ASYMMETRIC SYNTHESIS OF FURAN AND OXINDOLE DERIVATIVES WITH BIFUNCTIONAL AND MULTIFUNCTIONAL ORGANIC CATALYSTS DOU XIAOWEI NATIONAL UNIVERSITY OF SINGAPORE 2013 ASYMMETRIC SYNTHESIS OF FURAN AND OXINDOLE DERIVATIVES WITH BIFUNCTIONAL AND MULTIFUNCTIONAL ORGANIC CATALYSTS DOU XIAOWEI (B.Sc., Nanjing Univ.) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2013 PHD DISSERTATION 2013 DOU XIAOWEI Thesis Declaration I hereby declare that this thesis is my original work and it has been written by me in its entirety under the supervision of A/P Lu Yixin, Chemistry Department, National University of Singapore, between 08/2009 and 07/2013. I have duly acknowledged all the sources of information which have been used in the thesis. This thesis has not been submitted for any degree in any university previously. The content of the thesis has been partly published in: 1. Xiaowei Dou, Xiaoyu Han, Yixin Lu. Chem. Eur. J. 2012, 18, 85. 2. Xiaowei Dou, Fangrui Zhong, Yixin Lu. Chem. Eur. J. 2012, 18, 13945. 3. Xiaowei Dou, Yixin Lu. Chem. Eur. J. 2012, 18, 8315. 4. Xiaowei Dou, Yixin Lu. Org. Biomol. Chem. 2013, 11, 5217. 5. Xiaowei Dou, Weijun Yao, Bo Zhou, Yixin Lu. Chem. Commun. 2013, 49, 9224. 6. Xiaowei Dou, Bo Zhou, Weijun Yao, Fangrui Zhong, Chunhui Jiang, Yixin Lu. Org. Lett. 2013, 15, 4920. Dou Xiaowei Name Signature Date i PHD DISSERTATION 2013 ii DOU XIAOWEI PHD DISSERTATION 2013 DOU XIAOWEI Acknowledgements I would like to express my whole-hearted gratitude to all the people who have helped and inspired me during my PhD studies in the past years. This thesis could not have been accomplished without their supports. Foremost, my deepest appreciation and respect go to my supervisor, Prof. Lu Yixin, for his constant support and guidance throughout my studies. His profound knowledge, invaluable suggestions and encouragement benefit me a lot and will always accompany me in my future career. Every member of Prof. Lu’s group has been extremely supportive and I really appreciate their support and encouragement. I especially thank Dr. Wang Youqing, Dr. Xie Xiaoan, Dr. Wang Haifei, Dr. Wang Suxi, Dr. Yao Weijun, Dr. Wang Tianli, Dr. Vasudeva Rao Gandi, Dr. Zhu Qiang, Dr. Han Xiao, Dr. Liu Xiaoqian, Dr. Luo Jie, Dr. Liu Chen, Dr. Chen Guoying, Dr. Zhong Fangrui, Dr. Han Xiaoyu, Jolin Foo, Jacek Kwiatkowski, Liu Guannan, Jiang Chunhui, Wen Shan, Wong Yee Lin, Zhou Xin, Zhou Bo and other labmates for their help during my PhD studies. They are not only co-workers in chemistry, but also good friends in life. I also want to thank NUS for the research scholarship and financial support. Thanks also go to all the staff in department of chemistry for their help: I especially thank Madam Han Yanhui and Dr. Wu Ji'en (NMR analysis), Ms Tan Geok Kheng and Ms Hong Yimian (X-ray crystallography analysis), Madam Wong Lai Kwai and Madam Lai Hui Ngee (Mass analysis) for their great help. Last but not least, I am extremely grateful to my parents and my sister who give me their unconditional love and support. Finally, I thank my beloved wife, Li Yingying, for always being there for me, understanding and believing in me. My gratitude also goes to my parentsinlaw for their endless love and support. iii PHD DISSERTATION 2013 DOU XIAOWEI Table of Contents Thesis Declaration i Acknowledgements iii Table of Contents iv Summary ix List of