以硝基烯烴化合物合成具有生物活性的含氮氧雜環分子

全文

(1)EXPLORATION OF NITROALKENES TOWARDS THE SYNTHESIS OF BIOACTIVE O, N-HETEROCYCLES. A Dissertation Submitted to the National Taiwan Normal University for the Degree of Doctor of Philosophy in Chemistry. Submitted by Manoj R. Zanwar 899420049. 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: cheyaocf@ntnu.edu.tw TEL +886-2-29309092 FAX +886-2-29324249. CERTIFICATE This is to certify that the work incorporated in the thesis entitled “Exploration of nitroalkenes towards the synthesis of bioactive O, N-heterocycles” submitted by Manoj R. Zanwar 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 “Exploration of nitroalkenes towards the synthesis of bioactive O, N-heterocycles” 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. 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.. Manoj R. Zanwar Date: June 2014 Department of Chemistry, National Taiwan Normal University, Taipei 11677, TAIWAN R.O.C..

(4) Dedicated to my Family.

(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 a troubleshooting 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. TunCheng 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. Chun-Wei Kuo, Dr. Mustafa Jahir Raihan 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. Deepak Kumar Barange, Dr. Ram Ambre, Dr. Balraj Gopula, Dr. Donala Janreddy, Sachin Gawande, 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 in Taiwan. Especially, Pandit Ambre, Sachin Gawande, Dhananjay Magar, Balraj, Ram Ambre, Nagendra Kondekar, Deepak, Sandeep Mane, Sagar, Samir, Rahul, Ajit, Balaji Barve, Arun, Sachin Shivatare, Pratap Patil, Surendhar Reddy, Milind, Vatan, Shashi, Dr. Anwar, Dr. J. Damodar, Dr. Suparna Roy, Mamatha, Dr. Utpal Das, for their friendship and cooperation during my stay in Taiwan..

(6) Furthermore I am deeply indebted to my former supervisors Dr. Paresh Dhepe, Dr. Satynarayana Chilukuri at National Chemical Laboratories, Pune India, for their valuable guidance, support and encouragement and my friends in NCL Anupam, Deepa, Atul, Sahu, Sheetal, Aparna, Jijil, Rajesh, Nagesh Khupse, Mangesh, Satej, Laxman. I also thank my friends in Lupin Pharmaceuticals Dnyaneshwar Singare, Mahesh deshpande, Nitesh Amrutkar, Gopinath Khansole, Samir, Vijay, Amol deshmukh, Thakre, Yogesh Pawar, Dr. Varma, Sachin, Digambar, Uchit, Amol, Sandesh, Pradeep for their great friendship and help. My M.Sc. study at N. S. B. College, Nanded was made me enjoyable part in my life due to the support of my professors, Dr. S. P. Pachling, Dr. Shirodkar, Dr. Hangirgekar, Dr. Vanale, Dr. Joshi, Dr. Pandey, Dr. Rawande, Mrs. Kotgire and all college staff. I wish to thank all of my P.G Classmates. I would like to thank Primary and High School Teachers, Junior and Degree College Lecturers and P. G. College professors. Especially, Dr. Fugare, Dr. Kalamse, Dr. Pawde, Dr. Bondhar and all my K. B. D. H. Highschool teachers. They taught me discipline and good education to reach here. I take this opportunity to thank my best friends. Especially, Atul Deshmukh, Yuvraj Rathod, Gayatri, Vishnu, Rukhmaji, Manisha, Snehal, Dilip, Jyotiram, Khandu, Sandeep, Achyut, Venkatesh gopula, Vynkati, Raju, Nagesh, Manju, Rupesh, Alok, 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 my Brothers Sumit, Nandkishor and sister-in-law Varsha and their cute childrens Gayatri and Bhakti. I want to thank my sisters Godavari, Kaveri, Kalpana, brother-in-law Pavan Baheti, Mulchand Laddha, Sanjay Bhakkad, and other relatives for their constant support and encouragement. I would like to grateful thank my mother and father, they sacrificed for me a lot, and they are always in my heart when I am away from my home. Without their blessing I would not have been achieved my goal. There are no words to express gratitude for them. Thanks to my grandmother for showing a lot of love on me. My final, and most heartfelt, acknowledgment must go to my beloved wife Sunita. She is the best part of my life. Manoj R. Zanwar.

(7) TABLE OF CONTENTS Page Abbreviations. i-iv. Abstract. v-xi. Chapter-I: Overview on the synthesis and utility of nitroalkenes I.1. Introduction. 1. I.2. Synthesis of nitroalkenes. 1. I.3. Nitroalkenes as Michael acceptor. 3. I.4. Utility of nitroalkenes in Friedel-Crafts reactions. 6. I.5. Utility of nitroalkenes in natural product synthesis. 8. I.6. Synthesis of oxygen-containing heterocycles using nitroalkenes. 10. I.7. Synthesis of nitrogen-containing heterocycles using nitroalkenes. 14. I.8. References. 20. Chapter-II: Alcohol mediated synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylate derivatives from 4-hydroxycoumarins. II.1. Introduction. 25. II.2. Review of literature. 26. II.3. Results and discussion. 28. II.4. Conclusions. 40. II.5. Experimental section. 41. II.6. References. 50.

(8) Chapter-III: Synthesis of 2-amino-3-substituted naphtho[2,3-b]furan-4,9-dione from 2-hydroxy-1,4-naphthoquinone and nitroalkenes. III.1. Introduction. 53. III.2. Review of literature. 54. III.3. Results and discussion. 56. III.4. Conclusions. 67. III.5. Experimental section. 67. III.6. References. 74. Chapter-IV: FeCl3 catalyzed regioselective C-alkylation of indolylnitroalkenes with amino group substituted arenes. IV.1. Introduction. 77. IV.2. Review of literature. 78. IV.3. Results and discussion. 80. IV.4. Conclusions. 88. IV.5. Experimental section. 89. IV.6. References. 99. Chapter-V:. FeCl3-catalyzed. synthesis. of. highly. substituted. indolyl-. tetrahydroquinoline derivatives by using electron deficient dienophiles and its application towards the synthesis of indolo-benzonaphthyridine derivatives. V.1. Introduction. 102. V.2. Review of literature. 103. V.3. Results and discussion. 106. V.4. Conclusions. 118.

(9) V.5. Experimental section. 118. V.6. References. 136. X-ray Crystallographic Data. 139. 1. 148. H and 13C NMR Spectral Copies. List of Publications. 260.

(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. Cs2CO3. Cesium carbonate. d. Doublet (NMR). d. Day(s). dd. Doublet of doublet. DABCO. 1,4-diazabicyclo[2.2.2]octane i.

(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 ii.

(12) 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). 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 iii.

(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. iv.

(14) ABSTRACT OF THE THESIS. EXPLORATION OF NITROALKENES TOWARDS THE SYNTHESIS OF BIOACTIVE O, N-HETEROCYCLES The development of novel and efficient protocols for the synthesis of O, N -containing heterocyclic compounds is an important area of research in synthetic chemistry due to their versatile biological utility and potential application in medicinal as well as pharmaceutical chemistry. In this regards, we have utilized cheap and readily available starting material such as nitroalkenes for the synthesis of O, N- heterocycles.. The content of this dissertation is divided into five chapters, the Chapter-I deals with overview on the synthesis and utility of nitroalkenes and related literature review. The Chapter-II deals with alcohol mediated synthesis of 4-oxo-2-aryl-4H-chromene-3carboxylate derivatives from 4-hydroxycoumarins. The Chapter-III describes, synthesis of. 2-amino-3-substituted. naphtho[2,3-b]furan-4,9-dione. from. 2-hydroxy-1,4-. naphthoquinone and nitroalkenes. The Chapter-IV deals with FeCl3 catalyzed regioselective C-alkylation of indolylnitroalkenes with amino group substituted arenes. The Chapter-V describes FeCl3-catalyzed synthesis of highly substituted indolyltetrahydroquinoline derivatives by using electron deficient dienophiles and its application towards the synthesis of indolo-benzonaphthyridine derivatives.. Keywords:. Nitroalkenes,. hydoxynaphthoquinone,. 4-hydroxycoumarin,. chromenone-3-carboxylate,. 2-aminofuronaphthoquinone,. indolylnitroalkene,. indolylnitroalkane, indolyltetrahydoquinoline, indolo-benzonaphthyridine.. v. 2-.

(15) Chapter-I: Overview on the synthesis and utility of nitroalkenes. This Chapter describes overview on the synthesis and utility of nitroalkenes. This part also describes the literature survey on the synthesis and utility of nitroalkenes. Chapter-II: Alcohol Mediated Synthesis of 4-oxo-2-aryl-4H-chromene-3-carboxylate Derivatives from 4-Hydroxycoumarins This section deals with unusual alcohol mediated formation of 4-oxo-2-aryl-4Hchromene-3-carboxylate (flavone-3-carboxylate) derivatives from 4-hydroxycoumarins and β-nitroalkenes in alcoholic medium. The transformation occurs via the in situ formation of a Michael adduct, followed by the alkoxide ion mediated rearrangement of the intermediate. The effect of the different alcohol and non-alcohol media on the reaction was investigated. In addition, flavone derivatives synthesized via a three component reaction from 4-hydroxycoumarin and nitromethane with different aldehydes in the presence of TEA in methanol. The most plausible pathway for the conversion was explored by examining a wide variety of reaction conditions.. Scheme 1. Reaction of 4-hydroxycoumarin and (E)-1-methyl-4-(2-nitrovinyl)benzene. vi.

