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Ramani, Vaibhav N., 2011, “Studies on Nitrogen and Oxygen Containing 

Heterocyclic Compounds”, thesis PhD, Saurashtra University 

http://etheses.saurashtrauniversity.edu/id/eprint/546 

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© The Author

“STUDIES ON NITROGEN AND OXYGEN 

CONTAINING HETEROCYCLIC COMPOUNDS” 

A THESIS SUBMITTED TO 

THE SAURASHTRA UNIVERSITY 

IN THE FACULTY OF SCIENCE 

FOR THE DEGREE OF 

DOCTOR OF PHILOSOPHY 

IN 

CHEMISTRY 

BY 

VAIBHAV N. RAMANI 

Supervisor: 

Prof. Anamik Shah 

DEPARTMENT OF CHEMISTRY 

(DST-FIST FUNDED AND UGC-SAP SPONSORED) 

SAURASHTRA UNIVERSITY 

RAJKOT – 360 005 GUJARAT (INDIA) 

DECEMBER – 2011

Statement under O. Ph. D. 7 of Saurashtra University 

The work included in the thesis is done by me under the supervision of 

Prof. Anamik K. Shah and the contribution made thereof is my own 

work. 

Date: 

Place: Vaibhav N. Ramani

CERTIFICATE 

This is to certify that the present work submitted for the Ph.D. degree of Saurashtra University 

by Mr. Vaibhav N Ramani has been the result of work carried out under my supervision and is a 

good contribution in the field of organic, heterocyclic and synthetic medicinal chemistry. 

Date: 

Place: Prof. Anamik K. Shah

ACKNOWLEDGEMENT 

It is moment of gratification and pride to look back with a sense of 

contentment at the long traveled path, to be able to recapture some of the 

fine moments, to be think of the infinite number of people, some who 

were with me from the beginning, some who joined me at different stages 

during this journey, whose kindness, love and blessings has brought me 

to this day. I wish to thank each of them from the bottom of my heart. 

Therefore first and foremost I bow my head humbly before 

ALMIGHTY GOD for making me much capable that I could adopt and 

finish this huge task. 

I bow my head with absolute respect and pleasantly convey my 

heartily thankfulness to my research guide and thesis supervisor, most 

respectable Prof. Anamik Shah, who has helped me at each and every 

stage of my research work with patience and enthusiasm. I am much 

indebted to him for his inspiring guidance, affection, generosity and 

everlasting supportive nature throughout the tenure of my research work. 

I would like to bow my head with utter respect and convey my 

pleasant regards to my most adorable Mom and Dad, for believing in me 

and also for their blessing, constant support, courage and enthusiasm; 

they have shown throughout my work without which this thesis would 

not have appeared in the present form. I am equally thankful to my wife 

Ketaki, for her endless moral support and belief; I would also like to 

thank her for performing biological activity tests of my compounds. I am 

blessed to have my twin brother Vihar on my side with his concern and 

care during this tenure. I would also like to thank Papaji, Mumiji, Kaka,

Kaki, Dashu, Bhabhi, Saloni, Vicky, Harmeet, Rushi, Varun and 

Mira for encouraging me during my Research work. 

My Special thanks to Punitbhai, Dipak, Bharatbhai, 

Bhavinbhai, Dilip and Denish who gave me constant support during my 

Research work. 

I would like to express my feelings of gratitude to Prof. P.H. 

Parsania, Professor and Head, Department of Chemistry, Saurashtra 

University, Rajkot for providing adequate infrastructure facilities. 

I am also thankful to Kanakaka who has been for me whenever in 

need and given me constant support during all my Research work. 

Words are inadequate to thank my closest friends Hiten, Yash, 

Vijay, Rasesh, Mohit and Jay who are always with me and have helped 

me in each and every phase of my life. 

Many many special thanks and lots of love to my dearest 

colleagues Dhairya, Jignesh, Rakshitbhai, Nilaybhai, Hitesh, 

Harshad, Manisha, Mrunal, Ravi, Vaibhavbhai, Saileshbhai, 

Hardevbhai, Abhay, Ashish, Pratik, Vishwa, Sabera, Madhvi, Hetal. 

I would like to thank Dr. Preeti, Dr. Jyoti, Dr. Fatema, Dr. 

Rupesh for all their help and support. 

I would also like to express my deep sense of gratitude to Dr. 

Ranjanben A. Shah and Mr. Aditya A. Shah for their kind concern and 

moral support that made my second home in Rajkot. 

I am also thankful to my Collegues Bhavesh, Dr. Ram, Govind, 

Minaxi, Amit, Kapil, Piyush, Renish, Naimish, Dipti, Sagar, Anil,

Vipul Mahesh, Piyush, Jignesh, Suresh, Jignesh, Lina, Pooja, Sandip, 

Ritesh, Ashish, Rahul and Kataria. 

I am also thankful to Dr. Yogesh Naliapara, Dr. V.H. Shah, Dr. 

H. S. Joshi, Dr. Shipra Baluja, Dr. Manish Shah and Dr. Bhoya for 

their constant support. 

I would like to thank teaching and non-teaching staff members of 

Department of Chemistry, Saurashtra University, Rajkot. 

I am also grateful to Sophisticated Analytical Instrumentation 

Facility (SAIF), RSIC, Punjab University Chandigardh and Central 

Drug Research Institute (CDRI) Lucknow for 1 H NMR and 

Department of Chemistry Saurashtra University, Rajkot for IR, Mass and 

Elemental Analysis. 

I am thankful to “National Facility For drug discovery through 

new chemical entities development and instrumentation support to 

small manufacturing pharma enterprises” for instrument support and 

limited financial assistance. 

Lastly 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 once again bow my head before Almighty to facilitate me at 

every stage of my dream to accomplish this task. 

Vaibhav N. Ramani

General Remarks 

Abbreviations 

CONTENT 

CHAPTER – 1 MICROWAVE ASSISTED FACILE SYNTHESIS OF 

BENZOFURANS LINKED WITH SUBSTITUTED 1,3,4 

OXADIAZOLES 

Department of Chemistry, Saurashtra University, Rajkot – 360 005 

Content 

1.1 Introduction 1 

1.2 Pharmacology 3 

1.3 Synthetic Aspect 6 

1.4 Aim of Current Work 10 

1.5 Reaction Scheme 10 

1.6 Reaction Mechanism 11 

1.7 Experimental 12 

1.8 Physical Data 13 

1.9 Spectral Study 14 

1.10 Spectral Characterization 15 

1.11 Representative Spectra 18 

1.12 Result and Discussion 24 

1.13 Conclusion 24 

1.14 References 25 

CHAPTER – 2 SYNTHESIS AND CHARACTERIZATION OF 5,6,7,8 

SUBSTITUTED (3-AMIDO ADAMANTANE) 4-HYDROXY 

COUMARINS. 


2.2 Pharmacology 30 


2.4 Reaction Scheme 46


Content 

2.5 Plausible Reaction Mechanism 46 


2.7 Physical data 48 




2.11 Result and discussion 57 



CHAPTER – 3 SOLVENT FREE SOLID PHASE SYNTHESIS OF 

AZOMETHINE LINKED COUMARIN MOITIES. 



3.3 Green Chemistry Approach 74 








3.11 Result and discussion 94 



CHAPTER – 4 SYNTHESIS AND CHARACTERIZATION OF SOME 

4-SUBSTITUTED 2,6-DIMETHYL 3,5-DICARBONITRILE 

1,4-DIHYDROPYRIDINES AND THEIR MANNICH BASES 

USING VARIOUS SECONDARY AMINES. 


4.2 Biological profile of 1,4-dihydropyridine 99 

4.3 1,4-dihydropyridines and mannich reaction 105 

4.4 Aim of current work 111


Content 

4.5 Reaction scheme 111 

4.6 Plausible reaction mechanism 112 









CHAPTER – 5 FACILE SYNTHESIS OF SOME NOVEL FURO 

COUMARINS 













CHAPTER – 6 PREPARATION OF NOVEL PYRIDO PYRIMIDINE-2-ONE 

DERIVATIVES 




6.4 Reaction Scheme 178


Content 









CHAPTER – 7 PROCESS DEVELOPMENT AND YIELD OPTIMIZATION 

OF SOME IMPORTANT INTERMEDIATES. 










CHAPTER – 8 BIOLOGICAL EVALUATION OF SYNTHESIZED 

CHEMICAL ENTITIES 


8.2 Methods used for Screening 222 

8.3 Results and Discussion 225 


SUMMARY 

CONGERENCES/SEMINARS/WORKSHOPS ATTENDED

General Remarks 

GENERAL REMARKS 

1. Melting points were recorded by open capillary method and are uncorrected. 

2. Infrared spectra were recorded on Shimadzu FT IR-8400 (Diffuse reflectance 

attachment) using KBr. Spectra were calibrated against the polystyrene 

absorption at ‘1610 cm -1 . 

3. 

1 

H Spectra were recorded on Bruker Avance II 400 spectrometer. Making a 

solution of samples in DMSO d6 and CDCl3 solvents using tetramethylsilane 

(TMS) as the internal standard unless otherwise mentioned, and are given in 

the δ scale. The standard abbreviations s, d, t, q, m, dd, dt, brs refer to singlet 

doublet, triplet, quartet, multiplet, doublet of a doublet, doublet of a triplet, ab 

quartet and broad singlet respectively. 

4. Mass spectra were recorded on Shimadzu GC MS-QP 2010 spectrometer 

operating at 70 eV using direct injection probe technique. 

5. Analytical thin layer chromatography (TLC) was performed on Merck 

precoated silica gel-G F254 aluminium plates. Visulization of the spots on TLC 

plates was achieved either by exposure to iodine vapor or UV light. 

6. The chemicals used for the synthesis of intermediates and end products were 

purchased fro Spectrochem, Sisco Research Laboratories (SRL), Thomas 

baker, Sd fine chemicals, Loba chemie and SU-Lab. 

7. All the reactions were carried out in Samsung MW83Y Microwave Oven 

which was locally modified for carrying out chemical reactions. 

8. All evaporation of solvents was carried out under reduced pressure on 

Heidolph LABOROTA-400-efficient. 

9. % Yield reported are isolated yields of material judged homogeneous by TLC 

and before recrystallization. 

10. The structures and names of all compounds given in the experimental section 

and in physical data table were generated ChemBio Draw Ultra 10.0. 

11. Elemental analysis was carried out on Vario EL Carlo Erba 1108. 

Department of Chemistry, Saurashtra University, Rajkot – 360 005

List of Abbreviations 


NCEs New Chemical Entities 

R & D Research & Development 

HTS High Throughput Screening 

DHFR Dihydrofolate Reductase 

UTIs Urinary Tract Infections 

IDU Idoxuridine 

ARC AIDS - related complex 

Hsv Herpes simplex virus 

HIV Human Immunodeficiency Virus 

5-HT 5-hydroxytryptamine 

CNS Central Nervous System 

NSAID Non-Steroidal Anti-Inflammatory Drug 

COX Cyclooxygenase 

GnRH Gonadotropin-Releasing Hormone Antagonist 

PDE4 inhibitors Phosphodiesterase inhibitor 

FT-IR Fourier Transform- Infrared spectroscopy 

1 

H-NMR 

1 

H- Nuclear Magnetic Resonance spectroscopy 

DEPT Distortionless Enhancement Polarization Transfer 

Gl. Glacial 

TLC Thin Layer Chromatography 

Rf Retardation factor 

EtOH Ethanol 

Conc. Concentrated 

hrs / h. Hours 

GC-MS Gas Chromatograph- Mass Spectrometry 

DMSO Dimethyl sulfoxide 

mL Milliliter 

MeOH Methanol 

mp Melting Point 

Ms Mass


Anal. Calcd. Analytical Calculated 

IR Infrared 

TMS Trimethylsilane 

MHz Megahertz 

MIC Minimum Inhibitory Concentration 

MTBE Methyl tertiary butyl ether 

NCCLS National Committee for Clinical Laboratory Standards 

mg Miligram 

CDK-2 Cyclin-Dependent Kinase -2 

PPA Polyphosphoric Acid 

DMF Dimethylformamide 

MAOS Microwave-Assisted Organic Synthesis 

MW Microwave 

Min. Minute 

W Watt 

Pd Palladium 

SiO2 Selenium Dioxide 

InCl3 Indium Trichloride 

PTP Pyrazolotriazolopyrimidine 

GABA Gamma Amino Butyric Acid 

QSAR Quantitative Structure Activity Relationship 

SAR Structure Activity Relationship 

DNA Deoxyribonucleic Acid 

DBU Diazabicycloundecene 

EDG Electron Donating Group 

EWG Electron Withdrawing Group 

POCl3 Phosphorous oxychloride 

ZnCl2 Zinc chloride 

AlCl3 Aluminium trichloride 

EtOH Ethanol 

MeOH Methanol 

NaOH Sodium hydroxide 

HCl Hydrochloric acid


K2CO3 Potassium carbonate 

H2SO4 Sulphuric acid 

BH3.THF Borane in tetrahydrofuran 

KBr Potassium bromide 

CDCl3 Deuteriated chloroform 

BF3.Et2O Borone trifluoride in diethylether 

HCN Hydrogen cyanide 

TiCl4 Titanium tetrachloride 

KOH Potassium hydroxide 

NaH Sodium hydride 

LiH Lithium hydride 

KF Potassium fluoride 

Al2O3 Aluminium trioxide 

Br2 Bromine 

FeCl3 Ferric chloride 

DMAP Dimethylaminopyridine 

HMT Hexamethylene tetraamine 

PTD Pyrrolothienodiazepine 

TEA/Et3N Triethylamine 

aq. Aqueous 

Liq. Liquor 

CAN Cerric ammonium nitrate 

DCC N,N'-Dicyclohexylcarbodiimide 

SmI2 Samarium iodide 

SmCl2 Samarium chloride 

TsCl Tosylchloride 

NMP N-Methylpiperazine 

FDA Food and Drug Administration 

DMAPP Dimethyl allyl pyrophosphate 

DHPMs Dihydropyridine moities 

PTSA Para toluene sulphonic acid 

TEA Tri ethyl amine 

HMDS Hexamethylene disilazane 

CCl4 Tetra chloro methane

Chapter‐1 

MICROWAVE ASSISTED FACILE SYNTHESIS OF 

BENZOFURANS LINKED WITH SUBSTITUTED 1,3,4 

OXADIAZOLES

Chapter-1 1,3,4-Oxadiazole derivatives… 

1.1 INTRODUCTION 

Oxadiazoles belong to an important group of heterocyclic compounds having –N=C- 

O- linkage. 1,3,4-oxadiazole(1) is a thermally stable aromatic heterocycle and exist in 

two partially reduced forms; 2,3-dihydro-1,3,4-oxadiazole(1,3,4-oxadiazoline)(2) and 

2,5-dihydro-1,3,4-oxadiazole(1,3,4-oxadiazoline)(3) depending on the position of the 

double bond. The completely reduced form of the 1,3,4-oxadiazole is known as 

2,3,4,5-tetrahydro-1,3,4-oxadiazole (1,3,4-oxadiazolidine)(4) [1] 

N 

N N 

NH N 

N HN 

O O O O 

1 2 3 4 

1,3,4-Oxadiazole is a heterocyclic molecule with oxygen atom at 1 and two nitrogen 

atoms at 3 and 4 position. They have been known for about 80 years, it is only in the 

last decade that investigations in this field have been intensified. This is because of 

large number of applications of 1,3,4-oxadiazoles in the most diverse areas viz. drug 

synthesis, dye stuff industry, heat resistant materials, heat resistant polymers and scintillators. 

Reviews of the relevant literature prior to 1965 are available. 

Bactericidal and/or fungicidal activity was reported for oxadiazole (5a), aminooxadiazole 

(5b) [2] and oxadiazolinethiones (6a). [3] The tin derivatives (6b) are an effective 

fungicide and antimicrobial activite compound shown by thiones (6c). [4] Antiinflammatory, 

sedative and analgesic properties were reported for aryloxadiazoles 

(5c). [5] Amino-oxadiazoles (5d) show analgesic activity and amino-oxadiazoles (5e) 

exhibit both anti-inflammatory and antiproteolytic properties [6] . Anticonvulsant and 

nervous system depressant activity was reported for amino-oxadiazoles (5f), where R 

is quinazolin-3-yl group. [7] Aminooxadiazole (5g) show local anaesthetic activity. [8] 

The oxadiazolinone (6d) is an orally active antiallergic agent, for example in the 

treatment of asthma and allergy disease and is claimed to be more potent than sodium 

cromoglycate. [9] Examples of the many oxadiazolones for the many herbicidal activity 

(week killers) are (6e,6f) and “oxadiazon”(6g), which is the subject of many regular 

reports in the literature. Insecticidal activity is shown by oxadiazolones (6h, 6i the later 

is an aphicide), and oxadiazole (5h) 

NH 

1


R 1 

5a Ar CH2CONHCONHR 

5b AR OCH2 NHCOR 

5c Trimethoxy 3,4-dimethoxyphenyl 

5d 2-pyridyl 

Or 

NR2HCl 

5e 4-biphenylylmethyl 

NHAr 

5f Ar NHCH2CONHR 

5g Ar NHCO(CH2)nNRR'HCl(n=2or3) 

R 1 

N 

N 

R 2 

O 

X 

6(a-i) 

R 1 R 2 X 

6a heteroarylOCH2 H S 

6b 

6c 

1-methylcyclopropyl 

5-Cl-2-phenylindol-3- 

Sn(Ph)3 

H 

O 

S 

6d 

ylNH 

3-Cl-benzo[b]thiophen-2yl 

R 2 

H O 

6e 4-cyclohexylphenoxy H O 

6f 2,4-diCl-phenoxymethyl Bn O 

6g t-Bu 2,4-diCl--5-isopropoxyphenyl O 

6h OCH3 o-methoxyphenyl 

2,3-diH-2,2,4-triMebenzofuran- 

O 

6i CH3NH 

7-yl 

O 

2


1.2 PHARMACOLOGY 

1,3,4-Oxadiazole derivatives have been tested for various pharmacological 

activities, which have been summarized as under. 

1. Antibacterial [10] 

2. Antiinflammatory [11] 

3. Analgesic [12] 

4. Antiviral and anticancer [13] 

5. Antihypertensive [14] 

6. Anticonvulsant [15] 

7. Antiproliferative [16] 

8. Antifungal [17] 

9. Cardiovascular [18] 

10. Herbicidal [19] 

11. Hypoglycemic [20] 

12. Hypnotic and Sedative [21] 

13. MAO inhibitor [22] 

14. Insecticidal [23] 

1,3,4-Oxadiazole is a versatile scaffold and is being consistently used as a building 

block in organic chemistry as well as in medicinal chemistry for the synthesis of different 

heterocycles. The synthetic versatility of 1,3,4-oxadiazole has led to the extensive 

use of this compound in organic synthesis. 

3


Some new oxadiazole drugs & derivatives under Preclinical/Phase clinical trials. 

Sr. No 

1 

2 

3 

4 

5 

6 

Chemical structure 

Activity 

Antitussive, 

Bronchodilator 

Antirhinoviral, 

Antiviral 

Antihypertensive, 

Antianginal, 

Antiglaucoma 

agent, 

Beta-adrenoceptor 

antagonist 

Antidepressants, 

Anxiolytic, 5- 

HT1D Antagonist 

Antidepressants, 

Anxiolytic, 

5-HT1D Inverse 

agonist 

Cognition enhancing 

drug, 

GABA(A) receptor 

modulator, 

GABA(A) B2 site 

inverse 

agonist 

Phase 

Phase-I 

Phase-III 

Phase-II 

Biological 

testing 

Preclinical 

Preclinical 

Originator 

Sanofi- 

Synthlabo 

Viro 

pharma 

Center for 

Chemistry 

of Drugs 

Smithkline 

Beecham 

Smithkline 

Beecham 

Dainoppon 

pharma 

4


Some new oxadiazole drugs & derivatives under Preclinical/Phase clinical trials. 

Sr. No 

Chemical structure 

Activity 

Phase 

7 Analgesic Preclinical 

8 

9 

O 

10 O 

H 3CO 

HN 

S 

O 

OH 

CN 

N 

N O 

N 

N 

O N 

OCF 3 

CH 3 

Antiobesity drug, 

Antidiabetic drug, 

Beta3 adrenoce tor 

agonist 

Antiobesity drug, 

Antidiabetic drug, 

Beta3 adrenoceptor 

agonist 

Bronchodilator, 

Phosphodiesterase 

Inhibitor 

Originator 

Universidade 

federal pernambuco 

Preclinical Merck 

Preclinical Merck 

Preclinical 

11 Antitrypanosomal Preclinical 

12 

Antiepileptic 

drug,Neuronal Injury 

Inhibitor, 

AMPA antagonist,Sodium 

channel 

blocker 

Preclinical 

Smithkline 

Beecham 

Universidad 

de larepublica 

Boehringer 

Ingelaeim 

5


1.3 SYNTHETIC ASPECT 

There were several routes for the synthesis of 1,3,4-oxadiazoles reported in the literature 

among which the most important aspects of synthesis were discussed as under. 

2,5-Disubstituted 1,3,4-oxadiazole can be accomplished by cyclodehydration of 1,2diacylhydrazine 

either by using chlorosulphonic acid [24] or phenyl dichorophosphite in 

dimethylformamide. A nonaqueous, nonacedic, route involves treatment of hydrazine 

with hexamethyl disilazane (HMDS) and tetrabutylammoniumfluoride, the last step 

presumably being fluoride catalyzed cyclization of intermediate bis silyl ether. [25-26] 

R 1 

HN NH 

O O 

Diacyl hydrazine 

R1, R2 = alkyl, aryl 

R 2 

HMDS 

OSi(CH 3) 3 

ClSO 3H/Cl 2POPh 

N N 

R1 R2 R 1 

N 

O 

N 

R 2 

2,5-disubstituted-1,3,4-oxadiazole 

R1, R2 = alkyl, aryl 

(C4H9) 4N-F 

(H 3C) 3SiO 

In a related reaction, 1,1,2-triacetylhydrazine with trimethylsilylchloride/triethylamine 

gave oxadiazolinyl silylether. [27] Cyclodehydration (PCl5/POCl3) of hydrazinyl diester 

gave the diphenyloxyoxadiazol. [28] 

R 1 

COCH3 HN N 

(CH3) 3SiCl/(Et) 3N 

R 2 

O O 

1,1,2-triacylhydrazine 

R1, R2 = alkyl 

R 1 

N 

O 

O 

N 

OSi(CH 3) 3 

R 2 

CH 3 

PhO 

HN NH 

O O 

OPh 

POCl3/PCl5 PhO 

N N 

O OPh 

Hydrazine diester 2,5-diphenoxy-1,3,4-oxadiazol 

The malonate derivative (1) reacted with acylhydrazine (2) to give a mixture of diacylhydrazine 

monoamine (3) and oxadiazole (4). The later was also formed from (3) 

by heating. [29] 

6


H 2N 

OEt 

COOEt 

H2N NH 

O 

CN (Et) 3N, 

H2N NHNHCOCH2CN COOEt 

CH2CN N N 

O 

CH2COOEt 1 2 3 4 

Oxidation of acylhydrazones derived (5) from aldehydes has been developed into a 

useful route to disubstituted oxadiazoles (6). The use of potassium permanganate with 

acetone as solvent was claimed to give better yields than the use of other oxidizing 

agents (e.g.halogens). [30] An improved synthesis of bis-oxadiazolylbenzenes (8) involved 

oxidation of bishydrazones (7) with lead tetraacetate. [31] Acylhydrazones (9) 

were oxidized by iodosobenzene diacetate to oxadiazolinones (10), with acetates (11) 

also being formed in some cases. A similar oxidation of ethyl esters (9, X=OEt) gave 

oxadiazolyl ethers (11, X=OEt). [32] Oxidative cyclization(FeCl3/AcOH) of semicarbazone 

(12) yielded amino-oxadiazoles (13). [33] 

R 1 

R 1 

NNHCOX 

5 

R 1 

Iodosobenzene diacetate 

NNHCOX 

9 

R1 = alkyl, aryl, 

X=OBut 

R 1 

KMnO 4 

R 1, X = alkyl, aryl 

NNHCOX 

R1 = Ph, X=NHR 

12 

N 

O 

6 

N 

X 

FeCl 3/AcOH 

R 1 

R 1 

CH=NNHCOAr 

7 

N 

CH=NNHCOAr 

N NH N N 

O O R1 O 

10 11 

N 

O 

13 

(m - or p -) 

X 

Pb(OAc) 4 

OAc 

Ar 

N 

8 

O 

N 

Ar 

O 

(m - or p -) 

Important routes to monosubstituted oxadiazoles (14), aminooxadiazoles (15), oxadiazolinones 

(15a) and oxadiazolinethiones (16) involve reaction of hydrazides 

(R1CONHNH2) with triethyl orthoformate, cyanogen bromide, phosgene, or carbon 

disulphide (or CSCl2) respectively. 

N 

N 

7


R 1 

N NH 

O 

O 

15a 

R 1 

N 

O 

16 

NH 

S 

CS 2/CSCl 2 

COCl 2 

R 1 

O 

C(OC 2H 5) 3 

HN NH 2 

CNBr 

Reaction of hydrazide (17) with triethylorthoformate, or with CS2/KOH, allowed the 

synthesis of oxadiazolyl methyl ketones (18) and (19), respectively, after hydrolysis 

of the acetal group. [34] 

O O 

CH 3 

17 

O 

N 

H 

C(OC 2H 5) 3 

NH 2 

CS 2/KOH 

O 

O 

CH 3 

CH 3 

N 

O 

18 

N 

N 

O 

19 

An alternative to cyanogenbromide is phenyl cyanate (PhOCN), which reacted with 

hydrazines (R1CONHNH2) to give aminooxadiazoles (R1= 4,6- dimethyl-2pyrimidyl). 

[35] From oxadiazol-2-carbohydrazides (20) bioxadiazolyls ( 21) and (22) 

were prepared using cyanogen bromide [36] or thiophosgene [37] respectively. 

NH 

R1 O 

N 

H 

NH2 OCN 

R1 N N 

O 

20 

NH2 R1=4,6-dimethyl-2-pyridyl R1=4,6-dimethyl-2-pyridyl 

R 1 

O 

N N 

43 

O 

NH 

NH 2 

CNBr 

CSCl 2 

R 1 

N 

R 1 

N 

N 

O 

N 

O 

N 

O 

21 

N 

22 

O 

N 

N 

R 1 

R 1 

S 

NH 2 

NH 2 

N 

N 

N 

O 

14 

O 

15 

N 

NH 2 

8


It has been shown that o-aminobenzoylhydrazine reacted with (i) 1,1’-carbonylbisimidazole(a 

variation of the use of phosgene) to give oxadiazolinone(23) [38] and (ii) 

1,3 dicyclohexylcarbodiimide and an isothiocyanate RNCS to give aminooxadiazole 

(24). [39] 

HN 

NH 2 

O 

NH 2 

1, 1'-carbonylbisimidazole 

RNCS 

N C N 

N 

NH 

O 

NH 2 

23 

N 

NH 

O 

NH 2 

24 

O 

NHR 

A variation of the oxidative cyclization of acyl-thiosemicarbazides to aminooxadiazoles. 

[40] A variation of the reaction of acylhydrazines and carbon disulfide forming 

oxadiazolinethiones, is the reaction of thiosemicarbazide (RNHCSNHNH2) with carbon 

oxysulfide and benzyl chloride, which yields amino-oxadiazolyl thioeth- 

ers(25). [41] 

H2N HN 

S 

HN 

R 

O=C=S 

CH 2Cl 

S 

N 

25 

N 

O 

NHR 

9


1.4 AIM OF CURRENT WORK 

The aim of current work is to use green protocol to obtain hybridized molecules with 

less reaction time and high yield. 

1.5 REACTION SCHEME 

OH 

Ethyl bromo acetate 

O 

DMF, K2CO3 O 

O 

O 

64 % N2H4 O 

EtOH O NH 

H2N R 

O 

OH 

N 

O O 

N 

MW. 

POCl 3 

Up to 90 % yield 

2 min reaction time 

R 

10


1.6 PLAUSIBLE REACTION MECHANISM 

Step-1 

Step-2 

H + - 

O 

Step-3 

O 

O O 

O 

OC 2H 5 

H2N.. NH2 NH O 

.. 2 

NH + HO Ph 

O 

O 

H 

N 

HN 

NH 

C 

O 

Ph 

O 

NH 

.. 

O.. 

N 

O O 

Ph 

N 

: 

H 

Ph 

OH 

O 

-H 2O 

O - 

OC 

H 2H5 + 

C2H - 5 O 

N NH2 H 

- 

O 

O 

NH + 

NH2 H 

+ H2N 

NH 

O 

O 

C 

- 

HO 

Ph OH- O 

- 

O 

H 

N H 

N 

O 

+ 

O 

O 

- 

Ph 

.. 

N 

O O 

N 

Ph 

H + - 

H 

O 

H 

NH 

+ 

N 

O O 

O 

C 

O 

Ph 

H 

+ H 

N 

N 

Ph 

O 

- 

O 

NH2 NH 

11


1.7 EXPERIMENTAL 

Preparation of Ethyl benzofuran-2-carboxylate 

Salicaldehyde (0.01 mole) was charged into 250 ml round bottom flask. 30 ml of 

DMF was added into the flask. Then ethylbromo acetate (0.01 mole) and K2CO3 (0.03 

mole) was added. The reaction mixture was refluxed for 1.5 h at 110 ° C on oil bath. 

The progress and the completion of the reaction were checked by TLC using hexane: 

ethyl acetate (9:1) as a mobile phase. After the reaction was completed, reaction mixture 

was poured into ice water. Then product was extracted using ethyl acetate (50 ml 

× 3), the combined organic layer was washed using brine solution (20 ml × 2). The 

organic layer was dried on anhydrous sodium sulphate and the solvent was removed 

under reduced pressure to acquire the product in a viscous liquid form. Yield - 77 %, 

B.P.- 276 ° C. [42] 

Preparation of Benzofuran-2-carbohydrazides 

Ethyl benzofuran-2-carboxylate (0.01 mole) was charged into 250 ml round bottom 

flask. 15 ml of hydrazine hydrate was added dropwise at 0-5 ° C in above flask. The 

progress and the completion of the reaction were checked by silica gel-G F254 thin 

layer chromatography using hexane: ethyl acetate (4: 6) as a mobile phase. After the 

reaction was completed, the mixture was stirred at room temperature to give benzofuran-2-carbohydrazide 

as a white colored shining product. M.P.-190-194 ° C. [43] 

Preparation of N'-(2-chloroacetyl)benzofuran-2-carbohydrazide 

In a round bottom flask, Benzofuran-2-carbohydrazides (0.01 mole), substituted 

benzoic acid (0.01 mole) and POCl3 (0.015 mole) were irradiated in domestic 

microwave for 2 minutes at 600 watts. The reaction mix was cooled and poured into 

the ice, stirred for 30 minutes and filtered. The solids obtained were further washed 

with 50 ml 10% solution of sodium bicarbonate and followed by wash with 50 ml DM 

water. The resulting compound was purified by column chromatography by silica gel 

230-400 mesh using ethyl acetate: hexane (4: 6 v/v) as eluent. Yield : 85%. 

12


1.8 PHYSICAL DATA 

PHYSICAL DATA OF 2-(BENZOFURAN-2-YL)-5-(SUBSTITUTED 

PHENYL)-1,3,4-OXADIAZOLES 

Sr. 

No. 

Code R Mass Formula M.P o C Yield % 

1 VNRBF-101 4-Methyl 276.29 C17H12N2O2 145-147 79 

2 VNRBF-102 2-amino 277.28 C16H11N3O2 165-167 85 

3 VNRBF-103 

2-chloro, 4nitro 

341.71 C16H8ClN3O4 140 o C 88 

4 VNRBF-104 4-amino 277.28 C16H11N3O2 >300 o C 77 

5 VNRBF-105 3,5-dihydroxy 294.26 C16H10N2O4 170 o C 84 

6 VNRBF-106 3-methyl 276.29 C17H12N2O2 90 o C 90 

7 VNRBF-107 2-methyl 276.29 C17H12N2O2 94 o C 89 

8 VNRBF-108 

2-hydroxy, 

3,5-dinitro 

368.26 C16H8N4O7 125 o C 85 

9 VNRBF-109 2,4-dichloro 331.15 C16H8Cl2N2O2 140 o C 78 

10 VNRBF-110 4-chloro 296.71 C16H9ClN2O2 230 o C 87 

11 VNRBF-111 H 262.26 C16H10N2O2 145 o C 92 

N 

O O 

N 

6 

1 

5 

2 

4 

3 

R 

13


1.9 SPECTRAL STUDY 

IR spectra 

Infra Red spectra were taken on Shimadzu FT-IR-8400 spectrometer using KBr 

pellet method. The characteristic aromatic group in 1,3,4-oxadiazol moiety is 

observed at 3010-3090 cm -1 . Methyl (-CH3) observed at 1350 cm -1 . 

1 H NMR spectra 

1 

H NMR spectra were recorded on a Bruker AC 400 MHz NMR spectrometer using 

TMS (Tetramethyl Silane) as an internal standard and DMSO-d6 & CDCl3 as a 

solvent. In the NMR spectra of 2-(benzofuran-2-yl)-5-(substituted phenyl)-1,3,4oxadiazole 

derivatives various proton values of methylene (-CH2), amine (-NH), 

methyl (-CH3) and aromatic protons (Ar-H) etc. were observed. Individual data are 

given for each compound separately. 

13 C NMR spectra 

13 

C NMR spectra were recorded on a Bruker AC 400 MHz NMR spectrometer using 

DMSO-d6 & CDCl3 as a solvent. In the 13 C NMR spectra of 2-(benzofuran-2-yl)-5- 

(substituted phenyl)-1,3,4-oxadiazole derivatives, various carbon values of methylene 

(-CH2), keto (>C=O), methyl (-CH3) and aromatic carbon (Ar-H) etc. were observed. 

Mass spectra 

The mass spectrum of compounds were recorded by Shimadzu GC-MS-QP-2010 

spectrometer. The mass spectrum of compounds was obtained by positive chemical 

ionization mass spectrometry. The molecular ion peak and the base peak in all 

compounds were clearly obtained in mass spectral study. The molecular ion peak 

(M + ) values are in good agreement with molecular formula of all the compounds 

synthesized. 