Tables xi List of Figures xiii List of Schemes xiv List of Abbreviations xvii List of Publications xxi Chapter Introduction 1.1 1.2 Asymmetric Organocatalysis 1.1.1 Introduction 1.1.2 Development of Asymmetric Organocatalysis Chiral Hydrogen Bonding Based Organocatalysis 1.2.1 Introduction 1.2.2 Hydrogen Bonding Organocatalysis Based on Thiourea/Urea 1.2.2.1 Diamine Derived Thiourea/Urea Organocatalysts 10 1.2.2.2 Cinchona Alkaloids Derived Thiourea/Urea Organocatalysts 18 1.2.2.3 Binaphthyl Derived Thiourea/Urea Organocatalysts iv 22 PHD DISSERTATION 2013 DOU XIAOWEI 1.2.2.4 Indane Derived Thiourea/Urea Organocatalysts 24 1.2.2.5 Amino Acids Derived Thiourea/Urea Organocatalysts 26 1.2.3 Hydrogen Bonding Organocatalysis Based on Other Functionality 1.3 Project Objectives 28 34 Chapter From the FeistBénary Reaction to Organocatalytic Domino MichaelAlkylation Reactions: Asymmetric Synthesis of 3(2H)Furanones 2.1 Introduction 36 2.2 Results and Discussion 38 2.2.1 Catalysts Design and Synthesis 38 2.2.2 Reaction Optimization 40 2.2.3 Substrate Scope 43 2.2.4 Synthetic Manipulations of the 3(2H)-Furanone Product 45 2.2.5 Proposed Transition State 45 2.3 Conclusions 46 2.4 Experimental Section 47 2.4.1 Materials and General Methods 47 2.4.2 Catalysts Preparation 48 2.4.3 Representative Procedure 51 2.4.4 Derivatizations of the 3(2H)-Furanone Product 52 2.4.5 X-Ray Crystallographic Analysis and Determination of Configurations of the 3(2H)-Furanone Products 2.4.6 Analytical Data of the 3(2H)-Furanone Products 53 55 v PHD DISSERTATION 2013 DOU XIAOWEI Chapter A Highly Enantioslective Synthesis of Functionalized 2,3Dihydrofurans by a Modified FeistBénary Reaction 3.1 Introduction 65 3.2 Results and Discussion 67 3.2.1 Reaction Optimization 67 3.2.2 Substrate Scope 69 3.3 Conclusions 71 3.4 Experimental Section 71 3.4.1 Materials and General Methods 71 3.4.2 Representative Procedure 72 3.4.2 Analytical Data of the 2,3-Dihydrofuran Products 72 Chapter Diastereodivergent Synthesis of 3-Spirocyclopropyl-2-oxindoles through Direct Enantioselective Cyclopropanation of Oxindoles vi 4.1 Introduction 82 4.2 Results and Discussion 86 4.2.1 Reaction Optimization 86 4.2.2 Substrate Scope 92 4.3 Conclusions 95 4.4 Experimental Section 96 4.4.1 Materials and General Methods 96 4.4.2 Preparation of Multifunctional Catalysts 97 4.4.3 Representative Procedure 101 4.4.4 MS Spectrum of Ammonium Enolate Intermediate 103 Chapter Enantioselective Conjugate Addition of 3-Fluorooxindoles to Vinyl Sulfone MHz, CDCl3) δ 28.0, 84.6 (d, J = 190.4 Hz), 85.4, 117.0, 123.3 (d, J = 16.4 Hz), 126.1, 130.6 (d, J = 2.7 Hz), 131.7 (d, J = 2.7 Hz), 139.4 (d, J = 4.6 Hz), 148.5, 168.1 (d, J = 18.2 Hz); 19F NMR (282.38 MHz, CDCl3) δ -112.2 (d, J = 52.6 Hz); HRMS (ESI) m/z calcd for C13H13FClNO3Na [M+Na]+ = 308.0460, found = 308.0452. tert-Butyl 6-chloro-3-fluoro-2-oxoindoline-1-carboxylate 6-1c A white solid; 1H NMR (300 MHz, CDCl3) δ 1.64 (s, 9H), 5.68 (d, J = 51.1 Hz, 1H), 7.21-7.24 (m, 1H), 7.43 (dd, J = 1.1 Hz, 7.9 Hz, 1H), 7.97 (s, 1H); 13 C NMR (125 MHz, CDCl3) δ 28.0, 84.4 (d, J = 189.5 Hz), 85.6, 116.5, 120.0 (d, J = 16.4 Hz), 125.2 (d, J = 2.7 Hz), 126.8, 137.8 (d, J = 3.7 Hz), 141.9 (d, J = 4.6 Hz), 148.4, 168.4 (d, J = 18.2 Hz); 19F NMR (282.38 MHz, CDCl3) δ -110.8 (d, J = 51.6 Hz); HRMS (ESI) m/z calcd for C13H13FClNO3Na [M+Na]+ = 