Florida State University Libraries Electronic Theses, Treatises and Dissertations The Graduate School 2005 Ring-Closing Metathesis for the Synthesis of Carbocyclic and Heterocyclic Intramolecular Baylis-Hillman Adducts Eunho Song Follow this and additional works at the FSU Digital Library. For more information, please contact [email protected] THE FLORIDA STATE UNIVERSITY COLLEGE OF ARTS AND SCIENCES RING-CLOSING METATHESIS FOR THE SYNTHESIS OF CARBOCYCLIC AND HETEROCYCLIC INTRAMOLECULAR BAYLIS-HILLMAN ADDUCTS By EUNHO SONG A Thesis submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Master of Science Degree awarded: Summer semester, 2005 The members of the Committee approve the thesis of EUNHO SONG defended on April 26, 2005. Marie E. Krafft Professor Directing Thesis Armen Zakarian Committee Member Gregory B. Dudley Committee Member Joseph B. Schlenoff Committee Member The Office of Graduate Studies has verified and approved the above named committee members. TABLE OF CONTENTS List of Tables v List of Figures vi List of Schemes xi List of Abbreviations xii Abstract xv I. INTRODUCTION Baylis-Hillman Reaction 1 Proposed Mechanism 2 Amine-Catalyzed Baylis-Hillman Reaction 3 Intramolecular Baylis-Hillman Reaction 5 Ring-Closing Metathesis Reaction 6 Proposed Mechanism 7 II. RESULTS AND DISCUSSION Optimization of reaction conditions for Baylis-Hillman Reaction 14 Synthesis of Carbocyclic RCM Products from Baylis-Hillman Adducts 16 Synthesis of Fused ring RCM Products from Baylis-Hillman Adducts 22 Synthesis of 6-Membered Carbocyclic RCM Products from Baylis 25 -Hillman Adducts using substituted hexenal Synthesis of 6-Membered Heterocyclic RCM Products from Baylis 27 -Hillman Adducts using Chiral-Amino acids 29 Summary iii III. EXPERIMENTAL 31 REFERENCES 145 BIOGRAPHICAL SKETCH 147 iv LIST OF TABLES Table 1. Cross-Metathesis Reactions with Esters, Aldehydes and Ketones 10 Table 2. RCM reactions using Protected and Unprotected BH Adducts 11 Table 3. RCM reaction of Baylis-Hillman adducts 12 Table 4. Amine Catalyzed BH Reaction 15 Table 5. BH Reaction with Quinuclidine 16 Table 6. RCM reaction to form IMBH Adducts 18 Table 7. BH and RCM Reaction using electron-deficient alkenes and 21 Grubbs’ catalyst Table 8. RCM Reaction for the synthesis of Fused ring Products from BH 24 Adducts Table 9. RCM Reaction from BH Adducts using β-substituted hexenal 27 v LIST OF FIGURES Figure 1. Proposed Mechanism for the Morita-Baylis-Hillman Reaction 2 Figure 2. Proposed Mechanism for the Cross-Metathesis Reaction 8 Figure 3. A variety of olefin metathesis reactions 9 Figure 4. Oxy-Cope Rearrangement 25 Figure 5. 500 MHz 1H Spectrum of 2a 56 Figure 6. 75 MHz 13C Spectrum of 2a 57 Figure 7. IR Spectrum of 2a 58 Figure 8. 500 MHz 1H Spectrum of 2b 59 Figure 9. 75 MHz 13C Spectrum of 2b 60 Figure 10. IR Spectrum of 2b 61 Figure 11. 500 MHz 1H Spectrum of 2c 62 Figure 12. 75 MHz 13C Spectrum of 2c 63 Figure 13. IR Spectrum of 2c 64 Figure 14. 