Minisci coupling requires transition-metal catalyst for similar coupling reactions ... initiated domino reaction is highly efficient strategy for the construction of.
Ph.D. Thesis
Transition-Metal-Free Domino Annulation for the Construction of Aromatics and Heteroaromatics
Graduate School of Yeungnam University Department of Chemical Engineering and Technology Major in Chemical Engineering and Technology
Tej Narayan Poudel
Advisor: Prof. Yong Rok Lee
2016 January
Ph.D. Thesis
Transition-Metal-Free Domino Annulation for the Construction of Aromatics and Heteroaromatics
Advisor: Prof. Yong Rok Lee Presented as Ph.D. Thesis 2016 January
Graduate School of Yeungnam University Department of Chemical Engineering and Technology Major in Chemical Engineering and Technology
Tej Narayan Poudel
Acknowledgements
I would never have been able to finish my dissertation without the guidance of my supervisor, committee members, and help from friends, labmates and support from my family and relatives. Firstly, I would like to express my sincere gratitude to my advisor Prof. Yong Rok Lee for the continuous support of my Ph.D study and related research, for his patience, motivation, and immense knowledge. His professional guidance, expert supervision, encouragement, precise and strict direction, and invaluable comments and suggestions helped me in all the time of Doctoral research and writing of this thesis. Besides my advisor, I wish to extend my sincere gratefulness to thesis reviewing committee members; Prof. Moo Hwan Cho and Prof. Jae-Jin Shim from School of Chemical Engineering, Yeungnam University (YU), Prof. Choon Sup Ra from Department of Chemistry, Yeungnam University (YU), and Prof. Su-Jin Kim from Department of Cosmeceutical Science, Daegu Hanny University for their precious time for reviewing my Ph.D. thesis and providing creative criticism and valuable suggestions. My special gratitude goes to my senior lab-mate Dr. Xia Likai and Dr. Krishna Bahadur Somai Magar for their generous and non-stop help and scientific/technical guidance from the beginning to till date. Also, stimulating scientific discussion, kind help, co-operation and warm friendship from lab members; Dr. Nagaraj Basavegowda, Dr. Rameshwar Prasad Pandit, Dr. Kavita Sharma, Dr. Sanjaya Paul, Dr. T. V. M. Sreekanth, Dr. Raji Atchudan, Dr. Thomas Nesakumar Jebakumar Immanuel Edison, Mr. Ek Raj Baral, Mr. Hari Datta Khanal, Mr. Kanchan Mishra, Mr. Rajeev Shrestha, Mr. Sang Hyeon Yun, Mr. Muhammad Saeed Akhtar, Mr. Ramuel John Tamargo, Ms. Cai Hongyun, Ms. Shizuka Mei B. Maezono, Ms. Ga Eul Park III
and Ms. Jee Hyeon Ha are highly commendable. It is my pleasure to thank former lab members; Dr. Naushad Edayadulla, Dr. Srinivasu V. N. Vuppalapati, Dr. Akber Idhayadhulla, Ms. Ji Hyang Park, Ms. So Rang Kang, Ms. Ji Hye Lee for their scientific assistance, other required help and friendship. My sincere thanks also go to Dr. Young Kyu Lee at Centre for Research Facilities, YU for providing NMR spectroscopic analysis facility and her kind co-operation. Similarly, my grateful appreciation goes to Dr. Sung Hong Kim at Korea Basic Science Institute, Analysis Research Division, Daegu for mass spectroscopic analysis facility. I extend my deepest gratitude to Graduate School of YU for providing this opportunity with 100% scholarship, all the faculty members and staff at School of Chemical Engineering, YU for excellent facilities and their direct and indirect help. Equally, my great acknowledgement is reserved to BK21 plus program for the financial support. I am also indebted to Prof. Dr. Susan Joshi (Master’s Degree Thesis Supervisor), Prof. Dr. Shiva Prasad Dhaubhadel, Prof. Dr. Mangala Devi Manandhar, Prof. Dr. Tulsi Prasad Pathak, Prof. Dr. Mohan Bikram Gewali, Prof. Jaya Krishna Shrestha, Prof. Dr. Krishna Manandhar, Prof. Dr. Raja Ram Pradhananga, Prof. Dr. Sarbajna Man Tuladhar, Prof. Dr. Pooran Prasad Shrestha, Prof. Krishna Ram Palak, Prof. Dr. Kedar Nath Ghimire, Prof. Dr. Jagadeesh Bhattarai, Prof. Dr. Megh Raj Pokhrel (Head of Central Department of Chemistry, TU), Prof. Dr. Vinay Kumar Jha, Prof. Dr. Paras Nath Yadav, Prof. Dr. Rameshwar Adhikari, Prof. Dr. Surya Kanta Kalauni, Prof. Dr. Deb Bahadur Khadka, Assoicate Prof. Dr. Mina Rajbhandari, Dr. Nootan Bhattarai, Dr. Bimala Subba,
Dr.
Sushika Mulmi, Dr. Sabita Shrestha, Dr. Armila Rajbhandari and Mr. Santosh Khanal from Tribhuvan University (TU) for their invaluable guidance, inspiration and moral support during my graduate study and teaching period at TU. IV
My special thanks goes to all of my friends and staffs from Capitol Hill College, Teku, Kathmanud including Mr. Dhananjaya Sharma Adhikari, Mr. Toya Nath Adhikari, Mr. Bhola Nath Regmi, Mr. Bikash Sharma, Mr. Sagar Raj Khanal, Mr. Shambhu Ghimire, Mr. Min Prasad Pokhrel, Mr. Indra Krishna Dangol and all Capitol Hill family for their support and love during my teaching period at CHC. Finally, the most important of all, I have been greatly indebted to my parents (Liladhar Poudel and Buddhi Maya Poudel), father and mother in law (Danda Pani Sapkota and Sita Sapkota), elder uncle and aunt (Lok Nath Poudel and Draupati Poudel), uncle and aunt (Bhim Raj Poudel and Ujjeli Poudel) Brother Bhim Raj Poudel, sister in law Sita Poudel, elder sister and brother in law (Laxmi Poudel and Rajendra Bhattarai; Rabindra Sapkota and Laxmi Sapkota; Ishwari Prasad Kafle and Ranju Kafle) for their divine love, care, support and continuous encouragement throughout my entire life. Also, my warmest gratitude and love belong to my wife Kanti Sapkota, Lovely son Kristal Poudel, nephew (vanja) Krishna Bhattarai and lovely kids Kritish Poudel, Ritesh Kafle, Ritika Kafle, Angilika Sapkota and all the family members including their support and care during my Ph.D. study. Again, to everyone I have tried to list above, and to those whom I am sure I have missed or forgotten to include, thank-you for your incredible support and assistance over the years. I dedicate this thesis in the meory of my late grand mother Kushi Devi Poudel, her love, struggle, and encouragement to bring me at this stage will be unforgettable.
2016 January
Tej Narayan Poudel
V
Table of Contents Acknowledgements ………………………………………………………III Table of Contents …………………………………………………….…..VI List of Abbreviations ………………………………………….…….…..VII Abstract ……………………………………………………………..…...XII Part-I Introduction:…………………....………………………..…………1 1.1 Aromatics and Heteroaromatics…………………………………...2 1.2 Transition-Metal Catalyzed vs Transition-Metal-free Synthesis ….3 1.3 Domino Annulation Reactions…………………..……..……….....5 1.4 References ……………………………………………….………..9 Part-II Results and Discussion…………………………………………...13 2.1 Construction of Diverse Benzo[c]chromene-6-ones…………..14 2.1.1 Introduction………………………………………………...14 2.1.2 Results and Discussion…………………………………......18 2.1.3 Conclusion…………………………………………………26 2.1.4 Experimental Section………………………………………27 2.1.5 References………………………………………………….45 2.2 Multicomponent Benzannulation for Functionalized Biaryls..50 2.2.1 Introduction………………………………………………...50 2.2.2 Results and Discussion………………………...…………...54 2.2.3 Conclusion……………………………………….………...64 2.2.4 Experimental Section………………………………………65 2.2.5 References……………………………...……………...…...90 VI
2.3 Catalyst- and Solvent-Free Synthesis of Diverse 2-Pyridones..94 2.3.1 Introduction………………………………………………...94 2.3.2 Results and Discussion………………………………..........97 2.3.3 Conclusion………………………………………………..104 2.3.4 Experimental Section……………………………………..105 2.3.4 References………………………………………………...124 2.4 Construction of Highly Functionalized Carbazoles…………128 2.4.1 Introduction……………………………………………….128 2.4.2 Results and Discussion……………………………………131 2.4.3 Conclusion………………………………………………..141 2.4.4 Experimental Section……………………………………..142 2.4.5 References………………………………………………...163 Part-III Conclusions……………………………………………….....…167 Part-IV Appendix…………………...…………………………….....…..170 List of Publications ……………………………………………...………175 List of Papers Presented in Conferences ………………………………180 Korean Abstract (요약 )…………………………………………...……182
VII
List of Abbreviations General Abbreviation
anhyd aq bp br calcd cm-1 13 C NMR concn d dd d eq. equiv FAB FT g h HPLC 1 H NMR HRMS Hz IR J L
Term Chemical shift Anhydrous Aqueous Boiling point Broad (spectral) Calculated Wavenumber(s) Carbon nuclear magnetic resonance Concentration Day(s); doublet (spectral) Doublet of doublet Density Equation Equivalent(s) Fast atom bombardment Fourier transform Gram(s) Hour(s) High-performance liquid chromatography Proton nuclear magnetic resonance High-resolution mass spectrometry Hertz Infrared Coupling constant Liter(s) VIII
m m M m/z MHz min mL mmol mol mol. wt. mp MS MW NMR N-N bond o ppm p q rt s soln t Temp TLC UV v/v vis vol w/w wt
Multiplet (spectral) Meta Molar (moles per liter) Mass-to-charge ratio Megahertz Minute(s); minimum Milliliter Millimole(s) Mole(s) Molecular weight Melting point Mass spectrometry Microwave (in schemes) Nuclear magnetic resonance Nitrogen-Nitrogen bond Ortho Part(s) per million Para Quartet (spectral) Room temperature Singlet (spectral); second(s) Solution Triplet (spectral) Temperature (in tables) Thin-layer chromatography Ultraviolet Volume per unit volume (volume-to-volume ratio) Visible Volume Weight per unit weight (weight-to-weight ratio) Weight
IX
Reagents and Solvents Abbreviation AcOH Ac2O
Compound Name Acetic acid Acetic anhydride
alumina CCl4
Alumina / aluminum oxide Carbon tetrachloride / tetrachloromethane
CH2Cl2
Dichloromethane
CHCl3
Chloroform
CDCl3
Chloroform-d
CO2
Carbondioxide
DME DMF DMSO-d6 Et3N
1,2-Dimethoxyethane N,N-Dimethylformamide Dimethyl sulfoxide-d6 Triethylamine
EtOAc EtOH HCl HNO2 H2O KBr
Ethyl acetate Ethanol Hydrochloric acid Nitrous acid Water Potassium bromide
K2CO3
Potassium carbonate
MeCN MeOH MeOH-d4 MgSO4
Acetonitrile Methanol Methanol-d4 Magnesium sulfate
MS Na2CO3
Molecular sieves Sodium carbonate
Na2SO4
Sodium sulfate
NH4Cl
Ammonium chloride
NH2Cl
Chloramine
PhOH PhH PhF
Phenol Benzene Fluorobenzene X
SiO2 TEA THF THP TMS
Silica Triethylamine Tetrahydrofuran Tetrahydropyran Tetramethylsilane
Substituents and Protecting Groups Abbreviation Ac All Ar Bn t-Bu Bu Bz Cbz Et Me Ms OAc OMe Ph Pr i-Pr Pv R TMS Tol Ts
Substituent Name Acetyl Allyl Aryl Benzyl tert-Butyl Butyl Benzoyl Benzyloxycarbonyl Ethyl Methyl Mesyl / methanesulfonyl Acetoxy Methoxy Phenyl Propyl Isopropyl Pivaloyl Alkyl Trimethylsilyl 4-Methylphenyl Tosyl / p-toluenesulfonyl
XI
Ph.D. Thesis
Transition-Metal-Free Domino Annulation for the Construction of Aromatics and Heteroaromatics Tej Narayan Poudel
Department of Chemical Engineering and Technology Graduate School Yeungnam University (Supervised by Professor Yong Rok Lee)
Abstract
Aromatics and heteroaromatics are widely found in nature and biologically active compounds. They have shown to possess a variety of biological activities such as antiproliferative,
cytotoxic
agents,
antimicrobial,
antimalarial,
antitumor,
anticancer,
antibacterial, and fungicidal properties. They are also widely used as important scaffolds and building blocks for the construction of optical and functional materials. Due to their importance and usefulness of aromatics and heteroaromatics, several synthetic methods for aromatics and heteroaromatics have been reported using transition-metal catalysts. However, the transition-metal residues in the final product create challenges in pharmaceutical and electronic industries. In addition, the loading of catalyst tends to have a high economic cost
XII
in industrial processes. Therefore, this thesis aims to develop novel and efficient synthetic methodologies for the construction of biologically interesting diverse aromatics and heteroaromatics such as benzo[c]chromen-6-one, biaryl, 2-pyridone and carbazole derivatives using domino annulation reactions under transition-metal-free condition. First of all, a novel and efficient one-pot synthesis of a variety of benzo[c]chromen-6-one derivatives was accomplished using Cs2CO3-promoted reactions between substituted 2-hydroxychalcones
and
β-ketoesters.
These
reactions
involved
domino
Michael
addition/intramolecular aldol/oxidative aromatization/lactonization and provided a rapid synthetic route for the construction of biologically interesting novel benzo[c]chromen-6-one molecules. As an application of this methodology, synthesized benzo[c]chromen-6-ones were also transformed into highly functionalized novel terphenyls. Next, an efficient synthesis of highly functionalized and diverse biaryls via mild base-promoted transition-metal-free benzannulation was achieved in good yield from readily available β-ketoesters, β-ketoamides or 1,3-diketones with cinnamaldehydes or arylaldehydes. This transformation comprises a sequence of the formation of three new bonds through multi-component reactions as a one-pot procedure. This novel biaryl formation proceeds through domino Michael addition/intramolecular and intermolecular aldol/[1,5]-hydrogen shift/ tautomerization. This protocol provides a great advantage in introducing various functional groups on the aromatic ring of biaryls. Furthermore, a highly eco-friendly synthesis of diverse and functionalized 2-pyridone derivatives
in
good
yield
via
the
thermal
multicomponent
reaction
of
4-oxo-4H-chromene-3-carbaldehydes with 1,3-diketoesters and anilines or primary aliphatic
XIII
amines under catalyst- and solvent-free conditions is described. This reaction proceeds via domino Knoevenagel condensation/ Michael addition/ ring opening/ ring closure reactions. Finally, a novel synthesis of highly functionalized carbazoles via transition-metal-free and mild
base-promoted
condensations
of
readily
available
2-nitrocinnamaldehyde
or
2-nitrochalcones with various β-ketoesters or 1,3-diaryl-2-propanones is described. This method selectively forms four bonds by the intramolecular conjugate addition of an enolate to the enal or chalcone bearing a o-nitro group. This reaction then undergoes in situ N-O bond cleavage under non-reductive conditions in a one-pot procedure. This protocol allows for the introduction of various functional groups at all positions of the newly formed aromatic ring of the carbazole moiety. The utility of this methodology is further illustrated by the concise synthesis of naturally occurring hyellazole and chlorohyellazole. These newly developed synthetic strategies for the construction of aromatics and heteroaromatics are expected to be widely used for the synthesis of pharmacologically active molecules and heterocyclic compounds bearing these nucleus.
XIV
Part I Introduction
1
1.1 Aromatics and Heteroaromatics Aromatics and heteroaromatics are highly important class of organic compounds with numerous applications in industry as well as in academic laboratories (Figure 1 and Figure 2).1 They are important structural motifs in natural products, pharmaceuticals, agrochemicals, polymers and sensors.2 They are also widely used as important scaffolds and building blocks for the construction of optical and functional materials.3 In addition, modern medicinal and pharmaceutical chemists have found that aromatic and heteroaromatic cores are indeed “privileged structures” for the discovery of molecules with novel medicinal characteristics.
2
1.2 Transition-Metal Catalyzed vs Transition-Metal-free Synthesis The development of new synthetic methods for the construction of substituted aromatic, polyaromatic, and heteroaromatic compounds continues to command extensive interest due to their wide range of applications. Although a number of valuable approaches to construct aromatics and heteroaromatics have been reported, owing to the importance of these substances, there is still demand for novel synthetic methods for their preparation. The ongoing research of efficient synthetic methodology combined with the increasing emphasis on sustainability inspires chemists to develop novel methods to construct aromatics and heteroaromatics more efficiently under milder reaction conditions and in an environmentally benign manner. Most of the reported methods to synthesize 3
aromatics, heteroaromatics and their derivatives require the use of transition metals (TM). Transition-metal-catalyzed reactions are among the most powerful tools in organic and medicinal synthesis as they are effective promoters and catalysts for cross-coupling reactions (Figure 3a, 3c and 3e).4-7 Extensive research effort has been invested in the development of palladium-, ruthenium-, rhodium-, iridium-, copper-, gold-, silver-, and even nickelcatalyzed reactions. However, the difficulty associated with metal residues has led to concerns in the pharmaceutical and electronic industries. Hence, to get rid of the transition-metal impurities from the pharmaceutically important products, the residue metals should be removed carefully from the final products. Also, in the field of materials science, TM impurities might influence the physical properties of synthesized organic molecule. Furthermore, transition-metal catalyzed reactions have low selectivity, low tolerance of functional groups, high toxicity, needs co-catalysts and ligands, and expensive.8 To overcome the above limitations, development of transition-metal-free reactions is highly desirable. Recently, increasing attention has been given to transition-metal-free organic synthesis (Figure 3). For example, Li and co-workers reported transition-metal-free coupling between alkyne and alkyl iodide with light in water, unlike classical Sonogashira coupling which uses transition-metal catalyst (Figure 3a and 3b).9 In addition, Itami and Kuang’s groups reported transition-metal-free direct arylation of pyridines with aryl iodide or aryl hydrazine chloride to form various coupling products, while Suzuki and Minisci coupling requires transition-metal catalyst for similar coupling reactions (Figure 3c and 3d).10 Moreover, benzannulation reactions developed by Menon and Wu’s groups do not require transition-metal catalyst, while 4
Yamamoto and Chan’s benzannulation make use of transition-metal catalyst (Figure 3e and 3f).11 Therefore, this thesis aims to develop transition-metal-free methods for the preparation of a variety of aromatics and heteroaromatics.
5
1.3 Domino Annulation Reactions The general approach for the synthesis of organic molecules is the stepwise construction of the individual bonds in the target molecule. However, formation of several bonds in one pot operation without isolating the intermediates, changing the reaction conditions, or adding reagents would be much more efficient. This type of reaction would allow the minimization of cost, time, energy, solvents, reagents and waste generation compared to multistep reactions. Thus, these reactions would allow an ecologically and economically favorable production of complex organic molecules in one-pot procedure. This type of transformation is called as domino or cascade reaction.12 Thus domino reactions are considered as an efficient tool for constructing organic compounds with structural diversity, biologically active natural products and drugs usually in a stereo selective manner. Among them, Michael addition initiated domino reaction is highly efficient strategy for the construction of various organic molecules, heterocyclic compounds, and drugs.13 The chemical reaction discovered by Robert Robinson in 1935 by forming three C-C bonds is the key method of constructing a ring system. The method comprises by a domino Michael addition followed by intramolecular aldol condensation.14 It remains one of the key methods for the construction of six membered ring compounds. Formation of cyclohexanone and their derivatives is very important in synthetic organic chemistry for their application in many natural products and biologically interesting organic molecules such as antibiotics and steroids.15 There are many aspects of the reaction that have been investigated by varying substrates and reaction conditions.
6
The Robinson annulation reaction of 1,3-dicarbonyl compounds to α,βunsaturated compounds is widely recognized as one of the most important C-C bond forming reactions in organic synthesis. Recently, a number of Robinson annulation reactions of α,β-unsaturated compounds and various 1,3-dicarbonyl compounds (Scheme 1) has been extensively explored by various research groups to synthesize diverse organic molecules.16 This thesis also aims to develop several tandem annulation processes that are accompanied through Robinson annulation as the key step to construct biologically interesting and diverse carbazoles, biaryls and benzo[c]chromen-6-one derivatives utilizing α,β-unsaturated compounds and 1,3-dicarbonyl compounds as precursors under transition-metal-free conditions using Cs2CO3 as mild and efficient base.
Herein, novel approaches for the construction of diverse and biologically interesting aromatics and heteroaromatics are described via transition-metalfree domino annulation reactions (Scheme 2). In part II, the first section consists of a novel and efficient means for synthesizing benzo[c]chromen-6-one derivatives from readily available substituted 2-hydroxychalcones and βketoesters via domino Michael/intramolecular aldol/aromatization/lactonization reactions (Scheme 2a). Moreover, in the second section, a novel, facile and efficient one-pot biaryl formation through a three-component reaction starting 7
from commercially available β-ketoesters, β-ketoamides, or 1,3-diketones with α,β-unsaturated aldehydes or α,β-unsaturated aldehydes and aryl aldehydes in presence of mild base are described (Scheme 2b). In the third section, catalystand solvent free thermal multicomponent reactions of commercially available 4-oxo-4H-chromene-3-carbaldehydes with 1,3-diketoesters and anilines (or amines) for the synthesis of structurally diverse 2-pyridone derivatives are described (Scheme 2d). Finally, unique tandem annulation followed by N-O bond cleavage without any external reductant for the synthesis of various functionalized
3-hydroxycarbazoles
from
readily
available
2-
nitrocinnamaldehyde or 2-nitrochalcone and β-ketoesters or 1,3-diaryl-2propanone are described in the last section of part II (Scheme 2c).
8
9
1.4 References 1
(a) Bosin, T. R.; Campaigne, E. E. Adv. Drug Res. 1977, 11, 191; (b) Ukita, T.; Nakamura, Y.; Kubo, A.; Yamamoto, Y.; Takahashi, M.; Kotera, J.; Ikeo, T. J. Med. Chem. 1999, 42, 1293. (c) Watson, M. D.; Fechtenkotter, A.; Mullen, K. Chem. Rev. 2001, 101, 1267. (d) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45, 2670. (e) Kochanowska-Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.
2
(a) Shanmugasundaram, M.; Wu, M. S.; Jeganmohan, M.; Huang, C. W.; Cheng, C. H. J. Org. Chem. 2002, 67, 7724. (b) van Otterlo, W. A. L.; de Koning, C. B. Chem. Rev. 2009, 109, 3743. (c) Kinoshita, H.; Tohjima, T.; Miura, K. Org. Lett. 2014, 16, 4762. (d) Fuhr, L.; Rousseau, M.; Plauth, A.; Schroeder, F. C.; Sauer, S. J. Nat. Prod. 2015, 78, 1160. (e) Boland, S.; Bourin, A.; Alen, J.; Geraets, J.; Schroeders, P.; Castermans, K.; Kindt, N.; Boumans, N.; Panitti, L.; Fransen, S.; Vanormelingen, J.; Stassen, J. M.; Leysen, D.; Defert, O. J. Med. Chem. 2015, 58, 4309.
3
(a) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (b) Xie, P.; Huang, Y.; Chen, R. Chem.- Eur. J. 2012, 18, 7362.
4
(a) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642. (b) Gelman, D.; Buchwald, S. L. Angew. Chem. Int. Ed. 2003, 42, 5993. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
5
(a) Suzuki, A.; Brown, H. C. Organic Synthesis via Boranes, Vol. 3; Aldrich: Milwaukee, WI, 2003. (b) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489. (c) Minisci, F.; Fontana, F.; Vismara, E. J. 10
Heterocycl. Chem. 1990, 27, 79. (d) Harrowven, D. C.; Sutton, B. J. Prog. Heterocycl. Chem. 2004, 16, 27. 6
(a) Saito, S.; Salter, M. M.; Gevorgyan, V.; Tsuboya, N.; Tando, K.; Yamamoto, Y. J. Am. Chem. Soc. 1996, 118, 3970. (b) Gevorgyan, V.; Takeda, A.; Yamamoto, Y. J. Am. Chem. Soc. 1997, 119, 11313. (c) Saito, S.; Tsuboya, N.; Yamamoto, Y. J. Org. Chem. 1997, 62, 5042. (d) Gevorgyan, V.; Sadayori, N.; Yamamoto, Y. Tetrahedron Lett. 1997, 38, 8603. (e) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.; Radhakrishnan, U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391.
7
Teo, W. T.; Rao, W.; Ng, C. J. H.; Koh, S. W. Y.; Chan, P. W. H. Org. Lett. 2014, 16, 1248.
8
(a) Xu, Q.-L.; Gao, H.; Yousufuddin, M.; Ess, D. H.; Kurti, L. J. Am. Chem. Soc. 2013, 135, 14048; (b) Matcha, K.; Antonchick, A. P. Angew. Chem. Int. Ed. 2013, 52, 2082. (c) Antonchick, A. P.; Burgmann, L. Angew. Chem. Int. Ed. 2013, 52, 3638. (d) Majji, G.; Guin, S.; Gogoi, A.; Rout, S. K.; Patel, B. K. Chem. Commun. 2013, 49, 3031.
9
Liu, W.; Li, L.; Li, C.-J. Nat. Commun. 2015, 6, 6526.
10 Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673. 11 Li, Y.; Liu, W.; Kuang, C. Chem. Commun. 2014, 50, 7124. 12 (a) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 105,137. (b) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. 11
13 (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (c) Hayato, I.; Takaki, S.; Yujiro, H. Angew. Chem. Int. Ed. 2009, 48, 1304. 14 (a) Rapson, W. S.; Robinson, R. J. Chem. Soc. 1935, 1285. (b) Li, P.; Yamamoto, H. Chem. Commun. 2009, 5412. (c) Peng, F.; Dai, M.; Angeles, A. R.; Danishefsky, S. J. Chem. Sci. 2012, 3, 3076. (d) Yi, W.B.; Huang, X.; Caia, C.; Zhang, W. Green Chem. 2012, 14, 3185. 15 (a) Acheson, R.; Robinson, R. J. Chem. Soc. 1952, 1127. (b) Heathcock, C. H.; Ellis, J. E.; McMurry, J. E.; Coppolino, A. Tetrahedron Lett. 1971, 12, 4995. 16 (a) Sarkar, S. D.; Studer, A. Angew. Chem. Int. Ed. 2010, 49, 9266. (b) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080. (c) Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (d) Marigo, M.; Bertelsen, S.; Landa, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475.
12
Part II
Results and Discussion
13
2.1 Construction of Diverse Benzo[c]chromene-6-ones 2.1.1 Introduction Domino reactions have emerged as one of the most effective and powerful tool for the synthesis of a range of complex target molecules in organic and natural product synthesis.1 In particular, they are very useful to generate a variety of new compounds which have biological and pharmacological activities and properties.2
Molecules bearing benzo[c]chromen-6-one and its derivatives are extensively 14
distributed in nature (Figure 1).3 Some of these molecules exhibit biologically and pharmacologically important antitumor and antibiotic activities,4 promote endothelial cell proliferation, and inhibit oestrogene receptor growth activities.5 Benzo[c]chromen-6-ones have also been used as intermediates for the synthesis of pharmaceutically valuable compounds, such as, progesterone, androgen, and glucocorticoid
receptor
agonists.6
Furthermore, some of the known
benzo[c]chromen-6-one derivatives have promising optical properties as bluegreen fluorescing dyes, which is a rarer than fluorescence at other wavelengths.7 In addition, benzo[c]chromen-6-one derivatives are present in many foods, such as, citrus fruits, herbs, and vegetables,8 for example, autumnariol (1) was isolated from the bulbs of Eucomis autumnalis Gerab. (Liliaceae).9a Alternariol (2), another benzo[c]chromen-6-one derivative, is an important metabolite of toxin-producing Alternaria fungi, which causes significant crop losses by fouling of tomatoes, apples, and other fruits.9b However, interestingly, alternariol (2) has also been shown to have antiviral, antimicrobial, anticancer, and cytotoxic activities.9c,d,e Palmariols A (3) and B (4)
were
isolated
from
discomycete
Lachnumpalmae
and
exhibited
antimicrobial, antinematodal, and acetylcholinesterase inhibitory activities.9f,g Graphislactones A (5) and B (6) were isolated from the lichen Graphisscripta var. pulverrulenta.10 Graphislactone A (5) acts as an antioxidant and free radical scavenger,11 and was found to be active against the SW1116 cell line and an active inhibitors of AChE.10e Verrulactones A (7) and B (8) were isolated from a culture broth of the fungal strain Penicillium verruculosum F375,10 and inhibited Staphyococcus aureusenoyl-ACP reductase with an IC50 of 0.92 μM and exhibited antibacterial activity against S. aureus and MRSA with MICs of 8 μg/mL.12 Gilvocarcins M (9) and V(10), ravidomycin (11), and 15
chrysomycins A (12) and B (13), which have a sugar nucleus at the C-4 position, and defucogivocarcines M (14) and V (15), which do not bear the sugar moiety, were isolated from various other Streptomyces species found to be strong natural anticancer agents, and to exhibit important and potent antibacterial, antibiotic, and antitumor activities.13 Given the importance of these biological and pharmacological activities, several synthetic methods have been devised to produce benzo[c]chromen-6one derivatives. Of these methods, the most useful method involves a SuzukiMiyaura cross-coupling reaction followed by metal or Lewis acid mediated lactonization of ester and methoxy groups (eq 1, Scheme 1).14 Recently, a new reaction involving a microwave-assisted Diels-Alder reaction between 4cyanocoumarin and 1-oxygenated dienes followed by elimination and aromatization with a strong base was also described (eq 2).15 However, this synthetic approach included two-step reactions and required purification of the intermediate. In addition, the starting materials used for this transformation were synthesized from corresponding materials in two or more steps. Very recently,
novel
one-pot
reactions
were
devised
for
the
synthesis
benzo[c]chromen-6-one derivatives by palladium bis(acetoacetonate)/CuClcatalyzed decarboxylative cross-coupling and lactonization,16 or by palladium acetate-catalyzed
Suzuki-Miyaura
coupling
followed
by
oxidative
lactonization (eq 3 and 4).17 However, to complete these reactions, relatively expensive catalysts, reagents, and ligands are needed. Thus, a mild, general, and efficient one-pot synthetic route for benzo[c]chromen-6-one derivatives using inexpensive catalysts and reagents has yet to be devised. To the best of our knowledge, no previously report has been issued on the synthesis of tricyclic benzo[c]chromen-6-one derivatives via domino Michael 16
addition/intramolecular aldol/oxidative aromatization/lactonization reactions between substituted 2-hydroxychalcones and β-ketoesters.
We report herein a novel and efficient means for synthesizing benzo[c]chromen-6-one derivatives from readily available substituted 2hydroxychalcones
and
β-ketoesters
via
domino
Michael/intramolecularaldol/aromatization/lactonization reactions (Scheme 2).
17
2.1.2 Results and Discussion To afford benzo[c]chromen-6-one 16, the reaction between 2-hydroxychalcone (1a) and ethyl acetoacetate (2a) was first examined under several conditions (Table 1). Treatment of 1a with 2a in the presence of 2 equivalents of DBU in refluxing toluene for 7 h afforded product 16 in 50% yield, but using sodium methoxide in refluxing methanol for 12 h, 16 was produced in 40% yield. Using K2CO3 and Cs2CO3, the desired product 16 was produced with higher yields. For example, reaction with 2 equivalents of K2CO3 in refluxing toluene for 6 h provided product 16 in 66% yield, whereas reaction with 2 equivalents of Cs2CO3 afforded 16 in 71% yield. In recent years, Cs2CO3 has been widely used as an excellent base for a variety of transformations in organic synthesis.18 Importantly, we found that Cs2CO3 as a mild base and more efficient than other bases for the production of 16 in terms of yield and reaction time. However, one equivalent or a catalytic amount of Cs2CO3 (0.1 eq.), the desired products were produced with lower yields. Reactions in water or methanol under reflux condition did not provide the desired products. The structure of 16 was determined by analysing spectral data. The 1H-NMR spectrum of 16 showed a single OH peak at δ 11.30 ppm in downfield due to hydrogen bonding with the ester carbonyl group, and two single peaks at δ 7.69 and 7.20 ppm associated with two aromatic peaks on the benzo[c]chromen-6-one ring. The structure was further confirmed by 13C-NMR spectrum, which showed the expected carbonyl peak at δ 162.6 ppm due to the ester. In addition, the IR spectrum of 16 18
contained ester carbonyl absorption at 1684 cm-1.
To prepare a variety of benzo[c]chromen-6-one derivatives, additional reactions several
between substituted 3-(2-hydroxyphenyl)prop-2-en-1-ones
and
β-ketoesters were carried out under optimized reaction conditions.
Results are summarized in Table 2. Reactions between 1a and ethyl-3oxopentanoate (2b), methyl-3-oxo-4-phenyl butanoate (2c) or diethyl-3oxopentanedioate (2d) in the presence of 2 equivalents of Cs2CO3 in refluxing toluene for 2 h provided the desired products 17-19 in 51, 58, and 60% yield, respectively. The reaction of chalcone 1b with a methyl group on the 2-propen1-one skeleton was also successful. Treatment of 1b with 2b in the presence of Cs2CO3 in refluxing toluene for 2 h afforded product 20 in 50% yield. To investigate the influence of substituents on reactivities, the effects of a number of 2-hydroxychalcones (1c-1h) bearing electron-donating or -withdrawing groups on the benzene ring were next examined. Reactions between 1c 19
bearinga methyl group on the phenol moiety and 2a or 2b afforded products 2122 in 70 and 52% yield, respectively, whereas those of 1d with an electronwithdrawing group on the phenol ring provided 23-24 in 55 and 63% yield, respectively. The reactions of chalcones 1e and 1f bearing electron-donating groups on the two benzene rings were also examined. Treatment of 1e with 2a, 2b, or 2d provided compounds 25-27 in 70, 54, and 62% yield, respectively, whereas treatment of 1f with 2a-2c gave products 28-30 in 72, 54, and 60% yield, respectively. Reactions of chalcone 1g and 1h bearing substituents on the 1-phenyl ring with 2a or 2b gave products 31-32 in 69 and 55% yield, respectively.
Importantly,
yl)prop-2-en-1-one
(1i),
when
(E)-3-(2-hydroxyphenyl)-1-(pyridine-3-
(E)-3-(2-hydroxyphenyl)-1-(2,5-dimethylfuran-3-
yl)prop-2-en-1-one (1j), or (E)-3-(2-hydroxyphenyl)-1-(2,5-dimethylthiophen3-yl)prop-2-en-1-one (1k) were used, the desired products 33-40 were produced in 50-73% yield. Reactions between (E)-3-(2-hydroxyphenyl)-1(naphthalene-2-yl)prop-2-en-1-one (1l) and β-ketoesters were also successful. When 1l was treated with 2a, 2b, or 2c, products 41-43 were produced in 63, 51 and
50%
yields,
respectively.
When
(E)-1-cyclopropyl-3-(2-
hydroxyphenyl)prop-2-en-1-one (1m) was used, compounds 44 and 45 were obtained in 72 and 61% yield, respectively. These reactions provided a rapid route of synthesizing a variety of benzo[c]chromen-6-one derivatives bearing different substituents on the benzene ring. The structures of the synthesized compounds 16-45 were unambiguously confirmed by X-ray diffraction analysis of compound 26 (Figure 2). Interestingly, the unit of the compound 26 contains two same molecules.
20
21
Figure 2. X-ray structure of compound 26 containing two molecules in a unit
A proposed mechanism for the Cs2CO3-mediated domino reactions used to produce 16 is depicted in Scheme 3. In basic medium, the enolate of 2a first attacks to the unsaturated β-carbon to the carbonyl group of 1a to give intermediate 46, which undergoes intramolecular aldol reaction followed by oxidative aromatization to form intermediate 48. Finally, the lactonization of 48 under basic conditions results in 16.
22
As a synthetic application of this methodology, several synthesized benzo[c]chromen-6-ones were converted into biologically and physically interesting polysubstituted terphenyls. Molecules bearing the terphenyl moiety are found in a variety of natural products19 and exhibit a number of potent biological properties, which include antioxidant, neuroprotective, cytotoxic, antithrombotic, and anticoagulant activities.20 In addition, these molecules play a significant role in the fields of optical materials, liquid crystals, spacers in catenane, and porphyrin chemistry.21 Because of their important biological and physical properties, a number of synthetic methods have been devised to produce terphenyls.22 These reactions typically included aryl zinc reagents with functionalized
biphenyl
nonaflates,23
Grignard
reagents
containing
dihalobenzenes, and triazene-substitued arylboronic esters.24 Recently, other methodologies using Suzuki cross-coupling reactions between dihalobenzenes and arylboronic acids,25 the gold-catalyzed cycloaromatization of dienynes,26 DMEDA-catalyzed direct C-H arylation of unactivated benzenes,27 and rhodium-catalyzed formal [2+2+2] cycloaddition reactions of tethered diynes 23
containing 1-alkynylphosphine sulfides have been described.28 Although a number of methods have been reported for the synthesis of terphenyls, synthetic methods are still required for the production of polysubstituted terphenyls.
