3Bottor of Vbt'los;Opbp in CHEMISTRY F~F I
5
STUDIES IN CHEMISTRY OF OXYGEN AND NITROGEN HETEROCYCLES
THESIS SUBMITTED FOR THE AWARD OF THE DEGREE OF 3Bottor of Vbt'los;opbp IN CHEMISTRY F~F i
BY FARHEEN
UNDER THE SUPERVISION OF DR. (MRS.) ZEBA N. SIDDIQUI Li
DEPARTMENT OF CHEMISTRY ALIGARH MUSLIM UNIVERSITY AUGARH-202 002 (INDIA) 2013 ,~La&1 !.1►,.
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,, ally 2014
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My L.ovivu~ t cu-eviza-
DEPARTMENT OF CHEMISTRY DR ZrEBA N. SI~DrDIQ~I ~us4`;~' Aligarh Muslim University M.Phil., Ph.D. -~~' M y~' Aligarh-202 002 (India) Associate Professor T Ph. (Off) 0571-2703515 (Res) 0571-2702518 ' (Mob) 09412653054 E-mail: siddqui_zeba(a~yahoo.co.in
Certificate
This is to certify that the thesis entitled "Studies in Chemistry of Oxygen &
Nitrogen Heterocycles" submitted for the award of the degree of Doctor of
Philosophy (Ph.D.) in Chemistry to Aligarh Muslim University, Aligarh, India, is
a record of bonafide research work carried out by Miss. Farheen under my
guidance. It is further certified that the thesis embodies the work of candidate
herself and has not been submitted for any degree either of this or any other
university. The present work is suitable for submission for the above mentioned
purpose.
(Dr. Zeba N. Siddihui) Supervisor This thesis has benefited greatly .from the support of many people whose contribution in assorted ways to the research and the making of the thesis de.ser'ed special mention. It is a pleasant task to express my thanks to all those who contributed in many wars to the success of this study and made it an unforgettable experience for me. Therefore _first and foremost I pav all my homage and devote my emotions to ALMIGHTY ALLAH "Director of Life" to give a new direction to my study and for making me much capable that I could adopt and finish this huge task. Without whose blessings and benevolence my endeavours wouldn 't have reached to the zenith of success It is with great pleasure and proud privilege that I wish to express from the deepest core of my heart, the feelings of reverence and indebtedness to my respected Guide Dr. (Mrs.) Zeba N. Siddiqui, Associate professor, Department of Chemistry who has helped me at each and even' stage of my research ►cork with patience and enthusiasm. Her expert guidance and vast experience has contributed great extent to complete this work. I am much indebted to her for her faith in me, incessant encouragement, constructive suggestions, inspiring guidance. and everlasting supportive nature throughout the tenure of my research work without which the aims and objectives of the work could not have been achieved. I would like to express my thanks to Prof. Zafar Ahmad Siddiqui, Chairman, Department of Chemistr►• for providing all necessary facilities needed for the completion of my research work. I gratefully acknowledge University Grants Commission, New Delhi for their generous financial assistance, Sophisticated Analytical Instrumentation Facility (SAIFF, Central Drug Research Institute (CDRI) Lucknow and Punjab University Chandigarh for providing spectral data. I would also like to thank my senior Dr. Mohammed .Vusthafa T.A. for his most willing co- operation and comprehensive exchange of ideas during the course of nn research work. 1 would like to convey my pleasant heartily thankfulness to Mr. Vushtaq Ahmad, Area Business Manager, Bangalore, who has been always participating with my problems and disappointments and rebuilt my confidence at appropriate stages that made my research work success. I offrr my heartjull gratitude to Tubassum Aslam and Mohammed Aslam for their help, encouragement and friendship which lighten mti, day and did not make me feel alone in my research work. disappointments and rebuilt my confidence at appropriate stages that made my research work success. 1 offer my hear/full gratitude to Tabassum Aslam and Mohammed As/am for their help encouragement and friendship which lighten my day and did not make me feel alone in my research work 1 render my special and heartful thanks to my lab colleagues Miss. Tabassum Khan, Miss Kulsum. Miss Saima Tarannum and Mr. Nayeem Ahmad who ever stood beside me with their helping hands and moral support. I gratefully thank all for their help & coordination extended by them. I would also thank to Mr. Abdul Mannan for his help at the time of printing and formatting. I express my sincere gratitude Dr. Mohammad Naseeruddin. Assistant Professor, and Dr. Mohd. Fayazuddin, Senior resident, Department of Pharmacology, JNMC, AMU, Aligarh for their guidance and for animal experimental work of the research work. I also thank to Dr. Asad U. Khan, Associate Professor, Interdisciplinary Biotechnology Unit, Aligarh Muslim University Aligarh for carrying out antimicrobial activities. Where would I be without my family? I have no words (astute anything about my parents but at this occasion, I would like to thanks my father Mr. Farooq Ahmad and mother Mrs. Rosh an Ara. without their love, deep n(jection. heartful blessings and ever encouraging moral support it would have been impossible for me to finish my research work. I am equally thankful to my dearest sisters Arshi Farooq and Bushra Farooq for encouraging Inc and providing every help to fulfill my task Special thanks to the newest addition to my family. Mr. Arshad Yusuf my brother in law for providing me with reasons to smile and laugh which I needed often and for his moral support and courage in each moment. Finally, I would like to thank each and every one of them who helped me directly or indirectly during this wonderful and lots of experience gaining journey. I apologize if in any case lam missing out any q1 the names as lam thankful to one and all
Farheeri Pref 1: cc the S%nthcas Of hcterocsclie compounds has always drawn the attention of researchers over the
,,I:, ln,11rnl\ bcclal e ilice compounds have played vital roles in biological processes
W,chenlicms. pharmaceuticals and also in human life. Therefore, the development of simple, facile, efficient and en' 1ronmentally benign chemical processes or methodologies to synthesize novel heterocycles and their derivatives is one of the major aspects in organic synthesis.
The work embodied in this thesis entitled "Studies in Chemistry of Oxygen and Nitrogen heteroc' cle." deals s% itli the design and development of simple and efficient protocol to synthesize new biologically important heteroc\ dlie dens ativ es from cheap and readily available starting materials such as 4-h\droxvCoutuarin. ? t or;vlchrouioac. cltlo:o--tnethvl-l-phenylpyrazole 4- e irhoxaldeh\de and t-norm\ 1indole. To discuss systematically, thesis is divided into five chapters, ssiu:h are as follciw :
Chapter I
N raiolcs. I'cridine\. (uulnarir,. Chrontones and lndolcs are well known nitrogen and oxygen
heterocv'clic compounds which are employed as important skeletons in organic synthesis,
medicinal chemistry and pharmacology. Therefore, various applications associated with these
molecules motivated Its to ;elect them as potential candidates for the synthesis of novel
heterocycles. This chapter contains scope of present work and depicts a comprehensive survey of
literature on the synthesis and reactions of starting materials namely, 4-hydrosycoumarin, 3-
forme lchroinone, 5-chloro- 3-methyl- I -pnenylpvrazole--4-carboxaldeltvdc, 3-formylindole, which
were taken throughout the thesis and for their applications in the synthesis of different five and six
membered heterocycles such as !3-enaminones, pyrazoles, pyridines, dicoumarols, chromanones,
indolvI chalcone. indolvl pvrazolincs etc. Chapter 2
(t-Enaminones are important synthetic intermediates for the synthesis of various biologically active heterocyclic compounds due to presence of an coin group linked through a C-C to a carbonyl groiry. Thus, due to their in in pharmaceuticals and in organic synthesis as intermediates, in this section, we have described a simpler and clean method for the synthesis of heterocyclic (3- enammones (176a-d) by condensation of heterocyclic methyl ketones (174a-d) with DMF-DMA
(175) by thermal heating under solvent- and catalyst-free condition at lower temperature in excellent yields. Attempts were made to synthesize pyrazole (178a-h) and pyrnnyl pyridine derivatives (ISOa-h) by the reaction of~3-enaminone (176a) with different hydrazines (177a-b) and active methylene compounds (179a-h) respectively under thermal solvent-free condition in the
presence of NaH504-SiO_, As expected reactions proceeded efficiently and the desired products
were obtained in excellent yields. The catalytic system, NaHSO4-SiOo and products were
characterized by powder XRD, SEM and EDX and spectral analysis respectively.
Chapter 3
Dicoumacul is a naturally occurring anticoagulant drag that functions as a vitamin K antagonist
and possesses various other pharmacological activities such as insecticidal, anthelmintic, hypnotic,
antifungal, phytoalexin, HIV protcases inhibition. antimicrobial and antioxidant etc. In clinical
trials, such compounds have also demonstrated to have some activity against prostate cancer,
malignant melanoma and metastatic renal cell carcinoma. Homogeneous catalysis play a key role
in the development of greener, more sustainable chemical processes, and are powerful tools for the
synthesis of fine chemicals, pharmaceuticals and materials.This chapter is divided into two
sections and describes die synthesis of dicomnamis and 2-hydroxy-4-chmmanones in the presence
of 7,n[(L)prolinc]'as an efficient, environmentally benign, water-tolerant, Lewis acid catalyst in
green solvent. "water" as the reaction medium. Initially. attempt \\ cre made to synthesize dicoumarol derivatives ( 182a—j ) bV the reaction of 4-hydroxvcoumarin (29) with a variety of aromatic heteroaromatic aldehydes (181a—j) in the presence of 5 viol %Zn[(L)proline]2 in rellux water. The products were obtained in excellent yield in a short time period. In order to show the superiority of
Zn[(L)proline],:water catalytic system, a model reaction of 4-hydroxycoumarin and 4- hydroxybenzaldehyde was carried out in different catalysts, solvents and with different amount of catalysts. And it was observed that Zn[(L)proline]2 exhibited the highest catalytic activity over other catalyst and water as the best solvent for the formation of dicoumarols in tcriiis of reduced reaction time and the maximum yield of the products.
The catalyst was successfully recovered and recycled without significant loss in yield and selectivity. All the synthesized compounds were characterized by spectroscopic data.
Further Zn[(L)prulinc]2 as explored for the synthesis of new series of chrumanaone derivatives
(185a-j) by the reaction of 3-formylchromone (64) with various amines (183a-j) in refluxing
\+ater. All the reactions were found to be completed within 10-15 min and afforded chromanone
derivatives (185a-j) in excellent yields. The method was advantageous in terms of mild reaction
conditions, use of water as solvent, cleaner reaction proliles, simplicity in operation, excellent
yields of the products, faster reaction rates and reusability of the catalyst with no loss in its activity.
CHAPTER 4
Due to the widespread applications associated with pyrazole and their derivatives from
pharmacological, agrochemicals and industrial point of view, this chapter is divided int two
sections. Section A, deals with the synthesis of novel halopyrazole derivatives (187) and (189) in
good yields by using 5-chloro-3-methyl-l-phcnylpyrazolc-4-carboxaldchyde (105) as starting
material. The structures of the compounds isolated were characterized by elemental and spectral
analysis. The infections caused by various microorganisms pose a serious challenge to the medical community and need for an effective therapy led to a search For novel antimicrobial agents.
Therefore, all the newly synthesized compounds were evaluated for their in vitro antimicrobial activity against Streptococcus pvogenes, Methicillin resistant Staphylococcus aureus,
Pseudomwms aeruginosa. Klebsiella pneumonia, Bacillus subrllis, Salmonella typhimurium and
Escherichia colt bacterial strains and fungal cultures of Candida albicans, Aspergiffus fumigates,
Aspergillus niger. 7'richoplzyto;i ureruagrophytes and Penicilfium marneffei by disk diffusion assay.
The investigation of antibacterial and antifungal screening data revealed that all the tested compounds (187) and (189) showed moderate to good bactericidal and fungicidal activities. MIC
of compounds was in the range of 12.5-59 sgimL. The MBC of compounds was found to be two
or four folds higher than the corresponding MIC results.
Chapter 5
This section divided into two sections
Microwave-assisted organic reaction enhancement is well-established technique for rapid and
efficient synthesis of variety of heterocycles particularly from the viewpoint of green chemistry. In
the microwave environment chemical reactions usually proceed faster and give higher yields with
less by-products and allows fast optimization of chemical reactions compared In conventional
heating.
Chalcones (1,3-diaryl-2-propene-1-ones) are natural substances found in fruits, vegetables,
spices, tea and soy based foodstuff and has been subject of great interest for possessing
interesting pharmacological activities. On the other hand pyrazolino nucleus is a
ubiquitous feature of various compounds possessing many pharmacological and
physiological activities. Keeping in vie %% the potential biological activities of indole, chalcones and pyrazolines as well as the utilit\ of microwave irradiation in organic synthesis, this section of the chapter deals with the synthesis of indolyl chalcones (192a-c) and their substituted pyrazoline derivatives (193a-f) under
microwave irradiation. As visualized, the reaction proceeded smoothly under solvent-free condition and the products were obtained in excellent yield in shorter time period. The work also describes the Superiority of green synthetic methods over conventional heating procedure. All the
newly synthesized compounds were characterized by elemental and spectral analysis.
In recent \ears. there is a considerable therapeutic interest in novel anti-Inflammatory drugs with a
mode of action different from that of the classical acidic nonsteroidal anti-inflammatory drugs
(NSAIDs). mainly for use in patients with arthritis of varying degree of severity. The classical
NSAIDs do not prevent progression of such a disease and are subject to irritant side effects. The
most prevalent side effect of the use of NSAIDs is the occurrence of gastrointestinal damage with
gastric upset. bleeding. nephrotoxicity, intolerance and renal toxicity and irritation being the major
problems. Therefore, the discovery of new and safer anti-inflammatory drugs represents a
challenging goal for such a research area. A literature survey reveals that the compounds ith the
backbone of chalcone and pvrazolines attached to an indole nucleus may show improved anti-
inflammatory activity in carrageenan induced inflammation model. Thus, keeping this in view, in
this section the present stud% as undertaken to investigate the anti-inflammatory activity of the
synthesised compounds (indolvl chalcones and pyrazolines) (192a-c and 193a-f) in experimental
models using carrageenan induced paw edema assay model of inflammation on Wistar rats, using
aspirin as reference drug. Abbreviations and Symbols
AcOI i Acetic acid Ac2O Acetic anhydride CAN Ceric ammonium nitrate CDC 1: Deuterated chloroform CI ICI; Chloroform C'H,C 1, Dichloromethane l)BI 1 1,8-DiazabicycIo[5.4.0]undec-7-ene DMF N, N-Dimethylformamide DMF-DMA N, N-Dimethylformamide dimethyl acetal DMSO Dimethyl sulfoxide Equiv. Equivalent EtOH Ethanol h or hrs Hours H. Hertz I Iodine IR Infra-red N1e Methyl McOH Methanol mg Milligram nil. Millilitre mmol Millimole M.p. Melting point NMR Nuclear magnetic Resonance PEG Poly ethylene glycol p-TSA puru-Toluenesulfonic acid 11 IF Tetrahydrofuran MeCN Acetonitrile DMS Dimethyl sulfide LIST OF PUBLICATIONS
This thesis is based on the following papers:
(I) Zeba N. Siddiqui. Farheen Farooq, Silica supported sodium hydrogen sulfate (NaHSO4—Si02): A novel, green catalyst for synthesis of pyrazole and pyranyl pyridine derivatives under solvent-free condition via heterocyclic fl-enaminones. Journal of Molecular Catalysis A: Chemical 363— 364 (2012)451-459.
(II) Zeba N. Siddiqui, Farheen Farooq, Zn(Proline)2: a novel catalyst for the synthesis of Dicoumarols. ('analysis Science and Technology. 1 (2011) 810-816.
(III) Zeba N. Siddiqui, Farheen Farooq, A practical one pot synthesis of novel 2- hydroxy-4chromanone derivatives from 3-formylchromone. Journal of Chemical Sciences. 124 (2012) 1097-1105.
(IV) Zeba N. Siddiqui, Farheen Farooq, Synthesis, characterization and antimicrobial evaluation of novel halopyrazole derivatives. Journal of Saudi Chemical Society, 17(2013)237-243.
(V) Zeba N. Siddiqui, Farheen Farooq, T.N. Mohammed Musthafa. A highly efficient, simple, and ecofriendly microwave-induced synthesis of indolyl chalcones and pyrazolines. Green Chemistry Letters and Reviews, 4(2011)63-68. CONTENTS
Page No.
Preface List of Abbreviations List of Publications Chapter-I Theoretical
Review and Literature fl-Enaminones 2 4-Hydroxycoumarin 8 3-Formylchromone 18 5-Chloro-3-methyl-I-phenyl-lH-pyrazol-4-carboxaldehyde 31 3-Formylindole 41 Chapter II (1-Enaminones: Synthesis and its transformation to novel heterocycles employing NaHSOr-SiO1 as heterogeneous catalyst under solvent free condition
Review & literature 54 Results and discussion 57 Experimental 72
References 98 Chapter-III Zn(Proline)2-Water: A green catalytic system for the synthesis of benzopyran ring systems
Review & literature 106
Section A: Synthesis of dicoumarol 114
OH \ CHO OH n~ OH
W'rn, rcflu.
(.'J 0 \H
Results and discussion 115 Section B: Synthesis of 2-hydroxy-4-chromanones 123
„ 11
°) ' M—NIh—~—► \ 11 / CHO \t a1~T. Rtllu~
Results and discussion 125 Experimental 134 References 149 Chapter-I V Synthesis, characterization and in vitro antibacterial and antifungal evaluation of novel halopyrazole derivatives
Review & literature 157 Section A: Synthesis of novel halopyrazole derivatives 160 Results and discussion 160 Experimental 164 Section B: Antimicrobial evaluation of pyrazole derivatives 172 Antibacterial activities 172 Antifungal activities 174 References 178
Chapter-V Synthesis and anti-inflammatory evaluation of indale derivatives
HET 0.\NN NG MW
HM3N NH
Section A: Microwave-assisted solvent-free synthesis of indolyl chalcones and indolyl pyrazolines 183 Review & literature 183 Results and discussion 199 Experimental 203 References 215
Section B: Anti-inflammatory activities 224 Review & literature 224 Experimental 227 Results 230 Discussion 235 References 237 CHAPTER 1
THEORETICAL
1. REVIEW AND LITERATURE
The structural diversity and biological importance of nitrogen and oxygen containing , heterocycles have always drawn the attention of researchers over the years. Their importances as precursors to many biologically active compounds have focused a tremendous amount of attention on developing methods to functionalise these systems.
Synthetically produced heterocycles designed by organic chemists are used for instance as agrochemicals, pharmaceuticals and as additives with a variety of other functions which play an important role in human life.' The remarkable ability of heterocyclic nuclei to serve both as biornimetics and reactive pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs.`
Due to the widespread interest in heterocycles. the design of novel methods to prepare the privileged heterocyclic medicinal scaffold has always been among the most important research areas in synthetic chemistry. Taking in view of the applicability of heterocyclic compounds the present work was under taken to synthesized novel heterocycles such as pyrazoles and pyridine, dicoumarol, chromanones, halopyrazoles, indolyl chalcones, indolvl pyrazolines from different nitrogen and oxygen heterocycles such as R- enarninones. 4-hydroxvcoumarin. 3-formylchromone. 5-chloro-3-methyl- 1 - phem 1pvrazole-4-carboxaldehyde and 3-formylindole etc. Green chemistry aspect is used
for the synthesis of these heterocyclic compounds.
'l'herefore. intention of this chapter is to focus mainly on research work of the last ten
years dealing with the starting materials used in the thesis.
1 1.1. P-EnilII1lIlOIIes
3-Enaminones are the chemical compounds that contain the conjugate system NC=C-C=O.
From the structural point of view, enaminones are usually classified according to the degree of substitution on the nitrogen atom into primary (1°), secondary (2°) and tertiary
(3") enaminones (Scheme 1).
0 0 0
R~" \% ~N}{, R=CH3 R R ~% , _R 1~ ~1 R R
10 2° 30
Scheme I
Accordin~a to their carbon skeleton, enaminones are usually classified into acyclic 1,
endocyclic 2. exocyclic 3 and heterocyclic 4 enaminones (Scheme 2).
2 3 4
Scheme 2
A literature survey reveals that enaminones are very stable compounds that combine the
ambident nucleophilicity of enamines with the ambident cletrophilicity of enones and
constitute a versatile class of useful precursors in organic synthesis, in pharmaceutical
development and in heterocyclic synthesis.; Moreover, enaminones have been found to
exhibit several biological activities as antitumor, antibacterial and anticonvulsant agents.4
In the light of these facts a iv current examples on the application of enaminones for the
synthesis of heterocyclic compounds are discussed below:
K
1.1.1. Sti vthesis of pyridines
Kantevari et al developed one-pot, three-component condensation of (3-enaminones (5), ~3-
dicarbonyl compounds (6) and ammonium acetate in the presence of a catalytic amount of
K;Co W 12040.3 H2O as catalyst under solvent-free conditions, as well as in refluxing
isopropanol for the synthesis of trisubstituted pyridines (7) (Scheme 3).
0 0 ,Hc ,CH3 N _ KrCoWI2403H,I H~ Neat, 1 15°C CI / 1H4OAc
5 6 7
Scheme 3
1.1.2. Synthesis of dihydropyridines
\I-.A~vadi et a16 reported the synthesis of dihydropyridines (11) by the reaction of f-
enaminones (8). aromatic aldehyde (9) and ammonium acetate or aromatic amine (10)
in glacial acetic acid under reflux condition (Scheme 4).
o Ar' o 0
Ar I Ar Ar Ar AcOH. \111' 150°C t'41t) Ar = C6Ht R Ar' = C1-l3, p-('l-Cl1, 8 9 10 R=H,C<,IIS II
Scheme 4
3 1.1.3. Reactions with amines
(a) Synthesis of li-amino ketones
V ishvakartna et al reported the KHSO4 assisted Michael addition elimination
reaction of (3-enaminone (12) with different aromatic amines (13) in stirring water
at 50 --C to afford (3-amino ketones (14) (Scheme 5).
O ,H~ R O" 1~ RHSO4/1T)O + RNH,
:\s• \~1e, 50 GC
:fir = CHc, 4-MeCF1 I;, 4-CIC6H4 R = Me, Et
12 13 14
Scheme 5
(b) Synthesis of pyrimidine derivatives
Shawali et al' reported the reactions of the enaminone 15 with different heterocyclic
amine such as 5-amino-l.2.4-triazole 16a, 5-amino-3-phenylpyrazole 16b and 2-
aminobenzimidazole 16c, in acetic acid under retlux to yielded the respective fused
pyrimidine derivatives 17a-c (Scheme 6).
4
Ph
Ph~, \N / I~ ~I EtOOC
H 16 b AcOl I. reflux N Ph N 17 b 0 C1 6H4C1-p FtOOC "Me AcOH. N~Me ti Nom.N Ph
16a ~~ N 15 N EtOOC NN EtOOC Ph \' 16cH2
Ch114c1-/) Ac011. ref lux ~N Ph ti 17a 1 C6H4CI-p 17 c
Scheme 6
1.1.4. S1vzNtesis of tetraizydropyrimidine
Al-Mousawi et a19 reported the Biginelli reaction of 18 with equimolecular amounts of
benzaldehyde and urea in acetic acid to afford a 3:1 mixture of tetrahydropyrimidine
19 and dih} dropvridine 20. which were readily separated by fractional crystallization
(Scheme 7).
0 0 0
PhCHOIUrea I N O Ph NH, 0 Me2N AcOH o o I INI H 0 H 18 19 20 Scheme 7 1.1.5. S~•irthesis of pl'razoles
A. P. Martins et al l" reported a series of NH-pyrazoles 23 by reaction of the enaminones
21 \\ ith hvdrazine sulphate 22 on grinding in the presence of PTS. All the reactions proceeded smoothly at room temperature and the products were obtained in excellent yields in shorter time periods (Scheme 8).
U / 1
Grinding, R T e Nay VMS. + N{I•T:H, H,SC)4 - H PTS
21 22 / 23
Scheme 8
1.1.6. Reaction of enaminone with active methylene compounds
Ilamad Al-Matar et al l I reported the reaction of enaminone 24 with malononitrile 25 and ethyl acetoacetate 26 in the presence of catalytic amount of chitosan in refluxing ethanol to afford 27 and 28 respectively (Scheme 9).
CN NC
~C 2S R / N\1e, Chitosan, Ethanol. rcFlux i /
2i O
COV[iI 27 R 0 U 26
11:C O
R 28 R (111. Ph
Scheme 9
REFERENCES
1. (a) Varma. R. S. J. Heterocycl. Chem. 1999, 36, 1565.
(b) Eicher. T. S.: 1-lauptmann. The Chemistry of Heterocycles:Structure, Reactions,
Syntheses and Applicallons, second edition, Wiley-VCH, Weinheim, 2003.
(c) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in Life and
Society; Wiley: New York. 1997.
2. (a) Comprehensive Heterocyclic Chemistry II; Katritzky. A. R.; Rees, C. W.; Scriven,
E. F. V. Eds.; Pergamon: Oxford, 1996.
(b) Undheim, K.: Benneche, T. In Advances in Heterocyclic Chemistry; Gilchrist, T.
L., Dribble, G. W.. Eds.: Pergamon: Oxford, 1999, 11.21.
(c)Joule, J. A.; Mills, K. Heterocyclic Chemistry; Blackwell Science: Oxford, 2000.
(d) Katritzky. A.R.: Pozharskii, A. F. Handbook of Heterocyclic Chemistry;
Pergamon: Oxford. 2003
3. Greenhill, J. V. Chein. Soc. Rev. 1977, 6, 277.
4. Shawali, A. S.; Farghaly T. A.; Al-Dahshoury A. R. Arkivoc 2009. 14, 88.
5. Kantevari, S.: Chary. M. V.: Vuppalapati S. V. N. Tetrahedron 2007, 63, 1302.
6. Al-Aw adi. N. A.; Ibrahim, M. R.; Elnagdi, M. H.; John, E.; Ibrahim, Y. A. Beilstein
.1. Uri. (hem. 2012, 8. 441.
7. I)evi. A. S.; Dutta. M. C.: Nongkhlaw, R.: Vishwakarma, J. N. J. Ind. Chem. Soc.
2010, 87. 739.
8. Sha,, ali. A. S.. Farghaly. T. A.; Aldahshoury, A. I. R. Arkivoc 2010, 9, 19.
9. :11-Mousawi, S. M.: El-Apasery M. A.; Elnagdi. M. H. Molecules 2010, 15, 58.
10. Longhi. K.; Moreira. D. N.; Marzari. M. R. B.; Floss, V. M.; Bonacorso, H. G.;
7 Zanatta. N.; Martins. M. A. P. Tetrahedron Lett. 2010, 51, 3193. ii. Khalil, K.; Al-Matar, H.; Elnagdi, M. Ecnr. J. Chern. 2010, 1, 252.
1.2. 4-Hydroxy Coumarin
29
Coumarin and its derivatives are important core in building block of an ever growing number of natural and non-natural products which display an impressive array of
biological activities including antimicrobial,' antioxidant,2 analgesic,3 anti-
intlammatory,4 antithrombotic, anti-HIV,6 anti-viral,7 anticancer' antineoplastic9 etc. They
are %vidclv used as additives in food. perfumes, agrochemicals, cosmetics,
pharmaceuticals'" and in the preparations of insecticides, optical brightening agents,
dispersed fluorescent and tunable dye lasers.' Coumarins are extremely variable in
structure, due to the various types of substitutions in their basic structure, which influence
their biological activity as well. Among the various substituted coumarins, 4-
hydroxycoumarin represents a versatile scaffold and shows diversified chemical reactivity
in organic as well as in heterocyclic chemistry due to the presence of OH group at position
4 which gives nucleophilic character at position 3. It also acts as a cyclic (3-keto ester
which can be used as a convenient three-carbon synthon in processes accompanied by
recvclization of the chromene ring system.'2 The synthetic versatility of 4-
hydroxvcoumarin has led to the extensive use of this compound in organic synthesis. Thus,
0 a literature survey of last ten years was done and some relevant reactions of 4- hvdrox vcoumarin are discussed below.
1.2.1. Synthesis offurocoutnarins
A facile synthesis of furo[3,2-c]coumarins (31) has been reported via cyclocondensation of 4-hydroxycoumarin (29), a-tosyloxyketones (30) and acetic acid/ N1_14OAc in rcfluxing absolute ethanol (Scheme 10).''
off 0 \
Ar \ \ \ \ A.OHiNH.tonc Reflux,toluene/abs EtOH / O 0 0 O 31 29 30 (1382%)
Ar = Cba-15. 4-McC6H4, 4-OU1cC6H4. 4-CIC6H4. 4-E3rG6N4, 4-1(),C61 l,t, 4-FC'6114
Scheme 10
1.2.2. Reactions of 4-hydroxycoumarins with alkynes
Jie \Va et al'4 reported the palladium-catalyzed direct coupling reactions of 4- hvdroxycoumarins (29) with various alkynes (32) in the presence of p-toluenesulfonyl chloride under copper-free conditions to affords 33 ( Scheme 11).
R
0i I1
!tPrh\Et, McCN / Oóc= ?SCI, 60 °C O 32 29 33
R
\ / (>\te
Scheme 11
E 1.2.3. Domino Knoevenagel Iretero-Diels Alder reactions
J. S. Yadav and co-workers' ; described a novel protocol for the synthesis of sugar fused i'uro[ 3 2-b]pyrano[4,3 -dl pyrans (35) via domino Knoevenagel hetero-Diels--Alder reactions by the treatment of 4-hydroxycoumarin (29) with an O-prenyl derivative of a sugar aldehyde (34) in the presence of sodium acetate in acetic acid at 80 °C. This reaction is a highly stereoselective and proceeds via a tandem Knoevenagel and hetero-Diels—Alder pathway to afford product (35) in 82% yield (Scheme 12).
o}IC
ciiT AcCO U 0
29 3q 35 II
Scheme 12
1.2.4. Synthesis of aminoalkyhnaphthols
Multicomponent one-pot synthesis of aminoalkylnaphthols (36) and (37) is achieved by the reaction of (29). aromatic aldehydes and secondary amine (morpholine and dimethylamine respectively) in dichloromethane under catalyst-free conditions at room temperature. ' The reaction completes in 2 hrs and gives product in excellent yield
(Scheme 13).
10
Oil
O O 29 x CH() dl,cl_ furring, rt
H,C` N "CH, C) -.11 t)H
oil N I \ \ I \
037
30 x ci,
Scheme 13
1.2.5. Synthesis of diliydropyrano/clehrofnrenes
The reaction of (29), aromatic aldehydes (38) and malononitrile (25) in the presence of
magnetic nano-organocatatyst in water under reflux condition17 affords
dihydropyrano[c]chromenes derivatives (39) (Scheme 14).
Off
Ar Arc HO - 11,C o,reitux Catalyst O~O 0 0 29 38 '-S 39 N N~ Ar = C~15, 3-NO,C6Hy, 3-OMec6Ha, 5 '
Scheme 14 1.2.6. Synthesis of tctrahyydrobenzoIcixanthenedione
Xiao-Jun Sun et al'8 reported the one-pot condensation of 4-hydroxycoumarin (29), aromatic aldehydes (40), 5,5-dimethylcyclohexane-1,3-dione (41) and acetic acid in the presence of catalytic amount of iodine under microwave irradiation to give series of tetrahydrobenzo[c]xanthcne-1,1 1-dione derivatives (42) (Scheme 15).
ON CHO 0
I,! HOJ ~ mac O R 29 40 41 R— H. 2-Cl.4-C L 4-CII3.4-OCII .4-NO,. 4-OH
Scheme 15
1.2.7. Reaction of 4-Hydroxycoumarin with arylglyoxals
N. N. Kolos' reported one-pot condensation of4-hydroxycoumarin (29) with arylglyoxals
(43) and areas (44) to affords 4-aryl-5-(4-hydroxy-2-oxo-2H-clu•omcn-3-yl)-1H-imidazol-
2(3II)-ones (45) (Scheme 16).
Ar OH N 011 I~O O O LtOlI AcOH \ N\ / R, R,IIN MMIR , Ar O O
29 43 43 45
R , = R, = 1 I, :\r = Ph, a \fkC~l 14: 4-CICbl 14, 4-BrCbf i4, 4-IC'r,I 14 R, = Ph - II: Ar= Ph. 4-McC6I14: 4-CIC,H4, 4-BrC6H4.4-lCH4 R i = R,— Me: Ar = Ph: 4-Mfe('H4: 4-CIC,H4, 4-BrC,H4. 4-IC Fl,
Scheme 16
12 1.2.8. Synthesis of benzopyranopyrinridines via Biginelli reaction
Kid\ ai et a12`' reported an environmentally benign method fbr the synthesis of benzopyranopyrimidines (48) via Biginelli reaction of 4-hydroxycoumarin (29), different aldehydes (46) and urea or thiourea (47) under microwave irradiation in excellent yields
(Scheme 17). \IW EIIIlI::::IIIIII1:::J:::j___R 1G 17 29 OH HV AH R = Ph. 1,3-2f (henzodioxol-5-yl, 3-iudolyl, 2-uhloroquinuhn-3-yl y '
X O.S
48
Scheme 17
1.2.9. Synthesis o f
A facile, one pot solvent- free condensation of 4-hydroxycoumarin (29) with active
methylene esters (49) in refluxing pyridine give novel benzopyran derivatives (50). The
reaction completed in I h and the product obtained in 88 % yield (Scheme 18).21
OH
\ \ I ridme l 10 mol `ol • (O( IlCOOMe) --- r~ rusefl U()~ 49 5p
Scheme 18
1.2.10. Synthesis of novel benzylarnino counrarin derivatives via Mannich type reaction
Synthesis of benzylamino coumarin derivatives were reported by different researchers"
under different conditions via Mannich type reaction. Rao et al reported a convenient and
13 practical method for the synthesis of u-benzylamino coumarin (53) in the presence of InCl3 by the reaction of 4-hydroxycoutnarin (29), secondary amine (51) and aromatic aldehyde
(52) in good yields. Kumar et al and Ghosh et ul.22 developed multicomponent green synthesis of benzylamino coumarin in the presence of non-ionic surfactant (Triton X- 100) and nano crystalline ZnO via a Mannich type reaction in aqueous media at room temperature (Scheme 19).
fl
OH CIHU OH X
Toluene. rt
c> 53 U R 2 ) 51 52 R
Scheme 19
1.2.11. Synthesis of spire 2-nuttitto-3-cyanopyrano/3,2-cf chromette
three component reaction employing 4-hydroxycoumarin (29), cyclic aliphatic ketones
(55) and malononitrile (25) in boiling ethanol in the presence of morpholine (54) was reported by Yogesli T. Naliapara et al`' to affiord Spiro 2-amino-3-cyanopyrano[3,2- c]chromene derivatives (6(1). Initially, Knoevenagel reaction between cyclic ketones (55)
and malononitrile (25) produces the unsaturated nitrile (56) which is followed by Michael
reaction \ itli the base derived coumarin anion (57). The resulting Michael adduct (58)
undergoes intramolecular cyclization producing the annelated iminopyran (59) which,
undergoes a subsequent tautomeric [1,3]sigmatropic shift gives compound (60) (Scheme
20). NFL,
C A CN OIl
5 NCCN Morpholine I / 0 ~~ q (.V ) (;o NH
~I t I RCN CN
NH, CN
/ O 0 6))
Scheme 20
It was found that with the substituted acetophenones (61), unsaturated nitriles (62) were
Obtained rather than chromene derivatives (63) (Scheme 21).
—R
G3
Scheme 21
15 REFERENCES
1. Siddiqui, Z. N.; Musthafa, T. N. M. Ahmad, A.; Khan, A. U. Archie der
Pharmazie, 2011, 344, 394.
2. Vukovic, N. Sukdolak, S.; Solujic, S.; Niciforovic. N. Arch. Pharm. Res. 2010, 33,
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3. Ghate, M.; Kusanur, R. A.; Kulkarni, M. V. Eur, J Med. Chem. 2005, 40, 882.
