Synthesis, Structure, and Reactivity of Early Transition Metal

Home , Lanthanocene, Oxophilicity, Pyrrolidine, Salt metathesis reaction

SYNTHESIS, STRUCTURE, AND REACTIVITY OF EARLY TRANSITION METAL

PRECATALYSTS BEARING (N,O)-CHELATING LIGANDS

Philippa Robyn Payne

B.Sc., University of Ottawa, 2008

A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF

THE REQUIREMENTS FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES

(Chemistry)

THE UNIVERSITY OF BRITISH COLUMBIA

(Vancouver)

December 2013

The synthesis, structure, and reactivity of early transition metal complexes containing

(N,O)-chelating ancillary ligands are described. The ligands investigated include ureates, pyridonates, amidates, and sulfonamidates. These related ligands generate four-membered metallacycles when bound to the metal center in a κ2-(N,O) fashion. The zirconium and tantalum complexes have been examined in terms of their activity and selectivity as precatalyst systems

for hydroamination or hydroaminoalkylation.

A chiral cyclic ureate ligand has been synthesized from enantiopure L-valine for

application in zirconium-catalyzed asymmetric hydroamination of aminoalkenes. Chiral

zirconium complexes, prepared in situ from two equivalents of the urea proligand and

tetrakis(dimethylamido) zirconium, promote the formation of pyrrolidines and piperidines in up to 12% ee. Isolation of an asymmetric bimetallic zirconium complex containing three bridging

ureate ligands confirms that ligand redistribution occurs in solution and is most likely

responsible for the low enantioselectivities.

Mechanistic investigations focusing on the hydroaminoalkylation reactivity promoted by

a bis(pyridonate) bis(dimethylamido) zirconium precatalyst expose a complex catalytic system in

solution. Stoichiometric investigations reveal the formation of polymetallic complexes upon

addition of primary amines. The kinetic and stoichiometric investigations are most consistent

with a bimetallic catalytically active species.

A series of mono(amidate) tantalum amido complexes with varying steric and electronic

properties have been synthesized via protonolysis. Solid-state and solution-phase

characterization indicate that the amidate substituents influence the observed binding mode of ii

the ligand. Salt metathesis and protonolysis routes to the synthesis of mixed tantalum chloro amidate complexes are investigated. Sulfonamide proligands react with pentakis(dimethylamido) tantalum to generate well-defined monomeric complexes containing a κ2-(N,O) bound

sulfonamidate. The hemilabile (N,O)-chelating amidate ligands, which generate four-membered

metallacycles, are the most active of the precatalysts examined for the intermolecular

hydroaminoalkylation of terminal olefins with secondary amines.

The substrate scope of a mono(amidate) tetrakis(dimethylamido) tantalum complex has

been examined for the α-alkylation of unprotected piperidine, piperazine, and azepane N-

heterocyclic amines. The lack of reactivity with pyrrolidine substrates is examined by quantum

chemical calculations and isotopic labeling studies. Two (N,O)-chelating ureate ligands are also

successful ancillary ligands for this transformation and, with a C1-symmetric chiral ureate complex, enantioselective α-alkylation of piperidine is observed.

iii

PREFACE

Parts of the research conducted for this thesis were carried out collaboratively with other

members of the Schafer research group. I, in consultation with my supervisor Dr. Laurel Schafer,

designed and performed all of the experiments described herein except in the following

instances. The initial concept and synthetic approach to the synthesis of the cyclic urea proligand

was designed by Dr. David C. Leitch (Chapter 2). Compound 16 was synthesized and

characterized through X-ray diffraction by Dr. Patrick Eisenberger (Chapter 3). The amidate

ligands 22 and 23 (Chapter 4) and the related tantalum complexes were synthesized and characterized by Benedict J. Barron, an undergraduate researcher, under my supervision. The X-

ray diffraction data for the crystalline mixture of compounds 29 and 30 were refined by Dr.

Nicholas C. Payne. The DFT calculations were performed by Dr. J.M. Lauzon (Chapter 5). The

N-heterocyclic substrate screening was performed in collaboration with Dr. Patrick Eisenberger

(Table 5.1, Chapter 5). Jacky Yim performed the synthesis and characterization for compound 47

(Table 5.1, entry 3). The solid-state molecular data presented herein was collected by Neal

Yonson, Jacky Yim, or Scott Ryken while I performed the final refinements.

The following publications have been reported based on this work. Any work from these

papers that I did not directly carry out, with the exceptions listed previously, does not appear in

this thesis or is appropriately referenced. I wrote these manuscripts with editorial assistance from

the co-authors listed, except for the Tetrahedron where I was involved with the editing but not

the initial draft.

. Payne, P. R.; Bexrud, J. A.; Leitch, D. C.; Schafer, L. L. Can. J. Chem. 2011, 89, 1222.

(Chapter 2) iv

. Garcia, P.; Payne, P. R.; Chong, E.; Webster, R. L.; Barron, B. J.; Behrle, A. C.; Schmidt,

J. A. R.; Schafer, L. L. Tetrahedron 2013, 69, 5737. (Chapter 4)

. Payne, P. R.; Garcia, P.; Eisenberger, P.; Yim, J. C.-H.; Schafer, L. L. Org. Lett. 2013,

15, 2182. (Chapter 5)

TABLE OF CONTENTS

ABSTRACT ...... ii

PREFACE ...... iv

TABLE OF CONTENTS ...... vi

LIST OF TABLES ...... xi

LIST OF FIGURES ...... xiii

LIST OF SCHEMES ...... xix

LIST OF ABBREVIATIONS AND ACRONYMS ...... xxv

ACKNOWLEDGEMENTS ...... xxx

DEDICATION...... xxxi

CHAPTER 1: Synthesis, structure, and reactivity of early transition metal precatalysts bearing (N,O)-chelating ligands...... 1

1.1 Introduction ...... 1

1.2 Mono anionic, monodentate ligands based on N- and O-donors...... 5

1.2.1 Multidentate, monoanionic ligands of (O,O)-, (N,N)-, and (N,O)-compounds ...... 6

1.2.2 Amidate complexes for hydroamination and hydroaminoalkylation...... 11

1.2.3 Ureate complexes for hydroamination ...... 18

1.2.4 Pyridonate complexes for hydroamination and hydroaminoalkylation ...... 22

1.2.5 Sulfonamidate complexes for hydroamination ...... 25

1.3 Scope of thesis ...... 28

CHAPTER 2: C1-symmetric ureate complexes of zirconium for the asymmetric hydroamination of unactivated aminoalkenes ...... 31 vi

2.1 Introduction ...... 31

2.1.1 Asymmetric hydroamination of unactivated olefins ...... 31

2.1.2 Rare-earth metal systems ...... 33

2.1.3 Group 4 metal systems ...... 34

2.1.4 Expansion of substrate scope using a tethered bis(ureate) zirconium catalyst ...... 36

2.1.5 Scope of chapter ...... 37

2.2 Results and discussion ...... 38

2.2.1 Ligand and complex ...... 38

2.2.2 Intramolecular hydroamination ...... 41

2.2.3 Isolated bimetallic complex ...... 43

2.3 Conclusions ...... 47

2.4 Experimental ...... 48

2.4.1 General methods ...... 48

2.4.2 Materials ...... 49

2.4.3 General experimental procedure ...... 50

2.4.4 Compound synthesis and characterization ...... 50

CHAPTER 3: Mechanistic investigations of a bis(pyridonate) zirconium complex for intramolecular hydroaminoalkylation ...... 53

3.1 Introduction ...... 53

3.1.1 Titanium-based precatalysts...... 53

3.1.2 A zirconium pyridonate precatalyst ...... 58

3.1.3 Scope of chapter ...... 61

3.2 Results and discussion ...... 61 vii

3.2.1 Solution-phase behaviour of the precatalyst ...... 61

3.2.2 Stoichiometric reactivity ...... 65

3.2.3 Kinetic analysis of intramolecular hydroaminoalkylation ...... 71

3.3 Conclusions and mechanistic proposal ...... 77

3.4 Experimental ...... 79

3.4.1 Materials ...... 79

3.4.2 General experimental procedures ...... 79

3.4.3 Synthesis and characterization ...... 81

CHAPTER 4: Synthesis, structure, and reactivity of new tantalum complexes ...... 84

4.1 Introduction ...... 84

4.1.1 Chloro ancillary ligands ...... 84

4.1.2 (N,O)- and (O,O)-chelating ancillary ligands ...... 85

4.1.3 Scope of chapter ...... 88

4.2 Results and discussion ...... 89

4.2.1 Tantalum precatalysts with amidate ligand modifications ...... 89

4.2.2 Hydroaminoalkylation reactivity of modified tantalum amidate complexes ...... 99

4.2.3 Mixed chloro and amidate tantalum complexes ...... 102

4.2.4 Tantalum complexes supported by sulfonamidate ligands ...... 117

4.3 Conclusions ...... 125

4.4 Experimental ...... 127

4.4.1 Materials ...... 127

4.4.2 General experimental procedures ...... 127

4.4.3 Synthesis and characterization ...... 129 viii

4.4.3.1 Proligands ...... 129

4.4.3.2 Tantalum complexes ...... 135

CHAPTER 5: Synthesis of α-alkylated N-heterocycles via hydroaminoalkylation ...... 144

5.1 Introduction ...... 144

5.1.1 Functionalized N-heterocycles ...... 144

5.1.2 Stoichiometric α-lithiation and functionalization ...... 145

5.1.3 Oxidative functionalization of α-C–H bonds ...... 148

5.1.4 Directed transition metal-catalyzed C–H activation ...... 151

5.1.5 Hydroaminoalkylation of N-heterocycles with early transition metals ...... 153

5.1.6 Scope of chapter ...... 155

5.2 Results and discussion ...... 156

5.2.1 The hydroaminoalkylation of N-heterocyclic substrates ...... 156

5.2.2 Urea proligands for the hydroaminoalkylation of N-heterocycles ...... 163

5.2.3 Attempted α-alkylation with pyrrolidine and indoline ...... 164

5.2.4 Computational modeling of the catalytic cycles for the α-alkylation of amines .... 167

5.2.4.1 Previous investigation into the hydroaminoalkylation of acyclic amines ...... 167

5.2.4.2 Computational investigations with N-heterocyclic substrates ...... 169

5.2.4.3 Deuterium labeling...... 175

5.3 Conclusions ...... 180

5.4 Experimental ...... 182

5.4.1 Materials ...... 182

5.4.2 General experimental procedures ...... 182

5.4.3 Synthesis and characterization ...... 183 ix

5.4.4 Attempts towards the synthesis of bicyclic and tricyclic compounds ...... 196

5.4.5 Deuterium labeling experiments ...... 197

5.4.6 Computational methods ...... 197

CHAPTER 6: Summary, conclusions, and future directions ...... 199

6.1 Summary and conclusions ...... 199

6.2 Future directions ...... 201

6.2.1 Enantioselective hydroaminoalkylation with simple chiral ligands ...... 201

6.2.2 Reactivity with pyrrolidines ...... 202

6.2.3 Pyridonate complexes of tantalum ...... 204

6.3 Concluding remarks ...... 207

REFERENCES ...... 209

APPENDICES ...... 222

Appendix A X-ray crystallographic data ...... 222

Appendix B Selected NMR spectra ...... 228

Appendix C SFC analysis for determination of enantiomeric excess...... 261

LIST OF TABLES

Table 2.1 Relevant bond lengths (Å) and angles (°) for 8...... 40

Table 2.2 Reactivity studies using proligand 8 for intramolecular hydroamination with alkenes.

...... 42

Table 2.3 Relevant bond lengths (Å) and angles (º) for complex 10...... 45

Table 3.1 Relevant bond lengths (Å) and angles (º) for complex 16...... 67

Table 3.2 DOSY experiments of 5 and the reaction mixture of 5 with 1-bultylamine...... 70

Table 4.1 Selected bond lengths (Å) and angles (º) for complex 27...... 94

Table 4.2 Relevant bond lengths (Å) and angles (º) for complex 28...... 95

Table 4.3 Screening of new tantalum precatalysts for the hydroaminoalkylation of N- methylaniline and p-methoxy-N-methylaniline with 1-octene...... 101

Table 4.4 Relevant bond lengths (Å) and angles (º) for complexes 38 and 39...... 109

Table 4.5 Relevant bond lengths (Å) and angles (º) of 42...... 116

Table 4.6 Relevant bond lengths (Å) and angles (º) for complexes 43, 44, and 45...... 123

Table 5.1 Hydroaminoalkylation of saturated N-heterocycles...... 157

Table A.1 Crystallographic parameters for the cyclic urea proligand and the bimetallic ureate and pyridonate zirconium complexes (Chapter 2)...... 222

Table A.2 Crystallographic parameters for the bridging imido pyridonate complex (Chapter 3).

...... 223

Table A.3 Crystallographic parameters for the mono(amidate) tetrakis(dimethylamido) tantalum complexes (Chapter 4)...... 224

Table A.4 Crystallographic parameters for the mixed chloro amidate tantalum complexes

(Chapter 4)...... 225

Table A.5 Crystallographic parameters for the mono(sulfonamidate) tetrakis(dimethylamido)

tantalum complexes (Chapter 4)...... 226

Table A.6 Crystallographic parameters for the homoleptic indolinyl tantalum complex (Chapter

5)...... 227

xii

LIST OF FIGURES

Figure 1.1 Representative Nobel prize winning catalytic systems based on early, mid, and late transition metals...... 2

Figure 1.2 Representative metallocene complexes for the selective synthesis of polypropenes with diverse tacticities.48-51 ...... 4

Figure 1.3 Monodentate, monoanionic ligands based upon oxygen or nitrogen donors...... 5

Figure 1.4 Bidentate, monoanionic ligands with (O,O)- or (N,N)-donors...... 7

Figure 1.5 Fluxional behaviour of a metal complex containing a hemilabile bidentate ligand. .... 7

Figure 1.6 Bidentate, monoanionic ligands with (N,O)-donors...... 8

Figure 1.7 Protonolysis (top) and salt metathesis (bottom) synthetic strategies for the formation of early transition metal complexes and potential coordination modes of (N,O)-ligands...... 9

Figure 1.8 Catalytic hydroamination (A – D) and hydroaminoalkylation (E,F). The bonds broken are indicated in red and those formed in blue...... 10

Figure 1.9 Early transition metal complexes containing (N,O)-ligand(s) synthesized via protonolysis with organic amide proligands...... 12

Figure 1.10 Isocyanate insertion into a metal-amido bond to generate ureate complexes...... 19

Figure 1.11 The tautomeric equilibrium between 2-hydroxypyridine (2-pyridinol) and 2- pyridone...... 22

Figure 1.12 Bis(pyridonate) bis(dimethylamido) zirconium complex 5 that promotes both hydroamination and hydroaminoalkylation...... 24

Figure 1.13 Representative early transition metal systems containing sulfonamidate and sulfamide ligands. Mes = mesityl...... 26 xiii

Figure 2.1 Representative late transition metal, alkaline metal, and Brønsted acid based catalytic systems...... 32

Figure 2.2 Chiral lanthanide precatalysts for asymmetric hydroamination...... 33

Figure 2.3 Cationic and neutral zirconium systems for the asymmetric intramolecular

hydroamination of aminoalkenes...... 35

Figure 2.4 Untethered chiral amidate ligands for intramolecular asymmetric hydroamination. . 36

Figure 2.5 Tethered bis(ureate) zirconium hydroamination precatalyst 4...... 37

Figure 2.6 ORTEP depiction of the solid-state molecular structure of proligand 8. The ellipsoids are plotted at 50% probability and the majority of the hydrogen atoms are omitted for clarity.

The hydrogens displayed (N–H) have been located from unassigned electron density and their positions refined...... 39

Figure 2.7 Proximity to the zirconium center of steric bulk and source of chirality in the cyclic

ureate compared with the amidate ligand...... 43

Figure 2.8 ORTEP depiction of the solid-state molecular structure of complex 10. The ellipsoids

are plotted at 50% probability and the hydrogen atoms are omitted for clarity. In the simplified

structure (right) the methyl groups of dimethylamido ligands (N7-11) and the cyclohexyl groups

of the ureate ligands ((N1, N3, N5) are removed for clarity...... 44

Figure 2.9 ORTEP depiction of the solid-state molecular structure of complex 11. The ellipsoids

are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 47

Figure 3.1 Titanium precatalysts containing bidentate ligands for the hydroaminoalkylation of

secondary amines...... 58

1 Figure 3.2 Variable temperature H NMR spectra of the aryl region of complex 5 in d8-toluene.

...... 63 xiv

Figure 3.3 ORTEP representation of the solid-state molecular structure of complex 16, with a

simplified core structure shown on the right. Symmetry equivalent atoms (i) were generated with the symmetry operation (−x+1, −y, −z+1). The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 67

Figure 3.4 Variable 1H NMR spectroscopy of the reaction of 5 with 1.5 equivalents of

benzylamine in d6-benzene...... 69

Figure 3.5 Plot of consumption of 19 (c/c0) and ln(c/c0) as a function of time (min). The solid

trendline depicts the least-squares fit of the data points...... 73

Figure 3.6 Primary kinetic isotope effect observed for the cyclization of 19 compared with α- deuterated substrate 20...... 74

Figure 3.7 Observed rates of consumption of 19 as a function of catalyst concentration...... 76

Figure 3.8 Eyring plot in the temperature range of 85 – 110 °C and the relevant activation

parameters. Error on activation parameters estimated from regression analysis...... 77

Figure 4.1 Tantalum precatalysts for the α-alkylation of amines supported by (N,O)- and (O,O)-

chelating ligands...... 87

Figure 4.2 New amide proligands (top) based upon the amidate ligand of 2 and potential

alternative coordination geometries (bottom)...... 90

Figure 4.3 ORTEP representation of the solid-state molecular structure of complex 27. The

ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 93

Figure 4.4 ORTEP representation of the solid-state molecular structure of complex 28. The

ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 95

Figure 4.5 ORTEP depiction of solid-state molecular structure of the crystalline material obtained using proligand 22. The asymmetric unit cell contains two unique tantalum complexes, xv

29 and 30. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for

clarity...... 97

Figure 4.6 Key potential intermediates proposed by Porco and co-workers for the formation of amides using a dimeric zirconium alkoxide complex via an intramolecular transformation.288 .. 98

Figure 4.7 ORTEP depiction of the solid-state molecular structures of complexes 38 and 39. The

ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 108

1 Figure 4.8 H NMR spectrum of complex 40 in d6-benzene...... 113

Figure 4.9 ORTEP representations of the solid-state molecular structure of previously synthesized complex 42.297 The ellipsoids are plotted at 50% probability and the hydrogen atoms

are omitted for clarity...... 115

Figure 4.10 Phosphoramidate tantalum alkyl precatalyst 21 and the pKas of a series of amide,

phosphoramide and sulfonamide compounds.300 ...... 117

Figure 4.11 Early transition metal hydroaminoalkylation precatalysts supported by sulfur

containing ligands...... 118

Figure 4.12 ORTEP depictions of solid-state molecular structures of sulfonamidate complexes

43, 44, and 45. The ellipsoids are plotted at 50% probability and hydrogen atoms are omitted for

clarity...... 120

Figure 4.13 Proposed interconversion between κ1- and κ2-binding modes in solution...... 121

Figure 5.1 Natural products and pharmaceuticals containing an α-alkyl/aryl N-heterocycle. .. 144

Figure 5.2 ORTEP representation of the solid-state molecular structure of compound 47. The ellipsoids are plotted at 50% probability and the majority of the hydrogen atoms are omitted for clarity...... 160

xvi

Figure 5.3 ORTEP depiction of the solid-state molecular structure of complex 51. The asymmetric unit contains a disordered indoline molecule which has been successfully modeled.

The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity. . 165

Figure 5.4 Optimized geometry for transition state TS(III/IV) for the pyrrolidine and piperidine

substrates. The majority of the hydrogen atoms are omitted for clarity...... 172

Figure 5.5 Optimized geometry for the bis(amido) intermediates IIIpyrr and IIIpip (top) and the

metallaziridine intermediates IVpyrr and IVpip containing the neutral-bound α-alkylated product

(bottom). The majority of the hydrogen atoms are omitted for clarity...... 173

Figure 5.6 Optimized geometry for the tantalaziridine intermediates Vpyrr and Vpip. The

hydrogen atoms are omitted for clarity...... 174

Figure 5.7 Potential energy surface for the formation of the tantalaziridine intermediates V from

the bis(amido) tantalum complexes III...... 175

Figure 6.1 Optimized geometries for the tantalaziridines with pyrrolidine (left) and piperidine

(right)...... 203

Figure 6.2 Potential new precatalysts for the hydroaminoalkylation of N-heterocycles such as

pyrrolidine. ORTEP depiction of solid-state molecular structure of complex 42. The ellipsoids

are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 204

Figure 6.3 Preliminary synthesis and stacked 1H NMR spectra for the proligand and the crude

mono and bis(pyridonate) complexes 52 and 53 in d6-benzene...... 205

Figure 6.4 ORTEP depiction of solid-state molecular structure of complex 54. The three

equatorial pyridonate ligands are highly disordered, both orientations are shown. The ellipsoids

are plotted at 50% probability and the hydrogen atoms are omitted for clarity...... 206

xvii

Figure 6.5 Potential commercially available pyridone proligands (A) and pyridone precursor (B) as well as a reported synthetic route to highly substituted pyridones (C).410 ...... 207

xviii

LIST OF SCHEMES

Scheme 1.1 Regioselective hydroamination of terminal alkynes promoted by precatalyst 1...... 14

Scheme 1.2 Intramolecular hydroamination of primary aminoalkenes with neutral bis(amidate)

zirconium complexes.131,134...... 15

Scheme 1.3 Simplified [2+2] cycloaddition mechanism for the bis(amidate) titanium-catalyzed

intermolecular hydroamination of alkynes and the bis(amidate) zirconium-catalyzed intramolecular cyclization of aminoalkenes. [Zr] and [Ti] = bis(amidate) zirconium and titanium, respectively...... 16

Scheme 1.4 Intramolecular hydroaminoalkylation of unactivated olefins with secondary amines

catalyzed by mono and bis(amidate) tantalum amido complexes...... 17

Scheme 1.5 Proposed catalytic cycle for the hydroaminoalkylation of secondary amines with tantalum precatalysts...... 18

Scheme 1.6 Synthesis of bis(ureate) alkyl, chloro, or amido complexes of group 4 metals. DME

= 1,2-dimethoxyethane...... 20

Scheme 1.7 Proposed catalytic cycle for hydroamination using precatalyst 4 in which the key

step is a proton-assisted σ-bond insertion. [Zr] = tethered bis(ureate) ...... 22

Scheme 1.8 Proposed mechanism for hydroaminoalkylation promoted by complex 5 via a

bridging zirconaziridine. [Zr] = bis(pyridonate)...... 25

Scheme 2.1 Hydroamination of alkenes using a chiral catalyst to generate enantioenriched

alkylamines...... 31

xix

Scheme 2.2 Modular route for the synthesis of urea proligand 8. Boc = tert-butoxycarbonyl,

HOBt = hydroxybenzotriazole, DCC = N,N'-dicyclohexylcarbodiimide, DIPEA =

diisopropylethylamine, TFA = trifluoroacetic acid...... 39

Scheme 2.3 Precatalyst formation by the protonolysis reaction of Zr(NMe2)4 with 8...... 40

Scheme 3.1 Inter- and intramolecular hydroaminoalkylation of amines...... 53

Scheme 3.2 Select titanium precatalysts for the intramolecular hydroaminoalkylation of primary

and secondary aminoalkenes. a10 mol% [Ti]...... 54

Scheme 3.3 Simplified mechanism of titanium-catalyzed intramolecular hydroaminoalkylation.

...... 56

Scheme 3.4 Intermolecular hydroaminoalkylation of 1-octene promoted by complexes 12, 13

and 14...... 57

Scheme 3.5 Intramolecular hydroaminoalkylation with zirconium pyridonate precatalyst 5...... 59

Scheme 3.6 Proposed mechanism for intramolecular hydroaminoalkylation with precatalyst 5.

[Zr] = bis(pyridonate)...... 60

Scheme 3.7 Synthesis of bis(pyridonate) bis(dimethylamido) zirconium and ORTEP

representation of the solid-state molecular structure of complex 5.159 The ellipsoids are plotted at

50% probability and the hydrogen atoms are omitted for clarity...... 62

Scheme 3.8 Reported routes for the synthesis of monomeric metallaziridines of zirconium and tantalum...... 64

Scheme 3.9 Synthesis of dimeric imido zirconium complex 16 via aminolysis of complex 5. ... 66

Scheme 3.10 Synthesis of bimetallic titanaziridine 17...... 68

Scheme 3.11 Synthesis of kinetic substrate 19 and isotopically labeled 20...... 72

Scheme 4.1 Intermolecular hydroaminoalkylation of secondary amine substrates...... 84 xx

Scheme 4.2 The effect of chloro ancillary ligands in tantalum complexes for the intermolecular hydroaminoalkylation of 1-octene with of N-methylaniline...... 85

Scheme 4.3 New amide proligands 22 and 23 containing modified nitrogen substituents...... 91

Scheme 4.4 Synthesis of proligands 24, 25, and 26 bearing pendant methoxy or tertiary amine

donors...... 92

Scheme 4.5 Protonolysis methodology using amide proligands and Ta(NMe2)5...... 92

Scheme 4.6 In situ substitution of the ester moiety of the proligand to generate tantalum complex

29...... 96

Scheme 4.7 Substitution at the ester moiety of the proligand to generate tantalum complex 29. 98

Scheme 4.8 Salt metathesis (top) and protonolysis (bottom) approaches to new organometallic

compounds and potential mixed chloro amido tantalum precursors 32, 33, 35, and 36 (right). 103

Scheme 4.9 The syntheses of mixed dichloro, trichloro, and tetrachloro tantalum amido starting

materials...... 104

Scheme 4.10 Reaction of pentachloro tantalum starting material with the amidate sodium salt.

...... 105

Scheme 4.11 Non-productive ligand substitution reaction of the dimethylamido ligands of 2. 106

Scheme 4.12 Transformations investigated using via one-step protonolysis (top) and salt metathesis (bottom) procedures from mixed dichloro and trichloro amido tantalum starting materials...... 107

Scheme 4.13 Previously synthesized bis(amidate) tantalum complexes.146...... 110

Scheme 4.14 Synthetic methodologies that result in the formation of complex 40...... 111

Scheme 4.15 Unexpected reactivity observed with aryloxo ligands...... 114

Scheme 4.16 Synthesis of 42 via salt metathesis of the tantalum dichloro precursor 33...... 114 xxi

Scheme 4.17 Hydroaminoalkylation reactivity of precatalyst 42 using N-methylaniline and p-

methoxy-N-methylaniline and 1-octene...... 116

Scheme 4.18 Sulfonamide proligands with varied N-substituents...... 119

Scheme 4.19 Synthesis of mono(sulfonamidate) tetrakis(dimethylamido) tantalum complexes 43

– 46...... 119

Scheme 5.1 Multiple-step organolithium-mediated α-deprotonation/functionalization

methodology...... 146

Scheme 5.2 Organolithium-mediated α-deprotonation-transmetallation-Negishi coupling

strategy...... 147

Scheme 5.3 Ruthenium catalyzed α-cyanation of tertiary amines...... 148

Scheme 5.4 Copper-catalyzed cross-dehydrogenative coupling reactions of tertiary amines. .. 148

Scheme 5.5 α-Functionalization via an iminium cation...... 149

Scheme 5.6 Photoredox approach for the α-functionalization of tertiary amines via an iminium

ion (top) or an α-amino radical cation (bottom)...... 151

Scheme 5.7 Directed ruthenium-catalyzed α-arylation of N-substituted heterocycles...... 152

Scheme 5.8 Directed ruthenium-catalyzed α-alkylation of N-substituted heterocycles...... 153

Scheme 5.9 Intermolecular hydroaminoalkylation of alkenes with secondary amines...... 154

Scheme 5.10 Hydroaminoalkylation of piperidine with mono(amidate) tetrakis(dimethylamido) tantalum precatalyst 2...... 155

Scheme 5.11 Postulated mechanism for the tantalum-catalyzed hydroaminoalkylation of N-

heterocycles...... 159

Scheme 5.12 Proposed synthesis of bicyclic and tricyclic compounds following α-alkylation of

an N-heterocyclic amine...... 160 xxii

Scheme 5.13 α-Alkylation and ring-closure methodology using N-arylalkyl amines (top)284 and

attempts at the analogous methodology with 1,2,3,4-tetrahydroquinoline...... 161

Scheme 5.14 Hydroaminoalkylation with olefin substrate containing a protected carbonyl

moiety...... 162

Scheme 5.15 Attempted hydroaminoalkylation-hydroamination procedure catalyzed by tantalum and zirconium precatalysts, respectively...... 163

Scheme 5.16 α-Alkylation of piperidine catalyzed by in situ generated tantalum ureate

complexes...... 164

Scheme 5.17 Homoleptic tantalum species 51 produced from reaction of 2 with indoline...... 165

Scheme 5.18 No hydroaminoalkylation reactivity observed with pyrrolidine...... 166

Scheme 5.19 Idealized intermediates and transition states for the catalytic α-alkylation of dimethylamine with 1-octene, followed by the coordination/activation of an N-methylaniline substrate. Relative free energies (∆G) are reported in kcal/mol.146 ...... 168

Scheme 5.20 Simplified catalyst activation via hydroaminoalkylation of a dimethylamido ligand

(I – III, left) and proposed mechanistic cycle with N-heterocyclic substrates (IV – VI, right). 170

Scheme 5.21 Summary of calculated intermediates and the transition state for the C–H activation

of pyrrolidine (pyrr) and piperidine (pip) to form tantalaziridines V. Relative free energies (∆G)

are reported in kcal/mol...... 171

Scheme 5.22 Deuterium scrambling experiment reported with dimethylamine (top) and proposed

experiment with N-heterocyclic amines (bottom)...... 176

Scheme 5.23 Sites of deuterium incorporation for piperidine and pyrrolidine substrates...... 177

Scheme 5.24 Calculated intermediates leading to α- or β-arylation reported by Baudoin and co-

workers.394 ...... 178 xxiii

Scheme 5.25 Potential mechanism for the β-deuteration observed and the optimized geometry

for Vpyrr with the shortest dimethylamido–β-hydrogen distance indicated. The majority of the hydrogen atoms are omitted for clarity...... 179

Scheme 6.1 Urea proligands incorporating chirality in the carbon backbone (top) or the amino groups (bottom) for tantalum-catalyzed asymmetric hydroaminoalkylation...... 202

xxiv

LIST OF ABBREVIATIONS AND ACRONYMS

Å angstrom (10-10 m)

Ac acetyl

anal. analysis

Ar aryl

B3LYP Becke 3-parameter Lee-Yang-Par functional

Bhyd benzhydryl

Bn benzyl

Boc tert-butoxycarbonyl bpy 2,2'-bipyridine br broad

nBu, sBu, tBu normal butyl, sec-butyl, tert-butyl

C Celsius c concentration calcd. calculated

Cp cyclopentadienyl

Cp* pentamethylcyclopentadienyl

Cy cyclohexyl

° degree d deuterium d doublet

δ chemical shift xxv

DBU 1,8-diazabicycloundec-7-ene

DCC N,N'-dicyclohexylcarbodiimide

DCM dichloromethane

DEPT distortionless enhancement by polarization transfer

DFT density functional theory

∆G‡ Gibbs free energy of activation

∆H‡ enthalpy of activation

∆S‡ entropy of activation

DIPEA diisopropylethylamine

DMA dimethylacetamide

DME 1,2-dimethoxyethane

DMSO dimethylsulfoxide

DOSY diffusion ordered spectroscopy

d.r. diastereomeric ratio

E+ electrophile ee enantiomeric excess

EI electron impact

Et ethyl

e.u. entropy units (cal K-1 mol-1)

EWG electron withdrawing group fac facial gem geminal h hours xxvi

HMDS hexamethyldisilazane (N(SiMe3)2)

HOBt hydroxybenzotriazole

HRMS high resolution mass spectrometry

Hz Hertz

Ind indenyl

iPr isopropyl

J coupling constant

κ denticity

k rate constant

K kelvin

Ka acid dissociation constant

kB Boltzmann’s constant kcal kilocalorie

KIE kinetic isotope effect

L supporting ligand

Ln ligand set

Ln rare-earth metal

m multiplet

M metal, mol/L

M+ molecular ion

MAO methylaluminoxane

μ bridging ligand

Me methyl xxvii

Mes mesityl

min minute

mol mole

mol% mole percent

MP2 second order Møller-Plesset perturbation theory

MS mass spectrometry

Ms mesyl, methanesulfonyl

m/z mass-to-charge ratio

Naphth naphthyl

NMR nuclear magnetic resonance

Nu nucleophile

ORTEP Oak Ridge thermal ellipsoid plot p -log (as in pKa)

[P] photocatalyst

Ph phenyl pip piperidine

PMP p-methoxyphenyl ppm parts per million pyrr pyrrolidine py pyridine

[O] oxidant q quartet

R organic substituent xxviii

rac racemic s singlet, second sept septet

SET single-electron transfer t – Bu3SiO silox

Σ summation t triplet

T temperature

TBAF tetrabutylammonium fluoride

TBS tert-butyldimethylsilyl tert tertiary

TFA trifluoroacetic acid

THF tetrahydrofuran

TMS trimethylsilyl tol toluene

Ts tosyl, para-toluenesulfonyl

X halide

xxix

ACKNOWLEDGEMENTS

I sincerely thank my supervisor Dr. Laurel Schafer for the guidance, inspiration, encouragement, and unwavering support she provided throughout my graduate studies. Thank you for giving me so many opportunities to grow as both a scientist and an individual. You are a phenomenal teacher and mentor.

Thank you to my committee members, Dr. Glenn Sammis and Dr. Michael Fryzuk, for their valuable input and thorough critique of this thesis prior to submission. Thank you to Ken

Love for his tireless help with the GC-MS, Dr. Brian Patrick for his assistance with X-ray crystallography, Maria Ezhova and the NMR staff, and Marshall Lapawa for help with the mass spectrometry. I would like to acknowledge the following funding agencies that have supported my research: the University of British Columbia, the Natural Sciences and Engineering Research

Council of Canada, and Boehringer Ingelheim Ltd.

My heartfelt thanks to all past and present members of the Schafer group for creating such a supportive and fun lab environment. I have learnt so much from you all. Special thanks to

Dr. J.M. Lauzon, Dr. Erin Morgan, and Dr. Désirée Sauer for their input and guidance during the assembly of this thesis. Thank you to my proofreaders: Dr. J.M. Lauzon, Dr. Erin Morgan, Scott

Ryken, Mitch Perry, and Jacky Yim.

Thank you to Helen Huang-Hobbs, my thesis writing partner. Thank you to Peter

Christensen for his unending encouragement throughout the thesis writing process. Thanks to my siblings, Nicki and Alex, who are always available for pick-me-up phone calls. Much love to my parents, Nick and Jan, who truly understand what it takes to write a thesis. I am deeply grateful for your unfailing love and support. xxx

DEDICATION

This thesis is dedicated to my parents,

Dr. Gillian Janet Ann Payne

and

Dr. Nicholas Charles Payne

xxxi

CHAPTER 1: Synthesis, structure, and reactivity of early transition metal

precatalysts bearing (N,O)-chelating ligands.

1.1 Introduction

The first Nobel Prize in inorganic chemistry was awarded one hundred years ago, in

1913, to Alfred Werner for his work defining the basics of coordination chemistry.1 Currently,

the application of coordination and organometallic complexes spans many aspects of science and technology and their importance cannot be overemphasized.2-7 Arguably, the most significant application of metal complexes, in industry and academia, is the field of heterogeneous and homogeneous catalysis.8-13 The use of a catalyst allows for milder reaction conditions and the reduction or elimination of waste resulting in more sustainable and environmentally benign chemical processes.14,15 Homogeneous catalysis, in which the catalyst and the reactants share one

phase, affords active molecular species that can be identified and monitored spectroscopically.

Furthermore, a well-characterized catalytic system may allow for a mechanistic understanding of the performance of the catalyst at the molecular level. Such insight can be instrumental in the

rational design of catalytic systems with precise reactivity and selectivity.

One of the major applications of homogeneous catalysis is in the synthesis of commodity

chemicals. Notable large scale industrial processes include the Monsanto process for the

production of acetic acid through the carbonylation of methanol,16-19 and hydroformylation to

generate aldehydes and value-added chemicals from raw petrochemical materials.16,20-22

Homogeneous catalysis is also critical for the synthesis of intermediates and products in the fine

chemical, agrochemical, and pharmaceutical industries.11,13 Research in the field of

homogeneous catalysis involves both the development of new catalytic systems to improve

existing methodologies as well as the discovery of new catalytic reactions. The importance of

these advances has been recognized repeatedly; three Nobel Prizes in the last decade have been

awarded to four catalytic reactions: asymmetric hydrogenation and oxidation (Knowles,23

Noyori,24 Sharpless,25 2001), metathesis (Chauvin,26 Grubbs,27 Schrock,28 2005), and cross- coupling reactions (Heck,29,30 Negishi,31 Suzuki,32 2010).

iPr iPr Cl H N N Ar2 2 i , N P N Ti(O Pr)4 Cl Ph Ru Mo P EtO2C CO2Et O Ru N F3C Ph Ar2 Cl H Cl 2 F C O HO OH 3 Cy3P

F3C CF3 Noyori Sharpless Schrock Grubbs

Figure 1.1 Representative Nobel prize winning catalytic systems based on early, mid, and late transition metals.

Catalyst systems have been developed using metals from across the periodic table.

However, early transition metal systems, which contain the d-block elements of group 3

(scandium, yttrium), group 4 (titanium, zirconium, hafnium), and group 5 (vanadium, niobium,

tantalum), are especially appealing as they are inexpensive, naturally abundant, and biologically

benign metals particularly compared with the late transition metals.33,34 The properties and

reactivity of the resultant metal catalysts are as dependent on the supporting ligand environment as they are on the identity of the metal itself. The ancillary ligands influence physical properties of the metal complex (stability, solubility), the reactivity and, therefore, the required reaction

conditions (pressure, temperature, time), and the selectivity imparted by the catalyst.

A key example of the application of early transition metal catalysts, and the remarkable

impact of the supporting ligands, are the group 4 Ziegler-Natta catalysts35-38 for the controlled

polymerization of ethylene and propylene to generate α-polymers for plastics manufacturing, a

multi-billion dollar industry. In the early 1950’s, Ziegler and Natta showed that, under mild

reaction conditions using titanium tetrachloride in the presence of alkylaluminium activators, the

polymerization of ethylene39 and propylene40 could be achieved. The prochiral propene monomers can give rise to a variety of polymers containing different tacticities (Figure 1.2); control of the regio- and stereoselectivity of the polymerization can, therefore, result in a variety of polymeric microstructures, each with different physical and mechanical properties. However, the initial TiCl4/AlEt3 catalyst system is ill-defined. This results in limited control over polymer

structure and molecular weights and hampers a thorough mechanistic understanding. The

development of the well-defined, homogeneous single-site group 4 metallocene catalysts (Figure

1.2) activated by co-catalysts such as methylaluminoxane (MAO), represents a significant

advancement to the field.37,38,41-44 These complexes are soluble in hydrocarbon solvents and

impart control over the polydispersity and the microstructure of the polymer by the judicious

choice of the tunable ancillary ligands.42,45 Their well-defined active site and solubility means

their reactivity can be intimately studied and this thorough mechanistic understanding has been used as a guide for on-going catalyst design efforts.46,47

[Zr] 2n MAO n

Naphth

Si Si Ph Ph = Zr [Zr] Zr Cl Cl Zr Zr Cl Cl Cl Cl Cl Cl

Naphth C2v-symmetric C2-symmetric Cs-symmetric C1-symmetric

n n n n Atactic Isotactic Syndiotactic Hemiisotactic

Figure 1.2 Representative metallocene complexes for the selective synthesis of polypropenes with diverse tacticities.48-51

These catalyst design efforts and the wide-scale application of group 4 metallocenes in the synthesis of polyolefins is an illustrative example of the impact ancillary ligands can have on reactivity, selectivity, stability, and solubility of metal complexes. While the cyclopentadienyl

(Cp) ligand motif and its analogues continue to find diverse use in both catalytic and stoichiometric synthetic transformations,52 limitations, such as synthetic challenges, have

precipitated the departure from this scaffold to other ligand architectures.53-56 Ligand scaffolds

that are synthesized in a modular manner in minimal steps are particularly attractive, as this

allows for rapid tuning and optimization of a particular metal-ligand combination to suit the

transformation, substrate combination, or selectivity required. The majority of non-Cp ligands

for early transition metals are based upon oxygen- or nitrogen-donors, as these hard, multiple- electron donor atoms are effective at stabilizing the high oxidation states of the hard, Lewis-

acidic, oxophilic metals. An overview of relevant monoanionic non-Cp ligands will be discussed

in the following sections.

1.2 Mono anionic, monodentate ligands based on N- and O-donors. Common Cp-analogues are the monoanionic ligands based on nitrogen and oxygen

(Figure 1.3), such as the oxygen-donor alkoxo ligands.57 The alkoxo ligands appear simplistic,

however their use is not without challenges; in particular, the steric bulk of the ligand is further

removed from the metal centre and therefore these ligands are less sterically bulky than the Cp

ligands. The complexes formed are coordinatively unsaturated and the alkoxo ligands are able to

bridge metal atoms. These characteristics often result in the formation of bridged bimetallic

species or aggregates that can access low energy pathways for ligand exchange and redistribution

reactions that hamper controlled catalytic applications. One effective strategy to minimize

dimerization and aggregation is to increase the steric bulk of the ligand to access well-define

monomeric complexes.58-62 Highly sterically demanding alkoxides and phenoxides (Figure 1.3)

have been shown to support d0 alkylidene and alkylidyne complexes for olefin and acetylene

metathesis reactions.63

R1 O O O N 3 Si 3 1 R 1 R R2 R1 R 2 R 2 R R2 R1 R alkoxide phenoxide siloxide amido

Figure 1.3 Monodentate, monoanionic ligands based upon oxygen or nitrogen donors.

An alternative strategy are the siloxo ligands (Figure 1.3) pioneered by Wolczanski and co-workers.60,64,65 The presence of the silicon in the backbone decreases the electron-donating 5

ability of the siloxides compared with the alkoxides and results in a more electrophilic metal

centre.65,66 These ligands have been applied to generate a variety of early transition metal

t – complexes with rich and varied chemistry. The Bu3SiO ligand (termed “silox”) supports

reduced low-coordinate, and highly reactive early transition metal centres in the MIII oxidation

state (M = Ti, V, Ta, Nb, Mo), which have shown the notable reactivity in C–H bond activation

of hydrocarbons.64

The simple amido ligands (Figure 1.3) offer an advantage over the alkoxo, phenoxo, and

siloxo systems because of the potential for two substituents at the nitrogen.56,67-69 Homoleptic

70,71 amido systems are extensively applied in catalysis, including Ti(NMe2)4 that is a precatalyst

for hydroamination. Homoleptic amido metal complexes are also useful starting materials for the

preparation of new coordination complexes (vide infra). Importantly, the homoleptic dimethylamido complexes of titanium, zirconium, hafnium, tantalum, and niobium are

commercially available.

1.2.1 Multidentate, monoanionic ligands of (O,O)-, (N,N)-, and (N,O)-compounds

Polydentate ligand architectures containing multiple N- or O-donors are often applied to generate well-defined monomeric complexes. These compounds exhibit improved kinetic and thermodynamic stability because of the chelate effect.72 The more complex ligand scaffold also

contains additional sites for ligand modification and optimization; alterations to the rigidity or

flexibility of the tether, the distance between donor atoms and therefore different chelate ring

sizes, the orientation of the donors, and the identity of the chelating atoms all influence the

structure and reactivity of the resulting complex. Bidentate ligands incorporating two identical

donors have been extensively investigated and have many applications in homogeneous catalysis 6

including their role as ancillary ligands in post-metallocene catalysts for olefin and ring-opening

polymerization reactions,54,73 hydroamination,74-76 and hydroaminoalkylation.77,78 Representative

ligands of this type include the four-membered chelating amidinate,79-81 guanidinate,74,79,82,83 and

2-aminopyridonate75,78,84 ligands, as well as the five- and six-membered chelating aminotropionate,69,92 β-diketiminate,85,86 and β-diketonate87-91 ligands (Figure 1.4).68,76

R1 3 3 R1 R1 R3 R R N N N O O N N N 2 2 2 R 1 1 R (R )2N N R R R1 R1 R2 N N N R2 R2 R1 R1 R1 R1 amidinate guanidinate 2-aminopyridonate aminotroponiminate β-diketiminate β-diketonate

Figure 1.4 Bidentate, monoanionic ligands with (O,O)- or (N,N)-donors.

Chelating ligands that can bind to a metal centre through two different donor atoms are

another class of bidentate ligands.92 This ligand scaffold is especially appealing because the electronic asymmetry induced by the presence of two different donor atoms can promote ligand hemilability (Figure 1.5).93-95 Hemilabile ligands display dynamic coordination behaviour of the

more weakly bound donor allowing for the intermittent generation of vacant sites.

Z Y Z Y [M] [M]

Figure 1.5 Fluxional behaviour of a metal complex containing a hemilabile bidentate ligand.

The fluxional behaviour of the hemilabile ligands is particularly attractive for catalytic

systems; the ligand adds stability to the metal catalyst while retaining the potential for the open

coordination sites required for desirable reactivity. The ligand can also assist in the displacement

of coordinated products to regenerate the active catalyst. Ligand hemilability is governed by 7

subtle energy differences and is still difficult to control. However, it provides yet another facet of

ligand design that can be tuned and optimized and is, therefore, a useful approach to generating

new catalytic systems.96-98

One class of hemilabile ligands ideally suited to the coordination of early transition metal

complexes is (N,O)-chelating ligands (Figure 1.6). The amidate,99 ureate,100,101 pyridonate,102 and

sulfonamidate103 ligands, when bound in a κ2-(N,O) fashion, result in four-membered chelates with tight bite angles.

O O O O R2 O 2 2 N S R NH (R )2N N 2 N 1 1 R R R R1 R1 amidate ureate 2-pyridonate sulfonamidate

Figure 1.6 Bidentate, monoanionic ligands with (N,O)-donors.

The (N,O)-proligands are easily synthesized organic compounds that contain numerous

1 2 sites of potential modification and optimization (eg. R and R , Figure 1.6). Their modular

syntheses allow for straightforward structure-reactivity studies and adjustment of ligand steric

and electronic parameters to influence catalytic behaviour. The neutral proligands contain

protons of sufficiently acidity for the protonolysis of metal alkyl or amido ligands, which can be

used to advantage for the one-step synthesis of metal complexes (Figure 1.7, top). The by-

products of the protonolysis approach are volatile alkanes or amines that can be easily removed

from the reaction mixture under reduced pressure, simplifying the workup and purification

procedures. Another commonly used synthetic strategy involves deprotonation of the proligand

by alkali metal bases to generate a ligand salt that can then react with metal halide precursors via

salt metathesis (Figure 1.7, bottom). The resultant metal complexes can contain the ligands

bound in a variety of fashions. The most common of these binding modes include monodentate,

O- or N-bound, chelating (N,O)-bound, and a bridging motif involving multiple metal centres

(Figure 1.7).

O [M] O O O R R R [M] - HR MRx N,O- N N [M] N R = alkyl, amido ( ligand)MRx-1 NH R R R Monometallic

O [M] O [M] O - NaCl R Na MClx (N,O-ligand)MClx-1 R [M] N N [M] N R R Bimetallic

Figure 1.7 Protonolysis (top) and salt metathesis (bottom) synthetic strategies for the formation of early transition metal complexes and potential coordination modes of (N,O)-ligands.

The amidate, ureate, and pyridonate ligands have been extensively applied to generate

early transition metal complexes for applications in catalysis.99,104-112 These include, but are not

limited to, catalytic transamidation,108 the amidation of aldehydes,113 and the polymerization of ethylene,105 lactams,104 ε-caprolactone114 and rac-lactide.115 The most extensive application of these complexes is as precatalysts for two complementary atom-economic catalytic syntheses of

amines: hydroamination111,116,117 and hydroaminoalkylation112,118 (Figure 1.8).

R3 R3 Alkyne hydroamination R3 H 3 3 R R H H ( )n catalyst H ( )n catalyst 1 N 2 R R 3 A N B N 2 R N 1 1 R R1 R2 R R2 R

Alkene R3 hydramination R3 R3 3 ∗ H R ∗ R3 H H ( )n catalyst H ( )n catalyst N R3 1 2 N D N 2 R R C N 1 1 R R1 R2 R R2 R

Alkene H hydroaminoalkylation R3 3 H R3 H H R H R3 ∗ 1 N H 1 N catalyst H ∗ R catalyst R 1 N H N R E R1 R3 F ( )n 2 2 R3 ( )n R R R2 R2 2 2 R R

Figure 1.8 Catalytic hydroamination (A – D) and hydroaminoalkylation (E,F). The bonds broken are indicated in red and those formed in blue.

Hydroamination119,120 and hydroaminoalkylation121 are two hydrofunctionalization

reactions consisting of the formal addition of an N–H or C–H bond across a C–C unsaturation.

These are attractive methodologies for the synthesis of higher value amine products with increased molecular complexity from readily available starting materials. The amine compounds produced are relevant for a variety of applications including pharmaceutical drugs, agrochemicals, and natural product synthesis. These methodologies are both 100% atom- economic, in that all of the atoms in the reagents are retained in the product, eliminating the production of wasteful by-products. The push towards more environmentally benign methodologies and the inherent economic advantages means that technologies such as these are

attractive alternatives to established stoichiometric procedures. The kinetic and thermodynamic

factors of these reactions, as well the potential for a variety of regio- and stereoisomeric products

necessitate the mediation of highly active and selective catalysts.

The development of a general catalyst system, capable of promoting hydroamination

reactivity with unactivated alkenes and alkynes, primary and secondary amines, in both an intra-

and intermolecular fashion is an important goal. Transition metal catalysts from across the

periodic table have been investigated for this transformation.122,123 Early transition metal

catalysts124 are of particular interest due to their high reactivities, with minimized air- and

moisture-sensitivity compared with the rare-earth metal systems, and lower cost and toxicity

compared with the late transition metal catalysts. The (N,O)-ligands in Figure 1.6 have been studied in precatalysts for hydroamination and hydroaminoalkylation methodologies that display promising substrate scope and reactivity. The following sections will provide an overview of the coordination chemistry of early transition metals with amidate, ureate, pyridonate, and sulfonamidate ligands in the context of their application in the catalytic synthesis of amines.

1.2.2 Amidate complexes for hydroamination and hydroaminoalkylation

A modular class of easily synthesized (N,O)-ligands are the amidates, which are effective in supporting a range of early transition metal complexes.99 A salt metathesis synthetic route has

been used with limited success to generate mixed amidate chloro complexes; however this

methodology can result in intractable mixtures of products, including bridged dimeric or ill- defined multi-metallic species.99,101,114 On the other hand, protonolysis is a reliable route to a

variety of group 3, 4, and 5 metal amidate complexes (Figure 1.9).

O -n HR n MRx (N,O-ligand)nMRx-n M = Y (x = 3); Zr, Ti, Hf (x = 4); Ta (x = 5) NH R = NMe2, NEt2, N(SiMe3)2, Bn

n = 4 n = 3 n = 2 n = 1

O O O Not Group 3 R Y THF R Y(N(SiMe3)2) R Y(N(SiMe3)2)2 applicable N N N 3 2 THF THF Ar Ar Ar

NR O 2 O Ph Ti R M(NR2)2 N N 2 O O O Ar Ar 4 R1 M N Ph N Ph Ligand Group redistribution N Ar R 4 Ar M = Zr, Hf O O Ph Zr(NMe2) R M(NR2)2 N N 3 2 M = Hf Ar Ar Ti, Zr,

O R Ta(NMe2)3 O No reported attempts Group 5 N R Ta(NMe2)4 of n = 3 − 5 O Ar N N R Ar Ar

Figure 1.9 Early transition metal complexes containing (N,O)-ligand(s) synthesized via protonolysis with organic amide proligands.

In most cases, adjusting the ligand to metal stoichiometry allows for the selective

generation of targeted early transition metal complexes (Figure 1.9). Group 3 mono-, bis-, and tris(amidate) yttrium complexes have all been characterized and the amidate ligands are bound in a κ2-(N,O) chelating motif with a neutrally bound tetrahydrofuran (THF) solvent molecule in the coordination sphere. Of these three classes of yttrium amidate complexes, the tris(amidate)

complexes are the most active as precatalysts for the amidation of aldehydes113 and as initiators

for the polymerization of ε-caprolactone to generate high molecular weight polymers.114 Mono-

and bis(amidate) yttrium complexes are active precatalysts for intramolecular aminoalkene

hydroamination (Figure 1.8, D).117

Highly sterically crowded group 4 metal complexes bearing three or four amidate ligands

can be synthesized via protonolysis (Figure 1.9).125 The tris(amidate) complexes display different

coordination modes dependent on the size of the metal centre; the complex containing the

smaller titanium metal, less able to accommodate expanded coordination numbers and high steric crowding, contains two κ2 and one κ1(O)-bound amidate. The larger zirconium and hafnium metal centres are capable of accommodating three, and even four κ2-bound amidates, resulting in

complexes with expanded coordination numbers. These complexes, however, do not contain the

two reactive ligands required for application as hydroamination or hydroaminoalkylation

precatalysts.

The bis(amidate) bis(amido) complexes of titanium and zirconium (Figure 1.9) are a

broadly applicable class of precatalysts for hydroamination. The titanium complexes are the most

active for the hydroamination of alkynes126 and complex 1 has been identified as a regioselective

catalyst for the intramolecular126 and intermolecular hydroamination of alkynes,127,128 to generate

the aldimine products selectively (Scheme 1.1). The titanium catalyst functions well with both

aryl- and alkylamines, displays good tolerance to esters, silyl-protected alcohols, and aryl halide

functional groups, and promotes excellent regioselectivity. The reactive aldimine products can be

further elaborated using one-pot procedures to synthesize aldehydes,143,144 substituted

amines,143,144 α-cyano amines,129 α-amino acids,129 piperazines and morpholines,130 and

tetrahydroisoquinoline and benzoquinolizine alkaloids.128 13

NHR1 1 1 5 mol% 1 R HN 2 + R R2 R R2 O NH2 24 h, 65 °C Not observed Ph Ti(NEt2)2 iPr N 2 1 NR1 iPr R1N R2 + R2 Not observed

Scheme 1.1 Regioselective hydroamination of terminal alkynes promoted by precatalyst 1.

Group 4 bis(amidate) bis(amido) complexes have also been identified as precatalysts for

the more challenging hydroamination of alkenes. The majority of investigations in this field

focus on the intramolecular cyclization of aminoalkenes with zirconium based catalysts.131

Neutral group 4 bis(amidate) zirconium amido or imido complexes are efficient precatalysts for

the intramolecular cyclization of primary amines to form pyrrolidine and piperidine products

(Scheme 1.2). The monomeric imido complex can be generated by reaction of the bis(amido)

complex with 2,6-dimethylaniline and trapped with triphenylphosphine oxide.131 The bis(amido)

and imido complexes show comparable half-lives for the cyclization reactions, which implies both precatalysts share a common catalytically active species. The asymmetric version of this transformation, producing enantioenriched α-chiral amines, is an attractive goal. Following a

report by Bergman and co-workers of neutral bis(amido) zirconium precatalysts displaying ee

values of up to 80%,132 Schafer and co-workers described the use of neutral biaryl bis(amidate)

zirconium complexes for this transformation that are proficient at the cyclization of

aminoalkenes with enantiomeric excesses up to 93%.48,49,133 Research efforts concerning the

asymmetric hydroamination of unactivated olefins are covered in more depth in Section 2.1.

