硝基烯與環狀1,3-雙羰基化合物在水的條件下進行反應之探討以及內環磺胺類衍生物之合成

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(1)REACTIONS OF NITROALKENES WITH CYCLIC 1,3DICARBONYL COMPOUNDS UNDER “ON WATER” CONDITION AND NOVEL SYNTHESIS OF FUSED SULTAM DERIVATIVES. A Dissertation Submitted to the National Taiwan Normal University for the Degree of Doctor of Philosophy in Chemistry. Submitted by Deepak Kumar Barange 897420069. Advisor Prof. Dr. Ching-Fa Yao. Department of Chemistry National Taiwan Normal University Taipei – 116 TAIWAN, R.O.C. June 2012. 1.

(2) Prof. Dr. Ching-Fa Yao Department of Chemistry National Taiwan Normal University 88, Sec. 4, Tingchow Road Taipei, Taiwan 116 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 “Reactions of nitroalkenes with cyclic 1,3-dicarbonyl compounds under ‘on water’ condition and novel synthesis of fused Sultam derivatives” submitted by Deepak Kumar Barange, 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 –116 TAIWAN R.O.C.. 2.

(3) CANDIDATE’S DECLARATION I hereby declare that the work presented in the dissertation entitled “Reactions of nitroalkenes with cyclic 1,3-dicarbonyl compounds under ‘on water’ condition and novel synthesis of fused Sultam derivatives” submitted for Ph.D. degree to National Taiwan Normal University, Taipei, Taiwan. The work has been carried out by me 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 part of this work was not submitted by me for another degree or diploma to this or any other university. Mr. Yu-Chen Tu, has also written some part of this thesis (Part-I, Section-D and Part-II, section B) in his masters dissertation. In keeping with the general practice, due acknowledgements have been made, wherever the work described based on the findings of other investigators. Any inadvertent omissions that might have occurred, due to oversight or error in judgment are regretted.. Deepak Kumar Barange Date: June 2012 Department of Chemistry National Taiwan Normal University Taipei 116 TAIWAN R.O.C.. 3.

(4) Dedicated to my Late grandparents. 4.

(5) Acknowledgement I would like to express my sincere and humble gratitude to my Ph.D. advisor Prof. Dr. ChingFa Yao, for his valuable guidance and financial support during my Ph.D. study at National Taiwan Normal University. He provided continuous encouragement, good teaching and lots of a trouble shooting ideas during my Ph.D. career. He helped me a lot during tough situation in my Ph.D. study. 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. Tun-Cheng Chien, Prof. Dr. Jenghan Wang, Prof. Dr. Cheng-Huang Lin, Prof. Dr. Wen-Chang Huang, Prof. Dr. Way-Zen Lee, Prof. Dr. Kwunmin Chen, Prof. Dr. Ming-Chang P. Yeh, Prof. Dr. Wenwei Lin, for their excellent guidance during my course work. I am particularly thankful to Dr.Veerababurao Kavala, Dr. B. Ramaraju, Dr. William J. Bosco, Dr. Chun-Wei Kuo and Dr. Ju-Tsung Liu for their kind help and co-operation 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. Mustafa Jahir Raihan, Ram Ambre, Balraj Gopula, Donala Janreddy, Sachin Gawande, Manoj Zanwar, Rajawinslin, Chen Hsuan Tsai, Chi Tseng, Po Min Lei, Tze-Huei Yan, Ting-Wei Lin, YuChen Tu, Ying-tsang Lan, Qiao-Zhi Guan, Lin-Yin Chiu, Wei Chieh Yang, Yu-hsuan Wang, Wan-Yu Lin, Moe, Liu, Chen-Chuan Wang, Winnie, 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 also thank to government of Taiwan (MOFA) for providing me Taiwan Scholarship for doctoral study. I am grateful to all of my friends in Taiwan. Especially, Dhananjay Magar, Surendhar Reddy, Pandit Ambre, Sachin Shivatare, Sandeep Mane, Suman Alishety, Dr. Raju Reddy, Dr. Sheshu Babu, Dr. Anwar, Dr. Girish Kulkarni, Dr. Yedukondalu, Dr. J. Damodar, Dr. Santosh, for their friendship and cooperation during my stay in Taiwan.. 5.

(6) Furthermore I am deeply indebted to my former supervisors Dr. Manojit Pal at Dr. Reddy’s Laboratories, Hyderabad (India), and Dr. C.V Ramana, Dr. Mohan M, Bhadbhade, Dr. V.R.Peddireddi at National Chemical Laboratory, Pune (India), for their valuable guidance, support and encouragement. I also thank my colleagues Dr.V.R.Batchu, Dr. N.K.Swamy, Dr. Abdul Razzak, Dr. Mohosin Layak, Amar Reddy, Nishad T.C for their great friendship and help. I would like to thank, Prof. Dr. Ashok Kumar Sharma, Prof. Dr. Pratibha Sharma, Prof. Dr. Prasad, Prof. Dr. Pandey, Prof. Dr. Chouhan, Prof. Dr. Bajaj, and Prof. Dr. Savita Khare at Devi Ahilya University, Indore, Madhya Pradesh, INDIA. I also would like to thank to all my school and college level teachers and lecturers for their excellent teaching, valuable guidance and motivation. I take this opportunity to thank my childhood best friends especially Manish Patel, Mahesh Ingle, Mukaram Chouhan and Manish Thakre for helping me get through the difficult times, and for their emotional support and encouragement. I would like to thank my parents, they sacrificed a lot for me. Without their blessing I would not have been achieved my goal. There are no words to express my gratitude for them. My brother Dileep Barange, he is not only brother but also my guru (teacher), my best friend, guide and motivator. I also thank to my sister Deepti Parihar, and brother-in-law Mr. Satish Parihar and their cute childrens, Bhavya and Manan and sister-in-law Madhulika Barange, her cute baby Krishu, for their unconditional love and support throughout my life journey. My heartfelt, acknowledgment must go to my beloved wife Shweta Barange. She supported me, encouraged me and loved me during my PhD study in abroad. Last but not least I express my hearty thank to almighty Lord Shiva for his immense blessings on me throughout my life.. Deepak Kumar Barange. 6.

(7) TABLE OF CONTENTS Page Abbreviations. 10. Abstract. 14. Part I Part I, Section-A: Overview on “on water” reactions and Michael addition I.A.1 Introduction. 24. I.A.2 “On water” approaches. 25. I.A.3 Michael addition in the presence of water. 39. I.A.4 “On water” Michael addition. 40. I.A.5 References. 41. Part I, Section-B: Facile and highly efficient method for the C-alkylation of 2hydroxy-1,4-naphthoquinones to nitroalkenes under catalyst free ‘on water’ conditions I.B.1 Introduction. 46. I.B.2 Review of literature. 47. I.B.6 References. 50. Part I, Section-C: Synthesis of C3-nitroalkylated-4-hydroxycoumarin and hydroxyiminodihydrofuroquinolinone derivatives via Michael addition of cyclic 1,3-dicarbonyl compounds to -nitrostyrenes I.C.1 Introduction. 52. I.C.2 Review of literature. 54. I.C.6 References. 54. 7.

(8) Part I, Section-D: A mild and convenient one-pot, two-step synthesis of hydroxyiminodihydrobenzofurans mediated by silica gel under microwave activation conditions I.D.1 Introduction. 58. I.D.2 Review of literature. 58. I.D.6 References. 60. Part II Part-II, Section-A: Overview on cyclic sulfonamides (Sultam) and triazoles II.A.1 Introduction. 63. II.A.2 Synthetic approaches to sultam. 65. II.A.3 Overview on synthesis of triazoles. 75. II.A.6 References. 79. Part-II, Section-B: One-pot Synthesis of Triazolothiadiazepine-1,1-dioxide Derivatives via Copper Catalyzed Tandem [3+2] Cycloaddition/N-Arylation II.B.1 Introduction. 81. II.B.2 Review of literature. 81. II.B.6 References. 82. Part-II, Section-C: Synthesis of Angular Dibrominated Furosultam Scaffolds via NBS mediated Bromocyclization Strategy II.C.1 Introduction. 85. II.C.2 Review of literature. 85. II.C.6 References. 86. 8.

(9) Part-II, Section-D: Regioselective synthesis of 4-iodo-2,3,-disubstituted thiophene fused sultam derivatives via iodocyclization strategy and its application towards triazole linker II.D.1 Introduction. 88. II.D.2 Review of literature. 89. II.D.6 References. 89. LIST OF PUBLICATIONS. 91. 9.

(10) Abbreviations Å. angstrom. A. acetyl. Ac2O. acetic anhydride. AcOH. acetic acid. AgNO3. silver nitrate. AgOTf. oxo(trifluoromethylsulfonyl)silver. aq.. aqueous. Boc. butyloxycarbonyl. Bu. butyl. n-BuLi. butyllithium. t-Bu. tert-butyl. t-BuOH. tert-butanol. br. broad (IR). brs. broad singlet (NMR). Bz. benzoyl. o. C. degree Celsius. CDCl3. chloroform (deuterated). cm. centimeter. CH3NO2. nitromethane. 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. DEAD. diethyl azodicarboxylate. DIEPA. N,N-diisopropylethyl amine. DMF. N,N-dimethylformamide. DMSO. dimethyl sulfoxide. 10.