4. Jain, M.; Surin. W. R.; Misra, A.; Prakash, P.; Singh, V.; Khanna, V.; Kumar,
S.; Siddiqui, H. H.; Raj, K.; Barthwal. M. K.; Dikshit, M. Chem. Biol. Drug
Des. 2012 doi: 10.1111/j.1747-0285.2012.12000.x.
S. Kirkiacharian, S.; Thuy, D. T.: Sicslc, S.; Bakhchianion, K.; Kurklian. R.;
Tonnaire, T. 11 Farmaco 2002, 57, 703.
6. Marchenko, M. M.; Kopyl'chuk, G. P.; Shmarakov, 1. A; Ketsa, 0. V.; Kushnir, V.
N. Pharm. Chem. J. 2006, 40, 296.
7. Massimo, C.; Francesco. E.; Federica, M.; Carla, M. M.; Prieto. G. S.; Carlos, R. J
Aust, J Chem, 2003, 56. 59.
8. Wang, C. J.; Hsieh, Y. J.; Chu, C. Y.; Lin, Y. L.; Tseng, T. H. Cancer Lett. 2002,
183, 163.
9. Salinas-Jazmin, N.; Fuente, M. D.; Jaimez, R.; Perez-Tapia, M.; Perez-Torres, A.;
Velasco-Velazquez, M. A.; Cancer Chem. Pharrn. 2010, 65, 931.
10. Kennedy, R. Q.; Thames, R. D.; Coumarins: Biology, Applications and Mode of
Action, John Wiley and Sons, Chichester, 1997.
II. Zabradnik, M.; The production and application offluorescent brightening agents,
Wiley, New York. 1992.
16 12. (a) Hamdi, M.; Grech, 0.; SakeI Iaricu, R.; Spezia le, V.I. Heterocycl. Chem. 1994,
31. 509.
(b) Burgart, Y. V.: Shcherbakov, K.V.; Saloutin, V. I.; Chupakhin, O.N.; Irv. Ross.
Akad. NaukSer_ Khim.2004,p.1188.
(c) Tonkina, N.: Petrova, M.; Belyakov, S.; Strakovs, A. Late. Khim. Z. 2005, 1,
51.
(d) Kolos, N.N.; Gozalishvili, L.L.; Yaremenko, F.G.; Shishkin, O.V.; Shishkina,
S.V.; Konovalova. J.S. In'. Ross. Akad Nauk. Ser, Khim. 2007, p. 2200.
13. Prakash. 0.; Wadhwa, D.; Hussain, K.; Kumar, R. Synth. Commun. 2012, 42, 2947.
14. Luo, Y.; Wu, J. Tetrahedron 2009, 65, 6810.
15. Yadav, J. S.; Reddy, B. V. S.; Narsinthaswarry, D.; Naga Laksluni, P.; Narsimulu,
K.; Srinivasulub, G.; Kunwar. A. C. Tetrahedron Lett. 2004. 45, 3493.
16. Mukhopadhyay, C.; Rana, S.; Butcher, R. J. Synth. Commun. 2012, 42, 3077.
17. Khoobi, M.; Ma` mania, L.; Rezazadeh, F.; Zareieb, Z.; Foroumadia, A.;
Ramazanib, A.; Shafee. A. I. Mat. Catal. A: Chemical 2012, 359, 74.
18. Sun, X. I.; Zhou, J. F.; Zhi, S. J. Synth. Commun. 2012, 42, 1987.
19. Kolos, N. N. Gozalishvili, L. L.; Sivokon, E. N.; Knyazeva. I. V. Ru.r.s. J Org.
Chem. 2009, 45. 119.
20. Kidwai, M.; Saxena. S.; Mohan, R. Russ. J Org- Chern. 2006, 42, 52,
21. Sirisha, P.; Pednekar, S.; Kapdi, A. R.; Naik, M. J Chem. Sci. 2011, 123, 667.
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(b) Kumar, A.; Gupta, M. K.; Kumar, M. Tetrahedron Lett. 2011, 52, 4521.
17 23. Pansuriya, A. M.; Savant, M. M.; Bhuva, C. V.; Singh, J.; Naliapara, Y. T. Arkivoc
2009. 12, 254.
1.3. 3-Forrnvlchronione
64
Chromones constitute an important class of oxygen heterocycles and are widely distributed in plant lire, mostly as pigments in plant leaves, flowers, fruits, vegetables, nuts, seeds and
barks.1-3 They are an integral part of the human diet and have been reported to exhibit a wide range of biological activvitics.4 ' Chromone is also part of pharmacophores of a large
number of molecules of medicinal significance'`'" including anticancer agents such as
psorospermin and pluramycin A.
Chemistry of 3-formylchromone is arguably one of the most extensive and dynamic field
of present-day chromone research. Since 1973 when first report on the synthesis of 3
lonnvlchromonc was reported by the reaction of 2-hydroxyacetophenone under Vilsmeier
Haack conditions (DMF-POCI3)15 it became a universal method and the potential of this
compound in the construction of fused heterocyclic systems has attracted the attention of
chemists world-wide. Thus, this part of the chapter covers the synthetic exploitation of
nuelcophilic addition. cvcloaddition and other important reactions of 3-forniylchromone of
the last ten years.
18
1.3.1. Synthesis of pyrazoles
Trond Llven et ally' reported the synthesis of pyrazole derivatives (66) by base-catalyzed
condensation of 3-formylchromone (64) with arylhydrazines (65) in ethanolic KOH under
microwave in-adiation. Further, alkylation of (66) with ethyl bromoacetate followed by
alkaline hydrolysis with lithium hydroxide gave (2-(1 H-pyrazol-4-
ylcarbonyl)phenoxy)acetic acids (68) as selective orally active CRTH2 antagonists for
allergic inflammation treatment (Scheme 22).
CHO / I AOH• EtO \ y BrCIf1COOEt \ f UH '~ Acetone ~ 0 N~
64 65 Et000 67
LiOH "I"HP, %cater
N 0 N~ ff
L-1 WC 68
Scheme 22
1.3.2. Reaction with binucleophiles
An unexpected dithiazole derivative (71) in good yield has been reported by the reaction of
3-formvlchromone (64) with 2-phenyl-4-dimethylatnino-l-thia-3-azabuta-1,3-diene (69)
and thiobenzamide (70) as 1,3-NCS-binucleophiles in a sealed tube using toluene (5 mL)
as the solvent at 120 °C (Scheme 23).17
19
CH, N 5 \N I'h)LN}l,
S Ph 70 6) ir E1IIIIO 71
Scheme 23
1.3.3. Synthesis of 4-(2-hydroxybenzoy1)pyrro1es
A novel synthesis of 4-(2-hydroxybenzoyl)pyrroles (73) is reported by the reaction of chromone-3-carboxaldehyde (64) and tosylmethylisocyanide (TOSMIC) (72) in the
presence of DBU in THE at room temperature (Scheme 24).18
~ o j Cos II,C TIIP
/ CI 10 III anh}'drous DBU CQ
1)4
Tos 73
Scheme 24
20 1.3.4. Slvtthe.~is of' :'s'ove! Chromone-Containing Peptidontitnetics
Teimouri et al l`s developed an efficient and practical method for the diversity-oriented s,,lltlicsis of tripcptide chromone derivatives (77) via pseudo-five-component reaction between 3-fonnylchromone (64), meldrum acid (74), isocyanides (75) and primary aromatic amines (76) in dry CH2C12 at room temperature (Scheme 25).
C} C}\HR CHO Oc CH,CI, \ CONHAr RNC - 2 ArNI1, R 1 CONHAr ,S O (A 7a 76 77
C1{;
\ O O H;C' CH, Cli;
VNI I. lndcne.; -t Itiidure, r.- itruanlin. o-WWrQgniline
Scheme 25
The reaction may be rationalized by initial formation of conjugated electron-deficient
heterodlene, by Knoevenagel condensation of the 3-formylchromonc (64) and meldrum
acid (74), followed by [1-4} cycloaddition reaction with isocyanides to afford intermediate
(78) which reacts with arylaininc followed by subsequent loss of acetone to give
iminolactone (80). Finally. nucleophilic attack of the second molecule of arylamine to the
activated carbonyl moiety of (80), yields final product (77) (Scheme 26).
21 O O CHO OO \ \ O
~I ti 0 -O"O / O O O~ RNC 64 79
k R I N~ 0 O N C) \ / O ArNH2 ArNH2
Me_CO
80 Ar 78
Scheme 26
1.3.5. Synthesis of Pyranodhroinene.s• and Pyruuothiazines
Reaction of 3-fonnylchromone with 1,3-thiazines was reported by R. V. Shutov et al.2°
Reaction of (64) with 2-phenyl-4-hydroxy-6H-1,3-thiazin-6-one (81) in THE in the presence of pyridine as a catalyst at 60 °C leads to formation of a mixture of novel N- thiobenzovl-5-hydroxy-2-oxo-2H,5H-pvrano[3.2-c]-chromen-2-one-3-carboxamide (82),
5-(4-oxo-4H-chromcn-3-yl)-2-phenyl-5,6-dihydro-4H,7H-pyrano[2,3-d}[ 1,33thiazine-4,7- dione (83) and (2E)-3-(4-oxo-4H-chroinen-3-yl)prop-2-enoic acid (89) (Scheme 27).
o ull O H hI~ n O
off u1
64 Ph 81 82 8329°o) o n
89 lI4 )
Scheme 27
Because of the presence of two electrophilic sites on the chromone i.e. C-2 and CHO different types of products were formed. Initially, attack of the thiazine (81) at C-2 of the
22 chromone (64) results in the pyran ring-opening via 1,4-addition give intermediate (84) followed by the formation of (85) with further ring closure by way of the free formyl group. Addition of a water molecule allows enolization of the C-4 keto group to give (86) and subsequent cleavage of the thiazine ring form products (82). Alternatively, attack at the aldehyde group follows a Knoevenagel type reaction leading to ylidenothiazine
(intermediate 87), which combines with a second molecule of (81) to form bis(thiazine- 5- yl)methane (88). Subsequent intramolecular cyclization and hydrolysis leads to
pyranothiazinc (83). Fonnation of by product (89) occurs by direct hydrolysis of (87)
(Scheme 28).
lI7 O (1 U11 U H
CHO H.0 _ N 00H
O~ OSPh O> 0 SPh OH ' N 81 64 81 84 oS Ph
-PhCS~H
Ir, st
Pn 0 j 0 0 0 / Oil
OH
8S fl_V IMi V o S FM, 83 S ~11 V CO - PhG~H. O / OH OH O
OH N OH u O 0 S Ph 83 0 O S
Ph O I il~
II O H
82
Scheme 28
23 1.3.6. Diels Alder Reaction
Perumal et al'' reported an aza Dicls—Alder reaction of 3-fonrsylcluomone (64), amines
(90) and (91) for the synthesis of tetrahydroquinoline derivatives (92) mediated by CAN in an aqueous medium at room temperature stirring for 35-45 min which oxidized to the corresponding substituted quinolines (93) by reaction with 2.5 equiv of CAN in acetonitrile at 0 °C under \, atmosphere for 20 min (Scheme 29).
R
/ CFfO N O If._O, aqueous CHCN O R RT stirring 64 90 91 (R — II, Me, OMrj
2.5 eq. CAN; N, 92 O °C CI I,C`
R
193 / fR=H.Me) O
Scheme 29
1.3.7. Synthesis of hydrovymethyl chromone
Reduction of 3-formylchromone (64) in 2-propanol in the presence of basic alumina at 75
°C was reported byAraya-\taturana et a122 to obtained 3-hydroxymethyl chromone (94) in
good yield (61 `Yo) (Scheme 30).
24
~ o 0
Basico a o O _ -rr pun i CHO
O O OH 64 94
Scheme 30
1.3.8. Synthesis of hydroxymnethylphosphontate
Shin-are and co-workers23 reported the synthesis of dialkyl-l-chromonyl-1
hydroxyrnethylphosphonate (95) via Abramov reaction of 3-fonnyl chromone (64) and
trialkylphosphite using TM Sc! under solvent-free microwave irradiation. The compound
(95) was obtained in good yield within 5-6 min (Scheme 31).
t) o iROiiI' . TMSCI I MW, 150 `CC I (I~ Cl10 OR ,- IIlIIIII
0) 0 OH 64 95
Scheme 31
1.3.9. Synthesis of 3-cyanochromones
An efficient one step conversion of 3-formylchromone (64) into 3-cyanochromone (96)
was reported by Reddy et a!24 on heating (64) with hydroxylamine hydrochloride
(H,NOH.HC1) in refluxing acetonitrile in the presence of sodium iodide for 2 hrs (Scheme
32).
~.. o 0 H,\OILH('I i i —mss Acetovinle CHO Nal CN
O 0 NOII 0 64 96
Scheme 32
25
1.3.10. Sl•nthesis of hydantoin derivatives
Youssef' Lotfy Al? reported the condensation of 3-formylchromonc (64) with hydantoin
(97) and 2-thiohydantoin (98) in acetic acid at reflux temperature in the presence of fused
sodium acetate to afforded 5-chromonylidene-hydantoin and 2-thiohydantoin derivatives
(99) and (100). Compound (100) undergoes Mannich reaction with formaldehyde and
morpholine in methanol to give Mannich product (101) (Scheme 33).
HX \H u
L \H \ U
99 CHU //
U NR ` 'NR 64 lul
S 98
~ ~R=
0 IOU 0 5_S5 col R' R= = H. = CH,: R= = CZHS, HCHU R'=CHR'-Cr,Hy CO) fa011
O ti \R~
0 101 R' = If
Scheme 33
26 1.3.11. Reactions with nucleophiles
Knoevenagel reaction of 4-oxo-4H-benzopyran- 3-carbaldehyde (64) with 3-methyl-l- phenyl-1H-pyrazol- -(4H)-one (102) was reported by Shingare et a126 in solid-state by grinding without solvent at room temperature. Reaction was completed within 2 min and product (103) was obtained in excellent yield (83 %) (Scheme 34).
0 Ph 0 / Grinding N
/ Clio I C /N 11 i~ CH1 O CHi (4 102 103 (83°Q)
Scheme 34
They also reported the reaction of 3-formyl chromone (64) with meldrum acid (74) under
microwave irradiation in the presence of acidic alumina27 or under grinding condition
catalyzed by cellulose sulphuric acid28 to afford the product (104) in excellent yield
(Scheme 35).
o 0 0 0 CH() Cellulose sulphuric acid O ` / I Grinding
n Acidic alumina W '+ MW 104
Scheme 35
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28
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30 1.4. 5-Chloro-3-methy 1-1-phenyl-1H-pyyrazol-4-carboxaldehyde
(105) Pyrazole derivatives are important nitrogen containing heterocyclic compounds and have
attracted continued interest over the years due to use of this ring system as an important
core structure in many drug substances, having a wide range of applications in
pharmaceutical industry (e.g. Viagra,l Celebrex) as well as in the agrochemical field (e.g.
Tebufenp)rad insecticide3).4 In recent years, 4-substituted pyrazole derivatives have been
reported to show broad spectrum of biological activities such as herbicidal, antibacterial,6
antioxidant, antiviral.' anti-HIV," anti-inflammatory and neuroprotcctive10 etc. In this
regard 5-chloro-3-methyl- l-phenyl- I H-pyrazol-4-carboxaldehyde has been proved as a
valuable synthon due to the presence of a halogen and aldehydic function in an ortho-
relationship for the synthesis of various heterocyclic compounds. This part of the chapter
describes the synthesis, reactions and biological applications of -chloro-3-methyl-l-
phenyl-IH-pyrazol-4-carboxaldehyde from 2002 to the end of 2012.
1.4.1. Nucleophilic substitution reactions with phenol and 2-itap/tthol
Balakrishna Kalluraya and co-workers'' reported the nucleophilic substitution
reaction of (105) with phenol (106a) and 2-naphthol (106b) in DMSO in the presence
of potassium hydroxide at 60 °C to give substituted product (107) which undergoes
Claisen-Schmidt condensation to give 1-substituted aryl-3-(5-aryloxy-3-methyl-1-
31
phenyl-1 H-pyrazol-4-yl)-2-propen- l -one (108). Further treatment of (108) with
hydrazine hydrate in aceticipropionic acid at reflux temperature gave the 1-
acetyl,rpropyl-3-aryl-5-(5-aryloxy-3-methyl-] -phenyl-1 H-pyrazol-4-yl)-2-pyrazolines
(109) (Scheme 36).
H;(' CHO K H C ? Ck10 Cih H f: OH. D\4S( \ i ` + Ar—Ukl Ar .~ LtOl UO °C N CI Ph 1'h Ph 107 105 (U6(a-h) 108 :fir = Ph, 3-naphtha l R'COOH i112N1l2.11,0
O
K i~ N—N 1 I =( \ ~/
N Ar ~N O~
K=11,CH 3,CI Ph 109 R= CII3. CH2CII3
Scheme 36
1.4.2. Synthesis of'thiazolopyrimidine derivative
The aldehyde (105) condenses with 2-amino-4-(3-coumarinyl)thiazole (110) in the
presence of triethylarnine in DMF at reflux temperature for 48 hrs to afford 12 thiazolopyrimidine derivative (111). Compound (110) was obtained in good yield
via Biginelli reaction of 3-acetylcoumarin (112) with thiourea and iodine (Scheme 37).
32
S \H: S V OII H;C CHO Y 4 Y 113
N O O o U Vh 110 Ph I11 (75 %) 105
1, H,NNH, 0
UU
112
Scheme 37
1.4.3. Synthesis of lleterou►u►ulated pyrido f l,?-bJf l,2,4/triazepine
Magdy Ahmed Ibrahim et al l3 reported the synthesis of heteroannulated pyrido[1,2-
b][l 2.4]triazepine (114) by the reaction of (105) with 1,6-diamninopyridone (113) in
reflux ethanol containing few drops of acetic acid for 6 hrs. The synthesized compound
was screened for their antimicrobial activity (Scheme 38).
O N CH3 H,C CHO
`I NC \II, c) IIJ Ph 1'Vt 1(15
/ C\
113
Scheme 38
33 1.4.4. Synthesis of pyrimido thiazolo yuinoxaline b1.A. Gouda et al l ` synthesized pyrimido[2',1':2,3]thiazolo[4,5-b]quinoxaline derivative
(116) by the condensation of (105) with 2-aminopyrimido[2',1':2,3]thiazolo[4,5-b] quinoxaline-4-one (115) in glacial acetic acid. Reaction occurs at reflux temperature for 20 h and the compound (116) was obtained in 76 % yield (Scheme 39). Compound 115 was obtained by refluxing a mixture of 2,3-dichloroquinoxaline (A) and 6-aminothiouracil (B) in DMF in the presence of catalytic amount of triethylamine.
0 0 Clio N \ \ Aao°C NII Ci N ~ H_N ti S V CI N Ph I its li) (A) 105 Reilu41CHjc(0OR
N NSN
nc ,.
Scheme 39
1.4.4. Si'jithesis of heterocyclic analogues ofxannthofie and xt1nthiOile
Synthesis of lll-pyrano[2.3-c:6,5-c]dipyrazol-4(71-1)-ones (121a) and thiones (121b) were
described by Barbara Datter and Wolfgang Holzer et al.1 ' Oxidation of 5-chloropyrazole-
4-carbaldehyde (105) with potassium permanganate furnished (117). Transformation of
acid (117) with thionyl chloride in refluxing toluene afforded acid chloride (118). Reaction
of (118) with I -substituted 2-pyrazolin-5-ones (119) in the presence of calcium hydroxide
in refluxing 1,4-dioxane gave the corresponding 4-pyrazoloylpyrazol-5-ols (120), which
34
were cyclized into ift-pyrano[2,3-c:6,5-c]dipyrazol-4(7H)-ones (121 a) by treatment with
K-)CO3 DMF. Compound (121a) was converted into the corresponding thiones (121b)
upon reaction with Lawesson's reagent (Scheme 40).
H c II_c o R' 0110 coolI H;C K`1U: C N N \ 1 I U ti CI w l•1 Tolurnc \ N N Cl ki Ca(OII), Ph Pi, Dioxane Ph 1115 117 us 119
U cl{
a'.we son's reagent / \ K_(•U,
O \\ N O N OH CI Ph R: 121b Ph Ki Ph K 121a 120 R'= Ph. Me R==H,Me
Scheme 40
1.4.5. Sj,nthesis gf'dihydropyritdnes
Direct Hantzsch reaction of (105) with N-phenyl oxobutanamide (122) in the presence of
ammonia in methanol-DMF under reflux condition for 7-10 hrs afforded dihydropyridine
derivatives (123)1 `' (Scheme 41).
HN—N 1I;C CHO C~ k 1 OCZI) /
\1 II II R / y C R 2
Ph R I CH; I lN l Cl13 105 122 123 (53-75 %) R 3-Cl13, 3-NO,, 3-Cl, 4-Cl, 4-OCI-13, 4-NO,, 2-F. 4-F
Scheme 41
35
1.4.6. Synthesis of Schiff buses
Knoevenagel condensation of (105) with ethylcyanoacetate at 0 °C results in the
formation of ethyl-2-cyano-3-(5-chloro-3-methyl-l-phenyl-1H-pyrazole-4-yl)propionate,
followed by the reaction with hydrazine hydrate at room temperature to give 5-amino-4-
[(5-chloro- 3-methyl- I -phenyl- I H-pyrazol-4-yl)methylidine]-2,4-dihydro-31-l-pyrazo1-3-
one (124). Further treatment of (124) with substituted benzldehyde (125) in the presence of
a catalytic amount of acetic acid in ethanol at room temperature affords (126) (Scheme
42),1-
H;C CHO U II,C 0 (HO
r i) U^CH; 0 °C V / /NH
~N CI 0 ! hll\f l- fLU. K'f ti ~ R Cl II_N Nh I hl 125 124 10. AcOl I, GtOi I KT
N I J N NH CI U 1'h 126 (76-99) % R = I-I, 4-C113. 4-OC113. 4011, 4-NO,, 4-F, 4-Br, 3-NO,, 3- Hr. 4-Cl. 3,4-0C113. 3,4-CI Scheme 42
1.4.7. Synthesis of dihydropyrirnidin-2(IH)-one via Biginelli reaction
Synthesis of dihydropyrimidin-2(1H)-one derivatives (128) was achieved by the reaction
of (105) with 13-keto ester or 13-diketone (127) and urea (or substituted urea) (47) in the
presence of CuCl2iacetic acid, BF3.(OEt)2, in dry THE at reflux temperature in good yields
(50-71 %) (Scheme 43).1 s'
36 Ph / N—N CIIO
CI HzC IR II,N/\NI-IR' AcO1l,Tl[F.Ret1ux~
Ph
05 I 27 `-
128 R' (50-71 0/) R = OEt, OMc, Me It'= II, Mc, I'h
Scheme 43
1.4.8. Synthesis of pyrazolylquinolines
A series of 4-pyrazolyl-N-arylquinoline-2,5-diones (130) has been synthesized by one pot
cyclocondensation reaction of (105), meldrum acid (74) and 3-arylamino-5,5-disubstituted
cyclohex-2-enones (129) in the presence of piperidine as basic catalyst in ethanol for 6 hl`)
(Scheme 44).
Phi —N
FIt( \,___./ctlo Piperidine
Ph 129 R, 105 -4 R F,
R °H. Me
R (58.68 %) 130 Scheme 44
1.4.9. Synthesis o f pyruzolopyrones
A novel synthesis of pyrazolopyrones (133a), (133b) was achieved via Simonis
condensation employing 105 and triacetic acid lactone (131) /4-hydroxycoumarin (132) in
the presence of anhydrous sodium acetate in refluxing ethanol`° (Scheme 45).
37
Ph I33b (-1 i 0l Scheme 45
They also reported the synthesis of pyrazolyl chalcones (135) and pyrazolines (136) from
(105) and different heterocyclic active methyl compounds (134) (Scheme 46).
C 0 H' \ CHU 11---- i + 0 .IdNI, Reflux. Pipendmne
N CI Q C H, and N.. 1 Thermal solvent-tree NCI Ph Ph 134 105 135
Oli RN! (NI 12, Ethanol. reflux and Ihenmd solvent-Ire.:
Q Ii>~ O O R-H.I R OH
HiC Q
O U R=H. Ph c1 'h 136 t? - OJTV~~O R-H
l' - 11. CH,
Scheme 46 REFERENCES
1. "Terrett. N. K.: Bell, A. S.; Brown, D.; Ellis, P. Bioorg. Med. Chem. Lett. 1996, 6,
1819.
2. Penning. T. D.. Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.;
Docter, S.; Graneto, M. J.; Lee, L. F.: Malecha, J. W.; Miyashiro, J. M. Rogers, R.
S.; Rogier, D. J.; Yu. S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.;
Gregory, S. A.: Koboldt. C. M.: Perkins. W. E.; Seibert, K.: Veenhuizen, A. W.:
Zhang. Y. Y.; Isakson, P. C. J. Med.. Chem. 1997, 40, 1347.
3. Marcic. D.: Exp. App!. Acarol. 2005, 36, 177.
4. Elguero, J. in Comprenhensive Heterocyclic Chemistry II, ed. I. Shinkai, Elsevier,
Oxford. 1996. Vol. 3. p. 3.
5. Yong-Hao, C.: Xiao-Mao, Z.; Ying, G. Hua-Zheng, Y. Chem. J. Chinese U. 2004,
25. 2024.
6. Akbas. E.: Berber, I.; Sener, A.; Hasanov, B. II Farmaco 2005, 60, 23.
7. Manojkumar. P.: Ravi. T. K.; Gopalakrishnan, S. Eur. J. Med. Chem. 2009, 44,
4690.
8. Popsavin, M.: Spaic, L. T.; Stankov, S.: Kapor, A.; Tomic. Z.; Velirnir Popsavin,
V. Tetrahedron, 2002, 58, 569.
9. Rostom. S. A. F.: Shalaby, M. A.; E1-Demellawy, M. A. Eur. J. Med. Chem. 2003.
38.959.
10. Youssef, A. M.: White, M. S.; Villanueva, E. B.; El- Ashmawy, I. M.; Klegeris, A.
Bioorg. & alecf. Chem. 2010, 18, 2019.
11. Girisha, K. S.: Kalluraya, B.; Padmashree. Der Pharma Chemica 2011, 3, 18.
39 12. Hamama. W. S.; Berghot, M. A.; Baz, E. A.; Gouda, M. A. Arch. Pharm. Chem.
Life Sci. 2011, 344, 710. l3. Abdel-megid, M.: Ibrahim, M. A.; Gabr, Y.; El-Gohary, N. M.; Mohamed, E. A.;
15 international conference on synthetic organic chemistry (ECSOS-15, 1 to 30
November 2011).
14. Abu-Hashem, A. A.; Gouda, M. A.: Badria, F. A.; Eur. J. Med. Chem. 2010, 45,
1976.
15. Datterl, B.; Trostner. N.; Kucharski, D.; Holzer, W. Molecules 2010, 15, 6106.
16. Solanki, M. J.; Vachharajani, P. R.; Dubal, G. G.; Shah, V. H. Int.J. Chem Tech
Res. 2011, 3, 1139.
17. Girisha. K. S.; Kalluraya, B. Synth. Commun. 2012, 42, 3097.
18. Kumar, R.: Malik, S.: Chandra, R. Organic Preparations and Procedures
International: The New]. Org. Synth. 2007, 39, 101
19. Thumar, N. J.; Patel, M. P. Saudi Pharina. J. 2011, 19, 75.
20. Siddiqui. Z.N.; Asad. M. Indian J. Chem. 2009, 48, 1613.
40 1.5. 3-Formylindole
CHO
H
137
In the family of heterocyclic compounds, nitrogen containing heterocycles are important from medicinal chemistry point of view and also have contributed to the society from biological and industrial points and thus which helped to understand life processes.[
Among various nitrogen heterocycles, indole nucleus is one of the most ubiquitous scaffolds found in natural products, pharmaceuticals, functional materials, and agrochemicals `-1 Indole derivatives that occur in nature have occupied a unique place in the chemistry because of its varied biodynamic properties such as antimicrobial,' antidepressant,6 antihistamine.7 antidiabetic,8 anti-inflammatory,9 anthelmintic,10 antiallergic,1I cardiovascular 2 and also play a vital role in the immune system.i3 The important known bioactive alkaloids having indole moiety include uleine, aspidospermidine, ibophyllidine, brevicolline which exhibit remarkable biological activities.14 An indole core is also central component of many drugs like Sumatriptan,
Ondansetron which are used in the treatment of migraine, suppression of the nausea and
vomiting, caused by cancer chemotherapy and radiotherapy," Indomethacin is used for
the treatment of rheumatoid arthritis and LSD with high hallucinogenic activity.'6
Therefore, the development of new strategies to synthesize indole derivatives have been
41 the focus of active research in the present days. Among the various indole derivatives 3- formyl indole is widely used as a starting material for the synthesis of biologically active compounds. A review of the literature about 3-formyl indole is described below:
1.5.1. Sv,►thesis of symmetrical and ulzvyon»•tetricaI biv(iiidolyI)alkanes
Bis(indalvl)alkanes and their derivatives constitute an important group of bioactive metabolites of terrestrial and marine origin. Various methods for the synthesis of kiis(indolyl)alkanes have been reported in the literature. Kumar et all' investigated the ternary reaction of indole-3-carboxaldehyde (137) and indoles (138) with allyl bromide in
THE-water (2: 1) in a suspension of indium metal for the synthesis of symmetrical and
unsymmetrical bis(indolyl) alkanes (139) in excellent yields (Scheme 47).
[n THE li•0 2 I) R , C. Stir 1f 1
137 138 139 R R H. CH; (89-94 )
Scheme 47
Further. In order to broaden the scope of this ternary reaction, the reactions of indole- 3-
carboxaldehyde (137) and allyl bromide with other heterocyclic enamines such as 3,5-
dimethylpyrazole (140 a). l-benzyl-2,5-dimethylpyrrole (140 b), 6-aminouracil (140 c),
pyrazole (140 d), imidazole (14() e) was carried out to provide the corresponding indolyl-
heterocyclic alkane derivatives (141 a-e) (Scheme 48).
42 140a S*A. N N~ lI 141 a
140bPh N v CHO 0 11 I 141 b ~~ far H'C' . N 3U°C. Stir }1 i1F:H2O(2: ) 0~N NH, NCHa 137 140c C1I; i ` N N H,N N0 11 CH, 141c
ii laud _ N N H H' 111V N
N {-{ 141) c Orç N H H 141 e Scheme 48
1.5.2. Synthesis of'a-usnhzophospIiiwtes by Kabachnik—Fields reaction
C. S. Reddy et al{8 reported one-pot reaction of indole-3-carboxaldehyde (137) with 2- alninobenzothiazole, 3-amino- -methylisoxazole, phenylglycine ethyl ester, or cyclohexylamine, and dimethyl-, diethyl-, or diphenyl phosphite (142) in the presence of tetra methyl guanidine (TMG) (10 mole %) as catalyst in toluene at reflux temperature to afford u-aminophosphonates (143) in high yields (Scheme 49).
43
RO II
CHO O K'U
R-Nfl TM(' I I I NnR Toluene, rel u
i\ If 137 142 143 6O-85o)
I ~
(:' (!I. C,II: C..II; Scheme 49
1.5.3. Synthesis of Indolyl chalcone and their derivati,ation
J.S. Biradar et al synthesized a novel series of indolyl pyrimidine derivatives (146) by the
direct condensation of indolyl chalcone (144) and barbituric acid (145) in acetic acid in 55-
69 °.o yield and evaluated their antioxidant and DNA cleavage activities (Scheme 50).
(I;o
f{ fl\
(~ Pipcndm.. \ 145
R I R K H.cil.lici
HK VII
O O
14G
Scheme 50
P. Venkatcsan et al20 reported the reaction of indole-3-carbaldehyde (137) with o-hydroxy
acetophenones (147) for synthesis of indolyl chalcones (148) in ethanol using piperidine as
44 a basic catalyst. Further oxidative cyclization of these 2-hydroxy chalcones (148) were carried out using different reaction conditions such as DDQ,/DMSO-I2/diphenyl disulfide to obtained the indolyl flavones (149) in varied yield. Results showed that DMSO/12 gives comparably high yield with short time among the other methods (Scheme 51).
R'
\ ('HO R' \ OH R' OH - I P,pendm0. Rhar,ol
R t II
147 148
R. R. It' = H. R= - OCH, IlD(; or R'. R. R'= H. R3=OCH} UVSo1
R. R- - OC H,. R', R' = H, Ph S-ti-Ph h
- OCI1,
:iiiiiiiJhh1i3 I /
R4 O 1.9
Scheme 51
A. Agarwal et al.21 synthesized indolyl chalcones (151) by reacting indole
(137) with different substituted acetophenones (150) by refluxing in methanol in the
presence of piperidine. These chalcones (151) were further cyclized with amidine
hydrochlorides (152) in the presence of sodium isopropoxide (153) to afford the
substituted indole derivatives (154) and evaluated their antimalarial activities (Scheme
52).
45
0
C H Yipendine, Mc011 \
tIITiX Reflux cJ R e1N II E R 151 137 NH 150 Sodium isoprL}pO tdc ~~ (153) X N 4 .IICI Ssopropanoi NH, Reflux 152 —x
i N
154 R - 4-Me, H, 4-QCH1 3.4-OCI13. 2, 5-OC11, X N-rte, CH,, Nil. 0 Scheme 52
1.5.4. S}enthesis of beW;,eHesoIfDholtydrazide
S. M. Sandhi et al.'-' reported the condensation of indole-3-carbaldehyde (137) and
sulfonvlhydrazide (155) in acetic acid to obtain the benzenesulfonohydrazide derivatives
(156) in 37-57 % yield (Scheme 53).
R
CH(r ~N HHSO_ R
H II S3? ,O:NIINI1. R - Ii, CH,
N5 156 Scheme 53
46
1.5.5. Reaction of•ittdole-3-ecn•Galdehyde rtwith 2-acetyl bett:ofut•an
\laeadv et al ' reported the reaction of 2-acetyl benzofuran (157) with (137) and
cthvlc\anuacctate (158) in refluxing n-butanol in the presence of excess of anhydrous
ammonium acetate (159) to afford 6-(henzofura21 ?-yl) I.2-dihsdro-1-(11i-Indol- -y)-2
oxopvndine- 3-carhonitrile (160) (Scheme 54).
Ncc•II:(OOC:IL; -(lI,CO)Iiwt, —.
13 ' I :' I :Ss 159
Scheme 54
1.5.6. Reaction of iudo/e- c urbuldelr}'cic' and amino pyrazoles
Indole ring, acts as a biclelectrophiles by introducing an aldehyde moiety at the C-3
position and reacts with binucleophiles such as aminopyrazoles and hydrazines. Seung
Bum Park et a1'4 reported an efficient one-step synthesis of heterobiaryl p)razolo[3.4-
h]pyridines (162) by the reaction of indole-3-carbaldehyde (137) and amlllo pyrazoles
(161) as binucleophiles in the presence of acidic catalyst in reflux methanol (Scheme 55).
/ J \1eth;u:ol.tCIIun / R III \II_
13- IGI 162
Scheme 55
47
1.5.7. Stwthe.sis of Triindolt-/ntet apes
Triindolvlmethancs were firstly synthesized by treatment of indolc-3-carboxaldehyde
(137) with two equivalents of indole in acetic acid and ethanol with unsatisfactory yields.25
In 1984, another synthetic method was developed by Mueller and co-workers,26 in which
triindolvlmethanes were prepared by treatment of 3-substituted indoles with ethyl
orthotormate in acidic media but only symmetric triindolylmethanes prepared by this
method and the yields were low. Chakrabarty and co-workers27 catalyzed this reaction in
the presence of clay under solvent-free conditions and the yield could reach 78%, but
when indole was substituted, several kinds of triindolylmethanes were formed by side
reaction. Guolin Zhang et al-' reported the synthesis of triindolylnicthanes (165) in high
yields by treating indoles (163) with indole-3-carboxaldehyde (137) in acetic acid and
acetic anhydride under N, atmosphere at room temperature and in the presence of solid
acid catalyst zeolite [SO;H]-MSU) (164) in refluxinb ethanol (Scheme 56).
