Boron-Based Lewis Acids: Towards Intramolecular Frustrated Lewis Pairs and Enantioselective Catalysis

Jolie Zi Ning Lam

A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Chemistry University of Toronto

Jolie Zi Ning Lam

Doctor of Philosophy

Department of Chemistry University of Toronto

2020 Abstract

A rapid development of metal-free, main group compounds for small molecule activation and as hydrogenation catalysts was triggered after the disclosure of H2 activation by sterically hindered

Lewis acids and bases over a decade ago. The combination of a Lewis acid and base with unquenched reactivity was later coined as a “frustrated Lewis pair” (FLP).

In this research, boron-based Lewis acids were studied for their application as catalysts in FLP chemistry, with an emphasis on exploring the production of chiral FLPs and intramolecular FLPs.

In the exploration towards enantioselective catalysis, 3,5-bicyclic aryl piperidines were synthetically modified to produce B/N FLPs and were shown to activate dihydrogen, demonstrating the potential for expanding chiral FLP templates beyond the typical chiral ligands used in transition metal complexes. Chiral borenium cations were generated from different families of carbene-borane adducts, in which their chirality resides on either the carbene or the borane.

Catalytic studies found that they were able to effect imine reduction without epimerisation of the resulting chiral amine, and the reactivity and enantioselectivity of these cations were found to be inversely proportional to steric demands. In the exploration towards a cationic intramolecular FLP, a borenium cation with a pendant phosphine was synthesized through hydroboration of a phosphinoalkene with an isolable B-H borenium cation, and its FLP reactivity was investigated. ii

Finally, initial efforts towards the production of a bisborane-carbene as a tri-functionalized FLP were documented.

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Dedicated in loving memory of my grandmother,

Cheung Shou Wah

Acknowledgments

I was fortunate to meet many people along the way that made this 5-year journey fruitful beyond expectation. First and foremost, I would like to thank my supervisor Professor Doug Stephan for the privilege of working in his research group, for always having an open door for chemistry and career discussions, and your support in our endeavors outside of research. Your guidance and advice had been very helpful, both in my research and my professional development. Thank you also for willing to let your students freely explore their scientific interest. Not only was I able to work on what I find interesting, I was also able to simultaneously learn from others about chemistry far beyond the scope of this thesis. I must also extend my thanks to my committee members, Professor Robert Morris and Professor Mark Taylor, for your helpful suggestions and feedback in this research through committee meetings and seminars.

I would like to thank all the past and present Stephan group members for their patience, guidance and support. I have been fortunate to work with and learn from many talented chemists over the last five years from all over the world. Thank you for all the valuable discussions and your patience in passing on your knowledge. All of you has helped me grown so much as a researcher. Thank you also for the friendship, for all the fun times we’ve had outside of work, and for sharing your stories. You have taught me more than just chemistry. I must also extend my gratitude to Shanna Pritchard, who has kept us in check and helped this research group run smoothly. Special thanks must also be given to those that helped with the editing of this thesis: Ryan Andrews, Karlee Bamford, Levy Cao, Louie Fan, Felix Krischer, James LaFortune, Chris Major, Alex Waked, and Diya Zhu.

Thank you to my collaborators, Benjamin Günther, Dr. Jeffrey Farrell, Dr. Patrick Eisenberger, Brian Bestvater, Dr. Susanna Sampaolesi, Dr. Paul Newman, Dr. Jotham Coe, Professor Rebecca Melen, and Professor Cathleen Crudden, for the amazing work and insightful discussions. It has been a pleasure working with you and learning from you. I must also give my thanks to Rose Balazs from Analest, Chung Woo Fung from AIMS, and the wonderful past and present NMR staff, Dr. Darcy Burns, Dr Jack Sheng, Dr. Sergiy Nokhrin, Dmitry Pichugin, and Dr. Karl Demmans for analytical help beyond the call of duty.

A special shout out to my friends that I consider my brothers and sisters, both in Canada and in Hong Kong for their support. Thank you for believing in me and cheering me on when I needed v it. Thank you to Mom and Dad, for your unconditional love and support. Thank you for putting your complete trust in my career choices and allowing me to pursue my goals without worries and hesitation. Last and certainly not least, thank you to Louie Fan, for being my personal prescription of antidepressant. Words cannot describe my gratitude for everything you’ve gone through to make me smile.

Thank you all for making a mark in this chapter of my life. You have made it a lot easier to write it.

Table of Contents

Acknowledgments ...... v

Table of Contents ...... vii

List of Figures ...... xi

List of Schemes ...... xiv

List of Tables ...... xviii

List of Symbols and Abbreviations ...... xix

Chapter 1 Introduction ...... 1

1.1 Science and Humankind...... 1

1.2 Catalysis ...... 2

1.2.1 Background ...... 2

1.2.2 Properties, Sources and Uses of Boron ...... 3

1.2.3 Boron Chemistry ...... 4

1.3 Frustrated Lewis Pairs...... 6

1.3.1 History ...... 6

1.3.2 Mechanistic Investigation and FLP Reactivity ...... 8

1.3.3 FLP Hydrogenation Catalysis ...... 10

1.4 Scope of Thesis ...... 11

1.5 References ...... 14

Chapter 2 Synthesis and Reactivity of B/N FLPs Derived from 3,5-Bicyclic Aryl Piperidines ...... 22

2.1 Introduction ...... 22

2.1.1 Importance of Chirality ...... 22

2.1.2 Transition Metal-Catalyzed Asymmetric Hydrogenation ...... 24

2.1.3 FLP-Catalyzed Asymmetric Hydrogenation ...... 25

2.2 Results and Discussion ...... 28

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2.2.1 Synthesis of 3,5-Bicyclic Aryl Piperidines...... 28

2.2.2 Hydroboration of the Styrene Derivative ...... 30

2.2.3 Lewis Acidity Determination...... 35

2.2.4 FLP Reactivity ...... 38

2.3 Conclusion ...... 40

2.4 Experimental Section ...... 40

2.4.1 General Considerations ...... 40

2.4.2 Synthesis of Compounds ...... 42

2.4.3 Procedures of Gaseous Experiments ...... 48

2.4.4 Computational Details ...... 49

2.4.5 X-ray Crystallography ...... 49

2.5 References ...... 53

Chapter 3 Chiral Carbene-Borane Adducts as Precursors for Borenium Cations in Asymmetric Hydrogenation Catalysis ...... 59

3.1 Introduction ...... 59

3.1.1 Boron Cations ...... 59

3.1.2 Carbene-stabilized Borenium Cations in FLP Hydrogenations ...... 61

3.2 Results and Discussion ...... 63

3.2.1 Synthesis of Chiral Carbene-Boranes with Chiral Carbenes ...... 63

3.2.2 Synthesis of Chiral NHC-Boranes with Chiral Boranes ...... 71

3.2.3 Ring Expansion of NHC-Boranes ...... 76

3.2.4 Generation of Chiral Borenium Cations ...... 78

3.2.5 Hydrogenation Tests ...... 80

3.3 Conclusion ...... 85

3.4 Experimental Section ...... 85

3.4.1 General Considerations ...... 85

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3.4.2 Synthesis of Compounds ...... 86

3.4.3 Procedures of Gaseous Experiments ...... 99

3.4.4 Racemization Experiments ...... 100

3.4.5 X-ray Crystallography ...... 100

3.5 References ...... 104

Chapter 4 An Isolable B-H Borenium Cation as Template for Intramolecular Borenium- Based FLPs ...... 108

4.1 Introduction ...... 108

4.1.1 Intramolecular FLPs ...... 108

4.1.2 Hydroboration by NHC-Borenium Cations ...... 110

4.1.3 An Isolable B-H Borenium Cation through C-H Activation ...... 111

4.2 Results and Discussion ...... 112

4.2.1 Synthesis of B-H Borenium Cation...... 112

4.2.2 Lewis Acidity Determination...... 116

4.2.3 Reactivity Studies...... 118

4.3 Conclusion ...... 128

4.4 Experimental Section ...... 128

4.4.1 General Considerations ...... 128

4.4.2 Synthesis of Compounds ...... 130

4.4.3 Procedures of Gaseous Experiments ...... 137

4.4.4 Computational Details ...... 138

4.4.5 X-ray Crystallography ...... 139

4.5 References ...... 142

Chapter 5 Bisborane-functionalized Imidazolium Cation as Precursor Towards Intramolecular Carbene-bisborane Scaffold ...... 146

5.1 Introduction ...... 146

5.1.1 Intramolecular Cooperativity in FLPs ...... 146 ix

5.1.2 FLP Chemistry by Carbene and Lewis Acidic Borane ...... 148

5.2 Results and Discussion ...... 149

5.2.1 Hydroboration of Imidazolium Cation ...... 149

5.2.2 Deprotonation of Imidazolium Cation ...... 151

5.3 Conclusion ...... 152

5.4 Experimental Section ...... 153

5.4.1 General Considerations ...... 153

5.4.2 Synthesis of Compounds ...... 153

5.5 References ...... 156

Chapter 6 Conclusions and Future Work ...... 158

6.1 Summary of Thesis ...... 158

6.2 Future Work ...... 159

6.3 References ...... 161

List of Figures

Figure 1.1. Reaction coordinate diagram of an uncatalyzed (black) and catalyzed (green) reaction...... 2

Figure 1.2. Electron transfer model (left) and electric field model (right) of the encounter complex formed by B(C6F5)3 and tBu3P...... 9

Figure 2.1. Generic representation of enantiomers...... 22

Figure 2.2. Examples of planar chirality (left), axial chirality (middle), and helical chirality (right)...... 23

Figure 2.3. Ferrioxalate anions displaying chirality in handedness of the bidentate ligands...... 23

Figure 2.4. FLP catalysts for asymmetric hydrogenation, developed by Klankermayer (top left), Erker (top right), Repo (middle left), Wang (middle right) and Du (bottom)...... 27

Figure 2.5. Geometry of chiral 3,5-bicyclic aryl piperidines...... 28

11 Figure 2.6. B NMR spectrum of the crude reaction mixture of 2-1 and B(C6F5)3...... 32

Figure 2.7. POV-ray depiction of 2-10. Hydrogen atoms on the piperidine backbone have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink; O: red; H: white...... 32

Figure 2.8. POV-ray depiction of 2-11 enantiomers. Hydrogen atoms have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink...... 33

Figure 2.9. POV-ray depiction of one of the 2-11 enantiomers. Hydrogen atoms have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink...... 34

Figure 2.10. POV-ray depiction of 2-14. Hydrogen atoms have been omitted for clarity. B: yellow- green; C: black; N: blue; F: pink; P: orange...... 35

Figure 2.11. Surface contour plot of HOMO (top left) and LUMO (top right) of 2-11; and HOMO (bottom left) and LUMO (bottom right) of 2-12. B: yellow-green; C: grey; N: blue; F: pink; H: white...... 37

1 Figure 2.12. H NMR spectrum for HD scrambling experiment with 2-12 in toluene-d8...... 39

Figure 3.1. Classes of boron cations (top) and the first reported boronium ion (bottom left), crystallized borenium ion (bottom middle) and crystallized borinium ion (bottom right)...... 60

Figure 3.2. POV-ray depiction of 3-6. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; F: pink; H: white...... 65

Figure 3.3. POV-ray depiction of 3-8. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white...... 66

Figure 3.4. POV-ray depiction of 3-18. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; O: red; H: white...... 68

Figure 3.5. POV-ray depiction of 3-19. Hydrogen atoms were omitted for clarity except for the B- H bonds. B: yellow-green; C: black; N: blue; O: red; H: white...... 69

Figure 3.6. POV-ray depiction of 3-20. Hydrogen atoms were omitted for clarity. B: yellow-green; C: black; N: blue; O: red; Cl: green...... 69

Figure 3.7. POV-ray depiction of 3-21. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; O: red; H: white...... 70

Figure 3.8. POV-ray depiction of 3-28. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white...... 74

Figure 3.9. POV-ray depiction of 3-30. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white...... 75

Figure 3.10. POV-ray depiction of 3-31. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white...... 75

Figure 3.11. POV-ray depiction of 3-35. Hydrogen atoms were omitted for clarity. B: yellow- green; C: black; N: blue...... 77

Figure 3.12. POV-ray depiction of 3-38. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity. B: yellow-green; C: black; N: blue...... 79

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Figure 4.1. POV-ray depiction of 4-3. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity. B: yellow-green; C: black; N: blue; Cl: green...... 113

Figure 4.2. POV-ray depiction of 4-4. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white...... 115

Figure 4.3. Surface contour plot of HOMO (left) and LUMO (right) of 4-1; B: yellow-green; C: grey; N: blue; H: white...... 118

Figure 4.4. Surface contour plot of HOMO (left) and LUMO (right) of 4-2. B: yellow-green; C: grey; N: blue; H: white...... 118

Figure 4.5. Characteristic resonances in the 1H NMR spectrum of 4-12 showing distribution of regioisomers 4-12a (red) and 4-12b (green)...... 121

Figure 4.6. POV-ray depiction of 4-15. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white...... 124

Figure 4.7. Surface contour plot of HOMO (left) and LUMO (right) of 4-17. Hydrogen atoms were omitted for clarity. B: yellow-green; C: grey; N: blue; P: orange...... 127

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List of Schemes

Scheme 1.1. Hydroboration of alkene to produce alkylboranes, followed by either oxidation to give corresponding alcohol, or by cross-coupling with alkyl or aryl halide (where M = electrophilic organometallic species)...... 5

Scheme 1.2. Formation of active zirconocene species by B(C6F5)3 activation...... 5

Scheme 1.3. Early reports of FLPs...... 6

Scheme 1.4. B(C6F5)3-catalyzed hydrosilylation of aromatic aldehydes, ketones and esters...... 7

Scheme 1.5. The first reported H2 activation by an FLP...... 7

Scheme 1.6. FLP radical species formed by single electron transfer mechanism and the subsequent trapping by p-chloranil and triphenyltin hydride...... 9

Scheme 1.7. Examples of small molecule activation by B(C6F5)3 and phosphines...... 10

Scheme 1.8. Proposed mechanism for B(C6F5)3-catalyzed imine reduction...... 11

Scheme 2.1. Example of asymmetric hydrogenation of an aromatic ketone by a BINAP-Ru catalyst (top), and the catalytic production of (S)-Metolachlor (bottom)...... 24

Scheme 2.2. Synthesis of iPr-3,5 bicyclic aryl piperidine. Only one enantiomer is shown for clarity...... 29

Scheme 2.3. Synthesis of Ph-3,5-bicyclic aryl piperidine. Only one enantiomer is shown for clarity...... 30

Scheme 2.4. Hydroboration of 2-4 with excess 9-BBN...... 30

Scheme 2.5. Formation of adduct and iminium cation between 2-1 and various boranes...... 31

Scheme 2.6. Hydroboration of Ph-3,5-bicyclic aryl piperidine...... 33

Scheme 2.7. Formation of borane-phosphine adducts of 2-12...... 34

Scheme 2.8. FLP reactivity and catalytic tests of 2-11...... 38 xiv

Scheme 2.9. FLP reactivity of 2-1 with B(2,6-F2C6H3)3...... 40

Scheme 3.1. Resonance forms of phosphine-stabilized borenium cation (top) and dissociation of borenium cation for imine hydroboration catalysis (bottom)...... 61

Scheme 3.2. Proposed mechanism for borenium-catalyzed hydrogenation of imines...... 62

Scheme 3.3. General synthetic route for NHC-borenium salts...... 63

Scheme 3.4. Synthesis of enantiomerically pure camphoric acid-derived carbene precursors (top) and their respective carbene-borane adducts (bottom)...... 64

Scheme 3.5. Synthesis of fused oxazolium triflate salts as carbene precursors...... 67

Scheme 3.6. Synthesis of bisoxazolium carbene-borane adducts...... 67

Scheme 3.7. Synthesis of binaphthyl-derived triazolium tetrafluoroborate as a carbene precursor...... 71

Scheme 3.8. Synthesis of binaphthyl-derived triazolium carbene-borane adducts...... 71

Scheme 3.9. Attempted synthesis of the racemic NHC-9-BBD adduct...... 72

Scheme 3.10. Synthesis of the meso-ionic carbene-9-BBD adduct 3-27...... 72

Scheme 3.11. Attempted synthesis of the racemic 1,3,4-phenyl-meso-ionic carbene-9-BBD adduct...... 73

Scheme 3.12. Synthesis of Ipc2BH by hydroboration of α-pinene...... 73

Scheme 3.13. Synthesis of NHC-Ipc2BH adducts 3-28, 3-29, 3-30, 3-31, and 3-32...... 74

Scheme 3.14. Synthesis of ring-expanded boranes 3-33, 3-34, and 3-35...... 76

Scheme 3.15. Proposed ring expansion mechanism of carbene-borane adducts...... 77

Scheme 3.16. Chloride abstraction of 3-20 to generate the borenium cation...... 78

Scheme 3.17. Synthesis of enantiomerically pure camphoric acid-derived borenium cations 3-36, 3-37, 3-38, and 3-39...... 79

Scheme 3.18. Catalytic reduction of N-benzylidene-tert-butylamine by 3-27, 3-36, 3-37, 3-38, and 3-39...... 80

Scheme 3.19. Test for racemization of enantiopure amine...... 84

Scheme 4.1. Examples of intramolecular FLPs demonstrating greater catalytic activity (top), expanding the substrate scope (middle), and exhibiting different chemistry compared to intermolecular FLPs (bottom)...... 109

Scheme 4.2. Catalytic cycle of alkene hydroboration with NHC-borenium cation as the active species...... 110

Scheme 4.3. Reported synthesis of the diarylborenium cation by hydride abstraction and C-H activation of the phenyl group...... 111

Scheme 4.4. Formation of a trimer cation through benzylic arm deprotonation, and neutral diborane(4) formation by one-electron reduction...... 112

Scheme 4.5. Formation of B-Cl borenium cation 4-3...... 113

Scheme 4.6. Modified synthesis of isolable B-H borenium cation 4-1...... 114

Scheme 4.7. Synthesis of 4-4 by deprotonation of 1,3-dibenzylimidazolium bromide and 4-5 by in situ hydride abstraction...... 115

Scheme 4.8. Hydroboration of simple alkenes and the subsequent oxidation to generate the respective alcohols...... 119

Scheme 4.9. Hydroboration of diphenylacetylene and 1-hexyne with 4-1...... 120

Scheme 4.10. Hydroboration with 4-1 of 1-phenyl-1-propyne...... 121

Scheme 4.11. Formation of the borenium dimer cation 4-13 by deprotonation of the benzylic arm...... 122

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Scheme 4.12. Adduct formation of 4-1 with ethynyldiphenylphosphane (right) and 2-vinylpyridine (left)...... 123

Scheme 4.13. Formation of a phosphirenium system 4-16 by a diarylphosphinyl group migration...... 125

Scheme 4.14. Hydroboration of dimesityl(1-phenylvinyl)phosphane with 4-1 to form ethylene- bridged phosphine-borenium cation 4-17...... 126

Scheme 5.1. Intramolecular cooperativity in dihydrogen activation by a doubly Lewis acid functionalized naphthalene...... 146

Scheme 5.2. Synthesis of doubly Lewis acid functionalized anilines (top), and phosphines (bottom)...... 147

Scheme 5.3. Bidentate chelation of carbon dioxide by 1,1-bisboranes (top and middle right), geminal bisboranes (middle left) and tridentate chelation of small molecules (bottom)...... 148

Scheme 5.4. Hydrogen and amine activation by a bulky NHC and B(C6F5)3...... 149

Scheme 5.5. Anion exchange of 1,3-diallylimidazolium bromide to form 5-1 and 5-2...... 150

Scheme 5.6. Hydroboration of 1,3-diallylimidazolium tetrakis(pentafluorophenyl)borate with Piers’ borane to form 5-3...... 150

Scheme 5.7. Hydroboration of 1,3-diallylimidazolium salt with 9-BBN to form 5-4 and 5-5. . 151

Scheme 5.8. Deprotonation of 5-5 with KHMDS...... 152

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List of Tables

Table 2.1. Experimental and computational measures of the Lewis acidity of 2-11, 2-12, and electrophilic neutral boranes...... 36

Table 2.2. Selected crystallographic data for 2-10 and 2-11 enantiomers...... 51

Table 2.3. Selected crystallographic data for 2-11 and 2-14...... 52

Table 3.1. Hydrogenation catalysis of (E)-N,1-diphenylethan-1-imine by borenium cations derived from 3-18, 3-19, 3-21, 3-26, 3-28, 3-29, 3-30, 3-31, and 3-32...... 82

Table 3.2. Hydrogenation catalysis by borenium cations derived from 3-18, 3-19, and 3-21. .... 83

Table 3.3. Selected crystallographic data for 3-6, 3-8, and 3-18 ...... 101

Table 3.4. Selected crystallographic data for 3-19, 3-20, and 3-21...... 102

Table 3.5. Selected crystallographic data for 3-35, and 3-38...... 103

Table 4.1. Experimental values of the Lewis acidity of B(C6F5)3 and the borenium cations. .... 116

Table 4.2. Computational values of the Lewis acidity of B(C6F5)3 and the borenium cations... 117

Table 4.3. Attempted hydrogenations of unsaturated substances with 4-17...... 127

Table 4.4. Selected crystallographic data for 4-3 and 4-4...... 140

Table 4.5. Selected crystallographic data for 4-15 and dimesityl(1-phenylvinyl)phosphane. ... 141

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List of Symbols and Abbreviations

Ipc2BH (+)-diisopinocampheylborane BINOL [1,1’-binaphthalene]-2.2]-diol QPhos 1,2,3,4,5-Pentaphenyl-1’-(di-tert-butylphosphino)ferrocene BINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl 9-BBN 9-borabicyclo(3.3.1)nonane 9-BBD 10-phenyl-9-borabicyclo[3.3.2]decane

Ea Activation energy α Alpha Å Angstrom, 10-10 m atm Atmosphere ax Axial β Beta br Broad Bu Butyl Calc. Calculated Cat. Catalyst δ Chemical shift or Delta Anal. Combustion elemental analysis Conc. Concentrated CAACs Cyclic alkyl amino carbenes Cy Cyclohexyl ° Degrees °C Degrees Celsius ∆ Delta DFT Density functional theory dba Dibenzylideneacetone DCM Dichloromethane DMF Dimethylformamide DART Direct analysis in real time xix

d Doublet dd Doublet of doublets ddd Doublet of doublets of doublets ddq Doublet of doublets of quartets dq Doublet of quartets dt Doublet of triplets dtt Doublet of triplets of triplets EF Electron field EI Electron ionization ET Electron transfer eV Electron volts ESI Electrospray ionization ee Enantiomeric excess eq Equatorial equiv. Equivalents Et Ethyl FIA Fluoride ion affinity FLP Frustrated Lewis pair γ Gamma GC-MS Gas chromatography-mass spectrometry GEI Global electrophilicity index Hz Hertz HPLC High-performance liquid chromatography HR High resolution HOMO Highest occupied molecular orbital h Hour(s) IR Infrared iPr Isopropyl K Kelvin kJ Kilojoules

λ Lambda LC-MS Liquid chromatography-mass spectrometry LUMO Lowest unoccupied molecular orbital m/z Mass-to-charge ratio MS Mass Spectrometry MHz Megahertz Mes Mesityl m Meta Me Methyl mg Milligram mL Millilitre mmol Millimole min. Minute(s) M Molar concentration mol Mole m Multiplet n Jxy n-scalar coupling constant between X and Y atoms CAMP o-anisylmethylphenylphosphine obs. Observed o Ortho NHC N-heterocyclic carbene NBO Natural bond order N.R. No reaction n Normal N Normal concentration NMR Nuclear magnetic resonance p Para ppm Parts per million, 10-6 POV-Ray Persistence of Vision Raytracer Ph Phenyl

xxi

π Pi KHMDS Potassium bis(trimethylsilyl)amide PGMs Precious Group Metals q Quartet Rf Retention factor r.t. Room temperature σ Sigma s Singlet NaHMDS Sodium bis(trimethylsilyl)amide t Tertiary TBAF Tetra-n-butylammonium fluoride THF Tetrahydrofuran TMS Tetramethylsilyl TLC Thin layer chromatography OTf Trifluoromethanesulfonate t Triplet or time td Triplet of doublets TOF Turnover frequency UV Ultraviolet Vis Visible WBI Wiberg bond index

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Chapter 1 Introduction 1.1 Science and Humankind

Scientific advancement is transformative to humankind. New discoveries better our understanding of our world and scientific applications change how society functions and transform the human experience, defining one era from the next.

Modern science can be traced back to early modern Europe, where the emergence of the scientific revolution and the scientific method shaped how humankind acquires knowledge through systematic experimentation. Some of the discoveries made in chemical science still have an effect to this day. The Haber-Bosch process, an artificial nitrogen fixation process to produce ammonia, has allowed mass production of fertilizers and increased food production, triggering an explosive global population growth in the past century.1 Ziegler-Natta catalysts laid the foundation of today’s polymer industry and our reliance on plastic commodities.2-5 Development of chemical synthetic processes, purification, and analytical methods have allowed the rapid progression of modern medicine, and significantly bettered human health and life expectancy.6-7

Unfortunately, unchecked effects of new technologies and their applications can have detrimental results on human health and the environment. Failure to recognize the toxicity of medicinal drugs can be disastrous.8 For example, the racemization of thalidomide, a drug originally administrated to pregnant women to alleviate morning sickness, led to infants being born with deformations and fetal deaths.9 The mass production of plastic materials resulted in highly persistent waste, saturating landfills and endangering marine life.10 The large-scale production of ammonia not only led to an anthropogenic disruption of the nitrogen cycle through leaching and buildup of nitrates in the biosphere,11 but also provided unprecedented access to materials needed for explosive weaponry.1

Humanity must now remediate past mistakes and simultaneously provide for the ever-changing needs of today’s society. It is therefore crucial that scientific research learn from history and move forward to better the quality of human life with a social conscience.

1.2 Catalysis

1.2.1 Background

With a growing need to change the way research is approached, a new field of green chemistry emerged, emphasizing a need of sustainability.12 The 12 principles of green chemistry were developed to serve as a guideline to lessen the impact of science on human health and the environment.13 Catalysis has become a key focus, underlining the need for less energy intensive chemical processes.

Ea (Uncatalyzed)

Potential Intermediate Energy Ea (Catalyzed)

Reactants

Products

Reaction Progress

Figure 1.1. Reaction coordinate diagram of an uncatalyzed (black) and catalyzed (green) reaction.

The chemical term catalyst was defined, by Wilhelm Ostwald initially in 1895 and is still applicable today in its original form, as “a material that accelerates a chemical reaction without affecting the position of the equilibrium and thermodynamics of the reaction”.14 The catalyst does so by providing an alternative mechanistic pathway that bears less energetic requirement (Figure 1.1). The pathway goes through an intermediate of a lower energy and, typically, the transition state of the rate limiting step is lower in energy as compared to that of the uncatalyzed reaction. As a result, the overall reaction can proceed with reduced energetic requirements as the activation

energy (Ea) is lowered. Characteristically, the catalyst is unconsumed after the reaction and hence a substoichiometric amount may be added to the reaction. Given that the energy demand of the reaction is significantly reduced, catalyzed reactions frequently proceed under milder, safer 2

conditions compared to their uncatalyzed variety. This also allows chemical transformations that would be otherwise inaccessible due to high energetic requirements, such as the aforementioned ammonia synthesis by the Haber-Bosch process. In today’s world, catalysis is crucial to the production of a variety of materials, such as plastics, pharmaceuticals, and fuels.15

While catalysts have significantly reduced the energy requirement of chemical processes and have allowed access to more chemical transformations, catalysts that use rare precious metals, such as the Platinum Group Metals (PGMs), can have negative environmental and social impacts as they require mining and extraction and are inherently non-renewable resources.16 Despite the fact that these metals typically are recovered and reused in industrial production, it is necessary to transition to more readily available and environmentally benign materials to prevent the release of the PGM elements into the environment and to minimize waste processing and recovery costs. To this end, catalysts using abundant and less toxic d-block transition metals, such as iron,17-20 nickel,21-23 and zinc,24-26 have been extensively explored. These metals, similar to the PGMs, have valence d- orbitals that are energetically accessible, allowing the changes in oxidation state which are necessary for substrate activation and stabilization of transitions states. Through steric and electronic manipulation of the ligand framework, various chemical transformations can be accessed with these catalysts.27 In addition, s-block metals,28 such as calcium29 and magnesium,30- 31 have also demonstrated similar catalytic activities.

Alternatively, the metal-free approach employing main group elements has gained notable traction over the last decade. Boron, in particular, has experienced great developments in its chemistry over the past century.

1.2.2 Properties, Sources and Uses of Boron

Boron is a non-metallic, low-abundance element, and it constitutes about 9 ppm of the Earth’s crust.32 Its elemental form is not found in nature, but rather in the form of borates,33 and can be found in minerals such as kernite and rasorite. Currently, the largest known boron deposits are 34 found in Turkey. Boron-containing ores are mined and refined to boric acid (H3BO3) using strong 35 acids or to sodium tetraborate pentahydrate (Na2B4O7 • 5H2O). These compounds are then used to produce other boron materials, such as glass and ceramics. Borosilicate glass, which containing

12-15% B2O5, has good resistance to thermal shock and is used in consumer cookware and 3

laboratory glassware.36 Other common boron compounds can be found in detergents (borax: 37 Na2B4O7), bleaches (sodium perborate: NaBO3), and insecticides (boric acid).

It is difficult to produce pure elemental boron industrially due to refractory contamination by other elements, such as carbon. Production of pure boron can be carried out by reduction of boric oxide 38 (B2O3) with metals, or by reduction of boron halides at high temperatures with hydrogen gas. In

the semiconductor industry, ultrapure boron is produced by decomposition of diborane (B2H6) at high temperature and purified by zone melting.39 The pure boron thus obtained is of different allotropes, such as α-rhombohedral boron and β-rhombohedral boron.40 Boron of high purity has a variety of uses, such as rocket fuel igniter, thermistors, delay lines and high-strength, and lightweight reinforcing materials in commercial and military aircraft.41

1.2.3 Boron Chemistry

Boron compounds have a rich history in chemical transformation. Hydroboration, the anti- Markovnikov syn-addition of a B-H bond across the unsaturated bonds of substrates, allowed for the production of a wide variety of organoborane compounds. These compounds then be used as precursors in the production of amines, alcohols and alkyl halides in a regioselective and stereospecific fashion.42 For the contributions and the development of this chemistry, Herbert C. Brown was recognized by the Nobel Prize in Chemistry in 1979.43 Another impactful methodology is the use of organoboranes in the Suzuki-Miyaura cross-coupling reaction. In this named reaction, new C-C bonds are formed to give coupled products from C(sp2)-B or C(sp3)-B organoboranes through transmetalation and reductive elimination with an electrophilic organometallic species, typically involving metals such as Pd, Ni, Cu or Fe (Scheme 1.1).44-45 Due to the ease of use and widespread application of this reaction, Akira Suzuki was awarded the Nobel Prize in Chemistry in 2010.46 Other common applications of boron chemistry are the use of metal borohydrides as reducing agents,47-48 the transfer of an organic group to an electrophile from an anionic borate,49 and transfer of metal hydrides from metal alkoxide hydrides to form new metal borohydrides.50

The valence shell electron configuration of boron is 2s22p1, which commonly leads boron to form trivalent compounds of trigonal planar geometry that feature sp2 hybridized bonds. A non-bonding vacant p-orbital lies orthogonal to the trigonal plane, which can accept electrons and give rise to the Lewis acidic properties characteristic of boron compounds.51 Multiple methodologies have been designed to quantify Lewis acidity,52 such as the use of NMR spectroscopy in the Gutmann- Beckett test53-54 and Childs method,55 density functional calculations towards global electrophilicity index (GEI)56-57 and fluoride ion affinity (FIA)58-59 determination, calorimetry,60- 61 X-ray diffraction,62 IR spectroscopy,63-64 and UV-Vis spectroscopy.61, 65

Scheme 1.2. Formation of active zirconocene species by B(C6F5)3 activation.

The Lewis acidity of boron compounds is frequently utilized in chemical transformations. Boron trihalides, particularly BF3, are commonly used as initiators in cationic polymerization of olefins.

Notably, B(C6F5)3 was found to be an excellent activator for the Ziegler-Natta olefin polymerization catalysts, thus exhibiting significant Lewis acidity without any of the handling difficulties associated with boron trihalides. Treating zirconocene catalysts with B(C6F5)3 results in methyl anion abstraction to form the active catalyst species, stabilized by the weakly 66 coordinating [MeB(C6F5)3] anion (Scheme 1.2). Lewis acidic boranes were also used as catalysts

extensively in a variety of chemical transformations,67-69 such as hydrosilylation,70-74 cyclization,75 Friedel-Crafts propargylation,76 and Diels-Alder reaction.77 Recently, catalysis involving the Lewis acidity of boron compounds has expanded to include what is known as “frustrated Lewis pairs” (FLP) chemistry.

1.3 Frustrated Lewis Pairs

1.3.1 History

The acid-base theory proposed in 1923 by Gilbert N. Lewis describes a Lewis acid as an electron pair acceptor and a Lewis base as an electron pair donor respectively, and this theory is arguably one of the most important chemical theories.78 According to this theory, the Lewis base donates an electron pair to the Lewis acid and forms an adduct, quenching subsequent reactivity of both the Lewis acid and base individually. This concept was not only able to explain Lewis acid/base reactions but is also fundamental in most reactions involving the interaction of a nucleophile and an electrophile to form a favorable bond, such as a covalent bond and dative/coordination interactions.

Scheme 1.3. Early reports of FLPs.

The first exception to this theory was reported in 1942 by Herbert C. Brown, in which trimethylborane and 2,6-dimethylpyridine did not form an adduct, while the analogous reaction 79-80 with BF3 yielded the expected adduct formation. The authors attributed the anomaly to steric conflicts of the alkyl groups of both the acid and base, but did not further probe their reactivity. In 1959, Wittig reported the formation of a o-phenylene-bridged phosphonium-borate that resulted

when triphenylborane and triphenylphosphine was reacted with 1,2-didehydrobenzene.81 Tochtermann, a few years later, reported the 1,2-addition product of triphenylborane and trityl anion to olefins, rather than the expected polybutadiene product (Scheme 1.3). Both Wittig and Tochtermann noted the special nature of these bulky Lewis pairs, and Tochtermann described them with the German term “antagonistisches Paar”, meaning “antagonistic pair”.82 In the late 1990s, the Piers’ group reported the B(C6F5)3-catalyzed hydrosilylation of aldehydes, ketones and esters (Scheme 1.4), in which they described the catalysis was effected by the activation of the Si-H bond by the Lewis acidic borane and subsequent attack by the carbonyl group.70 This was further substantiated by the mechanistic work done by Oestreich and co-workers, in which they confirmed 83 the stereochemical inversion at the silicon centre of a chiral silane with B(C6F5)3. The cooperative action of the Lewis acid and Lewis base on the Si-H bond reported by Piers’ group is now recognized as the first example for FLP chemistry, and foreshadowed the cornerstone of FLP activation of H2 ten years later.

Scheme 1.4. B(C6F5)3-catalyzed hydrosilylation of aromatic aldehydes, ketones and esters.

The potential of these Lewis pairs was then fully realized when Stephan and co-workers reported the chemistry of a phosphonium borate linked zwitterion in 2006. Heating of the zwitterion to

150 °C allowed H2 elimination, but more remarkably the species was able to heterolytically split

H2 at room temperature (Scheme 1.5). The sterically congested boron and phosphorus centres precluded the classical intermolecular adduct formation and as such, this type of species was described for the first time as a “frustrated Lewis pair”. This was also the first reported non- transition-metal system to reversibly activate dihydrogen.84

Scheme 1.5. The first reported H2 activation by an FLP.

After the initial report, the unique chemistry of bulky Lewis pairs attracted immediate attention, and FLPs of different templates were developed. For example, intramolecular B/P FLPs with an ethylene linker were synthesized by Erker and co-workers by hydroboration of vinyl phosphines 85-86 with HB(C6F5)2. The Stephan group also reported that commercially available Lewis pair 87 combinations, such as B(C6F5)3 and tBu3P, can effect dihydrogen activation.

