39.. any“: Unwcemfi earn.“ 7:95., .5»; , .. tank! . . . a...“ gang to» ‘tll 'U s tn I. . J. 151...: . . xi. .. 1 . 1...: 2.3... r... .. Q «an 3.... A a. 1:. t. 2. .. 1 E. «nyrflgrnva .1 .v . . 1 l2! , m. :1... L 1 J02! {4:16‘, .Hnyr.;..3.. . .Itivdfiio ‘-.‘¢f.‘\.>l Rel; :gfin ”in 31. ~ . a .. s... . . . .: (n‘ a... I ’1 l .13....1113 to 1...-.. e 1...... 5...?! i €0- ; .6 3c 2111;..." .31.). » . y'ax... . q .30... It. 02‘! “Va 1. ‘lanlt...l.5 .x :. I... LIBRARY Michigan State UI liversity This is to certify that the dissertation entitled THE SYNTHESIS AND MODIFICATION OF HOMOCALIXARENES presented by ALEXANDER V. PREDEUS has been accepted towards fulfillment of the requirements for the Doctoral degree in Chemistry ajor Professor's Signature 4 2. /1 Y / 2,00 5 Date MSU is an Affirmative Action/Equal Opportunity Employer PLACE IN RETURN BOX to remove this checkout from your record. TO AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE DATE DUE 5108 K:/Prolecc&Pres/ClRC/Dateoue.indd THE SYNTHESIS AND MODIFICATION OF HOMOCALIXARENES By Alexander V. Predeus A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2009 ABSTRACT THE SYNTHESIS AND MODIFICATION OF HOMOCALIXARENES By Alelxander V. Predeus A series of homocalixarenes was prepared using the “triple annulation” approach, that employs the benzannulation reaction between bis-Fischer carbene complexes and bis- alkynes to create three rings of the macrocycle simultaneously. Both homocalix[3]arenes and homocalix[4]arenes were prepared successfully. Furthermore, it was shown that this approach remains effective on a very broad spectrum of ring sizes, allowing the construction of macrocycles ranging from 15 to 56 carbon atoms. The method also afforded the synthesis of a pyrrole-containing macrocycle, proving its tolerance to numerous functional groups. The method was applied to the synthesis of C3-symmetrical homocalix[3]arenes, that were prepared using cyclization reactions with protected intermediates followed by appropriate deprotection. The latter reaction was shown to be useful for homocalix[3]arene preparation on a gram scale. A number of homocalix[3]arene triflates were prepared and characterized. A series of coupling reactions were tested on appropriate model compounds, and several low rim modification reactions were attempted with homocalixarene triflates. Overall, efficient methods for the preparation of various homocalixarenes are developed. These methods are tolerant to many functional groups, allowing syntheses of a wide variety of ring sizes, and practical gram amounts of material, broadening the possibilities of homocalixarene use and applications. ACKNOWLEDGEMENT I would like to express my deep gratitude to Professor Wulff. His guidance gives an almost unbelievable amount of freedom to pursue things that truly fascinate and interest you, at the same time allowing you to face your challenges and grow personally and as a scientist. The doors of his office were always open, and he was always as helpful and as inspiring as advisor could be. This has been a life-changing experience for me. I also would like to thank my parents, Vladimir and Valentina, and my fiancee Meredith for their constant support and encouragement. It would not be an exaggeration to say that I would never have completed this work successfully without them in my life. It is a pleasure to thank all of my current and former colleagues. From what I learned, Wulff group always had very friendly and professional atmosphere, and I am very happy to have had a chance to breath in it (this by no means is a reference to Dr. Zhensheng Ding’s thiol reductions). I thank Dima Berbasov, Aman Desai, Zhensheng Ding, Wynter Gilson, Yong Guan, Anil Gupta, Li Huang, Keith Korthals, Nilanjana Majumdar, Munmun Mukherjee, Corey Newman, Victor Prutyanov, Hong Ren, James Woods, Andrei Vorogushin and many others for their friendship, and for creating truly inspiring and professional scientific environment in the group. I thank Daniel Holmes, Kermit Johnson, Richard Staples and Bev Chamberlin for their invaluable help with NMR, X-Ray and mass-spec analyses of my samples. MSU is indeed very lucky to have professionals like you. Finally, I-would like to thank my committee members, Professors Maleczka, Jackson and Odom, for their helpful research suggestions and for reading this manuscript. iii TABLE OF CONTENTS LIST OF TABLES .................................................................................. vii LIST OF FIGURES ................................................................................ viii LIST OF SCHEMES ................................................................................. x ABBREVIATIONS ............................................................................... xvii CHAPTER ONE: SYNTHESIS AND PROPERTIES OF HOMOCALIXAREN ES 1. Relevant terminology and the importance of homocalixarenes ..................... 1 2. Preparation of homocalixarenes ......................................................... 4 2.1. All-carbon macrocyclic cores ................................................ 5 A. Two-carbon linkers (all-homocalixarenes) ......................... 5 B. Three-carbon linkers (all—bishomocalixarenes) .................... 7 C. Homocalixarenes with larger (n 2 4) linkers ........................ 9 D. Homocalixarenes with mixed size linkers ........................ 10 2.2. Homooxacalixarenes ......................................................... 13 A. Three-member linkers ................................................ 13 B. Larger linkers ......................................................... 24 2.3. Other heteroatoms in homocalixarene linkers ........................... 25 A. Nitrogen ............................................................... 25 B. Sulfur ................................................................... 28 3. Homocalixarene conformations and receptor properties ........................... 31 3.1. Conformations of homocalixarenes ....................................... 31 3.2. Homocalixarenes as ligands and receptors ............................... 37 A. Neutral molecules .................................................... 37 B. Ammonium cations ................................................... 41 C. Metal cations .......................................................... 47 4. Ring modification of homocalixarenes ............................................... 51 4.1 .Goals and challenges of calixarene ring functionalization .............. 51 4.2. Upper rim modification ...................................................... 53 A. Homocalixarenes ...................................................... 53 B. Homooxacalixarenes ................................................. 56 4.3. Lower rim modification ..................................................... 61 A. Homocalixarenes ...................................................... 61 B. Homooxacalixarenes ................................................. 63 5. Concluding remarks ..................................................................... 67 CHAPTER TWO: BENZANNULATION REACTION IN MACROCYCLIZATIONS l. Benzannulation reaction of Fischer carbene complexes, its mechanism and selectivity ................................................................................. 69 1.1. Benzannulation reaction and its mechanism .............................. 69 1.2. The selectivity of benzannulation reaction ............................... 71 iv 2. Benzannulation reaction used to prepare macrocycles ............................. 76 2.1. Systematic intramolecular benzannulation investigation by Dr. Wang .................................................................................................. 76 2.2. Synthetic studies towards phomactin family ............................. 85 2.3. The synthesis of substituted calix[4]arenes by a “triple annulation” approach ...................................................................... 88 3. Concluding remarks ..................................................................... 92 CHAPTER THREE: PREPARATION OF HOMOCALIXARENES BY TRIPLE ANNULATION APPROACH 1. Initial project ............................................................................. 93 2. Preparation of aromatic alkynes ....................................................... 95 3. Preparation of vinyl halides .......................................................... 100 4. Preparation of carbene complexes ................................................... 103 5. Cyclization reactions giving homocalixarenes and their properties ............ 107 6. Testing the new method: synthesis and structure of pyrrole-containing macrocycle ............................................................................ 1 15 7. Concluding remarks .................................................................. 118 CHAPTER FOUR: HOMOCALIXAREN E MODIFICATION: INTRODUCTION 1. Pyrazole-based ligands and homocalixarene modification ....................... 120 2. Model studies for homocalixarene lower rim substitution ....................... 122 2.1. Model reactions with triflate 270 ......................................... 124 2.2. Deprotection of the model compounds .................................. 131 3. Homooxacalix[3]arene as an advanced model for substitution reactions ...... 132 3.1. Preparation of triflate derivatives of hexahomocalix[3]arene 9h. . ..134 3.2. An attempt at templatecl assembly of homooxacalix[3]arene core...138 4. Large scale preparation of C3-symmetrical homocalix[3]arenes ................ 140 4.1. Preparation of diynes 264 and the choice of protecting group ....... 140 4.2. Cyclization reactions and deprotection .................................. 144 5. Introduction of pyrazole functional groups into symmetrical homocalix[3 ]arenes ................................................................... 147 6. Concluding remarks ................................................................... 149 CHAPTER FIVE: APPLICATION OF CHROMIUM TRIMETHYLENEMETHANE COMPLEXES IN INTRAMOLECULAR CYCLIZATION REACTIONS 1 . Introduction ............................................................................. 150 2. Preparation of allenes .................................................................. 152 3. Preparation of TMM complexes and cyclization reactions ...................... 154 3.1. Preparation of carbene complexes ....................................... 154 3.2. Preparation of TMM complexes .......................................... 156 3.3. Cyclization reactions ....................................................... 159 4. Concluding remarks ................................................................... 161 CHAPTER SIX: EXPERIMENTAL SECTION 1. General considerations ................................................................ 162 2. Procedures for Chapter 3 ............................................................. 164 3. Procedures for Chapter 4 ............................................................. 194 4. Procedures for Chapter 5 ............................................................. 216 REFERENCES ..................................................................................... 236 vi LIST OF TABLES Table 1. 1. Conformational and spectral properties of selected calixarenes and homocalixarenes .................................................................................... 35 Table 1. 2. Lower rim substituents influence on rotation barrier .............................. 36 Table 3. 1. Selected physical prOperties of homocalixarenes 243 and 245 ................. 110 Table 4. 1. Attempts at carbonylation and Sonogashira coupling of 270 .................. 125 Table 4. 2. Attempted Suzuki-Miyaura couplings of the triflate 270 ....................... 128 Table 4. 3. Negishi coupling of the triflate 270 ............................................................... 130 Table 5. 1. Summary of attempted TMM complex syntheses ......................................... 157 vii LIST OF FIGURES Figure 1. 1. Calix[4]arene structure elements ..................................................... 2 Figure l. 2. Homocalixarenes and homooxacalixarenes ........................................ 4 Figure 1. 3. Conformations of Cs-symmetrical homocalix[3]arene .......................... 31 Figure 1. 4. Possible conformations of [2.1.2.1]metacyclophane ............................. 32 Figure 1. 5. Conformations of all possible oxahomocalix[4]arenes .......................... 33 Figure l. 6. F ullerene coordination in hydrophobic calixarene pocket ...................... 38 Figure l. 7. Receptors designed for primary ammonium ion binding ........................ 41 Figure 1. 8. Picrate extraction from water to organic phase ................................... 42 Figure 1. 9. Binding of tetramethylammonium picrate (TMAP) and N-methylpyridinium iodide (NMPI) by ligands 105-110 ............................................................... 45 Figure 1. 10. Quaternary ammonium ion binding by various methyl derivatives 110- l 1 1 ..................................................................................................... 46 Figure 1. 11. Quaternary ammonium ion binding by ester derivatives 112 ................. 46 Figure 1. 12. Examples of crystal structures involving homocalixarenes as ligands (L1 - trianion of 9b (see Scheme 1.21), L2 — tetraanion of 54g (see Scheme 1.26), L3 — tetraanion of 37 (see Scheme 1.12), L4 — dianion of 9g (see Scheme 1.21)) ............... 48 Figure l. 13. Binding of alkaline and alkali earth metals by ester and amide homooxacalix[3]arene derivatives ................................................................ 50 Figure 1. 14. Metal-selective ligands 119, 120a and 121a .................................... 50 Figure 1. 15. Selective extraction of metal cations ............................................. 51 Figure 2. 1. Two members of the phomactin family and a suggested intermediate for their synthesis .............................................................................................. 85 Figure 3. 1. Changes in 1H-NMR spectrum in homocalix[3]arenes 245 ................... 111 viii Figure 3. 2. "Missing" methoxy group in the 1H-NMR spectrum of 2453 ................ 111 Figure 3. 3. Crystal structures of macrocycles 245a-c and 243C ............................ 113 Figure 3. 4. Crystal structure of pyrrole-containing macrocycle 259 ....................... 118 Figure 4. 1. Changes in rotation barriers of model pyrazoles depending on protecting group ................................................................................................ 131 Figure 4. 2. Conformations of triflates 280, 266a and 266b .................................. 134 Figure 4. 3. NOESY-ID experiment saturating the unique methyl group (6 = 2.39 ppm) in paco-trilfate 280, showing no exchange with the other methyl groups (6 = 2.20 ppm) ................................................................................................. 1 3 7 Figure 4. 4. The C3-symmetrica1 macrocycle 260b in a crystal: conformation of a single molecule (left) and packing in the elementary cell along c-axis (right) .................... 146 ix LIST OF SCHEMES Scheme 1. 1. Various outcomes of base-catalyzed reaction of p-tert-butylphenol with formaldehyde .......................................................................................... 3 Scheme 1. 2. Preparation of homocalixarenes by Mfiller-Rbscheisen cyclization ........... 5 Scheme 1. 3. Preparation of homocalixpyridines by Mfiller-Rbscheisen cyclization ....... 6 Scheme 1. 4. Preparation of homocalixarene from a dimeric precursor ....................... 6 Scheme 1. 5. Preparation of homocalix[4]arene by sulfur extrusion method ................. 7 Scheme 1. 6. Homocalix[3]arene preparation by trimerization of dibromide 22 ............ 7 Scheme 1. 7. Malonate alkylation applied to homocalixarene preparation ................... 8 Scheme 1. 8. Cross-coupling of bis-aryllithium with alkyl bromide ........................... 8 Scheme 1. 9. Claisen rearrangement used to prepare homocalixarenes ....................... 9 Scheme 1. 10. Benzylic dianion cross-coupling for homocalix[3]arene preparation. ......9 Scheme 1. 11. Fischer carbene complex trimerization ......................................... 10 Scheme 1. 12. Base-catalyzed condensation of oligophenols with paraform ............... 11 Scheme 1. 13. The unexpected formation of homocalixarenes 41 and 42 ................... 11 Scheme 1. 14. Preparation of cross-linked [4.1.4.1]metacyclophanes ....................... 12 Scheme 1. 15. Acid-catalyzed homocalixarene preparation ................................... 12 Scheme 1. 16. Preparation of [2.2.1]metacyclophane by sulfur extrusion method. . . . . 1 3 Scheme 1. 17. Preparation of bishomooxacalix[4]arene 5 .................................... 14 Scheme 1. 18. Monooxacalixarene preparation ................................................. 14 Scheme 1. 19. Thermal trimerization of triol 4a ................................................ 15 Scheme 1. 20. Homooxacalix[3]arenes by thermal decomposition of triols ................ 16 Scheme 1. 21. Acid-catalyzed cyclization of triols 4 ........................................... 16 Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. Scheme 1. 22. Acid-catalyzed preparation of 9b in xylene ..................................... 17 23. Preparation of monooxacalixarene 5 from advanced precursor 55 ......... 17 24. Dioxahomocalix[4]arene preparation ........................................... 18 25. Dioxahomocalix[6]arene preparation ........................................... 18 26. Tetraoxohomocalic[4]arene preparation ....................................... 19 27. Preparation of acid-catalyzed cyclization precursors 64 ..................... 19 28. Acid-catalyzed homooxacalix[3]arene synthesis .............................. 20 29. Acid-catalyzed "2+1" cyclization ................................................ 21 30. Reductive homocoupling of diformylphenols ................................. 22 31. Heterocoupling of diforrnylphenols with TMS-protected triols ............ 23 32. The influence of 67/68 ratio on major product of the reaction .............. 24 33. Synthesis of larger homooxacalixarenes ....................................... 24 34. Synthesis of tetraoxahomocalix[3]arenes ....................................... 25 35. Thermal preparation of azahomocalixarenes .................................. 26 36. Preparation of azahomocalixarenes by nucleophilic substitution ........... 27 37. Unsubstituted azahomocalixarene preparation ................................. 27 38. Thiacalix[4]arene preparation ................................................... 28 39. Thiahomocalix[3]arene preparation ............................................. 29 40. Convergent "2+1" type synthesis of thiahomocalix[3]arenes ............... 29 41. Preparation of methylated thiahomocalixarene 92 ............................ 30 42. Synthesis of larger sulfur-containing homocalixarenes ...................... 30 43. Fullerene coordination to esters 96 in presence of lithium ions ............. 39 44. Dimeric palladium-based capsule preparation ................................. 39 xi Scheme 1. 45. [60]Fullerene encapsulation by 97 in presence of lithium ions ............. 40 Scheme 1. 46. Ditopic ammonium receptors and their coordination to guest ions. . . . . . ...43 Scheme 1. 47. The use of pyrene fluorescence for quantitative ammonium determination ........................................................................................ 44 Scheme 1. 48. Synthesis of phosphine-based homooxacalix[3]arene 113 metal complexes ............................................................................................ 49 Scheme 1. 49. Sonogashira reaction use for calix[4]arene modification ..................... 52 Scheme 1. 50. Tert-butyl group electrophilic removal from homocalixarenes ............. 53 Scheme 1. 51. Ipso-substitution of tert-butyl by nitration ..................................... 54 Scheme 1. 52. Preparation of molecular tweezers from [2.2.2]cyclophane 127 ............ 55 Scheme 1. 53. All-homocalix[4]arene derivatization .......................................... 56 Scheme 1. 54. Mild iodination of homooxacalix[3]arene 9a ................................. 57 Scheme 1. 55. Suzuki-Miyaura coupling applied to upper rim modification of 9 .......... 57 Scheme 1. 56. The use of Mannich reaction for selective derivatization of 9m ............ 58 Scheme 1. 57. Preparation of capped ligands 120 .............................................. 59 Scheme 1. 58. Self-threaded rotaxane 147 and molecular capsule 146 ...................... 60 Scheme 1. 59. Ester group introduction into homooxacalix[3]arene 8b ..................... 61 Scheme 1. 60. Preparation of partially capped derivatives 148 ............................... 62 Scheme 1. 61. Preparation of potassium-selective homocalixnaphtalene 119 .............. 62 Scheme 1. 62. Ester group introduction into homooxocalix[3]arene 9b ..................... 63 Scheme 1. 63. Selective addition of amide functionality to macrocycle 9b ................. 64 Scheme 1. 64. Synthesis of triacid 150 ........................................................... 64 Scheme 1. 65. Synthesis of capped ligands 99 and 100 ........................................ 65 Scheme 1. 66. Benzylation of homooxacalix[3]arene 9b ...................................... 66 xii Scheme 1. 67. Preparation of phosphine ligand 113 ............................................ 67 Scheme 2. 1. The benzannulation reaction of Fischer carbene complexes .................. 69 Scheme 2. 2. Possible work-up options for benzannulation products ........................ 70 Scheme 2. 3. Mechanistic outline of the benzannulation reaction ............................ 70 Scheme 2. 4. Cyclopentadiene (indene) formation ............................................. 71 Scheme 2. 5. Benzannulation resulting in cyclohexadienone formation ..................... 72 Scheme 2. 6. Formation of furan and cyclopentendione side products ...................... 73 Scheme 2. 7. Regioselectivity of the benzannulation reaction ................................ 74 Scheme 2. 8. Some examples of benzannulation regioselectivity ............................ 74 Scheme 2. 9. Intermolecular benzannulation reactions in syntheses of deoxyfrenolicin..75 Scheme 2. 10. Classification of intermolecular benzannulation reactions .................. 77 Scheme12. 11. Attempts at cyclizations of amidocarbene complexes... ... ..... .... ..........77 Scheme 2. l2. Regioselective O-endo macrocyclization ....................................... 78 Scheme 2. 13. Meta[2.2]cyclophane formation by benzannulation reaction ................ 79 Scheme 2. 14. Preparation of hetero-analogs of meta[2.2]cyclophane 193 .................. 79 Scheme 2. 15. Preparation of linear carbene complexes 199 ................................. 80 Scheme 2. l6. Cyclization of carbene complexes 199 with various tether lengths... . . ....81 Scheme 2. 17. Regioselectivity of cyclization in case of internal alkyne tether ............ 81 Scheme 2. 18. Cyclohexadienone formation in intramolecular benzannulation ............ 82 Scheme 2. 19. Preparation of bis-carbene complexes 211 ..................................... 82 Scheme 2. 20. Synthesis of meta[m.n]cyclophanes ............................................. 83 Scheme 2. 21. Synthesis of bis-carbene complexes 214 ....................................... 83 Scheme 2. 22. Synthesis of para[m.n]cyclophanes .............................................. 84 xiii Scheme 2. 23. Synthesis of metapara[6.6]cyclophane .......................................... 84 Scheme 2. 24. Extended study on cyclohexadienone preparation by intramolecular benzannulation reaction ............................................................................ 86 Scheme 2. 25. Preparation of advanced synthetic intermediates 226a and 226b ........... 87 Scheme 2. 26. Preparation of aromatic bis-carbene complexes 233 .......................... 88 Scheme 2. 27. Preparation of substituted calix[4]arenes ....................................... 89 Scheme 2. 28. Preparation of chiral calix[4]arene 237 ......................................... 90 Scheme 2. 29. First example of homocalix[4]arene synthesis using benzannulation reaction ................................................................................................ 91 Scheme 3. 1. Planned synthesis of homocalix[4]arenes ....................................... 94 Scheme 3. 2. Planned synthetic route to homocalix[3]arenes ................................. 95 Scheme 3. 3. Preparation of enyne 238a ......................................................... 96 Scheme 3. 4. Preparation of enynes 238b and 238c ............................................ 96 Scheme 3. 5. Preparation of bromides 244b and 244c ......................................... 97 Scheme 3. 6. Synthesis of 240b reported by Dr. Gopalsarnuthiram .......................... 97 Scheme 3. 7. Improved synthesis of aromatic diynes 240 ..................................... 98 Scheme 3. 8. Preparation of diyne 240a ......................................................... 99 Scheme 3. 9. Preparation of diyne 240a ........................................................ 100 Scheme 3. 10. The search for the best vinyl halide preparation method ................... 101 Scheme 3. 11. Preparation of vinyl iodides 241 ............................................... 102 Scheme 3. 12. Preparation of diyne 209g ...................................................... 102 Scheme 3. 13. Preparation of linear diiodides 210 ............................................ 103 Scheme 3. 14. Model studies on preparation of Fischer bis-carbene complexes ......... 104 Scheme 3. 15. Byproducts of bis-carbene complex preparation ............................. 105 xiv Scheme 3. Scheme 3. Scheme 3. Scheme 3. Scheme 3. Scheme 3. Scheme 3. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. Scheme 4. 16. Preparation of aromatic bis—carbene complexes 242 ........................ 106 17. Preparation of non-aromatic carbene complexes 211 ....................... 107 18. Preparation of homocalix[4]arenes by the “triple annulation” method... 108 19. Preparation of homocalix[3]arenes by the “triple annulation” method... 109 20. The strategy for the synthesis of macrocycle 259 ........................... 116 21. Preparation of heterocyclic diyne 257 ......................................... 116 22. Preparation of unprotected pyrrole-containing macrocycle 259 ........... 117 1. Retrosynthetic analysis for calixarene-based scorpionate ligands .......... 121 2. Tentative pathway of preparation of substituted homocalixarenes ......... 122 3. Preparation of model triflate 270 ................................................ 123 4. Suggested pathways for substitution of a hindered triflate group ........... 123 5. Preparation of MDG-protected pyrazoles ...................................... 124 6. Preparation of pinacolboronates 276 ............................................ 126 7. Tentative mechanism of protodeboronation .................................... 127 8. Deprotection of compound 277a ................................................ 131 9. Two-step deprotection of benzyloxy group .................................... 132 10. Preparation of homooxacalix[3]arene 9h ..................................... 135 11. Preparation of paw-280 ......................................................... 136 12. Attempts at preparation of cone-280 .......................................... 138 13. Suggested synthesis of ligand 284 ............................................. 139 14. Attempted coupling of triflate 281 and pyrazole 276a ...................... 139 15 . Preparation of MOM-protected diyne 264a .................................. 141 16. Preparation of homocalix[3]arene 260a using MOM-protected diyne 264a .................................................................................................. 142 XV Scheme 4. 17. Preparation of protected intermediate 263b .................................. 142 Scheme 4. 18. The byproducts of alkyl-aryl coupling with intermediate 263b. . . . . . . . ....143 Scheme 4. 19. Preparation of dyines 264b and 264c .......................................... 144 Scheme 4. 20. Triple annulation with diynes 264b and 264c ................................ 145 Scheme 4. 21. Preparation of macrocyclic triflates 266b and paw-266a .................. 147 Scheme 4. 22. Attempted couplings of macrocyclic triflate 266b ........................... 148 Scheme 5. 1. TM binding modes and typical palladium TMM preparation ............ 151 Scheme 5. 2. Preparation of TM complexes by reaction of Fischer carbene complexes with allenes ......................................................................................... 151 Scheme 5. 3. An example of [3+2] cycloaddition reaction involving chromium TMM complex ............................................................................................. 152 Scheme 5. 4. Proposed intramolecular cyclization reaction ................................. 152 Scheme 5. 5. Preparation of allenes 293a-h ................................................... 153 Scheme 5. 6. Preparation of allenes 293i and 293j ............................................ 154 Scheme 5. 7. Carbene complexes used for TMM preparation ............................... 155 Scheme 5. 8. Preparation of carbene complexes 298a and 298b ............................ 15 5 Scheme 5. 9. Preparative decomposition of complexes 298a and 298b .................... 156 Scheme 5. 10. Preparation of TMM complexes 303a and 303b ............................ 157 Scheme 5. 11. Preparation of TMM complexes 303e-e ....................................... 158 Scheme 5. 12. Preparation of TMM complexes 303g—l ....................................... 159 Scheme 5. 13. Cyclization of TMM complex 303a ........................................... 159 Scheme 5. 14. The competition between hydrogen elimination and cyclization .......... 160 Scheme 5. 15. Cyclization of TMM complex 303e ........................................... 160 xvi 1,2-DCE BTMA DME DMF DMSO ESI/MS EXSY FAB/MS HMPA HPLC LDA mCPBA N'MR NOE S-PHOS TBS THF TLC TMM TMS TosMIC TPE ABBREVIATIONS 1 ,2—Dichloroethane Benzyltrimethylammonium 1 ,2-Dimethoxyethane N,N-Dimethylformamide Dimethyl sulfoxide Electrospray Ionisation Mass-Spectroscopy Chemical Exchange Spectroscopy Fast Atom Bombardment Mass-Spectroscopy Hexamethylphosphoramide High Performance Liquid Chromatography Lithium Diisopropyl Amide meta-Chloroperoxybenzoic acid Nuclear Magnetic Resonance Spectroscopy Nuclear Overhauser Effect 2-Dicyclohexylphosphino-2’,6’-dimethoxybiphenyl tert-Butyl dimethylsilyl Tetrahydrofuran Thin Lawyer Chromatography Trimethylenemethane Trimethylsilyl (para-Toluenesulfonyl)methyl isocyanide Tetraphenylethylene xvii CHAPTER ONE SYNTHESIS AND PROPERTIES OF HOMOCALIXAREN ES The Universe is full of magical things, patiently waiting for our wits to grow sharper. Eden Phillpotts 1. Relevant Terminology and the Importance of Homocalixarenes. Calixarenes (from Latin calix, cup) are a popular and versatile class of macrocycle formed from the condensation of a p-substituted phenol (e.g. p-tert-butylphenol) with formaldehyde. Since they contain bridged aromatic rings, they are formally members of the cyc10phane family. In cyc10phane nomenclature, one of the simplest calixarenes la (Figure 1.1) is termed [1.1.1.1]metacyclophane. The number of phenolic residues is denoted by a number in square brackets. Thus the most common cyclic tetramer with four p-tert-butyl substituents 1b is termed p-tert-butyl-calix[4]areneI. Calixarenes have attracted reseachers due to their easy preparation and unique structural features. In the cone conformer (all 4 OH groups on the same side) of classic calix[4]arene, one can single out the following structural elements: 1) a hyrophobic binding pocket; 2) upper rim with substituents; 3) lower rim with substituents; 4) cation binding site (Figure 1.1). While the original idea was to use calixarenes to imitate the enzyme binding pocket, eventually calixarenes became some of the most popular host compounds for supramolecular host-guest complexation, self-organized systems, as well as ligands for selective metal extraction, etc. Figure l. 1. Calix[4]arene structure elements. hydrophobic binding upper rim ocket ' p 4:: substituents _ lower rim 13 IR - H) U substituentSI II) (R = t-BU) ' The active research of calixarenes have started when individual compounds resulting from condensation of p-tert-butylphenol with formaldehyde were fully characterized by the laboratory of C. David Gutsche2-4. Among many other things, his research group was the first to find effective ways of selective calixarene preparation. At that point it became obvious that calixarene preparations are extremely sensitive to reaction conditions, such as substituents in organic substrate, dilution, presence of metal cations, and temperature. This can be illustrated by reactions in Scheme 1.1, when different conditions lead to 5 . . 