Exploration of 3-Aminocoumarins for Construction of Pyridocoumarins and Pyrrolocoumarins & Synthesis of Fused Oxazoles and Thiazoles via Oxidative C-H Bond Functionalization A dissertation Submitted to the Indian Institute of Technology Guwahati As Partial Fulfillment for the Degree of DOCTOR OF PHILOSOPHY by Md. Belal Roll No. 126122027 Department of Chemistry Indian Institute of Technology Guwahati Guwahati – 781039 July 2017 Dedicated to My Parents TH-1700_126122027 STATEMENT I do hereby declare that the matter embodied in this thesis entitled “Exploration of 3- Aminocoumarins for Construction of Pyridocoumarins and Pyrrolocoumarins & Synthesis of Fused Oxazoles and Thiazoles via Oxidative C-H Bond Functionalization” is the result of investigations carried out by me under the supervision of Prof. Abu T. Khan in the Department of Chemistry, Indian Institute of Technology Guwahati, India. In keeping with the general practice of reporting scientific observations, due acknowledgements have been made wherever the work described is based on the findings of other investigators. IIT Guwahati June 16, 2017 Md. Belal INDIAN INSTITUTE OF TECHNOLOGY GUWAHATI Department of Chemistry TH-1700_126122027 Indian Institute of Technology Guwahati Guwahati – 781039, India Tel. No.: +91-361-2582305 Fax No.: +91-361-2582349 e-mail: atk@iitg.ernet.in Dr. Abu T. Khan Professor of Chemistry CERTIFICATE This is to certify that Md. Belal has been working under my supervision since July, 2012 as a regular registered Ph. D. student. His thesis entitled “Exploration of 3-Aminocoumarins for Construction of Pyridocoumarins and Pyrrolocoumarins & Synthesis of Fused Oxazoles and Thiazoles via Oxidative C-H bond Functionalization” contains the results obtained from the research work carried out by him in the Department of Chemistry, Indian Institute of Technology Guwahati, India. I am forwarding his thesis to submit for the Ph. D. (Science) degree from this institute as he has fulfilled all the requirements according to the rules of this institute and this work has not been submitted elsewhere for a degree. IIT Guwahati Prof. A. T. Khan June 16, 2017 (Thesis Supervisor) TH-1700_126122027 Indian Institute of Technology Guwahati Guwahati – 781039, India Tel. No.: +91-361-2583304 Fax No.: +91-361-2582349 e-mail: span@iitg.ernet.in Dr. Subhas C. Pan Associate Professor CERTIFICATE This is to certify that Md. Belal has completed his Thesis Work from July, 2012 as a regular registered Ph. D. student under my colleague Prof. Abu T. Khan. I have been appointed as a Co- Supervisor when Prof. Khan joined as Vice-Chancellor of Aliah University in West Bengal on deputation from IIT Guwahati. I am forwarding his thesis as a Co-Supervisor entitled “Exploration of 3-Aminocoumarins for Construction of Pyridocoumarins and Pyrrolocoumarins & Synthesis of Fused Oxazoles and Thiazoles via Oxidative C-H Bond Functionalization” being submitted for the Ph. D. (Science) degree from this institute. I certify that he has fulfilled all the requirements according to the rules of this institute regarding the investigations embodied in his thesis and this work has not been submitted elsewhere for a degree. IIT Guwahati June 16, 2017 Dr. S. C. Pan (Thesis Co-Supervisor) TH-1700_126122027 i Acknowledgement First and foremost, I thank my supervisor, Prof. Abu Taleb Khan for his constant encouragement, dynamic guidance and invaluable suggestions during my entire PhD. I am highly indebted to him for the liberty he gave me, to work in the laboratory and pursue my knowledge in chemistry. It was indeed a great pleasure working under him during my PhD tenure. I hereby express my deepest sense of gratitude to my co-supervisor Dr. Subhas Chandra Pan for his boundless support and assistance during my PhD. I am profoundly thankful to my doctorial committee chairman Prof. Bhisma Kumar Patel for his help and guidance during my PhD and also to the doctorial committee members Dr. Bhubaneswar Mondal and Prof. Mohammad Jawed for their extremely helpful suggestions. My deepest gratitude to my lab mates Dr. Deb Kumar Das, Dr. Sidick Basha, Dr. Prasanta Ray Bagdi, Dr. Ajaz Ahmed Dar, Dr. Arindam Ghosh, Dr. Satavisha Sarkar, Dr. Kobirul Islam, Dr. Suchandra Bhattarcharjee, Radhakrishna Gatuu and Karuna Mahato for their direct and indirect help during my PhD. I would like to thank Babulal Da, Dr. Samir Ghorai, Dr. Somnath Ghosh, Nibedita Behra and Soumen Ghosh for their assistance in solving crystallography related problems. I acknowledge IIT Guwahati for providing the financial assistance throughout my PhD, Department of Chemistry IIT Guwahati and Central Instrument facilities for providing various instrument facilities. I am highly thankful to all the staff in the Department of Chemistry, IIT Guwahati for their co-operation in providing the facilities of the Department. My heartiest thanks to all the friends, seniors and juniors in IIT Guwahati especially Sahnawaz Ahmed, Dr. Md. Palashuddin Sk, Dr. Julfikar Hassan Mondal, Dr. Arghya Banerjee, Kafeel Ahmed and Srinawas Rao for the beautiful memories in IIT Guwahati. Last but not least, I would like to thank my parents and my family members for their immense support. Their encouragement and belief in me to prosper in life always have been the driving force to my success. TH-1700_126122027 ii Content of the Thesis Chapter I Literature survey on the importance of aminocoumarins and 3- aminocoumarins for construction of pyridocoumarins and pyrrolocoumarins 1-16 I.1 Introduction 1 I.2 Importance of coumarins 1-2 I.3 Importance of 3-aminocoumarins 2-3 I.4 Synthesis of Pyridocoumarins and Pyrrolocoumarins 3-9 I.4.1 Synthesis of Pyridocoumarins 4-7 I.4.2 Synthesis of Pyrrolocoumarins 7-9 I.5 3-Aminocoumarins in Organic Synthesis 9-16 I.5.1 Synthesis of 3-Aminocoumarins 9-12 I.5.2 Synthesis of Fused Heterocycles Exploring 3-Aminocoumarins 12-16 Chapter IIA Synthesis of Pyrido(2,3-c)coumarin derivatives by an intramolecular Povarov reaction 17-38 Results and Discussion 17-22 Experimental Section 23-38 Chapter IIB PSTA.H2O catalyzed reaction of 3-aminocoumarin and phenylacetaldehyde derivatives: A route to access various Pyrido(2, 3-c)coumarin derivatives 39-62 Results and Discussion 39-44 Experimental Section 45-62 Chapter III Iodine catalyzed multicomponent approach to access various Pyrrolo(2,3-c)coumarin derivatives using 3-aminocoumarins, acetophenones and 4-hydroxycoumarin 63-87 Results and Discussion 63-68 Experimental Section 69-87 TH-1700_126122027 iii References Chapter (I-VI) 170-175 Chapter IV An introduction to oxidative C-H bond functionalization and coumarin fused oxazoles and thiazoles 88-100 IV.1 Introduction 88-89 IV.2 C-H bond Functionalization Adjacent to Nitrogen Atom 89-93 IV.3 Oxidative C-H Bond Functionalization for the Synthesis of Heterocycles 93-97 IV.4 Synthesis of Coumarin Fused Oxazoles 97-98 IV.5. Synthesis of Coumarin Fused Thiazoles 98-100 Chapter V Synthesis of fused oxazole containing coumarin derivatives via oxidative cross coupling reaction using a combination of CuCl2 and TBHP 101-126 Results and Discussion 101-106 Experimental Section 107-126 Chapter VI Oxidative cross coupling reaction mediated by I2/H2O2: A novel approach for construction of fused thiazole containing coumarin derivatives 127-169 Results and Discussion 127-133 Experimental Section 134-169 Appendix Conclusion and the Thesis Overview 176 Future Perspective 177 Publications 178 TH-1700_126122027 iv Abbreviations Ac acetyl BDMS bromodimethylsulfonium bromide Bn benzyl Boc tert-butoxycarbonyl Bu butyl t-Bu tert-butyl t-BuOH tert-butyalcohol Bz benzoyl CCDC cambridge crystallographic data centre CDC cross dehydrogenative coupling DCE 1,2- dichloroethane DCM dichloromethane DMAP N, N-4-dimethylaminopyridine DMF N, N-dimethylformaide DMSO dimethylsulfoxide ESI electron spray ionization Et ethyl EtOH ethanol Et3N trithylamine HRMS high resolution mass spectrometry IR infrared MCR multicomponent reaction Me methyl MP melting point MS molecular sieve MW microwave MWI microwave induced NMR nuclear magnetic resonance ORTEP oak ridge thermal ellipsoid program PDCA pyridine dicaboxylic acid i-pr isopropyl Ph phenyl PPA polyphosphoric acid ppm parts per million TH-1700_126122027 v pr propyl TBHP tert-butyl-hydroproxide p-TSA p-toulenulfonic acid PTSA p-toulenulfonic acid Py pyridine rt room temperature TEMPO 2,2,6,6-tetramethyl pyridine-N-oxide TFA trifluorocaetic acid TfOH trifluoromethansulfonic acid THF tetrahydrofuran TLC thin layer chromatography TsOH trifluoromethansulfonic acid XRD x-ray diffraction TH-1700_126122027 CHAPTER I Literature Survey on the Importance of Aminocoumarins and 3-Aminocoumarins for Construction of Pyridocoumarins and Pyrrolocoumarins TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 1  I.1. Introduction Coumarins are naturally occurring heterocyclic compounds. They are known as benzopyrones having a benzene ring fused with a pyrone ring and is also called as 2-H-chromen-2-one. Coumarins constitute the important class of heterocyclic compounds having a broad spectrum of biological activities.1 Both naturally occurring and synthesized coumarin containing heterocyclic compounds have shown interesting and valuable medicinal and pharmaceutical properties. Therefore, recently the synthetic chemists have given considerable effort to achieve these compounds in an easier and economically fruitful ways.2 Coumarin based heterocyclic compounds are the good chromophores and they are used as florescence probes and non-linear optical chromophores which give the chemists a further reason to explore the field of coumarin chemistry.3 Figure 1. Structure of coumarin and 3-aminocoumarin 3-Aminocoumarin itself does not occur naturally unlike many other coumarin derivatives but it is the core structures of natural antibiotics.4 Aminocoumarins, mostly 4-aminocoumarins and 6- aminocouamarins have been used widely for the synthesis of heterocyclic compounds whereas 3- aminocoumarin is very much less explored.5 Therefore the thesis work has been put forward for the synthesis of heterocycles exploring 3-aminocoumarins.  I.2. Importance of Coumarins Simple coumarin was first isolated from Tonka bean by Vogel in 1820. Since its isolation, a library of natural products containing coumarin moieties have been discovered and their biological activities are being explored (Fig. 2).6 Umbelliferone which is actually 7-hydroxycoumarin, found in carrots, coriander and garden angelica are used as sunscreen agent, a fluorescence indicator and as a dye indicator.7 Warfarin isolated from woodruff and lavender are used as anti-coagulant.8 Dicoumarol, isolated from mouldy, wet, sweet-clover hay, is also a good anticoagulant.9 Aesculitin and scopolin isolated from Santolina oblongifolia plant and Esculin found in Aesculus hippocastanum L. (Horse-chestnut) have been found as potent anti-inflammatory agents.10a,b Calophyllum species which are pyranocoumarins, well known for their anti HIV-1 RT activity. TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 2 (+)-Calanolide A was first isolated from Calophyllum lanigerum in 1987, is a non-nucleoside reverse transcriptase inhibitor with potent activity against HIV-1. (+)-Cordatolide A, isolated from the leaves of C. Cordatooblangum in 1985 also shows anti-HIV RT activity. (+)-Inophyllum B isolated from C. inophyllum was found to be most active against HIV-reverse transcriptase.11 Figure 2. Naturally occurring coumarins  I.3. Importance of 3-Aminocoumarins The 3-aminocoumarin moiety is found in marine alkaloid like Lamellarin D and Ningalin B. It is also the part of alkaloid santiagonamine (Fig. 3). Nigalin B is pyrrolocoumarin based drugs which shows multidrug resistance activities.12 Lamellarin D is also a pyrrolocoumarin and has potent cytotoxic activity. It has also found to be a good inhibitor of topoisomerase I and was first isolated in 1985 by Faulkner and co-workers from the marine prosobranch mollusc Lamellaria sp.13 Santiagonamine is an alkaloid containing pyridocoumarin moiety which shows excellent healing property and was isolated from the stems and branches of the South American shrub Berberis darwinii Hook in 1984 by Shamma et al.14 3-Aminocoumarin is the core structures of natural TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 3 antibiotics such as Novobiocin, Chlorobiocin and Coumermycin (Fig.3) and they are the inhibitors of bacterial gyrase.4 Figure 3. Naturally occurring 3-aminocoumarin derivatives Occurrence of 3-aminocoumarins derivatives in nature and their biological significance suggest that various new fused 3-aminocoumarin derivatives may show interesting biological activities.  I.4. Synthesis of Pyridocoumarins and Pyrrolocoumarins Pyridocoumarins and pyrrolocoumarins are important organic moieties. Pyridocoumarins have been found to possess anti-tumor, anti-bacteria and anti-inflammatory activities.15 Pyrroles are the part of many naturally occurring marine alkaloids.16 Moreover, coumarin fused pyrroles are the basic core of the biologically active alkaloids Ningalin B and Lamerallin D. Various groups have TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 4 synthesized these compounds to study their biological activities.17 Some of the methods for the synthesis of coumarin fused pyridines and pyrroles, have been discussed in this section.  I.4.1 Synthesis of Pyridocoumarins There are several routes for the synthesis of pyridocoumarins starting from substituted pyridine derivatives, substituted coumarins, and the condensation of salicylaldehydes and β-ketoesters. Recently, in some of the reports Aza Diel Alder reactions have been used to synthesize coumarin fused pyridine derivatives. Some of the reported methods for the synthesis of pyridocoumarins are listed below. Petrov et al. achieved pyridocoumarin derivatives by the cyclization of 4-(2-methoxyphenyl)- pyridine derivatives on heating in presence of 48% HBr as shown in Scheme 1.18 Scheme 1 O'Callaghan, accomplished the synthesis of coumarin fused pyridine derivatives by the oxidation of 2-(2-hydroxyphenyl)-l,2-dihydropyridines with con. HNO3 as depicted in Scheme 2. 19 Scheme 2 Koelesch and co-workers demonstrated the condensation of 3-acetylcoumarin, cynoacetamides and ketones leading to the formation of a number of pyrido(3,2-c)derivatives with 21-64% yields where the cynoacetamide was used as source of ammonia for the synthesis of the chromenone derivatives as represented in Scheme 3.20 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 5 Scheme 3 Buu-Hoi and co-workers reported the synthesis of pyrido(3,2-c)coumarin derivatives by the condensation of 4-hydroxycoumarin, arylamines and paraformaldehydes. 4-Hydroxycoumarin undergoes Ullmann-Fetvadjian-type condensation with the arylamines and para formaldehyde to generate pyrido(3,2-c)coumarin derivatives. Apart from aniline, various other arylmines like α- naphthylamine, β-naphthylamine, 5-amino-3-phenylthianaphthene, 4-aminofluorene and 5- amino-8-methylquinoline were used for the synthesis of structurally complex pyrido(3,2- c)coumarins. The pyridocoumarin was also obtained in good yield using the imine and 4- hydroxycoumarins as described in Scheme 4.21 Scheme 4 Joshi et al. reported that 4-hydroxycoumarin, on heating with AcONH4/AcOH gives the corresponding 4- aminocoumarin, without further purification, on addition of malondialdehydes into the same pot, pyrido(3,2)coumarin derivatives were obtained in 59-65% yield, shown in Scheme 5.22 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 6 Scheme 5 O'Callaghan described that when salicylaldehyde is condensed with a mixture of β-ketoester, AcOH with 30% aq.NH3 and EtOH, the dihydropyridine is formed which on oxidation with CrO3 provides the pyridocoumarin as represented in Scheme 6.19 Scheme 6 Palacios et al. synthesized the azadienes from Wittig reaction of N-vinylphosphazenes and corresponding allyloxy/propargyloxybenzaldehydes. The azadienes on heating at 140 °C undergo Aza Diels Alder reaction to give pyridine derivatives which on oxidation provide the pyridocoumarins as shown in Scheme 7.23 Scheme 7 Recently Balci et al. used propargylated salicylaldehydes and propargylamines in presence of DBU to obtain the chromene derivatives. The reaction takes place through an Aza Diel alder reaction of the imine formed from propargylated salicylaldehyde and the propargylamine forming TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 7 a chromenopyridine derivative which on further oxidation with CrO3 gives the corresponding pyridocoumarin derivative (Scheme 8).24 Scheme 8 Brahmbhatt et al. synthesized the pyridocoumarin derivatives via one pot three component reaction of the Manich base (3-amino-4-hydroxy coumarin derivatives), pyridinium salts and ammoniumacetate in refluxing glacial acetate as described in Scheme 9.25 Scheme 9  I.4.2. Synthesis of Pyrrolocoumarins There are numerous methods reported in literature for the synthesis of pyrroles but only very few methods are available for the synthesis of pyrrolocoumarins. Amongst the reported methods traditional as well as some transition metal catalyzed annulation reaction have been found in literature for the synthesis of pyrrolocoumarins. Some of the reported methods are described in the following section. TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 8 In 1987, Takagi et al. synthesized the pyrrolocoumarin derivative from 2-methyl-3- nitrochromenone and ethyl aminoethanoate in the presence of EtOH/KOH under reflux conditions. The nitro pyrrolocoumarin thus formed gaves 1-amino-2-methylchromeno[3,4-b]pyrrol-4(3H)- one in 44% yield on reduction with H2/Pd in EtOH as shown in Scheme 10. 26 Scheme 10 Langer et al. developed the synthesis of various chromeno[3,4-b]pyrrol-4(3H)-ones via base mediated cyclocondensation of 4-choloro-3-nitrocoumarin and beta-diketone. The reaction between 4-choloro-3-nitrocoumarin and beta-diketone in the presence of K2CO3 as base in DMF at 20 oC gives a condensed product which on reduction followed by cyclization affords the coumarin fused pyrrole as represented in Scheme 11.27 Scheme 11 Wang et al. demonstrated the synthesis of pyrrolocoumarin derivatives from 4- aminocoumarins and substituted acetylene derivatives via C-H activation employing Pd(OAc)2 as catalyst and Cu(OAc)2 as oxidant at room temperature as shown in Scheme 12. 28 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 9 Scheme 12 In another work, Langer and coworkers synthesized various pyrrolocoumarins by Pd catalyzed C-N bond formation. A number of chromeno[3,4-b]pyrrol-4(3H)-ones were reported from the alkynylated bromocoumarins which were synthesized by the Sonogashira reaction between, the coumarin bearing triflate and bromide group and the terminal alkynes, shown in Scheme 13.29 Scheme 13 Das and coworkers developed the synthesis of coumarin fused pyrrole derivatives using 4- aminocoumarin and nitroalkenes employing PEG-SO3H as a catalyst in refluxing MeOH as depicted in Scheme 14. They also showed that the product can also be achieved using a multicomponent strategy where 4-aminocoumarin, aldehyde and nitromethan were mixed together and CuFe2O4 was used as a catalyst. 30 Scheme 14  I.5. 3-Aminocoumarins in Organic Synthesis This section of the chapter describes various methodologies for the synthesis of 3-aminocoumrains and the use of 3-aminocoumarins for the synthesis of pyridocoumarins and pyrrolocoumarins.  I.5.1. Synthesis of 3-Aminocoumarins TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 10 There are several methods reported in the literature for the synthesis of 3-amincoumarins, all having their own merits and demerits. Some of them have been summarized in this section as follow. Bonsignore et al. synthesized various 3-aminocoumarin derivatives treating coumarin-3- carboxylic acids with triethylamine, diphenylphosphorylazide (DPPA) in t-butylalcohol to obtain tert-butyl (2-oxo-2H-chromen-3-yl)carbamates, which were transformed to the corresponding 3- aminocoumarins on treatment with gaseous HCl as described in Scheme 15.31 Scheme 15 Khoo and co-workers synthesized various 3-aminocoumarin derivatives by the condensation of salicylaldehydes and ethyl glycinate hydrochloride followed by heating of the ethyl N- hydroxyarylideneglycinates formed, at 150-170 °C (Scheme 16) 32 Scheme 16 Valizadeh et al. reported the synthesis of various 3-aminocoumarins from salicylaldehydes and benzylglycine, catalyzed by piperidine under microwave and solvent-free condition. Initially, salicylaldehydes react with benzoylglycine under microwave condition in presence of piperidine forming N-benzoylaminocoumarins which subsequently on acid hydrolysis in the next step give the 3-aminocoumarins shown in Scheme 17.33 Scheme 17 Bodwell et al. reported the synthesis of 3-aminocoumarins starting from 3- acetamidocoumarins which in turn were prepared from salicylaldehydes and N-acetylglycine. The TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 11 3-acetamidocoumarins were further converted to Boc-protected 3-aminocoumarins in the presence of DMAP and Boc-anhydride followed by reaction with hydrazine hydrate to remove the acetyl group. The Boc-protected 3-aminocoumarins were then deprotected to give 3-aminocoumarins through the action of 15% TFA/CHCl3 as depicted in Scheme 18. 34 Scheme 18 Alami et al. established the synthesis of different 3-aminocoumarins starting from 3- bromocoumarins via copper catalyzed C−N bond formation reactions in EtOH. They used pipecolinic acid as the ligand, ascorbic acid as the additive and NaN3 the source of nitrogen for the synthesis of various 3-aminocoumarins as shown in Scheme 19.35 Scheme 19 Proenca et al. synthesized 3-Aminocoumarines from the Zincke-ring opening reaction of the corresponding 2H-chromen-3-pyridinium chlorides using N-methylpiperazine. The 2H-chromen- 3-pyridinium chlorides were prepared by base-catalyzed Knoevenagel condensation of salicylaldehydes and 1-(cyanomethyl)pyridinium chloride followed by hydrolysis with 37 % HCl at 80 °C as shown in Scheme 20.36 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 12 Scheme 20 Our group has also developed a mild an efficient approach to access various 3-aminocoumarin derivatives. The 3-acetamidcoumarins synthesized from a Bidwell’s reported method, were hydrolyzed with 70% (w/w) H2SO4 to afford the corresponding 3-aminocoumarins in good to excellent yields with a large number of substrate scopes. The hydrolysis step was achieved in just 30 minutes when the reaction was carried out in 5 mmol scale (Scheme 21).37 Scheme 21  I.5.2. Synthesis of Fused Heterocycles Exploring 3-Aminocoumarins The 3-aminocoumarin moiety is not much explored for construction of heterocycles. However, there are some reports where 3-aminocoumarins and its derivatives have been used for the synthesis of fused heterocycles including the synthesis of coumarin fused pyridines and dihydropyridines from our own group. Xu et al. reported an straight forward synthesis of various pyrrolocoumarins derivatives by palladium catalyzed cyclization of acetylenyl 3-aminocoumarins (Scheme 22).38 Scheme 22 Soman et al. synthesized the pyrrolocoumarins from 3-acetamidocoumarins obtained from α- haloketones and 3-aminocoumarins using catalytic amount of TFA in AcOH (Scheme 23).39 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 13 Scheme 23 Majumdar et al. reported a multicomponent approach for the synthesis of coumarin fused 2- aminothiazole derivatives from 3-amino-4-bromocoumarin and secondary amines using CS2 in the presence of FeCl3 as catalyst in DMSO as shown in Scheme 24. 