500 MHz 1H Spectrum of 2d 65 Figure 15. 75 MHz 13C Spectrum of 2d 66 Figure 16. IR Spectrum of 2d 67 Figure 17. 500 MHz 1H Spectrum of 3a 68 Figure 18. 75 MHz 13C Spectrum of 3a 69 Figure 19. IR Spectrum of 3a 70 Figure 20. 500 MHz 1H Spectrum of 3b 71 Figure 21. 75 MHz 13C Spectrum of 3b 72 vi Figure 22 IR Spectrum of 3b 73 Figure 23. 500 MHz 1H Spectrum of 3c 74 Figure 24. 500 MHz 1H Spectrum of 3d 75 Figure 25. 500 MHz 1H Spectrum of 4 76 Figure 26. 75 MHz 13C Spectrum of 4 77 Figure 27. IR Spectrum of 4 78 Figure 28. 500 MHz 1H Spectrum of 8 79 Figure 29. 75 MHz 13C Spectrum of 8 80 Figure 30. IR Spectrum of 8 81 Figure 31. 500 MHz 1H Spectrum of 11 82 Figure 32. 75 MHz 13C Spectrum of 11 83 Figure 33. IR Spectrum of 11 84 Figure 34. 500 MHz 1H Spectrum of 6 85 Figure 35. 75 MHz 13C Spectrum of 6 86 Figure 36. IR Spectrum of 6 87 Figure 37. 500 MHz 1H Spectrum of 10d 98 Figure 38. 75 MHz 13C Spectrum of 10d 89 Figure 39. IR Spectrum of 10d 90 Figure 40. 500 MHz 1H Spectrum of 7 91 Figure 41. 75 MHz 13C Spectrum of 7 92 Figure 42. IR Spectrum of 7 93 Figure 43. 500 MHz 1H Spectrum of 9 94 vii Figure 44. 75 MHz 13C Spectrum of 9 95 Figure 45. IR Spectrum of 9 96 Figure 46. 500 MHz 1H Spectrum of 12 97 Figure 47. 75 MHz 13C Spectrum of 12 98 Figure 48. IR Spectrum of 12 99 Figure 49. 500 MHz 1H Spectrum of 14b 100 Figure 50. 75 MHz 13C Spectrum of 14b 101 Figure 51. IR Spectrum of 14b 102 Figure 52. 500 MHz 1H Spectrum of 14c 103 Figure 53. 75 MHz 13C Spectrum of 14c 104 Figure 54. IR Spectrum of 14c 105 Figure 55. 500 MHz 1H Spectrum of 16 106 Figure 56. 75 MHz 13C Spectrum of 16 107 Figure 57. IR Spectrum of 16 108 Figure 58. 500 MHz 1H Spectrum of 18 109 Figure 59. 75 MHz 13C Spectrum of 18 110 Figure 60. IR Spectrum of 18 111 Figure 61. 500 MHz 1H Spectrum of 17 112 Figure 62. 75 MHz 13C Spectrum of 17 113 Figure 63. IR Spectrum of 17 114 Figure 64. 500 MHz 1H Spectrum of 19 115 Figure 65. 75 MHz 13C Spectrum of 19 116 viii Figure 66. IR Spectrum of 19 117 Figure 67. 500 MHz 1H Spectrum of 24 118 Figure 68. 75 MHz 13C Spectrum of 24 119 Figure 69. IR Spectrum of 24 120 Figure 70. 500 MHz 1H Spectrum of 26 121 Figure 71. 75 MHz 13C Spectrum of 26 122 Figure 72. IR Spectrum of 26 123 Figure 73. 500 MHz 1H Spectrum of 25 124 Figure 74. 75 MHz 13C Spectrum of 25 125 Figure 75. IR Spectrum of 25 126 Figure 76. 500 MHz 1H Spectrum of 27 127 Figure 77. 75 MHz 13C Spectrum of 27 128 Figure 78. IR Spectrum of 27 129 Figure 79. 500 MHz 1H Spectrum of 28b 130 Figure 80. 75 MHz 13C Spectrum of 28b 131 Figure 81. IR Spectrum of 28b 132 Figure 82. 500 MHz 1H Spectrum of 30 133 Figure 83. 75 MHz 13C Spectrum of 30 134 Figure 84. IR Spectrum of 30 135 Figure 85. 500 MHz 1H Spectrum of 31 136 Figure 86. 75 MHz 13C Spectrum of 31 137 Figure 87. IR Spectrum of 31 138 ix Figure 88. 500 MHz 1H Spectrum of 32 139 Figure 89. 75 MHz 13C Spectrum of 32 140 Figure 90. IR Spectrum of 32 141 Figure 91. 500 MHz 1H Spectrum of 33 142 Figure 92. 