B.2. Reaction of anilines with Meldrum’s acid…………………………………….....6

B.3. Reaction between aniline and carbon suboxide………………………………..6

B.4. Reactions of carbanions with isatoic anhydrides………………………………7

B.5. Cyclization of N-acetylanthranilic acid……………………………………………8

C. METHODS FOR THE SYNTHESIS OF QUINOLINES…………………………..8

C.1. Skraup quinoline synthesis……………………………………….………………..9

C.2. Döbner-von Miller reaction………………………………………………………….9

C.3. Döbner reaction……………………………………………………………………….10

C.4. Combes quinoline synthesis……………………………………………………….10

C.5. Friedländer synthesis…………………………………………………… …………11

C.6. Synthesis of quinolines by the Pfitzinger reaction………………… ………..11

D. SYNTHETIC ROUTES FOR THE PREPARATION OF 4-

HYDROXYQUINOLONES AND QUINOLINES USED IN THIS

WORK………………………………………………………………………..…..….……12

E. FLUORESCENCE PROPERTIES OF CARBOSTYRILS…………….….………16

F. APPLICATION OF FLUORESCENCE RESONANCE ENERGY

TRANSFER (FRET)………………………………………………………………..…..18

G. OTHER IMPORTANT FIELDS OF FLUORESCENT DYES………………...…20

REFERENCES FOR INTRODUCTION…………………………………………...……24


CHAPTER 1: SYNTHESIS AND REACTIVITY OF 4-HYDROXY- 6-

AND 7-METHOXYQUINOLIN-2(1H)-ONES…….…..…...39

1.1. INTRODUCTION……………………………………………………….…………....39

1.2. RESULTS AND DISCUSSION…………………………………………….…….…39

1.2.1. Cyclocondensation of p-anisidin 1 and malonic acid 2 to

4-hydroxy-6-methoxyquinolin-2(1H)-one 3 as precursor…………...……39

1.2.1.1. Optimization of the reaction…………………………………………...……….41

1.2.1.2. Proposed mechanism of the formation of 4-hydroxy-6-

methoxyquinolin-2(1H)-one 3…………..……………………………………...42

1.2.1.3. Proposed mechanism of the formation of dianilide 4……………………..43

1.2.1.4. Structural elucidation : IR and 1H-NMR spectroscopy

study of compounds 3 and 4………………...………………………………..43

1.2.2. Chlorination of 4-hydroxyquinolone 3 to 2,4-dichloroquinoline 5

and 4-chloroquinolone 6…………………………………………………………44

1.2.2.1. Study of Infrared and 1H-NMR Spectra of 5 and 6………………………..45

1.2.2.2. 13C-NMR spectrum of 4-chloro-6-methoxyquinolin-

2(1H)-one 6………………………………………………………………………...46

1.2.3. Introduction of cyano substituents into 4-chloro-6-

methoxyquinolin-2(1H)-one 6…………………………………………………..46

1.2.4. Synthesis of 4-sulfinyloxyquinolin-2(1H)-one 8…………………………….49

1.2.4.1.Structure elucidation of 4-sulfinyloxyquinolin-2(1H)-one 8……………….50

1.2.4.2. 13C-NMR spectrum of 4-sulfinyloxyquinolin-2(1H)-one 8………………..51

1.2.5. Experiment to show the reaction pathway…………………………………..51

1.2.5.1. Cyanation of 4-sulfinyloxyquinolin-2(1H)-one 8 to 4-

cyanoquinolone 9 and 3,4-dicyanoquinolone 7…………..………………..52

1.2.5.2. One-pot synthesis of 3,4-dicyanoquinolone from 4-

sulfinyloxyquinolone 8…………………………………………………………..54

1.2.6. One-pot reaction to 4-cyano-3-unsubstituted quinolone 9……………...54

1.2.7. Chlorination reaction with sulfuryl chloride………………………………...55

1.2.8. Reduction reaction of 3,3-dichloroquinolin-2,4-dione 10 to

3-chloro-4-hydroxy-6-methoxyquinolin-2(1H)-one 11…………………….56

1.2.9. Bischlorination reaction of 3-chloro-4-hydroxyquinolone 11

with phosphoryl chloride…….………………………………………………..…57


1.2.10. Hydrolysis reaction of 2,3,4-trichloroquinoline 12………….……………57

1.2.11. Introduction of cyano substituents into 3,4-dichloro-

6-methoxyquinolin-2(1H)-one 13………………………………………….….58

1.2.12. Synthesis of 4-chloro-6-methoxy-3-nitroquinolin-2(1H)-

one 16……………………………..………………………………………………..59

1.2.12.1. Nitration reaction of 4-hydroxy-6-methoxyquinolin-2(1H)-one 3…..…..59

1.2.12.2. Bischlorination of 4-hydroxy-6-methoxy-

3-nitroquinolin-2(1H)-one 14…………………………………………………..60

1.2.12.3. Regioselective hydrolysis of 2,4-dichloro-6-methoxy-

3-nitroquinolin-2(1H)-one 15……………………………………………….....62

1.2.13. Synthesis of N-(4-chloro-6-methoxy-2-oxo-1,2-

dihydroquinolin-3-yl)acetamide 18………………………………………....63

1.2.13.1 Reduction of 4-hydroxy-6-methoxy-3-nitroquinolone 14 into

acetylaminoquinolone 17……………………………………………………….63

1.2.13.2. Regioselective chlorination of N-(4-hydroxy-6-

methoxy-2-oxo-1,2-dihydroquinolin-3-yl)acetamide 17………………….64

1.2.14. Amination of 3,3-dichloroquinoline-2,4-dione 10………………………..66

1.2.15. Reduction of 6-methoxy-3,3-di(piperidin-1-yl)quinoline-

2,4(1H,3H)-dione 19.……………………………………………………………66

1.2.16. Synthesis of 4-chloro-6-methoxy-3-(piperidin-1-

yl)quinolin-2(1H)-one 22………..…………………………….………….……67

1.2.17. Synthesis of 3,4-dicyanoquinolones 7 from

3-substituted 4-chloroquinolones…..…………..……………….…………..68

1.2.18. About an “isomer” of 6-methoxyquinoline-dicarbonitrile

7, compound 23a…….…………………………………………………….……70

1.2.19. Cyclocondensation of m-anisidin 27 and malonic acid 2

to 4-hydroxy-7-methoxy-2(1H)-one 28………………………………….…..75

1.2.20. Chlorination of 4-hydroxyquinolin-2(1H)-one 28 to

2,4-dichloroquinoline 30 and 4-chloroquinolin-2(1H)-one 31.……….76

1.2.21. Synthesis of 7-methoxyquinoline-carbonitriles 32 and 33…………....77

1.2.22. Synthesis of 6-methoxy 4-trifluoromethylquinolin-

2(1H)-one 38………………………………………………………………….…..80


1.2.23. Synthesis of 4-methoxy-N-methylaniline 41……………………….……...82

1.2.23.1. Selective monoalkylation of p-anisidine 1 to

N-(4-methoxyphenyl)-N-methylformamide 40……………………….…... 82

1.2.23.2. Acidic hydrolysis of N-(4-methoxyphenyl)-N-methylformamide 40…...83

1.2.24. Cyclocondensation of 4-methoxy-N-methylaniline 41 and malonic

acid 2 to 4-hydroxy-6-methoxy-1-methylquinolin-2(1H)-one 42……..83

1.2.25. Chlorination of 4-hydroxy-6-methoxy-1-methylquinolin-

2(1H)-one 42 with phosphoryl chloride …………………………………….84

1.2.26. Introduction of a cyano substituent into 4-chloro-6-methoxy-

1-methylquinolin-2(1H)-one 43…………………………………………….....85

1.2.27. N-Methylation of 6-methoxy-2-oxo-1,2-dihydroquinoline

-4-carbonitrile 9……………………………………………………………………85

1.2.28. N-Alkylation of 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile 7……………………………………………………………....86

1.2.28.1. N-Alkylation with iodomethane…………………………….………………..86

1.2.28.2. N-Alkylation reaction with ethyl bromoacetate………… ………….......87

1.2.29. O-Alkylation of 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile 7…………………………….…………………………………88

1.2.30. N-Methylation of 4-chloro-6-methoxyquinolin-2(1H)-one 6…………….89

1.2.31. N-Methylation of 3,4-dichloro-6-methoxyquinolin-2(1H)-one 13…......89

1.2.32. Nitration reaction 4-chloro-6-methoxyquinolin-2(1H)-one 6……………90

1.3 CONCLUSION……………………………………………………………………….92

CHAPTER 2. SYNTHESIS OF 4-CYANO-3-SUBSTITUTED

QUINOLIN-2(1H)-ONES….……………………………….94

2.1. INTRODUCTION……………………………………………………………………..94

2.2. RESULTS AND DISCUSSION………………………………………................94

2.2.1. Esterification reaction of arylacetic acid 52…………………………………94

2.2.2. Condensation reaction of arylethyl ester 53 with diethyl

carbonate 54…………………………………………………………………….…..95

2.2.3. Thermal cyclization of aryl malonates 55………….................................96

2.2.4. Bischlorination of 4-hydroxy-3-substituted quinolin-2(1H)-ones 57…..98


2.2.5. Regioselective hydrolysis of 2,4-dichloro-3-substituted

quinolines 58……………………………………………………………………100

2.2.6. Introduction of the cyano group into 4-chloro-6-methoxy-

3- substituted quinolin-2(1H)-ones 59…………………………………….101

2.2.7. Synthesis of 2-chloro-6-methoxy-3-phenylquinoline-4-

carbonitrile (61)………………………………………………………...103

2.2.8. Synthesis of ethyl 3-[(4-methylphenyl)amino]-

2-[(4-methoxyphenyl)carbamoyl]-3-oxopropanoate 64…………………103

2.2.9. Synthesis of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-

3-carboxylate (67)……………………………………………………………....105

2.2.10. Bischlorination of ethyl 4-hydroxy-2-oxo-1,2-dihydro

quinoline-3-carboxylate (67) with phosphoryl chloride………………107

2.2.11. Synthesis of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-

3-carboxylate (70)…………………………………………………………......108

2.2.12. Synthesis of 4-hydroxyquinolin-2(1H)-one 69………………………….110

2.2.13. N-Alkylation of 4-chloro-3-(4-chlorophenyl)-6- methoxy

quinolin-2(1H)-one 59b with ethyl bromoacetate……………..………111

2.3. CONCLUSION……………………………………………………………………..112

CHAPTER 3: SYNTHESIS OF 6,7-DIMETHOXY-2-OXO-1,2-

DIHYDROQUINOLINE-3,4-DICARBONITRILE…….114

3.1. INTRODUCTION…………………………………………………………..……..114

3.2. RESULTS AND DISCUSSION…………………………………………..….....114

3.2.1. Synthesis of 4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one

(74) as precursor………………………………………………………………...114

3.2.2. Bischlorination of 4-hydroxy-6,7-dimethoxyquinolin-

2(1H)-one (74) with phosphoryl chloride……………………………………115

3.2.3. Regioselective hydrolysis of 2,4-dichloro-

6,7-dimethoxyquinoline (75)………………………………………………….116

3.2.4. Chlorination of 4-hydroxy-6,7-dimethoxyquinolin-

2(1H)-one (74) with sulfuryl chloride……………………………………….117


3.2.5. Reduction of 3,3-dichloro 6,7-dimethoxyquinolin-

2,4(1H,3H)-dione (77) to 3-chloro-4-hydroxyquinolin-

2(1H)-one 78…………………………………………………………………......117

3.2.6. Bischlorination of 3-chloro-4-hydroxy-6,7-

dimethoxyquinolin-2(1H)-one 78……………………………………………..118

3.2.7. Regioselective hydrolysis of 2,3,4-trichloro-6,7-

dimethoxyquinoline 79………………………………………………………….119

3.2.8. Introduction of the cyano groups into 4-chloro

quinolin-2(1H)-ones 76 and 80………………………………………………119

3.2.9. Alkylation of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile (82)…………………………………………………………...121

3.2.9.1. N-Methylation of 6,7-dimethoxy-2-oxo-1,2-

dihydroquinoline-3,4-dicarbonitrile (82)……………………..……………..121

3.2.9.2. Alkylation of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline

-3,4-dicarbonitrile (82) with ethyl bromoacetate……..……………………122

3.2.10. N-Alkylation of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline

3,4-dicarbonitrile (82) with ethyl bromoacetate…………………..........123

3.3. CONCLUSION………………………………………………………..……………..124

CHAPTER 4: SYSTEMATIC INVESTIGATION OF

SUBSTITUENT EFFECTS ON FLUORESCENCE

AND PHOTOPHYSICAL PROPERTIES OF

4-CYANOCARBOSTYRIL DERIVATIVES………….126

4.1. INTRODUCTION………………………..…………………………………………126

4.2. RESULTS AND DISCUSSION…………………………………………..……….128

4.2.1. Influence of methyl, trifluoromethyl and cyano groups

on the fluorescence properties on quinolones core……………………….128

4.2.2. The effects of methoxy groups in positions 6 and/or 7………………….132

4.3. ELECTRONIC SPECTRA OF THE NEW CARBOSTYRILS...................135

4.3.1. Known 4-cyano-3-H-6,7-dimethoxy-carbostyrils …… ..……….135

4.3.2. O- versus N-Alkylation…………………………………………………………..141

4.3.3. Influence of differently substituted aryl groups

in position 3 on the fluorescence properties………………………………..141


4.3.4. Stacking cyanocarbostyrils……………………………………………..…...144

4.3.5. Fluorescence properties of 4-sulfinyloxycarbostyrils…………………..146

4.4. CONCLUSION……………..………………………………………………........147

GENERAL CONCLUSION……………………………………………….148

EXPERIMENTAL PART FOR CHAPTERS 1, 2 AND 3………….150

EXPERIMENTAL PART FOR CHAPTER 4…………………………214

REFERENCES OF THEORETICAL PART

FOR CHAPTERS 1, 2 AND 3………………………………………….218


FOR CHAPTER 4……………………………………………….……..…234

REFERENCES FOR EXPERIMENTAL PART………………………242

ABSTRACT 1


ABSTRACT

Carbostyrils have found in the last decade great interest as stable

fluorophors with excellent photophysical properties. In this thesis a number of

4-cyanocarbostyrils were investigated which show very interesting fluorescence

properties and offer the introduction of linkers to label biological material,

which make them particularly interesting as probes in biological, biochemistry

and medicine applications.

The syntheses started from methoxyanilines which gave with malonic acid or

arylmalonates either 3-unsubstituted or 3-aryl-4-hydroxycarbostyrils.

Functionalization of the 3-H derivatives at position 3 by bis-chlorination and

reduction gave 3-chloro derivatives. Amination of the dichloro derivatives with

piperidine and reduction gave 3-piperidinocarbostyrils. Nitration of the 3-H

derivatives gave 3-nitro derivatives; reduction afforded 3-

acetylaminocarbostyrils.

All these 4-hydroxycarbostyrils were chlorinated at position 2 and 4 and

hydrolyzed in acidic media regioselectively at position 2 to 4-chlorocarbostyrils.

The introduction of the cyano group in the 4-chloro-6-methoxycarbostyril

series gave 3,4-dicyanocarbostyrils. 7-Methoxy- and 3-aryl analogues gave

under the same conditions 4-cyanocarbostyrils. Alkylation of 3,4-dicyano-

carbostyrils led to the expected 1-alkyl derivatives.

Fluorescence spectra of 3,4-dicyano-6-methoxycarbostyril show λmaxexc at 470

nm, λmaxem at 560 nm, and a fluorescence quantum yield of ~15%. The

fluorescence of the 6,7-dimethoxycarbostyril analogue suffered a small blue-

shift, but exhibits an excellent quantum yield of ~50 %. The introduction of

alkyl groups at N-1 did not affect the fluorescence properties. Excitation and

emission maxima of 3-aryl-4-cyanocarbostyrils and 7-methoxycarbostyrils are

both ~50 nm blue-shifted, compared with dicyano analogues; the quantum

yield is ~25%.

GENERAL INTRODUCTION 2


GENERAL INTRODUCTION

A. INTRODUCTION

4-Cyanoquinolin-2(1H)-ones (4-cyanocarbostyrils) of type I (R2 = CN)

which synthesis and chemical modifications described in this thesis, are

heterocyclic compounds with two fused rings containing a benzene nucleus (II)

and pyridin-2(1H)-one moiety (III).

N O

H

R1

R2

R3

R4

R5

R6

R4

R3

R5

R6

N

R2

R1

O

H

I II III

Figure 1: Structure of quinolin-2(1H)-one I, benzene II and pyridine-2-(1H)-

one III

Quinolin-2(1H)-ones are also subunits of the pyrido[3,2,1-jk]carbazol-6-

ones VII and their tetrahydroderivatives VIII, which possess biologically

interesting combination of pharmacologically relevant core structures [1].

Pyridocarbazolones have gained attention in medicinal chemistry as blood

coagulation inhibitors, or antiallergics, analgesics and antipyretics. Few of

them can be used for the treatment of certain mental disorders [2].

Pyridocarbazolone derivatives are also useful in dye chemistry [3] as

fluorescent whiteners as greenish-yellow azodyes for polyester fibers.



N

OOH

R1

R3

R2

VII

N

OOH

R1

R3

R2

VIII

Pyrido[3,2,1-jk]carbazol-6-one 8,9,10,11-Tetrahydropyrido[3,2,1-jk]

carbazol-6-one

Figure 2: Structures of compounds VII and VIII.

Electron-donating groups such as methoxy groups on the quinolin-

2(1H)-one moiety have been chosen in this work, potentially serving as a

handle for further functionalization [4, 5, 6]. On the other side, methoxy

groups are common for many quinoline alkaloids [7a].

Quinolin-2(1H)-one, particularly the 4-hydroxyquinolin-2(1H)-one moiety

is a basic structure found in many natural products or is synthesized and used

in industries. It plays an important role as precursor in various reaction such

as transformation into quinoline nucleus, which is a very important class of

heterocyclic compound. The quinoline core is present in many alkaloids [7],

such as Swietinidine A [8], Daurine, Folidine [9], Glycolone A [10],

Glycocitridine [11], Flindersine [12, 13], or Almein [14].

Moreover, substituted quinolines are known to display a wide range of

pharmacological activities such as anti-inflammatory [15-19], antibacterial [18-

25], antiprotozoan [26-28], antimalarial [18, 19, 29-32], antiasthmatic [18, 19,

33], antituberculosis [34, 35 ], anti-Alzheimer [36], antihypertensive [18, 19,

37], anthelmintic [38], anti-HIV [39-41], anticancer [42-45], anti-platelet [18,

19] activity and tyro-kinase PDGF-RTK inhibiting agents.



4-Hydroxyquinolin-2(1H)-ones unsubstituted at the fused benzene ring

such as 4-hydroxyquinolin-2(1H)-one IX are considered as glycosyl acceptor

[46]. Glycosides are largely distributed in nature and play important roles in

living organisms.

N O

H

OH

IX

Figure 3: Structure of compound IX

Quinoline glycoalkaloides, in particular (β-D-glucopyranosyloxy)quinolines and

their quinolin-2(1H)-one analogues, were isolated from different natural

sources [46]. These include larvae, pupae and adults of some wasps (Vespa

levisi) and honey bees (Apis mellifera and others), [47], corn kernels [48] and

Chinese medicinal plant Echinops gmelinii (Compositae) [49]. Plants of the

Haplophyllum (Rutaceae) genus are especially rich sources of quinoline

alkaloids including glycoalkaloides of furanoquinoline structure [49c, 50].

Quinoline and quinolinone derivatives are metabolized in animals to

hydroxyl derivatives which then become conjugated with D-glucuronic acid

prior to their excretion [46]. β-D-glucopyranosiduronic acid derivatives of

quinoline, quinolin-2(1H)-one and quinolin-4(1H)-one were isolated from urine

of rabbits [51], rats [52], and mice [52b].

Several (β-D-glucopyranosyloxy)quinolines and their quinolin-2(1H)-ones were

prepared for treatments of chloroquinone-resistant malaria [53], tuberculosis

[54] and as anti-allergic agents [55].

A literature survey showed that quinolin-2-(1H)-ones could be obtained

in different pathways.



B. METHODS FOR THE SYNTHESIS OF 4-HYDROXYQUINOLONE

DERIVATIVES

Several methods for the preparation of quinolin-2(1H)-ones of type I have

been developed. Among them, some have been established for a wide range of

derivatives of 4-hydroxyquinolin-2(1H)-ones such as: Cyclization of

malondianilides with methane sulfonic acid, reaction of anilines with

Meldrum’s acid, reaction between aniline and carbon suboxide, reactions of

carbanions with isatoic anhydrides, cyclization of N-acetylanthranilic acid,

condensation of anilines or alkyl anthranilates with malonic acid

and/ormalonic acid esters.

B.1. Cyclization of malondianilides with methane sulfonic acid

Malondianilides X were treated with aluminium trichloride [56] or

polyphosphoric acid [57] to form by intramolecular cyclization the

corresponding 4-hydroxyquinolin-2(1H)-one XI in poor to moderate yields and

in some cases the reaction failed. However, the cyclization of X in the presence

of methanesulfonic acid containing 10 % of phosphoric pentoxide as catalyst

[58] afforded the corresponding 4-hydroxyquinolin-2(1H)-one XI in excellent

yield of 90 % after a simple work-up.

R3

R4

R5

R2

NH

CH

R5

R4

R3

R2

NH

O

O

R1

N

R4

R2

R5

R3

H

O

R1

OH

CH3SO

3H / P

2O

5

X XI

Scheme 1



B.2. Reaction of anilines with Meldrum’s acid

Quinolin-2(1H)-ones XV can readily be synthesized from anilines XII and

Meldrum’s acid XIII [59]. The reaction involves an intermediate Malonic acid

monoaryl ester XIV, which treated with cyclization reagent such as Eaton’s

reagent afforded quinolin-2(1H)-ones XV. The crucial problem in this

procedure is to reduce or eliminate the decarboxylation as the authors state.

Thus, Eaton’s reagent is used for the cyclization of the intermediate under mild

reaction conditions.

N

R3

R1

R2

H

O

OH

R3

R2

R1

NH2

O

O

O

O

CH3

CH3

- (CH3)2CO R

3

R2

R1

NH

O

COOH

- H2O

+

XII XIII XIV

Scheme 2

B.3. Reaction between aniline and carbon suboxide

The reaction between aniline XVI and carbon suboxide XVII usually

gives malonanilide [60] quantitatively. It was found that the reaction of aniline

XVI with carbon suboxide (C3O2) in the presence of aluminium chloride

produced in the first step an N-acetylated intermediate 3-oxo-N-

phenylacrylamide XVIII in good yield, which upon cyclization in benzene at



80 °C reflux conditions gave 4-hydroxycarbostyril IX in only 17 % yield [61].

N

H

O

OH

NH2

N

H

C

O

C O

AlCl3

Et2O C

6H

6

O C C C O

XVI XVII XVIII

IX

++

Scheme 3

B.4. Reactions of carbanions with isatoic anhydrides

A literature survey showed that some works have addressed on the

synthesis of quinolin-2(1H)-ones starting from isatoic anhydrides [62-67].

G. M. Coppola et al. [68] reported the synthesis of quinolin-2(1H)-ones XXI by

reaction of the sodium salt of diethylmalonate with isatoic anhydride XIX,

allowing the isolation of the intermediate ethyl 1-alkyl-4-hydroxy-2-oxo-1,2-

dihydroquinoline-3-carboxylate XX, which was then subsequently hydrolyzed

in alkaline media followed by decarboxylation to give the corresponding

quinolin-2(1H)-ones XXI.



N

R

O

OH

N

O

O

O

R

NaCH(COOEt)2

N O

OH

COOEt

R

OH -

86 %67 %

XIX XX XXI

Scheme 4

B.5. Cyclization of N-acetylanthranilic acid

N-Acetylanthranilic acid was heated with a strong base as sodium

hydroxide producing a sodium salt of the corresponding acid XXII [69, 70],

which was heated again with sodium hydroxide to give by intramolecular

cyclization the 4-hydroxyquinolin-2(1H)-one IX.

N

H

O

OH

N

H

ONa

O

COCH3

NaOH

XXII IX

Scheme 5

C. METHODS FOR THE SYNTHESIS OF QUINOLINES

During the last century, many efforts have been devoted to the

development of new regioselective synthetic methodologies for the production of

quinolines.

Among these methods, the classical known are: Skraup, Döbner-von

Miller, Döbner, Combes, Friedländer, Pfitzinger quinoline synthesis.



C.1. Skraup quinoline synthesis

The Skraup synthesis is a chemical reaction used to synthesize

quinolines. It is named after the Czech chemist Zdenko Hans Skraup (1850-

1910) and was developed at the chemistry institute of Graz. In the archetypal

Skraup reaction, aniline is heated with sulfuric acid, glycerol, and an oxidizing

agent, such as nitrobenzene to yield quinoline [71].

NNH2

OH

OH

OH

H2SO

4

PhNO2

XVI XXIII

Scheme 6

In this example, nitrobenzene serves as both the solvent and the oxidizing

agent. The reaction, which otherwise has a reputation for being violent ("the

Chemical Inquisition"), is typically conducted in the presence of ferrous sulfate

[72]. Arsenic acid may be used instead of nitrobenzene and the former is better

since the reaction is less violent [73].

C.2. Döbner-von Miller reaction

The Döbner-Miller reaction is the organic reaction of an aniline XVI with

α, β-unsaturated carbonyl compounds XXIV to form quinolines XXV [74].

N RNH2

H

O

R

XVI XXV

XXIV

Scheme 7

http://en.wikipedia.org/wiki/Chemical_reaction

http://en.wikipedia.org/wiki/Quinoline

http://en.wikipedia.org/wiki/Zdenko_Hans_Skraup

http://en.wikipedia.org/wiki/Aniline

http://en.wikipedia.org/wiki/Sulfuric_acid

http://en.wikipedia.org/wiki/Glycerol

http://en.wikipedia.org/wiki/Redox

http://en.wikipedia.org/wiki/Redox

http://en.wikipedia.org/wiki/Nitrobenzene

http://en.wikipedia.org/wiki/Nitrobenzene

http://en.wikipedia.org/wiki/Solvent

http://en.wikipedia.org/wiki/Iron%28II%29_sulfate

http://en.wikipedia.org/wiki/Arsenic_acid

http://en.wikipedia.org/wiki/Organic_reaction


http://en.wikipedia.org/wiki/%CE%91,%CE%B2-unsaturated_carbonyl_compound




This reaction is also known as the Skraup-Döbner-Von Miller quinoline

synthesis, and is named after the Czech chemist Zdenko Hans Skraup (1850-

1910), and the German chemists Oscar Döbner (Doebner) (1850-1907) and

Wilhelm von Miller (1848-1899). When the β-unsaturated carbonyl

compound is prepared in situ from two carbonyl compounds (via an Aldol

condensation), the reaction is known as the Beyer method for quinolines. The

reaction is catalyzed by lewis acids such as tin tetrachloride, scandium (III)

triflate or Brönsted acids such as p-toluenesulfonic acid, perchloric acid,

amberlite and iodine.

C.3. Döbner reaction

The Döbner reaction is the chemical reaction of an aniline XVI with an

aldehyde XXVII and pyruvic acid XXVI to form quinoline-4-carboxylic acids

XXVIII [71a, 71b].

N R

OHO

NH2

CH3

OH

O

O

R H

O

XVI XXVIII

XXVI

XXVII

Scheme 8

C.4. Combes quinoline synthesis

The Combes quinoline synthesis is a chemical reaction involving the

condensation of unsubstituted anilines (XVI) with β-diketones (XXIX) to form

substituted quinolines (XXXI) after an acid-catalyzed ring closure of an

intermediate Schiff base (XXX) [75].

http://en.wikipedia.org/wiki/Zdenko_Hans_Skraup

http://en.wikipedia.org/w/index.php?title=Oscar_D%C3%B6bner&action=edit&redlink=1

http://en.wikipedia.org/w/index.php?title=Wilhelm_von_Miller&action=edit&redlink=1

http://en.wikipedia.org/wiki/Carbonyl

http://en.wikipedia.org/wiki/In_situ

http://en.wikipedia.org/wiki/Aldol_condensation

http://en.wikipedia.org/wiki/Aldol_condensation

http://en.wikipedia.org/wiki/Lewis_acid

http://en.wikipedia.org/wiki/Tin_tetrachloride

http://en.wikipedia.org/wiki/Scandium%28III%29_triflate

http://en.wikipedia.org/wiki/Scandium%28III%29_triflate

http://en.wikipedia.org/wiki/Bronsted_acid

http://en.wikipedia.org/wiki/P-Toluenesulfonic_acid

http://en.wikipedia.org/wiki/Perchloric_acid

http://en.wikipedia.org/wiki/Amberlite

http://en.wikipedia.org/wiki/Iodine



http://en.wikipedia.org/wiki/Aldehyde

http://en.wikipedia.org/wiki/Pyruvic_acid


http://en.wikipedia.org/wiki/Carboxylic_acid


http://en.wikipedia.org/wiki/Condensation_reaction


http://en.wikipedia.org/wiki/Ketone


http://en.wikipedia.org/wiki/Acid

http://en.wikipedia.org/wiki/Schiff_base



N R1

R2

NH2

O

R2

O

R1

R1

O

R2 H

2SO

4

- H2O- H

2O

XVI XXX XXXI

XXIX

Scheme 9

C.5. Friedländer synthesis

The starting materials for this quinoline synthesis are o-aminoaryl

aldehydes or ketones XXXII and a ket -methylene group

XXXIII. After an initial amino-ketone condensation, the intermediate

undergoes base- or acid-catalyzed cyclocondensation to produce a quinoline

derivative XXXIV. It is named after the German chemist Paul Friedländer

(1857-1923) [76, 77].

N

R2

R3

R4

R2

O

NH2

R1

R1

R3

O

R4+

XXXII XXXIII XXXIV

Scheme 10

C.6. Synthesis of quinolines by the Pfitzinger reaction

The Pfitzinger reaction (also known as the Pfitzinger-Borsche reaction) is

the chemical reaction of isatin XXXV with a base and a carbonyl compound

XXXVI to yield substituted quinoline-4-carboxylic acids XXXVII [78].

http://en.wikipedia.org/wiki/Paul_Friedl%C3%A4nder_%28chemist%29


http://en.wikipedia.org/wiki/Isatin

http://en.wikipedia.org/wiki/Carbonyl


http://en.wikipedia.org/wiki/Carboxylic_acid



N

R2

R1

OHO

N

O

O

H

R1

O

R2

KOH

XXXVI

XXXV XXXVII

Scheme 11

D. SYNTHETIC ROUTES FOR THE PREPARATION OF 4-

HYDROXYQUINOLONES AND QUINOLINES USED IN THIS

WORK

Our synthetic routes for the preparation of 4-hydroxyquinolin-2(1H)-ones

were based on the cyclocondensation of methoxyanilines XXXVIII with malonic

acid XXXIX, heated in phosphoryl chloride to form the 4-hydroxyquinolin-

2(1H)-ones XL.

R3

R2

NH

R1

N

R3

R2

R1

O

OH

COOH

COOH

POCl3

XXXIX

XXXVIII XL

Scheme 12

Another approach to 4-hydroxyquinolin-2(1H)-ones was the synthesis of

3-aryl-4-hydroxyquinolin-2(1H)-ones XLV having substituents in the phenyl

moiety, which are connected via the conjugated bonds to the 2-quinolone dye

system.



The synthesis started from suitable substituted aryl acetates XLI which

were treated with diethyl carbonate XLII to give aryl malonates XLIII.

Thermal cyclization of aryl malonates XLIII with anilines XLIV gave the

corresponding 3-aryl-4-hydroxyquinolin-2(1H)-ones XLV.

O

OEt

R

O

EtO

EtO

O

OEt

O

OEtR

NaH / THF

+

XLI XLII XLIII

R3

NH2 N

R3

O

OH

H

RO

OEt

O

OEtR

Ph2O

+

XLIV XLIII XLV

> 250 °C

Scheme 13

On the other hand, 3-ethyloxycarbonyl-4-hydroxyquinolin-2(1H)-one XLVIII

was obtained from methyl anthranilate XLVI by treatment with

diethylmalonate XLVII in sodium ethoxide.

N O

OH

H

COOEt

NH2

O

OMe COOEt

COOEt

EtONa / EtOH

+

XLVI XLVII XLVIII

Scheme 14



Next, bischlorination with phosphoryl chloride at position 2 and 4 of 4-

hydroxyquinolin-2(1H)-ones XLIX gave the corresponding quinolines L which

were subsequently hydrolyzed in acidic media regiselectively at position 2,

affording 4-chloroquinolin-2(1H)-ones LI.

In the case of 4-hydroxy-N-alkylated analogue (R1 = alkyl), direct chlorination

at position 4 gave 4-chloro-6-methoxyquinolin-2(1H)-one LI.

N O

OH

R1

R2

R3

R4

N

R2

R3

R4

Cl

Cl

R1

N O

R2

R3

R4

Cl

R1

POCl3

H2O / H

R1

CH3

POCl3

R1

+

XLIX L LI

=

= H

Scheme 15

On the other hand, suitable substituents at position 3 of 4-

hydroxyquinolinones LII were obtained by multistep syntheses : Chlorination

with sulfuryl chloride followed by reduction with zinc-dust gave 3-chloro-4-

hydroxyquinolones LIII.

N O

OH

R3

R4

H

N O

R3

R4

Cl

OH

H

SO2Cl

2

Zn

LII LIII

1.

2.

Scheme 16

Nitration in position 3 of 4-hydroxyquinolone LII with concentrated nitric acid

using sodium nitrite as catalyst, followed by reduction/acetylation gave 3-nitro



and 3-acetylaminoquinolones LIV and LV respectively.

N O

OH

R3

R4

H

N

R3

R4

O

H

OH

NO2

N O

R3

R4

OH

H

NHCOCH3

HNO3 / NaNO

2 Zn/ Ac2O

LII LIV LV

Scheme 17

Amination of 3,3-dichloroquinolin-2,4-dione LVI with piperidine and

reduction of the resulting intermediate dipiperidine LVII with sodium dithionite

in ethanol-water mixture gave 4-hydroxy-3-piperidinoquinolone LVIII.

N O

H

OCl

ClR

3

R4

N

N O

H

OH

R4

R3

N

N

N O

H

O

R4

R3

Piperidine Na2S

2O

4

LVI LVII LVIII

Scheme 18

All these 4-hydroxyquinolones derivatives were chlorinated with

phosphoryl chloride at position 2 and 4, and subsequently hydrolyzed in acidic

media regioselectively at position 2 to give the 4-chloroquinolone derivatives. In

the case of 3-acetylaminoquinolones LV the chlorination reaction with

phosphoryl chloride gave directly 4-chloroquinolone.

The introduction of the cyano group upon 4-chloroquinolone derivatives

at position 4 and/or 3 was carried out by reaction with potassium cyanide in

the presence of sodium p-toluenesulfinate.

Interesting chromophores having the cyano groups at position 3 and 4



were alkylated with methyl iodide or ethyl bromoacetate at position N-1.

Also, 6-methoxy-4-trifluoromethylquinolin-2(1H)-one was synthesized

from p-anisidine and 4,4,4-trifluoroacetoacetate in the presence of sulfuric

acid in order to compare its fluorescence properties with those of 6-methoxy-2-

oxo-1,2-dihydroquinoline-4-carbonitrile.

E FLUORESCENCE PROPERTIES OF CARBOSTYRILS

Fluorescence is generally defined as a luminescence emission that is

caused by the flow of some form of energy into the emitting body, this emission

ceasing abruptly when the exciting energy is shut off.

In the literature of organic luminescence, the term fluorescence is used

exclusively to denote a luminescence which occurs when a molecule makes an

allowed optical transition.

The fluorescence properties of carbostyrils [quinolin-2(1H)-ones] were

first reported by O. A. Ponomarev. [79] Compared with similar coumarin

fluorophors, luminescence properties of most quinolin-2(1H)-ones have the

disadvantage of shorter absorption and emission wavelengths [80, 81]. In

contrast, the advantages of carbosytril systems are high stability against

chemicals, thermal and photochemical stress, for instance an aqueous solution

pH 6 of the europium-complex was kept in the dark at room temperature and

its luminescence was found to be unchanged after more than one year [58],

insensitivity to oxygen quenching, independence of luminescence in a broad pH

region, for instance an aqueous

Recently, our group investigated on the vastly improved luminescence

properties of a big number of carbostyril [quinolin-2(1H)-one) systems [82].

These properties we achieved by suitable substituents, e.g. acceptor

groups such as trifluoromethyl in position 4 (Acc) and donor groups such as

methoxy or amino in position 6 and 7 (Don1 and Don2). The molecules with

methoxy groups gave excitation/emission maxima at ~370/430 nm, together



with large Stoke' s shifts and sufficient quantum yields [4, 5, 83]. These

fluorescence properties are comparable with umbelliferon (7-

hydroxycoumarin), but the molecules have much better stability.

O OOH

Figure 4: Structure of umbelliferon

6,7-Amino groups show longer wavelengths and better quantum yields, but

have the big disadvantage of pH sensitivity [83b]. 4-Cyano substituents

improved the fluorescence properties with longer wavelengths and better

quantum yields [61].

N O

Acc

Don2

Don1

Linker

R

Donor: MeO, NHR, NR2

Acceptor: CF3, CN

Absorption: 360-390 nm

fluorescence: 420-450 nm;

Quantum yield up to 0.5

Figure 5

Fluorescence has many practical applications, including mineralogy,

gemology, chemical sensors, fluorescent labeling, dyes, biological detectors and

most commonly fluorescent lamps.



Fluorescence is used in the life sciences generally as a non-destructive

way of tracking or analysing biological molecules by means of fluorescence.

Some protein or small molecules in cells are naturally fluorescent, this is called

intrinsic or autofluorescence (such as NADH, tryptophan or endogenous

Chlorophyll, Phycoerythrin or green fluorescent protein), alternatively specific

or general proteins, nucleic acids, lipids or small molecules can be labeled with

an extrinsic fluorophore, a fluorescent dye which can be a small molecule,

protein or quantum dot.

F. APPLICATION OF FLUORESCENCE RESONANCE ENERGY

TRANSFER (FRET)

Förster resonance energy transfer (abbreviated FRET), also known as

fluorescence resonance energy transfer, resonance energy transfer (RET) or

electronic energy transfer (EET), is a mechanism describing energy transfer

between two chromophores.

Several techniques exist, often exploiting additional properties, such as

fluorescence resonance energy transfer, where the energy is passed non-

radiatively to a particular neighbouring dye, allowing proximity to be detected;

another is the change in properties, such as intensity, of certain dyes

depending on their environment allowing their use in structural studies [84].

Luminescence chromophores as entities of fluorescence resonance

energy transfer systems are important tools to study supramolecular

interactions with a special emphasis in the real of biomolecules like DNA, RNA,

and proteins [85]. FRET Systems allow monitoring distance-dependent

interactions on the molecular level, and in real-time mode. For instance the

group of Bannwarth [86] already used our fluorescent carbostyrils,

incorporated in peptides, in a Fluorescence-Resonance-Energy Transfer

(FRET)-system for distance determinations.



N

R

O

MeO

MeO

O

H-His-Ala-Lys-Tyr-His-Lys-Gly-NH2

Ru (II)-bathophenanthroline R = CF3, CN

Figure 6: FRET carbostyril with peptides

The FRET technology is also based on the non-emissive transfer of

energy between a donor and acceptor fluorophore, it decreases with r-6, r being

the distance the donor and the acceptor [87]. Thus, FRET molecules are used

for displaying distances or approaches by changing of fluorescence, the

distance markers between dyes and fluorescence of the molecule depend of the

cation (K+) complexation in the molecule [88]. Another field of application for

FRET is in diagnostics and drug research, where tools like molecular beacons

[89], TaqMan probes [90] or fluorescent protease substrates, for instance, use

the same principle [91].



Figure 7: Synthetic Valinomycin-Carbostyril, FRET with rhodamin after K+

Complexation

G. OTHER IMPORTANT FIELDS OF FLUORESCENT DYES

Another important field that has registered development is the

application of fluorescent labels for many compounds with potential biological

activity [92, 93].

Among them, the fluorescent peptides [94-98] have a big number of

applications in biochemistry and biology, mainly in studies of protein

interactions and conformational analysis. Fluorescent markers are also

investigated for in vivo imaging studies, such as in Alzheimer disease [99]. The

most used fluorescent markers for peptides are rhodamine, fluorescein,

coumarin and their derivatives [97, 100].

The fluorescence dyes of the coumarin type which are of interest not only

because of their pharmacological activity [101] but also because of their



applications as laser dyes [102], fluorescent labels [103, 104] (e.g. in biological

applications), emission layers in organic light-emitting diodes (OLED) [105],

and as optical brighteners [106].

Sugars have also been used in the development of fluorescent reagents

because they confer water solubility to organic fluorophores with no significant

change in absorption and fluorescence properties [107].

Molecules containing europium antenna chelates or europium complex

change the fluorescence properties by addition of small molecules like water or

carbon dioxide (CO2) [108].

Structure of Europium complex

N

O

O

CH3

CH3

CF3

N

O

H

Eu-chelate

O-

Structure of europium antenna chelate

Figure 8

Eu

O

N

NN

O

O

HN

O

NH

O

CF3

H3CO

H3CO

HO

OO

OO



Figure 9

Luminescence lanthanide (terbium and europium chelates) have many

useful applications, including as alternatives to standard fluorescent dyes

especially when there is significant autofluorescence [109] or as donors in

energy transfer experiments to measure both static and time-varying distance

[110]. These applications arise because of the chelates’ unsual spectral

characteristics, including millisecond lifetime, spiked emission (< 10 nm full

width at half-maximum), large Stoke’s shifts (> 150 nm) and excellent solubility

in aqueous solvents [111].

The new carbostyril chromophores 7 and 82 presenting a second

maximum above 300 nm have the possibility to be excited both in UV and

visible regions that make them to promising candidates for the construction of

FRET molecules, and might be useful as alternatives to established probes for

biological investigations.

N

O

CH3

O

H

CN

CN

7

N

O

CH3

O

H

CN

CN

O

CH3

82

Figure 10. Structures of compounds 7 and 82

REFERENCES FOR INTRODUCTION 23


REFERENCES FOR INTRODUCTION



REFERENCES FOR INTRODUCTION

[1] V. H. Dang, Ph.D. thesis, 2006, p. 1, University of Graz, Austria.

[2] a) E. Ziegler, U. Rossmann, F. Litvan , H. Meier, Monatsh. Chem. 1962,

93, 26; b) E. Ziegler, F. Litvan (Geigy Chemical Corp.), US Patent, 1959,

3 052 678, Chem. Abstr., 1963, 58, 3437e; c) Geigy Chemcal Corp., Brit.

Patent, 1960, 912 289; Chem. Abstr. 1963, 59, 645; d) M. Harfenist, E.

Magnien, J. Org. Chem., 1963, 28, 538; e) M. Harfenist, J. Org. Chem.,

1962, 27, 4326-31.

[3] a) O. S. Wolfbeis, E. Ziegler, A. Knierzinger, H. Wipfler, I. Trummer,

Monatsh. Chem., 1980, 111, 93; b) U. Zirngibl (Sandoz Ltd.), Ger. Offen.

DE 2 142 334, 19 720 302 (1972); DE 71-2 142 334-19710824 (1971).

[4] N. S. Badgujar, M. Pazicky, P. Traar, A. Terec, G. Uray, W. Stadlbauer,

Eur. J. Org. Chem. 2006, 2715–2722.

[5] A. B. Avhale, H. Prokopcová, J. Šefčovičová, W. Steinschifter, A. E.

Täubl, G. Uray, W. Stadlbauer. Eur. J. Org. Chem., 2008, 563-71.

[6] G. Uray, N. S. Badgujar, S. Kováčková, W. Stadlbauer, J. Heterocycl.

Chem., 2008, 45, 165-172.

[7] a) P. Michael, Nat. Prod. Rep., 2007, 24, 223-246; b) J. P. Michael, Nat.

Prod. Rep., 2005, 22, 627; c) J. P. Michael, Nat. Prod. Rep., 2004, 21,

650.



[8] G. M. Coppola, J. heterocycl. Chem. 1985, 22, 1087.

[9] J. Reisch, G. M. K. B. Gunaherath, Monatsh. Chem. 1988, 119, 1169.

[10] P. Bhattacharya, B. K. Chwdhury, Phytochemistry, 1985, 24, 634.

[11] a) Y. Tagawa, T. Kawaoka, Y. Goto, J. Heterocycl. Chem. 1997, 34, 1677;

b) T. S. Wu, F. C. Chang, P. L. Wu, Phytochemistry, 1995, 39, 1453.

[12] a) J. A. Bosson, M. Rasmussen, E. Ritchie, A. V. Robertson, W. C. Taylor,

Australian J. Chem., 1963, 16, 480; b) G. Brader, G. Wurz, H. Greger, O.

Hofer, Liebigs Ann. Chem., 1993, 355-358; c) R. F. C. Brown, J. J.

Hobbs, G. K. Hughes, E. Ritchie, Australian J. Chem., 1954, 7, 348.

[13] a) M. F. Grudon, V. N. Ramachandran, B. M. Sloan, Tetrahedron Lett.,

1981, 22, 3105; b) S. Mitaku, A. L. Skaltsounis, F. Tillequin, M. Koch, J.

G. Chauvier, J. Nat. Prod., 1985, 48, 772; c) A. Ulubelen, Photochemistry,

1985, 24, 372.

[14] J. Reisch, M. Iding, Monatsh. Chem., 1989, 120, 363.

[15] P. R. Kym, M. E. Kort, M. J. Coghlan, J. L. Moore, R. Tang, J. D.

Ratajczyk, D. P. Larson, S. W. Elmore, J. K Pratt, M. A. Stashko, H. D.

Falls, C. W. Lin, M. Nakane, L. Miller, C. M. Tyree, J. N. Miner, P. B.

Jacobson, D. M. Wilcox, P. Nguyen, B. C. Lane, J. Med. Chem. 2003, 46,

1016-1030;

[16] S. W. Elmore, M. J. Coghlan, D. D. Anderson, J. K. Pratt, B. E. Green, A.

X. Wang, M. A. Stashko, C. W. Lin, C. M. Tyree, J. N. Miner, P. B.

Jacobson, D. M. Wilcox, B. C. Lane, J. Med. Chem. 2001, 44, 4481-

4491.



[17] a) L. Savini, L. Chiasserini, C. Pellerano, W. Filippelli, G. Falcone,

Farmaco 2001, 56, 939-945; b) S. Falk, R. Goggel, U. Heydasch, F.

Brasch, K. M. Muller, A. Wendel, S. Uhlig, Am. J. Resp. Crit. Care 1999,

160, 1734-1742.

[18] a) Y. L. Chen, K. C. Fang, K. J.-Y. Sheu, S. L. Hsu, C. J. Tzeng, Med.

Chem. 2001, 44, 2374–2377; b) G. Roma, M. D. Braccio, G. Grossi, F.

Mattioli, M. Ghia, Eur. J. Med. Chem. 2000, 35, 1021–1035.

[19] a) M. P. Maguire, K. R. Sheets, K. McVety, A. P. Spada, A. Zilberstein, J.

Med. Chem. 1994, 37, 2129–2137; b) O. Bilker, V. Lindo, M. Panico, A.

E. Etiene, T. Paxton, A. Dell, M. Rogers, R. E. Sinden, H. R. Morris,

Nature 1998, 289–292.

[20] a) P. Narender, U. Srinivas, M. Ravinder, B. A. Rao, C. Ramesh, K.

Harakishore, B. Gangadasu, U. S. N. Murthy, V. Rao, V. J. Bioorg. Med.

Chem. 2006, 14, 4600-4609.

[21] a) B. S. Holla, K. N. Poojary, B. Poojary, K. S. Bhat, N. S. Kumari, Indian

J. Chem. B 2005, 44, 2114-2119; b) A. K. Sadana, Y. Mirza, K. R. Aneja,

O. Prakash, Eur. J. Med. Chem. 2003, 38, 533-536.

[22] a) R. N. Kumar, T. Suresh, P. S. Mohan, Indian J. Chem. B 2003, 42,

688-689; b) M. Kidwai, K. R. Bhushan, P. Sapra, R. K. Saxena, R. Gupta,

R. Bioorg. Med. Chem. 2000, 8, 69-72.

[23) a) M. Fujita, K. Chiba, Y. Tominaga, K. Hino, Chem. Pharm. Bull. 1998,

46, 787-796; b) M. G. Kayirere, A. Mahamoud, J. Chevalier, J. C. Soyfer,

A. Cremieux, J. Barbe, Eur. J. Med. Chem. 1998, 33, 55-63.

[24] a) P. Narender, U. Srinivas, M. Ravinder, B. A. Rao, C. Ramesh, K.

Harakishore, B. Gangadasu, U. S. N. Murthy, V. J. Rao, Bioorg. Med.



Chem. 2006, 14, 4600; b) B. S. Holla, K. N. Poojary, B. Poojary, K. S.

Bhat, N. S. Kumari, Indian J. Chem. B 2005, 44, 2114;

[25] a) A. K. Sadana, Y. Mirza, K. R. Aneja, O. Prakash, Eur. J. Med. Chem.

2003, 38, 533; b) R. N. Kumar, T. Suresh, P. S. Mohan, Indian J. Chem.

B 2003, 42, 688.

[26] a) A. G. Tempone, A. C. M. P. da Silva, C. A. Brandt, F. S. Martinez, S. E.

T. Borborema, M. A. B. da Silveira, H. F. de Andrade, Antimicrob. Agents

Chemother. 2005, 49, 1076-1080; b) X. Franck, A. Fournet, E. Prina, R.

Mahieux, R. Hocquemiller, B. Figadere, Bioorg. Med. Chem. Lett. 2004,

14, 3635-3638.

[27] N. P. Sahu, C. Pal, N. B. Mandal, S. Banerjee, M. Raha, A. P. Kundu, A.

Basu, M. Ghosh, K. Roy, S. Bandyopadhyay, Bioorg. Med. Chem. 2002,

10, 1687-1694;

[28] a) E. Chiari, A. B. Oliveira, M. A. F. Prado, R. J. Alves, L. M. C. Galvão, F.

G. Araujo, Antimicrob. Agents Chemother. 1996, 40, 613-615, b) A.

Fournet, A. A. Barrios, V. Munoz, R. Hocquemiller, A. Cave, J. Bruneton,

Antimicrob. Agents Chemother. 1993, 37, 859-863.

[29] a) A. A.Joshi, C. L. Viswanathan, Bioorg. Med. Chem. Lett. 2006, 16,

2613-2617; b) A. A. Joshi, S. S. Narkhede, C. L. Viswanathan, Bioorg.

Med. Chem. Lett. 2005, 15, 73-76; c) C. Portela, C. M. M. Alfonso, M. M.

M. Pinta, M. J. Ramos, Bioorg. Med. Chem. 2004, 12, 3313.

[30] a) G. S. Dow, M. L. Koenig, L. Wolf, L. Gerena, M. Lopez-Sanchez, T. H.

Hudson, A. K. Bhattacharjee, Antimicrob. Agents Chemother. 2004, 48,

2624-2632.



[31] a) J. Ziegler, R. Linck, D. W. Wright, Curr. Med. Chem. 2001, 8, 171-189;

b) O. Billker, V. Lindo, M. Panico, A. E. Etienne, T. Paxton, A. Dell, M.