2—6 . . . . . different main products from the same starting materials. It 18 also worth noticing that preparation of calix[4]arene from p-methylphenol completely fails under the same conditions that afford 1b from p-tert—butylphenol in 49% yield. Scheme 1. 1. Various outcomes of base-catalyzed reaction of p-tert-butylphenol with formaldehyde. 1. HCHO (1.25 eq) 1. HCHO (2.7 eq) NaOH (0.05 eq), KOH (0.34 eq). H20 H20,100-120°C, 2 h 100-120°C, 2 h 2. PhZO, 4 2. xylene, reflux, 4 h 6 OH OH 100 to 160°C OH 3. HCI, CHCl3/H20 OH then reflux, 4 h 88% 49% 1b 2 (HCHO)n (1.65 eq) 1. HCHO (2 eq) NaOH (0.03 eq), NaOH (1 eq). H20 xylene, reflux, 5 h 50°C, 5 d Dean-Stark trap 8 2. HCI, H20, 83% OH OH 3 OH 65% OH OH OH 4a (HCHO)n (1.77 eq) t—Bu t-Bu NaOH (0.03 eq), xylene O reflux, 45 min ‘ ' Dean-Stark trap 0” 24% While calixarenes have got a lot of attention from almost any possible point of view, their analogues with more then one carbon atom in the linker bonding the aromatic rings — homocalixarenes — are a lot less studied. This is mostly due to significantly harder preparation; still, numerous researchers have been attracted by the possibilities that homocalixarenes offer, such as larger cavity size, binding sites in aliphatic chains, easier lower rim modification due to reduced steric hindrance, and many others. There IS a certain amount of ambiguity in homocalixarene naming today . Some researchers only call compounds with one extra methylene group (like 6) homocalixarene, while structure 7a would be termed all-homocalixarene, structure 8a -— DJ all-(bis)homocalixarene, etc. The problems with this approach rise when larger rings or rings with different aliphatic linkers are considered. Another problem occurs when rings of the type 9a are described. In literature, they are often referred to as homooxacalixarenes, but sometimes are still described as members of more general class of “homocalixarenes”. Figure 1. 2. Homocalixarenes and homooxacalixarenes. 0 0 one? 00 c if It seems unreasonable to enforce any kind of strict nomenclature now. The possible ambiguity in naming, if necessary, can be removed with the help of additional descriptors (i.e. structure 93, if needed, can be called hexahomotrioxacalix[3]arene, etc.). Also, many researchers avoid naming such structures at all. 2. Preparation of Homocalixarenes. As it was mentioned before, most of the known homocalixarene preparation methods are inferior to ones used to prepare calixarenes. They often require high dilution and produce low yields of the target compounds; they also lack generality, and often give unpredictable results on non-standard substrates. Many of the synthetic methods used for homocalixarene preparation were borrowed from cyc10phane chemistry. Even though metacyclophanes can be viewed as homocalix[2]arenes, for the following overview we will not mention cyc10phane synthesis, and will concentrate our attention on substances with 3 or more aromatic rings in the molecule. 2.1. All-carbon Macrocyclic Cores. A. Two-carbon Linkers (All-Homocalixarenes). One of the earliest known ways to prepare all-homocalixarenes was the Muller- R‘o’scheisen cyclization, a variation of the Wurtz coupling, which is carried out at —70 to — 90°C using powdered sodium and tetraphenylethene (TPE) as a catalysts. The resulting mixtures of products were separated by chromatography, and can be demethylated to obtain phenolic compounds: Scheme 1. 2. Preparation of homocalixarenes by Muller-Roscheisen cyclization. X TPE Br Br Na THF Y 10(X=OMe, Y=H) 11 (X: H, Y=OMe) n x=oMe X=H n X=OH X=H Y=H Y=OM6 Y=H Y=OH 2 - 13a (21%) 2 - 15a (93%) 3 - 13b (10%) 3 - 155 (97%) 4 (trace) 13c (11%) 4 - 15c (99%) g g: (g (1 13d (3%) 5 12:85; 15d (87%) °o 13a 2% 6 °° 15e 93% 7 12¢ (4%) _( ) 7 14¢ (84%) (_ ) 8 12d (2%) _ 8 14d (74%) _ The method was also applied to pyridine derivativesgz Scheme 1. 3. Preparation of homocalixpyridines by Mfiller-Rfischeisen cyclization. OCH3 TPE Br N\ 3, Na 17a (n=3) 12% '/ —’ H300 OCH3 17b (n=4) 0.6% THF 170 (11:5) 2%) OCHa 17d (n=6) 0.6% 16 OCH3 “-3 Another option, making Muller-Réscheisen cyclization more predictable, consists of making more complex precursors, followed by the coupling itselfl 0: Scheme 1. 4. Preparation of homocalixarene from a dimeric precursor. t-Bu t-Bu t-Bu CH2' TPE/Na OCH3 OCH3 H300 OH OH O CHZI 34% O O t—Bu t—Bu t-Bu 1 8a 19 7b Sulfur extrusion method also allows to access all-homocalix[4]arene 7b in a more controllable way”. This method allows the macrocycle preparation by nucleophilic substitution under relatively mild conditions, due to high nucleophilicity of sulfur. After the oxidation into sulfone 21 by mCPBA, sulfur can be eliminated by vacuum pyrolysis (Scheme 1.5). Scheme 1. 5. Preparation of homocalix[4]arene by sulfur extrusion method. t-Bu t-Bu t-Bu t-Bu t-Bu t—Bu O2 1.470°C 0. HS 1.65014 0 s 0 0.4mm O 0 OCH3 + H3CO 30“ OCH3H3CO “9 OH OH OCH3 H300 —_’2 OCH3 H3CO ——’2 BBr3 H OH Cl HS m-ceeA s 40% D O 55% O 02 O O O t-Bu t-Bu t-Bu t-Bu t—Bu t-Bu 18b 20 21 7b B. Three-carbon Linkers (All-bishomocalixarenes). Several methods are known to work the best (or only) for making homocalixarenes with three carbons in the bridge between aromatic rings. Cyclization with TosMIC ((p-toluenesulfonyl)methyl isocyanide) has been frequently employed in cyc10phane and homocalixarene synthesis. Thus, triketone 23 was prepared using this reaction. Following Wolff-Kishner reduction and demethylation with BBr3 gives homocalix[3]arene 8b12: Scheme 1. 6. Homocalix[3]arene preparation by trimerization of dibromide 22. t-Bu 1. NH2NH2 t-BU OMe '1‘- 11331133: 2. KOH Br B. a ' 76% D t-BU 220/0 . O o 0 22 23 8b Homocalixarenes 24a and 24b (as well as many others) were prepared using condensation of diethylmalonate dianion with 1013. One drawback of this method is the necessity to get rid of carboxyethyl groups in the linkers if unsubstituted ring is desired. Scheme 1. 7. Malonate alkylation applied to homocalixarene preparation. 24a (11 = 3) 6% Br 24b ([1 = 4) 4°/o n—2 The cross-coupling reaction of the dianion of 25, generated by tert-butyllithium, with 26 yielded homocalix[4]arene 27 along with several linear byproducts14 Scheme 1. 8. Cross-coupling of bis-aryllithium with alkyl bromide. OCH3 OCH3 1. t—BuLi, Eth Brwar 2 OCH3 OCH3 = ' B B 'W ' 1 5-20% 25 Claisen rearrangement was used to prepare homocalix[4]arene 32, with double bonds in its bridges. Interestingly, transformation of 31 into 32 gives a very poor yield unless 2- methyl-Z-butene is used solvent (Scheme 19)”. Scheme 1. 9. Claisen rearrangement used to prepare homocalixarenes. t-Bu t-Bu Cl t-Bu Cl 0:): decalin HO O N8379MF O reflux, 8h HO TIT/l; 0:20 OH °o 61% O 450/0 CI OOtBU t-Bu 28 29 t-Bu (K t-Bu t—Bu .9 o o o O o o NaH, DMF Et2A|C| OH Ho '1’ > 50% 2-methyl- OH HO 2-butene "B” O 0 O O "B“ 46% O O Y t-Bu t—Bu 31 32 C. Homocalixarenes With Larger fit 2 fl Linkers. Dianion coupling was also used to prepare [5.5.5]metacyclophane 33 in 1% yield, but . l 6 from Simple precursors Scheme 1. 10. Benzylic dianion cross-coupling for homocalix[3]arene preparation. 0 Q OMe e G + BIMBI’ HZC OCH3H2 1% OMe MeO 3 O O 33 Another example involves benzannulation reaction, that is discussed in greater detail in Chapter 2 of this work. Using this approach, Wang was able to prepare [6.6.6]metacyclophane 35 in 19% yield”: Scheme 1. 11. Fischer carbene complex trimerization. MeO CH3CN fCT(CO)5 60°C, 181'] Z )6 19% 34 D. Homocalixarenes With Mixed Size Linkers. As one can envisage, the adjustability of ring size and conformations by changing the linkers size can add a great deal of possibilities to homocalixarene host properties. The existing methods are never general, and reserchers often rely on increasing of aromatic rings number to prepare bigger rings (such as, making calix[6]arene instead calix[4]arene, etc.). Often, the original calixarene preparation reaction — condensation with formaldehyde and other aldehydes — can be used for mixed homocalixarene preparation. Examples are given in Scheme 1.1218’19: 10 Scheme 1. 12. Base-catalyzed condensation of oligophenols with paraform. tBu tBu OH OH (HCHO)n O Nao“ : OH Ho OH HO p-xylene t-Bu t-Bu 90% O O 36 t-Bu 37 t-Bu OH OH O O (HCHOln. MOH ‘ ‘ p-xylene t-Bu t-Bu (M = Na, K, Cs) 38 39a (n = 1) 65% 395 (n = 2) 86% Despite looking predictable, even these simple reactions can be very surprising. For example, condensation of 40 with paraformaldehyde in xylene in the presence of NaOH unexpectedly gave compounds 41 and 42. The mechanism of these transformations is not yet fully elucidated (Scheme l.13)20. Scheme 1. 13. The unexpected formation of homocalixarenes 41 and 42. t-Bu O OH t-Bu O OH (HCHO)n tau NaOH xylene t-Bu O OH t-Bu O OH 40 41, 35% 42, 25% ll Using even this simple transformation, quite complicated frameworks were assembled. Thus, condensation of phenols 43 with formaldehyde and following Birch-type reduction afforded [4.1.4.1]metacyclophanes 45a and 45b, with pairs of aromatic rings linked for .. . . . . 21 additlonal conformational rlgidity : Scheme 1. 14. Preparation of cross-linked [4.1.4.1]metacyclophanes. (HCHO)n HOOH MOH Hoff/H30” 1. 0101120149 HoflI/HoOH I \ diglyme Q NaH ’ (M =CLi,n=5 2. Na _ M = S. n = 5) H H liq. NH3 H H (CH2), (C 2)n (C 2)n 3_ HCl (C 2)n (C 2)n 43a (n = 5) 443 (n = 5) 45a (n = 5) 43b (n = 6) 44b (n = 6) 450 (n = 6) In a somewhat analogous reaction, Nafion-H (acidic Teflon-based resin) catalyzed cyclobenzylation was used to obtain [3.1.1]metacyclophane22 Scheme 1. 15. Acid-catalyzed homocalixarene preparation. t-Bu 0H 1. Nafion-H O CHCI3, 17% OMe OMe MeOWOMe + © = 2. BBT3 t-Bu t—Bu t-Bu CH Cl 0 O 2 2 180 rBu 25% 46 47 Variations of earlier mentioned sulfone extrusion method also allow preparation of 7" several types of homocalix[3]- and [4]arenes“3 12 Scheme 1. 16. Preparation of [2.2.1]metacyclophane by sulfur extrusion method. Cl t-Bu t-Bu 1.450°c SH t-BUO OMe 1.CsOH fix 0.6 mm 0 02 + MeO t-Bu ———> OMe OMe OMe 2' BBQ», i-BUO OMe SH m-CPBA O O CH2C'2 O O 60°/° 380/0 Cl i-BU t-BU i-BU i-BU 48 49 50 51 Altogether, the known methods rarely offer the control and choice of the size of the macrocycle. 2.2. Homooxacalixarenes. A. Three-member Linkers. During the development of one-pot procedures for calix[n]arene preparation, Gutsche et al. discovered that condensation of 4-tert—butylphenol with formaldehyde in the presence of a base gives, in addition to the expected 4-tert-butylcalix[4]-, [6]— and [8]arenes, a fourth product — 4-tert-butylbishomooxacalix[4]arene 524. If the abovementioned condensation is carried out in xylene with KOH the yield of 5 rises to 20 — 22%, and the 7 combined yield of calixarenes drops to 63%“4’25 (Scheme 1.17). A special preparative method for 5 starting from 4-tert-butylphenol has also been described26 13 Scheme 1. 17. Preparation of bishomooxacalix[4]arene 5. t-Bu OH 73% (n = 4, 6, 8) Similarly, compounds 52 and 53, as well as several other ones with the same — CHzOCHz— linker were prepared in low yield327’28: Scheme 1. 18. Monooxacalixarene preparation. "'018H37 OH "‘C1eH37 HCHO, KOH "' 6 tetralin H‘C1BH37 OH ”‘C1BH37 52, 8% OH OH (HCHO)n t-Bu t-Bu 080” O O xylene 1'3“ Zn t-Bu t-Bu OH OH 53, 2.40/0 570/0 (n = 4, 6, 8) Fully symmetrical homooxacalix[3]arenes were attractive synthetic targets for several reasons: 14 - C3 symmetry of the molecule, which can possibly be very useful for binding to primary ammonium cations, etc; - Limited number of possible conformers. Fully symmetrical 9a (Figure 1.2) can only exist in two conformations, cone and partial cone (paco); — The presence of oxygen atoms in the linkers. Ether oxygen can possibly coordinate to metals or participate in hydrogen bonding; - The cavity size (18 carbons) of 9a is in between of calix[4]arene (16 carbons) and calix[6]arene (24 carbons). Despite the interest towards these molecules, the applications of homooxacalixarenes really only began when Gutsche et al. have published their study on thermal degradation of phenols and polyphenols containing CHZOH groups”. The methods of thermal and acid-catalyzed trimerization of inexpensive 2,6-bis(hydroxymethyl)phenols 4 have proven to be very effective in preparation of homooxacalix[3]arenes on gram and larger scale. Scheme 1. 19. Thermal trimerization of triol 4a. t-Bu 0.. r1 Ho OH xy'ene O OH O reflux OHHO t-Bu O t-Bu t-Bu 4a 9b, 30% Many researchers have found this thermal trimerization to be poorly reproducible. Later . 30 .. . . . . it was reported that traces Of acrd in starting material 4a were responSIble for the cyclization, and pure recrystallized 4a gave only traces of target product upon heating in xylene. Despite this, several more groups have used the thermal acid-free process and . . ”I 32 33 Obtained homooxacalixarenes 9bJ , 9c , 9d , and others. Scheme 1. 20. Homooxacalix[3]arenes by thermal decomposition of triols. 0H ii x Iene,A 9b(R =t-Bu), 27% HO O“ y 9c (R Br) 16% I OH HO | 9d (R: COzEt), 47% R R O R 4a-c 9b- -c O O I O The role of acid was studied and resulted in a detailed report by Daitch et al.34(Scheme 1.21). His method applied sodium sulfate to bind the produced water, and cyclizations were carried out at a high dilution of 4, in 1,2-dimethoxyethane (DME) or dichloromethane. Scheme 1. 21. Acid-catalyzed cyclization of triols 4. R CH3SO3H OH (MsOH) DME OOHg-lgo OHO HO R or CH2C12 Na2804 reflux 4a-e, 0.05M 9b, 9e-h 54b, 54e-hR Compound R solvent 9:54 ratio Yield of 9, % 9b t-Bu DME 5:1 32 9e i—Pr DME 12:1 30 91 Et DME 14:1 21 99 CI DME 5:1 12 9h Me DME 16:1 21 l6 Alternatively, trimerization of 4a in o-xylene with different acids was studied, and p- toluenesulfonic acid was found to be the most effective, giving 64% yield30 Scheme 1. 22. Acid-catalyzed preparation of 9b in xylene. t-Bu OH TsOH, MsOH or AcOH HO OH Dean- Stark trap 1M:%FH6213°é/2 t-Bu o-xylene, reflux ¢/<5E% (DI-8% AcOH: 41% t-Bu t-Bu 4a 913 It is important to notice that these preparations are limited only to homooxacalix[3]arenes with all the same substituents in the para position, that some substituents work significantly worse than the others, and there seems to be no way to predict which one will work better. Homooxacalixarenes have also been prepared from various bis(hyroxymethyl)polyphenols. Thus, abovementioned monooxacalix[4]arene 5 was obtained in nearly quantitative yield by intramolecular dehydration of tetramer 55, which in turn was obtained from p-tert-butylphenol in 3 steps29 Scheme 1. 23. Preparation of monooxacalixarene 5 from advanced precursor 55. t-Bu xylene, t—Bu t-Bu t-Bu t-Bu 55 5 l7 Dioxacalixarene 57 was the product of similar dehydration starting from dimer 56. Interestingly, homooxacalixarene 5 was also obtained in the cyclization of 56 in less then 1% yield”. Scheme 1. 24. Dioxahomocalix[4]arene preparation. t-Bu O t-Bu 8:13: 0 -B t-Bu 40% OOHHO O t u t-Bu O t-Bu 56 57 Dioxacalix[6]arene 59 was prepared in 63% yield from trimeric phenol 58; mono- and trioxacalix[6]arenes were found to be the side products with 0.4% and 0.5% yields respectively. The selective formation of 59 was attributed to the template effect of intramolecular hydrogen bondsos. Scheme 1. 25. Dioxahomocalix[6]arene preparation. bBu bBu O 0 O OH OH OH xylepg OH HO 1:; o .. .. o t-Bu t-Bu t-Bu OH HO O 0 O t-Bu t—Bu 58 59 Precursors with phenol units bridged with other than all methylene tethers have also been used in homooxacalixarenes preparation. Linear Oligomers of 2,6- 18 bis(hydroxymethyl)phenols have also been applied. Homooxacalix[4]arene 54g was obtained from dimer 60, although in low yieldzs. Scheme 1. 26. Tetraoxohomocalic[4]arene preparation. H3O CH3 OH OH QROCQ A OH HO Hofiofim g 0 O solvent OH HO CH3 CH3 0 60 549 In 1998 a very extensive work by Tsubaki et al. described the cyclization of linear trimers 64 into homooxacali[3]arenes 936. The trimer itself was assembled using selective protection of phenolic and benzylic hydroxide groups: Scheme 1. 27. Preparation of acid-catalyzed cyclization precursors 64. OH OH OH OMOM O MOMCI ,7 HO OH R o>< Adogen-464 4a-h R R O M82C(OM8)2 633'9 NaH TSOH > R OMOM DMF OH Oyo Br Oyo O CBr4, PPh3 = R O CH2C|2 K R R O 61 a-h 62a-h 64a-r Trimers 64 were then subject to HClO4 catalyzed cyclization in dilute wet chloroform solution. This method not only allowed the preparation of 17 different 19 homooxacalix[3]arenes 9, but also for the first time molecules with two and three different kinds of substituents in the para-position were prepared. Scheme 1. 28. Acid-catalyzed homooxacalix[3]arene synthesis. 0 R1 >< R1 0 HCIO4 6855 R M M 2 O 0 R2 R3 0 Compound R1 R2 R3 Yield, % 9a H H H 22 9a-w Rs 0 9; Me H Me 44 O 9 Et H Et 42 9| i-Pr H i-Pr 42 643-r 9m t-Bu H t-Bu 54 9n H t-Bu H 22 90 Me t—Bu Me 43 9p Et t-Bu Et 50 9q i-Pr t-Bu i-Pr 54 9b t-Bu t-Bu t-Bu 48 Sr Me H E1 45 9s Et t-Bu i-Pr 53 9t OMe OMe OMe 20 9u t-Bu Br t-Bu 51 - Br t-Bu Bu 0 9v Br Br t-Bu 34 9w Br Br Bu 4 In 2000 the synthesis of homooxacalix[3]arenes was performed as a condensation of dimers 65 with monomers 4 (condensation of "2+1" type) in acid medium at high . . 37 dilution 20 Scheme 1. 29. Acid-catalyzed "2+1" cyclization. V “d HCIO4, KCIO4 (9311;? R2 R3 DME 7 0 0H 0 652-] '1' U OH OH OH Compound R1 R2 F13 Yield. % R1 9r H Me Et 8 R 66a H Me i-Pr 9 9r,9s 4a,c,d 1 66b H Me t-Bu 9 663-1 66c H Et i-Pr 10 66d H Et t-Bu 1O 66e H i-Pr t-Bu 7 661 Me Et i-Pr 14 66 Me Et t-Bu 16 66 Me i-Pr t-Bu 13 98 E1 i-Pr t-Bu 20 This procedure was in many cases found to be more effective than linear trimer cyclization (see Scheme 1.28). Thus, compound 98 was prepared in 6 steps and in 12.4% overall yield using “2+1” method, while a 9-step transformation including linear trimer . . . . 36,37 cyclization gave target product in only 2.4% yield . Finally, 2,6-diformylphenols were also used in the synthesis of homooxacalixarenes. In 2001 Komatsu developed a new synthetic procedure for homooxacalix[n]arenes (n = 3, 4) - reductive homo- or heterocoupling of 4-substituted-2,6-diformylphenols 67 . Treating a mixture of 67 and Me3SiOTf in dichloromethane with triethylsilane at low temperature afforded a mixture of products 9(66) and 5438: 21 Scheme 1. 30. Reductive homocoupling of diformylphenols. 0H EtaSiH (2 eq) g g} ‘0’ Q OHOCFOHO MessIOTflt e9; 0 0H0 + O OH HO O CHQCIQ @Hlffi OH HO R O R O R 9b,9h,9c,9g R R 67a-h 66j-m 54b-m Compound R yield 9(66), % yield 54, % 9b t-Bu 38 22 9h Me 35 1 2 66' CH Ph 32 14 66 P11 11 18 661 F 29 24 99 CI 29 22 9c Br 28 26 66m I 13 - The reductive heterocoupling involves reaction of triethylsilane with two aromatic substrates, a substituted diformylphenol 67, and tris(trimethylsilyl)ether of 4-substituted 2,6-bis(hydroxymethyl)phenol, 68 (Scheme 1.31). 22 Scheme 1. 31. Heterocoupling of difonnylphenols with TMS-protected triols. OH OHC©CHO Et3SiH (2 eq) 67a-g R1 Me3SiOTf (1 eq) 4. = OTMS CH20|2 TMSO OTMS R 1 R2 683,b Compound R1 R2 Rm yield, % 9b t-Bu t-Bu t-Bu 26 90 Me t-Bu Me 19 9v Br t-Bu Br 8 66n CH Ph t—Bu CH Ph 15 660 51 t-Bu l 5 66p F t-Bu F 24 9u Br t-Bu t-Bu 6 66g Me t-Bu t-Bu 12 66r CH Ph t—Bu t-Bu 8 663 CI t-Bu t-Bu 7 66u t-Bu F t-Bu 22 Rm OH HO 0H0 HO 0 R2 93:23.1“ 54b-u Compound R1 R2 Rm yield, % 54b t-Bu t-Bu t-Bu 42 54h F t-Bu F 20 540 t-Bu F t-Bu 13 54p t-Bu Me Me 28 54q Me t—Bu t-Bu 32 54r CH Ph t—Bu t-Bu 26 543 l t—Bu t-Bu 20 54t Br t-Bu t-Bu 13 54u F t-Bu t-Bu 26 It was also shown that the ratio of initial reactants 67 and 68 significantly affected the distribution of cyclization products. The developed procedure provided a possibility, under appropriate choice of reaction conditions, initial substrates and their ratio, to prepare derivatives of homooxacalix[3]- and [4]arenes with one or two types of substituents. 23 Scheme 1. 32. The influence of 67/68 ratio on major product of the reaction. ., ,. , 68 (1.0 eq) Homocoupling 14] R1 R2 R1 R2 = > [3] R1 68 . [3] R1*R2*R1 e (0 5 eq’ 67 68 0.33e 681.0e,R=R [4] R1*Rzi'l:11*l:11 = ( q) ( q 1 2): [4] R1 Finally, the initial homocoupling conditions applied to methylated diformylphenols 69a and 69b afforded mixtures of homooxacalix[n]arenes having from 3 to 9 aromatic .39 nucle1 Scheme 1. 33. Synthesis of larger homooxacalixarenes. R Compound R n Yield, °/o . 703 Me 1 4 OMe EtaslH (2 eq) 70b Me 2 16 OHC CHO Me3$iOTf OMe ;8g Mg 2 g = 8M 0 70e Me 5 6 . 0' 1,430 7or Me 6 3 R BIBI’3 (1 eq) 709 Me 7 3 9129212 0 an 11: 812 5 18 71c SMe 4 8 69a (R = Me) 70a-g (R = Me) 69b (R = SMe) 71a-d (R = Me) 71d SMe 5 6 B. Larger Linkers. The cyclization of trimers 64 in the presence of HClO4 in wet CHCl3 in addition to the expected products 9(66) also afforded small amounts of derivatives of a new type of homooxacalixarenes, heptahomotetraoxacalix[3]arenes 72. Tsubaki et al. studied the possibility of improving this reaction for the preparation of these compounds, and found 24 that addition of trioxane to the starting reagents resulted in 23-40% yield of . 40 tetraoxacallxarenes 72a-f . Scheme 1. 34. Synthesis of tetraoxahomocalix[3]arenes. R:§< R2 Fl2 OMOM + O OH O CHC|3 00OH HO0 OH HO H20 0 trioxane R1 R1 F13 :Q§< 9b,m 7234 66d,q,v,w 54 Compound R1 R2 R3 Yield 72, % Yield 9(66), % 72a t-Bu H t-Bu 40 8 72b t-Bu Me t-Bu 23 7 72¢ t-Bu Et t-Bu 26 8 72d t—Bu i-Pr t-Bu 29 8 72e t-Bu t-Bu t—Bu 30 10 72f t—Bu H Et 25 8 2.3. Other Heteroatoms in Homocalixarene Linkers. A. Nitrogen. The literature on homoazacalixarenes is more sparse than that on homooxacalixarenes, but their chemistry is in principle even richer. Both the reactivity of amino groups and the interaction of the substituents in the side arms with those on the upper and the lower rim should be considered. This can possibly increase the flexibility in designing the host molecules and ligands based on nitrogen-containing macrocycles. 25 Compounds 73-75 were prepared through the thermal condensation of bis(hydroxymethyl)phenol 4d and polyphenols 55 and 56 with alkylamines4l’42. Water was azeotropically removed while heating relatively concentrated (~ 0.1M) solutions of the starting materials, and macrocycles 73a, 74a and 75 were obtained in fairly good yields, apparently due to template effects from hydrogen bonding. Scheme 1. 35. Thermal preparation of azahomocalixarenes. 0“ Ph HO OH PhCHZNHZ Ph/‘N OH NJ toluene, A OH H0 38% l: :l [ ] “t 4d 73a P“ PhW tBu fiBu o. or O N O PhCHgNHZ OH HO HO O O 0.. = xylene OH HO t-Bu t-Bu reflux, 20% O N O t-Bu p t-Bu 56 74a P“ t—Bu OH OH OH OH PhCH NH HO OH 2 2 O O O O ,y,,,, t-Bu t-Bu t-Bu t-Bu reflux, 22% 55 More electrophilic bis(chloromethyl)phenols 76a43 and 7744 can react with amino acid esters and their salts in presence of a base: 26 Scheme 1. 36. Preparation of azahomocalixarenes by nucleophilic substitution. OH ’O‘n/\NH3+CI‘ NCOgMe Cl Cl 0 e Me02C N OH K2003 OHN HON DMF, 60°C, 19% 763 NCOzMe HO t-Bu H OH OH O C >—NH3+CI- CI 0 O C) M9020 ; N OHHO N COzMe K2003, DMF, 30°C, 220/0 M9020 OH HO t-BU i—BU b ‘ 77 74b t-Bu t—Bu OH An N-unsubstituted azahomocalix[4]arene, 80, was obtained through reaction of 2,6- diformyl-4-methylphenol 67b with diamine 78 in presence of Ni(II) or Zn(II) salts, and reduction with NaBH4 of the Ni4 or Zn4 complexes of the intermediate macrocyclic Schiff base 7945 Scheme 1. 37. Unsubstituted azahomocalixarene preparation. CH3 H3C CH3 H3C CH3 OHCQCHO WQ’WN r-Q =gN fig 67b ?H OH HO NaBH4 OHH HO CH3 OH NHo NHNOH HOHN HC CH HO OH 3 3 3 78 27 B. S ultur. Thiacalixarenes have attracted considerable recent interest as alternatives to regular calixarenes. They have been made by both stepwise and single step procedures. The tetrathiacalix[4]arene 82 was prepared in 4.1% yield by treating the linear tetramer 81 with $01246 (Scheme 1.38). Scheme 1. 38. Thiacalix[4]arene preparation. t-Bu OH OHS OH S SClz S, NaOH t-Bu OHO OHHO t-Bu 230°C rBu rBu bBu tBu tBu t-Bu 81 82 Much more efficient, however, is the single step synthesis in which a mixture ofp—tert- butylphe'nol, elemental sulfur, and NaOH is heated to 230°C in a tetraethyleneglycol dimethyl ether solution to give 82 in yields up to 54%47 Homothiacalixarenes 21 and 50 already were mentioned above (Schemes 1.5, 1.16) as intermediates in the preparation of cyclophanes and homocalixarenes by the sulfur extrusion method. Their preparation is facilitated by the high nucleophilicity of sulfur atom; 8N2 reaction at high dilution provides the macrocycles in moderate yields. More symmetrical homothiacalix[3]arenes were prepared using similar chemistry. Thus, hexahomotrithiacalix[3]arene 833 was prepared in a simple two-stage process from 2,6- bis(hydroxymethyl)-4-tert-butylphenol 4a48 28 Scheme 1. 39. Thiahomocalix[3]arene preparation. t-Bu OH HCl OH KQN HO’\©/\OH (conc.) (DI/\Q/xa N328.9H20 S OH S CH2CI2 acetone OH HO I'BU I'BU H20 S 51°/o t-BU t'BU 4a 76b 83a Compounds 83a—c were also made in a “2+1” fashion using the same type of precursor — triol 4: Scheme 1. 40. Convergent "2+1" type synthesis of thiahomocalix[3]arenes. OH 1- (CH312CIOCH3lz OX0 CI OH HO OH st04 (cone) K©CHO HCl (conc.) CH0 2. FCC, CHZCIQ R R 85a-c 4a (R = t-Bu) 84a c 4d (R = Me) ' 48 (R = Cl) l NHQS'QHzo OH HO 2. SOCI2 OH HO CHZCI CHZCI CH0 CH0 87a-c 86a-c R OH R 9 Na s-9H O mSF/‘SQ + CIA©WCI 2 2 g S OH 3 OH HO CH20I CH2Cl R acetone/H20 fish R R 79b (R = t—Bu) 83a, 93% 79c (R = Cl) 830, 43% The hexahomotrithiacalix[3]arene methyl ether 92 has extremely high affinity for Ag+ cations, and was synthesized in the following four-stage process in 18% overall yield”: 29 Scheme 1. 41. Preparation of methylated thiahomocalixarene 92. OMe AgOAc ' OMe NazS/A'203H 80°C 0:50.12 t-Bu £521) t-Bu t-Bu t-Bu 22 ° 88 “3:32“ 89 SOCI2 (2.4 eq) dioxane t-Bu RT, 12h, 93% CsOH( (3eq) NaBH.,,(3eq)H OSMe e+SH Cl SC)Mee EIOH, C6H6H BUE 11148ng ] reflux, 72h _ t—B t—B Bu 32 /° tBu u u 91 90 Other, larger homothiacalixarenes were also prepared using nucleophilic substitution . 50 reactlons Scheme 1. 42. Synthesis of larger sulfur-containing homocalixarenes. Cl HS(CH2)QSH R2 O OHH :HO :0 1:12 N32CO3 OH 933 (R, = R22 = t—Bu) DMF 935 (R1 = R2 = Me) 30°C 936 (R1 = Me, R2 ; i-BU) R1R1 94a, °/o ”SICH2l3SH 945, 8’97:%0 N32100:; 94C, 890/0 DMF Re 30°C 0 958, 730/0 R1 OH0 HO 0 R1 955, 56% 95C, 43°/o SW8 30 3. Homocalixarene Conformations and Receptor Properties. Receptor (host) properties of any molecule are defined by its shape, conformational mobility, and coordination sites. Coordination sites define the forces that are responsible for binding. Often it is beneficial to have coordination sites rigidly placed at particular distances and to have symmetry that is ideal for binding; thus, shape is a very important factor in defining hosting ability. Lastly, conformational mobility often influences the rates of substrate coordination and release. For more dynamic coordination, more flexible hosts are preferred, while rigid systems are better for “permanent” binding. 3.1. Conformations of Homocalixarenes. Homocalixarenes may be designated in terms of the number of benzene rings as homocalix[2]arenes, homocalix[3]arenes, homocalix[4]arenes, and higher homocalix[n]arenes. For homocalix[2]arenes ([m.n.]cyclophanes), only syn- and anti- conformers are possible. In homocalix[3]arenes, if all three benzene rings are symmetrically bridged, there are only two conformers, cone and partial cone (paco). However, if one of the bridges differs from the other two, two partial cone conformations are possible, 2-paco and 3-paco, depending on the position of substituent directed to the opposite side. Figure 1.3 illustrates the total three possible conformers, where a bold line represents the different bridge. Figure 1. 3. Conformations of Cs-symmetrical homocalix[3]arene. R0081? 131003R R0 OR \A/ 1142 $1 OR OR cone 2-partial 3-partial cone cone 31 If all three bridges or substituents are different, there will be 3 different partial cones, and a total of 4 conformers. For homocalix[4]arenes with identical bridges, four conformers (cone, partial cone, 1,2- alternate, and 1,3-alternate) are possible, just like for normal calix[4]arene derivatives. In contrast, less symmetrical species such as [2.1.2.1]metacyclophane derivatives allow two inequivalent 1,2-alternate conformers, differing in the location of symmetry plane. In order to distinguish them, conformers with a plane of symmetry parallel to the longer bridge and the shorter bridge can be defined as 1,2-alternate and 1,4-alternate, respectively. Thus, there is a total of five conformers which are illustrated in Figure 1.4, where bold lines represent the longer bridges. Figure 1. 4. Possible conformations of [2.1.2.1]metacyclophane. OR OR 005 RofiR o o R ORDR on on #7. «cm on 08R OR OR OR OR cone partial cone 1,2-alternate 1 ,3-alternate 1,4-alternate The nature of conformational isomerism for homooxacalixarenes is even more complicated than described above. The main conformations in the whole homooxacalix[4]arenes family are shown in Figure 1.5; regular calixarene is also added . 52 for comparison 32 Figure l. 5. Conformations of all possible oxahomocalix[4]arenes. [1.1.1.1] [3.1.1.1] [3.3.1.1] [3.1.3.1] [3.3.3.1] [3.3.3.3] Cone OOROOR OOROOR OOROOR OOROOR OOROOR OOROOR Partlal Cone OR OR OR OR OR OR OR OR OR OR OR OR 1 O? | O 02 | O 029 | 0 OR OR OR OR OR OR OR OR OR OR 0 | 9051 2 OR OR OR OER 3 I OR OR R 4 O 0 OR Alternate OR OR OR 0 OR OR OR OR OR OR OR OR 1,2 2:?" W 3;? Jag-(J OR OR R OR OR OR OR OR OR OR OR OR on OR R 0 OR OR OR OR OR OH on OR OROR OROR OROR OROR OROR OROR R O R O R 1,4 li?’ 0 OR OR OR OR OR 33 As with regular calixarenes, the conformational interconversion of homocalixarenes has been investigated by dynamic 1H NMR, and the activation free energy (AGi) has been derived, mainly from coalescence temperatures (Tc) of suitable signals by conventional methods. The values of coalescence temperatures that can be measured with reasonable precision by this method in most of the solvents are between —90 and +150°C; thus, the calculated values of AG;6 fall between 9 and 25 kcal/mol. Table 1.1 offers a summary of conformation properties and many different kinds of calixarenes and homocalixarenes. 34 Table 1. 1. Conformational and spectral properties of selected calixarenes and homocalixarenes. IR 1H NMR [CDCI3] Tc (AGl‘) Compound v(OH), cm‘l 6(OH), ppm °C (kcal/mol) Reference p-t-Bu-calix[4]arene 3160 10.19 52 (15.7) 53 39 (14.9) 15 (13.7) p-H-calix[4]arene - - 36 (14.9) —//— 18 (13.9) —22 (11.8) p-t-Bu—calix[5]arene 3280 8.0 —2 (13.2) —//— p-t—Bu-calix[6]arene 3150 10.5 11 (13.3) —//— p-t-Bu-calix[7]arene 3155 10.3 —10 (12.3) -—//— p-t-Bu-calix[8]arene 3230 9.6 53 (15.7) —//— [2.4]cyclophane - - (> 25) 55 [2.6]cyclophane - - (20.6) 55 [2.2.1] - - 60-100 56 [3.1.1] - - (19.5) 22,57 Dimethoxy[3.1.1] - - 80 (16.7) —//— [3.3.3] - - (< 9) 12,57 Trioxa[3.3.3] 3410 8.56 < —90 (< 9) 53 Monooxa[4] 3300 9.0, 9.7 -8 (12.9) —//— Dioxa[4] 3370 9.0 —24 (11.9) —//— Monoaza[4] 2700-3000 10.7, 11.6 (15.9) 54 (17.8) [2.1.2.1] 3418 8.8 <—40 19,20 [2.2.2.2] 3220 10.40 < -40 —//— [3.1.3.1] 3254 9.35 0 (12.5) —//— [21.2.1.1] 3250 9.43, 9.83 85 (16.7) —//— [2.1.1.1.].1] 3175, 3250, 3450 8.15, 9.76, 10.52 35 (14.5) —//— [2.1.2.121] 3298 8.90 —60 (~ 10) —//— [2.1.2.1.2.1.2.1] 3355 9.80 40 (14.4) —//— Through-the-annulus rotation is also strongly influenced by modifications done to the lower rim of homocalixarenes. As the substituent size increases, rotation barrier increases, and at some point the conformers become separable stereoisomers. The following table illustrates the changes of rotation barriers in homocalix[3]arene and . . . 7 homooxacal1x[3]arene derlvatives : 35 X OR X Pr rigid flexiblea 6E2 Rh Bu rigid rigid t-Bu X t-Bu a The oxygen-through-the-annulus rotation Table 1. 