(11) DMAD. dimethyl acetylenedicarboxylate. EI. electron impact. Et3N. triethyl amine. EtOAc. ethyl acetate. Et2O. diethyl ether. EtOH. ethanol. equiv.. equivalent(s). FAB. fast atom bombardment. FT. Fourier transform. h. hour (s). hν. irradiation with light. HBr. hydrogen bromide. HCl. hydrochloric acid. H2 O. water. HRMS. high resolution mass spectrometry. Hz. hertz. IBX. o-iodoxybenzoic acid. IR. infrared spectrometry. KBr. potassium bromide (IR). K2CO3. potassium carbonate. KF. potassium fluoride. KOH. potassium hydroxide. LCMS. low resolution mass spectrometry. Me. methyl. Me2NH. dimethylamine. Me2SO4. dimethyl sulfate. mg. milligram. MgSO4. magnesium sulfate. MHz. megahertz. min. minutes. mL. milliliter(s). mmol. millimole(s). MnO2. manganese dioxide. mol. mole(s) 11.

(12) mp. melting point. MS. mass spectrometry. MW. microwave. μL. microliter (s). N. equivalents per liter (Normality). Na2CO3. sodium carbonate. NaH. sodium hydride. NaHCO3. sodium bicarbonate. NH4Cl. ammonium chloride. NaIO4. sodiumperiodate. NIS. N-iodosuccinimide. NBS. N-bromosuccinimide. NCS. N-chlorosuccinimide. NMR. nuclear magnetic resonance. NH2NH2. hydrazine. NH4OAc. ammonium acetate. Na2SO4. sodium sulfate. Ni2B. nickel boride. Nu. nucleophile. 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. ppm. parts per million. q. Quartet (NMR). Rf. retention factor. rt. room temperature. s. singlet (NMR). SiO2. silicon dioxide. SN2. substitution nucleophilic bimolecular. t. triplet (NMR). TsNBr2. N, N-dibromo-p-toluenesulfonamide 12.

(13) TBAF. tetrabutylammonium fluoride. TFA. trifluoroacetic acid. TFAA. trifluroacetic anhydride. TLC. thin layer chromatography. TMSN3. Trimethylsilyl azide. UV. ultraviolet. 13.

(14) ABSTRACT OF THE THESIS “Reactions of nitroalkenes with cyclic 1,3-dicarbonyl compounds under ‘on water’ condition and novel synthesis of fused Sultam derivatives” The content of this dissertation is divided into three parts. The part I is subdivided into four sections. Section A, illustrate the overview on ‘on water’ reactions and related literature review. Section B and C describes the ‘on water’ reactions of nitrosytrenes with cyclic 1,3-dicarbonyl compounds and also the synthesis of hydroxyiminodihydrofuroquinolinone derivatives. Section D deals with one-pot, twostep synthesis of hydroxyiminodihydrobenzofurans mediated by silica gel under microwave activation condition. Part II deals with the synthesis of fused sultam derivatives by using transition metal catalysed reactions and their appliation towards diversity oriented synthesis. Part II is subdivided into four sections. Section A, deals with overview, classification and synthetic approaches of fused Sultam derivatives. This section also describe the brief overview on triazole synthesis and literature survey. Section B, describes an efficient and one-pot synthesis of triazolothiadiazepine-1,1-dioxide derivatives via copper catalyzed tandem [3+2] cycloaddition/N-Arylation and utilization of this method to synthesize indoline and thiophene fused sultam. Section C deals with the novel synthesis of angular diborminated furosultam derivaitves via bromocyclization strategy. This method is also applicable for the synthesis of tetrahydrofuroisoquinolin5(9bH)-one. Section D, demonstrate an efficient and regioselective synthesis of 4iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide. derivatives. via. iodocyclization approach. The resulting 4-iodo-2,3-disubstituted-2H-thieno[3,2e][1,2]thiazine-1,1-dioxide utilized to couple with a array of boronic acids (Suzuki coupling) and activated alkenes (Heck coupling). The Sonogashira coupled product was efficiently transformed to azido precursor, which was exploited for the diversity oriented synthesis of triazole linked thieno-sultam derivatives. Part III comprises of 1H and 13C NMR spectral copies and X-Ray crystallograpic data of all the compounds incorporated in this thesis.. 14.

(15) PART-I Part-I, Section-A: Overview on “On water” reactions and Michael addition The sections describes the overview and importance of “on water” reactions and Micheal addition. This section also involves the literature survey of the “on water” Michael addition reactions. Part-I, Section-B: Facile and highly efficient method for the C-alkylation of 2hydroxy-1,4-naphthoquinones to nitroalkenes under catalyst free ‘on water’ conditions This section deals with C-alkylation of 2-hydroxy-1,4-naphthoquinones to nitroalkenes which is achieved under catalyst free ‘on water’ conditions. The mechanism for the formation is explained on the basis of dual activation of nitroalkene and 2-hydroxy-1,4-naphthoquinones via hydrogen bonding. Simple reaction conditions, high yields of the products, and environmentally acceptable medium are attractive features of this method. The reaction affords 2-hydroxy-3substituted naphthoquinone derivatives in excellent to good yields and purity, often without work up procedure. O. O. NO2. + R OH. H H OH. NO2. O. O. R O. O O O. O. R. N O H. H. O. O. H O. R. H. H. 15. O H. H N OH O.

(16) Scheme 1. Synthesis of C-alkylated of 2-hydroxy-1, 4-naphthoquinones via reaction of 2hydroxy-1,4-naphthoquinones to nitroalkenes. CH3 NO2 O. NO 2 O. H 3C. D2 O. NO2. H 2O. o. 80 C, 10h. D OH. NO2 OH. 80 o C, 16h. OH O. 85 %. O. O. 80 %. O. Scheme 2. Michael addition of 2-hydroxynaphthoquinone with 1-nitrocyclohexene ‘on water’ and C-alkylation with 4-methyl-β-nitrostyrene ‘on deuterated water’.. Part-I, Section-C: Synthesis of C3-nitroalkylated-4-hydroxycoumarin and hydroxyiminodihydrofuroquinolinone derivatives via Michael addition of cyclic 1,3-dicarbonyl compounds to β-nitrostyrenes This section demonstrates the 4-hydroxycoumarin and 4-hydroxy-1-methylquinolin2(1H)-one reacted smoothly with various β-nitrostyrenes to furnish C3-nitroalkylated 4-hydroxycoumarin. under. sonication. ‘on. water’. condition. and. hydroxyiminodihydrofuroquinolinone derivatives at ambient condition as a mixture of Z (minor) and E (major) isomers, respectively. Mild reaction conditions, easy isolation and excellent yields of the products are the important features of the methodology. OH N O Ar NO2. OH. Water Sonication. Ar X. O. 30 o C 6h to 16h X=O. OH. X NO2. X. + O Ar. DIPEA (10 mol %) ___________________ rt, 1h to 4h X = NCH3. O. Substituted phenyl Z ( minor) : E ( major) O. Ar N OH. X. Ar = Substituted phenyl, 2-furyl, 2-thienyl. O. ( Not observed ). Scheme 3. The reactivity of 1,3-dicarbonyl compounds to -nitrostyrenes.. In order to confirm the mechanism Michael addition of 4-hydroxycoumarin with nitrostyrenes in D2O under sonication was carried out, which proves that proton comes from water.. 16.

(17) CH 3. CH 3. OH. OH NO 2 O. OH +. ))), 18h 30 oC. D. O. D2 O O. O 2N. O. R. ))), 10h. O. 30 oC. R = 4-CH 3-C6 H 4. ( 94 %). NO 2. H2 O O. H. ( 92 %). Scheme 4. Reaction of 4-hydroxycoumarin and (E)-1-methyl-4-(2-nitrovinyl)benzene on H2O/D2O under sonication at 30 oC.. 4-hydroxy-N-methylquinolinone undergo for C-alkylation with -nitrostyrenes followed by cyclization to produce the angular hydroxyiminodihydrofuroquinolinone derivatives in regioselective manner under mild reaction condition at room temperature. OH N OH. O +. NO2. R. N O CH3. R. DIPEA (10 mol %) Methanol rt, 0.5-3 h. N O CH 3. 82-92 %. R = Substituted aryl. Scheme 5. Synthesis of angular hydroxyiminodihydrofuroquinolinone derivatives.. Part-I, Section-D: A mild and convenient one-pot, two-step synthesis of hydroxyiminodihydrobenzofurans mediated by silica gel under microwave activation conditions This section demonstrates a convenient one-pot, two-step procedure for the synthesis of hydroxyiminodihydrobenzofurans assisted by microwave irradiation in presence of silica gel. O. O Silica Gel R. NO2. R1 R2. O. MW 60 o C, MeOH. R = isopentyl, Ph, Ph-(CH 2) 2, 4-OMe-Ph, 4-Me-Ph, 4-SMe-Ph, 4-Br-Ph, 4-Cl-Ph, 2-OCH3 -Ph, 2-F-Ph, 2-furyl, 2-thienyl. R OH. R1 R2. N O E = 69% - 85% Z = 0% - 8%. R 1 = R2 = H or Me. Scheme 6. Synthesis of 2-hydroxyimino-3-substituted tetrahydrobenzofurans.. 17.

