Synthesis of Biologically Active Core Structures by Copper and Iodine Mediated Protocols Via C-C and C-N Bond Formation

SYNTHESIS OF BIOLOGICALLY ACTIVE CORE STRUCTURES BY COPPER AND IODINE MEDIATED PROTOCOLS VIA C-C AND C-N BOND FORMATION

A Dissertation Submitted to the National Taiwan Normal University for the Degree of Doctor of Philosophy in Chemistry

Submitted by Sachin Dadaji Gawande 899420051

Advisor Prof. Dr. Ching-Fa Yao

Department of Chemistry National Taiwan Normal University Taipei – 11677 TAIWAN, R.O.C. June 2014

Prof. Dr. Ching-Fa Yao Department of Chemistry National Taiwan Normal University 88, Sec. 4, Ting-Chow Rd E-mail: [email protected] Taipei, Taiwan 11677 TEL +886-2-29309092 R. O. C. FAX +886-2-29324249

CERTIFICATE

This is to certify that the work incorporated in the thesis entitled “Synthesis of biologically active core structures by copper and iodine mediated protocols via C-C and C-N bond formation” submitted by Sachin Dadaji Gawande was carried out by him under my supervision at the Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan.

Prof. Dr. Ching-Fa Yao Department of Chemistry National Taiwan Normal University Taipei – 11677 TAIWAN R.O.C.

CANDIDATE’S DECLARATION

I hereby declare that the work presented in the dissertation entitled “Synthesis of biologically active core structures by copper and iodine mediated protocols via C-C and C-N bond formation” submitted for Ph.D. degree to National Taiwan Normal University, Taipei, Taiwan. The work has been carried out by myself at the Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan, R.O.C., under the supervision of Prof. Dr. Ching-Fa Yao. The work is original and any of the part of this work was not submitted by me for another degree or diploma to this or any other university. Any inadvertent omissions that might have occurred, due to oversight or error in judgment are regretted.

Sachin Dadaji Gawande Date: June 2014 Department of Chemistry, National Taiwan Normal University, Taipei 11677, TAIWAN R.O.C.

Dedicated to My Father: Late Mr. Dadaji Bhaurao Gawande My Mother: Mrs. Nanda Dadaji Gawande

Acknowledgement I would like to express my sincere and humble gratitude to my supervisor Prof. Dr. Ching-Fa Yao, for his valuable advice and financial support during my Ph. D study at National Taiwan Normal University. He provided continuous encouragement, good teaching and lots of troubleshooting ideas during my Ph. D career. He helped me a lot during tough situation in my Ph. D. study. I would have been lost without him. I also like to extend my thanks to all the professors of the Department of Chemistry, National Taiwan Normal University. Especially, I would like to thank Prof. Dr. Kwunmin Chen, Prof. Dr. Ming-Chang P. Yeh, Prof. Dr. Tun-Cheng Chien, Prof. Dr. Jenghan Wang, Prof. Dr. Cheng-Huang Lin, Prof. Dr. Wen-Chang Huang, Prof. Dr. Way-Zen Lee, Prof. Dr. Wenwei Lin, for their excellent guidance during my course work. I am particularly thankful to Dr. Veerababurao Kavala, Dr. Chun-Wei Kuo, Dr. Mustafa Jahir Raihan and Dr. Ju-Tsung Liu for their kind help and cooperation during my research. I wish to thank all the past and present members of the Prof. Yao group, like Dr. Shivaji More, Dr. Sijay Gao, Dr. Pateliya Mujjamil Habib, Dr. Chintakunta Ramesh, Dr. Deepak Kumar Barange, Dr. Ram Ambre, Dr. Balraj Gopula, Dr. Donala Janreddy, Manoj Zanwar, R.R. Rajawinslin, Trimurtulu Kotipalli, Chen Hsuan Tsai, Chi Tseng, Po Min Lei, Tze-Huei Yan, Ting-Wei Lin, Yu-Chen Tu, Ying-tsang Lan, Qiao-Zhi Guan, Lin- Yin Chiu, Wei Chieh Yang, Yu-hsuan Wang, Wan-Yu Lin, Cheng-Chuan Wang, Tsai, Hsin-Yun, Chen Shiang Chi, Huang Chia Yu, Lin Lyu, Lin Ting Jyun, Huang Yi Hsiang, Kuo Chia Ming, Wang Ya Hsuan, Che-Hao Hsu, Tang Hau Yang, Chang Wei Hsiang, Jerry Sheu, for their friendly interaction and help during my research. I would like to thanks NMR operator Ms. Chiu-Hui and X-ray crystallographer Mr. Ting- Shan Kuo for providing me analytical support during my Ph. D study. I wish to thank all the office staff members of Department of Chemistry and Office of International Affairs, for their kind help during my Ph. D study at NTNU. I am grateful to all of my friends and their families in Taiwan. Especially, Manoj Zanwar, Pandit Ambre, Dhananjay Magar, Balraj Gopula, Ram Ambre, Deepak Huple, Sandeep Mane, Sagar Gawade, Samir Pawar, Sachin Shivatare, Vatan Kumar, Nagendra Kondekar, Milind, Ajit, Balaji, Samir, Rahul, Prakash, Pratap Patil, Shivaji More, Shashi, Dev, Amol, Dr. Anwar, Dr. J. Damodar, Mamatha, Khulan, Wanjay, Monique, Nancy, Myra, Giselle, Mandy, Grant, Shaheen, Bhanudas for their friendship and cooperation during my stay in Taiwan. Furthermore, I am deeply indebted to my former supervisors Dr. Ashok Konda, Dr. Vijay Dhondge, Rajesh Shanbhag, Mr. Sanjay Bhawsar, Dr. Sachin Madan, Dr. Shashikant Tiwari, Dr. V. Swamy, Dr. Rahul Nagwade, Dr. Manmohan Kapoor, Dr. Keshav Sathaye of Chembiotek research international, R.S.I.L. limited and Sai life Sciences Pune India, for their valuable guidance, support and encouragement. I also thank my colleagues Jigar Shah, Sanjay (Sam), Pramod Nagle, Nivrutti Wagmode, Gajanan, Dinesh, Anil, Deepak, Chandrashekhar, Bhaskar, Mahesh, Nilesh, Amit, Mangesh, Kamlesh, Ranjit, Leena, Minaz, Iqbal, Amol, Nayana, Dr. Shafi, Dr. Popat, Kanthi, Vishnu, Sanjay, Dnyaneshwar, Ranjit, Chitanya, Ruhima, Kishor, for their great friendship and help. My M.Sc. study at H.P.T. Arts and R.Y.K. Science College, Nashik was made enjoyable part in my life due to many good friends and I wish to thank all of my P.G Classmates. Especially, Vishwamitra Bhalerao, Lekha Nair, Minakshi Singh, Lalit Rajput, Rashmi Kanojiya, Manoj Gaware, Sonal Dani for their good friendship. I would like to thank Primary and High School Teachers, Junior and Degree College Lecturers and P. G. College professors. Especially, Dr. Bobade, Dr. Bhorhade, Dr. Toche, Hire Sir, Bagul Sir. They taught me discipline and good education to reach here. I take this opportunity to thank my best friends. Especially, Sharad Bedade, Jigar Shah, Sanjay Madurker, Rupesh Rajyadhyaksh, Dhanesh Mane, Pramod Nagle, Laxman Mande, Sachin Gunjal, Abhijit Shinde for helping me get through the difficult times, for their emotional support and encouragement. I am thankful to all the Well-Wishers from my relatives. Especially, Families of Chitra Martand Mama, Maushi, Late Sukhdev Gawande (Appa), Kamlaker Mama and other relatives for their constant support and encouragement. I am thankful to my father in law Mr. Kashinath Gharte and my mother in law for supporting me in all my decisions. I also thank my brother in law Suyog and family of my sister in law Suverna for their constant support and encouragement. I am at dearth of words to express my gratitude to my mother Mrs. Nanda Gawande and Father Late Mr. Dadaji Gawande, My hard-working parents have sacrificed a lot for me and they are always in my heart, when I am away from my home. This thesis is indeed a realization of their dream. I thank my sister Neelam Gawali, my Jijaji Mr. Bhagwan Gawali and their cute little angles Shruti and Kranti for their unconditional love and support. I am also thankful my brother Nitin Gawande. He is not only my brother but also good friend and motivator. I am deeply indebted for his support in these four years. I am very thankful to my sister in law Harshada and wish them both very happy married life. I always missed my little angel Shreyasi for her smiles, when I had to stop being with her to be with research. My final, and most heartfelt, acknowledgment must go to my beloved wife Dr. Sonali. She is the best part of my life. I never expected I would have ended up marrying such a wonderful person. She supported me, encouraged me and loved me during my Ph. D. Each and every moment I remember her when I am away from her and she is always in my heart. Words are not enough to express how much I love her.

Sachin Dadaji Gawande

TABLE OF CONTENTS

Page

Abbreviations i-iv

Abstract v-xi

Part-I Part-I, Section-A: Overview on Copper mediated Cross-coupling reactions I.A.1. Introduction of copper mediated reactions 1-3 I.A.2. C-O Bond formation reactions 3-4 I.A.3. C-N Bond formation reactions 4-6 I.A.4. C-C Bond formation reactions 6-8 I.A.5. Copper catalyzed cascade and domino reactions 8-12 I.A.6. Copper catalyzed Click Chemistry 12-13 I.A.7. Recent copper mediated protocols from our group 13-15 I.A.8. References 15-17

Section B: Catalyst free and Cu catalyzed reactions of cyanochromenes and sodium azide: Synthesis of benzofurans and chromenotetrazoles I.B.1. Introduction 18-19 I.B.2. Review of literature 19-21 I.B.3. Result and discussions 21-33 I.B.4. Conclusion 33 I.B.5. Experimental Section 33-41 I.B.6. References 41-43

Section C: Synthesis of Dibenzodiazepinones via Tandem Copper (I) Catalyzed C-N Bond Formation I.C.1. Introduction 44 I.C.2. Review of literature 45-46 I.C.3. Result and discussions 47-55 I.C.4. Conclusion 55 I.C.5. Experimental Section 55-67 I.C.6. References 67-69

Section D: One Pot Synthesis of 2-Arylquinazoline and Tetracylic-Isoindolo[1,2- a]quinazoline via Cyanation Followed by Rearrangement of o-Substituted 2-Halo-N- Arylbenzamide I.D.1. Introduction 60-71 I.D.2. Review of literature 71-73 I.D.3. Result and discussions 73-82 I.D.4. Conclusion 82 I.D.5. Experimental Section 82-96 I.D.6. References 96-98

Part II Section 1: Overview on Iodocyclization by activation of alkynes using molecular iodine II.A.1. Introduction 99 II.A.2. Cyclization via C-N bond formation 99-101 II.A.3. Cyclization via C-O bond formation 101-102 II.A.4. Cyclization via C-S bond formation 102-103 II.A.5. Cyclization via C-C bond formation 103-105 II.A.6. Iodine mediated recent protocols from our group 105-107 II.A.7. References 107-108

Section 2: Molecular Iodine Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives II.B.1. Introduction 109 II.B.2. Review of literature 109-110 II.B.3. Result and discussions 110-120 II.B.4. Conclusion 120 II.B.5. Experimental Section 120-134 II.B.6. References 134-137 X-ray Crystallographic Data 138-146 Fluorescence Data 147-151 List of Publications 152-153 Abbreviations

Å Angstrom

Ac2O Acetic anhydride AcOH Acetic acid

AgNO3 Silver nitrate AgOTf Oxo(trifluoromethylsulfonyl)silver

AlCl3 Aluminium chloride Ar Aryl aq. Aqueous B-H Baylis-Hillman

BF3.Et2O Boron trifluoride diethyl etherate (R)-BINAP 2,2'-bis(Dipenylphosphino)-1,1'-binaphthyl Bn Benzyl Boc Butyloxycarbonyl Bu Butyl n-BuLi n-Butyllithium t-Bu tert-Butyl t-BuOH tert-Butanol br Broad (IR) brs Broad singlet (NMR) Bz Benzoyl oC Degree celsius Cat. Catalyst

CDCl3 Chloroform (deuterated) Cm Centimeter

CH2ClCH2Cl 1,2-Dichloroethane

CH3NO2 Nitromethane Cu(Ι)I Copper(I) iodide

Cs2CO3 Cesium carbonate d Doublet (NMR) d Day(s) dd Doublet of doublet DABCO 1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE 1,2-Dichloroethane DCM Methylene chloride DEAD Diethyl azodicarboxylate DIEPA N,N-Diisopropylethyl amine DMF N,N-Dimethylformamide DMSO Dimethyl sulfoxide EI Electron impact Et Ethyl

Et3N Triethyl amine EtOAc Ethyl acetate

Et2O Diethyl ether EtOH Ethanol equiv. Equivalent(s) FAB Fast atom bombardment Fe Iron powder FT Fourier transform H Hour (s) hν Irradiation with light HBr Hydrogen bromide HCl Hydrochloric acid

H2O Water HRMS High resolution mass spectrometry Hz Hertz IBX o-Iodoxybenzoic acid

InBr3 Indium tribromide iProAc Isopropyl acetate IR Infrared spectrometry KBr Potassium bromide (IR)

K2CO3 Potassium carbonate KF Potassium fluoride KOH Potassium hydroxide LRMS Low resolution mass spectrometry M Moles per liter Me Methyl

Me2NH Dimethylamine

Me2SO4 Dimethyl sulfate Mg Milligram

MgSO4 Magnesium sulfate MHz Mega hertz Min Minutes mL Milliliter(s) mmol Millimole(s)

MnO2 Manganese dioxide mol Mole(s) mp Melting point

MS Mass spectrometry MVK Methyl vinyl ketone MW Microwave μL Microliter (s) N Equivalents per liter (Normality) NaCl Sodium chloride

Na2CO3 Sodium carbonate NaH Sodium hydride

NaHCO3 Sodium bicarbonate NBS N-Bromosuccinimide NCS N-Chlorosuccinimide

NH4Cl Ammonium chloride

NaIO4 Sodium periodate NIS N-Iodosuccinimide NMM N-Methylmorpholine NMR Nuclear magnetic resonance

NH2NH2 Hydrazine

NH4OAc Ammonium acetate

Na2SO4 Sodium sulfate

Ni2B Nickel boride Nu Nucleophile OAc Acetate OsO4 Osmium tetroxide Pd/C Palladium over charcoal

Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II)dichloride

Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0)

Pd(OAc)2 Palladium(II)acetate

PdCl2 Palladium(II)chloride

Ph2CO Benzophenone

Ph Phenyl ppm Parts per million q Quartet (NMR) Rf Retention factor rt Room temperature s Singlet (NMR)

Sc(OTf)3 Scandium triflate

SiO2 Silicon dioxide 2 SN Substitution nucleophilic bimolecular t Triplet (NMR) TBAF Tetrabutylammonium fluoride TFA Trifluoroacetic acid TFAA Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin layer chromatography

TMSN3 Trimethylsilyl azide UV Ultraviolet Zn Zinc powder

ABSTRACT OF THE THESIS

SYNTHESIS OF BIOLOGICALLY ACTIVE CORE STRUCTURES BY COPPER AND IODINE MEDIATED PROTOCOLS VIA C-C AND C-N BOND FORMATION The content of this dissertation is divided into two parts. Part Ι is subdivided into four sections. Section A, illustrates the overview on copper mediated cross-coupling reactions. This section also described a brief survey on ligand promoted copper catalyzed reactions. Section B, describes “The study of catalyst free and copper catalyzed reactions of cyanochromenes and sodium azide”. In this section, the synthesis of 3-cyanobenzofurans and chromenotetrazole derivatives were achieved by metal free and copper catalyzed reactions. In addition, we also discussed the utility of 2-aminoquinoline tetrazole as potential Zn2+ ion sensor. Section C, demonstrates the “synthesis of dibenzodiazepinones via tandem copper (I) catalyzed C-N bond formation”. Further, the dibenzodiazepinone derivative possessing nitro group at ortho position of phenyl ring was utilized for the synthesis of triaza-pentacyclic ring derivative. Section D, deals with a novel method for the “synthesis of 2-arylquinazoline and tetracylic-Isoindolo[1,2-a]quinazoline via cyanation followed by rearrangement of o-substituted 2-halo-N-phenylbenzamide”. The compound formation depends up on solvent and temperature used during the reaction. Part II is divided into two parts. Section A is about the overview of intramolecular iodocyclization with alkynes using molecular iodine. Further, in this section we discussed the important iodine mediated C-C, C-N, C-O and C-S bond formation reactions via iodocyclization by activation of internal alkynes. Section B demonstrates the “molecular iodine mediated cascade reaction of 2-alkynylbenzaldehyde and indole: an easy access to tetracyclic indoloazulene derivatives”. Further, the iodo-substituted tetracyclic indoloazulene derivative was then functionalized by using various C-C bond coupling reactions.

Keywords: Copper catalyzed, Copper(Ι)iodide, 3-Cyanobenzofurans, Chromenotetrazole, Dibenzodiazepinones, 2-Arylquinazoline, Isoindolo[1,2-a]quinazoline, Copper(Ι)cyanide, Cyanation, Rearrangement, Iodine, Iodocyclization, tetracyclic indoloazulene,

Part-Ι Part-Ι, Section-A: The Overview on Copper Mediated Cross-Coupling Reactions This section describes the early reports of copper mediated cross-coupling reactions. Further, the section also described the drawbacks of early reports and a brief survey on ligand promoted copper catalyzed reactions published in last decade. Moreover, the advantages of copper mediated cross coupling reactions over other transition metals are also described.

Part-Ι, Section-B: The study of Catalyst Free and Copper Catalyzed Reactions of Cyanochromenes and Sodium Azide This section discusses two different roles of sodium azide under two different reaction conditions along with the plausible mechanisms. When sodium azide was treated with cyanochromenes under catalyst free conditions, the azide anion acted as a base. Hence, a base mediated rearrangement of cyanochromenes was resulted in the formation of benzofuran derivatives. However, in the presence of catalytic amount of CuI, the azide anion acted as a diene to produce chromenotetrazoles.

Scheme 1: Catalyst free and copper catalyzed reactions of cyanochromenes and sodium azide

Further, the chromenotetrazole was treated under various reagents and under different conditions to afford important biologically active core structures such as chromeno oxadiazole, chromenopyrrazole, 3-methylmorpholine substituted chromenotetrazole derivatives in good yields. In addition, the report shows the utilities of the 2-amino quinoline tetrazole derivative as potential Zn2+ ion sensor.

Part-Ι, Section-C: Synthesis of Dibenzodiazepinones via Tandem Copper (I) Catalyzed C-N Bond Formation This section demonstrates the one pot synthesis of dibenzodiazepinone derivatives via Cu- catalyzed tandem C-N bond formation. The use of various halo amide and 2- iodoaniline derivatives permitted the synthesis of an array of dibenzodiazepinone derivatives in moderate to good yields.

Scheme 2: Copper catalyzed synthesis of dibenzodiazepinones derivatives Moreover, the dibenzodiazepinone derivative (A) was utilized to synthesize the triaza- pentacyclic ring derivative B in an excellent yield.

Scheme 3: Synthesis of the triaza-pentacyclic benzodiazepine by reductive cyclization

Part-Ι, Section-D: One Pot Synthesis of 2-Arylquinazoline and Tetracyclic- Isoindolo[1,2-a]quinazoline Derivatives via Cyanation Followed by the Rearrangement of o-Substituted 2-Halo-N-Arylbenzamides

This section discussed one pot synthesis of substituted 2-arylquinazoline derivatives and tetracylic-isoindolo[1,2-a]quinazoline via cyanation followed by rearrangement of o- substituted 2-halo-N-arylbenzamides. Using Dimethyl sulfoxide (DMSO) as the solvent, the cleavage of the tetracyclic isoindole fused quinazoline leads to the formation of 2- arylquinazoline drivatives.

Scheme 4: Synthesis of 2-arylquinazoline and tetracyclic isoindole fused quinazoline.

The wide range of substrates such as 2-phenylquinazolin-4-amine, 4-methyl-2- phenylquinazoline and long chain 2-phenyl-4-styryl-quinazoline derivatives were obtained in moderate to good yields. However, when 1,4-dioxane is used as the solvent, tetracyclic isoindole fused quinazolines were produced in good yield.. Various tetracyclic isoindole fused quinazoline derivatives were obtained in good yields.

Part-II Part-II, Section-A: Overview on Iodocyclization by Activation of Alkynes using Molecular Iodine This section illustrates the advantages of metal free cyclization by using molecular iodine via C-C, C-N, C-O, and C-S bond formation with alkynes. Further, the section also reviews the literature of important protocols for various iodocyclization involving iodine mediated activation of alkyne.

Part-II, Section-B: Molecular Iodine Mediated Cascade Reaction of 2- Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives. This section described molecular iodine mediated synthesis of iodo substituted tetracyclic indoloazulene derivatives by the reaction of 2-(substituted phenylethynyl)benzaldehydes and different indoles. The section further discussed the reaction mechanism, which involves bisindole from 2-(substituted phenylethynyl)benzaldehyde and indole followed by iodocyclization. Further, functionalization of iodo substituted tetracyclic indole fused azulene derivative was achieved by various palladium-catalyzed cross-coupling reactions to generate highly substituted tetracyclic indole fused azulene derivatives.

Scheme 6: Synthesis of tetracyclic indoloazulene

中文摘要

本論文主要可分為兩個章節。第一章可被細分為四個部分。在 A 部分，回顧銅催化耦合反應的相關文獻報導，除此之外，也對配位體促進銅催化的反應進行簡要的描述。B 部分是關於「氰基苯並吡喃與疊氮化鈉藉由無催化劑或銅催化的條件下反應之研究。」在此部分中，我們成功利用無金屬催化或銅催化的方式合成 3-氰基苯並呋喃與苯並吡喃四唑衍生物。另外，我們亦針對使用 2-胺基喹啉四唑作為鋅離子偵測劑的反應進行介紹。在 C 部分，我們描述「以銅催化碳- 氮鍵生成合成二苯二氮平類」的研究。再者，苯環上鄰位硝基的二苯二氮平類衍生物可被用來合成三氮雜-五環衍生物。於 D 部分，介紹「透過 2-鹵代-N-苯基苯甲醯胺的氰化並重排反應以合成 2 -苯基喹唑啉與四環-異吲哚基[1,2-a]喹唑啉」的研究結果，顯示化合物的生成決定於溶劑及溫度。

第二章可被分為兩個部分。A 部分關於碘催化炔類進行分子內環化的相關文獻報導，進一步，我們亦討論藉由碘催化碳-碳、碳-氮、碳-氧、碳-硫鍵的生成，使炔類進行分子內環化反應的相關文獻。B 部分描述「碘催化 2-炔基苯甲醛與吲哚反應生成四環吲哚薁 (indoloazulene) 衍生物的研究。」再者，碘取代的四環吲哚薁 (indoloazulene)衍生物可藉由多元碳-碳鍵耦合反應進行官能基化。

關鍵字：銅催化，碘化亞銅，3-氰基苯並呋喃，苯並吡喃四唑，二苯二氮平類， 2 -苯基喹唑啉，異吲哚基[1,2-a]喹唑啉，氰化銅，氰化，重排，碘，碘環化，四環吲哚薁

Part-I, Section-A Overview on Copper mediated Cross-coupling reactions I.A.1. Introduction Transition metal mediated coupling reactions are important tool in organic synthesis. Those reactions become the inseparable part of pharmaceutical industries for the synthesis of pharmaceutical drugs as well as the natural products synthesis. The transition metal mediated coupling reactions are more efficient than the traditional methods as they shorten the steps needed for the synthesis of target molecules and usually gave excellent yield of the desired target. Coupling reactions assisted by transition metal had very long history and numerous protocols were reported for C-C, C-N, C-O and C-S bond formation reactions by Palladium, Nickel, Rhodium, Iron and other transition metal complexes. However, the applicability of such protocols is very limited towards large scale or in industry due to moisture sensitivity of complexes and ligands, toxicity and economic viability. Copper is apparently more versatile and productive than other transition metals due to its vicinity to palladium in the periodic table. Further, copper have an easy access to four oxidation states from 0 to +3, but palladium has access only two stable oxidation states -0 and +2. The +1, +3 and +4 oxidation states for palladium are very rare and do not play any role in cross-coupling reactions. Most likely, the cross- coupling catalytic cycle with copper is serviced by +1/+3 oxidation states highly efficient catalytic systems.1 Further, copper catalyzed reaction have numerous advantages such as reactions are not much affected by air and moisture. Further, copper catalysts are less toxic, inexpensive and the most important they show good functional group compatibility. In fact, copper catalysts work more efficiently substrates contain coordinating functional groups. Ullmann-Goldberg in 1901

Scheme I.A.1.1 Coupling reactions associated with copper had very long history. The first report on copper mediated coupling was published in 1901 by Fritz Ullmann and his wife Irma Goldberg. The reaction of o-chloronitrobenzene on heating at 220oC with finely powdered

copper-bronze alloy for 6h leads to formation of 2,2'-dinitrobiphenyl (Scheme I.A.1.1).2 In 1903, Ullmann in his next publication reported, a new method for the formation of diphenylamine derivatives, by mixing aniline and ortho-chlorobenzoic acid in the presence of 1 equivalent metallic copper at reflux temperature. Aniline reacted with o- chlorobenzoic acid to form diarylamine in excellent yield (Scheme I.A.1.2).3 Ullmann in 1903

Scheme I.A.1.2 Goldberg in 1906

Scheme I.A.1.3 Ullmann in 1905

Scheme I.A.1.4 Hurtely in 1929

Scheme I.A.1.5 Further, the similar reaction was developed by Goldberg after three year in catalytic amount of copper (Scheme I.A.1.3).4 Synthesis of oxydibenzene was also achieved by Ullmann in 1905 by using bromo benzene and various potassium phenoxides in catalytic amount of metallic copper (Scheme I.A.1.4).5 After almost 20 years later, William Hurtely had reported an exceptional discovery over copper catalyzed C-C bond coupling

by catalytic amount of copper-bronze or copper acetate. When o-bromobenzoic acid and sodium salts of diketones and malonates was treated in ethanol using copper catalyst, formed corresponding C-C bond coupled derivative in good yield (Scheme I.A.1.5).6 These are some of the earlier reports on the copper mediated cross coupling reactions. However, these earlier reports in copper catalyzed reactions are often suffered due to limitations such as harsh reaction conditions, limited scope, need of stoichiometric amounts of copper and workability of these early reports only towards electron deficient halo-aryl substrates. However, similar methods parallelly developed by using palladium complexes are more efficient and had very wide scope. But in last few years, the development of highly efficient copper catalysts and compatible ligands allowed reactions to be conducted under mild reaction conditions and dramatically enhanced the reaction yields have change the face of copper catalyzed chemistry vastly. So in this chapter we discuss the advancement in copper mediated C-O, C-N, C-S, C-C bond cross-coupling reaction in the recent decade. I.A.2. C-O Bond formation reactions Several advancements were taken place in the copper mediated cross-coupling reactions in the last decade. Taillefer and co-workers in their publication “General and mild Ullmann-type synthesis of diaryl ethers” (Scheme I.A.2.1) have reported the synthesis of oxydibenzene.7 Various diary ether were synthesized by reacting different halobenzene derivatives and phenols in catalytic copper oxide and salicylaldoxime (salox) as a ligand. Notably, the reaction was carried out at much wild temperature (82-100oC). The reaction was successfully applied to electron donating halobenzenes as well as electron deficient phenols. In his another publication the o-arylation was successfully carried out under even more mild conditions using tetra dentate ligand 1 to obtained oxydibenzene (Scheme I.A.2.2).8 This method had wide scope and well with tolerated various functional groups.

Scheme I.A.2.1

Scheme I.A.2.2 Further, Zang et al. have developed a copper catalyzed o-arylation of phenols with aryl halides by using (2-Pyridyl)acetone as ligand (Scheme I.A.2.3).9 Similar to Taillefer’s work the reaction was carried out under mild conditions with wide substrates scope.

Scheme I.A.2.3 A new versatile method was developed by Sreedhar and co-workers using 1.25 mol% CuI nano particles to synthesize oxydibenzene in excellent yield (Scheme I.A.2.4).10 Especially, the reaction was carried out with aryl chlorides and no ligand was used to obtain corresponding diarylether derivatives in very good yields. The CuI nano particles were reused up to fifth cycle and obtained good yield of the desired oxydibenzene.

Scheme I.A.2.4 I.A.3. C-N Bond formation reactions N-heterocycles are ubiquitous structures in numerous pharmaceutical drugs as well as in natural products. Significant progress has been made in copper-catalyzed C-N bond coupling reactions to synthesize these N-heterocycles. Development of new ligands with copper catalyst is as good as the traditional Pd(0) coupling reactions. In 1998 researchers from different groups Lam11, Evans12 and Chan13 developed the copper-mediated O- arylation and N-arylation via reaction of aryl boronic acid and substituted anilines or

phenols by copper acetate/base/solvent system (Scheme I.A.3.1). The reaction conditions were much milder and improved.

Scheme I.A.3.1 Extensive mechanistic study was done by Paine on Ullman coupling and concluded that the cuprous ions is an active species.14 Further, Bryant and Capdevielle then reported the use of esters as ligand for copper(I) catalyst can improve the reaction.15,16 Then, Goodbrand and coworkers investigated Ullmann condensation via 1,10- phenanthroline as an efficient ligand.17 The triarylamines in the ligand could lower the temperature and shortened the reaction time. (Scheme I.A.3.2). In further study, numerous ligands were used to improve the reaction condition.

Scheme I.A.3.2 Fukuyama and co-workers described a ligand free arylation of primary aliphatic amines (Scheme I.A.3.3).18 The reaction was carried out in CsOAc as a base at 90oC with DMSO or DMF as the solvent.

Scheme I.A.3.3 However, in 2002, Prof. Buchwald found that the N-arylation of aryl halide with aliphatic amines could be carried out in the presence of ethylene glycol. The ligand was efficiently used for the coupling of various aryl halides with alkyl amines. Further, Fu and co- workers reported a Copper catalyzed efficient C-N bond formation reaction by using

pyrrolidine-2-phosphonic acid phenyl mono ester ligand (Scheme I.A.3.4).19 The efficient process was then further utilized for C-O bond formation reaction.

Scheme I.A.3.4 Recently, Ma and co-workers have reported DMPAO as an efficient ligand for copper catalyzed N-arylation of acyclic secondary amines under relatively milder conditions and lower catalyst loading (Scheme I.A.3.5).20 The combination of CuI and DMPAO also proved an efficient catalytic system for N-arylation of cyclic secondary amines. This method is inexpensive and has wide substrates scope.

Scheme I.A.3.5 Fu and co-workers have reported the Copper catalyzed mono alkylation of primary amides with unactivated secondary alkyl halides at room temperature in photo-induced process (Scheme I.A.3.6).21 The reaction was carried out with 10 mol % copper iodide, LiOtBu as a base in a solution of DMF and Acetonitrile. The solution was irradiated under UVC lamps at 254 nm. This method has wide scope and was successfully applied to acetal, olefin, carbamate, thiophene, and pyridine derivatives.

Scheme I.A.3.6

I.A.4. C-C Bond formation reactions C-C bond formation reactions are considered to be very important tool in synthetic organic chemistry. Among them transition metal catalyzed reaction occupies premier position. Numerous transition metal catalysts were used in C-C bond forming reactions,

the copper catalyzed reactions played a pivotal role in the present class. For instance, Do et al. have reported new efficient method for the direct C-C bond formation. The copper- catalyzed C-arylation at 2-position of various azoles was achieved by using aryl halides (Scheme I.A.4.1).22 The reaction has wide scope as the protocol was successfully applied to electron-rich five-membered heterocycles and electron-poor pyridine oxides. Catalytic system CuI/LiOtBu/DMF at 140oC was the optimal reaction condition for the protocol.

Scheme I.A.4.1 Next, Mao et al. have reported dehydrogenative cross-coupling between thiazoles and 23 oxazole by using Cu(OAc)2 (Scheme I.A.4.2). The synthetic protocol allowed to synthesize unsymmetrical biheteroarenes structures by very easy method.

Scheme I.A.4.2 Copper catalyzed Sonogashira-type reactions under mild conditions have been reported by Monnier et al. (Scheme I.A.4.3).24 This protocol was well tolerated under various functional groups and substrates. This method is inexpensive and can be substitute for traditional palladium catalyzed songashira reaction.

Scheme I.A.4.3 Jiang et al. have reported the Sonagashira type copper catalyzed coupling of o- iodoacetanilide derivatives and terminal alkyne using N-methylpyrrolidine-2-

carboxamide hydrochloride as a ligand (Scheme I.A.4.4).25 Interestingly, the reaction was carried out at room temperature.

Scheme I.A.4.4

Prof. Bolm and co-workers developed an efficient catalytic system for Sonogashira– Hagihara type reactions using DMEDA as an efficient ligand (Scheme I.A.4.5).26 various metal complex and copper complex study shows that the structure of the ligand plays a key role for the coupling efficiency. The method was successfully applied to wide variety of substrates. Moreover, the low catalyst loading is also important feature of this method.

Scheme I.A.4.5

I.A.5. Copper catalyzed cascade and domino reactions Copper-catalyzed cascade and domino reactions are powerful tools for the construction of a wide variety of heterocyclic frame works. Larger number of heterocycles including indoles, benzofurans, quinolines, isoqunolines, quinazalines, quinazolones, and many more fused heterocycles have been synthesized using this approach. In particular, transition metal catalyzed cascade reactions have tremendous advantages over stepwise reactions is that waste production is minimized, fewer reagents are needed, separation processes are simpler and energy, time, and costs are minimal. Copper catalyzed domino reactions are the important tool in recent research as the reaction went through multiband formation to afford fused ring structure. Numerous methods have been reported to synthesize important core structures via copper catalyzed reaction. Recently, Ma and co- workers have demonstrated the synthesis of 2-substituted indole by the reaction of N-(2- halophenyl)-2,2,2-trifluoroacetamide and terminal alkyne (Scheme I.A.5.1).27 Copper

iodide and L-proline was the effective catalytic system used to afford corresponding 2- substituted indole in good yield under cascade process. The protocol is an inexpensive and palladium free method for the synthesis indole derivatives

Scheme I.A.5.1

Further, Yang et al. have developed a copper catalyzed protocol for the preparation of substituted benzimidazoles via cascade process by the reaction of o-haloacetoanilides with amidine hydrochlorides (Scheme I.A.5.2).28 The ligand free protocol used easily available starting materials such as o-haloacetanilide derivatives and amidine hydrochlorides. The reaction was carried out in CuBr as a catalyst using Cs2CO3 as base in DMSO.

Scheme I.A.5.2

Recently, a synthesis of pyrazolo[5,1-a]isoquinolines was efficiently carried out by copper-catalyzed cascade reactions of 2-alkynylbromobenzene and pyrazole derivatives (Scheme I.A.5.3).29 The reaction afford the desired pyrazolo[5,1-a]isoquinoline derivatives in good yield via copper(I)-catalyzed hydroamination and C–H activation in cascade process.

Scheme I.A.5.3

Fu and co-workers have described the synthesis of 4-Oxopyrimido[1,2-a]indole derivatives via copper catalyzed domino reaction (Scheme I.A.5.4).30 The copper catalyzed reaction of N-(2-halophenyl)-3-oxoalkanamides and substituted benzyl cyanide

using picolinic acid as a ligand at 90-110oC heating gave corresponding 4- Oxopyrimido[1,2-a]indole derivatives in moderate to good yields. This cascade process, underwent via copper catalyzed C-arylation followed by the nucleophilic attack of amidic N-H to form 2-aminomsubstituted indole, which on further nucleophilic reaction with carbonyl formed corresponding of 4-oxopyrimido[1,2-a]indole derivative.

Scheme I.A.5.4

In recent studies the copper catalyzed oxidative addition and cyclization found much more effective than the palladium catalyzed methods. Gao et. al have demonstrated the synthesis of 2-halo-substituted Imidazo[1,2-a]pyridines, Imidazo[1,2-a]pyrazines and Imidazo[1,2-a]pyrimidines via reaction of 2-amino substituted N-heterocycles and alkyl- substituted haloalkynes.31 Synthesis of these heterocycles was developed by using copper acetate as a copper-catalyzed and molecular oxygen as oxidant in a one-pot process. The reaction was carried out under mild conditions and afforded corresponding compounds in good yields. In another report Monir et al. have reported aerobic oxidative coupling by the reaction of various chalcones and 2-amino pyridine by C-H amination for the synthesis of 3-arylimidazo[1,2-a]pyridine derivatives (Scheme I.A.5.5).32 The cascade process proceeds via first Michael addition and then an intramolecular oxidative amination.

Scheme I.A.5.5

In another report, the sequential copper catalyzed Ullmann coupling and then intramolecular C-H amidation was carried out to afford Imidazo/Benzoimidazoquinazolinone derivatives are published by Fu and co-workers

(Scheme I.A.5.6).33 This reaction is simple and used inexpensive copper catalyst to afford good to excellent yields of desired compounds.

Scheme I.A.5.6 An efficient protocol for the synthesis of 2-N-substituted Benzothiazoles was developed by Ma and co-workers by domino reaction of 2-haloaniline, carbon disulphide and various substituted secondary amines (Scheme I.A.5.7).34 In this process, first secondary amines react with carbon disulphide to give dithiocarbamate salts, this salt on Ullmann type C-S bond coupling with 2-haloaniline formed substituted 2-aminothiophenol intermediate. The thiophenol intermediate underwent cyclization due to presence of amino group and then removal of H2S gas formed the corresponding 2-N-substituted Benzothiazole derivatives in moderate to excellent yields. The protocol has wide scope and the 2-N-substituted Benzothiazole derivatives are prepared by using easily available starting material.

Scheme I.A.5.7 Recently, Qian and co-workers have reported the synthesis of complex N-heterocycles via copper catalyzed domino reaction (Scheme I.A.5.8).35 The reaction first underwent copper catalyzed alkyne-azide cycloaddition reaction. This click reaction further activate methylene group adjacent to carbonyl group for Goldberg amidation and Camps cyclization to form highly substituted quinolinone core. Further, when R3 substituent in quinolinone core was used as 2-bromoaryl group, the quinolinone core further underwent C-H arylation to form pentacyclic compound possessing triazole and quinolinone.

Scheme I.A.5.8 Numerous copper catalyzed cascade and domino reaction were published in last decade to synthesize biologically important core structures.36 these efficient protocols were carried out by very efficient and inexpensive copper catalyzed protocols than the traditional palladium and other expensive metal methodologies.

I.A.6. Copper catalyzed click chemistry The Cu(I)-catalyzed cycloaddition of azide-alkyne is excellent method for the synthesis of complex molecules, macrocyclic peptide, polymer and dendrimers. The Cu catalyzed efficient method was introduced by Sharpless and Meldal showed that the copper catalyst enhance the reaction rate dramatically at room temperature and affords 1,4-disubstituted triazole in excellent yield in aqueous medium (Scheme I.A.6.1).37,38 after this discovery, prof. Sharpless have introduced the term Click reaction. In his way “click reaction must be modular, wide in scope, high yielding, create only inoffensive by-products (that can be removed without chromatography), are stereospecific, simple to perform and that require benign or easily removed solvent”.39

Scheme I.A.6.1

Numerous improved methods have been published in this decade showing the utility of this protocol. Fukuzawa and co-workers have developed 1,4-diphenyl-1,2,3-triazol-5- ylidene [CuCl(TPh)] as an efficient catalyst for the synthesis of 1,4-substituted 1,2,3- triazoles (Scheme I.A.6.2).40 The catalyst effective in reducing the reaction time and efficiently worked with sterically hindered azides and alkynes.