Further. GU. Da-Gong and J1, Shun-June reprted an improved method for the synthesis of
symmetrical and unsymmetrical triindolylmethanes (165) using acidic ionic liquids
[hmim}HSO4; EtOH as an efficient and green catalyst system.
K1 K - 163 l3 t65 R, 11. Rte,n-liu. 1. R. H. Mc, LT _f i. L. x if t. l \icl „l i,
Scheme 56
48 1.5-8 . Reaction of 3 fornrylindole with the active htethylene compounds
M. Veakatanarayana ° reported the Knoevenavel condensation of 3-formylindole (137) and their N-methyl dcrivativcs (166) with ethyl cyanoacetate in the presence of 40 mol% of L-proline in ethanol at room temperature for 30 min resulted in the formation of (E)- ethyl 2-cyano-3-(1 H-indol-3-yl)acrylates (167) and (168) respectively. Treatment of (167) and (168) with 5 % aqueous NaOH under reflex for 30 min resulted in the formation of
(E)-3-(1H-indol-3-yl)acrylonitriles (169) and (E)-3-(1-methyl-lH-indol-3-yl)acrylonitrilcs
(170) in 84-90% yields. Each of the compounds (137), (167), and (169) could be smoothly transformed into their corresponding N-methyl derivatives (166), (168), and (170)
respectively in excellent yields by heating for I hat different temperatures with DMS in
PEG-600 as a facile and versatile reaction medium (Scheme 57).
0
HpC)LoE, D H 'Ci1D ~ UG CN ci Nii(1H L.pmLUU ~ ~ CN RT / H UT AT a Ifi9 H 169 515 P CI-'OG DMS PEGfGO ➢ ltin 5060 `C ➢M~4 PP4LW (1111 100.1]0'L D (Pln 50-c `C
Or ~ L HD C~0 LA
1 , L~%olii W—O NT H CN `90 / II
CH CH CH, 6 by 1-V
Scheme 57
49 1.5.9. Stvrthesis of 3,4-dih}?lropyri►uidinre-2(1 H)-ones via Biginelli reaction
P. B. Chaudliari et al reported synthesis of 3,4-dihydropyrimidine-2(1 H)-ones (172) in excellent yields via the Biginelli three-component condensation of 3-formylindole (137), urea. thiourea and ethyl acetoacctatc in the presence of acidic catalyst in ethanol at retlux temperature (Scheme 58).
13 \ . > I'2 Scheme 58
1.5.10. Sj•►tthesis of'4H-clu•ontene derivative
An ctiicient multicomponent synthesis of 4H-chromene derivative (173) has been reported
by the reaction of' malononitrilc (25) diinedone (41) and indole-3-carbaldehyde (137) in
water at retlux temperature in the presence of catalytic amount of tetrabutylannmonium
fluoride (TB.AF=) as a catalyst. Reaction was completed in 150 min and the product was
obtained in 70 "'0 yield (Scheme 59).32
I1 0 173 13-
Scheme 59
50 REFERENCES
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22. Sondhi, S. M.; Dinodia, M.; Kumar, A. Bioorg. Med. Chern. 2006, 14, 4657.
52
23. Magdy, I.; El-Zahar, Somania, S.; Abd El-Karim.; }iabiba. M. E. World J Chem,
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24. Lee, S.; Park, S. B.; Org. Lett. 2009, II, 5214.
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I*1 CHAPTER 2
(3-ENAMTNONES: SYNTHESIS AND ITS TRANSFORMATION TO NOVEL HETEROCYCLES EMPLOYING NaHSO4-SiO2 AS HETEROGENEOUS CATALYST UNDER SOLVENT-FREE CONDITION
(Journal of Molecular Catalysis A: Chemical 363— 364 (2012) 451— 459)
2.1. REVIEW AND LITERATURE
Chemistry of p-enaminones has been recognized as a significant field of study as they are composite of an a, n-unsaturated system with enone and enamine sub-units. As a result, these compounds have pronounced ambient character and can react both as nucleophiles and electrophiles. I An interesting feature of enaminones is that they serve as valuable starting materials for the synthesis of various heterocyclic compounds of therapeutic importance such as pyranones,z 2-isoxaaolcs,3 pyridines,4 pyrimidines,5 tetrahydropyrimidincs,° pvrazoles,7 isoquinolines,s dihydropyridines, triacylbenzcnes and naphthofurans9 etc. Thus, in spite of their importance in organic synthesis as intermediates and in pharmaceuticals, several methods for the preparation of (3-enaminones have been reported. The most common and convenient method for the synthesis of enaminones involves the direct condensation of (i- dicarbonyl compounds with amines in an aromatic solvent under reflux.10 Several catalysts have been also applied to achieve this transformation including cerric ammonium nitrate.' heteropolyacids,'2 BF3—Et20,13 ytterbium triflate,14 zirconium chloride, is alumina. montmorillonite, P205/SiO2,'' direct condensation of amines with diketones in water.1e Bi(TFA),,19 etc. Other synthetic approaches to p-enaminones include the cyclization of amino acids-0 reductive cleavage of isoxazoles; ' substitution of the
54 V~~~F~lim Lm.. Llu imidoylbenzotriazoles with trimethylsilyl (TMS) enol ethers22 and copper'aLetateffffediated aminolysis of dithioaceta1s.23 j3-Enaminones have been also synthesized by condensation of active methyl and active methylene compounds with DMF-DMA under reilux condition or by using microwave irradiation 24 These methods suffer from drawbacks such as higher temperature and longer reaction time to achieve moderate to high yields of the products.
Martins et.al. reported an efficient ionic liquid catalyzed synthesis of enaminones using
[Bmim].BF4 and [Omim].BF4 as catalysts under solvent-free conditions.2 However, ionic liquids especially imidazolium based systems containing BF4 anions are toxic in nature as they produce hazardous HF and their high cost and disposability make their utility limited2' Taking into consideration of all these limitations there is a stilt chance to develop a simpler and clean method for the synthesis of (3-enaminones at lower temperature.
In recent years the applications of catalysts to reduced toxicity systems, benign and renewable energy systems, and efficiency of reaction makes it a central focus area for green chemistry research." Among them heterogeneous catalysts have gained much importance in organic synthesis due to their inherent economic and environmental consideration. These catalysts make synthetic processes safe, clean, inexpensive as well as high yielding. A tremendous impact has sparked in various chemical transformations promoted by catalysts under heterogeneous conditions. These catalysts are advantageous over homogeneous catalysts as they are cheap, non toxic, easily available and can be easily recovered from the reaction mixture by simple filtration or precipitation through adding precipitating agents to the reaction medium, thereby making the process economically viable. Therefore, to maintain economic viability, a suitable heterogeneous system must
55 not only minimize the production of waste, but should also exhibit activities and selectivities comparable or superior to existing homogeneous routes. IV, 29,30
Literature survey reveals that silica supported sodium bisulphate (NaHSO4—SiO2) has been found to be an efficient, inexpensive, non toxic, recyclable and ecofriendly heterogeneous catalyst in various useful chemical transformations such as protection and deprotection;1 Friedlander condensation,32 Knovenagel condensation," and Biginelli reaction." It is also used in the synthesis of napthols; ' dihydropyridines,36 xanthenes" homoallylic amines, pyrazolines,J9 amides,40 yuinazolinones,41 and imidazoles.s'
2.2. PRESENT WORK
Due to increasing concern of the harmful effects of organic solvents on the environment, organic reactions that are operated under solvent-free condition have aroused the attention of organic and medicinal chemists. In recent years, the application of solvent-free reactions in organic synthesis is a widely accepted tool and it is often claimed that the best solvent is no solvent43 Researchers have demonstrated that the solvent-free organic syntheses are generally faster, cost savings, decreased energy consumption, reduced reaction times selective, higher yielding with cleaner products, environmentally benign and involve simple operational procedure as compared to the classical reaction.44
Therefore, based on the above findings, in this chapter, we describe the use of silica supported sodium bisulfate (NaHSOn—SiOz) as a mild, highly efficient, and recyclable heterogeneous catalyst for the synthesis of pyrazole and pyranyl pyridine derivatives by the reaction of p-enaminone with different hydrazines and active methylene compounds respectively under thermal solvent-free condition in excellent yields. The catalyst shows excellent activity and was recyclable up to four cycles. The structure and morphology of the catalyst was established for the first time with the help of powder XRD, scanning electron microscopy (SEM) and energy dispersion analytical X-ray (EDX).
2.3. RESULTS AND DISCUSSION
2.3.1. )Synthesis of heteroc j elic ft-enaminwnes
Initially. synthesis of hetercyclic 13-enaminones (176a-d) was investigated by condensation of hetercyclic methyl ketones (174a-d) with DMF-DMA (175) by thermal heating under solvent- and catalyst-free reaction at 70 °C for 5-10 min. The corresponding enarninones
(176a-d) were obtained in excellent yields (89-93%) (Table 1). The structure of the
isolated enaminones (176a-d) (Scheme 60) was confirmed by elemental and spectroscopic
data (I R. 'Fl NMR, 'C \MR and NIS).
Table I Synthesis of heterocyclic (i-cnaminones.
Entr\ HET Product Time (min) Yield (%)
176a J 93
176b 5 92
176c 89
176d 10 92
57
\ \, 1ltermal,Sulecm•irec
1..5 (H
V U , mC 14 ()
I IFT kIET ~ ~VCH,h H-
L-Im 1'6a-J
Scheme 60. .Si -nthesi.s of heterocyclic• /J-enanrinoncs (1 76a-d,
The IR spectrum of (176a) (Fig. 1) exhibited the broad hand for OH group at 3429 cm-1
and a sharp strong band at 1712 cm-1 for lactone carbonyl group. Another absorbtion bands
at 1609 cm along with a shoulder at 1649 cm•' was due to C=C and CO of a, 13-
unsaturated carbonyl system. The ' H N MR spectrum (Fig. 2) displayed two doublets at
6.65 and h.0D with coupling constant] = 12.3 Hz assignable to the two olelinic protons Ha
and IIb respectively. The coupling constant value indicates that the enaminones existed
predominantly in the L•--configuration (Scheme 60). The six protons of the two methyl
groups of —N(CH„), group appeared as two singlets at i'i 3.24 and 3.05. The remaining
protons of lactone moiety were present at their normal values. The °C NMR spectrum
(hg. 3) showed signal at d 155.9 for a, 13 unsaturated carbonyl group whereas olefinic
carbons C-2' and C-3' were present at 6 91.5 and 156.1 respectively. The signals for two
N-CI1: carbons were discernible at 37.6 and 45.6 respectively, whereas signals for other
carbons appeared at their appropriate positions. Further, evidence for the formation of”
(176a) was obtained by mass spectrum (Fig. 4) which showed molecular ion peak at rn/z
58 223. The spectral studies of the other compounds followed similar pattern and are given in experimental section.
2.3.2. Characterization of the catalyst
23.2a. Powder X-raydiffraction (XRD) analysis oft/re catalyst
The structure of the prepared catalyst (NaHSO4-S102) was identified by powder XRD.
X-ray patterns of the catalyst was recorded at 20 = 10-70° range (Fig 5). A broad peak centered at 20 angle in the range 18-30° confirmed the formation of amorphous silica-
NaHSO4 matrix.45
2 Sore. )
Fig 5. The powder XRD pattern q[Jresh caralysi.
59 2.3.2b. SE_ll-ED a,,altv.~is of the cutah'st
I o stud\ the surface morphology of the catalyst, SE1VI micrographs of the catalyst was employed. l'he SE\l intaL-cs of the catalyst (Fig. 6) showed an even distribution of
\al-lSO on the surface of the silica gel_ No conglomeration or layering of NaHSO4 was observed on the surface of silica gel.
1
/S A '• - 1 f M1
I ;&
Fig. 6. SL•:11 itrrcr<,c. ul the catalyst (.Va1TSO4 -SiO2) at dijferent uugnifXtrtiwns.
Further. [DX analysis tFig. 7) of the catalyst showed the presence of Na. S. 0 and Si
elements suggestin the l'brmation of expected catalytic system. The presence of C'
elements in the spectrum I. due to coating of the sample by carbons during the analysis. 0 2 4 6 8 10 12 14 16 18 Fiji Scale 295 cis Cursor D 000 hey
Fig. 7. EDX analysis of'the catalyst (NaHSO4-5i02).
The increased reactivity of NaHSO4 supported on silica material may be due to the catalyst and support interactions resulting in the changes in surface properties of reactive sites.
2.4. Synthesis of pyrazoles
The pyrazole derivatives are well known five member heterocyclic compounds found wide applications in pharmaceutical and agrochemical industry. Therefore, several methods for its synthesis have been developed in recent years, the most widespread synthetic strategies for the synthesis of pyrazoles includes the 1,3-dipolar cycloadditions of diazo compounds,46 reaction of chalcones and hydrazines,47 a four-component reaction of terminal alkynes, hydrazine, carbon monoxide and aryl iodidesd8 and the direct condensation of 1,3-diketones and hydrazines in fluoroalcohol,49 reaction ofaldehydes and diethoxy phosphoryl acetaldehyde tosylhydrazone.50 A variety of catalysts such as
H2SO4,51 polystyrene supported sulfonic acid,52 zirconium sulfophenyl phosphonates' Sc
(OTt) 3,54 Y-zcolite,55 Mg(C104)56 have been also reported in the literature.
In our initial investigations for optimization of appropriate reaction conditions, at first the synthesis of compound (178a) was selected as a model reaction. Thus, an equimolar mixture of (i-enaminone (176a) and hydrazine hydrate (177x) was heated at 70 °C under
61 solvent-free condition. The reaction proceeded very slowly and product was obtained in lower yield even after prolonged heating demonstrating the need of a catalyst. When the model reaction was performed in the presence of NaHSO4-SiO2 (1(10 mg) under solvent- free condition, product (178a) was obtained in excellent yield (94 %) within shorter time period (5 min) (Table 2).
Table 2 Synthesis of pyrazoles 178a-h.
Entry Product R Time (min) Yield (%)
1 178a H 5 94
2 1786 Ph 5 90
3 178c H 5 92
4 178d Ph 10 92
5 178e H 15 87
6 178f Ph 20 85
7 178g H 15 90
8 178h Ph 20 89
2.4.1. Effect of different supports
To establish the use of silica as the best support for NaHSO4, other supports were also
investigated (Table 3). The model reaction, thus, when carried out with NaHSO4-alumina
(acidic, basic, neutral). the TLC showed formation of product but the reaction did not
complete even after longer reaction time (entry 3,4,5). Further, when the silica gel alone
was employed in lieu of NaHSOa— Si02, no measurable product was obtained (entry 6)
while with NaHSO4 in pure form the reaction was again not successful (entry 7). Among
62
the examined supports, for Na1I504 silica gel showed the best results. Therefore, silica-
supported t aHSO4 was used as catalyst for all reactions. The increase in rate of reaction
employing NaHSO4-SiO2 may be due to increased surface area of the catalyst.
Table 3 The screening of different support on the model reaction
Entry Support Time Yield (%)
1 No catalyst 4 h 43
2 NaHSO,-SiO2 5 min 94
3 Nat 1SO4-allunina (acidic) - incomplete
4 NaHSO4-alumina (basic) - incomplete
5 NaHSO4-alumina (neutral) - incomplete
6 5i02 3.5 h trace
7 NaHSO.r 3 h 52
A plausible mechanism for the formation of 178a in the presence of NaHSO4-Si02 has
been shown in Scheme 61.
-Z Q "r : Z NaBSOa91O, " pH NH, O N—NH
RD " N(Cth IIFI ^:(Cn -HET g(LHl+ rlfv ¢O HFI
HN N Z0H TT1 -NH ~~ N—NH OH
NHfCH;I• HET HE. ~(CI1tf3 HFT I 'h N(CH3)1 H
Scheme 61
63 2.4 2. Effect of .olve,i ts
In order to established the superiority of solvent-tree reactions, the model reaction was carried out in different polar and non polar solvents such as acetic acid (CEI;COOE-l). dichloronlethane (CH,C I, ). acctonitrile (CHICN), methanol (MeOH), ethanol (EtOH) and isopropanol (Table 4). \'hell the reaction was performed in McOH. EtOH. iso-propanol lower yield of the product (178a) was obtained after longer time period (entry 3, 4. 5) whereas in Cl-I,CI, and Cl-i;CN, only trace amounts of the product was obtained (entry 6,
7). Using.; acetic acid relatively high yield of the product was obtained (entry 2) but reaction took longer time period for completion. Interestingly, when the reaction was carried out under solvent-free conditions, both the yield and reaction time Were significantly Improved (entry I).
Tahle 4 Comparative stud v of compound (178a) using solution conditions versus the
solv cnt-free method.
Entry Solvent Temperature Time Yield (%)
I Solvent-free 70 "C 5 mill 94
2 Acetic acid Reflux 7 h 76
EtOH Reblux 3 h 68
4 McOH Reilux 6 h 64
5 Isopropanol Reflux 8 h 58
6 CH,C1, Reflux 48 h 35
7 CII1,C'\ Reflux 48 h 38
64
2.4.3. Loadin, of the catalyst
In order to optimize the amount of catalyst used for the catalysis of the reaction to form
the desired product (178a) we analyzed the reaction by varying the loading amount to 40,
60. S0. 100 and 120 mg of NaHSO4-Si02. Generally, the rate of reaction and yield
increases over the amount of catalyst. It was found that the optimum amount of catalyst
turned out to be 100 im-, in order to obtain the best result. No such significant improvement
in the yield was observed on increasing the loading to 120 mg. whereas, decreasing the
amount of catalyst to 40 m- resulted in lowering of the yield (Table 5). Therefore, 100 mg
of catalyst was chosen for further studies because of satisfactory yield of the product in
reasonabl\ short time.
Table 5 Effect of catalyst loading on the synthesis of (178a).
Entry Catalyst (mu) Time (min) Yield (%)
40 45 58 2 60 35 74 i 80 10 89 4 100 5 94 5 120 5 94
2.4.4. Recycling study of 'the catalyst
We also investigated the reusability of the catalyst under solvent-free conditions using
model reaction of fi-enaminone (176a) with hydrazine hydrate (177a) in the presence of
'.oaf 1SO4-Si02 (100 m`,) (Taf)le 6). After completion of the reaction, the mixture was
cooled to room temperature, and the organic part was dissolved in ethyl acetate (10 niL).
The mixture was filtered for separation of the catalyst. The recovered catalyst was washed
65 with ethyl acetate (3x 10 mL), dried in oven at 100 °C for 3 h and used for the subsequent catalytic runs. The results (Table 6) showed that the catalyst was active up to four cycles.
Table 6 Recycling data of the catalyst for the model reaction.
Catalyst recycles Time Yield (%) I 5 min 94 11 5 min 94 [Il 5 min 94 IV 5 min 94 V 10min 89
The recyclability of the recovered catalyst after four runs was checked by powder XRD
(Fig. 8) and SEM analysis (Fig. 9). It was observed that peaks remained the same, and there was no change in the morphology of the catalyst as compared to that of the fresh catalyst.
d
10 20 30 40 50 60 2$ (degree)
Fig. 8. The powder XRD pattern of recovered ca1alusl after four runs. Fig. 9. "l ire' SE.%J image of rec o erecl catalyst after four runs.
Under these optimized reaction conditions the scope and generality of the present method was further demonstrated by reaction of different heterocyclic -enaminones (176a-d) with
various hvdrazine derivatives (177a-b) under same reaction conditions. All the reactions proceeded smoothly and the reaction was completed within 5-10 mite to afford the products (178a-h) in excellent yields (85-94%%i,) (Table 2). The structure of products 178a-
h (Scheme 62) was deduced from their elemental analysis and spectral data (IR. 11-I NMR,
1 'C-\\lR and e1S).
\alIso,SK HN—N kNII\I I. ICI Nit l l i, Solvent- lice 1-6a-d 'U ='C III. 1--
i1 ('II, Il;c . .Uu o 0
II, t Ii 1)1 (~ U 1 -6;i 1-6h 1?6c 1"6d
I?"a:K=fl
Scheme 62 Vn1iSO-;-SiO CitCtiv:etl svothe.ris of 1VrCzotes lmcler thC1•/iiQl solvent free
67 The AR spectrum of (178a) (Fig. 10) showed two broad absorption bands at 3171 cni t and
3045 cnf t due to the presence of OH, NH groups of lactone and pyrazole moieties respectively. A sharp and strong absorption hand for the lactone carbonyl group was discernible at 1696 cm '. In the 'H NMR spectrum (Fig. 11) the presence of pyrazole moiety was inferred by two doublets at 66.9! (J= 3 Hz) and a 7.89 (J= 3 Hz) for C-4', C-
3' protons respectively and a broad singlet for NH proton at a 13.36. The 13C NMR spectrum (Fig. 12) showed signal at r) 145.6, 100.6, and 130.1 for C-3'. U4'. and C-5' carbons of pyrazole moiety. The other peaks were present at their normal values and are mentioned in the experimental section. The structure of compound (178a) was further confirmed by mass spectrum (Fig. 13) which showed Mt at miz 192.
2.5. Synthesis of pyranyl pyridine derivatives
Pyridine is one of the most prevalent heterocycle being the core fragment of different natural products and pharmaceutical active agents"' The pyridine ring is also an integral part of agrochemicals,s8 preparative organic chemistry,59 and in coordination chemistry 60
In addition to classical pyridine syntheses such as the Krohnkc reaction, many new approaches have been also reported in the literature including condensation of amines and carbonyl compounds, cycloaddition reactions. multicomponcnt etc. Due to the remarkable biological activities of the pyran derivatives either in the form of substituents or as a fused component° efforts were also made to synthesize pyranyl pyridine derivatives (180a-h) employing (176a), different cycliclacyclic active methylene compounds (179a-h) and ammonium acetate in the presence of NaHSO4-SiO2 under same reaction conditions (Scheme 63).
m zN I. O11 y i o < - 011 N
II ;C O O / "C) 180c1;1=0
IRUa; R. ('l I R_ COOC',11, 0 18(1h: 1" =C1 I ; 1:,= COCII ; O11 O
C) O > I N
(179f-h)
II ;C O 0 (180f-h) 18(If; X-O Y- II 180g: \ = 0 y I8(k) 180h; \-S )'- II
Scheme 63. Reaction of (1760 with c/1fB1E'/1t active lNC'1hvlL'I1E compounds (179a-{l), cnlr1nulri!1/?1 acetate (3.00 /!/nul) and ,VaHSO,-SiO, (100 ing) ufuler solvent-free heating at
71) _:(•
All reactions proceeded ettiClentiv and the desired products were obtained in excellent yields (S 1-9 °o) in short reaction times (5-25 min) (Table 7). Table 7 Synthesis of compounds 180a-h
Entry Product Time (min) Yield (%) M.P.(°C)
)(II,CI-1;
180a E 93 129-13 1
180b 5 8S ?01-205
180c 89 >300
;0113
y 4 O1-1 N 1p U
180(1 n 0 10 84 >300 S 9 / 7 O \ 6
(A `~ O
180c Off() 15 M >300
FEB IXOf 25 89 >300
l80g IS 93 239-241
180h 20 90 >300
The structure of compounds (1K(la-h) was deduced on the basis of IR, I H NMR. '3C N\4R
and mass spectrometr.. The IR spectrum (Fig. 14) of the newly synthesized compound
(180a) exhibited characteristic abu»1ntion hands at 3065, 1717 and 1697 cm' due to the
presence of Oil, ester, and lactonc carbonyl groups respectively. 'H NMR (Fig. 15)
exhibited two doublets at () 8.85 and 8.44 for H4 and H5 proton of pyridine moiety.
Presence of ester group was in!Crrcd by quartet at o. 4.44 (J = 7.2 Hz) and triplet at O 1.42
(.1 — 6.9 Hz) ti,r OCH, and ('11; protons respectively. The ' 3C NMR spectrum (Fig. 16)
showed characteristic signals at r) 142.2 and 1 19.7 for C4 and C> carbons of pyridine
moiety respectively. Other peaks were at their normal values and discussed in the
71 experimental section. Further confirmation for the structure (180a) was provided by mass
spectrometry (Fig. 17) which showed M' at m/z 289.15 as base peak.
2.6. EXPERIMENTAL
Melting points of all synthesized compounds were taken in a Riechert Thermover
instrument and are uncorrected. I he 1R spectra (KBr) were recorded on Perkin Elmer RXI
spectrometer. 'H NMR and ''C NMR spectra were recorded on a Bruker DRX-300 and
Broker Avance II 400 spectrometer using tetramethylsilane (TMS) as an internal standard
and DMSO-db/CDCI3 as solvent. DART-MS were recorded on a JEOL-Accu TOF JMS-
TI 00LC mass spectrometer having a DART source. Elemental analyses (C, H and N) were
conducted using the Elemental vario El. III elemental analyzer and their results were
found to be in agreement with the calculated values. 5-Acetyl-barbituric acid, S-acetyl-l.3-
dimethylbarbituric acid. 3-acetyl-4-hydroxy coumarin were synthesized by reported
procedures.bb Other chemicals were of commercial grade and used without further
purification. The homogeneity of the compounds was checked by thin layer
chromatography (TLC) on glass plates coated with silica gel G254 (h. Merck) using
chloroform-methanol (3:1) mixture as mobile phase and visualized using iodine vapors. X-
ray diffraetoerams (XRD) of the catalyst were recorded in the 20 range of 10-70° with
scan rate of 4°/ min on a Rigaku Minifax X- ray diffractometer with Ni-filtered Cu Ka
radiation at a wavelength of 1.54060° A. The SEM-EDX characterization of the catalyst
was performed on a JEOL JSM-6510 scanning electron microscope equipped with energy
dispersive X-ray spectrometer operating at 20 kV. The catalyst Silica-supported sodium
hydrogen sulfate (NaTIS04-SiO2) was prepared by reported procedure.h7
72 2.6.1. General procedure for the synthesis of heteroaryl /J-enanrinones under thermal so/vent—free condition
A mixture of dehydroacetic acid/ 3-acetyl-4-hydroxycoumarin/ 5- acetylbarbituric acid i 5-acetyl-1,3-dimethylbarbituric acid (174a-d) (1.00 rumol) and DMF-DMA (175)
(1.00 mmnl) was added into a round bottom flask. The resulting mixture was heated at 70
°C in an oil bath for specified time. The progress of reaction was monitored by TLC. The reaction mixture (after being cooled to room temperature) was poured into ice cold water
(20 mL) and stirred for 5-10 min. The bright yellow solid, thus, obtained was filtered, washed with water, dried and recrystallized from ethanol to afford pure products (176a-d).
2.6.2. General procedure for the synthesis ofpyrazoles under thermal solvent-free
condition
To a mixture of (176a-d) (1.00 mmol) and hydrazine hydrate (177a) ;phenyl hydrazine
(177b) (1.00 minol), Na1SO4—Si02 (100 mg) was added. The reaction mixture was heated
at 70 °C for specified time. After completion of the reaction (checked by TLC), the
reaction mixture was cooled to room temperature and mixed thoroughly with 10 mL of
ethyl acetate. The solid inorganic material was filtered off. After separation of solid, the
solvent was evaporated under reduced pressure. The white solid, thus, obtained was
washed with water and dried. Further purification was made by recrystallization from
suitable solvents to afford pure products (178a-It).
73 2.6.3. General Procedure for the syntheses of pyranyl pyridine derivatives under solvent- free condition
lo a mixture of (3-enaminone (176a) (1.00 mmol), active methylene compounds (179a-h)
(I.00 mmol). ammonium acetate (3.00 mmol), NaHSOI-SiO? (1)0 mg) was added. The reaction mixture was heated at 70 °C over a heating mantle for specified time. After completion the reaction mixture, (monitored by TLC) the contents were cooled to room temperature and mixed thoroughly with (10 mL) or ethyl acetate. The catalyst was removed by filtration and reused. After separation of catalyst, the solvent was evaporated under reduced pressure. The resulting solid residue was washed with cold water to remove any unreacted ammonium acetate, filtered and dried to afford the crude products. The pure product (1811a-h) was obtained by recrystall ization from suitable solvents.
2.7. Spectral data of the compounds
3-[(E)-3-(N,N—dime0iylamino)acrylolyl)-l-(4-Aldroxy-6-merhyl-2-oxo-2H-1 pyran-3 yl)
(I76a)
Purified by recrystallization from ethanol.
Orange solid.
M.p- 199-202 °C.
IR (KHr) v,n„/cnit 3429 (OH), 1712 (C=O), 1649 (CO), 1609
(C=C).
H NMR (30(1 MHz, (:DCl3) O (ppm) 2.18 (s, 3H, C113).3.05 (s, 3H, N-
74 CFI), 3 24 (s. 3H, N-CH), 5.79 (s, I H. H-5),
6.65 (d, J = 12.3 Hz, 1 Ha), 8.05 (d, J = 12.3
Hz, I Hb), 18.8 (s, 1H. OH).
'(' N\IR (100 MHz., CDCi; ) <> 19.9 (C113), 37.6 (N-CH;), 45.6 (N-CH;),
91.5 (C-2'), 95.5 (C-3), 104.4 (('-5) 156.8
(C-3'), 162.5 (C-6), 164.4 (C-2), 184.3 (C-4),
185.9 (C-1').
ESI-\IS : (nr/) 223.08.
Elemental analysis for C1 i H 1 3N04 : Calculated C, 59.24; H, 5.87 N, 6.28.
Found C. 58. 95; H, 5.63, N, 6.58.
3-/( E)-3-(\,.V-ditmretht'lwrnninn)ac:ylolyl)/-1-(4-hydroxy-l-benzapyranr-2-one-3 yl)
(176b)
Purified by recrystallization from ethanol.
Li.ttht yellowy solid.
M.p. : 254-258 (dec) "C.
IR (KBr) cm-1 : 3400 (OH), 1699 (C=O), 165l(C=0), 1607
(C=C).
'H N\IR (300 MIIz. ('DCI3) v (pprn) 3.11 (s, 3H, N-CH;), 3.29 (s. 3H, N-
CH;), 6.82 (d, J = 12.3 Hz, IHa), 7.23- 8.06
(m. 4H. Ar- H), 8.16 (d, J = 12.3 Hz, l Hb).
18.8 (s. l H, OH).
''C NMR (100 MHz, CDC13) 6 (ppm) 38.0 (N-CH3), 46.0 (N-CH3), 92.1(C-
75 3), 96.6 (C-2'), 116.5, 118.6, 123.5, 125.4,
134.1, 154.0, (C-Ar), 156.9 (C-3). 161.6 (C-
2), 182.0 (C-4). 185.8 (C-I').
ESI-NIS (m/-) 259.1 1.
Elemental analysis for C 14H1 NO4 Calculated C, 64.92; H, 5.05; N, 5.40.
Found: C, 64.67; H. 5.31: N, 5.14.
3-/(E,-3-(V', :\'—diiiiethl ,laiizuzo)aciylolyl)-1-(2,1,6 pyi-iiiiitlittetrioize-3 yl) (1 76c)
Purified by recrystallization trom ethanol-DMF (8:2) mixture.
VL11Ovv solid.
X1.11. 218-222 °C.
IR (IKBr) cin 3200 (OH), 3100 (NH), 1719 (C—O), 1655
(C=O). 1611 (C=C).
(300 MHz, DMSO-d6 ): 6 = 2.97 (s, 3H, N-
CH). 3.26 (s, 31-1, N-C1-I;), 6.72 (d, J = 12.0
Hz, 8.13 (d, J = 12.0 Hz, 11-Ib), 10.48 (s, I1-1,
NH), 10. 94 (s, IH, NH).
1 'C N \ IR (100 MI-Iz. ('DCI;) ri (ppm) 37.5 (N-CH 3 ), 45.4 (N-CH ; ), 86.9
(C-5). 88.9 (C- 2'), 149.4 (C-3'). 156.2, (C-
2), 163.5 (C-4, C-6), 180.0 (C- I ' ).
ES1-MS (nz-) 225.13.
Elemental analysis for GHIt N:O4 Calculated C, 48.04: H. 4.92; N,18.67.
Found: C, 48.26; H. 5.22: N. 18.91.
76 7
3-f(E)-3-(.Y,:V-diinetlirlwnuwciylolyl)-1-(1,3-dimethyl-2,4,6 -pyrimidiizetrione-3-yl)
(1 764)
Purified by recrystallization from ethanol.
Yellow solid.
M.p : 230-232 °C.
IR (KBr) cm"' : 1690 (C=O), 1662 (C=O), 1623 (C=C).
1 H N v1R : (300 MHz, CDC13): 5= 3.05 (s, 6H, N-CH3),
3.33 (s, 6H, N-CH3), 6.96 (d, J = 12.0 Hz,
I Ha), 8.04 (d, J = 12.0 Hz, 1 Hb).
''C NMR (100 MHz. CDC1;) : 6 27.4 (N-CH3), 27.7 (N-CH3), 37.7 (N-CH3),
45.8 (N-CH3), 88.4 (C-5), 90.5 (C-2'), 151.0
(C-3'), 162.2 (C-4), 168.9 (C-6), 156.0 (C-2),
181.8 (C-1').
ESI-MS : (niiz) 253.08.
Elemental analysis for C11 H15N3O4 : Calculated C, 52.22; H, 5.97; N, 16.60.
Found: C, 52.51; H, 6.26; N, 16.29.
4-Ht-drox}y-6-iiiet/zy1-3-(2H pyrazol-3 y1) pyray:-2-oi:e (178a)
Purified by recrystallization from ethanol.
White solid.
M.h. : >300°C.
IR (KBr) cni1 : 3171 (OH), 3045 (NH), 1696 (C=O).
'H N\1R (300 MHz. D\1SO-J,) : (>2.23 (s, 3H. CH;), 6.91 (d, J= 3.0 Hz, H-
77 4'). 6.25 (s, Ill. H-5). 13.36 (s, 11-1, NI I), 7.89
(d. J= 3.0 Hz, 1-1-3').
'''C NMR (100 MI 1z, DMSO-d6) : O> 19.3 (C113). 93.1(C-3), 100.6 (C-4'). 103.5
(C-5), 130.1 ((-5'). 145.6 (C-3'), 161.6 (C-6).
161.8 (C-2), 167.8 (C-4).
ESI-MS : (m%) 192.06.
Elemental analysis for C9l IQN,03 : Calculated C, 56.30: H. 4.19; N. 14.59.
Found: C, 56.07; H, 4.43; N, 14.34.
4-Hh'droxt'-6-methyl-3-(2-PhenvI pyrazo/-3-~,1) pvran-2-one (178h)
Purified by recrystallization from ethanol.
White solid.
M.P. >300 °C.
IR (KBr) cm-' 3039 (OH), 1678 (C=O).
'II NMR (300 MI-Iz. DMSO-d(;) r) 2.19 (s, 3H, CH3), 6.03 (s, 111, H-5). 6.38
(d..1 = 2.4 Hz, H-4'). 7.31- 7.43 (m, 5H. Ar-
H), 7.68 (d, J = 2.4 Hz, 1-1-3'), 11.92 (s. 1 H,
OH).
''C NMR (100 Ml-lz. DMSO-c/6) O> (ppm) 19.4 (CH3). 92.5 (C-3), 99.6 (C-
4').109.6 (C-5), 139.6 (C-1"), 133.6 (C-5'),
123.0. 127.0, 128.8 (C-Ar), 140.4 (C-3'),
162.3 (C-6), 163.4(C-2), 167.9 (C-4).
ESI-!~1S (ni/) 268.08.
I:Iemental analysis for Ci f-11 2N,O; : Calculated C. 67.22: H, 4.51; N. 10.4.5.
78 Found: C, 66.94; H. 4.29: N. 10.19.
4-1I1'Arw.a•-3-(2H lA•ra; ol-3a'1)—beMzopt'vaff-2-onee (1.78c)
Pun tied by recrystallization from ethanol-chlorotbnn (4:lviv) mixture.