The conversions of several synthesized benzo[c]chromen-6-ones into substituted terphenyls were also attempted, as shown in Table 3. Treatment of 20 with methyl iodide in the presence of KOH in wet DMSO at room 24
temperature for 2 h provided 49 in 70% yield. Similarly, reactions of 23, 30, 39, 42, and 45 with methyl iodide also provided the desired polysubstituted terphenyls 50-54 into 78-87% yield. Importantly, these reactions rapidly provided various terphenyls bearing substituents, such as, -Br, -Me, -COOMe, –OMe, aryl, cyclopropyl, and furyl on their benzene rings.
25
2.1.3 Conclusions We described the Cs2CO3-promoted one-pot synthesis of biologically interesting benzo[c]chromen-6-one derivatives starting from substituted 2hydroxychalcones and β-ketoesters. These reactions were accomplished by domino
Michael
addition/intramolecular
aldol/oxidative
aromatization/lactonization reactions. The protocol developed has the advantages of mild reaction conditions and transition-metal-free domino onepot procedure. In particular, the synthesized molecules were readily converted under mild basic conditions into biologically interesting novel terphenyls bearing different substituents on their benzene rings.
26
2.1.4 Experimental All experiments were carried out under open air without using any inert gases protection. Ketoesters (2a-d) were purchased from Sigma- Aldrich. Merck precoated silica gel plates (Art. 5554) with a fluorescent indicator were used for analytical TLC. Flash column chromatography was performed using silica gel 9385 (Merck). Melting points were determined with micro-cover glasses on a Fisher-Johns apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-VNS (300 MHz) spectrometer in CDCl3 using 7.24 ppm as the solvent chemical shift.
13
C NMR spectra were recorded on a Varian-VNS (75 MHz)
spectrometer in CDCl3 using 77.0 ppm as the solvent chemical shift. IR spectra were recorded on a JASCO FTIR 5300 spectrophotometer. High resolution mass (HRMS) were obtained with a JEOL JMS-700 spectrometer at the Korea Basic Science Institute.
General procedure for the synthesis of 2-hydroxy chalcones (1a-m) To a solution of ketones (20.0 mmol) in ethanol (25 mL) was added KOH (5.6g, 100.0 mmol) and salicylaldehydes (20.0 mmol) at room temperature. The reaction mixture was stirred at room temperature for 48 h. Evaporation of ethanol, addition of water (20 ml) and 1N HCl (20 mL), extraction with EtOAc (3 x 30 mL), washing with brine (30 mL), and removal of the solvent followed by flash column chromatography on silica gel using hexane/EtOAc (10:1) gave 2-hydroxy chalcones (1a-1m) in the range of 53-84% yield.
27
General procedure for the synthesis of benzo[c[chromene-6-ones ( 16-45) To a solution of 2-hydroxychalcone compounds 1a-1m (1 mmol) and ketoesters 2a-2d (1.5 mmol) in toluene (4mL) was added Cs2CO3 (2 mmol). The reaction mixture was refluxed in open air for 2 hour. Then solvent was evaporated in rotary evaporator under reduced pressure to give the residue. The residue was purified by flash column chromatography on silica gel to give the product. Characterization data for all compounds 16-45 are as follows.
7-Hydroxy-9-phenyl-6H-benzo[c]chromen-6-one (16). Reaction of 1a (224 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 16 (204 mg, 71 %) as a solid: mp 213-215 C; 1H NMR (300 MHz, CDCl3) 11.30 (1H, s), 8.02 (1H, d, J = 7.8 Hz), 7.68
o
(1H, s), 7.60 (2H, d, J = 6.9 Hz), 7.44-7.36 (4H, m), 7.31-7.27 (2H, m), 7.20 (1H, s); 13C NMR (75 MHz, CDCl3) 162.6, 162.3, 150.7, 150.2, 139.4, 135.4, 130.7, 129.1, 129.0, 127.4, 125.1, 123.3, 118.3, 117.8, 114.9, 111.1, 104.8; IR (KBr) 3422, 3036, 2367, 1684, 1620, 1276, 1083, 757 cm-1; HRMS m/z (M+) calcd for C19H12O3: 288.0786. Found: 288.0788. 7-Hydroxy-8-methyl-9-phenyl-6H-benzo[c]chromen-6-one (17). Reaction of 1a (224 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 17 (154 mg, 51 %) as a solid: mp 166-168 oC; 1H NMR (300 MHz, CDCl3) 11.76 (1H, s), 7.99 (1H, d, J = 8.1 Hz), 7.51-7.28 (9H, m), 2.25 (3H, s); 13C NMR (75 MHz, CDCl3) 165.6, 160.7, 151.0, 150.4, 140.6, 131.6, 130.3, 128.7, 128.3, 127.8, 124.9, 123.9, 122.9, 118.4, 117.5,
28
113.3, 104.1, 13.0; IR (KBr) 3449, 3062, 2370, 1677, 1268, 1125, 754 cm-1; HRMS m/z (M+) calcd for C20H14O3: 302.0943. Found: 302.0943.
7-Hydroxy-8,9-diphenyl-6H-benzo[c]chromen-6-one (18). Reaction of 1a (224 mg, 1 mmol) and β-ketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 18 (211 mg, 58 %) as a solid: mp 213-215 C; 1H NMR (300 MHz, CDCl3) 11.77 (1H, s), 8.00 (1H, d, J = 7.5 Hz), 7.60
o
(1H, s), 7.47-7.31 (3H, m), 7.21-7.19 (6H, m), 7.16-7.13 (4H, m); 13C NMR (75 MHz, CDCl3) 165.6, 160.0, 150.5, 150.3, 140.2, 134.8, 133.6, 131.0, 130.5, 129.4, 128.4, 127.9, 127.7, 127.5, 127.1, 125.1, 123.1, 118.1, 117.6, 114.0, 1o4.8; IR (KBr) 3448, 3063, 1674, 1612, 1396, 1265, 1127, 752, 697 cm-1; HRMS m/z (M+) calcd. for C25H16O3: 364.1099. Found: 364.1098.
Ethyl-7-hydroxy-6-oxo-9-phenyl-6H-benzo[c]chromene-8-carboxylate (19). Reaction of 1a (224 mg, 1 mmol) and β-ketoester 2d (303 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 19 (216 mg, 60 %) as a solid: mp193195oC; 1H NMR (300 MHz, CDCl3) 11.67 (1H, s), 7.84 (1H, d, J = 7.5 Hz), 7.36-7.35 (7H, m), 7.24-7.17 (2H, m), 4.07 (2H, q, J = 7.2 Hz), 0.938 (3H, t, J = 7.2 Hz);
13
C NMR (75 MHz, CDCl3) 165.9, 164.7, 159.5, 150.5, 148.9,
139.0, 135.5, 131.2, 128.6, 128.4, 127.8, 125.2, 123.2, 121.4, 117.5, 117.2, 113.1, 104.3, 61.3, 13.5; IR (KBr) 3455, 3106, 1737, 1552, 1127, 1015, 858, 742 cm-1; HRMS m/z (M+) alcd for C25H16O5: 360.0998. Found: 360.0994. 7-Hydroxy-8,10-dimethyl-9-phenyl-6H-benzo[c]chromen-6-one
(20).
Reaction of 1b (238 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using 29
Cs2CO3 (650 mg, 2 mmol) afforded 20 (158 mg, 50 %) as a solid: mp 207209oC; 1H NMR (300 MHz, CDCl3) 12.07 (1H, s), 8.18 (1H, d, J = 8.1 Hz), 7.50-7.37 (5H, m), 7.29 (1H, t, J = 7.2 Hz), 7.14 (2H, d, J = 7.2 Hz), 2.36 (3H, s), 1.98 (3H, s), 1.73-1.60 (4H, m), 1.00-0.91 (6H, m);
13
C NMR (75 MHz,
CDCl3) 166.4, 158.9, 153.1, 150.4, 140.6, 129.2, 128.8, 128.3, 127.8, 127.8, 127.4, 125.1, 124.1, 123.3, 120.2, 117.5, 105.3, 22.0, 13.9; IR (KBr) 3437, 3067, 1685, 1616, 1272, 1124, 758 cm-1; HRMS m/z (M+) calcd for C21H16O3: 316.1099. Found: 316.1099.
7-Hydroxy-2-methyl-9-phenyl-6H-benzo[c]chromen-6-one (21). Reaction of 1c (238 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 21 (211 mg, 70 %) as a solid: mp 198-200 oC; 1H NMR (300 MHz, CDCl3) 11.27 (1H, s), 7.66 (1H, s), 7.57-7.54 (3H, m), 7.42-7.34 (3H, m), 7.15-7.06 (3H, m), 2.33 (3H, s);
13
C NMR (75 MHz,
CDCl3) 165.3, 162.5, 149.9, 148.7, 139.4, 135.3, 134.7, 131.5, 128.9, 128.9, 127.3, 123.0, 117.7, 117.3, 114.6, 110.7, 104.7, 21.0; IR (KBr) 3434, 3033, 1680, 1560, 1227, 1211, 1096, 758, 696 cm-1; HRMS m/z (M+) calcd for C20H14O3: 302.0943. Found: 302.0945. 7-Hydroxy-2,8-dimethyl-9-phenyl-6H-benzo[c]chromen-6-one
(22).
Reaction of 1c (238 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 22 (164 mg, 52 %) as a solid: mp 193-195 C; 1H NMR (300 MHz, CDCl3) 11.66 (1H, s), 7.61 (1H, s), 7.41-7.33 (3H,
o
m), 7.31-7.26 (3H, m), 7.10-7.06 (2H, m), 2.29 (3H, s), 2.11 (3H, s); 13C NMR (75 MHz, CDCl3) 165.7, 160.7, 150.8, 148.4, 140.6, 134.6, 131.6, 130.9, 30
128.7, 128.3, 127.8, 123.6, 122.8, 117.9, 117.1, 113.1, 104.1, 21.0, 13.0; IR (KBr) 3456, 2932, 1688 , 1602, 1513, 1375, 1190, 1014, 821, 745 cm-1; HRMS m/z (M+) calcd for C21H16O3: 316.1099. Found: 316.1097.
2-Bromo-7-hydroxy-8-methyl-9-phenyl-6H-benzo[c]chromen-6-one
(23).
Reaction of 1d (301 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 23 (209 mg, 55 %) as a solid: mp 216-218 C; 1H NMR (300 MHz, CDCl3) 11.59(1H, s), 8.02 (1H, s), 7.50-7.39 (4H,
o
m), 7.36-7.32 (3H, m), 7.17 (1H, d, J = 8.7 Hz), 2.20 (1H, s);
13
C NMR (75
MHz, CDCl3) 165.1, 160.8, 151.2, 149.2, 140.3, 132.8, 130.2, 128.7, 128.4, 128.0, 125.7, 125.0, 120.2, 119.2, 118.0, 113.5, 103.9, 13.1; IR (KBr) 3449, 3064, 1703, 1625, 1557, 1409, 1264, 1217, 1082, 853, 691 cm-1; HRMS m/z (M+) calcd for C20H13BrO3: 380.0048. Found: 380.0050.
2-Bromo-7-hydroxy-8,9-diphenyl-6H-benzo[c]chromen-6-one
(24).
Reaction of 1d (301 mg, 1 mmol) and β-ketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 24 (243mg, 63 %) as a solid: mp 215-217 C; 1H NMR (300 MHz, CDCl3 ) 11.67 (1H, s), 8.12 (1H, s), 7.55-7.53 (2H,
o
m), 7.22-7.19 (7H, m), 7.14-7.09 (4H, m); 13C NMR (75 MHz, CDCl3) 165.1, 160.2, 150.7, 149.5, 140.0, 134.6, 133.3, 132.3, 130.9, 129.4, 128.0, 127.8, 127.6, 127.2, 126.0, 120.0, 119.4, 118.2, 114.2, 104.7; IR (KBr) 3454, 3064, 1681, 1612, 1545, 1393, 1260, 1203, 1115, 880, 743, 701cm-1; HRMS m/z (M+) calcd for C25H15BrO3: 442.0205. Found: 442.0202.
31
7-Hydroxy-2-methyl-9-p-tolyl-6H-benzo[c]chromen-6-one (25).Reaction of 1e (252 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 25 (221 mg, 70 %) as a solid: mp 258-160 oC; 1H NMR (300 MHz, CDCl3) 11.40 (1H, s), 7.85 (1H, s), 7.72 (1H, s), 7.58 (2H, d, J = 7.5 Hz), 7.31-7.24 (5H, m), 2.45 (3H, s), 2.42 (3H, s);
13
C NMR (75
MHz, CDCl3) 165.7, 160.7, 151.0, 150.4, 137.7, 137.7, 131.6, 129.9, 129.0, 128.7, 124.9, 123.9, 122.9, 118.5, 117.5, 113.4, 104.0, 21.2, 13.1; IR (KBr) 3434, 2928, 1690, 1618, 1588, 1437, 1240, 1181, 1076, 926, 784, cm-1; HRMS m/z (M+) calcd for C21H16O3: 316.1099. Found: 316.1102.
7-Hydroxy-2,8-dimethyl-9-p-tolyl-6H-benzo[c]chromen-6-one
(26).
Reaction of 1e (252 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 26 (178 mg, 54 %) as a solid: mp 190-192 C; 1H NMR (300 MHz, CDCl3) 11.64 (1H, s), 7.59 (1H, s), 7.2 (1H, s), 7.21-
o
7.15 (4H, m), 7.11-7.04 (2H, m), 2.35 ( 3H, s), 2.28 ( 3H, s), 2.11 ( 3H, s) ; 13C NMR (75 MHz, CDCl3) 165.7, 160.6, 150.8, 148.4, 137.7, 137.6, 134.5, 131.5, 130.8, 128.9, 128.6, 123.6, 122.8, 117.9, 117.1, 113.2, 103.9, 21.2, 21.0, 13.0; IR (KBr) 3442, 3056, 1672, 1610, 1398, 1270, 1136, 1019, 862, 761cm-1; HRMS m/z (M+) calcd for C22H18O3: 330.1256. Found: 330.1256. Crystal refinement data for compound 26. C44H36O6, M = 660.73, Triclinic, Space group Pbca, a = 10.8607(14) Ao, b = 10.8607 (14) Ao, c = 15.2714 (19) Ao, V = 1644.3(4) Ao3, Z = 2, T = 200(2) K, ρcalcd = 1.335 mg/m3, 2Өmax. = 26.08, Refinement of 459 parameters on 6463 independent reflections out of 10459 collected reflections (Rint = 0.0454) led to R1 = 0.0642 [I >2σ(I)], wR2 = 0.2354 32
(all data) and S = 1.030 with the largest difference peak and hole of 0.307 and 0.429 e.Ao-3 respectively. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (CCDC 958927). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif.
Ethyl7-hydroxy-2-methyl-6-oxo-9-p-tolyl-6H-benzo[c]chromene-8carboxylate(27). Reaction of 1e (252 mg, 1 mmol) and β-ketoester 2d (303 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 27 (240 mg, 62 %) as a solid: mp 223-225 oC; 1H NMR (300 MHz, CDCl3) 11.78 (1H, s), 7.73 ( 1H, s), 7.46 ( 1H, s), 7.32-7.17 ( 6H, m), 4.12 ( 2H, q, J = 7.2 Hz), 2.37 (3H, s), 2.34(3H, s), 1.01 (3H, t, J = 7.2 Hz);
13
C NMR (75 MHz, CDCl3) 166.3,
165.2, 159.8, 149.1, 149.0, 138.7, 136.4, 135.8, 135.0, 132.2, 129.2, 128.0, 123.4, 121.6, 117.5, 117.3, 113.3, 104.8, 61.5, 21.2, 21.0, 13.7; IR (KBr) 3438, 2989, 2733, 1732, 1671, 1552, 1405, 1248, 1205, 1133, 1021, 824 cm-1; HRMS m/z (M+) calcd for C24H20O5: 388.1311. Found: 388.1313.
7-Hydroxy-3-methoxy-9-(3-methoxyphenyl)-6H-benzo[c]chromen-6-one (28). Reaction of 1f (284 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 28 (250 mg, 72 %) as a solid: mp 190-192 oC; 1H NMR (300 MHz, CDCl3) 11.26 (1H, s), 7.92 (1H, d, J = 8.7 Hz), 7.57 (1H, s), 7.35 (1H, t, J = 7.8 Hz), 7.20-7.18 (2H, m), 7.13-7.12 ( 2H, m), 6.94-6.80 (3H, m) 3.82 (6H, s); 13C NMR (75 MHz, CDCl3) 165.8, 162.1, 160.5, 159.4, 151.6, 150.9, 142.1, 132.1, 129.3, 123.9, 122.5, 121.1, 114.5, 113.1, 112.8, 112.5, 111.4, 103.3, 101.4, 55.6, 55.3; IR (KBr) 3449, 2930, 1679,
33
1632, 1623, 1464, 1396, 1266, 1092, 1029, 800, 725 cm-1; HRMS m/z (M+) calcd for C21H16O5: 348.0998. Found: 348.0999.
7-Hydroxy-3-methoxy-9-(3-methoxyphenyl)-8-methyl-6Hbenzo[c]chromen-6-one (29). Reaction of 1f (284 mg, 1 mmol) and βketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 29 (153 mg, 54 %) as a solid: mp 171-173 oC; 1H NMR (300 MHz, CDCl3) 11.57 (4H, s), 7.75 (1H, d, J = 8.7 Hz), 7.32-7.24 (2H, m), 6.89-6.72 (5H, m), 3.78 (3H, s), 3.77 (3H, s), 2.11(3H, s);
13
C NMR (75 MHz, CDCl3) 165.9,
161.1, 160.6, 159.4, 151.6, 150.9, 142.1, 132.1, 129.3, 123.9, 122.5, 121.1, 114.5, 113.1, 112.8, 112.5, 111.4, 103.3, 101.4, 55.6, 55.3, 12.9; IR (KBr) 3448, 2929, 1672, 1622, 1482, 1282, 1137, 1033, 798, 751 cm-1; HRMS m/z (M+) calcd for C22H18O5: 362.1154. Found: 362.1154.
7-Hydroxy-3-methoxy-9-(3-methoxyphenyl)-8-phenyl-6Hbenzo[c]chromen-6-one (30). Reaction of 1f (284 mg, 1 mmol) and βketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 30 (254 mg, 60 %) as a solid: mp 216-218 oC; 1H NMR (300 MHz, CDCl3) 11.69 (1H, s), 7.87 (1H, d, J = 9.0 Hz ), 7.47 (1H, s), 7.24-7.06 (6H, m), 6.886.80 (2H, m), 6.73-6.88 (2H, m), 6.56 (1H, s) 3.82 (1H, s), 3.52 (1H, s);
13
C
NMR (75 MHz, CDCl3) 165.8, 161.6, 160.0, 158.9, 151.9, 150.2, 141.6, 135.0, 134.2, 130.9, 129.0, 127.8, 127.1, 124.2, 121.8, 114.8, 113.5, 113.1, 111.1, 104.0, 101.4, 55.7, 55.1; IR (KBr) 3444, 2935, 1679, 1639, 1464, 1396, 1266, 1092, 1029, 805, 735 cm-1; HRMS m/z (M+) calcd for C27H20O5: 424.1311. Found: 424.1309. 34
7-Hydroxy-9-p-tolyl-6H-benzo[c]chromen-6-one (31). Reaction of 1g (238 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 31 (208 mg, 69 %) as a solid: mp 199-201 C; 1H NMR (300 MHz, CDCl3) 11.34 (1H, s), 8.07 (1H, d, J = 7.2 Hz), 7.73
o
(1H, s), 7.50-7.45 (1H, m), 7.37-7.25 (5H, m), 2.41 (3H, s); 13C NMR (75 MHz, CDCl3) 165.3, 162.5, 150.7, 150.2, 139.1, 136.5, 135.3, 130.6, 129.7, 127.2, 125.0, 123.3, 118.4, 117.7, 114.6, 110.8, 104, 12.2; IR (KBr) 3436, 3128, 1686, 1623, 1273, 1110, 944, 813, 752, 705 cm-1; HRMS m/z (M+) calcd for C20H14O3: 302.0943. Found: 302.0946.
7-Hydroxy-9-(4-methoxyphenyl)-8-methyl-6H-benzo[c]chromen-6-one (32). Reaction of 1h (254 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 32 (182 mg, 55 %) as a solid: mp 192-194 C; 1H NMR (300 MHz, CDCl3) 11.62 (1H, s), 7.87 (1H, d, J = 7.8 Hz)),
o
7.36-7.31 (2H, m), 7.24-7.17 (4H, m), 6.92 (2H, d, J = 8.4 Hz), 3.80 (3H, s), 2.14 ( 3H, s); 13C NMR (75 MHz, CDCl3) 165.6, 160.7, 159.3, 150.6, 150.3, 132.8, 131.5, 130.0, 129.9, 124.9, 123.9, 122.9, 118.4, 117.5, 113.7, 113.4, 103.8, 55.3, 13.1; IR (KBr) 3453, 3073, 1675, 1612, 1510, 1274, 1129, 1029, 834, 736 cm-1; HRMS m/z (M+) calcd for C21H16O4: 332.1049. Found: 332.1050.
7-Hydroxy-9-(pyridin-3-yl)-6H-benzo[c]chromen-6-one (33). Reaction of 1i (225 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 33 (220 mg, 70 %) as a solid: mp 243-245 oC; 1H NMR (300 MHz, CDCl3) 11.41 (1H, s), 8.93 (1H, s), 8.69 (1H, s), 8.07 (1H, d, J = 35
8.1 Hz), 7.97 (1H, d, J = 7.5 Hz), 7.72 (1H, s), 7.52-7.36 (4H, m), 7.22 (1H, s); C NMR (75 MHz, CDCl3) 164.6, 162.6, 150.5, 149.5, 149.5, 139.0, 133.9,
13
133.4, 129.2, 129.1, 127.3, 126.0, 120.1, 119.4, 118.1, 115.6, 111.1, 104.6; IR (KBr) 3425, 3043, 1685, 1621, 1276, 1207, 1086, 754, 707 cm-1; HRMS m/z (M+) calcd for C18H11NO3: 289.0739. Found: 289.0741.
7-Hydroxy-8-phenyl-9-(pyridin-3-yl)-6H-benzo[c]chromen-6-one
(34).
Reaction of 1i (225 mg, 1 mmol) and β-ketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 34 (229 mg, 63%) as a solid: mp 247-249 C; 1H NMR (300 MHz, CDCl3) 11.82 (1H, s), 8.48 (2H, d, J = 7.8 Hz), 8.03
o
(1H, d, J = 8.1 Hz), 7.59 ( 1H, s), 7.49 ( 1H, t, J = 6.9 Hz), 7.40-7.35 (3H, m), 7.23-7.24 (3H, m), 7.14-7.12 (3H, m);
C NMR (75 MHz, CDCl3) 165.4,
13
160.2, 150.6, 149.4, 148.3, 146.3, 137.0, 136.2, 134.1, 134.0, 131.0, 130.9, 128.7, 128.1, 127.5, 125.3, 123.1, 122.7, 117.8, 117.7, 113.6, 105.5; IR (KBr) 3443, 3056, 1663, 1610, 1391, 1264, 1129, 748 cm-1; HRMS m/z (M+) calcd for C24H15NO3: 365.1052. Found: 365.1049.
9-(2,5-Dimethylfuran-3-yl)-7-hydroxy-6H-benzo[c]chromen-6-one
(35).
Reaction of 1j (242 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 35 (217 mg, 71 %) as a solid: mp 141-143 C; 1H NMR (300 MHz, CDCl3) 11.29 (1H, s), 7.95 (1H, d, J = 8.7 Hz), 7.47-
o
7.41 (2H, m), 7.33-7.28 (2H, m), 7.00 (1H, s), 6.17 (1H, s), 2.47 (3H, s), 2.29 (3H, s); 13C NMR (75 MHz, CDCl3) 165.1, 162.3, 150.6, 150.5, 148.1, 143.8, 135.0, 130.5, 124.9, 123.1, 120.5, 118.2, 117.7, 114.4, 110.7, 106.2, 103.7, 13.5,
36
13.3; IR (KBr) 3449, 2930, 1719, 1511, 1278, 1128, 817, 557 cm-1; HRMS m/z (M+) calcd for C19H14O4: 306.0892. Found: 306.0890.
9-(2,5-Dimethylfuran-3-yl)-7-hydroxy-8-methyl-6H-benzo[c]chromen-6one (36). Reaction of 1j (242 mg, 1 mmol) and β-ketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 36 (169 mg, 53 %) as a solid: mp 144-146 oC; 1H NMR (300 MHz, CDCl3) 11.61 (1H, s), 7.89 (1H, d, J = 7.8 Hz), 7.39-7.34 (2H, m), 7.27-7.17 (2H, m), 5.93 (1H, s), 2.25 (3H, s), 2.16 ( 6H, s); 13C NMR (75 MHz, CDCl3) 165.7, 160.7, 150.4, 150.0, 147.0, 143.8, 131.5, 130.0, 125.0, 124.9, 122.9, 120.6, 118.5, 117.6, 113.6, 108.1, 103.9, 13.4, 13.0, 12.5; IR (KBr) 3449, 3067, 1686, 1624, 1272, 1124, 757 cm-1; HRMS m/z (M+) calcd for C20H16O4: 320.1049. Found: 320.1046.
9-(2,5-Dimethylfuran-3-yl)-7-hydroxy-8-phenyl-6H-benzo[c]chromen-6one (37). Reaction of 1j (242 mg, 1 mmol) and β-ketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 37 (248 mg, 65 %) as a solid: mp 208-210 oC; 1H NMR (300 MHz, CDCl3) 11.71(1H, s), 7.96 (1H, d, J = 7.8 Hz), 7.49 (1H, s), 7.43 (1H, t, J = 7.8 Hz), 7.33-7.18 (7H, m), 5.51 (1H, s), 2.08 (3H, s), 1.92 (3H, s);
13
C NMR (75 MHz, CDCl3) 165.6, 160.1, 150.6,
149.6, 147.2, 143.5, 135.1, 133.4, 130.6, 130.5, 127.8, 127.2, 125.1, 123.0, 120.6, 118.2, 117.7, 114.1, 108.2, 105.4, 104.5, 13.2, 12.5; IR (KBr) 3444, 3067, 1680, 1624, 1272, 1124, 759 cm-1; HRMS m/z (M+) calcd for C25H18O4: 382.1205. Found: 3821208.
37
2-Bromo-9-(2,5-dimethylthiophen-3-yl)-7-hydroxy-6H-benzo[c]chromen-6one (38). Reaction of 1k (337 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 38 (292 mg, 73 %) as a solid: mp 217-219 oC; 1H NMR (300 MHz, CDCl3) 11.16 (1H, s), 8.03 (1H, s), 7.49 (1H, d, J = 8.7 Hz), 7.39 (1H, s), 7.16 (1H, d, J = 8.7 Hz), 7.01 (1H, s), 6.70 (1H, s), 2.43 (3H, s), 2.39 (3H, s); 13C NMR (75 MHz, CDCl3) 164.6, 162.4, 149.6, 146.4, 136.7, 136.3, 134.6, 133.6, 133.4, 126.4, 126.0, 120.2, 119.5, 118.1, 116.9 112.6, 104.0, 15.0, 14.3 ; IR (KBr) 3451, 2377, 1677, 1390, 1268, 756 cm-1; HRMS m/z (M+) calcd for C19H13BrO3S: 399.9769. Found: 399.9771.
2-Bromo-9-(2,5-dimethylthiophen-3-yl)-7-hydroxy-8-methyl-6Hbenzo[c]chromen-6-one (39). Reaction of 1k (337 mg, 1 mmol) and βketoester 2b (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 39 (207 mg, 73 %) as a solid: mp 213-215 oC; 1H NMR (300 MHz, CDCl3) 11.63 (1H, s), 8.09 (1H, s), 7.54 (1H, d, J = 9 Hz), 7.36 (1H, s), 7.25 (1H, d, J = 8.7 Hz), 6.56 (1H, s), 2.50 (3H, s), 2.24 (3H, s), 2.19 (3H, s);
13
C NMR (75
MHz, CDCl3) 165.2, 160.8, 149.3, 146.7, 136.7, 136.5, 133.4, 132.8, 130.1, 126.6, 126.2, 125.8, 120.3, 119.3, 118.0, 113.7, 104.0, 15.1, 13.6, 12.9; IR (KBr) 3477, 1689, 1551, 1388, 1259, 1122, 734 cm-1; HRMS m/z (M+) calcd for C20H15BrO3S: 413.9925. Found: 413.9927.
Ethyl2-bromo-9-(2,5-dimethylthiophen-3-yl)-7-hydroxy-6-oxo-6Hbenzo[c]chromene-8-carboxylate (40). Reaction of 1k (337 mg, 1 mmol) and β-ketoester 2d (216 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 40 (207 mg, 64 %) as a solid: mp 203-205oC; 1H NMR (300 MHz, CDCl3) 38
11.63 (1H, s), 8.1 (1H, s), 7.6 (1H, d, J = 7.6 Hz), 7.39 (1H, s), 7.26 (1H, d, J = 8.7 Hz), 6.57 (1H, s), 4.15 (2H, q, J = 7.2 Hz), 2.50 (3H, s), 2.41 (3H, s), 2.29 (3H, s), 1.09 (3H, t, J = 7.2 Hz);
13
C NMR (75 MHz, CDCl3) 165.6, 164.4,
159.7, 149.8, 145.3, 136.5, 135.0, 134.4, 134.2, 134.1, 126.4, 126.3, 123.5, 119.6, 119.5, 118.4, 114.1, 104.9, 61.5, 15.0, 13.8, 13.7; IR (KBr) 3477, 1689, 1551, 1388, 1259, 1122, 734 cm-1; HRMS m/z (M+) calcd for C22H17BrO5S: 471.9980. Found: 471.9982.
7-Hydroxy-9-(naphthalen-2-yl)-6H-benzo[c]chromen-6-one (41).Reaction of 1l (274 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 41 (212 mg, 63 %) as a solid: mp 228-230 oC; 1H NMR (300 MHz, CDCl3) 11.40 (1H, s), 8.14 (2H, d, J = 6.9 Hz), 7.97-7.88 (4H, m), 7.78 (1H, d, J = 8.1 Hz), 7.55-7.48 (3H, m), 7.39-7.35 (3H, m);
13
C
NMR (75 MHz, CDCl3) 165.9, 161.8, 152.0, 150.8, 138.1, 133.1, 133.7, 131.7, 131.0, 128.2, 127.9, 127.8, 127.7, 126.7, 126.5, 126.4, 125.0, 124.5, 123.0, 118.4, 117.9, 113.5, 104.8; IR (KBr) 3422, 2370, 1683, 1620, 1557, 1272, 1081, 858, 755 cm-1; HRMS m/z (M+) calcd for C23H14O3: 338.0943. Found: 338.0943.
7-Hydroxy-8-methyl-9-(naphthalen-2-yl)-6H-benzo[c]chromen-6-one (42). Reaction of 1l (274 mg, 1 mmol) and β-ketoester 2b (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 42 (179 mg, 51 %) as a solid: mp 194-196 C; 1H NMR (300 MHz, CDCl3) 11.68 (1H, s), 7.90-7.79 (4H, m), 7.74 (1H,
o
s), 7.47-7.44 (3H, m), 7.41-7.33 (2H, m), 7.27-7.16 (2H, m), 2.17( 3H, s);
13
C
NMR (75 MHz, CDCl3) 165.7, 160.8, 151.0, 150.5, 138.1, 133.1, 132.7, 39
131.7, 130.0, 128.12, 127.9, 127.8, 127.7, 126.7, 126.5, 126.4, 125.0, 124.1, 123.0, 118.4, 117.6, 113.5, 104.3, 13.2 ; IR (KBr) 3447, 3053, 1676, 1268, 1123, 755 cm-1; HRMS m/z (M+) calcd for C24H16O3: 352.1099. Found: 352.1097.
7-Hydroxy-9-(naphthalen-2-yl)-8-phenyl-6H-benzo[c]chromen-6-one (43). Reaction of 1l (274 mg, 1 mmol) and β-ketoester 2c (288mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 43 (207 mg, 50 %) as a solid: mp199201oC; 1H NMR (300 MHz, CDCl3) 11.84 (1H, s), 8.09 (1H, d, J = 7.2 Hz), 7.76-7.47 (4H, m), 7.6 (1H, d, J = 8.4 Hz), 7.53-7.33 (5H, m), 7.22-7.18 (5H, m), 7.15-7.12 (1H, m);
C NMR (75 MHz, CDCl3) 165.9, 160.4, 150.9,
13
150.4, 138.2, 135.0, 134.0, 133.2, 132.5, 131.2, 130.9, 128.8, 128.3, 128.1,127.8, 127.5, 127.5, 127.4, 126.6, 126.5, 125.4, 123.4, 118.4, 117.9, 114.6, 105.2; IR (KBr) 3424, 3055, 1672, 1612, 1265, 857, 748 cm-1; HRMS m/z (M+) calcd for C29H18O3: 414.1256. Found: 414.1254.
9-Cyclopropyl-7-hydroxy-6H-benzo[c]chromen-6-one (44). Reaction of 1m (188 mg, 1 mmol) and β-ketoester 2a (195 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 44 (181 mg, 72 %) as a solid: mp 140-142 oC; 1H NMR (300 MHz, CDCl3) 11.19 (1H, s), 7.91 (1H, d, J = 7.5), 7.42-7.37 (1H, m), 7.28-7.19 (3H, m), 6.59 (1H, s), 1.95-1.89 (1H, m), 1.121.04 (2H, m), 0.85-0.78 (2H, m);
13
C NMR (75 MHz, CDCl3) 165.1, 162.4,
155.5, 150.6, 134.7, 130.3, 124.8, 123.1, 118.2, 117.6, 112.4, 109.8, 103.6, 16.5, 10.7; IR (KBr) 3394, 3069, 1663, 1563, 1422, 1333, 1276, 1207, 1080, 986, 759 cm-1; HRMS m/z (M+) calcd for C16H12O3: 252.0786. Found: 252.0785. 40
9-Cyclopropyl-7-hydroxy-8-phenyl-6H-benzo[c]chromen-6-one
(45).
Reaction of 1m (188 mg, 1 mmol) and β-ketoester 2c (288 mg, 1.5 mmol) using Cs2CO3 (650 mg, 2 mmol) afforded 45 (200 mg, 61 %) as a solid: mp 187-190 C; 1H NMR (300 MHz, CDCl3) 11.60 (1H, s), 7.99 (1H, d, J = 7.2 Hz), 7.51-
o
7.31 (8H, m), 7.03 (1H, s), 1.83-1.76 (1H, m), 1.00-0.92 (2H, m), 0.90-0.84 (2H, m); 13C NMR (75 MHz, CDCl3) 165.5, 159.4, 152.8, 150.6, 135.3, 133.8, 130.3, 130.0, 128.3, 127.5, 124.9, 122.9, 118.3, 117.6, 106.2, 103.5, 14.6, 10.9; IR (KBr) 3449, 3048, 1661, 1614, 1548, 1405, 1273, 1163, 760 cm-1; HRMS m/z (M+) calcd for C22H16O3: 328.1099. Found: 328.1100.
General procedure for the synthesis of terphenyls (49-54) To a solution of 2 mmol KOH in 3.5 mL DMSO and 0.5 mL water, 2 mmol of CH3I and 0.4 mmol of benzo[c]chromen-6-ones were added and the reaction mixture is stirred at room temperature for 1-2 h (progress of reaction was monitored by thin layer chromatography). The reaction mixture was extracted with ethyl acetate and evaporated in rotary evaporator under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the product. Characterization data for all synthesized terphenyls 49-54 are as follows.
Methyl2'',5'-dimethoxy-2',6'-dimethyl-[1,1':3',1''-terphenyl]-4'carboxylate (49). Reaction of 20 (126 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 49 (105 mg, 70 %) as a solid: mp 99-101oC; 1H NMR (300 MHz, CDCl3) 7.45-7.39 (2H, m), 7.357.26 (2H, m), 7.20-7.17 (1H, m), 7.13-7.09 (2H, m), 6.96-6.90 (2H, m), 3.82 41
(3H, s), 3.76 (3H, s), 3.48 (3H, s), 1.97 (3H, s), 1.66 (3H, s);
13
C NMR (75
MHz, CDCl3) 168.4, 156.9, 152.7, 144.6, 140.9, 134.6, 132.2, 131.2, 130.8, 128.9, 128.4, 128.1, 128.0, 126.8, 126.3, 120.2, 110.6, 62.1, 56.3, 51.6, 17.9, 14.0; IR (KBr) 3048, 1680, 1612, 1548, 1405, 1273, 1163, 768 cm-1; HRMS m/z (M+) calcd for C24H24O4: 376.1675. Found: 376.1677.
