Mechanistic Investigations of Zinc and Titanium Catalyzed Oxidation, Hydroamination and Cycloaddition Reactions

By

Riffat Un Nisa

CIIT/FA13-R66-002/ATD

PhD Thesis

In

Chemistry

COMSATS University Islamabad Abbottabad Campus - Pakistan

Spring, 2017

i

COMSATS University Islamabad

Mechanistic Investigations of Zinc and Titanium Catalyzed Oxidation, Hydroamination and Cycloaddition Reactions

A Thesis Presented to

COMSATS University Islamabad, Abbottabad Campus

In partial fulfillment

of the requirement for the degree of

PhD (Chemistry)

By

Riffat Un Nisa

CIIT/FA13-R66-002/ATD

Spring, 2017

ii Mechanistic Investigations of Zinc and Titanium Catalyzed Oxidation, Hydroamination and Cycloaddition Reactions

A Post Graduate Thesis submitted to the Department of Chemistry as partial fulfillment of the requirement for the award of Degree of Ph.D in Chemistry

Name Registration Number

Riffat Un Nisa CIIT/FA13-R66-002/ATD

Supervisor

Dr. Khurshid Ayub Associate Professor Department of Chemistry COMSATS University Islamabad Abbottabad Campus

Co-Supervisor

Dr. Tariq Mehmood Associate Professor Department of Chemistry COMSATS University Islamabad Abbottabad Campus

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iv

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vii

DEDICATION

Dedicated to my

Parents,

Husband and daughters

Omima and Ayesha

viii ACKNOWLEDGEMENTS

In the name of Allah, Most Gracious, Most Merciful

All praise and glory to Almighty Allah who bestowed me with everything and gave me courage to carry out this work. Peace and blessings of Allah be upon our last Prophet Hazrat Muhammad (Peace Be upon Him) the source of knowledge and blessing for entire mankind.

I feel great honor to express my utmost sincerest gratitude to my supervisor Dr. Khurshid Ayub, whose constant guidance, kindness, encouragement, excellent suggestions, valuable advices, enthusiasm, and great patience helped me to complete this thesis successfully and gave me extraordinary experience throughout the work. I offer my enthusiastic gratitude to my research co-supervisor Dr. Tariq Mehmood whose guidance, positive appreciation and affectionate behavior helped me to complete the present assignment in time.

I am really thankful to Prof. Dr. Abdur Rahman for his great co-operation, help and encouragement. I am also grateful to all my honorable teachers. I wish to acknowledge the members of Khurshid research group, especially Maria, Naveen, Saima, Saira, Rida and Sajida for their joyful gathering, positive criticism, and kind assistance in the whole work. I gratefully acknowledge the funding source i.e. Higher Education Commission that made my PhD work possible.

I owe my profound thanks to my husband, Khaliq ur Rehman whose unconditional support remained with me throughout this work and for encouragement in removing the impediments came in my way during this strenuous work. I appreciate my little daughters Omima and Ayesha for abiding my ignorance and the patience they showed during my research work. Words would never say how grateful I am to all of you.

A special thanks to my beloved late father, mother, sister, step father for their endless love, support, efforts and prayers for which I am forever grateful. My regard also goes to my in-laws for their moral support.

Riffat Un Nisa CIIT/FA13-R66-002/ATD

ix ABSTRACT

Mechanistic Investigations of Zinc and Titanium Catalyzed Oxidation, Hydroamination and Cycloaddition Reactions

The mechanism of the Zn(II) catalyzed oxidation of benzylic alcohol to benzaldehyde, ester and amide by three different oxidants (H2O2, TBHP, and CH3OOH) is investigated through density functional theory methods and compared with the similar oxidation mechanisms of other late transition metals. Inner sphere, intermediate sphere and outer sphere mechanisms have been analyzed. The effect of pyridine-2- carboxylic acid (ligand) and halides (Br2 and I2) is studied for benzaldehyde and ester formation reactions. Two new reactions are predicted such as oxidation of thiol to thioester and oxidation of benzylamine to benzaldimine and guanidine. The same set of calculations is repeated for newly predicted reactions as were performed for ester and amide formations. The inner sphere mechanism involving β-hydride elimination is found kinetically more demanding in all oxidation reactions. Ligand showed profound effect on rate of the reaction. In the presence of a ligand, intermediate sphere mechanism is found more plausible because of steric effect. In the absence of a ligand, the outer sphere mechanism is found more favorable. Mechanism of Zn(OTf)2 catalyzed hydroamination-hydrogenation of alkynes with amines is investigated through density functional theory methods. Both inner sphere and outer sphere mechanisms for nucleophilic attack of nitrogen on electrophilic alkyne centre to deliver imine have been investigated for the hydroamination reaction. Four different possibilities of hydrogen activation for the hydrogenation of imine to deliver amine have also been studied. These competitive reactions differ regarding the fate of proton and hydride generated from heterolytic cleavage of H2. The inner sphere mechanism is kinetically more demanding and is not believed to contribute significantly to the progress of the reaction under the experimental conditions. Outer sphere route for nucleophilic attack of non-coordinated amine on coordinated alkyne is found the most plausible. The overall energy barrier for outer sphere mechanism in amine adduct can also be surpassed under the reaction conditions, therefore this mechanism cannot be excluded safely. For hydrogenation reaction, heterolytic hydrogen cleavage involving proton shift on triflate ligand and hydride to metal is found most plausible over the competitive H2 cleavage reactions. The mechanism of TiCl4 mediated formal [3 + 3] cyclization of 1,3-bis(silyl enol ethers) with 1,3- dielectrophiles is also studied with B3LYP method of density functional theory (DFT) to rationalize the experimental regioselectivity. Methyl and trifluoromethyl substituted 1,3 dielectrophiles are studied theoretically since they show different regioselectivities. Four different mechanisms involving direct-direct, direct-conjugate, conjugate-direct and conjugate-conjugate addition of 1,3-bis(silyl enol ethers) on 1,3-dielectrophiles are studied for each dienophile. The intramolecular transition metal catalyzed and non-catalyzed dynamic shift of the silyl moiety are also studied. The structure of the 1,3 dienophile and the

x associated Mulliken charges are the driving forces for different regioselectivities in methyl and trifluoromethyl dienophiles.

xi TABLE OF CONTENTS

1 Introduction ...... 1

1.1 Catalyst and Catalysis ...... 2

1.1.1 Role of a Catalyst ...... 2

1.2 Importance of Catalysis...... 2

1.3 Characteristic Features of a Catalyst ...... 3

1.4 Classification of Catalysis ...... 3

1.4.1 Heterogeneous Catalysis ...... 3

1.4.2 Homogeneous Catalysis ...... 4

1.5 Transition Metals in Homogeneous Catalysis...... 4

1.6 Zinc Catalysis ...... 5

1.6.1 Zinc Catalyzed Copolymerization of Carbon Dioxide with Epoxide ...... 6

1.6.2 Zinc Catalysis in C-N Bond Formation Reactions ...... 8

1.6.3 Zinc Catalysis in Reactions of C-C Bond Formation ...... 10

1.6.4 Zinc Catalysis in C-O Bond Formation Reactions ...... 14

1.6.5 Zinc Catalysis in Friedel Crafts Reactions...... 16

1.6.6 Organozinc in Oxidative Cross Coupling Reactions ...... 17

1.6.7 Zinc Catalyzed Oxidation Reactions...... 17

1.6.8 Zinc Catalyzed Hydroamination Reactions ...... 22

1.6.9 Zinc Catalyzed Reduction Reactions ...... 27

1.7 Titanium Catalysis...... 31

xii 1.7.1 Titanium Catalyzed Intramolecular Cross Coupling Reaction ...... 32

1.7.2 Titanium Catalyzed C-X Bond Formation Reaction ...... 33

1.7.3 Titanium Catalyzed C-C Bond Formation Reactions ...... 35

1.8 Theoretical Approaches for the Mechanisms of Zn Catalyzed Reactions ....40

1.9 Theoretical Approaches for the Mechanisms of Ti Catalyzed Reactions .....43

1.10 Objectives ...... 44

1.10.1 Rationalization of the Experimental Regioselectivity ...... 44

1.10.2 Rationalization of the Product Distribution in Zn(II) Catalyzed Oxidative Esterification ...... 45

1.10.3 Comparison of Zn Catalysis with other Late Transition Metals Catalysis …………………………………………………………………………45

1.10.4 Prediction of New Reactions...... 46

1.10.5 Investigation of the Plausible Reaction Mechanism ...... 46

2 Computational Methodology ...... 48

3 Results & Discussion ...... 50

3.1 Mechanistic Insight of TiCl4 Catalyzed Formal Cycloaddition Reaction of Silyl enol ether with Dielectrophiles...... 51

3.1.1 Shift of the Silyl Group ...... 56

3.1.2 Complexation with Titanium ...... 58

3.1.3 Direct-Direct Addition of Fluorinated 1,3-Dielectrophile ...... 61

3.1.4 Direct-Conjugate Addition of Fluorinated 1,3-Dielectrophile...... 65

3.1.5 Direct-Direct Attack on CF3 Ketone ...... 68

3.1.6 Direct-Conjugate Attack on CF3 Ketone ...... 71

xiii 3.1.7 Conjugate-Conjugate Attack on CF3 Ketone ...... 73

3.1.8 Direct-Direct Addition on Methyl Ketone ...... 75

3.1.9 Direct-Conjugate Addition on Methyl Ketone ...... 79

3.1.10 Conjugate-Conjugate Addition on Methyl Ketone ...... 81

3.2 Theoretical Mechanistic Investigation of Zn(II) Catalyzed Oxidation of Alcohols to form Aldehydes and Esters...... 82

3.2.1 Inner Sphere Mechanism ...... 87

3.2.2 Intermediate Sphere Mechanism...... 93

3.2.3 Outer Sphere Mechanism...... 98

3.3 Theoretical Mechanistic Investigation of Zn(II) Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines ...... 105

3.3.1 Inner Sphere Mechanism ...... 108

3.3.2 Intermediate Sphere Mechanism...... 110

3.3.3 Outer Sphere Mechanism...... 114

3.4 Zn Catalyzed Oxidation of Thioacetal to Thioester & Oxidation of Benzylamine to Benzaldimine & Guanidine ...... 122

3.4.1 Intermediate Sphere Mechanism...... 124

3.4.2 Outer Sphere Mechanism...... 126

3.4.3 Inner Sphere Mechanism ...... 128

3.4.4 Intermediate Sphere Mechanism...... 129

3.4.5 Outer Sphere Mechanism...... 131

3.5 Mechanism of Zn(OTf)2 Catalyzed Hydroamination-Hydrogenation of Alkynes with Amines: Insight from Theory ...... 134

xiv 3.5.1 Hydroamination-Hydrogenation Reaction ...... 136

3.5.2 Inner Sphere Mechanism ...... 138

3.5.3 Outer Sphere Mechanism...... 141

3.5.4 Hydrogen Cleavage on Zinc and Nitrogen ...... 147

3.5.5 Hydrogen Activation on Triflate and Electrophilic Carbon ...... 148

3.5.6 Hydrogen Cleavage on Zinc and Triflate...... 149

3.6 Conclusions ...... 150

4 References ...... 153

xv LIST OF FIGURES

Figure 1.1 Comparison of a catalyzed and noncatalyzed reaction…………………….2

Figure 1.2 Different ligands on Zn for esterification reaction…………………...…..20

Figure 1.3 Possible sides of Zn catalyst modifications (90) and two tetranuclear Zn complexes(91,92……………………………………………………….…24

Figure 1.4 Structure of N-heterocyclic carbene………………..…………….………30

Figure 3.1.1 Four possible mechanisms of the titanium catalysis in cycloaddition of butadiene with dienophile……………………………………………… 54