1.3.2 Mechanistic Investigation and FLP Reactivity

The initial hypothesis for the H2 activation by an FLP was proposed to be a “side-on” or “end-on” coordination of dihydrogen to the Lewis acid or base moiety, followed by approach of the corresponding FLP partner to effect bond cleavage. Despite earlier observations to support this

“side-on” mechanism based on BH3-H2 adducts, computational calculations do not support this hypothesis.88-91 Alternatively, the computational studies performed by Pápai and co-workers on

the activation of H2 by the archetypical B(C6F5)3 and tBu3P FLP suggests the formation of an

“encounter complex” that is stabilized by H-F interactions between the C6F5 rings and tBu groups. In their electron transfer (ET) model, the authors inferred that since the Lewis pair fail to form a

dative bond due to steric congestion, H2 can occupy the reactive pocket between the pair in an almost linear P-H-H-B fashion, resulting in heterolytic cleavage (Figure 1.2, left).92-93 A similar

transition state in the activation of H2 by a carbene and borane was also reported through calculations done by Tamm’s group.94 In contrast, Grimme’s report proposed an electric field (EF) model, in which the donor/acceptor counterparts create a strong homogeneous electric field pocket

within the FLP complex and polarizes the H2 molecule to allow a barrierless process for heterolytic 95 H2 activation (Figure 1.2, right). There is still a debate about the validity of these two models, with various FLP reports each supporting one or the other model.96-98 Nonetheless, both models acknowledge the key formation of an “encounter complex” between the Lewis pairs, and 19F{1H} HOESY NMR spectroscopy studies showed experimental evidence of the complex formation

through demonstrating interactions of the fluorines of B(C6F5)3 and protons of R3P (R = tBu, Mes).99 In a recent metadynamics simulation study, it was suggested that the two models may be

complimentary of each other, in that the ET model is most fitting when H2 is less than 2.5 Å from

the reactive centres, while the EF model can still have an effect on H2 when it is further away from the reactive centres.100 In contrast to the heterolytic cleavage mechanistic models, the Stephan

group reported in 2017 a single-electron transfer mechanism between Mes3P and E(C6F5)3 (E = B,

- Al) which form the respective radical cation and anion. In the case of the borane, the [·B(C6F5)3] 2- anion was then able to react with p-chloranil to form the [(C6F5)3BOC6Cl4OB(C6F5)3] dianion, + + and the [·Mes3P] cation can subsequently react with triphenyltin hydride to form the [Mes3PH] phosphonium cation and Ph3SnSnPh3 (Scheme 1.6). The authors inferred to the possibility of 101 homolytic cleavage of H2 via a one-electron process in the encounter complex.

δ- σ* δ+ σ

Figure 1.2. Electron transfer model (left) and electric field model (right) of the encounter complex formed by B(C6F5)3 and tBu3P.

Scheme 1.6. FLP radical species formed by single electron transfer mechanism and the subsequent trapping by p-chloranil and triphenyltin hydride.

The chemistry of FLPs has significantly extended beyond dihydrogen activation since the initial report in 2006. In particular, the combination of B(C6F5)3 and phosphines has been reported to 102-107 108-109 110-111 112 113 activate a variety of small molecules, such as CO2, N2O, SO2, disulfides, alkenes114-115 and alkynes116-117 (Scheme 1.7). 9

Scheme 1.7. Examples of small molecule activation by B(C6F5)3 and phosphines.

1.3.3 FLP Hydrogenation Catalysis

In addition to the capture and activation of small molecules, a crucial development of FLP chemistry is the adaptation towards metal-free catalysis. Recognizing that a proton and a hydride are generated upon dihydrogen activation and may be suitable for delivery to an unsaturated substrate, the result would produce a reduced product and regenerate the FLP. Indeed, the initial phosphonium borate linked zwitterion was shown to effect catalytic hydrogenations of imines and 118 aziridines with 5 atm of H2. In 2008, Erker and co-workers also demonstrated that their system

R2P(H)(C6F4)B(H)(C6F5)2 (R = tBu, Mes) was able to catalytically (3-20 mol%) reduce imines and 119 enamines with 2.5 bar H2 at room temperature. Stephan and co-workers’ report further revealed that sterically hindered substrates can also act as the Lewis base in the FLP, eliminating the need

for an external base. In this case, a catalytic amount of B(C6F5)3 was able to reduce a variety of

bulky aldimines and ketimines at 120 °C with 5 atm of H2. They proposed that H2 is first cleaved

between B(C6F5)3 and the substrate, followed by hydride delivery to the iminium cation to produce 120-121 the amine product and regenerate B(C6F5)3 for the next catalytic cycle (Scheme 1.8).

Scheme 1.8. Proposed mechanism for B(C6F5)3-catalyzed imine reduction.

Following the initial reports of FLP-catalyzed imine hydrogenation, much of the evolution of these systems have been focused. Efforts to broaden the range of catalysts, improving stability, functional group tolerance, and expanding the range of substrates were undertaken, such as the reduction of a number of unsaturated substrates, including N-heterocycles,122-127 alkenes,128-133 aromatic hydrocarbons,134-136 ketones137-141 and oxime ethers,142-143 with various designs of FLPs.144-147 The majority of these catalysts systems have involved the use of boron-based Lewis acids, but Lewis acids utilizing other main group elements have been reported, such as phosphorus,148 tin,149-150 gallium and indium.151

1.4 Scope of Thesis

The work presented in this doctoral thesis aims to broaden the scope of boron-based Lewis acids in the field of FLP chemistry. Specifically, the research focuses on the development of metal-free asymmetric hydrogenation catalysis and intramolecular cooperativity of FLPs in small molecule activation. Chapter 2 describes the generation of B/N FLPs using 3,5-bicyclic aryl piperidines as a template and its potential for asymmetric hydrogenations. Taking the design considerations into account, modifications for N-heterocyclic carbene (NHC)-boranes to generate chiral borenium cations were made to produce families of chiral catalysts for imine reductions, and structural

effects on enantioselectivity and catalytic reactivity is explored (Chapter 3). Chapter 4 focuses on the use of an isolable B-H borenium cation and the production of an intramolecular B/P FLP through hydroboration of vinyl phosphines. Initial development of intramolecular B/C FLP is detailed in Chapter 5 through hydroboration of alkene-substituted imidazolium salts and deprotonation.

All synthetic work and characterization presented in this thesis was carried out by the author unless otherwise specified. High resolution mass spectroscopy and elemental analyses were carried out at the University of Toronto’s Advanced Instrumentation for Molecular Structure Laboratory and Analest respectively. X-ray experiments were carried out in house by the Stephan research group members. Synthesis and characterizations of 2-2, 2-3, 2-4, 2-6, 2-7, and 2-8 were carried out by Dr. Susanna Sampaolesi at Pfizer. Computational calculations in Chapter 2 were jointly carried out by the author and fellow PhD student James LaFortune. Final solution for the X-ray crystal structure 2-11 was arrived at by Dr. Alan J. Lough. Synthesis and characterizations of compounds 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-33, 3-34, 3-35, 3-36, 3-37, 3-38, and 3-39 were carried out by Benjamin Günther at Cardiff University and University of Toronto. Synthesis and characterizations of compounds 3-28, 3-29, 3-30, 3-31, and 3-32 were carried out by Dr. Jeffrey Farrell. Compound 3-27 was synthesized and characterized by Brian Bestvater at Queen’s University. Compounds 3-22, 3-23, 3-24, and 3-26 was synthesized and characterized by Dr. Patrick Eisenberger at Queen’s University. Catalytic reactions using 3-28, 3-29, 3-30, 3-31, and 3- 32 (Table 3.1, entries 11-20), and 3-26 (Table 3.1, entry 21) were performed by Dr. Jeffrey Farrell and Dr. Patrick Eisenberger respectively. Compound 5-2 were synthesized by undergraduate student Jenny Xiao, under the author’s supervision.

Portions of this thesis are either published or have been drafted at the time of writing:

Chapter 2:

Lam, J.; Sampaolesi, S.; LaFortune, J. H. W.; Coe, J.; Stephan, D. W. “Design considerations for chiral frustrated Lewis pairs: B/N FLPs derived from 3,5-bicyclic aryl piperidines” Dalton Trans. 2019, 48, 133-141.

Chapter 3:

Lam, J.; Günther, B. A. R.; Farell, J. M.; Eisenberger, P.; Bestvater, B. P.; Newman, P. D.; Melen, R.L.; Crudden, C. M.; Stephan, D. W. “Chiral carbene-borane adducts: precursors for borenium catalysts for asymmetric FLP hydrogenations” Dalton Trans. 2016, 45, 15303-15316.

Chapter 4:

Lam, J.; Cao, L. L.; Farrell, J. M.; Stephan, D. W. “Reactions of Carbene Stabilized Borenium Cations.” Drafted.

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109. Voicu, D.; Abolhasani, M.; Choueiri, R.; Lestari, G.; Seiler, C.; Menard, G.; Greener, J.; Guenther, A.; Stephan, D. W.; Kumacheva, E., J. Am. Chem. Soc. 2014, 136 (10), 3875-3880.

110. Neu, R. C.; Otten, E.; Lough, A.; Stephan, D. W., Chem. Sci. 2011, 2 (1), 170-176.

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112. Sajid, M.; Klose, A.; Birkmann, B.; Liang, L.; Schirmer, B.; Wiegand, T.; Eckert, H.; Lough, A. J.; Fröhlich, R.; Daniliuc, C. G.; Grimme, S.; Stephan, D. W.; Kehr, G.; Erker, G., Chem. Sci. 2013, 4 (1), 213-219.

113. Dureen, M. A.; Welch, G. C.; Gilbert, T. M.; Stephan, D. W., Inorg. Chem. 2009, 48 (20), 9910-9917.

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115. Ullrich, M.; Seto, K. S. H.; Lough, A. J.; Stephan, D. W., Chem. Commun. 2009, (17), 2335-2337.

116. Dureen, M. A.; Stephan, D. W., J. Am. Chem. Soc. 2009, 131 (24), 8396-8397.

117. Jiang, C.; Blacque, O.; Berke, H., Organometallics 2010, 29 (1), 125-133.

118. Chase, P. A.; Welch, G. C.; Jurca, T.; Stephan, D. W., Angew. Chem. Int. Ed. 2007, 46 (42), 8050-8053.

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121. Rokob, T. A.; Hamza, A.; Stirling, A.; Pápai, I., J. Am. Chem. Soc. 2009, 131 (5), 2029- 2036.

122. Geier, S. J.; Chase, P. A.; Stephan, D. W., Chem. Commun. 2010, 46 (27), 4884-4886.

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128. Greb, L.; Ona-Burgos, P.; Schirmer, B.; Grimme, S.; Stephan, D. W.; Paradies, J., Angew. Chem. Int. Ed. 2012, 51 (40), 10164-10168.

129. Ines, B.; Palomas, D.; Holle, S.; Steinberg, S.; Nicasio, J. A.; Alcarazo, M., Angew. Chem. Int. Ed. 2012, 51 (49), 12367-12369.

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131. Greb, L.; Daniliuc, C. G.; Bergander, K.; Paradies, J., Angew. Chem. Int. Ed. 2013, 52 (22), 5876-5879.

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Chapter 2 Synthesis and Reactivity of B/N FLPs Derived from 3,5- Bicyclic Aryl Piperidines 2.1 Introduction

2.1.1 Importance of Chirality

Figure 2.1. Generic representation of enantiomers.

Chirality describes a geometric property of compounds, stating a system is chiral if it cannot be superimposed with its mirror image (Figure 2.1). The chiral compound and its mirror image are then called enantiomers.1 The most common form of chirality is point chirality, which identifies the presence of a stereogenic centre in a molecule, such as a chiral carbon centre.2 Chirality can also arise from other spatial arrangements of an organic molecule, such as planar chirality – arrangement of out-of-plane groups with respect to a chirality plane (Figure 2.2, left);3 axial chirality – the non-planar arrangement of four groups in pairs about a chirality axis (Figure 2.2, middle);4 and helical chirality – the helical, propeller or screw-shaped geometry about an axis (Figure 2.2, right).5 In addition, metal coordination complexes also displays optical isomerism at the metal centre – “chiral at metal”, through coordination arrangement of the linear, bidentate or tetradentate ligands. Particularly, chirality can also arise from the handedness of the propeller twist of the coordinated bidentate ligands on the metal centre (Figure 2.3).6

Figure 2.2. Examples of planar chirality (left), axial chirality (middle), and helical chirality (right).

∆ ʌ

Figure 2.3. Ferrioxalate anions displaying chirality in handedness of the bidentate ligands.

Enantiomers have identical physical and chemical properties in a symmetric environment, but they exhibit different properties in a chiral environment. For example, they can rotate plane-polarized light to the same degree, but each enantiomer will rotate the light in the opposite direction of the other enantiomer. Hence, by using the plane-polarization measurement of an enantiopure isomer as a reference, one can then utilize a polarimeter to determine the enantiomeric excess (ee) in a mixture: the degree in which the amount of one enantiomer is greater than the other.7

Enantiomers also react differently with other chiral molecules. This characteristic is particularly prominent in biological systems, which are known to exhibit chirality. Most molecules of life consist of exclusively one isomer. The relationship between pharmacological effects and enantioselectivity was first reported in 1886 when (+)-asparagine was found to have a sweet taste whereas (-)-asparagine had no taste.8 Since then, many reports were published on the different properties of enantiomers, including the lock-and-key hypothesis for enzyme activity by Emil Fisher, which describes the stereospecific chemical activity between an enzyme and a substrate.9- 23

10 Indeed, the incorrect enantiomer can have detrimental effects on human health and the environment, such as the thalidomide tragedy11 mentioned in Chapter 1, accumulation of chiral pesticides and herbicides in the biosphere due to bacteria’s inability to biodegrade the enantiomer,12 and reduced longevity and survival of species by a selective enantiomer.13-15 Hence, the precise control of stereochemistry is crucial for chemical transformations, particularly in the industrial production process of agrochemicals,16 polymers,17 pharmaceuticals,18 and other biologically active molecules.19

2.1.2 Transition Metal-Catalyzed Asymmetric Hydrogenation

To produce enantiopure products, various synthetic methods, such as the use of chiral auxiliaries,20 chiral starting materials21 and kinetic resolution,22 and separation methods, such as chiral column chromatography,23 have been developed. However, these methods suffer from drawbacks such as decreased atom economy, limited theoretical yield, requiring additional purification steps, and expensive equipment.24 In comparison, asymmetric catalysis remains the most appealing approach in terms of lowered cost, environmental considerations, and better chiral economy.25 Consequently, intense research efforts were put into this field to expand the scope of catalytic reactions with higher efficiency and enantioselectivity.

Scheme 2.1. Example of asymmetric hydrogenation of an aromatic ketone by a BINAP-Ru catalyst (top), and the catalytic production of (S)-Metolachlor (bottom).

Hydrogenation, the addition of hydrogen across an unsaturated bond, is a common process to industrially produce many common materials, such as rubbers, fragrances, pharmaceuticals and fragrances.26 The first asymmetric hydrogenation was reported in 1968 with the use of chiral phosphine and Rh in the reduction of simple olefins, albeit achieving low enantioselectivity.27-28 Shortly after, William S. Knowles and co-workers reported the use of chiral o- anisylmethylphenylphosphine (CAMP) with Rh to give 80% ee of dehydroamino acids, which enabled the first industrial production of the anti-Parkinson’s drug L-DOPA using this technology in its synthesis.29 The use of 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP) reported by Ryōji Noyori and co-workers30 and replacement of Rh with Ru31 led to a significant extension of the reaction scope, such as the reduction of functionalized ketones32-33 and esters.34 BINAP-Ru- based catalysts (Scheme 2.1, top) were subsequently utilized in the production of several pharmaceuticals.35 In 2001, the Nobel prize was awarded to William S. Knowles and Ryōji Noyori for their development on chirally-catalyzed hydrogenation reactions, which they shared the prize with K. Barry Sharpless for his work on chirally-catalyzed oxidation reactions.36 There has been dramatic progress in the field of asymmetric hydrogenation since the first report in 1968.6, 37-40 For example, the industrial production of the common herbicide (S)-Metolachlor is achieved with an Ir-catalyzed asymmetric hydrogenation process in its synthesis (Scheme 2.1, bottom).41 Efforts to replace the PMG-based catalysts with cheaper, more abundant early transition metals, such as iron,42-43 have been realized.44 However, relatively few enantioselective catalytic reactions were adopted into industrial production.45 Indeed, given that enantiomers have identical thermodynamic properties and their chiral transition states may only differ by a few kcal/mol in energy,46-47 it can be particularly difficult to ensure the formation of one enantiomer selectively over the other, while simultaneously addressing production concerns such as availability, cost and recyclability of catalysts, chemoselectivity, and catalytic activity.48 As such, efforts in this field of research continue to aim for industrial adaptation.49-52

2.1.3 FLP-Catalyzed Asymmetric Hydrogenation

The developments of main-group FLP catalysts have mirrored the evolution of transition metal catalysts for hydrogenations: expanding the substrate scope, improving catalytic activity and stability, and modifying effective catalysts towards asymmetric hydrogenation.53 The aspect of FLP asymmetric hydrogenation is particularly attractive due to its elimination of using highly

expensive and toxic precious metals. Drawing inspiration from the successful use of chiral ligands in transition metal-catalyzed hydrogenations, the field of FLP-catalyzed enantioselective reductions has also utilized and modified such ligands. The first report on asymmetric hydrogenation was published by Klankermayer in 2008, in which reduction of the imine Ph(Me)C=NPh was achieved with an ee of 12%.54 Since then, the group has made modifications, such as installing a bulky phosphine on their camphor-templated borane catalysts and have achieved asymmetric ketimine reductions with ee up to 83% (Figure 2.4, top left).55-56 Erker and co-workers have synthesized ferrocene templated B/P FLPs57 and the optically pure zwitterion was used to catalytically reduce ketimines to give amines of 42-69% ee (Figure 2.4, top right).58 The Repo group has described the use of an intramolecular B/N FLP and achieved imine hydrogenations with stereoselectivities up to 37%.59 They then reported modifications using a binaphthyl backbone to generate an intramolecular B/N FLP system described as a “molecular tweezer”, and were able to reduce imines and enamines with ee up to 99% (Figure 2.4, middle 60 left). A C2-symmetric bicyclic bisborane was developed by Wang and co-workers by hydroboration of fused bicyclic dienes with HB(p-C6F4H)2, and the corresponding bisborane was able to catalytically reduce imines with ee up to 95% (Figure 2.4, middle right).61 The Du group reported the generation of chiral diboranes through hydroboration of diene- or diyne-substituted binaphthalenes, which were highly successful in the reduction of silyl enol ethers,62-63 ketimines64, quinolines,65-66 quinoxalines,67 and benzoxazines68 with high yield and selectivity (Figure 2.4, bottom). An alternative approach for enantioselective substrate reduction is through transfer hydrogenation with the use of a sacrificial reagent as a hydrogen source. Du and co-workers reported the use of Piers’ borane, (R)-tert-butylsulfinamide and ammonia-borane as the hydrogen source in the production of optically active amines with ee of 84-95%,69 and the reduction of 2,3- disubstitued quinoxalines with up to >99% ee.70

Figure 2.4. FLP catalysts for asymmetric hydrogenation, developed by Klankermayer (top left), Erker (top right), Repo (middle left), Wang (middle right) and Du (bottom).

The use of intramolecular FLPs is particularly attractive in asymmetric catalysis, as the Lewis pair is pre-organized for easy formation of the encounter complex.71 This leads to a feasible bimolecular reaction, allowing for milder reaction conditions for dihydrogen activation while also reducing the steric and electronic requirements of substrates, a criterion needed for catalytic reactions in which the substrate acts as the Lewis pair counterpart.72 This can then allow for a greater range of substrates for catalysis. More importantly, when the Lewis pair is locked within a rigid framework, it can potentially allow for improved asymmetric induction through stereoselective delivery of proton and hydride to the substrate.

To this end, chiral tricyclic amines developed at Pfizer for a drug discovery program for smoking cessation were noted (Figure 2.5), in which they proposed the compounds as dual agents for 27

craving and withdrawal relief and nicotinic acetylcholine receptors blockage.73 In this class of 3,5- bicyclic aryl piperidines, the substituent on the nitrogen is forced to assume the favoured equatorial position, which places the amine in a chiral pocket.74-76 We therefore set out to derivatize these amines for asymmetric intramolecular FLPs, with the goal to apply them towards catalytic hydrogenation.

Figure 2.5. Geometry of chiral 3,5-bicyclic aryl piperidines.

2.2 Results and Discussion

2.2.1 Synthesis of 3,5-Bicyclic Aryl Piperidines

To establish a scaffold for the generation of the desired B/N FLPs, synthetic procedures were

developed with the starting symmetric amine hydrochloric salt C6H2F2(C5H8NiPr)•HCl. Upon addition of an excess of sodium carbonate, the salt was neutralized and the symmetric amine

C6H2F2(C5H8NiPr) 2-1 was isolated as an orange oil by extraction with diethyl ether. Using n-

BuLi, oxirane and BF3, followed by quenching with aqueous sodium carbonate, an ethyl alcohol fragment was incorporated with near quantitative conversion to give

C6HF2(C5H8NiPr)(CH2CH2OH) 2-2 which was isolated as an oil by chromatography in 68% yield. Compound 2-2 was formed as a racemic mixture, in which the ethyl alcohol group can be installed on either of the ortho position with respect to the fluorine atoms. The mixture was further modified

without separation of the enantiomers. C6HF2(C5H8NiPr)(CH2CH2OSO2Me) 2-3 was produced in 65% yield after mesylation with methanesulfonyl chloride in DCM and the styrene-derivative

C6HF2(C5H8NiPr)(CH=CH2) 2-4 was obtained as a yellow oil in 67% yield through an elimination reaction by treating 2-3 with potassium tert-butoxide in THF (Scheme 2.2).

Scheme 2.2. Synthesis of iPr-3,5 bicyclic aryl piperidine. Only one enantiomer is shown for clarity.

For comparative purposes, synthetic modifications were performed on the amine by replacement of the iPr group with the less electron-donating Ph group. The primary amine C6H2F2(C5H8NH) 2-5 was prepared and the Ph group was then installed through a Buchwald-Hartwig cross-coupling reaction to produce C6H2F2(C5H8NPh) 2-6 as an off-white solid in 96% yield. To install an iodide group on the aryl ring at the ortho position with respect to the fluorine atoms, subsequent lithiation and iodination produced C6HIF2(C5H8NPh) 2-7 as a white solid in 98% yield. Compound 2-7 was formed as a racemic mixture and used without subsequent separation of the enantiomers. The styrene-derivative C6HF2(C5H8NPh)(CH=CH2) 2-8 was obtained as an off-white solid in 86% yield through a Pd-mediated cross-coupling of 2-7 with pinacol vinylborate (Scheme 2.3).

Scheme 2.3. Synthesis of Ph-3,5-bicyclic aryl piperidine. Only one enantiomer is shown for clarity.

2.2.2 Hydroboration of the Styrene Derivative

The vinyl group installed on the bicyclic aryl piperidines then allowed for hydroboration to generate B-C bonds. Unfortunately, efforts to perform hydroboration on 2-4 proved to be difficult. By integration of the relative intensity of the vinyl resonances in the 1H NMR spectrum, approximately 13% of the starting material remained after stirring overnight in DCM with 0.5 equivalent of 9-BBN dimer. The 11B NMR spectrum contained 3 signals at δ 87.4 ppm, 59.1 ppm and 27.9 ppm, which were assigned to the hydroborated product, the amine adduct, and unreacted 9-BBN respectively. An excess of 9-BBN was then added to ensure the complete consumption of the starting material. The absence of vinylic proton signals in the 1H NMR spectrum and the 3 3 appearance of two doublet of doublets at δ 142.3 ppm with JFF = 19 Hz and JFH = 10 Hz, and 3 4 19 δ 148.8 ppm with JFF = 19 Hz and JFH = 7 Hz as major species in the F NMR spectrum, support

the formation of the desired product C6HF2(C5H8NiPr)(CH2CH2BC8H14) 2-9 (Scheme 2.4). Unfortunately, isolation of this species from the remaining 9-BBN and minor side products was not successful after multiple recrystallization attempts, as shown in the persistence of the three peaks in the 11B NMR spectrum.

Scheme 2.4. Hydroboration of 2-4 with excess 9-BBN.

Switching to a more reactive hydroboration reagent, HB(C6F5)2, mixtures of multiple products were formed regardless of temperature and solvent as monitored in the 11B NMR and 19F NMR spectra. A similar observation was noted when 2-1 was reacted with one equivalent of HB(C6F5)2. Among the signals observed in 11B NMR spectrum, a singlet at δ -12.4 ppm and a doublet at δ -24.9 1 ppm with JBH = 84 Hz were observed. The singlet was ascribed to the borane-amine adduct and - the latter, the [HB(C6F5)3] anion. Therefore, it is thought that a hydride abstraction by the - HB(C6F5)2 at the iPr group occurs to form an iminium cation and the [H2B(C6F5)2] anion, which - 77 the latter is known to scramble its substituents to eventually form the stable [HB(C6F5)3] anion.

This was supported by a control reaction where addition of one equivalent of B(C6F5)3 to 2-1 (Scheme 2.5) generated the same two peaks observed in the 11B NMR spectrum (Figure 2.6). Single crystals suitable for X-ray crystallography were isolated from the synthetic mixture of 2-4 with HB(C6F5)2. Crystallographic data revealed the species to be

C6HF2(C5H8N(H)iPr)(CH2CH2BOH(C6F5)) 2-10 (Figure 2.7), indicating that hydroboration had occurred and is one of the products in the resulting synthetic mixture, with a subsequent reaction with adventitious water leading to hydrolysis of the hydroboration product. The B-O distance was found to be 1.498(3) Å, which is slightly longer than a typical B-O bond.78 We concluded that the iPr group is problematic towards the formation of B/N FLPs, as the combination of a strongly basic nitrogen atom and the iPr group leads to a hydridic methine proton, which can be abstracted by the desired Lewis acidic boranes suitable for hydroboration reactions, undermining the targeted synthetic protocol.

Scheme 2.5. Formation of adduct and iminium cation between 2-1 and various boranes.

11 Figure 2.6. B NMR spectrum of the crude reaction mixture of 2-1 and B(C6F5)3.

Figure 2.7. POV-ray depiction of 2-10. Hydrogen atoms on the piperidine backbone have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink; O: red; H: white.

In contrast, hydroboration of 2-8 proceeded successfully with 9-BBN and HB(C6F5)2 (Scheme 2.6). Compound 2-11 was isolated in 69% yield and a single broad resonance peak at δ 88 ppm was observed in the 11B NMR spectrum, consistent with a three-coordinate borane. Two signals 19 3 were observed in the F NMR spectrum: a doublet with JFF = 19 Hz at δ -149.6 ppm, and a 3 doublet of doublet at δ -146.9 ppm with JFH = 7 Hz. Single crystals suitable for X-ray crystallography were isolated by slow diffusion of pentane into a cold saturated DCM solution of 2-11. Two attempts at data collection for X-ray diffraction analysis were carried out. During the first attempt, the data was collected in the incorrect Laue group, resulting in insufficient data for a

complete solution. The unit cell from this data set showed the co-crystallization of both enantiomers of 2-11 with the fused phenyl ring pi-stacked on top of each other, with a distance of 3.395(9) – 3.65(1) Å (Figure 2.8). The second attempt for data collection was carried out and confirmed the formation of C6HF2(C5H8NPh)(CH2CH2BC8H14) 2-11 (Figure 2.9). The nitrogen atom is situated above the aromatic ring, while the boron atom exhibits a typical three-coordinate trigonal planar geometry and is situated at 6.947 (4) Å from the nitrogen. The solid-state data and the NMR spectra are consistent with no intramolecular interaction.

Scheme 2.6. Hydroboration of Ph-3,5-bicyclic aryl piperidine.

Figure 2.8. POV-ray depiction of 2-11 enantiomers. Hydrogen atoms have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink. 33

Figure 2.9. POV-ray depiction of one of the 2-11 enantiomers. Hydrogen atoms have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink.

Compound 2-12 was prepared in an analogous fashion as 2-11, and was isolated as a yellow oil, containing a broad singlet at δ 72.5 ppm in the 11B NMR spectrum. In the 19F NMR spectrum, a doublet was observed at δ -145.7 ppm and a doublet of doublets at δ 139.9 ppm, corresponding to the fluorine atoms on the phenyl backbone. Resonances for the C6F5 rings were found at δ -130.1, -146.4, and -160.7 ppm. The data are consistent with the formation of 2-12 with a three-coordinate boron centre.

Scheme 2.7. Formation of borane-phosphine adducts of 2-12.

To explore the reactivity of 2-12, it was reacted with phosphines to explore the accessibility of the three-coordinate boron centre towards Lewis adduct formation. A white powder immediately 34

precipitated upon the addition of PMe3 and the resulting product 2-13 was insoluble in polar aprotic solvents. As such, the product was unable to be isolated and further characterized. In hopes of

improving the solubility of the Lewis adduct, one equivalent of PPh3 was added to 2-12 and compound 2-14 was isolated in 34% yield (Scheme 2.7). The 11B NMR spectrum showed a signal at δ -6.2 ppm, suggesting a four-coordinate boron centre, and a single resonance at δ 10.1 ppm in the 31P NMR spectrum. A doublet and a doublet of doublets were observed at δ -146.9 and -141.0 ppm in the 19F NMR spectrum respectively, with additional signals at δ -127.1, -157.2 and -163.5

ppm corresponding to the C6F5 rings. Single crystals suitable for X-ray crystallography were formed by slow diffusion of pentane into a saturated DCM solution of 2-14 and crystallographic

study confirmed the formation of C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) 2-14 (Figure 2.10)

and the B-P and B-Calkyl distances were observed to be 2.083(5) and 1.634(6) Å respectively.

Figure 2.10. POV-ray depiction of 2-14. Hydrogen atoms have been omitted for clarity. B: yellow-green; C: black; N: blue; F: pink; P: orange.

2.2.3 Lewis Acidity Determination

The Gutmann-Beckett test was carried out for 2-11 and 2-12 by exposure to Et3PO and monitoring by 31P{1H} NMR spectroscopy. A resonance at δ 52.4 ppm was found for the adduct formed with

2-11, while a resonance was found at δ 73.4 ppm for that formed with 2-12. By comparing the shift to that of the free Et3PO (δ = 52.1 ppm in CDCl3), 2-11 is weakly acidic as demonstrated by the small shift (∆δ = 0.3 ppm). In comparison, the adduct formed with 2-12 shows a greater shift

(∆δ = 27.8 ppm) when compared to that of the free Et3PO (δ = 45.6 ppm in C6D6), demonstrating a significantly greater Lewis acidity (Table 2.1). The degree of Lewis acidity is only slightly less than that of the traditional Lewis acid B(C6F5)3 (∆δ = 30.0 ppm) typically used in frustrated Lewis pair chemistry.

Table 2.1. Experimental and computational measures of the Lewis acidity of 2-11, 2-12, and electrophilic neutral boranes.

Compound Gutmann-Beckett (∆δ) GEI (eV) FIA (kJ mol-1)

2-11 0.3 a 1.00 350.1

79 BPh3 21.1 2.04 328.3

79-81 B(2,6-F2C6H3)3 24.6 2.56 362.3

2-12 27.8 3.45 441.4

79-81 B(C6F5)3 30.0 3.78 452.6

a All values were obtained from experiments performed in C6D6 except CDCl3. GEI was calculated at the B3LYP/Def2-TZVP//B3LYP/def2-TZVP level of theory. FIA was calculated at the BP86/Def2-TZVP//MP2/def2-TZVPP level of theory. All computations were calculated in the gas phase.

Density functional theory (DFT) computations were performed to further probe the Lewis acidity of 2-11 and 2-12 (Table 2.1). Energies for fluoride ion affinity (FIA) were calculated using the MP282-84 method and the def2-TZVPP basis set, as previously described using the experimental FIA of carbonyl difluoride.85 The global electrophilicity index (GEI)80-81 was calculated using the B3LYP86-89 functional and the def2-TZVP basis set86-87. The computed GEI and FIA values of 2-12 are higher than those of 2-11, consistent with the experimental observations. Interestingly, the GEI of 2-11 is lower than that of BPh3, yet the FIA value is found to be higher. Similarly, the 36

FIA value and experimental value of B(2,6-F2C6H3)3 suggest a significantly higher Lewis acidity than 2-11 but exhibits a similar GEI value. We propose that the variations in the steric environment about the boron centres with di- and triaryl boron derivatives give rise to discrepancies among the measured and computed values of Lewis acidity. This also highlights the need for several measurement methods to provide a more accurate determination of Lewis acidity. NBO analysis were also performed with the M062X basis set90 and def2-TZVP functional using NBO 6.0. For both 2-11 and 2-12, it was revealed that the HOMOs contain significant nitrogen lone-pair character, while the LUMOs primarily reside at the vacant p orbital of the boron centre, as expected for both compounds (Figure 2.11).

Figure 2.11. Surface contour plot of HOMO (top left) and LUMO (top right) of 2-11; and HOMO (bottom left) and LUMO (bottom right) of 2-12. B: yellow-green; C: grey; N: blue; F: pink; H: white.

2.2.4 FLP Reactivity

Compound 2-11 was subjected to 4 atm of HD, but no evidence of HD scrambling to form H2 and 1 D2 was observed by H NMR spectroscopy, even heating at 70 °C in CDCl3. Similarly, no imine

reduction was observed when 2-11 and N-phenylbenzylimine were combined under H2, nor when 13 an external base, PMes3, was added. When 2-11 was subjected to 4 atm of CO2, no adduct formation was observed at ambient temperature or at -41 °C. No hydrosilylation was observed when 2-11 was added to 20 equivalents of triethylsilane and α-methylstyrene (Scheme 2.8). We attributed the lack of reactivity to the weak acidity of the borane site, as demonstrated by the experimental and computational values of the Lewis acidity of 2-11.

Scheme 2.8. FLP reactivity and catalytic tests of 2-11.

1 In contrast, the formation of isotopomeric mixtures of H2, HD, D2 was observed by H NMR spectroscopy when 2-12 was exposed to 4 atm of HD at room temperature after 12 hours, indicating reversible hydrogen activation (Figure 2.12). Unfortunately, no reduction of N-t- butylbenzylimine or N-phenylbenzylimine was observed from exposure of 2-12 and the imines to 38

11 4 atm of H2, even at elevated temperatures. A peak at δ -12.6 ppm was observed in the B NMR spectrum when 2-12 and N-t-butylbenzylimine were combined independently, suggesting a strong coordination of the imine to the boron centre.

t = 0 h, 25 °C • = HD

• = H2

• = DCM

t = 12 h, 25 °C

1 Figure 2.12. H NMR spectrum for HD scrambling experiment with 2-12 in toluene-d8.

In the presence of a weaker Lewis acid, B(2,6-F2C6H3)3, both the borane and 2-1 were found to remain as a free species with no formation of an adduct. When subjected to 4 atm of HD gas, the mixture was found to scramble HD at 80 °C overnight, suggesting reversible activation of the molecule. However, when 10 equivalents of (E)-N-tert-butyl-1-phenylmethanimine was added and subjected to H2 at 80 °C, no reduction of the imine was observed (Scheme 2.9). A separate hydrogenation experiment using only the imine and B(2,6-F2C6H3)3 showed no reduction. Upon inspection of the 11B NMR spectrum, a small shift from δ 62.8 ppm to δ 46.3 ppm was observed, suggesting a very weak coordination of the imine to the borane and that the addition of the imine did not completely quench the activation of H2 by the Lewis acid. From these reactions, we hypothesized that with slightly weaker Lewis acids, despite being able to activate dihydrogen with the amine, the iPr amine is too Lewis basic and will hinder the subsequent hydride delivery to the iminium cation to effect catalytic turnover for hydrogenation.

Scheme 2.9. FLP reactivity of 2-1 with B(2,6-F2C6H3)3.

The tests suggest the lack of threshold combination of Lewis acidity and basicity in 2-11 to induce

dihydrogen activation. In contrast, 2-12 and 2-1/B(2,6-F2C6H3)3 exceeds the requirement and H2 activation was indeed observed. Unfortunately, 2-12 does not have the steric requirement to preclude classic adduct formation with imine substrates to effect reduction, whereas 2-1 precludes protonation of the imine substrate due to the high basicity of the piperidine.

2.3 Conclusion

Overall, the 3,5-bicyclic aryl piperidines presented in this chapter provide new methodology towards chiral intramolecular FLP systems yet require judicious synthetic modifications to produce effective hydrogenation catalysts. This chapter demonstrates the requirement of careful balancing of the steric environment and the combination of Lewis acidity and basicity. The base and acid sites must be reactive to effect dihydrogen activation yet allow for proton and hydride delivery, and the steric environment must preclude strong adduct formation yet allow sufficient donor-acceptor interactions to induce small molecule activation. Lewis acidity measurements also highlight the need for several methods, both experimental and computational, for accurate determination, as each have their own limitations. In addition, facile synthetic methodology is required for meticulous tuning of reactivity and selectivity to produce suitable chiral hydrogenation catalysts.

2.4 Experimental Section

2.4.1 General Considerations

All manipulations were carried out under dry, O2-free N2 using an MBraun glovebox and Schlenk techniques. Commercial reagents and solvents were purchased from Sigma-Aldrich, TCI

Chemicals, Strem Chemicals or Alfa Aesar, and used without further purification unless indicated otherwise. Pentane and dichloromethane were collected from a Grubbs-type column system manufactured by Innovative Technology in thick-walled glass Schlenk bombs with Young-type Teflon valve stopcocks. Chloroform-d was obtained from Cambridge Isotope Laboratories, dried over CaH2, and vacuum-transferred into Young bombs. Toluene-d8 and benzene-d6 were obtained from Sigma-Aldrich, dried over Na/benzophenone and vacuum-transferred into Young bombs. All solvents were degassed after purification and stored over 4 Ǻ molecular sieves. Molecular sieves were purchased from Sigma Aldrich and dried at 250 °C for 2 days under vacuum before use.