H R1 R2 ∗ N 1 10 mol% R = Ph, Me [Zr] 2 NH2 ° R = Ph, Me, H ( )n 110 C ( )n R2 n = 1,2 R1

Ar O O O N N = [Zr] Ph Zr(NMe2)2 Ph Zr Zr(NMe2)2HNMe2 i i N Pr N Pr N O PPH3 2 2 O iPr iPr Ar Ar = 2,4,6-trimethylphenyl

Scheme 1.2 Intramolecular hydroamination of primary aminoalkenes with neutral bis(amidate) zirconium complexes.131,134

The majority of group 4 catalyzed hydroamination reactivity has been proposed to occur

via a [2+2] cycloaddition mechanism involving a catalytically active metal-imido species

(Scheme 1.3).131,135-140 Mechanistic investigations for the bis(amidate) catalysts are consistent

with this proposal, supported by the lack of reactivity observed with secondary amine

substrates.131,139-142 The reaction, therefore, involves initial formation of the zirconium-imido species, followed by [2+2] cycloaddition with the C–C unsaturation. The orientation of the alkyne or alkene during the cycloaddition step determines the regioselectivity of the reaction.

Successive protonation of the metallacycle and the new amine release the product and regenerates the catalytically active imido species.

NMe2 NMe2 [Ti] [Zr] NMe NMe 2 R R 2 NH 1 H2NR 2 H2N H 2 R2 2 HNMe2 HNMe2 R 1 2 [Ti] N R R H [Zr] N NH2 N R H H R R2 R R R NHR1 1 [Ti] [Ti] NR H2N NR1 R N H 2 R H [Zr] R R2

H NR1 2

Scheme 1.3 Simplified [2+2] cycloaddition mechanism for the bis(amidate) titanium-catalyzed intermolecular hydroamination of alkynes and the bis(amidate) zirconium-catalyzed intramolecular cyclization of aminoalkenes. [Zr] and [Ti] = bis(amidate) zirconium and titanium, respectively.

These precatalysts require two or more reactive ligands to allow for the open two coordination sites required for productive reactivity. Mono(amidate) complexes of group 4 metals would also fulfill this requirement; however, all attempted syntheses of these complexes have not been successful and ligand redistribution is observed resulting in the formation of the bis(amidate) bis(amido) and the homoleptic metal amido complexes. Group 5 mono(amidate) complexes have been successfully prepared and, along with bis(amidate) tris(dimethylamido) tantalum complexes, are active precatalysts for hydroaminoalkylation.118 In particular, mono(amidate) tantalum complex 2 is a broadly applicable precatalyst for the intermolecular α- alkylation of secondary amines (Scheme 1.4).118

H R4 R4 H − 5 10 mol% [Ta] H ∗ 1 N H R ° 1 N ∗ 3 3 130 C R R 2 R R R2

Ar Mes O N tBu Ta(NMe2)4 O N O N Ta(NMe2)3 i O [Ta] = Pr iPr Ta(NMe2)3 N N O Ar Mes Ar = 2,6-dimethylphenyl

2, Schafer Schafer 3, Zi

Scheme 1.4 Intramolecular hydroaminoalkylation of unactivated olefins with secondary amines catalyzed by mono and bis(amidate) tantalum amido complexes.

Complex 2 remains the most broadly applicable catalyst for this reaction, catalyzing the

α-alkylation of N-arylalkylamines, controlled mono-alkylation with dienes, and displays tolerance of oxygen-containing substrates.118 Most importantly, this remains the only catalytic

system capable of the α-alkylation of N-heterocyclic amine substrates, which are important

structural motifs for the pharmaceutical industry. In all cases thus far this precatalyst shows

regioselective hydroaminoalkylation to generate the branched product, and excellent

diastereoselectivity when applicable (Scheme 1.4). The axially chiral biaryl-based bis(amidate)

ligands support catalytic systems, such as 3 (Scheme 1.4), which are generally less reactive than

their mono(amidate) counterparts112,118,143 but promote enantioselective hydroaminoalkylation with ee’s reported of up to 93%.112

Mechanistic investigations indicate that the tantalum precatalysts all react by the formation of a catalytically active tantalaziridine following α-C–H activation (Scheme

1.5).118,144,145 The incoming olefin undergoes insertion into the reactive Ta–C bond, setting both 17

the diastereoselectivity and regioselectivity of the product and generating the five-membered metallacycle. Protonation of the metallacycle by an incoming amine substrate and subsequent α-

C–H activation results in the regeneration of the tantalaziridine and release of the α-alkylated product. Extensive computational experiments are consistent with this proposed mechanism.146

NMe2 [Ta] NMe2 HN R1

2 HNMe2

[Ta] H N N R1 R1 R2 A R2

N R2 R1 [Ta] [Ta] N N R1 R2 R1 C B

HN 1 R

Scheme 1.5 Proposed catalytic cycle for the hydroaminoalkylation of secondary amines with tantalum precatalysts.

1.2.3 Ureate complexes for hydroamination

The ureate ligand class, closely related to the amidates, contains an amino substituent in the backbone that is capable of engaging in resonance. This alters the electronic properties of the system, which improves the electron-donating abilities of these ligand via π-donation of the nitrogen lone-pair. Initial studies into the preparation of early transition metal ureate complexes used an isocyanate insertion approach to generate the ureate complexes from metal amido 18

species (Figure 1.10).147,148 However, this is a laborious approach, where modular changes to the

resultant metal complexes require a variety of metal amido and isocyanate starting materials. The

complexes formed are also susceptible to further isocyanate insertions leading to product

mixtures.149

O O [M] NR2 C Ph [M] NR2 N N Ph Figure 1.10 Isocyanate insertion into a metal-amido bond to generate ureate complexes.

The protonolysis route with urea proligands, analogous to that utilized for preparing

amidate complexes, is a much more attractive synthetic approach. Extensive work spearheaded

by Dr. David Leitch of the Schafer group describe the synthesis, structure, and reactivity of

titanium and zirconium bis(ureate) complexes bearing alkyl,150 chloro,101 and amido ligands

(Scheme 1.6).100 The ureate ligands examined include both tethered and untethered bis(urea)

proligands and studies show that the tethered ligand is often much more successful in generating

well behaved coordination complexes by eliminating the fluxional behaviour and coordination

isomerism observed with the untethered bis(ureate) complexes. The tethered motif also increases

steric accessibility to the metal centre, which is particularly attractive for catalytic applications.

The chloro complexes formed are electron deficient complexes and often retain a neutral ligand;

either the dimethylamine by-product or coordinating solvent. The larger alkyl ligands allow for the synthesis of complexes without a coordinating neutral donor ligand by affording greater steric protection of the metal centre.

O O

i i Pr2N NH HN N Pr2

Cl or Ti(NMe2)2 2 ZrBn4 Zr(NMe2)4 Zr(NMe2)2Cl2(DME)

i i i Pr2N Pr2N Pr2N O Cl O Ph O NMe2 N N N M L Zr Zr NMe N N N 2 O O O Cl Ph NMe2 i i i H Pr2 N Pr2 N Pr2 N 4 M = Ti, Zr = L HNMe2, THF

Scheme 1.6 Synthesis of bis(ureate) alkyl, chloro, or amido complexes of group 4 metals. DME = 1,2-dimethoxyethane.

The most extensively investigated class of metal ureate complexes are the bis(ureate)

bis(amido) complexes and their associated hydroamination reactivity.151 These precatalysts have

been extensively characterized and the metrical parameters in the solid-state molecular structures

provide firm evidence that the ureate-ligands are more electron-rich than their amidate counterpart leading to tighter metal-ligand interactions. The ureate ligands are consistently bound in the κ2-chelating motif irrespective of the steric bulk of the ligand. The solid-state data for the tethered complexes reveals planar sp2 geometry of the backbone nitrogen, consistent with lone-

pair donation into the π-system. This is not always consistent with solution-phase NMR spectroscopy that shows magnetic equivalence of the iso-propyl methyl groups, suggesting weak electron donation by the distal nitrogen, allowing for free rotation about the C–N bond in solution.100

Reactivity studies indicate that the zirconium bis(ureate) precatalysts examined are more

reactive for intramolecular hydroamination than the titanium analogues, consistent with what has

been observed with the amidate systems.131 The tethered systems show drastically improved

activity compared to the untethered systems. Complex 4 (Scheme 1.6) was identified, following

extensive catalytic screening, as a highly active, broadly applicable hydroamination

precatalyst.100 This system is applicable for the intramolecular hydroamination of alkynes as well

as the intramolecular hydroamination of aminoalkenes. Heteroatoms are also tolerated, though

unsaturated ester or amide functionalities are not, and this system functions well with a broad

variety of primary and secondary amines substrates. The reactivity with secondary amines is

particularly notable, as this implies that the bis(ureate) ligand is active via a different mechanistic

pathway than that followed by most group 4 hydroamination catalysts. Extensive mechanistic

studies support the catalytic cycle shown in Scheme 1.8, which has been independently corroborated by computational studies.152,153 The key step of this mechanism is a proton-assisted

σ-bond insertion via transition state A (Scheme 1.8). This novel reactivity has been attributed to increased nucleophilicity of the equatorial amido ligand because of the electron-rich ureate ligand, as well as the presence of the coordinated neutral amine that participates in proton transfer.152,153

[Zr](NMe2)2HNMe2

R2 R2 excess R1HN 3 HNMe2

R2 NR2 R2 R1 R1 R1HN [Zr] NR

R2N H

R2 NR2 [Zr] [Zr] NR1 2 NR2 H R R2N A R2 2 R R2 NR2 NR1 [Zr] N R1 R2 NR2

Scheme 1.7 Proposed catalytic cycle for hydroamination using precatalyst 4 in which the key step is a proton-assisted σ-bond insertion. [Zr] = tethered bis(ureate)

1.2.4 Pyridonate complexes for hydroamination and hydroaminoalkylation

The 2-pyridone ligand and its derivatives are an important ligand motif in coordination

chemistry.102,154 In this (N,O)-ligand system (Figure 1.11), the nitrogen is a part of an aromatic ring and is, therefore, both sterically and electronically distinctive from the acyclic amidate and ureate ligands described in the above sections.

H R6 N OH R6 N O

R3 R3

Figure 1.11 The tautomeric equilibrium between 2-hydroxypyridine (2-pyridinol) and 2-pyridone.

2-Pyridonates have been reported as ancillary ligands in a wide variety of monometallic and polymetallic structures with diverse coordination modes102,154 and are most commonly found

as bridging ligands in late transition metal systems. Monometallic complexes supported by κ1-O

and N-bound pyridonates often follow the trend of softer metal centres preferring the N-bound

hydroxypyridine, while the hard metals more commonly display the O-bound κ1-motif. Until

recently, the use of this ligand motif with early transition metals has been scarce.155-157

Preliminary examples early transition metal systems include mixed pyridonate/cyclopentadienyl

complexes that display both chelating and monodentate bonding, with the hard oxophilic early

transition metals bound preferentially to the oxygen donor.

Early transition metal complexes of group 4 have been investigation by the Schafer group

for application in a variety of catalytic transformations. These include titanium alkoxide

complexes supported by 3-substituted and 6-substituted pyridonates, which are discrete catalysts

for the random copolymerization of rac-lactide and ε-caprolactone.115 Bis(pyridonate) zirconium

complex 5, bearing sterically demanding pyridonate ligands, can be synthesized via protonolysis

(Figure 1.12), and is an active precatalyst for the intramolecular hydroamination of aminoalkenes

to generate pyrrolidine and piperidine products.158 Substrates that are more challenging for

hydroamination, such as those without gem-disubstituents, can undergo both hydroamination and

hydroaminoalkylation that results in undesirable product mixtures.159

R1 1 R1 R1 R ( )n ( )n 10 mol% 5 2 H N R2 R R1 R2 2 ( )n 110 - 145 °C N R1 toluene H NH2 hydroamination hydroaminoalkylation

Ph O Zr(NMe2)2 N 5 2 tBu

Figure 1.12 Bis(pyridonate) bis(dimethylamido) zirconium complex 5 that promotes both hydroamination and hydroaminoalkylation.

The C–C bond formation via hydroaminoalkylation has been proposed to occur via a zirconaziridine (Scheme 1.8), analogous to the tantalaziridine of the group 5 metal systems.

However, extensive mechanistic studies of this system have not yet been reported and are the focus of Chapter 3. Since the report of this group 4 metal system, a variety of titanium systems have been reported,160-163 including a system supported by related aminopyridonate ligands

(Figure 1.4),78 and their reactivity is discussed in Section 3.1.

NMe2 2 [Zr] NMe2 NH 2 2

4 HNMe2

[Zr] N ( )4 Hydroamination

NH2 [Zr] N ( )4 [Zr] 2

NH2

[Zr] [Zr] N N [Zr] [Zr] N ( )4 N ( )4 H H

Scheme 1.8 Proposed mechanism for hydroaminoalkylation promoted by complex 5 via a bridging zirconaziridine. [Zr] = bis(pyridonate).

1.2.5 Sulfonamidate complexes for hydroamination

Sulfonamidates, also termed sulfonamide and sulfonamido ligands, have a rich history as ancillary ligands in titanium complexes for application in synthesis.103 The majority of these ligand motifs are the bis(tosyl) ligands based on the a chiral diamine backbone (Figure 1.13).

These tethered ligands are chiral and, therefore, have the potential to afford enantioenriched products through catalytic asymmetric transformations. Indeed, these ligands have been extensively studied for the titanium-catalyzed asymmetric addition of dialkylzinc reagents to aldehydes.164-167

The initial studies used an in situ generated chiral catalyst and proposed an active bis(sulfonamidate) titanium species. Extensive solution phase and mechanistic investigations have since been performed, as well as extensive structural studies on the bonding of these bis(sulfonamidate) systems with titanium;103,168,169 common coordination motifs observed during these studies include κ3- and κ4-bound complexes (Figure 1.13). The addition of the sulfur into the backbone does significantly alter the coordination geometries of these complexes compared with the amidate, ureate, and pyridonate complexes discussed in the above sections. The most evident difference is the preferential binding to nitrogen in these systems; in almost all of these cases the Ti–N bond distance is shorter than that of the Ti–O.169

R1 O O R2 S S O O O O Ph N N S Ti(NMe2)2 Ti(NMe2)2 Ti(NMe2)2 N Ph N N 2 O O S S O O R1 R2 6 1 2 R = 4-tert-buyllphenyl R = 4-methylphenyl Gagné, 1998 Walsh, 1999 Nagashima

O Mes S N O O O Ta(NMe2)3 (NMe2)3Ti S Ti(NMe2)3 N N N O S Ph Ph O Mes Zi Doye

Figure 1.13 Representative early transition metal systems containing sulfonamidate and sulfamide ligands. Mes = mesityl.

Bergman and co-workers investigated the application of complex 6 for the hydroamination of alkynes and allenes.170,171 These complexes are significantly more reactive 26

and regioselective compared with Ti(NMe2)4 or Cp2TiMe2 precatalysts, which can be attributed to the increased electron withdrawing properties of the sulfonamidate ligand. The sulfonamidate titanium complexes are proposed to proceed via the [2+2] cycloaddition mechanism shown in

Scheme 1.3.170 Recently, the related sulfamide ligands have been used as ancillary ligands in a

bridging dimeric titanium precatalyst for hydroaminoalkylation by Doye and co-workers.172

These preliminary studies demonstrate the potential of this ligand motif; the precatalyst is able to

perform the first group 4 catalyzed α-alkylation of a dialkylamine substrate. There has been one report by Zi and co-workers that describes axially chiral bis(sulfonamidate) tantalum and

niobium complexes for application as precatalysts for hydroamination and hydroaminoalkylation

(Figure 1.13).143 Unfortunately, these complexes did not show any reactivity for either of these

applications.

This overview of the coordination behaviour of (N,O)-chelating ligands reveals their

successful application for the generation of monomeric, well-defined organometallic precatalysts. The complexes generated have interesting coordination chemistry that follows

trends based on the steric and electronic properties of the ligands, a quality that is very attractive

for catalytic application. Though these (N,O)-ligands appear to be very similar, their applications

are especially broad, and small changes to the ligand motif (eg. amidate vs. ureate vs. pyridonate) result in vast differences in selectivity and reactivity. Their chemistry and potential is by no means exhausted and early transition metals (N,O)-chelated complexes are deserving of extensive future research.

1.3 Scope of thesis

The research presented within this thesis focuses on the structure and reactivity of early

transition metals of group 4 and 5 complexes as precatalysts for hydroamination and

hydroaminoalkylation. Though the amidate, ureate, pyridonate, and sulfonamidate ligands are all related as modular classes of (N,O)-chelating ligands, their varied electronic and steric properties

result in different reactivity patterns. The precedent for the successful application of (N,O)-

ligated early transition metal complexes has been established in the preceding sections, however,

a myriad of studies investigating the synthesis, structure, and reactivity of these complexes is

required to realize their full potential as precatalysts for the catalytic synthesis of amines.

As outlined in Section 1.2.3, bis(ureate) zirconium precatalysts have shown impressive

application in the synthesis of amines via hydroamination. The tethered bis(ureate) system shows

vastly expanded substrate scope compared with its amidate counterparts. Chapter 2 focuses on

the synthesis of a new chiral ureate ligand to provide insight into ligand design trends and

highlight key principles to guide future catalyst development efforts. The asymmetric synthesis

of α-chiral amines with high enantioselectivity is particularly attractive. Therefore, the ability of

the C1-symmetric ureate ligand to support chiral zirconium precatalysts for the asymmetric

hydroamination is explored.

A related class of group 4 precatalysts supported by pyridonate ligands have been

examined as both hydroamination and hydroaminoalkylation precatalysts.158,159 The mechanism

for this precatalyst has not been extensively examined, though preliminary investigations have

indicated that a bimetallic species might be the catalytically active species. In Chapter 3,

investigations probe the solution phase behaviour of the precatalyst and the stoichiometric

reaction of complex 5 with aryl and alkyl amines. Kinetic investigations have been performed to 28

provide insight into the mechanism that will aid in the development of future generations of

catalysts for this reaction.

Tantalum complexes supported by amidate ligands successfully promote the

intermolecular α-alkylation of secondary amine substrates; however, high reaction temperatures,

long reaction times, and substrate scope limitations restrict the broad application of this

methodology. Chapter 4 details extensive ligand development efforts, including new amidate

ligands with tethered neutral donors and altered steric and electronic parameters. The Schafer

group and others have utilized electron-withdrawing ligands to promote improved reactivity and,

therefore, the synthesis and reactivity of mixed amidate chloro tantalum and

mono(sulfonamidate) tantalum complexes were examined. Reliable synthetic routes to generate

these new tantalum complexes, along with extensive characterization and catalytic screening data

provide a basis for on-going catalyst development.

In their 2009 communication, Schafer and co-workers reported the first example of the α-

alkylation of an N-heterocyclic substrate using a mono(amidate) tetrakis(dimethylamido)

tantalum precatalyst.118 Due to the ubiquitous nature of these functionalized N-heterocycles in

the agrochemical, fine chemical, and pharmaceutical industries, as well as the existing

limitations of current synthetic methods, a broad substrate scope investigation into the α- alkylation of this class of substrates is described in Chapter 5. A potential rational for the lack of reactivity observed with five-membered pyrrolidine substrates is presented based upon both in

silico as well as deuterium labeling studies.

Finally, a summary of the research is presented in Chapter 6 and potential avenues of

future research are highlighted. These include new ligand systems to address substrate scope

limitations of the mono(amidate) tantalum amido complex. New chiral urea proligands are also 29

proposed to generate enantioselective tantalum complexes based on simple mono(ureate

proligands) for application in asymmetric hydroaminoalkylation.

The work presented herein constitutes a broad investigation into the synthesis, structure,

and reactivity of early transition metal complexes featuring (N,O)-ancillary ligands. The development of reliable synthetic routes, the fundamental understanding of the structure and bonding of these complexes, and their associated reactivity profiles is essential for the development of highly reactive and selective precatalysts for hydroamination and hydroaminoalkylation.

CHAPTER 2: C1-symmetric ureate complexes of zirconium for the asymmetric hydroamination of unactivated aminoalkenes

2.1 Introduction

2.1.1 Asymmetric hydroamination of unactivated olefins

Asymmetric inter- and intramolecular hydroamination of alkene substrates can generate chiral amine products in a waste-free, highly atom-economical manner (Scheme 2.1). Therefore, an important focus of recent research is the development of catalyst systems supported by chiral ancillary ligands to promote enantioselective hydroamination.173-178 A particularly desirable, yet

challenging transformation is the asymmetric hydroamination of simple unactivated olefinic and

amine substrates.

NR2R3 H ∗ 1 ∗ 1 R N catalyst 1 H R R2 R3 R R1

2 ∗ H R H N R1 N catalyst ∗ R2 R

Scheme 2.1 Hydroamination of alkenes using a chiral catalyst to generate enantioenriched alkylamines.

Late-transition metal systems of iridium,179,180 palladium,181-184 gold,185-188 rhodium,189

and copper190 are almost exclusively applied for the intermolecular hydroamination of amines

and alkenes. These catalyst systems often take advantage of C2-symmetric axially chiral

phosphine ligands (Figure 2.1) to impart the desired enantioselectivity.180,189 The main disadvantage of these precatalysts is their requirement of activated olefinic substrates such as strained alkenes, dienes, styrenes, or allenes along with amines of reduced basicity such as 31

anilines, carboxamides, and sulfonamides. Alkali metal based systems are less populous in the

literature; however, bis(amido) dinaphthyl lithium systems have been used with limited success for the intramolecular cyclization of aminopentenes.191-193 Alkaline earth metal systems have

been more extensively studied but are often plagued with facile ligand exchange (Schlenk

equilibrium) or ligand cleavage upon substrate addition.194-197 These damaging side-reactions

result in low enantioselectivities and until recently the most selective catalysts, chiral pseudo C3-

symmetric monoanionic bulky tris(oxazolinyl)borato magnesium and calcium complexes, could

only achieve ee’s of up to 36%.198 A recent innovation in the field by Hultzsch and co-workers

describes chiral phenoxyamine magnesium catalysts, which, by circumventing ligand

redistribution reactions, can generate pyrrolidine products with ee’s of 51 – 93% (Figure 2.1).199

Metal-free catalytic systems have also been examined, such as binaphthol-derived dithiophosphoric acid compounds as chiral Brønsted acids to generate vinyl-pyrrolidines,200 and

(R)-glyceraldehyde for the intermolecular Cope-type hydroamination of allylic amines.201

Although metal and non-metal systems from across the periodic table have been developed, the

most successful systems for the intramolecular hydroamination of simple, unactivated

aminoalkenes are those based on rare-earth or group 4 metals.173,174

tBu N O Ar NMe O Mg 2

O PR OCHPh SiPh3 Ph O S 2 2 P O PR2 PCy2 O SH tBu N O Ar NMe Iridium Rhodium O Mg 2 Ar = 10-(2,4,6-trimethylphenyl)- SiPh3 Ph 9-anthracenyl = ° d.r. 9:1 at 25 C Figure 2.1 Representative late transition metal, alkaline metal, and Brønsted acid based catalytic systems.

2.1.2 Rare-earth metal systems

Rare-earth metal complexes are the most extensively studied systems for the

intramolecular asymmetric hydroamination of unactivated olefins.123,174,175,177,202 The first report of asymmetric hydroamination describes the use of C1-symmetric ansa-lanthanocene complexes containing a pendant chiral group (eg. R*= (–)-menthyl, (+)-neomenthyl) on one of the cyclopentadienyl groups (Figure 2.2).203 However, these catalysts are plagued by facile catalyst

epimerisation and the focus has since shifted to non-cyclopentadienyl based systems.

SiPh3 Me2N O Ph B Y CH SiMe Si Ln Ln N 2 3 X(SiMe3)2 O N t X = N, CH O O Bu Me2N ∗ Ln = La, Nd, Sm t R Ph Bu Lu, Y SiPh3 Marks Hultzsch Sadow to ee to ee − ee up 74% Sc; up 95% 89 96%

Figure 2.2 Chiral lanthanide precatalysts for asymmetric hydroamination.

Significant contributions from the research groups of Scott,204 Livinghouse,205 Marks,206

207 208,209 Schulz, and Hultzsch have described the use of C2-symmetric ligands, such as

biphenolate, binaphtholate, biarylamido, and bis(oxazolinato) compounds, for the generation of

chiral lanthanide precatalysts for intramolecular hydroamination. The binaphtholate catalysts of

yttrium, scandium, and lutetium developed by Hultzsch (Figure 2.2) are particularly noteworthy

as these remain the only rare-earth catalysts that are also active for the intermolecular

asymmetric hydroamination of alkenes. The C2-symmetric catalyst systems have dominated the

literature210 until a recent report by Sadow and co-workers that describes the synthesis and

reactivity of mixed cyclopentadienyl-bis(oxazolinyl)borate chiral yttrium complexes for the

intramolecular hydroamination of primary aminoalkenes (Figure 2.2).211

These chiral lanthanide complexes are attractive systems due to their high catalytic

activities without requiring protected or activated substrates. However, these precatalysts are restricted by very low functional group tolerance and extreme sensitivity to air and moisture. The focus has, therefore, shifted to group 4 metal systems as these complexes have low toxicity, low cost, and improved stability and functional group tolerance over lanthanide complexes while exhibiting excellent reactivity.

2.1.3 Group 4 metal systems

Initial catalyst development with group 4 systems focused on the use of cationic complexes,45,46 as these complexes are isoelectronic with the rare-earth systems.107,116 The first

asymmetric hydroamination by a chiral group 4 metal catalyst, reported by Scott and co-workers,

is an aminophenolate complex based on the axially chiral biaryl backbone (Figure 2.3).107 The

cationic zirconium complex readily catalyzes the cyclization of secondary aminoalkenes to

generate heterocyclic products in 14 – 82% ee. Neutral group 4 complexes are also active and

selective catalysts for the intramolecular hydroamination of unactivated alkenes. Bergman and

co-workers have developed chiral zirconium complexes, prepared in situ from the diphosphinic

amide proligands and Zr(NMe2)4, for the formation of pyrrolidines and piperidines in up to 80%

ee.132 Though these catalysts require heating (85 – 135 ºC), high catalyst loadings (20 mol%) and

are limited by ligand redistribution into inactive homoleptic species, they demonstrate that stable,

easier to handle, neutral zirconium complexes are effective catalysts for this transformation.

Indeed, in a 2007 report, the Schafer group described the use of neutral biaryl bis(amidate) 34

zirconium complexes for this transformation.141,142 These complexes can be easily synthesized

via a simple protonolysis reaction of the bis(amide) proligand with Zr(NMe2)4. The most

efficient of the complexes screened is proficient at the cyclization of aminoalkenes with

enantiomeric excesses up to 93% (Figure 2.3). The bis(amidate) complex is more reactive than the Bergman system requiring shorter reaction times and lower catalyst loadings (10 mol%).

Since these reports, numerous neutral group 4 metal systems with chiral biaryl-based ligands have been reported,133,212 though these complexes also require high reaction temperatures and do

not demonstrate significantly improved selectivity or reactivity. A recent report by Sadow and

co-workers describes the notable application of a C1-symmetric mixed cyclopentadienyl

bis(oxazolinyl)borate ligand (Figure 2.3), which catalyzes the hydroamination of primary aminoalkenes generating five-, six-, and seven-membered N-heterocyclic amines at room temperature with ee’s of up to 99%.213,214

tBu

tBu R R Ar P O F O B(C6 5)4 N O N NMe2 N Ph B Zr HNMe Zr NMe Zr(NMe2)2 Zr(NMe2)2 2 N 2 N Ph N O N O O O N P O tBu R R Ar R = 3,5-dimethylphenyl Ar = 2,4,6-trimethylphenyl tBu C2-symmetric C2-symmetric C2-symmetric C1-symmetric Scott Bergman Schafer Sadow

Figure 2.3 Cationic and neutral zirconium systems for the asymmetric intramolecular hydroamination of aminoalkenes.

Untethered amidate ligands synthesized from enantiomerically pure chiral ketones, such

as (–)-menthone, have been investigated for the intermolecular hydroamination of aminoalkenes

(Figure 2.4).215,216 The complex that is formed in situ using two equivalents of chiral acyclic

amide 7, and Zr(NMe2)4 catalyzes the formation of pyrrolidine products in ee’s of up to 26%.

The low selectivity of the complexes studied has been attributed to potential ligand redistribution

reactions in solution resulting in achiral catalytic species.

Ph O Ph NH ∗ N H >98% yield, 26% ee 7 ° 5 h, 110 C

Figure 2.4 Untethered chiral amidate ligands for intramolecular asymmetric hydroamination.

Overall, group 4 catalytic systems show potential in mediating the asymmetric intramolecular hydroamination of aminoalkenes. However, apart from the system developed by

Sadow and co-workers, excellent enantioselectivities (>90%) have only been reported for a select number of catalyst-substrate combinations, and have been restricted to catalyst systems supported by axially chiral tethered biaryl ligands. These systems also suffer from low tolerance

to polar functional groups leading to restricted substrate scope. While these contributions

illustrate the potential of group 4 catalytic systems, they are only a first step toward realizing the

goal of a broadly applicable asymmetric alkene hydroamination catalyst.

2.1.4 Expansion of substrate scope using a tethered bis(ureate) zirconium catalyst

A recent report from the Schafer group describes the reactivity of a tethered urea

proligand supporting an easily synthesized zirconium complex (4, Figure 2.5) that induces a

promising scope of reactivity for both inter- and intramolecular hydroamination.100 This ureate precatalyst is arguably the most generally useful group 4 metal complex reported to date, 36

promoting reactions with both primary and secondary amine substrates, exhibiting vastly

expanded substrate scope and tolerance of polar functional groups (eg. pyrrole, acid-sensitive

protected catechol) as well as excellent chemoselectivity for hydroamination.

i Pr2N O NMe2 N Zr NMe N 2 O 4 i HNMe2 Pr2N

Figure 2.5 Tethered bis(ureate) zirconium hydroamination precatalyst 4.

The chemoselectivity is of particular interest, as other group 4 systems can be plagued

with unwanted hydroaminoalkylation side-reactions to give amine substituted carbocycles rather

than heterocyclic products.159,161,162,172,217 The development of a chiral ligand system that imparts

both the high activity and selectivity of 4 and instills excellent enantioselectivity is of the utmost

importance for the efficient synthesis of chiral amines. Thus, the investigation of a new chiral

urea proligand would provide invaluable insight regarding the role of the urea functionality and

the tether in the reactivity accessed by such ureate zirconium complexes and potentially mediate

asymmetric hydroamination.

2.1.5 Scope of chapter

This chapter focuses on the reactivity and selectivity mediated by a new chiral ureate ligand for the asymmetric hydroamination of aminoalkenes. The modular synthesis of the chiral proligand from inexpensive enantiopure amino acids is presented, and its ability to support

complexes that mediate enantioselective intramolecular hydroamination is explored. This study

compares and contrasts the reactivity and selectivity of amidate versus ureate, cyclic versus

acyclic, and tethered versus untethered ligands, while exploring the use of an untethered chiral ureate ligand for affecting enantioselectivity. Through the characterization of the resultant coordination complex in this system, critical features required for improved reactivity and

selectivity are identified and discussed.

2.2 Results and discussion

2.2.1 Ligand and complex

Cyclic ureas, synthesized from the chiral pool of natural amino acid starting materials,

are an attractive modular class of proligands for the generation of group 4 asymmetric

hydroamination precatalysts. While cyclic ureas have been investigated for their medicinal

properties,218-220 examined for potential application as Lewis basic organocatalysts,221,222 used as

chiral auxiliaries for asymmetric syntheses,223,224 and utilized as substrates for intermolecular

hydroamination,225 these compounds represent a new proligand motif for coordination of early

transition metals. The coordination of related chiral 2-aminopyrrolines to titanium has been

studied226 and zirconium alkyl and amido complexes supported by related achiral imidazolone

ligands have been shown to be effective catalysts for intramolecular hydroamination.227

Proligand 8 is synthesized as white crystalline needles in five steps from L-valine

(Scheme 1). This modular synthetic route is attractive, as a wide variety of proligands can be generated from inexpensive enantiopure starting materials. A solid-state molecular structure has been obtained of the crystalline product and confirms the connectivity of proligand 8 (Figure

2.6).

O O O Boc2O, NEt3 CyNH2, HOBt, DCC Cy HO 1:1 dioxane:H O HO N 2 DIPEA, DCM H NH2 NHBoc NHBoc 94% yield 74% yield

TFA, DCM

O N Triphosgene Cy LiAlH4 Cy N ∆ N NH DCM H THF, H NH2 NH O 2 8 84 %yield 88% yield 90% yield 46% yield overall

Scheme 2.2 Modular route for the synthesis of urea proligand 8. Boc = tert-butoxycarbonyl, HOBt = hydroxybenzotriazole, DCC = N,N'-dicyclohexylcarbodiimide, DIPEA = diisopropylethylamine, TFA = trifluoroacetic acid.

N3 C13 N4 O2 H99

H98 O1 N2 C1 N1

Figure 2.6 ORTEP depiction of the solid-state molecular structure of proligand 8. The ellipsoids are plotted at 50% probability and the majority of the hydrogen atoms are omitted for clarity. The hydrogens displayed (N–H) have been located from unassigned electron density and their positions refined.

The cyclic urea crystalizes in the chiral P1 space group and the asymmetric unit includes

two urea molecules each displaying one of the two possible chair conformations of the N- cyclohexyl moiety. The urea proligand displays intermolecular hydrogen bonding between the

N–H and the carbonyl oxygen (O1–H99, 1.96(2) Å; O2–H98, 2.09(2) Å, Table 2.1) of the two

urea molecules. The presence of this interaction is further supported by the short donor-acceptor

distance (O1···N4, 2.874(2) Å; O2···N2, 2.883(2) Å) and the acceptor–H–donor angles that are close to 180° (O1–H99–N1, 177.1(19)°; O2–H98–N1, 170.6(18)°). Each atom of the urea fragment is sp2-hybridized consistent with signification delocalization of the nitrogen lone pairs

and indicated by the planar nature of the NC(O)N fragment.

Table 2.1 Relevant bond lengths (Å) and angles (°) for 8. N1–C1 1.371(2) N2–C1 1.356(2) N3–C13 1.364(2) N3–C13 1.358(2) O1–C1 1.233(2) O2–C13 1.241(2) O1–H99 1.96(2) O2–H98 2.09(2) O1···N4 2.874(2) O2···N2 2.883(2) O1 –H99–N1 177.1(19) O2–H98 –N1 170.6(18) ∑ N1 355.8(2) ∑ N2 356.7(2) ∑ C1 360.0(2)

Synthesis of the targeted bis(ureate) bis(amido) zirconium complex 9 via protonolysis of

Zr(NMe2)4 with 8 results in crude material that has elemental analysis data consistent with the

proposed complex (Scheme 2.3). However, the complicated 1H and 13C NMR spectra for this material suggest that multiple species are present in the solution phase. No free ligand remains, as is evident by loss of the diagnostic amide N–H signal at δ 7.18 ppm in the 1H NMR spectrum

(Appendix B).

iPr iPr

NH -n HNMe2 N 2 Zr(NMe2)4 Mixture of products, 9 N hexanes N Zr(NMe2)2 Cy Cy O O 2 8 Target

Scheme 2.3 Precatalyst formation by the protonolysis reaction of Zr(NMe2)4 with 8. 40

Unfortunately, high yielding crystalline material could not be obtained from the product mixture 9. Although rigorous characterization of the resultant coordination complexes could not be achieved, the in situ prepared complexes are suitable for screening for hydroamination reactivity.

2.2.2 Intramolecular hydroamination

The ability of 9 to mediate enantioselective hydroamination has been investigated for the cyclization of 2,2-diphenyl-1-amino-4-pentene, a standard test substrate202 (Table 2.2). The use

of cyclic ureate 8 in isolated 9 (entry 1) and the in situ procedure (entry 2) generates the

heterocyclic product in good yield, albeit with low enantioselectivity. One of the exceptional

elements of the tethered urea zirconium catalyst 4 (Figure 2.5) is the broadened substrate scope it

displays compared with other existing group 4 catalyst systems.100 In order to discern if this

improved scope of reactivity can be attributed to the urea functionality or to the ligand tether,

reactivity with a broader range of substrates was investigated using in situ prepared 9. The

substrate scope using complexes prepared with proligand 8 is very limited; reaction progresses in

good yield to generate five- and six-membered heterocycles (entries 2-6). However, no

conversion to product is observed with secondary amines, internal olefins, or substrates without

gem-disubstituents.

Table 2.2 Reactivity studies using proligand 8 for intramolecular hydroamination with alkenes.

R2 R2 R2 R2 20 mol% 8 ∗( )n 10 mol% Zr(NMe2)4 NH2 ( )n d8-toluene N H

Entry Substrate Product Conditions Yield, ee (%)c Ph Ph Ph Ph 1 NH2 12 h, 100 ºC 92, 11 N H Ph Ph Ph Ph b 2 NH2 4 h, 100 ºC >98 , 12 N H Ph Ph Ph Ph 3 NH2 8 h, 100 ºC 89, <5 N H

d 5 NH 18 h, 100 ºC 71 , nd 2 N H

b 6 NH2 24 h, 145 ºC >95 , nd N H a10 mol% in zirconium of crude product 9, reaction time not optimized bNMR yield determined by 1H NMR using 1,3,5-trimethoxybenzene as internal standard due to product volatility cee determined by 1H NMR spectroscopy of derivitized product with (+)-(S)-α- methoxy-α-trifluoromethylphenylacetyl chloride dDerivitized with tosyl chloride to aid in isolation.

This limited reactivity profile is reminiscent of substrate scope limitations previously

reported when Zr(NMe2)4 is used as a precatalyst for the intramolecular hydroamination of aminoalkenes.228,229 Ligand redistribution could be occurring under catalytic conditions to

generate Zr(NMe2)4 in solution which could also act as a catalyst for the transformation resulting

in the substrate scope limitations and poor enantioselectivities observed. Ligand redistribution

and disproportionation reactions have been observed previously with group 4 amidate systems230

and has been postulated to occur during the attempted synthesis of zirconium alkyl complexes

supported by acyclic untethered ureate ligands.150 The enantiomeric excesses achieved (up to

12%) are lower than those of related amidate chiral acyclic ligands based on (–)-menthone such

as 7 (up to 26%);215,216 this is consistent with increased ligand redistribution due to minimal steric bulk as well as the fact that the stereogenic centre is well removed from the metal centre of these cyclic ligands (Figure 2.7).

O Ph O R Ph [Zr] Ph N [Zr] N ∗ N vs. iPr N H iPr Proligand: 8 12% ee ee 7 26%

Figure 2.7 Proximity to the zirconium center of steric bulk and source of chirality in the cyclic ureate compared with the amidate ligand.

2.2.3 Isolated bimetallic complex

The only crystalline material that was obtained from a solution of 9 were isolated from a

saturated pentane solution of the crude material that was cooled to -30 °C for several weeks. The

solid state-molecular structure reveals a bimetallic species 10 with an unexpected ligand

stoichiometry, containing three ligands for two metal centers (Figure 2.8). This suggests that

ligand redistribution is indeed a complicating factor under catalytic conditions, and provides a

rationale for both the poor ee’s and limited substrate scope observed.

N3 C25 N6 N4 O3 C13 N9 Zr2 N8 Zr1 O2 O1 N10 N7 N2 N11 C1

Figure 2.8 ORTEP depiction of the solid-state molecular structure of complex 10. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity. In the simplified structure (right) the methyl groups of dimethylamido ligands (N7-11) and the cyclohexyl groups of the ureate ligands ((N1, N3, N5) are removed for clarity.

The isolated bimetallic complex 10 has three bridging ureate ligands, suggesting that the

steric bulk of the ligand is insufficient to support monomeric species of these highly electrophilic

metal centers. This compound is C1-symmetric with pseudo-octahedral geometry about each zirconium atom. Of the three bridging ureate ligands, two are bound in a simple bridging mode, and one (O1, N2) is also bound in a κ2-fashion to Zr1 while bridging Zr1 and Zr2. Selected bond

lengths and angles for complex 10 are summarized in Table 2.3. The C–N2,4,6 (1.317 – 1.325 Å)

and C–O (1.271 – 1.290 Å) bond lengths of the metal-bound ureate fragments are consistent with moderate delocalization within the ureate backbone. The respective C–N bonds to the tertiary amine (N1,3,5; 1.361 – 1.368 Å) are slightly longer than those of the bonding moiety, however

these, and the sum of 353º for the subtending angles, are indicative of sp2 hybridization and 44

limited lone-pair donation to the π-system. Interestingly, the Zr–N bonds to the ureate ligands

(2.2372(9) and 2.2459(9) Å) are slightly shorter than those of the tethered ureate complex

(2.279(1) Å),100 the exception being the Zr–N6 bond which is presumably lengthened due to the presence of the strongly donating trans dimethylamido ligand (N11). Comparable bis(amidate)

bis(amido) Zr–N(amidate) bonds are significantly longer (~2.32 Å).142,231 The Zr–O bond lengths in 10, excluding those related to O1 which is bridging two metal centers, are significantly shorter

(by >0.1 Å), than those of related monomeric bis(amidate) bis(amido)231,232 and bis(ureate)

100 bis(amido) zirconium complexes. Zr–NMe2 (2.035 – 2.130 Å) bond lengths in 10 are slightly

longer on average than Zr-N double bonds reported in the literature (<2.043 Å).231 Related tethered142 and untethered231 bis(amidate) bis(amido) zirconium complexes have Zr–N(amido)

bond lengths of 2.065 – 2.069 Å and 2.043(3) Å respectively. The tethered bis(ureate)

100 bis(amido) zirconium complex 4 has Zr–NMe2 bond lengths of 2.029(2) Å.

Table 2.3 Relevant bond lengths (Å) and angles (º) for complex 10. C1–N2 1.323(1) C1–O1 1.290(1) C1–N1 1.361(1) C13–N4 1.325(1) C13–O2 1.271(1) C13–N3 1.362(1) C25–N6 1.317(1) C25–O3 1.282(1) C25–N5 1.368(1) Zr1 –N2 2.2459(9) Zr1 –N4 2.2372(9) Zr1 –N7 2.073(1) Zr1–N8 2.035(1) Zr1–O1 2.4420(8) Zr1–O3 2.1386(8) Zr2–N6 2.3353(9) Zr2–N9 2.073(1) Zr2–N10 2.077(1) Zr2–N11 2.130(1) Zr2–O1 2.3286(8) Zr2–O2 2.1745(8) ∑ N1 348.7 ∑ N3 354.3 ∑ N5 355.6

The dimeric nature of this species with bridging (N,O)-chelating ligands is not unprecedented; the related zirconium imidazolone complexes, reported by Ong and co-workers

and synthesized with a 1:1 stoichiometry of proligand to Zr(NMe2)4 or Zr(Bn)4, also assume

dimeric solid-state geometries with two bridging imidazolone ligands.227 When a bulkier N-(2,6-

dimethylphenyl)imidazolone is used as the proligand with Zr(Bn)4 a complex mixture of products is obtained and the only low yielding, crystalline material isolated from the reaction mixture is once more a bimetallic species containing six imidazolone ligands to two zirconium metal centres. The imidazolone zirconium precatalysts have been applied with limited success for the hydroamination of primary and select secondary aminoalkenes.227 The substrates that are

successful are those bearing gem-disubstituents and that result in the formation of five- membered pyrrolidine products.

The attempted synthesis of related bis(2-pyridonate) bis(dimethylamido) zirconium, 11, via protonolysis with Zr(NMe2)4 (analogous to Scheme 2.3) also results in crystalline material

with a similar solid-state molecular structure to that of 10 (Figure 2.9).216 Optimization of the reaction conditions and slow recrystallization at room temperature from a saturated benzene solution allows for high-quality crystalline material. The fully refined solid-state molecular data demonstrate that the 2-pyridonate ligands also undergo ligand redistribution to form a bimetallic species with three sterically unhindered ligands bridging two zirconium centres. This dimeric species shows very poor catalytic reactivity (15% yield) for the cyclization of test substrate 2,2- diphenyl-1-amino-4-pentene after 24 hours at 110 °C.216

N N O O NMe2 Me N 2 Zr Zr NMe2 O Me2N NMe2 N

Figure 2.9 ORTEP depiction of the solid-state molecular structure of complex 11. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

2.3 Conclusions

Easily prepared chiral ureate proligands can be efficiently assembled from inexpensive

chiral amino acids. The in situ prepared complexes using the untethered urea proligand result in

modestly enantioselective cyclohydroamination reactions with reactivity reminiscent of

Zr(NMe2)4, suggesting that ligand redistribution may be occurring. Despite the moderate reactivity and poor selectivity observed, these results provide important insights for advanced ligand design; improvements in the state-of-the-art for these catalyst systems must take advantage of the enhanced stability and reactivity trends of tethered amidate and ureate ligands.

The role of the tether is not restricted to control of geometry at the metal center but can also dramatically improve stability by reducing the propensity for ligand redistribution. The cyclic motif of these, and related 2-pyridone and imidazolone proligands, results in steric bulk that is removed from the metal center and gives rise to bimetallic species with unexpected ligand to metal stoichiometry. Thus, ideal ligands possess an acyclic framework with sufficient steric bulk to minimize this formation of bimetallic species.

2.4 Experimental

2.4.1 General methods

All reactions were conducted using oven-dried (160 °C) glassware with magnetic stirring using Schlenk-line techniques or a glove box under an atmosphere of dry dinitrogen unless indicated otherwise. Experiments on the NMR tube scale were carried out in Teflon cap sealed J.

Young NMR tubes (5 mm). Toluene, benzene, hexanes, pentane, tetrahydrofuran (THF), and diethyl ether were purified and dried by passage over a column of activated alumina.

Dichloromethane (DCM) was distilled from calcium hydride under an atmosphere of dinitrogen. d6-Benzene and d8-toluene were dried over 4 Å molecular sieves and degassed by three freeze- pump-thaw cycles. Solvents for chromatography and non-moisture sensitive reactions were used as received from commercial sources and were at least of ACS reagent grade. Silica gel G60 (70-

230 mesh) and F60 (230-400 mesh) was purchased from Silicycle. Thin layer chromatography was run on silica gel coated glass plates with UV indicator obtained by Merck and analyzed by

UV/VIS and stained using a cerium ammonium molybdate solution.

NMR spectra were recorded on Bruker Avance 300, Bruker Avance 400, or Bruker

Avance 600 MHz instruments. The samples were measured as solutions in the indicated solvent at ambient temperature in non-spinning mode unless noted otherwise. To specify the signal multiplicity, the following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet; br = broad resonance, and app = apparent multiplicity. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard for 1H and 13C NMR spectra and calibrated against the residual protio solvent signal. Coupling constants, J, are given in Hertz (Hz).

Mass spectrometry data and elemental analyses were collected by the members of the

mass spectrometry and microanalysis service at the University of British Columbia. Mass spectra

were measured on a Kratos MS-50 by Mr. Marshall Lapawa. Fragment signals are given in mass

per charge number (m/z). Elemental analyses were performed on a Carlo Erba Elemental

Analyzer EA 1108 by Mr. Derek Smith. The content of the specified element is expressed in

percent (%).

All X-ray diffraction measurements were made on either Bruker X8 Apex or Bruker

DUO CCD area detectors with graphite-monochromated molybdenum radiation source (Mo Kα,

λ = 0.71073 Å) under a continuous flow of nitrogen (100(2) or 90(2) °C). These data were collected either by Neal Yonson, Jacky Yim, or Scott Ryken and refined by the author with advice from Dr. Brian O. Patrick when required. The data were processed233 and area detector

scaling and absorption correction were applied.234 The solid-state molecular structures were refined using SHELX-97235 via the WinGX graphical user interface.236 Structure validation was

performed when required using PLATON.237 All non-hydrogen atoms were refined with anisotropic thermal parameters. All solid-state molecular figures are generated using ORTEP-

3.236,238 Additional crystallographic details of all solid-state molecular structures are located in

Appendix A.

2.4.2 Materials

Reagents for substrate and proligand synthesis were purchased from commercial

suppliers and used without further purification. Zr(NMe2)4 was purchased from Strem and used as received. 1,3,5-Trimethoxybenzene, used as an internal standard, was purchased from Aldrich and purified by sublimation under reduced pressure. The following hydroamination substrates 49

were prepared using known literature procedures from commercially available starting materials:

2,2-diphenyl-1-amino-4-pentene,239 2,2-diphenyl-1-amino-5-hexene,239 and 2,2-dimethyl-1-

amino-hexene.240 The following hydroamination products are known and 1H NMR spectral data

is in agreement with reported values: 2-methyl-4,4-diphenylpyrrolidine,206 2-methyl-5,5- diphenylpiperidine,241 and 2,5,5-trimethylpiperidine.242

2.4.3 General experimental procedure

In situ intramolecular hydroamination: Urea proligand 8 (15.8 mg, 0.075 mmol) and

Zr(NMe2)4 (10.0 mg, 0.0375 mmol) were weighed into a small vial. d8-Toluene (0.47 mL) and

1,3,5-trimethoxybenzene (0.03 mL of a 1.25 M solution in d8-toluene) were added and the

solution was gently shaken.243 The hydroamination substrate was then added (0.375 mmol) and

the solution transferred to a J. Young NMR tube. The NMR tube was sealed and placed in a

preheated oil bath at the reaction temperature indicated. The reaction progress was monitored by

1H NMR spectroscopy.

2.4.4 Compound synthesis and characterization

(S)-1-cyclohexyl-4-isopropylimidazolidin-2-one, 8: The precursor (S)-

N 2-amino-N-cyclohexyl-3-methylbutanamide was prepared by the NH O procedure described in the literature244 from L-valine with 8 cyclohexylamine substituted for tert-butyl amine and purified by recrystallization from ethyl acetate prior to N-Boc deprotection which proceeded cleanly. (S)-N1-cyclohexyl-3-methylbutane-

245 1 1,2-diamine was prepared through reduction with LiAlH4 as described in the literature. (S)-N - cyclohexyl-3-methylbutane-1,2-diamine (2.62 g, 14.176 mmol) was dissolved in dry DCM and 50

the solution was cooled to 0 ºC. Triphosgene (1.472 g, 4.962 mmol) was added in one portion

followed by pyridine (2.28 mL, 28.352 mmol). The solution was warmed to room temperature

with stirring. After 3 hours the solution was diluted with 1M HCl and the organic layer was

collected. The aqueous layer was extracted with DCM (3x50 mL) and the organic layers were combined, dried over MgSO4, filtered, and concentrated by rotary evaporation. Recrystallization

from a minimal amount of DCM gave the title compound as colourless needles. Yield: 84%. 1H

3 NMR (d6-benzene, 600 MHz) δ 0.69 (d, JH,H = 6.8 Hz, 2H, CH3), 0.84-0.90 (m, 4H, CH3, CH2 of

Cy), 1.04-1.19 (m, 4H, CH2 of Cy), 1.38-1.44 (m, 2H, CH(CH3)2, CH2 of Cy), 1.54-1.68 (m, 4H,

3 3 CH2 of Cy), 2.68 (app t, JH,H = 7.68 Hz, 1H, N(Cy)CH2CH), 2.96 (app t, JH,H =8.6 Hz, 1H,

3 3 N(Cy)CH2CH), 3.03 (q, JH,H =7.42 Hz, 1H, NHCH), 3.95 (t, JH,H = 11.3 Hz, 1H, CH of Cy),

13 7.18 (s, 1H, NH); C (d6-benzene, 150 MHz) δ 18.4 (CH3), 18.9 (CH3), 26.2 (CH2), 26.3 (CH2),

26.3 (CH2), 30.4 (CH2), 31.3 (CH2), 34.0 (CH), 44.8 (CH2), 51.3 (CH), 56.8 (CH), 162.7 (C);

HRMS calcd. for C12H22N2O: 210.1733. Found: 210.1732; Anal. calcd. for C12H22N2O: C, 68.53;

24 H, 10.54; N, 13.32; Found: C, 68.48; H, 10.60; N, 13.09.; [α]D -21.0 (c 1.00, MeOH).

Characterized by X-ray crystallography (Appendix A).

Crude reaction mixture, 9:

0.5 Zr(NMe2)4 Urea proligand 8 (0.2003 g, N Complex mixture, 9 NH toluene O 0.9904 mmol) and Zr(NMe2)4

(0.1325 g, 0.495 mmol) were dissolved in toluene (2 mL) and stirred at room temperature

overnight (~18 h) and following removal of the volatiles under high vacuum a yellow foam was

obtained. The NMR spectra of this compound are complex and reveal the presence of multiple

species in solution. The 1H NMR spectrum is included in Appendix B. Anal. calcd. for

C24H44N4O2Zr: C, 56.24; H, 9.10; N, 14.05 Found: C, 56.13; H, 8.84; N, 13.38.

10: The crude reaction mixture 9 was dissolved in minimal CyN iPr NCy iPr N amount of pentanes and filtered through Celite to obtain a N O O NMe2 Me N saturated homogeneous solution, after which 1 equivalent of 2 Zr Zr NMe2 O NMe Me2N 2 pyridine was added. Crystals suitable for X-ray crystallography N NCy 10 were grown from this solution in very low yield at -30 ºC. iPr

Characterized by X-ray crystallography (Appendix A).

11: A solution of 2-hydroxypyridine (0.8576 g, 9.0 mmol) in

benzene (3 ml) was added dropwise over 5 minutes to a solution N N O O NMe2 Me N of tetrakis(dimethylamido)zirconium (0.946 g, 4.5 mmol) in 2 Zr Zr NMe2 O benzene (3 ml). The mixture was stirred at room temperature for Me2N NMe2 N 11 20 hours. The solvents were removed under high vacuum to

afford a bright yellow microcrystalline solid. Crystals suitable for X-ray crystallography were

1 obtained from a saturated solution in benzene at room temperature. Yield: 27%. H NMR (d6- benzene, 600 MHz): δ 3.28 (br s, 12H, N(CH3)2), 3.31 (br s, 12H, N(CH3)2), 6.04-6.21 (m, 3H,

3 3 CH), 6.62 (d, JH,H = 8.19 Hz, 3H, CH), 6.83-6.96 (m, 3H, CH), 7.81 (dd, JH,H = 5.5, 1.4 Hz, 3H,

13 CH); C NMR (d6-benzene, 150 MHz): δ ppm 44.3 (N(CH3)2), 46.0 (N(CH3)2), 113.9 (CH),

114.8 (CH), 141.1 (CH), 145.7 (CH), 170.1 (C=O).

CHAPTER 3: Mechanistic investigations of a bis(pyridonate) zirconium

complex for intramolecular hydroaminoalkylation

3.1 Introduction

Hydroaminoalkylation can proceed in an intra- or intermolecular fashion (Scheme 3.1) to

generate amines of higher complexity from readily available starting materials.121 The

intermolecular α-alkylation of secondary amines using early transition metal homoleptic

dimethylamido precatalysts was originally discovered by Maspero and Clerici,246 and

precatalysts based on zirconium, niobium, and tantalum are effective, selectively generating the

branched regioisomeric product in up to 38% yield over 20 hours at 160 °C. Since this report, a

series of group 5 metal systems of tantalum77,112,118,247-251 and niobium77,112 have been developed.