Methyl
5''-bromo-2'',5'-dimethoxy-6'-methyl-[1,1':3',1''-terphenyl]-4'-
carboxylate (50). Reaction of 23 (152 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 50 (149 mg, 85 %) as a solid: mp83-85oC; 1H NMR (300 MHz, CDCl3) 7.43-7.30 (7H, m), 7.00 (1H, s), 6.78-6.74 (1H, m), 3.87 ( 3H, s), 3.72 ( 3H, s), 3.67 ( 3H, s), 2.23 ( 3H, s),; C NMR (75 MHz, CDCl3) 167.7, 156.2, 155.3, 145.3, 140.6, 134.0, 133.1,
13
131.4, 131.0, 129.2, 129.0, 12801, 127.6, 127.2, 126.6, 112.6, 112.0, 61.8, 55.5, 51.7, 13.6; IR (KBr) 3018, 1712, 1614, 1548, 1405, 1273, 1163, 749 cm-1; HRMS m/z (M+) calcd for C23H21BrO4: 440.0623. Found: 440.0622.
Methyl 5'-(2,4-dimethoxyphenyl)-3,3'-dimethoxy-[1,1':2',1''-terphenyl]-4'carboxylate (51). Reaction of 30 (169 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 51 (164 mg, 85 %) as a solid: mp 68-70 oC; 1H NMR (300 MHz, CDCl3) 7.27-7.24 (7H, m), 7.09 (1H, t, J = 8.1 Hz), 6.72 (2H, d, J = 7.8 Hz), 6.57-6.54 (3H, m), 3.86 (3H, s), 3.79 (3H, s) 3.70 (3H, s) 3.57 (3H, s) 3.38 (3H, s);
13
C NMR (75 MHz, CDCl3)
168.1, 160.7, 158.8, 157.2, 155.2, 143.5, 141.8, 137.0, 136.0, 132.9, 131.2, 130.9, 128.7, 128.6, 127.8, 127.7, 126.7, 122.2, 121.4, 114.9, 113.0, 104.3, 98.4,
42
61.5, 55.3, 55.0, 51.8 ; IR (KBr) 2935, 1731, 1608, 1458, 1282, 1159, 1039, 703 cm-1; HRMS m/z (M+) calcd for C30H28O6: 484.1886. Found: 384.1886.
Methyl
5'-bromo-5-(2,5-dimethylthiophen-3-yl)-2',3-dimethoxy-[1,1'-
biphenyl]-2-carboxylate (52). Reaction of 39(104 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 52 (141 mg, 80 %) as a solid: mp 140-142 oC; 1H NMR (300 MHz, CDCl3) 7.40-7.35 (2H, m), 6.91 (1H, s), 6.89 (1H, s), 6.77 (1H, d, J = 8.7 Hz), 6.70 (1H, s), 3.88 (3H, s), 3.71 (3H, s), 3.62 (3H, s), 2.44 (3H, s), 2.42 (3H, s);
13
C NMR (75 MHz,
CDCl3) 167.5, 156.7, 155.3, 139.4, 137.2, 137.0, 136.0, 133.0, 132.7, 131.5, 131.1, 126.8, 123.2, 121.1, 112.5, 112.1, 110.7, 56.0, 55.5, 51.7, 15.0, 14.0; IR (KBr) 2939, 2369, 1733, 1599, 1443, 1251, 1108, 1072, 756, 704 cm-1; HRMS m/z (M+) calcd for C22H21BrO4S: 460.0344. Found: 460.0342.
Methyl
2',3-dimethoxy-4-methyl-5-(naphthalen-2-yl)-[1,1'-biphenyl]-2-
carboxylate (53). Reaction of 29 (140 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 53 (128 mg, 78 %) as a solid: mp 113-115oC; 1H NMR (300 MHz, CDCl3) 7.81-7.78 (3H, m), 7.72 (1H, s), 7.42-7.39 (3H, m), 7.25-7.17 (2H, m), 7.07 (1H, s), 6.92-6.82 (2H, m), 3.83 (3H, s), 3.69 (3H, s), 3.57 (3H, s), 2.2 (3H, s); 13C NMR (75 MHz, CDCl3)
167.8, 156.0, 155.5, 144.7, 138.2, 135.3, 132.9, 132.2, 130.5, 128.8, 128.7, 128.5, 127.9, 127.8, 127.7, 127.4, 127.3, 127.2, 126.8, 126.0, 125.8, 120.3, 110.3, 61.6, 55.1, 51.5, 13.5; IR (KBr) 3067, 1688, 1618, 1272, 1124, 751 cm-1; HRMS m/z (M+) calcd for C27H24O4: 412.1675. Found: 412.1676.
43
Methyl 5'-cyclopropyl-2,3'-dimethoxy-[1,1':4',1''-terphenyl]-2'-carboxylate (54). Reaction of 45 (131 mg, 0.4 mmol) and methyl iodide (284 mg, 2 mmol) using KOH (112 mg, 2 mmol) afforded 54 (133 mg, 86 %) as a solid: mp 8587oC; 1H NMR (300 MHz, CDCl3) 7.39-7.18 (7H, m), 6.94 (1H, d, J = 7.5), 6.87 (1H, d, J = 8.4), 6.61 (1H, s), 3.71 (1H, s), 3.54 (1H, s), 3.32 (1H, s), 1.68-1.59 (1H, m), 0.74-0.61 (4H, m);
C NMR (75 MHz, CDCl3) 167.9,
13
156.1, 154.9, 144.9, 137.4, 136.3, 135.0, 130.6, 130.5, 129.2, 129.0, 127.9, 127.0, 125.5, 121.5, 120.5, 110.5, 61.6, 55.3, 51.6, 13.5, 9.8; IR (KBr) 3009, 2942, 2842, 1731, 1604, 1544, 1280, 1143, 1022, 757, 706 cm-1; HRMS m/z (M+) calcd for C25H24O4: 388.1675. Found: 388.1673.
Acknowledgements This work was supported by the 2013 Yeungnam University Research Grant (213A367018).
44
2.1.5 References 1 (a) Tietze, L. F.; Beifuss, U. Angew. Chem. Int. Ed. Engl. 1993, 105,137. (b) Tietze, L. F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. 2 (a) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem. Int. Ed. 2006, 45, 7134. (b) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (c) Hayato, I.; Takaki, S.; Yujiro, H. Angew. Chem. Int. Ed. Engl. 2009, 48, 1304. 3 (a) Garazd, Ya. L.; Ogorodniichuk, A. S.; Garazd, M. M.; Khilya, V. P. Chem. Nat. Compd. 2002, 38, 424. (b) Ishiguro, K.; Yamaki, M.; Kashihara, M.; Takagi, S.; Isoi, K. Phytochemistry 1990, 29, 1010. (c) Abe, H.; Nishioka, K.; Takeda, S.; Arai, M.; Takeuchi, Y.; Harayama, T. Tetrahedron Lett. 2005, 46, 3197. (d) Koch, K.; Podlech, J.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005, 70, 3275. (e) Raistrick, H.; Stilkings, C. E.; Thomas, R. Biochemistry 1953, 55, 421. (f) Pero, R. W.; Harvan, D.; Blois, M. C. Tetrahedron Lett. 1973, 14, 945. 4 (a) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. Soc. 1994, 116, 1004. (b) James, C. A.; Snieckus, V. Tetrahedron Lett. 1997, 38, 8149. 5 (a) Schmidt, J. M.; Tremblay, G. B.; Page, M.; Mercure, J.; Feher, M.; DunnDufault, R.; Peter, M. G.; Redden, P. R. J. Med. Chem. 2003, 46, 1289. (b) Pandey, J.; Jha, A. K.; Hajela, K. Bioorg. Med. Chem. 2004, 12, 2239. 6 (a) Edwards, J. P.; West, S. J.; Marscheke, K. B.; Mais, D. E.; Gottardis, M. M.; Jones, T. K. J. Med. Chem.1998, 41, 303. (b) Coghlan, M. J.; Kym, P. R.; Elmore, S. W.; Wang, A. X.; Luly, J. R.; Wilcox, D.; Stashko, M.; Lin, C. W.; 45
Miner, J.; Tyree, C.; Nakane, M.; Jacobson, P.; Lane, N. C. J. Med. Chem. 2001, 44, 2879. 7 Appel, B.; Salesh, N. N. R.; Langer, P. Chem.-Eur. J. 2006, 12, 1221. 8 Myrray, R.; Mendez, J.; Brown, S. The Natural Coumarins: Occurrence, Chemistry and Biochemistry; John Wiley & Sons: New York, 1982. pp 97111. 9 (a) Sidwell, W. T. L. H.; Fritz H.; Tamm C. Helv. Chim. Acta 1971, 54, 207. (b) Koch, K.; Podlech, P.; Pfeiffer, E.; Metzler, M. J. Org. Chem. 2005, 70, 3275. (c) Cole, R. J. Cox, R. H. Handbook of Toxic Fungal Metabolites; Eds.; Academic Press: New York, 1981; p 614. (d) Tan, N.; Tao, Y.; Pan, J.; Wang, S.; Xu, F.; She, Z.; Lin, Y.; Jones, E. B. G. Chem. Nat. Compd. 2008, 44, 269. (e) Gu, W. World J. Microbiol. Biotechnol. 2009, 25, 1677. (f) Matsumoto, T.; Hosoya, T.; Shigemori, H. Heterocycles 2010, 81, 1231. (g) Meng, X.; Mao, Z.; Lou, J.; Xu, L.; Zhong, L.; Peng, Y.; Zhou, L.; Wang, M. Molecules 2012, 17, 11303. 10 (a) Tanahashi, T.; Kuroishi, M.; Kuwahara, A.; Nagakura, N.; Hamada, N. Chem. Pharm. Bull. 1997, 45, 1183. (b) Hamada, N.; Tanahashi, T.; Goldsmith, S.; Nash III, T. H. Symbiosis 1997, 23, 219. (c) Hamada, N.; Tanahashi, T.; Miyagawa, H.; Miyawaki, H. Symbiosis 2001, 31, 23. (d) Tanahashi T.; Takenaka, Y.; Nagakura, N.; Hamada, N. Phytochemisty 2003, 62, 71. (e) Hormazabal, E.; Schmeda-Hirschmann, G.; Astudillo, L.; Rodriguez, J.; Theoduloz, C. Z.; Naturforsch , C. Biosci. 2005, 60, 11. (f) Kock, I.; Krohn, K.; Egold, H.; Dreager, S.; Schulz, B.; Rheinheimer, J. Eur. J. Org. Chem. 2007, 2186.
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11 (a) Holler, U.; Wright, A. D.; Matthee, G. M.; Draeger, K. S.; Aust, H. J.; Schulz, B. Mycol. Res. 2000, 104, 1354. (b) Song, Y. C.; Huang, W. Y.; Sun, C.; Wang, F. W.; Tan, R. X. Biol. Pharm. Bull. 2005, 28, 506. 12 Kim, N.; Sohn, M-J.; Kim C-J.; Kwon, H. J.; Kim, W-G. Bioorg. Med. Chem. Lett. 2012, 22, 2503. 13 (a) Pahari, P.; Kharel, M. K.; Shepherd, M. D.; van Lanen, S. G.; Rohr, J. Angew. Chem. Int. Ed. 2012, 51, 1216. (b) Tibrewal, N.; Pahari, P.; Wang, G.; Kharel, M. K.; Morris, C.; Downey, T.; Hou, Y.; Bugni, T. S.; Rohr, J. J. Am. Chem. Soc. 2012, 134, 18181. (c) McGee, L.R.; Confalone, P. N. J. Org. Chem. 1988, 53, 3695. (d) Hart, D. J.; Mannino, A. Tetrahedron 1996, 52, 3841. (e) Fischer, C.; Lipata, F.; Rohr, J. J. Am. Chem. Soc. 2003, 125, 7818. (g) Suzuki, K. Pure Appl. Chem. 2000, 72, 1783. (h) Takemura, I.; Imura, K.; Matsumoto, T.; Suzuki, K. Org. Lett. 2004, 6, 2503. (i) Yamashita, N.; Shin-Ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H. J. Antibiotics, 1998, 51, 1105. 14 (a) Zhou, Q. J.; Worm, K.; Dolle, R. E. J. Org. Chem. 2004, 69, 5147. (b) Kemperman, G. J.; Ter Horst, B.; Van de Goor, D.; Roeters, T.; Bergwerff, J.; Van der Eem, R.; Basten, J. Eur. J. Org. Chem. 2006, 14, 3169. (c) Hussain, I.; Nguyen, V. T. H.; Yawer, T. T.; Fiscer, C.; Reinke, H.; Langer, P. J. Org. Chem. 2007, 72, 6255. (d) Carlson, E. J.; Riel, A. M. S.; Dahl, B. J. Tetrahedron Lett. 2012, 53, 6245. (e) Thasana, N.; Worayuthakarn, R.; Kradanrat, P.; Hohn, E.; Young, L.; Ruchirawat, S. J. Org. Chem. 2007, 72, 9379. 15 Jung, M. E.; Allen, D. A. Org. Lett. 2009, 11, 757. 16 Singha, R.; Roy, S.; Nandi, S.; Ray, P.; Ray, J. K. Tetrahedron Lett. 2013, 54, 657. 47
17 Luo, J.; Lu, Y.; Liu, S.; Liu, J.; Deng, G. J. Adv. Synth. Catal. 2011, 353, 2604. 18 (a) Sankar, U.; Raju C.; Uma, R. Curr. Chem. Lett. 2012, 1, 123. (b) Salvatore, R. N.; Nagle A. S.; Jung, K. W. J. Org. Chem. 2002, 67, 674. (c) Cuny, G. D. Tetrahedron Lett. 2003, 44, 8149. 19 Liu, J. K. Chem. Rev. 2006, 106, 2209. 20 (a) Simoni, D.; Rondanin, R.; Baruchello, R.; Rizzi, M.; Grisolia, G.; Eleopra, M.; Grimaudo, S.; Di Cristina, A.; Pipitone, M. R.; Bongiorono, M. R.; Arico, M.; Invidiata, F. P.; Tolomeo, M. J. Med. Chem. 2008, 51, 4796. (b) Kikuchi H.; Matsuo, Y.; Katou, Y.; Kubohara Y.; Oshima Y. Tetrahedron 2012, 68, 8884. 21 (a) Mullen, K.; Wegner, G. Electronic Materials: The Oligomer Approach; (Wiley-VCH: Weinhein, Germany, 1988). (b) Chen, B.; Baumeister, U.; Pelzl, G.; Das, M. K.; Zeng, X.; Ungar, G.; Tschierske, C. J. Am. Chem. Soc. 2005, 125, 16578. (c) Wright, R. S. Tetrahedron Lett. 2003, 44, 7129. (d) Udayakumar, B. S.; Schuster, G. B. J. Org. Chem. 1992, 57, 348. 22 (a) Kawada, K.; Arimura, A.; Tsuri, T.; Fuji, M.; Komurasaki, T.; Yonezawa, S.; Kugimiya, A.; Haga, N.; Mitsumori, S.; Inagaki, M.; Nakatani, T.; Tamura, Y.; Takechi, S.; Taishi,T.; Kishino, J.; Ohtani, M. Angew. Chem. Int. Ed. 1998, 37, 973. (b) Albrecht, M.; Schneider, M. Synthesis 2000, 1557. (c) Wu, C. J. J.; Xue, C. H.; Kuo, Y. M.; Luo, F. T. Tetrahedron 2005, 61, 4735. (d) Wu, C.-J.; Xue, C.; Kuo, Y.-M.; Luo, F.-T. Tetrahedron 2005, 61, 4735. (e) Hayashi, N.; Yoshikawa, T.; Ohnuma, T.; Higuchi, H.; Sako, K.; Uekusa, H. Org. Lett. 2007, 9, 5417. (f) Lin, D. W.; Masuda,T.; Biskup, M. B.; Nelson, J. D.; Baran, P. S. J. Org. Chem. 2011, 48
76, 1013. (g) Adrio, L. A.; Miguez, J. M. A.; Hii, K. K. Org. Prep. Proced. Int. 2009, 41, 331. 23 Monzon, G.; Knochel, P. Synlett 2010, 304. 24 (a) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, 2004. (b) Miyaura, N. CrossCoupling Reactions. Topics in Current Chemistry; Ed.; Springr: Berlin, 2002; Vol. 219. 25 (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Suzuki, A. J. Organomet. Chem. 2002, 653, 83. (c) Polshettiwar, V.; Decottignies, A.; Len, C.; Fihri, A. ChemSusChem 2010, 3, 502. (d) Molnar, A. Chem. Rev. 2011, 111, 2251. (e) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem., Int. Ed. 2012, 51, 5062 . (f) Liu, N.; Liu, C.; Jin, Z. Chin. J. Org. Chem. 2012, 32, 860. 26 Garcia-Garcia, P.; Fernandez-Rodriguez, M. A.; Aguilar, E. Angew. Chem. Int. Ed. 2009, 48, 5534. 27 Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. 28 Shibata, Y.; Tanaka, K. Synthesis 2012, 323.
49
2.2 Multicomponent Benzannulation for Functionalized Biaryls
2.2.1 Introduction Biaryl units are one of the most important structural motifs found in biologically active natural products, pharmaceuticals, and agrochemicals.1 They are widely used as important scaffolds and building blocks for the construction of optical and functional materials.2 Several methods for aryl-aryl bond formation have been reported. Among these, the transition-metal catalyzed traditional cross-coupling (Suzuki, Stille, Hiyama, etc.) has become one of the useful tools for constructing an Ar-Ar bond by the reaction of aryl halides and aryl metals (path a, Scheme 1).3 Recently, transition metal-catalyzed C-H arylation (path b, Scheme 1)4 and the oxidative cross-coupling of arenes (path c, Scheme 1),5 has emerged as an important cross-coupling strategy to form ArAr bonds. This direct arylation reduces the synthetic steps and has the advantages of lower cost and environmental benignity. Although a number of methods for the direct formation of an Ar-Ar bond by transition metal-catalyzed reactions have been well developed, the loading of catalyst tends to have a high economic cost in industrial processes.
50
Therefore, the development of a facile transition metal-free process is essential and quite significant. Recently, several transition metal-free methods for the formation of aryl-aryl bonds have been developed.6 These approaches include the arylation of arenes by aryl halides in the presence of strong alkali metal bases and ligand, which proceed via a radical-type mechanism. These reactions provide biaryl molecules by cross-coupling between the two aromatic rings of the aryl metals and aryl halides, arenes and aryl halides, or arenes and arenes.7 Recently, direct biaryl formation through the hydroarylation of arynes (path a, Scheme 2)8 or hexadehydro Diels-Alder reaction (path b, Scheme 2)9 has been reported without cross-coupling reactions between two aromatic compounds. These reactions provide various complex molecules bearing biaryl skeletons by benzannulation through aryne intermediates.
51
Currently, benzannulation is one of the most important reactions for the formation of substituted benzenes.10 Over the past decade, several synthetic methods for benzannulation have been reported by Diels-Alder reaction,11 Bergman cyclization,12 Danheiser annulation,13 ring closing metathesis,14 Dötz [3+2+1] reaction,15 Wulff [5+1] orthobenzannulation,16 and rhodium(II)catalyzed benzannulation.17 Moreover, synthesis of phenol derivatives by benzannulation from 1,3-dicarbonyls and Michael acceptors has been also reported.18 Herein, I report a novel, facile and efficient one-pot biaryl formation through a three-component reaction starting from commercially available βketoesters, β-ketoamides, or 1,3-diketones with α,β-unsaturated aldehydes (eq. 1) or α,β-unsaturated aldehydes and aryl aldehydes (eq. 2, Scheme 3) in presence of mild base.
52
Multicomponent reactions of 1,3-dicarbonyls have received great attention in the last few years to synthesize diverse and complex organic molecules.19 A number of Michael additions of 1,3-dicarbonyl compounds to α,β-unsaturated aldehydes have been explored by many groups to afford various useful organic molecules.20-21 Among these, representative approaches include N-heterocyclic carbene-catalyzed Michael addition for dihydropyranones,20 organocatalytic domino reactions for epoxycyclohexanones, and multicatalytic cascade reactions to furnish cyclopentanes.21
53
2.2.2 Results and Discussion To afford the biaryls, the reactions of methyl acetoacetate (1a) with cinnamaldehyde (2a) were first attempted under several bases and solvents. The results are listed in Table 1. Reaction of methyl acetoacetate (1a, 0.5 mmol) and cinnamaldehyde (2a, 0.5 mmol) in the presence of triethylamine (1.0 equiv.) in refluxing toluene for 12 h did not give any products, instead the starting materials were recovered (entry 1, Table 1). Upon the treatment of 1a (0.5 mmol) with 2a (0.5 mmol) in the presence of DBU (1.0 equiv.) in refluxing toluene for 12 h, unexpected aromatic compound 3 was produced in 15% yield through a pseudo three-component reaction between methyl acetoacetate and two cinnamaldehydes (entry 2). With 2 equivalents of cinnamaldehyde (2a), the yield of 3 was increased to 35%. To increase the yield, other bases were next examined. With NaOMe (1.0 equiv.) and K2CO3 (1.0 equiv.) in refluxing toluene, product 3 was formed in 63 and 71% yield, respectively. Importantly, the yield of 3 was increased to 83% when the reaction was carried out in the presence of Cs2CO3 (1.0 equiv.) in refluxing toluene for 4 h. Cs2CO3 was found to be superior to other bases in this cascade process. Recently, Cs2CO3 has been widely used as an excellent base in various organic transformations because of its mild base strength.22 With the use of higher (2.0 equiv.) or lower (0.2 equiv.) catalytic amounts of Cs2CO3 in refluxing toluene, the yield of 3 did not improve. For other solvents, the reaction in refluxing benzene or 1,2dichloroethane (DCE) provided compound 3 in 61 and 10% yield, respectively. However, product 3 was not formed in polar solvents, such as dimethyl sulfoxide (DMSO) or water. The structure of 3 was determined by analyzing the spectral data. The 1H-NMR spectrum of 3 showed a characteristic singlet 54
peak for the –OH group at 10.88 ppm, benzylic methylene protons at 3.60 ppm (J = 6.0 Hz) as a doublet, two vinylic protons at 6.46-6.37 ppm as multiplets and at 6.50 ppm as a doublet (J = 15.9 Hz). The coupling constant value of 15.9 Hz suggests the E-configuration of the double bond. The regio and stereochemistry of 3 was deduced from the X-ray crystallographic analysis of structurally-related compound 14 (Figure 1).
55
Figure 1. X-ray Structure of compound 14 To examine the generality and scope of this methodology, additional reactions of β-ketoesters, β-ketoamides or 1,3-diketones with several cinnamaldehydes were next carried out under optimized reaction conditions. The results are summarized in
Table 2. The reactions between methyl
acetoacetate (1a) and cinnamaldehydes 2b-2c bearing electron-donating (OMe) or electron-withdrawing group (-F) on the 4-position of benzene ring in the presence of Cs2CO3 in refluxing toluene provided produts 4 and 5 in good yields (entries 1-2, Table 2). Similarly, reactions of ethyl acetoacetate (1b) with cinnamaldehydes 2a-2c were also successful and afforded the products 6-8 in 56
good yields (entries 3-5, Table 2). With allyl 3-oxobutanoate (1c) or benzyl 3oxobutanoate (1d), the expected products 9-11 were produced in the range of 74-80% yield (entries 6-8). The substrate scope was also extended successfully with various β-ketoamides. The treatment of 2a or 2c with 3-oxo-Nphenylbutanamide (1e) provided compounds 12 and 13 in good yields (entries 9-10). With β-ketoamides bearing an electron-donating (-OMe, -Me) or electron-withdrawing group (-Cl) at 2 or 4-position on the benzene, the desired products were obtained with good yields. For example, with N-(4methoxyphenyl)-3-oxobutanamide (1f), 3-oxo-N-p-tolylbutanamide (1g), and 3-oxo-N-o-tolylbutanamide (1h) having electron-donating groups on the benzene ring, products 14-21 were produced in the range of 73-81% yield (entries 11-18). When N-(4-chlorophenyl)-3-oxobutanamide (1i) and N-(2chlorophenyl)-3-oxobutanamide (1j) bearing electron-withdrawing groups were used, products 22-28 were isolated in good yields (entries 19-25). On the other hand, reaction of 2,4-pentanedione (1k) with cinnamaldehyde (2a) provided desired compound 29 with decreased yield (48%) (entry 26) compared to that of ketoesters or ketoamides.
57
Scheme 4 presents a proposed mechanism for the formation of 3 through Cs2CO3-mediated multi-component cascade reaction. In basic medium, the Michael addition of the enolate 30 to 2a forms intermediate 31, which then undergoes intramolecular aldol reaction to give another intermediate 32. The 58
aldol-type reaction of 32 with 2a in the basic medium produces 33, which further undergoes 1,5-H shift followed by tautomerization to form the final product 3.
To prove this mechanism, control experiments were carried out. Isolation of the intermediate 31 under several bases such as K2CO3, NaHCO3, and Na2CO3 at room temperature was not successful. Therefore, we performed an additional experiment using cinnamaldehyde-3-d (2e) under optimized reaction condition (Scheme 5). Importantly, reaction of 1f with 2e in refluxing toluene for 5 h provided the desired product 34 bearing a deuterium on each of the benzylic carbon in 71% yield. This result shows that the reaction pathway proceeds through the formation of intermediate 33 followed by [1,5]-H shift.
59
The additional control experiments of Michael donor ability of two different 1,3-dicarbonyl compounds 1a and 1e were explored (Scheme 6). The reaction of β-ketoester 1a (0.5 mmol) and β-ketoamide 1e (0.5 mmol) with cinnamaldehyde (2a, 1.0 mmol) in the presence of 0.5 mmol of Cs2CO3 in refluxing toluene for 6 h provided products 3 and 12 in 30 and 45% yield, respectively (eq 1, Scheme 6). This result did not show a significant difference in the Michael donor ability between β-ketoester and β-ketoamide, but Nphenyl substituted β-ketoamide was found slightly better Michael donor than β-ketoester. A further control experiment was attempted to explore the reactivity of different cinnamaldehydes. The reactions of 1a (0.5 mmol) with three different cinnamaldehydes 2a-2c (1.0 mmol, each) bearing no substituent, electron-donating, and -withdrawing groups in refluxing toluene for 6 h provided compound 5 in 60% yield (eq. 2, Scheme 6). This result suggests that the electron withdrawing group on the cinnamaldehyde moiety acts as an excellent Michael acceptor compared to cinnamaldehyde bearing no substituent or electron-donating groups.
60
Having seen the general applicability of the multi-component reactions between β-ketoesters or β-ketoamides and cinnamaldehydes, other cross cascade reactions were next attempted for the synthesis of the benzyl substituted biaryls (Scheme 7). The reaction of β-ketoester 1a with cinnamaldehyde (2a) and benzaldehyde (35a) did not observe any desired biaryl product with 2a and 35a being incorporated, instead product 3 was isolated in 36% yield. With 4-fluorocinnamaldehyde (2c) and benzaldehyde (35a), compound 5 was produced in 37% yield. However, the reaction of 1a with 4-methoxycinnamaldehyde (2b) and 2-chlorobenzaldehyde (35b) in refluxing toluene for 6.5 h provided product 36 in 66% yield. With the combinations of β-ketoester 1b or β-ketoamides 1g and 1i with 2b and 35b or 35c provided the corresponding products 37-39 in 68, 65, and 63% yield, respectively.
61
To further demonstrate the versatility of this multi-component reaction, we examined the reactions with 3-(furan-2-yl)acrylaldehyde (2f) or 3-(anthracen-9yl)acrylaldehyde (2g) for the synthesis of various biaryls bearing furanyl or anthracenyl ring (Scheme 8). The reactions of 1a-1c or 1i with 2f in refluxing toluene for 4-5 h afforded the corresponding products 40-43 in the range of 7477% yield. With 2g bearing an anthracenyl ring, the desired products 44 and 45 were isolated in 62% and 60% yield, respectively.
62
As an application of this methodology, the conversion of the synthesized compounds 3 and 14 to new molecules using catalytic hydrogenation and cyclization reaction was next attempted (Scheme 9). The catalytic hydrogenation of 3 and 14 over Pd/C (30 psi) at room temperature for 8 h provided 46 and 47 in high yields. Treatment of 3 and 14 in the presence of DDQ in refluxing benzene for 12 h afforded the corresponding chromenes 48 and 49 in 63 and 65% yield, respectively.
63
2.2.3 Conclusions In summary, I have developed a simple, cost effective, transition metal-free, and mild base-promoted novel cascade reaction for the synthesis of diverse and polysubstituted biaryls starting from readily available β-ketoesters, βketoamides or 1,3-diketones with α,β-unsaturated aldehydes or arylaldehydes in good yield. This novel benzannulation involves the domino Michael addition/intramolecular and intermolecular aldol/[1,5]-hydrogen shift and tautomerization.
64
2.2.4 Experimental All experiments were carried out under open air without inert gases protection. Ketoesters (1a-d), ketoamides (1e-j) and cinnamaldehydes (2a-f) were purchased from Sigma- Aldrich. Merck precoated silica gel plates (Art. 5554) with a fluorescent indicator were used for analytical TLC. Flash column chromatography was performed using silica gel 9385 (Merck). Melting points were determined with micro-cover glasses on a Fisher-Johns apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-VNS (300 MHz) spectrometer in CDCl3 using 7.24 ppm as the solvent chemical shift. 13C NMR spectra were recorded on a Varian-VNS (75 MHz) spectrometer in CDCl3 using 77.0 ppm as the solvent chemical shift. IR spectra were recorded on a JASCO FTIR 5300 spectrophotometer. High resolution mass (HRMS) were obtained with a JEOL JMS-700 spectrometer at the Korea Basic Science Institute. General
procedure
for
the
synthesis
of
4-cinnamyl-3-hydroxy-N-
phenylbiphenyl-2-carboxamide and alkyl 4-cinnamyl-3-hydroxybiphenyl2-carboxylate derivatives (3-29) To a solution of cinnamaldehydes 2a-d (1.0 mmol) and ketoesters or ketoamides 1a-j (0.5 mmol) in toluene (5.0 mL) was added Cs2CO3 (0.5 mmol). Each reaction mixture was refluxed in for 4-8 hours. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the product. Characterization data for all compounds 3-29 are as follows: 65
Methyl 4-cinnamyl-3-hydroxybiphenyl-2-carboxylate (3). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and methyl 3-oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 3 (143 mg, 83 %) as a solid: mp 65-67 oC; 1H NMR (300 MHz, CDCl3) 10.88 (1H, s), 7.38-7.15 (11H, m), 6.75 (1H, d, J = 7.8 Hz), 6.50 ( 1H, d, J = 15.9 Hz), 6.46-6.37 (1H, m), 3.60 (2H, d, J = 6.0 Hz), 3.46 (3H, s);
13
C NMR (75 MHz, CDCl3) 171.7, 159.1,
142.9, 142.8, 137.5, 133.8, 131.3, 128.4, 128.1, 127.9, 127.7, 127.6, 127.0, 126.7, 126.1, 122.1, 115.7, 51.7, 53.1; IR (KBr) 3434, 3054, 1663, 1436, 1276, 970, 760, 516 cm-1; HRMS m/z (M+) calcd for C23H20O3: 344.1412. Found: 344.1413. (E)-methyl 3-hydroxy-4'-methoxy-4-(3-(4-methoxyphenyl)allyl)biphenyl-2carboxylate (4). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and methyl 3-oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 4 (155 mg, 77 %) as red liquid; 1H NMR (300 MHz, CDCl3) 10.82 (1H, s), 7.33-7.26 (3H, m), 7.15 (2H, d, J = 8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 6.83 (2H, d, J = 8.4 Hz), 6.75 (1H, d, J = 7.5 Hz), 6.45 (1H, d, J = 15.9 Hz), 6.33-6.24 (1H, m), 3.85 (3H, s), 3.80 (3H, s), 3.59 (2H, d, J = 6.6 Hz), 3.53 (3H, s);
13
C NMR (75 MHz, CDCl3) 171.9, 159.0, 158.8, 158.5,
142.4, 135.2, 133.7, 130.6, 130.4, 129.2, 127.5, 127.2, 125.7, 122.1, 113.9, 113.0, 111.8, 55.2, 55.2, 51.7, 33.0; IR (neat) 3465, 2924, 1662, 1608, 1513, 1438, 1246, 1033, 821, 516 cm-1; HRMS m/z (M+) calcd for C25H24O5: 404.1624. Found: 404.1622. (E)-methyl
4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxybiphenyl-2-
carboxylate (5). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 66
mmol) and methyl 3-oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 9 (148 mg, 78 %) as a solid: mp 70-72 oC; 1H NMR (300 MHz, CDCl3) 10.98 (1H, s), 7.34-7.29( 3H, m), 7.19-7.13 (2H, m), 7.06-6.93 (4H, m), 6.71 (1H, d, J = 7.5 Hz), 6.45 (1H, d, J = 15.9 Hz), 6.37-6.27 (1H, m), 3.58 (2H, d, J = 6.6 Hz), 3.5 (3H, s);
13
C NMR (75 MHz, CDCl3) 171.6,
159.3, 141.8, 138.9, 133.8, 130.0, 129.7, 129.6, 127.9, 127.6, 127.5, 122.1, 115.4, 115.1, 114.6, 114.3, 111.7, 51.8, 33.1; IR (KBr) 3410, 3039, 1664, 1605, 1511, 1434, 1227, 1153, 820, 764 cm-1; HRMS m/z (M+) calcd for C23H18F2O3: 380.1224. Found: 380.1227. Ethyl
4-cinnamyl-3-hydroxybiphenyl-2-carboxylate
(6).
Reaction
of
cinnamaldehyde (132 mg, 1.0 mmol) and β- ethyl 3-oxobutanoate (65 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 6 (141 mg, 79 %) as a yellow liquid; 1H NMR (300 MHz, CDCl3) 11.01 (1H, s), 7.31-7.12 (11H, m), 6.67 (1H, d, J = 7.8 Hz), 6.46-6.32 (2H, m), 3.89 (2H, q, J = 7.2 Hz), 3.54 (2H, d, J = 6.6 Hz), 0.66 (3H, t, J = 7.2 Hz);
C NMR (75 MHz, CDCl3)
13
171.3, 161.0, 159.2, 143.1, 143.0, 137.5, 133.6, 131.2, 128.4, 128.2, 127.9, 127.5, 127.0, 126.6, 126.1, 121.9, 111.8, 61.0, 33.1, 12.9; IR (neat) 3394, 2989, 1675, 1607, 1518, 1224, 1157, 1010, 825, 595 cm-1; HRMS m/z (M+) alcd for C24H22O3: 358.1569. Found: 358.1568. (E)-ethyl
3-hydroxy-4'-methoxy-4-(3-(4-methoxyphenyl)allyl)biphenyl-2-
carboxylate (7). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and ethyl 3-oxobutanoate (165 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 7 (148 mg, 71 %) as a yellow liquid; 1H NMR (300 MHz, CDCl3) 10.98 (1H, s), 7.30 (3H, d, J = 8.1 Hz), 7.15-7.12 (2H, m), 67
6.89-6.80 (4H, m), 6.73 (1H, d, J = 7.8 Hz), 6.44 (1H, d, J = 15.9 Hz), 6.326.22 (1H, m), 4.00 (2H, q, J = 7.2 Hz), 3.83 (3H, s), 3.78 (3H, s), 3.57 (2H, d, J = 6.6 Hz), 0.82 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) 171.4, 159.1, 158.8, 158.6, 142.5, 135.6, 133.5, 130.6, 130.4, 129.5, 127.6, 127.2, 125.8, 122.0, 113.9, 113.0, 112.0, 61.0, 55.3, 55.2, 33.0, 13.2; IR (neat) 3363, 2924, 1650, 1607, 1246, 1175, 1031, 825 cm-1; HRMS m/z (M+) calcd for C26H26O5: 418.1780. Found: 418.1781. (E)-ethyl
4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxybiphenyl-2-
carboxylate (8). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and ethyl 3-oxobutanoate (65 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 8 (159 mg, 81 %) as a yellow liquid; 1H NMR (300 MHz, CDCl3) 11.17 (1H, s), 7.24-7.29 (3H, m), 7.19-7.14 (2H, m), 7.06-6.93 (4H, m), 6.71 (1H, d, J = 7.8 Hz), 6.56 (1H, d, J = 17.3 Hz), 6.38-6.28 (1H, m), 3.99 (2H, q, J = 7.2 Hz), 3.59 (2H, d, J = 6.6 Hz), 0.82 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) 171.1, 159.5, 141.9, 133.6, 130.0, 129.7, 129.6, 127.8, 127.7, 127.6, 127.5, 127.4, 121.9, 115.4, 115.1, 114.5, 114.2, 61.1, 33.1, 13.0; IR (neat) 3316, 2985, 1660, 1605, 1511, 1227, 1157, 1019, 822, 592 cm-1; HRMS m/z (M+) calcd. for C24H20F2O3: 394.1381. Found: 394.1383. Allyl
4-cinnamyl-3-hydroxybiphenyl-2-carboxylate
(9).