B(C6F5)3 was purchased from Boulder Scientific and used without further purification for the synthesis of bis(pentafluorophenyl)borane. (E)-N-tert-butyl-1-phenylmethanimine and triethylsilane were purchased from Sigma-Aldrich and were dried and stored over 4 Ǻ molecular sieves. Hydrogen gas (Grade 5.0) was obtained from Linde and purified through a Matheson Nanochem WeldAssureTM gas purifier column prior to use. Deuterium hydride (extent of labeling: 96 mol% HD, 98 atom % D) and carbon 13C dioxide (99 atom % 13C, < 3 atom % 18O) were purchased from Sigma Aldrich. (1R,3S,5S)-7,8-difluoro-3-isopropyl-2,3,4,5-tetrahydro-1H-1,5- methanobenzo[d]azepin-3-ium chloride was received from Pfizer and used without further purification. (E)-N-(1-phenylethylidene)aniline,91 tris(2,6-difluorophenyl)borane,92 and bis(pentafluorophenyl)borane,93 were prepared according to literature methods.

NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer or a Varian Mercury Plus

400 MHz spectrometer at 25 ºC. Chemical shifts are given relative to SiMe4 and referenced to the 1 13 11 31 residual solvent signal ( H, C) or relative to an external standard ( B: 15% (Et2O)BF3, P: 85% 19 H3PO4, F: CFCl3). Chemical shifts (δ) are reported in ppm and coupling constants (J) as scalar values in Hz. Mass spectrometry was carried out using an AB/Sciex QStar mass spectrometer with an ESI source or on a Hewlett-Packard GC/MS 6890 N that works with the EI technique (70 eV). Elemental analyses (C, H, N) were performed in-house with a Perkin Elmer 2400 Series II CHNS Analyzer.

2.4.2 Synthesis of Compounds

Synthesis of C6H2F2(C5H8NiPr) (2-1): (1R,3S,5S)-7,8-difluoro-3-isopropyl-2,3,4,5- tetrahydro-1H-1,5-methanobenzo[d]azepin-3-ium chloride (30 mg, 0.1 mmol, 1

equiv.) and Na2CO3 (18 mg, 0.17 mmol, 1.7 equiv.) were added to 1 mL of water.

Diethyl ether was added, extracted and dried with Na2SO4. The organic extract was then filtered through Celite and dried in vacuo to obtain a clear orange oil. Yield: 18 1 3 mg (0.076 mmol, 76 %); H NMR (CDCl3, 400 MHz): δ 6.91 (t, JHF = 9 Hz, 2H, FCCH), 3.03 3 2 3 (d, JHH = 4 Hz, 2H, NCH2CH), 2.70 (d, JHH = 10 Hz, 2H, NCHeq). 2.55 (septet, JHH = 7 Hz, 1H, 2 2 3 iPr-CH), 2.54 (d, JHH = 10 Hz, 2H, NCHax), 2.23 (dt, JHH = 10 Hz, JHH = 5 Hz, 1H, 2 3 NCH2CHCHeq), 1.65 (d, JHH = 10 Hz, 1H, NCH2CHCHax), 0.87 (d, JHH = 7 Hz, 6H, CH3); 13 1 1 2 3 C{ H} NMR (CDCl3, 125 MHz): δ 149.0 (dd, JCF = 149 Hz, JCF = 15 Hz, CF), 142.5 (t, JCF = 2 3 5 Hz, FCCHC), 110.7 (dd, JCF = 12 Hz, JCF = 7 Hz, C2H2C4F2), 53.6 (iPr-CH), 51.6 (NCH2), 19 3 44.6 (NCH2CHCH2), 41.2 (NCH2CH), 18.4 (CH3); F NMR (CDCl3, 376 MHz): δ -142.2 (t, JHF + + = 9 Hz); MS (ESI) m/z: 238 [M+H] ; HR-MS (ESI): C14N17F2N [M+H] m/z (calc.): 238.1402, m/z (obs.): 238.1402.

Synthesis of C6HF2(C5H8NiPr)(CH2CH2OH) (2-2): A stirring solution of 2-1 (4003 mg, 16.87 mmol, 1 equiv.) in 42 mL of THF at -78 °C was treated dropwise with n-BuLi (1190 mg, 18.6 mmol, 6.87 mL, 2.7 M, 1.1 equiv.) with no apparent visual change. After 1 h at -78 °C, oxirane (892 mg, 20.2 mmol, 8.10 mL, 2.5 M, 1.2 equiv.) was added followed by boron trifluoride ethyl ether complex (5510 mg, 38.8 mmol, 4.79 mL, 2.3 equiv.), causing the reaction color to lighten. After 3.5 hours, the reaction was allowed to warm to room temperature, whereupon it was quenched with a saturated aqueous

solution of Na2CO3 and stirred for 20 minutes. The two phases were separated, and the aqueous phase was extracted with ethyl acetate (30 mL), then an acid-base wash was performed. The organic phase was dried over sodium sulfate, then filtered and stripped to an oil. TLC showed very little remaining starting material (3:1 ethyl acetate: heptane, starting material Rf = 0.9, product Rf = 0.55). The crude mixture was then filtered through a silica pad, with an eluent solution 3 : 1 ethyl acetate : heptane. An oil was obtained and used as a crude material in the next step. 1H NMR

(CDCl3, 500 MHz): δ 6.75 (dd, J = 9, 7 Hz, 1H), 3.73 – 3.60 (m, 2H), 3.11 (dd, J = 8, 4 Hz, 1H), 2.97 (dd, J = 8, 4 Hz, 1H), 2.88 – 2.72 (m, 3H), 2.66 (dd, br, J = 10, 2 Hz, 1H), 2.52 – 2.41 (m,

13 1 3H), 2.13 (s, 1H), 1.59 (d, J = 10 Hz, 1H), 0.82 (dd, J = 7, 1 Hz, 6H); C{ H} NMR (CDCl3, 126 MHz): δ 149.1 (dd, J = 244, 14 Hz), 148.0 (dd, J = 243, 14 Hz), 141.4, 121.6 (d, J = 14 Hz), 108.9 (d, J = 19 Hz), 61.9, 53.9, 51.9, 51.0, 44.4, 41.3, 39.1 (d, J = 2 Hz), 30.5, 18.4, 18.2; 19F NMR

(CDCl3, 376 MHz): δ -141.74 (dd, J = 20, 10 Hz), -146.94 (dd, J = 19, 7 Hz); GC-MS (EI, 70 eV) m/z: 266 (100%), 235, 191, 177, 164, 86.

Synthesis of C6HF2(C5H8NiPr)(CH2CH2OSO2Me) (2-3): To a stirring solution of 2-2 (1540 mg, 5.474 mmol, 1 equiv.) in dichloromethane (25 mL), triethylamine (1990 mg, 19.7 mmol, 2.69 mL, 3.6 equiv.) was added. Then, a solution of methanesulfonyl chloride (601 mg, 5.250 mmol, 0.406 mL, 0.96 equiv.) in dichloromethane (1 mL) was added dropwise to the reaction mixture. The reaction was monitored by TLC (100% ethyl acetate, starting material Rf = 0.52, product Rf = 0.84). Once the reaction was completed, water was poured into the reaction flask, the two phases were separated, and the organic layer was washed with water and a saturated solution of sodium bicarbonate. All the organic phases were combined and dried in vacuo. The product was purified on Isolera Biotage with a ramp 0-50% of ethyl acetate in heptane. Yield: 1226 mg (3.41 1 mmol, 65%); H NMR (CDCl3, 500 MHz): δ 6.77 (t, J = 8 Hz, 1H), 4.33 – 4.25 (m, 2H), 3.35 (s, br, 1H), 3.13 (s, br, 1H), 3.08 – 2.99 (m, 2H), 2.97 (s, br, 1H), 2.73 (s, 3H), 2.69 (d, J = 10 Hz, 1H), 2.62 (d, J = 9 Hz, 1H), 2.54 – 2.43 (m, 2H), 2.16 – 2.09 (m, 1H), 1.60 (d, J = 11 Hz, 1H), 13 1 0.85 – 0.74 (m, 6H); C{ H} NMR (CDCl3, 126 MHz): δ 148.7 (dd, J = 245, 14 Hz), 147.6 (dd, J = 242, 14 Hz), 142.3, 141.9, 118.9 (d, J = 14 Hz), 109.4 (d, J = 18 Hz), 68.9, 53.2, 51.1, 50.7, 19 44.3, 41.3, 39.1, 36.7 (d, J = 3 Hz), 26.7, 18.4, 17.5; F NMR (CDCl3, 376 MHz): δ -141.23 (dd, + J = 19, 10 Hz), -147.21 (dd, J = 19, 7 Hz); HR-MS: C17H24F2NO3S, [M+H] m/z (calc.): 360.1439, m/z (obs.): 360.1431.

Synthesis of C6HF2(C5H8NiPr)(CH=CH2) (2-4): To a stirring solution of 2-3 (35 mg, 0.097 mmol, 1 equiv.) in 1 mL of THF, potassium tert-butoxide (37 mg, 0.33 mmol, 3.4 equiv.) was added at room temperature. The reaction mixture was stirred for 1 h, after which monitoring by TLC (eluent 1 : 1 ethyl acetate: hexane) showed complete consumption of the starting material (Rf = 0.67) and the presence of a highly UV active and permanganate spot with Rf = 0.85. To the reaction was added a 1 N aqueous solution of HCl and the water phase was washed with ethyl acetate. The water phase was then 43

basified to pH 10 and back extracted with dichloromethane. The dichloromethane phase was then washed with brine and dried in vacuo, yielding the pure product as a yellow oil. Yield: 17 mg 1 (0.065 mmol, 67%); H NMR (CDCl3, 500 MHz): δ 6.69 (dd, J = 9, 7 Hz, 1H), 6.56 (dd, J = 18, 12 Hz, 1H), 5.75 (d, J = 18 Hz, 1H), 5.38 (dt, J = 12, 2 Hz, 1H), 3.15 (d, J = 4 Hz, 1H), 2.89 (t, J = 4 Hz, 1H), 2.66 – 2.62 (m, 1H), 2.59 – 2.55 (m, 1H), 2.46 – 2.40 (m, 3H), 2.11 – 2.05 (m, 1H), 13 1 1.53 (d, J = 10 Hz, 1H), 0.75 (d, J = 7 Hz, 6H); C{ H} NMR (CDCl3, 101 MHz): δ 149.3 (dd, J = 244, 14 Hz), 147.8 (dd, J = 247, 14 Hz), 141.6, 140.3, 128.5 (d, J = 10 Hz), 120.4, 109.7, 51.3, 19 50.5, 43.9, 41.1, 39.3, 29.7, 18.2, 18.1; F NMR (CDCl3, 376 MHz): δ 141.84 (s, br), -145.85 (s, br). GC-MS (EI, 70 eV) m/z: 263 (M+), 248 (100%), 204, 177, 164, 151, 115, 86, 56; HR-MS: + C16H19F2N, [M+H] m/z (calc.): 264.1558, m/z (obs.): 264.1548.

Synthesis of C6H2F2(C5H8NPh) (2-6): To a dry vial containing bromobenzene (173 mg, 1.10 mmol, 1.1 equiv.) and sodium tert-butoxide (99.1 mg, 1.00 mmol, 1 equiv.), a solution of (1R,5S)-7,8-difluoro-2,3,4,5-tetrahydro-1H-1,5-methanobenzo[d]azepine (201 mg, 1.00 mmol, 1 equiv.) in 6 mL toluene was added. The resulting solution was degassed with 3 vacuum-nitrogen cycles and then bis(dibenzylideneacetone)palladium(0) (5.75 mg, 0.0100 mmol, 0.01 equiv.) and 1,2,3,4,5- pentaphenyl-1'-(di-tert-butylphosphino)-ferrocene (14.2 mg, 0.0200 mmol, 0.02 equiv.) were added to the solution. The reaction mixture was heated to 100 °C for 24 hours, then it was cooled down and the crude mixture was filtered through a Celite pad to remove the black precipitate. The filtrate was stripped down and the product was purified as an off-white solid on Isolera Biotage with a ramp 0-20% of ethyl acetate in heptane. Yield: 260 mg (0.958 mmol, 96%); 1H NMR

(CDCl3, 500 MHz): δ 7.11 (dd, J = 9, 7 Hz, 2H), 6.94 (t, J = 9 Hz, 2H), 6.66 – 6.60 (m, 3H), 3.53 (ddd, J = 11, 3, 2 Hz, 2H), 3.24 (dt, J = 5.0, 3 Hz, 2H), 3.08 (dd, J = 11, 2 Hz, 2H), 2.33 (dtt, J = 13 1 11, 5, 2 Hz, 1H), 1.84 (d, J = 12 Hz, 1H); C{ H} NMR (CDCl3, 126 MHz): δ 150.6, 149.5 (dd, J = 247, 15 Hz), 141.7 (t, J = 4 Hz), 129.1, 117.5, 112.5, 111.3 (dd, J = 14, 6 Hz), 51.5, 41.7, 40.3; 19 + + F NMR (CDCl3, 376 MHz): δ -140.45 (t, J = 8 Hz); LC-MS (ESI ): 272 [M+H] ; GC-MS (EI, 70 eV) m/z: 271 (M+), 170, 151, 120 (100%), 91, 86.

Synthesis of C6HIF2(C5H8NPh) (2-7): Compound 2-6 (485 mg, 1.79 mmol, 1 equiv.) was stirred in 10 mL of THF in a vial under nitrogen at -78 °C. To this light amber solution, n-BuLi (172 mg, 2.68 mmol, 0.993 mL, 2.7 M, 1.5 equiv.) was added dropwise over 5 minutes. The solution was stirred for 1.5 hours at -78 °C, then iodine (681 mg, 2.68 mmol, 1.5 equiv.) was added in. The reaction was stirred for 3 hours at -78 °C and then removed from the bath and allowed to warm to approximately 0 °C. The mixture was quenched with a saturated aqueous solution of sodium bicarbonate and allowed to warm until reaching ambient temperature. The reaction was then poured with ethyl acetate and saturated aqueous sodium carbonate solution into a separating funnel. The two layers were separated, and the aqueous layer was back extracted (2 x 20 mL) with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulfate, filtered, and dried under vacuum to yield a white solid. Yield: 697 mg (1.75 mmol, 98%); TLC Rf = 0.30 with eluent 1 mixture 1 : 9 toluene : heptane; H NMR (CDCl3, 500 MHz): δ 7.43 (t, J = 8 Hz, 2H), 7.14 (dd, J = 8, 7 Hz, 1H), 6.98 (t, J = 7 Hz, 1H), 6.94 (d, J = 8 Hz, 2H), 3.92 (d, J = 11 Hz, 1H), 3.76 (d, J = 11 Hz, 1H), 3.59 (d, J = 8 Hz, 2H), 3.30 – 3.20 (m, 2H), 2.64 – 2.56 (m, 1H), 2.07 (d, J = 11 Hz, 13 1 1H); C{ H} NMR (CDCl3, 126 MHz): δ 150.6, 149.4 (dd, J = 250, 15 Hz), 148.0 (dd, J = 243, 15 Hz), 146.0 (d, J = 3 Hz), 141.8 (d, J = 3 Hz), 129.3, 118.0, 112.9, 111.6 (d, J = 19 Hz), 79.8 (d, 19 J = 23 Hz), 51.5, 49.5, 44.5, 42.4, 41.0; F NMR (CDCl3, 376 MHz): δ -120.41 (dd, J = 22, 7 Hz), -135.30 (dd, J = 22, 10 Hz); GC-MS (EI, 70 eV) m/z: 397 (M+), 292, 276, 268, 164, 120 (100%), 104, 91, 77, 65, 51; LC-MS (ESI+): 398 [M+H]+.

Synthesis of C6HF2(C5H8NPh)(CH=CH2) (2-8): To a vial containing 2-7 (768 mg, 1.93 mmol, 1 equiv.), sodium carbonate (1440 mg, 11.6 mmol, 6 equiv.) and tetrakis(triphenylphosphine) palladium(0) (55.3 mg, 0.0478 mmol, 0.025 equiv.) were added and the vial was flushed with nitrogen for 15 minutes. Then, 20 mL of degassed DMF and 4 mL of degassed water were added to the vial and the reaction mixture was degassed with 3 vacuum-nitrogen flow cycles. At the end, 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxoborolane (1070 mg, 6.77 mmol, 1.29 mL, 3.5 equiv.) was added and the reaction mixture was heated to 80 °C for 1 hour. Then, upon cooling, it was filtered through a pad of Celite, and washed with diethyl ether. The biphasic system was poured into a separating funnel and the water phase was extracted with ethyl acetate 3 times. The combined organic layers

were washed with water and brine, dried over sodium sulfate, filtered, and the volatiles were evaporated. The product was purified as a yellowish solid on Isolera Biotage with a ramp 0-15% of ethyl acetate in heptane. Yield: 494 mg (1.66 mmol, 86%, 92% product purity); 1H NMR

(CDCl3, 500 MHz): δ 7.12 – 7.04 (m, 1H), 6.81 (ddd, J = 9, 7, 3 Hz, 1H), 6.65 – 6.56 (m, 5H), 5.83 (dd, J = 18, 4 Hz, 1H), 5.46 – 5.52 (m, 1H), 3.53 (dd, J = 11, 2 Hz, 1H), 3.50 (dd, J = 13, 2 Hz, 1H), 3.44 (s, br, 1H), 3.18 (s, br, 1H), 3.02 (dd, J = 11, 2 Hz, 2H), 2.23 – 2.29 (m, 1H), 1.79 13 1 (d, J = 11Hz, 1H); C{ H} NMR (CDCl3, 100 MHz): δ 150.5, 149.8 (dd, J = 246, 14 Hz), 148.3 (dd, J = 249, 14 Hz), 141.0 (m), 139.6 (s, br), 129.1, 128.0 (d, J = 3 Hz), 122.0 (d, J = 10 Hz), 121.2 (d, J = 10 Hz), 117.6, 112.5, 110.0 (d, J = 19 Hz), 51.4, 50.3, 41.2, 40.4, 38.6; 19F NMR + (CDCl3, 376 MHz): δ -140.09 (dd, J = 18, 9 Hz), -144.20 (dd, J = 18, 7 Hz); LC-MS (ESI ): 298 + + [M+H] ; GC-MS (EI, 70 eV) m/z: 297 (M ), 177, 151, 120 (100%), 91, 77; HR-MS: C19H17F2N, [M+H]+: m/z (calc.): 298.1402, m/z (obs.): 298.139.

Synthesis of C6HF2(C5H8NPh)(CH2CH2BBN) (2-11): Compound 2-8 (25 mg, 0.0849 mmol, 1 equiv.) and 9-BBN dimer (10.5 mg, 0.0425 mmol, 0.5 equiv.) were dissolved in 4 mL DCM. The colourless solution was stirred overnight. The solution was then concentrated, layered with pentane, and stored in the freezer. Colourless crystals were formed, and the excess solvent was pipetted out. The solids were washed with cold pentane and dried in vacuo to a white powder. Single crystals suitable for X-ray crystallography were formed by slow diffusion of pentane into a cold saturated DCM solution of 2-11. Yield: 24.4 mg (0.058 1 3 mmol, 69 %); H NMR (CDCl3, 400 MHz): δ 7.21 – 7.15 (m, 2H, m-C6H5), 6.85 (dd, JHF = 9 Hz, 3 3 4 JHF = 7 Hz, 1H, FCCH), 6.71 – 6.65 (m, 3H, m-C6H5, p-C6H5), 3.61 (dt, JHH = 10 Hz, JHH = 5 2 Hz, 2H, NCH2eq), 3.44 (s, br, 1H, NCH2CH), 3.29 (s, br, 1H, NCH2CH), 3.14 (dt, JHH = 11 Hz, 4 JHH = 3 Hz, 2H, NCH2ax), 2.95 – 2.75 (m, 2H, BCH2), 2.42 – 2.32 (m, 1H, NCH2CHCHax), 1.90 2 (d, JHH = 10 Hz, NCH2CHCHeq), 1.94 – 1.83 (m, 7H, 9-BBN), 1.85 – 1.75 (m, 2H, BCH2CH2), 13 1 1.75 – 1.64 (m, 5H, 9-BBN), 1.28 – 1.23 (m, 2H, 9-BBN); C{ H} NMR (CDCl3, 125 MHz): δ 1 150.7 (BCH2CH2C), 140.0 (d, JCF = 153 Hz, FC), 129.2 (m-C6H5), 117.6 (p-C6H5), 112.6 (m- 2 C6H5), 108.5 (d, JCF = 19 Hz, FCCH), 51.7 (NCH2), 51.0 (NCH2), 41.6 (NCH2CHCH2), 40.7

(NCH2CH), 38.5 (NCH2CH), 33.4 (9-BBN), 31.4 (s, br, BCH2CH2), 29.0 (9-BBN), 23.4 (9-BBN), 11 21.7 (BCH2). Ipso carbons in phenyl rings were not observed.; B NMR (CDCl3, 128 MHz): δ

19 3 3 88.0 (s, br); F NMR (CDCl3, 376 MHz): -140.6 (dd, JFF = 19 Hz, JHF = 10 Hz, FCCF), -146.9 3 3 (dd, JFF = 19 Hz, JHF = 7 Hz, FCCH).

Synthesis of C6HF2(C5H8NPh)(CH2CH2B(C6F5)2) (2-12): Compound

2-9 (10 mg, 0.0336 mmol, 1 equiv.) and HB(C6F5)2 (11.6 mg, 0.0336 mmol, 1 equiv.) were added to 1 mL benzene. A clear yellow solution was formed immediately and dried in vacuo to produce an orangish-yellow oil. The oil is freshly generated and used immediately 1 in subsequent experiments. Yield: 18 mg (0.028 mmol, 83%); H NMR (C6D6, 400 MHz): δ 7.20 3 3 – 7.16 (m, 2H, m-C6H5), 6.77 (t, JHH = 7 Hz, 1H, p-C6H5), 6.65 (d, JHH = 8 Hz, 2H, o-C6H5), 6.55 3 2 2 (t, JHF = 8 Hz, 1H, FCCH), 3.46 (d, JHH = 11 Hz, 1H, NCHeq), 3.25 (d, JHH = 11 Hz, 1H, NCHax), 3 2 3.01 (d, JHH = 4 Hz, 1H, NCH2CH), 2.82 (d, JHH = 11 Hz, 1H, NCHax), 2.76 – 2.71 (m, 1H, 3 3 NCHeq), 2.69 (d, JHH = 10 Hz, 2H, BCH2CH2), 2.64 (d, JHH = 6 Hz, 1H, NCH2CH), 2.29 – 2.08 2 3 2 (m, 2H, BCH2), 2.00 (dt, JHH = 11 Hz, JHH = 5 Hz, 1H, NCH2CHCHeq), 1.43 (d, JHH = 11 Hz, 13 1 1 1H, NCH2CHCHax); C{ H} NMR (C6D6, 125 MHz): δ 151.1 (CCF), 150.0 (dd, JCF = 246 Hz, 2 1 2 1 JCF = 14 Hz, FCCH), 149.7 (dd, JCF = 240 Hz, JCF = 13 Hz, FCCFCH), 147.5 (d, JCF = 249 Hz, 1 1 o-C6F5), 143.8 (d, JCF = 262 Hz, p-C6F5), 141.6 (CHCC), 139.6 (CHC), 137.7 (d, JCF = 259 Hz, 2 m-C6F5), 129.3 (m-C6H5), 118.4 (p-C6H5), 113.0 (o-C6H5), 109.6 (d, JCF = 18 Hz, FCCH), 51.7

(NCH2), 51.0 (NCH2), 41.7 (NCH2CHCH2), 40.7 (NCH2CH), 38.6 (NCH2CH), 31.6 (BCH2), 22.1 11 (BCH2CH2). Ipso carbons in C6H5 and C6F5 rings were not observed.; B NMR (C6D6, 128 MHz): 19 3 3 δ 72.5 (s, br); F NMR (C6D6, 376 MHz): δ -130.1 (d, JFF = 18 Hz, o-C6F5), -139.9 (dd, JFF = 3 3 3 16 Hz, JHF = 9 Hz, FCCH), -145.7 (d, JFF = 16 Hz, FCCFCH), -146.4 (t, JFF = 21 Hz, p-C6F5), 3 3 + -160.7 (td, JFF = 14 Hz, JFF = 7 Hz, m-C6F5); MS (DART) m/z: 644.1 [M+H] ; HR-MS (ESI): + C31H19BF12N [M+H] m/z (calc.): 644.1411, m/z (obs.): 644.1409.

Synthesis of C6HF2(C5H8NPh)(CH2CH2B(C6F5)2)(PPh3) (2-14):

Compound 2-11 (30 mg, 0.1 mmol, 1 equiv.) and HB(C6F5)2 (35.8 mg, 0.1 mmol, 1 equiv.) were dissolved in 1 mL benzene. The clear yellow

solution formed was stirred for 5 minutes and was added to PPh3 (26.2 mg, 0.1 mmol, 1 equiv.). The solution was then dried in vacuo, re-dissolved in DCM and stored in the freezer with slow diffusion of pentane. Colourless crystals were formed, and the excess solvent was pipetted out. The crystals were washed with pentane and 47

1 dried. Yield: 31 mg (0.034 mmol, 34%); H NMR (CDCl3, 400 MHz): δ 7.56 – 7.47 (m, 3H), 7.48 3 4 3 – 7.25 (m, 12H), 7.19 – 7.12 (m, 2H, m-C6H5), 6.80 (dd, JHF = 9, JHF = 7 Hz, 1H), 6.71 (t, JHH 3 2 = 7 Hz, 1H, p-C6H5), 6.63 (d, JHH = 8 Hz, 2H, o-C6H5), 3.61 (d, JHH = 10 Hz, 1H, NCHax), 3.42 2 3 (d, JHH = 11 Hz, 1H, NCHax), 3.26 (d, JHH = 5 Hz, 1H, NCH2CH), 3.17 – 3.07 (m, 2H), 3.00 (dd, 2 3 2 3 JHH = 11 Hz, JHH = 3 Hz, 1H, NCHeq), 2.50 (td, JHH = 13 Hz, JHH = 4 Hz, 1H, CH2Ph), 2.38 (td, 2 3 2 3 JHH = 13 Hz, JHH = 4 Hz, 1H, CH2Ph), 2.30 (dt, JHH = 10 Hz, JHH = 5 Hz, 1H, NCH2CHCHeq), 2 13 1 1.85 (d, JHH = 11 Hz, 1H, NCH2CHCHax), 1.70 – 1.50 (m, 2H, CH2CH2Ph); C{ H} NMR 2 1 2 (CDCl3, 125 MHz): δ 150.8 (d, JCF = 14 Hz, CCF), 148.4 (dd, JCF = 249 Hz, JCF = 14 Hz, CF), 1 2 2 140.6 (CFCC), 140.0 (CFCHC), 137.3 (dd, JCF = 254 Hz, JCF = 20 Hz, FCCF), 134.3 (d, JCP = 3 10 Hz, PPh3), 131.5 (PPh3), 129.2 (m-C6H5), 128.7 (d, JCP = 10 Hz, PPh3), 117.4 (p-C6H5), 112.4 2 (o-C6H5), 108.3 (d, JCF = 19 Hz, CFCH), 51.7 (NCH2), 50.7 (NCH2), 41.6 (NCH2CHC), 40.7

(NCH2CH), 38.3 (NCH2CH), 25.3 (s, br, BCH2), 24.4 (BCH2CH2). C-F carbons in C6F5 and ipso 11 19 carbons in C6H5 ring were not observed.; B NMR (CDCl3, 128 MHz): δ -6.2 (s, br); F NMR 3 3 3 (CDCl3, 376 MHz): δ -127.1 (d, JFF = 24 Hz, o-C6F5), -141.0 (dd, JFF = 19 Hz, JHF = 10 Hz, 3 3 3 FCCH), -146.93 (d, JFF = 17 Hz, FCCFCH) -157.2 (t, JFF = 21 Hz, p-C6F5), -163.5 (td, JFF = 3 31 23 Hz, JFF = 8 Hz, m-C6F5); P NMR (CDCl3, 162 MHz): δ 10.1 (s, br); MS (DART) m/z: 263.1 + + + [PPh3+H] , 644.1 [M-PPh3+H] ; HR-MS (ESI): C18H16P [PPh3+H] m/z (calc.): 263.0990, m/z + (obs.): 263.0992, C31H18BF12N [M-PPh3+H] m/z (calc.): 644.1411, m/z (obs.): 644.1414; Anal.

Calc. for C49H33BF12NP: C 64.99%, H 3.67%, N 1.55%. Found C 62.82%, H 4.15%, N 1.47%.

2.4.3 Procedures of Gaseous Experiments

General procedure for HD scrambling experiments: In the glovebox, the necessary reagents were added to 1 mL of solvent. The reaction mixture was then transferred into an oven-dried Teflon screw cap J. Young NMR tube. The reaction tube was degassed by 3 cycles of freeze-pump-thaw and then filled with HD (4 atm) at -196 °C. The reaction was then heated to the desired temperature and monitored by 1H NMR spectroscopy.

General procedure for hydrogenation experiments: In the glovebox, the necessary reagents were added to 1 mL of solvent. The reaction mixture was then transferred into an oven-dried Teflon screw cap J. Young NMR tube. The reaction tube was degassed by 3 cycles of freeze-pump-thaw

and then filled with H2 (4 atm) at -196 °C. The reaction was then heated to the desired temperature and monitored by 1H NMR spectroscopy.

Procedure for carbon dioxide gas experiment with 2-11: In the glovebox, 4.2 mg of 2-11 was

added to 1 mL of CDCl3. The reaction mixture was then transferred into an oven-dried Teflon screw cap J. Young NMR tube. The reaction tube was degassed by 3 cycles of freeze-pump-thaw 13 and then filled with CO2 (4 atm). The reaction was then cooled to the desired temperature and monitored by 1H NMR spectroscopy.

2.4.4 Computational Details

Electronic structure calculations, including geometry optimizations and frequency calculations, were performed using Gaussian 16.94 X-ray coordinates were used as the starting geometries. Frequency calculations on the optimized structures showed the absence of imaginary frequencies confirming that minima on the potential energy hypersurfaces were located. Geometry optimizations and frequency calculations were performed using the BP8695-96 functional and the def2-TZVP basis set.94-95, 97-98 Energies for fluoride ion affinity (FIA) were calculated using the MP282-84 method and the def2-TZVPP basis set, as previously described using the experimental FIA of carbonyl difluoride.85 Geometry optimizations, frequency calculations and energies for the global electrophilicity index (GEI)80-81 was calculated using the B3LYP86-89 functional and the def2-TZVP basis set,86-87 as previously described. Natural bond orbital and natural population analyses were performed on optimized structures using the M062X functional 90 and def2-TZVP basis set using NBO 6.0.99 X-ray coordinates were used as the starting geometries. This work was made possible by the facilities of the Shared Hierarchical Academic Research Computing Network (SHARCNET:www.sharcnet.ca) and Compute Canada.

2.4.5 X-ray Crystallography

2.4.5.1 X-Ray Data Collection and Reduction

Crystals were coated in Paratone-N oil in an N2-filled glovebox, mounted on a MiTegen

all crystals using an Oxford cryo-stream cooler. Data were collected using Bruker APEX-2 software and processed using SHELX and an absorption correction applied using multi-scan within the APEX-2 program. All structures were solved and refined by direct methods within the SHELXTL package.100-101

2.4.5.2 Crystallographic Data Tables

Table 2.2. Selected crystallographic data for 2-10 and 2-11 enantiomers.

2-10 2-11 enantiomers

Formula C38.5 H33.5 B F12 N O C27 H32 B F2 N

Crystal System Monoclinic Monoclinic

Space Group C2/c P1211 a/ Å 31.615(3) 10.997(3)

b/ Å 11.1961(9) 7.9585(2) c/ Å 22.1924(18) 25.176(7) α/ ° 90 90

β/ ° 118.058(4) 90.135(14) γ/ ° 90 90 V/ Å3 6932.1(10) 2203.3 (9)

Z 8 4

T/ K 150(2) 150(2) -3 Dc/ g.cm 1.466 1.264 Total reflections 54014 9159

Unique reflections 7366 7962 Rint 0.0624 0.0445 2 2 R1[F >2 σ(F )] 0.0479 0.0856 wR2 (all data) 0.1228 0.2293

GoF 1.017 0.9363

Table 2.3. Selected crystallographic data for 2-11 and 2-14.

2-11 2-14

Formula C27 H32 B F2 N C49.88 H34.76 B Cl1.75 F12 N P

Crystal System Orthorhombic Triclinic

Space Group Pca21 P-1 a/ Å 25.1437(8) 10.7711(19) b/ Å 10.9915(4) 13.445(3) c/ Å 7.9724(3) 16.358(3) α/ ° 90 74.367(6) β/ ° 90 82.069(7) γ/ ° 90 81.633(6) V/ Å3 2203.31(13) 2244.9(7) Z 4 2 T/ K 150(2) 150(2)

-3 Dc/ g.cm 1.264 1.450 Total reflections 46674 23559 Unique reflections 3881 7896

Rint 0.0464 0.0667 2 2 R1[F >2 σ(F )] 0.0347 0.0639 wR2 (all data) 0.096 0.1786 GoF 1.036 1.028

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Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Keith, T.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Millam, J. M.; Klene, M.; Adamo, C.; Cammi, R.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Farkas, O.; Foresman, J. B.; Fox, D. J. Gaussian 09, Revision E.01. , Gaussian Inc., : Wallingford CT, 2016.

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Chapter 3 Chiral Carbene-Borane Adducts as Precursors for Borenium Cations in Asymmetric Hydrogenation Catalysis 3.1 Introduction

3.1.1 Boron Cations

The presence of electron-withdrawing groups, such as perfluoroaryl groups, on neutral boron centres, are important for hydrogen activation in FLP chemistry as they increase the boron’s Lewis acidity through decreasing its electron density.1 Manipulation of the number and type of electron- withdrawing groups on boron has shown to be effective in catalysis, with improvements including the air- and moisture-stable catalysts,2-3 reduction of electron-poor substrates,4-6 and auto-tandem catalysis.7

Alternatively, the Lewis acidity can be increased by the presence of a positive charge on the Lewis acidic site. In the case of boron, positively charged species can be classified into three classes: 1) boronium ions – tetrahedral, four-coordinated boron cations with two σ-bound substituents and two neutral donor ligands; 2) borenium ions – three-coordinated species with two σ-bound substituents and one neutral donor ligand; and 3) borinium ions – two-coordinated cations with two σ-bound substituents (Figure 3.1, top).8-10 Boronium ions are generally the most stable among the three classes of borocations, with their stability provided by the filled coordination sphere and donation of electron density by ligands. The first boron cation was reported in 1955 by Parry and co-workers through the reaction of ammonia with diborane and was originally misconstrued as a “diammoniate of diborane”.11 Subsequent experimental evidence later suggested the product was a tetra-coordinated dihydrodiamino-boronium cation (Figure 3.1, bottom left).12-16 In comparison, borinium ions are significantly more reactive and condensed-phase analysis of these species are often interfered by interactions with the counteranion or solvent molecules. Stabilization of these borinium species can be provided by steric protection or π donation of lone pairs from substituents to relieve electron deficiency on boron. In 1982, Nöth and co-workers reported the first borinium cation, a 2,2,6,6-tetramethylpiperidino-dimethylamido-borinium, which was characterized crystallographically (Figure 3.1, bottom right).17

Figure 3.1. Classes of boron cations (top) and the first reported boronium ion (bottom left), crystallized borenium ion (bottom middle) and crystallized borinium ion (bottom right).

The first borenium cation that was characterized crystallographically was reported by Narula and Nöth in 1984 (Figure 3.1, bottom middle)18 and an increasing number of borenium cations have been since synthesized and characterized.8 These cations are stabilized by a variety of donor ligands, such as amines8, 10 and phosphines,19 which exhibit a strong influence of the stability and Lewis acidity of the borenium cation.9 Stronger donors can result in increased bond strength of the dative bond between the donor and the boron centre and subsequently stabilize the cation, but this can decrease the Lewis acidity of the boron centre to this end. This was observed in Stephan and co-workers’ report on the [tBu3PBcat][HB(C6F5)3] cation, which is synthesized by the coordination of tBu3P to catecholborane and subsequent hydride abstraction by B(C6F5)3, a synthetic route typical of those reported for borenium cations. While this cation can be viewed as a borenium ion, DFT data suggested the species is more accurately described as a phosphonium cation rather that a borenium cation with significant diminished positive charge on the boron centre (Scheme 3.1, top).19 In contrast, if the donor is a weak donor, bond strength of the donor-boron dative bond is diminished and may induce dissociation of the donor and borinium motif. Crudden and co-workers have observed this phenomenon and utilized the dissociation towards imine hydroboration catalysts (Scheme 3.1, bottom).20

Scheme 3.1. Resonance forms of phosphine-stabilized borenium cation (top) and dissociation of borenium cation for imine hydroboration catalysis (bottom).