An overview of the existing catalytic systems and their scope of reactivity is presented in

Chapters 4 and 5.

H catalyst H H N H N N R2 R1 R2 R1 ≠ H R1 R2 R1 branched linear R1 H H N H 1 catalyst N N R R1 competing ( )n ( )n hydroamination ( )n

Scheme 3.1 Inter- and intramolecular hydroaminoalkylation of amines.

3.1.1 Titanium-based precatalysts

Doye and co-workers have developed a series of titanium complexes for application as precatalysts in the intramolecular hydroaminoalkylation of aminoalkenes to generate amino- substituted carbocycles.162,163,252 One unresolved challenge with the group 4 systems is that they 53

also promote hydroamination reactivity with these aminoalkene substrates (Scheme 3.1, bottom),

which can result in mixtures of products that are difficult to separate. Indeed, the first examples

of titanium-catalyzed hydroaminoalkylation were observed during an investigation into the

252 reactivity of Ti(NMe2)4 and Ind2ZrMe2 as hydroamination precatalysts. These hydroaminoalkylation side-products have also been detected during investigations into the synthesis of secondary amines by titanium-mediated transfer of alkenyl groups from alcohols.253

The issue of chemoselectivity between hydroamination and hydroaminoalkylation remains an

unsolved problem for group 4 metal systems.

The chain length of the aminoalkene has been observed to impact the ratio of the

products obtained.159,163 For example, intramolecular hydroamination to generate large seven-

membered azepanes is notoriously challenging159,252 and, therefore, 1-amino-6-heptenes are ideal substrates for catalyst reactivity studies focused on the preferential formation of the six- membered hydroaminoalkylation products (Scheme 3.2).

R2 2 R2 5 mol% [Ti] R R2 R2 72 h, 160 °C N R2 HN HN R1 R1 <5% yield R1

Me Ti(NMe2)4 Ti(CH2Ph) Ti Me 12 13 14 R1 = H, 46% 62% 0% R2 = Me 1 R = -Me-C H a a p 6 4, 26% n/d 3% 2 = R H

Scheme 3.2 Select titanium precatalysts for the intramolecular hydroaminoalkylation of primary and secondary aminoalkenes. a10 mol% [Ti].

Using this substrate-controlled strategy to disfavour hydroamination, a series of titanium-

based precatalyst systems have been investigated by Doye and co-workers (Scheme 3.2). The homoleptic dimethylamido titanium precatalyst 12, is moderately successful at mediating the formation of the α-alkylated product in 46% yield, albeit after prolonged heating at high temperature.163 The homoleptic benzyl precatalyst 13 is generally a more active system than its amido congener,162 promoting conversions of up to 62% under the same reaction conditions. The

related metallocene complex 14 bearing the indenyl ligands is not reactive for the intramolecular

hydroaminoalkylation under the reaction conditions examined.163

Another approach to minimize competing hydroamination is to utilize secondary

aminoalkene substrates, since these are unable to form the catalytically active titanium-imido

intermediate required for hydroamination.161,254 Unfortunately, the hydroaminoalkylation of secondary aminoalkenes using precatalyst 12 (Scheme 3.2) resulted in the formation of the

desired products in no more than 26% yield, despite high reaction temperatures and extended

reaction times (160 °C, 72 hours).163 The bis(indenyl) precatalyst 14 is once again less reactive

and results only in isomerization of the alkene.

Catalytic and stoichiometric investigations have been performed to probe the

intramolecular hydroaminoalkylation reactivity promoted by precatalyst 12 by Doye and co- workers (Scheme 3.3). The results of the mechanistic study have been corroborated by computational studies and are consistent with a catalytically active titanaziridine species.255

Deuterium labeling studies indicate that the α-C–H activation to form the titanaziridine is the

turnover-limiting step.

R R R R H ( )3 2 H2N = or ( )3 N L NMe2 L Ti Ti(NMe2)4 2 R R N ( )3 H H2N R R ( )3

R R H2N ( )3 NH L2Ti R R R ( R NH2 )3 R R H R R H N N L2Ti L2Ti ( )3 NH R R R H N R 2 ( )3 Scheme 3.3 Simplified mechanism of titanium-catalyzed intramolecular hydroaminoalkylation.

The titanium complexes 12-14 have been demonstrated to be reactive precatalysts for the

intermolecular hydroaminoalkylation of secondary amines with olefins (Scheme 3.4).78,160,161,172

The chemoselectivity of this methodology is once again substrate-controlled and takes advantage

of the fact that intermolecular hydroamination of unactivated olefins is rare and only a handful of

catalytic systems exist that are capable of promoting this reactivity.179,180,256-258 While use of this substrate combination does result in selective hydroaminoalkylation, the regioselectivity of the reaction is poor and use of precatalysts 12, 13, and 14 regularly generates mixtures of the branched and linear isomers.

H H H N 10 mol% n n [Ti] N N hexyl 1.5 n Ph hexyl 96 h, 160 °C Ph hexyl (branched : linear)

= : : : [Ti] 12 33% (93:7) 13 77% (90:10) 14 84% (>99:1)

Scheme 3.4 Intermolecular hydroaminoalkylation of 1-octene promoted by complexes 12, 13 and 14.

The bis(indenyl) titanium complex 14 is the most active titanium precatalyst reported for the intermolecular reactivity and promotes the α-alkylation of N-arylamines in good yields and often excellent selectivity (Scheme 3.4).161 The α-alkylation of N-methylaniline with 1-octene proceeds to 86% yield after 24 hours at reaction temperatures as low as 80 °C. This reduced reaction temperature allows for alkene substrate scope expansion, such as the use of styrenes that polymerize at higher reaction temperatures. Precatalyst 14 has since been shown to be effective at promoting the hydroaminoalkylation of styrenes with good selectivity (75:25 – 99:1, branched: linear)161 and of 1,3-conjugated butadienes160 to generate regioisomeric mixtures of homoallylic amines.

More complex chelating ligands such as sulfamides172 and 2-aminopyridinates78 have been used to generate novel titanium precatalysts. Use of the sulfamide ligand results in the formation of a bridged bimetallic titanium complex (Figure 3.1)172 that is active for the hydroaminoalkylation of styrene. In this case not only are both regioisomers formed, but also a small amount of the bis(alkylated) product is detected. Though the sulfamide precatalyst displays limited control of selectivity, it is capable of promoting the first example of group 4 metal catalyzed hydroaminoalkylation of a dialkylamine substrate, albeit in 36% yield. 2-

Aminopyridonate titanium complexes, generated in situ by the protonolysis reaction of

Ti(NMe2)4 with 1 or 2 equivalents of the proligand, are the first titanium precatalysts to

preferentially form the linear isomer, although always as a mixture of both regioisomeric

products.78

O O N Ti 1 or 2 Me (NMe2)3 S Ti(NMe2)3 N N N H Ph Ph Ti(NMe2)4

Figure 3.1 Titanium precatalysts containing bidentate ligands for the hydroaminoalkylation of secondary amines.

3.1.2 A zirconium pyridonate precatalyst

Though the initial report by Maspero and Clerici described Zr(NMe2)4 as a successful

precatalyst system for intermolecular hydroaminoalkylation,246 only one report of an active

zirconium precatalyst has since been reported.159 This bis(N,O)-chelating pyridonate system (5,

Scheme 3.5) is active in promoting the intramolecular hydroaminoalkylation of primary

aminoalkenes. Utilizing substrate-controlled strategies, moderate to good yields of the

hydroaminoalkylation products can be obtained (Scheme 3.5). Cyclohexane and cyclopentane

rings can be formed with good yields, even when the substrates do not contain gem- disubstituents. Sterically demanding quaternary stereocenters can be assembled with good stereoselectivity. Control of chemoselectivity remains a challenge for this precatalyst, and competing hydroamination side-products are often observed. High reaction temperatures, high catalysts loadings, and poor control of diastereo- and chemoselectivity impede the broad

application of this precatalyst system in the efficient synthesis of amines.

Ph O 2 2 ( )n R R 2 20-40 mol% 5 R Zr(NMe2)2 H2N 2 N n − R 5 ( ) 110 145 °C 1 R1 toluene R NH2 2 tBu (trans:cis)

(+/-) NH Ph NH 2 NH2 2 NH2 NH2 54% (2:1) 43% (2:1) 51% (1:19) 90% (3:1) 91% (2:1)

Scheme 3.5 Intramolecular hydroaminoalkylation with zirconium pyridonate precatalyst 5.

In an effort to address these limitations and to guide future catalyst development efforts, a

thorough understanding of the mechanism of action of the catalyst is desirable. The mechanism

proposed for this precatalyst is shown in Scheme 3.6.159 The initial step is the generation of a

monomeric zirconium imido species that subsequently dimerizes to generate a bridging imido

zirconium complex (A). The monomeric imido species is a catalytically active species for the competing hydroamination, consistent with the [2+2] cycloaddition mechanism proposed for the majority of group 4 catalyzed hydroamination (Section 1.2.2).131,135-140 The product distribution

of hydroaminoalkylation to hydroamination has been observed to vary depending on the catalyst

concentration, with increased catalyst loading favouring the C–C bond formation. This is

consistent with a dimeric zirconium intermediate as the active species for intramolecular

hydroaminoalkylation. Subsequent C–H activation adjacent to the nitrogen then yields a

dinuclear zirconaziridine intermediate (B). These metallaziridines are widely accepted as the

active species in both the group 4 and 5 catalyzed hydroaminoalkylation reaction118,144,250,255 and

zirconaziridines have extensive literature precedent as reagents in stoichiometric transformations.259,36 Insertion of the alkene into the reactive Zr–C bond generates the expanded

metallacycle that can then be protonated by a new aminoalkene substrate to regenerate the

bimetallic zirconium-imido species (A).

NMe2 2 [Zr] NMe2 NH 2 2

4 HNMe2

2 [Zr] N ( )4 Hydroamination

NH2 [Zr] N ( )4 [Zr] 2 A

NH2

[Zr] [Zr] N N [Zr] [Zr] N ( )4 N ( )4 H H B

Scheme 3.6 Proposed mechanism for intramolecular hydroaminoalkylation with precatalyst 5. [Zr] = bis(pyridonate).

In an effort to provide further insight into the proposed mechanism and to provide vital details to guide catalyst design efforts, a mechanistic investigation has been performed. This encompasses both the stoichiometric and catalytic activity of the bis(pyridonate) bis(dimethylamido) zirconium complex 5.

3.1.3 Scope of chapter

This chapter focuses on mechanistic investigations into the hydroaminoalkylation

performance of bis(pyridonate) zirconium precatalyst 5. Variable temperature studies have been

performed to probe the solution-phase behaviour of the precatalyst. The examination of the

stoichiometric reactivity of complex 5 with a variety of amines is also discussed. These studies focus on probing for potential bimetallic species in the solution phase and solid state.

Preliminary efforts toward the synthesis of a bis(pyridonate) zirconaziridine are also presented.

A kinetic analysis focusing on the cyclization of a primary aminoalkene substrate has been performed to gain insight into the behaviour of the reagents under catalytic conditions. These include determination of substrate order, the effect of changing catalyst concentration on reaction rates, determination of activation parameters, and kinetic isotope effects.

3.2 Results and discussion

3.2.1 Solution-phase behaviour of the precatalyst

Initial stoichiometric investigations focused on the ability of the bis(pyridonate) bis(dimethylamido) zirconium precatalyst to support dimeric species. The bridging coordination mode of the pyridonate ligand is common in late-transition metal complexes102 and the attempted synthesis of the related sterically accessible unsubstituted bis(2-pyridonate) bis(dimethylamido) zirconium complex results in a bimetallic complex with bridging pyridonate ligands (Chapter 2,

Figure 2.9). The precatalyst 5, first synthesized by Dr. Jason Bexrud via protonolysis,158,159 with

the more sterically bulky pyridonate ligands, is a monomeric species in the solid state (Scheme

3.7). Mass spectral analysis is also consistent with a monomeric formulation, with a signal

observed at m/z 631, and no evidence of higher molecular weight species.159 61

R OH 2 N Ph O -2 HNMe2 Zr(NMe2)2 benzene R N 5 2 tBu Zr(NMe2)4

Scheme 3.7 Synthesis of bis(pyridonate) bis(dimethylamido) zirconium and ORTEP representation of the solid-state molecular structure of complex 5.159 The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

The possibility that complex 5 exists as a mixture of equilibrating monomeric and

dimeric species in the solution phase could potentially be probed using variable temperature 1H

NMR studies. Low temperature studies (25 – -80 °C) of a d8-toluene solution of precatalyst 5

have been performed. While no new resonances are observed, the chemical shifts show a

dependence on temperature, most noticeable in the aryl region (Figure 3.2). If rapid, relative to

the NMR timescale, dynamic processes are occurring in solution then the signals observed are a

weighted average of all the species in solution.260-262 The change in temperature alters the relative population of these species, thereby altering the observed chemical shift.260-262 The

temperature dependence chemical shifts observed for 5 are consistent with ligand fluxionality on

the NMR timescale; however, this cannot be conclusively attributed to a monomer-dimer

equilibrium. Indeed, this is most likely due to a rapid change in coordination mode between the

κ2-(N,O) chelating motif to the κ1-(O) bound motif of the pyridonate ligand since the large steric

substituents of the pyridonate ligands most likely discourage bridging interactions. When the 1H

NMR spectra are examined for analogous unsubstituted bis(2-pyridonate) bis(dimethylamido)

titanium complex (monomeric in the solid state) over the same temperature range there is an

appearance of new signals at low temperatures (Appendix B). This could be due to decreased

steric requirements of the unsubstituted ligands allowing for aggregation in solution.

He Hd

c H O Zr(NMe2)2 b H N 5 2 d8-toluene Ha tBu

T(oC) c b d H H e a H H H 25.0

13.9

-12.3

-30.0

-50.2

-70.7

-80.9

8.0 7.5 7.0 6.5 Chemical Shift (ppm)

1 Figure 3.2 Variable temperature H NMR spectra of the aryl region of complex 5 in d8-toluene.

Precatalyst 5 contains two dimethylamido ligands with α-hydrogens that could undergo an intramolecular protonolysis reaction to generate a zirconaziridine. This α-C–H activation of

an amido ligand has been extensively used in the literature for the synthesis of zirconaziridines

such as 15 (Scheme 3.8, top).263,264 The reaction involves the loss of methane from an intermediate bis(cyclopentadienyl) zirconium alkyl amido complex to yield the zirconaziridine,

which can be isolated as the tetrahydrofuran adduct.263 α-C–H activation of a coordinated amine

has also been used for the synthesis of tantalaziridine complexes supported by amidate ligands,

both in the successful isolation of a bis(amidate) bis(dimethylamido) tantalaziridine complex118

and during the thermolysis of a mono(amidate) tetrakis(dimethylamido) tantalum species at 130

°C for 20 hours.146 The diastereotopic proton signals of the tantalaziridine methylene moiety are

particularly diagnostic at δ 2.27 and 2.32 ppm.146 Unfortunately, heating of precatalyst 5 under

analogous reaction conditions (130 °C, 24 h) does not result in any signals consistent with

zirconaziridine formation.

1 1 R L R 2 R1 NLi R - LiCl N L N Cp2ZrMeCl Zr Zr 2 Cp2 Cp2 - CH4 H R CH3 15 R2

L = PMe3, THF

Me2N O - O N tBu HNMe2 t Ta(NMe2)4 ° Bu Ta N 130 C, d8-toluene N Ar = Ar 2,6-diisopropylphenyl Ar NMe2 ~20% yield

Scheme 3.8 Reported routes for the synthesis of monomeric metallaziridines of zirconium and tantalum.

Diffusion Ordered Spectroscopy (DOSY)265,266 has been performed as alternative method

to probe the solution-phase structure of the precatalyst. This NMR technique provides

information regarding the diffusion coefficients of solutes in solution. Using the Stokes-Einstein

equation (Section 3.4.2), a value for the hydrodynamic radius of the species in solution can be

267 calculated. For a solution of precatalyst 5 in d6-benzene, the signal attenuation of the resonances of Ha and Hc (Figure 3.2) results in a calculated hydrodynamic radius of 4.0 Å. Since

the Stokes-Einstein equation assumes that the diffusing particle is a hard sphere this is not a

quantitative value, though the small magnitude is consistent with a monomeric species in

solution.

The solid-state molecular structure, the mass spectral analysis, and the solution phase

NMR studies of the precatalyst do not provide any evidence for a bridging coordination mode of the pyridonate ligands and indicate that the precatalyst is most likely a monomeric species.

3.2.2 Stoichiometric reactivity

Previous substrate scope investigations have established that there is no reactivity with secondary aminoalkene substrates for intramolecular hydroaminoalkylation.159 The intermolecular reaction, using N-methylaniline or p-methoxy-N-methylaniline with 1-octene in the presence of 20 mol% of precatalyst 5 also does not result in any α-alkylation. These results imply that an zirconium-imido intermediate is required and, therefore, stoichiometric investigations into the generation of bis(pyridonate) imido species have been targeted.

Catalytically active imido complexes are commonly invoked as the active species for most group 4 hydroamination catalysts.131,135-140 Group 4 imido species also exhibit notable reactivity as precatalysts for ethylene polymerization268,269 as well as stoichiometric C–H activation of hydrocarbons.270-275 One synthetic route that has been successfully applied for the synthesis of these reactive complexes is the direct aminolysis of L2M(NMe2)2 precursors, resulting in terminal and bridging imido zirconium complexes, of which examples include bis(amidate)131,276 and bis(ureate)150,152 complexes. These compounds, supported by similar

(N,O)-chelating ligands are particularly relevant to the bis(pyridonate) system of interest.

The aminolysis reactions of precatalyst 5 with one equivalent of aniline, 2,6- dimethylaniline (Figure 3.1), and 2,6-diisopropylaniline have been examined. These reactions result in mixtures of products, as evidenced by complex 1H NMR spectra. This could potentially be due to the presence of the dimethylamine that is liberated during the protonolysis or an 65

existing equilibrium between bridging and terminal imido moieties. Addition of the aniline

reagents results in a colour change of the reaction solution from the pale yellow of the precatalyst

to a bright yellow-orange. Not surprisingly, the addition of the aniline reagent vastly increases

the solubility of the product in common hydrocarbon solvents. Crystalline material has been

obtained from a layered toluene:pentane solution when 2,6-dimethylaniline is used.

NH2 Ph O O N O Zr(NMe2)2 Zr Zr N hexanes 5 N 2 N N 2 2 -2 HNMe2 tBu 16 32% yield

Scheme 3.9 Synthesis of dimeric imido zirconium complex 16 via aminolysis of complex 5.

The solid-state molecular structure reveals that the zirconium pyridonate compound reacts with 2,6-dimethylaniline to generate the bridging imido species, 16 (Figure 3.3). The two

halves of the complex are related by an inversion center and contain six-coordinate zirconium metal centers. The metrical parameters of complex 16 (Table 4.2) indicate that the pyridonate ligands are bound in an asymmetric κ2-fashion to the zirconium metal centers, with a much shorter Zr–O bond (2.099(8) and 2.103(8) Å) compared with the Zr–N bond lengths (2.481(10) and 2.437(10) Å). The binding modes of the pyridonate ligands are, therefore, most accurately described as aryloxide-imine and are analogous to those found in complex 5 (Zr–O, 2.092(1) Å;

Zr–N, 2.432(2) Å). The Zr-imido bond length of 2.039(1) Å in 16 is consistent with multiple bond character though slightly longer than the Zr–amido bond length of 2.019(2) Å in complex

5, presumably due to the bridging coordination motif. 66

O1 i N1 O2 N2i N3

i Zr Zr

N3i i N2 O1i N1 O2

Figure 3.3 ORTEP representation of the solid-state molecular structure of complex 16, with a simplified core structure shown on the right. Symmetry equivalent atoms (i) were generated with the symmetry operation (−x+1, −y, −z+1). The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

Table 3.1 Relevant bond lengths (Å) and angles (º) for complex 16. Zr–O1 2.099(8) Zr–O2 2.103(8) Zr–N1 2.481(10) Zr–N2 2.437(10) Zr–N3 2.039(10) Zr–Zri 3.111(2)

While this solid-state molecular structure provides evidence for the ability of these pyridonate ligands to support bridging imido species, the aniline substrates do not contain the α- hydrogens required for hydroaminoalkylation reactivity. Benzhydrylamine and benzylamine, containing activated benzylic C–H moieties, are more catalytically relevant amines whose reactivity with complex 5 could yield useful mechanistic insight.

The reaction of related bis(amidate) bis(dimethylamido) titanium complex (Scheme 3.10) with 1.5 equivalents of benzylamine at 65 °C generates binuclear tris(amidate) titanaziridine 17 as a dark green solid in 85% recrystallized yield.159 The solid-state molecular structure reveals that 17 contains three distinct bridging moieties: one imido, one amidate, and one bridging

metallaaziridine.159 This species is proposed to be formed from a monomeric imido that then

dimerizes to form a bridging imido species. Activation of the benzylic C–H bond of the imido

would then generate the bridging titanaziridine species and result in protonolysis of an amidate

ligand.

O N O O Ph N O Ph Ti(NMe2)2 3 Ph NH2 Ti Ti O 2 o N N + N 65 C, pentane 2 N NH Ar -4 HNMe2 NH2 17 Ar = 2,6-diisopropylphenyl Ph Ph

Scheme 3.10 Synthesis of bimetallic titanaziridine 17.

The analogous reactions using complex 5 and either benzyl- or benzhydrylamine have been performed. Upon addition of benzylamine (Scheme 3.10) and heating to 65 °C for 24 hours there is a noticeable colour change of the solution from pale yellow to yellow-orange. Removal of the volatiles under high vacuum and dissolution of the crude residue in d6-benzene for NMR spectral analysis reveals a complicated 1H NMR spectrum (Figure 3.4). The carbonyl region of

the 13C NMR spectrum shows at least five resonances indicating the presence of multiple unique

ligand environments in solution. There are no resonances consistent with the formation of free

proligand and the diagnostic sharp singlet of the metallacyclic C–H (δ 6.15 ppm in 17) is not

observed. Protonolysis of the dimethylamido ligands appears to be occurring as the diagnostic

broad singlet at δ 3.26 ppm of complex 5 disappears. The broad signals at δ 3.67, 3.97, and 5.60

ppm are assigned as methylene groups using 2D NMR spectroscopy and are, therefore, most

likely N-coordinated benzylamine though the precise bonding mode cannot be determined.

Removal of the volatiles under high vacuum results in an orange oil, and all attempts at isolating

crystalline material have not been successful. When benzhydrylamine is used as the amine 68

reagent, in hopes of accessing more crystalline material, the solution undergoes a colour change from pale yellow to orange-red. Disappearance of the α-C–H signal at δ 4.86 ppm is observed; however, spectra of the reaction mixture display a complex mixture of products (Appendix B) and no crystalline material could be obtained. 5.60

T( C) 3.97 3.67 58.2

52.3

46.4

40.5

34.6

30.3

25.9

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

1 Figure 3.4 Variable H NMR spectroscopy of the reaction of 5 with 1.5 equivalents of benzylamine in d6- benzene.

Another catalytically relevant amine is 1-butylamine, which contains the necessary α-sp3

C–H bond for hydroaminoalkylation and not as sterically hindered as benzyl- and benzhydrylamine. The addition of one equivalent of 1-butylamine to complex 5, analogous to the reaction with the anilines shown in Scheme 3.9, results in an oily product upon removal of the

volatiles. Since no crystalline material could be obtained, DOSY has been performed as a method to probe the solution-phase structure of the products in solution (Table 3.2).

Table 3.2 DOSY experiments of 5 and the reaction mixture of 5 with 1-bultylamine.

Ph O Zr(NMe2)2 N Reaction mixture, 18 NH2 d -benzene 5 6 tBu 2

Diffusion coefficient Hydrodynamic radius Entry Compound δ (ppm) (10-10 m2 s-1) (Å) 1 5 6.58 9.11 4.00 2 8.11 9.07 4.01 3 18 7.79 3.25 11.2 4 8.04 3.07 11.8

The DOSY of bis(pyridonate) bis(dimethylamido) complex 5, as presented in Section

3.2.1, provides a useful point of comparison (Table 3.2). Integration and fitting of the signal attenuation of two different resonances (entry 1 cf. 2) give analogous hydrodynamic radii of

~4.00 Å. The 1H NMR spectrum of reaction mixture 18 is a complex mixture of multiple species in solution. However, the rate of signal attenuation of two well resolved signals (δ 7.79 and 8.04 ppm) were monitored to determine the diffusion coefficients, from which the hydrodynamic radii of ~11 Å have been calculated. The DOSY results for the precatalyst and the reaction mixture are consistent with formation of a multi-metallic species in solution upon addition of the catalytically relevant amine since the hydrodynamic radius is significantly larger for reaction mixture 18 than for complex 5. While this does not provide insight into the structural features of

the species in solution, it provides evidence that multi-metallic species, like those observed in the

solid-state with 16, can also be generated with catalytically relevant alkylamine substrates.

The stoichiometric investigations detailed above demonstrate that, while precatalyst 5 is most likely monomeric in the solution-phase, upon addition of a primary aryl or alkyl amine multi-metallic species can be accessed. The formation of such bridged species is consistent with the catalytic cycle proposed (Scheme 3.6). However, the possibility that these multi-metallic species are off-cycle and catalytically inactive species cannot yet be discounted. To probe the catalytic behaviour of complex 5 preliminary kinetic investigations have been performed.

3.2.3 Kinetic analysis of intramolecular hydroaminoalkylation

One difficulty with the kinetic evaluation of precatalyst 5 is competing hydroamination, which has been observed with primary aminoalkene substrates.159 Monitoring of reaction

progression using 1H NMR spectroscopy is, therefore, potentially problematic since the hydroaminoalkylation and hydroamination product signals are not always well resolved.

Monitoring of the reaction progress via integration of the well resolved methylene olefin

resonances is a potential solution, provided the substrate was undergoing hydroaminoalkylation

selectively. Fortuitously, substrate 19, with the phenyl backbone linker, has been shown to

undergo cyclization to form the hydroaminoalkylation product in 90% isolated yield with no

formation of the hydroamination by-product.159 The substrate synthesis is also modular and the

deuterium labeled compound can be produced through use of deuterated dimethylformamide and

lithium aluminium deuteride reagents (Scheme 3.11).

1.5 E Br Br n BrMg 1) BuLi, THF O Br THF 2) DMF or d7-DMF

92% yield E = H, 91% yield D, 46% yield . NH2OH HCl, pyridine, ethanol

E E E or OH NH2 LiAlH4 LiAlD4 N

E = H, 19 = E D, 20

Scheme 3.11 Synthesis of kinetic substrate 19 and isotopically labeled 20.

Initial studies examined the cyclization of substrate 19 with 10 mol% 5 at 110 °C.

Monitoring of the conversion of substrate 19 by 1H NMR spectroscopy relative to an internal

standard (1,3,5-trimethoxybenzene) reveals that there is an exponential decay of the substrate

over a period of greater than three half-lives (Figure 3.5). The plot of ln(c/c0) versus time results

in a linear relationship consistent with a first-order dependence on substrate. This first order

dependence could indicate that the protonolysis step of the expanded metallacycle by incoming

amine substrate (Scheme 3.6) is the turnover-limiting step. A first-order dependence on the amine concentration has been observed previously by Hultzsch and co-workers during their mechanistic investigation into intermolecular hydroaminoalkylation catalyzed by group 5 metal binaphtholate complexes.144 Another possibility is that there exist slow, off-cycle equilibria involving amide exchange that hamper a simple interpretation of the kinetic data.

NH2 NH2 10 mol% 5

120 °C, d8-toluene

1.00 2.50

y = 0.0118x + 0.0303 R² = 0.9976 0.80 2.00

0.60 1.50 ) 0

c/c c/c0c/c0 0.40 1.00 ln(c/c ln(c/c0)ln(c/c0)

0.20 0.50

0.00 0.00 0 30 60 90 120 150 180 210 Time (min)

Figure 3.5 Plot of consumption of 19 (c/c0) and ln(c/c0) as a function of time (min). The solid trendline depicts the least-squares fit of the data points.

The data shown in Figure 3.5 were obtained from monitoring two different reaction

mixtures prepared using standard solutions of the precatalyst, substrate, and the internal standard.

These duplicate runs display good agreement when the same standard solutions were used.

Unfortunately, when a new set of standard solutions were prepared using a different catalyst and substrate batch, the observed rate constants were not consistent with those determined previously. Therefore, quantitative rate constants cannot be determined with confidence; however, the overall trends are analogous for both kinetic data sets and qualitative information can be gleamed from these kinetic experiments.

The hydroaminoalkylation reaction involves the breaking of the α-C–H bond to the amine moiety. If this C–H activation is the turnover-liming step of the catalytic cycle, a significant

primary kinetic isotope would be expected when the α-CD2 substrate 20 is employed. Indeed,

monitoring of the rate of substrate consumption for both 20 and 19 at 105 °C with 30 mol% 5

(Figure 3.6), reveals a significant decrease in reaction rate when the deuterated substrate is used.

The determined kinetic isotope effect (KIE) of kH/kD = 4.3 indicates that the C–H activation step is turnover-limiting. Doye and co-workers also observed a large KIE of kH/kD = 7.3 during their

255 kinetics studies of precatalyst Ti(NMe2)4 (Scheme 3.3).

NH2 NH2 30 mol% 5 CE2 105 °C, d8-toluene E = H, D 2.5

2.0 kH/kD = 4.3

) 1.5 0

α-αCH2-CH 2, 9

ln(c/c y = 0.0159x - 0.0001 1.0 α-αCD2-CD 2, 10 R² = 0.9971

0.5

y = 0.0037x - 0.0069 R² = 0.9918 0.0 0 30 60 90 120 150 Time (min)

Figure 3.6 Primary kinetic isotope effect observed for the cyclization of 19 compared with α-deuterated substrate 20.

The rate of substrate conversion has been measured for a series of precatalyst

concentrations (5-30 mol%). The plot of the kobs values versus the initial precatalyst concentration (Figure 3.7) reveals that the reaction is not well behaved over the range of catalyst concentrations and two different regimes are observed. Initially, increasing the concentration of

the precatalyst does result in an expected, almost linear, acceleration of the observed reaction

rate; however, saturation kinetics are observed above 20 mol%, and subsequent increase in

catalyst concentration to 30 mol% does not result in an acceleration of substrate consumption.

This sharp decrease in reaction order has also been observed for during the mechanistic

investigations of Doye and co-workers above catalyst concentrations of 12.5 mol%

255 Ti(NMe2)4. The authors attribute the observed zero-order in catalyst at increased precatalyst concentrations to potential formation of Ti–N–Ti aggregates or oligomers that are not catalytically active. This could also be occurring with precatalyst 5, though relatively high catalyst loadings (20 mol%) are accessed before the decrease in kobs is observed. Another

possibility is that dimethylamine, which is liberated through the aminolysis of the precatalyst by

the substrate, could be inhibiting the reaction, thereby slowing the rate at high catalyst loadings.

This potential inhibition has also been considered by Doye and co-workers with the Ti(NMe2)4

system,255 and has been observed in titanium-catalyzed hydroamination reactions.277 The pseudo

first-order dependence on catalyst concentration does not negate the possibility of a monomer-

dimer equilibrium (Scheme 3.6) as long as dimer formation is rapid compared with the rate of the turnover-limiting step.

NH2 NH2 5-30 mol% 5

120 °C, d8-toluene

1.8

1.6

1.4

1.2

) 2 - 1.0 (10 0.8 obs k 0.6

0.4

0.2

0.0 0 0.01 0.02 0.03 0.04 0.05 Precatalyst (M)

Figure 3.7 Observed rates of consumption of 19 as a function of catalyst concentration.

Additional kinetic studies have been performed at different temperatures to determine the

activation parameters for the cyclization of 19. The plot of the observed rate of substrate

consumption over a temperature range of 85 – 110 °C gives a linear correlation, from which the

activation parameters have been determined to be ΔH‡ = 18.7 ± 1.1 kcal/mol and ΔS‡ = -18 ± 3

e.u.. The calculated ΔS‡ value is moderately large, consistent with a highly-ordered transition state.

NH2 NH2 30 mol % 5 85 − 120 °C d -toluene 8

0.00252 0.00257 0.00262 0.00267 0.00272 0.00277 -9.5

y = -9440.6x + 14.481 -10.5 R² = 0.9833 ln(k/T)

-11.5 ΔH‡ = 18.7 ± 1.1 kcal/mol ΔS‡ = -18 ± 3 e.u.

-12.5 1/T (K-1)

Figure 3.8 Eyring plot in the temperature range of 85 – 110 °C and the relevant activation parameters. Error on activation parameters estimated from regression analysis.

3.3 Conclusions and mechanistic proposal

The kinetic and stoichiometric investigations performed to probe the reactivity of bis(pyridonate) bis(dimethylamido) zirconium complex 5 reveal a complex catalytic system.

Stoichiometric investigations consistently show the formation of mixtures of species in solution

upon addition of primary amines. Solid state X-ray diffraction studies as well as solution phase

DOSY experiments provide evidence for the formation of multi-metallic species and have demonstrated that the pyridonate ligands are capable of stabilizing bridging imido species that could be critical intermediates in the catalytic cycle.

In an effort order to gain further insight into the mechanism for the intramolecular α- alkylation of aminoalkenes using precatalyst 5, a series of kinetic investigations have been performed. The ill-defined nature of this precatalyst system in solution complicates the 77

mechanistic elucidation and does not allow for conclusive determination of the active species in solution. The stoichiometric and kinetic experiments performed do not refute either a catalytic cycle based on monomeric (analogous to Scheme 3.3) or dimeric (Scheme 3.6) active species.

However, the observation that increased catalyst loading results in a shift in product distributions towards the hydroaminoalkylation product when mixtures of hydroamination and hydroaminoalkylation are produced159 is most consistent with the dimeric species proposed in the catalytic cycle in Scheme 3.6.

3.4 Experimental

General materials and methods are outlined in Section 2.4.1.

3.4.1 Materials

The following compounds were synthesized as reported in the literature: 6-tert-butyl-3- phenyl-2-pyridone278 and bis(6-tert-butyl-3-phenyl-2-pyridonate) bis(dimethylamido) zirconium

159 complex 5. All commercial amines were distilled under reduced pressure from CaH2 and

degassed by 3 freeze-pump-thaw cycles. Zr(NMe2)5 was purchased from Strem and Ti(NMe2)4

was purchased from Aldrich and both were used as received.

3.4.2 General experimental procedures

Variable temperature NMR studies: A solution of the precatalyst was prepared in a J. Young

NMR tube, inserted into the probe and cooled to -80.9 °C. A spectrum was collected and the

NMR probe was warmed to the temperature indicated. After stabilization of the temperature (5 –

10 minutes) the 1H NMR spectrum was recorded.

DOSY experiments: Diffusion ordered spectra were acquired on a Bruker 400inv spectrometer

using a ledbpgp2s1d pulse program279 with 15 gradient increments equally spaced in g2 between

0.0222 and 0.0553 T m-1. 64 scans were recorded per gradient point. The data were subsequently

processed using Bruker’s TopSpin™ software package for NMR data analysis. The

267 hydrodynamic radii were calculated from the Stokes-Einstein Equation: D = kBT/(6πηr),

where D is the diffusion constant, kB is the Boltzmann’s constant, T is the temperature, η is the

viscosity of the solution (taken to be the same as benzene at 25 °C), and r is the radius of the

spherical particle.

Kinetics experiments: Standard solutions of the precatalyst, the aminoalkene, and 1,3,5- trimethoxybenzene (internal standard, 0.625 M) were prepared in d8-toluene in a nitrogen filled glove box. The appropriate volume of each standard was measured using a micropipette and transferred to a J. Young NMR tube. The initial substrate concentration examined is 0.025 M

159 consistent with the conditions used for the substrate scope analysis. d8-Toluene was then added to bring the total volume to 550 μL. The J. Young NMR tube was then inserted into a pre-

heated NMR probe of a Bruker 400inv spectrometer. The temperature of the probe was

calibrated using tabulated chemical shifts of ethylene glycol at five degree intervals by the NMR

staff at the spectroscopic facility at the University of British Columbia. The tube and its contents

were left to thermally equilibrate with the heated probe for five minutes before data acquisition was started. Each kinetic run was monitored by the acquisition of periodic 8 scan 1H NMR spectra using pre-set delay times that allowed for automatic data acquisition. The aminoalkene substrate concentration was quantified by integration of the HC=CH2 signal relative to the

aromatic signal of the internal standard. Representative spectra are included in Appendix B.

Error bars on raw kinetic data are derived from the standard deviation of duplicate experiments.

All errors on linear correlations were estimated from the standard error of the linear regression analysis performed using the Data Analysis Toolpack in Excel. These methods underestimate the

actual experimental error on the observed rate constants, which is mainly due to limitations on

the detection technique (NMR integration, ± 5%).

3.4.3 Synthesis and characterization

5: Synthesized following literature procedure.159 The crude pale yellow solid was washed with

1 hexanes (2x3 mL) and recrystallized from saturated hot benzene solution. H NMR (d8-toluene,

3 3 400 MHz) δ 1.15 (s, 18H), 3.36 (s, 11H), 6.52 (m, JH,H = 7.9 Hz, 2H, CH), 7.15 (t, JH,H = 6.8

3 3 3 Hz, 2H, CHPh), 7.33 (t, JH,H = 7.7 Hz, 4H, CHPh), 7.44 (m, JH,H = 8.1 Hz, 2H, CH), 7.97 (d, JH,H

= 7.5 Hz, 4H, CHPh).

16: Complex 5 (90.7 mg, 143.5 mmol) was weighed

into a large vial and dissolved in benzene (4 mL). 2,6- Me Me Ph O N O Ph Zr Zr dimethylaniline (52.2 mg, 430.6 mmol) dissolved in 2 N 2 N N 2 Me Me mL of benzene was added dropwise over the course of tBu tBu 16 2 minutes. The solution changed from a pale yellow

to bright yellow colour. The solvent was removed under high vacuum and crystalline material

was grown from a layered toluene:pentane solution at room temperature. Yield: 32%. The 1H and

13C NMR spectra are included in Appendix B. Characterized by X-ray crystallography

(Appendix A).

1-bromo-2-(but-3-enyl)benzene: Synthesized following literature Br

procedure280,281 using 2-bromobenzyl bromide (20.8 g, 83.7 mmol) and allyl

magnesium bromide (1.0 M in ether, 125 mL, 125 mmol) in THF (~250 mL). The title

compound was isolated as a white solid with analysis data matching literature reports.280 Yield:

1 16.2 g, 92%. H NMR (d1-chloroform, 300 MHz) δ 2.29-2.50 (m, 2H, CH2), 2.77-2.97 (m, 2H,

CH2), 4.96-5.17 (m, 2H, CHCH2), 5.85-5.98 (m, 1H, CHCH2), 7.05-7.11 (m, 1H, CH), 7.20-7.29

3 (m, 2H, CH), 7.56 (d, JH,H = 7.7 Hz, 1H, CH).

280 2-(but-3-en-1-yl)benzaldehyde: Synthesized following literature procedure O using 1-bromo-2-(but-3-enyl)benzene (7.10 g, 33.6 mmol), nBuLi (31 mL, H

50.46 mmol), and dimethylformamide (6.54 g, 84.11 mmol) in THF (~50 mL).

The title compound was isolated as a white solid with analysis data matching literature reports.282

1 3 Yield: 4.89 g, 91%. H NMR (d1-chloroform, 300 MHz) δ 2.35-2.43 (m, 2H, CH2), 3.15 (t, JH,H

= 7.6 Hz, 2H, CH2), 4.97-5.12 (m, 2H, CHCH2), 5.80-5.94 (m, 1H, CHCH2), 7.25-7.32 (m, 1H,

3 3 3 CH), 7.39 (td, JH,H = 7.9, 1.3 Hz, 1H CH), 7.52 (td, JH,H = 7.5, 1.9 Hz, 1H, CH), 7.85 (dd, JH,H

= 7.5, 1.37 Hz, 1H, CH), 10.28 (s, 1H, CHO).

Synthesized following literature procedure280 using 1-bromo-2-(but-3- O

n D enyl)benzene (3.51 g, 16.6 mmol), BuLi (15.6 mL, 24.95 mmol), and d7-

dimethylformamide (2.0 g, 24.95 mmol) in THF (~50 mL). The title compound was isolated as a

282 1 white solid with analysis data matching literature reports. Yield: 1.23 g, 46%. H NMR (d1-

3 chloroform, 300 MHz) δ 2.35-2.43 (m, 2H, CH2), 3.15 (t, JH,H = 7.6 Hz, 2H, CH2), 4.97-5.12 (m,

3 2H, CHCH2), 5.80-5.94 (m, 1H, CHCH2), 7.25-7.32 (m, 1H, CH), 7.39 (td, JH,H = 7.9, 1.3 Hz,

3 3 1H CH), 7.52 (td, JH,H = 7.5, 1.9 Hz, 1H, CH), 7.85 (dd, JH,H = 7.5, 1.37 Hz, 1H, CH),

2-(3-butene)benzylamine, 19: Synthesized by oxime formation following NH2 literature procedure283 with 2-(but-3-en-1-yl)benzaldehyde (6.04g, 37.8 mmol), hydroxylamine hydrochloride (6.52 g, 94.4 mmol), pyridine (4.6 mL, 56.6 mmol), in ethanol

(~50 mL). The volatiles were removed under reduced pressure, and the residue was taken up in 82

~200 mL of dry diethyl ether to be used directly for the reduction. The mixture was then cooled

to 0 °C and lithium aluminium hydride was added (7.2 g, 190 mmol). The solution was heated at

reflux overnight. The reaction mixture was cooled to 0 °C and 3 mL of H2O, 3mL of 1M NaOH,

and 6 mL of H2O were added sequentially. The reaction mixture was left to stir for 2 h, then

filtered, and concentrated by rotary evaporation. Flash chromatography (silica gel G60,

DCM/MeOH 95:5) gave the title compound as a clear, colorless oil with analysis data matching

159 1 literature reports. H NMR (d1-chloroform, 400 MHz) δ 1.89 (2H, br s, NH2), 2.39-2.47 (m,

2H, CH2), 2.81-2.86 (m, 2H, CH2), 3.97 (s, 2H, CH2NH2), 5.06-5.16 (m, 2H, CHCH2), 5.91-6.03

(m, 1H, CHCH2), 7.19-7.41 (4H, m, CH).

2-(3-butene)benzylamine-d2, 20: Synthesized by the analogous procedure to D D

1 NH2 that of α-protio 2-(3-butene)benzylamine (vide supra). H NMR (d1-

chloroform, 400 MHz) δ 1.70 (2H, br s, NH2), 2.39-2.46 (m, 2H, CH2), 2.78-2.86 (m, 2H, CH2),

1 5.05-5.18 (m, 2H, CHCH2), 5.88-6.02 (m, 1H, CHCH2), 7.19-7.43 (4H, m, CH). H NMR (d1-

chloroform, 400 MHz) δ 3.87 (s, 2H, CD2NH2).

CHAPTER 4: Synthesis, structure, and reactivity of new tantalum complexes

4.1 Introduction

A series of early transition metal complexes of titanium,78,160-163,172,255 zirconium,159 vanadium,112,143 tantalum,77,112,118,143,144,250,251 and niobium77,112,143,144 have been shown to be competent catalysts for the hydroaminoalkylation of unprotected amine substrates. The group 5 metal systems are particularly attractive, catalyzing intermolecular hydroaminoalkylation to generate the branched regioisomer almost exclusively (Scheme 4.1). Judicious tuning of the ancillary ligands has been shown to vastly improve the reactivity of these systems,77,112,118,143,144,250,251 which results in milder reaction conditions, expands substrate scope, and induces selectivity. These developments have focused on ancillary ligands such as chlorides250 and chelating ligands containing (N,O)-,110,112 (N,N)-,78 or (O,O)-donors.77

H H N R2 N R2 1 H 1 R N R2 R3 catalyst R R1 R3 R3 branched linear

Scheme 4.1 Intermolecular hydroaminoalkylation of secondary amine substrates.

4.1.1 Chloro ancillary ligands

The initial report detailing the catalytic hydroaminoalkylation of amines using group 5

246 systems focused on homoleptic amido complexes such as Ta(NMe2)5 and Nb(NMe2)5. These complexes catalyze the α-alkylation of secondary amines to generate the branched regioisomeric product in yields of up to 38%, at reaction temperatures of 160 ºC. Herzon and Hartwig have demonstrated that, by careful choice of substrates such as N-arylalkyl amines, Ta(NMe2)5 is an 84

effective precatalyst for the hydroaminoalkylation of terminal olefins in yields of up to 96% of the branched product.251 Hartwig and Herzon later showed introducing electron-withdrawing chloro ligands to generate a dimeric trichloro bis(diethylamido) tantalum precatalyst results in a more electrophilic and reactive metal centre. This precatalyst is capable of the hydroaminoalkylation of the more challenging N-dialkyl amines as well as decreasing the reaction temperatures to 90 ºC with some substrate combinations (Scheme 4.2).250 Conversely, addition of electron-donating alkoxo ligands results in a reduction of the catalytic ability of the complex obtained.251 Addition of four chloro ligands (Scheme 4.2) is detrimental and

demonstrates the requirement of two reactive ligands for efficient catalysis. The Herzon and

Hartwig reports have been critical in galvanizing interest in this atom-economic methodology

and have highlighted two necessary features of catalyst design: highly electrophilic metal centres

and the presence of two reactive ligands to provide a route to the required open coordination

sites.

H H N N n 4 mol% [Ta] hexyl 24 h, 90 °C d8-toluene

⋅ [Ta] = Ta(NMe2)5 [TaCl3(NMePh)2]2 TaCl4(NMePh) OEt2 0% 72% 14%

Scheme 4.2 The effect of chloro ancillary ligands in tantalum complexes for the intermolecular hydroaminoalkylation of 1-octene with of N-methylaniline.

4.1.2 (N,O)- and (O,O)-chelating ancillary ligands

The strategy of incorporating electron-withdrawing ligands to generate more electrophilic, and consequently more reactive, metal centres has been observed in the application

of (N,O)-chelating ligands supporting early transition metal complexes for hydroamination.99

Relevant examples include sulfonamidate ligands developed by Bergman and co-workers,170,171

and the N-perfluorophenyl amidate ligands126 and pyrimidinoxide ligands276 developed by

Schafer and co-workers. The more Lewis acidic bis(N,O-ligand) bis(dialkylamido) titanium

complexes produced display improved reactivity compared with the parent Ti(NMe2)4 complex.

Another benefit of these (N,O)-chelates with tight bite-angles is the availability of κ1-

coordination modes. The access to monodentate binding motifs could allow for release of steric

crowding about the metal centre while creating an open-coordination site for reagent binding.

Schafer and co-workers have applied simple, easily assembled amide proligands with great success to support tantalum precatalysts for the hydroaminoalkylation of secondary amines with unactivated olefins, identifying complex 2 as arguably the most broadly applicable hydroaminoalkylation precatalyst yet reported (Figure 4.1).118,284 Bis(amidate) tantalum

complexes, such as those based on axially chiral biaryl backbones, have also been developed and

screened for hydroaminoalkylation (Figure 4.1).112,143,146 The bis(amidate) complexes, while

requiring harsher reaction conditions compared with their mono(amidate) counterparts (130 –

160 ºC, 48 – 120 h), do give access to the α-alkylated amine products in up to 93% ee.112

Ar Mes O N tBu Ta(NMe2)4 O N O N O Ta(NMe2)3 iPr iPr Ta(NMe2)3 N N O Ar Mes Ar = 2,6-dimethylphenyl 2, Schafer Schafer Zi

SiPh2Me EtO O P TaClMe3 EtO N O M(NMe2)3HNMe2 O M = Nb, Ta

SiPh2Me

2 21, Schafer Hultzsch

Figure 4.1 Tantalum precatalysts for the α-alkylation of amines supported by (N,O)- and (O,O)-chelating ligands.

A recent noteworthy report describes a system which combines both chloro ligands and a

new (N,O)-chelating phosphoramidate ligand to great effect (21, Figure 4.1).249 This tantalum alkyl complex is able to catalyze the first examples of intermolecular hydroaminoalkylation of secondary amines at room temperature. Complex 21 is also remarkable as, with select substrates, the linear regioisomer is generated (Scheme 4.1), which has not been previously observed with any other group 5 transition metal precatalyst. The improved reactivity of the phosphoramidate supported complex is once more consistent with the trend of more electron-withdrawing ligands supporting more reactive catalytic precursors.

Ancillary ligands that bind in a symmetric fashion, such as (O,O)-chelates, have been examined by Hultzsch and co-workers through the use of silylated binaphtholate complexes of tantalum and niobium precatalysts (Figure 4.1).77 These catalytic systems require high reaction

temperatures (140 ºC) however the niobium species can promote enantiomeric excesses of 59 –

98% ee for the intermolecular α-alkylation of secondary amines.

An examination of all of the reported catalyst development work indicates several key ligand design elements which are critical for future catalyst development; most importantly, the

trend that increased electrophilicity at the metal results in improved reactivity. This has been

achieved using chloro ligands, as well as (N,O)-chelating ligands with small bite-angles. The presence of two reactive ligands is also critical for rapid catalyst activation and good reactivity, which is consistent with the requirement of two coordination sites for the proposed catalytically active tantalaziridine species.118,144,145,251 While significant advances have been reported for the generation of group 5 catalytic systems for the intermolecular hydroaminoalkylation of amines, these systems are still restricted in substrate scope, and the vast majority are plagued by harsh reaction conditions requiring high temperatures and/or long reaction times to access synthetically useful yields. The synthesis of new ligands and a detailed investigation into the effects of the

nature of the ancillary ligands on the catalytic activities of the complexes generated is of interest

for the development of improved catalysts for this highly desirable transformation.

4.1.3 Scope of chapter

Chapter 4 focuses on the development of new tantalum complexes for the intermolecular

α-alkylation of secondary amines. This includes the development of new amidate based ligands

with varied electronic and steric parameters. Solution-phase and solid-state data are presented to

investigate the impact of these alterations on the binding to the tantalum metal centre.

Modifications include electronic perturbations through the introduction of an electron-

withdrawing group on the nitrogen atom of the amide proligand. The incorporation of pendent 88

neutral heteroatom donors into the ligand framework to potentially access alternative

coordination geometries is also detailed. These new functional groups include donor atoms at

both the nitrogen substituent as well as the carbonyl backbone position.

Section 4.2.3 describes efforts to establish methodologies to generate mixed amidate chloro amido tantalum complexes. A discussion of suitable tantalum amido chloro starting materials and the challenges of preparing mixed systems will be discussed as well as the reactivity and decomposition reactions of these compounds.

Finally, exploration of new (N,O)-chelating sulfonamidate tantalum complexes will be

presented. This new ligand motif has not been extensively applied to group 5 transition metal

systems and, therefore, their organometallic coordination chemistry will be comprehensively

studied.

4.2 Results and discussion

4.2.1 Tantalum precatalysts with amidate ligand modifications

Complex 2 (Figure 4.1) is a noteworthy compound as it is the only catalytic system that is successful in the α-alkylation of challenging N-heterocyclic substrates such as piperidine.118 This

suggests that the asymmetric binding of the (N,O)-chelating motif, the resulting potential for hemi-lability, as well as the small bite-angle could be critical elements for future ligand design.

Initial investigations into tantalum amidate complexes by Dr. J.M. Lauzon focused on altering the steric bulk of the N-aryl substituents (phenyl, 2,6-dimethylphenyl, 2,6-diisopropylphenyl,

2,4,6-tri-tert-butylphenyl) as well as at the carbonyl position (tert-butyl, phenyl) of the amidate ligand.146 The binding mode of the amidate ligands is dependent on the amount of steric bulk of

the nitrogen substituent, with more sterically demanding substituents leading to a shift from the 89

κ2-(N,O)-binding mode to the κ1-(O). These structure-activity studies identified 2 (Figure 4.2) as

the most reactive precatalyst and, therefore, the ideal starting point for future catalyst

development and a benchmark for reactivity comparisons.118,146

The κ2-binding motif of the amidate ligand has been proposed to be a critical element of

highly reactive systems; however, extensive variations of the electronics of the amide proligands

have not been performed. Electronic perturbations via the inclusion of new functional groups

such as esters, amides, alkoxy groups, or pendant amines (Figure 4.2) could impact the binding

and reactivity of these precatalysts. Of particular interest is the potential for alternative

coordination geometries and the effect of such altered chelation modes on reactivity.

i Pr i R O O Pr O O t t R R Bu N Bu N N N N H i H H H Pr O R R OMe Parent amide O tBu t Ar N Bu Ta(NMe2)4 O O N N OMe 2 Ta(NMe2)4 iPr iPr Ta(NMe2)4 Ta(NMe2)4 i N N Pr O R O R R Mes Parent precatalyst

Figure 4.2 New amide proligands (top) based upon the amidate ligand of 2 and potential alternative coordination geometries (bottom).

Initial investigations focused on varying the electronic features of the amide nitrogen via

the installation of electron-withdrawing substituents such as amides or esters.285 These proligands can be prepared as crystalline compounds from commercially available L-valine (22

and 23, Scheme 4.3). Initially these proligands were of interest as chiral ligands to generate

tantalum precatalysts for application in asymmetric hydroaminoalkylation. However, the poor

reactivity observed with the tantalum precatalysts generated (vide infra) negates this application

and, therefore, the racemization of the stereogenic centre observed during the base hydrolysis has

not been addressed.

tBu NH NH2 NH2 pivaloyl chloride, SOCl2, MeOH i O i OH i O piperidine Pr Pr reflux Pr -60 → 23 °C O O 22 O 24% yield over 2 steps 2M NaOH Racemization O O 1) Et3N (1.1 equiv.) Ethyl chloroformate (1 equiv.) tBu NH tBu NH 2) Piperidine (1.1 equiv.) N → OH iPr -15 23 °C, THF iPr 23 O O 22% yield 93% yield

Scheme 4.3 New amide proligands 22 and 23 containing modified nitrogen substituents.

Pendant neutral donor moieties have also been integrated into the amide proligand framework, both on the nitrogen substituent as well as in the carbonyl backbone. The amidation reaction of 2-methoxyaniline with 2,4,6-trimethylbenzoylchloride generates compound 24 containing a o-methoxy donor fragment in 52% recrystallized yield (Scheme 4.4, top).

Integration of a tertiary amine donor moiety at the carbonyl position is achieved through a one- pot, two-step sequence that consists of amidation of 3-chloropropanoyl chloride with aniline, followed by a nucleophilic displacement of the pendant chlorine with an appropriate secondary amine. The neutral amine donors are linked to the amide fragment by a flexible carbon tether resulting in proligands 25 and 26 in 20 and 48% yield, respectively (Scheme 4.4). This modular

sequence allows for tunable steric and electronic properties of the tertiary amine segment as well as the amide N-substituent.