40 Scheme 24 Skraupe synthesis is a very familiar reaction to access quinolone derivatives. Khan et al. used this method for synthesizing pyrido(2,3-c)coumarin using 3-aminocoumarin as source of amine, glycerol, arsenic pentoxide and H2SO4 at 170 °C as shown in Scheme 25.41 Scheme 25 Povarov reaction has been a very useful tool for the synthesis of dihydrorpyridine and pyridine derivatives. The reaction has also been extended for the synthesis of coumarin fused dihydropyridine and pyridine derivatives. Bodwell et al. reported the synthesis of pyridocoumarins using Povarov reactions from 3-aminocoumarins, aldehydes and electron rich olefins in one pot three component reactions in the presence of Yb(OTf)3 as catalyst. Initially, the 1,2,3,4- tetrahydropyrido(2,3-c)coumarins are formed, which on oxidation with Br2 give the corresponding pyrido(2,3-c)derivatives shown in Scheme 26.42 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 14 Scheme 26 Our group has been working on 3-aminocoumarin for long time. Various pyridcoumarins and coumarin fused dihydropyridines were reported using 3-aminocoumarin as one of the starting material. The synthesis of pyrido(2,3-c)coumarin derivatives was reported in 72-94% yield by one pot three components reaction using 3-aminocoumarins, aldehydes and phenylacetylene as electron rich dienophile in the presence of I2 as catalyst in CH3CN under reflux conditions as described in Scheme 27.43 Scheme 27 A number of tetrahydropyrido(2,3-c)coumarin derivatives were synthesized from 3- aminocoumarins and aldehyde employing dihdrofuran as the electron rich dienophile using TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 15 Fe2(SO4)3 .x H2O as the catalyst. Two diastreomers endo-exo and endo-endo were reported where endo-exo was the major products (Scheme 27).44 In another Povarov reaction, dihyropyridine derivatives were applied as electron rich dinophile and Yb(OTf) as catalyst. Various tetrahydropyrido(2,3-c)coumarin derivatives were synthesized in good yield. Moreover, in this case only a single diastreomers were obtained (Scheme 27)45 Several coumarin fused dihydropyridine derivatives were achieved via Michael Initiated ring closure reaction using PTSA.H2O as catalyst. The three component reaction of 3-aminocoumarins, aldehyde and 1,3-cyclic diketons in the presence of PTSA.H2O and EtOH as solvent in reflux conditions gave a number of coumarin fused dihydroquinoline derivatives. The reaction was believed to proceed through Knoevengel condensation of the aldehyde and 1,3-cyclic diketones followed Michel addition of 3-aminocoumarin shown in Scheme 28.46 Scheme 28 Chan and co-workers demonstrated the synthesis of pyrido(2,3-c)coumarin derivatives by one pot three component reactions of 3-aminocoumarin, aromatic aldehyde and ketones in the presence of methansulphonic acid as catalyst in acetonitrile solvent in reflux conditions as depicted in Scheme 29.47 The reaction was a demonstration of inverse Diels Ader reaction to synthesize pyridocoumarins. Scheme 29 TH-1700_126122027 Chapter I Introduction: Pyridocoumarins, Pyrrolocoumarins, 3-Aminocoumarins 16 From the literature survey, it reveals that synthesis of pyridocoumarins and pyrrolocoumarins are not much explored. Some of the existing methods for their synthesis have very limited substrate scopes whereas the reaction conditions are very tedious in other cases. Moreover, there are very few reports where 3-aminocoumarin has been used to achieve pyridocoumarins and pyrrolocoumarins. Therefore, the research topic is chosen to explore 3-aminocoumarins for further construction of pyridocoumarins and pyrrolocoumarins having 3-aminocoumarin as the backbone. The next two chapters of the thesis namely Chapter IIA and IIB gives an account of the synthesis of various pyridocoumarins whereas chapter III describes the synthesis of pyrrolocoumarins, using 3-aminocoumarins as one of the starting material. TH-1700_126122027 CHAPTER IIA Synthesis of Pyrido(2,3-c)coumarin Derivatives by an Intramolecular Povarov Reaction RESULTS AND DISCUSSION TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 17  Results and Discussion The importance of 3-aminocoumarins as well as the synthesis of pyridocoumarins from aminocoumarins has been discussed in the previous chapter. The synthesis of pyridocoumarin from 3-aminocoumarin through inter molecular povarov reaction was reported from our group earlier.43 In this chapter, the synthesis of pyridocoumarins via intra molecular Povarov reaction from 3- aminocoumarins and propargylated salicylaldehydes is discussed. Previously, Bodwell and co- workers reported the synthesis of pyridocoumarin using 3-aminocoumarin and propargylated salicylaldehyde using Yb(OTf)3 and obtained 47 % yield in 9 days of heating. 48 Therefore, there was further scope for the synthesis of pyridocoumarin using 3-aminocoumarin in lesser time via intramolecular the Povarov reaction. TfOH as a catalyst has been reported by various group to achieve Povarov reaction.49 In this chapter of the thesis, the synthesis of pyridocoumarins by an intramolecular Povarov reaction using 3-aminocoumarins and propargylated salicylaldehydes employing TfOH as a catalyst is discussed (Scheme 30). Scheme 30. Synthesis of pyrido(2,3-c)coumarin derivatives The reaction was started with a mixture of 3-aminocoumarin (1a, 0.5 mmol) and 2- (propargyloxy)benzaldehyde (2a, 0.5 mmol) in presence of 5 mol% of TfOH in acetonitrile (3 mL) under reflux condition. A solid product precipitated out during the progress of the reaction and it was filtered and washed with a mixture of solvent such as ethyl acetate and hexane mixture (1:10). The light greenish solid compound was obtained in 56% yield and characterized by NMR, IR spectra and HRMS. The compound was found to be 3a (Table 1), characterized by the IR absorption peak of the lactone ring at 1738.84 cm-1, two singlet in the H1 NMR spectrum at δ 8.14 and 5.39 ppm characteristic of the C-CH= proton of the pyridine ring and OCH2- protons respectively (see page no. 33 for NMR spectra of compound 3a) and the HRMS peak at 302.0812. Later on, several reactions were performed to obtain the optimized reaction conditions. It was noted that the yield of the product was increased significantly to 77% by increasing the amount of catalyst from 5 mol% to 10 mol% whereas excess loading of the catalyst (15 mol %) decreased TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 18 the yield to 72% (Table 1, entry 2-3). The same reaction was unsuccessful when it was carried out at room temperature (Table 1, entry 4). To find out a suitable solvent system, the similar reactions were examined in various solvent systems such as ethanol, dichloroethane (DCE), toluene, DMF and DMSO under reflux conditions, respectively (Table 1, entries 5-9). It was noted that the shortest reaction time and best yield are obtained in acetonitrile (Table 1, entry 2) under reflux conditions. To examine the efficacy of TfOH as compared to other catalysts, several reactions were also performed in the presence of catalysts such as PTSA, I2, InCl3 and CuI, respectively (Table 1, entries 10-13). These catalysts provided lower yields and required longer reaction times. After optimization of the reaction conditions, it was found that the best yield is obtained in triflic acid as a catalyst in acetonitrile solvent. Notably, yield was very low when the reaction was carried out without any catalyst under reflux condition (Table 1, entry 14). Table 1. Optimization of reaction conditiona Entry Catalyst (mol %) Solvent Time (h) Yieldb (%) 1 TfOH (5) CH3CN 3 56 2 TfOH (10) CH3CN 3 77 3 TfOH (15) CH3CN 3 72 4c TfOH (10) CH3CN 24 NR 5 TfOH (10) EtOH 24 NR 6 TfOH (10) DCE 24 12 7 TfOH (10) Toluene 24 17 8 TfOH (10) DMF 24 NR 9 TfOH (10) DMSO 24 NR 10 p-TSA (10) CH3CN 24 60 11 I2 (10) CH3CN 24 25 12 InCl3 (10) CH3CN 24 54 13 CuI (10) CH3CN 24 32 14 No catalyst CH3CN 24 20 aAll the reactions were performed with 3-aminocoumarin 1a (0.5 mmol) and 2-(propargyloxy)benzaldehyde 2a (0.5 mmol) in 3 mL of solvent under reflux condition. bIsolated yield. croom temperature, NR = no reaction TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 19 Next, a mixture of 5-methoxy-2-(prop-2-yn-1-yloxy)benzaldehyde and 3-aminocoumarin under identical reaction conditions gave the desired product 3b in 71% yield (Table 2). To explore the synthetic scope further and the generality of the present protocol, various reactions were examined with other O-propargylated salicylaldehydes containing substituents in the aromatic ring such as Br, NO2 and Cl respectively with 3-aminocoumarin (1a). The reaction time and percentage yield of the products (3c-e) are shown in Table 2. For verifying the generality of the present method, other substituted 3-aminocoumarins such as 6-methoxy-3-aminocoumarin, 8-methoxy-3- aminocoumarin and 8-ethoxy-3-aminocoumarin were also scrutinized with O-propargylated salicylaldehydes under identical reaction conditions and the desired pyrido(2,3-c)coumarin derivatives 3f-n were obtained in good yields (Table 2). It was noted that O-propargylated salicylaldehydes containing electron withdrawing group provided better yield (Table 2, entries 3c- e, 3h, 3k, 3m and 3n) as compared to O-propargylated salicylaldehydes having electron donating group in the present reaction. Interestingly, the substituents of R1 in 3-aminocoumarin did not significantly affect the reaction and the yields of the products were remarkably similar (Table 2, entries 3a, 3f, 3i, 3o, 3p and 3q). The reactions occurred smoothly with 3-aminocumarin derivatives having Br, NO2, and Cl electron- withdrawing groups on it. In case with the NO2 substituent, the yield is comparatively low (62%, 3o, Table 2) Table 2. Scope of various propargylated aldehydes and 3-aminocoumarins a,b TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 20 aAll the reactions were performed with 3-aminocoumarins 1 (0.5 mmol) and 2-(propargyloxy)benzaldehydes 2 (0.5 mmol) in 3 mL of CH3CN in the presence of 10 mol% TfOH under reflux condition. bIsolated yield Compound 3a (CCDC number 981642) Compound 3l (CCDC 1003777) Figure 4.Crystallographic structure of 3a and 3l It is worthwhile to mention that the pure product was separated by filtration and washing with ethyl acetate and hexane mixture (1:10). After washing, the catalyst triflic acid goes into the filtrate and the pure unprotonated pyrido(2,3-c)coumarin derivatives were easily accomplished. The structures of products 3a-q were determined from their usual spectroscopic data. In its IR TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 21 spectra, it showed characteristic absorption peaks between 1729-1753 cm–1 due to lactone carbonyl group. The characteristic peaks for 3a-q in the 1H NMR spectra are two singlets for the –OCH2 protons between δ = 4.60-5.74 ppm and for C-CH= proton of pyridine ring at 14 position of the product at δ = 8.02–9.07 ppm (see pages 23-32 for NMR, IR and HRMS data). The structure of the representative compounds such 3a and 3l were also confirmed unambiguously by single crystal X-ray analysis (Figure 4). A probable mechanism for the intramolecular Povarov reaction for the synthesis of pyrido(2,3- c)coumarin derivatives is depicted in Scheme 31. The first step is the condensation reaction between 3-aminocoumarin (1) and O-propargylated salicylaldehyde (2) leading to the formation of intermediate imines A, which on protonation undergoes cyclization via intramolecular Povarov reaction to afford pyrido(2,3-c)coumarin derivatives 3 through the intermediate dihydropyridine D, followed by aerial oxidation as shown in Scheme 31. Scheme 31. Plausible reaction mechanism for the formation of 3 TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 22 In summary, an efficient and expedient protocol for the synthesis of pyrido(2,3-c)coumarin derivatives has been illustrated involving 2-(propargyloxy) benzaldehyde derivatives and 3- aminocoumarins using triflouromethanesulfonic acid (TfOH) as catalyst in acetonitrile. No co- oxidant was required for aromatization of the desired products. The reaction methodology is simpler, requires lesser time and the products are easily isolable without column chromatography and aqueous work up. TH-1700_126122027 CHAPTER IIA Synthesis of Pyrido(2,3-c)coumarin Derivatives by an Intramolecular Povarov Reaction EXPERIMENTAL SECTION TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 23  Experimental Section General procedure for the synthesis of pyrido(2,3-c)coumarin derivatives: Into a 25mL round bottomed flask was taken a mixture of 3-aminocoumarin (0.5 mmol) and propargylated salicylaldehyde (0.5 mmol) in 3 mL of CH3CN. Then 10 mol% triflic acid was added into it and the reaction mixture was refluxed in a preheated oil bath. The progress of the reaction was monitored by checking TLC time to time. Towards the end of the reaction, a solid precipitate starts appearing slowly after specified time as mentioned in the Table 2. The reaction flask was then removed from the oil-bath and it was brought to room temperature for complete precipitation. The solid precipitate was just filtered off through a Büchner funnel and it was washed with cold 10 mL of hexane-ethyl acetate mixture (10:1) to remove unreacted starting materials. Finally, it was dried through a vacuum pump and the pure product pyrido(2,3-c)coumarin derivatives 3a-q was obtained in 65-89% yield. Dichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3a): IR (KBr): 3078.49, 2959.14, 2848.11, 1738.84, 1606.39, 1235.89, 1090.80, 1052.83, 1037.76, 1013.21 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.47 (dd, J = 9.0, 1.2 Hz, 1 H), 8.14 (s, 1 H), 7.98 (t, J = 1.2 Hz, 1 H), 7.52 (m, 1 H), 7.38 (m, 3 H), 7.13 (t, J = 7.2 Hz, 1 H), 6.98 (d, J = 8.4 Hz, 1 H), 5.39 (s, 2 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 158.6, 150.7, 149.4, 136.7, 136.0, 133.6, 132.6, 131.7, 131.3, 126.7, 126.1, 124.1, 123.7, 118.7, 118.4, 117.0, 115.0, 67.6 ppm. HRMS (ESI) calcd for C19H11NO3 (M + H +) = 302.0812, found 302.0812. Elemental Analysis Calculated Found MF C19H11NO3 C 75.74 75.92 (301.30) H 3.68 3.60 N 4.65 4.54 Reaction Time: 3.0 h Colour & State: pale green solid Yield: 77% (166 mg) Melting Point: 230 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 24 9-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3b): IR (KBr): 2995.32, 2844.80, 1734.06, 1609.45, 1237.79, 1092.55, 1040.81, 1018.93 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.79 (s, 1 H), 8.31 (t, J = 7.8 Hz, 1 H), 7.41 (d, J = 3 Hz, 1 H), 7.63 (m, 1 H), 7.47 (dd, J = 14.4, 7.8 Hz, 2 H), 7.04 (m, 2 H), 5.43 (s, 2 H), 3.84 (s, 3 H).ppm. 13C NMR (100 MHz, CDCl3: TFA = 4:1): δ 156.4, 156.1, 154.8, 151.0, 148.1, 137.9, 135.0, 134.6, 133.6, 128.3, 127.7, 127.4, 124.0, 120.9, 116.2, 113.9, 113.7, 107.4, 67.4, 56.4 ppm. HRMS (ESI) calcd for C20H13NO4 (M + H +) = 332.0917, found 332.0918. Elemental Analysis Calculated Found MF C20H13NO4 C 72.50 72.32 (331.33) H 3.95 3.90 N 4.23 4.13 9-Bromodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3c): IR (KBr): 3092.37, 2909.18, 2853.66, 1748.32, 1606.15, 1235.66, 1091.97, 1051.54, 1009.40 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.82 (s, 1 H), 8.30 (dd, J = 8.4, 7.8 Hz, 2 H), 7.62 (m, 2 H), 7.47 (t, J = 6.6 Hz, 2 H), 7.07 (d, J = 8.4 Hz, 1 H), 5.54 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 159.0, 156.5, 151.3, 147.1, 142.3, 137.9, 135.8, 135.6, 134.5, 128.5, 127.8, 124.3, 121.4, 119.0, 115.1, 67.4 ppm. HRMS (ESI) calcd for C19H10BrNO3 (M + H +) = 379.9917, found 379.9917. Elemental Analysis Calculated Found MF C19H10BrNO3 C 60.02 59.81 Reaction Time: 3.0 h Colour & State: pale green solid Yield: 71% (118 mg) Melting Point: 300 °C Reaction Time: 3.0 h Colour & State: white solid Yield: 79% (150 mg) Melting Point: 230 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 25 (380.20) H 2.65 2.61 N 3.68 3.54 9-Nitrodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3d): IR (KBr): 3077.41, 2917.50, 1744.31, 1621.26, 1245.60, 1092.38, 1046.70, 1015.68 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 9.00 (d, J = 2.4 Hz, 1 H), 8.87 (s, 1 H), 8.31 (m, 2 H), 7.66 (m, 1 H), 7.49 (t, J = 7.8 Hz, 2 H), 7.30 (d, J = 9 Hz, 1 H), 5.74 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 163.4, 151.0, 147.6, 143.4, 135.7, 134.7, 134.5, 132.7, 132.2, 131.1, 127.5, 124.1, 122.7, 120.4, 118.8, 114.8, 68.2 ppm. HRMS (ESI) calcd for C19H10N2O5 (M + H +) = 347.0662, found 347.0662. Elemental Analysis Calculated Found MF C19H10N2O5 C 65.90 65.80 (346.30) H 2.91 2.87 N 8.09 7.99 9-Chlorodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3e): IR (KBr): 3085.37, 3060.74, 2918.40, 2847.23, 1749.88, 1602.43, 1234.48, 1088.33, 1051.54, 1008.03 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.82 (s, 1 H), 8.31 (t, J = 7.8 Hz, 1 H), 8.15 (d, J = 2.4 Hz, 1 H), 7.64 (dd, J = 8.4, 1.8 Hz, 1 H), 7.49 (m, 3 H), 7.13 (d, J = 8.4 Hz, 1 H), 5.54 (s, 2 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 158.3, 151.2, 147.4, 139.1, 138.9, 135.4, 135.3, 134.4, 130.7, 127.6, 125.5, 124.2, 121.1, 121.1, 118.9, 111.8, 67.7 ppm. HRMS (ESI) calcd for C19H10ClNO3 (M + H +) = 336.0422, found: 336.0425. Reaction Time: 3.0 h Colour & State: white solid Yield: 85% (147 mg) Melting Point: > 300 °C Reaction Time: 4.0 h Colour & State: pale green solid Yield: 78% (131 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 26 Elemental Analysis Calculated Found MF C19H10ClNO3 C 67.97 68.13 (335.74) H 3.00 3.07 N 4.17 4.08 2-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3f): IR (KBr): 2992.58, 1741.46, 1604.16, 1242.57, 1084.55, 1043.89, 1007.40 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.23 (dd, J = 7.8, 1.2, Hz, 1 H), 7.79 (d, J = 3.0 Hz, 1 H), δ 7.43 (m, 1 H), 7.40 (d, J = 9.6 Hz, 1 H), 7.20 (m, 2 H), 7.07 (d, J = 8.4 Hz, 1 H), 5.49 (s, 2 H), 3.89 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3: TFA = 4:1): δ 160.0, 158.2, 156.0, 148.0, 145.4, 139.70, 137.8, 135.8, 133.5, 127.5, 126.1, 124.8, 122.1, 119.9, 119.6, 114.3, 107.3, 67.5, 56.5 ppm. HRMS (ESI) calcd for C20H13NO4 (M + H +) = 332.0917, found 332.0918. Elemental Analysis Calculated Found MF C20H13NO4 C 72.50 72.41 (331.33) H 3.95 3.88 N 4.2 3.90 2,9-Dimethoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3g): IR (KBr): 3069.20, 2448.79, 1736.21, 1227.22, 1083.88, 1040.66, 1020.15 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.02 (s, 1 H), 6.96 (d, J = 3.0 Hz, 1 H), δ 6.87 (d, J = 3.0 Hz, 1 H), 6.58 (d, J = 9.0 Hz, 1 H), 6.37 (dd, J = 9.0, 2.4, Hz, 1 H), 6.22 (m, 2 H), 4.60 (s, 2 H), 3.07 (s, 3 H), 3.00 (s, 3 H) ppm. Reaction Time: 3.0 h Colour & State: yellowish solid Yield: 75% (125 mg) Melting Point: 280 °C Reaction Time: 5.0 h Colour & State:yellowish solid Yield: 65% (118 mg) Melting Point: 265 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 27 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 158.7, 156.7, 156.8, 155.7, 148.2, 145.7, 138.6, 136.1, 129.6, 126.9, 122.5, 121.5, 120.3, 114.5, 113.3, 107.9, 107.6, 67.9, 56.8, 56.7 ppm ppm. HRMS (ESI) calcd for C21H15NO5 (M + H +) = 362.1023, found: 362.1024. Elemental Analysis Calculated Found MF C21H15NO5 C 69.80 69.71 (361.35) H 4.18 4.15 N 3.88 3.70 9-Bromo-2-methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3h): IR (KBr): 2929.64, 2853.01, 1729.44, 1222.74, 1084.50, 1048.64, 1032.07 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.88 (s, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 7.80 (d, J =3 Hz, 1 H), 7.62 (dd, J = 7.8, 2.4 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 1 H), 7.21 (dd, J = 8.4, 2.4 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 5.54 (s, 2 H), 3.9 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3: TFA = 4:1): δ 158.0, 157.8, 148.0, 145.2, 139.8, 136.1, 133.2, 132.5, 128.4, 121.2, 120.7, 119.8, 118.8, 116.0, 107.0, 67.6, 56.4 ppm. HRMS (ESI) calcd for C20H12BrNO4 (M + H +) =; 410.0022, found 410.0022. Elemental Analysis Calculated Found MF C20H12BrNO4 C 58.56 58.51 (410.22) H 2.95 2.90 N 3.41 3.32 4-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3i): Reaction Time: 5.0 h Colour & State: pale green solid Yield: 81% (166) mg Melting Point: MP > 300 °C Reaction Time: 1.0 h Colour & State: brown solid Yield: 79% (131 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 28 IR (KBr): 3011.74, 2836.59, 1741.48, 1615.06, 1246.52, 1070.59, 1030.81 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.76 (s, 1 H), 8.24 (dd, J = 7.8, 1.8 Hz, 1 H), 7.84 (d, J = 7.2 Hz, 1 H), 7.46 (dd, J = 8.4, 1.8 Hz, 1 H), 7.40 (t, J = 8.4 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.20 (dd, J = 7.8, 1.2 Hz, 1 H), 7.07 (d, J = 8.4 Hz, 1 H), 5.50 (s, 2 H), 3.94 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 160.0, 155.7, 148.4, 148.2, 140.7, 139.7, 137.7, 135.5, 133.8, 127.6, 125.9, 124.9, 119.6, 117.6, 116.6, 114.9, 114.6, 67.2, 56.8 ppm. HRMS (ESI) calcd for C20H13NO4 (M + H +) = 332.0917; found 332.0917. Elemental Analysis Calculated Found MF C20H13NO4 C 72.50 72.32 (331.33) H 3.95 3.90 N 4.23 4.13 4, 9-Dimethoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3j): IR (KBr): 2992.58, 2926.90, 1739.13, 1613.76, 1245.06, 1085.53, 1073.13, 1036.77 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.76 (s, 1 H), 7.83 (t, J = 7.8 Hz, 1 H), 7.77 (d, J = 3.0 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 1 H), 7.03 (m, 2 H), 5.43(s, 2 H), 3.95 (s, 3 H), 3.83 (s, 3 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 156.6, 155.8, 155.6, 148.5, 148.2, 140.8, 138.5, 135.9, 134.3, 129.4, 128.0, 126.8, 121.4, 117.1, 115.2, 114.5, 107.3, 67.4, 56.9, 56.6 ppm. HRMS (ESI) calcd for C21H15NO5 (M + H +) = 362.1023; found 362.1030. Elemental Analysis Calculated Found MF C21H15NO5 C 69.80 69.72 (361.35) H 4.18 4.09 N 3.88 3.73 Reaction Time: 1.0 h Colour & State: yellowish brown solid Yield: 77% (140 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 29 9-Bromo-4-methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3k): IR (KBr): 3069.20, 2844.80, 1733.96 1617.09, 1241.82, 1080.99, 1071.88, 1047.79 cm -1. 1HNMR (600 MHz, DMSO-d6): δ 8.79 (s, 1 H), 8.29 (d, J = 2.4 Hz, 1 H), 7.84 (d, J = 7.8 Hz, 1 H), 7.62 (dd, J = 9.0, 3.0, Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), δ 7.07(d, J = 8.4 Hz, 1 H), 5.40 (s, 2 H), 3.95 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 158.2, 157.4, 148.3, 147.9, 140.5, 136.7, 134.1, 134.0, 130.1, 128.6, 127.4, 120.9, 117.0, 116.2, 115.3, 115.1, 67.8, 56.8 ppm. HRMS (ESI) calcd for C20H12BrNO4 (M + H +) = 410.0022, found: 410.0024. Elemental Analysis Calculated Found MF C20H12BrNO44 C 58.56 58.49 (410.22) H 2.95 2.89 N 3.41 3.38 4-Ethoxy-9-methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3l): IR (KBr): 2981.60, 2841.33, 1737.72, 1618.16, 1065.17, 1036.38, 1022.78 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.74 (s, 1 H), 7.81 (d, J = 7.8 Hz, 1 H), 7.70 (d, J = 2.4 Hz, 1 H), 7.37 (t, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.8 Hz, 1 H) 7.04 (m, 2 H), 5.42 (s, 2 H), 4.2 (q, J = 6.6 Hz, 2 H), 3.84 (s, 3H), 1.44 (t J = 6.6, 3 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 156.5, 156.2, 154.4, 148.6, 147.8, 140.8, 137.2, 134.0, 133.5, 128.8, 127.7, 127.2, 120.6, 117.1, 115.1, 114.9, 114.7, 107.3, 67.6, 65.9, 56.4, 14.6 ppm. HRMS (ESI) calcd for C22H17NO5 (M + H +) = 376.1179, found 376.1187. Reaction Time: 1.0 h Colour & State: silvery white solid Yield: 88% (181 mg) Melting Point: > 300 °C Reaction Time: 5.0 h Colour & State: pale green solid Yield: 67% (126 mg) Melting Point: 279 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 30 Elemental Analysis Calculated Found MF C22H17NO56 C 70.39 70.32 (375.38) H 4.56 4.52 N 3.73 3.60 4-Ethoxy-9-nitrodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3m): IR (KBr): 3093.83, 2987.11, 1739.92, 1618.85, 1246.42, 1065.43, 1049.12, 1000.97 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.98 (d, J = 2.4 Hz, 1 H), 8.82 (s, 1 H), 8.30 (dd, J = 8.4, 2.4, Hz, 1 H), 7.82 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.8 Hz, 1 H), 7.31 (d, J = 9.0 Hz, 1 H), 7.29 (d, J = 9.0 Hz, 1 H), 5.72 (s, 2 H), 4.21 (q, J = 6.6 Hz, 2 H), 1.45 (t, J = 6.8, 3 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 162.7, 148.4, 147.5, 143.2, 140.5, 134.5, 134.3, 133.8, 130.6, 130.4, 129.7, 127.0, 122.4, 119.7, 116.5, 114.9, 68.4, 66.1, 14.3 ppm. HRMS (ESI) calcd for C21H14N2O6 (M + H +) = 391.0925, found 391.0930. Elemental Analysis Calculated Found MF C21H14N2O6 C 64.62 64.56 (390.35) H 3.62 3.58 N 7.18 7.01 9-Bromo-4-ethoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3n): IR (KBr): 3080.15, 2981.63, 1744.57, 1244.35, 1098.22, 1065.12, 1048.66 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.77 (s, 1 H), 8.28 (d, J = 2.4 Hz, 1 H), 7.81 (d, J = 7 8 Hz, 1 H), 7.61 (dd, J = 9.0, 2.4, Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.29 (d, J = 7.8 Hz, 1 H), 7.06 (d, J = 9.0 Hz, 1 H), 5.53 (s, 2 H), 4.20 (q, J = 6.6 Hz, 2 H), 1.44 (t, J = 6.6 Hz, 3 H) ppm. Reaction Time: 4.0 hrs. Colour & State: white solid Yield: 89% (174 mg) Melting Point: > 300 °C Reaction Time: 5.0 h Colour & State: white solid Yield: 82% (175 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 31 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 157.8, 147.6, 140.6, 140.2, 139.8, 133.7, 128.6, 128.5, 127.3, 127.2, 120.8, 120.7, 117.2, 117.0, 116.9, 114.9, 111.8, 67.9, 66.1, 14.5 ppm. HRMS (ESI) calcd for C21H14BrNO4 (M + H +) = 426.0159; found 426.0162. Elemental Analysis Calculated Found MF C21H14BrNO4 C 59.45 59.40 (424.25) H 3.33 3.25 N 3.30 3.15 2-Nitrodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3o): IR (KBr): 2923.78, 2853.38, 1753.43, 1600.79, 1249.46, 1044.75, 1016.08 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 9.17 (d, J = 3.0 Hz, 1 H), 9.07 (s, 1 H), 8.43 (dd, J = 9.0, 3.0 Hz, 1 H), 8.27 (dd, J = 7.8, 1.2 Hz, 1 H), 7.71 (d, J = 9.0 Hz, 1 H), 7.48 (dd, J = 8.4, 1.8 Hz, 1 H), 7.22 (t, J = 7.8 Hz, 1 H), 7.09 (d, J = 8.4 Hz, 1 H), 5.53 (s, 2 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 160.8, 155.0, 154.8, 149.9, 146.1, 140.9, 139.0, 135.9, 132.4, 129.4, 128.5, 126.5, 125.4, 121.1, 120.7, 120.1, 115.2, 67.7 ppm. HRMS (ESI) calcd for C19H10N2O5 (M + H +) = 347.0668, found 347.0660. Elemental Analysis Calculated Found MF C19H10N2O5 C 65.90 65.69 (346.30) H 2.91 2.85 N 8.09 8.13 2-Chlorodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (2p): IR (KBr): 2923.87, 2841.75, 1749.49, 1600.47, 1239.49, 1075.42, 1050.28, 1036.43, 1015.91 cm-1. Reaction Time: 3.0 hrs. Colour & State: pale green solid Yield: 62 % (108 mg) Melting Point: > 300 °C Reaction Time: 3.0 h Colour & State: pale green solid Yield: 80 % (146 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 32 1HNMR (600 MHz, DMSO-d6): δ 8.87 (s, 1 H), 8.42 (d, J = 2.4 Hz, 1 H), 8.24 (dd, J = 7.8, 1.8 Hz, 1 H), 7.65 (d, J = 9.0, 2.4 Hz, 1 H), 7.51 (d, J = 9.0 Hz, 1 H), 7.47 (dd, J = 9.0, 1.2 Hz, 1 H), 7.21 (t, J = 7.2 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 5.48 (s, 2 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 159.9, 149.4, 139.8, 139.6, 134.7, 134.6, 133.4, 126.4, 126.3, 124.9, 123.8, 120.2, 119.6, 119.6, 115.2, 67.6 ppm. HRMS (ESI) calcd for C19H10ClNO3 (M + H +) =366.0422, found 336.0428. Elemental Analysis Calculated Found MF C19H10ClNO3 C 67.97 68.15 (335.74) H 3.00 3.08 N 4.17 4.10 2-Bromodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3q): IR (KBr): 2925.83, 