Reaction
of
cinnamaldehyde (132 mg, 1.0 mmol) and allyl 3-oxobutanoate (71 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 9 (148 mg, 80 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 10.92 (1H, s), 7.37-7.14 (11H, m), 6.74 (1H, d, J = 7.8 Hz), 6.52-6.38 ( 2H, m), 5.39-5.26 (1H, m), 4.95 (1H, d, J = 10.5 Hz), 4.86 (1H, d, J = 17.1 Hz), 4.41 (2H, d, J = 5.4 Hz), 3.60 (2H, d, J = 68
6);
13
C NMR (75 MHz, CDCl3) 171.0, 159.2, 142.9, 137.5, 133.8, 131.3,
130.7, 128.4, 128.2, 128.1, 127.9, 127.7, 127.6, 127.0, 126.6, 126.1, 122.0, 118.3, 111.7, 65.8, 33.1; IR (neat) 3415, 3056, 1660, 1416, 1271, 1147, 975, 756 cm-1; HRMS m/z (M+) calcd for C25H22O3: 370.1569. Found: 370.1570. (E)-allyl
4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxybiphenyl-2-
carboxylate (10). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and allyl 3-oxobutanoate (71 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 10 (160 mg, 79 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 11.01 (1H, s), 7.34-7.29 (3H, m), 7.19-7.14 (2H, m), 7.04-6.93 (4H, m), 6.71 (1H, d, J = 7.5 Hz), 6.45 (1H, d, J = 15.9 Hz), 6.37-6.27 (1H, m), 5.48-5.34 (1H, m), 5.03 (1H, d, J = 10.5), 4.94 (1H, d, J = 17.1 Hz), 4.44 (2H, d, J = 5.7 Hz), 3.58 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 170.8, 159.4, 141.9, 138.9, 133.8, 130.5, 130.0, 129.7, 129.6, 127.8, 127.5, 127.4, 122.1, 118.7, 115.4, 115.1, 114.6, 114.3, 111.7, 65.9, 33.1; IR (neat) 3532, 3039, 2926, 1660, 1511, 1420, 1226, 975, 820, 513 cm-1; HRMS m/z (M+) calcd for C25H20F2O3: 406.1381 Found: 406.1378. (E)-benzyl 3-hydroxy-2'-methoxy-4-(3-(2-methoxyphenyl)allyl)biphenyl-2carboxylate (11). Reaction of (E)-3-(2-methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and benzyl 3-oxobutanoate (86 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 11 (180 mg, 74 %) as a yellow liquid; 1H NMR (300 MHz, CDCl3) 11.02 (1H, s), 7.46 (1H, d, J = 8.1 Hz), 7.37 (1H, d, J = 7.5 Hz), 7.22-7.16 (6H, m), 6.98-6.81 (6H, m), 6.69 (1H, d, J = 7.5 Hz), 6.63 (1H, d, J = 8.1 Hz), 6.49-6.39 (1H, m), 5.01 (2H, s), 3.84 (3H, s), 3.64 (2H, d, J = 3.9 Hz), 3.50 (3H, s); 13C NMR (75 MHz, CDCl3) 171.1, 158.6, 156.3, 155.9, 69
138.3, 134.5, 133.9, 131.9, 129.3, 128.6, 128.3, 128.2, 128.1, 128.0, 127.99, 127.95, 126.6, 126.5, 125.9, 122.3, 120.5, 120.3, 112.7, 110.7, 109.9, 66.7, 55.4, 55.0, 33.5; IR (neat) 3480, 3013, 2950, 1680, 1519, 1450, 1221, 980, 840, 507 cm-1; HRMS m/z (M+) calcd for C31H28O5: 480.1937. Found: 480.1937. 4-Cinnamyl-3-hydroxy-N-phenylbiphenyl-2-carboxamide (12). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and 3-oxo-N-phenylbutanamide (89 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 12 (170 mg, 84 %) as a solid: mp 128-130 oC; 1H NMR (300 MHz, CDCl3) 12.03 (1H, s), 7.45-7.36 (5H, m), 7.32-7.26 (2H, m), 7.23-7.18 (3H, m), 7.15-7.09 (3H, m), 6.99-6.94 (2H, m), 6.85 (2H, d, J = 7.8 Hz), 6.69 (1H, d, J = 7.8 Hz), 6.49-6.31 (2H, m), 3.56 (2H, d, J = 6.6 Hz);
13
C NMR (75 MHz, CDCl3) 168.5, 159.3, 140.5,
138.9, 137.5, 136.4, 132.7, 131.2, 129.3, 129.2, 129.2, 128.8, 128.4, 127.9, 127.0, 126.1, 124.8, 121.4, 120.2, 120.1, 114.3, 33.2; IR (KBr) 3396, 3027, 1631, 1536, 1418, 1239, 1034, 827, 602, 519 cm-1; HRMS m/z (M+) calcd for C28H23NO2: 405.1729. Found: 405.1732. (E)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxy-N-phenylbiphenyl-2carboxamide (13). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and 3-oxo-N-phenylbutanamide (89 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 13 (171 mg, 78 %) as a solid: mp 68-70 oC; 1H NMR (300 MHz, CDCl3) 11.92 (1H, s), 7.54-7.49 (2H, m), 7.43-7.38 (3H, m), 7.34-7.26 (4H, m), 7.18-7.13 (1H, m), 7.09-7.01 (5H, m), 6.83 (1H, d, J = 7.8 Hz), 6.56 (1H, d, J = 15.9 Hz), 6.49-6.39 (1H, m), 3.69 (2H, d, J = 6.6 Hz); C NMR (75 MHz, CDCl3) 168.3, 159.2, 137.8, 136.3, 132.8, 131.0, 130.9,
13
130.1, 129.0, 128.9, 127.7, 127.6, 127.5, 127.4, 125.0, 121.6, 120.1, 116.5, 70
116.2, 115.4, 115.1, 33.2; IR (KBr) 3401, 2923, 1680, 1600, 1511, 1440, 1229, 819, 597 cm-1; HRMS m/z (M+) calcd for C28H21F2NO2: 441.1540. Found: 441.1542. 4-cinnamyl-3-hydroxy-N-(4-methoxyphenyl)biphenyl-2-carboxamide (14). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and N-(4-methoxyphenyl)-3oxobutanamide (104 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 14 (165 mg, 76%) as a solid: mp 125-127 oC; 1H NMR (300 MHz, CDCl3) 12.01 (1H, s), 7.44-7.33 (5H, m), 7.29 (2H, d, J = 7.2 Hz), 7.23-7.16 (3H, m), 7.12-7.06 (1H, m), 6.85 (1H, s), 6.76 (2H, d, J = 8.7 Hz), 6.68-6.62 (3H, t, J = 8.7 Hz), 6.47-6.32( 2H, m), 3.62 (3H, s), 3.54 (2H, d, J = 6.0 Hz); C NMR (75 MHz, CDCl3) 168.2, 159.2, 156.7, 140.5, 138.9, 137.5, 132.5,
13
131.2, 129.5, 129.2, 128.7, 128.4, 128.3, 128.0, 126.9, 126.0, 122.0, 121.9, 121.3, 114.4, 113.9, 55.3, 33.1; IR (KBr) 3404, 2929, 1603, 1512, 1420, 1231, 825, 594, 517 cm-1; HRMS m/z (M+) calcd for C29H25NO3: 435.1834. Found: 435.1832. Crystal refinement data for compound 14: Empirical Formula- C29 H25 N O3, M = 435.50, Monoclinic, Space group Pbca, a = 29.314(2) Å, b = 5.8408(4) Å, c = c = 26.737(2) Å, V = 4394.1(6) Å3, Z = 8, T = 173(2) K, ρcalcd = 1.317 mg/m3, 2Өmax. = 26.040, Refinement of 300 parameters on 4328 independent reflections out of 13044 collected reflections (Rint = 0.0704) led to R1 = 0.0520 [I >2σ(I)], wR2 = 0.1592 (all data) and S = 1.054 with the largest difference peak and hole of 0.572 and -0.540 e.Ao-3 respectively. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (CCDC
71
1047083). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif. (E)-3-hydroxy-4'-methoxy-N-(4-methoxyphenyl)-4-(3-(4methoxyphenyl)allyl)biphenyl-2-carboxamide (15).
Reaction of (E)-3-(4-
methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and N-(4-methoxyphenyl)3-oxobutanamide (104 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 15 (180 mg, 73%) as a solid: mp 62-64 oC; 1H NMR (300 MHz, CDCl3) 12.08 (1H, s), 7.37-7.27 (5H, m), 7.08 (1H, s), 7.00 (2H, d, J = 9.0 Hz), 6.93-6.89 (2H, m), 6.83-6.71 (5H, m), 6.45 (1H, d, J = 15.9 Hz), 6.34-6.24 (1H, m), 3.85 (3H, s), 3.77 (3H, s), 3.73 (3H, s), 3.58 (2H, d, J = 6.6 Hz;
13
C
NMR (75 MHz, CDCl3) 168.5, 159.8, 159.2, 158.7, 156.8, 138.5, 132.6, 132.5, 130.6, 130.5, 129.6, 128.6, 127.2, 125.9, 122.1, 122.0, 121.5, 114.6, 114.4, 114.0, 113.8, 55.5, 55.4, 55.2, 33.1; IR (KBr) 3413, 3056, 1663, 1610, 1391, 1264, 1129, 748, 592 cm-1; HRMS m/z (M+) calcd for C31H29NO5: 495.2046. Found: 495.2043. (E)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxy-N-(4methoxyphenyl)biphenyl-2-carboxamide
(16).
Reaction
of
(E)-3-(4-
fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and N-(4-methoxyphenyl)-3oxobutanamide (104 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 16 (190 mg, 81 %) as a solid: mp 117-119 oC; 1H NMR (300 MHz, CDCl3) 11.84 (1H, s), 7.45-7.38 (2H, m), 7.34-7.29 (3H, m), 7.20-7.15 (2H, m), 6.99-6.88 (5H, m), 6.78-6.73 (3H, m), 6.47 (1H, d, J = 15.9 Hz), 6.40-6.30 (1H, m), 3.74 (3H, s), 3.61 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 168.1, 159.0, 156.9, 137.7, 132.6, 131.0, 130.9, 130.0, 129.4, 128.8, 127.7, 72
127.6, 127.4, 121.9, 121.5, 116.4, 116.1, 115.4, 115.1, 114.7, 114.1, 55.4, 33.2; IR (KBr) 3404, 2929, 1603, 1512, 1420, 1231, 825, 517 cm-1; HRMS m/z (M+) calcd for C29H23F2NO3: 471.1646. Found: 471.1645. 4-Cinnamyl-3-hydroxy-N-p-tolylbiphenyl-2-carboxamide (17). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and 3-oxo-N-p-tolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 17 (160 mg, 77 %) as a solid: mp 98-100 oC; 1H NMR (300 MHz, CDCl3) 12.03 (1H, s), 7.45-7.36 (5H, m), 7.29 (2H, d, J = 7.5 Hz), 7.21-7.16 (3H, m), 7.12-7.06 (1H, m), 6.90 (3H, d, J = 7.5 Hz), 6.74-6.66 (3H, m), 6.47-6.32 (2H, m), 3.55 (2H, d, J = 6.6 Hz), 2.15 (3H, s) ;
13
C NMR (75 MHz, CDCl3) 168.3, 159.3, 140.5, 138.9,
137.5, 134.5, 133.9, 132.6, 131.2, 129.3, 129.2, 129.1, 128.7, 128.6, 128.4, 128.0, 126.9, 126.1, 121.3, 120.2, 114.4, 33.1, 20.8; IR (KBr) 3394, 3028, 2921, 1635, 1532, 1417, 1237, 816, 760, 507cm-1; HRMS m/z (M+) calcd for C29H25NO2: 419.1885. Found: 419.1888. (E)-3-hydroxy-4'-methoxy-4-(3-(4-methoxyphenyl)allyl)-N-p-tolylbiphenyl2-carboxamide (18). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and 3-oxo-N-p-tolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 18 (182 mg, 76 %) as a solid: mp 58-60 o
C; 1H NMR (300 MHz, CDCl3) 12.08 (1H, s), 7.37-7.27 (5H, m), 7.13 (1H, s),
7.03-6.98 (4H, m), 6.87 (2H, d, J = 8.7 Hz), 6.81 (2H, d, J = 8.7 Hz), 6.73 (1H, d, J = 7.5 Hz), 6.45 (1H, d, J = 15.9 Hz), 6.34-6.24 (1H, m), 3.84 (3H, s), 3.77 (3H, s), 3.59 (2H, d, J = 6.9 Hz), 2.25 (3H, s);
13
C NMR (75 MHz, CDCl3)
168.6, 159.8, 159.3, 158.7, 138.6, 134.6, 134.0, 132.6, 132.5, 130.6, 130.5, 130.4, 129.3, 128.7, 127.2, 125.9, 121.6, 120.3, 114.7, 114.4, 113.8, 55.4, 55.2, 73
33.1, 20.8; IR (KBr) 3409, 2933, 1675, 1612, 1510, 1274, 1129, 1029, 834, 736, 506 cm-1; HRMS m/z (M+) calcd for C31H29NO4: 479.2097. Found: 479.2095. (E)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxy-N-p-tolylbiphenyl-2carboxamide (19). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and 3-oxo-N-p-tolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 1.0 mmol) afforded 19 (182 mg, 80%) as a solid: mp 104-106 oC; 1H NMR (300 MHz, CDCl3) 11.84 (1H, s), 7.45-7.40 (2H, m), 7.34-7.29 (3H, m), 7.20-7.14 (2H, m), 7.04-7.86 (7H, m), 6.74 (1H, d, J = 7.8 Hz), 6.47 ( 1H, d, J = 15.9 Hz), 6.40-6.30 (1H, m), 3.60 (2H, d, J = 6.6 Hz), 2.26 (3H, s); 13C NMR (75 MHz, CDCl3) 168.2, 159.1, 137.7, 134.9, 133.8, 132.7, 131.0, 130.9, 130.0, 129.5, 128.8, 127.7, 127.6, 127.5, 127.4, 121.6, 120.2, 116.4, 116.1, 115.4, 115.1, 33.2, 20.8 ; IR (KBr) 3404, 2923, 1636, 1601, 1513, 1421, 1229, 1158, 817, 509 cm-1; HRMS m/z (M+) calcd for C29H23F2NO2: 455.1697. Found: 455.1698. 4-Cinnamyl-3-hydroxy-N-o-tolylbiphenyl-2-carboxamide (20). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and 3-oxo-N-o-tolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 20 (155 mg, 74 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 11.90 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.48 (2H, d, J = 7.2 Hz), 7.43 (2H, t, J = 7.8 Hz), 7.38-7.37 (3H, m), 7.33 (1H, d, J = 7.8 Hz), 7.28 (2H, t, J = 7.8 Hz), 7.18 (1H, t, J = 7.8 Hz), 7.16-7.13 (1H, m), 7.03-6.99 (3H, m), 6.76 (1H, d, J = 7.2 Hz), 6.53 (1H, d, J = 15.6 Hz), 6.48-6.43 (1H, m), 3.63 (2H, d, J = 6.6 Hz), 1.62 (3H, s); 13C NMR (150 MHz, CDCl3) 168.9, 159.1, 140.5, 138.9, 137.5, 134.8, 132.6, 131.3, 130.4, 129.5, 74
129.3, 129.2, 128.7, 128.5, 128.4, 128.0, 127.0, 126.5, 126.1, 125.5, 122.7, 121.9, 114.7, 33.2, 17.0; IR (neat) 3407, 3027, 1634, 1530, 1452, 1238, 754, 599, 517 cm-1; HRMS m/z (M+) calcd for C29H25NO2: 419.1885. Found: 419.1888. (E)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3-hydroxy-N-o-tolylbiphenyl-2carboxamide (21). Reaction of (E)-3-(4-fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and 3-oxo-N-o-tolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 21 (177 mg, 78 %) yellow liquid; 1H NMR (300 MHz, CDCl3) 11.72 (1H, s), 7.71 (1H, d, J = 8.7 Hz), 7.48-7.44 (2H, m), 7.35-7.30 (2H, m), 7.19-7.11 (4H, m), 7.08-7.03 (2H, m), 6.99-6.93 (3H, m), 6.73 (1H, d, J = 8.7 Hz), 6.48 (1H, d, J = 15.9 Hz), 6.40-6.30 (1H, m), 3.61 (2H, d, J = 6.6 Hz), 1.68 (3H, s);
13
C NMR (75 MHz, CDCl3) 168.7, 159.0,
137.7, 136.5, 137.6, 132.7, 131.0, 130.9, 130.5, 130.1, 128.8, 127.7, 127.6, 127.6, 127.5, 126.7, 125.7, 122.6, 122.0, 116.4, 116.1, 115.4, 115.1, 33.2, 17.0; IR (neat) 3414, 2926, 1636, 1513, 1229, 1157, 820, 755, 513 cm-1; HRMS m/z (M+) calcd for C29H23F2NO2: 455.1697. Found: 455.1698. N-(4-chlorophenyl)-4-cinnamyl-3-hydroxybiphenyl-2-carboxamide
(22).
Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and N-(4-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 22 (168 mg, 76%) as a solid: mp 80-82 oC; 1H NMR (300 MHz, CDCl3) 11.92 (1H, s), 7.48-7.38 (5H, m), 7.35-7.30 (2H, m), 7.28-7.21 (3H, m), 7.19-7.09 (3H, m), 6.99 (1H, s), 6.82 (2H, d, J = 8.7 Hz), 6.73 (1H, d, J = 8.7 Hz), 6.52-6.36 (2H, m), 3.59 (2H, 6.6 Hz);
13
C NMR (75 MHz, CDCl3)
168.5, 159.4, 140.4, 138.9, 137.5, 135.0, 132.9, 131.3, 129.8, 129.3, 129.2, 75
128.9, 128.8, 128.5, 128.4, 127.9, 127.0, 126.1, 121.5, 121.2, 114.1, 33.1; IR (KBr) 3390, 3057, 1636, 1532, 1413, 1236, 1096, 750, 506 cm-1; HRMS m/z (M+) calcd for C28H22ClNO2: 439.1339. Found: 439.1335. (E)-N-(4-chlorophenyl)-3-hydroxy-4'-methoxy-4-(3-(4methoxyphenyl)allyl)biphenyl-2-carboxamide (23). Reaction of (E)-3-(4methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and N-(4-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 23 (195 mg, 78 %) as a solid: mp 130-132 oC; 1H NMR (300 MHz, CDCl3) 11.94 (1H, s), 7.36-7.29 (5H, m), 7.16 (3H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.4 Hz), 6.93 (2H, d, J = 8.4 Hz), 6.81 (2H, d, J = 8.4 Hz), 6.73 (1H, d, J = 8.4 Hz), 6.46 (1H, d, J = 15.9 Hz), 6.33-6.24 (1H, m), 3.85 (3H, s), 3.77 (3H, s), 3.59 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 168.8, 159.9, 159.4, 158.8, 138.6, 135.2, 132.9, 132.5, 130.7, 130.5, 130.4, 129.8, 128.9, 128.9, 127.2, 125.8, 121.7, 121.3, 114.7, 114.1, 113.9, 55.5, 55.2, 33.1; IR (KBr) 3409, 2930, 1639, 1511, 1278, 1128, 817, 557 cm-1; HRMS m/z (M+) calcd for C30H26ClNO4: 499.1550. Found: 499.1550. (E)-N-(4-chlorophenyl)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3hydroxybiphenyl-2-carboxamide
(24).
Reaction
of
(E)-3-(4-
fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and N-(4-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 24 (185 mg, 78 %) as a solid: mp 127-129 oC; 1H NMR (300 MHz, CDCl3) 11.72 (1H, s), 7.44-7.40 (2H, m), 7.34-7.30 (3H, m), 7.21-7.17 (4H, m), 6.99-6.93 (5H, m), 6.75 (1H, d, J = 7.8 Hz), 6.47 (1H, d, J = 15.9 Hz), 6.39-6.39 (1H, m), 3.60 (2H, d, J = 6.6 Hz); 76
C NMR (75 MHz, CDCl3)
13
168.3, 159.2, 137.7, 136.3, 136.2, 134.9, 133.6, 133.0, 131.0, 130.9, 130.1, 129.0, 127.5, 127.4, 121.7, 121.2, 116.5, 116.2, 115.4, 115.1, 114.4, 33.1; IR (KBr) 3400, 2923, 1688, 1513, 1229, 1095, 823, 508 cm-1; HRMS m/z (M+) calcd for C28H20ClF2NO3: 475.1151. Found: 475.1150. (E)-N-(4-chlorophenyl)-3-hydroxy-2'-methoxy-4-(3-(2methoxyphenyl)allyl)biphenyl-2-carboxamide (25).
Reaction of (E)-3-(2-
methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and N-(4-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 25 (187 mg, 75 %) as a yellow liquid; 1H NMR (600 MHz, CDCl3) 11.90 (1H, s), 7.60-7.55 (3H, m), 7.54-7.49 (2H, m), 7.31-7.25 (4H, m), 7.076.96 (6H, m), 6.83 (1H, d, J = 7.2 Hz), 6.60-6.55 (1H, m), 3.96 (3H, s), 3.74 (2H, d, J = 6.6 Hz), 3.75 (3H, s); 13C NMR (150 MHz, CDCl3) 168.8, 158.5, 156.5, 156.3, 135.4, 134.5, 133.0, 130.6, 130.3, 129.8, 129.5, 129.2, 129.1, 128.8, 128.6, 128.0, 126.6, 126.0, 121.8, 121.6, 121.0, 120.5, 115.2, 111.2, 110.8, 55.6, 55.4, 33.6; IR (neat) 3430, 2941, 1680, 1525, 1235, 1080, 807, 509 cm-1; HRMS m/z (M+) calcd for C30H26ClNO4: 499.1550. Found: 499.1550. N-(2-chlorophenyl)-4-cinnamyl-3-hydroxybiphenyl-2-carboxamide
(26).
Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and N-(2-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 26 (162 mg, 74 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 11.43 (1H, s), 8.30 (1H, d, J = 8.1 Hz), 7.55 (1H, s), 7.38-7.06 (13H, m), 6.88 (1H, t, J = 7.5 Hz), 6.71 (1H, d, J = 7.8 Hz), 6.48-6.34 (2H, m), 3.55 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 169.0, 158.8, 139.8, 139.2, 137.5, 133.8, 133.0, 131.3, 129.4, 129.3, 129.1, 129.0, 128.6, 128.5, 128.4, 127.9, 127.4, 77
127.0, 126.1, 125.0, 122.1, 121.6, 114.9, 33.2; IR (neat) 3376, 3028, 2924, 1639, 1589, 1528, 1437, 1297, 1234, 966, 753, 609 cm-1; HRMS m/z (M+) calcd for C28H22ClNO2: 439.1339. Found: 439.1340. (E)-N-(2-chlorophenyl)-3-hydroxy-4'-methoxy-4-(3-(4methoxyphenyl)allyl)biphenyl-2-carboxamide (27). Reaction of (E)-3-(4methoxyphenyl)acrylaldehyde (162 mg, 1.0 mmol) and N-(2-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 27 (177 mg, 71 %) yellow liquid; 1H NMR (600 MHz, CDCl3) 11.54 (1H, s), 8.40 (1H, d, J = 8.4 Hz), 7.77 (1H, s), 7.37 (2H, d, J = 8.4 Hz), 7.30 (3H, t, J = 7.8 Hz), 7.22-7.17 (2H, m), 6.99-6.96 (1H, m), 6.93-6.91 (2H, m), 6.82-6.76 (2H, m), 6.76 (1H, d, J = 7.2 Hz), 6.45 (1H, d, J = 15.0 Hz) 6.32-6.27 (1H, m), 3.79 (3H, s), 3.77 (3H, s), 3.59 (2H, d, J = 6.0 Hz);
13
C NMR (150
MHz, CDCl3) 169.2, 160.1, 158.9, 158.7, 138.8, 133.9, 132.9, 132.1, 130.7, 130.6, 130.4, 129.0, 128.4, 127.4, 127.2, 125.8, 124.9, 123.0, 122.1, 121.6, 114.8, 114.6, 113.8, 55.4, 55.2, 33.1; IR (neat) 3415, 2950, 1609, 1530, 1422, 1230, 822, 594, 519 cm-1; HRMS m/z (M+) calcd for C30H26ClNO4: 499.150. Found: 499. (E)-N-(2-chlorophenyl)-4'-fluoro-4-(3-(4-fluorophenyl)allyl)-3hydroxybiphenyl-2-carboxamide
(28).
Reaction
of
(E)-3-(4-
fluorophenyl)acrylaldehyde (150 mg, 1.0 mmol) and N-(2-chlorophenyl)-3oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 28 (189 mg, 76 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 11.34 (1H, s), 8.39 (1H, d, J = 8.1 Hz), 7.59 (1H, s), 7.42-7.38 (2H, m), 7.317.27 (3H, m), 7.21-7.16 (2H, m), 7.06 (2H, t, J = 7.8 Hz), 6.99-6.90 (3H, m), 78
6.75 (1H, d, J = 7.8 Hz), 6.45 (1H, J = 15.9 Hz), 6.37-6.27 (1H, m), 3.58 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) 168.7, 158.7, 138.0, 135.8, 133.7, 133.6, 133.0, 131.1, 131.0, 130.1, 129.1, 128.6, 127.6, 127.5, 127.4, 125.1, 122.8, 122.2, 121.4, 116.3, 116.0, 115.4, 115.1, 33.2 ; IR (neat) 3380, 2924, 1640, 1594, 1524, 1435, 1228, 1157, 819, 754, 606, 516 cm-1; HRMS m/z (M+) calcd for C28H20ClF2NO2: 475.1151. Found: 475.1152. 1-(4-cinnamyl-3-hydroxy-[1,1'-biphenyl]-2-yl)ethan-1-one (29). Reaction of cinnamaldehyde (132 mg, 1.0 mmol) and pentane-2,4-dione (50 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 29 (78 mg, 48 %) as yellow liquid. 1
H NMR (600 MHz, CDCl3) 11.93 (1H, s), 7.41-7.26 (10H, m), 7.19-7.15
(1H, m), 6.78 (1H, d, J = 7.8 Hz), 6.50 ( 1H, d, J = 15.6 Hz), 6.44-6.39 (1H, m), 3.59 (2H, d, J = 6.6 Hz), 1.84 (3H, s);
13
C NMR (150 MHz, CDCl3)
207.4, 158.9, 142.8, 134.0, 131.3, 129.0, 128.9, 128.6, 128.4, 128.0, 127.9, 127.4, 127.0, 126.1, 121.6, 120.8, 118.7, 33.0, 31.7; IR (neat) 3380, 3042, 1720, 1426, 1266, 760, 508 cm-1; HRMS m/z (M+) calcd for C23H20O2: 328.1463. Found: 328.1462. General Procedure for the synthesis of cinnamaldehyde-3-d (2e) A mixture of (Triphenylphosphoranylidene)acetaldehyde (1 gm, 3.3 mmol) and benzaldehyde-α-d1 (321 mg, 3.0 mmol) was heated at 70 0C in a nitrogen protected two necked round bottom flask using toluene (8.0 mL) as solvent for 16 hour. The completion of the reaction was monitored by TLC. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel 79
to isolate the product. The characterization data of the compounds are as followsCinnamaldehyde-3-d (2e) The title compound was prepared according to the general procedure. The product was obtained colorless liquid. Yield: 53%.1H NMR (600 MHz, CDCl3)
9.68 (1H, d, J = 7.8 Hz), 7.54-7.53 (2H, m), 7.41-7.40 (3H, m), 6.68 (1H, d, J = 8.4 Hz);
13
C NMR (150 MHz, CDCl3) 193.5, 152.4, 152.1, 133.8, 131.1,
129.0, 128.4; IR (neat) 3045, 2825, 2740, 1685, 1492, 971, 605 cm-1; HRMS m/z (M+) calcd for C9H7DO: 133.0638. Found: 133.0636. (E)-3-hydroxy-N-(4-methoxyphenyl)-4-(3-phenylallyl-1,3-d2)-[1,1'biphenyl]-2-carboxamide (34). Reaction of cinnamaldehyde-3-d (133 mg, 1.0 mmol) and N-(4-methoxyphenyl)-3-oxobutanamide (104 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) in refluxing toluene afforded 34 (155 mg, 71%) as a solid: mp 126-128 oC; 1H NMR (600 MHz, CDCl3) 12.08 (1H, s), 7.50-7.44 (5H, m), 7.38 (2H, d, J = 7.8 Hz), 7.32 (1H, d, J = 7.2 Hz), 7.28 (2H, t, J = 7.8 Hz), 7.18 (1H, t, J = 7.8 Hz), 6.94 (1H, s), 6.85 (2H, d, J = 9.0 Hz), 6.77-6.72 (3H, m), 6.45( 1H, d, J = 6.6 Hz), 3.73 (3H, s), 3.62 (1H, m);
13
C NMR (75
MHz, CDCl3) 168.2, 159.2, 156.8, 140.6, 138.9, 137.5, 132.6, 129.5, 129.2, 128.7, 128.5, 128.44, 128.41, 127.9, 127.0, 126.1, 126.0, 122.0, 121.3, 114.4, 114.0, 55.4, 33.1; IR (KBr) 3404, 2929, 1603, 1512, 1420, 1231, 825, 594, 517 cm-1; HRMS m/z (M+) calcd for C29H23 D2NO3: 437.1960. Found: 437.1963.
80
General
procedure
for
the
synthesis
of
4-benzyl-3-hydroxy-N-
phenylbiphenyl-2-carboxamide and alkyl 4-benzyl-3-hydroxybiphenyl-2carboxylate derivatives (36-39) To a solution of (E)-3-(4-methoxyphenyl)acrylaldehyde (0.5 mmol), arylaldehydes 35a-35b (1.0 mmol) and ketoesters or ketoamides 1a, 1b, 1g or 1i (0.5 mmol) in toluene (5.0 mL) was added Cs2CO3 (0.5 mmol). Each reaction mixture was refluxed in for 5-6 hours. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the product. Characterization data for all compounds 36-39 are as follows: Methyl
4-(2-chlorobenzyl)-3-hydroxy-4'-methoxybiphenyl-2-carboxylate
(36). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (81 mg, 0.5 mmol), 2chloro benzaldehyde (140 mg, 1.0 mmol) and methyl 3-oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 36 (126 mg, 66 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 10.79 (1H, s), 7.31 (1H, d, J = 6.6 Hz), 7.17-7.16 (1H, m), 7.13-7.10 (2H, m), 7.07-7.03 (3H, m), 6.81 (2H, d, J = 8.4 Hz), 6.64 (1H, d, J = 6.6 Hz), 4.08 (2H, s), 3.76 (3H, s), 3.44 (3H, s);
13
C
NMR (150 MHz, CDCl3) 171.8, 159.1, 158.6, 142.6, 137.6, 135.2, 134.4, 134.0, 131.1, 129.4, 129.2, 127.6, 126.7, 126.5, 122.1, 113.0, 111.8, 55.2, 51.8, 33.0 ; IR (neat) 3450, 2960, 1663, 1594, 1523, 1435, 1225, 1147, 827, 754, 606, 552 cm-1; HRMS m/z (M+) calcd for C22H19ClO4: 382.0972. Found: 382.0969. Ethyl
4-(2-bromobenzyl)-3-hydroxy-4'-methoxybiphenyl-2-carboxylate
(37). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (81 mg, 0.5 mmol), 281
bromo benzaldehyde (184 mg, 1.0 mmol) and ethyl 3-oxobutanoate (65 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 37 (143 mg, 68 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 11.03 (1H, s), 7.57 (1H, d, J = 7.2 Hz), 7.27-7.22 (2H, m), 7.22-7.19 (2H, m), 7.12 (2H, d, J = 8.7 Hz), 7.08 (2H, d, J = 7.2 Hz), 6.86 (1H, d, J = 8.4 Hz), 4.14 (2H, s), 4.00 (2H, q, J = 7.2 Hz), 3.82 (3H, s), 0.81 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 171.4,
159.3, 158.6, 142.8, 139.4, 135.5, 133.8, 132.7, 131.1, 129.3, 127.8, 127.4, 126.5, 125.0, 122.0, 113.0, 112.0, 61.0, 55.3, 35.6, 13.2 ; IR (neat) 3371, 2932, 1675, 1530, 1435, 1251, 1138, 737, 521 cm-1; HRMS m/z (M+) calcd for C23H21BrO4: 440.0623. Found: 440.0622. 4-(2-chlorobenzyl)-3-hydroxy-4'-methoxy-N-p-tolylbiphenyl-2carboxamide (38). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (81 mg, 0.5 mmol), 2-chloro benzaldehyde (140 mg, 1.0 mmol) and 3-oxo-N-ptolylbutanamide (95 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 38 (155 mg, 65 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 12.17 (1H, s), 7.39-7.35 (3H, m), 7.29-7.27 (1H, m), 7.20-7.14 (3H, m), 7.08 (1H, d, J = 7.8 Hz), 7.02-6.98 (4H, m), 6.87 (2H, d, J = 9.0 Hz), 6.69 (1H, d, J = 7.8 Hz), 4.17 (2H, s), 3.84 (3H, s), 2.25 (3H, s);
13
C NMR (150 MHz, CDCl3) 168.5,
159.8, 159.5, 138.8, 137.7, 134.6, 134.4, 134.0, 132.8, 132.5, 131.3, 130.5, 129.4, 129.4, 129.3, 127.6, 126.8, 121.5, 120.3, 114.7, 114.4, 55.4, 33.1, 20.8; IR (neat) 3390, 2937, 1642, 1586, 1524, 1425, 1222, 1139, 850, 751, 614 cm-1; HRMS m/z (M+) calcd for C28H24ClNO3: 457.1445. Found: 457.1443. 4-(2-chlorobenzyl)-N-(4-chlorophenyl)-3-hydroxy-4'-methoxybiphenyl-2carboxamide (39). Reaction of (E)-3-(4-methoxyphenyl)acrylaldehyde (81 mg, 82
0.5 mmol), 2-chloro benzaldehyde (140 mg, 1.0 mmol) and N-(4chlorophenyl)-3-oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 39 (150 mg, 63 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 12.02 (1H, s), 7.39-7.34 ( 3H, m), 7.28 (1H, d, J = 7.2 Hz), 7.20-7.16 (5H, m), 7.09 (1H, d, J = 7.8 Hz), 7.00 (2H, d, J = 8.7 Hz), 6.93 (2H, d, J = 8.7 Hz), 6.69 (1H, d, J = 7.8 Hz), 4.16 (2H, s), 3.85 (3H, s); 13C NMR (150 MHz, CDCl3) 168.7, 159.9, 159.6, 138.8, 137.6, 135.2, 134.4, 133.1, 132.3, 131.3, 130.5, 129.8, 129.4, 128.9, 127.8, 127.6, 126.8, 121.6, 121.3, 114.7, 114.1, 55.5, 33.1; IR (neat) 3410, 2956, 1621, 1579, 1535, 1227, 1143, 749, 507 cm-1; HRMS m/z (M+) calcd for C27H21Cl2NO3: 477.0898. Found: 477.0897. General procedure for the synthesis of compounds 40-45 To the cinnamaldehydes 2e-2f (1.0 mmol) and ketoesters or ketoamides 1a-c or 1i (0.5 mmol) in toluene (5.0 mL) was added Cs2CO3 (0.5 mmol). Each reaction mixture was refluxed in for 4-8 hours. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the product. Characterization data for all compounds 40-45 are as follows: (E)-methyl 6-(furan-2-yl)-3-(3-(furan-2-yl)allyl)-2-hydroxybenzoate (40). Reaction of (E)-3-(furan-2-yl)acrylaldehyde (122 mg, 1.0 mmol) and methyl 3oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 40 (123 mg, 76 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 10.49 (1H, s), 7.43 (1H, s), 7.30-7.28 (2H, m), 6.92 (1H, d, J = 7.8 Hz), 6.44-6.23 (1H, m), 6.37 (1H, d, J = 3.0 Hz), 6.32-6.30 (2H, m), 6.25 (1H, d, J = 16.2 Hz), 6.14 (1H, d, J = 3.0 Hz), 3.70 (3H, s), 3.55 (2H, d, J = 6.6 Hz); 13C NMR (75 MHz, 83
CDCl3) 171.2, 158.6, 154.0, 152.9, 142.1, 141.4, 133.8, 130.8, 128.7, 126.6, 121.3, 119.9, 111.6, 111.1, 111.0, 107.0, 106.6, 52.5, 32.8; IR (neat) 3396, 2952, 1635, 1594, 1525, 1435, 1236, 1161, 829, 751, 512 cm-1; HRMS m/z (M+) calcd for C19H16O5: 324.0998. Found: 324.0999. (E)-ethyl
6-(furan-2-yl)-3-(3-(furan-2-yl)allyl)-2-hydroxybenzoate
(41).