O NH2 O Mes NH OMe + 5 NEt3 Cl OMe -78 → 23 °C, DCM

24, 52% yield NH2 R R O O 4 − 5 N NH N NH 2 − 2.5 O NH i i Na2CO3 Pr Pr + ∆ O toluene Cl NH H2O, 1.2 i R = Me, Pr Ar Cl Cl 25, 20% yield 26, 48% yield

Scheme 4.4 Synthesis of proligands 24, 25, and 26 bearing pendant methoxy or tertiary amine donors.

The syntheses of tantalum precatalysts supported by these new amidate ligands all

proceed by the protonolysis reaction of Ta(NMe2)5 with the appropriate proligand at room temperature (Scheme 4.5). Gratifyingly, the protonolysis reactions with proligands 22, 23, and

24 result in crystalline complexes suitable for solid-state molecular structure determination. The reactions of 25 and 26 containing the pendant neutral amine moieties result in crude material with solution phase NMR spectra consistent with complexation, apparent by the disappearance of the N–H signals at δ 10.30 ppm. Unfortunately, crystalline material suitable for analysis by X- ray diffraction could not be obtained.

NH N - HNMe2 Ta(NMe2)5 Ta(NMe2)4 O ° O hexanes, 23 C

Scheme 4.5 Protonolysis methodology using amide proligands and Ta(NMe2)5.

The protonolysis reaction of proligand 24 with Ta(NMe2)5 results in a yellow crystalline

solid in 72% yield following recrystallization from hot hexanes. The solid-state molecular

structure indicates that the resulting tantalum complex, 27, adopts a pseudo-trigonal bipyramidal

geometry with the κ2-bound amidate occupying one coordination site (Figure 4.3). The ortho-

methoxy group of the ligand is situated away from the metal center (4.8 Å) and is not acting as a

neutral donor in the solid state. The inclusion of the electron-donating methoxy group does not

appear to impact the metrical parameters of complex 27 in the solid-state (Table 4.1) compared to the related mono(amidate) tetrakis(dimethylamido) tantalum complexes.118,146 Indeed, 27 is

almost isostructural to previously reported mono(N-phenylpivalamidate) tetrakis(dimethylamido)

tantalum.146 This is most evident in the Ta–amidate bond lengths of 2.148(2) Å (Ta–O1) and

2.351(2) Å (Ta–N1) for 27 compared with 2.140(2)Å (Ta–O1) and 2.339(2) Å (Ta–N1) for the

N-phenylpivalamidate complex.146 Consistent with all previously reported mono(amidate)

tetrakis(dimethylamido) tantalum complexes146 the amidate ligand is bound with a shorter Ta–O

bond than Ta–N bond.

O1 Ta N4

N1 N3 N2

Figure 4.3 ORTEP representation of the solid-state molecular structure of complex 27. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

Table 4.1 Selected bond lengths (Å) and angles (º) for complex 27. Ta–O1 2.148(2) Ta–N1 2.351(2) Ta–N2 2.040(3) Ta–N3 1.981(3) Ta–N4 1.998(3) Ta–N5 2.037(3) C1–O1 1.308(3) C1–N1 1.308(4) Ta···OMe 4.8 O1–Ta–N1 57.70(8)

The solution-phase data for 27 are also consistent with a κ2-(N,O) monomeric complex.

The amidate signals in the 1H NMR spectrum are well resolved, while the dimethylamido signals

appear as one broad singlet consistent with exchange on the NMR timescale. The 13C NMR

resonance for the carbonyl carbon is at δ 177.3 ppm, which is consistent with other κ2-bound amidate complexes.146

In contrast, the analogous protonolysis reaction (Scheme 4.5) with proligand 23 results in

a monomeric tantalum complex displaying a new (O,O)-coordination mode in 56% recrystallized

yield (Figure 4.4). The ligand in 28 is bound to the tantalum centre through the two oxygen

atoms, generating a seven-membered chelate ring and a complex with pseudo-octahedral geometry. This new coordination mode is symptomatic of the oxophilicity of this early-transition metal species. The oxygen atoms are bound asymmetrically to the tantalum centre (Table 4.2), with the secondary amide bound in an alkoxide mode (Ta–O1 2.043(1) Å) and the other bound as a neutral donor (Ta–O2 2.283(1) Å). Similar to complexes 2 and 27, the nitrogen atoms of the dimethylamido ligands in 28 adopt a planar geometry with short Ta–N bond lengths (average

2.023 Å), consistent with a monoanionic, four-electron donor. The equatorial dimethylamido ligands (N3, N4) for both 27 and 28 are consistently more tightly bound to the metal centre compared to the axial dimethylamido ligands (N2,5) by 0.049 – 0.061 Å.

N6 N O2 C10 Ta N4 iPr O Ta(NMe2)4 N O1 O C5 N3 N7 tBu 28 N2

Figure 4.4 ORTEP representation of the solid-state molecular structure of complex 28. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

Table 4.2 Relevant bond lengths (Å) and angles (º) for complex 28. Ta–O1 2.043(1) Ta–O2 2.283(1) Ta–N2 2.047(2) Ta–N4 1.996(2) Ta–N3 1.996(2) Ta–N5 2.051(2) C5–O1 1.326(2) C5–N1 1.282(2) C10–O2 1.262(2) C10–N2 1.335(2) O1–Ta–O2 80.23(5)

The analogous protonolysis reaction with proligand 22, containing the ester moiety,

results in a yellow-orange solid with 1H NMR spectrum consistent with ligand coordination,

indicated by the disappearance of the N–H signal of the proligand at δ 6.03 ppm (Scheme 4.6).

However, amidation of the ligand has occurred resulting in the formation of compound 29. The

1H and 13C NMR data are consistent with this assignment, with a broad singlet corresponding to

the methoxide hydrogens at δ 4.10 ppm, shifted downfield from δ 3.21 ppm in the proligand. A

heteronuclear single quantum coherence (HSQC) NMR experiment indicates this proton signal is attached to the carbon resonance at δ 57.3 ppm. These chemical shifts are comparable to

literature complex Ta(OCH3)4(OCO2Me), which displays methoxide signals at δ 4.20 and 59.4 ppm in the 1H and 13C NMR spectra, respectively.286

tBu O iPr - O OMe HNMe2 N t Ta(NMe2)5 Ta(NMe2)3OMe Bu N 23 °C, hexanes H iPr O O 3 29 N

Scheme 4.6 In situ substitution of the ester moiety of the proligand to generate tantalum complex 29.

A small amount of crystalline material has been obtained for X-ray diffraction analysis.

Unfortunately the crystal is twinned and complete anisotropic refinement was not possible and attempts to isolate additional crystalline material have not been successful. However, the data is of sufficient quality to determine connectivity, and the asymmetric unit of the compound contains two unique tantalum complexes. One species is compound 29 (Scheme 4.6), consistent with the microanalysis and solution-phase data of the bulk material. The other tantalum species,

30, is a tetrakis(dimethylamido) tantalum compound, which is most likely a residual amount of an intermediate complex. The fortuitous co-crystallization of the product and an intermediate is consistent with the small amount of crystalline material obtained and the lack of success in obtaining additional crystalline material.

29 30 Figure 4.5 ORTEP depiction of solid-state molecular structure of the crystalline material obtained using proligand 22. The asymmetric unit cell contains two unique tantalum complexes, 29 and 30. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

The substitution at the ester moiety of the ligand could be occurring through several

different mechanisms depending on the source of the NMe2 fragment. These include

intermolecular attack by the dimethylamine formed during the protonolysis of the homoleptic

dimethylamido starting material or intramolecular amidation by a coordinated dimethylamido

ligand.

Both of these mechanisms are plausible, however, the isolation of compound 30 indicates

that nucleophilic attack by free dimethylamine is more likely (Scheme 4.7). This could proceed via the initial formation of compound 31, consistent with what was observed with the amide proligand 28 (Figure 4.4). The coordination of the ester group to the Lewis acidic tantalum centre would increase the likelihood of external nucleophilic attack by the dimethylamine liberated in the complexation step. This would result in formation of 30, which is observed in the solid-state molecular structure, and methanol. Protonolysis of a subsequent dimethylamine ligand by methanol would result in the methoxide ligand of 29. An analogous amido-alkoxy substitution reaction has been observed with bis and tris(pyridonate) dimethylamido complexes of titanium,

in which addition of isopropanol at room temperature readily displaces the amido ligand

generating the pyridonate alkoxide complexes in high to quantitative yields.287

tBu i O Pr O N OMe t Ta(NMe2)5 Ta(NMe2)4 HNMe Bu N 23 °C, hexanes 2 H iPr O O 31 MeO Not observed

tBu tBu O N O - HNMe2 N Ta(NMe2)3OMe Ta(NMe2)4 MeOH iPr O iPr O 29 30 N N

Scheme 4.7 Substitution at the ester moiety of the proligand to generate tantalum complex 29.

An intramolecular metal-directed ester-amide exchange mechanism has been proposed

for the group 4 metal alkoxide-catalyzed preparation of amides from unactivated esters and

amines by Porco and co-workers.288 In this system a coordinated ester substrate undergoes

nucleophilic attack from a coordinated amine (Figure 4.6). An analogous mechanism with the

tantalum system is plausible; however, intermolecular attack by the liberated dimethylamine is more consistent with the intermediate 30 observed in the solid-state molecular data.

R 3 1 At 2 OR R H N OR R 1 At RO 2 OR H N OR O 2 O Zr Zr O RO At Zr Zr OR O OR RO RO H N O OR O 2 RO H N R1 OR At 2 R2 R1 3 R O Figure 4.6 Key potential intermediates proposed by Porco and co-workers for the formation of amides using a dimeric zirconium alkoxide complex via an intramolecular transformation.288

Unfortunately, the reactions of 25 and 26 containing the pendant neutral donors at the

carbonyl position (Scheme 4.5) with Ta(NMe2)5 did not afford crystalline complexes, though the

crude 1H NMR spectra of the protonolysis reactions are consistent with metal complexation.289

This is evident by the disappearance of the free amide N–H resonances at δ 10.30 ppm and the

appearance of analogous signals to those observed with other amidate ligands; including a broad

resonance which integrates to 24 hydrogens for the dimethylamido ligands, and sharp resonances

for the amidate ligand shifted from those in the proligand. The 13C NMR signals of the carbonyl

carbon are found at δ 174.4 and 174.3 ppm respectively, consistent with the κ2-(N,O) binding motif analogous to 27. It is very unlikely with the κ2-bound amidate ligand that the pendant

amine is interacting with the tantalum centre.

These synthetic investigations have demonstrated that protonolysis with the homoleptic

pentakis(dimethylamido) tantalum starting material is an ideal pathway for accessing a variety of

complexes supported by a variety of (N,O)- and (O,O)-chelating ligands with varied electronic

and steric parameters. The rigorous understanding of the coordination behaviour of these ligands

in both the solid state and the solution phase provides an ideal platform for rationalizing trends in

catalytic reactivity.

4.2.2 Hydroaminoalkylation reactivity of modified tantalum amidate complexes

The effect of varying key ligand parameters and accessing alternative binding motifs can

be examined through a screening of the new precatalysts for the intermolecular

hydroaminoalkylation of 1-octene with N-methylaniline and p-methoxy-N-methylaniline (Table

4.3). The screening reactions are performed at 130 ºC or 110 ºC for 20 hours, and the reactivity

of parent complex 2 (entry 1)248 is used as a benchmark to evaluate the influence of the new 99

ligands. Complex 2 is effective for the catalysis of both amine substrates at 130 ºC, with

improved yields being obtained with p-methoxy-N-methylaniline. This more reactive substrate allows for low conversion (19% yield) even at a lower reaction temperature of 110 ºC.

Examination of the complexes 28 and 29 (entry 2, 3) show very poor reactivity with negligible conversions obtained after 20 hours. This clearly highlights that the larger seven-membered metallacycle, along with the (O,O)-chelation motif, dramatically decreases the reactivity of the tantalum catalyst generated. The lack of reactivity with larger-membered metallacycles has been observed previously with a related dianionic (N,O)-chelating ligand with a five-membered metallacycle.248 Use of complex 29 with the methoxide ligand resulted in no conversion (entry

2), which is in agreement with previous reports by Hartwig and Herzon that complexes with alkoxo ligands are poor catalysts for this transformation.251 However, 27, containing the four- membered metallacycle displays excellent reactivity and results in full conversions with both substrates within 20 hours (entry 4). Moderate reactivity can be achieved at lower reaction temperatures (110 °C) and the reactivity of the isolated complex and the in situ reaction are comparable, indicating that in situ catalyst preparation is a reliable approach to precatalyst screening. The reactivity obtained with 27 is superior to that of the parent tantalum complex, and indicates that while no interaction of the methoxy group was observed in the solid-state it is possible that under the reaction conditions different coordination modes may be accessed, thereby enhancing reactivity. The proligands with the attached pendant neutral amine do not show improved reactivity overall. However, increasing the steric bulk on the nitrogen substituent of the amide leads to improved reactivity (entry 5, 6), a trend which has been observed for other

N-2,6-disubstituted aryl pivalamide proligands.146

100

Table 4.3 Screening of new tantalum precatalysts for the hydroaminoalkylation of N-methylaniline and p- methoxy-N-methylaniline with 1-octene.

H H N N 1.5 5 mol% [Ta] n + n hexyl hexyl 130 °C, 20 h R d8-toluene R R = H, OMe

Yield (%)a Entry Proligand Complexes R = H R = OMe O tBu NH 87 1 i i 2 33 Pr Pr (19)b

O t Bu NH 28 2 5 2 N iPr O O t c Bu NH 3 O 29 <2 <2 iPr O O > 98 > 98 Mes NH (50)b (55)b 4 27 ,b,d b,d OMe (51) (60)

O N NH 5d 42 40

O N NH d 6 iPr iPr 53 50

aYield determined by 1H NMR spectroscopy. Representative spectra are included in Appendix B. b110 °C. c10 mol%. dIn situ prepared complexes from proligand and

Ta(NMe2)5.

101

The catalytic screening of the new tantalum precatalysts demonstrates that complexes

containing a four-membered metallacycle show the most promise. The incorporation of a

potentially labile donor atom on the N-substituent results in improved reactivity and provides a basis for ongoing ligand development efforts. Incorporation of alternative donors such as alkoxo ligands and/or (O,O)-chelating ligands, as well as larger metallacyclic species have been found to be detrimental to reactivity.

4.2.3 Mixed chloro and amidate tantalum complexes

The investigations in Section 4.2.2 demonstrate the successful application of tantalum complexes containing four-membered (N,O)-amidate ligands as catalyst systems for the hydroaminoalkylation of secondary amines with olefins. Previous investigations by Hartwig and

Herzon have also shown that improved reactivity can be accessed using chloro ancillary ligands.

For example, the improved reactivity accessed with [TaCl3(NMePh)2]2 compared with the

homoleptic dimethylamido tantalum complex (vide supra).250 Harnessing the positive attributes

of both of these ligand classes by synthesizing mixed amidate chloro tantalum complexes could

be beneficial for generating tantalum precatalysts with enhanced reactivity. Mixed amidate chloro complexes of tantalum have not yet been reported and, therefore, routes to synthesize

these complexes, along with their solution-phase and solid-state behaviour must be examined.

Two methodologies that have been successfully applied in the synthesis of amidate complexes

are salt metathesis and protonolysis (Scheme 4.8).99 The homoleptic pentachloro and

pentakis(dimethylamido) tantalum precursors are commercially available; however, alternative

mixed amido chloro tantalum starting materials must be synthesized. Several potential mixed

amido chloro tantalum precursors have been reported in the literature (Scheme 4.8).290-293 102

NNa N TaCl5 TaCl TaCl(NMe2)4 [TaCl2(NMe2)3]2 - NaCl 4 O O 32 33 ⋅ NH N TaCl3(NEt2)2 TaCl4(NEt2)2 H2NMe2 Ta(NMe2)5 - Ta(NMe2)4 35 36 O HNMe2 O

Scheme 4.8 Salt metathesis (top) and protonolysis (bottom) approaches to new organometallic compounds and potential mixed chloro amido tantalum precursors 32, 33, 35, and 36 (right).

The monochloro tetrakis(dimethylamido) tantalum precursor 32 has been synthesized in one step from pentachloro tantalum and dimethylamido lithium by Xue and co-workers.294

Unfortunately, this reaction is low yielding due to a propensity for ligand disproportionation in

solution and, therefore, 32 is not an ideal starting material for further studies. The dichloro

tris(dimethylamido) tantalum complex (33, Scheme 4.9, top) can be synthesized following

literature procedure290 in good yield resulting in a dimeric compound containing two bridging

chloro ligands. In the initial report, Chisholm and co-workers observe that the dimer is readily

290 cleaved by nitrogen donor ligands to form monomeric TaCl2(NMe2)3·L compounds. Indeed,

reaction of a suspension of the dimer in toluene and addition of pyridine results in the

monomeric pyridine adduct 34 that can be recrystallized from hot hexanes in the presence of

excess pyridine to give the product as yellow needles. The bound neutral pyridine remains

coordinated even under high vacuum and the complex has improved solubility in non-

coordinating non-polar solvents such as benzene or toluene over the dimeric precursor.

103

excess -TMS-NMe2 pyridine ⋅ Ta(NMe2)5 2.3 TMS-Cl [TaCl2(NMe2)3]2 2 TaCl2(NMe2)3 py 24 h, pentanes hexanes 33, 81% 34, 90% -196 °C → 25 °C yield yield

-TMS-Cl 2 TaCl5 8 TMS-NEt2 [TaCl3(NEt2)2]2 24 h, 25 °C 35, 73% 3:1 toluene:ether, yield

TaCl5 4 HNMe2 [H2NMe2][TaCl4(NMe2)2] 24 25 °C h, 36 ether

Scheme 4.9 The syntheses of mixed dichloro, trichloro, and tetrachloro tantalum amido starting materials.

The trichloro bis(diethylamido) tantalum starting material, 35, can be generated following

literature procedures291,292 using trimethylsilyl diethylamine as the dialkylamido transfer reagent

(Scheme 4.9). The reaction yields the trichloro bis(diethylamido) dimer 35 as a deep red crystalline solid after recrystallization from toluene:pentane solution. This dimeric complex is also susceptible to dimer disruption and adduct formation in the presence of good donors such as neutral amines (eg. pyridine, dimethylamine) or coordinating solvents (diethyl ether, tetrahydrofuran).291,292 This starting material is of interest as the tantalum complexes formed

using this starting material would contain diethylamido ligands, as opposed to the dimethylamido

ligands of previously examined complexes (vide supra).118,146,248 Finally, a salt complex, 36, has

been isolated from the reaction of the pentachloro tantalum precursor with dimethylamine

following a reported procedure by Rothwell and co-workers (Scheme 4.9).293

Initial explorations into the synthesis of mixed amidate chloro tantalum complexes began

with the reaction of the amidate ligand through salt metathesis with the pentachloro tantalum

starting material (Scheme 4.10). Installation of the amidate ligand through salt metathesis could

give a mono(amidate) tetrachloro intermediate after which a variety of amido ligands could be

104

installed. The dropwise addition of the ligand sodium salt to an ethereal solution of the tantalum

precursor leads to a visible colour change, from colourless to yellow solution. Following cannula

filtration to remove the sodium chloride by-product, the 1H NMR spectrum of the crude reaction

mixture is consistent with a mixture of products, and displays numerous isopropyl methylene

signals between δ 3.00 and 4.50 ppm. Attempts to purify the reaction mixture to obtain one pure

compound, including recrystallization and sublimation, were unsuccessful. Reaction of the crude

mixture of products with lithium dimethylamine results in new compounds, as evidenced by the

1H NMR spectrum; however, once more the crude product is composed of an intractable mixture

of compounds.

O i tBu TaCl O Pr 4 N TaCl5 Complex mixture i i Target tBu N ether Pr Pr Na iPr

Scheme 4.10 Reaction of pentachloro tantalum starting material with the amidate sodium salt.

Another approach to mixed amidate chloro tantalum compounds could be to use

precatalyst 2 and replace one or two amido ligands with chloro ligands (Scheme 4.9). This could

proceed via the same methodology used for the generation of dichloro tris(dimethylamido)

complex 33 from Ta(NMe2)5 with trimethylsilyl chloride. Unfortunately, this approach is not productive with 2 and 1H NMR spectroscopy of the reaction mixture after 20 hours yielded only

resonances of the unreacted starting material.

105

O t Bu Ta(NMe2)4 N i i 2 TMS-Cl No reaction Pr Pr 20 h, 25 °C hexanes

Scheme 4.11 Non-productive ligand substitution reaction of the dimethylamido ligands of 2.

As these procedures are not successful, salt metathesis and protonolysis reactions with

the mixed amido chloro tantalum starting materials 33 – 35 have been examined. One complex

that has been targeted is mono(amidate) dichloro bis(dimethylamido) tantalum 37 (Scheme

250 4.12). This complex is similar to the Hartwig and Herzon precatalyst [TaCl3(NMePh)2]2 with

one of the chloro ligands replaced with an amidate ligand and would retain the necessary two

reactive amido ligands for rapid catalyst activation. Initial attempts to synthesize this compound

via the protonolysis reaction of 33 result in crude material with a 1H NMR resonances consistent

with the formation of multiple different species (Scheme 4.12). Recrystallization of the crude

reaction mixture from hot toluene yields crystalline material suitable for X-ray analysis. The solid-state molecular structure reveals bis(amidate) dichloro mono(dimethylamido) tantalum 38, a new species with unexpected ligand stoichiometry (Figure 4.7). Due to the limited solubility of the dimeric starting material this reaction was performed in tetrahydrofuran. To ensure that the presence of the coordinating solvent is not promoting ligand redistribution reactions, the same procedure has been performed with the more soluble pyridine adduct 34 in benzene. Use of this starting material resulted in the formation, once again, of complex 38 as the major species in solution as determined by the diagnostic isopropyl methylene and dimethylamine resonances in the 1H NMR spectrum. Altering the reaction conditions, such as lowering the reaction

temperature to -78 °C and alternative solvents (eg. toluene, hexanes), did not result in clean

106

formation of 37. It is possible that the ligand redistribution observed could be arising from

bridging interactions via the chloro ligands. In an attempt to discourage the formation of such

dimeric species the reaction of 33 was performed in the presence of pyridine. However, once more the 1H NMR spectrum of the crude material indicated the formation of 38. Salt metathesis

using the trichloro starting material 35 gives the isolable crystalline 39 containing a diethylamido

ligand.

HL 0.5 [TaCl2(NMe2)3]2 THF 33 O Unidentifiable t L2TaCl2(NMe2) Bu TaCl products 2(NR2)2 HL N R = Me, Et TaCl ⋅ 38 2(NMe2)3 py benzene iPr iPr 34 37 Not observed

i O Pr NaL Unidentifiable 0.5 [TaCl3(NEt2)2]2 L2TaCl2(NEt2) L = benzene products tBu N 39 i Pr

Scheme 4.12 Transformations investigated using via one-step protonolysis (top) and salt metathesis (bottom) procedures from mixed dichloro and trichloro amido tantalum starting materials.

The solid-state molecular structures for 38 and 39 reveal two compounds with pseudo-

trigonal bipyramidal geometry with the amidate ligands each occupying one coordination site

(Figure 4.7). Despite the presence of the bulky diisopropylphenyl group on the nitrogen atom of the amidate ligand, both are bound in a κ2-fashion to the tantalum centre. The amidate ligands

and one chloro ligand define the equatorial plane. The two tantalum complexes are isostructural

in the solid state, and do not show any significant differences in the metrical parameters arising

from the different steric requirements of the two different dialkylamido ligands (Table 4.4). The

Ta–Cl bonds of complex 38 (Ta–Cl1, 2.434(1), Ta–Cl2 2.349(1) Å) and 39 (Ta–Cl1, 2.4370(5);

107

Ta–Cl2, 2.3428(5) Å) are comparable, with a slightly longer bond to the axial Cl1 ligand in both compounds, presumably due to the presence of the strongly donating trans dialkylamido ligand.

38 39

Figure 4.7 ORTEP depiction of the solid-state molecular structures of complexes 38 and 39. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

The κ2-amidate ligands are once more bound in an asymmetric fashion to the tantalum

centre with shorter Ta–O than Ta–N bond lengths. However, this difference (∆ 0.118 – 0.146 Å)

is reduced compared to the asymmetric binding of 2 (∆ 0.332 Å). This is most likely due to the

reduced steric requirements of the chloro ligands over the dimethylamido ligands in the

equatorial plane of 2. This release of steric strain could also be responsible for the slightly larger

bite-angles of the amidates (59.44(6) – 59.6(1)°) in 38 and 39 compared with the mono-amidate

species such as 27 (57.70(8)°) containing the pendant methoxy moiety. The delocalization of the

π-system in the backbone of the amidate ligands is once more observed, with almost equivalent

C–N and C–O bond lengths of ~1.31 Å, consistent with a multiple bond character.

108

Table 4.4 Relevant bond lengths (Å) and angles (º) for complexes 38 and 39. Cl1 O2 O1 C2 C1 N2 Ta N1 Cl2 N3

38 39 Ta–O1 2.101(2) 2.096(2) Ta–O2 2.092(2) 2.118(1) Ta–N1 2.242(3) 2.242(2) Ta–N2 2.238(3) 2.236(2) Ta–N3 1.968(3) 1.975(2) Ta–Cl1 2.434(1) 2.4370(5) Ta–Cl2 2.349(1) 2.3428(5) C1–O1 1.303(4) 1.312(4) C1–N1 1.311(4) 1.313(3) C2–O2 1.312(4) 1.302(2) C2–N2 1.303(4) 1.311(3) O1 –Ta–N1 59.5 (1) 59.45 (6) O2–Ta–N2 59.6(1) 59.44(6) C1 –Ta–Cl2 110.93(8) 110.01(5) Cl2–Ta–C2 111.14(8) 109.99(5) C2–Ta–Cl 136.7(1) 138.67(6)

The room temperature 1H NMR spectrum of the crystalline sample of 38 indicates that this complex does not undergo fluxional behaviour in solution.295 The sterically demanding isopropylphenyl groups on the nitrogen-bound aryl substituent exhibit hindered rotation consistent with non-fluxional κ2-binding leading to inequivalent isopropyl signals in the 1H and

13C NMR spectra. The dimethylamido methyl groups also do not exchange on the NMR timescale and show two independent resonances at δ 4.12 and 4.25 ppm, presumably due to the high steric requirements of the two κ2-bound amidate ligands. This is unique compared with

109

other reported amidate tantalum complexes,146 which almost exclusively display one broad

resonance for the dimethylamido ligands.

The presence of the chloro ligands in 38 and 39 drastically alter the coordination of the

complexes both in solution phase and the solid state compared with the previous bis(amidate)

tris(dimethylamido) complexes synthesized.118,146 The previous reports describe the formation of

two different products dependant on the steric bulk of the N-aryl substituent of the amide

proligand used (Scheme 4.13). When the N-phenyl amide proligand is used, a tantalum

bis(amidate) complex containing one κ1-(O) and one κ2-bound amidate is observed by NMR spectroscopy and X-ray diffraction studies. In particular, the 1H NMR spectrum shows broad resonances that are attributed to rapid interconversion between the κ2- and κ1-binding modes in the solution phase. When the steric bulk is increased at the nitrogen atom a spontaneous C–H

activation of one of the dimethylamido ligands and elimination of dimethylamine to form an isolable tantalaziridine is observed at room temperature.118,146 This is most likely a sterically

driven process, and is not observed with the bis(amidate) dichloro species, despite the sterically

demanding N-diisopropylphenyl substituents of the amidate ligand.

t Bu NMe O 2 2 NMe2 O O N t - HNMe2 NMe2 Bu NH Ta(NMe2)5 tBu Ta or Ta N 25 °C, hexanes R R N NMe2 N O t R = H: 96% yield O Bu N Me R = Me: 84% yield tBu

Scheme 4.13 Previously synthesized bis(amidate) tantalum complexes.146

Complex 38 has been tested for hydroaminoalkylation using N-methylaniline and 1-

octene at 130 °C for 20 hours, analogous to those used for catalytic screening of Table 4.3. Not 110

surprisingly, this complex did not display any productive reactivity, most likely due to the lack

of two reactive ligands. Thermal decomposition studies show that this complex is reactive at

high temperatures, and, following heating for one hour at 130 °C, the 1H NMR spectrum of the

solution contains two new isopropyl CH resonances at δ 2.94 and 3.10 ppm. The species, 40,

corresponding to the isopropyl methylene signal at δ 3.10 ppm is a common product observed in

many of the attempted synthetic methodologies examined in this study targeting mixed amidate

chloro tantalum species (Scheme 4.14). For example, this species, along with trace amounts of

compound 38, is produced during the protonolysis reactions of 33 when performed in

dichloromethane. Complex 40 is also generated from the salt metathesis reaction of 36 following

filtration of the crude reaction mixture and removal of the volatiles under high vacuum (Scheme

4.14).

O O t t Unidentifiable Bu TaCl2(NMe2) Bu TaCl3(NMe2) N 1 h, 130 °C products 2 N = 40 Ar Ar 2,6-diisopropylphenyl Ar

HL 0.5 [TaCl2(NMe2)3]2 DCM 33 O t L2TaCl2(NMe2) Bu TaCl3(NMe2) ⋅ HL N TaCl2(NMe2)3 pyr 38 40 DCM Ar 34 minor species i O Pr O L = NaL t tBu N [H2NMe2][TaCl4(NMe2)2] Bu TaCl3(NMe2) toluene iPr 36 N 40 Ar

Scheme 4.14 Synthetic methodologies that result in the formation of complex 40.

The 1H NMR spectrum of this compound displays a 1:1 integration ratio of amidate to dimethylamido ligand (Figure 4.8). This is consistent with two potential products: the

111

bis(amidate) monochloro bis(dimethylamido) complex 41 or the mono(amidate) trichloro

mono(dimethylamido) complex 40 (Figure 4.8). It is difficult to identify the composition of the product from such simple 1H NMR resonances; however, the sharp singlet for the dimethylamido

ligand is more likely to match compound 40, as in previous examples of tantalum species with

more than one dimethylamido ligands, these undergo exchange and are represented by broad

resonances.146 The 13C NMR spectrum is consistent with both products and contains a carbonyl

resonance for the amidate ligand(s) at δ 161.3 ppm. Unfortunately, attempts to obtain crystalline

material suitable for X-ray analysis have not been successful. Despite numerous efforts,

conclusive mass spectral (EI and MALDI) data displaying one of the predicted molecular ions

could not be obtained. A fragment at m/z 330 has been observed which could correspond to [40 –

amidate]+ displays a trichloro isotope pattern. However, it cannot be concluded with certainty that this fragment is representative of the bulk material. Quantitative 1H NMR studies have been

performed via the addition of a known amount of internal standard (1,3,5-trimethoxybenzene) to

a known amount of the unknown compound. These studies display integration values which

correspond to those predicted with 40. This tantalum complex is not an active

hydroaminoalkylation catalyst, which would be predicted for the formulation of 40, which lacks

the necessary two reactive dimethylamido ligands. These results point toward the tentative

assignment of this common by-product as 40, a mono(amidate) trichloro mono(dimethylamido)

tantalum complex.

112

O O 1.41 t t Bu TaCl3(NMe2) or Bu TaCl(NMe2)2 N N 2 Ar 40 Ar 41 2.34 1.30 1.29 7.16 7.18 3.10 3.12 3.08 7.09 7.07 7.20 3.13 3.07

4.77 1.90 3.83 12.26 18.00 23.91

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

1 Figure 4.8 H NMR spectrum of complex 40 in d6-benzene.

These investigations demonstrate that the attempted syntheses of these mixed amidate chloro tantalum species are plagued by ligand redistribution and/or the formation of products with unexpected ligand stoichiometry. It has been observed by Xue and co-workers that the mono(chloro) tetrakis(dimethylamido) tantalum complex exists in equilibrium with Ta(NMe2)5 and dimeric 33.294 Analogous equilibrium and ligand redistribution reactions could result in a variety of amido chloro tantalum species that might not always be identifiable by NMR spectroscopy and could give rise to the unexpected products that have been isolated. The amide proligand is very insoluble in hydrocarbon solvents and, therefore, any remaining amide proligand would be removed via filtration during the workup.

Unexpected reactivity with analogous mixed chloro amido tantalum and niobium starting materials has been observed previously by Rothwell and co-workers (Scheme 4.15).293,296 When

113

attempting to synthesize bis(aryloxide) chloro amido tantalum complexes, it has been observed

that the expected simple protonation of two dimethylamido ligands is not occurring, and the

products generate arise via elimination of one chloride ligand and one dimethylamido group. The

products are also produced as an isomeric mixture, which, upon heating are also found to

isomerize to a different product mixture containing trans-aryloxide ligands.

NMe2 OAr OAr Cl NMe2 2 HOAr Cl NMe2 Cl NMe2 Ta Ta Ta Me2NH2Cl Me2NH Cl Me2NH OAr Me2NH OAr Cl Cl Cl

Scheme 4.15 Unexpected reactivity observed with aryloxo ligands.

Since the synthesis of mono(amidate) dichloro tantalum amido species could not be

achieved, a reliable and high yielding synthesis of the mono(amidate) monochloro

tris(dimethylamido) tantalum complex 42 was targeted. This species has been successfully

297 synthesized from the TaCl(NMe2)4 via protonolysis of one dimethylamido ligand, however, as

discussed above, the synthesis of the mono(chloro) precursor is low yielding and undergoes ligand redistribution reactions in solution.294 Gratifyingly, the salt metathesis reaction of the

dichloro starting material 33 is a productive route to this compound and a yellow crystalline product is obtained following filtration to remove the sodium chloride by-product and purification by recrystallization. This product can also be obtained via the analogous reaction with the monomeric pyridine adduct tantalum starting material 34.

O iPr O tBu - NaCl TaCl(NMe2)3 0.5 [TaCl2(NMe2)3]2 N tBu N 3 h, 23 °C 33 iPr iPr 42, 75% Na iPr THF yield

Scheme 4.16 Synthesis of 42 via salt metathesis of the tantalum dichloro precursor 33. 114

The solid-state molecular structure of this compound has been obtained by Dr. Patrick

Eisenberger and demonstrates that this compound crystallizes in the Pbca orthorhombic space

group (Figure 4.9).297 The compound is pseudo-trigonal bipyramidal in which the chloro ligand

occupies one of the axial positions with Ta–Cl bond length of 2.4594(7) Å (Table 4.5). The fac

Ta–(NMe2)3 arrangement is not surprising as this avoids placing the strongly donating

dimethylamido ligands trans to one another. Comparison to the related mono(amidate) tetrakis(dimethylamido) tantalum complex 2 (Figure 4.1) indicates the Ta–amidate bond lengths are not significantly perturbed upon replacement of a dimethylamido ligand with a chloride (Ta–

O1, 2.078(2) Å; Ta–N1, 2.410(2) Å cf. Ta–O1, 2.097(2); Ta–N1, 2.445(2) Å for 2). However, the bond lengths to each of the dimethyl amido ligands are more consistent (1.996(2), 1.981(2), and 1.956(2) Å) compared with 2 in which the strongly donating trans dimethylamido ligands result in longer bond lengths for the axial dimethylamido ligands (2.066(2) and 2.065(2) Å) than for the equatorial dimethylamido ligands (1.969(2) and 1.987(2) Å).

Cl1

N1 N4 Ta

O1 N3

Figure 4.9 ORTEP representations of the solid-state molecular structure of previously synthesized complex 42.297 The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

115

Table 4.5 Relevant bond lengths (Å) and angles (º) of 42. Ta–O1 2.078(2) Ta–Cl 2.4594(7) Ta–N1 2.410(2) Ta–N2 1.981(2) Ta–N3 1.996(2) Ta–N4 1.956(2) C1–O1 1.315(3) C1–N1 1.293(3) O1–Ta–N1 113.2 (2)

This complex has been tested as a hydroaminoalkylation precatalyst and the reactivity observed with 4-methoxy-N-methylaniline and N-methylaniline is promising, with yields of 42 and 41%, respectively.

H H H N N N 1.5 5 mol% 42 n + n hexyl hexyl 110 °C, 20 h R d8-toluene R R = H, 41% yield Not productive

OMe, 42% yield substrates

Scheme 4.17 Hydroaminoalkylation reactivity of precatalyst 42 using N-methylaniline and p-methoxy-N- methylaniline and 1-octene.

Unfortunately, preliminary substrate scope investigations of 42 with more challenging substrates such as internal olefin cyclooctene, and piperidine have not been successful. Since the scope of reactivity of 42 is inferior to that accessed by precatalyst 2 and these mixed compounds are plagued by ligand redistribution and thermal stability issues, these are not ideal targets for easily synthesized early transition metal precatalysts. Therefore, efforts have been directed into the exploration of sulfonamide proligands, which as pseudohalogen-type compounds,298,299 with the potential for (N,O)- or (O,O)-chelating motifs generating four-membered metallacycles could be particularly interesting.

116

4.2.4 Tantalum complexes supported by sulfonamidate ligands

Recent catalyst development efforts have focused on the incorporation of a phosphorus heteroatom in the backbone of the amidate to generate a new modular class of tantalum precatalysts.249 The phosphoramidate tantalum complex shown in Figure 4.10 displays significantly improved reactivity for the hydroaminoalkylation of secondary amines eliminating the need for high reaction temperatures, catalyzing the hydroaminoalkylation of 1-octene with p- methoxyaniline in 37% yield after 20 hours at room temperature.249 This reactivity has been

attributed to the increased electron-withdrawing nature of the phosphoramidate ligand which

results in a more electropositive and reactive metal centre. One of the measurable properties of

the (N,O)-ligands which give an indication of their electronic nature is the pKa of the conjugate

300 acid. The low pKa of the sulfonamides, due to its highly electron-withdrawing character,

suggests that sulfonamides could be an important new ligand class (Figure 4.10).

O O O O O O P TaClMe3 O Ph MeO P Ph S Ph N Me N MeO N Me N 21 H H H

21.5 18.3 12.9 pKa (DMSO)

Figure 4.10 Phosphoramidate tantalum alkyl precatalyst 21 and the pKas of a series of amide, phosphoramide and sulfonamide compounds.300

Axially chiral bis(sulfonamidate) tantalum and niobium complexes have been examined

by Zi and co-workers for application as precatalysts for hydroamination and

hydroaminoalkylation (Figure 4.11).143 Unfortunately, these complexes did not show any

reactivity for either of these applications. However, the authors did not perform an extensive

study of structure activity relationship for sulfonamidate complexes and in particular did not

117

investigate mono(sulfonamidate) complexes. Related sulfamide complexes of early transition

metals have been reported, including those on tantalum where they act as chelating diamide

ligands,301 as well as on titanium172 where they support dimeric species, which have shown some

application in hydroaminoalkylation (Figure 4.11).

O Mes S O N O O Ta(NMe2)3 (NMe2)3Ti S Ti(NMe2)3 N N N O S Ph Ph O Mes Zi Doye

Figure 4.11 Early transition metal hydroaminoalkylation precatalysts supported by sulfur containing ligands.

The lack of catalytic reactivity observed by Zi and co-workers is intriguing as it is not immediately evident as to why these complexes are ineffective, especially considering the notable reactivity accessed by the phosphoramidate tantalum complexes. Mono(amidate) tantalum amido complexes have consistently been shown to be much more reactive than their bis(amidate) counterparts146 and therefore the most interesting targets for this study are the mono(sulfonamidate) tantalum complexes. It is well established that the identity of the nitrogen substituent has a large impact on reactivity (vide supra) and, therefore, a series of p-tosylamides with varied nitrogen substituents were envisioned as an ideal initial target. A modular group of proligands can be synthesized in one step via reaction of the primary amine with tosyl chloride in the presence of base (Scheme 4.18). Fortuitously, these sulfonamides proligands have been studied previously in the solid-state by X-ray diffraction for the tert-butyl,302 phenyl,303 and

118

dimethylphenyl304 substituted sulfonamides allowing for detailed examination of how the metrical parameters of the ligand changes upon coordination to the metal centre.

O NEt3 O H N R S 2 3 h, 130 °C S R Cl N O O H = t R Bu, 73% Ph, 54% 2,6-dimethylphenyl, 26% 2,6-diisopropylphenyl, 34%

Scheme 4.18 Sulfonamide proligands with varied N-substituents.

The syntheses of the tantalum complexes is achieved via a protonolysis reaction and results in the generation of the mono(sulfonamidate) tetrakis(dimethylamido) tantalum complexes 43 – 46 (Scheme 4.19). Recrystallization of the reaction mixture from hot pentanes affords crystalline material for complexes 43, 44, and 45 (Figure 4.12). Unfortunately, the N- diisopropylphenyl complex, 46 was not amenable to recrystallization with any conditions attempted.

O O - O HNMe2 S Ta(NMe2)4 Ta(NMe2)5 S R 3 h, 25 °C N N O H R R = t Bu, 96% Ph, 88% 2,6-dimethylphenyl, 95% 2,6-diisopropylphenyl, 18% Scheme 4.19 Synthesis of mono(sulfonamidate) tetrakis(dimethylamido) tantalum complexes 43 – 46.

119

43 43

44 45

Figure 4.12 ORTEP depictions of solid-state molecular structures of sulfonamidate complexes 43, 44, and 45. The ellipsoids are plotted at 50% probability and hydrogen atoms are omitted for clarity.

Upon coordination of these prochiral ligands, a racemic mixture of tantalum complexes is formed, due to the stereogenic centre generated at the sulfur atom. Complexes 43 and 45 both

crystallize in the centrosymmetric space group P21/c, thereby indicating that the crystalline

material examined is indeed composed of a racemic mixture of the tantalum complexes. This is

the most common method of crystallization of racemic compounds though racemates can also crystallize as conglomerates that are a mechanical mixture of enantiopure crystals.305 The first

example of a conglomerate is the famous report of Pasteur in 1848 detailing the crystallization of

sodium ammonium tartrate and establishing the concept of molecular chirality.306,307 The

incidence of conglomerate crystallization is relatively low, representing only 5 – 10% of 120

crystalized compounds and are most often discovered by serendipity not rationally

designed.308,309 Compound 44, with the N-phenyl substituent, crystallizes as a conglomerate in

chiral space group P21. The crystal chosen contains only (R)-sulfonamidate tantalum complexes, assigned with a Flack parameter310 of 0.009(3). The formation of conglomerates is a very interesting phenomenon, as this is a potential route for optical resolution via preferential

crystallization. However, in the case of compound 44, it is unlikely that this enantiopurity is

maintained in solution as racemization could occur via rapid interconversion of the two potential

κ2-coordination modes through an achiral κ1 species (Figure 4.2). This type of κ2-κ1-κ2

fluxionality has been proposed to occur with untethered bis(sulfonamidate) titanium complexes

reported by Nagashima and co-workers (Chapter 1, Figure 1.13).169

NMe2 NMe2 NMe2 O1 O1 NMe O1 O2 NMe NMe2 S 2 2 S Ta Ta S Ta O2 O2 N NMe2 N NMe2 N NMe2 NMe2 NMe2 NMe2

Figure 4.13 Proposed interconversion between κ1- and κ2-binding modes in solution.

These complexes display many similarities in the solid-state regardless of the nature of

the N-substituent (43, 44, and 45, Figure 4.12) and bear a strong resemblance to the related

mono(phosphoramidate) and mono(amidate) tetrakis(dimethylamido) tantalum complexes

previously synthesized by the Schafer group (Figure 4.12).118,146,249 These κ2-(N,O) mono(sulfonamidate) complexes each adopt a pseudo-trigonal bipyramidal geometry about the metal centre, in which the sulfonamidate ligand is considered to occupy one coordination site and, along with two dimethylamido ligands (N3,4), defines the equatorial plane. The assignment of pseudo-trigonal bipyramidal geometry is supported by an examination of the bond angles in 121

the plane of the sulfonamidate ligand (Table 4.6: N1–Ta1–N3, S1–Ta1–N3, S1–Ta1–N4); on

average these angles, calculated using an S–Ta vector, are close to 120° (Table 4.6). The

sulfonamidate ligands chelate with tight N1–Ta1–O1 bite angles (43, 62.12(7); 44, 61.45(4); 45

61.26(8)°), though the inclusion of the larger sulfur atom in the backbone results in a slightly

wider bite angle than those in the amidate complexes (~57°).146 The dimethylamido groups are

planar and display the short bond lengths consistent with Ta–N double bonds and mono(anionic)

four electron donors. The dimethylamido ligands in the axial position are consistently longer

(2.028(2) – 2.063(2) Å) than those that share the equatorial plane (1.965(3) – 1.995(3) Å) with the sulfonamidate ligand.

In the solid-state, each sulfonamidate ligand is bound in a κ2-(N,O) fashion and the coordination to the metal centre results in a perturbation of many of the metrical parameters compared to the sulfonamide proligand. These include a tightening of the Ta1–N1–S1 bond angles (43, 97.9(1); 44, 94.4(1); 45: 99.33(6)º) upon coordination. The O1–S1–N1 angle for the bound oxygen is compressed (99.42(7) – 100.1(2)º) while the O2–S1–N1 angle for the unbound

oxygen opens (114.83(7) – 117.5(1)º ) compared with the proligands (104.0(2) – 112.69(8)º).302-

304 The coordination of one sulfonamide oxygen (O1) results in a lengthening of the S1–O1 bond

(1.476(1) – 1.499(2) Å) compared the S1–O2 double bond to the unbound oxygen (1.436(2)-

1.437(1) Å). The sulfur in the backbone also results in a puckering of the four-membered chelate, with the torsion angles of Ta1-N1-S1-O1 (43: 11.7, 44: 11.2, 45: 5.8).

122

Table 4.6 Relevant bond lengths (Å) and angles (º) for complexes 43, 44, and 45. N5 O2 O1 N4 S1 Ta R N1 N3 N2

43 44 45

Space group P21/c P21 P21/c Ta1–O1 2.296(2) 2.333(1) 2.222(2) Ta1–N1 2.238(2) 2.246(1) 2.377(2) Ta1–N2 2.028(2) 2.055(1) 2.044(3) Ta1–N3 1.992(2) 1.981(1) 1.965(3) Ta1–N4 1.973(2) 1.967(1) 1.995(3) Ta1–N5 2.063(2) 2.063(1) 2.048(3)

S1–O1 1.484(2) 1.476(1) 1.499(2) S1–O2 1.436(2) 1.437(1) 1.436(2) S1–N1 1.572(2) 1.591(1) 1.561(2)

O1–Ta1– N1 62.12(7) 61.45(4) 61.26(8)

N1–Ta1–N3 111.96(9) 107.61(5) 92.6(1) S1–Ta1–N3 142.48(7) 138.65(4) 124.21(8) S1–Ta1–N4 112.80(7) 114.54(4) 138.05(7)

Ta1–N1–S1 97.9(1) 99.33(6) 94.4(1)

O1–S1–N1 99.9(1) 99.42(7) 100.1(2) O2–S1–N1 117.2(1) 114.83(7) 117.5(1)

Ta1-N1-S1-O1 11.2(1) 11.7(1) 5.98(7)

∑ N1 356.0 357.3 358.2

The solution-phase data for these mono(sulfonamidate) tantalum complexes are

consistent with the solid-state molecular structures. The 1H NMR resonances for the

sulfonamidate ligands are well resolved and are consistent with only one species in solution. The solution-state spectroscopy for the 2,6-disubstituted sulfonamidate complex 45 contains one well

123

resolved singlet for the methyl groups, indicating free rotation on the NMR timescale. The

isopropyl methyl and methyne signals in 46 are also equivalent, with a sharp doublet and septet respectively. The dimethylamido groups exchange freely on the NMR timescale, evidenced by a

1 13 single resonance for the NMe2 groups in the H and C NMR spectra. The dimethylamido resonances are sharp and do not show the significant broadening that is observed with the amidate complexes.146

While these complexes display many similarities to one another in the solution phase and

the solid state, the different nitrogen substituents of the sulfonamidate ligands do result in some

noteworthy distinctions. In particular, the Ta–N1 and Ta–O1 bonds are sensitive to the N- substituents; moving from the phenyl group in 44 to dimethylphenyl in 45 results in a lengthened

Ta–N1 bond and a shortening of the Ta–O1 bond. The increase of the steric bulk on the N-

substituent to 2,6-dimethylphenyl also alters the conformation of the phenyl ring. In 44 the aryl

ring lies flat in the equatorial plane but in complex 45 the ring twists out of the equatorial plane,

presumably to minimize steric interactions of the dimethyl substituents with the nearby

dimethylamido ligand. Complexes 43 and 44 have a Ta–N bond length that is shorter than that of

the Ta–O. This has also been observed with the bis(sulfonamidate) titanium.103,168,169 The

sulfonamidate ligands are bound much less asymmetrically bound to the tantalum centre

compared with the amidate complexes.

The mono(sulfonamidate) tantalum complexes were tested for reactivity as precatalysts

for the α-alkylation of p-methoxy-N-methylaniline and N-methylaniline substrates.

Unfortunately, no reactivity was observed at temperatures of 90 or 130 °C. Investigation of the thermal sensitivity of these compounds indicated that indeed 43, 45 and 46 decompose into a multitude of species after 5 hours at 130 °C, though they are slightly more robust at 90 ºC. 124

Though complex 44 did not show any signs of decomposition when monitored by 1H NMR

spectroscopy it is inactive for hydroaminoalkylation at all temperatures tested. It is not

immediately evident why these complexes are inactive, though this is consistent with the lack of

reactivity reported by Zi.143 It is possible that the secondary amine coordinates strongly to the highly electrophilic tantalum complexes and blocks the coordination site required for the tantalaziridine formation. The sulfonamidate is also firmly bound to the tantalum centre, consistent with the short Ta–O and Ta–N bond lengths (< 2.38 Å) thereby limiting the propensity for the hemilability which can liberate a coordination site.

4.3 Conclusions

A series of tantalum complexes have been synthesized to gain insight into reactivity trends to guide future catalyst development efforts. The effect of five new amide proligands

bearing new functional moieties have been examined for the tantalum catalyzed

hydroaminoalkylation of 1-octene with N-methylaniline and 4-methoxy N-methylaniline. The incorporation of neutral amine donors do not promote improved reactivity and there is currently no indication that these pendant moieties are interacting with the tantalum centre. Ligands which bind in larger seven membered (O,O)-metallacycles are not effective precatalysts, highlighting the critical nature of the four-membered (N,O)-chelate and the associated hemi-lability. An ester moiety has been found to be unstable when incorporated into the ligand framework and undergoes an amidation reaction by the dimethylamine generated in situ. A notable improvement in catalytic activity is observed using a proligand bearing an o-methoxyphenyl group on the nitrogen atom, with moderate reactivity accessed at lower reaction temperatures of 110 °C. This

125

could be due to additional coordination modes realized under catalytic conditions (high

temperature, solution phase) minimizing catalyst decomposition.

Synthetic approaches to the generation of mixed amidate chloro amido complexes of

tantalum have been examined, and indicate numerous difficulties in the synthesis of these

compounds. Ligand redistribution reactions have consistently been observed when targeting

mixed amidate dichloro tantalum complexes. Crystalline material of bis(amidate) dichloro mono(dialkylamido) complexes 38 and 39 demonstrate the lessened steric requirements of the

chloro ligands compared with the bis(amidate) tris(dimethylamide) complexes reported

previously as both amidate ligands are bound in a κ2-fashion. A high yielding synthetic

methodology for the synthesis of mono(amidate) monochloro tris(dimethylamido) tantalum 42

via salt metathesis with a dimeric tantalum dichloro tris(dimethylamido) starting material has

been described. This complex is active for hydroaminoalkylation of secondary amines however,

this complex is not as reactive as the parent mono(amidate) tetrakis(dimethylamido) tantalum

complex 2.

A series of tantalum complexes supported by sulfonamidate have been synthesized and

characterized in the solution phase and the solid state. These complexes form discrete

monomeric complexes and adopt a κ2-(N,O) binding motif. These signals are well resolved in the solution-state consistent with just one isomer in solution. Surprisingly, none of the sulfonamidate complexes examined are active precatalysts for hydroaminoalkylation of secondary amines. This could be due to reduced hemi-lability because of tight binding of the sulfonamidate to the tantalum centre and, therefore, a lack of the open coordination site required for tantalaziridine

formation.

126

4.4 Experimental

General materials and methods are outlined in Section 2.4.1.

4.4.1 Materials

The following compounds were synthesized as reported in the literature: (N-(2,6-diisopropylphenyl)pivalamidate)tetrakis(dimethylamido)tantalum, 2,118 dichloro tris(dimethylamido)

290 35,36 tantalum, 33, trichloro bis(diethylamido) tantalum, 35, tetrachloro bis(dimethylamido)

mono(dimethylamine) tantalum, 36. Reagents for the proligand syntheses were used as received

from commercial suppliers without further purification. The synthesized proligands were

rigorously dried by heating to 80 °C under vacuum over 18 hours. All commercial amines and

olefins for catalytic reactions were distilled under reduced pressure from CaH2 and degassed by 3 freeze-pump-thaw cycles or sublimed in the case of solids. Ta(NMe2)5 and TaCl5 were purchased

from Strem and used as received.

4.4.2 General experimental procedures

Synthesis of sulfonamide proligands (GP1): Adapted literature procedure.311,312 Tosyl chloride

(1.0 g, 5.25 mmol) was added to a solution of the appropriate primary amine (1 mL) in

triethylamine (3 mL) in a Schlenk-tube equipped with a Teflon cap and a magnetic stir bar. The

mixture was refluxed for 4 hours at 130 °C. The reaction mixture was poured, with stirring, into

2M HCl (250 mL) and stirred for 2 hours. The resultant solid was removed by filtration and

washed with hexanes (100 mL). The crude product was purified by recrystallization in the

indicated solvent.

127

Synthesis of mono(sulfonamidate) tetrakis(dimethylamido) tantalum complexes (GP2):

Ta(NMe2)5 was weighed into a large vial and dissolved in hexanes. The solid sulfonamide

proligand was then added in 3 – 5 portions over 2 minutes. After stirring for the indicated time the volatiles were removed under high vacuum and the crude product was purified by

recrystallization in the indicated solvent.

Tantalum catalyzed α-alkylation of N-heterocycles with isolated precatalysts (GP3): In a J.

Young NMR tube was added a solution of the corresponding N-methylaniline (0.5 mmol) and 1-

octene (112 µL, 0.75 mmol) in 0.30 g of d8-toluene. A solution of the complex (5 mol%, 0.025

mmol) in 0.50 g of d8-toluene was then added and the mixture warmed to 130 °C. In all cases,

conversion was determined by 1H NMR spectroscopy after 20 hours.

Tantalum catalyzed α-alkylation of N-heterocycles with in situ generated complexes (GP4):

To a solution of the Ta(NMe2)5 (0.025 mmol) in d8-toluene (0.30 g) was added the corresponding

proligand (0.025 mmol) at room temperature. After 10 minutes, the mixture was transferred to a solution of the corresponding N-methylaniline (0.5 mmol) and 1-octene (112 µL, 0.75 mmol) in

0.50 g of d8-toluene in a J. Young NMR tube. The mixture warmed to 130 °C. In all cases,

conversion was determined by 1H NMR spectroscopy after 20 hours. Representative 1H NMR spectra are included in Appendix B indicating the resonances of the amine substrate and the amine product used for NMR yield determination.