Scheme I.A.6.2 Recently, Shin et al. have presented the synthesis of 1,4-disubstituted triazole via Copper- Catalyzed Azide-Alkyne cycloaddition reaction in water using cyclodextrin as a phase transfer catalyst (Scheme I.A.6.3).41 The use of catalytic amount of cyclodextrin as a phase transfer catalyst enhance the solubility of starting materials and reduced the reaction time. Further, the one pot protocol using alkyl or aryl bromide, sodium azide, terminal alkynes and copper catalyst afforded the corresponding 1,4-disubstituted triazoles in excellent yields.

Scheme I.A.6.3 A reusable solid phase catalyst for click chemistry via self-assembly of copper sulfate and a poly(imidazole-acrylamide) amphiphile was used for the synthesis of 1,4-disubstituted triazole (Scheme I.A.6.4).42 The insoluble amphiphilic polymeric imidazole Cu catalyst is high in activity, reusable solid-phase provided the corresponding triazole compounds in excellent yields.

Scheme I.A.6.4

I.A.7. Recent copper mediated protocols from our group Recently, our group has proactively doing research on the copper catalyzed protocols for the synthesis of biologically active core structures. Recently, the synthesis of fused Triazolothiadiazepine1,1-dioxide derivatives was successfully achieved via copper catalyzed cascade reaction (Scheme I.A.7.1).43 The copper catalyzed reaction of 2-halo- N-(prop-2-yn-1-yl)benzenesulfonamide derivative with azidotrimethylsilane, DIPEA as a

base in DMF at 70oC. First, the cycloaddition reaction of terminal alkyne with azide takes place to produce N-((1H-1,2,3-triazol-5-yl)methyl)-2-halo-benzenesulfonamide, which underwent copper catalyzed N-arylation to obtained Triazolothiadiazepine 1,1-dioxide derivative.

Scheme I.A.7.1

In another report, one-pot synthesis of 2-arylbenzoxazoles via copper catalyzed C-N and C-O bond formation Scheme I.A.7.2 (Scheme I.A.7.2).44 The copper catalyzed reactions of 2-(2-halophenyl)halobenzamides with primary and secondary amines leads to formation in the formation of 2-arylbenzoxazole derivatives. This procedure involves copper-catalyzed tandem C-N and C-O coupling reactions. The reaction is ligand free in the cases of primary or secondary amides and formed corresponding 2-arylbenzoxazole derivatives in good to excellent yields. However, L-proline was used as ligand in the case of N-aromatic heterocycles like indole, imidazole and pyrazole derivatives.

Scheme I.A.7.2

Further, synthesis of isocoumarin derivatives were achieved via Copper-catalyzed tandem reaction of 2-halo-N-phenyl benzamide and 1,3-diketones. (Scheme I.A.7.3).45 One pot, cascade synthesis of isocoumarin derivatives was achieved by one-pot, efficient cascade process of copper catalyzed tandem C−C and C−O bond formation reaction. Methodology was further extended for the synthesis of various pyranoquinolinone derivatives.

Scheme I.A.7.3

Recently, A novel copper (I) catalyzed azide–alkene aerobic oxidative cycloaddition protocol was developed from our group for the regioselective synthesis of 1,4- disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles (Scheme I.A.7.4).46 When electron- deficient olefins were treated with alkyl and aryl azides in catalytic amount of CuI under an oxygen atmosphere, the highly substituted 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazole derivatives were obtained in good yields.

Scheme I.A.7.4

I.A.8. References 1. a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004, 248, 2337. b) A. J. Canty, in E. I. Negishi (Ed.), Handbook of Organopalladium Chemistry, vol. 1, Wiley, New York, 2002, 189. 2. a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054. b) Ullmann, F.; Bielecki, J. Ber. Dtsch. Chem. Ges. 1901, 34, 2174. 3. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382. 4. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691. 5. Ullmann, F.; Sponagel, P. Ber. Dtsch. Chem. Ges. 1905, 38, 2211. 6. Hurtley, W. R. H. J. Chem. Soc. 1929, 1870. 7. Cellier, P. P.; Cristau, H.-J.; Hamada, S.; Spindler, J.-F.; Taillefer, M.; Spindler, Org. Lett. 2004, 6, 913. 8. Cristau, H.-J.; Ouali, A.; Taillefer, M.; Spindler, J.-F. Adv. Synth. Catal. 2006, 348, 499. 9. Zhang, Q.; Wang, D.; Wang, X.; Ding, K. J. Org. Chem. 2009, 74, 7187. 10. Sreedhar, B.; Arundhathi, R.; Reddy, P. L.; Kantam, M. L. J. Org. Chem. 2009, 74, 7951. 11. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933. 12. Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39, 2937.

13. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941. 14. Paine, A. J. J. Am. Chem. Soc. 1987, 109, 1496. 15. Bryant, R. J.; Brit, Chem. Abstr. 1982, 97, 215738. (U.K. Patent Appl. GB 2,089, 672, 1982) 16. Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1993, 34, 1007. 17. Goodbrand, H. B.; Hu, N.-X. J. Org. Chem. 1999, 64, 670. 18. Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett. 2003, 5, 4987. 19. Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636. 20. Zhang, Y.; Yang, X.; Yao, Q.; Ma, D. Org. Lett. 2012, 14, 3056. 21. Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 2162. 22. Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. 23. Mao, Z. F.; Wang, Z.; Xu, Z. Q.; Huang, F.; Yu, Z. K.; Wang, R. Org. Lett. 2012, 14, 3854. 24. Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M. Org. Lett. 2008, 10, 3203. 25. Jiang, H.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Synthesis 2008, 2417. 26. Zou, L.-H.; Johansson, A. J.; Zuidema, E.; Bolm, C. Chem. Eur. J. 2013, 19, 8144. 27. Liu, F.; Ma, D. J. Org. Chem. 2007, 72, 4844. 28. Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 7841. 29. Pan, X.; Luo, Y.; Wu, J. J. Org. Chem. 2013, 78, 5756. 30. Wang, Y.; Wang, R.; Jiang, Y.; Tan, C.; Fu, H. Adv. Synth. Catal. 2013, 355, 2928. 31. Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H. Adv. Synth. Catal. 2013, 355, 2263. 32. Monir, K.; Kumar Bagdi, A.; Mishra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2014, 356, 1105. 33. Xu, H.; Fu, H. Chem. Eur. J. 2012, 18, 1180. 34. Ma, D.; Lu, X.; Shi, L.; Zhang, H.; Jiang, Y.; Liu, X. Angew. Chem. 2011, 123, 1150. 35. Qian, W.; Wang, H.; Allen, J. Angew. Chem. Int. Ed. 2013, 52, 10992. 36. a) Liu, T.; Zhu, C.; Yang, H.; Fu, H. Adv. Synth. Catal. 2012, 354, 1579. b) Yang, D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv. Synth. Catal. 2012, 354, 477. c) Sagadevan, A.; Hwang, K. C. Adv. Synth. Catal. 2012, 354, 3421. d) Shin, Y. H.; Maheswara, M.; Hwang, J. Y.; Kang, E. J. Eur. J. Org. Chem. 2014, 2305. e) Sun, L.; Zhu, Y.; Lu, P.; Wang, Y. Org. Lett. 2013, 15, 5894. f) Kiruthika, S. E.; Perumal, P. T. Org. Lett. 2014, 16, 484. g) Huang, A.; Chen, Y.; Zhou, Y.; Guo, W; Wu, X.; Ma, C. Org. Lett. 2013, 15, 5480. h)

Lee, C.-F.; Liu, Y.-C.; Badsara, S. S. Chem. Asian J. 2014, 9, 706. i) Yang, Y.; Shu, W.- M.; Yu, S.-B.; Ni, F.; Gao, M.; Wu, A.-X. Chem. Commun. 2013, 49, 1729. j) Cao, H.; Zhan, H.; Cen, J.; Lin, J.; Lin, Y.; Zhu, Q.; Fu, M.; Jiang, H. Org. Lett. 2013, 15, 1080. 37. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596. 38. Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. 39. Kolb, H. C.; Finn, M. G.; Sharpless, B. K. Angew. Chem. Int. Ed. 2001, 40, 2004. 40. Nakamura, T.; Terashima, T.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2011, 13, 620. 41. Shin, J.-A.; Lim, Y.-G.; Lee, K.-H. J. Org. Chem. 2012, 77, 4117. 42. Yamada, Y. M. A.; Sarkar, S. M.; Uozumi, Y. J. Am. Chem. Soc. 2012, 134, 9285. 43. Barange, D. K.; Tu, Y.-C.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Adv. Synth. Catal. 2011, 353, 41. 44. Kavala, V.; Janreddy, D.; Raihan, M. J.; Kuo, C.-W.; Ramesh, C.; Yao, C.-F. Adv. Synth. Catal. 2012, 354, 2229. 45. Kavala, V.; Wang, C.-C.; Barange, D. K.; Kuo, C.-W.; Lei, P.-M.; Yao, C.-F. J. Org. Chem. 2012, 77, 5022. 46. Janreddy, D.; Kavala, V.; Kuo, C.-W.; Chen, W.-C.; Ramesh, C.; Kotipalli, T.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. Adv. Synth. Catal. 2013, 355, 2918.

Part-I, Section B The study of Catalyst-Free and Copper Catalyzed Reactions of

Cyanochromenes and Sodium Azide

I.B.1. Introduction

Synthetic, medicinal and pharmaceutical applications of chromenes are well explored in a plethora of literatures.1-3 In different occasions, these derivatives are utilized as anti-HIV, antitumor, antimicrobial, fungicidal, insecticidal agents, photochromic materials and ingredients of antioxidants.2a In particular, chromenotetrazole had special medicinal importance, these scaffold had typical medicinal activity such as potassium channel activator (A), endothaline-A receptor bioisoster (B), antiallergic agents (C), anti- asthmatic agents and Leukotriene antagonist (D) (Figure I.B.1.1).

Figure I.B.1.1. Biologically active chromenotetrazole compounds

The chromenes with an electron withdrawing functionality at C-3 position are good Michael acceptors.2,3 By applying the same concept, recently, we have disclosed the protocols for the indole and azide addition on 3-nitrochromenes.3 However, as per the electron withdrawing functionalities at the C-3 of the chromene derivatives are concerned, the reactivity of the cyanochromenes are less explored than the nitrochromenes. Besides chromenes, Benzofuran derivatives are also important motifs, which are widely occurred in natural products and exhibit significant biological activities.4,5 Hence, a great effort has been paid towards the synthesis of these heterocycles. Several attempts have been made to achieve, particularly, the 3-cyanobenzofurans due to the huge synthetic

utility of the nitrile functionality.5 However, most of the protocols towards the synthesis of 3-cyanobenzofurans involve multistep reactions, application of toxic metal catalysts or complex combination of reagents.5 Hence, chemists are in search of more convenient and easy methods to synthesize 3-cyanobenzofuran derivatives. Over the last few decades, transition metal catalysts have been drawing the attention of the chemists due to their wide spectrum of utilities in numerous chemical transformations.6 These catalytic activities are mainly originated from the activation of a particular functionality towards a certain type of reaction via coordination.7 This type of activation promotes the other reagents to react with that functional group and thus the reaction achieve an added selectivity. As an example, in the present report, we wish to disclose our finding, which involve the activation of nitrile functionality of cyanochromenes by a Cu catalyst. This activation promotes the azide anion to react with the nitrile functionality selectively, as a 1,3-dipole, to produce chromenotetrazoles. In absence of the catalyst, the azide anion acts as a base and the cyanochromene undergo base mediated rearrangement to produce 3-cyanobenzofuran derivative. I.B.2. Review of Literature I.B.2.1. Chromenotetrazole Few methods are available for the synthesis of chromenotetrazole derivatives. Prof. Nicolaou and co-workers had developed the synthesis of chromenotetrazole from selenium supported cyanochromene via the reaction with trimethyl tin azide followed by acidification by trifluoroacetic acid. The compound was then methylated in methyl iodide. Finally, the solid support was removed by hydrogen peroxide to yield corresponding chromenotetrazole (Scheme I.B.2.1.1).8

Scheme I.B.2.1.1 Ishizuka and co-worker have reported the synthesis of chromenotetrazole via corresponding acid derivative (Scheme I.B.2.1.2).9 First, the acid was converted to its acid chloride and then on reaction with aqueous ammonia, it was converted to its amide. Further, the chromenoamide on reaction with sodium azide, selenium chloride in acetonitrile it afforded corresponding chromenotetrazole via multistep process. The

protocols towards the synthesis of chromenotetrazole derivatives are either multistep or the starting materials are difficult to prepare. So an easy and efficient protocol is highly desirable.

Scheme I.B.2.1.2 I.B.2.2. Benzofuran Numerous methods have been reported for the synthesis of benzofuran derivatives (Scheme I.B.2.2.1).10 Madhusudhan and co-workers have developed the method for the synthesis of cyano benzofuran using phosphorus ylide at high temperature (thermolysis) via Wittig reaction and then Claisen rearrangement into one pot process. This method lack of selectivity and the product obtained only at very high temperature.

Scheme I.B.2.2.1 Further, Chen and co-workers have described the synthesis of substituted benzo[b]furans via CuI catalyzed ring closure of 2-haloaromatic ketones (Scheme I.B.2.2.2).11 The methodology was tolerant to various functional groups, afforded benzofuran derivatives in good to excellent yields. The synthesis of starting material i.e. 2-haloaryl ketone derivatives are very difficult to prepare.

Scheme I.B.2.2.2

In another report Zhao and co-workers have reported FeCl3 catalyzed protocol for the synthesis of 2,3-substituted benzofuran (Scheme I.B.2.2.3).12 The synthesis of 3- functionalized benzo[b]furan derivatives was successfully carried out by the reaction

intramolecular reaction of R-aryl ketones. The electron rich aryl ketones on reaction with

FeCl3, underwent ring closure. This is a new protocol to construct the benzo[b]furan rings via direct oxidative aromatic C-O bond formation.

Scheme I.B.2.2.3

I.B.3. Results and discussions In a recent publication, we reported a protocol for the synthesis of chromenotriazoles from nitrochromenes (Scheme I.B.3.1).3a The triazoles were formed via the elimination of the nitro functionality of the nitrochromenes, when the nitrochromenes were treated with sodium azide in DMSO under catalyst-free conditions. Prompted by this success, we planned to use cyanochromenes, in the place of nitrochromenes, to synthesize triazole derivatives by the elimination of the cyano functionality. However, on heating cyanochromene (entry 2, I.B.3.1) with sodium azide at 160oC in DMSO, 2-methyl-3- cyanobenzofuran derivative was formed. The structure was verified by 1H NMR, 13C NMR, LRMS, HRMS and single crystal X-ray analysis data (Figure I.B.3.1). This result demonstrates an unprecedented type of transformation, which leads to the synthesis of 3- cyanobenzofuran derivatives directly from 3-cyanochromenes.

Scheme I.B.3.1. Reactivity of sodium azide towards nitro and cyanochromene

Figure I.B.3.1. X-Ray Crystal structure of 1a (ORTEP diagram)

Scheme I.B.3.2. Plausible mechanism for the conversion In this reaction, the cyanide functionality was shifted to the benzylic position and a six membered pyran ring was rearranged to a five membered furan ring. As the reaction was occurred only at high temperature, we first assumed a thermal reaction. Hence, our initial assumption was a thermal cleavage of the pyran ring, followed by the 1, 2-shift of the cyano functionality and cyclization to produce intermediate c (Pathway A, Scheme

Table I.B.3.1. Effect of different bases

a All reactions were carried out on 0.5 mmol scale. b Base (1.2 equiv) in DMSO at mentioned temp. c Yields refers to isolated and purified compound.

I.B.3.2). Aromatization of the intermediate c produces the final product. However, when we performed a reaction in the absence of sodium azide, no product was formed and the starting material was recovered. This experimental observation rules out the possibility, which is described in pathway A. Then we assumed a nucleophilic attack by azide anion to form intermediate e (Pathway B), which is followed by the ring opening via the cleavage of C-O bond in SN2 manner to form intermediate f. A base mediated E2 reaction on intermediate f, may produce intermediate b, which would be converted into final product as described earlier. To clarify this assumption, we screened the reaction with

bases, like DIPA, NaOMe and N,N-diethylethane-1,2-diamine as they may act as nucleophile as well as base (Table I.B.3.1). However, the reactions were either failed (entries 6 and 13) or produced the desired product in poor yields (entry 12). On the other hand, bases like DBU, K2CO3, Na2CO3 and Cs2CO3 produced better yields of the desired product. Among the different bases, K2CO3 produced better yields than the others. This fact tells more about a base mediated mechanism, which happened via the abstraction of a proton by a base at high temperature to produce the unstable anion g. This anion undergoes ring cleavage to produce the intermediate h. The 1,2-shift of the cyano functionality was occurred either via pathway D or E to produce the intermediate k (allene intermediate). Intermediate k undergoes cyclization and followed by the aromatization to produce the desired product. It is not clear whether the reaction was occurred via pathway D or E. However, in the crude 1H NMR, we did not observe the formation of product m under air and moisture. We prefer the pathway D as the most favorable route for the formation of the product d. From our studies with different bases, we found that a base of moderate strength, such as sodium azide, was more suitable than other strong or weak bases. Hence, we evaluated the scope of our methodology by using sodium azide in DMSO (entry 2) After determining the best conditions for the conversion, we utilized different cyanochromene derivatives, to evaluate the scope of this methodology (Table I.B.3.2). With unsubstituted cyanochromene, the reaction produced the expected benzofuran derivative in good yield (entry 1). A comparable result was observed with 6-methyl-3- cyanochromene (entry 2). However, the yields of the desired products were decreased in the case of methoxy substituted cyanochromenes (entries 3-4). The yield of the product was further decreased when the dimethoxy substituted cyanochromene derivative was used as substrate (entry 5). Moreover, the desired products were obtained in moderate yields from the 6-halo cyanochromene derivatives (entries 6, 7). However, the yield of the desired product was poor in case of 6-iododerivative (entry 8). Interestingly, when the benzene ring of the cyanochromene was replaced with naphthalene moiety (entry 9) the reaction furnished the corresponding product in good yield. On the other hand, the reaction of 6-acetyl-2H-chromene-3-carbonitrile in the present reaction conditions compounds resulted in the formation of an inseparable mixture of products even at lower temperature (entry 10). The crude 1H NMR did not show a trace amount of the desired product, although, all the starting materials were consumed. The present reaction conditions were found to be suitable even for the preparation of benzothiophene

Table I.B.3.2. Synthesis of benzofuran and benzothiophene derivatives

Continue…………..

a b o All reactions were carried out on 0.5 mmol scale. NaN3 (1.2 equiv.) in DMSO at 160 C. c Yields refer to isolated and purified compounds. d Inseparable mixture. e NR: Reaction was not occurred and only starting material was recovered. derivative (entry 11). However, in this case, the desired product was obtained in poor yield. The protocol failed to form corresponding compound, when the stable aromatic heterocycle, such as 2-amino-3-cyanoquinoline (entry 12), was treated with sodium azide under catalyst free. On the other hand, the result was completely different when the reaction of sodium azide and cyanochromene (1) was carried out in the presence of catalytic amount of CuI with DMSO as a solvent (Table I.B.3.3, entry 1). In this case, the reaction was occurred at lower temperature and the resulting product was chromenotetrazole (1a, Table 3), which was confirmed by 1H NMR, 13C NMR, LRMS, HRMS and single crystal X-ray analysis data (Figure I.B.3.2). With this exciting experimental outcome in hand, we focused our attention towards exploring the most favorable conditions for the reaction as depicted in Table I.B.3.3. During the reaction with DMSO, we faced difficulty in separation of compounds but when the reaction was carried out in DMF as a solvent, excellent yield of

compound 1b was obtained in 4h (entry 2). Next, we screened different copper catalysts such as Cu2O, CuSO4, Cu(OAc)2 in both DMF and DMSO but fail to improve the reaction yield and reduce the reaction time (entries 3 to 8). To find a better alternative of

CuI, other Lewis acids such as TiCl4, AlCl3 and ZnBr2 was screened but produced the desired product in lower yields (entries 9 to 11). Iodine was found to be ineffective for the conversion (entry 12). Hence, DMF as solvent and CuI as catalyst at 120oC was found to be optimal reaction condition for evaluating the scopes of this protocol.

Figure I.B.3.2. X-Ray Crystal structure of 1b (ORTEP diagram) Table I.B.3.3. Solvent and reagent screening

a All reactions were carried out on 0.5 mmol scale. b Yields refers to isolated and purified compounds.

Table I.B.3.4. Synthesis of chromenotetrazoles

Continue…………..

a b All reactions were carried out on 0.5 mmol scale. NaN3 (1.2 equiv)/ CuI (20 mol %) in DMF at 120oC. c Yields refers to isolated and purified compounds.

Under the present reaction conditions, several cyanochromenes underwent cycloaddition to form chromenotetrazoles as shown in Table I.B.3.4. The use of unsubstituted and methyl substituted cyanochromenes resulted in excellent yields of the product (entries 1 and 2). Moreover, comparable yields were obtained with methoxy substituted cyanochromenes (entries 3, 4, 11 and 12). The expected tetrazoles were obtained in excellent yields from cyanochromenes with electron withdrawing groups (entries 5, 6 and 8). Interestingly, the cyanobenzochromene (entry 9) is also produced the expected tetrazole in excellent yield under the present reaction conditions. From the Table I.B.3.4, it is evident that the reaction of cyanochromen possessing an electron donating group took longer time compared with unsubstituted cyanochromene and a cyanochromene with an electron withdrawing substituent to form their corresponding tetrazoles. It is worthy to note that the present reaction conditions were utilized for the nitrogen and sulphur

analogues of cyanochromenes like cyanothiochromene (11) and cyanoquinoline (12). Under these conditions the reaction furnished their corresponding products i.e. thiochromenotetrazole (11b) and 2-aminoquinolinotetrazole (12b) in moderate and excellent yields respectively The most notable point is that under these reaction conditions the chromene ring remained unaffected and the product formation was occurred via selective transformation of the cyano functionality into tetrazoles. The plausible mechanism is similar to the Zn2+ catalyzed transformation of nitriles into tetrazole, which was proposed earlier by Sharpless (Scheme I.B.3.3).12 We assume a similar type of activation of nitrile functionality by the coordination of Cu(I) with the nitrogen (intermediate x, Scheme I.B.3.3) and hence, the azide anion attacked at the nitrile functionality. To the best of our knowledge, these chromenotetrazole derivatives are new in the literature.

Scheme I.B.3.3. Plausible mechanism for the formation of chomenotetrazole

After exploring the scope of this protocol, we attempted to evaluate the synthetic applicability of the tetrazole derivatives (Scheme I.B.3.4). To pursue this goal, we transformed the tetrazole ring into oxadiazole and pyrazole rings. The chromeno oxadiazole derivatives (1c and 1d) were obtained by treating 1b with benzoyl chloride and 2-chloroacetyl chloride. To prepare the pyrazole (1f) derivative, the chromenotetrazole derivative (1b) was refluxed with dibromoethane in acetonitrile in the presence of triethylamine as a base to obtain 1e in good yield.

Scheme I.B.3.4. Synthetic utilities of chromenotetrazole

The compound 1e was heated at 150oC in xylene to obtain the desired pyrazole (1f). Next, in order to evaluate further utility of the chromenotetrazoles, compound 1b was treated with morpholine and formalin in methanol at room temperature and the 3- methylmorpholine substituted chromenotetrazole (1g) was selectively produced in moderate yield. The structure of the compound 1g was confirmed by single crystal X-ray analysis (Figure I.B.3.3). It is noteworthy that pyrazoles, oxadiazoles and morpholines are very important due to their synthetic and medicinal utilities as described in several literature.13 Further, studies on the biological activities of the tetrazole, oxadiazole and pyrazole derivatives are currently underway in our laboratory.

Figure I.B.3.3. X-Ray Crystal structure of 1g (ORTEP diagram)

Further, when we placed the solutions of different tetrazole derivatives in front of UV lamp, compound 12b displayed fluorescent properties. In this context, it is noteworthy to mention that the fluorescence sensing activities of quinoline derivatives are reported in the literature.14 Hence, we focused our attention towards exploring the metal sensing activity of the tetrazole derivative (Figure I.B.3.4). To pursue this goal, we prepared a 0.1M solution of ligand (12b, Table I.B.3.4) in DMF. A 0.1M solution of the metal ion in DMF was then added to 3 mL of a 0.1 M solution of the ligand (compound 12b) and the fluorescence enhancement was measured. With Zn2+, the maximum fluorescence enhancement was observed when 200 μL of the metal ion solution was added to the ligand solution. Later, we measured the fluorescence enhancement with other metal ions, including Na+, K+, Mn2+, Ca2+, Cd2+, Co2+, Cr3+, Cu2+, Hg2+ and Ni2+ (Figure I.B.3.4). With Ni2+, the fluorescence was quenched abruptly. Co2+ and Cu2+ also showed fluorescence quenching properties. On the other hand, Na+, K+, Mn2+, Ca2+, Cd2+, Cr3+ and Hg2+ showed comparable enhancement of fluorescence. However, with Hg2+, the enhancement is greater than Na+, K+, Mn2+, Ca2+, Cd2+, and Cr3+. As shown in Figure 3, compound 12b showed the highest fluorescence enhancement to Zn2+ ions, which was quite distinct from all the others. This selectivity of 12b towards Zn2+ is very important as Zn2+ is the second most abundant transition metal ion in the human body after iron.10a

25 Ligand NaCl

y 20 t

i KCl s

n MnCl2

e t

n 15 CaCl2 I

e CdCl2

c n

e 10 CoCl2

c s

e CrCl3 r

o CuCl2 u

l 5

F HgCl2 NiCl2 0 ZnCl2 350 400 450 500 550 600 650 Wavelength (nm) Figure I.B.3.4. Change of fluorescence intensity of 12b with different metal salts. 200 μL solution of the metal ion in DMF was added to 3 mL 0.1 M solution of the ligand (compound 12b) and the fluorescence enhancement was measured

I.B.4. Conclusion

In conclusion, we have demonstrated a novel method for the synthesis of 3- cyanobenzofuran derivatives from cyanochromenes under catalyst free conditions. The reaction was occurred via a sodium azide mediated rearrangement of the pyran ring into furan ring and a 1, 2-shift of the nitrile functionality. The mechanism was supported by the experimental outcomes. In the presence of CuI, a chromenotetrazole was formed due to the selective activation of the nitrile functionality. In addition, this report demonstrates the utilities of the tetrazole derivative as potential Zn2+ ion sensor as well as synthetic intermediate. Studies aimed at exploring more utilities of benzofurans and chromenotetrazoles in biological and synthetic fields are currently underway in our laboratory. I.B.5. Experimental Section I.B.5.1. General procedure for the Synthesis of 2-methylbenzofuran-3-carbonitrile (1a): To a stirred solution of cyanochromene (1 mmol) in DMSO (2 mL) in a 50 mL round bottom flask was added NaN3 (1.1 equiv.). The reaction mixture was then heated to 160oC. The progress of reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was quenched with ice water (25 mL) and extracted with ethyl acetate. Organic layer was dried over MgSO4 then filtered and evaporated. The crude compound was then column purified to yield corresponding pure compound.

I.B.5.2. General procedure for the Synthesis of Chromene tetrazole by using NaN3/ CuI (1b): To a stirred solution of cyanochromene (0.5 mmol) in DMF (2 mL) in a 50 mL round bottom flask was added NaN3 (1.1 equiv.) and CuI (20 mol%). The reaction mixture was then heated to 120oC. The progress of reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was quenched with ice water (25 mL) and acidified (pH = 3.5) by aq. HCl (4 M). The precipitate was filtered and washed with ice water (25 mL) to obtain the pure product. I.B.5.3. Synthesis of 2-(2H-chromen-3-yl)-5-phenyl-1,3,4-oxadiazole (1c): A mixture of 1b (1 mmol) and benzoyl chloride (1.1 mmol) in toluene (10 mL) in a 50 mL round bottom flask was refluxed overnight. The reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The crude compound was then purified by column chromatography to afford yellow solid. Compound 1d was prepared by following a similar procedure and by using chloroacetylchloride (1.1 mmol) in place of benzoyl chloride. I.B.5.4. Synthesis of 5-(2H-chromen-3-yl)-1-vinyl-1H-tetrazole (1e): To a stirred solution of dibromoethane (2 mmol) and 1b (1 mmol) in 5 mL acetonitrile in a 25 mL round bottom flask was added solution of Et3N (4 mmol) in acetonitrile (3 mL) dropwise. The reaction mixture was then refluxed and the progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature and acetonitrile was removed under reduced pressure. The residue was dissolved in dichloromethane (30 mL) and washed with H2O (25 mL). The organic solution was dried over MgSO4 and the solvent was evaporated. The product was purified by column chromatography. I.B.5.5. Synthesis of 5-(2H-chromen-3-yl)-1H-pyrazole (1f): A stirred solution of compound 1e (1 mmol) in xylene (15 mL) was heated at 140oC and the progress of the reaction was monitored by TLC. After the completion of the reaction, the solvent was evaporated under reduced pressure. The product was purified by column chromatography to yield yellow solid. I.B.5.6. Synthesis of 4-((5-(2H-chromen-3-yl)-1H-tetrazol-1-yl)methyl)morpholine (1g): To a ice cold solution of 1a (1 mmol) in methanol (2 mL) was added formalin (1.6 equiv) and stirred at room temperature for 15 minutes. Then morpholine (1 equiv) was added drop wise. The progress of the reaction was monitored by TLC. After the

completion of the reaction, the solvent was evaporated under reduced pressure. The compound was purified by column chromatography to yield off white solid I.B.5.7. Spectral Data 2-methylbenzofuran-3-carbonitrile (1a) Yield: (76 %); white solid; m.p.: 148-150oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.61-7.63 (m, 1H), 7.47-7.49 (m, 1H), 7.35-7.37 (m, 13 2H), 2.67 (s, 3H); C NMR (100 MHz, CDCl3) δ 165.0, 153.9, 126.2, 125.8, 124.6, 119.7, 113.6, 112.7, 91.6, 14.1; LRMS (EI) + + (m/z) (relative intensity) 157 (100) [M] ; HRMS calcd for C10H7NO [M] : 157.0528, Found 157.0532.

2,5-dimethylbenzofuran-3-carbonitrile (2a) Yield: (74 %); white solid; m.p.: 137-139oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.39 (s, 1H), 7.35 (d, J = 8.44 Hz, 1H), 7.15 (d, J = 13 8.44 Hz, 1H), 2.64 (s, 3H), 2.46 (s, 3H); C NMR (100 MHz, CDCl3) δ 164.9, 152.4, 134.4, 126.9, 126.3, 119.5, 113.7, 111.1, 91.2, 21.5, 14.1; LRMS (EI) (m/z) (relative intensity) 171 (100) [M]+, 156 (30), 115 (55); HRMS + calcd for C11H9NO [M] : 171.0684, Found 171.0683.

6-methoxy-2-methylbenzofuran-3-carbonitrile (3a) Yield: (59 %); yellow solid; m.p.: 158-160oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.45 (d, J = 8.56 Hz, 1H), 6.99 (dd, J = 2.0 Hz, 1H), 6.95 (dd, J = 2.16, 11.44 Hz, 1H), 3.85 (s, 3H), 2.61 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 163.9, 159.0, 154.9, 119.7, 119.2, 113.7, 113.2, 96.2, 91.2, 56.0, 13.9; LRMS (EI) (m/z) (relative intensity) 187 (97) [M]+, + 172 (100); HRMS calcd for C11H9NO2 [M] : 187.0633, Found 187.0636.

7-methoxy-2-methylbenzofuran-3-carbonitrile (4a) Yield: (54 %); yellow solid; m.p.: 151-153oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.25-7.29 (m, 1H), 7.20 (d, J = 8 Hz, 1H), 6.87 (d, J = 7.92 Hz, 1H), 4.02 (s, 3H), 2.68 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 164.6, 145.4, 143.2, 127.8, 125.5, 113.5, 111.8, 107.8, 91.9,

56.4, 14.1; LRMS (EI) (m/z) (relative intensity) 187 (100) [M]+, 144 (15); HRMS calcd + for C11H9NO2 [M] : 187.0629, Found 187.0633.

5,6-dimethoxy-2-methylbenzofuran-3-carbonitrile (5a) Yield: (35 %); off white solid; m.p.: 171-173oC; 1H NMR (400 13 MHz, CDCl3) δ (ppm) 7.02 (s, 2H), 3.95 (s, 3H), 2.62 (s, 3H); C

NMR (100 MHz, CDCl3) δ 163.5, 149.1, 148.6, 148.1, 118.2, 113.9, 100.9, 95.8, 56.7, 56.6, 14.1; LRMS (EI) (m/z) (relative intensity) + + 217 (100) [M] , 202 (40); HRMS calcd for C12H11NO3 [M] : 217.0739, Found 217.0741.

5-chloro-2-methylbenzofuran-3-carbonitrile (6a) Yield: (53 %); white solid; m.p.: 166-168oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.61 (d, J =1.96 Hz, 1H), 7.41 (d, J = 8.64 Hz, 1H), 13 7.28-7.34 (m, 1H), 2.67 (s, 3H); C NMR (100 MHz, CDCl3) δ 165.9, 152.3, 130.5, 127.5, 126.1, 119.4, 112.7, 91.4, 14.1; LRMS (EI) (m/z) + + (relative intensity) 191 (100) [M] , 165 (5); HRMS calcd for C10H6ONCl [M] : 191.0138, Found 191.0133.

5-bromo-2-methylbenzofuran-3-carbonitrile (7a) Yield: (60 %); white solid; m.p.: 169-171oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.76 (d, J = 1.96 Hz, 1H), 7.47 (dd, J = 1.80, 8.72 Hz, 1H), 7.37 (d, J = 8.76 Hz, 1H) 2.68 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 166.2, 152.8, 128.9, 128.0, 122.6, 117.9, 113.2, 112.8, 91.4, 14.1; LRMS (EI) (m/z) (relative intensity) 235 (100) [M]+, 156 (20); HRMS calcd for + C10H6NOBr [M] : 234.9633, Found 234.9634.

5-iodo-2-methylbenzofuran-3-carbonitrile (8a) Yield: (24 %); yellow solid; m.p.: 158-160oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.98 (d, J = 1.56 Hz, 1H), 7.67 (dd, J = 1.64, 8.60 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 2.69 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 165.9, 153.4, 134.6, 128.6, 113.6, 112.8, 111.9, 90.9, 88.1, 14.1; LRMS (EI) (m/z) (relative intensity) 283 (100) [M]+, 156 (20); HRMS calcd for + C10H7INO [M] : 282.9494, Found 282.9494. 2-methylnaphtho[1,2-b]furan-3-carbonitrile (9a)

Yield: (70 %); off white solid; m.p.: 163-165oC; 1H NMR (400

MHz, CDCl3) δ (ppm) 8.61 (d, J = 8.28 Hz, 1H), 7.97 (s, J = 8.20 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.67 (t, J = 7.72 Hz, 1H), 7.61 (d, J = 9.04 Hz, 1H), 7.67 (t, J = 7.32 Hz, 1H) 2.75 (s, 3H); 13C

NMR (100 MHz, CDCl3) δ 164.3, 151.6, 131.1, 129.1, 127.5, 126.9, 126.8, 125.8, 122.7, 120.2, 115.04, 111.9, 91.5, 14.0 ; LRMS (EI) (m/z) (relative intensity) 207 (100) [M]+ + HRMS calcd for C14H9NO [M] : 207.0684, Found 207.0683.

2-methylbenzo[b]thiophene-3-carbonitrile (11a) Yield: (25 %); white solid; m.p.: 138-140oC; 1H NMR (400 MHz,

CDCl3) δ (ppm) 7.85 (d, J = 7.92 Hz, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.46-7.50 (m, 1H), 7.38-7.42 (m, 1H), 2.79 (s, 3H); 13C NMR (100

MHz, CDCl3) δ 154.0, 138.1, 137.7, 126.0, 125.7, 122.5, 122.1, 114.4, 105.7, 15.9; LRMS (EI) (m/z) (relative intensity) 173 (100) [M]+, 172 (85); HRMS calcd + for C10H7NS [M] : 173.0299, Found 173.0298.

5-(2H-chromen-3-yl)-1H-tetrazole (1b) Yield: (89 %); white solid; m.p.: 208-210oC; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 7.44 (s, 1H), 7.22-7.28 (m, 2H), 6.96 (t, J = 7.4 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H); 13C NMR (100

MHz, DMSO-d6) δ 153.7, 153.0, 131.0, 128.2, 126.1, 121.9, 120.9, 116.9, 115.7, 64.3; LRMS (EI) (m/z) (relative intensity) 201 (100) [M+1]+, 172 (15); + HRMS calcd for C10H8N4O [M+1] : 201.0776, Found 201.0780.

5-(6-methyl-2H-chromen-3-yl)-1H-tetrazole (2b) Yield: (89 %); off white solid; m.p.: 235-237oC; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 7.39 (s, 1H), 7.03-7.06 (m, 2H), 6.77 (d, J = 8.0 Hz, 1H), 5.14 (s, 2H), 2.22 (s, 3H); 13C NMR (100

MHz, DMSO-d6) δ 153.0, 151.6, 131.4, 130.8, 128.4, 126.3, 120.8, 116.9, 115.5, 64.3, 20.0; LRMS (EI) (m/z) (relative intensity) 214 (55) [M]+, 185 + (100), 170 (38); HRMS calcd for C11H10N4O [M] : 214.0855, Found 214.0848

5-(7-methoxy-2H-chromen-3-yl)-1H-tetrazole (3b)

Yield: (81 %); off white solid; m.p.: 235-237oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.40 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 2.4, 8.4 Hz, 1H), 6.51 (d, J = 2.2 Hz, 1H), 5.17 (d, J = 1.1 Hz, 2H), 3.77 (s, 3H); 13C NMR (100

MHz, DMSO-d6) δ 161.8, 155.2, 152.9, 129.2, 126.2, 114.1, 113.4, 108.1, 101.5, 64.4, 55.4; LRMS (EI) (m/z) (relative intensity) 230 (67) [M]+, 201 (100), 186 (40); HRMS + calcd for C11H10N4O2 [M] : 230.0804, Found 230.0798.

5-(8-methoxy-2H-chromen-3-yl)-1H-tetrazole (4b) Yield: (80 %); light yellow solid; m.p.: 203-205oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.43 (s, 1H), 6.99 (d, J = 6.9 Hz, 1H), 6.88-6.93 (m, 2H), 5.17 (s, 2H), 3.77 (s, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 152.9, 147.6, 142.7, 126.3, 121.7, 121.6, 120.0, 116.9, 114.5, 64.2, 55.7; LRMS (EI) (m/z) + + (relative intensity) 230 (100) [M] ; HRMS calcd for C11H10N4O2 [M] : 230.0804, Found 230.0802.

5-(6-chloro-2H-chromen-3-yl)-1H-tetrazole (6b) Yield: (86 %); off white solid; m.p.: 237-239oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.34 (d, J = 2.5 Hz, 1H), 7.24 (s, 1H), 7.17 (dd, J = 8.5, 2.5 Hz, 1H), 6.86 (d, J = 8.6 Hz, 1H), 5.22 (d, J = 0.7 Hz, 2H); 13C NMR (100 MHz, DMSO- d6) δ 155.8, 152.1, 128.8, 126.6, 125.2, 123.9, 122.9, 119.9, 117.1, 65.5; LRMS (EI) (m/z) + + (relative intensity) 234 (100) [M] , HRMS calcd for C10H7 N4OCl [M] : 234.0304, Found 234.0308.