Elemental analysis 

Elemental analysis of the synthesized compounds was carried out on Vario EL-III 

Carlo Erba 1108 model at Saurashtra University, Rajkot which showed calculated 

14


and found percentage values of Carbon, Hydrogen and Nitrogen in support of the 

structure of synthesized compounds. The elemental analysis data are given for 

individual compounds. 

1.10 SPECTRAL CHARACTERIZATION 

2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole (VNRBF-101) 

Yield: 79%; IR (KBr) cm -1 : 1639 (>C=N, str), 1087 (C-O-C), 2852 (>CH2 ,str), 1438 

(>CH2 ,ben), 2868 (>CH3,str), 1390 (>CH3, ben), 3010 (=C-H, str), 3037 (Ar, C-H, 

str), 1564 (Ar, C=C, str). 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.45 (s, 2H), 7.31 (m, 

3H), 7.45 (m, 1H), 7.57 (s, 1H), 7.64 (d, 1H), 7.71 (d, 1H), 8.05 (d, 2H). 13 C NMR 

400 MHz: (DMSO-d6, δ ppm): 30.6, 39.3, 78.7, 86.2, 100.7, 111.7, 116.4, 117.5, 

119.3, 122.5, 124.1, 130.4, 132.6, 135.8, 154.3, 158.9, 166.2, 195.6; Mass: [m/z 

(%)], M. Wt.: 276. Elemental analysis, Calculated: C, 73.90; H, 4.38; N, 10.14 

Found: C, 73.87; H, 4.85; N, 10.79. 

2-(5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)benzenamine (VNRBF-102) 


(>CH2 ,ben), 3015 (=C-H, str), 3042 (Ar, C-H, str), 1513 (Ar, C=C, str), 3450 (>NH2, 

str), 1470 (>NH2, ben). Mass: [m/z (%)], M. Wt.: 277. Elemental analysis, 

Calculated: C, 69.31; H, 4.00; N, 15.15; Found: C, 69.10; H, 4.28; N, 15.65. 

2-(benzofuran-2-yl)-5-(2-chloro-5-nitrophenyl)-1,3,4-oxadiazole (VNRBF-103) 

Yield: 88%; IR (KBr) cm -1 : 3496 (-NH), 1616 (>C=N, str), 1077 (C-O-C), 2871 

(>CH2 ,str), 1445 (>CH2 ,ben), 3010 (=C-H, str), 3036 (Ar, C-H, str), 1520 (Ar, C=C, 

str), 1610 (>NO2, str) 952 (C-Cl str.). Mass: [m/z (%)], M. Wt.: 341(M+), 

343(M+2). Elemental analysis, Calculated: C, 56.24; H, 2.36; N, 12.30; Found: C, 

56.23; H, 2.68; N, 12.61. 

4-(5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)benzenamine (VNRBF-104) 


(>CH2 ,ben), 3015 (=C-H, str), 3042 (Ar, C-H, str), 1526 (Ar, C=C, str), 3456 (>NH2, 

str), 1484 (>NH2, ben). Mass: [m/z (%)], M. Wt.: 277. Elemental analysis, 


15


5-(5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)benzene-1,3-diol (VNRBF-105) 


(>CH2 ,ben), 3026 (=C-H, str), 3047 (Ar, C-H, str), 1533 (Ar, C=C, str), 1374 (-CH3, 

str.), 1180 (>C-O, str), 3550 (>O-H, str). Mass: [m/z (%)], M. Wt.: 294. Elemental 

analysis, Calculated: C, 65.31; H, 3.43; N, 9.52 Found: C, 65.42; H, 3.39; N, 9.88. 

2-(benzofuran-2-yl)-5-m-tolyl-1,3,4-oxadiazole (VNRBF-106) 


(>CH2 ,ben), 3025 (=C-H, str), 3052 (Ar, C-H, str), 1545 (Ar, C=C, str), 2872 

(>CH3,str), 1380 (>CH3, ben). 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.37 (s, 3H), 

7.32 (m, 4H), 7.55 (d, 1H), 7.62 (d, 1H), 7.87 (m, 2H). 13 C NMR 400 MHz: (DMSOd6, 

δ ppm): 109.7, 111.4, 121.6, 122.3, 123.4, 123.6, 126.6, 126.9, 128.6, 132.0, 

132.4, 138.4, 140.0, 154.4, 155.0, 157.0, 164.0, 164.11 Mass: [m/z (%)], M. Wt.: 

276. Elemental analysis, Calculated: C, 73.90; H, 4.38; N, 10.14; Found: C, 73.49; 

H, 4.86; N, 10.90. 

2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole (VNRBF-107) 


(>CH2 ,ben), 3023 (=C-H, str), 3056 (Ar, C-H, str), 1547 (Ar, C=C, str), 2885 

(>CH3,str), 1410 (>CH3, ben). 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.70 (s, 3H), 

7.28 (m, 3H), 7.35 (m, 2H), 7.49 (d, 2H), 7.56 (m, 1H), 7.62 (d, 1H), 7.96 (m, 1H). 

13 

C NMR 400 MHz: (DMSO-d6, δ ppm): 109.7, 111.4, 121.6, 122.3, 123.4, 123.6, 

126.6, 126.9, 128.6, 132.0, 132.4, 138.4, 140.0, 154.4, 155.0, 157.0, 164.0, 164.11; 

Mass: [m/z (%)], M. Wt.: 276. Elemental analysis, Calculated: C, 73.90; H, 4.38; 

N, 10.14; Found: C, 73.92; H, 4.65; N, 10.65. 

2-(5-(benzofuran-2-yl)-1,3,4-oxadiazol-2-yl)-4,6-dinitrophenol (VNRBF-108) 


(>CH2 ,ben), 3052 (=C-H, str), 3045 (Ar, C-H, str), 1565 (Ar, C=C, str), 1626 (>NO2, 

str), 3590 (>O-H, str) . Mass: [m/z (%)], M. Wt.: 368. Elemental analysis, 


16


2-(benzofuran-2-yl)-5-(2,4-dichlorophenyl)-1,3,4-oxadiazole (VNRBF-109) 


(>CH2 ,ben), 3052 (=C-H, str), 3039 (Ar, C-H, str), 1564 (Ar, C=C, str). Mass: [m/z 

(%)], M. Wt.: 331(M+), 333(M+2), 335(M+4). Elemental analysis, Calculated: C, 

58.03; H, 2.43; N, 8.46;Found: C, 58.22; H, 2.62; N, 8.48. 

2-(benzofuran-2-yl)-5-(4-chlorophenyl)-1,3,4-oxadiazole (VNRBF-110) 


(>CH2 ,ben), 3041 (=C-H, str), 3062 (Ar, C-H, str), 1574 (Ar, C=C, str). 1 H NMR 400 

MHz: (CDCl3, δ ppm): 1.27 (s, 1H), 7.35 (m, 1H), 7.47 (m, 1H), 7.51 (m, 2H), 7.54 

(s, 1H), 7.63 (d, 1H), 7.72 (d, 1H), 8.10 (m, 2H). 13 C NMR 400 MHz: (DMSO-d6, δ 

ppm): 110.0, 111.4, 121.2, 121.9, 123.6, 126.6, 126.7, 127.6, 127.8, 128.9, 129.0, 

137.7, 139.7, 155.1, 157.2, 163.1 Mass: [m/z (%)], M. Wt.: 296(M+), 298(M+2). 

Elemental analysis, Calculated: C, 66.77; H, 6.06; N, 15.44; Found: C, 66.38; H, 

6.35; N, 15.57. 

2-(benzofuran-2-yl)-5-phenyl-1,3,4-oxadiazole (VNRBF-111) 


(>CH2 ,ben), 3049 (=C-H, str), 3063 (Ar, C-H, str), 1579 (Ar, C=C, str). Mass: [m/z 

(%)], M. Wt.: 262. Elemental analysis, Calculated: C, 73.27; H, 3.84; N, 10.68; 

Found: C, 73.60; H, 3.38; N, 10.11. 

17


1.11 REPRESENTATIVE SPECTRA 

IR spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole (VNRBF-101) 

90 

%T 

80 

70 

60 

50 

40 

30 

20 

10 

0 

-10 

3600 3200 

VNRBF-101 

3126.71 

3057.27 

2928.04 

2868.24 

2679.21 

2492.11 

2800 

2400 

2000 

1800 

IR spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole (VNRBF-107) 

105 

%T 

90 

75 

60 

45 

30 

15 

0 

-15 

3132.50 

3061.13 

2914.54 

O O 

3600 3200 

VNRBF-107 

N 

N 

O O 

N 

N 

2800 

2370.59 

2366.74 

2353.23 

2341.66 

2400 

2000 

1800 

1691.63 

1693.56 

1633.76 

1581.68 

1554.68 

1633.76 

1600 

1595.18 

1600 

1492.95 

1442.80 

1548.89 

1469.81 

1440.87 

1346.36 

1400 

1400 

1344.43 

1284.63 

1255.70 

1176.62 

1200 

1255.70 

1172.76 

1200 

1078.24 

1145.75 

1084.03 

1068.60 

1018.45 

960.58 

912.36 

881.50 

1000 

968.30 

912.36 

1000 

825.56 

881.50 

796.63 

790.84 

800 

742.62 

800 

732.97 

729.12 

698.25 

613.38 

569.02 

688.61 

505.37 

453.29 

600 400 

1/cm 

613.38 

555.52 

505.37 

462.93 

441 71 

600 400 

1/cm


Mass spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole (VNRBF-101) 

N 

N 

O O 

Mass spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole (VNRBF-107) 

O O 

N 

N


1 H NMR spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole (VNRBF-101) 

N 

N 

O O 

Expanded 1 H NMR spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole 

(VNRBF-101) 

O O 

N 

N


1 H NMR spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole (VNRBF-107) 

N 

N 

O O 

Expanded 1 H NMR spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole 

(VNRBF-107) 

O O 

N 

N


13 

C NMR spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole (VNRBF- 

101) 

Expanded 13 C NMR spectrum of 2-(benzofuran-2-yl)-5-p-tolyl-1,3,4-oxadiazole 

(VNRBF-101) 

N 

N 

O O 

O O 

N 

N


13 

C NMR spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole (VNRBF- 

107) 

O O 

N 

N 

Expanded 13 C NMR spectrum of 2-(benzofuran-2-yl)-5-o-tolyl-1,3,4-oxadiazole 

(VNRBF-107) 

N 

N 

O O


1.12 RESULT AND DISCUSSION 

Present work covers the synthesis of some novel oxadiazole compounds clubbed with 

benzofuran moiety. The main significance of the present work is that the reaction is 

carried out under conventional microwave leading to a rapid reaction time, easy work 

up method, excellent yield and high chemical purity of the desired compounds. 

1.13 CONCLUSION 

Total 11 derivatives of 2-(benzofuran-2-yl)-5-(substituted phenyl)-1,3,4-oxadiazole 

were synthesized. All the newly synthesized compounds were characterized by IR, 1 H 

NMR, 13 C NMR, Mass spectral data and Elemental Analysis. 

24


1.14 REFERENCES 

[1] J. Hill, Comp. Heterocycl. Chem., 1984, 1 st edition, 6427. 

[2] K. Roda, R. Vansdadia, H. Parekh., J. Ind. Chem. Soc. 1988, 65, 807. 

[3] V. Adhikari, V. Badiger., Ind. J. Chem. Sect-B, 1988, 27, 542. 

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[6] K. Raman, S. Parmar, S. Salzman, J. Pharm. Sci., 1989, 78, 999. 

[7] N. Ergenc, S. Buyuktimkin, G. Capan, G. baktir, S. Rollas., Pharmazie, 1991, 

46, 290. 

[8] V. Saxena, A. Singh, R. Agarwal, S. Mehra., J. Ind. Chem. Soc., 1983, 60, 

575. 

[9] J. Musser., J. Med. Chem., 1984, 27, 121. 

[10] S. Chao, X. Li, S. Wang, Huaxue Yanjiu Yu Yingyong., 2010, 22(8), 1066- 

1071. 

[11] S. Gilani, S. Khan, N. Siddiqui, Bioorg. Med. Chem. Lett., 2010, 20(16), 4762- 

4765. 

[12] S. Bhandari, J. Parikh, K. Bothara, T. Chitre, D. Lokwani, T. Devale, N. 

Modhave, V. Pawar, S. Panda., Journal of enzyme inhibition and medicinal 

chemistry, 2010, 25(4), 520-530. 

[13] Gattige Vidya., PCT Int. Appl., WO 2009090548, 2009, 82. 

[14] G. Bankar, G. Nampurath, P. Nayak, S. Bhattacharya., Chemico-Biological 

Interactions, 2010, 183(2), 327-331. 

[15] M. Bhat, M. Al-Omar, N. Siddiqui., Pharma Chemica, 2010, 2(2), 1-10. 

[16] Q. Zheng, X. Zhang, Y. Xu, K. Cheng, Q. Jiao, H. Zhu., Bioorg. Med. Chem., 

2010, 18(22), 7836-7841. 

[17] L. Srikanth, U. Naik, R. Jadhav, N. Raghunandan, J. Rao, K. Manohar., 

Pharma Chemica, 2010, 2(4), 231-243. 

[18] Z. M. Zuhair, J. Ghada, A. Elham, N. Lina., Jord J. Chem, 2008, 3(3), 233- 

43. 

25


[19] R. Bankar , K. Nandakumar, G. Nayak, A. Thakur, C. Rao, N. Kutty., 

Chemico-Biological Interactions, 2009, 181(3), 377-382. 

[20] Wang Bao-Lei, Li Zheng-Ming, Li Yong-Hong, Wang Su-Hua., Gaodeng 

Xuexiao Huaxue Xuebao, 2008, 29(1), 90-94. 

[21] I. Fumio, K. Jun, K. Hiromi, K. Eiji, S. Morihisa, K. Tomohiro, I. Hiroki, M. 

Katsuhito., PCT Int. Appl. 2008, 531. 

[22] K. Sushil, V. Gupta, V. Kashaw, P. Mishra, J. Stables, N. Jain., Med. Chem. 

Research., 2009, 38(2), 157-159. 

[23] U. Ghani, N. Ullah., Bioorg. Med. Chem., 2010, 18(11), 4042-4048. 

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100,174735 

[25] C. Chiriac, Rev.Chim., (Bucharest), 1982, 27, 935, Chem. Abstr. 1983, 

98,107216. 

[26] B. Rigo, P. Cauliez, D. Fasseur, D. Couturier., Synth. Commun., 1986, 

16,1665. 

[27] A. Kalinin, B. Khasapov, E. Aposav, I. Kalikhman, S. Ioffe., Izv. Akad Nauk 

SSSR Ser. Khim. 1984, 694, Chem. Abstr. 1984, 101, 91045. 

[28] A. Theocharis, N. Alexandrou., J. Heterocycl. Chem., 1990, 27,1685. 

[29] M. Elnagdi, N. Ibrahim, F. Abdelrazek, A. Erian., Liebigs Ann. Chem., 1988, 

909. 

[30] P. Reddy., Ind. J. Chem. Sect-B, 1987, 26, 890. 

[31] S. Rekkas, N. Rodias, N. Alexandrou., Synthesis, 1986, 411. 

[32] H. Baumgarten, D. Hwang, T. Rao., J. Heterocycl. Chem., 1986, 23, 945. 

[33] S. Hiremath, N. Goudar, M. Purohit., Ind. J. Chem.Sect-B, 1982, 21,321. 

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[35] A. Hetzheim, G. Mueller, P. Vainilavicius, D. Girdziunaite., Pharmazie, 1985, 

40, 17. 

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26


[41] M. Chande, A. Karnik, I. Inamdar, S. Damle., Ind. J. Chem. Sect B., 1991, 

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27

Chapter‐2 

SYNTHESIS AND CHARACTERIZATION OF 

SUBSTITUTED 3‐(1‐AMIDO ADAMANTYL) 

4‐HYDROXY COUMARINS.

Chapter-2 Synthesis and characterization of… 


Coumarin are the best known aromatic lactones [1] .The isolation of coumarin was first 

reported by Vogel [2] in Munich in1820.He associated the pleasant odour of the tonka 

bean from Guiana with that of clover, Melilotous officinalis, which gives rise to the 

characteristic aroma of new –mown hay. Vogel then concluded that the long colorless 

crystals which he discovered on slicing open Tonka beans and which crystallized as 

glistening needles from aqueous alcohol, were identical with similar crystals he 

obtained, albeit in much lower yield, by extracting fresh clover blossoms [3] . The name 

coumarin originated [4] from a Caribbean word ‘coumarou’ for the tonka tree, which 

was known botanically at one time as Coumarouna odorata aubl.Coumarin is now 

well, accepted trivial name. The IUPAC nomenclature of the coumarin fing system is 

2H-1-benzopyran-2-one (I). 

The coumarin ring system has an easy acceptability in the biological system compared 

to its isomeric chromones and flavones nucleus [5] and is widely distributed in nature [6- 

9] 

.An excellent account of these naturally occurring coumarin is presented by Murray 

and Brown [10] 

O O 

Coumarin comprises a group of natural compounds found in a variety of plant 

sources. The very long association of plant coumarin with various animal species and 

other organisms throughout evolution may account for the extraordinary range of 

biochemical and pharmacological activities of these chemicals in mammalian and 

other biological systems. The coumarins that were studied have diverse biological 

properties and various effects on the different cellular systems. A lot of biological 

parameters should be evaluated to increase our understanding of mechanisms by 

which these coumarin act. Coumarin has important effects in plant biochemistry and 

physiology, acting as antioxidants, enzyme inhibitors and precursors of toxic 

28


substances. In addition, these compounds are involved in the actions of plant growth 

hormones and growth regulators, the control of respiration, photosynthesis, as well as 

defense against infection. The coumarin have long been recognized to possess antiinflammatory, 

antioxidant, antiallergic, hepatoprotective, antithrombotic, antiviral, 

and anticarcinogenic activities. The hydroxycoumarins are typical phenolic 

compounds and, therefore, act as potent metal chelators and free radical scavengers. 

They are powerful chain-breaking antioxidants. The coumarin display a remarkable 

array of biochemical and pharmacological actions, some of which suggest that certain 

members of this group of compounds may significantly affect the function of various 

mammalian cellular systems. The coumarin are extremely variable in structure, due to 

the various types of substitutions in their basic structure, which can influence their 

biological activity. Vast majority of coumarin, completely innocuous, may be 

beneficial in a variety of human disorders, in spite of some ongoing controversy. 

There has been, in recent years, a major rekindling of interest in pharmacognosy. 

Coumarin turns out to be present in many natural therapeutically utilized products. 

They hold a place apart in view of their cytotoxic activity. It was suggested that 

alterations in the chemical structure of coumarin could change their cytotoxic 

properties [11] . 

Coumarin and its hydroxy derivatives have been prominently accepted as natural 

pharmaceuticals [12] world wide, has revealed new biological activities with interesting 

therapeutic applications, besides their traditional employment as anticoagulants(antivitamin 

K activity) [13] , antibiotics(novobiocin and analogues [14] ) and anti AID [15] . 

Apart from this, they also possess anti-cancerous [11] , antibacte-rial [16] , neurotropic [17] , 

immunosuppressive [18] , anti inflammatory [19] , antiulcerous [20] , anti PAF(anti platelet 

activating factor) [21] and antimutagenic [22] effects. 

29


2.2 PHARMACOLOGY 

Numerous biological activities have been associated with simple coumarin and its 

analogues. Among them, antimicrobial, antiviral, anticancer, enzyme inhibition, antiinflammatory, 

antioxidant, anticoagulant and effect on central nervous system are 

most prominent. Coumarin nucleus possesses diversified biological activities that can 

be briefly summarized as under: 

1 Antimicrobial and Molluscicidal [23-45] 

2 Antiviral [46-50] 

3 Anticancer [51-61] 

4 Enzyme Inhibition [62-67] 

5 Antioxidant [68-71] 

6 Anti-inflammatory [72-76] 

7 Anticoagulant and Cardiovascular [77-80] 

8 Effect on Central Nervous System [81-82] 

4-hydroxycoumarin is a versatile scaffold and is being consistently used as a building 

block in organic chemistry as well as in heterocyclic chemistry for the synthesis of 

different heterocycles. The synthetic versatility of 4-hydroxycoumarin has led to the 

extensive use of this compound in organic synthesis. 4-hydroxy coumarin shows 

diversified chemical reactivity. 

Anti Cancer activity profile of Benzopyran derivatives 

Analysis of scientific literature revealed numerous reports on the antiproliferative and 

antitumor activities of a variety of coumarin compounds, e.g., both coumarin itself 

and 7-hydroxycoumarin have been reported to inhibit the proliferation of a number of 

human malignant cell lines in vitro [83-86] and have demonstrated activity against 

several types of animal tumors [87-91] . These compounds have also been reported in 

clinical trials to demonstrate activity against prostate cancer, malignant melanoma, 

and metastatic renal cell carcinoma [92-94] . 

30


O O HO O O HO O O 

Coumarin 7-Hydroxy coumarin Esculetin 

O 2N 

HO O O 

7-Hydroxy-6-nitro coumarin 

HO 

NO 2 

HO 

O 2N NO 2 

O O 

7-Hydroxy-3,6,8-trinitro coumarin 

For coumarins, generally the in vitro structure-activity relationship studies have 

shown that cytotoxicity is found with derivatives containing ortho dihydroxy 

substituents [85] . Also, the chemical-structure/ biological activity study of the 

coumarins showed that the addition of a cathecolic group to the basic structure 

induces increased cytotoxic activity in tumor cell lines [95] . The different cytotoxic 

values found for the coumarins could be related to presence and the positions of the 

hydroxyls in their structures. The cytotoxicity of 22 natural and semi-synthetic simple 

coumarins was evaluated in GLC4, a human small cell lung carcinoma cell line, and 

in COLO 320, a human colorectal cancer cell line [95] . From the structure cytotoxicity 

relationship, it is conspicuous that all the potentially active natural compounds 

possess at least two phenolic groups in either the 6, 7- or 6, 8-positions. In addition, 

the 5-formyl-6-hydroxy substituted semisynthetic analogue was found to be potent, 

reflecting the importance of at least two polar functions for high cytotoxicity. Several 

hydroxylated and/or methoxylated coumarin derivatives were tested for their relative 

cytotoxicity on four human tumor cell lines (oral squamous cell carcinoma HSC-2, 

HSC-3, melanoma A-375 and promyelocytic HL-60) and three normal human cells 

(gingival fibroblast HGF, periodontal ligament fibroblast HPLF and pulp cell 

HPC) [96] . Tumor cell-specific cytotoxicity was detected in all 6, 7-dihydroxysubstituted 

coumarins only. The observations indicated that the tumor-specific 

cytotoxicity of the naturally occurring coumarin esculetin (6, 7- dihydroxycoumarin) 

could be further enhanced by proper substitutions at 3- and/or 4-position(s) of the 

molecule. Agarose gel electrophoresis revealed that esculetin and its derivatives with 

tumor-specific cytotoxicity induce internucleosomal DNA fragmentation in HL-60 

cells. A selected group of natural and synthetic coumarin compounds, including the 

31


hydroxylated and nitrated derivatives, were assessed for their cytotoxic potential for 

cellular viability [97] . This study utilized both human skin malignant melanocytes (SK- 

MEL-31) and normal human skin fibroblastic cells (HS613.SK), allowing 

identification of those coumarin derivatives that are selectively toxic. Novel synthetic 

nitrated coumarins, 6-nitro-7- hydroxycoumarin and 3, 6, 8-nitro-7-hydroxycoumarin, 

were shown to be significantly more toxic to SK-MEL-31 than HS613.SK cells. In the 

malignant melanocyte skin cell line (SK-MEL-31), the cytotoxic effects of these 

nitroderivatives were shown to be dose and time dependent. Therefore, the cytotoxic 

potential of coumarins appears to be highly dependent on the nature and position of 

the functional group. In addition, nitration of 7- hydroxycoumarin produced 

compounds that were cytotoxic to malignant melanocytes, suggesting that these nitroderivatives 

may have a chemotherapeutic role in future. Protective effects of 

coumarins against cytotoxicity induced by linoleic acid hydroperoxide were examined 

in cultured human umbilical vein endothelial cells28. When the cells were incubated 

in medium supplemented with linoleic acid hydroperoxide and coumarins, esculetin 

(6, 7-dihydroxycoumarin) and 4-methylesculetin protected cells from injury by 

linoleic acid hydroperoxide. 

HO 

CH 3 

H 3CO 

O O HO O O HO O O 

Coumarin 4-Methyl Esculetin 

Fraxetin 

Esculetin and 4-methylesculetin provided synergistic protection against cytotoxicity 

induced by linoleic acid hydroperoxide with alpha-tocopherol. Furthermore, the 

radical-scavenging ability of coumarins was examined in electron spin resonance 

spectrometry. Esucletin, 4-methylesculetin, fraxetin, and caffeic acid showed the 

quenching effect on the 1, 1-diphenyl-2- picrylhydrazyl radical. These results indicate 

that the presence of an ortho catechol moiety in the coumarin molecules plays an 

important role in the protective activities against linoleic acid hydroperoixde-induced 

cytotoxicity [98] . 

32


An antioxidant auraptene (7-geranyloxycoumarin) isolated from the peel of citrus fruit 

(Citrus natsudaidai Hayata) has been reported to have chemopreventive effects on 

chemically induced carcinogenesis. Dietary administration of auraptene significantly 

increased the activities of detoxification (phase II) enzymes, such as quinone 

reductase and glutathione S-transferase, in the liver and colon of rats. In addition, 

expression of cell proliferation biomarkers, such as ornithine decarboxylase activity 

and polyamine biosynthesis, in the colonic mucosal epithelium was significantly 

inhibited by dietary feeding of auraptene. These biological functions of auraptene may 

contribute to its anti-tumorigenic effect [99] . In addition to this, auraptene have been 

demonstrated its anti-tumor promoting effect in mouse skin and anti-carcinogenesis 

activities in rattongue, esophagus and colon [100] . Murakami A. et al. [100] reported that 

Auraptene suppresses superoxide anion (O2 –) generation from inflammatory 

leukocytes in in vitro experiments. In the study, they investigated the antiinflammatory 

activities of Auraptene and compared them with those of Umbelliferone 

(7- hydroxycoumarin), a structural analog of Auraptene that is virtually inactive 

toward (O2 –) generation inhibition. Double pre-treatments of mouse skin with 

Auraptene, but not Umbelliferone, markedly suppressed edema formation, hydrogen 

peroxide production, leukocyte infiltration, and the rate of proliferating cell nuclear 

antigen-stained cells. These inhibitory effects by Auraptene are attributable to its 

selective blockade of the activation stage. Umbelliferone did not show any inhibitory 

effect. This contrasting activity profile between Auraptene and Umbelliferone was 

rationalized to be a result of their distinct differences in cellular uptake efficiencies, 

i.e. the geranyloxyl group in Auraptene was found to play an essential role in 

incorporation. 

H 3C 

CH 3 

O O O HO 

CH3 Auraptene 

O O 

Umbelliferon 

The rat hepatic toxicity of coumarin and methyl analogues (3- methylcoumarin, 4methylcoumarin 

and 3, 4-dimethylcoumarin) has been determined in vivo and in 

vitro [101] . Coumarin at a dose of approximately 1 mmol/kg produced clear histological 

33


evidence of centrilobular necrosis, while the methyl analogues at an equivalent dose 

were much less toxic. By use of a systematic random sampling protocol and 

quantitative morphometry it was determined that there was a lobar variation in the 

extent of hepatic damage but that this exhibited random inter-animal variation. The 

order of cytotoxicity in vitro was identical to that observed in vivo. 

CH 3 

CH 3 

O O HO O O 

HO O O 

3-Methyl Coumarin 4-Methyl 7-hydroxy Coumarin 3,4-Dimethyl 7-hydroxy Coumarin 

Geiparvarin, containing coumarin moiety, is an antiproliferative compound isolated 

from the leaves of Geijera parviflora, and may represent a new drug which targets 

tubulin. To better explore the potential use of this agent, A. Miglieta, et al [102] 

investigated the antimicrotubular and cytotoxic effects of new synthetic aromatic 

derivatives of geiparvarin. These drugs inhibited polymerization of microtubular 

protein, particularly when the assembly was induced by paclitaxel. 

Bocca C. et al. [103] investigated biological activity of ferulenol, a prenylated 4hydroxycoumarin 

from Ferula communis. Ferulenol stimulates tubulin polymerization 

in vitro, and inhibits the binding of radiolabeled colchicines to tubulin. It rearranges 

cellular microtubule network into short fibres, and alters nuclear morphology. 

Remarkably, ferulenol exerts a dose dependent cytotoxic activity against various 

human tumor cell lines. 

CH 3 

CH 3 

34


O CH 3 

O O 

Ferulenol 

Three new coumarin derivatives along with furanocoumarins and a novel dioxocane 

derivative were isolated from the fern Cyclosorus interruptus (Willd.)H.Ito [104] . Based 

on spectrometric and spectroscopic analysis (FAB or El mass spectrometry as well as 

1D and 2D NMR experiments) their structures were characterised as 5,7- dihydroxy - 

6 - methyl - 4 - phenyl - 8 - ( 3 - phenylpropionyl ) -benzopyran-2-one (1), 5, 7dihydroxy-6-methyl-4-phenyl-8- 

(3-phenyl-trans-acryloyl)-1-benzopyran-2-one (2), 

5,7-dihydroxy - 8 - (2 - hydroxy - 3 - phenylpropionyl) - 6 - methyl – 4 - phenyl-1benzopyran-2-one 

(3). Among which compounds 5,7- dihydroxy - 6 - methyl - 4 - 

phenyl - 8 - (3 - phenylpropionyl) - 1benzopyran-2-one and 5, 7-dihydroxy-6-methyl- 

4-phenyl- 8-(3-phenyl-trans-acryloyl)-1-benzopyran-2-one, were cytotoxic to a KB 

cell line 

H 3C 

HO 

O 

OH 

O O 

H 3C 

HO 

O 

OH 

O O 

H 3C 

HO 

CH 3 

O 

OH 

O O 

H 3CO 

HO 

1 2 3 4 

OH 

OCH 3 

O O 

A new coumarin, 5-(4-hydroxyphenethenyl)-4, 7-dimethoxycoumarin (4) was isolated 

from the combined ethylacetate extracts of the root bark, root wood and stem bark of 

Monotes engleri, and found to be cytotoxic against two cell lines in a human tumor 

panel [105] . Its structure was determined on the basis of spectroscopic methods. In a 

Chinese herb cytotoxicity screening test, the ethanol extract of Cnidii monnieri 

35


Fructus exhibited strong effects on human leukemia (HL-60), cervical carcinoma 

(HeLa) and colorectal carcinoma (CoLo 205) cells. Then, the Cnidii monnieri Fructus 

extract was subjected to silica gel column chromatography and recrystallization to 

give five coumarins:osthol (5), imperatorin (6), bergapten (7), isopimpinellin (8), and 

xanthotoxin (9). Among these compounds, osthol showed the strongest cytotoxic 

activity on tumor cell lines. The structure-activity relationship established from the 

results indicated that the prenyl group has an important role in the cytotoxic effects. 

However, imperatorin showed the highest sensitivity to HL-60 cells and the least 

cytotoxicity to normal PBMCs. Osthol and imperatorin both caused apoptotic bodies, 

DNA fragmentation, and enhanced PARP degradation in HL-60 cells by biochemical 

analysis. These results indicate that osthol and imperatorin can induce apoptosis in 

HL-60 cells. Therefore, osthol and imperatorin are cytotoxic marker substances in the 

fruits of Cnidium monnieri [106] . 

H3CO O O O O O 

O 

O O O 

H3C 5 

CH3 H3C 6 7 

O 

OCH 3 

OCH 3 

8 

O O 

CH 3 

O 

OCH 3 

9 

O O 

OCH 3 

Five coumarins (seselin, 5-methoxyseselin, suberosin, xanthyletin and xanthoxyletin) 

were isolated from the roots of Plumbago zeylanica [107] . All coumarins were not 

previously found in this plant. Cytotoxicity of these compounds to various tumor cells 

lines was evaluated, and they were significantly suppressed growth of Raji, Calu-1, 

HeLa, and Wish tumor cell lines. 

36


H 3C 

O 

CH 3 

R 

O O 

H 3C 

CH 3 

H 3CO 

Seselin, R = H 

5-methoxyseselin R = OCH3 

suberosin 

H 3C 

O O 

O 

CH 3 

R 

O O 

Xanthyletin R = H 

Xenthoxyletin R = OCH3 

Fractionation of the methanol extract of Angelica dahurica Benth et Hook resulted in 

the isolation of six furocoumarins, imperatorin, isoimperatorin, (+/-)-byakangelicol, 

(+)-oxypeucedanin, (+)-byakangelicin and (+)-aviprin [108] . Among these, compounds 

imperatorin and (+)-byakangelicin exhibited strong hepatoprotective activities, 

displaying EC50 values of 36.6 +/- 0.98 and 47.9 +/- 4.6 mM, respectively. 

O 

O 

O 

O 

O O 

CH3 O O O 

CH3 CH 3 

isoimperatorin 

CH 3 

Oxypeucedanin 

A coumestan derivative, psoralidin was found to be a cytotoxic principle of the seeds 

of Psoralea corylifolia L.(Leguminosae) with the IC50 values of 0.3 and 0.4 mg/mL 

against the HT-29 (colon) and MCF-7 (breast) human cancer cell lines, 

respectively [109] . 

H 3 

C 

CH 3 

HO 

psoralidin 

O O 

A series of styrylcoumarin derivatives had been designed by Xu Song et al [110] in 

order to find compounds of antitumor activities by screening in vitro. The title 

O 

OH 

37


compounds were synthesized by phase-transfer Wittig reaction and screened by 

several antitumor models in vitro.Thirty new compounds of 6- or 7-styrylcoumarin 

were synthesized and their configurations were determined. Seven compounds(10-16) 

showed different inhibitory effects on L-1210, HL-60, HCT-8, KB and Bel-7402 cell 

lines in vitro. The activity data representes as shown in Table-1. Some 6- or 7styrylcoumarin 

derivatives showed antitumor activities and is worth further study. 

In continuation with this, a series of 4-styryl coumarin had been synthesized for in 

vitro antitumor activity study [111] . The titled compounds were synthesized by Phase 

transfer Wittig reaction or Wittig-Horner reaction and screened by several antitumor 

38


modeles in vitro. Among a series of 20 compounds, only one had effects on KB cell 

lines in vitro and possesses certain antitumor activities and it was selected for further 

studies. 