Reaction of (E)-3-(furan-2-yl)acrylaldehyde (122 mg, 1.0 mmol) and ethyl 3oxobutanoate (65 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 41 (125 mg, 74 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 10.77 (1H, s), 7.43 (1H, s), 7.33-7.29 (2H, m), 6.90 (1H, d, J = 7.5 Hz), 6.44-6.28 (5H, m), 6.15 (1H, d, J = 2.7 Hz), 4.17 (2H, q, J = 7.2 Hz), 3.56 (2H, d, J = 6.0 Hz), 1.06 (3H, t, J = 7.2 Hz);
C NMR (75 MHz, CDCl3) 170.7, 158.9, 154.2, 152.9,
13
141.9, 141.7, 141.4, 133.7, 130.8, 128.8, 126.6, 121.6, 119.9, 111.9, 111.0, 106.8, 106.6, 61.4, 32.8, 13.7; IR (neat) 3378, 2950, 1655, 1594, 1529, 1435, 1228, 1153, 819, 754, 519 cm-1; HRMS m/z (M+) calcd for C20H18O5: 338.1154. Found: 338.1153. (E)-allyl
6-(furan-2-yl)-3-(3-(furan-2-yl)allyl)-2-hydroxybenzoate
(42).
Reaction of (E)-3-(furan-2-yl)acrylaldehyde (122 mg, 1.0 mmol) and allyl 3oxobutanoate (71 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 42 (134 mg, 77 %) as yellow liquid; 1H NMR (300 MHz, CDCl3) 10.59 (1H, s), 7.40 (1H, s), 7.32-7.29 (2H, m), 6.91 (1H, d, J = 7.8 Hz), 6.42-6.39 (2H, m), 6.32-6.22 (3H, m), 6.14 (1H, d, J = 2.7 Hz), 5.75-5.62 (1H, m), 5.17-5.12 (2H, m), 4.61 (2H, d, J = 5.7 Hz), 3.55 (2H, d, J = 6.3 Hz);
13
C NMR (75 MHz,
CDCl3) 170.5, 158.8, 154.1, 152.9, 142.0, 141.4, 133.9, 131.2, 130.8, 128.8, 126.6, 121.5, 119.9, 118.7, 111.6, 111.1, 111.0, 107.0, 106.6, 66.3, 32.8; IR 84
(neat) 3395, 2934, 1645, 1594, 1438, 1239, 1158, 813, 760, 609, 517 cm-1; HRMS m/z (M+) calcd for C21H18O5: 350.1154. Found: 350.1153. (E)-N-(4-chlorophenyl)-6-(furan-2-yl)-3-(3-(furan-2-yl)allyl)-2hydroxybenzamide (43). Reaction of (E)-3-(furan-2-yl)acrylaldehyde (122 mg, 1.0 mmol) and N-(4-chlorophenyl)-3-oxobutanamide (106 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 43 (157 mg, 75 %) as white solid: mp 85-87 oC ; 1H NMR (600 MHz, CDCl3) 11.23 (1H, s), 7.50 (1H, s), 7.287.26 (2H, m), 7.21-7.19 (5H, m), 6.91 (1H, d, J = 7.8 Hz), 6.57 (1H, d, J = 3.0 Hz), 6.2 (1H, brs), 6.34-6.24 (3H, m), 6.12 (1H, d, J = 3.0 Hz), 3.57 (2H, d, J = 6.6 Hz);
13
C NMR (150 MHz, CDCl3) 168.1, 158.6, 152.9, 152.0, 144.0,
141.4, 135.5, 133.0, 130.1, 130.0, 129.0, 127.3, 126.5, 121.7, 121.1, 120.0, 114.7, 111.7, 111.1, 109.8, 106.7, 32.9; IR (KBr) 3390, 2930, 1640, 1575, 1440, 1227, 1120, 826, 754, 528 cm-1; HRMS m/z (M+) calcd for C24H18ClNO4: 419.0924. Found: 419.0924. (E)-methyl
6-(anthracen-9-yl)-3-(3-(anthracen-9-yl)allyl)-2-
hydroxybenzoate (44). Reaction of 3-(anthracen-9-yl)acrylaldehyde (232 mg, 1.0 mmol) and methyl 3-oxobutanoate (58 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 44 (168 mg, 62 %) as yellow solid: mp 90-91 oC; 1H NMR (600 MHz, CDCl3) 11.70 (1H, s), 8.35 (1H, s), 8.33-8.29 (3H, m), 7.94-7.89 (4H, m), 7.60 (1H, d, J = 7.8 Hz), 7.50-7.21 (11H, m), 6.79 (1H, d, J = 7.8 Hz), 6.29-6.24 (1H, m), 3.96 (2H, d, J = 6.6 Hz) 2.78 (3H, s); 13C NMR (150 MHz, CDCl3) 171.4, 160.7, 139.3, 137.5, 136.3, 134.6, 133.2, 131.4, 131.1, 129.7, 129.6, 128.5, 128.4, 128.2, 127.2, 126.3, 126.2, 126.0, 125.8, 125.7, 125.2, 125.0, 124.9, 123.8, 113.4, 51.7, 34.0; IR (KBr) 3420, 2950, 85
1646, 1591, 1531, 1434, 1241, 823, 754 cm-1; HRMS m/z (M+) calcd for C39H28O3: 544.2038. Found: 544.2037. (E)-ethyl 6-(anthracen-9-yl)-3-(3-(anthracen-9-yl)allyl)-2-hydroxybenzoate (45). Reaction of 3-(anthracen-9-yl)acrylaldehyde (232 mg, 1.0 mmol) and ethyl 3-oxobutanoate (65 mg, 0.5 mmol) using Cs2CO3 (163 mg, 0.5 mmol) afforded 45 (167 mg, 60 %) as yellow solid: mp 92-94 oC; 1H NMR (600 MHz, CDCl3) 11.93 (1H, s), 8.44 (1H, s), 8.40-8.37 (3H, m), 8.01-7.98 (4H, m), 7.67 (1H, d, J = 7.8 Hz), 7.52 (2H, d, J = 7.8 Hz), 7.49-7.40 (6H, m), 7.33-7.28 (3H, m), 6.87 (1H, d, J = 7.8 Hz), 6.37-6.32 (1H, m), 4.04 (2H, d, J = 6.6 Hz) 3.45 (2H, q, J = 7.2 Hz), -0.20 (3H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3)
170.9, 160.9, 139.3, 136.3, 134.5, 131.4, 131.2, 129.8, 129.7, 128.5, 128.4, 128.1, 127.2, 126.4, 126.3, 126.2, 126.0, 125.6, 125.2, 125.1, 125.0, 124.95, 124.92, 123.6, 113.4, 60.5, 34.0, 11.9; IR (KBr) 3385, 2935, 1650, 1590, 1520, 1435, 1228, 1147, 819, 744, 612, 507 cm-1; HRMS m/z (M+) calcd for C40H30O3: 558.2195. Found: 558.2192. General experimental procedure for the hydrogenation (46-47) A solution of compounds 3 or 14 in 15 mL of dry ethyl acetate was placed in the reaction bottle of atmospheric pressure hydrogenation apparatus and to that was added 0.1 g of palladium-charcoal (10%). The air was displaced with hydrogen and the mixture was shaken for 8 h at room temperature. The progress of the reaction was monitored by TLC (petroleum ether/ethyl acetate, 4:1). After completion of the reaction, the palladium-charcoal was filtered and ethyl acetate was removed under vaccum to obtain the 46 and 47 in 99 % yields. 86
Methyl
3-hydroxy-4-(3-phenylpropyl)biphenyl-2-carboxylate
(46).
Hydrogenation of methyl 4-cinnamyl-3-hydroxybiphenyl-2-carboxylate (103 mg, 0.3 mmol), afforded 46 (102 mg, 99 %) as yellow liquid; 1H NMR (600 MHz, CDCl3) 10.79 (1H, s), 7.33 (2H, t, J = 7.8 Hz), 7.29-7.25 (4H, m), 7.20 (4H, t, J = 7.2 Hz), 7.16 (1H, t, J = 7.2 Hz), 6.72 (1H, d, J = 7.2 Hz), 3.45 (3H, s), 2.74-2.69 (4H, m), 2.01-1.96 (2H, m); 13C NMR (75 MHz, CDCl3) 171.8, 159.6, 142.9, 142.4, 142.3, 133.7, 129.6, 128.4, 128.2, 128.1, 127.5, 126.5, 125.6, 121.8, 111.6, 51.5, 35.7, 30.8, 29.6; IR (neat) 3440, 3050, 1660, 1436, 1276, 971, 767, 508 cm-1; HRMS m/z (M+) calcd for C23H22O3: 346.1569. Found: 346.1569. 3-hydroxy-N-(4-methoxyphenyl)-4-(3-phenylpropyl)biphenyl-2carboxamide
(47).
Hydrogenation
of
4-cinnamyl-3-hydroxy-N-(4-
methoxyphenyl)biphenyl-2-carboxamide (130 mg, 0.3 mmol) afforded 47 (129 mg, 99 %) as white solid: mp 142-144 oC; 1H NMR (600 MHz, CDCl3) 12.03 (1H, s), 7.55-7.49 (5H, m), 7.35-7.28 (5H, m), 7.23 (1H, t, J = 7.2 Hz), 6.98 (1H, s), 6.91 (2H, d, J = 9.0 Hz), 6.80-6.77 (3H, m), 3.78 (3H, s), 2.84-2.77 (4H, m), 2.11-2.05 (2H, m);
13
C NMR (150 MHz, CDCl3) 168.3, 159.4,
156.7, 142.4, 140.7, 138.5, 132.5, 130.6, 129.5, 129.26, 129.22, 128.4, 128.3, 128.2, 125.6, 121.9, 121.1, 114.3, 113.9, 55.3, 35.7, 30.8, 29.6; IR (KBr) 3430, 2940, 1608, 1512, 1231, 820, 590, 510 cm-1; HRMS m/z (M+) calcd for C29H27NO3: 437.1991. Found: 437.1990. General experimental procedure for the chromene (48-49) synthesis To a stirred solution of anhydrous benzene (4 mL), under an nitrogen atmosphere, were added above prepared compounds 3 or 14 (0.3 mmol) and 87
DDQ (7.0 mg, 10 mol%) was added. Then the reaction mixture was refluxed for 10-12 h until the completion of reaction. The solvent of the crude reaction mixture was partially removed in vacuo and the reaction mixture was purified by flash chromatography (Hexane/EtOAc) to give the desired chromenes 48 and 49. Methyl 2,7-diphenyl-2H-chromene-8-carboxylate (48). Reaction of methyl 4-cinnamyl-3-hydroxybiphenyl-2-carboxylate (103 mg, 0.3 mmol) and DDQ (7.0 mg, 10 mol%) afforded 48 (65 mg, 63 %) as yellow solid: mp 82-84 oC; 1H NMR (300 MHz, CDCl3) 7.45-7.42 (2H, m), 7.35-7.29 (8H, m), 7.07 (1H, d, J = 7.8 Hz), 6.88 (1H, d, J = 7.8 Hz), 6.54 (1H, d, J = 9.9 Hz), 6.01-6.02 (1H, m), 5.91 (1H, dd, J = 3.6, 9.9 Hz), 3.44 (3H, s); 13C NMR (75 MHz, CDCl3) 167.9, 150.3, 140.9, 140.5, 140.0, 128.5, 128.3, 128.1, 128.0, 127.5, 127.4, 126.4, 125.3, 123.0, 122.2, 121.7, 120.5, 79.9, 51.9; IR (KBr) 2980, 1675, 1588, 1520, 1435, 1225, 1150, 827, 610, 560 cm-1; HRMS m/z (M+) calcd for C23H18O3: 342.1256. Found: 342.1255. N-(4-methoxyphenyl)-2,7-diphenyl-2H-chromene-8-carboxamide Reaction
of
(49).
4-cinnamyl-3-hydroxy-N-(4-methoxyphenyl)biphenyl-2-
carboxamide (130 mg, 0.3 mmol) and DDQ (7.0 mg, 10 mol%) afforded 49 (84 mg, 65 %) as yellow solid: mp 153-155 oC; 1H NMR (300 MHz, CDCl3) 7.47-7.45 (4H, m), 7.34-7.24 (6H, m), 7.10-7.03 (3H, m), 6.92 (2H, d, J = 8.7 Hz), 6.74 (2H, d, J = 8.7 Hz), 6.63 (1H, d, J = 8.7 Hz), 6.00-5.93 (2H, m), 3.73 (3H, s); 13C NMR (75 MHz, CDCl3) 164.8, 156.4, 149.8, 141.1, 140.0, 139.8, 130.6, 128.6, 128.4, 128.3, 128.2, 127.6, 127.3, 126.9, 124.9, 124.8, 123.6, 122.7, 122.0, 120.8, 113.9, 76.6, 55.4; IR (KBr) 2960, 1660, 1580, 1523, 1438, 88
1220, 1140, 827, 754, 606, 550 cm-1; HRMS m/z (M+) calcd for C29H23NO3: 433.1678. Found: 433.1678.
Acknowledgement This research was supported by the Nano Material Technology Development Program of the Korean National Research Foundation (NRF) funded by the Korean Ministry of Education, Science, and Technology (Grant no. 2012-049675). This work was also supported by the Korean National Research Foundation (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A2A1A11052391).
89
2.2.5 References 1
Bringmann, G.; Gulder, T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563.
2
(a) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359. (b) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (c) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651.
3
(a) Suzuki, A.; Miyaura, N. Chem. Rev. 1995, 95, 2457. (b) Seechurn, C. C. C. J.; Kitching, M. O.; Colacot, T. J.; Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062.
4
(a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
5
(a) Dohi, T.; Ito, M.; Morimoto, K.; Iwata, M.; Kita, Y. Angew. Chem. Int. Ed. 2008, 47, 1301. (b) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837. (c) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (e) Kuhl, N.; Hopkinson, M. N.; WencelDelord, J.; Glorius, F. Angew. Chem. Int. Ed. 2012, 51, 10236.
6
(a) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng, S.-F.; Li, B.-J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044. (b) Shirakawa, E.; Itoh, K.-i.; Higashino, T. J. Am. Chem. Soc. 2010, 132, 15537. (c) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737. 90
7
(a) Yanagisawa, S.; Ueda, T.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673. (b) Stunder, A.; Curran, D. P. Angew. Chem. Int. Ed. 2011, 50, 5018. (c) Shirakawa, E.; Zhang, X.; Hayashi, T. Angew. Chem. Int. Ed. 2011, 50, 4671.
8
(a) Lee, N.-K.; Yun, S. Y.; Mamidipalli, P.; Salzman, R. M.; Lee, D.; Zhou, T.; Xia, Y. J. Am. Chem. Soc. 2014, 136, 4363. (b) Bandini, M. Chem. Soc. Rev. 2011, 40, 1358.
9
Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. Nature 2012, 490, 208.
10 (a) Zhu, S.; Xiao, Y.; Guo, Z.; Jiang, H. Org. Lett. 2013, 15, 898. (b) Zatolochnaya, O. V.; Gevorgyan, V. Org. Lett. 2013, 15, 2562. 11 (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238. (b) Corey, E. J.; Shibata, T.; Lee, T. W. J. Am. Chem. Soc. 2002, 124, 3808. (c) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122, 4243. 12 (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. (b) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25. (c) Mohamed, R. K.; Peterson, P. W.; Alabugin, I. V. Chem. Rev. 2013, 113, 7089. 13 Danheiser, R. L.; Carini, D. J.; Basak, A. J. Am. Chem. Soc. 1981, 103, 1605. 14 Yoshida, K.; Imamoto, T. J. Am. Chem. Soc. 2005, 127, 10470. 15 (a) Dötz, K. H. Angew. Chem. Int. Ed. 1975, 14, 644. (b) White, J. D.; Smits, H. Org. Lett. 2005, 7, 235. (c) Dötz, K. H. Angew. Chem. Int. Ed. 1984, 23, 587.
91
16 (a) Wulff, W. D.; Tang, P.-C.; McCallum, J. S. J. Am. Chem. Soc. 1981, 103, 7677. (b) Rawat, M.; Wulff, W. D. Org. Lett. 2004, 6, 329. (c) Lian, Y.; Wulff, W. D. J. Am. Chem. Soc. 2005, 127, 17162. 17 Dawande, S. G.; Kanchupalli, V.; Kalepu, J.; Chennamsetti, H.; Lad, B. S.; Katukojvala, S. Angew. Chem. Int. Ed. 2014, 53, 4076. 18 (a) Geirsson, J. K. F.; Johannesdottir, J. F. J. Org. Chem. 1996, 61, 7320. (b) Covarrubias-Zuniga, A.; Rios-Barrios, E. J. Org. Chem. 1997, 62, 5688. (c) Covarrubias-Zuniga, A.; Maldonado, L. A.; Rios-Barrios, E.; Gonzalez-Lucas, A. Synth. Commun. 1998, 28, 3461. (d) CovarrubiasZuniga, A.; Romero-Ortega, M.; Avila-Zarraga, J. G. Synthesis 2005, 527. (e) Covarrubias-Zuniga, A.; German-Sanchez, L. S.; Maldonado, L. A.; Romero-Ortega, M.; Avila-Zarraga, J. G. Synthesis 2005, 2293. (f) Terzidis, M. A.; Tsoleridis, C. A.; Stephanidou-Stephanatou, J.; Terzis, A.; Raptopoulou, C. P.; Psycharis, V. Tetrahedron 2008, 64, 11611. 19 (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957. (b) Lieby-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR Comb. Sci. 2006, 25, 432. (c) Bonne. D.; Coquerel, Y.; Constantieux, T.; Rodriguez. J. Tetrahedron: Asymmetry 2010, 21, 1085. (d) Bugaut, X.; Constantieux, T.; Coquerel, Y.; Rodriguez, J. Multicomponent Reactions in Organic Synthesis, Eds: Zhu, J.; Wang, Q.; Wang, M.-X. Wiley-VCH, Weinheim, 2014, Chapter 5, pp 109. 20 (a) Sarkar, S. D.; Studer, A. Angew. Chem. Int. Ed. 2010, 49, 9266. (b) Rong, Z.-Q.; Jia, M.-Q.; You, S.-L. Org. Lett. 2011, 13, 4080.
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21 (a) Lathrop, S. P.; Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (b) Marigo, M.; Bertelsen, S.; Landa, A.; Jorgensen, K. A. J. Am. Chem. Soc. 2006, 128, 5475. 22 Poudel, T. N.; Lee, Y. R. Org. Biomol. Chem. 2014, 12, 919.
93
2.3 Catalyst- and Solvent-Free Synthesis of Diverse 2Pyridones
2.3.1 Introduction 2-Pyridones are important compounds that are found in many active natural products and pharmaceuticals (Figure 1).1 These pyridone-based molecules have shown a broad range of biological properties such as antifungal,2 anti-HIV,3 antitumoral,4 anti-hepatitis B,5 MEK-1 inhibitors,6 receptor tyrosine kinase c-Kit inhibitors,7 anaplastic lymphoma kinase inhibitors,8 antimycobacterium tuberculosis agents,9 human rhinovirus 3C proteases10 and anti Pim-1 kinase activities.11
94
In addition, 2-pyridone derivatives are widely used as valuable building blocks for the synthesis of bioactive natural products12 and functional materials.13 They are also used as a versatile synthon for the synthesis of variety of other nitrogen-containing heterocyclic compounds like β-lactams, quinolizidines, pyridines, piperidines, and indolizidine alkaloids.14 Several synthetic methods have been developed for the synthesis of 2pyridones and their derivatives because of their importance and utility. 1525
The typical strategies involve Ni(0), Rh(I), or Ru(II)-catalyzed
cycloaddition of 1,6-diynes with isocyanates,15 ring-closing metathesis of α-amino acrylamides,16 t-BuOK-mediated condensation of enones with cyanoacetamides,17 tandem Blaise reaction of nitriles with propiolates, 18 FeCl3•6H2O-catalyzed
intramolecular
cascade
reaction
of
acetoacetanilide with 3-formyl chromone,19 CsF-catalyzed reaction of α,β-unsaturated diester chromones with aromatic amines, 20 Ni-catalyzed reaction of alkynes via azazirconacycles,21 1,4-addition reaction of 2(phenylsulfinyl)acetamido to α,β-unsaturated ketones followed by cyclization and elimination of sulfoxide,22 nucleophilic addition of malonic esters to alkynyl imines,23 intramolecular ketene trapping of functionalized
enamine-dioxinones,24
and
gold-catalyzed
cycloisomerization of N-alkenyl alkynylamides.25 Furthermore, other synthesis of 2-pyridones using 3-formyl chromones has been reported.26 Recently, various 2-pyridone-3-carboxylic acid derivatives have been also synthesized by the three-component reaction of 3-formyl chromone with Meldrum’s acid and primary amines.27 95
Although a number of methods for the synthesis of 2-pyridones have been developed, more environmentally benign and efficient approaches are still needed to reduce the use of expensive metal catalysts, solvents, and
toxic
reagents.
Among
these,
catalyst-
and
solvent
free
multicomponent reactions are preferred over the conventional synthetic methods.28 As part of an ongoing study of catalyst- and solvent-free multicomponent reactions as a powerful means of synthesizing heterocycles and novel compounds, I describe catalyst- and solvent free thermal multicomponent reactions of commercially available 4-oxo-4Hchromene-3-carbaldehydes with 1,3-diketoesters and anilines (or amines) for the synthesis of structurally diverse 2-pyridone derivatives (Scheme 1). This is the first example of the one-pot synthesis of a variety of 2pyridone derivatives under mild conditions without a catalyst and solvent.
96
2.3.2 Results and Discussion To optimize the reaction conditions, the reaction of 4-oxo-4H-chromene3-carbaldehyde (1a) with dimethyl malonate (2a) and aniline (3a), under catalyst- and solvent-free conditions at various temperatures was first investigated (Table 1). When the reaction was performed at room temperature for 24 h, products were not formed (entry 1). On the other hand, at 40 °C for 24 h, product 4a was obtained in 15% yield (entry 2). The reaction temperature was increased gradually to reduce the reaction time. As expected, the desired product was obtained in increased yield with reduced reaction time (entries 3-5). The optimal yield (78%) was obtained at 100 °C for 8 h. However, increasing the reaction temperature to 120 oC for 8 h failed to improve the yield. Moreover, when the reaction was performed under microwave irradiation at 100 oC for 1 h using 300 W power, the prodcut 4a was obtained in only 15% yield. The structure of 4a was assigned by its spectroscopic data and a comparison with structurally related compounds.19 The 1H NMR spectrum of 4a revealed two vinylic protons of a 2-pyridone ring at δ = 8.58 (d, J = 2.1 Hz) and 8.18 (d, J = 2.1 Hz) ppm as the two doublets due to long range coupling and a methoxy peak at 3.88 ppm as a singlet.
97
Under the optimized reaction conditions, the generality of this thermal multicomponent reaction was further explored by employing different 4oxo-4H-chromene-3-carbaldehydes, 1,3-diketoesters, and aniline (Table 2). The reaction of 1a with diethyl malonate (2b) and aniline (3a) at 100 o
C for 8 h provided 4b in 73% yield. The reactions were also successful
using the other 4-oxo-4H-chromene-3-carbaldehydes 1b-1g bearing electron-donating or electron-withdrawing groups on the aromatic ring. For example, the treatment of 1b-1e bearing electron-donating groups with 2a or 2b and 3a provided the desired products 4c-4f in 77, 75, 73 and 74% yield, respectively. The reactions of 4-oxo-4H-chromene-3carbaldehydes 1f and 1g with electron-withdrawing groups with 2b and 3a afforded products 4g and 4h in 73 and 75% yield, respectively. Furthermore, 4-oxo-4H-chromene-3-carbaldehyde 1h containing both 98
99
electron-donating and -withdrawing groups on aromatic ring was also transformed to product 4i in 71% yield. With other 1,3-diketoesters, such as dibenzyl malonate (2c) and methyl acetoacetate (2d), the desired products 4j and 4k were also produced in 76 and 78% yield, respectively. Interestingly, reaction of 4-oxo-4H-benzo[h]chromene-3-carbaldehyde (1i) with 2b and 3a provided hydroxyl naphthoyl substituted product 4l in 74% yield. Additional reactions of 1,3-diketoesters such as ethyl 3-oxo-3phenylpropanoate (2e), ethyl 3-(4-methoxyphenyl)-3-oxopropanoate (2f) and ethyl 3-(4-nitrophenyl)-3-oxopropanoate (2g) also afforded the desired products 4m-4o in 68, 65 and 64% yield, respectively. These reactions provide a rapid route for the synthesis of various 2-pyridone derivatives as a one-pot procedure. The multicomponent reaction with various substituted anilines bearing electron-donating and -withdrawing groups was next explored. The results are listed in Table 3. The reaction of 1a with 2b and 3b or 3c bearing electron donating-groups provided the desired products 5a (72%) and 5b (76%). Reactions of 1a with 2b and diamine 3d or amino benzyl alcohol 3e provided the desired products 5c and 5d in 72 and 68% yield, respectively. However, the reaction of 4-aminobenzenethiol or 3-amino phenol was not successful, instead inseparable mixtures were obtained. Further reactions of anilines 3f-3k bearing electron-withdrawing groups such as halo, nitro, cyano, or carbonyl substituents on the benzene ring afforded 5e-5k in the range of 41-77% yield. However, the reaction of 1a and 2b with 4-nitroaniline or 4-amino acetophenone were unsuccessful. The use of combinations of 1b or 1g, and 2b with 4-isopropylaniline (3c) 100
101
or 4-fluoroaniline (3i) provided the desired products 5l-5n in the range of 69-78% yield. Considering the general applicability of the multicomponent reaction by employing different anilines as the component, this study tested the possibility of using primary aliphatic amines, which will lead to the formation of other types of 2-pyridone derivatives (Table 4). Reactions of
1a, 1b or 1g with 2a-2c in combination of 2-phenylethylamine (3l) provided products 6a-6e in the range of 72-78% yield. With tryptamine (3m), the desired product 6f was obtained in 65% yield. Moreover, reaction of 1a with 2b and chiral amine L-(-)-α-methyl benzylamine (3n) 102
provided desired product 6g in 67% yield. Interestingly, reaction of 6nitro-4-oxo-4H-chromene-3-carbaldehyde
(1j)
with
2b
and
2-
phenylethylamine (3l) provided different product 6h in 58% yield.
Scheme 2 presents the proposed mechanism for the formation of 4a via domino reaction. Knoevenagel condensation between 1a and 2a first takes place to form intermediate 7, which then undergoes Michael addition through nucleophilic attack of aniline (3a) to provide another intermediate 8. Ring opening of 8 followed by ring closure affords the final product 4a.
103
2.3.3 Conclusions A highly sustainable and efficient multicomponent domino reaction of readily
available
4-oxo-4H-chromene-3-carbaldehydes
with
1,3-
ketoesters and anilines or primary aliphatic amines was developed for the synthesis of substituted 2-pyridone derivatives in good yield. The catalyst- and solvent-free multicomponent reaction readily allowed the synthesis of novel and diverse functionalized 2-pyridone derivatives, which could be used widely for the synthesis of bioactive natural products and pharmaceuticals.
104
2.3.4 Experimental All experiments were carried out under open air without inert gases protection. 3-formyl chromones (1a-1i), anilines and amines (3a-3k) and Ketoesters (2a2g) were purchased from Sigma- Aldrich. Merck precoated silica gel plates (Art. 5554) with a fluorescent indicator were used for analytical TLC. Flash column chromatography was performed using silica gel 9385 (Merck). Melting points were determined with micro-cover glasses on a Fisher-Johns apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-VNS or DPX (300 MHz) spectrometer in CDCl3 or DMSO-d6 using 7.24 or 2.5 ppm as the solvent chemical shift respectively.
13
C NMR spectra were recorded on a
Varian-VNS or DPX (75 MHz) spectrometer in CDCl3 or DMSO-d6 using 77.0 or 39.5 ppm as the solvent chemical shift respectively. IR spectra were recorded on a JASCO FTIR 5300 spectrophotometer. High resolution mass (HRMS) were obtained with a JEOL JMS-700 spectrometer at the Korea Basic Science Institute. Optical activity was measured using Atago Automatic Polarimeter AP-100. General procedure for the synthesis of benzoyl substituted 2-pyridone derivatives (4-6) To a solution of ketoesters 2a-2g (1.0 mmol) and anilines 3a-3k (1.0 mmol), 1.0 mmol of 3-formyl chromone (1a-1i) was added. Each reaction mixture was heated at 100 °C for 8-12 hours. Then the reaction mixture was subjected for crystallization using ethanol or mixture of hexane and ethylacetate (9:1) as solvent. However, some liquid compounds 4l, 4m, 5d, 5k and 6g were purified
105
by column chromatography using the mixture of hexane and ethyl acetate (5:1) as eluting solvent. Characterization data for all compounds 4-6 are as follows: Methyl
5-(2-hydroxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-
carboxylate (4a). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 186-188 oC. Yield: 78%; 1H NMR (300 MHz, CDCl3) 11.31 (1H, s), 8.58 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.57-7.45 (5H, m), 7.38 (2H, d, J = 7.8 Hz), 7.04 (1H, d, J = 7.8 Hz), 6.92 (1H, t, J = 7.8 Hz), 3.88 (3H, s);
13
C NMR (75 MHz,
CDCl3) 194.2, 164.6, 162.4, 158.3, 146.9, 144.4, 139.6, 136.5, 131.3, 129.5, 129.5, 126.3, 120.6, 119.2, 118.8, 118.5, 116.0, 52.6; IR (KBr) 3354, 3071, 1698, 1598, 1524, 1249, 787, 509 cm-1; HRMS m/z (M+) calcd for C20H15NO5: 349.0950. Found: 349.0948. Ethyl
5-(2-hydroxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-
carboxylate (4b). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 96-98 oC. Yield: 73%; 1H NMR (300 MHz, CDCl3) 11.24 (1H, s), 8.50 (1H, d, J = 2.1 Hz), 8.12 (1H, d, J = 2.4 Hz), 7.52-7.31 (7H, m), 6.97 (1H, d, J = 7.8 Hz), 6.86 (1H, t, J = 7.5 Hz), 4.29 (2H, q, J = 6.9 Hz), 1.29 (3H, t, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) 194.3, 164.1, 162.4, 158.4, 146.7, 144.1, 139.5, 136.5, 131.3, 129.5, 129.4, 126.3, 121.0, 119.2, 118.8, 118.4, 115.9, 61.6, 14.1; IR (KBr) 3342, 3072, 1680, 1586, 1495, 1289, 792, 520 cm-1; HRMS m/z (M+) calcd for C21H17NO5: 363.1107. Found: 363.1104. Methyl
5-(2-hydroxy-5-methylbenzoyl)-2-oxo-1-phenyl-1,2-dihydropyri-
dine-3-carboxylate (4c). The title compound was prepared according to the 106
general procedure. The product was obtained as a white solid, mp 167-169 oC. Yield: 77%; 1H NMR (300 MHz, CDCl3) 11.07 (1H, s), 8.57 (1H, d, J = 2.1 Hz), 8.17 (1H, d, J = 2.4 Hz), 7.49-7.28 (7H, m), 7.93 (1H, d, J = 7.8 Hz), 3.87 (3H, s), 2.27 (3H, s); 13C NMR (75 MHz, CDCl3) 194.1, 164.6, 160.2, 158.3, 146.8, 144.5, 139.6, 137.5, 131.1, 129.5, 129.4, 128.3, 126.3, 120.4, 118.5, 118.2, 116.1, 52.5, 20.5; IR (KBr) 3342, 3052, 1686, 1570, 1514, 1268, 781, 507 cm-1; HRMS m/z (M+) calcd for C21H17NO5: 363.1107. Found: 363.1106. Ethyl 5-(5-ethyl-2-hydroxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3carboxylate (4d). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 157-159 oC. Yield: 75%; 1H NMR (300 MHz, CDCl3) 11.10 (1H, s), 8.57 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.51-7.44 (3H, m), 7.38-7.32 (4H, m), 6.95 (1H, d, J = 7.8 Hz), 4.35 (2H, q, J = 7.2 Hz), 2.58 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz), 1.19 (3H, t, J = 7.2 Hz);
13
C NMR (75 MHz, CDCl3) 194.2, 164.0,
160.5, 158.4, 146.8, 144.2, 139.7, 136.5, 134.8, 129.9, 129.5, 129.4, 126.3, 120.8, 118.6, 118.2, 116.0, 61.6, 27.8, 15.6, 14.2; IR (KBr) 3337, 3075, 1686, 1587, 1504, 1281, 787, 512 cm-1; HRMS m/z (M+) calcd for C23H21NO5: 391.1420. Found: 391.1419. Ethyl
5-(2-hydroxy-5-isopropylbenzoyl)-2-oxo-1-phenyl-1,2-dihydropyri-
dine-3-carboxylate (4e). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 118-120 oC. Yield: 73%; 1H NMR (300 MHz, CDCl3) 11.12 (1H, s), 8.62 (1H, d, J = 2.1 Hz), 8.23 (1H, d, J = 2.4 Hz), 7.52-7.41 (7H, m), 7.03-6.96 (1H, m), 4.36 (2H, q, J = 6.9 Hz), 2.93-2.86 (1H, m), 1.36 (3H, t, J = 6.9 Hz), 1.25 (6H, d, J = 8.7 107
Hz);
13
C NMR (150 MHz, CDCl3) 194.2, 163.9, 160.4, 158.4, 147.0, 144.2,
139.6, 139.4, 135.3, 129.5, 129.5, 128.5, 126.3, 120.6, 118.5, 118.1, 115.9, 61.5, 33.0, 23.9, 23.9, 14.2; IR (KBr) 3347, 3071, 1694, 1584, 1514, 1290, 787, 517cm-1; HRMS m/z (M+) calcd for C24H23NO5: 405.1576. Found: 405.1573. Ethyl
5-(2-hydroxy-5-methoxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyri-
dine-3-carboxylate (4f). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 137-139 oC. Yield: 74%; 1H NMR (600 MHz, CDCl3) 10.84 (1H, s), 8.59 (1H, d, J = 3.0 Hz), 8.20 (1H, d, J = 3.0 Hz), 7.50-7.44 (3H, m), 7.38-7.36 (2H, m), 7.19 (1H, dd, J = 2.4, 8.4 Hz), 7.00-6.97 (2H, m), 4.35 (2H, q, J = 7.2 Hz), 3.73 (3H, s), 1.34 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 193.8, 164.1, 158.4,
156.6, 151.8, 146.8, 144.0, 139.6, 129.6, 129.5, 126.4, 124.4, 121.0, 119.8, 118.0, 115.9, 113.8, 61.6, 55.9, 14.2; IR (KBr) 3345, 2953, 1688, 1467, 1339, 1223, 1022, 781, 583 cm-1; HRMS m/z (M+) calcd for C22H19NO6: 393.1212. Found: 393.1209. Ethyl 5-(5-fluoro-2-hydroxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyridine3-carboxylate (4g). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 135-137 oC. Yield: 73%; 1H NMR (300 MHz, CDCl3) 10.92 (1H, s), 8.53 (1H, d, J = 2.1 Hz), 8.17 (1H, d, J = 2.1 Hz), 7.50-7.46 (3H, m), 7.37-7.34 (2H, m), 7.25-7.18 (2H, m), 7.01-6.97 (1H, m), 4.34 (2H, q, J = 6.9 Hz), 1.33 (3H, t, J = 6.9 Hz);
13
C
NMR (150 MHz, CDCl3) 193.3, 164.0, 158.4, 158.3, 154.7 (d, J = 239.1 Hz), 146.8, 143.7, 139.5, 129.6, 129.6, 126.4, 124.0 (d, J = 22.9 Hz), 121.3, 120.2 (d, J = 6.9 Hz), 118.1 (d, J = 5.7 Hz), 116.2 (d, J = 22.5 Hz), 115.5, 61.7, 14.1; 108
19
F NMR (564 MHz, CDCl3) -124.12 – -124.16 (1F,m); IR (KBr) 3444, 3080,
1678, 1589, 1437, 1286, 950, 760, 519 cm-1; HRMS m/z (M+) calcd for C21H16FNO5: 381.1013. Found: 381.1015. Ethyl 5-(5-bromo-2-hydroxybenzoyl)-2-oxo-1-phenyl-1,2-dihydropyridine3-carboxylate (4h). The title compound was prepared according to the general procedure. The product was obtained as a brown solid, mp 154-156 oC. Yield: 75%; 1H NMR (300 MHz, CDCl3) 11.10 (1H, s), 8.53 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 2.1 Hz), 7.68 (1H, d, J = 2.4 Hz), 7.57-7.45 (4H, m), 7.37 (2H, d, J = 7.8 Hz), 6.95 ( 1H, d, J = 8.1 Hz), 4.35 (2H, q, J = 6.9 Hz), 1.35 (3H, t, J = 6.9 Hz);
13
C NMR (75 MHz, CDCl3) 193.1, 163.8, 161.1, 158.2, 147.0,
143.6, 139.5, 138.9, 133.4, 129.6, 129.5, 126.3, 121.3, 120.8, 120.0, 115.3, 110.7, 61.7, 14.1; IR (KBr) 3350, 3097, 1687, 1582, 1514, 1290, 787, 513 cm-1; HRMS m/z (M+) calcd for C21H16BrNO5: 441.0212. Found: 441.0209. Ethyl
5-(5-chloro-2-hydroxy-4-methylbenzoyl)-2-oxo-1-phenyl-1,2-
dihydropyridine-3-carboxylate (4i).