128

4.4.3 Synthesis and characterization

4.4.3.1 Proligands

(S)-Methyl 2-amino-3-methylbutanoate: Synthesized following literature NH2 O procedure.313 L-valine (7.5 g, 64.6 mmol) was dissolved in methanol (25 mL) and O the solution was cooled to -78 °C (dry ice/isopropanol bath). Thionyl chloride (23 mL, 193

mmol) was added dropwise by syringe over the course of 5 minutes. The solution was warmed to

room temperature, the flask was fitted with a condenser, and the solution heated at reflux for 3

hours. After the solution had cooled to room temperature, the solution was basified with aqueous

K2CO3 and the extracted with DCM (3x50 mL). The solution was dried over MgSO4, filtered,

and concentrated by rotary evaporation followed by drying under high vacuum to give the title compound as a colourless oil with analysis data matching literature reports.314 Yield: 4.84 g,

1 57%. H NMR (d1-chloroform, 300 MHz) δ 0.88 (d, 3H, CH(CH3)2), 1.02 (d, 3H, CH(CH3)2),

3 1.42 (br s, 2H, NH2), 2.02 (m, 1H, CH(CH3)2), 3.30 (d, JH,H = 3.0 Hz, CHNH2), 3.73 (s, 3H,

OCH3).

(S)-Methyl 3-methyl-2-pivalamidobutanoate, 22: Synthesized following O tBu NH adapted literature procedure.315 (S)-Methyl 2-amino-3-methylbutanoate (4.45 O g, 33.9 mmol) was dissolved in pyridine (15 mL) and the solution was cooled O 22 to -78 °C (dry ice/isopropanol bath). Pivaloyl chloride (6.25 mL, 50.9 mmol) was added dropwise by syringe resulting in formation of a white precipitate. The solution was allowed to warm to room temperature and left to stir overnight. The reaction mixture was washed with 0.5M HCl (30 mL) and 0.5M Na2CO3 (30 mL) and the aqueous layer was extracted with

DCM (3x25 mL). The combined organic layers were dried over MgSO4, filtered, and 129

concentrated by rotary evaporation. The crude product was purified by recrystallization from

hexanes at -30 °C. The crystals were washed with cold hexanes to give the title compound as a

1 white crystalline solid. Yield: 3.00 g, 41%. Mp: 34 °C. H NMR (d6-benzene, 400 MHz) δ 0.79

3 3 (d, JH,H = 8.0 Hz, 3H, CH(CH3)2), 0.88 (d, JH,H = 8.0 Hz, 3H, CH(CH3)2), 1.10 (s, 9H,

C(CH3)3), 2.06 (m, 1H, CH(CH3)2), 3.21 (s, 3H, OCH3), 4.83 (dd, 1H, NCH), 6.03 (br s, 1H,

13 NH); C NMR (d6-benzene, 75 MHz) δ 17.6 (CH3), 18.8 (CH3), 27.3 (CH3), 31.5 (CH), 38.6

(C), 51.2 (OCH3), 56.7 (NCH), 172.7 (C=O), 177.2 (C=O). Anal. calcd. for C11H21NO3: C,

24 61.37; N, 6.51; H, 9.83; Found: C, 61.36; N, 6.48; H, 9.79. [α]D = -37.5 (c 1.00, MeOH).

3-Methyl-2-pivalamidobutanoic acid: (S)-Methyl 3-methyl-2- O tBu NH pivalamidobutanoate was dissolved in 1M NaOH and the solution was stirred OH vigorously for 1 hour. The solution was acidified by addition of 1M HCl and O extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and

concentrated by rotary evaporation followed by drying under high vacuum to give the racemized

title compound as a white powder with analysis data matching literature reports.316 Yield: 1.74 g,

1 3 3 93%. H NMR (d1-chloroform, 300 MHz) δ 0.97 (d, JH,H = 9.0 Hz, 3H, CH(CH3)2), 1.01 (d, JH,H

3 = 9.0 Hz, 3H, CH(CH3)2), 1.25 (s, 9H, C(CH3)3), 2.29 (m, 1H, CH(CH3)2), 4.51 (dd, JH,H = 9.0,

3.0 Hz, NCH), 6.10 (br s, 1H, NH).

O N-(3-methyl-1-oxo-1-(piperidin-1-yl)butan-2-yl)pivalamide, 23. H N N Synthesized following adapted literature procedure.191 3-Methyl-2- O

pivalamidobutanoic acid (2.0 g, 10 mmol) and triethylamine (1.53 mL, 23

11 mmol) were dissolved in dry THF (35 mL) and cooled to -15 °C. Ethyl chloroformate (0.96 130

mL, 10 mmol) and piperidine (1.09 mL, 11 mmol) were added dropwise successively over the

course of 10 minutes. The solution was stirred overnight at room temperature, and concentrated

by rotary evaporation. The residual yellow oil was diluted in EtOAc (20 mL), washed

successively with 0.5M aqueous NaHCO3, 1M aqueous HCl, and brine, dried over MgSO4 and

filtered. Removal of the volatiles by rotary evaporation and recrystallization from

hexanes/EtOAc at -10 °C gave the title compound as a white crystalline solid. Yield: 0.59 g,

1 3 22%. Mp: 114 °C. H NMR (d1-chloroform, 600 MHz) δ 0.84 (d, JH,H = 6.9 Hz, 3H, CH(CH3)2),

3 0.94 (d, JH,H = 6.8 Hz, 3H, CH(CH3)2), 1.21 (s, 9H, C(CH3)3), 1.48-1.68 (m, 6H, CH2); 1.91-

3 2.03 (m, 1H, CH(CH3)2), 3.43-3.50 (m, 2H, CH2), 3.50-3.63 (m, 2H, CH2), 4.85 (dd, JH,H =

3 13 8.58, 5.12 Hz, 1H, NCH), 6.54 (d, JH,H = 8.06 Hz, 1H, NH). C NMR (d1-chloroform, 150

MHz) δ 17.0 (CH3), 19.9 (CH3), 24.4 (CH2), 25.6 (CH2), 26.4 (CH2), 27.5 (CH3), 31.7 (CH), 38.8

(C), 43.1 (NCH2), 46.7 (NCH2), 52.7 (NCH), 170.0 (C=O), 178.2 (C=O). MS(CI): m/z = 269

+ (M+H) . Anal. calcd. for C15H28N2O2: C, 67.13; N, 10.44; H, 10.52; Found: C, 67.01; N ,10.20;

H, 10.52.

N-(2-methoxyphenyl)-2,4,6-trimethylbenzamide, 27: 2- O O Methoxyaniline (0.34 mL, 3 mmol) was dissolved in DCM (100 mL) in a N H round bottom flask equipped with a stir bar. After addition of 27 triethylamine (2.1 mL, 15 mmol), the mixture was cooled to -78 °C and 2,4,6- trimethylbenzylchloride (0.5 mL, 3 mmol) was added dropwise over the course of 5 minutes.

The reaction was left to warm to room temperature, stirred overnight, and then quenched with saturated aqueous NaHCO3, extracted with dichloromethane (3 x 20 mL) and dried over MgSO4.

After filtration and removal of volatiles by rotary evaporation a pinkish solid was obtained. 131

Recrystallization from dichloromethane/hexane, gave the title compound as a white solid. Yield:

1 0.42 g, 52%. H NMR (d1-chloroform, 400 MHz) δ 2.35 (s, 3H, CCH3), 2.40 (s, 6H, CCH3), 3.86

(s, 3H, OCH3), 6.87-6.96 (m, 3H, CHarom), 6.99-7.18 (m, 2H, CHarom), 7.95 (br s, 1H, NH), 8.62

3 13 (dd, JH,H = 7.9, 1.4 Hz, 1H, CHarom); C NMR (d1-chloroform, 100 MHz) δ 19.2 (CH3), 21.0

(CH3), 55.5 (OCH3), 109.9 (CH), 119.9 (CH), 121.0 (CH), 123.9 (CH), 127.5 (C), 128.3 (CH),

134.4 (C), 135.3 (C), 138.7 (C), 148.0 (COCH3), 168.4 (C=O). HRMS (EI) Calcd. for

+ + C17H19NO2: m/z 269.14158 (M ); Found: m/z 269.14142 (M ).

N-(2,6-dimethylphenyl)-3-(piperidin-1-yl)propanamide, 25: O

317,318 N N Synthesized following adapted literature procedure. 3- H 25 Chloropropanoic acid (2.35 g, 21.7 mmol) was dissolved in toluene in

a round bottom Schlenk flask equipped with a condenser and a stir bar. Thionyl chloride (15.7

mL, 216.6 mmol) was added through the top of the condenser and the solution heated to reflux

for 1.5 hours. The reaction mixture was cooled to room temperature and the excess thionyl

chloride and toluene were removed under high vacuum. Dry toluene (100 mL) and Na2CO3 (4.59

g, 43.3 mmol) were added to the crude residue. 2,6-Dimethylaniline (2.23 mL, 18.1 mmol) was added dropwise over 15 minutes resulting in a bright yellow solution. The reaction mixture was left to stir for 1 hour at room temperature. The mixture was then diluted with water (50 mL) and

piperidine (8.6 mL, 86.7 mmol) was added. The reaction mixture was heated at reflux for 8 hours. After cooling to room temperature the organic layer was collected and washed with water

(3 x 50 mL). The organic layer was then dried over MgSO4, filtered and concentrated by rotary

evaporation. Flash chromatography (silica gel F60, MeOH/DCM 1:99 → 5:95) and

recrystallization from hot hexanes afforded the title compound as a white solid. Yield: 0.95g, 132

1 20%. H NMR (d1-chloroform, 400 MHz) δ 1.45-1.57 (m, 2H, CH2), 1.59-1.64 (m, 4H, CH2),

2.25 (s, 6H, CH3), 2.42-2.64 (m, 6H, NCH2 and CH2CH2(CO)), 2.70-2.74 (m, 2H, NCH2), 7.09

13 (s, 3H, CHarom), 10.30 (br s, 1H, NH); C NMR (d1-chloroform, 100 MHz) δ 18.6 (CH3), 24.2

(CH2), 25.9 (CH2), 32.0 (CH2), 53.8 (CH2), 54.9 (CH2), 126.6 (CH), 128.0 (CH), 134.7 (C),

+ 134.8 (C), 170.9 (C=O). HRMS (EI) calcd. for C16H24N2O: m/z 260.18886 (M ); Found: m/z

260.18904 (M+).

N-(2,6-diisopropylphenyl)-3-(dimethylamino)propanamide, 26: O Synthesized following adapted literature procedure.43,44 3- N N H chloropropanoic acid (2.546 g, 23.46 mmol) was dissolved in toluene in 26 a round bottom Schlenk flask equipped with a condenser and a stir bar. Thionyl chloride (5.1

mL, 70.38 mmol) was added through the top of the condenser and the solution heated to reflux for 2 h. The reaction mixture was cooled to room temperature and the excess thionyl chloride and toluene were removed under reduced pressure. Dry toluene (80 mL) and Na2CO3 (4.14 g,

39.1 mmol) was added followed by 2,6-diisopropylaniline (3.69 mL, 19.55 mmol) added dropwise over 30 minutes. After addition the reaction mixture was left to stir for 1 h at room temperature and then diluted with water (50 mL). After addition of Na2CO3 (8.29 g, 78.20 mmol)

and Me2NH2Cl (6.38 g, 78.20 mmol) the reaction mixture was heated to reflux overnight. After

cooling to room temperature the organic layer was collected and washed with water (3 x 50 mL),

the organic layer dried over MgSO4, filtered and the solvent removed under reduced pressure.

The resulting solid was rinsed repeatedly with hexanes until a white powder was obtained.

Recrystallization from hot hexanes afforded the title compound as a white solid. Yield: 48%. 1H

NMR (d1-chloroform, 400 MHz) δ 1.12-1.42 (m, 12H, CH(CH3)2), 2.44 (s, 6H, N(CH3)2), 2.64- 133

3 2.71 (m, 2H, NCH2CH2), 2.77-2.83 (m, 2H, CH(CH3)2), 3.16 (dt, JH,H = 13.8, 6.8 Hz, 2H,

13 NCH2), 7.25 (s, 2H, CHarom), 7.32-7.38 (m, 1H, CHarom), 10.30 (br s, 1H, NH). C NMR (d1-

chloroform, 100 MHz) δ 23.6 (br, CH3), 28.8 (CH), 32.7 (CH2), 44.5 (CH3), 55.3 (CH2), 123.3

(CH), 127.7 (CH), 132.0 (C), 145.6 (C), 171.7 (C=O). HRMS (EI) Calcd. for C17H28N2O: m/z

276.22016 (M+); Found: m/z 276.22009 (M+).

N-(tert-butyl)-4-methylbenzenesulfonamide: Prepared following GP1 O S using tosyl chloride (1.0 g, 5.25 mmol), tert-butylamine (1.0 mL, 7.14 N O H mmol), and triethylamine (3.0 mL, 21.5 mmol). Recrystallization of the crude product from hot

hexanes/DCM gave the title compound as a white solid with analysis data matching literature

319 1 reports. H NMR (d6-benzene, 400 MHz) δ 1.02 (s, 9H, C(CH3)3), 1.89 (s, 3H, CTsCH3), 4.96

3 3 (br s, 1H), 6.78 (d, JH,H = 8.0 Hz, 2H, CHTs), 7.87 (d, JH,H = 8.0 Hz, 2H, CHTs).

4-methyl-N-phenylbenzenesulfonamide: Prepared following GP1 using O S tosyl chloride (1.0 g, 5.25 mmol), N-phenylamine (1.0 mL, 7.14 mmol), N O H and triethylamine (3.0 mL, 21.5 mmol). Recrystallization of the crude product from hot hexanes/DCM gave the title compound as a white solid with analysis gave the title compound as

320 1 a pale yellow oil with analysis data matching literature reports. H NMR (d6-benzene,

3 400 MHz) δ 1.73 (s, 3H, CTsCH3), 6.59 (d, JH,H = 8.0 Hz, 2H, CHPh), 6.68 (br s, 1H, NH), 6.70-

3 3 6.76 (m, 1H CHPh), 6.88 (app t, JH,H = 7.9 Hz, 2H, CHPh), 6.99 (d, JH,H = 8.2 Hz, 2H, CHTs),

3 7.67 (d, JH,H = 8.2 Hz, 2H, CHTs).

134

N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamide: Prepared O following GP1 using tosyl chloride (1.0 g, 5.25 mmol), N-(2,6- S N O H dimethylphenyl)amine (1.0 mL, 7.14 mmol), and triethylamine (3.0 mL,

21.5 mmol). Recrystallization of the crude product from hot ethanol gave the title compound as a

312 1 white solid with analysis data matching literature reports. H NMR (d6-benzene, 400 MHz) δ

3 1.81 (s, 3H, CTsCH3), 1.96 (s, 6H, CCH3), 5.50 (s, 1H, NH), 6.63 (d, JH,H = 8.2 Hz, 2H, CHTs),

3 6.73-6.83 (m, 2H, CH), 6.84-6.91 (m, 1H, CH), 7.58 (m, JH,H = 8.2 Hz, 2H, CHTs)

N-(2,6-diisopropylphenyl)-4-methylbenzenesulfonamide: Prepared iPr O following GP1 using tosyl chloride (1.0 g, 5.25 mmol), S N O H iPr diisopropylphenylamine (1.0 mL, 7.14 mmol), and triethylamine (3.0 mL,

21.5 mmol). Recrystallization of the crude product from hot ethanol gave the title compound as a

311 1 white solid with analysis data matching literature reports. H NMR (d6-benzene, 400 MHz) δ

3 3 1.01 (d, JH,H = 6.83 Hz, 12H, CH(CH3)2), 1.83 (s, 3H, CTsCH3), 3.34 (spt, JH,H = 6.83 Hz, 2H,

3 3 CH(CH3)2), 6.10 (br s, 1H, NH), 6.67 (d, JH,H = 8.2 Hz, 2H, CHTs), 7.01 (d, JH,H = 7.5 Hz, 2H,

3 3 CH), 7.10 (d, JH,H = 7.3 Hz, 1H, CH), 7.63 (d, JH,H = 8.2 Hz, 2H, CHTs).

4.4.3.2 Tantalum complexes

Mono(N-(2-methoxyphenyl)-2,4,6-trimethylbenzamidate) O tetrakis(dimethylamido) tantalum, 27: Proligand 24 (0.135 g, 0.5 Ta(NMe2)4 N 27 mmol) and Ta(NMe2)5 (0.200 g, 0.5 mmol) were stirred overnight OMe

(18 hours) in hexanes (5 mL) at room temperature. Removal of

volatiles under high vacuum afforded a yellow powder. Recrystallization from hexanes gave the 135

1 title compound as yellow crystals. Yield: 225 mg, 72%. H NMR (d6-benzene, 400 MHz) δ 1.98

(s, 3H, CCH3), 2.43 (s, 6H, CCH3), 3.10 (s, 3H, OCH3), 3.56 (s, 24H, N(CH3)2), 6.34-6.41 (m,

13 1H, CHarom), 6.57 (s, 2H, CHarom), 6.72-6.82 (m, 2H, CHarom), 7.06-7.22 (m, 2H, CHarom). C

NMR (d6-benzene, 100 MHz) δ 21.3 (CH3), 21.4 (CH3), 47.4 (N(CH3)2), 54.6 (OCH3), 111.9

(CH), 120.8 (CH), 125.3 (CH), 126.5 (CH), 129.0 (CH), 134.8 (C), 135.4 (C), 135.7 (C), 138.2

+ (C), 153.0 (C), 177.3 (C=O). MS (EI): m/z = 581 (M-NMe2) . Anal. calcd. for C25H42N2O2Ta: C,

48.00; N, 11.19; H, 6.77; Found: C, 48.02; N, 10.93; H, 7.01. Characterized by X-ray

crystallography (Appendix A).

28: Proligand 23 (36.1 mg, 0.135 mmol) and Ta(NMe2)5 (54.0 mg, 0.135

mmol) were stirred overnight (18 hours) in hexanes (3 mL) at room N iPr O temperature. Removal of volatiles under high vacuum and crystallization Ta(NMe2)4 N O 28 at 30 °C from hexanes afforded the title compound as a yellow crystalline tBu

1 3 solid. Yield: 47.3 mg, 56%. H NMR (d6-benzene, 600 MHz): δ 0.96 (d, JH,H = 6.8 Hz, 3H,

CH(CH3)2), 0.99-1.05 (m, 1H, CH2), 1.05-1.15 (m, 3H, CH2), 1.15-1.22 (m, 1H, CH2), 1.22-1.29

(m, 1H, CH2), 1.25 (d, J = 6.4 Hz, 3H, CH(CH3)2), 1.49 (s, 9H, C(CH3)3), 1.97-2.15 (m, 1H,

3 CH(CH3)2), 2.84 (br s, 2H, CH2), 3.53 (br s, 24H, N(CH3)2), 3.77 (d, JH,H = 11.5 Hz, 1H, NCH),

13 3.89 (br s, 2H, CH2). C NMR (d6-benzene, 150 MHz) δ 20.1, 21.8, 24.6, 25.8, 25.8, 25.9, 30.1,

31.6, 39.2, 45.2, 47.5, 47.6, 69.5 (NCH), 175.1 (C=O), 178.5 (C=O). MS (EI): m/z = 580 (M-

+ NMe2) . Anal. Calcd. for C23H51N6O2Ta: C, 44.22; N, 13.45; H, 8.23; Found: C, 44.00; N, 13.31;

H, 8.22. Characterized by X-ray crystallography (Appendix A).

136

29: Proligand 22 (0.108 g, 0.5 mmol) and Ta(NMe2)5 (0.200 g, 0. 5 N mmol) were stirred overnight in hexanes (5 mL) at room iPr O Ta(NMe2)3(OMe) N temperature. Removal of volatiles under high vacuum gave the title O 29 tBu compound as a yellow-orange solid. Crystals for X-ray crystallography were grown from

1 3 pentane at -30 °C. H NMR (d6-benzene, 400 MHz): δ 0.83 (d, JH,H = 8.0 Hz, 3H, CH(CH3)2),

1.19 (m, 3H, CH(CH3)2), 1.46 (s, 9H, C(CH3)3), 2.04 (m, 1H, CH(CH3)2), 2.50 (s, 3H, N(CH3)2),

13 2.63 (s, 3H, N(CH3)2), 3.50-3.71 (m, 19H, NCH, N(CH3)2), 4.10 (br s, 3H, OCH3). C NMR (d6-

benzene, 100 MHz) δ 19.3 (CH3), 21.5 (CH3), 29.6 (CH3), 30.8, 36.6 (N(CH3)2), 37.1 (N(CH3)2),

38.9, 47.1 (N(CH3)2), 57.3 (OCH3), 68.9, 175.15 (C=O), 179.15 (C=O). MS (EI): m/z = 540 ([M-

+ + OMe] ), 527 ([M-OMe-NMe2] ) Anal. Calcd. for C19H46N5O3Ta: C, 39.79; N, 12.21; H, 8.08;

Found: C, 39.79; N, 12.19; H, 7.79. Characterized by X-ray crystallography (Appendix A).

Mono(N-(2,6-dimethylphenyl)-3-(piperidin-1- N O Ta(NMe2)4 yl)propanamidate) tetrakis(dimethylamido) tantalum: In situ N screening procedure was used to evaluate catalytic activity as crystalline material could not be obtained. Proligand 25 (6.51 mg, 0.025 mmol) and Ta(NMe2)5

(10.0 mg, 0.025 mmol) were weighed into a small vial and d8-toluene was added (0.5 g). The solution was transferred to a J. Young tube and NMR spectroscopy is consistent with formation

1 of the mono(amidate) tetrakis(dimethylamido) tantalum complex. Yield: >98%. H NMR (d8-

3 toluene, 600 MHz) δ 1.26-1.33 (m, 2H, CH2), 1.45 (dt, JH,H = 11.1, 5.5 Hz, 4H, CH2), 2.12-2.17

3 (m, 6H, CH2), 2.33 (s, 6H, CCH3), 2.65 (t, JH,H = 7.0 Hz, 2H, NCH2) 3.40 (br s, 24H, N(CH3)2),

13 6.94-6.97 (m, 1H), 7.04-7.06 (m, 2H); C NMR (C6D6, 150 MHz) δ 18.2, 24.9, 26.3 (CH3),

137

30.5, 47.0 (br, N(CH3)2), 54.7 (NCH2), 55.0 (NCH2), 124.6, 128.3, 132.5 (CCH3), 143.5

(NCarom), 174.4 (C=O).

Mono(N-(2,6-diisopropylphenyl)-3- N O Ta(NMe2)4 (dimethylamino)propanamidate) tetrakis(dimethylamido) N iPr iPr tantalum: In situ screening procedure was used to evaluate catalytic

activity as crystalline material could not be obtained. Proligand 26 (6.91 mg, 0.025 mmol) and

Ta(NMe2)5 (10.0 mg, 0.025 mmol) were weighed into a small vial and d8-toluene was added (0.5

g). The solution was transferred to a J. Young tube and NMR spectroscopy is consistent with

formation of the mono(amidate) tetrakis(dimethylamido) tantalum complex. Yield: >98%. 1H

3 3 NMR (d8-toluene, 600 MHz) δ 1.26 (d, JH,H = 6.9 Hz, 6H, CH(CH3)2), 1.28 (d, JH,H = 6.8 Hz,

6H, CH(CH3)2), 1.95 (s, 6H, CH2N(CH3)2), 2.20-2.25 (m, 2H, CH2), 2.72-2.74 (m, 2H, CH2),

13 3.31 (br s, 24H, N(CH3)2), 3.40-3.47 (m, 2H, CH2), 7.05-7.11 (m, 3H, CHarom); C NMR (C6D6,

150 MHz) δ 25.1, 25.2, 27.0, 31.7, 45.3, 47.0 (br, N(CH3)2), 55.6, 123.9, 125.3, 140.2, 143.2,

174.3 (C=O).

Dichloro tris(dimethylamido) tantalum, pyridine adduct, 34: Synthesized ⋅ TaCl2(NMe2)3 py 290 1 following adapted literature procedure. H NMR (d6-benzene, 600 MHz) δ 34

3 3 3.64 (br s,18H, N(CH3)2), 6.50 (t, JH,H = 6.7 Hz, 2H, CHpyr), 6.80 (t, JH,H = 6.8 Hz, 1H CHpyr),

13 8.78 (br s, 2H, CHpyr),; C NMR (d6-benzene, 150 MHz) δ 49.3 (N(CH3)2), 124.4 (CH), 137.9

(CH), 151.7 (CH); MS (EI): m/z = 383 ([M-pyridine]+), 348 ([M-pyridine-Cl]+), 339 ([M-

+ pyridine-NMe2] ); Anal. calcd. for C11H23Cl2N4Ta: C, 28.52; H, 5.01; N, 12.10; Found C, 28.13;

H, 4.85; N, 11.75. 138

Bis(N-(2,6-diisopropylphenyl)pivalamidate) dichloro t Cl t Bu O O Bu mono(dimethylamido) tantalum, 38: Ta(NMe ) (0.500 iPr iPr 2 5 N Ta N Cl g,0.651) was weighed into a large vial equipped with a stir bar iPr iPr NMe2 and dissolved in benzene (5 mL). A suspension of N-(2,6- 38 diisopropylphenyl)pivalamide (0.340 g, 1.302 mmol) in benzene (2 mL) was added to the stirring solution at room temperature. The solution was left to stir for 1.5 hour and a colour change of yellow to orange-red was observed. The volatiles were removed under high vacuum.

Recrystallization from hot toluene gave the title compound as a red crystalline solid. 1H NMR

3 (d6-benzene, 600 MHz) δ 1.06 (s, 18H, C(CH3)3), 1.21 (d, JH,H = 6.9 Hz, 6H, CH(CH3)2), 1.26

3 3 3 (d, JH,H = 6.6 Hz, 6H, CH(CH3)2), 1.36 (d, JH,H = 6.9 Hz, 6H, CH(CH3)2), 1.47 (d, JH,H = 6.5

3 Hz, 6H, CH(CH3)2), 3.17 (dt, JH,H = 13.6, 6.9 Hz, 2H, CH(CH3)2), 4.12 (br s, 3H, N(CH3)2),

3 4.25 (br s, 3H, N(CH3)2), 4.42 (dt, JH,H = 13.4, 6.7 Hz, 2H, CH(CH3)2), 7.01-7.07 (m, 4H,

3 13 CHarom), 7.10 ( JH,H = 6.4, 2.9 Hz, 2H, CHarom); C NMR (d6-benzene, 150 MHz) δ 23.6, 24.6,

27.1, 27.6, 28.0, 28.2, 28.6, 42.5 (C), 50.1 (N(CH3)2), 54.9 (N(CH3)2), 123.7 (CH), 124.9 (CH),

127.9 (CH), 138.1 (C), 143.9 (C=O), 146.2 (C=O). EI MS (m/z): 816 ([M]+). Characterized by

X-ray crystallography (Appendix A).

(N-(2,6-diisopropylphenyl)pivalamido) tris(dimethylamino) tantalum O t chloride, 42: N-(2,6-Diisopropylphenyl)pivalamide (53.1 mg, Bu TaCl(NMe2)3 N iPr iPr 42 0.203 mmol) was dissolved in 2 mL of benzene and NaHMDS (37.2 mg,

0.203 mmol) was added in one portion. After stirring for 1 hour the

volatiles were removed under high vacuum. Pentane (2 mL) was added, the resultant suspension 139

was stirred for 5 minutes, and then the volatiles were removed under high vacuum. The

proligand salt was then dissolved in benzene and added dropwise over 5 minutes to a toluene

suspension of [TaCl2(NMe2)3]2 (78.0 mg, 0.102 mmol). The mixture was allowed to stir over

night (18 h) to give a clear yellow solution. All volatiles were removed under high vacuum. The

complex was dissolved in hexanes and filtered through a Celite™ plug to remove the sodium

chloride by-product. Removal of the volatiles under high vacuum and recrystallization from hot

hexanes or hot pentane at 25 °C, then -30 °C gave the title compound as a yellow crystalline

1 solid. Yield: 0.124 g, 75%. H NMR (d6-benzene, 400 MHz) δ 1.11 (s, 9H, C(CH3)3), 1.22 (br s,

3H, CH(CH3)2), 1.23 (br s, 3H, CH(CH3)2), 1.36 (br s, 3H, CH(CH3)2), 1.43 (br s, 3H,

CH(CH3)2), 3.22 (br s, 1H, CH(CH3)2), 3.49 (br s, 18H, N(CH3)2), 4.25 (br s, 1H, CH(CH3)2),

13 7.04-7.10 (m, 3H, CHarom.); C NMR (d6-benzene, 100 MHz) δ 23.7, 24.9, 25.7, 27.2 (br s,

CH(CH3)2), 27.9, 28.0 (br s, CH(CH3)2), 28.5 (C(CH3)3), 42.3 (C(CH3)3), 48.9 (br s, N(CH3)2),

123.3, 124.6 (br s, CHarom.), 126.4 (CHarom.), 140.4 (Carom.N), 142.5, 144.8 (br s, Carom.CH), 181.2

+ + (C=O). MS (EI): m/z = 564 ([M-NMe2] ), 348 ([M-amidate] ); Anal. Calcd. for C23H44ClN4OTa:

C, 45.36; H, 7.28; N, 9.20; Found C, 45.00; H, 7.22; N, 8.80; Characterized by X-ray

crystallography (Appendix A).

Monochloro bis(N-(2,6-diisopropylphenyl)pivalamidate) O t Bu TaCl3(NMe2) N 2 bis(dimethylamido) tantalum, 40: Sodium N-(2,6- i i Pr Pr 40 diisopropylphenyl)pivalamidate (0.1020 g, 0.360 mmol) and

TaCl4(NMe2)2H2NMe2 (0.1847 g, 0.360 mmol) were dissolved in 10 mL of benzene. The

resulting mixture was stirred for 18 hours at room temperature. The volatiles were removed

under high vacuum. The reaction mixture was dissolved in hexanes and filtered through a 140

Celite™ plug to remove the sodium chloride by-product to give the title compound as a yellow-

1 orange solid. H NMR (d6-benzene, 600 MHz) δ 1.30 (m, 12H, CH(CH3)2), 1.41 (s, 9H,

3 C(CH3)3), 2.33 (s, 6H, N(CH3)2), 3.10 (dt, JH,H = 13.8, 6.9 Hz, 2H, CH(CH3)2), 7.06-7.08 (m,

13 1H, CHarom), 7.16-7.19 (m, 2H, CHarom); C NMR (d6-benzene, 150 MHz) δ 22.8 (CH(CH3)2),

24.3 (CH(CH3)2), 29.1 (CH(CH3)2), 30.8 (C(CH3)3), 40.4 (C(CH3)3), 41.6 (N(CH3)2), 121.7

(CHarom), 122.9 (CHarom), 136.7 (Carom), 147.4 (Carom), 161.3 (C=O); MS (EI): m/z = 330 tentative

assignment ([M – amidate]+).

Mono(N-(tert-butyl)-4-methylbenzenesulfonamidate) O O S Ta(NMe2)4 tetrakis(dimethylamido) tantalum, 43: Prepared following GP2 N 43

using proligand 43 (0.170 g, 0.748 mmol) and Ta(NMe2)5 (0.300 g,

0.748 mmol). Recrystallization of the crude product from hot pentanes gave the title compound

1 as a yellow solid. Yield: 0.419 g, 96%. H NMR (d6-benzene, 400 MHz) δ 1.35 (s, 9H, C(CH3)3),

3 1.90 (s, 3H, CTsCH3), 3.54 (br s, 24H, N(CH3)2), 6.81 (m, JH,H = 8.19 Hz, 2H, CHTs), 7.95 (m,

3 13 JH,H = 8.19 Hz, 2H, CHTs); C (d6-benzene, 125 MHz) δ 21.5 (CH3), 32.8 (CH3), 48.34 (br,

N(CH3)2), 56.16 (NC), 129.4 (CHTs), 129.6 (CHTs), 142.6 (CTs), 143.3 (CTs); EI MS (m/z): 539

+ + + ([M-NMe2] ), 483 ([M-C(CH3)3-NMe2] ), 438 ([M-C(CH3)3-2NMe2] ), 395 ([M-C(CH3)3-

+ 3NMe2] ); Anal. calcd. for C19H40N5O2STa: C, 39.10; H, 6.91; N, 12.00; Found: C, 39.34; H,

6.78; N, 12.23. Characterized by X-ray crystallography (Appendix A).

Mono(4-methyl-N-phenylbenzenesulfonamidate) O O S Ta(NMe2)4 tetrakis(dimethylamido) tantalum, 44: Prepared following GP2 N 44

141

using proligand 44 (0.185 g, 0.748 mmol) and Ta(NMe2)5 (0.300 g, 0.748 mmol).

Recrystallization of the crude product from hot pentanes gave the title compound as a yellow

1 solid. Yield: 0.399 g, 88%. H NMR (d6-benzene, 400 MHz) δ 1.82 (s, 3H, CTsCH3), 3.45 (s,

3 3 24H, N(CH3)2), 6.70 (d, JH,H = 8.0 Hz, 2H, CHTs), 6.86 (t, JH,H = 7.4 Hz, 1H, CHPh), 7.22 (dd,

3 3 3 JH,H = 8.5, 7.5 Hz, 2H, CHPh), 7.54 (m, JH,H = 7.7 Hz, 2H, CHTs), 7.99 (d, JH,H = 8.2 Hz, 2H,

13 CHTs), C (d6-benzene, 125 MHz) δ 21.5 (CH3), 47.8 (N(CH3)2), 120.7, 122.2, 128.2, 128.3,

+ + 128.6, 129.7, 129.9, 139.9, 143.2 (CTs), 144.4 (CTs); EI MS (m/z): 603 ([M] ), 559 ([M-NMe2] );

Anal. calcd. for C23H40N5O2STa: C, 41.79; H, 6.01; N, 11.60; Found: C, 41.89; H, 6.22; N,

11.80. Characterized by X-ray crystallography (Appendix A).

Mono(N-(2,6-dimethylphenyl)-4-methylbenzenesulfonamidate)

O tetrakis(dimethylamido) tantalum, 45: Prepared following GP2 S Ta(NMe2)4 O N using proligand 45 (0.135 g, 0.491 mmol) and Ta(NMe2)5 (0.197 g, 45

0.491 mmol). Recrystallization of the crude product from hot

1 pentanes gave the title compound as a yellow solid. Yield: 0.294 g, 95%. H NMR (d6-benzene,

3 400 MHz) δ 1.88 (s, 3H, CTsCH3), 2.51 (s, 6H, CH3), 3.32 (s, 24H, N(CH3)2), 6.72 (d, JH,H = 8.0

3 3 Hz, 2H, CHTs), 6.84 - 6.99 (m, 1H, CHPh), 7.06 (d, JH,H = 7.3 Hz, 2H, CHPh), 7.79 (d, JH,H = 8.2

13 Hz, 2H, CHTs); C (d6-benzene, 125 MHz) δ 20.1, 21.5, 25.2, 28.7, 46.3, 46.9, 47.3 (br,

N(CH3)2), 124.2, 125.0, 127.6, 129.1, 129.2, 129.3, 137.7, 140.8, 141.8, 142.0; EI MS (m/z): 587

+ + ([M-NMe2] ), 357 ([M-sulfonamidate] ); Anal. Calcd. for C23H40N5O2STa: C, 43.74; H, 6.38; N,

11.09; Found: C, 44.09; H, 6.53; N, 10.81. Characterized by X-ray crystallography (Appendix

A).

142

Mono(N-(2,6-diisopropylphenyl)-4-

methylbenzenesulfonamidate) tetrakis(dimethylamido) O S Ta(NMe2)4 O N i i tantalum, 46: Prepared following GP2 using proligand 46 (0.170 g, Pr Pr 46

0.748 mmol) and Ta(NMe2)5 (0.300 g, 0.748 mmol).

Recrystallization of the crude product from hot pentanes gave the title compound as a yellow

1 3 solid. Yield: 90.5 mg, 18%. H NMR (d6-benzene, 400 MHz) δ 1.27 (d, JH,H = 6.8 Hz, 12H,

CH(CH3)2), 1.87 (s, 3H, CTsCH3), 3.22 (s, 24H, N(CH3)2), 4.02-4.08 (m, 2H, CH(CH3)2), 6.75 (d,

3 3 13 JH,H = 8.0 Hz, 2H, CHTs), 7.11-7.18 (m, 3H, CHPh), 7.83 (d, JH,H = 8.2 Hz, 2H, CHTs); C (d6-

benzene, 125 MHz) δ 21.4, 25.2, 28.7, 46.9 (br, N(CH3)2), 124.2, 125.0, 127.9, 129.3, 141.4,

146.8. In situ screening procedure was used to evaluate catalytic activity as crystalline material

could only be obtained in low yield.

143

CHAPTER 5: Synthesis of α-alkylated N-heterocycles via hydroaminoalkylation

5.1 Introduction

5.1.1 Functionalized N-heterocycles

Saturated N-heterocycles are key structural elements found in a wide variety of natural

products,321 agrochemicals,322,323 and pharmaceuticals324-327 (Figure 5.1). Familiar examples of

this heterocyclic motif include (S)-nicotine and coniine, naturally occurring alkaloids containing

a pyrrolidine and a piperidine core, respectively. Additional alkaloids containing a piperidine

ring include (–)-lobeline and (–)-spectaline, which have been used to aid with smoking

cessation328 and for analgesic applications.329 Saturated heterocyclic compounds containing

either a pyrrolidine or piperidine represent 33 of the top 200 prescription drugs sold in the US in

2010.330 Key examples include the naturally occurring opiates morphine and codeine, Concerta

(used to treat Attention Deficit Hyperactivity Disorder), and Vesicare (used to alleviate symptoms of an overactive bladder).

N H H N N N N ( )9 O O OH OH − − (S)-Nicotine Coniine ( )-Lobeline ( )-Spectaline RO O O H O H N N O O N N HO Morphine, R = H Concerta Vesicare = Codeine, R Me Johnson & Johnson Astellas

Figure 5.1 Natural products and pharmaceuticals containing an α-alkyl/aryl N-heterocycle. 144

Owing to these extensive applications, there is significant value in the development of a

selective and efficient route for the synthesis of a wide range of molecularly diverse N- heterocyclic compounds. A synthetic methodology which allows for the selective direct functionalization of the N-heterocyclic core to gain access to a variety of products is particularly attractive. A successful methodology would require simple, inexpensive, and readily available chemicals and would avoid the generation of stoichiometric by-products. To this end, catalytic

C–H functionalization has emerged as a selective and powerful tool for the direct functionalization of sp3-hybridized C–H bonds adjacent to the nitrogen of amine substrates.330-334

The current state-of-the-art for this strategy include stoichiometric α-lithiation strategies,335-337

copper-catalyzed cross-dehydrogenative couplings,338-340 radical-based C–H activation,341-343

photoredox functionalization,344 metal-catalyzed carbene insertions,345,346 and ruthenium

catalyzed α-alkylation and arylation strategies.347,348 The most relevant of these strategies are

discussed in the following sections.

5.1.2 Stoichiometric α-lithiation and functionalization

Initially pioneered by the Beak335 and Hoppe336 groups, the organolithium-mediated α-

deprotonation of cyclic amines, followed by functionalization with an electrophile, is one

methodology that has undergone extensive research (Scheme 5.1). This transformation is a

multiple-step process in which an N-protected amine heterocycle, classically pyrrolidine, is

deprotonated with an organolithium reagent to generate an α-lithiated species. This α-amino anion intermediate can then react with a variety of electrophiles (eg. Me3SiCl, benzophenone,

CO2) to generate the α-functionalized product. This transformation is restricted to protected

145

amine substrates, as secondary or primary amines undergo deprotonation of the more acidic N–H

group over the desired C–H abstraction.

H N H PG 1) RLi, L PG N N low temperature N E L = + N N 2) E H − + s n ( )-Sparteine ( )-Sparteine R = Bu, Bu, iPr n Surrogate PG = Boc, Et, Bu, CH2CH2OMe, trimethylallyl

Scheme 5.1 Multiple-step organolithium-mediated α-deprotonation/functionalization methodology.

This transformation can be performed in an enantioselective fashion using chiral diamine

ligands. Initial developments focused on the use of (–)-sparteine as the chiral ligand (Scheme

5.1),336 however, a broad range of chiral diamine ligands have been examined349 and have allowed for significant extension of the α-lithiation methodology. One such ligand is the (+)-

sparteine surrogate which mediates improved enantioselectivity and, more importantly, addresses

the N-protected amine substrate scope limitations of preceding systems (Scheme 5.1).350 The majority of systems for the α-lithiation strategy are restricted to N-protected pyrrolidine substrates, and low yields are observed when the less reactive six-membered piperidines are used.330,351-354 This is attributed to the relatively lower reactivity of these larger ring substrates and a greater sensitivity to ligand sterics resulting in a negative impact on yield when ligand sterics are increased to improve enantioselectivity. In their 2010 report, Sanderson and co- workers described the use of sBuLi/(+)-sparteine surrogate in the first communication of enantioenriched 2-substituted piperidines produced in high yields.355 This methodology has since

been extended to piperazines and azepanes, albeit with lower yields.356 The substrate scope of the electrophile has also been expanded via a transmetallation strategy to give an organozinc

146

intermediate suitable for subsequent Negishi cross-coupling to produce 2-aryl substituted products (Scheme 5.2).337,357-360 It is only recently that Fu and co-workers extended the scope to secondary alkyl iodide and bromide electrophiles for the enantioconvergent synthesis of 2-alkyl

N-Boc-pyrrolidines (Scheme 5.2).361 The cross-coupling reaction of the α-zincated N-Boc-

pyrrolidine is catalyzed by NiCl2·DME with a chiral diamine ligand. Previous to this report only

dimethyl sulfate and methyl iodide were useful coupling partners for the alkylation

transformation.330 Currently, the substrate scope of the amine when using alkyl electrophiles

remains restricted to N-Boc-pyrrolidine.361

Boc RX N R = Pd catalyst R Aryl Boc 1) RLi, L Boc N low temperature N Zn Negishi coupling Boc 2) ZnCl2 or ZnI2 N R R = Alkyl proposed RX Ni catalyst, L*

Scheme 5.2 Organolithium-mediated α-deprotonation-transmetallation-Negishi coupling strategy.

While significant developments in the synthetic potential of these α-lithiation strategies have been achieved, this methodology is not without disadvantages. For example, this approach is only compatible with tertiary or protected amines, and the required protection and deprotection synthetic steps are costly. The α-deprotonation methodology is also a multiple-step procedure and generates stoichiometric amounts of lithium by-products, both of which are undesirable for application in large-scale synthesis.

147

5.1.3 Oxidative functionalization of α-C–H bonds

In their 2003 report, Murahashi and co-workers described the RuCl3-catalyzed oxidative

α-cyanation of tertiary amines, using hydrogen peroxide or oxygen as the stoichiometric

oxidant.362,363 While the majority of the substrates reported are acyclic tertiary amines, two

examples of cyclic substrates, N-phenylpiperidine and N-phenyltetrahydroisoquinoline have been

used successfully (Scheme 5.3).

CN Ph 2 2 R 5 mol% RuCl3 R Ph N CN H O or O N N AcOH/NaCN 2 2 2 N CN R1 MeOH R1 R3 R3 76% yield 69% yield

Scheme 5.3 Ruthenium catalyzed α-cyanation of tertiary amines.

Since this seminal report, the majority of transition-metal catalyzed oxidative C–H

functionalization methodologies have involved the use of less expensive copper catalysts.338-340

Developed initially by Li and co-workers, copper-catalyzed cross-dehydrogenative couplings require a tertiary amine, a copper salt (eg. CuBr, CuOTf), a stoichiometric oxidant (eg. tert- butylhydroperoxide), and a nucleophile (Scheme 5.4).331,340

Nu Ar Ar N H Nu catalyst [Cu] N tBuOOH

R HN O O R O O2N R H Nu = RO OR H H H H H

Scheme 5.4 Copper-catalyzed cross-dehydrogenative coupling reactions of tertiary amines.

148

While the initial report describes the use of terminal alkynes as the nucleophiles,364

subsequent investigations have extended the substrate scope to encompass indoles, nitroalkanes,

and malonates.338 Ketones are also compatible with this strategy though they require the addition

of a co-catalyst such as pyrrolidine. Unfortunately, the substrate scope of the amine partner

remains limited and as a result, studies have mainly focused on the functionalization of the

activated benzylic position of tertiary tetrahydroisoquinolines. Less harsh oxidants such as

oxygen or air have been employed,365 and a variety of metals including iron,366-369

ruthenium,362,363,370-373 gold,374 and vanadium375 have been investigated for this approach.

To date, the mechanism of this reaction has not been rigorously established. However, it

is proposed to proceed initially via single-electron transfer (SET) from the tertiary amine to form an amino radical-cation (Scheme 5.5).376 Oxidative α-C–H activation at the benzylic position

generates an iminium ion intermediate that can be trapped by the nucleophilic partner. These

iminium cations can also be generated in a separate step via electrochemical methods. This

“cation pool” approach consists of the generation of large concentration of N-acyliminium cations,343 which can be subsequently trapped by nucleophiles377 or electron deficient olefins.343

Nu R R R R N SET N -H+ N Nu-X N

Scheme 5.5 α-Functionalization via an iminium cation.

The one-step copper-catalyzed cross-dehydrogenative coupling methodology shows a

great deal of promise for the functionalization of α-C–H bonds of cyclic amines. However,

numerous limitations currently restrict the application of this procedure, including a very narrow

amine substrate scope, restricted to tertiary amines with activated C–H bonds. Additionally, 149

while progress has been made in the use of non-toxic and low cost molecular oxygen as the oxidant, stoichiometric amounts of tert-butylperoxide are required in most cases.

The oxidative functionalization of α-C–H bonds has also been achieved using a photocatalysis for the generation of the iminium cation intermediates.344 This was first

demonstrated by Stephenson and co-workers in 2010 using an iridium species as the

photocatalyst.378 Visible light is proposed to initiate a series of single-electron transfers which

result in the oxidation of the amine to an amino radical-cation (Scheme 5.6, top). An external

oxidant regenerates the photocatalyst and abstracts the α-hydrogen of the amino radical-cation to

generate the iminium ion. Trapping of the iminium cation with a nucleophile generates the α-

functionalized product. The use of radicophiles as trapping agents for α-amino radicals which

can be formed following deprotonation of the amino radical cations have also been reported,

initially by MacMillan and co-workers (Scheme 5.6, bottom).379,380 A series of metal-based

378-380 photocatalysts (eg. [Ir(ppy)2(dtbbpy)]PF6, [Ru(bpy)3](PF6)2) as well as organic

photosensitizers (eg. Rose Bengal)341-343 are competent for this transformation, although this methodology is currently restricted by the need for highly-functionalized coupling partners and tertiary amine substrates.

150

n+ P [O] light Photoredox [O] cycle iminium ion intermediate R Pn+ * P(n-1)+ R R R N H N H -H N NuH N Nu R ≠ H

+ -H R R1 R1 N EWG EWG R N

EWG R NC N

EWG α -amino radical intermediate

Scheme 5.6 Photoredox approach for the α-functionalization of tertiary amines via an iminium ion (top) or an α-amino radical cation (bottom).

5.1.4 Directed transition metal-catalyzed C–H activation

Ruthenium complexes have been successfully applied for the α-alkylation and arylation of heterocycles. This technique uses to advantage a heteroatom directing group for selective

oxidative addition of the α-C–H bond of the N-heterocycle (Scheme 5.7).347,348 These directing

groups (eg. 2-pyrrolinyl or 2-pyridinyl), are critical to the success of this reaction, but in turn

limit substrate scope for this approach once more to tertiary amine substrates.

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N N N bis- 0 Ar N Ar arylation N Ar [Ru] N

( )n ( )n ( )n

N N N = N or N 0 N Rull Ar N [Ru]

Ru3(CO)12 precatalyst ( )n ( )n n = 1 − 3 N

O N Rull H H B

O O ( )n Ar B O

Scheme 5.7 Directed ruthenium-catalyzed α-arylation of N-substituted heterocycles.

The first application of α-arylation is described in a report by Sames and co-workers

381 using Ru3(CO)12 and arylboronate esters as the coupling partner. Once more, the lessened

reactivity of piperidine when compared with pyrrolidine is noted, and only one example of

piperidine arylation is described with yields too low to be synthetically useful. Extension of this

reactivity to piperidines was accomplished by Maes and co-workers using 2-pyridinyl as a

352,382 directing group with Ru3(CO)12. In all cases a stoichiometric amount of a ketone or alcohol

additive is required for productive reactivity and, along with the use of boronate esters as the

coupling partner, results in stoichiometric amounts of waste. The high catalyst loadings required

(6 – 8 mol% Ru3(CO)12) are also costly. In cases where the amine substrate contains two α-CH2

positions selective mono-arylation cannot be achieved and a mixture of the mono-arylated and

bis-arylated products is obtained.383

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The heteroatom-directed C–H activation strategy has also been used for the α-alkylation of N-heterocyclic substrates using olefinic substrates. The initial report of α-alkylation by Murai

and co-workers details pyrrolidine alkylation (Scheme 5.8) to give a mixture of mono- and bis- alkylated products.384 A more recent report by Maes and co-workers describes how the addition of a catalytic amount of trans-1,2-cyclohexanedicarboxylic acid is necessary to achieve high conversions with the more challenging piperidine substrates.385

N N N 8 mol% Ru3(CO)12, CO R N iPrOH, 140 °C N N n = 1 − 3 R R R ( )n ( )n ( )n

Scheme 5.8 Directed ruthenium-catalyzed α-alkylation of N-substituted heterocycles.

The selective mono-alkylation of N-heterocycles using this methodology has not yet been achieved and the amine substrate scope remains restricted to tertiary amines. Two systems using the expensive late transition metals iridium386 and ruthenium387 have been reported for the α-

alkylation of secondary amines, however, these systems have not been extended to N-

heterocyclic substrates.

5.1.5 Hydroaminoalkylation of N-heterocycles with early transition metals

Hydroaminoalkylation is an atom-economic strategy for alkylation at the α-position of

unprotected secondary amines (Scheme 5.9).217 This strategy is very attractive as it uses simple,

readily available feedstocks and, unlike the methodologies discussed above, is compatible with

unprotected amine substrates. This avoids costly protection/deprotection sequences that generate

waste without adding molecular complexity. 153

H H N R2 N R2 1 H 1 R N R2 R3 catalyst R R1 R3 R3 H H H N N N R R catalyst R

Scheme 5.9 Intermolecular hydroaminoalkylation of alkenes with secondary amines.

The use of low cost, non-toxic early transition metal-based systems for this promising

new approach has been the recent focus of much research. These reports describe numerous

group 478,159,160,162,163,172,255 and 577,112,118,143-145,247,250,251,284 based catalyst systems for the efficient

preparation of secondary arylalkyl and dialkyl acyclic amines. However, it is notable that substrate scope investigations of such systems have repeatedly shown that N-heterocycles are particularly challenging substrates. The majority of reports, which detail successful reactivity with N-heterocycles, focus on the direct C–H functionalization of 1,2,3,4- tetrahydroquinoline.118,143,162,251 The challenge of cyclic dialkyl amine substrates has been

explicitly conceded in several catalyst development reports.77,78,144,162 Even catalytic systems that

display vastly expanded substrate scope in the olefinic substrate247 or show unprecedented

reactivity at room temperature249 are not compatible with N-heterocyclic substrates. This

difficulty with N-heterocyclic substrates is exemplified in a recent report by Doye and co- workers that discloses the reaction of pyrrolidine with styrene catalyzed by a titanium aminopyridinate complex.78 Even with forcing reaction conditions (96 h, 140 ºC) and high catalyst loading (20 mol%), the authors could only achieve a mixture of the regioisomers of the alkylated pyrrolidine product in 17% yield. The most promising system for these challenging

154

substrates has been reported by Schafer and co-workers and uses mono(amidate)

tetrakis(dimethylamido) tantalum precatalyst 2 to access the mono-alkylated piperidine product

in good yield with excellent selectivity (Scheme 5.10).118

O t H H Bu Ta(NMe2)4 N N n N 10 mol% 2 hexyl 2 3 n i i hexyl 134 h, 165 °C Pr Pr toluene 74% yield

Scheme 5.10 Hydroaminoalkylation of piperidine with mono(amidate) tetrakis(dimethylamido) tantalum precatalyst 2.

5.1.6 Scope of chapter

The focus of Chapter 5 is the investigation of the substrate scope for the α-alkylation of

N-heterocyclic amines using mono(amidate) tantalum complex 2. This involves the direct α-

alkylation of a variety of N-heterocycles including piperidines, piperazines, and azepanes. The α- alkylated products are formed with remarkable chemo-, regio-, and stereoselectivity, and the mechanistic rational for the observed selectivity is discussed. Section 5.2.2 describes a potential reason for the unprecedented reactivity of precatalyst 2 and guiding principles that should be

taken into account for subsequent catalyst development efforts. The observed reactivity

differences between five- and six-membered amine substrates are examined by both experimental and in silico approaches in Section 5.2.3 – 5.2.4.

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5.2 Results and discussion

5.2.1 The hydroaminoalkylation of N-heterocyclic substrates

Typically, pyrrolidines are preferred over piperidine substrates for direct C–H functionalization strategies (eg. α-lithiation methodologies,330 ruthenium catalyzed α-alkylation

and arylation352,381). Thus, the direct alkylation of a wide variety of larger N-heterocycles such as

piperidines is complementary to other established approaches and an important target. The

exploration of substrate scope in both the alkene and the amine partner builds upon the single

successful report of the α-alkylation of piperidine with 1-octene (Table 5.1, entry 1).118 Using 5

mol% 2, the internal alkene norbornene can undergo hydroaminoalkylation with piperidine

(entry 2), indicating that this strategy is not restricted to terminal olefins. Protected alcohols can

be incorporated into the alkene substrate, providing a site for further functionalization of the

resultant amine product and demonstrating good functional group tolerance for this oxophilic

tantalum complex (entry 3). Interestingly, a piperidine with a protected carbonyl substituent is

also compatible with this early transition metal catalyst (entry 4). With such functional group

tolerance established for 2, olefinic silyl ethers can be used for the α-alkylation of 1,2,3,4-

tetrahydroquinoline (entries 5, 6). This aryl alkyl amine substrate is more reactive, and resulted

in good yields at lower reaction temperatures (145 ºC). Impressively, larger heterocyclic rings

such as azepane can also be used (entry 7), though decreased diastereoselectivity is observed.

Related amine substrates such as morpholine and piperazine are not viable substrates; however,

the direct alkylation of N-substituted piperazines is possible (entries 8 – 12). Remarkably, this

reaction is tolerant to various substituents on the distal nitrogen, including p-methoxyphenyl and

benzhydryl, which allow for subsequent deprotection. Good yields are also obtained with both

alkyl and benzylic olefins (entries 11, 12). 156

Table 5.1 Hydroaminoalkylation of saturated N-heterocycles.

H H H N N 10 mol% 2 R R 165 °C X X 1.5-2 equiv. toluene

Entry Product (+/-)a t (h) Yield (%)b d.r.c H H N n 1 hexyl 143 76 >20:1

H H 2 N 72 79 >20:1

H H N O Ph d 3 ( )3 47 96 26 >20:1 Ph H H N n hexyl 4 69 59 >20:1 O O

H H e,f N OTBS 5 ( )3 165 64 >20:1 48

H H e,f N OTBS 6 ( )4 118 78 >20:1

H H N n 7 hexyl 72 60 10:1

8 H H R = Me 72 43 >20:1 N n hexyl 9 Ph 72 68 >20:1 N 10 R PMP 69 69 >20:1

H H n 11 N R = hexyl 72 46 >20:1 R

12 N Bn 72 84 >20:1 Bhyd aStereochemistry assigned by analogy to 47. bIsolated after N-tosylation. cDetermined by 1H NMR spectrum of isolated product. dReaction time was not optimized. eReaction run at 145 °C and isolated as the free amine. f5 mol% 2.