Antiviral activity 

R 

O O 

4-Styrylcoumarin derivattives 

The ether soluble fraction of the roots of Ononis vaginalis Vahl. Symb. afforded three 

new compounds: 3-hydroxy-4, 9-dimethoxycoumestan, maginaldehyde [2-(4hydroxy-2-methoxyphenyl)-5, 

6-dimethoxy-3- benzofurancarboxaldehyde] and 5, 7, 

4'-trihydroxy-4-styrylcoumarin. The styrylcoumarin derivative showed significant 

antiviral activity against Herpes simplex type 1 and weak cytotoxicity. 

OH 

OH 

HO 

O O 

5,7,4'-Trihydroxy-4-Styrylcoumarin 

R 

39


Adamantane: 

Adamantane is a colorless, crystalline chemical compound with a camphor-like 

odor. With a formula C10H16, it is a cycloalkane and also the simplest diamondoid. 

Adamantane molecules consist of three cyclohexane rings arranged in the "armchair" 

configuration. It is unique in that it is both rigid and virtually stress-free. Adamantane 

is the most stable among all the isomers with formula C10H16, which include the 

somewhat similar twistane. The spatial arrangement of carbon atoms is the same in 

adamantane molecule and in the diamond crystal. 

The discovery of adamantane in petroleum in 1933 launched a new chemistry 

field studying the synthesis and properties of polyhedral organic compounds. 

Adamantane derivatives have found practical application as drugs, polymeric 

materials and thermally stable lubricants. 

Drug like compounds having adamantine moiety has many therapeutic value. 

Adafenoxate having Nootropic and Psychostimulant as its therapeutic function, has 

been prepared using 1-Aminoadamantine-2-ethanol, p-Chlorophenoxyacetyl chloride 

and p-Chlorophenoxyacetic acid [179] . 

HN 

O 

Adamexine having common names Adamexine and Broncostyl is used as a 

mucolytic drug, prepared using 2-Bromomemtyl-4,6-dibromo-N,N,diacetylaniline and 

N-Methyladamantyl [180] . 

O 

O 

Cl 

40


Br 

N 

NH 

Br O 

Adapalene used as Anti-acne drug is synthesized using 4-Bromophenol and 1- 

Adamantanol [181] . 

Adatanserin Hydrochloride [115,116] consisting of amide linkage formed by linking [4- 

(2-pyrimidinyl)piperazino]ethylamine with Adamantane acid chloride is an antidepressant 

drug [182] . 

O N H 

H Cl 

N 

N 

N N 

Biologically active heterocyclic containing amide linkage 

A number of drugs and drug like compounds have amide linkages. Coumarin 

carboxamide [112] has been prepared from the corresponding coumarin carboxylic acid 

and 2-amino-4-phenylthiazole [113] and tested for anti-fungal and antibacterial 

activity. [114] 

OCH3 O 

O 

C N H 

O 

N 

S 

41


Adatanserin Hydrochloride [115,116] consisting of amide linkage formed by linking [4- 

(2-pyrimidinyl)piperazino]ethylamine with Adamantane acid chloride is an antidepressant 

drug. 

O N H 

H Cl 

N 

N 

N N 

Aromatic polyamide dendrons HOOC-G1, were synthesized by Ishida et. al. [117] by an 

orthogonal approach, which utilizes the direct condensation reaction and palladium 

catalyzed carbon monoxide insertion reaction in an alternating fashion to form amide 

linkages. 

COCl COOH 

H 2N NH 2 

COOH 

HN NH 

O O 

HOOC-G1 

Nevirapine, [118] consisting of amide linkage, is used for inhibition of RT enzyme. 

H 3C 

HN 

O 

N N N 

42


Planarity of the CONH linkage 

The XC(CO)NHY linkage, under the assumption Y=H called the amide linkage, or 

referred to as the peptide linkage, is generally assumed to have a planar structure. [119] 

Conformation and atomic numbering of syn-methyl carbonate 

It is shown that formamide, considered prototype for the amide linkage, is not typical 

as it has a planar equilibrium amide linkage corresponding to a single-minimum 

inversion potential around N. In contrast, several molecules containing the CONH 

linkage seem to have pyramidal nitrogen at equilibrium and a double-minimum 

inversion potential with a very small inversion barrier allowing for an effective planar 

ground-state structure. [120] 

Many of the molecules containing the XC(CO)NHY linkage are not planar at 

equilibrium. The simple molecules containing the -C(CO)NH linkage can be divided 

into three groups: 

1) All of the atoms of the molecule lie in a plane, i.e., the point-group symmetry 

of the molecule is Cs. 

2) All of the atoms of the molecule lie in a plane except pairs of hydrogen atoms 

which are situated symmetrically about the plane of symmetry, i.e., the pointgroup 

symmetry of the molecule is Cs. 

3) Molecules which do not have a plane of symmetry. 

43


Amide linkage containing analogues: A collection of 

commercial analogues: 

CH 3 

CH 3 

H 

N 

CH 3 

CH 3 

CH 3 

CH 3 

O 

CH 3 

H 

N 

H 

N 

Lidofenin 

O 

CH 3 

N COOH 

COOH 

N 

Bupivacaine 

H 

N 

H 

N 

O 

Aptocaine 

O 

CH 3 

N 

H 

Prilocaine 

O 

CH 3 

CH 3 

N 

H 

Pyrrocaine 

HH3C 

N 

O 

CH 3 

N 

H 

Quatacaine 

N 

N 

CH 3 

CH 3 

CH 3 

Cl 

H 

N 

O 

CH 3 

COOCH 3 

H 3 

C 

H 3C 

S 

H 

N 

N 

H 

Butanilicain 

O 

CH 3 

CH 3 

H 

N 

CH 3 

CH 3 

Tylocain 

H 

N 

O 

CH 3 

Trimecain 

O 

CH 3 

COOCH 3 

CH 3 

N COOH 

N 

H 

Articain 

H 

N N 

CH 3 

COOH 

N CH 3 

CH 3 

O CH 3 

Mepivacaine 

H 

N 

O 

CH 3 

Tocainidin 

CH 3 

NH 2 

CH 3 

44



The literature survey revealed that some extensive work has been done on 4-hydroxy 

coumarin compounds. Also, due to the usefulness of traditional medicines like 

Auraptene, Ferulenol and Fraxetin, the coumarin moiety has been selected for the 

research criteria. 

Browsing through the literature of organomedicinal chemistry the most useful moiety 

found was substituted 3-amino 4-hydroxy coumarin derivatives. Because of the less 

toxicological properties and good to moderate activities, several compounds have 

been synthesized by our team in the laboratory. Though the chemistry of the 

synthesized compounds is unknown, the compounds are reported herein for the first 

time. 

In the current chapter two pharmacophoric moieties, coumarins and adamamtane were 

converted into a hybridized structure by means of amide linkage. 

45



R 

OH 

O O 

HNO 3 

CH 3COOH 

R 

OH 

O O 

NO 2 

Na 2S2O 4 

NaHCO 3 

2.5 PLAUSIBLE REACTION MECHANISM 

OH .. 

Cl 

+ 

O 

O O O O 

HN C 

O 

O O 

NH 2 

H + - 

H 

R 

R 

Cl 

OH 

+ H2N 

Cl- - 

H + 

N 

O 

C 

O O 

OH 

O O 

O - 

C 

NH 2 

OH HN 

Cl 

CHCl 3 

O 

O O 

O 

Triethyl amine 

46



Preparation of 3-amino 4-hydroxy coumarin 

3-nitro 4-hydroxy coumarin (0.01 mol) was dissolved in 100 ml saturated solution of 

sodium bicarbonate. Reaction mass was taken in a 500 ml beaker with constant 

mechanical stirring under fume hood. To which sodium dithionite 10 g was added in 

portions with constant stirring. As a result, solution colour changes from yellow to sea 

green to clear. Completion of reaction is checked using TLC. Reation mixture was 

then cooled to 0 oC and brought to pH-1 with conc. HCl dropwise. The resulting 

precipitates were filtered u/v, dried at 50 oC for 5-6 hours. Yield : 90%, M.P.: 226- 

228. [182] 

Preparation of substituted 3-(1-amido adamantyl) 4-hydroxy coumarins: 

To a stirred solution of substituted 3-amino 4-hydroxy coumarin (0.01 mol) in 50 ml 

methylene chloride, adamantane 1-carboxylic acid chloride (0.018 mol) and triethyl 

amine (0.015 mol) were added and stirring was continued overnight at room 

temperature. Reaction mass was washed with H2O, dried over sodium sulphate and 

evaporated under vacuum. Solids obtained were recrystallized using mixture of 

methylene dichloride and hexane. 

Note: Preparation of substituted 4-hydroxy coumarin (VNRINT-101) and 

substituted 3-nitro 4-hydroxy coumarin (VNRINT-103) are described in 

Chapter-7. 

47



Physical data of substituted 3-(1-amido adamantyl) 4-hydroxy 

coumarins derivatives. 

Sr. 

No 

1 

2 

3 

4 

5 

6 

7 

8 

9 

10 

Code Structure 

VNRAD- 

101 

VNRAD- 

102 

VNRAD- 

103 

VNRAD- 

104 

VNRAD- 

105 

VNRAD- 

106 

VNRAD- 

107 

VNRAD- 

108 

VNRAD- 

109 

VNRAD- 

110 

OH HN 

O 

O O 

OH HN 

O 

O O 

OH HN 

O 

O O 

OH HN 

O 

O O 

OH HN 

O 

O O 

OH HN 

O 

O O 

OH HN 

O 

O O 

Molecular 

formula 

Molecular 

weight 

M. P. 

( o C) 

% 

Yield 

C 20H 21NO 4 339.39 105 o C 68 

C21H 23NO 4 353.41 221 o C 66 

C 22H 25NO 4 367.44 170 o C 51 

C 22H 25NO 4 367.44 185 o C 64 

C 22H 25NO 4 367.44 238 o C 63 

C 21H 23NO 4 353.41 166 o C 71 

F C 20H 20FNO 4 357.38 208 o C 52 

OH HN 

Cl C 20H 20ClNO 4 373.83 223 o C 55 

HO 

O 

O O 

OH HN 

O 

O O 

O 

O O 

C 20H 21NO 5 355.38 188 o C 77 

OH 

HN 

MeO C21H23NO5 369.41 175 o C 75 

48


49



Infra Red spectra 

Infra Red Spectra were taken on SHIMADZU IR-435 Spectrometer using KBr Pellet 

method. The characteristic carbonyl group in coumarin moiety is observed at 1720- 

1750 cm -1 , while carbonyl value of –CONH- peaks are observed in the range 1630- 

1690 cm -1 . In some of the compounds, the moisture showed a broad peak between 

3000-3200 cm -1 . Secondary amine (> NH) observed a broad peak between 3000-3200 

cm -1 .Methylene gp (>CH2) observed at 2850-3000 cm -1 . methyl (-CH3) observed at 

1350 cm -1 . 


1 

H NMR Spectra were recorded on a Bruker AC 400 MHz FT-NMR Spectrometer 

using TMS (Tetramethyl Silane) as an internal standard and DMSO-d6 & CDCl3 as a 

solvent. In the NMR spectra of derivatives of 3-(1-amido adamantyl) 4-hydroxy 

coumarin various proton values of methylene (-CH2), amine (-NH), methyl (-CH3) 

and aromatic protons (Ar-H) etc. were observed as under. 

The values for methylene (-CH2) proton is observed between δ 2.50-3.55 ppm. In 

some cases, the value of methylene proton differs to δ 4.20 and 4.43 ppm. Aromatic 

protons shows the multiplet between δ 6.01-8.54 δ ppm. The signal due to NH proton 

of amide group (>CONH) was observed at 10.3 δ ppm value. 

Mass spectra 

The mass spectrum of compounds were recorded by GCMS-QP2010 spectrometer (EI 

method). The mass spectrum of compounds was obtained by positive chemical 



(M+) values are in good agreement with molecular formula of all the compounds 

synthesized. 


Elemental analysis of the synthesized compounds was carried out on Vario EL Carlo 

Erba 1108 model at Saurashtra University, Rajkot which showed calculated and found 

percentage values of Carbon, Hydrogen and Nitrogen in support of the structure of 

49


synthesized compounds. The spectral and elemental analysis data are given for 

individual compounds 


3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-101) 

Yield: 68%; IR (cm -1 ): 3355 (O-H str.), 3412 (N-H str.), 3040 (Ar C=C-H str.), 2980 (Asym 

C-H str. -CH3), 2930 (Asym C-H str. -CH2), 2870 (Sym C-H str. -CH3), 2845 (Sym C-H str. - 

CH2), 1735 (C=O str.), 1652 (N-H bend), 1580, 1545, 1500 (Ar C=C str.), 1475 (C-H bend – 

CH2), 1365 (C-H bend –CH3), 1340 (C-N sec amine vib), 1180 (C-O str.), 810 (C-H oop def); 

Mass: [m/z (%)], M. Wt.: 339; Elemental analysis, Calculated: C, 70.78; H, 6.24; N, 4.13; 

Found: C, 70.55; H, 6.17; N, 4.23. 

8-methyl 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-102) 

Yield: 66%; IR (cm -1 ): 3360 (O-H str.), 3385(N-H str.), 3040 (Ar C=C-H str.), 2904 (Asym 

C-H str. -CH3), 2948 (Asym C-H str. -CH2), 2850 (Sym C-H str. -CH3), 1730 (C=O str.), 

1602 (N-H bend), 1529, 1634 (Ar C=C str.), 1454 (C-H bend –CH2), 1356 (C-H bend –CH3), 

1332 (C-N sec amine vib), 1195 (C-O str.), 796 (C-H oop def); 1 H NMR 400 MHz: (CDCl3, 

δ ppm): 1.73 (m, 6H), 1.97 (s, 6H), 2.41 (s, 3H), 2.54 (m, 3H), 7.25 (t, 1H), 7.43 (d, 1H), 

7.74 (d, 1H), 8.52 (s, 1H), Mass: [m/z (%)], M. Wt.: 353 Elemental analysis, Calculated: 

C, 71.37; H, 6.56; N, 3.96; Found: C, 71.63; H, 6.41; N, 3.27. 

7,8- dimethyl 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-103) 

Yield: 51%; %; IR (cm -1 ): 3402 (O-H str.), 3397 (N-H str.), 3040 (Ar C=C-H str.), 2904 

(Asym C-H str. -CH3), 2903 (Asym C-H str. -CH2), 2850 (Sym C-H str. -CH3), 2845 (Sym C- 

H str. -CH2), 1703 (C=O str.), 1639 (N-H bend), 1608, 1545 (Ar C=C str.), 1454 (C-H bend – 

CH2), 1356 (C-H bend –CH3), 1319 (C-N sec amine vib), 1176 (C-O str.), 815 (C-H oop def); 

Mass: [m/z (%)], M. Wt.: 367 ; Elemental analysis, Calculated: C, 71.91; H, 6.86; N, 

3.81; Found: C, 71.11; H, 6.42; N, 3.54. 

50





1633 (N-H bend), 1586, 1537, 1504 (Ar C=C str.), 1448 (C-H bend –CH2), 1344 (C-H bend – 

CH3), 1317 (C-N sec amine vib), 1232 (C-O str.), 819 (C-H oop def); 1 H NMR 400 MHz: 

(CDCl3, δ ppm): 1.75 (m, 8H), 1.92 (s, 6H), 2.07 (m, 7H), 2.37 (t, 3H), 2.5 (s, 3H), 3.32 (s, 

8H), 7.06 (d, 1H), 7.35 (d, 1H), 6.60 (s, 1H). Mass: [m/z (%)], M. Wt.: 367 ; Elemental 

analysis, Calculated: C, 71.91; H, 6.86; N, 3.81; Found: C, 71.33; H, 6.14; N, 3.79. 





CH3), 1315 (C-N sec amine vib), 1223 (C-O str.), 815 (C-H oop def); Mass: [m/z (%)], M. 

Wt.: 367 ; Elemental analysis, Calculated: C, 71.91; H, 6.86; N, 3.81; Found: C, 71.68; H, 

6.19; N, 3.10. 

6- methyl 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-106) 






6.65; N, 3.14. 

6- fluoro 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-107) 


C-H str. -CH2), 1735 (C=O str.), 1637 (N-H bend), 1582, 1546, 1510 (Ar C=C str.), 1452 (C- 

H bend –CH2), 1338 (C-N sec amine vib), 1227 (C-O str.), 1215 (C-F str.), 817 (C-H oop 

def); Mass: [m/z (%)], M. Wt.: 357 ; Elemental analysis, Calculated: C, 67.22; H, 5.64; 

N, 3.92; Found: C, 67.26; H, 5.47; N, 3.81. 

51


6- chloro 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-108) 



H bend –CH2), 1317 (C-N sec amine vib), 1223 (C-O str.), 946 (C-Cl str.), 809 (C-H oop 

def); Mass: [m/z (%)], M. Wt.: 373(M+), 375(M+2); Elemental analysis, Calculated: C, 

64.26; H, 5.39; N, 3.75; Found: C, 64.32; H, 5.57; N, 3.64. 

7- hydroxy 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-109) 



H bend –CH2), 1314 (C-N sec amine vib), 1236 (C-O str.), 810 (C-H oop def); Mass: [m/z 

(%)], M. Wt.: 355 ; Elemental analysis, Calculated: C, 67.59; H, 5.96; N, 3.94; Found: C, 

67.34; H, 5.85; N, 3.86. 

6- methoxy 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD-110) 






6.23; N, 3.65. 

52



IR Spectrum of 8-methyl 3-(1-amido adamantyl) 4-hydroxy coumarin (VNRAD- 

102) 

97.5 

%T 

90 

82.5 

75 

67.5 

60 

52.5 

45 

3360.11 

4000 3600 3200 

VNRAD-102 

2904.89 

2848.96 

2800 

2400 

2000 

1755.28 

1730.21 

1683.91 

1643.41 

1602.90 

1800 

600 400 

1/cm 

IR Spectrum of 5,8- dimethyl 3-(1-amido adamantyl) 4-hydroxy coumarin 

(VNRAD-104) 

100 

%T 

90 

80 

70 

60 

50 

40 

30 

20 

10 

3562.64 

3352.39 

-0 

4000 3600 3200 

VNRAD-104 

2908.75 

2850.88 

2800 

2400 

2000 

1800 

1600 

1600 

1529.60 

1747.57 

1726.35 

1695.49 

1633.76 

1595.18 

1537.32 

1504.53 

1454.38 

1356.00 

1400 

1400 

1195.91 

1200 

1481.38 

1446.66 

1415.80 

1344.43 

1317.43 

1232.55 

1180.47 

1200 

1080.17 

1045.45 

977.94 

920.08 

OH HN 

1000 

1000 

796.63 

O 

O O 

1041.60 

985.66 

916.22 

OH HN 

748.41 

800 

819.77 

769.62 

O 

O O 

800 

534.30 

453.29 

418 57 

428.21 

600 400 

1/cm 

53


Mass spectrum of 8-methyl 3-(1-amido adamantyl) 4-hydroxy coumarin 

(VNRAD-102) 

OH HN 

O 

O O 

Mass Spectrum of 5,8- dimethyl 3-(1-amido adamantyl) 4-hydroxy coumarin 

(VNRAD-104) 

OH HN 

O 

O O 

54


1 

H NMR Spectrum of 8-methyl 3-(1-amido adamantyl) 4-hydroxy coumarin 

(VNRAD-102) 

OH HN 

O 

O O 

Expanded 1 H NMR Spectrum of 8-methyl 3-(1-amido adamantyl) 4-hydroxy 

coumarin (VNRAD-102) 

OH HN 

O 

O O 

55


1 

H NMR Spectrum of 5,8- dimethyl 3-(1-amido adamantyl) 4-hydroxy coumarin 

(VNRAD-104) 

OH HN 

O 

O O 

Expanded 1H NMR Spectrum of 5,8- dimethyl 3-(1-amido adamantyl) 4hydroxy 

coumarin (VNRAD-104) 

OH HN 

O 

O O 

56



In this Chapter, 10 different substituted 3-amino 4-hydroxy coumarins were prepared, 

preparation method of which is shown in chapter-7. These substituted 3-amino 4hydroxy 

coumarins were linked with adamantane through amide linkage. The main 

significance of present work that the reactions are carried out at room temperature 

under stirring, and desired product is obtained with easy work up method. 


Thus, substituted 3-amino 4-hydroxy coumarin are reacted with adamantane acid 

chloride in order to form an amide linkage. By doing so, a new class of coumarin 

derivatives are generated and their potential biological activity will be checked upon. 

57


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68

Chapter‐3 

SOLVENT FREE SOLID PHASE SYNTHESIS OF 

AZOMETHINE LINKED COUMARIN MOITIES.

Chapter-3 Solvent less Solid Phase Synthesis of … 


Schiff Bases: 

Formation of Schiff Bases 

A Schiff base is nitrogen analog of an aldehyde or ketone in which the C=O 

group is replaced by a C=N-R group. It is usually formed by condensation of an 

aldehyde or ketone with a primary amine according to the following scheme: 

R NH O 

R 

2 

R R 

R 

N R H2O Primary Amine Aldehyde or Ketone Schiff Base Water 

Where R may be an alkyl or an aryl group. Schiff bases that contain aryl substituents 

are substantially more stable and more readily synthesized, while those which contain 

alkyl substituents are relatively unstable. Schiff bases of aliphatic aldehydes are 

relatively unstable and readily polymerizable, [1-3] while those of aromatic aldehydes 

having effective conjugation are more stable [4-7] . 

The formation of a Schiff base from an aldehydes or ketones is a reversible reaction 

and generally takes place under acid or base catalysis, or upon heating. 

O 

R H 

R NH OH 

Aldehyde or Ketone 

2 

Primary Amine 

R R 

NHR 

Carbinolamine 

R 

R 

NR 

N-Substituted Imine 

H 2O 

Water 

The formation is generally driven to the completion by separation of the 

product or removal of water, or both. Many Schiff bases can be hydrolyzed back to 

their aldehydes or ketones and amines by aqueous acid or base. 

The mechanism of Schiff base formation is another variation on the theme of 

nucleophilic addition to the carbonyl group. In this case, the neuclophile is the amine. 

In the first part of the mechanism, the amine reacts with the aldehyde or ketone to 

give an unstable addition compound called carbinolamine. 

68


The carbinolamine loses water by either acid or base catalyzed pathways. 

Since the carbinolamine is and alcohol, it undergoes acid catalyzed dehydration. 

N R' 

OH H 

R2C H 

+ 

N R' 

OH2 R2C H 

R 

R 

R 

R 

N 

H 

N 

R' 

R' 

H 2O 

H 3O + 

(Acid Catalyzed Dehydration) 

Typically the dehydration of the carbinolamine is the rate-determining step of Schiff 

base formation and this is why the reaction is catalyzed by acids. Yet the acid 

concentration cannot be too high because amines are basic compounds. If the amine is 

protonated and becomes non-nucleophilic, equilibrium is pulled to the left and 

carbinolamine formation cannot occur. Therefore, many Schiff base syntheses are best 

carried out at mildly acidic pH. 

The dehydration of carbinolamines is also catalyzed by base. This reaction is 

somewhat analogous to the E2 elimination of alkyl halides except that it is not a 

concerted reaction. It proceeds in two steps through an anionic intermediate. 

The Schiff base formation is really a sequence of two types of reactions, i.e. addition 

followed by elimination [8] . 

The utility of Schiff bases lay in their usefulness as synthons in the synthesis of 

bioactive molecules such as 4-thiazolidinines, 2-azetidinones, benzoxazines, 

formazans, etc. Schiff bases are known to have useful biological activity like 

insecticidal [9] , antibacterial [10] , antituberculosis [11] , antimicrobial [12] , anticonvulsant 

[13] , antifeedant [14] etc. Schiff bases belongs to a widely used group of organic 

intermediates important for production of specially chemicals, e.g. pharmaceutical or 

rubber additives [15] , as amino protective groups in organic synthesis [16-19] . They also 

have used as liquid crystals [20] , in analytical [21] , medical [22] and polymer chemistry 

[23] . 

A classical synthesis of these compounds involves the condensation of acetophenones 

and anilines to give Schiff bases [24] . The combination of solvents and long reaction 

time makes this method environmentally hazardous. 

This provided the stimulus to synthesize new Schiff bases using classical as well as 

grindstone technique [25] . In grindstone technique reaction occur through generation of 

69


local heat by grinding of crystals of substrate and reagent by mortar and pestle. 

Reactions are initiated by grinding, with the transfer of very small amount of energy 

through friction. In some cases, a mixture and reagents turns to a glassy material. 

Such reaction are simple to handle, reduce pollution, comparatively cheaper to 

operate and may be regarded as more economical and ecologically favorable 

procedure in chemistry [26] .Solid state reaction occur more efficiently and more 

selectively than does the solution reaction, since molecules in the crystal are arranged 

tightly and regularly [27] . 

In present work grindstone technique was used for the synthesis of titled compounds. 

This method is superior since it is eco-friendly, high yielding, requires no special 

apparatus, non-hazardous, simple and convenient. A series of some new Schiff bases 

have been prepared. To best our knowledge earlier reports do not exist on the 

synthesis of these Schiff bases. 

70



Various methods for the preparation of azomethine derivatives have been cited 

in literature, some of the methods are as under. 

1. General account of the summary of reaction of aldehydes with amine 

(aromatic or aliphatic) has been reviewed by Murray [28] . 

R 

O 

R1 NH2 R N R1 2. E. C. Creencia and group [29] reported synthesis from ortho substituted aniline 

with 55 % yield in 2 hours in benzene. 

Ar 

NH 2 

O 

R 

Benzene 

3. D. Bleger et al. [30] have synthesized Schiff’s base of aniline and benzaldehyde 

in ethanol with short reaction time of 4 hours and reported E isomer as major 

product. 

NH 2 

O 

2h 

EtOH 

4. U. K. Roy and coworkers [31] have reported preparation of Schiff’s base with 

4h 

100 % of yield with toluene as a solvent. 

Ar 

N 

E 

N 

R 

71


NH 2 

O 

PhMe 

24h 

5. L. B. Pierre and coworkers [32] have synthesized (E)-N-phenyl 

ClHH 2N 

methyleneglycineethyl ester by the cyclocondensation of glycine ethyl ester 

hydrochloride, t-butylmethyl ether (TBME), benzaldehyde was added 

followed by anhydrous Na2SO4 and triethylamine. 

O 

O 

O 

Et3N,TBME Na2SO4 6. J. G. Amanda et al. [33] have prepared Schiff bases by condensation of 

O 

equimolar quantity of 3,6-diformylcatechol and substituted ophenylenediamine. 

OH 

O 

OH 

H 2N 

OR 

NH 2 

OR 

7. L. Somogyi [34] reported some azomethine derivatives of phenylhydrazide in 99 

% yield and with short reaction time of 3.5 hours in polar solvent. 

O 

OH 

N 

N 

OH 

N 

O 

O 

OR 

NH 2 

OR 

72


O 

H 

N NH2 

O 

3.5h 

O 

H 

N N 

8. Schiff’s base of o-phenelene diamine with substituted benzaldehyde was 

reported by M. Zintl and coworkers [35] . 

NH 2 

NH 2 

Ar O 

EtOH 

N 

N 

R 

Ar 

Ar 

73


3.3 GREEN CHEMISTRY APPROACH 

Microwave irradiation (MWI) has become an established tool in organic synthesis, 

because of 

the rate enhancements, higher yields, and often, improved selectivity, with respect to 

the 

conventional reaction conditions. 

In recent years, solvent –free reactions using either organic or inorganic solid supports 

have received increasing attention [36] . 

There are several advantages to performing synthesis in dry media: (i) short reaction 

times, (ii) increased safety, (iii) economic advantages due to the absence of solvent. In 

addition, solvent free MWI processes are also clean and efficient [37] . 

Owing to environmental restrictions on emissions covered in several legislations 

throughout the world, non-polluting and atom-efficient catalytic technologies are 

much sought after. The use of acid catalysts is very common in the chemical and 

refinery industries, and those technologies employing highly corrosive, hazardous and 

polluting liquid acids are being replaced with solid acids; for instance, acid treated 

clays, zeolites, zeotypes, ion-exchange resins and metal oxides. Of late, a number of 

organic syntheses have been conducted with solid acids like sulfated zirconia, leading 

to better regio- and stereo- selectivity [38] . 

The challenge in chemistry to develop practical processes, reaction media, conditions 

and/or utility of materials based on the idea of green chemistry is one of the important 

issues in the scientific community. 

Owing to our interest in solid-state reactions [39-40] , we attempted to synthesize Schiff 

bases from reaction of substituted amines of 4-hydroxy coumarin with 3-formyl 4hydroxy 

coumarin using mortar pestle. 

Greener Reactions under solventless conditions 

Due to the growing concern for the influence of the organic solvent on the 

environment as well as on human body, organic reactions without use of conventional 

organic solvents have attracted the attention of synthetic organic chemists. Although a 

number of modern solvents, such as fluorous media, ionic liquids and water have been 

extensively studied recently, not using a solvent at all is definitely the best option. 

Development of solvent-free organic reactions is thus gaining prominence. 

74


Catalyst and solvent-free conditions as an environmentally benign approach 

to 4-aryl-3-cyano-hexahydro-4H-1, 2-benzoxazine-2-oxides 

1,2-Oxazine-2-oxides are generally accessible via a catalyzed formal [4 + 2] 

cycloaddition reactions of nitroalkenes with electron-rich alkenes [41,42] . These 

heterocycles are valuable intermediates to prepare in a regio and stereoselectively 

manner a number of important building blocks or target heterocyclic compounds, such 

as pyrrolidines, β-lactam-N-oxides, pyrrolizidine and indolizidine alkaloids, 

enamines, ketoalcohols, nitroketones, etc. In 2008, Bellachioma et.al [45] reported that 

(E)-2-aryl-1-cyano-1- nitroethenes [43,44] are excellent Michael acceptors in water in 

the reactions with enantiopure alkyl vinyl ethers, allowing the preparation of various 

cyclic nitronates by a completely endo stereoselective [4 + 2] cycloaddition [46] 

(Scheme 1). 

MeO 

CN 

NO 2 

OSiMe 3 

Me 3SiO 

H 

O 

N 

OMe 

Scheme 1: Michael addition of 1-nitroethene with 1-(trimethylsilyloxy)-cyclohex-1ene 

Under solvent-free conditions, (E)-2-aryl-1-cyano-1-nitroethenes rapidly react with 1- 

(trimethylsilyloxy)-cyclohex-1-ene with a complete regio- and diasteroselectivity and 

leading to the exclusive formation of the cis-fused hexahydro-4H-benzoxazine-2oxides, 

which were isolated without the need for a work-up procedure in excellent 

yields. 

Solid-state regio and stereo-selective benzylic bromination of diquinoline 

compounds using N-bromosuccinimide 

The Wohl–Ziegler reaction, namely allylic or benzylic free radical bromination using 

N-bromosuccinimide (NBS) in a refluxing aprotic solvent, (Scheme 2) is a wellestablished 

synthetic organic procedure [47] . Benzene, chloroform and petrol have 

been employed as solvents, but the traditional choice has been carbon tetrachloride 

which combines optimum properties of solubility, reaction temperature and ease of 

product isolation. The succinimide by-product can be removed simply by filtration of 

the cooled reaction mixture and then evaporation of solvent from the filtrate affords 

the brominated product [48] . In 2005, Rahman et al. [49] synthesised a series of new 

O 

CN 

75


brominated diquinoline lattice inclusion hosts, some of which have potential in 

separation chemistry due to their selective properties. In each case, the final step 

involved a regio and stereoselective benzylic NBS bromination in refluxing CCl4. 

However, identical products can be obtained by means of solid-state reaction. 

R 

R 

N 

H 

H 

N 

R 

R 

R 

R 

N 

Br 

H 

Scheme 2: Benzylic bromination of diquinoline compounds using Nbromosuccinimide 

Metal and solvent-free conditions for the acylation reaction catalyzed by 

carbon tetrabromide 

Organocatalysis has attracted much attention as result of both the novelty of the 

concept and more importantly the fact that the efficiency and selectivity of many 

organocatalytic reactions meet the standards of established organic reactions. 

Catalysts of the same class may promote similar reactions or less closely related 

reactions e.g., Carbon tetrabromide (CBr4) is another example of this catalyst class is 

able to mediate an astonishing variety of transformations. Although carbon 

tetrabromide is considered a poisonous, irritating solid (skin contact can cause severe 

irritation; avoid inhalation of fumes; toxicity: irritating to skin, eyes and respiratory 

tract, irritating to mucous membranes, narcotic in high concentrations; possible liver 

and kidney damage;). It has been utilized as a mild Lewis acid imparting high regio 

and chemo-selectivity in various organic transformations [50] . In 2007, Zhang et al. [51] 

reported that an efficient and useful catalyst carbon tetrabromide (CBr4) was 

discovered to be highly effective for the acylation of phenols, alcohols and thiols 

under metal and solvent-free conditions (Scheme 3). 

OH 

Ac 2O 

CBr4 (5 mol%) 

Solvent free 

RT, air 

24 hr, 91% 

Scheme 3: Acylation reaction catalyzed by carbon tetrabromide 

H 

Br 

OAc 

N 

R 

R 

76


An environmentally benign solvent-free Tishchenko reaction 

The conversion of aldehydes to their dimeric esters, better known as the Tishchenko 

reaction has been known for more than a hundred years. This reaction is heavily used 

in industry and it is inherently environmentally benign since it utilizes catalytic 

conditions and is 100% atom economic. Over the years, chemists have looked to 

develop new reagents that are more efficient than the aluminum based catalysts 

traditionally used. Metal catalysts such as alkali metals, alkali metal oxides, 

lanthanides, and many others have been developed towards the improvement of 

Tishchenko chemistry. In 2009, Waddell et al. [52] reported that the solvent-free ball 

milling Tishchenko reaction. Using high speed ball milling and a sodium hydride 

catalyst, the Tishchenko reaction was performed for aryl aldehydes in high yields in 

0.5 hours (Scheme 4). The reaction was not affected by the type of ball bearing used 

and found to be successful in a liquid nitrogen environment. 

2 RCHO 

Scheme 4: Tishchenko reaction 

Catalyst 

R 

O 

O R 

Reformatsky and Luche Reaction in absence of solvent 

In 1990, Tanaka et al. [53] reported Reformatsky (scheme 5) and Luche reactions 

(Scheme 6) with Zn provide more economical C-C bond formation methods than 

Grignard reactions with more expensive Mg metal. 