2849.96, 1749.98, 1600.29, 1239.57, 1071.30, 1050.53, 1015.07 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 8.85 (s, 1 H), 8.55 (d, J = 2.4 Hz, 1 H), 8.24 (dd, J = 7.8, 1.8 Hz, 1 H), 7.76 (d, J = 9.0, 2.4, 1 H), 7.47 (dd, J = 8.4, 1.8, 1 H), 7.44 (d, J = 8.4 Hz, 1 H), 7.21 (t, J = 7.8 Hz, 1 H), 7.07 (d, J = 7.8, 1H), 5.48 (s, 2 H).ppm. 13C NMR (150 MHz, CDCl3: TFA = 4:1): δ 159.0, 157.5, 149.8, 149.7, 137.8, 136.7, 132.1, 131.5, 126.5, 126.3, 124.4, 120.2, 120.0, 118.9, 116.5, 67.6 ppm. HRMS (ESI) calcd for C19H10BrNO3 (M + H +) = 379.9922, found 379.9909. Elemental Analysis Calculated Found MF C19H10BrNO3 C 60.02 60.23 (380.20) H 2.65 2.63 N 3.68 4.62 Reaction Time: 5.0 hr Colour & State: pale green solid Yield: 76 % (144 mg) Melting Point: 279 °C TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 33 1H NMR (600 MHz, DMSO-d6): Dichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3a) 13C NMR (150 MHz, CDCl3: TFA = 4:1): Dichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3a) TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 34 1H NMR (600 MHz, DMSO-d6): 9-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3b) 13C NMR (100 MHz, CDCl3: TFA = 4:1): 9-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3b) TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 35 1H NMR (600 MHz, DMSO-d6): 4-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3i) 13C NMR (150 MHz, CDCl3: TFA = 4:1): 4-Methoxydichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3i) TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 36 1H NMR (600 MHz, DMSO-d6): 2-Bromodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3q) 13C NMR (150 MHz, CDCl3: TFA = 4:1): 2-Bromodichromeno[3,4-b:3',4'-e]pyridin-6(13H)-one (3q) TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 37 Crystallographic Description Crystal data were collected with Bruker Smart Apex-II CCD diffractometer using graphite monochromated MoKα radiation (λ = 0.71073 Å) at 296 K. Cell parameters were retrieved using SMART software and refined with SAINT on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS. The structure was solved by direct methods implemented in SHELX-97 program and refined by full-matrix least-squares methods on F2. All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Table 3. Crystal data and structure refinements of compounds 3a and 3l. For atomic coordinates, equivalent isotropic displacement parameters and bond angles, please check CIF. Parameters Compound 3a Compound 3l Empirical Formula C19H11NO3 C22H17NO5 Formula Weight 301.29 375.37 Temperature 293 K 296 K CCDC No. 981642 1003777 Wavelength (Ao ) 0.71073 0.71073 Crystal System Monoclinic Monoclinic Space group P c P 21/c Radiation type MoK\a MoK\a Radiation source 'fine-focus sealed tube' fine-focus sealed tube a (Ao) 7.4838(5) 15.1343(12) b (Ao) 8.9794(6) 7.9297(7) c (Ao) 21.4898(14) 15.8206(13) α(o) 90.00 90.00 β (o) 106.872(5) 111.832(6) γ (o) 90.00 90.00 Cell Voloume 1381.95(16) 1762.5(3) Å3 z 4 4 Density 1.448 1.415 TH-1700_126122027 Chapter IIA Synthesis of Pyridocoumarins 38 F (0 0 0) 624.0 784.0 Theta ranges 2.84 to 21.64 1.45 to 25.00 Index ranges -9 ≤ h ≥ 9, -11 ≤ k ≥ 0, -27 ≤ l ≥ 8 -17 ≤ h ≤ 17, -8 ≤ k ≤ 9, -18 ≤ l ≤ 18 Reflection collected 3164 13054 Independent reflections 3164 3018 Completeness to theta 1.000 0.974 Number of parameters 415 255 Number of restraints 2 0 Godness of fit (GOF)on F2 1.042 1.032 Refinement method Full- matrix least square on F2 Full- matrix least square on F2 TH-1700_126122027 CHAPTER IIB PTSA.H2O Catalyzed Reaction of 3-Aminocoumarins and Phenylacetaldehyde Derivatives; A Route to Access Various Pyrido(2, 3-c)coumarin Derivatives RESULTS AND DISCUSSION TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 39  Results and Discussion Haung et al. recently reported one pot C-C/C-N bond formation and C-C bond cleavage for the construction of substituted quinolone derivatives from anilines and phenylacetaldehydes using catalytic amount of Cu(II)/air and CF3SO3H as an additive. 50 Similar strategy was further expanded by Bharate et al using ionic liquid for the synthesis of quinolone derivatives.51 Taking cue from these two observations, 3-aminocoumarin was extended for the construction of fused pyridine derivatives. Previously in Chapter IIA, TfOH as a catalyst has been used for the synthesis of pyridocoumarins by an intramolecular Povarov reaction from 3-aminocoumarins and propargylated salicylaldehydes. The present chapter describes the synthesis of pyridocoumarins using 3-aminocoumarin and phenylacetaldehyde derivatives in presence of PTSA.H2O (Scheme 32). Scheme 32. Synthesis of various pyrido(2,3-c)coumarin derivatives For the initial study, a reaction of 3-aminocoumarin (1a) was carried out with phenylacetaldehyde (4a) using CF3COOH in acetonitrile in reflux condition. The product obtained was separated by column chromatography and characterized by IR, NMR spectra and HRMS. The isolated compound was found to be 5a (Table 4), characterized by IR peak at 1735.13 cm-1, the two meta coupled doublets at δ 9.15 and 8.57 ppm due to the two protons of the pyridine ring and the HRMS peak at 274.0861(see page no. 45 for NMR data and 56 for spectra of compound 5a). To reach the optimized conditions, several reactions were carried out using 3-aminocoumarin (1a) and phenyacetaldehyde (4a). The desired product 5a was obtained in 60% yield when the reaction was carried out in acetonitrile using 5 mol% CF3COOH as a catalyst (Table 4, entry 1). The yield was slightly improved to 66% when 10 mol% CF3COOH was used (Table 4, entry 2). Other protic acid like TfOH, PDCA and PTSA.H2O were also found effective as catalyst affording the desired product in good yield (Table 4, entry, 3-5). However, no product was achieved by using AcOH as catalyst (Table 3, entry 8). The best yield was obtained when PTSA.H2O was used as the TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 40 catalyst in acetonitrile under reflux condition (Table 4, entry 5-7). Employing 5% and 10 mol% of PTSA.H2O, 78% and 84% yields of the desired product were accomplished respectively whereas only a slight increase in yield was obtained loading the catalyst amount to 15 mol% (Table 4, entry 7). Moreover, with Lewis acid like I2, Yb(OTf)3 and FeCl3 as catalysts, the reaction was promoted with 70-74 % yield (Table 4, entry 9-11) but no desired product was obtained with CuI as a catalyst (Table 4, entry 12). Apart from acetonitrile, several other solvents such as EtOH, MeOH, DMSO, DMF and Toulene were also sreened to reach the optimized condition and a moderate to good yield was obtained in these solvents (Table 4, entry, 13-17) but the efficacy of CHCl3 as solvent was found to be very poor (Table 4, entry 18). Moreover the reaction was not feasible without any catalyst and the desired was obtained in low yield at ambient temperature (Table 4, entry 19-20). Table 4. Optimization of reaction conditiona Entry Catalyst (mol%) Solvent Time/h Yield(%) b 1 CF3COOH (5) CH3CN 14 60 2 CF3COOH (10) CH3CN 14 66 3 TfOH (10) CH3CN 14 78 4 PDCA (10) CH3CN 14 70 5 PTSA.H2O (10) CH3CN 14 84 6 PTSA.H2O (5) CH3CN 14 78 7 PTSA.H2O (15) CH3CN 14 86 8 AcOH (10) CH3CN 24 NR 9 I2 (10) CH3CN 14 70 10 Yb(OTf)3 (10) CH3CN 14 72 11 FeCl3 (10) CH3CN 14 74 12 CuI (10) CH3CN 24 NR 13 PTSA.H2O (10) EtOH 14 40 14 PTSA.H2O (10) MeOH 14 45 TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 41 15c PTSA.H2O (10) DMSO 14 60 16c PTSA.H2O (10) DMF 24 52 17c PTSA.H2O (10) Toulene 24 56 18 PTSA.H2O (10) CHCl3 24 10 19 ….. CH3CN 24 NR 20* PTSA.H2O (10) CH3CN 24 20 aUnless otherwise mentioned, all the reaction were carried out using 0 .5 mmol of 1a and 1.0 mmol of 4a under reflux condition. bIsolated yields. cIn case of DMF and DMSO and Toulene the temperature was maintained at 80 °C. *Room temperature. After achieving the optimized reaction condition, various derivatives of 3-aminocoumarin and phenylacetaldehye derivatives were scrutinized under the standard reaction conditions to explore the substrate scope of the reaction protocol. Initially, a number of phenylacetaldehyde derivatives were reacted with 3-aminocoumarins to transform them to the desired pyrido(2, 3-c)coumarins. Interestingly, the respective products were achieved in significant yields with both electron donating (5b and 5c) and withdrawing substituents (5d-g) on phenylacetaldehyde moiety (Table 5). Notably, the desired products were not obtained with aliphatic aldehydes. Furthermore a wide range of 3-aminocoumarins containing 7-MeO-, 8-MeO-, 8-EtO-, 6-Cl-, 6-Br, 6,8-dichloro, substituents were investigated and a good to excellent yield ware obtained with these substrates (Table 5, 5h-q). Table 5. Synthesis of various pyrido(2,3-c)coumarin derivatives a,b TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 42 aAll the reaction were carried out using 0 .5 mmol of 1 and 1.0 mmol of 4 with 10 mol% of PTSA in acetonitrile under reflux condition.b Isolated yields Moreover, when 4-aminocoumarin was evaluated for further scope of aminocoumarin moiety under the standard reaction conditions with phenylacetaldehyde, the product (7) was obtained in 80% yield (Scheme 33). Further, a different product (9) was obtained on replacing phenylacetaldehyde with 3-phenylpropionaldehyde (Scheme 34). Scheme 33. Synthesis of 3-phenyl-5H-chromeno[4,3-b]pyridin-5-one Scheme 34. Synthesis of 2-benzyl-3-phenethyl-5H-chromeno[3,4-b]pyridin-5-one TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 43 All the products (5a-q, 7 and 9) were characterized by their I.R, 1H NMR, 13C NMR, and HRMS spectra analysis (see pages 45-55 for IR, NMR and HRMS data.). Futher, compound 5i was characterized by crystallographic structure (Figure 5). Figure 5. Crystal structure of 5i (CCDC number1477324) From our experimental results and literature survey50, 51 a plausible mechanism has been drawn as shown in Scheme 35. Initially phenylacetaldehyde reacts with 3-aminocoumarin to form an imine (IIA) in the presence of PTSA.H2O. The imine (IIA) tautomerizes to an enamine (IIB). The reaction of imine (IIA) and enamine (IIB) gives IIC which tautomerizes to IID. The intermediate IID cyclizes to IIE. The intermediate IIE on protonation and loss of 3-aminocoumarin followed by aerial oxidation provides IIF and IIF on oxidation gives IIG which produces IIH. Finally, IIH on C-C bond cleavage followed by aromatization gives the final product 5a. TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 44 Scheme 35. Plausible mechanism of formation of 5a In conclusion, synthesis of various pyrido(2, 3-c)coumarin derivtives from phenylacetaldehyde derivatives and 3-aminoucoumarins has been demonstrated. The protocols gives an easy access to a number of substituted pyrido(2, 3-c)coumarins derivatives with large number of substrate scope. TH-1700_126122027 CHAPTER IIB PTSA.H2O Catalyzed Reaction of 3-Aminocoumarins and Phenylacetaldehyde Derivatives; A Route to Access Various Pyrido(2, 3-c)coumarin Derivatives EXPERIMENTAL SECTION TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 45  Experimental Section Synthesis of various derivatives of pyrido(2, 3-c)coumarin (5a-q, 7 and 9): Into a 25 mL round bottomed flask was taken 0.5 mmol of 3-aminocoumarin and 1.0 mmol of phenyacetaldehyde in 3 mL of acetonitrile. Then, 10 mol% of PTSA.H2O was added into it. The reaction mixture was refluxed for 12-16 h in a preheated oil bath. After completion of the reaction checked by TLC, acetonitrile was removed in a rotary evaporator and the reaction mixture was extracted with DCM. After removing DCM in a rotary evaporator, the crude residue was purified through column chromatography using hexane: ethylacetate = 3:1 mixture to obtain the pure products. In case of 5e, 5f, 5n-q and 9, after completion of the reaction checked by TLC, the solid precipitate was filtered off and it was washed with acetonitrile to remove the impurities. All the products after purification was characterized with IR. 1H NMR, 13C NMR and HRMS spectra. 2-Phenyl-5H-chromeno[3,4-b]pyridin-5-one (5a): IR (KBr): 3052.31, 2924.10, 2853.28, 1753.31, 1611.63, 1178.06, 1095.47 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.15 (d, J = 2.1 Hz, 1 H), 8.57 (d, J = 1.9 Hz, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.73 (d, J = 8 Hz, 2 H), 7.56 (m, 4 H), 7.41 (t, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.1, 151.4, 150.4, 141.6, 136.7, 136.2, 131.8, 131.7, 129.8, 129.7, 127.9, 127.8, 125.1, 123.2, 118.2, 116.8 ppm. HRMS (ESI) calcd for C18H11NO2 (M + H +) = 274.0863, found 274.0861. Elemental Analysis Calculated Found MF C18H11NO2 C 79.11 79.23 (273.29) H 4.06 3.99 N 5.13 5.05 2-(p-Tolyl)-5H-chromeno[3,4-b]pyridin-5-one (5b): Reaction Time: 12 h Colour & State: pale yellow solid Yield: 80% (110 mg) Melting Point: 192-194 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 46 IR (KBr): 3055.35, 2921.34, 1738.31, 1607.41, 1243.87, 1177.55, 1099.50 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.11 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 2.0 Hz, 1 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.61 (dd, J = 8.1, 1.7 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.38 (m, 4 H), 2.45 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.2, 151.4, 150.3, 141.6, 140.1, 136.4, 133.3, 131.8, 131.6, 130.4, 127.6, 127.4, 125.0, 123.2, 118.2, 117.0, 21.5 ppm. HRMS (ESI) calcd for C19H13NO2 (M + H +) = 288.1019, found 288.1018. Elemental Analysis Calculated Found MF C19H13NO2 C 79.43 79.30 (287.32) H 4.56 4.51 N 4.88 4.80 2-(4-Methoxyphenyl)-5H-chromeno[3,4-b]pyridin-5-one (5c): IR (KBr): 3050.73, 2925.83, 2834.23, 1752.89, 1605.66, 1250.25, 1179.11, 1087.48 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.08 (s, 1 H), 8.47 (s, 1 H), 8.08 (d, J = 7.9 Hz, 1 H), 7.65 (d, J = 7.9 Hz, 2 H), 7.53 (t, J = 7.8 Hz, 1 H), 7.37 (t, J = 8.4 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 2 H), 3.88 (s, 3 H). 13C NMR (150 MHz, CDCl3): δ 161.2, 159.2, 151.4, 150.0, 141.2, 136.1, 131.8, 131.6, 129.0, 128.4, 126.8, 125.0, 123.2, 118.2, 117.0, 115.2, 55.7 HRMS (ESI) calcd for C19H13NO3 (M + H +) = 304.0968, found 304.0968. Reaction Time: 13 h Colour & State: pale yellow solid Yield: 82% (118 mg) Melting Point: 242-245 °C Reaction Time: 13 h Colour & State: pale yellow solid Yield: 83% (126 mg) Melting Point: 190-193 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 47 Elemental Analysis Calculated Found MF C19H13NO3 C 75.24 75.35 (303.32) H 4.32 4.36 N 4.62 4.55 2-(4-Fluorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5d): IR (KBr): 2917.50, 2845.34, 1750.69, 1613.08, 1255.75, 1162.05, 1006.88 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.09 (d, J = 2.0 Hz, 1 H), 8.53 (d, J = 2.1 Hz, 1 H), 8.06 (d, J = 7.6 Hz, 1 H), 7.67 (m, 2 H), 7.56 (td, J = 8.0, 1.4 Hz, 1 H), 7.35 (m, 2 H), 7.22 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 165.2, 162.7, 158.9, 151.4, 150.0, 140.8, 136.5, 132.4, 131.9, 129.7, 129.6, 127.9, 125.2, 123.2, 118.2, 117.0, 116.8, 116.7 ppm. HRMS (ESI) calcd for C18H10FNO2 (M + H +) = 292.0768, found 292.0762. Elemental Analysis Calculated Found MF C18H10FNO2 C 74.22 74.11 (291.28) H 3.46 3.38 N 4.81 4.75 2-(4-Chlorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5e): IR (KBr): 1756.59, 1615.10, 1286.20, 1179.42, 1104.93, 1004.58 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.13 (s, 1 H), 8.56 (s, 1 H), 8.12 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.59 (m, 3 H), 7.44 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3: TFA = 10:1): δ 155.5, 151.6, 145.0, 144.1, 139.5, 135.8, 135.4, 135.3, 131.0, 129.2, 127.2, 124.0, 119.1, 113.7 ppm. Reaction Time: 14 h Colour & State: pale yellow solid Yield: 77% (112 mg) Melting Point: 218-221 °C Reaction Time: 14 h Colour & State: pale yellow solid Yield: 77% (118 mg) Melting Point: 188-190 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 48 HRMS (ESI) calcd for C18H10ClNO2 (M + H +) = 308.0473, found 308.0471. Elemental Analysis Calculated Found MF C18H10ClNO2 C 70.26 70.40 (307.73) H 3.28 3.24 N 4.55 4.50 2-(4-Bromophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5f): IR (KBr): 1752.19, 1684.27, 1285.53, 1179.41, 1102.59, 1070.98 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.13 (s, 1 H), 8.56 (s, 1 H), 8.12 (d, J = 7.9 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.60 (m, 3 H), 7.46 (d, J = 9.1 Hz, 1 H), 7.42 (d, J= 8.8 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 10:1): δ 155.8, 151.6, 144.6, 135.0, 133.8, 131.6, 129.8, 129.3, 128.6, 127.5, 127.0, 125.9, 123.9, 119.1, 114.0 ppm. HRMS (ESI) calcd for C18H10BrNO2 (M + H +) = 351.9968, found 351.9965 & 353.9947. Elemental Analysis Calculated Found MF C18H10BrNO2 C 61.39 61.25 (352.19) H 2.86 2.90 N 3.98 3.92 2-(2-Fluorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5g): IR (KBr): 3066.17, 2923.97, 2853.23, 1761.15, 1615.12, 1592.01, 1227.96, 1087.95 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.10 (s, 1 H), 8.64 (s, 1 H), 8.09 (d, J = 7.9 Hz, 1 H), 7.58 (m, 2 H), 7.51 (m, 1 H), 7.41 (m, 2 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.28 (m. 1 H) ppm. Reaction Time: 12 h Colour & State: pale yellow solid Yield: 80% (140 mg) Melting Point: 334-336 °C Reaction Time: 12 h Colour & State: pale yellow solid Yield: 78% (114 mg) Melting Point: 184-188 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 49 13C NMR (100 MHz,CDCl3): δ 161.4, 159.1, 158.9, 151.5, 151.4, 151.4, 136.9, 136.8, 131.8, 131.8, 131.7, 131.6, 130.74, 130.7, 130.3, 130.2, 125.38, 125.4, 125.2, 124.3, 124.1, 123.3, 118.2, 117.0, 116.8 ppm. HRMS (ESI) calcd for C18H10FNO2 (M + H +) = 292.0768, found 292.0771. Elemental Analysis Calculated Found MF C18H10FNO2 C 74.22 74.38 (291.28) H 3.46 3.39 N 4.81 4.76 8-Methoxy-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5h): IR (KBr): 2923.05, 2839.78, 1744.01, 1617.70, 1259.32, 1118.38, 1037.88 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.04 (d, J = 1.4 Hz, 1 H), 8.42 (d, J = 1.5 Hz, 1 H), 7.96 (d, J = 8.9 Hz, 1 H), 7.71 (d, J = 7.7 Hz, 2 H), 7.54 (m, Hz, 3 H), 6.95 (dd, J = 8.8, 2.4 Hz, 1 H), 6.87 (d, J = 2.3 Hz, 1 H), 3.89 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 162.5, 159.4, 152.8, 149.4, 141.6, 136.4, 135.5, 132.2, 129.7, 129.6, 127.8, 127.2, 124.2, 113.1, 109.8, 101.9, 56.0 ppm. HRMS (ESI) calcd for C19H13NO3 (M + H +) = 304.0968, found 304.0975. Elemental Analysis Calculated Found MF C19H13NO3 C 75.24 75.33 (303.32) H 4.32 4.47 N 4.62 4.54 7-Methoxy-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5i): IR (KBr): 3078.79, 2835.54, 1744.06, 1273.35, 1101.30 cm-1. Reaction Time: 12 h Colour & State: pale yellow solid Yield: 82% (124 mg) Melting Point: 196-199 °C Reaction Time: 12h Colour & State: pale yellow solid Yield: 83% (126 mg) Melting Point: 204-206 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 50 1HNMR (400 MHz, CDCl3): δ 9.14 (s, 1 H), 8.54 (s, 1 H), 7.72 (d, J = 7.4 Hz, 2 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.55 (m, 3 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.10 (d, J = 8.1 Hz, 1 H), 3.98 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.6, 150.5, 148.4, 141.6, 141.3, 136.8, 136.4, 132.0, 129.8, 129.7, 128.4, 127.8, 125.0, 117.7, 114.3, 113.5, 56.5 ppm. HRMS (ESI) calcd for C19H13NO3 (M + H +) = 304.0968, found 304.0974. Elemental Analysis Calculated Found MF C19H13NO3 C 75.24 75.12 (303.32) H 4.32 4.26 N 4.62 4.70 7-Methoxy-2-(p-tolyl)-5H-chromeno[3,4-b]pyridin-5-one (5j): IR (KBr): 3067.39, 3017.42, 2831.46, 1736.79, 1615.82, 1274.92, 1203.67, 1176.08, 1094.24 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.13 (s, 1 H), 8.51 (s, 1 H), 7.65 (d, J = 8.3 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 2 H), 7.36 (d, J = 7.8 Hz, 2 H), 7.31 (t, J = 8.1 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 1 H), 3.96 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.6, 150.4, 148.4, 141.5, 140.1, 136.5, 133.4, 132.0, 130.4, 127.9, 127.6, 124.9, 117.8, 114.3, 113.4, 56.5, 21.5 ppm. HRMS (ESI) calcd for C20H15NO3 (M + H +) = 318.1125, found 318.1132. Elemental Analysis Calculated Found MF C20H15NO3 C 75.70 75.83 (317.34) H 4.76 4.70 N 4.41 4.35 7-Ethoxy-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5k): Reaction Time: 12 h Colour & State: pale yellow solid Yield: 81% (128 mg) Melting Point: 260-263 °C Reaction Time: 14h Colour & State: pale yellow solid Yield: 80% (126 mg) Melting Point: 218-219 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 51 IR (KBr): 2923.05, 2845.34, 1751.17, 1596.54, 1275.63, 1094.35, 1082.17, 1042.26 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.14 (d, J = 1.9 Hz, 1 H), 8.53 (d, J = 1.9 Hz, 1 H), 7.72 (d, J = 7.1 Hz, 2 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.54 (m, 3 H), 7.29 (t, J = 8.1 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 1 H), 4.19 (q, J = 7.0 Hz, 2 H), 1.52 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.8, 150.4, 147.8, 141.6, 141.5, 136.8, 136.4, 132.0, 129.8, 129.7, 128.4, 127.8, 124.9, 117.8, 114.7, 114.2, 65.2, 15.0 ppm. HRMS (ESI) calcd for C20H15NO3 (M + H +) = 318.1125, found 318.1130. Elemental Analysis Calculated Found MF C20H15NO3 C 75.70 75.55 (317.34) H 4.76 4.80 N 4.41 4.35 7-Ethoxy-2-(4-methoxyphenyl)-5H-chromeno[3,4-b]pyridin-5-one (5l): IR (KBr): 2978.57, 2928.60, 1743.52, 1733.63, 1605.29, 1247.08, 1198.11, 1178.81, 1112.35, 1096.97 cm-1. 1HNMR (600 MHz, CDCl3): δ 9.10 (s, 1 H), 8.47 (s, 1 H), 7.67 (d, J = 7.7 Hz, 2 H), 7.63 (d, J = 7.9 Hz, 1 H), 7.28 (t, J = 8.1, Hz, 1 H), 7.07 (d, J = 7.8 Hz, 3 H), 4.18 (q, J = 6.5 Hz, 2 H), 3.89 (s, 3 H), 1.51 (t, J = 6.5 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 161.1, 158.9, 150.1, 147.8, 141.5, 141.1, 136.1, 132.0, 129.0, 128.6, 127.4, 124.9, 117.9, 115.2, 114.6, 114.2, 65.2, 55.7, 15.0 ppm. HRMS (ESI) calcd for C21H17NO4 (M + H +) = 348.1230, found 348.1234. Elemental Analysis Calculated Found MF C21H17NO4 C 72.61 72.76 (347.37) H 4.93 4.87 N 4.03 4.29 Reaction Time: 14 h Colour & State: pale yellow solid Yield: 84% (146 mg) Melting Point: 246-249 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 52 7-Ethoxy-2-(4-fluorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5m): IR (KBr): 2981.34, 2920.28, 2853.66, 1751.53, 1601.12, 1273.71, 1239.06, 1165.37, 1075.35 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.10 (s, 1 H), 8.51 (s, 1 H), 7.71 (dd, J = 8.6, 5.3 Hz, 2 H), 7.65 (d, J = 8.1 Hz, 1 H), 7.29 (m, 3 H), 7.10 (d, J = 8.1 Hz, 1 H), 4.20 (q, J = 7.0 Hz, 2 H), 1.53 (t, J = 7.0 Hz, 3 H) pm. 13C NMR (150 MHz, CDCl3): δ 164.8, 163.1, 158.7, 150.2, 147.8, 141.6, 140.7, 136.8, 132.6, 132.2, 129.8, 129.7, 128.3, 125.0, 117.7, 117.0, 116.8, 114.8, 114.2, 65.3, 15.0 ppm. HRMS (ESI) calcd for C20H14FNO3 (M + H +) = 336.1030, found 336.1037. Elemental Analysis Calculated Found MF C20H14FNO3 C 71.64 71.75 (335.33) H 4.21 4.16 N 4.18 4.24 9-Nitro-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5n): IR (KBr): 3064.61, 2917.50, 1757.02, 1619.10, 1269.30, 1101.64, 1079.82, 1037.77 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 9.56 (s, 1 H), 9.38 (s, 1 H), 9.34 (s, 1 H), 8.44 (d, J = 8.8 Hz, 1 H), 8.11 (d, J = 7.1 Hz, 2 H), 7.70 (d, J = 9.0 Hz, 1 H), 7.62 (d, J = 7.1 Hz, 2 H), 7.58 (d, J = 6.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3: TFA= 10:1): δ 154.9, 154.4, 147.0, 145.6, 136.4, 133.9, 132.8, 131.9, 130.7, 129.2, 128.1, 120.7, 120.5, 115.1 ppm. HRMS (ESI) calcd for C18H10N2O4 (M + H +) = 319.0713, found 319.0714. Elemental Analysis Calculated Found Reaction Time: 14 h Colour & State:pale yellow solid Yield: 81% (132 mg) Melting Point: 259-261 °C Reaction Time: 15 h Colour & State: pale yellow solid Yield: 78% (124 mg) Melting Point: 330-333 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 53 MF C18H10N2O4 C 67.93 68.04 (318.29) H 3.17 3.13 N 8.80 8.88 9-Chloro-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5o): IR (KBr): 1752.19, 1632.71, 1269.43, 1172.73, 1109.41, 1078.38 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.19 (d, J = 2.0 Hz, 1 H), 8.51 (d, J = 2.0 Hz, 1 H), 8.08 (d, J = 2.3 Hz, 1 H), 7.75 (d, J = 7.6, Hz, 2 H), 7.58 (m, 3 H), 7.52 (dd, J = 8.8, 2.4 Hz, 1 H), 7.39 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.5, 151.1, 150.0, 142.0, 136.8, 136.0, 131.7, 130.8, 130.7, 130.0, 129.8, 128.0, 127.9, 123.0, 119.7, 118.4 ppm. HRMS (ESI) calcd for C18H10ClNO2 (M + H +) = 308.0473, found 308.0474. Elemental Analysis Calculated Found MF C18H10ClNO2 C 70.26 70.14 (307.73) H 3.28 3.24 N 4.55 4.49 9-Bromo-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5p): IR (KBr): 3061.77, 1756.74, 1601.32, 1274.79, 1100.79, 1073.71 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.18 (s, 1 H), 8.50 (s, 1 H), 8.22 (d, J = 1.6 Hz, 1 H), 7.74 (d, J = 7.5 Hz, 2 H), 7.65 (dd, J = 8.7, 1.6 Hz, 1 H), 7.56 (m, 3 H), 7.32 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 158.5, 151.1, 150.4, 142.0, 136.7, 136.0, 134.5, 130.7, 130.0, 129.8, 127.9, 127.8, 126.0, 120.0, 118.8, 118.0 ppm. HRMS (ESI) calcd for C18H10BrNO2 (M + H +) = 351.9968, found 351.9974. Reaction Time: 14 h Colour & State: white yellow solid Yield: 80% (122 mg) Melting Point: 267-270 °C Reaction Time: 12 h Colour & State: white solid Yield: 81% (142 mg) Melting Point: 280-282 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 54 Elemental Analysis Calculated Found MF C18H10BrNO2 C 61.39 61.56 (352.19) H 2.86 2.90 N 3.98 3.90 7,9-Dichloro-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5q): IR (KBr): 3078.49, 2925.83, 2850.89, 1740.47, 1586.59, 1253.86, 1174.05, 1116.86, 1091.19, 1055.84 cm-1 1HNMR (400 MHz, CDCl3): δ 9.23 (s, 1 H), 8.52 (s, 1 H), 8.00 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 7.0 Hz, 2 H), 7.65 (d, J = 2.1 Hz, 1 H), 7.59 (m, 3 H) ppm. 13C NMR (150 MHz, CDCl3: TFA = 10: 1): δ, 154.4, 147.0, 146.1, 145.4, 136.4, 135.1, 134.0, 133.0, 132.9, 132.0, 130.8, 128.0, 127.6, 125.6, 122.3, 116.3 ppm. HRMS (ESI) calcd for C18H9Cl2NO2 (M + H +) = 342.0083, found 342.0083. Elemental Analysis Calculated Found MF C18H9Cl2NO2 C 63.18 63.30 (342.18) H 2.65 2.61 N 4.09 4.08 3-Phenyl-5H-chromeno[4,3-b]pyridin-5-one (7): IR (KBr): 3442.09, 1736.82, 1653.62, 1609.79, 1600.54, 1170.42, 1085.04 cm-1. 