2. Lower rim substituents influence on rotation barrier. t‘BU R X = CH2 X = O H flexible (TC < -60°C) flexible (Tc < —90°C) Me flexible (Tc < —50°C) flexible (T C < —50°C) Et flexible (T0 = 90°C) flexible (T0 = 50°C) is slower than the NMR timescale Several conclusions can be drawn from the information given in Tables 1.1 and 1.2. The influence of upper rim substituents on rotation barrier is minimal, but lower rim substituents change the barrier a lot; Solvents can change rotation barrier (and conformer distribution) significantly. Basic solvents like pyridine can lower the barrier significantly by breaking the hydrogen bond network. Also, polar solvents favor polar conformers; Since the value of the rotation barrier is defined by both steric factors and hydrogen bonding, it does not directly correlate with intramolecular hydrogen bond strength (see values for OH groups NMR shifts and IR frequencies); The presence of oxygen in the linkers makes the barrier somewhat lower, despite the difference in the bond lengths between C(sp3)-C(sp3), 1.54 A and C(sp3)-O, 1.43 A. This is possibly explained by both the staggered interactions of CH2 groups and the flexibility of ether linkages in homooxacalix[3]arene; Analogous homocalixarenes with nitrogen in the linkers have substantially higher rotation barrier. The reason for this is thought to lie in very strong hydrogen bonding between phenolic OH groups and nitrogen in the side chain. 36 The distribution of conformers becomes critically important when synthesis of receptors is attempted. If the conformers are rigid and do not inter-convert, the formation of the wrong conformers can occur which are often useless as hosts, thus, selectivity in the synthesis becomes a very important issue. For example, in the case of homocalix[3]arenes 8 or 9 (Figure 1.2), most researchers are attracted by their C3 symmetry. Thus, only cone conformer is often desired. 3.2. Homocalixarenes as Ligands and Receptors. Homocalixarenes offer great structural flexibility as receptors for neutral molecules and ions. The symmetry of the coordination centers is often an important factor; also, locking the conformation (making molecules more rigid) is used very often. Excellent hosts derived from homocalixarenes have been obtained by the introduction of fimctional groups similar to those found to be effective in calixarenes. This area has been very popular recently, and a great number of publications as well as . 71 . . several revrews on the subject are available. Thus, only several selected examples of each kind will be given. A. Neutral Molecules. In 1994, Shinkai et al. and Atwood et al. almost simultaneously reported that p-tert- butylcalix[8]arene selectively includes [60]fullerene from carbon soot and forms a precipitate with 1:1 stoichiometrysg. This was immediately used to obtain [60]fullerene in large quantities and with high puritysg. It was believed that that the origin of selective inclusion stems from the conformity of the [60]fullerene size with the calix[8]arene 37 cavity. However, when this complex was solubilized (by heating or using good solvents) it dissociated into its original components, and no spectroscopic indication of complex formation could be found. In order to find ligands that would bind fullerenes even in solution, Shinkai’s group studied the problem more systematically. They screened a number of calixarenes and homooxacalix[3]arenes and studied the complex formation using UV-Vis absorption spectroscopy. It was shown that calix[5]arene, calix[6]arene, and homooxacalix[3]arene form complexes in toluene (Kass are 330, 87 and 35 dm3 mol_], correspondingly)60. This was explained by the fact that the abovementioned calixarenes are known to exist as cone conformers in solution, and thus have a Jr-basic cavity of appropriate size and shape. Calix[4]arene’s cavity is too small, and calix[7]- and [8]arenes adopt a pleated loop or a pinched cone conformations in solution, and thus are incapable of effective binding. Figure 1. 6. Fullerene coordination in hydrophobic calixarene pocket. Next, it was assumed that lower association constant for homooxacalix[3]arene can be explained by its greater conformational flexibility. Also, cooperative binding of homooxacalix[3]arene ester derivatives w1th [60]fullerene 1n presence of L1 cation was 38 studied. While esters 96 themselves don’t show any binding of the fullerene, in presence of Li+ Kass between 96a (R = t-Bu), 96b (R = Br), 96c (R = Me) and C60 were found to be 460, 80 and 550 dm3 mol-l, correspondingly. Scheme 1. 43. Fullerene coordination to esters 96 in presence of lithium ions. EtOTStO 0 ijEt Etc 0 6 O O 0 U4”: Ceo ' ’ WAKE) 1* R w / R R R 96a—c In development of these discoveries, the dimeric capsule host 97 based on homooxacalix[3]arene was prepared61 . Scheme 1. 44. Dimeric palladium-based capsule preparation. EtO OEtOO OO—Et_l6+ r t r O O 0 AA, 39 The association constant between 97 and [60]fullerene in toluene was found to be 39 dm3 mol_1 at 30°C and 54 dm3 “101-1 at 60°C. In the presence of lithium cation the binding increased dramatically, just like in case of 96a-c. The association constant for 97-(Li+)2 with [60]fullerene was found to be 2100 dm3 mol—l. The same constant for 97-(Na+)2 was found to be less then 5 dm3 mol—l. Also, neither of the three — 97, 97-(Li+)2, or 97-(Na+)2 — have shown any binding with [70]fullerene. Scheme 1. 45. [60]Fullerene encapsulation by 97 in presence of lithium ions. EtO EtOOoéae'l' TOT 7 Li“, 060 _,=__ \ . 0,. 97 L0 01 E10 0 o OEt BO 0 It was also found that the nature of interactions between the host and guest fullerene molecules changes with a change of solvent. Analyzing the changes in UV-Vis spectra of - these complexes, Shinkai et al. came to the conclusion that in toluene most of the binding 40 occurs due to :rr—Jr interactions, while in more polar solvent (e.g. CH3CN) the CH(tert- . . . 62 butyl)-rr interaction operates more effiCiently B. Ammonium Cations. The match in symmetry of host and guest molecule binding sites is one of the most beneficial situations for supramolecular binding. That is why homooxacalix[3]arenes that possess C3 symmetry were often predicted to be very good receptors of primary . . + ammonium ions, RNH3 . Yamato et al. have studied modified homooxacalix[3]arenes for the purposes of selective primary ammonium ion binding. One of the earlier exmples includes derivative 98 and a cage-like molecule 9963 prepared in three steps from parent tertebutyl homooxacalix[3]arene (Figure 1.7). Figure 1. 7. Receptors designed for primary ammonium ion binding. 0 O\f OTC Oj’ O O 02/0 PhHZC O HN OowrCHgPh Oj/ O O O O O ’\ \ A @0 Om . \A t-Bu @ IO/ t-Bu t’B” t-Bu t-Bu tBu PB” p3” tBu 98 99 100 The selectivity and effectiveness of supramolecular complexation is often accessed by extractability (Ex., %), defined as percent of cation extracted into organic phase in a single extraction. In such expreriment, volumes of organic and aqueous phases, as well as initial concentration of ion and ionophore are equal; usually, the extracted salts are picrates. In the following Figure 1.8, molecules 98 and 99 were compared, and 98 was found to selectively extract primary ammonium ions. Figure 1. 8. Picrate extraction from water to organic phase. 100 .‘ 90 l I Compound 98 , 1 Compound 99 80 70 * .0 Ex.,% 50 l 40 . 3O ' 20 7 10 0 .5 Ll- + + + + Li Na K Cs Ag+ n-BuNH3+ Capped amide-based host 100 was also applied for ammonium ion binding. Compound 100 was found to bind the methyl ester of phenylalanine perchlorate 1500 times stronger then its open analog Molecular hosts 101-103 were found to be ditopic receptors, capable of binding both the cation and anion of primary ammonium halides (Scheme 1.46)65 When bound, ammonium ion's aliphatic residue is situated close to hydrophobic binding pocket, the ion itself is coordinated to the amide groups, and halogen is held in the top portion of the molecule with hydrogen bonding. It is worth noticing that larger cations, such as adamantylammonium, have shown virtually no binding with the abovementioned hosts. 42 Scheme 1. 46. Ditopic ammonium receptors and their coordination to guest ions. R F3 R 6 HN leI/O 0 NH 3 Q Me 101 H O O O R = 2 AA. A < ir—C Q—Me 102 H H t-Bu 2 t-Bu HBU 0 N Me 103 t i ‘5' Q .Vt, ,. I0/ 103 FBU FBU FBU Although C3 symmetry is of vital importance for the strongest binding, partial cone conformers of homooxacalix[3]arenes can also be useful in hosting ammonium cations. Ammonium ions were detected by means of fluorescence change in the pyrene . . . . . . 66 functionalized amme - homotrioxacalix[3]arene 104 binary system . It was shown that quantitative determination of ammonium ion microconcentrations in solution is possible due to the fact that pyrenemethylamine fluorescence is quenched by nitrogroups when it is bound to the host. When pyrenemethylamine is replaced with other cationic guests, it gives strong fluorescence. 43 Scheme 1. 47. The use of pyrene fluorescence for quantitative ammonium determination. 02N O OZN N02 R 0T0“ H. 3&0 We \ O / O Ci:::.li|"§'H.. O O o If: ‘0 “ _ "— + 0 iv o @LVV / Q \ a'M t-Bu Cl t-Bu [:th \ t-Bu O:L t-Bu o o o o D 0 N02 N02 Larger homooxacalixarenes were also tested for binding of various ammonium ions. Quaternary ammonium ion binding was studied by Masci et al. in a number of publications, starting with unmodified macrocycles 5, 9b and 57 (Schemes 1.1 and 1.24, Figure 1.2), that have shown relatively weak binding to seven different quaternary ammonium ions (Kass 8-90 dm3 molfil). When phenolic OH groups were methylated, significant increase in binding was detected. A systematic study was conducted in order to determine the best cavity size; the ligands and binding measurement results are listed in Figure 1.968. 44 Figure l. 9. Binding of tetramethylammonium picrate (TMAP) and N-methylpyridinium iodide (NMPI) by ligands 105-110. t'B” t-Bu t-Bu t-Bu o OMeO OMeMeO tB t'BU t'BU t-Bu O OMe O t—Bu ’ ” 106 O t'BU t-BU l'BU 107 t-Bu O O O Qefl OMeOMeO O OMeMeO O o o 1'3” PB” t-Bu t-Bu 108 109 tBu - tBu {é K(TMAP) K(NMPI) OMO compound dm3 mol‘1 dm3 mol‘1 e MeO o o 105 o o OMeMeO 106 24 40 O 107 270 120 133 610 77 1 450 190 "B” 110 "B” 110 470 190 Calix[4]arene derivative 105 did not show any detectable binding. The effect of substitution was studied in detail on derivatives of dioxahomocalix[4]arene 57 (see Scheme 1.24) such as 10869, which was found to have the best cavity size for quaternary ammonium ion binding: 45 Figure 1. 10. Quaternary ammonium ion binding by various methyl derivatives 110-111. Kass, dm3 mol'1 t-Bu t-Bu C AcO om- o o O R1 R2 R, R4 . «J 1: 2 821128 91., U 3 4 o 57 H H H H 15 15 30 10 O O 111b Me H H H 110 40 120 60 t—Bu t-Bu 111e Me Me H H 130 11 90 55 111d Me H M H 740 15 130 190 111e Me H H Me 410 7 80 110 11" Me Me H Me 490 4 70 140 e 11134, 110 110 Me Me Me 220 3 25 75 Still, maximum binding was found to occur when ester groups were introduced to promote additional weak binding7O Figure l. 11. Quaternary ammonium ion binding by ester derivatives 112. Kass, dm3 mol'1 Com- AcO pound R1 R2 Conformer I“ ill: / + \ l / :5“— 112a Ph Et flexible 40 - - 112b t-Bu Me flexible 130 25 30 112e t-Bu Et flexible 190 45 50 112d (.31) i—Pr cone 95 20 25 1 128 t-Bu i-Pr paco 3200 650 1 000 1 121 t-Bu i—Pr 1 ,4-alternate 1900 200 370 1129 t-Bu t-Bu cone 2100 560 760 It is interesting to notice that fixed partial cone isomer 112e was found to be the most effective host in the series, significantly surpassing the cone isomer. This was explained using X-ray diffraction data from crystals of the empty cone conformer; the cone macrocycle was found to be imperfectly preorganized for binding, with one of the tert- butyl groups partly occluding the cavity. 46 C. Metal Cations. Numerous metal complexes with homocalixarenes were prepared in crystalline form in order to study the nature of bonding with these ligands. Homooxacalixarenes were most popular, because of both availability and additional oxygen coordination centers-n Homooxacalix[3]arenes 9b (R = t-Bu), 9g (R = Me), 9h (R = Cl) (see Scheme 1.21) and others form complexes with a number of metal ions, including very stable compounds with trivalent metals. The constants of complex formation grow in the following + ,+ 2+ 2+ 3+ 3+ 3+ 3+ sequence: Na , Li , Ca < Mg < La << Y < Lu << Sc , and the constants for , 72 . . . . ligand 9b are smaller then those of 9h . With growmg ion Size the number of . . . 3+ coordinated oxygen atoms increases. In the complex of 9b With La all three ether . . . 73 . oxygen atoms are involved, and the complex is octacoordinate . The macrocyclic ligand 9 assumes the cone conformation resembling that of “classic” calixarenes in their complexes with metals. The X-ray diffraction data obtained indicate that “degree of cupping” (the ring tilt angle) increased with growing metal ion size. The study of the ability of macrocycles 9b and 9h to transfer cations Li+, Mg2+, and Sc3+ through a liquid membrane showed that oxacalixarene 9h selectively transferred scandium ion (44%) from solutions containing also lithium (transfer < 0.5%) and magnesium (< 0.2%). Unmodified, large homocalixarenes and homooxacalixarenes were extensively used in preparation of complexes of uranium (IV), (V) and (VI) due to large ligand cavity sizes and uranium oxophilicity. These are probably the most studied homocalixarene metal compexes up to date. 47 Figure 1. 12. Examples of crystal structures involving homocalixarenes as ligands (L1 - trianion of 9b (see Scheme 1.21), L; — tetraanion of 54g (see Scheme 1.26), L3 — tetraanion of 37 (see Scheme 1.12), L4 — dianion of 9g (see Scheme 1.21)).74-79 I n. i . u 0 ‘7 O I [UCI2(L3)(pr)l°2-5py [Re(CO)3|-4]' anion Cstmw 48 Phosphine containing macrocycle 113 was found to be an excellent ligand for “softer” metal cations (including noble metals such as silver, gold and rhodium). Complexes 114, 115 and 116 were obtained in very high yield80 Scheme 1. 48. Synthesis of phosphine-based homooxacalix[3]arene 113 metal complexes. #3” 93“ bBu #Bu PBu tBu QZOQJ/IQK 2V6? [Mo(CO)3(cycloheptatriene)] ”0 Eva Pth Oi THF A PPh2 0) 113 7 5.9 5.5 5.2 4.9 >7 >7 117b CH CONEt2 paco 5.1 6.2 6.0 5.5 - - - 118a Cl-lzzCOOEt cone 4.0 4.7 42 3.9 <2 <2 < Ligands 11982, 120a83 and 121384 show very good selectivity towards potassium, cesium and silver, correspondingly. Figure 1. 14. Metal-selective ligands 119, 120a and 1213. \ \ / \ \ \ O / l OA/g ,9 ’N ’an / IO' / O X 0 0 JR \, .. o o t-BU t-BU l‘BU 119 (R = CHZCOZEt) 120a 121a Figure 1. 15. Selective extraction of metal cations. , . Compound 119 90 1 Compound 120a 80 1 " Compound 121a l 70; 60 ‘ Ex.,% 50 g —— 40 30 l 20 E i 10 + + + + + + Li Na K Rb Cs Ag Many more extraction studies have been done, and often excellent selectivities were achieved. Even though this area is far from reaching its full potential, homocalixarenes were already called “macrorings with nearly unlimited opportunities”, and are often . . 85 referred to as “the third generation of hosts” 4. Ring Modification of Homocalixarenes. 4.1. Goals and Challenges of Calixarene Ring Functionalization. As it can be seen in the Section 3 of the current Chapter, very often effective usage of homocalixarenes requires introduction of additional functional groups. The options are limited to three choices: - upper rim modification; - lower rim modification; - methylene linkers modification. 51 Lower rim modification requires breaking the hydrogen bond network, and any kind of substitution or coupling is complicated by significant steric hindrance. Vast majority of lower rim modifications do not replace the phenolic oxygen. The only known example of consistent and effective introduction of carbon substituent into calix[4]arenes is described in Scheme 1.49. Sonogashira reaction using a bulky tri(tert-butyl)phosphine as palladium ligand was used, and harsh conditions (DMF, 100°C) were also required86. Scheme 1. 49. Sonogashira reaction use for calix[4]arene modification. R—3 (399) szdba3 HP(t-Bu)3+BF4‘ CUI, DBU, DMF 100°C, 4h Comp. R Yield, °/o 1 233“? 123a CBHS 89 1235 4-MeOC6H4 75 123a 4-MeCsH4 65 123d 4-C F3C6H4 70 1238 3,5'(C F3)2C6H3 75 As can be seen from Table 1.2, introduction of large enough substituents in the lower rim makes conformer interconversion impossible. Thus, the problem of selective preparation of the necessary stereoisomer is also often present. Upper rim modification is much more common, and has almost no limitations. Numerous couplings, selective and total substitutions have been reported. Upper rim substituents generally do not change “through the annulus” rotation barrier to any significant extent, which also reduces possible complications. 52 Modification of methylene linkers is very rare, and mostly occurs as a result of paiticular synthetic method used for preparation of the homocalixarene. Some examples can be seen in Schemes 1.7 and 1.9. This kind of homocalixarene derivatization will not be discussed here in detail. 4.2. Upper Rim Modification. A. Homocalixarenes. Since tert-butyl substituted calixarenes are by far the easiest to obtain, one of the first known upper rim transformations in calixarene chemistry was a tert—butyl group removal by ipso-substitution. The same transformations can be performed with homocalixarenes. For example, unsubstituted homocalix[4]arenes 125a-b and 7a were prepared in good yields from their tert-butylated derivatives (Scheme 1.50)l 1. Scheme 1. 50. Tert-butyl group electrophilic removal from homocalixarenes. (CH2)n (CHzln t-Bu OH t—Bu OH O HO O “03 O HO 0 Comp. n Yield, % CH3N02 : 125a 1 84 HO toluene/C82 H 0 7a 2 85 o on o o on o 3 8° (CH2ln (CH2)n 124a,7b,124b 125a,7a,125b Electrophilic ipso-substitution was found to be an effective way of nitro group introduction. The protection of phenolic hydroxy groups was required, and while ester and ether groups were stable under nitration conditions, amide derivatives 121e and 121f gave no identifiable products: 53 Scheme 1. 51. Ipso-substitution of tert-butyl by nitration. t'BU O O t'BU N02 OR R0 Fuming HNO3 0 OR = OR HOA / H CI 0 t—Bu 02N N02 121e-f 126a-f Compound R Conformation Reaction time (h) Yield of 126, % 126a Me flexible 0.5 95 126b Bu paco 0.5 90 1 26¢ CHZCOOEt cone 2.0 90 126d CHQCOOEt paco 0.5 89 1 26a CHZCONEtQ cone 0.5 0 126f CHZCONEtQ paco 0.5 0 Another ipso-nitration, selective monosubstitution with copper (II) nitrate, was used for a fairly complex derivatization of homo[3]calixarene 127, leading to the preparation of molecular tweezers 130 and 132 (Scheme 1.52)ng 54 Scheme 1. 52. Preparation of molecular tweezers from [2.2.2]cyclophane 127. \ UV MeO ‘ / t—Bu (350nm) ..._—_==h Q 0 Aor ‘OMe t-Bu VIS (> 400nm) OMe MeO (OMe MeO NaN02 129 In case of unsubstituted homocalixarenes, typical phenol transformations can be used effectively to introduce substituents in para-position. Bromination, oxidation and Claisen rearrangement gave products 134, 136 and 137 (Scheme 1.53)1 1. 55 Scheme 1. 53. All-homocalix[4]arene derivatization. H \ 4 4 THF/DMF 200°C O\/\ 4h, 670/0 OH 1% \ 7a 12hR 7 / 133 134 0 OAc T'(OCOCF3)3 Zn, HCI 4 4 t 4 CFSCOOH ACOH, ACQO . RT,13h,5°/o O reflux, OAC 7: 135 10 min, 59% 136 H Br 4 = 4 . CHCI3, RT OH 12h, 87% OH 7a 137 B. Homooxacalixarenes. Homooxacalixarenes cannot be ridden of para-tert-butyl group in the abovementioned way (Scheme 1.49) due to competing Lewis acid catalyzed ring opening reactions. This partly explains the necessity of synthetic methods described in Schemes 1.27, 1.28 and 1.30. Similar reasons make electrophilic substitution in presence of Lewis acid difficult. Still, if the reaction can proceed without such catalyst — for example, iodination with BnNMe3+IC12_, it can be used effectively for substituent(s) introduction89 56 Scheme 1. 54. Mild iodination of homooxacalix[3]arene 9a. 1. BnNMe3+1C12- ' N3HCO3 CHQCIZICH30H o OHC RIO-Sh _ o OHO 0 19h, 78% I o I 93 66m Suzuki-Miyaura coupling was also effectively used on halogenated homooxacalixarenes; . . . 90 numerous aromatic substituents were introduced (Scheme 1.55) Scheme 1. 55. Suzuki-Miyaura coupling applied to upper rim modification of 9. 1. MEMCI, NaH, THF, RT, 5h, 63% B’ 2. ArB(OH)2 (10 eq). Pd(0Ac)2 (10%), Ar Jothhos (20%), Na2C03 toluene/H20, rt, 48h (Procedure A), or o ArB(OH)2 (10 ed), Pd(PPh3)4 (20%), $6“ 136) N82C03, toluene/HZO/CH3OH 0“ ”0 Br 0 Br 80°C, 17h (Procedure 3) Ar 0 Ar 3. HCI, EtOAc, 12h 9c 138a-m Compound Ar Procedure Yield of 138, °/o 13:: A 77 p-Me-h A 90 138C p-MeO- 8 H4151 A 89 138d 01-? A 74 138e o-NC Cd 11 B 36 138f p-CHO- -58 11 B 59 138 o-MeO- 0 H4 B 78 1381 o-HO- o 1—1 B 67 138' o-EtOC OCH, 8 63 138 oMeCdNH 6H4 B 43 1381 3- -Pyridinyl B 50 138m 4- -Pyridinyl B 60 The Mannich reaction was applied for homooxacalix[3]arene monofunctionalization. MO“O‘UHSubstituted homooxacalix[3]arene 9m can be prepared by either acid-catalyzed 57 “2+1” condensation (see Scheme 1.28), or by palladium-catalyzed reduction of . . . . 91 bromohomooxacalix[3]arene 911. The latter is also obtained by “2+1” condensation Scheme 1. 56. The use of Mannich reaction for selective derivatization of 9m. W Pd(0Ac)2 (2%) NH4N03. A020 PPh3, HCOZH 6,0°C 5h EtaN N02 16% DMF Br 9,, 138n 50° c, 7. 5h 8 {if l-BU\=_R3 , RQRS _. 2 R1 \ R3 n, L Cr(CO)4 155 159 (5)450 R3 R2 R1 R1 R / OMe F12 \ BS OmRS 62=H _ ”0 R3 —’ o=° . \ R OMe ' R OMe \Cr(CO) L L \ RL 3 RS\Cr(CQ)3 RS Cr(CO)3 (5)451 152 155 As it can be seen from Scheme 2.3, there are six main steps that determine the outcome of the reaction: 1) CO dissociation; 2) alkyne coordination; 3) alkyne insertion; 4) CO 70 insertion; 5) ring closure; 6) tautometization. Each step is crucial, and changes in their relative rates can influence the outcome of the reaction dramatically. 1.2. The Selectivity of the Benzannulation Reaction. . . . . 96 The benzannulation reaction can produce a staggering number of various products While making its application sometimes challenging, this fact can also provide numerous synthetic opportunitites. The appearance of virtually all the side products can be explained by inclusion of branchpoints in the mechanism depicted in Scheme 2.3. In one of the most common side-products, CO insertion is interrupted. It is especially slow for molybdenum and tungsten complexes, which leads to the formation of cyclopentadiene 164 instead of the phenol (Scheme 2.4). For this reason, chromium carbene complexes are most popular in reactions where phenol formation is desired. Still, even for chromium complexes cyclopentadiene (or indene) formation can be a major side . . . . 99 reaction under certain conditions Scheme 2. 4. Cyclopentadiene (indene) formation. Rs R1 / \OMe—. OMe R R3 OMe R2 R \\ RS —.R1>¢‘RS L \\M(CO)4 2 R (E)-160 153 154 M = M0, W, Cr If neither substituent on the B-carbon of carbene complex is a hydrogen, the final . . . . . . . 100 aromatization can not occur, and the non-enolizable dienone 165 18 obtained instead 71 Scheme 2. 5. Benzannulation resulting in cyclohexadienone formation. F12 F11 R2 R1 RL \OMe RL OMe “8 Cr(CO)3 “8 (5)451 152 155 F urans, indanones, and other products can also be obtained. These products result from the insertion of the alkyne to give the (Z)-isomer of the n1,n3-vinyl carbene complexed intermediate 160. Normally alkyne inserts to selectively give the (E)-isomer, which has been attributed to the eletronic influence of alkoxy grouplm. Combined yield of products 167 and 170 thus does not normally exceed 20%, but under certain conditions they do . l 02 become major products 72 Scheme 2. 6. Formation of furan and cyclopentendione side products. R3 OMe R3 Fl [:11 " so)”: 17:: “8 (00).Cr=(_,52 Rf:— "- R: M90 512 2 RL \ 8 R3 R1 RL \\\ RS CT(CO)4 Cf(CO)4 (E)-160 159 (Z)-160 M 0 R3 R R (C0)” OM OMe e —-—-—:— L Cr 9 (2)160” \ 5.52 RF— RS %WZ ‘7 (:th :o \ \ / / / / RL 0400)., 0 “S Rs 0 “8 Rs R1 (2)461 166 167 Me R3 R1 F13 R1 R3 + O O (2)451 a OWRZ . _____’ Meosj—‘/E(F12___.Mer\—_/Z/§/R1 Cr(CO)n SCl’(CO)n RL RSR2 168 169 170 Phenol preparation from the reaction of chromium carbene complexes and terminal alkynes is usually very regioselective. The selectivity is such that the large substituent of the alkyne ends up ortho to phenol OH group (see Scheme 2.1), and thus has been explained with the help of theoretical calculations. According to Hofmannlooa, unfavourable interaction between the larger substituent and one of the CO ligands on chromium is present in the alkyne insertion product (E)-l7l but not in the regioisomeric insertion complex (E)-160. Thus, the equilibrium between these intermediates is shifted towards more stable (E)-160. Computational studies by modern methods provide somewhat different explanation, holding steric repulsion in transition state of irreversible . . . lO3b alkyne insertion responSible 73 Scheme 2. 7. Regioselectivity of the benzannulation reaction. R1 / R30Me 0” RL : RS_ R2 } R8 R2 = H R1 RL 7 RL \ R R 00-0500 3 /OM.3 S OMe 00 00 (00’s 0' (OC)4Cr:§: 00d 00 R3 /0M BL 00' b0 (“”30 e In case of internal alkynes, the selectivity is significantly diminished. Electronic factors are rarely of significant influence; only ketone and tributylstannyl substituents have been . . . . . 104 reported to reverse the regloselectmty from the one Imposed by steric factors Scheme 2. 8. Some examples of benzannulation regioselectivity. C’(CO)5 002Et 00% Lil 0:0: 00:8 A020 (2.5 eq) 002 Et Et3N (2 eq) OMe 173 174 175a 1.1 : 1 175b Cr(CO)s B 1. t-BuOMe 0TBS 6+ IS'In U3 55°C 1 h ”\e “SDBU3 2. TBSCI (4 eq) SnBu: Et3N (4 eq) Me RT, 3 h 10 : 1 173 176 1773 (R = H) 1770 177b (R =TBS) In order to solve the regioselectivity problem with internal alkynes, intramolecular cyclizations have been employed. The forming ring size was a limiting factor in isomer 74 distribution, preventing the formation of less stable intermediates (the tether usually was selected to be too short to allow the second isomer to be formed). For example, in an effort to synthesise deoxyfrenolicin 182, an advanced synthetic intermediate 181 was prepared by the groups of Semmelhack105 and Firm106 in two different ways, both involving intramolecular cyclizations of chromium carbene complexes: Scheme 2. 9. Intermolecular benzannulation reactions in syntheses of deoxyfrenolicin. P OMe — OMe ,_, Et20. 35°C 0mg ooo MeO o Pr OH 0 00 \\ > 00 Pr 0‘ r( )5 \ 1 h, 51% \ — _ OH 4 O 173 1. H2804, MeOH, 95% ‘79 2. NaBH4, RT, 24 h 3. D00, 0°C, 1 h 78% (2 steps) M92 1. hexane, MeO O’SLO 0%1 M MeO O Pr MeO 0 Fr re ux 3 ste s OH P O \\ “ A ——+ * J, -— HNO3 0 0 180 49 ' 53 /° 181 182 (deoxyfrenolicin) To sum up, in order to prepare phenols, vinyl carbene complexes of chromium should be used. Terminal alkynes are the most reliable partners in terms of regioselectivity prediction. This reaction was studied in much detail, and was found to work consistently in many different solvents; the choice of the latter usually depends on the nature of the Starting materials and can be made with the help of solvent screening studies. 75 2. Benzannulation Reaction Used to Prepare Macrocycles. The intramolecular benzannulation producing medium-sized rings has been relatively well studied (most commonly 5, 6 and 7-membered rings were made). For a comprehensive review of the intramolecular benzannulation see reference 96, Table 21, pp. 524 — 557. At the same time, no reports of all-carbon macrocycle preparation with alkynes tethered to the vinyl group of the carbene complex can be found in the literature . ll” . . . . prior to the work of Dr. Huan Wang 3. Most of the contrlbutlons 1n thls area were made lll-ll6Jl8 by Wulff laboratory , with the exception of several papers published by Dotz 107JO t al 8 (see Schemes 13 and 14 for examples). 2.1. Systematic Intramolecular Benzannulation Investigation by Dr. Wang. During what seems to be the first systematic study of the intramolecular benzannulation reaction, Dr. Wang logically classified all of the possible intermolecular cyclizations into 6 different types: X-exo, X-endo, ,B-exo, ,B-endo, a-exo, and a-endo (Scheme 2.10). Prior to his work only the reactions of X-exo type had been reported (see Scheme 2.9 for an example). 76 Scheme 2. 10. Classification of intermolecular benzannulation reactions. (00) )SMR?=RB XA\\R (OC)5Mfi_; (OC)5Me>/\\\ X=—F1 X- -ex% B\X- -endo (3 end/XR \B- —exo a-ex/ \\a\-\R -endo :QRO 0:0 Gem R / O . l l l 221.2? 2:35.911‘“ In order to develop more synthetically useful intramolecular X-exo processes, complexes 184 and 185 were prepared. Unfortunately, the acylation step proved to be very sluggish and gave low yield of impure products, and cyclization only afforded complex . . . l l‘a unlndentified mixtures of products 3 Scheme 2. 11. Attempts at cyclizations of amidocarbene complexes. 0 . 6 J / 2.TMS%(CH2)ZOCOCI 184a (R = Me) \ NHR 184b (R = Ph) (OC)sCr Unidentified Mixture RN 0 \ 1. KHMDS : (0050, L 100 C / _ : TMS 183a (R = Me) 185a (R = Me) 183b (R = Ph) 185D (R = Ph) 77 It was also suggested that with tethers that are long enough, the O—endo process should be achieved selectively with terminal alkynes. Indeed, the cyclization of complex 186 was found to give products 187 and 188 in 15 and 8% yields, correspondinglyl 13b Scheme 2. l2. Regioselective O-endo macrocyclization. 0A0 9 o O(CH2)9 OH\\ 1.THF,1OOC o (OC)5Cr=: \ 5 mM, 0.5 h CDC 2. PPh3, acetone, A020, Et3N, RT, 18h ”$011909 186 1 87, 1 5% c188, 8% In the course of further investigations, ,B-endo processes were studied. Interestingly, - .. 107 about the same t1me (1999) the Dotz group reported an example of [2,2]metacyclophane formation from carbene complex 191 containing internal alkyne. According to the abovementioned classification, this is a ,B-endo process as well. It is worth mentioning that product 193 was formed as a single diastereomer. 78 Scheme 2. 13. Meta[2.2]cyclophane formation by benzannulation reaction. 1.CH2=C=CHMgBr 2. LDA, 01131 I 3. 2-(2'-bromoethyl)- / Br / OCH3 a '1'3'd'0xane ‘ 1. t-BuLi _ 0r(00)5 4. CH3OH/HCl/A00H, \ 2- Cr(CO)e _ \ Br then HCI/AcOH \ 3- M639*BF4 \ 139 5. [Ph3P=CHzBr]+Br' 190 47 /o 191 13% overall 1. BUQO, 35 mM, OCH3 90°C,2h Q . ,4 0° O O 2 CAN 0/ HO 9 000113 01(00):; 192 193 In later work, the same laboratory published the synthesis of hetero-analogs of the abovementioned cyclophane108 (Scheme 2.14). Scheme 2. 14. Preparation of hetero-analogs of meta[2.2]cyclophane 193. / OCH3 [SAKKCQS THF, 65°C, 3 n _ O x/\ Holly—H C01:le3 01(00):; 194a (X = 0) 195a (X = O), 25% 194b (X = NMe) 195b (X = NMe), 20% A series of carbene complexes 199 were prepared using the aldol reaction of Fischer carbene complexes, first described by C. P. Casey109 (Scheme 2.15). The procedure was later improved by Wulff and Gilbertson, allowing the use of enolizable aldehydes by . . . . 110 . . . Virtue of LeWis a01d catalySIS . Unfortunately, this method also gave unsatisfactory 79 results with aldehydes 198, and further improvements were introduced and published 1 l l separately Scheme 2. 15. Preparation of linear carbene complexes 199. 1. Cr(CO)5 KH Swern H3O: CCIDHZ- OCH3 m OH OH 0' H n 4 (00) Cr l+——H: _ l f o ...__._._. 5 _ " 1,3-di “ “ PCC Z—Mn 2. MsCl n( : amino oxidation Et3N 196a—e propane 197a-h 198a-h CH2C|2’ RT 1993-11 Carbene 11 Yield of 197, °/o Oxidation Yield 198, % Yield 199, % 199a 2 - a Swern 84 42 199h 3 - 8‘ P00 47 29 1990 4 - b PCC 57b 37 199d 6 95 Swern 95 57 199e 8 - a Swern 95 48 1991 10 91 Swern or PCCC 90 60 1999 13 90 Swern 84 33 199h 1 7 82 PCC 73 8 a Commerciall available. P Combined yield over two steps ° The two met ods gave identical yield of the product Cyclization of complexes 199a-h afforded a range of metacyclophane products, including homocalix[3]arenes 202 in three cases (though only in the case of n = 6 can the method be synthetically useful). The thermolysis was carried out at 5 mM concentration in THF at 100°C, since hi her concentrations and non- olar solvents e. . hexane or benzene g P g were found to decrease the combined yield of products very significantlyl 12. While the concentration effect is expected because of the intramolecular nature of the cyclization, the solvent trend was the opposite from what it is known for the intermolecular benzannulation reaction. High reaction temperatures were also found to be beneficial. Cyclizations of carbenes 199a and 199b (n = 2 and 3) failed to give any identifiable products. 80 Scheme 2. 16. Cyclization of carbene complexes 199 with various tether lengths. H36 0 CF(CO)5 / ”5 1 99c-h 00H3 OCH3 g )00 OH THF + ( '42)?) :( H2)n + n (CH2) OH 0.005 M OH H0 100 C OCH3 H3CO (C 2)” OCH3 2000-h 201 c-h 2020-h Carbene n Yield 200, % Yield 201, °/o Yield 202, °/o 1990 4 - 29 6 199d 6 - 39 18 199e 8 43 25 2 1991 10 58 5 - 199 13 65 - - 199 17 6O - - (CH2) n Regiochemistry reversal was achieved with the help of internal alkynes. While complex 1 99g (R = H), as was mentioned before, gave product 200g selectively, introduction of sub stituents on the alkyne (Ph, TMS) lead to significant amounts of paracyclophanes via the flexo cyclization process. Also, in case of R = TIPS (triisopropylsilyl) group, the eye 1 ization failed utterly (Scheme 2.17). Scheme 2. 