(16) Scheme 2. Reactions in the presence of different alcoholic solvents. Scheme 3. Reactions in the presence and absence of nitromethane. Chapter-III: Synthesis of 2-Amino-3-Substituted Naphtho[2,3-b]Furan-4,9-Dione from 2-Hydroxy-1,4-Naphthoquinone and Nitroalkenes. This Chapter demonstrate the efficient base-catalyzed synthesis of 2-amino-3-substituted naphtho[2,3-b]furan-4,9-dione derivatives from readily available precursors such as 2hydroxy-1,4-naphthoquinone and nitroalkenes under aqueous conditions. Interesting features of this methodology are the conversion of nitro functionality into an amino functionality in the absence of a reducing agent. Further, to support the mechanism, we conducted control experiment by treating 2-hydroxy-1,4-naphthoquinone and 2-bromo-2phenylacetonitrile in presence of 4 equiv. of NH4OAc in water at 100 oC. In addition, the development of a three component reaction for accessing the same product from an aldehyde, 2-hydroxy-1,4-naphthoquinone and nitromethane make this strategy attractive.. Scheme 4: Reaction of 2-hydroxy-1,4-naphthoquinone and nitroalkene in the presence of base. vii.

(17) Conditions: (A) 4 equiv. NH4OAc, 7 mL H2O, 100 oC (10 h, 51%). (B) 4 equiv. KOAc, 7 mL H2O, 100 oC (11 h, 45%). Scheme 5. Reaction of 2-hydroxy-1,4-naphthoquinone and 2-bromo-2-phenylacetonitrile. Scheme 6: Three component Reaction of 2-hydroxy-1,4-naphthoquinone, aldehyde and nitromethane in the presence of base. Chapter-IV: FeCl3 Catalyzed Regioselective C-Alkylation of Indolylnitroalkenes with Amino Group Substituted Arenes This chapter describes, an efficient FeCl3 catalyzed protocol for the synthesis of amino functionalized indolylnitroalkanes from easily available precursor indolylnitroalkenes and substituted amines. Regioselective C-alkylation in the presence of free amino substituted arenes occurred. This procedure provides a novel approach towards the synthesis of various amino functionalized indolylnitroalkane derivatives in good to excellent yields. The scope of this methodology shows good functional group tolerance and further this protocol was used to prepare indolylquinoline and indolylacridone derivatives.. viii.

(18) Scheme 7. Reaction of indolylnitroalkene and 2-iodoaniline. Scheme 8. Synthesis of indolylquinoline derivative. Scheme 9. Synthesis of indolylacridone derivative. Chapter-V:. FeCl3-Catalyzed. Synthesis. of. Highly. Substituted. Indolyl-. Tetrahydroquinoline derivatives by using Electron Deficient Dienophiles and Its Application towards the Synthesis of Indolo-Benzonaphthyridine derivatives. This Chapter demonstrates an efficient FeCl3 catalyzed synthesis of highly substituted. indolyltetrahydroquinoline. derivatives. from. easily. available. starting. material. indolylnitroalkenes, substituted anilines and different aldehydes. The reaction was carried out using strong electron deficient dienophiles like indolylnitroalkene via Povarov approach. The broad substrate scope and good to excellent yields of the products made this methodology synthetically useful. Further, this methodology was used to prepare biologically active highly fused indolo-benzonaphthyridine derivatives in excellent yields.. ix.

(19) Scheme 10. Reaction of indolylnitroalkene, 2-bromoaniline and 4-methylbenzaldehyde. Reaction conditions: (a) 2 eq. DDQ, DCM, r.t.; (b) EtOH, 20 mol % (10 % W/W Pd/C), 60 oC, H2 balloon; (c) Ph-CHO, 3 eq. TFA, DCM, 50 oC. Scheme 11. Synthesis c][1,7]naphthyridine. of. 8-phenyl-6-(p-tolyl)-9H-benzo[f]. x. indolo[2,3-.

(20) 摘要. 由於含氮氧雜環分子廣泛的生物和藥物化學潛在的應用使之在合成化學研究中是炙手可熱的議題，因此發展了一個新穎、高效能且低成本的含氮氧雜環的合成方法。. 本篇論文可分為五個章節，第一章概述硝基烯類的合成與應用及其相關文獻。第二章敘述4-羥基香豆素在醇類存在下合成色烯酮-3- 羧酸鹽的衍生物。第三章描述以指甲花醌和硝基烯烴合成2-胺基呋喃萘醌。第四章介紹以三氯化鐵催化吲哚硝基烯類和苯胺衍生物進行C-烷基化反應。第五章敘述dienophiles以三氯化鐵催化合成高取代吲哚四氫喹啉衍生物及其合成應用。. 關鍵字：硝基烯類，4-羥基香豆素，色烯酮-3- 羧酸鹽，指甲花醌， 2-胺基呋喃萘醌，吲哚硝基烯，吲哚硝基烷，吲哚四氫喹啉，吲哚苯並萘啶. xi.

(21) Chapter-I Overview on synthesis and utility of nitroalkenes I.1. Introduction Nitroalkenes are of the great interest in organic synthesis.1 In addition, nitroalkenes are well known for their biological activity such as fungicides,2 insecticides,3 and in various pharmacologically active substrates.4 Very recently β-nitrostyrene motifs have also been reported as pro-apoptotic anticancer5 and antibacterial agents.6 As the nitro group is a powerful electron-withdrawing group, which dominates the all molecules containing this group. Due to strong electron deficient nature of nitroalkenes, they are widely used as versatile organic reagent in Michael addition,7 Friedal-Crafts alkylation,8 1,3-dipolar cycloaddition,9 Morita–Baylis–Hillman,10 Diels-Alder11 and domino reactions.12 In addition, the nitro group can be further converted into various functional groups such as nitroso compounds, carbonyl, amino, oxime.13 as well as utilized in different cyclization reaction. Due to versatile utility of nitroalkenes for generating molecules of biological and pharmaceutical relevance, various synthetic methods have been developed.. I.2. Synthesis of nitroalkenes The most common method for the preparation of nitroalkenes involves a Henry condensation reaction of a carbonyl compound with a nitroalkane that provides a β-nitro alcohol, which upon dehydration affords a nitroalkene (Scheme I.2.1).14 The Henry reaction is generally performed under mild basic conditions with a variety of bases, but the dehydration step requires harsh reaction conditions. Scheme I.2.1 Jana and co-workers developed an efficient and simple strategy for the synthesis of various substituted nitroalkenes, involving a co-operative catalytic action of FeCl3 and piperidine. This dual catalytic protocol simultaneously activates both electrophile and. 1.

(22) nucleophile and works under mild reaction conditions so that many sensitive functional groups were tolerated (Scheme I.2.2).15. Scheme I.2.2 Maity et al. developed an efficient and stereoselective nitration of mono and disubstituted olefins using AgNO2 and TEMPO for the synthesis of nitroalkenes. This work discloses a new and efficient approach wherein starting from olefin, nitroalkane radical formation and subsequent transformations lead to the desired nitroolefin in a stereoselective manner (Scheme I.2.3).16. Scheme I.2.3 Roy and co-workers developed an AIBN catalyzed nitrodecarboxylation of aromatic unsaturated carboxylic acids using nitric acid (3 equiv) in MeCN to prepare nitroalkenes. The nitrodecarboxylation is postulated to involve the generation of an acyloxy radical RCO2. by a NO3. radical followed by attack of a NO2. radical (Scheme I.2.4).17. Scheme I.2.4 Friedricha et al. developed procedure for the synthesis of indolylnitroalkenes by refluxing indolealdehyde, NH4OAc in nitromethane. Various indolylnitroalkenes were synthesized by this method in good yields (Scheme I.2.5).18. Scheme I.2.5 Su and co-workers developed a novel palladium catalyzed multidehydrogenative crosscoupling reaction of arenes with nitroethanes. Mechanistic experiments indicated that βnitroethylbenzene might be the intermediate in this transformation. The reaction was. 2.

(23) carried out between arenes or aromatic heterocyles and nitroethane using 10 mol % Pd(TFA)2, 4.0 equiv of AgOAc as oxidant in DMSO at 100 oC (Scheme I.2.6).19. Scheme I.2.6. I.3. Nitroalkenes as Michael acceptor Michael addition is one of the most important reactions for carbon-carbon bond formation. Due to strong electron-withdrawing nature of nitro group, nitroalkenes are acting as very good Michael acceptor for various nucleophiles. Over the past few years, various efficient methods have been developed for the enantioselective as well as racemic Michael addition to nitroalkenes. Rosa et al. reported, combination of water and microwave irradiation promoted catalystfree Michael addition of pyrroles and indoles to nitroalkenes under superheated conditions. In all the cases reaction produced excellent yields of the products in short time. (Scheme I.3.1).20. Scheme I.3.1 Zhao and co-workers developed an efficient strategy for the synthesis of nitro dicarbonyl esters. A CaCl2-catalyzed Michael reaction was carried out at room temperature with different substituted nitroalkenes. The mild reaction conditions, short reaction time, and satisfactory yields are scilent features of this methodology (Scheme I.3.2).21. Scheme I.3.2 3.