Figure 3.1.2 Numbering scheme for discussion and description of 1,2 and 1,4 addition………………………………………………………………… 56

Figure 3.1.3 Potential energy diagram for silyl shift between 162 and 162′. All values are relative to 162 at 0.0 kcal mol-1……………………………………. 57

Figure 3.1.4 Potential energy diagram for silyl shift between 193 and 193′. All values are relative to 193 at 0.0 kcal mol-1…………………………………….. 58

Figure 3.1.5 Potential energy diagram for complexation of 162 and 162′ with titanium to deliver 211 and 211′, respectively…………………………………... 59

Figure 3.1.6 Potential energy diagram for complexation of 193 and 193′ with titanium to deliver 214 and 214′, respectively…………………………………. 60

Figure 3.1.7 Mulliken charges analyses on carbon 2 and 4 in 211, 211′, 214 and 214′ …………………………………………………………..…………..61

Figure 3.1.8 Potential energy diagram for elimination of H3Si-Cl followed by C-C bond formation (212  216); All energies are relative to 212 at 0.0 kcal mol-1. Values in parenthesis correspond to trimethylsilyl substituted derivatives……………………………………………………………… 62

Figure 3.1.9 Optimized geometries of 212, TS3 and 215...... 63

Figure 3.1.10 Potential energy diagram for cyclization in 217 to generate 218. All energies are relative to 217 at 0.0 kcal mol-1………………………….. 64

Figure 3.1.11 Potential energy diagram for 1,4 addition in 215 to generated 218, followed by change in coordination to generate 219. Values in parenthesis correspond to trimethylsilyl substituted derivatives…………………… 66

Figure 3.1.12 Potential energy diagram for intramolecular cyclization in 220 to generate 221, the energy values are relative to 220 at 0.0 kcal mol-1…. 67

Figure 3.1.13 Potential energy diagram of Ti catalyzed 1,2 addition of enol on CF3 ketone, All values are relative to 222 at 0.0 kcal mol-1…………………69

Figure 3.1.14 Comparison of potential energy diagram for 1,2 addition (223’  225)

for SiH3 and SiMe3 (values in parenthesis) substituted systems, All energies are relative to 223’ at 0.0 kcal mol-1….. ………………………70

Figure 3.1.15 Potential energy diagram for cylization in 226. All energies are relative to 226 at 0.0 kcal mol-1………………………………………………… 71

Figure 3.1.16 Potential energy diagram for 1,4 addition on 223’ (223’  228). All energies are relative to 223’ at 0.0 kcal mol-1………………………….. 72

Figure 3.1.17 Potential energy diagram for cyclization in 229 (229  218), All energies are relative to 229 at 0 kcal mol-1…………………………….. 72

Figure 3.1.18 Potential energy diagram for conjugate-conjugate addition on 230 (230  231). All energies are relative to 230 at 0.0 kcal mol-1……………... 73

Figure 3.1.19 Potential energy diagram for cyclization in 232 (232  218), All energies are relative to 232 at 0.0 kcal mol-1…………………………... 74

Figure 3.1.20 Optimized geometries of 233, TS17, 234 and TS18 ...... 75

Figure 3.1.21 Potential energy diagram for elimination of silyl chloride followed by 1,2 addition of enol to methyl ketone to generate 235. All energy values are relative to 233 at 0.0 kcal mol-1……………………………………. 77

xvii

Figure 3.1.22 Potential energy diagram for migration of OTiCl3 to silyl moiety in 236 to generate 237. All energy values are with respect to 236 at 0.0 kcal mol-1 ………………………………………………………………………..78

Figure 3.1.23 Potential energy diagram for cyclization in 238. All values are with respect to 238 at 0.0 kcal mol-1………………………………………… 79

Figure 3.1.24 Potential energy diagram for Ti catalyzed 1,4 addition of enol to enone in 234. All values with respect to 234 at 0.0 kcal mol-1……………….. 80

Figure 3.1.25 Potential energy diagram for conjugate-conjugate addition on 242 (242 → 243). All energies are with respect to 242 at 0 kcal mol-1………….. 81

Figure 3.1.26 Potential energy diagram for cyclization in 244 (244  245), All energies are relative to 244 at 0.0 kcal mol-1…………………………... 82

Figure 3.2.1 Zinc catalyzed oxidation of alcohols to esters (ligand (L) = 79-83) ...... 84

Figure 3.2.2 Zn catalyzed inner, intermediate and outer sphere mechanisms ...... 86

Figure 3.2.3 Catalytic cycle for metal [Ru] catalyzed dehydrogenative ester formation…………………………………………………………………86

Figure 3.2.4 Numbering of the atoms of the structures under discussion...... 87

Figure 3.2.5 Energy profile for oxidation of alcohol to aldehyde through β-hydride elimination (inner sphere mechanism) by zinc catalyst. All energy values are relative to 253 at 0.0 kcal mol-1……………………………………. 88

Figure 3.2.6 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination in the presence of TBHP. ………………90

Figure 3.2.7 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination, All energy values relative to 258 at 0.0 kcal mol-1…………………………………………………………………… 91

Figure 3.2.8 Removal of water molecule...... 92

xviii

Figure 3.2.9 Energy profile for oxidation of hemiacetal to ester through β-hydride elimination by zinc catalyst. All energy values are relative to 262 at 0.0 kcal mol-1………………………………………………………………. 93

Figure 3.2.10 Energy profile for the oxidation of alcohol to aldehyde through intermediate sphere mechanism. All energy values are relative to 265 at 0.0 kcal mol-1………………………………………………………….. 94

Figure 3.2.11 Energy profile for the oxidation of hemiacetal to ester through intermediate sphere mechanism. All energy values are relative to 267 at 0.0 kcal mol-1………………………………………………………….. 95

Figure 3.2.12 Energy profile for the oxidation of alcohol to aldehyde through intermediate sphere mechanism. All energy values are relative to 269 at 0.0 kcal mol-1…………………………………………………………... 96

Figure 3.2.13 Energy profile for the exchange of hydrogen shift between ligands, All energy values are relative to 271 at 0.0 kcal mol-1…………………….. 97

Figure 3.2.14 Energy profile for the oxidation of hemiacetal to ester through intermediate sphere mechanism. All energy values are relative to 273 at 0.0 kcal mol-1………………………………………………………….. 98

Figure 3.2.15 Energy profile for the oxidation of alcohol to aldehyde through outer sphere mechanism. All energy values are relative to 275 at 0.0 kcal mol-1 ……………………………………………………………………..99

Figure 3.2.16 Optimized geometries and related structural parameters for 269, TS34, 275 and TS37…………………………………………………………..100

Figure 3.2.17 Energy profile for the oxidation of hemiacetal to ester through outer sphere mechanism. All energy values are relative to 277 at 0.0 kcal mol-1 ……………………………………………………………………..101

xix

Figure 3.2.18 Energy profile for the oxidation of alcohol to aldehyde through outer sphere mechanism. All energy values are relative to 279 at 0.0 kcal mol-1 ……………………………………………………………………..102

Figure 3.2.19 Energy profile for hydride shift to TBHP to regenerate the catalyst. All energy values are relative to 281 at 0.0 kcal mol-1…………………….. 103

Figure 3.2.20 Energy profile for the oxidation of hemiacetal to ester through outer sphere mechanism. All energy values are relative to 283 at 0.0 kcal mol-1 ………………………………………………………………………104

Figure 3.3.1 Oxidative amidation of benzylic alcohol with TBHP using ZnI2 catalyst…………………………………………………………………. 107

Figure 3.3.2 Numbering of atoms of structures under discussion ...... 108

Figure 3.3.3 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination, at B3PW91/6-311G(d,p) with pseudopotential for Zn and I (SDDALL). All values are relative to 246a at 0.0 kcal mol-1…………………………………………………………... 109

Figure 3.3.4 Energy profile for oxidation of alcohol to aldehyde through TBHP coordinated to zinc catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential for Zn and I. All energy values are with respect to 248a at 0 kcal mol-1……………………………………………………………. 111

Figure 3.3.5 Energy profile for proton exchange between oxy ligands to generate 288, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All values are with respect to 285 at 0.0 kcal mol-1…………. 112

Figure 3.3.6 Energy profile for oxidation of hemiaminal to amide through TBHP coordinated to zinc catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All values are relative to 289 at 0.0 kcal mol-1………………………………………………………….. 113

xx

Figure 3.3.7 Energy profile for oxidation of alcohol to aldehyde through outer sphere mechanism in complex 291, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All energy values are with respect to 291 at 0.0 kcal mol-1... ………………………………………115

Figure 3.3.8 Energy profile for oxidation of alcohol to aldehyde through outer sphere mechanism in complex 293, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All energy values are with respect to 293 at 0.0 kcal mol-1………………………………………… 116

Figure 3.3.9 Energy profile for hydride shift to TBHP to regenerate the catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I………………………………………………………………… 117

Figure 3.3.10 Energy profile for oxidation of hemiaminal to amide through outer sphere mechanism in complex 297, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I………………………… 118

Figure 3.3.11 Energy profile for oxidation of hemiaminal to amide through β-hydride elimination by zinc catalyst calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I.………………………………119

Figure 3.3.12 Reaction profile for the oxidative transformation of alcohol to amides

through TBHP and ZnI2 (outer sphere mechanism)…………………… 121

Figure 3.3.13 Catalytic cycle for zinc catalyzed oxidative amidation of benzylic alcohol………………………………………………………………….. 122

Figure 3.4.1 Zn catalyzed oxidation of thioacetal to thioester...... 124

Figure 3.4.2 Numbering of atoms of structures under discussion ...... 124

Figure 3.4.3 Energy profile for the oxidation of thioacetal to thioester through intermediate sphere mechanism. All energy values are relative to 302 at 0.0 kcal mol-1…………………………………………………………... 125

xxi

Figure 3.4.4 Energy profile for the oxidation of thioacetal to thioester through outer sphere mechanism. All energy values are relative to 305 at 0.0 kcal mol-1 ………………………………………………………………………127

Figure 3.4.5 Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine ……………………………………………………………………..128

Figure 3.4.6 Energy profile for oxidation of benzylamine to benzaldimine through β- hydride elimination (inner sphere mechanism) by zinc catalyst. All energy values are relative to 307 at 0.0 kcal mol-1…………………………….. 129

Figure 3.4.7 Energy profile for the oxidation of benzylamine to benzaldimine through intermediate sphere mechanism. All energy values are relative to 310 at 0.0 kcal mol-1…………………………………………………………... 130

Figure 3.4.8 Energy profile for the oxidation of diamine to guanidine through intermediate sphere mechanism. All energy values are relative to 312 at 0.0 kcal mol-1…………………………………………………………... 131

Figure 3.4.9 Energy profile for the oxidation of banzylamine to banzaldimine through outer sphere mechanism. All energy values are relative to 314 at 0.0 kcal mol-1……………………………………………………………………. 132

Figure 3.4.10 Energy profile for the oxidation of diamine to guanidine through outer sphere mechanism. All energy values are relative to 316 at 0.0 kcal mol-1 ………………………………………………………………………133

Figure 3.5.1 Hydroamination reaction by inner sphere and outer sphere mechanism ………………………………………………………………………137

Figure 3.5.2 Numbering of atoms under discussion ...... 138

Figure 3.5.3 Potential energy diagram for inner sphere hydroamination-hydrogenation reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1 ………………………………………………………141

xxii

Figure 3.5.4 Potential energy diagram for hydroamination and hydrogen transfer reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1………………………………………………………… 143

Figure 3.5.5 Potential energy diagram for hydroamination reaction through outer sphere mechanism and hydrogen transfer reaction calculated at B3LYP/6- 31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1……………. 145