157

Interestingly, selective monoalkylation is observed under these rather forcing reaction

conditions, despite the presence of excess alkene. This is encouraging, as the directed α- alkylation of unactivated olefinic substrates using Ru3(CO)12 results in a mixture of mono- and

bis-alkylated products (Scheme 5.8).384 This selective monoalkylation can be rationalized based

upon the sensitivity of this catalyst system to steric bulk. For example, no reaction is observed

when using 2-methylpiperidine or 3-methylpiperidine and 1-octene with these reaction

conditions.

In all cases the regio- and diastereoselectivity of this transformation are excellent and

typically only one isomer is detected when monitoring the reaction by NMR spectroscopy. Based

upon the mechanistic proposal for hydroaminoalkylation (Scheme 5.11),118,144,145 excellent

selectivity is anticipated due to the proposed formation of metallacyclic intermediates. The regio-

and diastereoselectivity of the α-alkylation are established during the olefin insertion step of the

catalytic cycle, generating intermediate B. For the hydroaminoalkylation of N-heterocycles,

alkene insertion occurs in an orientation that positions the alkene R substituent away from the

steric bulk of the ligands on the tantalum metal center. This regioselective alkene insertion into

the strained metallaziridine intermediate, generating the branched regioisomer, has been

consistently observed for group 5 hydroaminoalkylation.77,112,118,143,144,250,251 Only one example in

a recent communication reports the generation of mixtures of linear and branched regioisomers

using styrene or trimethylvinylsilane as the olefinic substrate and mono(phosphoramidate)

tantalum complex 21.249

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NMe2 O = t [Ta] [Ta] Bu Ta(NMe2)2 NMe2 N H N iPr iPr

2 HNMe2

[Ta] N H H N A R R

N R [Ta] [Ta] H N H N R H N B

Scheme 5.11 Postulated mechanism for the tantalum-catalyzed hydroaminoalkylation of N-heterocycles.

The diastereoselectivity of this reaction arises from the approach of the alkene to the less hindered face of the tantalaziridine A. This selectivity proposal and the resultant diastereomer have been confirmed by X-ray crystallography, in which derivatization of the crude product of entry 3 with tosyl chloride generates a white solid 47 that can be recrystallized for rigorous analysis (Scheme 5.11). The solid-state molecular structure of 47 shows the formation of the anticipated diastereomer of the branched, monoalkylated product (Figure 5.2).

159

Ts H N O Ph

Figure 5.2 ORTEP representation of the solid-state molecular structure of compound 47. The ellipsoids are plotted at 50% probability and the majority of the hydrogen atoms are omitted for clarity.

As shown in Table 5.1, hydroaminoalkylation precatalyst 2 can be used to efficiently

prepare a variety of α-alkylated N-heterocycles. The functional group tolerance and excellent

selectivity displayed by this precatalyst suggests that interesting bicyclic or tricyclic N- heterocyclic products could be synthesized following the α-alkylation via further functionalization of the secondary amine moiety (Scheme 5.12). The products afforded from

1,2,3,4-tetrahydroquinoline are particularly attractive for these investigations as the presence of the chromophore aids in product isolation and purification via column chromatography.

( )n ( )n ( )n H H N X N N N ( )n H H H R N R

Scheme 5.12 Proposed synthesis of bicyclic and tricyclic compounds following α-alkylation of an N- heterocyclic amine.

One approach that has been investigated utilizes an olefin containing a silyl protected

alcohol, which, after α-alkylation, could be converted into a suitable leaving group for

nucleophilic substitution and ring closure. A recently developed method of Gembus and co-

160

workers describes the one-pot conversion silyl ethers to tosylates using diazabicycloundecene

(DBU) and tosyl fluoride.388 This methodology has been extended by Dr. Pierre Garcia of the

Schafer group to a one-pot methodology for the synthesis of β-substituted N-heterocycles

following hydroaminoalkylation of acyclic N-arylamine substrates with olefins containing silyl

protected alcohols (Scheme 5.13, top).284 The analogous reaction conditions have been examined

using 1,2,3,4-tetrahydroquinoline and tert-butyldimethyl(pent-4-en-1-yloxy)silane, which are a successful substrate combination for hydroaminoalkylation (entry 5, Table 5.1). Unfortunately, the ring-closure step has not been successful, though monitoring by 1H NMR spectroscopy confirms that α-alkylation reaches full conversion. Attempts at applying a multiple-step approach consisting of hydroaminoalkylation to produce 48 (entry 5, Table 5.1), deprotection and

purification of the intermediate alcohol, followed by derivitization with mesyl or tosyl chloride

and heating to promote ring closure have also not been productive.

H TBSO N ( )n Ar 5 mol% 2 H TsF, DBU ( )n + N N 130 °C Ar 130 °C OTBS toluene toluene Ar ( )n n = 1-3

H N 1) 5 mol% 2 165 145 °C + OTBS h, N ( )3 2) TsF, DBU 48 h, 130 °C

H H N OTBS N OH or ( )3 TBAF, AcOH ( )3 MsCl TsCl N 1:1 H2O:THF toluene, reflux 2 h, 25 °C 48, Table 5.1 90% yield

Scheme 5.13 α-Alkylation and ring-closure methodology using N-arylalkyl amines (top)284 and attempts at the analogous methodology with 1,2,3,4-tetrahydroquinoline.

161

Transformation of the alcohol to the aldehyde followed by reductive amination is another

potential approach; however, oxidation of the alcohol without decomposition of the product

could not be achieved. A piperidine with a protected carbonyl substituent has been shown to be

compatible with the reaction conditions (entry 4, Table 5.1), and therefore acetal olefin 49 could

be a potential candidate for this reaction, as this would generate the desired aldehyde moiety

desired upon deprotection. Unfortunately, the hydroaminoalkylation reactions using piperidine

and 1,2,3,4-tetrahydroquinoline amine substrates have not been successful. Thermal stability

studies indicate that the lack of reactivity is due to decomposition of the olefinic substrate in the

presence of tantalum precatalyst 2 at elevated temperatures.

H H N N OEt OEt 5 mol% 2 48 h, 165 °C OEt 49 OEt toluene

Scheme 5.14 Hydroaminoalkylation with olefin substrate containing a protected carbonyl moiety.

Precatalyst 2 has previously been shown to selective for the monoalkylation of diene

substrates.118 Therefore, a tandem hydroaminoalkylation/hydroamination methodology could

potentially be used to generate the cyclic compounds. Indeed, the α-alkylation of p-methoxy-N-

methylaniline can be selectively achieved to generate the aminoalkene intermediate.

Unfortunately, both one-pot or multiple-step procedures for the cyclization of this substrate using

precatalyst 4 have not been effective (Scheme 5.15).

162

H iPr N N 2 O NMe2 10 mol% 4 N MeO 10 mol% 2 H ° Zr NMe2 40 h, 130 C N 48 130 °C N N Ar h, Ar O i HNMe2 Pr2N 4

Scheme 5.15 Attempted hydroaminoalkylation-hydroamination procedure catalyzed by tantalum and zirconium precatalysts, respectively.

5.2.2 Urea proligands for the hydroaminoalkylation of N-heterocycles

The substrate scope described in Table 5.1 demonstrates the potential of this methodology for the late-stage synthesis of a variety of N-heterocyclic compounds from readily available olefin starting materials without the need for protecting or directing groups. One intriguing element of this methodology is that this reactivity is unique to precatalyst 2. No other reported system is capable of the α-alkylation of piperidine, piperazine, or azepane substrates despite a great deal of catalyst development.77,112,143,144,160,172,247 This achievement highlights the

uniqueness of the amidate ligand, and indicates that the asymmetric binding of the mixed (N,O)-

ligand system and the potential for hemi-lability could be the source of this vastly expanded

substrate scope accessible by precatalyst 2 above all other (O,O)-77 and (N,N)-supported catalytic systems.78

If the asymmetric binding and the potential for hemi-lability is critical for this reactivity, then other (N,O)-chelating ligands may be suitable for the α-alkylation of N-heterocycles. To test this proposal, two urea proligands have been investigated as supporting ligands for tantalum precatalysts, 50 and 8 (Scheme 5.16). These in situ formed catalyst systems are indeed successful at promoting the α-alkylation of piperidine under analogous reaction conditions as those used

163

with 2. Gratifyingly, the chiral proligand 8 even mediates the enantioselective α-alkylation of

this six-membered heterocycle with 21% ee.389 This is the only example of enantioselective hydroaminoalkylation mediated by a non-C2-symmetric ligand system, and highlights an avenue

worthy of further research.

H N O 1) 5 mol% 50 or 8 Ts H 5 mol% Ta(NMe2)5 N n N N 143 h, 165 °C, toluene hexyl H 2) TsCl, 2M NaOH (+/-) 50 50: O n 82% yield 1.5 hexyl d.r. > 20:1 CyN NH 8: 68% yield, 21% ee d.r. > 20:1 iPr 8

Scheme 5.16 α-Alkylation of piperidine catalyzed by in situ generated tantalum ureate complexes.

5.2.3 Attempted α-alkylation with pyrrolidine and indoline

Despite the unprecedented reactivity with six and seven-membered N-heterocycles,

efforts to directly alkylate five-membered substrates such as pyrrolidine and indoline have not

been successful thus far. This is particularly surprising because pyrrolidines are typically

preferred over piperidine substrates for α-lithiation strategies and ruthenium catalyzed α-

alkylation.334,352,353,385 Indoline, which as an aryl alkyl amine substrate is expected to be more

reactive than pyrrolidine, does not undergo any α-alkylation reactivity. In fact, upon addition of

the amine to a solution of 2, a precipitate is observed concurrent with a dramatic colour change

of the solution from pale yellow to bright red-orange (Scheme 5.17).

164

O N t H Bu Ta(NMe2)4 N N N Ta N 10 <30 s, 25 °C N iPr iPr toluene N 2 51

Scheme 5.17 Homoleptic tantalum species 51 produced from reaction of 2 with indoline.

Filtration of the bright red-orange reaction mixture removes the amide proligand and

recrystallization from a mixture of pentane and benzene at room temperature yields red-orange crystals suitable for X-ray crystallographic studies (Figure 5.3).

N1 Ta N5 N3

Figure 5.3 ORTEP depiction of the solid-state molecular structure of complex 51. The asymmetric unit contains a disordered indoline molecule which has been successfully modeled. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

The solid-state molecular structure depicts the homoleptic indolinyl complex 51, which

adopts a trigonal bipyramidal geometry in the solid state with a disordered indoline molecule

present in the asymmetric unit. The Ta–N bond lengths are all consistent with Ta–N double

165

bonds and show shorter averaged bond lengths in the equatorial plane (2.001 Å) compared with

the axial bond lengths (2.065 Å). The five-membered pyrrolidine portion of the indoline ligand adopts a slightly puckered conformation and has an average CH2–CH2 bond length of 1.539 Å.

While catalyst decomposition is occurring in the presence of excess indoline, the reason

for the lack of reactivity with pyrrolidine is not immediately evident. Upon addition of

pyrrolidine to a solution of the precatalyst the significant colour change and formation of a precipitate which occurs with indoline are not observed. When pyrrolidine is subjected to analogous conditions as those in Table 5.1, derivatization of the reaction mixture yields quantitative isolation of the tosylated pyrrolidine substrate (Scheme 5.18). This indicates that analogous catalyst decomposition to a homoleptic pyrrolidinyl species is most likely not the source of the lack of reactivity observed.

Ts H 1) 5 mol% 2 N 48 h, 165 °C, toluene N 1.5 n hexyl 2) TsCl, 2M NaOH Quantitative

Scheme 5.18 No hydroaminoalkylation reactivity observed with pyrrolidine.

Comparison of basic parameters for pyrrolidine and piperidine does not provide a clear

rationale; the reported α-C–H bond dissociation energies are similar for piperidine (92 kcal/mol)

and pyrrolidine (90 kcal/mol).390 Indeed, with a smaller bond dissociation energy pyrrolidine is

more likely to be the reactive substrate, consistent with trends observed for other α- functionalization approaches. The pKa’s of the conjugate acids in water are essentially analogous

for piperidine and pyrrolidine (11.22 and 11.27 respectively),390 therefore providing no further

insight. Since the examination of basic metrical parameters of these substrates does not provide a

166

plausible explanation, preliminary in silico experiments were performed in collaboration with

Dr. J.M. Lauzon to investigate the lack of reactivity with pyrrolidine.

5.2.4 Computational modeling of the catalytic cycles for the α-alkylation of amines

5.2.4.1 Previous investigation into the hydroaminoalkylation of acyclic amines

In silico experiments using density functional theory (DFT) have been performed for the

2-catalyzed intermolecular α-alkylation of dimethylamine and N-methylaniline by Dr. J.M.

Lauzon of the Schafer group.146 This investigation probes each stage of the catalytic cycle,

detailing the formation of the catalytically active tantalaziridine, insertion of 1-octene into the

Ta–C bond, protonolysis of the expanded metallacycle by incoming amine, and subsequent C–H

activation to reform the tantalaziridine (Scheme 5.19).146

167

‡ R = O [Ta] Ta(NMe2)2 n [Ta] R = hexyl NMe2 O O N R O R R N O = tBu Ta [Ta] N iPr N N N R O 26.7 N N [Ta] NMe2 iPr N N 0.0 12.3 8.4

Me ‡ Ph N H O [Ta] H R Ph H N N R N Ph N O N O Ph [Ta] [Ta] R H O 42.2 N N N N N Ph [Ta] N N 8.4 20.6 0.2 R

Ph ‡ N CH O 2 [Ta] H N N Ph H Ph N NMe2 Ph N O R O N R O N [Ta] [Ta] Ta 50.3 H N N N N N H NMe2 N R 5.5 16.3 1.3 R R

These calculations describe both the optimized geometries of the intermediates and the transition states as well as the potential energy surface. Two key findings from this study are that reactivity occurring in the plane of the amidate ligand is consistently the lowest energy pathway, and that the hemi-lability of the amidate ligand is critical, as a change in binding mode, κ2-(N,O) 168

to κ1-(O), is observed at various stages during the catalytic cycle.146 These previously optimized intermediates and transitions states are ideal starting coordinates for the modeling of the α- alkylation of pyrrolidine and piperidine with 1-octene.

5.2.4.2 Computational investigations with N-heterocyclic substrates

A detailed examination of the catalytic cycle for the intermolecular α-alkylation of secondary amines with group 5 catalytic systems highlights potential intermediates to examine in silico (Scheme 5.20). Initial catalyst activation occurs with the dimethylamido ligands of tantalum precursor 2 in which C–H activation generates the active tantalaziridine I and produces an equivalent of dimethylamine. Insertion of the 1-octene occurs to generate the expanded metallacycle II, followed by protonolysis of the Ta–C bond by an incoming amine substrate

(piperidine or pyrrolidine) to generate the bis(amido) species III. Subsequent α-C–H activation generates the protonated amine by-product and, following de-coordination, the new bicyclic tantalaziridine V. Generation of these tantalum intermediates (V) has been selected as the step for further scrutiny as it is plausible that formation of the strained [2.5]-bicyclic tantalum intermediate with pyrrolidine could be energetically disfavoured (Scheme 5.21).

169

[Ta] = TaL(NMe2)2 NMe2 O [Ta] L = tBu NMe2 iPr N

i HNMe2 Pr

n [Ta] R = hexyl N n = 1, 2 R I ( )n catalyst activation [Ta] N H ( )n N R R H N N R II III [Ta] [Ta] IV N N R ( )n [Ta] H H N N N H V R

( )n ( )n R N-heterocyclic substrate

( )n R N H [Ta] VII VI [Ta] N ( )n N H

( )n H R N

( )n

Scheme 5.20 Simplified catalyst activation via hydroaminoalkylation of a dimethylamido ligand (I – III, left) and proposed mechanistic cycle with N-heterocyclic substrates (IV – VI, right).

170

( )n ‡

N O [Ta] H ( )n N N N R O N O N H R O N

[Ta] [Ta] ( )n [Ta] ( )n n = 1, pyrrolidine N N N N N 2, piperidine N H R R H R

IIIpyrr 0.0 TSpyrr(III/IV) 60.6 IVpyrr 26.1 Vpyrr 7.9 III IV V pip 0.0 TSpip(III/IV) 56.3 pip 18.0 pip 6.0

Scheme 5.21 Summary of calculated intermediates and the transition state for the C–H activation of pyrrolidine (pyrr) and piperidine (pip) to form tantalaziridines V. Relative free energies (∆G) are reported in kcal/mol.

The initial input coordinates for the calculations are based on the previously modeled system using dimethylamine/N-methylaniline as the substrates (Scheme 5.19, bottom);146 the substrate is then replaced with piperidine or pyrrolidine and optimized using density functional theory. A corresponding transition state has been found for each N-heterocyclic substrate (Figure

5.4) and, analogous to previous calculations with the acyclic systems,146 the negative vibrational mode corresponds to the transfer of a proton in the equatorial plane from the α-C–H of the heterocyclic substrate to the nitrogen of the dimethylamine product. The transition states for piperidine and pyrrolidine are essentially isostructural, regardless of the identity of the substrate.

The activation barriers (∆G≠) for this transformation are 60.6 and 56.3 kcal/mol for pyrrolidine and piperidine, respectively at 165 ºC in toluene. Gratifyingly, the activation barrier for the pyrrolidine system is 4.3 kcal/mol higher than the activation barrier for piperidine. This indicates that formation of the metallaziridine might be unfavourable. These activation barriers are significantly higher than those calculated for N-methylaniline (44.8 kcal/mol at 110 ºC in 171

toluene),146 which is consistent with experimental evidence that these cyclic dialkyl substrates are much less reactive than the acyclic substrates.

( )n ‡

N O [Ta] H N N R

TSpyrr(III/IV) TSpip(III/IV)

Figure 5.4 Optimized geometry for transition state TS(III/IV) for the pyrrolidine and piperidine substrates. The majority of the hydrogen atoms are omitted for clarity.

Relaxation of the transition states yield bis(amido) intermediates (III, Figure 5.5 top) as

well as metallaziridine intermediates with the bound neutral product (IV, Figure 5.5 bottom) as proposed. Once again, the geometries for both these intermediates are almost identical irrespective of the nature of the N-heterocyclic substrate. In both bis(amido) intermediates

(IIIpyrr and IIIpip), the N-heterocyclic substrate, the α-alkylated product, and the amidate ligand

all occupy the equatorial plane while the ancillary dimethylamido ligands occupy the axial

positions of these pseudo-octahedral complexes. This is once more consistent with the geometry

observed with the acyclic dimethylamine and N-methylaniline substrates.146 This is also the case

for the metallaziridine intermediates IVpyrr and IVpip; once again there is very little difference in

the geometries of these complexes and in both cases the ancillary dimethylamido ligands occupy

the axial positions, with the neutral bound product, the amidate ligand, and the tantalaziridine

located in the equatorial plane. This preference for reactivity in the equatorial plane was consistently observed in the calculations of the acyclic substrates, with axial reactivity

unfailingly resulting in higher energy intermediates.146

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( )n O N [Ta] N N R

IIIpyrr IIIpip

O N [Ta] ( )n N N H R

IVpy IVpip

Figure 5.5 Optimized geometry for the bis(amido) intermediates IIIpyrr and IIIpip (top) and the metallaziridine intermediates IVpyrr and IVpip containing the neutral-bound α-alkylated product (bottom). The majority of the hydrogen atoms are omitted for clarity.

Removal of the neutral bound α-alkylated product followed by geometry optimization results in the formation of two tantalaziridine complexes (Vpyrr and Vpip) with remarkably different geometries (Figure 5.6). When the tantalaziridine is formed with the piperidine substrate, the geometry observed is consistent with that of the previously modeled systems146 and the tantalaziridine moiety occupies the equatorial plane with the dimethylamine ligands distorted from the idealized octahedral geometry. However, when pyrrolidine is used as the substrate, the tantalaziridine is formed in a pseudo-axial position. This is indeed the lower energy configuration and attempts to access a more equatorial geometry by using the output coordinates of the Vpip geometry optimization results in isomerization to the pseudo-axial position. This indicates that insertion of the olefin would have to occur in the pseudo-axial position, a pathway 173

that has been shown to be much higher in energy.146 Therefore, olefin insertion for the five-

membered substrates might not be feasible, potentially explaining why pyrrolidine is not a

productive substrate for the hydroaminoalkylation of secondary amines with complex 2.

N NMe2 O O N Ta Ta N NMe2 N NMe2 NMe2

V V pyrr pip

Figure 5.6 Optimized geometry for the tantalaziridine intermediates Vpyrr and Vpip. The hydrogen atoms are omitted for clarity.

The potential energy surface for the modeled steps is shown in Figure 5.7. The overall

shape of the surface is similar for both N-heterocyclic substrates, though pyrrolidine has a higher activation barrier (60.6 kcal/mol) compared with the α-C–H activation of piperidine (56.3 kcal/mol).

174

70.0 ‡ ( )n 5 NH N membered O 60.6 n = 1 60.0 [Ta] H N N

6 NH R 56.3 membered 50.0 TS(III/IIV) n = 2 O N [Ta] ( )n 40.0 N IV N G (kcal/mol) H R Δ 30.0 26.1 N O ( )n 20.0 [Ta] Relative O N N 18.0 V [Ta] pyrr 10.0 N N 7.9 III R 6.0 0.0 0.0 O N [Ta] MP2/6-31G**//B3LYP/6-31G** N V pip

Figure 5.7 Potential energy surface for the formation of the tantalaziridine intermediates V from the bis(amido) tantalum complexes III.

The in silico examination of the formation of the tantalaziridine highlights two possible

explanations for the lack of reactivity observed with five-membered substrates: formation of the

active tantalaziridine might not be possible due to the large activation barrier, or insertion of the

olefin might be unfavourable due to the axial position of the tantalaziridine. In an attempt to

determine which explanation is more plausible, deuterium labeling experiments have been

performed to probe the formation of the tantalaziridine.

5.2.4.3 Deuterium labeling

Deuterated amine substrates have been used previously by Nugent and co-workers along with early transition metal homoleptic dimethylamido precatalysts to examine the reversible

175

metalation of the amido ligands at high temperatures (Scheme 5.22, top).145 This deuteration

reaction is proposed to occur via deuteration of the M–C bond of a metallaziridine intermediate.

Based on these results, an analogous experiment could be used to probe the C–H activation step

with the goal of determining whether tantalaziridine formation is occurring with the pyrrolidine

substrate (Scheme 5.22, bottom). Piperidine, which has been shown to be successful for

hydroaminoalkylation with 2, is an ideal control substrate for these experiments. If formation of

the tantalaziridine is occurring under the catalytically relevant reaction conditions (165 ºC) then

deuteration by an N-deuterium labeled substrate would result in partial deuteration of the α-

position of the N-heterocyclic substrate. This reaction could be monitored by 2H NMR spectroscopy and, since primary isotope shifts between 1H and 2H are typically less than 0.1

ppm,391-393 the chemical shifts of the deuterium signals can be directly compared to the 1H NMR

spectra.

D D M(NMe2)n N N H3C CH3 H3C CH2D

≠ ( )n D H/D N ~5 2 N N mol% O 7 165 ° C(H/D)2 via d, C, [Ta] D ( )n toluene ( )n N n = 1,2 N

( )n

Scheme 5.22 Deuterium scrambling experiment reported with dimethylamine (top) and proposed experiment with N-heterocyclic amines (bottom).

N-deuterated pyrrolidine and piperidine have been synthesized via washing of the parent

amine with D2O and rigorously dried using BaO and molecular sieves. Deuterium incorporation

has been confirmed for piperidine and pyrrolidine by the complete lack of N–H resonances in the 176

1H NMR spectra and a corresponding N–D signal at δ 0.74 (piperidine) and 0.81 (pyrrolidine) ppm in the 2H NMR spectra. After heating a toluene solution of the deuterated piperidine and 5 mol% 2 to 165 ºC for 143 hours (Scheme 5.23), the 2H spectrum contains two resonances at δ

2.60 and 2.21 ppm corresponding to α-deuterated piperidine and dimethylamine, respectively

(Appendix B). This is consistent with successful formation of the tantalaziridine with piperidine after activation and deuteration of the dimethylamido ligand of precatalyst 2 (Scheme 5.20).

Quantitative values for the percentage of deuterium incorporation could not be obtained due to messy baseline (isopropanol CH3 signals of the tantalum species in solution) around the α-H resonance in the 1H NMR spectrum. The volatility of the products made isolation difficult, and therefore these experiments are at present strictly qualitative.

D H N ~5 mol% 2 N H N 7 d, 165 °C, toluene

= New sites of deuterium incorporation

Scheme 5.23 Sites of deuterium incorporation for piperidine and pyrrolidine substrates.

When pyrrolidine is used as the substrate the 2H spectrum once again contains resonances at δ 2.65 and 2.21 ppm corresponding to α-deuterated pyrrolidine and dimethylamine compounds respectively (Scheme 5.23). The formation of the tantalaziridine and subsequent deuteration with pyrrolidine does appear qualitatively to be slower, as after 143 hours there still exists significant amount of the N-deuterated pyrrolidine in solution, while with piperidine only residual amounts

177

remain. Therefore, tantalaziridine formation with the five-membered substrate is occurring under

catalytic conditions and olefin insertion, with the tantalaziridine in the axial position, is most

likely the non-productive step with the five-membered substrates.

One notable difference between the piperidine and pyrrolidine substrates is a significant

amount of deuterium incorporation at a different position revealed by a large 2H resonance at δ

1.42 ppm when pyrrolidine is used. This signal is consistent with deuteration occurring at the β-

position of the pyrrolidine substrate. This β-deuteration is intriguing, and could potentially be

harnessed for β-alkylation reactivity. While the mechanism of this β-activation is not readily

apparent for this tantalum precatalyst system, this has been observed by Baudoin and co-workers

using palladium catalysis in their studies on the β-arylation of N-Boc piperidines.394 The authors

determined that the selectivity for β-arylation (over α-arylation) is induced by the choice of

ligand and restricted to piperidine substrates; pyrrolidine and azepane substrates undergo α-

arylation selectively. Following an extensive computational investigation into a potential

mechanism the authors proposed the formation of an allylamine intermediate via β-hydride elimination and migratory insertion (Scheme 5.24).

Ph L L H α-Arylation L Pd O Pd Ph H Pd Ph N OtBu NBoc NBoc i N P( Pr)2 L = L L Ph Pd O Ph Pd H β H -Arylation N t O Bu NBoc

Scheme 5.24 Calculated intermediates leading to α- or β-arylation reported by Baudoin and co- workers.394

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This type of β-hydride elimination is not likely to be occurring with these d0 tantalum

centers. However, close examination of intermediate Vpyr, which has been optimized during the

in silico experiments, indicates a close distance of 2.88 Å for one β-hydrogen to a dimethylamido

ligand and provides insight into a potential mechanism for β-C–H activation (Scheme 5.25). The

395 tantalaziridine Vpyrr is one of two limiting resonance structures for these compounds; the other

being an η2-imine tantalum(III) complex in which the metal center is interacting with the π-

system of the C–N double bond. Deprotonation of the β-hydrogen by the nearby dimethylamido ligand would generate an allylamine intermediate which, following neutral ligand exchange, could undergo deuteration to regenerate the tantalaziridine. The closest distance of a β-hydrogen to a dimethylamido ligand in the case of the piperidine is 3.01 Å, which is further away than in the pyrrolidine case consistent with the lack of β-deuteration observed when piperidine is used.

Me2N Me2N Me2N N NMe2 N NMe2 N NHMe2 V III β-H abstraction III Ta H Ta H Ta O O O N N H N H

Tantalaziridine η2-Imine complex D N HNMe2 +

2.88 Å Me2N Me2N N N N N D TaV D TaIII O O N H N V pyrr

Scheme 5.25 Potential mechanism for the β-deuteration observed and the optimized geometry for Vpyrr with the shortest dimethylamido–β-hydrogen distance indicated. The majority of the hydrogen atoms are omitted for clarity.

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5.3 Conclusions

The ability of 2 to catalyze the hydroaminoalkylation of challenging N-heterocyclic

substrates has been examined. This catalytic system is successful at promoting the α- alkylation

of unprotected piperidine, piperazine, and azepane substrates with a variety of simple unactivated

olefin substrates. These reactions proceed in the presence of oxygen-containing functional

groups, such as ketals or silyl-protected alcohols, establishing good functional group tolerance

for this hard oxophilic d0 tantalum metal center. These reactions proceed with exclusive

regioselectivity and excellent diastereoselectivity. These selectivity observations are consistent with the proposed mechanism proceeding via a tantalaziridine bicyclic intermediate.

Precatalyst 2 is the only system that catalyzes the α-alkylation of these challenging cyclic

dialkyl substrates. This unmatched reactivity is attributed to the asymmetric binding mode of the

N,O-chelated amidate ligand and the potential for hemilability. Other N,O-chelated supported

systems incorporating ureate ligands were shown to successfully catalyze the α-alkylation of

piperidine with comparable reactivity to complex 2. Interestingly the chiral ureate ligand

employed is successful in mediating the enantioselective hydroaminoalkylation of piperidine

with 1-octene with 21% ee. This is the first example of enantioselective hydroaminoalkylation of

piperidine catalyzed by non biaryl-based bis(chelating) ligands.

Interestingly, five-membered N-heterocycles are not productive substrates with this

catalytic system. Quantum chemical calculations have been performed to elucidate a potential

explanation for this lack of reactivity. These calculations detail intermediates and transition

states relevant to the formation of the tantalaziridine. The activation barrier for the formation of

the tantalaziridine with the pyrrolidine has been found to be 4.3 kcal/mol higher than the

activation barrier with the piperidine substrate. Supplemental deuterium experiments using N- 180

deuterated piperidine and pyrrolidine substrates further probed the formation of the

tantalaziridines. The α-deuteration of the substrate has been observed in both cases, indicating

that tantalaziridine formation, followed by deuteration with an incoming deuterated substrate is

occurring with both substrates. This indicates that, despite the higher activation barrier,

formation of the tantalaziridine with pyrrolidine is occurring, and this is most likely not the

primary reason for the lack of reactivity.

The located optimized geometries for the calculated transitions state and intermediates

are, for the most part, analogous regardless of the identity of the N-heterocycle (piperidine, pyrrolidine or previously calculated acyclic substrates146). The only remarkable difference was in

the optimized geometry of the final tantalaziridine. When piperidine is the substrate examined,

the bicyclic tantalaziridine is formed in the equatorial plane, while the tantalaziridine with

pyrrolidine exists in a pseudo-axial position. Previous calculations have consistently shown that

reactivity in the axial position is a much higher in energy pathway. These in silico and

experimental results suggest that olefin insertion may be inhibited with the five-membered

substrates, preventing productive reactivity.

These studies highlight critical features for future catalyst design as well as provide

insight into reactivity trends and substrate scope limitations. In particular, the use of asymmetric

(N,O)-chelating ligands is essential for the hydroaminoalkylation of challenging substrates such as N-heterocyclic amines. Judicious choice of the sterics and electronics of the amidate or ureate ligands is necessary to ensure that the active tantalaziridine formed is in the equatorial plane, which is most likely essential for accessing productive olefin insertion.

181

5.4 Experimental

General materials and methods are outlined in Section 2.4.1.

5.4.1 Materials

The following compounds were synthesized as reported in the literature: tert-butyldi-

methyl(pent-4-enyloxy)silane,396 tert-butyl(hex-5-enyloxy)dimethylsilane,396 ((pent-4-en-1-

yloxy)methylene)dibenzene,397 mono(N-(2,6-diisopropylphenyl)pivalamidate)

tetrakis(dimethylamido)tantalum, 2.118 All commercial amines and olefins for catalytic reactions

were distilled under reduced pressure from CaH2 and degassed by 3 freeze-pump-thaw cycles or

sublimed in the case of solids. Ta(NMe2)5 was purchased from Strem and used as received.

5.4.2 General experimental procedures

NMR-tube scale α-alkylation of N-heterocycles catalyzed by 2 (GP1): Complex 2 was

weighed in a small vial and the specified amount of solvent was added. The solution was

transferred to a J. Young NMR tube equipped a Teflon cap and the olefin followed by the amine

substrates were added sequentially by means of a μL-pipette. The NMR tube was closed, shaken, and 1H NMR spectrum was recorded. The NMR tube was placed in a preheated oil bath (165 ºC)

for the given time. The conversion was monitored by NMR spectroscopy. After the reaction was

complete, the contents of the tube were poured into a small vial, diluted with DCM and TsCl followed by 2M aqueous NaOH were added. After stirring at ambient temperature the reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were

dried over Na2SO4, filtered, and the solvent evaporated on a rotary evaporator.

182

Schlenk-tube scale α-alkylation of N-heterocycles catalyzed by 2 (GP2): Same procedure as

GP1, except a Schlenk-tube equipped with a Teflon cap and a magnetic stir bar were used instead of the J. Young NMR tube because of the larger scale of the reaction.

In situ mono(ureate) tetrakis(dimthylamido) tantalum catalyzed α-alkylation of N- heterocycles (GP3): Ta(NMe2)5 (10.0 mg, 0.025 mmol) and the urea proligand (0.025 mmol) were weighed in a small vial and 0.5 g of d8-toluene was added. After gentle shaking of the vial

for 5 minutes all of the proligand had dissolved and the solution changed from pale yellow to

orange. 1-octene (84.2 mg, 0.75 mmol) and piperidine (42.6 mg, 0.5 mmol) were then added and the solution was transferred to a J. Young NMR tube equipped a Teflon cap. The NMR tube was

closed, shaken, and 1H NMR spectrum was recorded. The NMR tube was placed in a preheated

oil bath (165 ºC) for 96 h.

The enantiomeric excess was determined using SFC analysis (TharSFC with a UV/VIS

detector, λ = 200 – 215 nm) of the tosylated amine product. The racemic product mixture obtained using N-(2,6-dimethylphenyl)piperidine-1-carboxamide as the proligand was used for

the method optimization. SFC analysis (AS-H column, 3% 2-propanol as modifier, 1.00 mL/min, major isomer tR 51.3 min, minor isomer tR 41.1 min) indicated an ee of 21%. The SFC traces are

included in Appendix C.

5.4.3 Synthesis and characterization

2-(bicyclo[2.2.1]heptan-2-yl)-1-(phenylsulfonyl)piperidine: Prepared Ts H N following GP2 using norbornene (300 mg, 3.19 mmol), piperidine (99 μL, (+/-)

183

1.00 mmol), and complex 2 (63.0 mg, 0.10 mmol) in toluene (0.510 g) at 165 °C for 72 h.

Derivitization with TsCl (300 mg, 1.57 mmol) and 2M aqueous NaOH (1.5 mL) in DCM (3 mL).

Flash chromatography (silica gel F60, hexanes/EtOAc + 1% NEt3 15:1) gave the title compound

1 as a clear, thick, colorless oil. Yield: 0.264 mg, 79%. H NMR (C6D6, 400 MHz) δ 0.93-1.31 (m,

9H, CH2), 1.44-1.53 (m, 5H, CH2), 1.76-1.82 (m, 1H, NCHCH), 1.91 (app s, 1H, CHbridge), 2.21

(app s, 1H, CHbridge), 2.37 (s, 3H, CH3 ), 2.83-2.95 (m, 1H, NCH2), 3.53 (m, 1H, NCH), 3.73 (m,

3 3 13 1H, NCH2), 7.23 (d, JH,H = 8.07 Hz, d, CHTs), 7.68 (d, JH,H = 8.22 Hz, 2H, CHTs.); C NMR

(C6D6, 100 MHz) δ 18.4 (CH2), 21.3 (CH3), 23.5 (CH2), 26.1 (CH2), 28.8 (CH2), 30.2 (CH2),

34.1 (CH2), 35.3 (CH2), 36.7 (CH), 39.5 (CH), 40.6 (NCHCH), 41.2 (NCH2), 56.9 (NCH), 126.9

(CHTs,), 129.5 (CHTs), 139.4 (CTs), 142.6 (CTs); Anal. Calcd. for C19H27NO2S: C, 68.43; H, 8.16;

N, 4.20; Found: C, 68.27; H, 8.13; N, 4.32.

2-(5-(benzhydryloxy)pentan-2-yl)-1-tosylpiperidine, 47: Prepared Ts H N O Ph

following a modified GP1, using ((pent-4-en-1- (+/-) Ph yloxy)methylene)dibenzene (238 mg, 0.939 mmol), complex 2 (30 mg, 0.049 mmol), and

piperidine (49.5 μL, 0.500 mmol) in d8-toluene (500 μL), at 165 °C for 96 h. Derivitization with

TsCl (101 mg, 0.529 mmol) and 1M aqueous NaOH (3 mL) in DCM (~5 mL). After stirring at

ambient temperature the reaction mixture was diluted with H2O and extracted with EtOAc. The

combined organic phases were washed with 1M sodium hydroxide solution (10 mL), water

(2x10 mL), and brine solution (3x10 mL), dried over MgSO4, and concentrated by rotary

evaporation. Flash chromatography (silica gel F60, hexanes/EtOAc + 1% NEt3 15:1 → 6:1)

followed by sublimation at 95 °C under reduced pressure yielded the title compound as a white

powder. Yield: 120 mg, 26%. Crystals suitable for analysis by X-Ray diffraction were grown 184

1 3 from ethyl acetate. H NMR (d1-chloroform, 600 MHz) δ 0.94 (d, JH,H = 7.2 Hz, 3H, CHCH3),

1.08-1.19 (m, 2H, CH2), 1.20-1.27 (m, 1H, NCHCH2), 1.34-1.44 (m, 3H, CH2), 1.50-1.56 (m,

1H, CH2), 1.57-1.64 (m, 1H, CH2), 1.68 (br d, 1H, NCHCH2), 1.74-1.80 (m, 1H, CH2), 1.94-1.98

(m, 1H, CHCH3), 2.43 (s, 3H, CTsCH3), 2.91-2.96 (m, 1H, NCH2CH2), 3.45 (m, 2H, CH2O), 3.67

3 (dd, JH,H = 10.2, 4.6 Hz, 1H, NCHCH2), 3.79-3.82 (m, 1H, NCH2CH2), 5.34 (s, 1H, OCHPh2),

3 13 7.24-7.36 (m, 12H, CHarom), 7.74 (d, JH,H = 8.7 Hz, 2H, CHarom); C NMR (d1-chloroform, 100

MHz,): δ 16.3 (CHCH3), 18.7 (CH2), 21.5 (CTsCH3), 23.9 (CH2), 24.7 (NCHCH2), 26.9 (CH2),

30.0 (CH2), 30.4 (CHCH3), 41.0 (NCH2CH2), 57.8 (NCHCH2), 69.3 (CH2O), 83.7 (OCHPh2),

126.9, 127.0, 127.3, 128.3, 129.6, 142.5; ESI MS (m/z): 514 ([M+Na]+); Anal. Calcd. for

C30H37NO3S: C, 73.28; H, 7.58; N, 2.85; Found: C, 72.88; H, 7.55; N, 2.80. Characterized by X- ray crystallography (Appendix A).

7-(Octan-2-yl)-8-tosyl-1,4-dioxa-8-azaspiro[4.5]decane: Prepared Ts H N following GP1 using 1-octene (158 μL, 1.01 mmol), 1,4-dioxa-8- (+/-) O O azaspiro[4.5]decane (64 μL, 0.50 mmol), and complex 2 (30.8 mg,

0.05 mmol) in d8-toluene (0.404 g) at 165 °C for 69 h. Derivatization with TsCl (150 mg,

0.787 mmol) and 2M aqueous NaOH (0.75 mL) in DCM (~2 mL). Flash chromatography (silica

gel F60, hexanes/EtOAc + 1% NEt3 15:1 → 6:1) gave the title compound as a clear, thick,

1 colorless oil. Yield: 0.121 g, 59%. H NMR (d1-chloroform, 400 MHz) δ 0.85 (m, 6H, CHCH3,

2 CH2CH3), 1.06 (m, 1H, CH2), 1.25-1.44 (m, 12H, NCHCH2C, NCH2CH2C, CH2), 1.83 (d, JH,H

= 14.8 Hz, 1H, NCHCH2C), 2.17 (m, 1H, CHCH3), 2.98 (s, 3H, CTsCH3), 3.12 (m, 1H,

3 NCH2CH2C), 3.70-3.89 (m, 6H, NCHCH2, NCH2CH2C, OCH2CH2O), 7.24 (d, JH,H = 8.1 Hz,

3 13 2H, CTs(CH3)CH), 7.70 (d, JH,H = 8.1 Hz, 2H, CHTs); C NMR (d1-chloroform, 100 MHz) δ 185

14.2 (CH2CH3), 15.6 (CHCH3), 21.6 (CTsCH3), 22.7, 26.4, 29.6 (CH2), 31.8 (CHCH3), 31.9

(CH2), 33.2 (NCHCH2C), 33.4 (NCH2CH2C), 33.5 (CH2), 39.2 (NCH2CH2C), 58.6 (NCHCH2C),

63.8, 64.8 (OCH2CH2O), 107.0 (OCO), 126.9 (CHTs), 129.8 (CTs(CH3)CH), 139.0 (CTsS), 143.1

+ + (CTsCH3); MS(EI): m/z 409 ([M] ), 296 ([M-C8H17] ); Anal. Calcd. for C22H35NO4S: C, 64.51;

H, 8.61; N, 3.42; Found: C, 64.71; H, 8.65; N, 3.39.

2-(5-(tert-butyldimethylsilyloxy)pentan-2-yl)-1,2,3,4-tetra- H H N OTBS hydroquinoline, 48: Prepared following GP2 using tert- (+/-) 48 butyldimethyl(pent-4-enyloxy)silane (964 mg, 4.81 mmol), 1,2,3,4-tetrahydroquinoline (378 μL,

3.01 mmol), and complex 2 (93.3 mg, 0.151 mmol) in toluene (3.0 g) at 145 °C for 165 h. Flash chromatography (silica gel F60, hexanes/EtOAc/NEt3 100:1:1 → 50:1:1) gave the title

1 compound as a clear, slightly yellow oil. Yield: 0.642 g, 64%. H NMR (d1-chloroform,

3 400 MHz) δ 0.15 (s, 6H, SiCH3), 1.00 (s, 9H, SiC(CH3)3), 1.05 (d, JH,H = 6.7 Hz, 3H, CHCH3),

1.20-1.83 (m, 6H, CH2 and CHCH3 and NCHCH2), 1.91-1.97 (m, 1H, NCHCH2), 2.81 (m, 1H,

3 3 3 Carom.CH2), 2.89 (m, 1H, Carom.CH2), 3.26 (ddd, JH,H = 2.9 Hz, JH,H = 4.2 Hz, JH,H = 10.2 Hz,

3 3 1H, NCH), 3.71 (t, JH,H = 6.3 Hz, 2H, OCH2), 3.75(br. s, 1H, NH), 6.54 (d, JH,H = 7.8 Hz, 1H,

3 3 13 CHarom.), 6.66 (dt, JH,H = 1.0 Hz, JH,H = 7.4 Hz, 1H, CHarom.), 7.03 (m, 2H, CHarom.); C NMR

(d1-chloroform, 100 MHz) δ -5.1 (SiCH3), 15.4 (CHCH3), 18.5 (SiC(CH3)3), 25.0 (NCHCH2),

26.2 (SiC(CH3)3), 27.1 (Carom.CH2), 28.9, 30.9 (CH2), 37.6 (CHCH3), 56.2 (NCH), 63.5 (OCH2),

114.2, 116.9 (CHarom.), 121.6 (Carom.CH2), 126.9, 129.3 (CHarom.), 145.3 (Carom.N); MS(EI): m/z

+ + 333 ([M] ), 132 ([M-C11H25OSi] ); Anal. Calcd. for C20H35NOSi: C, 72.01; H, 10.58; N, 4.20;

Found: C, 72.35; H, 10.68; N, 4.15.

186

2-(6-(tert-Butyldimethylsilyloxy)hexan-2-yl)-1,2,3,4-tetra- H H N OTBS hydroquinoline: Prepared following GP1 using tert-butyl(hex- (+/-) 5-enyloxy)dimethylsilane (146 mg, 0.68 mmol), 1,2,3,4-tetrahydroquinoline (63 μL,

0.502 mmol), and complex 2 (16.5 mg, 0.027 mmol) in d8-toluene (0.515 g) at 145 °C for 118 h.

Flash chromatography (silica gel G60, hexanes/EtOAc/NEt3 100:1:1 → 50:1:1) gave the title

1 compound as a clear, colorless oil. Yield: 0.137 g, 78%. H NMR (d1-chloroform, 400 MHz) δ

3 0.18 (s, 6H, SiCH3), 1.03 (s, 9H, SiC(CH3)3), 1.07 (d, JH,H = 6.8 Hz, 3H, CHCH3), 1.23-1.71 (m,

7H, CH2 and CHCH3), 1.75-1.85 (m, 1H, NCHCH2), 1.93-1.99 (m, 1H, NCHCH2), 2.79-2.96 (m,

3 3 2H, Carom.CH2), 3.28 (m, 1H, NCH), 3.74 (t, JH,H = 6.2 Hz, 3H, OCH2 and NH), 6.57 (d, JH,H =

3 13 8.0 Hz, 1H, CHarom.), 6.69 (t, JH,H = 7.4 Hz, 1H, CHarom.), 7.05 (m, 2H, CHarom.); C NMR (d1-

chloroform, 100 MHz) δ –5.1 (SiCH3), 15.3 (CHCH3), 18.5 (SiC(CH3)3), 23.9 (CH2), 25.0

(NCHCH2), 26.2 (SiC(CH3)3), 27.1 (Carom.CH2), 32.4, 33.3 (CH2), 37.8 (CHCH3), 56.3 (NCH),

63.2 (OCH2), 114.2, 116.9 (CHarom.), 121.5 (Carom.), 126.8, 129.3 (CHarom.), 145.3 (Carom.);

+ + MS(EI): m/z 347 ([M] ); HRMS(EI) Calcd. for C21H37NOSi: m/z 347.26444 ([M] ); Found: m/z

347.26461 ([M]+).

2-(Octan-2-yl)-1-tosylazepane: Prepared following GP2 using 1- Ts N octene (312 μL, 1.99 mmol), azepane (112 μL, 0.99 mmol), and complex 2 (30.9 mg, 0.05 mmol) in toluene (1.0 g) at 165 °C for 72 h. Derivatization with TsCl

(318 mg, 1.67 mmol) and 1M aqueous NaOH (3 mL) in DCM (~1 mL). Flash chromatography

(silica gel F60, hexanes/EtOAc 15:1 + 0.5% NEt3) gave the title compound as a colorless oil.

Yield: 0.220 g, 60%. 1H and 13C NMR data reveals an d.r. of 10:1; characterization data given

1 3 for major isomer. H NMR (d1-chloroform, 300 MHz) δ 0.70 (d, JH,H = 6.8 Hz, 3H, CHCH3), 187

3 0.84 (t, JH,H = 7.1 Hz, 3H, CH2CH3), 0.92-1.00 (m, 2H, CH2), 1.12-1.37 (m, 11H, CH2), 1.49-

1.73 (m, 5H, CH2), 1.89-1.97 (m, 1H, NCHCH2), 2.88 (m, 1H, NCH2), 3.70-3.76 (m, 1H, NCH),

3 3 3.77-3.84 (m, 1H, NCH2), 7.22 (d, JH,H = 8.0 Hz, 2H, CHTs), 7.69 (d, JH,H = 8.2 Hz, 2H, CHTs);

13 C NMR (d1-chloroform, 75 MHz) δ 14.2 (CHCH3), 16.9 (CH2CH3), 21.6 (CTsCH3), 22.8 (CH2),

24.8 (CH2), 27.3 (CH2), 29.2 (CH2), 29.3 (CH2), 29.8 (CH2), 30.1 (CH2), 31.4 (CH2), 32.0 (CH2),

+ + 37.3 (CHCH3), 45.2 (NCH2), 62.7 (NCH); MS(ESI): m/z 388.3 ([M+Na] ), 366.3 (MH ); Anal. calcd. for C21H35NO2S: C, 68.99; H, 9.65; N, 3.83; Found: C, 68.66 ; H, 9.54 ; N, 3.66.

4-Methyl-2-(octan-2-yl)-1-tosylpiperazine: Prepared following GP1 TsH N

using 1-octene (158 μL, 1.01 mmol), 1-methylpiperazine (55 μL, +/- N ( )

0.50 mmol), and complex 2 (31.3 mg, 0.051 mmol) in d8-toluene

(0.407 g) at 165 °C for 72 h. Derivatization with TsCl (150 mg, 0.787 mmol) and 2M aqueous

NaOH (0.75 mL) in DCM (1 mL). Flash chromatography (silica gel F60, hexanes/EtOAc + 1%

1 NEt3 10:1 → 6:1) gave the product a clear, thick, colorless oil. Yield: 0.088 g, 43%. H NMR

(d1-chloroform, 400 MHz) δ 0.85 (m, 6H, CHCH3, CH2CH3), 1.06 (m, 1H, CH2), 1.23-1.37 (m,

3 2 3 9H, CH2), 1.60 (dt, JH,H = 3.4 Hz, JH,H = 12.1 Hz, 1H, NCH2CH2N), 1.67 (dd, JH,H = 3.7 Hz,

2 JH,H = 11.9 Hz, 1H, NCH2CHN), 2.04 (s, 3H, NCH3), 2.11 (m, 1H, CHCH3), 2.39 (s, 3H,

2 2 Carom.CH3), 2.43 (d, JH,H = 12.0 Hz, 1H, NCH2CH2N), 2.70 (d, JH,H = 11.8 Hz, 1H,

NCH2CHN), 3.16-3.26 (m, 1H, NCH2CH2N), 3.50-3.55 (m, 1H, NCH2CHN), 3.69-3.74 (m, 1H,

3 3 NCH2CH2N), 7.25 (d, JH,H = 8.2 Hz, 2H, CTs(CH3)CH), 7.68 (d, JH,H = 8.3 Hz, 2H, CHTs);

13 C NMR (d1-chloroform, 100 MHz) δ 14.2, 16.4 (CH3), 21.6 (CTsCH3), 22.8, 26.7, 29.8 (CH2),

31.0 (CHCH3), 31.9, 33.9 (CH2), 41.5 (NCH2CH2N), 46.6 (NCH3), 53.8 (NCH2CH2N), 54.7

(NCH2CHN), 58.8 (NCHCH2N), 127.2 (CHTs), 129.7 (CTs(CH3)CH), 139.3 (CTsS), 143.0 188

+ + + + (CTsCH3); MS(EI): m/z 366 ([M] ), 253 ([M-C8H17] ), 211 ([M-Ts] ), 98 ([M-C8H17-Ts] );

+ + HRMS(EI) Calcd. for C20H34N2O2S: m/z 366.23410 ([M] ); Found: m/z 366.23432 ([M] ).

2-(Octan-2-yl)-4-phenyl-1-tosylpiperazine: Prepared following GP2 Ts H N

using 1-octene (316 μL, 2.01 mmol), 1-phenylpiperazine (152 μL, (+/-) N 1.00 mmol), and complex 2 (61.8 mg, 0.10 mmol) in toluene (0.800 g) Ph at 165 °C for 72 h. Derivatization with TsCl (300 mg, 1.57 mmol) and 2M aqueous NaOH

(1.5 mL) in DCM (3 mL). Flash chromatography (silica gel F60, hexanes/EtOAc + 1% NEt3

10:1 → 6:1) gave the title compound as a clear, thick, colorless oil. Yield: 0.291 g, 68%.

1 3 H NMR (C6D6, 600 MHz) δ 0.88 (t, JH,H = 7.1 Hz, 3H, CH2CH3), 1.03-1.11 (m, 1H, CH2), 1.09

3 (d, JH,H = 6.9 Hz, 3H, CHCH3), 1.17-1.23 (m, 7H, CH2), 1.25- 1.33 (m, 2H, CH2), 1.88 (s, 3H,

CTsCH3), 2.15-2.20 (m, 1H, CHCH3), 2.25 (td, JH,H = 12.0 Hz, 3.5 Hz, 1H NCH2CH2N), 2.47

(dd, JH,H = 12.6 Hz, 3.4 Hz, 1H, NCH2CH2N), 2.71-2.73 (app d, 1H, NCH2CH2N), 3.01-3.06 (m,

1H, NCH2CHN), 3.42 (app d, 1H, NCH2CH2N), 3.75 (app d, 1H, NCH2CHN), 3.79 (app d,

3 3 3 NCH2CHN), 6.60 (d, JH,H = 8.1 Hz, 2H, CHPh), 6.77 (t, JH,H = 7.3 Hz, 1H, CHPh), 6.80 (d, JH,H

3 3 = 7.9 Hz, 2H, CHTs), 7.09 (t, JH,H = 7.9 Hz, 2H, CHPh), 7.78 (d, JH,H = 8.2 Hz, 2H, CHTs);

13 C NMR (C6D6, 150 MHz) δ 14.7 (CH2CH3), 16.7 (CHCH3), 21.5 (CTsCH3), 23.4 (CH2), 27.4

(CH2), 30.3 (CH2), 31.4 (CHCH3), 32.5 (CH2), 34.5 (CH2), 41.8 (NCH2CHN), 48.4

(NCH2CH2N), 50.8 (NCH2CH2N), 59.5 (NCH2CHN), 117.4 (CHPh), 120.8 (CHPh), 127.8 (CHTs),

+ 129.7 (CHPh), 130.1 (CHTs), 140.7 (CTs), 143.0 (CHTs), 152.4 (CHPh); MS(EI): m/z 428 ([M] ),

+ + + 315 ([M-C8H17] ), 273 ([M-Ts] ); HRMS(EI) Calcd. for C25H36N2O2S: m/z 428.24975 ([M] );

Found: m/z 428.24965 ([M]+).