1HNMR (400 MHz, CDCl3): δ 9.26 (s, 1 H), 8.79 (s, 1 H), 8.60 (d, J = 7.8 Hz, 1 H), 7.70 (d, J = 7.6 Hz, 2 H), 7.56 (m, 3 H), 7.48 (d, J = 7.2 Hz, 1 H), 7.42 (m, 2 H) ppm. Reaction Time: 14 h Colour & State: white solid Yield: 80% (136 mg) Melting Point: 339-341 °C Reaction Time: 16 h Colour & State: pale yellow solid Yield: 80% (110 mg) Melting Point: 188-189 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 55 13C NMR (100 MHz, CDCl3): δ 161.6, 154.5, 152.7, 150.6, 137.1, 136.3, 135.8, 132.3, 129.6, 129.2, 127.3, 125.2, 124.9, 119.4, 117.5, 117.4 ppm. HRMS (ESI) calcd for C18H11NO2 (M + H +) = 274.0863, found 274.0868. Elemental Analysis Calculated Found MF C18H11NO2 C 79.11 79.22 (273.29) H 4.06 4.01 N 5.13 5.20 2-Benzyl-3-phenethyl-5H-chromeno[3,4-b]pyridin-5-one (9): IR (KBr): 3022.98, 2961.91, 2884.19, 1749.67, 1601.81, 1590.30, 1286.56, 1176.01, 1159.97, 1130.44 cm- 1. 1HNMR (400 MHz, CDCl3): δ 7.99 (s, 1 H), 7.82 (d, J = 7.9 Hz, 1 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.38 (t, J = 8.4 Hz, 1 H), 7.31 (m, 4 H), 7.22 (m, 3 H), 7.14 (d, J = 7.2 Hz, 2 H), 7.07 (d, J = 7.3 Hz, 2 H), 4.03 (s, 2 H), 3.28 (t, J = 8 Hz, 2 H), 3.09 (t, , J = 8 Hz, 2 H) ppm. 13C NMR (100 MHz,CDCl3): δ 163.1, 159.4, 151.2, 141.5, 141.1, 137.9, 136.0, 131.1, 131.0, 129.9, 129.2, 129.1, 128.8, 128.6, 127.2, 126.3, 124.8, 123.0, 118.0, 117.1, 38.8, 37.3, 35.4 ppm. HRMS (ESI) calcd for C27H21NO2 (M + H +) = 392.1645, found 392.1651. Elemental Analysis Calculated Found MF C27H21NO2 C 82.84 82.98 (391.47) H 5.41 5.38 N 3.58 3.50 Reaction Time: 16 h Colour & State:white solid Yield: 82% (160 mg) Melting Point: 224-226 °C TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 56 1HNMR (400 MHz, CDCl3): 2-Phenyl-5H-chromeno[3,4-b]pyridin-5-one (5a) 13C NMR (100 MHz, CDCl3): 2-Phenyl-5H-chromeno[3,4-b]pyridin-5-one (5a) TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 57 1HNMR (400 MHz, CDCl3): 2-(p-Tolyl)-5H-chromeno[3,4-b]pyridin-5-one (5b) 13C NMR (101 MHz ,CDCl3): 2-(p-Tolyl)-5H-chromeno[3,4-b]pyridin-5-one (5b) TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 58 1HNMR (400 MHz, CDCl3): 2-(4-Fluorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5d): 13C NMR (101 MHz,CDCl3): 2-(4-Fluorophenyl)-5H-chromeno[3,4-b]pyridin-5-one (5d): TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 59 1HNMR (400 MHz, CDCl3): 7-Ethoxy-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5k) 13C NMR (101 MHz,CDCl3): 7-Ethoxy-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5k): TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 60 1HNMR (400 MHz, CDCl3): 9-Chloro-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5o) 13C NMR (101 MHz, CDCl3): 9-Chloro-2-phenyl-5H-chromeno[3,4-b]pyridin-5-one (5o) TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 61 Crystallographic Description Crystal data were collected with Bruker Smart Apex-II CCD diffractometer using graphite monochromated MoKα radiation (λ = 0.71073 Å) at 298 K. Cell parameters were retrieved using SMART software and refined with SAINT on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS. The structure was solved by direct methods implemented in SHELX-97 program and refined by full-matrix least-squares methods on F2. All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Table 6. Crystal data and structure refinements of compounds 5j. For atomic coordinates, equivalent isotropic displacement parameters and bond angles, please check CIF. Parameters Compound 5j Empirical Formula C19H13NO3 Formula Weight 303.30 Temperature 298 K CCDC No. CCDC 1477324 Wavelength (Ao ) 0.71073 Crystal System triclinic Space group P -1 Radiation type MoK\a Radiation source fine-focus sealed tube a (Ao) 7.7181(10) b (Ao) 8.7813(9) c (Ao) 11.4970(10) α(o) 96.875(8) β (o) 105.660(10) γ (o) 97.672(10) Cell Voloume 733.60(14) z 2 Density 1.373 TH-1700_126122027 Chapter IIB Synthesis of Pyridocoumarins 62 F (0 0 0) 316 Theta ranges 3.25 to 24.99 Index ranges -9 ≤ h ≤ 8, -10 ≤ k ≤ 10, 13 ≤ l ≤ 13 Reflection collected 5135 Independent reflections 2584 Completeness to theta 0.998 Number of parameters 209 Number of restraints 0 Godness of fit (GOF)on F2 0.986 Refinement method Full-matrix least square on F2 TH-1700_126122027 CHAPTER III Iodine Catalyzed Multicomponent Approach to Access Various Pyrrolo(2,3-c)coumarin Derivatives using 3-Aminocoumarins, Acetophenones and 4-Hydroxycoumarin RESULTS AND DISCUSSION TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 63  Results and Discussion Multicomponent reactions (MCRs) have proven to be a useful tool for the synthesis of heterocyclic compounds because of its high atom economy and bond forming efficiency. MCRs is an easy approach to accomplishe very complex and diversified molecular frameworks starting from simple and readily available starting materials.52 Synthesis of phenylglyoxaldehyde (2-oxo-2- phenylacetaldehyde) from acetophenone using iodine and DMSO via Kornblum oxidation is a very familiar reaction.53 Recently, phenylglyoxaldehyde derivatives have been widely used in the synthesis of heterocyclic compounds.54 Bhuyan et al reported the synthesis of indole derivatives in presence of PTSA.H2O/FeCl3 as catalyst through reductive alkylation of the ketoimine, synthesized from aniline and phenylglyoxaldehyde monohydrate, by cyclic diketones/indoles.55 Moreover, Shi et al. demonstrated the synthesis of indole derivatives via three component reaction of phenylglyoxal monohydrate ,1,3-dicarbonyl compounds and enaminones.56 The present chapter of the thesis describes the iodine catalyzed multicomponent access to various coumarin fused pyrrole derivatives from 3-aminocoumarins and phenylglyoxaldehydes, generated, in situ, from acetophenones and 4-hydroxycoumarin in presence of iodine as a catalyst (Scheme 36). Scheme 36. Synthesis of pyrrolocoumarins Initially, 2-oxo-2-phenylacetaldehyde was synthesized from acetophenone in DMSO using 50 mol% of iodine at 110 °C. Then a reaction was carried out using 3-aminocoumarin, 4- hydroxycoumarin and the in situ generated phenyglyoxaldehyde employing FeCl3 .6H2O as a catalyst in CH3CN under reflux condition. A solid product was formed which was filtered off after completion of the reaction and the precipitate was washed with acetonitrile. The product was characterized by IR, NMR and HRMS spectra analysis. The compound was obtained in 66% yield and found to be 12a (Table 7) showing characteristic IR absorption peaks at 1701 cm-1 and 1684 TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 64 cm-1 for carbonyl groups of the two lactone rings and an 1H NMR peak corresponding to proton of the pyrrole ring at δ 13.17 (see page 81 for NMR spectra of compound 12a). To proceed further to obtain the optimized reaction conditions various other Lewis acid catalysts were tested. The desired product (11a) was obtained in 64% yield using CuI as a catalyst (Table 7, entry 2). The yield increased to 76% when 10 mol% of iodine was used as catalyst (Table 7, entry 3). Loading the amount of I2 to 5 mol%, the yield decreased to 70% (Table 7, entry 4) whereas compound 12a was obtained in 65% yield when Yb(OTf)3 was employed as a catalyst (Table 7, entry, 6). The reaction was also performed in presence of protic acid like PTSA, TfOH and AcOH in acetonitrile under reflux conditions. The expected product 12a was obtained in 77% and 79% yield using PTSA and TfOH as catalyst respectively whereas only 40% of the product was obtained having AcOH as catalyst (Table 7, entries, 7-9). A number of solvents like EtOH, MeOH, DMSO and DMF were also screened to get the optimized conditions. A moderate to good yield was obtained in these solvents (Table 7, entries 10-13). The desired product 12a was obtained in very poor yield at room temperature and also the yield was very low when the reaction was conducted without any catalyst (Table 7, entries 14-15). The best outcome was obtained in CH3CN using 20 mol% I2 as catalyst under reflux conditions (Table 7, entry 5). Table 7. Optimization of reaction conditionsa Entry Catalyst Solvent Time/h Yield (%) b 1 FeCl3.6H2O CH3CN 20 66 2 CuI CH3CN 20 64 3 I2 CH3CN 20 76 4 I2 CH3CN 20 70 5 I2 CH3CN 20 83 6 Yb(OTf)3 CH3CN 20 65 7 PTSA CH3CN 20 77 8 TfOH CH3CN 20 79 TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 65 9 AcOH CH3CN 20 40 10 I2 EtOH 20 70 11 I2 MeOH 20 72 12 I2 DMSO 20 25 13 I2 DMF 20 20 c14 I2 CH3CN 20 10 15 …. CH3CN 24 15 aAll the reaction has been carried out using 0.5 mmol each 3-aminocoumrin (1a), acetophenone (10a) and 4-hydroxycoumarin (11) in presence of 3 mL of solvent at 80 oC. b Isolated yield, croom temp. After the optimizing reaction conditions, various derivatives of pyrrolo(2,3-c)coumarin were synthesized in acetonitrile under reflux conditions using 20 mol% of I2. Initially, the substituents on the 3-aminocoumarin moiety were varied. A wide range of 3-aminocoumarin moieties containing both electron donating as well as electron withdrawing substituents afforded the respective desired product in appreciable yield (Table 8, entries 12b-j). Several derivatives of acetophenone (10) were also evaluated for their scope in the reaction protocols. Notably, acetophenones (10), with both electron donating and electron withdrawing groups on them at different position were tolerable and desired coumarin fused pyrrole derivatives were obtained in good to excellent yields (Table 8, entries 12k-o). For further substrate scope, 2-acetylthiophene and 2-acetonaphthone were also scrutinized and the respective desired products were obtained in 78% and 82% yields (Table 8, entries 12p and 12q). Table 8. Synthesis of various pyrrolo(2,3-c)coumarin derivatives TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 66 aAll the reaction has been carried out using 0.5 mmol of each 3-aminocoumrain (1), acetophenone (9) and 4- hydroxycoumarin (10) in presence of 3 mL of CH3CN and 20 mol% of Iodine at reflux condition °C. bIsolated yield Figure 6. Crystal structure of 12b (CCDC 1498213) Crystal structure of 12d (CCDC 1498412) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 67 All the compounds (12a-q) were characterized by IR, 1H NMR, 13C NMR, HRMS (see pages 69-80 for IR, NMR and HRMS data of compounds 12a-q). Further, compounds 12b and 12d were unambiguously confirmed by their crystallographic structures (Figure 6). From the experimental results, a plausible reaction mechanism has been drawn (Scheme 37). Initially, in situ generated glyoxalaldehyde from acetophenone reacts with 4-hydroxycoumarin in presence of iodine to form a Knoevenagel product (IIIA), which acts as a Michael acceptor and reacts subsequently with 3-aminocoumarin to provide the intermediate IIIB. Then, the intermediate IIIB undergoes condensation reaction to give intermediate IIIC, which finally rearranges to the desired product 12. Scheme 37. Plausible reaction mechanism for the formation of 12 TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 68 In conclusion, the synthesis of various coumarin fused pyrrole derivatives using I2 as a catalyst through multicomponent reaction has been demonstrated. The various acetophenones and 3-aminocoumarin derivatives were evaluated for the synthesis of substituted pyyrole derivatives. No need of column chromatography and aqueous work up are the salient features of the reaction protocol as the pure products were achieved simply by filtration and washing of the precipitate obtained after the stipulated time with acetonitrile. TH-1700_126122027 CHAPTER III Iodine Catalyzed Multicomponent Approach to Access Various Pyrrolo(2,3-c)coumarin Derivatives using 3-Aminocoumarins, Acetophenones and 4-Hydroxycoumarin EXPERIMENTAL SECTION TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 69  Experimental Section General procedure for the synthesis of various 1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2- phenylchromeno[3,4-b]pyrrol-4(3H)-one (12a-q): Step I In a 25 mL round bottomed flask was taken 0.50 mmol of acetophenone, 3 mL of DSMO, and 0.50 equivalent of iodine. The reaction mixture was heated at 110 °C till the acetophenone disappears to give 2-oxo-2-phenylacetaldehyde as a single product. The reaction mixture was extracted with ethyl acetate (15 x 2 mL) and the organic layer was washed with Na2S2O3 and brine solution. The organic layer dried over anhydrous Na2SO4. After removing the solvent, the aldehyde was used in next step without further purification. Step II Then, 0.50 mmol of each 4-hydroxycoumarin (11) and 3-aminocoumarin (1) were taken into a 25 mL round bottomed flask containing the 2-oxo-2-phenylacetaldehyde, synthesized in step I. Subsequently 4 mL of acetonitrile and 20 mol% of iodine were added into it. The content was refluxed on a preheated oil bath kept on a magnetic stirrer for 18-20 h. The solid precipitate obtained at the end which was filtered off and washed with CH3CN to get the pure products 12a- q. 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12a): IR (KBr): 3481.46, 3206.17, 1701.24, 1684.42, 1186.38, 1128.59, 1042.13 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 13.17 (s, 1 H), 7.91 (d, J = 7.7 Hz, 1 H), 7.69 (t, J = 7.6 Hz, 1 H), 7.56 (t, J = 6.5 Hz, 3 H), 7.47 (t, J = 9 Hz, 2 H), 7.38 (t, J = 7.5 Hz, 4 H), 7.33 (t, J = 7.2 Hz, 1 H), 7.19 (t, J = 7.5 Hz, 1 H) ppm. 13C NMR (150 MHz, DMSO-d6): δ 163.4, 162.1, 154.3, 153.0, 150.9, 142.3, 133.0, 130.9, 128.8, 128.7, 128.6, 127.9, 127.8, 124.6, 124.4, 124.1, 122.5, 118.3, 118.2, 117.1, 116.6, 116.0, 106.8, 98.4 ppm. Reaction Time: 18 h Colour & State: pale yellow solid Yield: 83% (175 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 70 HRMS (ESI) calcd for C27H15NO5 (M + H +) = 422.1023, found 422.1028. Elemental Analysis Calculated Found MF C26H15NO5 C 74.11 74.26 (421.41) H 3.59 3.66 N 3.32 3.41 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-7-methoxy-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12b): IR (KBr): 3480.96, 3311.64, 1717.06, 1617.46, 1242.79, 1125.00, 1111.20, 1026.12 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.02 (s, 1 H), 7.90 (d, J = 7.6 Hz, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.54 (d, J = 7.3 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.38 (m, 5 H), 7.05 (s, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 3.78 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.5, 162.0, 159.1, 154.4, 153.0, 152.2, 142.2, 132.9, 131.0, 129.1, 128.6, 127.6, 124.3, 124.0, 123.2, 116.6, 116.0, 115.7, 112.0, 111.3, 106.1, 101.7, 98.2, 55.6 ppm. HRMS (ESI) calcd for C27H17NO6 (M + H +) = 452.1129, found 452.1134. 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-6-methoxy-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12c): Reaction Time: 19 h Colour & State: brown solid Yield: 83% (187 mg) Melting Point: > 300 °C Elemental Analysis Calculated Found MF C27H17NO6 C 71.84 71.96 (451.43) H 3.80 3.85 N 3.10 3.17 Reaction Time: 19 h Colour & State: white solid Yield: 80% (180 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 71 IR (KBr): 3381.03, 3236.70, 1741.87, 1686.99, 1269.39, 1207.34, 1091.59 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.19 (s, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 2 H), 7.49 (d, J = 8.3 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 3 H), 7.33 (m, 1 H), 7.11 (m, 3 H), 3.91 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.2, 161.9, 153.8, 152.9, 147.3, 142.2, 140.1, 132.9, 130.8, 128.6, 127.7, 124.5, 124.3, 124.0, 118.8, 117.0, 116.5, 115.8, 113.8, 110.4, 106.8, 98.3, 55.9 ppm. HRMS (ESI) calcd for C27H17NO6 (M + H +) = 452.1129, found 452.1135. Elemental Analysis Calculated Found MF C27H17NO6 C 71.84 71.97 (451.43) H 3.80 3.77 N 3.10 3.18 6-Ethoxy-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12d): IR (KBr): 3410.53, 3211.72, 1738.08, 1695.86, 1271.88, 1193.31, 1085.82 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.20 (s, 1 H), 11.67 (s, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.54 (d, J = 7.1 Hz, 2 H), 7.49 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 7.0 Hz, 3 H), 7.34 (d, J = 6.6 Hz, 1 H), 7.08 (d, J = 11.2 Hz, 3 H), 4.15 (q, J = 6.3 Hz, 2 H), 1.42 (t, J = 5.9 Hz, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.2, 162.0, 154.0, 152.9, 146.6, 142.2, 140.2, 133.0, 130.8, 128.7, 127.7, 124.5, 124.4, 124.0, 118.9, 117.1, 116.6, 115.8, 113.7, 111.3, 106.7, 98.4, 64.2,14.8 ppm. HRMS (ESI) calcd for C28H19NO6 (M+H +) = 466.1285, found 466.1293. Elemental Analysis Calculated Found Reaction Time: 18 h Colour & State: white solid Yield: 81% (195 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 72 MF C28H19NO6 C 72.25 72.38 (465.46) H 4.11 4.06 N 3.01 2.92 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-8-nitro-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12e): IR (KBr): 3461.53, 3200.16, 1717.78, 1684.03, 1172.41, 1114.47, 1001.09 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.46 (s, 1 H), 8.33 (s, 1 H), 8.22 (d, J = 9.1 Hz, 1 H), 7.93 (d, J = 7.4 Hz, 1 H), 7.71 (m, 2 H), 7.59 (d, J = 6.8 Hz, 2 H), 7.52 (d, J = 8.1 Hz, 1 H), 7.39 (m, 4 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 164.2, 161.9, 154.6, 153.03, 152.99, 143.5, 142.9, 133.1, 130.6, 128.9, 128.7, 127.7, 126.9, 124.4, 124.1, 122.8, 118.6, 118.4, 118.0, 116.8, 116.5, 116.0, 107.6, 97.2 ppm. HRMS (ESI) calcd for C26H14N2O7 (M+H +) = 467.0874, found 467.0876. Elemental Analysis Calculated Found MF C26H14N2O7 C 66.96 66.83 (466.40) H 3.03 2.98 N 6.01 6.10 8-Chloro-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12f): IR (KBr): 3442.42, 3185.74, 1700.43, 1653.91, 1210.41, 1002.06 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.33 (s, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.55 (d, J = 7.6 Hz, 2 H), 7.51 (t, J = 7.8 Hz, 2 H), 7.38 (m, 6 H) ppm. Reaction Time: 20 h Colour & State: pale yellow Yield: 82% (191 mg) Melting Point: > 300 °C Reaction Time: 19 h Colour& State: pale yellow solid Yield: 80% (182 mg) Melting Point:> 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 73 13C NMR (100 MHz, DMSO-d6): δ 163.8, 161.9, 153.7, 152.9, 149.5, 142.5, 133.1, 130.7, 128.8, 128.7, 128.2, 127.7, 127.5, 127.1, 124.4, 124.1, 121.5, 119.7, 119.0, 117.1, 116.6, 115.9, 107.1, 97.6 ppm. HRMS (ESI): calcd for C26H14ClNO5 (M+H +) = 456.0633, found 456.0636. Elemental Analysis Calculated Found MF C26H14ClNO5 C 68.51 68.62 (455.85) H 3.10 3.14 N 3.07 3.02 8-Bromo-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4-b]pyrrol-4(3H)-one (12g): IR (KBr): 3394.82, 1723.95, 1270.45, 1158.59, 1111.09, 993.35 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.33 (s, 1 H), 7.92 (d, J = 7.9 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.54 (m, 4 H), 7.45 (m, 2 H), 7.35 (m, 4 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.9, 161.9, 153.7, 152.9, 149.9, 142.5, 133.1, 130.7, 130.3, 128.8, 128.7, 127.7, 127.0, 124.6, 124.5, 124.1, 120.2, 119.4, 117.1, 116.6, 116.2, 115.9, 107.1, 97.5 ppm. HRMS (ESI): calcd for C26H14BrNO5 (M+H +) = 500.0128, found 500.0128. Elemental Analysis Calculated Found MF C26H14BrNO5 C 62.42 62.56 (500.30) H 2.82 2.78 N 2.82 2.72 2-(4-Chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-6-methoxychromeno[3,4-b]pyrrol- 4(3H)-one (12h): Reaction Time: 16 h Colour & State: pale yellow solid Yield: 85% (212 mg) Melting Point: > 300 °C Reaction Time: 18 h Colour & State: white solid Yield: 84% (196 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 74 IR (KBr): 3517.04, 3203.39, 1713.08, 1678.80, 1275.14, 1106.66, 1041.03 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.28 (s, 1 H), 7.90 (d, J = 7.9 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.56 (m, 2 H), 7.48 (m, 3 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.11 (m, 3 H), 3.91 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.5, 161.9, 153.8, 153.0, 147.4, 140.9, 140.1, 133.5, 132.9, 129.7, 129.4, 128.8, 128.6, 124.5, 124.3, 124.0, 118.8, 117.2, 116.6, 115.9, 113.8, 110.4, 107.3, 97.9, 55.9 ppm. HRMS (ESI): calcd for C27H16ClNO6 (M+H +) = 486.0739, found 486.0735. Elemental Analysis Calculated Found MF C27H16ClNO6 C 66.74 66.60 (485.88) H 3.32 3.36 N 2.88 2.96 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(4-methoxyphenyl)-8-nitrochromeno[3,4-b]pyrrol- 4(3H)-one (12i): IR (KBr): 3508.71, 3325.52, 1738.09, 1675.74, 1262.45, 1127.55, 1042.58, 995.32 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.34 (s, 1 H), 8.32 (s, 1 H), 8.21 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 7.8 Hz, 1 H), 7.73 (t, J = 7.8 Hz, 1 H), 7.68 (d, J = 9.1 Hz, 1 H), 7.53 (t, J = 6.3 Hz, 3 H), 7.41 (t, J = 7.5 Hz, 1 H), 6.98 (d, J = 8.1 Hz, 2 H), 3.74 (s, 3 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 164.5, 162.2, 160.1, 155.0, 153.4, 153.3, 143.8, 143.4, 133.4, 129.4, 127.4, 124.7, 124.5, 123.3, 123.1, 119.0, 118.7, 118.3, 116.9, 116.7, 116.4, 114.6, 107.2, 97.8, 55.6 ppm. HRMS (ESI): calcd for C27H16N2O8 (M+H +) = 497.0979, found 497.0985. Elemental Analysis Calculated Found MF C27H16N2O8 C 65.33 65.19 Reaction Time: 19 h Colour & State: pale yellow solid Yield: 82% (203 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 75 (496.43) H 3.25 3.20 N 5.64 5.55 8-Bromo-2-(4-chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[3,4-b]pyrrol- 4(3H)-one (12j): IR (KBr): 3550.35, 3114.57, 1733.26, 1674.18, 1270.11, 1156.91, 998.05 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.41 (s, 1 H), 7.93 (d, J = 7.9 Hz, 1 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.57 (s, 1 H), 7.54 (m, 3 H), 7.54 (d, J = 8.3Hz, 1 H), 7.45 (m, 3 H), 7.40 (t, J = 7.7 Hz, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.9, 161.8, 153.6, 152.9, 149.8, 141.2, 133.6, 133.1, 130.3, 129.5, 129.4, 128.8, 126.9, 124.6, 124.4, 124.1, 120.1, 119.3, 117.3, 116.6, 116.2, 115.9, 107.4, 97.3 ppm. HRMS (ESI): calcd for C26H13BrClNO5 (M+H +) = 533.9738, found 533.9732. Elemental Analysis Calculated Found MF C26H13BrClNO5 C 58.40 58.56 (534.75) H 2.45 2.41 N 2.62 2.53 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(4-methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)- one (12k): IR (KBr): 3442.30, 3181.51, 1699.71, 1671.24, 1253.67, 1184.09, 1111.45 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.04 (s, 1 H), 7.90 (d, J = 7.9 Hz, 1 H), 7.70 (t, J = 7.7 Hz, 1 H), 7.49 (m, 5 H), 7.38 (m, 2 H), 7.19 (t, J = 7.5 Hz, 1 H), 6.95 (d, J = 8.5 Hz, 2 H), 3.73 (s, 3 H) ppm. Reaction Time: 19 h Colour & State: white solid Yield: 79% (210 mg) Melting Point: > 300 °C Reaction Time: 18 h Colour & State: white solid Yield: 86% (194 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 76 13C NMR (100 MHz, DMSO-d6): δ 163.5, 162.0, 159.5, 154.1, 153.0, 150.8, 142.2, 132.8, 129.0, 128.5, 127, 124.5, 124.2, 124.0, 123.2, 122.4, 118.3, 117.0, 116.6, 116.5, 114.1, 106.1, 98.1, 55.2 ppm. HRMS (ESI): calcd for C27H17NO6 (M+H +) = 452.1129, found 452.1129. Elemental Analysis Calculated Found MF C27H17NO6 C 71.84 71.96 (451.43) H 3.80 3.85 N 3.10 3.01 2-(4-Fluorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[3,4-b]pyrrol-4(3H)-one (12l): IR (KBr): 3480.96, 3211.72, 1699.00, 1684.42, 1269.77, 1110.34, 1040.04 cm-1. 