(24) Yao and co-workers developed an efficient catalyst free conjugate addition of reactive hetero aromatics (indoles) to nitroalkenes under solvent free condition (SFC) to produce indolyl adduct as well as bis-indolyl adduct in good to excellent yields. Simple reaction conditions, easy isolation, avoid the use of toxic and expensive reagents and low costs make this method useful and attractive over the existing reports (Scheme I.3.3).22. Scheme I.3.3 Yao and co-workers reported a catalyst-free, solvent-mediated addition of thiol to βnitrostyrene proceeded with regioselective control. When reaction was carried out without solvent at room temperature, reaction afforded thiol adduct while in the presence of N2 and toluene reflux vinyl sulfide was major product (Scheme I.3.4).23. Scheme I.3.4 Bartoli et al. developed method for the synthesis of indolylnitroalkane, the combination of cerium(III) chloride heptahydrate and sodium iodide supported on silica gel is used for Michael-type addition. Further, this nitro group reduced by hydrogenation with Raney nickel to give the α-substituted tryptamine derivative. Then this intermediate was converted. to. 4-substituted. 1,2,3,4-tetrahydro-α-carboline. by condensation. with. formaldehyde followed by Pictet-Spengler cyclization of the imine. Finally, the salt was. 4.

(25) converted to the free base and dehydrogenated in the presence of Pd/C to afford αcarboline in 83% yield (Scheme I.3.5).24. Scheme I.3.5 Perumal and co-workers reported a Michael addition of indoles to β-nitrostyrenes possessing o-propargyloxy groups to generate nitroalkanes. Further, the use of (Boc)2O, in combination with DMAP to convert the nitroalkanes into nitrile oxide to undergo intramolecular nitrile oxide-alkyne cycloaddition (INOC) to form isoxazolobenzoxepane derivatives (Scheme I.3.6).25. Scheme I.3.6 Wang et al. developed procedure for the enantioselective Michael addition of Nheterocycles to nitro-olefins using 10 mol % of cinchona alkaloid catalyst. In all the cases, reaction produced moderate to good yields of the product with high enantioselectivity (Scheme I.3.7).26. Scheme I.3.7. 5.

(26) Wang and co-workers reported asymmetric Michael addition of aliphatic aldehydes to indolylnitroalkenes using (S)-diphenylprolinol trimethylsilyl ether as an organocatalyst. Various substituted aliphatic aldehydes were used for Michael addition and in the entire cases reactions produced excellent yield with high enantioselectivity (Scheme I.3.8).27. Scheme I.3.8. I.4. Utility of Nitroalkenes in Friedel-Crafts reactions The Friedel-Crafts reaction is powerful reaction in organic synthesis for C-C bond formation. Friedel-Crafts alkylation of arenes with electron-deficient alkenes is one of the most important organic transformations. Due to strong electron-withdrawing nature of NO2 group, nitroalkenes are found to be very good acceptor which can be readily transformed into different functionalities.. Saidi and co-workers reported, an efficient Friedel-Crafts alkylation of indoles and pyrrole with nitroalkenes using heteropoly acid catalyst. When reaction was performed with indole, reaction produced single indolylnitroalkane product in 82-95% yield while in the case of pyrrole (1:1), it gave 2, 5 di-substituted pyrrole product (Scheme I.4.1).28. Scheme I.4.1 Yao and co-workers reported N-bromosuccinimide catalyzed an efficient and practical method for the synthesis of indolyl-nitroalkane derivatives. This method is applicable to a 6.

(27) wide range of nitroalkenes and various indoles. Low cost of the reagents and convenient isolation process of this reaction, makes this method an attractive alternative to existing methods (Scheme I.4.2).29. Scheme I.4.2 Jia et al. described the procedure for asymmetric Friedel-Crafts alkylation of indoles with nitroalkenes catalyzed by Zn(II)-bisoxazoline complexes. The all indolylnitroalkane product are formed in good yields with high enantioselectivities up to 90%. Reaction was carried out using 10 mol % Zn(OTf)2 and 12 mol % (S)-Ph-bisoxazoline ligand (Scheme I.4.3).30. Scheme I.4.3 Akiyama and co-workers reported a chiral phosphoric acid catalyzed Friedel–Crafts reaction of indoles with β-alkoxycarbonyl-β-disubstituted nitroalkenes. Reaction was carried out using 5 mol % catalyst in the mixture of cyclohexane/DCM (4:1) at room temperature. In all the cases yield and enantioselectivity of the products were excellent (Scheme I.4.4).31. Scheme I.4.4. 7.

(28) I.5. Utility of Nitroalkenes in Natural product synthesis Nitroalkenes are found to be very common intermediate for the synthesis of various natural products and biologically active drugs. Few protocols are depicted below.. Jiang and co-workers developed a method for the total synthesis of marine alkaloid Eudistomin and their analog. Biological studies revealed that all of the compounds showed moderate growth inhibitory activity against breast carcinoma cell line MDA-231 with IC50 of 15–63 μM. Indolylnitroalkene reduced with NaBH4 at room temperature and subsequently, reduced with Pd/C in methanol to give tryptamine. Further, tryptamine treated with phenyl gloxal in acetic acid afforded cyclized product via Pictet-Spengler reaction which was transformed into the target compound Eudistomins in the presence of BBr3 in CH2Cl2 at -78 °C with the yields of 65% (Scheme I.5.1).32. Scheme I.5.1 Namboothiri and co-workers reported the synthesis of variety of functionalized imidazo[1,2-a] pyridines derivatives 3 from Morita-Baylis-Hillman acetates of nitroalkenes and 2-aminopyridines. To achieve target molecule Alpidem (anxiolytic drug) and Zolpidem (hypnotic drug), the acetate 2a and 2b treated with 2-amino pyridine 1c and 1d, respectively, in MeOH at 30 oC to obtain compound 3a and 3b respectively in 92% and 89% yield. Further, hydrolysis of ester group at room temperature carried out. Finally, the resulting acids 4a and 4b, treated with corresponding acid chlorides with appropriate amines to get target molecules Alpidem (5a) and Zolpidem (5b) in 86% and 96% yields respectively (Scheme I.5.2).33. 8.

(29) Scheme I.5.2 Namboothiri and co-workers reported the first total synthesis of antifungal agent isoparvifuran from nitroalkene. Compound 2 treated with phenol in the presence of K2CO3 and toluene to get benzofuran in 76% yield. Further, alkaline hydrolysis of ester group proceeded to get compound 4. Then, 4 on was subjected to CaO/NaOH mediated decarboxylation in DMA under reflux conditions to give benzylated isoparvifuran 5 in 80% yield which was debenzylation by hydrogenolysis took place in quantitative yield to deliver the natural product isoparvifuran 6 in an overall yield of 47% (Scheme I.5.3).34. Scheme I.5.3 Burgey et al. developed route for the total synthesis of. (3R,6S)-3-amino-6-(2,3-. difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one of the CGRP receptor antagonist clinical candidate telcagepant (MK-0974) for the treatment of migraine headache. The commercially available D-glutamic acid derivative 1 was converted to ester 2 using. 9.

(30) literature conditions. Then, intermediate 2 was half reduced to 3 using DIBAL-H. Further, intermediate 3 treated with nitromethane in toluene and catalytic tetramethylguanidine and subsequent addition of methanesulfonyl chloride and triethylamine to the intermediate nitro alcohol effected elimination to give the nitro olefin 4 in good overall yield. Further, alkene intermediate 4 treated with key Hayashi-Miyaura Rh-catalyzed arylboronic acid addition using standard literature conditions to get compound 5. Pd/Ccatalyzed hydrogenolysis of nitroalkane ester 5 gave amino acid 6 which was directly subjected to EDC-mediated lactamization to afford the di-Boc caprolactam 7 in 65% average yield for the two steps. Finally, Selective deprotection with trifluoroacetic acid in dichloromethane effected conversion of 7 to expected compound 8 (Scheme I.5.4).35. Scheme I.5.4. I.6.. Synthesis. of. Oxygen-containing. heterocycles. using. nitroalkenes Heterocyles are an important class of compounds, making up more than half of organic compounds. Nitrogen, oxygen and sulfur are the most common heteroatoms found in heterocyclic compounds. Among heterocyclic compounds ‘Oxygen heterocycles’ is the second major class. Various naturally occurring oxygen containing heterocyclic compounds such as sugars, hormones, antibiotics, vitamins and pigments are biologically 10.