RCHO BrCH 2COOEt 

Scheme 5: Reformatsky Reaction 

Scheme 6: Luche Reaction 

RCHO BrCH 2CH=CH 2 

Zn 

NH 4Cl 

Zn 

NH 4Cl 

ArCH(OH)CH 2COOEt 

RCH(OH)CH 2CH=CH 2 

In addition, it was pointed out that Reformatsky and Luche reactions proceed 

efficiently in the absence of solvent, although Grignard reactions under similar 

conditions are not very efficient and give more reduction product than the normal 

carbonyl addition product. The nonsolvent Reformatsky and Luche reactions can be 

carried out by a very simple procedure and give products in higher yield than with 

solvent. In general, the nonsolvent reaction was carried out by mixing aldehyde or 

77


ketone, organic bromo compound and Zn-NH4C1 in an agate mortar and pestle and by 

keeping the mixture at room temperature for several hours. 

Oxidative coupling Reaction of phenols with FeCl3 

Oxidative couplings of phenols are usually carried out by treatment of phenols in 

solution with more than equimolar amount of metal salts such as FeCl3 or manganese 

tris(acetylacetonate), although the latter one is too expensive to use in a large 

quantity. The coupling reactions of phenols with FeCl3, however, sometimes give 

quinones as byproducts. 

OH 

FeCl3.6H2O solid 

Scheme 7: Oxidative coupling Reaction of phenols with FeCl3 

In 1989, Toda et al. [54] have reported that some oxidative coupling reactions of 

phenols with FeCl3 are faster and more efficient in the solid state than in solution 

(Scheme 7). Some coupling reactions in the solid state were accelerated by irradiation 

with ultrasound. Some coupling reactions are achieved by using a catalytic amount of 

FeCl3 

Solvent free synthesis of chalcones 

The synthesis of chalcones illustrates the reaction that proceeds with high atom 

economy and is relatively easy to perform in teaching labs. Chalcones are important 

compounds with applications in medicine and physics. 

O 

H 

O 

H 3C NaOH 

R2 R1 R1 Scheme 8: Synthesis of chalcones 

OH 

OH 

O 

R 2 

R 1 = 4-CH 3;4-OCH 3;3-Cl;4-Cl;-H 

R 2 = 4-CH 3;4-Br;4-OCH 3;-H 

In 2004, Palleros et al. [55] found that the reactions proceed rapidly and afford very 

good yields of product. Most of the chalcones can be obtained in a matter of minutes 

78


by mixing the corresponding benzaldehyde and acetophenone in the presence of solid 

NaOH in a mortar with pestle (Scheme 8); the yields of crude product were in the 

range 81–94%. 

A Practical and Green Approach towards Synthesis of Dihydropyrimidinones 

without Any Solvent or Catalyst 

In 2002, Ranu et al. [56] reported a simple, efficient, green and cost-effective 

procedure for the synthesis of dihydropyrimidinones by a solvent-free and catalystfree 

Biginelli’s condensation of 1,3- dicarbonyl compound, aldehyde and urea 

(Scheme 9). This approach of direct reaction in neat without solvent and catalyst 

showed a new direction in green synthesis. 

O O 

R 1 R 2 

R 3 -CHO 

X 

H 2N NH 2 

X=O,S 

Scheme 9: Synthesis of Dihydropyrimidinones 

100-105 o C 

1 h 

Dihydropyrimidinone derivatives are of considerable interest in industry as well as in 

academia because of their promising biological activities as calcium channel blockers, 

antihypertensive agents and anticancer drugs. Thus, synthesis of this heterocyclic 

nucleus is of much importance and quite a number of synthetic procedures based on 

the modifications of the century-old Biginelli’s reaction involving acid-catalyzed 

three-component condensation of 1,3- dicarbonyl compound, aldehyde and urea, have 

been developed. Basically these methods are all similar using different Lewis acid 

catalysts such as BF3, FeCl3, InCl3 and 6h in a solvent such as CH3CN, THF. A 

number of procedures under solvent-free conditions using Yb(OTf)3, montmorillonite 

and ionic liquid as catalysts have also been reported. Obviously, many of these 

catalysts and solvents are not at all acceptable in the context of green synthesis. Thus, 

as a part of green synthesis, they have discovered that Biginelli’s reaction proceeds 

very efficiently by stirring a mixture of neat reactants at 100-105°C for an hour, 

requiring no solvent and catalyst, and producing dihydropyrimidinones in high yields. 

R 2 

O 

R 1 

R 3 

N 

H 

NH 

X 

79



To synthesize Schiff bases under solvent free conditions from 3-formyl 4-hydroxy 

coumarins using different amines including substituted 3-amino 4-hydroxy 

coumarins. 


Preparation of 3-((E)-(substited phenylimino)methyl)-4-hydroxy-2Hchromen-2-one: 

OH 

O 

H 

C O 

O 

NH 2 

R' 

Solid State 

Mortal Pestle 

OH HC N 

O O 

Preparation of 3-((12E)-(substituted 4-hydroxy-2-oxo-2H-chromen-3ylimino)methyl)-4-hydroxy-2H-chromen-2-one: 

OH 

O 

H 

C O 

O 

R'' 

OH 

O 

NH2 Solid State 

Mortal Pestle 

OH 

HC 

N 

O O O 

O 

R' 

O 

OH 

80 

R"



Preparation of 3-((E)-(substituted phenylimino)methyl)-4-hydroxy-2Hchromen-2-one: 

A mixture of of 3-amino 4-hydroxy coumarin (0.02 mmol) and liquid substituted 

phenyl amines in excess (0.03 mmol) were taken into mortar pestle and grinded for 

about 20 minutes. Completion of reaction was checked over TLC. The mixture was 

then filtered and washed with hot methanol. The filered solids were dried and 

recrystallized from methanol. 

Preparation of 3-((12E)-(substituted 4-hydroxy-2-oxo-2H-chromen-3ylimino)methyl)-4-hydroxy-2H-chromen-2-one: 

A mixture of substituted 3-amino 4-hydroxy coumarin (0.02 mmol) and 3-formyl 4hydroxy 

coumarin (0.02 mmol) were taken into mortar pestle and grinded for about 

20 minutes. Completion of reaction was checked over TLC. If the reaction was not 

complete complete, drop of acetic acid was added to the mixture and grinded for 5 

more minutes. The mixture was then filtered and washed with hot methanol. The 

filered solids were dried and eluted over silica using Ethyl acetate/Hexane solvent 

mix. 

81



PHYSICAL DATA TABLE OF 3-((12E)-(SUBSTITUTED 4-HYDROXY-2- 

OXO-2H-CHROMEN-3-YLIMINO)METHYL)-4-HYDROXY-2H- 

CHROMEN-2-ONE 

Sr. 

No 

1 VNRSc-101 

2 VNRSc-102 

3 VNRSc-103 

4 VNRSc-104 

5 VNRSc-105 

6 VNRSc-106 

7 VNRSc-107 

8 VNRSc-108 

9 VNRSc-109 

10 VNRSc-110 


OH HC N 

O O 

O O 

O 

O 

OH HC N 

O O 

O 

OH HC N 

OH HC N 

O O 

O 

OH 

HC 

N 

O O 

O O 

O 

OH HC N 

OH HC N 

O O 

O O 

O 

O 

OH HC N 

OH HC N 

O O 

O O 

O 

O 

O 

OH 

O 

OH 

OH 

O 

O 

OH 

OH 

O 

OH 

O 

OH 

O 

OH 

F 

Cl 

O O OH 

O 

OH HC N 

OH 

O 

OH 

OMe 

Molecular 

formula 

Molecular 

weight 

M. P. 

( o C) 

% 

Yield 

C 19H 11NO 6 349.29 221-223 64% 

C 20H 13NO 6 363.32 252-254 72% 

C21H 15NO 6 377.35 231-233 57% 

C 21H 15NO 6 377.35 236-238 71% 

C21H 15NO 6 377.35 210-212 75% 

C 20H 13NO 6 363.32 241-243 66% 

C 19H 10FNO 6 367.28 233-235 64% 

C 19H 10ClNO 6 383.74 225-227 78% 

C 19H 11NO 7 365.29 214-216 72% 

C 20H 13NO 7 379.32 230-232 63% 

82


PHYSICAL DATA TABLE OF 3-((E)-(SUBSTITUTED 

PHENYLIMINO)METHYL)-4-HYDROXY-2H-CHROMEN-2-ONE 

Sr. 

No 

1 

2 

3 

4 

5 

6 


VNRSc- 

111 

VNRSc- 

112 

VNRSc- 

113 

VNRSc- 

114 

VNRSc- 

115 

VNRSc- 

116 

OH 

O O 

OH 

O O 

OH 

O O 

OH 

O O 

OH 

O O 

OH 

N 

N 

O O 

N 

Cl 

N F 

N 

N 

Cl 

F 

Molecular 

formula 

Molecular 

weight 

M. P. 

( o C) 

% 

Yield 

Cl C 16H 9Cl 2NO 3 334.15 165 82% 

F 

F 

CF 3 

C 18H 15NO 3 293.32 147 85% 

C 16H 9F 2NO 3 301.24 137 75% 

C 16H 10FNO 3 283.25 148 87% 

C 17H 9F 4NO 3 351.25 155 83% 

C 16H 10ClNO 3 299.71 132 81% 

83



Infra Red spectra 

Infra Red Spectra were taken on SHIMADZU IR-435 Spectrometer using KBr Pellet 

method. The characteristic carbonyl group in coumarin moiety is observed at 1720- 

1750 cm -1 , Methylene gp (>CH2) observed at 2850-3000 cm -1 . methyl (-CH3) 

observed at 1350 cm -1 . 


1 

H NMR Spectra were recorded on a Bruker AC 400 MHz FT-NMR Spectrometer 

using TMS (Tetramethyl Silane) as an internal standard and DMSO-d6 & CDCl3 as a 

solvent. In the NMR spectra of derivatives of 3-((12E)-(4-hydroxy-(substituted)-2oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy-2H-chromen-2-one, 

various proton 

values of amine (-NH) and aromatic protons (Ar-H) etc. were observed as under. 

The -NH protons of substituted aniline observed at δ 3.95-4.20 ppm. Aromatic 

protons shows the multiplet between δ 6.01-8.54 δ ppm. 

Mass spectra 

The mass spectrum of compounds were recorded by GCMS-QP2010 spectrometer (EI 

method). The mass spectrum of compounds was obtained by positive chemical 



(M+) values are in good agreement with molecular formula of all the compounds 

synthesized. 

Elemental Analysis 


Erba 1108 model at Saurashtra University, Rajkot which showed calculated and found 

percentage values of Carbon, Hydrogen and Nitrogen in support of the structure of 

synthesized compounds. The spectral and elemental analysis data are given for 


84



3-((12E)-(4-hydroxy-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy-2Hchromen-2-one 

(VNRSC-101) 

Yield: 68%; IR (cm -1 ): 3545 (O-H str.), 3035 (Ar C=C-H str.), 2982 (Asym C-H str. - 

CH3), 2849 (Sym C-H str. -CH3), 2833 (Sym C-H str. -CH2), 1740 (C=O str.), 

1522,1595 ,1506 (Ar C=C str.), 1176 (C-O str.), 740 (C-H oop def); Mass: [m/z 

(%)], M. Wt.: 349; Elemental analysis, Calculated: C, 65.33; H, 3.17; N, 4.01; 

Found: C, 65.43; H, 3.22; N, 4.16. 

3-((12E)-(4-hydroxy-8-methyl-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy- 

2H-chromen-2-one (VNRSC-102) 

Yield: 66%; IR (cm -1 ): 3531 (O-H str.), 3032,3256 (Ar C=C-H str.), 2973 (Asym C-H 

str. -CH3), 2855 (Sym C-H str. -CH3), 2836 (Sym C-H str. -CH2), 1756 (C=O str.), 

1587,1502 (Ar C=C str.),1324 (C-H bend –CH3), 1275 (C-O str.), 785 (C-H oop def); 

Mass: [m/z (%)], M. Wt.: 363 Elemental analysis, Calculated: C, 66.12; H, 3.61; 

N, 3.86; Found: C, 66.08; H, 3.67; N, 3.27. 

3-((12E)-(4-hydroxy-7,8-dimethyl-2-oxo-2H-chromen-3-ylimino)methyl)-4hydroxy-2H-chromen-2-one 

(VNRSC-103) 

Yield: 51%; %; IR (cm -1 ): 3508 (O-H str.), 3091, (Ar C=C-H str.), 2983 (Asym C-H 

str. -CH3),2864 (Sym C-H str. -CH3), 2845 (Sym C-H str. -CH2), 1734 (C=O str.), 

1595 ,1506 (Ar C=C str.),1356 (C-H bend –CH3), 1176 (C-O str.), 767 (C-H oop 

def); Mass: [m/z (%)], M. Wt.: 377 ; Elemental analysis, Calculated: C, 66.84; 

H, 4.01; N, 3.71; Found: C, 66.24; H, 4.45; N, 3.48. 


(VNRSC-104) 

Yield: 64%; IR (cm -1 ):3612 (O-H str.), 3084, (Ar C=C-H str.), 2976 (Asym C-H str. - 

CH3),2854 (Sym C-H str. -CH3), 2825 (Sym C-H str. -CH2), 1731 (C=O str.), 1575 

85


,1505 (Ar C=C str.),1346 (C-H bend –CH3), 1076 (C-O str.), 810 (C-H oop def); 

Mass: [m/z (%)], M. Wt.: 377 ; Elemental analysis, Calculated: C, 66.84; H, 4.01; 

N, 3.71; Found: C, 66.65; H, 4.19; N, 3.71. 


(VNRSC-105) 

Yield: 63%;(cm -1 ):3647,3537(O-H str.), 3097.3066, (Ar C=C-H str.), 3010 (Asym C- 

H str. -CH3), (Sym C-H str. -CH3), 1712, 1693 (C=O str.), 1591,1558, 1506 (Ar 

C=C str.)1356 (C-H bend –CH3), 1031,1111 (C-O str.), 785 (C-H oop def); 1 H 

NMR 400 MHz: (CDCl3, δ ppm): 2.12 (s, 3H), 2.82 (s, 3H), 6.76 (s, 1H), 6.83 (s, 

1H), 7.25 (m, 2H), 7.53 (m, 1H), 8.04 (m, 1H), 9.80 (d, 1H), 14.24 (d, 1H). Mass: 

[m/z (%)], M. Wt.: 377 ; Elemental analysis, Calculated: C, 66.84; H, 4.01; N, 

3.71; Found: C, 66.48; H, 4.11; N, 3.47. 

3-((12E)-(4-hydroxy-6-methyl-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy- 


Yield: 71%; IR (cm -1 ): 3615(O-H str.), 3071, (Ar C=C-H str.), 2973 (Asym C-H str. - 

CH3),2861 (Sym C-H str. -CH3), 2843 (Sym C-H str. -CH2), 1724 (C=O str.), 1595 

,1506 (Ar C=C str.),1352 (C-H bend –CH3), 1156 (C-O str.), 741 (C-H oop 

def);Mass: [m/z (%)], M. Wt.: 363 ; Elemental analysis, Calculated: C, 71.47; H, 

6.72; N, 3.16; Found: C, 71.15; H, 6.65; N, 3.14. 

3-((12E)-(6-fluoro-4-hydroxy-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy-2Hchromen-2-one 

(VNRSC-107) 

Yield: 52%; IR (cm -1 ): 3655 (O-H str.), 3101, (Ar C=C-H str.), 2993 (Asym C-H str. 

-CH3),2854 (Sym C-H str. -CH3), 2835 (Sym C-H str. -CH2), 1744 (C=O str.), 1585 

,1501 (Ar C=C str.),1354 (C-H bend –CH3), 1176 (C-O str.), 567 (C-F str.) 741 (C-H 

oop def); Mass: [m/z (%)], M. Wt.: 367 ; Elemental analysis, Calculated: C, 

62.13; H, 2.74; F, 5.17; N, 3.81; Found: C, 62.24; H, 2.52; N, 3.46. 

86


3-((12E)-(6-chloro-4-hydroxy-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy-2Hchromen-2-one 

(VNRSC-108) 



,1502 (Ar C=C str.),1345 (C-H bend –CH3), 1076 (C-O str.), 967 (C-Cl str.) 780 (C-H 


59.47; H, 2.63; Cl, 9.24; N, 3.65; Found: C, 59.36; H, 2.55; N, 3.87. 

3-((12E)-(4,7-dihydroxy-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy-2Hchromen-2-one 

(VNRSC-109) 





N, 3.83; Found: C, 62.58; H, 3.12; N, 3.77. 

3-((12E)-(4-hydroxy-6-methoxy-2-oxo-2H-chromen-3-ylimino)methyl)-4-hydroxy- 




,1501 (Ar C=C str.),1354 (C-H bend –CH3), 1176 (C-O str.), 745 (C-H oop 

def);Mass: [m/z (%)], M. Wt.: 379 ; Elemental analysis, Calculated: C, 63.33; H, 

3.45; N, 3.69; Found: C, 63.42; H, 3.64; N, 3.57. 

3-((E)-(2,3-dichlorophenylimino)methyl)-4-hydroxy-2H-chromen-2-one (VNRSC- 

111) 



,1505 (Ar C=C str.),1354 (C-H bend –CH3), 1046 (C-O str.), 965(C-Cl str.), 745 (C- 

87


H oop def);Mass: [m/z (%)], M. Wt.: 334 ; Elemental analysis, Calculated: C, 

57.51; H, 2.71; N, 4.19; Found: C, 57.15; H, 2.75; N, 4.12. 

3-((E)-(3,5-dimethylphenylimino)methyl)-4-hydroxy-2H-chromen-2-one (VNRSC- 

112) 


-CH3),2859 (Sym C-H str. -CH3), 2852 (Sym C-H str. -CH2), 1721(C=O str.), 1575 



N, 4.78; Found: C, 73.14; H, 5.42; N, 4.51. 

3-((E)-(3,4-difluorophenylimino)methyl)-4-hydroxy-2H-chromen-2-one (VNRSC- 

113) 



,1535 (Ar C=C str.),1347 (C-H bend –CH3), 1157(C-O str.),587,(C-F str.), 745 (C-H 


63.79; H, 3.01; N, 4.65; Found: C, 63.44; H, 3.21; N, 4.78. 

3-((E)-(4-fluorophenylimino)methyl)-4-hydroxy-2H-chromen-2-one (VNRSC-114) 



,1505 (Ar C=C str.),1344 (C-H bend –CH3), 1146 (C-O str.), 586(C-F str.), 745 (C-H 

oop def);Mass: [m/z (%)], M. Wt.: 283 ; Elemental analysis, Calculated: C, 67.84; 

H, 3.56; N, 4.94; Found: C, 67.49; H, 3.24; N, 4.36. 

88


3-((E)-(4-fluoro-3-(trifluoromethyl)phenylimino)methyl)-4-hydroxy-2H-chromen-2one 

(VNRSC-115) 



,1575 (Ar C=C str.),1354 (C-H bend –CH3), 1015 (C-O str.), 755 (C-H oop def) 541 

(C-F ); 1 H NMR 400 MHz: (CDCl3, δ ppm): 7.34 (m, 2H), 7.51 (m, 1H), 7.66 

(m, 1H), 8.00 (m, 2H), 8.12 (s, 1H), 8.96 (d, 1H). Mass: [m/z (%)], M. Wt.: 351 ; 


2.71; N, 3.85. 

3-((E)-(2-chlorophenylimino)methyl)-4-hydroxy-2H-chromen-2-one (VNRSC-116) 

Yield: 75%; IR (cm -1 ):), 3615 (O-H str.), 3014, (Ar C=C-H str.), 2983 (Asym C-H 

str. -CH3),2857 (Sym C-H str. -CH3), 2855 (Sym C-H str. -CH2), 1734 (C=O str.), 

1575 ,1505 (Ar C=C str.),1354 (C-H bend –CH3), 1046 (C-O str.), 962 (C-Cl str.), 

786 (C-H oop def);Mass: [m/z (%)], M. Wt.: 299 ; Elemental analysis, Calculated: 

C, 64.12; H, 3.36; N, 4.67; Found: C, 64.14; H, 3.42; N, 4.77. 

89



IR Spectrum of 3-((12E)-(4-hydroxy-7,8-dimethyl-2-oxo-2H-chromen-3ylimino)methyl)-4-hydroxy-2H-chromen-2-one 

(VNRSC-103) 

105 

%T 

90 

75 

60 

45 

30 

15 

0 

-15 

3508.63 

3600 3200 

VNRSC-103 

3091.99 

2983.98 

2864.39 

2800 

2364.81 

2400 

2000 

1734.06 

1800 

1695.49 

1668.48 

1595.18 

1539.25 

1514.17 

1491.02 

1433.16 

600 400 

1/cm 

IR Spectrum of 3-((12E)-(4-hydroxy-5,7-dimethyl-2-oxo-2H-chromen-3ylimino)methyl)-4-hydroxy-2H-chromen-2-one 

(VNRSC-105) 

105 

%T 

97.5 

90 

82.5 

75 

67.5 

60 

52.5 

45 

37.5 

30 

3647.51 

3537.57 

3097.78 

3066.92 

3010.98 

3600 3200 

VNRSC-105 

OH HC N 

O O 

O O 

2800 

O 

O 

OH HC N 

O 

OH 

2366.74 

O 

2400 

OH 

2000 

1800 

1712.85 

1693.56 

1600 

1622.19 

1591.33 

1558.54 

1600 

1506.46 

1400 

1400 

1317.43 

1465.95 

1435.09 

1323.21 

1269.20 

1211.34 

1145.75 

1200 

1200 

1112.96 

1155.40 

1111.03 

1018.45 

972.16 

1000 

1031.95 

1000 

896.93 

862.21 

887.28 

864.14 

767.69 

800 

800 

736.83 

785.05 

758.05 

682.82 

592.17 

534.30 

611.45 

600 400 

1/cm 

90

Chapter-3 

Solvent less Solid Phhase 

Synthe esis of … 

Mass spectrum 

oof 

3-((12EE)-(4-hydroxy-7,8-dimmethyl-2-oxxo-2H-chro 

omen-3- 

ylimino)meethyl)-4-hyydroxy-2H-chromen-2 

2-one (VNRRSC-103) 

O 

OHH 

HC 

N 

Mass Sppectrum 

oof 

3-((12EE)-(4-hydroxy-5,7-dimmethyl-2-oxxo-2H-chro 

omen-3ylimino)meethyl)-4-hyydroxy-2H--chromen-2 


O 

O 

OH 

HC H 

C 

N 

O O 

O 

O 

OH 

O 

OH 

91

Chapter-3 

1 

H NMR Spectrum of 3-((12EE)-(4-hydroxy-5,7-dimmethyl-2-oxxo-2H-chro 

omen-3- 

ylimino)meethyl)-4-hyydroxy-2H--chromen-2 


O 

OH 

HC 

C 

N 

O O 

O 

OH 

1 

Expanded H NMRR 

Spectrumm 

of 3-((12 2E)-(4-hydroxy-5,7-diimethyl-2-o 

oxo-2Hchromen-33-ylimino)mmethyl)-4-hhydroxy-2H 

H-chromen-2-one 

(VNNRSC-105) 

OH HC N 

O O 

O 

O 

OH 



92

Chapter-3 

1 

H NMR SSpectrum 

of 3-((E)-( (4-fluoro-3- -(trifluorommethyl)pheenylimino)m 

methyl)- 

4-hydroxy--2H-chrommen-2-one 

(VVNRSC-11 

15) 

1 H 



Expanded 

NMRR 

Spe ectrum of 3-((E)-(4-f fluoro-3 

(trifluorommethyl)phennylimino)mmethyl)-4-h 

hydroxy-2HH-chromen--2-one 

115) 

(V VNRSC- 

OOH 

OH 

O O 

O O 

N 

N 

F 

F 

CF 3 

CF 3 

93


3.11 RESULT & DISCUSSION 

Present work covers the synthesis of some novel Azomethine linked 4-hydroxy 

coumarin molecules. The main significance of the present work is that the reaction is 

carried out with help of Mortar and Pestle, leading to a solvent free facile synthesis 

with rapid reaction time, easy work up method and excellent yield of the desired 

compounds. 


Total 10 derivatives of 3-((12E)-(4-hydroxy-(substituted)-2-oxo-2H-chromen-3ylimino)methyl)-4-hydroxy-2H-chromen-2-one 

were synthesized. All the newly 

synthesized compounds were characterized by IR, 1H NMR, 13C NMR, Mass 

spectral data and Elemental Analysis. 

94



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[37] Diddams, P.; Butters, M. In Solid Supports and Catalysts in Organic 

Synthesis; Smith, K.; Ed.; Ellis Harwood and PTR Prentice Hall: New York 

and London, 1992, Chapters 1, 3 and 5. 

[38] Yadav, D. G.; Nair, J. J. Microporous and Mesoporous Materials, 1999, 33, 1. 

[39] Tundo, P.; Anastas, P. T. Green Chemistry: Challenging Perspectives, Oxford 

Science: Oxford, 1999. 

[40] (a) Gopalakrishnan, M.; Sureshkumar, P.; Kanagarajan, V.; Thanusu, J.; 

Govindaraju, R. J. Chem. Res. 2005, 5, 299. (b) Gopalakrishnan, M.; 

Sureshkumar, P.; Kanagarajan, V.;Thanusu, J. Lett. Org. Chem. 2005, 2, 136. 

(c) Gopalakrishnan, M.; Sureshkumar, P.;Kanagarajan, V.; Thanusu, J. Catal. 

Communications 2005, 6, 753. 

96


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[42] D. Seebach and M. A. Brook, Helv. Chim. Acta, 1985, 68, 319. 

[43] M. Miyashita, T. Yanami and A. Yoshikoshi, J. Am. Chem. Soc., 1976, 98, 

4679. 

[44] R. S. Varma and G. W. Kabalka, Heterocycles, 1986, 24, 2645. 

[45] G. Bellachioma, L. Castrica, F. Fringuelli, F. Pizzo and L. Vaccaro, Green 

Chem., 2008, 10, 327. 

[46] F. Fringuelli, M. Matteucci, O. Piermatti, F. Pizzo and M. C. Burla, J. Org. 

Chem., 2001, 66, 4661. 

[47] C. Djerassi, Chem. Rev., 1948, 43, 271. 

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3rd edn., 1972, 926–927. 

[49] A. N. M. M. Rahman, R. Bishop, R. Tan and N. Shan, Green Chem., 2005, 7, 

207. 

[50] A. V. Reddy, V. L. N. Reddy, K. Ravinder and Y. Venkateswarlu, 

Hetero.Commun., 2002, 8, 459 

[51] L.Zhang, Y. Luo, R. Fan and J.Wu, Green Chem., 2007, 9, 1022. 

[52] D. C. Waddell and J. Mack, Green Chem., 2009, 11, 79. 

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[54] F. Toda, K. Tanaka and S. Iwata, J. Org. Chem. 1989, 54, 3007. 

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97

Chapter‐4 

SYNTHESIS AND CHARACTERIZATION OF SOME 

4‐SUBSTITUTED 2,6‐DIMETHYL 

3,5‐DICARBONITRILE 1,4‐DIHYDROPYRIDINES 

AND THEIR MANNICH BASES USING VARIOUS 

SECONDARY AMINES.

Chapter-4 Synthesis and Characterizatin of… 


Dihydropyridines (DHPs) are the important class of organic compounds in view of its 

ample of application in the pharmaceuticals. [1,3] Arthur Hantzsch in 1882 [2] first 

reported the classical synthesis of 1,4-dihydropyridines(1,4-DHPs) which involves 

one pot three-component coupling reaction of 1 equivalent of alkyl or aryl aldehyde, 2 

equivalents of β-ketoester and 1 equivalent of ammonia at reflux temperature using 

either acetic acid or ethanol as a solvent. However, the yield of 1,4-DHPs are 

generally low. Hence numerous methodologies with improved reaction conditions 

have been documented. [3] Many of these still suffer some serious drawbacks such as 

unsatisfactory yields, tedious work-up procedure, occurrence of side reactions 

including aromatization, economically non-viable, long reaction rate, high reaction 

temperature etc. 

To overcome these problems, numerous modifications attempted including new Lewis 

acid catalyst, Zn[L-proline] [4] under microwave condition. The catalyst is also 

recycled up to five runs but it appreciably loss the catalytic activity for the next 

successive runs and ultimately yield loss were observed. 1,4-DHPs were also 

synthesized by using water-ethanol solvent [5] system using MWI, but this process fails 

at high microwave power, because reaction mixture is rapidly heated at high 

microwave power leading to solvent evaporation and hence precipitation of the 

reaction mixture were observed. The synthesis of 1,4-DHPs is also reported in room 

temperature ionic liquids [6] but the rate of reaction is sluggish than the microwave 

counterparts. Of all these methodologies, the ionic liquid medium is the sole protocol 

which allows the recycling of the solvent. There is despite the fact that, unlike several 

of ‘neoteric solvent’ like ionic liquids(ILs) where toxicity and environmental burden 

data are for the most part unknown while complete toxicity profiles are available for a 

range of polyethylene glycol(PEG) molecular weights and indeed, many are already 

approved for internal consumption by US-FDA. [7] Moreover, the vapor density for 

low molecular weight PEG is greater than 1 and this is consistent with the industry 

standard for selection of alternative solvents to Volatile Organic Chemicals (VOCs). [8] 

98


4.2 BIOLOGICAL PROFILE OF 1,4-DIHYDROPYRIDINE 

The DHP skeleton is common to numerous bioactive compounds which include 

various vasodilator, geroprotective, antihypertensive, bronchodilator, 

antiatherosclerotic, hepatoprotective, antitumor, antimutagenic and antidiabetic 

agents [9-14] . 

DHPs nucleolus has number of pharmacologically commercial utility as calcium 

channel blockers, as exemplified by therapeutic agents such as Nifedipine [15] 

Nitrendipine [16] and Nimodipine [17] . Second-generation calcium antagonists include 

DHP derivatives with improved bioavailability, tissue selectivity, and/or stability, 

such as the antihypertensive/antianginal drugs like Elgodipine [18] , Furnidipine [19,20] , 

Darodipine [21] , Pranidipine [22] , Lemildipine [23] , Dexniguldipine [24] , Lacidipine [25] , and 

Benidipine [26] . Number of DHP calcium agonists has been introduced as potential 

drug candidates for treatment of congestive heart failure [27, 28] . 

The key characteristic of calcium channel blockers is their inhibition of entry of 

calcium ions via a subset of channels, thereby leading to impairment of contraction. 

There are three main groups of calcium channel blockers, i.e. dihydropyridines, 

phenylalkylamines and benzothiazepines, classic examples of which are nifedipine, 

verapamil and diltiazem, respectively [29-32] . Each has a specific receptor on the 

calcium channel and a different profile of pharmacological activity. Dihydropyridines 

have a less negative inotropic effect than phenylalkylamines and benzothiazepines but 

can sometimes cause reflex tachycardia. Dihydropyridines are able to reduce 

peripheral resistance, generally without clinically significant cardiodepression. 

Among DHPs with other types of bioactivity, Cerebrocrast [33] has been recently 

introduced as a neuroprotectant and cognition enhancer lacking neuronal-specific 

calcium antagonist properties. In addition, a number of DHPs with platelet 

antiaggregatory activity have also been discovered [34] . These recent examples 

highlight the level of ongoing interest toward new DHP derivatives and have 

prompted us to explore this pharmacophoric scaffold to develope a fertile source of 

bioactive molecules. 

99


Some representative Ca 2+ antagonists of Dihydropyridine class are as shown below: 

H 3COOC COOCH 3 

N 

H 

Nifedipine 

NO 2 

In particular, DHP-CA (calcium channel antagonist DHP) are extensively used for the 

treatment of hypertension, [35] subarachnoid hemorrhage, [36,37] myocardial infarction [38- 

41] [42, 43] [44,45] 

and stable and unstable angina even though recently their therapeutic 

efficacy in myocardial infarction and angina has been questioned [46] . This class of 

compounds is also under clinical evaluation for the treatment of heart failure [47] , 

ischemic brain damage [48] nephropathies, and atherosclerosis [49] . 

1,4- DHPs having different pharmacological activities such as antitumor [50] , 

vasodilator [51] , coronary vasodilator and cardiopathic [52] , antimayocardiac ischemic, 

antiulcer [53] , antiallergic [54] , antiinflammatory [55] and antiarrhythmic [56] , PAF 

antagonist [57] , Adenosine A3 receptor antagonist [58] and MDR reversal activity [59,60] . 

It is found recently that when the imidazolyl moiety is linked to the phenyl ring by 

means of a C-N bridge, the activity tends to decrease. Finally, the replacement of 

DHP itself by a pyridine ring gives an inactive compound [61] . 

H 3CH 2CH 2COC 

H 3COOC 

N 

N 

H 

N 

N 

H 

Nicamcipin 

COCH 2CH 3 

NO 2 

O 

O 

H 3CH 2CH 2COC 

CH 2Ph 

N 

H 3COOC COOEt 

N 

N 

N 

H 

NO 2 

Amlodipine 

N 

O 

COCH 2CH 3 

100 

NH 2


Cozzi et al 56 have synthesized a series of 4-phenyl-1,4-dihydropyridines bearing 

imidazol-1-yl or pyridine-3-yl moieties on the phenyl ring, with the aim of combining 

Ca 2+ antagonism and thermboxane A2(TxA2) synthase inhibition in the same 

molecules. Some of the compounds showed significant combined activity in vitro, 

while other showed single activity. As far as Ca 2+ antagonism is concerned, two 

points deserve comment. First, the SAR, in most cases, does not differ substantially 

from that reported for classic DHP-CA, even though the potency is lower than that 

found with the most potent drugs of this class as, for example, reference compound 

nifedipine. In fact, Ca 2+ antagonism is dramatically reduced by (a) replacement of 

DHP by a pyridine ring, (b) substitution of DHP nitrogen N-1 by a methyl group, (c) 

para substitution on the phenyl ring, and (d) replacement of one ester function by a 

ketone or carboxy group. All these variations are also detrimental in classic DHP- 

CA. [62] 

Hernandez-Gallegos et al [63] have synthesized new 1,4-dihydropyridines and 

evaluated their relaxant ability (rat aorta), antihypertensive activity in spontaneously 

hypertensive rats and their microsomal oxidation rate (MOR) was determined. 

