Intermolecular Hydroamination of Allenes and the Synthesis

INTERMOLECULAR HYDROAMINATION OF ALLENES AND THE SYNTHESIS

OF NEW ZIRCONIUM AND TITANIUM AMIDO COMPLEXES

by

RASHIDAT OMOLABAKE AYINLA

B.Sc, Ahmadu Bello University, 2000

A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF

MASTER OF SCIENCE

in

THE FACULTY OF GRADUATE STUDIES

(Chemistry)

THE UNIVERSITY OF BRITISH COLUMBIA

September 2005

© Rashidat Omolabake Ayinla, 2005 Abstract

A bulky bis(amidate)-bis(amido) titanium complex 38 serves as a precatalyst for the intermolecular hydroamination of allenes. Reaction of benzylallene and phenylallene with aryl- and alkylamines produces branched imines in good yield. The resultant imines were either reduced to amines or hydrolyzed to ketones for full characterization.

Methoxyallene and 2,6-dimethylphenoxyallene also react with aryl- and alkylamines in good yield. However, with these substrates another regioisomer (allylamines, the unbranched products) are observed as the major products with all amines except 2,6- dimethylaniline. In this case, the branched imine is observed as the sole product. The change in regioselectivity is probably due to coordination of the oxygen to the metal catalyst, which then directs the addition of the nitrogen functionality to carbon 3 of the allene. This coordination is presumably absent with the bulky 2,6-dimethylaniline. Ether amines obtained after reduction of the ether imine products from oxyallene hydroamination serve as precursors to new N,0 chelating ligands for the formation of titanium and zirconium amido complexes. The reaction of one equivalent of proligand

with one equivalent of Zr(NMe2)4 or Ti(TSlMe2)4 results in new group 4 complexes with

N,0 chelating five-membered metallacycles. X-ray crystallographic studies show all complexes to be of distorted trigonal bipyramidal geometry with a dative bond between the oxygen atom and the metal centre. These new complexes are effective precatalysts for the intramolecular hydroamination/cyclization of aminoalkenes. The aminoalkenes

2,2-diphenyl-4-pentenylamine, 2,2-dimethyl-4-pentenylamine, and 2,2-diphenyl-5- hexenylamine were converted to either pyrrolidines or piperidines in good yield.

n Table of Contents

Abstract ii

Table of Contents iii

List of Schemes vi

List of Figures viii

List of Tables ix

List of Symbols and Abbreviations x

Acknowledgements xu

CHAPTER 1- INTRODUCTION 1

1.1 Background 1

1.2 Hydroamination Reaction 2

1.2.1 Thermodynamics of Hydroamination 3

1.3 Catalytic Systems 4

1.3.1 Catalyst Systems Containing Alkali and Alkaline Earth Metals 5

1.3.2 Catalyst Systems Containing Lanthanides 6

1.3.3 Catalyst Systems Containing Late Transition Metals 9

1.3.4 Catalyst Systems Containing Early Transition Metals 12

1.4 Scope of this Thesis 15

1.5 References 17

CHAPTER 2- INTERMOLECULAR HYDROAMINATION OF ALLENES 22

2.1 Introduction 22

2.2 Results and Discussion 26

2.2.1 Synthesis of the Allenes 26

in 2.2.2 Bis(amidate)-Bis(amido) Hydroamination Precatalysts 31

2.2.3 Intermolecular Hydroamination of Alkyl- and Aryl-Substituted Allenes with Arylamines 32

2.2.4 Intermolecular Hydroamination of Alkyl- and Aryl-Substituted Allenes with Alkylamines 36

2.2.5 Intermolecular Hydroamination of Ether-Substituted Allenes with Alkyl- and Arylamines 39

2.2.6 Possible Explanation for Change in Regioselectivity 43

2.3 Conclusions 45

2.4 Experimental Procedures 46

2.5 References 62

CHAPTER 3 - TITANIUM AND ZIRCONIUM METAL COMPLEXES WITH

N,0 CHELATING LIGANDS: APPLICATIONS IN INTRAMOLECULAR

HYDROAMINATION OF AMINOALKENES 65

3.1 Introduction 65

3.2 Results and Discussion 68

3.2.1 Synthesis of Proligands 68

3.2.2 Synthesis of Titanium and Zirconium Amido Complexes 69

3.3 Intramolecular Hydroamination/Cyclization of Aminoalkenes 78

3.4 Conclusions 82

3.5 Experimental Procedures 82

3.6 References 86

CHAPTER 4- SUMMARY AND FUTURE DIRECTIONS 89

iv 4.1 Summary 89

4.2 Future Directions 91

4.3 References 94

Appendix I. X-Ray Crystallographic Data for Complex 47 95

Appendix II. X-Ray Crystallographic Data for Complex 48 100

Appendix III. X-Ray Crystallographic Data for Complex 49 105

v List of Schemes

Scheme 1-1. Traditional Methods of Forming C-N Bond 2

Scheme 1-2. Intermolecular and Intramolecular Hydroamination Reactions 3

Scheme 1-3. Proposed Catalytic Cycle for the Hydroamination Reaction Mediated by Alkali Metals 6

Scheme 1-4. Proposed Mechanism for Organolanthanide-Catalyzed Aminoalkene

Hydroamination/Cyclization 8

Scheme l-5a. Catalytic Cycle Proposed for the Hydroamination Reaction Involving

Activation of the Unsaturated Bond by 7r-Coordination to the Transition Metal 10

Scheme l-5b. Catalytic Cycle Proposed for the Formation of Oxidative Amination

Product 10

Scheme 1-6. Proposed Mechanism for the Hydroamination Reaction Involving

Activation of the Amine by N-H Addition to the Transition Metal 11

Scheme 1-7. Proposed Catalytic Cycle for Group 4 Metal-Catalyzed Hydroamination

14

Scheme 2-1. Organolanthanide-Catalyzed Hydroamination/Cyclization of

Aminoallene 23

Scheme 2-2. Group 4 Metal-Catalyzed Intermolecular Hydroamination of Allenes 24

Scheme 2-3. Possible Products from the Intermolecular Hydroamination of Allenes ... 25

Scheme 2-4. Synthesis of Bis(amidate)-Bis(amido) Titanium Complex 26

Scheme 2-5. General Scheme Used in Allenes Synthesis 27

Scheme 2-6. Synthesis of Methoxyallene 28

Scheme 2-7. Synthesis of Benzylallene 29

vi Scheme 2-8. Synthesis of Phenylallene 29

Scheme 2-9. Synthesis of 3-Phenyl-l,2-pentadiene 30

Scheme 2-10. Synthesis of 2,6-Dimethylphenoxyallene 31

Scheme 2-11. Proposed Catalytic Cycle for the Formation of 41 44

Scheme 2-12. Proposed Catalytic Cycle for the Formation of 40 45

Scheme 3-1. Attempted Synthesis of Amido Complexes using 2 Equivalents of Pro ligands 70

Scheme 3-2. Synthesis of Zirconium Amido Complex 47 71

Scheme 3-3. Synthesis of Titanium Amido Complex 48 74

Scheme 3-4. Synthesis of Zirconium Amido Complex 49 76

Scheme 4-1. Proposed Synthesis of Metallacyclic Intermediates by Stoichiometry

Reaction 92

Scheme 4-2. Proposed Synthesis of Zirconium Dichloro Complexes 93

vn List of Figures

Figure 1-1. Proposed Alkali metal Catalysts and Alkaline Earth Metal Precatalyst for the

Hydroamination Reaction 6

Figure 1-2. Lanthanide Precatalysts for the Hydroamination Reaction 8

Figure 1-3. Structurally Characterized 2-Aminoalkyl Complexes 10

Figure 1-4. Structurally Characterized Hydrido-Amido Complexes 12

Figure 1-5. Structurally Characterized Precatalysts (33, 34), Imido metal Catalyst (35), and Metallacyclic Intermediates (36, 37) in Early Transition Metal-Catalyzed

Hydroamination 15

Figure 1-6. Bis(amidate)-Bis(amido) Precatalyst for Allene Hydroamination 16

Figure 2-1. Alkaloids Synthesized by Intramolecular Hydroamination/Cyclization of Allenes 24

Figure 2-2. Bis(amidate)-Bis(amido) Titanium Complexes 32

Figure 2-3. E and Z Isomers of Compound 40 34

Figure 2-4. Secondary Amines Obtained After Reduction of the Imines 36

Figure 2-5. Isolated Ketones 38

Figure 2-6. Isolated Amines and Observed Ketone in Oxyallene Hydroamination 42

Figure 3-1. Reduced Hydroamination Products used as Proligands 68

Figure 3-2. ORTEP Representation of Complex 47 with 50% Probability Ellipsoids ... 72

Figure 3-3. ORTEP Representation of Complex 48 with 50% Probability Ellipsoids ... 74

Figure 3-4. ORTEP Representation of Complex 49 with 50% Probability Ellipsoids ... 76

viii List of Tables

Table 2-1. Intermolecular Hydroamination of Alkyl- and Arylallenes with

Arylamines 34

Table 2-2. Intermolecular Hydroamination of Alkyl- and Arylallenes with

Alkylamines 37

Table 2-3. Intermolecular Hydroamination of Ether-Substituted Allenes with Aryl- and Alkylamines 41

Table 3-1. Selected Bond Distances and Angles of Complex 47 73

Table 3-2. Selected Bond Distances and Angles of Complex 48 75

Table 3-3. Selected Bond Distances and Angles of Complex 49 77

Table 3-4. Hydroamination/Cyclization of 2,2-diphenyl-4-pentenylamine (50) 79

Table 3-5. Hydroamination/Cyclization of 2,2-dimethyl-4-pentenylamine (52) 81

Table 3-6. Hydroamination/Cyclization of 2,2-diphenyl-5-hexenylamine (54) 81

ix List of Symbols and Abbreviations

A angstoms, (10~10m) Anal. Analytical AM anti-Markovnikov br broad Bu butyl Cat. catalyst °C degrees celcius Calcd. Calculated cm centimeters Cp cyclopentadienyl d day or doublet (NMR) or deuterated dd doublet of doublet (NMR) dt doublet of triplet (NMR) ee enantiomeric excess EI electronic ionization ESI electrospray ionization Et ethyl g gram GCMS gas chromatography-mass spectrometry h hours J coupling constant mg milligram ml milliliter M molar (mol L"1) or Markovnikov m multiplet Me methyl min minutes mmol millimole mol mole MS mass spectrometry n normal NMR nuclear magnetic resonance ph phenyl q quartet (NMR) rt room temperature s singlet t triplet t tertiary THF tetrahydrofuran TMS trimethylsilyl UV ultra violet VT variable temperature Alpha

X j8 Beta 7 Gamma 8 Delta 7T pi a sigma Acknowledgements

I thank God for giving me the strength, guidance, and good health required for all my endeavours. I sincerely and immensely thank my supervisor Dr. Laurel L. Schafer whose suggestions, advice, and patience throughout the course of this research made this work a success. I am grateful to my parents Mr. and Mrs. Ayinla for their love, prayers and continuing support toward my studies. My profound gratitude goes to my fiance

Nurudeen Olagunju for his love, faith, prayers, and help toward my success and for always being there. Special thanks are due to my uncle Alhaji A. Umar and his family for their invaluable assistant in all my undertakings. I am grateful to my future in-laws for their encouragement, love, and support. I also wish to thank all members of the

Schafer group: Mark, Louisa, Ali, Rob, Charles, Jason, and Dave for proof reading this thesis. I further appreciate the effort of Rob for helping in solving the crystal structures in this thesis; likewise I thank Jason who synthesized the aminoalkene substrates used in this work. I thank the NMR staff, mass spectrometry staff, Dr. Brian Patrick of X-ray crystallography laboratory, and mechanical workshop staff for all their help. I am grateful to the girls, Latifat, Bilikis, Silifat and Suliat, and the boys Ahmed and Ibrahim for their prayers and moral supports. I wish to thank the Ajiboyes for being a family to me in Canada. Finally, I am very grateful to my closest friends, Toyin Oluwatosin (nee

Bodunde) and Tawakalt Kehinde for always getting in touch. Thank you all.

xn CHAPTER 1 - INTRODUCTION

1.1 Background

Efficient C-N bond forming reactions are of great importance for the preparation of nitrogen containing molecules, which are frequently used in organic synthesis.

Valuable nitrogen containing compounds include: imines, enamines, amines, amino acids, a-cyanoimines, isoquinolines, indoles, iminoamines, and ammonium salts.1 Many of these compounds are reagent sources that have the potential to be synthetic precursors for a variety of biologically active products. Additionally, the synthesis of amines, imines, and enamines are key reactions in the production of chemicals on an industrial scale. In particular, amines are useful products and versatile intermediates industrially such that per year, several million tons of various amines are produced worldwide.10

A wide variety of methods have been developed for C-N bond formation.

Condensation reactions of alcohols, aldehydes, or ketones with ammonia or amines

(Scheme l-la),2a"c hydrocyanation of alkenes,2d"e and nucleophilic substitution reactions

9f 1 of alkyl halides (Scheme 1-lb), are just a few of these protocols. However, a number of drawbacks are associated with these methodologies, including the production of by• products, multiple synthetic steps, expensive starting materials, poor yields, and the need for protecting and deprotecting sensitive functional groups in the reaction steps. As examples, the synthesis of the imine shown in Scheme 1-1 a with the use of Si(OC2H5)4 as a dehydrating agent does not only produce ethanol as a side product, the product is also contaminated with oligomeric siloxanes.2a Aside from the production of a side product in

1 the synthesis of the amine shown in Scheme 1 -lb, the yield of the reaction is also

2f discouraging. Due to the aforementioned limitations, hydroamination, the addition of

N-H across C-C unsaturations has emerged as an atom-economic alternative to

3 conventional methods of C-N bond formation (Scheme 1-2).

O Scheme 1-1. Traditional Methods of Forming C-N Bond

1.2 Hydroamination Reaction

The hydroamination reaction can also be regarded as the alkylation of primary or secondary amines with alkenes, allenes, or alkynes. It has the advantage of being a single step, 100% atom-efficient process, thus offering economic and environmental benefits.3

Furthermore, the absence of any by-products allows direct addition of another reagent in

2 one-pot approaches, giving rise to tandem reaction pathways. A variety of isomeric products can be obtained from the hydroamination reaction. These include, the

Markovnikov (M) and the anti-Markovnikov (AM) regioisomeric products (Scheme 1-

2a) observed in the addition of amines to asymmetrically substituted alkynes and alkenes, the E and Z isomers of the imines obtained from the hydroamination of allenes (Scheme

l-2b), and stereoisomers formed from the hydroamination of prochiral alkenes such as that in Scheme l-2a.

.R' HN H * H R

+ R'NH2 R R" R" AM M

R R'NH, R R' =C= NR'

EorZ

NHR' R + NR' n\ >N R R'

Scheme 1-2. Intermolecular and Intramolecular Hydroamination Reactions

1.2.1 Thermodynamics of Hydroamination

The hydroamination reaction is only slightly exothermic, or approximately thermoneutral.lc'3a"c While this is thermodynamically reasonable, there are several

3 thermodynamic and kinetic aspects that inhibit the direct addition of amines across C-C multiple bonds under normal conditions, thereby necessitating the use of a catalyst: lc'3a"c

1. high activation barrier due to electrostatic repulsion resulting from the

nucleophilic attack of the amine nitrogen, bearing the lone pair, on the electron

rich non-activated multiple bonds,

2. high energy difference between the n (C-C) and a (N-H) orbitals,

3. negative reaction entropy for the intermolecular cases, which shifts the reaction

equilibrium toward the starting materials with the result that the reaction is

unfavored at high temperatures.

1.3 Catalytic Systems

A few examples of the uncatalyzed addition of amines to C-C multiple bonds have been reported, one of which is the treatment of cyanoacetylenic alcohol with diethylamine (eq 1). In most of these cases, the unsaturated system is highly activated by electron-withdrawing substituents. For slightly activated, or non-activated systems, a catalyst is required due to the previously listed reasons. A number of catalysts including

alkali metal, alkaline earth metal, actinide, lanthanide, late transition metal, and early transition metal10 complexes have been developed to promote these transformations under milder conditions. Depending on the catalytic system, either activation of the unsaturated system or the amine takes place.3a'c

4 (C2H5)2N.

+ (C2H5)2NH (D y C=N HO -A NH

1.3.1 Catalyst Systems Containing Alkali and Alkaline Earth Metals

Alkali metal amides are active precatalysts for hydroamination under various

conditions.6 Sodium and lithium amides are the most frequently used, because side reactions that lead to catalyst decomposition are often observed with the heavier alkali metals.3a~° The amides are either employed directly,63"6 or generated in situ from the

elemental metal,6f the metal hydride,6f"g or the alkyl metal reagent.6h"-i For example, this

reaction allows the addition of ammonia as well as primary and secondary amines to

ethylene.6b In some cases, (especially with lithium) the use of

tetramethylethylenediamine (TMEDA) as a co-catalyst increases the rate of the reaction

(Figure 1-1, complex l).6h TMEDA is needed for the solvation and deaggregation of the

alkyl lithium and the resulting lithium amides. Complexes 1 and 2 shown in Figure 1-1

are active catalyst complexes proposed for lithium-promoted hydroamination30 and 3 is a precatalyst for calcium-mediated hydroamination (Figure 1-1).6e

The mechanism proposed for C-N bond formation with these systems is based on

amine activation.3c'6b"c Deprotonation of the amine by the metal generates a highly

nucleophilic metal amide 4, which then adds to the unsaturated functionality to give the

very reactive aminoalkyl metal intermediate 5. Protonolysis of 5 affords the product, and

the metal amide is regenerated as the catalytically active species (Scheme 1-3). Recently

Hill and co-workers proposed an alternative amine activation mechanism, similar to that

for organolanthanide-catalyzed hydroamination (Scheme 1-4), for a calcium-mediated

5 intramolecular hydroamination of aminoalkenes.6e In general, poor selectivity, poor yields, and lability of the metal complex are among the drawbacks of these systems.

Also, alkali and alkaline earth metal catalysts are most effective for hydroamination reactions involving secondary amines.

H NR2 Me2

R2NS ,Li Ar^CaV ,Li-NEt \ , 2 \ •

V N H N' (Me3Si)2N 't>

Me2 R2 R = Et Ar = 2,6-di/sopropylphenyl 2

Figure 1-1. Proposed Alkali metal Catalysts and Alkaline Earth Metal Precatalyst for the Hydroamination Reaction

MR'

HNR2

HNR2

M= Li, Na

Scheme 1-3. Proposed Catalytic Cycle for the Hydroamination Reaction Mediated by Alkali Metals

1.3.2 Catalyst Systems Containing Lanthanides

Marks and co-workers pioneered the use of lanthanide complexes in

hydroamination when they published their investigations of aminoalkene

hydroamination.83 They developed a useful synthetic route to different cyclic amines, in

6 combination with a thorough analysis of the catalytic reaction mechanism. ' The proposed mechanism for organolanthanide-catalyzed hydroamination of aminoalkene is

shown in Scheme 1-4.8 Lanthanide complexes such as 6 undergo rapid protonolysis of

the M-C bond by the amine to produce the amide complex 7. This is followed by alkene

insertion into the M-N bond with the resultant formation of complex 8. Intermolecular protonolysis of the M-C bond formed affords the product heterocycle, and regenerates the

catalytically active amide species. Like 6, complexes 9 and 10 are other effective

hydroamination precatalysts described by Livinghouse et al.Sc'd

Lanthanide complexes have also been investigated for enantioselective N-H

or i

addition to C-C unsaturations. " In particular, Marks et al. implemented ansa-

metallocene precatalysts such as 11 in the enantioselective and diastereoselective

hydroamination/cyclization of aminoalkenes. Incorporation of a chiral moiety into the

organolanthanide complexes ensures the formation of diastereomeric complexes.8f'g For

example, complex 11 has been used for the hydroamination/cyclization of 4-

pentenylamine to 2-methylpyrrolidine, generating a new chiral centre adjacent to the N-

atom.8f The reactions generally proceed in good yield with enantiomeric excesses of up

to 74%. Apart from reports by Marks et al., there are other interesting examples of

lanthanide-catalyzed hydroamination in the literature.8h~k Recently, Livinghouse

described an yttrium complex that gave the highest ee (89%) ever reported for

enantioselective intramolecular aminoalkene hydroamination.8k Figure 1-2 shows

structures of effective achiral (9, 10) and chiral (11, 12) lanthanide hydroamination

precatalysts reported in the literature. Although the lanthanide complexes are efficient

catalysts for hydroamination, their high sensitivity to air and moisture has limited their

7 use in many applications10 and there is room for improvement of the highest ee obtained thus far.8k

Scheme 1-4. Proposed Mechanism for Organolanthanide-Catalyzed Aminoalkene Hydroamination/Cyclization

Figure 1-2. Lanthanide Precatalysts for the Hydroamination Reaction

8 1.3.3 Catalyst Systems Containing Late Transition Metals

Coulson and co-workers first reported transition metal-based homogenous hydroamination catalysis.3a'9a Investigations by this and other groups have led to the discovery of various late transition metal-based catalyst systems for hydroamination.9

The catalytic cycles proposed for late transition metal-catalyzed hydroamination involve either the multiple bond activation approach, or the amine activation approach to C-N bond formation. In the C-C multiple bond activation approach, coordination of the unsaturated bond to the metal complex renders it more susceptible to attack by the amine.