17. Regioselectivity of cyclization in case of internal alkyne tether. H3C0 Cr(CO)5 THF, 100°C then air / O + 1 3‘ \ or THF, 100°C H3CO O OCH3 \ R then TFA R. 203a, b 204a 205a 1999 2009 205b Precursor R R' Total yield, % Ratio meta/para 2038 Ph Ph 66 2o ; 80 203b TMS H 31 61 :39 1999 H H >65 > 30: 1 81 Cyclohexadienones were also obtained in a similar process, in which the carbene complex precursor 206c had a methyl group in )B-posi‘tion Scheme 2. 18. Cyclohexadienone formation in intramolecular benzannulation. 00H3 00H3 10 CH H3CO 0r(00)5 2 0 / THF 0 0 0 ( '1’ 1 H2) ( H2) 1' 6 H2) H2) 10 \\ 0.005010] 10 O 10 1 _ Q 10 0 00H3 00H3 2060 2070, 37% syn-2080, 7% anti-2080, 7% The double benzannulation of bis-carbene complexes and dialkynes (which still constitutes the ,B-endo process) was found to be an effective and selective way of metacyCIOphane preparation. The series of bis-carbene complexes 211a-d was prepared q . . l 1 d according to the followmg scheme 3 Scheme 2. 19. Preparation of bis-carbene complexes 211. 1. CpQZr(H)Cl n CSHG n gag/“7% *T’ Vfivkk/N'TT n YbMof YbMof 209a-d 2' '2 210a-d 210. °/0 211. % 2 61 33 1 - t-BuLi, THF, —78°C n 4 68"l 61 > H3CONWOCH3 5 74 46 2. Cr(CO)6, THF Cr(CO)5 CT(CO)5 10 72 42 —78°C to RT a 3. Me3OBF4, 211a-d THF used as a solvent CHQCIZ, H20, RT Cy clizations were performed at 2.5 mM concentration in THF at 100°C, and took 30 to 45 minutes except for the smallest members of metacyclophane family (Scheme 2.20). Cyelophanes with the tethers of different length (n at m) can also be prepared. 82 Scheme 2. 20. Synthesis of meta[m.n]cyclophanes. n m Product Yield, % H CO n/ OCH 2 2 212a 213 m 3 \ 3 4 4 2016 28 / \ + A 0r(00)5 Cr(CO)5 4 4 201° 30” 6 6 201d 31 6 6 201d 7b 209a-d 211a—d 10 10 201f 31 4 2 212b 44 4 6 2120 27 n 4 6 2120 27: 4 6 2120 33 13'ng CH2 4 6 2120 30CLe = HaCO OH HO OCH3 8‘ Reaction completed in 12 h 0.0025M b Syrin 6 pump addition 30-45 min (CH C Reac ion in presence of 10 2 in eq of phenylacetylene 212a-c, 2010, 201d, 201f Reaction run at 1mM e THF was degassed by Ar bubbling rather than freeze-thaw method I n the course of further studies, another series of Fischer carbene complexes, 214a-g, was prepared in the following way: Scheme 2. 21. Synthesis of bis-carbene complexes 214. n 1. 9-Br-9-BBN n Starting Yield of Yield of A = —» Material " 213, % 214, % 2. HOAc Br Br 209a 2 88 < 2 209a-g 213a-g 2090 3 - 258! 2090 4 - 35a 1 _ _ - _ 0 Cr CO Cr CO 2090 6 80 60 ...___ tBuLi, THF, 78 C: ( r25 ( )5 2099‘: 10 25: 36 2, Cr 00 , H CO OCH 20 13 19 38 TH,:(, 0.236 3 3 2099 16 19b 47 3. Me3OBF4, . . 214a- a - 0142012. H20, RT 9 5 $33,309 u eflggver 1W9 steps, mon romi e preparation. Reactions of these complexes with alkynes 209a-g afforded paracyclophanes ZISa-g. As one could expect, this reaction proved to be more sterically demanding: In case of n = 3, the cyclophane failed to form. Also, a lower concentration (0.001M) than in previous examples (0.0025 M) was found to be beneficial for this cyclization. 83 Scheme 2. 22. Synthesis of para[m.n]cyclophanes. Cr(CO)5Cr(CO)5 //‘A)\n\ + n _. / \ H3CO OCH3 2091. 2099 2131. 2139 6 0.005 215a 19 6 0.0025 215a 30 (C H2)” 6 0.001 21 5a 42 10 0.001 215b 35 THF, 100°C OH OH 13 0.001 2150 28 > 16 0.001 215d 31 30 min H3CO H3CO then air - (CH2)n 2153 d In the final demonstration of methods versatility, a mixed structure, metaparacyclophane 219, was prepared in the following synthetic sequence: Scheme 2. 23. Synthesis of metapara[6.6]cyclophane. | FF“ =CHI 1. B-Br-Q-BBN I 1. t-BuLi 6 O 3 6/ _ 6 A 72°/o 2. HOAC Br 2. CF(CO)5 81% 3. Me O+BF ' 198d 216 (90% brsm) 217 413% 4 (CH2) _, OMgeO Cr(CO)5 THF, 100°C OH / Av HO OMe (OC)5Cr 5 mM:19°/o MeO 1 mM: 32°/o (CH2)6 218 219 Thus, the work of Dr. Wang contained several very important findings. First, it was shown that various cyclophanes can be effectively prepared using the intramolecular benzannulation reaction. Second, the ring size was found to be of virtualy no significance with respect to the yield, except for very short tether lengths. Third, high temperatures, low concentrations, and polar ethereal solvents (namely THF) were found to be beneficial to the intermolecular cyclization. 84 2.2 Synthetic Studies Towards Phomactin Family. Phomactins are a family of macrocyclic marine natural products sharing a common bicyclo[9.3.1]pentadecane ring system (Figure 2.1). Having in mind the result depicted in Scheme 2.18, it was suggested that a common intermediate with the structure presented in Figure 2.1 would be useful in the synthesis of several phomactins, and in principle could be prepared by an intramolecular benzannulation reaction. Figure 2. 1. Two members of the phomactin family and a suggested intermediate for their synthesis. CHO H O Intermediate Phomactin D Phomactin 82 A series of model studies was undertaken for the intramolecular cyclohexadienone . 114 . . . . annulation , and the results reveal a reactiVity pattern very Similar to those found by Dr. Wang for the intramolecular benzannulation. As it can be seen from Scheme 2.24, larger rings produce only the products of the type 207. It is interesting to notice that the pure (E)-isomer of carbene complex 206c gives only 207c as the product, which suggests that it is the presence of the (Z)-isomer that is responsible for the formation of 208c in the example described earlier by Dr. Wang. This deduction appears reasonable considering that B,[3-disubstituted Fischer carbene complexes are configurationally stable under the conditions described. 85 Scheme 2. 24. Extended study on cyclohexadienone preparation by intramolecular benzannulation reaction. OCH3 OCH3 n CH H3CO Cr(CO)5 o 2) O O / Solvent n. + n1 H2) 1 H2), + n1 H2) ( H2)n \\ 0.005 M O = O OCH3 OCH3 206a—d 207a-d syn-208a-d anti-208a-d Carbene n Solvent Yield 207, % Yield 208, % Ratio anti/syn (E)-206a 6 THF3 18 1.3 : 1 (E)-206a 6 MeCNb 22 1.8 : 1 (E)-206a 6 benzenec 46 1.1 :1 (E)-206b 8 THF 45 (E)-206b 8 MeCN 45 (E)-206b 8 benzene 1 0 (Z)-2060 10 THF 15 d (Z)+(E)-2060° 10 THF 37 14 1 :1 (E)-2060 10 THF 43 (E )-2060 1 O MeCN 64 (E)-2060 1 0 benzene 36 (E)-206d 13 THF 64 (E)-206d 1 3 MeCN 51 (E)-206d 1 3 benzene 32 a 6% of the trimer isolated b 4% of the trimer isolated 31.3% of the trimer, ratio assessed b . , five other unidentified compounds were detected in the mixture 9 71 :29 ratio of E2 isomers Later in the course of this project, the intermediates 226a and 226b were prepared in a r1lultistep synthesis (Scheme 2.25). The synthesis started with the known bromide 220, Which can be prepared from geraniol in three steps, and which ultimately leads to carbene Complexes 225a and 225b (Scheme 2.25). The results of benzannulation were found to be dependent on both the cyclization conditions and on the substituents present in the 86 carbene complex 225; the best yield and diastereoselectivity were achieved in the case of the triisopropylsilyl—protected carbene complex 225a, when cyclization was performed at 60°C for 40 hours. Intermediate 226a was converted into (:I:)-phoma0tin B2 in 12 115 steps Scheme 2. 25. Preparation of advanced synthetic intermediates 226a and 226b. 1. LIHQC_:—’TMS \ 1 _ CPZZTC'Z 820 4 eq’ -20 \ A1M83 1 B r->_\_>_) to 0°C, 6 h HO (3 eq) _ HO ‘— 2. T8AF - T 2.12, THF —- T 220 71% (2 Step3) 221 67% 1. 220w3 2.8ngch 91% __ OPG TIPSCI,DMAP _ or MOMCI, i—Pr2NEt WW 224a, PG = TIPS, 100% 224b, PG = MOM, 80% 1. Cr (CO)6, -78°C, THF 2. PhLi, -78°C 3. n-BuLi, —78°C 4. M930+BF4-, RT, CH2C12/H20 OMe (0C)sCr _ \\ THF _ _ 9P9 60-100°C PG = TIPS, 60°C, 40 h, 60-66°/o, dr 3-4 I 1 PG = MOM, 80°C, 12 h, 26%, dr1 : 1 226a,b 2273,13 225a, PG = TIPS, 51% 225b, PG = MOM, 43% The studies on the synthesis of phomactins are still an ongoing project in our laboratory, and a number of other approaches are currently under development. 87 2.3. The Synthesis of Substituted Calix[4]arenes by a “Triple Annulation” Approach. In another logical course of Dr. Wang's project development, it was envisaged that calix[4]arenes bearing various useful functionalities can be selectively prepared using a similar strategy. Carbene complexes 233 were prepared according to the following 116 sequence Scheme 2. 26. Preparation of aromatic bis-carbene complexes 233. R2 1.Tf20, K3PO4 R2 R2 Q PhMe/HQO 1. NaBH4, MeOH OHC CH0 2. R4B(OH)2 OHC‘ : ‘CH0 2. PBr3 (2.4 eq) (QN OH Pd(PPh3)4 R4 CHCI3 Br R, Br K3PO4, 1,4-dioxane 228 229 230 1. TMSCZMgBr R2 R2 CuBr, THF, reflux O 1, Cp22r(H)CI IWI : 5 I or (TMSCQ)3In R 2- N'S Pd(dppf)C|2, 2% || 4 || R4 THF, reflux 2. AgNOQH KCN 231 232 Cr(CO)5 R, Cr(CO)5 1.t-BuL| = H3CO | I OCH3 2. Cr(CO)6 3. Me30+BF4- R, 233 Even though the presence of benzylic hydrogens in the propargyl benzene units in compounds 231, 232 and 233 makes them relatively unstable and potentially vulnerable to temperature, acidic/basic reagents, and light, they were found to be stable enough to give reproducible moderate yields in a process dubbed the “triple annulation”, a 88 cyclization involving one intermolecular and one intramolecular benzannulation reaction, forming three rings in one synthetic step: Scheme 2. 27. Preparation of substituted calix[4]arenes. R2 % // 231 R 1. 2,5mM in 1,2-DCE, 4 100°C, 20-40 min + = H C 2. Air Cr(CO)5 R1 Cr(CO)5 Ra 233 234a-I Compound R1 R2 R3 R4 Yield 234, % 234a Me OMe Me OMe 36 234D Me n-Hex Me n-Hex 22 234C Me Ph Me Ph 35 234d Ph OMe Ph OMe 41 234e Me OMe Me Ph 31 234f Ph OMe Me Ph 35 2349 Me OMe Me rrHex 22 234h Me n-Hex Ph OMe 35 234I Me OMe Ph OMe 4O Even though this reaction is very closely related to Dr. Wang's cyclization shown in Scheme 2.20, the ideal conditions were found to be somewhat different: heating 2.5 mM solutions of carbene complex and diyne in 1,2-dichloroethane for 20 to 40 minutes gave . . . . Il7 . . the best yields of the target molecules. There IS a report 1n the llterature describing 1,2—DCE as a solvent providing increased benzannulation reaction rates, but the reasons for such behaviour are not yet fully understood. Preparation of calixarenes with chiral centers in the methylene bridges was also considered an opportunity for this reaction, since these types of calix[4]arenes have not 89 been made before in optically active form and certainly envisioned to have applications in chiral supramolecular recognition processes. Several diynes with methoxy groups in benzylic positions were prepared in optically pure form and used to make carbene complexes and ultimately chiral calixarenes. One such example is given in Scheme 2.28'18. Scheme 2. 28. Preparation of chiral calix[4]arene 237. CH3 Q ¢ 1 “300 OCHOCHS 1. 2,5mM in 1,2-DOE, 235 3 100°C, 20-40 min + = 2. Air Cr(CO)5CH3 Cr(CO)5 H300 I I OCH3 4 30% yield H3CO OCH3 single conformer 236 00H3 237 Finally, Dr. Gopalsarnuthiram also described a single example of the synthesis of a homocalix[4]arene: 90 Scheme 2. 29. First example of homocalix[4]arene synthesis using benzannulation reaction. TMS 1. 9-BBN, THF // // 2h, reflux 2. K3PO4'H2O TMS __ Pd(OAc)2, TBAF,5eq _ \__. ¢ H3CO CH3 H300 CH3 S-PHOS, THF THF, 98% 24h, RT 2,6-dibromo- 4-meth lanisole 733% \\ \\ 238a 239 TMS 240b OC Cr __ ' ( )5_ OCH3 1. t—BuLi, —78°C 1. CpZZr(H)CI 2. Cr(CO)5 > H300 CH3 : H3CO CH3 2. NIS 3. MeaO+BF4‘ 63% CHZCIZIHZO, RT 36% l H3 (OC)5Cr 241b 242b OCH3 1,2-DOE 100°C 0” 242b + 240b WC 0 OCH3 H3CO O CH3 39% OH 2431: 00113 Overall, the work of Dr. Gopalsarnuthiram showed that the “triple annulation” is an efficient and highly convergent approach to the construction of various calix[4]arenes in a highly controllable way. This method does not have comparable analogs among known 91 calixarene synthesis methodologies, for it allows unprecedented generality and predictablility of substituent placement in the target molecules. 3. Concluding Remarks. The benzannulation reaction of 0t,[3-unsaturated chromium carbene complexes has proven to be a very useful method for macrocycle preparation. It was shown that the reaction remains effective even in the case of very large ring sizes. It was also demonstrated that this reaction can be used as a synthetic method for calixarene and homocalixarene preparation. From Chapter 1, one can see that there is a lack of general methods for homocalixarene synthesis, and that availibility of these molecules often seems to be the limiting factor in their application. The benzannulation reaction appears to be a very good candidate to provide for such a general method. The following chapters will be dedicated to the application of chromium carbene complex macrocyclizations in homocalixarene synthesis, to the preparation of homocalixarenes on a practically useful scale, and to the chemical modification of homocalixarenes. 92 CHAPTER THREE PREPARATION OF HOMOCALIXAREN ES BY TRIPLE ANNULATION APPROACH A science is any discipline in which the fool of this generation can go beyond the point reached by the genius of the last generation. Max Gluckman 1. Initial Project. As can be seen from Chapter I, while homocalixarenes are very attractive synthetic targets altogether, there seems to be a significant lack of general and selective methods for their preparation. In order to bring about such a method, the “triple annulation” was envisaged to potentially be a very useful and general approach. The planned synthetic route is presented in Scheme 3.]: 93 Scheme 3. 1. Planned synthesis of homocalix[4]arenes. 1.9-BBN 2. Pd-catalyzed OCH3 —: ' n n Br TMS e TMS—E—l-{L-Z coupling , é \\ “'2 HMPT 3. Deprotection 244 238 240 CH3 2. NBS or NIS 00113 OCHs H3CO \ n n/ 001-13 2 1.t-BuLi X \ n n/ X Cr(CO)5 Cr(CO)5 2. Cr(CO)6 CH3 242 3-MeaO*BF4‘ 241 CH3 A, high dilution + wfion" n n // \\ CH3 240 Key steps of this approach include: 1) preparation of aromatic diynes 240, 2) their conversion into appropriate vinyl halides 241, 3) making Fischer carbene complexes 242 via vinyl lithium derivatives, and 4) “triple annulation” by reacting carbene complexes 242 with the above-mentioned diynes 240. Somewhat later it was understood that homocalix[3]arenes 245 can also be prepared using aromatic diynes 240 and carbene complexes 211, that can be made starting from relatively cheap, commercially available alkynes 209: 94 Scheme 3. 2. Planned synthetic route to homocalix[3]arenes. - ' n 1.C ZrHCl HgCOMOCHa = 1"BUL' fl 2 p2 ( ) /H”\ or(co)5 Cr(co)5 2-Cr(CO)e l I 2. NBS or MS \\ // 3. Me3O+BF4' 211 210 209 CH3 + O H n OC 3n A, high dilution ( In // \\ = "triple annulation" O O CH3 240 245 H3CO OCH3 From what was known about similar reactions, it was not obvious what kind of solvent should be used for such cyclizations. Dr. Gopalsarnuthiram found 1,2-dichloroethane to be the best solvent for making calix[4]arenesl 18, while Dr. Wang's solvent of choice was THF1 13. Also, the effectiveness of the “triple annulation” had to be tested on large rings (e.g. for n = 11, 243 contains a 56-membered ring!) and on larger scale; due to high dilution, often significant amounts of solvents have to be used, which in turn limits the possbility of freeze-thaw degassing, etc. 2. Preparation of Aromatic Alkynes. In order to prepare diynes 240, we first had to find a (preferably general) method of making various enynes of type 238. Enyne 238a was prepared using facile copper- catalyzed coupling of Grignard reagent with 3-bromopropene (Scheme 3.3)”9. Albeit being simple and efficient on ~ 25 g scale, this method is only effective for this particular (allylic) bromide. 95 Scheme 3. 3. Preparation of enyne 238a. EtMgBr I CUCI (7.5 0/o) | -SF€EE = -—SF€E}—\L_ ' ABr 244a ' — 246 63% 238a In order to prepare larger enynes, one can take advantage of the many methods that have been developed for acetylene alkylation. Reactions in liquid ammonia are not applicable in the case of trimethylsilylacetylene 246, since alkali metal amides are known to break the C-Si bond of alkyneslzo. Thus, deprotonation of TMS—acetylene with n-butyllithium with subsequent addition of the corresponding bromide 244 in HMPT-THF mixture was usednl. Reactions turned out to be somewhat slow, but very efficient and clean (Scheme 3.4). No column purification or distillation are necessary. Scheme 3. 4. Preparation of enynes 238b and 238c. 1. BuLi, THF, -78°C 2. HMPT/THF1 :4 —78°C to RT, 2 d TMS-E = TMS—H: >3 WBr 244b, 86% ‘- 246 3 238b 1. BuLi, THF, —78°C TMS—Z = TMS——H: :9 2. HMPT/THF1 :4 '- —78°C to RT, 2 d mgr 244c, 92% 246 238c Bromides 244b and 244c were prepared according to the literature procedures employing cheap starting materials — 1,5-dibromopentane122 and 10-undecen—1-01123. 96 Scheme 3. 5. Preparation of bromides 244b and 244c. H MPT 195 to 220°C Br\/\/\/Br > MBr distillation 52% 244b CBI'4, PPh3 Ago” = %Br 0°C to RT 93% 244c The next step was a palladium-catalyzed double coupling of alkynyl 9-BBN derivatives with 1,3-dibromo-2-methoxy-5-methylbenzene 247. Dr. Gopalsarnuthiram has described the coupling of enyne 238a with aromatic dibromide 247 to proceed smoothly at room temperature in 24 h (1% palladium acetate, 2% S-PHOS ligand), as well as at 70°C in 8h (2% palladium acetate, 4% S-PHOS ligand) with almost no difference in the yield 124 ) (~70% . He has also discovered that column purification of the resulting silylated product is usually quite tedious. Deprotection with 5 equivalents of TBAF was found to give a more chromatographically polar product 240b. Scheme 3. 6. Synthesis of 240b reported by Dr. Gopalsarnuthiram. TMS // // 1. 9-BBN, THF TBAF TMS _ 2h, reflux 5eq — \_ > H3CO CH3 H300 CH3 2. K3PO4'H20 THF Pd(OAC)2, 98°/° S-PHOS, 247 THF, 24h, RT, 79% 238a 239 \\ 240b \\ TMS 97 Thus, it was decided to run the two steps without purification of the TMS-protected diynes. After simple work-up, the intermediate TMS-diynes were treated with TBAF. It was also found that 1/3 equivalent of TBAF in wet THF125 gives good yields of deprotected diynes 240. Final purification of the product was smooth and unproblematic; yields over two steps were around 70% (Scheme 3.7). Scheme 3. 7. Improved synthesis of aromatic diynes 240. 1. 9-BBN, THF, 2h, reflux 2. K3PO4-H20. Pd(OAc)2. OCH S-PHOS, 247, THF, 24h, RT n 3n 0 PC 2 : - Y 3. Short column (no separation) CH3 4. TBAF (1/3 eq). THF, H20 S-PHOS 238a-c Workup 8. Separation 240b-d n = 3, 68%; n = 5, 72%; n =11, 66% The preparation of diyne 240a (n = 2) was accomplished in a different fashion (Scheme 3.8). Iodination126 and methylation127 of para-cresol afforded 2,6-diiodo-4- methylanisole 250, which was converted into dialdehyde 251a by Heck reaction under Jeffery conditions (in presence of a quaternary ammonium salt and lithium acetate as a base). In the course of this reaction the double bond of the allylic alcohol is shifted to the end of the chain, giving the unbranched aldehyde as major productlzs. Finally, diyne 240a was prepared in 86% yield by treatment of 251a with Bestmann-Ohira reagent, dimethyl- l -diazo-2-oxopropylphosphonate 252129. 98 Scheme 3. 8. Preparation of diyne 240a. OH OH (CH3)2SO4 OCH3 NH3/H20 1,4-dioxane, CH3 90% CH3 65°C, 48% CH3 248 249 250 AOH N29CH3 OCH3 Pd(OAC)2 O OCH3 o \fuP-OCHa \ OCH3 I NBu4C| H H O O 252 \ LiOAC, LiCl, K2CO3, MeOH CH3 DMF, RT, 44% CH3 86% CH3 250 251a 240a It also should be noted that an approach analogous to the one in Scheme 3.8 could be envisaged for higher homologues of acetylene 240a due to the fact that under the conditions described, the double bond usually migrates down the carbon chain for a very significant distancelzs. Indeed, such a migration was found to take place. Unfortunately, the resulting aldehydes were also found to be contaminated by an inseparable impurity, most probably a branched isomer of the target dialdehyde. Even when the mixture was treated with Bestmann-Ohira reagent, the resulting diyne still had about 20% of an isomeric impurity that could not be separated. 99 Scheme 3. 9. Attempted alternative preparation of diynes 240. W91” OCH3 pd(OAC)2 n OCH3n CHsOCH3n ' ' NBU4C' = OHC CHO + 0:3 CH0 LIOAC, LiCI, CH3 DMF. RT CH3 CH3 n = 3, 560/0 250 n = 505407/0/ ~ 4 : 1, inseparable n = 1 , 00 251 b,c,e 253b,c,e N n n \ O O 5: M + nw K2003, MeOH n = 3, 80% CH3 CH3 3:107308/2/ ~ 4 : 1, inseparable = , o 240b,c,e 254b,c,e 3. Preparation of Vinyl Halides. Initially, both vinyl bromides and iodides were considered equally usable in Fischer bis- carbene complex preparation. Vinyl bromides have an advantage of being significantly more stable, while vinyl iodides provide significantly faster halide-lithium exchange in most solvents. The results of different methods tested on preparation of the diiodide 241b or the analogous bromides are shown in Scheme 3.10: 100 Scheme 3. 10. The search for the best vinyl halide preparation method. OCH3 3 OCH33 // Q Conditions: X \ / X (see table) 240b CH3 CH3 X Method Yield, % l Cp22r(H)Cl, 1 h, THF, then NIS, 4 h, THF 25 - 55 l Cp2ZrC|2 + SuperHydride, 1 h, then NIS, 4 h, THF 44 I HBBrz-SMez, 4 h, then NaOH, l2, Et20/H20, 0°C, 30 min 40-48 I Cp2Zr(H)CI, CH2c12, 15 min, then 12, 0°C to RT, 15 min 77 I Catecholborane, HQO, then NaOH, l2, EtQO/HZO, 0°C, 30 min 0 44 O O O 62 Br Cp22r(H)CI, 1 h, THF, then NBS, 4 h, THF Br Catecholborane, then H20, then NBS, CH3CN Br DIBAL-H, then NBS Br Catecholborane, then H20, then Hg(OAc) , then Br2 Br (cis) Catecholborane, then Br2, then CH3 Na Later from various experiments it came to be understood that the corresponding bis-vinyl lithium derivatives have a fairly poor stability in THF even at —78°C, and it was crucial to be able to exchange the halide for lithium rapidly. Also, vinyl iodides of type 241 that have more than 1 methylene group between the aromatic ring and the double bond were surprisingly found to possess significant thermal and photolytic stability. These observations have focused the scope of usable vinyl halides to only iodides. The drawbacks of using Schwartz reagent are its instability and cost. The use of . . . . . I30 dichloromethane as solvent, first reported 1n srmrlar reaction by Jacobsen , allows the reaction to proceed very fast and with minimal excess of the zirconium reagent, and also employs iodine instead of light-sensitive and relatively expensive N-iodosuccinimide. As an alternative to zirconium-based methods of vinyl iodide preparation, dibromoborane addition131 was employed for the same purpose with moderate effectiveness (~ 40 - 50% yield). While dibromoborane does provide a cheaper alternative to zirconium reagents, it 101 should be noted that in an attempt to run several reactions on larger scale (~ 20 mmol), even lower yields (~ 20%) were observed, while Schwartz reagent addition still provided excellent yields on the same scale. Thus, two methods were found generally usable to prepare vinyl iodides; the summary of those methods applied to aromatic diynes is presented in Scheme 3.11: Scheme 3. 11. Preparation of vinyl iodides 241. OCH3 HBBr2, then l2/NaOH/H20 OCHs n n (Method A) or \ n n/ é % = ' ' Cp22r(H)CI, then I2/CHQCI2 240a-d CH3 (Method B) 241“: CH3 Product n Method Yield, % 241a 2 A 37 241a 2 B 89 241b 3 A 48 241 b 3 B 77 241C 5 A 45 241C 5 B 80 241d 1 1 A 43 241d 1 1 B 93 In the case of aromatic alkynes 240 that have to be prepared in a multistep synthesis, the method involving Schwartz’s reagent actually becomes cheaper per gram of the target product due to the significantly higher yield. The situation is somewhat different with the cheap commercial alkynes 209a, 209c and 2091' (Scheme 3.13). Diyne 209g was prepared using the procedure described below from 1,11-dibromoundecanel Scheme 3. 12. Preparation of diyne 209g. 11 LiCCH-en 11 Br“ Br T // \\ 2099 DMSO, 55% 102 Scheme 3. 13. Preparation of linear diiodides 210. HBBrg, then l2/NaOH/HZO n Method A or n A ( ) = IWI C Zr H Cl, then I ICH Cl 209a,e,f,g p2 ( ()Method 3% 2 2 21 Oa,e,f,g Product n Method Yield, % 210a 2 A 40 210a 2 B 90 210e 3 A 46 210e 3 B 75 21 Of 5 A 63 21 Of 5 B 79 2109 11 A - 21 09 11 B 90 All of the resulting diiodides are stable compounds that can be stored at —20°C under argon in the dark for several months without any significant decomposition. 4. Preparation of Carbene Complexes. The most popular (and usually most effective) method for chromium carbene complex . . . . . 133 . . . . preparation remams the orlgmal method of Fischer , With some modifications 1n solvents, reaction temperatures, times, equivalents of reagents, etc. As described in Dr. Gopalsamuthiram’s dissertation, the yields for the bis-carbene complexes he prepared usually ranged from 20 to 40%, significantly decreasing the effectiveness of the method. Thus it was reasonable to try and improve the preparation of bis-carbene complexes by tweaking the above mentioned conditions. The results are summed up in the Scheme 3.14; just like with the diiodides, carbene complex 242b (n = 3) was chosen for model studies. 103 Scheme 3. 14. Model studies on preparation of Fischer bis-carbene complexes. OCH3 OCH3 X \ 3 3/ X Conditions H300 \ 3 3/ OCH3 (see Table) CI(CO)5 C Cr(CO)5 H H C 3 242b 3 x Method Yield, % I t-BuLi, —78°C, THF, 30 min; <-- Cr(CO)6, THF, -78°C tO RT, 3 ha 36 Br t-BuLi, —100°C, THF, 30 min; --> Cr(CO)5, THF, —100°C to RT, 3 h 10 Br t-BuLi, —78°C, Et20, 30 min; --> Cr(CO)5, EtQO, -78°C to RT, 3 h 5 l t-BuLi, —95°C, THF, 10 min; --> Cr(CO)5, THF, RT (40°C bath), 15 min 48 I t-BuLi, -95°C, THF; -> Cr(CO)6, THF, RT (40°C bath), 15 min 79 a Arrows "<--" and "-->" indicate which solution is being added via cannula into the other solution With these data in hand, several conclusions were made. First, it was understood that bis- vinyllithiums are not stable enough at -78°C, and lower temperatures should be employed. Second, the main byproducts whose formation results in the lowering of the yield of the target carbene complex were identified to be the partially reduced complex 255b and in addition red polymeric material of unknown nature, the latter being the predominant by-product. Even though the mechanism of the polymer formation is unknown, one can hypothesize that the a,B-unsaturated nature of the carbene complex allows the base catalyzed polymerization consisting of a series of Michael additions, catalyzed by the presence of excess organolithium species (Scheme 3.15): 104 Scheme 3. 15. Byproducts of bis-carbene complex preparation. OCH3 H300 \ 3 3/ OCH3 OCH3 Cr(CO)5 Cr(CO)s + 3 3/ . . 2. CI'(CO)5 CH3 3. Me3O+BF4‘ 3 OCH33 241b H300 \ / CFICOI5 + polymer 255b CH3 . LiO e I'm/You (0950, OLi Cr(CO)5 RflOLi B‘ RWOLI Crlcols n " OLi Cr(CO)5 B CrlCols B R R Cr(CO)5 suggested formation of the polymer Third, despite the poor solubility of Cr(CO)6 in THF at low temperatures, whenever the vinyllithium is added to chromium carbonyl even at —78°C in THF, the reaction mixture turns yellow immediately. This suggests that reaction has very low activation barrier, and should be nearly diffusion controlled at room temperature. Altogether, from the abovementioned facts about the side reactions one can suggest the following changes: 1) tert-butyllithium excess should be avoided, since strong bases can initiate carbene salt polymerization; 2) low reaction temperature should be maintained for bis-vinyllithium preparation; 3) fast addition of the bis-vinyllithium into warm chromium carbonyl solution might be beneficial for the overall yield of the process. When all these factors were taken into consideration, the best conditions (shown in Scheme 3.14 in bold) were achieved: bis-vinyllithium is generated in THF at —95°C, and immediately transferred into stirred chromium carbonyl solution, placed into a ~ 40°C water bath to 105 maintain constant positive reaction temperature. The sequence is very quick, and allows the formation of the target carbene complex in very high 79% yield. For carbene complexes with an aromatic nucleus, this protocol worked well for all tether lengths from n = 2 to 11. The yields are given in Scheme 3.16. Scheme 3. 16. Preparation of aromatic bis-carbene complexes 242. |\ n n/ I 1.t—BuLi,THF,-95°C H3CO \ n n/ OCH3 2. Cr(CO)5, THF, 40°C Crlcols Cr(CO)5 CH3 3. Me3OBF4, CHZCIZ CH3 241a'd H20, RT 242a_d Product n Yield, % 242a 2 67 242b 3 79 242C 5 68 242d 11 49 For non-aromatic bis-carbene complexes 211, this procedure was equally effective (Scheme 3.17). It is interesting to notice that, while for aromatic carbene complexes 242 the beneficial effect of immediate bis-vinyllithium transfer was very significant, the yield of non—aromatic complexes 211 remained virtually the same if the reaction mixture was allowed to stir for 15 min at —95°C after tert-butyllithium addition. 106 Scheme 3. 17. Preparation of non-aromatic carbene complexes 211. I WI 1. t-BuLi, THF, -95°C ‘ H300N3/YOCH3 2. Cr(CO)6, THF, 40°C Cr(CO)5 Cr(CO)5 3. Me308F4, CH20l2 21 0a,e,f,g H20, RT 21 1 a,e,f,g Product n Yield, % 211 a 2 65 211e 3 71 211f 5 75 211 g 1 1 67 Altogether, a very significant increase in the yield of bis-carbene complexes was achieved. Also, this procedure has proven to be quite clean, producing only trace amounts of abovementioned polymeric material and mono-carbene 255 (Scheme 3.15). Thus, preparation of multigram amounts of bis-carbene complexes in one loading was made possible. 5. Cyclization Reactions Giving Homocalixarenes and their Properties. Cyclization reactions were studied with two purposes: 1) finding the conditions giving the highest yield, and 2) finding the conditions that allow relatively large-scale preparations. The conditions for macrocyclizations were described by Dr. Wang and Dr. Gopalsarnuthiram in their Ph.D. dissertations. For such cyclizations, three solvents (THF, 1,2-dichloroethane, and 1,4-dioxane) were tested. 1,2-Dichloroethane gave the highest yields in the preparation of substituted calix[4]arenes1 18. Tetrahydrofuran was a solvent of choice in Dr. Wang’s work113. 1,4-Dioxane was expected to be similar to THF and would be expected to have an advantage of allowing the benzannulation reaction to be conducted at atmospheric pressure due to its high boiling point (101.1°C). This, together 107 with nitrogen bubbling instead of freeze-thaw degassing, could help increase the loads significantly. For homocalix[4]arenes, the results that were obtained are summarized in the Scheme 3.18. Scheme 3. 18. Preparation of homocalix[4]arenes by the “triple annulation” method. OCH3 H300 \ n n/ OCH3 Cr(CO)5 Cr(CO)5 1. Solvent 242a-d CH3 100°C 4. OCH3 2. AII’ n n é % 240a-d CH3 2435.411 CH3 Product n Solventa Yield, % THF 25 243a 2 1,2-DOE 35 1 ,4-dioxane 22 THF 25 2431: 3 1,2-DOE 39 1 ,4-dioxane 25 THF 27 243; 5 1,2-DCE 10 1 ,4-dioxane 17 THF 13 243:1 11 1,2—DCE o 1 ,4-dioxane 18b 3 Reactions in THF and 1,2-DCE were degassed by freeze-thaw method, while reactions in 1,4-dioxane were degassed by bubbling nitrogen through the solution for several hours; b Reaction was conducted at 115°C. Overall, 1,2-dichloromethane was found to give the highest yields for short tether lengths, but the yields dramatically fell with longer tether lengths. Only the 99.8% anhydrous 1,2-dichloroethane from Sigma - Aldrich can be used for this reaction; the 108 yields are drastically diminished with lower quality solvent, even if it is freshly distilled from calcium hydride. The ethereal solvents — THF and 1,4-dioxane - gave similar results, but reactions were a lot more reproducible and the yields did not fluctuate depending on the solvent quality. It is interesting to notice that the biggest macrocycle 243d that was prepared by this method gave a higher yield at 115°C (18%) than at 100°C (13%). Based on the results in Scheme 3.18, only THF and 1,4-dioxane were tested for homocalix[3]arene preparation (Scheme 3.19). Scheme 3. 19. Preparation of homocalix[3]arenes by the “triple annulation” method. H3COWWYOCH3 CH3 Cr(CO)5 Cr(CO)5 1. Solvent 0 + 100°C ( )n 21 1 a,e,f,g 00H3 2. Air 1 n O O m H300 n OCH3 240a-d CH3 245a-d Product n Solventa Yield, % TH F 9 245a 2 1 ,4-dioxane 17 TH F 30 245” 3 1 ,4-dioxane 31 TH F 28 245° 5 1 ,4-dioxane 25 TH F 1 0 245d 1 1 1,4-dioxane 1 1b 8 Reactions in THF were degassed by freeze-thaw method, while reactions in 1,4-dioxane were degassed by bubbling nitrogen through the solution for several hours; b Reaction was conducted at 115°C. The yield of 245d does not improve significantly at elevated temperature; reaction in 1,4- dioxane at 115°C gave a result practically identical to THF at 100°C (11 and 10%, respectively). Macrocycle 245a possesses significant ring strain and gives low yield in 109 THF (9%), but this improves to 17% in 1,4-dioxane at 100°C. If this cyclization is conducted at 115°C, the yield actually is slightly decreased (15%). All of the eight macrocycles described above have never been prepared before. Table 3.1 summarizes some of their physical and spectroscopic properties. Table 3. 