R = 3-NO 2, 4-F, 3,5-di-F, 3-Br-4-F 

R 1 = R 2 = Me, Et, -CH 2-CF 3, -CH 2CH 2-OPh, -(CH 2) 2-N(CH 3)-CH 3-Ph 

Christiaans and Timmerman [64] studied new molecules like CV-159 for possible 

variation at 3-position. 

H 3C 

R 1OOC 

N 

H 

NO 2 

O 

N 

H 

N 

N 

NO 2 

COOR 2 

N 

101


Carlos et al [65] reported 1,4-DHPs derivatives with a 1,2-benzothiazol-3-one-1sulphoxide 

group, linked through an alkylene bridge to the C3 carboxylate of the DHP 

ring, with both vasoconstricting and vasorelaxant properties were obtained. In 

blocking Ca 2+ evoked contractions of K + depolarized rabbit aortic strips. Many 

compounds were 10 times more potent than nifedipine. Their vascular versus cardiac 

selectivity was very pronounced. 

O 

OH OH 

O O 

N 

H 

Schramm and coworker [66] have proved that phenyl carbamoyl moiety in 

dihydorpyridine affords for cardiovascular selective activity. 

Reddy and coworkers [67] synthesized 4-aryl hetroaryl-2,6-dimethyl-3,5-bis-N-(2methyl 

/ 2-chloro phenyl)carbamoyl-1,4-dihydropyridines through one-pot synthesis 

using appropriate aromatic aldehydes and liquid ammonia. Pharmacological screening 

of the new 1,4-dihyropyridines were also carried out for CNS depresant 

(anticonvulsant and analgesic) and cardiovascular (inotropic and blood pressure) 

activities by standard methods. 

N 

H 

O O 

Similarly Kelvin Cooper (Pfitzer , USA) et al [68] found that DHP can be highly 

selective as platlet activating factor (PAF) antagonist. They found potent compounds 

and prove that platlet aggregating activity (PAF) exhibits a wide spectrum of 

biological activities elicited either directly or via the release of other powerful 

mediator such as Thromboxane A2 or the Leukotrienes. In vitro PAF stimulates the 

movement and aggregation and the release there from of tissue damaging enzymes 

and oxygen radicals. Accordingly compounds like UK-74505, antagonize the action 

N 

H 

R 

N 

H 

O 

O 

S 

N 

O 

102


of PAF and consequently also prevent mediator release by PAF, will have clinical 

utilities in the treatment of the variety of the allergic, inflammatory and 

hypersecretory conditions such as asthama, arthritis, rhinitis, bronchitis and utricaria 

in future. [69] 

Neamati and coworkers [70] reported that a 1,4-dihydorpyridine NCS-372643 came out 

with its anti-HIV activity, which has opened up the synthetic as well as 

pharmacological importance in antiviral area also. 

Sonja [71] and group have synthesized a new series of calcium channel agonists 

structurally related to Bay K8644, containing NO donor furoxans and the related 

furazans unable to release NO. The racemic mixtures were studied for their action on 

L-type Ca 2+ channels expressed in cultured rat insulinoma RINm5F cells. All the 

products proved to be potent calcium channel agonists. 

MeOOC 

N 

H 

N 

H 

OH 

OH 

O 

CF 3 

N 

H 

NO 2 

N 

H 

COOC 2H 5 

2-Heterosubstituted-4-aryl-l,4-dihydro-6-methyl-5-pyrimidinecarboxylic acid esters, 

which lack the potential C3 symmetry of dihydropyridine calcium channel blockers, 

were evaluated for biological activity. Biological assays using potassium- 

R 

N 

H 

R= 

O O 

N 

H 

OH 

OH 

N 

N 

CH 3 

MeOOC NO2 N 

N 

H 

N 

R 

O 

N 

103


depolarized rabbit aorta and radioligand binding techniques showed that some of 

these compounds are potent mimics of dihydropyridine calcium channel blockers. The 

combination of a branched ester (e.g. isopropyl, sec-butyl) and an alkylthio group 

(e.g. SMe) was found to be optimal for biological activity [72] . 

EtOOC 

R 2X 

N 

H 

NO 2 

COOEt 

R 2X 

Labedipinedilol-A, a novel dihydropyridine-type calcium antagonist, has been shown 

to induce hypotension and vasorelaxation. Liouand co-workers have studied to 

investigate the effect of labedipinedilol-A on vascular function of rat aortic rings and 

cultured human umbilical vein endothelial cells (HUVECs). [73] 

Recent reports show that efonidipine, a dihydropyridine Ca 2+ antagonist, has blocking 

action on T-type Ca channels, which may produce favorable actions on cardiovascular 

systems. However, the effects of other dihydropyridine Ca antagonists on T-type Ca 

channels have not been investigated yet. Therefore, Furukawa and group [74] have 

examined the effects of dihydropyridine compounds clinically used for treatment of 

hypertension on a T-type Ca channel subtype, alpha1G, expressed in Xenopus 

oocytes. Twelve DHPs amlodipine, barnidipine, benidipine, cilnidipine, efonidipine, 

felodipine, manidipine, nicardipine, nifedipine, nilvadipine, nimodipine, nitrendipine) 

and mibefradil were tested. Cilnidipine, felodipine, nifedipine, nilvadipine, 

minodipine, and nitrendipine had little effect on the T-type channel. The blocks by 

drugs at 10 muM were less than 10% at a holding potential of -100 mV. The 

remaining 6 drugs had blocking action on the T-type channel comparable to that on 

the L-type channel. These results show that many dihydropyridine Ca 2+ antagonists 

have blocking action on the alpha1G channel subtype. 

Joanna Rzeszowska-Wolny et al reported that compounds of the 1,4-dihydropyridine 

(1,4-DHP) series have been shown to reduce spontaneous, alkylation- and radiation 

induced mutation rates in animal test systems. Studies using AV-153, the 1,4-DHP 

derivative that showed the highestantimutagenic activity in those tests, to examine if it 

N 

N 

H 

R 1 

COOR 3 

104


modulates DNA repair in human peripheral blood lymphocytes and in two human 

lymphoblastoid cell lines. [75] 

1,4-Dihydropyridines are now established as heterocycles having numerous 

applications and having widened scope for its pronounced drug activity like calcium 

channel antagonism and antihypertensive action. Many other activities are associated 

with such compounds and they can be presented in the structure as 2,6-dimethyl-3,5diacetyl 

or dicarboxylate or dicarbamoyl or many other homoaryl or heteroaryl carbon 

chain having C2 to C8 1,4-dihydropyridines substituted at 4-position. [76-81] 

In continuation of earlier work on DHPs, an improved synthetic protocol is used to 

prepare several structurally diverse 1,4-dihydropyridines. 

In short, in viewing the benignity and superiority of PEG as a solvent over ionic 

liquids and other reported protocols for the synthesis of 1,4-DHPs as mentioned 

earlier, herein we disclose our findings by using PEG-400 as a solvent for the rapid 

microwave assisted multi component reaction (MCR). 

4.3 1,4-DIHYDROPYRIDINES AND MANNICH REACTION 

The Mannich reaction is an organic reaction which consists of an amino alkylation of 

an acidic proton placed next to a carbonyl functional group with formaldehyde and 

ammonia or any primary or secondary amine. The final product is a β-amino-carbonyl 

compound also known as a ‘Mannich Base’. Mannich bases are of particular in 

interest due to their application as synthetic building blocks and precursors of 

biologically active compounds. The reaction is named after chemist Carl Mannich. [82] 

The Mannich reaction is an example of nucleophilic addition of an amine to a 

carbonyl group followed by dehydration to the schiff base. The schiff base is an 

electrophile which reacts in the second step in an electrophilic addition with a 

compound containing an acidic proton (which is, or had become an enol). [83] The 

Mannich reaction is also considered a condensation reaction. The Mannich Reaction 

is an important carbon-carbon-bond forming reaction that is commonly employed in 

the synthesis of alkaloid natural products and is involved in a number of biosynthetic 

105


pathways. [84] Numerous examples of both direct and indirect Mannich reactions have 

been reported in the literature, some of recent are sited in reference. [85-110] 

Few references are found related to Mannich reaction of 1,4-dihydropyridines. Some 

of them are enlisted below. 

Jiro Aritomi et al [111-112] reported Mannich reaction of dialkyl 4-aryl-2,6-dimethyl 

1,4-dihydropyridine-3,5-dicarboxylates with secondary amines and found that the 

reaction proceeds on the 2- and 6- methyl carbon. 

R 

R2OOC COOR2 H3C N 

R1 CH3 (I) 

R 

R2OOC COOR2 H 3C 

R 

R2OOC COOR2 N 

R 1 

R3R2NH2CH2C N CH2CH2NR2R3 R 1 

(III) 

CH 2CH 2NR 2R 3 

V. V. Dotsenko et al [113,114] reported the reactions of N-methylmorpholinium 6amino-3,5-dicyano-1,4-dihydropyridine-2-thiolates 

with formaldehyde and primary 

aromatic amines produce 3,5,7,11-tetraaza-tricyclo[7.3.1.02,7]tridec-2-ene-1,9dicarbonitrile 

derivatives. 

(II) 

106


K. A. Frolov et al [115] gave synthesis of derivatives of 3,5,7,11-tetraazatricyclo- 

[7.3.1.02,7]tridec-2-ene-8-selenone yield by Mannich reaction of N-methylmorpholinium 

6-amino-3,5-di-cyano-4-(2-methoxy phenyl)-1,4-dihydropyridine-2selenolate 

with primary amines and excess HCHO. 

M Vijey Aanandhi et al [116] demonstrated synthesis, characterization and in-vitro 

antioxidant activity of Mannich bases of 1, 4-dihydro pyridines derivatives. 

R1 EtOOC COOEt 

H3C N CH3 H 

1) HCHO/EtOH 

2) PABA 

H 2N COOH 

R1 EtOOC COOEt 

H3C N CH3 NH 

COOH 

B. B. Subudhi et al [117] reported synthesis and anti-ulcer activity study of 1,4dihydropyridines 

and their mannich bases with sulfanilamides. 

107


EtOOC 

R 

COOEt 

H3C N CH3 H 

Where R=-OH, -OCH 3, etc 

HCHO/ EtOH 

H 2N SO 2NH 2 

EtOOC 

R 

COOEt 

H3C N CH3 NH 

SO 2NH 2 

Mane D. V. et al [118] synthesized 1,3-Bis- [N-substituted dihydropyridine methylc]benzimidazoline-2-thiones 

I (R= Ph, substituted phenyl; R1 = Me, OMe, OEt) from 

benz-imidazoline-2-thione, various dihydropyridines and paraformaldehyde by 

Mannich reaction and screened for their antimicrobial activities. 

[119] 

Sielemann Dirk et al gave synthesis of novel functionalized bi- and 

oligopyridines. An annelation reaction is presented in which 1,3-cyclohexanedione 

and Mannich bases derived thereof are used for the preparation of functionalized 

bipyridines I (R = H, n = 1; R = H, n = 0; R = CMe3, n = 1) and dihydropyridine 

derivatives II (n = 0, 1). All these products possess a keto group which will allow 

further transformations. The same concept was applied for the synthesis of the Sshaped 

terpyridine III. The reaction of a Mannich base derived from 1,2,3,4,5,6,7,8octahydro-4,5-acridinedione 

with 1,3-cyclohexanedione yielded a heptacyclic 

terpyridine, which is a key intermediate for the synthesis of torands and other 

tridentate clefts. Ketone I (R = H, n = 1) was used for the synthesis of a 

quaterpyridine. 

108


Apart from these, Michael et al [120] prepared antihypertensive and coronary 

vasodilator Mannich type N-substituted -1,4-dihydropyridine. 

Hung et al [121] were successful in synthesizing antihypertensive model of Flordipine, 

contrary to the belief proposed by Triggle that N-substituted 1,4-dihydropyridine will 

not give good antihypertensive activity, probably the concept of prodrug would not 

have been predicted at that time and –NH was believed to be essential for calcium 

channel antagonism. 

109


Earlier, Arthur P. Philips [122-124] reported Mannich bases derived from a Hantzsch 

pyridine synthesis products. Use of Mannich reaction on a phenolic Hantzsch 

synthesis product afforded an alternative type of compound containing a basic chain. 

O 

EtOOC 

O 

O 

OH 

CHO 

NH 3 

OH 

O 

O 

O 

COOEt 

H3C N CH3 H 

Hantzch Reaction 

HCHO 

R 2NH 

EtOOC 

EtOOC 

OH 

COOEt 

H3C N CH3 H 

OH 

COOEt 

H3C N CH3 H 

R 

N 

R 

Where R= NH(CH 3) 2,NI(CH 3) 3, NH(C 2H 5) 2, Piperidine & Morpholine 

110


4.4 AIM OF WORK 

Numerous Dihydropyridines and their derivatives have been reported for their various 

biological activities. These results promoted us to synthesize symmetric 

dihydropyridines and their mannich bases. 


Preparation of 4-(2-Hydroxy-3-(substitued-1-methyl) phenyl)-2,6-dimethyl- 

1,4-dihydropyridine-3,5-dicarbonitrile 

OH 

CHO 

3-Amino Crotono 

nitrile 

gl. CH 3COOH 

RT 

N 

N 

H 

N 

HCHO 

Secondary Amines 

Ethanol 

Reflux 

1-4 hrs 

Where NR1R2= Secondary amines like piperidine, morpholine etc. 

OH 


1,4-dihydropyridine-3,5-dicarbonitrile 

OH 

CHO 

OH 

3-Amino Crotono 

nitrile 

gl. CH 3COOH 

RT 

N 

N 

H 

N 

HCHO 

Secondary Amines 

Ethanol 

Reflux 

1-4 hrs 

Where NR1R2= Secondary amines like piperidine, morpholine etc. 

OH 

OH 

R 1 

N 

R 1 

N 

N 

N 

R 2 

OH 

N 

H 

R 2 

OH 

N 

H 

111 

N 

OH 

N


4.6 PLAUSIBLE REACTION MEHCANISM 

H 

Step-1 

O 

H 

H 

H R 1 

N 

R 2 

H + 

-H 2O 

HO 

H 2O 

Where NR1R2 = Secondary amines like morpholine, piperidine 

R3 & R4 = Phenyl ring 

R 3 

Step-2 

OH 

R 4 

H 

H R 1 

H 

N 

R 2 

R 3 

H 

H 

H 

H 

OH 

R 4 

N 

H 

R 1 

R 2 

N 

H H 

H 

N 

R 1 

R 2 

R 2 

R 1 

H + 

HO 

-H + 

H 

HO 

R 3 

H 

H 

N 

H 

H 

OH 

R 1 

R 4 

R 2 

-H + 

N 

R 1 

H H 

R 2 

N 

R 2 

R 1 

112



Materials and Methods 

Melting points were determined in open capillary tubes and are uncorrected. 

Formation of the compounds was routinely checked by TLC on silica gel-G plates of 

0.5 mm thickness and spots were located by iodine and UV. IR spectra were recorded 

in Shimadzu FT-IR-8400 instrument using KBr Powder method. Mass spectra were 

recorded on Shimadzu GC-MS-QP-2010 model using Direct Injection Probe 

technique. 1 H NMR was determined in DMSO-d6/CDCl3 solution on a Bruker 

Avance II 400 MHz NMR Spectrometer. Elemental analysis of the all the 

synthesized compounds was carried out on Elemental Vario EL III Carlo Erba 1108 

model. All the results are in agreements with the structures assigned. 

Preparation of 4-(4-Hydroxy phenyl)-2,6-di-methyl-1,4-dihydropyridine-3,5dicarbonitrile 

A mixture of 4-hydroxy benzaldehyde (0.01 M) and 3-amino crotononitrile (0.02 M) 

were taken in glacial acetic acid in a stoppered flask and stirred for 1 hour at 10º-15º 

C. During the reaction, progress and the completion of reaction were checked by 

silica gel-G F254 thin layer chromatography using ethyl acetate: hexane (3:2) as a 

mobile phase. After the completion of the reaction, the crystalline product was 

separated out which was filtered and washed with diethyl ether. 


1,4-dihydropyridine-3,5-dicarbonitrile (General Procedure) 

A mixture of 4-(4-hydroxy phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarbonitrile 

(0.01 M), secondary amine (0.0135 M) and formaldehyde (0.02 M) 

were taken in absolute alcohol in 250 mL round bottom flask. The reaction mixture 

was refluxed for 1-4 hrs at reflux temperature till TLC completed. The progress and 

the completion of the reaction were checked by silica gel-G F254 thin layer 

chromatography using ethyl acetate: hexane (3:2) as a mobile phase. After completion 

of the reaction, the reaction mixture was allowed to cool at room temperature to 

obtain the product. When crystalline product was separated out, it was filtered and 

washed with cold ethanol. Similarly other compounds were also prepared. 

113


Preparation of 4-(3,4-dihydroxy phenyl)-2,6-dimethyl-1,4-dihydropyridine- 

3,5-dicarbonitrile 

A mixture of 3,4-dihydroxy benzaldehyde (0.01 M) and 3-amino crotononitrile (0.02 

M) was taken in glacial acetic acid in a stoppered flask and stirred for 1 hour at room 

temperature. During the reaction, progress and the completion of reaction were 

checked by silica gel-G F254 thin layer chromatography using ethyl acetate: hexane (3: 

2) as a mobile phase. After the completion of the reaction, the crystalline product was 

separated out which was filtered and washed with diethyl ether. 

Preparation of 4-(3,4-dihydroxy-4-(substitued-1-methyl) phenyl)-2,6dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile 

(General Procedure) 

A mixture of 4-(3,4-dihydroxy phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarbonitrile 

(0.01 M), secondary amine (0.0135 M) and formaldehyde (0.02 M) 

were taken in absolute alcohol in 250 mL round bottom flask. The reaction mixture 

was refluxed for 1-4 hrs at reflux temperature till TLC complete. The progress and the 

completion of the reaction were checked by silica gel-G F254 thin layer 

chromatography using ethyl acetate: hexane (3:2) as a mobile phase. After completion 

of the reaction, the reaction mixture was allowed to cool at room temperature to 

obtain the product. When crystalline product was separated out, it was filtered and 

washed with cold ethanol. Similarly other compounds were also prepared. 

114



PHYSICAL DATA TABLE OF 4-(4-HYDROXY-3-(SUBSTITUED-1- 

METHYL) PHENYL)-2,6-DIMETHYL-1,4-DIHYDROPYRIDINE-3,5- 

DICARBONITRILES 

R 1 

N 

N 

H 3C 

R 2 

OH 

Sr. Sample Code Substitution Molecular M. Wt MP ºC Yield 

No. 

NR1R2 

Formula 

% 

1 VMMB 101 N-methyl piperazine C21H25N5O 363.46 211-213 63 

2 VMMB 102 N-ethyl piperazine C22H27N5O 377.48 218-220 66 

3 VMMB 103 N-benzyl piperazine C27H29N5O 439.55 247-249 76 

4 VMMB 104 Morpholine C20H22N4O2 350.41 233-235 72 

5 VMMB 105 N-phenyl piperazine C26H27N5O 425.53 245-247 55 

6 VMMB 106 Piperidine C21H24N4O 348.44 252-254 62 

7 VMMB 107 Pyrollidine C20H22N4O 334.41 242-244 73 

8 VMMB 108 N,N diethyl amine C20H24N4O 336.43 256-258 75 

9 VMMB 111 2-methyl piperidine C22H26N4O 362.47 150-152 75 

10 VMMB 114 Piperazine C20H23N5O 349.43 236-238 78 

N 

H 

CH 3 

N 

115


PHYSICAL DATA TABLE OF 4-(3,4-DIHYDROXY-5-(SUBSTITUED-1- 

METHYL) PHENYL)-2,6-DIMETHYL-1,4-DIHYDROPYRIDINE-3,5- 

DICARBONITRILES 

N 

HO 

CH 3 

OH 

N 

H 

Sr. Sample Code Substitution Molecular M. Wt MP ºC Yield % 

No. 

NR1R2 

Formula 

1 VMMB 501 Piperazine C19H21N5O2 351.4 256-258 64 

2 VMMB 502 N-methyl piperazine C21H25N5O2 379.46 244-246 52 

3 VMMB 503 N-ethyl piperazine C22H27N5O2 393.48 212-214 55 

4 VMMB 504 N-phenyl piperazine C25H25N5O2 427.5 230-232 66 

5 VMMB 505 N-Benzyl piperazine C27H29N5O2 455.55 215-217 72 

6 VMMB 506 Morpholine C20H22N4O3 366.41 233-235 78 

7 VMMB 507 Piperidine C20H22N4O2 350.41 252-254 53 

8 VMMB 508 2-Methyl piperidine C21H24N4O2 364.44 247-249 69 

9 VMMB 511 Pyrolidine C19H20N4O2 336.39 223-225 71 

10 VMMB 514 N,N-diethyl amine C19H22N4O2 338.4 216-218 69 

CH 3 

N 

N 

R 1 

R 2 

116



IR Spectra 

IR spectra of the synthesized compounds were recorded on Shimadzu FT-IR 8400 

model using KBr Powder method. Various functional groups present were identified 

by characteristic frequency obtained for them. 

The stretching frequency of OH group showed at 3650-3600 (O-H str.) cm -1 and 

bending vibration at 1410-1310 cm -1 . The characteristic band of secondary N-H group 

showed in the region of 3500-3200 cm -1 with a deformation due to in plane bending at 

1650-1550 cm -1 . Aromatic C-H stretching and bending frequencies showed between 

3070-3030 cm -1 and 1600-1400 cm -1 respectively. C-H stretching and bending 

frequencies for methyl and methylene group were obtained near 2950-2850 cm -1 and 

1450-1375 cm -1 . Characteristic frequency of C≡N showed at 2260-2200 cm -1 . 

Characteristic frequency of C-N stretching showed near 1350-1280 cm -1 . C-O 

stretching frequency showed at 1230-1140 cm -1 . 

Mass Spectra 

Mass spectra of the synthesized compounds were recorded on Shimadzu GC-MS-QP- 

2010 model using Direct Injection Probe technique. The molecular ion peak was 

found in agreement with molecular weight of the respective compound. 

1 H NMR Spectra 

1 H NMR spectra of the synthesized compounds were recorded on Bruker Avance II 

400 MHz NMR Spectrometer by making a solution of samples in DMSO-d6/CDCl3 

solvent using tetramethylsilane (TMS) as the internal standard unless otherwise 

mentioned. Number of protons identified from 1 H NMR spectra and their chemical 

shift (δ ppm) were in the agreement of the structure of the molecule. J values were 

calculated to identify o, m and p coupling. In some cases, aromatic protons were 

obtained as multiplet. Interpretations of representative spectra are discussed as under. 

117


13 C NMR Spectra 

13 C NMR spectra of the synthesized compounds were recorded on Bruker Avance II 

400 MHz NMR Spectrometer by making a solution of samples in DMSO-d6/CDCl3 

solvent using tetramethylsilane (TMS) as the internal standard unless otherwise 

mentioned. Types of carbons identified from NMR spectrum and their chemical shifts 

(δ ppm) were in the agreement with the structure of the molecule. 

Elemental Analysis 


Erba 1108 which showed calculated and found percentage values of Carbon, 

Hydrogen and Nitrogen in support of the structure of synthesized compounds. 

The analytical data for individual compounds synthesized in this chapter is mentioned 

below. 

118



1,4-dihydro-4-(4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-101) 

Yield: 63%; IR (cm -1 ): 3550 (O-H str.), 3440 (N-H str.), 3124 (Ar C=C-H str.), 2980 

(Asym C-H str. -CH3), 2930 (Asym C-H str. -CH2), 2870 (Sym C-H str. -CH3), 2845 

(Sym C-H str. -CH2), 2198 (C≡N str.), 1698(N-H bend), 1529,1498, 1500 (Ar C=C 

str.), 1437 (C-H bend –CH2), 1375 (C-H bend –CH3), 1340 (C-N sec amine vib), 1261 

(C-O str.), 767(C-H oop def); 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.04 (s, 6H), 

2.30 (s, 3H), 2.57 (m, 8H), 3.71 (s, 2H), 4.21 (s, 1H), 6.84 (d, 1H), 7.05 (m, 2H). 13 C 

NMR 400 MHz: (DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 109.9, 111.4, 

122.1, 123.7, 126.7, 126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], M. Wt.: 363; 


6.87; N, 19.12. 

4-(3-((4-ethylpiperazin-1-yl)methyl)-4-hydroxyphenyl)-1,4-dihydro-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-102) 

Yield: 66%; IR (cm -1 ): 3615 (O-H str.), 3425(N-H str.), 3090 (Ar C=C-H str.), 2972 


(Sym C-H str. -CH2), 2232 (C≡N str.), 1632 (N-H bend), 1595, 1545, 1420 (Ar C=C 


(C-O str.), 799 (C-H oop def); Mass: [m/z (%)], M. Wt.: 377 Elemental analysis, 

Calculated: C, 70.00; H, 7.21; N, 18.55; O, 4.24 Found: C, 70.36; H, 7.83; N, 18.17. 

4-(3-((4-benzylpiperazin-1-yl)methyl)-4-hydroxyphenyl)-1,4-dihydro-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-103) 

Yield: 76%; %; IR (cm -1 ): 3655 (O-H str.), 3546 (N-H str.), 3110 (Ar C=C-H str.), 

2972 (Asym C-H str. -CH3), 2933 (Asym C-H str. -CH2), 2840 (Sym C-H str. -CH3), 

2845 (Sym C-H str. -CH2), 2225 (C≡N str.), 1675 (N-H bend), 1480, 1498, 1500 (Ar 

C=C str.), 1460 (C-H bend –CH2), 1375 (C-H bend –CH3), 1340 (C-N sec amine vib), 

1180 (C-O str.), 810 (C-H oop def); 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.04 (s, 

6H), 2.57 (s, 8 H), 3.52 (s, 2H), 3.70 (s, 2H), 4.20 (s, 1H), 6.78 (m, 2H), 7.02 (d, 1H), 

119


7.27 (m, 5H. 13 C NMR 400 MHz: (DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 

109.9, 111.4, 122.1, 123.7, 126.7, 126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], 

M. Wt.: 439 ; Elemental analysis, Calculated: C, 73.78; H, 6.65; N, 15.93; Found: 

C, 73.11; H, 6.33; N, 15.40. 

1,4-dihydro-4-(4-hydroxy-3-(morpholinomethyl)phenyl)-2,6-dimethylpyridine-3,5dicarbonitrile 

(VMMB-104) 




str.), 1439 (C-H bend –CH2), 1384 (C-H bend –CH3), 1351-1329 (C-N sec amine 

vib), 1206 (C-O str.), 860-790 (C-H oop def); Mass: [m/z (%)], M. Wt.: 350 ; 


6.29; N, 15.59. 

1,4-dihydro-4-(4-hydroxy-3-((4-phenylpiperazin-1-yl)methyl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-105) 

Yield: 55%; IR (cm -1 ): 3536 (O-H str.), 3249 (N-H str.), 3140 (Ar C=C-H str.), 

2991(Asym C-H str. -CH3), 2937 (Asym C-H str. -CH2), 2862 (Sym C-H str. -CH3), 

2855 (Sym C-H str. -CH2), 2245 (C≡N str.), 1594 (N-H bend), 1565, 1485, 1465(Ar 


1151 (C-O str.), 802(C-H oop def); Mass: [m/z (%)], M. Wt.: 425 ; Elemental 

analysis, Calculated: C, 73.39; H, 6.40; N, 16.46; Found: C, 73.74; H, 6.48; N, 

16.05. 

1,4-dihydro-4-(4-hydroxy-3-((piperidin-1-yl)methyl)phenyl)-2,6-dimethylpyridine- 

3,5-dicarbonitrile (VMMB-106) 


(Asym C-H str. -CH3), 2912(Asym C-H str. -CH2), 2865 (Sym C-H str. -CH3), 2855 

(Sym C-H str. -CH2), 2215 (C≡N str.), 1615(N-H bend), 1589, 1555, 1495 (Ar C=C 


(C-O str.), 810 (C-H oop def); ); Mass: [m/z (%)], M. Wt.: 348 ; Elemental 

120



16.84. 

1,4-dihydro-4-(4-hydroxy-3-((pyrrolidin-1-yl)methyl)phenyl)-2,6-dimethylpyridine- 


Yield: 73%; IR (cm -1 ): 3650-3600 (O-H str.), 3500-3200 (N-H str.), 3040 (Ar C=C-H 

str.), 2980 (Asym C-H str. -CH3), 2930 (Asym C-H str. -CH2), 2870 (Sym C-H str. - 

CH3), 2845 (Sym C-H str. -CH2), 2260-2200 (C≡N str.), 1650-1580 (N-H bend), 

1580, 1545, 1500 (Ar C=C str.), 1460 (C-H bend –CH2), 1375 (C-H bend –CH3), 

1340 (C-N sec amine vib), 1180 (C-O str.), 810 (C-H oop def);Mass: [m/z (%)], M. 

Wt.: 334 ; Elemental analysis, Calculated: C, 71.83; H, 6.63; N, 16.75; Found: C, 

71.43; H, 6.88; N, 16.21. 

4-(3-((diethylamino)methyl)-4-hydroxyphenyl)-1,4-dihydro-2,6-dimethylpyridine- 




(Sym C-H str. -CH2), 2200 (C≡N str.), 1662 (N-H bend), 1580, 1516,1496 (Ar C=C 


(C-O str.), 810 (C-H oop def); 1 H NMR 400 MHz: (CDCl3, δ ppm): 1.10 (s, 6H), 

2.04 (s, 6 H), 2.62 (m, 4H), 3.77 (s, 2H), 4.20 (s, 1H), 6.82 (d, 1H), 7.02 (m, 1H), 

7.19 (s, 1H) 13 C NMR 400 MHz: (DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 

109.9, 111.4, 122.1, 123.7, 126.7, 126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], 

M. Wt.: 336 ; Elemental analysis, Calculated: C, 71.40; H, 7.19; N, 16.65; Found: 

C, 71.19; H, 7.24; N, 16.55. 

1,4-dihydro-4-(4-hydroxy-3-((2-methylpiperidin-1-yl)methyl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-111) 

Yield: 75%; IR (cm -1 ): 3645 (O-H str.), 3462(N-H str.), 3140 (Ar C=C-H str.), 2988 




121


(C-O str.), 820 (C-H oop def); Mass: [m/z (%)], M. Wt.: 362 ; Elemental analysis, 


1,4-dihydro-4-(4-hydroxy-3-((piperazin-1-yl)methyl)phenyl)-2,6-dimethylpyridine- 




(Sym C-H str. -CH2), 2260-2200 (C≡N str.), 1650-1580 (N-H bend), 1580, 1545, 

1500 (Ar C=C str.), 1460 (C-H bend –CH2), 1375 (C-H bend –CH3), 1340 (C-N sec 

amine vib), 1180 (C-O str.), 810 (C-H oop def); Mass: [m/z (%)], M. Wt.: 349 ; 


7.13; N, 16.58. 

1,4-dihydro-4-(3,4-dihydroxy-5-(piperazin-1-yl)phenyl)-2,6-dimethylpyridine-3,5dicarbonitrile 

(VMMB-501) 

Yield: 64%; IR (cm -1 ): 3596(O-H str.), 3514 (N-H str.), 3140 (Ar C=C-H str.), 2980 


(Sym C-H str. -CH2), 2218 (C≡N str.), 1650-1580 (N-H bend), 1580, 1545, 1500 (Ar 


1180 (C-O str.), 810 (C-H oop def); 1 H NMR 400 MHz: (CDCl3, δ ppm): 2.05 (s, 

6H), 2.04 (s, 6 H), 2.62 (m, 4H), 3.77 (s, 2H), 4.20 (s, 1H), 6.82 (d, 1H), 7.02 (m, 1H), 

7.19 (s, 1H) 13 C NMR 400 MHz: (DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 

109.9, 111.4, 122.1, 123.7, 126.7, 126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], 

M. Wt.: = 351; Elemental analysis, Calculated: C, 64.94; H, 6.02; N, 19.93; 

Found: C, 64.97; H, 6.57; N, 19.74. 

1,4-dihydro-4-(3,4-dihydroxy-5-((4-methylpiperazin-1-yl)methyl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-502) 


(Asym C-H str. -CH3), 2821 (Sym C-H str. -CH3), 2214 (C≡N str.), 1662 (N-H bend), 

1662, 1498 (Ar C=C str.), 1437 (C-H bend –CH2), 1346 (C-H bend –CH3), 1317 (C-N 

122


sec amine vib), 1188 (C-O str.), 823 (C-H oop def); 1 H NMR 400 MHz: (CDCl3, δ 

ppm): 2.07 (s, 6H), 2.14 (s, 3 H), 2.68 (m, 6H), 3.61 (m, 2H), 3.70 (s, 2H), 4.10 (s, 

1H), 6.39 (s, 1H), 6.67 (s, 1H), 7.63 (s, 1H), 9.00 (s, 1H) 13 C NMR 400 MHz: 

(DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 109.9, 111.4, 122.1, 123.7, 126.7, 

126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], M. Wt.: 379; Elemental 


18.22. 

4-(3-((4-ethylpiperazin-1-yl)methyl)-4,5-dihydroxyphenyl)-1,4-dihydro-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-503) 





(C-O str.), 819 (C-H oop def); Mass: [m/z (%)], M. Wt.: 393; Elemental analysis, 


1,4-dihydro-4-(3,4-dihydroxy-5-(4-phenylpiperazin-1-yl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-504) 


(Asym C-H str. -CH3), 2833 (Sym C-H str. -CH3), 2198 (C≡N str.), 1660 (N-H bend), 

1660, 1599 (Ar C=C str.), 1496 (C-H bend –CH2), 1388 (C-H bend –CH3), 1346 (C-N 

sec amine vib), 1197 (C-O str.), 862 (C-H oop def); H NMR 400 MHz: (CDCl3, δ 

ppm): 2.05 (s, 6H), 2.54 (s, 4H), 3.21 (s, 4H), 3.74 (s, 2H), 4.10 (d, 1H), 6.44 (d, 1H), 

6.63 (d, 1H), 6.80 (t, 1H), 6.91 (d, 2H), 7.21 (t, 2H), 9.26 (s, 1H) 13 C NMR 400 

MHz: (DMSO-d6, δ ppm): 11.5, 51.1, 51.5, 51.9, 52.0, 109.9, 111.4, 122.1, 123.7, 

126.7, 126.8, 140.0, 155.0, 157.7, 163.1 Mass: [m/z (%)], M. Wt.: 427; Elemental 


16.39. 