In comparison to their di-coordinated and tetra-coordinated counterparts, borenium cations possess a relative balance of stability with vacant p orbitals for electrophilic coordination to effect substrate activation and transformations.21 Hence, they are particularly attractive towards synthetic and catalytic applications. For example, recent literature has reported the use of these cations for FLP ring opening of tetrahydrofuran,22 haloboration of internal alkynes,23 1,2-carboboration,24 and hydrosilylation catalysis.25-26

3.1.2 Carbene-stabilized Borenium Cations in FLP Hydrogenations

Carbon-based donors, such as carbenes, were also reported and were particularly favoured for catalysis – they are strong donors that can stabilize the donor-boron bond but avoids the issue of diminishing Lewis acidity through lone pair donation into the vacant orbital of boron.9, 27-29 The application of carbene-stabilized borenium cations in FLP hydrogenation catalysis is particularly 61

relevant to this thesis. In 2012, Stephan and co-workers reported the use of NHC-stabilized borenium cations to effect imine and enamine hydrogenation30 while in 2015, Crudden and co- workers reported the use of triazolium-stabilized borenium cations to catalyze hydrogenation of aldimines, imines and N-heterocycles, and were found to be more active than the NHC-stabilized analogues.31 In the case of imine reductions, the borenium cation is presented as the Lewis acid and the imine substrate as the Lewis base in FLP-type hydrogen activation. This generates the corresponding borane and protonated iminium salt. Subsequent hydride delivery to the iminium salt affords the amine product and regenerates the borenium cation (Scheme 3.2). Mechanistic studies showed that hydride delivery to the iminium salt is immediate while the activation of hydrogen proceeds slowly, suggesting hydrogen activation is the rate-determining step.30 Further investigations reported by Stephan and co-workers revealed the electronic and steric impact on the borenium cation, in which decreased sterics and increased electron-withdrawing capability of the NHC ligand enhanced catalyst activity. They were able to achieve full reduction of N-benzylidene- tert-butylamine with [(ClCNMe)2CBC8H14][B(C6F5)4] at 0.25 mol% catalyst loading in 30 min at ambient temperature with 102 atm H2. To date, it is the highest TOF reported for metal-free imine hydrogenation catalysis.32

Scheme 3.2. Proposed mechanism for borenium-catalyzed hydrogenation of imines.

The synthesis of perfluoroarylboranes used in FLP chemistry can be challenging. Their syntheses often require the use of toxic mercury and tin reagents, moisture sensitive Grignard reagents and 62

explosive pentafluorophenyllithium, and subsequently increasing the production cost of the catalysts.33 In addition, small modifications to these boranes can be challenging and as such can prevent facile methodology to generate a family of catalysts for catalytic studies.2 In comparison, carbene-borenium ions are synthetically accessible which makes them suitable for catalytic screening. Typically, a carbene-borane adduct is formed by the addition of an isolated carbene to a borane or haloborane. Alternatively, a one-pot reaction can be carried out by in situ deprotonation of an imidazolium salt with the given borane. The resulting adducts are generally stable and easy to purify and handle. The free borenium salt can then be produced through subsequent hydride or halide abstraction with a strong cationic Lewis acid bearing a non-coordinating anion (Scheme 3.3).28 Given the straight-forward synthetic approach, we envision incorporating chirality through the carbene or the borane independently and investigating their potential in asymmetric hydrogenation catalysis.

Scheme 3.3. General synthetic route for NHC-borenium salts.

3.2 Results and Discussion

3.2.1 Synthesis of Chiral Carbene-Boranes with Chiral Carbenes

Taking inspiration from Klankermeyer’s work on enantioselective hydrogenation using camphor- templated borane catalysts,34-36 a camphor-derived borenium cation was first targeted. In an acid- mediated reaction with sodium azide, the enantiomerically pure (1R,3S)-camphoric acid was converted to the diamine 3-1 in 58% yield. The imidazolium salt 3-2 was then produced in 79% yield from a ring closing reaction of 3-1, triethyl orthoformate, and ammonium tetrafluoroborate. Various R-groups were then added by nucleophilic substitution reactions with iodoalkanes to give salts of carbene precursors, with yields of 60-95% (Scheme 3.4, top).

Scheme 3.4. Synthesis of enantiomerically pure camphoric acid-derived carbene precursors (top) and their respective carbene-borane adducts (bottom).

The salt 3-3 was deprotonated with KHMDS and reacted with Piers’ borane or 9-BBN. This resulted in the formation of 3-6 and 3-7 in 60% and 81% yield respectively (Scheme 3.4, bottom). 11 1 19 The B NMR spectrum of 3-6 showed a doublet with JBH = 91 Hz at δ -23.4 ppm and the F 3 NMR spectrum displayed JFF ~ 20 Hz at δ -165.5, -161.63, -161.57, -134.7 and -133.3 pm for the diastereotopic pentafluorophenyl groups. Slow evaporation of the solvent afforded crystals suitable for X-ray crystallography and confirmed the formulation of [(1R,5S)-5,8,8-Me3-2,4-

(NMe)2C6H6]BH(C6F5)2 3-6. Compound 3-6 was shown to have a pseudo-tetrahedral geometry at the boron centre and a B-CNHC bond distance of 1.654(2) Å, which is similar to observations made in previous reports (Figure 3.1, top).30, 32 Compound 3-7 also showed a doublet in the 11B NMR 1 spectrum with a JBH = 83 Hz at δ -14.2 ppm. Similarly, salts 3-4 and 3-5 were reacted in a similar fashion with 9-BBN to form 3-8 and 3-9 in 67% and 63% yield respectively. The 11B NMR spectra 1 for both boranes exhibit a doublet with JBH = 84 Hz at δ -14.3 ppm and -12.9 ppm respectively. Crystals suitable for X-ray crystallography were isolated by layering a DCM solution of 3-8 with 64

pentane and confirmed the formulation of [(1R,5S)-5,8,8-Me3-2,4-(NEt)2C6H6][HBC8H14] 3-8

(Figure 3.3, bottom). The B-CNHC bond distance was found to be 1.693(5) Å, which is longer than the typical single B-CNHC bond distance observed in other imidazole-derived NHC-borane adducts (1.63 – 1.65 Å).30, 32 We attributed the discrepancy to the steric repulsion between the 9-BBN and the ethyl groups.

Figure 3.2. POV-ray depiction of 3-6. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; F: pink; H: white.

Figure 3.3. POV-ray depiction of 3-8. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white.

A second group of chiral carbene precursors was selected for the synthesis of borane adducts. C2- symmetric fused oxazole rings with iPr and tBu groups were targeted and synthesized by modified literature procedures.37-38 Oxamide and the enantiopure amino alcohols were heated neat at 170 °C for 4 h and the bisamides 3-10 and 3-11 were obtained in 70% and 71% yield respectively. The corresponding alkyl chlorides 3-12 and 3-13 were obtained by chlorination of the hydroxy amides with thionyl chloride in 96% and 47% yield respectively. Subsequently, base-mediated intramolecular cyclizations resulted in the 2,2´-bisoxazolines 3-14 and 3-15 in 88% and 57% yield respectively. The diimines were then transformed to the imidazolium salts by reaction with chloromethyl pivalate and silver triflate, producing 3-16 and 3-17 in 34% and 57% yield respectively (Scheme 3.5).

Scheme 3.5. Synthesis of fused oxazolium triflate salts as carbene precursors.

Scheme 3.6. Synthesis of bisoxazolium carbene-borane adducts.

The triflate salts 3-16 and 3-17 were reacted with 9-BBN, BH3 and Cy2BCl in a similar in situ deprotonation methodology (Scheme 3.6). Carbene-9-BBN adducts 3-18 and 3-21 were formed in 58% and 80% yield respectively by the deprotonation of the triflate salts with KHMDS and 1 subsequent addition of 9-BBN. Doublets with JBH = 83 Hz and 86 Hz were found at δ -16.9 and -16.4 ppm in the 11B NMR spectrum for 3-18 and 3-21. Similarly, 3-19 was formed as a light- 1 11 yellow powder in 62% yield and a quartet with JBH = 88 Hz was found at δ -35.6 ppm in the B NMR spectrum. Compound 3-20 was formed in 35% yield by deprotonation of 3-16 with n-BuLi 11 and subsequent addition of ClBCy2, and a broad singlet at δ 3.2 ppm was found in the B NMR spectrum. Crystals suited for X-ray crystallography were obtained for 3-18 (Figure 3.4) and 3-21

(Figure 3.7) by slow evaporation of saturated pentane solutions and for 3-19 (Figure 3.5) and 3-20

(Figure 3.6) by slow evaporation of saturated toluene solutions. The B-CNHC bond distances were found to be 1.610(3) Å, 1.593(2) Å, 1.647(2) Å, and 1.641(2) Å for 3-18, 3-19, 3-20 and 3-21 respectively, and the data reflect the substituents’ steric impact at the boron centre. The longest B-

CNHC bond distance was found for the bulkiest carbene-borane 3-20 while the shortest distance was found for the smallest borane 3-19. The slight difference of B-CNHC bond distance between 3- 18 and 3-21 also reflects the steric conflict between the 9-BBN fragment and the tert-butyl substituents. With the exception of 3-20, we noted that these boranes had been previously used as reagents in the stoichiometric and enantioselective reduction of ketones.39

Figure 3.4. POV-ray depiction of 3-18. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; O: red; H: white.

Figure 3.5. POV-ray depiction of 3-19. Hydrogen atoms were omitted for clarity except for the B-H bonds. B: yellow-green; C: black; N: blue; O: red; H: white.

Figure 3.6. POV-ray depiction of 3-20. Hydrogen atoms were omitted for clarity. B: yellow- green; C: black; N: blue; O: red; Cl: green. 69

Figure 3.7. POV-ray depiction of 3-21. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; O: red; H: white.

Taking inspiration from the use of chiral BINOL and BINAP ligands in transition metal catalysis,40-42 a third carbene precursor with the incorporation of a chiral binaphthalene backbone was synthesized (Scheme 3.7). (S)-2-amino-2’-methoxy-1,1’-binaphthalene43 was reacted with trimethylsilyl azide and tert-butylnitrile to obtain the binaphthyl azide 3-22 in 82% yield. The azide 3-22 was then reacted with ethynyltrimethylsilane in a sluggish Huisgen cycloaddition using

[Cu(PPh3)Br] as a catalyst to obtain the trimethylsilyltriazole 3-23 in 90% yield. Deprotection with tetrabutylammonium fluoride was then carried out to obtain the triazole, and the crude product 3-24 was immediately used in an arylation reaction to obtain the 1,2,3-triazolium tetrafluoroborate 3-25 in 89% yield. Compound 3-25 was then deprotonated with NaHMDS and added to 9-BBN to give 3-26 in 82% yield (Scheme 3.8). The product obtained is noted to be a 10:1 mixture of two regioisomeric carbene-borane adducts by the integration ratio of the methoxy peaks at δ 3.80 ppm and δ 3.72 ppm in the 1H NMR spectrum. Separation of the two isomers was unsuccessful and therefore the regioisomeric mixture was used in subsequent reactions as synthesized. We

hypothesized that ratio of regioisomers was heavily influenced by the steric of the binaphthalene backbone during deprotonation.

Scheme 3.7. Synthesis of binaphthyl-derived triazolium tetrafluoroborate as a carbene precursor.

Scheme 3.8. Synthesis of binaphthyl-derived triazolium carbene-borane adducts.

3.2.2 Synthesis of Chiral NHC-Boranes with Chiral Boranes

Chiral boranes developed by Soderquist, which were reported to be excellent stoichiometric 44-47 asymmetric reagents, were considered. We hypothesized that the C1-symmetric environment about the boron centre of these boranes can induce selectivity in catalytic hydrogenation.40 To this end, we first synthesized the racemic 10-phenyl-9-borabicyclo[3.3.2]decane (9-BBD)46 and added

one equivalent of an imidazolium salt. In our attempts, KHMDS was added to generate the carbene in situ and then to give the NHC-borane adduct (Scheme 3.9). However, the reactions led to a mixture of products as evidenced by the multiple peaks observed in the 11B NMR spectra. In all of 1 our attempts, we observed quartets around δ -35 ppm with a JBH ~ 85 Hz, suggesting four- coordinated BH3 species. We propose that the 9-BBD had decomposed due to deprotonation of the relatively acidic proton at the α-carbon position by either the small in situ-formed carbene or by the base. In turn, lithium-B-H2-(10)-phenyl-9-borabicyclo[3.3.2]decane was prepared and reacted in a one-pot reaction: hydride abstraction of the borane by methyl iodide, followed by immediate deprotonation with NaHMDS of 1,3-diphenyl-1H-1,2,3-triazolium tetrafluoroborate and subsequent adduct formation lead to the formation of the targeted carbene-borane (Scheme 1 3.10). We were able to isolate 3-27 in 13% yield and a doublet at δ -15.1 ppm with JBH = 86 Hz was observed in the 11B NMR spectrum. We attribute the low yield to the potential decomposition of the 9-BBD as demonstrated in our previous attempts, and the steric demands of both carbene and borane. The use of the more hindered derivative, 1,3,4-triphenyl-1H-1,2,3-triazolium tetrafluoroborate, supported our hypothesis on steric demands as it failed to yield the adduct analogue (Scheme 3.11).

Scheme 3.9. Attempted synthesis of the racemic NHC-9-BBD adduct.

Scheme 3.10. Synthesis of the meso-ionic carbene-9-BBD adduct 3-27. 72

Scheme 3.11. Attempted synthesis of the racemic 1,3,4-phenyl-meso-ionic carbene-9-BBD adduct.

The chiral borane, (+)-diisopinocampheylborane (Ipc2BH), was produced from the hydroboration of α-pinene and BH3 (Scheme 3.12). Deprotonation of a variety of symmetric and dissymmetric imidazolium salts, followed by the addition of Ipc2BH, produced the corresponding adducts 3-28, 3-29, 3-30, 3-31, and 3-32 in 34%, 37%, 83%, 56% and 60% yield respectively (Scheme 3.13). Doublets were observed in the 11B NMR spectra of these products in the δ -6.8 to -9.7 ppm range 1 with JBH = 77 – 86 Hz. Compound 3-30 was found to decompose in chloroform, which we propose to be the result of the steric conflict between the isopinocampheyl groups and the carbene. Crystals suitable for X-ray crystallography were obtained for 3-28 (Figure 3.8), 3-30 (Figure 3.9), and 3- 31 (Figure 3.10), and the structural data confirmed the pseudo-tetrahedral geometries about the boron centre. The B-CNHC bond lengths were found to be 1.638(2) Å, 1.648(4) Å and 1.636(2) Å respectively for 3-28, 3-30, and 3-31.

Scheme 3.12. Synthesis of Ipc2BH by hydroboration of α-pinene.

Scheme 3.13. Synthesis of NHC-Ipc2BH adducts 3-28, 3-29, 3-30, 3-31, and 3-32.

Figure 3.8. POV-ray depiction of 3-28. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white.

Figure 3.9. POV-ray depiction of 3-30. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white.

Figure 3.10. POV-ray depiction of 3-31. Hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white. 75

3.2.3 Ring Expansion of NHC-Boranes

New species were observed when 3-7, 3-8, and 3-9 were left in solution for an extended amount of time. New signals at ca. δ 44 ppm were observed in the 11B NMR spectra and we hypothesized they may result from thermal rearrangements of the boranes (Scheme 3.14). Our group had previously documented similar rearrangement with various carbene-borane adducts.48 The rearrangement is proposed to begin with a hydride shift from the boron centre to the C2 carbon, followed by the coordination of the nitrogen to the boron centre which induces the cleavage of the

C-N bond. The intermediate then undergoes another rearrangement in which the B-C9-BBN bond is broken to form a new C-C bond with the carbene, giving the final ring expansion product (Scheme 3.15). Upon independent synthesis of the ring expanded products, we observed a difference in reactivity between the carbene-boranes. For 3-7, complete conversion was observed to give 3-33 upon mild heating at 50 °C for a few hours. For the diethyl-substituted derivative 3-8, compound 3-34 was obtained when heated at 50 °C but required 16 h of heating. In contrast, heating to 110 °C for 15 h was required for complete conversion for the bulkiest adduct 3-9 to 3-35. Crystals suitable for X-ray crystallography were obtained for 3-35, and we were able to confirm the structure of the ring expanded product. Interestingly, only a single diastereomer of 3-35 was confirmed by X-ray crystallography (Figure 3.11). This demonstrated that the ring expansion mechanism is stereoselective, presumably affected by the existing chirality of the carbene in 3-9. The B-C bond lengths were found to average to 1.581(3) Å, which is comparatively shorter than that of the carbene-borane adduct precursor. The B-N bond lengths averaged to 1.401(3) Å for the two molecules in the asymmetric unit, which is considerably shorter than the previously reported B-N bonds in similar ring-expanded carbene-boranes (1.44 – 1.46 Å).48-49

Scheme 3.14. Synthesis of ring-expanded boranes 3-33, 3-34, and 3-35. 76

Scheme 3.15. Proposed ring expansion mechanism of carbene-borane adducts.

Figure 3.11. POV-ray depiction of 3-35. Hydrogen atoms were omitted for clarity. B: yellow- green; C: black; N: blue.

3.2.4 Generation of Chiral Borenium Cations

Attempts to abstract the chloride from 3-20 to generate the corresponding borenium cation were carried out. There were no reactions even on extensive stirring when one equivalent of

[K][B(C6F5)4] or Me2SiHCl was added. When one equivalent of [Et3Si][B(C6F5)4] or Et3SiH was added, a mixture of products was formed as evidenced by the multiple peaks observed in the 11B NMR spectrum. We hypothesized that the Si centre is highly oxophilic and attacked the oxygen on the carbene backbone during the reaction, inducing decomposition of the carbene-borane. When

one equivalent of [Ag][B(C6F5)4] was added in the dark (Scheme 3.16), we observed solids forming and a shift in the 11B NMR spectrum from a broad singlet at δ 3.2 ppm to a broad singlet at δ 54.0 ppm, suggesting a three-coordinate boron centre of the formed borenium 3-20a. Unfortunately, due to the highly light-sensitive nature of silver salts, attempts to isolate 3-20a cleanly from the reaction mixture were unsuccessful.

Scheme 3.16. Chloride abstraction of 3-20 to generate the borenium cation.

The B-H borane adducts 3-6, 3-7, 3-8, and 3-9 were treated with trityl

tetrakis(pentafluorophenyl)borate for hydride abstraction to form Ph3CH and the corresponding borenium borate salts (Scheme 3.17). Compound 3-36 was isolated in 72% yield as a white solid. A broad and a sharp signal at δ 56 ppm and -16.7 pm were observed in the 11B NMR spectrum respectively, consistent with a cationic three-coordinate boron centre and the tetrakis(pentafluorophenyl)borate anion respectively, and the 19F NMR spectrum showed resonances consistent with the diastereotopic pentafluorophenyl groups. Compounds 3-37, 3-38, and 3-39 were isolated in 83%, 98%, and 93% yield respectively and the broad peaks at δ 89.1 ppm, 89.1 ppm and 85.8 ppm respectively in the 11B NMR spectra were consistent with the cationic three-coordinated boron centres. Crystals of 3-38 were formed by slow evaporation of the 78

toluene solution and were suitable for X-ray crystallography (Figure 3.12). The B-CNHC bond length was found to be 1.609(4) Å, which is longer than the typical bond length of previous reported borenium cations (1.577(3) Å30, 1.580(3) Å32), consistent with our previous reasoning of steric repulsion between the 9-BBN and the ethyl groups.

Scheme 3.17. Synthesis of enantiomerically pure camphoric acid-derived borenium cations 3-36, 3-37, 3-38, and 3-39.

Figure 3.12. POV-ray depiction of 3-38. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity. B: yellow-green; C: black; N: blue. 79

3.2.5 Hydrogenation Tests

Scheme 3.18. Catalytic reduction of N-benzylidene-tert-butylamine by 3-27, 3-36, 3-37, 3-38, and 3-39.

Compounds 3-27, 3-36, 3-37, 3-38, and 3-39 were first subjected to catalytic hydrogenation

reactions (Scheme 3.18). With a 5 mol% catalyst loading of 3-36 at 25°C and 4 atm of H2, we observed no reduction of N-benzylidene-tert-butylamine. Upon analysis of the reaction mixture by NMR spectroscopy, we observed the formation of the carbene-borane adduct 3-6 and the protonated iminium cation. We concluded that 3-36 and the imine forms an FLP that can induce hydrogen activation, but the high electrophilicity of the borane results in insufficient hydricity to deliver the hydride to the iminium cation, inhibiting catalytic turnover. Similarly, no reduction was

observed when 3-37, 3-38, and 3-39 were exposed to various imines and 102 atm of H2 at ambient temperature and at 110 °C (Scheme 3.18). In addition, no reactivity was observed when 3-37, 3-38,

and 3-39 were added to one equivalent of tBu3P and pressurized with 4 atm of H2. Upon heating

of the 3-37 reaction mixture to 110 °C for 24 h, we observed the formation of [HPtBu3][B(C6F5)4] in 26% yield as evidenced by 31P NMR spectroscopy. However, in the 11B NMR spectrum, we did not observe the signal for the borane adduct 3-7 but rather a broad signal at 44.0 ppm attributable to 3-33. While we see that hydrogen activation can proceed to some extent with this family of borenium cations, the ring expansion of these cations compete with the delivery of hydride and hence inhibit catalytic activity. In addition, the lack of activity of the bulkier derivatives 3-38 and 3-39 may be due to the inhibited access to the vacant p-orbital on boron by the substituents on the carbene. This hypothesis is consistent with the increase in steric demands stemming from the increased NCN-angle in these carbene ligands compared to those observed in the imidazole-based

carbene analogues. Compound 3-27 was first treated with one equivalent of [Ph3C][B(C6F5)4] to form the corresponding borenium cation and subsequently subjected to a similar catalytic hydrogenation reaction (Scheme 3.18). However, 3-27 also displayed no catalytic activity under

these conditions. We also attributed the lack of reactivity to the steric hindrance of both the carbene and borane, a condition that impeded the synthesis of this precursor as previously mentioned.

The carbene-borane adducts 3-18, 3-19, 3-21, 3-26, 3-28, 3-29, 3-30, 3-31, and 3-32 were treated with one equivalent of [Ph3C][B(C6F5)4] to generate the borenium cation in situ, which was then exposed to a substrate solution and pressurized to 102 atm of H2. The yields and products were then characterized by 1H NMR spectroscopy and chiral HPLC. Amongst the borane precursors derived from bisoxazoline-carbenes, the catalyst formed from 3-19 is inactive, giving 6% reduction of the prochiral (E)-N,1-diphenylethan-1-imine at best even with heating at 50 °C. We hypothesized that the minimal steric bulk surrounding the borenium centre is unable to preclude adduct formation with the amine product, thus inhibiting catalytic turnover. Chiral HPLC also revealed low ee values with the small amount of amine product (Table 3.1, entries 6-7). Compound 3-18 was able to effect the catalytic reduction of 50% of (E)-N,1-diphenylethan-1-imine after 3 h and was able to completely hydrogenate the imine after 24 h. It was able to maintain its reactivity in different temperatures, giving 94% yield at 0 °C for 12 h and 71% yield at 50 °C for 3 h. However, the selectivity remained low with ee values of 1-12% (Table 3.1, entries 1-5). For 3-21, we were hopeful that the greater steric demands can impart high asymmetric induction. However, no reaction was observed when 3-21 was exposed to the imine for 48 h (Table 3.1, entry 10). Independent control studies showed the formation of the borenium cation when 3-21 was reacted 11 with one equivalent of [Ph3C][B(C6F5)4], with a broad peak at δ 74.6 ppm in the B NMR spectrum for the three-coordinate cationic centre and a sharp peak at δ -16.6 ppm for the borate anion. Addition of one equivalent of the prochiral (E)-N,1-diphenylethan-1-imine showed no change by NMR spectroscopy, suggesting no formation of an adduct. This indicates that the lack of reactivity of 3-21 was not due to catalytic quenching by adduct formation, but rather that the increase of steric environment around the borenium centre precluded the encounter complex necessary for H2 activation. Screening the precursors derived from pinene-templated boranes, the reactivity of 3-28 is comparable to that of 3-18, giving 55% yield of the amine product in 4 h at ambient temperature. However, it has low asymmetric induction, with ee of 12%. Reducing the temperature to -30 °C improved the ee to 20%, but the yield was severely diminished to 5%. Changing the solvent to toluene and chlorobenzene unfortunately reduced the yield, presumably due to the reduced solubility of the cation in these solvents (Table 3.1, entries 11-14).

Table 3.1. Hydrogenation catalysis of (E)-N,1-diphenylethan-1-imine by borenium cations derived from 3-18, 3-19, 3-21, 3-26, 3-28, 3-29, 3-30, 3-31, and 3-32.

Entry Precursor Time (h) Temp. (°C) Yield (%) ee (%)

1 3-18 24 r.t. 100 7

2 3-18 6 r.t. 88 9

3 3-18 3 r.t. 50 12

4 3-18 12 0 94 1

5 3-18 3 50 71 8

6 3-19 24 r.t 3 5

7 3-19 3 50 6 7

8 3-21 3 r.t. 0 -

9 3-21 24 r.t. 0 -

10 3-21 48 r.t. 0 -

11 3-28 4 r.t. 55 12

12 3-28 24 -30 5 20

13 3-28 24 25 0 - a

14 3-28 24 25 12 15 b

15 3-29 24 -30 <5 8

16 3-30 4 25 47 13

17 3-30 24 -30 5 13

18 3-31 20 -30 <5 -

19 3-32 4 25 0 -

20 3-32 20 -30 0 -

21 3-26 18 r.t. 100 6

Reaction carried out in a 0.6 mL toluene and b 0.6 mL chlorobenzene.

The bulkier analogues 3-29 and 3-30 exhibited similar reactivity and selectivity, with a yield of 47% and 13% ee produced by 3-30. The largest precursors of this family, 3-31 and 3-32, showed no catalytic reactivity in imine reduction (Table 3.1, entries 15-20). The activated 3-26 is also an active catalyst, giving complete reduction of the imine at ambient temperature after 18 h, but selectivity is low with ee value of 6% (Table 3.1, entry 21).

Compound 3-18 was also able to catalytically reduce (Z)-1-(4-ethoxyphenyl)-N-phenylethan-1- imine in 91% yield with 11% ee (Table 3.2, entry 1). Catalytic activity is also substrate dependant as no amine was produced when 3-18 was exposed to (E)-N-benzyl-1-phenylethan-1-imine (Table 3.2, entry 2). We hypothesized that the benzylic group did not provide sufficient steric bulk for the imine to act as the Lewis base counterpart to H2 activation. Additionally, no hydrogenation was observed when 3-18 or 3-19 was exposed to heptan-4-one (Table 3.2, entries 3-4), presumably due to adduct formation with the carbonyl group and the oxyphilic borenium centre. Similarly, compound 3-18 and 3-21 also did not reduce acetophenone (Table 3.2, entries 5-6).

Table 3.2. Hydrogenation catalysis by borenium cations derived from 3-18, 3-19, and 3-21.

Time Temp. Yield ee Entry Substrate Precursor Product (h) (°C) (%) (%)

1 3-18 6 r.t. 91 11

2 3-18 6 r.t. 0 -

3 3-18 24 r.t. 0 -a

4 3-19 24 r.t. 0 -a

5 3-18 48 r.t. 0 -

6 3-21 48 r.t. 0 -

a Reaction carried out in 1 mL of Et2O.

With poor enantioselectivities observed for the different families of borenium cations, we probed the possibility of a reversible hydride delivery to the prochiral amine, which can lead to epimerisation of the resulting chiral amine. To this end, we reacted 3-18 with one equivalent of

[Ph3C][B(C6F5)4] to generate the borenium cation and the enantiopure, chiral secondary amine (+)- bis[(R)-1-phenylethyl]amine was added. The reaction was monitored by 1H NMR spectroscopy and no reaction was observed after 42 h at ambient temperature (Scheme 3.19). The achiral borane 9-(1,3-diphenyl-1,2,3-triazol-5-ylidene)-9-borabicyclo[3.3.1]nonane was treated in a similar fashion, and a trace amount of the meso amine was observed by 1H NMR spectroscopy. Only after heating to 65 °C for 42 h did a significant amount was observed, which allows us to conclude the low ee values were not due to racemization of the amine product. This also stands in strong contrast to the rapid epimerisation of the enantiopure amine by B(C6F5)3, which was reported in literature for transfer hydrogenation of imines.50

Scheme 3.19. Test for racemization of enantiopure amine.

3.3 Conclusion

Using both NHC- and triazolium-based carbenes, we have synthesized families of chiral carbene- borane adducts in which the chirality resides either on the borane or the carbene. We have found some of the species to be effective precursors for catalytic imine hydrogenation, while others were plagued by factors that inhibit catalysis. Species with pentafluorophenyl groups precluded hydride delivery due to the boranes’ electrophilicity and therefore inhibited amine production. Species with camphoric acid-derived carbenes were shown to undergo a thermally induced ring-expansion with carbene C-N bond cleavage at elevated temperatures, resulting in a new species that is not catalytically active. We have found bisoxazoline-derived NHC borenium cations, axially chiral

triazolium-borenium analogues and borenium cations derived from Ipc2BH to be active hydrogenation catalysts yet exhibited limited stereoselectivity. In screening through the catalytic activity of these borenium cations, we observed a common design dilemma with these families: the smallest borenium cations amongst each family have the highest catalytic activity but the lack of steric bulk produced limited stereoselectivity. By increasing the steric demands to impart asymmetric induction, we observed a significant decrease or complete elimination of catalytic activity, due to the preclusion of encounter complex formation. Nonetheless, we were able to show that the low selectivities observed were not caused by selectivity erosion by epimerization of the chiral product. These results support that further catalyst design may be fruitful in this venture.

3.4 Experimental Section

3.4.1 General Considerations

Unless otherwise stated, all reactions and manipulations were performed under an atmosphere of dry, oxygen-free, nitrogen in a glovebox (Innovative Technology or MBraun) or using standard Schlenk techniques. All deuterated and non-deuterated solvents were dried and stored over molecular sieves under a nitrogen atmosphere prior to usage. NMR spectra were recorded on a Bruker Avance III or Bruker 500 MHz spectrometer at 298 K unless otherwise stated. Chemical 1 13 shifts are given relative to SiMe4 and referenced to the residual solvent signal ( H, C) or relative 11 31 19 to an external standard ( B: 15% (Et2O)BF3, P: 85% H3PO4, F: CFCl3). Chemical shifts (δ) are reported in ppm and coupling constants (J) as scalar values in Hz. Chiral HPLC was performed on an Agilent HP 1100 or 1200 series operated by ChemStation LC 3D software, v.10.02. A

Perkin-Elmer 2400 Series II CHNS analyser was used for carbon, hydrogen, and nitrogen elemental analysis. (3S,7S)-3,7-diisopropyl-2,3,7,8-tetrahydroimidazo[4,3-b:5,1-b’]-bis (oxazole)-4-ium triflate 3-16, and (3S,7S)-3,7-di-tert-butyl-2,3,7,8-tetrahydroimidazo [4,3-b:5,1- b']bis(oxazole)-4-ium triflate 3-17,51-52 N-(1-phenylethylidene) aniline,53 (+)- diispinocampheylborane54 and 1,3-dimethylimidazolium iodide,55 1-methyl-3-phenylimidazolium iodide,56 (S)-2-amino-2'-methoxy-1,1'-binaphthalene,43 1-benzyl-3-methylimidazolium iodide,57 58 47 diphenyliodonium tetrafluoroborate, lithium-B-H2-(10)-phenyl-9-borabicyclo[3.3.2]decane, and silver tetrakis(pentafluorophenyl)borate59 were prepared by literature procedures. In some cases, repeated attempts to secure satisfactory elemental analysis led to low C content, despite the use of additional oxidant. Such situations are attributed to the formation of boron-carbide during combustion.

3.4.2 Synthesis of Compounds

Synthesis of (1R,3S)-1,2,2-Me3-1,3-(NH2)2C5H5 (3-1): To a solution of (1R,3S)- camphoric acid (18.94 g, 94.95 mmol, 1 equiv.) and 50 mL of conc. sulfuric acid in

300 mL chloroform was added NaN3 (17.99 g, 276.73 mmol, 2.9 equiv.) over a period of 3 h. The reaction mixture was stirred at 55 °C for 18 h while gas evolution was observed. After cooling to 25 °C, 1 L of water was added, and the aqueous phase was isolated. The aqueous phase was then basified by the addition of NaOH and the product was extracted with

CH2Cl2 (3 x 500 mL). The combined organic layers were dried over MgSO4 and the volatiles were removed in vacuo to provide the product as a colourless solid. Yield: 7.77 g (54.62 mmol, 58%); 1 3 3 H NMR (CDCl3, 500 MHz): δ 2.96 (dd, JHH = 9 Hz, JHH = 7 Hz, 1H), 2.04 – 1.96 (m, 1H), 1.66 13 1 – 1.54 (m, 6H), 1.32 – 1.24 (m, 1H), 1.00 (s, 3H), 0.79 (s, 3H), 0.77 (s, 3H); C{ H} NMR (CDCl3, + 126 MHz): δ 61.1, 60.9, 46.3, 38.5, 30.4, 26.0, 22.3, 16.4; HR-MS (ESI+): C8H19N2, [M+H] m/z (calc.): 143.1543, m/z (obs.): 143.1546.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NH)2C6H7][BF4] (3-2): A suspension of

camphoric diamine 3-1 (2.00 g, 14.06 mmol, 1 equiv.) and NH4BF4 (1.62 g, 15.45 mmol, 1.1 equiv.) in 15 mL triethylorthoformate was stirred at 110 °C for 2 h. Upon cooling to 25 °C, the precipitate was isolated by filtration and washed

with Et2O (3 x 30 mL). Removal of the volatiles in vacuo afforded the product as

1 a colourless solid. Yield: 1.84 g (10.84 mmol, 77%); H NMR (CD3CN, 500 MHz): δ 7.84 (s, br, 3 2H), 7.61 (s, 1H), 3.42 (d, JHH = 5 Hz, 1H), 2.35 – 2.29 (m, 1H), 2.17 – 2.02 (m, 3H), 1.22 (s, 13 1 3H), 1.11 (s, 3H), 0.98 (s, 3H); C{ H} NMR (CD3CN, 126 MHz): δ 152.4, 66.6, 62.5, 42.7, 39.5, + 34.0, 20.6, 16.8, 16.2; HR-MS (ESI+): C9H17N2, [M] m/z (calc.): 153.1386, m/z (obs.): 153.1388.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NMe)2C6H7][BF4] (3-3), [(1R,5S) 5,8,8-Me3-2,4-

(NEt)2C6H7][BF4] (3-4), [(1R,5S) 5,8,8-Me3-2,4-(NiPr)2C6H7][BF4] (3-5): These compounds were prepared as followed: Alkyl iodide (20.83 mmol, 5 equiv.) was added to a suspension of

1.00 g diamine 3-2 (4.17 mmol, 1 equiv.) and 1.44 g K2CO3 (10.41 mmol, 2.5 equiv.) in MeCN (25 mL). The reaction mixture was stirred under reflux for 44 h. Upon cooling to 25 °C, the solvent and remaining alkyl iodide were removed in vacuo. The residual solid was dissolved in CH2Cl2 and then filtered. The resulting filtrate was concentrated under reduced pressure to give the product.

1 3-3: Yield: 0.98 g (4.07 mmol, 86%); H NMR (CDCl3, 500 MHz): δ 9.02 (s, 3 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.12 (d, JHH = 5 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.37 – 2.31 (m, 1H), 2.13 – 2.05 (m, 1H), 1.93 – 1.87 (m, 1H), 1.27 (s, 3H), 1.13 13 1 (s, 3H), 1.08 (s, 3H); C{ H} NMR (CDCl3, 126 MHz): δ 153.7, 69.5, 68.8, + 41.1, 40.8, 38.5, 37.0, 30.6, 21.8, 16.9, 14.2; HR-MS (ESI+): C11H21N2, [M] m/z (calc.): 181.1699, m/z (obs.): 181.1701.

1 3-4: Yield: 0.89 g (3.00 mmol, 96%); H NMR (CDCl3, 500 MHz): δ 9.05 (s, 1H), 3.86 – 3.79 (m, 1H), 3.77 – 3.70 (m, 1H), 3.69 – 3.62 (m, 1H), 3.60 – 3.52 3 (m, 1H), 3.19 (d, JHH = 5 Hz, 1H), 2.55 – 2.49 (m, 1H), 2.31 – 2.26 (m, 1H), 3 2.17 – 2.10 (m, 1H), 2.01 – 1.94 (m, 1H), 1.38 (t, JHH = 7 Hz, 3H), 1.34 (s, 3 13 1 3H), 1.30 (t, JHH = 7 Hz, 3H), 1.15 (s, 3H), 1.03 (s, 3H); C{ H} NMR

(CDCl3, 126 MHz): δ 153.2, 69.9, 66.3, 48.7, 45.3, 40.8, 40.6, 32.1, 21.9, 17.3, 17.2, 14.3, 14.1; + HR-MS (ESI+): C13H25N2, [M] m/z (calc.): 209.2012, m/z (obs.): 209.2018.