Figure 3.5.6 Potential energy diagram for hydrogen activation on Zn and nitrogen calculated at B3LYP/6-31G(d). All energies are relative to 318 at 0.0 kcal mol-1……………………………………………………………………. 148

Figure 3.5.7 Potential energy diagram for hydrogen activation on triflate and carbon calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1………………………………………………………………. 149

Figure 3.5.8 Potential energy diagram for hydrogen activation reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1… 150

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LIST OF SCHEMES

Scheme 1.1 Zn catalyzed copolymerization of carbon dioxide with epoxide ...... 6

Scheme 1.2 Zn catalyzed depolymerization of polyethers to chloroester ...... 7

Scheme 1.3 Zn catalyzed transformation of polyesters into its monomers ...... 7

Scheme 1.4 Zn catalyzed bond activation of Si-O of polysiloxanes to Si-F bond ...... 8

Scheme 1.5 Zn catalyzed transformation of acid chloride to acyl azide...... 8

Scheme 1.6 Zn catalyzed transformation of monoester of malonic acid into amino acid……………………………………………………………………... 9

Scheme 1.7 Zn catalyzed aminosulfonation of 4-ethyl anisole ...... 9

Scheme 1.8 Zn catalyzed transformation of cyclopropane diesters to piperidine ...... 10

Scheme 1.9 Zn catalyzed ring opening of epoxides by amines ...... 10

Scheme 1.10 Zn catalyzed aldol reaction of aldehyde with acetophenone...... 11

Scheme 1.11 Zn catalyzed Mukaiyama-aldol reaction in the presence of a diazo moiety.……………………………………………………………………11

Scheme 1.12 ZnEt2 catalyzed Michael addition reaction……..………..……………11

Scheme 1.13 Zn(OTf)2 catalyzed enantioselective Aza-Henry reaction………….….12

Scheme 1.14 Zn(OTf)2 catalyzed Mannich reaction………………...………..…..….12

Scheme 1.15 Zn(OTf)2 catalyzed asymmetric Diels-Alder reaction…………..….....13

i Scheme 1.16 ZnCl2 catalyzed alkylation of propiophenone with PrMgCl………….13

Scheme 1.17 Zn(OTf)2 catalyzed enantioselective addition of alkyne to aldehyde…………………………………………………………………13

xxiv

Scheme 1.18 ZnCl2 catalyzed radical conjugate addition……..…………..….…14

Scheme 1.19 ZnCl2 catalyzed isomerization of but-3-yn-1-ones into substituted furans…………………………………………………………………14

Scheme 1.20 Zn4(OCOCF3)6O catalyzed conversion of esters………..……..…..15

Scheme 1.21 ZnCl2 catalyzed ring opening of cyclic ethers………………...... …15

Scheme 1.22 Zn catalyzed reaction of propargyl alcohol with 2-alkylidene-1,3- dicarbonyl……………………………………………………….……15

Scheme 1.23 ZnO catalyzed acylation of aromatics with acyl chlorides……...…16

Scheme 1.24 Zn(OTf)2 catalyzed Fridel-Craft alkylation of nitro olefins with indoles………………………………………………………………..16

Scheme 1.25 Cross-coupling of aryl Zn chloride…………………...……………17

Scheme 1.26 ZnEt2 catalyzed epoxidation of α,β-enones…...…………….….…..18

Scheme 1.27 Zn catalyzed oxidation of alcohol to ketones……………...……….18

Scheme 1.28 Zn catalyzed oxidation of alcohol to aldehyde and esters……...... 19

Scheme 1.29 Zn catalyzed oxidative esterification of aldehydes…………………21

Scheme 1.30 Zn catalyzed amide formation from hydroxylamine………………..21

Scheme 1.31 Zn catalyzed transformation of aldehyde into amide…………...…..22

Scheme 1.32 Zn/K-10 catalyzed hydroamination reaction……………………….24

Scheme 1.33 Zn catalyzed reductive amination…………….………………..…....25

Scheme 1.34 Zn catalyzed hydroamination reaction of secondary amines with alkynes……….………………………………..…………..………….26

xxv

Scheme 1.35 Zn catalyzed synthesis of indoles by hydroamination reaction…………………………………………………………………27

Scheme 1.36 Zn catalyzed hydroamination-hydrogenation of alkynes and amines...... 27

Scheme 1.37 Zn catalyzed chemoselective hydrosilylation of organic amide………………………………………………………………...…28

Scheme 1.38 Zn catalyzed transformations of aldehydes to ethers…………...... …28

Scheme 1.39 Zinc catalyzed hydrosilylation of ketimines….……………….…….29

Scheme 1.40 Zn catalyzed reduction of sulfoxides to sulfides………………..…..29

Scheme 1.41 Zn catalyzed hydroamination-hydraogenation………………..…….30

Scheme 1.42 Zn catalyzed transfer hydrogenation of imine………………...…….30

Scheme 1.43 Synthesis of enol-ethers from cross coupling of keto-esters……...... 31

Scheme 1.44 Synthesis of furan from cross coupling of keto-ester…………...…..32

Scheme 1.45 Oxidation of hydroazole…………………….……………….……...33

Scheme 1.46 Transformation of amine, alcohol and aldehyde into aminoalcohol…………………………………………………………..33

Scheme 1.47 TiCl3 catalyzed tansformation of an aldehyde, amine, and formamide into α-aminoamides………………………………………….……..…34

Scheme 1.48 Ti catalyzed cyclization of oxo-ester…….……………………….…34

Scheme 1.49 Hydroamination reaction for synthesis of indoles…………………..35

Scheme 1.50 Reductive coupling of carbonyl compounds for diol synthesis………………………………………..……………………...36

Scheme 1.51 TiCl3 catalyzed McMurry coupling of α,β-dialdehydes…..………...36

xxvi

Scheme 1.52 TiCl4 catalyzed Claisen rearrangment reaction…….…….37

Scheme 1.53 Asymetric aldol addition reaction…...……………………37

Scheme 1.54 Ti catalyzed 2+2 cycloaddition reaction………………….38

Scheme 1.55 Ti catalyzed 6+2 cycloaddition reaction………………….38

Scheme 1.56 TiCl4 catalyzed cyclization of 1,3 bis(silyl enol ether) with 1,1,3,3- tetramethoxypropane…………………………………..……39

Scheme 1.57 TiCl4 catalyzed formal 3+3 cycloaddition reaction…….…39

Scheme 1.58 Mechanistic investigations of Zn catalyzed alkynalation of aldehyde…………………………………………………….40

Scheme 1.59 Mechanistic investigations of Zn catalyzed hydroamination of alkenes………………………………………………..……..41

Scheme 1.60 Mechanistic investigations of oxidative homocoupling reaction….………………………………………....………..41

Scheme 1.61 Mechanistic investigations of Zn catalyzed hydrosilylation of imine…………………………………..…………….………42

Scheme 1.62 Mechanistic investigations of Ti catalyzed oxaza-Cope rearrangement…………………………..…………..……….43

Scheme 1.63 TiCl4 catalyzed formal [3+3] cyclization of 1,3-bis(silyl enol ethers)……………………………………..……..……..…...44

Scheme 1.64 Zn catalyzed oxidation of alcohols to aldehydes, and esters……………………………………………………..…44

Scheme 1.65 Zn catalyzed oxidation of alcohols to aldehydes, and amide………………………………………….…………….45

xxvii

Scheme 1.66 Zn catalyzed oxidation of thioacetal to thioester……………..45

Scheme 1.67 Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine……………………….…………….…...…………….45

Scheme 1.68 Zn catalyzed hydroamination-hydrogenation of alkynes with amines……………………………………..………...………….46

Scheme 3.1.1 TiCl4 catalyzed cyclization of 1,3 bis(silyl enol ether) with 1,1,3,3- tetramethoxypropane……………………….…………………..51

Scheme 3.1.2 TiCl4 catalyzed regioselectivitive [3 + 3] addition of 1,3-bis(silyloxy)- 1,3-butadienes with 3-silyloxy-2-en-1-ones……………………51

Scheme 3.1.3 Proposed mechanism of TiCl4 catalysed 3 + 3 addition of 1,3- bis(silyloxy)-1,3-butadienes with 3-silyloxy-2-en-1-ones………52

Scheme 3.1.4 Illustration of observed regioselectivities in [3 + 3] addition of 1,3- bis(silyloxy)-1,3-butadienes with 3-silyloxy-2-en-1-ones……….53

Scheme 3.1.5 Reversible silyl shifts between oxygens of 3-silyloxy-2-en-1- ones……………..…………………………………….…………..54

Scheme 3.5.1 Zn(OTf)2 catalyzed hydroamination-hydrogenation of alkynes with amines……………………………………………….………….….131

Scheme 3.5.2 Schematic presentation for inner sphere hydroamination-hydrogenation reaction……………………………………………………..……....135

Scheme 3.5.3 Zinc catalyzed hydrogenation of imines………...…...…..………141

Scheme 3.5.4 Iridium catalyzed hydrogenation of imines……………..….……142

xxviii

LIST OF TABLES

Table 1.1 Effect of different ligands and solvents on esterification reaction…….20

Table 1.2 Effect of different alkynes and amines for intermolecular hydroamination reaction…….……………………………………………….….……...25

Table 3.1.1 Comparison of some important geometric parameters in 222 and TS10…………………………………………....……………………...66

Table 3.2.1 Selected bond lengths of 253, 255 and TS28. All values are given in Angstroms……………………………………………..………………84

Table 3.2.2 Comparison of intermediate and outer sphere mechanism. All energy values are Gibbs free energies and are in kcal mol-1…………...….....100

Table 3.3.1 Effect of different oxidants on ZnI2 catalyzed reaction………….115

Table 3.3.2 Effect of different oxidants on ZnBr2 catalyzed reaction………...116

Table 3.4.1 Comparison of ZnBr2 and ZnI2 catalyzed intermediate and outer sphere activation energy………………………….….…….………..……122

Table 3.4.2 Activation energy for ZnBr2 and ZnI2 catalyzed oxidation of banzylamine to benzaldimine and guanidine……………………………………128

Table 3.5.1 Selected bond lengths of 328, 329 and TS61. All values are given in Angstroms…………………………………………………………137

xxix

LIST OF ABBREVIATIONS

β Beta

H2O2 Hydrogen peroxide

TBHP tert-butyl hydrogen peroxide

CH3OOH methyl hydroperoxide m-CPBA meta-chloroperoxybenzoic acid

TiCl4 Titanium tetrachloride

DFT Density Functional theory

Zn(OTf)2 Zinc trifluoromethanesulfonate

TS Transition state

CF3 Trifluoromethyl

Zn-H Zinc-hydride

TFA Trifluoroacetic acid

PMHS Polymethylhydrosiloxane

ZnI2 Zinc iodide

ZnBr2 Zinc bromide

TBDMS tert-butyl dimethylsilyl

xxx

Chapter 1

1 Introduction

1

Transition metal catalysis offers an efficient and economical approach to develop valuable organic transformations with high degree of regioselectivity, chemoselectivity, enantioselectivity and diastereoselectivity.

1.1 Catalyst and Catalysis

―Catalyst is a substance that can modify or speed up a reaction without suffering itself from any permanent change or being consumed[1]‖. The phenomenon of accelerating the reaction rate is called catalysis.

1.1.1 Role of a Catalyst

A catalyst work by changing the activation energy for a reaction and affects only the kinetics of a reaction without affecting thermodynamics[2]. A catalyst may provide an alternative mechanism with lower activation energy with multiple transition states in which intermediates are stabilized by the catalyst (Figure1.1).