The 2-aminoalkyl metal complex 13 formed can either undergo protonolysis (Route A) or intramolecular proton transfer (Route B) followed by reductive elimination to give the hydroamination product 14 and the starting metal complex (Scheme l-5a).3a

Alternatively, complex 13 can undergo ^-hydride elimination to afford the oxidative amination product 15 (Scheme l-5b).3c Very often 13 is isolable as analytically pure material.98"1 Compounds 16,9g 17,9h and 189' are examples of structurally characterized 2- aminoalkyl complexes (Figure 1-3). Most of the early work utilizing these complexes was stoichiometric because amines, in particular aliphatic amines are excellent ligands for these electrophilic metal centres, and often displace ligands rather than exclusively attack the coordinated multiple bond.3c

9 Scheme l-5b. Catalytic Cycle Proposed for the Formation of Oxidative Animation Product

Figure 1-3. Structurally Characterized 2-AminoaIkyl Complexes

10 In addition to the activation of the C-C multiple bond, there is another mechanistic possibility for late transition metal-catalyzed hydroamination for which the catalytic cycle is shown in Scheme 1-6.3a'c Activation of the amine by oxidative addition of the N-H bond to a transition metal in a low oxidation state results in the formation of a hydrido-amido complex 19. Insertion of the alkene into the M-N or M-H bond of 19 then generates intermediate 20 or 21 which can undergo reductive elimination to yield the hydroamination product, and the starting metal complex (Scheme 1-6). While insertions into M-N bonds have been reported,9-" insertions into M-H bonds have yet to be observed.

Figure 1-4 shows a few structurally characterized hydrido-amido complexes (22,9j and

239k) found in the literature. Advantages of late transition metal catalysts include functional group tolerance and lower sensitivity to air; however, high cost, short catalyst lifetimes, slow reaction rates, toxicity, and modest selectivity have been cited as their disadvantages.101^

Scheme 1-6. Proposed Mechanism for the Hydroamination Reaction Involving Activation of the Amine by N-H Addition to the Transition Metal

11 R = Me

R2 R2 22 23

Figure 1-4. Structurally Characterized Hydrido-Amido Complexes

1.3.4 Catalyst Systems Containing Early Transition Metals

Many recent advances in catalytic hydroamination are based on the chemistry of early transition metals.10 In the early 1990s, Bergman et al. reported that the zirconium

bis(amido) Cp2Zr(NHR)2 (R = 2,6-dimethylphenyl) acts as a precatalyst for the hydroamination of internal alkynes with 2,6-dimethylaniline.10a Unfortunately, this reaction did not proceed with other less sterically hindered amines and terminal alkynes.

At about the same time, Livinghouse and co-workers published their work on hydroamination/cyclization of aminoalkynes catalyzed by titanium imido complexes, but intermolecular hydroamination using these catalysts was not successful.10b Inspired by these results, Doye et al. developed an efficient and general method for the hydroamination of various internal alkynes using dimethyltitanocene as a catalyst.100

All the above-mentioned early transition metal complexes are metallocene-based systems. Odom and co-workers demonstrated that early transition metal-catalyzed hydroamination of alkynes is not limited to metallocene, or even Cp-based systems. By utilizing the commercially available titanium amido complex Ti(NMe2)4, the hydroamination of alkynes with arylamines was performed and selective formation of the

12 Markovnikov product with internal alkynes was also reported.10d However, polymerization was observed as a side reaction in some cases, which dramatically lowers the yield of the reaction. Our group reported N,0 chelating amidate complexes of titanium and zirconium (non-Cp-based) as precatalysts for the intermolecular and intramolecular hydroamination of alkynes. 10e'f Both alkyl- and arylamines were successfully employed and the reactions generally proceed faster than those reported for

Ti(NMe2)4. Group 4 metal complexes with guanidinate ligands108 and sulfonamide ligands10h have also been shown to be active precatalysts.

The catalytic cycle proposed in all of these cases is outlined in Scheme 1-7.

Protonolysis of the precatalyst 24 by amine 25 produces the imido complex 26, which is assumed to be the catalytically active species. This undergoes a [2+2] cycloaddition reaction with the alkyne to give the metallacycle 27. Further protonolysis of 27 by 25 generates 28, which can undergo intramolecular proton transfer to afford the enamine 29 that can tautomerize to the more stable imine 30. Alternatively, the precatalyst 24 can react with amine 25 to give 31 or 32, both of these complexes do not catalyze the hydroamination reaction.

Support for the outlined mechanism have been provided by kinetic measurements by Bergman103'1 and Doye.10-* Stoichiometric reactions have led to the trapping and X-ray crystal structure analysis of the proposed catalytically active species by almost all of the above mentioned groups including ours, and structural analysis of the metallacycle 27 by

Bergman,103 and Gade.10k The trapped catalysts were tested as viable catalysts for the hydroamination reaction to further support the proposed mechanism. Early transition metal-catalyzed hydroamination is not limited to group 4. In collaboration with the Piers

13 group we have reported cationic scandium-catalyzed hydroamination/cyclization of aminoalkenes.101 Also, a cationic tantalum imido catalyst has been developed for these reactions.10"1

L2Ti(NR2)2 R' 24

R'NH2 25

Scheme 1-7. Proposed Catalytic Cycle for Group 4 Metal-Catalyzed Hydroamination

Group 4 metal catalysts are inexpensive and nontoxic; they therefore offer

significant advantages compared to those based on toxic metals (Hg, Tl), or more

expensive complexes (U, Th, Ru, Pd, and Rh) and they are somewhat less sensitive to air

and moisture in comparison to the lanthanide complexes. Figure 1-5 shows some

structurally characterized precatalysts 33 and 34, imidometal catalyst 35, and

14 metallacyclic intermediates 36 and 37 that have been used for early transition metal- catalyzed hydroamination.

36 37

Figure 1-5. Structurally Characterized Precatalysts (33, 34), Imidometal Catalyst (35), and Metallacyclic Intermediates (36, 37) in Early Transition Metal-Catalyzed Hydroamination

1.4 Scope of this Thesis

Amidates are N,0 chelating ligands. While reports of their use as ligands in late transition metalUa'b and early transition metal110 complex formation exist in the literature, the number of well-defined amidate complexes of transition metals remains low. The

Schafer group has been developing group 4 metal complexes with these ligands. 10e'f

Variation of the substituents on the amide proligands for these complexes give rise to

15 complexes with different electronic and steric properties. e" The synthesis of the amido variant of these compounds is described in Chapter 2.

Another goal of the Schafer research group is to develop group 4 metal complexes for efficient intermolecular hydroamination of alkenes. As a step toward this, we have decided to probe the activity of our currently used precatalyst 38 (Figure 1-6) for the hydroamination of allenes, as hydroamination of allenes are intermediate in difficulty between that of alkynes and alkenes. This precatalyst has been shown to be highly active for intermolecular hydroamination of alkynes.10f

\ /2 38

Figure 1-6. Bis(amidate)-Bis(amido) Precatalyst for Allene Hydroamination

Unlike the hydroamination of alkynes and alkenes, there are only a few reports of the hydroamination of allenes. Early efforts to hydroaminate allenes involve the use of a stoichiometric amount of late transition metals.12 Lanthanide,81 early transition metal,10a,, 'm as well as late transition metal complexes13 were later described as catalysts or precatalysts for intermolecular or intramolecular allene hydroamination. However, early transition metal-catalyzed intermolecular hydroamination of allenes is still rare and the only reports that have been made are by Bergman and co-workers.10a '1,m Allene hydroamination is discussed in more detail in Chapter 2.

16 Allenes can be used as alternatives to alkenes, as has been demonstrated by Marks and co-workers. Despite some success achieved in alkene hydroamination by this group, the application of lanthanide-mediated hydroamination to alkaloids synthesis was only successful with the allenes. In Chapter 2 of this thesis, the results of intermolecular hydroamination of allenes are presented. The reactivity, regioselectivity, and limited substrate scope investigations will be discussed. In Chapter 3, the use of some of the reduced products, (ether amines) obtained from oxyallene hydroamination as new N,0 chelating ligands for group 4 metal complex formation is reported. These new complexes have been successfully used as precatalysts for the intramolecular hydroamination/cyclization of aminoalkenes.

1.5 References

(1) (a) Roundhill, D. M. Chem. Rev. 1992, 92, 1-27. (b) Layer, R. W. Chem. Rev. 1963,

63, 489-510. (c) Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104-114.

(2) (a) Love, B. E.; Ren, J. J. Org. Chem. 1993, 58, 5556-5557. (b) Eisch, J. J.; Sanchez,

R. J. Org. Chem. 1986, 51, 1848-1852. (c) Watanabe, Y.; Yamatoto, J.; Akazome, M.;

Kondo, T.; Mitsudo, T. J. Org. Chem. 1995, 60, 8328-8329. (d) Tolman, C. A.; Seidel,

W. C; Druliner, J. D.; Domaile, P. J. Organometallics 1984, 3, 33-38. (e) Hodgson, M.;

Parker, D.; Taylor, R. J.; Ferguson, G. Organometallics 1998, 7, 1761-1766. (f) Li, Y.;

Marks, T. J. J. Am. Chem. Soc. 1996,118, 9295-9306.

(3) For reviews, see (a) Taube, R. In Applied Homogeneous Catalysis with

Organometallic Compounds; Cornils, B., Herrmann, W. A., Eds.; Wiley-VCH:

17 Weinheim, 2002; vol. 1, pp 513-524. (b) Seayad, J.; Tillack, A.; Hartung, G. C.; Beller,

M. Adv. Synth. Catal. 2002, 344, 795-813. (c) Muller, T. E.; Beller, M. Chem. Rev. 1998,

98, 675-703. (d) Gacs, M. B.; Lattices, A.; Perie, J. J. Tetrahedron 1983, 39, 703-731.

(e) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113-1126. (f) Nobis, M.;

Driefien-Holscher, B. Angew. Chem., Int. Ed. 2001, 40, 3983-3985. (g) Hong, S.; Marks,

T. J. Acc. Chem. Res. 2004, 37, 673-686.

(4) (a) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 1757-1771. (b) Haak, E.;

Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2002, 457-463. (c) Cao, C.; Li, Y.; Odom, A.

L. Chem. Commun. 2004, 2002-2003. (d) Lee, A.; Schafer, L. L., manuscript in preparation.

(5) (a) Bozell, J. J.; Hegedus, L. S. J. Org. Chem. 1981, 46, 2561-2563. (b) Kawatsura,

M.; Hartwig, J. F. Organometallics 2001, 20, 1960-1964.

(6) (a) Closson, R. D.; Napolitano, J. P.; Ecke, G. G.; Kolka, A. J. J. Org. Chem. 1957,

22, 646-649. (b) Imai, N.; Narita, T.; Tsuruta, T. Tetrahedron Lett. 1971, 38, 3517-3520.

(c) Schlott, R. J.; Falk, J. C.; Narducy, K. W. J. Org. Chem. 1972, 37, 4243-4245. (d)

Radzan, R. K. Chem. Commun. 1969, 770-771. (e) Crimmin, M. R.; Casely, I. J.; Hill, M.

S. J. Am. Chem. Soc. 2005, 727, 2042-2043. (f) Howk, B. W.; Little, E. L.; Scott, S. L.;

Whitman, G. M. J. Am. Chem. Soc. 1954, 76, 1899-1902. (g) Zuech, A. E.; Kleinschmidt,

R. F.; Mahan, J. E. J. Org. Chem. 1966, 31, 3713-3718. (h) Hartung, C. G.; Breindl, C.;

Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157-5162. (i) Beller, M.; Breindl, C.;

Riermeier, T. H.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. 1998, 37, 3389-

3391. (j) Beller, M.; Breindl, C. Tetrahedron 1998, 54, 6359-6368.

18 (7) (a) Straub, T.; Frank, W.; Reiss, G. J.; Eisen, M. S. J. Chem. Soc., Dalton Trans.

1996, 2541-2546. (b) Haskel, A.; Straub, T.; Eisen, M. S. Organometallics 1996, 15,

3773-3775.

(8) (a) Gagne, M. R; Marks, T. J. J. Am. Chem. Soc. 1989, 111, 4108-4109. (b) Gagne,

M. R; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275-294. (c) Kim, Y. K.;

Livinghouse, T. Angew. Chem., Int. Ed. 2002, 41, 3645-3647. (d) Kim, Y. K.;

Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42, 2933-2935. (e) Hong, S.;

Marks, T. J. J. Am. Chem. Soc. 2002,124, 7886-7887. (f) Giardello, M. A.; Conticello, V.

P.; Brard, L.; Gagne, M. R; Marks, T. J. J. Am. Chem. Soc. 1994, 116, 10241-10254. (g)

Giardello, M. A.; Conticello, V. P.; Brard, L.; Sabat, M.; Rheingold, A. L.; Stern, C. L.;

Marks, T. J. J. Am. Chem. Soc. 1994,116, 10212-10240. (h) Gribkov, D. V.; Hultzsch, K.

C; Hampel, F. Chem. Eur. J. 2003, 9, 4796-4810. (i) O'Shaughnessy, P. N.; Knight, P.

D.; Morton, C; Gillespie, K. M.; Scott, P. Chem. Commun. 2003, 1770-1771. (j)

Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999, 64, 6515-6517. (k) Kim, J. Y.;

Livinghouse, T. Org. Lett. 2005, 7, 1737-1739. (1) Arredondo, V. M.; Tian, S.;

McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999, 121, 3633-3639. (m) Ryu, J-S.;

Li, G. Y.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605. (n) Zulys, A.; Panda,

T. K.; Gamer, M. T.; Roesky, P. E. Chem. Commun. 2004, 2584-2585. (o) Arredondo, V.

M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1998, 120, 4871-4872. (p) Li, Y.

W.; Marks, T. J. J. Am. Chem. Soc. 1998,120, 1757-1771.

(9) (a) Coulson, R. D. Tetrahedron Lett. 1971, 12, 429-430. (b) Tamaru, Y.; Hojo, M.;

Higashimura, H.; Yoshida, Z-I. J. Am. Chem. Soc. 1988,110, 3994-4002. (c) Hegedus, L.

S.; McKearin, J. M. J. Am. Chem. Soc. 1982, 104, 2444-2451. (d) Kawatsura, M.;

19 Hartwig, J. F. J. Am. Chem. Soc. 2000, 122, 9546-9547. (e) Tokunaga, M.; Eckert, M.;

Wakatsuji, Y. Angew. Chem., Int. Ed. 1999, 38, 3222-3225. (f) Hartung, C. G.; Tillack,

A.; Trauthwein, H.; Beller, M. J. Org. Chem. 2001, 66, 6339-6343. (g) Aumann, R.;

Henkel, G.; Krebs, B. Angew. Chem., Int. Ed. Engl. 1982, 21, 204-205. (h) Toman, K.;

Hess, G. G. J. Organomet. Chem. 1973, 49, 133-138. (i) Deacon, G. B.; Gatehouse, B.

M.; Guddat, L. W.; Ney, S. C. /. Organomet. Chem. 1989, 375, CI- C4. (j) Cowan, R. L.;

Trogler, W. C. J. Am. Chem. Soc. 1989, 111, 4750-4761. (k) Hsu, G. C; Kosar, W. P.;

Jones, W. D. Organometallics 1994, 13, 385-396. (1) Anderson, R. A.; Zalkin, A.;

Templeton, D. H. Inorg. Chem. 1981, 20, 622-623.

(10) (a) Walsh, P. J.; Baranger, A. N.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114,

1708-1719. (b) McGrane, P. L.; Jessen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992,114

5459-5460. (c) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 1999, 38, 3389-

3391. (d) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20, 3967- 3969.

(e) Li, C; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.

2003, 2462-2463. (f) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733-4736. (g) Ong, T-

W.; Yap, G. P. A.; Richeson, D. S. Organometallics 2002, 21, 2839-2841. (h)

Ackermannn, L.; Bergman, R. G.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-

11963. (i) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923-2924. (j)

Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305-2308. (k) Ward, B. D.;

Maisse-Francois, A.; Mountford, P.; Gade, L. H. Chem. Commun. 2004, 704-705. (1)

Lauterwasser, F.; Hayes, P.; Brase, S.; Piers, W. E.; Schafer, L. L. Organometallics 2004,

23, 2234-2237. (m) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6, 2519-

2522. (n) Cao, C; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853-2856. (o) Ackermarm,

20 L. Organometallics 2003, 22, 4367-4368. (p) Heutling, A.; Pohlki, F.; Doye, S. Chem.

Eur. J. 2004, 10, 3059-3071. (q) Castro, I. V.; Tillack, A.; Hartung, C. G.; Beller, M.

Tetrahedron Lett. 2003, 44, 3217-3221. (r) Van Otterlo, W. A. L.; Pathak, R.; Koning, C.

B.; Fernandes, M. A. Tetrahedron Lett. 2004, 45, 9561-9563. (s) Ackermann, L.; Kaspar,

L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824-2825. (t) Ackermann, L.; Born, R.

Tetrahedron Lett. 2004, 45, 9541-9544. (u) Cao, C; Shi, Y.; Odom, A. L. J. Am. Chem.

Soc. 2003, 125, 2880-2881. (v) Tillack, A.; Castro, I. G.; Hartung, C. G.; Beller, M.

Angew. Chem., Int. Ed. 2002, 41, 2541-2543.

(11) (a) Dolmella, A.; Intini, F. P.; Pacifico, C; Padovano, G.; Natile, G. Polyhedron

2002, 21, 275-280. (b) Malinski, J. D.; Zhu, T. P.; Hu, Z. S.; Kadish, K. M. J. Am. Chem.

Soc. 1982, 102, 5507-5509. (c) Giesbrecht, G. R.; Shafir, A.; Arnold, J. Inorg. Chem.

2001, 40, 6069-6072.

(12) (a) Wilson, R. M.; Musser, A. K. J. Am. Chem. Soc. 1980, 102, 1722-1723. (b)

Arseniyadis, S.; Gore, J. Tetrahedron Lett. 1983, 24, 3997-4000.

(13) (a) Besson, L.; Gore, J.; Cazes, B. Tetrahedron Lett. 1995, 36, 3857-3860. (b) Al-

Masum, M.; Meguro, M.; Yamamoto, Y. Tetrahedron Lett. 1997, 38, 6071-6074. (c)

Meguro, M.; Yamamoto Y. Tetrahedron Lett. 1998, 39, 5421-5424.

21 CHAPTER 2 - INTERMOLECULAR HYDROAMINATION OF ALLENES

2.1 Introduction

Allenes comprise the class of compounds characterized by a 1,2-diene moiety.

The last half of the past century saw a phenomenal growth in the chemistry of allenes due to the discovery of over thirty naturally occurring allenes in plants and organisms such as algae and fungi.1 The success of these endeavours has led to allenes being prepared and transformed in a variety of ways. The principal methods of synthesizing allenes include: carbene reactions,23 alkyne-allene rearrangements,2b Wittig reactions,20 and elimination reactions.2d Alkyne-allene rearrangement is the most useful and general method of preparing allenes because alkynes bearing a variety of functional groups are readily available and many new or modified procedures for converting alkynes into allenes are known.1

Unlike alkynes, hydroamination of alkenes has met with little success. As a step toward group 4 metal-catalyzed hydroamination of alkenes, intermolecular hydroamination of allenes was carried out to probe the application of precatalyst 38 that was previously developed for alkyne hydroamination.3 Generally, intermolecular hydroamination is more difficult to accomplish than intramolecular hydroamination and thus intermolecular hydroamination will be a more efficient approach to investigating the reactivity of complex 38. Furthermore, early transition metal-catalyzed intermolecular hydroamination of allenes has received limited attention, with the only reports being made by Bergman and co-workers.4

22 Allenes are highly reactive unsaturated systems and with respect to the hydroamination reaction are intermediate in difficulty between the reaction of alkynes and alkenes. Early reports of the use of late transition metals in N-H addition to allenes were based on the use of a stoichiometric amount of the complex.5 Catalytic reactions with silver and palladium were later reported,6 but in most of these cases additives such as acetic acid, triethylammonium iodide or protected amines were required for the reaction to proceed.