1. Selected physical properties of homocalixarenes 243 and 245. Compound 243a 2435 243a 243d 245a 2455 2451: 245d mp. °C 180 155 153 44 181 159 142 58 6(OH), ppm 5.48 5.67 4.58 4.29 4.01 5.74 4.77 4.29 -1 3490 3390 3453 3480 3499 3414 3455 3486 WOW cm 3613 3613 Interestingly, the series of homocalix[3]arenes 245 (n = 2, 3, 5, and 11) shows a very illustrative change in aromatic region of the 1H-NMR spectrum (Figure 3.1). While the aromatic hydrogens in the phenolic rings of larger cycles (11 = 5, 11) give singlets around 6.5 ppm, in case of n = 3 they present themselves as a classic AB quartet (J = 2.8 Hz, C = 2.6 Hz), shifting even more apart, to an almost perfect AX case, for n = 2 (2 doublets with J= 3.3 Hz). 110 Figure 3. 1. Changes in 1H-NMR spectrum in homocalix[3]arenes 245. 245a (n = 2) 245b (n = 3) d, 2H d, 2H AB quartet J=3.3 HzJ=3.3 Hz 4H, J=2.8 Hz 6, 2H s, 2H 245c (n = 5) 5 4H 245d (n = 11) s. 4H s 2H s 2H 1 3L I I, It is also worth noticing that the 1H-NMR spectrum of compound 245a lacks the signal from one of the —OCH3 groups, usually found in the region between 3.5 and 3.7 ppm. The corresponding signal in 1JC-NMR spectrum is still present (Figure 3.2). Figure 3. 2. "Missing" methoxy group in the 1H-NMR spectrum of 245a. 245a, 1H NMR 245a, ‘3 C NMR lll This can be explained by the possibility of shielding effect by one of the neighboring aromatic rings due to conformational rigidity of 245a. The hypothesis is confirmed by the integral intensity of multiplet at 2.78 -— 3.12 ppm (15 hydrogens instead of expected 12) As can be seen from the 3D-diagram of the macrocyclic molecule in the crystal form (Figure 3.3), this suggestion seems legitimate, because the lower rim methoxy group is positioned close to one of the benzene rings. For 4 out of the 8 target products, X-ray single crystal analysis was performed in order to confirm the structure, and to see the patterns in hydrogen bonding and crystal packing. In Figure 3.3, on the left the single molecule conformation is presented, while on the right the elementary cell structure is given. 112 Figure 3. 3. Crystal structures of macrocycles 245a-c and 243c. 113 For homocalix[3]arene 245a (n = 2), the structure was solved in the space group P21/n. The unit cell was found to belong to a monoclinic crystal system (a = y = 90°, 6 = 100.8°), with 4 molecules per cell. No intermolecular hydrogen bonding was discovered; the only hydrogen bond found was between two phenolic OH groups of the same molecule, with d(H:--O) = 2.160 A. For homocalix[3]arene 245b (n = 3), the structure was solved in the space group P1. The unit cell was found to belong to a triclinic crystal system (CL = 889°, 6 = 82.3°, y = 70.6°), with 2 molecules per cell. Both inter- and intramolecular hydrogen bonding was discovered. The intramolecular hydrogen bond between one of the phenolic OH groups and the lower rim OCH3 was found to have d(H---O) = 1.805 A, and the intermolecular hydrogen bond between two phenolic OH groups was found to have d(H---O) = 2.066 A. For homocalix[3]arene 2450 (n = 5), the structure was solved in the space group P1. The unit cell was found to belong to a triclinic crystal system (or = 883°, 8 = 71.8°, y = 77.6°), with 2 molecules per cell. Only intermolecular hydrogen bonding was discovered for this molecule. The intermolecular hydrogen bond between two phenolic OH groups was found to have d(H---O) = 1.993 A, and the intermolecular hydrogen bond between the phenolic OH group and the upper rim OCH3 was found to have d(H-~-O) = 2.178 A. Finally, homocalix[4]arene 2430 (n = 5) had the structure solved in the PM space group. The unit cell was found to belong to an orthorhombic crystal system (or = [3 = y = 90°), with 4 molecules per cell. Due to the symmetry of the crystal, only one kind on hydrogen bond was present: an intermolecular bond between a phenolic OH group and the lower rim OCH3 group that was 2.044 A long. l 14 It is interesting to notice that the series minimum for the O—H stretching in the IR spectra in the solid state and the maximum of the chemical shift (6, ppm) for the hydroxyl proton in the 1H NMR spectrum in chloroform solutions both fall on macrocycles 243b and 245b, having three-carbon tethers between aromatic rings (Table 3.1). Macrocycle 245b was also found to have the shortest H---O distance in the crystal among all determined structures. It seems reasonable to assume that the conformational strain is minimal in the case of n = 3, which facilitates intramolecular hydrogen bonding both in solution and in solid state. 6. Testing the New Method: Synthesis and Structure of a Pyrrole-Containing Macrocycle. In an attempt to demonstrate the usability of the new method in advanced homocalixarene preparation, a synthetic target containing a heterocyclic nucleus was chosen. It is known that homocalixarenes containing unprotected pyrroles interest . . . . . l34 . supramolecular chemlsts for then potential as anionic receptors . The syntheSIS of macrocycle 259 was envisaged to follow the basic strategy outlined in Scheme 3.20: 115 Scheme 3. 20. The strategy for the synthesis of macrocycle 259. deprotection H 30CO O30CH H3 COO O5,OCH E8 cyclization cou lin / \ BrflBrCZ p g N + HSCOWMOCHB PG Cr CO Cr CO 256 257 21 1f Diyne 257 (PG = Boc) was prepared as described in Scheme 3.21. Protected 2,5- dibromopyrrole 256 was prepared by NBS bromination of commercially available tert- butyl lH-pyrrole-l-carboxylate as has been described beforel35. The coupling of heterocyclic substrates is often problematic, so a higher-temperature, higher-catalyst load version of the Suzuki-Miyaura coupling procedure was employed. The resulting product was desilylated to afford 257 in 41% combined yield over two steps. Scheme 3. 21. Preparation of heterocyclic diyne 257. 1. 9- BBN, THF, 2h, reflux 2. K3PO4-,H20 Pd(OAC)2, art/Eh?” S- PHOS, B TMS : _ THF,12h, 70°C 256 0° 2' Q / \ ¢ 3. Short column (no separation) Soc 4. TBAF (1/3 eq), THF, H20 238a 257 41% The cyclization was attempted in two solvents, 1,2-dichloromethane and 1,4-dioxane. Reaction in 1,2-DCE proved to be less effective in this case, giving only a 9% yield of 116 the target product. The latter solvent provided 18% yield of the protected product 258 in pure form as well as 5% yield of a fraction that consisted mainly of the deprotected product 259. This deprotected material contained unidentified impurities that could not be removed by column purification, and was not used further. Thermal deprotection of 258 smoothly gave chemically pure 259 in 88% yield (Scheme 3.22). Scheme 3. 22. Preparation of unprotected pyrrole-containing macrocycle 259. H3COWOCH3 CI'(CO)5 Cr(CO)5 H,CO O O OCH3 2111 + 1.1000 180°C Boc 2- O2 25 min I é \N/ Q H,CO OCH, 257 258 1:2'9953 9% 259, 88% 1,4-dioxane: 18% Compound 259 is moderately sensitive to oxygen, and dark-red polymeric material precipitates over time from its nearly colorless solutions when open to air. Despite that, it was only by slow crystallization in an Open vial that a crystal good enough for an X—ray single crystal analysis could be obtained. The structures of the single molecule conformation and the elementary cell can be seen in Figure 3.4. 117 Figure 3. 4. Crystal structure of pyrrole-containing macrocycle 259. The structure of macrocycle 259 was solved in the space group C2/c. The unit cell was found to belong to the triclinic crystal system ((1 = y = 90°, (3 = 130.3°), with 8 molecules per cell. Intramolecular hydrogen bond was found between the two phenolic OH groups; d(H---O) = 1.993 A. The intermolecular hydrogen bond between a phenolic OH group and upper rim OCH3 group was found to have d(H---O) = 1.964 A, and the intermolecular hydrogen bond between pyrrole NH and the upper rim OCH3 was found to have d(H--°O) = 2.264 A. 7. Concluding Remarks. Overall, the “triple annulation” method has proven successful in the preparation of a wide variety of homocalixarenes, with ring size spanning from 15 to 56 members. The yields of the final cyclization are low to moderate, but the reaction did not fail in a single case, and all of the previous steps are high yielding, opening the way for gram-scale preparation of homocalixarenes. The sequence is also relatively insensitive to the presence of various functional groups (the benzannulation reaction of Fischer carbene 118 complexes tolerate all but the most acidic and basic functionalities). Previously unknown pyrrole-containing macrocycle 259 was prepared in 3 steps from the known pyrrole 256. 119 CHAPTER FOUR HOMOCALIXARENE MODIFICATION: INTRODUCTION OF CARBON SUBSTITUENTS INTO THE LOWER RIM Without change something sleeps inside us and seldom awakens. The sleeper must awaken. Duke Leto A rtreides, “Dune 1. Pyrazole-Based Ligands and Homocalixarene Modification. As can be seen from Chapter 1, homocalixarenes can have an enormous number of applications in supramolecular chemistry, as they can display an array of functionality and maintain a variety of rigid shapes at the same time. The method of homocalixarene preparation described in Chapter 3 via the “triple annulation” of carbene complexes is very general in terms of both ring size and tolerated functional groups. Logically, in order to make practical use of these homocalixarenes (as ligands, etc.) one would need to be able to modify these molecules in a systematic way. The search for efficient methods of such modification is the central theme of the current Chapter. Scorpionates are a class of ligands widely applied in organometallic catalysisb6. While not being very popular for quite a long time since their discovery in 1966, they have seen a lot of applications during last 25 years. One of the most typical ligands of this type, tris(pyrazolyl)borate (T p), is isoelectronic to cyclopentadienyl (CD), and makes stable complexes with metals from every group of the periodic table. 120 CNNDTP He During our collaboration project with Prof. Figueroa (University of California at San Diego), it was suggested to us that ligands of the type 262 could be very useful in stabilizing unusual geometries in noble metals. Thus, the target of our part of the project was to make direct precursors of such ligands, namely 261, based on homocalix[3]arenes 260, possessing a C3 axis of symmetry (Scheme 4.1): Scheme 4. 1. Retrosynthetic analysis for calixarene-based scorpionate ligands. H300 OCHs OCH3 H,CO OCH, OCH, t: t: H,Co OCH, OCH, OH OH OH 262 (X = BH‘, CH) 261 (n = 3, 5) 260 (n = 3, 5) In order to achieve this, the following tentative pathway was suggested (Scheme 4.2): 1) preparation of protected 2,6-dibromo-4—methoxyphenol 263; 2) Suzuki-Miyaura coupling of the protected phenol to obtain diynes 264; 3) “triple annulation” cyclization followed by deprotection; 4) preparation of triflate derivative; 5) coupling-based transformation (possibly multistep) to obtain the pyrazole substituents. 121 ‘NJ N:>N’ \ ' / ' / TP CN\ N/N:> 96 H During our collaboration project with Prof. Figueroa (University of California at San Diego), it was suggested to us that ligands of the type 262 could be very useful in stabilizing unusual geometries in noble metals. Thus, the target of our part of the project was to make direct precursors of such ligands, namely 261, based on homocalix[3]arenes 260, possessing a C3 axis of symmetry (Scheme 4.1): Scheme 4. 1. Retrosynthetic analysis for calixarene-based scorpionate ligands. H300 OCHs OCH, H300 OCH, OCH, 4: r: H300 OCH, OCH, 262 (X = BH‘, CH) 261 (n = 3, 5) 260 (n = 3, 5) In order to achieve this, the following tentative pathway was suggested (Scheme 4.2): 1) preparation of protected 2,6-dibromo-4-methoxyphenol 263; 2) Suzuki-Miyaura coupling of the protected phenol to obtain diynes 264; 3) “triple annulation” cyclization followed by deprotection; 4) preparation of triflate derivative; 5) coupling-based transformation (possibly multistep) to obtain the pyrazole substituents. 121 Scheme 4. 2. Tentative pathway of preparation of substituted homocalixarenes. H,COWJLI/\WOCH, CT(CO)5 CT(CO)5 1. 1,4-dioxane 21 1 + 1000C ‘ OPG 2- O2 4 % 14,00 n 264 OCH3 265 1 coupling H300 OCH3 OCH3 OPG Br Br OCH, 263 The studies have begun with the choice of appropriate model reactions allowing the preparation of target pyrazoles in the crowded environment of aromatic triflate 266. 2. Model Studies For Homocalixarene Lower Rim Substitution. In order to achieve the substitution shown in the last transformation of Scheme 4.2, several methods can be employed. Since we are inevitably starting with the phenol and are attempting to introduce carbon substituents (creating a C—C bond) into a crowded environment, our choices are limited to transition metal couplings with an aromatic triflate as an electrophile. Such aromatic triflates are undoubtedly a poor coupling partner, for both steric (ortho,ortho-disubstituted) and electronic (para-methoxy substituent) reasons. In order to allow easier and more broad experimetation, the easily available model triflate 270 was prepared according to Scheme 4.3. 122 Scheme 4. 3. Preparation of model triflate 270. Na,Cr,o7 O 1. N823204 OCH, “20 (2 eq) OCH, /©\ H2804 fl 2. H2804 Q 4-DMAP (5%) Q ether CH3OH PY/CH20I2 (1.1) 0H 50% 0 81% OH 0°C, 3h, 98% OTf 267 268 269 270 The overview of coupling methods that were considered useful is given in Scheme 4.4. These are certainly not all possible methods, but the reactions given have been broadly studied, and numerous advanced ligands and conditions are known, thus increasing the possibility of a successful outcome. Scheme 4. 4. Suggested pathways for substitution of a hindered triflate group. OCH, OCH, OCH, CH 1.3th PG N II N,H4 / _NNH H“ / NH 271 Pd cat. _ Pd cat. . (RUN HO [OI THF N 2. Deprotection 3 OCH, 1, OCH, E // O ‘ N2H4 Pd cat. 7 H W on Cul, R,N THF 270 CO 0 Pd cat. OCHS PG RaN OCH, — NN OCH 0 272 3 2LOHS,a Pd cat. > :NNH 2. Deprotection O COOMe 0 Among the methods described, routes that involve coupling with pre-made pyrazole nucleOphiles are the most convergent. Pyrazoles of type 271 can be most easily prepared if the protecting group on a nitrogen is a group capable of directing a metallation reaction 123 (metal-directing group, or MDG). Two of the most convenient MDGs that are used on pyrazoles and that are compatible with most coupling conditions are tetrahydropyran (THP) and benzyloxy (OBn). The preparation of corresponding pyrazoles is shown in Scheme 4.5: Scheme 4. 5. Preparation of MDG-protected pyrazoles. I . / NH (Oj ,TFA (cat) / N,THp + \‘N separation: / N’THP “N = “N N ‘N 940/0 THF 4 : 1 273 274a 275a 274a 1. NaH, then fNH (PhCOO)2,THF¢ fN'OBn + flu separation= /N-OBn ‘N 2. BnBr, EtN(i—Pr)2 ’N NOB” “N 53% over 2 steps 273 274b 275D 274b Neither oxidation nor acid-catalyzed reaction with DHP turned out to be completely selective, both providing ~ 4 : 1 mixtures of isomers, that can be separated later. It should be noticed that the minor isomer in both cases is not capable of metallation (pyrazoles 275 do not have hydrogens in ortho position to their protecting groups), and thus the separation of individual compounds 274a and 274b is not crucial for the preparation of the final product. 2.1. Model Reactions With Triflate 270. The reactions that were attempted are summarized in Tables 4.1 — 4.3. It should be noted that in order to be successful in triple substitution, reaction on a single-site model (like triflate 270) must be very clean and efficient, because statistically a 50% yield in a single substitution would only afford around 12.5% yield in a triple substitution. Alternatively 124 put, in order to obtain a minimum 50% yield in a triple substitution consisting of a series of three independent reactions, each individual reaction must have a yield of at least 79%. Table 4. l. Attempts at carbonylation and Sonogashira coupling of 270. H,COQ~R H300QOT1 + Nu Pd, L (phosphine) conditions (seeTable) Ar—OTf (270) Target Product (Ar—R) # Nu Conditions TP (Ar-R) Outcome 3% Pd(OAc),, 3% dppp, NEt,, ~ 20% 1 (1.1 eq), DMSO/CH,OH 3:2, conversion CC + CO (1 atm), 70°C, 48 h ‘37 O Ar—< CH,OH OCH 0 10% Pd(OAc),, 10% dppp, NEt, 3 003362330” 2 (1.1 eq), DMSO/CH,OH 3:2, ~ 40% red. CO (1 atm), 85°C, 12 h ‘37 elimination 3 2 eq Nu, 5% Pd(PPh,)CI2, Bu4Nl, n, Cul (50%), EtzNH, 70°C, 48 h ‘33 conversion 3 eq NU, 10°/o P(t-BU)3H+BF4_ ~ 100/0 4 OH 2.5% Pd,(dba),, DBU (4 eq), __ OH conversion é/K Cul (2.4 eq). DMF, 100°C, 18 h 86 AP—‘K— no TP 2 eq Nu, 3% Pd(PhCN)QC|2, 5 6% P(t—Bu),H+BF4‘ ~10°/<3 HN(i-Pr)2 (1.2 eq). Cul (2 %), 33233;?” 1,4-dioxane,100°C, 18 h 139 /—1 3 eq Nu, 2.5% Pd,(dba),, OW ... 10% 6 0 0 10% P(t-Bu),H+BF4", DBU (4 eq), A,__—__—_1§O conversion é Cul (2.4 eq). DMF, 100°C, 18 h 86 ”0 TP a The palladium-catalyzed carbonylationlfl of triflate 270 generated a mixture of compounds, but the GC yield of the target ester (ArCOOCH3) did not exceed 40%. The 125 main side reaction observed was reduction of the triflate insertion intermediate, which leads to 3,5-dimethylanisole as byproduct. 86138139 Sonogashira coupling was also a reaction of choice for reasons similar to that for palladium-catalyzed carbonylation: the incoming nucleophile has a very small angular size (sp-hybridized nucleophile) and should be able to couple with more crowded substrates easier. It is also the only known method of successful lower rim modification in classical calix[4]arenes86 (see Chapter 1, Scheme 1.49). Unfortunately, the conditions that were appropriate for triflate 122 (Chapter 1, Scheme 1.49) were not successful at effecting reaction of the much more electron rich triflate 270. In all cases studied, less than 10% conversion was observed, and most of the starting triflate was recovered unchanged (Table 4.1). Scheme 4. 6. Preparation of pinacolboronates 276. 1. BuLi, THF, -78°C, 30 min Yb 2. B(Oi-Pr)3, —78°C to RT, 111 | \ B i ”N . : N~ ' 1 3. AcOH (2 eq), p1nacol(1.1 eq) N O THP RT, 1h, 79% THP 274a 276a 1. BuLi, THF, —78°C, 30 min Y3 2. B(Oi-Pr)3. —78°C to RT, 1h | \ Sci N- = . - N 3. AcOH (2 eq), pinacol (1.1 eq) N N O OBn RT, 1h, 68% OBn 274b 276b In order to attempt Suzuki-Miyaura coupling, boronates 276a and 276b were prepared (Scheme 4.6). The preparation followed the standard procedure described for similar 1 40 substrates 126 Protodeboronation is a known problem in Suzuki-Miyaura couplings. The mechanism in Scheme 4.7 is formulated here based on discussions in the literatureMl. The coupling of heterocyclic boronates containing electron-donating heteroatoms is affected especially strongly. Higher temperatures and the presence of protic solvents, such as water or alcohols, further increase the rate of this process. Scheme 4. 7. Tentative mechanism of protodeboronation. H2O OH 05%|? H +HO\ ,OR OER COR—'QHB: *0 BR E? (1)86 OR OR 03R OR H2O IN \ @651 _. ©H+ +HO‘BEOR £611“ 6H on HO‘B’OR on Due to the mechanism described in Scheme 4.7, compounds with boron groups in positions analogous to the 2-positions in pyridines are particularly susceptible; successful Suzuki-Miyaura coupling of 2-pyridine boronic derivatives has been the subject of much targeted research effortMlb. For pyrazole, the 3-position would be similar to the 2- position in pyridine, and thus pyrazole partners of type 272 (Scheme 4.4) are anticipated to be problematic. Indeed, protodeboronation was found to be a problem for boronates 276, and complete conversion of the triflate 270 was never achieved in the Suzuki- Miyaura approach. In order to suppress this side reaction, anhydrous conditions were attempted. Also, higher catalyst and pyrazole loadings were used in attempt to make the couplings go faster than protodeboronation. Unfortunately, complete conversion was still not achieved (Table 4.2). 127 HfiOQOTf + Nu Table 4. 2. Attempted Suzuki-Miyaura couplings of the triflate 270. Pd, L (phosphine) conditions on R2 PCY2 (seeTable) L . R R _ OM R _ H T tht 1-112- 913- Ar-OTf (270) argfifig ”C L3: R, = R, = 1213 = i-Pr L4ZR1=R2=R3=H # Nu Conditions TP (Ar-R) Outcome 1.5 eq Nu, 2% Pd(OAC)2, 4% L1 ~ 50% conv. 1 K3PO4 (2 eq), BuOH/HZO 10:1, phenol (ArOH) 100°C, 13 h 142 deboronation 1.5 eq NU, 1°/o Pd2(dba)3, 4°/o L3 ~ 60%, conv. 2 K3PO4 (2 eq). BuOH/HZO 10:1, phenol (ArOH) 100°C, 18 h ‘42 deboronation 1.1 eq Nu, 1% Pd2(dba)3, numerous 3 2.4% PCy3K3PO4 (1.7 eq), byproducts, dioxane/H20 2:1, 100°C, 18 h ‘43 “0 TP 1.5 eq NU, 5°/o Pd(OAC)2, 100/0 L1 ~ 60%, COUV. 4 K3PO4 (2 eq), dioxane/HZO 10:1, clean TP 10060, 48 h 142 deboronation 3pm 1.5 eq Nu, 5% Pd(OAc)2, 10% L1 ~ 50% conv. 5 — K2CO3 (2 eq). CHacN/HZO 10:1, NW clean TF3 ‘ N 100°C 48 h 142 N'N deboronation N \OBn ’ ' 1.5 eq Nu, 5% Pd(OAc)2, 10% L3 03" ~ 75% conv. 6 K3PO4 (2 eq), dioxane/HQO 10:1, d (glean T? o 142 e orona 1011 276b 10° C' 48 h 2775 1.5 eq Nu, 5% Pd(OAc)2, 100/ 7 10%) L4, K3PO4 (2 GQ), ~ 9 dioxane/HZO 10:1, 100°C, 48 h ‘42 convers'on 3 eq NU, 5°/o Pd(OAC)2, 10°/o L1 ~ 80°43 COHV. 8 K3P04 (3 eq). clean TP dioxane, 100°C, 48 h ‘40 deboronation 3 eq NU, 5%: Pd(OAC)2, 10°/o L3 ~ 60% COHV. 9 K3PO4 (3 eq), clean TP dioxane, 100°C, 48 h ‘40 deboronation 3 eq Nu, 5% Pd(OAc)2, 10% L1 .. 50% conv. 1O K3PO4'H20 (2 GQ), Clean TP dioxane, 100°C, 48 h ‘40 deboronation 128 The Negishi coupling is known to be less tolerant towards functional groups due to the higher reactivity of organozinc species, but is not usually affected by the demetallation problem144. Thus, using advanced Buchwald ligands and conditions designed specifically for Negishi couplingMS, we were able to obtain the model coupling product 277a in 79% yield in the case of the THF-protected pyrazole. The conversion of the triflate conversion was found to be complete. An increase of the pyrazole to triflate ratio from 1.5 : 1 to 3 : l afforded an additional rise in yield to an excellent 90%. Surprisingly, the benzyloxy protecting group, which is expected to be more stable under high temperature conditions, gave a lower yield of the coupling product 277b. The best result was 73% yield obtained with a 3 : 1 ratio of pyrazole to triflate (Table 4.3). 129 Table 4. 3. Negishi coupling of the triflate 270. Pd, L R, (phosphine) H.0000Q __ 2, 0 0. O O COl'ldlthl‘lS (seeTable) R2 PCy2 Ar—OTf (270) Target Product (Ar—R) L2: R1 = R2 = Oi-Pr, R3 = H # Nu Conditions TP (Ar—R) Outcome 1 5 O 0 ~ 700/0 1 . eq Nu, 1 /o Pd2(dba)3, 4 A: L2 conversion THF/NMP 2:1, 100°C, 24 h ‘45 dean Tp 1.5 eq Nu, 2.5% Pd2(dba)3, ~ 90% 2 ZnCl 10% L2, THF/NMP 2:1 / conversion _N 100°C, 24 h 145 Ar“ Clean TP \ \ l N THP THP 100°/ 3 278,, 1.5 eq Nu, 5% Pd2(dba)3, 20% L2 277,, conversion THF/NMP 2:1, 100°C, 24 h ‘45 79% yield 11: 4 3 eq Nu, 5% Pd2(dba)3, 20% 1.2 002,323,)“ THF/NMP 221, 100°C, 24 h 145 90% yield TP 1 5 eq Nu 5°/ Pd (dba) 20°/ L 100% 5 ZnCl ' ' ° 2 3' ° 2 conversion . o 145 / X?” THF/NMP 2.1, 100 c, 24 h Ar-«EFNK 48% yield TP, OB“ 08" 100°/ 5 278b 3 ‘38 Nu, 5% Pd2(dba)31 20% L2 277b conversion THF/NMP 2:1, 100°C, 24 h 145 73% yield TPa 3 Isolated as mixture of 277b and 274b, yield of 277b calculated using NMR ratio Overall, Negishi coupling was found to be the most promising method based on the model studies with the triflate 270. 130 2.2. Deprotection of the Model Compounds. Despite the fact that THP group gave significantly better results than OBn in Negishi coupling with the triflate 270, it may not be wise abandon the latter at this stage of the model studies. The reason for that is that THP group hinders the rotation around the newly formed C—C bond, and in the 1H-NMR spectrum of 277a methyl groups of the benzene ring show up as two separate singlets. Molecular modeling suggests that 277b should have significantly lower rotation barrier around this C—C bond. Figure 4. 1. Changes in rotation barriers of model pyrazoles depending on protecting group. BnO 1 THE -N -N M OCH3 277b 1257 OCH3 277a If the steric environment in an actual calixarene gets too crowded after the first coupling, such rotation might provide the steric relief necessary for the next substitution. Thus, both pyrazoles 277a and 277b should be considered for coupling to homocalixarenes. Deprotection of 277a was achieved easily by an earlier reported methodMO: Scheme 4. 8. Deprotection of compound 277a. H CO / 1 1. HCI, MeOH H CO \ 3 . = 3 \ . N N 2. NaHC03 N N“ THP 81% 277a 279 Deprotection of 277b proved to be significantly harder to accomplish. There are no described methods for the cleavage of N—O bond in N-benzyloxy protected pyrazoles. However, the conversion of N—OBn unit into a N-OH group in pyrazoles using palladium 131 . . . 146 . . . on activated carbon IS a well established process . In addltlon, examples of reduction of a N—OH group on a pyrazole to a NH pyrazole are scarce188. Thus, a two-step procedure was developed: Scheme 4. 9. Two-step deprotection of benzyloxy group. 1. H2, 10% Pd/C, CH30H / 2. Zn, AcOH, reflux \ H3CO ' = H CO \ N” 3. NaHCO3, 50% 3 N'NH 277b 279 To sum up, both pyrazoles 274a and 274b can be useful in the Negishi coupling reaction, but the THP protecting group gives higher yields in coupling with the model triflate 270 and is easier to introduce and remove. 3. Homooxacalix[3]arene as an Advanced Model for Substitution Reactions. The original projected route for the preparation of ligands of type 262 (Scheme 4.1) allowed some flexibility in terms of their structure; only the overall shape and pyrazole binding sites were considered to be of importance (at least before any of the experiments on metal binding are done). Thus, homooxacalix[3]arene 9h, that can be prepared relatively easyfl”8 (see Chapter 1, Schemes 1.21 and 1.30), can be used as a secondary model system to test the preparation of the corresponding triflates and their coupling reactions to give target ligands. 132 As it was shown before in oxahomocalix[3]arene system (Chapter 1, Table 1.2), any three lower rim substituents attached to the phenol function that are bigger than a propoxy group will make the rotation barrier too high for conformer interconversion. Thus, the conformers (paco, for partial cone, and cone) become separable isomers. Simple . . 189 . . . . . . theoretlcal studles show that in case of trlflate 280, the rotation barrier 1S too hlgh to be crossed even at high temperatures; also, barriers are very similar for homooxacalix[3]arene and homocalix[3]arene triflates 280 and 266a (Figure 4.2). 133 Figure 4. 2. Conformations of triflates 280, 266a and 266b. Tf Tf Me . . If 0 O O O %),/f Me Me Me cone-280 Tf‘ Tf. OMe OMe cone-266a 266b free rotation In contrast to that, the cavity of homocalix[3]arene 266b (n = 5) is large enough for rotation of triflate to be free at room temperature. In fact, molecular modeling suggests that target (deprotected) pyrazole derivative 26lb (n = 5, Scheme 4.2) should also be able to rotate through the annulus at room. temperature. 3.1. Preparation of Triflate Derivatives of Homooxacalix[3]arene 9h. For reasons of convenience, the method of aldehyde reductive coupling was used for preparation of homooxacalix[3]arene 9h38. The aldehyde in turn was prepared by a modified Duff reaction, involving the use of hexamethylenetetramine in TFA as both solvent and catalyst 134 Scheme 4. 10. Preparation of homooxacalix[3]arene 9h. Me OH 05H,2N4, OH Et3SiH (2 eq) fl CF3COOH OHC CHO Me3SiOTf (1 eq) , e O OHO reflux 30% Me 40-60% Me @‘fb Me 0 Me 67b 9h The method used to introduce the trifluoromethanesulfonate moiety to the model compound 270 (see Scheme 4.3) was particularly targeted for sterically crowded phenols. Thus, it was considered a good candidate for the preparation of triflate 280. Surprisingly, the original conditions afforded only disubstituted triflate in 80% yield. In order to obtain the trisubstituted triflate 280, overnight reaction at room temperature with 6 eq of triflic anhydride had to be used. An increased excess of triflic anhydride afforded significantly higher yields of the target compound (Scheme 4.11). All reactions gave paco isomer of triflate 280 selectively. 135 Scheme 4. 1 1. Preparation of paco-280. Me /©\' x eq TfQO Tf‘ Tf,O (see Table) O 0 OH O : 2 W0, OH HO 4-DMAP \I/ ‘Tf Py/CH2Cl2 1 :1 Me Me Me 0 Me 9h paco-280 Method Yield, % 6 eq T120, 15% 4-DMAP, 0°C, 3 h 80a 6 eq T120, 15% 4-DMAP, 0°C to RT, 12 h 52 9 eq T120, 15% 4-DMAP, 0°C to RT, 12h 79 9 eq T120, 45% 4-DMAP, 0°C to RT, 12h 79 9 eq T120, 15% 4-DMAP, 0°C to RT, 12h, then again 9 eq TfQO, 0°C to RT, 6h 80 a Paco isomer of di-triflate obtained instead of trisubstituted compound 280 In order to prove that paco-triflate 280 does not rotate “through the annulus” at room temperature on the NMR timescale, an NOESY-ID experiment was undertaken. During the experiment, the signal of methyl group that is sterically opposite to the two others in paco-triflate was saturated, and NOE effect was observed. No polarization transfer was observed between methyl groups; the only signal that had NOE enhancement was a singlet due to the adjacent aromatic protons, as would be expected in the case when no “through the annulus” rotation is observed (Figure 4.3). 136 Figure 4. 3. NOESY-lD experiment saturating the unique methyl group (6 = 2.39 ppm) in paco-trilfate 280, showing no exchange with the other methyl groups (6 = 2.20 ppm). ’- ’~ v 5 VA N‘r ' ~p; ~" “3 \ -~ :1 an .V'1'Mmee-n m fr! rr-a {,4 ("Won-1w ~’v’~.\' 1 v with. \'-‘-‘.t .-- Mar."ué~".*¢'«,\‘~ \. ”3..."! t if NA 4 .‘ ’Msz-wf-‘r v.v- .. ..o“ s .. y .1. l. [1“ 1r1 ll 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 ppm Since it is more stable thermodynamically, the paco isomer of 280 is expected to be the main product in almost every case, unless chelation is involved. We have already seen similar behaviour in the preparation of homooxacalix[3]arene derivatives (see Chapter 1, Schemes 1.59, 1.62). Thus, in order to have a chance of preparing cone pyrazole derivatives, we must first try and solve the problem of the preparation of cone triflate 280. From Scheme 1.62 (Chapter 1) one can notice that the outcome of attempts to functionalize the lower rim phenols with electrophiles is influenced not only by the nature of the chelating metal, but also by the nature of the electrophile used. Among the metals, only sodium was found to be able to give necessary chelation, and thus only sodium-containing bases were used. There are several reagents that are available for triflate preparation, and most of them have been tested during our effort (Scheme 4.12). 137 Scheme 4. 12. Attempts at preparation of cone-280. Me Me 1. Base, THF r : ‘1 O OH O > O OTfO 2. Triflate donor X OTf <5o“<5 60555 Me 0 Me Me 0 Me 9h 280 Base X Method Result NaH T120 NaH at RT, then X, —78°C to RT, 18 h - 8‘ NaHMDS T120 NaHMDS at RT, then X, —78°C to RT, 18 h - a NaHMDS PhNTf2 NaHMDS at RT, then X, -78°C to RT, 18 h paco 280 NaHMDS (5-Cl-2-Py)NTf2 NaHMDS at RT, then X, —78°C to RT, 18 h - 8‘ a Complex mixture of products was obtained Unfortunately, the preparation of the cone triflate was never achieved. The reasons for this failure are not clear, but high electrophilicity of triflate donors might be responsible. 3.2. An Attempt at Templated Assembly of Homooxacalix[3]arene Core. Since the preparation of the cone isomer of the tris-triflate 280 has proven to be evasive, and since it is anticipated the coupling reactions of the triflates in such a crowded environment may also be very hard to achieve, an alternative route based on reductive aldehyde coupling (see Scheme 4.13) was appealing. Many scorpionate ligands contain a boron atom bound by pyrazole moieties, but this in fact is not necessary. Carbon atoms can be in the bridgehead position as well, and such (neutral) ligands can also be used for ’5 similar purposesb6. The outline of the proposed synthesis is given below: 138 Scheme 4. 13. Suggested synthesis of ligand 284. THP Pd CH3 T120 CH3 Spin ,(1 cataIyst Q (2:1 Q + IN C: H3C OHC CHO Py OHC CHO base OH OTf 67b 281 276a H3C Et3S|H CH3 Me3SiOTf CH0 CIT-(COO OHC OHC 283 . . . 