Figure 1.1 Comparison of a catalyzed and noncatalyzed reaction

1.2 Importance of Catalysis

About 90% of all chemical processes involve participation of catalysts[3] and 60% of all commercially available chemical products are manufactured in the presence of catalysts. Catalysts are very useful in chemical industries because products manufacturing rates become faster with the aid of catalysts which, in turn, reduce

2

manufacturing cost[4]. Catalysts also enhance the regioselectivities and stereoselectivities in reactions[5].

1.3 Characteristic Features of a Catalyst

 Selectivity A catalyst should be highly selective and specific to generate the desired product in high purity, with minimum quantity of waste product[6].

 Life time

A catalyst must have enough long life time to survive through excessive number of catalytic cycles. The catalyst efficiency can be expressed by turnover number (TON)[7]. Turnover number is the number of moles of reacting molecules that are converted into product molecules with one mole of a catalyst[8]. Turnover frequency is the turnover number per unit time. ―An ideal catalyst has a high turnover frequency and results in a quick reaction even at very low concentration[9]‖.

1.4 Classification of Catalysis

Catalysis is broadly classified as homogeneous and heterogeneous catalysis, based on the phase of both catalyst and substrate[10]. Electrocatalysis, biocatalysis, autocatalysis and organocatalysis are often considered as separate groups.

1.4.1 Heterogeneous Catalysis

In heterogeneous catalysis, reactants and catalyst are present in different phases. Most of catalysts in heterogeneous catalysis are in solid phase while reactants are in gaseous or liquid phases. These catalysts are further classified in three types based on the nature of the reactant and the catalyst. Heterogeneous catalysts are generally present in solid state but variations may exist[11].

 Solid and gas phases When reactants are in gas phase while catalyst is in solid phase.

3

Example: Synthesis of ammonia in the Haber process from nitrogen and hydrogen gases over iron catalysts (solid)[12].  Solid and liquid phases When reactants are in liquid phase while catalyst is in solid phase. Example: Fatty acids (liquid) hydrogenation with nickel (solid)[13].  Immiscible liquid phases When catalyst is in liquid phase while reactants are in non-aqueous phase. Example: Propene hydroformylation with liquid-phase Rh-phosphine catalyst[14].

1.4.2 Homogeneous Catalysis

In homogeneous catalysis, both reactants and catalyst are present in the same phase[15]. More commonly, the reactants and homogeneous catalysts are dissolved in same solvent. Homogeneous catalysis is of two types.

 Gas phase catalysis When both reactants and catalyst are in gas phase. Example: Methane activation by gas phase ligated transition metal cations[16].  Liquid phase catalysis When both catalyst and reactants are in liquid phase[17]. Example: Esters hydrolysis by water or dilute acid such as hydrochloric acid solution[18].

1.5 Transition Metals in Homogeneous Catalysis

Transition metals based catalysts modified with ligands are considered as a most successful homogeneous catalyst because of certain unique properties[19]. For example, transition metals:

 Can easily donate and withdraw electrons from other molecules, and it depends on reaction conditions[20].  Possess ability to exist in various oxidation states[21].  Have ability to make complexes with a variety of reacting molecules.

4

 Can act as catalyst in atomic form, radical form, and molecular form in which metal is bonded with different organic or inorganic ligands. In some cases, both organic and inorganic ligands are attached to a metal center.  Efficiency is affected tremendously by manipulating ligands through various contributing factors such as electronic effects, steric effects, bite angle etc[19].

The properties of transition elements vary along the periods (in periodic table) as it also dependent on certain factors such as oxidation state[22], coordination number[23] and nature of ligands[24]. Early transition metals are different from late transition metals in many properties, such as, early transition metals are electron deficient, can easily undergo oxidation reaction and have maximum coordination number. Moreover electron rich ligands are more susceptible to bind with early transition metals[25]. Late transition metals are electron rich, for which reduction reactions are more facile and have low coordination numbers. Moreover, electron deficient ligands are susceptible to bind with them[26].

1.6 Zinc Catalysis

The zinc catalysis, in general, is not well explored compared to other transition metal catalysis; however, a changed situation has been observed recently[27]. This can be attributed to its low cost or toxicity, biological relevance and high natural abundance (0.0076% in the earth crust)[28]. The more commonly used metals such as Pd, Rh, Ru, Ir suffer from their low abundance, high cost and toxicity[29]. Hence, recent research is focused on the replacement of high cost and toxic metals by cheaper, low toxic and biologically relevant metals, and to discover new protocols using such metals. In this regard, the use of zinc is of great interest. However, in organic chemistry, zinc was first time used by Edward Frankland in 1849 in the synthesis of diethyl zinc. Thereafter, zinc has been used in several organic transformations[30]. Some of the named reactions based on zinc catalysis are: Reformatskii reaction[31], Negishi reaction[32], Henry reaction[33], Mukiyama aldol reaction[34] and Fukuyama reaction[35]. Generally the zinc catalysis was underdeveloped compared to other transition metal catalysis. This may be attributed to position of Zn in periodic table, occupying transition position, between transition metals and main group elements. The d shell of

5

zinc metal is completely filled which is responsible for its difference in properties compared to other transition metals. Most of its properties are comparable with main group elements such as oxidation state. Zn is primarily found in II or 0 oxidation state, however, some +1 oxidation state complexes are also known recently[36]. Other transition metals are flexible in their different oxidation states, and are found in -I to - VII oxidation states, depending on their nature and position in the periodic table. This might also be one of the reasons of limited use of Zn in redox reactions. A shift in the trend has been observed recently, and importance of zinc catalysis has been exhaustively explored in several reports, including, copolymerization particularly of carbon dioxide and epoxide, depolymerization reactions, alkyne activation, Friedel– Crafts acylation and alkylations, formation of carbon-carbon, carbon-oxygen and carbon-nitrogen bonds, oxidative transformations, hydroamination reactions and reductions of unsaturated compounds. Some of the examples of zinc catalyzed reactions are shown here:

1.6.1 Zinc Catalyzed Copolymerization of Carbon Dioxide with Epoxide

CO2 is a very cheap and nontoxic source for synthesis of various materials and chemicals such as hydrocarbons, CO, urea, and methanol[37]. Initially, heterogeneous Zn catalysts were used for copolymerization reactions[38], but the disadvantages were the formation of side products. The use of homogeneous Zn complexes overcomes the limitations, and showed significant improvement for these reactions, particularly Zn containing the β-diketiminato ligand motifs[39]. Several other Zn catalysts are now available for CO2 transformation reactions, such as polycarbonates and cyclic carbonates formation by reacting carbon dioxide with epoxides[40] (Scheme 1.1).

Scheme 1.1 Zn catalyzed copolymerization of carbon dioxide with epoxide

6

Polymers are valuable materials in our current society but the major drawback associated with polymers is the accumulation of very large amount of end-of-life polymeric compounds[41]. Various methodologies have been applied to cleave the harmful polymers, but all of them required very harsh reaction conditions, such as 420 °C temperature[42]. Depolymerization is a significant reaction involving generation of monomers or synthons that can be repolymerized on demand. In this way, end-of-life polymers can act as a useful feedstock for developing other polymers. Preliminary investigation on Zn catalysis for depolymerization reaction demonstrated that the catalyst can actively participate in the reaction and depolymerizes polyethers, polyesters, and polysilicones. The first example of Zn catalyzed cleavage of tetrahydrofuran was described in 1949 in which benzoylchloride was used with the catalytic amount of Zn to yield chloroethers[43]. The concept was then used in the cleavage of polymeric materials (Scheme 1.2).

Scheme 1.2 Zn catalyzed depolymerization of polyethers to chloroester

Utilizing the methodology of the above reaction, a variety of cyclic ethers was then depolymerized in the presence of Zn catalyst with the aid of acid halides. Polyesters conversion into its monomers is also reported, in which Zn(OAc)2 acts as an active catalyst[44] (Scheme 1.3).

Scheme 1.3 Zn catalyzed transformation of polyesters into its monomers

7

Zn(OTf)2 or ZnCl2 are reported as efficient catalysts for activation of Si-O bond of polysiloxanes in the presence of benzyl fluoride to produce Si-F bonds (Scheme 1.4). Zn catalysis can also facilitate the recyclization of polymers[29].

Scheme 1.4 Zn catalyzed bond activation of Si-O of polysiloxanes to Si-F bond

1.6.2 Zinc Catalysis in C-N Bond Formation Reactions

A large number of organic compounds having pharmaceutical, biological and industrial importance possess C-N moiety in their backbone. Traditional approaches for synthesis of C-N bonds are based on very expensive metals. In the last decade, efforts were made to use inexpensive metals such as Zn[29]. Zn catalyzed hydroamination reaction (vide infra) for carbon-nitrogen bond formation is an important reaction in this regard. Other methodologies involve Zn catalyzed transformation of azides and diazocompounds in the presence of acid chlorides and [45] trimethylsilyl azide (TMSN3, Scheme 1.5).

Scheme 1.5 Zn catalyzed transformation of acid chloride to acyl azide

Zn(OTf)2 is also reported for synthesis of sodium azide and di-tert-butyl dicarbonate with carboxylic acids yield acyl azide. In a similar way, monoester of malonic acid is converted into amino acids[46] (Scheme 1.6)

8

Scheme 1.6 Zn catalyzed transformation of monoester of malonic acid into amino acid

Other related Zn catalyzed transformations involve tetrazoles formation from sodium azide and nitriles[47], pyrroles synthesis from dienyl azides[48], synthesis of 1,2- bromoazidation of alkenes using trimethylsilylazide and N-bromosuccinimide, and 1,5-substituted 1,2,3 triazole synthesis from a reaction of alkynes and azides[49]. In

2008, ZnBr2 catlayzed amino functionalization of allylic, benzylic, and tertiary C–H bonds have been observed in the presence of Ts-N = IPh[50] (Scheme 1.7).

Scheme 1.7 Zn catalysis in amino-sulfonation of ethyl anisole

Likewise, the amination of β-dicarbonyl compounds by zinc(II) perchlorate hexahydrate in the presence of p-toluenesulfonamide as the aminating agent and iodosobenzene as an oxidant has been reported[51]. Zn catalyzed cleavage of epoxides and cyclopropanes for C-N bond formation are also reported very recently. In 2009, Zn catalyzed reaction of propargyl amines and 1,1-cyclopropane diesters to yield functionalized piperidines has been reported (Scheme 1.8). The mechanism was proposed to involve ring opening followed by conia-ene cyclization[52]. Zn(II) perchlorate hexahydrate catalysis in epoxides ring opening reaction by amines (Scheme 1.9) was found very efficient and optimal in promoting quick reaction at room temperature[53].

9

Scheme 1.8 Zn catalyzed transformation of cyclopropane diesters to piperidine

Scheme 1.9 Zn catalysis in epoxides ring opening reaction by amines

1.6.3 Zinc Catalysis in Reactions of C-C Bond Formation

The pioneering studies on Zn catalysis in C-C reaction was reported in 1863 for synthesis of α-hydroxycarboxylates[54]. Some of the eminent classic named reactions that involves Zn catalysts are: Frankland–Duppa reaction, the Simmons–Smith reaction[55], Reformatsky reaction[56], cyclopropanation or the Negishi cross-coupling reaction[57]. Aldol and Mukaiyama-Aldol reactions[58] are also reported to be catalyzed by Zn. Brief description about modern named reactions are presented here:

 Zinc Catalyzed Aldol & Mukaiyama-Aldol Reactions

Aldol reaction is a key step in synthesis of valuable asymmetric products such as Fostriecin and biosynthesis of amino acids, ketoacids, carbohydrates and more complex biomolecules. Naturally, enzymes containing Zn cofactor catalyze the aldol reaction. Zn catalyzed Aldol reaction was first reported in 1980[58]. Recently, binuclear Zn catalyst was reported to promote aldol reaction of various aldehydes with variety of acetophenone derivatives[59] (Scheme1.10).