5-(6-bromo-2H-chromen-3-yl)-1H-tetrazole (7b) Yield: (85 %); off white solid; m.p.: 229-231oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.40 (d, J = 2.4 Hz, 1H), 7.22 (dd, J= 8.9, 2.5 Hz, 1H), 7.10 (bs, 1H), 6.76 (d, J = 8.5 Hz, 13 1H), 5.21 (d, J = 1.6 Hz, 2H); C NMR (100 MHz, DMSO-d6) δ 157.4, 152.3, 130.5, 128.8, 125.8, 125.3, 117.2, 116.2, 112.7, 66.0; LRMS (EI) (m/z) + + (relative intensity) 278 (46) [M] , 251 (100); HRMS calcd for C10H7N4OBr [M+H] : 278.9803, Found 278.9804.

5-(2H-benzo[h]chromen-3-yl)-1H-tetrazole (9b) Yield: (87 %); yellow solid; m.p.: 230-232oC; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 8.12 (d, J = 8.44 Hz, 1H), 7.94 (s, 1H), 7.85 (d, J = 8.04 Hz, 1H), 7.78 (d, J = 8.84 Hz, 1H), 7.52- 7.57 (m, 1H), 7.39 (t, J = 7.28 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 13 5.33 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 157.2, 151.6, 129.6, 129.3, 129.2, 128.9, 128.5, 127.0, 123.9, 121.8, 121.4, 117.3, 115.5, 65.6; LRMS + (EI) (m/z) (relative intensity) 250 (50.5) [M] , 221 (100); HRMS calcd for C14H10N4O [M]+: 250.0855, Found 250.0852.

1-(3-(1H-tetrazol-5-yl)-2H-chromen-6-yl)ethanone (10b) Yield: (88 %); yellow solid; m.p.: 228-230oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.81-7.85 (m, 2H), 7.45 (s, 1H), 6.94 (d, J = 8.3 Hz, 1H), 5.29 (s, 2H), 2.48 (s, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 196.5, 157.6, 153.8, 131.5, 131.2, 128.6, 124.4, 120.8, 118.7, 115.9, 65.3, 26.5; LRMS (EI) (m/z) (relative + + intensity) 242 (12) [M] , 241 (100), 185.2 (16); HRMS calcd for C12H10N4O2 [M] : 242.0804, Found 242.0760.

5-(2H-thiochromen-3-yl)-1H-tetrazole (11b) Yield: (66 %); yellow solid; m.p.: 191-193oC; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 7.52 (s, 1H), 7.31-7.37 (m, 2H), 7.20- 13 7.27 (m, 2H), 4.02 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 156.1, 131.7, 131.4, 129.6, 129.3, 129.2, 126.9, 126.0, 118.7, 24.8; LRMS (EI) (m/z) (relative intensity) 216 (55) [M]+,188 (68), 172 (100); HRMS + calcd for C10H8N4S [M] : 216.0470, Found 216.0472.

3-(1H-tetrazol-5-yl)quinolin-2-amine (12b)

Yield: (89 %); green solid; m.p.: 239-241oC; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 8.65 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.26 (t, J = 7.6 13 Hz, 1H), 6.92 (bs, 2H); C NMR (100 MHz, DMSO-d6) δ 155.9, 149.9, 145.6, 133.1, 128.7, 125.6, 123.0, 121.1, 116.6, 94.7; LRMS (EI) (m/z) + + (relative intensity) 212 (100) [M] , 184; HRMS calcd for C10H8N6 [M] : 212.0810, Found 212.0804.

5-(6,8-dimethoxy-2H-chromen-3-yl)-1H-tetrazole (13b) Yield: (84 %); light brown solid; m.p.: 206-208oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.43 (s, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.18 (d, J = 1.1 Hz, 2H), 13 3.81 (s, 3H), 3.72 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 154.8, 152.9, 147.1, 136.6, 126.5, 123.2, 115.6, 114.2, 105.7, 64.3, 60.3, 55.9; LRMS (EI) (m/z) (relative intensity) 260 (77) [M]+, 232 (100); HRMS + calcd for C12H12N4O3 [M] : 260.0909, Found 260.0911.

5-(6-bromo-8-methoxy-2H-chromen-3-yl)-1H-tetrazole (14b) Yield: (84 %); yellow solid; m.p.: 196-198oC; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 7.33 (s, 1H), 7.12 (s, 2H), 5.20 (d, 13 J = 1.1 Hz, 2H), 3.80(s, 3H) C NMR (100 MHz, DMSO-d6) δ 154.3, 148.5, 141.8, 123.7, 122.7, 121.7, 120.3, 116.3, 112.6, 64.8, 56.1; LRMS (EI) (m/z) (relative intensity) 308 + + (62) [M] , 281 (100); HRMS calcd for C11H9N4O2Br [M] : 307.9909, Found 307.9902.

2-(2H-chromen-3-yl)-5-phenyl-1,3,4-oxadiazole (1c) Yield: (75 %); white solid; m.p.: 145-147oC; 1H NMR

(400 MHz, CDCl3) δ (ppm) 8.12 (d, J = 7.9 Hz, 2H), 7.51-7.58 (m, 3H), 7.38 (s, 1H), 7.18-7.27 (m, 2H), 6.97 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 5.26 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 164.5, 162.0, 154.9, 132.1, 131.7, 129.3, 128.5, 127.9, 127.3, 123.9, 122.2, 121.3, 116.5, 116.2, 64.3; LRMS (EI) (m/z) (relative intensity) 276 + + (100) [M] ; HRMS calcd for C17H12N2O2 [M] : 276.0899, Found 276.0899. 2-(chloromethyl)-5-(2H-chromen-3-yl)-1,3,4-oxadiazole (1d)

Yield: (70 %); white solid; m.p.: 150-151oC; 1H NMR (400

MHz, CDCl3) δ (ppm) 7.33 (s, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 7.4 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.20 (s, 2H), 4.73 (s, 2H); 13C NMR (100 MHz,

CDCl3) δ 163.3, 161.9, 154.9, 132.0, 129.3, 128.7, 122.8, 120.9, 116.5, 115.4, 63.9, 33.1; + + LRMS (EI) (m/z) (relative intensity) 248 (100) [M] ; HRMS calcd for C12H9N2O2Cl [M] : 248.0353, Found 248.0359.

5-(2H-chromen-3-yl)-1-vinyl-1H-tetrazole (1e) Yield: (78 %); yellow solid; m.p.: 159-161oC; 1H NMR (400

MHz, CDCl3) δ (ppm) 7.58 (s, 1H), 7.53 (dd, J = 15.6, 8.7 Hz, 1H), 7.17-7.24 (m, 2H), 6.95 (m, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.22 (dd, J = 15.6, 1.4 Hz, 1H), 5.39 (dd, J = 8.7, 1.4 Hz, 1H), 13 5.29 (d, J = 1.2 Hz, 2H); C NMR (100 MHz, CDCl3) δ 162.1, 154.4, 130.6, 129.6, 127.9, 126.1, 121.8, 121.5, 118.9, 115.9, 108.4, 64.9; LRMS (EI) (m/z) (relative intensity) 226 + + (100) [M] , 200 (60); HRMS calcd for C12H10N4O [M] : 226.0855, Found 226.0850.

5-(2H-chromen-3-yl)-1H-pyrazole (1f) Yield: (60 %); yellow solid; m.p.: 144-146oC; 1H NMR (400

MHz, CDCl3) δ (ppm) 12.90 (bs, 1H), 7.78 (s, 1H), 7.08-7.14 (m, 2H), 6.98 (s, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 7.8 Hz, 13 1H), 6.66 (s, 1H), 5.15 (s, 2H); C NMR (100 MHz, CDCl3) δ 153.1, 147.5, 129.8, 128.6, 126.7, 122.8, 121.5, 117.9, 115.2, 102.9, 101.5, 65.3; LRMS (EI) (m/z) (relative intensity) 198 (100) [M]+, 197 (62), 169 (20); HRMS calcd for + C12H10N2O [M] : 198.0793, Found 198.0795.

4-((5-(2H-chromen-3-yl)-1H-tetrazol-1-yl)methyl)morpholine (1g) Yield: (76 %); white solid; m.p.: 132-134oC; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 7.51 (s, 1H), 7.34 (d, 1H) 7.15-7.22 (m, 1H), 6.94 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.60(s, 2H), 5.27 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 2.57 (t, J = 4.7 Hz, 4H); 13C NMR (100 MHz,

DMSO-d6) δ 153.6, 130.6, 128.1, 124.6, 124.5, 121.8, 121.3, 119.1, 115.6, 73.8, 65.9, 64.4, 49.2; LRMS (EI) (m/z) (relative intensity) 299 (100) [M]+; HRMS calcd for + C15H17N5O2 [M] : 299.1382, Found 299.1380.

I.B.6. References 1. (a) Graham, T. J. A.; Doyle, A. G. Org. Lett. 2012, 14, 1616. (b) Fernándaz-Bachiller, M. I.; Pérez, C.; Monjas, L.; Rademann, J.; Rodríguez-Franco, M. I. J. Med. Chem. 2012, 55, 1303. (c) Das, S. G.; Srinivasan, B.; Hermanson, D. L.; Bleeker, N. P.; Doshi, J. M.; Tang, R.; Beck, W. T.; Xing, C. J. Med. Chem. 2011, 54, 5937. (d) Erichsen, M. N.; Huynh, T. H. V.; Abrahamsen, B.; Bastlund, J. F.; Bundgaard, C.; Monrad, O.; Bekker- Jensen, A.; Nielsen, C. W.; Frydenvang, K.; Jensen, A. A.; Bunch, L. J. Med. Chem. 2010, 53, 7180. (e) Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Patel, S. T.; Iyer, P. K.; Jasra, R. V. Tetrahedron Lett. 2002, 43, 2665. (f) Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R.; Patel, S. T.; Jasra, R. V. Tetrahedron: Asymmetry 2001, 12, 433. 2. (a) Reddy, B. V. S.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J. S.; Vardhan, M. V. P. S. V. Bioorg. Med. Chem. Lett. 2012, 22, 1995. (b) Bera, K.; Sarkar, S.; Biswas, S.; Maiti, S.; Jana, U. J. Org. Chem. 2011, 76, 3539. (c) Conti, C.; Desideri, N. Bioorg. Med. Chem. 2010, 18, 6480. 3. (a) Habib, P. M.; Raju, B. R.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Tetrahedron 2009, 65, 5799. (b) Habib, P. M.; Kavala, V.; Raju, B. R.; Kuo, C.-W.; Yao, C.-F. Eur. J. Org. Chem. 2009, 4503. 4. (a) Melzig, L.; Rauhut, C. B.; Naredi-Rainer, N.; Knochel, P. Chem. Eur. J. 2011, 17, 5362. (b) Huang, X.-C.; Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Wang, F.; Li, J.-H. Org. Lett. 2008, 10, 1525. 5. (a) Okamoto, K.; Watanabe, M.; Murai, M.; Hatano, R.; Ohe, K. Chem. Commun. 2012, 48, 3127. (b) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. (c) Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412. (d) Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao, K. Org. Lett. 2009, 11, 4978. (e) Okitsu, T.; Nakazawa, D.; Taniguchi, R.; Wada, A. Org. Lett. 2008, 10, 4967. (f) RamaRao, V. V. V. N. S.; Reddy, G. V.; Maitraie, D.; Ravikanth, S.; Yadla, R.; Narsaiah, B.; Rao, P. S. Tetrahedron 2004, 60, 12231. (g) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N. C. J. Org. Chem. 1992, 57, 7246.

6. (a) Yamamoto, Y. Chem. Rev. 2012, 112, 4736. (b) Chelucci, G. Chem. Rev. 2012, 112, 1344; (c) Gladysz, J. A. Chem. Rev. 2011, 111, 1167. (d) Corma, A.; García, H. Chem. Rev. 2002, 102, 3837. 7. For recent reports please see (a) Ueda, S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2012, 51, 1. (b) Imae, K.; Konno, T.; Ogata, K.; Fukuzawa, S.-i. Org. Lett. 2012, 14, 4410. (c) Narumi, T.; Kobayakawa, T.; Aikawa, H.; Seike, S.; Tamamura, H. Org. Lett. 2012, 14, 4490. (d) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen, C.-Y.; Wang, J.- J. Org. Lett. 2012, 14, 4478. 8. Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G.-Q.; Barluenga, S.; Mitchell, H. J. J. Am. Chem. Soc. 2000, 122, 9939. 9. Ishizuka, N.; Matsumura, K.-i.; Sakai, K.; Fujimoto, M.; Mihara,S.-i.; Yamamori, T. J. Med. Chem. 2002, 45, 2041. 10. Rehman, H.; Rao, J. M. Tetrahedron 1987, 43, 5335. 11. Chen, C.-y.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964. 12. Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao K. Org. Lett. 2009, 11, 4978. 13. (a) Popova, E. A.; Trifonov, R. E.; Ostrovskii, V. A. Arkivoc 2012, i, 45. (b) Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945. 14. (a) Zheng, Y.; Batsanov, A. S.; Jankus, V.; Dias, F. B.; Bryce, M. R.; Monkman, A. P. J. Org. Chem. 2011, 76, 8300. (b) Katritzky, A. R.; El-Gendy, B. E. D. M.; Draghici, B.; Hall, C. D.; Steel, P. J. J. Org. Chem. 2010, 75, 6468. (c) Rusinov, G. L.; Ishmetova, R. I.; Chupakhin, O. N. Russ. J. Org. Chem. 1997, 33, 524. (d) Binda, M.; Dziklinska, A.; Hachiam, A. F. Plenkiewicz, J. Pol. J. Chem. 1992, 66, 1257. 15 (a) Zhou, X.; Li, P.; Shi, Z.; Tang, X.; Chen, C.; Liu, W. Inorg. Chem. 2012, 51, 9226. (b) Pramanik, A.; Das, G.; Tetrahedron 2009, 65, 2196. (c) Ito, H.; Matsuoka, M.; Ueda, Y.; Takuma, M.; Kuda, Y.; Iguchi, K. Tetrahedron 2009, 65, 4235. (d) Moody, C. J.; Rees, C. W.; Young, R. G. J. Chem. Soc. Perkin Trans.1 1991, 329. 16. (a) Sun, F.; Zhang, G.; Zhang, D.; Xue, L.; Jiang, H.; Org. Lett. 2011, 13, 6378. (b) Lee, J. H.; Lee, H.; Seo, S.; Jaworski, J.; Seo, M. L.; Kang, S.; Lee, J. Y.; Jung, J. H. New J. Chem. 2011, 35, 1054. (c) Popova, E. A.; Trifonov, R. E.; Ostrovskii, V. A. Arkivoc 2011, i, 552. (d) Rajesha, H. S.; Bhojya Naik, H. S.; Harish Kumar H. N.; Hosamani, K. M.; Mahadevan, K. M. Arkivoc 2009, ii, 11.

Part- I, Section-C Synthesis of Dibenzodiazepinones via Tandem Copper (I) Catalyzed C-N Bond Formation I.C.1. Introduction Synthesis of seven membered fused N-heterocycles is an area of considerable interest for synthetic organic chemists. Fused N-heterocycles such as dibenzoxazepinone, dibenzothiazepin, dibenzoazepine derivatives are ubiquitous structures that are found in numerous natural products as well as in the core structures of many best selling drugs.1 In particular, 1,4-dibenzodiazepinone derivatives are privilege scaffolds due to their diverse curative properties. The dibenzodiazepinone nucleus is a component of many pharmaceutical drugs that possess antidepressant (Figure I.C.1.1, A), antiobesity (B), antithrombotic, antitumor, antibiotics, anxiolytic, anticonvulsant, hypnotic, sedative, amnestic, properties.2 Further, they are also used in the treatment of diabetic ephropathy, the central nervous system and can function as novel inhibitors of HIV Protease, histone deacetylase (C), muscarinic acetylcholine (D) and nonpeptidyl endothelin receptors (E).3

Figure I.C.1.1. Biologically active dibenzodiazepinone derivatives

I.C.2. Review of literature Despite several advances in the synthesis of seven membered heterocycles, the synthesis of dibenzodiazepinone continues to be a cumbersome task. Very few methods are available to synthesize dibenzodiazepinone core structure. Recently, Buchwald and co- workers have reported highly efficient protocol for the synthesis of dibenzodiazepines and dibenzooxazepines using a 2-aminoaryl ketone with 1,2-dihaloarenes in the presence of a Pd(0) or Cu(I) catalyst in a step wise process (Scheme I.C.2.1).4a First, the palladium (0) or copper (I) catalyzed to coupled compound, which was further treated with ammonia using palladium (0) to form o-substituted aniline. The o-substituted aniline on intramolecular condensation leads to formation of dibenzodiazepinone analogues in good yields

Scheme I.C.2.1 In another report, Levy et al. have described the synthesis of dibendiazepinone at high temperature by the reaction of 2-chlorobenzoic acid and using copper powder in chlorobenzene (Scheme I.C.2.2).4b The dibenzodiazepinone derivative was afforded in good yield. The method need stoichiometric amount of copper powder and limited with only to few substrates.

Scheme I.C.2.2 Further, the multistep synthesis of dibenzodiapinone was achieved by Sum and co- workers (Scheme I.C.2.3).4c First, 1-bromo-2-nitrobenzene and anthranilic acid were

heated neat in the presence of copper and potassium carbonate to yield Ullmann coupled compound. Then, the nitro group of compound was reduced and then refluxed in xylene to obtain dibenzodiazepinone derivative in good yield. The high temperature and multistep are some of the limitations of the protocol.

Scheme I.C.2.3 Very recently, Ma and co-workers developed the method for the synthesis of dibenzodiazepinone using 2-bromo-N-(2-bromophenyl)benzamide and various primary amines using a Cu(I) catalyst (Scheme I.C.2.4).5 However, in our recent publication, we found that the product formed is, in fact, the N-substituted-2-(benzo[d]oxazol-2-yl) (B), as confirmed by 1H NMR, 13C NMR, LRMS, HRMS and single crystal X-ray analysis data.6 and is not the dibenzodiazepinone derivative (A).

Scheme I.C.2.4. Reaction of 2-halo-N-(2-halophenyl)benzamide and various primary amines. Further, limited available protocols towards the synthesis of dibenzodiazepinone derivatives are either multistep or lack in the selectivity.7 Thus, an efficient, one pot protocol for the synthesis of dibenzodiazepinone derivatives continues to be highly desirable.

I.C.3. Results and Discussion 2-Iodobenzamide is very useful substrate in organic synthesis. Smart structural manipulation at the amidic position leads to the formation of numerous interesting compounds.8 In recent years, our group has been interested in exploring copper catalyzed transformations and the synthesis of seven membered rings.9 In a continuation of our interest in copper catalyzed transformations, we were prompted to investigate the reaction of N-(2-cyanophenyl)-2-iodobenzamide derivatives and 2-iodoaniline derivatives in the presence of a copper catalyst. We envisioned that the reaction of 1a with 2-iodoaniline in the presence of copper iodide and a base would initially generate the Ullmann coupled product 3a. Further, it may form the fused benzoimidazole derivative (4a), via pathway a or the dibenzodiazepinone (5a), via pathway b (Scheme I.C.3.1).

Scheme I.C.3.1. Plausible pathway for the formation of products To test our hypothesis, in an initial experiment, we reacted N-(2-cyanophenyl)-2- iodobenzamide (1a) and 2-iodoaniline (2a) in the presence of a catalytic amount of o copper iodide (10 mol%) with K2CO3 as a base and DMSO as a solvent at 120 C. The reaction afforded compound 3a in 72% yield (Table I.C.3.1, entry 1) along with trace amounts of a polar compound. This polar compound was isolated and analyzed by 1H NMR, 13C NMR, LRMS, HRMS. Single crystal X-ray analysis data revealed that the compound formed was 5a (dibenzodiazepinone) instead of compound 4a (Figure I.C.3.1).

Figure I.C.3.1. ORTEP diagram of 5a

Table I.C.3.1. Optimization of reaction condition

a Reactions were performed on a 0.5 mmol scale. b Yields refer to the isolated and purified compound. c Reaction was performed in DMF as the solvent. Delighted by our initial results, we investigated the optimum conditions for this reaction. The yield of the product 5a was improved to 30% when reaction was conducted at 135oC (entry 2). However, further increases in temperature failed to result in further improvements in yield (entry 3). To examine the efficacy of the catalyst, we conducted the reaction with different quantities of copper catalyst. The use of 20 mol% CuI gave a better yield of compound 5a (entry 4). However, a further increase in the amount of CuI to 30 mol% failed to show any further improvement in the yield (entry 5). Next, in an attempt to improve product yield, several copper catalysts, including CuCl, CuBr, Cu2O,

CuOAc2 and CuSO4 were employed, but no improvement in yield was observed (entries 6-10).

Table I.C.3.2. Synthesis of dibenzodiazepinone from 1a and different 2-iodoanilines

a All reactions were performed on 0.5 mmol of 1a and 0.5 mmol of 2 (a-g) with CuI (20 o b mol%) and K2CO3 (2.5 equiv) in DMSO at 135 C. Yields refer to isolated and purified compound.c 10-15% of 2 is recovered.

Screening the reaction using various inorganic and organic bases either resulted in the formation of the intermediate 3a or a lower yield of compound 5a (entry 11-17). Except DMSO, the reaction proceeded in DMF but afford lower yield of compound 5a (entry 18). Finally, from the optimization studies, we found that, the reaction with 20 mol% copper o iodide with K2CO3 as a base in DMSO solvent at 135 C was found to be the best condition for the reaction, these conditions were used in further experiments. With optimized reaction in hand, we focused our attention on the scope and limitations of this protocol. In this regard, we initially investigated the scope of the reaction with respect to 2-iodoaniline derivatives with 1a as a model substrate (Table I.C.3.2). The reaction of an unsubstituted 2-iodoaniline with 1a furnished the corresponding dibenzodiazepinone derivative in 74% yield (entry 1). Moreover, moderate electron donating substitutions on 2-iodoaniline such as methyl and isopropyl groups resulted in the formation of the corresponding compounds 5b and 5c in good yields, respectively (entries 2 and 3). Further, the reaction of 2-iodoaniline bearing a strong electron donating group (OMe) afforded the corresponding compound 5d in 59% yield (entry 4). However, 2-iodoaniline possessing electron withdrawing substituents, such as fluoro and chloro groups, provided 48% and 55% yields of the corresponding compounds with a longer reaction time (entries 5 and 6). In both these cases about 10-15% unreacted 2-iodoaniline was recovered.

Scheme I.C.3.2. Smiles rearrangement during the synthesis of dibenzoxaazepinone10 Recently, Snieckus and co-workers and Ma and group observed a Smiles rearrangement during the synthesis of dibenzoxaazepinone (Scheme I.C.3.2).10 Based on literature reports, N-hetrocycles also can undergo a Smiles rearrangement.11 However, in our

reactions, no evidence was found to such a rearranged product, which is evident from the single crystal X-ray analysis of compound 5g (Figure I.C.3.2).

Figure I.C.3.2. ORTEP diagram of 5g

To extend the scope of this methodology, we subsequently, utilized various 2-halo-N- phenylbenzamides and 2-iodoanilines using the developed optimal reaction conditions and the results are shown in Table I.C.3.3. The reaction of unsubstituted phenyl 2- iodobenzamide (1b) with the 2-iodoanilines 2a and 2c resulted in the production of their corresponding compounds (5h and 5i) in good yields within a shorter reaction time (entries 1 and 2). Further, the amides derived from 2-iodobenzoic acid and ortho substituted anilines reacted smoothly with 2-iodoanilines (2a and 2c) to furnish the corresponding dibenzodiazepinone derivatives in moderate to good yields. It is worth noting that, the 2-halo-N-phenylbenzamides derived electron withdrawing ortho substituted anilines such as F, Cl, NO2 required a longer reaction time than that for electron donating groups (entries 3-9). Moreover, 2-iodobenzamides derived from m- methoxyaniline and p-isopropylaniline produce compounds 5q and 5r in moderate yields (entries 10 and 11). However, the yield dropped considerably to 44% when the electron withdrawing N-(4-chlorophenyl)-2-iodobenzamide (1k) was treated with 2-iodoaniline (entry 12).

Table I.C.3.3. Synthesis of dibenzodiazepinone from various 2-halo benzamides and different 2-iodoanilines

Continue......

a All reactions were performed on 0.5 mmol of 1 (b-o) and 0.5 mmol of 2 (a,c) with CuI o b (20 mol%) and K2CO3 (2.5 equiv) in DMSO at 135 C. Yields refer to isolated and purified compound. c 10-15% of 2 is recovered.

Furthermore, the reactions of 2-iodo-N-phenylbenzamides generated from 2-iodo-5- methoxybenzoic acid and 6-iodobenzo[d][1,3]dioxole-5-carboxylic acid formed the corresponding compounds 5t and 5u in moderate yields (entries 13 and 14). However, electron withdrawing substitution on 2-iodobenzoic acid such as Cl and F increased product yield as well as reduced the reaction time (entries 15 and 16).

Scheme I.C.3.3. Reaction with different amides

We next investigated the reactions of 2-iodobenzamides having less ortho effect such as 2-iodobenzamide (1p) and 2-iodo-N-methylbenzamide (1q) with 2-iodoaniline (Scheme 4). Under the present reaction conditions, 1p underwent decomposition and 1q yielded the N-arylated compound (3y). Furthermore, When 2-bromo-N-(2- bromophenyl)benzamide was used as substrate, we obtained 2-(benzo[d]oxazol-2-yl)-N- (2-iodophenyl)aniline (6a) as a sole product.7 Finally, the synthesis of the nitro-substituted dibenzodiazepinone (5n) provided us with the opportunity to carry out a reductive cyclization (Scheme I.C.3.4). The triaza- pentacyclic compound 7a was obtained in excellent yield, which was confirmed by single crystal X-ray (Figure I.C.3.1).

Scheme I.C.3.4. Synthesis of 7a ring by reductive cyclization

Figure I.C.3.1. ORTEP diagram of 7a I.C.4. Conclusion In conclusion, we herein report an efficient, copper catalyzed, one pot protocol for the synthesis of phenyl substituted dibenzodiazepinone derivatives in moderate to good yields from 2-halo-N-phenylbenzamides and 2-iodoaniline via a cascade process. Interestingly, no evidence was found for the compounds undergoing a Smiles rearrangement, as reported in the case of dibenzoxazepinone. Moreover, the nitro-substituted dibenzodiazepinone derivative 5n was utilized to synthesize compound 7a in an excellent yield by reductive cyclization.

I.C.5. Experimental Section I.C.5.1. General Information All chemicals were purchased from various sources and were used directly without further purification. Analytical thin-layer chromatography was performed using silica gel 60F glass plates and silica gel 60 (230–400 mesh) was used in flash chromatographic separations. NMR spectra were recorded in DMSO-d6 with DMSO and CDCl3 with 1 13 CHCl3 as the internal standards for H NMR (400 MHz) and C NMR (100 MHz).

Coupling constants are expressed in Hertz. HRMS spectra were recorded using MALDI, ESI- or ESI+ mode. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.

I.C.5.2. General Experimental for the Synthesis of 2-(11-Oxo-5H- dibenzo[b,e][1,4]diazepin-10(11H)-yl) benzonitrile (5a-5x). In an oven-dried, 10 mL round-bottom flask equipped with magnetic stirrer was added 1a (0.5 mmol), 2a (0.5 mmol), CuI (20 mol%), K2CO3 (1.25 mmol) in anhydrous DMSO (1.5 mL). The reaction mixture was then stirred at 135oC under a nitrogen atmosphere. After completion of the reaction, as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then purified by column chromatography without workup using Hexane-Ethyl acetate as the eluent to yield compound 5a.

I.C.5.3. Synthesis of 12-Chloro-8,15,22-triazapentacyclo[13.7.0.02,7.09,14.016,21] docosa-1(22),2,4,6,9(14),10,12,16(21),17,19-decaene (7a): In a stir-bar-equipped flame- dried 50 mL round-bottom flask, 5n (1 mmol) in acetic acid (20 mL) was added, followed by the addition of iron powder (5 mmol). The reaction mixture was then stirred at 80oC for 6h. After completion of the reaction as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then evaporated under reduced pressure and then basified by adding aq. Na2CO3 to pH 10. The resulting solution was then extracted with ethyl acetate (100 mL). The ethyl acetate layer was dried over MgSO4, filtered and evaporated under reduced pressure. The crude compound was then purified by column chromatography using Hexane-Ethyl acetate as the eluent to yield compound 7a.

I.C.5.4. Spectral Data of compounds N-(2-cyanophenyl)-2-iodobenzamide (1a) Yield: (78 %); white solid; m.p.: 181-183 oC; FT-IR (KBr) ν/cm−1 1 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.57 (d, J = 8.5 Hz, 1H), 7.96-7.97 (m, 2H), 7.64-7.71 (m, 2H), 7.57 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.25-7.29 (m, 1H), 7.22 (t, J = 7.8

13 Hz, 1H); C NMR (100 MHz, CDCl3) δ 167.6, 141.2, 140.6, 140.3, 134.5, 132.7, 132.3, 128.8, 128.7, 125.0, 121.8, 116.4, 108.9, 92.5; LRMS (EI) (m/z) (relative intensity): 348 + + (100) [M] , 322 (40); HRMS calcd for C14H9IN2O [M] : 347.9760, Found 347.9765.

1-bromo-N-(2-chlorophenyl)-2-naphthamide (1d) Yield: (69 %); white solid; m.p.: 169-171 oC; FT-IR (KBr) −1 1 ν/cm 3588; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.34 (bs, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.07-8.12 (m, 2H), 7.76-7.80 (m, 2H), 7.64-7.72 (m, 2H), 7.57 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H); 13C NMR (100 MHz, DMSO- d6) δ 166.8, 137.1, 134.4, 134.0, 131.1, 129.7, 128.53, 128.49, 128.4, 128.2, 127.6, 127.5, 127.4, 127.3, 126.8, 125.0, 118.9; LRMS (EI) (m/z) (relative intensity): 358 (100) [M]+, + 360 (96), 278 (40); HRMS calcd for C17H11BrClNO [M] : 358.9713, Found 358.9718.

2-iodo-N-(4-isopropylphenyl)benzamide (1j) Yield: (83 %); white solid; m.p.: 148-150 oC; FT-IR (KBr) −1 1 ν/cm 3504; H NMR (400 MHz, CDCl3) δ (ppm) 8.27 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.67-7.69 (m, 2H), 7.58 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.27-7.29 (m, 1H), 7.16-7.18 (m, 1H), 2.84-2.91(m, 1H), 1.26 (s, 3H), 1.24 (s, 13 3H); C NMR (100 MHz, CDCl3) δ 167.4, 145.8, 142.4, 140.1, 135.4, 131.5, 128.7, 128.4, 127.1, 120.5, 92.6, 33.8, 24.2; LRMS (EI) (m/z) (relative intensity): 365 (100) + + [M] , 239 (38); HRMS calcd for C16H16INO [M] : 365.0277, Found 365.02783.

4-fluoro-2-iodo-N-phenylbenzamide (1l) Yield: (64 %); white solid; m.p.: 145-147 oC; FT-IR (KBr) −1 1 ν/cm 3600; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.41 (s, 1H), 7.84 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.53-7.57 (m, 1H), 7.34-7.40 (m, 3H), 7.11 (t, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 166.8, 161.6 (J = 249 Hz), 139.8 (J = 3.3 Hz), 138.9, 129.6 (J = 8.8 Hz), 128.7, 125.7 (J = 23.6 Hz), 123.8, 119.6, 115.1 (J = 21.3 Hz), 94.2 (J = 8.1 Hz); LRMS (EI) (m/z) (relative intensity): 340 (100) [M]+, 214 (25); HRMS calcd + for C13H9FINO [M] : 340.9713, Found 340.9722.

6-iodo-N-phenylbenzo[d][1,3]dioxole-5-carboxamide (1m) Yield: (73 %); white solid; m.p.: 188-190 oC; FT-IR (KBr) −1 1 ν/cm 3360; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.28 (bs, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.45 (s, 1H), 7.34 (t, J = 7.0 Hz, 2H), 7.08-7.14 (m, 2H), 6.12 (s, 2H); 13C NMR (100 MHz,

DMSO-d6) δ 167.0, 148.8, 147.6, 139.1, 136.6, 128.8, 123.6, 119.6, 118.2, 108.6, 102.1, 82.8; LRMS (EI) (m/z) (relative intensity): 367 (100) [M]+, 241 (33); HRMS calcd for + C14H10INO3 [M] : 366.9705, Found 366.9711.

N-(2-cyanophenyl)-2-(2-iodophenylamino)benzamide (3a) Yield: (84 %); white solid; m.p.:157-159 oC; FT-IR (KBr) ν/cm−1 1 3431, 2305, 1560; H NMR (400 MHz, CDCl3) δ (ppm) 9.09 (brs, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.48(brs, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.63-7.67 (m, 2H), 7.37-7.40 (m, 2H), 7.21-7.31 (m, 3H), 6.96 (t, J = 7.5 Hz, 1H), 6.79 (t, J = 7.5 Hz, 13 1H); C NMR (100 MHz, CDCl3) δ 167.3, 145.6, 142.8, 140.7, 140.1, 134.4, 133.5, 132.5, 129.1, 127.9, 124.9, 124.5, 121.8, 121.3, 119.8, 118.6, 117.1, 116.7, 102.7, 93.6; LRMS (EI) (m/z) (relative intensity): 440 (95) [M+H]+, 314 (100); + HRMS calcd for C20H15IN3O [M+H] : 440.0260, Found 440.0257.

2-(11-Oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl) benzonitrile (5a) Yield: (74 %); yellow solid ; m.p.: 213-215 oC; FT-IR (KBr) ν/cm−1 1 3478, 2305, 1590; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.12 (brs, 1H), 7.98 (d, J = 7.52 Hz, 1H), 7.82 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.56-7.61 (m, 2H), 7.42 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 13 6.90 (t, J = 7.6 Hz, 1H), 6.58 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ 167.9, 151.8, 145.4, 144.6, 134.7, 133.8, 133.4, 133.0, 132.2, 130.9, 128.8, 126.4, 124.8, 123.9, 123.6, 121.9, 121.2, 119.4, 116.4, 113.0; LRMS (ESI) (m/z) (relative intensity): + + 334 (100) [M+Na] , 323 (40); HRMS calcd for C20H13N3NaO [M+Na] : 334.0956, Found 334.0964.

2-(8-Methyl-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (5b) Yield: (67 %); yellow Solid; m.p.: 216-218 oC; FT-IR (KBr) −1 1 ν/cm 3310, 2280, 1560; H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.5 Hz, 1H), 7.68-7.76 (m, 2H), 7.62 (d, J = 7.80 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.0 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.82-6.86 (m, 2H), 6.71 (d, J = 7.8 Hz, 1H), 6.54 (d, 13 J = 8.1 Hz, 1H), 5.57 (brs, 1H), 2.26 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.3, 150.9, 146.1, 144.1, 136.8, 133.9, 133.7, 133.3, 133.2, 131.4, 131.3, 128.1, 125.5, 125.0, 124.7, 122.9, 121.5, 119.1, 116.4, 113.8, 20.8; LRMS (ESI) (m/z) (relative intensity): 348 (100) + + [M+Na] , 286 (60); HRMS calcd for C21H15N3NaO [M+Na] : 348.1113, Found 348.1120. 2-(8-Isopropyl-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (5c) Yield: (79 %); grey solid ; m.p.: 196-198 oC; FT-IR (KBr) −1 1 ν/cm 3500, 2305, 1650; H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.04 (t, J = 7.60 Hz, 1H), 6.89-6.94 (m, 2H), 6.85 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H), 5.64 (brs, 1H), 2.66 (m, 1H), 13 1.05 (m, 3H), 1.03(s, 3H); C NMR (100 MHz, CDCl3) δ 168.4, 151.1, 146.1, 145.1, 142.0, 133.8, 133.6, 133.5, 133.23, 133.20, 131.4, 128.1, 124.7, 124.4, 123.7, 122.8, 120.9, 119.0, 116.4, 113.9, 33.4, 23.9 ; LRMS (ESI) (m/z) (relative intensity): 376 (100) + + [M+Na] , 354 (80); HRMS calcd for C23H19N3NaO [M+Na] : 376.1426, Found 376.1419.

2-(8-Methoxy-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (3d) Yield: 59%; white solid; m.p.: 216-218oC; FT-IR (KBr) ν/cm−1 1 3480, 3494, 2280, 650; H NMR (400 MHz, DMSO-d6) δ (ppm) 7.92 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.68- 7.71(m, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.56-6.59 (m, 2H), 6.45 (dd, J = 2.2 Hz, 8.8 Hz, 1H), 5.79 (brs, 1H), 3.71(s, 13 3H); C NMR (100 MHz, DMSO-d6) δ 168.2, 158.2, 150.5, 146.2, 145.7, 133.9, 133.6, 133.2, 133.1, 131.3, 127.9, 126.9, 126.7, 124.8, 123.1, 119.1, 116.4, 113.6, 109.9, 106.2, 55.7; LRMS (ESI) (m/z) (relative intensity): 340 (100) [M-H]-, 386 (65); HRMS calcd for - C21H14N3O2 [M-H] : 340.1086, Found 340.1082.

2-(7,8-Difluoro-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (5e) Yield: (48 %); yellow solid ; m.p.: 208-210 oC; FT-IR (KBr) −1 1 ν/cm 3328, 2291, 1524; H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.9 Hz, 1H), 7.74-7.80 (m, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.6 Hz, 1H), 6.84-6.88 (m, 2H), 6.50 (dd, J = 7.7 Hz, 11.1 Hz, 13 1H), 5.67 (brs, 1H); C NMR (100 MHz, DMSO-d6) δ 167.2, 150.6, 144.5, 141.58 (d, J = 2.3 Hz), 141.51 (d, J = 2.1 Hz), 134.5, 133.9, 133.4, 132.1, 130.9, 129.14 (d, J = 2.2 Hz), 129.07 (d, J = 2.3 Hz), 128.8, 123.5, 122.2, 119.2, 115.9, 113.5, 113.3, 112.4, 109.2, 109.0; LRMS (ESI) (m/z) (relative intensity): 347 (100) [M]+, 318 (80); HRMS calcd for + C20H11F2N3O [M] :347.0870, Found 347.0863.

2-(8-Chloro-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (5f) Yield: (55 %); white solid; m.p.: 246-248 oC; FT-IR (KBr) −1 1 ν/cm 3446, 3422, 1620, 745; H NMR (400 MHz, CDCl3) δ (ppm) 7.91 (d, J = 7.6 Hz, 1H), 7.73-7.79 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.06 (d, J = 7.5 Hz, 1H), 6.93-6.98 (m, 2H), 6.85 (d, J = 8.0 Hz, 13 1H), 6.62 (s, 1H), 5.86 (brs, 1H); C NMR (100 MHz, CDCl3) δ 168.1, 150.5, 145.4, 143.0, 134.6, 134.1, 133.9, 133.6, 133.2, 131.6, 129.0, 128.6, 126.6, 125.3, 124.2, 123.2, 122.2, 119.2, 116.2, 113.4.; LRMS (EI) (m/z) (relative intensity): 345 (100) [M]+, 311 + (30); HRMS calcd for C20H12ClN3O [M] : 345.0669 Found 345.0665.

2-(8-Bromo-11-oxo-5H-dibenzo[b,e][1,4]diazepin-10(11H)-yl)benzonitrile (5g) Yield: (63 %); yellow solid; m.p.: 230-232 oC; FT-IR (KBr) −1 1 ν/cm 3500, 3455, 1650; H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (d, J = 7.8 Hz, 1H), 7.73-7.79 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.84-6.90 (m, 2H), 6.76 (s, 1H), 5.83(brs, 1H); 13 C NMR (100 MHz, CDCl3) δ 168.0, 150.4, 145.4, 143.5, 134.9, 134.2, 133.9, 133.6, 133.3, 131.6, 129.5, 128.6, 128.3, 124.3, 123.3, 122.5, 119.2, 116.3, 116.1, 113.5; LRMS + (EI) (m/z) (relative intensity): 389 (100) [M] , 310 (65); HRMS calcd for C20H12BrN3O [M]+: 389.0164, Found 389.0168.