4 Trlflate 281 1S known'16 and was prepared the usmg standard procedure1 8 Unfortunately, the successful coupling between triflate 281 and pyrazole 276a was found to be very hard to achieve, and numerous attempts failed utterly (Scheme 4.14). Scheme 4. l4. Attempted coupling of triflate 2811 and pyrazole 276a. i—Pr Nr=1N i-Pr 0 THP +BP'nl F)Pd catalyst = H30 \ 1 cu- Pd- Cl OHC CH8- base N OTf \ O | / 281 276a 282 PEPPSl-lPr Pd salt Ligand Conditions Result P(1201136118 PCYs 3 eq K3PO4, 1,4-dioxane, 80°C 0% TM, 100% conv. Pd(OAC)2 S'PHOS 2 eq K3PO4, n—BuOH, 80°C 0% TM, deboronation PEPPSl-IPr 2 eq K2003, 1,4-dioxane, RT 0% TM, 100% conv. Pd(OAc)2 PCy:3 2.4 eq KF, THF, RT 0%: TM, 100°/o COHV. Pd2(dba)3 P(t-Bu)3H+BF4' 2.4 eq KF, THF, RT 0% TM, 100% conv. 139 It was discovered that in all cases triflate 281 was consumed completely, but only insoluble material (and no target product) were obtained. The reason for these failures remains unclear, but the large gap in reactivities of the electrophile (active dialdehyde triflate) and the nucleophile (hard-to—activate heterocyclic boronate) could possibly be responsible. 4. Large Scale Preparation of C3-Symmetrical Homocalix[3]arenes. In order to prepare our initial target molecules of the type 262 (Scheme 4.1), the C3- symmetrical homocalix[3]arenes 260 (Scheme 4.2) had to be prepared using appropriate protecting groups and preferrably on a large scale. Homocalix[3]arenes 260 are also of interest in many other respects because of their symmetry. The synthesis commenced with the preparation of appropriate protected diynes 264. 4.1. Preparation of Diynes 264 and the Choice of Protecting Group. Initial studies on the protection of phenol 286180 have shown that any method involving the use of base (and thus preparation of the phenolate) fails to produce any identifiable individual products, generating a mass of a deep colored, soluble polymer instead. The reason for such behaviour is unclear, but this certainly narrows the usable protecting groups very significantly. With this forced shift to acid-catalyzed methods, it was discovered that the only reported method of MOM protection that uses acidic . 149 . . catalySIS works inconsistently on scales larger than 1 g: 140 Scheme 4. 15. Preparation of MOM—protected diyne 264a. 1. NaH in THF or DMF OCHB OCHs 2. MOMCI, or OCHS BnMe3N+Br3‘ @ CHZC'ZICHCiOH 3' 3’ DIPEA,MOMC|,CH20|2 3' 3' OH OH OMOM 285 286 263a ,OVO\ OCH3 OCH3 TSOH, CHQCIQ Br’ : ‘Br Soxhlet extractor 7 Br Br OH Mol. sieves 4A OMOM 72% on 19 scale, 286 0-15% on 259 scale 263a B.— OMgM 1. WSW E OMOM r Br PleAC)2. S-PHOS, K3PO4-H20, RT ¢ // OCH3 2. TBAF, TH F, 58% overall CH3 263a 264a The coupling of the MOM—protected dibromide 263a went smoothly at room temperature, and after the desilylation afforded 58% yield of the diyne 264a. The benzannulation with complex 211e gave only one product, the protected macrocycle 260a in 25% yield. The removal of MOM group with trifluoroacetic acid afforded 50% yield of260a (Scheme 4.16). 141 Scheme 4. 16. Preparation of homocalix[3]arene 260a using MOM-protected diyne 264a. (OC)SCT \ / CT(CO)5 OMe OMe 1. 1,4-dioxane, 2‘16 100°C, 24h + 2. 02, 25% OMOM 3. TFA, 50% é \\ OCH3 264a H300 O O OCH3 O OCH3 260a While the protection-deprotection approach to C3-symmetrical homocalix[3]arenes was shown to be generally effective, the inability to produce the intermediate 263a reliably on a large scale made it impossible to produce 260a in quantities sufficient for further studies. Thus, a different approach was tested. In contrast to the difficulties associated with the preparation of the MOM-protected dibromide 263a, a THP protecting group was introduced easily150 and afforded the target intermediate 263b in ca. 20 g by simple crystallization (Scheme 4.17). The protected phenol 263b is unstable at room temperature, and in a few days of storage it completely turns into the original phenol 286 even under nitrogen. However, it can be stored virtually indefinitely under a nitrogen atmosphere at —20°C. Scheme 4. 17. Preparation of protected intermediate 263b. OCH3 OCH3 E: BTMA+Br3‘ CHZCIQICH3OH Br Br OH 90% OH 285 286 I42 1. DHP (neat), HCI 2. Crystallization 4298 OCH3 Br£>\ Br OTH P 263b The coupling reaction of 263b turned out to be somewhat more troublesome. Due to the increased bulk of the O—THP group in comparison with O—CH3 or O—MOM groups, the coupling did not proceed at room temperature at all. At elevated temperatures (50 — 70°C) the same coupling reaction produced significant amounts of the alkyne reduction product 288 and the bromide reduction product 289 (Scheme 4.18). Scheme 4. 18. The byproducts of alkyl-aryl coupling with intermediate 263b. TMS OTHP /\/ \\ / Br Br TMS / +9-BBN ”3 ; H3CO OTHP + Pd(OAC)2, S-PHOS OCH3 K3PO4-H20 ( )3 263b ‘7 TMS TMS 287, 20% | l )3 H + H3CO OTHP + H3CO OTHP ( )3 ( )3 // // TMS TMS 288, 40% 289, 20% The side reactions indicated in Scheme 4.18 have decreased the yield of 287 dramatically, and the separation was also much more tedious then for analogous couplings described earlier. Thus, some reaction condition tuning was undertaken, and a much more practical result was achieved (Scheme 4.19). 143 Scheme 4. 19. Preparation of dyines 264b and 264c. n-2 / / - OTHP 1- TMS/%J) + 9 BEN n OTHPn B’ 3’ Pd(OAc)2, S-PHOS, K3PO4-H2O é \\ OCH3 2. TBAF, THF OCH3 263b 264b,c n Conditions Yield,% Notes 3 RT, 1% Pd, 9-BBN : 238 : 263b = 2.75 : 2.5 : 1, 12 h 0 no reaction 3 70°C, 2% Pd, 9-BBN : 238 : 263b = 2.75 12.5 : 1, 12 h 22 lots of 289 3 60°C, 2% Pd, 9-BBN : 238 : 263b = 2.75 22.5 : 1, 12 h 35 - // - 3 50°C, 2% Pd, 9-BBN : 238 : 263b = 2.75 :2.5 : 1, 12 h 34 — ll— 5 70°C, 2% Pd, 9-BBN : 238 : 263b = 2 :2 : 1, 12 h 39 some 289 3 70°C, 4% Pd, 9-BBN : 238 : 263b = 2 : 2 : 1, 4 h 50 clean reaction 5 70°C, 4% Pd, 9-BBN 2238 : 263b = 2 :2 : 1, 4 h 52 clean reaction The key to the successful and clean coupling was in having no excess 9-BBN and enyne reagents relatively to 263b, higher catalyst loading (4% Pd, 8% S-PHOS ligand), and a shorter reaction time of 4 hours. The resulting diynes 264b and 264c were isolated as transparent yellowish oils, completely stable in open air. Preparations were exercised on a scale giving about 4 g of final product in one loading. 4.2. Cyclization Reactions and Deprotection. The cyclization reaction of dyines 264b and 264c with their respective carbene complexes 211e and 211f also gave somewhat unexpected results. Analysis of the reaction mixture by TLC showed two spots, that were identified as the protected and unprotected target phenols 265 and 260 (Scheme 4.20): 144 Scheme 4. 20. Triple annulation with diynes 264b and 264c. meow/Mom, Cr CO Cr CO n ‘ ‘. 1:. O O ’ . , - onane 100°C + %- ( )n + OTHP 2. Air ( )n / n 'K o O / \ H,CO OCH, OCH3 OCH, 264b,c 265a,b 260a,b TSOHHQO CH2Cl2/MeOH Yields ‘ (cyclization + deprotection): 2603: 24% 260b: 20% The reason for the instability of the THP group in these macrocycles is unknown; one can suggest both thermal and acid-catalyzed (from the newly formed phenolic OH groups) pathways. At any rate, such deprotection is not problematic to the preparation of the final target molecule. Deprotection Of the mixture of phenols with p-toluenesulfonic acid monohydrate in methanol — dichloromethane (1:1)151 afforded 260a and 260b cleanly. Macrocycle 260a (n = 3) was found to be very poorly soluble in most organic solvents (e. g., its NMR spectra had to be taken in pyridine-d5!) Crystallization from hot benzene gave very small staticky yellow crystals; crystallization from ethyl acetate — dichloromethane afforded white crystalline powder. In contrast to that, homocalix[3]arene 260b (n = 5) was crystallized from a mixture of hexane and 145 dichloromethane (~ 5:1) affording crystals good enough for X-Ray single crystal study (see Figure 4.4). Figure 4. 4. The C3-symmetrical macrocycle 260b in a crystal: conformation of a single molecule (left) and packing in the elementary cell along c-axis (right). Similarly to the preparation of Boo-protected pyrrole macrocyle 258 (Chapter 3, Scheme 3.22), the yields are somewhat lower than 30% expected for this ring size (Scheme 3.19), and this is probably due to the loss of the protecting group and subsequent related side reactions. At any rate, the reaction is efficient on a large scale, affording more than 1 g of the final material in a single preparation that is carried out in a 5L flask, with 4L of solvent (2.5 mM concentration of the reagents) degassed by bubbling nitrogen through the reaction mixture for several hours. On a separate note, different protecting groups may be useful in this preparation, and a broader study could be beneficial in the future. Most of the appropriate silicon groups are too bulky and cannot be installed on phenol 286 (Scheme 4.18) using acid-catalyzed methods. However, ester protecting group, such as acetate, should be more stable to the 146 benzannulation reaction, and also make the alkyl—aryl Suzuki-Miyaura couplings go smoother. 5. Introduction of Pyrazole Functional Groups into Symmetrical Homocalix[3]arenes. As expected, homocalix[3]arenes 260a and 260b can be converted to their corresponding tris-triflates in good to excellent yields, using the method employed for preparation of paco-280 (Scheme 4.11). Triflate 266b was shown to have free rotation through the annulus at room temperature by 1H NMR spectrum. Triflate 266a was prepared exclusively as the paco isomer. Scheme 4. 21. Preparation of macrocyclic triflates 266b and paco-266a. 1. TfZO (9 eq). 4-DMAP (45%) PY/CH2012 1:1, 0°C to RT, 8 h 2. T120 (9 6(1). 0°C to RT, 8 h 95% 1. TfZO (9 eq). 4-DMAP (45%) Py/CHZCIZ 1:1, 0°C to RT, 8 h 2. TfZO (9 eq), 0°C to RT, 8 h 78o/o MeO paco-266a The coupling reactions of 266b reflect that the original concerns about bulkiness of the THP protectiong group were in fact legitimate. The reaction with the THP-protected organozinc nucleophile 278a gave no identifiable products, even when larger excess of 147 nucleOphile (6 eq per triflate group) and more polar solvent (THF/NMP 1:1) were used (see Scheme 4.22). Scheme 4. 22. Attempted couplings of macrocyclic triflate 266b. OCH 3 2784b ZnCl H300 OCH3 OCH, Pd2(dba)3 (5%), , L1 or L2 (20%) OCHs THF/NMP 2:1 or 1:1, 100°C Ligand Nu PG Equiv. Nu THF:NMP Yield 290, % 278a THP 9 2:1 0 278a THP 18 1:1 0 278b OBn 18 1 1 0 L1 278b OBn 18 1 1 0 L1IR1= R2 = OMe, L2: R1 = R2 = Oi—Pr Unfortunately, use of the pyrazole zinc species 278b with a benzyloxy protecting group did not result in successful substitution either. Used in combination with the diisopropoxy ligand L2, nucleophile 278b failed to produce macrocycle 290, giving a complex mixture of products instead. The use of S-PHOS (L1) as a ligand (which could have possibly been beneficial in this very crowded environment, being structurally similar to L2 yet less bulky) proved even less efficient, leaving the original triflate 266b unchanged. The complex product mixtures obtained in the Negishi coupling of 266b can be explained as follows. After the first (or the second) coupling happens, the steric environment in the molecule becomes too crowded for the third coupling to happen effectively, but still allows palladium to insert into the remaining triflate. The resulting active palladium 148 complex, being unable to react with the pyrazole nucleophile, decomposes, giving a complex mixture of products rather then a single product of partial substitution. 6. Concluding Remarks. The method of “triple annulation” that have proven effective in the synthesis of homocalixarenes, was successfully applied to the gram-scale synthesis of C3-symmetrical homocalix[3]arenes. Unfortunately, the task of lower rim modification of these homocalix[3]arenes was discovered to be quite challenging, and successful substitution conditions were not found. 149 CHAPTER FIVE APPLICATION OF CHROMIUM TRIMETHYLENEMETHAN E COMPLEXES IN INTRAMOLECULAR CYCLIZATION REACTIONS TMM: Too Much Maintenance (relationship slang) http://acronyms. t‘hefi‘eedictionary. com/ 1. Introduction. Trimethylenemethane, or TMM, complexes have become well known because of series of studies by Barry Trost, starting in early 80’3152. In his papers, Trost used palladium TMM complexes, generated from bipolar precursors (Scheme 5.1). Using these complexes he successfully developed methods for various cycloadditions, including [3+2]153, [4+3]154, [6+3]155, regiocontrolled cycloadditions to (LB-unsaturated carbonyl 156 . compounds , and related reactions. TMM complexes of the following metals are known: iron, molybdenum, ruthenium, osmium, iridium, palladium, tantalum, chromium, tungsten, zirconium, and platinum. For a long period of time, their structure was subject to discussion. Two coordination patterns, which are possible for TMM ligand, are n3 and r14 coordination (Scheme 5.1). Currently most of the known TMM complexes, except for palladium and platinum157, are thought to be n4. 150 Scheme 5. 1. TMM binding modes and typical palladium TMM preparation. e e R 9 (J\ 1‘13 /L = 4+VR =2 l or 714 I MLn MLn Maw O M: Fe, MO, Ru, Os, Ir, Pd, Pt, Ta, Cr,W, Zr. SNeeA 9 =(SiMe, Pdme i 3 C _ "JP: OAC l‘ —SiMe,OAc PdLn gdL" e In 1987 Rudolph Aumann reported a novel method for synthesis of TMM complexes, applicable to Group 6 metals (Cr, Mo, W)158. This method included heating a mixture of an allene and a Fischer carbene complex. This reaction is thought to proceed through a metallacyclobutane intermediate (Scheme 5.2). Scheme 5. 2. Preparation of TMM complexes by reaction of Fischer carbene complexes with allenes. OC H 00sz th (OC)4M I pF, 5 Phfi>bi_.” 0 50°C,Et20 . + o : 1. (OC),Cr=‘”<\ Ph CKCOM 298a 293a 303a g > 03 50°C, Eth . Q + ' > 1‘ (OC),Cr= _._ 50°C,Et202 //O—-> O + /— _ ,. (OC)Scr=(Ph n-C6H13 430/0 U'CGH13‘>T (Cc) C #9 + Of'= 50°C,EI2O .‘ O r 2 ,. 5 Ph 54% WP“ CT(CO)4 2983 293h 303d // > CC C 3 i: ( )5 r=(Ph ¥ 53% MP?! Cr(CO)4 298a 293j 303e Phenylallene and 4,5-nonadiene afforded mixtures Of isomers. Due to instability of the TMM complexes (and thus paramagnetic chromium impurities) NOESY analysis targeted to the determination of the stereochemistry was not successful for complexes 303g-l. Instead, tentative assignment was done by comparison with the 1H NMR spectra of related complexes reported by Aumannlsg’159 (Scheme 5.12): 158 Scheme 5. 12. Preparation of TMM complexes 303g-I. / / // > + PIKE 50°C,Et20 fir /(;> :Dr 0 O .. + ~ (QC)50'=——> Ph ’ / \ 2. O2/CH2CI2, 2 days Ph H3C Ph CT(CO)4 303d 304b, 17% 305b, 56% While the reasons for such behaviour were unclear, it was obvious that some kind of B- hydride elimination is happening instead of cycloaddition. Quite logically, it was found that TMM complex 303e, not having any hydrogens in the [ii-position that could possibly be eliminated, gave an amazing 97% yield of the cycloaddition product 304c as a single diastereomer. Scheme 5. 15. Cyclization of TMM complex 303e. / -. O) 1. PhMe, 70°C, 4 h i \ Ph 2. O2/CH2CI2, 2 days / Poh Or(OO)4 97% 3039 304c 160 With this knowledge in hand, it seemed that in order for the cyclization reaction to have broad enough scope to have significant applications, a way to suppress the B-hydride elimination had to be found. It was hypothesised that the presence of a coordinating solvent or ligating additive could suppress this elimination, if the mechanism involves CO dissociation from the chromium center. Unfortunately, neither change of solvents (THF, CH2C12, CH3CN) nor use of phosphines (1-5 equivalents of PPh3, PBu3) as additives have improved the situation to any detectable degree, and the project was stopped at that time. 4. Concluding Remarks. While TMM complexes generated from 1,2-cyclononadiene, as well as tert—butylallene, afford excellent yields of intramolecular [3+2] cycloadditions, TMM complexes from other allenes have not proven to be as synthetically useful. At the same time, the very high degree of diastereoselectivity, as well as high yields of cyclization products for tertiary alkyl substituent on the allene, suggest that for certain substitution patterns this could be a useful reaction. 161 CHAPTER SIX EXPERIMENTAL SECTION Life is a hideous thing, and from the background behind what we know of it peer daemoniacal hints of truth which make it sometimes a thousandfold more hideous. Science, already oppressive with its shocking revelations, will perhaps be the ultimate exterminator of our human species -- if separate species we be -- for its reserve of unguessed horrors could never be borne by mortal brains if loosed upon the world. HP. Lovecraft, "F acts Concerning the Late Arthur Jermyn and His Family " 1. General Considerations. All reactions were performed using either oven-dried or flame-dried glassware under an inert atmosphere of nitrogen. Chemicals used were of commercial quality and used as supplied unless otherwise noted. Whenever the following solvents had to be dry and oxygen-free, they were distilled from the listed drying agents: Tetrahydrofuran (Na, benzophenone), ether (Na, benzophenone), toluene (Na), dichloromethane (CaHz). Anhydrous 1,2-dichloroethane (99.8%) was purchased from Aldrich and used under nitrogen. Chromatographic purification was performed using Sorbent Technologies 230x400 mesh Standard Grade silica gel, and TLC analyses were performed on Merck Silica Gel 60 coated aluminum TLC plates. Compounds were visualized by dipping into KMnO4 stain solution (prepared by mixing 3 g KMnO4, 20 g of K2C03, 5 mL of 5% NaOH, and 300 mL of water) followed by heating with heat gun. Hydrogen 1H NMR 162 data were obtained either on a Varian 300 MHz or 500 MHz instrument. Chemical shifts are reported in parts per million (6, ppm) relative to tetramethylsilane (O = 0.00 ppm) or chloroform (O = 7.24 ppm) for spectra run in CDC13, and multiplicities are indicated by s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sext (sextet), dd (doublet of doublets), dt (doublet of triplets) and br (broad). Carbon 13C NMR data were obtained on a Varian 300 MHz or 500 MHz instrument (working frequencies for 13C NMR are 75 MHz and 125 MHz, correspondingly), and chemical shifts are reported in parts per million (6, ppm) relative to the middle peak of CDC13 triplet (O = 77.00 ppm). Infrared spectra were recorded on a Perkin Elmer FT IR instrument and the peaks are reported in -—l . . . cm . Mass spectral data and high-resolution mass spectra were obtained from the Michigan State University Biochemistry Mass Spectrometry Facility. The mass spectra were obtained using one of the following methods: 1) Direct probe EI (electron impact); 2) FAB (fast atom bombardment), using various matrices; 3) E81 (electrospray ionization). Data are reported in the form of m/z (intensity relative to base peak = 100). Organolithium and Grignard reagents were purchased from Aldrich and used as is. The indicated reaction temperatures are of the oil bath temperature monitored by digital temperature controller. Melting points (uncorrected) were recorded on a Thomas Hoover capillary melting point apparatus using 1.5-1.8x90 mm capillary tubes. Compounds that used in preparations that are not commercially available were prepared according to the referenced published procedures. 163 2. Procedures for Chapter 3. Preparation of TMS-protected enynes. EtMgBr l CUCl (7.5 0/0) SI -sr—-=- 4v - i———\: ' ABr 244a ' — 246 63% 238a Trimethyl(pent—4-en-l-ynyl)silane (238a). A dry 500 mL round-bottom flask was charged with trimethylsilylacetylene (178 mmol, 25.0 mL, 17.4 g) and dry THF (170 mL). The mixture was cooled to —78°C and ethylmagnesium bromide (210 mmol, 70.0 mL, 3.0 M solution in THF) was added drOpwise. After stirring for 0.5 h at —78°C, copper (I) chloride (13.3 mmol, 1.32 g) was added and stirring continued for 0.5 h at room temperature. The slurry was then cooled down to 0°C and allyl bromide (350 mmol, 30.0 mL, 42.0 g) was added. The reaction mixture was stirred at 0°C for an additional 2 h and quenched by the addition of saturated ammonium chloride solution (100 mL). The organic layer was separated, and the water layer was extracted with 2x100 mL of ether; combined organic extracts were dried over MgSO4, concentrated, and distilled in vacuo, collecting the fraction boiling at 44°C/1 mm Hg (receiver was cooled in ice - NaCl - H20 mixture, —10 to —20°C) which afforded 15.5 g (112 mmol, 63%) of trimethyl(pent-4-en-1-ynyl)silane 238a as a colorless liquid; 1H NMR (CDC13, 300 MHz) 6 0.17 (s, 9H), 3.01 (m, 2H), 5.10 - 5.14 (m, 1H), 5.30 - 5.36 (m, 1H), 5.74 - 5.87 (m, 1H); 13C NMR (CDCI3, 75 MHz) 50.04, 24.11, 87.00, 103.38, 116.19, 132.11. . l 19 These spectral data match those reported for this compound . I64 1. BuLi, TH F, -78°C TMS-E *7 TMS-——H: 13 2. HMPT/THF1 :4 — 246 —78 Cto RT,2d 238b WSB’ZMD, 86% 1. BuLi, THF, -78°C TMS-E > TMS—bl: 9 2. HMPT/THF1 :4 _ -78°C to RT, 2 d WE’zuc, 92% 246 238c General procedure for (trimethylsilyl)acetylene alkylation. A dry 250 mL round- bottom flask was charged with trimethylsilylacetylene (60 mmol, 5.9 g, 8.5 mL) and dry THF (120 mL). The mixture was stirred and cooled to —78°C, and butyllithium (64 mmol, 25.6 mL, 2.5 M solution in hexane) was added drOpwise. The mixture was allowed to stir for 30 min at —78°C, after which dry HMPA (30 mL) was added, reaction mixture was stirred for 15 min at —78°C, and then the appropriate bromide (244b122 or 244cm), 40 mmol) was added drOpwise. The reaction mixture was allowed to warm up to room temperature and stir for 36 h. The mixture was poured into 200 mL of water and 200 mL of ether. The layers were separated and the water layer was extracted with 100 mL of ether. The combined organic extracts were washed with 4x200 mL of water and 200 mL of brine, dried over MgSO4, and the solvents removed on a rotovap. The residue was dissolved in pentane and filtered through silica gel and concentrated on a rotovap again. In the case of (hept-6-en-1-ynyl)trimethylsilane 238b (n = 3), distillation at reduced pressure can be used to obtain the product free of solvent and trimethylsilylacetylene 165 impurities. In case of trimethyl(tridec-l2-en-1-ynyl)silane 238c (n = 9), the product can just be dried in vacuo and used without further purification. (Hept-6-en-l-ynyl)trimethylsilane (238b) was obtained as a colorless liquid (86% yield); 1H NMR (CDC13, 300 MHz) 6 0.16 (s, 9H), 1.62 (m, 2H), 2.11 - 2.26 (m, 4H), 4.95 - 5.07 (m, 2H), 5.75 - 5.84 (m, 1H); 13C NMR (CDC13, 75 MHZ) 6 0.17, 19.24, 27.84, 32.74, 84.68, 107.18, 115.15, 137.84. These spectral data match those reported for . 168 thls compound . Trimethyl(tridec-lZ-en-l-ynyl)silane (238c) was obtained as a colorless liquid (92% yield); 1H NMR (CDC13, 500 MHz) 6 0.14 (s, 9H), 1.26 - 1.42 (m, 12H), 1.51 (quint, 2H, J: 7.3 Hz), 2.04 (q, 2H, J: 7.3 Hz), 2.21 (t, 2H, J= 7.3 Hz), 4.91 — 5.01 (m, 2H), 5.78 - 5.83 (m, 1H); l3C NMR(CDC13, 125 MHz) 6 0.17, 19.85, 28.63, 28.78, 28.95, 29.06, 29.12, 29.42, 29.43, 33.81, 84.21, 107.72, 114.11, 139.16; IR (neat) 3079, 2928, 2856, 2176, 1641, 1464, 1250 cm“; MS (EI), m/z (% rel. intensity) 235 (M+—CH3, 0.5), 179 (12), 176 (15), 154 (28), 139 (57), 125 (47), 109 (30), 99 (36), 85 (25), 73 (100), 59 (80); HRMS (El) calcd for M+—CH3 (C15H27Si) m/z 235.1882, found 235.1884. General procedure for aromatic diynes preparation. 166 1. 9-BBN, THF, 2h, reflux 2. K3PO4‘H20, Pd(OAC)2, OCH3 O S-PHOS, 247, THF, 24h, RT n n PCy2 // \\ H3CO O OCH3 TMS—N: :2 3. Short column (no separation; 4. TBAF (1/3 eq), THF, H20 CH3 Workup & Separation S-PHOS 238a-c n = 3’ 68° /0; 240b-d n = 5, 720/0; n = 11, 660/0 The appropriate TMS—protected enyne (20 mmol) was put in a dry 100 mL Schlenk flask and 9-BBN (22 mmol, 44.0 mL, 0.5 M in THF) was added. The resulting solution was heated at 70°C for 2 h, cooled down to room temperature and transferred via cannula to a 250 mL Schlenk flask containing 2,6-dibromo-4-methylanisole 247169 (8 mmol, 2.24 g), potassium phosphate monohydrate (16 mmol, 3.68 g), palladium acetate (0.08 mmol, 18 mg), S-PHOS ligand (0.16 mmol, 66 mg), and 40 mL of dry THF under nitrogen atmosphere. The Schlenk flask solution was degassed using freeze-thaw method (3 cycles), warmed up to room temperature, and stirred at RT for 24 h. The reaction mixture was poured over a Celite pad, which was then rinsed with 4x25 mL of ether. The solvent was removed, the residue dissolved in 5% ethyl acetate in hexane and passed through a thick pad of silica gel (100 g) placed on a large Schott filter. The resulting solution was concentrated in vacuo, diluted with 100 mL of THF, and then water (0.2 mL) and TBAF (4 mmol, 4 mL, 1.0 M solution in THF) were added, and the mixture was stirred for l h (monitored by TLC)125. The reaction mixture was extracted with 100 mL of water, the organic layer was separated, and water layer was extracted with 50 mL of ether. The combined organic extracts were washed with brine, dried over MgSO4, concentrated on a 167 rotovap, and subjected to column chromatography (silica gel, 3% ethyl acetate in pentane forn=3and5,2%forn=11). 2-Methoxy-5-methy1-l,3-di(pent-4-ynyl)benzene (240b, n = 3) was obtained as a yellowish oil in 68% yield, Rf 0.54 (5% EtOAc in hexane); 1H NMR (CDC13, 300 MHz) 6 1.80 - 1.86 (m, 4H), 1.98 (1, 2H, J= 2.7 Hz), 2.24 (td, 4H, J: 7.0 Hz, 2.7 Hz), 2.25 (s, 3H), 2.70 (1, 4H, J = 7.8 Hz), 3.71 (s, 3H), 6.85 (s, 2H); 13C NMR(CDC13, 75 MHz) 6 18.33, 20.77, 28.91, 29.42, 61.22, 68.45, 84.32, 128.69, 133.25, 134.20, 154.42; IR (neat) 3299, 2940, 2850, 2116, 1477, 1458, 1431, 1223, 1134, 1014 cm—1; MS (EI), m/z (% rel. intensity) 254 (M+, 100), 239 (20), 223 (30), 211 (25), 195 (13), 187 (53), 171 (25), 155 (20), 141 (16), 115 (19), 105 (15), 91 (21), 77 (11), 65 (5); HRMS (El) calcd for M+ (C18H220) m/z 254.1671, found 254.1662. 1,3-Di(hept-6-ynyl)-2-methoxy-S-methylbenzene (240c, n = 5) was obtained as a yellowish oil in 72% yield, Rf 0.31 (20% CHzClz in hexane); 1H NMR (CDCl3, 500 MHz) 6 1.47 - 1.53 (m, 4H), 1.54 — 1.64 (m, 8H), 1.93 (t, 2H, J= 2.5 Hz), 2.19 (td, 4H, J = 7.0 Hz, 2.5 Hz), 2.25 (s, 3H), 2.59 (t, 4H, J= 7.8 Hz), 3.69 (s, 3H), 6.83 (s, 2H); 13C NMR (CDC13, 125 MHZ) 6 18.33, 20.85, 28.35, 28.87, 29.68, 30.35, 61.21, 68.11, 84.63, 128.28, 133.13, 135.09, 154.17; IR (neat) 3299, 2938, 2860, 2110, 1478, 1464, 1431, 1219, 1016 cm_l; MS (FAB+, NBA matrix), m/z (% rel. intensity) 310 (M+, 28), 229 (8), 168 187 (12), 173 (18), 161 (19), 149 (15), 135 (26), 119 (18), 105 (14), 73 (100); HRMS (FAB+, NBA matrix) calcd for M+ (C22H3OO) m/z 310.2297, found 310.2296. 1,3-Di(dodec-1l-ynyl)-2-methoxy-S—methylbenzene (240d, 11 = 11) was obtained as a yellowish oil in 66% yield, Rf 0.45 (20% CH2C12 in hexane); 1H NMR (CDC13, 500 MHz) 6 1.24 - 1.43 (m, 2811), 1.49 - 1.56 (m, 4H), 1.57 - 1.62 (m, 4H), 1.92 (t, 2H, J= 2.7 Hz), 2.17 (td, 4H, J: 7.3 Hz, 2.7 Hz), 2.26 (s, 3H), 2.57 (t, 4H, J: 8.0 Hz), 3.70 (s, 3H), 6.82 (s, 2H); 13C NMR (CDC13, 125 MHz) 818.35, 20.84, 28.46, 28.72, 29.07, 29.46, 29.49, 29.53, 29.56, 29.81 (integrates to 2 carbons), 30.92, 61.16, 68.00, 84.70, 128.15, 132.98, 135.34, 154.13; IR (neat) 3312, 2928, 2855, 2150, 1477, 1468, 1219, 1 142, 1018 cm_]; MS (F AB+, NBA matrix), m/z (% rel. intensity) 478 (M+, 65), 339 (2), 313(9), 187 (12), 175 (32), 161 (52), 149 (66), 135 (100), 119 (44), 105 (22), 81 (31), 67 (25), 55 (35); HRMS (FAB+, NBA matrix) calcd for M+ (C34H54O) m/z 478.4175, found 478.4171. ooH3 WC” 0 OCH3 o 1\©/1 Pd(OAc)2, NBu4C| HWH LiOAc, LiCl, CH3 DMF, RT, 44% CH3 250 251a 1,3-Di(3-oxopropyl)-2-methoxy-5—methylbenzene (251a).128 Palladium acetate (0.3 mmol, 67.2 mg), tetrabutylammonium chloride (20 mmol, 5.55 g), lithium acetate (25 mmol, 1.65 g), lithium chloride (10 mmol, 425 mg), 1,3-diiodo-2-methoxy-5- 169 126,127 methylbenzene 250 (5 mmol, 1.87 g), allyl alcohol (10 mmol, 0.58 g, 0.68 mL) and 20 mL of dry DMF were stirred in a 50 mL Schlenk flask under N2 atmosphere for 4 days at room temperature. The resulting mixture was diluted with 50 mL of water and extracted with 2x50 mL ether; the combined organic layers were washed with 7x50 mL of water, 50 mL of brine, and dried over MgSO4. The solvents were removed, and the residue was subjected to column chromatography (silica gel, 20% ethyl acetate in pentane). Dialdehyde 251a was obtained as a yellowish oil (514 mg, 2.20 mmol, 44%), Rf 0.18 (20% EtOAc in hexanes); lH NMR(CDC13, 500 MHz) 8 2.25 (s, 3H), 2.76 (m, 4H), 2.92 (t, 4H, J = 7.8 Hz), 3.72 (s, 3H), 6.85 (s, 2H), 9.82 (t, 2H, J = 1.5 Hz); "C NMR (CDCl3, 125 MHz) 8 20.57, 22.46, 44.30, 60.86, 128.77, 133.11, 133.64, 154.15, 201.58; IR (neat) 3430, 2936, 2828, 2715, 1725, 1480, 1448, 1438, 1223, 1140, 1010 cm_l; MS (FAB+, TEGDME matrix), m/z (% rel. intensity) 234 (M+, 28), 223 (100), 221 (76), 191 (12), 177 (10), 147 (46), 133 (14), 103 (91), 89 (12), 87 (10), 73 (5), 59 (86); HRMS (FAB+, TEGDME matrix) calcd for M+ ((314111803) m/z 234.1256, found 234.1255. N o OCH3 o \‘1212 [OCHFf p- HWH O 0 OC 3 252 Q // K2C03, MGOH CH3 86% CH3 251a 240a 170 1,3-Di(but-3-ynyl)-2-methoxy-5-methylbenzene (240a).129 In a dry 250 mL round bottom flask, dialdehyde 251a (1.59 g, 6.78 mmol) was dissolved in 180 mL of anhydrous methanol under nitrogen, and potassium carbonate (3.74 g, 27.1 mmol) and dimethyl 1-diazo-2-oxopropy1phosphonate 252129 (3.12 g, 16.3 mmol) were added to the solution. The reaction mixture was stirred at RT for 5 h (TLC completion control), after which the mixture was diluted with ether (250 mL), washed with 150 mL of 5% NaHCO3 (sat.), 150 mL of NaCl (sat.), dried over MgSO4, concentrated on a rotovap, and subjected to column chromatography (silica gel, 3% ethyl acetate in pentane). Diyne 240a was obtained as a yellowish oil (1.32 g, 5.84 mmol, 86%), Rf 0.52 (5% EtOAc in hexanes); 1H NMR(CDC13, 500 MHz) 8 1.98 (t, 2H, J = 2.7 Hz), 2.26 (s, 3H), 2.47 (td, 4H, J = 8.0, 2.7 Hz), 2.84 (1, 4H, J = 7.7 Hz), 3.72 (s, 3H), 6.91 (s, 2H); 13C NMR (CDC13, 125 MHz) 8 19.47, 20.76, 29.12, 61.31, 68.62, 84.09, 128.96, 133.04, 133.30, 154.28; IR (neat) 3292, 2937, 2838, 2805, 2115, 1480, 1451, 1435, 1223, 1136, 1013 cufl; MS (EI), m/z (% rel. intensity) 226 (M+, 56), 211 (12), 195 (15), 187 (100), 172 (23), 159 (17), 141 (30), 135 (23), 128 (20), 115 (26), 105 (21), 91 (18), 77 (18), 65 (5); HRMS (E1) calcd for M+ (C14H1303) m/z 226.1358, found 226.1351. fl NBS, THF _ Br A131 ' N I -78 to 0°C ' Boc 84°/o BOC 256 171 tert—Butyl 2,5-dibromo-lH-pyrrole-l-carboxylate (256).135 To a stirred solution of tert-butyl lH-pyrrole-l-carboxylate (29.9 mmol, 5.00 g) in 200 mL of anhydrous THF at —78°C, freshly recrystallized N-bromosuccinimide (60.0 mmol, 10.60 g) was added in portions. The reaction mixture was stirred at —78°C for 1 h, after which it was warmed up to 0°C and stirred at this temperature for 18 h. Sodium sulfite (3.9 g) was added to the mixture, the solvent evaporated on a rotovap, and carbon tetrachloride (170 mL) added. The resulting precipitate was filtered off, and the solution was concentrated on a rotovap again, and subjected to column chromatography (silica gel, 2.5% ethyl acetate in hexane). tert—Butyl 2,5-dibromo-1H—pyrrole-1-carboxylate 256 was obtained as a colorless oil (8.18 g, 25.2 mmol, 84%), Rf 0.66 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 81.64 (s, 9H), 6.24 (s, 2H); 13C NMR (CDC13, 125 MHz) 827.75, 86.27, 100.23, 1 16.08, 147.12. These spectral data match those reported for this compoundbs. 1. 9-BBN, THF, 2h, reflux A 2. K3PO4'H20, Pd(OAC)21 / \ S-PHOS 5' N 3’ _ THF 12h 70°C Boo 256 \ / TMS——\— ’ ’ — \ / \ / _ . 