(18) Cyclic 1,3-dicarbonyl compounds reacted smoothly with various nitroolefins to furnish hydroxyiminodihydrobenzofuran derivatives as the mixture of E and Z isomers. Clean reaction conditions, no workup procedure, easy isolation and good yields of the products are the salient features of the methodology.. O O 2N. O NO2. Me. Me. Silica gel. +. Methanol MW 60 o C, 2 h 85 %. Me O. Me O. Scheme 7. Michael addition of pentane-2,4-dione and β-nitrostyrene.. PART-II Part-II, Section-A: Overview of cyclic sulfonamide (Sultam) and triazoles The section deals with the overview and importance of cyclic sulfonamide (Sultam) and triazoles. This section also involves the literature survey of the Sultam and triazoles. Part-II, Section-B: One-pot synthesis of triazolothiadiazepine-1,1-dioxide derivatives via copper catalyzed tandem [3+2] Cycloaddition/N-Arylation This section demonstrates a practical and efficient synthesis of triazolothiadiazepine1,1-dioxide derivatives via copper catalyzed [3+2] cycloaddition, followed by Narylation. The method is also applicable to the synthesis of indoline and thiophene fused triazolothiadiazepine-1,1-dioxide derivatives. N3. Z Path A. S X. Z. S O. O. CuI (30 mol %) TMSN 3 (2.5 equiv.) N O. R. N-Arylation. O. CH3 Z. DIPEA (3 equiv.). H N. DMF, 70 oC, 2-6 h 40-82 %. Path B. N. X. Z. [3+2] Cycloaddition. N N N. N H. S N O O R. N S. N. R O X = Br, I Z = substituted phenyl, thiophene, indoline R = CH 3, CH 2CH3 , (CH 2) 3CH 3, (CH 2 )3-OCH3 , 3,4-OMe-C 6H 3 -(CH 2) 2 O. Sultam. Scheme 8. One-pot Synthesis of Triazolothiadiazepine-1,1-dioxide Derivatives.. 18.

(19) Br. H3 C. H3 C. O. O. N. S. O. O. H3C. O d. N N. Br. f H3 C. Cl. N. N. N H. N. Br c. b. a. N N S O O H C O 3. H 3C. N O. Br. e N. S O. H 3C. H N H 3C. N. S. O. O H 3C. O. O. Scheme 9. Synthesis of indoline fused triazole sultam. Reagents and conditions. (a) (CH3CO)2O, CH2Cl2, rt, 30 min, 79 % ; (b) Br2, AcOH, rt, 10 min, 71 % ; (c) ClSO3H, neat, 80 oC, 12h, 35 % ; (d) CH3NH2, Et3N, reflux, 2h, 87 % ; (e) propargyl bromide, K2CO3, Acetone, reflux, 12h, 81 % ; (f) 30 mol % , CuI, 2.5 equiv TMSN3, 3 equiv DIPEA, DMF, 70 oC, 12h, 40 % ; TMSN3 = Trimethylsilyl azide, DIPEA = N,N-Diisopropylethylamine (Hunig's base).. Br. Br. Br. b. a S. S. SO2 Cl. c S. N N. Br. SO 2NHR. d S. SO2 NR. R = CH3 , CH2 CH 2 CH 2OMe. S. N. S N O2 R. Scheme 11. Synthesis of thiophene fused 1,2,3-triazolo-thiadiazepine-1,1-oxides. Reagents and conditions. (a) ClSO3H, -78 oC, 1h, 82 % ; (b) RNH2, CH2Cl2, rt ; (c) propargyl bromide, K2CO3, Acetone ; (d) 30 mol %, CuI, 2.5 equiv TMSN3, 3 equiv DIPEA, DMF, 70 oC.. Part-II, Section-C: Synthesis of Angular Furosultam Scaffolds via NBS mediated Bromocyclization Strategy This section demonstrates novel one pot NBS mediated synthesis of dibrominated angular furosultam derivatives via bromohydrin pathway. This method is equally applicable for thiophene and substituted phenyl fused furosultam derivatives. The presence of bromine in the cyclized compound can be efficiently coupled with potential traizole moiety. The generality of this method was also demonstrated by the synthesis of tetrahydrofuro isoquinolinone scaffold. This is the first example that describes the tandem formation of a bromohydrin, followed by bromocyclization in a one-pot reaction using NBS as brominating agent and water as an external nucleophile leading to the dibrominated furosultam as well as tetrahydrofuroisoquinolinone derivatives.. 19.

(20) O. H N. S. R1. O. DMF. S. R1. O. O. N O. H. H Br. O (2.5 equiv). R2. Pd(OAc) 2 ( 10 mol % ) R3. Br. Br N. Br R2. R3 THF : H 2O (2:1) 0 o C to rt ( 2-6 h). O R2 S. R1. O. N O. +. R3. = thiophene, substituted phenyl R 2 = substituted phenyl. N. S. R1. R3. O. O. Syn (Minor). Anti (Major). R1. Br O 2 R. Br. Yield = 40-75 % dr = up to 4 : 1. R3 = alkyl. Scheme 12. Synthesis of dibrominated furosultam derivatives. N. MeOOC. N N. N3. Br. MeOOC Br. Br. O. S. S O2. O. NaN 3 ( 2.5 equiv.). N. DMF, 80 oC, 6h. S. S O2. 85 %. N. DMAD ( 3.0 equiv. ) CuI ( 5 mol % ). Br. DMF, 80 oC, 3h 78 %. O. S. S O2. N. NaN 3 ( 2.5 equiv.) 6h then DMAD (3.0 equiv.) and CuI ( 5 mol % ), 2h DMF, 80 oC, 40 %. Scheme 13. Synthesis of thiophene fused furosultam with triazololinker. I. N N N. MeOOC OH (i) NaN ( 2.5 equiv.) 3 Ph DMF, 80 oC, 3h. Ph NIS ( 2.5 equiv. ) S. S O2. N. THF : Water (2 :1) 0 o C to rt 8h, 65 %. S. S O2. N. MeOOC. (ii) CuI ( 5 mol % ) DMAD ( 3.0 equiv.) DMF, 80 oC, 6h ( 2 steps 55 % ). OH Ph S. S O2. N. Scheme 14. Synthesis of thiophene fused Sultam with triazolohydrin. Br Ph Pd(PPh 3)Cl2 ( 10 mol % ). Br H N O. Br Ph Pd(OAc) 2. CuI ( 5 mol %) H N. DIPEA ( 3 equiv.) DMF, 70. o C,. 1h. Ph. ( 10 mol %). O. DMF, 80 oC, 12h 68 %. 78 %. NBS (2.5 equiv.). NH THF : Water (2 :1) O 0 oC to rt 62 %. Br. O NH O (anti). Scheme 15. Synthesis of dibrominated tetrahydrofuro [2,3-c]isoquinolin-5(9bH)-one (anti).. Part-II, Section-D: Regioselective synthesis of 4-iodo-3,4-disubstituted thiophene fused Sultam derivatives via iodocyclization approach and their application towards triazole linker.. 20.

(21) This section exhibits an efficient regioselective synthesis of a variety of 4-iodo-2,3disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide. derivatives. via. iodocyclization approach using iodine under mild reaction condition. This couplingiodocyclization strategy tolerated a variety of functional groups such as alkyl, cycloalkyl, phenyl producing the six-membered heterocyclic ring selectively. The resulting. 4-iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide. was. coupled with a variety of boronic acids (Suzuki coupling) and activated alkenes (Heck coupling). The iodo group was utilized for Sonogashira coupling followed by efficiently transformation to azido precursor, which was used for the synthesis of various thieno-sultam linked with triazole. N N. R3 R2 S. S O2. N. Br. N R4. R3. R2 R1. S. S. R1 = CH 3 R2 = Phenyl R3 = substituted phenyl, thiophene,. R1 R2 R3 R4. G G = COOEt, COMe, CN. = = = =. S O2. N. R1. CH 3 Phenyl, Alkyl Ph, COOMe H, COOMe, allyl. Scheme 16. Synthesis of 2,3,4-trisubstituted thiophene fused Sultam.. I I. S I2 (2.5 equiv.) K2CO3 (3 equiv.). Br S. SO2NHCH3. Pd(PPh3 )Cl2 CuI, DIPEA. S. SO2 NHCH3. N CH3 or S O2. N CH3 S O2 Thermodynamically less stable. DCM 6h, rt. S. I. DMF S. S O2. N. CH3. More stable six membered ring system. Scheme 17. Regioselective formation of six membered Sultam ring fused with thiophene.. 21.

(22) R. I. S. S O2. R-B(OH)2 (1.0 equiv.) Pd(PPh3)4 (5 mol %). N. S. 2M Na2 CO 3. S O2. N. DMF, 80 °C 1-3h R = 4-C6H4, 4-CH3-C6H4 , 4-OMe-C6 H4, 4-F-C6H4, 4-CF3-C6H4, 4-Cl-C6 H4, 4-t-Bu-C6H4. Scheme 18. Functionalization at C-4 position via Suzuki coupling strategy.. S. (HO)2 B. Ph S. S O2. N. (HO)2 B. I. S. Ph. Ph Pd(PPh3) 4 ( 5 mol % ) + S. CH3. traces. S O2. N. S. 2M Na2 CO 3. CH3. DMF, 40 °C, 6h. S O2. N. S. S Ph. Pd(PPh3 )4 ( 5 mol % ) S. 2M Na2 CO3. CH3. S O2. DMF, 80 °C, 2h. N. Ph + S. CH3. CH3. 5%. 68 %. 78 %. S O2. N. Scheme 19. Temperature dependent Suzuki coupling of thiophene-2-boronic acid with 4iodo-2,3-disubstituted-2H-thieno[3,2-e][1,2]thiazine-1,1-dioxide.. R I. R (4.0 equiv.) Pd(OAc)2 (5 mol % ). S. S O2. N. Na 2CO3 (2.5 equiv.). S. n-Bu4 NCl (1.0 equiv.). S O2. N. DMF, 80 °C 1-2h R = COOEt, COMe, CN. Scheme 20. Functionalization at C-4 position via Heck coupling strategy. HO. I. S. S O2. N. CH 3. N3. MsO. a. b S. S O2. N. c S. CH3. S O2. N. CH3. S. S O2. N. CH 3. Scheme 21. Synthetic route for the preparation of azido precursor of thieno-sultam. Reagents and conditions : (a) Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%), DIPEA (3.0 equiv.), hex-5-yn-1-ol (3.0 equiv.), DMF, 80 oC, 2h, 65 %; (b) CH3SO2Cl (1.2 equiv.), Et3N (2.2 equiv.), DCM, 0 oC to rt, 1.5h, 95 %; (c) NaN3 (4.0 equiv.), DMF, 80 oC, 1h, 82 %.. 22.