1 3-5: Yield: 2.46 g (6.43 mmol, 96%); H NMR (CDCl3, 500 MHz): δ 8.13 (s, 3 3 1H), 4.39 – 4.31 (m, 1H), 3.85 (sept, JHH = 7 Hz, 1H), 3.28 (d, JHH = 5 Hz, 1H), 2.42 – 2.36 (m, 1H), 2.20 – 2.13 (m, 1H), 2.09 – 2.04 (m, 1H), 1.98 – 1.92 3 3 3 (m, 1H), 1.47 (d, JHH = 7 Hz, 3H), 1.36 (d, JHH = 7 Hz, 3H), 1.27 (d, JHH = 3 7 Hz, 3H), 1.32 (s, 3H), 1.20 (d, JHH = 7 Hz, 3H), 1.12 (s, 3H), 0.90 (s, 3H); 13 1 C{ H} NMR (CDCl3, 126 MHz): δ 151.1, 71.5, 61.4, 55.9, 51.1, 41.1, 40.4, + 33.4, 25.1, 23.6, 22.2, 21.7, 20.7, 17.7, 14.9; HR-MS (ESI+): C15H29N2, [M] m/z (calc.): 237.2325, m/z (obs.): 237.2330.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NMe)2C6H6]BH(C6F5)2 (3-6): A suspension of 3-3 (107 mg, 0.40 mmol, 1 equiv.) and KHMDS (80 mg, 0.40 mmol, 1 equiv.) in 2 mL THF was stirred at ambient temperature for 60 h. After filtration over Celite and removal of the volatiles in vacuo, the free carbene was re-dissolved in 2 mL toluene. A solution of Piers’ borane (138 mg, 0.4 mmol, 1 equiv.) in 1 mL toluene was then added. The reaction mixture was stirred at 25 °C for 2 h. The volatiles were removed in vacuo and the product was extracted with toluene to give the pure 1 product as an orange solid. Yield: 127 mg (0.24 mmol, 60%); H NMR (CD2Cl2, 500 MHz): δ 2.88 3 (s, 3H), 2.64 (s, 3H), 2.27 – 2.20 (m, 1H), 1.90 – 1.84 (m, 1H), 1.75 (d, JHH = 5 Hz, 1H), 1.68 – 13 1 1.59 (m, 1H), 0.98 (s, 3H), 0.89 (s, 3H), 0.88 (s, 3H); C{ H} NMR (CD2Cl2, 126 MHz): δ 153.6, 149.4, 147.5, 140.2, 138.2, 136.3, 71.5, 70.7, 42.3, 41.6, 39.3, 36.9, 36.4, 29.6, 22.8, 16.8, 15.5; 11 1 19 B NMR (CD2Cl2, 128 MHz): δ -23.4 (d, JBH = 91 Hz); F NMR (CD2Cl2, 377 MHz): δ -165.49 3 3 3 – -165.72 (m), -161.63 (t, JFF = 20 Hz), -161.57 (t, JFF = 20 Hz), -134.7 (d, JFF = 22 Hz), -133.3 3 + (d, JFF = 22 Hz); HR-MS (ESI+): C23H20BF10N2, [M] m/z (calc.): 524.1591, m/z (obs.):

524.1593; Anal. Calc. for C23H20BF10N2: C 52.50, H 4.02, N 5.32 %; Obs. C 53.24, H 3.33, N 5.11 %.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NMe)2C6H6][HBC8H14] (3-7), [(1R,5S)-5,8,8-Me3-2,4-

(NEt)2C6H6][HBC8H14] (3-8), [(1R,5S)-5,8,8-Me3-2,4-(Ni-Pr)2C6H6][HBC8H14] (3-9): These compounds were prepared in a similar fashion: The carbene precursor (0.4 mmol, 1 equiv.) and

K[N(SiMe3)2] (80 mg, 0.40 mmol, 1 equiv.) were suspended in 2 mL of THF and stirred at 25 °C for 20 min. The reaction mixture was then filtered through Celite and the volatiles were removed in vacuo to give the free carbene. The carbene was re-dissolved in 2 mL toluene and added to a 88

suspension of 9-BBN dimer (48.8 mg, 0.20 mmol, 0.5 equiv.) in 2 mL of toluene. The mixture was stirred for 30 min and the volatiles were then removed under reduced pressure. The residue was extracted with pentane (4 x 2 mL), which was subsequently removed in vacuo to provide the product.

1 3-7: Yield: 98 mg (0.32 mmol, 81%); H NMR (C6D6, 500 MHz): δ 3.04 (s, 6H), 2.57 – 2.37 (m, 3H), 2.30 – 2.21 (m, 2H), 2.19 – 2.05 (m, 3H), 2.01 – 1.95 (m, 3H), 1.69 – 1.56 (m, 4H), 1.51 (bs, 1H), 1.32 – 1.15 (m, 3H), 1.05 – 0.97 (m, 1H), 0.74 (s, 3H), 0.58 (s, 3H), 0.36 (s, 3H); 13C{1H} NMR

(C6D6, 126 MHz): δ 70.2, 69.0, 41.5, 40.5, 39.0, 38.8, 35.6, 34.6, 31.4, 31.0, 28.7, 25.5, 23.3, 22.2, 11 1 17.0, 15.4; B NMR (C6D6, 128 MHz): δ -14.2 (d, JBH = 83 Hz); HR-MS (ESI+): C19H36BN2, [M]+ m/z (calc.): 302.3008, m/z (obs.): 302.3009.

1 3-8: Yield: 220 mg (0.67 mmol, 67%); H NMR (C6D6, 500 MHz): δ 4.39 3 3 – 4.30 (m, 1H), 3.67 (sept, JHH = 7 Hz, 1H), 3.60 (sept, JHH = 7 Hz, 1H), 3.14 (m, 1H), 2.54 (m, 2H), 2.41 (m, 1H), 2.27 (m, 3H), 2.09 (m, 6H), 1.93 (m, 1H), 1.67 (m, 1H), 1.49 (m, 3H), 1.35 (m, 1H), 1.22 (m, 2H), 1.05 (t, 3 3 13 1 JHH = 7 Hz, 3H), 0.94 (t, JHH = 7 Hz, 3H), 0.74 (s, 3 H), 0.69 (s, 3H), 0.43 (s, 3H); C{ H} NMR

(C6D6, 126 MHz): δ 69.7, 59.8, 52.8, 49.9, 40.6, 40.5, 39.7, 37.7, 32.8, 32.1, 30.8, 25.8, 25.4, 24.6, 11 1 22.6, 21.7, 20.9, 20.3, 18.3, 18.1; B NMR (C6D6, 128 MHz): δ -14.3 (d, JBH = 84 Hz); HR-MS + (ESI+): C21H40BN2, [M] m/z (calc.): 330.3321, m/z (obs.): 330.3325; Anal. Calc. for C21H40BN2: C 76.35, H 11.40, N 8.48 %; Obs. C 76.53, H 10.57, N 8.00%.

1 3-9: Yield: 227 mg (0.63 mmol, 63%); H NMR (C6D6, 500 MHz): δ 5.56 3 3 (sept, JHH = 7 Hz, 1H), 5.47 (sept, JHH = 7 Hz, 1H), 2.71 – 2.09 (m, 12H), 2.04 – 1.93 (m, br, 3H), 1.52 – 1.45 (m, br, 2H), 1.41 (s, br, 1H), 1.27 (s, 3 3 br, 2H), 1.24 (d, JHH = 7 Hz, 3H), 1.15 (d, JHH = 7 Hz, 3H), 0.97 – 0.93 13 1 (m, 9H), 0.66 (s, 3H), 0.45 (s, 3H); C{ H} NMR (C6D6, 126 MHz): δ 69.8, 59.9, 52.9, 50.1, 40.8, 40.7, 39.9, 37.8, 33.0, 32.3, 30.9, 27.1 (br), 26.0, 25.6, 25.0 (br), 24.8, 22.7, 21.9, 21.0, 20.5, 18.5, 11 1 + 18.2; B NMR (C6D6, 128 MHz): δ -12.9 (d, JBH = 85 Hz); HR-MS (ESI+): C23H44BN2, [M] m/z (calc.): 358.3634, m/z (obs.): 358.3624; Anal. Calc. for C23H44BN2: C 77.08, H 12.09, N 7.82 %; Obs. C 76.76, H 12.91, N 7.76 %.

Synthesis of [(3S,7S)-3,7-iPr2-2,3,7,8-C7H6O2N2][HBC8H14] (3-18), [(3S,7S)-3,7-iPr2-2,3,7,8-

C7H6O2N2][BH3] (3-19), [(3S,7S)-3,7-iPr2-2,3,7,8-C7H6O2N2][BClCy2] (3-20), [(3S,7S)-3,7- tBu2-2,3,7,8-C7H6O2N2][HBC8H14] (3-21): These compounds were prepared in a similar fashion and thus one preparation is given in details as follows. Compound 3-16 (110 mg, 0.285 mmol, 2 equiv.) and 9-BBN dimer (35 mg, 0.1425 mmol, 1 equiv.) were dissolved in 2.5 mL THF at -35 °C.

KHMDS (58 mg, 0.29 mmol, 2 equiv.) was dissolved in 2 mL THF at -35 °C and was added dropwise to the mixture. The mixture was stirred overnight at ambient temperature and the volatiles were removed in vacuo. The residue was extracted with 20 mL pentane, filtered through Celite, and dried in vacuo.

3-18: A light yellow powder. Crystals for X-ray crystallography were obtained by slow evaporation of pentane. Yield: 60 mg, (0.167 mmol, 58%); 1 3 4 2 H NMR (C6D6, 400 MHz): δ 4.10 (ddd, JHH = 7 Hz, JHH = 3 Hz, JHH = 1 3 3 4 Hz, 2H), 3.92 (dd, JHH = 9 Hz, JHH = 1 Hz, 2H), 3.72 (ddd, JHH = 9 Hz, 3 2 JHH = 7 Hz, JHH = 1 Hz, 2H), 2.77 – 1.87 (m, 15H), 1.52 – 1.41 (m, 2H), 3 3 13 1 0.63 (d, JHH = 7 Hz, 6H), 0.44 (d, JHH = 7.0 Hz, 6H); C{ H} NMR (C6D6, 125 MHz): δ 124.0, 11 75.7, 62.3, 37.0, 36.6, 33.6, 30.0, 26.5, 26.0, 18.6, 14.6; B NMR (C6D6, 128 MHz): δ -16.9 (d, 1 + + JBH = 83 Hz); MS (DART+) m/z: 357 [M-H] ; HR-MS (ESI+): C21H34BN2O2, [M-H ] m/z

(calc.): 357.2713, m/z (obs.): 357.2724; Anal. Calc. for C21H35BN2O2: C 70.39, H 9.85, N 7.82 %. Found: C 69.30, H 9.34, N 7.42 %.

3-19: A light yellow powder. Crystals for X-ray crystallography were obtained by 1 slow evaporation from toluene. Yield: 44 mg (0.176 mmol, 62%); H NMR (C6D6, 3 400 MHz): δ 4.06 – 3.91 (m, 4H), 3.86 – 3.74 (m, 2H), 2.89 (ddq, JHH = 10 Hz, 4 3 3 JHH = 7 Hz, JHH = 4 Hz, 2H), 2.40 – 1.65 (m, 1H), 0.65 (d, JHH = 7 Hz, 6H), 0.44 3 13 1 (d, JHH = 7 Hz, 6H); C{ H} NMR (C6D6, 125 MHz): δ 76.1, 61.1, 29.0, 22.7, 11 1 + 18.3, 14.3; B NMR (C6D6, 128 MHz): δ -35.6 (q, JBH = 88 Hz); MS (DART) m/z: 249 [M-H] ; + HR-MS (ESI+): C13H22BN2O2, [M-H] m/z (calc.): 249.1774, m/z (obs.): 249.1771; Anal. Calc. for C13H23BN2O2: C 62.42, H 9.27, N 11.20 %. Found: C 62.02, H 9.27, N 11.10 %.

3-20: A white powder. Crystals for X-ray crystallography were obtained by slow evaporation of toluene. Yield: (50 mg, 0.111 mmol, 35%); 1H 3 2 NMR (C6D6, 400 MHz): δ 4.56 (dd, JHH = 7 Hz, JHH = 2 Hz, 2H), 3.91 3 3 4 3 (dd, JHH = 9 Hz, JHH = 1 Hz, 2H), 3.71 (ddd, JHH = 9 Hz, JHH = 7 Hz, 2 3 3 4 JHH = 1 Hz, 2H), 3.02 (dtd, JHH = 14 Hz, JHH = 7 Hz, JHH = 3 Hz, 2H), 3 3 2.39 (s, br, 1H), 2.36 (s, br, 1H), 2.09 – 0.95 (m, 18H), 0.68 (d, JHH = 7 Hz, 6H), 0.55 (d, JHH = 13 1 7 Hz, 6H); C{ H} NMR (C6D6, 125 MHz): δ 75.9, 64.5, 32.8, 32.4, 31.4, 31.2, 31.1, 30.2, 29.7, 11 29.6, 29.5, 28.4, 28.3, 28.2, 28.0, 18.7, 14.4; B NMR (C6D6, 128 MHz): δ 3.2 (s, br); MS + + (DART+) m/z: 413 [M-Cl] ; HR-MS (ESI+): C25H42BN2O2, [M-Cl] m/z (calc.): 413.33393, m/z (obs.): 413.33381.

3-21: A white powder. Crystals for X-ray crystallography were obtained by slow evaporation of pentane. Yield: 88 mg (0.228 mmol, 80 %); 1H NMR 3 3 (C6D6, 400 MHz): δ 4.15 (d, JHH = 5 Hz, 2H), 4.04 (d, JHH = 9 Hz, 2H), 3 3 3.78 (dd, JHH = 9 Hz, JHH = 6 Hz, 2H), 2.82 – 1.74 (m, 14H), 1.55 (s, br, 13 1 1H), 1.16 (s, br, 1H), 0.88 (s, 18H); C{ H} NMR (C6D6, 125 MHz): δ 124.3, 11 1 78.6, 68.3, 39.4, 35.3, 33.1, 32.4, 27.5, 26.6, 25.9; B NMR (C6D6, 128 MHz): δ -16.4 (d, JBH = + + 86 Hz); MS (ESI+) m/z: 385 [M-H] ; HR-MS (ESI+): C23H38BN2O2, [M-H] m/z (calc.):

385.3026, m/z (obs): 386.3032; Anal. Calc. for C23H39BN2O2: C 71.50, H 10.17, N 7.25 %; Found: C 70.45, H 10.16, N 6.79 %.

Synthesis of (S)-2-N3-2'-OMe-1,1'-C20H12 (3-22). Compound 3-22 was synthesized using a modified literature procedure.60 In a 100 mL round bottom flask open to air, (S)-2-amino-2'-methoxy-1,1'-binaphthalene (4.97 g, 16.6 mmol, 1 equiv.) was dissolved in MeCN (60 mL) and tert-butylnitrite

(3.3 mL, 24.9 mmol, 1.5 equiv.). Me3SiN3 (2.8 mL, 20.0 mmol, 1.2 equiv.) was added dropwise at 0 °C and stirred for 2 h. The mixture was then warmed to ambient temperature and stirred for 24 h. The precipitate was filtered and washed with a minimal amount of MeCN followed by copious amounts of pentanes. The product was obtained as an ochre powder. Yield: 3.36 g (10.31 mmol, 62%). All volatiles were removed in vacuo from the mother liquor and another 1.09 g (3.34 mmol, 20%) of the product was isolated after flash column chromatography 1 (silica 10 cm x 4 cm, CH2Cl2/MeOH 50:1). Combined yield: 4.44 g, (13.7 mmol, 82%); H NMR 91

3 3 3 (CDCl3, 400 MHz): δ 8.06 (d, JHH = 9 Hz, 1H), 8.03 (d, JHH = 9 Hz, 1H), 7.93 (d, JHH = 8 Hz, 3 3 3 3 2H), 7.53 (d, JHH = 9 Hz, 1H), 7.50 (d, JHH = 9 Hz, 1H), 7.45 (t, JHH = 7 Hz, 1H), 7.38 (t, JHH 3 13 1 = 7 Hz, 1H), 7.34 – 7.25 (m, 2H), 7.09 (d, JHH = 8 Hz, 1H), 3.83 (s, 3H); C{ H} NMR (CDCl3, 125 MHz): δ 155.0, 136.0, 134.0, 133.8, 131.2, 130.4, 129.8, 129.1, 128.3, 128.2, 127.1, 126.9, + 126.0, 125.3, 125.0, 124.1, 123.9, 118.7, 117.8, 113.7, 56.8; HR-MS (EI+): C21H15N3O, [M] m/z (calc.): 325.1215, m/z (obs.): 325.1206.

Synthesis of (S)-2-N3C(SiMe3)CH-2'-OMe-1,1'-C20H12, (3-23): A 4- dram vial was charged with (S)-2-azido-2'-methoxy-1,1'-binaphthalene

3-22 (500 mg, 1.54 mmol, 1 equiv.) and [Cu(PPh3)Br] (32.0 mg,

0.078 mmol, 0.05 equiv.). The solids were dissolved in 2 mL CH2Cl2 and ethynyltrimethylsilane (1 mL, 7.08 mmol, 4.5 equiv.) was added. The reaction mixture was stirred at ambient temperature for 3 weeks. The product was isolated by flash column chromatography (silica 20 cm x 4 cm, CH2Cl2/MeOH 100:0 → 100:5). Yield: 1 3 589 mg (1.39 mmol, 90%); H NMR (CDCl3, 500 MHz): δ 8.15 (d, JHH = 9 Hz, 1H), 8.05 (d, 3 3 3 3 JHH = 8 Hz, 1H), 8.00 (d, JHH = 9 Hz, 1H), 7.99 (d, JHH = 9 Hz, 1H), 7.86 (d, JHH = 8 Hz, 1H.), 3 3 7.58 (t, JHH = 7 Hz, 1H), 7.26 – 7.44 (m, 5H.), 7.12 (d, JHH = 8 Hz, 1H), 7.05 (s, 1H), 3.67 (s, 13 1 3H), 0.10 (s, 9H); C{ H} NMR (CDCl3, 126 MHz): δ 155.0, 145.0, 134.5, 133.8, 133.5, 133.1, 130.8, 130.2, 129.5, 128.8, 128.4, 128.3, 128.1, 127.4, 127.2, 127.1, 126.9, 124.5, 124.0, 123.4, + 117.6, 113.0, 56.4, -1.4; HR-MS(EI+): C26H25N3OSi, [M] m/z (calc.): 423.1767, m/z (obs.): 423.1771.

Synthesis of (S)-2-N3C2H2-2'-OMe-1,1'-C20H12, (3-24): A 50 mL round bottom flask was charged with a solution of 3-23 (1.20 g, 2.83 mmol, 1 equiv.) in 15 mL THF. A solution of TBAF (3.2 mL, 1.0 M in THF, 3.2 mmol, 1.1 equiv.) was added dropwise. After stirring the reaction mixture at ambient temperature for 2 h. 30 mL H2O was added, and the aqueous phase was extracted with CH2Cl2. The combined organic phases were washed with saturated brine, dried over

MgSO4, filtered, and all volatiles were removed in vacuo. The product was obtained as a slightly brown solid. The crude product 3-24 was monitored by 1H NMR spectroscopy on the disappearance of the trimethylsilyl peak and used without further manipulations in the next step.

Synthesis of [(S)-2-N3(3-Ph)C2H2-2'-OMe-1,1'-

C20H12][BF4], (3-25): Compound 3-25 was synthesized following a modified literature procedure.61 A Schlenk tube was charged with crude 3-24 (855 mg, 2.43 mmol, 1 equiv.), diphenyliodonium tetrafluoroborate (1.39 g, 3.76 mmol, 1.5 equiv.), CuSO4 (22 mg, 0.138 mmol, 0.05 equiv) and 5 mL DMF. The reaction mixture was stirred at 95 °C for 16 h. The mixture was then cooled to ambient temperature and all volatiles removed in vacuo. The resulting oil was subjected to flash-column chromatography (silica, 4 cm x 8 cm, 1 CH2Cl2/MeOH 100:1 → 20:1) to give a slightly ochre solid. Yield: 1.121 g (2.17 mmol, 89%); H 3 3 NMR (CDCl3, 500 MHz): δ 8.87 (s, 1H), 8.51 (s, 1H), 8.23 (d, JHH = 9 Hz, 1H), 8.08 (d, JHH = 3 3 8 Hz, 1H), 8.00 (m, 2H), 7.85 (d, JHH = 8 Hz, 1H), 7.68 (t, JHH = 8 Hz, 1H), 7.54 – 7.24 (m, 10H), 3 13 1 7.02 (d, JHH = 8 Hz, 1H), 3.75 (s, 3H); C{ H} NMR (CDCl3, 126 MHz): δ 154.7, 134.8, 134.4, 133.5, 132.7, 132.6, 132.1, 132.0, 131.9, 131.8, 130.6, 130.3, 128.7, 128.6, 128.6, 128.4, 128.3, + 127.7, 127.3, 124.1, 124.1, 121.8, 121.3, 114.7, 112.9, 56.3; HR-MS(EI+): C29H22N3O, [M] m/z (calc.): 428.1757, m/z (obs.): 428.1739.

Synthesis of of (S)-2-N3C(B(H)C8H14)CH-2'-OMe-1,1'-C20H12, (3- 26a/b): A 2 dram vial was charged with triazolium salt 3-25

(129.0 mg, 0.25 mmol, 1 equiv.), Na[N(SiMe3)2] (95% pure, 48.5 mg, 0.25 mmol, 1 equiv.), and 9-borabicyclo[3.3.1]nonane-dimer (30.5 mg, 0.125 mmol, 1 equiv.). At ambient temperature THF (2 mL) was added and the reaction mixture was stirred at ambient temperature overnight (20 h). 11B NMR spectroscopy of an aliquot in THF confirmed the clean formation of the product. The reaction mixture was filtered through a syringe filter and all volatiles were removed in vacuo. The residue was taken up in a minimal amount of toluene, layered with pentane, and kept at –25 °C. The supernatant was decanted and the solid was washed with pentane and dried in vacuo to give the product as an ochre solid. Yield: 114 mg (0.207 mmol, 82%); NMR data for 1 3 the major isomer 34a only is reported. H NMR (CD2Cl2, 500 MHz): δ 8.23 (d, JHH = 9 Hz, 1H), 3 3 3 8.12 (d, JHH = 8 Hz, 1H), 8.05 (d, JHH = 9 Hz, 1H), 7.99 – 7.86 (m, 1H), 7.83 (d, JHH = 9 Hz, 3 1H), 7.68 (m, 1H), 7.52 (s, 1H), 7.50 – 7.21 (m, 10H), 7.08 (d, JHH = 9 Hz, 1H), 3.80 (s, 3H), 1.96 13 1 – 1.24 (m, 10H), 1.06 (m, 3H), 0.54 (s, 1H), 0.16 (s, 1H); C{ H} NMR (CD2Cl2, 126 MHz):

δ 155.2, 138.3, 134.8, 133.8, 133.4, 133.3, 132.4, 132.0, 131.8, 130.4, 130.2, 129.3, 128.9, 128.9, 128.7, 128.6, 128.3, 127.7, 127.5, 125.5, 124.5, 124.4, 122.5, 116.0, 113.1, 56.5, 36.6, 36.2, 31.6, 11 1 31.6, 26.4, 26.0, 22.9; B NMR (CD2Cl2, 128 MHz): δ -18.4 (d, JBH = 84 Hz).

Synthesis of rac-9-(1,3-Ph2-N3CCH)-B(H)C9H15(10-Ph) (3-27): A 4 dram

vial was charged with lithium-B-H2-(10)-phenyl-9-borabicyclo[3.3.2]decane (62 mg, 0.25 mmol, 1 equiv.) and 2 mL THF was added. To this solution, iodomethane (0.03 mL, 0.5 mmol, 2 equiv.) was added dropwise with stirring and after 1 h at ambient temperature the mixture turned into a white milky colour. The reaction mixture was filtered through Celite and dried in vacuo. To the remaining solid was added 1,3- diphenyl-1H-1,2,3-triazolium tetrafluoroborate (77 mg, 0.25 mmol, 1 equiv.). The contents of the vial were dissolved in 4 mL THF and a solution of Na[N(SiMe3)2] (46 mg, 0.25 mmol, 1 equiv.) in 1 mL THF was added dropwise with stirring. The reaction mixture is then stirred overnight. The reaction mixture was filtered through a syringe filter and all volatiles removed in vacuo. Crystallization from toluene and pentane at –25 °C gave the product. Yield: 15 mg (0.034 mmol, 1 3 13%); H NMR (C6D6, 600 MHz): δ 7.90 (s, 1H), 7.75 (m, 2H), 7.42 (m, 2H), 7.31 (t, JHH = 8 Hz, 2H), 7.10 (m, 1H), 7.06 – 6.82 (m, 6H), 6.80 – 6.76 (m, 2H), 3.17 – 2.48 (m, 4H), 2.38 – 2.05 13 (m, 11H), 1.94 (m, 1H), 1.47 (m, 1H); C{H} NMR (C6D6, 125 MHz): δ 172.9, 157.5, 138.0, 135.3, 130.4, 130.1, 129.8, 129.7, 128.8, 128.4, 128.1, 127.3, 126.1, 123.4, 121.0, 48.9 (BCHPh), 11 1 44.2, 37.8, 36.2, 32.5, 30.9, 28.6, 26.1, 25.3; B NMR (C6D6, 128 MHz): δ -15.1 (d, JBH = 86 Hz).

Synthesis of (Me2-N2C3H2)(Ipc2BH) 3-28, (iPr2-N2C3H2)(Ipc2BH) 3-29, (BnMe-

N2C3H2)(Ipc2BH) 3-30, (PhMe-N2C3H2)(Ipc2BH) 3-31, (tBuMe-N2C3H2)(Ipc2BH) 3-32: These compounds were prepared in a similar fashion and thus one preparation is detailed. Ipc2BH (396 mg, 1.38 mmol, 1 equiv.), K[N(SiMe3)2] (290 mg, 1.45 mmol, 1.05 equiv.) and 1,3- dimethylimidazolium iodide (310 mg, 1.34 mmol, 1 equiv.) were added to a Schlenk flask. 20 mL of THF was added and the solution was stirred for 20 h at 25 °C. The solvent was removed in vacuo and the white residue was washed with pentane (3 x 2 mL). These washings were filtered through Celite and the residue was washed with toluene (3 x 2 mL). The washings were filtered through the same Celite plug into a separate vial. The vials were capped and put in a -35 °C freezer

where colourless crystals formed. The crystals were washed with cold pentane (3 x 1 mL) and dried in vacuo.

1 3-28: Yield: 198 mg (0.516 mmol, 37%); H NMR (CDCl3, 500 MHz): δ 6.81 (s, 1H), 6.74 (s, 1H), 3.88 (s, br, 6H), 2.18 (m, 1H), 2.13 – 2.07 (m, 2H), 2.05 – 1.96 (m, 1H), 1.92 – 1.83 (m, 2H), 1.75 – 1.63 (m, 3H), 1.59 – 1.52 (m, 1H), 1.43 – 1.34 (m, 1H), 1.32 – 1.23 (m, 1H), 1.19 – 1.02 (m, 2H), 1.122 (s, 3H), 3 1.117 (s, 3H), 1.09 (overlapping s, 6H), 1.08 (d, JHH = 7 Hz, 3H), 0.95 (d, br, 3 3 3 JHH = 9 Hz, 2H), 0.71 (d, br, JHH = 9 Hz, 2H), 0.59 (d, JHH = 7 Hz, 3H), No 13 1 B-H peak found.; C{ H} NMR (CDCl3, 125 MHz, partial): δ 121.1, 120.0, 50.8, 49.9, 45.0, 43.4, 43.1, 42.7, 39.3, 39.1, 37.8, 37.5, 36.2, 35.3, 33.6, 33.3, 28.7, 28.5, 23.8, 23.4, 23.13, 23.11; 11B 8 1 + NMR (toluene-d , 128 MHz): δ -9.1 (d, JBH = 86 Hz); HR-MS (EI+): C25H42BN2, [M-H] m/z (calc.): 381.34410, m/z (obs.): 381.34507.

1 3-29: Yield: 198 mg (0.45 mmol, 34%); H NMR (CDCl3, 500 MHz): δ 6.97 3 3 3 (d, JHH = 2 Hz, 1H), 6.92 (d, JHH = 2 Hz, 1H), 5.84 (septet, JHH = 7 Hz, 1H), 3 5.13 (septet, JHH = 7 Hz, 1H), 2.29 – 2.25 (m, 1H), 2.19 – 2.04 (m, 4H), 1.89 3 – 1.83 (m, 1H), 1.75 – 1.67 (m, 2H), 1.65 – 1.54 (m, 3H), 1.46 (d, JHH = 7 Hz, 3 3 3 3H), 1.459 (d, JHH = 7 Hz, 3H), 1.459 (d, JHH = 7 Hz, 3H), 1.37 (d, JHH = 7 3 3 Hz, 3H), 1.36 (d, JHH = 7 Hz, 3H), 1.12 (s, 3H), 1.11 (s, 3H), 1.10 (d, JHH = 7 3 3 Hz, 3H), 1.08 (s, 3H), 1.06 (s, 3H), 0.95 (d, JHH = 9 Hz, 1H), 0.84 (d, JHH = 9 Hz, 1H), 0.48 (d, 3 13 1 JHH = 7 Hz, 3H); C{ H} NMR (CDCl3, 125 MHz, partial): δ 115.8, 115.4, 50.6, 49.9, 49.3, 48.9, 44.9, 43.3, 43.1, 42.1, 39.0, 38.9, 37.1, 35.4, 33.8, 32.7, 28.38, 28.36, 24.10, 24.08, 23.8, 23.7, 11 8 1 23.4, 23.3, 23.0, 22.9; B NMR (toluene-d , 128 MHz): δ -8.2 (d, JBH = 86 Hz); Anal. Calc. for

C29H51BN2: C 79.43, H 11.72, N 6.39 %. Found: C 79.30, H 11.90, N 6.39 %.

1 3-30: Yield: 667 mg (1.451 mmol, 83%); H NMR (CD2Cl2, 500 MHz): δ 7.42 – 7.21 (m, br, 5H), 6.88 (s, br, 1H, minor), 6.80 (s, br, 1H, major), 6.76 (s, br, 2 1H, major), 6.66 (s, br, 1H, minor), 5.74 (d, JHH = 15 Hz, 1H, minor), 5.66 (d, 2 2 2 JHH = 15 Hz, 1H, major), 5.57 (d, JHH = 15 Hz, 1H, major), 5.17 (d, JHH = 15 Hz, 1H, minor), 3.94 – 3.88 (overlapping singlets, 3H, minor/major), 2.25 – 13 1 0.60 (m, 34H), No B-H peak found.; C{ H} NMR (CDCl3, 125 MHz, partial,

major only): δ 136.6, 129.0, 128.5, 128.2, 120.6, 119.8, 52.8, 50.8, 49.9, 44.7, 43.4, 43.0, 42.7, 11 39.4, 39.1, 37.6, 36.3, 35.3, 33.5, 33.4, 28.6, 28.5, 23.9, 23.4, 23.4; B NMR (CD2Cl2, 128 MHz): 1 δ -8.7 (obscured, minor), 9.11 (d, JBH = 85 Hz, major); Anal. Calc. for C31H47BN2: C 81.20, H 10.33, N 6.11 %. Found: C 80.72, H 10.81, N 6.16 %.

1 3-31: Yield: 407 mg (0.914 mmol, 56%); H NMR (CDCl3, 500 MHz): δ 7.45 3 – 7.40 (m, br, 5H), 6.95 (d, JHH = 2 Hz, 1H), 6.90 (br, 1H), 4.01 (s, 3H) 2.15 – 1.55 (m, br, 10H), 1.15 – 0.60 (m, br, 15H), 1.11 (s, 3H), 1.08 (s, 3H), 0.72 (d, 3 13 1 JHH = 8 Hz, 3H); C{ H} NMR (CD2Cl2, 125 MHz, partial): δ 140.6, 129.0, 128.8, 128.4, 122.4, 121.2, 51.2, 50.3, 44.5, 43.7, 43.5, 42.8, 39.6, 39.4, 38.3, 11 36.4, 35.3, 33.6, 33.3, 28.7, 28.5, 23.9, 23.8, 23.2, 23.1; B NMR (CD2Cl2, 128 1 MHz): δ -9.74 (d, JBH = 75 Hz); Anal. Calc. for C30H45BN2: C 81.06, H 10.20, N 6.30 %. Found: C 80.63, H 10.66, N 6.22 %.

1 3-32: Yield: 498 mg (1.17 mmol, 60%); H NMR (CD2Cl2, 500 MHz): δ 7.09 3 3 (d, JHH = 2 Hz, 1H), 6.73 (d, JHH = 2 Hz, 1H), 3.87 (s, 6H), 2.41 – 2.32 (m, 1H), 2.27 – 2.15 (m, 1H), 2.11 – 1.95 (m, 3H), 1.82 (s, 9H), 1.77 – 1.60 (m, 3 3H), 1.58 – 1.48 (m, 2H), 1.22 – 1.00 (m, br, 20H), 0.63 (d, JHH = 7 Hz, 3H); 13 1 C{ H} NMR (CDCl3, 125 MHz, partial): δ 119.5, 118.1, 60.9, 52.0, 50.2, 43.5, 43.2, 43.0, 42.6, 39.7, 39.5, 38.6, 38.6, 34.1, 32.8, 32.2, 32.2, 28.5, 28.3, 11 1 24.7, 24.2, 23.5, 23.4; B NMR (CD2Cl2, 128 MHz): δ -6.85 (d, JBH = 87 Hz); Anal. Calc. for

C28H49BN2: C 79.22, H 11.63, N 6.20 %. Found: C 78.64, H 11.51, N 6.65 %.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NMe)2C6H6][HBC8H14] (3-33), [(1R,5S)-5,8,8-Me3-2,4-

(NEt)2C6H6][HBC8H14] (3-34), [(1R,5S)-5,8,8-Me3-2,4-(Ni-Pr)2C6H6][HBC8H14] (3-35): These compounds were prepared in a similar fashion and thus one preparation is given in details. Carbene-borane adduct 3-7 (50 mg, 0.17 mmol) was dissolved in 4 mL pentane and heated to 50 °C for 4 h. The solvent was then removed in vacuo to provide the pure product.

1 3-33: A white powder. Yield: 50 mg (0.17 mmol, >99%); H NMR (C6D6, 3 500 MHz): δ 2.64 (s, 3H), 2.62 (d, JHH = 5 Hz, 1H), 2.59 (s, 3H), 2.53 (s, br, 1H), 2.38 (s, br, 1H), 2.25 – 2.09 (m, 3H), 1.95 – 1.63 (m, 13H), 1.60 – 1.53 (m, 4H), 1.42 – 1.35 (m, 1H), 1.15 (s, 3H), 0.97 (s, 3H), 0.78 (s, 3H); 13C{1H} 96

NMR (C6D6, 126 MHz): δ 79.2, 69.8, 68.7 (br), 67.6, 44.5, 41.0, 40.1, 38.5, 38.3, 35.2, 34.2, 30.8, 11 30.5, 28.4, 25.6, 24.9 (br), 22.7, 21.8, 20.6, 16.6, 5.0; B NMR (C6D6, 128 MHz): δ 44.2 (s, br); + HR-MS (ESI+): C19H36BN2, [M] m/z (calc.): 302.3002, m/z (obs.): 302.3003.

1 3-34: A white solid. Yield: 20 mg (0.06 mmol, >99%); H NMR (C6D6, 500 3 MHz): 3.35 – 3.20 (m, 2H), 2.69 (s, 1H), 2.64 (d, JHH = 5 Hz, 1H), 2.58 – 2.43 (m, 3H), 2.24 – 2.12 (m, 2H), 2.01 – 1.53 (m, 15H), 1.43 – 1.36 (m, 1H), 1.22 3 3 (s, 3H), 1.20 (t, JHH = 7 Hz, 3H), 0.92 (t, JHH = 7 Hz, 3H), 0.85 (s, 3H), 0.81 13 1 (s, 3H); C{ H} NMR (C6D6, 125 MHz): δ 76.2, 66.3, 51.9, 50.4, 47.3, 46.9, 42.5, 41.8, 39.3, 11 39.0, 38.8, 37.6, 31.5, 31.0, 30.8, 30.6, 29.8, 21.7, 18.2, 17.1, 15.7, 14.3; B NMR (C6D6, 128 + MHz): δ 44.0 (s, br); HR-MS (ESI+): C21H38BN2, [M] m/z (calc.): 328.3164, m/z (obs.):

328.3175; Anal. Calc. for C21H38BN2: C 76.35, H 11.90, N 8.48 %; Obs. C 76.57, H 11.63, N 8.09 %.

1 3-35: A white solid. Yield: 45 mg (0.13 mmol, >99%); H NMR (C6D6, 500 3 3 MHz): δ 3.93 (sept, JHH = 7 Hz, 1H), 3.49 (sept, JHH = 7 Hz, 1H), 3.31 (s, 3 1H), 2.94 (d, JHH = 6 Hz, 1H), 2.32 – 2.23 (m, 3H), 1.97 – 1.86 (m, 6H), 1.81 3 – 1.71 (m, 6H), 1.55 – 1.49 (m, 2H), 1.25 (s, 3H), 1.22 (d, JHH = 7 Hz, 6H), 3 3 13 1 1.00 (d, JHH = 7 Hz, 3H), 0.86 (d, JHH =7 Hz, 3H), 0.85 (s, 3H), 0.74 (s, 3H); C{ H} NMR

(C6D6, 125 MHz): δ 70.0, 66.9, 54.6 (br), 49.6, 48.6, 48.1, 47.2, 42.0, 33.4, 33.2, 32.2, 31.3, 29.0, 11 28.2, 27.1, 25.4, 25.0 (br), 23.8, 22.1, 21.9, 21.3, 20.7; B NMR (C6D6, 128 MHz): δ 44.0 (s, br); + HR-MS (ESI+): C23H42BN2, [M] m/z (calc.): 356.3477, m/z (obs.): 356.3484; Anal. Calc. for

C23H42BN2: C 77.08, H 12.04, N 7.82 %; Obs. C 77.10, H 12.36, N 7.75 %.