Marks and co-workers demonstrated that organolanthanide complexes are active catalysts for intramolecular hydroamination/cyclization of aminoallenes (Scheme 2-1).7

This chemistry was further applied to the synthesis of some naturally occurring alkaloids

(+)-pyrrolidine 197B and (+)-xenovenine (Figure 2-1), which are heterocycles bearing a- substituents. Attempts to prepared these alkaloids by intramolecular hydroamination/cyclization of aminoalkenes failed.7

precatalyst

Scheme 2-1. Organolanthanide-Catalyzed Hydroamination/Cyclization of Aminoallene

23 (+)-Pyrrolidine 197B (+)-Xenovenine

Figure 2-1. Alkaloids Synthesized by Intramolecular Hydroamination/Cyclization of Allenes

Bergman and co-workers pioneered the use of group 4 metals in catalytic hydroamination of allenes with the development of a bis(amido) zirconium precatalyst

for the intermolecular hydroamination of unsubstituted allene (1,2-propadiene) with 2,6-

dimethylaniline (Scheme 2-2).4a They later reported a titanium imido complex as an

active catalyst for the hydroamination of both unsubstituted allene with alkyl- and

4b

arylamines and substituted allenes with arylamines (Scheme 2-2). However, the

hydroamination of heteroatom-substituted allenes was unsuccessful and the

hydroamination of substituted allenes with alkylamines was not mentioned.411 Of note is

the use of group 4 bis(sulfonamido)8a and chiral titanium amino-alcohol complexes8b'c as

precatalysts for the intramolecular version of this reaction.

Ar = 2,6-dimethylphenyl, py = pyridine

Scheme 2-2. Group 4 Metal-Catalyzed Intermolecular Hydroamination of Allenes

24 There are 3 observable regioisomeric products, 40, 41, and 42, that can be obtained from the intermolecular hydroamination of allenes. Early transition metal- catalyzed intermolecular hydroamination of allenes usually produces regioisomer 40, and both the E and Z isomers of this product have been observed (Scheme 2-3),4b while reported late transition metal-catalyzed intermolecular hydroamination of allenes affords

41 and/or 42 sometimes with the double hydroamination side product.6c"d

NR'H

NR' 40

Scheme 2-3. Possible Products from the Intermolecular Hydroamination of Allenes

Bis(amidate)-bis(amido) complexes of titanium and zirconium are utilized as precatalysts for hydroamination in the Schafer lab. The amide proligands for these complexes are easily prepared from commercially available acid chlorides and primary amines (Scheme 2-4). Both R and R' substituents on the proligands can be varied to probe the electronic and steric properties of the resulting complexes.3'9 A protonolysis reaction between the proligands and commercially available tetrakis(dialkylamido)titanium or tetrakis(dialkylamido)zirconium starting materials generally affords the precatalysts in yields greater than 70% (Scheme 2-4).

25 This chapter describes the synthesis of allenes and their subsequent transformation by hydroamination. A number of the final isolated products (amines) are new compounds and were fully characterized by NMR spectroscopy, mass spectrometry, and elemental analysis.

O NEti CHCI2 ,2 3 + R'NH2 FACI 0 °C to rt H

Et20 Ti[NEt2]4 -78 °C to rt

R' ,Et ITU o-

Scheme 2-4. Synthesis of Bis(amidate)-Bis(amido) Titanium Complex

2.2 Results and Discussion

2.2.1 Synthesis of the Allenes

Different allenes, that is alkyl-, aryl-, and heteroatom (oxygen)-substituted allenes, were prepared to investigate substituents effect when the allenes are subsequently used with alkyl- and arylamines in the hydroamination reaction. These allenes are not commercially available and were therefore synthesized using modified literature procedures. The method of synthesis used is the alkyne-allene rearrangement. One

26 common feature in the preparation of all the allenes is the use of alkyl or aryl propargyl ether as a starting material (Scheme 2-5).

ROH

Scheme 2-5. General Scheme Used in Allenes Synthesis

Methoxyallene (39a)10

Methoxyallene (39a) was both a catalyst substrate for hydroamination and a reagent in the synthesis of 3-phenyl-1-propyne, which is a precursor to benzylallene

(39b). Methoxyallene was prepared in the following fashion. Methyl propargyl ether was synthesized in very good yield by adding 1.1 equivalents of potassium hydroxide to

1 equivalent of propargyl alcohol at 0 °C followed by dropwise addition of 1.1

equivalents of dimethyl sulphate (Scheme 2-6), then simple distillation of the reaction

mixture gave the desired ether as a colourless liquid in 85% yield. The product required

drying over molecular sieves for at least 24 hours before proceeding with the next step in

the synthesis. The second step involved heating 1 equivalent of methyl propargyl ether

and 0.1 equivalents of vacuum dried potassium f-butoxide to reflux for 16 hours. This is

to ensure adequate purification by distillation. After purification, 39a was obtained as a

colourless liquid in 65% yield.

27 KOH ,0. (CH3)2S04 H 0 °C to rt 85% 24 h

10 mol% f-BuOK

75°C,16 h

-=C= 65% 39a

Scheme 2-6. Synthesis of Methoxyallene

Benzylallene (39b)u

Benzylallene (39b) was prepared in the following way. Phenylmagnesium bromide and methoxyallene (39a) were reacted in a 1.1:1 ratio to give the intermediate product 3-phenyl-1-propyne in 73% isolated yield. This intermediate was then treated with 2 equivalents of dizsopropylamine, 2.5 equivalents of paraformaldehyde, and 0.5 equivalents of copper(I) bromide in dioxane (Scheme 2-7) to afford crude benzylallene.

Both column chromatography and vacuum distillation (over calcium chloride) with a vigreux column were used in the purification of this compound as a small quantity of phenylallene (5%, probably due to isomerization of 3-phenyl-1-propyne) was also formed. The yield of the reaction is 54% and the compound is colourless. Benzylallene was stored over molecular sieves in the freezer under inert atmosphere as slow decomposition is observed at room temperature.

28 MgBr +

(H2CO)n 39b 73% CuBr, dioxane 110°C,16 h 54%

Scheme 2-7. Synthesis of Benzylallene

Phenylallene (39c)12

Using the method of Brandsma and Verkruijsse,12 1.75 equivalents of phenylmagnesium bromide was treated with 0.04 mol% of copper(I) bromide and 1 equivalent of methyl propargyl ether (Scheme 2-8). A much smaller amount of copper(I) bromide (0.04 mol%) than that reported (3.5 mol%) was required, as larger quantities produce exclusively 3 -methoxy-1 -phenyl- 1-propene, formed by hydrolysis of the intermediate adduct. The reaction was stirred overnight at room temperature and phenylallene was obtained as a colourless oil in 54% yield following work-up and purification by both distillation and column chromatography. This compound was stored in the freezer under inert atmosphere because it undergoes slow decomposition at room temperature.

39c 54%

Scheme 2-8. Synthesis of Phenylallene

29 3-Phenyl-l,2-pentadiene (39d)12

In THF, 1.2 equivalents of methyl propargyl ether was lithiated with 1.4 equivalents of «-BuLi and treated with 1 equivalent of ethylbromide (Scheme 2-9). After refluxing overnight and working up the reaction mixture, l-methoxy-2-pentyne was obtained in 52% yield as a colourless oil. This was then reacted with 1.35 equivalents of phenyl magnesium bromide in the presence of a catalytic amount (5 mol%) of copper(I) bromide to produce the desired product as a colourless oil in 53% yield.

1. n-BuLi, THF -78°C to rt /CL ^ ^—=— 2. ^Br THF 76 °C, 20 h PhMgBr

CuBr

Et20 46°C/16 h v

53%

39d

Scheme 2-9. Synthesis of 3-Phenyl-l,2-pentadiene

2,6-Dimethylphenoxyallene (39e)13

A literature procedure was followed in the preparation of this compound.13 The

synthesis involves reacting 1 equivalent of 2,6-dimethylphenol in ethanol with 1

30 equivalent of sodium metal and 1 equivalent of propargyl bromide. The resulting alkyne was treated with 0.5 equivalents of potassium ^-butoxide to give the desired allene as colourless oil in modest yield of 66% (Scheme 2-10). This allene was reported to

13 undergo decomposition when distillation was attempted for purification. However, it was discovered that the compound could be easily purified by column chromatography on silica gel using pure hexanes as the eluting solvent.

OH

Na, C2H5OH ~ H 70% 95 °C, 5 h

f-BuOK

f-BuOH

95 °C, 5h

:C= 66% O

39e

Scheme 2-10. Synthesis of 2,6-Dimethylphenoxyallene

2.2.2 Bis(amidate)-Bis(amido) Hydroamination Precatalysts

A variety of bis(amidate)-bis(amido) complexes of zirconium and titanium

hydroamination precatalysts have been prepared by the method outlined in Scheme 2-4 in

the Schafer lab. Due to the high activity observed when both complexes shown in Figure

2-2 were employed as precatalysts for the hydroamination of alkynes, ' preliminary

investigations of the hydroamination of allenes was carried out using both complexes.

31 Figure 2-2. Bis(amidate)-Bis(amido) Titanium Complexes

2.2.3 Intermolecular Hydroamination of Alkyl- and Aryl-Substituted Allenes with

Arylamines

A quick screening of the complexes shown in Figure 2-2 revealed that neither displayed a superior catalytic activity over the other, but due to the ease of handling of complex 38, this compound was chosen as the precatalyst for the intermolecular hydroamination investigations discussed below. Benzylallene (39b) and phenylallene

(39c) were the first to be subjected to hydroamination because the hydroamination of alkyl- and aryl-substituted allenes exists in the literature and comparison of our system to the reported systems can be made.

In the presence of 5 mol% of 38, 1 equivalent of benzylallene (39b) was reacted with 1 equivalent of 2,6-dimethylaniline and the progress of the reaction was followed by

]H NMR spectroscopy (Table 2-1, entry 1). The total disappearance of the allene peaks between 4.55 ppm and 5.20 ppm and the appearance of new peaks including two singlets at 1.48 and 1.92 ppm indicated that the product was formed in greater than 95% conversion within 24 hours at 85-90 °C. These singlets are diagnostic of the terminal methyl group for the E and Z isomers (Figure 2-3) of compound 40 (Scheme 2-3).

32 Regioisomer 40 was the only product observed. Olefinic peaks that would correspond to the other isomers (41 and 42) were absent in the 'H NMR spectrum. The exact ratio of the E and Z isomers could not be determined due to overlapping peaks in the 'H NMR spectrum. Benzylallene also reacts with aniline in a 1:1 ratio in the presence of 38 to give product 40b (entry 2) exclusively. The diagnostic terminal methyl protons for the E isomer appear at 1.45 ppm while that for the Z isomer is at 1.94 ppm in the 'H NMR spectrum. The E:Z ratio determined by integration of these peaks in the 'H NMR spectrum is 5.7:1. The E and Z isomers were assigned based on the assumption that they would appear in a similar region to that of a similar compound (40c, see below) reported in the literature.4b The reaction time (24h) and temperature (90 °C) for 39b using precatalyst 38, are similar to those reported for group 4 metal-catalyzed intermolecular hydroamination of monosubstituted allenes using other known catalysts.4b~c

The reaction of phenylallene (39c) with arylamines in the presence of 38 (entries

3 and 4) was faster (7 hours) than that of benzylallene with the arylamines described

above. Regioisomer 40 was once again the only observed product. Both the E and Z

isomers were formed in all these reactions. The terminal methyl protons peak

corresponding to the E isomer for 40c appear at 1.30 ppm while that for the Z isomer is at

1.98 ppm and the ratio is 4.4:1. This ratio was assigned based on literature assignments

of the same compound. Product peaks for 40d are observed at about the same region as

that in 40c and here the E:Z ratio is 2.8:1. The reaction time for the formation of 40c (7

hours at 90 °C) is shorter than that reported for the same compound in the literature (24

hours at 90 °C) using a titanium imido catalyst.4b In general, this reaction is slower than

the hydroamination of terminal alkynes using precatalyst 38,3 which was reported to

33 occur at room temperature for some substrates, and temperatures of 65 °C for the most difficult substrates, but the reaction times compare favourably with those reported in the literature in the case of benzylallene and are better for phenylallene.

R R Y

Nx N R' R

Figure 2-3. E and Z Isomers of Compound 40

Table 2-1. Intermolecular Hydroamination of Alkyl- and Arylallenes with Arylamines

R LiAIH ^=c= + R'NH2 5 mol% 38 ^ R'"~Y 4 ^ R'T"

NHR drtoluene 85-90 °C NR' Et O 16 h '

Entry Allene Amine Observed product Temp Yield3

(Time)

1 85 °C 933

(24h) 39b 40a

3 2 NH2 85 °C 83

(24h) 39b 6 40b

34 3 90 °C 76a

Cu (7h) 39c

40c

a 4 NH2 90 °C/ 64

CU 7h 39c 6 40d

5 120 °C

- (24h) - / c=

39d

6 NH2 120 °C / C== 6 - (24h) - 39d

Isolated yield of the corresponding secondary amine.

Hydroamination reactions of disubstituted allene 39d with arylamines (entries 5 and 6) were unsuccessful using 38 even with a high precatalyst loading of 10 mol% at 90

°C for 24 h. Decomposition of the allene was observed by *H NMR spectroscopy when the temperature of the reaction was increased to 120 °C.

To avoid isolation of the imine products, which are susceptible to hydrolysis, 40a-

d were reduced with lithium aluminium hydride to the corresponding secondary amines

43a-d respectively (Figure 2-4). The yields of the amines obtained vary from 64% to

93% after purification by column chromatography. Compound 43a is a new compound

35 and was fully characterized by NMR spectroscopy, mass spectrometry and elemental analysis.

43d

Figure 2-4. Secondary Amines Obtained After Reduction of the Imines

2.2.4 Intermolecular Hydroamination of Alkyl- and Aryl-Substituted Allenes with

Alkylamines

Encouraged by the results obtained with arylamines, hydroamination with alkylamines was carried out. It is worth mentioning that the Bergman report of the intermolecular hydroamination of substituted allenes using a titanium complex does not include hydroamination with alkylamines.4b Reaction of benzylallene (39b) with wopropylamine was slower and higher temperature (120 °C) as well as higher precatalyst loadings (10 mol%) were required for complete conversion of the allene within 24 hours

(Table 2-2, entry 1). Due to the volatility of wopropylamine, 3 equivalents of this amine were used. Similar to the aforementioned arylamines, both the E and Z isomers were formed in a ratio of 4.4:1. The diagnostic methyl protons resonate in similar regions to those discussed above. Benzylallene also reacts with ^-butylamine and benzylamine in

36 the presence of 10 mol% of 38, with the same temperature and reaction time (entries 2 and 3) as that for the reaction of this substrate with wopropylamine. The E:Z ratios are

5.7:1 and 4.6:1 for 40f and 40g respectively. An internal standard, 1,3,5- trimethoxybenzene was used in determining the yields of compounds 40e, 40f, and 40g by 'if NMR spectroscopy and then these yields were confirmed after the hydrolysis of the imines and isolation of corresponding ketone products. Compound 44a was the ketone isolated in all these cases (Figure 2-5).

Table 2-2. Intermolecular Hydroamination of Alkyl- and Arylallenes with Alkylamines

10mol% 38 SiO,

+ R'NH2

C6D5Br NR' O CH2CI2 120°C,24 h

Entry Allene Amine Observed product Yield

1 91a (97)b

NH2 39b

2 71a (95)b

—^—NH2 39b ^^^^ 40f Y

3 85a(98)b

Q^NH2 39b 40g

37 4 Cu 65a ^>—NH 39c 2 40 h

5 60a

\ fl 1 N

39c -V-NH2 40 i

6 75a

Q^NH2 39c cuoo 40j c Isolated yield of corresponding ketone product. Yield of imine determined by H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard.

O

44a 44b

Figure 2-5. Isolated Ketones

Like benzylallene (39b), phenylallene (39c) reacts smoothly with z'sopropylamine

(entry 4), J-butylamine (entry 5) and benzylamine (entry 6). All these reactions occur within 24 hours at 120 °C. In these three situations, accurate determination of the E:Z ratio could not be made due to overlapping peaks in the 'H NMR spectrum. Compound

44b (Figure 2-5) was isolated from these reactions after hydrolysis of the imine products.

Generally, the intermolecular hydroamination of 39b and 39c with alkylamines

38 proceeded smoothly although with higher temperature and higher precatalyst loading than that required for arylamines.

2.2.5 Intermolecular Hydroamination of Ether-Substituted Allenes with Alkyl- and

Arylamines

The successful use of precatalyst 38 for the hydroamination of alkyl- and aryl-

substituted allenes with alkylamines prompted us to investigate the more challenging task

of mediating hydroamination of heteroatom-substituted allenes using this precatalyst.

Attempted hydroamination of these substrates with a group 4 metal complex was reported by Bergman et al. to be unsuccessful.415 Complex 38 has been reported to have some

functional group tolerance in alkyne hydroamination3 and we thought this may apply to

the allene reactions as well.

Hydroamination of ether-substituted allenes (oxyallenes) 39a and 39e proceeds

smoothly in the presence of 5 mol% of 38 (Table 2-3). With 2,6-dimethylaniline, regioisomer 40 (40k 4.3:1 and 401 4.3:1 E:Z ratios) is observed as the sole product

(entries 1 and 2). Reduction of 40k and 401 gives the ether amines 43e and 43f

respectively (Figure 2-6). The diagnostic methyl protons for 401 and 40k resonate at

about the same region as those discussed earlier. It is worth mentioning that while

complex 38 tolerates some oxygen functionality in alkyne hydroamination, the

hydroamination of propargyl ethers was not successful. This is likely due to catalyst

decomposition.

39 Interestingly, regioisomer 41 (Scheme 2-3) was the major product observed in the reaction of all the other amines (aniline, zsopropylamine, benzylamine, and f-butylamine) with either 39a or 39e. The diagnostic signal for all of these reactions is a doublet of triplets (for the olefinic proton adjacent to the ether group) that appears between 5.60 and

5.80 ppm in the NMR spectrum. Reaction of mefhoxyallene (39a) with aniline gave

41a as the only product in 52% yield (entry 3). Reaction of this same substrate with

/sopropylamine produced 41b as well as 40m (entry 4) with 41b being the major product

(89% of the total product). Efforts to separate this mixture of products by column chromatography failed. Given the small scale of this reaction and low molecular weight of the desired amine product, it is possible that this product evaporated before the column chromatography could be completed. Distillation of the crude product (formed from 39a and wopropylamine) after extraction with diethylether produces both the ketone 44c

(formed from hydrolysis of 40m, Figure 2-6) and the product corresponding to regioisomer 41 in 95% total yield (89% of 41b and 11% of 40m). This reaction was then carried out at 65 °C to see if the lower temperature would favor the formation of one regioisomer. At this temperature the reaction went to completion after 6-7 days and both regioisomers were still formed in amounts similar to those reported above. Separation of the desired amine product 41b from the ketone 44c by simple acid/base extraction protocol also failed. Intense yellow colour was observed when 3 M or 1 M hydrochloric

acid was added to the mixture of products ('H NMR spectrum contains unidentified peaks). This is possibly due to the acid sensitivity of the methoxy group. As a result of the difficulty encountered, the reaction of substrate 39a with the other alkylamines is not reported.

40 Table 2-3. Intermolecular Hydroamination of Ether-Substituted Allenes with Aryl- and Alkylamines

OR

40

Entry Allene Amine Observed Yield Temp

Product (Time)

1 68a 90 °C

39a (24h)

40 k

2 76a 90 °C

(24h)

39e 401

a 3 NH2 52 90 °C

39a 6 /O 41a (24h) 4 H 95b 90 °C

NH (24h) 2 /° 41b ' 39a X

40 m

41 a 5 NH2 82 rt 6 (3h) 39e

6 73a 65 °C H fl (16h) ce- 41d 39e dx° 7 70a 65 °C

(12h) ^>—NH2

39e

8 45a 100 °C

(48h) —NH CC~ 2 39e

a Yield of iso ated product. bYield of isolated combined products

Figure 2-6. Isolated Amines and Observed Ketone in Oxyallene Hydroamination

Interestingly, reaction of substrate 39e with aniline in the presence of 10 mol% of

38 was complete before the *H NMR spectrum could be recorded (less than 20 minutes).

With 5 mol% of 38, the same reaction went to completion within 3 hours at room temperature (entry 5). The reaction with alkylamines (entries 6-8) required elevated

42 temperatures (65-100 °C) but the temperatures were lower than that used for substrates

39b and 39c (120 °C). Hydroamination products from 39e and alkylamines were isolated in pure form by simple acid/base extraction protocol (entries 6-8). Unlike the imines, these products do not have to be reduced. The crude reaction mixture was first poured into water to decompose the catalyst and then extracted with diethylether. Addition of 3

M hydrochloric acid to the ether extract produced the ammonium salt, which was later basified with 3 M NaOH (after separation from the ether layer) to regenerate the amine.

Products isolated this way are pure by elemental analysis. Generally, greater reactivity was observed with substrates 39a and 39e compared to 39b and 39c, and this is attributed to the presence of the electron rich ether substituents. Product 43f and all the amines 41 are new compounds and were fully characterized (41b is an exception) by NMR spectroscopy, mass spectrometry and elemental analysis.

These reactions are believed to occur through the mechanistic pathway that has been widely proposed for group 4 metal-catalyzed hydroamination of alkynes, alkenes, and allenes.4'14 In this respect, intense mechanistic investigations have been reported by

Bergman and co-workers4a"b as well as Doye et a/.14a Nevertheless, the change in regioselectivity is interesting and warrants further efforts.