10

Scheme 1.10 Zn catalyzed aldol reaction of aldehyde with acetophenone

Zn(OTf)2 showed efficient activity for Mukaiyama-aldol reaction compared to other catalysts using silanyloxy derivative and aldehydes in the presence of a diazo moiety (Scheme 1.11). The catalyst is also active in enantioselective hydroxymethylation of cyclohexanone with a good yield in water[60].

Scheme 1.11 Zn catalysis in Mukaiyama-aldol reaction

 Zinc Catalyzed Michael Addition Reactions

Michael addition reactions provide a simple and convenient route for synthesis of 1,5- dicarbonyl compounds form unmodified ketones and enone derivatives. Profound effect of nature of ligands and substrates were observed in Zn catalyzed 1,4- or Michael addition reaction. Zn catalyzed chiral synthesis are also reported[61] (Scheme 1.12).

Scheme 1.12 ZnEt2 catalyzed Michael addition reaction

11

 Zinc Catalyzed Henry & Aza-Henry Reactions

Henry reaction, also known as nitroaldol reaction, is used for synthesis of valuable compounds. High enantioselectivity was observed in a Zn(OTf)2 catalyzed reaction of protected aryl imines with nitromethane in the presence of N-methylephedrine as a ligand[62] (Scheme 1.13).

Scheme 1.13 Zn(OTf)2 catalyzed enantioselective Aza-Henry reaction

 Zinc Catalyzed Mannich-type Reactions

Mannich reactions involve synthesis of β-Amino alcohols, which are biologically active compounds, and also act as chiral ligands. Zn(OTf)2 is an efficient catalyst to promote high diastereoselectivity[63] in Mannich type reaction (Scheme 1.14) .

Scheme 1.14 Zn(OTf)2 catalyzed Mannich reaction

 Zinc Catalyzed Cycloaddition Reactions

Zn acts as lewis acid to accelerate cycloaddition reactions. Zn catalysts are highly efficient for cycloaddition reactions, compared to other late transition metal catalyzed reactions. Zn(OTf)2 catalyzed Diels-Alder reaction using bisoxazoline gave efficient yield with high enantioselectivity[64] (Scheme 1.15).

12

Scheme 1.15 Zn(OTf)2 catalyzed asymmetric Diels-Alder reaction

Zinc catalysis in carbonyl compounds and organometallic reagent addition reaction for C-C bond generation are also reported[65]. In this regard, Grignard reagent is treated with ZnCl2 to generate catalytically active specie R3ZnMgCl (Scheme 1.16). In classical approaches, the Grignard reagent gave undesired products when reacted with carbonyl compounds.

i Scheme 1.16 ZnCl2 catalyzed alkylation of propiophenone with PrMgCl

Zn catalysis in reaction of organometallic reagents such as propargylation, allylation and allenylation are also interesting reactions[66]. Zn acids showed higher enantioselectivities compared to other acids in these reactions. Zn catalyzed alkyne addition to C-N and C-O bonds for synthesis of propargyl alcohols or amines are reported recently (Scheme 1.17). The reaction is useful in various valuable natural products, such as, (R)-strogylodiols[67].

Scheme 1.17 Zn(OTf)2 catalyzed enantioselective addition of alkyne to aldehyde

13

Cross coupling reactions such as Negishi reaction is also based on a C–C bond formation reaction (vide infra). Some of the radical reactions in which ZnCl2 acts as a radical initiator for allylation reaction of 2-bromoester derivatives were reported by [68] Yamamoto and coworkers . Zn(OTf)2 catalyzed radical conjugate addition reaction is shown in scheme 1.18.

Scheme 1.18 ZnCl2 catalyzed radical conjugate addition

Zn catalyzed Fridal-Craft reactions (vide infra), alkyne activation[69] and cyclopropanation reactions[70] are also common examples of Zn catalyzed C-C bond formation reaction.

1.6.4 Zinc Catalysis in C-O Bond Formation Reactions

To avoid the harsh reaction conditions required for classical approaches, transition metal catalysts are employed. Most of the advancements on Zn catalysis in this regard were carried out during the last decade. ZnCl2 catalyzed isomerization of 3-butynones in dichloromethane to generate high yield of substituted furans have been reported in 2007[71] (Scheme 1.19).

Scheme 1.19 ZnCl2 catalyzed isomerization of but-3-yn-1-ones into substituted furans

Further improvement is achieved when μ-oxo-tetranuclear zinc cluster

Zn4(OCOCF3)6O is used for synthesis of furopyrimidine nucleosides. The catalyst is also efficient for transesterifications and amide cleavages even in the case of N- protected amino esters and dipeptides. Zn4(OCOCF3)6O catalyzed transformations of

14

carboxylic acid derivatives (esters, lactones, and carboxylic acids) to oxazolines is also reported[72] (Scheme 1.20).

Scheme 1.20 Zn4(OCOCF3)6O catalyzed conversion of esters

Several Zn catalysts have been reported for synthesis of different chloroesters in the presence of acid chlorides by ring opening reaction of cyclic ethers[43b] (Scheme 1.21, n=1-3).

Scheme 1.21 ZnCl2 calayzed ring opening of cyclic ethers

Zn based Michael addition/cyclization is reported in which Zn(OTf)2/Et3N combination was found as the best precatalyst system[69]. The catalyzed 1,4-addition followed by cyclization of propargyl alcohol and alkylidene dicarbonyl compounds is presented in scheme 1.22.

Scheme 1.22 Zn catalyzed reaction of propargyl alcohol and alkylidene dicarbonyl

The ability of Zn catalyst to promote multicomponent reaction has also been reported which offers more advantage compared to classical approaches. Zinc catalysis in the synthesis of chromenes through sequence of Knoevenagel condensation followed by pinner reaction and finally Friedel Crafts reaction[73] is an example of this type.

15

1.6.5 Zinc Catalysis in Friedel Crafts Reactions

Zinc catalyzed Fridal Crafts reaction of nucleophilic aromatic compound and acyl chloride for synthesis of ketones at room temperature is an important advancement in the recent years. The catalyst is non-hygroscopic, non-corrosive and can be regenerated easily[74]. Acylation of aromatic compounds with acyl chlorides by ZnO is shown in the scheme 1.23.

Scheme 1.23 ZnO catalyzed aromatics acylation with acyl chlorides

Asymmetric reaction is promoted by applying various chiral ligands such as bisoxazolines (Box), and pyridine 2,6-bis(5′,5′-diphenyloxazoline)[75]. Variety of

Zn(OTf)2 or bisoxazoline precatalysts for enantioselective reaction using nitro olefin with indoles or pyrroles have been disclosed (Scheme 1.24).

Scheme 1.24 Zn(OTf)2 catalyzed Fridel-Craft reaction of nitro olefins with indoles

Dinuclear chiral Zn(II) catalysts such as Trost’s dinuclear Zn catalyst was employed previously for enantioselective Fridel-Craft alkylation of variety of nitroalkenes with pyrroles[76]. The reaction has importance in the synthesis of various natural products. Chiral (R)-BINAM([1,1′]binaphthalenyl-2,2′-diamine), chiral diamines/thiourea, chiral bipyridine, and chiral schiff base-zinc(II) complexes are also reported as precatalyst for Fridel-Crafts alkylation of indoles with a large number of nitroalkenes[77].

16

1.6.6 Organozinc in Oxidative Cross Coupling Reactions

Oxidative cross coupling reactions are superior and more convenient compared to classical synthetic approaches. Organozinc is an ancient organometallic compound that acts as an excellent nucleophile compared to other nucleophiles because of its low toxicity, easy preparation, high functional group tolerance, and more reactivity than C-H containing nucleophile[78]. Oxidative cross coupling reaction is an effective reaction for generation of various C-C and C-X (X=N, O, S, etc.) by reaction of an organozinc reagent with a variety of nucleophile C (sp2, sp3 and sp) and heteroatoms. Negishi coupling reaction (1977) is a famous and versatile (palladium or nickel catalyzed) cross coupling reaction of organozinc with various halides (aryl, vinyl, benzyl, or allyl) for C-C bond formation reaction[79] (Scheme 1.25).

Scheme 1.25 Cross-coupling of aryl Zn chloride

1.6.7 Zinc Catalyzed Oxidation Reactions

Oxidation processes involve transfer of electrons and changes in oxidation states of participating species. Extensive research has been carried out using different oxidants such as KMnO4, K2CrO4, or K2S2O8, tert-BuOOH, (tert-BuO)2, or m-CPBA (meta- chloroperoxybenzoic acid)[80]. Catalyst accelerates the reaction with low energy consumption with low waste production. Moreover, reactions are environmentally benign with high atom economy. To date, most of the late transition metals (Ru, Pd and Ir) were applied for the reaction but due to their high toxicity, high cost, and low abundance, alternative catalysts have also been searched for[81]. Zn proved an excellent catalyst which overcomes most of the drawbacks of other late transition metals. Lewis acidic nature of Zn(II) salts is responsible for most of the oxidation reactions. A brief discussion about Zn catalyzed oxidation of alkenes, alcohols and aldehydes is shown here:

17

 Oxidative Transformation of Alkenes

Inorganic Zn salts and organometallic Zn reagents are used for oxidation of electron deficient and neutral alkenes. First example of zinc-catalyzed epoxidation of α,β- enones with excellent chemoselectivity was proposed in 1989 utilizing atmospheric oxygen as an oxygen source[82] (Scheme 1.26).

Scheme 1.26 ZnEt2 catalyzed epoxidation of α,β-enones

Thereafter, Zn catalyst was also employed for a variety of oxidation reactions. For example, polybinaphthol zinc catalysts was employed for α,β-unsaturated ketones epoxidation reaction[83].

 Zinc Catalyzed Oxidation of Alcohols

Zn catalyzed oxidation of alcohol to generate aldehyde (vide infra) and ketones in the [84] presence of diethyl azodicarboxylate (DEAD) is initially disclosed in 2009 . ZnBr2 was used as a catalyst and product were obtained in good to excellent yields (Scheme 1.27). A variety of oxidants such as chloramine-T (N-chloro 4- methylbenzenesulfonamide sodium salt), H2O2 (vide infra) were then tested for the reaction. A solvent also showed pronounced effect on the reaction[85].

Scheme 1.27 Zn catalyzed oxidation of alcohol to ketones

Different ZnO and Zn salts with N-containing ligands were also tested and it was found that ZnO in combination with 1,4-diazabicyclo[2.2.2]octane (DABCO) is an effective catalytic system for oxidation of benzoin[86].

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 Oxidative Transformation of Aldehydes

Importance of Zn catalysis in several transformations of aldehyde such as esterification and amidation has been demonstrated in several recent reports. The details of both reactions are presented here:

Zn catalyzed benzyl alcohol oxidation to generate aldehyde and esters were reported [87] for the first time by Xiao-Feng Wu in 2012 . ZnBr2 catalyzed the reaction in a presence of H2O2 as a green oxidant at room temperature (Scheme 1.28). Only water was obtained as byproduct.

Scheme 1.28 Zn catalyzed benzyl alcohol oxidation to generate aldehyde and esters

A variety of catalysts such as ZnBr2, ZnI2, Zn(CN)2, Zn(OTf)2, Zn(OAc)2, Zn(TFA)2 with AcOH as additives were tested for the improvement of the reaction. Best results were obtained with ZnBr2. Thereafter, ZnBr2 was tested with different quantities of other additives such as AcOH , Pivalic acid (PivOH) and trifluoroacetic acid (TFA). TFA showed improved yields among all others. Significant improvement in yields was then observed with the addition of ligands. Solvent also showed pronounced effect on the reaction. Various ligands and their effect are shown in Figure 1.2. Efficiencies of 79 and 82 are much better than 80, 81, and 83. Table 1.1 also shows the effect of various ligands on the rate of the reaction.