189

4-(4-Methoxyphenyl)-2-(octan-2-yl)-1-tosylpiperazine: Prepared Ts H N following GP1 using 1-octene (158 μL, 1.01 mmol), 1-(4- N (+/-) methoxyphenyl)piperazine (96.6 mg, 0.50 mmol), and complex 2

(31.2 mg, 0.051 mmol) in d8-toluene (0.408 g) at 165 °C for 69 h. OMe Derivatization with TsCl (150 mg, 0.787 mmol) and 2M aqueous NaOH (0.75 mL) in DCM (1 mL). Flash chromatography (silica gel F60, hexanes/EtOAc + 1% NEt3 15:1 → 6:1) gave the

1 title compound as a clear, thick, colorless oil. Yield: 0.158 g, 69%. H NMR (d1-chloroform,

3 3 400 MHz) δ 0.88 (t, JH,H = 6.7 Hz, 3H, CH2CH3), 0.97 (d, JH,H = 6.8 Hz, 3H, CHCH3), 1.16-

1.52 (m, 10H, CH2), 2.23 (m, 1H, CHCH3), 2.35-2.46 (m, 2H, NCH2CH2N and NCH2CHN),

2 2.40 (s, 3H, Carom.CH3), 3.07 (d, JH,H = 11.3 Hz, 1H, NCH2CH2N), 3.33 (m, 1H, NCH2CH2N),

2 3 3.41 (d, JH,H = 12.4 Hz, 1H, NCH2CHN), 3.67 (d, JH,H = 10.5 Hz, 1H, NCH2CHN), 3.73 (s, 3H,

2 3 OCH3), 3.88 (d, JH,H = 14.4 Hz, 1H, NCH2CH2N), 6.77 (m, 4H, CHPMP), 7.27 (d, JH,H = 8.0 Hz,

3 13 2H, CTs(CH3)CH), 7.75 (d, JH,H = 8.2 Hz, 2H, CHTs); C NMR (d1-chloroform, 100 MHz) δ

14.2 (CH2CH3), 16.1 (CHCH3), 21.5 (Carom.CH3), 22.7, 26.7, 29.7 (CH2), 30.5 (CHCH2), 31.9,

33.8 (CH2), 41.5 (NCH2CH2N), 49.1 (NCH2CH2N), 51.7 (NCH2CHN), 55.6 (OCH3), 58.9

(NCHCH2N), 114.5, 118.9 (CHPMP), 127.1 (CHTs), 129.8 (CTs(CH3)CH), 139.3, 143.1, 145.9,

+ + 154.3 (C); MS(EI): m/z 458 ([M] ), 303 ([M-Ts] ); Anal. calcd. for C26H38N2O3S: C, 68.09; H,

8.35; N, 6.11; Found: C, 68.46; H, 8.50; N, 6.02.

4-Benzhydryl-2-(octan-2-yl)-1-tosylpiperazine: Prepared following Ts H N GP1 using 1-octene (158 μL, 1.01 mmol), 1-(4- N (+/-)

methoxyphenyl)piperazine (128 mg, 0.507 mmol), and complex 2 Ph Ph

(32.9 mg, 0.053 mmol), in d8-toluene (0.404 g) at 165 °C for 72 h. Derivatization with TsCl 190

(150 mg, 0.787 mmol) and 2M aqueous NaOH (0.75 mL) in DCM (2 mL). Flash

chromatography (silica gel F60, hexanes/EtOAc + 1% NEt3 10:1 → 6:1) gave the title compound

1 as a clear, thick, colorless oil. Yield: 0.121 g, 46%. H NMR (d1-chloroform, 400 MHz) δ 0.96 (t,

3 3 JH,H = 7.0 Hz, 4H, CH2CH3 and CH2), 1.00 (d, JH,H = 6.8 Hz, 3H, CHCH3), 1.16-1.48 (m, 9H,

3 2 3 2 CH2), 1.60 (dt, JH,H = 3.2 Hz, JH,H = 12.2 Hz, 1H, NCH2CH2N), 1.68 (dd, JH,H = 3.4 Hz, JH,H =

2 12.0 Hz, 1H, NCH2CHN), 2.44 (s, 3H, CTsCH3), 2.44 (m, 1H, CHCH3), 2.59 (d, JH,H = 10.8 Hz,

2 1H, NCH2CH2N), 2.86 (d, JH,H = 12.0 Hz, 1H, NCH2CHN), 3.27 (m, 1H, NCH2CH2N), 3.52 (d,

2 JH,H = 10.3 Hz, 1H, NCH2CHN), 3.73 (m, 1H, NCH2CH2N), 3.99 (s, 1H, NCH(CPh)2), 7.16-7.21

3 (m, 2H, CHarom.), 7.26 (m, 6H, CHarom., CTs(CH3)CH)), 7.36 (m, 4H, CHarom.), 7.70 (d, JH,H =

13 8.2 Hz, 2H, CHTs); C NMR (d1-chloroform, 100 MHz) δ 14.3 (CH2CH3), 16.1 (CHCH3), 21.6

(CTsCH3), 22.8, 27.4, 29.9 (CH2), 31.3 (CHCH3), 32.1, 33.9 (CH2), 41.9 (NCH2CH2N), 50.8

(NCH2CH2N), 51.3 (NCH2CHN), 59.2 (NCHCH2N), 76.1 (NCH(Ph)2), 127.1 (CHTs), 127.2,

127.3 127.8, 127.9, 128.6, 128.6 (CHPh), 129.7 (CTs(CH3)CH), 139.4 (CTs), 142.2 (CPh), 142.9

+ + (CTsCH3); MS(EI): m/z 518 ([M] ), 363 ([M-Ts] ); Anal. calcd. for C32H42N2O2S: C, 74.09; H,

8.16; N, 5.04; Found: C, 73.76; H, 8.11; N, 5.44.

4-Benzhydryl-2-(1-phenylpropan-2-yl)-1-tosylpiperazine: Prepared Ts H N Ph

following GP2 using allylbenzene (400 μL, 3.02 mmol), 1-(4- (+/-) N

methoxyphenyl)piperazine (252 mg, 1.0 mmol), and complex 2 (62.1 mg, Ph Ph

0.10 mmol) in toluene (1.0 g) at 165 °C for 72 h. Derivatization with TsCl (300 mg, 0.787 mmol)

and 2M aqueous NaOH (0.75 mL) in DCM (2 mL). Flash chromatography (silica gel F60,

hexanes/EtOAc 15:1) gave the title compound as a colorless solid. Yield: 0.441 g, 84%. 1H NMR

3 (d1-chloroform, 400 MHz) δ 0.92 (d, JH,H = 6.4 Hz, 3H, CHCH3), 1.64-1.70 (m, 1H, 191

NCH2CH2NTs), 1.81-1.85 (m, 1H, NCH2CHNTs), 2.04-2.10 (m, 1H, CH2Ph), 2.45 (s, 1H,

CTsMe), 2.67-2.75 (m, 2H, NCH2CH2NTs, CHCH3), 2.81-2.85 (m, 1H, CH2Ph), 3.03 (app. d, 1H,

NCH2CHNTs), 3.07-3.35 (m, 1H, NCH2CH2NTs), 3.69 (app d, 1H, NCH2CHNTs), 3.80 (app. d,

1H, NCH2CH2NTs), 4.08 (s, 1H, CHPh2), 7.14-7.50 (m, 17H, CHarom.), 7.70-7.75 (m, 2H,

13 CHarom.); C NMR (d1-chloroform, 100 MHz) δ 15.8 (CHCH3), 21.5 (CTsCH3), 33.2 (CHCH3),

40.2 (CH2Ph), 41.9 (CH2NTs), 50.7 (NCH2CH2NTs), 51.4 (NCH2CHNTs), 59.1 (CHNTs), 76.0

(CHPh2), 126.0 (CH), 127.0 (CH), 127.2 (CH), 127.4 (CH), 127.7 (CH), 127.8 (CH), 128.3

(CH), 128.6 (CH), 129.1 (CH), 129.7 (CH), 139.1 (CTs), 140.6 (C), 141.9 (C), 142.0 (C), 142.1

+ + (C), 142.9 (CTs); MS(EI): m/z 524 ([M] ), 369 ([M-Ts] ); Anal. calcd. for C33H36N2O2S: C,

75.54; H, 6.92; N, 5.34; Found: C , 75.19; H, 6.97; N, 5.34.

4-(1,2,3,4-tetrahydroquinolin-2-yl)pentan-1-ol: Compound 48 H N OH (0.424 g, 1.127 mmol) was dissolved in THF (25 mL) and water (25

mL) and acetic acid was added (50 mL). Tetrabutylammonium fluoride (0.4987 g, 1.907 mmol)

was added and the solution was stirred for 3 hours. The solution was neutralized with

concentrated NaOH and extracted with diethyl ether (4x50 mL). The organic layers were

combined, washed with brine, dried over MgSO4, filtered, and concentrated by rotary evaporator.

Flash chromatography (silica gel F60, hexanes/Et2O 3:7→ 2:8) gave the title compound as a

1 3 yellow oil. Yield: 0.250 g, 90%. H NMR (d1-chloroform, 400 MHz) δ 1.05 (d, JH,H = 6.8 Hz,

3H, CHCH3), 1.21-1.24 (m, 2H), 1.54-1.72 (m, 5H), 1.85-1.91 (m, 1H), 2.71-2.87 (m, 2H), 3.19-

3 3 3.23 (m, 1H), 3.49 (q, JH,H = 7.13 Hz, 1H, NCH), 3.67 (app t, JH,H = 6.3 Hz, 2H, CH2OH), 6.49

3 3 (d, JH,H = 7.7 Hz, 1H, CHarom), 6.60 (t, JH,H = 7.3 Hz, 1H, CHarom), 6.97 (m, 2H, CHarom);

13 C NMR (d1-chloroform, 100 MHz) δ 15.2 (CH3), 24.7 (CH2), 26.9 (CH2), 28.5 (CH2), 30.7 192

(CH2), 37.5 (CH), 56.1 (CH), 63.1 (CH2OH), 114.1 (CH), 116.8 (CH), 121.4 (C), 126.7 (CH),

+ + 129.1 (CH), 145.1 (C); MS(ESI): m/z 242 ([M+Na] ), 220 ([M+H] ); Anal. calcd. for C14H21NO:

C, 76.67; H, 9.65; N, 6.39; Found: C, 76.33; H, 9.90; N, 5.87.

5,5-diethoxypent-1-ene, 49: Allyl bromide (5 mL, 57.7 mmol) was added OEt

dropwise to a suspension of oven dried magnesium turnings (21.1 g, 866.6 49 OEt

mmol) in dry diethyl ether (100 mL). After the addition is complete the reaction was heated to

reflux for 2 h. Upon cooling the allyl magnesium bromide solution was cannula transferred

(dropwise) into a THF (35 mL) solution of 2-bromo-1,1-diethoxyethane (7.82 mL, 51.9 mmol).

The resultant reaction mixture was heated at reflux for 3 h. Flash chromatography (silica gel F60, methanol/DCM 1:400) gave the title compound as a colourless oil analysis data matching

398 1 3 literature values. H NMR (C6D6, 400 MHz) δ 1.11 (t, JH,H = 7.1 Hz, 6H, OCH2CH3), 1.72-

3 1.77 (m, 2H, CH2CH(OEt)2), 2.12-2.17 (m, 2H, CH2CHCH2), 3.34 (dq, JH,H = 9.3, 7.0 Hz, 2H,

3 3 OCH2CH3), 3.52 (dq, JH,H = 9.3, 7.0 Hz, 2H, OCH2CH3), 4.44 (t, JH,H = 5.7 Hz, 1H, CH(OEt)2),

13 4.95-5.07 (m, 2H, CHCH2), 5.75-5.82 (m, 1H, CHCH2); C NMR (C6D6, 400 MHz) δ 16.0

(CH3), 29.8 (CH2), 33.6 (CH2), 61.2 (CH2), 102.8 (CH), 115.1 (CH2), 138.9 (CH). MS(EI): m/z

+ + 129 ([M-C2H6] ), 113 ([M-OEt] ).

4-methoxy-N-(2-methylhex-5-en-1-yl)aniline: Prepared H N following GP1 using hexa-1,5-diene (0.493 g, 6.0 mmol), p- O

methoxy-N-methylaniline (0.274 g, 2.0 mmol), and complex 2 (61.7 mg, 0.1 mmol), in d8-

toluene (0.5 g) at 130 °C for 40 h. Flash chromatography (silica gel F60, hexanes/Et2O 50:1 →

1 20:1) gave the title compound as a pale yellow oil. H NMR (d1-chloroform, 300 MHz) δ 0.99 (d, 193

3 JH,H = 6.5 Hz, 3H, CHCH3), 1.20-1.35 (m, 2H, NH, CH), 1.51-1.62 (m, 1H, CHCH2), 1.72-1.81

3 (m, 1H, CH2), 2.01-2.18 (m, 2H, CH2CHCH2), 2.87 (dd, JH,H = 12.0, 7.3 Hz, NCH2), 3.04 (dd,

3 JH,H = 12.0, 5.8 Hz, NCH2), 3.76 (s, 3H, OCH3), 4.95 (m, 2H, CHCH2), 5.83 (m, 1H, CHCH2),

3 3 6.60 (d, JH,H = 8.6 Hz, CHarom), 6.79 (d, JH,H = 8.6 Hz, CHarom).

N-(2,6-dimethylphenyl)piperidine-1-carboxamide, 50: Prepared O following a modified literature procedure101 in which 2,6-dimethylaniline N N H (2.55 g, 2.08 mL, 11.0 mmol) was dissolved in DCM (250 mL). The 50

solution was cooled to 0 °C and triphosgene (1.31 g, 3.50 mmol) was added in one portion. The

solution was stirred for five minutes after which N,N-diisopropylethylamine (2.13 mL, 15.0

mmol) was added and the cold bath removed. The solution was stirred for 1 hour and then

piperidine (0.99 mL, 10.0 mmol) and N,N-diisopropylethylamine (2.13 mL, 15.0 mmol) were

added. The solution was stirred for an additional hour, and then diluted with 1M HCl (100 mL).

The organic phase was washed with 1M HCl (3x50 mL), dried over MgSO4, filtered, and

concentrated by rotary evaporation. Recrystallization of the crude solid from hot hexanes/DCM

1 gave the title compound as a colorless solid. Yield: 1.93 g, 83%. H NMR (d1-chloroform, 400

MHz) δ 1.48-1.73 (m, 6H, CH2), 2.23 (s, 6H, CH3), 3.30-3.58 (m, 4H, NCH2) 5.86 (br s, 1H,

13 NH), 7.05 (s, 3H, CHarom); C NMR (d1-chloroform, 400 MHz) δ 18.4 (CH3), 24.5 (CH2), 25.8

(CH2), 45.5 (NCH2), 126.2 (CH), 128.0 (CH), 135.3 (C), 135.5 (C); MS (CI) (m/z): 148 ([M- piperidine]+).

194

Pentakis(indolinyl) tantalum, 51: Complex 2 (55.0 mg, 0.089 mmol) was

N dissolved in ~5 mL of hexanes in a large vial equipped with a stir-bar. N Ta N Indoline (0.110 g, 0.939 mmol) was added and a rapid colour change (< 30 N N seconds) from pale yellow to bright red was observed accompanied by formation of a precipitate. The solution was filtered and the solvent was removed under high vacuum. The solid was dissolved once more in hexanes, and filtered once more through a plug of

Celite™. Crystalline material suitable for X-ray crystallographic studies was grown from a

hexanes/benzene solution at room temperature over 3 weeks. Characterized by X-ray

crystallography (Appendix A).

d1-Piperidine: Neat piperidine (3 mL) was added to a round bottom flask equipped with D N

a magnetic stir-bar under an atmosphere of dry dinitrogen. Excess D2O (3 mL) was

added to the round bottom flask and the mixture was stirred for 30 minutes at room temperature.

Piperidine was extracted with dry DCM (3x15 mL) using a pipette. DCM was removed carefully

on a rotary evaporator using an ice/water bath. The deuterated piperidine was dried by stirring

overnight with BaO, distilled under nitrogen, and degassed by three freeze-pump-thaw cycles.

The resulting clear liquid was then dried once more over BaO and filtered through a Celite plug.

Any residual deuterated water was removed from a toluene solution of the substrate using 3 Å

2 molecular sieves over a one week period. H NMR (d8-toluene, 400 MHz) δ 1.12 (br s, 1H, ND).

d1-Pyrrolidine: Neat pyrrolidine (3 mL) was added to a round bottom flask equipped D N

with a magnetic stir-bar under an atmosphere of dry dinitrogen. Excess D2O (3 mL) was

added to the round bottom flask and the mixture was stirred for 30 minutes at room temperature. 195

Pyrrolidine was extracted with dry ether (6x15 mL) using a pipette. The ether was removed

carefully on a rotary evaporator using an ice/water bath. The deuterated pyrrolidine was dried by

stirring overnight with BaO, distilled under nitrogen, and degassed by three freeze-pump-thaw

cycles. The resulting clear liquid was then dried once more over BaO and filtered through a

Celite plug. Any residual deuterated water was removed from a toluene solution of the substrate

2 using 3 Å molecular sieves over a one week period. H NMR (d8-toluene, 400 MHz) δ 1.00 (br

s, 1H, ND).

5.4.4 Attempts towards the synthesis of bicyclic and tricyclic compounds

Tosyl fluoride cyclization procedure: Compound 48 (0.060 g, 0.180 mmol) N was dissolved in d8-toluene (0.5 mL) and tosyl fluoride (0.094 g, 0.540 mmol) H

and DBU (0.0832 g, 0.540 mmol) were added to the solution. The reaction Not observed

mixture was placed in a preheated oil bath (130 °C) for 48 hours. The 1H NMR spectrum

recorded did not show any resonances of the desired tricyclic product.

Attempted hydroamination procedure: 4-methoxy-N-(2-methylhex-5- N en-1-yl)aniline (40.3 mg, 0.173 mmol) and complex 4 (10.0 mg, 0.0173 O mmol) were dissolved in d6-benzene (0.5 mL) in a small vial. The Not observed

solution was transferred to a J. Young NMR tube and heated for 40 h at 130 °C. The 1H NMR

spectrum recorded did not show any resonances of the desired cyclic product and still contained

olefinic resonances.

196

5.4.5 Deuterium labeling experiments

Deuterium NMR spectroscopy: The deuterium NMR spectra were collected using a Bruker

Avance 400inv spectrometer through the X-nuclei channel. 2H spectra were referenced to δ 2.09 ppm (CD3) using the deuterium signal (natural abundance) of the non-deuterated toluene NMR solvent. d8-Toluene samples were used to set the shim values to be used for the deuterium spectra in toluene, thus improving the line-widths of the signals in the 2H spectra.

Representative procedure for the isotope exchange in the presence of complex 2: N- deuterated pyrrolidine (15.6 mg, 0.216 mmol) was weighed into a small vial and diluted with 600

μL of toluene. To this vial was added ten 3 Å molecular sieves, and the solution was left to dry over the period of one week. Complex 2 (6.68 mg, 0.011 mmol) was then added to the vial and the contents were transferred to a J. Young tube. A 2H NMR spectra was collected. Concurrently, an analogous solution was prepared in d8-toluene (600 μL) using N-deuterated pyrrolidine (18.2 mg, 0.252 mmol) and complex 2 (7.79 mg, 0.0126 mmol). A 1H NMR spectrum was collected.

The NMR tubes were then place in a preheated oil bath (165 ºC) for 143 h after which the final

1H and 2H NMR spectra were collected.

5.4.6 Computational methods

The computational calculations were performed in an analogous fashion to those reported previously.146 The system was modeled using density functional theory with the Gaussian suite of programs399,400 on the Glacier or Orcinus clusters maintained by WestGrid, a division of

ComputeCanada. The compound geometries were optimized using the B3LYP hybrid functional, and the double zeta 6-31G Pople basis set was modified to include polarization functions for the 197

carbon, hydrogen, oxygen, and nitrogen atoms.401-404 The tantalum center was modeled using the

Los Alamos LANL2DZ basis set with an effective core potential that included f-orbitals.405,406

The geometric optimizations of the transition states and minima were confirmed using

vibrational analysis; transition states had one imaginary (negative) vibrational mode and minima

had only positive frequencies. Intermediates were located by relaxation of the transition state

along the potential energy surface and confirmed using intrinsic reaction coordinate analysis.

The initial geometries for the relaxed intermediates were generated by multiplying the Cartesian

displacement values of the imaginary vibrational mode by a scale factor and adding to the

transition state geometries. These calculations were performed under the default conditions in the

Gaussian program (298.15 K, 1 atm) without any solvent models since previous studies showed a

negligible difference between gas-phase optimization and calculations including solvent.146 All

of the single-point energy calculations were performed using MP2, a second-order implementation of Møller-Plesset perturbation theory and the 6-31G(d,p) basis set.407 At this

stage, an integral equation formalization polarizable continuum model (IEFPCM) was introduced

to mimic toluene solvation based on an empirically derived dielectric constant. No discrete

solvent molecules were added to the model. The reported free energies were calculated by the

summation of the MP2 single point energy and the thermal correction to the Gibbs free energy

calculated using optimized geometries at 165 ºC. The ball-and-stick figures of the calculated structures have been generated using GaussView5.408

198

CHAPTER 6: Summary, conclusions, and future directions

6.1 Summary and conclusions

The investigations reported in this thesis highlight many aspects of catalyst development

for (N,O)-ligated complexes of early transition metals. This includes ligand development, synthesis and characterization of new organometallic complexes, structure-activity relationships for their application in catalysis, and extensive substrate scope investigations for the synthesis of amines. The overall focus is twofold; firstly to establish the extensive potential of these amidate, ureate, and pyridonate complexes in the selective atom-economic synthesis of amines, and

secondly, to gain insight into the subtle effects that the different electronic and steric properties

of these related ligands have on the reactivity of their complexes.

Chapter 2 describes the development of chiral ureate ligands for application in the

zirconium-catalyzed enantioselective hydroamination of aminoalkenes. Though these ligands were only moderately successful for this application, these studies indicate that the inclusion of an ureate moiety is not sufficient to impart greater catalytic activity and substrate scope than analogous amidate precatalysts. The presence of the ureate binding motif is also not the only source for the mechanism change observed for a related tethered bis(ureate) system. A tethered ligand motif and the well-behaved geometry at the metal centre, as well as suppressing ligand redistribution reactions must be part of the catalyst design of future systems.

The kinetic and stoichiometric investigations into the reactivity of bis(pyridonate) bis(dimethylamido) zirconium complex 5 in Chapter 3 reveal a complex catalytic system.

Stoichiometric investigations consistently show the formation of numerous species in solution upon addition of primary amines. Solid state X-ray diffraction studies as well as solution phase 199

DOSY experiments provide evidence for the formation of multi-metallic species in the presence

of amines. The kinetic evaluation indicates that the C–H activation to form a zirconaziridine is

the turnover-limiting step, though off-cycle equilibrium reactions involving amine coordination

are most likely occurring at comparable rates in solution consistent with the observed first-order in aminoalkene substrate. The ill-defined nature of this precatalyst system complicates the mechanistic elucidation.

Chapter 4 describes catalyst development work toward the generation of new tantalum complexes for the catalytic α-alkylation of amines. The (N,O)-chelating motif has been established to be critical for good reactivity, and an amide proligand containing a pendant methoxy donor has been highlighted as an avenue for future research. Challenges in the synthesis of mixed chloro amidate systems have been investigated and highlight both the difficulties with the systems and the thermal instability of the complexes that can hinder extensive catalytic application. Well-defined sulfonamidate complexes have been generated and display an κ2-

(N,O)-coordination motif. These complexes are not reactive for hydroaminoalkylation despite their similarity to the amidate-supported tantalum complexes. This is proposed to be due to decreased hemilability due to the firmly bound κ2 sulfonamidate resulting in a lack of the

necessary open coordination sites for metallaziridine formation.

For the previously reported mono(N-(2,6-diisopropylphenyl pivalamidate)

tetrakis(dimethylamido) tantalum precatalyst 2 to find widespread application in synthesis, a

broad substrate scope must be established. The substrate scope analysis presented in Chapter 5

demonstrates the potential of this system for the late-stage α-alkylation of pharmaceutically

relevant piperidines, piperazines, and azepanes with excellent regio- and diastereoselectivity.

Preliminary studies with the related ureate ligands firmly establishes hemilabile (N,O)-chelating 200

ligands as privileged motifs for this methodology. The first example of asymmetric

hydroaminoalkylation with simple monodentate chiral ligands has also been established and

offers a potential route to enantioselective α-alkylation without the need for biaryl-based axially chiral ligands that suffer from laborious syntheses and reduced reactivity. The lack of reactivity with pyrrolidine substrates has been extensively examined and ligands promoting metallaziridine formation in the equatorial plane are essential for targeted reactivity.

6.2 Future directions

6.2.1 Enantioselective hydroaminoalkylation with simple chiral ligands

While the mono(amidate) tetrakis(dimethylamido) tantalum complex 2 displays an admirable scope of reactivity and consistently shows excellent regio- and diastereoselectivity, this catalyst, supported by an achiral amidate ligand, does not promote intermolecular hydroaminoalkylation in an enantioselective fashion. Preliminary investigations in Chapter 4 and

5 highlight the necessity of the (N,O)-chelate and provide precedent for the application of mono(ureate) tantalum amido complexes for this application. Especially intriguing is the ability of the simple chiral urea proligand 8 to afford enantioenriched products, albeit with low enantiomeric excess. This indicates that a tethered motif is not required to impart a chiral environment at the metal centre. The ease of synthesizing these ligands (Scheme 6.1, top), the readily available pool of enantiomerically pure amino acids, and therefore the potential for rapid screening of precatalysts to improve enantiomeric excesses makes this ligand class particularly attractive.

Acyclic ureate ligands have also been established as a viable ligand motif. The proligands can be synthesized via the reaction of a primary amine with triphosgene in the presence of a 201

tertiary amine to generate an isocyanate intermediate which can be directly reacted with a secondary amine (Scheme 6.1, bottom). The commercially available chiral amines shown in

Scheme 6.1 are a brief selection of inexpensive, commercially available enantiopure starting materials, and represent a potential starting point for subsequent catalyst optimization.

O O R R R RNH2 R R N HO N NH DCC coupling H 3 steps NHBoc NH2 O O O O Ph Amino acids = HO HO HO

NH2 NH2 NH2 Leucine Isoleucine (R)-phenylglycine

O DIPEA R1 1) triphosgene, 1 NH 2 R 2 2) (R )2NH, DIPEA N NR2 H

R1 = NH2 NH2 NH2 NH2 NH2

2 = H (R )2NH H H N N Ph N Ph

Scheme 6.1 Urea proligands incorporating chirality in the carbon backbone (top) or the amino groups (bottom) for tantalum-catalyzed asymmetric hydroaminoalkylation.

6.2.2 Reactivity with pyrrolidines

The lack of α-alkylation observed with the pyrrolidine substrates was investigated through in silico experiments. The optimized geometry of the tantalaziridine formed with the five-membered substrate contains the reactive moiety in a pseudo-axial position (Figure 6.1, left), where olefin insertion is not favoured. 202

V V pyrr pip

Figure 6.1 Optimized geometries for the tantalaziridines with pyrrolidine (left) and piperidine (right).

Ancillary ligands that promote tantalaziridine formation in the equatorial position could

allow for effective α-alkylation of five-membered substrates. The geometry of this intermediate is governed by the steric and electronic parameters of all of the ancillary ligands and can be very difficult to predict. However, a series of calculations could be useful in highlighting potential ligand sets for subsequent experimental investigations. These include chloro or alkyl ligands, as

well as alternative (N,O)-chelating ligands such as ureates or pyridonates (Figure 6.2). The

mono(chloro) mono(amidate) tris(dimethylamido) tantalum complex 42 reveals that the chloro

ligand is preferentially situated in the axial position in the solid-state (Figure 6.2); if this

geometry is maintained in the solution-phase these simple ligands could favour tantalaziridine

formation in the equatorial position. Geometry optimizations of the metallaziridine intermediate

could be very useful to identify ligand combinations that are good candidates for experimental

consideration.

203

Cl R1 O O R O O 1 Ta = (R )2N N N R N N 2 R R R2 R = NMe2, Me 42

Figure 6.2 Potential new precatalysts for the hydroaminoalkylation of N-heterocycles such as pyrrolidine. ORTEP depiction of solid-state molecular structure of complex 42. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

6.2.3 Pyridonate complexes of tantalum

Pyridonate ligands have been shown to be effective in supporting zirconium precatalysts for the hydroaminoalkylation of primary aminoalkenes. These ligands generate metal complexes containing four-membered metallacycles and can display hemilability due to the available κ1-(O) monodentate motif, two facets of ligand design demonstrated to be crucial in the Chapters 4 and

5. However, tantalum pyridonate precatalysts have not been extensively investigated.

Preliminary reactivity studies into the synthesis of these complexes have been performed via protonolysis (Figure 6.3). The reactions for the generation of the mono and bis(pyridonate) tantalum amido complexes resulted in crude material (52 and 53, respectively) with 1H NMR spectra consistent with formation of the predicted product. However, attempts to isolate crystalline material of high purity have so far been unsuccessful.

204

1 R OH R1 O 1 2 n -n HNMe2 Ta(NMe2)5-n 52: n = 1; R , R = H N Ta(NMe2)5 N benzene 53: n = 2; R1, R2 = H − 2 n = 1 3 n R R2

14.07 OH

0.98 N offset

1.03 1.01 1.05 1.00

1.36 2.00 1.60 2.02 20.93

53 1.00 1.16 0.91 0.98 38.09

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

Figure 6.3 Preliminary synthesis and stacked 1H NMR spectra for the proligand and the crude mono and

bis(pyridonate) complexes 52 and 53 in d6-benzene.

The use of the more sterically bulky 6-tert-butyl-3-phenyl-2-pyridonate ligand investigated in Chapter 3 (R1 = Ph, R2 = tBu, Figure 6.3) results in complex mixtures of products

and is not the most promising ligand for subsequent studies. The unsubstituted 2-pyridone ligand

is also subject to redistribution reactions and formation of multiple isomers in solution, as three

equivalents resulted in a complex mixture. The solid-state molecular structure of isolated

crystalline material reveals a highly disordered complex 54 containing pyridonate ligands bound

both in a κ1 and κ2-fashio (Figure 5.3). This complex establishes the potential hemilability of the

205

pyridonate ligands, a feature of ligand design that has been highlighted to be important thereby providing support for the concept that these ligands would be active precatalysts for the

hydroaminoalkylation of amines.

Figure 6.4 ORTEP depiction of solid-state molecular structure of complex 54. The three equatorial pyridonate ligands are highly disordered, both orientations are shown. The ellipsoids are plotted at 50% probability and the hydrogen atoms are omitted for clarity.

Proligands that contain a moderate amount of steric bulk are proposed to be good initial

targets such as such as the commercially available 6- and 3-methylpyridone (A, Figure 6.5). 3-

Bromopyridone (B) can be functionalized by a protection-Suzuki-coupling-deprotection methodology to install a variety of aryl substituents at the 3-position.409 A recent paper by

Fukuyama and co-workers also describes the synthesis of highly substituted pyridones (C) using

α,β-substituted ketones and 2-substituted acetamides.410

206

O O Br O NH NH NH

A B

O O 1) O Ph NH2 O LiCl DBU, 1 MeCN, 50 °C R NH R1 R3 2) AcOH, reflux R2 R2 R3 C

Figure 6.5 Potential commercially available pyridone proligands (A) and pyridone precursor (B) as well as a reported synthetic route to highly substituted pyridones (C).410

These synthetic strategies allow for the modular formation of a variety of pyridonate

complexes with altered steric and electronic parameters. This will allow for rapid screening and

optimization procedures to determine proligands worthy of further investigation.

6.3 Concluding remarks

The (N,O)-chelating ligands presented are a noteworthy class of ligands for the

generation of catalytically active complexes of early transition metals. While these ligands at

first glance appear to be structurally similar, their subtle electronic and steric differences play a

vital role in mediating both the mechanism of action and the chemoselectivity of the resultant

metal complex. These ligands hold numerous advantages to others in the field, in particular the

rapid and modular synthesis of a variety of related yet distinctive (N,O)-chelating proligands with finely tuned steric and electronic parameters. The investigation into these amidate, pyridonate, and ureate ligand sets allow for control of chemoselectivity, enable vastly expanded

207

substrate scope, and promote enantio-, regio- and diastereoselectivity. Fundamental studies such as those presented above highlight key design principles to guide future research into the application of (N,O)-chelating complexes as precatalysts for hydroamination and hydroaminoalkylation.

208

REFERENCES

1 Constable, E. C.; Housecroft, C. E. Chem. Soc. Rev. 2013, 42, 1429. 2 Lawrance, G. A. Introduction to Coordination Chemistry; Wiley: Hoboken, NJ, USA, 2009. 3 Transition Metal Organometallic Chemistry; Mathey, F., Ed.; Springer: Singapore, 2013. 4 Jones, C. J.; Thornback, J. Medicinal applications of coordination chemistry; Royal Society of Chemistry: Cambridge 2007. 5 Bignozzi, C. A.; Argazzi, R.; Boaretto, R.; Busatto, E.; Carli, S.; Ronconi, F.; Caramori, S. Coord. Chem. Rev. 2013, 257, 1472. 6 Whittell, G. R.; Hager, M. D.; Schubert, U. S.; Manners, I. Nat. Mater. 2011, 10, 176. 7 Steed, J. W. Chem. Soc. Rev. 2009, 38, 506. 8 Fine chemicals through heterogeneous catalysis; Sheldon, R. A.; van Bekkum, H., Eds.; Wiley- VCH: Weinheim, Germany, 2008. 9 Ammonia: Catalysis and Manufacture; Nielsen, A., Ed.; Springer: Berlin Heidelberg, 1995. 10 van Leeuwen, P. W. N. M. Homogeneous catalysis: understanding the art; Springer: Berlin, Germany, 2004. 11 Beller, M. Homogeneous catalysis for fine chemical synthesiss — New trends and perspectives —; Elsevier, 1997; Vol. Volume 108. 12 Organometallics as Catalysts in the Fine Chemical Industry; Beller, M.; Blaser, H.-U., Eds.; Springer: Berlin Heidelberg, 2012; Vol. 42. 13 Organic Synthesis Using Transition Metals, Second Edition; Bates, R., Ed.; John Wiley & Sons, Ltd: Chichester, West Sussex, 2012. 14 Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301. 15 Dunn, P. J. Chem. Soc. Rev. 2011. 16 Cornils, B.; Herrmann, W. A. J. Catal. 2003, 216, 23. 17 Cheung, H.; Tanke, R. S.; Torrence, G. P. In Ullmann's Encyclopedia of Industrial Chemistry; Wiley-VCH Verlag GmbH & Co. KGaA: 2000. 18 Howard, M. J.; Jones, M. D.; Roberts, M. S.; Taylor, S. A. Catal. Today 1993, 18, 325. 19 Maitlis, P. M.; Haynes, A.; Sunley, G. J.; Howard, M. J. J. Chem. Soc., Dalton Trans. 1996, 2187. 20 Cornils, B.; Herrmann, W. A.; Rasch, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 2144. 21 Rhodium Catalyzed Hydroformylation; Leeuwen, P. W. N. M. V.; Claver, C., Eds.; Springer: Netherlands, 2002; Vol. 22. 22 Pospech, J.; Fleischer, I.; Franke, R.; Buchholz, S.; Beller, M. Angew. Chem., Int. Ed. 2013, 52, 2852. 23 Knowles, W. S. Angew. Chem., Int. Ed. 2002, 41, 1999. 24 Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. 25 Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2024. 26 Chauvin, Y. Angew. Chem., Int. Ed. 2006, 45, 3740. 27 Grubbs, R. H. Angew. Chem., Int. Ed. 2006, 45, 3760. 28 Schrock, R. R. Angew. Chem., Int. Ed. 2006, 45, 3748. 29 Heck, R. F. Nobel Lecture: Palladium Reactions for Organic Syntheses; Nobelprize.org: Nobel Media AB, 2013. 209

30 Heck, R. F. Synlett 2006, 2006, 2855. 31 Negishi, E. I. Angew. Chem., Int. Ed. 2011, 50, 6738. 32 Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6722. 33 Stohs, S. J.; Bagchi, D. Free Radical Biol. Med. 1995, 18, 321. 34 Garrett, C. E.; Prasad, K. Adv. Synth. Catal. 2004, 346, 889. 35 Soga, K.; Shiono, T. Prog. Polym. Sci. 1997, 22, 1503. 36 Kaminsky, W. Macromol. Chem. Phys. 2008, 209, 459. 37 Kaminsky, W. J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 3911. 38 Kaminsky, W. J. Chem. Soc., Dalton Trans. 1998, 1413. 39 Ziegler, K.; Holzkamp, E.; Breil, H.; Martin, H. Angew. Chem., Int. Ed. 1955, 67, 541. 40 Natta, G.; Pino, P.; Corradini, P.; Danusso, F.; Mantica, E.; Mazzanti, G.; Moraglio, G. J. Am. Chem. Soc. 1955, 77, 1708. 41 Huang, J.; Rempel, G. L. Prog. Polym. Sci. 1995, 20, 459. 42 Resconi, L.; Cavallo, L.; Fait, A.; Piemontesi, F. Chem. Rev. 2000, 100, 1253. 43 Alt, H. G.; Köppl, A. Chem. Rev. 2000, 100, 1205. 44 Kaminsky, W.; Funck, A.; Hahnsen, H. Dalton Trans. 2009, 8803. 45 Coates, G. W. Chem. Rev. 2000, 100, 1223. 46 Grubbs, R. H.; Coates, G. W. Acc. Chem. Res. 1996, 29, 85. 47 Brookhart, M.; Green, M. L. H. J. Organomet. Chem. 1983, 250, 395. 48 Resconi, L.; Jones, R. L.; Rheingold, A. L.; Yap, G. P. A. Organometallics 1996, 15, 998. 49 Stehling, U.; Diebold, J.; Kirsten, R.; Roell, W.; Brintzinger, H. H.; Juengling, S.; Muelhaupt, R.; Langhauser, F. Organometallics 1994, 13, 964. 50 Razavi, A.; Atwood, J. L. J. Organomet. Chem. 1995, 497, 105. 51 Ewen, J. A.; Elder, M. J.; Jones, R. L.; Haspeslagh, L.; Atwood, J. L.; Bott, S. G.; Robinson, K. Makromol. Chem., Macromol. Symp. 1991, 48-49, 253. 52 Halterman, R. L. Chem. Rev. 1992, 92, 965. 53 Britovsek, G. J. P.; Gibson, V. C.; Wass, D. F. Angew. Chem., Int. Ed. 1999, 38, 428. 54 Gibson, V. C.; Spitzmesser, S. K. Chem. Rev. 2003, 103, 283. 55 Piers, W. E.; Emslie, D. J. H. Coord. Chem. Rev. 2002, 233, 131. 56 Kempe, R. Angew. Chem., Int. Ed. 2000, 39, 468. 57 Bradley, D. C.; Mehrotra, R. C.; Rothwell, I. P.; Singh, A. Alkoxo and Aryloxo Derivatives of Metals; Academic Press: London, 2001. 58 Healy, M. D.; Power, M. B.; Barron, A. R. Coord. Chem. Rev. 1994, 130, 63. 59 Mehrotra, R. C.; Singh, A.; Tripathi, U. M. Chem. Rev. 1991, 91, 1287. 60 Wolczanski, P. T. Polyhedron 1995, 14, 3335. 61 Rothwell, I. P. Acc. Chem. Res. 1988, 21, 153. 62 P. Rothwell, I. Chem. Commun. 1997, 1331. 63 Schrock, R. R. Acc. Chem. Res. 1990, 23, 158. 64 Wolczanski, P. T. Chem. Commun. 2009, 740. 65 Krempner, C. Eur. J. Inorg. Chem. 2011, 1689. 66 Chisholm, M. H.; Cotton, F. A.; Extine, M. W.; Kelly, R. L. J. Am. Chem. Soc. 1978, 100, 3354. 67 Togni, A.; Venanzi, L. M. Angew. Chem., Int. Ed. Engl. 1994, 33, 497. 68 Roesky, P. W. Z. Anorg. Allg. Chem. 2003, 629, 1881.

210

69 Anwander, R. In Organolanthoid Chemistry: Synthesis, Structure, Catalysis; Springer Berlin Heidelberg: 1996; Vol. 179, p 33. 70 Shi, Y. H.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 3967. 71 Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. 72 Crabtree, R. H. The organometallic chemistry of the transition metals; 5th ed.; Wiley: Hoboken, N.J. , 2009. 73 Edelmann, F. T. Chem. Soc. Rev. 2012, 41, 7657. 74 Ong, T. G.; Yap, G. P. A.; Richeson, D. S. Organometallics 2002, 21, 2839. 75 Chong, E.; Qayyum, S.; Schafer, L. L.; Kempe, R. Organometallics 2013, 32, 1858. 76 Burgstein, M. R.; Berberich, H.; Roesky, P. W. Organometallics 1998, 17, 1452. 77 Reznichenko, A. L.; Emge, T. J.; Audörsch, S.; Klauber, E. G.; Hultzsch, K. C.; Schmidt, B. Organometallics 2011, 30, 921. 78 Dörfler, J.; Doye, S. Angew. Chem., Int. Ed. 2013, 52, 1806. 79 Edelmann, F. T. In Advances in Organometallic Chemistry, Vol 57; Hill, A. F., Fink, M. J., Eds. 2008; Vol. 57, p 183. 80 Stewart, P. J.; Blake, A. J.; Mountford, P. J. Organomet. Chem. 1998, 564, 209. 81 Hagadorn, J. R.; Arnold, J. Organometallics 1998, 17, 1355. 82 Duncan, A. P.; Mullins, S. M.; Arnold, J.; Bergman, R. G. Organometallics 2001, 20, 1808. 83 Coles, M. P.; Hitchcock, P. B. Organometallics 2003, 22, 5201. 84 Smolensky, E.; Kapon, M.; Eisen, M. S. Organometallics 2005, 24, 5495. 85 Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. Rev. 2002, 102, 3031. 86 Mindiola, D. J. Acc. Chem. Res. 2006, 39, 813. 87 Garnovskii, A. D.; Sadimenko, A. P.; Sadimenko, M. I.; Garnovskii, D. A. Coord. Chem. Rev. 1998, 173, 31. 88 Mehrotra, R. C.; Bohra, R.; Gaur, D. P. Metal β-Diketonates and Allied Derivatives; Academic Press: New York, 1978. 89 Fay, R. C. Coord. Chem. Rev. 1996, 154, 99. 90 Grillo, V. A.; Seddon, E. J.; Grant, C. M.; Aromı, G.; Bollinger, J. C.; Folting, K.; Christou, G. Chem. Commun 1997, 1561. 91 Aromi, G.; Gamez, P.; Reedijk, J. Coord. Chem. Rev. 2008, 252, 964. 92 Zhang, W.-H.; Chien, S. W.; Hor, T. S. A. Coord. Chem. Rev. 2011, 255, 1991. 93 Braunstein, P.; Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680. 94 Bassetti, M. Eur. J. Inorg. Chem. 2006, 2006, 4473. 95 Slone, C. S.; Weinberger, D. A.; Mirkin, C. A. Prog. Inorg. Chem. 1999, 48, 233. 96 Bader, A.; Lindner, E. Coord. Chem. Rev. 1991, 108, 27. 97 Espinet, P.; Soulantica, K. Coord. Chem. Rev. 1999, 193–195, 499. 98 Weng, Z.; Teo, S.; Hor, T. S. A. Acc. Chem. Res. 2007, 40, 676. 99 Lee, A. V.; Schafer, L. L. Eur. J. Inorg. Chem. 2007, 2243. 100 Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 18246. 101 Leitch, D. C.; Beard, J. D.; Thomson, R. K.; Wright, V. A.; Patrick, B. O.; Schafer, L. L. Eur. J. Inorg. Chem. 2009, 2691. 102 Rawson, J. M.; Winpenny, R. E. P. Coord. Chem. Rev. 1995, 139, 313. 103 Walsh, P. J. Acc. Chem. Res. 2003, 36, 739. 104 Arndt, P.; Lefeber, C.; Kempe, R.; Tillack, A.; Rosenthal, U. Chem. Ber. 1996, 129, 1281. 211

105 Giesbrecht, G. R.; Shafir, A.; Arnold, J. Inorg. Chem. 2001, 40, 6069. 106 Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43, 5542. 107 Knight, P. D.; Munslow, I.; O'Shaughnessy, P. N.; Scott, P. Chem. Commun. 2004, 894. 108 Kissounko, D. A.; Guzei, I. A.; Gellman, S. H.; Stahl, S. S. Organometallics 2005, 24, 5208. 109 Reznichenko, A. L.; Hultzsch, K. C. Organometallics 2010, 29, 24. 110 Eisenberger, P.; Schafer, L. L. Pure Appl. Chem. 2010, 82, 1503. 111 Zhang, F.; Zhang, J.; Song, H.; Zi, G. Inorg. Chem. Commun. 2011, 14, 72. 112 Zi, G.; Zhang, F.; Song, H. Chem. Commun. 2010, 46, 6296. 113 Thomson, J. A.; Schafer, L. L. Dalton Trans. 2012, 41, 7897. 114 Stanlake, L. J. E.; Beard, J. D.; Schafer, L. L. Inorg. Chem. 2008, 47, 8062. 115 Webster, R. L.; Noroozi, N.; Hatzikiriakos, S. G.; Thomson, J. A.; Schafer, L. L. Chem. Commun. 2013, 49, 57. 116 Gribkov, D. V.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2004, 43, 5542. 117 Stanlake, L. J. E.; Schafer, L. L. Organometallics 2009, 28, 3990. 118 Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M. P.; Schafer, L. L. Angew. Chem., Int. Ed. 2009, 48, 8361. 119 Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104. 120 Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36, 1407. 121 Roesky, P. W. Angew. Chem., Int. Ed. 2009, 48, 4892. 122 Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. 123 Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. 124 Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935. 125 Payne, P. R.; Thomson, R. K.; Medeiros, D. M.; Wan, G.; Schafer, L. L. Dalton Trans. 2013, Accepted, n/a. 126 Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun. 2003, 2462. 127 Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733. 128 Zhang, Z.; Leitch, D. C.; Lu, M.; Patrick, B. O.; Schafer, L. L. Chem. Eur. J. 2007, 13, 2012. 129 Lee, A. V.; Schafer, L. L. Synlett 2006, 2973. 130 Zhai, H.; Borzenko, A.; Lau, Y. Y.; Ahn, S. H.; Schafer, L. L. Angew. Chem., Int. Ed. 2012, 51, 12219. 131 Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25, 4069. 132 Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. 133 Ayinla, R. O.; Gibson, T.; Schafer, L. L. J. Organomet. Chem. 2011, 696, 50. 134 Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354. 135 Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708. 136 Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305. 137 Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923. 138 Li, Y. H.; Shi, Y. H.; Odom, A. L. J. Am. Chem. Soc. 2004, 126, 1794. 139 Gott, A. L.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Chem. Commun. 2008, 1422. 140 Allan, L. E. N.; Clarkson, G. J.; Fox, D. J.; Gott, A. L.; Scott, P. J. Am. Chem. Soc. 2010, 132, 15308. 141 Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2009, 48, 6938.

212

142 Wood, M. C.; Leitch, D. C.; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354. 143 Zhang, F.; Song, H.; Zi, G. Dalton Trans. 2011, 40, 1547. 144 Reznichenko, A. L.; Hultzsch, K. C. J. Am. Chem. Soc. 2012, 134, 3300. 145 Nugent, W. A.; Ovenall, D. W.; Holmes, S. J. Organometallics 1983, 2, 161. 146 Lauzon, J. M. P. Development of Group 4 and 5 Complexes with N,O-Chelating Supporting Ligands as Catalysts for the α-Alkylation of Amines. Ph.D., University of British Columbia, 2013. 147 Lappert, M. F.; Sanger, A. R. J. Chem. Soc. A 1971, 1314. 148 Chandra, G.; Jenkins, A. D.; Lappert, M. F.; Srivastava, R. C. J. Chem. Soc. A 1970, 2550. 149 Wang, H.; Chan, H. S.; Xie, Z. W. Organometallics 2005, 24, 3772. 150 Leitch, D. C.; Schafer, L. L. Organometallics 2010, 29, 5162. 151 Leitch, D. C. Group 4 Ureate Complexes: Synthesis, Reactivity, and Catalytic Carbon- Element Bond Formation, University of British Columbia, 2010. 152 Leitch, D. C.; Platel, R. H.; Schafer, L. L. J. Am. Chem. Soc. 2011, 133, 15453. 153 Tobisch, S. Inorg. Chem. 2012, 51, 3786. 154 Parsons, S.; Winpenny, R. E. P. Acc. Chem. Res. 1997, 30, 89. 155 Fandos, R.; Hernandez, C.; Otero, A.; Rodriguez, A.; Ruiz, M. J.; Terreros, P. Eur. J. Inorg. Chem. 2003, 493. 156 Antinolo, A.; Carrillo-Hermosilla, F.; Corrochano, A. E.; Fandos, R.; Fernandez-Baeza, J.; Rodriguez, A. M.; Ruiz, M. J.; Otero, A. Organometallics 1999, 18, 5219. 157 Cotton, F. A.; Lewis, G. E.; Mott, G. N. Inorg. Chem. 1983, 22, 378. 158 Bexrud, J. A.; Schafer, L. L. Dalton Trans. 2010, 39, 361. 159 Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.; Schafer, L. L. J. Am. Chem. Soc. 2009, 131, 2116. 160 Preuß, T.; Saak, W.; Doye, S. Chem. Eur. J. 2013, 19, 3833. 161 Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2010, 49, 2626. 162 Prochnow, I.; Kubiak, R.; Frey, O. N.; Beckhaus, R.; Doye, S. ChemCatChem 2009, 1, 162. 163 Kubiak, R.; Prochnow, I.; Doye, S. Angew. Chem., Int. Ed. 2009, 48, 1153. 164 Takahashi, H.; Kawakita, T.; Ohno, M.; Yoshioka, M.; Kobayashi, S. Tetrahedron 1992, 48, 5691. 165 Takahashi, H.; Kawakita, T.; Yoshioka, M.; Kobayashi, S.; Ohno, M. Tetrahedron Lett. 1989, 30, 7095. 166 Lutz, C.; Knochel, P. J. Org. Chem. 1997, 62, 7895. 167 Vettel, S.; Lutz, C.; Diefenbach, A.; Haderlein, G.; Hammerschmidt, S.; Kühling, K.; Mofid, M. R.; Zimmermann, T.; Knochel, P. Tetrahedron: Asymm. 1997, 8, 779. 168 Armistead, L. T.; White, P. S.; Gagné, M. R. Organometallics 1998, 17, 216. 169 Hamura, S.; Oda, T.; Shimizu, Y.; Matsubara, K.; Nagashima, H. J. Chem. Soc., Dalton Trans. 2002, 1521. 170 Ackermann, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956. 171 Ackermann, L.; Bergman, R. G. Org. Lett. 2002, 4, 1475. 172 Jaspers, D.; Saak, W.; Doye, S. Synlett 2012, 23, 2098. 173 Hannedouche, J.; Schulz, E. Chem. Eur. J. 2013, 19, 4972. 174 Hultzsch, K. C. Org. Biomol. Chem. 2005, 3, 1819. 175 Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367. 213

176 Chemler, S. R. Org. Biomol. Chem. 2009, 7, 3009. 177 Roesky, P. W.; Muller, T. E. Angew. Chem., Int. Ed. 2003, 42, 2708. 178 Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans. 2007, 5105. 179 Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119, 10857. 180 Zhou, J.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 12220. 181 Hii, K. K. Pure Appl. Chem. 2006, 78, 341. 182 Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 4366. 183 Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546. 184 Hu, A. G.; Ogasawara, M.; Sakamoto, T.; Okada, A.; Nakajima, K.; Takahashi, T.; Lin, W. B. Adv. Synth. Catal. 2006, 348, 2051. 185 Widenhoefer, R. A. Chem. Eur. J. 2008, 14, 5382. 186 Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45, 3314. 187 LaLonde, R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007, 129, 2452. 188 Hamilton, G. L.; Kang, E. J.; Mba, M.; Toste, F. D. Science 2007, 317, 496. 189 Shen, X.; Buchwald, S. L. Angew. Chem., Int. Ed. 2010, 49, 564. 190 Turnpenny, B. W.; Hyman, K. L.; Chemler, S. R. Organometallics 2012, 31, 7819. 191 Horrillo-Martinez, P.; Hultzsch, K. C.; Hampel, F. Chem. Commun. 2006, 2221. 192 Deschamp, J.; Olier, C.; Schulz, E.; Guillot, R.; Hannedouche, J.; Collin, J. Adv. Synth. Catal. 2010, 352, 2171. 193 Deschamp, J.; Collin, J.; Hannedouche, J.; Schulz, E. Eur. J. Org. Chem. 2011, 3329. 194 Buch, F.; Harder, S. Z. Naturforsch., B: Chem. Sci. 2008, 63, 169. 195 Horrillo-Martinez, P.; Hultzsch, K. C. Tetrahedron Lett. 2009, 50, 2054. 196 Wixey, J. S.; Ward, B. D. Chem. Commun. 2011, 47, 5449. 197 Wixey, J. S.; Ward, B. D. Dalton Trans. 2011, 40, 7693. 198 Neal, S. R.; Ellern, A.; Sadow, A. D. J. Organomet. Chem. 2011, 696, 228. 199 Zhang, X.; Emge, T. J.; Hultzsch, K. C. Angew. Chem., Int. Ed. 2012, 51, 394. 200 Shapiro, N. D.; Rauniyar, V.; Hamilton, G. L.; Wu, J.; Toste, F. D. Nature 2011, 470, 245. 201 Dion, I.; Beauchemin, A. M. Angew. Chem., Int. Ed. 2011, 50, 8233. 202 Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673. 203 Gagné, M. R.; Brard, L.; Conticello, V. P.; Giardello, M. A.; Stern, C. L.; Marks, T. J. Organometallics 1992, 11, 2003. 204 O'Shaughnessy, P. N.; Knight, P. D.; Morton, C.; Gillespie, K. M.; Scott, P. Chem. Commun. 2003, 1770. 205 Kim, J. Y.; Livinghouse, T. Org. Lett. 2005, 7, 1737. 206 Hong, S. W.; Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 14768. 207 Hannedouche, J.; Collin, J.; Trifonov, A.; Schulz, E. J. Organomet. Chem. 2011, 696, 255. 208 Gribkov, D. V.; Hultzsch, K. C. Chem. Commun. 2004, 730. 209 Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. 210 Zi, G. Dalton Trans. 2009, 0, 9101. 211 Manna, K.; Kruse, M. L.; Sadow, A. D. ACS Catal. 2011, 1, 1637. 212 Zi, G. J. Organomet. Chem. 2011, 696, 68. 213 Manna, K.; Xu, S.; Sadow, A. D. Angew. Chem., Int. Ed. 2011, 50, 1865. 214 Manna, K.; Everett, W. C.; Schoendorff, G.; Ellern, A.; Windus, T. L.; Sadow, A. D. J. Am. Chem. Soc. 2013, 135, 7235. 215 Payne, P. R.; Bexrud, J. A.; Leitch, D. C.; Schafer, L. L. Can. J. Chem. 2011, 89, 1222. 214