Rogers, R. E. Sinden, H. R. Morris, Nature 1998, 392, 289-292.

[32] a) F. M. D. Ismail, M. J. Dascombe, P. Carr, S. A. M. Merette, P.

Rouault, J. Pharm. Pharmacol. 1998, 50, 483-492; b) M. L. Go, T. L.

Ngiam, A. L. C. Tan, K. Kuaha, P. Wilairat, Eur. J. Pharm. Sci. 1998, 6,

19-26.

[33] a) H. Heitsch, Curr. Med. Chem. 2002, 9, 913-928; b) C. Buccellati, F.

Fumagalli, S. Viappiani, G. Folco, G. Farmaco 2002, 57, 235-242; c) D.

Dube´, M. Blouin, C. Brideau, C. C.Chan, S. Desmarais, D. Ethier, J. P.

Falgueyret, R. W. Friesen, M. Girard, Y. Girard, J. Guay, D. Riendeau, P.

Tagari, R. N. Young, Bioorg. Med. Chem. Lett. 1998, 8, 1255-1260.

[34] a) A. Nayyar, A. Malde, R. Jain, E. Coutinho, Bioorg. Med. Chem. 2006,

14, 847; b) A. Nayyar, R. Jain, Curr. Med. Chem. 2005, 12, 1873; c) V.

Monga, A. Nayyar, B. Vaitilingam, P. B. Palde, P. B. Jhamb, S. S. Kaur,

P. P. Singh, R. Jain, Bioorg. Med. Chem. 2004, 12, 6465.

[35] a) S. Vangapamdu, M. Jain, R. Jain, S. Kaur, P. P. Singh, Bioorg. Med.

Chem. 2004, 12, 2501-2508; b) R. Jain, B. Vaitilingam, A. Nayyar, P. B.

Palde, Bioorg. Med. Chem. Lett. 2003, 1051-1054.

[36] (a) P. Camps, E. Gómez, D. Muňoz-Torrero, A. Badia, N. M. Vivas, X.

Barril, M. Orozco, F. J. Luque, J. Med. Chem. 2001, 44, 4733-4736; b) P.

Camps, R. El Achab, J. Morral, D. Muňoz-Torrero, A. Badia, J. E. Baňos,

N. M. Vivas, X. Barril, M. Orozco, F. J. Luque, J. Med. Chem. 2000, 43,

4657-4666; c) T. Suzuki, T. Usui, M. Oka, T. Suzuki, T. Kataoka, Chem.

Pharm. Bull. 1998, 46, 1265-1273.

[37] a) N. Muruganantham, R. Sivakumar, N. Anbalagan, V. Gunasekaran, J.

T. Leonard, Biol. Pharm. Bull. 2004, 27, 1683-1687, b) R. H. Bradbury,



C. P. Allott, M. Dennis, J. A Girdwood, P. W. Kenny, J. S. Major, A. A.

Oldham, A. H. Ratcliffe, J. E. Rivett, D. A. Roberts, P. J. Robins, J. Med.

Chem. 1993, 36, 1245-1254.

[38] a) S. Rossiter, J. M. Peron, P. J. Whitfield, K. Jones, Bioorg. Med. Chem.

Lett. 2005, 15, 4806-4808; b) B. Kalluraya, S. Sreenivasa, Farmaco

1998, 53, 399-404.

[39] a) X. Franck, A. Fournet, E. Prina, R. Mahieux, R. Hocquemiller, B.

Figadere, Bioorg. Med. Chem. Lett. 2004, 14, 3635; b) C. Bénard, F.

Zouhiri, M. Normand-Bayle, M. Danet, D. Desmaële, H. Leh, J. F.

Mouscadet, G. Mbemba, C. M. Thomas, S. Bonnenfant, M. Le Bret, J.

d’Angelo, Bioorg. Med. Chem. Lett. 2004, 14, 2473.

[40] a) M. A. Fakhfakh, A. Fournet, E. Prina, J. F. Mouscadet, X. Franck, R.

Hocquemiller, B. Figadere, Bioorg. Med. Chem. 2003, 11, 5013-5023.

[41] a) A. Fournet, R. Mahieux, M. A. Fakhfakh, X. Franck, R. Hocquemiller,

B. Figadere, Bioorg. Med. Chem. Lett. 2003, 13, 891-894; b) F. Zouhiri,

D. Desmaele, J. d'Angelo, M. Ourevitch, J. F. Mouscadet, H. Leh, M. Le

Bret, Tetrahedron Lett. 2001, 42, 8189-8192.

[42] a) A. Tsotinis, M. Vlachou, S. Zouroudis, A. Jeney, F. Timar, D. E.

Thurston, C. Roussakis, Lett. Drug Des. Discov. 2005, 2, 189-192; b) A.

R. Martirosyan, R. Rahim-Bata, A. B. Freeman, C. D. Clarke, R. L.

Howard, J. S. Strobl, Biochem. Pharmacol. 2004, 68, 1729-1738.

[43] a) A. Perzyna, F. Klupsch, R. Houssin, N. Pommery, A. Lemoine, J. P.

Hénichart, Bioorg. Med. Chem. Lett. 2004, 14, 2363-2365; b) A. H. Abadi,

R. Brun, Arzneimittel-Forsch. 2003, 53, 655-663; c) J. Charris, P.

Martinez, J. Dominguez, S. Lopez, J. Angel, G. Espinoza, Heterocycl.

Commun. 2003, 9, 251-256.



[44] a) C. Lamazzi, S. Leonce, B. Pfeiffer, P. Renard, G. Guillaumet, C. W.

Rees, T. Besson, Bioorg. Med. Chem. Lett. 2000, 10, 2183-2185; b) J.

Osiadacz, L. Kaczmarek, A. Opolski, J. Wietrzyk, E. Marcinkowska, K.

Biernacka, C. Radzikowski, M. Jon, W. Peczynska-Czoch, Anticancer Res.

1999, 19, 3333-3342.

[45] a) L. Kaczmarek, W. Peczynska-Czoch, J. Osiadacz, M. Mordarski, W. A.

Sokalski, J. Boratynski, E. Marcinkowska, H. Glazman-Kusnierczyk, C.

Radzikowski, Bioorg. Med. Chem. Lett. 1999, 7, 2457-2464; b) W.

Peczynskaczoch, F. Pognan, L. Kaczmarek, J. Boratynski, J. Med. Chem.

1994, 37, 3503-3510.

[46] R. Kimmel, S. Kafka, J. Košmrlj, Carbohydrate Research, 2010, 345,

768-779.

[47] I. Ishiguro, T. Ikeno, H. Matsubara, Yakugaku Zasshi, 1974, 94, 116–

123; Chem. Abstr. 1974, 80, 118417.

[48] a) K. Tateishi, H. Shibata, Y. Matsushima, T. Iijima, Agric. Biol. Chem.

1987, 51, 3445–3447; b) K. Tateishi, Y. Matsushima, H. Shibata, Agric.

Biol. Chem. 1989 53, 2545–2551; c) H. Shibata, T. Nanbu, K. Tateishi, S.

Shimizu, Agric. Biol. Chem. 1989, 53, 849–850.

[49] a) Y.–F. Su, Y. Luo, C.-Y. Guo, D.-A. Guo, J. Asian Nat. Prod. Res. 2004,

6, 223–227; b) J. P. Michael, Nat. Prod. Rep. 2007, 24, 223–246; c) V. M.

Dembitsky, Lipids 2005, 40, 1081–1105.

[50] a) K. A. Rasulova, I. A. Bessonova, M. R. Yagudaev, S. Y. Yunusov, Khim.

Prirod. Soed. 1987, 6, 876–879; b) V. I. Akhmedzhanova, K. A. Rasulova,

I. A. Bessonova, A. S. Shashkov, N. D. Abdullaev, L. Angenot, Chem. Nat.

Compd. 2005, 41, 60–64.



[51] J. N. Smith, Biochem. J. 1953, 55, 156–160; b) J. N. Smith, R. T.

Williams, Biochem. J. 1954, 56, 325–329; c) J. N. Smith, R. T. Williams,

Biochem. J. 1955, 60, 284–290.

[52] a) C. Baglioni, P. Fasella, C. Turano, N. Siliprandi, Biochem. J. 1960, 74,

521–525, b) L. T. Burka, J. M. Sanders, H. B. Matthews, Xenobiotica

1996, 26, 597–611.

[53] a) H. Suzuki, H. Igarashi, I. M. Igarashi, I. Tanaka, N. Suzuki, Jpn. Kokai

Tokyo Koho JP 2006056872, 2006; Chem. Abstr. 2006, 144, 205733; b)

H. Suzuki, N. S. M. Aly, Y. Wataya, H.-S. Kim, I. Tamai, M. Kita, D.

Uemura, Chem. Pharm. Bull. 2007, 55, 821–824.

[54] T. Nógrádi, L. Vargha, G. Ivánovics, I. Koczka, Acta Chim. Acad. Sci.

Hung. 1955, 6, 287–293.

[55] H. Takagaki, S. Nakanishi N. Kimura, S. Yamaguchi, Y. Aoki, Eur. Pat.

Appl. EP 1999, 933378, Chem. Abstr. 1999, 131, 116454. 18.

Hirayama, B. A.; Diez-Sampedro, A.; Wright, E.

[56] a) E. Ziegler, H. Junek, Monatsh. Chem. 1956, 87, 503; b) E. Ziegler, R.

Wolf, T. Kappe, Monatsh. Chem. 1965, 96, 418.

[57] C. M. Mehta, G. H. Patel, J. Ind. Res.(India), 1959, 18B, 391.

[58] T. Kappe, A. S. Karem, W. Stadlbauer, J. Heterocycl. Chem., 1988, 25,

857-862.

[59] W.-T. Gao, W.-D. Hou, M.-R. Zheng, L.-J. Tang, Synth. Commun. 2010,

40, 732-738.

[60] L. H. Reyrson, K. Kobe, Chem. Rev., 1930, 7, 479.



[61] A. Omori, N. Sonoda, S. Tsutsumi, Bull. Chem. Soc. Jpn., 1970, 43,

1135-1138.

[62] G. M. Coppola, J. Heterocycl. Chem., 1985, 22, 1087.

[63] G. M. Coppola, G. E. Hardtmann, J. Heterocyl. Chem., 1979, 16, 1605.

[64] a) L. A. Mitscher, H. E. Gracey, G. W. Clark, T Suziki, J. Med. Chem.,

1978, 21, 485; b) L. A. Mitscher, D. L. Flynn, H. E. Gracey, S. D. Drake,

J. Med. Chem., 1979, 22, 1354.

[65] M. R. Bell, A. W. Zalay, R. Oesterlin, P. Shane, G. O. Potts, J. Med.

Chem., 1970, 13, 664.

[66] D. R. Shridar, C. V. Reddy Sastry, A. K. Mehrotra, c. Seshagiri Rao, V.

Taneja, India J. Chem., 1979, 17b, 488.

[67] K. Tsuji, G. W. Spears, K. Nakamura, T. Tojo, N. Seki, A. Sugiyama, M.

Matsuo, Bioorg. Med. Chem. Lett., 2002, 12, 85-88.

[68] G. M. Coppola, G. E. Hardtmann, O. R. Pfister, J. Org. Chem., 1976, 41,

825-831.

[69] Farbenfabrik Hoechst, D. R. P. 102, 894; Chem. Zblt., 1899, I, 462.

[70] Badische Anilin- und Sodafabrik, D. R. P. 117, 167; Chem. Zblt., 1901, I,

236.

[71] a) Z. H. Skraup, Monatsh. Chem., 1880, 1, 316; b) R. H. F. Manske,

Chem. Rev., 1942, 30, 113.

[72] H. T. Clarke, A. W. Davis, Org. Synth. 1941, 1, 478.



[73] ]I. L. Finar, Org. Chem., 1973, 1, 857.

[74] a) O. Doebner, O.; W. v. Miller, Ber. Dtsch. Chem. Ges 1881, 14, 2812.,

b) O. Doebner, O.; W. v. Miller, Ber. Dtsch. Chem. Ges 1883, 16, 1664 & 2464;

c) O. Doebner, O.; W. v. Miller, Ber. Dtsch. Chem. Ges.,1884, 17, 1712; d F. W.

Bergström, Chem. Rev. 1944, 35, 153. (Review).

[75] a) A. Combes, Bull. Chim. Soc. France 1888, 49, 89; b) F. W. Bergstrom

Chem. Rev., 1944, 35, 156 (Review).

[76] a) C.-S. Jia, Z. Zhang, S.-J. Tu, G.-W. Wang, Org. Biomol. Chem., 2006,

4, 104-110; b) J. Wu, H.-G. Xia, K. Gao, Org. Biomol. Chem., 2006, 4,

126-129; c) R. Martínez, D. J. Ramón, M. Yus, J. Org. Chem., 2008, 73,

9778-9780; d) J. S. Yadav, B. V. S. Reddy, P. Sreedhar, R. S. Rao, K.

Nagaiah, Synthesis, 2004, 2381-2385.

[77] a) R. Varala, R. Enugala, S. R. Adapa, Synthesis, 2006, 3825-3830; b) S.

S. Palimkar, S. A. Siddiqui, T. Daniel, R. J. Lahoti, K. V. Srinivasan, J.

Org. Chem., 2003, 68, 9371-9378; c) P. G. Dormer, K. K. Eng, R. N. Farr,

G. H. Humphrey, J. C. McWilliams, P. J. Reider, J. W. Sager, R. P.

Volante, J. Org. Chem., 2003, 68, 467-477.

[78] W. Pfitzinger, W. J. Prakt. Chem. 1886, 33, 100; b) W. Pfitzinger, J. Prakt.

Chem. 1888, 38, 582.

[79] O. A. Ponomarev, E. R. Vasina, V. G. Mitina, A. A. Sukhorukov, Zh. Fiz.

Khim., 1990, 64, 974.

http://en.wikipedia.org/w/index.php?title=J._Prakt._Chem.&action=edit&redlink=1





[80] a) J. Chen, P. R. Selvin, J. Photobiol. 2000, 135A, 27-32; b) C. Marzano,

A. Chilin, A. Guitto, F. Baccichetti, F. Carlassare, F. Bordin, Farmaco

2000, 55, 650-658; c) G. Saroja, N. B. Samanta, Chem. Phys. Lett. 1996,

249, 392-398; d) M. Li, P. R. Selvin, J. Am. Chem. Soc. 1995, 117, 8132-

8138; e) R. Nakagaki, N. Kitamura, I. Aoyama, H. Ohtsubo, J. Photochem.

Photobiol. 1994, A80, 113-119.

[81] a) O. A Ponomarev, Yu F. Pedash, O. V. Prezhdo, Zh. Fiz. Khim. 1991, 65,

1846-1850; b) O. A. Ponomarev, E. R. Vasina, S. N. Zarmolenko, V. G.

Mitina, N. S. Pivnenko, Zhurn. Obshch. Khim. 1990, 60, 1161-1170; J

Gen. Chem. USSR. (Transl. Plenum Pub. Corp.) 1990, 60, 1035-1042.

[82] A. Lobnik, N. Majcen, K. Niederreiter, G. Uray, Sensors and Actuatrors B

2001, 74, 200-2056.

[83] a) W. M. F. Fabian, K. S. Niederreiter, G. Uray, W. Stadlbauer J. Mol.

Structure, 1999, 477, 209-220; b) G. A. Strohmeier, W. M. F. Fabian, G.

Uray, Helv. Chim. Acta, 2004, 87, 215-226; c) G. Uray, K. H. Niederreiter,

F. Belaj, W. M. F. Fabian, Helv. Chim. Acta, 1999, 82, 1408-1417.

[84] a) J. R. Lakowicz, Principles of Fluorescence Spectroscopy 3 rd Ed. 2006,

New York: Springer, XXVI, 954 p;

b) http://www.invitrogen.com/site/us/en/home/References/Molecular-

Probes-The-Handbook/Introduction-to-Fluorescence-Techniques.html.

[85] K. E. Sapsford, L. Berti, I. L. Medintz, Angew. Chem., Int. Ed. 2006, 45,

4562.

[86] R. A. Kramer, R. Flehr, M. Lay, M. U. Kumbe, W. Bannwarth, Helv. Chim.

Acta., 2009, 92, 1933-1943.

[87] T. Förster, Ann., Phys., 1948, 2, 55.

http://www.invitrogen.com/site/us/en/home/References/Molecular-%20%20%20Probes-The-Handbook/Introduction-to-Fluorescence-Techniques.html

http://www.invitrogen.com/site/us/en/home/References/Molecular-%20%20%20Probes-The-Handbook/Introduction-to-Fluorescence-Techniques.html



[88] G. Uray, Sallegger, unpublished results.

[89] S. Tyagi, F. R. Kramer, Nat. Biotechnol., 1996, 14, 303-308.

[90] P. M. Holland, R. D. Abramson, R. Waston, D. H. Gelfand, Proc. Nat.

Acad. Sci. U. S. A., 1991, 88, 7276-7280.

[91[ E. K. Kainmüller, E. P. Ollé, W. Bannwarth, Chem. Commun., 2005,

5459-5461.

[92] A. Cuppoletti, C. Younjin, P. Jin-Seong, C. Strässler, E. T. Kool,

Bioconjugate Chem., 2005, 16, 528-534.

[93] B. Wetlz, M. Gruber, B. Oswald, A. Dürkop, B. Weidgans, M. Probst, O.

Wolfbeis, J. Chromatogr. B 2003, 793, 83-92.

[94] S. J. Danishefsky, J. R. Allen, Angew. Chem., Int. Ed. 2000, 39, 836-863.

[95] J. Fernandez-Carteado, M. J. Kogan, S. Castel, E. Giralt, Angew. Chem.,

Int. Ed. 2004, 43, 1811-1814.

[96] R. David, Z. Machova, A. G. Beck-Sickinger, Biol. Chem., 2003, 384,

1619-1639.

[97] M.-P. Faure, P. Gaudreau, I. Shaw, N. R. Cashman, A. Beaudet, J.

Histochem. Cytochem., 1994, 42, 755-763.

[98] S. Fuchs, H. Otto, S. Jehle, P. Henklein, A. D. Schüter, Chem. Commun.

2005, 1830-1832.

[99] V. J. Mayo, J. Prabhakaran, J. J. Mann, J. S. D. Kumar, Tetrahedron

Lett. 2003, 44, 8535-8537.



[100] F. A. Bennett, D. J. Barlow, A. N. O. Dodoo, R. C. Hider, A. B. Lansley,

M. J. Lawrence, C. Marriott, S. S. Bansal, Anal. Biochem., 1999, 270,

15-23.

[101] a) K. R. Romines, J. K. Morris, W. J. Howe, P. K. Tomich, M.-M. Horng,

K.-T. Chong, R. R. Hinshaw, D. J. Anderson, J. W. Strohbach, S.-R.

Turner, S. A. Miszak, J. Med. Chem. 1996, 39, 4125-4130; b)

Coumarins–Biology, Applications and Mode of Action (Eds.: R.

O×Kennedy, R. D. Thornes), Wiley, Chichester, 1997.

[102] a) R. Raue in Ullmannns Encyclopedia of Industrial Chemistry, Vol. A15,

5thed. (Eds.: B. Elvers, S. Hawkins, G. Schulz), VCH, Weinheim, 1990,

pp. 155-157; b) R. S. Koefod, K. R. Mann, Inorg. Chem. 1989, 28, 2285-

2290.

[103] a) P. D. Edwards, R. C. Mauger, K. M. Cottrell, F. X. Morris, K. K. Pine,

M. A. Sylvester, C. W. Scott, S. T. Furlong, Bioorg. Med. Chem. Lett.

2000, 10, 2291-2294; b) M. Adamczyk, M. Cornwell, J. Huff, S. Rege, T.

V. S. Rao, Bioorg. Med. Chem. Lett. 1997, 7, 1985-1988; c) C. A. M.

Seidel, A. Schulz, M. H. M. Sauer, J. Phys. Chem. 1996, 100, 5541-

5553.

[104] a) A. Adronov, S. L. Gilat, J. M. Fre¬ chet, K. Ohta, F. V. R. Neuwahl, G.

R. Fleming, J. Am. Chem. Soc. 2000, 122, 1175-1185; b) K. H.

Shaughnessy, P. Kim, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 2123-

2132.

[105] a) J. Kido, Y. Lizumi, Appl. Phys. Lett. 1998, 73, 2721-2723; b) A. Niko,

S. Tasch, F.Meghdadi, C. Brandstätter,G. Leising, J. Appl. Phys. 1997,

82, 4177-4182; c) S. Tasch, C. Brandstätter, F. Meghdadi, G. Leising, G.

Froyer, L. Athouel, Adv. Mater. 1997, 9, 33-36.



[106] A. E. Siegrist, H. Hefti, H. R. Meyer, E. Schmidt, Rev. Prog. Coloration

1987, 17, 39-55.

[107] M. J. V. Reddington, J. Chem. Soc., Perkin Trans. 1, 1998, 143-147.

[108] a) J. Hynes, T. C. O'Riordan, A. V. Zhdanov, G. Uray, Y. Will, D. B.

Papkovsky, Analyt. Biochemistry, 2009, 390, 21-28, b) Ribitsch; Uray,

unpublished results.

[109] a) L. Seveus, M. Vaisala, S. Syrjanen, M. Sandberg, A. Kuusito, R. Harju,

J. Salo, I. Hmmila, H. Kojola, E. Soini, Cytometry, 1992, 13, 329-335; b)

L. Seveus, M. Vaisala, I. Hemmilä, H. Kojola, E. Soini, Microsc. Res.

Technol. 1994, 28, 149-153.

[110] P. R. Selvin, T. M. Rana, J. E. Hearst, J. Am. Chem. Soc., 1994, 116,

6029-6032.

[111] A. Lobnik, N. Majcen, K. Niederreiter, G. Uray, Sens. and Actuators B,

2001, 74, 200-206.

Chapter 1: SYNTHESIS AND REACTIVITY OF 4-HYDROXY-6- AND 7-METHOXYQUINOLIN-2(1H)-ONES 38


CHAPTER 1

SYNTHESIS AND REACTIVITY OF 4-HYDROXY-

6- AND 7-METHOXYQUINOLIN-2(1H)-ONES



Chapter 1: SYNTHESIS AND REACTIVITY OF 4-HYDROXY-

6- AND 7-METHOXYQUINOLIN-2(1H)-ONES

1.1. INTRODUCTION

4-Hydroxyquinolin-2(1H)-one and 4-hydroxycoumarin derivatives are

naturally occurring biologically active compounds [1, 2]. The key step in our

overall synthetic scheme is methoxyquinolin-2(1H)-ones of type 3 having the

hydroxide group in position 4. These heterocycles are useful intermediates for

many industrial products such as dyes [3, 4], herbicides [5, 6] and anticancer

agents [7].

On the other hand the 4-hydroxy group of the 2-quinolone moiety can

easily be substituted by various nucleophiles and converted to reactive

derivatives such as 4-chloroquinolines 6, or 4-azido-2-quinolones [8], which

are suitable precursors for further syntheses. For instance, exchange of the 4-

hydroxy group in 4-hydroxyquinolin-2(1H)-one against the arylthio moiety

leads to compounds with potent HIV-1 reverse transcriptase inhibitory

properties [9]. 4-Hydroxyquinolone derivatives of type 3 are important

biosynthetic [10] and synthetic [11] precursors of quinoline alkaloids.

1.2. RESULTS AND DISCUSSION

1.2.1 . Cyclocondensation of p-anisidin 1 and malonic acid 2 to

4-hydroxy-6-methoxyquinolin-2(1H)-one 3 as precursor.

The synthesis of 4-hydroxyquinolones was first described in 1923

starting from quinoline by heating with potassium hydroxyde to 225 °C under

anhydrous conditions [12].



Recently, Gao et al. [13] reported a one-pot formation of 4-hydroxy-6-

methoxyquinolin-2(1H)-one from Meldrum’s acid and p-anisidin using

phosphoric anhydride/methanesulfonic acid as cyclization agent. However,

this method gave a moderate yield of 61 %. Recently, it could be shown [14,

15] that 3-acyl-4-hydroxy-2-quinolones could be readily converted to 3-acyl-4-

azido-2-quinolones and further cyclized to isoxazoles.

The presented synthetic procedure using phosphoryl chloride as both

reagent and solvent is a convenient, simple and fast alternative for

synthesizing 4-hydroxyquinolin-2(1H)-one derivatives.

NH2

O

CH3

COOH

COOH

N

OH

O

H

O

CH3

N

N

O

O H

H

OCH

3

OCH

3

POCl3

+

1 2

95 °C, 90 min.

+

73 % 19 %

4

Scheme 1

Malonic acid 2 is not reactive enough to react with dinucleophile 1 [16].

However, conversion of malonic acid in situ with phosphoryl chloride [17a]

gave the corresponding reactive acid chloride, which was treated with p-

anisidine similar as described in ref. [17b] to give 3 in 63 % yield besides the

by-product 4 in 32 %.



1.2.1.1. Optimization of the reaction

In order to optimize the reaction, several methods were attempted:

increasing of the equivalents of p-anisidine or malonic acid, longer reaction

time, direct dissolution of the raw product in aqueous sodium hydroxide; in all

cases the overall yield of the compound 3 was between 41-63 %. It was found

that, large excess of phosphoryl chloride should be avoid in order to prevent

subsequent reaction between phosphoryl chloride with the 4-hydroxy group

and the 2-oxo group of the formed 4-hydroxyquinolone 3 [18].

Best results were obtained at temperatures in the range of 90-95 °C for

1.5 hour and following reaction work-up with ice/water. Dissolving the crude

product into large excess of sodium hydroxide (1 M, 1000 mL) allowed the

isolation of product 3 in 73 % yield as well as 19 % of the dianilide by-product

4.



1.2.1.2. Proposed mechanism of the formation of 4-hydroxy-6-

methoxyquinolin-2(1H)-one 3

Scheme 2



1.2.1.3. Proposed mechanism of the formation of dianilide 4

Scheme 3

1.2.1.4. Structural elucidation : IR and 1H-NMR spectroscopy

study of compounds 3 and 4

Compounds 3 and 4 were characterized by infrared and 1H-NMR spectra.

The infrared spectrum of compound 3 showed a medium band in the region of

3434-3290 cm-1, ascribable to the vibration of NH and a carbonyl band at 1663

cm-1 confirming the presence the lactam function. The 1H-NMR spectrum of 3

revealed a singlet at 5.79 ppm for C-3 proton. It should be noted that the

corresponding NH group in amines, amides and/or lactams also exhibit

hydrogen bonding NMR shifts although to a lesser degree. Furthermore, OH

and NH groups can undergo rapid proton exchange with each signal at an

average chemical shift and often only one of them could be observed. The

sharp singlet at 11.08 ppm was assigned to NH.



Infrared spectrum of dianilide 4 exhibited the absorption bands at 1655

cm-1 and 1620 cm-1 ascribable to carbonyls groups and a broad NH absorption

at 3435 cm-1. The 1H-NMR spectrum of 4 showed two doublets at 6.88 ppm

and 7.45 ppm typical of the para-substituted patterns of benzene ring, a

singlet at 3.49 ppm was due to the methylene proton.

1.2.2. Chlorination of 4-hydroxyquinolone 3 to 2,4-

dichloroquinoline 5 and 4-chloroquinolone 6

Survey of the literature showed that the quinoline moiety is an important

class of various pharmacologically active compounds and is present in many

biologically active natural products, particularly in alkaloids [20a-c] as outlined

in the general introduction. The quinoline scaffold display an important role as

intermediate in the synthesis of fluorescence compounds such as 2-

aminoquinolines and 2-amino-arylpeptides quinoline [21].

In order to prepare 4-chloro-6-methoxyquinolone 6, 4-hydroxy-6-

methoxyquinolone 3 was refluxed in excess amount of phosphoryl chloride for

8 hours to provide 83 % yield of 2,4-dichloroquinoline 5. The latter was then

regioselectively converted into 4-chloro-2-oxo-quinoline 6 in excellent yield of

95 % by reaction with 70 % methanesulfonic acid in ethanol; selective

monochlorination in position 4 of the N-1 unsubstituted quinolin-2(1H)-one 3

was not possible.



N

OH

O

H

O

CH3

POCl3

N

Cl

Cl

O

CH3

N

Cl

O

H

O

CH3CH

3SO

3H / EtOH

73 %

3

reflux, 8 h83 %

reflux, 28 h

95 %

5 6

Scheme 4

1.2.2.1. Study of Infrared and 1H-NMR Spectra of 5 and 6

Comparison of spectral data of compound 5 and 6 showed that the

infrared spectrum of 5 did not exhibit the carbonyl band, which was present in

the compound 6 at 1623 cm-1. In the 1H-NMR spectrum of 5, the signal of NH

proton was not observed, which is present in the compound 6. However, the

signal of C-3 proton appeared at 7.92 ppm for the compound 5 due to the

strong electronegativity of an additional chlorine in position 2, and in

compound 6 this signal was shifted up field at 6.82 ppm.



1.2.2.2. 13C-NMR spectrum of 4-chloro-6-methoxyquinolin-

2(1H)-one 6

The 13C-NMR spectrum of compound 6 was simple. The methoxy carbon

appeared at 56.0 ppm.

The carbon of the lactam function appeared at 160.4 ppm, those of

phenyl nuclei undergo different electronic effects of pyridine ring. Thus,

carbons 9-C and 10-C recognizable as carbon 2-C of lactam function by

their small size appeared at 133,6 ppm and 1178.2 ppm respectively.

The complete assignment of 4-chloro-6-methoxyquinolini-2(1H)-one 6 is

given below.

N

O

Cl

O

H

CH3

56.0

121.2

117.8133.6

160.4

106.3

143.8118.2121.7

155.1

Figure 1: 13C-NMR values of compound 6

The mass spectral and elemental analysis were in accordance to the

corresponding structure.

1.2.3. Introduction of cyano substituents into 4-chloro-6-


The synthesis of 2-chloroquinolin-4-carbonitrile and 4-chloroquinolin-2-

carbonitrile is described in the literature, however not via direct chloro

exchange [22]. So far, it is still a challenge to substitute a halide group of



benzene, pyridones, quinolones moieties or related compounds by nucleophilic

substitution against nitrile. Whereas C-C coupling in aromatic chemistry

follows in most cases the mechanism of electrophilic substitution, in

heterocyclic chemistry the nucleophilic substitution is preferred for the large

-deficient heterocycles such as pyridine and its related heterocycles

[23].

N O

Cl

H

O

CH3

N O

CN

H

CNO

CH3

6

KCN/ p-tol.sulfinate Na, DMF

140 °C, 43 h

64 %

6 7

(Pathway A)

Scheme 5

Survey of the literature shows that the introduction of a cyano group into

the similar 4-chloro-N-substituted quinolones of type 6 using cyanide anion,

cyanide or crown ether failed [23]. In early experiments [24], attempts to

introduce the cyano by using Rosenmund-Braun aromatic cyanation with

copper (I) cyanide in high-boiling solvents failed.

The use of p-toluenesulfinate as catalyst [25] or via heavy metal cyanides

such as zinc or copper cyanides [26] is described for the cyanide introduction

into chloro heterocycles. The reaction of similar compounds of type 6 with zinc

cyanide gave the corresponding 4-cyanoquinolones which were however

cumbersome to purify [23].

The introduction of the cyano group in position 3 and/or 4 of 4-

chloroquinolin-2(1H)-one 6 was carried out by reaction with dry potassium

cyanide using dry sodium p-toluenesulfinate in dry dimethylformamide as

recently described in our group [18] and [19], in continuation of early work on

the synthesis of highly fluorescent carbostyrils.



We wanted to prepare 4-cyanoquinolone from one equivalent of 4-

chloroquinolone 6 with 2.1 equivalents of dry potassium cyanide and 2.5

equivalents of dry sodium p-toluenesulfinate as a catalyst in dry

dimethylformamide as solvent. It should be noted that the reaction requires

strict anhydrous conditions. The mixture was heated to 110 °C, after 25 hours

reaction time, we obtained a mixture of two UV-active compounds, but very

difficult to separate and purify. This means, at 110 °C during 25 hours the

reaction involves an intermediate sulfinate and a cyano compound in the same

time. Thus, when a longer reaction time (43 hours) at 140 °C was used, a

single yellow-green fluorescence cyano carbostyril appeared, which could be

isolated. The structure was identified by spectroscopic and analytical methods.

According to the spectral data, infrared spectrum of compound 7 showed

the signal of cyano group at 2228 cm-1 and another signal at 1650 cm-1

ascribable to lactam carbonyl. Surprisingly, the assignment of 1H-NMR showed

that the C-3 proton was missing; it was also exchanged against the cyano

group visible from the mass spectrum and elemental analysis data. The NH

proton appeared at 13.08 ppm. The assignment of 13C-NMR showed the main

relevant carbons such as 2-C for the lactam carbonyl at 157.0 ppm, the 6-C

bonded to the methoxy group was observed at 156.1 ppm, and at 118.8 ppm,

almost the same value as described in the literature [20d] with benzonitrile,

probably two cyano carbons are in the same position because the intensity of

the signals is twice the usual size.

Crystallization of compound 7 from acetone gave single crystals that

were suitable for X-ray analysis, which confirmed the structure of 7. One can

think that the mechanism from 4-chloro-6-methoxyquinolin-2(1H)-one 6 to 6-

methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 7 proceeds via a

Meisenheimer type sulfinyl addidtion of p-toluene sulfinate in position 3,

followed by elimination of the 3-substituent.



Figure 2: Molecular structure of 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile 7 (ORTEP presentation).

1.2.4. Synthesis of 4-sulfinyloxyquinolin-2(1H)-one 8

The reaction of 4-chloroquinolone 6 into the reactive 4-

sulfinyloxyquinolone 8 was achieved according to procedure used in our group

[18] by treatment of 6 with sodium p-toluenesulfinate in dimethylformamide as

solvent. The reaction allowed the nucleophilic substitution of the sulfinate as

more reactive good leaving group in position 4 in good yields of 69 %.

N

Cl

H

O

O

CH3

N

H

O

OS

O

CH3

O

CH3

6

8

sodium p-toluene sulfinate, DMF 120 °C, 20 h

69 %

(Pathway A)

Scheme 6



1.2.4.1.Structure elucidation of 4-sulfinyloxyquinolin-2(1H)-one

8

The structural elucidation of 4-sulfinyloxyquinolone 8 was based on

spectral analyses. In the infrared spectrum, the lactam carbonyl stretching was

observed at 1667 cm-1. Assignment of all signals and H-H coupling constants

in 1H-NMR measurements encountered some difficulties due to the roof effect

[27] and also to the overlap between the carbon components, because of the

big number of aromatic rings in compound 8.

There is an overlap from 7.23 to 7.26 ppm between 3-H and 7-H, which

was not easy to distinguish the signal from each proton. Gratifyingly, the roof

effect technique allowed a conclusive assignment to be made. Thus, the signal

of 7-H appeared in singlet at 7.23 ppm, the signal of 3-H appeared in doublet

of doublets at 7.26 ppm (J = 9.0 Hz). At 7.33 ppm a doublet is accounted for 8-

H (J = 9.17 Hz). From 7.45 to 7.50 ppm, there was also another overlap

between 5-H and protons from aromatic substituent patterns HBB’ again with

the roof effect we could distinguished each of them. The signal of 5-H proton

appeared in doublet at 7.46 ppm (J = 2.8 Hz), the two protons HB and HB’ which

are equal were observed in doublet at 7.48 ppm (J = 8.2 Hz) and the doublet (J

= 8.2 Hz) corresponding to the protons HA’ and HA’ was shifted down at 7.96

ppm due to the influence of SO2 group, and the signal of NH-proton was

observed at 12.31 ppm.

N

O

OCH

3

O

H

SO

H7

H8

H5

H3

HB'

HA' HA

HB

CH3

Scheme 3: Structure of compound 8



1.2.4.2. 13C-NMR spectrum of 4-sulfinyloxyquinolin-2(1H)-one 8

The 13C-NMR of compound 8 exhibited aromatic peaks between 106.7

and 154.6 ppm and a peak at 159.8 ppm for the lactam carbon. The peaks of

two carbons CBB’ and for carbon 2-C appeared in the same position at 130.9

ppm, and the peaks of two aryl carbons CAA’ appeared also in the same position

at 136.2 ppm. However the intensities of the signals are 3 times and two times

respectively the usual size.

Mass spectrum showed with APCI negative method the base peak with

100 %. However, using ESI (electrospray ionization) mass spectral method,

additional signals could be observed which could be assigned as adducts of

compound 8. It showed only very few peaks: the ratio of intensities varies is

dependent on the fragmentor voltage: At 50 V, a base peak with the high mass

681 could be identified as the combination between 2 molecules carbostyril

and one sodium ion, [2M + Na+]. At 100V this peak is less intense but can still

easily identified (56 %) and the base peak is 352, identified as MNa+. MH+ is

typically of minor intensity, 11 % at 50 V and 15 % at 100 V fragmentor

voltage. Further the mass 368 can be identified as MK+, 7 % with fragmentor

50 V and 3 % with 100 V. In case of 4-sulfinyloxyquinolone 8, also an

additional cluster peak (mass 703) was found. We interpreted it as a double

molecule containing two sodium ions having lost a proton. The formation of

such adducts with alkali metal ions in ESI mass spectra were investigated

recently by Takayama [28].

1.2.5. Experiment to show the reaction pathway

The reaction of one equivalent of 4-sulfinyloxyquinolin-2(1H)-one 8 with

1.5 equivalent of dry potassium cyanide in dry dimethylformamide was carried

out by heating to 130 °C for 30 hours.



After worked up, the thin layer chromatography (TLC) analysis showed a

mixture of two compounds, which could not separated. Thus, we though there

could be two pathways to form 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile 7 from 4-sulfinyloxyquinolone 8, since the experiment from

compound 9 to compound 7 worked at about the same rate as experiment from

compound 8 to compound 7, most probably the rate determining step was

experiment from 8 to 9.

N

H

O

OS

O

CH3

O

CH3

N

H

O

CN

O

CH3

N

H

O

CN

CNO

CH3

8

97

KCN / DMF 70 °C, 5 h 67 %

KCN / DMF140 °C, 72 h58 %

Sodium p-toluene sulfinate, DMF 140 °C, 65 h

72 %

(Pathway B)(Pathway B)

(Pathway C)

KCN

Scheme 7

1.2.5.1. Cyanation of 4-sulfinyloxyquinolin-2(1H)-one 8 to 4-

cyanoquinolone 9 and 3,4-dicyanoquinolone 7

For the conversion into the intermediate 4-cyanoquinolone 9, one

equivalent of 4-sulfinyloxyquinolone 8 was treated with 3 equivalents of dry

potassium cyanide at 140 °C in dry dimethylformamide as solvent. The

exchange of sulfinate as reactive good leaving group against cyano at position 4



was complete after 5 hours reaction time, leading the compound 9, which was

then isolated, purified and characterized by analysis and spectroscopic

methods.

Infrared spectrum exhibited the most relevant signal for cyano at 2227

cm-1 and the signal corresponding for lactam carbonyl was observed at 1655

cm-1. The number of proton signals observed in the 1H-NMR spectrum and

their chemical shifts also supported the proposed structure; the most relevant

signals being a singlet at 8.68 ppm ascribable to C-3 proton and the singlet at

12.40 ppm for NH proton. In the 13C-NMR spectrum, the signals of aromatic

carbons were observed between 106.7 and 158.7 ppm, the most relevant were

observed at 118.7 ppm for cyano and at 158.7 ppm for lactam carbonyl.

The mass spectrum analysis showed with APCI ionization-negative method, the

base peak with 100 %, a weak peak (M-15) with 11 % intensity corresponding

to the loss of methyl group and another weak peak (M+1) with only 13 %,

which supported the proposed structure 9. The purification was found to be

difficult.

Comparison of 1H-NMR data of compounds 3, 6 and 9 having

respectively hydroxide, chloro and cyano at position 4 indicate that the

chemical shift of C-3 proton of compound 9 is more shifted down fields caused

by the greater electronegativity of cyano group position 4.

Then, one equivalent of the resulting 6-methoxy-2-oxo-1,2-

dihydroquinoline-4-carbonitrile 9 was subsequently converted into 6-methoxy-

2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 7 by reaction with 2.4

equivalents of dry sodium p-toluenesulfinate as catalyst and 3 equivalent of

dry potassium cyanide in dry dimethylformamide as solvent with 72 % of yield.

The substitution of hydrogen in position 3 of compound 9 was assumed.

The findings were confirmed by analytical and spectroscopic data (IR, 1H

and 13C-NMR, MS, and elemental analysis) similar to those obtained in chapter

1.2.3.



1.2.5.2. One-pot synthesis of 3,4-dicyanoquinolone from 4-

sulfinyloxyquinolone 8

To react the 4-sulfinyloxyquinolone 8 with dry potassium cyanide in this

way, 1:3 molar ratio of 8 and potassium cyanide, in dry dimethylformamide

was heated to 140 °C to give 3,4-dicyanoquinolone 7 after 72 hours reaction

time in moderate yield of 58 %. The structure was confirmed by spectroscopic

data.

1.2.6. One-pot reaction to 4-cyano-3-unsubstituted quinolone 9

The one-pot synthesis of 4-cyanoquinolone 9 could be achieved by

treatment of 4-chloroquinolone 6 with dry potassium cyanide using dry sodium

p-toluenesulfinate as catalyst. The reaction gave a mixture of 4-cyanoquinolone

9 and 4-sulfinyloxyquinolone 8 after 27 hours reaction time. The separation of

8 and 9 could be accomplished by simple recrystallization from freshly distilled

dioxane.

N

Cl

O

H

O

CH3

N O

H

CN

O

CH3

N O

H

O

O

CH3

SO

CH3

KCN / p-tol.sulfinate Na DMF, 130 °C, 27 h

85 %

6 9 8

+

(Pathway B)

Scheme 8



1.2.7. Chlorination reaction with sulfuryl chloride

Survey of the literature showed that 3,3-disubstituted quinoline-2,4-

dione systems have found interest because of their biological activity (e.g. 1-

substituted 3,3-diazido-quinolinediones as platelet aggregation inhibitors [29,

30], 3-hydroxy-3-alkylquinoline-2,4-diones as contents of bacteria with

antibiotic activity [31-33].

Electrophilic substitution of the hydrogen atom at position 3 of 4-

hydroquinolone 3 by chlorine was easily achieved by substitution reaction with

sulfuryl chloride as chlorination agent, which is known as Cl+ source for

electrophilic ionic reactions at these conditions. A radical process can be ruled

out because all requirements for this reaction type such as high temperature,

radical starters, light irradiation or catalyst were missing. Furthermore, it is

described in the literature [34] that reactive hydroxypyridones and quinolones

react already at room temperature or need cooling which is again a strong hint

for an electrophilic mechanism.

A simple reaction uses sulfuryl chloride as source of chloronium ions

[30, 31, 34c, 35]. Another chlorination method was found by reaction of t-

butyloxy chloride with carbocyclic 1,3-dicarbonyl compounds [36].

The chlorination reaction was performed with sulfuryl chloride, because the

chlorination with chlorine gas is not easy to handle [37].

The chlorination of 4-hydroxyquinolone 3 to 3,3-dichloroquinolin-2,4-

dione 10 proceeds in 73 % yield. The temperature should not exceed 60 °C,

otherwise many unwanted by-products might be formed, which are very

difficult to separate. This matter can be explained by the fact that also the

benzene nucleus can be chlorinated in an electrophilic aromatic substitution

by sulfuryl chloride at high temperature [34a].



N

OH

O

H

O

CH3

N O

H

OCl

ClO

CH3SO

2Cl

2 / dioxane

60 °C

73 %

3 10

Scheme 8

The infrared spectrum of 10 exhibited the absorption bands at 1688 cm-1

and at 1622 cm-1 ascribable to lactam carbonyl and another band at 1725 cm-1

for carbonyl at C-4. The band at 3434 cm-1 was assigned to NH absorption.

1H-NMR spectrum showed the proton signal of NH lactam at 12.27 ppm.

1.2.8. Reduction reaction of 3,3-dichloroquinolin-2,4-dione 10

to 3-chloro-4-hydroxy-6-methoxyquinolin-2(1H)-one 11

By reacting 3,3-dichloroquinolin-2,4-dione 10 in ethanol/acetic acid

mixture using zinc-dust as reduction agent, the reaction allowed to remove one

atom of chlorine of 3,3-dichloroquinolin-2,4-dione 10 and so to obtain 3-

chloro-4-hydroxyquinolin-2(1H)-one 11 in excellent yield of 89 %. The end of

the reaction step could be easily observed by the changing of the color from

yellow to greenish. Attention must be paid for the amount of zinc-dust to be

used, otherwise, both chlorine atoms might be removed and the reaction

recovers the starting material 4-hydroxyquinolone 3 if more zinc-dust is used

or the reaction can not take place if less zinc-dust is used.

Spectral data were consistent with the structure. Comparison of infrared

data of 10 and 11 indicates the absence of additional carbonyl band at C-4 in

compound 11, caused by the formation of hydroxide at this position.



N O

H

OCl

ClO

CH3

N O

H

OH

ClO

CH3Zn / AcOH, EtOH

reflux

89 %

10 11

Scheme 10

1.2.9. Bischlorination reaction of 3-chloro-4-hydroxyquinolone

11 with phosphoryl chloride

The nucleophilic displacement of the 4-hydroxy group and conversion of

2-oxo of 3-chloro-4-hydroxyquinolone 11 by chlorine was easily achieved by

treatment with phosphoryl chloride to give 2,3,4-trichloroquinoline 12.

Comparison of spectral data of compounds 11 and 12 showed that in the

infrared spectrum of 12 the carbonyl band was not observed, and in the 1H-

NMR spectrum of 12, the signal of NH proton disappeared. The elemental

analysis was in good agreement with the proposed structure.

N O

H

OH

ClO

CH3

POCl3

N

Cl

Cl

Cl

O

CH3

11

110 °C, 8 h

90 %

12

Scheme 11

1.2.10. Hydrolysis reaction of 2,3,4-trichloroquinoline 12

2,3-Dichloroquinolin-2(1H)-one 13 was obtained by regioselective

hydrolysis of compound 12 at position 2 using 70 % methanesulfonic acid in



n-butanol, as described in chapter 1.2.2, to form 13 in excellent yield of 88 %.

Survey of the literature showed that alkaline hydrolysis gave significantly lower

yield [18].

Compound 13 was characterized by analytical and spectroscopic

methods. Infrared spectrum clearly showed the presence of lactam carbonyl

band at 1657 cm-1 and an absorption at 3467 cm-1 corresponding to NH. The

1H-NMR showed again the signal of NH protons at 12.47 ppm. The elemental

analysis confirmed the structure.

CH3SO

3H / n-BuOH

N

Cl

Cl

O

H

O

CH3

N

Cl

Cl

Cl

O

CH3

reflux, 45 h

88 %

1312

Scheme 12

1.2.11. Introduction of cyano substituents into 3,4-dichloro-6-


In order to check this unusual reaction pathway (replacing of 3-H by

cyano in position 3 of 4-chloro-6-methoxyquinolone 6) and to install properly

the cyano groups in both position 3 and 4 of the quinolone core, we prepared

independently 3,4-dichloroquinolone 13 starting from the known 4-hydroxy-6-

methoxyquinolone 3 via dichloro derivative 10, subsequently followed by

reduction, bischlorination at position 2 and 4 of 11 and hydrolysation in acidic

media regioselectively at position 2 to give 13, which was found to be highly

reactive for the introduction of dicyano substituents.



N

Cl

Cl

O

H

O

CH3

N O

H

O

CH3

CN

CN

13 7

72 %

(Pathway D)

KCN / sodium p-toluene sulfinate, DMF 140 °C, 46 h

Scheme 13

Treatment of 13 with dry potassium cyanide in the presence of dry

sodium p-toluenesulfinate as catalyst in dry dimethylformamide at 140 °C

leaded to a clean 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 7.

Spectroscopic and analytical investigations are similar to those of compound 7

obtained in chapter 1.2.7.

Moreover, using ESI (electrospray) ionization method, some higher mass

fragments from alkali metal complexes were observed. A base peak with the

high mass 248 could be identified as the combination between one molecule

carbostyril and one sodium ion [MNa]+, the peaks corresponding to [MH]+,

[MK]+ and [2M + Na]+ complexes are respectively less intense 8, 17, and 21 %.

1.2.12. Synthesis of 4-chloro-6-methoxy-3-nitroquinolin-2(1H)-

one 16

1.2.12.1. Nitration reaction of 4-hydroxy-6-methoxyquinolin-

2(1H)-one 3

Survey of the literature showed that 4-hydroxy-3-nitroquinolin-2(1H)-

ones were selective glycine site antagonists related to several central nervous

system disorders including stroke, epilepsy, schizophrenia, Parkinson disease,

and Alzheimer disease [13, 38-43].



The 2-quinolone 3 was nitrated by reaction of concentrated nitric acid in

acetic acid according to ref. [8, 44]. The electrophilic substitution at position 3

of 4-hydroxy-6-methoxyquinolin-2(1H)-one 3 was catalyzed by sodium nitrite

to accelerate its velocity and allow to give at room temperature the expected 4-

hydroxy-6-methoxy-3-nitroquinolin-2(1H)-one 14 in good yield of 76 %.

The catalytic effect of sodium nitrite could be explained by an initial nitrosation

in position 3 of compound 3 and subsequent oxidation of the nitroso to the

desired nitro group [44]. The nitration reaction of the similar quinolone

systems using nitric acid in boiling acetic acid [45] should lead to a direct

oxidation of the C-H acid in position 3 of 4-hydroxy-6-methoxyquinolin-2(1H)-

one 3 by the oxidative agents present in the mixture such as nitrous and nitric

acid or by exchange of the already formed nitro group against the hydroxy

group [37], or again leads to the nitration of the benzo part of the 2-quinolone

3. The similar substituted 3-nitro and 3-bromo-4-hydroquinolin-2(1H)-ones

showed biological activities such as antituberculosis activity [46].

1H-NMR spectrum of compound 14 clearly showed the absence of C-3 proton

and the signal of NH proton was observed at 11.89 ppm. The infrared spectrum

exhibited the lactam carbonyl band at 1688 cm-1, the signal at 1530 cm-1 was

assigned to the nitro group.

N

OH

O

H

O

CH3

N

OH

O

H

NO2O

CH3HNO

3 / NaNO

2, AcOH

r.t., 30 min.

76 %

3 14

Scheme 14

1.2.12.2. Bischlorination of 4-hydroxy-6-methoxy-

3-nitroquinolin-2(1H)-one 14

The chlorination of the similar 4-hydroxy-3-nitro compounds with

phosphoryl chloride or phosphoryl chloride/phosphorous pentachloride gave



impure products in poor yields [47]. Recently, it was shown in our work group

that the addition of triethylamine as a basic catalyst to the mixture of

phosphoryl chloride and and similar carbostyrils accelerated the exchange of

the hydroxyl against chloro group and allowed to obtain the desired product in

excellent yields of 92-94 % after 1 hour reaction time [8].

Treatment of one equivalent of 4-hydroxy-6-methoxy-3-nitroquinolin-

2(1H)-one 14 with 1.2 equivalent of triethylamine in phosphoryl chloride

afforded the expected 2,4-dichloro-6-methoxy-3-nitroquinoline 15 in excellent

yield of 91 %.