\\Iinc Solid.
N.I.P. >300 °C.
IR (K13r) cm- ' 318 (OH), 3054 (NH). 1684 (C=O).
'FT \AIR(300Vll-lz.CDCb) ô7.70 (d,.1 3.0 Hz, H-4'), 7.14- 7.57 (in.
4H, Ar-H), 8.04 (d. J= 3.0 Hz, H-3'), 10.58
(s, 1H• NH), 11.8 (s, 1 H, 011).
'C \MR (100 MHz, DMSO-i,,) (> (ppm) 94.5 (C-3), 104.1 (C-4'). 152.1,
132.6. 124.1, 123.6, 116 2, 116.1 (C-Ar).
130.0 (C-5'). 146.4 (C-3'). 160.1 (C-2),
164.1 (C-4).
ESI-\1S (,n/_-) 22$.12.
Elemental analysis for C l H,N,O; Calculated C. 63.21: H, 3.53; N, 12.28.
Found: C, 62.91: H. 3.28; N. 12.49.
1- f /yrlro. -3-(2 p/u'nl'1- ptiaazo1-3 }yl)—be»;op1'tau-2 -olte (178d)
Purified b' recrystallization From ethanol-chloroform (8:2 v;v) mixture.
Light yellow' solid.
M.p. : 260-263 "C.
IR (KBr1 em- ' : 3384 (OH), 1695 (C—Q).
I II NMR (300 v11-lz, DMSO-i,) : o6.55 (d, J= 3.0 Hz, H-4'), 7.2-7.9 (m, 9H,
Ar- H). 7.80 (d. J = 3.0 Hz, H-3').
79 ''C NMR (100 Ml-lz. DMSO-d6) O 96.1(C-3). 1 10.4 (C-4'), 115.6, 116.4,
123.2. 123.9. 124.2, 127.2, 128.8. 133.1,
152.7. (C-Ar). 133.0 (C-5'), 139.9 (C-1"),
140.1 (C-3'). 160.5 (C- 2), 163.4 (C-4).
ESI-MS (in/:) 304.12.
Elemental analysis For C1 I 11 N2O3 Calculated C, 71.11; H. 3.97; N, 9.21.
Found: C, 70.86; H, 3.74, N, 9.45.
5-(2H-pt•razol-3-y/)ntrinzidinre-2,4,6Irioee (1 78e)
Purified by recrystallization from ethanol-DNMF (8:2 v/v) mixture.
White solid.
M.p. >300°C.
IR (KBr) cm-' 3372 (01-1), 3316 (NH), 3148 (NI-1), 1719
(C=O).
' I 1 N\MMR (300 M11 , DMSO-d6) O6.65 (d, J = 33 Hz. H-4'). 7.31 (d, 1= 3.3
llz, 1-1-3'). 9.59 (s. 1H, NII), 10.38 (s, 111.
NH). 1325 (s, I H, NH).
13C NMR (100 MHz, DMSO-d) ()72.2 (C-5), 104.6 (C-4'). 135.1 (C-5'),
145.7 (C- 3'). 153.7 (C-2), 161.0 (C-4. C-6).
ESI-MS (m%:) 194.07.
Elemental analysis for C7HNO; Calculated C, 43.33: H. 3.11: N, 28.87;
Found: C, 43.04; H. 2.81; N, 28.59.
I-H 5-(2-Phenyl-pyrazol-3-9Q-pyrimidine-2,4,6 (none (178f)
Purified by recrystallization from ethanol-DMF (8:2 v/v) mixture
Yellow solid.
M.p. >300 "C.
IR (K1r) can 3189 (NH), 3018 (NH), 1716 (C=0).
'El NMR (300 MHz. DMSO-d6) 6 6.76 (d, J= 2.7 Hz, 1I-4'), 7.14 - 7.52 (m,
5H, Ar-H), 7.81(d, J 2.7 Hz, H-3'), 10.64
(s, (H, NH), 11.33 (s, IH, NH).
'3C NMR (100 MHz, DMSO-dr) ô79.8 (C-5), 104.5 (C-4'), 139.9 (C-I"). 131.
(C-5'), 117.4, 127.2, 128.1, (C-Ar), 141.2 (C-
3'), 160.5 (C-2), 164.4 (C-4, C-6).
ESI-MS m./z 270.04.
Elemental analysis for C i ~H j,N401 Calculated: C, 57.82; H, 3.73; N, 20.74.
Found: C, 57.53; H, 3.43; N, 21.12.
1,3-Dimethyl-5 -(2H pyrazol-3-y7)pyrimidine-2,4,6 trione (178g)
Purified by recrystallization from ethanol-chloroform (8:2 v/v) mixture.
White solid.
M.p. >300 °C.
IR (KBr) cm ' 3084 (NH), 1684 (C=O).
'H NMR (300 MHz, DMSO-d6) d 3.19 (s. 6H, 2 N-CH3), 7.18 (d, J= 3 Hz, H-
4'), 8.01 (d,.7=2.7 Hz, H-3'), 11.59 (s, (H,
NH)
13C NMR (100 MHz, DMSO-d6) S 26.9 (N-CI1,), 79.2 (C-5), 101.6 (C-4'),
81 132.1 (C-5'), 145.8 (C-3'), 151.7 (C-2),
161.5 (C-4, C-6'.
ESI-NIS (in') 222.13.
Elemental analysis for CHi,,N4U; Calculated C, 48.09; II. 4.54: N, 25.23.
Found: C. 48.92: 11.4.26; N. 24.91.
1,3-l)inie[/rl!-5-(2 -pllen►'I-h►'i'uzol-3-►y!) /a'Y!oodiWe-2,4,6 triune (I78h) f'uritiocl by rccrystalllzation from ethanol-chloroform (8:2 v:'v) mixture
\fhite solid.
Ni. p. >300 °C.
IR (KBr) cin-' 1697 (C=O).
1-1 \\IR (300 MI 17, 1)N1SO-d,,) O 3.07 (s, 61-1, 2 N-Cl I;), 7.81 (d. .1 = 3.0 Hz,
1-I- 4'). 7.26 — 7.81 (m, 51-1, Ar-H), 8.65 (d, .1-
3.0 Hz. H-3').
13C N\IR (100 MI Iz. I)`ISO-d,) v 27.9 (N-C1-l;), 82.6 (C-5), 105.7 (C-4'),
117.6, 118.3. 126.8, (C-Ar), 129.8 (C-5'),
141.5 (C-1"), 142.6 (C-3'), 157.8 (C-2),
160.4 (C-4, C-6).
ESI-'CIS (nl/) 298.09.
Elemental analysis for C 1;H l.,N.Oz : Calculated C, 60.45; 1-1, 4.73; N, 18.80.
Found: C, 60.25; H, 4.49; N, 18.54.
82 3-F_t/rniucurfio►itl-(--(/-Irvcruxv-6-arct!lvl-2-uxu-2H-1 pyf'un-3 yl)-2-nretlit,,I pyridine
(180a)
Purified by rerrytalHstion from ethanol.
Li,ht vet lo v solid.
\.p. 129-131 °C.
IR (KBr) ci n" : 3065 (OH), 1717 (C=0), 1697 (C=0), 1614
(C=N).
'H \NIR (300 MHz. CDC1:) J 1.42 (t, 3H, 6.9 Hz, 0CH2CH3 ), 2.22 (s,
3H, C1-1-), 2.92 (s, 3H, CH), 4.44 (q, .I = 7.2
Hz, 211, OCfi, ), 5.86 (s. 1H, 11-5'), 8.44 (d, J
= 9.3 Hz, I H, pyridine H-5), 8.85 (d, J = 9.3
I Iz, 111. pyridine 11-4).
C XMR (1(1) MHz, DMMSO-cJ,,) : O 14.2 (CHI), 20.0 (C-3"), 21.5 (CH;). 61.7
(C -2"), 91.9 (C -3'), 106.2(C-5'), 119.7 (C-5),
120.2(C-3). 1422(C-4), 151.2 (C-2). 156.19
(C-6), 163 2, (C-6'), 163.4 (C-2'), 164.4 (C-
1"), 1$2.5 (C-4').
[Si-MS : (m/:) 289.15.
Elemental analysis for C,<1INO Calculated C, 62.34; H, 5.23: N, 4.84;
Found: C. 62.22; H, 5.14, N, 4.71.
83 3-. I cett'I-6-(!-lyrfro•11-6-metlzrl-2-oxo- II-1 -pyrun-3-y1)-2-»ictlr} 1 ridi,ze (180 b)
Purified by recrystallization from ethanol-chloroform (3:2 v/v) mixture.
Light VL'llo\v solid.
N1.1i. 201-205 °C.
IR (KRr) cm- ' 3336 (011), 1695 (C=O), 1672 (C=O), 1621
(C=N).
1-I N.IR i; 30O NIIIz. CD('I:) r) 2.17 (s, 3I-I, C1-I 3), 2.69 (s, 311, CH). 2.75
(s, 31-1, COCI-I,), 5.96 (s, I H, H-5'), 8.62 (d, J
= 9.0 Hz, 1H, pyridine H-5), 8.68 (d, J = 9.3
Hz, 1 H. pyridine H-4).
C \\IR ( 100 Mllz. MISO-4l(;) O 14.3 (CH3), 20.2 (C-2•).21.7 (CH;), 92.4
(C-3'), 105.27 (C-5')• 120.0 (C-5), 121.5 (C-
3), 142.3 (C-4), 151.2 (C-2), 156.2 (C-6),
163.2 (C-6'), 163.4 (C-2'), 180.29 (C-4'),
196.76 (C-I").
(ES!-\1S) (ml) 259.12.
Elcmcatal analysis for C'141K;NO4 : Calculated C, 64.92; H, 5.05; N. 5.40:
Found: C, 64.81; H, 4.92, N, 5.28.
94 -I)inretlrvl-5-oxo-2-(d-/ndroty-6-methyl-2-oxo-2H-1 pyran-3-y1)-5,6,7,8 tetralivdr•oquinoline (I 81)c
Pusif 26 by re crystallization from eth rnol.
Light v ello%% solid.
Nip. : ==300 T.
IR KBr) cni 3088 (011), 1692 (C=0), 1616 (C-N).
'II N\iR (300 Mlllz. ('DC1;) v 1.17 (s, 6H, 2XCH3). 2.22 (s, 3H, CH,),
2.57 (s. 21-1, CH,), 3.02 (s, 2H, Cl-1,), 5.93 (s,
) H, 1-1-5'), 8.42 (d, J = 9.0 Hz, ) H, pyridine
H-3), 8.93 (d, J= 9.9 Hz, 1H, pyridine 11-4).
1 'C' NN1R (100 \)Il lz. DNISO-d';) ()20.10 (CH3), 28.2 (CH3), 30.9 (CH3), 33.2
(Cl-!;). 42.6 (C-8), 51.3 (C-6), 92.9 (C-3'),
105.7 (C-5'), 120.7 (C-3), 122.9 (C-10).
137.8 (C-4),153.2 (C-2), 157.9 (C-9), 163.0
(C-6"), 163.7 (C-2'), 182.2 (C-4'), 194.0 (C-
6).
ESI-NIS (ml) 299.16.
Elemental analysis for C: -Hi-NO4 Calculated C, 68.28; H, 5.73, N, 4.54.
Found: C. 6$.15, H, 5.61, N. 4.54.
85 -(.J-IIydI y-6aa iet{•(-2-oxa-2II-pyran-3- I)-2,2-dh;wthyi-l,3-dloxu-8-u u-quinoline_4- one (IS'Od)
Purified by rectystallization from ethanol-chloroform (4:1 viv) mixture.
Brown solid.
M.p. >300 "C'.
IR (KBr) cm-1 3283 (01-1), 1735 (C=O), 1688 (C=O), 1616
(C—N).
H \\IR (300 %11Iz. C1)(1:) O 1.61 (s, 6H, 2XCH;), 2.22 (s, 3H, CH3),
5.89 (s, IH, H-5'), 8.45 (d, J = 9.0 Hz, 1H,
pyridine H-6), 9.06 (d, J = 9.0 llz, 111,
pyridine 1-1-5).
1 C \\ I R ( 100 M 11 . 1)\ ISO-c1,) 620.1 (CHI), 27.1(CH;). 27.8 (CH). 92.9 (C-
3'), 105.7 (C-5'), 106.0 (C-2), 115.5 (C-10),
119.4 (C-6), 138.4 (C-5), 151.2 (C-7), 153.4
(('-9). 163.1 (C-6'), 163.5 (C-2'), 164.0 (C-
4), 183.2 (C-4')
ESI-\lS (,n.ih) 303.11.
1::I.mentaI analysis f or C r 4 I ::~O~, Calculated: C. 59.40: 1-1, 4.29: N, 4.60;
Found: C, 59.53; H, 4.13, N, 4.72.
86 2-(1-1{t'1ruxt -G-nretht'! Z-uxo-21I-1-pti run-3 y!)-p}'rldu/2,3-G/-ctiruncuri- -uiie (180ee)
Purified bv- recrvstallization from ethanol-DMF (8:2 v/') mixture.
White solid.
Nip. : >300'C'.
IR (KBr) cm1 3445 (OH), 3085 (OH), 1707 (C=O), 1670
((=0), 1612 (C=N).
11 NAIR (300 v1Hz. CDCI:) : ri 2.22 (s, 3H, CH;), 5.94 (s, 1H, H-5'), 7.41-
8.10 (m, 4H, Ar-H), 8.57 (d, J = 9.6 Hz, 1H,
pyridine H-3), 8.92 (d, J = 9.0 Hz, 1H,
pyridine 11-4).
'C N\IR (100 MHz. 1)\iSO-d,,) ri 19.4 (CH3), 94.9 (C-3'). 105.9 (C-5'). 1 18.4
(C-4a), 117.8 (C-6), 120.1 (C-3), 127.5 (C-
Sa), 129.8 (C-7), 137.7 (C-8), 138.7 (C-9),
139.9 (C-4), 152.5 (C-1), 154.4 (C-9a). 162.1
(C-2'), 162.7 (C-lOa), 164.5 (C-6'),172.7 (C'-
5). 180.2 (C-4')
F:SI-\IS : (rni_) 321.30.
1lemcntal analysis for 01 ,111 i N0 : Calculated C, 67.35; 1-1, 3.45. N; 4.35.
Found: C, 67.20; H, 3.56, N. 4.48.
87 -(I-)Idray►-6-nrct1t►'1-2-o.vo-3H-1 pl'run-3 .rl)-I 1I,31I p vrido/2,3-dJpt-rinriditte-2,4- dione (180J)
I'Lu I l d by recrystaIIIzation ti,om ethanol-chloroform (8:2 v: v) mixture.
( )rari.e "Aid.
\l n. >300 T. lR KBrI ctu 3396 (011), 322 (NH). 3038 (NH), 1684
(C=O), 1620((.'-N).
II N\iR (30O MIIz. CD('l;) J2.12 (s, 3H, CH;), 5.83 (s. 1H, H-5'). 8.07
(d, J = 10.9 Hz, pyridine H-6), 8.48 (d, J =
1().9 1 Iz. pyridine 11-5), 9.97 (s, 1 H. NI-I),
10.10 (s, III. NI1).
C NNIR I 100 Nillz. I)\ISO-(/,,) ,> 19.5 (CI-I3), 96.1 (C-3'). 104.6 (C-5'), 119.6
(C-10). 125.6 (C-6), 147.6 (C-5), 151.1 (C-9).
153.8 (C-7), 155.5 (C-2), (163.6 (('-4). 161.7
(C-2't. 164.6 (C-6'). 194.4 (C-4')
F l-\lS (nriz) 287.13.
Elemental analysis for C ; :I I.,NIM Calculated C, 54.40; 1-1, 3.16: N. 14.64;
Found: C. 54.26.: F1, 3.08, N. 14.51.
88 1,3-/)iWzsdzt•/-7-(4-/r;•drox v-6-»ret/z v/-2-uxu-211-1-pav-an-3 yI)-111,311-pyrido[2,3-dj j,yiurIciric-2,-l-diU!le (18(h) lwitkd b\ rervs11izition from ethanol-chlorotbrm (8:2 v v) mixture.
Oratt'c solid.
NI h. 239-241 °C.
I R KBr) em 3169 (OH), 1700 (C=O), 1620 (C=N).
II \\IR 03O0 %I11i. C1-)(1:) a 2.13 (s, 31-1, CII;), 3.14 (s, 611, 2xNCH3),
5.86 (s. H. H-5'), 8.20 (d. .1 = 9.6 Hz. IH.
pyridine H-6), 8.57 (d, J = 9.6 Hz, 1H.
pyridine 11-5).
C \NIR (I00 MitIz. D\1SO-~1,.) O19.6 (C113), 27.0 (2N-CIh). 95.9 (C-3'),
105.0 (C-5'), 124.4 (C-6), 125.2 (C-10),
148.3 (('-5), 151.9 (C-9), 154.6 (C-7), 160.9
(C-6'), 163.9 (C-2'), 164.8 (C-2), 164.9 (C-
4). 182.4(C-4')
(mi) 315.16.
E1en natal analysis for C: -ll; ,.H;OS Calculated C. 5.19: 1-1, 4.16: N. 3.31.
Found: C. 57.08; H, 4.04, N, 3.18. TI: ioxo-"-(4-!rt•droxt•-h-nretht'1-2-oxo-211-1 pyran-3 _yl)-1H,311 pi'ridof2,3 d/pFrimidinc!--1-otiC (1(S'(lli)
Purified by rcovsiallization from ethanol-DMF (8:2 viv) mixture.
\I. . >300 °C.
II. (I'Br)em 3392 (O11), 3201 (NH), 3026 (NI-I), 1707
(('-=0). 1620 (C—N).
H \\IR ( 00 \11-1i. ("D('l:) Ji 1.15 (s, 31-I, CH). 5.90 (s, 1H, H-5'). 8.20
(d. J = 9.9 Hz, I H, pyridine H-6), 8.46 (d. J =
11).4 Hz. 111, pyridine 1-1-5), 10.20 (s, IH, NH).
10.92 (s, IH, N11).
: IC N\1R (I ((0 \illz. D\ISO-J .,) r) 19.6 (Cl-h), 97.0 (C-3'). 104.1(C-5'). 121.1
(('-10), 123.2 (C-6), 146.4 (C-5), 151.6 (C-9),
154.2 (C-7), 161.3 (C-6'), 162.0 (C-2'), 164.6
(('-4). 175.6 (C=S). 184.4 (C-4).
FS1-\1S (nil) 303.15.
Elemental analysis for C ;N;U.4S : Calculated C. 51.53: H. 2.99. N. 1-1.`2;
Found: C, 51.39: H, 3.14, N, 13.65.
Mo 2.8. (oXCLIS10N
In conclusion. in this chapter we have described it convenient and efficient process fir the >\ titkesis of novel py raurle and pyranyl pyridine derivatives from -enaminones under thermal solvent-tree condition usine NaHSO4—Si02 as an efficient catalyst. Present niethodologv offers very attractive features as excellent yields of the product in shorter reaction time, simple work-up procedure. economic viability and reusability of the catalyst. \Ve believe that this method has provided a better scope for the synthesis of pN riclinc and pyrazole derivatives and will be a more practical alternative to the other exiStin-, methods.
91 X.21I63Y Cd.-E2
100
424 $ , 3*!s !i1 !
I
Fig. 1. IR spectrum of 176a
I-43C 0 0 ,CH3 N
OH 0
__ IHJJHL_
iA
Fig. 2. 'H NMR spectrum of 176a n. v U 11 1 11 ~1 1 ,1•R. n. 111 1.1 •. N\CND
i111Y1• 1.•
w ~ ,
1!1 Ila.w. •'I 1 u~1 .IR •~ .1 tm h::t.. .11~ 1111\\I I ! ~ 11NP1.: •.M.i4 \I1: 111 n M: Fir MN. n r11 r'..a VI!! YYl illt. Sill
1: r..n... p,.s...n ~I Ij'u
NRx 1 V \~Y 1t 1.• M1 I It
Fig. 3. "C NMR spectrum of 176a
Fig. 4. Mass spectrum of 176a
93 Coda- H2. Ph a K0. L Z!W H.SW"" [Ms. Tbeui 10-104,12,2010 16 N0.3557
...... rr~;%r:•`1-L ...... _~.:,.:.. ---•--•---.. _...-----...... -- { 8 £ ;
II
2000 1000
X-2205.5Y•92.6606 wwenta1 s Iu ' J
Fig. 10. IR spectrum of 178a
H3C O O
OH HN N
Fig. 11. `H NMR spectrum of 178a
94 Fig. 12. 13C NMR spectrum of 178a
N .MElM ;lWI L A. 4 I.n -'k
IC
r~ !
Fig. 13. Mass spectrum of 178a
X •2109MY-100 SOB ...... _ - ...._ f00...... _...... - -
....._...... _...... -.. 00 ...... --- .. T ...... - . >
20
4000 3500 3000 2500 2000 1500 1000 500
X - 2199.55 Y -100.596 NtawManD~s Icm ))
Fig. 14. IR spectrum of 180a
$ • O •• h n.. ..w nr O / I
CH, O
OH N I H_CH)
H
II
I I
it I. ! 1 1 1 S A 3 2 1 0 ppE
Fig. 15. `H NMR spectrum of 180a
F.. Fig. 16. 'C NMR spectrum of 180a
Fig. 17. Mass spectrum of 180a
97 2.9. REFERENCES
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105 CHAPTER 3
Zn[(L)PROLINE]1-WATER: A GREEN CATALYTIC SYSTEM FOR
THE SYNTHESIS OF BENZOPYRAN RING SYSTEMS
Catalysis Science and Technology, 1, 2011, 810-816. Journal of Chemical Sciences, 124, 2012, 1097-1105.
3.1. REVIEW & LITERATURE
the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances has led to the design and application of catalysts and catalytic systems to achieve the dual goals of environmental protection and economic benefit.' Catalysts are distinguished into homogeneous and heterogeneous catalyst.
Homogeneous catalysis play a key role in the development of greener, more sustainable chemical processes and are powerful tools for the synthesis of tine chemicals, pharmaceuticals and materials. Homogeneous catalysts offer a number of important advantages over their heterogeneous counterparts. For example, in homogeneous catalysis all catalytic sites for reactants are accessible. Therefore, they are higher yielding, more
selective, reactive and easily studied from chemical mechanistic aspects for a single
product, and more easily modified for optimizing selectivity. However, their exploitation
on an industrial scale is often held back due to the challenges of separating and recycling
the catalyst. Therefore, development of new recoverable, and recyclable homogeneous
catalysts is an important area of research for both industry and academia alike.2 To reduce the dependence on ecologically unsafe chemicals, it is advantageous to carry out reactions in water? In recent years, water-mediated organic synthesis without using organic solvents has been accepted for wide range of organic transformation including stereoselective Diels-Alder reaction,4 Clasien rearrangement 5 Aldol reaction,6 allylation reaction.7 oxidation including asymmetric epoxydation. hydrogenation of alkenesv etc.
This strategy becomes more attractive if such reactions could be carried out using recyclable catalyst. So there is an urgent need to develop such methodologies which can fulfill both these requirements efficiently.
On the other hand, Lewis-acid catalyzed organic reactions in water are currently one of the most challenging topics in organic synthesis because they allow environmentally friendly processes under mild conditions. 10 Over recent years, Zn[(L)proline]2 mediated Lewis acid catalyzed reactions have attracted tremendous interest throughout scientific communities due to their low toxicity, ease of handling, low cost, stability and easy recoverability from water' 'This complex is soluble in water but insoluble in organic solvents, which allows simple and quantitative recovery of the catalyst.12 Its ability to work both in a solvent and under solvent-free conditions is also the salient feature of this catalyst.Thus,
Zn[(L)proline]2 has emerged as powerful catalyst for a wide range of organic
transtormations.
107
3.1.1. Some recent examples of Zn~(L)proline]2 catalyzed organic reactions under
green environment
3.11a. Zn((L,iprolinej2 catalyzed direct aqueous aldol reactions of aldehydes and ketones
for the synthesis of carbohydrates
llarbe et.al in 2005 first time report the Zn[(L)proline]2 catalyzed synthesis of
carbohydrate by the reaction of a-hydroxy aldehydes and ketones via aldol condensation in
water in varied yields. 13
O OH 0 t H Zn[(LlProlineJl ~~ >mal%,Water X X X= 2-NO7, 4-NO2, 2 Br, 4-F, 4-CN, 2-CL 4-CL 2-CHI, 2-OCH3, 4-OCR3, 3-OCH3, 4-CF3. n,htlryl
3.1.1 b. Znffl)prnlinj2 as a reusable catalyst for the synthesis of pyrirzoles.
An efficient synthesis of pyrazole derivatives in pure water at room temperature in the
presence of 2 mol % of Zn[(L)proline]2 catalyst is reported . This reaction proceeds
smoothly and affords the product in moderate to excellent yields (80-90%). 14
R3 O O Zn(Proline)i. ` R3NHNH, wa[eq el. lil R~, Ra
R, = CH;, OC,H5, R3 = Ph, H, Ph,CH,CO, PhCO, 2,4(NO2 hCH3 R; = CI I], OC2H5
108
3.1.1 c. Microwave assisted Zn((L)proline/1 catnfyzed synthesis of 1,4-dilrydropyridines
via tfantzsch reaction and 1,5-benzodiazepine derivatives
Sivanurugan etal.'5 developed an efficient green synthesis of 1,4-DHP derivatives
catalyzed by Zn[(L)proline]z complex in aqueous medium under microwave irradiation
via Hantzsch reaction. This synthetic methodology provides easier separation of products
in excellent yields.
O R, O 0 R, 0 O~~II R i Rx02mmol R______H;C O O MW H,C N CH, R, - C41c, 2-fun!, 3-indolyl R, = OC,H,, CH3. OCH, 34-(CI 13())C611,, 4-0I CH, OCblh
X NOz, OH, Cl x - In 2010 they also described microwave assisted green protocol for the synthesis of 1,5-
ben(zodiazepine derivatives in excellent yields." In each conversion, the catalyst was
successfully recovered and recycled without significant loss in yield and selectivity.
Ri RI~ H Ri R, NH, N O Zn((L)Prnlinc)i
(12 mmol. iw N~ NII ~ RI R Ri - CHj, CH,CH3, CH3(CH2)s Ri X=OH,CI X~- It_ =CI 1). CH,CI1, (CI 12)4, H
109
3.1.1 d. Znf(L)proliue/,mediated Henry reaction in aqueous media
Reddy et. aL" reported an efficient synthesis of 2-nitro alcohols through Henry reaction
under ambient conditions catalyzed by Zn[(L)proline]2 complex using environmentally
benign solvent, water, as the reaction medium. The advantages of this protocol are high
catalytic activity under very mild conditions, easy operation, and recyclability.
O OH Oz I \ H tnI0.11'rollneJ2, 10 Xif I + CH,NO, —~ Water, rt x /
X = p-NO,, o- NO,, NC, 0-Br! OMe
3.1.1 c. Zn((L)prolinel2 as a water-soluble and recyclable Lewis acid catalyst for the
syntitesis of 1,2-disubstituted benzimidazoles
Rao et al reported an efficient procedure for the selective synthesis of 1,2-disubstituted
benzimidazole derivatives from various electronically divergent aromatic aldehydes and o-
phenvlendiamine using Zn[(L)proline]2 complex as an efficient Lewis acid catalyst.
R Nil, Ho R \ \ I Zn(L)Vrollnc],, 5
NH1 R, II2425C
R,Ri =II R=CII,, R,= CH; R=CI,RCI \R z
Rz = CHy OCH;, NO,
110 3.1.1 f. Zn j(L)prolineJ2 catalyzed synthesis of Quinoxaline and pyranoJ2,3-d]pyrirnidine
Heravi et.al'9 reported a simple, efficient, and ecof iendly method for the synthesis of functionalized quinoxalines from various 1.2-diketones and 1,2-diamines at room temperature in excellent yields within a short period of time.
R R ~ O Hi Zn(LPraline)2 N IOmol% \ N Acetic acid, r%. K R R, H,CH3 N% R = H, OCH„ F, CI
These authors also reported the Zn[(L)proline]2 catalyzed synthesis of pyrano[2,3- d]pyrimidine derivatives from aldehydes, malononitrile, and barbituric acid in refluxing ethanol.`'
O 0 Ar yII~ H CN HN eN Zn(L-Proline)z 17 mni% N A,CHO—~ CN FuOH, Ref L, ONO O~ i O NH, H H Ar = p-Me, p-NO,, o-CI
3.1.1p,. Zn((L)proline/z as a reusable catalyst for the synthesis of p-amino carbonyls via
Mannich reaction
Recently. Zn[(L)proline]2 catalyzed stereoselective synthesis of /l-amino carbonyl compounds in excellent yields via Mannich reaction has been reported by Kidwai et.al?I
Reactions took 10-12 hat room temperature for completion with yields 85-93%.
111
0 CHO NH1 0 0 kIN R. H i 0.
\ R2 SYn RI-H R?H, 4-Cl 4-Cl, 4-CUB 3-CII, furvl Ph 4-OCM 3
3.1.1 h. Zn/(L)prolineJ2 catalyzed synthesis of chromonyl chalcone
Synthesis of chromonyl chalcones by reaction of 3-formylchromone with various
substituted heteroaryl methyl ketones in water using Zn[(L)prolincj2 as an efficient Lewis
acid catalyst was reported by Siddiqui et al .22 Reactions were completed at room
temperature in 15-30 min and products were obtained in excellent yields.
o o O O R R H Zn(ymline)x + HNC—C—Q / II Wnleq eflax O 0 R = H. CH, Cl
\ }OII~ O OII H OH f
O N O p N O O N 5 O O CHI p o
3.1.1 i. Zn[(L)protineJ2 catalyzed Knoevenagel condensation under solvent-free/aqueous
conditions
They also reported the Knoevenagel condensation of 5-chloro-3-methyl-l-phenylpyrazole-
4-earboxaldehyde with different cyclic active methylene compounds in water as well as
under microwave irradiation in the presence of catalytic amount of Zn[(L)protinc]z? The
112
reaction proceeded smoothly and afforded the products in excellent yield (90-95%) within
5-9 min.
H Z—O
I10 O Znhl )Prolhalz 0 - 2h —~ N CI Water N\N1 OZ Ph
Water ~Zn [(L)pro line]i Ph H CH=C-CH3 I ILY N Ph V Ph o 0 Y
o H O O Y tET= tl / S I/ ~ N 0 Y-H, CHI Ch I x=O.S
N O 0 / O O CHo IIL
3.2. PRESENT WORK
In continuation of our efforts in developing selective, efficient, mild and ecofriendly
synthetic methodologies for the preparation of biologically relevant benzopyran
derivatives herein, this chapter we describe mild, practical and convenient synthetic
protocol for the synthesis of benzopyran derivatives using Zn[(L)proline]2 complex as a
water-tolerant Lewis acid catalyst in water. Use of water soluble catalyst has the practical
advantage that the catalysts can be reused after simple extraction of the water-insoluble
products, provided that the catalysts show high catalytic activity in water.
This chapter is divided into two sections.
113 SECTION A: SYNTHESIS OF DICOUMAROLS
In this section, we have described the synthesis of dicoumamis in the presence of
Zn[(L)proline)2 as an efficient, environmentally benign, water-tolerant, Lewis acid catalyst in water.
[he dicoumarol is a naturally occurring anticoagulant drug that functions as a vitamin K antagonist and obtained from metabolism of coumarin in the sweet clover (Melilotus alba and Melilotus offieinalis) by bacteria Penicillium nigricans and Penicillium jensi.24
Dicoumarol and its synthetic derivative warfarin sodium (coumadin) have shown to decrease metastases in animal models25 In clinical trials, these compounds have also demonstrated to have some activity against prostate cancer, malignant melanoma, and metastatic renal cell carcinoma.21 Compounds with this ring system also possess various other pharmacological activities such as insecticidal. anthelmintic, hypnotic, antifungal, phytoalexin, HIV processes inhibition, antimicrobial and antioxidant.2' Further,
lanthanum(lll) complexes of dicoumarol have been reported to show potent cytotoxic activity 2e During the last decades, due to the importance of dicoumarols, several methods have been adopted for its synthesis viz use of DB1J,29 (Et2AIC13), 0 refluxing ethanol or acetic acid,31 molecular iodine?' POCl3 in dry DMF,33 manganous chloride b4 and thermal solvent-free reaction conditions35 etc. However, in spite of their potential utility some of
the reported methods suffer from certain drawbacks such as long reaction Lime, expensive
reagents, harsh conditions, low product yields and use of toxic catalysts that are harmful to
environment.
therefore. it was thought worthwhile to develop a new and mild protocol that overcomes
the drawbacks of classical catalysis for the synthesis of dicoumarol derivatives in terms of
114 operational simplicity. reusability of the catalyst and economic viability. The present protocol provides a better alternative to the existing methods due to its shorter reaction time period, simpler reaction procedure and the formation of cleaner products in excellent vieIcl:.
3.3. RESULTS AND DISCUSSION
4-11,, droxvcoumav-in (29) ring at position I is highly reactive due to the presence of an elcen-on donatin t OH `Lroup and an electron withdrawing carbonyl group. The presence of a carbon Carbon double bond and a lone pair of electrons from oxygen make the euumarin ring very convenient at position 3 to react with the carbonyl group of aldehydes (181a—j) to give dicQtnnarD1 derivatives (182a—j ). In the present study various dicoumarol derivatives were synthesized employing a variety of aromatics heieroaroWlatIe aldehydes
181 a—j) and 4-hyclrox\coumarin (29) in the presence of Zn[(L)proline]2 using water as reaction merunc (Table 8. Scheme 64).
115
Table 8 Reaction of 4-hydroxycotunarin with aromatic`heteroaroinatic aldehydes
catalyzed by Zn((L)proline]: complex in water
Entry Aldehv de Product Time (nun) Yield (°/u)
C110
182a c, o ~, ' 5 92 Oil
I \ 0110
182b II '5 96
' OIf CIIO Oil (>H
~ ~ I 182c aoll ' o 0 0 0 / 9 92
4 ~ CHIO 182d ('I 6 94
('Ho cJl~ ~~Ci~HI
1822 / Cl o (~ (~ o 5 96 NO-
OH / OH
1821 NO2 ~!~U'~O o u j 93
116 CHO
ills
182g OCII 8 91
Cl 10 i)tI OH
182h O O 7 73 Mc C 110 \ S S
1821 Mc O(1 r) O 6 92 N CI K)
1 821 \ O 0 OHO 5 91
To validate our hypothesis and achieve catalytic evaluation of Zn[(L)prolinc]2, initial studies were carried out using 4-hydroxycoumarin (29) and 4-hydroxybcnzaldcltydc
1 181 b) a: a model reaction under various rCaction conditions.
117 R
OH ZO[OH CHO 'Hazer reflus p p ~O O R 29 181a-j 182a-j
Scheme 64. Synthesis of dicoumarol derivatives using Zn[(L)proline]2 catalyst in water
3.3.1. Effect of various catalysts
In order to show the superiority of Zn[(L)proline]2 over other catalysts various Lewis acids for the model reaction were used (Table 9).Our investigation revealed that the catalytic activity was found to be of the order: Zn[(L)proline]2 >AICI3> P_,05/silica gel >NiC12> 6M
HCI>CuCl2>L-Proline>FeCI1>ZnCh>PTS. Initial examination indicated that
Zn[(L)proline]2 was superior to other catalysts in terms of yield and reaction time. When the reaction was examined with AICl3. P205/silica gel, 6 M lid. NiClz, CuCl2, the reaction was completed in relatively short time (15-35 min) and the product was also obtained in good to moderate yields, but they generated harmful waste, which were harmful to the environment. Using L-Proline. ZnCl2 and FeCl3 the reaction furnished desired product
(1826) in low yields whereas in the presence of PTS (p-toluene sulfonic acid) no product formation was observed. From Table 9 it is, thus, clear that Zn[(L)proline]2 exhibited the highest catalytic activity over other catalyst for the synthesis of 1826.