(23) N N. N. MeOOC. S. N N N. N3. COOMe. MeOOC COOMe CuI (5 mol %) S O2. N. CuI (10 mol %). o. S. DMF, 80 C, 2h. CH 3. S O2. 80 % Ph ( 3.0 equiv.). N. CH3. DMF, 80 oC, 12h. S. S O2. N. CH3. ( Not observed ). CuI (5 mol %), DMF, 80 oC, 1h 76 %. N. N. N. S. S O2. N. CH 3. Scheme 22. Reactivity of azido precursor with alkynes for the formation of various triazole linkers. N3. S. S O. N O. CH 3. Br CuI (5 mol %) THF, rt, 24 h N N. N N N. N. N. N. N I. S. S O2 30 %. N. CH 3. +. S. S O2. N. 45 %. + CH 3. S. N CH 3 S O2 Trace. Scheme 23. Synthesis of thiophene fused Sultam with functionalized triazole linker.. Keywords: "On water" , 1,3-dicarbonyl compounds , nitrostyrenes, [3+2]cycloaddition, Suzuki coupling, Heck coupling, Sonogashira coupling.. 23.

(24) Part-I, Section-A Overview on “On water” reactions A.1 Introduction Water is the most abundant liquid on our planet, which is essential to all forms of life. It is the dispersion medium for all kind of biochemical and physiological reactions of the living process and participates in many of these reactions. In spite of the chemical simplicity of the water molecule; its characteristic physical properties are quite remarkable.1-3. A.1.1 Hydrogen bonding in water Water has unique ability to form extended hydrogen bonding properties.4 One water molecules can bind with four other water molecules via four hydrogen bonds, which make tetrahedral structures. The hydrogen bonding in water makes it unique and robust. The hydrogen bonding remains water to its liquid state, over a wide range of temperature than is found for any other molecule of its size. The energy required to rupture multiple hydrogen bonds in water need a high heat of vaporization; that is why, a large amount of energy is required to vaporize liquid water, where the molecules are attracted through extended hydrogen bonding. (1) H. H O H. (4). O H. H. O. H. (2) H. O. (3). H O H. H. Figure A.1.1 Hydrogen bonding in water molecule. 24.

(25) By utilising hydrogen bonding properties of water, it can be used as a reaction medium and amphiphilic catalyst via interaction with reactants on surface to afford the product in high yields. Hydrogen bonding of water molecule with organic compounds plays an important role in organic synthesis.4 There are many organic reactions proceeds through hydrogen bonding. Therefore the use of water by replacing the organic solvents has emerged extensively in the litrature.2,5. A.1.2 “On water” and “In water” reactions Recently Sharpless and co-worker has described “On water” reaction.3a In case of “On water” reactions generally organic reactants are insoluble and reaction takes place in the emulsion suspension. Sharpless described that “On water” reaction proceeds via vigorous stirring of insoluble reactants by increasing the surface area between the organic and aqueous phase. Whereas in case of “In water” reaction,6 reactants dissolve in the solution, which allow direct interaction and addition of reactants to each other. “On water” reactions have advantages over “in water” reactions in terms of ease of product isolation and less contamination of side products. The reactions of water-insoluble organic compounds that take place in aqueous suspensions have received a great deal of attention because of their high efficiency and straightforward synthetic protocols.1-3 The advantages of conducting organic reactions “on water” can be attributed enhancement in the efficiency and rate, convenient ease of operation, improved safety profile owing to the excellent heat capacity of water.3f From a green chemistry perspective, highly efficient and environmentally benign synthetic methodology is often regarded as a goal in modern organic chemistry. Thus, development of an efficient and convenient synthetic methodology under “on water” conditions is an important subject in the recent days.. A.2 “On water” approaches A.2.1 Claisen Rearrangement In 2005 Sharpless demonstrated various “On water” reactions of aromatic Claisen rearrangement at room temperature with quantitative yield. Surprisingly by using other organic solvents they could not get satisfactory yield (Scheme A.2.1.1). 3a. 25.

(26) O. OH 23 o C 120 h H2 O 100 %. Cl. Cl. Other solvents screened: Toluene (16 %), DMF (21 %), CH3CN (27 %), MeOH (56 %). Scheme A.2.1.1 Gajewski co-workers demonstrated the accelerating effect of water as a solvent on the rate of the Claisen rearrangement using various substrates, thus this reaction has immense potential for the synthesis of natural and unnatural products (Scheme A.2.1.2).23-24 O. CHO. H. H H 2O-MeOH (2.5:1). HO. 80 oC, 24 h 85 %. H. HO. HO. H. HO. Scheme A.2.1.2. A.2.2 Nucleophilic Opening of three memebred ring Another interesting “On water” method described nucelophilic opening of an epoxide at little more elevated temperature, 50. o. C to afford the (1R*, 6R*)-6-(4-(3-. chlorophenyl)piperazin-1-yl)cyclohex-3-enol with excellent yield (Scheme A.2.2.1).3a. Cl 50 o C O. + HN. OH. N H2 O, 12 h 88 %. N N. Cl. Other solvents screened: Toluene (120 h, 10 %), Ethanol (60 h, 56 %), Neat (72 h, 76 %). Scheme A.2.2.1 Saidi and Azizi has demonstrated a practical and efficient aminolysis of various epoxides by aliphatic and aromatic amines under ‘on water’ condition. The aminoalcohols were obtained in high yields without using any catalyst and solvents (Scheme A.2.2.2).31 26.

(27) O N H. N. O. O. O. O. H 2O, 24 h. OH. 97 %. Scheme A.2.2.2 The reaction of amines and carbon disulfide produced, dithiocarbamate anions which open the epoxide to produce the β-dithiocarbamate derivatives in excellent yields under ‘on water’ condition (Scheme A.2.2.3).32. S NH 2. +. CS2. +. H2 O. O. N H. 18 h. S OH. Scheme A.2.2.3 Vilotijevic et al. have developed a remarkable and attractive example of the using water to open epoxide and cascade cyclization reaction to produce the ladder type cyclic polyethers. As shown in Scheme A.2.2.4, diepoxide and triepoxide were easily converted into the fused tetrahydropyranes with maintaining absolute stereocontrol.33. HO. H H 2O. O O. H. HO O. 70 o C, 24 h. O. OH. H. H. O. H. H. O. 70 o C,72 h. Scheme A.2.2.4. 27. HO. H. O. H. O. H2 O. O O. HO. H. H. OH. H. O. O. H. H. O. H. H. O.

(28) A.2.3 “On water” Cycloaddition reactions Grieco et al. described the Diels-Alder reaction of an acyclic diene having a carboxylic acid with dienophile to undergo cycloaddition in aqueous suspension.7 This reaction produced very high yield with excellent selectivity (Scheme A.2.3.2).. OMe. CO2R. X. H. O. H 2O 5 h, 100 %. OMe. OMe. X. CO2 R H O. H. + H. X. CO2 R H O. X = CHO. Scheme A.2.3.2 Sharpless and co-workers effectively used water-insoluble trans, trans-2,4-hexadienyl acetate and N-propylmaleimide under “On water” condition to afford the product with 81 % in 8 hours (Scheme A.2.3.2).3a By using other solvents such as toluene and methanol took longer time and without using any solvent (neat reaction) reaction taken 10 hours, which is relatively higher than the time taken to complete the reaction in water.. CH 3. H O. O o. 23 C +. N O. N. Water 8 h, 81 %. H O A O. Scheme A.2.3.2 In 1980 Breslow and co-workers reported the Diels alder reaction of cyclopentadiene and butanone in water with good selectivity and good yield. The reaction was much faster in water with compare to other aprotic nonpolar organic solvents (Scheme A.2.3.3).8. O +. COCH 3. H2 O 20 oC. COCH3 endo. 28. + exo.

(29) Scheme A.2.3.3 Later the same author illustrated that endo selectivity was much higher in water than in ethanol or in the absence of solvent.9 This reaction could be consider as a first example of ‘on water’ reaction which notably enhanced the rate of reaction with higher selectivity. The increment in the rate of reaction was described based on hydrophobic effect.10,11. A.2.4 Cycloaddition of Azodicarboxylates C-N bond forming reactions are important and powerful way to construct the complex compounds via reactions of azodicarboxylates with unsaturated hydrocarbons. An interesting “On water” accelerated 2σ+2σ+2π cycloaddition reaction between quadricyclane and dimethyl azodicarboxylate have been developed by Sharpless and co-workers (Scheme A.2.4.1).3a Previously, Lemal and co-workers. discovered this novel reaction using organic solvents such as toluene or benzene at 80 oC for 24 hours to 5 days.12 Although, Sharpless demonstrated that 1,2-azetidines also can be synthesized in ‘On water’ vigorous stirring in very short time at 23 oC. The vigorous stirring is the driving force for this reaction by increasing the area of surface between the organic and aqueous phases. This reaction needs longer reaction time (18 hours to 5 days) and heating when it is carried out in organic solvents or under neat condition.13,14 In contrary, when this reaction completed in 10 min at room temperature under ‘on water’ condition.. + MeOOC. N N. COOMe. N CO2Me N CO2Me. H2O 25 o C 82 %. Scheme A.2.4.1 Leblanc et al. have described Ene reaction of amination of olefins under heating condition.15 In nonpolar organic solvents this cycloaddition reaction took longer time and afforded less product yield with compare to ‘on water’ reaction. Sharpless and co-workers carried out this reaction at 50 oC under ‘on water’ condition, the reaction mixture initially formed a dissolved organic phase, which produced white solid as a precipitate (Scheme A.2.4.2).3a. 29.