(31) active compounds. Many natural and semi synthetic oxygen heterocyclic derivatives are known for their promising medicinal activity such as Digoxin (CHF treatment), Taxol (anticancer), Lovastatin (hypolipidemic) and Cyclosporine A (immunosuppressant).36 Due to wide activity in medicinal area, various synthetic methods have been developed to prepare oxygen heterocylces such as, coumarin, chromene, chromane, benzofuran, tetrahydropyran, furan. Among the developed synthetic methods, nitroalkenes are found to be the important intermediates shown in below.. Liu and co-workers reported the synthesis of nitro benzofuran, from common intermediate (2-nitroethyl)phenols via a hypervalent iodine-induced oxidative cyclization. Various aliphatic as well as aromatic substituted benzofurans were produced in good yields using this strategy (Scheme I.6.1).37. Scheme I.6.1 Yao. and. co-workers. reported. the. one-pot. two-step. synthesis. of. hydroxyiminodihydrobenzofurans involving the Michael addition of nitroalkenes with 1,3-dicarbonyl compounds followed by intramolecular cyclization in the presence of silica gel under microwave irradiation. Reaction produced two isomers, between them E isomer is the major while Z isomer is minor (Scheme I.6.2).38. Scheme I.6.2 Yao and co-workers described an efficient method for the synthesis of 2,2-di-alkyl-3nitrochromene from salicyladehyde and nitroalkenes using DABCO under solvent free. 11.

(32) reaction condition at 40 oC. While in case of bisnitroalkene, 2 eq. of salicyladehyde were used to get di-nitrochromene substituted benzene (Scheme I.6.3).39. Scheme I.6.3 Hajra and co-workers reported indium-triflate catalyzed coupling of phenol and nitroalkenes in DCE solvent to generate arenofurans in quantitative yield. Presumably, this process involves Michael addition of phenol/naphthols to α,β-unsaturated nitroalkenes followed by subsequent cyclization (Scheme I.6.4).40. Scheme I.6.4 Zhou et al. developed the procedure for the synthesis of 2-arylideneamino-3-aryl-4Hfuro[3,2-c]chromen-4-ones via four-component reaction from substituted nitrostyrenes, aromatic aldehydes, 4-hydroxycoumarins, and ammonium acetate under very mild conditions. The reaction occurs via Michael addition of nitrolalkene to 4hydroxycoumarin and aza-nucleophilic addition, of the imine to the double bond, an intermolecular nucleophilic addition and a dehydration reaction to get desired product (Scheme I.6.5).41. 12.

(33) Scheme I.6.5 Rodriguez and co-workers described the regioselective synthesis of highly substituted 2carbonyl and 2-phosphorylfurans by exploiting the dual nucleophilic character of 1,2dicarbonyls and the dual electrophilic properties of (2-chloro-2-nitroethenyl) benzenes in a one-pot, formal [3+2] cycloaddition. Reaction was carried out using DBU as a base in THF at 0 oC and all the products were formed in 10-30 min in good yields (Scheme I.6.6).42. Scheme I.6.6 Du and co-workers developed an efficient methodology for the synthesis of chiral 2amino-4H-chromene-3-carbonitrile derivatives from organocatalytic enantioselective tandem Michael addition–cyclization of malononitrile to nitroalkenes. Reaction was carried out using different substituted 2-hydroxynitroalkenes in the presence of 10 mol % catalyst at 60 oC, in chloroform solvent (Scheme I.6.7).43. Scheme I.6.7. 13.

(34) Yang et al. reported chiral bifunctional squaramide tertiary amine catalyzed asymmetric cascade sulfa-Michael/Michael. addition reaction. for the synthesis of highly. functionalized chroman derivatives with three contiguous streocentres. The cascade reactions with 1 mol % of squaramide catalyst proceeded well to furnish the corresponding. chromans. in. high. yields. with. high. diastereoselectivity. and. enantioselectivity (up to 95:5 dr, 95% ee) (Scheme I.6.8).44. Scheme I.6.8. I.7. Synthesis of Nitrogen-containing heterocycles using nitroalkenes Nitrogen containing compound has drawn much interest in the field of heterocyclic chemistry. The nitrogen containing compounds have considerable biological and pharmacological activites such as antiasthmatic, antimalarial, anti-inflammatory, antiviral, antibacterial, antitumor agents, and anti-HIV. Due to wide activity in medicinal area, various synthetic methods have been developed to prepare nitrogen containing heterocylces. Few interesting protocols are described below.. Dong and co-workers described the first transition metal-catalyzed transformation of conjugated nitroalkenes into indoles. Reaction was carried out using Pd(OAc)2 (2 mol %), phen (4 mol %), CO (1 atm), in DMF at 110 oC and in all the cases yields of the products were found to be excellent (Scheme I.7.1).45. Scheme I.7.1 14.

(35) Balalaie and co-workers reported the procedure for the synthesis of 1,2,3,4-tetrasubstituted pyrroles using Iron(III) chloride catalyst from primary amines, dialkyl acetylenedicarboxylates and β-nitrostyrene derivatives. The reaction involves the initial reaction of primary amines with dimethyl acetylenedicarboxylate to form the desired enaminone, then β-nitrostyrene could be activated by FeCl3 and undergo the nucleophilic addition (Scheme I.7.2).46. Scheme I.7.2 Chen et al. described an easy and efficient copper-catalyzed protocol for the synthesis of quinoxalines from o-phenylenediamines and nitroolefins. Reaction was performed in the presence of various substituted nitroalkenes with o-phenylenediamines in ethanol at 110 o. C (Scheme I.7.3).47. Scheme I.7.3 Wang and co-workers reported copper acetate-catalyzed [3 + 2] annulation reaction of readily accessible aziridines and nitroalkenes for the synthesis of polysubstituted pyrroles under aerobic condition. The reaction involves a regioselective C–C bond cleavage of aziridines to give an azomethine ylide, which would undergo [3 + 2] cycloaddition with β-nitroalkenes. Reaction was performed using 5 mol % Cu(OAc)2 catalyst in DMSO at 110 oC (Scheme I.7.4).48. Scheme I.7.4 15.

(36) Chen and co-workers reported novel and facile copper-catalyzed [3 + 2] cycloaddition reaction between arylamidines and nitroalkenes for the synthesis of multisubstituted imidazole derivatives using oxygen as an oxidant. Various substituted arylamidines and nitroalkenes treated using 10 mol % CuI catalyst and 20 mol % bipy ligand in DMF at 90 o. C (Scheme I.7.5).49. Scheme I.7.5 Lu and co-workers described copper-catalyzed three component synthesis of polysubstituted pyrroles from α-diazoketones, nitroalkenes, and amines under aerobic conditions. The cascade process involves an N-H insertion of carbene, a copper-catalyzed oxidative dehydrogenation of amine, and a [3+2] cycloaddition of azomethine ylide. Electronic Effect of various electron donating as well as withdrawing groups were studied (Scheme I.7.6).50. Scheme I.7.6 Arigela et al. developed one-pot protocol for the synthesis of indole-based polyheterocycles via a sequential Lewis acid catalyzed intermolecular Michael addition and an intramolecular azide/internal alkyne 1,3-dipolar cycloaddition. Reaction was carried out using 10 mol % Yb(OTf)3 in toluene at 120 oC. Different aromatic/aliphatic 2alkynyl indoles treated with substituted (E)-1-azido-2-(2-nitrovinyl)benzenes to furnish annulated tetracyclic indolo[2,3-c][1,2,3]triazolo[1,5-a][1]benzazepines in good yields (Scheme I.7.7).51. 16.

(37) Scheme I.7.7 Hajra and co-workers reported synthesis of imidazo-[1,2-a]pyridines derivatives from nitro-olefins and 2-aminopyridines using iron (III)-catalyst. Reaction was carried out using 20 mol % catalyst in DMF at 80 oC in DMF. Further, this methodology could be successfully applicable for the synthesis of Zolimidine, a useful drug for the treatment of peptic ulcer (Scheme I.7.8).52. Scheme I.7.8 Menendez and co-workers described a simple and efficient one-pot three-component synthesis. of. novel. 6-amino-8-aryl-2-methyl/benzyl-7-nitro-1,2,3,4-. tetrahydroisoquinoline-5-carbonitriles from the reaction of 1-methyl/benzylpiperidin-4one with nitroalkenes and malononitrile using morpholine in the presence of ethanol under reflux (Scheme I.7.9).53. Scheme I.7.9 Yao and co-workers reported synthesis of 2-Aryl-3-nitro-1,2-dihydroquinolines from the reaction of β-nitrostyrenes and 2-aminobenzaldehyde using DABCO in benzene under reflux condition. After the formation of 2-Aryl-3-nitro-1,2-dihydroquinolines silica gel 17.

(38) was added in reaction mixture to convert in to 3-nitro-2-substituted-quinolines (Scheme I.7.10).54. Scheme I.7.10 Driver and co-workers described Rh2(II) carboxylates catalyzed a fundamental change in the reactivity of nitrostyrylazide to form 3-nitroindole as the exclusive product, thereby providing a new synthetic method for N-heterocycle formation. Reaction was carried with different substituted starting material using 1 mol % Rhodium carboxylate complexes and 4 Å MS in toluene at 75 oC (Scheme I.7.11).55. Scheme I.7.11 Kumar et al. reported base mediated reaction of α-diazo-β-ketosulfone with nitroalkenes affords sulfonylpyrazoles as single regioisomers in excellent yield in onepot room temperature reaction. Reaction was carried out with different substituted nitroalkenes such as aryl, heteroaryl, styrenyl, alkyl, hydroxymethyl, and hydrazinyl (Scheme I.7.12).56. Scheme I.7.12. 18.