1HNMR (600 MHz, DMSO-d6): δ 13.18 (s, 1 H), 7.90 (d, J = 7.7 Hz, 1 H), 7.70 (t, J = 7.7 Hz, 1 H), 7.58 (dd, J = 8.3, 5.6 Hz, 2 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.47 (t, J = 9.0 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H), 7.25 (t, J = 8.8 Hz, 2 H), 7.20 (t, J = 7.5 Hz, 1 H).ppm. 13C NMR (150 MHz, DMSO-d6): δ 163.6, 163.0, 162.0, 161.4, 154.2, 153.0, 150.8, 141.2, 132.9, 130.0, 129.9, 128.4, 127.9, 127.3, 124.6, 124.3, 124.0, 122.4, 118.2, 117.0, 116.9, 116.6, 116.0, 115.8, 115.6, 106.8, 98.0 ppm. HRMS (ESI): calcd for C26H14FNO5 (M+H +) = 440.0929, found 440.0923. Elemental Analysis Calculated Found MF C26H14FNO5 C 71.07 71.22 (439.40) H 3.21 3.15 N 3.19 3.11 Reaction Time: 18 h Colour & State: white solid Yield: 79% (173 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 77 2-(4-Chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[3,4-b]pyrrol-4(3H)-one (12m): IR (KBr): 3481.51, 3160.55, 1699.74, 1623.45, 1282.53, 1186.65, 1040.38, 1013.75 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.27 (s, 1 H), 7.91 (d, J = 7.2 Hz, 1 H), 7.69 (d, J = 6.7 Hz, 1 H), 7.55 (s, 3 H), 7.47 (d, J = 7.6 Hz, 4 H), 7.39 (s, 2 H), 7.20 (s, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.5, 161.9, 154.1, 153.0, 150.8, 140.8, 133.4, 132.9, 129.7, 129.4, 128.7, 128.4, 127.8, 124.6, 124.2, 124.0, 122.5, 118.1, 117.2, 117.0, 116.6, 116.0, 107.1, 97.8 ppm. HRMS (ESI): calcd for C26H14ClNO5 (M+H +) = 456.0633, found 456.0633. Elemental Analysis Calculated Found MF C26H14ClNO5 C 68.51 68.69 (455.85) H 3.10 3.00 N 3.07 3.14 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(3-methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)- one (12n): IR (KBr): 3448.09, 3258.17, 1706.03, 1683.46, 1231.28, 1130.73 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.16 (s, 1 H), 7.91 (d, J = 7.1 Hz, 1 H), 7.70 (d, J = 7.2 Hz, 1 H), 7.54 (d, J = 7.3 Hz, 1 H), 7.47 (t, J = 8.8 Hz, 2 H), 7.39 (s, 2 H), 7.26 (d, J = 8.0 Hz, 1 H), 7.19 (d, J = 7.7 Hz, 2 H), 7.11 (d, J = 7.3 Hz, 1 H), 6.89 (d, J = 7.8 Hz, 1 H), 3.68 (s, 3 H) ppm. Reaction Time: 19 h Colour & State: pale yellow solid Yield: 78% (177 mg) Melting Point: > 300 °C Reaction Time: 18 h Colour & State: pale yellow solid Yield: 80% (180 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 78 13C NMR (100 MHz, DMSO-d6): δ 163.5, 162.0, 159.2, 154.2, 153.0, 150.8, 141.8, 132.9, 132.0, 129.8, 128.5, 127.9, 124.6, 124.3, 124.0, 122.5, 119.8, 118.2, 117.02, 116.95, 116.6, 116.0, 114.6, 112.9, 106.9, 98.3, 55.0 ppm HRMS (ESI): calcd for C27H17NO6 (M+H +) = 452.1129 (found 452.1124). Elemental Analysis Calculated Found MF C27H17NO6 C 71.84 71.95 (451.43) H 3.80 3.75 N 3.10 3.16 2-(2-Chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)chromeno[3,4-b]pyrrol-4(3H)-one (12o): IR (KBr): 3504.06, 3185.45, 1700.96, 1619.85, 1280.85, 1110.98 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.18 (s, 1 H), 7.85 (d, J = 7.8 Hz, 1 H), 7.64 (t, J = 7.7 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.45 (m, 3 H), 7.36 (m, 5 H), 7.21 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 163.4, 161.8, 154.6, 153.2, 151.2, 140.1, 133.3, 133.1, 132.5, 131.1, 130.6, 130.0, 128.23, 128.18, 127.3, 124.9, 124.5, 124.3, 123.3, 118.7, 117.3, 117.2, 116.8, 116.4, 109.3, 98.1 ppm. HRMS (ESI): calcd for C26H14ClNO5 (M+H +) = 456.0633, found 456.0639. Elemental Analysis Calculated Found MF C26H14ClNO5 C 68.51 68.40 (455.85) H 3.10 3.02 N 3.07 3.03 Elemental Analysis Calculated Found MF C30H17NO5 C 76.43 76.56 (471.46) H 3.63 3.68 Reaction Time: 18 h Colour & State: pale yellow solid Yield: 80% (182 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 79 N 2.97 3.04 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(thiophen-2-yl)chromeno[3,4-b]pyrrol-4(3H)-one (12p): IR (KBr): 3445.90, 3168.01, 1706.35, 1680.36, 1191.68, 1128.92, 1007.86 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.24 (s, 1 H), 7.96 (d, J = 7.8 Hz, 1 H), 7.88 (d, J = 2.5 Hz, 1 H), 7.74 (t, J = 7.8 Hz, 1 H), 7.57 (d, J = 7.8 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.48 (d, J = 5.0 Hz, 1 H), 7.41 (m, 3 H), 7.19 (t, J = 7.5 Hz, 1 H), 7.12 (t, J = 3.8 Hz, 1 H) ppm. 13C NMR (100 MHz, DMSO-d6): δ 165.2, 162.2, 154.5, 153.6, 151.2, 136.6, 133.6, 132.3, 129.1, 128.4, 128.2, 127.9, 127.0, 125.0, 124.7, 124.6, 122.7, 118.4, 117.4, 117.2, 117.0, 116.6, 106.8, 97.7 ppm. HRMS (ESI): calcd for C24H13NO5S (M+H +) = 428.0587, found 428.0593. Elemental Analysis Calculated Found MF C24H13NO5S C 67.44 67.56 (427.43) H 3.07 3.01 N 3.28 3.35 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(naphthalen-2-yl)chromeno[3,4-b]pyrrol-4(3H)-one (12q): IR (KBr): 3446.32, 3112.98, 1700.01, 1653.77, 1252.57, 1123.87, 1046.08 cm-1. 1HNMR (400 MHz, DMSO-d6): δ 13.34 (s, 1 H), 8.17 (s, 1 H), 7.91 (t, J = 6.4 Hz, 2 H), 7.86 (t, J = 9.4 Hz, 2 H), 7.69 (t, J = 7.8 Hz, 1 H),7.63 (m, 2 H), 7.51 (m, 4 H), 7.39 (m, 2 H), 7.23 (t, J = 7.6 Hz, 1 H) ppm. Reaction Time: 18 h Colour & State: white solid Yield: 78% (167 mg) Melting Point: > 300 °C Reaction Time: 18 h Colour & State: white solid Yield: 82% (193 mg) Melting Point: > 300 °C TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 80 13C NMR (100 MHz, DMSO-d6): δ 163.5, 162.0, 154.2, 153.0, 151.8, 142.0, 132.8, 132.62, 132.56, 128.5, 128.4, 128.1, 128.0, 127.8, 127.6, 127.2, 126.82, 126.75, 125.1, 124.6, 124.2, 124.0, 122.6, 118.3, 117.2, 117.0, 116.5, 116.0, 107.2, 98.3 ppm. HRMS (ESI): calcd for C30H17NO5 (M+H +) = 472.1179, found 472.1186. TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 81 1HNMR (600 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4-b]pyrrol- 4(3H)-one (12a) 13C NMR (150 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-phenylchromeno[3,4- b]pyrrol-4(3H)-one (12a) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 82 1HNMR (400 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-6-methoxy-2- phenylchromeno[3,4-b]pyrrol-4(3H)-one (12c) 13C NMR (100 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-6-methoxy-2- phenylchromeno[3,4-b]pyrrol-4(3H)-one (12c) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 83 1HNMR (400 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-8-nitro-2-phenylchromeno[3,4- b]pyrrol-4(3H)-one (12e) 13C NMR (100 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-8-nitro-2-phenylchromeno[3,4- b]pyrrol-4(3H)-one (12e) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 84 1HNMR (400 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(4- methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)-one (12k) 13C NMR (100 MHz, DMSO-d6): 1-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-2-(4- methoxyphenyl)chromeno[3,4-b]pyrrol-4(3H)-one (12k) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 85 1HNMR (400 MHz, DMSO-d6): 2-(2-Chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3- yl)chromeno[3,4-b]pyrrol-4(3H)-one (12o) 13C NMR (100 MHz, DMSO-d6): 2-(2-Chlorophenyl)-1-(4-hydroxy-2-oxo-2H-chromen-3- yl)chromeno[3,4-b]pyrrol-4(3H)-one (12o) TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 86 Crystallographic Description Crystal data were collected with Bruker Smart Apex-II CCD diffractometer using graphite monochromated MoKα radiation (λ = 0.71073 Å) at 298 K. Cell parameters were retrieved using SMART software and refined with SAINT on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS. The structure was solved by direct methods implemented in SHELX-97 program and refined by full-matrix least-squares methods on F2. All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Table 9. Crystal data and structure refinements of compounds 4b and 4d. For atomic coordinates, equivalent isotropic displacement parameters and bond angles, please check CIF. Parameters Compound 12b Compound 12d Empirical Formula C31H27NO8S2 C32H31NO8S2 Formula Weight 605.66 621.70 Temperature 298 (2) K 296 (2) K CCDC No. 1498213 1498412 Wavelength (Ao ) 0.71073 0.71073 Crystal System triclinic Monoclinic Space group P -1 P 21/n Radiation type MoK\a MoK\a Radiation source fine-focus sealed tube a (Ao) 11.1717(4) 9.2820(2) b (Ao) 11.6891(6) 18.5563(4) c (Ao) 12.2032(9) 18.4475(5) α (o) 70.452(6) 90.00 β (o) 80.727(5) 101.5990(10) γ (o) 82.641(4) 90.00 Cell Voloume 1477.38(15) 3112.50(13) z 2 4 TH-1700_126122027 Chapter III Synthesis of Pyrrolocoumarins 87 Density 1.362 1.327 F (0 0 0) 632 1304.0 Theta ranges 3.5510 to 27.7570 2.47 to 24.45 Index ranges -13 ≤ h ≤ 14 -10 ≤ k ≤ 14 -15≤ l ≤ 16 -11 ≤ h ≤ 11 -21 ≤ k ≤ 22 -22 ≤ l ≤ 22 Reflection collected 11823 39886 Independent reflections 6667 5611 Completeness to theta 0.957 0.996 Number of parameters 392 394 Number of restraints 0 0 Godness of fit (GOF)on F2 1.055 1.051 Refinement method Full-matrix least square on F2 Full-matrix least square on F2 TH-1700_126122027 CHAPTER IV An Introduction to Oxidative C-H Bond Functionalization and Coumarin Fused Oxazoles and Thiazoles TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 88  IV.1. Introduction C-H bond functionalization has emerged as an ideal and versatile synthetic tool for the chemists to construct C-C and C-heteroatom bonds. The above strategy has advantage over the classical synthesis where the reaction is failed using the classical methods. Synthetic route following C-H bond functionalization provides an alternative to the chemists avoiding prefuntionalization and defunctionalization involving in the tradition synthesis and thus make synthetic schemes shorter, more efficient and highly desirable for C-C and C-X (X = N, O, S) bond formation.57 There is a rapid competition amongst the researchers to develop different reaction conditions like new catalysts and oxidants to achieve C-H bond functionalization in a simplified manner. A number of transition metal catalyzed and also metal free reaction protocols have been developed in recent decades which give an access to varieties of heterocyclic compounds of biological significance.58 The fast growing field of C-H functionalization has made its route in the arena of total synthesis and the synthetic chemists are exploring these new methodologies presently to architect complex molecular structures of biological and pharmaceutical importance.59 C-H bond functionalization to construct C-C and C-X bonds can be achieved in various ways. In the following chapter, oxidative functionalization of an sp3 C-H bond adjacent to alpha to a nitrogen atom will be discussed. Oxazole and thiazole derivatives are biologically very important scaffolds (Fig. 7). Many naturally occurring marine drugs and synthetic compounds containing these moieties have valuable medicinal properties.60 Moreover, coumarin containing thiazoles shows anti-convulsant and anti-inflammatory properties.61 There are various methodologies reported in literature for the synthesis of oxazoles and thiazoles including numerous methods based on C-H bond functionalization.62 On the other hand, very few methods are reported for the synthesis of coumarin fused oxazoles and thiazoles as described in section IV.4 and IV.5 of this chapter, respectively. Therefore, synthesis of these compounds has been carried out using mild reaction conditions exploring 3-aminocoumarin derivatives. TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 89 Figure 7. Biologically active oxazoles and thiazoles  IV.2. C-H bond Functionalization Adjacent to Nitrogen Atom Oxidative C-H bond functionalization alpha to a nitrogen atom to build various C-C and C- heteroatom bonds has been a fascinating strategy to access various molecular transformations. Electron rich amines having C-H bond alpha to nitrogen, easily undergo oxidation to generate iminium ions which are trapped by various nucleophiles to accomplish C-C, C-O, C-N, and C-S bonds. Murahashi et al. demonstrated a straight forward synthesis of α- aminonitriles via ruthenium catalyzed oxidative cynation of tertiary amines with sodium cynides in presence of AcOH. The mechanism was believed to proceed through an [iminium ion]-RunOOH complex which is attacked by HCN generated from AcOH and NaCN to give various α-aminonitriles as shown in Scheme 38.63 Scheme 38 Li and co-workers were inspired from Murahashi work and reported first catalytic alkynylation reaction of Csp3-H bond adjacent to a nitrogen atom via oxidative coupling as represented in Scheme 39.64 Later on the concept was expanded in the form of Cross Dehydrogaenative Coupling reaction (CDC) achieving various C-C bond formation. TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 90 Scheme 39 Li’s group first reported various indoles derivatives as Csp2 nucleophile in the cross dehydrogenative alkenylation of tetrahydroisoquinoline derivatives using Cu salt and TBHP. (Scheme 40).65 In 2005, the first broadly applicable procedure for the cross-dehydrogenative aza- Henry reaction was introduced by the group of Li. Various N-arylated tetrahydroisoquinolines were successfully coupled with an excess of the nitroalkanes as Csp3-C-H nucleophiles in the presence of catalytic quantities of CuBr and 1.2 equivalents of TBHP at room temperature (Scheme 40).66 Scheme 40 Secondary amines as substrates for cross dehydrogenative alkynylation was introduced by Li et al. in 2008. Various glycine derivatives were functionalized by alkynylation using CuBr as a catalyst and TBHP as an oxidant in DCM at room temperature as described in Scheme 41.67 Scheme 41 TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 91 Several other oxidants were also used in CDC reactions which led to the introduction of various metal free reaction protocols. In 2009, DDQ was introduced as an efficient oxidant to mediate the aza-Henry reaction at room temperature under neat conditions by Todd et al.68 The organic oxidant (diacetoxy)iodobenzene (DIB) was introduced for this reaction type by Liang and co-workers.69 Itoh and co-workers demonstrated that catalytic amounts of iodine in combination with hydrogen peroxide effectively catalyze the nitroalkylation of various tetrahydroisoquinoline derivatives by generating, the catalytic active hypoiodous acid (HIO) in situ (Scheme 42).70 Scheme 42 Su et al. demonstrated the alkynylation of tetrahydroisoquinolines in the presence of 1 equivalent of the oxidant DDQ under solvent-free, high-speed, ball-milling conditions (Scheme 43).71 The reaction proceeded smoothly with both aliphatic and aromatic alkynes. However, slightly better yields were obtained with aromatic substrates. Scheme 43 Lambert et al. described the tropilium ion mediated alpha cynation of amines. The oxidation of amine by tropilium ion gave the iminium ion which was trapped by KCN to give the α- aminonitriles as shown in Scheme 44.72 TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 92 Scheme 44 Iron-catalyzed direct C−N bond formation between azoles and amides was reported by Chen et al. The oxidative coupling reactions of sp3 C−H bonds adjacent to a nitrogen atom in amides and sulfonamides with the N−H bond in azoles were carried out in the presence of FeCl2 and di-tert- butyl peroxide (DTBP) as described in Scheme 45.73 They used various amides and sulfonamides as substrates for the oxidative C-H bond functionalization to construct C-N bonds. Scheme 45 Nakamura et al. used ZnBr2 as a catalyst to construct C-C bond between propargylic amines and terminal alkyne via redox cross dehydrogenative coupling reaction. They designed the substrate structures with an internal oxidant where reduction of the internal oxidant and catalytic oxidation of the C1(sp3)−H bond adjacent to the nitrogen atom of tertiary amine provided a reactive iminium intermediate which was attacked by the terminal alkyne to give the final product as shown in Scheme 46.74 Scheme 46 Wu et al. demonstrated the C−H bond functionalization without any oxidant using Ru(bpy)3(PF6)2 and Co(dmgH)2pyCl as a catalyst and photosensitizer respectively, as represented in Scheme 47. The C-C bond formation between glycine esters with β-keto esters or indoles derivatives was achieved under visible light irradiation. They proposed a mechanism where TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 93 electron transfer from glycine to photo excited Ru(bpy)3(PF6)2 takes place which in turn transfer electron to the photosensitizer. The photosensitizer, Co(dmgH)2PyCl oxidizes glycine radical to an iminium ions which by the attack of nucleophile produces final products.75 Scheme 47  IV.3. Oxidative C-H Bond Functionalization for the Synthesis of Heterocycles Cross dehydrogenative coupling reaction through functionalization of Csp3-H bond adjacent to nitrogen atom has led to the synthesis of various heterocyclic compounds. Some of the methods for the synthesis of heterocycles are being discussed in the following section. Wang and co-workers illustrated a Cu-catalyzed synthesis of polysubstituted oxazoles from benzylamines and β-diketones as represented in Scheme 48.76 The intermediates, formed by the reaction of benzylamines and β-diketones derivative in the presence of iodine undergo oxidative C-H bond functionalization which is followed by intramolecular cyclization and further oxidation to give oxazole derivatives. Scheme 48 Long and co-workers developed an efficient metal free approach to access various polysubstituted benzimidazoles using TEMPO−air/cat.TEMPO−O2 combination via oxidative C- H bond functionalization employing N1-benzyl/alkyl-1,2-phenylenediamines as substrates (Scheme 49).77 They also extended the protocol to synthesize oxazole derivatives using 2- benzylaminophenol as the starting material. TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 94 Scheme 49 Liang et al. synthesiszed various thiazole derivatives from N-benzyl-2-iodoanilines using K2S and CuBr in NMO via oxidative C-H bond functionalization of C-H bond alpha to nitrogen atom as shown in Scheme 50.78 Scheme 50 Patel and co-workers described the synthesis of 3-aroylindoles using CuBr as the catalyst and TBHP as the oxidant via intramolecular oxidative functionalization of o-alkynylated N, N- dimethylamines (Scheme 51).79 The reaction process involves Cu-catalyzed oxidative dehydrogenation followed by C−C and C−O bonds formation to give the indole derivatives. Scheme 51 Fu et al. developed a new method for the synthesis of quinazolinones via Cu-catalyzed oxidative dehydrogenation (Scheme 52). The reaction of substituted 2-halobenzamides and benzylamines using CuBr as the catalyst and air as an oxidant provides the quinazolinone derivatives. The domino reaction undergoes sequential Cu-catalyzed Ullmann-type coupling, aerobic oxidation, an intramolecular nucleophilic addition, and then a further oxidation process to afford the final quinazolinone derivatives.80 Scheme 52 TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 95 Zhang and co-workers depicted the construction of six-membered N-heterocycles via Cu- catalyzed oxidative dehydrogenation as shown in Scheme 53. The reaction of 2-(2-halophenyl)- 1H-indoles and benzylamines using air as an oxidant provided indolo(1,2-c)quinazolines. The reaction involves Cu catalyzed intermolecular N-arylation followed by an intramolecular aerobic oxidative C−H amination.81 Scheme 53 Maiti and co-workers recently synthesized various dihydrooxazinones via cross dehydrogenative coupling reaction of salicylamides employing CuCl2 as a catalyst as shown in Scheme 54.82 The reaction is a good example of CDC reaction to construct C-O bond. Scheme 54 Nachtsheim et al. demonstrated direct oxidative sp3C-H bond functionalization forming C-O bond between phenols and α-aminoacetophenones (Scheme 55) using TBAI as catalyst. The above methodology was further extended toward an intramolecular variant which gave direct access to a range of dihydro-4H-benzo[e][1,3]oxazin-4-ones as depicted in (Scheme 55).83 Scheme 55 Long and co-workers reported the synthesis of quinolinone derivatives via direct oxidative C- H functionalization adjacent to the nitrogen atom of N-arylmethyl-2-aminophenylketones. The reaction is like an intramolecular manich type reaction where oxidation of N-arylmethyl-2- TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 96 aminophenylketones by TEMPO gives an imine which by intramolecular nucleophilic attack followed by oxidation gives the quinolinone derivatives as shown in Scheme 56.84 Scheme 56 Various groups have reported oxidative Povarov reaction trapping the iminium ion formed in the oxidative C-H bond functionalization reaction adjacent to a nitrogen atom. Mancheno et al. reported the TEMPO oxoammonium salt-mediated oxidative Povarov reaction where several derivatives of substituted quinolones were synthesized using iron chloride as the catalyst. The iminium ion formed from the oxidation of N-alkyl anilines underwent Povarov reaction with olefins to provide the quinolone derivatives (Scheme 57).85 Scheme 57 Huo et al. synthesized various quinolone derivatives fused with lactone rings via oxidative dehyrogenation of glycine derivatives and THF followed by Povarov reaction of the intermediates using iron chloride as catalyst. The final product was obtained by the opening of THF ring in the dihydroquinoline adduct by HCl followed by ester exchange and aerial oxidation (Scheme 58).86 Scheme 58 Itami and co-workers synthesized the thiophene fused oxazepine derivative which has good binding affinity towards alpha receptor protein, via the iron catalyzed oxidative coupling of the thiophene moeity with methylamines. The reaction involves a metal-bound iminium species, TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 97 which then undergoes electrophilic substitution of the thiophene moiety giving the coupling product (Scheme 59).87 Scheme 59  IV.4. Synthesis of Coumarin Fused Oxazoles Literature survey reveals that oxazoles containing fused coumarins are very much less explored. There are only few methodologies available in literature to achieve the synthesis of coumarin fused oxazoles, mostly from 3-amino-4-hydroxy coumarins and its derivatives which are described below. Merchant and coworkers synthesized the oxazole derivatives using 3-amino-4- hydroxycoumarin and urea. The reaction proceeds through the formation of a urea derivative from 3-amino-4-hydroxycoumarin and urea, which undergo cyclization in the presence of Ac2O to give the coumarin fused oxazole (Scheme 60).88 Scheme 60 Gelin and co-workers demonstrated the synthesis of the coumarin fused oxazoles from oxime of 3-acetyl-4-hydroxycoumarin. The Oxime on refluxing in AcOH provides the oxazole derivative in 50% yield along with minor product isoxazole derivatives in 12% yield (Scheme 61).89 Scheme 61 Reddy et al. established the synthesis of various coumarin fused oxazoles from 3-amino-4- hydroxycoumarin on treatment with CS2 in the presence of alcoholic KOH producing TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 98 mercaptobenzopyranoxazolone which is followed by the alkylation/acylation to give the respective thio ether/ thio ester (scheme 62).90 Scheme 62 Ponomarev et al. developed the synthesis of coumarin fused oxazoles starting from 3-nitro-4- hydroxycoumarin. Initially, 3-nitro-4-hydroxycoumarin was reduced with alk. aq. Na2S2O4 to corresponding amine salt which was condensed with benzoylchloride to yield the respective oxazoles deivatives of coumarins (Scheme 63).91 Scheme 63 Majumdar et al. reported the synthesis of various 2-phenyl-7H-chromeno[6,5-d]oxazol-7-one derivatives by the intramolecular cyclization of coumarin containing amides in DMSO in the presence of Cs2CO3 at 130 °C . The oxazoles derivatives were obtained through a nucleophilic addition of amide to form the C–O bond (Scheme 64).92 Scheme 64  IV.5. Synthesis of Coumarin Fused Thiazoles Methods available for the synthesis of coumarin fused thiazoles are very limited. Some traditional methods to access various coumarin fused thiazoles are discussed in this section. TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 99 Cecchi and co-workers synthesized coumarin fused thiazole derivatives by the reductive cyclization of 4-aroyl-3-nitrocoumarin which were synthesized by the reaction of triethylammonium salt of 4-mercapto-3-nitrocoumarin with aroyl chlorides (Scheme 65).93 Scheme 65 Tevakovic et al. developed the synthesis of 2-methyl-chromeno[3,4-d)]hiazole-4-one from 3- thioacetamidochromeno-2-one using tetraethylammoniumperchlorate in CH3CN through electrochemical oxidation as shown in Scheme 66.94 Scheme 66 Majumdar et al. synthesized various coumarin annulated 2-aminothiazole derivatives using 6- bromo-7-aminocoumarin, carbondisulphide and a secondary amine in the presence of Cu(OTf)3 in DMF at 120 oC (Scheme 67).95 Scheme 67 They also developed the synthesis of 7H-chromeno[6,5-d]thiazol-7-one derivatives using FeCl3 as a catalyst in DMF at 120 °C from the acetyl derivatives of 6-amino-4-bromocoumarin derivatives (Scheme 68).96 TH-1700_126122027 Chapter IV Introduction: C-H Functionalization, Oxazoles & Thiazoles 100 Scheme 68 Thus the literature survey reveals that only traditional methods have been employed so far to achieve coumarin fused oxazoles and thiazoles. The main lacuna in the existing methods is very limited substrate scopes, poor yield and use of harsh reaction condition in some cases. Synthesis of these compounds via oxidative C-H bond functionalization provides an alternative, shorter and atom economic route. The next two chapters of the thesis deals with the synthesis of coumarin fused oxazoles and thiazole using oxidative C-H bond functionalization. TH-1700_126122027 CHAPTER V Synthesis of Fused Oxazole Containing Coumarin Derivatives via Oxidative Cross Coupling Reaction using a Combination of CuCl2 and TBHP RESULTS AND DISCUSSION TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 101  Results and Discussion In chapter IV, literature on oxidative C-H bond functionalization has been discussed in detail. Li and co-workers explored the tetrahydroisoquinoline moiety to achieve various C-C bonds using TBHP and Cu-salts.57 The concept is based on the oxidative functionalization of the C-H bond adjacent to nitrogen of tetrahydroisoquinoline to an iminium salt followed by trapping of the imine with various nucleophiles. In this chapter V, similar strategy is used for synthesizing fused oxazoles containing coumarin derivatives by employing CuCl2 as a catalyst and TBHP as an oxidant from various 3-(benzylamino)-2H- chromen-2-one (Scheme 69). Scheme 69. Synthesis of various coumarin fused oxazoles Initially, 3-(benzylamino)-2H-chromen-2-one (13a) was synthesized using 3- aminocoumarin and benzyl bromide in the presence of K2CO3 in DMF at 100 °C and characterized by NMR. The starting material (13a) was then treated with 10 mol% CuI and TBHP in DCM at room temperature and the reaction was monitored by checking TLC. The major product obtained after completion of the reaction, was separated by column chromatography and characterized by IR, NMR and HRMS. The compound was obtained in 50% yield and found to be 14a (Table 10), an oxazole derivative of coumarin after analyzing the IR, NMR and HRMS data (see page 120 for NMR spectra of compound 14a). To find out the optimal reaction condition, a number of reactions were executed using different copper salts like CuBr, CuBr2, Cu(OAc)2 .H2O, CuCl2, CuCl, Cu(NO2)2, CuSO4 as the catalyst and TBHP as the oxidant in DCM at room temperature. The desired product 14a was obtained from moderate to good yields (Table 10, entries 2-5 