118 Table 9 Effect of various catalysts on the synthesis of 182b in water.
Entr\ Catalyst Time Yield(%)
I Znj(L)proline], 5 min 96 AICI; 15 min 89 P O silica gel 20 min 79
4 NiCI- 15 m111 75
S 6N1 1101 15 mill 68 6 Cu('1- 35 mill 54 L-Proline 25 min 40
FeC l ; 35 1111 25
9 ZnCI- 48 h 24
10 PTS - -
No reaction
3.3.2. Loadin oft/ice eatali-st
The et'tcct of catalyst loading on the synthesis of 182b was investigated by varying the catalyst amount lrom tJ to 15 niol % (Table 10). When the reaction was performed by
using less catalyst loa. hlrg t0 to 2.5 viol ",/u) reactions were either incomplete or took longer
time for completion. An increase in the quantity of Zn[(L)proline]; from 2.5 to 5 mol %
not only decreased the reaction time but also increased the product yield from 52 to 96 % .
Further increases in the amount of catalyst had no significant change in the product
formation. Thus. optimum catalyst loading was found to be 5 nlol % for the formation oi-
111Coltt11arols.
119 "Table 10 Effect of catalyst loading; on the synthesis of (182b).
Intro Catalyst (mo1 %) Time Yield (%)
1 (1 48h 52
' 2.5 1it 72
5 mill 96
4 10 5 mill 96
IS 5 inln 96
3.3.3. Effect of','aI uuS solvents
To compare the efficiency as well as capacity of the reaction under aqueous conditions, the
Model reaction was also examined in various other protic and aprotic solvents (Table 11).
It was uhservc(l that usint relatively less polar aprotic solvent Cl 12C12 the product was obtained in very low yield after a long period of time (entry 4). Employing aprotic solvents of relatively high polarity, 0 ];CN (entry 5), only trace amount of product formation was observed. In polar probe solvents CH;OH and CH;COOH relatively high yield of the
product was obtained but reaction took longer reaction time period for completion (entries
2 and 3. 1 lowever, when the reaction was performed in water, the reaction was completed
S inn and the product %\ as obtained in excellent yield (entry 1).Thus, our study revealed
that water was the best solvent for the ZnL(L)prolinel2 catalyzed formation of dicoumarols
in terms of reduced reaction time and the maximum yield of the products.
120 Fable 11 Solvent Effect on the synthesis of (182b) in the presence of Zn[(L)proline], (5 nlul °o).
Entry Solvent Time Yield (%)
1 H-O 5 min 96
yleOI I 35 min 85
CH:C'00H 45 min 65
4 C11 1C1- 24 hr 32
5 CH:C'N reaction not completed trace
3.3.4. Catalyst recj•clin, crhilitt'
Recycling study of Zn[(L)prolinc]2 was checked by using model reaction. Reaction of 4- hvdroxycoumarin (2 mniol). 4-hydroxybenLaldehydc (1 mmol) and Zn[(L)proline]_ (5 mol
„) itti water t 10 ml .i were thoroughly mixed and retluxed for an appropriate time. The progress of the reaction \\ as monitored by TLC (Table 12). After completion of the reaction the crude product was extracted with dichloromethane and the catalyst was recovered by separation of aqueous and organic phases. The catalyst was recovered by
precipitatifi,, the aqueous hi er by simple addition of acetone. Then, the catalyst was
tiltered, dried at 80 ''C' for 2 h and used for the next cycle, adopting the same procedure for
all the recycling studies. The results ("Table 12) revealed that the catalyst exhibited good
catal\ tic activity up to three cycles without appreciable loss of its catalytic activity and no
iimartinal difference +ii the yield of the product. After three cycles there was slight decrease
in the VICKI of the product and it may be due to loss of catalytic activity of the catalyst as a
rc alt of decomposition.
121 Table 12 Rccvclin<, studies of catalyst for model reaction
Catalyst recycle Time (nmin) Yield (%)
1I 5 95 III 5 95 IV 6 92
The scope of the reaction was further investigated with different aldehydes with viable catal st. and the results obtained were satisfactory.
The structural assignment of all the compounds (182a—j) was done by elemental analysis and spectroscopic data (IR. NMR and mass). The IR spectrum (Fig. 18) of the newly sFtuthe:itcd dicoumarol L182j) exhibited strong absorption bands at 1610 cfn* 1689 cm"I and 31 ;" cm _1 for C=C. ccn marin carbonyl and OH groups respectively. The 'H NMR
(Fig. 19) exhibited a sharp singlet at 6 6.42 for methine proton. Twelve aromatic protons
( tour protons of a pyridine moiety and eight protons of a couniarin unit) were discernible as multiplet in the range ci 6.90 18.64. Further confirmation for the structure (182j) was prov ided by mass spcctroscopv (Fig. 20) Inch showed M at ni/ 413 as base peak. The spectral iiata of other compounds followed similar pattern and are given in experimental section.
The proposed mechanism for the Zn[(L)proline~_ complex catalyzed synthesis of
dicoumarol derivatives can be visualized as given in Scheme 65.
122 181
(on
\ Ii\
~~ rl r> / it
n
-IL0r - /nll'rufirx),
Ii\
Ult 4i
IIv ir:
OdQ '1I5 U f> U M, Scheme 6; SECTION B: SYNTHESIS OF 2-HYDROXY-4-CHROi IANON E:S This section of the chapter tacuses on the application of the Zn[L(proline)J2-water catalytic ;v,tems for the synthesis ut ? hydroxt'-4 ebromaaQne derivatives by the reaction of 3- t(tnl\Ic1ronlonc (64) with different primary aromatic and hcteroarotmatic amine (183a-j). It is worth mentioning that chromone moiety forms an important component of pharmacophores of a number of biologically active molecules of synthetic as well as Itatural origin.'" Chromone and their derivatives are found in nature as pigments in plant 123 leaves and flowers. They are important for the synthesis of various oxygen heterocycles including xanthones and transition metal chelates"They are widely present in nature and exhibit low Ioxicily along with n wide variety of useful properties." They are also reported to exhibit signi ticant biological activities including anti-inflammatory's and iallergic.40 antibacterial,4 L neuroprotective,12 anti IIN;' antioxidant,1"1 antifungal4' etc. They also display spasmolytic. cardiotonic, antiarrhyth micand anticancer properties.'s "t Among the various chrrnnonc derivatives, 3-forrnylehromone (4-oxo-411-1-benzopyran- 3-caiboxaldchydc) have attracted considerable attention as highly reactive compounds, which can serve as the starting materials in syntheses of a whole series of heterocycles with useful properties due to three strong electron deficient centers viz u. unsaturated kern function, a carbonyl group in the form of formyl group at position 3 and a very reactive electrophilic centre at C-2 ever since its convenient synthesis was reported by Noltara et.al.'s On the other hand, chromanones are widely distributed in many natural products.49 Synthesis of ehromanones is of great interest in the field of organic chemistry because they display 'a remarkable domain of biochemical and pharmacological actions 5° They exhibit a wide variety of well documented biological activity including antioxidant?' antibaemrial,52 antimalarial,' anticancer,-' antifungal,°! topoisomerase I inhibitor.'6 antidiabetic', antiarrhylhmic53, psychoanaleptic, antiarnocbic and antidepressant properties s1 etc. Some ehtummnorc derivatives have been evaluated for I,, viirn antiviral activities against human immunodeficiency vu-us (HIV) and Simian immunodeficiency virus? °' They have also been claimed to be active in photosvnthesisb and have hereditary bleaching affect (similar to antibiotics) on the plastid system of Euglena grad//s. ss Other 4-chromanones 124 derivati\ es have also been tt and useful in the treatment of bronchial asthma.` 0 As a result, or the synthesis o}- 4-chromanone derivatives, different methods have been developed."4-`'' Unfortunately. many of these methods have certain drawbacks such as prolonged reaction time. use of toxic and volatile organic solvents and varied yields. The replacement of these hai.ardous Solvents with the environmentally benign solvents is one of the key areas of iireen c11emistry."', Hence. a more general and efficient method for preparing 4- cbnitNanQnes in high yield needs to be developed. 3.4. RESULTS AND DISCUSSION Due to the exceptional reactivity of formyl group in 3-formylchrolnone as well as versatile biological activities of chromone, a series of 2-hydroxy-4-chromanone derivatives were svnthcsized employing ;-formylchromone (64) and different aromatic /heteroaromatic atitUfes (1$3a-.1). Usually. chrGltllonCs undergo ring, opening reactions via nitcleoplillc attack at the C-? position.`' The reaction between equimofar quantities of (64) and aromatic amines (1 S3a-j) affords a mixture of (184a) and (184b) which are difficult to 5el rZIte (Scheute 66 _ , I \ 6 4 010 CH =N 64 18-la R U Nil \ ii ,V • txab / Scheme 66 12S The Schitt base (l84a), however, has been obtained when a mixture of (64) and aromatic w»inc, is retluxed 161, two to several hours in organic solvents (benzeneitoluene,r" u ethanol ' In the presence of p-toluene-sulphouic acid (PTS) in varied yield (low to good). ]n order to achieve the synthesis of(I8-1a) under orccn environment, a mixture of'(64) and different aromatic hetcroaromatie amines (183a-j) was relluxed in water in the presence of 7.n[(L)prolincj2 . All the reactions were found to be completed within 10-15 min and aatlorded unexpected chroinanonc derivatives (1 85 -j) in excellent yields (87-93%) instead of' Schiff base (184a) (Table 13, Scheme 67). To further evaluate the scope of this protocol and following our catalysis objective, a variety of amines possessing both electron-releasing and electron-Withdrawn;, groups were employed. According to the table. the nature of' the substituent on the benzene ring did not affect the reaction time and the yields were excellent. 126 Fable 13 Ln [(1.)pro1inc], catalyzed reaction of 3-formylchromone (1 inmol) with amines (1 mmol) in e ater. Entry Reactant Product Time (min) Yield (%) 183a , `— 10 93 2 18311 10 92 cll-xH-~N O (III 183c J _ 12 $9 C11—\i4 \ / Ctl; / l 183d 1J 89 (I 183e 10 90 Q 1, 183t' 15 SS o 011 183g _ 10 90 0 Oil 183h 2 p Ulf 183i I v \ / 1 q" H—NII` \ ~ -CI U \ U OH 9~ 1$3j 12 127 n I II :1r—NH7 ~ cIIIiIIuiiiI,,11uIrzi 1,,,,.,4 S l {1 Ar IY3:i-j 11i5a-j S ISia: 1836 ON 183c ISMd 183c 183f 110-0—: ('I \ / 183h 1831 Scheme 67 \ll The newly synthesized compounds were characterized using elemental and spectroscopic data. Thus, the infrared (IR) spectrum (Fig. 21) of (185a) displayed an absorption band at 3 355 eni ' and 3280 cm' due to the presence of Oil and \II groups respectively. The absorption bands at 1650 and 1376 cm-I indicated the presence of C=0 128 and C-N groups respectively. The 1 II NNIR (Fig. 22) showed the singlet of H-2 proton at 6 x.71. (TI'he diagnostic singlet li,r H-2 proton in chromone appears at 6 7.88. 2 A downfield doublet intc~.:rating for one proton at d 8.33 (J = 11.4 Hz) was assigned to H-9 proton. The doublet of H-5 proton appeared at i 7.99 (J = 7.8 Hz). Another downfield doublet discernible at 6 12.09 (J =1 1.-4 Ilz) was assigned to NH proton. The relatively hitter downfield effect on \11 proton was due to intramolecular H-bonding in its Z- configuration. The remaining three protons of chromanone and four protons of pyridine moieties were present in the form of multiplets at d 6.84-7.66. Further confirmation for the structure was provided by mass spectrum (Fig. 23), which showed 1' at nt/z 268.15.Thc spectral data oi' other compounds followed similar pattern and are given in experimental section. The plausible mechanism for the synthesis of (185a-j) in the presence of Zn [(L)proline], has been depicted in Scheme 68. Zn is capable of binding with the carbonyl oxygen mctnasin_ the reactivity of parent carbonyl group in (64). Subsequently. formation of inmine (64a1 with proline takes place. This is followed by nucleophilic attack of amines (1S3a-j) to the imine t64a) to form hydrogen bonded adduct (64b). Finally, water as noeleopbiM: attacks on elecuiophilic C-2 centre with the expulsion of Zn[(L)proline]: to give the desired 2-hydroxv chromanones (1 85a-j ). 129 64 Scheme 68 Further, attempts were made to get ( 184a) via dehydration of ( 185a-j ) under different conditions such as heating in the presence of PTS, AIO. H2SO4. P,Oi etc. The dehdration of (185a-j) did not succeed probably due to the formation of stable hydrogen bonded keto-amine system (Scheme 67). 130 Then. we Studied the efficacy of the catalyst to establish the feasibility of our strate,y and to optimize the reaction conditions using different Lewis acid catalysts, different molar ratios of catalyst and ditterent temperatures. Initially, model reaction was performed at room temperature in the presence of Zn[(L)prolinej,/H2() and the product was obtained in \ cry lo \\ vield after a lone reaction of time (Table 14, entry 2). In the absence of Zn[( L )proline]2, under reflux condition the result was not promising, and a very low yield as obtained (Table 1-I. entry 3). 3.4.1. Ef fret of catall•.st loading Theft we. studied the e tact of catalyst amount on the reaction rate and product yield by the reaction of (64) with ?-anlinopyridine (183x) as model reaction. After systematic screening. we observed that the best results were obtained when the reactions were carried out with 10 mol °;, of Zn[(L)proline1, in water at rellux temperature. With amount Tess than I 0 tllol of the catalyst the reaction either did not complete or took several hours to complete whereas. further. Increasing the amount of catalyst more than 10 rnol % did not increase the product v field or the reaction rate. 3.4.2. Effect of different catalysts and temperature For purposes of comparison, we also scrutinized the reaction under the same conditions by ci pkoyine various other Lewis acids including CuSO4. CuCI;, Z.nCl2, A1CI,. Zn(OAc)2, L-praline, FeCI; (Tahle 14). Result showed that using L-proline alone product (185a) was obtained within short reaction time but in very low yields (entry 4). In the presence of ZntO.-\c1_. the reaction \\a, not successful, to give any desirable product tentry 5). When CuSO4. CuCI_ (entries (,. ") were used to promote the reaction, a mixture of products was obtained in low yield. Further. the catalysts with high Lewis acidity such as ZnCl2, AIC13 131 and FeC!; tailed to catalyze the reaction efticiently and resulted in poor yields of the corresponding product; (entries 8. 9. 10). At room temperature in the presencc of Ln{kl.)prolinC!, HO and in the absence of Zn[(L)prolinc121H20 at reflux temperature \\ c:: prolott ,d and yield of the product was very low (entries ? and 3). TL reults confirmed the high catalytic activity of Zn[(L)proline], in the current synthesis. Table 14 Reaction of 3-forntvlchromone (1 n,nlol) with 2-aminopyridine (1 mniol) in the presence of various catalysts in water. Entry Catalyst Temperature Time Yickt (%) 1 Znr(L )prolinc] relax 10 min 93 7n((1_)pruline] r.t 6 h 46 3 - reflux 1011 42 4 L prolinc reilux 50 mill 42 7.n(U:Ac) reflux S h 15 retlux 7 Ii 40 CuC'1, rcllux 5 h 40 Zn( -I , reflux 6 It 34 rellux 6 h 35 11) FeC1; reflex 45 [hill 25 132 3.4.3. Keu abilitt- of the cola/i's! For practical applications of any catalyst. the lifetime of' the catalyst and its level of tCt1s,thlI1t\' are very Ht1[ortanit factors. Although recycling of hoinogclieous catalysts is difficult and generally not preferred. Since we arc using water as the reaction medium and one of the special properties of Zn[(L)proline], is its insolubility in organic solvents and solubility in water which is tairlv good for a homogenous catalyst. Therefore, we studied the possibility of recycling and reusing the catalyst for the model reaction of 3- tOtm% lchyorc ne (64) \v ith 2-aminnpyriBne (183a) in the presence of Zn[tL)pro1incj, and the react ioiis were carried Out lltldcr similar conditions in water. After completion of reaction in specified time, by cooling the reaction mixture to room temperature, the crude product was extracted with dichloromethane and the catalyst was recovered by separation of aqueous and organic phases. The catalyst was recovered by precipitating the aqueous layer by simple addition of acetone and drying at 80 °C for 2.5 h. To rule out the possibihitv of catalyst leaching the recovered catalyst was recycled to promote the model reaction att'ordin, the corresponding products (Table 15). The results revealed that catalyst exhibited excellent catalytic activity up to three cycles. Table 1-5 Reevclin stud\ of the Zn L)hroline]:(10 mol",4,) for the model reaction. Catalyst recycle Time (min) Yield (`%,) 10 93 IT 10 93 III 10 9, IV 10 90 V it) $7 133 3.1. l V\( I.l StON In :unrinar . we h,,\ c developed a practical, efficient, and scalable one-pot synthesis of different benzopvran derivatives (dicotunarols and 2-hydroxy-4-cluronlanoncs) using stable. iiicxpeiiSi\e. easily preparahlc and recyclable Zn[(L)proliiiej catalyst in green soli ent water. The catalyst Showed a unique class of catalysis in comparison with other catal\ st<. I he po ertitl catalytic activity of 7n[(L)prolineJz for these transformations can be sustained) by mild reaction conditions. use of water as solvent, cleaner reaction profiles, simplicit\ in operation. excellent yields of the products, faster reaction rates and reusahilit\ oi'the catalyst %\ itlt no loss in its activity. 3.6. EXPERIMENTAL \1eItln ponhf, were taken in Riechert Thermover instrument and are uncorrected. The IR spectra were recorded on a Perkin Elmer spectrometer in KBr,1 II NMMR spectra on a Bruker DRX- 0O Spectrometer using tetra methyl silane (TIvlS) as an internal standard and D\ISO-,/, ('DCI , as solvent. Chemical shifts are reported in hpm doww ntield front THIS as internal standard and coupling constants J are given in Hz. Mass spectra were obtained on a D \RT-AIS recorded on a JEOL-Aces TOF JMS-T1OOLC mass spectrometer having a I):\R"l source. The micro analytical data were collected on an Elementar vario EL Ill elemental analyzer. 4-I f\ dhroxvcoumarin and aldehydes were of commercial grade and \\ re used without further purification. 3-Formylchromolnc 4 and Zn[(L)proliiie ' were synthesized by reported procedures. The purity of all compounds was checked by TLC on _lass plates coated with silica gel (E-Merck G254). 134 3.6.1. 5ntlzcsis of the Ziz/(L)prolinc/2 catalyst (L)Proliine t20 mmuh \vas dissolved in absolute ethanol (50 mL) containing potassium hv dh,xide 120 annol i and tua ZutN0,),.6H,0 was dissolved in a small quantity of double distilled water and added in drops to the (L)l'roline solution. The contents were vigorously stirred at room temperature 1r h h by using a tua2setic stirrer. The ZnI(L)prolinej2 complex was obtained as a white solid. It as collected by iiltraitiun and dried at 70 °C. in vacuum for 6 h. 3.6.2. (;erreral procedure for the synthesis of dicouinarols (182u j) .1 mixture of 4-hvdrox\-coumarin (29) (2 mmol), aldehyde (181a-j) (1 mmol), /n[(L )proline]: (5 mul 'd and water (10 mL) was taken in a round bottomed flask and rednzcd on it heating mantle at 1 10 °C for specified time. The progress of the reaction was monitored by thin-la\ eI chromatography (TLC). Upon completion of the reaction, the mixture was cooled to roost temperature. The crude product was extracted with dichlorontethanc. dried over anhydrous Na2SO4 and concentrated to furnish (182a—j). The catal\ st was recovered by simple separation of aqueous and organic pleases. The catalyst present in the aqueous layer was rccovcrcd by precipitating the aqueous layer by addition of acetone and used for the subsequent cycle. 3.6.3. Genera! procedure for the st'hthes'!s of 2-lrti•llroxyy-4-drronznnonres (18 ec j ;A mixture u1 3-1en-nn kduomcae (64) (I.00 mmul), niuines (183a—j) (1.00 mniol), Zn [(L)prolinej- ( 10 awl °,.) and water (10 mL) was rcfluxcd in it heating mantle at reflux temperature for an appropriate time..-\fzcr completion of reaction, as monitored by TLC, reaction mixture was Fooled to room temperature. The crude product was extracted with 135 tichdoioinethaiie. as lid with water, dried over anhydrous sodium sultate and concentrated to furnish (I 85a-j). The pure compounds were obtained by recrysfallizafiQH frunl mctlltol chorti,rnl mixture (8:2 V V). The catalyst was recovered by simple separation of aqueous and organic phases. The catalyst present in the aqueous layer was reco%creel by precipitating the aqueous laver by addition of acetone and used for the lll?~C'lllellt C%CIe. 3.6.4. Spectral data of compounds 3,3 "-(P/zen) l,netl{t•lc,u')hl.-(-1-M•dru.ya'-211-c•ht•oH:eu-2-Hire) (182u) Puritied h\ rccr\stallh;alion from (.hlorotorlll-methanol (1:4 V V) mixture. \V htte crystalline solid. N1.p 228-230 C. I R I K 13) 1):,",\ Lill 3083 (011), 3027 (011), 1670 (C-0),1614 (C0). 1I N\IR (I)\1SO-Jr. 3(I() \11-{z) 6. 1$ (I 1 I, s. CH), 7.21-8.42(131-I. in. Ar-1-i ); ESI-\1S 412.2$ (N1.). a=len1eHfa1 analysis tar ('•;H .•O,. Calculated C, 72.8$; H. 3.91. Found: C. 72.69; 11, 3.3 (182b) Purlticd by re r\;tal 1/;itloll from Chloroform-il1etl1a1lUl (1:4 V V ) mixture White crystalline solid. Nip. 222-225 °C: IR 11:13x1 t,,,:.."cnl 3448 (OH). 3060 (OH). 1668 (('-0). 1611 (C=O) 136 II N\1R (t)XISO-J,,. $O) Nil lzy : 6.19 t 11-1. s. Cl-H), 6.57--7.88(_131-I,m.Ar-H). FSI-\IS : 428.02(M-). Li in~ntal analysis tier t •:H i ,,O- : Calculated C:,70.I5; H. 3.76: Found: C. 70.35: H, 3.964%,. 3.3 "-(2-lydrox1X el{htniet/r lent)bis-(4-hrdtudv-2f -I-chructtell-2-Dire) (I82c) Purified by recrvstallizatl'.)ll from (Iiloro60rm-methanol (1:4 V/V) mixture. Yellowy crystalline solid. ~l.p 254-257°C. IR(KBr) u,;,, cnC : 3338 (OH), 3065 (OH), 1714 (C=O). 1673 (C=O). 'II NMR (DNlSO-,1,,, 300 \1Hz) : 6.29 (1H, s, CI1), 6.67-7.88(131-I,rn,Ar-H). ES1-MS : 428.30 (M'). Elemental analysis for C,;H IbO- : Calculated C,70.15; H, 3.76%; Found: C, 69.94: H, 3.55%. 3,3'-(4-ChIutopkcIc1-(nret1r)'Iefe)bis-(4-Inydruxy-2H-chrovLea-2-litre) (182d.1 Purified by recrystallization from Chloroform -methanol (1:4 V/V) mixture White crystalline solid. Nip. : 250-253 °C IR(KBr) u crn t 3030 (OH), 1670 (C=O), 1605 (CO), 768 (C-Cl). 'H NNIR (DN1SO-d,,. 300 N1llz) : 6.19 (1 H, s, C11). 7.09-7.98(13H, n1, Ar-H). FSI-N1S : 446.18 (MT). Elemental analysis for C,SH,;C1O~, : Calculated C, 67.25; H, 3.38%; Found: C. 67.04. H. 3.58%. 137 3.3 -( 2-Chlurophe►rt'Inirtb'lene)Gis-(1-/r1'rlroxti'-211-eIltQrtterr-2 orrc) (182e) Pun lied by rccrvvsttllll /MI011 lfoni hlorolorn-mmethano] (1:4 V/V) mixture. \V'hits .l\ stalline solid. \I.1). : 198-200 C. IRiKBr) v,,,,\ cm : 3079 (OH), 1670 (C=O), 1615 (CO). 769 (C- CI). \IR (DNISO-c/,.3n(t \I1Iz) : 6.08 (111. s. Cl I), 7.05-7.8$(13H, in. Ar-H) ES1-Alti -1-16.16 (M ). Elemental analysis : Calculated C, 67.25: H. 3.38%: for C -Al 1C1O,. Found: C. 67.20; H, 3.5$. 3.3 -(3-.\its-uDhem1l'1ruu't/r1'Ie,ue)6is-(J-!ryrlruz }•-211-c•!rrQnterr-2-uire) (182/) I'l1CtI1ed by I"cCf1'Slallt /:Ills)!! !YUln ehlUl'ulOfal-methanol (1:4 V.t) mixture. \\ hit,: solid. \1.t). : 123-125 'C lk (Ken) u..,, ells' : 3064 (011), 1660 (C=0), 1616, (CO), 1565 (.NO). 'II \\IR (DNISO-d,,. 300 \II-Iz) : 6.37 (11-1. s• CII),6.59-7.89 (12H. m. Ar-H). F.SI-\IS : 457.14(N1 ). 1.1 nl,ntal analysis : Calculated C, 65.70; 11, 3.30: N. 3.06Yu torC .11 -AO. Found: 0,65.49; H, 3.49: N, 3.26'/0. 3.3 (182x) P e-itied by reervstallii.nloll from chlol-o orm-methanol (1:4 V V) mixture Light yellow crystalline solid. 138 Nip. : 254-259 "C. IR ({'Hr) uWJ\ cm : 3495 (011), 3074 (OH), 1668(0—O). 1612 (C=O). H \\ill (DN1SO-c/.. 300 \IHz) : 3.58 (3H, s. OC'H;)1 6.26 (1H. s, CH). 6.55 7.92 (1 111, m. gar-II). FSi-\[S 458.15(.M'). 1Ilcmc.iltal analysis : Calculated C. 68.18: 11, 3.96';%%: I'Or C -,.H ,O, Found: C. 67.97: H. 4.16%. 3.3 "-(2- TIiopIze,n'lzr1etht•lc'rzc')bi.,-(4-!nd1ro.vti•-2H-c•hronrerr-2-isr1e) (1821x) !s : h\ sc rsaalliiat,. ', !1o!?? (hlurilUSm tl?~tlnoi (1:4 \ V! mixtuc: Gr«ru crystalline soli( \1.1. : 210-21 3(dec) °C. IR (KRr) u.:,. c;m-' : 3074 (011), 1660 (C=O) , 1612 (CO): Ii \NIR(DNISO-J(,. 300 \lllz) : 6.19 (1 H. s, CH), 6.$6-7.22 (31-I. m,CH), 7.30--8.04 (SH, m, Ar-11): 1.ISI-\IS : 418.09: (M'). Elemental analvyis : Calculated C. 66.08: H. 3.31%; tr (,:H.4O„S Found: C, 66.27:1-1, 3.52%. 3,3 (182i) Pisritied h\ recrvstaliiz.U1rn from Chloroform-methanol (1:4 N' \-•) mixture Yellt crystal line ,ulid. Nip. : 1R tKBr v,_, cm” : 3078 (OH). 1664 (C=O), 1616 (CO). 139 'H NMR (DMSO-d,;, 300MIIz) : 6.15 (IH, s, CH), 2.41 (3H, s,C113), 6.58-- 6.62 (2H, m, CH), 7.26-8.05 (8H, m, Ar-H). ESI-NIS : 432.12.(Ivl-). Elemental analysis : Calculated C, 66.72; H, 3.73%; for C'41-I:(,O,S Found: C, 66,50; H, 3.53%. 3,3 '-(.V-pti ridt bnetlt 1e,ic)bis-(l-It t'[!i'o.YV-2Ji-Chromei1-2-one) (182]) Purified by recrystallization from Chloroform-methanol (1:4 V'V) mixture White crystalline solid. M.p. 252--254 °C. IR (KBr) u;,,a.;'cm-I 3184 (OI1), 3137(OH), 1689 (C=O), 1610 (C=O). ' H NN1R(DMSO-d. 300 M1-1z) 6.42 (1 H, s, CH), 7.23-8.64 (121-I, m, Ar-H). ESI-\1S 413.13(M`). Elemental analysis : Calculated C, 69.79; H, 3,36; N, 3.39%; for C'41-I i;NO~, Found C, 70.01; 1-I, 3.55; N, 3.19%. 3-(P'rid}'!ruuiaon:etlrtvlene)-2-)zydroxy-cIiromunr-4-oize (185u) Purified by recrystallization from methanol-chloroform (8:2 V/V) mixture. Light yellow solid. M.p. : 121-124°C. IR (KBr) u,, /cm : 3355(01-I), 3280 (NI I), 1650 (C=C), 1376 (C-N). 'II NMR (300 MHz, C'DC1) : 6 (ppm) 3.53 (s, 1II, 01I), 5.71 (s, 1II, I1-2), 6.84-7.66 (m, 7H, ArH), 7.99 (d, J = 7.8 Hz, 1 H, C-5), 8.33 (d, J= 11.4 Hz, H-9), 12.09 (d, J = 11.4 Hz, I H, NH, D20 exchangeable). ESI-MS : m/ 268.15 (M-). 140 Elemental analysis for : Calculated. C. 67.22; H, 4.51; N, 10.45. C:;1l i 2N,O; Found: C, 67.02; I-I, 4.28; N, 10.66. 3-(Berrothiuzolylunriiionzethv1c'ne)-2-h}'droxychroinan-4-ones (1856). Purified by recrystallization from methanol-chloroform (8:2 V/V) mixture. Light yellow solid. NM.p. : 142-145°C. IR (KBr) u,,,;,,,/cni- ' 3209 (OH), 3078 (NH), 1648 (C=O), 1373(C- N). '[-I \\iR (300 MHz, CDCI3) S (ppm) 3.53 (s, 11I, 011), 5.72 (s, III, H-2), 7.05 (d, J =11.4 Hz, 1 H, H-9), 7.10 — 7.99 (m, 7H, ArH), 8.06 (d, J = 7.8 Hz, C-5), 12.31 (d, J = 11.4 Hz, I1-i, NH, D2O exchangeable). ESI-MS : m.%z 324.15 (M-). Elemental analysis for : Calculated C, 63.02; H, 3.73; N 8.64. C:-H.O:S: Found : C. 62.80: 14, 3.95; N, 8.41. 3-(p-Toh•luniinometh}•le;ie)-2-lij,droxy-chronnati-J-one (185c). Purified by recrystallization from methanol-chloroform (8:2 V/V) mixture. Light yellow solid. hip. : 150-155 °C. IR (KBr) u /cm ' : 3320 (OH), 3200 (NH), 1653 (C=O), 1365 (C-N). 'H NNIR (300 MHz. CDCL) 6 (ppm) 2.51(s, 3H, CH3), 3.18 (s, IH. OH), 5.91 (s, 111, H-2), 6.80 — 7.73 (nl, 7H, ArH), 7.89 (d, J = 7.8 Hz, C-5), 8.33 (d, J = 12.3 Hz, 1H, H-9), 12.19 (d, J = 12.3 Hz, I H, NH, D2O exchangeable). 141 ESI-\IS n,/± 281.14 (M+) Elemental analysis for : Calculated C, 72.66; H, 5.380; N, 4.98. C,-H,5NO;: Found: C, 72.89; H, 5.61; N. 4.72. 3-(1p-.1letlzoxypheiijiuuiiIzo;rtetliyle!ze,-2-liydroxy-chrontait-4-one, (18Sd) Purified by recrystallization from methanol-chloroform (8:2 V/V) mixture. Yellow crystals. M.p. : 120 -123°C. IR (KBr) u,:,~,,: cm i : 3376 (OH), 3078 (NH), 1672 (C=O), 1378(C- N). 11 \SIR (300 MHz, CDC1 ) 6 (ppm) 3.64 (s, 3H, OCH3), 6.51 (s, IH, OH), 6.57 (s, 1H, H- 2), 7.09 — 8.34 (m, 7H, ArH), 7.91 (d, J=10.5Hz, 1H, H-9), 8.41 (d, J=7.8 Hz, C-5), 1228 (d, J=10.50 Hz, 1H, NH, D2O exchangeable). ESI-MS : m/_ 297.14 (M-). Elemental analysis for : Calculated C, 68.74; H, 5.09; N, 4.71. Found: C, 68.50; H, 4.85; N. 4.90. 3-(p-:\'itropheizylufriiitoiiietliylette)-2-1iydroxy-c/cromeari-4-oite (185e) Purified b~' recrystallization from methanol-chloroform (8:2 V/V) mixture. Light yellow crystals. M.p. : 170-173 °C. IR (KBr) u/ cm : 3184 (OH), 1656 (C=O), 1369 (C-N) cm' 142 H N NIR (300 MHz. CDCl3,) : 6 (ppm) 5.81 (s, I H, OH), 6.16 (s, 1 H, H-2), 6.64 (d, J=12.0 Hz, 1 H, H-9), 6.92-8.27 (m, 7 H, ArH), 8.32 (d, J=8.1 Hz,C-5), 12.21 (d, J=1 1.7 Hz, 1H, NH, D20 exchangeable). ESI-\IS nil: 312.13 (M). Elemental analysis for : Calculated C. 61.54; 1-1, 3.87; N, 8.97. C : ,;H i ,N_O; Found: C. 61.34; H, 4.10; N, 9.20. 3-(n,-.\'itrophe„ylan,i„on,ethylene)-2-l,ydroxy-chron,a„-4-oize (I8Sf) Purified by recrystallizatioW from methanol-chloroform (8:2 V/V) mixture. Yellow solid. 168-172 °C. IR (KBr) u,,1, /cm 3410 (OH), 3263 (NH), 1665 (C=O), 1343(C-N). 'H N lx (300 MI-lz. CDCI:) 6 (ppm) 2.80 (s, 11-1, OH), 6.17 (s, I H, 1-1-2), 6.97 (d, J=13.5 I Iz, 111, 1-1-9), 7.00-8.36 (m, 7 H, ArH), 8.89 (d, J=9.6 Hz, C-5). ESI-MS : m/ 312.15 (M`). Elemental analysis for : Calculated C, 85.70; H, 6.55; N, 8.27. Found: C, 85.24; H, 6.56; N, 8.15. 3-(a- \'up/itl,ylun,r„o,nerllti•lencee-2-Irl-droty-chron,a„-d-one (185x) Purified by rccrystallization from methanol-chloroform (8:2 V/V) mixture. Vcllo solid. N1.p. : 150-153 °C. 143 IR (KBr) umax /cm - ' 3245 (OH), 3099 (NH). 1678 (C=0), 1337 (C-N). I H NMR (300 MI-iz CDC1;) 6 (ppm) 3.55 (s, 1H, OH), 6.52 (s, 1H, H-2), 7.10-8.35 (m, 10 H, ArH), 7.93 (d, J =10.8 Hz, 1 H, H-9), 8.41 (d, J = 8.1 Hz, C-5), 13.75 (d, J = 11.1 H, Nil, D20 exchangeable). ESI-\lS m/ 317.06 (M+). Elemental analysts for Calculated C. 75.77; H, 4.73; N, 4.41. cNO, Found: C, 75.98; 1-1, 4.93; N, 4.62. 3-(p-Hj'dvoxfiphebl},1uninane1hhylene)-2-Irydroxy-chromxn-4-one (185h) Purified by recrystallization from methanol-chloroform (8:2 V/V) mixture. Yellow solid. M.P. 160-162 °C. IR (KBr) u,,:'c m 3340 (OH), 3220 (OH), 3284 (NH), 1645 (C=O), 1362 (C-N) 'H NMR (300 MHz, CDCl, 6 (ppm) 5.57 (s, I H, OH) 6.66-7.76 (m, 71-1, Arl1), 6.58 (s, 1 H, 1-I-2), 8.39 (d, J = 8.1 Hz, C-5), 8.84 (d, J = 12.9 1iz, 1H, H-9), 1 1.52(s, 11-i, OH), 12.84 (d, J = 12.9. I H, NI-I, D20 exchangeable). ESI-MS m, 283.11 (M'). Elemental analysis for Calculated C, 67.92; 11, 4.63; N, 4.94. C.~,H..-,NO, Found: C, 68.11; H, 4.83; N, 4.68. 144 3-(p-Chlot•ophenlplunii»ouiethj,lene)-2-{tydr•oxyy-ehi•onlanr-4-ogre (1851). Purified by recrystallization from methanol-chloroform (8:2 VN) mixture. Light yellow solid. M.P. 142-145 °C. IR (KBr) iu - 1 3441(01-I), 3267(NH), 1669 (C=O), 1 380 (C-N). 'Ii NyIR (300 MHz, CDCIO.) 6 (ppm) 4.99 (s, 1 H, OH), 5.27 (s, 1H, H-2), 7.19 -8.12 (m, 7H, ArH), 8.06 (d, J = 13.8 Hz, I H, H-9), 8.17 (d, J = 8.1 Hz, C-5), 10.33 (d, J= 13.8, 1H, NH, D20 exchangeable). ESI-\IS nz/z 301.12 (M-). Elemental analysis for Calculated C, 63.73; H, 3.98; N, 4.64. C~<,H12NO;C1 Found: C, 63.50; H, 4.19; N, 4.38. 3-(Phenj,1arnin urn eflij,lease)-2-hydauxy-chro,nun-4-one (18Sj) Purified by recrystallization from methanol-chloroform (8:2 VN) mixture. Yellow solid. M. p. 135-138 °C. IR (KBr) I11J.1a icm 3184 (OH), 1653 (C=O), 1317(C-N). 1H NMR (300 MHz. CDCI~ 6 (ppm) 2.92 (s, IH, OH), 5.65 (s, 1H. H-2), 6.84 - 7.66 (in, 7H, ArH), 7.89 (d, J— 7.8 Hz, C-5), 8.34 (d, J = 10.8 Hz, 11-1, H-9), 11.59 (d, J = 10.5 Hz, 11-1, NH, D,0 exchangeable). ESI-vlS min 267.10 (Me). Elemental analysis for Calculated C, 71.97; H, 4.90: N, 5.04. C:<,H iaNO3 Found C, 71.75; H, 5.13; N, 5.04. 14S X - 21 $.SI r - 103.$S C.d.-04. PeasU•KBc. &26ba M&ddigW (W.KuIwinn 29.03201e i.e.po.212 100 ...... - i Y *0 ...... _.. I1...... _...... p ... .. tp... R.p ...... R A R.• t. 7.~ R q R 4100 3. — _M 1A00 _ X - ztu.p v.183.863 _ _ y~•,,,"~6•s 1cmA1 Fig. 18. IR spectrum of 182j 11 10 9 I: 7 6 5 4 3 2 1 rpm Fig. 19. !H NNIR spectrum of 182j 146 Fig. 20. Mass spectrum of 182j X = 2190 87 Y • 99 4885 Co4a- F-I Pheee- K8r. 03 Q 2QI I 100 1 . .._.- 90 1 ...... -- ...... - ...... _.. .. "..... Q a is Y R 70 . r ._...... ae a--- e•-- s- u----~ . . ... _ ...... 60 - 4000 3000 2000 1000 X•2190.87Y-9®.4985 Fig. 21. IR spectrum of 185a 147 Fig. 22. 'H NMR spectrum of 185a Fig. 23. Mass spectrum of 185a 148 3.7. 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REVIEW AND LITERATURE Research and development of potent and effective antimicrobial agents represent one of the most important advances in therapeutics, in the control of serious infections as well as in the prevention and treatment of some infectious complications of other therapeutic modalities such as cancer chemotherapy and surgery.' In recent years, the number of life- threatening infectious diseases caused by multi-drug resistant Gram-positive and Gram negative pathogen bacteria have reached an alarming level in many countries around the world.