Synthesis of [(1R,5S)-5,8,8-Me3-2,4-(NMe)2C6H6B(C6F5)2][B(C6F5)4] (3-36), [(1R,5S)-5,8,8-

Me3-2,4-(NMe)2C6H6BC8H14][B(C6F5)4] (3-37), [(1R,5S)-5,8,8-Me3-2,4-

(NEt)2C6H6BC8H14][B(C6F5)4] (3-38), [(1R,5S)-5,8,8-Me3-2,4-(Ni-

Pr)2C6H6BC8H14][B(C6F5)4] (3-39): These compounds were prepared in a similar fashion and thus one preparation is detailed. A solution of [Ph3C][B(C6F5)4] (287 mg, 0.31 mmol, 1 equiv.) in toluene was added dropwise to a solution of borane-adduct 3-3 (95 mg, 0.31 mmol, 1 equiv.) in toluene at -40 °C. The reaction mixture was then allowed to warm slowly to 25 °C and was stirred

for 18 h, and an insoluble oil was formed. The volatiles were evaporated in vacuo and the crude product was washed with pentane (3 x 3 mL) to afford the desired product.

3-36: A white solid. Yield: 252 mg (0.26 mmol, 83%); 1H NMR 3 (CD2Cl2, 500 MHz): δ 3.15 (d, JHH = 5 Hz, 1H), 3.05 (s, 3H), 2.93 (s, 3H), 2.44 – 2.37 (m, 1H), 2.31 – 2.23 (m, br, 5H), 2.23 – 2.15 (m, 3H), 2.07 – 1.94 (m, br, 6H), 1.87 – 1.83 (m, br, 1H), 1.72 – 1.63 (m, br, 13 1 3H), 1.34 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H); C{ H} NMR (CD2Cl2, 1 1 1 125 MHz): δ 173.2, 148.7 (d, JCF = 241 Hz), 138.8 (d, JCF = 246 Hz), 136.4 (d, JCF = 243 Hz), 124.9 (br), 124.0 (br), 71.2, 71.1, 42.3, 41.0, 38.9, 38.0, 37.4, 36.7, 36.5, 33.2 (br), 32.4 (br), 31.2, 11 19 30.8, 30.7, 22.9, 21.8, 17.0, 14.4; B NMR (CD2Cl2, 128 MHz): δ 56.0 (s, br), -16.8 (s); F NMR

(CD2Cl2, 377 MHz): δ -124.1 (s, br), -126.1 (s, br), -130.7 (s, br), -133.2 (s, br), -137.9 (s, 3 3 br), -156.3 (s, br), -157.4 (s, br), -163.7 (t, JFF = 20 Hz), 167.6 (t, JFF = 19 Hz); HR-MS (ESI+): + C19H35BN2, [M+H ] m/z (calc.): 302.3002, m/z (obs.): 302.2999.

3-37: A white solid. Yield: 252 mg (0.26 mmol, 83%); 1H NMR 3 (CD2Cl2, 500 MHz): δ 3.15 (d, JHH = 5 Hz, 1H), 3.05 (s, 3H), 2.93 (s, 3H), 2.37 – 2.44 (m, 1H), 2.23 – 2.31 (m, br, 5H), 2.15 – 2.23 (m, 3H), 1.94 – 2.07 (m, br, 6H), 1.83 – 1.87 (m, br, 1H), 1.63 – 1.72 (m, br, 13 1 3H), 1.34 (s, 3H), 1.15 (s, 3H), 1.10 (s, 3H); C{ H} NMR (CD2Cl2, 1 1 1 125 MHz): δ 173.2, 148.7 (d, JCF = 241 Hz), 138.8 (d, JCF = 246 Hz), 136.4 (d, JCF = 243 Hz), 124.9 (br), 124.0 (br), 71.2, 71.1, 42.3, 41.0, 38.9, 38.0, 37.4, 36.7, 36.5, 33.2 (br), 32.4 (br), 31.2, 11 19 30.8, 30.7, 22.9, 21.8, 17.0, 14.4; B NMR (CD2Cl2, 128 MHz): δ 89.1 (s, br), -16.8 (s); F NMR

(CD2Cl2, 377 MHz): δ -167.6 (s, br), -163.9 – -163.7 (m), 133.1 (s, br); HR-MS (ESI+): + C19H35BN2, [M+H ] m/z (calc.): 302.3002, m/z (obs.): 302.2999.

1 3-38: Yield: 299 mg (0.29 mmol, 98%); H NMR (CD2Cl2, 500 MHz): 3 2 δ 3.53 (dq, JHH = 7 Hz, JHH = 16 Hz, 1H), 3.29 – 3.22 (m, 2H), 3.09 3 2 3 2 (dq, JHH = 7 Hz, JHH = 15 Hz, 1H), 2.75 (dq, JHH = 7 Hz, JHH = 16 Hz, 1H), 1.05 (s, 3H), 2.47 – 2.42 (m, 1H), 2.37 – 2.27 (m, 5H), 2.25 – 2.21 (m, 1H), 2.18 – 2.14 (m, 1H), 2.12 – 2.07 (m, 1H), 2.02 – 3 1.89 (m, 6H), 1.81 (s, br, 1H), 1.70 – 1.64 (m, 3H), 1.41 (s, 3H), 1.37 (t, JHH = 7 Hz, 3H), 1.27 (t,

3 13 1 1 JHH = 7 Hz, 3H), 1.16 (s, 3H); C{ H} NMR (CD2Cl2, 125 MHz): δ 171.3, 148.4 (d, JCF = 238 1 1 Hz), 138.2 (d, JCF = 240 Hz), 136.5 (d, JCF = 237 Hz), 69.4, 66.2, 48.6, 46.4, 40.0, 39.5, 36.4, 11 36.3, 36.0, 35.7, 31.5, 31.2 (br), 30.9 (br), 22.0, 21.8, 20.4, 16.7, 16.3, 13.3; B NMR (CD2Cl2, 19 3 128 MHz): δ 89.1 (s, br), -16.7 (s); F NMR (CD2Cl2, 377 MHz): δ -167.6 (t, JFF = 18 Hz), -163.7 3 + (t, JFF = 20 Hz), -133.1 (s, br); HR-MS (ESI+): C21H38BN2, [M ] m/z (calc.): 329.3123, m/z

(obs.): 329.2739; Anal. Calc. for C21H38BN2: C 53.60, H 3.80, N 2.78 %; Obs. C 54.21, H 2.60, N 2.50 %.

1 3-39: Yield: 276 mg (0.26 mmol, 93 %); H NMR (CD2Cl2, 500 3 3 MHz): δ 3.32 (d, JHH = 5 Hz, 1H), 3.10 (sept, JHH = 7 Hz, 1H), 2.68 3 (sept, JHH = 7 Hz, 1H), 2.61 – 2.55 (m, 1H), 2.39 – 2.23 (m, br, 7H), 2.13 – 2.03 (m, 3H), 1.94 – 1.90 (m, br, 2H), 1.89 – 1.87 (m, br, 1H), 1.85 – 1.81 (m, br, 2H), 1.81 – 1.78 (m, br, 1H), 1.70 – 1.64 (m, 1H), 3 3 3 1.61 (d, JHH = 7 Hz, 3H), 1.53 (s, 3H), 1.46 (d, JHH = 7 Hz, 3H), 1.34 (d, JHH = 7 Hz, 3H), 1.26 3 13 (d, JHH = 7 Hz, 3H), 1.15 (s, 3H), 1.09 (s, 3H); C{H} NMR (CD2Cl2, 125 MHz): δ 171.6, 148.2 1 1 1 (d, JCF = 241 Hz), 138.0 (d, JCF = 240 Hz), 136.1 (d, JCF = 242 Hz), 71.4, 61.0, 59.8, 55.9, 40.6, 39.7, 36.5, 36.4, 35.7, 35.5, 33.0, 29.4, 29.2, 21.8, 21.6, 21.3, 20.3, 19.7, 19.3, 16.8, 16.2, 13.9; 11 19 B NMR (CD2Cl2, 128 MHz): δ 85.8 (s, br), -16.7 (s); F NMR (CD2Cl2, 377 MHz): δ -167.6 (t, 3 3 + JFF = 18 Hz), -163.8 (t, JFF = 21 Hz), -133.1 (s, br); HR-MS (ESI+): C23H42BN2, [M ] m/z (calc.): 356.3472, m/z (obs.): 356.3477.

3.4.3 Procedures of Gaseous Experiments

General procedure for high pressure hydrogenation: Carbene-borane adduct (0.0261 mmol, 1

equiv.), [Ph3C][B(C6F5)4] (24 mg, 0.0261 mmol, 1 equiv.), and substrate (0.522 mmol, 20 equiv.)

were weighed into vials. 0.4 mL of solvent was used to dissolve the [Ph3C][B(C6F5)4] and the orange solution was transferred to the vial with the NHC-borane adduct, which turned colourless upon mixing. The colourless solution was transferred to the vial with the substrate using an additional 0.2 mL of solvent and was equipped with a stir bar and placed in a Parr pressure reactor.

The reactor was sealed, removed from the glovebox, purged 10 times with 20 atm of H2, and then

pressurized to 102 atm of H2. The reactor was stirred magnetically at the specified temperature for

the specified time and then vented slowly. NMR samples were taken in CDCl3. Conversions were

determined by 1H NMR spectroscopy from an aliquot. The sample was then concentrated in vacuo, dissolved in 9:1 hexanes : ethyl acetate and passed through a short silica plug. The sample was concentrated in vacuo and enantiomeric excess was determined by chiral HPLC (Chiralcel OD-H, 98.0 hexanes, 1.0 isopropanol) with comparison to a racemic sample prepared by 1,3- dimethylimidazol-2-ylidene-9-borabicyclo[3.3.1]nonane in the same hydrogenation process.

3.4.4 Racemization Experiments

With 3-18: Compound 3-18 (5.8 mg. 0.0162 mmol, 1 equiv.) and trityl tetrakis(pentafluorophenyl)borate (14.9 mg, 0.0162 mmol, 1 equiv.) was added in 1 mL DCM. A 1 mL DCM solution of (+)-bis[(R)-1-phenylethyl]amine (78.3 μL, 0.341 mmol, 21.1 equiv.) was then added. The solution was stirred at ambient temperature for 42 h and was dried in vacuo.

With 9-(1,3-diphenyl-1,2,3-triazol-5-ylidene)-9-borabicyclo[3.3.1]nonane: 9-(1,3-diphenyl- 1,2,3-triazol-5-ylidene)-9-borabicyclo[3.3.1]nonane (21 mg, 0.060 mmol, 1 equiv.) and trityl tetrakis(pentafluorophenyl)borate (55 mg, 0.060 mmol, 1 equiv.) were placed in a vial and 31 dissolved in CD2Cl2 (0.5 mL) generating [[CH)(NR)2CB(C8H14)][B(C6F5)4]. The resulting solution was transferred to a J. Young NMR tube equipped with a Teflon stopper. To this solution (+)-bis[(R)-1-phenylethyl]amine (140 µL, 0.612 mmol, 10.2 equiv.) was added by syringe and the

NMR tube was capped and shaken. A separate NMR tube was charged with a mixture of B(C6F5)3

(31 mg, 0.060 mmol, 1 equiv.) and (R,R)-(PhC(Me)H)2NH 35 (140 µL, 0.612 mmol, 10.2 equiv.) 1 in CD2Cl2 (0.5 mL). The reaction progress was monitored by H NMR spectroscopy.

3.4.5 X-ray Crystallography

3.4.5.1 X-Ray Data Collection and Reduction

Single crystals were coated in paratone oil, mounted on a cryo-loop, and frozen under a stream of cold nitrogen. Data were collected on a Bruker APEX2 X-ray diffractometer using graphite monochromated Mo-Kα radiation (0.71073 Å). The temperature was maintained at 150(2) K using an Oxford Cryo-stream cooler for initial indexing and full data collection. Data was collected using Bruker APEX-2 software and processed using SHELX and Olex2. An absorption correction was applied using multi-scan within the APEX-2 program. All structures were solved by direct methods within the SHELXTL package 62-63and refined with Olex2.64-65

100

3.4.5.2 Crystallographic Data Tables

Table 3.3. Selected crystallographic data for 3-6, 3-8, and 3-18

3-6 3-8 3-18

Formula C23 H21 B F10 N2 C21 H36 B N2 C21 H35 B N2 O2 Crystal System Orthorhombic Monoclinic Orthorhombic

Space Group P212121 P21 P212121 a/ Å 11.8584(10) 9.860(4) 6.692(2) b/ Å 11.9181(10) 9.940(4) 16.559(6) c/ Å 16.5677(14) 10.962(4) 17.724(8) α/ ° 90 90 90 β/ ° 90 111.93(2) 90 γ/ ° 90 90 90 V/ Å3 2341.5(3) 996.6(7) 1964.1(13) Z 4 2 4 T/ K 150(2) 150(2) 150(2)

-3 Dc/ g.cm 1.4926 1.1009 1.2117 Total data 39383 6701 8687 Unique data 5384 3958 4295

Rint 0.0309 0.0690 0.0552 2 2 R1[F >2 σ(F )] 0.0284 0.0679 0.0554 wR2 (all data) 0.0781 0.1688 0.1140 GoF 1.0421 0.9969 0.9964

101

Table 3.4. Selected crystallographic data for 3-19, 3-20, and 3-21.

3-19 3-20 3-21

Formula C13 H23 B N2 O2 C25 H42 B Cl N2 O2 C23 H39 B N2 O2 Crystal System Orthorhombic Orthorhombic Orthorhombic

Space Group P212121 P212121 P212121 a/ Å 8.0304(5) 11.2135(5) 10.0880(4) b/ Å 9.0974(5) 13.8015(6) 10.1235(5) c/ Å 19.4205(11) 16.3539(8) 21.6378(10) α/ ° 90 90 90 β/ ° 90 90 90 γ/ ° 90 90 90 V/ Å3 1418.78(14) 2531.0(2) 2209.78(17) Z 4 4 4 T/ K 150(2) 150(2) 150(2) -3 Dc/ g.cm 1.1710 1.1779 1.1613 Total data 10303 43135 90922 Unique data 3244 5839 5096

Rint 0.0357 0.0525 0.0318

2 2 R1[F >2 σ(F )] 0.0378 0.0393 0.0329 wR2 (all data) 0.0875 0.0963 0.0861 GoF 1.0359 1.0246 1.0868

102

Table 3.5. Selected crystallographic data for 3-35, and 3-38.

3-35 3-38

Formula C23 H43 B N2 C23 H21 B F10 N2 Crystal System Triclinic Orthorhombic

Space Group P1 P212121 a/ Å 9.4015(3) 11.8584(10) b/ Å 9.5499(3) 11.9181(10) c/ Å 12.9102(4) 16.5677(14) α/ ° 91.586(2) 90 β/ ° 109.357(3) 90 γ/ ° 93.844(3) 90 V/ Å3 1089.60(6) 2341.5(3) Z 2 4 T/ K 150(2) 150(2) -3 Dc/ g.cm 1.0924 1.5607 Total data 18560 41777 Unique data 10164 17623

Rint 0.0256 0.0305

2 2 R1[F >2 σ(F )] 0.0480 0.0386 wR2 (all data) 0.1254 0.1100 GoF 1.0711 1.0421

103

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Chapter 4 An Isolable B-H Borenium Cation as Template for Intramolecular Borenium-Based FLPs 4.1 Introduction

4.1.1 Intramolecular FLPs

As mentioned in Chapter 2, the Lewis pair in an intramolecular FLP is pre-organized for easy formation of the encounter complex. This brings about the attractive advantage of greater catalytic activity of the FLP and requiring milder catalytic conditions. This can be observed by comparing the two reports published separately by Stephan and co-workers, and Erker and co-workers in 2008 (Scheme 4.1, top). The Stephan group reported the catalytic hydrogenation of imines with the 1 archetype B(C6F5)3 and was able to achieve reduction at 120 °C with 5 bar H2. In stark contrast,

Erker and co-workers reported the four-membered ring system Mes2P(CH2)2B(C6F5)2 produced through hydroboration of dimesityl(vinyl)phosphane with Piers’ borane, and was able to effect complete imine reduction with significantly milder conditions at room temperature with 2.5 bar 2 H2. The increased catalytic activity of intramolecular FLPs can also allow for a broader range of substrates for reduction, including those that were previously restricted by steric or electronic requirements for a Lewis base in FLP hydrogenation. This was demonstrated in 2008 by Repo and co-workers, in which they developed an intramolecular B/N FLP that was able to completely reduce (E)-N-methyl-1-phenylethan-1-imine, a substrate with very little steric hindrance for a Lewis base in FLP hydrogenation (Scheme 4.1, middle).3 In addition, intramolecular FLPs can exhibit different chemistry than their intermolecular analogue. This was showcased in Erker and co-worker’s report in 2011, in which their ethylene-linked B/P FLP was able to capture NO as a heterocyclic N-oxyl radical, while the intermolecular counterpart undergo a disproportionation 4 reaction to give tBu3PN2OB(C6F5)3 and tBu3POB(C6F5)3 (Scheme 4.1, bottom).

108

The development of intramolecular FLPs has greatly expanded the scope of FLP chemistry beyond hydrogenation catalysis, such as the activation of carbon halides,5 the Staudinger reaction,6 7-11 catalytic hydroboration of CO2, and photochemical- and thermal-dependent stereoselective alkyne activation.12

109

4.1.2 Hydroboration by NHC-Borenium Cations

In the generation of intramolecular FLPs, the uncatalyzed hydroboration reaction of unsaturated reagents with electrophilic boranes has been frequently utilized.13-18 The addition of a B-H bond across an unsaturated bond in an Anti-Markovnikov manner allows for facile production of a single FLP product. Typically, electrophilic neutral trivalent B-H boranes, such as Piers’ borane, are used for this purpose.

Scheme 4.2. Catalytic cycle of alkene hydroboration with NHC-borenium cation as the active species.

Lewis base complexes of borane, such as amine-boranes, were also shown to undergo hydroboration. These Lewis bases are found to be labile and can undergo exchange with the alkene substrate to under hydroboration.19-22 In contrast, phosphine-boranes23 and NHC-boranes are stable and do not undergo hydroboration reactions even under heating. With the strong σ-donating abilities of the Lewis base, they resist decomplexation and as a result, they lack a vacant coordination site to facilitate hydroboration. In 2012, Curran and Vedejs demonstrated that by removal of a hydride, the NHC-borenium ion formed from NHC-borane mimics that of a free borane and can undergo hydroboration of simple alkenes.24 The resulting alkylated borenium

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cation can subsequently abstract a hydride from another NHC-borane, resulting in an overall catalytic hydroboration of alkenes with NHC-boranes, with the borenium cation as the active hydroborating species. Retrohydroboration resulted in migration of the boron centre along the alkane chain, and subsequent oxidative work-up produced the corresponding alcohol isomers (Scheme 4.2). A similar strategy was also applied, using iodine as the activator, and was found to selectively produce mono-hydroborated product.25 Silyl-substituted alkenes and alkynes were also reported to undergo similar hydroboration with NHC-borane, in which the substrate can effect an overall mono- or di-hydroborated product and produce isomers by 1,2-hydroboration or 1,1- hydroboration through silyl migration.26

4.1.3 An Isolable B-H Borenium Cation through C-H Activation

Our group has previously reported the formation of planar NHC-stabilized diarylborenium ions by dehydrogenative cationic borylation.27 1,3-dibenzylimidazolyl-2-ylidene-borane

(CHNCH2Ph)2CBH3 was reacted with one equivalent of [Ph3C][B(C6F5)4] to give

triphenylmethane and a BH2 borenium ion, which immediately activated one of the ortho C-H

bonds on the phenyl groups to give H2 gas and a B-H borenium cation. The cation is isolable at room temperature and shows a close contact with the chlorine atom of chlorobenzene in the solid state (2.937(3) Å) but maintaining an overall three-coordinate boron centre. The second C-H activation of the other phenyl group to form the planar diarylborenium cation only proceeds when the B-H borenium cation is heated to 130 °C (Scheme 4.3). Reactivity of the planar cation was reported, including the formation of a trimer cation through benzylic arm deprotonation, and the neutral diborane(4) formation by one-electron reduction (Scheme 4.4).28

Scheme 4.3. Reported synthesis of the diarylborenium cation by hydride abstraction and C-H activation of the phenyl group. 111

Scheme 4.4. Formation of a trimer cation through benzylic arm deprotonation, and neutral diborane(4) formation by one-electron reduction.

In contrast, the reactivity of the B-H borenium cation was not probed. We envision the cation to act as an analogue to Piers borane, and hydroborate alkenes and alkynes functionalized with a Lewis base to generate an intramolecular cationic FLP.

4.2 Results and Discussion

4.2.1 Synthesis of B-H Borenium Cation

One equivalent of [Ph3C][B(C6F5)4] was reacted with (CHNCH2Ph)2CBH3 in DCM to abstract a hydride to form 4-1. However, we found that 4-1 would decompose in DCM over time. Out of the decomposition products, we were able to obtain single colourless crystals that were suitable for X- ray crystallography, and the crystallographic data showed the formation of a B-Cl borenium cation

[PhCH2(CHN)2CCH2C6H4BCl][B(C6F5)4] 4-3 (Figure 4.1), although the mechanism for its

formation was unclear (Scheme 4.5). Compound 4-3 was crystallized in P21/n space group and the

B-Cl bond was found to be 1.694(1) Å. The B-CNHC bond was found to be 1.54(1) Å, which is similar to those reported for 4-1 (1.544(4) Å).27 The 360° sum of the bond angles at the boron centre supports the retention of planarity. We hypothesized that the decomposition of 4-1 may be due to traces of HCl in DCM. Unfortunately, our attempt to synthesize and isolate 4-3 independently was unsuccessful. The reaction of 4-1 with one equivalent of triethylamine hydrochloride as a mild source of HCl resulted in multiple peaks in the δ -2 – -12 ppm observed in the 11B NMR spectrum, suggesting multiple four-coordinate boron species rather than the desired three-coordinate 4-3. We have since modified the synthesis of 4-1 to be performed in toluene (Scheme 4.6) to avoid decomposition. The new synthetic route resulted retention of toluene

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in the product, even after extended drying in vacuo. The proportion of toluene retained was determined through integration of the relative resonances in the 1H NMR spectrum of 4-1.

Figure 4.1. POV-ray depiction of 4-3. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity. B: yellow-green; C: black; N: blue; Cl: green.

Scheme 4.5. Formation of B-Cl borenium cation 4-3.

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Scheme 4.6. Modified synthesis of isolable B-H borenium cation 4-1.

For comparative purposes, the 9-BBN borane analogue 4-4 was synthesized by in situ deprotonation of 1,3-dibenzylimidazolium bromide with one equivalent of KHMDS in the presence of half an equivalent of the 9-BBN dimer, and we were able to obtain compound 4-4 as a white powder in 67% yield (Scheme 4.7). Crystals suitable for X-ray crystallography were obtained from a concentrated toluene solution at -35 °C and crystallographic studies confirmed the formation of (PhCH2NCH)2CB(H)C8H14 4-4 (Figure 4.2). The crystals were formed in the P-1 space group and the boron centre is in a pseudo-tetrahedral geometry. The B-CNHC bond distance was found to be 1.639(3) Å, which falls within the range of the typical single B-CNHC bond distance previously observed in other imidazole-derived NHC-9-BBN adducts (1.63 – 1.65 Å),29-30 and the NCN bond angle was found to be 103.6(2)°. We were then able to generate the respective borenium cation [(PhCH2NCH)2CBC8H14][B(C6F5)4] 4-5 by subsequent hydride abstraction with one equivalent of [Ph3C][B(C6F5)4] and we were able to isolate 4-5 as a white powder in 96% yield (Scheme 4.7). A broad singlet peak at δ 83.1 ppm and a sharp singlet resonance at δ -16.7 ppm were observed in the 11B NMR spectrum, corresponding to the three-coordinate borenium cation and the four-coordinate borate anion. The 1H NMR spectrum confirmed the symmetric environment of the borenium species, and no activation of the phenyl groups was observed.

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Scheme 4.7. Synthesis of 4-4 by deprotonation of 1,3-dibenzylimidazolium bromide and 4-5 by in situ hydride abstraction.

Figure 4.2. POV-ray depiction of 4-4. Hydrogen atoms were omitted for clarity except for the B- H bond. B: yellow-green; C: black; N: blue; H: white.

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4.2.2 Lewis Acidity Determination

The Lewis acidity of the borenium cations 4-1, 4-2, and 4-5 were determined experimentally by the Gutmann-Beckett test (Table 4.1).31-32

Table 4.1. Experimental values of the Lewis acidity of B(C6F5)3 and the borenium cations.

31 1 Compound δ P{ H} (ppm) ∆ vs Et3PO AN

Et3PO 52.4 - -

33 Et3PO with B(C6F5)3 77 24.6 79.6

a Et3PO with 4-1 82.0 29.6 90.6

27 Et3PO with 4-2 79.2 28.9 84.4

Et3PO with 4-5 76.5 24.1 78.5

a All values were obtained from experiments performed in DCM, except CDCl3.

The borenium cations 4-1 and 4-2 were found to be more Lewis acidic than the archetypal Lewis

acid B(C6F5)3, while 4-5 was found to be slightly less Lewis acidic than B(C6F5)3. We attribute the comparable Lewis acidity to the positive charge on boron of these cations, which had been similarly observed in previous literature.34-35 In addition, the lack of steric bulk about the boron

centre for the cations 4-1 and 4-2 also allowed a stronger adduct formation with Et3PO as compared

to B(C6F5)3, giving rise to the increased experimental Lewis acidity. Comparing 4-1 with 4-2, we find 4-1 to be slightly more Lewis acidic than 4-2, and we attribute the difference to a lesser donation of the aryl group to the central boron of 4-1. Comparing the data to 4-5, we again see 4- 1 as the most Lewis acidic and we denote the difference in acidity due to more steric hindrance

around 4-5, resulting in a comparatively weaker adduct formation with Et3PO.

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Table 4.2. Computational values of the Lewis acidity of B(C6F5)3 and the borenium cations.

FIA (kJ/mol) GEI (eV) GEI (eV) a GEI (eV) b

36-37 B(C6F5)3 452.6 3.78 1.23 1.31

4-1 699.5, 699.9 c 8.96 3.62 5.08

4-2 669.6 8.17 3.48 4.86

4-5 679.1 6.80 2.79 3.92

FIA was calculated at the MP2/def2-TZVPP//BP89/def2-TZVP level, while GEI was calculated with the B3LYP/def2-TZVP basis set, in gas phase and with a DCM and b toluene solvent effect. c Two possible geometries are possible with the computed B-F complex for FIA calculations.

The Lewis acidity of the borenium cations were studied computationally (Table 4.2). Based on the computed values of FIA and GEI, 4-1 was the most Lewis acidic, followed by 4-2, which aligned with the experimental observations. Interestingly, while the experimental results suggested that

B(C6F5)3 and 4-5 have similar Lewis acidity, the FIA and GEI values suggest 4-5 is more Lewis acidic than B(C6F5)3. We attribute the discrepancies between the experimental and computational values to the different steric conditions around the boron centres, giving rise to the different strength of the adducts formed in the Gutmann-Beckett test. NBO analysis of the optimized structure revealed the HOMOs of 4-1 reside on the free phenyl ring (Figure 4.3, left), while the LUMOs primarily reside on the boron, with some delocalization over the ring-closed carbene (Figure 4.3, right). Similarly, the HOMOs of 4-2 are delocalized on the aryl substituents (Figure 4.4, left). In contrast, the LUMOs of 4-2 are delocalized through the entire planar borenium cation, with primary composition on the boron (Figure 4.4, right), which could attribute to the lesser Lewis acidity of 4-2 compared to 4-1.

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Figure 4.3. Surface contour plot of HOMO (left) and LUMO (right) of 4-1; B: yellow-green; C: grey; N: blue; H: white.

Figure 4.4. Surface contour plot of HOMO (left) and LUMO (right) of 4-2. B: yellow-green; C: grey; N: blue; H: white.

4.2.3 Reactivity Studies

4.2.3.1 Hydroboration

Addition of 4-1 with terminal or internal alkenes proceeds through a typical 1,2-hydroboration to produce trialkylborenium cations (Scheme 4.8). With the addition of one equivalent of cyclohexene, we were able to obtain a new borenium species

[PhCH2(CHN)2CCH2C6H4BCy][B(C6F5)4] 4-6 as a white powder in 92% yield. We observed the disappearance of the alkene signals in the 1H NMR spectrum and the formation of cyclohexane 118

signals at δ 1.16 – 2.27 ppm. A broad singlet at δ 55.5 ppm and a sharp singlet at δ -16.7 ppm were observed in the 11B NMR spectrum for the three-coordinate borenium centre and the borate anion respectively. Similarly, with the addition of one equivalent of 3,3-dimethyl-1-butene, we were able to obtain [PhCH2(CHN)2CCH2C6H4BCH2CH2tBu][B(C6F5)4] 4-7 as a white powder in 96% yield. We also observed the disappearance of the alkene resonances in the 1H NMR spectrum and the formation of ethylene signals at δ 1.17 – 2.16 ppm. A broad singlet at δ 58.9 ppm and a sharp singlet at δ -16.7 ppm in the 11B NMR spectrum were observed for the three coordinate borenium centre and the borate anion respectively. The isolated borenium cations can then undergo subsequent oxidation with hydrogen peroxide and sodium hydroxide, as typically seen in hydroboration-oxidation reactions. Cyclohexanol 4-8 and 3,3-dimethylbutan-1-ol 4-9 were observed in the 1H NMR spectra after acidic workup. In comparison to the report by Curran and Vedejs,24 no retrohydroboration was observed and no isomers were formed in these reactions.

Scheme 4.8. Hydroboration of simple alkenes and the subsequent oxidation to generate the respective alcohols.

Compound 4-1 also undergoes 1,2-hydroboration with terminal and internal alkynes. When one equivalent of diphenylacetylene was reacted with 4-1, we were able to obtain a new borenium species [PhCH2(CHN)2CCH2C6H4BC(Ph)C(H)Ph][B(C6F5)4] 4-10 quantitatively as an orange powder (Scheme 4.9). A singlet was observed at δ 6.97 ppm in the 1H NMR spectrum for the alkenyl proton and in the 11B NMR spectrum, a broad singlet was observed at δ 52.1 ppm for the three-coordinate borenium centre. Similarly, we were able to obtain

[PhCH2(CHN)2CCH2C6H4BCHCHC4H9][B(C6F5)4] 4-11 as a white powder in 95% yield when

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3 one equivalent of 4-1 was reacted with 1-hexyne (Scheme 4.9). A double of triplet with JHH = 3 18 Hz and JHH = 6 Hz was observed for the alkenyl proton cis to the boron centre at δ 6.94 ppm 1 3 4 in the H NMR spectrum, while a double of triplet with JHH =18 Hz and JHH = 1 Hz was observed for the geminal alkenyl proton at δ 6.77 ppm. A broad singlet at δ 50.5 ppm was observed in the 11B NMR spectrum, which corresponds to the three-coordinate borenium centre. In comparison, when one equivalent of the dissymmetric alkyne 1-phenyl-1-propyne was added to 4-1, we observed the formation of 2 regioisomeric products 4-12a/b in quantitative yield in a 3:2 ratio 4 (Scheme 4.10). A quartet at δ 6.84 ppm and a doublet at δ 2.28 ppm with JHH = 2 Hz were observed for the alkenyl proton and methyl resonances respectively for the major product 4-12a, while a 3 quartet at δ 6.28 ppm and a doublet at δ 2.14 ppm with JHH = 7 Hz were observed for the alkenyl proton and methyl resonances respectively for the minor product 4-12b. An overall broad singlet at δ 55.4 ppm was observed for the borenium cation, potentially due to the overlapping signals of the two species. We attribute the formation of regioisomers to the distribution of steric demands of the alkyne and we determined the ratio of regioisomeric products formed through integration of the relative peaks in the 1H NMR spectrum (Figure 4.5).

Scheme 4.9. Hydroboration of diphenylacetylene and 1-hexyne with 4-1.

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Scheme 4.10. Hydroboration with 4-1 of 1-phenyl-1-propyne.

Figure 4.5. Characteristic resonances in the 1H NMR spectrum of 4-12 showing distribution of regioisomers 4-12a (red) and 4-12b (green).

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4.2.3.2 Deprotonation by a Base

With the addition of one equivalent of tBu3P to 4-1, we observed the formation of a phosphonium 1 31 salt that has a resonance with a JPH = 430 Hz at δ 60.5 ppm in the P NMR spectrum and a doublet 1 1 at δ 4.93 ppm in the H NMR spectrum with the same JPH coupling. We attributed this to be the formation of [HPtBu3][B(C6F5)4] from proton abstraction of the benzylic arm, as previously reported in the analogous reaction with 4-2.27 This was confirmed by the addition of half an equivalent of tBu3P, and we observed the formation of [HPtBu3][B(C6F5)4], which can be isolated and is confirmed through X-ray crystallography studies, and the formation of a borenium dimer cation 4-13 (Scheme 4.11). A broad singlet at δ -22.2 ppm was observed in the 11B NMR spectrum for the four-coordinate B-H boron centre. In addition, a broad resonance at δ 3.80 ppm in the 1H 3 1 11 spectrum, which becomes a doublet with a JHH = 14 Hz in the H{ B} spectrum, was observed for this boron centre. In contrast, the resonance for the three-coordinate B-H boron centre was not observed in the 11B NMR spectrum and a broad singlet was observed in both the 1H and 1H{11B} NMR spectrum at δ 4.22 ppm.

Scheme 4.11. Formation of the borenium dimer cation 4-13 by deprotonation of the benzylic arm.

4.2.3.3 Hydroboration of Base-Functionalized Alkenes and Alkynes

When 4-1 is reacted with alkenes functionalized with a small Lewis base, we observed immediate adduct formation with no hydroboration. When 4-1 was reacted with one equivalent of ethynyldiphenylphosphane, we were able to isolate the phosphine-borenium adduct

[PhCH2(CHN)2CCH2C6H4B(H)P(Ph2)CCH][B(C6F5)4] 4-14 as a white powder in 90% yield 122

(Scheme 4.12, right). We observed an upfield shift in the 11B NMR spectrum to a broad singlet at δ -22.0 ppm and the 31P{1H} NMR spectrum showed a shift from δ -34.1 ppm to a singlet at δ -8.3 ppm, suggesting a four-coordinate boron species. The 1H NMR spectrum showed a broad 3 B-H peak at δ 3.96 ppm and a doublet at δ 3.47 ppm with a JHP = 9 Hz for the terminal alkyne proton, suggesting no hydroboration had occurred. Similarly, we observed only adduct formation when 4-1 was reacted with one equivalent of 2-vinylpyridine, and the pyridine-borenium adduct 4-15 was isolated in 98% yield (Scheme 4.12, left). A broad singlet at δ -9.0 ppm in the 11B NMR spectrum was observed, suggesting a four-coordinate boron centre, and the C=C bond remained unreacted as suggested from the persistent alkene resonances in the 1H NMR spectrum. Single colourless crystals suitable for X-ray crystallography were isolated by evaporation from a saturated chloroform solution at ambient temperature and crystallographic data confirmed the formulation of the product as [PhCH2(CHN)2CCH2C6H4B(H)NC5H4C(H)CH2][B(C6F5)4] 4-15 (Figure 4.6).

Compound 4-15 crystallized in a P-1 space group and the B-N bond was found to be 1.604(3) Å. Adduct formation was also observed when 4-1 was reacted with similar unsaturated substrates with Lewis bases, such as diphenyl(vinyl)phosphane, di-t-butyl(ethynyl)phosphane, di-tert- butyl(phenylethynyl)phosphane and dimesityl(vinyl)phosphane, as monitored by multinuclear NMR spectroscopic data. Heating of the adducts to 60 °C resulted in either no reaction or decomposition of the borenium cation. We attribute the lack of hydroboration with these compounds to the lack of steric hindrance around the vacant p orbital on the boron centre to prevent adduct formation with the Lewis bases.

Scheme 4.12. Adduct formation of 4-1 with ethynyldiphenylphosphane (right) and 2- vinylpyridine (left). 123

Figure 4.6. POV-ray depiction of 4-15. The tetrakis(pentafluorophenyl)borate anion and hydrogen atoms were omitted for clarity except for the B-H bond. B: yellow-green; C: black; N: blue; H: white.

We then synthesized bulkier mesitylphosphino-alkenes and alkynes to preclude adduct formation.

When 4-1 was added to one equivalent of ethynyldimesitylphosphane HC≡CPMes2, a mixture of products was observed as evidenced by the formation of multiple peaks in the 31P NMR spectrum. With the high Lewis acidity of 4-1 and the prevention of adduct formation by the greater steric environment about the phosphine, we hypothesized that the borenium cation and the phosphine can act as an FLP and activate the alkyne either by hydride abstraction or an addition reaction. However, in comparison to previous reports on the activation of terminal alkynes by FLPs,38-39 this led to the decomposition of the reaction components as the alkyne and the Lewis base reside on the same molecule. To address this, we synthesized dimesityl(phenylethynyl)phosphane

PhC≡CPMes2 and reacted one equivalent of the phosphine with 4-1 at -35 °C. We observed a broad singlet in the 31P{1H} NMR spectrum at δ -21.2 ppm which we propose to be the adduct species. As the temperature increases, multiple peaks in the 31P{1H} NMR spectrum start to appear. Of 31 1 those, we were able to identify a singlet at δ -144.5 ppm with v1/2 = 20 Hz in the P{ H} NMR spectrum. In a parallel experiment, when 4-2 was reacted with the phosphine and an identical peak 124

31 1 was observed in P{ H} NMR spectrum. We also observed a broad singlet at δ -19 ppm with v1/2 = 162 Hz in the 11B NMR spectrum, suggesting a four-coordinate boron centre. We concluded the product was a phosphirenium system 4-16 formed by the migration of the diarylphosphinyl group (Scheme 4.13).40 This was observed also by Erker’s group in a previous report, in which they produced the B(C6F5)3 analogue of 4-16 when they reacted the phosphine with one equivalent of 31 1 B(C6F5)3 and reported similar observations in the P{ H} NMR spectrum (δ = -137.4 ppm, v1/2 ~ 10 Hz).41 Compound 4-16 was found to decompose in solution overnight at ambient temperature.