and 9-11). Among various copper salts, CuCl2 was found to be the optimized catalyst for the reaction. The desired product 14a was obtained in 64%, 66% and 72% yield with 10 mol%, 15 mol% and 20 mol% of CuCl2 respectively employing 3 equivalent of TBHP as oxidant in DCM at room temperature (Table 10, entry 5-7). TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 102 Lowering the amount of catalyst from 10 mol% to 5 mol%, yield of desired product was decreased to 61% (Table 10, entry 8). Apart from DCM, the desired oxazole product was also obtained in 1,2-dichloroethane (DCE), acetonitrile and chloroform (Table 10, entries 12-15) whereas no product was formed in DMF or DMSO (Table 10, entry 16 and 17). Furthermore, iron salts like FeCl2 and FeCl3 were found ineffective to produce the desired product (Table 10, 18 and 19). Also, the reaction was unsuccessful without any catalyst or oxidant (Table 10, entry 20 and 21) indicating that both are crucial for the formation of product. The reaction was not feasible with other oxidants like H2O2 and benzoyl peroxide (Table 10, entry 22 and 23). Table 10. Optimization of reaction conditiona Entry Catalyst (mol%) Solvent Oxidant Time/h Yield (%)b 1 CuI (10) DCM TBHP 18 50 2 CuBr (10) DCM TBHP 18 50 3 CuBr2 (10) DCM TBHP 20 52 4 Cu(AcO)2.H2O (10) DCM TBHP 24 10 5 CuCl2 (10) DCM TBHP 18 64 6 CuCl2 (15) DCM TBHP 18 66 7 CuCl2 (20) DCM TBHP 20 72 8 CuCl2 (5) DCM TBHP 18 61 9 CuCl (10) DCM TBHP 12 58 10 Cu(NO2)2 (10) DCM TBHP 20 60 11 CuSO4 (10) DCM TBHP 20 57 12 CuCl2(10) DCE TBHP 14 62 13 CuCl2(20) DCE TBHP 14 69 14 CuCl2 (10) CH3CN TBHP 24 45 15 CuCl2 (10) CHCl3 TBHP 32 45 16 CuCl2 (10) DMF TBHP 32 NR 17 CuCl2 (10) DMSO TBHP 32 NR 18 FeCl2 (10) DCM TBHP 24 NR 19 FeCl3 (10) DCM TBHP 24 NR 20 CuCl2 (10) DCM ------- 24 NR 21 ------- DCM TBHP 24 NR 22 CuCl2 (10) DCM H2O2 24 NR 23 CuCl2 (10) DCM Ph2(CO)2O2 24 NR aUnless otherwise stated all the reactions were carried out with 0.3 mmol of 13a , 3 equiv. of oxidant, in 3 mL of solvent at rt. bIsolated yield TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 103 A number of 3-(benzylamino)-2H-chromen-2-one derivatives were synthesized using various 3-aminocoumarin and benzyl bromide derivatives and was examined to evaluate the substrates scope of the present protocol. At first, the group tolerance on the benzyl moiety was studied. Interestingly, the desired oxazole derivatives of coumarin were afforded in good yield with both electron donating- (Table 11, 14b, 14e, 14h and 14i,) and withdrawing substituents (Table 11, 14c, 14d, 14f and 14g,). Product 14j was obtained in 68 % yield containing a heteroatom in the benzyl ring. Whereas replacing benzyl moiety with naphthyl moiety, the desired product 14k were obtained in significant yield, but in lesser time compared to the benzyl derivatives under the optimized conditions (Table 11). The yields were comparable with substituent at the meta- and para position of the benzyl group indicating no significant role of steric hindrance for the formation of products (Table 11, 14e-h). Notably, no product was obtained on replacing benzyl moiety with alkyl moiety. Table 11. Synthesis of coumarin fused oxazole derivatives TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 104 All the reaction were carried out with 0.3 mmol of 13, 3 equiv. of TBHP, 20 mol % of the CuCl2 in 3 mL of DCM at rt. b Isolated yield. Similarly, 3-(benzylamino)-2H-chromen-2-one with substituents on the coumarin moiety such as 7-MeO, 8-MeO and 8-EtO were also examined and the desired products 14l-u were isolated in satisfactory yield (Table 11 ). Unfortunately, the present protocol is not feasible with electron withdrawing substituents like 6-NO2, 6-Cl and 6-Br on the coumarin moiety. All the products were characterized by H1 NMR, 13C NMR and HRMS spectra (see pages 107-119 for NMR, IR and HRMS data of compounds 14a-u). Further, the structure of 14a was also established from single XRD data (Figure 8). Figure 8.ORTEP diagram of 14a (CCDC number 1405370) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 105 From literature survey97 and our experimental results, a plausible mechanism is presented for the formation of 14 from 13. Initially an iminium ion VA (Scheme 70) might be formed from 13 with the help of TBHP/CuCl2 and then another molecule of TBHP attacks the electrophilic centre of VA to form intermediate VB. Then the intermediate VB cyclizes to intermediate VD through VC and finally VD on aerial oxidation provides the desired product 14. Scheme 70. Plausible reaction mechanism for the formation of 14 TH-1700_126122027 Chapter V Synthesis of Coumarin Fused oxazoles 106 In summary, a novel approach have been demonstrated for the construction of various fused oxazole containing coumarin derivatives under mild reaction conditions. C-H bond functionalization followed by cyclization to various oxazoles under mild reaction condition are the salient features of the protocol. The synthesized compounds may exhibit interesting biological activity as from literature survey it reveals that coumarin and oxazole both moieties have interesting biological activates. TH-1700_126122027 CHAPTER V Synthesis of Fused Oxazole Containing Coumarin Derivatives via Oxidative Cross Coupling Reaction using a Combination of CuCl2 and TBHP EXPERIMENTAL SECTION TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 107  Experimental Section General procedure for the synthesis of various derivatives of 3-(benzylamino)-2H-chromen- 2-one (13a-u): Into a 25 mL round bottom flask was taken a mixture of 3-aminocomarin (1 mmol), benzyl bromide (1 mmol) and K2CO3 (1.2 mmol) in 3 mL of DMF. The reaction mixture was heated at 100 °C for 2-8 h and after completion of the reaction, the reaction mixture was worked-up with ethyl acetate. The crude product obtained after evaporation of the solvent in rotary evaporator was treated with ethanol to remove impurities. Finally a solid pure product (1a-u) was obtained in 75- 85 %. General procedure for the synthesis of various derivatives of 2-phenyl-4H-chromeno[3,4- d]oxazol-4-one (14a-u): Into a 10 mL round bottom flask 0.3 mmol of 1 was taken and then 3 mL of DCM was added into it. Then after adding 20 mol % of CuCl2 and 3 equivalent of TBHP, the reaction mixture was stirred at room temperature 18-24 h. The progress of the reaction was checked by TLC. After completion of the reaction, the reaction mixture was worked up with DCM and the crude product obtained after rotary evaporator was purified with column chromatography eluting with hexane and ethylacetate mixture (9:1). The pure product obtained after column chromatography was characterized by 1H NMR, 13C NMR and HRMS. 2-Phenyl-4H-chromeno[3,4-d]oxazol-4-one (14a): IR (KBr): 2958.00, 2923.26, 1756.03, 1606.03, 1261.51, 1156.54, 1103.31, 1064.16cm-1. 1HNMR (400 MHz, CDCl3): δ 8.26 (d, J = 7.2 Hz, 2 H), 7.94 (d, J = 7.6 Hz, 1 H), 7.52 (m, 5 H), 7.44 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.6, 156.4, 155.5, 153.2, 132.3, 131.9, 129.3, 127.7, 126.1, 126.0, 125.2, 121.6, 118.0, 111.8 ppm. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 72% (57 mg) Melting Point: 188-190 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 108 HRMS (ESI) calcd for C16H9NO3 (M+H +) = 264.0655, found 264.0655. Elemental Analysis Calculated Found MF C16H9NO3 C 73.00 72.85 (263.25) H 3.45 3.50 N 5.32 5.24 2-(p-Tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14b): IR (KBr): 3062.59, 2920.20, 1756.65, 1639.88, 1261.33, 1155.35, 1101.03, 1065.66 cm1. 1HNMR (400 MHz, CDCl3) δ 8.13 (d, J = 8 Hz, 2 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.50 (d, J = 8 Hz, 1 H), 7.42 (t, J = 4.8 Hz, 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 2.44 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 156.4, 155.2, 153.1, 143.0, 131.7, 130.0, 127.6, 126.1, 125.1, 123.2, 121.6, 117.9, 111.8, 21.9 ppm. HRMS (ESI) C17H11NO3 (M+H +) = 278.0812, found 278.0813. Elemental Analysis Calculated Found MF C17H11NO3 C 73.64 73.77 (277.28) H 4.00 3.96 N 5.05 4.98 2-(4-Fluorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14c): IR (KBr): 2924.10, 2853.13, 1737.29, 1634.64, 1229.50, 1097.64, 1068.25, 1027.01 cm1. Reaction Time: 22 h Colour & State: pale yellow solid Yield: 68% (56 mg) Melting Point: 246 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 64% (54 mg) Melting Point: 233 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 109 1HNMR (600 MHz, CDCl3): δ 8.27 (t, J = 7.8 Hz, 2 H), 7.93 (d, J = 7.8 Hz, 1 H), 7.62 (t, J = 7.8 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.25 (t, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 166.6, 164.0, 162.7, 156.3, 155.5, 153.2, 132.0, 130.0, 129.95, 125.2, 122.3, 121.6, 118.0, 116.8, 116.6, 111.7 ppm. HRMS (ESI) C16H8FNO3 (M+H +) = 282.0561, found 282.0567. Elemental Analysis Calculated Found MF C16H8FNO3 C 68.33 68.46 (281.24) H 2.87 2.91 N 4.98 4.90 2-(4-Chlorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14d): IR (KBr): 2963.49, 2925.09, 2845.34, 1760.06, 1604.80, 1261.57, 1093.47, 1020.06 cm1. 1HNMR (400 MHz, CDCl3) δ 8.18 (d, J = 8.4 Hz, 2 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.61 (t, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.6 Hz, 3 H), 7.43 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3: CD2Cl2 = 5:1): δ 162.5, 156.1, 155.6, 153.2, 138.5, 132.0, 129.7, 128.8, 125.5, 125.2, 124.4, 121.6, 117.8, 111.5 ppm. HRMS (ESI) calcd for C16H8ClNO3 (M+H +) = 298.0265 (found 298.0278). Elemental Analysis Calculated Found MF C16H8ClNO3 C 64.55 64.69 (297.69) H 2.71 2.75 N 4.71 4.78 Reaction Time: 24 h Colour & State: pale yellow solid Yield: 60% (54 mg) Melting Point: 226-229 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 110 2-(m-Tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14e): IR (KBr): 2956.72, 2918.40, 1753.81, 1639.30, 1102.98, 1060.65, 1031.94 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.08 (s, 1 H), 8.04 (d, J = 6.8 Hz, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.50 (d, J = 8.4 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 2 H), 7.37 (d, J = 7.2 Hz, 1 H), 2.45 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.7, 155.4, 153.2, 139.2, 133.1, 131.8, 129.2, 128.2, 125.8, 125.1, 124.8, 121.6, 117.9, 111.8, 21.5 ppm. HRMS (ESI) calcd for C17H11NO3 (M+H +) = 278.0812, found 278.0817. Elemental Analysis Calculated Found MF C17H11NO3 C 73.64 73.79 (277.28) H 4.00 3.95 N 5.05 4.97 2-(3-Chlorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14f): IR (KBr): 2923.34, 2852.57, 1755.61, 1638.29, 1286.06, 1096.19, 1052.92, 1029.17 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.26 (t, J = 1.8 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H),7.95 (dd, J = 7.8, 1.8 Hz, 1 H) 7.64 (m, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.53 (d, J = 8.4 Hz, 1 H), 7.50 (t, J = 8.4 Hz, 1 H), 7.45 (t, J = 7.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 162.1, 156.2, 155.7, 153.3, 135.5, 132.3, 132.2, 130.7, 127.6, 127.5, 126.1, 125.7, 125.3, 121.7, 118.0, 111.6 ppm. HRMS (ESI) calcd for C16H8ClNO3 (M+H +) = 298.0265, found 298.0271. Reaction Time: 22 h Colour & State: pale yellow solid Yield: 62% (52 mg) Melting Point: 188 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 56% (50 mg) Melting Point: 232-234 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 111 Elemental Analysis Calculated Found MF C16H8ClNO3 C 64.55 64.33 (297.69) H 2.71 2.77 N 4.71 4.62 2-(2-Chlorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14g): IR (KBr): 2924.13, 2852.45, 1757.06, 1641.27, 1167.90, 1068.50, 1034.42cm-1. 1HNMR (400 MHz, CDCl3): δ 8.23 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 7.6 Hz, 1 H), 7.63 (t, J = 8.8 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.49 (dd, J = 7.6, 1.6 Hz, 1 H), 7.46 (d, J = 3.6 Hz, 1 H), 7.45 (d, J = 3.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 161.6, 156.2, 155.8, 153.3, 133.6, 132.8, 132.2, 131.7, 127.4, 125.8, 125.2, 125.0, 121.9, 118.0, 111.7 ppm. HRMS (APCI) calcd for C16H8ClNO3 (M+H +) = 298.0265, found 298.0268. Elemental Analysis Calculated Found MF C16H8ClNO3 C 64.55 64.68 (297.69) H 2.71 2.66 N 4.71 4.65 2-(2-Methoxyphenyl)-4H-chromeno[3,4-d]oxazol-4-one (14h): IR (KBr): 2956.26, 2924.46, 2853.39, 1751.49, 1652.71, 1265.42, 1161.69, 1069.43, 1021.09 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.16 (d, J = 7.2 Hz, 1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.59 (m, 1 H), 7.52 (t, J = 8.4 Hz, 2 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.11 (m, 2 H), 4.02 (s, 3 H) ppm. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 55% (49 mg) Melting Point: 171-173 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 65 % (57 mg) Melting Point: 168-170 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 112 13C NMR (150 MHz, CDCl3): δ 162.4, 158.6, 156.4, 155.2, 153.2, 138.5, 133.6, 131.7, 131.4, 125.0, 121.7, 121.0, 117.8, 115.0, 112.3, 111.9, 56.2 ppm. HRMS (ESI) calcd for C17H11NO4 (M+H +) = 294.0761, found 294.0778. Elemental Analysis Calculated Found MF C17H11NO4 C 69.62 69.80 (293.28) H 3.78 3.70 N 4.78 4.87 2-(4-(tert-butyl)phenyl)-4H-chromeno[3,4-d]oxazol-4-one (14i): IR (KBr): 3066.92, 2949.93, 1753.50, 1684.67, 1285.19, 1167.19, 1063.56, 1041.90 cm-1 1HNMR (400 MHz, CDCl3): δ 8.19 (d, J = 8.4 Hz, 2 H), 7.94 (d, J = 7.6 Hz, 1 H), 7.61 (t, J = 7.4 Hz, 1 H), 7.56 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.43 (t, J = 7.2 Hz, 1 H), 1.38 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 156.6, 156.1, 155.3, 153.1, 131.8, 127.5, 126.3, 126.1, 125.1, 123.1, 121.6, 117.9, 111.8, 35.4, 31.3 ppm. HRMS (APCI+) calcd for C19H17NO3 (M+H +) = 320.1281, found 320.1280. Elemental Analysis Calculated Found MF C20H17NO3 C 75.22 75.38 (319.36) H 5.37 5.41 N 4.39 4.29 Reaction Time: 24 h Colour & State: pale yellow solid Yield: 67% (64 mg) Melting Point: 207-209 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 113 2-(Thiophen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14j): IR (KBr): 3095.65, 2924.28, 2853.43, 1752.86, 1634.11, 1210.78, 1101.71, 1068.24, 1032.66 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.95 (d, J = 3.2 Hz, 1 H), 7.90 (dd, J = 7.6, 1.2 Hz, 1 H), 7.60 (m, 2 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.42 (t, J = 7.6 Hz, 1 H), 7.21 (t, J = 4.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 159.5, 156.2, 155.0, 153.1, 131.9, 131.3, 130.8, 128.6, 128.0, 126.0, 125.2, 121.6, 117.9, 111.5 ppm. HRMS (ESI) calcd for C14H7NO3S (M+H +) = 270.0219, found 270.0240. Elemental Analysis Calculated Found MF C14H7NO3S C 62.45 62.33 (269.27) H 2.62 2.57 N 5.20 5.12 2-(Naphthalen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14k): IR (KBr): 2925.03, 2852.61, 1755.81, 1605.26, 1101.74, 1067.46, 1029.24 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.77 (s, 1 H), 8.30 (d, J = 8.8 Hz, 1 H), 7.99 (d, J = 8 Hz, 3 H), 7.90 (d, J = 8.8 Hz, 1 H), 7.61 (m, 3 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.46 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 156.4, 155.5, 153.2, 135.1, 133.0, 131.9, 129.3, 129.2, 128.4, 128.36, 128.2, 127.4, 126.6, 125.2, 123.7, 123.2, 121.7, 118.0, 111.8 ppm. HRMS (ESI) calcd for C20H11NO3 (M+H +) = 314.0812, found 314.0816. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 68% (55 mg) Melting Point: 170-172 °C Reaction Time: 18 h Colour & State: pale yellow solid Yield: 80% (75 mg) Melting Point: 245 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 114 Elemental Analysis Calculated Found MF C20H11NO3 C 76.67 76.81 (313.31) H 3.54 3.47 N 4.47 4.37 7-Methoxy-2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14l): IR (KBr): 2924.88, 2852.86, 1748.58, 1638.71, 1151.36, 1117.36, 1061.23, 1029.99 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.22 (d, J = 6.4 Hz, 2 H), 7.81 (d, J = 8.4 Hz, 1 H), 7.54 (m, 3 H), 7.00 (d, J = 8.8 Hz, 2 H), 3.91(s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 162.7, 162.3, 156.3, 155.7, 154.8, 131.7, 129.0, 127.2, 125.8, 123.4, 122.3, 113.3, 104.6, 101.6, 55.8 ppm. HRMS (ESI) calcd for C17H11NO4 (M+H +) = 294.0761, found 294.0774. Elemental Analysis Calculated Found MF C17H11NO4 C 69.62 69.82 (293.28) H 3.78 3.83 N 4.78 4.86 7-Methoxy-2-(p-tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14m): IR (KBr): 2923.23, 2854.65, 1767.39, 1638.09, 1270.71, 1103.27, 1059.04, 1023.23 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.4 Hz, 2 H), 7.79 (d, J = 8.4 Hz, 1 H), 7.32 (d, J = 6.4 Hz, 2 H), 6.98 (s, 2 H) 3.83 (s, 3 H), 2.36 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 162.9, 156.7, 155.9, 155.0, 142.7, 130.0, 127.5, 123.7, 123.4, 122.5, 113.6, 105.0, 101.9, 56.1, 21.9 ppm. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 54% (47 mg) Melting Point: 209 °C Reaction Time: 22 h Colour & State: pale yellow solid Yield: 58% (53 mg) Melting Point: 220 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 115 HRMS (ESI) calcd for C18H13NO4 (M+H +) = 308.0917, found 308.0931. Elemental Analysis Calculated Found MF C18H13NO4 C 70.35 70.49 (307.30) H 4.26 4.20 N 4.56 4.49 6-Methoxy-2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14n): IR (KBr): 3063.33, 2997.68, 2928.07, 2844.55, 1759.97, 1640.76, 1277.78, 1075.41, 1043.28, 1002.19 cm-1 1HNMR (400 MHz, CDCl3): δ 8.26 (d, J = 6.0 Hz, 2 H), 7.56 (m, 3 H), 7.50 (d, J = 8 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 1 H), 4.00(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.6, 155.8, 155.6, 148.2, 132.3, 129.3, 129.0, 127.7, 126.2, 126.0, 125.4, 113.9, 112.9, 112.5, 56.6 ppm. HRMS (ESI) calcd for C17H11NO4 (M+H +) = 294.0761, found 294.0766. Elemental Analysis Calculated Found MF C17H11NO4 C 69.62 69.45 (293.28) H 3.78 3.74 N 4.78 4.70 6-Methoxy-2-(p-tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14o): Reaction Time: 24 h Colour & State: pale yellow solid Yield: 66% (58 mg) Melting Point: 220 °C Reaction Time: 22 h Colour & State: pale yellow solid Yield: 66% (61 mg) Melting Point: 238 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 116 IR (KBr): 2923.41, 2850.78, 1753.51, 1610.64, 1275.99, 1081.42, 1048.66, 996.21 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.11 (d, J = 7.2 Hz, 2 H), 7.62 (d, J = 8.0 Hz, 1 H), 7.33 (t, J= 8.0 Hz, 3 H), 7.11 (d, J = 7.6 Hz, 1 H), 3.99 (s, 3 H), 2.43 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 155.9, 155.3, 148.1, 143.0, 142.9, 130.0, 127.6, 126.2, 125.3, 123.2, 113.7, 112.9, 112.5, 56.6, 21.9 ppm. HRMS (ESI) calcd for C18H13NO4 (M+H +) = 308.0917, found 308.0923. Elemental Analysis Calculated Found MF C18H13NO4 C 70.35 70.50 (307.30) H 4.26 4.31 N 4.56 4.48 2-(4-Fluorophenyl)-6-methoxy-4H-chromeno[3,4-d]oxazol-4-one (14p): IR (KBr): 2923.84, 2852.00, 1751.45, 1637.57, 1277.09, 1100.90, 1081.26, 1046.33 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.26 (dd J = 7.6, 5.2 Hz, 2 H), 7.49 (d, J = 8 Hz, 1 H), 7.36 (t, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.01 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 166.6, 164.0, 162.7, 155.8, 155.7, 148.2, 143.0, 130.0, 129.95, 126.2, 125.4, 122.3, 116.8, 116.6, 113.9, 112.9, 112.4, 56.6 ppm. HRMS (ESI) calcd for C17H10NO4 (M+H +) = 312.0667, found 312.0682. Elemental Analysis Calculated Found MF C17H10FNO4 C 65.60 65.78 (311.27) H 3.24 3.20 N 4.50 4.42 Reaction Time: 24 h Colour & State: pale yellow solid Yield: 56% (52 mg) Melting Point: 248 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 117 6-Ethoxy-2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14q): IR (KBr): 2967.46, 2920.28, 2845.34, 1752.51, 1603.25, 1276.85, 1081.11, 1045.09, 1017.41 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.26 (d, J = 6.4 Hz, 2 H), 7.55 (m, 3 H), 7.49 (d, J = 7.6 Hz, 1 H), 7.34 (t, J = 8.4 Hz, 1 H), 7.14 (d, J = 8.0 Hz, 1 H), 4.22 (q, J = 6.4 Hz, 2 H), 1.54 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.6, 156.1, 155.7, 147.6, 143.2, 132.3, 129.3, 127.7, 126.0, 125.4, 115.1, 112.9, 112.6, 65.4, 15.0 ppm. HRMS (ESI) calcd for C18H13NO4 (M+H +) = 308.0917, found 308.0917. Elemental Analysis Calculated Found MF C18H13NO4 C 70.35 70.51 (307.30) H 4.26 4.21 N 4.56 4.64 6-Ethoxy-2-(p-tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14r): IR (KBr): 2959.14, 2923.05, 2844.49, 1752.97, 1637.36, 1276.51, 1262.41, 1081.73, 1102.88, 1017.50 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 1 H), 7.23 (m, 3 H), 7.04 (d, J = 7.6 Hz, 1 H), 4.14 (q, J = 6.4, 2 H), 2.37 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 156.1, 155.4, 147.5, 143.1, 142.9, 130.0, 127.6, 126.1, 125.3, 123.2, 115.0, 112.8, 112.6, 65.4, 21.9, 15.0 ppm. HRMS (ESI) calcd for C19H15NO4 (M+H +) = 322.1074, found 322.1077. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 64% (59 mg) Melting Point: 218 °C Reaction Time: 21 h Colour & State: pale yellow solid Yield: 58% (56 mg) Melting Point: 195-197 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 118 Elemental Analysis Calculated Found MF C19H15NO4 C 71.02 71.21 (321.33) H 4.71 4.75 N 4.36 4.26 6-Ethoxy-2-(m-tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14s): IR (KBr): 2924.09, 2852.21, 1747.07, 1640.50, 1278.12, 1104.94, 1047.03, 1019.35 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.08 (s, 1 H), 8.03 (d, J = 7.2 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.36 (t, J = 5.6 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.12 (d, J = 7.6 Hz, 1 H), 4.21 (q, J = 6.8 Hz, 2 H), 2.45 (s, 3 H), 1.52 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.7, 156.0, 155.6, 147.5, 143.1, 139.2, 133.1, 129.2, 128.2, 126.1, 125.8, 125.3, 124.8, 115.0, 112.8, 112.5, 65.4, 21.5, 15.0 ppm. HRMS (ESI) calcd for C19H15NO4 (M+H +) = 322.1074, found 322.1079. Elemental Analysis Calculated Found MF C19H15NO4 C 71.02 71.20 (321.33) H 4.71 4.66 N 4.36 4.28 6-Methoxy-2-(naphthalen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14t): IR (KBr): 2924.69, 2852.94, 1759.34, 1603.15, 1603.15, 1273.60, 1111.62, 1048.71 cm-1. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 59% (57 mg) Melting Point: 189 °C Reaction Time: 18 h Colour & State: pale yellow solid Yield: 78% (80 mg) Melting Point: 270 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 119 1HNMR (400 MHz, CDCl3): δ 8.76 (s, 1 H), 8.29 (d, J = 8.4 Hz, 1 H), 7.99 (d, J = 8 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 1 H), 7.59 (t, J = 3.6 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.01 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.8, 155.8, 155.7, 148.2, 135.1, 133.1, 129.3, 129.2, 128.4, 128.36, 128.2, 127.4, 126.4, 125.4, 123.8, 123.2, 113.9, 113.0, 112.5, 56.6 ppm. HRMS (ESI) calcd for C21H13NO4 (M+H +) = 344.0917, found 344.0923. Elemental Analysis Calculated Found MF C21H13NO4 C 73.46 73.31 (343.34) H 3.82 3.77 N 4.08 3.99 6-Ethoxy-2-(naphthalen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14u): IR (KBr): 2924.43, 2852.64, 1760.02, 1605.56, 1272.39, 2080.36, 1051.17, 1013.12 cm1. 1HNMR (400 MHz, CDCl3): δ 8.76 (s, 1 H), 8.29 (d, J = 8.4 Hz, 1 H), 7.98 (d, J = 8.4 Hz, 2 H), 7.89 (d, J = 8.4 Hz, 1 H), 7.59 (t, J = 4 Hz, 2 H), 7.54 (d, J = 7.6 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 1 H), 4.23 (q, J = 7.2 Hz, 2 H), 1.54 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.7, 156.1, 155.8, 147.6, 135.1, 133.1, 129.3, 129.2, 128.4, 128.3, 128.2, 127.4, 126.3, 125.4, 123.7, 123.2, 115.2, 112.9, 112.6, 65.4, 15.0ppm. HRMS (ESI) calcd for C22H15NO4 (M+H +) = 358.1074, found 358.1096. Elemental Analysis Calculated Found MF C22H15NO4 C 73.94 74.11 (357.36) H 4.23 4.18 N 3.92 3.86 Reaction Time: 18 h Colour & State: pale yellow solid Yield: 81% (87 mg) Melting Point: 221 °C TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 120 1HNMR (400 MHz, CDCl3): 2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14a) 13C NMR (100 MHz, CDCl3): 2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14a) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 121 1HNMR (400 MHz, CDCl3): 2-(p-Tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14b) 13C NMR (100 MHz, CDCl3): 2-(p-Tolyl)-4H-chromeno[3,4-d]oxazol-4-one (14b) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 122 1HNMR (400 MHz, CDCl3): 2-(2-Chlorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14g) 13C NMR (100 MHz, CDCl3): 2-(2-Chlorophenyl)-4H-chromeno[3,4-d]oxazol-4-one (14g) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 123 1HNMR (400 MHz, CDCl3): 2-(Thiophen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14j) 13C NMR (100 MHz, CDCl3): 2-(Thiophen-2-yl)-4H-chromeno[3,4-d]oxazol-4-one (14j) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 124 1HNMR (400 MHz, CDCl3): 6-Methoxy-2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14n) 13C NMR (100 MHz, CDCl3): 6-Methoxy-2-phenyl-4H-chromeno[3,4-d]oxazol-4-one (14n) TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 125 Crystallographic Description Crystal data were collected with Bruker Smart Apex-II CCD diffractometer using graphite monochromated MoKα radiation (λ = 0.71073 Å) at 298 K. Cell parameters were retrieved using SMART software and refined with SAINT on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS. The structure was solved by direct methods implemented in SHELX-97 program and refined by full-matrix least-squares methods on F2. All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Table 12. Crystal data and structure refinements of compounds 14a. For atomic coordinates, equivalent isotropic displacement parameters and bond angles, please check CIF. Parameters Compound 14a Empirical Formula C16H9NO3 Formula Weight 263.24 Temperature 296(2) K CCDC No. 1405370 Wavelength (Ao ) 0.71073 Crystal System monoclinic Space group P2(1)/n Radiation type MoK\a Radiation source fine-focus sealed tube a (Ao) 7.1596(4) b (Ao) 13.3572(7) c (Ao) 13.0999(6) α (o) 90.00 β (o) 98.358(4) γ (o) 90.00 Cell Voloume 1239.47(11) z 4 Density 1.411 F (0 0 0) 544 Theta ranges 2.19 to 27.50 Index ranges -9 ≤ h ≤ 9, -17 ≤ k ≤ 13, -16 ≤ l ≤ 16 Reflection collected 14724 Independent reflections 2784 Completeness to theta 0.977 Number of parameters 181 TH-1700_126122027 Chapter V Synthesis of Coumarin Fused Oxazoles 126 Number of restraints 0 Godness of fit (GOF)on F2 0.976 Refinement method Full-matrix least square on F2 TH-1700_126122027 CHAPTER VI Oxidative Cross Coupling Reaction Mediated by I2/H2O2: A Novel Approach for Construction of Fused Thiazole Containing Coumarin Derivatives RESULTS AND DISCUSSION TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 127  Results and Discussions Previously in chapter V, the synthesis of fused oxazole containing coumarin derivatives has been described where 3-(benzylamino)-2H-chromen-2-one was used for synthesizing oxazole derivative of coumarin via oxidative C-H bond functionalization employing TBHP and CuCl2. The bromination of 3-(benzylamino)-2H-chromen-2-one using stoichiometric amount of bromodimethylsulphonium bromide (BDMS) provides 3-(benzylamino)-4-bromo-2H-chromen-2- one (Table 14, 15a). Liang and co-workers synthesized benzothiazole derivatives from N-benzyl- 2-iodoanilines using K2S and CuBr in NMO via oxidative C-H bond functionalization. 