308.0460, found = 308.0452. tert-Butyl 5-bromo-3-fluoro-2-oxoindoline-1-carboxylate 6-1d - 210   PHD DISSERTATION 2013 DOU XIAOWEI A white solid; 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 9H), 5.69 (d, J = 50.9 Hz, 1H), 7.55-7.59 (m, 1H), 7.63 (s, 1H), 7.76-7.82 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 28.0, 84.4 (d, J = 190.4 Hz), 85.5, 117.1, 117.3, 123.6 (d, J = 16.4 Hz), 128.9 (d, J = 34.6 Hz), 134.7 (d, J = 3.7 Hz), 139.9, 148.5, 168.1 (d, J = 21.0 Hz); 19 F NMR (282.38 MHz, CDCl3) δ -112.1 (dd, J= 2.1 Hz, 27.3 Hz); HRMS (ESI) m/z calcd for C13H13F79BrNO3Na [M+Na]+ = 351.9951, found = 351.9926, C13H13F81BrNO3Na [M+Na]+ = 353.9937, found = 353.9918. tert-Butyl 3,7-difluoro-2-oxoindoline-1-carboxylate 6-1e F O F N Boc 6-1e A white solid; 1H NMR (300 MHz, CDCl3) δ 1.61 (s, 9H), 5.75 (d, J = 50.8 Hz, 1H), 7.17-7.24 (m, 2H), 7.31-7.34 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 27.6, 76.5, 84.6 (d, J = 160.4 Hz), 86.1 (d, J = 2.2 Hz), 119.8 (d, J = 3.3 Hz), 120.1 (d, J = 2.7 Hz), 121.8 (d, J = 3.3 Hz), 124.7 (d, J = 15.3 Hz), 126.2 (d, J = 2.7 Hz), 126.3, 146.7 (d, J = 14.2 Hz), 150.2, 168.4 (d, J = 18.5 Hz); 19F NMR (282.38 MHz, CDCl3) δ -111.0 (d, J = 50.5 Hz), (-42.2) (t, J =7.2 Hz); HRMS (ESI) m/z calcd for C13H13F2NO3Na [M+Na]+ = 292.0761, found = 292.0753. tert-Butyl 7-chloro-3-fluoro-2-oxoindoline-1-carboxylate 6-1f - 211   Chapter Enantioselective Conjugate Addition of 3-Fluorooxindoles to Vinyl Sulfone A white solid; 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 9H), 5.74 (d, J = 50.8 Hz, 1H), 7.15-7.21 (m, 1H), 7.41-7.44 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 27.7, 85.1 (d, J = 191.3 Hz), 86.3, 119.5, 124.5, 125.0 (d, J = 21.9 Hz), 125.8, 133.3, 138.2, 147.1, 169.2 (d, J = 20.0 Hz); 19F NMR (282.38 MHz, CDCl3) δ -112.5 (d, J = 50.5 Hz); HRMS (ESI) m/z calcd for C13H13FClNO3Na [M+Na]+ = 308.0460, found = 308.0452. tert-Butyl 3-fluoro-5-methyl-2-oxoindoline-1-carboxylate 6-1g A colorless oil; 1H NMR (300 MHz, CDCl3) δ 1.63 (s, 9H), 2.37 (s,3H), 5.68 (d, J = 51.3 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.8, 28.0, 84.8, 85.1 (d, J = 187.6 Hz), 115.3 (d, J = 1.6 Hz), 121.6 (d, J = 16.4 Hz), 126.3, 132.1 (d, J = 3.3 Hz), 134.8 (d, J = 2.7 Hz), 138.4 (d, J = 5.5 Hz), 148.6, 169.0 (d, J = 17.5 Hz); 19 F NMR (282.38 MHz, CDCl3) δ -110.8 (d, J = 51.6 Hz); HRMS (ESI) m/z calcd for C14H16FNO3Na [M+Na]+ = 288.1006, found = 288.1020. tert-Butyl 3-fluoro-5-methoxy-2-oxoindoline-1-carboxylate 6-1h - 212   PHD DISSERTATION 2013 DOU XIAOWEI F MeO O N Boc 6-1h A white solid; 1H NMR (500 MHz, CDCl3) δ 1.63 (s, 9H), 3.83 (s,3H), 5.69 (d, J = 51.1 Hz, 1H), 6.95-6.98 (m, 1H), 7.06 (s, 1H), 7.79 (dd, J = 1.3 Hz, 8.8 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 28.1, 55.8, 84.9, 85.2 (d, J = 188.6 Hz), 111.4, 116.7, 117.0 (d, J = 3.6 Hz), 122.8 (d, J = 16.4 Hz), 134.1 (d, J = 3.6 Hz), 148.7, 157.2 (d, J = 3.7 Hz), 169.0 (d, J = 19.1 Hz); 19F NMR (282.38 MHz, CDCl3) δ -111.4 (t, J = 25.8 Hz); HRMS (ESI) m/z calcd for C14H16FNO4Na [M+Na]+ = 304.0956, found = 304.0965. tert-Butyl 3-fluoro-5,7-dimethyl-2-oxoindoline-1-carboxylate 6-1i F Me O N Boc Me 6-1i A white solid; 1H NMR (300 MHz, CDCl3) δ 1.62 (s, 9H), 2.19 (s, 3H), 2.32 (s, 3H), 5.67 (d, J = 51.3 Hz, 1H), 7.05 (s, 1H), 7.14 (s, 1H); 13 C NMR (75 MHz, CDCl3) δ 19.3, 20.7, 27.7, 85.1, 85.6 (d, J = 188.7 Hz), 123.0 (d, J = 16.4 Hz), 124.0, 124.2 (d, J = 1.6 Hz), 134.7 (d, J = 3.3 Hz), 135.0 (d, J = 3.3 Hz), 136.8 (d, J = 4.9 Hz), 148.5, 170.1 (d, J = 17.5 Hz); 19 F NMR (282.38 MHz, CDCl3) δ -110.6 (d, J = 51.6 Hz); HRMS (ESI) m/z calcd for C15H17FNO3 [M-H]- = 278.0810, found = 278.0818. 