(39) Zhou and co-workers described synthesis of optically active 2H-thiopyrano [2,3b]quinolones derivatives with three contiguous stereocenters using chiral bifunctional squar-amide-catalyzed tandem Michael–Henry reaction between 2-mercaptoquinoline-3carbaldehydes and nitroolefins. The reactions proceed excellent with to give the title compounds in high yields with high levels of diastereo- and enantioselectivity (up to >99/1 dr and >99% ee, respectively) (Scheme I.7.13).57. Scheme I.7.13 Yadav and co-workers reported highly enantio- and diastereoselective synthesis of octrahydroquinolines. incorporating. three. contiguous. chiral. centres. from. 1,3-. cyclohexanedione, nitroalkenes and N-tosyl aldimines. The reaction was carried out using 20 mol % of diphenylprolinol silyl ether catalyst and K2CO3 base in 1,4 dioxane solvent at room temperature. The reaction involves diphenylprolinol silyl ether-catalyzed Michael addition of 1,3-cyclohexanedione to nitroalkenes followed by potassium carbonatepromoted aza-Henry reaction with N-tosyl aldimines, intramolecular hemiaminalisation and dehydration reaction in a one-pot operation (Scheme I.7.14).58. Scheme I.7.14 Wang et al. described enantioselective protocol for the synthesis of highly substituted tetracarbazole. through. hydrogen. bonding. mediated. double. Michael. addition-. aromatization cascade of 2-propenylindoles and nitroolefins. Reaction was performed using 10 mol % catalyst, 10 mol % acetic acid as additive in H2O-saturated CH2Cl2 at -78 19.

(40) °C. The methodology allows an efficient synthesis of diverse and structurally complex tetrahydrocarbazoles in good to excellent enantioselectivities and diastereoselectivities (Scheme I.7.15).59. Scheme I.7.15 Xu and co-workers reported bifunctional thiourea-catalyzed (1) asymmetric Michael addition of oxindoles to nitroolefins for the Synthesis of 2,2-disubstituted oxindoles having adjacent quaternary and tertiary stereocenters in high yields and excellent stereoselectivities. Further, this product was reduced with Zn/HCl in EtOH followed by treatment with AcCl/TEA in CH2Cl2, the desired substituted hexahydropyrrolo[3,2b]indole was obtained in moderate yields and high enantioselectivity (Scheme I.7.16).60. Scheme I.7.16. I.8. Refrences 1. a) Barrett, A.G.M.; Graboski, G.G. Chem. Rev. 1986, 86, 751; b) Sibi, M.P.; Manyem, S.; Tetrahedron 2000, 56, 8033; c) Barratt, A. G. M. Chem. Soc. Rev. 1991, 20, 95. 20.

(41) 2. a) Brian, P. W.; Grove, J. F.; McGowan, J. C. Nature 1946, 158, 876; b) McGowan, J. C.; Brian, P. W.; Hemming, H. G. Ann. Appl. Biol. 1948, 35, 25. 3. Boelle, J.; Schneider, R.; Gerardin, P.; Loubinoux, B.; Maienfisch, P.; Rindlisbacher, A. Pestic. Sci. 1998, 54, 304. 4. a) Schales, O.; Graefe, H. A. J. Am. Chem. Soc. 1952, 74, 4486; b) Plenevaux, A.; Dewey, S. L.; Fowler, J. S.; Guillaume, M.; Wolf, P. J. Med. Chem. 1990, 33, 2015; c) Dann, O.; Moller, E. F. Chem. Ber. 1949, 82, 76; d) Zee-Cheng, K.-Y.; Cheng, C. C. J. Med. Chem. 1969, 12, 157; e) Rosowsky, A.; Mota, C. E.; Wright, J. E.; Freisheim, J. H.; J. J. Heusner, McCormack, J. J.; Queener, S. F. J. Med. Chem. 1993, 36, 3103. 5. Pettit, R. K.; Pettit, G. R.; Hamel, E.; Hogan, F.; Moser, B. R.; Wolf, S.; Pon, S.; Chapuis, J.-C.; Schmidt, J. M. Bioorg. Med. Chem. 2009, 17, 6606. 6. Kaap, S.; Quentin, I.; Tamiru, D.; Shaheen, M.; Eger, K.; Steinfelder, H. J. Biochem. Pharmacol. 2003, 65, 603. 7. Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583; b) Berner, O. M.; Enders, L.; Tedeschi, D. Eur. J. Org. Chem. 2002, 1877. 8. a) Takenaka, N.; Chen, J.; Captain, B.; Sarangthem, R. S.; Chandrakumar, A. J. Am. Chem. Soc. 2010, 132, 4536; b) Wu, J.; Li, X.; Wu, F.; Wan, B. Org. Lett. 2011, 13, 4834. 9. Kurth, M. J.; O’Brien, M. J.; Hope, H.; Yanuck, M. J. Org. Chem.1985, 50, 2626. 10. a) Amarante, G.W.; Benassi, M.; Milagre, H.; Braga, A.A.C.; Maseras, F.; Eberlin, M. N.; Coelho, F. Chemistry A European Journal 2009, 15, 12460; b) Mazzotta, S.; Gramigna, L.; Bernardi, L.; Ricci, A. Organic Process Research and Development 2010, 14, 687. 11. Liu, Y.; Nappi, M.; Arceo, E.; Vera, S.; Melchiorre, P. J. Am. Chem. Soc. 2011, 133, 15212. 12. a) Enders, D.; Hüttl, M.R.M.; Grondal, C.; Raabe, G. Nature 2006, 441, 861; b) Enders, D.; Hüttl, M.R.M.; Runsink, J.; Raabe, G.; Wendt, B. Angew. Chem. Int. Ed. 2007, 46, 467. 13. (a) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583; (b) March, J. Advanced Organic Chemistry, 3rd ed.; John Wiley & Sons: New York, 1985; (c) Corma, A.; Serna, P.; Garcia, H. J. Am. Chem. Soc. 2007, 129, 6358; (d) Corey, E.; Estreicher, H. Tetrahedron Lett. 1980, 21, 1113; (e) Dampawan, P. Tetrahedron Lett. 1982, 23, 135; (f) Noland, W. E. Chem. Rev. 1955, 55, 137.. 21.

(42) 14. (a) Bauer, H. H.; Urbas, L. The Chemistry of the Nitro and Nitroso Group; Feuer, H., Ed.; Interscience: New York, 1970, part 2, pp 75; (b) Seebach, D.; Colvin, E. W.; Lehr, F.; Weller, T. Chimia 1979, 31, 1; (c) Rosini, G. in: Comprehensive Organic Synthesis, vol. 2 (Eds.: C. H. Heathcock, B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, chapter 1.10, p. 321. 15. Jalal, S.; Sarkar, S.; Bera, K.; Maiti, S.; Jana, U. Eur. J. Org. Chem. 2013, 4823. 16. Maity, S.; Manna,S.; Rana, S.; Naveen,T.; Mallick, A.; Maiti, D. J. Am. Chem. Soc. 2013, 135, 3355. 17. Das, J. P.; Sinha, P.; Roy, S. Org. Lett. 2002, 4, 3055. 18. Friedricha, A.; Brase, S.; O’Connor, S. E. Tetrahedron Lett. 2009, 50, 75. 19. Zhang, M.; Hu, P.; Zhou, J.; Wu, G.; Huang, S.; Su, W. Org. Lett. 2013, 15, 1718. 20. Rosa, M. D.; Soriente, A. Tetrahedron 2010, 66, 2981. 21. Jia, C.; Chen, D.; Zhang, C.; Zhang, Q.; Cao, B.; Zhao, Z. Tetrahedron 2013, 69, 7320. 22. Habib, P. M.; Kavala, V.; Kuo, C. -W.; Raihan, M. J.; Yao, C. -F. Tetrahedron 2010, 66, 7050. 23. Chu, C.-M.; Tu, Z.; Wu, P.; Wang, C. -C.; Liu, J. -T.; Kuo, C. -W.; Shin, Y. -H.; Yao, C. -F. Tetrahedron 2009, 65, 3878. 24. Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941. 25. Ramachandiran, K.; Karthikeyan, K.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2010, 51, 3006. 26. Wang, J.; Li, H.; Zu, L.; Wang, W. Org. Lett. 2006, 8, 1391. 27. Chen, J.; Geng, Z.-C.; Li, N.; Huang, X. -F.; Pan, F. -F.; Wang, X. -W. J. Org. Chem. 2013, 78, 2362. 28. Azizi, N.; Arynasab, F.; Saidi, M. R. Org. Biomol. Chem. 2006, 4, 4275. 29. Kuo, C.-W.; Wang, C. -C.; Fang, H. -L.; Raju, B. R.; Kavala, V.; Habib, P. M.; Yao, C. -F. Molecules 2009, 14, 3952. 30. Jia, Y. -X.; Zhu, S. -F.; Yang, Y.; Zhou, Q. -L. J. Org. Chem. 2006, 71, 75. 31. Mori, K.; Wakazawa, M.; Akiyama, T. Chem. Sci. 2014, 5, 1799. 32. Jin, H.; Zhang, P.; Bijian, K.; Ren, S.; Wan, S.; Alaoui-Jamali, M. A.; Jiang, T. Mar. Drugs 2013, 11, 1427. 33. Nair, D. K.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2012, 14, 4580. 34. Kumar, T.; Mobin, S. M.; Namboothiri, I. N. N. Tetrahedron 2013, 69, 4964. 22.