78 Further, Itoh et al. reported the nitroalkylation of tetrahydroisoquinoline derivatives using I2 as a catalyst and H2O2 as a terminal oxidant. 70 The present chapter of the thesis describes the construction of fused thiazole derivatives of coumarin via oxidative C-H bond functionalization using I2/H2O2 combination. Various 3-(benzylamino)-4-bromo-2H-chromen-2-one derivatives have been explored where Na2S is used as the source of sulphur atom, shown in Scheme 71. Scheme 71. Synthesis of coumarin fused thiazole derivatives Initially, bromination of 3-(benzylamino)-2H-chromen-2-one (13a) was carried out using bromodimethylsulphonium bromide to achieve its bromo derivatives, 3-(benzylamino)-4-bromo- 2H-chromen-2-one (15a, Table 14) which was characterized by IR, NMR, and HRMS spectroscopic techniques. Then a reaction of 15a was carried out with Na2S (3 equiv.) using H2O2 (5 equiv.) in the presence of 20 mol% of I2 in acetonitrile under reflux condition. The reaction was monitored by checking TLC and the major product obtained was isolated by column chromatography. The pure product obtained was found to be 16a (Table 13), a coumarin fused thiazole derivative as characterized by IR, NMR and HRMS (see page 163 for NMR spectra of 16a). TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 128 To improve the yield of the product (16a), reactions in various solvents were carried out with different catalysts. A comparable yield was obtained by replacing acetonitrile with DMSO (Table 13, entry 2). No desired product was obtained with H2O, MeOH, EtOH, CHCl3 or DCM as a solvent (Table 13, entries 3-7). DMF was found to be the best solvent producing the desired product in reasonable yield (Table 13, entry 8). To understand the role of the catalyst and the oxidant, a reaction was executed in the presence of H2O2 without molecular iodine but the required product was obtained in poor yield (Table 13, entry 9). Interestingly, only 15 % yield was obtained when the same reaction was performed with 20 mol% of molecular iodine without using H2O2 (Table 13, entry 10). A significant reduction in yield was observed on decreasing the amount of the catalyst to 10 mol% (Table 13, entry 11). Further attempts were made to improve the yield of the reaction product by using different catalysts and oxidizing agents. However, on replacing H2O2 with TBHP, the yield of the desired product was further decreased to 20 % (Table 13, entry 12). With the same oxidizing agent, the yield was increased to some extent when DMSO was used as solvent in place of DMF (Table 13, entry 13). Apart from molecular iodine, the efficacy of other iodine sources like NIS, TBAI and KI as catalysts were also examined, but the expected thiazole derivative was obtained in poor yields (Table 13, entries 14-16). Notably, the reaction was unproductive at ambient temperature (entry 17). Table 13.Optimization of the reaction conditiona Entry Solvent Catalyst (mol %) Co-oxidant Yield (%)b 1 CH3CN I2 (20) H2O2 60 2 DMSO I2 (20) H2O2 50 3c H2O I2 (20) H2O2 NR 4c MeOH I2 (20) H2O2 NR 5c EtOH I2 (20) H2O2 NR 6c CHCl3 I2 (20) H2O2 NR 7c CH2Cl2 I2 (20) H2O2 NR TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 129 8 DMF I2 (20) H2O2 86 9 DMF --- H2O2 10 10 DMF I2 (20) --- 15 11 DMF I2 (10) H2O2 60 12 DMF I2 (20) TBHP 20 13 DMSO I2 (20) TBHP 70 14 DMF NIS (20) H2O2 10 15 DMF TBAI (20) H2O2 15 16 DMF KI (20) H2O2 40 17* DMF I2 (20) H2O2 NR aUnless otherwise stated all the reaction have been carried out with 0.3 mmol of 15a and 0.9 mmol of Na2S in the presence of 20 mol % of the catalyst and 5 equivalent of the oxidants in 2 ml of the solvent at 120 °C for 24 h. bIsolated yield. c at reflux condition. *at room temperature After achieving the optimized conditions several derivatives of 3-(benzylamino)-4-bromo- 2H-chromen-2-one (Table 14, 15a-v) were synthesized and used for the synthesis of various thiazole derivatives of coumarin. The effect of different groups attached with the coumarin and benzyl moieties were thoroughly examined. Initially, the benzyl moiety with electron donating (Table15, 16b and 16f,) as well as electron withdrawing substituents (Table15, 16c-e and 16g) on it were evaluated. Interestingly, in both the cases, the reaction underwent smoothly to produce the desired products in good yields. Even a similar outcome was observed in the presence of methoxy- , ethoxy-, chloro- and bromo- group on the coumarin moiety (Table15, 16j-t). Table 14. Synthesis of various 3-(benzylamino)-4-bromo substituted chromenone derivatives TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 130 i) All the reactions have been carried out with 1 mmol of each 1 and 17 and 1.2 equiv. of K2CO3 in DMFat 100 °C. ii) Bromination is carried out using 0.5 mmol of C in DCM at rt. iii) Isolated yield To explore the diversity of our protocol, the benzyl moiety was replaced with 2- methylnapthalene functionality (Table14, 15i, 15u and 15v). The reactions of 15i, 15u and 15v and Na2S were carried out under the optimized reaction conditions. The corresponding products 16i, 16u and 16v (Table 15) were obtained in 85-89 % yields. Notably, the substituents (R1) on aryl rings of various coumarin derivatives were found to have no significant effect on the yield of the reaction. In the present case, the yields were comparable to the benzyl derivatives however the reactions were much faster (Table 15, 16i, 16u and 16v). TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 131 Table 15. Preparation of 2-phenyl-4H-chromeno(3,4-d)thiazol-4-one derivativesa,b TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 132 aAll the reaction have been carried out with 0.3 mmol of 15 and 0.9 mmol of Na2S in the presence of 20 mol % of Iodine and 5 equivalent of H2O2 in 2 ml of DMF at 120 oC. b Isolated yield Unfortunately, no product was obtained with ortho substituted benzyl moiety in the chromenone ring. The failure of the reaction with ortho substitution on the benzyl moiety may be attributed to steric hindrance. Using benzyl moiety containing heteroatom in the ring such as 4- bromo-3-((thiophen-2-ylmethyl)amino)-2H-chromen-2-one (15h), the desired thiazole derivative (16h) was isolated in 66 % yield ( Table 15). All the compounds were characterized by IR, 1H NMR, 13C NMR, and HRMS spectra analysis (see pages 145-157 for NMR, IR and HRMS data for all the compounds 16a-v). The structure of the thiazole derivative (16a) was also confirmed by single crystal X-ray diffraction analysis (Figure 9). Figure 9.Single crystal structure of 16a (CCDC: 1013314) Based on literature survey70 and our experimental results, a plausible mechanism can be drawn. Initially, Na2S reacts with 15 to generate the intermediate VIA (see Scheme. 15) and then VIA is oxidised by iodine to generate an iminium ion intermediate VIB. HI generated in the above step is oxidized by H2O2 to recycle I2. The cyclized compound VIC is produced via intramolecular TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazole 133 nucleophilic attack by the sulfur atom at the electrophilic carbon of the iminium ion (VIB). Finally, VIC on aerial oxidation provides the desired product 16. Scheme 72. Plausible reaction mechanism for the formation of 16 An efficient protocol for the synthesis of various fused thiazole containing coumarin derivatives has been demonstrated. The metal free C-H activation for C-S bond formation by I2/H2O2 is less expensive and more environmentally benign compared to the metal catalyzed C-H activation. The protocol is diverse and the thiazoles derivatives are obtained in good to excellent yields. Finally, the protocol represents a useful alternative tool to achieve multifarious medicinally active coumarin fused thiazoles. TH-1700_126122027 CHAPTER VI Oxidative Cross Coupling Reaction Mediated by I2/H2O2: A Novel Approach for Construction of Fused Thiazole Containing Coumarin Derivatives EXPERIMENTAL SECTION TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 134  Experimental Section General procedure for the synthesis of various 3-(benzylamino)-4-bromo-2H-chromen-2- one derivatives (15a-v): Step I: Into a 25 mL round bottom flask was taken a mixture of 3-aminocomarin (1 mmol), benzyl bromide (1 mmol) and K2CO3 (1.2 mmol) in 3 mL of DMF. The reaction mixture was heated at 100 °C for 2-8 h and after completion of the reaction, the reaction mixture was worked-up with ethyl acetate. The crude product obtained after evaporation of the solvent in rotary evaporator was treated with ethanol to remove impurities. Finally the solid pure product obtained in 75-85% yield, which was used in the next step. Step II: The solid product (0.5 mmol) obtained in step I was taken in a 25 ml round bottom flask and it was dissolved in 4 mL of dry DCM. Then 1.2 equivalent of bromodimethylsulphonium bromide (BDMS) was added into it and the reaction mixture was stirred for 1-1.5 h. After completion of the reaction, the reaction mixture was worked-up with DCM. After evaporating the solvent, the solid residue was purified by column chromatography. The product was eluted in ethyl acetate and hexane mixture (1:24). The pure products (15a-v) are obtained in 82-93 % yield, which are characterized by 1H NMR, 13C NMR and HRMS. 3-(Benzylamino)-4-bromo-2H-chromen-2-one (15a): 1HNMR (400 MHz, CDCl3): δ 7.70 (d, J = 7.6 Hz, 1 H), 7.34 (m, 4 H), 7.30 (d, J = 8 Hz, 1 H), 7.26 (m, 3 H)), 4.83 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.4, 147.7, 139.5, 132.8, 128.9, 128.1, 127.8, 127.7, 125.8, 125.2, 120.9, 116.1, 112.6, 50.0 ppm. HRMS (APCI) calcd for calcd for C16H12BrNO2 (M+H +) = 330.0124, found 330.0101. Elemental Analysis Calculated Found MF C16H12BrNO2 C 58.20 58.06 (330.18) H 3.66 3.71 Reaction Time: 1 h Colour & State: white solid Yield: 82% (135 mg) Melting Point: 89-92 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 135 N 4.24 4.16 4-Bromo-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15b): 1HNMR (600 MHz, CDCl3): δ 7.69 (d, J = 7.8 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.25 (d, J = 8.4 Hz, 3 H), 7.15 (d, J = 7.8 Hz, 2 H), 4.99 (s, 1 H), 4.79 (s, 2 H), 2.33 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.4, 147.7, 137.4, 136.5, 132.9, 129.6, 128.0, 127.8, 125.8, 125.1, 121.0, 116.1, 112.4, 49.8, 21.3 ppm. HRMS (APCI) calcd for C17H14BrNO2 (M+H +) = 344.0281, found 344.0291. Elemental Analysis Calculated Found MF C17H14BrNO2 C 59.32 59.50 (344.21) H 4.10 4.14 N 4.07 4.00 4-Bromo-3-((4-fluorobenzyl)amino)-2H-chromen-2-one (15c): 1HNMR (400 MHz, CDCl3): δ 7.71 (d, J = 8 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H), 7.33 (m, 2 H), 7.28 (t, J = 4.8 Hz, 2 H), 7.02 (t, J = 8.4 Hz, 2 H), 4.96 (s, 1 H), 4.78 (d, J = 6.8 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 163.6, 161.2, 157.4, 147.8, 135.3, 132.7, 129.6, 129.5, 128.3, 125.9, 125.2, 120.9, 116.1, 115.9, 115.7, 113.1, 49.3 ppm. HRMS (ESI) calcd for C16H11BrFNO2 (M+H +) = 348.0030, found 348.0035. Elemental Analysis Calculated Found MF C16H11BrFNO2 C 55.20 55.35 (348.17) H 3.18 3.14 Reaction Time: 1 h Colour & State: white solid Yield: 90% (155 mg) Melting Point: 90-92 °C Reaction Time: 1 h Colour & State: white solid Yield: 82% (135 mg) Melting Point: 78-80 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 136 N 4.02 4.10 4-Bromo-3-((4-chlorobenzyl)amino)-2H-chromen-2-one (15d): 1HNMR (400 MHz, CDCl3): δ 7.68 (d, J = 8 Hz, 1 H), 7.32 (m, 5 H), 7.25 (t, J = 8 Hz, 2 H), 4.78 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.3, 147.9, 138.0, 133.6, 132.5, 129.3, 129.1, 128.5, 126.0, 125.3, 120.8, 116.2, 113.8, 49.3 ppm. HRMS (APCI) calcd for C16H11BrClNO2 (M+H +) = 363.9734, found 363.9736. Elemental Analysis Calculated Found MF C16H11BrClNO2 C 52.71 52.85 (364.62) H 3.04 3.09 N 3.84 3.76 4-Bromo-3-((4-bromobenzyl)amino)-2H-chromen-2-one (15e): 1HNMR (600 MHz, CDCl3): δ 7.70 (d, J = 8.4, Hz, 1 H), 7.45 (d, J = 8 Hz, 2 H), 7.35 (t, J = 8.4 Hz, 1 H), 7.30 (t, J = 7.8 Hz, 1 H), 7.27 (d, J = 7.8, 1 H), 7.23 (d, J = 7.8 Hz, 2 H), 4.77 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.4, 147.9, 138.6, 132.6, 132.1, 129.6, 128.4, 126.0, 125.3, 121.6, 120.8, 116.2, 113.4, 49.3 ppm. HRMS (APCI) calcd for C16H11Br2NO2 (M+H +) = 407.929, found 407.9230. Elemental Analysis Calculated Found MF C16H11Br2NO2 C 46.98 47.15 (409.08) H 2.71 2.67 N 3.42 3.33 Reaction Time: 1 h Colour & State: white solid Yield: 92% (159 mg) Melting Point: 85-87 °C Reaction Time: 1 h Colour & State: white solid Yield: 86% (176 mg) Melting Point: 115-117 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 137 4-Bromo-3-((3-methylbenzyl)amino)-2H-chromen-2-one (15f): 1HNMR (600 MHz, CDCl3): δ 7.62 (d, J = 7.2 Hz, 1 H), 7.24 (t, J = 7.2 Hz, 1 H), 7.21 (d, J = 6.6 Hz, 1 H), 7.18 (dd, J = 7.2 Hz, 1 H), 7.14 (d, J = 7.8 Hz, 1 H), 7.09 (s, 1 H), 7.07 (d, J = 7.2 Hz, 1 H), 7.03 (d, J = 7.8 Hz, 1 H), 4.70 (s, 2 H), 2.26 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.5, 147.7, 139.4, 138.6, 132.9, 128.8, 128.7, 128.5, 128.1, 125.8, 125.2, 124.9, 121.0, 116.1, 112.4, 50.1, 21.6 ppm. HRMS (ESI) calcd for C17H14BrNO2 (M+H +) = 344.0281, found 344.0288. Elemental Analysis Calculated Found MF C17H14BrNO2 C 59.32 59.21 (344.21) H 4.10 4.14 N 4.07 3.99 4-Bromo-3-((3-chlorobenzyl)amino)-2H-chromen-2-one (15g): 1HNMR (600 MHz, CDCl3): δ 7.69 (t, J = 7.2 Hz, 1 H), 7.34 (d, J = 11.4 Hz, 2 H), 7.29 (t, J = 7.2 Hz, 1 H), 7.25 (m, 4 H), 5.00 (s, 1 H), 4.80 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.3, 147.8, 141.7, 134.7, 132.4, 130.2, 128.4, 127.92, 127.87, 125.9, 125.8, 125.2, 120.8, 116.2, 113.2, 49.3 ppm. HRMS (APCI) calcd for C16H11BrClNO2 (M+H +) = 363.9734, found 363.9774. Elemental Analysis Calculated Found MF C16H11BrClNO2 C 52.71 52.87 (364.62) H 3.04 2.98 N 3.84 3.76 Reaction Time: 1 h Colour & State: white solid Yield: 83% (143 mg) Melting Point: 65-68 °C Reaction Time: 1.5 h Colour & State: white solid Yield: 85% (155 mg) Melting Point: 86-88 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 138 4-Bromo-3-((thiophen-2-ylmethyl)amino)-2H-chromen-2-one (15h): 1HNMR (600 MHz, CDCl3): δ 7.71 (d, J = 7.8 Hz, 1 H), 7.34 (t, J = 7.2 Hz, 1 H), 7.31 ( d, J = 7.2 Hz, 1 H), 7.28 (d, J = 4.8 Hz, 1 H), 7.21 (d, J = 4.8 Hz, 1 H), 6.99 (s, 1 H), 6.94 (d, J = 4.2 Hz, 1 H), 5.00 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.2, 148.0, 142.4, 129.8, 128.4, 126.3, 126.0, 125.4, 125.3, 125.2, 120.8, 116.2, 114.4, 44.6 ppm. HRMS (ESI) calcd for C14H10BrNO2S (M+H +) = 335.9688, found 335.9708. Elemental Analysis Calculated Found MF C14H10BrNO2S C 50.02 50.20 (336.20) H 3.00 3.04 N 4.17 4.25 4-Bromo-3-((naphthalen-2-ylmethyl)amino)-2H-chromen-2-one (15i): 1HNMR (400 MHz, CDCl3): δ 7.82 (m, 4 H), 7.70 (d, J = 7.2 Hz, 1 H), 7.47 (dd, J = 10.4, 7.2 Hz, 3 H), 7.32 (t, J = 7.2 Hz, 1 H), 7.27 (m, 2 H), 5.12 (s, 1 H, broad.), 4.99 (d, J = 5.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.4, 147.7, 136.9, 133.5, 132.9, 132.7, 128.7, 128.1, 128.0, 127.8, 126.6, 126.4, 126.1, 125.9, 125.8, 125.1, 120.9, 116.0, 112.8, 50.1 ppm. HRMS (ESI) calcd for C20H14BrNO2 (M+H +) = 380.0281, found 380.0286. Elemental Analysis Calculated Found MF C20H14BrNO2 C 63.18 63.32 (380.24) H 3.71 3.76 N 3.68 3.59 Reaction Time: 1 h Colour & State: Gummy black solid Yield: 82% (138 mg) Reaction Time: 1 h Colour & State: white solid Yield: 84% (160 mg) Melting Point: 100-103 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 139 3-(Benzylamino)-4-bromo-6-methoxy-2H-chromen-2-one (15j): 1HNMR (600 MHz, CDCl3): δ 7.34 (s, 4 H), 7.30 (s, 1 H), 7.18 (d, J = 9.0 Hz, 1 H), 7.10 (s, 1 H), 6.88 (d, J = 6.9 Hz, 1 H), 5.04 (s, 1 H, broad), 4.83 (s, 2 H), 3.85 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.5, 156.9, 142.1, 139.5, 133.1, 128.9, 127.9, 127.7, 121.7, 117.2, 115.3, 112.0, 108.9, 56.0, 50.0 ppm. HRMS (ESI) calcd for C17H14BrNO3 (M+H +) = 360.0230, found 360.0239. Elemental Analysis Calculated Found MF C17H14BrNO3 C 57.77 57.88 (360.21) H 3.92 3.87 N 3.89 3.80 4-Bromo-6-methoxy-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15k): 1HNMR (600 MHz, CDCl3): δ 7.23 (m, 2 H), 7.17 (d, J = 9.0 Hz, 1 H), 7.13 (m, 3 H), 6.88 (dd, J = 9.0, 2.4, Hz, 1 H), 5.01 (s, 1 H, broad), 4.78 (s, 2 H), 3.85 (s, 3 H), 2.32 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.6, 156.9, 142.1, 137.4, 136.5, 133.2, 129.6, 127.9, 121.8, 120.9, 117.2, 115.2, 108.9, 56.0, 49.9, 21.3 ppm; HRMS [ESI+] m/z: calcd for C18H16BrNO3 [M+H] = 374.0392 (found 374.0395). HRMS (ESI) calcd for C18H16BrNO3 (M+H +) = 374.0386, found 374.0395. Elemental Analysis Calculated Found MF C18H16BrNO3 C 56.69 56.56 (374.23) H 4.31 4.27 Reaction Time: 1.5 h. Colour & State: white solid Yield: 90% (162 mg) Melting Point: 106-109 °C Reaction Time: 1 h Colour & State: white solid Yield: 92% (172 mg) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 140 N 3.74 3.81 3-(Benzylamino)-4-bromo-8-methoxy-2H-chromen-2-one (15l): 1HNMR (400 MHz, CDCl3): δ 7.34 (s, 4 H), 7.29 (d, J = 9.2 Hz, 2 H), 7.21 (t, J = 8.4 Hz, 1 H), 6.92 (d, J = 7.6 Hz, 1 H), 4.83 (s, 2 H), 3.95 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 156.9, 147.0, 139.5, 137.6, 133.1, 128.9, 127.9, 127.7, 124.8, 121.8, 117.6, 110.5, 110.2, 56.6, 50.1 ppm. HRMS (APCI) calcd for C17H14BrNO3 (M+H +) = 360.0230, found 360.0240. Elemental Analysis Calculated Found MF C17H14BrNO3 C 57.77 57.89 (360.21) H 3.92 3.87 N 3.89 3.81 4-Bromo-8-methoxy-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15m): 1HNMR (400 MHz, CDCl3): δ 7.27 (t, J = 8 Hz, 2 H), 7.21 (t, J = 8 Hz, 2 H), 7.12 (d, J = 8 Hz, 2 H), 6.90 d, J = 8 Hz, 1 H), 4.77 (s, 2 H), 3.94 (s, 3 H), 2.31(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 156.8, 146.7, 137.2, 136.4, 133.0, 129.5, 129.2, 129.1, 127.8, 124.6, 121.6, 117.3, 110.2, 56.4, 49.7, 21.2 ppm. HRMS (APCI) calcd for C18H16BrNO3 (M+H +) = 374.0386, found 374.0394. Elemental Analysis Calculated Found MF C18H16BrNO3 C 56.69 56.54 (374.23) H 4.31 4.26 N 3.74 3.66 Reaction Time: 1 h Colour & State: white solid Yield: 93% (167 mg) Melting Point: 102-106 °C Reaction Time: 1 h. Colour & State: white solid Yield: 92% (172 mg) Melting Point: 123-126 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 141 Bromo-3-((4-chlorobenzyl)amino)-8-methoxy-2H-chromen-2-one (15n): 1HNMR (600 MHz, CDCl3): δ 7.28 (s, 5 H), 7.20 (t, J = 8.4 Hz, 1 H), 6.91 (d, J = 7.8 Hz, 1 H), 5.00 (s, 1 H), 4.78, (d, J = 6 Hz, 2 H), 3.94 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 156.7, 146.9, 138.1, 137.5, 133.4, 132.7, 129.2, 129.0, 124.8, 121.5, 117.5, 113.2, 110.5, 56.5, 49.1 ppm. HRMS (ESI) calcd for C17H13BrClNO3 (M+H +) = 393.9840, found 393.9846. Elemental Analysis Calculated Found MF C17H13BrClNO3 C 51.74 56.91 (394.65) H 3.32 3.26 N 3.55 3.62 3-(Benzylamino)-4-bromo-8-ethoxy-2H-chromen-2-one (15o): 1HNMR (400 MHz, CDCl3): δ 7.32 (m, 4 H), 7.25 (t, J = 1.2 Hz, 2 H), 7.18 (dd, J = 14.8, 6.4 Hz, 1 H), 6.89 (d, J =7.6 Hz, 1 H), 4.81 (s, 2 H), 4.15 (q, J = 6.8 Hz, 2 H), 1.48 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 157.0, 146.2, 139.6, 133.0, 128.9, 127.9, 127.7, 124.7, 121.8, 117.4, 112.7, 111.7, 106.0, 65.2, 50.0, 15.0 ppm. HRMS (APCI) calcd for C18H16BrNO3 (M+H +) = 374.0386, found 374.0350. Elemental Analysis Calculated Found MF C18H16BrNO3 C 56.69 56.86 (374.23) H 4.31 4.36 N 3.74 3.64 4-Bromo-8-ethoxy-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15p): Reaction Time: 1 h. Colour & State: white solid Yield: 86% (169 mg) Melting Point: 124-126 °C Reaction Time: 1 h Colour & State: white solid Yield: 90% (168 mg) Melting Point: 116-122 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 142 1HNMR (600 MHz, CDCl3): δ 7.26 (d, J = 7.8 Hz, 1 H), 7.22 (d, J = 7.2 Hz, 2 H), 7.16 (t, J = 8.4, Hz, 1 H), 7.11 (d, J = 7.8 Hz, 2 H), 6.88 (d, J =7.8 Hz, 1 H), 4.99 (s, 1 H, broad), 4.76 (s, 2 H), 4.15 (q, J = 6.6 Hz, 2 H), 2.31 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 157.0, 146.2, 137.7, 137.3, 136.5, 133.1, 129.6, 127.9, 124.7, 121.8, 117.4, 112.6, 111.6, 65.2, 49.8, 21.3, 15.0 ppm. HRMS (APCI) calcd for C19H18BrNO3 (M+H +) = 388.0543, found 388.0506. Elemental Analysis Calculated Found MF C19H18BrNO3 C 58.78 58.65 (388.26) H 4.67 3.71 N 3.61 3.56 4-Bromo-8-ethoxy-3-((4-fluorobenzyl)amino)-2H-chromen-2-one (15q): 1HNMR (600 MHz, CDCl3): δ 7.29 (m, 3 H), 7.19 (t, J =7.8 Hz, 1 H), 7.00 (t, J = 8.4 Hz, 2 H), 6.91 (d, J = 7.2 Hz, 1 H), 4.78 (s, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 1.49 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 163.2, 161.6, 160.6, 157.0, 146.3, 137.8, 135.4, 132.9, 129.62, 129.56, 124.8, 121.7, 117.5, 115.8, 115.7, 113.4, 111.8, 65.2, 49.2, 15.0 ppm. HRMS (ESI) calcd for C18H15BrFNO3 (M+H +) = 392.0292, found 392.0292. Elemental Analysis Calculated Found MF C18H15BrFNO3 C 55.12 55.32 (392.22) H 3.85 3.80 N 3.57 3.47 Reaction Time: 1 h Colour & State: white solid Yield: 89% (173 mg) Melting Point: 107-110 °C Reaction Time: 1 h Colour & State: white solid Yield: 86% (69 mg) Melting Point: 111-113 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 143 4-Bromo-3-((4-chlorobenzyl)amino)-8-ethoxy-2H-chromen-2-one (15r): 1HNMR (400 MHz, CDCl3): δ 7.34 (d, J = 4.4 Hz, 1 H), 7.28 (m, 4 H), 7.19 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8 Hz, 1 H), 4.78 (s, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 1.49 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 156.9, 146.3, 138.1, 133.4, 132.7, 129.2, 129.0, 128.1, 124.8, 121.6, 117.5, 113.5, 111.9, 65.2, 49.2, 15.0 ppm. HRMS (APCI) calcd for C18H15BrClNO3 (M+H +) = 407.9997, found 407.9958. Elemental Analysis Calculated Found MF C18H15BrClNO3 C 52.90 53.06 (408.68) H 3.70 3.67 N 3.43 3.70 3-(Benzylamino)-4-bromo-6-chloro-2H-chromen-2-one (15s): 1HNMR (400 MHz, CDCl3): δ 7.67 (d, J = 2 Hz, 1 H), 7.34 (m, 5 H), 7.25 (d, J = 2.4 Hz, 1 H), 7.19 (d, J = 8.8 Hz, 1 H), 4.86 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ 156.9, 145.9, 139.2, 133.3, 130.8, 129.0, 127.9, 127.86, 127.81, 125.2, 122.5, 117.5, 109.6, 50.0 ppm. HRMS (ESI) calcd for C16H11BrClNO2 (M+H +) = 363.9734, found 363.9740. Elemental Analysis Calculated Found MF C16H11BrClNO2 C 52.71 52.86 (364.62) H 3.04 2.99 N 3.84 3.75 3-(Benzylamino)-4,6-dibromo-2H-chromen-2-one (15t): Reaction Time: 1 h Colour & State: white solid Yield: 83% (169 mg) Melting Point: 103-106 °C Reaction Time: 1.5 h Colour & State: white solid Yield: 92% (167 mg) Melting Point: 103-106 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 144 1HNMR (600 MHz, CDCl3): δ 7.82 (d, J = 2.4 Hz, 1 H), 7.40 (dd, J = 8.4, 2.4 Hz, 1 H), 7.34 (m, 4 H), 7.13 (d, J = 8.4 Hz, 2 H), 4.86 (s, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ 156.8, 146.3, 139.2, 133.3, 130.6, 129.0, 128.8, 128.1, 127.85, 127.81, 122.8, 117.7, 109.2, 49.9 ppm. HRMS (ESI) calcd for C16H11Br2NO2 (M+H +) = 407.9229, found 407.9260. Elemental Analysis Calculated Found MF C16H11Br2NO2 C 46.98 46.86 (409.08) H 2.71 2.76 N 3.42 3.32 4-Bromo-8-methoxy-3-((naphthalen-2-ylmethyl)amino)-2H-chromen-2-one (15u): 1HNMR (400 MHz, CDCl3): δ 7.80 (t, J = 7.6 Hz, 4 H), 7.46 (t, J = 4.4 Hz, 3 H), 7.27 (t, J = 11.6 Hz, 1 H), 7.19 (t, J = 16.4 Hz, 1 H), 6.90 (d, J = 7.6 Hz, 1 H), 4.99 (s, 2 H), 3.94 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 156.9, 147.0, 137.6, 137.0, 133.6, 133.1, 133.0, 128.8, 128.1, 127.9, 126.7, 126.4, 126.1, 126.0, 124.8, 121.8, 117.6, 112.8, 110.5, 56.7, 50.1 ppm. HRMS (APCI) calcd for C21H16BrNO3 (M+H +) = 410.0386, found 410.0391. Elemental Analysis Calculated Found MF C21H16BrNO3 C 61.48 61.33 (410.27) H 3.93 3.87 N 3.41 3.31 4-bromo-8-ethoxy-3-((naphthalen-2-ylmethyl)amino)-2H-chromen-2-one (15v): Reaction Time: 1.5 h Colour & State: white solid Yield: 90% (184 mg) Melting Point: 99-101 °C Reaction Time: 1 h Colour & State: white solid Yield: 85% ( 174 mg) Melting Point: 116-118 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 145 1HNMR (400 MHz, CDCl3): δ 7.69 (t, J = 8 Hz, 4 H), 7.35 (t, J = 8.8 Hz, 3 H), 7.13 (d, J = 8.4 Hz, 1 H), 7.04 (t, J = 8 Hz, 1 H), 6.75 (d, J = 6.8 Hz, 1 H), 4.87 (s, 2 H), 4.02 (q, J =7.2 Hz, 2 H), 1.37 