19

Figure 1.2 Different ligands on Zn for esterification reaction

Table 1.1 Effects of different ligands and solvents on esterification reaction[87]

Entry Ligand Solvent Yield Yield of of aldehyde ester

1 79 MeOH 23 61

2 80 MeOH 16 50

3 81 MeOH 14 43

4 82 MeOH 18 53

5 83 MeOH 21 47

6 79 MeOH 89 0

7 79 THF 0 91

20

8 79 1,4- 0 60 dioxane

9 79 MeCN 0 80

10 79 H2O 0 49

[88] Heteroaryl substituted esters were also obtained in a good yield . In a similar approach, Zn catalyzed transformations of aromatic aldehydes into aromatic esters have been reported in the presence of H2O2 as an oxidant with a product yield of 60- 89% (Scheme 1.29).

Scheme 1.29 Zn catalyzed esterification of aldehydes by oxidation reaction

The conversion of aldehydes and hydroxylamine hydrochloride into amides with good yield and efficient chemoselectivites was first reported in 2010[89]. The catalyst exhibits wider activity for aromatic, alkenyl and alkyl substrates. Solvent also showed enhanced effect on reaction (Scheme 1.30). Utilizing the concept of oxidative esterification, transformation of various benzyl alcohols and amines to amide (Scheme 1.31) is also reported in 2013[90].

Scheme 1.30 Zn catalyzed amide formation from hydroxylamine

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Scheme 1.31 Zn catalyzed transformation of aldehyde into amide

Initially, different reaction conditions were applied for amide synthesis from benzyl alcohol and n-butylamine. ZnI2 (5 mol%) with TBHP in the absence of a solvent at 40°C showed improved yield. No product was obtained in the absence of a catalyst. Solvent does not show tremendous effect on yields. Variety of amines and benzyl alcohols are then tested using the ideal conditions obtained previously (ZnI2 as catalyst and TBHP as oxidant) (vide supra). Better results were obtained using isobutylamine and hexylamine with benzyl alcohols. Among substituted benzyl alcohols, methyl substitution improved the yield. Thiomethyl substituted benzyl alcohol also showed good results. Halogen substituents decreased the reactivity and yields. Reaction of thiophen-2-yl methanol with butylamine or pentaamine further decreased the quantity of amide products.

1.6.8 Zinc Catalyzed Hydroamination Reactions

Hydroamination involves N-H bond addition across unsaturated C-C bonds for synthesis of amines and its derivatives. The reaction is feasible thermodynamically but requires high activation energy because of the presence of electronic repulsions between an electron rich π bond and lone pair of nitrogen atom. To overcome the high activation energy due to electrostatic repulsion, a variety of catalysts are employed for this transformation reaction. Mercury, thalium, f block elements (Sm, Lu, Nd, U, Th), and early transition elements (Ti, Zr, V, Ta) were reported earlier[91] in this regard. Late transition metals (Pd, Pt, Rh, Ru, Au, and Ir) are also used as a catalyst. Most of the late transition metal shows limited scope for unactivated substrates, sluggish reaction rates, shorter catalyst life times and moderate selectivities[92]. Zinc based catalysts have the advantages of higher functional group tolerance, longer lifetime, non-toxic, cheaper and environmentally benign nature of the catalyst/reaction. The discovery of Zn catalysis for hydroamination reaction dates back to 1999[93]. During

22

the last decade, several zinc catalysts that mostly based on Zn Aminotroponiminate and simple Zn salts have been used for intermolecular and intramolecular hydroamination reactions.

 Aminotroponiminate (ATI) Zinc Complexes as a Hydroamination Catalysts

Aminotroponiminate Zn alkyl and amido complexes have been introduced by Roesky, Blechert and coworkers as homogeneous catalyst for intramolecular hydroamination reaction[94]. During catalytic reaction, the alkyl moiety acts as a leaving group and ATI as a spectator. The first example was reported in 2005 where [95] [{ATI(iPr)2}ZnMe] was used as a catalyst , which showed high tolerance towards polar functional group using [PhNMe2H][B(C6F5)4] as an activator. The experiment o was performed at 120 C in C6D6. Most of the reactions show good to excellent yields. Later, the catalyst was further improved by modification at three possible sides, i.e. by altering a ring substituent to control electronic properties, by variation of substituents on the ATI ligand to control a steric effect and by changing the leaving group[96] (Figure 1.3). Most of the catalysts showed better results after modification compared to parent catalyst.

 Other Zn–N Complexes as Hydroamination Catalyst

The catalyst system for hydroamination reaction inspired scientists to develop other Zn-N based catalysts. In this regard, two new zinc aminosalicylideneimine tetranuclear catalysts (Figure 1.3) were prepared and their catalytic activity was evaluated for hydroamination reaction. Both catalysts were found more efficient than Zn–ATI complexes for aminoalkenes intramolecular hydroamination using [97] [PhNMe2H][B(C6F5)4] activator at room temperature .

23

Figure 1.3 Possible sides of Zn catalyst modifications (90) and two tetranuclear Zn complexes (91,92)

Zn(Et)2 also showed efficiency for synthesis of indole derivatives by intramolecular [98] hydroamination of alkynyl amides . Cp2Zn2 is reported as precatalyst in the reaction of anilines with different arylethyne and various functional groups[98]. All the reactions showed outstanding Markovnikov regioselectivities.

 Inorganic Zinc Salts as Hydroamination Catalysts

Zn(OTf)2 was proposed initially in 1999 by Muller and coworkers as an efficient homogeneous catalyst for intramolecular hydroamination reaction of 6-aminohex-1- yne to 2-methyl-1,2-dehydropiperidine in toluene. Thereafter, the catalyst was used for variety of other aminoalkynes to undergo intramolecular hydroamination reaction. In most of the reactions, the obtained yields were greater than 99 % which reflect greater efficiency of the catalyst. Later on, Zn2+ exchanged K-10 montmorillonite clay (Zn/K-10) was used as a catalyst for intermolecular hydroamination reactions which yielded 77% imine[99] (Scheme 1.32).

Scheme 1.32 Zn/K-10 catalyzed hydroamination reaction

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Reductive amination of aldehyde using polymethylhydrosiloxane (PMHS) as reductant is reported by Enthaler using 5 mol% Zn(OTf)2 as precatalysts (Scheme 1.33).

Scheme 1.33 Zn catalyzed reductive amination

Soon after, Beller and coworkers observed efficient catalytic activity of Zn(OTf)2 for intermolecular hydroamination reaction of various anilines with alkynes. Table 1.2 shows the synthesis of series of secondary amines by reaction of different alkynes with various anilines followed by reduction with NaBH3CN and ZnCl2. The products show excellent Markovnikov regioselectivity and best yields[100]. Reaction of secondary amines gave tertiary amines but with a comparatively low yield (Scheme 1.34).

Table 1.2 Effect of different alkynes and amines for intermolecular hydroamination reaction[100]

Entry Alkyne Amine Product Yield (%)

1 98

2 99 `

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3 98

4 95

5 97

6 91

Scheme 1.34 Zn catalyzed hydroamination reaction of secondary amines with alkynes

Chiral amines were also explored for hydroamination of alkynes followed by reduction of intermediate imine with hydrogen molecule but racemic mixture was obtained as a product. Zn salts such as Zn(OTf)2 or ZnX2 (X = halide) catalyzed synthesis of indoles with good to excellent yields have been reported by hydrohydrazination of terminal alkynes. This was the first example of

26

pharmacologically important indole synthesis directly from alkynes. Scheme 1.35 shows Zn salts catalyzed reaction of various substituted alkynes with N- phenylhydrazine or N-methyl-N-phenylhydrazine for indoles production[101].

Scheme 1.35 Zn catalyzed synthesis of indoles by hydroamination reaction

[102] Effective synthesis of imidazole is also reported by Zn(OTf)2. Some of the other important hydroamination reaction catalyzed by Zn salts are: synthesis of pyrrole from cyclization of C-propargyl vinyl amides[103], gem-dipyrazolylalkanes synthesis from a reaction of pyrazoles with alkynes[104], 2-substituted indoles from cyclization of 2-alkynylanilines[105]; pyrazolines synthesis from addition of aryl hydrazines to 1,3- enynes and aniline addition to vinylarenes[106]. More recently, hydroamination- hydrogenation of alkynes to amines through homogeneous zinc (OTf)2 catalyst has been reported by Beller and coworkers using environmentally benign, cheap and readily available H2 as the reductant (Scheme 1.36).

Scheme 1.36 Zn catalyzed hydroamination-hydrogenation of alkynes and amines

1.6.9 Zinc Catalyzed Reduction Reactions

The reaction involves addition of hydrogen to unsaturated system. Most of the valuable products such as amines, alcohols and alkanes are produced by reduction reaction of C=O, C=N, and C=C. The reaction becomes more selective and efficient with the aid of a catalyst. Variety of catalysts has been used for the reaction (Ru, Rh, Ir, Pt, Cu and Pd). In the last decade, homogeneous Zn catalysis has been extensively used for different reduction reactions involving hydrosilylation reaction of C=O, C=N

27

and S=O, hydrogenations and transfer hydrogenations reactions. A brief discussion about these subsections is presented here:

 Zinc Catalyzed Hydrosilylation Reaction of C=O

Efforts for using Zn salts as active catalysts for hydrosilylation reactions of multiple bonds were made during 1960s and 1970s[107]. After that, the topic was underdeveloped until recently the Zn catalysis has been rediscovered, and outstanding improvements have been made for reduction reaction using silanes as reductant. Pioneering work on Zn catalysis is actually reported for reduction of aldehydes and ketones. Later the same methodology was applied using different reductants on a variety of substrates. Zn(2-ethylhexanoate)2 catalyzed hydrosilylation reactions of aldehydes, esters, ketones, and epoxides in the presence of NaBH4 and polymethylhydrosiloxane as a reductant have been reported[108] in 1999. The reaction showed an excellent yield and high tolerance towards unsaturated compounds.

Reduction of amide (Scheme 1.37), esters, lactones and CO2 to amines, alcohols, silyl ethers and formamides respectively, by using different Zn salts and silanes are also [109] reported. Zn(OTf)2 catalyzed conversion of aliphatic aldehyde to ethers by in the presence of triethylsilane or 1,1,3.3-tetramethyldisiloxane has been reported (Scheme 1.38).

Scheme 1.37 Zn catalyzed chemoselective hydrosilylation of organic amides

Scheme 1.38 Zn catalyzed transformations of aldehydes to ethers

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With the passage of time, several studies related to ligands and solvent effects have appeared in the literature. Ligands, solvents, nature of reductants and substrates showed pronounced effect on the rate of the reaction.

 Zinc Catalyzed Hydrosilylation Reaction of C=N

Reduction of imines using non-precious metal catalysts such as Cu, Fe, Ti and Zn has been disclosed in the past 10-15 years[110]. Among different reductants, polymethylhydroxysilane (PMHS) was found more reactive[111]. The first example of Zn system catalysis in the reduction of imine was discovered by Carpenter and coworkers[112] (Scheme 1.39).

Scheme 1.39 Zinc catalyzed hydrosilylation of ketimines

Zn(OTf)2 was found as an active catalyst in combination with binaphthol, and 3,3′- dibromosubstituted binaphthol. The combination of Zn(OTf)2 with PMHS gave excellent yields with high functional group tolerance.