10-Phenyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5h) Yield: (74 %); white solid; m.p.: 236-238 oC; FT-IR (KBr) ν/cm−1 1 3525, 3425, 1635, 746; H NMR (400 MHz, CDCl3) δ (ppm) 7.93 (d, J = 7.6 Hz, 1H), 7.40-7.47 (m, 4H), 7.29-7.35 (m, 2H), 7.06 (t, J = 7.5 Hz, 1H), 6.98-7.01 (m, 1H), 6.94-6.96 (m, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.79-6.84 (m, 2H), 5.61 (brs, 1H); 13C NMR (100

MHz, CDCl3) δ 168.3, 150.9, 144.0, 143.6, 135.3, 133.2, 132.8, 129.3, 129.2, 127.4, 126.8, 125.9, 125.6, 124.1, 122.9, 120.7, 118.8; LRMS (EI) (m/z) (relative intensity): 286 + + (100) [M] ; HRMS calcd for C19H14N2O [M] : 286.1106, Found 286.1106. 8-Chloro-10-phenyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5i) Yield: (83 %); red solid ; m.p.: 223-225 oC; FT-IR (KBr) −1 1 ν/cm 3439, 3400, 1530, 1360; H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (d, J = 8.0 Hz, 1H), 7.45-7.49 (m, 2H), 7.34-7.39 (m, 3H), 7.30-7.34 (m, 1H), 7.07 (t, J = 7.5 Hz, 1H), 6.96 (dd, J = 2.2 Hz, 8.4 Hz, 1H), 6.81-6.89 (m, 2H), 6.77 (d, J = 2.2 Hz, 13 1H), 5.56 (brs, 1H); C NMR (100 MHz, CDCl3) δ 168.0, 150.5, 143.1, 142.6, 136.4, 133.3, 133.0, 129.6, 129.2, 129.1, 127.9, 126.6, 125.8, 125.3, 123.3, 121.7, 118.8; LRMS + + (EI) (m/z) (relative intensity): 320 (100) [M] ; HRMS calcd for C19H13ClN2O [M] : 320.0716, Found 320.0719.

10-(2-Chlorophenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5j) Yield: (59 %); yellow solid; m.p.:180-181 oC; FT-IR (KBr) −1 1 ν/cm 3468, 1636, 339; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.01 (brs, 1H), 7.61-7.65 (m, 2H), 7.38-7.49 (m, 4H), 7.19 (d, J = 7.1 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.98-7.06 (m, 2H), 6.87 (t, J = 6.9 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H); 13C NMR (100 MHz,

DMSO-d6) δ 167.4, 151.6, 144.2, 140.4, 132.9, 132.8, 132.3, 132.1, 131.8, 130.2, 129.6, 128.2, 125.8, 124.3, 124.1, 123.3, 121.7, 120.9, 119.1; LRMS (ESI) (m/z) (relative + + intensity): 321 (100) [M+H] , 323 (95); HRMS calcd for C19H14ClN2O [M+H] : 321.0795, Found 321.0792.

8-(2-Chlorophenyl)-8,13-dihydro-7H-benzo[b]naphtho[1,2-e][1,4]diazepin-7-one (5k) Yield: (63 %); yellow solid; m.p.: 223-225 oC; FT-IR (KBr) −1 1 ν/cm 3410, 1530; H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (d, J = 8.6 Hz, 1H), 7.85-7.91 (m, 2H), 7.51-7.64 (m, 5H), 7.33-7.41 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.93 (t, J = 7.9 Hz, 1H), 6.78 (d, J = 8.0 Hz, 1H), , 6.44 (brs, 1H), ; 13C

NMR (100 MHz, CDCl3) δ 168.8, 146.9, 143.4, 140.8, 136.1, 135.1, 133.7, 131.7, 130.8, 129.4, 129.3, 128.3, 128.0, 127.9, 126.9, 125.8, 124.9, 124.7, 124.6, 122.8, 121.8, 121.4, 120.5; LRMS (EI) (m/z) (relative intensity): 370 (100) [M]+, + 337 (55); HRMS calcd for C23H15ClN2O [M] : 370.0873, Found 370.0875. 10-(2-Fluorophenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5l) Yield: (78 %); violet solid ; m.p.: 230-232 oC; FT-IR (KBr) ν/cm−1 1 3461, 1636, 551; H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J = 7.7 Hz, 1H), 7.35-7.46 (m, 3H), 7.24-7.31 (m, 2H), 7.10 (d, J = 7.5 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 13 5.66 (brs, 1H); C NMR (100 MHz, CDCl3) δ 168.1, 160.3, 157.8, 150.8, 143.5, 134.4, 133.3, 133.0, 131.1, 129.7 (d, J = 7.8 Hz), 126.1, 125.5, 125.0 (d, J = 8.5 Hz), 124.9, 124.2, 122.9, 120.8, 118.9, 116.8, 116.6; LRMS (ESI) (m/z) (relative intensity): 305 + + (100) [M+H] , 383 (20); HRMS (ESI) calcd for C19H14FN2O [M+H] : 305.1090, Found 305.1091.

10-(2-Nitrophenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5m) Yield: (57 %); yellow solid ; m.p.: 238-240 oC; FT-IR (KBr) −1 1 ν/cm 3350, 1537, 1357; H NMR (400 MHz, CDCl3) δ (ppm) 8.07 (d, J = 7.9 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.29-7.34 (m, 2H), 6.96-7.09 (m, 3H), 6.89-6.95 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 5.65 (brs, 1H); 13 C NMR (100 MHz, CDCl3) δ 167.8, 150.6, 148.1, 143.9, 136.8, 134.2, 134.1, 133.4, 133.3, 131.4, 128.4, 126.6, 126.5, 124.9, 124.5, 124.45, 123.1, 120.7, 118.9; LRMS (ESI) + (m/z) (relative intensity): 354 (100) [M+Na] , 535 (20); HRMS calcd for C19H13N3NaO3 [M+Na]+: 354.0855, Found 354.0855.

8-Chloro-10-(2-nitrophenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5n) Yield: (65 %); white solid; m.p.: 219-212 oC; FT-IR (KBr) −1 1 ν/cm 3480, 1545, 1378, 719; H NMR (400 MHz, CDCl3) δ (ppm) 8.06 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.23-7.29 (m, 2H), 6.97-7.01 (m, 2H), 6.89 (d, J = 8.5 Hz, 1H), 6.85 (s, 1H), 6.78 13 (d, J = 7.92 Hz, 1H), 5.79 (brs, 1H); C NMR (100 MHz, CDCl3) δ 167.7, 150.4, 147.9, 142.6, 136.2, 135.0, 134.5, 133.6, 133.3, 131.2, 129.2, 128.9, 126.5, 126.1, 124.9, 124.1, 123.2, 121.8, 119.1; LRMS (ESI) (m/z) (relative intensity): 366 (93) [M+H]+, 331 (67); + HRMS calcd for C19H13ClN3O3 [M+H] : 366.0645, Found 366.0641.

9-(2-methylphenyl)-2,9diazatricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13- hexaen-10-one (5o) Yield: (78 %); red solid ; m.p.: 208-210 oC; FT-IR (KBr) ν/cm−1 1 3445, 1580, 1385; H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (dd, J = 1.2 Hz, 7.8 Hz, 1H), 7.42-7.44 (m, 1H), 7.28-7.35 (m, 4H), 7.06 (t, J = 7.5 Hz, 1H), 6.98-7.01 (m, 1H), 6.93-6.94 (m, 1H), 6.84- 6.90 (m, 2H), 6.75 (dd, J = 0.9 Hz, 8.0 Hz, 1H), 5.55 (brs, 1H), 13 2.22 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.2, 150.8, 143.5, 142.2, 136.1, 134.3, 133.1, 132.8, 131.6, 130.2, 128.1, 126.9, 125.9, 125.8, 125.5, 124.1, 123.0, 120.7, 118.8, + 17.9; LRMS (EI) (m/z) (relative intensity): 300 (100) [M ]; HRMS calcd for: C20H16N2O [M+]: 300.1263, Found 300.1268.

8-Chloro-10-(2-methoxyphenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5p) Yield: (75 %); yellow solid; m.p.: 167-169 oC; FT-IR (KBr) −1 1 ν/cm 3520, 3489, 670; H NMR (400 MHz, CDCl3) δ (ppm) 7.88 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 7.1 Hz, 1H), 7.29-7.31 (m, 2H), 7.02-7.08 (m, 3H), 6.91 (dd, J = 2.2 Hz, 8.4 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 6.76-6.80 (m, 2H), 5.76 (brs, 1H), 3.86 (s, 13 3H); C NMR (100 MHz, CDCl3)) δ 168.1, 155.9, 150.3, 141.9, 135.8, 133.0, 132.9, 132.0, 130.3, 129.9, 128.7, 125.5, 125.4, 124.9, 122.9, 121.6, 121.5, 118.9, 112.8, 56.2; LRMS (EI) (m/z) (relative intensity): 350 (100) [M+], 315 (60); HRMS calcd for: + C20H15ClN2O2 (M ): 350.0822, Found 350.0819.

10-(3-Methoxyphenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5q) Yield: (74 %); yellow solid; m.p.: 199-201 oC; FT-IR (KBr) −1 1 ν/cm 3472, 3431, 1590, 1379; H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (dd, J = 1.5 Hz, 7.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.28-7.32 (m, 1H), 7.01-7.07 (m, 2H), 6.97-7.00 (m, 2H), 6.93- 6.97 (m, 1H), 6.85-6.91 (m, 3H), 6.83 (d, J = 8.0 Hz, 1H), 5.67 13 (brs, 1H), 3.80 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.3, 160.5, 151.0, 144.7, 143.9, 135.1, 133.1, 132.8, 129.9, 126.6, 125.9, 125.6, 124.1, 122.9, 121.7, 120.8, 118.9, 115.1, 113.3, 55.6; LRMS (EI) (m/z) (relative intensity): 316 (100) [M]+, 243 (30); HRMS calcd + for C20H16N2O2 [M] : 316.1212, Found 316.1219. 10-(4-Isopropylphenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5r) Yield: (66 %); pink solid; m.p.: 188-190oC; FT-IR (KBr) ν/cm−1 1 3530, 3470, 1635, 540; H NMR (400 MHz, CDCl3) δ (ppm) 7.93 (d, J = 7.7 Hz, 1H), 7.28-7.34 (m, 5H), 7.04 (t, J = 7.5 Hz, 1H), 6.93 (m, 2H), 6.89 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 7.8 Hz, 2H), 5.64 (brs, 1H), 2.95 (m, 1H), 1.29 (s, 3H), 1.27 (s, 3H); 13C NMR

(100 MHz, CDCl3) δ 168.5, 151.2, 147.9, 144.1, 141.2, 135.3, 133.0, 132.6, 128.8, 127.2, 126.7, 125.7, 125.5, 123.8, 122.7, 120.7, 118.9, 33.9, 24.1; LRMS (EI) m/z) (relative intensity): 328 (100) [M]+, 313 (80); HRMS calcd for + C22H20N2O [M] : 328.1576, Found 328.1572.

10-(4-Chlorophenyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5s) Yield: (44 %); light red solid; m.p.: 193-195 oC; FT-IR (KBr) −1 1 ν/cm 3490, 1580, 1360; H NMR (400 MHz, CDCl3) δ (ppm) 7.92 (d, J = 7.8 Hz, 1H), 7.39-7.41 (d, J = 8.7 Hz, 2H), 7.34-7.36 (m, 2H), 7.30-7.32 (m, 1H), 7.00-7.08 (m, 2H), 6.95 (d, J = 7.0 Hz, 1H), 6.91 (t, J = 8.1 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 13 8.0 Hz, 1H), 5.63 (brs, 1H); C NMR (100 MHz, CDCl3) δ 168.2, 150.9, 144.1, 142.1, 134.9, 133.2, 133.1, 132.9, 130.5, 129.5, 126.8, 126.2, 125.2, 124.2, 123.0, 120.8, 118.9; LRMS (EI) (m/z) (relative intensity): 320 (100) [M]+; HRMS calcd + for C19H13ClN2O [M] : 320.0716, Found 320.0710.

2-Methoxy-10-phenyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5t) Yield: (56 %); white Solid ; m.p.: 218-220 oC; FT-IR (KBr) −1 1 ν/cm 3490, 3410; H NMR (400 MHz, CDCl3) δ (ppm) 7.39- 7.46 (m, 5H), 7.31-7.35 (m, 1H), 6.98-7.01 (m, 1H), 6.93-6.95 (m, 1H), 6.85-6.91 (m, 2H), 6.76-6.80 (m, 2H), 5.46 (brs, 1H), 13 3.78 (s, 3H); C NMR (100 MHz, CDCl3) δ 168.2, 155.5, 144.9, 144.7, 143.7, 135.7, 129.3, 129.2, 127.4, 126.8, 126.2, 125.9, 123.9, 120.9, 120.5, 120.2, 115.8, 55.9; LRMS (EI) (m/z) (relative intensity): 316 (100) [M]+, 314 (55); + HRMS (EI) calcd for C20H16N2O2 [M] ;: 316.1212, Found 316.1215.

9-Phenyl-14,16-dioxa-2,9diazatetracyclo[9.7.0.03,8.013,17]octadeca1(18),3(8),4,6,11, 13(17)-hexaen-10-one (5u) Yield: (48 %); yellow solid ; m.p.: 210-212 oC; FT-IR (KBr) ν/cm−1 3477, 3410, 599; 1H

NMR (400 MHz, DMSO-d6) δ (ppm) 7.81 (brs, 1H), 7.41-7.45 (m, 2H), 7.28-7.34 (m, 3H), 7.16 (d, J = 7.8 Hz, 1H), 7.10 (s, 1H) , 7.03 (t, J = 7.3 Hz, 1H), 6.89 (t, J = 7.7 Hz, 1H), 6.72 (s, 13 1H), 6.67 (d, J = 8.0 Hz, 1H), 6.01 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 166.7, 150.9, 148.3, 145.2, 143.3, 142.4, 134.7, 128.94, 128.92, 126.9, 125.9, 125.6, 123.2, 120.5, 116.7, 109.9, 101.7, 99.4; LRMS (EI) (m/z) (relative intensity) 330 (100) [M]+; + HRMS calcd for C20H14N2O3 [M] : 330.1004, Found 330.1008.

3-Chloro-10-phenyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5v) Yield: (62 %); white solid; m.p.: 243-245 oC; FT-IR (KBr) −1 1 ν/cm 3579, 1565, 735; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.21 (brs, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.43-7.47 (m, 2H), 7.31- 7.36 (m, 3H), 7.19-7.24 (m, 2H), 7.05-7.09 (m, 2H), 6.91 (t, J = 7.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,

CDCl3) δ 166.3, 152.9, 143.7, 143.0, 136.8, 134.2, 134.2, 129.0, 128.9, 127.2, 126.2, 125.8, 123.6, 123.2, 121.6, 120.8, 118.3; LRMS (EI) (m/z) (relative intensity) 320 (100) + 35 + [M] ; 319 (75) HRMS calcd for C19H13N2OCl [M] : 320.0716, Found 320.0708.

3-Fluoro-10-phenyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (5x) Yield: (69 %); white solid; m.p.: 281-283 oC; FT-IR (KBr) −1 1 ν/cm 3479, 1669, 545; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.24 (brs, 1H), 7.74-7.78 (m, 1H), 7.42-7.46 (m, 2H), 7.31-7.35 (m, 3H), 7.20 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.82- 6.97 (m, 3H), 6.70 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz,

CDCl3) δ 166.3, 165.6, 163.1, 153.8 (d, J = 10.5 Hz), 143.8, 143.1, 135.1 (d, J = 10.6 Hz), 134.3, 129.0, 128.9, 127.2, 126.1, 125.8, 123.6, 120.9 (d, J = 2.4 Hz), 120.8, 109.0 (J = 22.0 Hz), 105.1 (J = 23.6 Hz); LRMS (EI) (m/z) (relative + + intensity) 304 (100) [M] ; 303 (80) HRMS calcd for C19H13N2OF [M] : 304.1012, Found 304.1013.

2-(2-Iodophenylamino)-N-methylbenzamide (3y) Yield: (83 %); light yellow solid; m.p.: 189-191 oC; FT-IR (KBr) −1 1 ν/cm 3490, 3410, 1700; H NMR (400 MHz, CDCl3) δ (ppm) 9.28 (brs, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.23-7.30 (m, 3H), 6.83 (t, J = 7.6 Hz, 1H), 6.27 (t, J = 7.7 Hz, 1H), 6.28 (brs, 1H), 3.00 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 169.9, 144.4, 143.3, 140.1, 132.1, 128.9, 127.8, 124.0, 120.0, 119.9, 119.3, 116.7, 92.8, 26.9. LRMS (ESI) (m/z) (relative intensity): 352 (100) + + [M] , 226 (65); HRMS calcd for C14H13IN2O [M] : 352.0073, Found 352.0068.

2-(Benzo[d]oxazol-2-yl)-N-(2-iodophenyl)aniline (6a) Yield: (83 %); white solid; m.p.: 177-179 oC; FT-IR (KBr) −1 1 ν/cm 3490, 3410, 2899, 1735; H NMR (400 MHz, CDCl3) δ (ppm) 10.33 (brs, 1H), 8.22 (d, J = 7.8 Hz, 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.76-7.79 (m, 1H), 7.60-7.63 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.32-7.40 (m, 4H), 7.23 (d, J = 8.4 Hz, 1H), 6.95 (t, J = 13 7.6 Hz, 1H), 6.86 (t, J = 7.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 162.7, 149.5, 144.8, 143.2, 141.7, 140.3, 132.4, 129.4, 129.1, 125.4, 125.2, 124.7, 123.1, 119.8, 118.6, 114.7, 110.9, 110.5, 95.2; LRMS (EI) (m/z) (relative intensity): 412 (100) [M]+, 286 (60); + HRMS calcd for C19H13IN2O [M] : 412.0073, Found 412.0069

12-Chloro-8,15,22-triazapentacyclo[13.7.0.02,7.09,14.016,21]docosa1(22),2,4,6,9(14), 10,12,16(21),17,19-decaene (7a) Yield: (87 %); light yellow solid; m.p.: 238-240oC; FT-IR (KBr) ν/cm−1 3490, 550; 1H NMR

(400 MHz, CDCl3) δ (ppm) 8.17 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 7.3 Hz, 1H), 7.63-7.65 (m, 2H), 7.29-7.36 (m, 3H), 7.12-7.19 (m, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.89 (d, J = 7.8 Hz, 1H), 5.53 (brs, 13 1H); C NMR (100 MHz, CDCl3) δ 152.3, 149.0, 144.2, 142.0, 134.8, 131.8, 131.3, 130.2, 129.1, 127.7, 124.0, 123.9, 123.86, 123.81, 123.0, 121.6, 120.5, 119.8, 111.5; LRMS (EI) (m/z) (relative intensity): 317 (100) [M]+, 319 (31); HRMS calcd for + C19H12ClN3 [M] : 317.0720, Found 317.0715.

I.C.6. References 1. a) Bhana, N.; Foster, R. H.; Olney, R.; Plosker, G. L. Drugs 2001, 61, 111. b) DeSarro, G.; Chimirri, A.; DeSarro, A.; Gitto, R.; Grasso, S.; Zappala, M. Eur. J. Med. Chem. 1995, 30, 925. c) Gan, J.; Ma, D. Org. Lett. 2009, 11, 2788. d) Sakaki, J.; Konishi, K.; Kishida, M.; Gunji, H.; Kanazawa, T.; Uchiyama, H.; Fukaya, H.; Mitani, H.; Kimura, M. Bioorg. Med. Chem. Lett. 2007, 17, 4808. e) Lu, S.-M.; Howard, A. J. Am. Chem. Soc. 2008, 130, 6451. f) Hartwig, J.; Ceylan, S.; Kupracz, L.; Coutable, L.; Kirschning, A. Angew. Chem. Int. Ed. 2013, 52, 9813. 2. a) Charan, R. D.; Schlingmann, G.; Janso, J. E.; Bernan, V.; Feng, X. D.; Carter, G. T. J. Nat. Prod. 2004, 67, 1431. b) Mandrioli, R.; Mercolini, L.; Raggi, M. A. Curr. Drug Metab. 2008, 9, 827. c) Zhao, H.-Y.; Liu, G. J. Comb. Chem. 2007, 9, 1164. d) Pettersson, B.; Hasimbegovic, V.; Bergman, J. J. Org. Chem. 2011, 76, 1554. 3. a) Hansen, A. J.; Jorgensen, T. K. U.B. Olsen, WO2000032193, 2000. b) Duarte, C. D.; Barreirzo, E. J.; Fraga, C. A. M. Mini-Rev. Med. Chem. 2007, 7, 1108. c) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347. 4. a) Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 14228. b) Levy, O.; Erez, M.; Varon, D.; E. Keinan, Bioorg. Med. Chem. Lett. 2001, 11, 2921. c) Sum, F.- W.; Dusza, J.; Santos, E. D.; Grosu, G.; Reich, M.; Du, X.; Albright, J. D.; Chan, P.; Coupet, J.; Ru, X.; Mazandarani, H.; Saunders T. Bioorg. Med. Chem. Lett. 2003, 13, 2195.

5. Diao, X.; Xu, L.; Zhu, W.; Jiang, Y.; Wang, H.; Guo, Y.; Ma, D. Org. Lett. 2011, 13, 6422. 6. Kavala, V.; Janreddy, D.; Raihan, M. J.; Kuo, C.-W.; Ramesh, C.; Yao, C.-F. Adv. Synth. Catal. 2012, 354, 2229. 7. a) Binaschi, M.; Boldetti, A.; Gianni, M.; Maggi, C. A.; Gensini, M.; Bigioni, M.; Parlani, M.; Giolitti, A.; Fratelli, M.; Valli, C.; Terao, M.; Garattini, E. ACS Med. Chem. Lett. 2010, 1, 411. b) Al-Tel, T. H.; Al-Qawasmeh, R. A.; Schmidt, M. F.; Al-Aboudi, A.; Rao, S. N.; Sabri, S. S.; Voelter, W. J. Med. Chem. 2009, 52, 6484. c) Leyva-Perez, A.; Cabrero-Antonino, J. R.; Corma, A. Tetrahedron 2010, 66, 8203. 8. a) Glorius, F.; Grohmann, C.; Wang, H. Org. Lett. 2013, 15, 3014. b) Liu, T.; Zhu, C.; Yang, H.; Fu, H. Adv. Synth. Catal. 2012, 354, 1579. c) Adepu, R.; Sunke, R.; Meda, C. L. T.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Deora, G. S.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2013, 49, 190. d) Kshirsagar, U. A.; Argade, N. P. Org. Lett. 2010, 12, 3716. e) Sunke, R.; Adepu, R.; Kapavarapu, R.; Chintala, S.; Meda, C. L. T.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2013, 49, 3570. f) Li, L.; Wang, M.; Zhang, X.; Jiang, Y.; Ma, D. Org. Lett. 2009, 11, 1309. g) Bianchi, G.; Marinelli, F.; Rossi, L.; Arcadi, A.; Chiarini, M. Adv. Synth. Catal. 2010, 352, 136. h) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2012, 51, 5170. i) Liu, T.; Zhu, C.; Yang, H.; Fu, H. Adv. Synth. Catal. 2012, 354, 1579. j) Kshirsagar, U. A.; Puranik, V. G.; Argade, N. P. J. Org. Chem. 2010, 75, 2702. k) Fuller, P. H.; Chemler, S. R. Org. Lett. 2007, 9, 5477. l) Xu, L.; Jiang, Y.; Ma, D. Org. Lett. 2012, 14, 1150. m) Diao, X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 7974. 9. a) Janreddy, D.; Kavala, V.; Kuo, C.-W.; Chen, W.-C.; Ramesh, C.; Kotipalli, T.; Kuo, T.-S.; Chen, M.-L.; He, C.-H.; Yao, C.-F. Adv. Synth. Catal. 2013, 355, 2918. b) Gawande, S. D.; Kavala, V.; Zanwar, M. R.; Kuo, C.-W.; Huang, H.-N.; He, C.-H.; Yao, C.-F. Adv. Synth. Catal. 2013, 355, 3022. c) Gawande, S. D.; Raihan, M. J.; Zanwar, M. R.; Kavala, V.; Janreddy, D.; Kuo, C.-W.; Chen, M.-L.; Kuo, T.-S.; Yao, C.-F. Tetrahedron 2013, 69, 1841. d) Kavala, V.; Wang, C.-C.; Barange, D. K.; Kuo, C.-W.; Lei, P.-M.; Yao, C.-F. J. Org. Chem. 2012, 77, 5022. e) Barange, D. K.; Tu, Y.-C.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Adv. Synth. Catal. 2011, 353, 41. 10. a) Kitching, M. O.; Hurst, T. E.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 2925. b) Liu, Y.; Chu, C.; Huang, A.; Zhan, C.; Ma, Y.; Ma, C. ACS Comb. Sci. 2011, 13, 547. 11. a) Panagopoulos, A. M.; Steinman, D.; Goncharenko, A.; Geary, K.; Schleisman, C.; Spaargaren, E.; Zeller, M.; Becker, D. P. J. Org. Chem. 2013, 78, 3532. b) Zhao, Y.; Wu,

Y.; Jia, J.; Zhang, D.; Ma, C. J. Org. Chem. 2012, 77, 8501. c) Huang, A.; Qiao, Z.; Zhang, X.; Yu, W.; Zheng, Q.; Ma, Y.; Ma, C. Tetrahedron 2012, 68, 906. 12. CCDC No:266965-266967 contain the supplementary crystallographic data for this paper (compound 7a, 5g, 5a respectively). This data can be obtained free of charge from The Cambridge crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

Part-Ι, Section-D One Pot Synthesis of 2-Arylquinazoline and Tetracyclic- Isoindolo[1,2-a]quinazoline Derivatives via Cyanation Followed by the Rearrangement of o-Substituted 2- Halo-N-Arylbenzamides

Ι.D.1. Introduction The synthesis of N-heterocycles via transition metal mediated cross-coupling reactions had become an area of interest. This may be due to the fact that traditional synthetic methods are often laborious and the desired products are produced in relatively lower yields. The synthesis of these N-heterocycles via copper catalyzed and copper mediated C-C and C-N bond coupling reactions are very popular. Copper catalysts are inexpensive, less toxic and the use of air sensitive and expensive ligands that are used on palladium and other metal complex-based methodologies can be avoided. Further, applications of such copper mediated handy protocols on 2-haloarylbenzamide derivatives with structural changes at the amidic position leads to the formation of multicyclic fused rings via multibond formation. Structural motifs such as dibenzoxazepinones, indoloquinolines and tetracyclic fused N-heterocyclic compounds can be easily synthesized using these methodologies, compared to traditional multistep synthesis.1

Figure Ι.D.1.1. Biologically active quinazoline derivatives

2-arylquinazolines are an important class of structural motifs that possess remarkable pharmacological properties with anticonvulsant, antibacterial, antiviral, antitubercular, antiplasmodial, anticancer and topoisomerase I inhibitory activities (Figure Ι.D.1.1).2 Besides tetracyclic isoindolo[1,2-a]quinazoline derivatives are ubiquitous structural motifs and possess excellent biological activities (Figure Ι.D.1.2). A structural analogue such as Batracylin has potent activity against colon carcinomas, cisplatin and doxorubicin resistant tumors. A Luotonin derivative was also reported to be effective against leukemia cells. Recent reports indicate that tryptanthrin can be used effectively as a chemotherapeutic agent in the treatment of sleeping disorders.3

Figure Ι.D.1.2. Biologically active tetracyclic isoindolo[1,2-a]quinazoline derivatives

Ι.D.2. Review of literature Ι.D.2.1. 2-phenylquinazolin Numerous approaches are available for the synthesis of 2-arylquinazoline derivatives.4 However, the synthesis of 2-arylquinazoline derivatives is a cumbersome task, since it involves either the use of starting materials such as 2-(aminomethyl)aniline, benzimidamide, 2-(bromomethyl)aniline, 2-(aminomethyl)aniline, benzimidamide, which are not readily available, dangerous peroxides or hazardous reagents (Scheme Ι.D.2.1).5 Wang and co-workers in their publications in 2001 demonstrated the synthesis of substituted quinazoline using copper oxide nano particles and iodine using TBHP as oxygen source in heating. The corresponding quinazoline derivatives was furnished good yields.6

Scheme Ι.D.2.1 In another report, Han and co-workers had reported aerobic oxidative synthesis of 2- substitutes phenylquinazoline. The reaction was conducted in catalytic amount of CuCl

and DABCO as ligand in oxygen balloon pressure to afford 2-substituted phenylquinazoline derivatives (Scheme Ι.D.2.2).7

Scheme Ι.D.2.2

Excellent method have been reported by Wang and co-workers for the synthesis of multi- substituted quinazoline derivatives (Scheme Ι.D.2.3).8 Iodine-catalyzed oxidative amination of C(sp3)-H bonds adjacent to nitrogen or oxygen atoms have developed by the reaction of 2-carbonyl anilines, ammonia, solvents such as ethers, amides and alcohols with TBHP was used as oxygen source for the conversion.

Scheme Ι.D.2.3

Thus, We wish to report herein on the solvent-dependent one pot synthesis of multi- substituted 2-arylquinazoline and tetracyclic isoindolo[1,2-a]quinazoline derivatives via cyanation followed by rearrangement of the resulting o-substituted 2-halo-N- arylbenzamide.

Ι.D.2.1. Tetracyclic isoindolo[1,2-a]quinazoline Very few methods are available for the synthesis of isoindolo[1,2-a]quinazoline. Pal and co-workers have presented the synthesis of isoindolo[1,2-a]quinazoline derivatives by a green and efficient domino reaction.9 The multicomponent reaction was carried out by using isatoic anhydride, various aniline derivatives, 2-formylbenzoic acid and 5% (w/w) Montmorillonite K10 resine in ethanol. The authors also found 6,6a-dihydroisoindolo- [2,1-a]quinazoline-5,11-diones as novel inhibitors of TNF-a in vitro analysis.

Scheme Ι.D.2.1.1

In another report, Martínez-Viturro et al. have developed the stepwise synthesis of antitumoural agent batracylin and isoindolo[1,2-b]quinazolin-12(10H)-one derivatives (Scheme Ι.D.2.2).10 The preparation of tetracyclic isoindolo[1,2-a]quinazoline derivatives was achieved by step wise process. First, the benzyl alcohol required for the Mitsunobu reaction was obtained from 2-acyl aniline by sodium borohydride reduction. Next, the substituted benzyl alcohol underwent Mitsunobu reaction followed by spontaneous cyclodehydration to form and isoindolo[1,2-b]quinazolin-12(10H)-one derivatives.

Scheme Ι.D.2.2 Ι.D.3. Results and Discussion: Our group previously reported on numerous protocols for the synthesis of medicinally active N-heterocycles.11 In a continuation of this interest, we noted the recently published articles on copper catalyzed reactions of ethyl cyanoacetate and ethyl 2-(2- bromobenzamido)benzoate for the synthesis of isoquinolino[2,3-a]quinazolinones by Fu and co-workers 12a and Pal and co-workers12b. Based on these reports, we hypothesized, the reaction of 1a with CuCN would first undergo cyanation followed by cyclization in the presence of an amidic N-H, which would lead to the formation of the tetracyclic compound 2a (Scheme Ι.D.3.1). Further, the hydroxyl group can be easily functionalized using various protocols. To investigate this hypothesis, we treated 1a in the presence of o CuCN in DMSO and K2CO3 as a base at 100 C. The reaction resulted in multiple spots on TLC after 2h, however, when the reaction was continued for a period of up to 16h, a new compound was observed with a higher Rf than the starting material (entry 1). The compound was isolated and purified by column chromatography. Further characterization by 1H NMR, 13C NMR, LRMS, HRMS, single crystal X-ray diffraction revealed that the

compound was 2-phenylquinazoline (3a, Figure Ι.D.3.1) and not compound 2a (Scheme

Ι.D.3.1).

Figure Ι.D.3.1. X-Ray Crystal structure of 3a (ORTEP diagram)

Scheme Ι.D.3.1. Synthesis of tetracyclic compound 2a from 1a

Interestingly, the combination of such a strained five membered ring and a strong base leads to base catalyzed cleavage of the C-N bond in compound 2a. Moreover, further decarboxylation resulted in the formation of compound 3a (Scheme Ι.D.3.1). To our knowledge, such types of cleavages have not been reported in the literature. This motivated us to study this reaction further. To optimize the reaction conditions, we increased the reaction temperature from 100oC to 120oC and then to 135oC. An elevation in the temperature resulted in an increase in yield to 24% and 74%, respectively (entries 2-3). However, a further increase in temperature failed to result in any improvement in yield (entry 4). Next, various inorganic bases such as Na2CO3, NaHCO3, K3PO4, Cs2CO3 we examined for the reaction (entries 5-8) but these resulted in, either a lower yield of the desired product or no product being formed. Further, the use of organic bases also resulted in lower yields of compound 3a (entries 9-11). Based on this information, it was concluded that K2CO3 was the preferred base for use in this transformation. Different solvents were then examined. However, we found that the product was formed in DMF and DMA but afforded a lower yield of 3a (entries 12-13).

Table Ι.D.3.1. Optimization of reaction condition

a Reactions were performed on 0.5 mmol of 1a, CuCN (1 equiv) and Base (2.5 equiv). b Yields refer to isolated and purified compounds.

We next examined the use of refluxing 1,4-dioxane as the solvent for 12h. Interestingly, a highly polar compound was produced, as evidence by its TLC properties. The compound was isolated and purified. 1H NMR, 13C NMR, LRMS, HRMS data revealed that the compound formed was a tetracyclic isoindole fused quinazoline (2a) and was produced in 79 % yield (entry 14). Further screening of the reaction using other solvents such as acetonitrile and ethanol failed to improve product yield (entries 15, 16). Fine tuning of organic and inorganic bases also failed to improve reaction yield (entries 17-22). Finally, based on the optimization study, the reaction of 1a with 1 equivalent of CuCN o using K2CO3 as a base in 1,4-dioxane at 101 C were the optimal conditions for the preparation of tetracyclic isoindole fused quinazoline (2a) and the reaction with K2CO3 as a base and DMSO as a solvent at 135oC were the optimized conditions for the preparation of 2-phenyl quinazoline (3a). After optimizing the reaction conditions, the scope of the reaction was studied, first with unsubstituted cyclic compounds A and cyclic compounds B with aldehyde, ketone and cyanide groups at the ortho position. The reaction of CuCN with a model substrate 1a containing an aldehyde at the ortho position afforded the 2-phenylquinazoline derivative (3a) in 74% yield (entry 1, table Ι.D.3.2). However, the reaction of CuCN with 1b and 1c bearing ketone and cyanide groups at the ortho position yielded 4-methyl-2- phenylquinazoline 3b and 2-phenylquinazolin-4-amine 3c in 77% and 57% yields, respectively, with longer reaction time. The longer reaction time for compound 3b and 3c may be due to less electrophilic nature of the ketone and the nitrile functional groups. Next, electron donating amides were examined. The reaction afforded the corresponding quinazoline derivatives in moderate to good yields but a longer reaction time was needed in most cases (entries 4 to 9). Surprisingly, the reaction with N-(2-cyanophenyl)-2-iodo- 4,5-dimethoxybenzamide (1h) reached completion within 9h, producing a product yield of 74% (entry 8). Further, a similar trend was observed, when electron withdrawing amide-containing substrates were used in the reaction. Nitro substituted amides formed the corresponding 2-arylquinazoline derivatives in good yields, but a longer reaction time was needed (entries 10-12). However, the use of electron withdrawing amides afforded better product yields than electron donating amides. The reaction also proceeded when amides bearing bromo and bulkier naphthyl groups were used, resulting in the formation of the corresponding products 3m and 3n in good yield.

Table Ι.D.3.2. Synthesis of 2-Arylquinazoline from 1a and different 2-halo benzamides

Continue………………..

a Reactions were performed on 0.5 mmol of 1, CuCN (1 equiv) and K2CO3 (2.5 equiv) at 135oC. b Yields refer to isolated and purified compounds.

As an expansion of this study, we further explored the scope of the protocol with amidic linkages using chalcone derivatives as depicted in scheme Ι.D.3.2. The reaction of CuCN with the unsubstituted chalcone amide (1o) resulted in the formation of the corresponding 2-aryl-4-styrylquinazoline (3o) in 76% yield. In the case of an electron donating substituent on the chalcone, the yield of the respective compound 3p was reduced to 67% and a longer reaction time was needed. However, an electron withdrawing substituent on the chalcone (1q) resulted in a slightly increased product yield and a reduced reaction time for the synthesis of 4-(4-chlorostyryl)-2-phenylquinazoline (3q).

Scheme Ι.D.3.2. Synthesis of 2-arylquinazoline from 2-halo-N-phenyl benzamide

Further, we used the optimum reaction conditions to check the scope of tetracyclic isoindole fused quinazoline, as depicted in table 3. First, the reaction was screened when the ring B contained aldehyde, ketone and cyanide groups at the ortho position. The reaction of N-(2-formylphenyl)-2-iodobenzamide (1a) with CuCN in 1,4-dioxane afforded the hydroxy substituted tetracyclic isoindole fused quinazoline derivative in 79%

Table Ι.D.3.3. Synthesis of tetracyclic isoindolo[1,2-a]quinazoline

a Reactions were performed on 0.5 mmol of 1, CuCN (1 equiv) and K2CO3 (2.0 equiv) at 101oC.b Yields refer to isolated and purified compounds.CInseparable mixtures of products

(entry 1). Whereas, when a ketone group was located at the ortho position, the corresponding tetracyclic derivative (2b) was obtained in good yield. The lower yield of compound 2c was observed, when the reaction was carried out with the ortho-cyano substituted N (2-phenyl)-2-iodobenzamide as a substrate (entry 3). Further, when ring A contained an electron donating dioxymethylene group, a produced moderate yield the desired product (2r) and a slightly longer reaction time was needed (entry 4). However, electron withdrawing bromo substituents on ring A and ring B afforded moderate yields of compounds 2m and 2s. Further, the protocol failed to form compound 2k, when the strong electron withdrawing nitro substituted 1k was used as a substrate. A plausible mechanism for the formation both 2 and 3 is depicted in Scheme Ι.D.3.3. The reaction is initiated by the formation of intermediate I through cyanation in the presence a base and CuCN, which may undergo intramolecular cyclization via the nucleophilic addition of the amidic nitrogen to the cyanide functionality to generate the imine intermediate II. This intermediate further undergoes an intramolecular cyclization via the nucleophilic addition of the imine nitrogen to the aldehyde functionality to produce the tetracyclic compound 2. The tetracyclic compound 2 then undergoes decarboxylation in the presence of the base to form compound 3.

Scheme Ι.D.3.3. Plausible mechanism for the synthesis of compound 2 and 3

To support our proposed mechanism, we carried out, two control experiments. In the first experiment, we carried out the reaction of 1b with CuCN and potassium carbonate in 1,4- dioxane as the solvent to obtain 2b. After the complete conversion of 1b to the tetracyclic compound 2b, which was confirmed by TLC, DMSO was then added and the reaction

mixture heated at 110oC. The reaction produced 3b in 51% yield after 16h of reaction (Scheme Ι.D.3.4).

Scheme Ι.D.3.4. Control experiment 1

In the second controlled experiment, we treated the tetracyclic compound 2b with potassium carbonate in the absence copper in DMSO as the solvent at 135oC. Under these conditions, we observed the conversion of 2b into the corresponding 2-arylquinazoline derivative in 50 % yield (Scheme Ι.D.3.5). The findings from the control experiments indicate that the formation of 2-arylquinazoline derivative from the thermal decomposition of tetracyclic compound is facilitated by the base.