(43) 35. Burgey, C. S.; Paone, D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C. M.; Graham, S. L.; Vacca, J. P.; Williams, T. M. Org. Lett. 2009, 10, 3235. 36. (a) Willenbring, D.; Dean, J. Russian Journal of General Chemistry. 2008, 7231; (b) Koehn, F. E.; Carter, G.T. Nature Reviews-Drug Discovery. 2005, 4, 206. 37. Lu, S. -C.; Zheng, P. -R.; Liu, G. J. Org. Chem. 2012, 77, 7711. 38. Barange, D. K.; Raju, B. R.; Kavala, V.; Kuo, C. -W. Tu, Y. -C.; Yao, C. -F. Tetrahedron 2010, 66, 3754. 39. Yan, M. -C.; Jang, Y. -J.; Yao, C. -F. Tetrahedron Lett. 2001, 42, 2717. 40. Kundu, D.; Samim, Md.; Majee, A.; Hajra, A. Chem. Asian J. 2011, 6, 406. 41. Zhou, Z.; Liu, H.; Li, Y.; Liu, J.; Li, Y.; Liu, J.; Yao, J.; Wang, C. ACS Comb. Sci. 2013, 15, 363. 42. Raimondi, W.; Dauzonne, D.; Constantieux, T.; Bonne, D.; Rodriguez, J. Eur. J. Org. Chem. 2012, 6119. 43. Gao, Y.; Yang, W.; Du, D. -M. Tetrahedron: Asymmetry 2012, 23, 339. 44. Yang, W.; Yang, Y.; Du, D. -M. Org. Lett. 2013, 15, 1190. 45. Hsieh, T. H. H.; Dong, V. M. Tetrahedron 2009, 65, 3062. 46. Ghabraie, E.; Balalaie, S.; Bararjanian, M.; Bijanzadeh, H. R.; Rominger, F. Tetrahedron 2011, 67, 5415. 47. Chen, Y.; Li, K.; Zhao, M.; Li, Y.; Chen, B. Tetrahedron Lett. 2013, 54, 1627. 48. Wang, S.; Zhu, X.; Chai, Z.; Wang, S. Org. Biomol. Chem. 2014, 12, 1351. 49. Tang, D.; Wu, P.; Liu, X.; Chen,Y. -X.; Guo, S. -B.; Chen, W. -L.; Li, J. -G.; Chen, B. -H. J. Org. Chem. 2013, 78, 2746. 50. Hong, D.; Zhu, Y.; Li, Y.; Lin, X.; Lu, P.; Wang, Y. Org. Lett. 2011, 13, 4668. 51. Arigela, R. K.; Mandadapu, A. K.; Sharma, S. K.; Kumar, B.; Kundu, B. Org. Lett. 2012, 14, 1804. 52. Santra, S.; Bagdi, A. K.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1065. 53. Balamurugan, K.; Jeyachandran, V.; Perumal, S.; Menendez, J. C. Tetrahedron 2011, 67, 1432. 54. Yan, M. -C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C. -F. J. Org. Chem. 2004, 69, 1565. 55. Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702. 56. Kumar, R.; Namboothiri, I. N. N. Org. Lett. 2011, 13, 4016. 57. Wu, L.; Wang, Y.; Song, H.; Tang, L.; Zhou, Z.; Tang, C. Adv. Synth. Catal. 2013, 355, 1053. 23.

(44) 58. Rai, A.; Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 1354. 59. Wang, X. -F.; Chen, J. -R.; Cao, Y. -J.; Cheng, H. -G.; Xiao, W. J. Org. Lett. 2010, 12, 1140. 60. Jin, C. -Y.; Wang, Y.; Liu, Y. -Z.; Shen, C.; Xu, P. -F. J. Org. Chem. 2012, 77, 11307.. 24.

(45) Chapter-II Alcohol Mediated Synthesis of 4-oxo-2-aryl-4Hchromene-3-carboxylate Derivatives from 4Hydroxycoumarins II.1. Introduction Flavones are an important class of oxygen heterocycles belonging to the flavonoid group that occurs in fruits, seeds, vegetables, nuts, and flowers. The most common flavone in the diet is quercetin. It is present in various fruits and vegetables, but the highest concentrations are found in onion. Several natural products that contain this heterocyclic framework, have antiviral, anticancer, anti-inflammatory, and antioxidant properties.1 Some. of the flavones shows promising biological activity such as, querceitin. (antioxidative and anti-inflammatory activity), chrysin (aromatase inhibitor in vitro), nobiletin (anti-inflammatory), semiglabarin (antifungal) as well as flavones are found to be useful intermediates in the fields of medicinal, pharmaceutical and synthetic chemistry (Figure II.1.1).1-4. Figure II.1.1 Biologically active 4H-chromen-4-one derivatives 25.

(46) In addition to controlling the efficacy of a reaction, the medium used also has a significant role in determining the reaction pathway.2 The polarity of the solvent used in a reaction is a major determinant of the fate of the reaction. The reaction pathway is determined by the stability of a particular transition state that is produced in a specific medium. Thus, the effect of the medium on a chemical transformation is a very important issue in the field of chemistry.2. II.2. Review of literature Among the members of the flavone family, 4-oxo-4H-chromene-3-carboxylate derivatives are very interesting scaffolds, since they can act both as a Michael acceptor and a 1, 3-diketone, due to the presence of an ester functionality at C-3.3-5 However, concerning the poly-substituted counterparts, the chemistry of 2-alkyl substituted derivatives have been explored much more extensively than the 2-aryl derivatives.4,5 Although many methods are available in the literature that describes the synthesis of 3carboxylate flavone scaffold, herein, some efficient and attractive protocols are depicted.. Geahlen and co-workers deveoped a method for the synthesis of flavone-3-carboxylate derivatives by the treatment of 2-hydroxyacetophenone with excess of lithium bis(trimethylsily1)amide followed by dialkylcarbonates gave alkyl 3-(2-hydroxyaryl)-3oxopropanoate. Further, this intermediate on treatment with magnesium chelate with benzoyl chloride to give desired product (Scheme II.2.1).6. Scheme II.2.1 Hormi and co-workers reported that, when β-Chloroarylidenemalonate treated with phenol. in. the. presence. of. K2CO3. in. DMF. solvent. to. produce. β-. (ary1oxy)arylidenemalonates intermediate which further on PPA catalyzed intramolecular cyclization to give flavone 3-carboxylate derivative (Scheme II.2.2).7 26.

(47) Scheme II.2.2 Dean and co-workers reported, flavones are first lithiated by using. lithium di-. isopropylamide in tetrahydrofuran at -78 oC. Later, this intermediate on treatment with 1 eq. of electrophile gave flavone 3-carboxylate derivative (Scheme II.2.3).8. Scheme II.2.3 Lu and co-workers reported an efficient Et3N-mediated reaction of salicylaldehyde with methyl (Z)-2-bromo-4,4,4-trifluoro-2-butenoate that provides easy access to 4-hydroxy-2(trifluoromethyl)-4H-chromene derivatives. Various, substituted salicylaldehydes were used and in all the case yields of the products were found to be excellent (Scheme II.2.4).9. Scheme II.2.4 Long and co-workers have described a highly efficient method for the synthesis of 2substituted-3-carboxy chromone derivatives. The condensation was carried out between halogen-substituted 3-oxo-3-arylpropanoate and acetyl chloride in the presence of K2CO3 and DIPEA in DMF at 0 oC to get intermediate which further, on heating at 110 oC to afford chromone derivatives (Scheme II.2.5).10. 27.

(48) Scheme II.2.5 Doi and co-workers reported Lewis base PBu3 catalyzed synthesis of chromone 3carboxylate derivatives. Initially, starting materials were prepared via Pd(0)-catalyzed carbonylative Sonogashira coupling reaction of iodobenzene and phenylacetylene. Then, Tributylphosphine efficiently induced the tandem acyl transfer-cyclization of carbonates to afford 3-methoxycarbonylflavone derivatives in excellent yields (Scheme II.2.6).11. Scheme II.2.6 In fact, all of the reported methodologies for the synthesis of these esters consist of a multistep process or involve the use of complex mixtures of reagents. As a result, a demand exists for a more straightforward and cost effective procedure for the synthesis of 4H-chromen-4-one moieties. Our long term goal is directed at exploring the utility of (E)-(2-nitrovinyl)benzenes in organic synthesis.12 In a continuation of our research dealing with nitro olefins, we wish to report, herein on the, unprecedented solvent mediated synthesis of 4-oxo-2-aryl-4Hchromene-3-carboxylates from 4-hydroxycoumarins and β-nitroalkenes.. II.3. Results and discussion In a recent publication, we reported on the synthesis of a series of oxime, hydroxyiminodihydrofuroquinolinone derivatives, from 4-hydroxy-1-methyl quinolin2(1H)-one and (E)-(2-nitrovinyl)benzenes, using methanol as the solvent, in the presence of a catalytic amount of diisopropylethylamine.12a We proposed that the conversion occurred via the formation of a Michael adduct. The Michael adduct underwent base mediated C-O bond formation to produce an oxime. However, when we examined the 28.