2.2.6 Possible Explanation for Change in Regioselectivity

The change in regioselectivity observed with the oxyallenes may be due to the coordination of the oxygen of the allenes to the titanium in the reactions involving aniline; this could result in the nitrogen being directed to carbon 3 of the allene as shown

43 in the metallacyclic intermediate 45 in the proposed catalytic cycle (Scheme 2-11). With

2,6-dimethylaniline, sterics may prevent such coordination and addition therefore occurs at the middle carbon of the allene (Scheme 2.12) such that the exocyclic olefin is placed (3 to the metal centre in the metallacyclic intermediate 46. This proposal of the [2+2] cycloaddition reaction (Scheme 2-12) occurring between carbons 2 and 3 rather than 1 and 2 of the allene (that could potentially give the same product, Scheme 2-3) is based on the anti-Markovnikov selectivity observed when 38 was used in alkyne hydroamination.3

Schemes 2-11 and 2-12 are proposed based on the catalytic cycle proposed for group 4 metal-catalyzed hydroamination by the aforementioned groups.4,14a

Scheme 2-11. Proposed Catalytic Cycle for the Formation of 41

44 Scheme 2-12. Proposed Catalytic Cycle for the Formation of 40

2.3 Conclusions

Intermolecular hydroamination of substituted allenes was investigated using a bis(amidate)-bis(amido) titanium precatalyst 38. Similar to what has generally been observed in the hydroamination reaction,14 arylamines react faster requiring lower temperature (90 °C) and lower precatalyst loading (5 mol%) than alkylamines that required a temperature of 120 °C and 10 mol% of the precatalyst to go to completion within 24 hours. In contrast to the reaction with methyl propargyl ether that resulted in the decomposition of precatalyst 38,3 hydroamination of oxyallenes proceeded smoothly.

A change in regioselectivity was observed for all the amines with the exception of the bulky 2,6-dimethylaniline. Regioisomer 41 was either the only or the major product for all reactions of oxyallenes with aniline and alkylamines while imines were the sole

45 product from hydroamination of oxyallenes with 2,6-dimethylaniline. The change in regioselectively is attributed to steric effects brought about by coordination of the oxygen of the allene to the titanium centre. Hydroamination reactions with oxyallenes (ether- substituted allenes) generally proceed faster than that with alkyl- or aryl-substituted allenes. The presence of electron rich substituents on the oxyallenes resulted in greater reactivity.

2.4 Experimental Procedures

General methods

All reactions were carried out under an atmosphere of dry nitrogen using standard

Schlenk line techniques or an MBraun Unilab glove box unless otherwise stated. *H and

13C NMR spectra were recorded on 300 MHz or 400 MHz Bruker Avance spectrometers in the solvents indicated. Thin layer chromatography was performed on silica gel

(Macheney-Nagel Silica Gel 60) aluminium plates (layer 0.20 mm). Column chromatography was performed using Silicycle silica gel 70-230 mesh. GCMS spectra were obtained on an Agilent series 6890 gas chromatography system with a 5973 mass selective detector. Mass spectrometry and elemental analysis were performed at the

Department of Chemistry, University of British Columbia.

46 Materials

Diethyl ether, THF, hexanes and toluene were purified over columns of alumina.

Ethanol was distilled over magnesium. Dioxane was distilled over sodium. Amines were

dried over CaH2 and distilled under vacuum or nitrogen. Ti(NEt2)4 was purchased from

Strem and used as received. rfg-Toluene and c?5-bromobenzene were degassed by freeze- pump-thaw process, and stored over molecular sieves in the glove box. Bis(amidate)- bis(amido) precatalyst 38 was prepared as described in the literature.3 Allenes were synthesized by slight modifications of literature procedures as described below. All other reagents were purchased from Aldrich, Acros, or Fisher Scientific and used without further purification.

Methyl Propargyl Ether

This reaction was done in air; 32.0 g of potassium hydroxide (0.57 mol) was added to

35.0 g (0.63 mol) of propargyl alcohol in a 500 mL round bottom flask at 0 °C. This was followed by slow addition of 79.0 g (60.0 mL, 0.63 mol) of dimethyl sulphate. The reaction was warmed to room temperature and stirred for 24 hours. After 24 hours, a distillation apparatus was fitted on the reaction flask and methyl propargyl ether was distilled off at 61 °C (760 mmHg) in 85% yield. The NMR data obtained were consistent with those reported.15 *H NMR (CDCh, 300 MHz): 5 2.42 (1H, t, J = 2.4 Hz, CCH),

13 3.38 (3H, s, C7/3OCH2), 4.08 (2H, d, J= 2.4 Hz, CH3OC//2); C NMR (CDC13 75 MHz):

5 57.31,59.40, 74.40, 79.34.

47 39a Methoxyallene (39a)1

A 50 mL round bottom flask charged with 2.40 g of potassium f-butoxide was evacuated on a high vacuum line (~ 0.01 mmHg) for 15 minutes, then 15.0 g (0.21 mol) of methyl propargyl ether was added to the solid and the mixture heated to reflux for 16 hours. The reflux condenser was replaced with a distillation apparatus and methoxyallene was distilled off at 52 °C in 65% yield. The NMR data obtained were consistent with those

10 l reported. R NMR (CDC13, 300 MHz): 8 3.40 (3H, s, CH30), 5.46 (2H, d, J= 5.9 Hz,

13 CCH2), 6.75 (1H, t, J= 5.9 Hz, CH3OCr7); C NMR (C6D6, 75 MHz): 8 55.57, 90.96,

123.40, 201.67.

3-Phenyl-l-propyne 1 1

A 500 mL Schlenk flask charged with 0.95 g (6.60 mmol) of CuBr and 5.00 g (72.6 mmol) of methoxyallene in 100 mL of diethylether was treated with a Grignard reagent prepared from 10.4 g (6.94 mL, 66.0 mmol) of bromobenezene and 3.20 g (14.0 mmol) of magnesium in diethylether at room temperature, and the reaction was stirred for 3 hours. The reaction was quenched by addition of a mixture of 1.00 g KCN and 10.0 g

NH4CI in 200 mL of water. The layers were separated and the aqueous layer extracted with 3 x 25 mL diethylether. The combined organic layers were dried over magnesium

48 sulphate and the mixture concentrated by rotary evaporation. The crude product was purified by distillation under vacuum (46 °C/0.01 mmHg). Yield: 73%; 'H NMR

(CDCI3, 300 MHz): 5 2.17 (1H, t, J= 2.7 Hz, CCH), 3.60 (2H, d, J= 2.7 Hz, Av-CH2),

13 7.28-7.36 (5H, m, Ai-H); C NMR (CDC13, 100 MHz): 5 24.75, 70.42, 81.93, 126.68,

127.82, 128.53, 136.06.

39b Benzylallene (39b)11 1 1

A solution of 3.00 g (25.9 mmol) of 3-phenyl-1-propyne in 50 mL of dioxane was added to a mixture of 1.85 g (12.9 mmol) of CuBr and 1.94 g (64.7 mmol) of paraformaldehyde

in 200 mL of dioxane in a 500 mL Schlenk flask. The mixture was treated with 5.20 g

(7.27 mL, 51.7 mmol) of diz'sopropylamine and then refluxed overnight. Work-up was

done by pouring the reaction mixture into a mixture of water and pentane and extracting

the aqueous layer with pentane (3 x 30 mL). The combined pentane layers were washed

several times with water, dried over magnesium sulphate and concentrated by rotary

evaporation. The concentrate was purified by column chromatography (eluting solvent: hexanes) and vacuum distilled (43-44°C/0.01 mmHg) over calcium hydride to give the

! desired product in 54% yield. H NMR (CDC13, 300 MHz): 8 3.15-3.19 (2H, m,

13 CH2CU), 4.56-4.60 (2H, m, CCH2), 5.14-5.19 (1H, m, CH2Gf7); C NMR (C6D6, 75

MHz): 5 35.33, 75.16, 90.00, 126.46, 128.62, 128.72, 140.43, 209.31.

49 —c= 39c

Phenylallene (39c)12

A solution of phenylmagnesium bromide prepared from 31.3 g (21.0 mL, 0.20 mol) of bromobenzene and 9.60 g (0.40 mol) of magnesium in diethylether was decanted into a

500 mL Schlenk flask from the excess magnesium. A catalytic amount 0.04 mol% of

CuBr (this amount could not be accurately weighed) was added at 0 °C, followed by dropwise addition of 8.00 g (0.11 mol) of methyl propargyl ether in 50 mL of diethylether. The reaction mixture was stirred at room temperature overnight and then

quenched by addition of a mixture of 1.00 g KCN and 10.0 g NH4C1 in 70 mL of water.

The layers were separated and the aqueous layer extracted with 3 x 25 mL diethylether.

The combined ethereal solutions were dried over magnesium sulphate and concentrated by rotary evaporation. Column chromatography of the crude product followed by vacuum distillation (69-70 °C/15 mmHg) via a 20 cm vigreux column gave the desired

] product in 54% yield. H NMR (CDC13, 300 MHz): 5 5.13 (2H, d, J= 6.8 Hz, CCH2),

6.15 (1H, t,J= 6.8 Hz, ArCH), 7.15-7.21 (1H, m, Ai-H), 7.28-7.30 (4H, m, Ax-H); 13C

NMR (C6D6, 75 MHz): 5 78.63, 94.41, 127.07, 127.13, 128.85, 134.27, 210.09.

50 l-Methoxy-2-pentyne

A solution of 5.00 g (71.4 mmol) of methyl propargyl ether in 150 mL of THF in a 500 mL Schlenk flask was treated with 52.1 mL (83.3 mmol) of n-butyl lithium at -78°C.

The mixture was stirred at -5 °C for 1 hour and slowly transferred via cannula to 6.49 g

(4.44 mL, 59.5 mmol) of bromoethane in 50 mL of THF at 0 °C. The reaction mixture was heated at reflux for 20 hours. It was then poured into water and extracted with diethylether. The organic extracts were dried over magnesium sulphate and the ether distilled off. Distillation of the concentrate under vacuum (50-52°C/20 mmHg) produced

! the desired product in 52% yield. H NMR (CDC13, 300 MHz): 8 1.13 (3H, t, J= 7.5 Hz,

C//5CH2), 2.22 (2H, q,J= 7.5 Hz, C/£CH3), 3.34 (3H, s, OCH3), 4.06 (2H, t, J= 2.1 Hz,

13 CH20); C NMR (CDCI3, 75 MHz): 8 12.32, 13.71, 57.28, 60.11, 74.98, 88.35.

3-Phenyl-l,2-pentadiene (39d) 12

A catalytic amount 5 mol% (0.16 g, 1.12 mmol) of CuBr was added to a solution of phenyl magnesium bromide (prepared from 4.75 g of bromobenzene and 1.45 g of magnesium) in diethyl ether at 0 °C. This was followed by the addition of 2.20 g (22.5 mmol) of l-methoxy-2-pentyne at room temperature and the reaction mixture refluxed

51 overnight. Quenching was done by slow addition of 70 mL aqueous solution of 1.00 g

KCN and 10.0 g of NH4C1. The layers were separated and the aqueous layer extracted with diethylether. The combined ethereal solutions were dried over magnesium sulphate and concentrated by distillation. Distillation under vacuum (95-96°C/20 mmHg) via a 20 cm vigreux column gave the desired product in 53% yield. The NMR data obtained were consistent with those reported.17 *H NMR (CDCh, 300 MHz): 5 1.14 (3H, t,J= 7.4 Hz,

13 CU2CH3), 2.38-2.44 (2H, m, Gr72CH3), 5.09 (2H, t, J = 3.6 Hz, CCH2); C NMR

(CDC13, 75 MHz): 5 12.46, 22.36, 78.73, 106.68, 125.89, 126.53, 128.33, 136.53, 208.38.

2,6-Dimethylphenyl Propargyl Ether13 ' 1

To a solution of 15.4 g (0.13 mol) of 2,6-dimethylphenol in 200 mL of ethanol was added

2.90 g (0.13 mol) of sodium metal. After the evolution of hydrogen has ceased, 18.8 g

(14 mL) of propargyl bromide was added. The mixture was heated at reflux for 5 hours.

This was then poured into a mixture of pentane and water. The layers were separated and the aqueous layer extracted thrice with 30 mL of pentane. The organic extracts were washed with 50 mL of 10% NaOH solution, dried over magnesium sulphate and concentrated using rotary evaporation. Distillation of the concentrate under vacuum (54-

56°C/0.01 mmHg) gave the product in 70% yield. lR NMR (CDCh, 300 MHz): 5 2.31

(6H, s, Ax-CH3), 2.49 (1H, t,J= 2.4 Hz), 4.49 (2H, d, J= 2.4 Hz), 6.91-6.99 (3H, m, Ar-

H); I3C NMR (CDCh, 75 MHz): 8 16.48, 59.73, 74.88, 79.36, 124.40, 128.83, 131.16,

155.25.

52 39e 2,6-Dimethylphenoxyallene (39e)13

A solution of 12.0 g (75.0 mmol) of 2,6-dimethylphenyl propargyl ether and 4.20 g (37.5 mmol) of potassium r-butoxide in 200 mL of ^-butanol were refluxed for 5 hours. The reaction mixture was poured into a mixture of pentane and water after cooling. The layers were separated and the aqueous layer extracted thrice with 30 mL of pentane. The combined organic layers were washed several times with water, dried over magnesium sulphate and concentrated by rotary evaporation. Purification of the concentrate by column chromatography (eluting solvent: hexanes) gave the pure product in 66% yield.

] H NMR (CDC13, 300 MHz): 5 2.22 (6H, s, Ar-CH3), 5.22 (2H, d, J= 5.9 Hz, CCH2),

13 6.87 (1H, t, J= 5.9 Hz), 6.91-7.01 (3H, m, Ar-//); C NMR (C6D6, 75 MHz): 5 16.34,

90.61, 121.66, 125.07, 128.85, 131.11, 153.28, 201.25.

Representative Procedures for Intermolecular Hydroamination of Allenes

Method A

Example: Synthesis of N-(2',6'-dimethyphenyl)-4-phenyl-2-butylamine (43a)

A mixture of 200 mg (1.54 mmol) of benzylallene, 186 mg (1.54 mmol) of 2,6- dimethylaniline, 5 mol% (58.0 mg) of complex 38, and few drops of dg-toluene were heated in a J. Young NMR tube. After 24 hours, the reaction mixture was cooled to room

53 temperature, and then added to 0.12 g (3.08 mmol) of lithium aluminium hydride in 15 mL of diethyl ether at 0 °C. This was warmed up to room temperature and stirred overnight. The reaction was quenched by dropwise addition of saturated NH4CI solution, filtered through Celite, and the residue washed with dichloromethane (25 mL). The solvents were removed by rotary evaporation and the crude product purified by column chromatography. Yield: 93%.

Method B

Example: Synthesis of 4-Phenyl-2-butanone 44a

A mixture of 50.0 mg (0.38 mmol) of benzylallene, 68.0 mg (1.15 mmol) of

/sopropylamine, 10 mol% (29.0 mg) of precatalyst 38, 65 mg (0.38 mmol) of 1,3,5- trimethoxybenzene and 1 mL of c?5-bromobenzene were heated at 120 °C in a J. Young

NMR tube. After 24 hours the reaction mixture was pour into a suspension of silica gel in dichloromethane and stirred for 10 hours. The mixture was filtered and the residue washed with dichloromethane. The solvents were removed by rotary evaporation and the hydrolyzed product purified by column chromatography to give the ketone in 91% yield.

The NMR data obtained for ketones 44a and 44b were consistent with those of the authentic samples from commercial sources.

54 Method C

Example: Synthesis of N-(2',6'-dimethylphenyl)-3-(2',6-dimethylphenoxy)-2- propylamine (43c)

A mixture of 200 mg (1.25 mmol) of 2,6-dimethylphenoxyallene, 116 mg (1.25 mmol) of aniline, 5 mol% (47.0 mg) of 38, and 0.50 mL of (/5-bromobenezene in a J. Young NMR tube was left at room temperature for 3 hours. It was then poured into a mixture of water

(5 mL) and dichloromethane (30 mL). The layers were separated and the aqueous layer extracted with (3x15 mL) dichloromethane. The combined organic layer was dried over magnesium sulphate and concentrated by rotary evaporation. Column chromatography of the crude product with hexanes/ethyl acetate 60:1 affords the product in 82% yield.

Method D

Example: Synthesis of N-isopropyl-3-(2',6'-dimethylphenoxy)prop-2-enylamine

(41e)

A mixture of 200 mg (1.25 mmol) of 2,6-dimethylphenoxyallene, 221 mg (3.75 mmol) of

z'sopropylamine, 5 mol% (47.0 mg) of precatalyst 38, and few drops of d5-bromobenzene were heated in a J. Young NMR tube at 65 °C for 24 hours. This was poured into a mixture of water (5 mL) and diethylether (20 mL). The mixture was filtered and the organic layer extracted with 3 M HC1 (3x15 mL). The acid wash was treated with 3 M

NaOH until the solution became strongly basic as tested by litmus paper. The basic solution was extracted with diethylether (3 x 20 mL) and the organic extract was dried

55 over magnesium sulphate, filtered and concentrated by rotary evaporation to afford the product in 70% yield.

N-phenyI-3-methoxyprop-2-enylamine (41 a)

Method C was used in the preparation of this compound; the isolated yield was 68%. 1H

NMR (CDCI3, 300 MHz): 8 3.63 (3H, s, OCH3), 3.78 (2H, dd, J= 1.3, 6.8 Hz, CRCH2),

4.52 (1H, q, J= 6.7 Hz, CHCU2), 6.00 (1H, br td, J= 1.3, 6.8 Hz, CH3-OGr7), 6.61-6.68

(3H, m, Ar-H), 7.13-7.18 (2H, m, Ax-H); 13C NMR (CDCI3, 75 MHz): 8 38.27, 59.86,

103.71, 113.06, 117.32, 129.12, 148.25, 148.30; MS(ESI): mlz 163(M++H), 132(M+-

OCH3); Anal. Calcd. For Ci0H13NO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.98; H,

7.99; N, 8.98.

N-isopropyI-3-methoxyprop-2-enylamine (41b)

The preparation of this compound was achieved by method D; the isolated yield was

89%. 'H NMR (CDCI3, 300 MHz): 8 1.03 (6H, d, J= 6.2 Hz, CR(CH3)2), 2.77-2.85 (1H,

m, C#(CH3)2), 3.25-3.33 (2H, m, CRCH2), 3.58 (3H, s, CH30), 4.43-4.50 (1H, m,

13 C//CH2), 5.92-5.94 (1H, m, CH3OC#); C NMR (CDC13, 75 MHz): 8 22.92, 41.07,

48.03, 59.68, 105.24, 147.52; MS(ESI): mlz 130(M++H).

56 H N

.0

41c

N-phenyl-3-(2',6'-dimethylphenoxy)prop-2-enylamine (41c)

The preparation of the titled compound was done using method C; after column chromatography the compound was isolated in 82% yield. *H NMR (CDCh, 300 MHz):

8 2.25 (6H, s, Ac-CH3), 3.86 (1H, br s, CH2Nf7), 4.03 (2H, br dd, J = 1.3, 6.7 Hz,

C/fcNH), 4.68-4.75 (1H, m, GfYCH2), 6.07-6.10 (1H, m, C//CH), 6.68-6.73 (3H, m, Ar-

H), 6.94-7.04 (3H, m, Ar-//), 7.16-7.21 (2H, m, Ar-//); 13C NMR (CDCI3, 75 MHz): 8

16.29, 38.31, 105.01, 113.11, 117.43, 124.81, 128.82, 129.17, 130.50, 145.98, 148.22

+ + 154.40; MS(ESI): mlz 254(M +H), 161(M -NHPh); Anal. Calcd. For Ci7H19NO: C,

80.60; H, 7.56; N, 5.53. Found: C, 81.00; H, 7.58; N, 5.92.

N-benzyl-3-(2',6'-dimethylphenoxy)prop-2-enylamine (41 d)

This compound was synthesized by method D; the compound was isolated in 73% yield.

*H NMR (CDCI3, 300 MHz): 8 2.21 (6H, s, A1-CH3), 3.54-3.56 (2H, m, CHCifr), 3.86

(2H, s, CH2-A1), 4.69-4.75 (1H, m, C//CH2), 6.05-6.07 (1H, m, Ar-OC//), 6.92-7.02 (3H, m, Ar-//), 7.20-7.37 (5H, m, Ar-H); 13C NMR (CDCh, 100 MHz), 8 16.26, 42.98, 53.44,

57 105.92, 124.69, 126.90, 128.22, 128.37, 128.75, 130.52, 140.36, 145.79, 154.42;

+ + MS(ESI): mlz 268(M +H), 161(M -NHCH2Ph); Anal. Calcd. For Ci8H2iNO: C, 80.86;

H, 7.92; N, 5.24. Found: C, 80.93; H, 8.05; N, 5.60.