The addition of triethylamine could be explained in terms of destruction

of the hydrogen bonds between the 3-nitro and the 4-hydroxy group, which

prevented or retarded the attack of phosphoryl chloride and accelerated the

reaction speed [8, 48]. A similar hindrance was found in the chlorination of 3-

amido-4-hydroxyquinolone and also in the chlorination of 3-acyl-4-

hydroxyquinolones [15a], which will be described in the chapter 2.2.10.

The structure of compound 15 was confirmed by infrared and 1H-NMR

spectroscopic data.

N

OH

O

H

NO2O

CH3

N

NO2

Cl

Cl

O

CH3POCl

3 / Et

3N

91 %

14

reflux, 1 h

15

Scheme 15



1.2.12.3. Regioselective hydrolysis of 2,4-dichloro-6-methoxy-3-

nitroquinolin-2(1H)-one 15

4-Chloro-3-nitroquinolone derivatives of type 16 and the corresponding

2-pyridones are found to be useful as intermediates of synthetic routes

because of their reactivity [8, 23, 48-50].

N

NO2

Cl

Cl

O

CH3 CH

3SO

3H / n-BuOH

N

Cl

O

H

NO2O

CH3

110 °C, 45 h

67 %

15 16

Scheme 16

Hydrolysis of 2,4-dichloro-6-methoxy-3-nitroquinolin-2(1H)-one 15 was

attempted in the presence of 70 % methanesulfonic acid using various

conditions (solvents, temperatures, and reaction time) as listed in the table 1.

In all these cases, a mixture of two compounds was obtained which were found

to be difficult to resolve.

Table 1. Attempts reactions condition from 15 to 16

Solvent Temperature (C) Time (h)

Ethanol

78 35

n-butanol

110 35

AcOH/H2O 115 35

1-dodecanol

150 30

C6H5Br

150 30

DMF 150 44

DMF

150 64

1-dodecanol 210 40

N-methyl-2-pyrrolidone 200 48



Finally, the best conditions for the regioselective hydrolysis at position 2

of compound 15 in the presence of 70 % methanesulfonic acid were obtained

by heating the mixture to 110 °C in n-butanol for 45 hours. A careful column

chromatography using chloroform/acetone 3:7 as eluent afforded the expected

4-chloro-6-methoxy-3-nitroquinolin-2(1H)-one 16 in 76 % yield.

Structural investigations showed the most relevant band in the infrared

spectrum at 1663 cm-1 ascribable as lactam carbonyl and the absorption band

in the range of 3437-2916 cm-1 was assigned to the NH. 1H-NMR spectrum

showed a singlet at 12.99 ppm due to the presence of NH proton.

The mass spectrum showed with APCI negative and positive methods the

base peak with 100 % intensity. The proposed structure was supported by the

elemental analysis.

1.2.13. Synthesis of N-(4-chloro-6-methoxy-2-oxo-1,2-

dihydroquinolin-3-yl)acetamide 18

1.2.13.1 Reduction of 4-hydroxy-6-methoxy-3-nitroquinolone

14 into acetylaminoquinolone 17

Survey of the literature showed that reduction of compounds of type 14

using sodium dithionit failed [14].

4-Hydroxy-6-methoxy-3-nitroquinolone was treated with zinc-dust in

acetic acid in the presence of acetic anhydride according to ref. [51], to avoid

the isolation of the sensitive free amino derivatives. The corresponding

acetylaminoquinolone 17 was obtained after 30 minutes reaction time.

Similar reactions heated for a long time leaded to the formation of oxazolo

[5,4:4,5]pyrido [2,2-d] pyrimidinetriones [52], and oxazolo [4,5-c]quinolines or

oxazoloquinolones [14].

Comparison 1H-NMR data of 14 and 17 indicated the appearance of the

additional NH proton signal at 9.74 ppm and a methyl signal at 2.24 ppm



caused by the formation of the amide group at position 3, which was formed by

reduction of nitro (NO2) to amide (-NHCOCH3). The signal at 11.73 ppm is

accounted for NH proton from lactam, and the signal at 11.98 ppm is assigned

to OH proton. Infrared also showed an additional amide carbonyl band at 1645

cm-1, the lactam carbonyl band was observed at 1640 cm-1. Elemental analysis

was in accordance with the proposed structure.

N

OH

O

H

NO2O

CH3

Zn / Ac2O, AcOH

N

H

O

OH

O

CH3

N CH3

O

H

reflux, 30 min.

68 %

1417

Scheme 17

1.2.13.2. Regioselective chlorination of N-(4-hydroxy-6-

methoxy-2-oxo-1,2-dihydroquinolin-3-yl)acetamide 17

The chlorination reaction of N-(4-hydroxy-6-methoxy-2-oxo-1,2-

dihydroquinolin-3-yl)acetamide 17 to the 4-chloroquinolone 18 was performed

similar as described for compound 15. To our surprise, analytical and

spectroscopic investigations revealed that only the 4-hydroxide of compound

17 was exchanged against the chloro atom to give directly compound 18 with

excellent yield of 90 %.

N

H

O

Cl

O

CH3

N CH3

O

POCl3 / Et

3N

N

H

O

OH

O

CH3

N CH3

O

HH

1718

reflux, 1 h

90 %

Scheme 18



Infrared spectrum of 18 showed two carbonyl bands assigned for the

lactam carbonyl at 1620 cm-1 and for amide at 1651 cm-1 as already observed

with compound 17. 1H-NMR spectrum also exhibited the main NH proton

signals at 9.60 ppm for NH-amide and at 12.18 ppm ascribable for the NH-

lactam; moreover the signal of OH proton observed at 11.98 ppm in 17

disappeared, caused by the exchange of hydroxyl group against the chloro

atom. These findings clearly confirm that the 2-oxo function of compound 17

did not react with phosphoryl chloride.

Since the carbonyl group in position 2 of the quinolone ring participates only in

the formation of significantly less stable intramolecular hydrogen bonds (IMHB)

with the hydrogen from 3-amide, this lactam carbonyl becomes surrounded;

thus, the chlorination at position 2 was hampered, probably by steric reasons.

The elemental analysis showed a small deviation of 0.09 % from the theoretical

percentage for the carbon component. Mass spectrum with APCI ionization

showed the base peak with 100 %, and exhibited a weak peak (M-43) with only

8 % intensity corresponding to the loss of acylium radical CH3CO+ (m/e = 43)

as shown below.

N O

H

Cl

NH

MeO CH3

ON O

H

Cl

NH

MeO CH3

O

N O

H

Cl

MeO NH

CH3 O

e -

+

.

.

+ +

M-43

m/e = 43

Scheme 19Fragmentation process of M-43



1.2.14. Amination of 3,3-dichloroquinoline-2,4-dione 10

3,3-Dipiperidinylquinolinedione 19 was prepared similar as described in

ref. [53] by treatment of 3,3-dichloroquinolinedione 10 with piperidine in

dimethylformamide at room temperature. The nucleophilic exchange of both

chlorine atoms against secondary aliphatic amine such as piperidine leads to

19 in 78 % yield. Infrared spectrum confirm the carbonyl bands of ketone at

1668 cm-1 and for lactam at 1657 cm-1. In the 1H-NMR spectrum, the signal of

NH proton was observed at 8.31 ppm.

N O

H

OCl

ClO

CH3

N

N

N O

H

O

O

CH3piperidin / DMF

10 19

78 %

0 °C, 30 min.

Scheme 20

1.2.15. Reduction of 6-methoxy-3,3-di(piperidin-1-yl)quinoline-

2,4(1H,3H)-dione 19

For the reduction of compound 19 to compound 20 we have used the

procedure described in ref. [54]. 3,3-Dipiperidinylquinolinedione 19 was

treated with sodium dithionite as a reduction agent in a mixture of

ethanol/water (1:1) as solvent to give 4-hydroxy-6-methoxy-3-(piperidin-1-

yl)quinolin-2(1H)-one 20 with an excellent yield of 96 % in pure form. The

structure was confirmed by analytical and spectroscopic methods (IR, 1H-NMR,

MS, and elemental analysis). Infrared showed only one carbonyl band at 1638

cm-1 assigned to –HN-C=O lactam.



N

N O

H

OH

O

CH3

N

N

N O

H

O

O

CH3 Na

2S

2O

4, EtOH / H

2O

reflux, 30 min.

96 %

2019

Scheme 21

1.2.16. Synthesis of 4-chloro-6-methoxy-3-(piperidin-1-

yl)quinolin-2(1H)-one 22

4-Chloro-3-piperidinylquinolone 22 was first prepared from 20 in a two

pot synthesis, similar as described in chapters 1.2.9 and 1.2.10.

Bischlorination of one equivalent of 4-hydroxy-3-piperidinylquinolone 20 with

excess amount of phosphoryl chloride at positions 2 and 4 formed 2,4-

dichloro-6-methoxy-3-(piperidin-1-yl)quinoline 21 in moderate yield of 47 %.

Following hydrolysis in acidic media regioselectively at position 2 of 21 allowed

the conversion of 2-chloro into 2-oxo in 53 %. In this way, the overall yield was

low, the step reactions took longer time and the compound 22 was not easy to

isolate. It was next developed a one-pot synthesis of 4-chloroquinolone 22

directly from the corresponding hydroxy compound 20, using less phosphoryl

chloride and shorter reaction time. A careful treatment of compound 20 with

phosphoryl chloride at 80-90 °C allowed as expected the nucleophilic

substitution of 4-hydroxy to 4-chloro and gave 22 in good yield of 82 %. It

should be noted that in this chlorination step the exchange of the 4-hydroxy

group by chlorine occurs rapidly. Even after 15 minutes the starting 4-

hydroxy-3-piperidinylquinolone 20 was not found in the reaction mixture and

the single reaction product was 22 obtained after 25 minutes of reaction time.

The structure was confirmed the spectral data.



N

N

OH

O

H

O

CH3

N

N Cl

Cl

O

CH3

N

N O

H

Cl

O

CH3

POCl3

POCl3

CH3SO

3H / n-BuOH

20 21

22

110 °C, 8 h

80-90 °C, 25 min.

82 %

47 %

reflux, 48 h53 %

Scheme 22

1.2.17. Synthesis of 3,4-dicyanoquinolones 7 from 3-

substituted 4-chloroquinolones

It was shown that the reaction of nucleophiles with 4-chloroquinolin-

2(1H)-ones usually affords the corresponding 4-substituted quinolin-2(1H)-

ones. The reaction rate was found to be strongly dependent on the electronic

effects of substituents in position 3 of the quinolone moiety. For instance,

electron-withdrawing groups facilitate the substitution, whereas electron-

donating groups impair or prevent the reaction [8].

According to these findings, the 4-chloro atom of compound 16 should

be exchanged easily against nucleophiles by the influence of the nitro group in

position 3. It was shown that in 4-chloro-3-nitrocoumarin [55], both the 4-

chloro and 3-nitro group could be exchanged depending on the nature of the

nucleophiles, and these results should be extended to the 2-quinolone



nucleus. Thus, in the reaction of 16 with dry potassium cyanide in the

presence of sodium p-toluenesulfinate as catalyst in dry dimethylformamide,

the C-Cl bond in position 4 on the quinolone moiety could be activated by the

strong electron-withdrawing effect of the neighboring nitro group, thus

enabling the substitution by p-sulfinate, which is a good leaving group and

allowed easily the introduction of the cyano groups in positions 3 and 4, to give

7 in excellent yield of 93 % after 2.5 hours reactions times (Pathway E).

N

Cl

H

O

NO2O

CH3

N

Cl

H

O

N CH3

O

O

CH3

N

N

Cl

H

O

O

CH3

N

H

O

CN

CN

O

CH3

H

16

18

22

KCN / p-tol.sulfinate Na, DMF 140 °C, 2.5 h

KCN / p-tol.sulfinate Na, DMF 70-140 °C, 17-45 h

KCN / p-tol.sulfinate Na, DMF 140 °C, 5 days

65-86 %

93 %

7

(Pathway E)

(Pathway F)

(Pathway G)

Scheme 23

Attempts to react compound 18 having a 4-chloro substituent and amide

in position 3 even in short reaction time and at low temperature in order to

exchange only the 4-chloro atom and to favor a kinetically controlled reaction

at C-4 position of compound 18, resulted again in the formation of 7 with

overall yield of 65-86 % (Pathway F).

Spectroscopic and analytical investigations of compounds 7 obtained

from 16 and 18 were similar with those obtained previously.



However, in the case of 22, the presence of amine in position 3 gave less

reactivity after 5 days (Pathway G). The pure product was obtained by HPLC-

chromatography. The structural investigations of this compound could not be

done, but its fluorescence investigations were very interesting, with an

absorption maximum at 450 nm, an emission maximum at 570 nm in the

mixture of n-heptane/dioxane/DCM 45, and an excellent quantum yield of

0.786.

1.2.18. About an “isomer” of 6-methoxyquinoline-dicarbonitrile

7, compound 23a

In order to investigate the formation of dicyano compound 7 using a

short reaction time, 3,4-dichloro-6-methoxyquinolone 13 was treated with

potassium cyanide in presence of sodium p-toluenesulfinate as catalyst at 140

°C, surprisingly we isolated an obvious isomer of 7, compound 23a.

UV and fluorescence investigations of the isolated intermediate 23a showed

remarkable fluorescence properties. An absorption wavelength up to 497 nm

and an emission maximum of about 570 nm in acetonitrile, never observed

previously with carbostyrils. The structure elucidation by means of

spectroscopic methods (IR, 1H and 13C-NMR, MS) showed that the most

relevant signal of carbonyl lactam in the infrared spectrum was not observed.

However, a stronger peak of cyano group was observed at 2213 cm-1. In the 1H-

NMR spectrum, the signal of NH proton was not observed, but the number of

proton signals in the benzo part and their chemical shifts also support this

part of carbostyril. The most relevant signal being a doublet at 6.84 ppm (J =

1.9 Hz) corresponding to C-5 proton, a multiplet at 7.17-7.21 ppm assigned to

two protons of C-7 and C-8.

13C-NMR spectrum showed the main carbons such as 2-C at 153.9 ppm,

6-C at 148.5 ppm and probably two cyano carbons in the same position at

118.0 ppm because of the intensity of the signal is twice the usual size



N

O

CH3

Cl

Cl

O

H

CN

N

O

CH3

O

H

CN

CN

O

CH3

N CN

OHKCN / Na p-toluene sulfinate, DMF 140 °C, 3 h

76 %

13 23A

7

soution acetic acid

Scheme24

Mass spectrum analysis showed with APCI-negative the base peak of 23a

corresponding to the molecular ion with 100 %. Efforts to elucidate the

structure by X-ray crystal analysis failed, because it was not possible to get a

single crystal. However, after a second recrystallization of compound 23a in

glacial acetic acid, the 1H-NMR spectrum showed a completely expected

spectrum of 7 with a signal of NH proton at 13.08 ppm, and in the infrared

spectrum, the band of lactam carbonyl was observed at 1655 cm-1 and the

usual band of cyano observed at 2233 cm-1.

The question arises is, where this hydrogen of NH come from ? Whereas

it was not observed in the same sample before the recrystallization from glacial

acetic acid. We attempted to understand this phenomenon.



To test if this unknown compound 23a was the sodium salt (compound

24), several experiments have been done.

N

O

ONa

CH3

CN

CN

24

Figure 4

We prepared a 10-2 M stock solution in aqueous concentrated ammonia

and diluted 10 L respectively with 1 mL water (pH = 9), sodium hydroxide 5 M

(pH = 10 and pH = 12); In all cases the UV spectra were almost similar to the

reference compound 23a.

We next added HCl (pH = 1) to the stock solution, we observed a 10 % intensity

increasing spectrum, but the wavelength maximum was still the same. HClO4

(6 M) was added to the stock solution, we just observed a small red-shift of

wavelength value. This means, protonated and deprotonated of compound 23a,

the UV spectra were very similar. The results of the different tests showed that

the compound 23a was not the sodium salt.

We also considered that compound 23a might have the structure 25

resulting from a rearrangement between 3-cyano and oxygen at position 2, but

in this case the formation of structure 7 after recrystallization from glacial

acetic acid could not be explained.

N

O

CH3

OH

CN

CN

25

Figure 5



We also envisaged the possibility of 4-pyridon structure 26 based on the

strong peak at 1583 cm-1 in the infrared spectrum. A literature survey showed

that 4-pyridon derivatives are known to possess carbonyl signals below 1600

cm-1 [56] similar to 26, in this case the signal of the NH, which should also be

seem in the tautomer 26a should be observed in the 1H-NMR spectrum.

N

CNO

CH3

H

O

CN N

CNO

CH3

CN

OH

26 26aaa

Scheme 25

One more probable hypothesis of compound 23a is 2-hydroxy-6-

methoxyquinoline-3,4-dicarbonitrile 7a, which could be explained by the fact

that the stronger signal of cyano observed at 2213 cm-1 is caused not by the

two cyano groups, but because the cyano groups are not close to 2-hydroxide

as observed in the previous cases. In this case, the cyano and 2-hydroxide are

coplanar, that increase strongly the intensity of the band ascribable to cyano

group [57] and a broad-strong band observed in the range of 3600-3200 cm-1 is

due to the presence of OH.

N

CNO

CH3

OH

CN

7a

Figure 6

Since it is speculated that, a tautomeric equilibrium between lactam

form 7 and lactim form 7a could be more easily shifted



N

O

CH3

O

H

CN

CN

N

O

CH3

CN

CN

OH

7 7a

Scheme 26

and knowing that the lactim form 7a is usually less stable than the lactam

form 7, the molecule could then be stacking in the lactim form (23b), the

tautomeric equilibrium could not be shifted towards the lactam form 7.

N

O

OH

CN

CN

N

O

OH

CN

NC

23b

(2 motives)

Figure 7

The lack of the lactam carbonyl band in the infrared was then caused by

the presence of the bridged 2-hydroxy group, and the absence of the signal OH

proton in the 1H-NMR spectrum is probably due to the quick exchange of this

OH against heavy water (D2O) which is not visible in 1H-NMR.

However, when 23a was dissolved in glacial acetic acid, the stacking form (23b)

which clearly confirms the presence of a OH group either at the position 2 was

broken and the tautomeric equilibrium shifted to the predominate lactam form.

This is a convincing argument to proof that this stacking molecule was the

lactim form of carbostyril.



1.2.19. Cyclocondensation of m-anisidin 27 and malonic acid 2

to 4-hydroxy-7-methoxy-2(1H)-one 28

4-Hydroxy-7-methoxyquinolin-2(1H)-one 28 was prepared according to

the previously reported procedure described in chapter 1.2.1, by heating at 95

°C m-anisidin 27 with malonic acid 2 using phosphoryl chloride as solvent and

condensation agent. The reaction afforded mainly 28 in 72 % besides the

isomer 4-hydroxy-5-methoxyquinolin-2(1H)-one 29 in 6 % yield and 2,4-

dichloro-7-methoxyquinoline 30 in 16 % yield.

NH2

OCH

3

COOH

COOH

N

OH

H

OOCH

3 N O

OH

H

OCH

3

N

Cl

ClOCH

3

POCl3

+

27 2

28 2930

95 °C, 90 min.

16 % 72 % 6 %

+ +

Scheme 27

The formation of the isomer 29 could be explained by the fact that the

electron-donating group methoxy is ortho- and para-directing (Hollemann’s

rules), therefore in the last step of the formation of the 2-quinolone ring as

described in chapter 1.2.1.2, the attack of carbonyl took place both in position

6 of m-anisidin moiety to form 28 and in position 2 to form the isomer 29.



The lower yield of 4-hydroxy-5-methoxyquinolin-2(1H)-one 29 in this

reaction is due to the fact that para-electrophilic substitution on the benzene

ring having donor substituent is more favored to give preferentially compound

28.

The formation of 2,4-dichloro-7-methoxyquinoline 30 is due as described

in chapter 1.2.1, to the excess amounts of phosphoryl chloride, which reacted

with the 4-hydroxy group and the 2-oxo group of the formed 4-

hydroxyquinolone 28 to form 30.

Comparison of 1H-NMR data of 28 and 29 indicated that the methoxy

group in position 7 (compound 28) or in position 5 (compound 29) did not

influence the signal of C-3 proton which appeared at 5.60 and 5.61 ppm

respectively, in contrast NH was influenced, the signal was observed at 11.02

ppm for compound 28 and at 10.00 ppm for compound 29.

1.2.20. Chlorination of 4-hydroxyquinolin-2(1H)-one 28 to 2,4-

dichloroquinoline 30 and 4-chloroquinolin-2(1H)-one

31

4-Hydroxyquinolin-2(1H)-one 28 was brought to reaction with

phosphoryl chloride for 28 hours to form 2,4-dichloroquinoline 30 in 81 %

yield. The product was pure enough for further use.

In the infrared spectrum, the characteristic band of carbonyl disappeared and

in the 1H-NMR spectrum, the signal of NH proton was not observed. Infrared

and 1H-NMR data confirmed the structure of compound 30.

Next, the resulting 2,4-dichloroquinoline 30 was then regioselectively

hydrolyzed in position 2 by reaction with 70 % methanesulfonic acid in n-

butanol to give the desired 4-chloro-7-methoxyquinolin-2(1H)-one 31 in

excellent yield of 96 %.



N

Cl

ClOCH

3N

OH

H

OOCH

3

POCl3

N

H

O

Cl

OCH

3

CH3SO

3H / n-BuOH

3028

reflux, 8 h

81 %

31

110 °C, 28 h 96 %

Scheme 28

Compound 31 was characterized by infrared and 1H-NMR spectra. In

infrared, the main carbonyl lactam stretching was observed at 1669 cm-1 and

in the 1H-NMR the signal of NH proton appeared at 11.87 ppm.

1.2.21. Synthesis of 7-methoxyquinoline-carbonitriles 32 and

33

In order to influence the fluorescence properties of 4-cyanocarbostyrils

with methoxy groups in position 6 and/ or 7-methoxy-2-oxo-1,2-

dihydroquinoline-4-carbonitrile 33 was planed to be synthesized.

Reaction of 4-chloro-7-methoxyquinolone 31 with dry potassium cyanide in the

presence of dry sodium p-toluenesulfinate as catalyst at 120 °C during 30

hours, afforded compound 32.



N

H

O

Cl

OCH

3 NOCH

3

CN

OH

3132

KCN / sodium p-tol.sulfinate, DMF 120 °C, 30 h

79 %

Scheme 29

Structural investigations revealed the absence of lactam carbonyl in the

infrared spectrum, and the presence of a strong peak at 2220 cm-1 ascribable

to cyano group, in the 1H-NMR spectrum the signal of C-3 proton clearly

appeared at 7.98 ppm. The number of protons in the benzo part and their

chemical shifts supported this part of structure with a doublet of doublets at

6.46 ppm (J = 8.7 + 2.5 Hz) corresponding to C-6 proton, a doublet at 6.50

ppm (J = 2.50 Hz) for C-8 proton, another doublet at 7.28 ppm (J = 8.7 Hz)

assigned to C-5 proton, and the protons of methoxy group appeared at 3.76

ppm. However, the signal of NH proton was not observed.

Mass spectal analysis showed with APCI-negative and positive methods, very

clean spectra with only one peak with 100 % with 199 and 201 respectively

corresponding to the base peak for each of them.

Here also, we considered that compound 32 might have the 4-pyridonic

structure 34 because of the strong peak at 1614 cm-1 in the infrared spectrum.

However, the lack of NH signal in the 1H-NMR spectrum and the stronger peak

at 2220 cm-1 in the infrared spectrum corresponding to the cyano group could

not confirmed the 4-pyridonic structure 34.

Figure 8

N

H

O

MeO CN

34



Survey of the literature revealed that K. Kim et al. achieved since 2000 in

a short communication the synthesis of 2-cyano-4-quinolone 34 [58], which

was obtained by intramolecular cyclocondensation of 2-(2,2-dimethyl-4,6-

dioxo-1,3-dioxane-5-ylidene)-3-(3-methoxyphenyl)propanenitrile A, heated in

diphenyl ether as solvent or without a solvent at 200 to 220 °C for 3 to 5

minutes. However, there is no spectroscopical proof of the data.

H

O O

O

O

CN

OMe

N

H

O

MeO CN

Ph2O, reflux

or neat 200-220°C 3-5 min

63 %

34A

Scheme 30

Through a similar approach as described in chapter 1.2.18, we assume

that the structure of compound 32 might be the stacking form of compound

35.

N OH

CN

OCH

3

35

Figure 9

When 4-chloro-7-methoxyquinolin-2(1H)-one 31 was treated with dry

potassium cyanide in dry sodium p-toluenesulfinate at 140 °C for 46 hours,

the expected compound 7-methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile

33 was isolated and characterized by spectroscopic methods. The infrared

spectrum exhibited the relevant peak at 2220 cm-1 assigned to cyano and the



peak at 1661 cm-1 was accounted for lactam carbonyl band. 1H-NMR spectrum

showed the signal of C-3 proton at 8.66 ppm as already observed with 6-

methoxy analogue (compound 9 ) in chapter 1.2.5.1.

N

H

O

Cl

OCH

3 N O

H

CN

OCH

3

31 33

KCN / sodium p-tol.sulfinate, DMF 140 °C, 46 h

87 %

Scheme 31

Mass spectrum showed with APCI-positive and negative methods the

base peak with mass 201 and 199. However, using ESI (electrospray) mass

spectral method, four peaks were observed, these additional signals observed

could be assigned as adducts of compound 33 with sodium and potassium

cations.

A base peak with the high mass 423 corresponds to the complex [2M +

Na] +, and the complex [M + Na]+ is also much stable with an intensity of 95 %,

the peaks of the complexes [M +K] + and [M + H] + are less stable with 11 % and

23 % intensities respective.

It should be noted that, the substitution of 3-H against cyano in position

3 was not assumed in the case of 4-chloro-7-methoxyquinolin-2(1H)-one 31, as

observed with 4-chloro-6-methoxyquinolin-2(1H)-one 6.

1.2.22. Synthesis of 6-methoxy 4-trifluoromethylquinolin-

2(1H)-one 38

2-Quinolone moieties play an important role in organic chemistry as

outlined in the introduction. The introduction of trifluoromethyl group into

bioactive molecules such as 2-quinolones often increases their therapeutic



efficiency due to an increasing in their lipophilicity [59].

For comparison purposes with 4-cyanoquinolone derivatives on the

fluorescence properties, compound 38 was also synthesized.

The cyclocondensation of p-anisidine 1 with ethyl 4,4,4-trifluoroacetoacetate

36 to 6-methoxy-4-trifluoromethylquinolin-2(1H)-one 38 was performed as

described in ref. [60, 61] in one-pot reaction via an intermediate 4,4,4-trifluoro-

N-(4-methoxyphenyl)-3-oxobutanamide 37, which was cyclized without

isolation by treatment with 76 % sulfuric acid as catalyst to form only the

expected compound 38 in 71 % yield.

The structural investigations using analytical and spectroscopic data (IR,

1H-and 13C-NMR, MS and elemental analysis) confirmed the proposed

structure.

In the infrared spectrum, the lactam carbonyl band was observed at

1672 cm-1, and the absorption band of NH at 3432 cm-1, in the 1H-NMR

spectrum the signal of NH proton appeared at 12.24 ppm, a singlet observed at

6.98 ppm was assigned to C-3 proton, a doublet at 7.05 ppm ascribable to C-5

proton was not well resolved, it seemed to get a roof effect.

NH2

O

CH3

O CF3

OO

N O

CF3

H

O

CH3

H2SO

4

N

CF3

O

O

H

O

CH3

+

90 °C, 12 h71 %

136

38

1) 130 °C, 1 h

2) 76 %

37

Scheme 32



Comparison of 1H-NMR data of compounds 9 and 38 indicated that the

chemical shift of C-3 proton of compound 9 is more shifted down field caused

by the greater electronegativity of cyano group in position 4.

N

CN

O

O

CH3

H

9

N O

O

CH3

H

CF3

38

Figure 20

1.2.23. Synthesis of 4-methoxy-N-methylaniline 41

1.2.23.1. Selective monoalkylation of p-anisidine 1 to N-(4-

methoxyphenyl)-N-methylformamide 40

Treatment of p-anisidine 1 with the corresponding orthoformate 39 in

the presence of sulfuric acid as catalyst gave via a Chapman rearrangement

[62] N-(4-methoxyphenyl)-N-methylformamide 40. Other monoalkylation

approaches described in the literature did not show any advantages [63-65].

The structural study by 1H-NMR showed a singlet at 8.33 ppm assigned to the

formyl proton (-CH=O), the signal of the methoxy group was observed at 3.81

ppm, the additional signal observed at 3.26 ppm ascribable to N-CH3 was

caused by selective monoalkylation. At 6.92 and 7.12 ppm two doublets

accounted for the benzene substituent patterns.



NH2

O

CH3

N

CH3

CHO

O

CH3

H2SO

4 conc.

OO

OCH

3

CH3

CH3

+

103 °C, 3.5 h

70 %

40391

Scheme 33

1.2.23.2. Acidic hydrolysis of N-(4-methoxyphenyl)-

N-methylformamide 40

The reaction of compound 40 in 10 % hydrochloric acid was heated

under reflux for 90 minutes similar as described in a text-book procedure [66],

and afforded 4-methoxy-N-methylaniline 41 in 74 % yield.

Structural assignment by 1H-NMR spectrum showed a doublet of N-CH3 at

2.62 ppm and a quadruplet at 5. 14 ppm assigned to N-H proton.

N

CH3

CHO

O

CH3

N

CH3

H

O

CH3

4041

10 % HClreflux, 90 min.

74 %

Scheme 34

1.2.24. Cyclocondensation of 4-methoxy-N-methylaniline 41

and malonic acid 2 to 4-hydroxy-6-methoxy-

1-methylquinolin-2(1H)-one 42

4-Hydroxy-6-methoxy-1-methylquinolin-2(1H)-one 42 was prepared in

moderate yield of 47 %, similar as described in chapter 1.2.29 by reaction of



N-methylaniline 41 with dry malonic acid 2 using phosphoryl chloride as

solvent and condensation agent.

The formation of compound 42 was supported in the 1H-NMR spectrum by the

observation of peaks in the expected shifts of N-CH3 and O-CH3 protons as

singlets at 3.52 and 3.81 ppm respectively. The singlet at 5.93 ppm was due to

C-3 proton and at 11.46 ppm another singlet for OH proton. In the infrared

spectrum, the amide carbonyl band was observed at 1643 cm-1.

NH

CH3

O

CH3

COOH

COOH N O

CH3

OH

O

CH3POCl

3

+95 °C, 90 min.

47 %

41 2 42

Scheme 35

1.2.25. Chlorination of 4-hydroxy-6-methoxy-1-methylquinolin-

2(1H)-one 42 with phosphoryl chloride

The nucleophilic displacement of the 4-hydroxy group of compound 42

by chlorine was easily achieved by treatment with phosphoryl chloride, to form

4-chloro-6-methoxy-1-methylquinolin-2(1H)-one 43 in 82 % yield. It should be

noted that 2-oxo function of compound 42 could not be chlorinated, hampered

by the N-methyl substituent. The structure was characterized by infrared and

1H-NMR spectroscopic data. Infrared clearly showed the amide carbonyl band

at 1642 cm-1.

N O

CH3

OH

O

CH3

N O

CH3

Cl

O

CH3POCl

3

4243

reflux, 8 h

82 %

(Method A)

Scheme 36



1.2.26. Introduction of a cyano substituent into 4-chloro-6-

methoxy-1-methylquinolin-2(1H)-one 43

4-Chloro-6-methoxy-1-methylquinolin-2(1H)-one 43 was treated at 120

°C with dry potassium cyanide in the presence of dry sodium p-

toluenesulfinate in dry dimethylformamide. The reaction was monitored by thin

layer chromatography (TLC). By stirring the reaction mixture at this

temperature for 28 hours, the starting material totally disappeared. However,

the purity of the resulting 6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-

carbonitrile 44 was not sufficient. Then we decided to prepare compound 44 by

N-alkylation from the previous 6-methoxy-2-oxo-1,2-dihydroquinoline-4-

carbonitrile 9 synthesized in chapter 1.2.5.1.

N O

CH3

Cl

O

CH3

N O

CH3

CN

O

CH3

43 44

KCN/ p-tol.sulfinate Na, DMF

120 °C, 28 h

(Method A)

84 %

Scheme 37

1.2.27. N-Methylation of 6-methoxy-2-oxo-1,2-dihydroquinoline

-4-carbonitrile 9

The methylation reaction of 2-quinolones using NaOH/CH2Cl2 or

K2CO3/CH3CN heated to 20-50 °C for 3-5 hours afforded a mixture of N- and

O-methylated products in the ratio 4:1 respectively [18].

The reaction of 4-cyanoquinolone 9 with methyl iodide (CH3I) was performed

using dry sodium carbonate as base in dry dimethylformamide at 90 °C for 15

minutes. A simple recrystallization from ethanol afforded the expected 6-

methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile 44 in 82 %.



It should be noted that methyl iodide is an excellent reagent for

methylation, but there are some disadvantages to its use. It has a high

equivalent weight: one mole of methyl iodide weights almost three times as

much as one mole of methyl chloride. Moreover, iodides are generally expensive

to the more common chlorides and bromides, though methyl iodide is

reasonably affordable.

1H-NMR spectrum revealed an additional methyl group at 3.64 ppm

caused by the substitution of a hydrogen by methyl at N-1 position. Infrared

spectrum showed the relevant peak of amide carbonyl at 1644 cm-1, the peak

at 2229 cm-1 was assigned to cyano group. The 13C-NMR supported the

proposed structure.

N

O

O

H

CH3

CN

N

O

O

CH3

CH3

CNCH3I / Na

2CO

3, DMF

90 °C, 15 min.

9 44

82 %

(Method B)

Scheme 38

1.2.28. N-Alkylation of 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile 7

1.2.28.1 N-Alkylation with iodomethane

The reaction of compound 7 with iodomethane to produce N-methylated

compound 45 was performed similar as described in chapter 1.2.27. It involves

in the first step the attack of hydrogen at N-1 by the base on the compound 7,

then followed by electrophilic substitution to give 6-methoxy-1-methyl-2-oxo-

1,2-dihydroquinoline-3,4-dicarbonitrile 45 in 65 % yield. The structure was

confirmed by infrared and 1H-NMR data.



Mass spectral using ESI (electrospray ionization) method showed very

few peaks. The high mass observed could be identified as the combination

between one and 2 molecules carbostyrils and alkaline metal ions such as Na+

and K+.

N O

H

CN

CNO

CH3

N O

CN

CN

CH3

O

CH3

CH3I /Na

2CO

3, DMF

120 °C, 25 min.

65 %

7

45

Scheme 39

1.2.28.2 N-Alkylation reaction with ethyl bromoacetate

To attach a reactive linker group at the N-1 position, compound 7 was

brought to reaction with ethyl bromoacetate and dry sodium potassium in dry

dimethylformamide similar as described in chapter 1.2.27, to give the expected

ethyl [3,4-dicyano-6-methoxy-2-oxoquinolin-1(2H)-yl]acetate 46 in 84 % yield.

In addition to the simple reaction conditions, this procedure has the

advantages of very short reaction time, easy experimental and work-up.

procedures.

N O

H

CN

CNO

CH3

N O

CN

CNO

CH3

O

O

CH3

BrCH2COOEt / Na

2CO

3, DMF

7

46

90 °C, 15 min.

84 %

Scheme 40



Infrared spectrum showed the amide carbonyl band at 1656 cm-1 and

the ester carbonyl band at 1746 cm-1. The signal of cyano was observed at

2230 cm-1. The 1H-NMR spectrum showed a triplet at 1.22 ppm assigned to

CH3 protons, caused by the formation of N-ester, a quadruplet at 4.17 ppm

assigned to O-CH2 and the singlet corresponding to N-CH2 was observed at

5.20 ppm. 13C-NMR showed the relevant signals of cyano at 117.4 and 118.6

ppm, the signal at 156.6 ppm was ascribable for lactam carbonyl (C-2) and at

167.6 ppm a signal accounted for ester carbonyl. Elemental analysis was

consistent with the proposed structure.

Furthermore, mass spectrum using ESI method at 50 V showed a base

peak with high mass 334, which could be identified as the combination

between one molecule carbostyril 46 and one sodium ion [M + Na]+. The peaks

corresponding to the complexes [M + H]+ and [M + K]+ are respectively 62 %

and 51 % intensities.

The peak corresponding to the combination between 2 molecules

carbostyril 46 and one sodium ion was not observed.

1.2.29. O-Alkylation of 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile 7

The reaction of 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile

7 with halide such as benzyl chloride 47 in dry dimethylformamide using dry

potassium carbonate as base was performed similar as described in ref. [60a].

Surprisingly, after worked-up the analysis of the reaction mixture by thin layer

chromatography (TLC) revealed only the presence of one compound, which was

isolated, purified by dry flash chromatography using toluene-dichloromethane

(3:1) as eluent and characterized by spectroscopic analyses, to give 2-

benzyloxy-6-methoxyquinoline-3,4-dicarbonitrile 48. Infrared spectrum did not

show the lactam carbonyl band and in the 1H-NMR spectrum, the signal of N-H

proton was not observed confirming the O-alkylation. ESI-MS confirmed the

proposed structure. No N-alkylated product was obtained by this reaction.



N O

H

CN

CN

O

CH3

N

O

CH3

O

CN

CNCl K

2CO

3, DMF

7

+

1) 80 °C, 3 h2) 110 °C, 2 h

47 48

61 %

Scheme 41

1.2.30. N-Methylation of 4-chloro-6-methoxyquinolin-2(1H)-one

6

4-Chloro-6-methoxyquinolin-2(1H)-one 6 was treated at 120 °C with

iodomethane and dry sodium carbonate in dry dimethylformamide as

described in chapter 1.2.27, to give the desired 4-chloro-6-methoxy-1-

methylquinolin-2(1H)-one 43 in 81 %.

The spectroscopic data were consistent with those obtained in chapter 1.2.25.

N O

H

O

CH3

Cl

N O

CH3

O

CH3

ClCH3I / Na

2CO

3, DMF

6 43

120 °C, 25 min.

81 %

(Method B)

Scheme 42

1.2.31. N-Methylation of 3,4-dichloro-6-methoxyquinolin-2(1H)-

one 13

The reaction of 3,4-dichloro-6-methoxyquinolin-2(1H)-one 13 with

iodomethane and dry sodium carbonate in dry dimethylformamide at 120 °C

afforded the desired 3,4-dichloro-6-methoxy-1-methylquinolin-2(1H)-one 49 in



80 % yield.

1H-NMR spectrum showed the additional signal of N-CH3 at 3.67 ppm

caused by substitution of hydrogen against methyl group. The elemental

analysis supported the proposed structure.

N O

H

O

CH3

Cl

Cl

N O

CH3

O

CH3

Cl

Cl

CH3I / Na

2CO

3, DMF

13 49

120 °C, 25 min.

80 %

Scheme 43

1.2.32. Nitration reaction 4-chloro-6-methoxyquinolin-2(1H)-

one 6

The one-pot synthesis of 4-chloro-6-methoxy-7-nitroquinolin-2(1H)-one

50 was achieved by reaction of 4-chloro-6-methoxyquinolin-2(1H)-one 6 with

concentrated nitric acid in acetic acid and sodium nitrite at 110 °C.

The ortho directing substitution leaded by methoxy in position 6 was applied

successfully for the electrophilic substitution of hydrogen against nitro in

position 7 of 4-chloro-6-methoxyquinolin-2(1H)-one 6, to form this rare

chemical compound 50 in excellent yield of 82 %. The reaction showed

excellent selectivity in the synthesis of compound 50 because the attack of

nitro in position 5 of compound 6 is very low.



N O

H

O

CH3

Cl

N

O

CH3

Cl

O

H

O2N

HNO3 / AcOH, NaNO

2

N

O

CH3

O

H

O2N

CN

110 °C, 3 h

6

82 °C

50

KCN / p-toluene sulfinate Na, DMF 100-140 °C, 20-72 h

51

Scheme 44

The stretching frequency in infrared spectrum at 1534 cm-1 supported

the nitro group and the lactam carbonyl band was observed at 1659 cm-1. The

1H-NMR spectrum showed the signal of C-3 at 6.95 ppm and at 12.32 ppm a

singlet corresponding to N-H proton. The C-5 proton appeared as a singlet at

7.56 ppm and at 7.78 ppm another singlet assigned to C-8 proton, its chemical

shift is inflenced by the nitro group at position 7. However, the signal of C-7

proton has disappeared, caused by the replacing of C-7 hydrogen against nitro

group.

Mass spectrum using the ESI (electrospray) gave the correct mass of

base peak, with some additional signals assigned to adducts with alkali metal

ions.

However, attempts to introduce the cyano in position 4 of the obtained 4-

chloro-6-methoxy-7-nitroquinolin-2(1H)-one 50 failed.



1.3 CONCLUSION

In conclusion, we have developed efficient and convenient methods for the

preparation of 3,4-dicyanocarbostyrils. The results of these syntheses showed

that the presence of chloro, nitro or acetylamino group in position 3 of 4-

chloroquinolin-2(1H)-ones in the reaction to 3,4-dicyanocarbostyrils leads to

excellent yields. However, the reactive intermediate 4-chloro-3-nitroquinolin-

2(1H)-one 16 was found to be very difficult to purify. The structure of 6-

methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 7 has been confirmed

by X-ray diffraction analysis. 3,4-Dicyanocarbostyril derivatives 7 showed

excellent fluorescence properties, absorption wavelengths and large Stoke’s

shifts. 4-Sulfinyloxycarbostyril 8 also showed encouraging UV absorption and

fluorescence spectra.

Chapter 2: SYNTHESIS OF 4-CYANO-3-SUBSTITUTED QUINOLIN-2(1H)-ONES 93


CHAPTER 2

SYNTHESIS OF 4-CYANO-3-SUBSTITUTED

QUINOLIN-2(1H)-ONES



Chapter 2: SYNTHESIS OF 4-CYANO-3-SUBSTITUTED

QUINOLIN-2(1H)-ONES

2.1. INTRODUCTION

3–Substituted quinolin-2(1H)-ones are an important class of heterocyclic

compounds having interesting biological activities [67-72], and particularly 3-

aryl-4-hydroxyquinolin-2(1H)-ones [69c] recently described as novel and potent

tyrosine kinase (RTK) receptor

Survey of the literature show that 4-hydroxyquinolin-2(1H)-ones are

selective glycine site antagonists [73-75], related to several central nervous

systems disorders including stroke, epilepsy, schizophrenia, Parkinson disease,

Alzheimer disease [76-81], and serotonin (5-HT3) receptor antagonists [82].

Moreover, 3-aryl-4-hydroxyquinolin-2(1H)-ones have been found to serve as

key intermediates in the synthesis of non-peptide GnRH (Gonadotropin

releasing hormone) receptor antagonists [83]. Such compounds are of interest

for the treatment of sex hormone related conditions [84].

In this chapter the synthesis, isolation and analysis of various 4-cyano-

3-alkyl or aryl substituted quinolin-2(1H)-ones is described.


2.2.1. Esterification reaction of arylacetic acid 52

Esterification of arylacetic acid 52a-d with primary alcohol such as ethanol in

the presence of catalytic amounts of concentrated sulfuric acid in chloroform

leads to the formation of the corresponding arylacetic acid ethyl ester 53a-d



in moderate to excellent yields. The water formed during the reaction was

removed by the terms of Dean-Stark apparatus. The reaction was finished

upon ceased water formation.

Infrared spectra of compound 53a-d contained strong ester bands in the range

of 1730–1736 cm-1. The ethyl group appeared clearly in the 1H-NMR spectra as

triplet and quadruplet. The singlets at 3.57-3.87 ppm correspond to a

methylene group (CH2).

COOH

O

O

R REtOH

H2SO

4 / CHCl

3

reflux, 5 h

52 53

+

p-NO2

52, 53 R

a

b

c

d

p-MeO

p-Cl

m-Cl

Yield (%)

76

75

87

56

Scheme 1

2.2.2. Condensation reaction of arylethyl ester 53 with diethyl

carbonate 54

The condensation reactions between arylacetate 53a,b,d and diethyl carbonate

54 were promoted by a strong base such as 60 % sodium hydride in dry

tetrahydrofuran and were achieved as described in ref. [85]. The reaction

mechanism involves a Claisen condensation in which the enolizable -hydrogen

at the arylacetate reacts with diethyl carbonate to give the expected

arylmalonates 55a,b,d. The yields were within 48-83 %.



Infrared spectra showed ester carbonyl bands at 1733-1736 cm-1 and

additionally at 1752-1754 cm-1 corresponding to the presence of second ester.

In the 1H-NMR spectra, the signal of methyne (-CH-) protons appeared at 4.86-

5.03 ppm.

O

O

R OOEt

OEt

NaH / THFO

O

OEt

OEt

R

53

+reflux

54 55

53, 55 R

a

b

d

p-MeO

p-Cl

m-Cl

Yield (%)time (h)

72 69 %

2 83 %

7 48 %

Scheme 2

2.2.3. Thermal cyclization of aryl malonates 55

The reaction of p-anisidine 1 with diethyl malonates 55a-g was performed

similar as described in ref. [9, 86]. In our hands 2-aryl malonates of type 55

proved as good starting materials at reaction temperatures above 250 °C for

the simple and quick cyclization reaction [16, 86], probably via intermediates

arylketene ester 56 [87]. Moreover, the only disadvantage of this reaction

sequence is the high reaction temperature, which prevents its use for sensitive

substituents [16]. The ketene mechanism is also supported by observations

obtained during the reaction [16]: at temperature below 200 °C, the first mole

of alcohol is observed to be liberated when the open chain ester or amide is



formed, then it needs a temperature of more than 250 °C to liberate the second

mole of alcohol to form the ketene intermediates 56.

Previously we have also performed [87] the thermal investigations of similar

reaction between phenol and malonate. Differential scanning calorimetry (DSC)

showed that, at about 160 °C a first exothermic reaction starts immediately

after the endothermic boiling point of phenol, then a weak exothermic reaction

begins at about 240 °C followed by a strong exothermic reaction (onset 260 °C).

Thus, the thermal reactions of p-anisidine 1 with diethyl malonates 55a-g in

diphenyl ether as solvent were performed similarly as described in ref. [88-89]

to give the corresponding 4-hydroxy-3-substituted quinolin-2(1H)-ones 57a-g

in moderate to excellent yields of 43-98 %. It should be noted that diphenyl

ether had to be used as solvent in the case of 55f-g having boiling points below

200 °C (respectively 198-199 °C, 75-77 °C) in order to raise the reaction

temperature of about 250 °C and to liberate the second molecule of ethanol,

otherwise no reaction took place. However, in the case of 55a,b,d,e having

boiling points above 250 °C the solvent diphenyl ether had to be used to

maintain the reaction temperature stable at about 250 °C, and to obtain the

corresponding 4-hydroxy-3-substituted quinolones 57a,b,d in pure form,

without such a temperature control, the reaction temperature reaches more

than 300 °C and the by-product dianilide could be formed besides the desired

products 57a,b,d.

Each reaction was heated until the distillation of ethanol ceased, indicating

completion of the reaction.

Spectroscopic investigations showed in the infrared spectra the lactam

carbonyl bands at 1644-1648 cm-1 for all compounds 57a-g, and in the 1H-

NMR spectra the signals of N-H protons were observed at 10.00-10.30 ppm and

at 11.22-11.44 ppm the singlets assigned to OH protons for compounds 57a-f.

In the case of the known compound 57g, only the signal of N-H was observed

at 11.27 ppm, but the 13C-NMR of compound 57g was consistent with the

structure.



NH2

O

CH3

N

OH

R1

O

H

O

CH3

Ph2O

R1

O O

O

O

Et

Et

CR1

O O Et

O

- EtOH

- EtOH

250 °C, 3 h

1

55a-g

57a-g

>

56a-g

CH3

R1

CH3CH

2m-Clp-Cl

a b d e f

R p-MeO

Yield (%) 98 80 73 97 94 43

g

Scheme 3

2.2.4. Bischlorination of 4-hydroxy-3-substituted

quinolin-2(1H)-ones 57

Transformation of 4-hydroxy-3-substituted quinolin-2(1H)-ones 57a-g to the

reactive 4-chloro-3-substituted analogues 59a-g were started by reaction of

57a-g with an excess amount of phosphoryl chloride under reflux, which

allowed the conversion of 4-hydroxy and 2-oxo of compounds 57a-g into



2,4-dichloro-3-substituted quinolines 58a-g in good to excellent yields of 79-97

%. The presence of meta substituent on the phenyl moiety gave rise to the high

reaction yields (compound 58d compared with compound 58a), and when a

short reaction time was used, the additional para substituent on the phenyl

moiety gave rise to low reaction yields (compound 58b compared with

compound 58e), also a long alkyl chain in position 3 of compounds 57

decreases the reaction yields (compound 58f compare with compound 58g).

Finally, the reactions are more sluggish with alkyl in position 3 than aryl in the

same position.

N

OH

R1

O

H

O

CH3

N

R1

Cl

Cl

O

CH3POCl

3

57 58

reflux

CH3 CH

3CH

2R

1p-Cl

a b d e f

p-MeO m-Cl

g

79 82 97 97 92 84

time (h)12 8 12 8 24 24

Yield (%)

Scheme 4

All structures were confirmed by spectroscopic and analytical data (IR, 1H-and

13C-NMR, and elemental analyses). In the 1H-NMR spectrum of compound 58g,

the meta coupling between H-5 and H-7 was not well resolved, thus the signal

of C-5 proton appeared as singlet at 7.35 ppm and the signal C-7 proton

coupled with C-8 appeared as doublet at 7.47 ppm (J = 8.8 Hz).



The signal of C-8 proton observed at 7.86 ppm also appeared as doublet (J =

8.8 Hz). In contrast, in the case of compound 58b, the 1H-NMR spectrum

showed the overlap correlation signals between H-7 and two protons from aryl

ring at 7.57-7.64 ppm, on the other hand between H-5 and two others protons

from aryl ring at 7.45-7.48 ppm. Thus, the conclusive assignment could be

possible with the roof effect technique as described below:

A doublet at 7.45 ppm (J = 1.8 Hz) corresponding to C-5 proton.

A doublet at 7.47 ppm (J = 8.2 Hz) corresponding to two protons aryl

patterns (HBB’).

A doublet at 7.59 ppm (J = 9.2 + 2.0 Hz) corresponding to C-7 proton.

A doublet at 7.63 ppm (J = 8.2 Hz) corresponding to two protons aryl

patterns (HAA’).

A doublet at 7.99 ppm (J = 9.2 Hz) corresponding to C-8 proton.

2.2.5. Regioselective hydrolysis of 2,4-dichloro-3-substituted

quinolines 58

Reaction of 2,4-dichloro-3-substituted quinolines 58a-g in the presence of 70

% methanesulfonic acid in n-butanol under reflux allowed the regioselective

conversion of 2-chloro substituted compounds 58a-g into the 2-oxo derivatives

59a-g in excellent yields of 80-94 %.

All structures were characterized by spectroscopic and analytical data, with the

presence of the lactam carbonyl bands at 1640-1666 cm-1 in infrared spectra,

and the signals of N-H protons in the 1H-NMR were observed at 11.95-12.21

ppm. The complete assignment of compounds 59a and 59e in the 1H-NMR

spectra could not obtained because of many overlaps between the aromatic

rings.