(30) Cl3 C O. O. + Cl3C. N N. O. O. CCl3. O N. H2 O o. N H. 50 C. O O CCl3. O. Scheme A.2.4.2. A.2.5 Nucleophilic Substitution Reaction In 2009 Tandon et al.38 described an unprecedented nucleophilic substitution reactions of 2,3-dichloro-1,4-benzoquinone in aqueous suspension with various aromatic amines, aliphatic primary amines, amino acids, esters of amino acids, heterocyclic amine, hydrazine, amide, and thioethers can be used in the absence of catalyst (Scheme A.2.5.1). O. O Nu. X. Nu X. H 2O. Y. O Nu. -X. Y. Y. O. O. O. X or Y = Cl Nu = primary or secondary amine. Scheme A.2.5.1 The resulting derivatives of benzoquinone have potential biological activity as antitumour, as oxidative inhibitor, HIV transcriptase inhibitor, anti-malarial, anti-viral, anti-platelet, anti-proliferative, anti-cancer activities, hair dyeing and electrochemical fluorescent switching properties. N3. S N3. NaN 3. H 2O, Reflux. 25 oC. NCS S SCN. Cl. NaSCN. S. H 2O. Cl. 100 o C NH 3. H 2N. SCN S NCS. H 2O. S NH2. Scheme A.2.5.2. 30.

(31) Sharpless and co-workers developed an interesting nucleophilic substitution reaction. The precursor dichlorothiabicyclooctane was treated with sodium azide or ammonia to produce diazide and diamine respectively in excellent yields. The reaction of same electrophile with NaSCN at different temperatures afforded either thiocyante at 25 oC or isothiocyanate at 100 oC (Scheme A.2.5.2).34-35 HN H N. OH. H2 O Fe. Fe. 80 o C, 24 h. Scheme A.2.5.3 Cozzi and Zoli have demonstrated an attractive example of on water nucleophilic substitution reaction of ferrocenyl alcohol. The reaction does not require additive or catalyst. Variety of substituted indoles, pyrroles, thiophenols and imidazoles used in this reaction worked well and afforded the desired product in good yields (Scheme A.2.5.3).36-37. A.2.6 ‘On water’ Oxidation The oxidation of aldehyde to acid under “On water” in open air has recently been reported by Shapiro et.al.3l This reaction proceeds by increase in surface interaction of aldehyde with water in the presence of oxygen (Scheme A.2.6.1). O H. R. H 2O. 1 O H. R. OH 2. O R. O. Air or O2. O. O2. R. O. R. R O. 1. O _. O. H O. O. R. O H. R O R. O O. O. O. + H. R. H. [ Intermedaite ] R. OH 2. Scheme A.2.6.1 The aromatic aldehydes undergo very smooth and facile oxidation by simply stirring of aqueous emulsion in air to produce variety of carboxylic acids in high yield. Acid. 31.

(32) precipitates from the reaction mixture and could be easily isolated simply by filtration. Interestingly, very low amounts of by-products were observed.. A.2.7 On water 1,3-dipolar cycloaddition 1,3-dipolar cycloaddition reaction has been used extensively to construct the complex heterocyclic and biologically active compounds. There are many several methods are documented in the literature describing about effectiveness of water as a solvent. Portmann (Novartis AG) has recently developed a practical and efficient synthesis of cyanotriazole from organic azide and 2-chloroacrylonitrile (cyanoacetylene equivalent) (Scheme A.2.7.1).4i F. F Cl. N3 F. +. H2 O CN. 24 h, 98 %. (1.5 equiv.). N F. N N CN. Scheme A.2.7.1 The main problem of this reaction is, 2-chloroacrylonitrile can polymerize under acidic and basic condition. When azide and 2-chloroacrylonitrile heated at 80 oC for 24 hours which produced triazoles in very high yield. Sharpless and co-workers described that the 1,3-dipolar cycloaddition of dimethyl acetylenedicarboxylate (electron deficient acetylene) and organic azides can react cleanly and readily under ‘on water’ condition. As shown in Scheme A.2.7.2 when isomeric diepoxides were treated with sodium azide and ammonium chloride, azido alcohol were obtained.16 The azido alcohol were obtained regioselectively and subsequently treated with dimethyl acetylenedicarboxylate using ‘on water’ condition. The bistriazoles were isolated by simple filtration using crystallization. The easy isolation, purification and environmentally benign solvent (water) is the selective feature of this methodology. These cycloaddition reactions are thermodynamically favoured therefore they require relatively higher temperature and transition metal catalyst to accomplish the reaction. The electron deficient acetylenes in the absence of transition metal catalysts can act as a reactive dipolarophile.. 32.

(33) CO2Et. HO OH. O. O. HO. NaN 3, NH 4Cl H 2O, Reflux. OH. N3. EtO2 C. CO2 Et. N. EtO2C. H 2O, 70 o C. N3. N N N N N. EtO 2C. CO2Et. OH OH. O. O. NaN 3 , NH4 Cl H 2 O, Reflux. CO 2Et. N3. OH. HO. N3. EtO2C. CO2Et. N. EtO2C. H 2 O, 70 oC. N N N. CO 2Et. N N. EtO 2C. Scheme A.2.7.2 Ju and co-workers developed ‘on water’ 1,3-dipolar cycloaddition of organic azides and electron deficient alkynes (both terminal and internal alkynoates). This reaction is feasible at room temperature and proceeded to complete in 6-12 hours. Notably, 1,4disubstituted-1,2,3-triazoles were isolated regioisomerically in the pure form (Scheme A.2.7.3).17 O O N N N 82 %. MeOOC MeO. O N3. H 2O. OEt. O. OEt. 6-12 h. O. EtOOC. N N N. EtO. OE 92 %. Scheme A.2.7.3 Butler and. co-workers. showed the 1,3-dipolar cycloaddition. reaction. of. phthalazinium-2-dicyanomethanide with methyl methacrylate, substituted styrenes and 2-buteneone produced dihydropyrrolophthalazines in high product yield when the reaction was performed in water (Scheme A.2.7.4).18-19 N CN. N. O. CN. H2 O. COOMe 63 %. O N N. N N. CN. CN CN. CN H2 O O. 96 %. N N. OCH 3. CN CN. H2O 87 % OCH 3. Scheme A.2.7.4 33.

(34) Gracia-Tellado and co-workers have developed a ‘on water’ cycloaddition of nitrones with allenoates, which were generated from propiolate and catalytic amount of triphenylphosphine and tertiary amine to produced 1:1 mixture of trisubstituted isoxazoline and hydroxylamine (Scheme A.2.7.5).20-21 CO2R 2. O. OR 2. Bn +. R1. Nu. N. O-. R. R1. Nu. Bn. Bn N O. R. R. OR2. N O. 2. CO2 R. R1. 1. R1. Nu. O. Nu = PPh 3 or NR 3. Scheme A.2.7.5 Bala et al. have developed the intramolecular 1,3-dipolar cycloadditon reactions of nitrile oxides, which was generated in situ by halogenation/dehydrogenation of oximes with olefins. By using this methodology benzopyrans, quinolines and isoxazoline in good to excellent (Scheme A.2.7.6).22. OH N. N O Ph NaOCl. X. H. H2 O. X X = O, 72 h, 90 % X = NH, 48 h, 92 %. Scheme A.2.7.6 Sharpless et al. have described a practical and efficient synthesis of tetrazoles and their analog of α-amino acid from aryl nitrile and sodium azide using ‘on water’ condition. After screening various catalyst, zinc (II) bromide was found to best catalyst (Scheme A.2.7.7).23. 34.

(35) N N. 1.0 equiv. ZnBr2. N. + 1.1 equiv. NaN3. R. Water, reflux M. two step mechanism. R. MN 3. N. M N N. N. N. NH. N. R. N N. R. N. N. R N concerted mechanism R. N N M. N N. N R. N. N M. M = H, LnZn, other metals. Scheme A.2.7.7. A.2.8 Passerini and Ugi reactions Multicomponent reactions are the excellent approach to access complexity and diversity via combing several reactants together to construct new molecules. Passerini and Ugi reactions are most commonly used multicomponent reactions. 26-28 The use of water in these reactions was described by Pirrung and Sarma.29-30 They showed the considerable improvement in the rate of reaction with compare to organic solvents (Scheme A.2.8.1). O O +. H. OH. H 2O. i. Bu. +. N. iBu O O. 3.5 h. O. H N. Scheme A.2.8.1 The synthesis of β-lactam derivatives were achieved using β-amino acid in very high yield under ‘on water’ condition. Interestingly, this reaction did not proceed in organic solvent such as methanol, tetrahydrofuran, or dichloromethane (Scheme A.2.8.2). iBu O. OH + NH 2. H. H2O. iBu + O. N. 3h C. N. H N. O O. Scheme A.2.8.2. A.2.9 Transition metal catalysed reactions Aqueous mediated transition metal catalysed reactions such as oxidation, reduction, carbon-carbon bond forming, and carbon-heteroatom bond forming transformations. 35.