6.4.3 Representative Procedure for the Conjugate Addition Reactions - 213   Chapter Enantioselective Conjugate Addition of 3-Fluorooxindoles to Vinyl Sulfone Oxindole 6-1 (0.05 mmol) was at room temperature added to a mixture of vinylsulfone 6-2a (0.05 mmol), catalyst 6-6 (1.5 mg, 0.0025 mmol) and Å molecular sieves (10 mg) in CHCl3 (1.0 mL) in a sample vial, and the resulting mixture was sealed and stirred at room temperature for the time specified in Table 6.2. At the end of the reaction, the reaction mixture was filtered and concentrated in vacuo to yield the crude product, which was purified by flash column chromatography (ethyl acetate/hexane = 1:2) to afford the desired adducts 6-3. The enantiomeric excessess of 6-3 were determined by chiral HPLC analysis. 6.4.4 X-Ray Crystallographic Analysis and Determination of Configurations of the Conjugate Addition Products The absolute configuration of the product 6-3e was assigned based on the X-ray crystallographic analysis of a single crystal of 6-3e (Figure 6.2). The configurations of other products 6-3 were assigned by analogy. - 214   PHD DISSERTATION 2013 DOU XIAOWEI Figure 6.2 X-ray structure of 6-3e Table 6.3 Crystal Data and Structure Refinement for c009. Identification code c009 Empirical formula C27 H25 F2 N O7 S2 Formula weight 577.60 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Orthorhombic Space group P2(1)2(1)2(1) Unit cell dimensions a = 8.2718(7) Å = 90°. b = 13.6799(13) Å = 90°. c = 23.831(2) Å = 90°. Volume 2696.7(4) Å3 Z - 215 -   Chapter Enantioselective Conjugate Addition of 3-Fluorooxindoles to Vinyl Sulfone Density (calculated) 1.423 Mg/m3 Absorption coefficient 0.258 mm-1 F(000) 1200 Crystal size 0.60 x 0.20 x 0.08 mm3 Theta range for data collection 1.71 to 27.50°. Index ranges -10[...]... Analysis and Determination of Configurations of the 3-Fluorooxindole Products 6.4.5 Analytical Data of the Conjugate Addition Products viii 214 216 PHD DISSERTATION 2013 DOU XIAOWEI Summary This thesis describes the development of asymmetric synthesis of furan and oxindole derivatives with tertiary amine thiourea organocatalysts, including enantioselective synthesis of 3(2H)-furanones and 2,3-dihydrofurans... 3(2H)-furanones and 2,3-dihydrofurans with novel Lthreonine derived bifunctional catalysts, asymmetric formation of 3-spirocyclopropyl2-oxindoles and 3-heteroatom-substituted-oxindoles with L-threonine-incorporating multifunctional catalysts, and a quinine-derived bifunctional catalyst catalyzed chiral 3-fluorooxindoles synthesis Chapter 1 gave a brief introduction and development of asymmetric organocatalysis... Crystallographic Analysis and Determination of Configurations of the Spirooxindole Products 4.4.6 Analytical Data of the Spirooxindole Products 104 109 Chapter 5 A Facile and Versatile Approach for the Asymmetric Synthesis of Oxindoles with a 3-Heteroatom-substituted Quaternary Stereocenter 5.1 Introduction 130 5.2 Results and Discussion 134 5.2.1 Reaction Optimization for the Synthesis of Chiral 3Chlorooxindoles... field of catalysis are described Chapter 2 described the first organocatalytic asymmetric synthesis of 3(2H)furanones derivatives In the presence of L-threonine-based bifunctional tertiaryamine thiourea catalysts, a highly enantioselective modified FeistBénary reaction between ethyl 4-bromoacetoacetate and nitroolefins afforded optically enriched 3(2H)-furanone derivatives Moreover, the furanone derivatives. .. 