The title compound was prepared
according to the general procedure. The product was obtained as a yellow solid, mp 185-187 oC. Yield: 71%; 1H NMR (300 MHz, CDCl3) 11.13 (1H, s), 8.51 (1H, d, J = 2.1 Hz), 8.15 (1H, d, J = 2.1 Hz), 7.51-7.43 (4H, m), 7.37-7.34 (2H, m), 6.89 (1H, s), 4.33 (2H, q, J = 6.9 Hz), 2.33 (3H, s), 1.33 (3H, t, J = 6.9 Hz); C NMR (75 MHz, CDCl3) 192.8, 163.8, 160.6, 158.3, 146.7, 145.7, 143.7,
13
139.5, 130.7, 129.5, 129.4, 126.3, 124.4, 121.0, 120.7, 117.5, 115.5, 61.6, 20.7, 14.1; IR (KBr) 3340, 3091, 1675, 1584, 1517, 1280, 771, 514 cm-1; HRMS m/z (M+) calcd for C22H18ClNO5: 411.0874. Found: 411.0872.
109
Benzyl
5-(2-hydroxy-5-methylbenzoyl)-2-oxo-1-phenyl-1,2-dihydropyri-
dine-3-carboxylate (4j). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 134-136 oC. Yield: 76%; 1H NMR (300 MHz, CDCl3) 11.11 (1H, s), 8.58 (1H, d, J = 2.1 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.50-7.30 (12H, m), 6.95 (1H, d, J = 8.1 Hz), 5.34 (2H, s), 2.25 (3H, s);
13
C NMR (75 MHz, CDCl3) 194.2, 163.8, 160.4,
158.3, 146.9, 144.4, 139.6, 137.6, 135.6, 131.1, 129.6, 129.5, 128.5, 128.3, 128.1, 128.1, 126.3, 120.4, 118.6, 118.2, 116.0, 67.1, 20.5; IR (KBr) 3320, 3084, 1680, 1583, 1517, 1271, 760, 508 cm-1; HRMS m/z (M+) calcd for C27H21NO5: 439.1420. Found: 439.1417. 3-acetyl-5-(2-hydroxy-5-methylbenzoyl)-1-phenylpyridin-2(1H)-one (4k). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 115-117 oC. Yield: 78%; 1H NMR (300 MHz, CDCl3) 11.13 (1H, s), 8.53 (1H, d, J = 2.1 Hz), 8.21 (1H, d, J = 2.4 Hz), 7.53-7. 47 (3H, m), 7.38 (2H, d, J = 7.8 Hz), 7.29 (2H, d, J = 7.8 Hz), 6.92 (1H, d, J = 8.1 Hz), 2.67 (3H, s), 2.26 (3H, s);13C NMR (75 MHz, CDCl3)
196.4, 194.5, 160.4, 160.4, 146.9, 143.2, 139.5, 137.6, 131.2, 129.6, 129.6, 128.4, 126.8, 126.3, 118.5, 118.1, 116.8, 30.9, 20.5; IR (KBr) 3330, 3081, 1685, 1580, 1508, 1270, 781, 516 cm-1; HRMS m/z (M+) calcd for C21H17NO4: 347.1158. Found: 347.1158. Ethyl
5-(1-hydroxy-2-naphthoyl)-2-oxo-1-phenyl-1,2-dihydropyridine-3-
carboxylate (4l). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 74%; 1H NMR (600 MHz, CDCl3) 13.35 (1H, s), 8.61 (1H, d, J = 3.0 Hz), 8.45 (1H, d, J = 110
8.4 Hz), 8.20 (1H, d, J = 3.0 Hz), 7.74 (1H, d, J = 8.4 Hz), 7.63 (1H, t, J = 7.4 Hz), 7.54-7.48 (4H, m), 7.45 (1H, t, J = 7.2 Hz), 7.40 (2H, d, J = 7.2 Hz), 7.28 (1H, d, J = 9.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 1.35 (3H, t, J = 7.2 Hz);13C NMR (150 MHz, CDCl3) 194.1, 164.2, 163.5, 158.4, 146.5, 144.2, 139.7, 137.2, 130.6, 129.5 (*3C), 129.4, 127.5, 126.4 (*2C), 126.3, 125.2, 124.4, 121.0, 118.6, 116.2, 111.7, 61.6, 14.2; IR (neat) 3365, 3060, 2980, 1685, 1589, 1534, 1233, 1143, 711, 581 cm-1; HRMS m/z (M+) calcd for C25H19NO5: 413.1263. Found: 413.1261. 3-Benzoyl-5-(2-hydroxybenzoyl)-1-phenylpyridin-2(1H)-one (4m). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 68%; 1H NMR (600 MHz, CDCl3) 11.35 (1H, s), 8.19 (1H, d, J = 3.0 Hz), 8.14 (1H, d, J = 3.0 Hz), 7.87 (2H, d, J = 7.2 Hz), 7.62 (1H, dd, J = 1.8, 7.8 Hz), 7.55 (1H, t, J = 7.8 Hz), 7.51-7.48 (3H, m), 7.46-7.41 (5H, m), 7.05 (1H, d, J = 8.4 Hz), 6.92 (1H, td, J = 1.2, 8.4 Hz); 13C NMR (150 MHz, CDCl3) 194.5, 193.0, 162.5, 159.3, 145.7, 141.2, 139.5, 136.6, 136.6, 133.5, 131.4, 130.3, 129.6, 129.5, 129.5, 128.5, 126.3, 119.2, 118.9, 118.5, 116.8; IR (neat) 3312, 3059, 1930, 1661, 1593, 1534, 1534, 1233, 1157, 750, 696 cm-1; HRMS m/z (M+) calcd for C25H17NO4: 395.1158. Found: 395.1159. 5-(2-Hydroxybenzoyl)-3-(4-methoxybenzoyl)-1-phenylpyridin-2(1H)-one (4n). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 170-172 oC. Yield: 65%; 1H NMR (600 MHz, CDCl3) 11.34 (1H, s), 8.15 (1H, d, J = 3.0 Hz), 8.07 (1H, d, J = 3.0 Hz), 7.87-7.85 (2H, m), 7.61 (1H, dd, J = 1.2, 7.8 Hz), 7.49-7.47 (3H, 111
m), 7.45-7.41 (3H, m), 7.03 (1H, d, J = 7.8 Hz), 6.92-6.89 (3H, m), 3.82 (3H, s);
C NMR (150 MHz, CDCl3) 194.6, 191.4, 164.0, 162.5, 159.3, 145.3,
13
140.5, 139.5, 136.5, 132.1, 131.4, 130.9, 129.5, 129.4, 129.3, 126.3, 119.2, 118.8, 118.6, 116.7, 113.8, 55.5; IR (KBr) 3365, 3054, 1644, 1496, 1237, 1020, 757, 615 cm-1; HRMS m/z (M+) calcd for C26H19NO5: 425.1263. Found: 425.1262. 5-(2-Hydroxybenzoyl)-3-(4-nitrobenzoyl)-1-phenylpyridin-2(1H)-one (4o). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 201-203 oC. Yield: 64%; 1H NMR (600 MHz, CDCl3) 11.31 (1H, s), 8.36 (1H, d, J = 2.4 Hz), 8.27-8.24 (3H, m), 7.93 (2H, d, J = 8.4 Hz), 7.61 (1H, d, J = 7.8 Hz), 7.53-7.45 (4H, m), 7.39 (2H, d, J = 7.8 Hz), 7.07 (1H, d, J = 8.4 Hz), 6.94 (1H, t, J = 7.8 Hz); 13C NMR (150 MHz, CDCl3) 194.2, 191.8, 162.7, 159.4, 150.0, 146.9, 143.3, 142.1, 139.1, 136.8, 131.3, 129.8 (*2C), 129.7 (*3C), 128.3, 126.2 (*2C), 123.6 (*2C), 119.3, 119.0, 118.4, 117.2; IR (KBr) 3366, 3055, 1651, 1584, 1416, 1331, 1237, 702 cm-1; HRMS m/z (M+) calcd for C25H16N2O6: 440.1008. Found: 440.1008. Ethyl
5-(2-hydroxybenzoyl)-1-(3-methoxyphenyl)-2-oxo-1,2-dihydropyri-
dine-3-carboxylate (5a). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 138-140 oC. Yield: 72%; 1H NMR (300 MHz, CDCl3) 11.31 (1H, s), 8.55 (1H, d, J = 2.1 Hz), 8.16 (1H, d, J = 2.4 Hz), 7.57-7.46 (2H, m), 7.38 (1H, d, J = 8.4 Hz), 7.056.89 (5H, m), 4.35 (2H, q, J = 6.9 Hz), 3.80 (3H, s), 1.34 (3H, t, J = 6.9 Hz); C NMR (75 MHz, CDCl3) 194.3, 164.1, 162.5, 160.3, 158.3, 146.7, 144.0,
13
112
140.7, 136.5, 131.3, 130.3, 121.2, 119.2, 118.8, 118.5, 118.4, 115.9, 115.5, 112.3, 61.7, 55.6, 14.2; IR (KBr) 3350, 3071, 1687, 1581, 1518, 1290, 787, 506 cm-1; HRMS m/z (M+) calcd for C22H19NO6: 393.1212. Found: 393.1208. Ethyl 5-(2-hydroxybenzoyl)-1-(4-isopropylphenyl)-2-oxo-1,2-dihydropyridine-3-Carboxylate (5b). The title compound was prepared according to the general procedure. The product was obtained as yellow solid, mp 68-70 oC. Yield: 76%; 1H NMR (300 MHz, CDCl3) 11.27 (1H, s), 8.51 (1H, d, J = 2.1 Hz), 8.12 (1H, d, J = 2.4 Hz), 7.51 (1H, d, J = 8.1 Hz), 7.43 (1H, t, J = 8.1 Hz), 7.29-7.21 (4H, m), 6.98 (1H, d, J = 8.1 Hz), 6.86 (1H, t, J = 8.1 Hz), 4.29 (2H, q, J = 6.9 Hz), 2.93-2.84 (1H, m), 1.29 (3H, t, J = 6.9 Hz), 1.16 (6H, d, J = 8.7 Hz);
13
C NMR (150 MHz, CDCl3) 194.3, 164.2, 162.4, 158.5, 150.4, 146.9,
144.1, 137.2, 136.5, 131.4, 127.6, 126.1, 121.0, 119.2, 118.8, 118.5, 115.8, 61.7, 33.8, 23.9, 23.8, 14.2; IR (KBr) 3340, 3078, 1682, 1540, 1521, 1267, 788, 509 cm-1; HRMS m/z (M+) calcd for C24H23NO5: 405.1576. Found: 405.1574. Ethyl 1-(4-aminophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine3-carboxylate (5c). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 153-155 oC. Yield: 72%; 1H NMR (600 MHz, CDCl3) 11.35 (1H, s), 8.52 (1H, d, J = 3.0 Hz), 8.14 (1H, d, J = 3.0 Hz), 7.54 (1H, d, J = 8.4 Hz), 7.47 (1H, t, J = 8.4 Hz), 7.07 (2H, d, J = 8.4 Hz), 7.02 (1H, d, J = 8.4 Hz), 6.90 (1H, t, J = 7.8 Hz), 6.65 (2H, d, J = 8.4 Hz), 4.33 (2H, q, J = 7.2 Hz), 3.94 (2H, brs), 1.33 (3H, t, J = 7.2 Hz); C NMR (150 MHz, CDCl3) 194.2, 164.1, 162.1, 158.8, 147.7, 147.4, 143.7,
13
136.2, 131.3, 129.8, 127.0, 120.5, 119.1, 118.6, 118.6, 115.5, 114.9, 61.4, 14.1;
113
IR (KBr) 3356, 3063, 2979, 1730, 1610, 1274, 1155, 833, 756, 519 cm-1; HRMS m/z (M+) calcd for C21H18N2O5: 378.1216. Found: 378.1215. Ethyl
5-(2-hydroxybenzoyl)-1-(2-(hydroxymethyl)phenyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (5d). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 68%; 1H NMR (600 MHz, CDCl3) 11.28 (1H, s), 8.61 (1H, d, J = 1.2 Hz), 8.08 (1H, d, J = 2.4 Hz), 7.58 (1H, d, J = 8.4 Hz), 8.08 (1H, d, J = 7.2 Hz), 7.47-7.44 (2H, m), 7.40 (1H, t, J = 7.8 Hz), 7.15 (1H, d, J = 7.8 Hz), 7.01 (1H, d, J = 8.4 Hz), 6.87 (1H, t, J = 7.8 Hz), 4.43 (2H, d, J = 2.4 Hz), 4.32 (2H, q, J = 7.2 Hz), 3.09 (1H, brs), 1.33 (3H, t, J = 7.2 Hz);
13
C NMR (150
MHz, CDCl3) 194.2, 163.8, 162.3, 159.1, 147.4, 144.6, 138.3, 137.3, 136.5, 131.5, 130.4, 130.3, 129.3, 127.1, 120.8, 119.2, 118.7, 118.6, 116.0, 61.7, 61.4, 14.1; IR (neat) 3429, 3066, 2980, 1722, 1600, 1532, 1229, 1022, 750 cm-1; HRMS m/z (M+) calcd for C22H19NO6: 393.1212. Found: 393.1212. Ethyl
1-(3-bromophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyri-
dine-3-carboxylate (5e). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 148-150 oC. Yield: 74%; 1H NMR (300 MHz, CDCl3) 11.22 (1H, s), 8.51 (1H, d, J = 2.1 Hz), 8.11 (1H, d, J = 2.4 Hz), 7.54-7.43 (4H, m), 7.36-7.28 (2H, m), 6.99 (1H, d, J = 8.4 Hz), 6.89 (1H, t, J = 8.1 Hz), 4.31 (2H, q, J = 6.9 Hz), 1.31 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) 194.0, 163.7, 162.2, 158.0, 146.2, 144.1, 140.4, 136.4, 132.5, 131.2, 130.6, 129.6, 125.1, 122.6, 121.0, 119.1, 118.7, 118.4, 116.1, 61.6, 14.0; IR (KBr) 3345, 3045, 1665, 1590, 1521, 1280, 771,
114
509 cm-1; HRMS m/z (M+) calcd for C21H16BrNO5: 441.0212. Found: 441.0210. Ethyl 1-(3-fluorophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine3-carboxylate (5f). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 143-145 oC. Yield: 75%; 1H NMR (300 MHz, CDCl3) 11.24 (1H, s), 8.52 (1H, d, J = 2.1 Hz), 8.13 (1H, d, J = 2.4 Hz), 7.55-7.40 (3H, m), 7.15 (3H, d, J = 7.8 Hz), 7.01 ( 1H, d, J = 8.4 Hz), 6.90 (1H, t, J = 7.5 Hz), 4.31 (2H, q, J = 6.9 Hz), 1.32 (3H, t, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) 194.1, 163.9, 162.5 (d, J = 248.4 Hz), 162.5, 158.1, 146.2, 144.1, 140.6 (d, J = 10.3 Hz), 136.6, 131.3, 130.9 (d, J = 9.1 Hz), 122.2 (d, J = 3.4 Hz), 121.3, 119.2, 118.8, 118.4, 116.7 (d, J = 20.7 Hz), 116.2, 114.5 (d, J = 24.1 Hz), 61.7, 14.1; 19F NMR (564 MHz, CDCl3) 111.25 – -111.30 (1F, m); IR (KBr) 3360, 3089, 1685, 1596, 1527, 1290, 761, 512 cm-1; HRMS m/z (M+) calcd for C21H16FNO5: 381.1013. Found: 381.1011. Ethyl 5-(2-hydroxybenzoyl)-1-(3-nitrophenyl)-2-oxo-1,2-dihydropyridine3-carboxylate (5g). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 179-181 oC. Yield: 52%; 1H NMR (600 MHz, CDCl3) 11.22 (1H, s), 8.55 (1H, d, J = 3.0 Hz), 8.29-8.28 (2H, m), 8.17 (1H, d, J = 3.0 Hz), 7.78-7.76 (1H, m), 7.69 (1H, t, J = 9.0 Hz), 7.55 ( 1H, dd, J = 1.2, 7.8 Hz), 7.50-7.47 (1H, m), 7.02 (1H, d, J = 8.4 Hz), 6.91 (1H, t, J = 7.2 Hz), 4.32 (2H, q, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz); C NMR (150 MHz, CDCl3) 194.0, 163.5, 162.4, 158.0, 148.5, 145.7, 144.4,
13
140.2, 136.7, 132.8, 131.3, 130.5, 124.3, 122.1, 121.3, 119.3, 118.8, 118.3,
115
116.7, 61.8, 14.1; IR (KBr) 3430, 3065, 2970, 1720, 1602, 1522, 1225, 1020, 755 cm-1; HRMS m/z (M+) calcd for C21H16N2O7: 408.0958. Found: 409.0958. Ethyl 1-(4-fluorophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine3-carboxylate (5h). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 170-172 oC. Yield: 77%; 1H NMR (300 MHz, CDCl3) 11.28 (1H, s), 8.54 (1H, d, J = 2.1 Hz), 8.13 (1H, d, J = 2.4 Hz), 7.56-7.46 (2H, m), 7.39-7.34 (2H, m), 7.16 (2H, t, J = 7.8 Hz), 7.03 (1H, d, J = 7.8 Hz) , 6.91 (1H, t, J = 7.8 Hz), 4.34 (2H, q, J = 6.9 Hz), 1.33 (3H, t, J = 6.9 Hz);
13
C NMR (150 MHz, CDCl3) 194.3, 164.0,
162.7 (d, J = 248.2 Hz), 162.6, 158.4, 146.5, 144.2, 136.6, 135.5 (d, J = 3.4 Hz), 131.3, 128.4 (d, J = 7.9 Hz), 121.2, 119.2, 118.9, 118.4, 116.6 (d, J = 22.9 Hz), 116.1, 61.8, 14.2;
19
F NMR (564 MHz, CDCl3) -111.96 – -112.01 (1F,
m); IR (KBr) 3360, 3083, 1687, 1584, 1528, 1275, 786, 517 cm-1; HRMS m/z (M+) calcd for C21H16FNO5: 381.1013. Found: 344.1013. Benzyl
1-(4-fluorophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyri-
dine-3-carboxylate (5i). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 148-150 oC. Yield: 73%; 1H NMR (300 MHz, CDCl3) 11.29 (1H, s), 8.58 (1H, d, J = 2.1 Hz), 8.15 (1H, d, J = 2.4 Hz), 7.55-7.48 (2H, m), 7.43-7.28 (7H, m), 7.18 (2H, t, J = 7.8 Hz), 7.05 (1H, d, J = 7.8 Hz), 6.91 (1H, t, J = 7.8 Hz), 5.34 (2H, s); C NMR (150 MHz, CDCl3) 194.1, 163.8, 162.7 (d, J = 248.2 Hz), 162.5,
13
158.3, 146.8, 144.6, 136.6, 135.4 (d, J = 4.6 Hz), 131.3, 128.5, 128.4, 128.4, 128.2, 128.1, 120.6, 119.2, 118.9, 118.4, 116.6 (d, J = 22.9 Hz), 116.0, 67.2; 19
F NMR (564 MHz, CDCl3) -111.89 – -111.93 (1F, m); IR (KBr) 3350, 116
3071, 1695, 1590, 1507, 1268, 788, 507 cm-1; HRMS m/z (M+) calcd for C26H18FNO5: 443.1169. Found: 443.1167. Ethyl 1-(4-cyanophenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine3-carboxylate (5j). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 188-190 oC. Yield: 41%; 1H NMR (600 MHz, CDCl3) 11.25 (1H, s), 8.55 (1H, d, J = 3.0 Hz), 8.11 (1H, d, J = 3.0 Hz), 7.79 (2H, d, J = 7.8 Hz), 7.56-7.49 (4H, m), 7.04 (1H, d, J = 8.4 Hz), 6.92 (1H, t, J = 7.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 1.33 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 194.0, 163.6, 162.5, 157.9, 145.5,
144.3, 143.0, 136.8, 133.4, 133.1, 131.2, 127.6, 119.3, 119.0, 118.3, 117.4, 116.7, 113.6, 61.8, 14.1; IR (KBr) 3363, 3078, 1734, 1657, 1599, 1269, 1144, 556, 647 cm-1; HRMS m/z (M+) calcd for C22H16N2O5: 388.1059. Found: 388.1059. Ethyl
1-(2-(4-bromobenzoyl)phenyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (5k). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 53%; 1H NMR (600 MHz, CDCl3) 11.36 (1H, s), 8.53 (1H, d, J = 2.4 Hz), 8.16 (1H, d, J = 3.0 Hz), 7.75 (1H, dd, J = 1.8, 8.4 Hz), 7.68-7.65 (3H, m), 7.57-7.54 (3H, m), 7.52-7.47 (2H, m), 7.38 (1H, d, J = 8.4 Hz), 7.04 (1H, d, J = 7.8 Hz) , 6.92 (1H, t, J = 7.2 Hz), 4.27 (2H, q, J = 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz);
C NMR (150 MHz, CDCl3) 194.4, 193.9, 163.6, 162.5,
13
158.3, 147.5, 144.3, 138.2, 136.5, 136.3, 135.0, 132.4, 131.9 (*2C), 131.8 (*3C), 130.0, 129.3, 128.9, 128.3, 121.1, 119.3, 118.7, 118.6, 115.3, 61.5, 14.1;
117
IR (KBr) 3369, 3070, 1730, 1666, 1595, 1269, 1148, 571, 640cm-1; HRMS m/z (M+) calcd for C28H20BrNO6: 545.0474. Found: 545.0475. Ethyl
1-(4-fluorophenyl)-5-(2-hydroxy-5-methylbenzoyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (5l). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 174-176 oC. Yield: 78%; 1H NMR (300 MHz, CDCl3) 11.10 (1H, s), 8.55 (1H, d, J = 2.1 Hz), 8.14 (1H, d, J = 2.4 Hz), 7.39-7.31 (4H, m), 7.18 (1H, t, J = 8.1 Hz), 6.95 (1H, d, J = 8.1 Hz), 4.35 (2H, q, J = 6.9 Hz), 2.28 (3H, s), 1.35 (3H, t, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) 194.2, 164.0, 162.7 (d, J = 248.2 Hz), 160.5, 158.4, 146.5, 144.3, 137.7, 135.5 (d, J = 3.4 Hz), 131.1, 128.4 (d, J = 3.4 Hz), 128.3, 121.0, 118.7, 118.1, 116.6 (d, J = 22.9 Hz), 116.3, 61.7, 20.6, 14.2; 19F NMR (564 MHz, CDCl3) -112.00 – -112.04 (1F, m); IR (KBr) 3434, 3054, 1663, 1436, 1276, 970, 760, 516 cm-1; HRMS m/z (M+) calcd for C22H18FNO5: 395.1169. Found: 395.1170. Ethyl
5-(5-bromo-2-hydroxybenzoyl)-1-(4-isopropylphenyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (5m). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 80-82 oC. Yield: 69%.; 1H NMR (300 MHz, CDCl3) 11.18 (1H, s), 8.54 (1H, d, J = 2.1 Hz), 8.17 (1H, d, J = 2.4 Hz), 7.68 (1H, d, J = 2.1 Hz), 7.57 (1H, dd, J = 2.1, 8.1 Hz), 7.37-7.28 (4H, m), 6.97 (1H, d, J = 8.1 Hz), 4.37 (2H, q, J = 6.9 Hz), 3.00-2.89 (1H, m), 1.36 (3H, t, J = 6.9 Hz), 1.26 (6H, d, J = 8.7 Hz); C NMR (150 MHz, CDCl3) 193.3, 164.0, 161.3, 158.4, 150.6, 147.1, 143.7,
13
139.0, 137.1, 133.4, 127.7, 126.1, 121.3, 120.8, 119.9, 115.3, 110.7, 61.7, 33.9,
118
23.8, 14.2; IR (KBr) 3310, 3051, 1690, 1584, 1530, 1268, 793, 509 cm-1; HRMS m/z (M+) calcd for C24H22BrNO5: 483.0681. Found: 483.0681. Ethyl
5-(5-bromo-2-hydroxybenzoyl)-1-(4-fluorophenyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (5n). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 195-197 oC. Yield: 75%.; 1H NMR (300 MHz, CDCl3) 11.19 (1H, s), 8.58 (1H, d, J = 2.1 Hz), 8.19 (1H, d, J = 2.4 Hz), 7.18 (1H, d, J = 2.1 Hz), 7.62 (1H, dd, J = 2.1, 8.7 Hz), 7.44-7.7.40 (2H, m), 7.28-7.21 (2H, m), 7.02 (1H, d, J = 7.8 Hz), 4.41 (2H, q, J = 6.9 Hz), 1.40 (3H, t, J = 6.9 Hz); 13C NMR (150 MHz, CDCl3) 193.2, 163.8, 162.8 (d, J = 249.6 Hz), 161.3, 158.3, 146.8, 143.8, 139.2, 135.4 (d, J = 3.4 Hz), 133.4, 128.4 (d, J = 9.3 Hz), 121.4, 120.9, 119.8, 116.7 (d, J = 22.9 Hz), 115.5, 110.8, 61.8, 14.2; 19F NMR (564 MHz, CDCl3) -111.75 – -111.79 (1F, m); IR (KBr) 3350, 3054, 1663, 1560, 1276, 760, 516 cm-1; HRMS m/z (M+) calcd for C21H15BrFNO5: 459.0118. Found: 459.0115. Methyl
5-(2-hydroxybenzoyl)-2-oxo-1-phenethyl-1,2-dihydropyridine-3-
carboxylate (6a). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 148-150 oC. Yield: 78%; 1H NMR (300 MHz, CDCl3) 11.21 (1H, s), 8.49 (1H, s), 7.56 (1H, s), 7.39 (1H, t, J = 7.5 Hz), 7.28-7.26 (3H, m), 7.10-7.08 (2H, m), 6.93 (1H, d, J = 8.4 Hz), 6.76-6.67 (2H, m), 4.19 (2H, t, J = 6.3 Hz), 3.86 (3H, s), 3.10 (2H, t, J = 6.3 Hz);
13
C NMR (75 MHz, CDCl3) 193.8, 164.5, 162.1, 158.4, 147.1,
144.3, 137.0, 136.0, 130.9, 129.0, 128.9, 127.0, 119.7, 119.0, 118.5, 118.2, 114.9, 53.9, 52.4, 34.1; IR (KBr) 3342, 3074, 1687, 1592, 1509, 1281, 791, 508 cm-1; HRMS m/z (M+) calcd for C22H19NO5: 377.1263. Found: 377.1263. 119
Ethyl
5-(2-hydroxybenzoyl)-2-oxo-1-phenethyl-1,2-dihydropyridine-3-
carboxylate (6b). The title compound was prepared according to the general procedure. The product was obtained as a light yellow solid, mp 175-177 oC. Yield: 76%; 1H NMR (300 MHz, CDCl3) 11.24 (1H, s), 8.49 (1H, s), 7.45 (1H, s), 7.45-7.39 (1H, m), 7.30-7.23 (3H, m), 7.11-7.10 (2H, m), 6.97 (1H, d, J = 8.4 Hz), 6.77-6.69 (2H, m), 4.36 (2H, q, J = 6.9 Hz), 4.21 (2H, t, J = 6.3 Hz), 3.13 (2H, t, J = 6.3 Hz), 1.36 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) 193.9, 164.0, 162.2, 158.5, 147.0, 143.9, 137.1, 136.0, 131.0, 129.1, 129.0, 127.1, 120.3, 119.1, 118.6, 118.3, 114.9, 61.5, 54.0, 34.2, 14.2; IR (KBr) 3348, 3071, 1693, 1587, 1513, 1274, 778, 512 cm-1; HRMS m/z (M+) calcd for C23H21NO5: 391.1420. Found: 391.1418. Benzyl
5-(2-hydroxybenzoyl)-2-oxo-1-phenethyl-1,2-dihydropyridine-3-
carboxylate (6c). The title compound was prepared according to the general procedure. The product was obtained as a white solid, mp 65-67 oC. Yield: 75%; 1H NMR (300 MHz, CDCl3) 11.23 (1H, s), 8.50 (1H, d, J = 2.4 Hz), 7.57 (1H, d, J = 2.4 Hz), 7.45-7.26 (9H, m), 7.12-7.10 (2H, m), 6.96 (1H, d, J = 8.1 Hz), 6.79-6.69 (2H, m), 5.33 (2H, s), 4.21 (2H, t, J = 6.3 Hz), 3.12 (2H, t, J = 6.3 Hz);
13
C NMR (150 MHz, CDCl3) 193.9, 163.8, 162.3, 158.5, 147.1,
144.2, 137.1, 136.1, 135.6, 131.0, 129.1, 129.0, 128.6, 128.2, 128.2, 127.1, 119.9, 119.0, 118.6, 118.3, 114.9, 67.1, 54.0, 34.2; IR (KBr) 3434, 3054, 1663, 1575, 1436, 1276, 970, 760, 526 cm-1; HRMS m/z (M+) calcd for C28H23NO5: 453.1576. Found: 453.1573. Ethyl 5-(2-hydroxy-5-methylbenzoyl)-2-oxo-1-phenethyl-1,2-dihydropyridine-3-carboxylate (6d). The title compound was prepared according to the 120
general procedure. The product was obtained as a yellow solid, mp 197-199 oC. Yield: 77%; 1H NMR (300 MHz, CDCl3) 11.06 (1H, s), 8.52 (1H, d, J = 2.1 Hz), 7.87 (1H, d, J = 2.4 Hz), 7.37-7.24 (4H, m), 7.22-7.20 (3H, m), 7.18 (1H, d, J = 8.1 Hz), 4.41 (2H, q, J = 6.9 Hz), 4.29 (2H, t, J = 6.3 Hz), 3.15 (2H, t, J = 6.3 Hz), 2.30 (3H, s), 1.41 (3H, t, J = 6.9 Hz);
13
C NMR (75 MHz, CDCl3)
193.9, 163.9, 160.0, 158.4, 146.7, 143.7, 137.1, 136.9, 130.8, 128.7, 128.1, 127.0, 119.6, 118.3, 118.2, 115.3, 61.3, 53.3, 34.6, 20.4, 14.1; IR (KBr) 3340, 3091, 1678, 1582, 1508, 1272, 783, 517 cm-1; HRMS m/z (M+) calcd for C24H23NO5: 405.1576. Found: 405.1575. Ethyl
5-(5-bromo-2-hydroxybenzoyl)-2-oxo-1-phenethyl-1,2-dihydropyri-
dine-3-carboxylate (6e). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 183-185 oC. Yield: 72%; 1H NMR (300 MHz, CDCl3) 11.12 (1H, s), 8.53 (1H, d, J = 2.1 Hz), 7.90 (1H, d, J = 2.4 Hz), 7.65-7.62 (1H, m), 7.56 (1H, s), 7.35-7.28 (3H, m), 7.24-7.21 (2H, m), 7.03 (1H, d, J = 8.1 Hz), 4.45 (2H, q, J = 6.9 Hz), 4.35 (2H, t, J = 6.3 Hz), 3.19 (2H, t, J = 6.3 Hz), 1.46 (3H, t, J = 6.9 Hz); 13C NMR (75 MHz, CDCl3) 192.8, 163.7, 160.9, 158.3, 147.0, 143.3, 138.7, 136.8, 133.1, 128.9, 128.8, 127.1, 120.6, 120.0, 114.7, 110.6, 61.5, 53.3, 34.7, 14.2; IR (KBr) 3340, 3097, 1693, 1585, 1524, 1294, 771, 524 cm-1; HRMS m/z (M+) calcd for C23H20BrNO5: 469.0525. Found: 469.0523. Ethyl
1-(2-(1H-indol-3-yl)ethyl)-5-(2-hydroxybenzoyl)-2-oxo-1,2-
dihydropyridine-3-carboxylate (6f). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 240-242 oC. Yield: 65%; 1H NMR (300 MHz, CDCl3) 10.69 (1H, s), 121
10.44 (1H, s), 8.42 (1H, d, J = 2.1 Hz), 7.63 (1H, d, J = 2.1 Hz), 7.41-7.26 (3H, m), 7.05 (1H, t, J = 8.1 Hz), 6.94-6.84 (3H, m), 6.61 (1H, t, J = 7.5 Hz), 6.48 (1H, d, J = 7.8 Hz), 4.31 (2H, q, J = 6.9 Hz), 4.22 (2H, t, J = 6.3 Hz), 3.20 (2H, t, J = 6.3 Hz), 1.34 (3H, t, J = 6.9 Hz);
13
C NMR (75 MHz, CDCl3) 192.5,
163.5, 159.4, 158.2, 147.8, 143.1, 136.1, 134.4, 130.1, 126.6, 123.0, 121.1, 119.7, 119.0, 118.7, 118.6, 117.4, 117.2, 114.3, 111.3, 109.5, 60.6, 52.3, 23.6, 13.8; IR (KBr) 3434, 3340, 3054, 1696, 1580, 1276, 970, 767, 506 cm-1; HRMS m/z (M+) calcd for C25H22N2O5: 430.1529. Found: 430.1526. Ethyl
(S)-5-(2-hydroxybenzoyl)-2-oxo-1-(1-phenylethyl)-1,2-dihydropyri-
dine-3-carboxylate (6g). The title compound was prepared according to the general procedure. The product was obtained as a light green liquid. Yield: 67%; 1H NMR (600 MHz, CDCl3) 11.26 (1H, s), 8.42 (1H, d, J = 3.0 Hz), 7.86 (1H, d, J = 3.0 Hz), 7.39 (6H, m), 7.10 (1H, dd, J = 1.2, 7.8 Hz), 6.93 (1H, d, J = 8.4 Hz), 6.63 (1H, t, J = 7.8 Hz), 6.46 (1H, q, J = 7.2 Hz), 4.33 (2H, q, J = 7.2 Hz), 1.70 (3H, d, J = 6.6 Hz), 1.33 (3H, t, J = 6.6 Hz);
13
C NMR (150
MHz, CDCl3) 193.9, 164.0, 162.2, 158.3, 144.1, 142.7, 138.6, 136.0, 130.9, 129.1, 128.6, 127.4, 120.1, 118.6, 118.5, 118.2, 115.4, 61.3, 54.2, 18.7, 14.1; IR (neat) 3350, 2981, 1831, 1727, 1600, 1539, 1228, 1027, 710, 551 cm-1; HRMS m/z (M+) calcd for C23H21NO5: 391.1420. Found: 391.1420; [α]D26 = - 87.73 (c1.0, CH3OH). Diethyl
(Z)-2-((6-nitro-4-(phenethylimino)-4H-chromen-3-yl)methylene)
malonate (6h). The title compound was prepared according to the general procedure. The product was obtained as a yellow solid, mp 180-182 oC. Yield: 58%; 1H NMR (600 MHz, CDCl3) 9.21 (1H, d, J = 2.4 Hz), 8.38 (1H, dd, J = 122
2.4, 9.0 Hz), 7.89 (1H, s), 7.64 (1H, s), 7.50 (1H, d, J = 9.6 Hz), 7.29-7.25 (3H, m), 7.06 (2H, d, J = 7.2 Hz), 4.41 (2H, t, J = 7.2 Hz), 4.31 (2H, q, J = 6.6 Hz), 4.27 (2H, q, J = 7.2 Hz), 3.16 (2H, t, J = 7.2 Hz), 1.31 (6H, t, J = 7.2 Hz); 13C NMR (150 MHz, CDCl3) 174.2, 166.3, 164.6, 146.1, 143.8, 142.2, 135.8, 135.1, 129.2, 128.6, 127.7, 126.6, 126.4, 125.8, 124.3, 116.9, 116.4, 61.6, 61.5, 55.4, 35.2, 14.1, 14.1; IR (KBr) 2979, 1713, 1483, 1335, 1231, 1022, 747 cm-1; HRMS m/z (M+) calcd for C25H24N2O7: 464.1584. Found: 464.1585.