123


4-(3-((4-benzylpiperazin-1-yl)methyl)-4,5-dihydroxyphenyl)-1,4-dihydro-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-505) 







1,4-dihydro-4-(3,4-dihydroxy-5-(morpholinomethyl)phenyl)-2,6-dimethylpyridine- 






(C-O str.), 870-795 (C-H oop def); Mass: [m/z (%)], M. Wt.: 366; Elemental 


15.79. 

1,4-dihydro-4-(3,4-dihydroxy-5-(piperidin-1-yl)phenyl)-2,6-dimethylpyridine-3,5dicarbonitrile 

(VMMB-507) 



(Sym C-H str. -CH2), 2205 (C≡N str.), 1650-1580 (N-H bend), 1680, 1555, 1498 (Ar 


1020 (C-O str.), 710 (C-H oop def); Mass: [m/z (%)], M. Wt.: 350; Elemental 


15.10. 

124


1,4-dihydro-4-(3,4-dihydroxy-5-(2-methylpiperidin-1-yl)phenyl)-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-508) 




str.), 1465 (C-H bend –CH2), 1378 (C-H bend –CH3), 1365 (C-N sec amine vib), 

1210(C-O str.), 815 (C-H oop def); Mass: [m/z (%)], M. Wt.: 364; Elemental 


15.75. 

1,4-dihydro-4-(3,4-dihydroxy-5-(pyrrolidin-1-yl)phenyl)-2,6-dimethylpyridine-3,5dicarbonitrile 

(VMMB-509) 







4-(3-(diethylamino)-4,5-dihydroxyphenyl)-1,4-dihydro-2,6-dimethylpyridine-3,5dicarbonitrile 

(VMMB-510) 


(Asym C-H str. -CH3), 2925 (Asym C-H str. -CH2), 2845(Sym C-H str. -CH3), 2814 

(Sym C-H str. -CH2), 2248 (C≡N str.),1580 (N-H bend), 1548, 1535, 1487 (Ar C=C 

str.), 1465 (C-H bend –CH2), 1385 (C-H bend –CH3), 1345(C-N sec amine vib), 

1012(C-O str.), 805(C-H oop def); Mass: [m/z (%)], M. Wt.: 338; Elemental 


16.55. 

125


4.11 REPRASENTATIVE SPECTRA 

IR Spectrum of 1,4-dihydro-4-(4-hydroxy-3-((4-methylpiperazin-1yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-101) 

100 

%T 

90 

80 

70 

60 

50 

40 

30 

20 

110 

%T 

100 

90 

80 

70 

60 

50 

40 

30 

20 

10 

3747.81 

NC 

10 

-0 

H3C N 

H 

4000 3600 3200 

VMMB-101 

IR Spectrum of 4-(3-((diethylamino)methyl)-4-hydroxyphenyl)-1,4-dihydro-2,6dimethylpyridine-3,5-dicarbonitrile 

(VMMB-108) 

NC 

H 3C 

3317.67 

OH 

3288.74 

3230.87 

3124.79 

OH 

N 

H 

3600 3200 

VMMB-108 

3248.23 

3124.79 

CN 

2976.26 

2854.74 

CN 

N 

CH 3 

N 

CH 3 

2800 

2829.67 

N 

2800 

2400 

2400 

2200.85 

2198.92 

2000 

2000 

1800 

1800 

1662.69 

1606.76 

1658.84 

1599.04 

1600 

1516.10 

1516.10 

1496.81 

1496.81 

1600 

1498.74 

1437.02 

1383.01 

1340.57 

1400 

1438.94 

1384.94 

1400 

1278.85 

1282.71 

1261.49 

1200 

1200 

1112.96 

1062.81 

1022.31 

1004.95 

1000 

1000 

918.15 

891.14 

800 

765.77 

800 

767.69 

694.40 

642.32 

642.32 

617.24 

600 400 

1/cm 

559.38 

470.65 

428.21 

600 400 

1/cm 

126


Mass Spectrum of 1,4-dihydro-4-(4-hydroxy-3-((4-methylpiperazin-1yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-101) 

Mass Spectrum of 4-(3-((diethylamino)methyl)-4-hydroxyphenyl)-1,4-dihydro- 

2,6-dimethylpyridine-3,5-dicarbonitrile (VMMB-108) 

NC 

H 3C 

NC 

H 3C 

OH 

N 

H 

OH 

N 

H 

CN 

N 

CH 3 

CN 

N 

CH 3 

N 

127


1H NMR Spectrum of 1,4-dihydro-4-(4-hydroxy-3-((4-methylpiperazin-1yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-101) 

Expanded 1H NMR Spectrum of 1,4-dihydro-4-(4-hydroxy-3-((4methylpiperazin-1-yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-101) 

NC 

H 3C 

NC 

H 3C 

OH 

N 

H 

OH 

N 

H 

CN 

N 

CH 3 

CN 

N 

CH 3 

N 

N 

128


1 H NMR Spectrum of 4-(3-((diethylamino)methyl)-4-hydroxyphenyl)-1,4dihydro-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-108) 

Expanded 1 H NMR Spectrum of 4-(3-((diethylamino)methyl)-4-hydroxyphenyl)- 

1,4-dihydro-2,6-dimethylpyridine-3,5-dicarbonitrile (VMMB-108) 

NC 

H 3C 

OH 

N 

H 

CN 

N 

CH 3 

NC 

H 3C 

OH 

N 

H 

CN 

N 

CH 3 

129


1 H NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-((4-methylpiperazin-1yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-502) 

HO 

NC 

H 3C 

OH 

N 

H 

CN 

N 

CH 3 

N 

1 

Expanded H NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-((4methylpiperazin-1-yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-502) 

HO 

NC 

H 3C 

OH 

N 

H 

CN 

N 

CH 3 

N 

130


1 H NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-(4-phenylpiperazin-1yl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-504) 

Expanded 

1 

H NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-(4phenylpiperazin-1-yl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

504) 

(VMMB- 

HO 

NC 

H 3C 

NC 

H 3C 

OH 

N 

H 

HO 

N 

CN 

CH 3 

OH 

N 

H 

N 

N 

CN 

CH 3 

N 

131


13 C NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-((4-methylpiperazin-1yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-502) 

H 3C 

N 

H 

13 

Expanded C NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-((4methylpiperazin-1-yl)methyl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-502) 

HO 

NC 

H 3C 

HO 

NC 

OH 

N 

H 

OH 

CN 

CN 

CH 3 

N 

CH 3 

N 

N 

N 

132


13 C NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-(4-phenylpiperazin-1yl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

(VMMB-504) 

HO 

NC 

H 3C 

OH 

N 

H 

N 

CN 

CH 3 

N 

Expanded 

13 

C NMR Spectrum of 1,4-dihydro-4-(3,4-dihydroxy-5-(4phenylpiperazin-1-yl)phenyl)-2,6-dimethylpyridine-3,5-dicarbonitrile 

504) 

(VMMB- 

HO 

NC 

H 3C 

OH 

N 

H 

N 

CN 

CH 3 

N 

133



Present work covers the synthesis of some novel Mannich base compounds using 

hydroxy substituted dihydropyridines and different secondary amines with 

formaldehyde. The main significance of the present work is the very rapid and easy 

reaction condition, facile work up method, excellent yield and high chemical purity of 

the desired compounds for biological as well as pharmacological interest. 


Herein we reported a Mannich reaction of 1,4-dihydropyridines at C4 phenyl ring 

containing hydroxyl group, as an alternative of N-1 position of 1,4-dihydropyridines. 

The newly synthesized compounds are well characterized by IR, Mass, 1 H NMR, 13 C 

NMR and Elemental analysis. 

134



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142

Chapter‐5 

FACILE SYNTHESIS OF SOME NOVEL 

FURO COUMARINS

Chapter-5 Facile Synthesis of some novel… 


Furanocoumarins or furocoumarins, are a class of organic chemical 

compounds produced by a variety of plants. They are biosynthesized partly through 

the phenylpropanoid pathway and the mevalonate pathway, which is biosynthesized 

by a coupling of dimethylallyl pyrophosphate(DMAPP) and 7- 

hydroxycoumarin (umbelliferone). 

The chemical structure of furanocoumarins consists of a furan ring fused 

with coumarin. The furan may be fused in different ways producing several isomers. 

The compounds that form the core structure of the two most common isomers 

are psoralen and angelicin. Derivatives of these two core structures are referred to 

respectively as linear and angular furanocoumarins. [1] 

Many furanocoumarins are toxic and are produced by plants as a defense mechanism 

against various types of predators ranging from insects tomammals. [2] This class 

of phytochemical is responsible for the phytophotodermatitis seen in exposure to the 

juices of the wild parsnip and the Giant Hogweed. 

Furanocoumarins have other biological effects as well. For example, in 

humans, bergamottin and dihydroxybergamottin are responsible for the "grapefruit 

juice effect", in which these furanocoumarins affect the metabolism of certain 

drugs. [3] 

Furocoumarins, such as psoralene and the angelicine derivatives are naturally 

occurring compounds. They are known to possess a high photobiological activity [4] . 

Psoralene derivatives have been used for many years in the treatment of skin diseases 

[5] . Furocoumarin/ultraviolet therapy, known as photopheresis, has recently become an 

effective treatment of cutaneous T cell lymphoma, Sezary syndrome and related 

diseases [6, 7] . The photochemotherapeutic effects of furocoumarins are based on 

intercalation of the molecules between the pyrimidine bases of the microorganism’s 

DNA. The intercalation is then followed by the UV light activated cycloaddition 

reactions of furocoumarins with the pyrimidine bases. These [2+2] 

photocycloaddition reactions result in a cross-linking of DNA and prevent a 

microorganism’s reproduction. 

143


Psoralens, which are linear furocoumarins, have the highest photosensitivity. Their 

molecules have two active sites in the [2+2] photocycloaddition reactions: the pyrone 

ring and furan ring double bonds. This kind of difunctionality of the psoralens (and of 

the angelicines in to a lesser extent) has been suggested to cause undesirable side 

effects in their medical use. Mutagenicity and carcinogenicity should be mentioned 

among these side effects of some psoralens [8‐14] . 

Even though some methods of furocoumarin synthesis have been known for a long 

time, the 

successful use of furocoumarins as effective medicines requires access to as many 

new derivatives as possible. For example, it has been found that furocoumarin analogs 

that contain other heteroatoms besides the oxygen atom in the lactone ring are free of 

some side effects [7] . Better intercalation properties and higher hydrophilicity should 

be also specific for new furocoumarins recommended for pharmaceutical testing. 

Therefore, the search for new synthetic approaches to the fucoumarins and their 

analogous heterocyclic compounds is a promising trend in photochemotherapy [15‐22] . 

Natural Furo coumarins: 

Linear Furo coumarins 

Psoralen [23] (also called psoralene) is the parent compound in a family of natural 

products known as furocoumarins. It is structurally related tocoumarin by the addition 

of a fused furan ring, and may be considered as a derivative of umbelliferone. 

Psoralen occurs naturally in the seeds of Psoralea corylifolia, as well as in 

the common fig, celery, parsley and West Indian satinwood. It is widely used 

in PUVA (=Psoralen +UVA) treatment for psoriasis, eczema, vitiligo, and cutaneous 

T-cell lymphoma. Many furocoumarins are extremely toxic to fish, and some are 

indeed used in streams in Indonesia to catch fish. 

O O O 

Bergamottin [24] is a natural furocoumarin found principally in grapefruit juice. It is 

also found in the oil of bergamot, from which it was first isolated and from which its 

144


name is derived. To a lesser extent, bergamottin is also present in the essential oils of 

other citrus fruits. Along with the chemically related compound 6’,7’dihydroxybergamottin, 

it is believed to be responsible for the grapefruit juice effect in 

which the consumption of the juice affects the metabolism of a variety of 

pharmaceutical drugs. 

O 

O O 

O 

Bergapten [25] (5-methoxypsoralen) is a psoralen (also known as furocoumarins) 

found in bergamot essential oil and many other citrus essential oils, and is the 

chemical in bergamot oil that causes phototoxicity. 

O 

O O O 

Imperatorin [26] is a furocoumarin and a phytochemical that has been isolated from 

Urena lobata L. (Malvaceae). It is biosynthesized from umbelliferone, a coumarin 

derivative. Psoralen (also called psoralene) is the parent compound in a family of 

natural products known as furocoumarins. It is structurally related to coumarin by the 

addition of a fused furan ring, and may be considered as a derivative of umbelliferone. 

Psoralen occurs naturally in the seeds of Psoralea corylifolia, as well as in the 

common fig, celery, parsley and West Indian satinwood. It is widely used in PUVA 

(=Psoralen +UVA) treatment for psoriasis, eczema, vitiligo, and Cutaneous T-cell 

Lymphoma. 

O 

O O 

O 

145


Although safe to mammals, it should be used with care since many furocoumarins are 

extremely toxic to fish, and some are indeed used in streams in Indonesia to catch 

fish. 

Xanthotoxin [27] , also known as Methoxsalen (marketed under the trade name 

Oxsoralen) is a drug used to treat psoriasis, eczema, vitiligo, and some cutaneous 

Lymphomas in conjunction with exposing the skin to sunlight. Methoxsalen modifies 

the way skin cells receive the UVA radiation, allegedly clearing up the disease. The 

dosage comes in 10mg tablets, which are taken in the amount of 30mg 75 minutes 

before a PUVA light treatment. The substance is also present in bergamot oil which is 

used in many perfumes and aromatherapy oils. 

Angular Furo coumarins: 

O O O 

O 

Angelicin [28] is an angular furocoumarin, a DNA intercalator and crosslinker with 

diverse photobiological effects. Upon long wavelength UV irradiation, forms 

monoadduct with double-stranded DNA and react with unsaturated fatty acids. 

Inhibits DNA and RNA synthesis and cell replication in Ehrlich ascites tumor cells. 

Angelicin is used as tranquilliser, sedative, or anticonvulsant. 

O 

O O 

5,6-Dihydroxyangelicin [29] is a natural angular furocoumarin isolated from the root of 

Angelica glabra Makino and from the fruits of Ligusticum acutilobum. 

O 

OH 

OH 

O O 

146


Lanatin [30] is a natural furocoumarin extracted from Heracleum thomsoni. 

O 

O 

O O 

Heratomin [31] is a furocoumarin extracted from Heracleum Thomsoni. Inhibitor of 

insect cytochromes P450. 

O 

O 

O O 

Synthesis of some Naturally occurring furo coumarins: 

O 

H 3CO 

O 

Angelicin 

O 

O 

Sphondin 

O 

O 

O 

NH 2 

OH 

Phenylalanine 

HO O O 

7-hydroxy coumarin 

O O O 

O 

Imperatorin 

O O 

Psoralen 

O 

O O 

OCH3 O 

Xanthotoxin 

OCH 3 

O O 

Bergapton 

O 

147



Acylhydroxyheteroarenes are convenient intermediates in furoheteroarene synthesis. 

The key reaction for preparation of these intermediates is the Fries rearrangement of 

acyloxyheteroarenes. 

Nevertheless, this reaction with heteroarene derivatives has not been studied much 

when compared with that of benzene derivatives. 

Condensation of α-haloketones, as shown in Scheme 14 for the preparation of 

angelicine derivative [32] . 

HO O O X 

O 

R 2 

O 

R 1 

R1=CH3, C6H5, p-CH3OC6H4, p-ClC6H4, OC2H5 R2= H, CO2C2H5 X=Cl, Br 

K 2CO 3 

CH O O 

3CN O 

Base-catalyzed condensation of acylhydroxycoumarins with ethyl chloroacetate is 

also a useful reaction for preparation of psoralen derivatives, as exemplified in 

Scheme 15 by the synthesis of a substituted psoralen [32] . 

O 

HO 

O O 

Cl 

O 

OC 2H 5 

K 2CO 3 

C 2H 5O 

R 1 

CH3CN O O O O 

The microwave promoted tandem Claisen rearrangement-cyclization reaction of 

allyloxycoumarins in the presence of BF3 / ether directly produces the 

dihydrofuranocoumarins in good yields, the products obtained by microwave 

O 

148


irradiation in N-methylformamide, NMF, can be purified with more ease, since NMF 

is soluble in water. The results clearly show that the rearrangement of 

allyloxycoumarins to allylcoumarins and preparation of 

dihydrofuranocoumarins via tandem Claisen rearrangement-cyclization reaction of 

allyloxycoumarins in the presence of BF3 / ether using microwave irradiation are the 

best alternative for preparation of these compounds [33] . 

O O O 

N,N-DEA 

Reflux, 24 h 

HO O O 

H 2SO 4 

HO O O O O O 

New derivatives of coumarin and angelicin, 8-acetyl-7-cyanomethoxy-4-methylchromen-2-one, 

8-acetyl-7-ethoxycarbonylmethoxy-4-methyl-chromen-2-one, 8- 

cyano-4,9-dimethyl-2H-furo[2,3-h]-1-chromen-2-one, and 8-ethoxycarbonyl-4,9- 

dimethyl-(2H-furo[2,3-h]-1-chromen-2-one) were obtained by conventional synthesis 

and by efficient and high-yielding microwave-assisted synthesis [34] . 

R 1O 

O 

O 

O 

R 1= -CH 2CN, CH 2COOC 2H 5 

chloroacetonitrile or 

ethyl chloro acetate 

K2CO3 Acetone 

HO 

O 

O 

O 

chloroacetonitrile or 

ethyl chloroacetate 

K 2CO 3 

1-methyl-2-pyrrolidone 

O 

R 2 

O O 

R2= CN, COOC 2H 5 

7-Chloroacetoxycoumarins 1a-d undergo unusual Fries rearrangement with 

dihydrofuro[2,3-h]coumarin-9-ones 2a-d formation (Scheme 1) [35] 

149


Cl 

O 

R 2 

O 

R 1 

O O 

AlCl 3 

a: R 1=R 2=H; b: R 1=Me, R 2=H; c: R 1=Me, R2=Cl; d: R 1=Me, R 2=Et 

R 2 

R 1 

O O O 

O O O 

O 

2 a-d 3 a-b 

Propargyloxycoumarins with BF3/Et2O and DMF resulted to pyranocoumarins, while 

with NMF gave furocoumarins. 

The treatment of 8-propargyloxy-benzo[f]coumarin with boron trifluoride diethyl 

etherate in N,N-dimethylformamide under reflux or MW irradiation resulted in 

pyrano[3,2-h]benzo[f] coumarin , while the furo[3,2-h]benzo[f]coumarin is received 

from the treatment with N-methylformamide under MW irradiation [36] . 

O 

O 

BF 3/Et 2O 

DMF 

NMF 

O O O 

O 

O 

O 

Regioselective synthesis of dihydrofurocoumarins and dihydropyranocoumarins in 

excellent yields from 4-prop-2-ynyloxy coumarin via a thiol mediated radical reaction 

is described. Alkenyl radicals are generated from easily available terminal alkynes 

and thiophenol. Thiophenol catalyzed the Claisen rearrangement of the 4-prop-2- 

ynyloxycoumarin ethers [37] . 

R 

O 

O O 

H 

SPh 

R 

O 

O O 

R 

O 

O 

O O 

R 1 

150 

O 

SPh


A simple and efficient synthesis of furo[3,2-c]coumarin derivatives from 4- 

hydroxycoumarin and α-haloketones via a tandem O-alkylation/cyclisation protocol is 

described [38] . 

OH 

O O 

X R 

R 1 

O 

AcOH/AcONH4 or piperidine 

Toluene 

O 

R 

O O 

R 1 

151



Even though some methods of furocoumarin synthesis have been known for a long 

time, the successful use of furocoumarins having effective biological activity requires 

access to as many new derivatives as possible. With this aim several furo coumarins, 

having substituted aromatics attached to furan ring of furo coumarins were 

synthesized. 


R 1 

OH 

O 

Br 

O 

R 1 = -CH 3, -diCH 3 

OH 

O 

Br 

O 

O 

R 2 = -OH, -OCH 3, -Cl, -F etc. 

HCHO 

EtOH 

R 2 

R 1 

EtOH 

Reflux 

O 

OH 

O 

R 2 

O 

OH 

O 

O 

O 

R 1 

O 

O 

152



Preparation of 2,3-dihydro-2-[2-hydroxybenzoyl]-4H-furo[3,2-c][1]benzopyran- 

4-one. (General Method) 

3-bromo 4-hydroxy coumarin (0.01 mmol) was dissolved in ethanol (40 ml) and 

further water was added (40 ml). To this formaldehyde (0.004 mmol) was added and 

the solution heated on boiling water-bath for 15 min. The yellowish mass which 

separated was filtered, washed with water, dried and crystallized from methanol to 

give 2,3-dihydro-2-[2-hydroxybenzoyl]-4H-furo[3,2-c][1]benzopyran-4-one as 

feathery needles. The purity of the compound is checked by TLC. (Chloroform: 

Methanol :: 9:1). [39] 

Preparation of 2,3-dihydro-2-(2-hydroxybenzoyl)-3-phenyl-4H-furo[3,2c][1]benzopyran-4-one. 

(General Method) 

To 3-bromo 4-hydroxy coumarin (0.01 mmol) in ethanol (25 ml) was added 

substituted benzaldehyde (0.012 mmol) and the mixture refluxed for 10-18 hr. Workup 

and crystallization from ethanol yielded 2,3-dihydro-2-(2-hydroxybenzoyl)-3phenyl-4H-furo[3,2-c][1]benzopyran-4-one. 

The purity of the compound is checked 

by TLC. (Chloroform: Methanol :: 9:1). [39] 

Similarly other derivatives were also synthesized on basis of above two general 

methods. 

153



PHYSICAL DATA TABLE OF 3-((12E)-(SUBSTITUTED 4-HYDROXY-2- 

OXO-2H-CHROMEN-3-YLIMINO)METHYL)-4-HYDROXY-2H- 

CHROMEN-2-ONES 

Sr. 

No 


1 VNRFC-101 

OH 

O 

OMe 

OMe 

2 VNRFC-102 O 

3 VNRFC-103 

OH 

O 

OH 

O 

OH 

O 

O 

OMe 

O 

O 

OH 

4 VNRFC-104 O 

5 VNRFC-105 O 

6 VNRFC-106 

O 

OH 

O 

OH 

O 

Cl 

OH 

7 VNRFC-107 O 

8 VNRFC-108 

O 

O 

OH 

O 

F 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

Molecular 

formula 

C 26H 20O 7 

C24H 16O 6 

C 25H 18O 6 

C 28H 18O 5 

C 24H 16O 5 

C 24H 15FO 5 

C 24H 15ClO 5 

C 21H 18O 5 

Molec 

u-lar 

weight 

444.12 

400.38 

414.41 

434.44 

384.38 

402.37 

418.83 

350.36 

M. P. 

( o C) 

148- 

150 

190- 

192 

135- 

137 

188- 

190 

125- 

127 

187- 

189 

122- 

124 

110- 

112 

% 

Yield 

35% 

18% 

35% 

27% 

55% 

26% 

28% 

30% 

154


9 VNRFC-109 O 

10 VNRFC-110 

11 VNRFC-115 

12 VNRFC-116 

13 VNRFC-117 

14 VNRFC-118 

15 VNRFC-119 

S 

OH 

O 

O 

OH 

OH 

O 

OH 

O 

OH 

OH 

O 

O 

OH 

O 

Me 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

O 

C 22H 18O 5S 394.44 

C 25H 18O 5 

C 18H 12O 5 

C 20H 16O 5 

C 22H 20O 5 

C 22H 20O 5 

C 22H 20O 5 

398.41 

308.28 

336.34 

364.39 

364.39 

364.39 

152- 

154 

170- 

172 

212- 

214 [39] 

198- 

200 

208- 

210 

192- 

194 

180- 

182 

15% 

38% 

67% 

62% 

55% 

57% 

55% 

155



IR spectra 


pellet method. The characteristic aromatic group in furocoumarin moiety is observed 

at 3010-3090 cm -1 . Methylene (-CH2) observed at 1375 cm -1 . 


1 


TMS (Tetramethyl Silane) as an internal standard and DMSO-d6 as a solvent. In the 

NMR spectra of 2-(2-hydroxy benzoyl) 3-(substituted phenyl) 2,3-dihydrofuro[3,2c]chromen-4-one 

derivatives various proton values of methylene (-CH2), methyl (- 

CH3) and aromatic protons (Ar-H) etc. were observed. 

Mass spectra 






synthesized. 







156



2-(2-hydroxy benzoyl) 3-(3,4-dimethoxy phenyl) 2,3-dihydrofuro[3,2-c]chromen-4one 

(VNRFC-101) 

Yield: 35%; IR (cm - 1): 3535 (O-H str.), 3052 (Ar C=C-H str.), 2980 (Asym C-H str. - 

CH3), 2950 (Asym C-H str. -CH2), 2885 (Sym C-H str. -CH3), 2825 (Sym C-H str. - 

CH2), 1740 (-C=O str.), 1632, 1617, 1575 (Ar C=C str.), 1458 (C-H bend –CH2), 

1371 (C-H bend –CH3), 1176 (C-O str.) , 965 (-C-Cl str.), 715 (C-H oop def); Mass: 

[m/z (%)], M. Wt.: 444; Elemental analysis, Calculated: C, 70.26; H, 4.54; O, 

25.20 Found: C, 70.27; H, 4.12; O, 25.67. 

2-(2-hydroxy benzoyl) 3-(2-hydroxy phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-102) 


CH2), 2833 (Sym C-H str. -CH2), 1727 (-C=O str.), 1648, 1619, 1568 (Ar C=C str.), 

1477 (C-H bend –CH2), 1164 (C-O str.), 958 (-C-Cl str.), 721 (C-H oop def); Mass: 

[m/z (%)], M. Wt.: 400 Elemental analysis, Calculated: C, 72.00; H, 4.03; O, 23.98 

Found: C, 72.09; H, 4.15; O, 23.53. 

2-(2-hydroxy benzoyl) 3-(4-methoxy phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-103) 

Yield: 35%; %; IR (cm -1 ): 3547 (O-H str.), 3070 (Ar C=C-H str.), 2970 (Asym C-H 

str. -CH3), 2938 (Asym C-H str. -CH2), 2882 (Sym C-H str. -CH3), 2833 (Sym C-H 

str. -CH2), 1735 (-C=O str.), 1643, 1624, 1562 (Ar C=C str.), 1475 (C-H bend –CH2), 

1369 (C-H bend –CH3), 1177 (C-O str.), 722 (C-H oop def); Mass: [m/z (%)], M. 

Wt.: 414 ; Elemental analysis, Calculated: C, 72.46; H, 4.38; O, 23.16; Found: C, 

72.61; H, 4.33; O, 23.26. 

157


2-(2-hydroxy 

(VNRFC -104) 

benzoyl) 3-(naphthalene) 2,3-dihydrofuro[3,2-c]chromen-4-one 





77.21; H, 4.28; O, 18.51. 

2-(2-hydroxy benzoyl) 3-(phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one (VNRFC - 

105) 

Yield: 55%; IR (cm - 1):3556 (O-H str.), 3073 (Ar C=C-H str.), 2949 (Asym C-H str. - 




74.15; H, 4.27; O, 20.05. 

2-(2-hydroxy benzoyl) 3-(4-fluoro phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC -106) 



1464 (C-H bend –CH2), 1177 (C-O str.), 720 (C-H oop def), 668 (C-F str.); Mass: 

[m/z (%)], M. Wt.: 402 ; Elemental analysis, Calculated: C, 71.64; H, 3.76; O, 

19.88; Found: C, 71.65; H, 3.44; O, 19.78. 

2-(2-hydroxy benzoyl) 3-(2-chloro phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-107) 



1469 (C-H bend –CH2), 1176 (C-O str.), 962 (-C-Cl str.), 719 (C-H oop def); 1 H 

NMR 400 MHz: (CDCl3, δ ppm): 4.22 (s, 1H), 6.33 (s, 1H), 7.39 (m, 8H), 7.53 (s, 

158


1H), 4.20 (s, 1H), 6.82 (d, 1H), 7.02 (m, 1H), 7.19 (s, 1H); Mass: [m/z (%)], M. Wt.: 

334(M+), 336(M+2) ; Elemental analysis, Calculated: C, 68.82; H, 3.61; O, 19.10 

Found: C, 68.73; H, 3.58; O, 19.05. 

2-(2-hydroxy benzoyl) 3-(isopropyl) 2,3-dihydrofuro[3,2-c]chromen-4-one (VNRFC 

-108) 


CH2), 2857 (Sym C-H str. -CH3), 2833 (Sym C-H str. -CH2), 1738 (-C=O str.), 1642, 

1619, 1574 (Ar C=C str.), 1463 (C-H bend –CH2), 1362, 1380 (isopropyl bend.), 1374 

(C-H bend –CH3), 1174 (C-O str.), 718 (C-H oop def); Mass: [m/z (%)], M. Wt.: 

350 ; Elemental analysis, Calculated: C, 71.99; H, 5.18; O, 22.83; Found: C, 71.89; 

H, 5.22; O, 22.67. 

2-(2-hydroxy benzoyl) 3-(tetrahydrothiophen-2-yl) 2,3-dihydrofuro[3,2-c]chromen- 

4-one (VNRFC -109) 





66.83; H, 4.62; N, 20.31. 

2-(2-hydroxy benzoyl) 3-(tetrahydrothiophen-2-yl) 2,3-dihydrofuro[3,2-c]chromen- 

4-one (VNRFC -110) 






75.33; H, 4.17; O, 20.12. 

159


2-(2-hydroxy benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one (VNRFC -115) 

Yield: 67%; IR (cm -1 ): 3565 (O-H str.), 3082, 3049 (Ar C=C-H str.), 2906 (Asym C- 

H str. -CH2), 2880 (Sym C-H str. -CH2), 1743 (-C=O str.), 1624, 1595, 1546 (Ar C=C 

str.), 1450 (C-H bend –CH2), 1153 (C-O str.), 962 (-C-Cl str.), 719 (C-H oop def); 1 H 

NMR 400 MHz: (CDCl3, δ ppm): 3.11 (m, 1H), 3.65 (m, 1H), 6.97 (t, 1H), 7.04 (d, 

1H), 7.41 (m, 2H), 7.53 (t, 1H), 7.67 (m, 1H), 7.74 (m, 1H), 7.85 (m, 1H) Mass: [m/z 

(%)], M. Wt.: = 308; Elemental analysis, Calculated: C, 70.13; H, 3.92; O, 25.95; 

Found: C, 70.08; H, 3.85; O, 25.78. 

2-(2-hydroxy 6-methyl benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one (VNRFC - 

116) 





Wt.: 336; Elemental analysis, Calculated: C, 71.42; H, 4.79; O, 23.78 Found: C, 

71.35; H, 4.74; O, 23.82. 

2-(2-hydroxy 3,4-dimethyl benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one (VNRFC 

-117) 





Wt.: 364; Elemental analysis, Calculated: C, 72.51; H, 5.53; O, 21.95; Found: C, 

72.38; H, 5.85; O, 21.77. 

160



-118) 

Yield: 57%; IR (cm -1 ): 3550 (O-H str.), 3074(Ar C=C-H str.), 2968 (Asym C-H str. - 





72.63; H, 5.59; O, 21.44. 


-119) 






72.45; H, 5.59; O, 21.88. 

161



IR spectrum of 2-(2-hydroxy benzoyl) 3-(2-chloro phenyl) 2,3-dihydrofuro[3,2c]chromen-4-one 

(VNRFC-107) 

105 

%T 

90 

75 

60 

45 

30 

15 

0 

-15 

3600 3200 

VNRFC-107 

3068.85 

2912.61 

2800 

2400 

1938.52 

1919.24 

2000 

1795.79 

1730.21 

1800 

600 400 

1/cm 

IR spectrum of 2-(2-hydroxy benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-115) 

100 

%T 

90 

80 

70 

60 

50 

40 

30 

20 

10 

OH 

O 

3600 3200 

VNRFC-115 

OH 

O 

3196.15 

3055.35 

2924.18 

O 

O 

O 

O 

Cl 

O 

2800 

O 

2357.09 

2341.66 

2400 

2000 

1707.06 

1800 

1670.41 

1639.55 

1572.04 

1600 

1649.19 

1606.76 

1600 

1494.88 

1442.80 

1384.94 

1572.04 

1487.17 

1417.73 

1338.64 

1400 

1332.86 

1400 

1309.71 

1284.63 

1217.12 

1176.62 

1111.03 

1051.24 

1200 

1298.14 

1263.42 

1238.34 

1190.12 

1159.26 

1091.75 

1033.88 

1200 

962.51 

922.00 

1000 

1000 

920.08 

871.85 

835.21 

761.91 

800 

825.56 

800 

719.47 

696.33 

650.03 

582.52 

754.19 

729.12 

694.40 

611.45 

553.59 

534.30 

466.79 

443.64 

449.43 

600 400 

1/cm 

162


Mass spectrum of 2-(2-hydroxy benzoyl) 3-(2-chloro phenyl) 2,3dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-101) 

OH 

O 

OMe 

OMe 

O 

O 

O 

Mass spectrum of 2-(2-hydroxy benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one 

(VNRFC -115) 

OH 

O 

O 

O 

O 

163


1 H NMR spectrum of 2-(2-hydroxy benzoyl) 3-(2-chloro phenyl) 2,3dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-107) 

OH 

O 

O 

O 

Expanded 1 H NMR spectrum of 2-(2-hydroxy benzoyl) 3-(2-chloro phenyl) 2,3dihydrofuro[3,2-c]chromen-4-one 

(VNRFC-107) 

OH 

O 

O 

O 

Cl 

O 

Cl 

O 

164


1 

H NMR spectrum of 2-(2-hydroxy benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4one 

(VNRFC -115) 

Expanded 1 H NMR spectrum of 2-(2-hydroxy benzoyl) 2,3-dihydrofuro[3,2c]chromen-4-one 

(VNRFC -115) 

OH 

O 

OH 

O 

O 

O 

O 

O 

O 

O 

165


5.10 RESULT & DISCUSSION 

Present work covers the synthesis of some novel furocoumarin compounds. The main 

significance of the present work is that the said molecules are synthesized in a one pot 

synthetic process with reaction time ranging from 10 hr to 18 hr. It was found that 

VNRFC-102 and VNRFC-109 were obtained in extremely less yields. 


Total 15 derivatives of 2-(substituted 2-hydroxy benzoyl) 2,3-dihydrofuro[3,2c]chromen-4-one 

and 2-(2-hydroxy benzoyl) 3-(substituted phenyl) 2,3dihydrofuro[3,2-c]chromen-4-one 

were synthesized. All the newly synthesized 

compounds were characterized by IR, 1 H NMR, 13 C NMR, Mass spectral data and 

elemental analysis. 