7 N 3. Short column (no separatlon) Boo 4. TBAF (1/3 eq). THF, H20 238a 257 41% tert-Butyl 2,5-di(pent-4-ynyl)-1H-pyrrole-l-carboxylate (257). Trimethyl(pent-4-en-1- ynyl)silane 238a (16.3 mmol, 2.25 g) was put in a dry 100 mL Schlenk flask and 9-BBN (17.9 mmol, 35.9 mL, 0.5 M in THF) was added. The resulting solution was heated at 70°C for 2 h, cooled down to room temperature and transferred via cannula to a 250 mL Schlenk flask containing tert-butyl 2,5-dibromo-1H—pyrrole-1-carboxylate 256 (6.52 172 mmol, 2.12 g), potassium phosphate monohydrate (13.0 mmol, 3.00 g), palladium acetate (0.13 mmol, 29 mg), S-PHOS ligand (0.26 mmol, 107 mg), and 40 mL of dry THF under a nitrogen atmosphere. The Schlenk flask solution was then degassed using the freeze- thaw method. (3 cycles), warmed up to room temperature and back-filled with nitrogen, after which the flask was sealed and heated at 70°C for 12 h. Reaction mixture was poured over a Celite pad which was rinsed with 4x25 mL of ether. The solvent was removed, the residue dissolved in 5% ethyl acetate in hexane and passed through a thick pad of silica gel (100 g) and placed on a large Schott filter. The resulting filtrate was concentrated in vacuo, diluted with 50 mL of THF, and then TBAF (4.9 mmol, 1.8 mL, 75% solution in water) was added, and mixture was stirred for l h (monitored by TLC). The reaction mixture was extracted with 100 mL of water, the organic layer was separated, and the water layer was extracted with 50 mL of ether. The combined organic extracts were washed with brine, dried over MgSO4, concentrated on a rotovap, and subjected to column chromatography (silica gel, 3% ethyl acetate in hexane). tert-Butyl- 2,5-di(pent-4-ynyl)-lH-pyrrole-l-carboxylate 257 was obtained as a colorless oil (0.80 g, 2.68 mmol, 41%) that darkens over time and should be stored under an inert atmosphere, Rf 0.53 (5% EtOAc in hexane); IH NMR(CDC13, 500 MHz) 8 1.60 (s, 9H), 1.82 (quint, 4H, J = 7.3 Hz), 1.96 (1, 2H, J = 2.8 Hz), 2.23 (1d, 4H, J = 7.0 Hz, 2.5 Hz), 2.89 (1, 4H, J = 7.5 Hz), 5.86 (s, 2H); 1’C NMR (CDC13, 125 MHz) 8 17.98, 27.86, 28.01, 28.60, 68.51, 83.56, 84.23, 109.65, 134.80, 150.23; IR (neat) 3297, 2978, 2936, 2869, 2118, 1736, 1534, 1480, 1456, 1435, 1389, 1323, 1256, 1172, 1115, 1022 cm“; MS (ES+), m/z 173 (% rel. intensity) 300 (M+H+, 20), 298 (6), 244 (100), 216 (14), 200 (50), 198 (5); HRMS (ES+) calcd for (M+H)+ (C19H26N02) m/z 300.1964, found 300.1968. +Li‘CECH-en 11 1 1 BrMBr T A DMSO 55% 2099 Pentadeca-1,14-diyne (209g).132 To a dry 250 mL round bottom flask, lithium acetylide — ethylenediamine complex (34 mmol, 3.13 g) was added and then the flask was flushed with nitrogen, and 50 mL of dry DMSO was added. The solution was stirred, cooled down to 8°C, and 1,11-dibromoundecane (16 mmol, 5.00 g) was added dropwise over a period of 1 h, after which the solution was allowed to warm up to room temperature and. stirred for an additional 2 h. Water (50 mL) was added, the mixture poured into 100 mL of water, and extracted with 3x50 mL of pentane. The combined organic layers were dried over MgSO4, evaporated to dryness, and the residue subjected to column chromatography (silica gel, gradient: pure pentane —> 1% ethyl acetate in pentane) to afford pentadeca-1,14-diyne (1.80 g, 8.82 mmol, 55%) as a colorless liquid, Rf 0.42 (pentane); 1H NMR (CDC13, 500 MHz) 6 1.24 — 1.32 (m, 10H), 1.38 — 1.43 (m, 4H), 1.49 — 1.55 (m, 4H), 1.93 (t, 2H, J= 2.8 Hz), 2.17 (td, 4H, J= 7.1 Hz, 2.8 Hz); 13C NMR (CDC13, 125 MHz) 618.38, 28.49, 28.74, 29.08, 29.45, 29.51, 68.01, 84.70. These . 1‘2 spectral data match those reported for thls compound 3 . 174 General procedures for bis-vinyliodides preparation H8312, then l2/NaOH/l-120 Method A or n A < l : 1W1 Cp Zr(H)C|, thenl /CH Cl 209a,e,f,g 2 (Method 3% 2 2 210a,e,f,g OCH3 HBBrz, then |2/NaOH/H20 OCH3 n n (Method A) or \ n n/ // \\ e ' ' Cp22r(H)Cl, then |2/CHZCI2 CH3 (Method B) CH3 240a-d 241a-d Method A (using dibromoborane).1)1 At room temperature, the appropriate diyne (4 mmol) was dissolved in 10 mL of dry CH2C12, and dibromoborane-dimethyl sulfide complex (8 mmol, 8.0 mL of 1M solution in CH2C12) was added dropwise. The solution was stirred for 4h, after which it was cooled down to 0°C and transferred via cannula to a vigorously stirring mixture of 100 mL ether and 50 mL of water, which were also precooled to 0°C in an ice bath. After 15 min of stirring, an ice-cold solution of sodium hydroxide (40 mmol, 1.60 g NaOH in 10 mL of water) was added in one portion, and then an ice-cold ether solution of iodine (9.6 mmol, 2.46 g 12 in 40 mL of ether) was added dropwise with a pipette. The resulting mixture was allowed to stir for 30 min at 0°C, then the layers were separated, and the water layer was extracted with 2x30 mL of ether. The combined organic layers were washed with 25 mL saturated sodium thiosulfate and 25 mL saturated brine. After drying and evaporating on a rotovap (room temperature bath), the residue was subjected to column chromatography (silica gel, 2% 175 ethyl acetate in pentane for 241a-c, 1% ethyl acetate in pentane for 241d, and pure pentane for 210a, e, f, g). Method B (using Schwartz’s reagent)”0 The appropriate diyne (4 mmol) was dissolved in 10 mL of dry CH2C12 was added in one portion to Schwartz’s reagent187 (2.50 g, 9.69 mmol) dispersed in 20 mL of dry CH2C12 in 100 mL round bottom flask, shielded from light with foil. After stirring at RT for 15 min, the resulting transparent yellow solution was cooled to 0°C, part of the foil shield was removed for observation purposes, and iodine (2.54 g, 10 mmol) dissolved in 50 mL of dry CH2C12 was slowly added dropwise until the color of the solution abruptly changed from yellow to orange. The solution was allowed to stir for an additional 30 min, after which the reaction mixture was poured out into the beaker containing 300 mL of pentane and 100 mL of saturated sodium hydrosulfite, and stirred for 30 min. The water layer was removed, and the organic layer was washed consecutively with 100 mL of saturated sodium bicarbonate, water, saturated sodium bicarbonate, and brine. The resulting organic solution was dried with MgSO4 and filtered through a pad of silica gel. The filtrate was evaporated to dryness on a rotovap (room temperature bath) and subjected to column chromatography (silica gel, 2% ethyl acetate in pentane for 24la-c, 1% ethyl acetate in pentane for 241d, and pure pentane for 210a, e, f, g). (1E,5£)-1,6-diiodohexa-1,5-diene (210a, n = 2) was obtained as a light-pink solid (Method B: 90% yield, Method A: 40% yield), mp 43 — 46°C, Rf 0.49 (pentane); 1H 176 NMR (CDC13, 500 MHz) 8 2.14 — 2.17 (m, 4H), 6.06 (dd, 2H, J = 15.5 Hz, 1.0 Hz), 6.45 — 6.51 (m, 2H); 13C NMR (CDC13, 125 MHz) 8 34.70, 75.78, 144.60; IR (neat) 3048, 3009, 2930, 2909, 2841, 1609, 1442, 1294, 1213, 1182, 1130, 943 cm-1; MS (EI), m/z (% rel. intensity) 334 (M+, 55), 207 (10), 167 (100), 153 (5), 127 (23), 80 (55), 79 (53), 77 (7); HRMS (E1) calcd for M+ (C6H312) m/z 333.8716, found 333.8720. (lE,6E)-l,7-diiodohepta-l,6-diene (210e, n = 3) was obtained as a light-pink oil (Method B: 86% yield, Method A: 46% yield), Rf 0.59 (pentane); 1H NMR (CDC13, 300 MHz) 6 1.48 (quint, 2H, J = 7.5 Hz), 2.04 (qd, 4H, J = 7.5 Hz, 1.5 Hz), 5.99 (dt, 2H, J = 14.3 Hz, 1.5 Hz), 6.47 (dt, 2H, J = 14.3 Hz, 7.2 Hz); 13C NMR (CDC13, 75 MHz) 6 26.81, 35.05, 75.17, 145.60; IR (neat) 3046, 3005, 2932, 2855, 1604, 1452, 1435, 1277, 1205, 1184, 1132, 943 cm—1; MS (EI), m/z (% rel. intensity) 348 (M+, 18), 221 (16), 180 (28), 167 (100), 155 (8), 127 (17), 94 (63), 93 (84), 79 (31), 77 (13); HRMS (E1) calcd for M+ (C7H1012) m/z 347.8872, found 347.8876. (1E,8E)-1,9-diiodonona-1,8-diene (210f, n = 5) was obtained as a light-pink oil (Method A: 63% yield), Rf 0.63 (pentane); IH NMR (CDC13, 500 MHz) 6 1.23 — 1.30 (m, 2H), 1.32 — 1.39 (m, 4H), 2.02 (qd, 4H, J = 7.3 Hz, 1.5 Hz), 5.96 (dt, 2H, J = 14.3 Hz, 1.5 Hz), 6.47 (dt, 2H, J = 14.3 Hz, 7.1 Hz); 13C NMR (CDC13, 125 MHz) 6 27.99, 28.09, 35.81, 74.57, 146.31; IR (neat) 3048, 3005, 2928, 2855, 1605, 1460, 1435, 1282, 1205, 177 1194, 943 cm—1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 376 (M+, 30), 307 (6), 249 (26), 195 (8), 167 (100), 121 (51), 81 (40); HRMS (FAB+, NBA matrix) calcd for M+ (C9H1412) m/z 375.9186, found 375.9183. (1E,l4E)-l,15-diiodopentadeca-1,14-diene (210g, = 11) was obtained as a light-pink solid (Method B: 90% yield), mp 33 — 35°C, Rf 0.65 (pentane); 1H NMR (CDC13, 500 MHz) 6 1.24 — 1.30 (m, 14H), 1.38 (quint, 4H, J = 7.3 Hz), 2.02 (qd, 4H, J = 7.3 Hz, 1.5 Hz), 5.96(d1, 2H,J = 14.5 Hz, 1.5 Hz), 6.50 (dt, 2H, J = 14.5 Hz, 7.5 Hz); 13C NMR (CDC13, 125 MHz) 8 28.31, 28.87, 29.29, 29.45, 29.51, 36.00, 74.27, 146.69; IR (neat) 3048, 2926, 2851, 1605, 1476, 1456, 1281, 1219, 1142, 1019.945 cm—1;MS(EI),m/z(% rel. intensity) 460 (M+, 65), 333 (96), 180 (17), 167 (100), 123 (13), 109 (24), 97 (14), 95 (31), 83 (23), 81 (34), 69 (19), 67 (24), 55 (15); HRMS (E1) calcd for M+ (C15H2612) m/z 460.0124, found 460.0118. Aromatic vinyl iodide 241a (n = 2) was obtained as a light-pink solid (Method B: 89% yield, Method A: 37% yield), mp 47 — 48°C, Rf 0.69 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 8 2.26 (s, 3H), 2.32 — 2.37 (m, 4H), 2.65 — 2.69 (m, 4H), 3.68 (s, 3H), 6.02 (d1, 2H, J = 14.6 Hz, 1.5 Hz), 6.57 (d1, 2H, J = 14.6 Hz, 7.2 Hz), 6.81 (s, 2H); 13C NMR (CDC13, 125 MHz) 6 20.80, 28.81, 36.94, 61.27, 75.18, 128.70, 133.36, 133.52, 178 145.81, 154.22; IR (neat) 3046, 2930, 2857, 2826, 1605, 1477, 1448, 1431, 1289, 1221, 1149, 1012, 939 cm—1; MS (EI), m/z (% rel. intensity) 482 (M+, 53), 315 (60), 228 (32), 188 (30), 187 (70), 173 (100), 159 (25), 128 (22), 115 (17), 105 (6), 91 (10), 77 (6); HRMS (BI) calcd for M+ (C16H20012) m/z 481.9604, found 481.9601. Aromatic vinyl iodide 241b (n = 3) was obtained as a colorless oil (Method B: 77% yield, Method A: 48% yield), Rf 0.70 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 1.70 (quint, 4H, J = 7.5 Hz), 2.11 (qd, 4H, J = 7.3 Hz, 1.3 Hz), 2.25 (s, 3H), 2.58 (t, 4H, J = 8.0 Hz), 3.68 (s, 3H), 6.02 (dt, 2H, J = 14.3 Hz, 1.3 Hz), 6.54 (dt, 2H, J = 14.3 Hz, 7.1 Hz), 6.81 (s, 2H); 13C NMR (CDC13, 125 MHz) 6 20.82, 29.07, 29.30, 35.81, 61.19, 74.79, 128.52, 133.24, 134.44, 146.21, 154.27; IR (neat) 3046, 3005, 2930, 2858, 2824, 1605, 1477, 1458, 1348, 1282, 1219, 1147, 1130, 1014, 945 cm_1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 510 (M+, 20), 384 (43), 383 (44), 355 (10), 329 (66), 281 (18), 257 (25), 221 (33), 201 (53), 161 (35), 135 (85), 73 (100); HRMS (FAB+, NBA matrix) calcd for M+ (C13H24012) m/z 509.9917, found 509.9919. Aromatic vinyl iodide 241c (n = 5) was obtained as a colorless oil (Method B: 86% yield, Method A: 45% yield), Rf 0.70 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 1.35 — 1.47 (m, 8H), 1.59 (quint, 4H, J = 7.5 Hz), 2.06 (qd, 4H, J = 7.3 Hz, 1.1 Hz), 2.26 (s, 3H), 2.57 (t, 4H, J = 7.8 Hz), 3.69 (s, 3H), 5.96 (dt, 2H, J = 14.2 Hz, 1.4 Hz), 6.50 (d1, 2H, J = 14.3 Hz, 7.3 Hz), 6.82 (s, 2H); 13(: NMR (CDC13, 125 MHz) 8 179 20.88, 28.18, 28.96, 29.69, 30.54, 35.92, 61.20, 74.36, 128.27, 133.11, 135.08, 146.61, 154.16; IR (neat) 3046, 3005, 2926, 2855, 2824, 1605, 1476, 1350, 1287, 1219, 1144, 1017, 947 cm_l; MS (FAB+, NBA matrix), m/z (% rel. intensity) 566 (M+, 41), 437 (18), 397 (17), 383 (13), 357 (27), 229 (31), 215 (26), 189 (38), 167 (53), 149 (92), 135 (100), 119 (82), 95 (50), 55 (28); HRMS (FAB+, NBA matrix) calcd for M+ (C22H32012) m/z 566.0543, found 566.0545. Aromatic vinyl iodide 241d (11 = 11) was obtained as a colorless oil (Method B: 93% yield, Method A: 43% yield), Rf 0.83 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 8 1.25 — 1.40 (m, 32H), 1.59 (quint, 4H, J = 7.5 Hz), 2.03 (qd, 4H, J = 7.5 Hz, 1.4 Hz), 2.25 (s, 3H), 2.57 (1, 4H, J = 8.0 Hz), 3.69 (s, 3H), 5.96 (d1, 2H, J = 14.3 Hz, 1.3 Hz), 6.50 (d1, 2H, J = 14.3 Hz, 7.5 Hz), 6.82 (s, 2H); 13C NMR (CDC13, 125 MHz) 8 20.88, 28.33, 28.89, 29.32, 29.49, 29.54, 29.58, 29.82 (integrates to 3 carbons), 30.92, 36.01, 61.19, 74.25, 128.15, 132.96, 135.33, 146.72, 154.13; IR (neat) 3048, 3006, 2924, 2853, 1605, 1466, 1367, 1330, 1288, 1219, 1142, 1019, 945 cm_1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 734 (M+, 30), 608 (8), 467 (3), 441 (7), 314 (10), 275 (2), 175 (20), 149 (100), 135 (76), 119 (56), 55 (26); HRMS (FAB+, NBA matrix) calcd for M+ (C34H56012) m/z 734.2421, found 734.2423. . . 170 General procedure for preparation of chromium carbene complexes. 180 1. t-BuLi, THF, —95°C 1W1 . Hacon/Yocn, 2. 01(00),, THF, 40°C 01(00)5 01(00):, 3. Me3OBF4, CH2012, H20, RT 21 0a,e,f,g 21 1 a,e,f,g 00H3 o0H3 1 \ n ”/ 1 1. t-BuLi, THF, -95°0 _ H300 \ n n/ 001-13 2. Cr(CO)5, THF, 40°C C'(CO)5 0'10015 CH3 3. Me3OBF4, 0H2012, CH3 241a-d ”20' RT 242a-d Two 250 mL round bottom flasks were charged with the proper diiodide (4 mmol) and chromium hexacarbonyl (16 mmol, 3.52 g), respectively. The diiodide was dissolved in 100 mL of dry THF and chromium carbonyl was dissolved in 50 mL of dry THF (sometimes dissolution is not complete). The flask containing chromium carbonyl was then placed into a 40°C warm water bath. The diiodide solution was cooled down to — 95°C with stirring (acetone — liquid nitrogen bath), and tert-butyllithium (16 mmol, 9.4 mL of 1.7M solution in pentane) was added dropwise until the solution color changed abruptly from nearly colorless to yellow (90 — 100% of the tert-butyllithium solution is usually added at this point). Immediately after this moment, the resulting solution was quickly transferred into the vigorously stirred chromium hexacarbonyl solution via a large diameter (~ 2 mm, preferably Teflon) cannula (transfer process takes 1 — 2 min). The resulting yellow-orange solution was allowed to stir at room temperature for an additional 30 min, 1 mL of water was added, and then the mixture was evaporated to dryness on a rotovap and dried in vacuo for 45 min. The resulting lithium acylate salt was dissolved in a mixture of 75 mL of CH2C12 and 50 mL of water, and then trimethyloxonium tetrafluoroborate (26 mmol, 3.85 g) was added to the vigorously stirred solution in one portion. The mixture was stirred for 30 min, then poured into 150 mL of ether and water 181 layer was separated. The organic layer was washed with saturated sodium bicarbonate, brine, dried over MgSO4, and concentrated on a rotovap (bath temperature not above 40°C). The residue was subjected to column chromatography (silica gel, 10% ethyl acetate in pentane for n = 2, 3 and 5, 5% ethyl acetate in pentane for n = 11). Carbene complex 211a (n = 2) was obtained as a dark-red solid (65% yield), mp 88 — r 90°C (dec.), Rf 0.35 (10% EtOAc in hexane); 1H NMR (013013, 500 MHz) 8 2.36 — 2.38 (m, 4H), 4.73 (s, 6H), 6.12 — 6.25 (m, 2H), 7.32 (d, 2H, J = 14.7 Hz); '3 C NMR (00013, ‘ 125 MHz) 8 30.72, 66.49, 132.90, 144.94, 216.57, 223.87, 335.82; IR (neat) 3049, 2961, i 2056, 1912, 1614, 1451, 1333, 1306, 1246, 1171, 1084, 968 cm"; MS (ES—), m/z(% rel. intensity) 549 (M—H‘, 100), 520 (4), 373 (8), 257 (5), 132 (8); HRMS (ES—) calcd for (M—H)’ (020H13012012) m/z 548.9217, found 548.9219. Carbene complex 211e (n = 3) was obtained as a dark-red solid (71% yield), mp 78 — 80°C (dec.), Rf 0.31 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 1.68 (quint, 2H, J = 7.5 Hz), 2.20 -— 2.25 (m, 4H), 4.74 (s, 6H), 6.26 (dt, 2H, J = 14.8 Hz, 7.5 Hz), 7.30 (d, 2H, J = 15.5 Hz); 13C NMR (CDC13, 125 MHz) 6 26.80, 31.56, 66.40, 135.32, 144.70, 216.67, 223.90, 335.97; IR (neat) 3049, 3005, 2961, 2924, 2851, 2060, 1935, 1726, 1456, 1267, 1233, 1171, 1119 cm_1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 564 (M+, 17), 452 (12), 424 (33), 368 (46), 340 (90), 312 (100), 284 (54), 248 182 (19), 181 (5), 154 (24), 120 (16), 90 (10), 52 (24); HRMS (FAB+, NBA matrix) calcd for M+ (C21H16012Cr2) m/z 563.9452, found 563.9456. Carbene complex 2111' (n = 5) was obtained as a dark-red oil (75% yield), Rf 0.36 (5% EtOAc in hexane); 1H NMR (013013, 500 MHz) 8 1.35 — 1.41 (m, 2H), 1.50 (quint, 4H, J = 7.5 Hz), 2.18 (qd, 4H, J = 7.3 Hz, 1.1 Hz), 4.73 (s, 6H), 6.29 (d1, 2H, J = 14.8 Hz, 7.5 Hz), 7.28 (d1, 2H, J = 14.8 Hz, 1.4 Hz); 130 NMR (CDCl3, 125 MHz) 8 28.01, 28.68, 32.15, 66.35, 136.75, 144.47, 216.74, 223.92, 335.86; IR (neat) 3049, 2919, 2851,2060, 1933, 1727, 1603, 1456, 1238, 1233, 1170, 978 cm_1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 592 (M+, 16), 536 (6), 452 (94), 424 (8), 396 (10), 368 (36), 340 (100), 312 (96), 276 (12), 239 (16), 154 (25), 136 (16), 120 (15), 90 (10), 52 (26); HRMS (FAB+, NBA matrix) calcd for M+ (C23H20012Cr2) m/z 591.9765, found 591.9767. Carbene complex 211g (11 = 11) was obtained as a dark-red oil (67% yield), Rf 0.48 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 1.25 — 1.36 (m, 14H), 1.47 (quint, 4H, J = 7.3 Hz), 2.17 (q, 4H, J = 7.0 Hz), 4.71 (s, 6H), 6.33 (dt, 2H, J = 14.8 Hz, 7.3 Hz), 7.28 (d, 2H, J = 15.0 Hz); 130 NMR (00013, 125 MHz) 8 28.23, 29.16, 29.31, 29.41, 29.48, 32.35, 66.24, 137.76, 144.37, 216.78, 223.96, 335.98; IR (neat) 3019, 2930, 2857, 2060, 1923, 1727, 1605, 1453, 1233, 1173, 1086, 978 cm"; MS (ES—), m/z (% rel. 183 intensity) 675 (M—H', 100); HRMS (ES—) calcd for (M—H)“ (C29H31012Cr2) m/z 675.0626, found 675.0601. Aromatic carbene complex 2423 (n = 2) was obtained as a dark-red oil (67% yield), Rf 0.21 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 2.26 (s, 3H), 2.49 (q, 4H, J = 7.3 Hz), 2.76 (t, 4H, J = 8.0 Hz), 3.70 (s, 3H), 4.72 (s, 6H), 6.35 (dt, 2H, J = 14.7 Hz, 7.3 Hz), 6.85 (s, 2H), 7.33 (d, 2H, J = 15.0 Hz); 13,C NMR (CDC13, 125 MHz) 6 20.75, 28.79, 33.20, 61.15, 66.33, 128.79, 133.47, 133.71, 135.98, 144.40, 154.27, 216.71, 223.95, 336.23; IR (neat) 2977, 2926, 2857, 2060, 1943, 1605, 1455, 1328, 1350, 1232, 1152, 1121, 1076, 982 cm“; MS (ES—), m/z (% rel. intensity) 697 (M—H‘, 100); HRMS (ES—) calcd for (M—H)" (C30H25013Cr2) m/z 697.0105, found 697.0095. Aromatic carbene complex 242b (n = 3) Was obtained as a dark-red oil (79% yield), Rf 0.39 (1090 EtOAc in hexane); 1H NMR (013013, 500 MHz) 81.79 (quint, 4H, J = 7.5 Hz), 2.24 (q, 4H, J = 7.3 Hz), 2.26 (s, 3H), 2.63 (1, 4H, J = 7.8 Hz), 3.68 (s, 3H), 4.73 (s, 6H), 6.36 (d1, 2H, J = 15.0 Hz, 7.5 Hz), 6.84 (s, 2H). 7.31 (d, 2H, J = 15.0 Hz); ”C NMR (013013, 125 MHz) 8 20.82, 29.34, 29.44, 32.27, 61.25, 66.32, 128.70, 133.48, 134.36, 137.26, 144.51, 154.37, 216.77, 223.93, 336.01; IR (neat) 2928, 2857, 2060, 1925, 1725, 1603, 1478, 1453, 1339, 1231, 1171, 1078, 1015, 974 cm“; MS (FAB+, NBA matrix), m/z (% rel. intensity) 726 (M+, 7), 695 (3), 614(6), 586 (17), 474 (18), 446 184 (53), 410 (13), 394 (31), 351 (100), 332 (55), 307 (22), 289 (10), 154 (77), 136 (49), 120 (21 ), 90 (14), 52 (28); HRMS (FAB+, NBA matrix) calcd for M+ (C32H30013Cr2) m/z 726.0497, found 726.0494. Aromatic carbene complex 242c (n = 5) was obtained as a dark-red oil (68% yield), Rf 0.42 (10% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 1.42 (quint, 4H, J = 7.3 Hz), 1.53 (quint, 4H, J = 7.4 Hz), 1.62 (quint, 4H, J = 7.4 Hz), 2.24 (q, 4H, J = 7.2 Hz), 2.26 (s, 3H), 2.63 (1, 4H, J = 8.0 Hz), 3.69 (s, 3H), 4.73 (s, 6H), 6.32 (d1, 2H, J = 15.0 Hz, 7.5 Hz), 6.82 (s, 2H), 7.29 (d, 2H, J = 15.0 Hz); 130 NMR (00013, 125 MHz) 8 20.85, 28.18, 29.33, 29.69, 30.65, 32.31, 61.23, 66.32, 128.31, 133.21, 135.09, 137.36, 144.37, 154.14, 216.76, 223.96, 335.88; IR (neat) 2932, 2856, 2060, 1923, 1603, 1478, 1453, 1289, 1232, 1173, 1084, 1017, 978 cm‘1;Ms (FAB+, NBA matrix), m/z (% rel. intensity) 782 (M+, 5), 698 (5), 642 (14), 586 (3), 558 (10), 530 (27), 502 (100), 450 (40), 419(8), 388 (21), 357(7), 307 (10), 289(8), 185 (14), 154 (38), 136 (28), 91 (10), 52 (22); HRMS (FAB+, NBA matrix) calcd for MJr (C36H33013Cr2) m/z 782.1123, found 782.1119. Aromatic carbene complex 242d (n = 11) was obtained as a dark-red oil (49% yield), Rf 0.41 (5% EtOAc in hexane); 1H NMR (00013, 300 MHz) 8 1.24 — 1.40 (m, 28 H), 1.47 (quint, 4H, J = 7.0 Hz), 1.59 (quint, 4H, J = 7.4 Hz), 2.24 (qd, 4H, J = 7.3, 1.0 Hz), 2.26 (s, 3H), 2.63 (1, 4H, J = 8.0 Hz), 3.69 (s, 3H), 4.72 (s, 6H), 6.33 (dt, 2H, J = 14.7 185 Hz, 7.4 Hz), 6.82 (s, 2H), 7.29 (d1, 2H, J = 15.0 Hz, 1.4 Hz); 1”0 NMR (CDC13, 75 MHz) 6 20.85, 28.28, 29.21, 29.37, 29.49, 29.51, 29.55, 29.59, 29.84 (integrates to 2 carbons), 30.95, 32.39, 61.20, 66.27, 128.18, 133.02, 135.37, 137.70, 144.34, 154.17, 216.77, 223.95, 335.93; IR (neat) 2928, 2855, 2060, 1929, 1605, 1454, 1230, 1173, 1142, 1088, 1019, 978 cm—1; MS (FAB+, NBA matrix), m/z (% rel. intensity) 866 (M+—3CO, 3), 835 (2), 810 (1), 760 (1), 670 (100), 618 (18), 541 (10), 289(8), 149 (82), 135 (78), l" 119 (62), 91 (44), 52 (45); HRMS (FAB+, NBA matrix) calcd for M+—3CO (C45H62010Cr2) m/z 866.3153, found 866.3156. . i! General macrocyclization procedures. OCH3 H300 \ n / OCH3 CF(CO)5 Cr(CO)5 1 Solvent CH3 100°C 242a-d + OCH3 2. Air é \\ 240a-d CH3 H300 \ n/ OCH3 m CO 1. Solvent r( )5 r( )5 100°C 21 1 a,e,f,g + OCH3 2. A1r / \ 240a-d / \ CH3 186 Method A (in THF, freeze-thaw degassing): The proper carbene complex (1 mmol) and the appropriate diyne (1 mmol) were dissolved in 400 mL of freshly distilled anhydrous THF and placed in a 1L Schlenk flask. The flask was then degassed by the freeze-thaw method (3 cycles), warmed up to room temperature, backfilled with nitrogen, and the flask was sealed and heated for 24 h at 100°C in an oil bath. The reaction mixture was then cooled, and the resulting solution was placed in an open 1L beaker in the hood, and stirred open to air overnight. The resulting solution was filtered through a cotton plug to get rid of insoluble chromium-containing material, evaporated to dryness, and subjected to column chromatography (silica gel, 20% ethyl acetate in pentane for n = 2, 3 and 5, 10% ethyl acetate in pentane for n = 11). Method B (in 1,2-dichloroethane, freeze-thaw degassing): The proper carbene complex (1 mmol) and the appropriate diyne (1 mmol) were dissolved in 400 mL of Aldrich anhydrous 99.8% 1,2-dichloroethanel7l, the solution was placed in a 1L Schlenk flask, and the contents of the flask were then degassed by the freeze-thaw method (4-5 cycles), warmed up to room temperature, backfilled with nitrogen, and the flask was sealed and heated for 0.5 - l h at 100°C in an oil bath. The reaction mixture was then cooled and the resulting solution was placed in an open 1L beaker in the hood, and stirred open to air overnight. The resulting solution was filtered through the cotton plug to get rid of insoluble chromium-containing material, evaporated to dryness, and subjected to column chromatography. Method C (in 1,4-dioxane, no freeze-thaw): The proper carbene complex (1 mmol) and the appropriate diyne (1 mmol) were dissolved in 400 mL of 1,4-dioxane which had been freshly dried by passing through an alumina drying column. The solution was placed in a 187 1L Schlenk flask, and nitrogen was bubbled slowly through it for 3 h. The flask was then sealed and heated for 24 h at 100°C (unless stated otherwise) in an oil bath. The reaction mixture was then cooled, and the resulting solution was placed in an open 1L beaker in the hood, and stirred open to air overnight. The resulting solution was filtered through the cotton plug to get rid of insoluble chromium-containing material, evaporated to dryness, and subjected to column chromatography. In case of the largest macrocycles (n = 11), it was found that cyclization at 115°C gives the best yield of the target product. Homocalix[4]arene 243a (n = 2) was obtained was obtained as a yellow solid (Method A: 25% yield, Method B: 35% yield, Method C: 22% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give yellow crystals, mp 180°C, Rf 0.32 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 6 2.14 (s, 6H), 2.80 (m, 16H), 3.63 (s, 6H), 3.69 (s, 6H), 5.48 (s, 2H), 6.46 (s, 4H), 6.69 (s, 4H); 13C NMR (CDC13, 125 MHz) 6 20.71, 30.79, 31.27, 55.60, 61.12, 112.78, 129.13, 129.34, 133.45, 134.37, 146.96, 152.72, 154.27; IR (neat) 3490, 2934, 2856, 1604, 1478, 1348, 1226, 1194, 1143, 1057, 1012 cm—1; MS (ES+) m/z (% rel. intensity) 597 (M+H+, 100); HRMS (ES+) calcd for (M+H)+ (C33H45O6) m/z 597.3216, found 597.3224. Homocalix[4]arene 243b (n = 3) was obtained as a yellowish solid (Method A: 25% yield, Method B: 39% yield, Method C: 25% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give colorless 188 crystals, mp 155°C, Rf 0.32 (20% EtOAc in hexane); 1H NMR(CDC13, 500 MHZ) 6 1.93 (quint, 8H, J = 7.3 HZ), 2.24 (s, 6H), 2.52 (t, 8H, J: 7.8 Hz), 2.64 (t, 8H, J= 7.3 HZ), 3.55 (s, 6H), 3.74 (s, 6H), 5.67 (s, 2H), 6.54 (s, 4H), 6.83 (s, 4H); 13C NMR (CDC13, 125 MHZ) 6 20.78, 29.54, 29.78, 31.07, 55.61, 60.96, 112.63, 129.18, 130.48, 133.82, 134.72, 146.11, 153.15, 154.16; IR (neat) 3390, 2932, 2850, 1605, 1477, 1439, 1317, 1211, 1190, 1151, 1130, 1061 cm_]; MS (FAB+, NBA matrix), m/z (% rel. intensity) 652 (M+, 100), 531 (4), 397(8), 339 (6), 325 (12), 299 (6), 257 (13), 173 (40), 135 (68), 95 (62), 55 (92); HRMS (FAB+, NBA matrix) calcd for M+ (C42H5206) m/z 652.3764, found 652.3768. Homocalix[4]arene 243c (n = 5) was obtained as a yellowish solid (Method A: 27% yield, Method B: 10% yield, Method C: 17% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give yellowish crystals, mp 153°C, Rf 0.49 (20% EtOAc in hexane); 11H NMR (CDC13, 500 MHZ) 6 1.40 (quint, 8H, J = 7.4 HZ), 1.62 (sext, 16H, J = 7.5 HZ), 2.25 (s, 6H), 2.53 (t, 8H, J = 7.8 HZ), 2.64 (t, 8H, J= 7.5 HZ), 3.67 (s, 6H), 3.72 (s, 6H), 4.58 (s, 2H), 6.51 (s, 4H), 6.81 (s, 4H); 13C NMR (CDC13, 125 MHZ) 6 20.83, 29.10, 29.66, 29.72, 30.58, 30.77, 55.56, 61.35, 112.80, 128.59, 129.89, 133.30, 135.24, 145.49, 153.11, 154.34; IR (neat) 3453, 2932, 2857, 1601, 1477, 1439, 1348, 1250, 1199, 1152, 1077, 1043, 1005 cm-l; MS (FAB+, NBA matrix), m/z (% rel. intensity) 764 (M+, 70), 391 (10), 307 (40), 289 (28), 219 (34), 154 (100), 136 (100), 119 (62), 105 (50), 91 (71), 81 (57), 69 (77), 55 (82); 189 HRMS (FAB+, NBA matrix) calcd for M+ (C50H6806) m/z 764.5016, found 7645023. Single crystal X-Ray analysis is also available for this molecule (see Appendix). Homocalix[4]arene 243d (11 = 11) was obtained as a colorless oil (Method A: 13% yield, Method C (24 h at 115°C): 18% yield), which can be crystallized from a pentane solution at —20°C to give white crystals, mp 44°C, Rf 0.69 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.24 — 1.38 (m, 56H), 1.54 - 1.63(m, 16H), 2.25 (s, 6H), 2.53 — 2.58 (m, 16H), 3.69 (s, 6H), 3.74 (s, 6H), 4.29 (s, 2H), 6.53 (s, 4H), 6.82 (s, 4H); lDC NMR (CDC13, 125 MHZ) 6 20.87, 29.41 (integrates to 4 carbons), 29.46, 29.52, 29.66, 29.80, 29.85, 30.51, 30.91, 55.59, 61.21, 112.77, 128.25, 129.26, 133.03, 135.39, 145.34, 153.09, 154.21; IR (neat) 3613, 3480, 2924, 2855, 1707, 1607, 1477, 1466, 1346, 1294, 1219, 1194, 1147, 1095, 1059, 1018 cm_l; MS (FAB+, NBA matrix), m/z (% rel. intensity) 1100 (M+, 100), 550(2), 391 (2), 289(6), 219 (10), 189 (12), 175 (26), 161 (32), 151 (92), 149 (84), 135 (84), 119 (56), 105 (38), 91 (30), 81 (27), 69 (36), 55 (43); HRMS (FAB+, NBA matrix) calcd for M+ (C74H116O6) m/z 1100.8772, found 1 100.8760. Homocalix[3]arene 245a (n = 2) was obtained as a white solid (Method A: 9% yield, Method C: 17% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give colorless crystals, mp 181°C, 190 11,039 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 8 2.26 (s, 3H), 2.77 — 3.06 (m, 15H), 3.69 (s, 6H), 4.01 (s, 2H), 6.44 (d, 2H, J = 3.0 Hz), 6.49 (d, 2H, J = 3.3 Hz), 6.95 (s, 2H); 130 NMR (013013, 125 MHz) 8 20.82, 30.50, 30.56, 31.24, 55.58, 61.05, 113.96, 114.14, 129.37, 130.02, 130.33, 134.46, 134.54, 146.26, 153.77, 155.07; IR (neat) 3499, 2924, 2857, 1734, 1605, 1432, 1352, 1307, 1289, 1235, 1196, 1146, 1055, _- 1007 cm_l; MS (ES+), m/z (% rel. intensity) 449 (M+H+, 100), 237 (4); HRMS (ES+) calcd for (M+H)Jr (C23H33O5) m/z 449.2328, found 449.2320. Single crystal X-Ray analysis is also available for this molecule (see Appendix). Homocalix[3]arene 245b (n = 3) was obtained as a yellowish solid (Method A: 30% yield, Method C: 31% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give colorless crystals, mp 159°C, Rf 0.46 (20% EtOAc in hexane); IH NMR (00013, 500 MHz) 8 1.86 — 1.95 (m, 4H), 2.00 (quint, 2H, J: 7.3 Hz), 2.26 (s, 3H), 2.52 — 2.64 (m, 8H), 2.61 (1, 4H, J: 7.0 Hz), 3.53 (s, 3H), 3.75 (s, 6H), 5.74 (s, 2H), 6.55 (AB quartet, 4H, J = 2.8 Hz, C = 2.6 Hz), 6.85 (s, 2H); '30 NMR (013013, 125 MHz) 8 20.80, 29.77, 30.12, 30.19, 30.38, 31.50, 55.56, 60.60, 112.97, 113.37, 129.58, 132.35, 132.83, 134.30, 135.24, 145.86, 153.46, 153.74; IR (neat) 3414, 2920, 2851, 1705, 1603, 1477, 1344, 1203, 1150, 1062, 1012 cm_l; MS (FAB+, NBA matrix), m/z (% rel. intensity) 490 (M+, 32), 460 (4), 391 (2), 341(2), 307 (30), 289 (16), 219(10),154(100),136(63),117(12),107(18), 89 (14), 77 (13); HRMS (FAB+, NBA matrix) calcd for M+ (C31H3305) m/z 490.2719, found 191 490.2722. Single crystal X-Ray analysis is also available for this molecule (see Appendix). Homocalix[3]arene 245c (n = 5) was obtained as a yellowish solid (Method A: 28% yield, Method C: 25% yield), which can be recrystallized by slow evaporation of hexane/CH2C12 (4:1) solution at room temperature to give yellowish crystals, mp 142°C, Rf 0.51 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 8 1.30 — 1.39 (m, 6H), 1.60 — 1.67 (m, 12H), 2.26 (s, 3H), 2.54 (t, 4H, J: 7.8 Hz), 2.57 (1, 8H, J: 7.8 Hz), 3.65 (s, 3H), 3.73 (s, 6H), 4.77 (s, 2H), 6.51 (s, 4H), 6.81 (s, 2H); 1’0 NMR (00013, 125 MHZ) 6 20.83, 28.10, 28.15, 29.14, 29.61, 29.75, 30.06, 30.13, 30.59, 55.51, 61.53, 112.78, 112.93, 128.66, 130.20, 130.36, 133.57, 135.17, 145.49, 153.31, 154.30; IR (neat) 3455, 2930, 2856, 1604, 1477, 1350, 1215, 1149, 1072, 1040, 1014 cm_1; MS (FAB+, Gly matrix), m/z (% rel. intensity) 574 (M+, 3), 553 (8), 461 (17), 369 (45), 277 (99), 215 (8), 185 (100), 93(100), 75 (86), 57 (70), 45 (56); HRMS (FAB+, Gly matrix) calcd for M+ (C37H5005) m/z 574.3658, found 574.3662. Single crystal X-Ray analysis is also available for this molecule (see Appendix). Homocalix[3]arene 245d (11 = 11) was obtained as a colorless oil (Method A: 10% yield, Method C (24 h at 115°C): 11% yield), which can be crystallized from pentane solution at —20°C to give white crystals, mp 58°C, Rf 0.70 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.22 — 1.38 (m, 42H), 1.55 — 1.62 (m, 12H), 2.25 (s, 3H), 2.53 — 192 2.58 (m, 12H), 3.69 (s, 3H), 3.73 (s, 6H), 4.29 (s, 2H), 6.53 (s, 4H), 6.82 (s, 2H); ]’0 NMR (CDCI3, 125 MHZ) 6 20.86, 29.26, 29.28, 29.30 (integrates to 5 carbons), 29.32, 29.33, 29.35, 29.42, 29.51, 29.80, 29.81, 29.87, 30.52, 30.86, 55.60, 61.18, 112.81, 112.84, 128.29, 129.28, 133.02, 135.38, 145.38, 153.11, 154.28 (1 aromatic carbon not found); IR (neat) 3616, 3486, 2926, 2853, 1605, 1478, 1346, 1190, 1148, 1055, 1018 cm‘ 1; MS (ES+), m/z (% rel. intensity) 828 (M+H+, 100), 814 (1), 510 (3); HRMS (ES+) calcd for (M+H)+ (C55H37O5) m/z 827.6554, found 827.6530. H3COMOCH3 0r(00)5 01(00)5 H300 O OCH3 2111 + 1. 100°C 180°C B00 2. 02 25 min // \N/ % H300 OCH3 257 258 259 Unprotected Pyrrole Macrocycle 259.172 Macrocyclization was achieved using Methods B (9% yield) of C (18% yield) (see procedures above). The latter cyclization provided 18% yield of the protected product 258 in pure form as well as 5% yield of a fraction that consisted mainly of the deprotected product 259. This deprotected material contained unidentified impurities that could not be removed by column purification and was not used further. A solution of product 258 (105 mg, 0.187 mmol) was then evaporated on a rotovap and dried in vacuo to afford a thin film in a 250 mL round bottom flask. The flask was then filled with nitrogen and heated at 180°C in an oil bath for 25 minutes, cooled down, and subjected to column chromatography (silica gel, 20% 193 ethyl acetate in hexane). Macrocycle 259 was obtained as a beige solid (76 mg, 0.164 mmol, 88% yield), which can be recrystallized by slow evaporation of a hexane/CH2C12 (4:1) solution at room temperature to give yellowish crystals, Rf 0.51 (20% EtOAc in hexane); IH NMR (00013, 500 MHz) 8 1.31 (quint, 2H, J = 6.8 HZ), 1.64 (quint, 4H, J = 7.3 Hz), 1.90 (quint, 4H, 6.5 Hz), 2.54 (t, 4H, J = 7.5 Hz), 2.58 — 2.63 (m, 8H), 3.74 (s, 6H), 4.64 (s, 2H), 5.87 (d, 2H, J = 2.5 Hz), 6.54 (AB quartet, 4H, J = 3.0 Hz, C = 4.8 Hz), 8.64 (s, 1H); 130 NMR (013013, 125 MHz) 8 26.35, 27.13, 29.16, 29.33, 29.39, 30.59, 55.57, 105.94, 113.30, 130.25, 130.61, 130.68, 145.16, 153.91 (1 aromatic carbon not found); IR (neat) 3376, 2926, 2857, 1603, 1476, 1439, 1348, 1335, 1196, 1150, 1067, 1044 cm_l; MS (ES+), m/z (% rel. intensity) 464 (M+H+, 100); HRMS (ES+) calcd for (M+H)+ (C29H33NO4) m/z 464.2801, found 464.2792. Single crystal X-Ray analysis is also available for this molecule (see Appendix). 3. Procedures for Chapter 4. 0 ,TFA cat. . / NH O l =1 / N’THP + \.N separatlon; / N’THP —N 94% ‘N NTHP —N 4 : 1 273 274a 275a 274a 194 3-Methyl-l-(tetrahydro-2H-pyran-2-y1)-lH-pyrazole (274a).173 In a 100 mL round bottom flask, 12.0 mL (12.3 g, 0.15 mol) of 3-methylpyrazole 273, 20.8 mL g (19.3 g, 0.23 mol) of 3,4-dihydro-2H-pyran, and 0.1 mL of trifluoroacetic acid were mixed and refluxed for 12 h under nitrogen atmosphere. The reaction mixture was allowed to cool down to room temperature, 0.6 g of sodium hydride (60% suspension in mineral oil) was added, and the mixture was distilled in vacuo, affording 23.4 g (14.1 mmol, 94%) of 4 : 1 mixture of 3-methy1-1-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole 274a (major product) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole 275a (minor product). Pure 3- methyl-l-(tetrahydro-2H—pyran-2-yl)-1H—pyrazole 274a can be obtained by column chromatography (silica gel, 35% ether in hexane) as a colorless oil, Rf 0.19 (35% EtzO in hexane); 1H NMR (00013, 500 MHz) 8 1.55 — 1.60 (m, 1H), 1.65 — 1.72 (m, 2H), 1.95 — 2.06 (m, 2H), 2.08 — 2.15 (m, 1H), 2.30 (s, 3H), 3.65 — 3.70 (m, 1H), 4.05 — 4.09 (m, 1H), 5.28 (dd, 1H, J: 10.5 Hz, 2.5 Hz), 6.07 (d, 1H, J= 2.5 Hz), 7.47 (d, 1H, J= 2.0 Hz); 1’0 NMR (00013, 125 MHz) 8 13.52, 22.67, 24.88, 30.37, 67.87, 87.34, 105.65, 128.17, 148.96; IR (neat) 3114, 2942, 2857, 1530, 1443, 1389, 1363, 1279, 1250, 1202, 1177, 1130, 1084, 1042 em—l; Ms (ES+), m/z (% re1. intensity) 167 (M+H+, 47), 83 (M— THP+H+, 100); HRMS (E1) calcd for M+ (C9H14N20) m/z 166.1106, found 166.1106. 