N-isopropyl-3-(2',6'-dimethylphenoxy)prop-2-enylamine (41 e)

The titled compound was prepared by method D; the isolated yield was 70%. 'HNMR

(CDC13, 300 MHz): 8 1.09 (6H, d, J= 6.2 Hz, CU(CH3)2), 2.21 (6H, s, Ar-H), 2.89-2.96

(1H, m, C#(CH3)2), 3.50 (2H, dd, J = 1.3, 6.9 Hz, CiftNH), 4.66 (1H, q, J = 6.8 Hz,

13 C//CH2), 6.02 (1H, br dt, J= 1.3, 6.9 Hz, Ai-OCH), 6.93-7.03 (3H, m, Ai-H); C NMR

(CDCI3, 75 MHz): 8 16.24, 22.94, 40.94, 47.86, 106.41, 124.66, 128.75, 130.54, 145.39,

+ + 154.43; MS(ESI): mlz 220 (M +H), 161 (M -NHCH(CH3)2); Anal. Calcd. For C,4H2iNO:

C, 76.67; H, 9.65; N, 6.39. Found: C, 76.58; H, 9.46; N, 6.79.

N-M>utyl-3-(2',6'-dimethyphenoxy)prop-2-enylamine (41 f)

The preparation of this compound was achieved by method D; the isolated yield was

45%. 'H NMR (CDCI3, 400 MHz): 8 1.15 (9H, s, C(CH3)3), 2.22 (6H, s, Ax-CH3), 3.43-

58 3.49 (2H, m, CHCH2), 4.70 (1H, q, J = 6.8 Hz CHCH), 5.98-5.99 (1H, m, Ai-OCH),

13 6.93-7.01 (3H, m, Ar-H); C NMR (CDC13, 75 MHz): 5 16.24, 29.07, 36.72, 50.46,

107.28, 124,64, 128.75, 130.56, 144.91, 154.43; MS(ESI) 234 (M++H), 161 (M+-

NHC(CH3)3); Anal. Calcd. For C15H23NO: C, 77.21; H, 9.93; N, 6.00. Found: C, 77.00;

H, 9.77; N, 6.30.

N-(2',6'-dimethyphenyl)-4-phenyl-2-butyIamine (43a)

The preparation of the titled compound was achieved by method A; after column

j chromatography the compound was isolated in 93% yield. H NMR (CDC13, 300 MHz):

8 1.16 (3H, d, J= 6.3 Hz, CHCH3), 1.73-1.93 (2H, m, C/fcCH), 2.26 (6H, s, Ar-CH3),

2.71-2.82 (2H, m, Ar-C//2CH2), 2.90 (1H, br s, Ar-NH), 3.31-3.35 (1H, m, Gr7CH3),

6.82 (1H, t, J= 1.4 Hz, Ax-H), 7.01 (2H, d, J= 7.4 Hz, Ar-H), 7.19-7.22 (3H, m, Ar-H),

13 1.29-134 (2H, m, Ar-H); C NMR (C6D6, 75 MHz): 8 19.16, 21.46, 33.10, 40.44, 51.98,

121.67, 126.06, 128.62, 129.17, 129.23, 142.47, 145.57; MS(ESI): mlz 254(M++H); Anal.

Calcd. For C18H23N: C, 85.32; H, 9.15; N, 5.53. Found: C, 85.26; H, 8.94; N, 5.90.

59 N-phenyl-4-phenyl-2-butylamine (43b)

The title compound was synthesized by method A; 83% was the isolated yield. The

18 1

analytical data obtained were consistent with those reported. H NMR (CDCI3, 300

MHz): 5 1.20 (3H, d, J= 6.2 Hz, CRCH3), 1.72-1.91 (2H, m, Ar-CH2C7/2), 2.71 (2H, t, J

= 7.9 Hz A1-CH2), 3.41 (1H, br s, Ar-Nfl), 3.44-3.53 (1H, m, GfYCH3), 6.50-6.53 (2H, m, Ar-H), 6.65 (1H, t,J= 7.3 Hz, Ar-H), 7.10-7.27 (5H, m, Ar-H); 13C NMR (CDCI3, 75

MHz): 8 20.84, 32.47, 38.82, 47.89, 113.14, 116.92, 125.83, 128.37, 128.41, 129.26,

141.98, 147.54.

43c N-(2',6'-dimethylphenyl)-l-phenyl-2-propylamine (43c) 1 1

Method A was followed in synthesizing the titled compound; the yield obtained was 76%

after purification by column chromatography. The analytical data obtained were

consistent with those reported.19 ]H NMR (CDCh, 300 MHz): 8 1.02 (3H, d, J= 6.3 Hz,

CHCH3), 2.21 (6H, s, Ax-CHj), 2.53 (1H, dd, J = 8.4, 13.0 Hz, CH2CH), 2.88-2.94 (2H,

br m, Ar-N//, CH2CH), 3.44-3.51 (1H, m, C//CH3), 6.78 (1H, br t, J = 7.3 Hz, Ar-H),

60 13 6.96 (2H, br d, J= 7.3 Hz, Ar-//), 7.10-7.29 (5H, m, M-H); C NMR (CDC13, 75 MHz):

8 19.01, 20.78, 44.39, 54.03, 121.39, 126.09, 128.23, 128.85, 129.19, 129.36, 139.38,

144.75.

N-phenyl-l-phenyl-2-propylamine(43d)

Method A was followed in synthesizing the titled compound; the yield obtained was 64% after purification by column chromatography. The analytical data obtained were

20 ! consistent with those reported. H NMR (CDC13, 300 MHz): 8 1.15 (3H, d,J= 6.4 Hz,

CHCH3), 2.69 (1H, dd, J = 7.3, 13.4 Hz, Gr72CH), 2.94 (1H, dd, J = 4.8, 13.4 Hz,

C//2CH), 3.52 (1H, br s, NiTPh), 3.71-3.79 (1H, m, CH2C//), 6.60-6.68 (3H, m, Ar-//),

13 7.15-7.29 (7H, m, Ar-//); C NMR (CDC13, 75 MHz): 8 20.18, 42.30, 49.31, 113.33,

117.16, 126.25, 128.31, 129.35, 129.49, 138.53, 147.21.

N-(2 ',6 '-dimethyIphenyl)-3-methoxy-2-propylamine (43e)

This compound was prepared in 68% yield using Method A. The NMR data obtained

21 ] were consistent with those reported. H NMR (C6D6, 300 MHz): 8 1.15 (3H, d,J= 6.3

61 Hz, CRCH3), 2.19 (6H, s, A1-CH3), 2.98-3.02 (4H, br m, CH30, OCH2), 3.08 (1H dd, J =

3.9, 8.8 Hz, OCH2), 3.24-3.26 (1H, m, CH2CH), 3.35 (1H, br s, Ar-NH), 6.87 (1H, t,J =

13 7.4 Hz, Ar-H), 6.99 (2H, d, J = 7.4 Hz); C NMR (CDC13, 75 MHz) 5 18.63, 18.68,

52.38, 59.04, 76.37, 121.40, 128.76, 129.39, 144.95.

N-(2 ',6'-dimethyIphenyl)-3-(2 ',6 '-dimethylphenoxy)-2-propylamine (43f)

Method A was followed in synthesizing this compound; 76% yield was obtained after

purification by column chromatography. *H NMR (CDC13, 400 MHz): 8 1.33 (3H, d, J =

6.4 Hz, CHGfli), 2.23 (6H, s, A1-CH3), 2.29 (6H, s, A1-CH3), 3.47 (1H, br s, Ai-NH),

3.65-3.68 (1H, br m, C//CH3), 3.72 (1H, br dd, J = 5.1, 8.7, C/fcCH), 3.82 (1H, br dd, J =

5.1, 8.7 Hz, C7£CH), 6.79 (1H, t, J= 7.5 Hz, Ar-H), 6.88-6.92 (1H, m, Ar-H), 6.96-6.99

13 (4H, m, Ax-H); C NMR (CDC13, 75 MHz): 8 16.30, 18.64, 19.01, 52.37, 75.35, 121.43,

123.85, 128.91, 129.08, 130.92, 144.47, 155.43; GC-MS (EI): m/z 283(M+); Anal. Calcd.

For C19H25ON: C, 80.57; H, 8.83; N, 4.95. Found: C, 80.33; H, 8.83; N, 5.20.

2.5 References

(1) Landor, S. R. The Chemistry of the Allenes; Academic Press Inc.: New York, NY,

1982; pp 1-74.

62 (2) (a) Moore, W. R.; Ward, H. R. J. Org. Chem. 1962, 27, 4179-4181. (b) Moore, W. R.;

Ward, H. R. J. Am. Chem. Soc. 1963, 85, 86-89. (c) Gilman, H.; Tomasi, R. A. J. Org.

Chem. 1962, 27, 3647-3650. (d) Kirby, F. J3.; Kofron, W. G.; Hauser, C. R. J. Org.

Chem. 1963,25,2176-2179.

(3) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733-4736.

(4) (a) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. Am. Chem. Soc. 1992, 114,

1708-1719. (b) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923-2924.

(c) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6, 2519-2522.

(5) (a) Wilson, R. M.; Musser, A. K. J. Am. Chem. Soc. 1980, 102, 1722-1723. (b)

Arseniyadis, S.; Gore, J. Tetrahedron Lett. 1983, 24, 3997-4000.

(6) (a) Lathbury, D.; Gallagher, T. J. Chem. Soc, Chem. Commun. 1986, 114-115. (b)

Arseniyadis, S.; Sartoretti, J. Tetrahedron Lett. 1985, 26, 729-732. (c) Besson, L.; Gore,

J.; Cazes, B. Tetrahedron Lett. 1995, 36, 3857-3860. (d) Al-Masum, M.; Meguro, M.;

Yamamoto, Y. Tetrahedron Lett. 1997, 38, 6071-6074. (e) Meguro, M.; Yamamoto Y.

Tetrahedron Lett. 1998, 39, 5421-5424.

(7) Arredondo, V. M.; Tian, S.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc. 1999,

121, 3633-3639.

(8) Ackermann, L.; Bergman, R.; Loy, R. N. J. Am. Chem. Soc. 2003, 125, 11956-11963.

(b) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R. Organometallics 2004, 23,

4614-4620. (c) Petersen, J. R.; Hoover, J. M.; Kassel, W. S.; Rheingold, A. L.; Johnson,

A. R. Inorg. Chim. Acta 2005, 358, 687-694.

(9) Li, C.; Thomson, R. K.; Gillion, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.

2003, 2462-2463.

63 (10) Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1985, 50, 5308-5314.

(11) (a) Crabbe, P.; Fillion, H.; Andre, D.; Luche, J-L. J. Chem. Soc., Chem. Commun.

1979, 859-862. (b) Trost, B. M.; Pinkerton, A. B.; Seidel, M. J. J. Am. Chem. Soc. 2001,

123, 12466-12467.

(12) Brandsma, L.; Verkruijsse, A. D. Synthesis of Acetylenes, Allenes and Cummulenes;

Elsevier: New York, NY, 1981; pp 159-161.

(13) Borrensen, S.; Crandall, J. L. J. Org. Chem. 1976, 41, 678-681.

(14) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305-2308. (b) Haak, E.;

Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 1999, 38, 3389-3391. (c) McGrane, P. L.;

Jensen, M.; Livinghouse, T. J. Am. Chem. Soc. 1992, 114, 5459-5460. (d) Li, Y.; Shi, Y.;

Odom, A. L. J. Am. Chem. Soc. 2004,126, 1794-1803.

(15) Shirota, F. N.; Demister, E. G.; Elberling, J. A.; Nagasawa, H. T. J. Med. Chem.

1980, 23, 669-673.

(16) Meijer, J.; Vermeer, P. Reel. Trav. Chim. 1974, 93, 183.

(17) Frey, H.; Kaupp, G. Synthesis 1990,10, 931-934.

(18) Ryu, J-S.; Li, G. W.; Marks, T. J. J. Am. Chem. Soc. 2003, 125, 12584-12605.

(19) Heutling, A.; Pohlki, F.; Doye, S. Chem. Eur. J. 2004,10, 3059-3071.

(20) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron 2000, 56, 5157-

5162.

(21) Dorta, R; Broggini, D.; Kissner, R.; Togni, A. Chem. Eur. J. 2004,10, 4546-4555.

64 CHAPTER 3 - TITANIUM AND ZIRCONIUM METAL COMPLEXES WITH

N,0 CHELATING LIGAND: APPLICATIONS IN INTRAMOLECULAR

HYDROAMINATION OF AMINOALKENES

3.1 Introduction

In the past decade there have been many new reports of transition metal-amido complexes.1 This is due in part to the role of these complexes as catalysts, starting materials, or intermediates in important transformations such as hydroamination,2 polymerization,3 and C-N coupling reactions.4 These recent advances are also a result of

the realization that the amido functionality (R2N-) may be used to promote a variety of structural motifs around the reactive metal centre.1 The amido group may be incorporated into polydentate ligand structures and combined with other donor functionalities, which possess a different formal charge and chemical hardness to influence the thermodynamic and kinetic stability of the nitrogen interaction with the metal centre.13 The substituents on the nitrogen atom can also be varied to probe the electronic and steric properties of the resulting metal complexes. Amido units are thus desirable tools for ligand design of transition metal complexes.

One of the interests of the Schafer group is the development of bidentate N,0 chelating ligands for early transition metal complexes. A number of bis(amidate)- bis(amido), bis(amidate) dichloro, bis(amidate) dialkyl as well as bis(amidate) imido complexes have been structurally characterized in the Schafer lab. Previous to this work only amidate N,0 chelating ligands have been investigated within the group. Thus, we

65 decided to use the ether amine products 43e and 43f obtained from the hydroamination of oxyallenes in the preceeding chapter, as precursors to new N,0 chelating ligands for group 4 metal complex formation.

In contrast to the previously studied titanium and zirconium amidate complexes,5"

8 in which the ligand forms a four-membered metallacycle, 43e and 43f are expected to form five-membered metallacyclic complexes with titanium and zirconium. Five- membered metallacycles with N,0 coordination are not without precedence.9 Such complexes with chiral amino-alcohol ligands have been developed for the intramolecular hydroamination of aminoallenes.9a'b These complexes were dimeric in nature, with the oxygen bridging the two metal centres. N,0 coordinated five-membered metallacyclic complexes of palladium with mono and dialkyl azobenzenephosphonate ligands have also been described.9c "d

The structural difference between the bis(amidate)-bis(amido) complexes and the new amido complexes derived from 43e and 43f is expected to reflect in the catalytic activity of these new complexes with respect to the previously explored hydroamination reaction. In particular, the catalytic hydroamination of alkenes is a subject of intense research as this reaction, as previously mentioned, provides direct access to amines, which are useful end products as well as versatile intermediates in many chemical processes.

While a variety of catalysts are available for the hydroamination of alkynes, only

a few complexes have been developed for the hydroamination of alkenes. Most of the

successful alkene hydroamination catalysts are based on late transition metal systems e.g. ruthenium10 rhodium,11 iridium,12 nickel,13 palladium,14 and platinum.15 Both

66 intermolecular and intramolecular alkene hydroamination have been mediated by late transition metal complexes, although the intermolecular reactions are largely limited to activated olefins such as vinylarenes investigated by Beller and co-workers,11 or cyanoolefins studied by Togni et al.u and Trogler et al.X5h Also, the groups of Marks and

Molander have demonstrated that lanthanide complexes are efficient intermolecular and intramolecular alkene hydroamination catalysts,15 while Hill and co-workers developed a calcium complex for the intramolecular version of this reaction with select substrates.

The few reported examples of early transition metal complexes for alkene hydroamination are TiCLt reported by Ackermann et al. for intermolecular hydroamination of highly strained norbornene with arylamines,18 a tantalum imido complex developed by Bergman and co-workers for the hydroamination of norbornene with aniline,19 a scandium complex reported by our group in collaboration with the Piers group for the intramolecular reaction,203 and Ti(NMe2)4 recently reported by our group for the intramolecular version of this reaction.2011 Despite all of these efforts, the hydroamination of alkenes is a desirable process for which there is no efficient, generally applicable catalytic system.

This chapter focuses on the synthesis of zirconium and titanium amido complexes with N,0 chelating ligands that furnish five-membered metallacycles. Efforts toward the synthesis of new complexes that may display unprecedented reactivity will be presented.

The full characterization of these complexes by NMR spectroscopy, elemental analysis, mass spectrometry and X-ray crystallography will be shown. The application of these complexes as precatalysts for aminoalkene hydroamination will also be discussed.

67 Throughout the remainder of this thesis, compounds 43e and 43f will be referred to as

HL1 and HL2 respectively (Figure 3-1).

HL1 (43e) HL2 (43f)

Figure 3-1. Reduced Hydroamination Products used as Proligands

3.2 Results and Discussion

3.2.1 Synthesis of Proligands

Our goal is to prepare titanium and zirconium amido complexes using the two proligands: N-(2',6'-dimethylphenyl)-3-methoxy-2-propylamine HL1 and N-(2',6'- dimethylphenyl)-3-(2',6'-dimethylphenoxy)-2-propylamine HL2 (Figure 3-1). The catalytic activity of the resulting metal complexes for the hydroamination reaction will be explored. We are interested in these ligand sets because they contain chiral centres and we envision that metal complexes obtained using enantiomerically pure ligands could mediate enantioselective hydroamination. In addition, these complexes may provide

some insight into the nature of the metal-oxygen binding interaction. This binding was proposed as the reason for the change in regioselectivity observed in the hydroamination reaction discussed in Chapter 2. Proligands HL1 and HL2 are isolated as oils and can be prepared as described in Section 2.6 of the previous chapter on gram scale. It should be noted that these proligands might also be synthesized by reductive amination of the

68 corresponding ether-substituted carbonyl compound and 2,6-dimethylaniline. Dorta et al. have applied this method in the synthesis of both HL1 and its imine precursor (40k) both of which were subsequently utilized in iridium complex formation.

3.2.2 Synthesis of Titanium and Zirconium Amido Complexes

Initial efforts toward the synthesis of titanium and zirconium amido complexes with HL1 and HL2 focused on using 2 equivalents of the racemic proligands with 1

equivalent of tetrakis(dialkylamido)titanium or zirconium complexes. The complexes were anticipated to have an octahedral coordination sphere in which two ligands

displaced two amido units (Scheme 3-1). This structural motif would be analogous to the

structure of the known bis(amidate)-bis(amido) complexes5 that were synthesized by the

same protonolysis procedure.

First, reactions between tetrakis(dialkylamido)titanium and HL1 in diethyl ether were performed, but these were unsuccessful even after stirring for 24 hours at room

temperature. Then the solvent was changed to toluene and higher temperatures (60 °C

and 100 °C) were employed. Still the desired complex was not obtained. This lack of

reactivity is presumably due to the weak proton acidity of the amido unit of the ligand.

Steric factors were also considered a possible reason for the failure of these reactions;

therefore the metal centre was switched from the small titanium to the slightly larger

zirconium.

69 Scheme 3-1. Attempted Synthesis of Amido Complexes Using 2 Equivalents of Proligands

Once again, no reaction was observed by 'H NMR spectroscopy when 2 equivalents of HL1 were reacted with 1 equivalent of tetrakis(dimethylamido)zirconium at room temperature or 60 °C. However, the !H NMR spectrum of the mixture that was heated at 100°C overnight shows the presence of several new peaks, along with the peaks associated with the proligand and the starting titanium complex. This spectrum contains two doublets, one at 0.56 ppm and the other at 1.15 ppm. The peak at 1.15 ppm corresponds to the protons of the methyl group adjacent to the chiral centre in the proligand, the other new doublet can be assigned to the protons of the same methyl group in the ligand now attached to the metal centre. The ratio of integration of the peaks corresponding to the methyl group adjacent to the chiral centre and the methyl groups attached to the aryl ring in the proligand to those of the same peaks in the complex formed, was consistent with just one ligand bound to the titanium in this complex. Thus, the reaction of 1 equivalent of HL1 with 1 equivalent of tetrakis(dimethylamido)zirconium in toluene at 100 °C was performed.

Proligand HL1 reacts cleanly with tetrakis(dimethylamido)zirconium in a 1:1 ratio in toluene at 100 °C within 24 hours to give exclusively the N,0 coordinated complex

70 1 [ZrL (NMe2)3] (47) (Scheme 3-2) as a colourless solid in 78% yield after filtration of the reaction solution through Celite and removal of the solvent in vacuo. The same reaction was attempted in diethyl ether at room temperature but no product formation was observed by !H NMR spectroscopy after 24 hours.

toluene Zr(NMe2)4 MeoN 100 °C/24 h

Me2N

-HNMe2

Scheme 3-2. Synthesis of Zirconium Amido Complex 47

X-ray quality crystals of 47 were obtained by dissolving the solid in a minimum amount of hexanes while heating and then allowing the solution to slowly cool to room temperature. Complex 47 can also be purified by recrystallization from hexanes with slow evaporation at room temperature. It is worth mentioning that X-ray quality crystals were later obtained from the reaction mixture containing 2 equivalents of the proligand

HL1 and tetrakis(dimethylamido)zirconium and this product was identified as 47. This further supports the conclusions drawn from the !H NMR spectrum discussed earlier.