 Zinc Catalyzed Reduction Reaction of S=O

Zn(OTf)2 catalyzed reductions of a variety of sulfoxides using PhSiH3 as a reductant have been reported, recently. The reaction showed excellent selectivity in the [113] presence of CN, NO2, ester, and sulfonyl moietes (Scheme 1.40)

Scheme 1.40 Zn catalyzed sulfoxides reduction to sulfides

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 Zinc Catalyzed Hydrogenation Reactions

Recently, an interesting reaction involving H activation by Zn complexes for hydrogenation reaction gained considerable interest. In the reaction, zinc triflate was used as a catalyst for hydrogenation of imines to amines, using hydrogen molecule as reductant. Moreover, Zn(OTf)2 catalyzed reductive hydroamination of alkynes for synthesis of amines has been reported[114]. Initially, hydroamination of amines with terminal alkynes was performed, followed by reduction of imines for generation of secondary amines (Scheme 1.41). The catalyst showed high tolerance towards polar functional group, and the yields were also very high. The reactivity of Zn(OTf)2 with the aid of nitrogen-containing ligands and chiral mono- and bidentate phosphorus was explored for hydrogenation reaction. Monodentate binaphthophosphepine was found the best ligand for promoting enantioselectivities. The effect of temperature and amount of ligands showed enhances effect on the catalytic reaction[115].

Scheme 1.41 Zn catalyzed hydroamination-hydraogenation

[Zn(H)(Cp*)(NHC)] also showed greater reactivity for hydrogenation reaction. The catalyst acts as a frustrated Lewis pair in which NHC (Figure 1.4) behaves as base [116] while Zn(OTf)2 acts as an acid for heterolytic activation of molecular hydrogen .

Figure 1.4 Structure of N-heterocyclic carbene

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 Transfer Hydrogenation of Unsaturated Compounds

Transfer hydrogenation is a sustainable alternative to hydrosilylation reactions. A reaction involves transfer of hydrogen from hydrogen donor reactant (2-propanol, formic acid, hydrazine or Hantzsch ester) to hydrogen acceptor product[115]. Only handful numbers of Zn(OTf)2 catalyzed hydrogen transfer of imines to amines have been reported so far (Scheme 1.42).

Scheme 1.42 Zn catalyzed transfer hydrogenation of imine

1.7 Titanium Catalysis

Titanium is the ninth most abundant atom and constitutes 0.63% of the earth crustal rocks. Applications of titanium as a catalyst has expanded to a large extend since its first use in 1970’s. Titanium is mostly found in IV oxidation state, however few compounds of I, II, and III oxidation state also exist. Oxides, sulfides, alkoxides, nitrides, carbides, organometallics and halides of titanium are known. These titanium reagents have proved themselves as promising catalyst for a variety of organic transformations due to their non-toxic, inexpensive and easily available nature. Some of the reactions catalyzed by titanium are alkene production from molecular reductive coupling of carbonyl compounds (aldehydes, ketones, acylsilanes, ketoesters, and oxoamides), various cycloaddition reactions[117], coupling and rearrangement reactions[118]. Titanium tetrachloride having tetrahedral geometry is an active Lewis acid catalyst that promotes numerous synthetic reactions. Titanium chloride is particularly used in intramolecular cross coupling reactions such as ketone-ester cyclization and oxidation of hydroazo derivatives, C-X bond formation reactions (synthesis of aminoalcohols, α-Aminoamide, indoles and pyrroles) and C-C bond formation reactions (pinacol and McMurry coupling reaction, Claisen

31

rearrangements, asymmetric aldol reactions and cycloaddition reactions such as 2+2 cycloaddition, 6+2 cycloaddition, 3+3 formal cycloaddition reaction) are the most prominent examples of titanium chloride catalyzed reaction. A brief discussion of all subsections is presented here:

1.7.1 Titanium Catalyzed Intramolecular Cross Coupling Reaction

 Ketone-ester Cyclization

McMurry et al, disclosed synthesis of cyclanones in a sequence of cross coupling of keto-esters followed by acidic workup (Scheme 1.43). Esters undergo intramolecular alkylidenation in the reaction. Combinations of different catalytic system were evaluated for better yield and TiC13/LiAlH4 was found the best in this regard. Some of the examples of intramolecular cross coupling reaction of α,β- unsaturated ester with ketone include synthesis of acoragermacrone, cembrene, generation of nine- membered ring of isocaryophyllene, and C-ring closure of capnellene.

Scheme 1.43 Synthesis of enol ethers from cross coupling of keto-esters

The reaction has importance in a synthesis of various valuable natural products. The same methodology is applied for titanium catalyzed synthesis of aromatic heterocycles such as furans and substituted furans (benzofurans, Scheme 1.44).

Friedel–Crafts type intramolecular cyclization catalyzed by TiCl4 is also reported for a synthesis of antimicrobial natural product (±)-Zenkequinone.

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Scheme 1.44 Synthesis of furan from cross coupling of keto-ester

 Titanium Catalyzed Oxidation of Hydroazo Derivatives

Oxidation of several hydroazo derivatives, treated with TiCl3 and HBr in the presence of H2O2 has been reported by Drug and Gozin (Scheme 1.45). The reaction showed fast kinetics, and proceeds at room temperature.

Scheme 1.45 Oxidation of hydroazo compound

1.7.2 Titanium Catalyzed C-X Bond Formation Reaction

Titanium catalyzed C-X bonds (X= N, O, etc.) formation reactions has been reported in several articles[119].

 Synthesis of Amino Alcohols

1,2-aminoalcohols holds an important position in medicinal chemistry because of their involvement in various valuable products synthesis. TiCl3/hydroperoxide shows excellent catalytic activity for one pot transformation of amine, alcohol and aldehyde into aminoalcohol under aqueous conditions (Scheme 1.46).

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Scheme 1.46 Transformation of amine, alcohol and aldehyde into aminoalcohol

t t Several other catalytic systems such as TiCl3/ butyl hydroperoxide ( BuOOH), TiCl4– t Zn, and TiCl3/ BuOOH are also reported that catalyzed synthesis of variety of functionalized aminoalcohols either through radical reaction or electrophilic- nucleophilic cascade process.

 α-Aminoamide Synthesis

Ti(III)/H2O2 catalyzed one pot reaction of aldehyde, amine, and formamide yields a variety of α-aminoamides (Scheme 1.47). TiCl3 catalyzed Barbier reaction has also been reported. Among various catalytic systems, TiCl4/Zn/H2O2 was found very efficient for the synthesis of several tert-alkyl-amino derivatives.

Scheme 1.47 TiCl3 catalyzed transformation of an aldehyde, amine and formamide into α-aminoamides

 Synthesis of Indoles & Pyrroles

Titanium catalyst is an active participant in intramolecular coupling of carbonyl groups possessing different redox potential. This reaction was a large breakthrough in organometallics for synthesis of hetero aromatic compounds, particularly, pyrroles, indoles, furans and benzofurans (vide supra). The rection involves reductive cyclization of oxo amides and oxo esters (Scheme 1.48).

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Scheme 1.48 Ti catalyzed cyclization of oxo-ester

Synthesis of some of the indole derivatives such as indolopyridocoline, secofascaplysin, and endothelin– receptor antagonist are also reported using titanium catalyst. Regioselective TiCl4/t-BuNH2 catalyzed hydroamination reaction is another interesting method of C-N bond generation. In this method, active intermediate imine is formed by reaction of hydrazine with substituted alkynes followed by cyclization reaction for production of indole (Scheme 1.49).

Scheme 1.49 Hydroamination reaction for synthesis of indoles

1.7.3 Titanium Catalyzed C-C Bond Formation Reactions

Extensive research has been carried out and is still continued to develop most convenient and sensitive/selective methodologies for C-C bond formation reaction. In this regard, titanium chloride proved to be an excellent catalyst. Claisen rearrangement and aldol addition reaction are most famous titanium based reactions

35

for generation of C-C bond formation. A brief discussion about both reactions is illustrated here:

 Pinacol Coupling Reaction

The use of titanium chloride to accelerate the reductive coupling of carbonyl compounds has steadily got importance in organometallic chemistry. In pinacol coupling reactions[120], reductive coupling of carbonyl compounds are catalyzed by titanium chloride to synthesize 1,2 diols under ambient conditions (Scheme 1.50). The reaction is powerful tool for production of numerous valuable natural products. Variety of titanium based reagents, and reductants have been tested for the reaction.

Examples include TiCl4-La-CH3COOEt under ultrasound irradiation, TiCl4/Zn system in THF, TiCl3-Mg in THF, aqueous TiCl3 in basic media, TiCl3 in dichloromethane,

TiCl4(THF)2-Zn in CH2Cl2, TiCl4-Mg(Hg) in THF, TiCl4–THF–Zn, TiCl4–THF–Al,

TiCl4(THF)2 with a low valent Ti Schiff base (TiCl3–Mg), TiCl3-Mg in ethanol, TiCl3

(DME)-1.5-Zn(Cu), and TiCl4-Bu4NI. The catalyst systems showed high diastereoselectivity and good to excellent yields in many cases.

Scheme 1.50 Ti catalyzed diol synthesis by reductive coupling of carbonyl compounds

 McMurry Coupling Reaction

McMurry coupling reaction involves production of alkenes from carbonyl compounds at moderate temperature. Initially, the reaction was reported by McMurry for reductive coupling of α,β -dialdehydes in the presence of TiCl3(DME)-1.5-Zn(Cu) (Scheme 1.51).

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Scheme 1.51 TiCl3 catalyzed McMurry coupling of α,β-dialdehydes

Later, the reaction was further explored by using different catalyst systems, substrates, reductants and reaction conditions. For example, Fleming and McMurry reported a reaction of different aldehydes with ketones in the presence of TiCl3-LiAlH4 catalyst.

TiCl3-C8K system is a superior catalyst for all carbonyl compounds, and is involved in key cyclization reaction for (+)-compactin generation. Some of the other effective catalytic systems involve TiCl4-Zn, TiCl3-Li-napthalene-THF reagent, and

SnCl2/TiCl3.

 Claisen Rearrangements Reaction

The charge induced pericyclic reaction of C-C bond formation is a valuable organic reaction which is catalyzed by titanium tetrachloride[121]. The Claisen reaction is an example of charge induced pericyclic reaction that involves synthesis of alkylated aldehydes by rearrangement of N-allylenamines and aldehydes (Scheme 1.52). The uncatalyzed aza claisen rearrangements require very harsh reaction conditions (250°C), whereas a catalyzed reaction to proceed even at room temperature.

Scheme 1.52 TiCl4 catalyzed Claisen rearrangment reaction

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 Asymmetric Aldol Addition Reaction

Titanium chloride catalyzed aldol addition reactions give quite high yields[122]. Asymetric aldol addition reaction of oxazolidinethione, N-acyloxazolidinone and thiazolidinethione propionates catalyzed by titanium tetrachloride to synthesize Evans or non-Evans syn product are reported during the last decade (Scheme 1.53).

Scheme 1.53 Asymetric aldol addition reaction

Variety of substrates and catalytic combinations with different quantities were tested.

The combination of 2.5 equiv of (-)-sparteine with 1.0 equiv of TiCl4 and 1 equiv of N-methyl-2-pyrrolidinone showed outstanding selectivity for the production of Evans syn aldol product. For non-Evans syn aldol products, the combination of 2 equiv of

TiCl4 with 1.1 equiv of (-)-sparteine provided best selectivity.

 Titanium Catalyzed Cycloaddition Reaction

Pericyclic reactions, catalyzed by titanium gained much importance during last few decades. Uncatalyzed reaction required high temperature or light for activation. Lewis acidic nature of titanium accelerates the pericyclic reactions. Titanium catalyzed reaction of alkenes containing an alkylthio group with electron deficient olefins for synthesis of organo cyclic compounds has been reported (Scheme 1.54). The reaction showed asymmetric 2+2 cycloaddition with high enantioselectivity.