166



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[27] C. M. Wu et al, Appl Microbiol. 1972 May; 23(5): 852–856. 

[28] Chem. Abstr., 1986, 40, 291 

[29] R. Mahajan, Nematol. Medit., 1992, 20, 217-219. 

[30] Banerjee S.K. et al, Phytochemistry, 1980, 19(6), 1256 - 1258. 

[31] William D. Wulff et al J. Am. Chem. Soc., 1988, 110(22), 7419–7434. 

[32] Valery F. Traven, Molecules 2004, 9, 50-66. 

[33] Mohammad S., ECSOC-5, 2001, paper-e0002. 

[34] Elżbieta Hejchman et. al., Synthetic Communications, 2011, 41(16), 2392- 

2402. 

168


[35] Valery F. Traven, Arkivoc, 2000 (iv) 523-562. 

[36] Konstantinos E. Litinas et. al Tetrahedron, 66, 2010, 6, 1289-1293. 

[37] K.C. Majumdar; P. Debnath; P.K. Maji; Tetrahedron Letters, 2007, 48(30), 

5265-5268. 

[38] Francesco Risitano, Tetrahedron Letters, 2001, 42(20), 3503-3505. 

[39] Rahman K.; Khan K.; Indian Journal of Chemistry, 1990, 29B, 941-943. 

169

Chapter‐6 

PREPARATION OF NOVEL 

PYRIDO PYRIMIDINE‐2‐ONE DERIVATIVES

Chapter-6 Preparation of novel pyrido pyrimidine-2-one… 


Pyrimidine is a heterocyclic aromatic organic compound similar 

to benzene and pyridine, containing two nitrogen atoms at positions 1 and 3 of the six- 

member ring. [1] It is isomeric with two other forms of diazine: Pyridazine, with the 

nitrogen atoms in positions 1 and 2; and Pyrazine, with the nitrogen atoms in 

positions 1 and 4. 

N 

N 

pyrimidine 

A pyrimidine has many properties in common with pyridine, as the number of 

nitrogen atoms in the ring increases the ring pi electronsbecome less energetic 

and electrophilic aromatic substitution gets more difficult while nucleophilic aromatic 

substitution gets easier. An example of the last reaction type is the displacement of 

the amino group in 2-aminopyrimidine by chlorine [2] and its reverse. [3] Reduction 

inresonance stabilization of pyrimidines may lead to addition and ring cleavage 

reactions rather than substitutions. One such manifestation is observed in the Dimroth 

rearrangement. 

Compared to pyridine, N-alkylation and N-oxidation is more difficult, and 

pyrimidines are also less basic: The pKa value for protonated pyrimidine is 1.23 

compared to 5.30 for pyridine. Pyrimidine also is found in meteorites, although 

scientists still do not know its origin. Pyrimidine also photolytically decomposes into 

Uracil under UV light. [4] 

Heterocyclic rings have played an important role in medicinal chemistry, serving as 

key templates central to the development of numerous important therapeutic agents 

[5] 

. Pyrimidine derivatives have found application in a wide range of medicinal 

chemistry because of their diverse biological activities, such as antimicrobial [6] , 

antitumor and antifungal activities [7] , also these compounds are considered to be 

important for drugs and agricultural chemicals [8-10] . These chemotherapeutic 

applications of pyrimidine derivatives prompted us to the synthesis of some 

170


substituted pyrimidines in a facil pathway. Recently, several methods have been 

reported for the synthesis of pyrimidine derivatives. In one method aldehydes, βdicarbonyl 

compounds, and urea/thiourea were reacted in the presence of a catalytic 

amount of tetrachlorosilane in DMF at normal ambient temperature [11] . The synthesis 

of 2-thiopyrimido benzimidazole derivatives under condensation of 4-isothiocyanato- 

4-methyl-2-pentanone and 3,3-diaminobenzidine in absolute methanol under refluxing 

conditions is the other method [12] . Pyrimidine derivatives also can be prepared by 

reaction of certain amides with carbonitriles under electrophilic activation of the 

amide with 2-chloro-pyridine and trifluoromethanesulfonic anhydride [13] . However, 

these methods suffer from drawbacks, such as longer reaction time, complicated 

workup, and low yield. 

In recent years, dihydropyrimidine-2(1H)one derivatives have gained much interest 

for their biological and pharmaceuticals Properties such as HIV gp-120-CD4 

inhibitors [14] , calcium channel blockers [15] , α-adrenergic and neuropeptide Y 

antagonists [16] , as well as antihypertensive, antitumor, antibacterial, antiinflammatory 

[17] agent. The scope of this pharmacophore has been further increased 

by the identification of the Monostrol as a novel as a cell-permeable lead compound 

for the development of the new anticancer drugs [18] bearing the dihydropyrimidones 

core. Thus the development of facile and environmental friendly synthetic method 

towards dihydropyrimidines constitute active area of investigation of in organic 

synthesis, the first synthetic method for the preparation of dihydropyrimidine-2(1H) 

ones (DHPMs) was recorded by Biginelli [19] , that involves the one pot three 

component condensation of aldehyde, 1, 3-dicarbonyl compounds and urea or 

thiourea in ethanol under strongly acidic conditions producing DHPMs, albeit in low 

yields. In the view of the pharmaceuticals importance of these compounds many 

improved catalytic methods have been developed [20-24] . Although these methods have 

their long reaction time, harsh reaction conditions, unsatisfactory yield and use of 

large quantity of catalyst. Therefore improvements with respect to the above have 

been continuously sought. In this paper we wish to report an efficient environment 

friendly procedure for the synthesis of DHPMs for aryl aldehyde using 5sulphosalicyclic 

acid catalyst in microwave irradiation system. 

171


Several catalysts like PPA, AlCl3, H3BO3, conc., BF3OEt, NH4Cl, CAN, NBS, 

triflates of lanthanide compounds and In, Bi, Cu, along with microwave irradiation 

etc. have been tried [25-29] to improve yields and conditions of Biginelli reaction. 

However, all these several methods involving these various catalyst suffer from one 

or the other drawback like, expensive reagents i.e., triflates of Bi, Cu, lanthanides etc., 

prolonged reaction time, and strongly acidic conditions, unsatisfactory yields and 

tedious workup procedures (e.g. acidic alumina) for the isolation of the pure product 

in good yields. Catalysts like, ferric oxide nano composites is effective and give good 

result, but the preparation procedure of this catalyst is very difficult. This requires the 

development of a new catalyst for high yield and the lack of inexpensive reagent, 

which requires shorter reaction time and with easier workup procedure. In this paper 

we wish to report an efficient environment friendly procedure for the synthesis of 

DHPMs for aryl aldehyde using 5- 

sulphosalicyclic acid catalyst in microwave irradiation system. 

Three nucleobases found in nucleic acids, cytosine (C), thymine (T), and uracil (U), 

are pyrimidine -2-ones: 

NH 2 

N 

O 

NH 

NH 

N 

H 

O N 

H 

O N 

H 

O 

Cytosine Thymine Uracil 

P. Biginelli reported the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones 

(DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea, 

and ethyl acetoacetate. In the past decade, this multicomponent reaction has 

experienced a remarkable revival, mainly due to the interesting pharmacological 

properties associated with this dihydropyrimidine scaffold. 

O 

O 

O 

+ 

H 

H3C O H2N R 

NH 2 

O 

H + 

EtOH/Heat 

O 

O 

O 

H 3C 

N 

H 

R 

NH 

O 

172


H 

O N O 

HN 

a 

F 

H 

O N O 

HN 

b 

H 

O N O 

Gielen-Haertwig, et. al., have reported diaryl-dihydropyrimidin-2-ones as human 

neutrophil elastase inhibitors [30] . 

Coskun et. al., has reported N-Substituted pyrimidines - quinazolin-1-oxides [31] 

R 

N 

Ozaki, et. al., has reported pyrimidine derivative having potential anti-inflammatory 

activity [32]. 

R 

Lowe, et. al., have reported quinazolinedione inhibitors of calcium independent 

phosphodiesterase [33] 

N 

NH 

N 

N 

SH 

O 

CF 3 

N 

O 

O 

HN 

O 

c 

173


OH 

N 

N 

O 

COOMe 

Tuan P. has reported A facile synthesis of substituted 3-amino-1H quinazoline-2,4diones 

[34] 

F 

F 

Me 

Baraka, et. al., have reported 2,4(1H,3H)-quinaolinedione derivatives with analgesic 

and antiinflammatory activities [35] 

Kashima, et. al., have reported Antiinflammatory activity of 2(1H)-pyrimidinones and 

their salts [36] 

N 

O 

N 

OH 

N 

NH 

N 

NH 

R 

O 

O 

OEt 

O 

174



Synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component 

condensation reaction of an aromatic aldehyde, urea, and ethyl acetoacetate [37] . 

R 1 

O 

H 

O 

H 2N 

R 2 

O 

O 

O R 3 

NH 2 

EtOH 

H 

H 

R 1 

N 

O 

N 

O O 

Pyrimidine-2-one reacted with all three alkylating agents furnishing the respective N1alkylated 

products (a), (b) and (c) in 60, 95, and 60% yields, respectively [38] . 

CCl 3 

N 

H 

N 

O 

(i) 

60% 

95% 

60% 

H 2N 

O 

CCl 3 

N 

N 

CCl 3 

N 

O 

R 3 

N O 

EtO OEt 

Cl 3C 

O 

O 

CCl 3 

N 

OMe 

(i) 2-chloroacetamide 

(ii) Diethyl 2-bromomalonate 

(iii) 5-bromo-1,1,1-trichloro-4-methoxypent-3-en-2one 

(ii) 

(iii) 

O 

N 

O 

(a) 

H 

R 2 

(b) 

(c) 

175


S. Balalaie reported reaction with 1,3-dicarbonyl compound, phenylglyoxal 

monohydrate, urea and zinc chloride by heating in ethanol under reflux condition to 

obtain dihydropyrimidine-2-ones [39] . 

O 

O 

O O 

Ph O 

H2N NH2 H 

A:ZnCl2, EtOH, Reflux 

B:ZnCl2;AlCl3(1:3), Silica gel, M.W 

J. Ghomi, showed approach to synthesis of pyrimidine-2-ones under ultrasound 

irradiation by reacting chalcone derivatives with urea in the presence of potassium 

hydroxide in ethanol to produce the pyrimidine-2-one derivatives [40] . 

O 

R H 2N NH 2 

O 

R 

KOH 

EtOH 

R= H,2-CH 3,3 -CH 3, 4 -CH 3, 2 -OCH 3, 4 -OCH 3, 2,4 -OCH 3, N(Me) 2 

A 

B 

R 

O 

O 

N 

H 

Ph 

NH 

HN NH 

The facile preparation of 3,4-dihydropyrimidine-2-one derivatives with traceless 

solid-phase sulfone linker strategy is described. Key steps involved in the solid-phase 

synthetic procedure include (i) sulfinate acidification, (ii) condensation of urea or 

thiourea with aldehydes and sulfinic acid, and (iii) traceless product release via a onepot 

cyclization−dehydration process. A library of 18 compounds was synthesized [41] . 

SO 2 - Na + 

steps 

(i) - (iii) 

HN 

R 

O N R3 H 

4-Alkyl and 4-cycloalkyl substituted 1H-pyrimidin- 2-ones were prepared from the 

corresponding b-keto acetals by reaction with urea. 4-Ph derivative 3 was prepared 

R 1 

R 2 

O 

O 

176


from 2,4-dichloro-pyrimidine by selective Suzuki coupling and subsequent hydrolysis 

of the remaining chloride [42] . 

R 

Cl 

O 

Cl 

N N 

O 

H OMe 

NaOMe, DEE 

H 2SO 4, MeOH 

aq. KOH 

O 

OMe 

R OMe 

R= (a) Me, (b) cyclopr. (c) cyclobut. (d) cyclohex. 

Cl 

PhB(OH) 2, Pd(PPh3) 4 

K2CO3, PhCH3, MeOH N N 

Ph 

Urea, HCl 

EtOH 

conc. HCl 

Ph 

O 

N NH 

O 

N NH 

177



The aim of current work was to synthesize fused Pyrido[4,3-d] pyrimidine-2-ones having 

methyl sulfonyl group. These compounds are not reported in literature and therefore, it was 

aimed develop methyl sulfonyl bearing compounds. 


O 

N 

SO2Me N 

H N 

PTSA,Toluene 

N 

SO2CH3 F 3C 

O 

TEA, Toleune 

Cl 

R' 

O 

O 

N 

SO2CH3 H 

N NH 2 

R' 

O 

N 

O 

N 

N 

SO2CH3 Ethanol 

HCl 

178 

CF 3 

CF 3



Preparation of N-(mathanesulphonyl) 3-ene 4-(4-methyl piperidyl) 

piperidine. 

Take 1-methane sulfonyl-piperidin-4-one (0.01 mole) and catalytic amount of ptoluene 

sulfonic acid (PTSA) monohydrade (0.5 g) in 9 ml toluene at room 

temperature and add 4-methyl pyridine (0.011 mole) at room temperature. Raise temp 

to 55-60 o C for 90 minutes. Maintain it for 1 hrs with azeotropic distillation and then 

maintain for 6 hrs at 80-85 o C. Cool it at 60 o C and then distill toluene under vacuum. 

Cool it at 0-5 o C. Add 60 ml Methyl tert-butyl ether (MTBE) and stir for 20 min, filter 

and wash with 20 ml MTBE. [43] 

Preparation of 1-methanesulfonyl 3-(4-(trifluoromethyl)benzoyl) piperidin-4one. 

N-(mathanesulphonyl) 3-ene 4-(4-methyl piperidyl) piperidine (0.01 mole) is 

reacted with a 4-(trifluoromethyl) benzoyl chloride (0.011 mole) in presence of tri 

ethyl amine (0.015 mole) in 10 ml toluene. The reaction was kept under stirring at 15- 

20 o C for 4-5 hours. Completion of reaction was checked with TLC. The slurry 

obtained was filtered to obtain 1-methanesulfonyl-piperidin-4-one 3-(4- 

(trifluoromethyl)phenyl)methanone. M.P: 122. [43] 

Preparation of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 

(methylsulfonyl)-1-(substituted phenyl)pyrido[4,3-d]pyrimidin-2(1H)-one 

Take 30 ml ethanol into RBF, charge 1-methanesulfonyl-piperidin-4-one 3-(4- 

(trifluoromethyl)phenyl)methanone (0.005) and substituted urea (0.011 mole). 

Dissolve reaction mass under stirring. Slowly add 1 ml HCl into RBF. Heat to reflux 

for 20 hrs. Check TLC for completion of reaction. RBF put under cool condition over 

night. Precipitated product was filtered and washed with ethanol to obtain 4-(4- 

(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(substituted 

phenyl)pyrido[4,3-d]pyrimidin-2(1H)-one. TLC solvent system: Toluene:Ethyl 

acetate - 7:3. M.P: 146. [43] 

179



Sr. 

No 

R' 

Code Structure Molecular 

formula 

N 

N 

O 

N 

SO 2CH 3 

CF 3 

Molecular 

weight 

M. P. 

( o C) 

% 

Yield 

1 VNRUR-101 H C15H14F3N3O3S 373 210-212 70 

2 VNRUR-102 C6H5 C21H18F3N3O3S 449 142-144 68 

3 VNRUR-103 4-Cl C6H4 C21H17ClF3N3O3S 483 152-154 66 

4 VNRUR-104 3- NO2 C6H5 C21H17F3N4O5S 494 178-180 71 

5 VNRUR-105 4-F C6H5 C21H17F4N3O3S 467 158-160 70 


7 VNRUR-107 3,4Cl C6H5 C21H16Cl2F3N3O3S 517 176-178 58 

8 VNRUR-108 2,4 Me C6H5 C23H22F3N3O3S 477 156-158 49 

9 VNRUR-109 2-F C6H5 C21H17F4N3O3S 467 172-174 45 


180

Chapter-6 Preparation of novel pyrimidine-2-one… 


IR spectra 


pellet method. The characteristic aromatic group in furocoumarin moiety is observed 

at 3010-3090 cm -1 . Methylene (-CH2) observed at 1375 cm -1 . 


1 


TMS (Tetramethyl Silane) as an internal standard and DMSO-d6 as a solvent. In the 

NMR spectra of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)pyrido[4,3-d]pyrimidin-2(1H)-one 

derivatives various proton values of methylene (- 

CH2), methyl (-CH3) and aromatic protons (Ar-H) etc. were observed. 

Mass spectra 






synthesized. 







181



4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-pyrido[4,3d]pyrimidin-2(1H)-one 

(VNRUR-101) 

Yield: 70%; IR (cm - 1): 3529, 3412 (N-H str.), 3010 (Ar C=C-H str.), 2933 (Asym C- 

H str. -CH3), 2933 (Asym C-H str. -CH2), 2872 (Sym C-H str. -CH3), 1730 (-C=O 

str.), 1643, 1633 (Ar C=C str.), 1404 (C-H bend –CH2), 1329 (C-H bend –CH3), 1165 

(C-O str.) , 719 (C-H oop def), 586 (C-F str.); 1 H NMR 400 MHz: (CDCl3, δ ppm): 

2.04 (s, 6H), 2.30 (s, 3H), 2.57 (m, 8H), 3.71 (s, 2H), 4.21 (s, 1H), 6.84 (d, 1H), 7.05 

(m, 2H); Mass: [m/z (%)], M. Wt.: 444; Elemental analysis, Calculated: C, 70.26; 

H, 4.54; O, 25.20 Found: C, 70.27; H, 4.12; O, 25.67. 

4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1phenylpyrido[4,3-d]pyrimidin-2(1H)-one 

(VNRUR -102) 

Yield: 68%; IR (cm -1 ): 3583, 3412 (N-H str.), 3072 (Ar C=C-H str.), 2902 (Asym C- 


str.), 1568, 1539, 1496 (Ar C=C str.), 1408 (C-H bend –CH2), 1329 (C-H bend –CH3), 

1159 (C-O str.) , 707 (C-H oop def), 561 (C-F str.); 1 H NMR 400 MHz: (CDCl3, δ 

ppm): 2.93 (s, 1H), 2.95 (s, 3H), 3.14 (s, 1H), 3.48 (s, 2H), 3.84 (s, 2H), 7.07 (d, 1H), 

7.27 (s, 1H), 7.35 (d, 1H), 7.51 (m, 3H), 7.66 (d, 2H); Mass: [m/z (%)], M. Wt.: 400 

Elemental analysis, Calculated: C, 72.00; H, 4.03; O, 23.98 Found: C, 72.09; H, 

4.15; O, 23.53. 

4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(4-chloro 

phenyl)pyrido[4,3-d]pyrimidin-2(1H)-one (VNRUR -103) 

Yield: 66%; %; IR (cm -1 ): 3577, 3423 (N-H str.), 3081 (Ar C=C-H str.), 2915 (Asym 

C-H str. -CH3), 2931 (Asym C-H str. -CH2), 2874 (Sym C-H str. -CH3), 1752 (-C=O 


1149 (C-O str.) , 705 (C-H oop def), 564 (C-F str.); Mass: [m/z (%)], M. Wt.: 

414(M+), 416(M+2) ; Elemental analysis, Calculated: C, 72.46; H, 4.38; O, 23.16; 

Found: C, 72.61; H, 4.33; O, 23.26. 

182


4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(3-nitro 





1145 (C-O str.) , 714 (C-H oop def), 566 (C-F str.); Mass: [m/z (%)], M. Wt.: 434 ; 

Elemental analysis, Calculated: C, 77.41; H, 4.18; O, 18.41; Found: C, 77.21; H, 

4.28; O, 18.51. 

4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(4-fluoro 


Yield: 70%; IR (cm - 1): 3575, 3411 (N-H str.), 3076 (Ar C=C-H str.), 2914 (Asym C- 





4.27; O, 20.05. 








Found: C, 71.65; H, 3.44; O, 19.78. 

183


4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(3,4-dichloro 






334(M+), 336(M+2), 338(M+4) ; Elemental analysis, Calculated: C, 68.82; H, 

3.61; O, 19.10 Found: C, 68.73; H, 3.58; O, 19.05. 

4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(2,4-dimethyl 







5.22; O, 22.67. 

4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(2-fluoro 







4.62; N, 20.31. 

184









Found: C, 75.33; H, 4.17; O, 20.12. 

185



IR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 

(methylsulfonyl)-pyrido[4,3-d]pyrimidin-2(1H)-one (VNRUR-101) 

100 

%T 

90 

80 

70 

60 

50 

40 

30 

20 

10 

-0 

3529.85 

3412.19 

3298.38 

3184.58 

3010.98 

2933.83 

2872.10 

2789.16 

3600 3200 

VNRUR-101 

2800 

2713.93 

2351.30 

2400 

2000 

1730.21 

1800 

1714.77 

1705.13 

600 400 

1/cm 

IR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 

(methylsulfonyl)-1-phenylpyrido[4,3-d]pyrimidin-2(1H)-one (VNRUR -102) 

105 

%T 

90 

75 

60 

45 

30 

15 

0 

-15 

3583.86 

HN 

3412.19 

O 

N 

N 

SO2CH3 3072.71 

N 

3600 3200 

VNRUR-102 

O 

2902.96 

N 

N 

SO2CH3 2800 

CF 3 

2387.95 

2306.94 

CF 3 

2400 

2000 

1901.88 

1747.57 

1800 

1643.41 

1633.76 

1600 

1568.18 

1539.25 

1600 

1487.17 

1448.59 

1404.22 

1400 

1496.81 

1408.08 

1396.51 

1400 

1329.00 

1352.14 

1329.00 

1253.77 

1165.04 

1128.39 

1200 

1247.99 

1159.26 

1130.32 

1200 

1114.89 

1068.60 

1068.60 

1018.45 

966.37 

1000 

1000 

935.51 

852.56 

794.70 

1024.24 

966.37 

941.29 

856.42 

821.70 

781.20 

800 

771.55 

800 

719.47 

707.90 

597.95 

586.38 

563.23 

659.68 

547.80 

522.73 

511.15 

561.30 

507.30 

455.22 

600 400 

1/cm 

186


Mass spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 


HN 

O 

N 

N 

SO2CH3 CF 3 

Mass spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 


N 

O 

N 

N 

SO2CH3 CF 3 

187


1 H NMR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 


HN 

O 

N 

N 

SO2CH3 CF 3 

Expanded 

1 

H NMR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8tetrahydro-6-(methylsulfonyl)-pyrido[4,3-d]pyrimidin-2(1H)-one 

(VNRUR-101) 

HN 

O 

N 

N 

SO2CH3 CF 3 

188


1 H NMR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6- 


N 

O 

N 

N 

SO2CH3 CF 3 

1 

Expanded H NMR spectrum of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8tetrahydro-6-(methylsulfonyl)-1-phenylpyrido[4,3-d]pyrimidin-2(1H)-one 

(VNRUR -102) 

N 

O 

N 

N 

SO2CH3 CF 3 

189



In the current work, synthesis of some novel pyrimidine-2-one derivatives by reaction 

of substituted urea with a diketone was carried out. The main significance of the 

present work is that the process for synthesis of pyrimidine-2-one derivatives is novel, 

with facile work up method, and high chemical purity. It is for biological as well as 

pharmacological screening for further study. 


A convenient method for preparation of 4-(4-(trifluoromethyl)phenyl)-5,6,7,8- 

tetrahydro-6-(methylsulfonyl)-1-(substitutedphenyl)pyrido[4,3-d]pyrimidin-2(1H)- one was developed. After three step reaction, the final product obtained was pure 

along with good yields. 

190



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34, 1551, (b) S. Tu, F.Fang, S. Zhu, T Li, X. Zhang., Q.Zhuang, Synlett, 

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193

Chapter‐7 

PROCESS DEVELOPMENT AND YIELD 

OPTIMIZATION OF SOME IMPORTANT 

INTERMEDIATES.

Chapter-7 Rapid Synthesis and Process… 


Heterocycles containing Oxygen and Nitrogen possess many biological and 

pharmacological properties. Besides, these they are also known to exhibit properties 

and application such as anti-oxidant, heat stabilizers, photo sensitizers, indicator, 

lubricants and many more. 

Six membered oxygen heterocycles constitute a group of compounds, which occur 

widely throughout the plant kingdom. Coumarin (2H-1-benzopyran-2-one) is one of 

the naturally occurring heterocycles in many natural products. It is widely distributed 

in Plant world either in free state or in combined state. It was first isolated from tonka 

beans (Dipteryx odorata). It also occurs in sweet clover (Melilotus Officinalis and 

Melilotus Alba) and woodruff (Aperula odorata) 

It is the parent substance of a very large group of derivatives, many of which occur 

naturally and are of economic importance for example Umbelliferone, Aesculetin, 

Herniarin etc. 

HO 

HO 

O O 

HO 

Coumarin Umbelliferone 

Aesculetin 

O O 

O O MeO 

O O 

Herniarin 

Coumarin chemistry has become important because of the discovery of varied 

biochemical properties, industrial uses and analytical applications. Coumarins have 

been found to be physiologically a ctive for animals as well as humans. It acts as 

narcotic for rabbits, frogs and many other animals. 3-Chlorocoumarin have proved to 

be sedative as well as hypnotic for mice and humans. However, it is toxic to dogs and 

humans [1] . Werder synthesized over hundred derivatives of coumarin-3-carboxylic 

194


acids – they were found to be sedative in small doses and hypnotic in large doses [2] 

Coumarin also shows various other biological activities such as antifungal [3] , 

anticoagulants [4] , anti-psorasis [5] , carcinogen [6] , antibacterial [7] and insecticidal [8] . 

Some of the commercial drugs having an application as vasodialators are Chromonar 

and Visnadin, Haloxon antihelminthics, diuretics like mercumallylic acid, and 

systemic insecticidehymecromone. Antibiotic novobiocin produced by streptomyces 

spheroids and niveus has been marketed as antibacterial or antimicrobial preparation. 

HO 

(OEt) 2 

O 

(ClCH 2CH 2O) 2 

O 

P 

Chromonar 

O 

Haloxan 

O 

CH 3 

Hymercromone 

O O 

CH 3 

O 

O O 

ch 3 

O 

Cl 

NEt 2 

OMe 

O O 

Coumarin is also used as synthetic intermediates for preparation of many heterocyclic 

compounds of biological and pharmacological importance [9-12] . Some biological 

activities such antiHIV [13] and Antitumor agents [14] are also reported. 

4-hydroxy coumarins - a metabolite of coumarin are oxygen heterocycles, which are 

studied for their tautomeric structures [15] . It can exist in 2 forms as shown below. 

H 3C 

H 3C 

O 

O 

Visnadin 

O Et 

OMe 

Mercumallylic Acid 

O O 

OH 

NH 2 

O O O 

CH 3 

Novobiocin 

Me 

O O 

OH 

O 

HgOH 

CH 2CH(CH 3) 2 

OH 

195


O O 

OH 

4-hydroxy-2H-chromen-2-one 

O OH 

O 

2-hydroxy-4H-chromen-4-one 

Chemically, it is acidic in nature and therefore reacts easily at 3 rd position. 

196



Preparation of Coumarin: 

1) The biosynthesis of coumarin in plants is via hydroxylation, glycolysis and 

cyclization of cinnamic acid. Coumarin can be prepared in a laboratory in a Perkin 

reaction between salicylaldehyde and acetic anhydride [16] 

CHO 

OH 

H3C O 

2-hydroxybenzaldehyde Acetic anhydride 

O 

O 

CH 3 

CH 3COONa 

O O 

+ 

CH 3COOH 

2) One of the most reliable method for preparation of coumarin and it’s derivatives is 

Pechmann condensation. It is a condensation starting from a phenol and a carboxylic 

acid or ester containing a β-carbonyl group under under acidic conditions. It was 

discovered by the German chemist Hans von Pechmann [17] 

HOOH C 

H 3 

3) Cyclization of 3-amino-3-phenyl propanoic acid in presence of HBr results in 58% 

of coumarin. [18] 

NH 2 

C 

H 3 

O 

COOH 

O 

O 

HBr 

H 2SO 4 

4) O-demethylation and lactonisation of E-Cinnamic acid in presence of Pyridine and 

HCl gives 55% of coumarin [19] 

RT 

HO 

3-amino-3-phenylpropanoic acid Coumarin 

CH 3 

O O 

O O 

197


COOH O O 

O 

Coumarin 

CH C6H5N, HCl 

3 

20 min, 

E-Cinnamic Acid 

5) Malonic acid diethyl ester condenses with salicylaldehyde to give coumarin [20] 

6) Manimaran et al synthesized coumarins, thiocoumarins and carbostyrils in presence 

of AlCl3 [21] 

O 

Ph 

Phenyl Cinnamate 

OH 

Cl 

Phenol 

OH 

Phenol 

+ 

Ph 

O 

cinnamoyl chloride 

HO 

O 

cinnamic acid 

Ph 

AlCl 3 

AlCl 3 

AlCl 3 

O O 

7) Substituted coumarins and benzocoumarins were prepared by esterification of 2furanacrylic 

acid with substituted phenols in presence of POCl3 and Pyridine. Further, 

cyclisation of furanacrylates were effected in presence of AlCl3 to yield 73% of 

coumarin [22] 

O O OH 

EtO OEt 

diethyl malonate 

+ 

CHO 

2-hydroxybenzaldehyde Coumarin 

O O 

198


O 

O 

2-furanacrylic acid 

OH 

Phenol 

POCl 3 

Coumarin 

73% 

O O 

AlCl 3 

O 

O 

Furanacrylate 

O Ph 

8) Coumarin was also prepared via cyclization-elimination followed by 

cyclocondensation reaction between 2-hydroxybenzaldehyde and trimethylsilylketene 

in presence of NaH [23] 

9) 3-Ethoxy acrolyl chloride with phenol in presence of triethyl amine and diethyl 

ether yielded phenyl ester which on treatment with H2SO4 and SO3 cyclised to give 

coumarins in good yields (69%) [24] 

OH 

+ 

H 3C 

H 3C 

H 3C 

O 

Si HC C O 

Cl OEt 

(E)-3-ethoxyacryloyl chloride 

69% 

N-Et 3 

Et 2O 

NaH 

O O 

PhO 

H 2 SO 4 

SO 3 

O 

92% 

O 

O O 

OEt 

199


10) Koepp Erich et al used Cs (OAc)2 instead of NaOAc in Perkin synthesis of 

cinnamic acid to yield coumarin 79% [25] 

OH 

CHO 

Ac 2 O 

Cs(OAc) 2 

O O 

Some another coworkers discussed a new approach of using aromatic metallation 

reaction of aldehydes such as 1 with LiCH2-CO-NMe2 and deblocking and cyclisation 

of the adducts with AcOH [26] 

11) European patent disclosed preparation of coumarin catalytically by 

dehydrogenation followed by cyclization of the cyclohexanoyl propionic acid esters at 

100-300 o C in presence of catalyst comprising of a carrier having Pd supported either 

on CrO3 or Cr(OH)3. [27] 

O 

methyl 3-(2-oxocyclohexyl)propanoate 

12) Zhou, Chengdong et al described an improved synthesis of coumarin by using 

salicylaldehyde. Salicyaldehyde was heated with Ac2O and PEG at 185 o C for 1 hour 

to give 2-acetoxy-benzaldehyde. It was further heated with Ac2O and KF at 180-190 

o C for 4-5 hours to give 76% of coumarin [28] 

OH 

+ Ac 2O 

CHO 

O OMe 

H3C CHO 

2-(methoxymethoxy)benzaldehyde 

+ 

O 

H 3C 

180 

Polymer 

OMe 

Pd 

O 

N Li CH2 OAc 

Ac2O OH 

THF 

AcOH 

42% 

O O O O 

26% 

O O 

O O 

200


13) Flash Vacuum Pyrolysis of Salicylaldehyde and triphenyl phosphine adduct in 

presence of methylendichloride gave coumarin in 87% yields [29] 

OH 

+ 

CHO 

MeO 

O 

P 

87% 

Ph 3 

O O 

Preparation of 4-hydroxycoumarin 

CH 2 Cl 2 

1) Zeigler and coworkers cyclised malonic acid diphenyl ester in presence of AlCl3 

using Friedal Craft’s alkylation to give 4-hydroxycoumarin in 85% yield [30] 

O O 

PhO OPh 

Diphenyl Malonate 

AlCl 3 

180-185 

85% 

O O 

2) Shah et al synthesized 4-hydroxy coumarin by fusion of equimolar malonic acid 

and phenol in 2-3, moles of POCl3 and ZnCl2 – which gave 64% yield [31] 

O O 

HO OH 

Malonic Acid 

+ 

OH 

Phenol 

ZnCl 2 

POCl 3 

64% 

OH 

CHO 

O O 

OH 

O 

OMe 

201


3) Sheikh et al synthesized trimethoxy and tetramethoxy substituted 4hydroxycoumarins 

by Friedal Craft’s acylation [32] 

4) Selenium catalysed carbonylation of 4-hydroxy acetophenone in THF containing 

PhNO2 under Carbon Monoxide atomosphere at 90 o C for 30 hours giving 68% yield 

[33] 

5) A facile synthesis of 4-Hydroxycoumarin in presence of sulfur from 2hydroxyacetophenone 

with carbon monoxide in presence of triethylamine and THF 

yielded 96% of 4-hydroxycoumarin [34] 

OH 

+ CO 

Ac 

N-Et 3 , S 

THF 

96% 

O O 

6) Coumarins were also prepared by treating malonic acid diesters with MgCl2 and 

acetylsalicylic chloride (II) and further cyclisation of resulting dialkyl2-(2acetoxybenzoyl)malonate 

by alkali. Di ethylmalonate, MgCl2 and acetylsalicylic 

chloride were treated with acetonitrile and triethylamine mixture at 0 o C for one 

hour.The product obtained was heated with KOH in MeOH at 50 o C for 3 hours to 

give 77.4% target compound [35] 

O O 

EtO OEt 

diethyl malonate 

+ 

OH 

C 

O 

+ CO 

O 

Se , THF 

Cl 

MgCl 2 

N-Et3 

MeCN, KOH in MeOH 

Ac 

2-acetylbenzoyl chloride 

O O 

OH 

OH 

96% 

O O 

OH 

202


7) Intramolecular Claisen Condensation of methylacetylsalicylate with NaOMe in 

liquid paraffin at 160-260 o C for 5 hours gave 20% of 4-hydroxycoumarin [36] 

OAc 

OMe 

O 

methyl 2-acetoxybenzoate 

NaOMe 

HCl/H2O 20% 

O O 

8) Substituted 4-hydroxycoumarin was synthesized via new Baker-Venkatraman 

rearrangement [37] 

Et 

O 

N OPh 

Et 

phenyl diethylcarbamate 

+ AcCl 

BuLi , THF 

ZnCl2 O O 

OH 

OH 

Ac 

O 

O 

2-acetylphenyl butyrate 

NaH, THF 

CF3-COOH, PhMe 

9) One-pot synthesis of coumarin, 4-hydroxythiocoumarin and 2-quinolones by 

acylation followed by internal ring closure [38] 

OH 

OAc 

2-hydroxyphenyl acetate 

+ Et 2CO 3 

NaH, PhMe 

O O 

10) Salicylic Acid was esterified and acetylated. It was further cyclised with metallic 

sodium in dry Toluene [39] 

OH 

Et 

203


OH 

+ 

COOH 

2-hydroxybenzoic acid 

Ac2O MeOH 

Na / Toluene 

E) Further reactions of 4-hydroxycoumarins: 

O O 

4-hydroxycoumarins frequently reaction with aromatic aldehydes to give 3- 

benzylidene-2,4-chromandiones [41-44] 

O O 

OH 

4-Hydroxycoumarin 

+ 

R 2 

CHO 

Substituted Benzaldehyde 

However, reactions using Salicyaldehyde or it’s analogues multicyclic compounds as 

shown below was obtained either solely or in addition to salicylidene derivatives of 

type as shown. [45] 

CHO 

OH 

2-hydroxybenzaldehyde 

+ 

O O 

OH 


OH 

O O 

O 

3-benzylidene-2,4-chromanediones 

O O 

O O 

OH 

O 

O 

O 

O 

+ 

OH 

R 2 

204


The proportions of the products were dependent on reaction conditions used – for 

example when salicylaldehyde and 4-hydroxycoumarin was refluxed in ethanol were 

dimeric type of structure in addition to benzylidene derivative was obtained [46] 

Of two moles of salicylaldehyde was reacted with 4-hydroxy-6-iodocoumarins, it 

gave appropriate benzylidene derivative only. However, one mole of salicylaldehyde 

with two moles of 4-hydroxycoumarin gave the dicoumaryl structure. [47] 

2 

Similarly, reaction of 4-hydroxycoumarin with acetylated aldehydohexoses in ethanol 

for 24 hours gave substance of type below [48] 

Reaction between 4-hydroxycoumarin and hydroxylamine hydrochloride gave 

corresponding 2,4-chromadione-4-oximes. [49] 

O O 

OH 

CHO 

OH 


CHO 

+ 

+ 2 

OH 



+ NH 2OH 

O O 

OH 


O O 

OH 


O O 

OH 

O 

O 

(Z)-3-(hydroxyimino)-3H-chromene-2,4-dione 

O 

O 

O 

N 

O 

O O 

O O 

OH 

CH(CHOAc) 4CH 2OAc 

O 

OH 

OH 

205


Reaction of Chlorine with 4-hydroxycoumarins in suitable solvent or sulfuryl chloride 

led to formation 3,3-dichloro-2,4-dichromandiones. [50-54] Halogenations of 3substituted 

4-hydroxycoumarin afforded 3-chloro-2,4-chromandiones. When 3,3’ 

methylenebis (4-hydroxycoumarin) was treated with sufuryl chloride, 3,3’ 

methylenebis (3-chloro-2,4-chromandione) was isolated. 

