以銅與碘催化碳-碳、碳-氮鍵生成的方式合成具有生物活性的核心結構

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(1)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.

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

(3) 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..

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

(5) 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, LinYin 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. TingShan 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..

(6) 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.

(7) 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.

(8) 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.

(9) Section D: One Pot Synthesis of 2-Arylquinazoline and Tetracylic-Isoindolo[1,2a]quinazoline via Cyanation Followed by Rearrangement of o-Substituted 2-Halo-NArylbenzamide 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.

(10) 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. o. C. 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.

(11) 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.

(12) 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.

(13) 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. SN2. 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.

(14) 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,.

(15) 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..

(16) 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 2iodoaniline 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 triazapentacyclic 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 TetracyclicIsoindolo[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 osubstituted 2-halo-N-arylbenzamides. Using Dimethyl sulfoxide (DMSO) as the solvent, the cleavage of the tetracyclic isoindole fused quinazoline leads to the formation of 2arylquinazoline drivatives..

(17) Scheme 4: Synthesis of 2-arylquinazoline and tetracyclic isoindole fused quinazoline.. The wide range of substrates such as 2-phenylquinazolin-4-amine, 4-methyl-2phenylquinazoline 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.

(18) 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.

(19) 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.

(20) 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 crosscoupling 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 1.

(21) 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 ochlorobenzoic 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 2.

(22) 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. 3.

(23) 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 Oarylation and N-arylation via reaction of aryl boronic acid and substituted anilines or 4.

(24) 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 coworkers reported a Copper catalyzed efficient C-N bond formation reaction by using. 5.

(25) 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, 6.

(26) 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 coppercatalyzed 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 oxazole by using Cu(OAc)2 (Scheme I.A.4.2).23 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 oiodoacetanilide. derivatives. and. terminal. 7. alkyne. using. N-methylpyrrolidine-2-.

(27) 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 coworkers have demonstrated the synthesis of 2-substituted indole by the reaction of N-(2halophenyl)-2,2,2-trifluoroacetamide and terminal alkyne (Scheme I.A.5.1).27 Copper 8.

(28) iodide and L-proline was the effective catalytic system used to afford corresponding 2substituted 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 9.

(29) using picolinic acid as a ligand at 90-110oC heating gave corresponding 4Oxopyrimido[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 alkylsubstituted 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. 10.

(30) (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.. 11.

(31) 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-5ylidene [CuCl(TPh)] as an efficient catalyst for the synthesis of 1,4-substituted 1,2,3triazoles (Scheme I.A.6.2).40 The catalyst effective in reducing the reaction time and efficiently worked with sterically hindered azides and alkynes.. 12.

(32) Scheme I.A.6.2 Recently, Shin et al. have presented the synthesis of 1,4-disubstituted triazole via CopperCatalyzed 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-haloN-(prop-2-yn-1-yl)benzenesulfonamide derivative with azidotrimethylsilane, DIPEA as a 13.

(33) 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 14.

(34) Recently, A novel copper (I) catalyzed azide–alkene aerobic oxidative cycloaddition protocol was developed from our group for the regioselective synthesis of 1,4disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles (Scheme I.A.7.4).46 When electrondeficient 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.. 15.

(35) 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) 16.

(36) 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.. 17.

(37) 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), antiasthmatic 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 18.

(38) 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 19.

(39) 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 3functionalized benzo[b]furan derivatives was successfully carried out by the reaction 20.

(40) 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-3cyanobenzofuran derivative was formed. The structure was verified by 1H NMR,. 13. C. 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 3cyanobenzofuran derivatives directly from 3-cyanochromenes.. Scheme I.B.3.1. Reactivity of sodium azide towards nitro and cyanochromene. 21.

(41) 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 22.

(42) 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. c. mentioned temp. 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 23.

(43) 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-3cyanochromene (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 24.

(44) Table I.B.3.2. Synthesis of benzofuran and benzothiophene derivatives. Continue………….. 25.

(45) a. All reactions were carried out on 0.5 mmol scale. b NaN3 (1.2 equiv.) in DMSO at 160oC.. 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 26.

(46) 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.. 27.

(47) Table I.B.3.4.. Synthesis of chromenotetrazoles. 28.

(48) Continue…………... a. All reactions were carried out on 0.5 mmol scale. b 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 29.

(49) 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.. 30.

(50) 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 3methylmorpholine 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.. 31.

(51) 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. 32.

(52) 25. Fluorescence Intensity. Ligand NaCl. 20. KCl MnCl2. 15. CaCl2 CdCl2 CoCl2. 10. CrCl3 CuCl2. 5. 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 3cyanobenzofuran 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.. 33.

(53) 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. 34.

(54) 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, 2H), 2.67 (s, 3H);. 13. 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 = 8.44 Hz, 1H), 2.64 (s, 3H), 2.46 (s, 3H); 13C 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);. 13. C NMR (100 MHz,. CDCl3) δ 164.6, 145.4, 143.2, 127.8, 125.5, 113.5, 111.8, 107.8, 91.9,. 35.

(55) 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 MHz, CDCl3) δ (ppm) 7.02 (s, 2H), 3.95 (s, 3H), 2.62 (s, 3H);. 13. 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), 7.28-7.34 (m, 1H), 2.67 (s, 3H); 13C 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);. 13. C 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);. 13. C 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) 36.

(56) 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);. 13. C. 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);. 13. C 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);. 13. C 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) 37.