(36) has advantageous in terms of avoiding the toxic solvents and reagents. These types of reactions have been studied extensively in the literature. Sharpless and co-workers have developed a copper (I) catalyzed azide-alkyne cycloaddition (CuAAC) reaction in water with catalyst. The reaction proceeds cleanly and produced quantitative yield and does not require any ligand (Scheme A.2.9.1).39 In contrary to this Meldal, reported that when the reaction was performed in organic solvents using copper(I) iodide along with base N,N-diisopropylethylamine, the reaction produced other byproducts as well.40 Whereas, the side reactions are minimized when the reaction was carried out under in water condition. HOOC Ph. S. N H. N3. O N. CuSO4 (1 mol %). +. O. Na ascobate (10 mol %). HOOC O N O. H 2O/ tBuOH, 1:1, 25 o C. Ph. S. N. N. N H. N. 93 % pure product was isolated by filtration. Scheme A.2.9.1 Li and co-workers have developed three component aldehyde-alkyne-amine coupling reaction and its asymmetric version. These three component coupling reactions were catalyzed by chiral copper complexes and produced optically active propargyl amines in good yields and high enantioselectivity (Scheme A.2.9.2).41-42 CHO. Cu(OTf) 10 mol % L. +. H N. H2 O, 35 o C, 2d. O L=. O. N N. N. NH 2. Scheme A.2.9.2 Chen and Li have demonstrated 1,4-addition of terminal alkynes to α,β-unsaturated ketones under “on water” condition. The method is very efficient and practical to access a wide variety of γ,δ-alkynyl ketones (Scheme A.2.9.3).43 Pd(OAc)2 (5 mol %) PMe 3. + O. H2 O, 60 oC, 40 h. Scheme A.2.9.3. 36. O.

(37) Bhattacharya et al. have described practical and efficient Sonogashira reactions of aryl iodides and bromides. The reactions are rapid and proceeds under water condition in the presence of base. When the reaction was carried out in organic solvents, the rate of the reaction was sluggish and many side products were formed (Scheme A.2.9.4).44. Pd(PPh 3) 4 (0.4 mol %) CuI (1 mol %), Pyrrolidine. Br + CHO. H 2O, 70 o C, 30 min. CHO. Scheme A.2.9.4 The Suzuki-Miyaura reactions are generally carried out at higher temperature.45-47 Recently Buchwald and co-workers has demonstrated that aryl halides readily reacted with boronic acids at room temperature in the presence of catalyst in water, while this reaction required more temperature when it is perfomed in organic solvents (Scheme A.2.9.5).48 B(OH)2 Pd(OAc) (2 mol %) HOOC 2. HOOC. MeO. SO3 Na. Ligand ( 4 mol %) Br +. Ligand =. K2CO3, H 2O, 2 h rt. PCy 3 OMe. Scheme A.2.9.5. A.2.10 Bromination reactions Guss and Rosenthal have demonstrated a very practical and robust method to prepare bromohydrin by vigorously stirring the olefins with N-Bromosuccinimide (NBS) under on water condition. The product can be easily separated from the water phase. They showed that NBS could be easily precipitated from the crude aqueous solution. (Scheme A.2.10.1)49 OH. O Br. NBS H 2O, rt. NaOH. H 2O, 60 o C. 82 %. 85 %. Scheme A.2.10.1 Iskra and co-workers have shown the efficient bromination of 1,3-diketone, βketoesters, cyclic ketones, aryl alkyl, and dialkyl ketones using H2O2-HBr system. 37.

(38) under “on water” condition. The bromination reaction was carried out at room temperature and exclusively mono brominated products were obtained (Scheme A.2.10.2).50 O. O Br. 30 % aq. H 2O 2/ 48 % aq. HBr 24 h O. Br. Br. O. O. O. O. Br. O Br. Br. O. Scheme A.2.10.2 Iskra also showed, the benzylic bromination was accomplished using Nbromosuccinimide under on water condition with excellent yields. This reaction initiated at ambient light (40 W incandescent bulb) to produce the products (Scheme A.2.9.3). O N Br Br. O O. o. H 2O, 24 C, 22 h. O. Ambient light. Scheme A.2.10.3 Stavber and co-workers developed an interesting example of bromination using aqueous condition to get the particular cite selectivity. It is noteworthy that under solvent free condition, α-bromo methyl product was obtained as a sole product when ortho-substituted bnzophenone treated with NBS with acidic condition. On the other hand when same reaction was performed in water, bromination occurred at aromatic ring (Scheme A.2.10.4).51 Br O. O. O OCH3. OCH3. NBS (1.0 equiv.). PTSA or H 2SO4. PTSA or H2SO 4 Br. NBS (1.0 equiv.). Water. neat. Scheme A.2.10.4. 38. OCH3.

(39) A.2.11 Supramolecular Chemistry in water The use of water in supramolecular chemistry is growing research area because of noncovalent hydrogen bonding in aqueous media allow for better understanding the formation of supramolecules. The major aim of supramolecular chemistry is the construction of novel synthetic receptors that have high affinity and high selectivity for the binding of guests in water. Water has a particular role in molecular recognition, host-guest chemistry and formation of self assembly. The unique features and applications of supramolecular chemistry in aqueous media is very well documented.52. A.3 Michael addition in the presence of water The C-C bond formation via Michael addition is a convenient and well explored method. Organocatalysis53 has emerged as an excellent tool for the construction of CC bond formation by using Michael addition. A great deal of efforts has been made to develop environmentally friendly organic reactions in the presence of water by replacing organic solvents. There are many reports available in the literature using organocatalyst, in the presence of water as solvent. Few of those important Michael addition using organocatalyst in the presence of water has been displayed herein. Wang and co-workers54 has described a highly enantio- and diastereoselective Michael addition of ketones and Aldehydes to nitroolefins in water. They used reusable fluorous(s)-pyrrolidine sulfonamide organocatalyst. This organocatalyst can be conveniently recovered from the reaction mixture by fluorous solid phase extraction and next it can be reused without a significant loss of catalytic activity and stereoselectivity (Scheme A.3.1). H N. N H. O +. R1 R2. Ar. O S n-C4 H9 O ( 10 mol % ). NO2 rt, H 2O. O. Ar NO 2. R1 R2. 7-24 h yield = 56-98 Organocatalyst can be recovered and reused. ee = 68-93 dr = upto 50 : 1. Scheme A.3.1. 39.

(40) Ma and co-wokers55-56 has demonstrated a highly efficient and practical Enantioselective Michael addition of aldehydes to 3-nitroacrylates. They have developed a novel method for the asymmetric Michael addition using diarylprolinol ether catalyst (Scheme A.3.2). Ph Ph OTMS. N H. O +. H. R2. NO2. R. NO2. H. 0 oC to rt, H 2O. 1. R2. O. ( 10 mol % ). 1. R. 2-15 h yield = 74-90. R 1 = alkyl or Pheyl. ee = 96-99. R 2 = CO2 Me, CO2 t-Bu, CO 2Bn. dr = upto 98 : 2. Scheme A.3.2 Mechanistically this reaction proceeds via combination of the excellent asymmetric induction ability of the o-TMS-protected diphenylprolinol compounds, rapid formation of enamine species in the presence of benzoic acid under aqueous media (Scheme A.3.2). In order to demonstrate the utility of this methodology they have synthesized known amino acid by using simple chemistry. Hydrogenation of compound Ma-1, followed by protection with benzyl chloroformate, provided pyrrolidine Ma-2, further it was subjected to deprotection to afford the Ma-3 with 48 % of overall yield (Scheme A.3.3). O H. COOMe NO2. Me. Me. Me COOMe. (i) Pd(OH) 2, H2 , MeOH. Ma-1. Me COOMe. (iii) aq. LiOH, MeOH, THF N. (ii) benzyl chloroformate, Et 3N, DMAP, DCM ( two steps 54 % ). Cbz. (iv) Pd/C, H 2, MeOH ( two steps 90 % ). Ma-2. N Cbz Ma-3. Scheme A.3.3. A.4 “On water” Michael addition Since Sharpless has demonstrated the “On water” concept, there have been many “on water” promosted reactions developed. Some of the practical and useful methods are shown here. Yao and co-workers57 has described several “On water” Michael addition of various nucleophiles to nitro alkenes. They have used Indole, pyrrole, 2hydroxynaphthoquinone, 4-hydroxycoumarin as a nucleophile for the Michael addition with nitroalkenes (Scheme A.4.1).. 40.

(41) NO2 NO2. R R N H. N 2O H. H. N H. 10 0. N H. O. H2. 1 00. o. C. R. oC. NO2. R = Aromatic or aliphatic O H2 oC 80. NO 2. O. H. O. OH 80. 2O. NO2. OH. o. C. R. R OH. OH. O. O. O. O. O. O. Scheme A.4.1. In another interesting protocol they have demonstrated an environmentally benign method for the synthesis of indolyl (nitro) chromans from indoles and 2-aryl-3-nitro2Hchromenes under catalyst-free conditions by use of an “on water” concept (Scheme A.4.2). O. Ph. Ph. Water +. O. O Ph. NO 2 N H. NO2. Reflux ( 10- 18 h). +. NO 2. N H major. N H minor major : minor = upto 99 : 1 ( yield = 54-86 % ). Scheme A.4.2 They achieved high diastereoselectivities, when 2-substituted indoles were used as an nucleophile. Simple experimental conditions, the green reaction medium (water as a solvent), and easy isolation of the products are the merits of this protocol.57c. A.5 References 1. (a) Lindström U. M. Organic reactions in water: Principles, Strategies and Applications Blackwell publishers, New York, 2007; (b) Polshettiwar, V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629. 2. (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (b) Li, C. J.; Chang, T. H. Organic Reactions in Aqueous Media, Wiley, New York, 1997, 7950; (c) Lindström, U. M. Chem. Rev. 2002, 102, 275; (d) Shu, K.; Kei, M. Acc. Chem. Res. 2002, 35, 209; (e) Li, C.-J.; Chem. Rev. 2005, 105, 3095; (f) Pirrung, M. C. Chem. Eur. J. 2006, 12, 1312. 41.