Acknowledgements This research was supported by the Nano Material Technology Development Program of the Korean National Research Foundation (NRF) funded by the Korean Ministry of Education, Science, and Technology (Grant no. 2012-049675). This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2014R1A2A1A11052391).
123
2.3.5 References 1 (a) Du, W. Tetrahedron 2003, 59, 8649. (b) Ravinder, M.; Mahendar, B.; Mattapally, S.; Hamsini, K. V.; Reddy, T. N.; Rohit, C.; Srinivas, K.; Banerjee, K.; Rao, V. J. Bioorg. Med. Chem. Lett. 2012, 22, 6010. (c) Pfefferkorn, J. A.; Lou, J.; Minich, M. L.; Filipski, K. J.; He, M.; Zhou, R.; Ahmed, S.; Benbow, J.; Perez, A.; Tu, M.; Litchfield, J.; Sharma, R.; Metzler, K.; Bourbonais, F.; Huang, C.; Beebe, D. A.; Oates, P. J.; Bioorg. Med. Chem. Lett. 2009, 19, 3247. (d) Cinelli, M. A.; Morrell, A.; Dexheimer, T. S.; Scher, E. S.; Pommier, Y.; Cushmann, M. J. Med. Chem. 2008, 51, 4609. (e) Chen, J.; Lu, M.-M.; Liu, B.; Chen, Z.; Li, Q.B.; Tao, L.-J.; Hu, G.-Y.; Bioorg. Med. Chem. Lett. 2012, 22, 2300. (f) Nakao, Y.; Idei, H.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2009, 131, 15996. 2 (a) Breinholt, J.; Ludvigesen, S.; Rassing, B. R.; Rosendahl, C. N. J. Nat. Prod. 1997, 60, 33. (b) Singh, S. B.; Liu, W.; Li, X.; Chen, T.; Shafiee, A.; Card, D.; Abruzzo, G.; Flattery, A.; Gill, C.; Thompson, J. R.; Rosenbach, M.; Dreikorn, S.; Hornak, V.; Meinz, M.; Kurtz, M.; Kelly, R.; Onishi, J. C. ACS Med. Chem. Lett. 2012, 3, 814. 3 Storck, P.; Aubertinb, A.-M.; Grierson, D. S. Tetrahedron Lett. 2005, 46, 2919. 4 (a) Cocco, M. T.; Congiu, C.; Onnis, V. Eur. J. Med. Chem. 2003, 38, 37. (b) Cocco, M. T.; Congiu, C.; Onnis, V. Eur. J. Med. Chem. 2000, 35, 545. 5 Lv, Z.; Sheng, C.; Wang, T.; Zhang, Y.; Liu, J.; Feng, J.; Sun, H.; Zhong, H.; Niu, C.; Li, K. J. Med. Chem. 2010, 53, 660. 124
6 Wallace, E. M.; Lyssikatos, J.; Blake, J. F.; Seo, J.; Yang, H. W.; Yeh, T. C.; Perrier, M.; Jarski, H.; Marsh, V.; Poch, G.; Livingston, M. G.; Otten, J.; Hingorani, G.; Woessner, R.; Lee, P.; Winkler, J.; Koch, K. J. Med. Chem. 2006, 49, 441. 7 Hu, E.; Tasker, A.; White, R. D.; Kunz, R. K.; Human, J.; Chen, N.; Burli, R.; Hungate, R.; Novak, P.; Itano, A.; Zhang, X.; Yu, V.; Nguyen, Y.; Tudor, Y.; Plant, M.; Flynn, S.; Xu, Y.; Meagher, K. L.; Whittington, D. A.; Ng, G. Y. J. Med. Chem. 2008, 51, 3065. 8 Li, R.; Xue, L.; Zhu, T.; Jiang, Q.; Cui, X.; Yan, Z.; McGee, D.; Wang, J.; Gantla, V. R.; Pickens, J. C.; McGrath, D.; Chucholowski, A.; Morris, S. W.; Webb, T. R. J. Med. Chem. 2006, 49, 1006. 9 Lenaerts, A. J.; Bitting, C.; Woolhiser, L.; Gruppo, V.; Marietta, K. S.; Johnson, C. M.; Orme, I. M. Antimicrob. Agents Chemother. 2008, 52, 1513. 10 Dragovich, P. S.; Prins, T. J.; Zhou, R.; Johnson, T. O.; Hua, Y.; Luu, H. T.; Sakata, S. K.; Brown, E. L.; Maldonado, F. C.; Tuntland, T.; Lee, C. A.; Fuhrman, S. A.; Zalman, L. S.; Patick, A. K.; Matthews, D. A.; Wu, E. Y.; Guo, M.; Borer, B. C.; Nayyar, N. K.; Moran, T.; Chen, L.; Rejto, P. A.; Rose, P. W.; Guzman, M. C.; Dovalsantos, E. Z.; Lee, S.; McGee, K.; Mohajeri, M.; Liese, A.; Tao, J.; Kosa, M. B.; Liu, B.; Batugo, M. R.; Gleeson, J.-P. R.; Wu, Z. P.; Liu, J.; Meador, J. W.; Ann Ferre, R. J. Med. Chem. 2003, 46, 4572. 11 Cheney, I. W.; Yan, S.; Appleby, T.; Walker, H.; Vo, T.; Yao, N.; Hamatake, R.; Hong, Z.; Wu, J. Z. Bioorg. Med. Chem. Lett. 2007, 17, 1679. 125
12 (a) Padwa, A.; Heidelbaugh, T. M.; Kuethe, J. T. J. Org. Chem. 2000, 65, 2368. (b) Henry, C.; Haupt, A.; Turner, S. C. J. Org. Chem. 2009, 74, 1932. 13 Burger, S.; Cherioux, F.; Monnier-Jobe, K.; Laude, B.; Maillotte, H. Adv. Funct. Mater. 2002, 12, 339. 14 (a) Torres, M.; Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757. (b) Jayasinghe, L.; Abbas, H. K.; Jacob, M. R.; Herath, W. H. M. W.; Nanayakkara, N. P. D. J. Nat. Prod. 2006, 69, 439. 15 (a) Duong, H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438. (b) Tanaka, K.; Wada, A.; Noguchi, K. Org. Lett. 2005, 7, 4737. (c) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda, S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605. (d) Yamamoto, Y.; Takagishi, H.; Itoh, K. Org. Lett. 2001, 3, 2117. 16 Chen, Y.; Zhang, H.; Nan, F. J. Comb. Chem. 2004, 6, 684. 17 Carles, L.; Narkunan, K.; Penlou, S.; Rousset, L.; Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67, 4304. 18 Chun, Y. S.; Ryu, K. Y.; Ko, Y. O.; Hong, J. Y.; Hong, J.; Shin, H.; Lee, S.-G. J. Org. Chem. 2009, 74, 7556. 19 Sengupta, T.; Gayen, K. S.; Pandit, P.; Maiti, D. K. Chem.-Eur. J. 2012, 18, 1905. 20 Pintiala, C.; Lawson, A. M.; Comesse, S.; Daich, A. Tetrahedron Lett. 2013, 54, 2853. 21 Takahashi, T.; Tsai, F.-Y.; Li, Y.; Wang, H.; Kondo, Y.; Yamanaka, M.; Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 2002, 124, 5059. 22 Fujii, M.; Nishimura, T.; Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2013, 15, 232. 126
23 Hachiya, I.; Ogura, K.; Shimizu, M. Org. Lett. 2002, 4, 2755. 24 Patel, B. H.; Mason, A. M.; Barrett, A. G. M. Org. Lett. 2011, 13, 5156. 25 Imase, H.; Noguchi, K.; Hirano, M.; Tanaka, K. Org. Lett. 2008, 10, 3563. 26 Ryabukhin, V.; Plaskon, A. S.; Volochnyuk, D. M.; Tolmachev, A. A. Synlett 2004, 2287. 27 Mehrparvar, S.; Balalaie, S.; Rabbanizadeh, M.; Ghabraie, E.; Rominger, Mol Divers F. 2014, 18, 535. 28 (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025. (b) Rothenberg, G.; Downie, A. P.; Raston, C. L.; Scott, J. L. J. Am. Chem. Soc. 2001, 123, 8701. (c) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P.; Chem. Rev. 2009, 109, 4140. (d) Cave, G. W. V.; Raston, C. L.; Scott, J. L. Chem. Commun. 2001, 2159. (e) Kaupp, G. CrystEngComm 2003, 5, 117. (f) Tanaka, K. Solvent-free Organic Synthesis, Wiley-VCH, Weinheim, 2003. (g) Schneider, F.; Szuppa, T.; Stolle, A.; Ondruschka, B.; Hopf, H. Green Chem. 2009, 11, 1894. (h) Choudhary, G.; Peddinti, R. K. Green Chem. 2011, 13, 276. (i) Cheng, C.; Jiang, B.; Tu, S.-J.; Li, G. Green Chem. 2011, 13, 2107.
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2.4 Construction of Highly Functionalized Carbazoles
2.4.1 Introduction The carbazole framework is found in a wide range of bioactive natural products and pharmaceuticals (Figure 1).1-2 These carbazole-containing molecules show antiviral,3 antimalarial,4 and antitumor activity.5 Some of them are currently used as lead compounds for drug development.6 Carbazoles are also used as building blocks for the synthesis of functional materials, such as organic light-emitting diodes (OLED), because of their wide band gap, high luminescence efficiency, and flexibility to modify its parent skeleton.7-8
Owing to the importance and usefulness of these carbazole-based compounds, various approaches for their construction have been developed. The general and representative strategies can be classified into two main types depending on how the carbazole ring is constructed. The 128
first strategy relies on the formation of a C–C or a C–N bond to construct the middle pyrrole ring starting from arene building blocks (Methods AB, Figure 2).9-16 Also, reaction of arynes with nitrosoarene and nitrogenation of biphenyl halides have been reported.17 The second strategy involves the installation of a new aromatic ring onto functionalized indole derivatives via benzannulation (Methods C-D, Figure 2).18-23
Despite their own merits, most, if not all, of these methods suffer from certain drawbacks, including low tolerance of functionality, limited 129
substrate scope, not-easily accessible starting materials, the necessity of complex and expensive transition-metal catalysts, and harsh reaction conditions. In particular, many existing methods require either highly elaborated biaryls or biarylamines to construct the central pyrrole moiety or pre-functionalized indole derivatives for benzannulation. Therefore, more
environmentally
benign
and
modular
multi-bond
forming
approaches accommodating structurally simple building blocks as the feedstock are highly sought-after to improve on these shortcomings. In related to the synthesis of 3-hydroxy carbazoles, iron-mediated reactions have also been reported.24 A recently-reported rhodium-catalyzed tandem annulation uses a new approach, where the [5+1] cycloaddition of 3hydroxy-1,4-enynes with CO generates three bonds and two rings. 25 Yet, even for this transformation, various 3-hydroxy-1,4-enyne reagents must be prepared by a multi-step route. In this regard, the new approach, depicted in E, accommodating a novel double annulation through the consecutive construction of a pyrrole and a benzene moiety reflects further innovation (Figure 2). A unique feature of the current reaction compared to all other reported pyrrole formations or benzannulations is to form the carbazole nitrogen atom by electrophilic attack on a nitro group rather than by using an amine nucleophile. Herein, I describe a unique tandem annulation followed by N-O bond cleavage without any external reductant for the synthesis of various functionalized 3-hydroxycarbazoles from readily available 2nitrocinnamaldehyde or 2-nitrochalcone and β-ketoesters or 1,3-diaryl-2propanone. 130
2.4.2 Results and Discussion First, the reaction of 2-nitrocinnamaldehyde (1a) and methyl 2oxobutanoate (2a) was examined with several bases and solvents to optimize the reaction conditions (Table 1). The initial attempt with NaOMe (1 equiv.) in refluxing toluene for 12 h did not provide product 3a (Table 1, entry 1), but produced an intractable mixture. With triethylamine (1 equiv.), product 3a was also not formed (Table 1, entry 2), but with DBU (1 equiv.), 3a was produced in 10% yield (Table 1, entry 3). Encouraged by this result, other bases were screened. With K2CO3 (1 equiv.) for 6 h, the yield of 3a increased to 67% (Table 1, entry 4). The highest yield (81%) was achieved with 1.0 equivalent of Cs 2CO3 in refluxing toluene for 4 h (Table 1, entry 5). Increasing the amount of Cs2CO3 to 1.5 equivalents (entry 6) or decreasing it to 0.1 equivalent (Table 1, entry 7) lowered the yield of 3a. Based from these results, this transformation was found to be sensitive towards the base strength used. For example, strong bases like NaOMe (1 equiv.) or DBU (1 equiv.) provided very less or no desired product, while weak bases provided better yields. Among the screened bases, Cs 2CO3 was superior in terms of both reaction time and yield for this reaction, probably due to its mild and optimum base strength.26 In two other nonpolar solvents (benzene or dichloroethane), 3a was produced in 35 and 51% yield, respectively, whereas 3a was not obtained in a more polar solvent, such as methanol, DMSO, or water (Table 1, entries 8-12). The structure of 3a was established by its spectroscopic analysis. The 1H NMR of 3a showed a 131
characteristic singlet of OH group at 11.12 ppm and another broad singlet for the NH proton at 8.17 ppm. The
13
C NMR showed the
expected characteristic ester carbonyl carbon at 171.6 ppm and an aromatic carbon containing OH at 157.7 ppm. The structural confirmation of 3a was further determined by X-ray crystallographic analysis of related compound 7a (Figure 3).
132
Figure 3. X-ray Structure of compound 7a containing two molecules in a unit With the optimized conditions in hand, the generality of this reaction was explored by employing different β-ketoesters 2b–2i (Table 2). Reaction of 2-nitrocinnamaldehyde (1a) with several β-ketoesters such as ethyl 2-oxobutanoate (2b), allyl 3-oxobutanoate (2c) and benzyl 3oxobutanoate (2d), afforded the desired products 3b–3d in 79, 82 and 77% yield, respectively. Moreover, reactions of other β-ketoesters such as ethyl 3-oxopentanoate (2e), ethyl 3-oxohexanoate (2f), methyl 3oxooctanoate (2g), methyl 3-oxododecanoate (2h), and methyl 3-oxo-4-
133
phenylbutanoate (2i) provided the desired carbazoles 3e–3i in 73–78% yield.
The scope of the reaction was further extended by employing a series of 2-nitrochalcones and β-ketoesters (Table 3). When 2-nitrochalcone 4a was treated with allyl 3-oxobutanoate (2c), ethyl 3-oxopentanoate (2e) or 3-oxo-4-phenylbutanoate (2i) under optimized reaction conditions, the desired products 5a, 5b and 5c were formed in 75, 73 and 78% yield respectively. Furthermore, 2-nitrochalcones 4b–4c bearing electron134
donating or -withdrawing groups, such as methyl or bromo substituent on 1-phenyl group and β-ketoesters 2b, 2d and 2e also provided the desired products 5d–5f in 76, 75, and 70% yield, respectively. In addition, 2nitrochalcones 4d–4f having electron-donating or -withdrawing groups, such as methoxy, bromo and chloro substituent on the 3-phenyl group produced the expected carbazoles 5g–5k in good yield (70–78%).
135
The reactions between 2-nitrocinnamaldehyde (1a) or 2-nitrochalcones 4a, 4c, 4d, 4e, 4f and 1,3-diarylpropan-2-ones 6a and 6b were examined to further demonstrate the versatility of this carbazole formation (Table 4). The reaction of 1a with 6a or 6b in refluxing toluene for 4 h afforded the corresponding products 7a–7b in 81 and 80% yield, respectively. Similarly, the treatment of nitrochalcones 4a, 4c, 4d, 4e, and 4f with 6a or 6b provided the products 7c–7g in the range of 68–78% yield.
Having confirmed the general applicability of the reaction by using 2nitrocinnamaldehyde and 2-nitrochalcones as starting materials, the possibility of using 2-nitrochalcones bearing heteroatom was examined, which will lead to the formation of carbazole derivatives of extended 136
structural space. To our delight, the reactions of 8a or 8b with βketoesters 2b, 2d, and 2e provided the expected products 9a–9f in the range of 71–75% yield (Table 5).
We propose that the formation of the observed carbazole products may involve a mechanism shown in Scheme 1. In a basic medium, enolate 10 derived from 2a undergoes Michael addition onto 1a to give new enolate intermediate 11, which subsequently reacts with the nitro group to form bicyclic intermediate 12.27 The reorganization of the O–N– OH moiety in 12 to N–O–OH would generate 15 via 13 or 14. Baseinduced elimination of the hydrogen peroxide from 15 would generate 16, which then undergo sequential double tautomerization via 17 or 18 to generate the observed product 3a. 137
To obtain an evidence for the formation of H2O2 during the reaction sequence, a control experiment was carried out with an added aryl boronic acid (Scheme 2). To our delight, this reaction involving 1a, 2a and 2-naphthyl boronic acid 19 under the standard reaction conditions provided product 3a (61%) together with 2-naphthol 20 in 31% yield. The formation of 2-naphthol 20 implies the existence of in situ generated H2O2 in the reaction, although other mechanistic possibilities cannot be excluded.28
138
Next, we broaden the carbazole structures to those that do not carry a carboethoxy group at the 4-position (Scheme 3). By carrying out the reaction at higher temperature (145 oC) for prolonged time using 2 equivalents of Cs2CO3 for decarboethoxylation, carbazoles 21a–21d were obtained in 68–75% yield.
The utility of this new protocol was demonstrated by the conversion of 21b and 21d to biologically active natural products (Scheme 4). Upon treating 21b and 21d with iodomethane in refluxing acetone in the presence of K2CO3, hyellazole (22) and chlorohyellazole (23) were 139
obtained in 94% and 92% yields, respectively. The concise synthesis of hyellazole and chlorohyellazole was achieved in two steps from commercially available starting materials in 67% and 63% overall yields, respectively. This protocol has several advantages such as higher yields, lower cost, fewer steps, transition metal-free, and environmentally benignity.29-30 The identity of these two natural products was confirmed by comparison of their spectroscopic data with those previously reported.29-30
140
2.4.3 Conclusions A highly efficient, transition-metal-free, modular and operationally simple tandem annulation process was developed for the synthesis of diverse carbazole derivatives starting from readily available 2nitrocinnamaldehydes or 2-nitrochalcones and β-ketoesters or 1,3-diaryl2-propanones. This synthetic approach for rapid construction of various functionalized carbazoles involves an intramolecular addition of an enolate to a nitro group and a unique in situ N–O bond cleavage under non-reductive conditions. As an application of this new synthetic methodology, a concise synthesis of naturally occurring bioactive hyellazole and chlorohyellazole has been realized in two steps.
141
2.4.4 Experimental General experimental information All experiments were carried out under open air without inert gases protection. 2-Nitrochalcones, 2-nitrocinnamaldehyde, 1,3-diphenyl-2propanone and
Ketoesters were purchased from Sigma- Aldrich or
prepared by reported methods. Merck precoated silica gel plates (Art. 5554) with a fluorescent indicator were used for analytical TLC. Flash column chromatography was performed using silica gel 9385 (Merck). Melting points were determined with micro-cover glasses on a FisherJohns apparatus and are uncorrected. 1H NMR spectra were recorded on a Varian-VNS (300 or 600 MHz) spectrometer in CDCl3 using 7.24 ppm as the solvent chemical shift.
13
C NMR spectra were recorded on a Varian-
VNS (75 or 150 MHz) spectrometer in CDCl 3 using 77.0 ppm as the solvent chemical shift. IR spectra were recorded on a JASCO FTIR 5300 spectrophotometer. High resolution mass (HRMS) were obtained with a JEOL JMS-700 spectrometer at the Korea Basic Science Institute.
General procedure for the synthesis carbazole derivatives (3-9) A general procedure for the base catalyzed synthesis of carbazoles 3-9 is as follows: An oven dried two-neck round bottom flask was charged with ketoesters (1.0 mmol) or ketone (1.0 mmol) and 1.0 mmol of 2nitrocinnamaldehyde or 2-nitrochalcone in 5 mL toluene and Cs2CO3 (1 equiv.) was added. Then, the flask was fitted with condenser. Each reaction mixture was refluxed 3-5 hours in open air without using nitrogen balloon until the completion of the reaction as indicated by TLC. 142
Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the pure product. Characterization data for all compounds 3-9 are as follows:
Spectroscopic data of compounds 3-9 Methyl
3-hydroxy-9H-carbazole-4-carboxylate
(3a).
The
title
compound was prepared according to the general procedure. The product was obtained as a solid, mp 141-143 oC. Yield: 81% (195 mg). 1H NMR (300 MHz, CDCl3) 11.12 (1H, s), 8.43 (1H, d, J = 8.4 Hz), 8.17 (1H, s), 7.52 (1H, d, J = 8.7 Hz), 7.41-7.40 (2H, m), 7.22-7.16 (1H, m), 7.09 (1H, d, J = 8.7 Hz), 4.16 (3H, s);
13
C NMR (75 MHz, CDCl3) 171.6, 157.7,
140.6, 133.6, 126.2, 124.9, 122.2, 119.9, 119.2, 118.6, 116.5, 110.8, 105.7, 51.9; IR (KBr) 3391, 1618, 1340, 1274, 758, 540 cm-1; HRMS m/z (M+) calcd for C14H11NO3: 241.0739. Found: 241.0738. Ethyl 3-hydroxy-9H-carbazole-4-carboxylate (3b). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 112-114 oC. Yield: 79% (201 mg). 1H NMR (300 MHz, CDCl3) 11.19 (1H, s), 8.56 (1H, d, J = 8.4 Hz), 8.15 (1H, s), 7.47 (1H, d, J = 8.7 Hz), 7.44-7.36 (2H, m), 7.21-7.16 (1H, m), 7.09 (1H, d, J = 8.7 Hz), 4.67 (2H, q, J = 6.9 Hz), 1.56 (3H, t, J = 6.9 Hz);
13
C NMR
(75 MHz, CDCl3) 171.2, 157.6, 140.5, 133.6, 126.1, 125.3, 122.2, 119.9, 118.8, 118.4, 116.5, 110.8, 106.2, 61.7, 14.3; IR (KBr) 3399, 1648, 1311,
143
1083, 750, 628 cm-1; HRMS m/z (M+) calcd for C15H13NO3: 255.0895. Found: 255.0897.
Allyl 3-hydroxy-9H-carbazole-4-carboxylate (3c). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 114-116 oC. Yield: 82% (218 mg).1H NMR (300 MHz, CDCl3) 11.14 (1H, s), 8.53 (1H, d, J = 8.4 Hz), 8.15 (1H, s), 7.46-7.33 (3H, m), 7.14 (1H, t, J = 7.8 Hz), 7.08 ( 1H, d, J = 8.7 Hz), 6.24-6.11 (1H, m), 5.50 (1H, d, J = 17.4 Hz), 5.38 (1H, d, J = 10.2 Hz), 5.08 (2H, d, J = 6.0 Hz);
13
C NMR (75 MHz, CDCl3) 170.8, 157.6,
140.5, 133.6, 131.3, 126.1, 125.4, 122.1, 120.0, 119.9, 118.9, 118.6, 116.4, 110.7, 105.8, 66.3; IR (KBr) 3386, 3012, 1666, 1435, 1276, 760, 526 cm-1; HRMS m/z (M+) calcd for C16H13NO3: 267.0895 Found: 267.0891.
Benzyl
3-hydroxy-9H-carbazole-4-carboxylate
(3d).
The
title
compound was prepared according to the general procedure. The product was obtained as a solid, mp 170-172 oC. Yield: 77% (244 mg). 1H NMR (300 MHz, CDCl3) 11.17 (1H, s), 8.36 (1H, d, J = 8.4 Hz), 8.10 (1H, s), 7.45-7.48 (3H, m), 7.42-7.33 (5H, m), 7.09 (1H, d, J = 9.0 Hz), 6.94-6.88 (1H, m), 5.62 (2H, m);
13
C NMR (75 MHz, CDCl3) 171.0, 157.9, 140.5,
134.7, 133.6, 129.1, 128.7, 128.7, 126.1, 125.6, 122.1, 120.0, 118.8, 118.6, 116.5, 110.6, 105.9, 67.5; IR (KBr) 3397, 2985, 1686, 1251, 970, 534 cm-1; HRMS m/z (M+) calcd for C20H15NO3: 317.1052. Found: 317.1050. 144
Ethyl 3-hydroxy-2-methyl-9H-carbazole-4-carboxylate (3e). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 140-142 oC. Yield: 78% (209 mg). 1H NMR (600 MHz, CDCl3) 11.54 (1H, s), 8.51 (1H, d, J = 8.4 Hz), 7.90 (1H, s), 7.38 (1H, t, J = 7.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.26 (1H, s), 7.18 (1H, t, J = 7.2 Hz), 4.64 (2H, q, J = 7.2 Hz), 2.38 (3H, s), 1.54 (3H, t, J = 7.8 Hz);
13
C NMR (150 MHz, CDCl3) 171.7, 156.5, 140.1, 133.2, 125.8,
125.5, 124.9, 122.4, 118.9, 118.7, 117.8, 110.6, 105.4, 61.7, 16.9, 14.3; IR (KBr) 3359, 2972, 1632, 1435, 1227, 1026, 737, 502 cm-1; HRMS m/z (M+) calcd for C16H15NO3: 269.1052. Found: 269.1053. Ethyl 2-ethyl-3-hydroxy-9H-carbazole-4-carboxylate (3f). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 154-156 oC. Yield: 75% (212 mg). 1H NMR (300 MHz, CDCl3 + DMSO-d6) 11.46 (1H, s), 8.98 (1H, s), 8.47 (1H, d, J = 8.4 Hz), 7.35-7.33 (3H, m), 7.13-7.09 (1H, m), 4.62 (2H, q, J = 7.2 Hz), 2.77 (2H, q, J = 7.2 Hz), 1.51 (3H, t, J = 7.2 Hz), 1.25 (3H, t, J = 7.2 Hz);
13
C NMR (75 MHz, CDCl3 + DMSO-d6) 171.7, 155.9, 140.3,
133.6, 131.4, 125.1, 124.7, 122.2, 121.1, 118.2, 117.4, 110.7, 105.2, 61.4, 23.5, 14.2, 13.6; IR (KBr) 3412, 1658, 1320, 1081, 771, 625 cm -1; HRMS m/z (M+) calcd for C17H17NO3: 283.1208. Found: 283.1208. Methyl 2-butyl-3-hydroxy-9H-carbazole-4-carboxylate (3g). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 153-155 oC. Yield: 74% (219 mg). 1H NMR 145
(600 MHz, CDCl3) 11.48 (1H, s), 8.38 (1H, d, J = 8.4 Hz), 8.00 (1H, s), 7.38-7.37 (3H, m), 7.19-7.17(1H, m), 4.15 (3H, s), 2.78 (2H, t, J = 7.2 Hz ), 1.69-1.64 (2H, m), 1.44-1.38 (2H, m), 0.95 (3H, t, J = 7.2 Hz);
13
C
NMR (150 MHz, CDCl3) 172.2, 156.4, 140.2, 133.3, 130.5, 125.6, 124.6, 122.5, 119.0, 118.3, 117.8, 110.7, 105.1, 51.9, 31.6, 30.4, 22.6, 14.0; IR (KBr) 3434, 3054, 1663, 1436, 1276, 970, 760, 516 cm -1; HRMS m/z (M+) calcd for C18H19NO3: 297.1365. Found: 297.1368. Methyl 3-hydroxy-2-octyl-9H-carbazole-4-carboxylate (3h). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 133-135 oC. Yield: 73% (257 mg). 1H NMR (300 MHz, CDCl3) 11.46 (1H, s), 8.38 (1H, d, J = 8.4 Hz), 8.01 (1H, s), 7.38-7.37 (3H, m), 7.20-7.15(1H, m), 4.15 (3H, s), 2.77 (2H, t, J = 7.8 Hz), 1.70-1.58 (2H, m), 1.34-1.26 (10H, m), 0.87 (3H, t, J = 7.2 Hz)
13
C
NMR (75 MHz, CDCl3) 172.1, 156.4, 140.2, 133.3, 130.6, 125.5, 124.5, 122.5, 119.0, 118.3, 117.9, 110.7, 105.1, 51.8, 31.8, 30.6, 29.6, 29.53, 29.51, 29.29, 22.6, 14.0; IR (KBr) 3361, 2926, 1657, 1436, 801, 650 cm -1; HRMS m/z (M+) calcd for C22H27NO3: 353.1991. Found: 353.1988. Methyl 3-hydroxy-2-phenyl-9H-carbazole-4-carboxylate (3i). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 149-151 oC. Yield: 77% (244 mg). 1H NMR (600 MHz, CDCl3) 11.53 (1H, s), 9.78 (1H, s), 8.34 (1H, d, J = 8.4 Hz), 7.59-7.57 (3H, m), 7.40-7.37 (3H, m), 7.35-7.32 (1H, m), 7.30-7.28 (1H, m), 7.11 (1H, t, J = 7.8 Hz), 4.12 (3H, s); 146
13
C NMR (150 MHz, CDCl3)
172.0, 154.8, 141.0, 138.0, 133.8, 129.4, 128.8, 127.9, 127.0, 125.8, 124.6, 121.8, 119.4, 118.9, 118.6, 110.9, 105.4, 51.9; IR (KBr) 3408, 2997, 1689, 1105, 740 cm-1; HRMS m/z (M+) calcd for C20H15NO3: 317.1052. Found: 317.1048.
Allyl 3-hydroxy-1-phenyl-9H-carbazole-4-carboxylate (5a). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 75% (257 mg). 1H NMR (300 MHz, CDCl3) 11.09 (1H, s), 8.56 (1H, d, J = 8.4 Hz), 8.31 (1H, s), 7.64 (2H, d, J = 7.5 Hz), 7.57-7.53 (2H, m), 7.48 (1H, d, J = 7.2 Hz), 7.437.37 (2H, m), 7.19-7.12 (2H, m), 6.26-6.13 (1H, m), 5.52 (1H, d, J = 17.1 Hz), 5.40 (1H, d, J = 10.5 Hz), 5.11 (2H, d, J = 6.0 Hz);
13
C NMR (75
MHz, CDCl3) 170.8, 157.9, 140.5, 137.4, 132.9, 131.7, 131.4, 129.3, 128.8, 128.6, 128.3, 126.2, 125.5, 122.4, 120.0, 119.0, 116.1, 110.8, 105.0, 66.3; IR (neat) 3464, 1655, 1506, 1340, 1161, 724, 563 cm -1; HRMS m/z (M+) calcd for C22H17NO3: 343.1208. Found: 343.1212.
Ethyl 3-hydroxy-2-methyl-1-phenyl-9H-carbazole-4-carboxylate (5b). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 145-147 oC. Yield: 73% (252 mg). 1
H NMR (600 MHz, CDCl3) 11.69 (1H, s), 8.54 (1H, d, J = 8.4 Hz),
7.76 (1H, s), 7.57-7.55 (2H, m), 7.50-7.48 (1H, m), 7.38 (2H, d, J = 7.8 Hz), 7.35-7.33 (1H, m), 7.29 (1H, d, J = 7.8 Hz), 7.17-7.14 (1H, m), 4.70 (2H, q, J = 7.2 Hz), 2.21 (3H, s), 1.58 (3H, t, J = 7.2 Hz);
13
C NMR (150
MHz, CDCl3) 171.8, 156.9, 139.8, 136.5, 132.5, 132.1, 129.4, 129.1, 147
128.2, 125.5, 125.1, 123.5, 122.6, 118.7, 117.1, 110.6, 104.6, 61.7, 14.4, 13.6; IR (KBr) 3433, 2929, 1711, 1680, 1452, 1262, 747, 557 cm -1; HRMS m/z (M+) calcd for C22H19NO3: 345.1365. Found: 345.1363. Methyl 3-hydroxy-1,2-diphenyl-9H-carbazole-4-carboxylate (5c). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 211-213 oC. Yield: 78% (306 mg). 1
H NMR (300 MHz, CDCl3) 11.46 (1H, s), 8.43 (1H, d, J = 8.4 Hz),
7.95 (1H, s), 7.37-7.17 (13H, m), 4.17(3H, s);
13
C NMR (75 MHz, CDCl3)
171.9, 155.7, 140.4, 136.1, 136.0, 132.5, 131.9, 131.1, 129.9, 128.6, 128.3, 127.7, 127.5, 126.7, 126.1, 124.9, 122.4, 119.2, 119.0, 110.8, 104.9, 52.0; IR (KBr) 3395, 3021, 142, 1509, 1157, 743, 635 cm-1; HRMS m/z (M+) calcd for C26H19NO3: 393.1365. Found: 393.1365. Ethyl 3-hydroxy-1-(p-tolyl)-9H-carbazole-4-carboxylate (5d). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 105-107 oC. Yield: 76% (262 mg). 1H NMR (600 MHz, CDCl3) 11.21 (1H, s), 8.58 (1H, d, J = 8.4 Hz), 8.32 (1H, s), 7.54 (2H, d, J = 8.1 Hz), 7.41-7.35 (4H, m), 7.18 (1H, t, J = 7.8 Hz), 7.10 (1H, s), 4.69 (2H, q, J = 7.2 Hz), 2.45 (3H, s), 1.58 (3H, t, J = 7.2 Hz); 13
C NMR (150 MHz, CDCl3) 171.2, 157.9, 140.4, 138.5, 134.4, 132.8,
131.8, 130.0, 128.2, 126.1, 125.4, 122.5, 120.3, 118.9, 116.0, 110.8, 105.0, 61.7, 21.2, 14.4; IR (KBr) 3385, 2962, 1656, 1463, 750, 658 cm -1; HRMS m/z (M+) calcd for C22H19NO3: 345.1365. Found: 345.1362.
148
Ethyl
3-hydroxy-2-methyl-1-(p-tolyl)-9H-carbazole-4-carboxylate
(5e). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 200-202 oC. Yield: 75% (269 mg). 1H NMR (300 MHz, CDCl3) 11.70 (1H, s), 8.55 (1H, d, J = 8.4 Hz), 7.81 (1H, s), 7.38-7.26 (6H, m), 7.19-7.13 (1H, m), 4.70 (2H, q, J = 7.2 Hz), 2.47 (3H, s), 2.22 (3H, s), 1.58 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3) 171.8, 156.9, 139.8, 138.0, 133.5, 132.7, 132.2, 129.8, 129.2, 125.4, 125.0, 123.5, 122.6, 118.6, 117.0, 110.6, 104.4, 61.6, 21.3, 14.4, 13.5; IR (KBr) 3399, 3040, 1647, 1508, 1310, 1157, 749, 635 cm -1; HRMS m/z (M+) calcd for C23H21NO3: 359.1521. Found: 359.1520.
Benzyl
1-(2-bromophenyl)-3-hydroxy-9H-carbazole-4-carboxylate
(5f). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 70% (329 mg). 1H NMR (300 MHz, CDCl3) 11.20 (1H, s), 8.41 (1H, d, J = 8.4 Hz), 7.88 (1H, s), 7.75 (1H, d, J = 7.8 Hz), 7.54-7.30 (10H, m), 7.04 (1H, s), 6.926.90 (1H, m), 5.65 (2H, s);
13
C NMR (75 MHz, CDCl3) 170.9, 157.6,
140.4, 137.8, 134.7, 133.4, 131.9, 131.8, 131.2, 130.2, 129.2, 129.2, 128.7, 127.8, 126.2, 125.8, 122.9, 122.3, 120.2, 118.9, 117.1, 110.7, 105.7, 67.5; IR (neat) 3390, 1635, 1509, 1212, 760, 638 cm -1; HRMS m/z (M+) calcd for C26H18BrNO3: 471.0470. Found: 471.0474.
Ethyl
3-hydroxy-8-methoxy-1-phenyl-9H-carbazole-4-carboxylate
(5g). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 118-120 oC. Yield: 75% (270 149
mg). 1H NMR (600 MHz, CDCl3) 11.22 (1H, s), 8.48 (1H, s), 8.14 (1H, d, J = 8.4 Hz), 7.66 (2H, d, J = 6.9 Hz), 7.56 (2H, t, J = 7.2 Hz), 7.48 (1H, t, J = 7.5 Hz), 7.12-7.09 (2H, m), 6.86 (1H, d, J = 7.8 Hz), 4.68 (2H, q, J = 7.2 Hz), 3.95 (3H, s), 1.57 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz,
CDCl3) 171.2, 157.9, 145.5, 137.4, 133.0, 131.5, 131.4, 129.3, 128.5, 128.3, 123.9, 120.8, 118.9, 117.7, 116.1, 105.4, 105.2, 61.7, 55.4, 14.4; IR (KBr) 3440, 3065, 1624, 1435, 1162, 1128, 756, 516 cm-1; HRMS m/z (M+) calcd for C22H19NO4: 361.1314. Found: 361.1315.