N

R1

Cl

Cl

O

CH3

N

R1

Cl

O

H

O

CH3CH

3SO

3H / n-BuOH

58 59

reflux

CH3

CH3CH

2R1

p-Cl

58, 59 a b d e f

p-MeO m-Cl

g

Yield (%)

time (h) 84 45 45 30 48 48

93 94 90 89 92 80

Scheme 5

2.2.6. Introduction of the cyano group into 4-chloro-6-methoxy-

3- substituted quinolin-2(1H)-ones 59

The introduction of the cyano group in position 4 of 4-chloro-6-methoxy-3-

substituted quinolin-2(1H)-ones 59a-g was carried out by reaction with dry

potassium cyanide mediated by sodium p-toluenesulfinate, similar as

described in chapter 1.2.11. The substitution of 4-chloro of 3-aryl-4-

chloroquinolin-2(1H)-ones 59a,b,d,e with p-methoxy, p-chloro, m-chloro and

hydrogen as substituents at the 3-phenyl moiety worked cleanly, the phenyl

ring and its substituents remained unaffected and the yields of 96-98 %

obtained were excellent. The substituents on the phenyl moiety and the

reaction time did not influence the yields.

However, the substitution of 4-chloro against cyano in the case of compounds

59f, g having either methyl or ethyl in position 3 did not proceed, probably due



to the low reactivity of electron-donating group such as ethyl or methyl in

position 3 of compounds 59f, g, the starting materials were recovered.

The compounds 60a,b,d,e were characterized by spectroscopic and analytical

methods. The most relevant signals of lactam carbonyl in the infrared spectra

corresponded to an intense absorption bands at 1658-1670 cm-1, and weak

peaks at 2229-2236 cm-1 assigned to nitrile. In the 13C-NMR spectrum of

compound 60a, the two carbons CAA’ and two carbons CBB’ of pattern benzene

ring appeared at 113.8 and 132.1 ppm respectively and their intensities are

higher. In the case of compound 60e, the 13C-NMR spectrum also exhibited two

higher peaks at 129.8 and 130.2 ppm respectively corresponding to two

carbons CAA’ and two carbons CBB’ of pattern benzene ring. Mass spectra of

compounds 60a,d,e using APCI and/or ESI methods showed the base peaks

with 100 %.

N

R1

Cl

O

O

CH3

N

R1

O

H

CN

O

CH3KCN / p-toluenesulfinate Na, DMF

120-130 °C

59 60

R1

CH3

CH3CH

2m-Clp-MeO p-Cl

a b d e f

Yield (%)

g59, 60

time (h) 72 63 43 45 48 48 72

96 98 97 96

Scheme 6



2.2.7. Synthesis of 2-chloro-6-methoxy-3-phenylquinoline-4-

carbonitrile (61)

The conversion of the 2-oxo compound 60e to the reactive 2-chloro moiety in

compound 61 could be performed by reaction with phosphoryl chloride under

reflux at 110 °C to give 2-chloroquinoline-4-carbonitrile 61 in excellent yield of

95 %.

Similar results were obtained [21] by reacting 6,7-dimethoxy-4-

(trifluoromethyl)quinolin-2(1H)-one in phosphoryl chloride using conventional

heating.

The infrared spectrum of the obtained 2-chloro-4-carbonitrile did not show the

carbonyl band and in the 1H-NMR spectrum the signal of NH proton

disappeared, compared with the starting material 6-methoxy-2-oxo-3-

phenylquinoline-4-carbonitrile 60e.

N O

H

O

CH3

CN

N

O

CH3

Cl

CNPOCl3

110 °C, 12 h

95 %

60e 61

Scheme 7

2.2.8. Synthesis of ethyl 3-[(4-methylphenyl)amino]-

2-[(4-methoxyphenyl)carbamoyl]-3-oxopropanoate 64

Attempts to prepare ethyl 4-hydroxy-6-methoxy-2-oxo-1,2-dihydroquinoline-

carboxylate 63 from primary arylamine such as p-anisidine 1 and triethyl

methanetricarboxylate 62 by conventional heating to 160-220 °C without any

solvent similar as described in ref. [90] using secondary benzo amine such as

tetrahydro-indole or 1,2,3,4-tetrahydroquinoline failed.



When diphenyl ether was added as solvent to the mixture of compounds 1 and

62 under a nitrogen atmosphere for 3 hours, the starting material was

consumed, however the product was not isolated. The reaction of 1 and 62 was

also unsuccessfully attempted in N-methyl-2-pyrrolidone (NMP) at 210 °C

during 5 days.

In the best case, the reaction of 1 with 62 in bromobenzene under reflux gave

an unexpected dianilide 64 in 84 % yield. The structure was confirmed by

infrared and 1H-NMR data.

A. Kutyrev and T. Kappe [91] have obtained the compounds of type B (R 2-

hydroxy-4-oxo-1,9a-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylate), C

(methyl 4-oxo-4H-pyrimido[1,2-a]pyrimidine-3-carboxylate), and D (methyl 7-

hydroxy-5-oxo-8,8a-dihydro-5H-[1,3]thiazolo[3,2-a]pyrimidine-6-carboxylate)

by reacting respectively pyridine-2-amine, pyrimidin-2-amine or 1,3-thiazol-2-

amine as primary amines with trialkyl methanetricarboxylate under

conventional heating.

N

N

O

OH

O

O

R

B

N

N

N

O

OH

O

O

CH3

C

N

NS

O

OCH

3

O

OH

D

Figure 1

J. Jampilek et al. [92] have reported the synthesis of ethyl -4-hydroxy-2-oxo-

1,2-dihydroquinoline-3-carboxylate 67 (Scheme 27) in 50 % yield using aniline

and triethyl methanetricarboxylate under microwave conditions.

According to these findings, it was speculated that no quinolin-2(1H)-ones can

be obtained from primary aniline derivatives using conventional heating.

Moreover, the methods of the preparation of 3-ethoxycarbonylquinolin-2(1H)-

ones can greatly depend on the character of their substituents at the nitrogen

atom or in the benzene part of the molecule.



NH

O

CH3

O

NHO

OCH

3

O

O

CH3

O

NH2

CH3

EtOOC

EtOOC

COOEtO

CH3

NH

O

OH

COOEt

64

PhBrreflux, 6 h

86 %

+

1 62 63

Scheme 8

2.2.9. Synthesis of ethyl 4-hydroxy-2-oxo-1,2-

dihydroquinoline-3-carboxylate (67)

Compounds of type 67 are known as powerful acylating agents [93]. They

readily react with primary and many secondary aliphatic, aromatic and

heterocyclic amines to give the corresponding amides in high yields [94-97].

They also are good synthons for the synthesis of thiosemicarbazones which

present a broad spectrum of pharmacological activities such as

antiproliferative [98] and antiamebal [99] activity. Thiosemicarbazones are

effective in the fight against malaria [100], the herpes simplex virus [101],

carcinoma of the prostate gland [102], hormone dependent breast cancer [103],

and other types of malignat neoplasms [104, 105]. Also, the large use of the

thiosemicarbazones is found in the treatment of various microbial infections

[106-113].



In the literature [114] a rather complicated procedure is used, and in the

literature [115] no exact reaction conditions are described for the preparation

of compounds of type 67. Compound 67 was obtained according the procedure

described in ref. [116], starting from the commercially available methyl

anthranilate 65 which was treated with diethylmalonate and sodium ethoxide.

During the reaction, the formed ethanol was distillated off and the solid

mixture heated for 15 hours at about 140-150 °C until no further ethanol was

liberated.

O

O

CH3

NH2 N

OH

O

H

COOEt

O

O

OEt

OEt

EtONa / EtOH, HCl

+140-150 °C, 15 h

77 %

65 66 67

Scheme 9

The compound was isolated, purified and characterized by spectroscopic

analyses. Infrared spectrum showed the lactam carbonyl signal at 1638 cm-1

and at 1669 cm-1 the absorption band for the ester carbonyl. The low frequency

for an ester carbonyl group is well known [117] and is caused by strong

intramolecular hydrogen bonding [118]. In the 1H-NMR spectrum, the signal of

OH proton was observed at 13.40 ppm and the signal of NH proton at 1.50

ppm. The presence of the ester in the 1H-NMR was confirmed by a triplet at

1.31 ppm and a quadruplet at 4.34 ppm assigned respectively to methyl and to

methylene of the ethyl group.



2.2.10. Bischlorination of ethyl 4-hydroxy-2-oxo-1,2-

dihydroquinoline-3-carboxylate (67) with phosphoryl

chloride

Bischlorination at positions 2 and 4 of ethyl 4-hydroxy-2-oxo-1,2-

dihydroquinoline-3-carboxylate (67) in phosphoryl chloride using triethyl

amine as catalyst in order to prevent slow and incomplete reactions caused by

hydrogen bonding between hydrogen group and the ester carbonyl group,

occurs readily and the expected ethyl 2,4-dichloroquinoline-3-carboxylate 68

could be isolated in excellent yield of 98 %.

By reacting compound 67 in phosphoryl chloride at 100 °C without the use of

triethyl amine, I. V. Ukrainetes et al. [119] obtained 68 in only 12 % yield

besides a side compound ethyl 2-chloro-4-hydroxyquinoline-3-carboxylate E in

69 % yield.

N

OH

O CH3

O

Cl

E

Figure:2

The presented synthetic procedure using triethyl amine as catalyst is a simple,

convenient and practical route to transform compound 67 to compound 68 as

a single product and in an excellent yield.

The infrared spectrum of compound 68 showed only the ester carbonyl band at

1728 cm-1, the signal of lactam carbonyl disappeared, and in the 1H-NMR

spectrum the signal of NH proton was not observed.

N

OH

O

H

COOEt

N

COOEt

Cl

ClPOCl3 / Et

3N

67 68

60 °C, 2 h

98 %

Scheme 10



2.2.11. Synthesis of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-

3-carboxylate (70)

The reaction of one equivalent of ethyl 2,4-dichloroquinoline-3-carboxylate 68

in the presence of 3.1 equivalent of 70 % methanesulfonic acid was performed

in different solvents such as methanol, ethanol or n-butanol, under reflux for

20-24 hours. In all cases the unexpected reaction product 4-hydroxyquinolin-

(1H)-one 69 was isolated in which not only the chloro atoms in position 2 and

4 of ethyl 2,4-dichloroquinoline-3-carboxylate 68 was exchanged against the

hydroxy group but surprisingly also the ester group in position 3 was cleaved.

The use of a lower reaction temperature and/or a shorter reaction time in order

to prevent the cleavage of ester in position 3 of 68 were unsuccessful. The

cleavage of 3-ester might be attributed to the use of excess amount of stronger

Brönsted acid such as methanesulfonic acid.

Infrared spectrum of the obtained compound 69 showed only the lactam

carbonyl band at 1653 cm-1 and a broad signal in the range of 3093-2560 cm-1

was ascribable to NH. The 1H-NMR spectrum clearly showed that the 3-ester

group was cleaved, it rather showed a singlet at 5.72 ppm assigned to C-3

proton. The signal of NH proton appeared at 11.29 ppm. The reported melting

point (mp > 350 °C) was in accordance with the literature [120-128].



N

COOEt

Cl

Cl

N O

H

OH

N O

H

COOEt

Cl

CH3SO

3H

CH3SO

3H

68

69 70

3.1 equiv.

MeOHor n-BuOHor EtOH

in

71-77 %

1.54 equiv.

in

EtOH67 %

reflux, 24 hreflux, 48 h

Scheme 11

Finally, the best reactions conditions were found by using one equivalent of 68

in the presence of 1.54 equivalent of 70 % methanesulfonic acid in n-butanol.

The reaction mixture was refluxed for 48 hours to form the desired 4-chloro-2-

oxo-1,2-dihydroquinoline-3-carboxylate (70) in 67 % yield.

The structure elucidation was based on the spectroscopic analyses. Infrared

spectrum of compound 70 showed the lactam carbonyl band at 1649 cm-1 and

a strong signal of ester carbonyl clearly appeared at 1736 cm-1. In the 1H-NMR,

the ethyl group of ester appeared as a singlet at 1.31 ppm corresponding to

methyl (CH3) and at 4.34 ppm a quadruplet corresponding to methylene (CH2).

The infrared and 1H-NMR spectra of compound 70 were in accordance with the

literature [116].



2.2.12. Synthesis of 4-hydroxyquinolin-2(1H)-one 69

Cyanation attempts upon 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate

70 with dry potassium cyanide in the presence of sodium p-toluenesulfinate as

catalyst in dry dimethylformamide were unsuccessful. Surprisingly the infrared

spectrum of the isolated compound 69 did not show the signal of ester

carbonyl. The signal of the lactam carbonyl was observed at 1653 cm-1 In the

1H-NMR spectrum a broad signal was observed at 11.29 ppm assigned to OH

proton, caused by the replacement of chloro by the hydroxy in position 4 of 70

and an additional singlet observed at 5.72 ppm due the presence of C-3 proton

indicating the cleavage of 3-ester group, which confirmed the structure of

compound 69, similar as already obtained in chapter 2.2.11.

N

Cl

O

H

COOEt

N O

H

COOEt

CN

N

OH

O

H

70

7169

KCN / p-toluenesulfinate Na, DMF 130 °C, 24 h

97 %

Scheme 12



2.2.13. N-Alkylation of 4-chloro-3-(4-chlorophenyl)-6-

methoxyquinolin-2(1H)-one 59b with ethyl

bromoacetate

Treatment of 3-aryl-4-chloroquinolin-2(1H)-one 59b with ethyl bromoacetate in

the presence of dry sodium carbonate gave as expected ethyl [4-chloro-3-(4-

chlorophenyl)-6-methoxy-2-oxoquinolin-1(2H)-yl]acetate (72) in excellent yield

of 95 % but it was found to be very difficult to purify.

Comparison of infrared data of 59b and 72 indicated the appearance of an

ester carbonyl band at 1737 cm-1 in compound 72, caused by the formation of

the N-ester at position N-1, the amide carbonyl band was observed at 1638 cm-

1. In the 1H-NMR spectrum, the NH proton disappeared, however, the presence

of a singlet at 5.14 ppm was observed corresponding to N-CH2 proton, at 4.16

ppm a quadruplet corresponding to O-CH2 proton, the methyl group of ester

function appeared as triplet at 1.21 ppm.

N O

H

O

CH3

ClCl

N

O

CH3

Cl

O

O

O

CH3

ClBrCH

2COOEt / Na

2CO

3, DMF

120 °C, 25 min.

95 °C

59b

72

Scheme 13



2.3. CONCLUSION

3-Aryl-4-cyanoquinolones are readily obtained in excellent yields from the

starting 4-chloro analogues after easy work-up. The phenyl ring and its

substituents remained unaffected. These compounds showed encouraging

emission spectra and may prove to be potential candidates for FRET

experiments due to their long and favorable emission wavelength values (λmax

emis. = ~510 nm). But in the case of compounds 60b and 60d having chlorine

on the aryl moiety, the purification was very difficult. However, in the case of

ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate 70, the reaction to 4-

cyano analogue gave an unwanted product.

Chapter 3: SYNTHESIS OF 6,7-DIMETHOXY-2-OXO-1,2-DIHYDROQUINOLINE-3,4-DICARBONITRILE 113


CHAPTER 3

SYNTHESIS OF 6,7-DIMETHOXY-2-OXO-1,2-

DIHYDROQUINOLINE-3,4-DICARBONITRILE



Chapter 3: SYNTHESIS OF 6,7-DIMETHOXY-2-OXO-1,2-

DIHYDROQUINOLINE-3,4-DICARBONITRILE

3.1. INTRODUCTION

It was shown previously that 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile derivatives exhibited excellent spectroscopic properties but have

the disadvantage of the low quantum yield of fluorescence (see chapter 4).

Knowing that an additional methoxy group in position 7 is required to

improved the quantum yield, we envisioned to synthesized 3,4-

dicyanocarbostyrils in order to increase the quantum yield of 3,4-

dicyanocarbostyrils compounds.

On the other hand, the advantages of 6,7-dimethylcarbostyrils were

shown in their use as fluorescence energy transfer systems [129, 130a], in the

study of luminescence resonance transfer techniques [129a], incorporated in a

time resolved pH-sensor as covalently attached europium complex [129b], for

the use in sensor and luminescence devices [130b-e].

3.2. RESULTAS AND DISCUSSION

3.2.1. Synthesis of 4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one

(74) as precursor

4-Hydroxyquinolin-2(1H)-one moiety is the basic structure found in

many natural products such as flavipucine, the long known and highly toxic

ricinime and the yellow pigments bassianin and tellenin [37], it plays also an



important role as precursor in various reactions such as transformation into

quinoline nucleus, which is a framework of many pharmacologically active

compounds with antiasthmatic [131], antibacterial [132], antifungal [133],

antimalarial [134], anti-viral [135], and anti-inflammatory [136] activities.

Commercially available 4-aminoveratrol (73) was treated with dry

malonic acid 2 in phosphoryl chloride as condensing agent similar as described

in ref. [18] to form 4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one (74) in 84 %.

Infrared spectrum of 74 showed the lactam carbonyl band at 1682 cm-1. 1H-

NMR spectrum revealed the signal of NH proton as singlet at 11.06 ppm and

the singlet of C-3 proton was observed at 5.64 ppm.

O

CH3

O

CH3

NH2 NO

CH3

O

CH3

H

OH

O

COOH

COOH

POCl3

1) 50 °C, 3 h2) 90 °c, 30 min.

+84 %

73 2 74

Scheme 1

3.2.2. Bischlorination of 4-hydroxy-6,7-dimethoxyquinolin-

2(1H)-one (74) with phosphoryl chloride

The nucleophilic displacement of the 4-hydroxy group and the

conversion of 2-oxo of compound 74 by chlorine was easily performed by

reaction with phosphoryl chloride to form 2,4-dichloro-6,7-dimethoxyquinoline

(75) in 84 %.

Comparison of spectral data of compounds 74 and 75 clearly showed the

absence of lactam carbonyl signal in the infrared spectrum of 75, and in the

1H-NMR spectrum of 75, the signal of NH proton disappeared indicating the

conversion of the 2-oxo into 2-chloro group.



NO

CH3

O

CH3

H

OH

O NO

CH3

O

CH3

Cl

Cl

POCl3

7475

reflux, 8 h

84 %

Scheme 2

3.2.3. Regioselective hydrolysis of 2,4-dichloro-6,7-

dimethoxyquinoline (75)

2,4-Dichloroquinoline 75 in n-butanol, was hydrolyzed regioselectively in

the presence of 70 % methanesulfonic acid at position 2, to give 4-chloro-6,7-

dimethoxyquinolin-2(1H)-one (76) in excellent yield of 96 %.

The structure was confirmed by infrared and 1H-NMR spectra. Infrared showed

again a strong lactam carbonyl signal at 1656 cm-1, the absorption band at

3418 cm-1 was assigned to NH. In the 1H-NMR spectrum the signal of NH

proton appeared at 11.84 ppm.

Comparison of the signal of C-3 proton of compounds 75 and 76 showed

that the chemical shift of C-3 proton shifted down field with the

electronegativity of the neighboring group.

NO

CH3

O

CH3

Cl

Cl NO

CH3

O

CH3

H

O

ClCH3SO

3H / n-BuOH

75 76

reflux, 48 h

96 %

Scheme 3



3.2.4. Chlorination of 4-hydroxy-6,7-dimethoxyquinolin-

2(1H)-one (74) with sulfuryl chloride

Electrophilic substitution of the hydrogen atom at position 3 of 4-

hydroxy-6,7-dimethoxyquinolin-2(1H)-one 74 by chlorine was easily achieved

by substitution reaction with sulfuryl chloride as chlorination agent, which is

well known as Cl+ generator for electrophilic ionic reactions at these conditions,

to give 3,3-dichloroquinolin-2,4-dione 77 in 82 % yield. The reaction was

performed at a temperature below 60 °C to avoid many unwanted by-products,

which are very difficult to separate.

Infrared spectrum showed a strong lactam carbonyl band at 1673 cm-1 and at

1709 cm-1 a ketone carbonyl band. In the 1H-NMR spectrum the signal of NH

proton was observed at 11.29 ppm. The elemental analysis was consistent with

the proposed structure.

NO

CH3

O

CH3

H

OH

O NO

CH3

O

CH3

H

O

Cl

Cl

OSO2Cl

2 / dioxane

74 77

40-60 °C

82 %

Scheme 4

3.2.5. Reduction of 3,3-dichloro 6,7-dimethoxyquinolin-

2,4(1H,3H)-dione (77) to 3-chloro-4-hydroxyquinolin-

2(1H)-one 78

The reduction reaction of 3,3-dichloroquinolin-2,4-dione 77 was

achieved by treatment with ethanol/acetic acid mixture using zinc-dust as

reduction agent under reflux, similar as described in chapter 1.2.8, to form 78

in 87 %.



The assignment of 3-chloro-4-hydroxyquinolin-2(1H)-one 78 was confirmed by

1H-NMR, IR, and elemental analysis. Infrared showed the absence of ketone

carbonyl at C-4 position.

NO

CH3

O

CH3

H

O

Cl

Cl

O

NO

CH3

O

CH3

H

OH

O

ClZn / EtOH, AcOH

77 78

reflux

87 %

Scheme 5

3.2.6. Bischlorination of 3-chloro-4-hydroxy-6,7-

dimethoxyquinolin-2(1H)-one 78

It was shown in chapter 1.2.11 that 3,4-dichloroquinolin-2(1H)-one is

suitable reactive for the introduction of dicyano groups. The follow-up step in

the introduction of 3,4-dicyano groups in the 2-quinolone core was the

chlorination of 78 at positions 2 and 4 with phosphoryl chloride to give 2,3,4-

trichloroquinoline 79 in excellent yield of 92 %.

The structure was characterized by spectroscopic and analytical data (IR, 1H-

NMR, and elemental analysis). Comparison of 1H-NMR data of 78 and 79

revealed the absence of NH proton in 79 and in the infrared spectrum, the

lactam carbonyl band was not observed.

NO

CH3

O

CH3

H

OH

O

Cl

NO

CH3

O

CH3

Cl

Cl

ClPOCl

3

78 79

reflux, 8 h

92 %

Scheme 6



3.2.7. Regioselective hydrolysis of 2,3,4-trichloro-6,7-

dimethoxyquinoline 79

2,3,4-Trichloroquinoline 79 was hydrolyzed regioselectively at position 2

by reaction with 70 % methanesulfonic acid in n-butanol to form 3,4-

dichloroquinolone 80 in 73 % yield. Compound 80 was found to be highly

reactive for the introduction of the dicyano groups.

In the infrared the signal of lactam carbonyl appeared at 1671 cm-1 and in the

1H-NMR spectrum the singlet of NH proton was observed at 12.37 ppm. The

elemental analysis confirmed the proposed structure.

NO

CH3

O

CH3

Cl

Cl

Cl

NO

CH3

O

CH3

Cl

Cl

O

H

CH3SO

3H / n-BuOH

79 80

110 °C, 24 h

73 %

Scheme 7

3.2.8. Introduction of the cyano groups into

4-chloroquinolin-2(1H)-ones 76 and 80

The introduction of the cyano at positions 3 and 4 of compounds 76 and

80 were achieved by nucleophilic substitution of chlorine, mediated by sodium

p-toluenesulfinate as catalyst.

In the case of 4-chloro-3-unsubstituted quinolone 76 the purity and the

yield of the obtained product are not sufficient, the reaction needs longer time

and involves probably the intermediate 81a (R = H), which is less reactive in

the formation of 3,4-dicyanocarbostyril 82. However, with the highly reactive

3,4-dichloroquinolin-2(1H)-one 80, the clean 3,4-dicyanocarbostyril 82 could

be easily obtained in 80 % just after 5 hours reaction time.



NO

CH3

O

CH3

H

O

R

Cl

NO

CH3

O

CH3

O

CN

CN

H

KCN / Na p-toluenesulfinate, DMF

NO

CH3

O

CH3

O

CN

R

H

H Cl

76, 80

82

130 °C

81a, b

R

82

Yield (%)

time (h) 86 5

57 80

76: R = H80: R = Cl

Scheme 8

In the infrared spectrum, an intensive absorption band observed at 1665 cm-1

was assigned to the lactam carbonyl and the signal of cyano appeared at 2230

cm-1. 1H-NMR spectrum showed the signal of NH proton at 12.94 ppm. The

elemental analysis found was in accordance with the theoretical percentages.

Mass spectrum using APCI negative method showed only one peak with 100 %

corresponding to the base peak with the mass 254. However, using ESI positive

method with the fragmentor voltage 50 V, mass spectral analysis showed

additional signals which could be assigned as adducts of compound 82. The

base peak with the mass 278 could be identified as the combination between

one molecule of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile

82 and one sodium ion [M + Na]+. Furthermore, the mass 533 can be identified

as the combination between two molecules of 82 and one molecule of sodium

ion with 49 % intensity, the mass 294 and 256 of the complex [M + K]+ and



[M + H]+ could be observed with 39 and 36 % intensities respectively. The mass

of 209 corresponding to the loss of a methyl radical was also observed; its

intensity was weak (24 %) because the resulting radical is less stable.

Additionally, the dimeric material was observed, which means this compound

is very interesting for the study of its reactivity towards polymers for instance.

3.2.9. Alkylation of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile (82)

3.2.9.1. N-Methylation of 6,7-dimethoxy-2-oxo-1,2-

dihydroquinoline-3,4-dicarbonitrile (82)

Methylation of 82 with methyl iodide as alkylation agent in the presence

of dry sodium carbonate as the base was achieved similar as described in

chapter 1.2.27, to give the expected 6,7-dimethoxy-1-methyl-2-oxo-1,2-

dihydroquinoline-3,4-dicarbonitrile (83) in excellent yield of 88 %.

Infrared spectrum of 83 exhibited a strong absorption signal at 1637 cm-1

ascribable to amide carbonyl, the 1H-NMR spectrum showed an additional

singlet at 4.06 ppm assigned to N-CH3.

NO

CH3

O

CH3

O

CN

CN

H

NO

CH3

O

CH3

O

CN

CN

CH3

CH3I / Na

2CO

3, DMF

8283

90-100 °C, 15 min.

88 %

Scheme 9



3.2.9.2. Alkylation of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline

-3,4-dicarbonitrile (82) with ethyl bromoacetate

When compound 82 was treated with ethyl bromoacetate as alkylation

agent and dry sodium carbonate as the base, thin layer chromatography (TLC)

analysis showed a mixture of two products, which were separated by

recrystallization from toluene-acetone (9:1), to give the ethyl [3,4-dicyano-6,7-

dimethoxy-2-oxoquinolin-1(2H)-yl]acetate 84 in 56 % yield besides the isomer

O-alkylated product 85 in 29 %.

Infrared spectrum of compound 84 showed the an intensive absorption

band at 1659 cm-1 ascribable to amide carbonyl and another strong band at

1732 cm-1 assigned to ester carbonyl. Infrared spectrum of compound 85 did

not show the amide carbonyl, however, the ester carbonyl was observed 1761

cm-1. 1H-NMR spectrum of compound 84 showed a triplet at 1.23 ppm

corresponding to CH3 and a quadruplet at 4.19 ppm corresponding to CH2 of

the ethyl group. A singlet observed at 5.26 ppm corresponds to CH2 of acetate.

1H-NMR spectrum of compound 85 exhibited the signals almost at the same

positions, with a triplet a 1.21 ppm corresponding to CH3 of ethyl, a quadruplet

at 4.19 ppm corresponding to CH2 of ethyl and a singlet at 5.22 ppm

corresponding to CH2 of the acetate. It should be noted that the similar

chemical shift values for N-ester and O-ester in the 1H-NMR spectra have been

already obtained in our group with similar compounds [18, 60a].

In the 13C-NMR spectrum of compound 84, the most relevant signals

were observed at 167.6 ppm corresponding to the ester-C=O, at 157.4 ppm the

signal of the lactam-C=O, at 114.7 ppm the signal of CN at position 4 and at

113.5 ppm the signal of CN at position 3. The structure was confirmed by the

elemental analysis.



NO

CH3

O

CH3

O

CN

CN

H

NO

CH3

O

CH3

O

CN

CN

O

CH3

O

BrCH2COOEt / Na

2CO

3, DMF

ONO

CH3

O

CH3

CN

CN

O

CH3

O

84

80 °C, 15 min.

85

+

56 %

29 %

82

Scheme 10

3.2.10. N-Alkylation of 6,7-dimethoxy-2-oxo-1,2-

dihydroquinoline 3,4-dicarbonitrile (82) with ethyl

bromoacetate

In order to prevent the side O-alkylation reaction in the reaction of 6,7-

dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 82 with ethyl

bromoacetate, the modified procedure described by W. J. Bannwarth et al.

[130a] was used appliying lithium diisopropylamide (LDA) as base for the

deprotonation at N-1 position instead of sodium carbonate. The lithium

diisopropylamide led to a quantitative deprotonation of compound 82 under

the mild conditions followed by the attack of ester to give 84 in 65 % yield. This

way avoid at the same time the formation of the O-alkylated product. The

structural investigations were similar to those obtained previously.



NO

CH3

O

CH3

O

CN

CN

H

NO

CH3

O

CH3

O

CN

CN

O

CH3

O

LDA / THF

BrCH2COOEt

82

84

0 °C, 30 min.

3) r.t., 15 h

2)

1) 0 °C, 1 h

65 %

Scheme 11

3.3. CONCLUSION

As previously reported in chapter 1, an additional methoxy group in

position 7 of 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 7 was

necessary to improve the quantum yield of fluorescence and the resulting

compound 82 and its N-alkylated analogues exhibited interesting fluorescence

properties.

It was observed that in the reaction of the N-alkylation of 6,7-dimethoxy-

2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile 82, with ethyl bromo acetate,

using sodium carbonate as base, a mixture of N- and O-alkylated product was

obtained. To avoid such a side O-alkylated by-product, lithium

diisopropylamine (LDA) has been used instead of sodium carbonate.

Chapter 4: Systematic investigation of substituent effects on Fluorescence and photo. properties125

PhD-Thesis-Universiy of Graz/Austria-2010 ENOUA Guy Crépin

CHAPTER 4

SYSTEMATIC INVESTIGATION OF SUBSTITUENT

EFFECTS ON FLUORESCENCE AND

PHOTOPHYSICAL PROPERTIES OF

4-CYANOCARBOSTYRIL DERIVATIVES



Chapter 4: SYSTEMATIC INVESTIGATION OF SUBSTITUENT

EFFECTS ON FLUORESCENCE AND

PHOTOPHYSICAL PROPERTIES OF

4-CYANOCARBOSTYRIL DERIVATIVES

4.1. INTRODUCTION

Coumarins both naturally occurring as well as from syntheses are used

in a great number of fluorescence applications [1-7], such as fluorescent dyes

[8], photosensitizers [9], laser dyes [10-14] or pH indicators in biochemistry

and medicine [15-16].

Survey of the literature showed that only a few studies have been paid to

their aza-analogues quinolin-2(1H)-ones (carbostyrils) [10, 17-26], probably

because of their lower extinction coefficients, shorter absorption and emission

wavelengths, and more-cumbersome tuning of photophysical properties [27-

30]. However, the important advantages of carbostyrils are their high stability

against chemicals compared with coumarins [6b, 6c], and to many other

fluorescent dyestuffs [38] such as fluorescein, thermal and photochemical

stress (e.g. compared with azodyes), and they are not sensitive to oxygen

quenching (compared with e.g. 1,10-phenanthroline complexes). All these

properties make them very useful as for instance fluorescence markers in e.g.

natural polymers [32-36].

O. A. Ponomarev and coworkers published their efforts on the

photochemical data of a reasonably number of analytes [18-22].

Recently, our group has shown that by systematic investigation substituent

effects using the push-pull concept [37] with two electron donating group

(EDG) such as methoxy or amino in the position 6 and/or 7, and an electron



withdrawing group (EWG) such as trifluoromethyl (CF3) in the position 4 of

carbostyrils, we could improve their absorption, emission and fluorescence

quantum yields comparable to those of coumarins [37, 38]. About 140

structures were calculated and synthesized, and we found out absorption

maxima in a range of 350-380 nm, emission maxima at 410-425 nm and

fluorescence quantum yields up to 0.41, almost the same fluorescence

properties like umbelliferone (7-hydroxycoumarin).

More recently [31], our group investigated on the effect of a strong

electron withdrawing cyano group in the position 4 combined with methoxy as

electron donor groups in the positions 6 and 7 of the carbostyril derivatives.

The spectra revealed a broad double maximum at 385 nm and 410 nm in polar

and apolar solvents, independent of the pH value (pH 1-11), an emission range

of 430-440 nm in all solvents, and fluorescence quantum yields up to 0.5 were

obtained. This means, 4-cyanocarbostyril derivatives were useful new

fluorophores and well suited as fluorescence standards [31].

The construction of Fluorescence Resonance Energy Transfer (FRET)

carbostyril complexes such as Valinomycin-carbostyrils, FRET with rhodamin

[39] or FRET peptides with [RuII(bathophenanthroline)] complex [40] is suited

for the characterization of biochemical events both in vitro and in vivo, and also

it involves binding of ligands to their pertinent protein receptors [41-42], DNA-

protein complexation [43-45], and RNA-folding and catalysis [46-47].

In this chapter, we describe the fluorescence of 3,4-dicyano carbostyril

derivatives and compare their photophysical properties with others carbostyrils

previously investigated, differently substituted, and also with some dimeric

carbostyrils [bisquinolin-2(1H)-ones]. In addition, fluorescence properties of 4-

sulfinyloxycarbostyrils 8 and U are also described.




4.2.1. Influence of methyl, trifluoromethyl and cyano groups on

the fluorescence properties on quinolones core

Coumarins with electron donating group such as methoxy in position 7

(e.g. coumarin A1) compared with simple coumarin A, show blue fluorescence

of 415 nm wavelengths and good quantum yield up to 0.6. But in alkaline

solution, coumarins suffer ring opening, this losing fluorescence properties.

O

CH3

OMeO O

CH3

O

N

CH3

O

H

A1 A B 7-methoxy-4-methylcoumarin 4-methylcoumarin 4-methylcarbostyril

Figure 1

Table 1. Photophysical data for absorption and emission of compounds A1, A and B

A1 A B

Absorption (nm) 320 330 330

Emission (nm) 415 380 375

Quantum yield 0.6 0.002 0.02

In comparison with coumarins analogues, methoxy group in position 7 of

4-methyquinolone C (Table 2) lowers fluorescence properties, but shows good

pH-stability, almost no solvent dependency; the quantum yield of 0.052 is very

low, therefore not suitable for fluorescence applications. Compared with 6-

methoxyquinolone D (Table 2), 7-methoxyquinolone C has a high extinction

coefficient (ε =10000) and the emission maximum of 342 nm.



Table 2. Photophysical data for published carbostyril derivatives (letter

assigned in order to be distinguished from the new Compounds)

Cpd

Structure

Solvent

λmax 1

UV-Vis (nm)

2

λmax 2

UV-Vis

(nm)

2

λmax

em. (nm)

Φ

C N

CH3

O

H

MeO

DMSO

340

10000

-

-

370

0.052

D N

CH3

O

H

MeO

DMSO

-

6550

-

-

353

0.033

E

N

CH3

O

H

MeO

MeO

DMSO

346

9000

-

-

392

0.08

F

N

CF3

O

H

MeO

MeO

DMSO

H2O

368

365

9400

10400

-

-

-

438

428

0.470

0.450

G

N O

H

MeO

MeO

CN

DMSO

397

11300

385

11200

440

0.308

H

N

CF3

O

MeO

CH3

MeO

DMSO

H2O

365

365

9700

10100

-

-

435

428

0.340

0.160

I

N O

MeO

CH3

MeO

CN

DMSO

H2O

390

380

12400

11000

-

-

-

-

436

432

0.610

0.500

J

N

Cl

O

MeO

CH3

MeO

DMSO

*

358

372

-

-

-

412

0.017

* Double maximum

(continued on next page)



Table 2 (continued)

Cpd

Structure

Solvent

λmax 1

UV-

Vis (nm)

2

λmax 2

UV-

Vis

(nm)

2

λmax

em. (nm)

Φ

K NNH

2

CF3

O

H

MeO

DMSO

373

438

L N

CF3

O

H

NH2

MeO

DMSO

404

7350

533

0.380

M N

CF3

O

H

MeO

(CH3)2N

DMSO

384

8470

557

0.280

N N O

CN

MeO

O

O

CH3

MeO

DMSO

EtOH

H2O

390

385

380

12400

13100

11000

-

-

-

-

-

-

436

432

432

O N O

MeO

O

O

CH3

MeO

CF3

DMSO

368

8000

-

-

430

0.269

P N O

MeO

MeO

CF3

O

O

CH3

DMSO

350

9280

337

8300

384

0.143



Table 2b: Photophysical data for selected new synthesized carbostyril

derivatives.

Cpd

Structure

Solvent

λmax 1

UV-Vis (nm)

2

λmax 2

UV-Vis

(nm)

2

λmax

em. (nm)

Φ

7

N O

H

CN

CN

MeO

DMSO

460

4760

319

7310

545

0.130

9 N O

MeO

H

CN

DMSO

394

5400

-

-

461

0.106

33

N O

H

MeO

CN

DMSO*

372

357

7550

7930

310

8410

406

0.110

38 N O

MeO

H

CF3

DMSO

374

5220

-

-

450

0.058

44 N O

MeO

CH3

CN

DMSO

396

4960

-

-

460

0.075

45 N O

CH3

CN

CN

MeO

DMSO

459

5720

321

8600

543

0.080

46 N O

CN

CN

MeO

O

O

CH3

CH3CN

DMSO

451

455

5400

5400

1.000

0.944

10000

9440

535

550

0.150

0.018

82

N O

H

CN

CN

MeO

MeO

CH3CN

DMSO

443

451

13200

12270

341

345

8775

8360

520

525

0.460

0.235

83 N O

CH3

CN

CN

MeO

MeO

DMSO

455

5000

349

3300

521

0.171

* Double maximum (continued on next page)



Table 2b (continued)

84 N O

CN

CN

MeO

O

O

CH3

MeO

CH3CN

DMSO

CH3OH

H2O

442

451

440

440

9250

10850

9320

9520

344

350

344

347

6440

7540

6160

6190

520

520

520

520

0.300

0.088

0.359

0.078

85 N O

CN

CN

MeO

MeO

O

O

CH3

DMSO

406

10000

353

7000

472

*

* The compound was not completely free of N-alkylated carbostyril isomer 84.

4.2.2. The effects of methoxy groups in positions 6 and/or 7

Spectral data of 7-methoxy and 6-methoxy 4-methylquinolone C and D (Table

2) show compared with those of 6,7-dimethoxy-4-methylquinolone E (392 nm,

Table 2) an 20 respectively 40 nm redshifted absorption maximum. The

fluorescence quantum yield of E (Φ = 0.08) is only slightly higher than the

monomethoxy 4-methylanalogues. Extinction coefficient of C is with about

10000 about 25% higher than that of D and E. When the electron donating 4-

methyl group was replaced by an electron-withdrawing 4-trifluoromethyl

group, 6,7-dimethoxyquinolone F (Table 2) exhibited a red shifted emission at

438 nm in DMSO. The fluorescence quantum yield (Φ = 0.47) is 83 % higher

than for the 6,7-dimethoxyquinolone E, the absorption maximum is about 20

nm red shifted, whereas the extinction coefficient is rather similar.

N

CH3

O

H

MeO

N

CH3

O

H

MeO

N

CH3

O

H

MeO

MeO

N O

H

MeO

MeO

CF3

C D E F

Figure 2



4-Trifluoromethyl-6,7-dimethoxyquinolone F and 6-methoxy-4-

trifluoromethylquinolone 38 (Table 2b) show that the removal of the methoxy

0.47 vs 0.06) and 50 % reduction of the extinction coefficient. However, note

the slightly blue shifted absorption and emission maxima of F.

N O

H

MeO

MeO

CF3

N O

H

MeO

CF3

N O

H

MeO

CF3

NH2

N O

H

MeO

CF3

NH2

F 38 K L

Figure 3

Comparison of 6,7-dimethoxy-4-trifluoromethylquinolone F with 7-

amino-6-methoxy analogue K (Table 2) [48] shows that absorption and

emission maxima are very similar. One can conclude that the amino group in

position 7 of the 2-quinolone has the same effect on the fluorescence properties

as a methoxy group at the same position.

In contrast, by comparing the data of 4-trifluoromethylquinolone F with

those of 6-amino-7-methoxy-4-trifluoromethylquinolin-2(1H)-one L (Table 2)

[37a], there were not the same effects observed. A bathochromic shift was

found for the latter with an absorption maximum of 403 nm and an emission

maximum of 533 nm, whereas the fluorescence quantum yield of 0.38 is about

20 % lower than F.

N O

CH3

MeO

MeO

CF3

H M

Figure 4

N

CF3

O

H

MeO

(CH3)2N



The N-methylation of 6,7-dimethoxy-4-trifluoromethylquinolone F

yielded 6,7-dimethoxy-1-methyl-4-trifluoromethylquinolone H (Table 2), which

presents almost the same absorption and emission maxima, and extinction

coefficient in DMSO and in water. However, the fluorescence quantum yield is

much less in water for N-methylderivative H. When F is compared with 6-

dimethylamino-7-methoxy-4-trifluoromethylquinolin-2(1H)-one M (Table 2)

[37a], replacement of the 6-methoxy by the 6-dimethylamino group leads to the

highest fluorescence wavelength of 557 nm, which is 120 nm red shifted

compared with F. This increasing of fluorescence can be deduced from the

strongly electron delivering dimethylamino group, whereas the quantum yield

of 0.28 is 2 times less than for F.

Similarly, 6,7-dimethoxy-1-methyl-4-trifluoromethylquinolone H and 4-

chloro-6,7-dimethoxy-1-methylquinolone J (Table 2) bearing respectively

trifluoromethyl and a chloro group in position 4 show that, their absorption

maxima do not differ significantly, but emission maxima of H (λmax em. = 435

nm) having a strong acceptor group trifluoromethyl (CF3) in position 4 is only

23 nm longer wavelength compared with compound J, and the chloro

substituent in position 4 (compound J,

fluorescence quantum yield compared with compounds H I

0.61). As also can be seen in Table 2, more strongly fluorescing 4-cyano

derivative I absorbs also with 390 nm about 20 nm blueshifted compared with

trifluoromethyl analogue H). Also the fluorescence quantum yield in water is 68

% better.

N O

CH3

MeO

MeO

CF3

N O

H

MeO

CF3

(CH3)2N

N

Cl

CH3

O

MeO

MeO

N O

CH3

MeO

MeO

CN

H M J I

Figure 5



N O

R

MeO

CN

N O

MeO

CN

MeO

R

N O

R

MeO

CN

4.3. ELECTRONIC SPECTRA OF THE NEW CARBOSTYRILS

4.3.1. Known 4-cyano-3-H-6,7-dimethoxy-carbostyrils

Figure 6

6- And 7-methoxy substituted 4-cyanoquinolones 9 and 33 (Table 2b)

showed that methoxy in position 7 shifted in the absorption and emission

maxima to shorter wavelength, but have a somewhat better extinction

coefficient (ε = 7550), versus 5400 for compound 9 having the methoxy in

position 6. This confirms once again that only a methoxy in position 7

increases the extinction coefficient.

3,4-Dicyanocarbostyril 7 (Table 2b) is absorbing and emitting at higher

wavelength than 3-H-4-cyano analogue 9 (Table 2b) and 3-arylsubstituyed-4-

cyanoanalogue 60a-e. In contrast, 3-aryl substituted-4-cyanoanalogue 60a-d

show no change in the absorption wavelength compared with 3-H-4-cyano

analogue 9. However, emission of 60a-d is red shifted by about 50 nm, the

quantum yield is about 54 % higher than 9. For compound 60e which contains

only a phenyl in position 3, the fluorescence quantum yield is about 50 %

lower compared with 9.

N

MeO

CN

O

H

CN

N

MeO

CN

O

H

R

7 60a-e

Figure 7



4-Trifluoromethylquinolone F (Table 2) [38] and 4-cyanoquinolone G

(Table 2) [31] which are different only at the acceptor group in position 4, and

dicyanocarbostyril 7 (Table 2b) show that the fluorescence spectra of these

three dyes F, G and 7 are significantly red-shift in more polar solvent (DMSO).

Emission maxima of F and G are nearly similar due to the fact that the main

electron withdrawing group cyano in F has almost the same electro negativity

effect as that of trifluoromethyl in G. However, in the similar 4-trifluoromethyl

H (Table 2) and 4-cyano-6,7-dimethoxycarbostyrils I (Table 2) containing an

additional methyl group at N-1, we observed an excellent fluorescence

quantum yield for I ( = 0.61 in DMSO). In both cases, the absorption intensity

is higher for G and I having cyano in position 4.

N O

H

MeO

MeO

CF3

N

MeO

CN

O

H

MeO

N O

CH3

MeO

MeO

CN

N O

CH3

MeO

MeO

CF3

F G I H

Figure 8

Until this work was done, compounds F and G were the most push-pull

efficiently substituted known carbostyrils. To our surprise, the effect of an

additional 3-cyano substituted (compound 7) showed a dramatic increment of

absorption maximum to 460 nm at pH = 1, and emission maximum to 545 nm

but this absorption is less bright at pH = 9.2 (λmax. = 322 nm), with a large

Stoke’ s shift of 85 nm compared with 4-cyanocarbostyrils 9 (Table 2b) and

60a-e (Table 3), this is due to the presence of the additional cyano group in

position 3 of 4-cyanocarbostyril 7. However, the lack of a methoxy group in

position 7 of 4-cyanocarbostyril 7 lowered the fluorescence quantum yield and

extinction coefficient. These disadvantages (low fluorescence quantum yield

and extinction coefficient) were overcome with the introduction of an additional

methoxy group in position 7, compound 82 which will be described later.



In the case of coumarins, it has been observed that the presence of a

strong electron withdrawing group, such as cyano or ester group in position 4

on the parent chromophore leads to enhanced non-radiative rates for

coumarins [49-55] and in differents solvents.

Rettig and El-Kemary [56] have shown that the cyano group in position 4

of coumarins (coumpounds Q and R) exhibited a strong red shift compared to

the corresponding primary coumarin C153 [57], indicating that the effective

size of the -system is larger for coumarins Q and R than for compound C153.

ON O

S

NCN

ON O

O

NCN

Cl

Q R

ON

CF3

O

Coumarin 153 (C153)

Figure 9

However, different from our carbostyrils, they exhibit a strong

dependence on solvent polarity, being most effective in non polar solvents. In

Acetonitrile and especially in DMSO, quantum yields are lowered by 50 % and

80 % respectively. Data in water were not published.

These findings are however also in contrast to 4-trifluorometyl coumarin

C153, which does not show this solvent polarity dependence.



By comparing the data of 6,7-dimethoxy-1-methyl-2-oxo-1,2-

dihydroquinoline-4-carbonitrile I (Table 2) with those of 6-methoxy-1-methyl-2-

oxo-1,2-dihydroquinoline-4-carbonitrile 44 (Table 2b), one can confirm once

again that methoxy in position 7 combined with N-methyl (compound I) have a

significant increment on the fluorescence quantum yield and absorption

I

44 in DMSO). The highest increasing of fluorescence quantum yield is

especially due to the presence of a strong acceptor group in position 4 and a

strong donor group in position 7 at the carbostyril. In contrast, with electron

donating group such as methyl in position 4, this increasing of fluorescence

quantum yield is not substantial even if carbostyrils contain methoxy groups

in positions 6 and 7 (compound E Table 2). However, in the case of 3,4-

dicyanoquinolones 82 and 83 (Table 2b) the effects of N-methyl are

exceptionally reversed. The reasons of this quenching are not clear, since we

did not observe it in the case of 4-cyanoquinolones G versus I.

N

MeO

CN

O

H

MeO

N O

CH3

MeO

MeO

CN

N

CH3

O

H

MeO

MeO

N

MeO

CN

O

CH3

G I E 44

N

MeO

CN

O

H

CN

MeO

N

MeO

CN

O

CH3

CN

MeO

82 83

Figure 10



The shape and wavelength of the absorption and emission bands are not

affected by the three 4-cyanocarbostyril derivatives 7, 45 and 46 (Table 2b)

differently substituted at position N-1; however their fluorescence quantum

yields are affected. The fluorescence quantum yield of 0.08 for the N-

methylquinolone 45 is about 38 % less when compared to compound 7 having

NH at position 1. This weak fluorescence quantum yield is more pronounced

when compound 7 -1 to give N-methylquinolone 46

= 0.018).

N

MeO

CN

CN

O

H

N

MeO

CN

O

CH3

CN

N

MeO

CN

O

CN

O

O

CH3

7 45 46

Figure 11

In order to optimize the low fluorescence quantum yield of 0.13 obtained

with 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (compound 7,

Table 2b), 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile

(compound 82, Table 2b) was prepared; the UV-visible absorption spectrum of

compound 82 shows absorption maximum at 443 nm and epsilon coefficient of

ε = 13200 in acetonitrile, and absorption maximum at 451 nm, epsilon

coefficient of ε = 12270 in DMSO, while for compound 7 the absorption

maximum was observed at 460 nm and extinction coefficient was only ε = 4760

in DMSO. The emission maximum of 525 nm for compound 82 in DMSO is

only 20 nm blue-shifted compared to compound 7. However, compound 82

shows large Stoke’s shift of about 80 nm with an excellent fluorescence

quantum yield of about 50 %, which is 20 % more than fluorescein at pH 3.3 in

acetonitrile, due to the replacement of hydrogen against the methoxy group at

position 7. The new chomophore (compound 82) which showed intense

luminescence, exhibited a double maximum and can be therefore excited at a

wavelength range of 350-430 nm, is a promising probe for further



investigations as an optical sensor for pH measuring, oxygen or environmental

important gases such as ammonia.

0

50

100

320 370 420 470 520 570 620

Figure 12: Excitation (dotted line) and emission (continuous line) spectra for

carbostyrils 7 (red curves), 82 (blue curves) and fluorescein (black

curves).

Comparison of 3,4-dicyanocarbostyrils 82, 83 (Table 2b) and 84 (Table

2c) leads to the same observations as for 3,4-dicyanocarbostyrils 7, 45, and 46

(Table 2b), with the only difference that the absorption coefficient is about 50

% less for 83 compared to 82 and 84. However, in all solvents compound 84

shows similar absorption and emission spectra with the main peaks around

450 nm and 520 nm respectively, which means that the spectra show virtually

no solvent dependence, but there is an increasing in the fluorescence quantum

yields along the series H2O < DMSO < CH3CN < CH3OH.



N

MeO

CN

O

H

CN

MeO

N

MeO

CN

O

CH3

CN

MeO

N

MeO

CN

O

CN

O

O

CH3

MeO

82 83 84

Figure 13

4.3.2. O- versus N-Alkylation

A side product of N- alkylation of 82 was at position 2 O-linked 3,4-

dicyanoquinoline 85 (Table 2b), which causes a small blue shift of absorption

and emission maxima compared to N-alkylated 3,4-dicyanoquinolone 84 (Table

2b), The fluorescence data of N-alkylated-4-cyanocarbostyril N are almost

solvent insensitive for the absorption and emission wavelengths.

O

O

CH3

N

MeO

CN

OMeO

O

O

CH3

N

MeO

CN

O

CN

MeO

84 85

Figure 14

4.3.3. Influence of differently substituted aryl groups in

position 3 on the fluorescence properties

3-Aryl substituted-6-methoxyquinolone derivatives have not been

described previously. We investigated substituent effects in position 3 on the



fluorescence properties. 3-Arylquinolone derivatives (table 3) have been

synthesized and 3-aryl-4-hydroxy (57) and 3-aryl-4-cyanoquinolone (60)

derivatives were selected for fluorescence investigations.