2.1 Synthesis of furanones through a modified FeistBénary reaction 38 Scheme 2.2 Synthetic route for preparation of catalyst 2-8a 40 Scheme 2.3 Synthesis of furanone employing bromodiketone 44 Scheme 2.4 Preparation of tetronic acid and -lactam from furanone 2-3a 45 Scheme 2.5 A plausible transition state model 46 Scheme 3.1 Modified FeistBénary reaction for synthesis of functionalized 2,3dihydrofurans... oxindoles 133 Scheme 5.3 Synthesis of various 3-heteroatom-substituted prochiral oxindoles 139 Scheme 5.4 Introducing different heteroatoms to 3-chlorooxindole adduct 5-3a 145 Scheme 5.5 Synthetic manipulations of oxindoles with a 3-substituted heteroatom 147 Scheme 6.1 Catalytic asymmetric synthesis of 3-fluoro-3-substituted oxindoles 202 Scheme 6.2 Reaction of 3-fluorooxindole with different electrophiles... Cyclopropanation of Oxindole 4-1a Catalyzed by Different Tertiary Amine Thiourea Catalysts Table 4.2 68 Substrate Scope of the Asymmetric Synthesis of 2,3-Dihydrofurans via a 3-3b-Catalyzed Domino MichaelAlkylation Reaction Table 4.1 43 Domino MichaelAlkylation Reaction between β-Ketoester and Bromonitroolefin Table 3.2 42 88 Survey of Additives, Temperature and Catalyst Loading Effects on 4-7g Catalyzed Asymmetric. .. Materials and General Methods 148 5.4.2 Preparation of the Prochiral 3-Heteroatom Oxindoles 149 vii PHD DISSERTATION 2013 DOU XIAOWEI 5.4.3 Representative Procedure 156 5.4.4 Synthetic Manipulation of 3-Heteroatom Oxindole Products 158 5.4.5 X-Ray Crystallographic Analysis and Determination of Configurations of the 3-Chlorooxindole and 3Sulfenyloxindole Products 5.4.6 Analytical Data of the 3-Heteroatom Oxindole. .. 3Chlorooxindoles 134 5.2.2 Substrate Scope for the Synthesis of Chiral 3Chlorooxindoles 136 5.2.3 Facile Synthesis of Various 3-Heteroatom-substituted Oxindoles 138 5.2.4 Substrate Scope for the Synthesis of Chiral 3Heteroatomoxindoles 139 5.2.5 Introducing a Heteroatom to the 3-Chlorinated Oxindole Adduct 143 5.2.6 Synthetic Elaborations of Oxindoles with a 3-Substituted Heteroatom 145 5.3 Conclusions... Synthetic values of the oxindole adducts were demonstrated, and useful oxindoles, indolines and indole derivatives were asymmetrically prepared Chapter 6 showed the first asymmetric conjugate addition of prochiral 3fluorinated oxindoles to vinyl sulfones catalyzed by quinine-derived bifunctional tertiaryamine thiourea catalyst, furnishing biologically important chiral 3-fluoro-3substituted oxindoles in . development of asymmetric synthesis of furan and oxindole derivatives with tertiary amine thiourea organocatalysts, including enantioselective synthesis of 3(2H)-furanones and 2,3-dihydrofurans with. NATIONAL UNIVERSITY OF SINGAPORE 2013 ASYMMETRIC SYNTHESIS OF FURAN AND OXINDOLE DERIVATIVES WITH BIFUNCTIONAL AND MULTIFUNCTIONAL ORGANIC CATALYSTS . ASYMMETRIC SYNTHESIS OF FURAN AND OXINDOLE DERIVATIVES WITH BIFUNCTIONAL AND MULTIFUNCTIONAL ORGANIC CATALYSTS DOU XIAOWEI