The molecular structure of 47 determined by X-ray crystallography shows that the geometry about zirconium is a distorted trigonal bipyramidal with the oxygen of L1 and one of the amido nitrogens (N2) occupying the axial positions (Figure 3-2). This assignment is based on the fact that the angle 0-Zr-N2 (167.65(9) A) is the closest to being linear. The torsion angles indicate that the chelate ring is significantly distorted from planarity. The Zrl-Nl bond distance of 2.127(2) A (Table 3-1) of the ligand L1 is

71 significantly longer than the average Zr-N bond distance of 2.066 A observed for the dimethylamido units. The Zr-0 distance (2.369(3) A) falls within the range seen in the few examples of CH3O—*"Zr dative interactions in the literature (2.264-2.426 A).22 The

X-ray analysis shows there is a mirror plane in the asymmetric unit that passes through the aryl ring and between N3 and N3_8. The structure solved is slightly incorrect (a chiral molecule residing on a mirror plane) but this is the model that can be refined satisfactorily. Crystallographic data for complex 47 are given in Appendix I.

Figure 3-2. ORTEP Representation of Complex 47 With 50% Probability Ellipsoids

The 'li NMR spectrum of purified complex 47 reveals that the methyl protons adjacent to the chiral carbon atom in L1 resonate at a higher field (0.56 ppm) relative to those of HL1 (1.15 ppm) whereas the methyl protons of the N-aryl group in L1 are shifted downfield and are inequivalent as manifested by two distinct singlets (2.35 and 2.45 ppm). This inequivalence suggests that there is hindered rotation about the N1-C5 bond.

72 Considering that this complex was made with a racemic proligand, the H NMR spectrum gave no indication of the formation of stereoisomeric metal complexes.

Table 3-1. Selected Bond Distances and Angles of Complex 47

Atoms Bond Distances (A) or Angles (°) Zrl-Nl 2.127(2) Zrl-N2 2.064(2) Zrl-N3 2.0677(19) Zrl-N3_8 2.0677(19) Zrl-Ol 2.369(3) N2-Zrl-01 167.65(9) Nl-Zrl-N3 119.45(6) C3-01-Zrl 112.2(2) N2-Zrl-Nl 100.22(9) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

Reaction of 1 equivalent of HL1 with 1 equivalent of

tetrakis(dimethylamido)titanium was much slower (Scheme 3-3). After 24 hours at 100

1 ] °C, the conversion to [TiL (NMe2)3] (48) was only 17% as determined by H NMR

spectroscopy. The reaction was subsequently carried out in deuterated solvents so as to

enable monitoring by NMR spectroscopy. After 48 hours at 110 °C the conversion to

48 was 72%. The 'H NMR spectrum of this particular mixture shows two different

doublets between 0 and 1.5 ppm, the one at higher field (0.53 ppm) was assigned to

protons of the methyl group attached to the chiral centre in L1 and is diagnostic of the

formation of metal complex 48. This peak is shifted about 0.5 ppm upfield from the

proligand doublet that corresponds to the protons of the same methyl group. Once again,

the methyl protons on the aryl group in the complex are inequivalent and they appear at

73 2.32 and 2.43 ppm. They are shifted downfield from the aryl-methyl protons on the proligand, which appear as a single peak at 2.19 ppm.

dg-toluene Me,N, Ti(NMe2)4 + i 110°C/48 h

Me2N'

-HNMe2 NMe2 48

Scheme 3-3. Synthesis of Titanium Amido Complex 48

Figure 3-3. ORTEP Representation of Complex 48 with 50% Probability Ellipsoids

Crystals suitable for X-ray crystallographic studies were obtained from a concentrated benzene solution. The structure solved is isostructural to that of complex 47

(Figure 3-3). Similar distorted trigonal bipyramidal coordination geometry can be seen about the metal centre with the oxygen atom datively bonded to the titanium and the ligand L1 forming a chelate ring. X-ray analysis also shows that there is a mirror plane in the asymmetric unit that passes through the aryl ring and between two of the nitrogen

74 atoms (N2 and N2_8). Selected bond distances and angles of complex 48 are given in

Table 3-2. Crystallographic data for complex 48 are in Appendix II.

Table 3-2. Selected Bond Distances and Angles of Complex 48

Atoms Bond Distances (A) or Angles (°) Til-Nl 1.984(3) Til-N2 1.925(2) Til-N3 1.921(3) Til-N2_8 1.925(2) Til-Ol 2.255(3) N3-TH-N2 96.17(8) N2- Til-N2_8 114.78(13) N3-Til-Nl 99.53(12) N2- Til-Ol 94.47(11) N3-Til-Ol 169.27(11)

At about the same time that HL1 was used as a proligand for complex 47, a parallel reaction with HL2 as a proligand was also carried out. We envision that complexes formed from HL2 would have different electronic properties from that formed from HL1 due to the presence of an aryl group, rather than an alkyl group on the oxygen

2 functionality. Proligand HL reacts with Zr(NMe2)4 in a 1:1 ratio at 100 °C in toluene to

2 afford [ZrL (NMe2)3] (49) in 86% yield (Scheme 3-4). Complex 49 was recrystallized from hot hexanes in 80% yield. X-ray analysis shows that 49 is a C\-symmetric complex with an N,0 chelating ligand in which the oxygen atom interacts with the zirconium centre in a dative fashion (Figure 3-4). The geometry about zirconium is again a distorted trigonal bipyramid with the oxygen of the ligand and one of the amido nitrogens

75 (N2) in the axial position. The chelate ring is significantly distorted from planarity. The bond distance between the oxygen atom and the zirconium atom 2.4876(15) A (Table 3-

3) is much longer than that in complex 47 2.346(6) A (Table 3-2). This suggests a much weaker interaction of the oxygen functionality with the metal centre likely due to derealization of the lone pairs on the oxygen into the aryl ring. It should be noted that

O—*-Zr bond distance as long as 2.519 A has been previously reported.2'8

Crystallographic data for complex 49 are given in Appendix III.

Zr(NMe2)4

Scheme 3-5. Synthesis of Zirconium Amido Complex 49

C11

Figure 3-4. ORTEP Representation of Complex 49 with 50% Probability Ellipsoids

76 The !H NMR spectrum of complex 49 indicates a shift in the resonances of the protons similar to that observed for complex 47. The methyl protons adjacent to the chiral centre in complex 49 appear as a doublet at 0.92 ppm and is shifted upfield by about 0.3 ppm from that in the proligand. The methyl protons of the aryl ring attached to nitrogen are inequivalent and they appear as singlets at 2.85 and 2.80 ppm. The methyl protons of the aryl ring attached to oxygen resonate as a singlet at 2.59 ppm. All the aryl- methyl protons in HL2 appeared as a singlet at 2.18 ppm. Attempts to prepare the corresponding titanium complex were unsuccessful even with temperatures as high as

130 °C and reaction times of up to 3 days. The lack of reactivity could be attributed to the reduced tendency of the ligand L2 to chelate to the metal centre, as well as more demanding steric factors.

Table 3-3. Selected Bond Distances and Angles of Complex 49

Atoms Bond Distances (A) or Angles (°) Zr-Nl 2.1263(18) Zr-N2 2.077(2) Zr-N3 2.086(2) Zr-N4 2.062(2) Zr-0 2.4876(15) 0- Zr-Nl 70.23(6) C3-0-Zr 106.70(12) Cl-Nl-Zr 124.58(14) N2-Zr-0 161.95(7)

Variable temperature (VT) H NMR spectroscopy was carried out on complexes

47, 48, and 49 (as these complexes were made with racemic proligands) to investigate the

77 presence of stereoisomers and estimate the barrier to rotation about the C-N bond of the

1 2 ligands L and L . However, the two inequivalent aryl-methyl protons did not coalesce at

170 °C. This is close to the upper limit of the temperature range (-150 - 180 °C) accessible for VT NMR spectroscopy at the Department of Chemistry, University of

British Columbia. The low temperature VT !H NMR spectroscopy of these complexes did not show the presence of stereoisomers even at temperatures as low as -80 °C.

The *H NMR spectrum of complex 47 taken at -30 °C shows three singlets corresponding to the methyl protons of the dimethylamido units. These protons appear as a broad singlet in the room temperature ]H NMR spectrum. A similar splitting of this particular peak was observed for complex 48 at -40 °C. The low temperature VT NMR spectrum of complex 49 was much like that at room temperature with the exception that the peaks were broader. Neither resolution of stereoisomers nor clear peak splitting occurred. The absence of clear splitting may be due to the slightly different environment at the metal centre in 49, which arises from the much weaker interaction of the oxygen atom with the metal in this complex.

3.3 Intramolecular Hydroamination/Cyclization of Aminoalkenes

Since the goal of making these complexes is to probe their effectiveness in alkene hydroamination, they were used as precatalysts in a preliminary screen of some select

aminoalkene substrates. Specific substrates were selected to enable comparison with known catalytic systems, specifically Ti(NMe2)4. The aminoalkene 2,2-diphenyl-4- pentenylamine (50) was the first used because cyclization of this compound reportedly

78 occurs faster than most aminoalkenes. The high reactivity of this compound has been explained by the Thorpe-Ingold effect.20b Aminoalkene 50 was converted to 2-methyl-

4,4-diphenylpyrrolidine (51) in greater than 95% yield (determined by 'H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard) by all three complexes at 110 °C within 24 hours (Table 3-4). The reactivity of these complexes is comparable to that of the commercially available Ti(NMe2)4 recently reported by our group.20b The catalytic activity of complexes 47, 48, and 49 observed using this substrate does not clearly show any effect induced by the ligands. Thus, the more difficult hydroamination substate 2,2-dimethyl-4-pentenylamine (52) was tried.

Table 3-4. Hydroamination/Cyclization of 2,2-diphenyl-4-pentenylamine (50)

Ph. Ph 5 mol% precatalyst Ph 110°C, 24 h Ph 50 51

Entry Precatalyst Yield3

1 1 ZrL (NMe2)3 (47) 96

2 TiL'(NMe2)3 (48) 97

2 3 ZrL (NMe2)3 (49) 99 internal standard

Complexes 47, 48, and 49 were employed in the intramolecular hydroamination/cyclization of the more challenging 2,2-dimethyl-4-pentenylamine (52) to 2-methyl-4,4-dimethylpyrrolidine (53) (Table 3-5). Unlike aminoalkene 50,

79 hydroamination/cyclization of 52 using 47 and 49 took as long as 48 hours to go to completion at 110 °C (entries 1 and 3). The yields as determined by 'H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard were 91% and 86% respectively. On the other hand, cyclization of 52 by complex 48 did not go to completion even after 72 hours, and the yield was only 63% (entry 2). Titanium complexes have been reported to be more active than their zirconium counterpart in the alkyne and allene hydroamination reactions,23 but this is not the case here. One possible experimental error is that crude precatalyst 48 was used and was known to contain unreacted proligand HL1 and therefore the catalytic loading was less than 5 mol%.

However, recent unpublished results in our group show some zirconium complexes to be more active than their titanium counterparts in aminoalkene hydroamination.80

Compared to Ti(NMe2)4 which converts 52 to 53 in 52% yield after 96 hours these zirconium complexes are definitely more active. Like aminoalkene 50, compound 54 was cyclized to 55 by complexes 47, 48, and 49 within 24 hours with yields greater than

95% (Table 3-6), however, Ti(NMe2)4 also performs the same cyclization with a similar yield and reaction time.

The hydroamination/cyclization reaction is believed to occur through a mechanism that involves the formation of a catalytically active imido species and a metallacyclic intermediate formed by a [2+2] cycloaddition reaction between the imido complex and the unsaturated substrates. This mechanism has been widely proposed for early transition metal-catalyzed hydroamination of alkynes,5 allenes,23 and alkenes20b and was discussed at length in Chapters 1 and 2 of this thesis. The hydroamination/cyclization of aminoalkenes with complexes 47, 48 and 49 deserves

80 further effort. More substrates, especially those that were cyclized poorly by Ti(NMe2)4, need to be screened to determine if the introduction of these ligands results in significant catalytic activity enhancement.

Table 3-5. Hydroamination/Cyclization of 2,2-dimethyl-4-pentenylamine (52)

5 mol% precatalyst

110°C

52 53

Entry Precatalyst Yield3 Time (h)

1 1 ZrL (NMe2)3 (47) 91 48

1 2 TiL (NMe2)3 (48) 63 72

2 3 ZrL (NMe2)3 (49) 86 48 internal standard

Table 3-6. Hydroamination/Cyclization of 2,2-diphenyl-5-hexenylamine (54)

5 mol% precatalyst Ph 110°C, 24 h Ph 55

Entry Precatalyst Yield3

1 ZrL'(NMe2)3 (47) 99

2 TiL'(NMe2)3 (48) 98

2 3 ZrL (NMe2)3 (49) 99 internal standard

81 3.4 Conclusions

The versatile bis(amidate)-bis(amido) titanium-catalyzed intermolecular hydroamination of oxyallenes provides an efficient route to new N,0 chelating ligands for titanium and zirconium metal complex formation. Only one of the amido units of the titanium and zirconium starting complexes could be replaced by the ligand using the protonolysis method in the synthesis of these complexes. While the reaction involving zirconium goes to completion within 24 hours at 100 °C, that of titanium never went to completion with L1 as ligand and did not even occur with L2 as ligand. This is presumably due to the poorer donating character of L2, although steric factors cannot be ruled out. The structures solved by X-ray crystallography show all complexes to have distorted trigonal bipyramidal geometry. This work has also shown that the resulting complexes can function as effective aminoalkene hydroamination/cyclization precatalysts. The activity observed for these complexes are comparable to or better than those reported for Ti(NMe2)4- In this regard, more substrates need to be explored in order to conclusively determine whether these are more active precatalysts.

3.5 Experimental Procedures

General methods

All reactions were carried out under an atmosphere of dry nitrogen using standard

Schlenk line techniques or an MBraun Unilab glove box. ]H and 13C NMR spectra were recorded on 300 MHz or 400 MHz Bruker Avance spectrometers in the solvents

82 indicated. Mass spectrometry, elemental analysis, and X-ray crystallographic studies were performed at the Department of Chemistry, University of British Columbia.

Materials

Diethyl ether, THF, hexanes and toluene were purified over columns of alumina.

1 2

HL' and HL were degassed by freeze-pump-thaw cycles prior to use. Ti(NMe2)4 and

Zr(NMe2)4 were purchased from Strem and used as received. Jg-Toluene, ^-benzene,

and

Fisher Scientific and used without further purification.

1 ZrL (NMe2)3(47)

A solution of 0.30 g (1.55 mmol) of N-(2',6'-dimethylphenyl)-3-methoxy-2-propylamine

1 HL in 10 mL of toluene was added to 0.42 g ( 1.55 mmol) of Zr(NMe2)4 in 20 mL of toluene at 0 °C via cannula. The reaction was stirred at 100 °C overnight. The solvent was removed in vacuo and the solid product formed was dissolved in hexanes and filtered

83 through Celite in the glove box. The hexanes were removed in vacuo to give a colourless solid in 78% yield. Crystals were obtained by dissolving the solid in a hot hexanes solution and slowly cooling to room temperature. ]H NMR (CeD6, 400 MHz): 5 0.56

(1H, d, J= 6.4 Hz, CRCH3), 2.35 (3H, s,Ar-CH3), 2.45 (3H, s, Ar-CH3), 2.93-3.00 (21H,

br m, OCH3, N(C/f»2), 3.16-3.20 (1H, m, C/fcCH), 3.26 (1H, dd, J = 4.6, 7.5 Hz,

CH2CH), 3.82-3.84 (1H, m, CU2CH), 6.90 (1H, t, J= 7.4 Hz, Ar-H), 7.11 (1H, d, J= 7.4

13 Hz, Ai-H), 7.20 (1H, d,J= 7.4 Hz, Ar-H); C NMR (C6D6, 100 MHz): 8 16.85, 19.40,

21.00, 42.92, 55.93, 59.74, 82.34, 122.48,128.36, 133.80, 135.80, 150.71; MS(EI): mlz

+ 414 (M ); Anal. Cacld. For C18H36N4OZr: C, 52.00; H, 8.73; N, 13.48. Found: C, 51.93;

H, 8.69; N, 13.71.

NMe2

1 1 1 TiL (NMe2)3 (48)

Note: The characterization of this complex is incomplete because it was difficult to isolate in the pure form free from unreacted proligand. The method of synthesis is analogous to that described above for complex 47, with the difference being that tetrakis(dimethylamido)titanium was used instead of the corresponding zirconium

] complex. H NMR (C6D6, 300 MHz): 8 0.53 (3H, d, J= 6.4 Hz, CHCH3), 2.32 (3H, s,

Ax-CH3), 2.43 (3H, s, Ar-CH3), 3.00-3.11 (21H, br m, OCH3, N(CH3)2), 3.20-3.31 (2H,

+ m,CH2CR), 4.00-4.02 (1H, m,CH2C#), 6.91-7.20 (3H, m, Ar-H); mlz 372 (M ), 328

+ (M -NMe2).

84 2 ZrL (NMe2)3 (49)

This complex was synthesized using the same procedure outlined above for complex 47,

2 1 ! with HL being used instead of HL . Yield: 86%; H NMR (C6D6, 300 MHz): 5 0.92

(3H, d, J= 5.7 Hz, CHC//5), 2.59 (6H, s, Ai-CH3), 2.80 (3H, s, Ar- CH3), 2.85 (3H, s,

Ar-C//3), 3.10 (18H, s, N(C//5)2), 3.76-3.78 (1H, m, C//2CH), 4.45-4.47 (2H, m, C//2CH,

CH2C//), 7.23 (1H, t,J = 7.4 Hz, Ar-//), 7.44-7.46 (1H, br d, Ar-H), 7.54 (1H, d, J= 7.4

13 Hz, Ar-H); C NMR (C6D6, 75 MHz): 5 16.69, 16.80, 19.50, 21.17, 42.96, 57.32, 82.26,

122.79, 125.43, 128.56, 128.59, 129.58, 131.00, 133.90, 136.71, 150.96, 156.97; MS(EI):

+ mlz 504 (M ), Anal. Cacld. For C25H42N4OZr: C, 59.36; H, 8.37; N, 11.08. Found: C,

58.96; H, 7.97; N, 10.74.

Representative Procedure for Intramolecular Hydroamination/Cyclization of

Aminoalkenes

Example: Synthesis of 2-Methyl-5,5-diphenylpiperidine (55)

A mixture of 50.0 mg (0.20 mmol) of 2,2-diphenyl-4-hexenylamine, 4.00 mg (5 mol%) of complex 47, and 30.0 mg (0.20 mmol) of 1,3,5-trimethoxybenzene and 1 mL of toluene-c/g were heated in a J. Young NMR tube at 110 °C. After 24 hours, the ]H NMR spectroscopy of the reaction mixture was taken and the yield determined by comparison of the integration of the product peaks to that of the internal standard.

85 3.6 References

(1) (a) Gade, L. H. Chem. Commun. 2000, 173-181. (b) Fulton, J. R; Holland, A. W.;

Fox, D. J.; Bergman, R. G. Acc. Chem. Res. 2002, 35, 44-56. (c) Kempe, R. Angew.

Chem., Int. Ed. 2000, 39, 468-493. (d) Brynda, H. E.; Tarn, W. Chem. Rev. 1988, 88,

1163-1188.

(2) (a) Pohlki, F.; Doye S. Chem. Soc. Rev. 2003, 32, 104-114. (b) Taube, R. In Applied

Homogeneous Catalysis with Organometallic Compounds; Cornils, B., Herrmann, W. A.,

Eds.; Wiley-VCH: Weinheim, 2002; vol. 1, pp 513-524. (c) Hong, S.; Marks, T. J. Acc.

Chem. Res. 2004, 37, 673-686. (d) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675-

703.

(3) Gibson, V. C.; Spitzmesser, S. K. Chem. Rev. 2003,103, 283-316.

(4) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J-F.; Buchwald, S. L. Acc. Chem. Res. 1998,

31, 805-818. (b) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067.

(5) (a) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer, L. L. Chem. Commun.

2003, 2462-2463. (b) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733-4736.

(6) Beard, J. D.; Schafer, L. L., manuscript in preparation.

(7) Thomson, R. K.; Schafer, L. L. Can. J. Chem., in Press.

(8) (a) Li, C. M.Sc Thesis, University of British Columbia, BC, 2003. (b) Zhe, Z.;

Schafer, L. L., unpublished results, (c) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L., manuscript in preparation.

86 (9) (a) Hoover, J. M.; Petersen, J. R.; Pikul, J. H.; Johnson, A. R. Organometallics 2004,

23, 4614-4620. (b) Petersen, J. R; Hoover, J. M.; Kassel, W. S.; Rheingold, A. L.;

Johnson, A. R. Inorg. Chim. Acta 2005, 358, 687-694.

(10) (a) Utsunomiya, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 2702-2703. (b)

Sangwon, K.; Chang, S. Org. Lett. 2003, 5, 2687-2690.

(11) (a) Beller, M.; Trauthwein H.; Eichberger, M.; Breindl, C; Herwig, J.; Muller, T. E.;

Thiel, O. R. Chem. Eur. J. 1999, 5, 1306-1319. (b) Beller, M.; Trauthwein H.;

Eichberger, M.; Breindl, C; Herwig, J.; Muller, T. E. Eur. J. Inorg. Chem. 1999, 1121-

1132.