Luminescence spectra of these 3-aryl-4-cyanoquinolones show the

similar absorption maxima of about 410 nm and emission maxima of about

510 nm, which are respectively 20-40 nm and 50-70 nm shifted to the longer

wavelengths compared to the simple 4-cyano or 4-trifluoromethylquinolones

derivatives such as compounds F, G (Table 2), 9, 33 and 38 (Table 2b).

However the fluorescence quantum yields are bellow to 10 %.

The influence of substituents at the aryl moiety is weak and has almost

no effect on the fluorescence, while one can see some differences regarding the

quantum yield of fluorescence depending of the meta or para substituent at the

aryl moiety (compounds 60b, 60d, Table 3).



Table 3. Photophysical data of selected 3-arylcarbostyril derivatives.

Cpd

Structure

Solvent

λmax 1

UV-

Vis (nm)

2

λmax 2

UV-

Vis

(nm)

2

λmax

em. (nm)

Φ

S

N

CN

O

MeO

CH3

MeO

DMSO

-

-

485

0.500

T N O

MeO

H

MeO

CF3

OMe

DMSO

368

20800

-

-

435

0.210

57b

N O

MeO

H

OHCl

DMSO

352

8720

-

-

416

0.034

57e N O

MeO

H

OH

DMSO

-

8070

-

-

351

0.040

60a

N

CN

O

MeO

H

OMe

DMSO

405

10370

341

8490

503

0.198

60b N

CN

O

MeO

H

Cl

DMSO

406

6840

311

9270

510

0.228

60d N

CN

O

MeO

H

Cl

DMSO

408

5500

310

7080

510

0.113

60e N

CN

O

MeO

H

DMSO

H2O

4850

5100

-

-

-

-

505

500

0.057

0.050



4.3.4. Stacking cyanocarbostyrils

Table 4. Photophysical data of stacking cyanocarbostyrils.

Cpd

Concentration

Solvent

λmax 1

UV-Vis (nm)

2

λmax 2

UV-Vis

(nm)

2

λmax

em. (nm)

23

2 mm cell

4.00E-05 CH3CN 497 5025 264 5025 567

0.081

DMSO 470 4320 320 5200 557

0.102

H2O 454 5400 322 6450 553

0.130

4.00E-06 CHCl3 452 5250 320 10500 522

0.203

N

O

O

CN

CN

N

O

O

CN

NC

N

CN

O

MeO

H

CN

Concentration dependence in DMSO only

1.00E-05 DMSO 460

8.00E-05 DMSO 479 4320 320 5200 557 0.102

1.00E-04 DMSO 483 4640 319

2.20E-04 DMSO 490 4668 316

4.30E-04 DMSO 497

3.00E-03 DMSO 507

32

NMeO

CN

OH

DMSO

425

1100

-

-

500

0.019



These stacking cyanocarbostyrils 23 and 32 (table 4) were prepared

under the same conditions as for 4-cyanocarbostyril derivatives 7 and 33 (table

2b) respectively, using a short reaction time. To our surprise, compound 23,

which is the lactim form of compound 7 exhibits remarkable fluorescence

properties with an absorption maximum at 497 nm and an emission maximum

of about 570 nm in acetonitrile, ever observed so far with carbostyrils. In

DMSO and in water, compound 23 is absorbing in the range of 454-470 nm,

emitting at about 560 nm, and shows the fluorescence quantum yield of about

10-13 %, with an excellent Stoke’ s shift of about 100 nm in water. The

fluorescence quantum yield is 2-times higher than those of the best

biscarbostyrils published [49]. This means that the new 3,4-dicyanocarbostyril

derivatives far outclass all biscarbostyrils in terms of absorption, emission

maxima, fluorescence quantum yields and Stoke’ s shifts data.

N

O

OH

CN

CN

N

O

OH

CN

NC

NMeO

CN

OH

23 32

Figure 15

It should be noticed that the fluorescence data of 23 are nearly the same

as those of its isomer compound 7 in DMSO with the only difference for the

extinction coefficient. The values of Stoke’s shifts increase with increasing

solvent polarity.

The absorption maxima of 23 are concentration and solvent dependence,

which means the absorption maxima increase with increasing of concentration.

However, spectral data of 23 in chloroform at 4.10-6 M. lowered slightly the

absorption and emission maxima, but exhibited a high extinction coefficient (ε

= 10500) and a better fluorescence quant F = 0.203). Interestingly,

when compound 23 was more diluted in DMSO to 3.10-3 M. in 2 mm cell the

absorption maximum moved up to 520 nm.



In contrast, in the case of 7-methoxy-cyanocarbostyril 32, the absorption

maximum of 425 nm and the emission maximum of 500 nm are respectively

53 nm and 94 nm shifted to longer wavelength regions compared with its

lactam form 33 (table 2b), whereas the fluorescence quantum yield and

extinction coefficient are much lower.

4.3.5. Fluorescence properties of 4-sulfinyloxycarbostyrils

Table 5. Photophysical data of 4-sulfinyloxycarbostyrils.

Cpd

Concentration

Solvent

λmax 1

UV-

Vis (nm)

2

λmax 2

UV-

Vis

(nm)

2

λmax

em. (nm)

Φ

8 N O

MeO

H

OS

O

CH3

DMSO

385

7750

-

-

490

0.180

U

N O

MeO

H

OS

O

CH3

MeO

DMSO

378

9180

-

-

486

0.270

The absorption maximum of 4-toluenesulfinyloxycarbostyril 8 (Table 5)

does not differ significantly from that of 4-cyanoquinolone 9 (Table 2b). To our

surprise, the emission maximum is 490 nm, 30 nm red-shifted compared with

9 higher than

the quantum yield observed for 4-cyanoquinolone 9, the epsilon coefficient (ε =

7700) is higher than 4-cyanoquinolone 9 (ε = 5400). We conclude that p-

toluenesulfinate at position 4 of carbostyrils is stronger electron-withdrawing

than a cyano group. These findings prompted us to measure also the

absorption and emission data of the already previously published 6.7-

dimethoxy analogue U. As hoped, the presence of sulfinate in position 4 and



two electron delivering groups in pos 6 and 7 revealed a strongly redshifted

emission maximum at 486 nm, which is compared with F even 10 nm and

about 50 nm shifted to longer wavelength regions. Not so exciting is the

fluorescence quantum yield because it is about 50 % of F. The absorption

maximum is 386 nm hence we observed in case U a 100 nm Stoke´s shift.

4.4. CONCLUSION

Compared with published 4-cyano-6,7-dimethoxy push-pull substituted

carbostyrils, the novel 3,4-dicyano analogues show vastly improved absorption

and emission properties. For example, 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile 7 shows a red shift of 66 nm compared with 6-methoxy-2-

oxo-1,2-dihydroquinoline-4-dicarbonitrile 9 and 6,7-dimethoxy analogue 82

absorbed with 451 nm, a red shift of 57 nm compared with 9.

6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7) shows excellent

spectroscopic properties. In addition, a methoxy group in position 7 is

required to improve the fluorescence quantum yield. The new carbostyril

chromophores 7 and 82 presenting a second maximum above 300 nm have

the possibility to be excited both in UV and visible regions that make them to

promising candidates for the construction of FRET molecules, and might be

useful as alternatives to established probes for biological investigations.

GENERAL CONCLUSION 148


GENERAL CONCLUSION

In conclusion, the current study demonstrates that the synthesis of 3,4-

dicyanoquinolones via the reactive 3-acetylamino-, 3-chloro- or 3-nitro-4-

chloroquinlones derivatives in presence of sodium p-toluenesulfinate and

potassium cyanide is an efficient and convenient method for the introduction of

the cyano groups into the heterocyclic moiety. The higher and interesting

spectroscopic properties of compounds 7 and 82 as well as their N-linkers

make them the probes of potential interest for attachment to biomolecules

such as peptides, proteins, carbohydrates.

The synthesis of 3,4-dicyanoquinolones via 3-H-4-chloroquinolones were

found to be very difficult to obtain. In this way the purity and the yields were

not sufficient. The syntheses of 3-aryl-4-cyanoquinolones are characterized by

an easier work-up and good yields. Absorption and emission of N-H

carbostyrils and their N-alkylated are very similar.

In view of possible applications of the new dyes (e.g. as fluorescent labels

in biological systems), compounds 7, 82 as well as their N-linkers have

greatest interest since these dyes can be linked to biomolecule through N-1

position and are well suited as fluorescence standards for FRET applications.

EXPERIMENTAL PART 149


EXPERIMENTAL PART

FOR

CHAPTERS 1, 2 AND 3



EXPERIMENTAL PART

General Remarks:

Melting points (Mp) were determined with a Stuart SMP3 melting point

apparatus in open capillary tubes.

1H and 13C NMR spectra were recorded with a Bruker AMX 360 instrument

(360 or 90 MHz) or a Bruker Avance III instrument (300 MHz), or a Bruker

Avance DRX 500 instrument (500 or 125 MHz). The operator gives a locator

number called the Chemical Shift having units of parts per million (ppm) and

designated by the symbol , from the internal TMS standard. Data are reported

as follows: (recorded as: s, singlet; d, doublet; dd, doublet of doublets; t, triplet;

q, quadruplet and m, multiplet), coupling constants (J in Hertz, Hz),

integration, and assignment (phenyl, Ph; aryl, Ar).

Infrared spectra (IR) were recorded with a Mattson Galaxy Series FTIR 7020

instrument with potassium bromide discs or a Bruker Alpha –P, with

Attennated Total Reflectance (ATR) measurement, using a reflexion method and

are reported in terms of frequency of absorption (, cm-1), end expressed as: s,

strong; m, medium; w, weak; br, broad.

Elemental analyses were performed at the Microanalytical laboratory of the

University of Vienna, Austria.

Mass spectra (MS) were obtained with a HP 1100 LC/MSD mass spectral

instrument (positive or negative APCI ion source, 50–200 V, nitrogen) or

(positive or negative ESI ion source, 50–200 V, nitrogen). Mass spectral data

are reported as m/z.



UV/Vis spectra were recorded with a Shimadzu UV/Vis scanning

spectrophotometer UV-2101 PC; concentration: 1x10–4 M.

Fluorescence data: Excitation and emission spectra were recorded with a

Perkin-Elmer LS50B luminescence spectrometer.

Determination of quantum yields: emission signals were set in relation to the

known area of the emission signal of quinine sulfate at pH 1. Corrections were

made for other solvents by using the factor (nwater/nsolvent) [ex-1].

Analytical HPLC was performed with a Shimadzu LC 20 system equipped with

a diode array detector (215 and 254 nm) with a Pathfinder AS reversed phase

(4.6150 mm, 5 µm) column, running an acetonitrile/water gradient (30–100 %

acetonitrile).

All reactions were monitored by thin-layer chromatography (TLC) on 0.2-mm

silica gel F-254 (Merck) plates by using UV light (254 and 366 nm) for

detection, and are expressed in reference frontal (Rf).

Dry column flash chromatography [ex-2] was carried out on silica gel 60 H

(5-40 µm) (Merck, Darmstadt, Germany). Common reagent-grade chemicals

were either commercially available and were used without further purification

or prepared by standard literature procedures. All optical measurements were

performed by using analytical-grade solvents.

X-Ray structures were solved by Prof. Dr. U. WAGNER at the Karl Franzens

University of Graz, Austria. The structure determination was performed on an

automatic four-circle Siemens P3/PC diffractometer, using graphite

monochromatized MoK radiation (0.71069 ) at 293 K, /2 scanning, 2

max.50°. The structure was solved by direct methods using the SHELX97

program package [83].



4-Hydroxy-6-methoxyquinolin-2(1H)-one (3)

A mixture of p-anisidin (1: 18.90 g, 154.0 mmol) and dry malonic acid (2:

23.40 g, 225.0 mmol) in phosphoryl chloride (24.0 mL, 40.08 g, 261.0 mmol)

was heated in an open flask to 95 °C for 90 minutes under stirring with a

thermometer, then cooled to 20 °C, poured onto ice/water (500 mL) and filtered

by suction. The precipitate was dissolved in aqueous sodium hydroxide (1000

mL, 1 M) under warming to 60 °C. The remaining insoluble solid [mainly N,N'-

bis (4-methoxyphenyl)malonamide (4)] was filtered.

To the alkaline filtrate, concentrated hydrochloric acid was added until pH = 1–

2 was reached, the precipitate filtered by suction, washed with water and dried

at 40 °C under reduced pressure, which afforded 4-hydroxy-6-

methoxyquinolin-2(1H)-one (3). The yield was 21.290 g (73 %), yellow prisms,

mp 324-328 °C (methanol), lit. mp 298–320 °C [ex-3, ex-4].

Rf = 0.23 (chloroform/aceton 3:7).

IR (ATR-measurement): 3434 (m), 3290 (s), 1663 (w), 1642 (s), 1616 (w), 1602

(w), 1539 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO-d6): = 3.77 (s, 3 H, CH3O), 5.79 (s, 1 H, 3-H),

7.14 (dd, J = 8.9 + 2.7 Hz, 1 H, 7-H), 7.20 (d, J = 8.8 Hz, 1 H, 8-H), 7.21 (d, J =

2.8 Hz, 1 H, 5-H), 11.08 (s, 1 H, NH).

C10H9NO3 (191.19).

N,N'-Bis(4-methoxyphenyl)malonamide (4)

This compound was obtained as insoluble solid during the work-up of

compound 3. The solid was purified by recystallization from acetic acid-

methanol (1:3). The yield was 9.167 g (19 %), grey prisms, mp 228.1–231.1 °C

(acetic acid-methanol), lit. mp 226–240 °C [ex-3a-c, ex-5, ex-6, ex-7, ex-8].


IR (KBr): 3435 (m), 1655 (w), 1620 (s), 1588 (s) cm -1.



1H-NMR (360 MHz, CDCl3): = 3.49 (s, 2 H, CH2), 3.81 (s, 6 H, 2 CH3O), 6.88

(d, J = 8.8 Hz, 4 H, Ar-H), 7.45 (d, J = 8.8 Hz, 4 H, Ar-H), 8.64 (s, 2 H, NH).

C17H18N2O4 (314.34).

2,4-Dichloro-6-methoxyquinoline (5)

A solution of 4-hydroxy-6-methoxyquinolin-2(1H)-one (3: 3.710 g, 19.42 mmol)

in phosphoroxychloride (45.0 mL) was heated under reflux for 8 hours. The

excess amount of phosphoroxychloride was removed under reduced pressure.

The residue was poured onto ice/water (300 mL) and brought to pH = 4–6 with

aqueous sodium hydroxide (5 M), filtered by suction, and washed with water.

The solid was dried at 40 °C under reduced pressure, to give 2,4-dichloro-6-

methoxyquinoline (5). The yield was 3.733 g (83 %), brown prisms, mp 175–

177 °C (ethanol), lit. mp: 130 °C [ex-9].


IR (KBr): 3439 (s), 1622 (m), 1564 (m) cm-1.

1H-NMR (360 MHz, [D6]DMSO): = 3.95 (s, 3 H, CH3O), 7.43 (d, J = 2.6 Hz, 1

H, 5-H), 7.57 (dd, J = 9.1 + 2.7 Hz, 1 H, 7-H), 7.92 (s, 1 H, 3-H), 7.95 (d, J =

9.2 Hz, 1 H, 8-H).

C10H7Cl2NO (228.08).

4-Chloro-6-methoxyquinolin-2(1H)-one (6)

A solution of 2,4-dichloro-6-methoxyquinoline (5: 13.30 g, 58.33 mmol) and 70

% methanesulfonic acid (37.0 g, 25 mL, 385.42 mmol) in ethanol (300.0 mL)

was heated under reflux for 28 hours. The mixture was cooled to 20 °C and

poured into ice/water (100 mL), brought to pH = 4–6 with sodium hydroxide (2

M), filtered by suction, washed with water and dried at 40 °C under reduced

pressure, to give 4-chloro-6-methoxyquinolin-2(1H)-one (6). The yield was

11.552 g (94 %), brownish prisms, mp 296–300 °C (toluene).




IR (KBr): 1645 (s), 1623 (m), 1576 (w), 1569 (w), 1558 (w), 1541 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.83 (s, 3 H, CH3O), 6.82 (s, 1 H, 3-H), 7.27

(dd, J = 7.6 + 2.5 Hz, 1 H, 7-H), 7.31 (d, J = 2.6 Hz, 1 H, 5-H), 7.34 (d, J = 8.5

Hz, 1 H, 8-H), 11.95 (s, 1 H, NH).

13H-NMR (360 MHz, [D6]DMSO): = 56.0 (CH3O), 106.3 (3-C), 117.8 (8-C),

118.2 (10-C), 121.7 (5-C), 112.1 (7-C), 133.6 (9-C), 143.8 (4-C), 155.1 (6-C),

160.4 (lactam-C=O).

MS (APCI pos): m/z (%) = 212 (30, M + 2), 211 (13, M + 1), 210 (100, M).

MS (APCI neg): m/z (%) = 210 (35, M +2), 209 (10, M + 1), 208 (100, M), 193 (7,

M - 15).

Anal. for C10H8ClNO2 (209.63).

Calcd: C 57.30, H 3.85, N 6.68

Found: C 57.21, H 3.70, N 6.62

6-Methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7)

Pathway A

A mixture of 4-chloro-6-methoxyquinolin-2(1H)-one (6: 0.600 g, 2.86 mmol),

sodium p-toluenesulfinate (1.068 g, 6.0 mmol), and potassium cyanide (0.465

g, 7.15 mmol) in dry dimethylformamide (17.0 mL) was heated to 140 °C for 43

hours with vigorous stirring. The solution was cooled to 20 °C, poured into

ice/water (100 mL) and acidified with concentrated hydrochloric acid to pH =

1–2. Then it was filtered by suction, washed with water and dried at 40 °C

under reduced pressure, to afford 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile (7). The yield was 0.41g (64 %), yellow prisms, mp 303–305 °C

(acetonitrile).




Pathway B

A mixture of compound 6-methoxy-2-oxo-1,2-dihydroquinolin-4-yl 4-

methylbenzenesulfinate (8: 1.00 g, 3.04 mmol) and potassium cyanide (0.600


hours, and worked up as described for the pathway A, to give 6-methoxy-2-

oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7). The yield was 0.396 g (58 %),

yellow prisms, mp 307–310 °C (acetic acid).


Pathway C

A mixture of 6-methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (9: 1.00 g,

5.0 mmol), sodium p-toluenesulfinate (2.140 g, 12.02 mmol) and potassium

cyanide (0.975 g, 15 mmol), in dry dimethylformamide (30.0 mL) was heated to

140 °C for 65 hours with vigorous stirring and worked-up using the procedure

described for the pathway A, to give 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile (7). The yield was 0.812 g (72 %), red prisms, mp 309–312 °C

(acetone).


Pathway D

A mixture of 3,4-dichloro-6-methoxyquinolin-2(1H)-one (13: 0.620 g, 2.54

mmol), sodium p-toluenesulfinate (0.950 g, 5.34 mmol) and potassium cyanide

(0.413 g, 6.35 mmol), in dry dimethylformamide (15.0 mL) was heated to 140

°C for 46 hours with vigorous stirring and worked-up using the procedure

described for the pathway A, to give 6-methoxy-2-oxo-1,2-dihydroquinoline-

3,4-dicarbonitrile (7). The yield was 0.408 g (72 %), red prisms, mp 302–306 °C

(acetone).


Pathway E

A mixture of 4-chloro-6-methoxy-3-nitro-quinolin-2(1H)-one (16: 32.0 mg, 0.13

mmol), potassium cyanide (30.0 mg, 0.46 mmol) and sodium p-

toluenesulfinate (50.0 mg, 0.27 mmol) in dry dimethylformamide (1.0 mL), was



heated to 140 °C for 2.5 hours and worked-up using the procedure described

for the pathway A, to give 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile (7). The yield was 0.026 g (93 %), red prisms, mp 301–304 °C

(acetonitrile).


Pathway F

A mixture of N-(4-chloro-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)acetamide

(18: 1.670 g, 6.27 mmol), potassium cyanide (1.018 g, 15.67 mmol) and

sodium p-toluenesulfinate (2.342 g, 13.16 mmol) in dry dimethylformamide

(38.0 mL), was heated to 140 °C for 45 hours with vigorous stirring and worked

up using the procedure described for the pathway A, to give 6-methoxy-2-oxo-

1,2-dihydroquinoline-3,4-dicarbonitrile (7). The yield was 1.373 g (86 %), red

prisms, mp 300–302 °C (acetonitrile).


Pathway G

A mixture of 4-chloro-6-methoxy-3-piperidin-1-ylquinolin-2(1H)-one (22:

0.338 g, 1.16 mmol), sodium p-toluenesulfinate (0.440 g, 2.47 mmol) and

potassium cyanide (0.200 g, 2.90 mmol), in dry dimethylformamide (7.0 mL)

was heated to 140 °C for 5 days with vigorous stirring and worked up using the

procedure described for the pathway A, to give 6-methoxy-2-oxo-1,2-

dihydroquinoline-3,4-dicarbonitrile (7). The yield was (66 %), red-green prisms.


IR (KBr): 2972–2742 (w, br), 2228 (w), 1650 (s), 1615 (w), 1555 (w), 1498 (m)

cm-1.


H, 5-H), 7.42 (d, J = 9.2 Hz, 1 H, 8-H), 7.52 (dd, J = 9.2 + 2.7 Hz, 1 H, 7-H),

13.08 (s, 1 H, NH).

13C-NMR (360 MHz, [D6]DMSO): = 56.3 (CH3O), 106.5 (3-C), 113.4 (8-C),

114.6 (10-C), 116.7 (5-C), 118.8 (CN), 126.4 (7-C), 129.5 (9-C), 135.8 (4-C),

156.1 (6-C), 157.0 (lactam-C=O).



MS (API-ESI neg): m/z (%) = 225 (15, M + 1), 224 (100, M), 209 (6, M – 15).

Anal. For C12H7N3O2 (225.21).

Calcd: C 64.00, H 3.13, N 18.66

Found: C 63.70, H 3.00, N 18.33

6-Methoxy-2-oxo-1,2-dihydroquinolin-4-yl

4-methylbenzenesulfinate (8)

Pathway A


and sodium p-toluenesulfinate (6.880 g, 38.66 mmol) in dry

dimethylformamide (150.0 mL) was heated to 120 °C for 20 hours. The

resulting solution was cooled to 20 °C and poured into ice/water (500 mL). The

obtained solid was filtered by suction, washed with water and dried at 40 °C

under reduced pressure to afford 6-methoxy-2-oxo-1,2-dihydroquinolin-4-yl 4-

methylbenzenesulfinate (8). The yield was 5.836 g (69 %), yellow prisms, mp

255–258 °C (dioxane).


Pathway B

This compound was obtained during the work-up of the compound 9 from 3-

chloro-6-methoxyquinolin-2(1H)-one (6) by crystallization from dioxane and the

separated solid was recrystallized from dioxane to yield 8, 1.256 g (32 %),

yellow prisms, mp 256–259 °C (dioxane).


IR (ATR-measurement): 3146 (w), 2955 (w), 2839 (w), 1667 (s), 1622 (w), 1596

(w), 1559 (w), 1503 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 2.38 (s, 3 H, CH3), 3.73 (s, 3 H, CH3O),

7.24 (s, 1 H, 3-H), 7.26 (dd, J = 9.0 + 2.7 Hz, 1 H, 7-H), 7.33 (d, J = 9.1 Hz, 1

H, 8-H), 7.46 (d, J = 2.8 Hz, 1 H, 5-H), 7.48 (d, J = 8.2 Hz, 2 HBB´ Ar-H), 7.96 (d,

J = 8.4 Hz, 2 HAA´ Ar-H), 12.31 (s, 1 H, NH).



13C-NMR (300 MHz, [D6]DMSO): = 21.6 (CH3), 66.8 (CH3O), 106.7 (3-C),

118.3 (Aromatic-C), 121.4 (Aromatic-C), 125.7 (Aromatic-C), 128.4 (Aryl-C),

130.9 (9-C + 2 x Aryl-CBB´), 136.2 (2 x Aryl-CAA´), 146.1 (Aryl-C), 147.5 (4-C),

154.6 (6-C), 159.8 (lactam-C=O).

MS (API-ESI neg): m/z (%) = 329 (21, M + 1), 328 (100, M).

Anal. for C17H15NO4S (329.38).

Calcd: C 61.99, H 4.59, N 4.25 O 19.43

Found: C 61.83, H 4.38, N 4.50 O 19.67

6-Methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (9)

Methode A

A mixture of compound 6-methoxy-2-oxo-1,2-dihydroquinolin-4-yl 4-

methylbenzenesulfinate (8: 1.00 g, 3.04 mmol) and potassium cyanide (0.30 g,

4.62 mmol) in dry dimethylformamide (150.0 mL) was heated to 70 °C for 5

hours. The solution was cooled to room temperature, poured into ice/water

and acidified with concentrated hydrochloric acid to pH = 1–2. The resulting

solid was filtered by suction, washed with water and dried at 40 °C under

reduced pressure to afford 6-methoxy-2-oxo-1,2-dihydroquinoline-4-

carbonitrile (9). The yield was 0.455 g (67 %), brown prisms, mp 290–293 °C

(acetone).


Methode B


sodium p-toluenesulfinate (4.460 g, 25.05 mmol), and potassium cyanide

(1.940 g, 29.83 mmol) in dry dimethylformamide (71.0 mL) was heated to 130

°C for 27 hours with vigorous stirring and worked up as described for 7,

pathway A. TLC analysis showed two products: 6-methoxy-2-oxo-1,2-

dihydroquinolin-4-yl 4-methylbenzenesulfinate (8) and 6-methoxy-2-oxo-1,2-

dihydroquinoline-4-carbonitrile (9).



The yield of the mixture was 2.027 g (85 %). The 2 products were separated by

recrystallization from dioxane to give first compound 9 and secondly compound

8 in 0.87 g (32 % yield), respectively.

6-Methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (9) was recrystallized

from methanol, to give 1.068 (49 %), gold prisms, mp 293–295 °C (methanol).


IR (ATR-measurement): 3156 (w), 3082 (w), 2991 (w), 2914 (w), 2825 (w), 2227

(w), 1655 (s), 1622 (m), 1571 (w), 1499 (m) cm-1.


H, 5-H), 7.31 (d, J = 8.4 Hz, 1 H, 8-H), 7.36 (dd, J = 9.0 + 2.6 Hz, 1 H, 7-H),

8.68 (s, 1 H, 3-H), 12.40 (s, 1 H, NH).


116.5 (7-C), 117.6 (8-C), 118.7 (CN), 124.3 (4-C), 135.3 (9-C), 149.4 (3-C),

155.1 (16-C), 158.7 (lactam-C=O).

MS (API-ESI neg): m/z (%) = 200(13, M + 1), 199 (100, M), 184 (11, M – 15).

Anal. for C11H8N2O2 (200.20).

Calcd: C 66.00, H 4.03, N 13.99

Found: C 65.16, H 3.85, N 13.59

The elemental analysis showed a small deviation of 0.84 % for carbon

component due to the fact that the compound 9 was not well soluble in almost

all organic solvents.

3,3-Dichloro-6-methoxyquinoline-2,4(1H,3H)-dione (10)

A suspension of 4-hydroxy-6-methoxyquinolin-2(1H)-one (3: 35.00 g, 183.25

mmol) in dioxane (400.0 mL) was warmed to 40–50 °C, and then under

vigorous stirring, keeping the temperature between 50–60 °C, sulfuryl chloride

(35.00 mL, 439.80 mmol ) was added dropwise. As soon as the temperature

reached 60 °C, the reaction was stopped and cooled to 20 °C. The mixture was

filtered and the filtrate was poured into ice/water (1500 mL) under stirring,

and then filtered by suction, washed with water and dried at 40 °C under

reduced pressure, to yield 3,3-dichloro-6-methoxyquinoline-2,4(1H, 3H)-dione



(10). The product was pure for further reactions. The yield was 34.983 g (73

%), yellow prisms, mp 219–223 °C, lit. mp 215–216 °C [ex-3a].


IR (KBr): 3434 (m), 3198 (m), 3118 (w), 3076 (m), 2976 (m), 2915 (m), 2839 (w),

1725 (s), 1688 (s), 1622 (m), 1500 (s) cm-1.

1H-NMR (360 MHz, [D6] DMSO): = 3.79 (s, 3 H, CH3O), 7.07 (d, J = 8.5 Hz, 1

H, 8-HH), 7.28 (d, J = 2.8 Hz, 1 H, 5-H), 7.30 (dd, J = 8.6 + 2.9 Hz, 7-H), 11.27 (s,

1 H, NH).

C10H7Cl2NO3 (260.08).

3-Chloro-4-hydroxy-6-methoxyquinolin-2(1H)-one (11)

To a solution of 3,3-dichloro-6-methoxyquinoline-2,4(1H,3H)-dione (10: 5.250

g, 20.20 mmol), in ethanol (52.0 mL), and acetic acid (26.0 mL), zinc-dust

(5.210 g, 79.66 mmol) was added in small portions, the solution was kept to

boiling. The yellow solution got decolorized (from yellow to grey-greenish),

which indicated the end of reaction. The solution was cooled to room

temperature and filtered from zinc. To the filtrate, ice/water (500 mL) was

added. The colorless precipitate was filtered by suction, washed with water and

dried at 40 °C under reduced pressure to give 3-chloro-4-hydroxy-6-

methoxyquinolin-2(1H)-one (11). The yield was 4.023 g (89 %), colorless

powder, mp 270–273 °C (ethanol), lit. mp not given [ex-10].


IR (KBr): 3432 (m), 3281 (w), 2960 (w), 2835 (w), 1633 (w), 1586 (s), 1537 (m)

cm-1.

1H-NMR (360 MHz, [D6]DMSO): = 3.68 (s, 3 H, CH3O), 7.00 (dd, J = 8.7 + 2.6

Hz, 1 H, 7-H), 7.12 (d, J = 8.8 Hz, 1 H, 8-H), 7.41 (d, J = 2.5 Hz, 1 H, 5-H ),

10.84 (s, 1 H, NH).

C10H8ClNO3 (225.63).



2,3,4-Trichloro-6-methoxyquinoline (12)

A solution of 3-chloro-4-hydroxy-6-methoxyquinolin-2(1H)-one (11: 6.00 g,

28.64 mmol) in phosphoroxychloride (31.50 mL) was brought to the reaction

and worked up according to the method described for 5. The yield was 6.244 g

(90 %), beige powder, mp 276–279 °C (toluene).


IR (ATR-measurement): 3012 (w), 2944 (w), 2359 (w), 2339 (w), 1619 (m), 1546

(m), 1486 (s) cm-1.


H, 5-H ), 7.57 (dd, J = 9.2 + 2.7 Hz, 1 H, 7-H ), 7.96 (d, J = 9.2 Hz, 1 H, 8-H).

Anal. for C10H6Cl3NO (262.52).

Calcd: C 45.75, H 2.30, N 5.34

Found: C 45.71, H 2.44, N 5.27

3,4-Dichloro-6-methoxyquinolin-2(1H)-one (13)

A solution of 2,3,4-trichloro-6-methoxyquinoline (12: 6.500 g, 24.76 mmol),

and 70 % methanesulfonic acid (6.50 mL) in n-butanol (130.0 mL) was heated

under reflux for 45 hours. The mixture was cooled to 20 °C and poured into ice

/ water (50 mL), brought to pH = 4–6 with sodium hydroxide (2 M), filtered by

suction, washed with water and dried at 40 °C under reduced pressure to give

3,4-dichloro-6-methoxyquinolin-2(1H)-one (13). The yield was 13.439 g (88 %),

beige prisms, mp 264–265 °C (xylen).


IR (KBr): 3467 (m), 2840 (m), 2720 (w), 1657 (s), 1599 (s) cm-1.


H, 5-H), 7.30 (dd, J = 8.9 + 2.4 Hz, 1 H, 7-H), 7.36 (d, J = 8.9 Hz, 1 H, 8-H),

12.47 (s, 1 H, NH).

Anal. for C10H7Cl2NO2 (244.08).

Calcd: C 49.21, H 2.89, N 5.74

Found: C 49.24, H 2.83, N 5.68



4-Hydroxy-6-methoxy-3-nitroquinolin-2(1H)-one (14)

A solution of 4-hydroxy-6-methoxyquinolin-2(1H)-one (3: 13.60 g, 71.20 mmol)

in glacial acetic acid (140.0 mL) was treated with concentrated nitric acid (14.0

mL) and with sodium nitrite (0.60 g, 8.70 mmol) to start a strongly exothermic

reaction. The starting material dissolved, followed immediately by precipitation

of the product. The mixture was stirred for 30 minutes and poured onto

ice/water (1500 mL), stirred, filtered by suction and washed with water. The

solid was dried at 40 °C under reduced pressure to give 4-hydroxy-3-nitro-7-

methoxyquinolin-2(1H)-one (14). The yield was 12.731g (76 %), yellow prisms,

mp 253.5–256.8 °C (methanol), lit. mp. not given [ex-11].


IR (KBr): 3435 (w), 3001 (m), 2896 (m), 2847 (m), 2785 (w), 2839 (w), 1668 (s),

1636 (w), 1609 (s), 1530 (s) cm-1.



11.89 (s, 1 H, NH).

C10H8N2O5 (236.19).

2,4-Dichloro-6-methoxy-3-nitroquinoline (15)

A solution of 4-hydroxy-6-methoxy-3-nitroquinolin-2(1H)-one (14: 0.862 g,

3.65 mmol) and dry triethylamine (0.60 mL, 4.40 mmol) in phosphor-

oxychloride (4.50 mL) was refluxed for 1 hour. The excess amount of phosphor-

oxychloride was removed under reduced pressure. The residue was poured

onto ice/water (100 mL) and the solution was brought to pH = 4–6 with

aqueous sodium hydroxide (5 M), filtered by suction, and washed with water.

The solid was dried at 40 °C under reduced pressure. The yield was 0.905 g (91

%), brown prisms, mp 195–196 °C (dioxane), lit. mp: not given [ex-12].


IR (KBr): 3437 (s), 2970 (w), 1617 (s), 1566 (m), 1547 (s) cm-1.




H, 5-H), 7.75 (dd, J = 9.3 + 2.7 Hz, 1 H, 7-H), 8.10 (d, J = 9.3 Hz, 1 H, 8-H).

C10H6Cl2N2O3 (273.08).

4-Chloro-6-methoxy-3-nitroquinolin-2(1H)-one (16)

A solution of 2,4-dichloro-6-methoxy-3-nitroquinoline (15: 2.00 g, 7.33 mmol),

and 70 % methanesulfonic acid (6.0 mL) in n-butanol (40.0 mL ) was heated to

110 °C for 45 hours. The mixture was cooled to room temperature and poured

into ice/water (100 mL), the solution was brought to pH = 4–6 with sodium

hydroxide (2 M), filtered by suction, washed with water and dried at 40 °C

under reduced pressure. The purification was performed by dry flash

chromatography using chloroform-acetone (3:7) as eluent, which afforded 4-

chloro-6-methoxy-3-nitroquinolin-2(1H)-one (16). The yield was 1.244 g (67 %),

mp 274–276 °C (chloroform/acetone 3:7), yellow-green prisms.


IR (KBr): 3437 (m), 2997 (w), 2916 (w), 2866 (m), 2761 (w), 1663 (s), 1626 (w),

1596 (w), 1543 (s) cm-1.

1H-NMR (360 MHz, [D6] DMSO): = 3.87 (s, 3 H, CH3O), 7.30-7.39 (m, 1 H, 7-

H), 7.42-7.49 (m, 2 H, 5-H and 8-H), 12.99 (s, 1 H, NH).

MS (APCI pos): m/z (%) = 257 (30, M + 2), 256 (10, M + 1), 255 (100, M).

MS (APCI neg): m/z (%) = 255 (34, M + 2), 254 (10, M + 1), 253 (100, M).

Anal. For C10H7ClN2O4 (254.63).

Calcd: C 47.17, H 2.77, N 11.00

Found: C 47.26, H 2.62, N 10.87



N-(4-Hydroxy-6-methoxy-2-oxo-1,2-dihyroquinolin-3-

yl)acetamide (17)

A solution of 4-hydroxy-6-methoxy-3-nitroquinolin-2(1H)-one (14: 10.750 g,

45.55 mmol) in acetic acetic (350.0 mL) and acetic anhydride (236.0 mL) was

heated to reflux. Then, zinc-dust (about 20 g, 300 mmol) was added until the

yellow color was decolorized, then the mixture was refluxed 30 minutes. The

mixture was filtered from zinc salt, the filtrate was taken to dryness at reduced

pressure. The residue was dissolved in aqueous sodium hydroxide (600 mL, 1

M), kept for 10 minutes at 20 °C and then under stirring, acidified with

concentrated hydrochloric acid to pH = 1. The precipitate was filtered by

suction, washed with water and dried at 40 °C under reduced pressure to

afford N-(4-hydroxy-6-methoxy-2-oxo-1,2-dihyroquinolin-3-yl)acetamide (17).

The yield was 7.702 g (68 %), beige powder, mp 300–303 °C (toluene).


IR (ATR-measurement): 3434 (m), 3326 (m), 2964 (m), 2913 (m), 2873 (w),

2837 (m), 1654 (w), 1640 (w), 1615 (s), 1530 (s), 1502 (m) cm-1.



2.1 Hz, 1 H, 5-H), 9.74 (s, 1 H, NHAc), 11.73 (s, 1 H, NH), 11.98 (s, 1 H, OH).

Anal. for C12H12N2O4 (248.24).

Calcd: C 58.06, H 4.87, N 11.28

Found: C 57.92, H 4.62, N 11.01

N-(4-Chloro-6-methoxy-2-oxo-1,2-dihydroquinolin-3-

yl)acetamide (18)

To a solution of N-(4-hydroxy-6-methoxy-2-oxo-1,2-dihyroquinolin-3-

yl)acetamide (17: 5.50 g, 22.20 mmol) in phosphoroxychloride (26.50 mL), dry

triethylamine was added (3.70 mL, 26.60 mmol), then the solution was

refluxed for 1 hour. The excess amount of phosphoroxychloride was removed



under reduced pressure. The residue was poured onto ice/water (400 mL) and

brought to pH = 4–6 with sodium hydroxide (2 M). The solution was filtered by

suction, washed with water, and dried at 40 °C under reduced pressure to

afford N-(4-chloro-6-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)acetamide (18).

The yield was 5.248 g (90 %), dark-brown powder, mp 283–285 °C (dioxane).


IR (ATR-measurement): 3435 (m), 3225 (m), 3169 (w), 3094 (w), 3010 (w), 2937

(w), 2874 (w), 1651 (s), 1620 (m), 1518 (m) cm-1.


7.25 (d, J = 2.4 Hz, 1 H, 5-H), 7.31-7.35 (m, 2 H, 7-H and 8-H), 9.60 (s, 1 H,

NHAc), 12.18 (s, 1 H, NH).

MS (APCI pos): m/z (%) = 269 (30, M + 2), 268 (12, M + 1), 267 (100, M), 225

(8, M – 43),

Anal. for C12H11ClN2O3 (266.69).

Calcd: C 54.05, H 4.16, N 10.50

Found: C 54.30, H 3.97, N 10.46

6-Methoxy-3,3-di(piperidin-1-yl)quinoline-2,4(1H,3H)-dione (19)

A solution of 3,3-dichloro-6-methoxyquinolin-2,4(1H,3H)-dione (10: 4.60 g,

17.70 mmol) was dissolved in dry dimethylformamide (20.0 mL), and cooled to

0 °C, then piperidine (12 mL, 10.32 g, 121.41 mmol) was added, which gave a

dark color of the mixture, the temperature raised to 35 °C, and piperidine

hydrochloride precipitated. The mixture was stirred for 30 minutes, cooled to 0

°C, and water (80 mL) added dropwise. The solution was filtered by suction,

washed with water and dried at 40 °C under reduced pressure, to afford 6-

methoxy-3,3-di(piperidin-1-yl)quinoline-2,4(1H,3H)-dione (19). The yield was

4.917 g (78 %), yellow-green prisms, mp 162–164 °C (ethanol).


IR (KBr): 3435 (s), 3202 (m), 3088 (w), 3059 (w), 2988 (w), 2932 (s), 2851 (m),

2796 (w), 1688 (s), 1657 (s), 1616 (w), 1502 (s) cm-1.



1H-NMR (360 MHz, [D6]CDCl3): = 1.47-1.54 (m, 12 H, piperidin-H), 2.62-2.64

(m, 8 H, NCH2 of piperidin), 3.86 (s, 3 H, CH3O), 6.82 (d, J = 8.7 Hz, 1 H, 8-H ),

7.11 (dd, J = 8.7 + 2.7 Hz, 1 H 7-H), 7.39 (d, J = 2.7 Hz, 1 H, 5-H), 8.36 (s, 1 H,

NH).

C20H27N3O3 (357.46).

The elemental analysis of 19 could not be obtained because of the easy

decomposition, but elemental analysis for its follow-up compound is correct.

4-Hydroxy-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (20)

6-Methoxy-3,3-di(piperidin-1-yl)quinoline-2,4(1H,3H)-dione (19: 2.00 g, 5.60

mmol) were dissolved in water/ethanol (1:1, 32.0 mL), the solution heated to

reflux and sodium dithionite (2.00 g, 13.0 mmol) added The mixture was

stirred for 30 minutes under reflux, cooled to 5 °C and kept it 2 hours at this

temperature. The product precipitated, was filtered by suction, washed with

water and dried at 40 °C under reduced pressure, to give 4-Hydroxy-6-

methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (20). The product was sufficiently

pure for further reactions. The yield was 1.44 g (96 %), beige prisms, mp 228–

231°C.


IR (KBr): 3439 (m), 2991 (m), 2952 (m), 2851 (m), 2831 (w), 1638 (s), 1597 (s),

1544 (s) cm-1.

1H-NMR (360 MHz, [D6]DMSO): = 1.50-1.52 (m, 2 H, piperidin-H), 1.70-1.80

(m, 4 H, piperidin-H), 3.39 (s, 3 H, CH3O), 3.73-3.76 (m, 4 H, piperidin-NH),


2.7 Hz, 1 H, 5-H), 10.66 (s, 1 H, NH).

MS (APCI neg): m/z (%) = 274 (5, M + 1), 273 (100, M).

MS (APCI pos): m/z (%) = 276 (18, M + 1), 275 (100, M).

Anal. for C15H18N2O3 (274.32).

Calcd: C 65.68, H 6.61, N 10.21

Found: C 65.67, H 6.37, N 10.22



2,4-Dichloro-6-methoxy-3-(piperidin-1-yl)quinoline (21)

A solution of 4-hydroxy-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (20:

0.90 g, 3.30 mmol) in phosphoroxychloride (10.0 mL) was brought to the

reaction and worked up as described for 5, to give 2,4-Dichloro-6-methoxy-3-

(piperidin-1-yl)quinoline (21). The yield was 0.482 g (47 %), brown prisms, mp

182–185 °C (methanol).


IR (KBr): 3433 (m), 2932 (m), 2847 (w), 1620 (s), 1556 (w) cm-1.

1H-NMR (360 MHz, [D3] CDCl3): = 1.66-1.81 (m, 6 H, piperidin-H), 3.23-3.25

(m, 4 H, piperidin-NH), 3.97 (s, 3 H, CH3O), 7.30 (dd, J = 9.1 + 2.6 Hz, 1 H, 7-

H), 7.39 (d, J = 2.4 Hz, 1 H, 5-H), 7.86 (d, J = 9.2 Hz, 1 H, 8-H).

C15H16Cl2N2O (311.21).

4-Chloro-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (22)

Method A

A solution of 2,4-dichloro-6-methoxy-3-(piperidin-1-yl)quinoline (21: 2.00 g,

6.43 mmol) and 70 % methanesulfonic acid (1.50 mL) in n-butanol (15.0 mL)

was refluxed for 48 hours and worked up as described for 6 to give 4-chloro-6-

methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (22). The yield was 0.997 g (53

%), pale green prisms, mp 210–214 °C (ethanol).


Method B

A solution of 4-hydroxy-6-methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one

(20:1.00 g, 3.65 mmol) in phosphoroxychloride (8.0 mL) was heated to 80 °C

for 25 minutes and worked up as described for 5 to form directly 4-chloro-6-

methoxy-3-(piperidin-1-yl)quinolin-2(1H)-one (22). The yield was 0.875 g (82

%), pale green prisms, mp 213–215.9 °C (ethanol).




IR (KBr): 3454 (s), 2991 (w), 2924 (m), 2840 (m), 1643 (s), 1599 (w), 1554 (w)

cm-1.

1H-NMR (360 MHz, [D6]DMSO): = 1.56-1.60 (m, 6 H, piperidin-H), 3.12-3.14

(m, 4 H, piperidin-NH), 3.82 (s, 3 H, CH3O), 7.11 (dd, J = 8.8 + 2.7 Hz, 1 H, 7-

H), 7.22 (d, J = 8.9 Hz, 1 H, 8-H), 7.26 (d, J = 2.7 Hz, 1 H, 5-H), 11.83 (s, 1 H,

NH).

MS (APCI pos): m/z (%) = 295 (33, M + 2), 294 (20, M + 1), 293 (100, M).

C15H17ClN2O2 (292.77).

Dicyano-6-methoxyquinoline (23)



(2.52 g, 38.77 mmol), in dry dimethylformamide (50.0 mL) was heated to 140

°C for 3 hours with vigorous stirring and worked up using the procedure

described for 7 (pathway A), to give the compound 23. The yield was 31.747 g

(76 %), red prisms, mp > 350 °C (acetonitrile).


IR (KBr): 3433 (m), 2213 (s), 1657 (w), 1628 (w), 1583 (s), 1550 (s), 1500 (s) cm-

1.

1H-NMR (360 MHz, [D6]DMSO): = 3.80 (s, 3 H, 6-CH3O), 6.84 (d, J = 1.9 Hz, 1

H, 5-H), 7.17-7.21 (m, 2 H, 7-H and 8-H).

13C-NMR (300 MHz, [D6]DMSO): = 55.7 (CH3O), 102, 115.0, 116.7, 118.0

(CN), 122.5, 125.0, 127.0, 148.5, 153.8 .

MS (APCI neg): m/z (%) = 225 (8, M + 1), 224 (100, M), 209 (6, M – 15).

Anal. For C12H7N3O2 (225.21).

Calcd: C 64.00, H 3.13, N 18.66 O 14.21

Found: C 63.87, H 3.00, N 18.27 O 14.47



4-Hydroxy-7-methoxyquinolin-2-(1H)-one (28)

A mixture of m-anisidin (27: 18.950 g, 17.30 mL, 154.06 mmol) and dry

malonic acid (2: 23.40 g, 225.0 mmol) in phosphoryl chloride (24.0 mL) was

heated in an open flask to 95 °C for 90 minutes under stirring with a

thermometer, then cooled to 20 °C, poured onto ice/water (500 mL) and filtered

by suction. The precipitate was dissolved in aqueous sodium hydroxide (450

mL, 1 M) under warming to 60 °C. The remaining insoluble solid (mainly 2,4-

dichloro-7-methoxyquinoline, 30) was filtered.

To the alkaline filtrate, concentrated hydrochloric acid was added until pH = 1–

2 was reached, the precipitate filtered by suction, washed with water (150 mL)

and dried at 40 °C under reduced pressure.

The solid was separated by recrystallization from methanol which afforded as

first crop 4-hydroxy-5- methoxyquinolin-2(1H)-one (29) and as second crop the

main compound, 4-hydroxy-7-methoxyquinolin-2(1H)-one (28). The yield was

19.348 g (72 %), brown prisms, mp 347–348.8 °C (methanol), lit. mp 318-332

°C [ex-4b, ex-13].


IR (KBr): 3427 (w), 3132 (w), 3075 (w), 3009 (w), 2966 (w), 1638 (s), 1607 (w),

1565 (w) cm-1.


(d, J = 2.4 Hz, 1 H, 8-H), 6.75 (dd, J = 9.2 + 2.4 Hz, 1 H, 6-H), 7.67 (d, J = 9.1

Hz, 1 H, 5-H), 11.02 (s, 1 H, NH), 11.15 (s, 1 H, OH).

C10H9NO3 (191.19).

4-Hydroxy-5-methoxyquinolin-2-(1H)-one (29)

This compound was obtained during the recristallization of compound 28 from

methanol. The yield was 1.765 g (6 %), yellow prisms, mp 255–258 °C

(methanol), lit. mp 255–256 °C [ex-14].




IR (KBr): 3430 (w), 3317 (m), 2973 (w), 2941 (w), 2840 (w), 1657 (s), 1619 (w),

1567 (w) cm-1.


(d, J = 8.1 Hz, 1 H, 6-H), 6.89 (d, J = 8.3 Hz, 1 H, 8-H), 7.40 (t, J = 8.3 Hz, 1 H,

7-H), 10.00 (s, 1 H, NH), 11.24 (s, 1 H, OH).

C10H9NO3 (191.19).

2,4-Dichloro-7-methoxyquinoline (30)

Method A

This compound was obtained as insoluble solid during the work-up of

compound 28. The solid was purified from methanol. The yield was 5.62 g (16

%), grey prisms, mp 139–142 °C (methanol), lit. mp 120–156 °C [ex-9, ex-15].


Method B

A solution of 4-hydroxxy-7-methoxyquinolin-2(1H)-one (28: 16.450 g, 86.13

mmol) in phosphoroxychloride (103.0 mL) was heated under reflux for 8 hours

and worked up using the procedure described for 5, which afforded 2,4-

dichloro-7-methoxyquinoline (30), brown prisms, pure enough for further use.

The yield was 15.974 g (81 %), brown prisms, mp 135 -138 °C (methanol), lit.

mp 120–156 °C [ex-9, ex-15].


IR (KBr): 3437 (m), 3090 (w), 1624 (m), 1574 (m) cm-1.


H, 8-H), 7.44 (d, J = 8.4 Hz, 1 H, 5-H), 7.77 (s, 1 H, 3-H), 8.10 (dd, J = 8.4 +

2.6 Hz, 1 H, 6-H).

C10H7Cl2NO (228.08).



4-Chloro-7-methoxyquinolin-2-(1H)-one (31)

A solution of 2,4-dichloro-7-methoxyquinoline (30: 7.00 g, 30.70 mmol) and 70

% methanesulfonic acid (5.0 mL) in n-butanol (30.0 mL) was reacted according

to the method described for 6, to give 4-chloro-7-methoxyquinolin-2-(1H)-one

(31). The yield was 6.138 g (96 %), grey prisms, mp 244–246 °C (methanol), lit.

mp 252 °C [ex-15a].


IR (KBr): 3416 (w), 2965 (w), 2924 (w), 2851 (w), 1669 (s), 1626 (m), 1553 (w),

1507 (w) cm-1.



Hz, 1 H, 5-H), 11.87 (s, 1 H, NH).

C10H8ClNO2 (209.63).

Cyano-7-methoxyquinoline (32)


sodium p-toluenesulfinate (2.00 g, 11.24 mmol), and potassium cyanide


°C for 30 hours with vigorous stirring, and worked up as described in the

procedure for compound 7 (pathway A), to furnish the compound 32. The yield

was 0.829 g (79 %), green prisms, mp 328–331 °C (acetonitrile).