Scheme 4.13. Formation of a phosphirenium system 4-16 by a diarylphosphinyl group migration.

When 4-1 was reacted with one equivalent of dimesityl(1-phenylvinyl)phosphane at -35 °C, we observe a broad singlet in the 31P NMR spectrum at δ 4.2 ppm which we conclude to be the adduct. As the temperature increases, we observed the disappearance of this signal and the appearance of 31 a doublet with a JPH coupling of 100 Hz at δ 32.5 ppm in the P NMR spectrum. In addition, we 11 observed a broad singlet at δ -1.8 ppm with a v1/2 ~ 1000 Hz in the B NMR spectrum. The experimental values obtained were similar to that of the Piers’ borane analogue reported by Erker 31 3 11 42 ( P NMR: δ 40.3 ppm (d, JPH = 110.1 Hz); B{H} NMR: δ 2.5 ppm (s, br, v1/2 = 600 Hz)). We hypothesized that a 1,2-hydroboration with the phosphinoalkene produced 4-17 and there is an electronic donation from the phosphine to the boron centre to give a four-coordinate boron environment (Scheme 4.14). The structure of 4-17 was modelled via computational studies at the M06-2X/def2-SVP level of theory. The loss of planarity at the borenium centre suggested a coordination of the phosphine, giving 4-17 a pseudo-tetrahedral geometry at the boron centre. The

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HOMO was found to primarily reside on the mesitylphosphine with some delocalization to the boron centre, while the LUMO primarily resides on the borenium with some delocalization to the phosphine (Figure 4.7). Furthermore, NBO calculations were computed at the M06-2X/Def2- TZVP//M06-2X/def2-SVP level of theory.43-44 A bonding NBO was found between the boron and the phosphorus centre, with an occupancy of 1.90 e-. 38% of the bond was contributed from boron orbitals, which have a hybridization of 17% s orbitals and 83% p orbitals, and 62% of the bond was contributed from phosphorus orbitals, which have a hybridization of 30% s orbitals and 70% p orbitals. The Wiberg bond index (WBI) was also found to be 0.8186 a.u. for the B-P bond. In addition, the 31P and 11B NMR chemical shift was computed at the GIAO-B97D/def2-TZVP//M06- 2X/def2-SVP level of theory, setting the dimesityl(1-phenylvinyl)phosphane and 4-1 as the reference standard respectively. The computed 31P and 11B isotropic shifts for 4-17 were found to be δ 26.6 and -1.6 ppm respectively, which correlate well with the experimental values of δ 32.5 and -1.8 ppm. Computational studies suggest the formation of 4-17 through hydroboration, in which there is a significant donation of the phosphine to the borenium centre, which correlates to experimental NMR spectroscopy interpretation.

Scheme 4.14. Hydroboration of dimesityl(1-phenylvinyl)phosphane with 4-1 to form ethylene- bridged phosphine-borenium cation 4-17.

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Figure 4.7. Surface contour plot of HOMO (left) and LUMO (right) of 4-17. Hydrogen atoms were omitted for clarity. B: yellow-green; C: grey; N: blue; P: orange.

Table 4.3. Attempted hydrogenations of unsaturated substances with 4-17.

Substrate Equivalents Pressure (atm) Time (h) Yield (%)

1 86 66 0

2 86 66 0

1 86 66 0

2 86 66 0

1 100 24 0

2 100 24 0

1 100 24 0

2 100 24 0

Compound 4-17 was generated in situ and immediately subjected to H2/D2 scrambling and high- pressured reduction experiments. However, no HD gas was observed by 1H NMR spectroscopy,

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and 4-17 was shown to be inactive in hydrogenation as it does not reduce 1,1-diphenylethylene, diphenylacetylene, (E)-N-tert-butyl-1-phenylmethanimine, nor benzophenone (Table 4.3). With the computational data suggesting a significant coordination of the phosphine to the borenium centre, we hypothesize that this prevents the formation of the encounter complex to effect FLP reactivity.

4.3 Conclusion

Investigations of the reactivity of the borenium cation 4-1 were carried out to ultimately generate a borenium-phosphine cation 4-17 by hydroboration. The borenium cation 4-1 was found to be highly Lewis acidic, both by experimental and computational methods, and is capable of 1,2- hydroboration of alkenes and alkynes. Subsequent oxidation reaction of the alkyl-borenium cation generated the corresponding alcohols. However, with the open vacant p orbital of the boron centre, hydroboration is inhibited by the presence of a Lewis base through adduct formation. In addition, strong bulky phosphines were found to deprotonate the methylene bridge of the activated phenyl group of 4-1, and we were able to generate a new cationic dimeric boron species 4-13.

Screening of different phosphinoalkenes and phosphinoalkynes demonstrated the need of a large steric environment to preclude adduct formation and effect hydroboration. Dimesityl(1- phenylvinyl)phosphane was shown to be able to generate the borenium-phosphine cation 4-17 through hydroboration and computational modelling of NMR isotropic shifts correlates well with experimental values. In addition, it suggests a significant donation of the phosphine to the borenium cation and resulting in a pseudo-tetrahedral geometry. The resulting cation was found to be inactive in dihydrogen activation and catalytic reduction. Nonetheless, we demonstrated the potential of generating an active intramolecular borenium-phosphine FLP species through NHC- borenium cation hydroboration. We envision judicious catalyst design, such as modification on steric demands and electronics of the borenium cation and the phosphine can be fruitful.

4.4 Experimental Section

4.4.1 General Considerations

All manipulations were carried out under dry, O2-free N2 using an MBraun glovebox and a Schlenk vacuum-line. Pentane and dichloromethane were collected from a Grubbs-type column system

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manufactured by Innovative Technology and into thick-walled glass Schlenk bombs with Young- type Teflon valve stopcocks. Spectrograde chloroform was obtained from ACP Chemicals, dried over CaH2, and vacuum-transferred into Young bombs. Tetrahydrofuran was obtained from Sigma-Aldrich, dried over Na/benzophenone, and vacuum-transferred into Young bombs.

Dichloromethane-d2 and chloroform-d were obtained from Cambridge Isotope Laboratories, dried over CaH2, and vacuum-transferred into Young bombs. All solvents were degassed after purification and stored over 4 Ǻ molecular sieves. Commercial reagents were purchased from Sigma-Aldrich, TCI Chemicals, Strem Chemicals or Alfa Aesar, and used without further purification unless indicated otherwise. 1,3-dibenzylimidazolium bromide,45 1,3- dibenzylimidazolyl-2-ylidene-borane,27 di-t-butyl(ethynyl)phosphane,46 di-tert- butyl(phenylethynyl)phosphane47 and dimesityl(vinyl)phosphane,2 dimesityl(phenylethynyl)phosphane,2 and dimesityl(1-phenylvinyl)phosphane42 were prepared using literature methods. Crystals of dimesityl(1-phenylvinyl)phosphane suitable for X-ray studies were produced from a concentrated toluene solution at -35 °C.

NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer or a Varian Mercury Plus

400 MHz spectrometer at 25 ºC. Chemical shifts are given relative to SiMe4 and referenced to the 1 13 11 31 residual solvent signal ( H, C) or relative to an external standard ( B: 15% (Et2O)BF3, P: 85% 19 H3PO4, F: CFCl3). Chemical shifts (δ) are reported in ppm and coupling constants (J) as scalar values in Hz. Mass spectrometry was carried out using an AB/Sciex QStar mass spectrometer with an ESI source. GC-MS spectra were obtained on an Agilent Technologies 5975C VL MSD with Triple Axis Detector and 7890A GC System Column Agilent 19091S-433 (30m x 250 μm x 0.25 μm). Helium was used as the carrier gas. Elemental analyses (C, H, N) were performed in-house with a Perkin Elmer 2400 Series II CHNS Analyzer.

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4.4.2 Synthesis of Compounds

Synthesis of [PhCH2(CHN)2CCH2C6H4BH][B(C6F5)4] (4-1): 1,3- dibenzylimidazolyl-2-ylidene-borane (200 mg, 0.763 mmol, 1 equiv.) was added to 8 mL of toluene. Trityl tetrakis(pentafluorophenyl)borate (703.5 mg, 0.763 mmol, 1 equiv.) in 8 mL of toluene was added slowly to the solution. The solution was stirred, and gas bubbles were evolved. The solution was concentrated after 4 hours of stirring and pentane was added. A white powder was formed, and the mixture was stirred overnight. The mixture was then left to settle, and excess solvent was pipetted out. Toluene was added to the white solid and the mixture was centrifuged. Excess solvent was pipetted out. Two more toluene washes were carried out and the remaining white solid was washed with pentane and dried. Toluene remained in sample after extensive drying and resulting composition was determined by 1H NMR spectroscopy. Yield: 605 1 3 mg (0.649 mmol, 85 %); H NMR (CDCl3, 400 MHz, toluene omitted): δ 8.15 (d, JHH = 8 Hz, 3 3 1H, BCCH), 7.85 (t, JHH = 8 Hz, 1H, p-Arring), 7.63 (t, JHH = 8 Hz, 2H, m-Arring), 7.52 (s, 1H, 3 3 HCN), 7.48 (d, JHH = 8 Hz, 1H, Ph), 7.46 – 7.40 (m, 3H, Ph), 7.29 (d, JHH = 2 Hz, 1H, HCN), + 13 1 7.29 – 7.26 (m, 1H, Ph), 6.15 (s, br, BH ), 5.65 (s, 2H, CringH2), 5.53 (s, 2H, CH2); C{ H} NMR 1 (CDCl3, 125 MHz, toluene omitted): δ 148.2 (d, JCF = 243 Hz, o-C6F5), 142.6 (BCCH), 138.3 (d, 1 1 JCF = 247 Hz, p-C6F5), 137.0 (p-Arring), 136.3 (d, JCF = 247 Hz, m-C6F5), 130.3 (Ph), 130.0 (Ph),

129.1 (m-Arring), 128.2 (Ph), 125.9 (HCN), 125.2 (HCN), 53.8 (CringH2), 52.0 (s, 2H, CH2). Ipso 11 + carbons are not observed.; B NMR (CDCl3, 128 MHz): δ 48.1 (s, br, BH ), -16.6 (s, B(C6F5)4); 19 3 3 F NMR (CDCl3, 376 MHz): δ -132.7 (d, JFF = 10 Hz, o-C6F5), -162.4 (t, JFF = 21 Hz, p-C6F5), 3 -166.5 (t, JFF = 20 Hz, m-C6F5).

Synthesis of (PhCH2NCH)2CB(H)C8H14 (4-3): 1,3-dibenzylimidazolium bromide (1 g, 3.04 mol, 1 equiv.) and 9-BBN dimer (0.371 g, 1.52 mol, 0.5 equiv.) were added to 10 mL of THF at -35 °C. KHMDS (0.61 g, 3.05 mol, 1 equiv.) in 7 mL of THF was added slowly to the mixture while stirring. A cloudy beige solution was formed and stirred overnight. The mixture was dried and washed with pentane. Toluene was then added, and the mixture was filtered through Celite. The toluene extract was concentrated and stored in a -35 °C freezer. Colourless crystals were formed, washed with cold toluene and pentane, and dried

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1 to a white powder. Yield: 756 mg (2.04 mmol, 67%); H NMR (CDCl3, 400 MHz): δ 7.38 – 7.29

(m, 6H, m-Ph, p-Ph), 7.22 – 7.20 (m, 4H, o-Ph), 6.56 (s, 2H, NCH), 5.44 (s, 2H, NCH2), 1.89 – 1.88 (m, 3H, 9-BBN), 1.78 – 1.74 (m, 5H, 9-BBN), 1.54 – 1.48 (m, 3H, 9-BBN), 1.34 – 1.30 (m, 13 1 3H, 9-BBN). B-H peak is not observed.; C{ H} NMR (CDCl3, 125 MHz): δ 136.7 (NCN), 128.9

(o-Ph), 128.1 (p-Ph), 127.8 (m-Ph), 119.8 (NCH), 51.8 (NCH2), 37.4 (9-BBN), 31.2 (9-BBN), 25.1 11 (9-BBN), 23.7 (9-BBN), 22.5 (9-BBN). Ipso carbons are not observed.; B NMR (CDCl3, 128 1 + MHz): δ -16.1 (d, JBH = 96 Hz, B-H); MS (DART) m/z: 369.2 [M-H] HR-MS (ESI): C25H30BN2 + [M-H] m/z (calc.) 269.2502, m/z (obs.) 269.2501; Anal. Calcd. for C25H31BN2: C 81.08, H 8.44, N 7.56 %. Found C 81.17, H 8.63, N 7.44 %.

Synthesis of [(PhCH2NCH)2CBC8H14][B(C6F5)4] (4-5): 1,3-dibenzyl- imidazol-2-ylidene-9-borabicyclo[3.3.1]nonane (45 mg, 0.122 mmol, 1

equiv.) was added to 2 mL CHCl3. Trityl tetrakis(pentafluorophenyl)borate (112 mg, 0.122 mmol, 1 equiv.) in

approximately 5 mL of CHCl3 was added to the solution and stirred for 15 min to form a clear colourless solution. The solution was dried to a light-yellow oil, washed with pentane and dried to a white powder. 1 Yield: 122 mg (0.117 mmol, 96 %); H NMR (CDCl3, 400 MHz): δ 7.46

– 7.39 (m, 5H, Ph), 7.24 (s, 2H, NCH), 7.12 – 7.06 (m, 5H, Ph), 5.40 (s, 4H, NCH2), 2.24 – 2.04 13 1 1 (m, 8H, 9-BBN), 1.85 – 1.72 (m, 4H, 9-BBN); C{ H} NMR (CDCl3, 125 MHz): δ 148.3 (d, JCF 1 3 1 = 240 Hz, o-C6F5), 138.3 (dt, JCF = 247 Hz, JCF = 14 Hz, p-C6F5), 136.4 (d, JCF = 247 Hz, m-

C6F5), 132.3 (Ph), 127.2 (Ph), 126.4 (NCH), 125.6 (Ph), 54.0 (NCH2), 34.4 (9-BBN), 33.4 (s, br, 11 9-BBN), 22.4 (9-BBN). Ipso carbons are not observed.; B NMR (CDCl3, 128 MHz): δ 83.1 (s, + 19 3 br, B ), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.6 (d, JFF = 13 Hz, o-C6F5), - 3 3 162.8 (t, JFF = 21 Hz, p-C6F5), -166.8 (t, JFF = 20 Hz, m-C6F5).

Synthesis of [PhCH2(CHN)2CCH2C6H4BCy][B(C6F5)4] (4-6): Compound 4-1 • 0.8 tol (50 mg, 0.049 mmol, 1 equiv.) was dissolved in

1 mL of CHCl3. Cyclohexene (5 μL, 0.049 mmol, 1 equiv.) was added. A clear colourless solution was formed and stirred for 3 h. The solution was dried, washed with pentane and dried to a white powder. Yield: 46.7 1 3 mg (0.0457 mmol, 92 %); H NMR (CDCl3, 400 MHz): δ 8.47 (d, JHH 131

3 4 = 8 Hz, 1H, BCCH), 8.00 (t, JHH = 8 Hz, JHH = 1 Hz, 1H, p-Arring), 7.64 – 7.56 (m, 2H, m-Arring), 3 3 7.49 (s, 1H, HCNCH2), 7.46 (d, JHH = 2 Hz, 2H, o-Ar), 7.45 (d, JHH = 2 Hz, 1H, p-Ar), 7.38 (d, 3 JHH = 2 Hz, HCNCH2), 7.14 (m, 2H, m-Ar), 5.71 (s, 2H, CringH2), 5.52 (s, 2H, CH2), 2.27 (m, 1H, BCH), 1.96 – 1.74 (m, 7H, Cy), 1.52 – 1.37 (m, 1H, Cy), 1.34 – 1.16 (m, 2H, Cy); 13C{1H} NMR 1 1 (CDCl3, 125 MHz): δ 148.2 (d, JCF = 243 Hz, o-C6F5), 138.2 (d, JCF = 239 Hz, p-C6F5), 137.9 1 (BCCH), 136.3 (d, JCF = 256 Hz, m-C6F5), 135.9 (p-Arring), 130.2 (p-Ar), 130.2 (o-Ar), 128.6 (m-

Arring), 127.2 (m-Ar), 127.1 (HCNCH2), 126.4 (HCNCH2), 54.8 (CringH2), 52.3 (CH2), 33.9 (s, br, 11 BCH), 29.2 (Cy), 27.7 (Cy), 26.5 (Cy). Ipso carbons are not observed.; B NMR (CDCl3, 128 + 19 3 MHz): δ 55.5 (s, br, B ), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.7 (d, JFF = 13 3 3 Hz, o-C6F5), -162.6 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 20 Hz, m-C6F5).

Synthesis of [PhCH2(CHN)2CCH2C6H4BCH2CH2tBu][B(C6F5)4] (4-7): Compound 4-1 • 0.8 tol (50 mg, 0.049 mmol, 1 equiv.) was added

to 1 mL of CHCl3. 3,3-dimethyl-1-butene (6.4 μL, 0.05 mmol, 1 equiv.) was added. A clear colourless solution was formed and stirred for 3 h. The solution was dried, washed with pentane and dried to a while 1 3 powder. Yield: 48.4 mg (0.0473 mmol, 96 %); H NMR (CDCl3, 400 MHz): δ 8.30 (d, JHH = 8 3 4 3 Hz, 1H, BCCH), 7.87 (td, JHH = 8 Hz, JHH = 1 Hz, 1H, p-Arring), 7.69 (t, JHH = 7 Hz, 1H, m- 3 3 Arring), 7.66 (d, JHH = 2 Hz, 1H, HCNCH2), 7.54 (d, JHH = 8 Hz, 1H, m-Arring), 7.51 – 7.47 (m, 3 3H, Ar), 7.44 (d, JHH = 2 Hz, 1H, HCNCH2). 7.21 – 7.16 (m, 2H, Ar), 5.77 (s, 2H, CringH2), 5.64

(s, 2H, CH2), 2.16 – 2.09 (m, 2H, BCH2), 1.17 – 1.29 (m, 2H, BCH2CH2), 1.00 (s, 9H, tBu); 13 1 1 1 C{ H} NMR (CDCl3, 125 MHz): δ 148.2 (d, JCF = 242 Hz, o-C6F5), 138.3 (d, JCF = 261 Hz, p- 1 C6F5), 136.6 (BCCH), 136.5 (p-Arring), 136.3 (d, JCF = 250 Hz, m-C6F5), 130.3 (Ar), 130.2 (Ar),

129.1 (m-Arring), 127.3 (Ar), 126.9 (HCNCH2), 126.2 (m-Arring), 125.1 (HCNCH2), 54.2 (CringH2), 11 52.1 (CH2), 39.0 (BCH2CH2), 28.9 (tBu), 15.0 (s, br, BCH2). Ipso carbons are not observed.; B + 19 NMR (CDCl3, 128 MHz): δ 58.9 (s, br, BCH2 ), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): 3 3 3 δ -132.7 (d, JFF = 11 Hz, o-C6F5), -162.5 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 18 Hz, m-

C6F5).

Synthesis of cyclohexan-1-ol (4-8) and 3,3-dimethylbutan-1ol (4-9): These compounds were prepared in a similar fashion: 0.0137 mmol of the borenium cation (1 equiv.) was added to 1 mL of CHCl3. 0.5 mL MeOH, 0.25 mL 10% NaOH and 0.25 mL 35% H2O2 were added and stirred 132

overnight. The solution was then concentrated, acidified with 1 mL 1M HCl, and extracted with

DCM. The organic solution was dried with MgSO4, filtered and concentrated carefully to a clear colourless liquid.

1 3 4-8: H NMR (CDCl3, 400 MHz, showing only the alcohol): δ 3.65 (tt, JHH = 9 3 2 3 Hz, JHH = 4 Hz, 1H, CHOH), 1.90 (dt, JHH = 11 Hz, JHH = 4 Hz, 2H, Cy), 1.73 2 3 2 3 (dt, JHH = 9 Hz, JHH = 5 Hz, 2H, Cy), 1.56 (dt, JHH = 12 Hz, JHH = 3 Hz, 1H, Cy), 1.23 – 1.28 13 1 (m, 5H, Cy); C{ H} NMR (CDCl3, 125 MHz, showing only the alcohol): δ 70.8 (CHOH), 25.4 (Cy), 25.3 (Cy), 24.1 (Cy); GC-MS (EI) m/z: 84.9, 82.9, 71.0, 67.0, 57.0.

1 4-9: H NMR (CDCl3, 400 MHz, showing only the alcohol): δ 3.78 – 3.68 (m, 2H, 13 1 CH2OH), 1.57 – 1.48 (m, 2H, CH2CH2OH), 0.93 (s, 9H, tBu); C{ H} NMR

(CDCl3, 125 MHz, showing only the alcohol): δ 60.5 (CH2OH), 46.3 (CH2CH2OH), 29.7 (tBu); GC-MS (EI) m/z: 82.9, 69.1, 57.0.

Synthesis of [PhCH2(CHN)2CCH2C6H4BC(Ph)C(H)Ph][B(C6F5)4] (4-10): Diphenylacetylene (8.8 mg, 0.049 mmol, 1 equiv.) in 1 mL

CHCl3 was added to 4-1 • 0.8 tol (50 mg, 0.049 mmol, 1 equiv.) in 1

mL of CHCl3. A clear yellow solution was formed and stirred for 2 h. The solution was dried, washed with pentane and dried to an orange 1 powder. Yield: 57.2 mg, >99%; H NMR (CDCl3, 400 MHz, toluene 3 3 omitted): δ 8.30 (d, JHH = 8 Hz, 1H, BCCH), 7.87 (td, JHH = 8 Hz, 4 3 JHH = 1 Hz, 1H, p-Arring), 7.67 – 7.59 (m, 1H, m-Arring), 7.63 (d, JHH = 2 Hz, 1H, HCNCH2), 7.56 3 3 3 (d, JHH = 8 Hz, 1H, m-Arring), 7.39 (d, JHH = 7 Hz, 1H, Ar), 7.34 (d, JHH = 8 Hz, 2H, Ar), 7.31 3 3 (d, JHH = 2 Hz, 1H, HCNCH2), 7.29 – 7.14 (m, 5H, Ar), 7.23 – 7.19 (m, 3H, Ar), 7.04 (d, JHH = 3 7 Hz, 2H, Ar), 6.97 (s, 1H, alkenyl-H), 6.89 (d, JHH = 8 Hz, 2H, Ar), 5.71 (s, 2H, CringH2), 5.55 13 1 1 (s, 2H, CH2); C{ H} NMR (CDCl3, 125 MHz, toluene omitted): δ 148.2 (d, JCF = 244 Hz, o- 1 C6F5), 140.4 (s, br, BCCH), 140.0 (s, br, alkenyl-CH), 138.4 (d, JCF = 236 Hz, p-C6F5), 137.0 (p- 1 Arring), 136.8 (d, JCF = 254 Hz, m-C6F5), 130.0 (Ar), 129.9 (Ar), 129.8 (Ar), 129.7 (Ar), 129.4 (m-

Arring), 129.0 (HCNCH2), 127.8 (Ar), 126.7(HCNCH2), 126.1 (Ar), 126.1 (m-Arring), 125.6 (Ar), 11 54.2 (CH2), 52.2 (CringH2). Ipso carbons are not observed.; B NMR (CDCl3, 128 MHz): δ 54.1

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+ 19 3 (s, br, BC ), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.6 (d, JFF = 14 Hz, o-C6F5), 3 3 -162.5 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 20 Hz, m-C6F5).

Synthesis of [PhCH2(CHN)2CCH2C6H4BCHCH

C4H9][B(C6F5)4] (4-10): 1-hexyne (7 μL, 5 mg, 0.06 mmol, 1.2 equiv.) was added to 4-1 • 0.8 tol (50 mg, 0.049 mmol, 1 equiv.) in

1 mL CHCl3. A clear light-yellow solution was formed and dried in vacuo. The yellow oil was washed with pentane and dried to a white powder. Yield: 48.1 mg (0.047 mmol, 95%); 1H NMR 3 4 (CDCl3, 400 MHz): δ 8.19 (dd, JHH = 8 Hz, JHH = 1 Hz, 1H, 3 4 BCCH), 7.79 (td, JHH = 8 Hz, JHH = 2 Hz, 1H, p-Arring), 7.65 – 7.56 (m, 1H, m-Arring), 7.59 (d, 3 3 JHH = 2 Hz, 1H, HCNCH2), 7.51 – 7.46 (m, 1H, m-Arring), 7.46 – 7.41 (m, 3H, Ph), 7.38 (d, JHH 3 3 = 2 Hz, 1H, HCNCH2), 7.18 – 7.14 (m, 2H, Ph), 6.94 (dt, JHH = 18 Hz, JHH = 6 Hz, 1H, 3 4 BCH=CH), 6.77 (dt, JHH = 18 Hz, JHH = 1 Hz, 1H, BCH), 5.72 (s, 2H, CringH2), 5.57 (s, 2H, CH2), 3 3 2.43 (dt, JHH = 8 Hz, JHH = 7 Hz, 2H, CH2C3H7), 1.53 – 1.41 (m, 2H, CH2CH2CH3), 1.42 – 1.30 3 13 1 (m, 2H, CH2CH3), 0.90 (t, JHH = 7 Hz, 3H, CH3); C{ H} NMR (CDCl3, 125 MHz): δ 165.1 1 1 (BCH), 148.2 (d, JCF = 238 Hz, o-C6F5), 138.5 (BCCH), 138.2 (d, JCF = 238 Hz, p-C6F5), 135.7 1 (p-Arring), 136.4 (d, JCF = 252 Hz, m-C6F5), 130.14 (Ph), 130.05 (Ph), 128.9 (m-Arring), 128.5

(BCH=CH), 127.5 (Ph), 126.4 (m-Arring), 126.1 (HCNCH2), 124.7(HCNCH2), 54.6 (CH2), 52.2

(CringH2), 37.2 (CH2C3H7), 30.4 (CH2CH2CH3), 22.5 (CH2CH3), 14.0 (CH3). Ipso carbons are not 11 + 19 observed.; B NMR (CDCl3, 128 MHz): δ 50.5 (s, br, BC ), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 3 3 3 376 MHz): δ -132.7 (d, JFF = 13 Hz, o-C6F5), -162.6 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 20

Hz, m-C6F5).

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Synthesis of [PhCH2(CHN)2C6H4BC(Me)C(H)Ph][B(C6F5)4] 4-12a/b: 4-1 • 0.8 tol (50 mg, 0.049 mmol, 1 equiv.) was added to 1

mL CHCl3. 1-phenyl-1-propyne (6.2 μL, 5.75 mg, 0.049 mmol, 1 equiv.) was added to the solution. A clear yellow solution was formed and stirred for 1 h. The solution was dried, washed with pentane and dried to an orange-yellow powder. Yield: 52.4 mg (>99%); 1H

NMR (CDCl3, 400 MHz): δ 7.85 – 6.76 (m, overlapping phenyl and carbene), 4- 3 4 12a: δ 8.28 (d, JHH = 8 Hz, 1H, BCCH), 6.84 (q, JHH = 2 Hz, 1H, MeCCH), 5.70 (s, 2H, CringH2), 4 3 5.67 (s, 2H, CH2), 2.28 (d, JHH = 2 Hz, 3H, Me), 4-12b: δ 8.18 (d, JHH = 8 Hz, 1H, BCCH), 6.28 3 3 (q, JHH = 7 Hz, 1H, MeCH), 5.66 (s, 2H, CringH2), 5.42 (s, 2H, CH2), 2.14 (d, JHH = 7 Hz, 3H, 13 1 1 1 Me); C{ H} NMR (CDCl3, 125 MHz): δ 148.3 (d, JCF = 242 Hz, o-C6F5), 138.3 (d, JCF = 248 1 Hz, p-C6F5), 137.0 (p-Arring), 136.3 (d, JCF = 233 Hz, m-C6F5), 132.5 (Ar), 132.1(Ar), 130.2 (Ar), 130.0(Ar), 129.9 (Ar), 129.7 (Ar), 129.6 (Ar), 129.5 (Ar), 129.2, (Ar), 129.1 (Ar), 129.0 (Ar), 128.9 (Ar), 128.5 (Ar), 128.4 (Ar), 128.3 (Ar), 127.9 (Ar), 127.7 (Ar), 126.9 (Ar), 126.4 (Ar), 126.4 (Ar), 126.0 (Ar), 125.6 (Ar), 125.5 (Ar), 4-12a: δ 139.3 (BCCH), 137.8 (MeCCH), 54.0

(CringH2), 52.1 (CH2), 17.8 (Me), 4-12b: δ 140.3 (BCCH), 139.6 (MeCH), 52.1 (CringH2), 54.1 11 + (CH2), 16.5 (Me). Ipso carbons are not observed.; B NMR (CDCl3, 128 MHz): δ 55.4 (s, br, B ), 19 3 -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.7 (d, JFF = 14 Hz, o-C6F5), -162.5 (t, 3 3 JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 19 Hz, m-C6F5).

Synthesis of [PhCH2(CHN)2CCH2C6H4B(H)P(Ph2)CCH][B(C6F5)4] (4-14): Ethyldiphenylphosphane (11.4 mg, 0.054 mmol, 1.02 equiv.)

was added to 1 mL CHCl3. The clear colourless solution formed was added to 4-1 • 0.66 tol (50 mg, 0.053 mmol, 1 equiv.). The solution was dried to a white sludge. The solid was washed with pentane and dried to 1 a white powder. Yield: 55 mg (0.048 mmol, 90 %); H NMR (CDCl3, 400 MHz): δ 7.70 – 7.61 (m, 5H, Ar), 7.58 – 5.53 (m, 2H, Ar), 7.48 – 7.43 (m, 2H, Ar), 7.41 – 7.36 (m, 3H, Ar), 7.31 – 7.24

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(m, 3H, Ar), 7.19 – 7.15 (m, 2H, Ar), 7.14 (s, 1H, HCNC), 7.04 – 7.02 (m, 2H, Ar), 6.96 (s, 1H, 2 2 5 HCNC), 5.33 (d, JHH = 15 Hz, 1H, CH2), 4.98 (dd, JHH = 16 Hz, JHP = 4 Hz, 1H, CringH2), 4.66 2 2 + 3 (d, JHH = 15 Hz, 1H, CH2), 4.64 (d, JHH = 16 Hz, 1H, CringH2), 3.96 (s, br, 1H, BH ), 3.47 (d, JHP 13 1 1 = 9 Hz, 1H, HCC); C{ H} NMR (CDCl3, 125 MHz): δ 148.4 (d, JCF = 241 Hz, o-C6F5), 138.3 1 3 1 3 (dt, JCF = 244 Hz, JCF = 17 Hz, p-C6F5), 136.4 (d, JCF = 249 Hz, m-C6F5), 136.3 (d, JCP = 5 Hz, 3 5 4 BCCCH), 136.0 (d, JCP = 6 Hz, BCCH), 133.9 (d, JCP = 3 Hz, BCCCHCH), 133.9 (d, JCP = 3 2 2 Hz, BCCHCH), 133.1 (B-ipso-C6H4), 132.3 (d, JCP = 11 Hz, P-o-C6H5), 132.2 (d, JCP = 11 Hz, 2 2 P-o-C6H5), 130.3 (d, JCP = 12 Hz, P-o-C6H5), 129.9 (d, JCP = 11 Hz, P-o-C6H5), 129.6 (CH2-p- 3 4 C6H5), 129.5 (CH2-m-C6H5), 128.2 (d, JCP = 4 Hz, P-m-C6H5), 128.1 (d, JCP = 4 Hz, P-p-C6F5), 4 4 128.0 (CH2-o-C6H5), 126.1 (d, JCP = 4 Hz, HCNCBP), 122.4 (d, JCP = 38 Hz, HCNCBP), 122.3 1 1 2 (d, JCP = 65 Hz, P-ipso-C6F5), 120.3 (d, JCP = 68 Hz, P-ipso-C6F5), 102.3 (d, JCP = 9 Hz, HCCP), 1 4 70.4 (d, JCP = 109 Hz, HCCP), 52.9 (CH2), 52.4 (d, JCP = 3 Hz, CringH2). Some ipso carbons are 31 1 11 not observed.; P{ H} NMR (CDCl3, 162 MHz): δ -8.31 (s); B NMR (CDCl3, 128 MHz): δ -16.0 + 19 3 (s, B(C6F5)4), -22.0 (s, br, BH ); F NMR (CDCl3, 376 MHz): δ -132.5 (d, JFF = 10 Hz, o-C6F5), 3 3 -162.8 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 20 Hz, m-C6F5).

Synthesis of [PhCH2(CHN)2CCH2C6H4B(H)NC5H4C(H)CH2][B(C6F5)4] (4-15): Compound 4-1 • 0.66 tol (40 mg, 0.04 mmol, 1 equiv.) was added to 1 mL of chloroform and 2-vinylpyridine (4.3 μL, 4.2 mg, 0.04 mmol, 1 equiv.) were added. A cloudy solution was formed and dried to colourless crystals. The crystals were washed with pentane and dried to a white powder. Crystals suitable for X-ray crystallography were formed from slow evaporation of the chloroform solution before drying. Yield: 41 mg (0.039 mmol, 98 %); 1H NMR 3 3 (CD2Cl2, 400 MHz): δ 8.56 (d, JHH = 6 Hz, 1H, BCCH), 8.00 (t, JHH = 8 Hz, 1H, p-Arring), 7.53 3 3 3 (t, JHH = 8 Hz, 2H, m-Arring), 7.39 (d, JHH = 2 Hz, 1H, HCNCH2), 7.36 (m, 2H, py), 7.31 (d, JHH 3 3 = 3 Hz, 1H, HCNCH2), 7.27 – 7.20 (m, 5H, Ar), 7.09 (d, JHH = 8 Hz, 1H, o-py), 6.77 (d, JHH = 7 3 3 3 Hz, 1H, m-py), 6.70 (dd, JcisHH = 18 Hz, JtransHH = 11 Hz, 1H, HCCH2), 5.64 (d, JcisHH = 17 Hz, 2 1H, HCCH2), 5.59 (s, 2H, CH2Ph), 5.54 (d, JtransHH = 25 Hz, 1H, HCCH2), 5.04 – 4.85 (m, 2H, + 13 1 CringH2), 4.59 – 4.00 (s, br, BH ); C{ H} NMR (CD2Cl2, 125 MHz): δ 149.2 (BCCH), 148.6 (d, 1 1 1 JCF = 243 Hz, o-C6F5), 143.7 (p-Arring), 138.6 (d, JCF = 239 Hz, p-C6F5), 136.7 (d, JCF = 249 Hz, m-C6F5), 133.5 (o-py), 130.7 (HCCH2), 129.5 (Ar), 129.3 (Ar), 128.4 (Ar), 128.0 (py), 126.7 (m-

136

py), 126.0 (m-Arring), 125.8 (HCCH2), 123.2 (HCNCH2), 121.9 (HCNCH2), 52.4 (CH2Ph), 51.8 11 1 (CringH2). Some ipso-carbon’s are not observed.; B NMR (CD2Cl2, 128 MHz): δ -9.0 (d, JBH = + 19 100 Hz, BH ), -16.6 (s, B(C6F5)4); F NMR (CD2Cl2, 376 MHz): δ -132.6 (m, br, o-C6F5), -162.9 3 3 (t, JFF = 21 Hz, p-C6F5), -166.7 (t, JFF = 19 Hz, m-C6F5).