Scheme Ι.D.3.5. Control experiment 2

Ι.D.4. Conclusions In conclusion, we report on the synthesis of a series of substituted 2-arylquinozaline derivatives and tetracyclic isoindolo[1,2-a]quinazoline derivatives in moderate to good yield in a one pot process simply by changing solvent and temperature. A novel base catalyzed cleavage of tetracyclic isoindolo[1,2-a]quinazoline was observed during the synthesis of the 2-arylquinazoline. Further, the synthesis of 2-arylquinazolin-4-amine and 2-phenyl-4-styrylquinazoline were achieved very efficiently compared to currently used methods. The synthesis of good yields of tetracyclic isoindolo[1,2-a]quinazoline derivatives was achieved using 1,4-dioxane as the solvent.

Ι.D.5. Experimental Section Ι.D.5.1. General All chemicals were purchased from various sources and were used directly without further purification. Analytical thin-layer chromatography was performed using silica gel

60F glass plates and silica gel 60 (230–400 mesh) was used in flash chromatographic separations. NMR spectra were recorded in DMSO-d6 with DMSO and CDCl3 with 1 13 CHCl3 as the internal standards for H NMR (400 MHz) and C NMR (100 MHz). Coupling constants were expressed in Hertz. HRMS spectra were recorded using MALDI, ESI- or ESI+ mode. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.

Ι.D.5.2. General procedure for synthesis of substituted 2-halo-N-arylbenzamide 1(a- s): In a stir-bar-equipped flame-dried 50 mL round-bottom flask containing 2-halobenzoic acid (A) (4 mmol) was added SOCl2 (2 mL) carefully followed by one drop of DMF. The reaction mixture was then stirred at 80oC for 3h. The reaction mixture was then o evaporated under reduced pressure at 40-45 C temperature to remove excess of SOCl2. The resultant acid chloride was diluted in DCM (15 mL) and then added drop wise to ice cold solution of substituted aniline (B) (6 mmol), pyridine (3 mL) in DCM (10 mL). The reaction mixture was then allowed to warm to room temperature and stirred overnight. After completion of the reaction as determined by TLC analysis, the reaction mixture was evaporated under reduced pressure and the poured on crushed ice (50 gm). The resultant solid was washed with excess of ice cold water to afford pure compound 1(a-s).

Ι.D.5.3. General Experimental for the Synthesis of 2-arylquinazoline (3a-3q): In an oven-dried, 10 mL round-bottom flask equipped with magnetic stirrer was added 1a (0.5 mmol), CuCN (1.0 equiv), K2CO3 (2.5 equiv) in DMSO (2 mL). The reaction mixture was then stirred at 135oC under a nitrogen atmosphere. After completion of the reaction, as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then purified by column chromatography without workup using Hexane-Ethyl acetate as the eluent to yield compound 3a.

Ι.D.5.4. General Experimental for the Synthesis of isoindole fused quinazoline derivatives (2a-2c, 2m, 2r and 2s): In an oven-dried, 10 mL round-bottom flask

equipped with magnetic stirrer was added 1a (0.5 mmol), CuCN (1.0 equiv), K2CO3 (2.5 equiv) in 1.4-dioxane (2 mL). The reaction mixture was then stirred at 101oC under a nitrogen atmosphere. After completion of the reaction, as determined by TLC, the reaction mixture was allowed to cool to room temperature. The crude reaction mixture was then purified by column chromatography without workup using dichloromethane- methanol as the eluent to yield compound 2a.

Ι.D.5.4. Spectral Data of compounds N-(2-formylphenyl)-2-iodobenzamide (1a) Yield: (61 %); white solid; m.p.:133-135oC; FT-IR (KBr) ν/cm−1 1 1641; H NMR (400 MHz, CDCl3) δ (ppm) 11.47 (bs, 1H), 9.95 (bs, 1H), 8.92 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.68- 7.75 (m, 2H), 7.57 (d, J = 7.6 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 13 7.32 (t, J = 7.5 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H); C NMR (100 MHz, CDCl3) δ 195.7, 168.3, 141.7, 140.8, 140.7, 136.5, 136.3, 131.9, 128.6, 128.4, 123.8, 122.3, 120.4, 92.9; LRMS (EI) (m/z) (relative intensity): 352 (100) [M+H]+, 324 (33); HRMS (MALDI) + calcd for C14H10INO2 [M+H] : 351.9834, Found 351.9844.

N-(2-acetylphenyl)-2-iodobenzamide (1b) Yield: (79 %); white solid; m.p.:122-124oC; FT-IR (KBr) ν/cm−1 1 1641; H NMR (400 MHz, CDCl3) δ (ppm) 12.07 (bs, 1H), 8.93 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.62-7.66 (m, 1H), 7.55-7.57 (m, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.14-7.22 (m, 2H), 13 2.68 (m, 3H); C NMR (100 MHz, CDCl3) δ 202.8, 167.4, 142.0, 139.7, 138.6, 134.3, 131.7, 128.5, 127.9, 124.6, 123.7, 120.7, 93.2, 28.7; LRMS (MALDI) (m/z) (relative + + intensity): 366 (100) [M+H] , 333 (40); HRMS (MALDI) calcd for C15H12INO2 [M+H] : 365.9991 Found 366.0001.

N-(2-formylphenyl)-2-iodo-5-methoxybenzamide (1d) Yield: (59 %); yellow solid; m.p.: 165-167oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 11.45 (bs, 1H), 9.95 (s, 1H), 8.91 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.68-7.74 (m, 2H), 7.31 (t, J = 7.5

Hz, 1H), 7.12 (t, J = 2.9 Hz, 1H), 6.78 (dd, J = 8.7 Hz, 2.9 Hz, 1H), 3.84(s, 3H); 13C

NMR (100 MHz, CDCl3) δ 195.6, 168.1, 160.2, 142.5, 141.4, 140.7, 136.5, 136.3, 123.8, 122.4, 120.4, 118.5, 114.3, 81.1, 55.8; LRMS (MALDI) (m/z) (relative intensity): 382 + + (100) [M+H] , 351 (43); HRMS calcd for C15H12INO3 [M+H] : 381.9940, Found 381.9948.

N-(2-acetylphenyl)-2-iodo-5-methoxybenzamide (1e) Yield: (59 %); white solid; m.p.: 163-165oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, DMSO-d6) δ (ppm) 11.66 (bs, 1H), 8.49 (d, J = 8.3 Hz, 1H), 8.05 (dd, J = 7.9 Hz, 1.2 Hz. 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.68 (m, 1H), 7.29 (m, 1H), 7.17 (d, J = 3.0 Hz, 1H), 6.91 (dd, J = 8.7 Hz, 3.0 Hz, 1H), 3.79(s, 3H), 2.64 (s, 3H); 13C NMR (100 MHz,

CDCl3) δ 202.9, 168.0, 160.1, 142.9, 141.3, 140.8, 135.5, 131.9, 123.3, 122.5, 121.3, 118.3, 114.3, 81.1, 55.8, 28.7; LRMS (MALDI) (m/z) (relative intensity): 396 (100) + + [M+H] , 365 (65); HRMS calcd for C16H14INO3 [M+H] : 396.0096, Found 396.0100.

N-(2-cyanophenyl)-2-iodo-5-methoxybenzamide (1f) Yield: (59 %); white solid; m.p.: 159-161oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.56 (d, J = 8.2 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.64-7.71 (m, 2H), 7.25-7.29 (m, 1H), 7.12 (d, J = 2.9 Hz, 1H), 6.80 (dd, J = 8.7 Hz, 3.0 Hz, 1H), 6.91 (dd, J = 8.7 Hz, 3.0 Hz, 1H), 3.85(s, 13 3H); C NMR (100 MHz, CDCl3) δ 167.3, 160.3, 141.9, 141.3, 140.2, 134.5, 132.7, 125.0, 121.8, 118.9, 116.4, 114.6, 102.9, 80.5, 55.9; LRMS (EI) (m/z) (relative intensity): + + 378 (100) [M] , 352 (59); HRMS calcd for C15H11IN2O2 [M] : 378.9865, Found 378.9870.

N-(2-acetylphenyl)-2-iodo-4,5-dimethoxybenzamide (1g) Yield: (59 %); white solid; m.p.: 198-200oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.90 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.18 (t, J = 7.6 Hz, 13 1H), 7.14 (s, 1H), 3.92 (s, 3H), 2.67 (s, 3H); C NMR (100 MHz, CDCl3) δ 202.9, 167.7, 151.1, 149.5, 141.0 135.5, 134.1, 131.9, 123.1, 123.0, 122.5, 121.2, 111.9, 82.0, 56.5,

56.3, 28.7; LRMS (MALDI) (m/z) (relative intensity): 426 (100) [M+H]+, 300 (48); + HRMS calcd for C17H16INO4 [M+H] : 426.0202, Found 426.0210.

N-(2-cyanophenyl)-6-iodobenzo[d][1,3]dioxole-5-carboxamide (1h) Yield: (59 %); white solid; m.p.: 232-234oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.61 (bs, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.73-7.77 (m, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 7.42 (t, J = 7.6 Hz, 13 1H), 7.13 (s, 1H), 6.14 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 167.3, 149.3, 147.6, 139.7, 134.9, 133.8, 133.3, 126.3, 126.1, 118.6, 116.7, 108.7, 108.2, 102.3, 83.0; LRMS + (EI) (m/z) (relative intensity): 393 (100) [M+H] , 362 (45); HRMS calcd for C15H9IN2O3 [M+H]+: 393.9736, Found 393.9740.

N-(2-formyl-4,5-dimethoxyphenyl)-2-iodobenzamide (1i) Yield: (63 %); white solid; m.p.: 157-159oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 11.66 (bs, 1H), 9.76 (s, 1H), 8.60 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.54-7.55 (m, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.14-7.18 (m, 1H), 7.09 (s, 1H), 4.05 (s, 3H), 3.93 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 193.4, 168.3, 155.8, 145.1, 141.7, 140.7, 137.3, 131.8, 128.6, 128.5, 116.8, 115.2, 103.5, 92.8, 56.8, 56.5; LRMS (EI) (m/z) (relative intensity): + + 411 (100) [M] , 285 (36); HRMS calcd for C16H14INO4 [M] : 410.9968, Found 410.9962.

N-(2-formylphenyl)-2-iodo-5-nitrobenzamide (1j) Yield: (63 %); white solid; m.p.: 225-227oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 11.61 (bs, 1H), 9.97 (s, 1H), 8.88 (d, J = 8.4 Hz, 1H), 8.37 (t, J = 2.5 Hz, 1H), 8.18 (d, J = 8.6 Hz, 1H), 8.01 (dd, J = 8.6 Hz, 2.6 Hz, 1H), 7.72-7.79 (m, 2H), 7.38 (t, J = 7.5 Hz, 1H); 13C NMR

(100 MHz, CDCl3) δ 195.6, 166.3, 148.2, 143.4, 142.0, 140.2, 136.7, 136.4, 125.8, 124.5, 123.0, 122.4, 120.6, 101.2; LRMS (EI) (m/z) (relative intensity): 396 (100) [M]+, 368 + (67); HRMS calcd for C14H9IN2O4 [M] : 395.9607, Found 395.9610.

N-(2-acetylphenyl)-2-bromo-5-nitrobenzamide (1k) Yield: (63 %); white solid; m.p.: 177-179oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 11.30 (bs, 1H), 8.87 (d, J = 8.4 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 8.16 (dd, J = 8.8 Hz, 2.6 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.68 (s, 13 3H); C NMR (100 MHz, CDCl3) δ 203.3, 164.5, 147.3, 140.2, 139.9, 135.6, 135.2, 132.0, 127.2, 125.8, 124.1, 123.8, 122.5, 121.2, 28.6; LRMS (EI) (m/z) (relative + + intensity): 411 (100) [M+H] , 367 (47); HRMS calcd for C15H11IN2O4 [M+H] : 410.9842, Found 410.9850.

N-(2-acetylphenyl)-2-iodo-5-nitrobenzamide (1l) Yield: (54 %); yellow solid; m.p.: 158-160oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, DMSO-d6) δ (ppm) 11.0 (bs, 1H), 8.28-8.31 (m, 2H), 8.06 (dd, J = 2.5 Hz, 8.6 Hz, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.74-7.82 (m, 2H), 13 7.47 (t, J = 7.6 Hz, 1H); C NMR (100 MHz, DMSO-d6) δ 166.2, 147.2, 143.0, 141.1, 139.2, 133.9, 133.4, 126.7, 126.2, 125.3, 122.4, 116.6, 108.1, 103.3; LRMS (EI) (m/z) + + (relative intensity): 411 (100) [M+H] , 367 (47); HRMS calcd for C15H11IN2O4 [M+H] : 410.9842, Found 410.9850.

N-(2-acetylphenyl)-5-bromo-2-iodobenzamide (1m) Yield: (63 %); white solid; m.p.: 163-165oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 12.08 (bs, 1H), 8.88 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.63-7.65 (m, 2H), 13 7.21-7.31 (m, 2H), 2.69 (s, 3H); C NMR (100 MHz, CDCl3) δ 203.1, 166.8, 144.1, 141.9, 140.6, 135.6, 134.8, 131.9, 131.4, 123.6, 122.9, 122.5, 121.3, 90.8, 28.7; LRMS (EI) (m/z) (relative intensity): 443 (65) [M]+, 445 (60) [M+2]+, 322 (40); HRMS calcd for + C15H11IBrN2O [M] : 442.9018, Found 442.9023.

N-(2-acetylphenyl)-1-bromo-2-naphthamide (1n) Yield: (63 %); white solid; m.p.: 190-192oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, DMSO-d6) δ (ppm) 11.76 (bs, 1H), 8.49 (d, J = 8.2 Hz, 1H), 8.31 (d, J = 8.4 Hz, 1H), 8.04-8.15(m, 3H), 7.79 (t, J = 7.7 Hz, 1H), 7.66-7.75 (m, 3H), 7.32 (t, J = 7.6 Hz, 1H), 2.63 (s, 3H); 13C NMR (100

MHz, DMSO-d6) δ 202.8, 166.4, 138.3, 136.3, 134.3, 134.2, 131.6, 131.1, 128.9, 128.8, 128.6, 128.0, 127.1, 125.0, 124.7, 123.9, 120.9, 118.8, 28.8; LRMS (EI) (m/z) (relative + + intensity): 367 (100) [M] , 289 (55); HRMS calcd for C19H15INO2 [M] : 289.1103, Found 289.1109.

(E)-N-(2-cinnamoylphenyl)-2-iodobenzamide (1o) Yield: (56 %); yellow solid; m.p.: 165-167oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.76 (d, J = 7.3 Hz, 2H), 8.46 (d, J = 15.4 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 15.4 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.53-7.61 (m, 162.1, 160.3, 152.2, 139.6, 138.7, 136.3, 133.6, 130.6, 129.8, 129.5, 129.1, 128.8, 128.7, 128.2, 127.0, 124.0, 121.8, 121.1; LRMS (EI) (m/z) (relative + + intensity): 453 (100) [M] , 430 (20); HRMS calcd for C22H16INO2 [M] : 453.0226, Found 453.0223.

(E)-N-(2-(3-(benzo[d][1,3]dioxol-5yl)acryloyl)phenyl)2-iodobenzamide (1p) Yield: (45 %); yellow solid; m.p.: 177-179oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.90 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.71 (t, J = 15.4 Hz, 1H), 7.58-7.66 (m, 2H), 7.39-7.48 (m, 2H), 7.22-7.27 (m, 1H), 7.10-7.18 (m, 3H), 6.84 (d, J = 8.0 13 Hz, 1H), 6.02 (d, J = 4.9 Hz, 2H); C NMR (100 MHz, CDCl3) δ 193.3, 168.1, 150.5, 148.7, 145.9, 142.1, 140.8, 140.7, 134.8, 131.7, 130.6, 129.2, 128.6, 128.4, 125.9, 124.2, 123.3, 121.6, 120.7, 108.9, 106.9, 101.9, 92.9; LRMS (EI) (m/z) + + (relative intensity): 497 (100) [M] , 231 (68); HRMS calcd for C23H16INO4 [M] : 497.0124, Found 497.0118.

(E)-N-(2-(3-(4-chlorophenyl)acryloyl)phenyl)-2-iodobenzamide (1q) Yield: (63 %); white solid; m.p.: 158-160oC; FT-IR (KBr) −1 1 ν/cm 3468, 2283, 1590; H NMR (400 MHz, CDCl3) δ (ppm) 8.91 (d, J = 8.4 Hz, 1H), 8.01 (dd, J = 8.0 Hz, 1.2 Hz, 1H), 7.96 (dd, J = 8.0 Hz, 0.6 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 7.64- 7.68 (m, 1H), 7.54-7.60 (m, 4H), 7.45-7.49 (m, 1H), 7.39-7.41 (m, 2H), 7.22-7.26 (m, 1H), 7.18-7.15(m, 1H); 13C NMR (100

MHz, CDCl3) δ 193.2, 168.1, 144.5, 142.1, 140.7, 137.1, 135.1, 133.2, 131.7, 130.8, 129.9, 129.5, 128.6, 128.4, 123.9, 123.3, 123.2, 121.7, 92.9; LRMS (EI) (m/z) (relative + + intensity): 487 (100) [M] , 489 (32); HRMS calcd for C22H15ClINO2 [M] : 486.9836, Found 486.9842.

N-(2-acetylphenyl)-6-iodobenzo[d][1,3]dioxole-5-carboxamide (1r) Yield: (55 %); white solid; m.p.: 191-193oC; FT-IR (KBr) 1 ν/cm−1 3466; H NMR (400 MHz, CDCl3) δ (ppm) 12.0 (bs, 1H), 8.88 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 6.04 (s, 2H), 2.67 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.9, 167.7, 150.1, 148.6, 140.9, 135.6, 135.5, 131.9, 123.1, 122.4, 121.1, 120.0, 108.8, 102.4, 82.2, 28.7; LRMS (ESI) (m/z) (relative intensity): 409 (100) [M+], 283 (44); HRMS calcd for + C16H12INO4 [M] : 409.9811, Found 409.9818.

2-phenylquinazoline (3a) Yield: (74%); white solid; m.p.:100-101oC; FT-IR (KBr) ν/cm−1 1 1641; H NMR (400 MHz, CDCl3) δ (ppm) 9.09 (brs, 1H), 8.62- 8.64 (m, 2H), 8.11 (d, J = 8.4 Hz, 1H), 7.90-7.95 (m, 2H), 7.63 (t, 13 J = 7.5 Hz, 1H), 7.52-7.58 (m, 3H); C NMR (100 MHz, CDCl3) δ 161.3, 160.7, 151.0, 138.3, 134.3, 130.8, 128.9, 128.83, 128.80, 127.5, 127.3, 123.8; LRMS (EI) (m/z) + (relative intensity): 207 (100) [M+H] , 314 (100); HRMS (MALDI) calcd for C14H11N2 [M+H]+: 207.0922, Found 207.0924.

4-methyl-2-phenylquinazoline (3b) Yield: (77 %); yellow solid ; m.p.: 88-90oC; FT-IR (KBr) ν/cm−1 1 1635; H NMR (400 MHz, CDCl3) δ (ppm) 8.62.8.64 (m, 2H), 8.08-8.11 (m, 2H), 7.85-7.89 (m, 1H), 7.56-7.61 (m, 2H), 7.51- 13 7.54 (m, 2H), 3.03 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.4, 160.3, 150.6, 138.5, 133.6, 130.5, 129.4, 128.7, 127.0, 125.1, 123.2, 22.2; LRMS + + (ESI) (m/z) (relative intensity): 220 (100) [M] , 204 (40); HRMS calcd for C15H12N2 [M] : 220.1000, Found 220.1003.

2-phenylquinazolin-4-amine (3c) Yield: (57 %); yellow Solid; m.p.: 144-145oC; FT-IR (KBr) −1 1 ν/cm 3470, 3350, 1644, 1250; H NMR (400 MHz, CDCl3) δ (ppm) 8.51 (d, J = 6.7 Hz, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.73- 7.80 (m, 2H), 7.44-7.51 (m, 4H), 5.72 (bs, 2H); 13C NMR (100

MHz, CDCl3) δ 162.1, 159.7, 150.4, 138.6, 132.9, 129.9, 128.2, 127.8, 127.7, 125.2, 123.6, 113.3; LRMS (ESI) (m/z) (relative intensity): 222 (100) [M+H]+, 189 (20); HRMS + calcd for C14H12N3 [M+H] : 222.1031, Found 222.1023.

2-(4-methoxyphenyl)quinazoline (3d) Yield: (70 %); white solid ; m.p.: 92-94oC; FT-IR (KBr) −1 1 ν/cm 1650, 1240, 1125; H NMR (400 MHz, CDCl3) δ (ppm) 9.42 (bs, 1H), 8.59 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 8.4 Hz, 1H), 7.86-7.90 (m, 1H), 7.57 (t, J = 7.4 Hz, 1H), 13 7.06 (d, J = 8.7Hz, 2H), 3.90 (s, 3H); C NMR (100 MHz, CDCl3) δ 162.1, 161.1, 160.6, 151.1, 134.2, 131.0, 130.4, 128.7, 127.3, 126.9, 123.6, 114.2, 55.6; LRMS (ESI) + (m/z) (relative intensity): 237 (100) [M+H] , 179 (20); HRMS calcd for C15H13N2O [M+H]+: 237.1028, Found 237.1022.

2-(4-methoxyphenyl)-4-methylquinazoline (3e) Yield: (75 %); yellow solid; m.p.: 68-70oC; FT-IR (KBr) −1 1 ν/cm 1648, 1220, 1130; H NMR (400 MHz, CDCl3) δ (ppm) 8.60 (d, J = 8.6 Hz, 2H), 8.04 (t, J = 7.2 Hz, 2H), 7.83 (t, J = 7.6 Hz, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.6

13 Hz, 2H), 3.89 (s, 3H), 2.99 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.2, 161.9, 160.2, 150.6, 133.6, 131.2, 130.4, 129.6, 125.2, 122.9, 114.1, 55.6, 22.2; LRMS (MALDI) + + (m/z) (relative intensity): 251 (100) [M] , 221 (65); HRMS calcd for C16H15N2O [M+H] : 251.1184, Found 251.1191.

2-(4-methoxyphenyl)quinazolin-4-amine (3f) Yield: (54 %); yellow solid ; m.p.: 179-181oC; FT-IR (KBr) ν/cm−1 3470, 3350, 1641, 1250, 1220, 1130; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 8.41 (d, J = 8.6 Hz, 2H), 8.22 (d, J = 8.1 Hz, 1H), 7.70-7.77 (m, 4H), 7.42 (t, J = 6.9 Hz, 1H), 7.04 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H); 13C NMR (100 MHz,

DMSO-d6) δ 161.9, 160.9, 159.5, 150.3, 132.9, 130.9, 129.4, 127.3, 124.7, 123.6, 113.5, 113.0, 55.2; LRMS (MALDI) (m/z) (relative intensity): 251 (100) [M+H]+; HRMS calcd + for C15H14N3O [M+H] :252.1137, Found 252.1142.

2-(3,4-dimethoxyphenyl)-4-methylquinazoline (3g) Yield: (57 %); yellow solid; m.p.: 179-181oC; FT-IR (KBr) −1 1 ν/cm 1650, 1156, 1239; H NMR (400 MHz, CDCl3) δ (ppm) 8.27 (dd, J = 8.44, 1.76 Hz, 1H), 8.22 (d, J = 1.52 Hz, 1H), 8.05 (t, J = 6.9 Hz, 2H), 7.84 (t, J = 7.96 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 4.07 (s, 3H), 3.98 (s, 3H), 2.99 (s, 3H); 13C

NMR (100 MHz, CDCl3) δ 168.2, 160.0, 151.5, 150.7, 149.3, 133.6, 131.4, 129.2, 126.6, 125.2, 122.9, 122.2, 111.5, 111.1, 56.2, 56.2, 22.2; LRMS (ESI) (m/z) (relative intensity): + + 281 (100) [M+H] , 220 (40); HRMS calcd for C17H17N2O2 [M+H] : 281.1290, Found 281.1284.

2-(benzo[d][1,3]dioxol-5-yl)quinazolin-4-amine (3h) Yield: (74 %); white solid; m.p.: 193-195oC; FT-IR (KBr) ν/cm−1 FT-IR (KBr) ν/cm−1 3470, 3350, 1641, 1250, 1150; 1 H NMR (400 MHz, DMSO-d6) δ (ppm) 8.21 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.70-7.76 (m, 4H), 7.43 (t, J = 7.1 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.10 (bs, 2H); 13C NMR (100 MHz,

CDCl3) δ 161.9, 159.6, 150.4, 148.9, 147.4, 132.9, 132.8, 127.5, 124.8, 123.5, 122.4,

113.1, 107.9, 107.6,101.3; LRMS (MALDI) (m/z) (relative intensity): 266 (100) [M+H]+, + 243 (30); HRMS calcd for C15H11N3O2 [M+H] : 266.0930 Found 266.0935.

6,7-dimethoxy-2-phenylquinazoline (3i) Yield: (67 %); white solid; m.p.: 176-178oC; FT-IR (KBr) −1 1 ν/cm 1635, 1230, 1140; H NMR (400 MHz, CDCl3) δ (ppm) 9.23 (bs, 1H), 8.55 (d, J = 8.3 Hz, 2H), 7.48-7.55 (m, 3H), 7.38 (m, 1H) 7.11 (s, 1H), 4.09 (s, 3H), 4.04 (s, 3H); 13 + C NMR (100 MHz, CDCl3) δ 160.2, 157.3, 156.5, 150.6, 148.8, 138.6, 266 (100) [M] , + 265 (80); HRMS calcd for C16H14N2O2 [M] : 266.1055, Found 266.1049.

2-(4-nitrophenyl)quinazoline (3j) Yield: (73 %);dark yellow solid; m.p.: 218-220oC; FT-IR (KBr) ν/cm−1 3439, 3400, 1520, 1350; 1H NMR (400 MHz,

CDCl3) δ (ppm) 9.52 (s, 1H), 8.82 (d, J = 8.8 Hz, 2H), 8.37 (d, J = 8.8 Hz, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.96-8.00 (m, 2H), 13 7.71(t, J = 7.5 Hz, 1H),; C NMR (100 MHz, CDCl3) δ 160.9, 159.0, 150.8, 149.4, 144.0, 134.8, 129.6, 129.1, 128.5, 127.4, 124.1, 124.0; LRMS (EI) (m/z) (relative intensity): 251 + + (100) [M] , 205 (40); HRMS calcd for C14H9N3O2 [M] : 251.0695, Found 251.0690.

4-methyl-2-(4-nitrophenyl)quinazoline (3k) Yield: (79 %); red solid; m.p.:174-176oC; FT-IR (KBr) −1 1 ν/cm 3468, 1636, 1520, 1350; H NMR (400 MHz, CDCl3) δ (ppm) 8.81 (d, J = 8.9 Hz, 2H), 8.35 (d, J = 8.9 Hz, 2H), 8.10-8.15 (m, 2H), 7.93 (t, J = 7.6 Hz, 1H), 7.67 (t, J = 7.6 13 Hz, 1H), 3.05 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 168.9, 158.0, 150.3, 149.2, 144.3, 134.2, 129.6, 129.5, 128.1, 125.2, 123.8, 123.4, 22.2; LRMS (MALDI) (m/z) (relative intensity): 265 (100) [M+H]+, 220 (28); HRMS calcd for + C15H11N3O2 [M] : 265.0851, Found 265.0846.

2-(4-nitrophenyl)quinazolin-4-amine (3l) Yield: (73 %); dark yellow solid; m.p.: 220-222oC; FT-IR (KBr) ν/cm−1 FT-IR (KBr) ν/cm−1 3470, 3350, 1641, 1520, 1 1350; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.66 (d, J = 8.6 Hz, 2H), 8.35 (d, J = 8.6 Hz, 2H), 8.28 (d, J = 8.2 Hz, 1H), 8.00 (bs, 2H), 7.81 (bs, 2H), 7.53 (s, 1H); 13C NMR

(100 MHz, CDCl3) δ 162.3, 157.8, 150.1, 148.3, 144.6, 133.3, 128.8, 127.9, 126.0, 123.6, 123.5, 113.4; LRMS (MALDI) (m/z) (relative intensity): 267 (100) [M]+, 221 (45); + HRMS calcd for C14H10N4O2 [M+H] : 267.0882, Found 267.0893.

2-(4-bromophenyl)-4-methylquinazoline (3m) Yield: (76 %); yellow solid; m.p.: 105-107oC; FT-IR (KBr) −1 1 ν/cm 1636, 585; H NMR (400 MHz, CDCl3) δ (ppm) 8.52 (d, J = 8.4 Hz, 2H), 8.05-8.10 (m, 2H), 7.82 (t, J = 7.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H), 3.01 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 168.6, 159.5, 150.6, 137.5, 133.9, 131.9, 130.4, 129.5, 127.3, 125.4, 125.2, 123.3, 22.2; LRMS (ESI) (m/z) (relative + + intensity): 298 (98) [M] , 300(100); HRMS (ESI) calcd for C15H11BrN2 [M] : 298.0106, Found 298.0111. 4-methyl-2-(naphthalen-1-yl)quinazoline (3n) Yield: (77 %); white solid; m.p.: 119-121oC; FT-IR (KBr) −1 1 ν/cm 1645, 1537, 1357; H NMR (400 MHz, CDCl3) δ (ppm) 8.66 (d, J = 8.4 Hz, 1H), 8.15-8.20 (m, 3H), 7.99 (d, J = 8.2 Hz, 1H), 7.92-7.96 (m, 2H), 7.68 (t, J = 7.66 Hz, 1H), 7.63 (t, J = 7.68 Hz, 1H), 7.53-7.56 (m, 2H), 3.09 (s, 3H); 13C NMR (100

MHz, CDCl3) δ 168.6, 162.9, 150.3, 136.8, 134.4, 134.0, 131.5, 130.3, 129.5, 129.4, 128.6, 127.6, 126.9, 126.2, 126.0, 125.5, 125.2, 122.8, 22.2; LRMS (MALDI) (m/z) + + (relative intensity): 271 (100) [M+H] ; HRMS calcd for C19H14N2 [M+H] : 271.1235, Found 271.1241.

(E)-2-phenyl-4-styrylquinazoline (3o) Yield: (73 %); yellow solid; m.p.: 138-140oC; FT-IR (KBr) −1 1 ν/cm 3480, 1545, 1378, 719; H NMR (400 MHz, CDCl3) δ (ppm) 8.76 (d, J = 7.3 Hz, 2H), 8.46 (d, J = 15.4 Hz, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 15.4 Hz, 1H), 7.87 (t, J = 7.7 Hz, 1H), 7.77 (d, J = 7.4 Hz, 2H), 7.53-7.61 (m, 4H), 7.42-7.50 (m, 3H); 13C NMR (100

MHz, CDCl3) δ 162.1, 160.3, 152.2, 139.6, 138.7, 136.3, 133.6, 130.6, 129.8, 129.5, 129.1, 128.8, 128.7, 128.2, 127.0, 124.0, 121.8, 121.1; LRMS (ESI) (m/z) (relative + + intensity): 308 (100) [M] , 307 (80); HRMS calcd for C22H16N2 [M] : 308.1313, Found 308.1317.

(E)-4-(2-(benzo[d][1,3]dioxol-5-yl)vinyl)-2-phenylquinazoline (3p) Yield: (67 %); yellow solid; m.p.:169-171oC; FT-IR (KBr) ν/cm−1 1643, 1230, 1150, 1140; 1H NMR (400 MHz,

CDCl3) δ (ppm) 8.71 (d, J = 6.8 Hz, 2H), 8.37 (d, J = 15.3 Hz, 1H), 8.26 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 7.5 Hz, 1H), 7.78 (d, J = 15.4 Hz, 1H), 7.52-7.61 (m, 4H), 7.29 (s, 1H), 7.23 (d, J = 8.0 Hz, 13 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.02 (s, 2H); C NMR (100 MHz, CDCl3) δ 162.2, 160.3, 152.2, 149.3, 148.6, 139.4, 138.8, 133.6, 130.9, 130.5, 129.5, 128.8, 128.7, 126.9, 124.2, 124.0, 121.8, 119.2, 108.9, 106.8, 101.7; LRMS (EI) (m/z) (relative intensity): 352 (100) + + [M ], 351 (60); HRMS calcd for: C23H16N2O2 [M ]: 352.1212, Found 352.1209.

(E)-4-(4-chlorostyryl)-2-phenylquinazoline (3q) Yield: (76 %); yellow solid; m.p.: 150-152oC; FT-IR −1 1 (KBr) ν/cm 1635, 715; H NMR (400 MHz, CDCl3) δ (ppm) 8.71 (d, J = 8.2 Hz, 2H), 8.37 (d, J = 15.4 Hz, 1H), 8.24 (d, J = 8.3 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.85- 7.92 (m, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.53-7.61 (m, 4H), 13 7.43 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl3)) δ 161.7, 160.3, 152.3, 138.7, 138.1, 135.6, 134.8, 133.7, 130.7, 129.6, 129.4, 129.3, 128.8, 128.7, 127.1, 123.9, 121.8, 121.6; LRMS (EI) (m/z) (relative intensity): 342 (100) [M+], + 341 (75); HRMS calcd for: C22H15ClN2 (M ): 342.0924, Found 342.0922.

5-hydroxyisoindolo[2,1-a]quinazolin-11(5H)-one (2a) Yield: (76 %); white solid; m.p.: 151-152oC; FT-IR (KBr) ν/cm−1 1 3379; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.48 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.78-7.88 (m, 2H), 7.53 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, CDCl3)) δ 165.1, 146.4, 134.2, 133.3, 132.8, 131.4, 131.1, 128.7, 127.9, 125.4, 123.5, 123.4, 121.8, 114.7, 76.9; LRMS (ESI) (m/z) (relative intensity): 251 + - (100) [M+H ]; HRMS (ESI) calcd for: C15H9N2O2 (M-H ): 249.0664, Found 249.0665.

5-hydroxy-5-methylisoindolo[2,1-a]quinazolin-11(5H)-one (2b) Yield: (76 %); white solid; m.p.: 180-182oC; FT-IR (KBr) ν/cm−1 1 3467; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.50 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 7.2 Hz, 1H), 7.78-7.87 (m, 2H), 7.65 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 6.48 (s, 1H), 1.59 (s, 3H); 13C NMR (100 MHz,

CDCl3)) δ 165.1, 144.4, 134.2, 133.3, 132.7, 131.1, 130.5, 128.2, 128.0, 127.1, 125.4, 123.4, 121.8, 114.5, 81.3, 33.2; LRMS (ESI) (m/z) (relative intensity): 251 (100) [M+H+], + 247 (39); HRMS (ESI) calcd for: C16H13N2O2 (M+H ): 265.0977, Found 265.0977.

5-iminoisoindolo[2,1-a]quinazolin-11(5H)-one (2c) Yield: (76 %); white solid; m.p.: 178-180oC; FT-IR (KBr) ν/cm−1 1 3489; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.76 (bs, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.77 (t, J = 7.5 Hz, 1H), 7.64-7.66 (m, 1H), 7.51-7.57 (m, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.25-7.29 (m, 1H), 6.72 (d, J = 7.3 Hz, 1H), 6.17 (d, J = 7.2 Hz, 13 1H); C NMR (100 MHz, CDCl3)) δ 167.8, 141.8, 139.6, 139.2, 133.8, 133.3, 131.4, 128.2, 128.1, 126.4, 126.1, 116.7, 108.3, 93.4; LRMS (ESI) (m/z) (relative intensity): 248 + + (50) [M+H ], 231(75); HRMS calcd for: C15H9N2O (M+H ): 248.0824, Found 248.0830.

5-hydroxy-5-methyl-[1,3]dioxolo[4',5':5,6]isoindolo[2,1-a]quinazolin-12(5H)-one (2r) Yield: (76 %); grey solid; m.p.: 187-189oC; FT-IR (KBr) −1 1 ν/cm 3334, 3459; H NMR (400 MHz, DMSO-d6) δ (ppm)

8.41 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.36-7.40 (m, 3H), 7.26 (t, J = 7.4 Hz, 13 1H), 6.41 (s, 1H), 6.27 (s, 2H), 1.57 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 164.6, 152.7, 151.5, 144.1, 130.6, 129.1, 128.2, 127.8, 127.0, 126.0, 125.0, 114.1, 103.1, 101.7, 81.3, 33.2; LRMS (ESI) (m/z) (relative intensity): 309 (100) [M+H+], 291 (82); HRMS + calcd for: C17H13N2O4 (M+H ): 309.0875, Found 309.0871.

9-bromo-5-hydroxy-5-methylisoindolo[2,1-a]quinazolin-11(5H)-one (2m) Yield: (76 %); white solid; m.p.: 166-168oC; FT-IR (KBr) −1 1 ν/cm 3379, 717; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.46 (d, J = 8.2 Hz, 1H), 7.10 (s, 1H), 8.01-8.03 (m, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.65 (d, J = 7.4 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.51 (bs, 1H), 1.59 (s, 3H); 13 C NMR (100 MHz, DMSO-d6 ) δ 163.7, 143.8, 136.9, 133.2, 132.3, 130.3, 128.3, 127.9, 127.2, 126.1, 125.9, 125.7, 123.7, 114.6, 81.5, 33.2; LRMS (ESI) (m/z) (relative + + intensity): 343 (100) [M+H ], 345 (95); HRMS calcd for: C16H12N2O2 (M+H ): 343.0082, Found 343.0078.

3-bromo-5-hydroxy-5-methylisoindolo[2,1-a]quinazolin-11(5H)-one (2s) Yield: (60 %); white solid; m.p.: 174-176oC; FT-IR (KBr) ν/cm−1 3570, 1 3348; H NMR (400 MHz, DMSO-d6) δ (ppm) 8.42 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 7.4 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.84 (t, J = 7.4 Hz, 1H), 7.75-7.80 (m, 2H), 7.60 (dd, J = 8.8 13 Hz, 1.8 Hz, 1H), 1.60 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 165.0, 144.2, 134.4, 133.2, 132.9, 131.1, 131.0, 130.4, 129.8, 129.6, 123.5, 121.9, 117.3, 116.8, 81.2, 33.1; LRMS (ESI) (m/z) (relative intensity): 342 (100) [M+], 344 (95); HRMS calcd for: + C16H11N2O2 (M ): 342.0004, Found 342.0006

Ι.D.6. References 1. (a) Tsvelikhovsky, D.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 14228. (b) Priebbenow, D. L.; Becker, P.; Bolm, C. Org. Lett. 2013, 15, 6155. (c) Monir, K.; Bagdi, A. K.; Mishra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2014, 356, 1105. (d) Wang, Y.; Wang, R.; Jiang, Y.; Tan, C.; Fu, H. Adv. Synth. Catal. 2013, 355, 2928. (e) Glorius, F.; Grohmann, C.; Wang, H. Org. Lett. 2013, 15, 3014. (f) Liu, T.; Zhu, C.;

Yang H.; Fu, H. Adv. Synth. Catal. 2012, 354, 1579. (g) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem. Int. Ed. 2012, 51, 5170. (h) Li, L.; Wang, M.; Zhang, X.; Jiang Y.; Ma, D. Org. Lett. 2009, 11, 1309. (i) Yang, D.; Wang, Y.; Yang, H.; Liu, T.; Fu, H. Adv. Synth. Catal. 2012, 354, 477. 2. (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (b) Michael, J. P. Nat. Prod. Rep. 2007, 24, 223. (c) Cho, S.-H.; Cho, W.-J.; Khadka, D. B.; Le, T. N.; Van, H. T. M.; Yang, S. H.; Kwon, Y.; Lee, E.-S.; Lee, K.-T. Bioorg. Med. Chem. 2011, 19, 4399. (d) Russu, W. A.; Shallal, H. M. Eur. J. Med. Chem. 2011, 46, 2043.