IR (KBr): 3433 (m), 2939 (w), 2220 (m), 1614 (s), 1537 (m), 1517 (w), 1499 (w)

cm-1.


Hz, 1 H, 6-H), 6.50 (d, J = 2.5 Hz, 1 H, 8-H), 7.28 (d, J = 8.7 Hz, 1 H, 5-H),

7.98 (s, 1 H, 3-H).

MS (APCI pos): m/z (%) = 201 (100, M).

MS (APCI neg): m/z (%) = 199 (100, M).

C11H8N2O2 (200.20 ).



7-Methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (33)


sodium p-toluenesulfinate (1.121 g, 6.30 mmol), and potassium cyanide (0.540


hours with vigorous stirring, and worked up as described in the procedure for

compound 7 (pathway A), to form 7-methoxy-2-oxo-1,2-dihydroquinoline-4-

carbonitrile (33). The yield was 0.525 g (87 %), pale green prisms, mp 304–308

°C (acetonitrile).



(w), 1661 (s), 1623 (s), 1562 (m), 1506 (m), 1489 (m) cm-1.



8.66 (s, 1 H, 3-H), 12.31 (s, 1 H, NH).

MS (APCI pos): m/z (%) = 202 (15, M + 1), 201 (100, M).

MS (APCI neg): m/z (%) = 200 (13, M + 1), 199 (100, M).

Anal. For C11H8N2O2 (200.20).

Calcd: C 66.00, H 4.03, N 13.99 O 15.98

Found: C 65.86, H 3.82, N 13.81 O 16.17

4-Trifluoromethyl-6-methoxyquinolin-2(1H)-one (38)

To ethyl 4,4,4-trifluoroacetoacetate (36: 2.99 g, 16.25 mmol) at 130 °C in an

open flask p-anisidin (1.00 g, 8.13 mmol) was added dropwise under stirring,

the reaction mixture was kept for 1 hour at this temperature and then cooled

to 40–45 °C. The excess amount of ester was removed under reduced pressure

to give 4,4,4-trifluoro-N-(4-methoxyphenyl)-3-oxobutanamide (37) as a dark

residue. This amide 37 was cyclized without isolation. To this residue, 76%

sulfuric acid (3.0 mL) was added and the mixture was heated to 90 °C for 12

hours, cooled at room temperature, then water (100 mL) was added with

stirring and a beige precipitate was formed, which was filtered by suction,



washed with water until neutral and dried at 40 °C under reduced pressure to

give the corresponding compound 38. The yield was 1.402 g (71 %), beige

prisms, mp 253–254 °C (ethanol).


IR (KBr): 3432 (m), 2982 (w), 2847 (w), 1672 (s), 1621 (m), 1505 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.80 (s, 3 H, CH3O), 6.98 (s, 1 H, 3-H),

7.05 (d, J = 2.4 Hz, 1 H, 5-H), 7.35 (dd, J = 9.1 + 2.5 Hz, 1 H, 7-H), 7.40 (d, J =

9.1 Hz, 1 H, 8-H), 2.24 (s, 1 H, NH).

13C-NMR (300 MHz, [D6]DMSO): = 56.0 (CH3O), 106.3 (Aromatic-C), 113.9

(Aromatic-C), 118.2 (Aromatic-C), 121.1 (Aromatic-C), 134.7 (Aromatic-C),

136.1 (4-C), 154.9 (6-C), 159.9 (lactam-C=O).

MS (API-ESI neg): m/z (%) = 243 (12, M + 1), 242 (100, M).

Anal. for C11H8F3NO2 (243.19).

Calcd: C 54.33, H 3.32, N 5.76

Found: C 54.18, H 3.10, N 5.68

N-(4-methoxyphenyl)-N-methylformamide (40)

A mixture of p-anisidin (1: 29.90 g, 243.10 mmol), trimethyl orthoformate (39:

40.0 mL, 32.00 g, 301.88 mmol) and concentrated sulfuric acid (1.0 mL) was

slowly heated under stirring to 103–105 °C and the formed methanol was

distilled over a short vigreux column. During 2.5 hours the bath temperature

was increased to 170–185 °C until no more methanol was formed, then the

mixture was kept at this temperature for further 60 minutes, and cooled to 50

°C. Distillation under reduced pressure afforded N-(4-methoxyphenyl)-N-

methylformamide (40). The yield was 28.156 g (70 %), yellow oil, bp 165–170

°C/14–21 mbar, lit. bp 86–171 °C/0.2–20 torr. [Ex-17, ex-18, ex-19, ex-20].


1H-NMR (300 MHz, [D3]CDCl3): = 3.26 (s, 3 H, NCH3), 3.81 (s, 3 H, CH3O),

6.92 (d, J = 8.9 Hz, 2 H, PhH), 7.12 (d, J = 9.0 Hz, 2 H, PhH), 8.33 (s, 1 H,

CHO).

C9H11NO2 (165.19).



4-Methoxy-N-methylbenzenamine or 4-Methoxy-

N-methylaniline (41)

A mixture of N-(4-methoxyphenyl)-N-methylformamide (40: 17.00 g, 103.0

mmol) and 10 % hydrochloric acid (53.0 mL) was stirred and heated under

reflux for 90 minutes. Then the mixture was cooled to room temperature,

neutralized and satured with potassium carbonate. The amine separated as

colorless oil, was then extracted with diethyl ether (3 x 40 mL), the ether phase

was washed with water (50 mL) and dried over potassium carbonate. The

solvent was removed under reduced pressure and the orange product distilled

under reduced pressure to afford 4-methoxy-N-methylbenzenamine (41). The

yield was 10.445 g (74 %), pale yellow oil, bp 120–125°C/17-18 mbar, lit. bp

45–136 °C/ 0.1–19 torr. [Ex-21, ex-22, ex-23, ex-24, ex-25, ex-26, ex-27, ex-

28, ex-29, ex-30].


1H-NMR (300 MHz, [D6] DMSO): = 2.62 (d, J = 5.3 Hz, 3 H, NCH3), 3.62 (s, 3

H, CH3O), 5.14 (d, J = 8.9 Hz, 1 H, NH), 6.49 (d, J = 8.9 Hz, 2 H, PhH), 6.72 (d,

J = 8.9 Hz, 2 H, PhH).

C8H11NO (137.18).

4-Hydroxy-6-methoxy-1-methylquinolin-2(1H)-one (42)

A mixture of 4-methoxy-N-methylbenzenamine (41: 16.193 g, 118.20 mmol)

and dry malonic acid (2: 23.320 g, 224.23 mmol) in phosphoryl chloride (23.50

mL), was well stirred with thermometer, and heated to 95 °C for 90 minutes.

The crude product was cooled to 20 °C and poured onto ice/water (200 mL).

The solution was filtered and the precipitate dissolved in aqueous sodium

hydroxide (450 mL, 1 M) under warming (60 °C), then filtered from the

insoluble precipitate. The filtrate was acidified with concentrated hydrochloric

acid to pH = 1-2, and the product was filtered by suction, washed with water

and dried at 40 °C under reduced pressure to give 4-Hydroxy-6-methoxy-1-

methylquinolin-2(1H)-one (42).



The yield was 11.384 g (47 %), rose prisms, mp 247-250 °C (methanol), lit. mp

278-293 °C [ex-31].


IR (KBr): 3445 (s), 2961 (w), 2934 (w), 1643 (w), 1617 (m), 1583 (m), 1583 (w),

1524 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.52 (s, 3 H, NCH3), 3.81 (s, 3 H, CH3O),

5.93 (s, 1 H, 3-H), 7.25 (dd, J = 9.1 + 2.9 Hz, 1 H, 7-H), 7.33 (d, J = 2.9 Hz, 1

H, 5-H), 7.43 (d, J = 9.2 Hz, 1 H, 8-H), 11.46 (s, 1 H, OH).

C11H10NO2 (205.22).

4-Chloro-6-methoxy-1-methylquinolin-2(1H)-one (43)

Methode A

A solution of 4-hydroxy-6-methoxy-1-methlylquinolin-2(1H)-one (42: 2.390 g,

11.66 mmol) in phosphoroxychloride (14.0 mL) was reacted for 8 hours under

reflux and worked up using the procedure described for 5, to give 4-chloro-6-

methoxy-1-methylquinolin-2(1H)-one (43). The yield was 2.127 g (82 %), brown

prisms, mp 158-161 °C (methanol), lit. mp 161–163 °C [ex-32].


Methode B


iodomethane (0.70 mL, 1.60 g, 11.26 mmol), and dry sodium carbonate (1.30

g, 11.95 mmol) in dry dimethylformamide (35.0 mL) was heated to 120 °C for

25 minutes. The solution was cooled to 20 °C and poured into ice/water (50

mL). The obtained solid was filtered by suction, washed with water and dried at

40 °C under reduced pressure to afford the corresponding compound 43. The

yield was 0.861 g (81 %), brown prisms, mp 157–160 °C (methanol), lit. mp

161–163 °C [ex-32].


IR (ATR-measurement): 3437 (m), 3078 (w), 1642 (s), 1579 (w), 1564 (m), 1503

(m) cm-1.




6.96 (s, 1 H, 3-H), 7.35 (d, J = 2.7 Hz, 1 H, 5-H), 7.39 (dd, J = 9.1 + 2.9 Hz, 1

H, 7-H), 7.59 (d, J = 9.1 Hz, 1 H, 8-H).

C11H10ClNO2 (223.66).

6-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile

(44)

Method A

A mixture of 4-chloro-6-methoxy-1-methylquinolin-2(1H)-one (43: 0.300 g,

1.34 mmol), sodium p-toluenesulfinate (0.500 g, 2.81 mmol) and potassium

cyanide (0.220 g, 3.38 mmol) in dimethylformamide (8.0 mL) was heated to 120

°C for 28 hours and worked up according to the procedure described for 7, to

give 6-methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile (44). The

yield was 0.241 g (84 %), black-green prisms.


Method B

A mixture of 6-methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (9: 100 mg,

0.50 mmol), sodium carbonate (200 mg, 1.88 mmol) and iodomethane (0.10

mL, 0.23 g, 1.60 mmol) in dry dimethylformamide (5.0 mL) was heated to 90 °C

for 15 minutes. The solution was cooled at room temperature and poured on

ice / water (5 mL). The resulting precipitate was filtered by suction, washed

with water and dried at 40 °C under reduced pressure to give 6-methoxy-1-

methyl-2-oxo-1,2-dihydroquinoline-4-carbonitrile (44). The yield was 88 mg (82

%), brown prisms, mp 233–236 °C (ethanol).


IR (KBr): 3032 (w), 2944 (w), 2841(w), 2229 (w), 1644 (s), 1592 (m), 1573 (m),

1559 (w), 1541(w), 1505 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.64 (s, 3 H, NCH3), 3,83 (s, 3 H, CH3O),


9.3 Hz, 1 H, 8-H), 8.68 (s, 1 H, 3-H).



13C-NMR (300 MHz,[D6]DMSO): = 30.5 (CH3), 56.1 (CH3O), 106.2 (Aromatic-

C), 111.6 (Aromatic-C), 116.5 (Aromatic-C), 117.4 (Aromatic-C), 119.6

(Aromatic-C), 123.8 (Aromatic-C), 136.1 (Aromatic-C), 148.2 (3-C), 155.1 (6-C),

158.2 (lactam-C=O).

Anal. for C12H10N2O2 (214.23 ).

Calcd: C 67.28, H 4.71, N 13.08 O 14.94

Found: C 66.39, H 4.49, N 13.08 O 15.25

6-Methoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile (45)

A mixture of 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7: 0.422

g, 1.87 mmol), iodomethane (0.30 mL, 0.684 g, 4.82 mmol), and dry sodium

carbonate (0.588 g, 5.55 mmol) in dry dimethylformamide (17.0 mL), was

heated to 120 °C for 25 minutes, and worked up as described for 43 method B,

to afford the corresponding compound 45. The yield was 0.347 g (65 %), red



IR (KBr): 3459-3438 (w, br), 3026 (w), 2978 (w), 2942(w), 2238 (w), 1657 (s),

1586 (w), 1554 (m), 1499 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.70 (s, 3 H, NCH3), 3.91 ( s, 3 H, CH3O),

7.21 (d, J = 2.3 Hz, 1 H, 5-H), 761 (dd, J = 9.4 + 2.5 Hz, 1 H, 7-H), 7.76 (d, J =

9.4 Hz, 1 H, 8-H).

13C-NMR (300 MHz,[D6]DMSO): = 31.5 (CH3), 56.1 (CH3O), 107.29 (Aromatic-

C), 112.5 (Aromatic-C), 113.3 (Aromatic-C), 114.6 (Aromatic-C), 117.3 (CN),

118.87 (CN), 125.8 (Aromatic-C), 128.5 (Aromatic-C), 136.5 (Aromatic-C),

155.9 (6-C), 156.7 (lactam-C=O).

MS (ESI pos): m/z (%) = 501 (58, [2M + Na]+), 278 (11, [M + K]

+), 262 (100, [M + Na]

+), 240

(47, [M + H]+).

Anal. for C13H9N3O2 ( 239.24 ).

Calcd: C 65.27, H 3.79, N 17.56 O 13.38

Found: C 65.10, H 3.59, N 17.17 O 13.59



Ethyl (3,4-Dicyano-6-methoxy-2-oxoquinolin-1(2H)-yl)-acetate

(46)

A mixture of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7:

0.500 g, 2.22 mmol), ethyl bromoacetate (0.6 mL, 0.906 g, 5.43 mmol) and dry

sodium carbonate (0.711 g, 6.71 mmol) in dry dimethylformamide (15.0 mL)

was heated to 90 °C for 15 minutes, and worked up as described for 43

(method B), to give ethyl (3,4-dicyano-6-methoxy-2-oxoquinolin-1(2H)-yl)-

acetate (46). The yield was 0.579 g (84 %), yellow prisms, mp 216–219 °C

(ethanol).


IR (KBr): 3143 (w), 3108 (w), 3002 (w), 2980 (w), 2942 (w), 2230 (w), 1746 (s),

1656 (s), 1557 (s), 1503 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 1.22 (t, J = 7.0 Hz, 3 H, CH3), 3.92 (s, 3 H,

CH3O), 4.17 (q, J = 7.0 Hz, 2 H, CH2), 5.20 (s, 2 H, NCH2), 7.26 (d, J = 2.7 Hz, 1

H, 5-H), 77.60 (dd, J = 9.4 + 2.8 Hz, 1 H, 7-H), 7.73 (d, J = 9.5 Hz, 1 H, 8-H).

13C-NMR (360 MHz, [D6]DMSO): = 14.5 (CH3), 45.6 (NCH2), 56.4 (CH3O), 62.1

(OCH2), 108.5 (aromatic-C), 112.0 (aromatic-C), 113.2 (aromatic-C), 114.2

(aromatic-C), 117.4 (aromatic-C), 118.6 (CN), 125.9 (aromatic-C), 129.8

(aromatic-C), 135.9 (4-C), 156.2 (6-C), 156.6 (lactam-C=O), 167.6 (ester-C=O).

MS (ESI pos): m/z (%) = 305 (51, [M + K]+), 334 (100,[ M + Na]

+), 312 (62, [M + H]

+).

Anal. for C16H13N3O4 ( 311.30 ).

Calcd: C 61.73, H 4.21, N 13.50

Found: C 61.48, H 4.06, N 13.34

2-Benzyloxy-6-methoxyquinoline-3,4-dicarbonitrile (48)

A mixture of 6-methoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (7: 0.90

g, 4.00 mmol), potassium carbonate (0.745 g, 5.40 mmol), and benzylchloride

(47: 0.80 mL, 0.880 g, 6.75 mmol) in dry dimethylformamide (65.0 mL) was

heated slowly to 80 °C, the mixture was kept at this temperature for 3 hours



until tlc showed no more starting material.

Then, the temperature was raised to 110 °C for 2 hours. The solution was

filterated and the solvent was removed under reduced pressure. A thick brown

oil was obtained, which crystallized after standing over night. The purification

was performed by dry flash chromatography using toluene-dichloromethane

(3:1) as eluent to form 2-benzyloxy-6-methoxyquinoline-3,4-dicarbonitrile (48).

The yield was 0.768 g (61 %), yellow prisms, mp 318–323 °C

(toluene/dichloromethane 3:1).


IR (KBr): 3435 (s), 2924 (w), 2231 (w), 1620 (w), 1584 (m), 1505 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.98 (s, 3 H, CH3O), 5.61 (s, 2 H, CH2),

7.30-7.55 (m, 5 H, Ph-H), 7.58 (d, J = 1.6 Hz, 1 H, 5-H), 7.70 (dd, J = 9.3 + 2.8

Hz, 1 H, 7-H), 7.96 (d, J = 9.2 Hz, 1 H, 8-H).

C19H13N3O2 (315.33).

3,4-Dichloro-6-methoxy-1-methylquinolin-2(1H)-one (49)


mmol), iodomethane (0.70 mL, 1.60 g, 11.24 mmol), and dry sodium carbonate

(1.025 g, 9.68 mmol) in dry dimethylformamide (20.0 mL) was heated to 120 °C

for 25 minutes, and worked up as described for 43 (method B), to afford the

corresponding compound 49. The yield was 0.798 g (80 %), light yellow prisms,

mp 170–179 °C (methanol).



(m), 1494 (m) cm-1.



9.2 Hz, 1 H, 8-H).

13C-NMR (300 MHz, [D6]DMSO): = 31.5 (CH3), 56.1 (CH3O), 107.7 (aromatic-

C), 117.7 (aromatic-C), 118.8 (aromatic-C), 121.1 (aromatic-C), 126.1

(aromatic-C), 132.5 (aromatic-C), 139.8 (4-C), 155.5 (6-C), 156.2 (lactam-C=O).



Anal. For C11H9Cl2NO2 (258.11)

Calcd. : C 51.91 H 3.51 N 5.43

Found : C 51.06 H 3.37 N 5.41

4-Chloro-6-methoxy-7-nitroquinolin-2(1H)-one (50)

A solution of 4-chloro-6-methoxyquinolin-2(1H)-one (6: 4.00 g, 19.10 mmol) in

glacial acetic acid (35.0 mL) was treated with concentrated nitric acid (3.50 mL,

83.69 mmol) and with sodium nitrite (1.00 g, 14.50 mmol) to start a strongly

exothermic reaction. The starting material was dissolved, followed immediately

by precipitation of the product. The mixture was heated to 110 °C for 3 hours,

the solution was cooled at room temperature and poured into ice/water (150

mL). The solution was filtered by suction, washed with water and dried at 40

°C under reduced pressure to give 4-chloro-6-methoxy-7-nitroquinolin-2(1H)-

one (50). The yield was 3.991 g (82 %), yellow prisms, mp 333-336 °C

IR (KBr): 3464-3432 (m, br), 3060 (w), 2982 (w), 2949 (w), 2850 (w), 1702 (s),

1659 (s), 1628 (m), 1590 (w), 1534 (s), 1499 (m) cm-1.


(s, 1 H, 5-H), 7.73 (s, 1 H, 8-H), 12.32 (s, 1 H, NH).

13C-NMR (300 MHz, [D6]DMSO): = 57.9 (CH3O), 108.8 (aromatic-C), 119.2

(aromatic-C), 119.5 (aromatic-C), 126.6 (aromatic-C), 133.9 (aromatic-C), 135.4

(7-C), 138.2 (4-C), 146.3 (6-C), 159.4 (lactam-C=O) .

C10H7ClN2O4 (254.63)

Ethyl (p-Methoxyphenyl)acetate (53a)

A solution of p-methoxyphenylacetic acid (52a: 35.60 g, 214.45 mmol), ethanol

(25.0 mL) and concentrated sulfuric acid (0.65 mL, 1.20 g, 12.24 mmol) in

chloroform (72.0 mL) was heated under reflux at the reversed water separator

for 5 hours. When no further water was separated, the mixture was cooled to

room temperature, and then the chloroform solution was washed with water



(50 mL), saturated with NaHCO3-solution (50 mL), and again washed with

water (50 mL). The solvent was removed under reduced pressure and a clear

red oil was formed, which was purified by vacuum distillation to furnish ethyl

(p-methoxyphenyl)acetate (53a). The yield was 31.750 g (76 %), colorless oil,

b.p 140–155 °C/34 mbar, lit. bp 100–158.5 °C / 0.3–20 torr.[ex-33, ex-34, ex-

35, ex-36, ex-37, ex-38, ex-39, ex-40].


IR (liquid film, ATR-measurement): 2981 (w), 2960 (w), 2937 (w), 2837 (w),

1736 (s), 1613 (m), 1513 (s) cm-1.


CH2), 3.73 (s, 3 H, CH3O), 4.05 (q, J = 7.1 Hz, 2 H, OCH2), 6.87 (d, J = 8.7 Hz, 2

HBB´ Ar-H), 7.17 (d, J = 8.7 Hz, 2 HAA´ Ar-H).

C11H14O3 (194.23).

Ethyl (4-Chlorophenyl)acetate (53b)

A solution of 4-chlorophenylacetic acid (52b: 31.20 g, 183.0 mmol), ethanol

(24.0 mL) and concentrated sulfuric acid (0.60 mL, 1.104 g, 11.26 mmol) in

chloroform (70.0 mL) was reacted and worked up as described for 53a, to form

ethyl (4-Chlorophenyl)acetate (53b). The yield was 27.346 g (75 %), colorless

oil, b.p 135–140 °C/30 mbar, lit. bp 78–260 °C [ex-36b, ex-37c, ex-40a, ex-41,

ex-42, ex-43, ex-44].


IR (liquid film): 2982 (m), 1737 (s), 1493 (s) cm-1.


CH2), 4.07 (q, J = 7.1 Hz, 2 H, OCH2), 7.29 (d, J = 8.6 Hz, 2 HAA´ Ar-H), 7.37(d,

J = 8.5 Hz, 2 HBB´ Ar-H).

C10H11ClO2 (198.65).



Ethyl (4-Nitrophenyl)acetate (53c)

A solution of 4-nitrophenylacetic acid (52c: 35.60 g, 196.68 mmol), ethanol

(23.0 mL, 397.13 mmol) and concentrated sulfuric acid (0.60 mL, 1.104 g,

11.26 mmol) in chloroform (66.0 mL) was refluxed at the reversed water

separator for 5 hours. When no further water was separated, the mixture was

cooled to room temperature, which got quickly solid in contact with air. The

solid was digested with water (100 mL) under stirring, the solution was filtered

by suction, and the obtained solid was mixed with saturated NaHCO3-solution

(100 mL), filtered by suction and again mixed with water (100 mL), filtered by

suction and dried at 40 °C under reduced pressure. The solid was purified by

vacuum distillation, the product crystallized quickly in contact with air, to give

ethyl (4-nitrophenyl)acetate (53c). The yield was 35.892 g (87 %), yellowish oil,

bp. 200 °C/39mbar, lit. bp 125–197 °C / 0.1–20 torr. [ex-45].

Yellowish prisms, mp 63–65 °C, lit. mp 55.5–66 °C [ex-45a, ex-46, ex-47, ex-

48, ex-49, ex-50].


IR (KBr): 3441 (w), 3118 (w), 3058 (w), 2985 (m), 2962 (w), 2939 (w), 2907 (w),

2872 (w), 2850 (w), 2452 (w), 2337 (w), 1943 (w), 1730 (s), 1688 (w), 1604 (m),

1513 (s) cm-1.


CH2), 4.09 (q, J = 7.1 Hz, 2 H, OCH2), 7.56 (d, J = 8.8 Hz, 2 HAA´ Ar-H), 8.18 (d,

J = 8.8 Hz, 2 HBB´ Ar-H).

C10H11NO4 (209.20).

Ethyl (3-Chlorophenyl)acetate (53d)

A solution of 3-chlorophenyl-acetic acid (52d: 33.20 g, 195.0 mmol), ethanol

(24.0 ml) and concentrated sulfuric acid (0.60 mL, 1.104 g, 11.26 mmol) in

chloroform (70.0 mL) was reacted at the reversed water separator for 5 hours

and worked up as described for 53a, to give ethyl (3-chlorophenyl)acetate



(53d). The yield was 21.682 g (56 %), colorless oil, b.p 140–145 °C/33–39

mbar, lit. bp 95-148 °C / 0.3–26 torr. [ex-41a, ex-50a, ex-51, ex-52].


IR (liquid film): 3065 (w), 2982 (m), 2938 (w), 2907 (w), 1736 (s), 1598 (w), 1574

(w) cm-1.


CH2), 4.08 (q, J = 7.1 Hz, 2 H, OCH2), 7.22 (dd, J = 6.4 + 2.0 Hz, 1 H, 5-H),

7.24 (t, J = 1.3 Hz, 1 H, 2-H), 7.32 (d, J = 5.2 Hz, 1 H, 4-H), 7.36 (d, J = 5.8 Hz,

1 H, 6-H).

C10H11ClO2 (198.65).

Diethyl (4-Methoxyphenyl)malonate (55a)

To a mixture of sodium hydride 60 % in mineral oil (15.00 g, 625.0 mmol)

and00000000000 diethyl carbonate (57.5 g, 59.0 mL, 487.28 mmol) in dry

tetrahydrofuran (115.0 mL), was added dropwise a solution of ethyl (4-

methoxyphenyl)acetate (53a: 18.30 g, 94.33 mmol) in dry tetrahydrofuran

(38.0 mL). The mixture was refluxed for 87 hours, cooled to room temperature,

and the solution was neutralized with a saturated aqueous solution of

ammonium chloride (150 mL). The organic phase was separated and then the

aqueous phase was extracted with diethylether (2 x 150 mL). The combined

organic phases were washed with saturated NaHCO3 solution (150 mL) and

brine (150 mL), and dried over sodium sulfate. After evaporation of the solvent

under reduced pressure, the residue was purified by vacuum distillation to give

diethyl (4-methoxyphenyl) malonate (55a). The yield was 17.368 g (69 %), clear

yellow oil, bp 190–206 °C/36.5 mbar, lit. bp 136–198 °C / 0.05–13 torr [ex-53,

ex-54, ex-55, ex-56, ex-57].


IR (liquid film): 2982 (w), 2937 (w), 2908 (w), 2839 (w), 1752 (w), 1733 (s), 1613

(w), 1514 (s) cm-1.



1H-NMR (300 MHz, [D6]DMSO): = 1.16 (t, J = 7.1 Hz, 6 H, 2 x CH3), 3.74 (s, 3

H, CH3O), 4.07-4.18 (m, 4 H, 2 x CH2), 4.86 (s, 1 H, CH), 6.92 (d, J = 8.7 Hz, 2

HBB´ Ar-H), 7.31 (d, J = 8.7 Hz 2 HAA´ Ar-H).

C14H18O5 (226.30).

Diethyl (4-Chlorophenyl)malonate (55b)

To a mixture of sodium hydride 60 % in mineral oil (9.80 g, 408.33 mmol) and

diethyl carbonate (114.73 g, 118.0 mL, 972.30 mmol) in dry tetrahydrofuran

(300.0 mL), was added drop wise a solution of ethyl (4-chlorophenyl)acetate

(53b: 38.60 g, 194.50 mmol) in dry tetrahydrofuran (100 mL). The mixture was

refluxed for 2 hours, and worked up as described for 55a, to give diethyl (4-

chlorophenyl)malonate (55b). The yield was 43.695 g (83 %), colorless oil, bp

170–180 °C /27 mbar, lit. bp 116–180 °C /0.05-25 torr. [ex-41a, ex-43b, ex-

44b, ex-54b, ex-55c, ex-56b, ex-57c, ex-58, ex-59, ex-60].


IR (liquid film): 2983 (w), 2935 (w), 2872 (w), 1900 (w), 1736 (s), 1597 (w), 1493

(s) cm-1.

1H-NMR (500 MHz, [D6]DMSO): = 1.17 (t, J = 7.1 Hz, 6 H, 2 x CH3), 4.10-4.17

(m, 4 H, 2 x OCH2), 5.03 (s, 1 H, CH), 7.40 (d, J = 9.1 Hz, 2 HAA´ Ar-H), 7.43 (d,

J = 9.0 Hz, 2 HBB´ Ar-H).

C13H15ClO4 (270.72).

Diethyl (3-Chlorophenyl)malonate (55d)

To a mixture of sodium hydride 60 % in mineral oil (6.00 g, 250 mmol) and

diethyl carbonate (58.20 g, 60.0 mL, 493.22 mmol) in dry tetrahydrofuran

(180.0 mL) was added dropwise a solution of ethyl (3-chlorophenyl)acetate

(53d: 19.30 g, 97.23 mmol) in dry tetrahydrofuran (60.0 mL).



The mixture was refluxed for 7 hours, and worked up as described for 55a, to

give diethyl (3-chlorophenyl)malonate (55d). The yield was 12.597 g (48 %),

colorless oil, bp 178–184 °C/22.7 mbar, lit. bp 145 –178 °C / 1.2–17 torr. [ex-

41a, ex-60b].


IR (liquid film): 2983 (m), 2937 (w), 1736 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 1.17 (t, J = 7.1 Hz, 6 H, 2 x CH3), 4.07-4.23

(m, 4 H, 2 x CH2), 4.86 (s, 1 H, CH), 7.36-7.40 (m, 3 H, Ar-H), 7.48 (s, 1 H, Ar-

H).

C13H15ClO4 (270.72).

4-Hydroxy-6-methoxy-3-(4-methoxyphenyl)quinolin-2(1H)-one

(57a)

A solution of p-anisidin (1: 5.30 g, 43.10 mmol) and diethyl (p-methoxyphenyl)

malonate (55a: 11.460 g, 50.71 mmol) in diphenyl ether (49.0 mL) was refluxed

at about 250–300 °C for 3 hours in the metal bath. During this time, ethanol

(3.90 mL, 67.0 mmol) was liberated. The solution was cooled to 20 °C, diluted

with cyclohexane (25.0 mL) and filtered by suction. The solid was dissolved in

warm aqueous sodium hydroxide (250.0 mL, 1 M), and filtered. To the alkaline

filtrate, concentrated hydrochloric acid was added until pH = 1–2 was reached,

the precipitate filtered by suction, washed with water and dried at 40 °C under

reduced pressure, which afforded 4-hydroxy-6-methoxy-3-(4-methoxyphenyl)-

quinolin-2(1H)-one (57a). The yield was 12.588 g (98 %), colorless prisms, mp

325 –328 °C (ethanol).


IR (ATR-measurement): 3435 (m), 3126 (w), 3054 (w), 3003 (w), 2958 (m), 2838

(w), 1647 (w), 1611 (s), 1587 (w), 1515 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.78 (s, 3 H, 6-CH3O), 3.79 (s, 3 H, Ar-

CH3O), 6.96 (d, J = 8.8 Hz, 2 HBB´ Ar-H), 7.14 (dd, J = 8.9 + 2.7 Hz, 1 H, 7-H),

7.23 (d, J = 8.9 Hz, 1 H, 8-H), 7.30 (d, J = 8.8 Hz, 2 HAA´ Ar-H),



7.44 (d, J = 2.6 Hz, 1 H, 5-H), 10.00 (s, 1 H, NH), 11.33 (s, 1 H, OH).

Anal. for C17H15NO4 (297.31).

Calcd: C 68.68, H 5.09, N 4.71, O 21.64

Found: C 68.31 H 4.86, N 4.72, O 21.54

3-(4-Chlorophenyl)-4-hydroxy-6-methoxyquinolin-2(1H)-one

(57b)

A solution of p-anisidin (1: 1.680 g, 13.66 mmol) and diethyl p-chlorophenyl

malonate (55b: 3.70 g, 14.66 mmol) in diphenyl ether (16.0 mL) of was

refluxed for 3 hours in the metal bath. During this time, ethanol (1.40 mL,

24.04 mmol) was liberated. The reaction was worked up as described for 57a,

to give 3-(4-chlorophenyl)-4-hydroxy-6-methoxyquinolin-2(1H)-one (57b). The

yield was 3.274 g (80 %), colorless prisms, mp 347–355 °C (ethanol).


IR (KBr): 3122 (w), 3055 (w), 2999 (w), 2949 (s), 2899 (w), 2829 (w), 2741 (w),

2623 (w), 1896 (w), 1648 (s), 1607 (s), 1585 (s), 1564 (w), 1510 (s) cm-1.


Hz, 1 H, 7-H), 7.24 (d, J = 8.9 Hz, 1 H, 8-H), 7.39 (d, J = 8.8 Hz, 2 HAA´ Ar-H),

7.44 (d, J = 2.6 Hz, 1 H, 5-H), 7.45 (d, J = 8.8 Hz, 2 HBB´ Ar-H), 10.20 (s, 1 H,

1-NH), 11.42 (s, 1 H, OH).


Calcd: C 63.69, H 4.01, N 4.64

Found: C 63.56, H 3.83, N 4.63

3-(3-Chlorophenyl)-4-hydroxy-6-methoxyquinolin-2(1H)-one

(57d)

A solution of p-anisidin (1: 5.273 g, 42.87 mmol) and diethyl m-chlorophenyl

malonate (55d: 11.597 g, 42.87 mmol) in diphenyl ether (50.0 mL) was refluxed



for 3 hours in the metal bath. During this time, ethanol (3.60 mL, 61.83 mmol)

was liberated. The reaction was worked up as described for 57a, to give 3-(3-

chlorophenyl)-4-hydroxy-6-methoxyquinolin-2(1H)-one (57d). The yield was

9.413 g (73 %), colorless prisms, mp 322–325 °C (ethanol).


IR (KBr): 3127 (w), 3059 (w), 2993 (w), 2964 (s), 2936 (w), 2831 (w), 1644 (w),

1607 (s), 1587 (w), 1506 (m) cm-1.


Hz, 1 H, 7-H), 7.25 (d, J = 8.9 Hz, 1 H, 8-H), 7.37 (s, 1 H, Ar-H), 7.34–7.42 (m,

3 H, Ar-H), 7.45 (d, J = 2.0 Hz, 1 H, 5-H), 10.30 (s, 1 H, NH), 11.44 (s, 1 H,

OH).


Calcd: C 63.69, H 4.01, N 4.64

Found: C 63.67, H 3.78, N 4.63

4-Hydroxy-6-methoxy-3-phenylquinolin-2(1H)-one (57e)

A solution of p-anisidin (1: 10.014 g, 81.41 mmol), and diethyl phenylmalonate

(19.344 g, 81.96 mmol) in diphenyl ether (50.0 mL) was refluxed for 3 hours in

the metal bath. During this time, ethanol (6.0 mL, 103.03 mmol) was liberated.

The reaction was worked up as described for 57a, to give 4-hydroxy-6-

methoxy-3-

phenylquinolin-2(1H)-one (57e). The yield was 21.089 g (97 %), colorless

prisms, mp 324–327 °C (ethanol), lit. mp 319–326 °C [ex-61].


IR (in KBr): 3430 - 3295 (m, br), 3126 (w), 3058 (w), 2998 (w), 2959 (w), 2832

(w), 1648 (s), 1611 (s), 1509 (m) cm-1.


Hz, 1 H, 7-H), 7.24 (d, J = 8.9 Hz, 1 H, 8-H), 7.28–7.41 (m, 5 H, Ar- H), 7.46

(d, J = 2.6 Hz, 1 H, 5-H), 10.03 (s, 1 H, NH), 11.37 (s, 1 H, OH).

C16H13NO3 (267.29).



4-Hydroxy-6-methoxy-3-methylquinolin-2(1H)-one (57f)

A solution of p-anisidin (1: 10.00 g, 81.30 mmol) and diethylmethyl malonate

(55f: 14.0 mL, 81.30 mmol) in diphenyl ether (50.0 mL), was refluxed for 3

hours in a metal bath. During this time, ethanol (6.90 mL, 118.50 mmol) was

liberated. The reaction was worked up as described for 57a, to give 4-hydroxy-

6-methoxy-3-methylquinolin-2(1H)-one (57f). The yield was 15.715 g (94 %),

colorless prisms, mp 234–236 °C (ethanol).


IR (ATR-measurement): 3431 (s), 3290 (w), 3242 (w), 2961 (w), 2926 (w), 2834

(w), 1647 (s), 1612 (s), 1566 (w), 1509 (w) cm-1.



2.7 Hz, 1 H, 5-H), 10.03 (s, 1 H, NH), 11.22 (s, 1 H, OH).

C11H11NO3 (205.22).

Calcd: C 64.38, H 5.40, N 6.83

Found: C 64.32, H 5.26, N 6.85

3-Ethyl-4-hydroxy-6-methoxyquinolin-2(1H)-one (57g)

A solution of p-anisidin (1: 12.50 g, 101.63 mmol) and diethylmethyl malonate

(55g: 18.0 mL, 101.11 mmol) in diphenyl ether (60.0 mL), was refluxed for 3

hours in a metal bath and worked up as described for 57a, to give 3-ethyl-4-

hydroxy-6-methoxyquinolin-2(1H)-one (57g). The yield was 9.50 g (43 %),

colorless prisms, mp 160–162 °C (ethanol), lit. mp 172 °C [ex-61a].


IR (ATR-measurement): 3368 (w), 3100-2835 (m, br), 1647 (m), 1606 (s), 1558

(m), 1508 (s) cm-1.



1H-NMR (300 MHz, [D6]DMSO): = 1.01 (t, J = 7.3 Hz, 1 H, CH3), 2.57 (q, J =

7.3 Hz, 2 H, CH2), 3.78 (s, 3 H, CH3O), 7.09 (dd, J = 8.9 + 2.7 Hz, 1 H, 7-H),

7.21 (d, J = 8.9 Hz, 1 H, 8-H), 7.39 (d, J = 2.7 Hz, 1 H, 5-H), 11.27 (s, 1 H, NH).

13C-NMR (300 MHz, [D6]DMSO): = 13.7 (CH3), 16.9 (CH2), 55.9 (CH3O), 104.7

(10-C), 113.8 (3-C), 116.4 (8-C), 116.8 (5-C), 119.3 (7-C), 132.2 (9-C), 154.3 (6-

C), 156.9 (4-C), 163.3 (lactam-C=O).

C12H13NO3 (219.24).

2,4-Dichloro-6-methoxy-3-(4-methoxyphenyl)quinoline (58a)

A solution of 4-hydroxy-6-methoxy-3-(4-methoxyphenyl)quinolin-2(1H)-one

(57a: 11.10 g, 37.37 mmol) in phosphoroxychloride (45.0 mL) was brought to

reaction under reflux for 12 hours, and worked up as described for 5, to give

2,4-dichloro-6-methoxy-3-(4-methoxyphenyl)quinoline (58a). The yield was

9.771 g (79 %), colorless prisms, mp 169–170 °C (ethanol).


IR (ATR-measurement): 3439 (s), 3059 (w), 3008 (w), 2969 (w), 2934 (w), 2837

(w), 2359 (w), 2041 (w), 1954 (w), 1898 (w), 1617 (s), 1565 (m), 1513 (s), 1490

(s) cm-1.


CH3O), 7.08 (d, J = 8.7 Hz, 2 HBB´ Ar-H), 7.32 (d, J = 8.6 Hz, 2 HAA´ Ar-H), 7.44


Hz, 1 H, 8-H).

Anal. For C17H13Cl2NO2 (334.20 ).

Calcd. : C 61.10, H 3.92, N 4.19, O 9.57

Found : C 61.08, H 3.72, N 4.17, O 9.80

2,4-Dichloro-3-(4-chlorophenyl)-6-methoxyquinoline (58b)

A solution of 3-(4-chlorophenyl)-4-hydroxy-6-methoxyquinolin-2(1H)-one (57b:

13.380 g, 44.38 mmol) in phosphoroxychloride (70.0 mL) was refluxed for 8

file:///prisms



hours, and worked up as described for 5, to give 2,4-dichloro-3-(4-

chlorophenyl)-6-methoxyquinoline (58b). The yield was 12.910 g (86 %),



IR (KBr): 3503 (w), 3002 (w), 2978 (w), 2944 (w), 2913 (w), 2612 (w), 2435 (w),

2359 (w), 2042 (w), 1920 (w), 1788 (w), 1687 (w), 1619 (s), 1567 (m), 1492 (s)

cm-1.


H, 5-H), 7.47 (d, J = 8.2 Hz, 2 HBB´ Ar-H), 7.59 (d, J = 9,2 + 2.0 Hz, 1 H, 7-H),

7.63 (d, J = 8.2 Hz, 2 HAA´ Ar-H), 7.99 (d, J = 9.2 Hz, 1 H, 8-H).

Anal. For C16H10Cl3NO (338.62 ).

Calcd. : C 56.75, H 2.98, N 4.14

Found : C 56.70, H 2.77, N 4.14

2,4-Dichloro-3-(3-chlorophenyl)-6-methoxyquinoline (58d)

A solution of 4-hydroxy-3-(3-chlorophenyl)-6-methoxyquinolin-2(1H)-one (57d:

7.00 g, 23.22 mmol) in phosphoroxychloride (30.0 mL) was reacted under

reflux for 12 hours, and worked up as described for 5, to give 2,4-dichloro-3-

(3-chlorophenyl)-6-methoxyquinoline (58d). The yield was 7.597 g (97 %), beige



IR (KBr): 3073 (w), 2965 (w), 2943 (w), 2911 (w), 2845 (w), 1618 (w), 1599 (s),

1567 (m), 1492 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.97 (s, 3 H, CH3O), 7.41-7.42 (m, 1 H, Ar-

H), 7.48 (d, J = 2.6 Hz, 1 H, 5-H), 7.58-7.60 (m, 3 H, Ar-H), 7.62 (dd, J = 9.2 +

2.6 Hz, 1 H, 8-H), 8.02 (d, J = 9.2 Hz, 1 H, 8-H).


Calcd. : C 56.75 H 2.98 N 4.14

Found : C 56.46 H 2.66 N 4.09



2,4-Dichloro-6-methoxy-3-phenylquinoline (58e)

A solution of 4-hydroxy-6-methoxy-3-phenylquinolin-2(1H)-one (57e: 18.50 g,

69.30 mmol) in phosphoroxychloride (80.0 mL) was brought to reaction under

reflux for 8 hours and worked up as described for 5, to give 2,4-dichloro-6-

methoxy-3-phenylquinoline (58e). The yield was 20.409 g (97 %), colorless



IR (KBr): 3438 (m), 3027 (w), 2959 (w), 2939 (w), 2908 (w), 1620 (m), 1572 (m)

cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.97 (s, 3 H, CH3O), 7.39-7.40 (m, 1 H, 7-

H), 7.42 (d, J = 1.8 Hz, 1 H, 5-H), 7.48-7.62 (m, 5 H, PhH), 8.02 (d, J = 9.2 Hz,

1 H, 8-H).


Calcd. : C 63.18, H 3.65, N 4.60

Found : C 63.05, H 3.44, N 4.58

2,4-Dichloro-6-methoxy-3-methyl-quinoline (58f)

A solution of 4-hydroxy-6-methoxy-3-methylquinolin-2(1H)-one (57f: 9.50 g,


reflux for 24 hours, and worked up as described for 5, to give 2,4-dichloro-6-

methoxy-3-methylquinoline (58f). The product was pure enough for further

use. The yield was 10.278 g (92 %), light yellow prisms, mp 149–151 °C

(ethanol).


IR (KBr): 3459 (s), 1622 (m), 1572 (w), 1560 (w) cm-1.



9.1 Hz, 1 H, 8-H).




Calcd. : C 54.57, H 3.75, N 5.79

Found : C 54.36, H 3.55, N 5.69

2,4-Dichloro-3-ethyl-6-methoxyquinoline (58g)

A solution of 3-ethyl-4-hydroxy-6-methoxyquinolin-2(1H)-one (57g: 3.150 g,


reflux for 24 hours and worked up as described for 5, to give 2,4-dichloro-3-

ethyl-6-methoxyquinoline (58g).

The yield was 3.090 g (84 %), colorless prisms, mp 115–118 °C (ethanol).



(w), 2340 (w), 1619 (m), 1568 (m), 1557 (m), 1493 (m) cm-1.


7.2 Hz, 2 H, CH2), 3.94 (s, 3 H, CH3O), 7.35 (s, 1 H, 5-H), 7.47 (d, J = 8.8 Hz, 7-

H), 7.86 (d, J = 8.8 Hz, 1 H, 8-H).

13C-NMR (300 MHz, [D6]DMSO): = 12.8 (CH3), 25.3 (CH3O), 56.2 (CH2), 102.6


(aromatic-C), 140.6 (4-C), 141.8 (9-C), 147.8 (2-C), 159.3 (6-C) .

Anal. for C12H11Cl2NO ( 256.13 ).

Calcd: C 56.27, H 4.33, N 5.47

Found: C 56.10, H 4.13, N 5.43

Chloro-6-methoxy-3-(4-methoxyphenyl)quinolin-2(1H)-one (59a)

A solution of 2,4-dichloro-6-methoxy-3-(4-methoxyphenyl)quinoline (58a: 7.40

g, 22.16 mmol), and 70 % methanesulfonic acid (8.0 mL) in n-butanol (55.0

mL) was heated under reflux for 48 hours and worked up following the method

described for 6, to give 4-chloro-6-methoxy-3-(4-methoxyphenyl)quinolin-



2(1H)-one (59a). The yield was 6.467 g (93 %), beige prisms, mp 275–277 °C

(ethanol).


IR (ATR-measurement): 3435 (m), 3179 (m), 3092 (w), 3046 (w), 3008 (w), 2951

(w), 2929 (w), 2832 (w), 1649 (s), 1622 (w), 1609 (w), 1595 (w), 1572 (w), 1513

(m), 1495 (m) cm-1.


CH3O), 7.01 (d, J = 8.7 Hz, 2 HAA Ar-H), 7.27-7.36 (m, 3 H, 5-H, 7-H, 8-H, and

2 H, HBB´ Ar-H), 12.09 (s, 1 H, NH).


Calcd: C 64.67, H 4.47, N 4.44

Found: C 64.48, H 4.27, N 4.42

4-Chloro-3-(4-chlorophenyl)-6-methoxyquinolin-2(1H)-one (59b)

A solution of 2,4-dichloro-3-(4-chlorophenyl)-6-methoxyquinoline (58b: 6.00 g,

17.73 mmol), and 70 % methanesulfonic acid (6.0 mL) in n-butanol (60.0 mL)

was heated under reflux for 45 hours and worked up following the method

described for 6, to give 4-chloro-3-(4-chlorophenyl)-6-methoxyquinolin-2(1H)-

one (59b). The yield was 5.330 g (94 %) beige prisms, mp 296–298 °C (ethanol).


IR (KBr): 3427 (m), 2957 (w), 2922 (w), 2848 (m), 2766 (w), 1666 (s), 1624 (w),

1593 (m), 1494 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.83 (s, 3 H, CH3O), 7.30-7.35 (m. 3 H, 5-

H, 7-H and 8–H), 7.49 (d, J = 7.7 Hz, 2 HAA´ Ar-H), 7.52 (d, J = 7.8 Hz, 2 HBB´

Ar-H), 12.18 (s, 1 H, NH).


Calcd: C 60.02, H 3.46, N 4.37

Found: C 60.23, H 3.39, N 4.36



4-Chloro-3-(3-chlorophenyl)-6-methoxyquinolin-2(1H)-one (59d)

A solution of 2,4-dichloro-3-(3-chlorophenyl)-6-methoxyquinoline (58d: 6.00 g,

17.73 mmol), and 70 % methanesulfonic acid (3.0 mL) in n-butanol (50.0 mL)

was heated under reflux for 45 hours, and worked up following the method

described for 6, to give 4-chloro-3-(3-chlorphenyl)-6-methoxyquinolin-2(1H)-

one (59d). The compound obtained was pure enough for further use. The yield

was 5.100 g (90 %), beige prisms, mp 285–288 °C (ethanol).


IR (KBr): 2832 (w), 1658 (s), 1623 (m), 1500 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.83 (s, 3 H, CH3O), 7.32-7.33 (m, 3 H, Ar-

H), 7.37 (d, J = 8.6 Hz, 1 H, 8-H), 7.44 (s, 1 H, Ar-H), 7.43-7.50 (m, 2 H, 5-H,

and 7-H ), 12.21 (s, 1 H, NH).


Calcd: C 60.02, H 3.46, N 4.37

Found: C 59.90, H 3.31, N 4.35

4-Chloro-6-methoxy-3-phenylquinolin-2(H)-one (59e)

A solution of 2,4-dichloro-6-methoxy-3-phenylquinoline (58e: 7.00 g, 23.03

mmol) and 70 % methanesulfonic acid (11.50 mL) in n-butanol (92.0 mL) was

heated to 110 °C for 30 hours and worked up following the method described

for 6, to afford 4-chloro-6-methoxy-3-phenylquinolin-2(H)-one (59e). The yield

was 5.860 g (89 %), colorless prisms, mp 278–281 °C (ethanol).


IR (ATR-measurement): 3523 (w), 3437 (m), 3251 (w), 3192 (s), 3087 (w), 3055

(w), 3005 (w), 2953 (w), 2926 (w), 1640 (s), 1595 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.38 (s, 3 H, CH3O), 7.29-7.48 (m, 3 H, 5-

H, 7-H 8-H, and 5-H, Ph-H), 12.14 (s, 1 H, NH).


Calcd: C 67.26, H 4.23, N 4.90

Found: C 67.25, H 3.99, N 4.90



4-Chloro-6-methoxy-3-methylquinolin-2(1H)-one (59f)

A solution of 2,4-dichloro-6-methoxy-3-methylquinoline (58f: 8.50 g, 35.12

mmol) and 70 % methanesulfonic acid (7.0 mL) in ethanol (80.0 mL) was

heated to reflux for 48 hours and worked up following the method described for

6, to afford 4-chloro-6-methoxy-3-methylquinolin-2(1H)-one (59f).

The yield was 7.189 g (92 %), light yellow prisms, mp 253–256 °C (ethanol).


IR (KBr): 3431 (w), 2982 (w), 2955 (w), 2925 (w), 2818 (w), 2767 (w), 2733 (w),

1649 (s), 1625 (w), 1600 (w), 1566 (w), 1501 (s) cm-1.


7.18-7.23 (m, 2 H, 5-H and 7-H), 7.30 (d, J = 8.7 Hz, 1 H, 8-H), 11.95 (s, 1 H,

NH).


Calcd: C 59.07, H 4.51, N 6.26

Found: C 58.95, H 4.32, N 6.17

4-Chloro-3-ethyl-6-methoxyquinolin-2(1H)-one (59g)

A solution of 2,4-dichloro-3-ethyl-6-methoxyquinoline (58g: 2.150 g, 8.40

mmol) and 70 % methanesulfonic acid (2.0 mL) in n-butanol (20.0 mL) was

heated to reflux for 48 hours and worked up following the method described

for 6, to afford 4-chloro-3-ethyl-6-methoxyquinolin-2(1H)-one (59g). The

compound was pure without recrystallization. The yield was 1.589 g (80 %),




(w), 1651 (s), 1620 (w), 1597 (s), 1562 (w), 1498 (s) cm-1.


7.4 Hz, 2 H, CH2), 3.81 (s, 3 H, CH3O), 7.19 (dd, J = 8.7 + 2.8 Hz, 1 H, 7-H),

7.22 (d, J = 2.3 Hz, 1 H, 5-H), 7.28 (d, J = 8.7 Hz, 1 H, 8-H), 11.95 (s, 1 H, NH).