(49) reactions of 4-hydroxycoumarin (a, Scheme II.3.1) and (E)-(2-nitrovinyl)benzenes (2) at the same conditions, the reaction was sluggish. From these two experimental outcomes, it appeared that the nitrogen heterocycle, 4-hydroxy-1-methylquinolin-2(1H)-one, itself acts as a base and, because of this, the basicity of the medium appears to be an important factor in the formation of an oxime derivative. Taking cues from these observations, we used 2 equiv of diisopropylethylamine to synthesize an oxime derivative (2a’, Scheme II.3.1), from 4-hydroxycoumarin (a) and (E)-(2-nitrovinyl)benzenes derivatives (2). At room temperature, only the corresponding Michael adduct was observed. At this point, with the desired oxime in mind, we carried out the reaction at 70 oC. However, the desired oxime was not formed, but the result was more exciting and interesting than our expectation. 1H and. 13. C NMR, IR, Mass, and single crystal X-ray analysis data (Figure. II.3.1 and supporting information) revealed that the product was methyl 4-oxo-2-p-tolyl4H- chromene-3-carboxylate (2a), which was formed in 33% yield. The use of 4 equiv of diisopropylethylamine improved the yield to 51%. This finding presents a novel and straightforward route for the preparation of a relatively unexplored member of the flavone family. In this context, recently, Balalaie and co-workers disclosed that the treatment of 4hydroxycoumarin with (E)-(2-nitrovinyl)benzenes in acetonitrile, in the presence of ammonium acetate, resulted in the formation of the (3E)-3-[amino(aryl)methylidene) chromane-2,4-dione derivative (Scheme II.3.1).13 However, in our case, when methanol was used as solvent instead of acetonitrile, a flavone derivative was produced as the major product. Hence, these results explain the effect of the medium in chemical transformations in a more comprehensive fashion.. Scheme. II.3.1.. Reaction. of. 4-hydroxycoumarin. nitrovinyl)benzene 29. and. (E)-1-methyl-4-(2-.

(50) Figure II.3.1. X-ray Crystal structure of 2a (ORTEP diagram) This exciting experimental outcome prompted us to determine the optimal conditions for the conversion. To pursue this goal, we first ran the reaction using different bases (Table II.3.1). No product was obtained with diethylamine (entry 3), piperidine (entry 7) and amberlyst A-25, a basic ion exchange resin (entry 8). However, the use of ammonium acetate (entry 4), DABCO (entry 5), NaHCO3 (entry 6) and DBU (entry 11) resulted in the formation of an inseparable mixture. On the other hand, bases like DIPEA (entry 1), pyridine (entry 2), TEA (entry 9), KF (entry 10), and N,N-dimethyl cyclohexyl amine (entry 12) were found to be more effective. Among them, TEA was found to be superior to the other bases used. When the reaction was carried out at room temperature, only the Michael adduct was formed and no evidence of the desired product was observed. However, at 70 °C the desired product (2a) was obtained in good yield and the yield was not improved when the reaction was conducted at higher temperatures. Hence, the substrate scope was explored by carrying out the reaction at 70 oC with TEA as the base. The scope of the methodology was examined, first, by treating 4-hydroxycoumarin with a series of β-nitroalkene derivatives. To accomplish this, we used several o-, m-, p- as well as unsubstituted (E)-(2-nitrovinyl)benzenes, containing both electron donating and withdrawing groups (Table II.3.2). We also tested a variety of 4-hydroxycoumarin derivatives (Scheme II.3.2) and alcohols (Table II.3.3) to elaborate the chemistry further. In the case of 4-hydroxycoumarin, the yields of the desired products were found to be dependent on the electronic nature of the substituents on the phenyl moiety of (E)-(2nitrovinyl)benzene (Table II.3.2). With the unsubstituted (E)-(2-nitrovinyl)benzene the expected product was obtained in 72% yield (Table II.3.2, entry 1). The desired products were obtained in moderate to good yields when electron donating groups were present on the phenyl ring (entries 2-7). 30.

(51) Table II.3.1. Effect of different bases. a. All reactions were performed on a 2 mmol scale. b Yield refers to the isolated yield of. the purified compound. c No product was observed. d An inseparable mixture was formed. However, the introduction of an electron withdrawing group (such as a nitro group), resulted in a lower product yield (entry 10). Halide substituted (E)-(2-nitrovinyl)benzenes (entries 8 and 9) also produced lower product yields than the (E)-(2-nitrovinyl)benzenes with methoxy, methyl, ethyl, and amine functionalities, presumably, the electron withdrawing inductive effect of the halide functionality makes the phenyl ring electron deficient. The effect of steric factors on product yields was quite interesting. When more sterically hindered (E)-(2-nitrovinyl)benzenes were used, the yields were improved. The presence of an o-substituent resulted in good to excellent yields of the desired products ((Table II.3.2, entries 11 and 12). (E)-(2-nitrovinyl)benzenes, derived from 2napthaldehyde, produced the expected product in good yield (entry 13). However, a low product yield was obtained in the case of (E)-2-(2-nitrovinyl)thiophene (entry 14). With other heterocyclic nitroalkenes, like pyridine, pyrrole, indole and furan, we did not. 31.

(52) observe the desired product and an inseparable mixture of products were obtained in all the cases. Table II.3.2. Reaction of 4-hydroxycoumarin with different nitroalkene derivatives. a. Yields refer to isolated and purified compounds. Parentheses indicate the yield calculated. by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as an internal standard. bAll reactions were performed on a 2 mmol scale. 32.

(53) Continued………. a. Yields refer to isolated and purified compound. Parentheses indicate the yield calculated. by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. bAll reactions were performed on a 2 mmol scale. Next, to explore the diversity of our protocol further, we treated halo (1b, Scheme II.3.2) and methyl (1c, Scheme II.3.2) substituted 4-hydroxycoumarin derivatives with (E)-133.

(54) methyl-4-(2-nitrovinyl)benzene. Presumably, due to the electron donating inductive effect of the methyl functionality, the latter produced a higher product yield (1c) than the former (1b). The presence of strong electron withdrawing group, like 4-hydroxy-6-nitro-2Hchromen-2-one, the desired product (1d) was obtained in poor yield. However, with 6(dimethylamino)-4-hydroxy-2H-chromen-2-one, the expected flavone derivative (1e) was obtained in good yield.. a. Yields refer to isolated and purified compound. Parentheses indicate the yield calculated. by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. b All reactions were performed on a 2 mmol scale. Scheme II.3.2. Reaction of substituted 4-hydroxycoumarin and (E)-1-methyl- 4-(2nitrovinyl) benzene. After. studying. the. different. reactions. of. (E)-(2-nitrovinyl)benzenes. and. 4-. hydroxycoumarins, we focused our attention on determining the effect of the medium used in the reaction (Table II.3.3). To pursue this goal, the reaction of (E)-1-methyl-4-(2nitrovinyl)benzene and 4-hydroxycoumarin were performed in different alcoholic media. We observed that, the presence of a sp2 carbon α to the C-O bond resulted in a higher yield of the flavone derivative than bulkier sp3 counterparts. Hence, benzyl alcohol (entry 3, Table II.3.3) and allylic alcohol (entry 4) were more productive than ethanol (entry 1), n-propyl alcohol (entry 2), and ethylene glycol (entry 5). The low yields of the desired products with thiophene methanol (entry 6) and furfuryl alcohol (entry 7) is probably due to the instability of the sulfur and oxygen heterocycles at the high temperature used.. 34.

(55) Table II.3.3. Reaction in different alcoholic medium. a. Yields refer to isolated and purified compounds. Parentheses indicate the yield calculated. by 1H NMR spectroscopy of the crude reaction mixture using CH2Br2 as the internal standard. b All reactions were performed on a 2 mmol scale.. 35.

(56) To further explore the effect of medium, we used methylamine and ethylmercaptan as solvents (Scheme II.3.3). In these cases, no expected product (2b and 2c) was obtained. However, compounds 2d and 2e were formed as the primary amine and the thio nucleophiles underwent a faster Michael addition with (E)-(2-nitrovinyl)benzene than the C-nucleophile, 4-hydroxycoumarin, in the presence of a base. However, with less activated nitrogen containing nucleophiles, like aniline and N-methylaniline, a complex mixture of products was obtained.. Scheme II.3.3. Reaction in non-alcoholic medium To study the efficacy of other Michael acceptors in this transformation, we used cinnamylnitrile (i, Scheme II.3.4) and cinnamyl gemdicarboxylate (ii). However, no Michael adduct was formed and only the starting materials were recovered.. Scheme II.3.4. The use of different Michael acceptors The phenomenon could be explained by considering the role of the methoxide ion in the reaction, which is formed from the solvent methanol in the presence of a base (Scheme II.3.5). The initially formed Michael adduct (A) is either attacked by a methoxide ion to form intermediate B via C-O bond cleavage (Pathway a, Scheme II.3.5), or, the elimination of nitromethane occurs, accompanied by the formation of intermediate M (Pathway b). Intermediate B (Pathway a) undergoes tautomerism and C-C bond rotation. 36.