(12) (a) Casalnuovo, A. L.; Calabrese, J. C; Milstein, D. J. Am. Chem. Soc. 1988, 110,

6738-6744. (b) Dorta, R.; Egli, P.; Zurcher, F.; Togni, A. J. Am. Chem. Soc. 1997, 119,

10857-10858.

(13) Fadini, L.; Togni, A. Chem. Commun. 2003, 30-31.

(14) (a) Kawatsura, M.; Hartwig, J. F. /. Am. Chem. Soc. 2000, 122, 9546-9547. (b)

Lober, O.; Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 2001,123, 4366-4367.

(15) (a) Brunet, J-J.; Cadena, M.; Chu, N. C; Diallo, O.; Jacob, K.; Mothes, E.

Organometallics 2004, 23, 1264-1268. (b) Cowan, R. L.; Trogler, W. C. Organometallics

1987,6,2451-2453.

(16) (a) Gagne, M. R; Marks, T. J. J. Am. Chem. Soc. 1989, Ul, 4108-4109. (b) Gagne,

M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1992, 114, 275-294. (c) Hong, S.;

Tian, S.; Metz, M. V.; Marks, T. J. J. Am. Chem. Soc. 2003,125, 14768-14783.

(17) (a) Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1998, 63, 8983-8988. (b)

Molander, G. A.; Dowdy, E. D. J. Org. Chem. 1999, 64, 6515-6517.

87 (18) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Org. Lett. 2004, 6, 2515-2518.

(19) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett. 2004, 6, 2519-2522.

(20) (a) Lauterwasser, F.; Hayes, P.; Brase, S.; Piers, W. E.; Schafer, L. L.

Organometallics 2004, 23, 2234-2237. (b) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.;

Schafer, L. L. Org. Lett. 2005, 7, 1959-1962.

(21) Dorta, R.; Broggini, D.; Kissner, R.; Togni, A. Chem. Eur. J. 2004,10, 4546-4555.

(22) (a) Amor, F.; Butt, A.; Du Ploy, K. E.; Spaniol, T. P.; Okuda, J. Organometallics

1998, 17, 5836-5849. (b) Evans, W. J.; Ansari, M. A.; Ziller, J. W. Inorg. Chem. 1999,

38, 1160-1164. (c) van der Zeijden, A. A. H.; Mattheis, R.; Frohlich, R.; Zippel, F. Inorg.

Chem. 1997, 36, 4444-4450. (d) Caselli, A.; Giannini, L.; Solari, E.; Floriani, C.; Re, N.;

Chiesi-Cilla, A.; Rizolli C. Organometallics 1997,16, 5457-5849. (e) van der Zeijden, A.

A. H.; Mattheis, R.; Frohlich, R. Organometallics 1997, 16, 2651-2658. (f)

O'Shaughnessy, P. N.; Gillespie, K. V.; Morton, C.; Westmoreland, I.; Scott, P.

Organometallics 2002, 21, 4496-4504. (g) Porter, R. M.; Danopoulos, A. D.; Reid, G.;

Titcomb, L. S. Chem. Commun. 2005, 427-428.

(23) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001,123, 2923-2924.

(24) Kondo, T.; Okada, T.; Mitsudo, T-A. J. Am. Chem. Soc. 2001, 724,186-187.

(25) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida, Z-I. J. Am. Chem. Soc. 1988, 110,

3994-4002.

88 CHAPTER 4 - SUMMARY AND FUTURE DIRECTIONS

4.1 Summary

In this thesis, a variety of allenes including alkyl-, aryl-, and heteroatom-

substituted allenes were synthesized by slightly modified literature procedures. We have

shown that these allenes are excellent precursors to imines via intermolecular hydroamination of the allenes with alkyl- or arylamines. In particular, precatalyst 38 has been shown to mediate this hydroamination reaction of alkyl- or arylallenes with alkyl- or

arylamines. The reaction occurs faster with arylamines, requiring less catalytic loading

(5 mol%) and lower reaction temperature (90 °C) than with alkylamines, which requires a

temperature of (120 °C) and a catalyst loading of 10 mol% for the reaction to be

completed in 24 hours. This is not surprising as arylamines are more reactive than

alkylamines.

Reaction of heteroatom-substituted allenes, specifically, oxyallenes with amines

also proceeds smoothly. A change in regioselectivity was generally observed with

allylamines (41) being the major product. It should be noted that 2,6-dimethylaniline is

an exception here and this amine gives the branched imine (40) as the sole product. The

change in regioselectivity is attributed to the coordination of the substrate through the

oxygen atom to the titanium catalyst thereby directing addition to carbon 3 of the allene, presumably due to steric effects. The allylamines obtained from reactions involving

oxyallene 39e were easily isolated in good yield by a simple acid/base extraction and did not require reduction, hydrolysis or column chromatography. The resultant imines may

89 be reduced with lithium aluminium hydride to the corresponding secondary amines or hydrolyzed to the ketones with silica gel and water. Reaction with ether-substituted allenes (oxyallenes) generally occurs faster than with alkyl- or aryl-substituted allenes.

The presence of the electron rich substituents is believed to be responsible for the enhanced reactivity of these substrates. Unfortunately, 1,1-disubstituted allene 39d did not react with the arylamines under a variety of experimental conditions.

The interest of the Schafer group in the development of N,0 chelating ligands for early transition metal complex formation prompted the use of the ether amines HL1 and

HL obtained from hydroamination and subsequent reduction of the imines 40k and 401 as precursors to new N,0 chelating ligands for titanium and zirconium metal complex formation. Formation of these complexes required high temperatures and only occurred in a 1:1 ratio of proligand to metal. The zirconium complexes were characterized by 'H

13

NMR and C NMR spectroscopy, elemental analysis, mass spectrometry and X-ray crystal structure analysis while the titanium complex was characterized by 'H NMR, mass spectrometry, and X-ray crystal structure analysis. The structures solved by X-ray crystallography show all complexes to have a distorted trigonal bipyramidal coordination geometry with five membered N,0 chelate rings and the oxygen atoms datively bound to the metal centres. The dative bond between L2 and the metal centre is weaker than that between L1 and the metal centre.

Room temperature *H NMR spectroscopy gave no indication of stereoisomers and neither did low temperature (up to -80 °C) 'H NMR spectroscopy. These complexes were then employed as precatalysts in the preliminary screening of some select aminoalkene substrates. Hydroamination/cyclization of aminoalkenes in the presence of

90 5 mol% of these complexes produce pyrrolidines (5-membered heterocycles) or piperidines (6-membered heterocycles) generally in very good yield as determined by 'H

NMR spectroscopy. The catalytic activity of these complexes compares favourably with that of Ti(NMe2)4. More substrates need to be tested for hydroamination using these complexes as they may be more efficient than Ti(NMe2)4.

4.2 Future Directions

Some of the work described in this thesis requires further investigation. One area of interest is the hydroamination of 1,1-disubstituted allenes. While there is no apparent explanation for why this reaction did not occur, steric reasons could not be ruled out.

Replacement of one or both substituents on the disubstituted allene with an alkoxy or aryloxy group and the use of the zirconium analogue of complex 38 may result in successful hydroamination. Intermolecular hydroamination of 1,3-disubstituted allenes with amines also deserves some attention.

The change in regioselectivity observed in the hydroamination of ether- substituted allenes is not well understood at present. To fully understand the interaction of the metal centre with these substrates, the synthesis, isolation, and full characterization of the metallacyclic intermediate should be carried out. Specifically, stoichiometric reactions between the allenes, anilines and the precatalyst should be carried out (Scheme

4-1). Another approach to isolating this metallacycle would be to prepare and isolate the catalytically active imido species and then react this stoichiometrically with the allenes.

91 Successful applications of this method for other known catalytic systems exist in the literature. '

Scheme 4-1. Proposed Synthesis of Metallacyclic Intermediates by Stoichiometry Reaction

While the synthesis of L2M(NR2)2 complexes was unsuccessful, it may be possible to prepare bis(ligated) complexes with less bulky reactive ligands. Therefore, the synthesis of such complexes with 2 equivalents of the proligands HL1 and HL2 may be realized by using tetrachloro complexes of titanium and zirconium instead of the tetrakis(dialkylamido) complexes. This may be done by using a salt metathesis reaction, which involves deprotonating the ligand with a base and then reacting the deprotonated ligand with tetrachloro titanium or zirconium complexes (Scheme 4-2). A number of dichloro complexes have been synthesized via the salt metathesis route using sodium bis(trimethylsilyl)amide as a base in the Schafer lab; however, the amide proligands for these dichloro complexes are more acidic than the amines used in this thesis. Therefore a stronger base such as n-butyl lithium may be required for this reaction.

92 2 n-BuLi

Scheme 4-2. Proposed Synthesis of Zirconium Dichloro Complexes

Furthermore, enantiomerically pure HL and HL need to be prepared to enable the application of the resulting metal complexes made with optically active proligands in enantioselective hydroamination of aminoalkenes. One way of making enantiomerically pure HL1 and HL2 would be to hydrogenate the imine precursors (40k and 401) to the desired enantioenriched proligands using chiral catalysts such as iridium complexes with chiral phosphine ligands.4 Alternatively, racemic HL1 and HL2 could be resolved by reacting with chiral organic acids such as camphor sulphonic acid or D- or L- tartaric acid to give diastereomers that can be separated by repeated recrystallization or column chromatography. Lanthanide complexes with L1 and L2 as ligands should also be prepared as the large coordination sphere of these metals may favor the formation of bis(ligated) complexes with five-membered chelate rings.

93 4.3 References

(1) Walsh, P. J.; Baranger, A. M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708-

1719.

(2) Ward, B. D.; Maisse-Francois, A.; Mountford, P.; Gade, L. H. Chem. Commun. 2004,

704-705.

(3) Beard, J. D. Schafer, L. L., manuscript in preparation.

(4) (a) Xiao, D.; Zhang, X. Angew. Chem., Int. Ed. 2001, 40, 3425-3438. (b) Vargas, S.;

Rubio, M.; Suarez, A.; Pizzano, A. Tetrahedron Lett. 2005, 46, 2049-2052. (c) Sablong,

R.; Osborn, J. A. Tetrahedron Lett. 1996, 37, 4937-4940.

94 Appendix I: X-Ray Crystallographic Data for Complex 47

A. Crystal Data

Emprical Formula C18H36N4OZr Formula Weight 415.73 Crystal Colour, Habit clear, block Crystal System orthorhombic Unit Cell Dimensions a = 17.2760(12) A a = 90° b = 13.5998(9) A 0 = 90° c = 9.8227(5) A 7=90° Volume 2307.8(3) A3 Space Group Pnma Z Value 4 1.196 g/cm3 DCalc T 173(2)K •Foot) 880 fl (Moka) 0.487 mm'1

B. Intensity Measurements, ire Solution and Refinement

Diffractometer Rigaku/ADSC CCD Radiation MoKa(\= 0.71073 A) graphite monochromated Detector Aperture 94mm x 94mm 20max 55.5° Total Reflections 46460 Independent Reflections 2818 Parameters 139

95 Structure Solution Direct Methods (SIR97) Refinement Full-matrix least squares on F Goodness of Fit Indicator 1.069 Final R Indices [I>2a(I)] Rl = 0.0290, wR2 = 0. 0743 R Indices (all data) Rl =0.0421, wR2 = 0.0816

Table 1. Atomic Coordinates (x 104) and Equivalent Isotropic Displacement Parameters (A2 x 103)

Atom X Y Z Ueq C3 -2402(2) 2500 3631(3) 73(1) C5 -1252(2) 2500 442(3) 46(1) C6 -946(1) 3389 -34(3) 64(1) C7 -324(2) 3365(3) -966(3) 86(1) C8 -24(2) 2500 -1416(4) 94(2) C9 -1272(2) 4365(3) 412(4) 95(1) C10A -2644(2) 1635(2) -2312(3) 92(1) C11A -4336(2) 3932(3) -316(5) 133(2) C12 -3578(2) 4657(2) 1401(4) 105(1) Nl -1901(1) 2500 1358(2) 44(1) N2 -2802(2) 2500 -1507(2) 42(1) N3 -3688(1) 3781(2) 551(1) 31(1) Zrl -3043(1) 2500 980(3) 161(4) CIA -1727(3) 2256(3) 2937(3) 50(2) C2A -994(3) 2290(30) 3339(5) 136(12) C4A -3793(3) 2410(30) 3717(5) 88(5)

Table 2. Bond Distances (A) Atom Atom Distance Atom Atom Distance Zrl N2 2.064(2) Nl C5 1.436(4) Zrl N3 2.0677(19) Nl CI 1.497(5) Zrl N3 8 2.0677(19) C7 C8 1.359(4) Zrl Nl 2.127(2) C7 C6 1.413(4) Zr 1 Ol 2.369(3) Ol C3 1.420(4) N3 C12 1.442(3) C2 CI 1.379(7) Ol C4 1.442(7) C3 CI 1.483(6) C6 C5 1.400(3) N3 Cll 1.449(4) N2 C10 8 1.443(3) C6 C9 1.508(5) N2 C10 1.443(3) C5 C6 8 1.400(3) C8 C7 8 1.359(4) Nl CI 8 1.497(5) Zrl 01 8 2.369(3) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

96 Table 3. Bond Angles (°) Atom Atom Atom Angle Atom Atom Atom Angle N2 Zrl N3 97.50(7) N2 Zr NI 100.22(9) N2 Zrl N3 8 97.50(7 N3 Zr NI 119.45(6) N3 Zrl N3 8 114.75(12) NI Zr N3 8 119.45(6) N2 Zrl 01 167.65(9) N2 Zr 01 167.65(9) Cl C3 01 109.6(3) N3 Zr 01 94.30(10) C3 01 C4 114.6(7) C6 C5 NI 120.25(16) C4 01 Zrl 122.5(4) C2 Cl C3 118.8(8) 01 Zrl NI 70.58(9) C2 Cl NI 121.7(8) C5 NI Cl 115.7(3) C3 Cl NI 107.0(3) C5 NI Zrl 119.38(17) Cl NI Zrl 122.5(2) C12 N3 Zrl 129.59(19) C3 01 Zrl 114.2(2) C8 C7 C6 121.3(4) C5 C6 C7 119.0(3) C5 C6 C9 121.5(2) C7 C6 C9 119.5(3) 01 Zr N3 8 80.76(10) CIO N2 CIO 8 109.2(3) C12 N3 Cll 108.9(2) Zrl N2 CIO 8 125.06(15) Zr N2 CIO 125.06(15) Zrl N3 Cll 121.46(18) C6 C5 C6 8 119.4(3) NI C5 C6 8 120i25(16) N3 Zrl 01 8 80.76(10) C7 C8 C7 8 119.9(4) C5 NI Cl 8 115.7(3) Zr NI Cl 8 122.5(2) NI Zr 01 8 70.58(9) C3 01 C4 8 111.3(6) Zr 01 C4 8 119.7(6) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

Table 4. Anisotropic Displacement Parameters (A x 103) Atom U11 U22 U33 u23 U13 u12 C3 52(2) 139(4) 27(2) 0 -5(1) 0 C5 34(1) 76(2) 29(1) 0 -5(1) 0 C6 47(1) 97(2) 47(1) 9(2) -5(1) -13(1) C7 51(2) 151(4) 55(2) 27(2) 0(1) -24(2) C8 43(2) 200(7) 39(2) 0 2(2) 0 C9 92(2) 86(2) 107(3) 17(2) 2(2) -21(2) CIO 152(3) 80(2) 45(2) -3(2) 20(2) 51(2) Cll 109(3) 83(3) 209(5) -66(3) -90(3) 53(2) C12 144(3) 67(2) 103(3) -43(2) -30(2) 26(2) NI 35(1) 69(2) 26(1) 0 0(1) 0 N2 46(1) 52(2) 28(1) 0 -3(1) 0 N3 56(1) 44(1) 64(1) -17(1) -6(1) 11(1) Zrl 34(1) 33(1) 25(1) 0 -2(1) 0 Cl 45(2) 132(9) 28(2) 6(3) -5(2) 8(3) 01 39(1) 83(5) 29(1) 1(1) 4(1) -2(2) C2 56(3) 310(40) 39(2) 16(8) -14(2) 51(12) C4 51(2) 168(14) 44(2) 24(10) 20(2) 26(1)

97 Table 5. Torsion Angles (°) Atom Atom Atom Atom Angle N3 Zrl N2 CIO 8 37.1(3) N3 8 Zrl N2 CIO 8 -37.1(10) Nl Zrl N2 CIO 8 -84.7(3) 01 Zrl N2 CIO 8 -84.8(10) C6 8 C5 C6 C7 -1.3(5) Nl C5 C6 C7 -178.1(2) C6 8 C5 C6 C9 178.0(2) Nl C5 C6 C9 1.2(4) C5 C6 C7 C8 0.7(5) C9 C6 C7 C8 -178.6(3) C6 C7 C8 C7 8 0.1(6) C6 C5 Nl CI 8 -74.2(4) C6 C5 Nl CI 8 109.0(4) C6 C5 Nl CI 8 -109(4) C6 8 C5 Nl CI 74.2 C6 C5 Nl Zrl 88.4(2) C6 8 C5 Nl Zrl -88.4(2) CIO 8 N2 Zrl N3 8 153.4(3) CIO N2 Zrl Nl 84.7(3) CIO 8 N2 Zrl 01 8 -43.9(6) CIO N2 Zrl 01 8 125.6(4) CIO 8 N2 Zrl 01 -125.6(4) CIO N2 Zrl 01 43.9(6) C12 N3 Zrl N2 -123.9(3) Cll N3 Zrl N2 52.2(3) C12 N3 Zrl N3 8 134.2(3) Cll N3 Zrl N3 8 -49.7(3) C12 N3 Zrl Nl -17.6 Cll N3 Zrl Nl 158.4(3) C12 N3 Zrl 01 8 43.7(3) Cll N3 Zrl 01 8 140.2(3) C12 N3 Zrl 01 52.4(3) Cll N3 Zrl 01 -131.5(3) C5 Nl Zrl N2 0.0 CI 8 Nl Zrl N2 161.4(3) CI Nl Zrl N2 -161.4(3) C5 Nl Zrl N3 8 104.72(8) CI 8 Nl Zrl N3 8 -93.9(3) CI Nl Zrl N3 8 -56.7(3) C5 Nl Zrl N3 -104.72(8) CI 8 Nl Zrl N3 56.7(3) CI Nl Zrl N3 93.9(3) C5 Nl Zrl 01 8 -171.47(10) CI 8 Nl Zrl 01 8 -10.1(3) CI Nl Zrl 01 8 27.2(3) C5 Nl Zrl 01 171.47(10) CI 8 Nl Zrl 01 -27.2(3) CI Nl Zrl 01 10.1(3) 01 C3 CI C2 -174(2) 01 C3 CI Nl 43.2(5) C5 Nl CI C2 24(2) CI 8 Nl CI C2 -74(2) Zrl Nl CI C2 -174(2) C5 Nl CI C3 165.4(2) CI 8 Nl CI C3 67.6(4) Zrl Nl CI C3 -32.6(5) CI C3 01 C4 173.6(18) CI C3 01 C4 8 177.2(16) CI C3 01 Zrl -37.9(4) N2 Zrl 01 C3 58.9(6) N3 8 Zrl 01 C3 141.8(2) N3 Zrl 01 C3 103.8(2) Nl Zrl 01 C3 15.91(19) 01 8 Zrl 01 C3 -71.2(2) N2 Zrl 01 C4 -155(2) N3 8 Zrl 01 C4 -72(2) N3 Zrl 01 C4 42(2) Nl Zrl 01 C4 162(2) 01 8 Zrl 01 C4 75(2) N2 Zrl 01 C4 8 -165.4(17) N3 8 Zrl 01 C4 8 -82.5(7) N3 Zrl 01 C4 8 31.9(17) Nl Zrl 01 C4 8 151.6(17) 01 Zrl 01 C4 8 64.5(17) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

99 Appendix II. X-Ray Crystallographic Data for Complex 48

A. Crystal Data

Emprical Formula Ci8H36N4OTi Formula Weight 372.41 Crystal Colour, Habit red, block Crystal System orthorhombic Unit Cell Dimensions a = 17.289(2) A a = 90° b= 13.0762(13) A 8 = 90° c = 9.6677(8) A 7=90° Volume 2185.6(4) A3 Space Group Pnma Z Value 4 3 Dcalc 1.132 g/cm T 173(2)K

^000 808 /x (Moka) 0.403 mm"1

B. Intensity Measurements, ire Solution and Refinement

Diffractometer Rigaku/ADSC CCD Radiation MoKa(\= 0.71073 A) graphite monochromated Detector Aperture 94mm x 94mm 20max 55.5° Total Reflections 17022 Independent Reflections 2046

100 Parameters 136 Structure Solution Direct Methods (SIR97) Refinement Full-matrix least squares on F2 Goodness of Fit Indicator 1.046 Final R Indices [I>2a(I)] Rl =0.0413, wR2 = 0. 1036 R Indices (all data) Rl =0.061 l,wR2 = 0.1148