13C-NMR (300 MHz, [D6]DMSO): = 12.5 (CH3), 21.9 (CH2), 55.9 (CH3O), 106.5


(aromatic-C), 134.2 (aromatic-C), 139.8 (4-C), 155.0 (6-C), 160.9 (lactam-C=O).


Calcd: C 60.64, H 5.09, N 5.89

Found: C 60.43, H 4.89, N 5.82

6-Methoxy-3-(4-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-4-

carbonitrile (60a)

A mixture of 4-chloro-6-methoxy-3-(4-methoxyphenyl)quinolin-2(1H)-one (59a:

1.60 g, 5.11 mmol), sodium p-toluenesulfinate (0.910 g, 5.10 mmol), and dry

potassium cyanide (0.995 g, 15.31 mmol) in dry dimethylformamide (30.0 mL)

was heated to 120 °C for 72 hours, with vigorous stirring, and worked up

following the method described for 7, to give 6-methoxy-3-(4-methoxyphenyl)-

2-oxo-1,2-dihydroquinoline-4-carbonitrile (60a). The yield was 1.495 g (96 %),

yellow prisms, mp 275–278 °C (acetone).


IR (KBr): 3432 (m), 3148 (w), 2839 (m), 2229 (w), 1658 (s), 1624 (m), 1606 (s),

15748 (w), 1515 (w), 1501 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.84 (s, 3 H, Ar-CH3O), 3.85 (s, 3 H, 6-

CH3O), 7.06 (d, J = 8.7 Hz, 2 HBB´ Ar-H), 7.16 (d, J = 2.4 Hz, 1 H, 5-H), 7.32

(dd, J = 9.0 + 2.4 Hz, 1 H, 7-H), 7.38 (d, J = 9.0 Hz, 1 H, 8-H), 7.58 (d, J = 8.6

Hz, 2 HAA´ Ar-H), 12.41 (s, 1 H, NH).

13C-NMR (300 MHz, [D6]DMSO): =55.7 (C-6-CH3O), 55.9 (aryl-CH3O), 106.6

(aromatic-C), 113.8 (2 x aromatic-CAA´), 115.6 (aromatic-C), 1176 (aromatic-C),

118.3 (CN), 121.2 (aromatic-C),125.7 (aromatic-C),132.1 (2 x aromatic-

CBB´),132.9 (aromatic-C), 140.8 (aromatic-C), 155.4 (6-C), 159.4 (C-aryl-CH3O),

160.7 (lactam-C=O).

MS (ESI neg): m/z (%) = 306 (21, M + 1), 305 (100, M).



Anal. for C18H14N2O3 (306.32).

Calcd: C 70.58, H 4.61, N 9.15

Found: C 70.00, H 4.40, N 9.01

The elemental analysis showed a small deviation of 0.58 %.for carbon

component due to the fact that the compound 60a was not well soluble in

almost all organic solvent.

3-(4-Chlorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-

carbonitrile (60b)

A mixture of 4-chloro-3-(4-chlorophenyl)-6-methoxyquinolin-2(1H)-one (59a:

1.60 g, 5.10 mmol), sodium p-toluenesulfinate (0.890 g, 5.0 mmol), and dry


was heated to 120 °C for 63 hours and the solution was worked up following

the method described for 7, to give 3-(4-chlorophenyl)-6-methoxy-2-oxo-1,2-

dihydroquinoline-4-carbonitrile (60b). The yield was 1.523 g (98 %), yellow

prisms, mp 332–333.5 °C (acetone).

Rf = 0.45 (petrolether/EtOAc 1:3).

IR (ATR-measurement): 3434 (m), 2997 (w), 2916 (w), 2857 (w), 2764 (w), 2231

(w), 1670 (s), 1623 (w), 1607 (w), 1595 (w), 1503 (w), 1495 (w) cm-1.



7.58 (d, J = 8.6 Hz, 2 HAA´ Ar-H), 7.63 (d, J = 8.6 Hz, 2 HBB´ Ar-H), 12.50 (s, 1

H, NH).


117.4 (4-C), 117.8 (7-C), 119.5 (CN), 121.8 (8-C), 130.8 (2 x aromatic-CBB´),

132.4 (2 x aromatic-CAA´), 132.6 (9-C), 133.4 (aryl-C), 134.7 (aryl-C), 139.9 (3-

C), 155.5 (6-C),

159.1 (lactam-C=O).

MS (ESI neg): m/z (%) = 311 (35, M + 1), 309 (100, M).




The elemental analysis of compound 60b could not be obtained because

compound 60b was not at all soluble in almost all organic solvent.

3-(3-Chlorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-4-

carbonitrile (60d)

A mixture of 4-chloro-3-(3-chlorophenyl)-6-methoxyquinolin-2(1H)-one (59d:

2.50 g, 7.81 mmol), sodium p-toluenesulfinate (1.60 g, 8.98 mmol) and dry


was heated to 130 °C for 43 hours with vigorous stirring and the solution was

worked up following the method described for 7, to give 3-(3-chlorophenyl)-6-

methoxy-2-oxo-1,2-dihydroquinoline-4-carbonitrile (60d). The yield was 2.347

g (97 %), green prisms, mp 328–330 °C (acetone).


IR (ATR-measurement): 2823 (w), 2230 (w), 1661 (w), 1623 (m), 1501 (w) cm-1.



7.57 (m, 3 H, Ar-H), 7.70 (s, 1 H, Ar-H), 12.54 (s, 1 H, NH).


Calcd: C 65.71, H 3.57, N 9.01

Found: C 65.30, H 3.45, N 8.86

6-Methoxy-2-oxo-3-phenyl-1,2-dihydroquinoline-4-carbonitrile

(60e)

A mixture of 4-chloro-6-methoxy-3-phenylquinolin-2(1H)-one (59e: 3.00 g,

10.51 mmol), sodium p-toluenesulfinate (1.870 g, 10.51 mmol) and dry


was heated at 120 °C for 45 hours with vigorous stirring and the solution was



worked up following the method described for 7, to give 6-methoxy-2-oxo-3-

phenyl-1,2-dihydroquinoline-4-carbonitrile (60e). The yield was 2.775 g (96 %),

yellow prisms, mp 263–265 °C (acetone).


IR (KBr): 3449 (m), 2971 (w), 2912 (w), 2849 (w), 2823 (w), 2763 (w), 2236 (w),

1667 (s), 1624 (w), 1602 (w), 1495 (m) cm-1.



7.48-7.5 (m, 3 H, PhH), 7.59 (dd, J = 7.5 + 2.4 Hz, 2 H, PhH), 12.44 (s, 1 H,

NH).

13C-NMR (360 MHz, [D6]DMSO): = 55.9 (CH3), 106.6 (aromatic-C), 115.2

(aromatic-C), 117.7 (aromatic-C), 119.2 (CN), 121.5 (aromatic-C), 128.4 (PhC),

129.8 (2 x aromatic-CAA´), 130.4 (2 x aromatic-CBB´), 133.2(9-C), 133.7 (PhC),

141.1 (3-C), 155.4 (6-C), 159.3 (lactam-C=O).

MS (APCI pos): m/z (%) = 277 (100, M).

MS (APCI neg): m/z (%) = 276 (19, M + 1), 275 (100, M).

Anal. for C17H12N2O2 (276.30).

Calcd: C 73.90, H 4.38, N 10.14

Found: C 73.62, H 4.11, N 9.92

2-Chloro-6-methoxy-3-phenylquinoline-4-carbonitrile (61)

A solution of 6-methoxy-2-oxo-3-phenyl-1,2-dihydroquinoline-4-carbonitrile

(60e: 1.373 g, 5.0 mmol) in phosphoroxychloride (6.0 mL) was refluxed at 110

°C for 12 hours. The solution was cooled to 50 °C and the excess amount of

phosphoroxychloride was removed under reduced pressure. The residue was

poured onto ice/water (100 mL), filtered by suction and washed with water to

afford 2-chloro-6-methoxy-3-phenylquinoline-4-carbonitrile (61). The yield was

1.390 g (95 %), yellowish prisms, mp 242–245 °C (ethanol).

IR (KBr): 3439 (s), 2959 (w), 2236 (w), 1618 (m), 1561 (w), 1497 (m) cm-1.




H, 5-H), 7.59 (s, 5 H, PhH), 7.68 (dd, J = 9.3 + 2.7 Hz, 1 H, 7-H), 8.11 (d, J =

9.3 Hz, 1 H, 8-H).

C17H11ClN2O (294.74).

Ethyl3–[(4-methoxyphenyl)amino]-

2-[(4-methoxyphenyl)carbamoyl]-3-oxopropanoate (64)

A mixture of p-anisidine (1: 0.615 g, 5.0 mmol) and triethyl

methanetricarboxylate (62: 2.320 g, 10.0 mmol) in bromobenzene (50.0 mL)

was heated under reflux to 155 °C for 6 hours. The solvent was evaporated

under reduced pressure. The crude product was digested with diethyl ether (25

mL), filtered by suction and washed with water to give ethyl 3–[(4-

methoxyphenyl)amino]-2-[(4-methoxyphenyl)carbamoyl]-3-oxopropanoate (64).

The yield was 1.570 g (88 %), grey prisms, mp 168–170 °C (ethanol).


IR (ATR-measurement): 3262 (m), 1747 (m), 1671 (s), 1609 (w), 1553 (w), 1533

(m), 1511 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 1.21 (t, J = 7.1 Hz, 3 H, CH3), 3.72 (s, 2 x 3

H, 2 x CH3O), 4.16 (q, J = 7.1 Hz, 2 H, OCH2), 4.65 (s, 1 H, CH), 6.90 (d, J = 8.9

Hz, 2 x 2 H, Ar-H), 7.48 (d, J = 8.9 Hz, 2 x 2 H, Ar-H), 10.12 (s, 2 x 1 H, 2

x NH).

C20H22N2O6 (386.41).



Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (67)

To a solution of sodium ethoxide in ethanol, prepared from sodium (3.450 g,

0.15 mol) in anhydrous ethanol (112.50 mL), a mixture of diethyl malonate

(66: 23.0 mL, 24.15 g, 0.15 mol ) and methyl anthranilate (65: 19.50 mL,

22.65 g, 0.15 mol) was added. The mixture was heated to 140–150 °C for 5

hours and the excess amount of ethanol (116.60 mL) was removed by

distillation using a short column. The resulting yellow solid material was

heated to 140–150 °C for 10 hours, the solid was cooled at ambient

temperature and triturated with diethyl ether (150.0 mL).

The solution was filtered by suction and washed with diethyl ether, the product

got dry immediately. Then it was dissolved in water (500 mL) at 50 °C, filtered

from insoluble parts and the filtrate was acidified with hydrochloric acid (2 M).

The light yellow precipitate was filtered by suction, washed several times with

water and dried at 40 °C under reduced pressure to give ethyl 4-hydroxy-2-

oxo-1,2-dihydroquinoline-3-carboxylate (67). The yield was 26.795 g (77 %),

mp 205–207 °C (methanol), lit. mp 194–304 °C [ex-62–64].



(s), 1609 (s), 1558 (w), 1494 (s) cm-1.


7.1 Hz, 2 H, CH2), 7.22 (t, J = 6.6 Hz, 1 H, 6-H), 7.28 (d, J = 8.3 Hz, 1 H, 8-H),

7.62 (t, J = 7.7 Hz, 1 H, 7-H), 7.94 (d, J = 8.0 Hz, 1 H, 5-H), 11.50 (s, 1 H, NH),

13.40 (s, 1 H, OH).

C12H11NO4 (233.23).

Ethyl 2,4-dichloroquinoline-3-carboxylate (68)

A mixture of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (67:

3.00 g, 12.87 mmol), in phosphoroxychloride (20.0 mL) and triethylamine (2.0

mL, 1.460 g, 14.46 mmol) was heated to 60 °C under stirring for 2 hours.



Then the mixture was poured onto crushed ice (200 mL), the obtained mixture

of yellow oil and precipitate was stirred until all solidified. The mixture was

brought to pH = 5–6 with concentrated sodium hydroxide solution, the

precipitate was filtered by suction and washed with water and dried at 40 °C

under reduced pressure, which afforded ethyl 2,4-dichloroquinoline-3-

carboxylate (68). The yield was 3.402 g (98 %), light pillow needles, mp 119–

121 °C (methanol), lit. mp 85–104 °C [ex-62b, ex-65, ex-66].


IR (ATR-measurement): 2986 (w), 1728 (s), 1613 (w), 1560 (m), 1481 (m) cm-1.


7.1 Hz, 2 H, CH2), 7.89 (t, J = 7.9 Hz, 1 H, 6-H), 8.03 (t, J = 7.6 Hz, 1 H, 7-H),

8.10 (d, J = 8.3 Hz, 1 H, 8-H), 8.28 (d, J = 8.3 Hz, 1 H, 5-H).

C12H9Cl2NO2 (270.12).

4-Hydroxyquinolin-2(1H)-one (69)

Method A

A solution of ethyl 2,4-dichloroquinoline-3-carboxylate (68: 1.350 g, 5.0 mmol)

and 70 % methanesulfonic acid (3.1 equiv., 1.480 g, 1.00 mL, 15.42 mmol) in

ethanol ( 15.0 mL) was heated under reflux for 48 hours. The mixture was

cooled to 20 °C and poured onto ice/water (50 mL), brought to pH = 4–6 with

sodium hydroxide (2 M), filtered by suction, washed with water and dried at 40

°C under reduced pressure, to give 4-hydroxyquinolin-2(1H)-one (69). The yield

was 0.966 g (77 %), colorless prisms, mp 344–346 °C (ethanol).


Method B

A mixture of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (70: 0.60

g, 2.40 mmol), sodium p-toluenesulfinate (0.892 g, 5.01 mmol), and dry


was heated to 120 °C for 28 hours and the solution was worked up following



the method described for 7, to form 4-Hydroxyquinolin-2(1H)-one (69). The

yield was 0.372 g (97 %), dark green prisms, mp > 350 °C (ethanol), lit. mp

250–360 °C [ex-3c, ex-3d, ex-67, ex-68, ex-69, ex-70, ex-71, ex-72, ex-73, ex-

74].


IR (ATR-measurement): 3093–2560 (m, br), 1653 (s), 1632 (s), 1611 (w), 1593

(s), 1505 (w) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 5.72 (s, 1 H, 3-H), 7.15 (t, J = 7.6 Hz, 1 H,

6-H), 7.25 (d, J = 8.2 Hz, 1 H, 5-H), 7.48 (d, J = 7.7 Hz, 1 H, 7-H), 7.76 (d, J =

7.9 Hz, 1 H, 8-H), 11.18 (s, 1H, NH), 11.29 (s, 1 H, OH).

C9H7NO2 (161.16).

Ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (70)

A solution of ethyl 2,4-dichloroquinoline-3-carboxylate (68: 15.00 g, 55.56

mmol) and 70 % methanesulfonic acid (1.54 equiv., 8.140 g, 5.50 mL, 84.80

mmol) in ethanol ( 90.0 mL) was heated under reflux for 48 hours. The mixture

was cooled to 20 °C and poured into ice/water (250 mL), brought to pH = 4–6

with sodium hydroxide (2 M), filtered by suction, washed with water and dried

at 40 °C under reduced pressure, to give ethyl 4-chloro-2-oxo-1,2-

dihydroquinoline-3-carboxylate (70). The compound was pure for further steps.

The yield was 9.39 g (67 %), colorless prisms, mp 198–200 °C, lit. mp 194–203

°C [ex-65, ex-75, ex-76].



(s), 1649 (s), 1619 (w), 1596 (m), 1566 (w), 1497 (w) cm-1.


7.1 Hz, 2 H, CH2), 7.33–7.38 (m, 1 H, 7-H), 7.41 (dd, J = 8.1 + 1.0 Hz, 1 H, 8-

H), 7.66–7.72 (m, 1 H, 6-H), 7.90 (dd, J = 8.1 + 0.9 Hz, 1 H, 5-H), 12.50 (s, 1 H,

NH).

C12H10ClNO3 (251.67).



Ethyl [4-chloro-3-(4-chlorophenyl)-6-methoxy-2-oxoquinolin-

1(2H)-yl]acetate (72)

A mixture of 4-chloro-3-(4-chlorophenyl)-6-methoxyquinolin-2(1H)-one (59b:

1.00 g, 3.13 mmol), ethyl bromoacetate (1.310 g, 7.84 mmol) and dry sodium

carbonate (0.831 g, 7.84 mmol) in dry dimethylformamide (25.0 mL) was

heated to 120–140°C for 25 minutes. The solution was cooled to room

temperature and poured into ice/water (25 mL). The obtained solid was filtered

by suction, washed with water and dried at 40 °C under reduced pressure to

afford ethyl [4-chloro-3-(4-chlorophenyl)-6-methoxy-2-oxoquinolin-1(2H)-

yl]acetate (72). The yield was 1.199 g (95 %), colorless prisms, mp 122–124 °C

(ethanol).


IR (ATR-measurement): 2980 (w), 2838 (w), 1737 (m), 1638 (s), 1596 (w), 1570

(m), 1501 (w) cm-1.


CH3O), 4.16 (q, J = 7.1 Hz, 2 H, CH2 ), 5.14 (s, 2 H, NCH2), 7.36 (dd, J = 9.3 +

2.8

Hz, 1 H, 7-H), 7.38 (d, J = 8.6 Hz, 2 H, Ar-H), 7.49 (d, J = 2.8 Hz, 1 H, 5-H),

7.53 (d, J = 8.6 Hz, 2 H, Ar-H), 7.56 (d, J = 9.0 Hz, 1 H, 8-H).

C20H17Cl2NO4 (406.27).

4-Hydroxy-6,7-dimethoxyquinolin-2(1H)-one (74)

A mixture of 3,4-dimethoxyanilin (73: 6.12 g , 40.0 mmol) and dry malonic acid

(2: 4.38 g, 42.12 mmol) in phosphoryloxychloride (4.0 mL) was heated in an

open flask to 50 °C for 2 hours, then the temperature was raised slowly up to

90 °C and kept there for 30 minutes. The obtained residue was dissolved in

aqueous sodium hydroxide (150 mL, 0.5 M) under warming to 60 °C and the

solution was filtered. The alkaline filtrate was acidified with concentrated

hydrochloric acid to pH = 1–2.



The formed precipitate was filtered by suction, washed with water and dried at

40 °C under reduced pressure and afforded 4-hydroxy-6,7-dimethoxyquinolin-

2(1H)-one (74). The yield was 7.417 g (84 %), pale green prisms, mp 346–349

°C (ethanol), lit. mp > 320 °C [ex-76, ex-78, ex-79].


IR (KBr): 3429 (s), 2999 (w), 2941 (w), 2834 (w), 2796 (w), 1682 (m), 1642 (w),

1617 (s), 1518 (m) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.77 and 3.79 (2 s, 2 x 3 H, 6-CH3O and 7-

CH3O), 5.64 (s, 1 H, 3-H), 6.82 (s, 1 H, 8-H), 7.16 (s, 1 H, 5-H), 11.06 (s, 1 H

NH).

C11H11NO4 (221.21).

2,4-Dichloro-6,7-dimethoxyquinoline (75)

A solution of 4-hydroxy-6,7-dimethoxyquinolone(74: 7.828 g, 35.42 mmol) in

phosphoryl chloride (42.0 mL) was heated under reflux to 110 °C for 8 hours.

The solution was cooled to 50 °C and the excess amount of phosphoryl chloride

was removed under reduced pressure. The residue was poured onto ice/water

(400 mL), and brought to pH = 4–6 with aqueous sodium hydroxide (5 M).

The resulting precipitate was filtered by suction and washed with water to

afford 2,4-dichloro-6,7-dimethoxyquinoline (75). The yield was 7.640 g (84 %)

greyish prisms, mp 174–176 °C (ethanol), lit. mp 160–161 °C [ex-77, ex-80].


IR (KBr): 3435 (s), 3008 (w), 985 (w), 1622 (m), 1571 (m), 1505 (s) cm-1.


CH3O), 7.35 (s, 1 H, 3-H), 7.42 (s, 1 H, 8-H), 7.72 (s, 1 H, 5-H).

C11H9Cl2NO2 (258.11).



4-Chloro-6,7-dimethoxyquinolin-2(1H)-dione (76)

A solution of 2,4-dichloro-6,7-dimethoxyquinoline (75: 4.00 g, 15.50 mmol),

and 70 % methanesulfonic acid (4.0 mL) in n-butanol (50.0 mL) was heated

under reflux for 28 hours. The solution was cooled to room temperature and

poured onto ice/water (25 mL), brought to pH = 4–6 with sodium hydroxide (2

M), filtered by suction, washed with water and dried at 40 °C under reduced

pressure to give 4-chloro-6,7-dimethoxy-quinolon-2(1H)-one (76). The yield was

3.573 g (96 %), beige prisms, mp 272–274 °C (ethanol), lit. mp 258–259 °C [ex-

77].


IR (KBr): 3418 (m), 3261 (w), 3019 (w), 2931 (w), 2853 (w), 1656 (s), 1624 (m),

1606 (w), 1513 (s) cm-1.


CH3O ), 6.60 (s, 1 H, 3-H), 6.91 (s, 1 H, 8-H), 7.17 (s, 1 H, 5-H), 11.84 (s, 1 H,

NH).

C11H10ClNO3 (239.66).

3,3-Dichloro-6,7-dimethoxyquinoline-2,4(1H,3H)-dione (77)

A suspension of 4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one (74: 10.940 g,

49.50 mmol) in dioxane (198.0 mL) was warmed to 40–50 °C and then, under

vigorous stirring, keeping the temperature between 50–60 °C, sulfuryl chloride

(10.0 mL) was added dropwise. As soon as the temperature reached 60 °C, the

reaction was stopped and cooled to 20 °C. The mixture was filtered and the

filtrate was poured onto ice/water (500 mL) under stirring, filtered by suction,

washed with water and dried at 40 °C under reduced pressure to give 3,3-

dichloro-6,7-dimethoxyquinoline-2,4(1H,3H)-dione (77). The yield was 11.751 g

(82 %), green-yellow prisms, mp 229–231 °C (ethanol).




IR (KBr): 3430 (m), 3245 (m), 3009 (w), 2939 (w), 2849 (w), 1717 (s),

1709 (s), 1673 (s), 1612 (s), 1515 (s), 1515 (s), 1503 (w) cm-1.


CH3O), 6.68 (s, 1 H, 8-H), 7.25 (s, 1 H, 5-H), 11.29 (s, 1 H, NH).


Calcd. C 45.54, H 3.13, N 4.83

Found C 45.49, H 2.96, N 4.72

3-Chloro-4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one (78)

To a solution of 3,3-dichloro-6,7-dimethoxyquinoline-2,4(1H,3H)-dione (77:

5.50 g, 26.32 mmol) in ethanol (46.0 mL) and acetic acid (23.0 mL), zinc-dust

(2.00 g, 30.58 mmol) was added in small portions and the solution was kept to

boiling. The yellow solution got decolorized (from yellow to grey-greenish),

which indicated the end of reaction. The solution was cooled to 20 °C and

filtered from zinc and salts. To the filtrate, ice/water (300 mL) was added.

The formed colorless precipitate was filtered by suction, washed with water and

dried at 40 °C under reduced pressure to form 3-chloro-4-hydroxy-6,7-

dimethoxyquinolin-2(1H)-one (78). The yield was 4.215 g (87 %), beige prisms,

mp 289–291 °C (ethanol).


IR (KBr): 3438 (m), 1525 (w), 2965 (m), 2828 (w), 1641 (s), 1620 (s), 1605 (w),

1514 (s) cm-1.


CH3O), 6.83 (s, 1 H, 8-H), 7.29 (s, 1 H, 5-H), 11.58 (s, 1 H, NH).


Calcd. C 51.68, H 3.94, N 5.48

Found C 51.88, H 3.84, N 5.40



2,3,4-Trichloro-6,7-dimethoxyquinoline (79)

A solution of 3-chloro-4-hydroxy-6,7-dimethoxyquinolin-2(1H)-one (78: 3.50 g,

13.70 mmol) in phosphoryl chloride (17.0 mL) was brought to reaction under

reflux for 8 hours and worked up following the method described for 5, to form

2,3,4-trichloro-6,7-dimethoxyquinoline (79). The yield was 3.938 g (92 %),



IR (KBr): 3434 (s), 3010 (w), 1620 (m), 1549 (w), 1505 (s) cm-1.


CH3O), 7.33 (s, 1 H, 8-H), 7.44 (s, 1 H, 5-H).


Calcd. C 45.16, H 2.76, N 4.79

Found C 44.92, H 2.59, N 4.59

3,4-Dichloro-6,7-dimethoxyquinolin-2(1H)-one (80)

A solution of 2,3,4-trichloro-6,7-dimethoxyquinoline (79: 3.158 g, 10.80 mmol)

in 70 % methanesulfonic acid (3.0 mL) and n-butanol (30.0 mL) was heated to

110 °C for 24 hours and worked up as described for 6, to form 3,4-dichloro-

6,7-dimethoxyquinolin-2(1H)-one (80). The yield was 2.159 g (73 %), colorless



IR (KBr): 3436 (m), 3003 (w), 2962 (w), 2900 (w), 2835 (w), 2793 (w), 1671 (s),

1626 (w), 1603 (w), 1511 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 3.84 (s, 2 x 3 H, 6-CH3O and 7-CH3O), 6.92

(s, 1 H, 8-H), 7.19 (s, 1 H, 5-H), 12.37 (s, 1 H, NH).


Calcd. C 48.20, H 3.31, N 5.11

Found C48.32, H 3.18, N 5.00



6,7-Dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile

(82)

Pathway A

A mixture of 4-chloro-6,7-dimethoxyquinolin-2(1H)-one (76: 1.760 g, 7.35

mmol), sodium p-toluenesulfinate (5.233 g, 29.40 mmol) and potassium

cyanide (2.40 g, 36.75 mmol) in dry dimethylformamide (44.0 mL) was heated

to 130 °C for 86 hours and worked up as described for 7, to give 6,7-

dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (82). The yield was

1.068 g (57 %), red-black prisms, mp 349–350 °C (acetone).


Pathway B

A mixture of 3,4-dichloro-6,7-dimethoxyquinolin-2(1H)-one (80: 1.270 g, 4.64



°C for 5 hours and worked up as described for 7, to give 6,7-dimethoxy-2-oxo-

1,2-dihydroquinoline-3,4-dicarbonitrile (82). The yield was 0.944 g (80 %), red

prisms, mp 348 °C (acetone).


IR (KBr): 3437 (w), 2975 (w), 2946 (w), 2900 (w), 2850 (w), 2784 (w), 2700 (w),

2230 (w), 1911 (w), 1665 (s), 1619 (m), 1597 (w), 1516 (s) cm-1.


CH3O), 6.88 (s, 1 H, 8-H), 6.98 (s, 1 H, 5-H), 12.94 (s, 1 H, NH).

13C-NMR (300 MHz, [D6]DMSO): = 56.4 (6-CH3O), 56.8 (7-CH3O), 98.4

(aromatic-C), 105.3 (aromatic-C), 113.5 (aromatic-C), 114.9 (CN), 138.3

(aromatic-C), 147.5 (6-C), 156.8 (7-C), 157.6 (lactam-C=O).

MS (API-ES neg): m/z (%) = 255 (15, M + 1), 254 (100, M).

Anal. for C13H9N3O3 (255.23).

Calcd. C 61.18, H 3.55, N 16.46

Found C 60.96, H 3.43, N 15.90



6,7-Dimethoxy-1-methyl-2-oxo-1,2-dihydroquinoline-3,4-

dicarbonitrile (83)


0.170 g, 0.67 mmol), sodium carbonate (0.25 g, 2.36 mmol), and iodomethane

(0.19 g, 1.34 mmol) in dry dimethylformamide (5.0 mL) was heated to 90–100

°C for 15 minutes and worked up as described for 45, to form 6,7-dimethoxy-

1-methyl-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile (83). The yield was

0.157 g (88 %), red prisms, mp 329–333 °C (ethanol).



(s), 1545 (m), 1513 (s) cm-1.


CH3O), 4.06 (s, 3 H, CH3), 7.14 (s, 1 H, 8-H), 7.15 (s, 1 H, 5-H).

Anal. for C14H11N3O3 (269.26).

Calcd. C 62.45, H 4.12, N 15.61

Found C 61.94, H 3.77, N 15.11

Ethyl [3,4-Dicyano-6,7-dimethoxy-2-oxoquinolin-1(2H)-

yl]acetate (84)

Method A


1.54 g, 6.0 mmol), ethyl bromoacetate (1.50 mL, 2.30 g, 13.56 mmol) and dry

sodium carbonate (1.272 g, 12.0 mmol) in dry dimethylformamide (25.0 mL)

was heated to 80 °C for 15 minutes, The mixture was cooled to room

temperature and poured onto ice/water (100 mL). The obtained solid was

filtered by suction, washed with water and dried at 40 °C under reduced

pressure. TLC analysis showed two compounds: ethyl [3,4-dicyano-6,7-

dimethoxy-2-oxoquinolin-1(2H)-yl]acetate (84) and ethyl [(3,4-dicyano-6,7-

dimethoxyquinolin-2-yl)oxy]acetate (85).



The yield of the mixture was 1.852 g (90 %). The 2 products were separated by

recrystallization from toluene/acetone (9:1), to give as first crop compound 85

and as second crop compound 84, respectively.

The yield of compound 84 was 1.153 g (56 %), yellow prisms, mp 256–259 °C

(toluene/acetone 9:1).


Method B

To a solution of 6,7-dimethoxy-2-oxo-1,2-dihydroquinoline-3,4-dicarbonitrile

(82: 0.50 g, 1.96 mmol) in dry tetrahydrofurane (15.0 mL), was added dropwise

a solution of lithium diisopropylamide (1.8 M in tetrahydrofurane/

heptane/ethylbenzene, 3.0 mL). The resulting mixture was stirred at 0 °C for 1

hour, then ethyl bromoacetate (1.50 mL, 2.30 g, 13.56 mmol) was added. The

mixture was stirred for 30 minutes to 0 °C and at room temperature for 15

hours. The solution was poured onto ice/water (10 mL), filtered by suction,

washed with water and dried at 40 °C under reduced pressure, to give ethyl

(3,4-dicyano-6,7-dimethoxy-2-oxo-1,2-dihydroquinolin-1-yl)acetate (84). The

yield was 0.434 g (65 %), yellow-gold prisms, mp 251–253 °C (ethanol).

IR (ATR-measurement): 3027 (w), 2976 (w), 2226 (w), 1732 (s), 1659 (s), 1618

(m), 1542 (m), 1519 (s) cm-1.


1H-NMR (300 MHz, [D6]DMSO): = 1.23 (t, J = 7.1 Hz, 3 H, CH3), 3.93 and

3.99 (2 s, 2 x 3 H, 6-CH3O and 7-CH3O), 4.19 (q, J = 7.1 Hz, 2 H, CH2), 5.26 (s,

2 H, N-CH2), 7.13 (s, 1 H, 8-H), 7.17 (s, 1 H, 5-H).

13C-NMR (300 MHz, [D6]DMSO): = 14.5 (CH3), 46.0 (N-CH2), 56.5 (6-CH3O),

57.6 (7-CH3O), 61.9 (CH2), 99.2 (aromatic-C), 106.0 (aromatic-C), 107.0

(aromatic-C), 110.9 (aromatic-C), 113.5 (CN), 114.7 (CN), 128.4 (aromatic-C),

138.7 (4-C), 147.4 (6-C), 157.3 (7-C), 157.4 (lactam-C=O), 167.6 (ester-C=O).

Anal. for C17H15N3O5 (341.33).

Calcd. C 59.82, H 4.43, N 12.31

Found C 59.81, H 4.41, N 12.09



Ethyl [(3,4-Dicyano-6,7-dimethoxyquinolin-2-yl)oxy]acetate (85)

This compound was obtained as solid during the work-up of compound 84,

and recystallized from ethanol. The yield was 0.602 g (29 %), yellow prisms, mp

187-189 °C (ethanol).


IR (ATR-measurement): 2983 (w), 2938 (w), 2227 (w), 1761 (m), 1616 (w), 1571

(m), 1504 (s) cm-1.

1H-NMR (300 MHz, [D6]DMSO): = 1.21 (t, J = 7.0 Hz, 3 H, CH3), 3.99 and

4.00 (2 s, 2 x 3 H, 6-CH3O and 7-CH3O), 4.19 (q, J = 7.1 Hz, 2 H, CH2), 5.22 (s,

2 H, N-CH2), 7.24 (s, 1 H, 8-H), 7.27 (s, 1 H, 5-H).

C17H15N3O5 (341.33).



EXPERIMENTAL PART

FOR

CHAPTER 4



ELECTRONIC SPECTRA

UV-Vis spectra

The absorption measurements were carried out using 1 cm polystyrene PS cell

(1.50 mL, diameter = 1.0 cm, Brand, Germany) for all experiments if not

specified otherwise. UV/Visible spectra were recorded using a Shimadzu

UV/Visible scanning spectrophotometer UV-2101 PC; concentration: 10-4

mol/L.

Fluorescence data

Standard excitation and emission spectra were recorded in the same

polystyrene cells using a Perkin-Elmer LS50B luminescence spectrometer.

Fluorescence quantum yield ( ) is the fraction of molecules that emit a photon

after direct excitation by a source. Quantum yields were calculated from the

area (integration) of the uncorrected emission spectra by comparison to the

area of fluorescein at pH 13 (exc = 493, em = 512 nm, = 0.9 and at pH 3.3

(abs = 437 nm, em = 512 nm, = 0.3) [ex-81] or, in the case of absorption

maxima below 400 nm, with the known quantum yield of 6,7-dimethoxy-4-

trifluoromethylcarbostyril in DMSO (exc = 368, em = 438 nm, = 0.41) and

water (exc = 365, em = 428 nm, [ex-82].



Fluorescence quantum yield was calculated using the equation:

Sc

S

refc

ref

refA

SA

refS

Where the meaning of the letters is:

Subscript S: data of the substance.

Subscript ref: data of the reference substance.

: quantum yield.

A: absorbance data at UV/Vis maxima.

ε: excitation coefficient.

C: molar concentration (mol/L).

n: refractive index.

Excitation and emission maxima of the standard should not be too far from the

investigated substances. Absorption in the 1.0 cm cell was usually about

0.005-0.010. If fluorescence standards were measured in solvents which were

different to the sample, the following correction factors for the calculated

quantum yield were applied:

2

newn

refn

f



Preparation of the stock solutions and measurement

Purity of the compounds was confirmed by elemental analyses.

For each sample, about 1-2 mg of the dye was dissolved in exactly the volume

of dimethylsulfoxide to result in a 1x10-2 M stock solution.

Recording of spectra

For UV/visible measurement, 10 L of each stock solution were diluted to 1.0

mL in the corresponding solvent; the concentration was then 1x10-4 M.

For excitation and emission spectra, the UV/visible solution were diluted 100

times again resulting in a 1x10-6 M solution.

General slit width: 5 nm; in cases of strong fluorescence 3 nm.

For solvent not compatible with polystyrene, 1.0 cm optical glass cells (3.0 mL)

were used.

standard in: refr. index n f (CH3CN) f (H2O) f (DMSO)

CH3CN 1.344 1.000 0.984 1.224

DMSO 1.487 0.817 0.804 1.000

CH3OH 1.329 1.023 1.006 1.252

H2O 1.333 1.017 1.000 1.244

CH2Cl2 1.490 0.814 0.800 0.996

REFERENCES OF THEORETICAL PART FOR CHAPTERS 1, 2 NAD 3 217



FOR

CHAPTERS 1, 2 AND 3



REFERENCES OF THEORETICAL PART FOR

CHAPTERS 1, 2 AND 3

[1] O. S. Park, B. S. Jang, Arch. Pharm. Res. 1995, 18, 277–281.

[2] D. R. Buckle, B. C. C. Cantello, H. Smith, B. A. Spicer, J. Med. Chem.

1975, 18, 726–732.

[3] E. Ziegler, T. Kappe, Angew. Chem. 1964, 3, 754–754.

[4] E. Ziegler, T. Kappe, R. Salvador, Monatsh. Chem. 1963, 94, 453–459.

[5] Bayer AG., British Patent 721, 171, 1954. Chem. Abstr. 1956, 2685e.

[6] Bayer AG., (U. Hörlein Inv), British Patent 733, 123, 1955. Chem. Abstr.

1956, 5010799f.

[7] C. F. Neville, M. F. Grundon, V. N. Ramchandran, J. Reisch, J. Chem.

Soc., Perkin Trans. 1 1991, 259–262.

[8] P. Roschger, W. Fiala, W. Stadlbauer, J. Heterocycl. Chem. 1992, 29,

225-231.

[9] V. Dollé, E. Fan, C. H. Nguyen, A.-M. Aubertin, A. Kirn, M. L. Andreola,

G. Jamieson, L. Tarrago-Litvak, E. Bisagni, J. Med. Chem. 1995, 38,

4679-4686.

[10] M. Cobet, M. Lucker, Phytochemistry 1971, 10, 1031.



[11] a) K. C. Majumdar, P. P. Mukhopadhyay, Synthesis, 2003, 97, b) R. L.

Yong, K. Hyuk, S. K. Wha, R. M. Kyung, K. Youngsoo, H. L. Seung,

Synthesis, 2001, 1851.

[12] Tschitschibabin, Ber. Dtsch. Chem. Ges.., 1923, 59, 1883; Ger. Pat., 406,

208; Chem. Zentr., 1925, I, 1536; Friedl Fortschr D. Teerfarbenfabrik. 14,

515.

[13] W. T. Gao, W. D. Hou, M. R. Zheng, L. J. Tang, Synth. Commun. 2010,

40, 732-738.

[14] W. Steinschifter, W. Fiala, W. Stadlbauer, J. Heterocycl. Chem., 1994,

31, 1647-52.

[15] a) P. Roschger, W. Stadlbauer, Liebigs Ann. Chem. 1990, 821; ibid., 401;

b) W. Fiala, W. Stadlbauer, J. Prakt. Chem., 1993, 335, 128.

[16] W. Stadlbauer, El-S. Badawey, G. Hojas, P. Roschger, T. Kappe,

Molecules, 2001, 6, 338-352.

[17] a) E. Ziegler, H. Junek, E. Nölken, K. Gelfert, R. Salvador, Monatsh.

Chem. 1961, 92, 814-819; b) E. Ziegler, H. G. Forraita, T. Kappe,

Monatsh. Chem. 1967, 98, 322-328.

[18] A. B. Avhale, H. Prokopcová, J. Šefčovičová, W. Steinschifter, A. E.

Täubl, G. Uray, W. Stadlbauer. Eur. J. Org. Chem., 2008, 563-71.

[19] G. C. Enoua, G. Uray, W. Stadlbauer, Proceedings of ECSOC-13, The

Thirteenth International Electronic Conference on Synthetic Organic

Chemistry, http://www.usc.es/congresos/ecsoc/13/index.htm,

November 1-30, 2009; J. A. Seijas, Shu-Kun Lin, M. P. Vázquez Tato

(Eds). CD-ROM, edition ISBN 3-906980-23-5, Published in 2009 by

MDPI, Basel, Switzerland.



[20] a) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223; b) J. P. Michael, Nat.

Prod. Rep., 2005, 22, 627; c) J. P. Michael, Nat. Prod. Rep., 2004, 21,

650; d) H.-O. Kalinowski, S. Berger, S. Braun, 13C-NMR Spektroskopie,

1984, Georg Thieme Verlag Stuttgart-New York.

[21] W. Stadlbauer, A. B. Avhale, N. S. Badgujar, G. Uray, J. Heterocycl.

Chem., 2009, 46, 415-420.

[22] a) M. L. Belli, G. Illuminati, G. Marino, Tetrahedron, 1963, 19, 345; b) H.

Wohjan, Arch. Pharm., 1936, 274, 83-106; c) M. Henye, Ber. Dtsch.

Chem. Ges., 1836, 69, 1566; d) H. Rupe, A. Gassmann, Helv. Chem.

Acta. 1939, 22, 1241.

[23] W. Stadlbauer, H. Prokopcová, J. Šefčovičová, A. E. Täubl, Proceedings of

ECSOC-7, The Seventh International Electronic Conference on Synthetic

Organic Chemistry 2003; J. A. Seijas, D.-C. Ji, S.-K . Lin (Eds). CD-ROM,

edition ISBN 3-906980-13-8, MDPI, Basel (Switzerland) 2003.

[24] a) A. Hassner, C. Stumer, Tetrahedron Organic Chemistry Series Vol. 11:

Organic Syntheses Based on Name Reactions and Unnamed Reactions

(Eds.: J. E. Baldwin, P. D. Magnus), Pergamon, Elsevier Science Ltd.,

Oxford, 1994; b) H. Krauch, W. Kunz, E. Nonnenmacher, Reaktionen der

Chemie, Dr. Alfred Hüthig Verlag, Heidelberg, 1976.

[25] A. Miyashita, Y. Suziki, K. Ohta, T. Higashino, Heterocycles, 1994, 39,

345-55.

[26] a) C. Liangzhen, L. Xin, T. Xiaochun, S. Dong, Synth. Commun., 2004,

34, 1215-1221; b) J. X. Wu, B. Beck, R. X. Ren, Tretrahedron Lett., 2002,

43, 387-389; c) S. Takao, O. Kaxutoshi, J. Chem. Soc., Perkin Trans 1,

1999, 16, 2323-2326.



[27] Manfred Hesse, Herbert Meier, Bernd Zeek, Spektroskopische Methoden

in der Organischen Chemie, (3., überarbeitete Auflage; 199 Abbildungen,

94 Tabellen), 1987, Georg Thieme Verlag Stuttgart-New york.

[28] M. Takayama, J. Mass Spectrom. Soc. Jpn. 1995, 43, 177-188.

[29] a) C. O. Kappe, T. Kappe, Progress Heterocycl. Chem., 1996, 8, 1-13; b)

These results were obtained at LIPHA (Lyonnaise Industrielle

Pharmaceutique), Lyon, France.

[30] E. Malle, W. Stadlbauer, G. Ostermann, B. Hofmann, H. J. Leis, G. M.

Kostner, Eur. J. Med. Chem., 1990, 25, 137-142.

[31] R. Laschober, W. Stadlbauer, Liebigs Ann. Chem. 1990, 1083.

[32] S. Kitamura, K. Hashizume, T. Iida, E. Miyashitsa, K. Shirata, H. Kase,

J. Antibiot., 1986, 39, 1160.

[33] a) W. Neuenhaus, H. Budzikiewicz, H. Korth, G. Pulverer, Naturforsch.,

1979, 34b, 313; b) H. Budzikiewicz, U. Schaller, H. Korth, G. Pulverer,

Monatsh. Chem., 1979, 110, 974.

[34] a) W. Stadlbauer, R. Laschober, H. Lutschounig, G. Schindler, T. Kappe,

Monatsh. Chem., 1992, 123, 617-636; b) E. Ziegler, T. Kappe, Monatsh.

Chem., 1964, 94, 447-452; c) E. Ziegler, R. Salvador, T. Kappe, Monatsh.

Chem., 1962, 93, 1376-1381.

[35] a) E. Ziegler, T. Kappe, Monatsh. Chem., 1963, 94, 447; b) C. Fournier, J.

Decombe, 1967, Bull. Soc. Chem. Fr., 1967: 3367, 1967, C. R. Acad. Sci.

Paris, Ser. C. 265: 1169.



[36] a) T. Witoszynsky, PhD thesis, 1972, University of Graz/Austria, p. 58; b)

F. A. Lakhvich, V. A. Kozinetes, D. B. Rubinov, A. A. Akhrem, Zh. Org.

Khim., 1987, 23, 2626.

[37] V. H. Dang, PhD thesis, 2006, University of Graz/Austria.

[38] K. J. Hwang, Arch. Pharm. Res. 2000, 23, 31–34.

[39] A. M. Mcleod, S. Grimwood, C. Barton, L. Bristow, K. L. Saywell, G. R.

Marshall, R. G. Ball, J. Med. Chem. 1995, 38, 2239–2243.

[40] R. W. Carling, P. D. Leeson, K. W. Moore, J. D. Smith, C. R. Moyes, I. M.

Mawer, S. Thomas, T. Chan, R. Baker, A. C. Foster, S. Grimwood, J. A.

Kemp, G. R. Marshall, M. D. Tricklebank, K. L. Saywell, J. Med. Chem.

1993, 36, 3397–3408.

[41] R. W. Carling, P. D. Leeson, K. W. Moore, C. R. Moyes, M. Duncton, M. L.

Hudson, R. baker, A. C. Foster, S. Grimwood, J. A. Kemp, G. R.

Marshall, M. D. Tricklebank, K. L. Saywell, J. Med. Chem. 1997, 40,

754–765.

[42] B. S. Meldrum, Excitatory Amino Acid Antagonists, Blackwell Scientific:

Oxford, 1991.

[43] S. X. Cai, Z. L. Zhou, J. C. Huang, E. R. Whittemore, Z. O. Egbuwoku, J.

E. Hawkinson, R. M. Woodward, E. Weber, J. F. W. Keana, J. Med. Chem.

1996, 39, 4682–4686.

[44] W. Seidenfadden, D. Pawellek, in Houben-Weyl, Methoden der Org.

Chem., 4th Ed (E. Müller, ed), 1971, 10, 849.

[45] D. R. Buckle, B. C. C. Cantello, H. Smith, B. A. Spicer, J. Med. Chem.

1975, 18, 726.



[46] N. Dodia, A. Shah, Indian J. Heterocycl. Chem., 2000, 10, 69-70.

[47] W. Stadlbauer, Monatsh. Chem., 1986, 117, 1305.

[48] W. Stadlbauer, W. Fiala, M. Fischer, G. Hojas, J. Heterocycl. Chem.

2000, 37, 1253-1256.

[49] W. Stadlbauer, A. E. Täubl, H. V. Dang, C. Reidlinger, K. Zangger, J.

Heterocycl. Chem., 2006, 23, 117-125.

[50] A. E. Täubl, W. Stadlbauer, Heterocycl. Chem., 1997, 34, 989.

[51] a) S. Gabriel, Ber., 1918, 51, 1501; b) G. Lang, Dissertation, University of

Graz/Austria, 1972.

[52] V. T. Dang, Dissertation, University of Graz/Austria, 1996.

[53] T. Kappe, E. Lender, E. Ziegler, Monatsh. Chem.,1968, 99, 990-4.

[54] a) T. Kappe, E. Lender, E. Ziegler, Monatsh. Chem., 1968, 99, 2157-66;

b) T. Kappe, M. Hariri, E. Pongratz, Monatsh. Chem., 1981, 112, 1211-

1219.

[55] K. Tabacovic, I. Tabacovic, M. Trkovnik, N. Trinajstic, Liebigs Ann.

Chem., 1983, 1901.

[56] a) H.-J. Knops, L. Born, Tetrahedron Lett., 1983, 24, 2973-2976; b) L. J.

Bellamy, R. E. Rogasch, Spectrocim. Acta., 1960, 16, 30; c) A.R.

Katritzky, R.A. Jones, J. Chem. Soc., 1960, 2947.

[57] R. M. Sylverstein, G. C. Bassler, Identifcation Spectrométrique des

Composés Organiques, Masson et Cie, Gauthier-Villars, Paris-1968.



[58] M-K. Jeon, K. Kim, Tetrahedron Lett., 2000, 41, 1943-1945.

[59] a) P. Lin, J. Jiang, Tetrahedron Lett., 2000, 56, 3635-3671; b) J. T.

Welch, Tetrahedron Lett. 1987, 43, 3123-3197.

[60] a) N. S. Badgujar, M. Pazicky, P. Traar, A. Terec, G. Uray, W. Stadlbauer,

Eur. J. Org. Chem. 2006, 2715–2722; b) G. Uray, K.-H. Niederreiter, F.

Belaj, W. M. F. Fabian, Helv. Chim. Acta 1999, 82, 1408–1417; c) W. M.

F. Fabian, K. S. Niederreiter, G. Uray, W. Stadlbauer, J. Mol. Struct.

1999, 477, 209–220; d) G. A. Strohmeier, W. M. F. Fabian, G. Uray,

Helv. Chim. Acta., 2004, 87, 215–226.

[61] a) L. Limpach, Ber. Dtsch. Chem. Ges. 1931, 64, 970–971; b) W. Werner,

Tetrahedron, 1969, 25, 255.

[62] J. W. Schulenberg, S. Archer, Org. React. 1965, 14, 1.

[63] a) K. Selvakumar, K. Rangareddy, J. F. Harrod, Can. J. Chem. 2004, 82,

1244; b) N. S. Wilson, C. R. M. Sarko, G. P. Roth, Tetrahedron Lett.

2002, 43, 581.

[64] a) S. Sasatani, T. Miyazaki, K. Maruoka, H. Yamamoto, Tetrahedron Lett.

1983, 24, 4711; b) H. Agui, T. Mitani, M. Nakashita, T. J. Nakagome,

Heterocycl. Chem. 1971, 8, 357.

[65] a) J. A. F. Gardner, R. Y. Moir, C. B. Purves, Can. J. Research 1948,

26B, 681; b) R. Y. Moir, C. B. Purves, Can. J. Research, 1948, 26B, 694;

c) H. J. Burton, Chem. Soc. 1932, 546.

[66] a) L-F. Tietze, T. Eicher, Reaktionen und Synthesen im organisch-

chemischen Praktikum, 2nd ed., G. Thieme, Stuttgart, New York, 1991; b)

R. M. Roberts, P. J. Vogt, J. Am. Chem. Soc. 1956, 78, 4778.



[67] a) C. Battram, S. Charlton, B. Cuenoud, M. Dowling, R. Fairhurst, D.

Farr, J. Fozard, J. Leighton-Davies, Ch. Lewis, L. McEvoy, R. Turner, A.

Trifilieff, J. Pharmacol. Exp. Ther. 2006, 317, 762–770; b) M. Singh, A.

Chandra, B. Singh, R. Singh, Tetrahedron Lett. 2007, 48, 5987–5990.

[68] a) N. Shirode, K. Kulkarni, V. Gumaste, A. Deshmukh, Arkivoc 2005, 1,

53–64; b) Ch. Beadle, J. Boot, N. Camp, N. Dezutter, J. Findlay, L.

Hayhurst, J. Masters, R. Penariola, M. Walter, Bioorg. Med. Chem. Lett.

2005, 15, 4432–4437.

[69] a) G. Muscia, M. Bollini, A. Bruno, S. Asís, J. Chil. Chem. Soc. 2006, 51,

859–863; b) G. Moore, C. Papamicaël, V. Levacher, J. Bourguignon, G.

Dupas, Tetrahedron 2004, 60, 4197–4204; c) Ch. Mitsos, A. Zografos, O.

Igglessi-Markopoulou, J. Org. Chem. 2003, 68, 4567–4569.

[70] a) P. Renhowe, S. Pecchi, C. Shafer, T. Machajewski, E. Jazan, C. Taylor,

W. Antonios-McCrea, C. McBride, K. Frazier, M. Wiesmann, G. Lapointe,

P. Feucht, R. Warne, C. Heise, D. Menezes, K. Aardalen, H. Ye, M. He, V.

Le, J. Vora, J. Cansen, M. Wernette-Hammond, A. Harris, J. Med. Chem.

2009, 52, 278–292.

[71] a) J. Kuethe, A. Wong, C. Qu, J. Smitrovich, I. Davies, D. Hughes, J. Org.

Chem. 2005, 70, 2555–2567; b) J. Kuethe, A. Wong, I. Davies, Org. Lett.

2003, 5, 3975–3978.