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(46) Part-I, Section-B Facile and highly efficient method for the Calkylation of 2-hydroxy-1,4-naphthoquinones to nitro alkenes under catalyst free ‘on water’ conditions I.B.1 Introduction Quinone and naphthoquinone moieties are prevalent motifs in various natural products, and are associated with diverse biological activities.1 Among the naphthoquinones, 2-hydroxy naphthoquinone derivatives are the molecules of interest as pigments2 and biological entities.3 Besides, they are constitute a potential synthetic precursors of carbocyclic and heterocyclic quinones, including 5H-benzo[b]carbazole6,11-diones,4 naphtho[2,3-b]furan-4,9-diones5 and benzo[b]naphtha[2,3-d] furan6,11-diones.6 In particular the derivatives of C-alkylated 2-hydroxy naphthoquinones possess inhibitory effects on Epstein–Barr virus early antigen (EBV-EA) activation,7 in vitro activity against the parasites such as Toxoplasma gondii and Plasmodium falciparum.8 Lapachol, Atovaquone are two important compounds of C-alkylated 2hydroxynapthoquinone derivatives, which display a number of biological activities such as antibacterial, antiplasmodial, antioxidant, trypanocidal, anti-microbial, antiprotozoal, antimalarial and anti-HIV.9 In perspective of their important biological features in medicinal chemistry, a large number of quinone derivatives and related compounds have been synthesized in order to explore the novel bioactive agents with enhanced pharmacological properties. The C-alkylation of nitroalkenes with various electron rich donors is a well known CC bond forming reaction, which provides easy access to useful synthetic precursors such as nitroalkane. Nitroalkanes can be transformed into diverse functionalities due to the strong electron withdrawing character of the nitro group. In particular, the conjugative adducts derived from naphthoquinone and nitroalkenes are interesting because it produces a precursor compounds of several bioactive molecules.10 To our knowledge, a very few methods have been appeared in the literature for this. 46.

(47) transformation using base10 or organocatalyst.11 In continuation of our interest on the development of green synthetic methodologies12, herein have reported an efficient and catalyst free protocol for the C-alkylation of 2-hydroxy naphthoquinone.. I.B.2 Review of Literature Estévez et.al.10a reported Michael addition of 1-nitro-cyclohexene with 2hydroxynapthoquinone in the presence of base at moderate temperature. Subsequently the nitro group was reduced using followed by cyclization under reflux condition to afford two isomeric products, which were confirmed based on IR spectroscopy (Scheme I.B.2.1). O. O K2 CO 3. + OH O. 50 oC, 2h NO 2 THF, 89 %. O. HN (i) H2 , Pd/C, MeOH rt, 24h, 100 % NO2 OH (ii) dioxane, reflux, 8 h, 45 %. O + O. O. O. IR : 1670 and 1628 cm-1. N H. IR : 1681 cm-1. Scheme I.B.2.1 Du et al. demonstrated the first organocatalytic enantioselective Michael addition of 2-hydroxy-1,4-naphthoquinones to nitroalkenes for the direct synthesis of chiral nitroalkylated. naphthoquinone. derivatives.. Good. yields. and. excellent. 11. enantioselectivities (up to >99% ee) was achieved (Scheme I.B.2.2). CF3 S F 3C. N H. N. H 3C. O R1. N H. OH +. CH 3. (10 mol %) R2. NO2. O. R1. OH. o. CH2 Cl2 , 25 C, 12 h. O. * O. NO 2. R2. up to > 99 % ee 14 example yield : 61- 85 %. Scheme I.B.2.2 The proposed transition model for this Michael addition is shown in Figure I.B.2.1. The nitro group forms hydrogen bonds with the thiourea part of organocatalyst. The hydroxyl group of the 2-hydroxy-1,4-napthoquinone is getting protonated by tertiary. 47.

(48) amine part of catalyst. Two N-H—O hydrogen bonding interaction between two vicinal oxygen atoms of napthoquinone fixes the conformation of the nuecleophile. Consequently, enhances the entiocontrol in the transition state. The nucleophile approaches the β-carbon of the nitroalkene from the Re face with the influence of tertiary amine group and produced the S product. CF3 S F 3C. N H. N H. O. O O. N H. N. O. O. Figure I.B.2.1 Tansition state proposed for the Michael addition A very recently Estevz et al.10b reported interesting studies in the Michael addition of napthoquinone. to. sugar. nitro. olefins.. This. is. the. first. synthesis. of. polyhydroxylatedhexahydro-11H-benzo[a]carbazole-5,6-diones and hexahydro-11bHbenzo[b] carbazole-6,11-diones. These two novel compounds probably could be potential biological active compounds because of structural relationship with benzo[b]carbazolediones and (+)-pancrastistatin, which are shown in figure I.B.2.3. OH HO. O. OH. R. B. C. OH. O. OH. A. B. NH. C N H. (+)-pancratistatin. R3. D A. O. R2. R1. D. D O A O. O B. C N H. R4. O R1 , R 2, R 3, R4 = H, OH. 5H-benzo[b]carbazole-6,11-diones. Hexahydro-11H-benzo[b]carbazoles -6,11-diones. Figure I.B.2.3 Their synthetic strategy was started with Michael addition of 2-hydroxy naphthoquinone to sugar nitro olefin, which produced the Michael adduct with high. 48.

(49) diastereoslectivity and excellent yields. Further after several steps they synthesized indoloquinones derivative A and B (Scheme I.B.2.3 and Scheme I.B.2.4). O. O2N O. + OH. THF, rt, 35 h 96 % de, 98 % yield. O. TFA, rt, 5 h. O. OH OBn. O. DCM, H2O. O. OH OBn. OH OH. O. O J = 11.0 Hz. OH H2N O. OH. H. H2 (1atm) Raney-Ni. OBn OH. NO2. O. O. K2CO3. O. BnO. O. NO2. O. R. H. OBn. HO. O. O2N OHC O. Na2CO3 MeOH. OH H. MeOH rt, 5 h. OH. NO2. OBn OH. H2O, rt, 12 h. OH. 90 %. J = 11.0 Hz. HO. OH. O. 1,4-dioxane, reflux, 12 h, 32 % OBn OH. HO O. 1,4-dioxane, reflux, 12 h. OH OH. OH. OBn. HO O. OH. OH. HN. OBn. OH. NH2. O OH. NH. O. O connfirmed based on IR spectrum : two peaks obtained -1 at 1671 and 1623 ( cm ). O. Scheme I.B.2.4 Synthesis of indoloquinones derivative (A). NO2. O OMe. OMe. Li. Br BuLi. O. +. OBn. O. O. THF OMe. -78 o C. O. O2N. O. BnO. OMe. THF,-78 oC, 4 h. I NO2. O. 96 % de, 98 %. O O. O OBn. O O. O II [ 77 % of I+II obtained, after crystallization 54 % yield of II afforded ] O. NO2 O OH OBn. NO2 O O. O. 1, 4-Dioxane H2O, TFA, 50 oC, 16 h. O2N OHC. O. OH. R BnO. OH. R OH. OH. Na2CO3 MeOH. J = 10.3 Hz R. HO OBn H2O, rt, 12 h BnO 90 %. H NO2. HO. OH. H H. J = 10.3 Hz OBn. OBn HO O. HO O. OH. CAN. THF NH O. OH o 60 C, 12 h 20 %. OH. OH H2N. OH. OH NH2 O. CH3CN, H2O R o 0 C, 1 h 92 %. OBn OH. H2 ( 1atm ) Raney-Ni MeOH rt, 3h, 95 %. connfirmed based on IR spectrum : One peak obtained at 1661 cm-1. Scheme I.B.2.5 Synthesis of indoloquinones derivative (B).. 49.