Table 1. Atomic Coordinates (x 10 ) and Equivalent Isotropic Displacement Parameters (A2 x 103)

Atom X Y Z Ueq C3 7479(2) 2500 8652(3) 52(1) C5 8652(2) 2500 5452(3) 41(1) C6 8968(1) 3424(2) 4988(3) 59(1) C7 9593(2) 3407(3) 4073(3) 77(1) C8 9899(3) 2500 3617(4) 91(2) C9 8641(2) 4440(2) 5456(3) 76(1) C10 6453(2) 4639(2) 6426(3) 79(1) Cll 5659(2) 3919(3) 4659 (5) 114(2) C12 7327(2) 3393(2) 2844(4) 71(1) N2 63339(1) 3740(1) 5595(2) 45(1) N3 7146(2) 2500 3661(3) 34(1) N(l) 8000(2) 2500 6358(3) 36(1) Til 6933(1) 2500 5604(1) 30(1) Cl 8165(3) 2167(4) 7810(4) 49(2) C2 8917(3) 2500 8378(4) 93(2) 01 6819(2) 2253(3) 7904(3) 44(2) C4 6112(2) 2500 8634(4) 67(1) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

Table 2. Bond Distances (A) Atom Atom Distance Atom Atom Distance C3 01 1.416(4) C3 Cl 1.479(6) C5 C6 1.400(3) C5 C6 8 1.400(3) C5 NI 1.427(4) C6 C7 1.397(4) C6 C9 1.513(4) C7 C8 1.371(4) C10 N2 1.439(3) Cll N2 1.446(4) N2 Til 1.925(2) N3 C12 8 1.437(3) N3 Til 1.921(3) NI Cl 1 1.497(5) NI Til 1.984(3) Til N2 8 1.925(2) Til 01 8 2.255(3) Til 01 2.255(3) Cl C2 1.476(6) 01 C4 8 1.448(4) 01 C4 1.448(4) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

101 Table 3. Bond Angles (°) Atom Atom Atom Angle Atom Atom Atom Angle 01 C3 C7 107.4(3) C6 C5 C6 8 119.3(3) C6 C5 NI 120.32(17) C6 8 C5 NI 120.32(17) C7 C6 C5 119.4(3) C7 C6 C9 119.5(3) C5 C6 C9 121.1(3) C8 C7 C6 121.1(4) C7 8 C8 C7 119.8(4) CIO N2 Cll 109.1(2) CIO N2 Til 127.4(2) Cll N2 Til 123.42(17) C12 N3 C12 8 108.6(3) C12 N3 Til 125.33(14) C12 8 N3 Til 125.33(13) C5 NI Cl 8 115.1(3) C5 NI Cl 115.1(3) Cl 1 NI Cl 115.1(3) C5 NI Til 120.6(2) Cl 1 NI Til 121.4(2) Cl NI Til 121.4(2) N3 Til N2 8 96.17(8) N3 Til N2 96.17(8) N2 8 Til N2 114.78(13) N3 Til NI 99.53(12) N2 8 Til NI 120.20(7) N2 Til NI 120.27(7) N3 Til 01 8 168.27(11) N2 Til Ol 8 94.47(11) N2 Til 01 8 80.60(11) NI Til 01 8 73.73(11) N3 Til 01 169.27(11) N2 8 Til 01 80.60(11) N2 Til 01 94.47(11) NI Til 01 73.73(11) C2 Cl C3 113.3(4) C2 Cl NI 115.5(4) C3 Cl NI 106.4(3) C3 01 C4 8 113.3(3) C3 01 C4 113.6(3) C3 01 Til 113.4(2) C4 8 01 Til 121.5(2) C4 01 Til 121.5(2) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

Table 4. Anisotropic Displacement Parameters (A x 103) Atom Un TJ22 U33 u23 u13 u12 C3 44(2) 83(4) 28(2) 0 -3(1) 0 C5 28(2) 71(2) 25(1) 0 -3(1) 0 C6 42(2) 94(2) 41(2) 15(2) -5(1) -8(2) C7 39(2) 142(4) 50(2) 30(2) -1(1) -17(2) C8 36(3) 203(7) 35(2) 0 4(2) 0 C9 65(2) 72(2) 91(2) 23(2) -1(2) -17(2) CIO 118(3) 45(2) 74(2) -24(2) -9(2) 11(2) Cll 82(3) 66(3) 195(4) -59(3) -72(3) 37(2) C12 120(3) 51(2) 40(2) 5(1) 12(2) -24(2) N2 . 44(1) 37(1) 53(1) -15(1) -2(1) 5(1) N3 41(2) 31(1) 30(1) 0 1(1) 0 NI 31(2) 52(2) 25(1) 0 1(1) 0 Til 31(1) 32(1) 26(1) 0 0(1) 0 Cl 40(3) 77(5) 30(2) 5(2) -4(2) 4(2) C2 48(3) 193 (6) 37(2) 0 -13(2) 0 01 36(3) 67(5) 29(1) -2(2) 6(1) -1(2) C4 42(3) 114(4) 43(2) 0 15(2) 0

102 Table 5. Torsion Angles (°) Atom Atom Atom Atom Angle C6 8 C5 C6 C7 0.1(5) Nl C5 C6 C7 -178.3(3) C6 8 C5 C6 C9 179.6(2) Nl C5 C6 C9 1.4(4) C5 C6 C7 C8 0.3(5) C9 C6 C7 C8 -179.3(3) C6 C7 C8 C7 8 0.5(7) C6 C5 Nl CI 8 -72.2(4) C6 8 C5 Nl CI 8 109.7(3) C6 C5 Nl CI -109.7(3) C6 8 C5 Nl CI 72.2(4) C6 C5 Nl Til 89.1(3) C6 8 C5 Nl Til -89.1(3) C12 N3 Til N2 8 153.4(3) C12 8 N3 Til N2 _8 -37.5(3) C12 N3 Til N2 37.5 C12 8 N3 Til N2 -153.4(3) C12 N3 Til Nl -84.6(4) C12 8 N3 Til Nl 84.6(3) C12 N3 Til 01 8 -34.3(8) C12 8 N3 Til 01 _8 134.8(5) C12 N3 Til 01 -134.8(5) C12 N3 Til 01 34.3(8) CIO N2 Til N3 -124.8(3) Cll N2 Til N3 51.9(3) CIO N2 Til N2 8 135.5(2) Cll N2 Til N2 _8 -47.9(3) CIO N2 Til Nl ,20.0(3) Cll N2 Til Nl 156.7(3) CIO N2 Til 01 8 44.9(3) Cll N2 Til 01 _8 -138.5(3) CIO N2 Til 01 53.8(3) Cll N2 Til 01 -129.6(3) C5 Nl Til N3 0.0 CI 8 Nl Til N3 160.1(2) CI Nl Til N3 -160.1(2) C5 Nl Til N2 8 102.93(9) CI Nl Til N2~" 8 -97.0(2) CI Nl Til N2 _8 -57.1(3) C5 Nl Til N2 -102.93(9) CI 8 Nl Til N2 57.1(3) CI Nl Til N2 97.0(2) C5 Nl Til 01 8 -171.42(10) CI 8 Nl Til 01 [8 -11.4(3) Cl NI Til 01 8 28.5(3) C5 NI Til 01 8 171.42(10) Cl 8 NI Til 01 -28.5(3) Cl NI Til 01 11.4(3) 01 C3 Cl C2 172.3(3) 01 C3 Cl NI 44.3(4) C5 NI Cl C2 37.3(4) Cl 8 NI Cl C2 -60.9(4) Til NI Cl C2 -161.6(2) C5 NI Cl C3 164.0(2) Cl 8 NI Cl C3 65.8(3) Til NI Cl C3 -34.9(4) Cl C3 01 C4 8 177.6(3) Cl C3 01 C4 177.6(3) Cl C3 01 Til -38.2(3) N2 8 Til 01 C3 141.3(2) N2 Til 01 C3 -104.3(2) NI Til 01 C3 15.88(19) 01 8 Til 01 C3 -71.7(2) N3 Til 01 C4 8 -150.9(3) N2 8 Til 01 C4 8 -77.7(3) N2 Til 01 C4 8 36.7(3) NI Til 01 C4 8 156.9(3) 01 8 Til 01 C4 8 69.3(3) N3 Til 01 C4 -150.9(5) N2 8 Til 01 C4 -77.7(3) N2 Til 01 C4 36.7(3) NI Til 01 C4 156.9(3) 01 8 Til 01 C4 69.3(3) Symmetry transformations used to generate equivalent atoms: _8 x, -y+1/2, z

104 Appendix III. X-Ray Crystallographic Data for Complex 49

C11

A. Crystal Data

Emprical Formula C25H42N4OZr Formula Weight 505.85 Crystal Colour, Habit clear, block Crystal System orthorhombic Unit Cell Dimensions a = 16.5820(15) A a = 90° b = 17.7264(17) A P = 90° c= 18.8172(15) A 7 = 90° Volume 5531.11(18) A3 Crystal System orthorhombic Space Group Pbca Z Value 9 3 Dcalc 1.367 g/cm T 173 K •^000 2412 JLI (Mokcv) 0.471 mm"1

B. Intensity Measurements, Structure Solution and Refinement

Diffractometer Rigaku/ADSC CCD Radiation MoKa (X = 0.71073 A) graphite monochromated Detector Aperture 94mm x 94mm 20max 55.5°

105 Total Reflections 154892 Independent Reflections 6474 Parameter 280 Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares on F Goodness of Fit Indicator 1.028 Final R Indices [I>2a(I)] Rl = 0.0347, wR2 = 0.0864 R Indices (all data) Rl = 0.0622, wR2 = 0.0964

Table 1. Atomic Coordinates (x 104) and Equivalent Isotropic Parameters (A x

Atom X Y Z Ueq Zr 3371(1) 3394(1) 5865(1) 29(1) O 3716(1) 2113(1) 6312(1) 28(1) NI 2647(1) 3132(1) 6764(1) 28(1) C4 4355(1 1587(1) 6212(1) 30(1) N2 3146(1) 4546(1) 5825(1) 43(1) C3 2979(1) 1803(1) 6626(1) 32(1) Cl 2639(1) 2389(1) 7131(1) 32(1) N4 2767(2) 3084(1) 4953(1) 46(1) N3 4624(1) 3470(1) 5795(1) 43(1) C9 4533(2) 1346(1) 5524(1) 35(1) C5 4795(1) 1349(1) 6810(1) 32(1) C12 2324(1) 3733(1) 7198(1) 30(1) C13 1556(2) 4038(1) 7049(1) 39(1) C14 2780(2) 4031(1) 7769(1) 35(1) C7 5631(2) 608(2) 6011(2) 45(1) C18 1254(2) 4619(2) 7487(2) 50(1) C16 2440(2) 4519(2) 8197(2) 49(1) Cll 4609(2) 1616(1) 7554(1) 42(1) C6 5434(2) 847(1) 6690(2) 41(1) C8 5186(2) 856(1) 5436(1) 42(1) C10 4052(2) 1598(2) 4882(1) 52(1) C19 1047(2) 3749(2) 6414(2) 62(1) C17 1683(2) 4881(2) 8060(2) 55(1) C2 1795(2) 2128(2) 7362(2) 57(1) C21 5243(2) 3215(2) 6290(2) 52(1) C15 3635(2) 3768(2) 7911(2) 48(1) C24 2033(2) 2636(2) 4900(2) 65(1) C23 3600(2) 5074(2) 6268(2) 61(2) C22 2480(2) 4935(2) 5476(2) 72(1) C20 5002(2) 3879(2) 5206(2) 87(1) C25 3039(3) 3310(2) 4247(2) 82(1)

106 Table 2. Bond Distances (A) Atom Atom Distance Atom Atom Distance Zr N4 2.062(2) Zr N2 2.077(2) Zr N3 2.086(2) Zr NI 2.1263(18) Zr 0 2.4876(15) 0 C4 1.424(3) 0 C3 1.465(3) NI C12 1.445(3) NI Cl 1.488(3) C4 C9 1.395(3) C4 C5 1.404(3) N2 C22 1.459(4) N2 C23 1.463(4) C3 Cl 1.517(3) Cl C2 1.537(3) N3 C21 1.458(4) N3 C20 1.466(4) N4 C24 1.456(4) N4 C25 1.460(4) C9 C8 1.398(3) C9 CIO 1.516(4) C5 C6 1.402(3) C5 Cll 1.510(3) C12 C13 1.410(3) C12 C14 1.416(3) C13 C18 1.410(4) C13 C19 1.511(4) C14 C16 1.398(3) C14 C15 1.516(4) C7 C8 1.382(4) C7 C6 1.385(4) C18 C17 1.374(4) C16 C17 1.379(4)

Table 3. Bond Angles (°) Atom Atom Atom Angle Atom Atom Atom Angle N4 Zr N2 98.33(9) N4 Zr N4 116.66(9) N2 Zr N3 96.49(9) N4 Zr Nl 109.25(9) N2 Zr Nl 98.18(8) N3 Zr Nl 128.81(8) N4 Zr 0 98.59(7) N2 Zr 0 161.95(7) N3 Zr 0 81.44(7) Nl Zr 0 70.23(6) C4 0 C3 115.31(1[6 ) C4 0 Zr 136.45(13) C3 0 Zr 106.70(112 ) C12 Nl Cl 112.83(17) C12 Nl' Zr 119.85(114 ) Cl Nl Zr 124.58(14) C9 C4 C5 122.8(2) C9 C4 0 118.7(2) C5 C4 0 118.5(2) C22 N2 C23 110.1(2) C22 N2 Zr 128.1(2) C23 N2 Zr 121.08(18) 0 C3 Cl 107.82(117 ) Nl Cl C3 108.17(18) NI Cl C2 113.9(2) C3 Cl C2 108.1(2) C24 N4 C20 110.2(3) C24 N4 Zr 127.47(19) C25 N4 Zr 122.3(2) C21 N3 C20 109.6(2) C21 N3 C8 117.6(2) C4 C9 CIO 122.6(2) C8 C9 CIO 119.8(2) C6 C5 C4 117.1(2) C6 C5 Cll 120.1(2) C4 C5 Cll 122.9(2) C13 C12 C14 119.4(2) C13 C12 Nl 120.3(2) C14 C12 Nl 120.3(2) C18 C13 C12 118.9(2) C18 C13 C19 119.4(2) C12 C13 C19 121.6(2) C16 C14 C12 119.0(2) C16 C14 C15 119.7(2) C12 C14 C15 121.3(2) C8 C7 C6 119.9(2) C17 C18 C13 121.5(3) C17 C16 C14 121.6(3)

107 C7 C6 C5 121.4(2) C7 C8 C9 121.3(2) C18 C17 C16 119.4(3)

Table 4. Anisotropic Displacement Parameters (A x 103) Atom Uu U22 u33 u23 U13 u12 Zr 39(1) 26(1) 23(1) 1(1) 1(1) 2(1) 0 32(1) 25(1) 28(1) 2(1) 3(1) 1(1) Nl 33(1) 25(1) 25(1) -2(1) -1(1) 2(1) C4 33(1) 21(1) 36(1) 1(1) 2(1) -1(1) N2 61(1) 29(1) 38(1) 3(1) 1(1) 6(1) C3 31(1) 28(1) 36(1) -2(1) -2(1) -4(1) CI 35(1) 28(1) 33(1) -1(1) 5(1) -3(1) N4 66(2) 42(1) 28(1) -1(1) -13(1) 13(1) N3 44(1) 37(1) 47(1) 9(1) 11(1) -2(1) C9 44(1) 28(1) 34(1) -2(1) 6(1) 0(1) C5 34(1) 26(1) 37(1) 2(1) -1(1) -5(1) C12 35(1) 28(1) 26(1) 1(1) 2(1) 1(1) C13 39(1) 39(1) 38(1) -2(1) -1(1) 7(1) C14 40(1) 33(1) 33(1) -4(1) -1(1) Kl) C7 37(1) 35(1) 63(2) 1(1) 9(1) 4(1) C18 46(2) 44(2) 59(2) -1(1) 4(1) 17(1) C16 59(2) 45(2) 44(2) -17(1) -2(1) -2(1) Cll 37(1) 33(1) 53(2) 7(1) -6(1) 0(1) C8 49(2) 32(1) 43(2) -4(1) 13(1) 0(1) CIO 74(2) 52(2) 30(1) -8(1) 0(1) 16(2) C19 50(2) 81(2) 56(2) -11(2) -17(2) 23(2) C17 62(2) 43(2) 60(2) -17(1) 11(2) 9(2) C2 51(2) 41(2) 78(2) -2(2) 27(2) -6(1) C21 42(2) 48(2) 67(2) 2(1) 2(1) -10(1) C15 46(2) 51(2) 46(2) -15(1) -12(1) -1(1) C24 75(5) 64(2) 57(2) -16(2) -31(2) 14(2) C23 84(2) 33(2) 66(2) -1(1) -1(2) -3(2) C22 91(3) 46(2) 79(2) 1(2) -17(2) 24(2) C20 74(2) 104(3) 83(3) 42(2) 25(2) -5(2) C25 131(4) 86(3) 30(2) 9(2) -11(2) 10(3)

Table 5. Torsion angles (°) Atom Atom Atom Atom Angle Atom Atom Atom Atom Angle N4 Zr 0 C4 87.4(2) N2 Zr 0 C4 -113.1(3) N3 Zr 0 C4 -28.46(19) Nl Zr 0 C4 -165.1(2) N4 Zr 0 C3 -77.02(14) N2 Zr 0 C3 82.5(3) N3 Zr 0 C3 167.12(14) Nl Zr 0 C3 30.44(12) N4 Zr Nl C12 -113.19(16) N2 Zr Nl C12 -11.35(17)

108 N3 Zr Nl C12 93.85(17) 0 Zr Nl C12 154.37(17) N4 Zr Nl Cl 86.95(18) N2 Zr Nl Cl -171.20(17) N3 Zr Nl Cl -66.0(2) 0 Zr Nl Cl -5.49(16) C4 0 C3 Cl 141.81(19) Zr 0 C3 Cl -50.00(19) C3 0 C4 C9 106.9(2) Zr 0 C4 C9 -56.5(3) C3 0 C4 C5 -74.9(2) Zr 0 C4 C5 121.7(2) N4 Zr N2 C22 24.9(3) N3 Zr N2 C22 143.2(3) Nl Zr N2 C22 -86.0(3) 0 Zr N2 C22 -134.6(3) N4 Zr N2 C23 -165.6(2) N3 Zr N2 C23 -47.4(2) Nl Zr N2 C23 83.4(2) O Zr N2 C23 34.9(4) N2 Zr N4 C24 -112.1(2) N3 Zr N4 C24 146.3(2) Nl Zr N4 C24 -10.4(2) 0 Zr N4 C24 61.6(2) N2 Zr N4 C25 67.1(3) N3 Zr N4 C25 -34.5(3) Nl Zr N4 ' C25 168.8(2) 0 Zr N4 C25 -119.2(2) N4 Zr N3 C21 -137.2(2) N2 Zr N3 C21 120.0(2) Nl Zr N3 C21 14.1(3) 0 Zr N3 C21 -41.9(2) N4 Zr N3 C20 47.9(3) N2 Zr N3 C20 -54.8(3) Nl Zr N3 C20 -160.8(2) 0 Zr N3 C20 143.3(3) C12 Nl Cl C3 179.26(18) Zr Nl Cl C3 -19.7(3) C12 Nl Cl C2 59.1(3) Zr Nl Cl C2 -139.83(19) 01 C3 Cl Nl 46.5(2) 0 C3 Cl C2 170.3(2) C5 C4 C9 C8 -1.0(4) 0 C4 C9 C8 177.1(2) C5 C4 C9 CIO 179.4(2) 0 C4 C9 CIO -2.5(3) C9 C4 C5 C6 -0.1(3) 0 C4 C5 C6 -178.20(19) C9 C4 C5 Cll 179.3(2) 0 C4 C5 Cll 1.1(3) C18 C13 C12 C14 -1.8(4) C19 C13 C12 C14 179.3(3) C18 C13 C12 Nl 179.3(2) C19 C13 C12 Nl 0.4(4) Cl Nl C12 C13 -106.7(2) Zr Nl C12 C13 91.2(2) Cl Nl C12 C14 74.4(3) Zr Nl C12 C14 -87.6(2) C13 C12 C14 C16 3.6(4) Nl C12 C14 C16 -177.5(2) C13 C12 C14 C15 -174.8(2) Nl C12 C14 C15 4.1(4) C12 C13 C18 C17 -1.2(4) C19 C13 C18 C17 177.7(3) C8 C7 C6 C5 -0.9(4) C4 C5 C6 C7 1.0(4) Cll C5 C6 C7 -178.3(2) C12 C14 C16 C17 -2.5(4) C15 C14 C16 C17 175.9(3) C6 C7 C8 C9 -0.2(4) C4 C9 C8 C7 1.1(4) CIO C9 C8 C7 -179.2(3) C13 C18 C17 C16 2.4(5) C14 C16 C17 C18 -0.5(5)

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