` ' Over the past decades, these enteric bacterial infections are responsible for morbidity and mortality in immuno-compromised individuals such as those suffering from tuberculosis, cancer or AIDS and in organ transplant cases mostly in developing countries and areas such as the Indian sub-continent, part of South America, tropical part of Africa, etc.'{' Every year millions of people are being killed by some or the other Gram-positive and Gram-negative strains of bacteria. These bacteria mostly lead to food poisoning, rheumatic, salmonellosis and diarrhea.' Thus, antibiotics provide the main basis for the therapy of microbial (bacterial and fungal) infections. However, overuse of antibiotics has become the major factor for the emergence and dissemination of multi-drug resistant strains of several groups of microorganisms.8 Furthermore, the pharmacological drugs available are either too expensive or have undesirable side effects or contraindications .9 A number of clinical reports in the United States and worldwide have independently 157 described the emergence of vancomycin resistance in methicillin-resistant Staphylococcus aureus (MRSA) isolates and other human pathogen Gram-negative isolates1°. Escherichia coli are responsible for the world's most common and serious infectious diseases like invasive dysentery and diarrhea. septicemia. inflammations of liver and gall bladder, appendix, meningitis, pneumonia etc.''-' 3 Generally, there are complains of abscess of the brain which is a very bad problem of E. coli infection.'4 In case of E. coli infection amoxicillin. norfloxacin and ciprofloxacin are generally used, but have harsh side effects.15 Toxicity and resistance to the drugs also play important role in the treatment failure." The different parasitic bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Salmonella tlphlnlll/7I[I)I, E. coli have important effects on the human's mucosal health. The infections with these microorganisms may have significant impact on huge demolition of host tissue and severe diseases. More than 90 % of the cases of vaginitis are of candidiasis, trichomoniasis, and bacterial vaginosis17. Thus, these microorganisms commonly infect healthy people in large communities, thus creating a serious health problem around the globe. Therefore, the discovery of novel and potent antimicrobial agents is the best way to develop effective therapies. For this reason, the present stratagem for the synthesis of new compounds is aimed in the direction of developing new pyrazole derivatives to inhibit the growth of Gram-positive, Gram-negative bacteria, and fungi. Antibacterial and antifungal activities of the azoles are the most widely studied and some of them are in clinical practice as antimicrobial agents.18 In particular, pyrazoles gained much attention as antimicrobial agents after the discovery of natural pyrazole C-glycoside pyrazofurin which showed broad spectrum antimicrobial activity.19 158 NH2 C-glycoside pyrazofurin Pvrazoles have been studied for over a century as an important class of heterocyclic compounds and still continue to attract considerable attention , as they are the core structure of numerous biologically active compounds, including blockbuster drugs such as Celebrex an inhibitor of cyclooxygenase (COX-2) used as potent anti-inflammatory,20 Viagra, an inhibitor of 5-phosphodiesterase, used for the treatment of erectile dysfunction, 21 Acomplia. antagonist of the CB-1 cannabinoid receptor, used for the treatment of obesity.'" Mepiprazole for the treatment of anxiety neuroses.23 Besides this, pyrazole derivatives are reported to have the broad spectrum of biological activities, such as anti- inflammatorv24, herbicidal25, cytotoxic26, analgesic,27 cholesterol-lowering,28 hypoglycemic."' anti hypertensive '0. antidepressant, anticonvulsant,3' antiviral,32 antiangiogenic activity'' and A3 adenosine receptor antagonists34 etc. They are also found applications as pharmaceuticals. agrochemicals, photographic, sunscreen materials etc. Some of the pyrazole containing drugs having wide variety of activities are given below: H2 o ~N O CH3 / N H 0 \ 0 NI I NON \ N cl CI / CF3 H3C' CH3 CH3 CI Celebrax Viagra Acomplia 159 HN i N~ CI Mepiprazole 4.2. PREI:NF WORK A systematic invvc.tiation of this class of heterocyclic moiety revealed that pyrazole containine pharmacoactive agents play important role in medicinal chemistry. The prevalence of pyrazole cores in biologically active molecules has stimulated the need for eletant and efficient ways to make these heterocyclic lead. Therefore, in view of the abo~'e-mentioned findings and to identify new candidates that may be of value in designing new. potent. selective and less toxic antimicrobial agents, this chapter describes the synthesis and antimicrobial evaluation of halopyrazole derivatives. This chapter is divided into two sections. Section :X: Synthesis of novel halo pyrazole derivatives In this section synthesis of t\Vo novel halopvrazo(es (187 and 189) is described using 5- chlon,- 3-methvl- l -hhcnvlhv razole-4-carboxaldehydc (105) as starting material. 4.3. REST LTS AND DISCUSSION 5-chloro-3-methyl-l-phenvlpvrazole-4-carbozaldehyde was obtained by Vilsmeier Haack reaction of pyrazolone."' 1)ue to the exceptional reactivity of formyl group in 5-chloro-3- methyl- I -phenylpyrazole-4-carboxaldehyde (105), it was taken as synthon for the generation of novel halopyrazoles. Thus, in an initial attempt to synthesize (187), (105) was heated With 5-acetyl- I , 3-dimethylbarbituric (174d) acid in the presence of piperidine in ethanol followed by addition of bromine at room temperature (Scheme 69). 160 As expected. ( 187) was obtained in good yield. A plausible mechanism for the formation of t 1K7) has been depicted in Scheme 70. As clear from Scheme 70, Claisen Schmidt condensation takes place between heteroaldehyde (105) and 5-acetyl 1,3-diroeth}1 barbituric acid (1744) in the presence of piperidine to give heterochalcone (186a) which reacts With bromine to ftn-m dibromodihydro derivative (186b). Subsequently the intermediate (186b E undergoes dehydrobromination to give final product (187). In order to synthesize a library of bromopqrazoles, similar reaction was carried out employing hetcroaldehyde (105) and (188) under retlux conditions followed by addition of bromine at room temperature i Scheme 69), However, the reaction stopped at the Stage of (189) and did not gi\ e bromop%razole ( 190) alter addition of' bromine. The failure of reaction of (189) with bromine to give expected dibromo dehydro derivatives is may be due to the steric hindrance from bulky aromatic and heteroaromatic ring (Scheme 69). 161 NU_ II:C GtOH-Bn 1 Fig RT. scirrmg N I br NO: I ('1 l I'W or i:~ CtOH-PNndine lii) Br- RT. Stirring CH; NC). W. ISri u, o :c_ _ (! u ~ v CH; I)C\ N CHl LtUfi-Pcriama I. N Cl ~.I 1; CI I : I CH; 10: 174d 187 ') C I)\II P(X'I iI:C\ ,CII, U 1 O N() C„tS, I CO Scheme 69 Sv,ithetic route of compounds (187) and (189) The structures of the compounds isolated were characterized by elemental and spectral analysis (IR. I H NNIR. "'C N\IR and Mass spectrometry). The IR spectrum (Fig. 24) of (187) showed the carbonyl absorption band of harbituric acidity moiety at 1730 cii . The absorption bands for carbonyl group and carbon—carbon double bond of the a, 13- unaturat (1 system appeared at 1689 and 1623 cm-I. respectively. The 'H NMR spectrum Fig. 251 showed 1-1, proton as sharp upheld singlet at 6 7.81. The aromatic protons of the N-phenyl-p}-razole-moiety were present in the form of multiplet at 6 7.46 7.62. Six protr)ns of N ('III groups Were discernible as two sharp singlets at O 3.32 and 3.45 \\ herea> protons of' CI I : group of pyrazole unit were present in the form of another sharp 162 singlet at o 2.61. Further confirmation of the structure was done by mass spectrum (Fig. 26), which showed I' at 450.6 as base peak. The 'C NMR spectrum (Fig. 27) was also in accordance with the proposed structure given in the experimental section. The IR spectrum (Fig. 28) of showed two strong absorption band at 1597 and 1535 cm- f r C=C' and C—N bonds respectively. The 1 H NMR (Fib. 29) exhibited a sharp sin_I.t at (> 2.54 for three methyl protons of pyrazole moiety. Five aromatic protons of p\ n1coce unit appeared a; ulultiplet in the region 6 7.35-7.57. The protons H„ and Ht, were present as trans coupled doublets at (i 7.20 (.1 16.5= Hz) and 7.66 (J =16.5 Hz). Further confirmation of the structure was provided by mass spectrometry (Fig. 30) which showed N1' at 384.12 as base peak. The "C NMR spectrum (Fig. 31) was also in accordance with the proposed structure.The other peaks were observed at their normal position and are in the experimental BCetloli. 163 it e tnH C) Ill H;C CI I; i rr N CI C H3 CoV 1 c Jos 1'ld {I,O II 1 _ IL . iI V~.N CI 186a cu; 1 IIr II It v i} -llllr .~ CI Cl!3 ,g. CVS; CnH. 186b C,.II, Scheme 0. Rr,uc riots sequence Jor theJormation of product 187. 4.4. ExPER1M1:\TAl. \leltin_i points were taken to Reichert Thermover instrument and are uncorrected. The IR spectra were recorded on Perkin Elmer RXI spectrometer in KBr. 'H NMR spectra were recorded on E3rukcr DR\- 0O and Brukcr Avance 11-400 spectrometer using tetramcthyl silane GYMS) as an internal standard. -'C NMR spectra were recorded on a Bruker DR\-100 Spectrometer (100 MHz.) with DMSO. Mass spectra were recorded on JEOL- \ee a TOF JMS-T I UOLC DART-AIS spectrometer. MV licroanalytical data were collected using Carlo Erba anal\ zer model 1108. The purity of all compounds was checked by TLC on glass plates (20 <5 cm) coated with silica gel (E-Merck G254, 0.5 mm thickness). The plates «ere run in chloroform—methanol (4:1 V V) mixture and were visualized by iodine vapors. The Cllloro J metI1vS-L pIlenylpyrazole-4-carbuxaldehyeie r ' and 5-acetyl-l3- 164 dinlethvIbarbituric acid were synthesized from 3-methyl-l-phenylpyrazole-5-one and l .? dimeth\ lbarhiturie acid. respectively by reported procedures. 4.4.1. Getleral Proceriure for the synthesis of compound 187 To a \%ell stirred solution of 5-acetyl-1.3-dimcthv'lharbituric acid (1744) (4.52 Innlol) in ethanol ( 1- mL) containing pyridine (0.5 mL), 5-chloro-3-methyl-1-phenylpyrazole-4- ;,Irhrx,tldch\'dc (105) (4.52 tnnlol) was added in the portion. The reaction mixture was then ,tarred at room t,:mperaturc tier I It. Bromine (4.52 mnlol) was then added dropwise to the vizorously stirred solution over a period of 20 min. After complete addition of Br, the reaction mixture was further stirred for another 3 h. The monobronloderivative (187) was precipitated. filtered off. and washed with 15 mL of ether to remove the excess of bromine. Further purification was made by recrystalllzatiotl from the chloroform -methanol (4:1 \' \ i mixture. 4.4.2. General Procedure for the .st'nlhc's1S of 'compound 189 .\ nfixttnre of J T'Illuru ? mcih\'I I phenvlp)'razule 4 carbuxcldehy4e (105) (4.52 nlmol), ?. } dinitrutoluene (188j (4.52 mnfoll and pyridine (0.3 mL) in ethanol (12 mL) was relluxed in a hcatln~ii mantle for about 2.5 h. On completion of reaction (as checked by TLC ). the reaction mixture was poured into 25 mL ice cold water, acidified with cone- 11(1. The solid. thus. Obtained was filtered washed with water. methanol. dried and purified by rzoystallization from chloroform—methanol (3:2 V/V) mixture. 165 4.5. Spectral Data (Z/-?-I~rnntu-3-(5-chlnru-3-meth}•!-1 /)l:e,i}'lpl-i"a;,u!-d yl)-1-(1,3-dintetht•!-?,4,6 V'inlidiwutrionre•-?-tv/)prop-2-em-1-uwit (187) Pucilicatiov was made by reergstallization from the chloroform—methanol (4:1 V/V) mixture. ['ale yellow crystals. \1.1,. : 180-182°C. IIZ (KBr) u,.,,,,;cm, : 1730 (C=O), 1689 (C~O). 1623 (C=C). 'H NNIR (400 MHz. C[).1> : 3 2.61 (s, 3H, C'H,,), 3.32 (s, 3H, N -CH;), 3.45 (;, 31-1, N -CI1;), 7.16-7.62 (m. 511. AT 1-1), 7.81 (s, I H, 11,). C NNIR ( 100 Ml Iz. D.\ISO) : O 14.27, 27.73, 29?8, 38.94. 105.52, 124.53. 124.99. 128.40, 128.67, 128.79, 137.13. 148.57, 157.13, 165.12, 174.42. r.SI MS : lit/_ 490.6 (M`). Elemental analysis For C';.,H ;,,\,O.,I3r('l Calculated C. 47.57, H. 3.35: N. 11.67. Found: C. 47.42: H, 3.49: N, 11.56 166 5-('h1oro-4-/2-(2,4-dinritroophen 'l)-tiniti•1/-3-»tc'tl>1,1-1-phenyl-1!I pyrazole (189) Purifieatiom was made by recrystallization from the chloroform—methanol (3:2 VV) 1Vi\tllrc. c11U11 crystals. \1p. 122-125 °C. IR i hHrj u v cm 1597 (C=C), 1535 (C=N). 1345 (C—N). 11 \\IR (300 \Il lz. CDCI-,) : 6 2.54 (s, 31-1, C1-13), 7.20 (d, 1 H, J= 16.5 Hz, H„), 7.35-7.57 (m, 5H, Ar—H), 7.66 (d, 1H, J= 16.5 Hz, Hb), 8.00 (4, 1H, J= 8.7 Hz, He), 8.45 (d. 111, J= 8.7 Hz, Hd), 8.85 (s, 1 H, He). ( N\IR (100 M111z. D`ISO) : 14.65, 115.1 1, 117.54, 120.84, 120.99, 124.98, 125.28, 128.72, 129.28, 129.39, 139.37, 147.12, 149.05, 151.85. 1 Sl \IS : nt'- 354.12 (M ) F: L 111cntal analysis For C1 ,,HEN404Cl Calculated C, 56.19; 1-1, 3.40; N, 14.56. Found: C. 56.06: 1-1, 3.53: N, 14.51 167 x. rsa,s r. s,srr Gods-Cl. Pis.. K. a ZoM M L4 q.r IM,. M. .~ 3 as ow.aea i.aila. ,ri M S...... -_...... ~...... J. `1y.,,..v...... i...... ~ A...{.`.tom^. ,:~ J hi i 7 ! Y RRt It t q t q it atG i I l:s M0~ — 2000 IM Xumt,ar.s1.m4 VAIN .,r,1vil Fig.24. IR spectrum of 187 Fig.25.'H NMR spectrum of 187 168 Fig.26. Mass spectrum of 187 Fig.27. '3C NMR spectrum of 187 169 X ■ 2iskes Y ■ 46.0251 Code- CDT. Phase- KBr, Dr Zeha N.SWdIglti [Ms- Fwheen( 27.03.2009 LB.No 1566 60° ...... ... 1. I _1 iiQ l'; ...... s...... i... a..a...... I. Zs 4000 3000 2000 1000 X=215df5Y=56.0251 ~ +I Fig.28. IR spectrum of 189 ~~ V11. \♦ Fi g In I flely III:.•- ~'• ( - ii, Y.1. IIM •[1.1. ... IN II 111./..• yl [I 'I I11\\\I I 'I Mt 111 I-I nfllr .~-, -4thi NI;i N'lt\..I; illy 1\1 v , Fig.29. 'H NMR spectrum of 189 170 Fig.30. Mass spectrum of 189 i aCz !3C 'W: W. :1: '.cu .•J 6C a0 iC 0 FFm Fig. 31. 13C NMR spectrum of 189 171 Section B: Antimicrobial evaluation of pyrazole derivatives The synthesized compounds described in the section A have been screened for their in vitro antibacterial and antifunual activities. 4.6. In vitro antibacterial studies of compounds 187 and 189 4.6.1. Microorganism used The newly synthesized compounds were screened for their antibacterial activity against Streptococcus pyogenes (clinical isolate), Melhicillin resistant Staphylococcus aureus (MRSA+ve), P.scudomonas aeruginosa ( ATCC-27853), Kiebsiela pneumaniae (clinical isolate) and Escherichia co/ (ATCC- 25922) bacterial strains by disk diffusion method." A standard inoculwns (1-2 X 10' c.f ii ml 03 Mc Farland standards) was introduced onto the surface of sterile agar plates and a sterile glass spreader was used for even distribution of the inuculums. The disks measuring 6 min in diameter were prepared from W'hatman no. ! filter paper and sterilized by dry heat at 140 °C for I Ii. The sterile disks previously soaked in a known concentration of the test compounds were placed in nutrient agar medium. Solvent and growth controls were kept. Ciprofoxacin (30 µg) was used as pnsirice control while the disk poured in DMSO was used as negative control. The plates were inverted and incubated for 24 h at 37 °C. The susceptibility was assessed on the basis of diameter of zone of inhibition against Gram positive and Gram-negative strains of bacteria. Inhibition zones were measured and compared with the controls. The bacterial zones of inhibition values are given in Table 16. 172 Cable 16 Antibacterial activity of compounds 187. 189 and positive control ciprofloxacin. Diameter of zone of inhibition (111111). Compounds (iram-positi\'e bacteria Gram-negative bacteria S. pl'Ql'P1lex .IIRSA'. P. QLfl1gi!osa K. pneuinoniae E. coh 187 19.40.4 19.4=0.4 26.3±0.4 14.6±0.2 18.7=0.4 189 19.2-0.2 1 R.2±0.'_ 25.2±0.2 14.1=0.4 17.5=0.2 Bta!idarL1 22.5:0.4 2 ] .;_i-0.4 31.0-0.2 19.0--O.2 27.00. I l)\1SO - - - l u iav onirol (stanvi.finEi fi;N11xo:ioxac1n and negative control (DMSO) measured by the Halo Zone Test (Unit, mm). .\Lih cilhn resistant Sap) iv o tits oureus (NIRSA } Ve). Nlln11llll111 inhibitor\ concentrations (MICs) were determined by broth dilution technique. The nutrient broth, which contained logarithmic serially two fold diluted amount ut test compound and controls was inoculated with approximately 5 X 10' c.f.u. mL of actively d1% iding bacteria cells. The cultures were incubated for 24 h at 37 °C and the growth was monitored visually and spectrophotornetrically. The lowest concentration (highest dilution) required to arrest the growth of bacteria was regarded as 11M1inium inhibitory concentration (MIC). To obtain the minimum bactericidal concentration (MBC), 0.1 mL volume was taken from each tube and spread on agar plates. The number of c. fit, was counted after 18— 24 h of incubation at 35 °C. MBC was defined as the lowest drug concentration at which 99.9"o of the imoculums were killed. The minimum inhibitory concentration and minimum bactericidal concentration are given in [able 17. 173 Table 17 \IIC and \113C results of compounds 187, 189 and positive control ciprofloxacin. Compounds Cram-positive bacteria Gram-negative bacteria S. plogL'tles _IIR31-1 P. ueiugiirosu K. pneurHotule E. coil NIIC NIBC MIC MBC NIIC MBC MIC MBC MIC MBC 187 12.5 50 25 50 25 100 25 100 50 100 189 12.E 100 25 50 5)) 100 50 100 25 100 Stndard 25 12.5 6.25 12.E 12.5 25 6.25 25 6.25 25 NI IC (ug mL). minimum inhibitory concentration, i.e., the lowest concentration of the compound to inhibit the growth of bacteria completely NIBC (1t g inL), minimum bactericidal concentration. i.e.. the lowest concentration of the compound for killing the bacteria colnpletely. 4.7. In vitro antifunl;al studies of compounds 187and 189 47. I. Micruur tutism used For assaying antifun,al activity Caflclicla cilhicns, Aspergillus fumigants, Trichophvtotn n:('n1u,Jr)l)1v1c., and Pe,ticillium tnurtne)Jci were recultured in DNISO by agar diffusion method. Sabourauds ai.tar media as prepared by dissolving peptone (I g). D-glucuse (4 g) and agar l2 g) in distilled water l 100 nQ and adjusting pH to 5.7. Normal saline was used to nuke a suspension of spore of fungal strain for lawnin_g. A loopful of particular fungal strain was transferred to 3 mL saline to get a suspension of corresponding species. 20 mL of agar media was poured into each Petri dish. Excess of suspension was decanted and the plates were dried by placing in an incubator at 37 °C for 1 h. Using an agar punch. wells were male and each well was labeled. A control was also prepared in triplicate and maintained at 37 -(.' for 3-4 days. The fungal activity of each compound was compared with uriscofulvin as standard drug. Inhibition Zones were measured and compared with the controls. The fungal zones of Inhibition values are given in "fable 18. 174 Table 18 Antifungal activity of compounds (187, 189). Positive control (Griseofulvin) and negative control (DMSO) measured by the halo Zone Test (Unit, mm). Diameter of zone of inhibitioa (nun)- Compounds CA AF TM PM 187 21.4±0.2 19.9=0.3 16.2±0.2 13.5+0.4 1R9 212±0.4 19.4±0.2 153±0.4 12.2±02 Standard 30.5±0.2 26.5=0.2 23.5±0.3 21.5,0.5 D19SO - - - - CA; Candida albicans, AF; Aspergilhis fgmigatus, TM; Trichophyton rnentagrophyles, PM, PeWiei1fiim, marnefjef. The nutrient broth, which contained logarithmic serially Iwo fold diluted amount of test compound and controls was inoculated with approximately 1.6 X 10'— 6 X 10° c.fu./mL. The cultures were Incubated for 48 It at 35 °C and the growth was monitored. The lowest concentration (highzst dilution) required to arrest the growth of fungi was regarded as minimum inhibitory concentration (MIC). To obtain the minimum fungicidal concentration (MFC), 0.1 mL volume was taken from each tube and spread on agar plates. The number of c.Cu. was counted after 48 h of incubation at 35 °C. MFC was defined as the lowest drug concentration at which 99.9% of the inoeulums were killed. The minimum Inhibitory concentration and minimum fungicidal concentration are given in Table 19. 175 Table 19. \IIC and NIFC of compounds 187, 189. Positive control griseofulvin. Cimp. ('.\ AF TM PM \11C \1FC MIC NIFC MIC NIFC MIC MFC 187 25 50 25 100 12.E 50 50 100 181) 50 100 50 100 25 100 50 100 Standard 6.25 25 12.5 25 6.25 25 12.E 25 CA: Candldw a/hicuns, :\F:I-1.,per,illu.; firin1gatlrs, TM; Tric/1uplrvton nieHtagrophrtc.. P\1. Peicill11lu uru;ilellri. `IIC (Fl`_ mL), minimum inhibitory concentration, i.e., the lowest concentration of the compound to inhibit the growth of fungi completely: MFC (Lt,, n1L), minimum fungicidal concentration. i.e., the lowest concentration of the compound for killing the fungi completely. The PBE 1pereentaa1 bacteriostatic efficiency. %) was obtained as, PBE = 100-"MIC and fungicidal tlmgistatic activity (MFC M1IC) as obtained are presented in Table 20. The ratio NIFC NIIC was calculated in order to determine if the compound had a fungistatic (\IFC NIIC >> 4) or tun ideal (MFC \IIC _ 4) activity and the results have been summarized in Table 20. Table 20 PBF and funweidal fungistatic activity (,'v1FC. MIC) of compounds 187 and 189. Compounds PI3F=111u NIIC' MMFC'MIC Bacteria tested FunI-*i tested SP \l1fS:l PA KP EC CA AF T\4 PM 18' 5 4 4 4 1 2 4 4 2 189 8 4 2 2 4 2 2 4 2 ('ipr>tlo\acin 16 I0 S 16 16 - - - - CiruL'otiilvin - - - - - 4 2 4 2 SP: S. pl-ogeues, r IRS.A: Methicillin resistant Staphylococcus aureus• PA; P. ueruginosa KP: K. pneumuniae. E(': E. coli, CA: C albicuns, AF: .-1. Jilmigalus, TM: T. i )itot;'ruhhl'tcs, P`I: P mw1a1/tei. 176 The investigation of antibacterial screening data (Cables 16 and 17) revealed that all the tested compounds (187) and (189) showed moderate to good bacterial inhibition. All the compound showed good inhibition against S. pyogenes, Methicillin resistant Stapinlococcu.s aureus (MRSA +ve), P. uentginoso, K. pneumonia and E. eoli species. MIC of compounds was in the range of 12.5-50 µg/rnL. The MBC of compounds was found to be two or four folds higher than the corresponding MIC results. The anlifungal screening data (Tables 18 and 19) showed moderate to good activity. The compounds (l87 and 189) showed good fungicidal activity against C. alIicans, A. fumigates, T mentagrophyres and P. marnefjei fungal strains. MIC of compounds was in the range of 12.5-50 p ml. The MBC of the compounds was found lo he two or four folds higher than the corresponding MIC results. Most of the compounds showed good fungicidal activity against various fungal strains (Table 20). 4.8. CONCLUSION In summary, a convenient method for the synthesis of novel halopyrazole derivatives has been developed. The procedure offers advantages such as mild reaction conditions as well as simple experimental and product isolation procedures, thus, making the current protocol as useful and inleres[ng methodology for the synthesis of novel halopyrazoles in good yields from cheap and readily available starting materials. 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Medicinal Microbiology, Vol. 2 Churchill Livingstone, London, p. 196. 181 39. Varma, R.S.. 1998. Antifungal agents: past, present and. future prospects, National Academy of Chemistry & Biology, Lucknow, India. 182 CHAPTER 5 SYNTHESIS AND ANTI-INFLAMMATORY EVALUATION OF INDOLE DERIVATIVES Section A: Microwave-Assisted Solvent-Free Synthesis of Indolylchalcones and pyrazolines (Green Chemistry Letters and Reviews 4,2011,63-68) 5.1. REVIEW AND LITERATURE In recent years, green chemistry has been focus of considerable attention and is becoming an increasingly popular technology.' The aim of green chemistry is to reduce chemical- related impacts on human health and virtually eliminate contamination of the environment through dedicated sustainable prevention program. Therefore, several newer strategies such as solvent-free (dry media), solid-supported with and without microwave (MW) irradiation.'-" mechanochemical mixing (grinding),'9 use of room temperature ionic liquids,10''' supercritical carbon dioxide, t-' and water 1 ' as reaction media and many more techniques include approaches for the creation of "benign-by-design" are now accepted worldwide by different researchers for the synthesis of a variety of organic compounds. The processes which are designed by green routes help in the promotion of resource and energy utilization efficiently. It involves low level of waste, and is inherently safe making the processes economically and environmentally beneficial. In recent years, Microwave-assisted organic reaction enhancement (MORE) is well- established technique for rapid and efficient synthesis of variety of heterocycles particularly from the viewpoint of green chemistry. It provides a safe, clean and convenient way to heat reactions to elevated temperatures, accelerates many syntheses 183 providing selective activation and allows fast optimization of chemical reactions compared to conventional heating.'4 Generally, most of the organic synthesis are carried out by conductive heating with an external heat source such as Bunsen burner, hot plate mantle, water bath, oil bath etc. This technique is comparatively slow and inefficient for transii rring energy into the system. It depends on the thermal conductivity of the various materials that must be penetrated and results in the temperature of the vessel being higher than that of the reaction mixture leading to formation of side product or decomposition of product. substrate and reagent. In microwave heating, microwave irradiation passes through the walls of the reaction vessel and produces efficient internal heating by direct coupling of microwave energy with molecules (solvent, reagents, catalysts) that are present in the reaction mixture by avoiding the local overheating at the reaction walls, which can lead to high product yield with less side product. Molecules with a permanent dipole that are subjected to the high frequency oscillating electromagnetic field associated with microwaves will try to align themselves with this field. As the field oscillates, these molecules are continuously aligning and realigning with this field. The rapid motion and resulting intermolecular friction cause intense internal heat that can increase up to 10 °C per second. Due to this rapid increase in temperature the heating profile is different from conventional thermal heating and this is the main contributing factor to accelerate the rate of reactions under microwaves irradiation. Another phenomenon encountered when performing microwave heating is the specific microwave effect. This can be expected when the polarity is increased during the reaction from the ground state to the transition state. When stabilization by dipole-dipole electrostatic interactions of the transition state is more effective than that of the ground state, this results in an enhancement of reactivity by 184 lowering the activation energy. It also provides an opportunity to work with open vessels, thus. avoiding the risk of high pressure and hazards of inflammable solvents.!` Microwave technologies have also found especially extensive application in medicinal chemistry in the field of drug discovery processes. 16 Chalcone or 1,3-diary!-2-propene-1-ones, are essential group of natural as well as synthetic products with widespread distribution in fruits, vegetables, spices, tea and soy based foodstuff and has been subject of great interest for possessing interesting pharmacological activities.!' Chemically, chalcones consist of open-chain flavanoids in which two aromatic or heteroaromatic rings are joined by three carbons, a,(3-unsaturated carbonyl system. The presence of a reactive a. (3- unsaturated keto function in chalcones is found to be responsible for their biological activities such as antimicrobial,'8 anti- l (J 20 -)1 23 inflammatory. anticancer,` cytotoxic chemo preventive,"22 antilieshmanial, antifociceptive,2-1 atiprolifirative.25 antimalarial,2 6 antiviral27 anti—HI V,28 antioxidant 29 etc. Due to this diversity of bioattivity, chalcone could be considered a `privileged structure', as described by Evans and coworkers.30 Chalcones also belong to the class of the anihochlor pigments which usually give yellow to orange colours to the tissues in which they are located. Although chalcones are not responsible for pigmentation in the most yellow-coloured flowers, but they are still attractive to insects and in such a way they contribute to the flowers' pollination31. Some of the synthesized chalcones with important biological activities are highlighted below. 185 5.1.1. AntilieslJmanial chalcones Mei-Lin Go and his co-workers synthesized different substituted chalcones and studied their antilieshmanial activvit\.'- Me MeO / —R MeO R = 4-CH3, 4-CI, 3-CI, 2.4- F, 4-NO,, 4-OCH3, 3-Quinolinyl, 4-Quinolinyl O MeO R= 2, 4-difluoro. 2.4-dimethoxy, 3-quinolinyl, 4- quinolinyl 5.1.2. Antimicrobial activity A. Geronikaki et al33 synthesized novel thiazole based chalcone and evaluated their antimicrobial activities. CH, \ ~ R H:C. \ ii s O R = H. 4-NO., 4-OMe, 3-CI, 3-OMe Baviskar et al334 have synthesized novel chalcones and studied their antimicrobial activities. - I s R = (:,11~, 3-NO.0:,.II,. 4-N(CI1,)2 C,,I1 . 4-(X'H;C:H,. 3.4,5-(()C'H,)2, G.H,, 4-O}G,Hi, 3-E3rC,,H,, 3-PC'c,H, 186 Batovska and his co-workers3i have prepared chalcones and studied their antifungal activities. 0 H / OH Cl H 5.1.3. Antioxidant chalcones Kayees Ahmad et al3l, synthesized novel chalcones and evaluated for antioxidant activity. l 1 Ar (, O 0 NO, X-o-Ct.3.\L,.. NOZ - CHI Ar- Br H3C C'H, 5.1.4. Antiinflam►natorj, chalcones Kumar and et al'' have synthesized heterocyclic indole derivatives and reported anti- inflammatory activity [72]. R = p-OS. m-OCH;, SS. KtCNz1_, p-OCSi,, rr- 0001 Okunrobo and co-workers'8 have prepared novel chalcone and studied their anti- inflammatory and gastroprotective activities. 187 0 Y x , \ 4-NO, 2,4.6-0CH 3 4-NO, 3-Br X-- 4-OCH3 ti 3-Br 4-0C113 2.4.6.00}13 2.4-011 H 4-NO, 4-CI Ramaa et.a139 have prepared fluorinated chalcones and studied their anti-inflammatory activities. F R I \ F O R 4-OCH,. 3-NO.. 1 Me, 2-CI, 3-Br, 2-NO,. 4-CI, 4-F 5.1.5. Anticancer chalcones Khan et. a140 synthesized novel boronic and bis chalcones and evaluated their anticancer activity. 0 0 0 I0 13 () OII Me 5.1.6. Antimalarial chalcone Liu et al41 studied invitro antimalarial activity of some novel cahlcone. R, R i =H.R;= Cl. H R 1 =R,-R1=OCll RI =H.R=OCH,,R,=H Chalcones are good accessible starting materials for the synhesis of various biologically important heterocyclic compounds such as benzothiazepine.42 pyrazolines.' 1,4- diketones,'' flavones,4' pvrazoles.46 dihydropyrimidines,46 isoxazolines46 etc. Additionally, 188 these are also important intermediates in many addition reactions of nucleophiles due to inductive polarization of carbonyl group present at the p-position. Thus, the synthesis of chalcones has generated vast interest to organic as well as for medicinal chemists. "Therefore, several strategies for the synthesis of these systems have been reported in the literature;'. The most common method involves the Claisen-Schmidt condensation of equimolar quantities of substituted acetophenone with substituted benzaldehyde in the presence of an aqueous alcoholic alkali.48 A number of acid-catalyzed methods are also 5' reported in the literature which includes the use of A1C13 39 dry HC1,50 Zn(bpy)(OAc)2, TiCL'2 Cp2ZrFI2/NiC125' and RuCl3.54 Recently various modified methods for the synthesis of chalcones has been also reported in the literature , such as using SOCl2,15 lithium nitrate.,' amino grafted zeolites,5 zinc oxide,'8 , water,59 Na2CO3,hO PEG- 400,61 silica- sulfuric acid,62 ionic liquid°' and microwave irradiation.6' Unfortunately, many of these methods have drawbacks such as use of organic solvents either during condensation reactions or during isolation of the products by way of extraction, use of expensive stoichiornetric amount of reactants, use of hazardous and environmentally polluting solvents, low yields, extended time, tedious procedure etc. Although, several modifications have also been made to counter these problems, yet, the development of selective and better strategies for the synthesis of a, n-unsaturated carbonyl compounds is still in high demand. 