3. Jedhe, R.; Paike, V.; Sun, C.-M. Green Process Synth. 2013. 2, 251. 4. (a) Liu, X. W.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Angew. Chem., Int. Ed. 2009, 48, 348. (b) Li, J. R.; Chen, X.; Shi, D. X.; Ma, S. L.; Li, Q.; Zhang, Q.; Tang, J. H. Org. Lett. 2009, 11, 1193. (c) Hill, M. D.; Movassaghi, M. J. Am. Chem. Soc. 2006, 128, 14254. (d) Baskakova, A.; Beifuss, U.; Conrad, J.; Malakar, C. C. Chem, Eur. J. 2012, 18, 8882. (e) Li, J.-X.; Shen, Q.; Zhao, D.; Zhou, Y.-R. Org. Biomol. Chem. 2013, 11, 5908. (g) Wang, Z.; Yan, Y. Chem. Commun. 2011, 47, 9513. (h) Alonso, R.; Caballero, A.; Campos, P. J.; Rodriguez, M. A.; Sampedro, D. Tetrahedron 2010, 66, 4469. 5. (a) Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew. Chem. Int. Ed. 2012, 51, 8077. (b) Duan, X.-Y.; Fang, R.; Han, B.; Han, R.-F.; Wang, C.; Yang, X.-L.; Yu, W. Chem. Comm. 2011, 47, 7818. (e) Hua, R.; Ju, J.; Su, J. Tetrahedron 2012, 68, 9364. (f) Li, Y.; Liu, Q.; Lv, Y.; Pu, W.; Sun, K.; Xiong, T.; Zhang, H.; Zhang, Q. Chem. Commun. 2013, 49, 6439. (g) Fujii, N.; Ohno, H.; Ohta, Y.; Oishi, S.; Tokimizu, Y. Org. Lett. 2010, 12, 3963. (h) Li, J.-X.; Shen, Q.; Zhao, D.; Zhou, Y.-R. Org. Biomol. Chem. 2013, 11, 5908. (i) Chen, Y-C.; Yang, D.-Y. Tetrahedron 2013, 69, 10438. (j) Bergman, R. G.; Ellman, J. A.; Lewis, J. C.; Wu, J. Y. Angew. Chem. Int. Ed. 2006, 45, 1589. (k) Fang, J.; Zhou, J.; Fang, Z. RSC Adv. 2013, 3, 334. (l) Hill, M. D.; Movassaghi, M. Chem. Eur. J. 2008, 14, 6836; 6. (a) Wan, C.; Wang, Z.; Yu, C.; Zhang, J.; Zhu, D. Org. Lett. 2010, 12, 2841. (b) Wan, C.; Wang, S.; Wang, Z.; Yu, C.; Zhang, J. Chem. Comm. 2010, 46, 5244. 7. Han, B.; Yang, X.-L.; Wang, C.; Bai, Y.-W.; Pan, T.-C.; Chen, X.; Yu, W. J. Org. Chem. 2012, 77, 1136. 8. Yan, Y.; Zhang, Y.; Feng, C.; Zha, Z.; Wang, Z. Angew. Chem. Int. Ed. 2012, 51, 8077.

9. Kumar, K. S.; Kumar, P. M.; Kumar, K. A.; Sreenivasulu, M.; Jafar, A. A.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Kapavarapu, R.; Shivakumar, K.; Priya, K. K.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2011, 47, 5010. 10. Martı´nez-Viturro, C. M.; Domı´nguez, D. Tetrahedron Lett. 2007, 48, 1023. 11. (a) Gawande, S. D.; Kavala, V.; Zanwar, M. R.; Kuo, C.-W.; Huang, H.-N.; He, C.-H.; Yao, C.-F. Adv. Synth. Catal. 2013, 355, 3022. (b) Gawande, S. D.; Raihan, M. J.; Zanwar, M. R.; Kavala, V.; Janreddy, D.; Kuo, C.-W.; Chen, M.-L.; Kuo, T.-S.; Yao, C.-F. Tetrahedron 2013, 69, 1841. (c) Kavala, V.; Wang, C.-C.; Barange, D. K.; Kuo, C.-W.; Lei, P.-M.; Yao, C.-F. J. Org. Chem. 2012, 77, 5022. (d) Barange, D. K.; Tu, Y.-C.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Adv. Synth. Catal. 2011, 353, 41. 12. (a) Liu, T.; Zhu, C.; Yang, H.; Fu, H. Adv. Synth. Catal. 2012, 354, 1579. b) Sunke, R.; Adepu, R.; Kapavarapu, R.; Chintala, S.; Meda, C. L. T.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2013, 49, 190.

Part-II, Section-A Overview on Iodocyclization by activation of alkynes using molecular iodine

II.A.1. Introduction The intramolecular iodocyclization of carbanion and heteroatoms with alkynes is widely popular due to inexpensive, non-toxic and readily availability of molecular iodine.1 Contrary, transition metal catalyzed cyclization are often expensive, needs dry reaction conditions, heating and also lack in selectivity. Molecular iodine mediated reaction are conducted under mild reaction conditions, have high regioselectivity and afford excellent yields of the desired products are the key features of these protocols. Usually, the iodo cyclization reaction in alkyne proceeds through initial activativtion of the -bond via iodonium ion intermediate, this was cleaved by a nucleophilic attack by hetero atom or carbanion either endo or exo way depending upon the stereochemistry of substrates and steric factor during nucleophilic attack on iodonium ion intermediate. Further, during iodocyclization, the iodine functionality was added to one of the side of bond, which allows to do further functionalization via various C-C and C-Hetero atom coupling reactions, which add further diversity in molecular development. Large number of biologically active structural motifs such as pyrroles,2 indoles,3 benzo[b]furans,4 furans,5 pyrazoles6 were synthesized by the iodocyclization protocols. In this chapter, we discuss the important reports over the intramolecular iodocyclization of alkyne using molecular iodine via C-N, C-O, C-S and C-C bond formation.

II.A.2. Cyclization via C-N bond formation Synthesis of N-heterocycles is very important area of research as various natural products, alkaloids, pharmaceutical drugs possess N-heteroatom as key unit. Larock and co-workers have reported the synthesis of substituted 3-iodoindole via Sonagashira coupling of terminal alkyne with N,N-dialkyl-o-iodoanilines and then iodocyclization (Scheme II.A.2.1).7 The stepwise process was first underwent Sonagashira coupling in Pd and copper catalysts, then the resultant compounds was further treated under iodocyclization condition to yield desired 3-iodoindole in excellent yield.

Scheme II.A.2.1 In similar fashion, Flynn and co-workers have demonstrated the synthesis of 1, 2, 3 trisubstituted indole and highly substituted quinoline derivatives by iodocyclization (Scheme II.A.2.2).8 The highly selective 5-exo and 6-endo-digonal iodocyclization leads to indoles and quinolone derivatives via solvent switching from ethanol to acetonitrile respectively.

Scheme II.A.2.2 Gong and co-workers have described the enantioselective synthesis of Azatricyclic hexahydrochromeno[4,3-b]pyrrole (Scheme II.A.2.3).9 The highly stereospecific iodocyclization was conducted in 3 equivalents of molecular iodine and potassium carbonate as a base in acetonitrile. The fused azatricyclic hexahydrochromeno[4,3- b]pyrrole product having three adjacent chiral carbon atoms was obtained in excellent yield with very high enantioselectivity via iodocyclization.

Scheme II.A.2.3 Prof. Yamamoto and co-workers have presented the synthesis of highly substituted isoquinoline by the intramolecular iodocyclization reaction of 2-alkynyl benzyl azide (Scheme II.A.2.4).10 First, the triple bond was activated via formation of iodinium ion and + then nucleophilic cyclization followed by elimination of N2 and H to form isoquinoline derivative. This new method has wide scope and it is also applied to the short synthesis of norchelerythrine.

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Scheme II.A.2.4 In another report, Zora and co-workers have developed, the step wise synthesis of highly substituted pyrrazoles via iodocyclization (Scheme II.A.2.5).11 The step wise synthesis was achieved by stepwise reaction of propargyl ketone or aldehyde with hydrazines to form R,β-alkynic hydrazones, which on further iodocyclization formed corresponding pyrrazole derivatives in moderate to excellent yields. The cyclization tolerated the presence of various functional groups.

Scheme II.A.2.5

II.A.3. Cyclization via C-O bond formation Iodine mediated triple bond activation, followed by C-O bond formation is versatile method. The heterocyclic structures such as benzo[b]furans, furans can easily be synthesized by iodocyclization. Larock and group have developed the regioselective synthesis of iodo substituted isochromenes, dihydroisobenzofurans and pyranopyridines under mild conditions by the molecular iodine mediated iodocyclization of 2-(1- alkynyl)benzylic alcohols and 2-(1-alkynyl)-3-(hydroxymethyl)pyridines (Scheme 12 II.A.3.1). The reaction was carried out in molecular iodine and mild base NaHCO3 in acetonitrile at room temperature. The compound selectivity was depends upon the substitution on starting material. The presence of tertiary alcohol group in the starting material leads to 5-exo-dig cyclization to form dihydroisobenzofuran derivative. But in the case of primary or secondary alcoholic group in substrates, the 6-endo-dig cyclization leads to formation of isochromene or pyranopyridines.

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Scheme II.A.3.1 In another reports Peng et al have reported the synthesis of 4-halophosphaisocoumarins via halocyclization of 2-(1-alkynyl)phenylphosphonates (Scheme II.A.3.2).13 The iodo phosphaisocoumarins were synthesized by the reaction of 2-(1- alkynyl)phenylphosphonic acid diesters and molecular iodine in chloroform at room temperature. The Iodo, bromo and chlorophosphaisocoumarins were obtained in good to excellent yield under the mild reaction conditions.

Scheme II.A.3.2 Recently, Wang et al. have developed the one-pot process for the synthesis of 3- trifluoromethylbenzofurans via tandem iodocyclization and trifluoromethylation of 2- alkynylanisole derivatives (Scheme II.A.3.3).14 The reaction was carried out in molecular iodine, CF3SiMe3, CuI and KF to synthesize variety of 3-trifluoromethylbenzofuran derivatives in moderate to good yields.

Scheme II.A.3.3

II.A.4. Cyclization via C-S bond formation Iodine-Induced cascade reaction for the rapid construction of Benzothiophene derivatives (Scheme II.A.4.1).15 The iodine mediated 5-exo-dig cyclization of propynols with 2- thioxyphenyl substitutents, first underwent cyclization then tandem rearrangement and

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elimination to afford acyl or 2-(1-iodoalkeny)-benzo[b]thiophene derivatives in good yields

Scheme II.A.4.1 In another report, Flynn and co-workers accomplished the novel tubulin binding agents by stepwise process (Scheme II.A.4.2).16 In novel approach the 2,3-disubstituted Benzo[b]thiophenes was synthesized in step wise process. First, the 2-Bromoiodobenzene was coupled with benzylmercaptan and zinc acetylides to give benzyl o-ethynylphenyl sulfides. Further, the benzyl o-ethynylphenyl sulfide on iodocyclization leads to 3- iodobenzo[b]thiophenes via C-S bond formation. The iodo thiophene was functionalized to yield novel tubulin binding agents.

Scheme II.A.4.2

Gabriele and co-workers have described the synthesis of 3-Iodothiophenes by iodocyclization approach (Scheme II.A.4.3).17 The molecular iodine mediated cyclization of alkynylthiol derivatives were carried out using sodium bicarbonate as a base at 25oC in acetonitrile. The method was successfully applied to synthesize various 3-Iodothiophenes in moderate to excellent yields.

Scheme II.A.4.3

II.A.5. Cyclization via C-C bond formation Synthesis of heterocycles by molecular iodine mediated reaction through intramolecular C-C bond formation is very efficient method. The multicyclic ring formation by iodine mediated activation of triple bond and then the nucleophilic attack by double bond adjacent to hetero atom lead to cyclization to form corresponding compounds. The metal

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free C-C bond formation reaction in iodine mediated protocol was reported by Yao and co-workers for the synthesis of azanthraquinone derivatives via 6-endo-dig iodocyclization (Scheme II.A.5.1).18 The reaction proceeds first by iodocyclization and then oxidative aromatization leads to formation of azanthraquinone.

Scheme II.A.5.1 In another report, Yu et al. have reported the Electrophilic ipso-Iodocyclization of N-(4- Methylphenyl)propiolamides via C-C bond formation (Scheme II.A.5.2).19 The synthesis of 8-methyleneazaspiro[4,5]trienes was developed by the reaction of 4-(4-methylaryl)-1- alkynes with Iodine or Iodine monochloride. Further, the obtained iodo substituted 8- methylene-1-azaspiro[4,5]triene compound was utilized for the synthesis of bioactive compounds.

Scheme II.A.5.2 Electrophilic iodine mediated cyclization via C-C bond formation reaction to synthesized 3,4-Disubstituted 2H-Benzopyrans was carried out by Larock and his co-workers (Scheme II.A.5.3).20 Electrophile such as Iodine, ICl and PhseBr were employed to synthesize I, Se substituted 3,4-Disubstituted 2H-Benzopyran derivatives. The method has good scope and the desired Benzopyrans was obtained in good yields.

Scheme II.A.5.3 Iodonium-induced carbocyclizations of alkenes with alkyne substitution at γ position (Scheme II.A.5.4).21 The iodine mediate cyclization via iodonium ion to afford products such as highly substituted benzenes, 1,4-cyclohexadienes, and 4-fluorocyclohexenes. The

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iodine mediated carbocyclization was further applied to the total synthesis of cybrodol, a sesquiterpenoid.

Scheme II.A.5.4

II.A.6. Iodine mediated recent protocols from our group Numerous synthetic protocols involving molecular iodine have been reported by our group. An efficient molecular iodine catalyzed method for the synthesis of quinoxaline derivatives was established by the reaction of 1,2-diketones and 1,2-diamines (Scheme II.A.6.1).22 The reaction was carried out in 10 mol% molecular iodine at room temperature in acetonitrile. The methodology was tolerated various functional groups and substrates and formed the corresponding quinoxaline derivatives in good yields.

Scheme II.A.6.1 Further, The synthesis of 1,4-dihydroquinoline derivatives were achieved by the molecular iodine catalyzed Hantzsch reaction (Scheme II.A.6.2).23 The efficient method was developed to prepare a variety of 4-substituted 1,4-dihydropyridines from the reaction of different aryl or alkyl aldehydes, 1,3-cyclohexanedione, ethyl acetoacetate and ammonium acetate in the presence of catalytic amount of iodine at room temperature.

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Scheme II.A.6.2 In another report, the synthesis of trans-endo-decahydroquinolin-4-one was achieved by domino reaction of aldehydes, anilines and 1-acetylcyclohexene in the presence of iodine in a one-pot reaction at room temperature (Scheme II.A.6.3).24 The one-pot process proceeds in diethyl ether solvent at room temperature with excellent yields and diastreoselectivity.

Scheme II.A.6.3 The variety of functionalized flavanone derivatives and tetrahydropyrimidine derivatives were synthesized by the manich reaction of substituted benzaldehyes, 2-hydroxy acetophenone derivatives and various aryl amines in catalytic molecular iodine (Scheme II.A.6.4).25 The reaction conditions are mild and easy work up procedure and wide substrates scope are the important features of this methodology.

Scheme II.A.6.4

An easy route for the synthesis of variety of structurally diverse indolylquinolines, indolylacridines, and indolylcyclopenta[b]quinoline derivatives via the stepwise Michel addition and then reductive cyclization reaction between acyclic, cyclic Baylis-Hillman adducts and indole derivatives (Scheme II.A.6.5).26 An unusual in situ [1,3]-sigmatropic rearrangement of the indole nucleus was observed during the reductive cyclization of α- regioselective B-H adducts containing indoles to produce indolylacridines and indolylcyclopenta[b]quinoline derivatives.

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Scheme II.A.6.4 Several iodine mediated reactions to synthesized biologically active core structures have been studied by our group.27

II.A.7. References 1. a) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460. b) Chen, Y.; Huang, C.; Liu, X.; Perl, E.; Chen, Z.; Namgung, J.; Subramaniam, G.; Zhang, G.; Hersh, W. H. J. Org. Chem. 2014, 79, 3452. c) Gao, Q.; Wu, X.; Liu, S.; Wu, A. Org. Lett. 2014, 16, 1732. d) Yu, W.; Huang, G.; Zhang, Y.; Liu, H.; Dong, L.; Yu, X.; Li, Y.; Chang, J. J. Org. Chem. 2013, 78, 10337. e) Batchu, H.; Bhattacharyya, S.; Batra, S. Org. Lett. 2012, 14, 6330. f) Zheng, G.; Ma, X.; Liu, B.; Dong, Y.; Wang, M. Adv. Synth. Catal. 2014, 356, 743. g) Mishra, N. M.; Vachhani, D. D.; Modha, S. G.; Van der Eycken, E. V. Eur. J. Org. Chem. 2013, 693. h) Lee, W.-C.; Shen, H.-C.; Hu, W.-P.; Lo, W.-S.; Murali, C.; Vandavasi, J. K.; Wang, J.-J. Adv. Synth. Catal. 2012, 354, 2218. j) Wang, T.; Zhang, H.; Han, F.; Long, L.; Lin, Z.; Xia, H. Angew. Chem. Int. Ed. 2013, 52, 9251. k) He, Y.; Zhang, X.-Y.; Cui, L.-Y.; Fan, X.-S. Chem. Asian J. 2013, 8, 717. l) Mahapatra, T.; Jana, N.; Nanda, S. Adv. Synth. Catal. 2011, 353, 2152. 2. a) Hessian, K. O.; Flynn B. L. Org. Lett. 2006, 8, 243; b) Knight, D.W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc. Perkin Trans. I 2001, 2874; c) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc. Perkin Trans. I 2002, 622. 3. a) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037. b) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539. 4. a) Banwell, M. G.; Flynn, B. L.; Wills, A. C.; Hamel, E. Aust. J. Chem. 1999, 52, 767; b) Arcadi, A.; Cacchi; S.; Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432. 5. a) El-Tach, G. M. M.; Evans, A. B.; Knight, D. W.; Jones, S. Tetrahedron Lett. 2001, 42, 5945. b) Sniady, A. A.; Wheeler, K. A.; Dembismski, R. Org. Lett. 2005, 7, 1769.

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6. Zora, M.; Kivrak, A.; Yazici, C. J. Org. Chem. 2011, 76, 6726. 7. Yue, D.-W.; Larock, R. C. Org. Lett. 2004, 6, 1037. 8. Hessian, K. O.; Flynn, B. L. Org. Lett. 2006, 8, 243. 9. Zhou, Y.; Zhu, Y.; Yan, S.;Gong, Y. Angew. Chem. Int. Ed. 2013, 52, 10265. 10. a) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Yamamoto, Y. Angew. chem. Int. Ed., 2007, 46, 4764; b) Fischer, D.; Tomeba, H.; Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc. 2008, 130, 15720. 11. Zora, M.; Kivrak, A.; Yazici, C. J. Org. Chem. 2011, 76, 6726. 12. Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.; Larock, R. C. J. Org. Chem. 2010, 75, 897. 13. Peng, A.-Y.; Ding, Y.-X. Tetrahedron 2005, 61, 10303. 14. Wang, W.-Y.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. Tetrahedron Lett. 2014, 55, 1501. 15. Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5, 4377. 16. Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651. 17. Gabriele, B.; Mancuso, R.; Salerno, G.; Larock, R. C. J. Org. Chem. 2012, 77, 7640. 18. Fei, N.; Hou, Q.; Wang, S.; Wang, H.; Yao, Z.-J. Org. Biomol. Chem. 2010, 8, 4096. 19. Yu, Q.-F.; Zhang, Y.-H.; Yin, Q.; Tang, B.-X.; Tang, R.-Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008, 73, 3658. 20. Worlikar, S. A.; Kesharwani, T.; Yao, T.; Larock, R. C. J. Org. Chem. 2007, 72, 1347. 21. Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem. Int. Ed. 2010, 49, 4661. 22. More, S. V.; Sastry, M. N. V.; Wang, C.-C.; Yao, C.-F. Tetrahedron Lett. 2005, 46, 6345. 23. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C.-F. Tetrahedron Lett. 2005, 46, 5771. 24. Lin, C.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. J. Org. Chem. 2006, 71, 6588. 25. Kavala, V.; Lin, C.; Kuo, C.-W.; Fang, H.; Yao, C.-F. Tetrahedron 2012, 68, 1321. 26. Ramesh, C.; Lei, P.-M.; Janreddy, D.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. J. Org. Chem. 2012, 77, 8451. 27. a) Chu, C.-M.; Gao, S.; Sastry, M. N. V.; Yao, C.-F. Tetrahedron Lett. 2005, 46, 4971. b) Gao, S.; Tseng, C.; Tsai, C. H.; Yao, C.-F. Tetrahedron 2008, 64, 1955. c) Ko, S.; Lin, C.; Tu, Z.; Wang, Y.-F.; Wang, C.-C.; Yao, C.-F. Tetrahedron Lett. 2006, 47, 487.

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Part-II, Section-B

Molecular Iodine Mediated Cascade Reaction of 2- Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives II.B.1. Introduction Medium-ring annulated indole derivatives are an important class of pharmaceutically active compounds, which exhibit a wide variety of biological activities.1 Particularly, seven membered ring (azulene) annulated tetracyclic indole occurs in numerous biologically active natural products and pharmaceutical intermediates, which displays potent anticancer (Figure II.B.1.1, A and B), anti-histaminic, anti-microbial (C), and anti-neoplastic (D) activities.1,2 In general, construction of medium size rings are unambiguously considered to be the cumbersome task due to a combination of the trans annular interactions and unfavourable entropic and enthalpic factors.3 However, there are some reports described the synthesis of seven membered ring (azulene) annulated indole derivatives in the literature.4 Most of the reported methodologies for the construction of tetracyclic indole derivatives are associated with the use of expensive metal catalysts like gold, palladium and very few of them are non-metallic protocols which require higher temperatures or having less substrate scope.5 Hence, developing an efficient and non- metallic protocol for the synthesis of azulene annulated indole tetracycle is highly desirable.

Figure II.B.1.1 Biologically active indolozulene tetracyclic derivatives

II.B.2. Review of literature Chernyakn et al. have reported Pd-catalyzed cascade carbopalladation-annulation to synthesize tetracyclic indoloazulene and indeno[1,2-b]indol-10(5H)-one via switching

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bases.6 The chemo selectivity of compound was totally depends upon the base used in the reaction. This palladium catalyzed carbopalladation annulation reaction have wide scope as electron withdrawing and donating both alkynes forms their corresponding compounds in moderate to good yields.

Scheme II.B.2.1 In another report, an enantioselective synthesis of tetracyclic indoloazulene was done by Enders and co-workers via sequential combination of quinolinium thioamide as a organo 7 catalyst and [Au(PPh3)]NTf2 as a gold catalyst. The reaction went first through Friedel– Crafts type reaction which is assisted by organo catalyst by hydrogen binding to form enantio-selective 3-substituted indole then further then 7 endo-dig cyclization to afford corresponding tetracyclic compound in good yield and excellent enantio-selectivity.

Scheme II.B.2.2 Recently, Xu et al. one-pot, Michael addition and intramolecular cyclization cascade reaction by gold catalyst and trifluoroacetic acid as a cocatalyst.8 The microwave assisted reaction in aqueous medium is operationally simple and afforded the tetracyclic indoloazulene derivatives in moderate to excellent yields.

Scheme II.B.2.3

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II.B.3 Results and discussion The electrophilic iodine-triggered cyclization of ortho substituted arylalkynes is one of the prominent methods for the synthesis of iodine containing fused heterocyclic derivatives.9 A wide variety of fused heterocycles including 5-iodopyrrolo[1,2- a]quinolines, fused benzimidazoles, iodoisoquinoline-fused benzimidazoles, iodofuro[2,3-b]chromones, iodo-indoloazepinones, 2-iodo-spiro[indene-1,10- isobenzofuran]-30-ones, dihydrocyclopenta[b]indole, furo[2,3-b]quinoline, iodopyrano[4,3-b]quinolines and pyrralopyridines ...... etc. were constructed using iodocyclization strategy.10

Scheme II.B.3.1 Plausible pathway for the formation of products On the other hand, 2-alkynylbenzaldehyde is a handy and an interesting structural motif for the generation of functionalized polycyclic compounds and is also very good electrophilic species for iodocyclization.11 Our group have been interested in exploring the iodine mediated transformations for long time.12 In this context, we found that the reaction of aldehyde with various indoles in the presence catalytic amount of iodine produced corresponding bisindole in high yields. On the other hand, recently, Verma and his co-workers have reported the synthesis of indolo[1,2-a]quinolines via (6-endo-dig) iodocyclization using molecular iodine.10d Moreover, recently, Enders and co-workers observed the formation of seven membered (7-endo-dig) fused tetracyclic azulene derivatives using gold catalyst.7 Based on these two observations, we envisioned that the reaction of 2-(phenylethynyl)benzaldehyde and indole in the presence of iodine could initially produce corresponding bisindole which further can undergoes iodocyclization to produce either indole fused azulene compound 3a or benzofusedcarbazole derivative 4a (Scheme 1).

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To investigate our assumption, we choose 2-(phenylethynyl)benzaldehyde and indole as model substrates. In our initial reaction, we treated 2-(phenylethynyl)benzaldehdye (1 equiv) and indole (2 equiv) in the presence of 2 equiv of iodine (I2) in dichloromethane at 0oC to room temperature (Table II.B.3.1, entry 1). Under these conditions, the reaction produced bisindole derivative (i) as a sole product. However, when 2 equiv of sodium bicarbonate was used as base (entry 2), two products were formed. Among the two products, the major product was bisindole and the 1H NMR, 13C NMR, LRMS, HRMS, single crystal X-ray diffraction revealed that the minor product was indole fused azulene compound 3a (Figure II.B.3.1). Interestingly, indole fused azulene derivatives exhibit anti-cancer and anti-neoplastic properties.2 In fact, the synthesis of few indole fused tetracyclic azulene derivatives have reported in the literature using various metal catalysts.4 However, to our knowledge, there is no efficient, non-metallic protocol is available for the construction of indole fused azulene tetracyclic derivatives. This fact prompted us to investigate iodocyclization reaction in more details.

Figure II.B.3.1 ORTEP Diagram of Single X-ray Diffraction Structure of 3a.15

To determine the best conditions for the formation of indole fused azulene (3a), we screened various reaction conditions. In this regard, we first evaluate the efficiency of iodine reagent by the reaction of 2-(phenylethynyl)benzaldehdye (1 equiv), indole (2 equiv) and sodium bicarbonate (2 equiv) in dichloromethane at 0oC. The reaction results indicate that the use of molecular iodine below 3 equiv produces desired indole fused azulene 3a along with bisindole as a minor product. However, the reaction with 3.2 equiv iodine and 2 equiv NaHCO3 resulted in 66% of compound 3a as a single product (entry 4). Next, we screened the reaction with different solvents such as acetonitrile, 1,4-dioxane,

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Table II.B.3.1 Optimization of reaction condition

a Reactions were performed on 0.25 mmol scale. b Yields refer to isolated and purified compound. Parentheses correspond to the NMR yield using CH2Br2 as an internal standard.

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THF and diethyl ether. The reaction worked in most of the solvents but not produce high yields, however, chloroform produced the best yield of the desired product (entry 9).

After solvent screening, we screened different bases such as K2CO3, Cs2CO3 and t-BuOK. The desired product was obtained in poor yields (entries 11, 12 and 14). However, the reactions furnished good yields of the expected product, when the mild bases such as

Na2CO3 and K3PO4 were used in the reaction (entries 10 and 13). Moreover, we screened the reaction in the presence of organic bases. When the reaction was carried out in the presence of strong organic bases such as DIPEA (N,N-Diisopropylethylamine), DBU (1,8-Diazabicycloundec-7-ene) and weak base such as DABCO (1,4- diazabicyclo[2.2.2]octane), the desired product obtained in moderate yields (entries 16, 17 and 18). To our delight, in the presence of TEA (Triethylamine) the reaction gave the best result with 84% isolated yield (100% NMR yield) of the desired product in 9 hours (entry 15). Further, we also screened different iodine sources for this reaction. NIS (N- Iodosuccinimide) and ICl (Iodine monochloride) gave the desired product in poor yields (entries 19 and 20). Molecular iodine was found to be the best choice for this reaction. The reaction was also tested on varied quantities of Iodine with TEA as a base (entries 21-23). However, in the presence of iodine less than 3.2 equiv, the reactions were incomplete and resulted in poor yield of the desired product. To compare the stepwise and one pot reactions, the intermediate bisindole (i) was prepared by the reaction of 1 equiv of aldehyde (1a) and 2 equiv of indole (2a) in the presence of catalytic amount of iodine. Then, bisindole was treated with 2.2 equiv of iodine and 2 equiv of triethylamine. The reaction resulted in 100% NMR yield and 88% isolated yield of the desired product in 8 hours. The stepwise and one pot reaction produced almost similar results. Hence, the scope of reaction was examined with one pot reaction conditions. After the optimization of reaction conditions, the scope and limitations of this one-pot tandem iodocyclization of the indole fused tetracyclic azulene was further investigated by using various 2-(phenyethynyl)benzaldehyde and substituted indole derivatives. The reaction of 1a with unsubstituted indole under the optimized reaction conditions, gave the corresponding product 3a in excellent yield (Table II.B.3.2, entry 1). However, moderate electron withdrawing groups such as chloro and bromo on indoles produces corresponding compounds 3b and 3c in good yields in shorter reaction time (entries 2 and 3). Indoles with moderate electron donating groups (methyl and ethyl) also provided the desired product 3d and 3e in good yields with longer reaction time (entries 4 and 5). On

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the other hand, the reaction of 1a with indole bearing strong electron donating group such as methoxy gave the desired product 3f in moderate yield (entry 6). It is worth noting that reactions of indole possessing electron donating groups took longer reaction time compared to indoles with electron withdrawing groups. Furthermore, under the standard reaction conditions, the indole derivatives possessing strong electron withdrawing groups like nitro, cyano furnishes only trace of intermediate bisindole derivatives. However, when the reactions were carried out at 60oC, the reactions produced corresponding tetracyclic derivatives 3g and 3h in good yields. The need of higher temperature is may be due to the less nucleophilic nature of the indoles. Next, we investigated the tandem iodocyclization of various substituted 2- (phenethynyl)benzaldehydes and substituted indoles. As depicted in Table II.B.3.3, the reactions of both electron donating (OMe) and electron withdrawing (NO2) substitutions on 2-(phenylethynyl)benzaldehyde with indole delivered the desired products 3i and 3j in good yields (entries 1 and 2). However, nitro aldehyde forms corresponding compound faster than methoxy aldehyde. Moreover, the aldehydes possessing strong electron donating groups such as 1d and 1e gave the expected products 3k and 3l in moderate yields, with longer reaction time (entries 3 and 4). On the other hand, the reactions of methyl indole (2d) with aldehyde 1b and 1c furnished the desired products 3m and 3n in good yields but nitro aldehyde 1c took longer time. Similar trend were observed, when ethyl indole (2e) was used as indole component (entries 7 and 8) to obtain corresponding products 3o and 3p. The reactions of indoles containing moderate electron withdrawing groups such as chloro and bromo gave the desired products in good yields with 5- methoxy-2-(phenylethynyl)benzaldehyde (1b) and 5-nitro-2- (phenylethynyl)benzaldehyde (1c) (entries 9-12). Furthermore, the scope of the reaction was examined with mild and strong electron donating substitution at aromatic alkynes. The moderate electron donating methyl substituted alkyne aldehyde 1f produced the compound 3v in better yield in shorter reaction time than compound 3w when strong electron donating methyleneoxy alkyne aldehyde was used as a substrate (entries 14 and 15). This protocol failed to produce corresponding product with aliphatic 2-(hex-1-yn-1- yl)benzaldehyde Probably the bulky long chain alkyl group may prevent the attack of indole on intermediate iodonium ion to form corresponding tetracyclic compound. This may leads to decomposition or formation of several other products. (entry 16).

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Table II.B.3.2. Iodine mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and various indole derivatives

a All reactions were performed on 0.25 mmol of aldehyde 1a and 0.5 mmol of indole 2a- b c 2h. Iodine (3.2 equiv) and triethylamine (2.0 equiv) in CHCl3. Yields refer to isolated and purified compound. d The reactions were carried out at 60oC.

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Table II.B.3.3. Iodine mediated tandem cyclization of 2-(phenylethynyl)benzaldehyde and various indole derivatives

Continue......

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a All reactions were performed on 0.25 mmol of aldehyde 1a-1h and 0.5 mmol of indole b c 2a-2f. Iodine (3.2 equiv) and triethylamine (2.0 equiv) in CHCl3. Yields refer to isolated and purified compound. d Inseparable mixture of products.

In order to extend the scope of our protocol, we synthesized N-((1H-indol-3-yl)(2- (phenylethynyl)phenyl)methyl)-N-methylaniline (5a) using N-methylaniline (2 equiv), 2- (phenylethynyl)benzaldehyde (1 equiv) and indole (1 equiv) in ethanol with Bromodimethylsulfonium bromide (BDMS, 20 mol%) to obtain crude compound 5a.13 Further, the crude compound (5a) was treated with iodine (2 equiv) and triethylamine (2 equiv) to yield compound (6a) in 65% and 10% unreacted starting material (Scheme

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II.B.3.2). The unreacted starting material was not consumed even after the addition of extra iodine to the reaction mixture.

Scheme II.B.3.2. Synthesis of amino substituted tetracyclic indole fused azulene (6a)

Scheme II.B.3.3. Functionalization of Indolotetracyclic azulene (3a) The presence of iodo group in the tetracyclic system gave us the opportunity to generate diverse functionalized indole fused tetracyclic azulene derivatives by various palladium- catalyzed C-C bond coupling reactions (Scheme II.B.3.3).14 In this regard, the compound 3a was treated with 4-methoxy phenyl boronic acid in Suzuki reaction condition to afford

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compound 7a in 76% yield.14a Next, 3a was treated with ethyl acrylate in the presence of bis(triphenylphosphine)palladium(II) dichloride and K2CO3 as a base in DMF to get the Heck type product 8a in excellent yield (98%).14b Finally, the compound 3a were deiodinated in tetrakis(triphenylphosphine)palladium (0) and sodium formate gave the product 9a in moderate yield (74%).14c

II.B.4. Conclusion In conclusion, we have developed an easy, efficient and non-metallic protocol for the construction of tetracyclic indoloazulene derivatives by the sequential iodocyclization of 2-(phenylethynyl)benzaldehyde and indole via bisindole in the presence of molecular iodine and base. A wide range of 2-(substituted phenylethynyl)benzaldehydes and indoles were utilized in this reaction to derive a diverse iodo substituted tetracyclic indole fused azulene derivatives in good to moderate yields. Interestingly, the reaction is completely regioselective and only iodo substituted tetracyclic indole fused azulene derivatives were obtained. The present method was applied to synthesize the amino substituted tetracyclic indole fused azulene derivative (6a). Finally, the iodo compound (3a) was successfully utilized for further functionalization with the C-C bond coupling reactions such as Suzuki, Heck and deiodination to furnish a diverse functionalized tetracyclic indole fused azulene derivatives.

II.B.5. Experimental Section II.B.5.1. General Information All chemicals were purchased from various sources and were used directly without further purification. Analytical thin-layer chromatography was performed using silica gel 60F glass plates and silica gel 60 (230–400 mesh) was used in flash chromatographic separations. NMR spectra were recorded in DMSO-d6 with DMSO and CDCl3 with 1 13 CHCl3 as the internal standards for H NMR (400 MHz) and C NMR (100 MHz). Coupling constants were expressed in Hertz. HRMS spectra were recorded using MALDI, ESI- or ESI+ mode. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.

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II.B.5.2. General Experimental for the Synthesis of 2-(1H-indol-3-yl)-9-iodo-10- phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca1(11),3(8),4,6,9,13(18,14,16- octaene (3a-3w): To the ice cold solution of 1a (0.25 mmol) and indole (0.5 mmol) in

CHCl3 (5 mL) was added a solution of I2 (1.1 equiv) in CHCl3 (5 mL) dropwise. After stirring the reaction mixture for 10 min, triethylamine (2 equiv) was added dropwise. To this resulting mixture, additional solution of I2 (2.1 equiv) in CHCl3 was added then allowed the reaction mixture for stirring at room temperature. The progress of reaction was monitored by TLC. After the completion of the reaction, saturated aq. Na2S2O3 (5 mL) was added to the mixture, which was further stirred for 2 min. The resulting mixture was then extracted with CHCl3 (2 x 20 mL). The organic layer washed with water and brine. Organic layer was dried over MgSO4, filtered and then concentrated under reduced pressure to obtain the crude product. The crude compound was then purified by column chromatography using Hexane-Ethyl acetate as the eluent to yield compound 3a.

II.B.5.3. The synthesis of 9-iodo-N-methyl-N,10-diphenyl-12-azatetracyclo[9.7.0. 03,8.013,18]octadeca-1(11),3(8),4,6,9, 13,15,17-octaen-2-amine (6a) To a stirred solution of 1a (0.5 mmol) and N-methylaniline (1 mmol) in EtOH (2 mL) was added BDMS (10 mol%). The mixture was then stirred at room temperature for 20 min followed by the addition of Indole (0.5 mmol). The reaction mixture was then stirred at room temperature for 15 h. The progress of reaction was monitored by TLC. After the completion of the reaction, the solution was diluted with water (25 mL) and then extracted with ethyl acetate (3 x 30 mL). The organic layer was washed with water and brine. Organic layer was dried over MgSO4, filtered and then concentrated under reduced pressure to obtain the crude product (5a). the crude compound was directly used for next step due to less stability.

To ice cold solution of 5a in CHCl3 (10 mL) was added solution of I2 (2 equiv) in CHCl3 (20 mL) dropwise. Then to this was added TEA (2 equiv) dropwise. The reaction was then stirred at room temperature. The progress of reaction was monitored by TLC. After the completion of the reaction, CHCl3 (20 mL) was added. The excess of iodine was removed by washing with saturated aq. Na2S2O3, water and brine successively. Organic layer was dried over MgSO4, filtered and then concentrated under reduced pressure to yield crude product. The crude compound was then purified by column chromatography using Hexane-Ethyl acetate as the eluent to yield compound 6a white solid.

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II.B.5.4. 2-(1H-indol-3-yl)-9-(4-methoxyphenyl)-10-phenyl-12-azatetracyclo[9.7.0. 03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (7a) To a solution of 3a (1 equiv) and 4-methoxyphenylboronic acid (1.2 equiv) in DMF (10 mL) was added PdCl2(PPh3)2 (10 mol%). The reaction was then stirred at room temperature for 15 min followed by the addition of K2CO3 (2 equiv). The reaction mixture was the stirred at 110oC for 8 h. The progress of reaction was monitored by TLC. After the completion of the reaction, The solution was allowed to cool and diluted with ice water (25 mL) and then extracted with ethyl acetate (3 x 40 mL). The organic layer washed with water and brine. Organic layer was dried over MgSO4, filtered and then concentrated under reduced pressure to obtain the crude product. The crude compound was then purified by column chromatography using Hexane-Ethyl acetate as the eluent to yield compound 7a light pink solid.

II.B.5.5. Ethyl(2E)-3-[2-(1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0.03,8.013, 18]octadeca-1(11),3(8),4,6,9,13,15,17-octaen-9-yl]prop-2-enoate (8a)

To a stirred solution of 3a (1 mmol) in 5 ml DMF in a 10 mL was added PdCl2(PPh3)2

(10 mol%) and stirred for 15 min under argon atmosphere. Then ethyl acrylate (2.5 equiv) was added to the reaction mixture. After 15 min, K2CO3 (2.5 equiv) was added. The reaction mixture was then stirred at 100oC for 7 h. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature and the ice water (50) and extracted with ethyl acetate (3 x 50 mL). The organic layer was washed with cold water (100 mL) and finally with brine (50 mL).