(57) to form intermediate D. The base mediated elimination of nitromethane from intermediate D, results in the formation of E. The intermediate E could also be formed from intermediate M via the participation of the solvent. E then undergoes cyclization via an intramolecular Michael addition of the phenolic OH to form F. The thermal dehydrogenation of F results in the formation of the product, G. The driving force behind this thermal dehydrogenation is the extensive conjugation, which is achieved by the product, due to the formation of multiple bonds. Presumably, the presence of an electron withdrawing ester group drives the intermediate, F, towards this dehydrogenation. The possible alternative route (Pathway c), for this conversion would involve the SN2 type attack of the phenolic OH at the benzylic carbon which, on the elimination of nitromethane, would produce intermediate F. However, probability of an SN2 attack would be controlled by steric factors.. Scheme II.3.5. Plausible mechanism for the formation of methyl 4-oxo-2-phenyl-4H chromene-3-carboxylate derivatives. The proposed mechanism of the reaction (Scheme II.3.5) indicates that the elimination of nitromethane in an intermediate step leads to the formation of the final product and hence, the likely active reactants are 4-hydroxycoumarin and benzaldehyde. Based on this 37.

(58) assumption, we examined the reaction of 4-hydroxycoumarin and benzaldehyde in the presence triethylamine (Scheme II.3.6). However, 3,3'-(phenylmethylene)bis(4-hydroxy2H-chromen-2-one) (1x) was produced as the sole product. This result can be explained by considering the formation of intermediate M (Scheme II.3.5) from 4-hydroxycoumarin and benzaldehyde. The attack of the second molecule of 4-hydroxycoumarin at intermediate M, results in the formation of 1x. On the other hand, the desired product (1a) was obtained along with traces of an inseparable mixture of byproducts, when the same reaction was carried out in the presence of nitromethane. The probable explanation for this outcome is that the nitromethane attacks intermediate M faster than the second molecule of 4-hydroxycoumarin to form the Michael adduct A, which was observed during the reaction. This provides convincing evidence to support that the elimination of nitromethane actually occurred after the cleavage of the C-O bond (Pathway a, Scheme II.3.5). This finding, rules out the possibility that pathway b is operative. To confirm this, we examined the reaction between 4-hydroxycoumarin and (E)-(2-nitrovinyl)benzene in a 2:1 ratio. No biscoumarin product (1x) was detected. Moreover, to determine whether the reaction occurs via the intermediate formation of 1x, we carried out a reaction between biscoumarin (1x) and nitromethane in the presence of TEA in methanol at 70 oC. However, the desired product (1a) was not produced, even after 48 h and the starting material was recovered.. Scheme II.3.6. Reactions in the presence and absence of nitromethane Besides elaborating the reaction mechanism, this experiment revealed the possibility that our desired flavone could be synthesized via a three component reaction (Table II.3.4). Hence, we focused our attention towards on the possibility of such a multicomponent protocol. This goal was pursued by the treatment of 4-hydroxycoumarin and nitromethane 38.

(59) with different aldehydes in the presence of TEA in methanol. In all the cases, the products were obtained in moderate yields (entries 1, 2, 4, and 5), however, the expected flavone was obtained in poor yield in the case of 4-chlorobenzaldehyde (entry 3). Table II.3.4. Multicomponent protocol for the synthesis of flavone derivatives. a. Yields refer to isolated and purified compounds. b The reaction was performed on a 2. mmol scale.. In this context, to determine whether the medium participates in this step via the in situ generation of alkoxide ions, we isolated the Michael adduct and carried out the reaction in methanol in the presence and absence of a base (Scheme II.3.7). The reaction clearly. 39.

(60) proceeded more efficiently in the presence of a base than in the absence of base. Hence, in the presence of base the alcohol produces alkoxide ions in situ. The alkoxide ion plays a key role in the formation of the final product from the Michael adducts.. Scheme II.3.7. Role of base in the formation of flavone derivatives from a Michael adduct. We next, carried out a reaction between 4-hydroxycoumarin and (E)-1-methyl-4-(2nitrovinyl)benzene at room temperature in the presence of sodium methoxide to determine whether the direct use of sodium methoxide would enhance the efficiency of the reaction (Scheme II.3.8). Only the Michael adduct was detected in the reaction mixture and no expected product was produced in 48 h. However, the desired product was formed on heating, but, the yield was low. Although, this experiment did not result in an increase in the yield of the desired product, it explains the role of temperature and base in a more comprehensive manner. The former is required to excite the methoxide ion to participate in a nucleophilic attack at the carbonyl carbon of the Michael adduct and the latter mediates the formation of a Michael adduct by the abstraction of an alcoholic proton of the 4-hydroxycoumarins as well generating a methoxide ion in situ.. Scheme II.3.8. Reaction in the presence of methoxide ion. II.4. Conclusions In conclusion, we demonstrate, here, a simple and cost effective method for the synthesis of a wide variety of 4-oxo-2-aryl-4H-chromene-3-carboxylate derivatives. The method, which permits the synthesis of many new 4-oxo-2-aryl-4H-chromene-3-carboxylate. 40.

(61) derivatives, overcomes many of the previous limitations, and provides a route to producing these moieties for use in the fields of medicinal and synthetic chemistry. The reaction occurs through the in situ generation of a Michael adduct and followed by the CO bond cleavage of the coumarin moiety of the Michael adduct via participation by the alcoholic medium. The most plausible pathway for the conversion was explored by examining a wide variety of reaction conditions.. II.5. Experimental Section II.5.1. General Information All chemicals were purchased from various sources and were used directly without further purification. Analytical thin-layer chromatography was performed using silica gel 60F glass plates and silica gel 60 (230–400 mesh) was used in flash chromatographic separations. NMR spectra were recorded in CDCl3 with tetramethylsilane and Chloroform as the internal standards for 1H NMR (400 MHz) and CDCl3 solvent as the internal standard for. 13. C NMR (100 MHz). Coupling constants were expressed in Hertz. HRMS. spectra were recorded using FAB-TOF, ESI or EI+ mode. Melting points were recorded using an electro thermal capillary melting point apparatus and are uncorrected.. II.5.2. General. Procedure for preparation of. 4-oxo-2-aryl-4H-chromene-3-. carboxylate derivatives To a stirred solution of 4-hydroxycoumarin (0.32 g, 2 mmol) and (E)-1-methyl-4- (2nitrovinyl)benzene (0.65 g, 4 mmol) in alcohol (6 mL) was added triethylamine (1.10 mL, 4 equiv). The reaction mixture was heated at 70-80oC and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuum. The resulting residue was further purified by flash column chromatography (Ethyl acetate / hexane) on silica gel.. II.5.3. General procedure for the one-pot preparation of 4-oxo-2-aryl-4H-chromene3-carboxylate derivatives via three component reaction. 41.

(62) To a stirred solution of 4-hydroxycoumarin (0.32 g, 2 mmol), benzaldehyde (0.42 g, 4 mmol) and nitromethane (0.42 mL, 8 mmol) in alcohol (6 mL) was added triethylamine (1.10 mL, 4 equiv). The reaction mixture was heated at 70oC and the progress of the reaction was monitored by TLC. After completion of the reaction, the solvent was evaporated in vacuum. The resulting residue was further purified by flash column chromatography (Ethyl acetate / hexane) on silica gel. II.5.4. Procedure for preparation of 3,3'-(phenylmethylene)bis(4-hydroxy-2Hchromen- 2-one) To a stirred solution of 4-hydroxycoumarin (0.32 g, 2 mmol) and benzaldehyde (0.42 g, 4 mmol) in alcohol (6 mL) was added triethylamine (1.10 mL, 4 equiv). The reaction mixture was heated at 70 oC and the progress of the reaction was monitored by TLC. After the completion of the reaction, the solvent was evaporated in vacuum. The resulting residue was further purified by flash column chromatography (Ethyl acetate / hexane) on silica gel.. II.5.5. Spectral Data Methyl 4-oxo-2-phenyl-4H-chromene-3-carboxylate (1a). Yield: 72 %; Off white solid; m.p.: 100-102 oC; FT-IR (KBr) ν/cm-1 1736, 1643, 1569, 1466, 1384, 1092, 760; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.27 (d, J = 8.0 Hz, 1H), 7.76-7.70 (m, 3H), 7.57-7.50 (m, 4H), 7.45 (t, J = 7.6 Hz, 1H), 3.80 (s, 3H) ; 13. C NMR (100 MHz, CDCl3) δ 175.2, 165.8, 163.3, 156.0, 134.5, 132.2, 131.9, 129,. 128.2, 126.4, 125.9, 123.4, 118.3, 118.3, 52.9; LRMS (FAB) (m/z) (relative intensity) 281 (M++1, 88), 273 (9); HRMS (FAB) calcd for C17H13O4 (M+H)+: 281.0814, found 281.0810. Methyl 4-oxo-2-p-tolyl-4H-chromene-3-carboxylate (2a). Yield: 68 %; Brown solid; m.p.: 126-128 oC; FT-IR (KBr) ν/cm-1 1737, 1644, 1619, 1564, 1466, 1383, 1091, 762; 1H NMR (400. 42.