[72] a) M. Fraley, W. Hoffman, K. Arrington, R. Hungate, G. Hartman, R.

McFall, K. Coll, K. Rickert, K. Thomas, G. McGaughey, Curr. Med. Chem.

2004, 11, 709–719; b) M. Fraley, S. Hambaugh, R. Hungate, Patent

WO/2001/028993.

[73] J. J. Kulagowski, R. Baker, N. R. Curtis, P. D. Leeson, I. M. Mawer, A. M.

Moseley, M. P. Ridgill, M. Rowley, I. Stansfield, A. C. Foster, S.



Grimwood, R. G. Hill, J. A. Kemp, G. R. Marshall, K. L. Saywell, M. D.

Tricklebank, J. Med. Chem. 1994, 37, 1402–1405.

[74] A. D. Chapman, N. Duermueller, B. L. Harrison, B. M. Baron, N. Parvez,

B. S. Meldrum, Eur. J. Pharmacol. 1995, 274, 83–88.

[75] M. Rowley, J. J. Kulagowski, A. P. Watt, D. Rathbone, G. I. Stevenson, R.

W. Carling, R. Baker, G. R. Marshall, J. A. Kemp, A. C. Foster, S.

Grimwood, R. Hargreaves, C. Hurley, K. L. Saywell, M. D. Tricklebank, P.

D. Leeson, J. Med. Chem. 1997, 40, 4053–4068.

[76] K. J. Hwang Arch. Pharm. Res. 2000, 23, 31–34.

[77] A. M. Mcleod, S. Grimwood, C. Barton, L. Bristow, K. L. Saywell, G. R.

Marshall, R. G. Ball, J. Med. Chem. 1995, 38, 2239–2243.

[78] R. W. Carling, P. D. Leeson, K. W. Moore, J. D. Smith, C. R. Moyes, I. M.

Mawer, S. Thomas, T. Chan, R. Baker, A. C. Foster, S. Grimwood, J. A.

Kemp, G. R. Marshall, M. D. Tricklebank, K. L. Saywell, J. Med. Chem.

1993, 36, 3397–3408.

[79] R. W. Carling, P. D. Leeson, K. W. Moore, C. R. Moyes, M. Duncton, M. L.

Hudson, R. Baker, A. C. Foster, S. Grimwood, J. H. A. Kemp, G. R.

Marshall, M. D. Tricklebank, K. L. Saywell, J. Med. Chem. 1997, 40,

754–765.

[80] B. S. Meldrum, Excitatory Amino Acid Antagonists; Blackwell Scientific:

Oxford, 1991.

[81] S. X. Cai, Z. L. Zhou, J. C. Huang, E. R. Whittemore, Z. O. Egbuwoku, J.

E. Hawkinson, R. M. Woodward, E. Weber, J. F. W. Keana, J. Med. Chem.

1996, 39, 4682–4686.



[82] H. Hayashi, I. Miwa, S. Ichikawa, N. Yoda, I. Miki, A. Ishii, M. Kono, T.

Yasuzawa, F. J. Suzuki, Med. Chem. 1993, 36, 617–626.

[83] R. J. DeVita, D. D. Hollings, M. T. Goulet, M. J. Wyvratt, M. H. Fisher,

J.-L. Lo, Y. T. Yang, K. Cheng, R. G. Smith, Bioorg. Med. Chem. Lett.

1999, 9, 2615–2620.

[84] J. H. M. Lange, C. P. Verveer, S. J. M. Osnabrug, G. M. Visser,

Tetrahedron Lett., 2001, 42, 1367-1369.

[85] R. Chênevert, M. Desjardins, Can. J. Chem. 1994, 72, 2312.

[86] a) T. Kappe, W. Stadlbauer, Molecules, 1997, 1, 255-263; b) T. Kappe,

Tetrahedron Lett., 1968, 5327.

[87] a) E. Zielgler, Österr. Chem. Ztg. 1958, 59, 155-159; b) Chimia 1970, 24,

62-64; c) E. Ziegler, H. Sterk, Monatsh. Chem., 1968, 99, 1958-1961.

[88] T. Kappe, Il Farmaco, 1999, 54, 309-315.

[89] T. Kappe, S. Ajili, W. Stadlbauer, J. Heterocycl. Chem., 1988, 25, 463-

468.

[90] A. Kutyrev, T. Kappe, J. Heterocycl. Chem., 1997, 34, 969-972.

[91]] A. Kutyrev, T. Kappe, J. Hetercyocl. Chem., 1999, 36, 237-240.

[92] J. Jampilek, R. Musiol, M. Pesko, K. Kralova, M. Vejsova, J. Carroll, A.

Coffey, J. Finster, D. Tabak, H. Niedbala, V. Kozik, J. Polanski, J. Csollei,

J. Dohnal, Molecules, 2009, 14, 1145-1159.

[93] I. V. Ukrainets, L. V. Sidorenko, E. N. Svechnikova, O. V. Shishkin,

Chem. Heterocycl. Compd. 2007, 43, 1275-1279.



[94] S. Jönsson, G. Andersson, T. Fex, T. Fristedt, G. Hedlund, K. Jansson, L.

Abramo, I. Fritzson, O. Pekarski, A. Runström, H. Sandin, I. Thuvesson,

A. Björk, J. Med. Chem., 2004, 47, 2075.

[95] K. Tsuji, G. W. Spears, K. Nakamura, T. Tojo, N. Seki, A. Sugiyama, M.

Matsuo, Bioorg. Med. Chem. Lett., 2002, 12, 85.

[96] X. Collin, J. M. Robert, M. Duflos, G. Wielgosz, G. Le Baut, C. Robin-

Dubigeon, N. Grimaud, F. Lang, and J. Y. Petit, J. Pharm. Pharmacol.,

2001, 53, 417.

[97] T. Kappe, C. Nuebling, K.–O. Westphalen, U. Kardorff, W. Deyn, M.

Gerber, and H. Walter, Ger. Pat. 1993, 4138820.

http://ep.espacenet.com.

[98] D. S. Kalinowski, P. C. Sharpe, P. V. Bernhardt, D. R. Richardson, J.

Med. Chem., 2007, 50, 6212.

[99] K. Husain, M. Abid, A. Azam, Eur. J. Med. Chem., 2007, 42, 1300.

[100] C. Biot, B. Pradines, M. H. Sergeant, J. Gut, P. J. Rosenthal, K. Chibale,

Bioorg. Med. Chem. Lett., 2007, 17, 6434.

[101] T. Varadinova, D. Kovala-Demertzi, M. Rupelieva, M. Demertzis, P.

Genova, Acta Virol., 2001, 45, 87.

[102] M. J. Mackenzie, D. Saltman, H. Hirte, J. Low, C. Johnson, G. Pond, M.

J. Moore, Invest. New Drugs, 2007, 25, 553.

[103] P. Jütten, W. Schumann, A. Härtl, H. M. Dahse, U. Gräfe, J. Med. Chem.,

2007, 50, 3661.



[104] D. S. Kalinowski, Y. Yu, P. C. Sharpe, M. Islam, Y. T. Liao, D. B. Lovejoy,

N. Kumar, P. V. Bernhardt, D. R. Richardson, J. Med. Chem., 2007, 50,

3716.

[105] A. C. Caires, Anticancer Agents Med. Chem., 2007, 7, 484.

[106] C. Kirilmis, M. Koca, A. Cukurovali, M. Ahmedzade, C. Kazaz, Molecules,

2005, 10, 1399.

[107] M. Koca, M. Ahmedzade, A. Cukurovali, C. Kazaz, Molecules, 2005, 10,

747.

[109] B. A. Wilson, R. Venkatraman, C. Whitaker, Q. Tillison, Int. J. Environ.

Res. Public Health, 2005, 2, 170.

[110] H. Elo, Z. Naturforsch, C: Biosci., 2007, 498.

[111] G. Turan-Zitouni, J. A. Fehrentz, P. Chevallet, J. Martinez, Z. A.

Kaplancikli, A. Ozdemir, M. Arslanyolu, M. T. Yildiz, Arch. Pharm.

(Weinheim), 2007, 340, 310.

[112] I. Kizilcikli, Y. D. Kurt, B. Akkurt, A. Y. Genel, S. Birteksöz, G. Otük, B.

Ulküseven, Folia Microbiol. (Praha), 2007, 52, 15.

[113] T. Rosu, A. Gulea, A. Nicolae, R. Georgescu, Molecules, 2007, 12, 782.

[114] M. F. Grundon, N. J. McCorkindale, N. M. Rodger, J. Chem. Soc. 1955,

4284.

[115] A. Khattab, PhD Thesis, Monofeia University, Egypt, 1990, pp 31 ff.

[116] W. Stadlbauer, S. Prattes, W. Fiala, J. Heterocycl. Chem., 1998, 35, 627-

636.



[117] T. Kappe, G. Baxevanidis, E Ziegler, Monatsh. Chem., 1971, 102, 1392.

[118] P. E. Hansen, S. Bolvig, T. Kappe, J. Chem. Soc., Perkin Trans., 1995, 2,

1901.

[119] I. V. Ukrainets, O. V. Gorokhova, L. V. Sidorenko, Chem. Heterocycl.

Compd. 2005, 41, 1019-1021.

[120] a) N. Shobana, P. Yeshosda, P. Shanmugam, Tetrahedron 1989, 45, 757–

762; b) V. Nadaraj, S. T. Selvi, R. Sasi, ARKIVOC 2006, 10, 82–89.

[121] a) K. Arya, M. Agarwal, Bioorg. Med. Chem. Lett. 2007, 17, 86-93; b) D.

C. Dittmer, Q. Li, D. V. Avilov, J. Org. Chem. 2005, 70, 4682-4686; c)

B. Bhudevi, P. V. Ramana, A. Mudiraj, A. R. Reddy, Indian J. Chem.

2009, 48B, 255-260.

[122] a) S.-J. Park, J.-C. Lee, K.-I. Lee, Bull. Korean Chem.Soc. 2007, 28,

1203-1205; b) J. Mpilek, R. Musiol, M. Pesko, K. Kralova, M. Vejsova,

J. Carroll, A. Coffey, J. Finster, D. Tabak, H. Niedbala, V. Kozik, J.

Polanski, J. Csollei, J. Dohnal, Molecules 2009, 14, 1145-1159.

[123] a) D. Sicker, A. Rabe, A. Zakrzewski, G. Mann, J. Prakt.Chem. (Leipziz)

1987, 329, 1063-70; b) E. Ziegler, R. Wolf, Th. Kappe, Monatsh. Chem.

1965, 96, 418-22; c) St. V. Niementowski, Ber. Dtsch. Chem. Ges.

1908, 40, 4285-94.

[124] a) F. Arndt, L. Ergener, O. Kutlu, Ber. Dtsch. Chem. Ges. 1953, 86, 951-

7; b) C. Schopf, G. Koepke, B. Kowald, F. Schulde, D. Wunderlich, Ber.

Dtsch. Chem. Ges. 1956, 89, 2877-86; c) R. T. Coutts, D. G. Wibberley,

J. Chem. Soc. 1963, 4610-12.

[125] a) I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, S. V. Slobodzyan,

Chem. Heterocycl. Compd. 2006, 42, 882-885; b) G. Koller, Ber. Dtsch.

Chem. Ges. 1927, 60B, 1108-11; c) C. L. Arcus, R. E. Marks, M. M.



Coombs, J. Chem. Soc. 1957, 4064-9.

[126] a) A. E. Chichibabin, Zhur. Russ. Fiz.-Khim. Obshch. 1924, 55, 7-18; b)

Cassella Farbwerke Mainkur A.-G. 1963, GB Pat. 916103; Chem. Abstr.

1963, 59, 48294.

[127] a) J. Ficini, A. Krief, Tetrahedron Lett. 1968, 8, 947-51; b) A. Meyer, P.

Heimann, Compt. Rend. 1936, 203, 264-6; c) M. C. Pirrung, F. Blume,

J. Org. Chem. 1999, 64, 3642-3649; d) S. Yu. Yunusov, G. P. Sidyakin,

Doklady Akademii Nauk USSR 1953, 12, 22-4.

[128] a) R. F. C. Brown, J. J. Hobbs, G. K. Hughes, E. Ritchie, Aust. J. Chem.

1954, 7, 348-77; b) E. H. Huntress, J. Bornstein, J. Am. Chem. Soc.

1949, 71, 745-6.

[129] a) E. K. Kainmüller, E. P. Olle, W. J. Bannwarth, J. Chem. Soc., Chem.

Commun. 2005, 5459; b) M. Turel, M. Cajlakovic, E. Austin, J. Dakin, G.

Uray, A. Lobnik, Sens. Actuators B 2008, 131, 247.

[130] a) R. A. Kramer, R. Flehr, M. U. Kumke, W. J. Bannwarth, Helv. Chem.

Acta, 2009, 92, 1933-1943; b) J. Kido, Y. Iizumi, Appl. Phys. Lett., 1998,

73, 2721; c) A. Niko, S. Tasch, F. meghdadi, C. Brandstatter, G. Leising,

J. Appl. Phys. 1997, 82, 4177; d) S. A. Van Slyke, C. H. Chen, C. W.

Tang, Appl. Phys. Lett. 1996, 69, 2160; e) S. Miyata, H. S. Nalwa, Eds.

Orgganic Electroluminescent Materials and Devices, Gordon and Breach:

Amsterdam, 1997.

[131] D. Doube, M. Blouin, C. Brideau, C. Chan, C. Desmarais, D. Ethier, J. P.

Falgueyret, R. W. Friesen, M. Girard, Y. Girard, J. Guay, P. Tagari, R. N.

Young, Bioorg. Med. Chem. Lett. 1998, 8, 1255.

[132] M. Kidwai, K. R. Bhushan, P. Sapra, R. K. Saxena, R. Gupta, Bioorg.

Med. Chem. 2000, 8, 69.



[133] I. K. Moissev, M. N. Yemtsova, P. L. Trakhtenberg, D. A. Kulikowa, I.

Pskobkina, G. N. Neshchadim, N. V. Ostapchuk, Khim. Farm. Zh. 1998,

22, 1448.

[134] J. C. Craig, P. E. Person, J. Med. Chem. 1971, 14, 1221.

[135] D. Narsinh, S. Anamik, Ind. J. Pharm. Sci. 2001, 63, 211.

[136] R. D. Dillard, D. E. Pavey, D. N. Benslay, J. Med. Chem. 1973, 16, 251.

REFERENCES OF THEORETICAL PART FOR CHAPTERS 4 233



FOR

CHAPTER 4




FOR

CHAPTER 4

[1] a) R. Raue, in: Ullmannns Encyclopedia of Industrial Chemistry, vol. A15,

5th ed. (Eds.: B. Elvers, S. Hawkins, G. Schulz), VCH Verlagsgesellschaft,

Weinheim, 1990, 155–157; b) B. B. Snavely, in: Organic Molecular

Photophysics, Vol. 1 (Ed.: J. B. Birks); Wiley, Chichester, 1973, chapter

5.

[2] a) R. P. Haughland, in: Handbook of Fluorescence Probes and Research

Chemicals (Ed.: K. D. Larison); Molecular Probes Inc., Eugene, USA,

1992, b) O. S. Wolfbeis, in: Molecular Spectrosopy: Methods and

Applications (Ed.: S. G. Schulman); John Wiley & Sons, New York, 1985,

chapter 3.

[3] a) H. Gold , in: Environmental quality and safety, Supplement Volume IV:

The Chemistry of Fluorescent Whitening Agents (Eds.: R. Anliker, G.

Müller, R. Raab, R. Zinkernagel), Georg Thieme, Stuttgart, 1975, 25–46;

c) J. Kido, Y. Lizumi, Appl. Phys. Lett. 1998, 73, 2721–2723.

[4] a) A. Niko, S. Tasch, F. Meghdadi, C. Brandstätter, G. Leising, J. Appl.

Phys. 1997, 82, 4177–4182; b) A. E. Siegrist, H. Hefti, H. R. Meyer, E.

Schmidt, Rev. Prog. Coloration 1987, 17, 39–55.

[5] a) Organic Luminescent Materials (Eds.: B. M. Krasovitskii, B. M. Bolotin),

Wiley-VCH, Weinheim, 1988; b) R. M. Christie, Rev. Prog. Coloration



1993, 23, 1–18; c) N. A. Kuznetsova, O. L. Kaliya, Russ. Chem. Rev.

1992, 61, 683–696.

[6] a) O. A. Ponomarev, E. R. Vasina, V. G. Mitina, A. A. Sukhorukov, Russ.

J. Phys. Chem. 1990, 64, 518–521; b) R. M. Christie, C.-H. Lui, Dyes

Pigm. 1999, 42, 85–93; c) C. Eggeling, R. R. J. Widengren, C. A. M.

Seidel, Anal. Chem. 1998, 70, 2651–2659.

[7] a) J. B. Gallivan, Molecular Photochem. 1970, 2, 191–211; b) G. Piszczek,

B. P. Maliwal, I. Gryczynski, D. Jonathan, J. R. Lakowicz, J. Fluoresc.

2001, 11, 101–107.

[8] M. S. Schiedel, C. A. Briehn, P. Bäuerle, Angew. Chem., Int. Ed. 2001, 40,

4677-4680.

[9] R. S. Becker, S. Chakravorti, C. A. Gartner, M. de Graca Miguel, J. Chem.

Soc., Faraday Trans. 1993, 89, 1007.

[10] U. Brackmann, Lambdachromew Laser Dyes, Lambda Physik GmbH,

Göttingen, 1986.

[11] B. B. Snavely, in: J.B. Birks (Ed.), Organic Molecular Photophysics, 1,

John Wiley and Sons, London, 1973 Chapter 5.

[12] C. V. Shank, A. Dienes, A. M. Trozzolo, J. A. Myer, Appl. Phys. Lett. 1970,

16, 405.

[13] G. A. Reynolds, K. H. Drexhage, Opt. Commun. 1975, 13, 222.

[14] A. N. Fletcher, D. E. Bliss, J. M. Kauffman, Opt. Commun. 1983, 47, 57.

[15] H. H. Grunhagen, H. T. Witt, Z. Naturforsch. 1970, 25b, 373.



[16] R. P. Haughland, in K. D. Larison (Ed.), Handbook of Fluorescent Probes

and Research Chemicals, Molecular Probes Inc, Eugene, USA, 1992.

[17] R. T. Williams, J. Roy. Inst. Chem. 1959, 83, 611.

[18] O. A. Ponomarev, E. R. Vasina, A. O. Doromenko, V. G. Mitina, Khim. Fiz

1989, 8, 854.

[19] O. A. Ponomarev, E. R. Vasina, V. G. Mitina, A. A. Sukhorukov, Zh. Fiz.

Khim. 1990, 64, 974.

[20] O. A. Ponomarev, E. R. Vasina, S. N. Yarmolenko, V. G. Mitina, N. S.

Pivnenko, Zh. Obshch. Khim. 1990, 60, 1161.

[21] O. A. Ponomarev, Yu. F. Pedash, O. V. Prezhdo, Zh. Fiz. Khim 1991, 65,

1846.

[22] R. Nakagaki, N. Kitamura, I. Aoyama, H. Ohtsubo, J. Photochem.

Photobiol. 1994, A80, 113.

[23] S. G. Schulman, A. C. Capomacchia, B. Tussey, Photochem. Photobiol.

1971, 14, 733.

[24] O. S. Wolfbeis, E. Lippert, Z. Naturforsch. 1978, 33a, 238.

[25] O. A. Ponomarev, E. P. Vasina, A. O. Doroshenko, V. G. Mitina, Zh.

Obshch. Khim. 1989, 59, 2072.

[26] G. Saroja, N. B. Sankaran, A. Samanta, Chem. Phys. Lett. 1996, 249,

392.

[27] a) R. Nakagaki, N. Kitamura, I. Aoyama, H. Ohtsubo, J. Photochem.

Photobiol. 1994, A80, 113–119; b) G. Saroja, N. B. Sankaran, A.



Samanta, Chem. Phys. Lett. 1996, 249, 392–398.

[28] a) O. A. Ponomarev, Yu. F. Pedash, O. V. Prezhdo, Zh. Fiz. Khim. 1991,

65, 1846–1850; b) J. Chen, P. R. Selvin, J. Photochem. Photobiol. A 2000,

135, 27–32.

[29] a) M. Li, P. R. Selvin, J. Am. Chem. Soc. 1995, 117, 8132–8138; b) C.

Marzano, A. Chilin, A. Guiotto, F. Baccichetti, F. Carlassare, F. Bordin,

Farmaco 2000, 55, 650–658.

[30] a) O. A. Ponomarev, E. R. Vasina, S. N. Yarmolenko, V. G. Mitina, N. S.

Pivnenko, Zh. Obshch. Khim. 1990, 60, 1161–1170; J. Gen. Chem. USSR,

Transl. Plenum Pub. Corp. 1990, 60, 1035–1042; b) E. K. Kainmüller, E.

P. Olle, W. Bannwarth, Chem. Commun. 2005, 43, 5459–5461.

[31] A. B. Ahvale, H. Prokopcová, J. Šefčovičová, W. Steinschifter, A. E. Täubl,

G. Uray, W. Stadlbauer, Eur. J. Org. Chem. 2008, 563–571.

[32] a) F. A. Bennett, D. J. Barlow, A. N. O. Dodoo, R. C. Hider, A. B. Lansley,

M. J. Lawrence, C. Marriott, S. S. Bansal, Anal. Biochem. 1999, 270, 15–

23; b) C. Charitos, G. Kokotos, C. Tzougraki, J. Heterocycl. Chem. 2001,

38, 153–158.

[33] a) J. E. T. Corrie, V. Munasinghe, N. Ranjit, J. Heterocycl. Chem. 2000,

37, 1447–1454; b) A. P. Esteves, L. M. Rodrigues, M. E. Silva, S. Gupta,

A. M. F. Oliveira-Campos, O. Machalicky, A. J. Mendonca, Tetrahedron

2005, 61, 8625–8632; c) J. Fernandez-Carneado, M. J. Kogan, S. Castel,

E. Giralt, Angew. Chem. Int. Ed. 2004, 43, 1811–1814; d) X. Luo, X.

Naiyun, L. Cheng, D. Huang, Dyes Pigm. 2001, 51, 153–159.

[34] a) M. C. Rideout, A. C. Raymond, A. B. Burgin Jr, Nucleic Acids Res.

2004, 32, 4657–4664.



[35] a) P. D. Edwards, R. C. Mauger, K. M. Cottrell, F. X. Morris, K. K. Pine, M.

A. Sylvester, C. W. Scott, S. T. Furlong, Bioorg. Med. Chem. Lett. 2000,

10, 2291–2294; b) C. A. M. Seidel, A. Schulz, M. H. M. Sauer, J. Phys.

Chem. 1996, 100, 5541–5553.

[36] a) A. Adronov, S. L. Gilat, J. M. Frechet, K. Ohta, F. V. R. Neuwahl, G. R.

Fleming, J. Am. Chem. Soc. 2000, 122, 1175–1185; b) K. H.

Shaughnessy, P. Kim, J. F. Hartwig, J. Am. Chem. Soc. 1999, 121, 2123–

2132.

[37] a) G. A. Strohmeier, W. M. F. Fabian, G. Uray, Helv. Chim. Acta 2004, 87,

215–226; b) G. Uray, K.-H. Niederreiter, F. Belaj, W. M. F. Fabian, Helv.

Chim. Acta 1999, 82, 1408–1417; c) W. M. F. Fabian, K. S. Niederreiter,

G. Uray, W. Stadlbauer, J. Mol. Struct. 1999, 477, 209–220.

[38] N. S. Badgujar, M. Pazicky, P. Traar, A. Terec, G. Uray, W. Stadlbauer,

Eur. J. Org. Chem. 2006, 2715–2722.

[39] Uray, Sallegger, unpublished results.

[40] R. A. Kramer, R. Flehr, M. Laya, M. U. Kumke, W. Bannwarth, Helv.

Chim. Acta 2009, 92, 1933–1943.

[41] a) M. Parsons, B. Vojnovic, S. Ameer-Beg, Biochem. Soc. 2004, 431; b) Y.

Sako, S. Minoguchi T. Yanagida, Nat. Cell Biol. 2000, 2, 168; c) S.

Brasselet, E. J. G. Peterman, A. Miyawaki, W. E. Moerner, J. Phys. Chem.

2000, 104, 3676.

[42] a) A. Cha, G. E. Snyder, P. R. Selvin F. Bezanilla, Nature (London) 1999,

402, 809; b) Y. Suzuki, T. Yasunaga, R. Ohkra, T. Wakabayashi, K.

Sutoh, Nature (London) 1998, 396, 380.



[43] a) I. Rasnik, S. Myong, W. Cheng, T. M. Lohman T. Ha, J. Mol. Biol. 2004,

336, 395; b) W. Shen, M. F. Bruist, S. D. Goodman, N. C. Seeman,

Angew. Chem., Int. Ed. 2004, 43, 4750.

[44] a) D. A. Hiller, J. M. Fogg, A. M. Martin, J. M. Beechem, N. O. Reich, J. J.

Perona, Biochemistry 2003, 42, 14375; b) A. I. Dragan, J. Klass, C. Read,

M. E. A. Churchill, C. Crane-Robinson, P. L. Privalov, J. Mol. Biol. 2003,

331, 795.

[45] P. J. Rothwell, S. Berger, O. Kensch, S. Felekyan, M. Antonik, B. M.

Wçhrl, T. Restle, R. S. Goody, C. A. M. Seidel, Proc. Natl. Acad. Sci. U.S.A.

2003, 100, 1655.

[46] a) M. K. Nahas, T. J. Wilson, S. Hohng, K. Jarvie, D. M. J. Lilley, T. Ha,

Nat. Struct. Mol. Biol. 2004, 11, 1107; b) Z. Xie, N. Srividya, T. R. Sosnick,

T. Pan, N. F. Scherer, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 534.

[47] H. D. Kim, G. U. Nienhau, T. Ha, J. W. Orr, J. R. Williamson S. Chu, Proc.

Natl. Acad. Sci. U.S.A. 2002, 99, 4284.

[48] H-K Lee, H. Cao, T. M. Rana, J. Ccomb. Chem., 2005, 7, 279-284.

[49] G. Uray, A. M. Kelterer, J. Hashim, T. N. Glasnov, C. O. Kappe, W. M. F.

Fabian, J. Mol. Struct. 2009, 929, 85-96.

[49] G. Jones II, W. R. Jackson, Chem. Phys. Lett. 1980, 72, 391.

[50] G. Jones II, in Dye Laser Principles with Applications, ed. F. J. Duarte, L.

W. Hillman, Academic Press, New York, 1990.

[51] G. Jones-II, W. R. Jackson, S. kanoktanaporn, A. M. Halpern, Opt.

Comm., 1980, 23, 315.



[52] G. Jones II, W. R. Jackson, C. Y. Choi, W. R. Bergmark, J. Phys. Chem.,

1985, 89, 294.

[53] K. Rechthaler, G. Köhler, Chem. Phys. 1994, 189, 99.

[54] G. Jones-II, J. A. Jimenez, J. Photochem. Photobiol. B, 2001, 65, 5.

[55] W. Rettig, A. Klock, Can. J. Chem., 1986, 63, 1649.

[56] M. El-Kemary, W. Rettig, Phys. Chem. Chem. Phys. 2003, 5, 5221-5228.

[57] R. S. Moog, W. W. Davis, S. G. osttrowski, G. L. Wilson, Chem. Phys. Lett.,

1999, 299, 265.

REFERENCES FOR EXPERIMENTAL PART 241


REFERENCES FOR EXPERIMENTAL

PART



REFERENCES FOR EXPERIMENTAL PART

[ex-1] a) R. M. Christie, C. H. Lui, Dyes Pigm. 1999, 42, 85-93; b) C.

Eggeling, R. R. J. Widengren, C. A. M. Seidel, Anal. Chem. 1998, 70,

2651–2659.

[ex-2] L. M. Harwood, Aldrichim. Acta 1985, 18, 25.

[ex-3] a) E. Ziegler, H. G. Forraita, T. Kappe, Monatsh. Chem. 1967, 98, 324–

28; b) B. Berinzaghi, A. Muruzabal, R. Labriola, V. Deulofeu, J. Org.

Chem. 1945, 10, 181–3; c) N. Shobana, P. Yeshosda, P. Shanmugam,

Tetrahedron 1989, 45, 757–762; d) V. Nadaraj, S. T. Selvi, R. Sasi,

ARKIVOC 2006, 10, 82–89.

[ex-4] a) V. I. Akhmedzhanova, I. A. Yunosov, S. Yu, Chem. Nat. Compd.

1976, 12, 282-288; Khim. Prirod. Soedin. 1976, 12, 320-328; b) A.

Omori, N. Sonoda, S. Tsutsumi, Bull. Chem. Soc. Jpn. 1970, 43, 1135-

1138; c) W. T. Gao, W. D. Hou, M. R. Zheng, L. J. Tang, Synth.

Commun. 2010, 40, 732–738.

[ex-5] a) W. Kutney, I. W. J. Still, Can. J. Chem. 1980, 58, 1233-8; b) E. A.

Pauw, Rec. Trav. Chim. Pays-Bas 1936, 55, 215–26; c) W. R. Vaughan,

J. Am. Chem. Soc. 1946, 68, 324–5; d) G. Barnikow, J. Prakt. Chem.

1966, 34, 251-61.

[ex-6] a) A. V. Prosyanik, Z. Y. Zorin, E. L. Solov'ev, J. Org. Chem. USSR

1985, 1353–360; Zhur. Org. Khim. 1985, 21, 1485–1493; b) A. K. Sen,

P. Sengupta, J. Indian Chem. Soc. 1969, 46, 857–859.

[ex-7] a) E. Castellaneta, Gazz. Chim. Ital. 1895, 25, 538-539; b) A. K. Sen,

K. Mitra, J. Indian Chem. Soc. 1965, 42, 851–854; c) H. Nishino, K.

Ishida, H. Hashimoto, K. Kurosawa, Synthesis 1996, 888–896.



[ex-8] M. Sechi, M. P. Delussu, N. Pala, U. Azzena, R. Dallocchio, A. Dessi, A.

Cosseddu, N. Neamati, Molecules 2008, 13, 2442–2461.

[ex-9] G. A. Prakash, S. P. Rajendran, Heterocycl. Commun. 2001, 7, 353–358.

[ex-10] G. H. Patel, C. M. Mehta, J. Indian Chem. Soc. 1973, 50, 215–16.

[ex-11] N. Dodia, A. Shah, Indian J. Heterocycl. Chem. 2000, 10, 69–70.

[ex-12] H. Kato, J. Sakaguchi, M. Aoyama, T. Izumi, PCT Int. Appl. Hokuriku

Seiyaku EP 1104764A1 Co. LTD 2000, WO 2000009506; Chem. Abstr.

2000, 132, 180573.

[ex-13] a) K. Faber, H. Steininger, T. Kappe, J. Heterocycl. Chem. 1985, 22,

1081–5; b) A. Knierzinger, O. S. Wolfbeis, J. Heterocycl. Chem. 1980,

17, 225–229.

[ex-14] B. Berinzaghi, A. Muruzabal, R. Labriola, V. Deulofeu, J. Org. Chem.

1945, 10, 181–3.

[ex-15] a) R. Hardman, M.W. Partridge, J. Chem. Soc. 1958, 614–20; b) N. S.

Narasimhan, R. S. Mali, Tetrahedron 1974, 30, 4153, 4154, 4156.

[ex-16] J. Moon-Kook, K. Kyongtae, Tetrahedron Lett. 2000, 41, 1943–1946.

[ex-17] a) F. Dallacker, F. E. Eschelbach, Liebigs Ann. Chem. 1965, 689, 171–

178; b) V. Vosatka, A. Capek, Z. Budesinsky, Collect. Czech. Chem.

Commun. 1977, 42, 3186–91.

[ex-18] a) M. Sekiya, S. Takayama, K. Ito, J. Suzuki, K. Suzuki, Y. Terao,

Chem. Pharm. Bull. 1972, 20, 2661, 2665, 2667; b) M. Sekiya, O.

Matsuda, J. Suzuki, M. Tomie, Sekiya Chem. Pharm. Bull. 1973, 21,

372, 376; c) Z. B. Kiro, B. I. Stepanov, J. Org. Chem. USSR, 1971, 7,

2279; Zhur. Org. Khim. 1971, 7, 2196–8.



[ex-19] a) V. Vosatka, A. Capek, Z. Budesinsky, Coll. Czech. Chem. Commun.

1977, 42, 3186–3191; b) M. Sekiya, M. Tomie, N. J. Leonard, J. Nelson,

J. Org. Chem. 1968, 33, 318–322.

[ex-20] a) Y. Ogata, K. Tagaki, K. Mizuno, J. Org. Chem. 1982, 47, 3684–3687;

b) J. Deutsch, H. J. Nicolas, Synth. Commun. 1993, 23, 1561–1568; c)

O. Meth-Cohn, D. L. Taylor, Tetrahedron 1995, 51, 12869–12882.

[ex-21] a) E. Froehlich, E. Wedekind, Ber. Dtsch. Chem. Ges. 1907, 40, 1010;

b) W. Koenig, G. A. Becker, J. Prak. Chem. [2], 1912, 85, 353-85; c) M.

Julia, J. Bagot, Bull. Soc. Chim. France 1964, 8, 1924–1938.

[ex-22] a) A. M. Hjort, E. J. de Beer, J. S. Bruck, W. S. Ide, Pharm. Exp. Therap.

1935, 55, 152, 153, 156; b) F. Benington, R. D. Morin, L. C. Clark Jr.,

J. Org. Chem. 1958, 23, 19, 22.

[ex-23] a) K. Horiki, Heterocycles 1976, 5, 203–6; b) M. Sekiya, K. Ito, Chem.

Pharm. Bull. 1967, 15, 1339, 1340, 1342.

[ex-24] a) M. Julia, J. Lenzi, Bull. Soc. Chim. France 1962, 1051, 1054; b) J. W.

Rakshys Jr., Inorg. Chem. 1970, 9, 1521.

[ex-25] a) M. Sekiya, K. Ito, Chem. Pharm. Bull. 1966, 14, 1007–9; b) I.

Bacaloglu, K. Nadolski, R. Bacaloglu, D. Martin, J. Prakt. Chem. 1971,

313, 839–848; c) J. R. Crochet, J. R. Blanton, Synthesis 1974, 55.

[ex-26] a) W. R. Abrams, R. G. Kallen, J. Am. Chem. Soc. 1976, 98, 7777–7789;

b) B. L. Fox, R. J. Doll, J. Org. Chem. 1973, 38, 1136–1140; c) A. H.

Beckett, R. W. Daisley, J. Walker, Tetrahedron 1968, 24, 6093–6109.

[ex-27] V. K. Sharma, A. Kumar, K. P. Agarwal, Indian J. Chem. 1983, 22,

1153.

[ex-28] a) S. Padmanabhan, N. L. Reddy, J. G. Durant, Synth. Commun. 1997,

27, 691–700; b) H. Suhr, Liebigs Anna. Chem. 1965, 689, 109–17.



[ex-29] a) E. Spath, O. Brunner, Ber. Dtsch. Chem. Ges. 1925, 58B, 518–23.

[ex-30] N. L. Owen, C. Sflomos, J. Chem. Soc. Perkin Trans. 1. 1979, 4, 943–9.

[ex-31] a) C. M. Pirrung, F. Blume, J. Org. Chem. 1999, 64, 3642–3649; b) J. A.

Lamberton, J. R. Price, Aust. J. Chem. 1953, 6, 173-9; c) V. I. Frolowa,

A. D. Kuzovkov, P. N. Kibalchich, J. Gen. Chem. USSR 1964, 34, 3542.

[ex-32] H. Jamshed, N. T. Glasnov, M. J. Kremsner, C. O. Kappe, J. Org. Chem.

2006, 71, 1707–1710.

[ex-33] a) T. F. Dankova, T. N. Bokova, N. A. Preobrazhenskii, A. E.

Petrushchenko, I. A. Il'shtein, N. I. Shvetsov, Zhur. Obsh. Khim. 1951,

21, 787- 800; b) J. C. Cain, J. L. Simonsen, C. Smith, Proceedings J.

Chem. Soc. 1913, 29, 172; c) J. C. Cain, J. L. Simonsen, C. Smith, J.

Chem. Soc. 1913, 103, 1035–9.

[ex-34] a) L. Novak, M. Borovicka, M. Protiva, Coll. Czech. Chem. Commun.

1962, 27, 1261–72; b) R.P. Quelet, J. Gavarret, Compt. Rend. 1950,

230, 394–6; c) R. P. Quelet, J. Gavarret 1951, 987235, Fr. Pat; Chem.

Abstr. 1956, 50, 40586.

[ex-35] a) H. Sadeghian, N. Attaran, Z. Jafari, M. R. Saberi, M. Pordel, M. M.

Riazi, Bioorg. Med. Chem. 2009, 17, 2327–2335; b) R. L. Huang, K. T.

Lee, J. Chem. Soc. 1955, 4229–32.

[ex-36] a) J. Dutta, R. N. Biswas, J. Indian Chem. Soc. 1963, 40, 629–637; b) F.

Leonard, A. Wajngurt, M. Klein, H. Meyer, J. Med. Chem. 1963, 6, 539-

541; c) H. C. Brown, C. J. Kim, J. Am. Chem. Soc. 1968, 90, 2082–

2096.

[ex-37] a) P. J. Smith, A. N. Bourns, Can. J. Chem. 1974, 52, 749 - 760; b) B.

M. Bhawal, S. P. Khanapure, E. R. Biehl, Synthesis 1991, 112–114;



c) S. Kiyooka, Y. Ueda, K. Suzuki, Bull. Chem. Soc. Jpn. 1980, 53,

1656–1660.

[ex-38] a) K. Kindler, W. Metzendorf, D. Kwok, Ber. Dtsch. Chem. Ges. 1943,

76, 308, 317; b) R. P. Quelet, J. Gavarret, Bull. Soc. Chim. France 1950,

1075, 1078.

[ex-39] a) P. R. Carter, D. H. Hey, J. Chem. Soc. 1948, 147–9; b) K. Kindler,

Liebigs Ann. Chem. 1927, 452, 90–120; Arch. Pharm. (Weinheim,

Germany) 1929, 544; c) W. Wieniawski, Acta Pol. Pharma. 1962, 19,

285–92.

[ex-40] a) J. G. Watkinson W. Watson, B. L. Yates, J. Chem. Soc. 1963, 5437–

5444; b) Y. Izawa, H. Tomioka, M. Kutsuna, Y. Toyama, Bull. Chem.

Soc. Jpn. 1979, 52, 3465–6; c) E. M. Arnett, G. B. Klingensmith, J. Am.

Chem. Soc. 1965, 87, 1032–1037.

[ex-41] a) M. Carissimi, I. Grasso, E. Grumelli, E. Milla, F. Ravenna, Farmaco

Ed. Sci. 1962, 17, 390-413; b) M. Carissimi, F. Ravenna, (Maggioni &

C. S. p. A.), 1963, Fr. Pat. M1687; Chem. Abstr. 1963, 59, 48427.

[ex-42] a) R. Walther, A. Wetzlich, J. Prakt. Chem. [2], 1900, 61, 169-198; b) T.

Curtius, J. Prakt. Chem. [2], 1914, 89, 500, 512; c) T. Curtius, J. Prakt.

Chem., [2], 1975, 91, 7; d) J. Hooz, J. N. Bridson, J. G. Calzada, H. C.

Brown, M. M. Midland, A. B. Levy, J. Org. Chem. 1973, 38, 2574–6.

[ex-43] a) Y. Yukawa, Y. Tsuno, M. Sawada, Bull. Chem. Soc. Jpn. 1966, 39,

2274–86.

[ex-44] a) V. N. Sokolova, O. Yu. Magidson, Chem. Heterocycl. Compd. 1968, 4,

385; Khim. Geterotsikl. Soedin. 1968, 3, 519–23; b) R. Chenevert, M.

Desjardins, Can. J. Chem. 1994, 72, 2312–2317.

[ex-45] a) C. S. Rondestvedt Jr., A. H. Filbey, J. Org. Chem. 1954, 19, 119–28;

b) W. Borsche, Ber. Dtsch. Chem. Ges. 1909, 42, 3600.



[ex-46] a) P. Yao, X. Zhai, D. Liu, B. H. Qi, H. L. Tan, Y. C. Jin, P. Gong, Arch.

Pharm. (Weinheim, Germany), 2010, 343, 17–23; b) G. W. hielcke, E. I.

Becker, J. Org. Chem. 1950, 15, 1241–5.

[ex-47] a) A. Pathak, P.M. Mishra, Asian J. Chem. 2007, 19, 988–994, b) J. R.

Knowles, R. O. C. Norman, J. Chem. Soc. 1961, 2938–47; c) O.

Masanori, N. Yoshikazu, K. Masayuki, M. Toshihiko, Bull. Chem. Soc.

Jpn 1985, 58, 3383–4.

[ex-48] J. F. J. Dippy, J. E. Page, J. Soc. Chem. Industry 1936, 55, 190–2T.

[ex-49] a) H. P. Ward, E. F. Jenkins, J. Org. Chem. 1945, 10, 371–3; b) E.

Ferber, H. Bendix, Ber.Dtsch. Chem. Ges. 1939, 72B, 839-848; c) H. A.

Selling, Tetrahedron, 1975, 31, 2387–2390; d) J. F. Fauvarque, A.

Jutand, J. Organomet. Chem. 1979, 177, 273–281.

[ex-50] a) J. G. Watkinson, W. Watson, B. L. Yates, J. Chem. Soc. 1963, 5437-

5444; b) P M. Pailer, P. Bergthaller, Monatsh. Chem., 1968, 99, 103–

111; c) G. G. Smith, K. K. Lum, J. A. Kirby, J. Posposil, J. Org. Chem.

1969, 34, 2090; d) P. Kristian, S. Kovac, O. Hritzova, Coll. Czech.

Chem. Commun. 1969, 34, 563–571.

[ex-51] a) W. R. Boon, H. C. Carrington, N. Greenhalgh, C. H. Vasey, J. Chem.

Soc. 1954, 3263–72, b) B. Marcot, J. C. Dore, S. Munavalli, C. Viel,

Rev. Roum. Chim. 1975, 20, 91–106; c) R. M. Claramunt, R. Granados,

M. C. Repolles, Anal. Quim. 1975, 71, 206.

[ex-52] a) R. O. C. Norman, P. D. Ralph, J. Chem. Soc. 1963, 5431, 5436; b) R.

C. Cambie, S. A. Coulson, L. G. Mackay, S. J. Janssen, P. S. Rutledge,

P. D. Woodgate, J. Organomet. Chem. 1991, 3, 409, 385–409.

[ex-53] a) G. Darzens, A. Levy, Compt. Rend. 1935, 200, 469–71; b) J. C.

Bardhan, Chem. Ind. (London, U. K.), 1940, 369; c) J. B. Niederl, US.

Pat. 1942, 2297911; Chem. Abstr. 1943, 37, 8511.



[ex-54] a) F. Leonard (Geigy Chemical Corp.), US. Pat. Appl. 1964, 3125583;

Chem. Abstr. 1964, 60, 75223; b) S. M. M. Elshafie, Chimia 1982, 36,

343–5; c) A. Citterio, R. Santi, T. Fiorani, S. Strologo, J. Org. Chem.

1989, 54, 2703–2712.

[ex-55] a) W. M. Lauer, L. I. Hansen, J. Am. Chem. Soc. 1939, 61, 3039–41; b)

J. B. Niederl, R. T. Roth, A. A. Plentl, J. Am. Chem. Soc. 1937, 59,

1901–3; c) G. Zvilichovsky, U. Fotadar, Org. Prep. Proced. Int. 1974, 6,

5–9.

[ex-56] a) B. Cavalleri, E. Bellasio, A. Wajngurt, M. Vigevani, E. Testa,

Farmaco Ed. Sci. 1969, 24, 451–70; b) F. Leonard, A. Wajngurt, M.

Klein, H. Meyer, J. Med. Chem. 1963, 6, 539, 540.

[ex-57] a) H. Schubert, H. Zaschke, J. Prakt. Chem. 1970, 312, 494–506; b) A.

J. De Gee, J. W. Verhoeven, I. P. Dirkx, T. J. De Boer, Tetrahedron

1969, 25, 3407–3412; c) A. South Jr., R. J. Ouellette, J. Am. Chem.

Soc. 1968, 90, 7064–72; d) Geigy Chem., US. Pat., 1960, 3125583;

Chem. Abstr. 1964, 60, 13192.

[ex-58] V. N. Sokolova, O. Yu. Magidson, Chem., Heterocycl. Compd. 1968, 4,

385; Khim. Geterotsikl. Soedin. 1968, 3, 519–23.

[ex-59] P. C. U. Kuhlmann, Ger. Pat. 2362331; Chem. Abstr., 1974, 81, 91567.

[ex-60] F. M. Beringer, P. S. Forgione, Tetrahedron 1963, 19, 739–748.

[ex-61] a) W. Stadlbauer, T. Kappe, Monatsh. Chem., 1985, 116, 1005–11; b)

H. Nishimura, Y. Nagai, T. Suziki, T. Sawayama, Yakugaku Zasshi,

1970, 90, 818–828.

[ex-62] a) J. Reisch, R. A. Salehi-Artimani, A. Bathe, M. Mueller, Monatsh.

Chem., 1988, 119, 781–792; b) M. F. Grundon, N. J. McCorkindale, M.

N. Rodger, J. Chem. Soc. 1955, 4284–90.



[ex-63] a) I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, S. V. Slobodzyan,

Chem. Heterocycl. Compd. 2006, 42, 882–885; Khim. Geterotsikl.

Soedin. 2006, 42, 1022–1025; b) J. Jampilek, R. Musiol, M. Pesko, K.

Kralova, M. Vejsova, J. Carroll, A. Coffey, J. Finster, D. Tabak, H.

Niedbala, V. Kozik, J. Polanski, J. Csollei, J. Dohnal, K. S. Zentiva,

Molecules 2009, 14, 1145–1159.

[ex-64] a) M. Rowley, P. D. Leeson, G. I. Stevenson, A. M. Moseley, I. Stansfield,

I. Sanderson, L. Robinson, R. Baker, J. A. Baker, J. Med. Chem. 1993,

36, 3386–3396; b) A. Detsi, V. Bardakos, J. Markopoulos, O. Igglessi-

Markopoulou, J. Chem. Soc., Perkin Trans. 1, 1996, 24, 2909–2914.

[ex-65] a) I. V. Ukrainets, S. G. Taran, O. V. Gorokhova, N. A. Marusenko, S. N.

Kovalenko, A. V. Turov, N. I. Filimonova, S. M. Ivkov, Chem. Heterocycl.

Compd. 1995, 31, 167–175; Khim. Geterotsikl. Soedin. 1995, 2, 195–

203; b) W. Stadlbauer, S. Prattes, W. Fiala, J. Heterocycl. Chem. 1998,

35, 627–636.

[ex-66] a) I. V. Ukrainets, N. L. Bereznyakova, A. A. Davidenko, S. V.

Slobodzian, Chem. Heterocycl. Compd. 2009, 45, 952–956; Khim.

Geterotsikl. Soedin. 2008, 45, 1198–1203.

[ex-67] a) K. Arya, M. Agarwal, Bioorg. Med. Chem. Lett. 2007, 17, 86-93; b) D.

C. Dittmer, Q. Li, D. V. Avilov, J. Org. Chem. 2005, 70, 4682-4686; c)

B. Bhudevi, P. V. Ramana, A. Mudiraj, A. R. Reddy, Indian J. Chem.

2009, 48B, 255-260.

[ex-68] a) S-J. Park, J-C. Lee, K-I. Lee, Bull. Korean Chem.Soc. 2007, 28, 1203-

1205; b) J. Mpilek, R. Musiol, M. Pesko, K. Kralova, M. Vejsova, j.

Carroll, A. Coffey, J. Finster, D. Tabak, H. Niedbala, V. Kozik, J.

Polanski, J. Csollei, J. Dohnal, Molecules 2009, 14, 1145-1159.

[ex-69] a) D. Sicker, A. Rabe, A. Zakrzewski, G. Mann, J. Prakt.Chem. (Leipzig)

1987, 329, 1063-70; b) E. Ziegler, R. Wolf, Th. Kappe, Monatsh. Chem.

1965, 96, 418-22;



c) St. V. Niementowski, Ber. Dtsch. Chem. Ges. 1908, 40, 4285-94.

[ex-70] a) F. Arndt, L. Ergener, O. Kutlu, Ber. Dtsch. Chem. Ges. 1953, 86,

951-7; b) C. Schopf, G. Koepke, B. Kowald, F. Schulde, D. Wunderlich,

Ber. Dtsch. Chem. Ges. 1956, 89, 2877-86; c) R. T. Coutts, D. G.

Wibberley, J. Chem. Soc. 1963, 4610-12.

[ex-71] a) I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, S. V. Slobodzyan,.

Chem. Heterocycl. Compd. 2006, 42, 882-885; b) G. Koller, Ber. Dtsch.

Chem. Ges. 1927, 60B, 1108-11; c) C. L. Arcus, R. E. Marks, M. M.

Coombs, J. Chem. Soc. 1957, 4064-9.

[ex-72] a) A. E. Chichibabin, Zhur. Russ. Fiz.-Khim. Obshch. 1924, 55, 7-18; b)

Cassella Farbwerke Mainkur A.-G. 1963, GB Pat. 916103; Chem.

Abstr. 1963, 59, 48294.

[ex-73] a) J. Ficini, A. Krief, Tetrahedron Lett. 1968, 8, 947-51; b) A. Meyer, P.

Heimann, Compt. Rend. 1936, 203, 264-6; c) M. C. Pirrung, F. Blume,

J. Org. Chem. 1999, 64, 3642-3649; d) S. Yu. Yunusov, G. P. Sidyakin,

Doklady Akademii Nauk USSR 1953, 12, 22-4.

[ex-74] a) R. F. C. Brown, J. J. Hobbs, G. K. Hughes, E. Ritchie, Aust. J. Chem.

1954, 7, 348-77; b) E. H. Huntress, J. Bornstein, J. Am. Chem. Soc.

1949, 71, 745-6.

[ex-75] I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, S. V. Slobodzyan,

Chem. Heterocycl. Compd. 2006, 42, 882–885; Khim. Geterotsikl.

Soedin. 2006, 42, 1022 –1025.

[ex-76] M. F. Grundon, N. J. McCorkindale, J. Chem. Soc. 1957, 2177–85.

[ex-77] A. B. Ahvale, H. Prokopcova, J. Sefcovicova, W. Steinschifter, A. E.

Taubl, G. Uray, W. Stadlbauer, Eur. J. Org. Chem. 2008, 563–571.



[ex-78] F .A. L. Anet, P. T. Gilham, P. Gow, G. K. Hughes, E. Ritchie, J. Sci.

Res., A: 1952, 5, 412–19.

[ex-79] M. O. Abe, D. A. H. Taylor, Phytochemistry (Elsevier) 1971, 10, 1167–

1169.

[ex-80] N. S. Narasimhan, R. S. Mali, A. M. Gokhale, Indian J. Chem. B, 1979,

18, 115.

[ex-81] M. M. Martin and L. Lindqvist, J. Luminescence 1975, 10, 381–390.

[ex-82] N. S. Badgujar, M. Pazicky, P. Traar, A. Terec, G. Uray, W. Stadlbauer,

Eur. J. Org. Chem. 2006, 2715–2722.

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