216 Bexrud, J. A. Hydroamination and C–H activation reactivity of tetrakis(amido), bis(amidate), and bis(2-pyridonate) complexes of titanium and zirconium. Ph.D., University of British Columbia, 2008. 217 Roesky, P. W. Angew. Chem., Int. Ed. 2009, 48, 4892. 218 Anormed Inc. WO 2007022371 (A2) 219 MacNevin, C. J.; Moore, R. L.; Liotta, D. C. J. Org. Chem. 2008, 73, 1264. 220 Rotstein, D. M.; Gabriel, S. D.; Manser, N.; Filonova, L.; Padilla, F.; Sankuratri, S.; Ji, C.; deRosier, A.; Dioszegi, M.; Heilek, G.; Jekle, A.; Weller, P.; Berry, P. Bioorg. Med. Chem. Lett. 2010, 20, 3219. 221 Hernández-Rodríguez, M.; Avila-Ortiz, C. G.; del Campo, J. M.; Hernández-Romero, D.; Rosales-Hoz, M. J.; Juaristi, E. Aust. J. Chem. 2008, 61, 364. 222 Hernández-Rodríguez, M.; Melgar-Fernández, R.; Juaristi, E. J. Phys. Org. Chem. 2005, 18, 792. 223 Roos, G. H. P. S. S. Afr. J. Chem. 1997, 50, 1. 224 Nguyen, Q. P. B.; Kim, J. N.; Kim, T. H. Tetrahedron Lett. 2009, 50, 4015. 225 Zhang, Z.; Lee, S. D.; Widenhoefer, R. A. J. Am. Chem. Soc. 2009, 131, 5372. 226 Ward, B. D.; Risler, H.; Weitershaus, K.; Bellemin-Laponnaz, S.; Wadepohl, H.; Gade, L. H. Inorg. Chem. 2006, 45, 7777. 227 Hu, Y.-C.; Liang, C.-F.; Tsai, J.-H.; Yap, G. P. A.; Chang, Y.-T.; Ong, T.-G. Organometallics 2010, 29, 3357. 228 Kim, H.; Livinghouse, T.; Lee, P. H. Tetrahedron 2008, 64, 2525. 229 Majumder, S.; Odom, A. L. Organometallics 2008, 27, 1174. 230 Zi, G. F.; Zhang, F. R.; Xiang, L.; Chen, Y.; Fang, W. H.; Song, H. B. Dalton Trans. 2010, 39, 4048. 231 Thomson, R. K.; Zahariev, F. E.; Zhang, Z.; Patrick, B. O.; Wang, Y. A.; Schafer, L. L. Inorg. Chem. 2005, 44, 8680. 232 Xiang, L.; Song, H. B.; Zi, G. F. Eur. J. Inorg. Chem. 2008, 1135. 233 Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Polidori, G.; Spagna, R. J. Appl. Crystallogr. 1999, 32, 115. 234 Bruker, SADABS-2008/1, Bruker AXS Inc., Madison, Wisconsin, USA, 2008 235 Sheldrick, G. M. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112. 236 Farrugia, L. J. J. Appl. Crystallogr. 2012, 45, 849. 237 Spek, A. L. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 148. 238 Burnett, M. N.; Johnson, C. K., Ortep-III, Report ORNL-6895 Oak Ridge National Laboratory, Oak Ridge, TN, USA, 1996 239 Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186. 240 Quinet, C.; Jourdain, P.; Hermans, C.; Ates, A.; Lucas, I.; Markó, I. E. Tetrahedron 2008, 64, 1077. 241 Lauterwasser, F.; Hayes, P. G.; Braese, S.; Piers, W. E.; Schafer, L. L. Organometallics 2004, 23, 2234. 242 Riegert, D.; Collin, J.; Meddour, A.; Schulz, E.; Trifonov, A. J. Org. Chem. 2006, 71, 2514. 243 The 1H NMR spectra of the solution after this time period is consistent with ligand coordination. 244 Levkin, P. A.; Ruderisch, A.; Schurig, V. Chirality 2006, 18, 49. 245 Katritzky, A. R.; He, H.-Y.; Verma, A. K. Tetrahedron: Asymm. 2002, 13, 933. 215

246 Clerici, M. G.; Maspero, F. Synthesis-Stuttgart 1980, 1980, 305. 247 Zhang, Z.; Hamel, J.-D.; Schafer, L. L. Chem. Eur. J. 2013, 19, 8751. 248 Garcia, P.; Payne, P. R.; Chong, E.; Webster, R. L.; Barron, B. J.; Behrle, A. C.; Schmidt, J. A. R.; Schafer, L. L. Tetrahedron 2013, 69, 5737. 249 Garcia, P.; Lau, Y. Y.; Perry, M. R.; Schafer, L. L. Angew. Chem., Int. Ed. 2013, 52, 9144. 250 Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 14940. 251 Herzon, S. B.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 6690. 252 Müller, C.; Saak, W. G.; Doye, S. Eur. J. Org. Chem. 2008, 2731. 253 Ramanathan, B.; Odom, A. L. J. Am. Chem. Soc. 2006, 128, 9344. 254 Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001, 40, 4632. 255 Prochnow, I.; Zark, P.; Müller, T.; Doye, S. Angew. Chem., Int. Ed. 2011, 50, 6401. 256 Li, Y. W.; Marks, T. J. Organometallics 1996, 15, 3770. 257 Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 14286. 258 Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702. 259 Cummings, S. A.; Tunge, J. A.; Norton, J. R. Topics Organomet. Chem. 2005, 10, 1 260 Aymard, P.; Durand, D.; Nicolai, T. Int. J. Biol. Macromol. 1996, 19, 213. 261 Ghasemi, J.; Niazi, A.; Westman, G.; Kubista, M. Talanta 2004, 62, 835. 262 Spencer, W.; Sutter, J. R. J. Phys. Chem. 1979, 83, 1573. 263 Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J. Am. Chem. Soc. 1991, 113, 2321. 264 Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan, J. C. J. Am. Chem. Soc. 1989, 111, 4486. 265 Johnson, C. S. Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203. 266 Morris, K. F.; Johnson, C. S. J. Am. Chem. Soc. 1992, 114, 3139. 267 Macchioni, A.; Ciancaleoni, G.; Zuccaccia, C.; Zuccaccia, D. Chem. Soc. Rev. 2008, 37, 479. 268 Adams, N.; Arts, H. J.; Bolton, P. D.; Cowell, D.; Dubberley, S. R.; Friederichs, N.; Grant, C. M.; Kranenburg, M.; Sealey, A. J.; Wang, B.; Wilson, P. J.; Cowley, A. R.; Mountford, P.; Schroder, M. Chem. Commun. 2004, 434. 269 Adams, N.; Arts, H. J.; Bolton, P. D.; Cowell, D.; Dubberley, S. R.; Friederichs, N.; Grant, C. M.; Kranenburg, M.; Sealey, A. J.; Wang, B.; Wilson, P. J.; Zuideveld, M.; Blake, A. J.; Schroder, M.; Mountford, P. Organometallics 2006, 25, 3888. 270 Cummins, C. C.; Baxter, S. M.; Wolczanski, P. T. J. Am. Chem. Soc. 1988, 110, 8731. 271 Walsh, P. J.; Hollander, F. J.; Bergman, R. G. J. Am. Chem. Soc. 1988, 110, 8729. 272 Hirsekorn, K. F.; Veige, A. S.; Marshak, M. P.; Koldobskaya, Y.; Wolczanski, P. T.; Cundari, T. R.; Lobkovsky, E. B. J. Am. Chem. Soc. 2005, 127, 4809. 273 Bashall, A.; Collier, P. E.; Gade, L. H.; McPartlin, M.; Mountford, P.; Trosch, D. J. M. Chem. Commun. 1998, 2555. 274 Hoyt, H. M.; Bergman, R. G. Angew. Chem., Int. Ed. 2007, 46, 5580. 275 Hoyt, H. M.; Michael, F. E.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 1018. 276 Lee, A. V.; Schafer, L. L. Organometallics 2006, 25, 5249. 277 Gräbe, K.; Pohlki, F.; Doye, S. Eur. J. Org. Chem. 2008, 2008, 4815. 278 Overman, L. E.; Roos, J. P. J. Org. Chem. 1981, 46, 811. 279 Wu, D. H.; Chen, A. D.; Johnson, C. S. Journal of Magnetic Resonance, Series A 1995, 115, 260. 280 Watson, I. D. G.; Ritter, S.; Toste, F. D. J. Am. Chem. Soc. 2009, 131, 2056. 281 Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. 216

282 Li, Y.; Jardine, K. J.; Tan, R.; Song, D.; Dong, V. M. Angew. Chem., Int. Ed. 2009, 48, 9690. 283 Clark, A. J.; Deeth, R. J.; Samuel, C. J.; Wongtap, H. Synlett 1999, 1999, 444. 284 Payne, P. R.; Garcia, P.; Eisenberger, P.; Yim, J. C. H.; Schafer, L. L. Org. Lett. 2013, 15, 2182. 285 Barron, B. J. Investigations into chiral mono-amidate ligands in hydroaminoalkylation catalysis B.Sc. Honours, University of British Columbia, 2011. 286 Dibenedetto, A.; Pastore, C.; Aresta, M. Catal. Today 2006, 115, 88. 287 Ryken, S., Unpublished Results. 288 Han, C.; Lee, J. P.; Lobkovsky, E.; Porco, J. A. J. Am. Chem. Soc. 2005, 127, 10039. 289 Representative 1H and 13C NMR spectra are included in Appendix B. 290 Chisholm, M. H.; Huffman, J. C.; Tan, L.-S. Inorg. Chem. 1981, 20, 1859. 291 Chao, Y. W.; Polson, S.; Wigley, D. E. Polyhedron 1990, 9, 2709. 292 Chao, Y. W.; Wexler, P. A.; Wigley, D. E. Inorg. Chem. 1989, 28, 3860. 293 Schweiger, S. W.; Tillison, D. L.; Thorn, M. G.; Fanwick, P. E.; Rothwell, I. P. J. Chem. Soc., Dalton Trans. 2001, 2401. 294 Chen, S.-J.; Cai, H.; Xue, Z.-L. Organometallics 2009, 28, 167. 295 See Appendix B for NMR spectral data. 296 Son, A. J. R.; Schweiger, S. W.; Thorn, M. G.; Moses, J. E.; Fanwick, P. E.; Rothwell, I. P. Dalton Trans. 2003, 1620. 297 Eisenberger, P., Unpublished results. 298 Naqvi, F.; Rauf, A.; Siddiqui, M. M.; Ahmad, M. S., Jr.; Osman, S. M. J. Am. Oil Chem. Soc. 1997, 74, 713. 299 Zhang, S.; Chang, Z.; Xu, K.; Angell, C. A. Electrochim. Acta 2000, 45, 1229. 300 Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. 301 Mills, R. C.; Doufou, P.; Abboud, K. A.; Boncella, J. M. Polyhedron 2002, 21, 1051. 302 Zhang, X.-L.; Yan, Y.-P.; Ding, L.; Luo, L.-T. Acta Crystallogr., Sect. E: Struct. Rep. Online 2006, 62, o5809. 303 Gowda, B. T.; Foro, S.; Nirmala, P. G.; Terao, H.; Fuess, H. Acta Crystallogr., Sect. E: Struct. Rep. Online 2009, 65, o1219. 304 Nirmala, P. G.; Gowda, B. T.; Foro, S.; Fuess, H. Acta Crystallogr., Sect. E: Struct. Rep. Online 2010, 66, o1168. 305 Moss, G. P. Pure Appl. Chem. 1996, 68, 2193. 306 Pasteur, L. C. R. Acad. Sci. 1848, 26, 535. 307 Flack, H. Acta Crystallogr., Sect. A: Found. Crystallogr. 2009, 65, 371. 308 Dryzun, C.; Avnir, D. Chem. Commun. 2012, 48, 5874. 309 Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; Krieger Publishing Co.: Malabar, FL, USA, 1994. 310 Flack, H. Acta Crystallogr., Sect. A: Found. Crystallogr. 1983, 39, 876. 311 Carver, F. J.; Hunter, C. A.; Livingstone, D. J.; McCabe, J. F.; Seward, E. M. Chem. Eur. J. 2002, 8, 2847. 312 Cockroft, S. L.; Perkins, J.; Zonta, C.; Adams, H.; Spey, S. E.; Low, C. M. R.; Vinter, J. G.; Lawson, K. R.; Urch, C. J.; Hunter, C. A. Org. Biomol. Chem. 2007, 5, 1062. 313 Brenner, M.; Huber, W. Helv. Chim. Acta 1953, 36, 1109. 314 Yamada, T.; Lukac, P. J.; Yu, T.; Weiss, R. G. Chem. Mater. 2007, 19, 4761. 315 Corr, L. T.; Berstan, R.; Evershed, R. P. Rapid Commun. Mass Spectrom. 2007, 21, 3759. 217

316 Dydio, P.; Rubay, C.; Gadzikwa, T.; Lutz, M.; Reek, J. N. H. J. Am. Chem. Soc. 2011, 133, 17176. 317 Sparapani, S.; Haider, S. M.; Doria, F.; Gunaratnam, M.; Neidle, S. J. Am. Chem. Soc. 2010, 132, 12263. 318 Costa, J. C. S.; Neves, J. S.; de Souza, M. V. N.; Siqueira, R. A.; Romeiro, N. C.; Boechat, N.; e Silva, P. M. R.; Martins, M. A. Bioorg. Med. Chem. Lett. 2008, 18, 1162. 319 Taniguchi, N. Eur. J. Org. Chem. 2010, 2670. 320 Barluenga, J.; Fananas, F. J.; Sanz, R.; Marcos, C.; Ignacio, J. M. Chem. Commun. 2005, 933. 321 Heterocycles in Natural Product Synthesis; Majumdar, K., C.; Chattopadhyay, S. K., Eds.; Wiley-VCH, 2011. 322 Bayer CropScience AG. WO 2012104273 (A1) 323 Bayer CropScience AG. WO2012052491 (A2) 324 Dua, R.; Shrivastava, S.; Sonwane, S. K.; Srivastava, S. K. Advan. Biol. Res. 2011, 5, 120. 325 Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein J. Org. Chem. 2011, 7, 442. 326 Couty, F.; Drouillat, B.; Evano, G.; David, O. Eur. J. Org. Chem. 2013, 2013, 2045. 327 McGrath, N. A.; Brichacek, M.; Njardarson, J. T. J. Chem. Educ. 2010, 87, 1348. 328 Stead, L. F.; Hughes, J. R. Cochrane Database of Systematic Reviews 2012, Art. No.: CD000124. DOI: 10.1002/14651858.CD000124.pub2. . 329 Alexandre-Moreira, M. S.; Viegas Jr, C.; Palhares de Miranda, A. L.; da Silva Bolzani, V.; Barreiro, E. J. Planta Med. 2003, 69, 795. 330 Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2012, 18, 10092. 331 Li, C.-J. Acc. Chem. Res. 2009, 42, 335. 332 Doye, S. Angew. Chem., Int. Ed. 2001, 40, 3351. 333 Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443. 334 Campos, K. R. Chem. Soc. Rev. 2007, 36, 1069. 335 Beak, P.; Basu, A.; Gallagher, D. J.; Park, Y. S.; Thayumanavan, S. Acc. Chem. Res. 1996, 29, 552. 336 Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2283. 337 O'Brien, P.; Bilke, J. L. Angew. Chem., Int. Ed. 2008, 47, 2734. 338 Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. 339 Li, C.-J. Acc. Chem. Res. 2008, 42, 335. 340 Li, C. J.; Li, Z. P. Pure Appl. Chem. 2006, 78, 935. 341 Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005, 127, 11610. 342 Yoshimitsu, T.; Matsuda, K.; Nagaoka, H.; Tsukamoto, K.; Tanaka, T. Org. Lett. 2007, 9, 5115. 343 Suga, S.; Suzuki, S.; Yoshida, J.-I. J. Am. Chem. Soc. 2001, 124, 30. 344 Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687. 345 Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J. Am. Chem. Soc. 2003, 125, 6462. 346 Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2009, 110, 704. 347 Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654. 348 Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902. 349 O'Brien, P. Chem. Commun. 2008, 655. 218

350 McGrath, M. J.; Bilke, J. L.; O'Brien, P. Chem. Commun. 2006, 2607. 351 Barker, G.; O'Brien, P.; Campos, K. R. Org. Lett. 2010, 12, 4176. 352 Prokopcová, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout, W.; Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2010, 16, 13063. 353 Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. 354 Bailey, W. F.; Beak, P.; Kerrick, S. T.; Ma, S. H.; Wiberg, K. B. J. Am. Chem. Soc. 2002, 124, 1889. 355 Stead, D.; Carbone, G.; O'Brien, P.; Campos, K. R.; Coldham, I.; Sanderson, A. J. Am. Chem. Soc. 2010, 132, 7260. 356 Coldham, I.; Raimbault, S.; Whittaker, D. T. E.; Chovatia, P. T.; Leonori, D.; Patel, J. J.; Sheikh, N. S. Chem. Eur. J. 2010, 16, 4082. 357 Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.; Chen, C.-y. J. Am. Chem. Soc. 2006, 128, 3538. 358 Seel, S.; Thaler, T.; Takatsu, K.; Zhang, C.; Zipse, H.; Straub, B. F.; Mayer, P.; Knochel, P. J. Am. Chem. Soc. 2011, 133, 4774. 359 Beng, T. K.; Gawley, R. E. Org. Lett. 2011, 13, 394. 360 Barker, G.; McGrath, J. L.; Klapars, A.; Stead, D.; Zhou, G.; Campos, K. R.; O'Brien, P. J. Org. Chem. 2011, 76, 5936. 361 Cordier, C. J.; Lundgren, R. J.; Fu, G. C. J. Am. Chem. Soc. 2013. 362 Murahashi, S. I.; Komiya, N.; Terai, H.; Nakae, T. J. Am. Chem. Soc. 2003, 125, 15312. 363 Murahashi, S.-I.; Zhang, D. Chem. Soc. Rev. 2008, 37, 1490. 364 Li, Z. P.; Li, C. J. Org. Lett. 2004, 6, 4997. 365 Baslé, O.; Li, C.-J. Green Chem. 2007, 9, 1047. 366 Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.; Schnuerch, M. Chem. Commun. 2010, 46, 8836. 367 Ghobrial, M.; Schnürch, M.; Mihovilovic, M. D. J. Org. Chem. 2011, 76, 8781. 368 Kumaraswamy, G.; Murthy, A. N.; Pitchaiah, A. J. Org. Chem. 2010, 75, 3916. 369 Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701. 370 Murahashi, S. I.; Nakae, T.; Terai, H.; Komiya, N. J. Am. Chem. Soc. 2008, 130, 11005. 371 Murahashi, S. I.; Komiya, N.; Terai, H. Angew. Chem., Int. Ed. 2005, 44, 6931. 372 Jovel, I.; Prateeptongkum, S.; Jackstell, R.; Vogl, N.; Weckbecker, C.; Beller, M. Chem. Commun. 2010, 46, 1956. 373 North, M. Angew. Chem., Int. Ed. 2004, 43, 4126. 374 Xie, J.; Li, H.; Zhou, J.; Cheng, Y.; Zhu, C. Angew. Chem., Int. Ed. 2012, 51, 1252. 375 Sud, A.; Sureshkumar, D.; Klussmann, M. Chem. Commun. 2009, 0, 3169. 376 Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062. 377 Yoshida, J.-i.; Suga, S.; Suzuki, S.; Kinomura, N.; Yamamoto, A.; Fujiwara, K. J. Am. Chem. Soc. 1999, 121, 9546. 378 Condie, A. G.; González-Gómez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. 379 McNally, A.; Prier, C. K.; MacMillan, D. W. C. Science 2011, 334, 1114. 380 Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran, D. P.; Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823. 381 Pastine, S. J.; Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220.

219

382 Peschiulli, A.; Smout, V.; Storr, T. E.; Mitchell, E. A.; Eliáš, Z.; Herrebout, W.; Berthelot, D.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2013, doi: 10.1002/chem.201204438. 383 Only when heteroarene boronic esters are used can selective mono-arylation be achieved 384 Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2001, 123, 10935. 385 Bergman, S. D.; Storr, T. E.; Prokopcová, H.; Aelvoet, K.; Diels, G.; Meerpoel, L.; Maes, B. U. W. Chem. Eur. J. 2012, 18, 10393. 386 Pan, S.; Endo, K.; Shibata, T. Org. Lett. 2011, 13, 4692. 387 Jun, C.-H. Chem. Commun. 1998, 0, 1405. 388 Gembus, V.; Marsais, F.; Levacher, V. Synlett 2008, 2008, 1463. 389 Determined using SFC analysis of the tosylated product, see experimental for more details 390 Hall, H. K. J. Am. Chem. Soc. 1957, 79, 5441. 391 Batiz-Hernandez, H.; Bernheim, R. A. Prog. Nucl. Magn. Reson. Spectrosc. 1967, 3, 63. 392 Bernheim, R. A.; Batiz-Hernandez, H. J. Chem. Phys. 1966, 45, 2261. 393 Marconi, G. C.; Orlandi, G. Chem. Phys. 1975, 10, 439. 394 Millet, A.; Larini, P.; Clot, E.; Baudoin, O. Chemical Science 2013, 4, 2241. 395 Lauzon, J. M. P.; Schafer, L. L. Dalton Trans. 2012, 41, 11539. 396 Corey, E. J.; Venkates.A J. Am. Chem. Soc. 1972, 94, 6190. 397 Okada, M.; Kitagawa, O.; Fujita, M.; Taguchi, T. Tetrahedron 1996, 52, 8135. 398 Bakina, E.; Wu, Z.; Rosenblum, M.; Farquhar, D. J. Med. Chem. 1997, 40, 4013. 399 Gaussian 03, Revision E.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al- Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian, Inc., Wallingford CT, 2004. 400 Gaussian 09, Revision C.01, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 220

401 Becke, A. D. J. Chem. Phys. 1993, 98, 5648. 402 Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. 403 Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58, 1200. 404 Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. The Journal of Physical Chemistry 1994, 98, 11623. 405 Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270. 406 Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299. 407 Møller, C.; Plesset, M. S. Phys. Rev. 1934, 46, 618. 408 GaussView, Version 5, Dennington, R.; Keith, T.; Millam, J. Semichem Inc., Shawnee Mission KS, 2009. 409 Gissot, A.; Rebek, J. J. Am. Chem. Soc. 2004, 126, 7424. 410 Fujii, M.; Nishimura, T.; Koshiba, T.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2013, 15, 232.

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APPENDICES

Appendix A X-ray crystallographic data

Table A.1 Crystallographic parameters for the cyclic urea proligand and the bimetallic ureate and pyridonate zirconium complexes (Chapter 2). 8 10 11

Empirical formula C12H22N2O C71H78N4O3Zr C25H42N8O3Zr2

Fw 210.32 1030.75 685.11 Habit, colour Needle, colourless Prism, yellow Yellow, prism Crystal dimensions (mm) 0.5 × 0.5 × 0.2 0.40 × 0.30 × 0.20 0.37 x 0.28 x 0.21 Crystal system Triclinic Orthorhombic Orthorhombic

Space group P1 P212121 Pbca Z 2 4 8 a (Å) 5.4527(4) 12.493(1) 16.0128(7) b (Å) 10.4649(6) 20.562(2) 17.5415(7) c (Å) 11.5266(7) 20.876(2) 21.932(1) α (°) 71.667(3) 90 90 β (°) 79.932(4) 90 90 γ (°) 77.365(3) 90 90 Collection ranges h = -7→7 h = -17→17 h = -22→21 k = -13→13 k = -29→29 k = -24→20 l = -14→14 l = -29→29 l = -27→30 Temperature (K) 100 100 90 Volume (Å3) 605.22(7) 5362(1) 6160.3(8) -3 Dcalcd (Mg m ) 1.154 1.277 1.477 Radiation (Mo Kα) λ = 0.71073 Å λ = 0.71073 Å λ = 0.71073 Å Absorp. coeff. μ (mm-1) 0.07 0.44 0.72 F(000) 232 2200 2816

θmin – θmax (°) 1.9 – 27.6 1.9 – 30.1 2.5 to 30.2 Measured reflections 19616 231343 38480

Independent reflections 5463 (Rint=0.030) 15815 (Rint = 0.025) 9066 (Rint = 0.038) Data/restraints/parameters 5463/3/279 15815/0/576 9066/0/353 Maximum shift/error < 0.001 0.003 0.003 Goodness-of-fit on F2 1.057 1.087 1.028 Final R indices (I > 2σ(I)) R1 = 0.037 R1 = 0.017 R1 = 0.034 wR2 = 0.095 wR2 = 0.045 wR2 = 0.057 R indices (all data) R1 = 0.044 R1 = 0.018 R1 = 0.044 wR2 = 0.100 wR2 = 0.045 wR2 = 0.063 absolute structure parameter N/A 0.000(11) N/A Largest diff. peak -3 0.317 and -0.214 0.447 and -0.249 0.589 and -0.493 and hole (e Å ) 222

Table A.2 Crystallographic parameters for the bridging imido pyridonate complex (Chapter 3). 16

Empirical formula C38H41N3O2Zr

Fw 662.96 Habit, colour Prism, yellow Crystal dimensions (mm) 0.20 × 0.50 × 2.0 Crystal system Triclinic Space group P-1 Z 2 a (Å) 12.485(3) b (Å) 12.683(3) c (Å) 12.752(2) α (°) 77.817(8) β (°) 74.324(7) γ (°) 66.739(7) Collection ranges h = -13→12 k = -13→13 l = -13→13 Temperature (K) 100 Volume (Å3) 1773.6(9) -3 Dcalcd (Mg m ) 1.24 Radiation (Mo Kα) λ = 0.71073 Å Absorp. coeff. μ (mm-1) 0.345 F(000) 692

θmin – θmax (°) 2.6 – 23.0 Measured reflections 14843

Independent reflections 4283 (Rint=0.055) Data/restraints/parameters 4283/0/397 Maximum shift/error < 0.001 Goodness-of-fit on F2 1.087

Final R indices (I >2σ(I)) R1 = 0.111 wR2 = 0.326 R indices (all data) R1 = 0.126 wR2 = 0.336 Largest diff. peak 4.204 and -0.646 and hole (e Å-3)

223

Table A.3 Crystallographic parameters for the mono(amidate) tetrakis(dimethylamido) tantalum complexes (Chapter 4). 27 28 29 and 30

Empirical formula C25H42N5O2Ta C23H51N6O2Ta C39H91N11O5Ta2

Fw 890.88 624.65 Mr = 578.06 Habit, colour Needle, yellow Plates, yellow Prisms, yellow Crystal dimensions (mm) 0.19 × 0.27 × 0.40 0.10 × 0.20 × 0.30 0.70 × 0.50 × 0.45 Crystal system Triclinic Monoclinic Monoclinic

Space group P-1 P21/n P21/b Z 1 4 2 a (Å) 8.5888(5) 10.8598(4) 9.3614(4) b (Å) 10.7640(7) 16.2003(7) 9.2391(5) c (Å) 16.082(1) 16.4794(6) 29.5826(15) α (°) 102.439(3) 90 90 β (°) 98.884(3) 94.948(2) 90.050(2) γ (°) 108.086(3) 90 90 Collection ranges h = -12→11 h = -15→15 h = -12→12 k = -15→14 k = -22→22 k = -12→12 l = 0→22 l = -21→23 l = -38→38 Temperature (K) 100 100 100 Volume (Å3) 1340.3(2) 2888.5(2) 2558.6(2) -3 Dcalcd (Mg m ) 1.551 1.436 1.50 Radiation (Mo Kα) λ = 0.71073 Å λ = 0.71073 Å λ = 0.71073 Å Absorp. coeff. μ (mm-1) 4.131 3.83 4.32 F(000) 632 1280 1176

θmin – θmax (°) 2.1 – 30.1 1.8 – 30.1 7.0 – 27.9 Measured reflections 14346 60267 110773

Independent reflections 14353 (Rint = 0.000) 8422 (Rint = 0.052) 11937 (Rint = 0.046) Data/restraints/parameters 14353/0/311 8422/0/302 11937/60/270 Maximum shift/error 0.005 0.002 0.043 Goodness-of-fit on F2 1.270 1.01 1.058

Final R indices (I >2σ(I)) R1 = 0.029 R1 = 0.022 R1 = 0.037 wR2 = 0.078 wR2 = 0.043 wR2 = 0.097 R indices (all data) R1 = 0.030 R1 = 0.031 R1 = 0.038 wR2 = 0.078 wR2 = 0.046 wR2 = 0.101 absolute structure parameter N/A N/A 0.00 Largest diff. peak 1.467 and -2.772 0.68 and -1.09 1.232 and -1.681 and hole (e Å-3)

224

Table A.4 Crystallographic parameters for the mixed chloro amidate tantalum complexes (Chapter 4). 38 39 42

Empirical formula C36H58Cl2N3O2Ta C38H62 Cl2N3O2Ta C23H44ClN4OTa

Fw 816.70 844.76 609.02

Habit, colour Prism, colourless Plates, yellow Prism, yellow Crystal dimensions (mm) 0.30 × 0.20 × 0.20 0.40 × 0.40 × 0.10 0.50 × 0.40 × 0.30 Crystal system Orthorhombic Orthorhombic Orthorhombic Space group Pbca Pbca Pbca Z 8 8 8 a (Å) 19.008(1) 19.037(2) 17.2866(8) b (Å) 15.7548(8) 16.097(2) 16.7801(8) c (Å) 26.607(1) 25.588(3) 18.422(1) α (°) 90 90 90 β (°) 90 90 90 γ (°) 90 90 90 Collection ranges h = -24→14 h = -26→26 h = -22→21 k = -20→15 k = -22→22 k = -21→20 l = -24→33 l = -36→30 l = -23→23 Temperature (K) 100 100 100 Volume (Å3) 7673(1) 7841(2) 5343.6(6) -3 Dcalcd (Mg m ) 1.414 1.431 1.514 Radiation λ = 0.71073 Å λ = 0.71073 Å λ = 0.71073 Å Absorp. coeff. μ (mm-1) 3.04 2.98 4.23 F(000) 3344 3472 2464

θmin – θmax (°) 1.9 – 27.5 1.6 – 30.1 2.4 – 27.5 Measured reflections 29740 152638 23966

Independent reflections 8710 (Rint = 0.042) 11492 (Rint = 0.043) 6040 (Rint = 0.027) Data/restraints/parameters 8710/0/413 11492/0/431 6040/0/284 Maximum shift/error 0.008 0.010 0.002 Goodness-of-fit on F2 1.04 1.06 1.02

Final R indices (I >2σ(I)) R1 = 0.034 R1 = 0.022 R1 = 0.019 wR2 = 0.088 wR2 = 0.048 wR2 = 0.045 R indices (all data) R1 = 0.046 R1 = 0.037 R1 = 0.030 wR2 = 0.097 wR2 = 0.055 wR2 = 0.048 Largest diff. peak 2.061 and -1.260 2.064 and -0.603 0.633 and -0.637 and hole (e Å-3)

225

Table A.5 Crystallographic parameters for the mono(sulfonamidate) tetrakis(dimethylamido) tantalum complexes (Chapter 4). 43 44 45

Empirical formula C19H40N5O2STa C21H36N5O2STa C23H40N5O2STa

Fw 583.57 603.56 1263.22

Habit, colour Prism, yellow Prism, yellow Prism, yellow Crystal dimensions (mm) 0.22 × 0.21 × 0.15 0.33 × 0.26 × 0.24 0.25 × 0.24 × 0.17 Crystal system Monoclinic Monoclinic Monoclinic

Space group P21/c P21 P21/c Z 4 2 2 a (Å) 11.331(1) 8.5716(6) 9.858(1) b (Å) 15.224(2) 14.784(1) 19.023(2) c (Å) 14.063(2) 9.5932(6) 14.021(2) α (°) 90 90 90 β (°) 93.926(2) 99.360(1) 92.421(4) γ (°) 90 90 90 Collection ranges h = -14→16 h = -12→12 h = -13→13 k = -18→21 k = -21→21 k = -26→26 l = -14→19 l = -13→13 l = -19→19 Temperature (K) 90 90 90 Volume (Å3) 2420.3(7) 1199.5(2) 2627.3(9) -3 Dcalcd (Mg m ) 1.602 1.671 1.597 Radiation λ = 0.71073 Å λ = 0.71073 Å λ = 0.71073 Å Absorp. coeff. μ (mm-1) 4.65 4.70 4.29 F(000) 1176 604 1272

θmin – θmax (°) 2.0 – 30.4 2.2 – 30.5 1.8 – 30.2 Measured reflections 37430 22531 64364

Independent reflections 7126 (Rint = 0.061) 7075 (Rint = 0.019) 7771 (Rint = 0.054) Data/restraints/parameters 7126/0/265 7075/1/280 7771/0/300 Maximum shift/error 0.001 0.001 0.002 Goodness-of-fit on F2 1.04 0.846 1.17

Final R indices (I >2σ(I)) R1 = 0.025 R1 = 0.012 R1 = 0.028 wR2 = 0.049 wR2 = 0.027 wR2 = 0.067 R indices (all data) R1 = 0.038 R1 = 0.012 R1 = 0.033 wR2 = 0.054 wR2 = 0.027 wR2 = 0.070 absolute structure parameter N/A 0.0086(30) N/A Largest diff. peak -3 2.084 and -1.087 0.434 and -0.628 1.324 and -1.749 and hole (e Å )

226

Table A.6 Crystallographic parameters for the homoleptic indolinyl tantalum complex (Chapter 5). 51

Empirical formula C48H49N6Ta

Fw 890.88 Habit, colour Prism, orange Crystal dimensions (mm) 0.56 × 0.45 × 0.35 Crystal system Triclinic Space group P-1 Z 2 a (Å) 11.918(1) b (Å) 12.068(1) c (Å) 15.455(1) α (°) 98.412(1) β (°) 108.485(2) γ (°) 108.125(1) Collection ranges h = -16→16 k = -16→17 l = -21→21 Temperature (K) 90 Volume (Å3) 1928.1(5) -3 Dcalcd (Mg m ) 1.534 Radiation (Mo Kα) λ = 0.71073 Å Absorp. coeff. μ (mm-1) 2.89 F(000) 904

θmin – θmax (°) 1.4 – 30.1 Measured reflections 41775

Independent reflections 11285 (Rint = 0.018) Data/restraints/parameters 11285/1012/540 Maximum shift/error 0.028 Goodness-of-fit on F2 1.098

Final R indices (I >2σ(I)) R1 = 0.017 wR2 = 0.042 R indices (all data) R1 = 0.019 wR2 = 0.043 Largest diff. peak 1.374 and -1.524 and hole (e Å-3)

227

Appendix B Selected NMR spectra

1 Reaction mixture, H NMR spectrum (d6-benzene, 400 MHz)

0.5 Zr(NMe2)4 N Reaction mixture NH toluene O

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

228

1 5, H NMR spectrum (d8-toluene, 600 MHz)

1.15

Ph O Zr(NMe2)2 N

5 3.16

tBu 2

7.32 7.93 7.94 7.40

7.42 6.47 6.46 2.09 7.31 2.09 2.09 7.15 7.16

7.14

1.94 1.00 1.89 0.90 0.98 6.01 9.03

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 5, C NMR spectrum (d6-benzene, 100 MHz) 29.6 Ph O Zr(NMe2)2 N 5 tBu 2 128.8 137.5 127.8 128.4 110.1 127.3 42.5 124.9 129.0 140.6 20.4 125.1 20.5 20.3 20.1 20.7 165.3 36.4 121.0 137.0 20.0 20.8 129.2

200 180 160 140 120 100 80 60 40 20 0 229 Chemical Shift (ppm)

1 Variable temperature H NMR spectra of 5 (d8-toluene, 400 MHz)

Ph O Zr(NMe2)2 N 5 tBu 2

T(oC)

25.0

13.9

-12.3

-30.0

-50.2

-70.7

-80.9

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

230

1 Variable temperature H NMR spectra (d8-toluene, 400 MHz)

O 3.49

Ti(NMe2)2 N

6.98 2.09 7.10 6.36 6.34 5.97 7.46 7.44 o 6.92 7.02 5.98 5.95 6.90 T( C) 6.94 25.0

13.9

-12.3

-30.0

-50.2

-70.7

-80.9

1.95 2.00 2.01 1.99 12.15

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

Expanded views:

6.98 7.10 6.36 6.34 5.97 7.44 7.46 6.92 7.02 5.98 o 5.95 6.90 T( C) 6.94 25.0

13.9

-12.3

-30.0

-50.2

-70.7

-80.9

1.95 2.00 2.01 1.99 1.95

7.5 7.0 6.5 6.0 8.5 8.0 7.5 C h e m ic a l S h ift (p p m ) Chemical Shift (ppm)

231

1 Variable temperature H NMR spectra (d6-benzene, 300 MHz)

Ph O 3 Ph NH Zr(NMe2)2 2 N d -benzene 5 6 R = Ph or H tBu 2 T(oC)

58.2

52.3

46.4

40.5

34.6

30.3

25.9

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

1 Variable temperature H NMR spectra (d6-benzene, 300 MHz)

Ph Ph O 3 Ph NH Zr(NMe2)2 2 N d -benzene 5 6 R = Ph or H tBu 2 T(oC)

58.2

52.3

46.4

40.5

34.6

30.3

25.9

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 232

1 16, H NMR spectrum (d6-benzene, 300 MHz) 1.22

Me Me

Ph O N O Ph Zr Zr 2 2 N N N Me Me tBu tBu

1.20

1.89 16 1.18

2.65 7.16

7.17 7.33 6.61 7.52 6.59 7.54 7.93 7.94 7.95 6.91 7.02

7.01 7.34 6.93 7.03

5.47 2.90 5.22 6.44 9.53 2.89 4.61 3.15 6.18 8.54 36.00

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 16, C NMR spectrum (d6-benzene, 100 MHz) 128.6 128.4 128.1

Me Me Ph O N O Ph Zr Zr N 2 N N 2 Me Me tBu tBu

16 30.7 129.9 17.9 30.5 20.4 127.7 139.9 37.0 127.4 109.6 118.5 130.3 121.7 122.2 166.3 139.5 169.2 118.0 37.4 36.9 140.8 155.8 143.6 42.7 167.1 166.0

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 233

Typical 1 H NMR spectra for kinetic experiment monitoring the conversion of substrate 19 (δ 4.87-4.95 ppm) relative to 1,3,5-trimethyoxybenzene (δ 6.11 ppm). (d6-benzene, 400 MHz)

NH2 NH 2 10 mol% 5

120 °C, d8-toluene

1.00 1.79

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

234

1 H NMR spectrum (d6-benzene, 600 MHz) 3.95 O

Mes Ta(NMe2)4 N

OMe

2.82

3.49 2.37 6.96 7.16

7.55 7.51 7.17 7.15 7.52 6.79 6.78 6.76 7.18 6.77

1.74 2.032.00 1.00 25.59 3.17 6.37 3.14

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d6-benzene, 150 MHz)

O Mes Ta(NMe2)4 128.15 128.39 N 128.63 OMe 47.36 128.96 21.44 54.56 111.92 120.79 135.68 126.47 125.26 21.34 138.19 152.97 177.27

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 235

1 H NMR spectrum (d6-benzene, 400 MHz) 2.33

N O Ta(NMe2)4 N

3.40

2.27 2.26 × HNMe2

2.13 2.14 1.45 2.65

1.44 7.05 1.46 2.12 7.06 2.64 2.66 6.95 1.44 1.47 1.30 6.97 6.94 7.16

2.13 0.96 21.57 2.31 5.746.69 4.33 2.20

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d6-benzene, 100 MHz)

N O 26.3 137.5 Ta(NMe2)4 N 127.8 54.7 128.3 128.7 128.8 20.4 124.9 24.9 129.0 20.3 30.5 55.0 124.6 18.2

HNMe 20.7 132.5 2 38.9 143.5 174.4 × 47.0

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 236

1 Representative H NMR spectra for determination of NMR yield (d8-toluene, 400 MHz)

iPr 5 mol% O

N N H H iPr H H H N 5 mol% Me N + Ta(N 2)5 n 1.5 n hexyl hexyl 130 °C, 20 h H d8-toluene H δ 6.33 ppm δ 6.43 ppm

6.44 6.42 6.34 6.32

t = 20 h

t = 0

1.13 1.00

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

237

1 Representative H NMR spectra for determination of NMR yield (d8-toluene, 400 MHz)

iPr 5 mol% O

N N H H iPr H H H N 5 mol% Me N + Ta(N 2)5 n 1.5 n hexyl hexyl 130 °C, 20 h MeO H d8-toluene MeO H δ 6.31 ppm δ 6.40 ppm

6.41

6.32 6.30 6.39

t = 20 h

t = 0

0.99 1.00

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

238

1 34, H NMR spectrum (d6-benzene, 400 MHz) 3.65 ⋅ TaCl2(NMe2)3 pyr 34

7.16 6.52 6.54 8.82 6.49 6.81 6.79

2.00 0.931.89 18.03

9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13 34, C NMR spectrum (d6-benzene, 150 MHz) ⋅ TaCl2(NMe2)3 pyr 128.5 128.4 34 128.2

124.4 49.3 151.7 137.9

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 239

1 38, H NMR spectrum (d6-benzene, 600 MHz) 1.06 t Cl t Bu O O Bu i iPr Pr Ta N N Cl iPr iPr NMe2 38

1.36 1.22 1.47 1.26 7.04 4.12 7.04 4.25 7.16 7.09

4.42 3.17 4.43 4.41 3.19 3.16 4.45 3.20 3.15

2.07 3.99 1.99 2.89 3.00 2.02 6.11 6.53 6.566.54 17.57

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 38, C NMR spectrum (d6-benzene, 125 MHz)

t Cl t Bu O O Bu

128.2 i iPr Pr 128.4 N Ta N

Cl 128.5 iPr iPr NMe2 38 28.0 28.6 27.1 27.6 23.6 24.6 124.9 127.9 123.7 128.7 143.9 146.2 50.1 54.9 42.5 138.1 189.9

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 240

1 40, H NMR spectrum (d6-benzene, 600 MHz) O 1.46 t Bu TaCl3(NMe2) N 2.38 iPr iPr 40 1.35

1.34

7.21

7.22 3.15 3.13 3.16 7.12 7.13 7.11 3.12 3.17 7.24

4.47 1.96 3.97 13.06 19.66 24.00

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 40, C NMR spectrum (d6-benzene, 150 MHz)

O 24.3

t 22.8 Bu TaCl3(NMe2) N

30.8 iPr iPr 40 128.2 122.9 128.4 29.1 128.5 41.6 121.7 136.7 122.9 40.4 147.4 161.3

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 241

1 43, H NMR spectrum (d6-benzene, 400 MHz) O O 3.54 S Ta(NMe2)4 N 43

1.35

1.90

7.94 7.96 6.82 6.80 7.16

1.91 1.88 23.73 2.89 8.85

9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13 43, C NMR spectrum (d6-benzene, 100 MHz)

O O 128.6 S Ta(NMe2)4 128.4 128.1 N 43

32.8

129.4

129.6

48.3 21.5 142.6 56.2 143.3

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 242

44, H NMR spectrum (d6-benzene, 400 MHz) 3.45

O O S Ta(NMe2)4 N

1.82 7.98 8.00 7.53 7.22 6.71 7.55 6.69 7.22 7.24 7.20 7.16 6.86 6.87 7.23

2.00 2.061.99 0.99 1.98 25.13 3.02

9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13 44, C NMR spectrum (d6-benzene, 100 MHz) O O 128.6 128.4 S Ta(NMe2)4 128.1 N 44 120.7 129.6 129.9 122.2 47.8 21.5 144.4 143.2 139.9

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 243

1 45, H NMR spectrum (d6-benzene, 400 MHz) 3.32

O S Ta(NMe2)4 O N 45

2.51 3.26 1.88 7.05 7.78 7.80 6.73 6.71

7.07 6.95 6.97 7.16 6.93

1.88 2.00 1.21 2.14 23.88 2.40 6.35 3.35

9 8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13 C NMR spectrum (d6-benzene, 100 MHz) 128.6 128.4 128.1 47.3 O S Ta(NMe2)4 O N 45 127.6 129.0 129.2 20.1 21.5 46.3 46.9 125.0 25.2 137.7 141.7 28.7 124.2 141.9

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 244

1 Crude 45, H NMR spectrum (d6-benzene, 400 MHz) 3.22

O S Ta(NMe2)4 O N iPr iPr 45

1.26 1.28 2.16 1.87

7.16 7.82 7.84 6.76 6.74 7.18 7.12 7.11 4.06 4.07 4.04 7.09 4.02 HNMe2 x

1.93 3.97 1.91 2.05 21.77 3.00 11.22

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 Crude 45, C NMR spectrum (d6-benzene, 100 MHz)

128.4 128.1 O 128.6 S Ta(NMe2)4 O N iPr iPr 45

HNMe2 46.9 25.2 129.3 28.7 127.9 124.2 39.3 21.4 146.7 125.0 141.4 x

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 245

1 2, H NMR spectrum (d6-benzene, 400 MHz) 1.10 O t Bu Ta(NMe2)4 N iPr 2 iPr

3.31 1.35 1.27 1.37

7.05

3.51 7.16 3.53

2.98 3.2121.62 6.00 6.37 9.29

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 2, C NMR spectrum (d6-benzene, 75 MHz) O 128.7 t 128.4 128.1 Bu Ta(NMe2)4 N iPr 2 iPr 29.6 123.9 24.8 26.6 27.3 143.0 42.4 177.7 141.3 47.4

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 246

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.41

Ts H N

(+/-)

7.72 7.29 7.74 7.27 1.53 1.58 1.55 1.17 1.37 1.96 1.40 1.08 2.25 1.10 1.23 1.61 2.94 3.57 3.77 1.87 3.59 3.60 3.80 3.56 1.04 1.05 2.97 2.90

1.01

1.95 2.02 1.01 1.00 0.98 3.02 1.14 0.99 1.09 5.06 9.61

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 126.6 129.3 Ts H N

(+/-)

36.5 56.6 39.2 29.9 40.4 28.5 21.1 23.2 25.8 41.0 33.8 18.2 35.3 142.3 139.1 77.0 76.7 77.3

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

247

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.37 Ts H N

(+/-) O O 0.84

0.82 0.86

1.26 1.25 3.86 7.69 3.85 7.71 7.25 7.23 1.29 0.87 3.82 1.30 1.41

3.81 3.78 3.80 1.81 1.43 3.88 1.84 3.12 3.71 1.00 1.02 2.15 3.09 3.08 2.13

7.27

1.97 2.01 5.94 0.97 2.971.00 1.03 12.101.08 6.00 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 129.6

Ts H 126.7 N

(+/-) O O 31.6 22.5 29.4 64.6 63.6 58.4 16.4 14.0 26.1 21.3 33.3 106.7 39.0 142.8 77.3 76.7 77.0 138.8

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

248

48, 1H NMR spectrum ( -chloroform, 400 MHz) d1 0.99 H H N OTBDMS 0.15 (+/-) 48

1.06 3.70 7.03 7.01 0.15 3.69 3.72 6.66 6.55 6.53 1.65 3.75 1.69 1.66 6.68 2.82 1.68 3.25 3.27 1.93 2.89 2.83 2.87 1.92 1.29 1.95

1.99 0.96 0.98 3.02 0.97 2.00 0.96 5.11 1.14 2.88 9.40 6.15 8 7 6 5 4 3 2 1 0 -1 Chemical Shift (ppm)

13 48, C NMR spectrum (d1-chloroform, 100 MHz) 25.9 H H N OTBDMS

(+/-) 48 -5.3 28.6 56.0 126.6 30.7 129.1 15.1 63.3 116.7 37.3 114.0 24.8 121.3 18.3 77.3 145.1 77.0 76.7

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

249

1 H NMR spectrum (d1-chloroform, 400 MHz) H H 1.03 N OTBDMS (+/-)

0.18

1.08 3.74 7.05 7.03 1.66 3.75 3.72 1.64 1.62 1.65 6.69 6.58 6.56

1.67 6.70 2.84 6.67 3.27 3.29 7.07 2.83 1.95 1.94 2.92 3.27 2.85 1.45

2.01 0.99 1.00 2.94 1.00 2.04 1.02 1.09 5.11 1.21 1.21 3.11 9.06 6.04

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 25.9 H H N OTBDMS (+/-) -5.3 126.6 33.0 32.2 114.0 129.0 37.6 56.0 23.7 63.0 15.0 116.6 145.1 121.3 18.3 76.7 77.3 77.0

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

250

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.39 Ts N

0.87

0.75 0.73

7.72 7.74 7.26 0.89

7.24 1.26 1.24 1.17 1.27 1.23

1.64 1.65 2.47 1.63 1.14 1.67 1.29 3.78 3.75 3.82 3.86 2.95 3.76 1.38 3.77 1.75 2.94 2.95 2.98 2.91 2.92 7.89 7.91 1.72 7.41

1.03

0.19 2.00 0.191.99 1.00 1.01 0.98 0.29 3.00 0.88 5.00 11.851.77 3.17 2.88

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) Ts N 129.2 127.0 31.7 13.9 22.4 27.0 29.4 31.0 62.4 16.6 37.0 24.5 21.2 44.9 142.3 139.4 76.7 77.0 77.3 130.1 126.8 126.9 142.4 37.1 61.7 34.0 56.7 139.2

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 251

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.04 Ts H N 2.39 0.85 (+/-) N

0.87

1.23 7.67 7.69

7.26 7.24 0.83

1.26 1.33 2.68 2.71 1.68 2.42 1.69 3.16 3.67 1.59 3.66 3.49 3.67 3.49 3.49 3.70 3.51 1.07 2.10 1.57 2.12 1.09

3.90 4.05 1.99 2.00 1.97 1.95 2.126.012.04 6.04 4.00 18.42 2.32 10.46

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 129.5 Ts H N 127.0 (+/-) N 22.5 31.7 29.6 30.8 58.6 16.1 33.7 21.4 46.4 14.0 53.5 54.5 41.2 77.0 77.3 76.7 139.1 142.8 129.6

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

252

1 H NMR spectrum (d6-benzene, 400 MHz) Ts H N

(+/-) N Ph

7.16 1.88

1.10 0.88 1.09

7.78 7.77 1.14 6.81 0.89 0.86 6.61 6.79 6.60 7.09 1.22 7.08 1.23 1.16 3.43 3.41 1.39 2.48 2.48 2.46 2.45 2.26 3.80 3.78 3.73 2.71 3.76 3.03 2.73 1.07

2.00 2.05 1.99 1.00 2.05 2.07 1.10 1.07 1.01 1.01 1.00 1.01 3.16 2.94 8.21 4.09 3.21 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d6-benzene, 100 MHz)

Ts H 128.5 128.4 N 128.2

(+/-) N Ph 1.7 129.7 117.3 130.1 127.8 32.5 30.3 16.7 23.4 59.5 27.4 31.4 14.7 34.4 41.8 50.8 48.4 120.8 21.5 152.4 143.0 140.8

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 253

1 H NMR spectrum (d6-benzene, 400 MHz) 3.76 Ts H N

N (+/-) 2.42

OMe 1.29

0.97 0.95 7.28 6.80 6.76 0.89 7.74 7.77 7.30

6.83 0.87 6.73 2.40 3.40 2.46 2.39 3.44 2.47 3.86 3.65 3.06 1.46 3.34 3.68 1.21 3.90 2.36 1.49 2.28 2.25

1.99 2.45 3.91 1.05 2.86 1.07 1.99 1.00 6.06 10.60 2.87 3.26

8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d6-benzene, 100 MHz) 118.7 Ts H 114.3 N 129.6 N (+/-) 126.9

OMe 55.4 22.5 15.9 31.7 14.0 29.5 58.7 33.6 21.3 77.3 77.0 76.7 41.3 51.5 48.9 145.8 142.9 139.1 154.1

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

254

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.44 Ts H N

N (+/-) Ph Ph

7.26 0.96

0.99 1.01

7.28 7.35 7.69 7.24 7.71 0.94 3.99 7.36 1.32 1.33 7.19 1.34 7.17 1.36 1.30 1.37 2.84 2.87 1.66 1.69 1.69 3.72 1.27 2.60 3.51 3.27 3.53 3.75 3.27 7.15 1.44

2.02 4.09 6.20 2.20 0.99 1.00 1.01 1.02 1.00 1.02 4.16 2.02 9.71 7.32

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz)

Ts H 126.9 N 128.4 129.5 N (+/-)

Ph Ph 22.6 31.8 14.0 29.6 15.8 21.4 75.8 59.0 27.1 33.6 41.6 50.5 51.1 142.0 77.0 77.3 139.1 142.7

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 255

1 H NMR spectrum (d1-chloroform, 400 MHz) 2.47 Ts H N Ph

(+/-) N Ph Ph

7.28 7.30 7.27 0.88 0.86 7.25 7.70 7.37 7.72 7.25 4.04

7.41 7.23 7.43 7.21 7.23 7.16 2.68 7.18 1.41 2.98 2.72 3.01 2.07 2.06 1.78 1.81 1.64 1.65 2.10 1.78 2.66 3.75 3.29 3.64 3.66 7.15 7.67

1.03 2.75

2.33 6.97 13.14 1.00 1.00 1.05 1.04 1.02 1.09 2.23 3.13 1.05 1.19 1.313.08

8 7 6 5 4 3 2 1 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 128.5 Ts H N Ph

(+/-) N

Ph Ph 127.7 129.0 126.9 129.6 77.0 77.3 76.7 15.6 59.0 76.0 125.9 33.1 40.1 21.5 50.7 41.8 51.4 140.6 141.9 142.0 139.0 142.8

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm)

256

1 H NMR spectrum (d1-chloroform, 400 MHz) 1.01 H 0.99 N OH

1.22 3.67 6.97

6.95 1.24 6.60

6.50 3.66 3.69 6.48 1.21 1.60 7.27 3.49 3.50 1.59 1.62 1.63 2.76 1.72 6.62 1.70 3.20 2.75 1.88 3.22 1.57 6.99 1.57 2.77 2.83 0.97 2.72 1.52 2.71 1.91 2.84 2.86 3.70

2.02 0.99 1.00 2.06 0.74 1.00 2.05 1.045.62 2.05 3.10

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 C NMR spectrum (d1-chloroform, 100 MHz) 77.0

H 76.7 N OH 77.3 129.1 37.5 56.1 126.7 30.7 28.5 26.9 116.8 24.7 114.1 15.2 63.1 145.1 121.4

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 257

1 49, H NMR spectrum (d6-benzene, 400 MHz) 1.11 OEt

49 OEt

7.16

1.13 1.09

3.34 3.51 3.36 4.44 3.50

3.52 1.76 3.54 3.33 3.32 1.74 1.75 2.14 1.74 2.16 2.13 1.77 4.46 5.06 5.06 4.98 4.43 4.95 5.77 5.79 2.12 2.17 5.75 5.07 3.55 5.03 3.30 5.82 5.76

1.00 2.06 1.01 2.08 2.07 2.14 2.09 6.18

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

13 49, C NMR spectrum (d6-benzene, 100 MHz) OEt 128.2 128.6 128.4 49 OEt 16.0 61.2 29.8 33.6 102.8 115.1 138.9

200 180 160 140 120 100 80 60 40 20 0 Chemical Shift (ppm) 258

1 H NMR spectrum (d6-benzene, 300 MHz) 1.39 H N

2.61

2.62 1.04

7.16

4.00 6.10 0.93

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

2H NMR spectrum (toluene, 400 MHz) D H/D N ~5 mol% 2 N H 2.21 C(H/D)2 7 d, 165 °C, N

CH D 2.09 ND toluene 2 2.60

7.02 × d-tol 7.14

H N × d-tol CHD 0.74 1.11 0.05

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 259

1 H NMR spectrum (d6-benzene, 300 MHz) H N 1.41

2.65

2.65 2.63 1.42 1.40 2.67 1.44 1.39

1.08

7.16

3.97 4.00 1.00

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm)

2H NMR spectrum (toluene, 400 MHz) H N H/D D 1.42 N N ~5 2 mol% C(H/D)2 CHD 7 d, 165 °C, toluene ND 2.09

7.03 × d-tol 7.14

H 0.83 N 2.20 × d-tol CH2D

H 2.65 N CHD 0.06

8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 260

Appendix C SFC analysis for determination of enantiomeric excess

1. 5 mol% 50 or 8 Ts H H 5 mol% Ta(NMe2)5 N N n n 143 h, 165 °C, toluene hexyl 1.5 hexyl 2. TsCl, 2M NaOH (+/-)

N N H

50, racemic

AS-H column, 3% 2-propanol as modifier, 1.00 mL/min

CyN NH

iPr 8, chiral

AS-H column, 3% 2-propanol as modifier, 1.00 mL/min

261