189 5.2. Some recent examples for the synthesis of Chalcones under green environment (a) Solvent-free synthesis of chalcone under Ultrasound irradiation catalyzed by alkaline doped carbons Ultrasound irradiation has been increasingly used in organic synthesis in last three decades. Comparing with traditional methods, this method is more conveniently and easily controlled Recently, Aranda et.al°5 presented a green protocol for the Claisen-Schmidt condensation between benzaldehyde and acetophenone catalyzed by alkaline-doped carbons (solid phase) under ultrasonic activation in the absence of any solvent to yield the chalcone in excellent yields. (b) 1,AG03 mediated synthesis of chalcone under microwave irradiation A simple and convenient method for the synthesis of chalcones using 12-A1203 under microwave irradiation has been reported.°° Reaction completed in short time period (80sec) with excellent yields (79-95%) of the products. i_nyo~. Mw I \ 60 iec R / C\R - II 0 O R=H4-0H4L0.NO, 4-OM 3.0.0n3 OMe. 2NO CH2n K = H 2-OH, 4-0H. 4-OMe. 2 J-OMe, (c) Bronsted acidic Ionic liquid mediated synthesis of chalcones ss According to Liu et.a1 7 the -SOJH- functionalized acidic ionic liquids was found to be an efficient dual catalyst and solvent for Claisen-Schmidt condensation of benzaldehyde and acetophenone by providing an easy synthesis of chalcones under mild reaction conditions. 190 0 11 v 0 Acidic catal\ st (93.8°o) (d) Bismuth (III) chloride mediated synthesis of chalcones under solvent free condition Sandhu et. a168 reported an environmentally benign protocol for the synthesis of chalcones by the Claisen Schmidt condensation of aldehydes with ketones using eco-friendly. non- toxic hismuth(lll)chloride catalyst under solvent-free condition. In this protocol, the reaction time is very short, yields are high and there are no other pollutants formed. p 0 O a Solvent-free R Ri R1 = H, CH3, Cl O (85-90%) R i R I I EtO G5O OcMe (e) Srnthesis of chalcones using C-200 as solid support under grinding conditions Kumar et a169 reported an easy. safe and effective method for the synthesis of pyrazolyl chalcones by grinding pyrazole aldehydes and acetophenones in the presence of activated barium hydroxide (C-200) in high yield within short span of time. Ar CI-t0 0 OII Ba(OH), Ph u R \ Grinding Ph Ar (90-96%) X Ar=Ph, X 4-CH;, 4-OCH, 4-F, 4-Br, 4-Cl, 4-NO-,, 4-C,H5 R= Y = 4-Br, 4-OCH,, 4-C,HS,CH3, 2-Furyl, 2-Thienyl 1' 191 Among the various derivatives of chalcones, the pyrazoline nucleus is a ubiquitous feature of various compounds possessing many pharmacological and physiological activities and are present in a number of pharmacologically active molecules such as phenazone/ amidopyrene/ methampyrone (analgesic and antipyretic), azolid/ tandearil (anti- inflammatory), indoxacarb (insecticide) and anturane (uricosurie).1° The pyrazoline function is quite stable and has inspired chemists to utilize this stable fragment in biouclive moieties to synthesize new compounds such as cyclopropane'I and pyrazole.'Z The discovery of this class of drugs provides an outstanding case history of modem drug development and points out the unpredictability of biological activity from structural modification of a prototype drug molecule. Literature survey reveals that numerous pyrazoline derivatives have found their clinical applications as non-steroidal anti- inflammatory drugs (NSAIDs) such as felcubuzone, famprofazone, and ramifenazone.73 Certain compounds containing the pyrazoline moiety have been demonstrated to have an important therapeutic potential, such as anti-inflammatory,74 antibacterial,k antipycetic,J6, anticonvulsant,77 antidepressant,' antihypertensive,'9 antioxidant,eo antitumor, anticancer and antidiabetic83 agents etc. Some recently explored pyrazoline derivatives with important biological activity are listed below. 5.2.1. Antimicrobial activity liharmal et a184 synthesized some pyrazoline derivatives as biologically active agents. All the compounds showed antimicrobial activity against S. typhosa and A. niger. 192 Basa~varaj et al synthesized some 111-pyrazolines bearing benzofuran as biologically active agents. They exhibited high antimicrobial activity against S. aureus and moderate activity against E. coil. CFl_; CI 1'h n NON` 'R l~lhf R CI. Ph 5.2.2. Antinociceptive pyyrazolines Kaptancikli et al8` synthesized 1-[(Benzoxazole/13enzimidazole-2-yl) thioacetyl] pyrazoline derivatives and evaluated for antinociceptive activity. NON N / \ I 5.2.3. Antidepressant pyrazolines Palaslca et alb' synthesized ten new 3, 5-diphenyl-2- pyrazoline derivatives and evaluated their antidepressant activities by the 'Porsolt Behavioural Despair Test' on Swiss-Webster mice. R1 R, OCH1 1 ocH, N N11 R, = 11, CI, Br. CH;. OC113 R+ = II. CI 193 5.2.4. Atttimrcobacterial pvrazolines Ozdemir et al synthesized new 1-[(N, N-disubstituted thiocarbamoylthio) acetyl]-3-(2- thienyl)-5-aryl-2-pyrazoline derivatives 1361 and evaluated for in vitro antimycobacterial activity against Al. tuberculosis H37Rv. o~ y~s 0 Mamolo et a!89 synthesized 5-aryl-l-isonicotinoyl-3- (pyridin-2-yl)-4, 5-dihydro-1f1- pyrazole derivatives and tested for their in vitro antimycobacterial activity. The compounds showed an interesting activity against a strain of M. tuberculosis and a human strain of Al. tuberculosis 1-14. 5.2.5. Analgesic and Anti inflammatory pyrazoline Khode S et.al.'° synthesized a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-l- phenyl-2-pyrazolines and evaluated significant anti-inflammatory activity in acute inflammation such as carrageenan induced paw edema in rat model. ~4 NN X O o X = C6H5, 4-OMe-C6H4, -CH=CH-C6H4, 4-Cl-C6H4. 4-OH 194 Panneer Selvam et al`" synthesized a series of 1- (4-substitutedphenyl)-3-phenyl-lH- pyrazole-4- carbaldehyde and tested for their anti-inflammatory and analgesic activities. `tip C'HO R — H, far. CI, F. NFC0CI13 5.2.6. Antinnalarial pr•razolines B.N. Acharya et at - Synthesized a series of 1,3,5-trisubstituted pyrazolines and evaluated for in vitro antimalarial efficacy against chloroquine sensitive (MRC-02) as well as chloroquine resistant (RKL9) strains of Plasmoditun.Mciparum. Rio OCHE \ / OCZHy O Pyrazoline, derivatives as typical ICT (Intramolecular Charge Transfer) compounds are known as fluorescent brightening agent, which exhibit excellent fluorescent property93. It can absorb light of 300-400 nm and emit blue fluorescence. Pyrazoline contains two nitrogen atoms, one of which forms an electron-donating p-it conjugated system. Therefore, it is able to function as hole-transporting materials used in Organic electroluminescent devices (OELD).94 A variety of methods have been reported for the preparation of this privileged class of compounds but one of the most convenient method for the synthesis of 2-pyrazolines was described by Fischer and Knoevenagel in the late nineteenth century by the reaction of a, (3-unsaturated ketones ( acrolein) with phenyl 195 hydrazine in acetic acid under refluxing condition.95 However depending on the reactivity of molecules and need of the chemist they have synthesized the pyrazolines under different solvent media & acidic or basic conditions. Later. Auwers et al.96 corraborated that the product of this reaction was I -phenyl 2-pyrazoline. During the last century, after these pioneering studies, numerous 2-pyrazolines were synthesized by the reaction of u, (3- enones with hydrazines. This simple and convenient procedure has remained one of the most popular method for the preparation of 2-pyrazolines. 5.3. Sonic recent examples for the synthesis of pyrazolines under green environment (a) Stvnthesis of 1,3,5- triaryl-2 p►yrazolines under ultrasound irradiation Ji-Tai 1.i et.al9 reported an efficient and practical procedure for the synthesis of 1,3,5- triarvl-2-pyrazolines by the reaction of chalcones and phenylhydrazine hydrochloride in sodium acetate-acetic acid aqueous solution under ultrasound irradiation in in 83-96% yield in 1.5-2 h. x 0 NHNH2CI N— + I H2O, UV Y~ CH3COOH. CH3COONa / X (83-96%) Y X= C6H5, 4-CI, 3-NO2, Y= 4-OCH3, 4-CH3, 4-CI, 3-CI, 2-CI, 2-Br, 4-NO2 (b) Synthesis of 3,5-arj'lated 2-pyrazolines under microwave irradiation Azaritar et.al `'s demonstrates a rapid, efficient and environmentally friendly method for the synthesis of 3,5-arylated 2-pyrazolines under microwave heating, at 80 'C in excellent yields and the results obtained confirmed the superiority of the microwave irradiation method over the classical heating. 196 O R, R~ N—N R'=H CI (82-99%) R2 = Me. CI, OMe. NN, R3- H, Ph. CONH, (c) Basic alumina mediated synthesis of pyrazolines under microwave irraduiation 99 A new and efficient synthesis of pyrazoline derivatives was described by Desai et.al using basic alumina under microwave irraduiation. With this environmentally benign approach, the reaction time brought down from hours to minutes along with a yield enhancement. It s CI CI / c—cH=uH t II Basic AmminaAK,CO3 II_N NHNH, MW R NON H2NS (62-82%). R II, 2-NO,, 3-NO„ 2-CI. 4-CI. 4-N(MC),, 4-OCT,. 3-0c6115, 4.0CH3, 3-OH, 3,4,5(OCH3)3 (d) Synthesis of pyrazolines using Poly(ethylene glycol) (PEG-400) as green solvent Dawane et.al100 prepared a series of 2-pyrazolines by the base catalyzed treatment of appropriate chalcones with 4-(4'-chlorophenyl)-2-hydrazino-thiazole using poly (ethylene glycol) (PEG-400) as a green reaction medium. 197 RZ Ra / N PEG ç c l R' li / N S N}HNli_ 1 R ;= H. OH H R. 11, I, 13r R a =11. CI. Me. NH.,OMe CI R.=H,CI.Me,1,Br X= s 5.4. PRESENT WORK The indole nucleus is an important structure in various natural or synthetic alkaloids and in medicinal chemistry.101 Indole derivatives have been reported to possess several biological activities including anticancer.'° antioxidant, l°' antirheumatoidall°4 anti-HIV,1° anti- inflammatory.106 antimicrobial.107 antiviral1°8 and also play a vital role in the immune system. )9 Indole derivatives also display diverse variety of pharmacological activities that are useful in the treatment of fibromyalgia, chronic fatigue and irritable bowel I"-112 s~ ndrome.I The substituted indoles have been referred to as privileged structures since they are capable of binding to many receptors with high affinity.' l' Prompted by the above-mentioned biological properties of indoles, chalcones, pyrazolines as well as the utility of microwave irradiation in organic synthesis, it was worthwhile to prepare novel series of indolyl chalcones and their substituted pyrazoline derivatives via microwave irradiation method. The present study also compares the efficacy of reaction techniques under the conventional and the microwave irradiation methods. 198 5.S RESU1; f 5 AN I) DISCUSSION During the present ;tide. the synthesis of indolyl chalcone (192a-c) was carried out by Claisen-Schmidt condensation employing indole-3-carhoxaldchyde (137) and hetcroaryl active methyl compound, (191 a-c) undcr conventional heating method in the presence of piperidine as a basic catalyst and methanol as solvent. The reaction took longer time period (~9-12 h for completion of reaction with moderate yield (65-70 "i%) of the products. Keel nn in mind the key principles of 'green chemistry' and to obtain chalcones in a short ;pan of time with unproved yield, the reaction was carried out using microwave irradiation technique under solvent-tree condition (Scheme 71). As visualized, the reaction proceeded smoothl\ under solvent-free condition and the chalcones (192a-c) were obtained with substantial increase in yield (82-92 %0') within few minutes (6-13 min) (Table 21). The assigned molecular structures of all indolvi chalcones (192a-c) were based on spectroscopic analysis (1R. '11 \\IR and \1S) and elemental analysis data. The IR spectrum (Fig. 32) of (192a) showed characteristic absorption band at 3251 cm-t and 3 384 Cn: Llac to the pres nicc \11 and Oil groups of indole and coumarin moiety respectively. The :out11,u,in carbon %I ahsorption band was present at 1689 cin". The 1 H NMIZ spectrum (Fig. 33) showed traes olclinic protons Ha and 11b of u,O-unsaturated carbonyl system as ortho coupled doublets at a 8.43 (J = 16 Hz) and 8.58 (J =16 liz). The Value of spin-spin coupling constant J,,:. itl the ranee 15-16 1Iz is indicative of the E-contiguration of chalcone for the oletinic bond of the CO-Cl1—CI-1 group. Four aromatic protons of coumarin and live protons ol indolc moieties including I-1;\ proton were discernible in the form of tiultipta at v 7.29-8.21. Further support for the formation of(192a) was provided by mass 199 spectrum (Fig. 34) which showed molecular ion peak at nu/_ 331 (M * ). The spectral data of other compounds followed similar pattern and are explained in experimental section. Table 21 Synthesis of indolyl chalcones (1 92a-c) under conventional heating and Microwave irradiation method. Entry Product Conventional heating Microwave irradiation Time (Ii) Yield (%) Time (min) Yield (%) 1 192a 10 — 65 11 87 192b 12 70 13 92 192c 9 69 6 82 Ilb 0 \icthanol.'Piericiinr I \ C~~,{ 13- 191a-e 11 192a-c CH / V ItFT / oil O c)II 191a 192b 192c Scheme 71. Svnthesis o/fifrdo/t I chalcones (192a-c) Et•forts were made for the synthesis of novel pyrazolines (193a-t) by the reaction of incIO1Vl chalcones with hydrazines both under conventional heating method and microwave irreadiatiop. Under eons entional method pyrazolines synthesized by rcfluxinb of indolyl chalcones (192a-c) with hydrazine hydrate (177a) and phenyl hydrazine (177b) in niapanol in the presence of catalytic amount of piperidine (Scheme 72). The reaction took loitecr time (7-15 h) for completion with lower yield (57-68 °/%) of the products. When the 200 same reaction was carried out under microwave-irradiation reaction in solvent- and catalyst-free environment, the reaction proceeded efficiently and the reaction time brought down from hours to minutes (5-1 i min) with excellent yield of products (76-89%) (Table 22 ). I ormation of pyraiolines ( 193a-f) was confirmed on the basis of IR :11 NMR, and mass spectral analysis. The IR spectrum (Fig. 35) of(193a) showed two broad absorption bands at ,189 cm"' and 3270 cm'' due to the presence of NH groups of pyrazoline and indole muicties. The absorption band for the coumarin carbonyl group was discernible at 1680 cm . The 'H NN,IR spectrum (Fig. 36) showed a broad singlet (D2O exchangeable) at O 10.3', due to the presence of NII proton of indole moiety. The aromatic region of the spectrum exhibited nine protons in the range () 7.09-8.11 due to four protons of coumarin and live protons of indole moieties including I [A proton. The presence of pyrazoline unit W,H c~tabilishcd by the presence of two doublet of doublets at O 4.01 (He), 4.16 (Hf) and a triplet at r) 5.41 (1-Id). Further evidence for the formation of pyrazoline (193a) was provided h recording the mass spectrum (Fig. 37) which showed molecular ion peak at in: 345.15 ( \-1+). 201 Table 22 Synthesis of indolyl pyrazolines 193a-f under conventional heating and %1igiro%%ave irradiation method. Entry Product Conventional heating Microwave irradiation Time (h) Yield ('%,) Time (min) Yield ('%) I 193a 7 66 5 SQ 193b 10 61 8 78 193c 13 68 10 95 4 193d 15 57 13 76 193gi 11 61 12 85 6 193f 9 68 7 89 R \lrlbamQl piperidinc 1 Hf He 193a-f 193x: R-H W1 I / 193b: R-C„H; 1"a. R II OH 'f 1; 193c: IZ-I1 193d: R - c II' .111 'I 193e. RII 1931'. R=Cv11; I1F 1 1{ oil Scheme 72. St';iillcsis u/ prra ohm' derii•atri'e.5 front inclolvl chalconcs (I 93a-I) 202 5.(6. CO\CLlS1O\ Itt search of potentially active molecules containing indole moiety we have developed an efficient. facile. and practiLally convenient _,rcen: methodology for the synthesis of indolyl chaleoncs and corresponding pyrazolines employing WiCro\raVe irradiation protocol. The notable leanures such as simplicity in operation, excellent yields of the products. faster reaction rate:, and cleaner reaction profiles make the current protocol feasible and .Mfrs, tiv C. 5.7. EXPERI1IE\"1'.AI. Melting points of all Synthesized compounds were taken in Riechert Thermover instrument and are uncorrected. The IR spectra were recorded on Perkin Elmer RXI spectrometer in Kl3r. 'H \\IR spectra \\crc recorded on a Rruker DRX-300 and Broker Avance II 400 spectrometer using ts1rau11tE \ cilane (THIS) as an internal standard and DMSO-d(, CDCI,, as solvent. FAB may; acorn were obtained on Jeol-SX-102 spectrometer and DART-MS was recorded on a JEOL-Acct 'I OF JNIS-Tl00LC mass spectrometer having a DART source. Elemental anal\ ses C. I-1 and N) were conducted using the Elemental vario EL III elemental analyzer and their results were found to be in agreement with the calculated values. 5-Acetvl-l-3-dintethyl barbituric acid and 3-acetyl-4-hydroxycoumarin were synthesized by reported procedures 114. I1'. Other chemicals were of commercial grade and used Without further purification. The homogeneity of the compounds was checked by thin laver chrontatographyiTLO on glass plates coated with silica gel G254(E. Merck) using, cli harotd1"Ill nie fhanol ( 311 I mixture as mobile phase and visualized by iodine vapors. All cx )eriinents under nlicro\v av e irradiation were carried out using an unmodified domestic 203 microwave oven (National. Model NN-SSS7WF, 1.3 KW. 2450. mltimode equipment. full power). 5.7.1. Sivithesis of inelol►'/ chulcones (192u-e•) ulu/er• conventional heron method lo a solution of 3-oCet\ l-4-hVdroxy couinarin (Iminol)/ 5-acetyl-1. 3-Clnlcthyl barbituric acid (1 mmol) u dcl]ydroacetic acid (191a-c) (1 mmol) in methanol (10 mL) containing 0.2 fill f hipericliWe v a; added lnc]ole- 3-carboxaldchydc (137) (1 mmol). The reaction mixture va; heated under reflox on a water bath tar 9-12 h. Ater completion of the reaction (Winnitored by T1.( 1. the reaction mixture was cooled at room temperature. The solid, thus, obtained was filtered, washed with eater, alcohol and dried to afford the i 1)2a-c). 5.7.2. Si'ntlie.\i.c of i,ulol 1 c•/ia/cones (192a-c) uncles- microwave irrucliatiun imetlod \ mixture of ii tole ; carho~tildchyde (137) (l mmol), 3-acety1-4-h\droxycoutslarin (1 1]]llb)1) 5-aeet\ 1-1.3-dimeth\ lbarbituric acid (l mmol ) dchvdroacctie acid (191 a-c) (1 nlmol) and hiheridine (0.2 ml,) was placed in an open pyrex beaker and subjected to nucrowave irradiation wing domestic microwave oven and Irradiated for appropriate time till the reaction was completed. The progress of the reaction was monitored by TLC. On completion of the reaction, reaction mixture was slurred in cold water (50 ml,) and the yellow solid obtained was filtered, dried and recvrstallised from CHCI;-N/1eOH (2:3) mixture to give (I 92a-c) in excellent yields. 204 5.7.3. Spectral data of compounds 2E-I- (1-!/t'droxt'-1-hc►r;,nhtrwr-2-one-3-ti!)-3-(I H- iiidol-3yI)-2 ppropeiw-l-orne (192a) Ptnrilied by recrystallization from chloroform-methanol (2:3 vv) mixture. Orange crystals M.p. >300°C. IR (KBr) u113 .Y;cm'' 1689 (C=O), 3251(NH), 3384 (01-1). 'H NMR (400 MHz, CDCI3) 6 (ppm) 7.29-8.21 (m, 9H, Ar-H+HA), 8.43 (d, l H, J=16 Hz, Ha), 8.58 (d, 1 H, J=16 Hz, Hb), 8.68 (s, 1H, NH), 19.27(s, 1H, OH). ESI-MS m/: 331.13 (M ) Elemental analysis for C20H,,NO4 : Calculated C, 72.57; H, 3.98; N 4.23 Found C, 72.84; H, 4.02; N, 4.21 %. 2E-1-(1,3-Dinuctlti'1-2,4,6-pr riinidiizetrioize-5'-v!,)-3-(JH-indo!-3 yl)-21propcnt-1-one (1 9 2b) Purified by recrystallization from chloroform-methanol (2:3 v, v) mixture. Yellow crystals M.P. >300 °C. IR (KBr) vmax/Cm 1654 (C=O), 3276 (OH). 'H NMR (400 MHz, DMMISO- d„) J (ppm) 3.35 (s, 611, 2 N-C11.), 7.25- 7.50 (m, 5H, Ar-H+HA), 7.82 (d, 1H, J=16.1 Hz, Ha), 8.31 (d.11-1, J=15.9 Hz, Hb), 11.05(s, 1H, NH). 205 ESI-NlS nt/_ 325.15 (;VI-). Elemental analysis for Calculated C, 62.80; H, 4.65; N, 12.92; C,-Hi;N;O4 Found C, 62.97; H, 4.81; N, 12.90 %. (2G)-1-(4-Hrdrort-6-nret/rt1-2-oxo-2-H pti•t•utt-3-v1)-3-(IH-indolvl-3-y1)-2 propene-1- one (192c) Purified by recrystallization from chloroform-methanol (2:3 v. v) mixture. Light Orange crystals NI.p 295-298 °C. I 1. (KB r) u ,,:.,`cnl I 1699 (C=O), 3048 (NH), 3170 (OH). 1 I I \NIR (100 i✓v111z, D\'ISO- d,) ii (ppm) 2.28 (s, 311, CI 1), 5.96 (s, I11, 1-I'), 7.25-7.58 (m, 5H, Ar-H+H:~), 7.78 (d. 1H, .1=15.5 Hz. Ha), 8.13 (d, 1H..1-=15.4 Hz, Hb), 11.6 (s. 11-1, NH) 18.74(111, s• Oil) FSI-NIS m/ 295.1? (M ). Elcilcnfal analysis for Calculated C, 69.21; H, 4.43; N, 4.74 C Found C. 69.29: 11, 4.46: N. 4.70. S7.4 Preparation of i,relolt•l j'•u;•o/iHes (193a f) u„der conventional heating; method ;\ mixture of itidoly lehaleones (192a-c) (2.5 mmol), hydrazine hydrate (177x) (2.5 mmoll phenyl hydrazine (177b1 (2.5 mmol) and 0.1 mL of piperidine was retluxed in methanol on water bath for appropriate time. After completion of reaction (checked by TI.C' ). reaction mixture %%as cooled at room temperature until yellow color crystals (193a- f) '.'. cre obtained. It %va-s tiItered, washed with N1eOI I. dried and recrvstalIised from CHICI-,- \leOIl (2:; \ \.') mixture. 5.7.5. Preparation of indolvi p1,razolines (1 93a-J) under microwave irradiation method \ i.1ixuI:c of indol\ l ;halrOncs (192a-c) (2.5 mmol) and substituted hydrazine (2.5 mmol) (177a-h i were taken in an open Pyrex vessel and irradiated in a microwave oven for the ahhr hriute time until the Completion of reaction (monitored by TLC). After completion, the reaction mixture \v au cooled at room temperature and was poured into cold water (50 mL i. The solid as obtained was filtered, dried and recrystallised from CHC1.-McOH. 5..6. Spectral dal. $-( 1 Ht dro.v 1-hey► opt ran-?-ogre-3 ,1'1) - 5-(I fI indol-3-v!) pvruzolrc (1 93a) Puri tied b\ reery talliaation from chlorotorus-methanol (2:3 VN) mixture. \:Itw. 0 I coaipound Pale yellow crystals \I.l~. 250-253 °C, I l (1<13r) u,, cm 1680 (C=O), 3189 (NH), 3270 (OH). ~11 \\1R (400 M1ir. Cl)C1:1 (i (ppm) 4.01 ((1 H. dd, J=1$.$ Hz, 7.8 Hz, He). 4.16 (111. dd. .J=1 S.9 l lz, 9.72 1 Iz, Ht), 5.41 (1 11, t,1= 17.9 Hz, 1-{d), 7.09-8.11 (m, 91-1, Ar-H-H.A), 10.35 (s, 111. Ni I). I l-N IS ni;= 345.15 (MV). 1;1ela1esttal tilllalvsIs tar Calculated C. 69.62; 11, 4.38: N. 12.17, C, 11i:N c): Found C, 69.59: H. 4.36; N, 12.13 %. 207 1- !'he►►'I-3-(4-lt►vl►ox►-1-ben uh►'ran-2-une-3-t1)-5-(111 indol-3-t•!) jt•ra--oliue (193b) Purified by rcewst,IIilaticm from chloroform-methanol (2:3 VV) mixture. \~ll&\\ "n,tals Ni 287-290 ''C 1R (N..Br) k),,.i,%em 1695 (C=O), 3058 (NH). 3344 (OH). 11\\IRt4(.IoiMllr.([)CI;I () (ppm) 3.80 ((11-1, dd. J=18.9 1 Iz. 8.1 IIz, 1-le), 4.32 (11-1, dd, J= 18.9 I Iz, 12.0 Hz, Hf). 5.53 (1H, t, J= 12.0 Hz, Hd), 6.83-8.06 (m, 14H, Ar-H-~H.. ), 8.24 (s, IH. NI-I), 14.2 (IH, s. 011). F.\H - NIS m, 421 (\1 f ). F1cmGm:II anal sis tur Calculated C. 74.17; 11, 4.54: N, 9.98: Found C, 74.29: 1-I, 4.66; N, 9.94 %. 3-(I • $-1)ittrc'tlr I.1-', 4, h I.'t rirgi(lirrc tf icing-5 .► l)-3-(1 H inrlol-3 _y/)p1•ruzolirrc (193c) Puri lied h\ reel\ sta11iNation flow cliOrOt0rtn-methanol (2:3 V L') mixture. Yellow crystals \1.1, : 253-255 `C. I R i K13r) u:,..,. cm 1716 (C=0), 3224 (NII). 3344 (NIl). `H N.,IR 1400 NIHi. CCUCI,I )(ppm) 3.35 (6H, s. 2N-C'H-,), 3-95 (1 H. dd, J18.- I Iz. 8.1 IIz. IIc)• 1.16 (111, del. J-18.7 1 Iz. 8.8 1 Iz. Hf). 5.22 (11-1. t..J= 17.1 1 Iz. Hd). 6.99-7.63 (m, 51-1, :1r H-rH v ), 10.41 (s, IH, Ni 1). 208 l Sl \1S m:. 339.18 (M`). FI mental analy is for : Calculated 0.60.23; I1, 5.05; N, 20.65: Found C, 60.33: H. 5.39: N. 20.63 %. 1-Phe,rlrl-3-(1,3-dinretht•1-2.-1,6-pvrii ziditretrio►re-5-y!)-3-(1I!-iiidol-3 }'1) ppyrazoline (1 93I) Purified b% recrystallization from chloroform-methanol (2:3 V V) mixture. Yellow crystals \1. p. 257-290 °C. 1R (KBr) t, v. cm 1694 (C=O), 3384 (NH). 11 N\IR (-10O villz. ('DCI,) 6 (ppm) 3.35 (6H, s, 2N-CH;), 3.97 (1H, dd. J=18.311z, 8.1 Hz, Ile), 4.21 (111, dd, J=18.3 Hz, 8.7 Hz, HI j, 5.17 (III, t, J= 11.7 I Iz, Hd), 7.14-7.66 (m. I I H, Ar-H-H;\ ), 8.17 (s, I H, Nil). FSI-NIS ,n;'. 415.15 (VI ) Flcmcntal analysis fur Calculated C. 66.56; H, 5.10: N, 1.68; ('-:1I2 N.0: Found C. 66.65; H, 5.1 1, ; N. 1.65%. 209 3-Il-lltrlro.e►' G-yncr/1tI-?-oso-?-H-Arian-3 .GI)-3-(III-i,Tdult/-3 y1)-ptru;.ulrrc (193e) Puntied by rccrvtitalliration from chloroform-methanol (2:3 \' V) mixture. Nip. 234-237 °C. IR iKBr) v: em' : 1690 (C=O), 3085 (NH), 3199 NH), 3426 (OH). 1I NNIR 1400 Nil lz. CDCI:) : O (ppm) 2.28 (311. s, CH;), 3.66 ((111, dd. J=19.0 Hz. 6.0 1-iz. 1-He), 4.01 (1 H, dd, J=19.0 Hz, 9.8 Hz, Hi), 4.87(1 H, dd, J= 9.7 Hz, 6.0 Hz. lId), 7.42-8.20 (m, 5H, Ar-H+H), 12.1 (III, s, NH). ESL-AIS : nuz 310.17 (M ). Elemental anaalvi; for : Calculated C, 66.07: H, 4.89: N, 1.35: (',-11 •:A:O Found C. 66.10: 11, 4.96. N. 1.30%. I -Pitt tt,1- 3-r 1 l:, drrlx,-G-n~etlit l-Z-uxo-?-H-Ayr un-3-} 1)-3-(IH-iitdo1y1-3- 1)-jgvu o1ine (19 3/) Purified by reerystallizatlon from chloroform-methanol (2:3 \' V) mixture. Red crystals \1.1). 238-240 C. IR i KBr) u,,. c ni 1695 l('=O), 307$ (NH), 3351 (OH). 'El \NIR 140() Mllz. ('l)CI:) )(ppm)2.28(31-1, s, CH-,), 3.68 (Ill, dd, J= 18.8 Hz, 8.0 1-lz, lie), 4.21(1 11. dd, J— 18.8 Hz, 210 12.0 lIz. lift 5.47(1H. dd,J= 12.0 liz. 8.0 Hz, lid), 6.05(] H. s, I I), 6.80-7.61 (1 OH, iii, Ar-H--H.), 8.05 (1H. s. NH), 13.52 (IH, s. OH). ESI-NIS : ni: 386.22 (M) Elemental analysis for : Calculated C, 71.75: H. 4.97; N, 1.09: .11 N O Found C, 71.72; 11, 4.99, N, 1.06. %. 211 X • 2190.16 Y 51.2607 Code. FA4, Phase- KBr, Dr. Zeba N.Siddiqul [Ms. FwhoonJ 29.07.2009 ULM.1793 60 U SO -... a 7 .... _.... .. _ _. _ ._...-. ..._~ ...... S c a. x s• 40 a i....R 35- 4000 3000 2000 1000 X~2190.16Y■51.2!7 [cm+I Fig. 32. IR spectrum of 192a Fig. 33. 'H NMR spectrum of 192a 212 Fig. 34. Mass spectrum of 192a X-2198.96Y-52.3056 Code- Al. PhaswKB,, Dr. LN.Siddlqui [Ms. Farlwan] 21.07.2009 LB.No. 1767 - 65 OQ 66 -~ 60 45 - I0-- - ...... R.~ A...... 35.. I E3 i 3000 2000 1000 X = 2198.98 Y = 52.3051 Fig. 35. IR spectrum of 193a 213 T'/AACF 'f 4C( MR tali .~ fW : l\tai V II __ L__ I Fig. 36. 'H NMR spectrum of 193a Fig. 37. Mass spectrum of 193a 214 5.8. REFERENCE 1. Clark. J. H. Green Chem. 1999, 1, 1. 2. Varma. R. S.: Ju. Y. in Loupy A (ed). Microwaves in Organic Synthesis 2006, Weinheim: Wiley-VCH, pp 362. 3. Varma. R. S. Pure Appl Chem. 2001. 73, 193. 4. Chen. Y.: Wu. S.: Tu. S.; Li, Ci.: Shi, F. J. of Heterocyclic Chem. 2008, 45, 931. 5. Pillai, U.: Sahle-Demessie E.: Varma, R. S. J. Mat. Chem. 2002. 12, 3199. 6. Varma. R S. Tetrahedron 2002, 58, 1235. 7. Lonouz A. M.: Moghani, D. Synth. Commun. 2011, 41, 2152. 8. Feng , G. L. Chinese Chem. Lett. 2010. 21, 1057. 9. Longhi, K.; Moreira. D. N.; Marzari, M. R. B.; Floss, V. M.; Bonacorso, H. G.; Zanatta, N.: Martins. M. A. P. Tetrahedron Lett. 2010. 51. 3193. 10. Peng, J.: Deng Y. Tetrahedron Letters 2001, 42, 5917. 11. Martinez-Palou. R. J. Mex. Chem. Soc. 2007, 51, 252. 12. Kwon. C. H.: Lee. J. H.: Kim, S. W. Kang, J. W. J. aiicrobiol. 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REVIEW & LITERATURE Inflammation is a defensive response of body, which induces physiological adaptations to minimize tissue damage and to remove the pathogenic infections. Such mechanisms involve a complex series of cellular and modular events including dilation of arterioles, venulcs and capillaries with increased vascular permeability and exudation of fluids containing plasma proteins as well as migration of leukocytes into the inflammatory area. A chronic inflammation is however an important contributory factor in morbidity and mortality. At macroscopic level such inflammatory disorders include rheumatoid arthritis, osteoarthritis, inflammatory bowl diseases, retinitis, multiple sclerosis, psoriasis and atherosclerosis.' In recent years, there is considerable therapeutic interest in novel anti-inflammatory drugs with mode of action different from that of the classical non-steroidal anti- inflammatory drugs (NSAIDs), mainly for use in patients with arthritis of varying degree of severity. The most prevalent side effects of NSAIDs is the occurrence of gastrointestinal damage such as gastritis, gastric ulcer, and renal toxicity.2-5 Therefore, the discovery of new and safer anti-inflammatory drugs represents challenging goal for such a research area.' A number of heterocyclic bioactive compounds are used in various traditional systems of medicine to relieve inflammation.' The indolc nucleus is present in an astonishing variety of natural products endowed with potent and multiform biological activities. Indole nucleus is the active principle in a number of natural drugs, such as reserpine, strychnine, ergotamine and other alkaloids. Indole and their derivatives have been reported to possess wide spectrum of activities of pharmacological importances 224 These pharmacological activities have been the major interest behind the syntheses of the indole and their derivatives. Indole ring also constitutes an important template for drug design such as the classical NSAIDs indomethacin, tanidap and indoxole.9 0 NH, OI N O 0 OH I.domethaoin ludoxnk Icnidap In addition, the importance of lead molecules for the discovery of new synthetic drugs, several chemical structures are used as a starting point for chemical modifications in order to improve potency, selectivity or pharmacokinetic parameters. Furthermore, a systematic variation of substituents around the indole ring at 3-position has led to the exploration of a large number of potent biologically active compounds.1° A literature survey reveals that the compounds with the backbone of chalcone and pyrazolines attached to an indole nucleus may show an improved anti-inflammatory activity in carrageenan induced inflammation model.' Edema formation, leukocyte infiltration and granuloma formation represents such components of inflammation.i2 Edema formation in the paw is the result of a synergism between various inflammatory mediators that increase vascular permeability or the mediators that increase blood flow. 13 The carrageenan-induced edema in the rat hind paw most widely used for the screening of new arrti-inflammatory agents.' Carrageenan is the phlogistic agent of choice for testing anti-inflammatory drugs as it is not known to be antigenic and is devoid of apparent 225 systemic eftccts. It has been used to evaluate the effect of anti-inflammatory agents like NSAIDs, which primarily inhibits the cyclooxygenase involved in prostaglandin synthesis. Thu;. keeping this in view, the present study has been undertaken to investigate the anti- intl,iinnlatorV activit\ Of' the synthetic heterocyclic compounds (indolyl chalconcs and 11yrazoline~) by carraeenan induced pa%v edema method. The evaluation of anti- intlamnlatory activity vas carried out in the Department of Pharmacology, JNMC, Aligarh Muslim University, •\lie,ch. 5.9.1. Screening of anti-intlammator~' activity of indolyl chalcone and pyrazoline compounds in rats Thy anti-intlaulnlator\ acti\ity of all the synthesised compounds was evaluated using ciira c;nan induced pen\ edema assay model of inflammation on \Vi:.tar rats, by adopting the method of \inter ei al.'' using aspirin as standard drug. Structure for the compounds evaluated for anti-iutlamtnatory activity listed in Scheme 73 and 74. 5.9.1 a. Animals \\'iStar rats (1 50-2(X) _I of either sex were used for anti-inflammatory studies. They were housed at the temperature 24 1 ? °C with 12 h light:'dark cycles in polypropylene cages in groups of six animals each. The animals were fasted overnight before the experiment and given Water ad libitum. The study controncd to the guiding principles of Institutional Animal Ethics Committee (I.AIiC). J. N. Medical College, Aligarh, India. 226 5.9.1b. Experimental Design and drug treatment fhe animals are weighed and divided into three groups of six animals each. Group I- Received 2.5 °/o DMSO in the dose of 2 mLikg. p.o. I h prior to carrageenan and served as control. Group 1I- Received aspirin in dose of 100 mg/kg. p.o. I h before injection of carrageenan. Group III to XI — Received test compounds (192a-c and 193a-f) in the dose of 200 mg/kg. po. I h before injection of'carrageenan. 5.9.1 c. Carrageenan - induced paw oedema in rats The animals were handled gently to avoid too much of stress on them which could result in an increased adrenal output. A mark was made at the lateral maleous of the left hind paw so that the dipping was done to the same level \\hile measuring the paw volume. After I h of administration of a standard and the test compounds. the animals were injected subcutaneously with 0.1 mL of freshly prepared suspension of carrageenan (I % /V) into the subplantar region of right hind pa\\ of each rats. Immediately thereafter, the paw was immersed in water exactly to the mark. The measurement of the hind paw volume was carried out using digital Plethysmometer for animals in all the groups before treatment and after 1. 