O 

OH 

O O 

OH 

+ 

O O 

OH 

O 

O 

+ 

R 

O 

OH 

Cl 2 

Cl 2 

SO2Cl 2 

SO2Cl 2 

Cl 2 

O O 

OH 

Cl 

Cl 

O O 

When 3-amino-4-hydroxycoumarin was reacted with nitrous acid gave 3-diazo-2,4chromandiones. 

The same product was also obtained in 72% yield when sodium 

nitrite in dilute hydrochloric acid was added to 3-amino-4-hydroxycoumarin. [55] 

OH 

O O 

However, reaction of 4-hydroxycoumarin with aqueous sodium nitrite afforded 2,3,4chromantrione-3-oxime 

which forms a silver salt. [56] 

OH 

O O 

OH 

N 

N 2 

O 

OH 

OH 

Cl 

R 

O 

Cl 

Cl 

O 

O 

OH 

206



Our aim was to exploit the 3 rd position on 4-hydroxy coumarin skeleton and also their 

substituted derivatives in the benzenoid part using substitution of various functional 

groups i.e –Br, –CHO, -NO2, -NH2, -CN, thereby developing and optimizing the 

process, yield and purification techniques for the same. 


Preparation of various 3-substituted 4-hydroxy coumarins: 

Scheme-1 

Scheme-2 

R 

OH 

O O 

OH 

substituted phenol 

O 

OH 

OH 

O 

malonic acid 

ZnCl 2 

POCl 3 

Triethyl ortho formate 

M.W. 

180 W 

PTSA 

R 

OH 

O O 

OH 

O O 

CHO 

207


Scheme-3 

OH 

Scheme-4 

O O 

Acetic Acid 

HNO 3 

OH 

O O 

OH 

O O 

OH 

O O 

Br 2 

NO 2 

CN 

MeOH 

H 2O 

NaHCO 3 

Na2S2O4 HCl 

HNO 3 

HCl 

NaCN CuCN 

H 2O 

OH 

Br 

O O 

OH 

O O 

OH 

NaOH 

H2O 

E.A. 

O O 

NH 2.HCl 

NH 2 

208



Step 1 –Procedure for synthesizing 4-hydroxycoumarin: 

4-hydroxycoumarin was prepared according to the method of Shah and co-workers. 

Phenol (0.1 mole) and malonic acid (10.4 gm; 0.1 moles) were added to a mixture of 

phosphorous oxychloride (40 ml) and anhydrous zinc chloride (30 gms) which was 

preheated to get rid of any moisture. The reaction mixture was heated on a water bath 

at 70 o C for 8-10 hours. It was cooled and decomposed with ice and water to afford 

buff-yellow coloured solid. 

The solid was then filtered and washed thoroughly with water. It was then triturated 

with 10% sodium carbonate solution and filtered. The filterate was slowly acidified 

with dilute HCl till the effervescence ceased. The product was filtered and dried and 

recrystallised with methanol. [31] 

Step 2 –Procedure for synthesizing 3-substituted 4-hydroxycoumarins: 

3-formyl 4-hydroxy coumarin using microwave irradiation: 

4-hydroxy coumarin 1.0 g (0.01 mole) was taken in a 50 ml RBF to which was added 

triethyl ortho formate 7 ml (4.21 mol) and 0.02 g p-toluene sulphonic acid. The 

reaction mass was then put under microwave irradiation having 180 Watts for 5 

minutes. As a result, solid slurry obtained, which was then filtered. This solid slurry 

was dissolved in 15 ml saturated solution of sodium bicarbonate and filtered. To the 

filtrate was added conc. HCl dropwise until pH 4.0 is achieved. The resulted slurry 

was filtered u/v and dried at 50 o C for 3 – 4 hrs. M.P.: 138-140 o C. [57] 

3-nitro 4-hydroxy coumarin: 

4-hydroxy coumarin 1.62 g (0.01 mole) was taken into a conical flask 50 ml to which 

was added 10 ml acetic acid and 1.5 ml nitric acid. The reaction mass was heated to 

60 o C on water bath with constant stirring under a fume hood. The reaction mass was 

heated for 15-20 minutes until the solids obtained. Completion of reaction was 

209


checked using TLC. Slurry filtered u/v and washed with acetic acid followed by 

petroleum ether. It was then dried at 50 o C for 2-3 hrs. M.P.: 176-178 o C. [58] 

3-amino 4-hydroxy coumarin: 

3-nitro 4-hydroxy coumarin (0.01 mol) was dissolved in 100 ml saturated solution of 

sodium bicarbonate. Reaction mass was taken in a 500 ml beaker with constant 

mechanical stirring under fume hood. To which sodium dithionite 10 g was added in 

portions with constant stirring. As a result, solution colour changes from yellow to sea 

green to clear. Completion of reaction is checked using TLC. Reation mixture was 

then cooled to 0 o C and brought to pH-1 with conc. HCl dropwise. The resulting 

precipitates were filtered u/v, dried at 50 o C for 5-6 hours. M.P.: 226-228. [59] 

Diazonium salt of 3-amino 4-hydroxy coumarin: 

To a stirred reaction of 1:1 (1.61 ml HCl and 1.61 ml H2O) was added 1.0 g 3-amino 

4-hydroxy coumarin at 0-5 o C. To this was added sat. solution of NaNO2 dropwise 

until starch paper turned blue. Preparation of diazonium salt was tested with Bnaphthol 

by doing dye test. 

3-cyano 4-hydroxy coumarin: 

1.68 g CuCN and 0.68 g NaNO2 in 2 ml H2O were taken in RBF with condenser, 

which was heated at 60 o C with continuous stirring. To which was added diazonium 

salt of 3-amino 4-hydroxy coumarin portion wise. After completion of addition the 

reaction mass was heated to reflux for 30 minutes. Completion of reaction was 

checked using TLC. To the reaction mass was added ethyl acetate. Organic layer was 

extracted and concentrated u/v to give solid 3-cyano 4-hydroxy coumarin. M.P: 265- 

269. [60] 

3-bromo 4-hydroxy coumarin: 

In a round bottom flask was taken 4-hydroxy coumarin (0.01 mmol) which was 

dissolved in 20 ml methanol. The reaction mass was kept under stirring at room 

temperature. Bromine (0.02 mmol) was added dropwise from addition funnel in 15-20 

minutes. The reaction mass after addition was stirred for 2-3 hours. Completion of 

reaction was checked with help of TLC. After completion, reaction mass was poured 

210


in water 50ml. Reaction was further stirred for 10-15 minutes. Slurry obtained was 

filtered and dried at room temperature to obtain 3-bromo 4-hydroxy coumarin. M.P.: 

194-195. [61] 

211



PHYSICAL DATA OF 3-SUBSTITUTED 4-HYDROXY COUMARINS 

OH 

R 

O O 

R = -Br, -CHO, -NO 2, -NH 2, -CN 

Sr. 

No 

. 

Sample 

Code 

Substitution 

Molecular 

Formula 

M. Wt M.P o R 

C 

(Reported) 

Yield 

% 

1 VMINT 101 -Br C9H5BrO3 241.04 194-195 94% 

2 VMINT 102 -CHO C10H6O4 190.15 138-140 90% 

3 VMINT 103 -NO2 C9H5NO5 207.14 176-178 92% 

4 VMINT 104 -NH2 C9H7NO3 177.16 226-228 90% 

5 VMINT 105 -CN C10H5NO3 187.15 265-269 85% 

212



Present work covers the synthesis of some 3-substituted 4-hydroxy coumarins. Sole 

purpose for synthesizing these molecules was to explore set of different unreported 4hydroxy 

coumarin derivatives. For this, all the intermediates were prepared by 

altering classical methods or developing altogether new process, to get intermediates 

with very less reaction time, of high chemical purity and better yields. 


Total 5 intermediates, 3-bromo 4-hydroxy coumarin, 3-formyl 4-hydroxy coumarin, 

3-nitro 4-hydroxy coumarin, 3-amino 4-hydroxy coumarin and 3-cyano 4-hydroxy 

coumarin were synthesized. All 5 intermediates were confirmed with their reported 

melting points from literature and were used as starting material for synthesizing 4hydroxy 

coumarin derivatives. 

213


7.11 REFERENCE 

[1] Bose P.K., Journal of Indian Chemical Society, 1958, 35, 367. 

[2] Werder F.W., Merck’s Jal Resberichit., 1936, 50, 88. 

[3] Sangwan N.K., Verma B.S., Malik O.P. and Dhindsa K.S., Indian Journal 

of Chemistry, 1990, 29B, 294. 

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216


217

Chapter‐8 

BIOLOGICAL EVALUATION OF SYNTHESIZED 

CHEMICAL ENTITIES

Chapter-8 Biological Evaluation of Synthesized … 


Alexander Fleming discovered penicillin and set in motion a medical revolution. In 

1943, penicillin was mass produced and saved many wounded soldiers from death by 

bacterial infection. Yet as we enjoy the benefits of antibiotics, their use promotes 

antibiotic resistance in bacteria. By confronting bacteria with antibiotics, we select for 

those that are resistant and change the course of their evolution. Microbes are 

mutating and evolving in their ways that make them resistant in commonly occurring 

microbial infections. Knowledge of Antimicrobial activity of newly synthesized 

organic compounds is necessary for combating resistance of resistant and virulent 

strains. Day by day resistance of commensals and pathogenic strains grow higher and 

higher. However, our knowledge is restricted to less than 1% of the facts about causes 

of resistant strains and their sensitivity. In present era many antimicrobial drugs have 

been rendered ineffective due to the microbial resistance to the then efficient drugs. 

This warrants a search for an effective antimicrobial drug against the resistant clinical 

strains. 

Organic compounds with antimicrobial potential are being synthesized in laboratory and 

referred as “Novel Compounds”. The synthetic organic compounds are synthesized and 

purified through analytical techniques to get the fine powder. New organic synthetic 

compounds synthesized in laboratory are likely to be new on this earth and hence, their 

characteristics and activities are never evaluated and analyzed. However, they must be 

investigated properly before used as an alternative medicine for in vitro and in vivo antimicrobial 

activity. 

An anti-microbial is a substance that kills or inhibits the growth of microorganisms 

such as bacteria, fungi, or protozoans. Antimicrobial drugs either kill microbes 

(microbicidal) or prevent the growth of microbes (microbistatic). Disinfectants are 

antimicrobial substances used on non-living objects. [1] 

Antibiotic resistance is a serious concern worldwide as it would result in 

strains against which currently available antibacterial agents will be ineffective. In 

general, bacterial pathogens may be classified as either gram-positive or gram- 

218


negative pathogens. Antibiotics compounds with effective activity against both grampositive 

and gram-negative pathogens are generally regarded as having a broad 

spectrum of activity. The synthesized compounds were preliminary screened grampositive 

and gram-negative pathogens. For evaluation of antibacterial activity in our 

case, we have used Staphylococcus aureus and Bacillus cereus from gram positive 

group of bacteria and Escherichia coli and Salmonella Typhimurium from gram 

negative Group of bacteria. 

BACTERIA:- 

In 1928, a German scientist C.E. Chrenberg first used the term “Bacterium” to denote 

small microscopic organism with a relatively simple and primitive form of the cellular 

organization known as “Prokaryotic”. 

Bacteria are generally unicellular e.g. Cocci, Bacilli, etc… Filamentous, Eg. 

Actinomycetes, some being sheathed having certain cells specialized for reproduction. 

The microorganisms are capable of producing diseases in host are known as 

‘Pathogenic’. Most of the microorganisms present on the skin and mucous membrane 

are non pathogenic and are often referred to as “Commensals” or if they live on food 

residues as in intestine, they may be called “Saprophytes”. Generally, the pathogenic 

Cocci and Bacilli are gram positive and the pathogenic coco bacilli are gram negative. 

STAPHYLOCOCCUS AUREUS : - 

Genus: Staphylococcus [Microccaceae] 

Staphylococci are differentiated from micrococcus, a genus of the same family 

by its ability to utilize glucose, mannitol and pyruvate anaerobically. Cells of 

staphylococci are usually to be found on the skin or mucous membranes of the animal 

body, especially of the nose and mouth where they occur in large numbers even under 

normal conditions. 

219


Species: Staphylococcus Aureus 

The individual cells of S.Aureus are 0.8 to 0.9 micro in diameter. They are 

ovoid or spherical, non motile, non capsulated, non sporing stain with ordinary aniline 

dyes and gram positive, typically arranged in groups of irregular clusters like 

branches of groups found in pus, singly or in pairs. The optimum temperature for the 

growth is 370 C, optimum pH is 7.4 to 7.6. They produce golden yellow pigment, 

which develops best at room temperature. They cause pyoregenic of pus forming 

[Suppurative] conditions, mastitis of women and cows, boils, carbuncles infantile 

impetigo, internal abscess and food poisoning. In recent years, there has been a 

dramatic increase in the incidence of hospital associated nosocomial infections caused 

by strains of Staphylococcus aureus that are resistant to multiple antibiotics. [2] 

ESCHERICHIA COLI : - 

Genus: Escherichia [Enterobacteriaceae] 

This genus comprises escherichia and several variants and are of particular 

interest to the sanitarian since they occur commonly in the formal intestinal tract of 

man and animals. Their presence in foods or in drinking water may indicate faecal 

pollution. E.Coli is the most distinctively recognized feacal species. [3] 

Species: Escherichia coli 

E.Coli is the most important type in this species, which contains a number of 

other types. Escherichia in 1885 discovered in from the faces of the newborn and 

showed the organisms in the infesting within three days after birth. It is a commensals 

of the human intestine and found in the intestinal tract of men and animals and is also 

found in the sewage water, land, soil contaminated by feacal matters. The gram 

negative rods are 2 to 4 micro by 0.4 micro in size, commonly seen in coccobacillary 

form and rarely in filamentous form. They are facultative anaerobes and grow in all 

laboratory media. Colonies are circular, raised, and smooth and emit a faecal odour. 

E.Coli are generally non pathogenic and are incriminated as pathogens because in 

certain instances some strains have been found to produce septicemia, inflammations 

of liver and gall bladder, appendix, meningitis, pneumonia and other infections and 

this species is a recognized pathogen in the veterinary field. [4] 

220


SALMONELLA TYPHI:- 

Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, 

predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths 

from 2 to 5 µm, and flagella which grade in all directions (i.e. peritrichous). They 

are chemoorganotrophs, obtaining their energy from oxidation and reduction reactions 

using organic sources, and are facultative anaerobes. Salmonella are found worldwide 

in cold- and warm-blooded animals (including humans), and in the environment. They 

cause illnesses like typhoid fever, paratyphoid fever, and foodborne illness. [5] 

Serovar Typhimurium has considerable diversity and may be very old. The majority 

of the isolates belong to a single clonal complex. Isolates are divided into phage types, 

but some phage types do not have a single origin as determined using mutational 

changes. Phage type DT104 is heterogeneous and represented in multiple sequence 

types, with its multidrug-resistant variant being the most successful and causing 

epidemics in many parts of the world. [6] 

BACILLUS CEREUS:- 

Bacillus cereus is an endemic, soil-dwelling, Gram-positive, rod-shaped, beta 

hemolyticbacterium. Some strains are harmful to humans and cause foodborne illness, 

while other strains can be beneficial as probiotics for animals. B. cereus bacteria 

are aerobes, and like other members of the genus Bacillus can produce 

protective endospores. Its virulence factors include cereolysin and phospholipase C. [7] 

B. cereus is responsible for a minority of foodborne illnesses (2–5%), causing 

severe nausea,vomiting and diarrhea. [8] Bacillus foodborne illnesses occur due to 

survival of the bacterial endospores when food is improperly cooked. [9] B. cereus is 

also known to cause chronic skin infections that are difficult to eradicate though less 

aggressive than necrotizing fasciitis. B. cereus can also cause keratitis. [10] 

221


8.2 METHODS USED FOR SCREENING: 

The antimicrobial activity was assayed by Cup plate agar diffusion method by 

measuring inhibition zones in mm. In vitro antimicrobial activity of all synthesized 

compounds and standard drug have been evaluated against four strains of bacteria 

which include two Gram +ve bacteria namely Staphylococcus aureus, Bacillus cereus 

and two Gram-ve bacteria such as Escherichia coli, S.typhi. These strains were 

selected for their known pathogenesis of Human diseases. 

The antibacterial activity was compared with standard drug Ampicillin. It is a beta- 

lactam antibiotic that has been used extensively to treat bacterial infections since 

1961. Ampicillin is able to penetrate Gram-positive and some Gram-negative bacteria. 

Ampicillin acts as a competitive inhibitor of the enzyme transpeptidase, which is 

needed by bacteria to make their cell walls. [11] It inhibits the third and final stage of 

bacterial cell wall synthesis in binary fission, which ultimately leads to cell lysis. 

Ampicillin has received FDA approval for its mechanism of action. 

Antibacterial activity 

The purified products were screened for their antibacterial activity by using cup-plate 

agar diffusion method. The nutrient agar broth prepared by the usual method, was 

inoculated aseptically with 0.5 mL of 18 h old actively growing subculture of S. 

aureus, B. cereus, E. coli and S.typhi in separate conical flasks at 40-50° C and mixed 

well by gentle shaking. About 25 mL of the contents of the flask were poured and 

evenly spread in petridish (90 mm in diameter) and allowed to set for two h. The cups 

(6 mm in diameter) were formed by the help of sterile borer in agar medium and filled 

with 0.04 mL (400μg/mL) solution of sample in DMSO. The compounds were 

allowed to diffuse into the plate for 2 h at 2-8˚ C. 

The plates were then incubated at 37° C for 24 h. The control was maintained with 

0.04 mL of DMSO and Standard drug 0.04 mL (400μg/mL) was prepared in similar 

manner. The zone of inhibition of the bacterial growth were measured in millimeter 

and recorded in Table. 

222


Table 8.1 

ff 30.00 

25.00 

20.00 

15.00 

10.00 

5.00 

0.00 

VMMB 101 

VMMB 102 

VMMB 103 

VMMB 104 

VMMB 105 

VMMB 106 

VMMB 107 

VMMB 108 

VMMB 109 

VMMB 110 

B. cereus 

S. aureus 

control 

blank 

B. cereus 14 16 0 11 0 0 16 11 0 0 0 0 

S. aureus 0 11 0 0 0 0 12 11 10 14 0 25 

E.coli 0 0 0 0 0 0 0 0 0 0 0 18 

S.typhi B 0 0 0 9 0 0 0 0 0 0 0 0 

E.coli 

S.typhi B 

223 

Ampicillin


Table 8.2 

30 

25 

20 

15 

10 

5 

0 

VMMB 501 

VMMB 502 

VMMB 503 

VMMB 504 

VMMB 505 

VMMB 506 

VMMB 507 

VMMB 508 

VMMB 509 

VMMB 510 

B. cereus 

S. aureus 

S.typhi B 

E.coli 

Contro 

Blank 

B. cereus 12 10 10 0 18 0 22 23 15 15 0 0 

S. aureus 18 12 17 15 22 21 20 14 19 11 0 25 

S.typhi B 11 0 12 0 0 0 10 0 0 0 0 0 

E.coli 0 0 0 0 0 0 0 0 0 0 0 18 

224 

Ampicillin


8.3 RESULTS & DISCUSSION 

Clinical isolates of opportunist and pathogenic cultures of Gram Positive and 

Negative bacteria were obtained which were resistant to several antibiotics. 

The compounds VMMB 104 and VMMB 110 shown antibacterial activity against 

S.typhi. Many compounds of the VMMB series have shown good antibacterial 

activity against B. cereus and S. aureus. None of the compounds from the VMMB 

Series have been active against E.coli. 

All the compounds of VMMB Series have shown good activity against S.aureus. 

Compounds have shown high activity equivalent to the standard drug. The 

compounds VMMB 501, VMMB 503 and VMMB 507 showed activity against 

S.typhi. Many compounds of the VMMB series have shown good antibacterial 

activity against B. cereus as compared to Standard drug. None of the compounds from 

the VMMB Series have been active against E.coli. 

All microbial cultures showed characteristic pattern of their sensitivity for all 

synthetic compounds. 

The antimicrobial activities of Gram Negative, Gram Positive bacteria which can 

grow under normal laboratory conditions were analyzed. Still many other problematic 

resistant strains are to be screened for large number of synthetic compounds being 

synthesized every day. Among them, several synthetic series and biological extracts 

have attracted considerable attention during the last several years. Loss of sensitivity 

of microorganism against antimicrobials may be due to many factors including 

change in their genetic makeup. The antimicrobial activity of any antimicrobial 

depends on many external and internal influences. The major part of their capacity to 

inhibit Prokaryotes depends on the major ring structure skeleton of the synthetic 

compound and the external moieties – additional groups attached to main skeleton. 

The physical and chemical properties of synthetic compound are also detrimental 

factor in exhibiting their activity. 

225


The results were recorded at the end of 24 hours to give complete growth cycle for a 

bacterium so that uniformity of growth could be maintained for all bacterial cultures. 

Upon further incubation of the Nutrient Agar plates, not a single cell of the bacterial 

culture could grow if once proved to be sensitive. The possible reason for no growth 

might be the damages to vital cellular parts by the synthetic compounds. 

Detailed account of physic-chemical properties of the organic compounds could be 

correlated with high antimicrobial activities. Further studies on these aspects could 

focus on the DNA profiles of microorganisms. Understanding the genetic and 

biochemical basis of sensitivity and resistance of microbes would also be quite 

interesting to explore. 

Each of the organic compounds under study has generated a typical 

antimicrobiogram, reflecting a significant diversity amongst them. Majority of the 

synthetic organic compounds were dispersed into the medium when added into Petri 

dishes and killed the target organisms and shown no growth at the site of inoculation. 

Interestingly, in case of few organic compounds, they could not show inhibition of 

microbes and organisms could grow in the form of small colonies which could then be 

further investigated for the number of cells present. 

Further studies such as finding their physicochemical basis at macromolecular level of 

the detection of the cause of their success and failure as antimicrobials, would be 

quite interesting. 

From the table it can be inferred that most of the compounds from VMMB Series are 

active against Gram positive bacteria. The compounds can be studied further for their 

activity against other Gram positive organisms and for their mode of action. The 

compounds however are less effective against Gram negative bacteria. Coumarin 

bearing DHPs, Diazepines and Cyano pyridine are good scaffold for anti 

microbial activity. On the basis of the above interesting results, new synthetic 

programmes can be planned to develop more active compounds. 

226



[1] Abigail fraser, et. al.; Journal of anti-microbial Chemotherapy, 2006, 

58(3), 489-491. 

[2] Kluytmans J, van Belkum A, Verbrugh H; "Nasal carriage 

of Staphylococcus aureus: epidemiology, underlying mechanisms, and 

associated risks", Clin. Microbiol. Rev., 1997, 10(3), 505–20. 

[3] Madigan M; Martinko J, Brock Biology of 

Microorganisms,2005 (11th ed.), Prentice Hall 

[4] Facts about E. coli: dimensions, as discussed in bacteria: Diversity of 

structure of bacteria: – Britannica Online Encyclopedia". 

Britannica.com. Retrieved, 2011. 

[5] Ryan KJ, Ray CG; Sherris Medical Microbiology (4th ed.), 2004, 

pp. 362–8 

[6] Clark MA, Barret EL "The phs gene and hydrogen sulfide production 

by Salmonella typhimurium.". J Bacteriology,1987, 169(6): 2391–2397 

[7] Ryan KJ, Ray CG; Sherris Medical Microbiology (4th ed.), 2004. 

[8] Kotiranta A, Lounatmaa K, Haapasalo M "Epidemiology and 

pathogenesis of Bacillus cereus infections". Microbes Infect, 

2000, 2(2): 189–98 

[9] Turnbull PCB Bacillus. In: Baron's Medical Microbiology (Barron 

S et. al., eds.) (4th ed.). Univ of Texas Medical Branch, 1996. 

[10] Pinna A, Sechi LA, Zanetti S et al., "Bacillus cereus keratitis 

associated with contact lens wear".Ophthalmology, 2001, 108 (10): 

1830–4 

[11] AHFS Drug Information, American Society of Health-System 

Pharmacists, 2006. 

227

Summary 

SUMMARY 

The work represented in the thesis entitled “Studies On Nitrogen And Oxygen 

Containing Heterocyclic Compounds” is divided into seven chapters which can be 

summarized as under. 

Chapter-1 deals with Microwave protocols for the synthesis of Benzofuran 

derivatives linked with 1,3,4 oxadiazoles. Ethyl benzofuran 2-carboxylate was 

synthesized via condensation of ethyl bromo acetate and salicaldehyde which was 

then reacted with hydrazine hydrate to yield benzofuran-2-carbohydrazide. 

Furthermore, reaction of benzofuran-2-carbohydrazide with substituted benzoic acids 

in presence of phosphorous oxychloride in microwave gave 2-(benzofuran-2-yl)-5substituted 

phenyl - 1,3,4-oxadiazoles in good to excellent yields. The compounds 

were well characterized by IR, 1 H and 13 C NMR and Mass spectrometry. 

Chapter-2 is related to preparation of various substituted 3-amino 4-hydroxy 

coumarins and their reaction with 1-adamantane carboxylic acid chloride in presence 

of triethyl amine to give 3-(1-amido adamantyl) 4-hydroxy coumarins. The 

synthesized compounds were well characterized by IR, 1 H NMR and Mass 

spectrometry. 

Chapter-3 deals with grindstone technique used for the synthesis of titled 

compounds. This method is superior since it is eco-friendly, high yielding, requires no 

special apparatus, non-hazardous, simple and convenient. A series of some new Schiff 

bases have been prepared. The synthesized compounds were well characterized by IR, 

1H NMR and Mass spectrometry. The major benefit of this approach is solvent free 

conditions, easy work up process and shorter reaction time.

Summary 

Chapter-4 encompasses the cyclization reaction of 3-aminocrotononitrile with 

substituted benzaldehydes to give 4-substituted 2,6-dimethyl 3,5-dicarbonitrile 1,4dihydropyridines. 

Futhermore, their reaction with formaldehyde and various 

secondary amines yielded various mannich bases. The synthesized compounds were 

well characterized by IR, 1 H and 13 C NMR and Mass spectrometry. 

Chapter-5 covers the synthesis of some novel furocoumarin compounds. The main 

significance of the present work is that the said molecules are synthesized in a one pot 

synthetic process with reaction time ranging from 10 hr to 18 hr. Total 15 derivatives 

of 2-(substituted 2-hydroxy benzoyl) 2,3-dihydrofuro[3,2-c]chromen-4-one and 2-(2hydroxy 

benzoyl) 3-(substituted phenyl) 2,3-dihydrofuro[3,2-c]chromen-4-one were 

synthesized. All the newly synthesized compounds were characterized by IR, 1 H 

NMR, Mass spectral data and elemental analysis. 

Chapter-6 represents some novel pyrimidine-2-one derivatives synthesized by 

reaction of substituted urea with a diketone. The main significance of the present 

work is that the process for synthesis of pyrimidine-2-one derivatives is novel, with 

facile work up method, and high chemical purity for biological as well as 

pharmacological interest. A convenient method for preparation of 4-(4- 

(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-6-(methylsulfonyl)-1-(substituted 

phenyl)pyrido[4,3-d]pyrimidin-2(1H)-one was developed. After three step reaction, 

the final product obtained was pure along with good yields. 

Chapter-7 is related to substitution of various functional groups i.e –Br, –CHO, - 

NO2, -NH2, -CN, -COOH at 3 rd position of 4-hydroxy coumarin skeletal, thereby 

developing and optimizing the process, yield and purification techniques for the same. 

The synthesized compounds were well characterized by IR, 1 H and 13 C NMR and 

Mass spectrometry. 

Chapter-8 covers Biological Activity part, wherein the antimicrobial activity of 

VMMB series was assayed by Cup plate agar diffusion method by measuring

Summary 

inhibition zones in mm. In vitro antimicrobial activity of all synthesized compounds 

and standard drug have been evaluated against four strains of bacteria which include 

two Gram +ve bacteria namely Staphylococcus aureus, Bacillus cereus and two 

Gram-ve bacteria such as Escherichia coli, S.typhi. These strains were selected for 

their known pathogenesis of Human diseases.

CONFERENCES, SEMINARS & WORKSHOPS ATTENDED: 

ISCB Conference “International conference on chemical biology for 

discovery: perspectives and Challenges” at CDRI, Lucknow, 15-18 Jan., 

2010. 

ISCB Conference “Interplay of Chemical and Biological Sciences: Impact 

on Health and Environment” at Delhi University, on 26 th February - 1 st 

March 2009 

“International Seminar on Recent Developments in Structure and Ligand 

based Drug Design” jointly organized by Schrodinger LLC, USA; National 

Facility for Drug Discovery through New Chemicals Entities Development & 

Instrumentation support to Small Manufacturing Pharma Enterprises and DST 

FIST, UGC-SAP & DST-DPRP Funded Department of Chemistry, Saurashtra 

University, Rajkot, dated December, 23 rd , 2009. 

“National seminar on Alternative Synthetic Strategies for Drugs & Drug 

Intermediates” at Institute of Pharmacy, Nirma University, Ahmedabad on 

13 th November, 2009. 

“Two Days National Workshop on Patents & Intellectual Property Rights 

Related Updates” Sponsored by TIFAC & GUJCOST and Organized by 

DST-FIST, UGC-SAP & DST-DPRP Funded Department of Chemistry, 

Saurashtra University, Rajkot, dated September, 19-20, 2009. 

DST-FIST, UGC (SAP) supported and GUJCOST sponsored “National 

Conference on Selected Topics in Spectroscopy and Stereochemistry” 

organized by the Department of Chemistry, Saurashtra University, Rajkot, 

dated March, 18-20, 2009. 

“A National Workshop On Updates In Process and Medicinal Chemistry” 

jointly organized by National Facility for Drug Discovery through New 

Chemicals Entities Development & Instrumentation support to Small 

Manufacturing Pharma Enterprises and DST FIST, UGC-SAP & DST-DPRP 

Funded Department of Chemistry, Saurashtra University, Rajkot dated March, 

3-4, 2009.

DST-FIST, UGC (SAP) supported and GUJCOST Sponsored “National 

Workshop on Management and Use of Chemistry Database and Patent 

Literature” organized by GUJCOST & Dept. of Chemistry of Saurashtra 

University, Rajkot, (Gujarat), dated February, 27-29, 2008. 

PAPER/POSTER PRESENTED AT THE INTERNATIONAL 

CONFERENCE: 

“Synthesis and antimicrobial screening of some substituted (3E) – 3 – 

benzylidene – 2 H – chromene 2,4 (3H) – diones.” 

Vaibhav Ramani, Chetna Rajyaguru and Anamik Shah* 

Poster presented at 13 th ISCB International Conference was organized on 

“Interplay of Chemical and Biological Sciences: Impact on Health and 

Environment” at Delhi University, Delhi on 26 th February - 1 st March 2009 

“Synthesis and anti-bacterial activity of poly-substituted pyrrole derivatives” 

Vaibhav Ramani, Chintan Dholakiya and Anamik Shah* 

Poster presented at 14 th ISCB International conference on chemical biology for 

discovery: perspectives and challenges, CDRI, Lucknow, 15-18 Jan., 2010.

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