The ethyl acetate later was dried over MgSO4, filtered and then concentrated under reduced pressure. The crude compound was then purified by column chromatography using Hexane-Ethyl acetate as the eluent to yield compound 8a white solid.

II.B.5.6. 2-(1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca- 1(11),3(8),4,6,9,13,15,17-octaene (9a) To a stirred solution of compound 3a (0.5 mmol) and sodium formate (3 equiv) in DMF o (5 mL) was added Pd(PPh3)4 (5 mol%) heated at 110 C for 6 h. The progress of the reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was cooled to room temperature. The solution was diluted with water (25 mL) and then extracted with ethyl acetate (3 x 30 mL). The organic layer washed with water and brine. Organic layer was dried over MgSO4, filtered and then concentrated under

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reduced pressure to obtain the crude product. The crude compound was the purified by column chromatography using Ethyl acetate-Hexane for afford pure compound 9a white Solid. II.B.5.7. Spectral Data of compounds 3,3'-((2-(phenylethynyl)phenyl)methylene)bis(1H-indole) (i) Yield: (89 %); white solid; m.p.:250-252oC; FT-IR (KBr) −1 1 ν/cm 3431, 1635, 754; H NMR (400 MHz, CDCl3) δ (ppm) 10.86 (brs, 2H), 7.57 (d, J = 7.16 Hz, 1H), 7.38 (m, 2H), 7.35 (m, 8H), 7.24-7.31 (m, 2H), 7.05 (t, J = 7.44 Hz, 2H), 6.85 - 13 6.90 (m, 4H), 6.44 (s, 1H); C NMR (100 MHz, CDCl3) δ 147.2, 137.1, 132.4, 131.6, 129.1, 129.0, 128.9, 127.2, 126.6, 124.3, 122.9, 122.0, 121.5, 119.1, 118.8, 117.9, 112.0, 93.9, 88.9, 37.9; LRMS (ESI) - (m/z) (relative intensity) 421 (80) [M-H] , 127 (20); HRMS (ESI) calcd for C31H22N2 [M- H]-: 421.1705, Found 421.1704. 2-(1H-indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca 1(11),3(8),4,6,9, 13(18),14,16-octaene (3a) Yield: (84 %); white solid; m.p.:209-211oC; FT-IR (KBr) ν/cm−1 3468, 3431, 1635, 704; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.74 (brs, 1H), 10.25 (brs, 1H), 8.08- 8.09 (m, 1H), 7.89 (d, J = 7.56 Hz, 1H), 7.60-7.62 (m, 2H), 7.36-7.40 (m, 2H), 7.28-7.33 (m, 5H), 7.13-7.15 (m, 3H), 6.96-6.99 (m, 2H), 6.71 (t, J = 7.48 Hz, 1H), 6.62 (s, 1H), 6.06 (s, 1H); 13C NMR (100

MHz, DMSO-d6) δ 144.7, 144.1, 139.5, 138.8, 136.8, 134.9, 130.3, 129.2, 128.9, 128.0, 127.7, 127.4, 126.4, 126.4, 125.5, 123.0, 122.3, 121.2, 120.5, 119.1, 118.9, 117.9, 117.8, 113.5, 111,7, 111.2, 105.3, 38.8; LRMS (EI) (m/z) (relative intensity): 549 (90) [M+H]+, + 307 (40); HRMS calcd for C31H21IN2 [M+H] : 549.0828, Found 549.0826. 16-chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo[9.7.0.03, 8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3b) Yield: (77 %); yellow solid ; m.p.: 213-215oC; FT-IR (KBr) −1 1 ν/cm 360, 3400, 580; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.99 (brs, 1H), 10.49 (brs, 1H), 8.22 (s, 1H), 7.88 (d, J = 7.72 Hz, 1H), 7.67 (d, J = 7.60 Hz, 2H), 7.39-7.42 (m, 2H), 7.31- 7.34 (m, 4H), 7.29 (s, 1H), 7.14-7.16(m, 2H),

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6.99 (dd, J = 1.19 Hz, 8.52 Hz, 1H), 6.89 (d, J = 1.96 Hz, 1H), 6.70 (s, 1H), 6.11 (s, 1H); 13 C NMR (100 MHz, DMSO-d6) δ 144.5, 143.4, 139.2, 138.8, 135.1, 135.0, 134.9, 131.9, 129.4, 128.9, 128.2, 127.9, 127.4, 127.4, 126.5, 125.6, 124.8, 123.8, 122.5, 122.4, 120.5, 120.3, 118.1, 117.1, 113.4, 113.3, 112.8, 106.5, 38.1; LRMS (ESI) (m/z) (relative - - intensity): 615 (100) [M-H] , 553 (60); HRMS calcd for C32H21Br2IN2O [M-H] : 614.9892, Found 614.9898.

16-bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo[9.7.0.03, 8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3c) Yield: (80 %); light yellow solid ; m.p.: 245-246oC; FT-IR (KBr) ν/cm−1 3808, 3372, 1447, 585; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 11.0 (brs, 1H), 10.50 (brs, 1H), 8.36 (s, 1H), 7.87 (d, J = 7.68 Hz, 1H), 7.67 (d, J = 6.92 Hz, 1H), 7.39-7.42 (m, 3H), 7.31-7.34 (m, 2H), 7.28 (m, 1H), 7.25- 7.26 (m, 3H), 7.10-7.11 (m, 1H), 7.07-7.08 (m, 2H), 6.68 13 (s, 1H), 6.11 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 144.4, 143.6, 139.1, 138.8, 135.3, 135.0, 131.6, 129.4, 128.9, 128.2, 128.1, 127.9, 127.4, 127.2, 125.6, 124.9, 124.5, 122.9, 121.2, 120.3, 120.2, 117.4, 113.7, 113.3, 113.2, 111.8, 110.5, 106.4, 38.8; LRMS (ESI) - (m/z) (relative intensity): 703 (65) [M-H] , 643 (80); HRMS calcd for C31H19Br2IN2 [M- H]-: 702.8881, Found 702.8878.

9-iodo-14-methyl-2-(7-methyl-1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0.03,8. 013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3d) Yield: (80 %); white solid; m.p.: 246-248oC; FT-IR (KBr) ν/cm−1 3446, 3422, 1620, 745; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.69 (brs, 1H), 9.93 (brs, 1H), 7.89 (dd, J = 15.08 Hz, 7.96 Hz, 2H), 7.56-7.59 (m, 2H), 7.32- 7.37 (m, 2H), 7.29-7.30 (m, 3H), 7.04-7.08 (m, 2H), 6.92-6.97 (m, 2H), 6.79 (d, J = 6.84 Hz, 1H), 6.64-6.67 (m, 2H), 6.00 (s, 1H), 2.41 (s, 3H), 2.32 (s, 3H); 13C NMR (100 MHz,

DMSO-d6) δ 144.4, 144.4, 139.6, 139.2, 136.3, 135.9, 134.9, 130.2, 129.5, 129.1, 127.7, 127.6, 127.3, 126.1, 125.5, 125.3, 123.2, 122.7, 121.1, 120.8, 119.9, 119.4, 118.0, 116.5, 115.5, 114.6, 113.7, 105, 39.0, 16.9, 16.6; LRMS (EI) (m/z) (relative intensity): 577 (100) + + [M+H] , 578 (60); HRMS calcd for C33H25IN2 [M+H] : 577.1141 Found 577.1135.

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14-ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-10-phenyl-12-azatetracyclo[9.7.0.03,8.013, 18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3e) Yield: (79 %); yellow Solid; m.p.: 216-218oC; FT-IR (KBr) ν/cm−1 3489, 3469, 650; 1H NMR (400 MHz,

CDCl3) δ (ppm) 8.07 (d, J = 7.68 Hz, 1H), 7.96 (d, J = 7.92 Hz, 1H), 7.85 (brs, 1H), 7.49-7.51 (m, 3H), 7.34- 7.41 (m, 3H), 7.25-7.32 (m, 3H), 7.12-7.14 (m, 2H), 6.96-7.02 (m, 2H), 6.85 (t, J = 7.44 Hz, 1H), 6.72 (brs, 1H), 6.03 (s, 1H), 2.83 (q, J = 7.48 Hz, 15.0 Hz, 2H), 2.67 (q, J = 7.28 Hz, 14.80 Hz, 2H), 1.35 (t, J = 7.52 Hz, 3H) 1.25 (t, J = 7.5 Hz, 3H); 13C NMR (100 MHz,

DMSO-d6) δ 144.8, 143.7, 139.3, 139.1, 135.6, 135.5, 130.2, 129.6, 129.3, 128.8, 128.6, 128.2, 127,7, 126.6, 126.4, 126.2, 125.7, 122.9. 122.6, 121.8, 120.5, 120.5, 119.6, 117.6, 116.1, 115.6, 105.4, 40.3, 23.9, 23.6, 13.9, 13.4; LRMS (EI) (m/z) (relative intensity): + + 604 (100) [M] , 603 (40); HRMS calcd for C35H29IN2 [M] : 604.1376, Found 604.1372.

9-iodo-16-methoxy-2-(5-methoxy-1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0. 03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3f) Yield: (68 %); grey solid ; m.p.: 220-222oC; FT-IR (KBr) ν/cm−1 3500, 3450, 1650; 1H NMR (400 MHz,

CDCl3) δ (ppm) 8.07 (d, J = 7.56 Hz, 1H), 7.79 (s, 1H), 7.52 (m, 3H), 7.38-7.47 (m, 2H), 7.29-7.36 (m, 3H), 7.06-7.15 (m, 3H), 6.90 (d, J = 7.92 Hz, 1H), 6.74 (d, J = 7.32 Hz, 1H), 6.62 (s, 1H), 6.40 (s, 1H), 5.92 (s, 2H), 13 3.96 (s, 3H), 3.32 (s, 3H); C NMR (100 MHz, CDCl3) δ 154.8, 153.6, 152.2, 144.9, 143.9, 139.6, 138.9, 135.1, 132.2, 131.5, 130.9, 129.3, 129.1, 128,0, 127.6, 126,7, 125.9, 125.3, 123.5, 121.0, 113.5, 112.9, 112.5, 111.6, 110.3, 105.1, 101.3, 99.5, 55.5, 54.6, 38.8; LRMS (EI) (m/z) (relative intensity): 608 (100) [M]+, 607 (95); HRMS calcd for + C33H25IN2O2 [M] : 608.0961, Found 608.0959.

2-(5-cyano-1H-indol-3-yl)-10-iodo-9-phenyl-12-azatetracyclo[9.7.0.03,8.013,18] octadeca-1(11),3(8),4,6,9,13,15,17-octaene-16-carbonitrile (3g) Yield: (77 %); white Solid; m.p.: 216-218oC; FT-IR (KBr) ν/cm−1 3480, 3494, 2280, 650; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 11.46 (bs, 1H), 10.97 (bs, 1H), 8.79 (s,

125

1H), 7.88 (d, J = 7.61 Hz, 1H), 7.68-7.70 (m, 2H), 7.46-7.52 (m, 5H), 7.35 (m, 4H), 7.22 13 (m, 2H), 6.87 (s, 1H), 6.27(s, 1H); C NMR (100 MHz, DMSO-d6) δ 144.1, 143.3, 138.9, 138.8, 138.3, 135.2, 132.7, 129.8, 128.5, 128.3, 127.5, 127.4, 126.2, 126.0, 125.8, 125.8, 125.3, 125.1, 124.4, 124.1, 123.4, 121.2, 120.8, 120.7, 114.6, 113.1, 112.9, 107.5, 101.5, 100.1, 37.8; LRMS (EI) (m/z) (relative intensity): 598 (100) [M]+; HRMS calcd for + C35H19IN4 [M] : 598.0654, Found 598.0650.

10-iodo-16-nitro-2-(5-nitro-1H-indol-3-yl)-9-phenyl-12-azatetracyclo[9.7.0.03,8. 013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3h) Yield: (71 %); yellow solid; m.p.: 220-222oC; FT-IR (KBr) ν/cm−1 3500, 3455, 1650; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 11.62 (bs, 1H), 11.13 (bs, 1H), 9.29 (s, 1H), 8.07 (dd, J= 1.76 Hz, 7.28 Hz, 1H), 7.89-7.91 (m, 2H), 7.82-7.87 (m, 2H), 7.80(s, 1H), 7.49-7.44(m, 4H), 13 7.38-7.35 (m, 4H), 6.92(s, 1H), 6.46 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 144, 143.1, 141.2, 139.9, 139.9, 139.7, 138.9, 138.8, 135.2, 133.8, 129.9, 128.5, 128.3, 127.6, 126.9, 126.1, 125.6, 124.9, 122.5, 117.9, 116.3, 116.2, 116.1, 115.8, 112.3, 112.3, 111.9, 107.9, 37.8. LRMS (EI) (m/z) (relative intensity): 638 (100) [M]+, 637 (95); HRMS calcd + for C31H19IN4O4 [M] : 638.0451, Found 638.0459.

2-(1H-indol-3-yl)-9-iodo-5-methoxy-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18] octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3i) Yield: (83 %); yellow solid; m.p.:180-181oC; FT-IR (KBr) ν/cm−1 3468, 1636, 339; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.73 (brs, 1H), 10.19 (brs, 1H), 8.09 (s, 1H), 7.81 (d, J = 8.64 Hz, 1H), 7.27-7.29 (m, 5H), 7.13-7.20 (m, 4H), 6.95-7.00 (m, 2H), 6.88-6.90 (d, J = 8.24 Hz, 1H), 6.69 (t, J = 7.32 Hz, 1H), 6.63 (s, 1H), 6.01 (s, 1H), 3.83 (s, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 160.0, 145.5, 144.9, 138.3, 136.7, 136.6, 136.4, 131.7, 130.5, 129.0, 127.9, 127.6, 126.4, 125.7, 122.2, 120.6, 120.5, 119.0, 118.9, 117.9, 117.8, 113.6, 112.0, 111.7, 111.3, 111.1, 105.6, 55.3, 38.9; LRMS (m/z) (relative intensity): 579 (100) + + [M+H] , 541 (80), 527 (30); HRMS calcd for C32H23IN2O [M+H] : 579.0933, Found 579.0934.

126

2-(1H-indol-3-yl)-9-iodo-5-nitro-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18] octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3j) Yield: (78 %); yellow solid; m.p.: 223-225oC; FT-IR (KBr) ν/cm−1 3450, 1530, 1365, 600; 1H NMR (400 MHz, DMSO-

d6) δ (ppm) 10.81 (brs, 1H), 10.40 (brs, 1H), 8.65 (s, 1H), 8.19-8.22 (s, 1H), 8.12-8.13 (m, 2H), 7.31-7.34 (m, 4H), 7.28-7.29 (m, 2H), 7.15-7.19 (m, 3H), 6.98 (t, J = 7.32 Hz, 1H), 6.86-6.88 (m, 1H), 6.70 13 (t, J = 7.40 Hz, 1H), 6.62 (s, 1H), 6.39 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 147.3, 145.1, 144.9, 144.1, 141.6, 137.1, 136.5, 136.2, 130.2, 128.8, 128.1, 127.9, 126.2, 125.4, 123.8, 122.8, 121.9, 120.9, 120.6, 119.9, 119.3, 118.8, 118.5, 117.9, 112.3, 111.8, 111.3, 101.8, 38.3; LRMS (EI) (m/z) (relative intensity): 593 (100) [M]+, 547 (55); HRMS calcd + for C31H20IN3O2 [M] : 593.0600, Found 593.0591.

2-(1H-indol-3-yl)-9-iodo-5,6-dimethoxy-10-phenyl-12-azatetracyclo[9.7.0.03,8.013, 18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3k) Yield: (61 %); white solid ; m.p.: 230-232oC; FT-IR (KBr) ν/cm−1 3461, 3444, 1636, 551; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.72 (brs, 1H), 10.17 (brs, 1H), 8.09 (s, 1H), 7.41 (m, 3H), 7.25-7.29 (m, 5H), 7.12-7.15 (m, 3H), 7.04 (d, J = 7.88 Hz, 1H), 6.97 (t, J = 7.40 Hz, 1H), 6.71 (t, J = 7.52 Hz, 1H), 6.65 (s, 1H), 5.99 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 149.7, 145.7, 145.0, 138.6, 137.4, 136.8, 136.4, 130.9, 130.8, 130.4, 128.8, 128.0, 127.6, 126.4, 125.5, 122.9, 122.2, 121.2, 120.4, 119.1, 118.8, 118.0, 117.8, 114.1, 111.6, 111.1, 110.9, 105.9, 55.7, 55.6, 38.2; LRMS (EI) (m/z) (relative + + intensity): 608 (100) [M] , 481 (80); HRMS (ESI) calcd for C33H25IN2O2 [M+H] : 609.1039, Found 609.1038.

2-(1H-indol-3-yl)-13-iodo-12-phenyl-17,19-dioxa-10-azapentacyclo[12.7.0.03,11. 04,9.016,20]henicosa-1(14),3(11),4,6,8,12,15,20-octaene (3l) Yield: (69 %); pink Solid ; m.p.: 238-240oC; FT-IR (KBr) −1 1 ν/cm 3550, 3480, 590; H NMR (400 MHz, DMSO-d6) δ (ppm) 10.71 (brs, 1H), 10.31 (brs, 1H), 8.05 (d, J = 7.12 Hz, 1H), 7.86 (d, J = 7.64 Hz, 1H), 7.56 (d, J = 7.40 Hz, 1H), 7.35 (t, J = 7.24 Hz, 1H), 7.26-7.29 (m, 3H), 7.11-7.17 (m, 3H), 6.95-6.98 (m, 3H), 6.65-6.69

127

13 (m, 2H), 6.57 (s, 1H), 5.99 (s, 1H), 5.96 (s, 2H); C NMR (100 MHz, DMSO-d6) δ 147.1, 147.0, 144.5, 139.3, 139.1, 138.9, 137.1, 136.8, 135.4, 130.8, 128.7, 127.7, 126.6, 125.9, 125.8, 123.5, 122.9, 121.4, 121.0, 119.6, 119.2, 118.3, 113.9, 112.1, 111.7, 108.4, 105.9, 101.3, 38.9; LRMS (EI) (m/z) (relative intensity): 591 (100) [M+H]+, 535 (20); HRMS + calcd for C32H21IN2O2 [M+H] : 591.0933, Found 591.0933.

9-iodo-5-methoxy-14-methyl-2-(7-methyl-1H-indol-3-yl)-10-phenyl-12-azatetra cyclo[9.7.0.03,8.013,18]octadeca1(11),3(8),4,6,9,13,15,17- octaene(3m) Yield: (75 %); white solid; m.p.: 219-212oC; FT-IR (KBr) ν/cm−1 3445, 1650, 700; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.73 (brs, 1H), 9.92 (brs, 1H), 7.95 (d, J = 7.88 Hz, 1H), 7.82 (d, J = 8.76 Hz, 1H), 7.27 (m, 3H), 7.19-7.20 (m, 2H), 7.06-7.09 (m, 2H), 6.96-6.98 (m, 2H), 6.90 (dd, J = 2.44 Hz, 8.76 Hz, 1H), 6.80 (d, J = 6.88 Hz, 1H), 6.65-6.69 (m, 2H), 5.99 (s, 13 1H), 3.83 (s, 3H), 2.43 (s, 3H), 2.34 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 159.9, 145.8, 144.6, 138.5, 13.5, 13.2, 135.9, 131.9, 130.4, 129.6, 127.6, 127.5, 126.1, 123.1, 122.6, 122.1, 121.1, 120.8, 119.9, 119.3, 118.1, 116.5, 115.5, 113.8, 111.9, 111.2, 105.6, 55.3,39.09, 17.0, 16.3; LRMS (EI) (m/z) (relative intensity): 606 (60) [M]+, 605 (100); + HRMS calcd for C34H27IN2O [M] : 606.1168, Found 606.1161.

9-iodo-14-methyl-2-(7-methyl-1H-indol-3-yl)-5-nitro-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15, 17-octaene(3n) Yield: (61 %); red solid ; m.p.: 208-210oC; FT-IR (KBr) ν/cm−1 3445, 1580, 1385; 1H NMR (400 MHz, DMSO-

d6) δ (ppm) 10.77 (brs, 1H), 10.13 (brs, 1H), 8.61 (d, J = 2.04 Hz, 1H), 8.08-8.12 (m, 2H), 8.03 (d, J = 7.88 Hz, 1H), 7.31 (m, 4H), 7.08 (t, J = 7.78 Hz, 1H), 6.98 (d, J = 7.04 Hz, 1H), 6.78-6.83 (m, 3H), 6.63-6.67 (m, 2H), 6.34 13 (s, 1H), 2.39 (s, 3H), 2.32 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 147.2, 145.6, 145.4, 143.8, 141.7, 136.6, 136.2, 136.0, 130.2, 129.5, 128.0, 127.8, 125.9, 125.4, 123.7, 122.9, 122.4, 121.8, 121.2, 120.9, 120.1, 119.9, 119.6, 118.2, 116.5, 116.1, 112.5, 101.7, 38.4, 17.0, 16.6; LRMS (EI) (m/z) (relative intensity): 621(100) [M+], 595.2 (70); HRMS calcd + for:C33H24IN3O2[M ]: 621.0913, Found 621.0909.

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14-ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-5-methoxy-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17- octaene(3o) Yield: (75 %); yellow Solid; m.p.: 167- 169oC; FT-IR (KBr) ν/cm−1 3520, 3489, 670; 1H NMR

(400 MHz, DMSO-d6) δ (ppm) 10.71 (brs, 1H), 9.87 (brs, 1H), 7.91 (d, J = 7.92 Hz, 1H), 7.78 (d, J = 8.76 Hz, 1H), 7.24-7.27 (m, 4H), 7.15-7.16 (m, 2H), 7.09 (t, J = 7.52 Hz, 1H), 6.97-6.99 (m, 3H), 6.88 (dd, J = 2.60 Hz, 8.80 Hz, 1H), 6.79-6.81 (m, 1H), 6.68 (d, J = 7.62 Hz, 1H), 6.65 (s, 1H), 5.95 (s, 1H), 3.81 (s, 3H), 2.78 (q, J = 11.4 Hz, 7.4 Hz, 2H), 2.69 (m, 2H) 1.19 (t, J 13 = 7.48 Hz, 3H), 1.09 (t, J = 7.48 Hz, 3H); C NMR (100 MHz, DMSO-d6) δ 145.9, 144.7, 138.6, 136.6, 135.4, 135.1, 132.0, 130.3, 129.6, 128.0, 127.6, 127.5, 127.0, 126.6, 126.4, 125.8, 122.5, 122.3, 121.1, 119.5, 119.3, 118.2, 116.6, 115.5, 113.8, 111.9, 111.2, 105.7, 55.3, 39.1, 23.5, 23.1, 14.4, 14.1; LRMS (EI) (m/z) (relative intensity): 634 (80) [M+], + 508 (45); HRMS calcd for: C36H31IN2O (M ): 634.1481, Found 634.1475.

14-ethyl-2-(7-ethyl-1H-indol-3-yl)-9-iodo-5-nitro-10-phenyl-12-azatetracyclo[9.7.0. 03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3p) Yield: (68 %); yellow solid; m.p.: 199-201oC; FT-IR (KBr) ν/cm−1 3472, 3431, 1590, 1379; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 10.79 (brs, 1H), 10.12 (brs, 1H), 8.16 (d, J = 0.2Hz, 1H), 8.07-8.14 (m, 2H), 8.03 (d, J = 7.92 Hz, 1H), 7.29-7.31 (m, 4H), 7.01-7.13 (m, 3H), 6.88 (d, J = 7.84 Hz, 1H), 6.81 (d, J = 6.96 Hz, 1H), 6.69 (d, J = 7.60 Hz, 1H), 6.64-6.66 (m, 1H), 6.34 (s, 1H), 2.69-2.81 (m, 4H), 1.19 (t, J = 7.48 Hz, 3H), 1.10 (t, J = 7.44 Hz, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 147.2, 145.6, 145.5, 143.8, 141.7, 136.2, 135.8, 135.1, 130.0, 129.6, 127.9, 127.7, 127.3, 126.6, 126.1, 125.5, 122.8, 122.5, 121.7, 121.6, 119.9, 119.7, 119.3, 118.3, 116.5, 116.1, 112.4, 101.7, 38.9, 23.4, 23.1, 14.3, 14.1; LRMS (EI) + + (m/z) (relative intensity): 649 (100) [M] , 603 (50); HRMS calcd for C35H28IN3O2 [M] : 649.1226, Found 649.1224.

129

16-chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-5-methoxy-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene(3q) Yield: (73 %); pink solid; m.p.: 188-190oC; FT-IR (KBr) ν/cm−1 3530, 3470, 1635, 540; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.99 (brs, 1H), 10.44 (brs, 1H), 8.22 (s, 1H), 7.81 (d, J = 8.76 Hz, 1H), 7.28-7.34 (m, 7H), 7.13-7.15 (m, 2H), 6.89-7.00 (m, 3H), 6.73 (s, 1H), 6.06 13 (s, 1H), 3.85 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 160.2, 145.1, 144.7, 138.0, 136.7, 135.1, 134.9, 132.1, 131.6, 128.9, 128.2, 127.9, 127.4, 126.7, 124.8, 123.9, 122.6, 122.3, 120.5, 119.8, 118.1, 117.3, 113.5, 113.3, 112.8, 112.1, 111.6, 106.8, 55.4, 38.2; LRMS (EI) m/z) (relative + + intensity): 647 (95) [M+H] , 521 (80); HRMS calcd for C32H22Cl2IN2O [M+H] : 647.0154, Found 647.0150. 16-chloro-2-(5-chloro-1H-indol-3-yl)-9-iodo-5-nitro-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3r) Yield: (85 %); light Red Solid; m.p.: 193-195oC; FT-IR (KBr) ν/cm−1 3490, 1580, 1360; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 11.08 (brs, 1H), 10.66 (brs, 1H), 8.72 (s, 1H), 8.35 (s, 1H), 8.09-8.14 (m, 2H), 7.36-7.38 (m, 3H), 7.31-7.34 (m, 3H), 7.17-7.19 (m, 2H), 7.00 (dd, J = 8.56 Hz, 1.80 Hz, 1H), 6.80 (d, J = 1.52 Hz, 1H), 13 6.74 (s, 1H), 6.43 (s, 1H); C NMR (100 MHz, DMSO-d6) δ 147.4, 145.1, 144.6, 143.9, 141.2, 136.4, 135.7, 134.9, 131.8, 128.8, 128.3, 128.2, 127.2, 126.4, 125.2, 124.2, 122.9, 122.7, 122.0, 120.6, 120.3, 119.8, 118.0, 117.8, 113.6, 112.1, 103.2, 37.5; LRMS (EI) + + (m/z) (relative intensity): 662 (100) [M+H] ; HRMS calcd for C31H18Cl2IN3O2 [M+H] : 661.9899, Found 661.9891. 16-bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-5-methoxy-10-phenyl-12-azatetra cyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3s) Yield: (77 %); white Solid; m.p.: 236-238oC; FT-IR (KBr) ν/cm−1 3525, 3425, 1635, 746; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 11.0 (brs, 1H), 10.44 (brs, 1H), 8.35 (s, 1H), 7.79 (d, J = 8.68 Hz, 1H), 7.31 (m, 5H), 7.28 (m, 1H), 7.26 (m, 1H), 7.24 (m, 2H), 7.13 (s, 1H), 7.09 (d, J =

130

8.52 Hz, 1H), 6.91 (d, J = 8.24 Hz, 1H), 6.70 (s, 1H), 6.06 (s, 1H), 3.85 (s, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 160.2, 145.0, 144.7, 137.9, 136.7,135.3, 135.0, 131.9, 131.6, 129.1, 128.3, 128.1, 127.9, 127.4, 124.8, 124.5, 123.0, 121.3, 120.4, 119.0, 113.7, 113.4, 112.0, 111.8, 111.6, 110.6, 106.9, 55.4, 38.1; LRMS (EI) (m/z) (relative intensity): 736 + + (100) [M+H] , 734 (80); HRMS calcd for C30H18N2Br2I [M+H] : 733.9065, Found 733.9062.

16-bromo-2-(5-bromo-1H-indol-3-yl)-9-iodo-5-nitro-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (3t) Yield: (78 %); red Solid ; m.p.: 223-225oC; FT-IR (KBr) ν/cm−1 3439, 3400, 1530, 1360; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 11.08 (brs, 1H), 10.66 (brs, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.09-8.15 (m, 2H), 7.34- 7.38 (m, 3H), 7.26-7.29 (m, 4H), 7.09-7.12 (m, 2H), 6.97 (s, 1H), 6.72 (s, 1H), 6.44 (s, 1H); 13C NMR (100

MHz, DMSO-d6) δ 147.4, 145.1, 144.7, 143.9, 141.3, 136.4, 135.7, 135.1, 131.6, 128.9, 128.4, 128.3, 127.9, 127.1, 125.4, 124.9, 123.2, 122.2, 121.2, 120.9, 120.3, 119.9, 113.9, 113.4, 112.1, 110.7, 103.2, 37.4; LRMS (EI) (m/z) (relative intensity): 750 (100) [M+H]+; + HRMS calcd for C31H18Br2IN3O2 [M+H] : 749.8889, Found 749.8894.

22)9-iodo-5,16-dimethoxy-2-(5-methoxy-1H-indol-3-yl)-10-phenyl-12-azatetracyclo [9.7.0.03,8.013,18]octadeca-1(11),3(8),4,6,9,13, 15,17- octaene (3u) Yield: (62 %); white Solid ; m.p.: 218- 220oC; FT-IR (KBr) ν/cm−1 3490, 3410; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 10.56 (brs, 1H), 9.99 (brs, 1H), 7.83 (d, J = 8.80 Hz, 1H), 7.66-7.67 (m, 1H), 7.30 (m, 2H), 7.25-7.29 (m, 3H), 7.16-7.19 (m, 3H), 6.91 (dd, J = 2.60 Hz, 8.80 Hz, 1H), 6.79 (dd, J = 2.52 Hz, 8.76 Hz, 1H), 6.62- 6.64 (m, 2H), 6.57 (d, J = 2.12 Hz, 1H), 5.98 (s, 1H), 3.87 (s, 3H), 13 3.85 (s, 3H), 3.37(s, 3H); C NMR (100 MHz, DMSO-d6) δ 159.9, 153.6, 152.2, 145.3, 145.2, 138.5, 136.7, 132.1, 131.7, 131.5, 131.2, 128.9, 128.0, 127.5, 126.7, 126.1, 123.4, 120.4, 113.5, 112.7, 112.4, 112.2, 111.6, 111.2, 110.3, 105.4, 101.3, 99.6, 55.5, 55.3, 54.6, 38.9; LRMS (EI) (m/z) (relative intensity): 638 (100) [M]+, 637 (55); HRMS (ESI) calcd + for C34H27IN2O3 [M+H] ;: 639.1145, Found 639.1152.

131

2-(1H-indol-3-yl)-9-iodo-10-(4-methylphenyl)-12-azatetracyclo[9.7.0.03,8.013,18] octadeca-1(11),3(8),4,6, 9,13,15,17-octaene (3v) Yield: (68 %); yellow solid ; m.p.: 210-212oC; FT-IR (KBr) ν/cm−1 3477, 3410, 599; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.74 (brs, 1H), 10.23 (brs, 1H), 8.07-8.09 (m, 1H), 7.88 (d, J = 7.76 Hz, 1H), 7.59-7.61 (m, 2H), 7.37 (t, J = 7.16 Hz, 1H), 7.28-7.31 (m, 4H), 7.13-7.15 (m, 4H), 6.96-7.00 (m, 2H), 6.71 (t, J = 7.38 Hz, 1H), 6.62 (s, 1H), 6.05 (s, 1H), 13 2.29 (s, 3H); C NMR (100 MHz, DMSO-d6) δ 144.2, 141.9, 139.5, 138.9, 136.9, 136.8, 136.4, 135.1, 130.5, 129.5, 129.2, 128.7, 127.4, 126.4, 125.6, 125.4, 123.0, 122.3, 121.1, 120.5, 119.1, 118.9, 117.9, 117.8, 113.6, 111.8, 111.2, 105.2, 38.9, 20.8; LRMS (EI) + (m/z) (relative intensity) 563 (100) [M+H] , 562 (80); HRMS calcd for C32H23IN2 [M+H]+: 563.0984, Found 563.0982.

24) 10-(2H-1,3-benzodioxol-5-yl)-2-(1H-indol-3-yl)-9-iodo-12-azatetracyclo[9.7.0.03,8. 013,18]octadeca-1(11),3(8),4,6,9,13, 15,17-octaene (3w) Yield:(62 %); yellow solid; m.p.: 225-227oC; FT-IR (KBr) ν/cm−1 3590, 3450, 1630, 558; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 10.74 (brs, 1H), 10.22 (brs, 1H), 8.07 (d, J = 5.09 Hz, 1H), 7.34 (m, 3H), 7.26- 7.29 (m, 3H), 7.24 (m, 2H), 7.12-7.14 (m, 3H), 6.95- 6.99 (m, 2H), 6.67-6.72 (m, 2H), 6.09 (s, 1H), 5.98 (d, J = 11.69 Hz, 2H); 13C NMR (100

MHz, DMSO-d6) δ 148.2, 144.8, 144.8, 139.0, 138.9, 136.9, 136.5, 132.5, 130.5, 128.9, 128.0, 127.7, 126.4, 125.5, 123.0, 122.3, 121.2, 120.5, 119.1, 118.9, 117.9, 117.8, 114.3, 113.7, 111.7, 111.2, 107.1, 105.3, 101.5, 38.4; LRMS (EI) (m/z) (relative intensity); 592 + (100) [M] ; HRMS calcd for C32H21IN2O2: 592.0648, Found 592.0639.

9-iodo-N-methyl-N,10-diphenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca- 1(11),3(8),4,6,9,13,15,17-octaen-2-amine (6a) Yield: (65 %); light yellow solid ; m.p.: 238-240oC; FT-IR −1 1 (KBr) ν/cm 3490, 550; H NMR (400 MHz, DMSO d6) δ (ppm) 10.28 (brs, 1H), 7.91 (d, J = 7.72 Hz, 1H), 7.85 (d, J = 7.63 Hz, 1H), 7.45-7.47 (m, 2H), 7.33-7.37 (m, 3H), 7.27- 7.31 (m, 2H), 7.24 (m, 1H), 7.11 (t, J = 7.04 Hz, 1H), 7.03-7.07 (m, 2H), 6.58 (d, J = 8.28

132

Hz, 2H), 6.36 (d, J = 8.40 Hz, 2H), 5.76 (s, 1H), 5.37 (brs, 1H), 2.58 (s, 3H); 13C NMR

(100 MHz, DMSO-d6) δ 147.9, 144.9, 144.0, 139.9, 138.9, 136.9, 134.9, 130.1, 129.1, 128.9, 128.7, 128.2, 128.2, 127.8, 127.3, 126.3, 125.4, 122.4, 121.9, 119.1, 117.1, 111.7, 110.9, 104.6, 44.3, 29.9; LRMS (EI) (m/z) (relative intensity): 538 (100) [M]+, 537 (40); + HRMS calcd for C30H23IN2 [M] : 538.0906, Found 538.0904.

2-(1H-indol-3-yl)-9-(4-methoxyphenyl)-10-phenyl-12-azatetracyclo[9.7.0.03,8.013, 18]octadeca-1(11),3(8),4,6,9,13,15,17-octaene (7a) Yield: (76 %); light pink Solid; m.p.: 189-191oC; FT- IR (KBr) ν/cm−13490, 3410, 1700; 1H NMR (400 MHz,

DMSO-d6) δ (ppm) 10.77 (brs, 1H), 10.22 (brs, 1H), 7.96 (d, J = 7.36 Hz, 1H), 8.00 (d, J = 7.28 Hz, 1H), 7.37-7.40 (m, 2H), 7.33 (d, J = 8.08 Hz, 1H), 7.11 (m, 6H), 6.96-6.99 (m, 2H), 6.84-6.88 (m, 3H), 6.69 (t, J = 7.12 Hz, 1H), 6.58 (s, 1H), 6.42 (d, J = 8.36 Hz, 2H), 6.36 (d, J = 8.08 Hz, 2H), 6.08 (s, 1H), 3.56 (s, 3H); 13C NMR (100

MHz, DMSO-d6) δ 156.9, 144.3, 140.1, 139.8, 138.1, 137.3, 136.6, 134.9, 132.5, 131.6, 131.4, 131.4, 129.6, 127.9, 126.8, 126.2, 126.0, 124.8, 123.2, 121.8, 120.5, 119.4, 118.9, 118.8, 117.9, 117.8, 115.4, 112.3, 111.7, 111.4, 54.7, 38.9; LRMS (EI) (m/z) (relative + + intensity): 528 (100) [M] , 412 (65); HRMS calcd for C38H28N2O[M] : 528.2202, Found 528.2208. ethyl(2E)-3-[2-(1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18] octadeca-1(11),3(8),4,6,9,13,15,17-octaen-9-yl] prop-2-enoate (8a) Yield: (98 %); white Solid; m.p.: 177-179oC; FT-IR (KBr) ν/cm−13490, 3410, 2899, 1735; 1H NMR (400

MHz, DMSO-d6) δ (ppm) 10.57 (brs, 1H), 10.43 (brs, 1H), 8.06 (d, J = 7.40 Hz, 1H), 7.43 (d, J = 7.60 Hz, 1H), 7.56-7.57 (m, 1H), 7.39-7.45 (m, 4H), 7.25-7.31 (m, 4H), 7.11-7.19 (m, 3H), 6.86-6.94 (m, 3H), 6.67 (t, J = 7.24 Hz, 1H), 6.50 (s, 1H), 6.04 (s, 1H), 5.58 (d, J = 15.6 Hz, 1H), 3.94-3.97 (m, 2H), 13 1.09 (t, J = 7.08 Hz, 3H); C NMR (100 MHz, DMSO-d6) δ 166.3, 146.2, 144.6, 138.4, 137.9, 137.6, 136.4, 135.2, 133.9, 132.4, 131.6, 130.2, 128.5, 128.4, 128.4, 128.1, 126.3, 125.8, 124.6, 123.8, 123.0, 122.7, 120.5, 119.3, 118.9, 118.4, 117.8, 113.9, 111.9, 59.7,

133

39.9, 14.0; LRMS (EI) (m/z) (relative intensity): 520 (100) [M]+, 404 (60); HRMS calcd + for C36H28N2O2[M] : 520.2151, Found 520.2148.

2-(1H-indol-3-yl)-10-phenyl-12-azatetracyclo[9.7.0.03,8.013,18]octadeca-1(11),3(8),4, 6,9,13,15,17-octaene (9a) Yield: (74 %); White Solid; m.p.: 250-252oC; FT-IR (KBr) ν/cm−1 3490, 3410; 1H

NMR (400 MHz, DMSO-d6) δ (ppm) 10.74 (brs, 1H), 10.54 (brs, 1H), 7.99 (d, J = 7.52 Hz, 1H), 7.82 (d, J = 7.48 Hz, 1H), 7.52-7.58 (m, 3H), 7.37-7.49 (m, 5H), 7.25-7.32 (m, 2H), 7.10-7.20 (m, 3H), 7.06 (s, 1H), 6.94 (t, J = 7.12 Hz, 1H), 6.80 (t, J = 7.05 Hz, 1H), 6.54 (s, 1H), 6.11 (s, 1H); 13C NMR (100 MHz, DMSO- d6) δ 141.6, 140.3, 137.2, 136.4, 134.7, 133.6, 131.5, 131.0, 129.6, 129.1, 128.6, 128.5, 128.3, 127.9, 126.4, 126.2, 125.5, 122.4, 121.9, 120.5, 118.9, 118.8, 117.9, 117.9, 117.8, 114.8, 111.7, 111.2, 38.8; LRMS (ESI) (m/z) (relative intensity): 421 (80) [M-H]-, 467 + (100); HRMS calcd for C31H22N2 [M] : 422.1783, Found 422.1779.