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 156.9, 146.1, 137.0, 133.5, 132.9, 128.6, 127.9, 127.8, 127.75, 126.5, 126.3, 126.0, 125.8, 124.8, 124.6, 121.6, 117.3, 112.9, 111.5, 65.1, 50.0, 15.0 ppm. HRMS (ESI) calcd for C22H18BrNO3 (M+H +) = 424.0543, found 424.0548. Elemental Analysis Calculated Found MF C22H18BrNO3 C 62.28 62.48 (424.29) H 4.28 4.24 N 3.30 3.23 General procedure for the synthesis of various 2-phenyl-4H-chromeno(3,4-d)thiazol-4-one derivatives (16a-v): Into a 10 mL round bottomed flask was taken 0.3 mmol of 15 and 0.9 mmol of Na2S. After adding 2 mL of DMF, 20 mol% of iodine and 5 mmol of H2O2 were added into it and the reaction mixture were heated at 120 °C in a preheated oil bath for 16-24 h. The progress of the reaction was checked by TLC time to time. When the reaction was complete, the reaction mixture was worked-up with ethyl acetate and the crude product obtained after evaporating the solvent in rotary evaporator. Finally it was purified by column chromatography with ethyl acetate and hexane mixture (1:9). The pale yellow solid products were obtained, which were characterized by IR, 1H NMR, 13C NMR and HRMS. 2-Phenyl-4H-chromeno[3,4-d]thiazol-4-one (16a): IR (KBr): 2924.97, 2854.00, 1737.29, 1616.79, 1284.21, 1091.91, 1036.64 cm-1. Reaction Time: 1 h Colour & State: white solid Yield: 90% (191 mg) Melting Point: 113-116 °C Reaction Time: 22 h Colour & State: pale yellow solid Yield: 86% (71.98 mg) Melting Point: 164-167 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 146 1HNMR (400 MHz, CDCl3): δ 8.12 (d, J = 7.2 Hz, 2 H), 7.68 (d, J = 8 Hz, 1 H), 7.52 (m, 5 H), 7.38 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 168.7, 155.8, 151.6, 145.0, 140.0, 132.3, 131.9, 131.4, 129.4, 127.6, 125.5, 125.3, 117.8, 116.1 ppm. HRMS (ESI) calcd for C16H9NO2S (M+H +) = 280.0427, found 280.0430. Elemental Analysis Calculated Found MF C16H9NO2S C 68.80 68.93 (279.31) H 3.25 3.29 N 5.01 5.10 2-(p-Tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16b): IR (KBr): 2956.04, 2924.37, 2853.39, 1743.17, 1602.99, 1182.85, 1088.29, 1033.51 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.98 (d, J = 7.6 Hz, 2 H), 7.64 (d, J = 7.6 Hz, 1 H), 7.54 (t, J = 8.4 Hz, 1 H), 7.45 (d, J = 8 Hz, 1 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.28 (t, J= 8 Hz, 2 H), 2.41 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 168.8, 155.8, 151.5, 144.6, 142.5, 139.8, 131.2, 130.0, 129.6, 127.5, 125.4, 125.2, 117.7, 116.1, 21.7 ppm. HRMS (ESI) calcd for C17H11NO2S (M+H +) = 294.0583, found 294.0589. Elemental Analysis Calculated Found MF C17H11NO2S C 69.61 69.75 (293.34) H 3.78 3.73 N 4.78 4.85 2-(4-Fluorophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16c):- Reaction Time: 21 h Colour & State: pale yellow solid Yield: 79% (69.44 mg) Melting Point: 212-216 °C Reaction Time: 22 h Colour & State: pale yellow solid Yield: 83% (73.95 mg) Melting Point: 229-231 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 147 IR (KBr): 2923.96, 2853.36, 1754.15, 1602.53, 1266.85, 1159.65, 1091.14, 1034.07 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.13 (dd, J = 8.4, 4.8 Hz, 2 H), 7.67(d, J = 7.2 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.48 (d, J = 8.8 Hz, 1 H), 7.38 (t, J = 8 Hz, 1 H), 7.21 (t, J = 8.4 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ 167.1, 166.0, 163.5, 155.5, 151.4, 144.8, 139.7, 131.3, 129.6, 129.5, 128.50, 128.47, 125.2, 125.1, 117.7, 116.5, 116.3, 115.7 ppm. HRMS (ESI) calcd for C16H8FNO2S (M+H +) = 298.0333, found 298.0333. Elemental Analysis Calculated Found MF C16H8FNO2S C 64.64 64.78 (297.30) H 2.71 2.75 N 4.71 4.66 2-(4-Chlorophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16d): IR (KBr): 2923.28, 1753.17, 1604.98, 1266.21, 1087.93, 1034.74 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.4 Hz, 2 H), 7.60 (d, J = 7.6 Hz, 1 H), 7.50 (t, J = 14.4 Hz, 1 H), 7.42 (m, 3 H), 7.31 (t, J = 6.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 167.3, 155.7, 151.7, 145.2, 140.0, 138.1, 131.6, 130.8, 129.7, 128.8, 125.5, 125.4, 117.9, 115.9 ppm. HRMS (ESI) calcd for C16H8ClNO2S (M+H +) = 314.0037, found 314.0046. Elemental Analysis Calculated Found MF C16H8ClNO2S C 61.25 61.40 (313.76) H 2.57 2.62 N 4.46 4.54 2-(4-Bromophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16e): Reaction Time: 22 h Colour & State: pale yellow solid Yield: 80% (75.29 mg) Melting Point: 250-253 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 148 IR (KBr): 2923.68, 2852.63, 1760.49, 1604.61, 1265.09, 1085.68, 1033.77 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2 H), 7.66 (t, J = 5.6 Hz. 3 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.48 (d, 8.4 Hz, 1 H) 7.38 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ 167.4, 155.7, 151.7, 145.3, 140.0, 132.7, 131.6, 131.2, 129.0, 126.5, 125.5, 125.4, 125.3, 117.9, 115.9 ppm. HRMS (ESI) calcd for C16H8BrNO2S (M+H +) = 357.9532, found 357.9533. Elemental Analysis Calculated Found MF C16H8BrNO2S C 53.65 53.80 (358.21) H 2.25 2.19 N 3.91 3.98 2-(m-Tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16f): IR (KBr): 3059.06, 2924.29, 2853.49, 1739.16, 1602.24, 1267.26, 1084.42, 1031.69 cm-1. 1HNMR (600 MHz, CDCl3): δ 7.99 (s, 1 H), 7.87 (d, J = 7.8 Hz, 1 H), 7.66 (d, J = 7.8 Hz, 1 H), 7.56 (t, J = 7.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz, 1 H), 7.38 (m, 2 H), 7.34 (d, J = 7.2 Hz, 1 H), 2.45 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 169.0, 155.9, 144.9, 140.0, 139.4, 132.7, 132.3, 131.4, 129.3, 129.0, 128.2, 125.8, 125.3, 124.9, 117.9, 116.1, 21.5 ppm. HRMS (ESI) calcd for C17H11NO2S (M+H +) = 294.0583, found 294.0588. Elemental Analysis Calculated Found MF C17H11NO2S C 69.61 69.50 (293.34) H 3.78 3.73 Reaction Time: 24 h Colour & State: pale yellow solid Yield: 78% (83.77 mg) Melting Point: 262-264 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 78% (68.56 mg) Melting Point: 193 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 149 N 4.78 4.71 2-(3-Chlorophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16g): IR (KBr): 2923.48, 2851.76, 1742.82, 1605.49, 1231.94, 1077.30, 1031.99 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.15 (t, J = 1.2 Hz, 1 H), 7.98 (d, J = 7.2, 1 H), 7.68 (dd, J = 7.8, 1.2 Hz, 1 H), 7.58 (t, J = 7.8, 1 H), 7.50 (t, J = 7.8 Hz, 2 H), 7.45 (t, J = 7.8, 1 H), 7.39 (t, J = 7.8, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 166.9, 155.8, 151.7, 145.4, 135.7, 133.9, 131.8, 131.7, 130.7, 127.5, 125.7, 125.5, 125.4, 118.0, 115.9, 110.2 ppm. HRMS (ESI) calcd for C16H8ClNO2S (M+H +) = 314.0037, found 314.0043. Elemental Analysis Calculated Found MF C16H8ClNO2S C 61.25 61.41 (313.76) H 2.57 2.61 N 4.46 4.53 2-(Thiophen-2-yl)-4H-chromeno[3,4-d]thiazol-4-one (16h): IR (KBr): 2924.50, 2853.25, 1739.72, 1605.08, 1094.67.43, 1027.29 cm-1. 1HNMR (600 MHz, CDCl3): δ 7.70 (d, J = 2.4 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.55 (m, 2 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.15 (t, J = 3.6 Hz, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ 169.0, 162.0, 155.6, 151.6, 144.5, 139.6, 135.9, 131.4, 130.6, 129.3, 128.4, 125.3, 117.9, 115.9 ppm. HRMS (ESI) calcd for C14H7NO2S2 (M+H +) = 285.9991, found 285.9997. Elemental Analysis Calculated Found Reaction Time: 23 h Colour & State: pale yellow solid Yield: 65% (61.17 mg) Melting Point: 180 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 66% (56.43 mg) Melting Point: 172-175 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 150 MF C14H7NO2S2 C 58.93 59.06 (285.34) H 2.47 2.53 N 4.91 4.85 2-(Naphthalen-2-yl)-4H-chromeno[3,4-d]thiazol-4-one (2i): IR (KBr): 2931.38, 2853.66, 1744.62, 1219.59, 1083.99 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.59 (s, 1 H), 8.17 (d, J = 8.8 Hz, 1 H), 7.94 (d, J = 7.6 Hz, 2 H), 7.86 (d, J = 4.8 Hz, 1 H), 7.67 (d, J = 8 Hz, 1 H), 7.61 (m, 3 H), 7.46 (d, J = 1.2 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 168.6, 155.7, 151.5, 144.9, 139.9, 134.8, 133.1, 131.3, 129.5, 129.2, 129.0, 128.0, 127.7, 127.3, 125.4, 125.2, 124.1, 117.7, 115.9 ppm. HRMS (ESI) calcd for C20H11NO2S (M+H +) = 330.0583, found 330.0589. Elemental Analysis Calculated Found MF C20H11NO2S C 72.93 73.10 (329.37) H 3.37 3.33 N 4.25 4.34 8-Methoxy-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16j): IR (KBr): 2956.07, 2924.27, 2853.57, 1733.31, 1613.58, 1243.59, 1093.08, 1052.14 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.11 (m, 2 H), 7.52 (m, 3 H), 7.40 (d, J = 8.8 Hz, 1 H), 7.12 (dd, J = 9.6, 3.2 Hz, 1 H), 7.05 (d, J = 3.2 Hz, 1 H), 3.90 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 168.7, 156.8, 156.0, 146.1, 144.8, 140.3, 132.4, 131.9, 129.4, 127.7, 119.0, 118.8, 116.5, 108.0, 56.2 ppm. HRMS (ESI) calcd for C17H11NO3S (M+H +) = 310.0532, found 310.0543. Reaction Time: 16 h Colour & State: pale yellow solid Yield: 89% (87.84 mg) Melting Point: 226-228 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 85% (78.79 mg) Melting Point: 197-200 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 151 Elemental Analysis Calculated Found MF C17H11NO3S C 66.01 66.20 (309.34) H 3.58 3.53 N 4.53 4.46 8-Methoxy-2-(p-tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16k): IR (KBr): 2923.91, 2853.23, 1752.78, 1612.11, 1299.66, 1090.87, 1026.53 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.6 Hz, 2 H), 7.38 (d, J = 9.6 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 2 H), 7.10 (dd, J = 8.8, 2.8 Hz, 1 H), 7.03 (d, J = 2.4 Hz, 1 H), 3.90 (s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ 168.8, 156.7, 156.0, 146.0, 144.4, 142.5, 140.1, 130.1, 129.8, 127.6, 118.9, 118.7, 116.5, 108.0, 56.2, 21.8 ppm. HRMS (ESI): calcd for C18H13NO3S (M+H +) = 324.0689, found 324.0696. Elemental Analysis Calculated Found MF C18H13NO3S C 66.86 66.74 (323.36) H 4.05 4.11 N 4.33 4.24 6-Methoxy-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16l): IR (KBr): 2956.33, 2924.60, 2853.64, 1738.67, 1605.66, 1270.11, 1094.15, 1013.73 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.8 Hz, 2 H), 7.51 (m, 3 H), 7.28 (m, 2 H), 7.08(d, J = 8.4 Hz, 1 H), 3.97 (s, 3 H) ppm. Reaction Time: 20 h Colour & State: pale yellow solid Yield: 82% (79.46 mg) Melting Point: 218-220 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 85% (78.79 mg) Melting Point: 214-217 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 152 13C NMR (150 MHz, CDCl3): δ, 168.8, 155.5, 148.2, 145.2, 141.6, 140.1, 132.4, 131.8, 129.4, 127.7, 125.4, 116.8, 113.3, 56.6 ppm. HRMS (ESI) calcd for C17H11NO3S (M+H +) = 310.0532, found 310.0539. Elemental Analysis Calculated Found MF C17H11NO3S C 66.01 66.21 (309.34) H 3.58 3.53 N 4.53 4.60 6-Methoxy-2-(p-tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16m): IR (KBr): 2924.32, 2853.45, 1737.93, 1607.12, 1272.09, 1098.89, 1016.59 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.98 (d, J = 8 Hz, 2 H), 7.29(d, J = 8.4 Hz. 3 H), 7.20 (dd, J = 7 .6, 1.6 Hz, 1 H), 7.07 (dd, J = 7.6, 1.2 Hz, 1 H), 3.40(s, 3 H), 2.42 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 169.0, 155.3, 148.2, 144.8, 142.5, 141.5, 140.0, 130.1, 129.8, 127.6, 125.3, 116.8, 113.2, 56.6, 21.8 ppm. HRMS (ESI) calcd for C18H13NO3S (M+H +) = 324.0689, found 324.0687. Elemental Analysis Calculated Found MF C18H13NO3S C 66.86 66.97 (323.36) H 4.05 4.01 N 4.33 4.23 2-(4-Chlorophenyl)-6-methoxy-4H-chromeno[3,4-d]thiazol-4-one (16n): IR (KBr): 2914.91, 2851.04, 1739.32, 1271.85, 1098.82, 1012.97 cm-1. Reaction Time: 22 h Colour & State: pale yellow solid Yield: 86% (83.33 mg) Melting Point: 247-250 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 84% (86.64 mg) Melting Point: 209-214 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 153 1HNMR (400 MHz, CDCl3): δ 7.97 (d, J = 8 Hz, 2 H), 7.41 (d, J = 7.6 Hz. 2 H), 7.23 (t, J = 7.6 Hz, 1 H), 7.15 (d, 8 Hz, 1 H) 7.03 (d, J = 8 Hz, 1 H), 3.93(s, 3 H),) ppm. 13C NMR (100 MHz, CDCl3): δ 167.4, 155.2, 148.2, 147.9, 145.3, 141.6, 138.0, 130.8, 129.7, 128.8, 125.5, 116.8, 116.6, 113.5, 56.6.ppm. HRMS (ESI) calcd for C17H10ClNO3S (M+H +) = 344.0143, found 344.0146. Elemental Analysis Calculated Found MF C17H10ClNO3S C 59.39 59.25 (343.78) H 2.93 2.99 N 4.07 4.16 6-Ethoxy-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16o): IR (KBr): 2990.00, 2969.05, 2927.46, 1735.89, 1606.16, 1273.88, 1194.97, 1095.46, 1035.45 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.10 (m, 1 H), 7.50 (m, 3 H), 7.26 (m, 2 H), 7.22 (d, J = 1.6 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H), 4.21 (q, J = 6.8 Hz, 2 H), 1.51 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 168.7, 155.4, 147.6, 145.3, 141.7, 140.1, 132.4, 131.8, 129.4, 127.7, 125.3, 116.8, 116.7, 114.5, 65.4, 15.0 ppm. HRMS (ESI) calcd for C18H13NO3S (M+H +) = 324.0689, found 324.0695. Elemental Analysis Calculated Found MF C18H13NO3S C 66.86 66.99 (323.36) H 4.05 4.01 N 4.33 4.24 6-Ethoxy-2-(p-tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16p): Reaction Time: 23 h Colour & State: pale yellow solid Yield: 82%(79.46 mg) Melting Point: 205-208 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 154 IR (KBr): 3071.35, 2911.06, 1738.27, 1273.34, 1183.01, 1081.48, 1034.69 cm-1. 1HNMR (400 MHz, CDCl3): δ 7.99 (d, J = 7.6 Hz, 2 H), 7.28 (m, 3 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 4.21 (q, J =7.2 Hz, 2 H), 2.43 (s, 3 H), 1.52 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 168.9, 155.5, 147.5, 144.9, 142.4, 139.9, 130.0, 129.8, 127.6, 125.3, 116.8, 116.6, 114.3, 65.3, 21.7, 15.0 ppm. HRMS (ESI) calcd for C19H15NO3S (M+H +) = 338.0845, found 338.0855. Elemental Analysis Calculated Found MF C19H15NO3S C 67.64 67.82 (337.39) H 4.48 4.53 N 4.15 4.07 6-Ethoxy-2-(4-fluorophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16q): IR (KBr): 2924.18, 2855.07, 1740.43, 1606.15, 1273.67, 1095.69, 1040.43 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.10 (m, 2 H), 7.27 (m, 2 H), 7.19 (m, 2 H), 7.08 (dd, J = 7.6, 1.2 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 167.3, 166.2, 163.7, 155.4, 147.5, 145.2, 141.6, 140.0, 129.7, 129.6, 128.7, 128.65, 125.4, 116.7, 116.6, 116.5, 114.5, 65.3, 14.9 ppm. HRMS (ESI) calcd for C18H12FNO3S (M+H +) = 342.0595, found 342.0599. Elemental Analysis Calculated Found MF C18H12FNO3S C 63.33 63.24 (341.36) H 3.54 3.50 Reaction Time: 24 h Colour & State: pale yellow solid Yield: 80% (80.88 mg) Melting Point: 208-210 °C Reaction Time: 20 h Colour & State: pale yellow solid Yield: 85% (86.95 mg) Melting Point: 193-196 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 155 N 4.10 4.01 2-(4-Chlorophenyl)-6-ethoxy-4H-chromeno[3,4-d]thiazol-4-one (16r): IR (KBr): 2923.05, 2848.11, 1735.13, 1275.51, 1088.12, 1036.74 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.03 (d, J = 7.8 Hz, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.27 (t, J = 5.4 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 4.21 (q, J = 6.6 Hz, 2 H), 1.53 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 167.3, 155.4, 147.6, 141.7, 140.1, 138.0, 130.9, 129.7, 128.8, 125.4, 116.65, 116.60, 114.6, 65.3, 15.0 ppm. HRMS (ESI) calcd for C18H12ClNO3S (M+H +) =358.0299, found 358.0300. Elemental Analysis Calculated Found MF C18H12ClNO3S C 60.42 60.60 (357.81) H 3.38 3.30 N 3.91 3.81 8-Chloro-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one(16s): IR (KBr): 2958.46, 2923.42, 2852.10, 1747.32, 1603.59, 1258.19, 1081.96, 1025.50 cm-1. 1HNMR (400 MHz, CDCl3): δ 8.10 (d, J = 6.8, 2 H), 7.64 (s, 1 H), 7.51 (m, 4 H), 7.42 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 169.5, 155.2, 150.0, 143.6, 140.4, 132.2, 131.3, 130.6, 129.5, 129.1, 127.7, 124.8, 119.3, 117.2 ppm. HRMS (ESI) calcd for C16H8ClNO2S (M+H +) = 314.0037, found 314.0043. Elemental Analysis Calculated Found Reaction Time: 22 h Colour & State: pale yellow solid Yield: 78% (83.72 mg) Melting Point: 204-206 °C Reaction Time: 24 h Colour & State: pale yellow solid Yield: 70% (65.73 mg) Melting Point: 226 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 156 MF C16H8ClNO2S C 61.25 61.41 (313.76) H 2.57 2.61 N 4.46 4.55 8-Bromo-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16t): IR (KBr): 2922.61, 2851.76, 1753.56, 1600.71, 1278.36, 1086.66, 1052.63 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.10 (d, J = 6.6 Hz, 2 H), 7.80 (d, J = 1.8 Hz, 1 H), 7.64 (dd, J = 8.4, 1.8 Hz, 1 H), 7.53 (m, 3 H), 7.36 (d, J = 9.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ 169.6, 155.2, 150.5, 143.4, 140.4, 134.1, 132.2, 132.1, 129.5, 127.8, 127.7, 119.6, 117.9, 117.7 ppm. HRMS (ESI) calcd for C16H8BrNO2S (M+H +) = 357.9532, found 357.9537. Elemental Analysis Calculated Found MF C16H8BrNO2S C 53.65 53.79 (358.21) H 2.25 2.30 N 3.91 3.81 6-Methoxy-2-(naphthalen-2-yl)-4H-chromeno[3,4-d]thiazol-4-one (16u): IR (KBr): 2924.34, 2853.58, 1734.86, 1268.44, 1077.43, 1010.71 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.61 (s, 1 H), 8.19 (d, J = 8.4 Hz, 1 H), 7.95 (d, J = 7.8 Hz, 2 H), 7.88 (d, J = 6 Hz, 1 H), 7.57 (t, J = 4.2 Hz, 2 H), 7.31 (t, J = 7.8, Hz, 1 H), 7.25 (d, J = 7.8 Hz, 1 H), 7.10 (d, J = 8.4 Hz, 1 H), 4.1 (s, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 168.9, 155.4, 153.5, 148.2, 145.2, 141.6, 140.2, 138.5, 135.0, 133.3, 129.7, 129.3, 129.1, 128.1, 127.9, 127.4, 125.4, 124.2, 116.8, 113.3, 56.6 ppm. HRMS (ESI) calcd for C21H13NO3S (M+H +) = 360.0689, found 360.0694. Reaction Time: 24 h Colour & State: pale yellow solid Yield: 72% (77.33 mg) Melting Point: 236 °C Reaction Time: 16 h Colour & State: pale yellow solid Yield: 87% (93.70 mg) Melting Point: 223-226 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 157 Elemental Analysis Calculated Found MF C21H13NO3S C 70.18 70.28 (359.40) H 3.65 3.70 N 3.90 3.99 6-Ethoxy-2-(naphthalen-2-yl)-4H-chromeno[3,4-d]thiazol-4-one (16v): IR (KBr): 2959.40, 2924.94, 2853.89, 1753.02, 1652.49, 1272.56, 1079.48, 1034.26 cm-1. 1HNMR (600 MHz, CDCl3): δ 8.58 (d, J = 5.4 Hz, 1 H), 8.16 (d, J = 7.8 Hz, 1 H), 7.94 (t, J = 1.8 , 2 H), 7.85 (s, 1 H), 7.55 (d, J = 3.6 Hz, 2 H), 7.26 (s, 1 H), 7.21 (d, J = 7.2 Hz, 1 H), 7.07 (d, J = 7.2 Hz, 1 H), 4.20 (q, J = 7.2 Hz, 2 H), 1.53 (t, J = 6.6 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ 168.8, 155.5, 147.5, 145.2, 141.7, 140.1, 135.0, 133.2, 129.7, 129.2, 129.1, 128.1, 127.8, 127.4, 125.4, 124.2, 116.8, 116.7, 114.4, 65.3, 15.0 ppm. HRMS (ESI) calcd for C22H15NO3S (M+H +) = 374.0845, found 374.0845. Elemental Analysis Calculated Found MF C22H15NO3S C 70.76 70.92 (373.43) H 4.05 3.11 N 3.75 3.82 Reaction Time: 18 h Colour & State: pale yellow solid Yield: 85% (95.11 mg) Melting Point: 187-190 °C TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 158 1HNMR (400 MHz, CDCl3): 3-(Benzylamino)-4-bromo-2H-chromen-2-one (15a) 13C NMR (100 MHz, CDCl3): 3-(Benzylamino)-4-bromo-2H-chromen-2-one (15a) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 159 1HNMR (600 MHz, CDCl3): 4-Bromo-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15b) 13C NMR (150 MHz, CDCl3): 4-Bromo-3-((4-methylbenzyl)amino)-2H-chromen-2-one (15b) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 160 1HNMR (600 MHz, CDCl3): 4-Bromo-3-((4-bromobenzyl)amino)-2H-chromen-2-one (15e) 13C NMR (100 MHz, CDCl3): 4-Bromo-3-((4-bromobenzyl)amino)-2H-chromen-2-one (15e) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 161 1HNMR (400 MHz, CDCl3): 3-(Benzylamino)-4-bromo-8-ethoxy-2H-chromen-2-one (15o) 13C NMR (100 MHz, CDCl3): 3-(Benzylamino)-4-bromo-8-ethoxy-2H-chromen-2-one (15o) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 162 1HNMR (400 MHz, CDCl3): 3-(Benzylamino)-4-bromo-6-chloro-2H-chromen-2-one (15s) 13C NMR (100 MHz, CDCl3): 3-(Benzylamino)-4-bromo-6-chloro-2H-chromen-2-one (15s) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 163 1HNMR (400 MHz, CDCl3): 2-Phenyl-4H-chromeno[3,4-d]thiazol-4-one (16a) 13C NMR (100 MHz, CDCl3): 2-Phenyl-4H-chromeno[3,4-d]thiazol-4-one (16a) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 164 1HNMR (400 MHz, CDCl3): 2-(p-Tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16b) 13C NMR (100 MHz, CDCl3): 2-(p-Tolyl)-4H-chromeno[3,4-d]thiazol-4-one (16b) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 165 1HNMR (400 MHz, CDCl3): 2-(4-Bromophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16e) 13C NMR (150 MHz, CDCl3): 2-(4-Bromophenyl)-4H-chromeno[3,4-d]thiazol-4-one (16e) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 166 1HNMR (400 MHz, CDCl3): 6-Ethoxy-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16o) 13C NMR (150 MHz, CDCl3): 6-Ethoxy-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16o) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 167 1HNMR (400 MHz, CDCl3): 8-Chloro-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16s) 13C NMR (100 MHz, CDCl3): 8-Chloro-2-phenyl-4H-chromeno[3,4-d]thiazol-4-one (16s) TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 168 Crystallographic Description: Crystal data were collected with Bruker Smart Apex-II CCD diffractometer using graphite monochromated MoKα radiation (λ = 0.71073 Å) at 298 K. Cell parameters were retrieved using SMART software and refined with SAINT on all observed reflections. Data reduction was performed with the SAINT software and corrected for Lorentz and polarization effects. Absorption corrections were applied with the program SADABS. The structure was solved by direct methods implemented in SHELX-97 program and refined by full- matrix least-squares methods on F2. All non-hydrogen atomic positions were located in difference Fourier maps and refined anisotropically. The hydrogen atoms were placed in their geometrically generated positions. Table 16. Crystal data and structure refinements of compounds 16a. For atomic coordinates, equivalent isotropic displacement parameters and bond angles, please check CIF. Parameters Compound 16a Empirical Formula C16H9NO2S Formula Weight 279.30 Temperature 296(2) K CCDC No. 1013314 Wavelength (Ao ) 0.71073 Crystal System monoclinic Space group P-1 Radiation type MoK\a Radiation source fine-focus sealed tube a (Ao) 8.2110 (2) b (Ao) 8.9277 (2) c (Ao) 9.0926 (2) α (o) 89.3770 (10) β (o) 82.5790 (10) γ (o) 80.8590 (10) Cell Voloume 652.53 (3) z 2 Density 1.422 F (0 0 0) 288 Theta ranges 2.26 to 24.99 TH-1700_126122027 Chapter VI Synthesis of Coumarin Fused Thiazoles 169 Index ranges -9 ≤ h ≤ 9, -10 ≤ k ≤ 10, -10 ≤ l ≤ 10 Reflection collected 6773 Independent reflections 2174 Completeness to theta 0.946 Number of parameters 181 Number of restraints 0 Godness of fit (GOF)on F2 1.049 Refinement method Full-matrix least square on F2 TH-1700_126122027 REFERENCES CHAPTER (I-VI) REFERENCES  TH-1700_126122027 Chapter I-VI References 170  References 1. Costa, M.; Dias, T. A.; Brito, A.; Proença, F. Eur. J. Med. Chem. 2016, 123, 487-507. 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A large number of different pyridocoumarins have been achieved using protic acid as catalysts with simple reaction procedures. Moreover, using multicomponent approach and iodine as a catalyst, substituted pyrrole fused coumarin derivatives were obtained with good to excellent yields. Further, oxidative C-H bond functionalizationhas been used to accomplish various fused oxazole and thiazole derivatives of coumarin. TH-1700_126122027 Future Perspective 177 Future Perspective Coumarin fused heterocyclic compounds exhibit important biological activities. Thus, the synthesized compounds can be explored for their biological evaluation. Acylation of electron deficient pyridine rings is a very challenging but recently cross dehydrogenative coupling (CDC) reactions have been used to overcome this difficulty. The acylation of the pyridocoumarins moieties can be achieved via CDC reactions to synthesize the respective acylated pyridocoumarin derivatives which may have valuable biological properties as acylated heterocycles are parts of many naturally occurring compounds (Scheme I). Scheme I. CDC reaction for acylation of pyrido(2,3-c)coumarins Further, the synthesized oxazole and thiazole derivatives can be explored further for C-H activation where the thiazole and oxazole moieties can act as directing groups and this can lead to the development of new organic molecules of biological importance (Scheme II). Scheme II.Thiazole and oxazole moieties as directing groups TH-1700_126122027 Publications 178 Publications  Md. Belal and Abu T. Khan; Synthesis of fused oxazole-containing coumarin derivatives via oxidative cross coupling reaction using a combination of CuCl2 and TBHP RSC Advances 2016, 6, 18891-18894.  Md. Belal and Abu T. Khan; Oxidative cross coupling reaction mediated by I2/H2O2: a novel approach for the construction of fused thiazole containing coumarin derivatives RSC Advance, 2015, 5, 104155-104163.  Md. Belal, Deb K. Das and Abu T. Khan; Synthesis of Pyrido(2,3-c)coumarin Derivatives by an Intramolecular Povarov Reaction Synthesis 2015, 47, 1109-1116.  Deb K. Das , Satavisha Sarkar , Musawwer Khan , Md. Belal and Abu T. Khan; A mild and efficient method for large scale synthesis of 3-aminocoumarins and its further application for the preparation of 4-bromo-3-aminocoumarins Tetrahedron Lett. 2014, 55, 4869–4874.  Md. Belal and Abu T. Khan; PSTA.H2O catalyzed reaction of 3-aminocoumarin and phenylacetaldehyde derivatives: A route to access various Pyrido(2,3-c)coumarin derivatives ( Manuscript communicated).  Md. Belal and Abu T. Khan Iodine catalyzed multicomponent approach to access various Pyrrolo(2,3-c)coumarin derivatives using 3-aminocoumarins, acetophenone derivatives and 4-hydroxycoumarin (Manuscript communicated). TH-1700_126122027