2. and 3 h of carrageenan injection. The initial volume of a pa\\ as measured \\ithin thirty seconds of the injection of carrageenan. The anti- inflammator\ activit\ \gas expressed as percent inhibition of the inflammation in the drug treated group in comparison with the control group. 227 The percent inhibition of edema was calculated by using the following formula: Inhibition — UU(\-l')"Xj'`100} X— mean increase in la volume of rats in the control group, V - mean increase in pw volume of rats in the treated group 5.9.2. lndol I chaleoues screened for anti-intlasnmatory activities The ,eneml synthetic trate;v employed to prepare indolyl chalcone and indolyl h\-razolmm analogues were based on Claisen-Schmidt condensation, which has been previously explained in section A. i~ (lil 1921) ~ J 1. IU.I Scheme 73 228 5.9.3. Indolyl pyraiolines screened for in vivo anti-inflammatory activity [IN N O1-{ N—N ()H 1931b II 193a I I N—\ 0 Cl I: N fl (I1: II (I1, I 193d FIN—N Oil N t OCFl FI US 1931 Scheme 74 5.9.3 a. Statistical unu/t'%i.% \Il the values x%ere expressed as Mean = SEM. Statistical significance was calculated by one way :\NOVA iollowcd by post lioc Dunnett's multiple comparison test. Rats in each group were six (n=6) and P < 0.05 was considered to be statistically sitnniticant. The software SPSS-20 was used to carry out all the statistical tests. 229 5.10. RESULTS Carry eeenan indoeced paw edema is one of the most commonly employed method fur the screening of acute inflammation. The anti-inflammatory activity was evaluated by recrdiiie Illean hind pa' volumes at 0, 1. 2 and 3 hours following carrageenan injection in control and test groups. 'l he results of the anti-inflammatory effect of the indolvl chalcone (1 92a-c)and hyrazolincs (193a-t) are presented in Table 24, 25 & 26, 27. As shown in Tables, the entire invcstieated compounds (192a-c and 193a-f) exhibited moderate to good anti- inflammatory activity with the percentage inhibition of edema formation ranged from 41.9 to 93.5 "o at the end of 3 h. whereas, at the same time, the standard drug aspirin (100 mg kg) showed 85.4"„ inhibition of inflammation in comparison with control. As indicated in Table 24 & 25, the indolvl chalcones 192a, 1921) and 192c decreased the paw edema at the end of 1. 2 and 3 h but test compound 192a showed the significant decrease in paw edema at I h (P < 0.05) whereas at the end of three hours all the compounds exhibited ,1,,nit1cant anti-inflammatory activity (P < 0.01) with the percentage inhibition of edema formation ranged from 41.9 to 69.3 % as compared to control group. 230 Fable 24 Et ect of indolvl chalcones compounds on carrageenan Induced paw oedema Mean paw volume ± SEM (nil) (;roup~ 0 11 1 11 2 Ii 3 h Control 0.74±0.005 1.04±0.01 1.15±0.01 1.36±0.005 l Clill 1:,) :aspirin 0.7t - 0.005 0.94 :- 0.01 * 0.97 -I- 0.01 ** 0.87 -=- 0.005** (100 lug kg) 1 C 192a 0.-5 - 0.02 0.93 - 0.02* 0.97 ± 0.02** 0.94 w 0.04** (20)) 111,._' ke. i( 1921) 0.79-0.01 0.97-0.02 0.97-0.03* 1.15~- 0.02** (20)111 g kg) T( 192c 0.51 = 0.04 0.97 - 0.03 1.01 ± 0.04** 1.01 = 0.03** (20O Ill_, kg) TC = Test compound * 1'<0.05 * * P <0.01 Each avcraie value represents the mean -- SEM (n=6). 1 he dhteleIHcz 111 results were considered significant when *pm,l.)J, and ** P<0.01 its compared with the control group. 231 Table 25 Percentage Inhibition of paw edema by indolyl chalcones compounds in carrageenan induced paw Groups Time intervals lh 2h 3h Control (DN1SO) (2mlkg) Aspirin 46.6 70.7 85.4 (1 t)t) Inge kg TC 192a 40.0 46.3 69.3 (200 mg kg) TC 192b 36.64 56.0 41.9 (200 m° kg► TC 192c 46.6 51.2 67.7 (200 tnc ke) TC — Test compound C%ctiLation of these indoM chalcone into their corresponding pyrazolines also decrease the paw edema at the end of I. 2, and 3 h but significant decrease in paw edema was seen in compound 193a. 193b. 193f (P < 0.01) and 193d (P < 0.05) at the end of I h. whereas at the end of three hours all the compounds exhibited significant decrease in paw edema t P 0.01) with the percentage inhibition of edema formation ranged from 60.9 to 93.E % a: compared to controlgroup. The percentage inhibition of edema of' indolylpyrazolines (193a-f) was found to be greater as compared to their parent compounds (192a-c) Table 26 & 27. 232 fable 26 hffect of indolvl pyrazolines compounds on carrageenan induced paw oedema Mean paw volume 1SEM (till) Groups 0 h 1 h 2 h 3 h Control (D11SO) 0.74 =0.005 1.04 ± 0.01 1.15 =.008 1.36 = 0.005 (2 ml k) Aspirin 0.78 =0.005 0.94 = 0.01 * 0.97 ± 0.01 **0.87 t 0.005** (100 mg kg) TC 193a 0.77 - 0.04 0.88- 0.02** 0.98 0.03* 0.94 = 0.02** (200 in k) TC 193b 0.06 - 0.02 0.73 = 0.04** 0.75 = 0.02** 0.70 ± 0.02** (200 m._ k,-,) TC 193c 0.85 t 0.03 0.90 ± 0.02 0.95 ± 0.03* 0.91 ± 0.02** (200 m;; keg) T(.' 193d 0.0=0.02 0.90 = 0.02* 0.95 = 0.01 ** 0.91 = 0.02** (200 fig kg) T('193e 0.8310.03 1.01 ± 0.04 0.96 ± 0.03** 0.94 ±0.03** 200 m .keg) TC 193f U.78 = 0.04 0.94 0.03** 0.91 ± 0.04** 0.87 = 0.04** (200 mg kg) Tc = lest Compounds XP<0.05 **1'<0.01 Each average value represents the mean = SEM (w 6). The (11i tercncc in results was considered significant when *P<0.05. and **P<0.01 as compared with the control group 233 Table 27 Perccntaige Inb hition of paw edema by indolyl pyrazolines compounds in carra zcCnall i iduced paw Time Interval Groups I h 2 h 3h Control (DNISO) - - - (2m1k,) ~piri» 46.6 70.7 95.4 10) m<, k,l 'TC 193a 63.3 48.7 72.5 (200 m k ) TC 193b 76.6 78.0 93.5 (2I)0 ni L'_' TC 193c 33.3 39.0 60.9 (200 m k ) TC 193d 43.3 53.6 64.5 (20O lll'Zrk TC 193c 40.0 43.9 70.9 (200 m k i TC 193f 46.6 68.2 85.4 (200m"ki) TC = Tc~t compounds 234 5.11. DISCUSSION The carraceenan induced paw edema model was used to screen the anti-inflammatory activity of the test compounds in acute phase of inflammation. Edema induced by c.trra`aeenau is believed to be biphasic: the tirst phase (l Ii) involves the release of serotonin and histamine and the second phase (over 3 h) is mediated by prostazlandins, cvcluoxy cnase products. Continuity between the two phases is provided by kinins.'` An insi,2ht to the anti-inflammatory actix itv with respect to the chemical structure of synthesized compound. revealed that compounds having chalcone and pyrazoline moiety at position of indole nucleus exhibited significant (P < 0.01) anti-inflammatory activity when compared with control group. Among the indolvl chalconc. compounds (192a) and (192c) with hydroxyl group on the 4 position of Coummarin and py ran moiety showed good anti-inflammatory activity (P < 0.01) at :It,: cud of third hour; alter can'aicenan injection with 69.3 and 67.7 % reduction in the 1,:i IcI:Ia respcetich. t. iilpoond (192b1 also shows significant ail1i-lnf1ammatory acn\ itv (P - 0.01) nth 41.9 0 edema inhibition indicating that the presence of groups forming hydrogen bonds in compounds (192a) and (192c) may be helpful in snore efficient binding with the receptors. 11 hereas the presence of bulky substitution dimethv l group in compound 192b reduced the activity Which may be due to the improper attachment with the receptor. Among the indolyl pyrazolines 1931), 193d and 193f (addition of phenyl hydrazine to compound 192a, 1921) and 192c respectively), compound (193b) was found to he highly active and exhibited signiticant anti-inflammatory activity (P <0.01) at first, second and third hours with 7(~.(, 78.() and 93.5 h reduction of paw volume respectively compared to 235 control group and inflam111atory activity was better than standard drug aspirin which decreased paw volume by`5 .4 % at the end o1' ihirLl hour. Compound (193t) and (193d) exhibited significant anti-inflammatory activity (P < 0.05) at the end of 1 It with 46.6 o and 43.3 % inhibition of paw edema which increases (P <0.01) at the end of second (68.2 and 53.6 a ul and third hi (\ 5.4 °.'b and 64.5 °,'n) respectt\ CI V. On the other hand compounds 193a, 193c and 193e in the pyrazoline series where phenyl group was replaced by hydrogen (addition of hydrazine hydrate to 192a, 192b and 192c respccti\ elv) also exhibited significant anti-inflammatory activity (P < 0.01) at the end of three hrs but to a lesser extent than 193b, 193d and 193E (addition of phenyl hydrazine to 192a, 1921) and 192c re pecti\ cly) indicating that addition of phenyl hydrazine markedly improved the anti-inflammatory activity. Compound (193x) of the coumarin moiety shows the significant decrease in paw edema at the end of I (P < 0.05) and third hrs (P < 0.001) which reduced paw edema by the value of 63.3 and 72.5 °i% respectively, whereas compound (193e) and (1 93c) exhibited significant anti-inflammatory activity (P < 0.01) at the end of three his with -'0.9 and 60.9 % of edema inhibition. From the rctiults it is evident that all the chalcones and pyrazoli nes having indole substituent showed significant anti-1nflatrvnlatory activity from first hour onwards and reached the maximum at the third hour- and is comparable to that of the standard drug (aspirin►. This type of anti-inflammatory activity for this chalcone is understandable since tudol, derivatives are known to possess significant atitl-entlainmatog activity and a number of drugs belonging to this class are also being used as it NSAIDs. 236 5.12. CONCLUSION It I< concluded that all the chalcones and pyrazolines (192a-c and 193a-t) having indole moiety showed siunificant anti-inflammatory activity from first hour onwards and reached the niasimum at the third hour and is comparable to that of the standard drug (aspirin). 5.13. REFERENCES: t Alv aio-Graeia, J. M. R(tewnutolog - 2004, 43, 121. Ilcrlla'. J.: Lauritsen. ,I.: Villadsen. II. D.: Gram. L. F. Scand. J. (iostroeutterol 1995. 30, 43. 3. McCarthy. D.: lot . 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N.; Bhosale, A. V. lnt. J. Pharm. Biomed. Res. 2010. 1, 12. Mitchell, R. N.; Cotran, R. S. Robinson's basic pathology. 7th ed. New Delhi: Harcourt (India) Pvt Ltd: 2000. 13. Ialenti. A.; lanaro, A.: Moncada, S.; Di Rosa, M. Eur. J. Pharm. 1992, 211, 177. 14. Somchit, M. N.; Nur, S. M. H. Incl. J. Phur. 2003, 35, 181. 15. Winter. C. A.: Risley, E. A.; Nuss, G. W. Proc. Soc. Exp. Biol. 1962, 111, 544. 16. Gupta, S. K.: Drug screening methods, 2nd edition 2009. Jaypee brothers medical publications. 486. 239 Journal of Molecular Catalysis A: Chemical 363-364(2012)451-459 Contents lists available at SciVerse ScienceDirect `CATALY Journal of Molecular Catalysis A: Chemical ELSEVIF R journal homepage: www.elsevier.com/locate/molcata Silica supported sodium hydrogen sulfate (NaHSO4-Si02 ): A novel, green catalyst for synthesis of pyrazole and pyranyl pyridine derivatives under solvent-free condition via heterocyclic 3-enaminones Zeba N. Siddiqui •, Farheen Farooq Department of Chemistry, Aligarh Muslim University. Aligarh. 202 002, India ARTICLE INFO ABSTRACT Article history: NaHSO4-SiO2 is used as an efficient, mild and reusable catalyst for the synthesis of novel heterocyclic Received 14 May 2012 pyrazole (Sa-h) and pyranyl pyridine (7a-h) derivatives via heterocyclic (3-enaminones (3a-d) under Received in revised form 19 July 2012 thermal solvent-free conditions. The remarkable features of this green, new methodology are high con- Accepted 20 July 2012 versions, cleaner reaction profile, simple experimental and work-up procedures. Structures of the newly Available online 27 July 2012 synthesized compounds have been elucidated on the basis of elemental analysis and spectral data (IR. H NMR. 3C NMR and mass spectrometry). The catalyst is characterized for the first time by using scanning Keywords: NaHSO4-Si02 electron microscopy-energy dispersive X-ray (SEM-EDX) and powder XRD. The catalyst can be reused Heterocyclic O-enaminones several times without significant loss of its catalytic activity. Pyrazoles O 2012 Elsevier B.V. All rights reserved. Pyranyl pyridines Heterogeneous catalyst 1. Introduction (NaHSO4-Si02) has been found to be an efficient, inexpensive, non toxic, recyclable and ecofriendly heterogeneous catalyst in various Development of new solid-phase (solvent-free) reactions and useful chemical transformations such as protection and deprotec- transferring solution phase reactions to solid-phase are subjects of tion [5), Knovenagel condensation [6], and Biginelli reaction [7). It recent interest in the context of generating libraries of molecules for is also used in the synthesis of dihydropyridines [8]. xanthenes (9J, the discovery of biologically active leads and also for the optimiza- homoallylic amines )l0[. pyrazolines ] 11 J, amides [12). quinazoli- tion of drug candidates [ 1). Hence, the challenges facing chemist nones 1131, and imidazoles 114). this century is to develop new transformations that are not only Pyrazole ring is an important structural motif present in numer- efficient, selective and high yielding but also environmentally ous pharmacological and agrochemically important compounds. benign. A solvent-free organic reaction is an important synthetic including inhibitors of HIV-1 reverse transcriptase (15) and cele- strategy from the viewpoint of green and sustainable chemistry. coxib derivatives as anti inflammatory agent (16). Pyrazoles can Researchers have demonstrated that the solvent-free organic syn- be synthesized by 1,3-dipolar cycloadditions of diazo compounds theses are generally faster, selective, higher yielding with cleaner 117). reaction of chalcones and hydrazines [ 18 ], a four-component products, environmentally benign and involve simple operational coupling of terminal alkynes, hydrazine, carbon monoxide and procedure as compared to the classical reaction (2]. aryl iodides [ 19( and the direct condensation of 1,3-diketones and Heterogeneous catalysts have gained much importance in hydrazines in fluoroalcohol [20]. A variety of other catalysts such recent years due to economic and environmental considerations. as H2SO4 (21). polystyrene supported sulfonic acid [22], zirconium These catalysts are advantageous over homogeneous catalysts as sulfophenyl phosphonate [23], Sc (OTf)3 1241, Y-zeolite (25), Mg they can be easily recovered from the reaction mixture by simple (CI04 ) (26] have been also employed to affect this transformation. filtration and can be reused after activation, thereby making the On the other hand, pyridine is one of the most prevalent het- process economically viable. A tremendous interest has sparked erocycle being the core fragment of different natural product! in various chemical transformations promoted by catalysts under and pharmaceutical active agents (271. In addition to classics heterogeneous conditions [3,4(. Silica supported sodium bisulfate pyridine syntheses such as the Krohnke reaction, many nev, approaches have been also reported in the literature including condensation of amines and carbonyl compounds, cycloadditior • Corresponding author. Tel.: -91 9412653054. reactions, multicomponent reaction (28-31) etc. Despite the wide E-mail address: siddiqui ebalUyahoo.co.in (ZN. Siddiqun). range of conceptually different syntheses of pyrazole and pyridine 1381-1169/S - see front matter 2012 Elsevier B.V. All rights reserved. htt p://dx.doi.org/10.1016j.molcata.2012.07.024 dLdIY WN Science & Technology Cite this: Catal. Sci. Technol., 201 1,1810-816 www.rsc.org/catalysis PAPER Zn(Proline)2: a novel catalyst for the synthesis of dicoumarols Zeba N. Siddiqui* and Farheen Farooq Received 29th March 2011, Accepted 23rd April 2011 DO!: 10.1039/c l cv00l l Oh A novel, greener approach was adopted for the synthesis of dicoumarols (3a-j) using Zn(Proline). as a mild, non-toxic. Lewis acid catalyst in water employing 4-hydroxycoumarin (1) and aromatic heteroaromatic aldehydes (2a-j). The catalytic activity results suggest that the methodology adopted offers several advantages such as mild reaction conditions, low loading of catalyst, quantitative yields, short reaction time and operational simplicity. Introduction manganous chloride,25 and thermal solvent free reaction con- ditions26 etc. However, in spite of their potential utility some Dicoumarol I la) (Scheme 1) is it naturally occurring anticoagulant of the reported methods suffer from certain drawbacks such as drug that functions as a vitamin K antagonist. Chemically. it long reaction time, expensive reagents, harsh conditions, low is designated as 3.3'-methvlenehis[4-hydroxycoumarin] and product yields and use of toxic catalysts that are harmful to obtained from metabolism of coumarin in the sweet clover environment. Therefore, to avoid these limitations there is still (Melilutus alhu and Afeli(ottcc ofcinulis) by bacteria Pcnic•illiurn a need for the development of a new protocol for the synthesis of nigric•ans and Penicillium jensi.'•2 Dicoumarol and its synthetic dicoumarol derivatives in terms of operational simplicity, reusa- derivative warfarin sodium (coumadin) have shown to decrease bility of the catalyst and economic viability. metastases in animal models.; Moreover, warfarin sodium The current environmental concerns encourage development therapeutically as an anticoagulant has emerged as one of the of greener reaction conditions, where possible, and the tight most substantial classes of drugs for the treatment of a variety legislation on the maintenance of green conditions in synthetic of cancers and has shown to improve tumor response rates.''' processes that insist on preventing the generation of waste products, In clinical trials, such compounds have also demonstrated to avoiding the use of hazardous organic solvents, and minimizing have some activity against prostate cancer. malignant melanoma. the energy requirements. 27 The use of aqueous reaction media and metastatic renal cell carcinoma.7 "A recent study has revealed has received considerable attention in the context of green that the inhibition of NAD (P) H: quinone oxidoreductase chemistry. During recent years. water has attracted great interest (NQO,) with dicoumarol induces cell killing and oxidative stress as an inexpensive and environmentally benign solvent due to in pancreatic cancer cells.'0 Further, lanthanum(ut) complexes its specific properties.' When organic compounds are suspended of dicoumarol have been reported to show potent cytotoxic in water, their relative insolubility causes them to associate, activity.'1 Compounds with this ring system also possess diminishing the water-hydrocarbon interfacial area.293° In various other pharmacological activities such as insecticidal, other words, the hydrophobic effect of water generates internal anthelmintic. hypnotic, antifungal, phytoalexin. HIV proteases pressure and promotes the association of the reactants in the inhibition, antimicrobial and antioxidant.'2-'9 During the last solvent cavity during the activation process and accelerates the decades, several methods have been adopted for the synthesis reaction:1112 of this important class of compounds and include use of DBU Lewis-acid catalyzed organic reactions in water have attracted (1,8-diartbicyclo[5.4.0]undec-7-ene),20 (Et2AICl,).2' refluxing much attention in organic synthesis because they allow environ- ethanol or acetic acid.`= molecular iodine,'' POCI1 in dry DM F.24 mentally friendly processes under mild reaction conditions." Proline is the most prominent amino acid for the coordination OH OH of Zn, its secondary amino group and carhoxylate function being ideally suited for Zn2 in low coordination number, which makes Zn complex a moderately soft Lewis acid. Zn(Proline)2 is an efficient, stable, inexpensive. recyclable, water compatible. la Lewis acid catalyst which is not dissociated under reaction Scheme I Structure of dicoumarol. conditions." This complex is soluble in water hut insoluble in organic solvents, which allows simple and quantitative recovery of the catalyst." Zn(Proline), appears to be a particularly Department of ('hemi.ctrt•, Aligarh Muslim Univer.cirr, Aligarh 20201)2, India. E-mail siddiyui_:ehrrra rahoo.co.in. efficient catalyst for both enamine and enolate type catalyses.;c' Tel: +91 09412653054 Among the various zinc-amino acid complexes. the Zn(Proline)2 810 1 Catal. Sci. Technol., 201 1, 1, 810-816 ~. ,,:,~ ,. • ; ;,~ c :1• - .. u > I J. Chem. .Sc i. Vol. 12- . No. 5. September 2012, pp. 1097-1105. U Indian Academy of Sciences. A practical one pot synthesis of novel 2-hydroxy-4-chromanone derivatives from 3-formylchromone LIRA N SIDDIQUI* and F:ARIIEFN FAROOQ Department of Chemiar~, Aligarh Muslim Uni%ersit%, Aligarh 202 On2. India e-mail: siddiqui_reha@a ahtx>.cu.in MS receised 3(1 August 20I I: revised 19 March 2012; accepted I9 April 21)1' Abstract. A one pot synthesis of 4-chmntanone derivatives (Sa—j) is described using Zn((L)(proline)]2 as catal'st in aqueous media. The compounds have been characterized on the basis of elemental and spectral data SIR, 'H NM R and mass). The adsantages of this pnnocul include high yields, mild reaction conditions, ens ironmentally benign and simple operational procedure. The use of water as solvent and Znf (l.)prolinel, as recyclable, non-toxic catal\ si make such sN nthesis a truly green pnxcess. Keywords. 3-Forntvlchrontone: "Zn((I.tprolinej,, -t-chrosnanone: water: ;green synthesis. 1. Introduction matic/heteroaromatic amines under green reaction con- ditions have been invcstigated. It is pertinent to men- Chromone moiety forms an important component of tion that chromanones represent an important group pharrnacophores of it number of biologically active of compounds which display it remarkable domain of molecules of synthetic as well as natural origin.' biochemical and pharmacological actions. They have Chromone and their derivatives are found in nature been examined for antioxidant.' antibacterial, "' anti- as pigments in plant leaves and bowers. They are malarial.' anticancer. ' antifungal,'' topoisomerase important for the synthesis of various oxygen heterocy- inhibitor, "' psychoanaleptic. antianloebic and antide- cles including xanthones and transition metal chelates. pressant properties.'' Some chromanone derivatives They are widely present in nature and exhibit low toxi- have been evaluated for in vitro antiviral activities city along with a wide variety of useful properties. ' They against human immunodeficiency virus (HIV) and are reported to exhibit significant biological activities Simian immunodeficiency virus (SIV).'~ ~' They have including anti inflarnnmatory. antiallergic.' antibacte- also been claimed to be active in photosynthesis'' and rial,'' ncuroprotective, anti HIV,' antioxidant.'' anti- have hereditary bleaching effect (similar to antibiotics) fungal. "' etc. They also display spasmolytic, car- on the plastid system of Euglena s,'racilis..` Other 4- diotonic, antiarrhythmic" and anticancer properties.'' chromanone derivatives have also been found useful in 3-Forms Ichromone (4-oxo-4H- I -benzopyran-3-car- the treatment of bronchial asthma. boxaldehyde) has been frequentlyy used for the svn- As it result, for the synthesis of 4-chromanone deriva- thesis of various heterocyclic derivatives ever since its tives different methods have been developed. These convenient synthesis was reported by Nohara et al.' methods have certain drawbacks such as prolonged Derivatives of 3-formvl chromone are useful synthetic reaction time. use of toxic and volatile organic solvents building blocks in both organic and medicinal chem- and varied yields. The replacement of these hazardous istry.' ` 3-Formvlchromone has been chosen for the solvents with the environmentally benign solvents is one present study due to the reason that it carries three elec- of the key areas of green chemistry. Among various tron deficient centres viz. a.f -unsaturated keto func- green solvents, water is the most popular as it is inex- tion. a carbonyl group in the form of formyl group at pensive. thermally stable, recoverable, biologically com- position 3 and a sery reactive electrophilic centre at patible, and non-toxic. In recent years. water-mediated C-2. In the present paper. the products (chromanones) organic synthesis has become one of the most impor- of reaction of 3-formvlchromone with primary aro- tant aspects in organic chemistry in order to meet the environmental demands.-"' '['his strategy becomes one of the most powerful green chemical technologies if such `For correspondence reactions could be carried out using homogeneous or 1097 Journal of Saudi Chemical S cien (201 3) 17. 237 243 King Saud University Journal of Saudi Chemical Society 1, ~~ N% ww.kiericcdircct com ORIGINAL ARTICLE Synthesis, characterization and antimicrobial evaluation of novel halopyrazole derivatives Zeba N. Siddilvi a,', Farheen Farooq a, T.N. Mohammed Musthafa aAnis Ahmad b, Asad U. Khan Department of Chemistri. Aligarh Muslim University. Aligarh 202 002. India Interdisciplinary Biotechnology Unit, Aligarh Muslin University, Aligarh 202 002, India Received 9 February 201 I; accepted 29 March 2011 Available online 3 April 2011 KEYWORDS Abstract Two novel halopyrazole derivatives (3, 5) were synthesized from 5-chloro-3-methyl-l- 5-Chloro-3-methyl-l-phenyl- phenvlpyrazole-4-carboxaldehvde (t) using appropriate synthetic routes. Newly synthesized com- pyrazole-4-carboxaldehyde: pounds were characterized using elemental analysis, spectral data (IR, 'H NMR. '`C NMR and Pyrazoics; mass spectrometry) and were evaluated for their in vitro antimicrobial activity. The minimum inhib- Antibacterial activity: itory concentration (MIC), minimum bactericidal concentration (MBC) and minimum fungicidal Antifungal activity concentration (MF(') were determined for the test compounds as well as nix reference standards. The investigation of antimicrobial screening revealed that compounds (3, 5) showed good antibac- terial and antifungal activities, respectively. Z 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. 1. Introduction Mitscher et al., 1999). Morbidity and mortality because of en- teric bacterial infection are the major health problems in some In recent years. the number of life-threatening infectious dis- areas like the Indian subcontinent, portions of South America eases caused by multi-drug resistant Gram-positive and and tropical fraction of Africa (Qadri et al., 2005: I)evasia Gram-negative pathogen bacteria has reached an alarming le- et al., 2(X16). Every year millions of people are being killed vel in many countries around the world (Berher et al., 2003; by some or the other Gram-positive and Gram-negative strains of bacteria. These bacteria mostly lead to food poisoning, - Corresponding author. Tel.: +91 09412653054. rheumatic, salmonellosis and diarrhea (Khan et al.. 2008). E-mail address: ,iddiquJ_7cha .' }ahoo.co in (Z.N. Siddiqui). Thus, antibiotics provide the main basis for the therapy of microbial (bacterial and fungal) infections. However, overuse 1319-6103 © 2011 King Saud University. Production and hosting by of antibiotics has become the major factor for the emergence Elsevier A.V. All rights reserved. and dissemination of multi-drug resistant strains of several groups of microorganisms (Harbottle ct al.. 2006). Further- Peer review under responsibility of King Saud University. doi:10.1016j.jus.201 I 01.(116 more. the pharmacological drugs available are either too expensive or have undesirable side effects or contraindications (Berger. 19S5). Thus, in light of the evidence of rapid global Production and hosting by Elsevier spread of resistant clinical isolates, the need to find new anti- microbial agents is of paramount importance. Green Chemistry Letters and Reviews i , Taylor&Francis Vol. 4. No. I, March 2011, 63-68 RESEARCH LETTER r A highly efficient, simple, and ecofriendly microwave-induced synthesis of indolyl chalcones and pyrazolines Zeba N. Siddiqui*, Farheen Farooq and T.N. Mohammed Musthafa Department of Chemistry, Aligarh .Muslim University. Aligarh 202002. India (Received 29 April 2010; final version received 9 June 20101 One-pot synthesis of indolyl chalcones (3a—c) employing indole-3-carboxaldehyde (I) and heteroaryl active methyl compounds (2a-'e) under microwave irradiation is described. The indolyl chalcones (3a-c) are transformed into medicinally important pyrazolines (5a—f) using different hydrazines. Application of microwave irradiation leads to many remarkable advantages, such as solvent- and catalyst-free reaction conditions, simple work up procedure. shorter reaction time, in addition to ecofriendly 'green chemistry' economical and environmental impacts. Keywords: green chemistry: microwave irradiation; indole-3-carboxaldchyde; chalcones; pyrazolines Introduction derivatives display diverse variety of pharmacological activities that are useful in the treatment of In recent years, green chemistry has been focus of fibromyalgia, chronic fatigue, and irritable bowel considerable attention and is becoming an increasingly syndrome (17-19). Besides being biologically active. popular technology (1). The aim of green chemistry they are also used extensively as synthons in organic is to reduce chemical-related impacts on human synthesis that possess potentially reactive health and virtually eliminate contamination of the site for a variety of chemical reactions. Indole-3- environment through dedicated sustainable preven- carboxaldchyde is a naturally occurring component of tion program. For organic reactions there is an urgent Brassica vegetables (cabbage, broccoli). It induces a need for reducing toxic, volatile solvents in use. Many G- I cell cycle arrest of human breast cancer (20). The green synthetic methods have been studied by different diversity of the iodole nucleus has motivated research researchers for the synthesis of it variety of organic aimed at the development of new economical efficient molecules (2). Microwave irradiation is a newly and selective synthetic strategies. As a part of our established, convenient synthetic method and con- ongoing research work in the identification of new tinues to affect synthetic chemistry significantly by chemical entities (21) with variety of pharmacological enabling rapid, reproducible, and scaleable chemistry activities, we herein report microwave-assisted access development (3,4). This technique has been applied to a series of indolyl chalcones and their conversion to to a variety of reactions resulting in reduction of other heterocycles like pyrazolines from indole-3- reaction time, higher yield, greater selectivity, cleaner carboxaldchyde and demonstrate its superiority over reaction products, and easier manipulations (5). It also classical heating methods. It is worth mentioning provides an opportunity to work with open vessels. that chalcones are the precursor of flavonoids, thus avoiding the risk of high pressure and hazards of isoflavonoids, and have displayed an impressive array inflammable solvents (6). of biological activities (22-25). Particularly, indolyl Indole nucleus annulated to carbocyclic and chalcones have been reported as anti-inflammatory heterocyclic ring(s) is one of the most ubiquitous (26), antiproteolytic (27), anthelmintic (28), anti- scaffolds found in an astonishing variety of pharma- cancer (29), and antiproliferative (30). They are also ceuticals (7), functional materials (8-10), agrochern- reported as antitumor, immunodepressant, carcino- icals (11), and alkaloids (12) endowed with potent and genic, and therapeutic agents for autoimmune diseases multiform biological activities. They are also reported (31), whereas pyrazolines are pharmacologically ac- to possess anti-inflammatory (13), antimicrobial (14), tive compounds and have been reported to possess antifungal (15), antioxidant (16), etc. activities. Indole antiandrogenic (32), antibacterial (33), antifungal *Corresponding author. Email: siddiqui_zeba(ayahoo.co.in; zns.siddiquiiu;gmail.com 41 ISSN 1751-8253 print ISSN 1751-7192 online r 2011 Taylor & Francis 1)O1: 10.l0s0r17518253.2010.500624 http:l; www.inlnrmaworld.com