Synthesis of [(C6H4CH2NCH)2BC(CPMes2)CPh][B(C6F5)4] (4-16): Compound 4-1 • 0.66 tol (30.1 mg, 0.03 mmol, 1 equiv.) was added to 1 mL of chloroform. Dimesityl(phenylethynyl)phosphane (11.2 mg, 0.03 mmol, 1 equiv.) in 1 mL of chloroform was added. A clear yellow solution was formed and dried. The sludge was washed with multiple 1 pentane washes and dried to a yellow powder. H NMR (CDCl3, 400 4 MHz): δ 7.57 (d, JPH = 8 Hz, 2H, o-Ph), 7.41 – 7.34 (m, 2H, Ph), 7.31 – 7.26 (m, 2H, Ph), 7.26 – 7.16 (m, 3H, Ph), 7.15 (s, 2H, NCH), 7.15 – 7.04 (m, 2H, Ph), 6.79 (d, 4 3 2 JPH = 6 Hz, 4H, m-Mes), 6.59 (d, JHH = 7 Hz, 2H, Ph), 5.12 (d, JHH = 8 Hz, 4H, NCH2), 2.26 (s, 13 1 1 6H, p-CH3), 1.90 (s, 12H, o-CH3); C{ H} NMR (CDCl3, 125 MHz): δ 148.4 (d, JCF = 243 Hz, 2 1 o-C6F5), 144.7 (s, p-Mes), 142.2 (d, JPC = 14 Hz, o-Mes), 138.3 (d, JCF = 250 Hz, p-C6F5), 136.4 1 3 (d, JCF = 250 Hz, m-C6F5), 135.6 (=CPh), 133.7 (Ph), 131.5 (Ph), 130.8 (d, JPC = 14 Hz, m-Mes), 4 3 129.6 (d, JPC = 7 Hz, m-Ph), 129.5 (Ph), 128.8 (Ph), 126.8 (d, JPC = 14 Hz, o-Ph), 120.6 (NCH), 3 51.7 (NCH2). 21.8 (d, JPC = 8 Hz, o-CH3), 21.2 (p-CH3). Some ipso carbons are not observed.; 31 1 11 P{ H} NMR (CDCl3, 162 MHz): δ -143.4 (s, v1/2 = 20 Hz); B NMR (CDCl3, 128 MHz): δ -16.6 + 19 3 (s, B(C6F5)4), -19.0 (s, br, v1/2 = 162 Hz, B ); F NMR (CDCl3, 376 MHz): δ -132.5 (d, JFF = 3 3 13 Hz, o-C6F5), -163.0 (t, JFF = 21 Hz, p-C6F5), -166.7 (t, JFF = 19 Hz, m-C6F5).

4.4.3 Procedures of Gaseous Experiments

Procedure for HD scrambling experiments: Dimesityl(1-phenylvinyl)phosphane (14.7 mg, 0.04

mmol, 1 equiv.) was added to 1 mL CHCl3. The solution was added to 4-1 (40 mg, 0.04 mmol, 1 equiv.) and the clear light-yellow solution formed was stirred overnight. The reaction mixture was then transferred into an oven-dried Teflon screw cap J. Young NMR tube. The reaction tube was

degassed by 3 cycles of freeze-pump-thaw and then filled with H2 (1 atm) at ambient temperature 1 and D2 (1 atm) at -196 °C. The reaction was then monitored regularly by H NMR spectroscopy.

137

General procedure for hydrogenation experiments: Dimesityl(1-phenylvinyl)phosphane (3.92

mg, 0.011 mmol, 1 equiv.) was added to 1 mL CHCl3. The solution was added to 4-1 (10.52 mg, 0.011 mmol, 1 equiv.) and the clear light-yellow solution formed was stirred overnight. The solution was added to a 2 dram vial charged with a stir bar. The respective substrate was added to the solution and the vial was put in a Parr pressure reactor. The reactor was then sealed, removed

from the glovebox, and then subjected to 3 cycles of H2 addition at 20 atm and purge, and finally pressurized to the respective pressures. The reaction was carried out at ambient temperature for the respective time duration.

4.4.4 Computational Details

Electronic structure calculations, including geometry optimizations, frequency calculations, and the energy calculations were performed using Gaussian 16.48 Geometry optimizations and frequency calculations were performed using the BP8649 functional and the def2-TZVP basis set for computational Lewis acidity measurements.48-51 X-ray coordinates were used as the starting geometries when available. Frequency calculations on the optimized structures showed the absence of imaginary frequencies confirming that minima on the potential energy hypersurfaces were located. Energies for fluoride ion affinity (FIA) were calculated using the MP252-54 method and the def2-TZVPP basis set, as previously described using the experimental FIA of carbonyl difluoride.55 The global electrophilicity index (GEI)36-37 was calculated using the B3LYP56-59 functional and the def2-TZVP basis set, as previously described. Natural bond orbital and natural population analyses were performed using the M062X functional 60 and def2-TZVPP basis set using NBO 6.0.61 Geometry optimizations, frequency calculations and isotropic shifts for 4-1, 4-17 and dimesityl(1-phenylvinyl)phosphane were computed at the B97D/def2-TZVP//M062X/def2- SVP level of theory, using the phosphane and 4-1 as the reference. All calculations were carried out in the gas phase, unless otherwise indicated. Solvent interactions for toluene (ε = 2.3741), chloroform (ε = 4.7113), and dichloromethane (ε = 8.93) were treated implicitly using a polarizable continuum model.48, 62

138

4.4.5 X-ray Crystallography

4.4.5.1 X-Ray Data Collection and Reduction

Crystals were coated in Paratone-N oil in an N2 filled glovebox, mounted on a MiTegen

Micromount, and placed under a N2 stream to maintain a dry, O2-free environment for each crystal. The data were collected on a Bruker Kappa Apex II diffractometer using a Triumph monochromator with Mo Kα radiation (λ = 0.71073 Å). The data were collected at 150(2) K for all crystals using an Oxford cryo-stream cooler with the exception for dimesityl(1- phenylvinyl)phosphane (273(2) K). Data were collected using Bruker APEX-2 software and processed using SHELX and an absorption correction applied using multi-scan within the APEX- 2 program. All structures were solved and refined by direct methods within the SHELXTL package.63-64

139

4.4.5.2 Crystallographic Data Tables

Table 4.4. Selected crystallographic data for 4-3 and 4-4.

4-3 4-4

Formula C44.5 H19 B2 Cl N2 F20 C25H31BN2 Crystal System Monoclinic Triclinic

Space Group P21/n P-1 a/ Å 15.240(9) 9.1250(10) b/ Å 14.234(5) 11.5698(10) c/ Å 18.602(7) 12.0107(1) α/ ° 90 114.481(5) β/ ° 100.383(17) 100.740(5) γ/ ° 90 105.997(6) V/ Å3 3969(3) 1041.82(19) Z 4 2 T/ K 150(2) 150(2)

-3 Dc/ g.cm 1.705 1.1805 Total data 20697 46049 Unique data 6847 4780

Rint 0.1131 0.0664 2 2 R1[F >2 σ(F )] 0.0742 0.0496 wR2 (all data) 0.2282 0.1417 GoF 0.920 1.0855

140

Table 4.5. Selected crystallographic data for 4-15 and dimesityl(1-phenylvinyl)phosphane.

4-15 Dimesityl(1-phenylvinyl)phosphane

Formula C48H24B2N3F20 C26 H29 P Crystal System Triclinic Triclinic Space Group P-1 P-1 a/ Å 11.1220(5) 8.3111(5) b/ Å 14.2342(6) 11.7381(8) c/ Å 15.0759(6) 12.3188(8) α/ ° 114.156(2) 113.951(3) β/ ° 90.165(2) 93.481(3) γ/ ° 100.617(3) 103.338(3) V/ Å3 2132.26(16) 1052.45(12) Z 2 2 T/ K 150(2) 273(2) -3 Dc/ g.cm 1.627 1.175 Total data 66218 49348 Unique data 9428 10183

Rint 0.0829 0.1081 2 2 R1[F >2 σ(F )] 0.0450 0.0619 wR2 (all data) 0.1242 0.1524 GoF 0.992 1.003

141

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Chapter 5 Bisborane-functionalized Imidazolium Cation as Precursor Towards Intramolecular Carbene-bisborane Scaffold 5.1 Introduction

5.1.1 Intramolecular Cooperativity in FLPs

Typically, an FLP comprises of one Lewis acid and one Lewis base to effect FLP chemistry. However, multi-Lewis acid functionalized moieties have been shown to demonstrate unique FLP chemistry. Berke and co-workers reported a doubly Lewis acid functionalized naphthalene that was able to split H2 heterolytically with 2,2,6,6-tetramethylpiperidine, and the resulting hydride was found to be in the bridging position between the two Lewis acidic boranes (Scheme 5.1).1 This bridging hydride motif was also computationally calculated as a global minimum in the doubly Lewis-acid functionalized aniline reported by Mitzel and co-workers, in which they had synthesized the functionalized aniline by hydroboration of N,N-diallylaniline with Piers’ borane (Scheme 5.2, top). The doubly functionalized aniline showed increased catalytic activity in imine hydrogenation compared to the singly Lewis-acid functionalized analogue, and they attributed the comparatively high reactivity to the cooperative hydride stabilization by the second Lewis-acid site during hydrogen activation.2 Mitzel and co-workers also further reported the synthesis of doubly Lewis-acid functionalized phosphine analogues (Scheme 5.2, bottom), but were found inactive in H/D-scrambling. Computational studies also revealed a global minimum for a bridging hydride between the two Lewis acidic sites, similar to that found with the previously reported aniline analogue. However, the ring-opening reaction energies were found to be significantly 3 higher, thus inhibiting a reactive open form for H2 activation.

Scheme 5.1. Intramolecular cooperativity in dihydrogen activation by a doubly Lewis acid functionalized naphthalene. 146

Scheme 5.2. Synthesis of doubly Lewis acid functionalized anilines (top), and phosphines (bottom).

In addition to dihydrogen activation, FLPs with more than one Lewis acidic site were also reported to have interesting activity towards small molecule activations. In 2011, Zhao and Stephan had synthesized 1,1-bisboranes and were shown to capture CO2 by bidentate chelation in the presence 4 of tBu3P (Scheme 5.3, top). Similar geminal bisboranes were also reported by Erker and co- workers and were found to exhibit similar chelation behavior with CO2 in the presence of tBu3P 5 (Scheme 5.3, middle). They were able to isolate the product formed from activation of H2, in which a bridging hydride was found between the two boranes. A similar borata-diene framework reported by Erker’s group also demonstrated cooperative binding of CO and benzaldehyde by the two Lewis acidic boranes.6 Remarkably, in 2017, Erker and co-workers reported a trifunctional framework by double hydroboration of a divinylphosphane, in which they were able to capture 7 CO2 and SO2 in a tridentate fashion within a single molecule (Scheme 5.3, bottom left). Modification of the framework to a B-H borane also allowed CO capture and subsequent formation of a formyl moiety (Scheme 5.3, bottom right), demonstrating a potential for metal-free carbon monoxide reduction.

147

Scheme 5.3. Bidentate chelation of carbon dioxide by 1,1-bisboranes (top and middle right), geminal bisboranes (middle left) and tridentate chelation of small molecules (bottom).

5.1.2 FLP Chemistry by Carbene and Lewis Acidic Borane

The development of FLP chemistry has also extended to other acid/base combinations beyond the archetypal borane Lewis acid and phosphorus Lewis base, such as the use of silicon,8-9 sulphur,10 aluminum,11-14 and zinc Lewis acids.15-16 While carbenes have been typically used to stabilize Lewis acidic cations used in FLP reactions, Chase and Stephan reported, in 2008, that a bulky

NHC can serve as the Lewis base with B(C6F5)3 in the FLP activation of hydrogen and amine (Scheme 5.4).17 Similarly, Tamm and co-workers showed THF ring-opening, phenylacetylene activation and carbon dioxide capture by 1,3-di-tert-butylimidazolin-2-ylidene and B(3,5- 18 (CF3)2C6H3)3. They further demonstrated N2O fixation with the carbene and B(C6F5)3, which the 148

fixation can also be achieved with the carbene alone but will thermally decompose to corresponding urea derivative.19 Indeed, carbenes have been shown to activate small molecules independently, such as the capture of nitrous oxide20-21 and carbon dioxide.22-23 Bertrand and co- workers also demonstrated that cyclic (amino)-(alkyl)carbenes (CAACs) can mimic metalloid oxidation addition processes and react with dihydrogen and ammonia directly.24 In addition, NHCs have been used as organocatalysts on their own to effect chemical transformations.25-28

Scheme 5.4. Hydrogen and amine activation by a bulky NHC and B(C6F5)3.

With reports on the various chemistry achieved by carbenes and boranes, independently and together as Lewis acid/base counterparts, we envision interesting FLP chemistry that can be achieved by an intramolecular carbene-bisborane scaffold. To this end, we propose a bisborane- functionalized imidazolium salt, prepared by double hydroboration of vinyl imidazolium salts, as a precursor for this scaffold.

5.2 Results and Discussion

5.2.1 Hydroboration of Imidazolium Cation

1,3-diallyimidazolium bromide29 was prepared by alkylation of allyimidazole with allyl bromide. Subsequent anion exchange was carried out in DCM with one equivalent of sodium tetrafluoroborate and potassium tetrakis(pentafluorophenyl)borate separately and we were able to isolate 5-1 as a clear yellow oil in 88% yield and 5-2 as a white powder in 82% yield (Scheme 5.5).

149

Scheme 5.5. Anion exchange of 1,3-diallylimidazolium bromide to form 5-1 and 5-2.

Reaction of 1,3-diallylimidazolium bromide with two equivalents of Piers’ borane resulted in two peaks at δ 40.9 ppm and -2.5 ppm in the 11B NMR spectrum, suggesting a three-coordinate and four-coordinate species respectively. In the 1H NMR spectrum, vinyl signals were observed, suggesting incomplete hydroboration. We hypothesized that the bromide anion can coordinate with the Piers’ borane and interfered with the hydroboration reaction. A similar anion interference was observed when we reacted 5-1 with two equivalents of Piers borane. Multiple products were formed as evidenced by multiple resonances in the 19F NMR spectrum and the 11B NMR spectrum, and vinyl proton signals persisted in the 1H NMR spectrum. We hypothesized a fluoride abstraction from the tetrafluoroborate anion by the Piers’ borane led to degradation of electrophilic borane.

Scheme 5.6. Hydroboration of 1,3-diallylimidazolium tetrakis(pentafluorophenyl)borate with Piers’ borane to form 5-3.

We were able to successfully hydroborate 5-2 with two equivalents of Piers’ borane to give 5-3 as a light beige powder in 78% yield (Scheme 5.6). Hydroboration was evidenced by the disappearance of vinyl proton signals in the 1H NMR spectrum and the 11B NMR spectrum showed 150

a broad singlet at δ 41.6 ppm and a sharp singlet at δ -16.7 ppm, corresponding to a three- coordinate alkyl boron centre and the tetrakis(pentafluorophenyl)borate anion respectively.

Hydroboration with 9-BBN proceeded slowly but was successful with both 1,3-diallylimidazolium bromide and 5-2. The imidazolium salts were reacted with excess 9-BBN for 48 h and we were able to isolate both 5-4 and 5-5 as a white powder in 45% and 94% yield respectively (Scheme 5.7). Disappearance of the vinyl proton signals in the 1H NMR spectra demonstrated successful hydroboration and the 11B NMR spectrum showed a broad singlet at δ 87.8 ppm, suggesting a three-coordinate alkyl boron centre. We attribute the difference in hydroboration of the imidazolium salts with different counteranions to the Lewis acidity difference of the boranes. The less Lewis acidic 9-BBN interacted less strongly with the bromide anion, as compared to the stronger interaction of the bromide anion with the more Lewis acidic Piers’ borane, and as a result was able to proceed with hydroboration.

Scheme 5.7. Hydroboration of 1,3-diallylimidazolium salt with 9-BBN to form 5-4 and 5-5.

5.2.2 Deprotonation of Imidazolium Cation

Compound 5-5 was reacted with one equivalent of KHMDS in toluene overnight, and subsequent work up resulted in a white powder. We observed in the 1H NMR spectrum of the disappearance of the singlet of the C2 proton on the imidazolium, suggesting successful deprotonation. In addition, the 19F NMR spectrum is silent, suggesting the loss of the tetrakis(pentafluorophenyl)borate anion during workup, and two broad singlets were observed in

151

the 11B NMR spectrum at δ -15.5 and -16.4 ppm, suggesting two different four-coordinate boron centres. We hypothesize the formation of 5-6, which one of the alkyl-9-BBN formed a carbene- borane adduct upon deprotonation and the other formed an adduct with the bis(trimethylsilyl)amine formed from deprotonation (Scheme 5.8).

Scheme 5.8. Deprotonation of 5-5 with KHMDS.

While deprotonation can be carried out to generate the bisborane-carbene, the formation of 5-6 demonstrated the need of steric hindrance around the carbene to prevent carbene-borane formation. In addition, the need of a non-coordinating conjugate acid is required after deprotonation to avoid quenching of a free borane. Judicious screening on both ends will then be required to achieve the desired trifunctionalized FLP. Carbene generation in the presence of excess substrate may also be fruitful as a means to competitively inhibit the aforementioned quenching pathways.

5.3 Conclusion

We have synthesized dialkenyl-imidazolium salts with different counteranions and we found that the anion can affect hydroboration through halide donation. Bisborane-imidazolium salts were subsequently generated through di-hydroboration, and deprotonation to produce the intramolecular carbene was found viable by the addition of a base. Further template design of the trifunctionalized molecule and screening of non-coordinating conjugate acid may lead to promising ends for intramolecular cooperativity in FLP chemistry.

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5.4 Experimental Section

5.4.1 General Considerations

All manipulations were carried out under dry, O2-free N2 using an MBraun glovebox and a Schlenk vacuum-line. Pentane, toluene and dichloromethane were collected from a Grubbs-type column system manufactured by Innovative Technology and into thick-walled glass Schlenk bombs with Young-type Teflon valve stopcocks. Chloroform-d was obtained from Cambridge Isotope

Laboratories, dried over CaH2, and vacuum-transferred into Young bombs. All solvents were degassed after purification and stored over 4 Ǻ molecular sieves. Commercial reagents were purchased from Sigma-Aldrich, TCI Chemicals, Strem Chemicals or Alfa Aesar, and used without further purification unless indicated otherwise. 1,3-diallyimidazolium bromide29 was prepared by literature procedures.

NMR spectra were recorded on a Bruker Avance 400 MHz spectrometer or a Varian Mercury Plus

400 MHz spectrometer at 25 ºC. Chemical shifts are given relative to SiMe4 and referenced to the 1 13 11 19 residual solvent signal ( H, C) or relative to an external standard ( B: 15% (Et2O)BF3, F:

CFCl3). Chemical shifts (δ) are reported in ppm and coupling constants (J) as scalar values in Hz.

5.4.2 Synthesis of Compounds

Synthesis of [HC((H2C=CHCH2)NCH)2][BF4] (5-1): 1,3- diallylimidazolium bromide (141.5 mg, 0.618 mmol, 1 equiv.) and

[Na][BF4] (67.8 mg, 0.618 mmol, 1 equiv.) were added to 10 mL DCM. A cloudy white solution was formed and stirred for overnight. The mixture was filtered through Celite, dried, washed with hexanes and dried to a clear yellow oil. 1 4 Yield: 128.6 mg (0.544 mmol, 88 %); H NMR (CDCl3, 400 MHz): δ 9.67 (t, JHH = 2 Hz, 1H, 4 3 3 3 NCHN), 7.42 (d, JHH = 2 Hz, 2H, NCH), 5.89 (ddt, JHH = 17 Hz, JHH = 10 Hz, JHH = 7 Hz, 2H, 3 4 13 1 CH2CH), 5.54 – 5.42 (m, 4H, HC=CH2), 4.94 (dt, JHH = 7 Hz, JHH = 1 Hz, 4H, CH2); C{ H}

NMR (CDCl3, 125 MHz): δ 136.7 (NCHN), 129.8 (CH2CH), 123.0 (HC=CH2), 122.3 (NCH), 52.3 11 19 (CH2); B NMR (CDCl3, 128 MHz): δ -1.01 (s, BF4); F NMR (CDCl3, 376 MHz): δ -151.4 (s,

BF4).

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Synthesis of [HC((H2C=CHCH2)NCH)2][B(C6F5)4] (5-2): 1,3- diallylimidazolium bromide (63.8 mg, 0.278 mmol, 1 equiv.) and

[K][B(C6F5)4] (200 mg, 0.278 mmol, 1 equiv.) were added to 5 mL DCM. The mixture was stirred for 90 min, filtered through Celite and dried. The white powder was dissolved in minimal DCM, layered with pentane and stored in freezer. Colourless crystals were formed and excess solvent was pipetted out. The crystals were washed with pentane and dried to a fine white powder. Yield: 188.8 mg (0.228 mmol, 82 %); 1H 4 4 NMR (CDCl3, 400 MHz): δ 8.08 (t, JHH = 2 Hz, 1H, NCHN), 7.26 (d, JHH = 2 Hz, 2H, NCH), 3 3 3 3 4 5.89 (ddt, JHH = 17 Hz, JHH = 10 Hz, JHH = 7 Hz, 2H, CH2CH), 5.58 (dt, JHH = 10 Hz, JHH = 1 3 4 3 Hz, 2H, HC=CHtrans), 5.48 (dt, JHH = 17 Hz, JHH = 1 Hz, 2H, HC=CHcis), 4.67 (dt, JHH = 7 Hz, 4 13 1 JHH = 1 Hz, 4H, CH2); C{H} NMR (CDCl3, 125 MHz): δ 148.3 (d, JCF = 239 Hz, o-C6F5), 1 3 1 138.3 (dt, JCF = 242 Hz, JCF = 17 Hz, p-C6F5), 136.4 (d, JCF = 248 Hz, m-C6F5), 133.3 (NCHN), 11 127.7 (CH2CH), 125.0 (HC=CH2), 122.9 (NCH), 52.9 (CH2). Ipso carbons are not observed.; B 19 3 NMR (CDCl3, 128 MHz): δ -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.8 (d, JFF = 3 3 11 Hz, o-C6F5), -162.4 (t, JFF = 21 Hz, p-C6F5), -166.6 (t, JFF = 18 Hz, m-C6F5).

Synthesis of [HC(C8H14B(CH2)3NCH)2][Br] (5-4): 1,3- diallylimidazolium bromide (27.6 mg, 0.12 mmol, 1 equiv.) and 9- BBN dimer (36 mg, 0.15 mmol, 1.2 equiv.) were added to 5 mL of DCM. A clear colourless solution was formed and stirred for 48 h. The solution was then filtered through Celite and dried to a colourless oil. The oil was washed with hexane and dried to a white powder. 1 Yield: 46.7 mg (0.054 mmol, 45 %); H NMR (CDCl3, 400 MHz): 4 4 δ 10.83 (t, JHH = 2 Hz, 1H, NCHN), 7.34 (d, JHH = 2 Hz, 2H, NCH), 4 4.40 (t, JHH = 8 Hz, 4H, NCH2), 2.18 – 2.06 (m, 4H, NCH2CH2), 1.89 – 1.78 (m, 12H, 9-BBN), 13 1 1.71 – 1.57 (m, 12H, 9-BBN), 1.44 – 1.38 (m, 4H, CH2B), 1.24 – 1.13 (m, 4H, 9-BBN); C{ H}

NMR (CDCl3, 125 MHz): δ 128.0 (NCHN), 121.7 (NCH), 52.4 (NCH2), 33.3 (9-BBN), 31.3 (s, 11 br, BCH), 26.0 (NCH2CH2), 23.9 (s, br, CH2B), 23.2 (9-BBN); B NMR (CDCl3, 128 MHz): δ 87.8 (s, br, 9-BBN).

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Synthesis of [HC(C8H14B(CH2)3NCH)2][B(C6F5)4] (5-5): 1,3- diallylimidazolium tetrakis(pentafluorophenyl)borate (50 mg, 0.06 mmol, 1 equiv.) and 9-BBN dimer (26.8 mg, 0.11 mmol, 1.8 equiv.) were added to 4 mL of DCM. A clear colourless solution was formed and stirred for 48 h. The solution was then filtered through Celite and dried to a colourless oil. The oil was washed with pentane and dried to a white powder. Yield: 60.7 mg (0.0566 mmol, 94 %); 1H 4 NMR (CDCl3, 400 MHz): δ 8.05 (t, JHH = 2 Hz, 1H, NCHN), 7.27 4 4 (d, JHH = 2 Hz, 2H, NCH), 4.10 (t, JHH = 8 Hz, 4H, NCH2), 2.13 – 2.00 (m, 4H, NCH2CH2), 1.91

– 1.83 (m, 12H, 9-BBN), 1.68 – 1.56 (m, 12H, 9-BBN), 1.40 – 1.31 (m, 4H, CH2B), 1.25 – 1.13 13 1 (m, 4H, 9-BBN); C{H} NMR (CDCl3, 125 MHz): δ 148.3 (d, JCF = 233 Hz, o-C6F5), 138.3 (d, 1 3 1 JCF = 264 Hz, JCF = 17 Hz, p-C6F5), 136.3 (d, JCF = 254 Hz, m-C6F5), 133.3 (NCHN), 122.8

(NCH), 53.1 (NCH2), 33.3 (9-BBN), 31.4 (s, br, BCH), 25.8 (NCH2CH2), 23.6 (s, br, CH2B), 23.2 11 (9-BBN). Ipso carbons are not observed.; B NMR (CDCl3, 128 MHz): δ 87.8 (s, br, 19 3 9-BBN), -16.7 (s, B(C6F5)4); F NMR (CDCl3, 376 MHz): δ -132.6 (d, JFF = 12 Hz, o- 3 3 C6F5), -162.4 (t, JFF = 21 Hz, p-C6F5), -166.5 (t, JFF = 20 Hz, m-C6F5).

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5.5 References

1. Jiang, C.; Blacque, O.; Berke, H., Chem. Commun. 2009, (37), 5518-5520.

2. Körte, L. A.; Blomeyer, S.; Heidemeyer, S.; Mix, A.; Neumann, B.; Mitzel, N. W., Chem. Commun. 2016, 52 (64), 9949-9952.

3. Korte, L. A.; Blomeyer, S.; Heidemeyer, S.; Nissen, J. H.; Mix, A.; Neumann, B.; Stammler, H. G.; Mitzel, N. W., Dalton Trans. 2016, 45 (43), 17319-17328.

4. Zhao, X.; Stephan, D. W., Chem. Commun. 2011, 47 (6), 1833-1835.

5. Liu, Y.-L.; Kehr, G.; Daniliuc, C. G.; Erker, G., Chem. Sci. 2017, 8 (2), 1097-1104.

6. Yu, J.; Kehr, G.; Daniliuc, C. G.; Erker, G., Chem. Commun. 2016, 52 (7), 1393-1396.

7. Wang, L.; Zhang, S.; Hasegawa, Y.; Daniliuc, C. G.; Kehr, G.; Erker, G., Chem. Commun. 2017, 53 (40), 5499-5502.

8. Weicker, S. A.; Stephan, D. W., Chem.: Eur. J. 2015, 21 (37), 13027-13034.

9. Waerder, B.; Pieper, M.; Körte, L. A.; Kinder, T. A.; Mix, A.; Neumann, B.; Stammler, H.-G.; Mitzel, N. W., Angew. Chem. Int. Ed. 2015, 54 (45), 13416-13419.

10. Tsao, F. A.; Waked, A. E.; Cao, L.; Hofmann, J.; Liu, L.; Grimme, S.; Stephan, D. W., Chem. Commun. 2016, 52 (84), 12418-12421.

11. Ménard, G.; Hatnean, J. A.; Cowley, H. J.; Lough, A. J.; Rawson, J. M.; Stephan, D. W., J. Am. Chem. Soc. 2013, 135 (17), 6446-6449.

12. Appelt, C.; Slootweg, J. C.; Lammertsma, K.; Uhl, W., Angew. Chem. Int. Ed. 2013, 52 (15), 4256-4259.

13. Keweloh, L.; Klöcker, H.; Würthwein, E.-U.; Uhl, W., Angew. Chem. Int. Ed. 2016, 55 (9), 3212-3215.

14. Ménard, G.; Tran, L.; McCahill, J. S. J.; Lough, A. J.; Stephan, D. W., Organometallics 2013, 32 (22), 6759-6763.

15. Dobrovetsky, R.; Stephan, D. W., Isr. J. Chem. 2015, 55 (2), 206-209.

16. Jochmann, P.; Stephan, D. W., Angew. Chem. Int. Ed. 2013, 52 (37), 9831-9835.

17. Chase, P. A.; Stephan, D. W., Angew. Chem. Int. Ed. 2008, 47 (39), 7433-7437.

18. Kolychev, E. L.; Bannenberg, T.; Freytag, M.; Daniliuc, C. G.; Jones, P. G.; Tamm, M., Chem.: Eur. J. 2012, 18 (52), 16938-16946.

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19. Theuergarten, E.; Bannenberg, T.; Walter, M. D.; Holschumacher, D.; Freytag, M.; Daniliuc, C. G.; Jones, P. G.; Tamm, M., Dalton Trans. 2014, 43 (4), 1651-1662.

20. Tskhovrebov, A. G.; Solari, E.; Wodrich, M. D.; Scopelliti, R.; Severin, K., J. Am. Chem. Soc. 2012, 134 (3), 1471-1473.

21. Tskhovrebov, A. G.; Vuichoud, B.; Solari, E.; Scopelliti, R.; Severin, K., J. Am. Chem. Soc. 2013, 135 (25), 9486-9492.

22. Feroci, M.; Chiarotto, I.; Ciprioti, S. V.; Inesi, A., Electrochim. Acta 2013, 109, 95-101.

23. Holbrey, J. D.; Reichert, W. M.; Tkatchenko, I.; Bouajila, E.; Walter, O.; Tommasi, I.; Rogers, R. D., Chem. Commun. 2003, (1), 28-29.

24. Frey, G. D.; Lavallo, V.; Donnadieu, B.; Schoeller, W. W.; Bertrand, G., Science 2007, 316 (5823), 439.

25. Enders, D.; Balensiefer, T., Acc. Chem. Res. 2004, 37 (8), 534-541.

26. Enders, D.; Niemeier, O.; Henseler, A., Chem. Rev. 2007, 107 (12), 5606-5655.

27. Marion, N.; Díez-González, S.; Nolan, S. P., Angew. Chem. Int. Ed. 2007, 46 (17), 2988- 3000.

28. Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T., Chem. Rev. 2015, 115 (17), 9307-9387.

29. Toure, M.; Chuzel, O.; Parrain, J.-L., J. Am. Chem. Soc. 2012, 134 (43), 17892-17895.

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Chapter 6 Conclusions and Future Work 6.1 Summary of Thesis

The work presented in this thesis detailed the synthesis and application of boron-based Lewis acids as catalysts in FLP chemistry. Catalytic hydrogenation of imines was the primary target of these Lewis acid catalysts. In the course of this research, electrophilic boranes and borenium cations were explored, with an emphasis on the production of chiral FLPs and intramolecular FLPs.

Chapter 2 described the modification of 3,5-bicyclic aryl piperidines, initially synthesized as drug targets, towards chiral intramolecular B/N FLP systems by hydroboration. The chapter highlighted the potential for expanding chiral FLP templates beyond ligands used in transition metal-catalyzed 1 hydrogenation. While it was demonstrated that FLP H2 activation can be achieved, further synthetic manipulation of the template is required to effect catalytic turnover. For design considerations, the steric environment and the combination of Lewis acidity and basicity must be carefully tailored to preclude strong adduct formation and simultaneously effect dihydrogen activation. To this end, a facile synthetic methodology was considered for tuning of reactivity and selectivity for effective chiral hydrogenation catalysts in the next project.

With this consideration, Chapter 3 reported the facile synthesis of chiral carbene-borane adducts as precursors towards chiral borenium cations for catalytic imine hydrogenations, in which the chirality resides on either the carbene or the borane.2 It was found that catalytic amine production is inhibited by preclusion of hydride delivery due to electrophilic C6F5 groups on the borenium cations, and thermally induced ring-expansion of the bulky borenium cations rendered some of the species inactive in catalytic hydrogenations. Nonetheless, borenium cations generated from bisoxazoline-based carbenes, chiral triazolium-based carbene and Ipc2BH were found to be active hydrogenation catalysts. With limited stereoselectivity, the systematic catalytic study revealed a design dilemma amongst these cations: the relationship of steric with reactivity and enantioselectivity of these cations respectively are inversely proportional, in which less steric bulk will induce higher reactivity but less enantioselectivity, and vice versa. Regardless, the non-zero enantioselectivity and the absence of selectivity erosion by chiral product epimerization suggest that further catalyst design can be fruitful.

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Extension of the application of borenium cation towards FLP chemistry was described in Chapter 4, in which an intramolecular borenium/phosphine system was produced. The isolable B-H

borenium cation [PhCH2(CHN)2CCH2C6H4BH][B(C6F5)4] 4-1 was found to be highly Lewis acidic and capable of 1,2-hydroboration of alkenes and alkynes. With the open p orbital on the boron centre, small Lewis bases can inhibit hydroboration by the formation of an adduct, while bulky phosphines can deprotonate the methylene bridge of the activated benzylic substituent. Successful generation of a borenium cation with a pendant base was achieved by hydroboration of

the bulky dimesityl(1-phenylvinyl)phosphane, but was found inactive in H2 activation and catalytic reduction of unsaturated substrates. Overall, this demonstrated that the hydroboration of phosphinoalkenes by a B-H borenium cation can be used to produce cationic intramolecular B/P FLPs.

Initial efforts into the production of bisborane-carbene as a trifunctionalized scaffold for intramolecular FLP chemistry are documented in Chapter 5. Dihydroboration of imidazolium salts were able to afford bisborane-imidazolium salts, which can serve as a precursor towards the generation of bisborane-carbenes.

It is also noted throughout the work of this thesis that several methods, both experimental and computational, should be performed for the measurement of Lewis acidity of a Lewis acid, as each method has their own limitations. Comparisons can then be more accurately drawn on electrophilicity and steric effects of the Lewis acids in FLP chemistry.

6.2 Future Work

The disclosure of H2 activation by a phosphonium borate linked zwitterion over a decade ago prompted a rapid development of metal-free, main group compounds for small molecule activation and as hydrogenation catalysts. Yet, compared to the rich history of transition metal-based catalysts, the exploration of main group catalysts is still in its infancy.

In particular, the field of metal-free enantioselective catalysis remains to be an attractive avenue due to the ever-increasing need for enantiopure products in the industrial production of biologically active molecules. This thesis has addressed several design considerations in the production of chiral FLP catalysts, with a need of facile synthetic methodology for fine tuning of reactivity and

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selectivity. Inspiration can be taken from Du’s and Wang’s recent work in enantioselective hydrogenations, using C2-symmetric templates as a precursor to generate effective enantioselective hydrogenation catalysts with high enantioselectivity.3-8 In addition, with concerns for stability and recyclability of catalysts for industrial adaptation, inspiration can also be taken from Ashley and Soós to incorporate air- and moisture-stable boranes into the chiral templates.9-11 Furthermore, the scope of enantioselective FLP catalysis developed to this date remains focused on simple substrates, and as such, adaptation towards catalytic enantioselective transformation of complex molecules bearing multiple functional group would be favourable towards industrial application.

With the ever-increasing scope of small molecule activation and transformations effected by neutral intramolecular FLPs, it will be interesting to explore the chemistry effected by cationic intramolecular FLPs based on borenium ions, an area of FLP chemistry not fully explored in comparison. In addition, with previous reports of borenium cations demonstrating single-electron transfer reactions12-14 and the use of mesitylphosphine as a Lewis base in radical FLP reactivity,15 borenium cations with a pendant mesitylphosphine may demonstrate intriguing radical reactivity as an intramolecular FLP.16

The production and chemistry of bisborane-carbenes described in Chapter 5 is still unexplored and their intramolecular cooperativity in catalysis and small molecule activation will be of fundamental interest.

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6.3 References

1. Lam, J.; Sampaolesi, S.; LaFortune, J. H. W.; Coe, J. W.; Stephan, D. W., Dalton Trans. 2019, 48 (1), 133-141.

2. Lam, J.; Gunther, B. A.; Farrell, J. M.; Eisenberger, P.; Bestvater, B. P.; Newman, P. D.; Melen, R. L.; Crudden, C. M.; Stephan, D. W., Dalton Trans. 2016, 45 (39), 15303-15316.

3. Liu, Y.; Du, H., J. Am. Chem. Soc. 2013, 135 (18), 6810-6813.

4. Wei, S.; Du, H., J. Am. Chem. Soc. 2014, 136 (35), 12261-12264.

5. Zhang, Z.; Du, H., Angew. Chem. Int. Ed. 2015, 54 (2), 623-626.

6. Zhang, Z.; Du, H., Org. Lett. 2015, 17 (11), 2816-2819.

7. Zhang, Z.; Du, H., Org. Lett. 2015, 17 (24), 6266-6269.

8. Tu, X.-S.; Zeng, N.-N.; Li, R.-Y.; Zhao, Y.-Q.; Xie, D.-Z.; Peng, Q.; Wang, X.-C., Angew. Chem. Int. Ed. 2018, 57 (46), 15096-15100.

9. Scott, D. J.; Fuchter, M. J.; Ashley, A. E., Angew. Chem. Int. Ed. 2014, 53 (38), 10218- 10222.

10. Gyömöre, Á.; Bakos, M.; Földes, T.; Pápai, I.; Domján, A.; Soós, T., ACS Catal. 2015, 5 (9), 5366-5372.

11. Scott, D. J.; Fuchter, M. J.; Ashley, A. E., Chem. Soc. Rev. 2017, 46 (19), 5689-5700.

12. Cao, L. L.; Stephan, D. W., Organometallics 2017, 36 (16), 3163-3170.

13. Matsumoto, T.; Gabbaï, F. P., Organometallics 2009, 28 (15), 4252-4253.

14. Ledet, A. D.; Hudnall, T. W., Dalton Trans. 2016, 45 (24), 9820-9826.

15. Liu, L.; Cao, L. L.; Shao, Y.; Ménard, G.; Stephan, D. W., Chem 2017, 3 (2), 259-267.

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16. Cardenas, A. J. P.; Culotta, B. J.; Warren, T. H.; Grimme, S.; Stute, A.; Fröhlich, R.; Kehr, G.; Erker, G., Angew. Chem. Int. Ed. 2011, 50 (33), 7567-7571.

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