1. NaH, then g: NH (PhCOO)2, THF= fN’OBn + f.” separatlo: / N’OBn N 2. BnBr, EtN(i-Pr)2 N ”~03“ ‘N 53% over 2 steps 4 , 1 273 274b 275b 274b 195 1-(Benzyloxy)-3-methy1-lH-pyrazole (274b). A. Pyrazole oxidation.174 Pure 3- methylpyrazole 273 (12.0 mL, 12.3 g, 0.15 mol) was slowly added via syringe to a stirred suspension of 6.6 g (0.165 mol) of sodium hydride (60% suspension in mineral oil, washed 2x50 mL of dry E120) in 250 mL of dry THF at room temperature. After hydrogen evolution had ceased the mixture was cooled to 5°C and a solution of benzoyl peroxide (12.1 g, 0.05 mol, dried overnight in vacuo to get rid of water stabilizer) in 250 mL of dry THF was added in such a manner that the temperature of the reaction mixture did not exceed 25°C. After the addition was complete, stirring was continued for 30 min. The reaction mixture was then poured on 150 mL of water, concentrated on a rotovap removing all the THF, and the residue adjusted to pH 10 — 11 with 50% aqueous sulfuric acid (by universal indicator). The unreacted pyrazole was removed by extraction 8x50 mL ethyl acetate. The aqueous phase was then neutralized to pH 7 and the mixture extracted with vigorous shaking 8x50 mL ethyl acetate. The combined extracts were dried over sodium sulfate, evaporated to dryness, and dried in vacuo affording 4.3 g (43.9 mmol, 88%) of crude pyrazole oxides mixture (approximately 4 : 1 mixture of 3-methyl- 1H-pyrazol-1-ol and 5-methyl-1H-pyrazol-l-ol, by lH-NMR), which was used directly in the next step (NOTE: It was found that pyrazole oxides bind to silica gel irreversibly during chromatography, thus, it can cause significant loss of material and is not recommended). . . 175 . . . . B. Pyrazole ox1de benzylatlon. To a solution of the crude ox1de mlxture mentloned above (4.3 g, 44 mmol) and N-ethyldiisopropyl amine (9.8 mL, 7.2 g, 56 mmol) in 60 mL of dry CH2C12 at 0°C was added 6.7 mL (9.6 g, 56 mmol) of benzyl bromide. Stirring 196 was continued at room temperature for 16 h. The reaction mixture was then concentrated on a rotovap and subjected to column chromatography (silica gel, 20% ethyl acetate in hexane), giving a 5.0 g (26.6 mmol, 53%) of 4 : 1 mixture of 1-(benzyloxy)-3-methyl- lH-pyrazole 274b (major) and 1-(benzyloxy)-5-methyl-lH-pyrazole 275b (minor). Complete separation (several runs through the same large column, 20% EtzO in hexane as eluent, combining pure fractions) afforded pure 1-(benzyloxy)-3-methyl-lH-pyrazole 274b, Rf 0.38 (20% 13th in hexane) as a colorless liquid; 1H NMR (CDC13, 500 MHZ) 6 2.26 (s, 3H), 5.23 (s, 2H), 5.80 (d, 1H, J= 2.0 HZ), 6.88 (d, 1H, J= 2.0 Hz), 7.30 — 7.36 (m, 5H); 13C NMR (CDC13, 125 MHZ) 6 13.76, 80.27, 102.14, 123.24, 128.51, 129.02, 129.54, 134.05, 142.61; IR (neat) 3142, 3067, 3034, 2928, 2882, 1514, 1499, 1456, 1406, 1346, 1258, 1211, 1188, 1082, 1046, 993 cm"; MS (ES+), m/z (% rel. intensity) 189 (M+H+, 100); HRMS (ES+) calcd for M+ (C11H12N20) m/z 188.0950, found 188.0951. 1. BuLi, THF, —78°C, 30 min W 2. B(Oi-Pr)3, —78°C to RT, 1h , e . \ B N'N . MN '0 1 3. ACOH (2 eq), p1na00| (1.1 eq) 1 THP RT, 1h, 79% THP 274a 276a 1. BuLi, THF, —78°C, 30 min W 2. B(OI-Pr)3. —78°C to RT, 1h : | \ BO N‘N - ”N 'o 1 3. AcOH (2 eq), p1na00| (1.1 eq) 1 080 RT, 1h, 68% 080 274b 276b . . . . 4 Preparation of pinacolboronate derivatives of protected pyrazoles.l 0 Protected pyrazole (10 mmol) was placed in a dry 50 mL round bottom flask and diluted with 15 197 mL of dry THF. The stirred solution was cooled to —78°C and n-butyllithium solution (10.5 mmol, 4.2 mL of 2.5M solution in hexanes) was added dropwise. The mixture was allowed to stir for 30 min at —78°C, after which triisopropyl borate (2.54 mL, 2.07 g, 11 mmol) was added dropwise, and the mixture was allowed to warm up to room temperature and stir for 1 h. Pinacol (1.30 g, 11 mmol) and glacial acetic acid (1.14 mL, 1.20 g, 20 mmol) were added in one portion and the solution was stirred for an additional 1 h at room temperature. The mixture was diluted with 100 mL of ether and 50 mL of water. The organic phase was separated, washed with brine, and dried over magnesium sulfate. The resulting solution was concentrated on a rotovap and subjected to column chromatography (silica gel, 20% ethyl acetate in hexane). 3-Methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-lH-pyrazole (276a) was obtained as a colorless oil (79% yield), Rf 0.25 (long band; 20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.33 (s, 12H), 1.51 — 1.55 (m, 1H), 1.64 — 1.78 (m, 2H), 1.90 — 1.95 (m, 1H), 2.02 — 2.08 (m, 1H), 2.29 (s, 3H), 2.40 — 2.48 (m, 1H), 3.62 — 3.69 (m, 1H), 4.07 (dquint, 1H, J= 11.5 Hz, 2.0 Hz), 5.77 (dd, 1H, J = 10.8 Hz, 2.3 Hz), 6.51 (d, 1H, J: 0.5 Hz); 130 NMR (00013, 125 MHz) 8 13.13, 23.01, 24.45, 24.75, 24.89, 29.91, 67.97, 83.83, 86.13, 115.92, 148.48; IR (neat) 2978, 2940,2851,1550,1466,1373,1308,1271,1204,1181,1144,1084,1068,1043,1016 em"; Ms (ES+), m/z (% rel. intensity) 293 (M+H+, 100), 209 (M—THP+H+, 69), 127 (BPin+, 24); HRMS (ES+) calcd for (M+H)+ (C15H26BN203) m/z 293.2036, found 293.2042. 198 1-(Benzyloxy)-3-methyl-5-(4,4,5,S-tetramethyl-1,3,2-dioxaborolan-2-yl)-lH-pyrazole (276b) was obtained as a colorless oil (68% yield), Rf 0.38 (long band; 20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.30 (s, 12H), 2.26 (s, 3H), 5.28 (s, 2H), 6.32 (s, 1H), 7.32 — 7.36 (m, 3H), 7.46 — 7.50 (m, 2H); 130 NMR (00013, 125 MHz) 8 13.12, 24.53, 80.71, 83.86, 111.66, 128.06, 128.62, 129.67, 133.84, 141.92 (1 aromatic C not located); IR (neat) 3067, 3034, 2978, 2932, 2886, 1545, 1460, 1391, 1381, 1373, 1354, 1325, 1294, 1269, 1167, 1143, 1059 cm‘l; Ms (ES+), m/z (% re1. intensity) 337 (M++Na+, 65), 315 (M+H+, 100), 233 (3), 189 (5); HRMS (ES+) calcd for (M+H)+ (C17H24BN203) m/z 315.1880, found 315.1873. NagC r207 0 H2804 fl ; ‘ ether OH 50% O 267 268 2,6-Dimethyl-1,4-benzoquinone (268).176 A round-bottom flask (1 L) equipped with a dropping funnel with pressure equalizer and big magnetic stirbar, was charged with 2,6- dimethylphenol (164 mmol, 20.0 g), and 250 mL of ether. Jones reagent (a mixture of 1 10 g NazCr207-2H20, 150 mL of water, and 70 mL of concentrated H2804) was added dropwise slowly (3 - 4 h) on cooling in an ice bath. After complete addition the mixture was stirred at room temperature for 48 h, afterwhich it was poured into 900 mL of water. 199 The ether layer was separated and the water layer was extracted with 2x200 mL of ether. The combined organic extracts were washed with 3x200 mL of water, dried over MgSO4 and evaporated to dryness. The yellow-orange residue was heated with 150 mL of hexane and the solution decanted. This operation was performed 3 more times. The hexane solution was concentrated to 100 mL and left to cool down and crystallize. Filtration and drying in vacuo gave 11.2 g (82 mmol, 50%) of 2,6-dimethyl-1,4-benzoquinone as needle-like orange crystals, mp 60 — 66°C (111.176 70 — 72°C); 1H NMR (013013, 300 MHz) 8 2.06 (q, 6H, J: 0.6 Hz), 6.56 (d, 2H, J= 0.6 Hz); 130 NMR (013013, 75 MHz) 8 15.88, 133.19, 145.71, 187.56, 188.09. These spectral data match those reported for this 176 compound . O 1. Na28204 OCH3 m 2. H2804 CH3OH O 81 % OH 268 269 4-Methoxy-2,6—dimethyl-phenol (269). A. Reduction.176 Fresh177 sodium dithionite (120 mmol, 21.2 g) was dissolved in 150 mL of water, and 2,6-dimethyl-l,4- benzoquinone (30 mmol, 4.08 g), dissolved in the mixture of 75 mL of ether and 40 mL of methanol, was added at room temperature with stirring. After stirring for 15 min, the solution was extracted with 2x100 mL of ether, combined organic extracts were washed with 100 mL of water, 100 mL of brine, dried over MgSO4, and evaporated to dryness. After drying in vacuo, 3.46 g (25.1 mmol, 84%) of 2,6-dimethyl-1,4-hydroquinone were 200 obtained as yellowish solid, mp 143 — 146°C (lit.176 145 — 148°C); 1H NMR (00013 - DMSO-d6, 300 MHz) 8 2.13 (s, 6H), 6.34 (s, 2H), 6.90 (s, 1H), 8.17 (s, 1H). These . 176 spectral data match those reported for thls compound . B. Methylation.178 Round-bottom flask (25 mL) was charged with 1.50 g (10.9 mmol) of 2,6-dimethy1-1,4-hydroquinone, 12 mL of methanol, and 1.5 mL of concentrated sulfuric acid, and refluxed for 1 h. After reaction mixture cooled down to room temperature, 10 g of ice were added, and resulting mixture extracted with 4x10 mL of ether. Combined organic extracts were washed with water (10 mL), brine (10 mL), dried over Na2804, evaporated to dryness and subjected to column chromatography (silica gel, 20% ethyl acetate in hexane), yielding 1.59 g (10.5 mmol, 96%) of 4-methoxy-2,6-dimethylphenol 269 as beige solid, mp 78°C (lit.178 76 — 77°C); 1H NMR (00013, 300 MHz) 8 2.22 (s, 6H), 3.73 (s, 3H), 4.28 (s, 1H), 6.54 (s, 2H); 13C NMR (CDC13, 75 MHZ) 6 16.23, 55.62, 113.76, 124.13, 146.10, 152.97. These spectral data match those reported for this 1 78 compound . OCH3 T120 (2 eq) OCH3 4-DMAP (5%) : OH 0°C, 3h, 86% OTf 269 270 4-Methoxy-2,6-dimethylphenyl trifluoromethanesulfonate (270).179 A dry round bottom flask was charged with 4-methoxy-2,6-dimethyl phenol 269 (6 mmol, 912 mg), 4— 201 DMAP (5%, 0.3 mmol, 37 mg), dry dichloromethane (15 mL) and dry pyridine (15 mL). The solution was stirred at 0°C and trifluoromethanesulfonic anhydride (12 mmol, 3.38 g, 2.0 mL) was added dropwise. The stirring continued for 3 h at 0°C, after which all the phenol was consumed (TLC control). The mixture was evaporated to dryness and subjected to column chromatography (3% triethylamine in pentane) to afford 1.67 g (5.88 mmol, 98%) of 4-methoxy-2,6-dimethylpheny1 trifluoromethanesulfonate 270 as a colorless liquid; 1H NMR (CDC13, 500 MHZ) 6 2.34 (s, 6H), 3.76 (s, 3H), 6.61 (s, 2H); 1’0 NMR (013013, 125 MHz) 8 17.32, 55.41, 114.61, 118.66 (q, —S02CF3 carbon, J= 318 HZ), 132.59, 140.39, 158.32; IR (neat) 3007, 2970, 2946, 2845, 1597, 1483, 1404, 1381, 1337,1292,1246,1211,1189, 1142,1103,1061,10010m‘1;MS(EI),m/z(% rel. intensity) 284 (M+, 25), 151 (M-Tf, 100), 123 (27), 91 (15), 77 (10), 69 (8); HRMS (E1) calcd for M+ (CIOHl 104F3S) m/z 284.0330, found 284.0332. 5°/oPd dba , 20% L H3COQOTf + CIZn—K/jNK 2 3 g H3CO [(1151 '1‘ THF/NMP 2:1 , PG 100°C PG 270 274a,b 277a,b Model Negishi couplings.145 A dry 25 mL round bottom flask with a stir bar was charged with 1.5 mmol of protected pyrazole (274a or 274b) and 4 mL of dry THF under nitrogen, cooled to —78°C, and n-butyllithium solution (1.65 mmol, 0.66 mL of 2.5M solution in hexane) was added dropwise. The reaction mixture was allowed to stir at — 78°C for 30 min, after which Zinc chloride solution (1.8 mmol, 3.6 mL of 0.5M solution 202 in THF) was added dropwise. The reaction mixture was then allowed to warm up to room temperature. After being stirred for 10 min at room temperature, the solution of organozinc reagent was transferred via cannula into a dry 25 mL Schlenk flask charged with a stir bar, 4-methoxy-2,6-dimethylphenyl trifluoromethanesulfonate 270 (284 mg, 1 mmol), szdba3 (46 mg, 0.05 mmol), and 2-dicyclohexylphosphino-2’,6’- diisopropoxybiphenyl (93 mg, 0.2 mmol) under nitrogen. The remains of the organozinc reagent were washed from the round bottom flask and transferred using the same cannula and 4 mL of dry 1-methyl-2-pyrrolidinone (NMP). The Schlenk flask was then sealed with Teflon screw cap and heated at 100°C for 24 h with stirring. The reaction mixture was cooled down to room temperature, diluted with 100 mL of ether, and quenched with 50 mL of NH4C1 (sat.). The organic phase was separated, washed with 50 mL of water, 50 mL of brine, dried over MgSO4, evaporated on rotovap, and subjected to column chromatography (silica gel, 20% ethyl acetate in hexane). (NOTE: Pyrazoles 274a and 274b are hard to separate from coupling products 277a and 277b, respectively. In the case of PG = THP, the original pyrazole 274a is volatile under the vacuum of the oil pump, and pure 277a can be obtained by drying the mixture of 274a and 277a (obtained after chromatography) in vacuo overnight. In the case of PG = OBn, separation is a lot more tedious, and requires several column separations. For this reason the yields of 277b given are calculated using NMR signal ratios and the mass of 274b+277b mixtures obtained after chromatography). 203 AL. 5-(4-Methoxy-2,6-dimethylphenyl)—3-methyl-l-(tetrahydro-2H-pyran-2-yl)-1H- pyrazole (277a) was obtained as a white solid (yield: 79% when 1.5 eq of 274a used, 90% when 3 eq of 2743 used), mp 104°C, Rf 0.30 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.39 — 1.52 (m, 2H), 1.62 — 1.76 (m, 2H), 1.94 — 1.98 (m, 1H), 1.99 (s, 3H), 2.09 (s, 3H), 2.34 (s, 3H), 2.41 — 2.49 (m, 1H), 3.32 (1d, 1H, J = 12.0 Hz, 2.0 Hz), 3.82 (s, 3H), 3.96 — 4.00 (m, 1H), 4.62 (dd, 1H, J= 10.5 Hz, 2.5 Hz), 5.89 (s, 1H), 6.66 (AB quartet, 2H, J = 2.5 Hz, C = 4.3 Hz); 130 NMR (CDC13, 125 MHz) 8 13.92, 20.37, 20.38, 23.07, 24.82, 30.27, 55.07, 67.96, 83.90, 106.33, 112.43, 112.62, 122.45, 139.38, 140.72, 142.19, 149.07, 159.68; IR (neat) 2930, 2847, 1609, 1491, 1458, 1442, 1424, 1395, 1316, 1209, 1198, 1150, 1084, 1063, 1044 em"'; MS (EI), m/z (% rel. intensity) 300 (M+, 12), 216 (M—THP, 100), 201 (10), 174 (40), 160 (28), 144(6), 84 (10); HRMS (E1) calcd for M+ (C13H24N202) m/z 300.1838, found 300.1848. 1-(Benzyloxy)-5-(4-methoxy-2,6-dimethylphenyl)—3-methyl-lH-pyrazole (277b) was obtained as a colorless oil (yield: 48% when 1.5 eq of 274b used, 73% when 3 eq of 274b used), Rf 0.47 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 2.00 (s, 6H), 2.31 (s, 3H), 3.82 (s, 3H), 5.03 (s, 2H), 5.82 (s, 1H), 6.63 (s, 2H), 6.98 — 7.00 (m, 2H), 7.18 — 7.22 (m, 2H), 7.24 — 7.28 (m, 1H); 13C NMR (CDC13, 125 MHZ) 6 13.95, 20.45, 55.15, 79.92, 103.92, 112.60, 120.76, 128.31, 128.68, 129.21, 133.94, 134.54, 139.92, 141.72, 159.77; IR (neat) 3070, 3034, 2924, 2849, 1607, 1582, 1489, 1456, 1375, 1345, 1318, 204 1283, 1203, 1192, 1154, 1069 cm’l; MS (ES+), m/z (% rel. intensity) 323 (M+H+, 100); HRMS (ES+) calcd for (M+H)+ (C20H23N202) m/z 323.1760, found 323.1753. / 1. HCI, MeOH \ H300 I = H300 \ N” 2. Ncho3 ””11 THP 81% 277a 279 Removal of THP group.I40 Protected pyrazole 277a (237 mg, 0.79 mmol) was placed in a round bottom flask with a stir bar and 8 mL of stock HCl solution in methanol was added (solution was prepared by slow addition of 10 mL of acetyl chloride to 100 mL of anhydrous methanol on stirring at 0°C). The resulting mixture was stirred at room temperature for 12 hours, after which it was diluted with 50 mL of diethyl ether and vigorously shaken with 50 mL of saturated NaHCO3. The organic phase was separated, water layer extracted with 2x50 mL of ether, combined organic phase washed with brine, dried over magnesium sulfate, concentrated on a rotovap and subjected to column chromatography (silica gel, 40% ethyl acetate in hexane), affording 139 mg (0.64 mmol, 81%) of 3-(4-methoxy-2,6-dimethylpheny1)-5-methyl-lH-pyrazole 279 as a yellow solid. The product can be recrystallized by slow evaporation from hexane, affording large yellowish crystals, mp 119°C, Rf 0.25 (30% EtOAc in hexane); 1H. NMR (CDC13, 500 MHZ) 6 2.04 (s, 6H), 2.05 (s, 3H), 3.78 (s, 3H), 5.85 (s, 1H), 6.56 (s, 2H), 12.20 (s, 1H); 13C NMR (CDC13, 125 MHZ) 6 11.77, 20.54, 54.93, 105.16, 112.48, 124.44, 139.23, 144.90, 159.01 (1 aromatic C not located); IR (neat) 3191, 3133, 2923, 2850, 1607, 1462, 205 1377, 1316, 1289, 1198, 1152, 1080, 1057, 1026, 1009 cm’l; MS (ES+), m/z (% rel. intensity) 217 (M+H+, 100); HRMS (ES+) calcd for (M+H)+ (C13H17N20) m/z 217.1341, found 217.1345. 1. H2, 10% Pd/C, CH3OH / 2. Zn, ACOH, reflux CO \ H3CO ,' = “3 ‘ . I? N 3. NaHCo3 N NH OBn 500/0 2771) 279 Removal of OBn group.I46 Protected pyrazole 277b (0.376 mmol, as a mixture with pyrazole 274b) was dissolved in 10 mL of anhydrous methanol, 120 mg of 10% Pd/C was added, and hydrogen was gently bubbled through the mixture for 5 minutes, after which the reaction flask was sealed with a septum under a balloon with H2 and stirred overnight. The resulting mixture was filtered to get rid of all solids, the solution was evaporated to dryness, and the residue dissolved in 10 mL of acetic acid, 540 mg of Zinc dust was added, and the mixture was refluxed for additional 12 h. The reaction mixture was then cooled down to room temperature, and carefully neutralized by pouring into 100 mL of saturated NaHCO3. The solution was then extracted with 3x50 mL of ether, the combined organic phase washed with brine, dried over magnesium sulfate, concentrated on rotovap, subjected to column chromatography (silica gel, 40% ethyl acetate in hexane) and additionally dried in vacuo overnight (to get rid of 3-methylpyrazole) affording 41 mg (0.19 mmol, 50%) of 3-(4-methoxy-2,6-dimethy1phenyl)-5-methyl-1H-pyrazole 279 as a yellow solid. 206 o0H3 00H3 CCH3 Q BTMA+BF3- Q 1. DHP (neat), HCI Q CHzclz/CHsoH Br Br 2. Crystallization Br Br OH 90% OH 42% OTHP 285 286 2631) 2-(2,6—dibromo-4-methoxyphenoxy)tetrahydro-2H-pyran (263b). A. Benzyltrimethylammonium tribromide.180 In a 2 L glass equipped with a large stir bar hydrobromic acid (48%, 1.2 mol, 203 g) was added to a stirred solution of benzyltrimethylammonium chloride (0.4 mol, 74.4 g) and potassium bromate (0.133 mol, 22.2 g) in 450 mL of water. The resulting precipitate was filtered off, washed with water (5x100 mL) and pressed onto a filter to maximum dryness. The resulting solid was dissolved in CH2C12 on heating, dried with magnesium sulfate, filtered hot and cooled down in an ice bath. The resulting crystals were collected, the mother liquor concentrated and cooled down to 0°C again. Two crops were combined and dried in vacuo to afford 126.3 g of benzyltrimethylammonium tribromide as large orange crystals. B. 2,6-Dibromo-4-methoxyphenol.180 To a vigorously stirred solution of 4- methoxyphenol (0.147 mol, 18.2 g) in 1300 mL of CH2C12 and 500 mL of dry methanol benzyltrimethylammonium tribromide (126.3 g, 0.323 mmol) was added. The resulting solution was stirred for 2 h, after which the mixture was evaporated to dryness and extracted with 6x100 mL of ether (vigorous shaking). The combined organic extracts were dried with magnesium sulfate, evaporated on a rotovap, filtered through a thick pad of silica gel (using ether as eluent) and evaporated to dryness to afford 2,6-dibromo-4- 207 methoxyphenol 286 (37.2 g, 132 mmol, 90%) as a tan solid that can be used in the next step directly. C. 2-(2,6-Dibromo-4-methoxyphenoxy)tetrahydro-2H—pyran.150 Obtained 2,6-dibromo- 4-methoxyphenol 286 (37.2 g, 132 mmol) was mixed with 3,4-dihydro-2H—pyran (14.4 g, 172 mmol) and 0.3 mL of concentrated HC1, and vigorously stirred overnight. The reaction mixture was then dilute with 300 mL of ether, washed with 5x100 mL of 5% aqueous NaOH, dried over potassium carbonate, and solvent was removed on a rotovap. The remaining oil was dissolved in 75 mL of pentane and placed in —20°C freezer overnight, producing large yellow crystals. The mother liquor was removed using nitrogen pressure and a thick cannula, and the product was dried in vacuo, affording 20.3 g (55.5 mmol, 42%) of 2-(2,6-dibromo-4-methoxyphenoxy)tetrahydro-ZH—pyran 263b as yellow crystals. (NOTE: chromatography of the product should be avoided because of its significant instability towards acids). The compound can be further purified by dissolving it in a 10:1 mixture of pentane and CH2C12 on heating, and letting the solution crystallize at —20°C overnight. This affords 2-(2,6-dibromo-4-methoxyphenoxy)tetrahydro-ZH— pyran 263b as white crystals, mp 78°C; 1H NMR (CDC13, 500 MHZ) 6 1.62 — 1.68 (m, 3H), 1.88 — 1.94 (m, 1H), 1.95 — 2.04 (m, 1H), 2.12 — 2.17 (m, 1H), 3.59 — 3.63 (m, 1H), 3.74 (s, 3H), 4.35 — 4.40 (m, 1H), 5.30 (t, 1H, J = 3.5 HZ), 7.07 (s, 2H); 13C NMR (CDC13, 125 MHZ) 6 18.90, 25.02, 30.33, 55.87, 63.69, 103.02, 118.11, 118.36, 146.30, 156.04; IR (neat) 3083, 2975, 2946, 2851, 1591, 1547, 1488, 1431, 1391, 1356, 1289, 1227, 1202, 1186, 1124, 1111, 1040, 1022 cm-1; MS (ES+), m/z (% rel. intensity) 283 208 (M—THP+H+, 35), 281 (M—THP+H+, 100), 279 (M—THP+H+, 38); HRMS (EI) calcd for (M—THP+H)+ (C7H6Oz7gBr2) m/z 279.8735, found 279.8735. n-2 1' W + 9-BBN OTHP TMS 238a.b OTHP Br Br Pd(OAC)2, S-PHOS, K3PO4-H20 / ” “\ t / \ 2. TBAF, THF OCHs CCH3 263b 264b,c Preparation of THP-protected diynes 264. TMS-protected enyne (238a or 238b, 40 mmol) was put in a dry 100 mL Schlenk flask with a stir bar and 9-BBN (40 mmol, 80.0 mL of 0.5 M solution in THF) was added under nitrogen. The resulting solution was heated and stirred at 70°C for 2 h, cooled down to room temperature and transferred via cannula to a 250 mL Schlenk flask containing 2-(2,6-dibromo-4- methoxyphenoxy)tetrahydro-2H-pyran 263b (20 mmol, 7.32 g), potassium phosphate monohydrate (40 mmol, 9.20 g), palladium acetate (0.64 mmol, 143 mg) and S-PHOS ligand (1.28 mmol, 530 mg) under a nitrogen atmosphere. The Schlenk flask solution was then degassed using the freeze-thaw method (3 cycles), warmed up to room temperature, back-filled with nitrogen, sealed and heated at 70°C for 4 h. Reaction mixture was poured over a Celite pad which was then rinsed with 4x25 mL of ether. The solvent was removed on a rotovap and the residue was subjected to column chromatography (silica gel, 5% EtOAc in hexane). (NOTE: In this coupling it was found that column purification of intermediate silylated diyne cannot be avoided, in contrast to analogous preparations for diynes 240). The protected diyne obtained after column chromatography was then 209 dissolved in 100 mL of THF. TBAF (9 mmol, 3.3 mL of 75% solution in water) was added and the mixture was stirred for 1 h (controlled by TLC). The reaction mixture was then extracted with 100 mL of water, the organic layer was separated, and the water layer was extracted with 50 mL of ether. The combined organic extracts were washed with brine, dried over MgSO4, concentrated on a rotovap, and subjected to column chromatography (silica gel, 5% ethyl acetate in hexane). 2-(4-Methoxy-2,6-di(pent-4-ynyl)phenoxy)tetrahydro-2H-pyran (264b, n = 3) was obtained as a transparent yellowish oil (3.40 g, 10.0 mmol, 50% yield), Rf 0.22 (5% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.53 — 1.61 (m, 3H), 1.80 — 1.88 (m, 5H), 1.91 — 2.02 (m, 2H), 1.97 (1, 2H, J = 2.5 Hz), 2.20 — 2.24 (m, 4H), 2.66 — 2.74 (m, 2H), 2.77 — 2.84 (m, 2H), 3.44 — 3.49 (m, 1H), 3.75 (s, 3H), 4.01 — 4.06 (m, 1H), 4.70 (dd, 1H, J: 6.5 Hz, 2.5 Hz), 6.58 (s, 2H); 130 NMR (00013, 125 MHz) 8 18.21, 20.86, 25.10, 29.06, 29.96, 31.44, 55.24, 64.74, 68.46, 84.38, 103.80, 112.91, 135.99, 148.11, 155.61; IR (neat) 3293, 2944, 2865, 2840, 2116, 1603, 1468, 1441, 1379, 1358, 1215, 1198, 1178, 1146, 1101, 1072, 1032 cm"]; MS (ES+), m/z (% rel. intensity) 341 (M+H+, 100), 309 (5), 118 (13); HRMS (ES+) calcd for (M+H)+ (C22H2903) m/z 341.2117, found 341.2120. 2-(2,6-Di(hept-6—ynyl)-4-methoxyphenoxy)tetrahydro-2H-pyran (264c, n = 5) was prepared as a transparent yellowish oil (4.12 g, 10.4 mmol, 52% yield), Rf 0.31 (5% 210 EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.44 — 1.50 (m, 4H), 1.52 — 1.65 (m, 11H), 1.78 — 1.86 (m, 1H), 1.93 (t, 2H, J= 2.5 HZ), 1.92 — 1.98 (m, 2H), 2.19 (td, 4H, J= 7.0 Hz, 2.5 Hz), 2.57 — 2.64 (m, 2H), 2.64 — 2.72 (m, 2H), 3.44 — 3.49 (m, 1H), 3.75 (s, 3H), 4.02 — 4.07 (m, 1H), 4.68 (dd, 1H, J = 6.5 HZ, 2.0 HZ), 6.55 (s, 2H); 13C NMR (CDC13, 125 MHZ) 6 18.32, 20.93, 25.19, 28.37, 28.77, 29.91, 30.69, 31.51, 55.31, 64.75, 68.08, 84.67, 103.82, 112.48, 136.91, 148.08, 155.62; IR (neat) 3295, 2938, 2861, 2116, 1605, 1468, 1441, 1379, 1354, 1213, 1198, 1178, 1148, 1103, 1072, 1036 cm'l; MS (ES+), m/z (% rel. intensity) 397 (M+H+, 100), 379 (16), 235 (5), 118 (28); HRMS (ES+) calcd for (M+H)+ (C26H37O3) m/z 397.2743, found 397.2749. H3COWMOCH3 Cr(CO)5 Cr(CO)5 1. 1,4-dioxane 211e,f 1000C + = OTHP 2. Air / n n\ 3. TSOH-H20, / \ MeOH/CH2C12 1 I1 CCH3 264b,c 260a,b Large-scale preparation of C3-symmetric macrocycles 260. A round bottom oven- dried three-necked 5 L flask was equipped with a reflux condenser and a nitrogen inlet, charged with Teflon boiling chips (ca. 50 pieces, approx 1 mm in size) and cooled by a stream of nitrogen. Then, from the solvent purification apparatus in which 1,4-dioxane (~ 4.5 L) was refluxed over sodium metal for several hours, the solvent was distilled out into 211 the 5 L flask using a Teflon tube. (Overall, about 4 L of oxygen-free, dry 1,4-dioxane were placed into the flask). The solvent was then cooled down in the mild flow of nitrogen, and carbene complex 211 (10 mmol) and diyne 264 (10 mmol) were added to the 5 L flask. Nitrogen was then vigorously bubbled through the deep red solution for additional 2 h, the flask was sealed using glass stoppers with Teflon sleeves and Teflon film, and the solution was refluxed under positive nitrogen pressure using heating mantle for 24 h. The resulting yellow solution was placed in two large crystallizer dishes and allowed to oxidize in the air for 2 days (with occasional stirring). The remaining mixture was then filtered through cotton to get rid of insoluble chromium residue, evaporated to dryness on 50 g of silica gel, and washed off the silica gel on a glass filter using ethyl acetate. The filtrate was concentrated on a rotovap and dissolved in 30 mL of CH2C12 and 30 mL of methanol. To this solution, p-toluenesulfonic acid monohydrate (0.25 g, 1.3 151 . . mmol) was added , the mlxture was stlrred for 4 h at room temperature, evaporated on a rotovap, and subjected to column chromatography (silica gel, 20% EtOAc in CH2C12 for 260a, 20% EtOAc in hexane for 260b). Homocalix[3]arene 2603 (n = 3) had to be additionally purified after the column due to its extremely poor solubility in most organic solvents. The product after the column was taken up in 30 mL of ethyl acetate and 500 mL of dichloromethane, and concentrated on a rotovap to approximately 50 mL. Filtration afforded 260a as white crystalline powder (24% yield), mp 171°C, Rf 0.58 (10% EtOAc in CH2C12); 1H NMR (C5D5N, 500 MHZ) 8 2.09 (quint, 6H, J = 7.0 HZ), 2.71 (t, 12H, J= 7.3 Hz), 3.55 (s, 9H), 5.50 (s, 3H), 6.68 212 (s, 6H); 13C NMR (C5D5N, 125 MHz) 8 30.99, 31.19, 55.48, 113.93, 133.06, 147.39, 153.90; IR (KBr pellet) 3446, 3405, 3054, 2961, 2933, 2871, 2863, 2834, 1606, 1478, 1437, 1342, 1326, 1297, 1256, 1222, 1199, 1174, 1151, 1122, 1070, 1063, 1038 cm"; Ms (ES+) m/z (% rel. intensity) 985 (2M+H+, 90), 510 (8), 493 (M+H+, 100), 338 (16); HRMS (ES+) calcd for (M+H)+ (C30H3706) m/z 493.2590, found 493.2582. Homocalix[3]arene 260b (n = 5) was obtained as yellowish solid (20% yield), which can be recrystallized by slow evaporation of hexane/CH2C12 (10:1) solution at room temperature to give colorless crystals, mp 155°C, Rf 0.34 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.40 (quint, 6H, J = 7.0 HZ), 1.65 (quint, 12H, J= 7.5 Hz), 2.57 (1, 12H, = 7.8 JHz), 3.74 (s, 9H), 4.83 (s, 3H), 6.52 (s, 6H); 130 NMR (CDC13, 125 MHz) 8 27.66, 29.19, 29.61, 55.53, 112.98, 129.92, 145.21, 153.42; IR (neat) 3397, 2930, 2857, 1603, 1478, 1350, 1194, 1150, 1071, 1040 cm“; Ms (ES+) m/z (% rel. intensity) 1153 (2M+H+, 27), 577 (M+H+, 100), 343 (6); HRMS (ES+) calcd for (M+H)+ (C36H4906) m/z 577.3529, found 577.3538. R 1. 4-DMAP (45%) m PYICHQCIZ 111 X OH X 9 eq T120, 0°C to RT, 8 h X OTfX OH HO 7 ml 2. 9 eq T120, 0°C to RT, 8 h TfO R X R R X R 213 Calixarene triflate preparation. Homocalix[3]arene (0.407 mmol) and 4-DMAP (22 mg, 0.183 mmol) were placed in a dry pear shaped flask with a triangular stir bar under nitrogen, and dissolved in 3 mL of dry pyridine and 3 mL of dry CH2C12. The solution was then cooled down to 0°C, and trifluoromethanesulfonic anhydride (0.62 mL, 1.03 g, 3.66 mmol) was added dropwise via syringe. The solution was then allowed to warm up to room temperature and stirred for 8 h, after which cooled down to 0°C again, and second portion of trifluoromethanesulfonic anhydride (0.62 mL, 1.03 g, 3.66 mmol) was added. The reaction mixture was stirred for another 8 h, and then diluted with 50 mL of ether and poured into 50 mL of water. Layers were separated, and water layer extracted with 2x50 mL of ether. Combined organic extracts were then washed with 50 mL of 2M HCl, 50 mL of brine, dried over magnesium sulfate, concentrated on a rotovap, and subjected to column chromatography (silica gel, 10% EtOAc in hexane for paco-280, 20% EtOAc in hexane for paco-266a and 266b). Paco-triflate 280 (X = O, R = CH3) was obtained as a white solid (80% yield), which can be recrystallized by slow evaporation of hexane/CH2C12 4:1 solution to give large colorless crystals, mp 154°C, Rf 0.58 (10% EtOAc in hexane); 1H NMR (CDC13, 500 MHz) 8 2.20 (s, 6H), 2.39 (s, 3H), 4.07 (d, 2H, J = 13.5 Hz), 4.26 (1, 4H, J = 13.5 Hz), 4.54 (d, 2H, J = 13.5 Hz), 4.64 (d, 2H, J = 14.0 Hz), 4.97 (d, 2H, J = 13.0 Hz), 6.98 (d, 2H, J: 2.5 Hz), 7.19 (d, 2H, J: 1.5 Hz), 7.24 (s, 2H); 1’0 NMR (CDC13, 125 MHz) 8 20.50, 20.54, 64.26, 67.66, 68.16, 118.59 (q, —802CF3 carbon, J: 318 Hz), 118.61 (q, two ~SOgCF3 carbons, J = 318 HZ), 129.44, 130.80, 130.88, 131.49, 131.56, 132.69. 214 138.23, 138.58, 140.04, 142.56; IR (neat) 2938, 2876, 1603, 1462, 1399, 1300, 1246, 1211, 1140, 1092, 1011 cm_]; MS (ES+) m/z (% rel. intensity) 864 (M+NH4+, 100), 847 (M+H+, 65), 613 (6), 338 (9); HRMS (ES+) calcd for (M+H)+ (C30H23012F983) m/z 847.0599, found 847.0588. Paco-triflate 266a (X = CH2, R = OCH3) was obtained as a colorless oil solidifying on standing (78% yield), which can be recrystallized (50 mL of boiling hexane per 400 mg, cooled to RT) to give white needle-like crystals, mp 149°C, Rf 0.31 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.50 — 1.67 (m, 1H), 1.90 — 2.38 (m, 9H), 2.42 — 2.54 (m, 2H), 2.58 — 2.70 (m, 2H), 2.72 — 2.84 (m, 2H), 2.87 — 2.96 (m, 2H), 3.76 (s, 6H), 3.78 (s, 3H), 6.63 (s, 4H), 6.69 (s, 2H); 13C NMR (CDC13, 125 MHZ) 6 25.88, 27.51, 28.30, 28.48, 29.68, 55.34, 55.41, 112.60, 113.34, 117.87 (q, —SOZCF3 carbon, J: 319 HZ), 118.31 (q, two —SOzCF3 carbons, J = 318 HZ), 135.15, 135.39, 136.94, 138.23, 138.90. 159.00, 159.02 (1 aromatic C not located); IR (neat) 2942, 2876, 2847, 1593, 1484, 1398, 1348, 1321, 1246, 1213, 1187, 1148, 1100, 1065, 1047, 1033 cm_]; MS (ES—) m/z (% rel. intensity) 933 (M+COOH‘, 100); HRMS (ES—) calcd for (M+COOH)' (C34H34014F983) m/z 933.0967, found 933.0948. Triflate 266b (X = (CH2)3, R = OCH3) was obtained as a colorless oil solidifying on standing (95% yield), which can be recrystallized (30 mL of boiling hexane per 1 g, 215 cooled to RT, then to 0°C) to give white needle-like crystals, mp 118°C, Rf 0.42 (20% EtOAc in hexane); 1H NMR (CDC13, 500 MHZ) 6 1.23 (quint, 6H, J = 7.3 Hz), 1.54 (quint, 12H, J= 7.5 HZ), 2.64 (t, 12H, = 7.5 JHz), 3.76 (s, 9H), 6.57 (s, 6H); l3C NMR (00013, 125 MHz) 8 27.84, 29.57, 30.63, 55.42, 113.72, 118.51 (q, —SOZCF3 carbon, J: 318 Hz), 137.17, 139.16, 158.57 ; IR (neat) 3003, 2938, 2863, 1593, 1464, 1441, 1401, 1345, 1213, 1167, 1140, 1100, 1036 cm"; MS (ES+) m/z (% rel. intensity) 973 (M+H+, 25), 886 (13), 883 (19), 849 (26), 827 (90), 613 (23), 475 (12). 338 (100), 271 (14), 212 (18), 155 (23), 110 (27); HRMS (ES+) calcd for (M+H)+ (C39H46012F9S3) m/z 973.2008, found 973.1985. 4. Procedures for Chapter 5. (Please note: Chapter 5 is included as a collection of preliminary results. The compounds described in Chapter 5 lack full characterization data and the procedures are included “as is”). R3 R‘J’R3 CHBr3, NaOH ‘ R1j>
H #9130 1.PhMe,70°C,4h_ ”05 {Ly—(OF: n'CsH13 \ Ph 2. 02/CH2CIZ, 2 days' ph 74% Cr(Co)4 303e 305a Triene 305a was obtained in 74% yield as a colorless oil; 1H NMR (CD3CN, 500 MHZ) 6 0.89 (t, 3H, J: 7.3 HZ), 1.15 — 1.37 (m, 6H), 1.67 — 1.75 (m, 2H), 1.98 — 2.05 (m, 2H), 2.15 — 2.20 (m, 2H), 3.38 — 3.43 (m, 1H), 3.49 — 3.55 (m, 1H), 4.96 — 5.07 (m, 3H), 5.22 — 5.24 (m, 2H), 5.85 — 6.03 (m, 3H), 7.27 — 7.43 (m, 5H); 130 NMR (CD3CN, 125 MHz) 6 14.34, 21.18, 29.62, 29.98, 31.22, 31.92, 33.63, 68.85, 83.03, 114.27, 115.10, 127.97, 128.24, 128.99, 129.52, 133.42, 139.57, 142.31, 147.22; MS (EI), m/z (% rel. intensity) 298 (M+, 30), 213 (100), 175 (60), 143 (25), 107 (50), 69 (12). I7_C:5f+IJ—- ()._/f__\\::: DEPT analysis for \—>/.—