(50) I.B.6 References 1. (a) The chemistry of functional Groups: The chemistry of the quinonoid compounds; Patai, S.; Rappoport, Z.; Eds.; Wiley: New York, 1988; (b) Thompson, R. H. Naturally Occuring Quinones, 4th ed.; Chapman and Hall: London, 1997. (c) Duke, J. A. CRC Hanbook of Medicinal Herbs; CRC:Boca Raton, 1985, p 470. (d) Spyroudis, S. Molecules 2000, 5, 1291; (e) O’ Brien, P. J. Chem. Biol. Interact. 1991, 80, 1. 2. Karci, F.; Ertan, N. Coloration Tech. 2005, 121, 153. 3. (a) Wagner, H.; Kreher, B.; Lotter, H.; Hamburger, M. O.; Cordell, G. A.. Helv.. Chim. Acta 1989, 72, 659. (b) Oliveira, A. B.; Raslan, D. S.; Khuong-Huu, F. Tetrahedron Lett. 1990, 31, 6873. (c) Sendl, A.; Chen, J. L.; Jolad, S. D.; Stoddart, C.; Rozhon, E.; Kernan, M.; Nanakorn, W.; Balick, M. J. Nat. Prod. 1996, 59, 808. (d) Khambay, B. P. S.; Batty, D.; Beddie, D. G.; Denholm, I.; Cahill, M. R. Pest. Sci. 1997, 50, 291. (e) Hudson, A. T.; Randall, W. U.S. patent No. 5,175, 319, 1992; (f) Khambay, B. P. S.; Jewess, P. Crop Protection 2000, 19, 597; (g) Vanelle, P.; Terme, Th.; Giraud, L.; Crozet, M. P. Tetrahedron Lett. 2001, 42, 391. (h) Ball, M. D.; Bartlett, M. S.; Shaw, M.; Smith, J. W.; Nasr, M.; Meshnick, S. R. Antimicrob. Agents Chemother. 2001, 1473. (i) Camara, C. A.; Pinto, A. C.; Rosa, M. A.; Vargas, M. D. Tetrahedron 2001, 57, 9569. (j) De Moura, K. C. G.; Emery, F. S.; Neves-Pinto, C.; Pinto, M. C. F. R.; Dantas, A. P.; Salomaõ, K.; de Castro, S. L.; Pinto, A. V. J. Braz. Chem. Soc. 2001, 12, 325. (k) Oliveira, M. F.; Lemos, T. L. G.; de Mattos, M. C.; Segundo, T. A.; Santiago, G. M. P.; BrazFilho, R. An. Acad. Bras. Cien. 2002, 74, 211. (l) da Silva, M. N.; da Souza, M. C. B. V.; Ferreira, V. F.; Pinto, A. V.; Pinto, M. C. R. F.; Wardell, S. M. S. V.; Wardell, J. F. Arkivoc 2003, 10, 156. (b) Perez, A. L.; Lamoureux, G.; Zhen-Wu, B. Y. Tetrahedron Letters 2007, 48, 3995. ( references therein) 4. Cheng, C. C. Structural aspects of antineoplastic agents-A new approach, in progeress in medicinal chemistry, Vol 25, Ellis, G. P.; West, G. B., Eds.; Elsevier: Amsterdam, 1988, pp 35. (b) Kobayashi, K.; Taki, T.; Kawakita, M.; Uchida, M.; Morikawa, O.; Konishi, H. Heterocycles 1999, 51, 349. 5. (a) Kobayashi, K.; Shimizu, H.; Sasaki, A.; Suginome, H. J. Org. Chem. 1991, 56, 3204. (b) Chuang, C.-P.; Wang, S.-F. Tetrahedron 1998, 54, 10043. (c). 50.

(51) Kobayashi, K.; Uneda, T.; Kawakita, M.; Morikawa, O.; Konishi, H. Tetrahedron Lett. 1997, 38, 837. 6. (a) Martínez, E.; Martínez, L.; Estévez, J.C.; Estévez, R. J.; Castedo, L. Tetrahedron Lett. 1998, 39, 2175. (b) Martínez, A.; Estévez, J. C.; Estévez, R. J.; Castedo, L. Tetrahedron Lett. 2000, 41, 2365. 7. Sacau, E. P.; Este´vez-Braun, A.; Ravelo A. G.; Ferro, E. A.; Tokuda, H.; Mukainakac, T.; Nishino, H. Bioorg. & Med. Chem. 2003, 11, 483. 8. Baramee, A.; Coppin, A.; Mortuaire, M.; Pelinski, L.; Tomavoc, S.; Brocard, J. Bioorg. & Med. Chem. 2006, 14, 1294. 9. Eyong, K.; Kumar, P. S.; Kuete, V.; Folefoc, G. N.; Nkengfack, E. A.; Baskaran S. Bioorg. & Med. Chem. Lett. 2008, 18, 5387. (references cited therein) 10. (a) Barcia, J. C.; Otero, J. M.; Estévez, J. C.; Estévez ,R. J. Synlett 2007, 1399. (b) Otero, J. M.; Barcia, J. C.; Salas, C. O.; Thomas, P.; Estévez , R. J. Tetrahedron 2012, 68, 1612. 11. Zhou, W.-M.; Liu, H.; Du, D.-M. Org. Lett. 2008, 10, 2817. 12. (a) Habib, P. M.; Kavala, V.; Kuo, C.-W.; Yao, C.-F. Tetrahedron Lett. 2008, 49, 7005. (b) More, V.; Sastry, M. N. V.; and Yao, C. -F. Green Chem. 2006, 8, 91.. 51.

(52) Part-I, Section-C Synthesis of C3-nitroalkylated-4-hydroxycoumarin and hydroxyiminodihydrofuroquinolinone derivatives via Michael addition of cyclic 1,3-dicarbonyl compounds to βnitrostyrenes I.C.1 Introduction Ultrasound irradiation is commonly used in both industry and academia owing to the green value of harmless acoustic waves. Sonochemistry1,2 has several advantages in terms of waste reduction, energy savings and can avoid the use of high reaction temperatures. Organic reactions in aqueous media or ‘on water’3,4 have attracted considerable recent interest, primarily because of environmental and safety issues. The use of water as a solvent in sonochemistry is good combination from the point of view of green chemistry. Therefore, to develop a green protocol using ‘on water’ conditions in conjunction with sonication condition would be highly desirable. Coumarin5 and furoquinoline6 scaffolds are commonly found in diverse natural products, biologically active compounds and pharmaceuticals. Among the various coumarin derivatives, 3-substituted- 4-hydroxycoumarin has significant biological properties, which includeanti-HIV, anticancer, antibiotic, antiviral and anticoagulants properties.7Warfarin7f 1 and coumatetralyl 2 are used for pesticides, specifically as a rodenticide and an anticoagulant. O OH. O. OH. O. O. O 2 Coumatetralyl. 1 Warfarin OH O. N Me. O. O. N Me. 3. O. 4 almeine. (+)-araliopsine. Figure I.C.1.1 Biologically active coumarin and angular furoquinolinone derivatives.. 52.

(53) Warfarin 1 and C3-nitroalkylated 4-hydroxycoumarin 5 have some resemblance in terms of functional group arrangement. If we look at the structure of Warfarin and C3-nitroalkylated 4-hydroxycoumarin 5 then we can find that both possess similar basic core unit of 4-hydroxycoumarin (Figure I.C.1.2). The only distinction between these two structures is having different functionalities at C3 carbon. Warfarin is an anticoagulant, which may be due to coumarin and ketonic group, whereas C3nitroalkylated coumarin has coumarin unit with aliphatic nitro group at C3 position that could be transformed to the biologically active compound.. O N O. OH. O. O OH. O. O. O. 5. 1. C 3-nitroalkylated 4-hydroxycoumarin. Warfarin. Figure I.C.1.2 Comparison between warfarin 1 and C3-nitroalkylated 4-hydroxycoumarin 5. On the other hand, furoquinoline derivatives are essentially important because they belong to the known family of furoquinoline alkaloids, which possess a wide array of biological properties.8 Among, linear and angular furoquinolinones, angular furoquinolinones9 (Figure. I.C.1.1, structure 3 and 4) has its own importance in terms of synthetic and biological utilities. The Michael addition with nitroalkenes is an important C-C bond forming reaction, which provides an easy access to synthetically important nitroalkanes. For the last decade our group has been developed several methodologies on Michael addition of nitroalkenes10 with various Michael acceptors. Recently, we have shown that the reaction. of. nitroalkenes. with. cyclic. 1,3-diketones. 6. produces. the. hydroxyiminodihydrobenzofurans 7 in presence of silica gel in methanol11a and with 2-hydroxynaphthoquinone 8 generate Michael adduct 9 under ‘on water’ condition at elevated temperature (Scheme 1).11b These results encouraged us to study the reaction. 53.

(54) of nitroalkenes with other 1,3-diketones such as 4-hydroxycoumarin and 4-hydroxy-1methylquinolin-2(1H)-one.. I.C.2 Review of Literature There are several methods available for the synthesis of C3-alkylation/substitution of 4-hydroxycoumarin.12,13 To our knowledge, there is no direct method reported for the C3-alkylation of 4-hydroxycoumarin with nitroalkenes. Similarly, the synthesis of linear and angular furoquinolinones can be achieved via a number of methods.9,14 Saito et al. reported the base catalyzed synthesis of benzofurans, but they could not isolate the cyclic oxime intermediate.15 A general methodology for the synthesis of angular hydroxyiminodihydrofuroquinolinone has not been reported so far. Hence, in continuation of our interest on the development of green, efficient and catalyst free methodologies16 using nitroalkenes, herein we wish to report on the study of 4hydroxycoumarin and 4-hydroxy-1-methylquinolin-2(1H)-one with nitroalkenes under different conditions. O. R OH N. R1. O. 7a E isomer (major) (69 - 85%) O. R1 R2. O. O. R2. R1 R2. +. OH. O 6. R. O 2N R. O 7b. 8. O. Water, 80 oC (8 - 20h). Silica gel, Methanol Microwave, 60 oC N (1 - 8h) OH R = Aryl, Alkyl. R = Aryl, Alkyl. O. NO 2 R. OH O 9 (80 - 90%). R 1 = R 2 = H or Me. Z isomer (minor) (0 - 8%). Scheme I.C.2.1 Our previous synthetic approaches using nitroalkenes with cyclic 1,3dicarbonyl compounds. I.C.6 References 1. (a) Meciarova, M.; Toma, S.; Magdolen, P. Ultrasonics Sonochem. 2003, 10, 265; (b) Practical Sonochemistry. Power Ultrasound : Uses and Applications; Mason,. 54.