75 MHz 13C Spectrum of 33 143 Figure 93. IR Spectrum of 33 144 x LIST OF SCHEMES Scheme 1. BH Reaction for synthesis of densely functionalized molecules 1 Scheme 2. BH Reaction with imidazolium-based ionic liquids 4 Scheme 3. BH reaction cyclic IMBH Adducts using DMAP 6 Scheme 4. RCM reaction using Grubbs catalyst 7 Scheme 5. Possible Products of Olefin Metathesis 13 Scheme 6. Proposed Pathway for the synthesis of intramolecular Baylis- 14 Hillman adducts Scheme 7. Synthesis of BH Adducts using nonsubstituted alkene aldehydes 17 and methyl acrylate Scheme 8. Reversible-CM-based macrocycle formation 19 Scheme 9. Synthesis of RCM Products from BH Adducts using 20 monosubstituted alkene aldehydes Scheme 10. Preparation of 2,3-dimethyl-4-pentenal for the BH reaction 22 Scheme 11. Preparation of Cyclic-BH substrates 23 Scheme 12. Preparation of 3-methyl-5-hexenal for BH reaction 25 Scheme 13. Preparation of 3,3-dimethyl-5-hexenal for BH reaction 26 Scheme 14. Preparation of (allyl-tosyl-amino)-acetaldehyde for BH 28 Reactions Scheme 15. Synthesis of Heterocyclic-RCM Products from BH Adducts 29 Scheme 16. Proposed combinatorial application for the construction of 29 Hydropyridinol derivatives xi LIST OF ABBREVATIONS br broad (spectral) Bu butyl n-Bu normal butyl oC degrees Celsius CI chemical ionization (in mass spectrometry) CM cross metathesis cm centimeters concd concentrated δ chemical shift in parts million d day(s); doublet (spectral) DABCO 1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DMAP 4-(Dimethylamino)pyridine DMSO Dimethyl sulfoxide EI electron impact (in mass spectrometry) Et ethyl FT Fourier transform g gram(s) h hour(s) HQD hydroxy quinuclidine xii Hz hertz IMBH Intramolecular Baylis-Hillman Reaction IR infrared J coupling constant (in NMR) LAH lithium aliminium hydride m multiplet (spectral) Me methyl MHz megahertz min minute(s) mol mole(s) MS mass spectrometry m/z mass to charge ratio (in mass spectrometry) MVK methyl vinyl ketone NMR nuclear magnetic resonance Tf trifluoromethanesulfonyl Ph phenyl ppm parts per million ( in NMR) pr propyl q quartet (spectral) RCM ring-closing methathesis RDS rate-determining step Rf retention factor (in chromatography) xiii ROM ring-opening metathesis TBS tert-butyldimethylsilyl THF tetrahydrofuran Ts toluenesulfonyl UV untraviolet xiv ABSTRACT We have investigated optimum conditions for the Baylis-Hillman and ring-closing metathesis (RCM) reactions. In our experiments, we obtained the best results with quinuclidine (0.25 eq), and MeOH (0.75 eq) for the Baylis-Hillman reaction and 10 mol % of Grubbs #2 with DCM (0.01 M) for the RCM. We performed further reactions based on these optimum conditions. We examined the Baylis-Hillman and RCM reactions the under same conditions in order to extend the ring size from 5-membered to 8-membered and succeeded in the generation of 5-, 6- and 7- membered ring RCM products in 46 %, 67 % and 66 % yields.