II.B.6. References

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H.; Edington, D. G.; Griffith, T. E.; James, J. J. Tetrahedron Lett. 1999, 40, 7189. e) Narisada, M.; Horibe, I.; Watanabe, F.; Takeda, K. J. Org. Chem. 1989, 54, 5308. 15. CCDC No: 930945 contain the supplementary crystallographic data for this paper (compound 3a). This data can be obtained free of charge from The Cambridge crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif

137

X-Ray Crystallographic Data

(Recorded on Nonius Kappa CCD Diffractometer)

138

X-ray crystallographic structure and crystal data of 1a (CCDC No: 891973)

Identification code a13273b Empirical formula C10 H7 N O Formula weight 157.17 Temperature 200(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 21/c Unit cell dimensions a = 7.068(3) Å 90°. b = 9.504(4) Å 105.45(2)°. c = 12.272(6) Å 90°.

Volume 794.6(6) Å3 Z 4

Density (calculated) 1.314 Mg/m3

Absorption coefficient 0.086 mm-1 F(000) 328

Crystal size 0.49 x 0.34 x 0.04 mm3 Theta range for data collection 2.99 to 25.08°. Index ranges -8<=h<=8, -10<=k<=11, -14<=l<=7 Reflections collected 3860 Independent reflections 1315 [R(int) = 0.0702] Completeness to theta = 25.08° 93.1 % Absorption correction None Max. and min. transmission 0.9966 and 0.9589

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1315 / 0 / 109

Goodness-of-fit on F2 2.333 Final R indices [I>2sigma(I)] R1 = 0.2016, wR2 = 0.5564 R indices (all data) R1 = 0.2333, wR2 = 0.5701

Largest diff. peak and hole 0.629 and -0.586 e.Å-3

139

X-ray crystallographic structure and crystal data of 1b (CCDC No: 873992)

Identification code 12076 Empirical formula C10 H10 N4 O2 Formula weight 218.22 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 21/n Unit cell dimensions a = 7.2927(3) Å b = 11.3393(6) Å = 105.405(2)°. c = 13.2441(7) Å = 90°.

Volume 1055.86(9) Å 3 Z 4

Density (calculated) 1.373 Mg/m3

Absorption coefficient 0.100 mm-1 F(000) 456

Crystal size 0.47 x 0.22 x 0.13 mm3 Theta range for data collection 2.40 to 25.06°. Index ranges -8<=h<=4, -13<=k<=12, -15<=l<=14 Reflections collected 4051 Independent reflections 1849 [R(int) = 0.0519] Completeness to theta = 25.06° 98.5 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.0582 and 0.9019

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1849 / 0 / 155

Goodness-of-fit on F2 0.929 Final R indices [I>2sigma(I)] R1 = 0.0525, wR2 = 0.1435 R indices (all data) R1 = 0.0800, wR2 = 0.1734

Largest diff. peak and hole 0.311 and -0.360 e.Å -3

140

X-ray crystallographic structure and crystal data of 1g (CCDC No: 880572)

Identification code 13248 Empirical formula C15 H16 N5 O2 Formula weight 298.33 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C 2/c Unit cell dimensions a = 16.9660(5) Å 90°. b = 6.7000(2) Å = 110.2820(10)°. c = 28.0050(10) Å = 90°.

Volume 2986.01(16) Å3 Z 8

Density (calculated) 1.327 Mg/m3

Absorption coefficient 0.093 mm-1 F(000) 1256

Crystal size 0.49 x 0.37 x 0.07 mm3 Theta range for data collection 2.49 to 24.99°. Index ranges -15<=h<=20, -7<=k<=7, -32<=l<=32 Reflections collected 8125 Independent reflections 2511 [R(int) = 0.0868] Completeness to theta = 24.99° 95.7 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.2682 and 0.8497

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2511 / 0 / 199

Goodness-of-fit on F2 1.043 Final R indices [I>2sigma(I)] R1 = 0.0739, wR2 = 0.1908 R indices (all data) R1 = 0.1178, wR2 = 0.2274

Largest diff. peak and hole 0.386 and -0.267 e.Å-3

141

X-ray crystallographic structure and crystal data of 5a (CCDC No: 966267)

Table 1. Crystal data and structure refinement for ch14062. Identification code ch14062 Empirical formula C20 H13 N3 O Formula weight 311.33 Temperature 296(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 21/n Unit cell dimensions a = 11.0522(13) Å b = 12.9284(15) Å c = 11.5645(14) Å

Volume 1617.4(3) Å 3 Z 4

Density (calculated) 1.279 Mg/m3

Absorption coefficient 0.081 mm-1 F(000) 648

Crystal size 0.49 x 0.30 x 0.24 mm3 Theta range for data collection 2.39 to 25.07°. Index ranges -13<=h<=11, -10<=k<=15, -12<=l<=13 Reflections collected 9198 Independent reflections 2867 [R(int) = 0.0329] Completeness to theta = 25.07° 99.8 % Absorption correction multi-scan Max. and min. transmission 0.9807 and 0.9612

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2867 / 0 / 217

Goodness-of-fit on F2 1.059 Final R indices [I>2sigma(I)] R1 = 0.0469, wR2 = 0.1211 R indices (all data) R1 = 0.0843, wR2 = 0.1601

Largest diff. peak and hole 0.309 and -0.390 e.Å -3

142

X-ray crystallographic structure and crystal data of 5g (CCDC No: 966266)

Table 1. Crystal data and structure refinement for 14128. Identification code 14128 Empirical formula C20 H12 Br N3 O Formula weight 390.24 Temperature 298(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P -1 Unit cell dimensions a = 8.5347(10) Å b = 13.1716(17) Å c = 16.084(2) Å

Volume 1736.2(4) Å 3 Z 4

Density (calculated) 1.493 Mg/m3

Absorption coefficient 2.380 mm-1 F(000) 784

Crystal size 0.30 x 0.14 x 0.07 mm3 Theta range for data collection 1.30 to 25.01°. Index ranges -10<=h<=10, -15<=k<=15, -18<=l<=19 Reflections collected 13988 Independent reflections 6046 [R(int) = 0.0472] Completeness to theta = 25.01° 98.9 % Absorption correction multi-scan Max. and min. transmission 0.8511 and 0.5354

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 6046 / 0 / 451

Goodness-of-fit on F2 0.978 Final R indices [I>2sigma(I)] R1 = 0.0495, wR2 = 0.1172 R indices (all data) R1 = 0.1232, wR2 = 0.1723

Largest diff. peak and hole 0.408 and -0.578 e.Å -3

143

X-ray crystallographic structure and crystal data of 7a (CCDC No: 966265)

Table 1. Crystal data and structure refinement for ch15072. Identification code ch15072 Empirical formula C19 H12 Cl N3 Formula weight 317.77 Temperature 200(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group C 2/c Unit cell dimensions a = 16.3952(7) Å b = 9.7990(4) Å c = 19.2289(8) Å

Volume 2962.2(2) Å 3 Z 8

Density (calculated) 1.425 Mg/m3

Absorption coefficient 0.260 mm-1 F(000) 1312

Crystal size 0.69 x 0.52 x 0.44 mm3 Theta range for data collection 2.53 to 25.05°. Index ranges -19<=h<=19, -11<=k<=11, -22<=l<=22 Reflections collected 10030 Independent reflections 2601 [R(int) = 0.0270] Completeness to theta = 25.05° 99.0 % Absorption correction multi-scan Max. and min. transmission 0.8942 and 0.8410

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2601 / 0 / 208

Goodness-of-fit on F2 1.180 Final R indices [I>2sigma(I)] R1 = 0.0361, wR2 = 0.1000 R indices (all data) R1 = 0.0434, wR2 = 0.1157 Largest diff. peak and hole 0.329 and -0.415 e.Å

144

X-ray crystallographic structure and crystal data of 2a (CCDC No: 993227)

Table 1. Crystal data and structure refinement for 14791. Identification code 14791

Empirical formula C14H10N2 Formula weight 206.24 Temperature 296(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group P c a 21 Unit cell dimensions a = 18.5777(8) Å b = 5.0513(2) Å c = 11.2138(5) Å

Volume 1052.32(8) Å 3 Z 4

Density (calculated) 1.302 Mg/m3

Absorption coefficient 0.078 mm-1 F(000) 432

Crystal size 0.22 x 0.19 x 0.07 mm3 Theta range for data collection 2.19 to 25.10°. Index ranges -22<=h<=22, -5<=k<=6, -13<=l<=13 Reflections collected 6499 Independent reflections 1795 [R(int) = 0.0362] Completeness to theta = 25.10° 98.7 % Absorption correction multi-scan Max. and min. transmission 0.9945 and 0.9829

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 1795 / 1 / 145

Goodness-of-fit on F2 1.034 Final R indices [I>2sigma(I)] R1 = 0.0489, wR2 = 0.1204 R indices (all data) R1 = 0.0765, wR2 = 0.1499 Absolute structure parameter 7(5)

Largest diff. peak and hole 0.241 and -0.299 e.Å -3

145

X-ray crystallographic structure and crystal data of 3a (CCDC No: 930945)

Table 1.Crystal data and structure refinement for 12807. Identification code 12807 Empirical formula C31 H21 I N2 Formula weight 548.40 Temperature 293(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P -1 Unit cell dimensions a = 10.6783(2) Å b = 11.2244(2) Å c = 12.2039(2) Å

Volume 1196.22(4) Å 3 Z 2

Density (calculated) 1.523 Mg/m3

Absorption coefficient 1.361 mm-1 F(000) 548

Crystal size 0.4 x 0.31 x 0.22 mm3 Theta range for data collection 2.04 to 25.01°. Index ranges -12<=h<=12, -13<=k<=13, -13<=l<=14 Reflections collected 9097 Independent reflections 4212 [R(int) = 0.0344] Completeness to theta = 25.01° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.6859 and 0.608

Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4212 / 0 / 307

Goodness-of-fit on F2 1.248 Final R indices [I>2sigma(I)] R1 = 0.0329, wR2 = 0.0998 R indices (all data) R1 = 0.0425, wR2 = 0.1303

Largest diff. peak and hole 0.491 and -0.994 e.Å -3

146

Fluorescence Data Part -Ι, Section-B

(Varian Carry Eclipse Fluorescence spectrophotometer)

The study of Catalyst Free and C opper Catalyzed Reactions

of Cyanochromenes and Sodium Azide

147

Fluorescence Data Wavelength Vs Fluorescence Intensity.

Legand NaCl KCl MnCl2 CaCl2 CdCl2 CoCl2 CrCl3 CuCl2 HgCl2 NiCl2 ZnCl2

Wavelength Intensity Intensity Intensity Intensity Intensity Intensity Intensity Intensity Intensity Intensity Intensity Intensity (nm) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) (a.u.) 370 0.357338 0.318268 0.274771 0.225206 0.301634 0.331476 0.287715 0.296478 1.844093 0.411842 0.032294 0.12244

371.07 0.327345 0.404603 0.26299 0.415869 0.317785 0.401321 0.463239 0.547737 1.977678 0.55144 0.033438 0.158043

372 0.43144 0.464936 0.415641 0.495845 0.438723 0.500258 0.718691 0.762332 2.031816 0.595427 0.021662 0.212425

373.07 0.62507 0.654402 0.646519 0.688542 0.558615 0.69397 0.930158 0.911575 2.078657 0.674296 0.014702 0.277736

374 0.90519 0.914069 0.778765 0.810092 0.834509 1.008204 1.088121 1.099437 2.077837 0.824454 0.035139 0.270149

375.07 1.107689 1.177774 0.931241 1.074578 0.967279 1.323091 1.391834 1.371032 2.214841 1.164049 0.053325 0.376736

376 1.355716 1.396091 1.203639 1.430104 1.293944 1.722387 1.797171 1.810047 2.306002 1.60165 0.052862 0.459469

377.07 1.572014 1.901379 1.559099 1.790796 1.730064 2.350363 2.358873 2.359585 2.416768 2.053454 0.049584 0.468527

378 1.91267 2.320637 2.066084 2.236993 2.313412 3.096214 2.841859 3.121546 2.34876 2.432771 0.039134 0.459621

379.07 2.404157 3.042108 2.635572 2.833091 2.842531 3.848155 3.28595 3.887558 2.432496 2.953233 0.042633 0.566741

380 2.997612 3.867644 3.29833 3.819224 3.668382 4.690478 3.862586 4.855981 2.375494 3.62644 0.046261 0.770861

381.06 3.678038 4.983144 4.152533 4.686858 4.517199 5.681571 4.496118 5.667852 2.438943 4.841745 0.066338 1.010701

381.96 4.470187 6.294235 5.331309 5.508496 5.396885 6.733039 5.076545 6.886927 2.311855 6.296742 0.065689 1.238763

383.03 5.151128 7.416772 6.247731 6.677358 6.390412 7.93536 5.50885 7.920607 2.334208 7.73933 0.071927 1.376921

383.93 5.90801 8.455127 7.308477 8.166589 7.871933 9.178044 6.130099 9.048643 2.488346 9.081997 0.058531 1.622305

385 6.648671 9.33322 8.321785 9.391527 8.938187 10.40936 6.596552 9.946671 2.52833 10.54466 0.076479 1.891123

386.06 7.334542 10.99165 10.18418 10.48941 10.06711 11.762 6.884439 11.05253 2.596238 11.832 0.087455 2.239443

386.96 7.912348 12.46516 11.82371 11.49637 10.9495 12.59831 7.144387 12.14727 2.515136 13.04418 0.086337 2.523189

388.03 8.380829 13.46795 13.00173 12.25263 11.91204 13.29483 7.567694 12.83351 2.743149 14.04521 0.052716 2.765584

388.93 8.754122 13.74781 13.77158 13.00906 12.9839 13.84524 7.982025 13.28128 2.730898 14.95022 0.048878 3.050928

390 9.055948 14.42871 14.56627 13.8307 14.07855 14.5453 8.075912 13.73494 2.971202 15.22066 0.066409 3.360728

391.07 9.297061 15.61276 14.96986 14.51184 14.36026 14.65069 8.078767 14.63949 2.921988 15.95091 0.066409 3.829784

392 9.456803 15.94943 14.81779 14.65656 14.32753 14.93095 7.96806 14.53073 2.986473 16.92975 0.062271 4.260099

393.07 9.541451 15.73705 15.69358 14.94977 14.25195 15.18139 8.000062 14.70868 2.904809 18.09169 0.072433 4.884954

394 9.78428 16.05534 16.70739 15.32615 14.53548 15.43213 8.081452 14.98006 2.939108 17.98735 0.092357 5.298954

395.07 9.702566 16.43697 17.03576 15.56008 14.6017 15.7402 8.428314 15.59689 3.051195 17.96133 0.093075 5.705477

396 9.779817 16.37011 16.96332 15.5326 14.93118 15.99116 8.224073 14.95248 3.199486 17.69937 0.076231 6.283175

397.07 9.720322 16.32045 17.49154 15.28962 14.40793 16.14035 7.987459 15.13287 3.256965 17.98887 0.070051 6.986117

398 9.872073 16.85097 17.48092 15.22779 14.03267 15.85917 7.810217 15.15043 3.248541 17.60094 0.073515 7.651872

399.07 9.734965 16.78338 17.11896 15.40756 14.20701 15.84701 8.016065 15.25104 3.246633 17.93584 0.096762 8.29164

400 9.82082 16.79901 17.17333 15.81027 14.49694 15.62354 8.241375 14.84596 3.174788 17.94296 0.109148 9.269084

401.06 9.789699 16.42924 17.60613 15.76578 14.81842 16.05722 8.222389 15.13718 3.139509 18.17237 0.10237 10.43185

401.96 9.871278 16.69675 17.42589 15.60282 15.09248 16.63909 8.662144 15.60422 3.208395 17.97358 0.09035 11.54525

403.03 9.791863 16.79953 17.09366 15.59399 15.55379 17.27296 8.834531 15.74242 3.162203 17.68655 0.092787 12.71908

403.93 10.03746 17.23098 17.3679 15.9658 15.23338 16.91824 8.987184 15.34192 2.98082 17.88 0.090013 13.59978

405 10.24687 16.8556 17.94893 15.92872 15.69342 16.96546 8.898507 15.40154 2.974635 18.2252 0.091181 14.51617

406.06 10.45692 17.05379 18.15069 16.10975 15.90064 17.27553 9.064392 16.11748 3.040927 18.64246 0.088392 15.21316

406.96 10.37557 17.16618 18.22493 16.39558 16.23443 17.175 9.199216 16.36453 2.995486 18.58055 0.100924 16.27728

408.03 10.50199 17.21676 18.13974 16.51787 16.15229 17.05118 8.975271 16.28131 2.914877 19.38466 0.094967 17.08187

408.93 10.56169 17.21365 18.13791 16.09292 16.36489 17.36462 8.980977 16.40657 2.997818 19.74661 0.113977 17.8273

148

410 10.52009 17.25127 18.56314 16.31534 15.98407 17.64238 8.701705 16.90639 2.983461 19.56774 0.109722 18.27849

411.06 10.30886 17.46802 18.85866 17.1484 16.06439 17.49087 8.708795 16.66669 2.689675 19.26296 0.107465 18.69529

411.96 10.40116 17.68351 18.56782 17.09553 16.12291 17.38457 8.784326 16.50939 2.447107 19.516 0.094496 18.80764

413.03 10.2741 17.49151 18.10937 16.63803 15.78689 17.3088 8.709715 16.19736 2.370327 19.69874 0.112071 18.61748

413.93 9.996448 17.04504 18.31052 15.61735 15.11572 17.14289 8.462693 15.90806 2.369296 18.78189 0.114179 18.65278

415 9.697026 16.63218 18.06775 15.16274 15.10599 16.35392 8.297638 15.50032 2.458328 18.55274 0.104813 18.84322

416.06 9.704212 16.7007 17.42503 14.85265 14.9517 15.40954 8.112797 15.05523 2.536333 18.34916 0.116489 19.16498

416.96 9.410051 16.52499 17.19488 15.37948 14.75385 15.07727 7.680627 14.69996 2.453587 17.51387 0.132483 19.41082

418.03 9.251976 15.97336 16.58968 14.81457 14.35502 14.9882 7.589471 14.46337 2.220471 16.23057 0.128732 19.57925

418.93 8.998427 14.98692 16.62775 13.9465 13.84443 14.33443 7.677501 14.01707 2.21709 15.99805 0.120765 19.57619

420 8.703856 14.80011 16.38259 13.34129 13.45666 13.978 7.213218 13.40913 2.251542 16.57774 0.130633 19.48123

421.06 8.258915 15.06178 16.14372 13.34732 13.17814 13.68166 6.784193 13.034 2.130598 16.16492 0.121985 19.55204

421.96 8.085884 14.93219 15.33381 13.37898 13.00188 13.55366 6.67333 12.75781 2.005602 15.47476 0.112595 19.76994

423.03 8.01919 14.09566 14.84911 12.97796 12.29967 13.13219 6.730073 12.01715 1.850366 14.93087 0.125534 20.11087

423.93 7.728213 13.36284 14.62225 12.65581 12.10763 13.24851 6.52161 11.67179 1.832552 14.72685 0.10066 20.35375

425 7.41535 12.73404 13.62076 11.89557 11.86662 12.37496 6.335494 11.58055 1.92229 14.4675 0.088454 20.58695

426.06 7.12627 12.26518 13.19868 11.39135 11.60048 11.55038 6.027695 11.35761 1.911713 13.81848 0.084707 20.93783

426.96 7.006253 11.76771 12.67096 11.09137 10.94276 10.99267 5.732522 10.68487 1.777539 13.23798 0.091654 21.13778

428.03 6.777296 11.55588 12.36905 10.88251 10.65901 11.03636 5.771875 10.44035 1.602222 12.64513 0.09227 21.1846

428.93 6.545314 11.36253 11.98252 10.78363 10.31659 10.82243 5.459584 10.14339 1.706752 12.27911 0.115747 21.25292

430 6.381044 11.03216 12.00996 10.44617 9.943871 10.09909 5.313716 9.827968 1.725322 11.86026 0.122786 21.49764

431.07 6.189059 10.29318 11.70185 10.28771 9.519052 9.801689 5.032978 9.559813 1.689056 11.54281 0.086051 21.57321

432 5.964405 10.13307 10.94076 9.549022 9.409914 9.571471 5.251888 9.346874 1.519367 11.42327 0.076599 21.64595

433.07 5.730799 9.845742 10.50975 9.256233 9.040242 9.604572 5.020657 8.928691 1.482068 11.10664 0.088383 21.40957

434 5.64515 9.737327 10.10824 8.919421 8.755035 9.396541 4.953983 8.478365 1.495838 10.84719 0.077956 21.13281

435.07 5.506098 9.29532 9.517776 8.620372 8.637897 9.160012 4.590285 8.348787 1.517925 10.05146 0.062267 20.81868

436 5.259907 9.311521 9.402434 8.186223 8.526816 8.488997 4.67384 8.088802 1.4544 9.825503 0.081959 20.64701

437.07 5.092881 8.57165 9.558364 8.006386 8.047561 7.899426 4.571834 7.881826 1.406406 9.62698 0.114002 20.04416

438 4.968572 8.116432 9.506181 8.095245 7.458319 7.983075 4.532119 7.657056 1.31857 9.544088 0.110755 19.51532

439.07 4.811688 7.733559 8.886318 7.758006 7.075624 8.114674 4.275204 7.499734 1.35395 9.159792 0.125177 19.41821

440 4.595332 7.811169 8.57235 7.130063 6.896142 7.724737 4.203615 7.430311 1.313676 9.003014 0.112053 19.3348

441.04 4.391744 7.426099 8.246289 6.611942 6.73791 7.070737 3.865674 7.123536 1.286764 8.448316 0.094408 18.9008

441.94 4.147783 7.13733 8.07956 6.580037 6.728498 6.6396 3.631497 6.812408 1.188998 7.980416 0.083116 18.31829

442.98 3.996305 6.613475 7.560431 6.397546 6.503977 6.549874 3.427191 6.362555 1.189809 7.673948 0.08453 17.9691

444.02 3.861804 6.658994 7.292354 6.144245 6.083419 6.369799 3.604097 6.262983 1.12688 7.304643 0.0864 17.7581

445.07 3.693604 6.670869 7.030214 5.997821 5.729361 6.339575 3.573107 5.904196 1.027939 6.692469 0.105868 17.67639

445.97 3.50492 6.46128 6.812643 5.903816 5.925839 6.027306 3.281683 5.922671 0.98673 6.544014 0.103252 17.18772

447.01 3.413805 6.116995 6.44007 5.568869 5.84463 5.981502 3.160454 5.728723 1.080161 6.354157 0.106115 16.63613

448.05 3.295156 6.001639 6.009693 5.154478 5.397331 5.582983 3.274274 5.276283 1.170779 6.127129 0.10312 16.25776

448.95 3.174117 5.784727 5.814116 4.979864 5.148864 5.476754 3.203941 4.781677 1.093913 5.900756 0.112748 15.85428

450 3.084732 5.320241 5.458577 4.810772 5.089453 5.270808 2.898478 4.546183 0.984172 5.433801 0.082372 15.50706

451.06 2.974525 4.946373 5.257731 4.691273 4.878254 5.124762 2.883233 4.464553 0.869679 5.406704 0.093956 15.20812

451.96 2.824295 4.620942 4.948689 4.323491 4.622315 4.781593 2.79747 4.20869 0.86104 5.389433 0.091705 15.13989

453.03 2.678215 4.704318 4.823478 4.171028 4.509858 4.516017 2.627929 4.049915 0.895946 5.116172 0.097174 14.9491

149

453.93 2.596341 4.601802 4.603527 4.142786 4.16642 4.392956 2.447907 3.913169 0.966189 4.760702 0.095986 14.89008

455 2.545656 4.295969 4.6295 3.992452 3.89581 4.100993 2.396996 3.797243 0.966207 4.694675 0.094842 14.69717

456.06 2.507966 4.144136 4.436852 3.661996 3.863575 3.996615 2.402818 3.697968 0.875584 4.679414 0.073243 14.53084

456.96 2.387737 4.154444 4.196004 3.574466 3.844699 3.846569 2.38108 3.55166 0.814371 4.273742 0.060765 14.5184

458.03 2.243887 3.979381 3.777502 3.514294 3.525686 3.68629 2.36671 3.375558 0.813328 4.038784 0.058251 14.32522

458.93 2.171457 3.609342 3.762784 3.361158 3.440257 3.177975 2.246057 3.290195 0.847661 3.922516 0.087779 14.02484

460 2.142478 3.576504 3.765554 3.256544 3.516291 3.165331 2.108432 3.055645 0.836737 3.887991 0.105629 13.67767

461.06 2.053049 3.431878 4.04374 3.4416 3.352368 3.348966 1.971876 3.076212 0.813578 3.804801 0.102481 13.44349

461.96 1.936013 3.411809 3.848891 3.238316 3.055623 3.255747 1.90745 2.996451 0.740975 3.608785 0.072398 13.23551

463.03 1.796332 3.206307 3.513508 2.972784 2.910703 2.836896 1.809574 2.89857 0.607252 3.303292 0.076181 13.00784

463.93 1.721669 3.180753 3.008088 2.607553 2.980472 2.676452 1.72947 2.54985 0.603994 3.154346 0.078906 12.56552

465 1.73454 2.832715 3.067172 2.587466 2.704569 2.801197 1.692791 2.731949 0.663821 3.045152 0.072753 12.14872

466.06 1.706441 2.434602 3.134744 2.611048 2.661808 2.5976 1.658933 2.887488 0.713251 2.767855 0.058081 11.88214

466.96 1.591759 2.366119 3.149722 2.7151 2.573141 2.407177 1.584295 2.677198 0.618056 2.565415 0.062075 11.68051

468.03 1.557742 2.619571 2.795572 2.728425 2.480251 2.295789 1.6894 2.373527 0.684252 2.739904 0.056885 11.37914

468.93 1.610002 2.611838 2.697815 2.631143 2.316861 2.388271 1.588457 2.341415 0.728994 2.719946 0.075791 11.22195

470 1.481887 2.383293 2.665811 2.404911 2.323605 2.165027 1.465584 2.212564 0.655522 2.526315 0.085532 10.89219

471.04 1.431444 2.339146 2.598185 2.225178 2.332079 2.128624 1.385416 2.103677 0.568958 2.504742 0.080223 10.4055

471.94 1.373697 2.30863 2.488875 2.138959 2.141588 2.245834 1.415668 2.003164 0.562603 2.49763 0.053671 9.839501

472.98 1.378343 2.328795 2.261892 2.040521 1.945057 2.340445 1.353951 1.922917 0.584892 2.366224 0.065931 9.466042

474.02 1.247297 2.253046 2.285372 1.846296 1.851001 2.14758 1.352038 1.790821 0.567806 2.108496 0.074523 9.298311

475.07 1.271051 2.189065 2.382612 1.866628 1.837706 1.965417 1.298528 1.80693 0.602152 1.946768 0.059494 9.18562

475.97 1.195929 1.964572 2.454607 1.971798 1.784629 1.940883 1.205726 1.776265 0.536506 1.826408 0.038298 8.836132

477.01 1.073569 1.94761 2.173569 1.967514 1.667477 1.811739 1.155652 1.699052 0.496206 1.918492 0.025349 8.466685

478.05 0.982597 1.896329 2.03614 1.658731 1.760499 1.76848 1.227139 1.689511 0.490501 2.042153 0.03737 8.098327

478.95 0.967304 1.778321 1.946412 1.563153 1.793468 1.766402 1.086731 1.667042 0.529211 1.970163 0.056141 7.818152

480 1.019912 1.579134 1.853805 1.741588 1.703179 1.723316 0.926541 1.594306 0.515422 1.737929 0.056981 7.547624

481.06 0.953052 1.519951 1.785153 1.769513 1.501767 1.388497 0.875792 1.430063 0.454877 1.596337 0.036412 7.368653

481.96 0.916025 1.667997 1.86834 1.575044 1.475671 1.277996 1.005532 1.439214 0.426729 1.66962 0.038739 7.128667

483.03 0.90761 1.528094 1.874267 1.386759 1.316271 1.21127 1.081149 1.422214 0.454127 1.682243 0.053684 6.957518

483.93 0.970354 1.413687 1.780805 1.374952 1.296037 1.358006 1.002852 1.385744 0.511447 1.563843 0.050211 6.800912

485 0.940077 1.450293 1.427397 1.453185 1.340274 1.441172 0.856174 1.297939 0.4743 1.415109 0.06018 6.688668

486.06 0.882467 1.664134 1.336903 1.419513 1.430383 1.439531 0.786008 1.290458 0.501724 1.429081 0.068023 6.518078

486.96 0.774917 1.529348 1.289264 1.338628 1.183578 1.269105 0.855963 1.179385 0.429184 1.282761 0.069097 6.292657

488.03 0.732297 1.364303 1.397454 1.145594 1.116937 1.249818 0.950817 1.101092 0.476975 1.208595 0.059237 6.038095

488.93 0.787868 1.203003 1.316874 1.158986 1.110039 1.253083 0.82184 1.073289 0.448871 1.128358 0.043288 5.77824

490 0.732069 1.21672 1.235571 0.932049 1.172257 1.154695 0.754762 1.102288 0.426367 1.209319 0.047414 5.503687

491.04 0.6352 1.105622 1.191498 0.891149 1.074419 0.960758 0.682749 1.110436 0.336802 1.147943 0.061475 5.370266

491.94 0.616322 1.091684 1.133715 0.93559 1.005419 0.891788 0.576912 1.042983 0.35222 1.151788 0.07404 5.252993

492.98 0.685828 0.96821 1.084972 1.008384 0.934083 0.878122 0.42479 0.947155 0.376723 1.143087 0.038192 5.104867

494.02 0.642936 1.012303 1.067367 0.906418 0.898122 1.049491 0.567842 0.948373 0.383663 1.092773 0.024888 4.913668

495.07 0.620426 0.96467 1.074548 0.939784 0.93309 0.952645 0.7052 0.86016 0.406665 1.04587 0.030257 4.862017

495.97 0.592483 0.896913 0.981477 0.887433 0.968603 0.896075 0.706036 0.786729 0.400203 1.052112 0.051571 4.674525

497.01 0.628693 0.903055 0.937148 0.788594 0.96818 0.835278 0.680765 0.69324 0.425366 0.923582 0.052457 4.456454

150

498.05 0.677215 0.967568 0.953583 0.665574 0.867768 0.899433 0.731537 0.683468 0.385049 0.862626 0.046174 4.260889

498.95 0.624164 1.042679 0.941849 0.751795 0.872417 0.758676 0.635203 0.741607 0.31123 0.887331 0.049743 4.16463

500 0.603262 0.956477 0.961674 0.783702 0.878745 0.781527 0.506275 0.873967 0.258492 1.039927 0.045597 4.039943

501.04 0.533159 0.888766 0.987318 0.875956 0.779193 0.791975 0.507097 0.886193 0.337857 0.917515 0.040014 4.017083

501.94 0.480186 0.808368 0.903385 0.886164 0.748844 0.797566 0.664276 0.842395 0.447196 0.805488 0.014773 3.985564

502.98 0.474755 0.812709 0.816891 0.853065 0.795514 0.791235 0.679999 0.640489 0.459905 0.762399 0.024332 3.879355

504.02 0.486894 0.780618 0.84672 0.705621 0.7645 0.808183 0.655959 0.594166 0.446825 0.879932 0.032197 3.695063

505.07 0.471703 0.763639 0.807319 0.533545 0.734087 0.793552 0.644532 0.611416 0.396888 0.878688 0.025591 3.545655

505.97 0.401726 0.700229 0.913214 0.593171 0.677825 0.805396 0.612782 0.691176 0.364899 0.850274 0.018857 3.257583

507.01 0.513489 0.734542 0.949958 0.818428 0.721221 0.885151 0.510653 0.686732 0.290769 0.732711 0.054421 3.104338

508.05 0.53156 0.795107 0.926757 0.908026 0.65997 0.877144 0.512488 0.734486 0.312275 0.819781 0.063543 3.104284

508.95 0.481312 0.816485 0.833112 0.771706 0.790317 0.832691 0.502268 0.787149 0.344171 0.842285 0.054905 3.126093

510 0.344048 0.752622 0.853383 0.629734 0.775413 0.72268 0.477662 0.697995 0.376465 0.854088 0.032344 2.906307

511.04 0.33316 0.712854 0.791276 0.543555 0.758725 0.748644 0.455252 0.768248 0.292281 0.75542 0.032478 2.711366

511.94 0.408243 0.64471 0.811804 0.532958 0.723802 0.696609 0.499964 0.819869 0.296333 0.702732 0.034697 2.643179

512.98 0.49228 0.518872 0.798701 0.53322 0.7561 0.768047 0.504658 0.81496 0.359073 0.690353 0.037615 2.676877

514.02 0.478953 0.510047 0.765788 0.515811 0.717502 0.722921 0.505494 0.706376 0.394333 0.806634 0.019851 2.636376

515.07 0.439506 0.560378 0.737185 0.422498 0.652256 0.74414 0.51813 0.678322 0.384232 0.703382 0.003933 2.44178

515.97 0.405551 0.702652 0.795405 0.453009 0.653424 0.6388 0.535019 0.78968 0.34604 0.731294 0.009341 2.320555

517.01 0.409722 0.732361 0.882446 0.527504 0.709716 0.706003 0.542948 0.778606 0.380276 0.739008 0.017915 2.218939

518.05 0.460152 0.77434 0.920894 0.665878 0.718389 0.65658 0.515272 0.74853 0.416318 0.916375 0.019212 2.134729

518.95 0.408962 0.75895 0.786763 0.596316 0.726492 0.599648 0.500903 0.768302 0.564843 0.896766 0.02737 1.928468

520 0.395374 0.753407 0.582518 0.705339 0.774054 0.645923 0.584108 0.790583 0.550968 0.916698 0.032265 1.924798

521.04 0.387059 0.728249 0.712577 0.702946 0.784542 0.814744 0.582249 0.713299 0.428888 0.854067 0.046672 2.000742

521.94 0.500665 0.714061 0.923194 0.787867 0.785344 0.906188 0.532706 0.742893 0.364653 0.796079 0.026107 1.948397

522.98 0.511432 0.841205 0.981598 0.651979 0.750658 0.885634 0.423515 0.829144 0.448521 0.796753 0.004498 1.809987

524.02 0.553025 0.922547 0.823191 0.666396 0.764768 0.985484 0.556285 0.745446 0.426787 0.800464 -0.00257 1.683942

525.07 0.607109 1.039613 0.73248 0.642969 0.767029 0.980429 0.655766 0.678572 0.359625 0.872779 0.043091 1.674196

525.97 0.604201 0.959636 0.737747 0.725088 0.81927 0.919233 0.669285 0.739557 0.427357 0.870843 0.046073 1.608562

527.01 0.615151 0.931029 0.778858 0.757472 0.806674 0.830165 0.526352 0.853524 0.512106 0.957885 0.031641 1.579869

528.05 0.634846 0.986202 0.876853 0.862895 0.815843 0.878852 0.510176 0.843042 0.472435 0.949301 0.024163 1.496776

528.95 0.680778 1.038536 0.897528 0.912222 0.860535 0.945758 0.624171 0.924088 0.42754 0.920263 0.037127 1.433163

530 0.620789 0.962541 0.984244 0.964441 0.932674 1.009018 0.701838 0.892843 0.422561 0.881346 0.027292 1.390767

531.02 0.637158 0.881875 1.008356 0.928342 0.944659 1.056075 0.723654 0.999283 0.459851 1.020385 0.021269 1.340625

532.05 0.59812 0.980436 0.995419 1.000214 0.961155 1.12641 0.641458 0.997975 0.453825 1.011559 0.02784 1.330711

532.94 0.576237 1.072538 1.037001 0.854952 0.977907 1.13776 0.675047 0.974524 0.394275 1.013093 0.030681 1.321825

151

LIST OF PUBLICATIONS

1) Catalyst free and Cu catalyzed reactions of cyanochromenes and sodium azide: Synthesis of benzofurans and chromenotetrazoles Sachin D. Gawande, Mustafa J. Raihan, Manoj R. Zanwar, Veerababurao Kavala, Donala Janreddy, Chun-Wei Kuo, Mei-Ling Chen, Ting-Shen Kuo, Ching-Fa Yao* Tetrahedron 2013, 69 (8), 1841-1848. 2) Molecular Iodine-Mediated Cascade Reaction of 2-Alkynylbenzaldehyde and Indole: An Easy Access to Tetracyclic Indoloazulene Derivatives Sachin D. Gawande, Veerababurao Kavala, Manoj R. Zanwar, Chun-Wei Kuo, Hsiu-Ni Huang, Chiu-Hui He, Ting-Shen Kuo, and Ching-Fa Yao,* Adv. Synth. Catal. 2013, 355, 3022 – 3036. 3) Synthesis of Dibenzodiazepinones via Tandem Copper (I) Catalyzed C-N Bond Formation Sachin D. Gawande, Veerababurao Kavala, Manoj R. Zanwar, Chun-Wei Kuo, Wen- Chang Huang,* Ting-Shen Kuo, Hsiu-Ni Huang, Chiu-Hui He, and Ching-Fa Yao* Adv. Synth. Catal. 2014, Early View DOI: 10.1002/adsc.201301020 4) One Pot Synthesis of 2-Arylquinazoline and Tetracyclic-Isoindolo[1,2- a]quinazoline Derivatives via Cyanation Followed by the Rearrangement of o- Substituted 2-Halo-N-Arylbenzamides Sachin D. Gawande, Manoj R. Zanwar, Veerababurao Kavala, Chun-Wei Kuo, Ching-Fa Yao* Adv. Synth. Catal. 2014, Manuscript under revision

5) FeCl3 Catalyzed Regioselective C-Alkylation of Indolylnitroalkenes with Amino Group Substituted Arenes Manoj R. Zanwar, Veerababurao Kavala, Sachin D. Gawande, Chun-Wei Kuo, Wen- Chang Huang,* Ting-Shen Kuo, Hsiu-Ni Huang, Chiu-Hui He, and Ching-Fa Yao* J. Org. Chem. 2014, 79, 1842-1849. 6) Synthesis of 3-Substituted 2-Aminonaphtho[2,3-b]furan-4,9-diones from 2- Hydroxy-1,4-Naphthoquinone and Nitro alkenes Manoj R. Zanwar, Veerababurao Kavala, Sachin D. Gawande, Chun-Wei Kuo, Hsiu-Ni Huang, Chiu-Hui He, Ting-Shen Kuo, Ching-Fa Yao Eur. J. Org. Chem 2013, 8288- 8298.

152

7) Alcohol Mediated Synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylate Derivatives from 4-Hydroxycoumarins Manoj R. Zanwar, Mustafa J. Raihan, Sachin D. Gawande, Veerababurao Kavala, Donala Janreddy, Chun-Wei Kuo, Ram Ambre, and Ching-Fa Yao*J. Org. Chem. 2012, 77(15), 6495-6504. 8) Iron/Acetic acid Mediated Intermolecular Tandem C-C and C-N Bond Formation: An Easy Access to Acridinone and Quinoline Derivatives Rajawinslin. R. R, Sachin D. Gawande, Veerababurao Kavala, Yi-Hsiang Huang, Chun- Wei Kuo, Ting-Shen Kuo, Mei-Ling Chen, Chiu-Hui He and Ching-Fa Yao*RSC Adv., 2014, Accepted Manuscript

153