Methyl
3-hydroxy-8-methoxy-1,2-diphenyl-9H-carbazole-4-
carboxylate (5h). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 238-240 oC. Yield: 78% (329 mg). 1H NMR (300 MHz, CDCl3) 11.56 (1H, s), 8.20 (1H, s), 8.07 (1H, d, J = 8.4 Hz), 7.36-7.14 (11H, m), 6.91 (1H, d, J = 7.5 Hz), 4.24 (3H, s), 3.98 (3H, s);
13
C NMR (150 MHz, CDCl3) 171.9,
155.9, 145.5, 136.2, 136.1, 132.34, 132.31, 131.3, 131.1, 129.9, 128.5, 128.3, 127.7, 127.5, 126.7, 123.3, 119.3, 119.1, 117.3, 105.5, 104.8, 55.3, 52.0; IR (KBr) 3464, 3058, 1655, 1581, 1249, 722, 564 cm -1; HRMS m/z (M+) calcd for C27H21NO4: 423.1471. Found: 423.1469.
Methyl 7-bromo-3-hydroxy-1-phenyl-9H-carbazole-4-carboxylate (5i). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 177-179 oC. Yield: 70% (276 mg). 1
H NMR (600 MHz, CDCl3) 11.17 (1H, s), 8.32 (1H, d, J = 8.4 Hz),
8.29 (1H, s), 7.62 (2H, d, J = 7.2 Hz), 7.56 (2H, t, J = 7.8 Hz), 7.53 (1H, 150
s), 7.49 (1H, t, J = 7.8 Hz), 7.28 (1H, dd, J = 1.8, 9.6 Hz), 7.13 (1H, s), 4.17 (3H, s);
13
C NMR (150 MHz, CDCl3) 171.2, 158.3, 141.1, 137.0,
133.0, 131.7, 129.4, 128.8, 128.3, 126.4, 122.6, 121.5, 120.0, 119.9, 116.7, 113.7, 104.6, 52.1; IR (KBr) 3384, 3054, 1653, 1426, 1226, 940, 770, 536 cm-1; HRMS m/z (M+) calcd for C20H14BrNO3: 395.0157. Found: 395.0158.
Ethyl
6-chloro-3-hydroxy-2-methyl-1-phenyl-9H-carbazole-4-
carboxylate (5j). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 148-150 oC. Yield: 73% (276 mg). 1H NMR (300 MHz, CDCl3) 11.57 (1H, s), 8.37 (1H, d, J = 1.8 Hz), 7.53 (1H, s), 7.36-7.25 (3H, m), 7.16-7.13 (2H, m), 7.06 (1H, dd, J = 1.8, 8.7 Hz), 6.99 (1H, t, J = 7.8 Hz), 4.46 (2H, q, J = 7.2 Hz), 1.98 (3H, s), 1.41 (3H, t, J = 7.2 Hz); 13C NMR (75 MHz, CDCl3)
171.6, 157.5, 138.0, 136.3, 133.2, 132.3, 129.3, 129.2, 128.3, 125.5, 124.8, 124.6, 124.2, 123.6, 116.3, 111.4, 104.4, 62.0, 14.3, 13.6; IR (KBr) 3466, 2980, 1708, 1511, 1315, 903, 630 cm-1; HRMS m/z (M+) calcd for C22H18ClNO3: 379.0975. Found: 379.0979.
Benzyl
6-chloro-3-hydroxy-1-phenyl-9H-carbazole-4-carboxylate
(5k). The title compound was prepared according to the general procedure. The product was obtained as brown liquid. Yield: 71% (303 mg). 1H NMR (300 MHz, CDCl3) 11.24 (1H, s), 8.42 (1H, s), 8.29 (1H, s), 7.57-7.36 (10H, m), 7.25-7.17 (2H, m), 7.07 (1H, s), 5.59 (2H, s);
13
C
NMR (75 MHz, CDCl3) 170.6, 158.4, 138.5, 137.0, 134.4, 133.1, 132.2, 151
129.5, 129.3, 128.8, 128.7, 128.2, 127.9, 126.2, 125.1, 124.4, 123.3, 119.5, 116.9, 111.6, 104.8, 67.7; IR (neat) 3423, 2989, 1694, 1521, 1375, 703, 635 cm-1; HRMS m/z (M+) calcd for C26H18ClNO3: 427.0975. Found: 427.0976.
2,4-Diphenyl-9H-carbazol-3-ol (7a). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 193-195 oC. Yield: 81% (271 mg). 1H NMR (300 MHz, CDCl3) 7.89 (1H, s), 7.67-7.59 (7H, m), 7.49-7.44 (2H, m), 7.39-7.30 (4H, m), 6.99-6.89 (2H, m), 4.97 (1H, m);
13
C NMR (150 MHz, CDCl3) 143.4,
140.6, 138.7, 135.3, 134.1, 130.3, 129.6, 129.4, 128.4, 128.4, 127.6, 127.2, 125.6, 122.9, 121.9, 121.8, 121.6, 118.8, 111.3, 110.4; IR (KBr) 3394, 3091, 1649, 1518, 1320, 1187, 749, 635 cm-1; HRMS m/z (M+) calcd for C24H17NO: 335.1310. Found: 335.1309. Crystal refinement data for compound 7a: Empirical Formula- C24H17NO, M = 335.39, Monoclinic, Space group Pbca, a = 12.9997(10) Ao, b = 21.3361 (15) Ao, c = 13.5020 (10) Ao, V = 3592.6(5) Ao3, Z = 8, T = 200(2) K, ρcalcd = 1.240 mg/m3, 2Өmax. = 26.030, Refinement of 471 parameters on 7075 independent reflections out of 22336 collected reflections (Rint = 0.0875) led to R1 = 0.0484 [I >2σ(I)], wR2 = 0.1209 (all data) and S = 0.906 with the largest difference peak and hole of 0.158 and -0.195 e.Ao-3 respectively. The crystal structure has been deposited at the Cambridge Crystallographic Data Centre (CCDC 1046362). The data can be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/data_request/cif. 152
2,4-Bis(4-methoxyphenyl)-9H-carbazol-3-ol (7b). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 155-157 oC. Yield: 80% (316 mg). 1H NMR (300 MHz, CDCl3 + DMSO-d6) 9.25 (1H, s), 7.53 (2H, d, J = 8.7 Hz), 7.43 (2H, d, J = 8.7 Hz), 7.31-7.18 (3H, m), 7.07 (2H, d, J = 8.7 Hz), 6.986.90 (3H, m), 6.81 (1H, t, J = 7.8 Hz), 5.14 (1H, s), 3.86 (3H, s), 3.78 (3H, s);
13
C NMR (75 MHz, CDCl3 + DMSO-d6) 159.2, 158.4, 143.1, 140.6,
134.2, 131.3, 131.0, 130.4, 127.2, 126.9, 124.9, 122.6, 121.4, 121.1, 121.0, 117.9, 114.5, 113.5, 110.9, 110.3, 55.1, 55.0; IR (KBr) 3371, 2936, 1659, 1446, 1308, 801, 851, 540 cm-1; HRMS m/z (M+) calcd for C26H21NO3: 395.1521. Found: 395.1519. 1,2,4-triphenyl-9H-carbazol-3-ol (7c).The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 275-277 oC. Yield: 78% (320 mg). 1H NMR (300 MHz, CDCl3) 8.17 (1H, s), 7.95-7.83 (5H, m), 7.59-7.50 (12H, m), 7.35 (1H, d, J = 8.4 Hz), 7.21-7.17 (1H, m), 5.18 (1H, s); 13C NMR (75 MHz, CDCl3) 143.8, 140.2, 137.0, 136.1, 135.7, 132.8, 131.3, 130.4, 130.3, 129.2, 128.5, 128.5, 128.2, 128.2, 127.1, 126.1, 125.6, 123.8, 123.1, 122.1, 121.1, 120.8, 118.7, 110.4; IR (KBr) 3440, 3066, 1612, 1391, 1128, 752 cm-1; HRMS m/z (M+) calcd for C30H21NO: 411.1623. Found: 411.1623. 1-(2-Bromophenyl)-2,4-diphenyl-9H-carbazol-3-ol
(7d).
The
title
compound was prepared according to the general procedure. The product was obtained as a solid, mp 213-215 oC. Yield: 72% (352 mg). 1H NMR 153
(300 MHz, CDCl3) 7.92-7.88 (2H, m), 7.85-7.75 (5H, m), 7.57-7.55 (2H, m), 7.48-7.47 (3H, m), 7.44-7.40 (4H, m), 7.37-7.29 (2H, m), 7.147.08 (1H, m), 5.07 (1H, s);
13
C NMR (75 MHz, CDCl3) 143.6, 140.4,
138.0, 135.9, 135.7, 132.8, 132.6, 130.7, 130.5, 129.21, 129.2, 129.1, 128.2, 128.1, 127.3, 127.2, 126.5, 125.6, 124.6, 123.2, 123.0, 122.1, 121.1, 121.1, 118.8, 110.5; IR (KBr) 3433, 3058, 1711, 1608, 1262, 747 cm-1; HRMS m/z (M+) calcd for C30H20BrNO: 489.0728. Found: 489.0726.
8-Methoxy-1,2,4-triphenyl-9H-carbazol-3-ol (7e). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 244-246 oC. Yield: 78% (343 mg). 1H NMR (300 MHz, CDCl3) 8.04 (1H, s), 7.68-7.51 (5H, m), 7.32-7.19 (10H, m), 6.86-6.76 (2H, m), 6.67 (1H, d, J = 7.2 Hz), 4.88 (1H, s), 3.91 (3H, s); 13
C NMR (75 MHz, CDCl3) 155.9, 145.4, 143.8, 137.1, 136.2, 135.8,
132.7, 131.3, 130.7, 130.4, 130.3, 129.0, 128.5, 128.2, 128.1, 127.0, 126.3, 124.3, 124.1, 121.6, 120.8, 118.9, 114.7, 105.6, 55.3; IR (KBr) 3394, 3084, 1693, 1456, 1266, 870, 751, 517 cm-1; HRMS m/z (M+) calcd for C31H23NO2: 441.1729. Found: 441.1729. 7-Bromo-1,2,4-triphenyl-9H-carbazol-3-ol (7f). The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 252-254 oC. Yield: 74% (361 mg). 1H NMR (300 MHz, CDCl3) 7.98 (1H, s), 7.75-7.66 (5H, m), 7.54 (1H, s), 7.44-7.37 (10H, m), 7.11 (1H, d, J = 8.4 Hz), 7.00 (1H, d, J = 8.7 Hz), 5.00 (1H, s); 154
13
C NMR (75 MHz, CDCl3) 144.2, 141.0, 136.8, 135.9, 135.5, 132.9,
131.2, 130.2, 130.2, 129.2, 129.1, 128.6, 128.3, 128.2, 127.3, 126.7, 124.1, 123.3, 122.2, 122.1, 120.8, 120.7, 119.2, 113.4; IR (KBr) 3359, 3064, 1673, 1446, 1296, 960, 740, 505 cm-1; HRMS m/z (M+) calcd for C30H20BrNO: 489.0728. Found: 489.0726. 5-Chloro-1,2,4-triphenyl-9H-carbazol-3-ol
(7g). The title compound
was prepared according to the general procedure. The product was obtained as a solid, mp 240-242oC. Yield: 68% (302 mg). 1H NMR (600 MHz, CDCl3) 7.75-7.72 (2H, m), 7.68-7.64 (4H, m), 7.59 (1H, t, J = 7.8 Hz), 7.40 (2H, d, J = 7.2 Hz), 7.33-7.26 (4H, m), 7.26-7.24 (3H, m), 7.227.18 (1H, m), 7.13 (1H, d, J = 7.8 Hz), 6.96-6.94 (1H, m), 4.93 (1H, s); 13
C NMR (150 MHz, CDCl3) 144.0, 138.5, 136.8, 135.9, 135.1, 133.5,
131.2, 130.2, 130.1, 129.3, 129.1, 128.6, 128.5, 128.2, 127.2, 127.0, 126.9, 125.7, 124.3, 124.1, 121.7, 120.4, 113.2, 111.3; IR (KBr) 3353, 3058, 1685, 1446, 1296, 960, 742, 509 cm-1; HRMS m/z (M+) calcd for C30H20ClNO: 445.1233. Found: 445.1235.
Ethyl
1-(2,5-dimethylfuran-3-yl)-3-hydroxy-9H-carbazole-4-
carboxylate (9a). The title compound was prepared according to the general procedure. The product was obtained as a brown liquid. Yield: 74% (258 mg). 1H NMR (600 MHz, CDCl3) 11.24 (1H, s), 8.58 (1H, d, J = 9.0 Hz), 8.20 (1H, s), 7.40-7.39 (2H, m), 7.19-7.17 (1H, m), 6.99 (1H, s), 6.21 (1H, s), 4.68 (2H, q, J = 7.2 Hz), 2.36 (3H, s), 2.33 (3H, s), 1.57 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 171.3, 157.8, 151.1, 147.9, 155
140.3, 132.4, 126.1, 125.7, 125.4, 122.6, 119.9, 118.9, 116.9, 116.1, 110.9, 106.8, 104.8, 61.7, 14.4, 13.5, 12.6; IR (neat) 3380, 2923, 1650, 1392, 1309, 1240, 740 cm-1; HRMS m/z (M+) calcd for C21H19NO4: 349.1314. Found: 349.1314.
Ethyl
1-(2,5-dimethylthiophen-3-yl)-3-hydroxy-9H-carbazole-4-
carboxylate (9b). The title compound was prepared according to the general procedure. The product was obtained as brown liquid. Yield: 73% (266 mg). 1H NMR (600 MHz, CDCl3) 11.22 (1H, s), 8.58 (1H, d, J = 8.4 Hz), 8.10 (1H, s), 7.40-7.39 (2H, m), 7.18-7.17 (1H, m), 6.99 (1H, s), 6.77 (1H, s), 4.68 (2H, q, J = 7.2 Hz), 2.50 (3H, s), 2.34 (3H, s), 1.57 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 171.2, 157.6, 140.3, 137.5,
134.9, 133.1, 132.4, 128.0, 126.1, 126.1, 125.4, 122.5, 119.9, 118.9, 116.7, 110.8, 105.1, 61.7, 15.2, 14.4, 13.8; IR (neat) 3385, 2935, 1681, 1397, 209, 1140, 743 cm-1; HRMS m/z (M+) calcd for C21H19NO3S: 365.1086. Found: 365.1085.
Benzyl
1-(2,5-dimethylfuran-3-yl)-3-hydroxy-9H-carbazole-4-
carboxylate (9c). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 73% (300 mg). 1H NMR (300 MHz, CDCl3) 11.23 (1H, s), 8.39 (1H, d, J = 8.4 Hz), 8.16 (1H, s), 7.54-7.52 (2H, m), 7.40-7.29 (6H, m), 6.99 (1H, s), 6.20 (1H, s), 5.64 (2H, s), 2.35 (3H, s), 2.32 (3H, s);
13
C NMR (75 MHz,
CDCl3) 171.0, 158.0, 151.1, 147.9, 140.2, 134.9, 132.4, 129.1, 128.73, 128.70, 126.0, 125.9, 125.7, 122.5, 120.0, 118.8, 117.0, 116.0, 110.7, 156
106.8, 104.5, 67.3, 13.5, 12.5; IR (neat) 3395, 2963, 1667, 1389, 1307, 1262, 756 cm-1; HRMS m/z (M+) calcd for C26H21NO4: 411.1471. Found: 411.1471.
Benzyl
1-(2,5-dimethylthiophen-3-yl)-3-hydroxy-9H-carbazole-4-
carboxylate (9d). The title compound was prepared according to the general procedure. The product was obtained as brown liquid. Yield: 75% (320 mg). 1H NMR (300 MHz, CDCl3) 11.21 (1H, s), 8.41 (1H, d, J = 8.4 Hz), 8.07 (1H, s), 7.55-7.53 (2H, m), 7.41-7.32 (5H, m), 7.00 (1H, s), 6.94-6.90 (1H, m), 6.76 (1H, s), 5.65 (2H, s), 2.49 (3H, s), 2.33 (3H, s); 13
C NMR (150 MHz, CDCl3) 170.9, 157.9, 140.3, 137.5, 134.96,
134.93, 133.2, 132.5, 129.1, 128.8, 128.7, 128.3, 126.2, 126.1, 125.8, 122.5, 120.1, 118.9, 116.8, 110.7, 104.9, 67.4, 15.2, 13.8; IR (neat) 3387, 2989, 1675, 1397, 209, 1140, 743 cm-1; HRMS m/z (M+) calcd for C26H21NO3S: 427.1242. Found: 427.1239.
Ethyl
1-(2,5-dimethylfuran-3-yl)-3-hydroxy-2-methyl-9H-carbazole-
4-carboxylate (9e). The title compound was prepared according to the general procedure. The product was obtained as brown liquid. Yield: 71% (257 mg). 1H NMR (600 MHz, CDCl3) 11.68 (1H, s), 8.53 (1H, d, J = 8.4 Hz), 7.95 (1H, s), 7.36-7.35 (2H, m ), 7.16-7.14 (1H, m), 6.02 (1H, s), 4.68 (2H, q, J = 7.2 Hz), 2.37 (3H, s), 2.25 (3H, s), 2.10 (3H, s), 1.57 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 171.8, 156.8, 151.0, 147.6,
139.6, 133.0, 125.4, 125.0, 124.6, 124.5, 122.7, 118.6, 116.6, 115.6, 110.7, 107.8, 104.4, 61.6, 14.4, 13.6, 13.6, 12.4; IR (neat) 3398, 2990, 157
1670, 1383, 1318, 1228, 747 cm-1; HRMS m/z (M+) calcd for C22H21NO4: 363.1471. Found: 363.1467.
Ethyl
1-(2,5-dimethylthiophen-3-yl)-3-hydroxy-2-methyl-9H-
carbazole-4-carboxylate (9f). The title compound was prepared according to the general procedure. The product was obtained as brown liquid. Yield: 72% (272 mg). 1H NMR (600 MHz, CDCl3) 11.69 (1H, s), 8.54 (1H, d, J = 8.4 Hz), 7.83 (1H, s), 7.35-7.34 (2H, m), 7.17-7.14 (1H, m), 6.58 (1H, s), 4.69 (2H, q, J = 7.2 Hz), 2.50 (3H, s), 2.20 (3H, s), 2.13 (3H, s), 1.57 (3H, t, J = 7.2 Hz);
13
C NMR (150 MHz, CDCl3) 171.8,
156.7, 139.7, 137.4, 134.7, 132.9, 132.4, 127.3, 126.3, 125.4, 125.0, 124.6, 122.6, 118.6, 116.7, 110.7, 104.6, 61.7, 15.3, 14.4, 13.6, 13.4; IR (neat) 3394, 2963, 1690, 1381, 1330, 1250, 751 cm-1; HRMS m/z (M+) calcd for C22H21NO3S: 379.1242. Found: 379.1244.
General procedure for control experiment: An oven dried two-neck round bottom flask was charged with ketoesters 2a (1.0 mmol) and 1.0 mmol of 2-nitrocinnamaldehyde (1a) and 1.0 mmol of naphthyl boronic acid (19) in 5 mL toluene and Cs2CO3 (1 equiv.) was added. Then the flask is fitted with condenser. The reaction mixture was refluxed for 5 hours. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the pure products 3a and 2-naphthol (20) in 61% (155 mg) and 31% (44 mg) yields respectively. 158
General procedure for the synthesis carbazole derivatives (21a-21d) A general procedure for the base catalyzed synthesis of carbazoles 21a21d is as follows: An oven dried two-neck round bottom flask was charged with ketoesters (1.0 mmol) and 1.0 mmol of 2-nitrochalcone in 5 mL toluene and, Cs2CO3 (2 equiv.) was added. Then, the flask was fitted with condenser. Each reaction mixture was heated at 145 0C for 10 hours in open air without using nitrogen balloons until the completion of the reaction as indicated by TLC. Then solvent was evaporated in rotary evaporator under reduced pressure to obtain the residue. The residue was purified by flash column chromatography on silica gel to isolate the pure product. Characterization data for all compounds 21a-21d are as follows:
1-Phenyl-9H-carbazol-3-ol (21a). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 74% (191 mg). 1H NMR (600 MHz, CDCl3) 8.09 (1H, s), 7.99 (1H, d, J = 8.4 Hz), 7.65 (2H, d, J = 7.8 Hz), 7.53 (2H, t, J = 6.6 Hz), 7.48 (1H, d, J = 1.8 Hz), 7.42 (1H, t, J = 7.8 Hz), 7.39-7.34 (2H, m), 7.19-7.17 (1H, m), 7.00 (1H, d, J = 1.8 Hz), 4.73 (1H, brs);
13
C NMR
(150 MHz, CDCl3) 149.6, 140.3, 138.5, 129.2, 128.3, 128.2, 127.7, 126.0, 125.7, 124.4, 123.2, 120.5, 119.1, 114.6, 110.7, 104.9; IR (neat) 3340, 3022, 1421, 1151, 748, 650 cm-1; HRMS m/z (M+) calcd for C18H13NO: 259.0997. Found: 259.0999. 2-Methyl-1-phenyl-9H-carbazol-3-ol (21b). The title compound was prepared according to the general procedure. The product was obtained as 159
a solid, mp 177-179 oC. Yield: 71% (193 mg). 1H NMR (600 MHz, CDCl3) 7.95 (1H, d, J = 7.8 Hz), 7.58 (1H, brs), 7.53 (2H, t, J = 7.8 Hz), 7.46-7.44 (2H, m), 7.41 (2H, d, J = 6.6 Hz), 7.32 (1H, t, J = 7.8 Hz), 7.26 (1H, d, J = 7.2 Hz), 7.15 (1H, t, J = 7.8 Hz), 4.40-4.00 (1H, brs), 2.23 (3H, s).;
13
C NMR (150 MHz, CDCl3) 148.1, 139.7, 137.4, 133.6, 129.8,
129.1, 129.0, 127.6, 125.3, 123.2, 121.2, 120.8, 120.1, 118.8, 110.5, 104.4, 13.4; IR (KBr) 3433, 2950, 1640, 1452, 1267, 748, 590 cm -1; HRMS m/z (M+) calcd for C19H15NO: 273.1154. Found: 273.1151. 8-Methoxy-1-phenyl-9H-carbazol-3-ol (21c). The title compound was prepared according to the general procedure. The product was obtained as a yellow liquid. Yield: 75% (216 mg). 1H NMR (600 MHz, CDCl3) 8.30 (1H, s), 7.65 (2H, d, J = 7.8 Hz), 7.59 (1H, d, J = 7.8 Hz), 7.51 (2H, t, J = 7.8 Hz), 7.45 (1H, d, J = 1.8 Hz), 7.41 (1H, t, J = 7.8 Hz), 7.11 (1H, t, J = 7.8 Hz), 6.99 (1H, d, J = 1.8 Hz), 6.86 (1H, d, J = 7.8 Hz), 4.97 (1H, brs), 3.95 (3H, s);
13
C NMR (150 MHz, CDCl3) 149.5, 145.6, 138.5,
132.0, 130.6, 129.1, 128.3, 127.6, 126.0, 124.7, 124.1, 119.4, 114.6, 112.9, 105.9, 104.9, 55.3; IR (neat) 3320, 3010, 1508, 1320, 1154, 741 cm-1; HRMS m/z (M+) calcd for C19H15NO2: 289.1103. Found: 289.1101. 6-Chloro-2-methyl-1-phenyl-9H-carbazol-3-ol
(21d).
The
title
compound was prepared according to the general procedure. The product was obtained as a solid, mp 187-188 oC. Yield: 68% (208 mg). 1H NMR (600 MHz, CDCl3) 7.90 (1H, s), 7.57 (1H, brs), 7.53 (2H, t, J = 7.8 Hz), 7.45 (1H, d, J = 7.8 Hz), 7.40-7.39 (3H, m), 7.25 (1H, d, J = 8.4 Hz), 7.17 160
(1H, d, J = 8.4 Hz), 4.72 (1H, brs), 2.22 (3H, s);
13
C NMR (75 MHz,
CDCl3) 147.0, 138.0, 136.8, 134.2, 130.1, 129.6, 129.1, 128.0, 127.01, 125.5, 124.2, 123.2, 120.6, 117.9, 111.3, 109.8, 14.0; IR (KBr) 3345, 2950, 1530, 1463, 758 cm-1; HRMS m/z (M+) calcd for C19H14ClNO: 307.0764. Found: 307.0764.
General procedure for the synthesis Hyellazole and Chlorohyllazole (22-23) To a mixture of compound 21b or 21d (0.18 mmol) and K2CO3 (50 mg, 0.36 mmol) in acetone (6 mL) was added MeI (23 μL, 0.37 mmol) under nitrogen atmosphere and the reaction was refluxed for 16 h. The reaction mixture was concentrated in vacuo and the obtained residue was subjected to silica gel (60–120 mesh) column chromatograpy to obtain compounds hyellazole 22 and chlorohyellazole 23 in pure form.
3-Methoxy-2-methyl-1-phenyl-9H-carbazole (22). (Hyellazole) The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 132-134 0C: 94% (46 mg). 1H NMR (600 MHz, CDCl3) 8.02 (1H, d, J = 7.8 Hz), 7.60 (1H, brs), 7.54-7.51 (3H, m), 7.45 (1H, d, J = 7.2 Hz), 7.42 (2H, d, J = 7.8 Hz), 7.32 (1H, t, J = 7.2 Hz), 7.28 (1H, d, J = 8.4 Hz), 7.18 (1H, t, J = 8.4 Hz), 3.99 (3H, s), 2.21 (3H, s);
13
C NMR (150 MHz, CDCl3) 152.7, 139.4, 137.5, 133.2,
129.8, 128.9, 127.5, 125.5, 125.0, 123.8, 123.6, 120.3, 119.9, 118.8, 110.6, 100.3, 56.2, 13.7; IR (KBr) 3400, 3360, 3065, 2945, 1550, 1495,
161
1380, 720 cm-1; HRMS m/z (M+) calcd for C20H17NO: 287.1310. Found: 287.1308.
6-Chloro-3-methoxy-2-methyl-1-phenyl-9H-carbazole (23) (Chlorohyellazole) The title compound was prepared according to the general procedure. The product was obtained as a solid, mp 163-164 0C: 92% (50 mg). 1H NMR (300 MHz, CDCl3) 7.94 (1H, s), 7.59 (1H, brs), 7.51-7.47 (2H, m), 7.43-7.34 (4H, m), 7.21-7.13 (2H, m), 3.93 (3H, s), 2.15 (3H, s);
13
C NMR (75 MHz, CDCl3) 152.8, 137.6, 137.1, 133.8,
129.8, 129.0, 127.7, 125.7, 125.0, 124.8, 124.7, 124.2, 119.6, 119.4, 111.5, 99.9, 56.0, 13.8; IR (KBr) 3355, 3058, 2950, 1545, 1485, 1370, 725 cm-1; HRMS m/z (M+) calcd for C20H16ClNO: 321.0920. Found: 321.0923.
Acknowledgements This research was supported by the Nano Material Technology Development Program through the Korean National Research Foundation (NRF) funded by the Korean Ministry of Education, Science, and Technology (2012M3A7B4049675) and by the Korea government (MSIP) (NRF-2014R1A2A1A11052391).
162
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166
Part-III Conclusions
167
In this thesis, synthesis of novel and diverse aromatics and heteroaromatics such as benzo[c]chromen-6-ones, biaryls, 2-pyridone and carbazole derivatives has been described under transition-metal-free conditions. Firstly, Cs2CO3-promoted one-pot synthesis of biologically interesting benzo[c]chromen-6-one derivatives was carried out in good yield starting from substituted 2-hydroxychalcones and β-ketoesters and the synthesized molecules were transformed into novel terphenyls bearing different substituents on their benzene rings. The second study consists of the development of a simple, cost effective, transition metal-free, and mild base-promoted novel cascade reaction for the synthesis of diverse and polysubstituted biaryls starting from readily available β-ketoesters, β-ketoamides or 1,3-diketones with α,β-unsaturated aldehydes or arylaldehydes in good yield. As an application of this methodology, the synthesized biaryl compounds were successfully transformed into hydrogenated product and chromene derivatives. In the next study, a highly sustainable and efficient multicomponent domino reaction of readily available 4-oxo-4H-chromene-3-carbaldehydes with 1,3ketoesters and anilines or primary aliphatic amines was developed for the synthesis of 2-pyridone derivatives under catalyst- and solvent-free conditions. Finally, a highly efficient and transition-metal-free tandem annulation process was developed for the synthesis of diverse carbazole derivatives starting from readily available 2-nitrocinnamaldehydes or 2-nitrochalcones and βketoesters or 1,3-diaryl-2-propanones. As an application of this new synthetic methodology, a concise synthesis of naturally occurring bioactive hyellazole and chlorohyellazole has been accomplished in two steps. A number of molecules bearing aromatics and heteroaromatics such as 168
benzo[c]chromen-6-ones, biaryls, 2-pyridone and carbazole skeletons have been found in nature. These newly developed methodologies and the synthesized novel compounds could be expected to be widely used in pharmaceutical and electronic industries.
169
Part-IV
Appendix
170
NMR Spectra for Representative Compounds from Part-II (Section-2.1 to 2.4) Section-2.1
171
Section-2.2
172
Section-2.3
173
Section-2.4
174
List of Publications 1. Poudel, T. N.; Lee, Y. R., “An advanced and novel one-pot synthetic method for diverse benzo[c]chromen-6-ones by transition metal free mild base-promoted domino reactions of substituted 2-hydroxychalcones with β-ketoesters and its application to polysubstituted terphenyls.” Org. Biomol. Chem, 2014, 12, 919-930. DOI: 10.1039/c3ob41800f 2. Poudel, T. N.; Lee, Y. R., “Transition-metal-free benzannulation for diverse and polyfunctionalized biaryl formation.” Org. Lett. 2015, 17, 2050-2053. DOI: 10.1021/acs.orglett.5b00996
3. Poudel, T. N.; Lee, Y. R.; Kim, S. H., “Eco-friendly synthesis of diverse and valuable 2-pyridones by catalyst- and solvent-free thermal multicomponent domino
reaction.”
Green
Chem.
2015,
17,
4579-4586.
DOI:
10.1039/C5GC01526J
4. Poudel, T. N.; Lee, Y. R., “Construction of highly functionalized carbazoles via condensation of an enolate to a nitro group.” Chem. Sci. 2015, 6, 7028-7033. DOI: 10.1039/c5sc02407b
175
Published Papers
176
177
178
179
List of papers presented in conferences 1
Poudel, T. N.; Lee, Y. R., “ One-Pot Synthesis for Biologically Interesting Diverse Benzo[c]chromene-6-ones by Base-Promoted Domino Reactions” 1st Shanghai University – Yeungnam University Kyushu University joint Symposium on Green Chemistry and Clean Technology, Shanghai University, November 22 to 24, 2013, Shanghai, China.
2
Poudel, T. N.; Lee, Y. R., “Biosynthesis of gold nanoparticles using Hovenia dulcis fruit extract and their biomedical potentials” 113th Korean Chemical Society National Meeting, April 16 to 18, 2014, KINTEX, Goyang, South Korea.
3
Poudel, T. N.; Lee, Y. R., “ One-Pot Synthesis for Biologically Interesting Diverse Benzo[c]chromene-6-ones by Base-Promoted Domino Reactions” BK21 Plus Workshop and Seminar, April 4 to 5, 2014, Gumi, South Korea.
4
Poudel, T. N.; Lee, Y. R., “Efficient One-pot synthesis of diverse benzo[c]chromene-6-ones International
Conference
by
base-promoted
“Molecular
cascade
Complexity
reactions” in
Modern
Chemistry" (MCMC-2014), September 13 - 19, 2014, Moscow, Russia.
180
5
Poudel, T. N.; Lee, Y. R., “One-Pot Synthesis of Polycycles by FeCl3-Mediated [2+2] Cycloaddition” 114th Korean Chemical Society National Meeting, October 15 to 17, 2014, Kimdaejung Convention Center, Gwangju, Korea.
6
Poudel, T. N.; Lee, Y. R., “Synthesis of diverse and polyfunctionalized biaryls via transition-metal-free benzannulation” in the International Conference “16th Tetrahedron Symposium 2015" June 16 – 19, 2015, Grand Hyatt Berlin, Germany.
7
Poudel, T. N.; Lee, Y. R., “Mild Base Mediated Novel Benzannulation for Polyfunctionalized Biaryls” in the International Conference “45th World Chemistry Congress (IUPAC-2015)" August 9 – 14, 2015, BEXCO (Busan Exhibition & Convention Center), Busan, Republic of Korea.
181
Korean Abstract 방항족 및 헤테로방향족 구축을 위한 전이금속 부재 도미노 고리화반응 테즈나라얀포우델 영남대학교 대학원 화학공학과 화학공학전공 (지도교수 이용록)
요약
방향족과 헤테로방향족 화합물은 자연에 널리 분포되어 있고, 이들은 생리활성을 가지고 있다. 그리고 이들은 항증식, 항균성,
항말라리아, 항종양, 항암 및 항진균
등에 활성을 보이고 있으며, 또핚 광학 및 기능 소재의 합성을 위핚 중요핚 원천물질 이다. 이러핚 중요성 때문에, 본 연구에서는 전이금속 촉매를 사용하지 않는 조건 하에서
도미노고리화반응을
벤조[c]크로멘-6-온,
2-피리돈과
사용하여 카바졸
182
흥미로운 유도체를
생화학적 합성하기
활성을 위해
가진
효율적인
합성방법을 개발하고자 핚다. 첫 번째로, 2-하이드록시찰콘과 β-케토에스터를 세슘카보네이트 염기 하에서 원-팟으로 반응시켜 다양핚 벤조[c]크로멘-6-온 유도체들을 효율적이고 성공적으로 합성했다.
이
반응들은
도미노
마이클첨가반응,
알돌반응,
산화고리화반응,
락톤고리화반응 등과 관련 있다. 이 반응들은 흥미로운 생화학적 활성을 가진 새로운 벤조[c]크로멘-6-온 합성물을 맊들기 위핚 빠른 길을 제시하였고, 합성된 벤조[c]크로멘-6-온 유도체들은 여러 치환기를 가진 터페닐 화합물로 전환되었다. 더 나아가, 상업적으로 구입이 가능핚 β-케토에스터, β-케토아마이드 또는 1,3-다이케톤에 시남알데하이드 또는 아릴알데하이드와 염기 하에서 반응시켜 여러 치환기를 가진 바이아릴 화합물들을 좋은 수율로 합성하였다. 이 반응의 핵심 전략(키스텝)은 다중성분(multi-component) 반응을 통해 원-팟으로 세 개의 새로운 결합을
순차적으로
맊드는
것이다.
이
새로운
바이아릴
반응은
도미노
마이클첨가반응, 알돌반응, [1,5]-수소이동, 이성질화 반응을 통해 일어난다. 이 합성방법은 바이아릴의 벤젠고리에 다양핚 치환기를 가진 생성물을 합성하는데 좋은 장점을 보이고 있다. 또핚, 4-옥소-4H-크로멘-3-카브알데하이드에 1,3-다이케토에스터, 아닐린 또는 1 차 지방족(aliphatic)아민을 반응시켜 2-피리돈 유도체를 좋은 수율로 합성하였다. 이 반응은 촉매와 용매를 사용하지 않았기 때문에 환경 친화적인 반응이라고 말핛 수 있으며, 이 반응의 반응 과정은 도미노 노에베나글축합반응, 마이클첨가반응, 고리열림반응, 고리닫힘반응을 통해 진행되었다. 183
마지막으로, 맋은 치환기를 가진 카바졸 화합물들은 전이금속촉매를 사용하지 않고,
염기
하에서
축합반응
2-나이트로시남알데하이드
또는
반응을
통해,
상업적으로
2-나이트로찰콘에
다양핚
구입이
가능핚
β-케토에스터
또는
1,3-다이아릴-2-프로판온을 사용하여 합성되었다. 이 반응은 엔올레이트의 o-니트로 에날
분자내
콘쥬게이션
첨가반응
또는
o-니트로
찰콘
분자내
콘쥬게이션
첨가반응을 통해 4 개의 새로운 결합을 형성하고, 환원제없이 원-팟으로 N-O 결합이 NH 로 전환하는 반응을 포함하고있다. 이 방법은 새롭게 생성된 벤젠고리와 카바졸 유도체들의 고리 위에 다양핚 치환기를 쉽게 도입핛 수 있는 장점을 가지고 있으며, 특히 이 합성방법을 사용하면 자연에서 발견되는 헬라졸(hyellazole)과 클로로헬라졸(chlorohyellazole)을 쉽고 간단하게 합성하였다. 이러한 새로운 전략을 통해 합성한 다양한 형태의 방향족과 헤테로방향족 화합물들은 싞약개발을 위핚 약리활성과 생리활성 측정을 위해 사용될 것이다.
184