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Scheme 1.54 Ti catalyzed 2+2 cycloaddition reaction

The reaction of a terminal 1,2-dienes with 1,3,5-cycloheptatriene to yield endo- bicyclo[4.2.1]nona-2,4-dienes has been reported to be catalyzed by TiCl4–Et2AlCl in benzene (Scheme 1.55)

Scheme 1.55 Ti catalyzed 6+2 cycloaddition reaction

The reaction was further explored by using same experimental conditions with modifying substrates such as 1,2-cyclononadiene.

Chan and coworkers (1979) reported the synthesis of functionalized arenes, for the first time, by cycloaddition reaction of silyl enol ethers with dielectrophiles, using titanium (IV) as a lewis acid (Scheme 1.56). Functionalized arenes are valuable class of organic compounds and have a wide range of applications in natural products (flavonoids), polymers (nylons), pharmaceutical products (α-tocopherol). The term formal is used because the reaction is not specific cycloaddition and to distinguish the reaction from the pericyclic cycloaddition reaction[123].

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Scheme 1.56 TiCl4 catalysis in cycloaddition of butadiene 159 with tetramethoxypropane 160

The 3+3 cyclization of butadiene 159 with tetramethoxypropane 160 is one of the acyclic approaches which have advantages over the other acyclic reactions. The reaction is used for synthesis of many important functionalized aromatics. For example, titanium tetrachloride catalyzed reaction of butadiene 162 with enone 163 is a valuable reaction for a synthesis of biphenyl derivative (Scheme 1.57).

Scheme 1.57 TiCl4 catalysis in 3+3 cycloaddition reaction

The significance of the reaction includes its excellent yields, moderate reaction conditions, high regioselectivity and commercial availability of the catalyst. TiCl4 shows significant affinity for carbonyl containing organic compounds, and has the ability to form five or six membered ring with dielectrophile, resulting in selective activation of one electrophilic centre than the other. The reaction was explored widely and used for synthesis of valuable functionalized arenes.

1.8 Theoretical Approaches for the Mechanisms of Zn Catalyzed Reactions

Zn catalysis gained a lot of importance in the last decade experimentally, but theoretical insights are still incomplete, and only a handful number of articles related to mechanistic studies are reported. Copolymerization of CO2 with epoxide is investigated theoretically by DFT studies with solvation corrections. The studies

40

showed that epoxide ring opening is the rate determining step and acetate group is accelerated by Zn. Chiral Zn catalyzed alkynalation of aldehyde such as acetaldehyde and propyne is computed theoretically which reveals that the formation of six membered complex is the rate determining step (Scheme 1.58).

Scheme 1.58 Mechanistic investigations of Zn catalyzed alkynalation of aldehyde

Zn catalyzed hydroamination of alkenes is investigated theoretically by means of DFT studies and alkene activation is found plausible with low activation energy, compared to alternative amine activation. Fridal Crafts reactions are also studied theoretically using MP3 semiemperical methods and it was found that the reaction involves iminium cation intramolecular cyclization. Scheme 1.59 shows the mechanism in which Zn catalyst facilitates the formation of iminium ions intermediate by the loss of benzotriazolyl (Bt) anion followed by intramolecular Fridal Craft reaction.

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Scheme 1.59 Mechanistic investigations of Zn catalyzed hydroamination of alkenes

Oxidative homocoupling reactions catalysed by Zn are investigated theoretically with the help of DFT methods. The calculations reveal that first transmetalation reaction proceeds by oxidative addition followed by second transmetalation reaction, which is also a key step of the reaction. The mechanism is shown in the scheme 1.60 in which Pd and organozinc participate in the reaction.

Scheme 1.60 Mechanistic investigations of oxidative homocoupling reaction

Zn catalysed hydrosilylation of imines are also investigated theoretically by DFT calculations. The calculations reveal the existence of N(H)……O(=P) interactions which orient the ketimine group to the catalyst. The hydride attack was found possible

42

from both re face or si face and the product configuration depends on the coordination style of the substrate (Scheme 1.61).

Scheme 1.61 Mechanistic investigations of Zn catalyzed hydrosilylation of imines

1.9 Theoretical Approaches for the Mechanisms of Ti Catalyzed Reactions

Theoretical studies on Ti catalyzed reactions are also not well explored. Most of the experimentally observed reactions need theoretical investigation for elucidating the operational mechanism. Some of the reactions for which theoretical studies are reported are discussed here: Titanium catalysed McMurry and pinacol coupling reactions have been investigated theoreticaly[124]. The results showed that nucleophilic mechanism is preferred over the competitive radical mechanism for C-C coupling reactions. Titanium catalyzed oxaza-Cope rearrangement of nitrosobutenes is investigated using DFT methods. Calculations demonstrated that concerted oxaza- Cope rearrangement mechanism proceeds compared to alternative sigmatropic shift, associative or dissociative pathways (Scheme 1.62).

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Scheme 1.62 Mechanistic investigations of Ti catalyzed oxaza-Cope rearrangement

Different cycloaddition reactions have been investigated theoretically. In this regard, variety of reagents has been tested for 2+2 cycloaddition of vinylidine. Incase of a polar reagent, donor-acceptor complex of vinylidine was formed with the titanium, whereas, for nonpolar reagents, the 2+2 cycloaddition was found preferred over the electrophilic-nucleophilic complex formation. Benzoylcyanation of aldehydes was also investigated, and it was found that Ti(OiPr)4 mixtures catalyzed the reaction in a non-Curtin–Hammett-like mechanism compared to the Curtin–Hammett-like mechanism.

1.10 Objectives

The main objectives of the work are:

1.10.1 Rationalization of the Experimental Regioselectivity

Our objective was to rationalize the experimentally observed regioselectivity for TiCl4 catalysis in 3+3 cycloaddition of butadiene 191 with enones 192 and 194 (Scheme 1.63).

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Scheme 1.63 TiCl4 catalysis in cycloaddition of butadiene 192 with enones 162 and 193

1.10.2 Rationalization of the Product Distribution in Zn(II) Catalyzed Oxidative Esterification

We were interested to rationalize the experimentally observed product distribution for Zn(II) catalysis in the oxidation of alcohols to form aldehydes and esters (ligand effect is also studied, Scheme 1.64)

Scheme 1.64 Zn catalysis in alcohols oxidation for aldehydes and esters formation

1.10.3 Comparison of Zn Catalysis with other Late Transition Metals Catalysis

Our objective was to compare the effect of Zinc catalysis with other late transition metal catalysis. We have studied the comparison for Zn(II) catalyzed alcohol oxidation to generate aldehydes and amides (ligandless study, Scheme 1.65)

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Scheme 1.65 Zn catalysis in oxidation of alcohols to amides

1.10.4 Prediction of New Reactions

Our aim was also to predict new reactions that are not reported previously, such as:

 Zinc(II) catalyzed oxidation of thioacetal to thioester (Scheme 1.66).

Scheme 1.66 Zn catalyzed oxidation of thioacetal to thioester

 Zinc(II) catalyzed oxidation of benzylamine to benzaldimine and guanidine (Scheme 1.67).

Scheme 1.67 Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine

1.10.5 Investigation of the Plausible Reaction Mechanism

We were interested to investigate the plausible mechanism for hydroamination and hydrogen activation followed by hydrogenation reaction of alkynes with amines catalyzed by Zinc(OTf)2 (Scheme 1.68).

46

Scheme 1.68 Zn catalyzed hydroamination-hydrogenation of alkynes with amines

47

Chapter 2

2 Computational Methodology

48

All calculations are performed with GAUSSIAN 09[125]. Optimization of geometries of the structures for TiCl4 catalyzed formal 3+3 cycloaddition of butadiene with enones is performed at hybrid B3LYP[126] with basis set 6-31G*. Geometries of the structures for Zn catalyzed oxidation reactions are optimized at hybrid B3PW91 using 6-311G**[127] basis set for carbon, nitrogen, hydrogen and oxygen, and SDDALL pseudopotential[128] for Zn, Br and I, unless otherwise noted. The B3PW91 method, consisting of three parameter hybrid functional of Becke in conjunction with the gradient corrected correlation functional of Perdew and Wang,[129] is chosen since it has been shown to reliably model the similar reaction using Ru metals[130].

Optimization of geometries of the structures for Zn(OTf)2 catalyzed hydroamination- hydrogenation of alkynes with amines is performed at hybrid B3LYP with basis set 6- 31G*. The method has been shown to reliably model the similar hydroamination reaction using Gold(I)[131]. Each optimized structure is confirmed (by frequency analysis at the same level) complex as a true minimum (no imaginary frequency) or a transition state (with one imaginary frequency). Intrinsic reaction coordinates (IRC) calculations are performed to confirm that the transition states connect to the right starting materials and products. IRC is performed until the stationary point was reached with RMS gradient less than 1×10-4. Stationary points located through IRC are then completely optimized at the above mentioned method. The reported energies for all structures of Ti catalyzed reaction and Zn catalyzed hydroamination- hydrogenation reaction are zero point corrected energies. The reported energies for all structures of Zn catalyzed oxidation reactions are Gibbs free energies. The unit used for all reported energies is kcal mol-1. The hydrogen atoms which are not necessary in all structures are eliminated to clarify the structures. The bond lengths of all structures are in the unit of Angstroms.

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Chapter 3

3 Results & Discussion

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3.1 Mechanistic Insight of TiCl4 Catalyzed Formal Cycloaddition Reaction of Silyl enol ether with Dielectrophiles

Substituted arenes are interesting group of organic molecules in natural products[132], polymers[133] and medicinal chemistry[134]. The traditional approaches for their synthesis involve substitution reaction of benzene scaffold. For example, nucleophilic [135] [136] substitution , electrophilic substitution reactions, and transition metal catalyzed coupling reactions[137]. However, these strategies suffer from some serious drawbacks such as activating/deactivating effects of electron-donating/withdrawing groups[138], sequences of multistep reaction, low yields and decreased availability of functionalized arenes as starting materials[139]. A significant alternative method is the ―acyclic strategy‖ for highly functionalized benzene synthesis, based on acyclic precursors. Mostly cyclocondensation reactions involve Dotz reaction [140], [2 + 2 + 2] cycloaddition reaction catalyzed by transition metals[117], [4 + 2] Danheiser alkyne cyclobutenone cyclization[141], 1,6-electrocyclization reactions[142], and cyclocondensations of dielectrophiles with dinucleophiles. However, these annulations proceed in harsh reaction conditions, require highly expensive catalysts, suffer from regiochemical ambiguities and lack of substrate generality.

The 3+3 cycloaddition of butadiene with enones is an important TiCl4 mediated one pot cyclization reaction based on the ―acyclic approach‖[143]. The significance of the reaction includes its high regioselectivity, excellent yields, moderate reaction conditions, and commercial availability of the catalyst. TiCl4 is an efficient Lewis acid and shows significant affinity for oxygen containing organic compounds. The catalyst is effective in many organic transformations[144], particularly in pinacol coupling reaction[120], pyrollidine synthesis[145], Claisen rearrangements and asymmetric aldol reaction[122]. The alkene production from molecular reductive coupling of carbonyl compounds are also prominent applications of titanium in organic chemistry. Chan and coworkers (in 1979) reported the synthesis of arenes by formal 3+3 cycloaddition of butadiene with enones, using titanium (IV) as a catalyst (Scheme 3.1.1)[123]. The reaction is widely used for synthesis of valuable functionalized arenes.

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For example, reaction of butadiene 159 with 160 delivers functionalized biphenyl compound 161.

Scheme 3.1.1 TiCl4 catalysis in cycloaddition of butadiene with tetramethoxypropane.

Similarly, a biphenyl derivative 164 can be generated (Scheme 3.1.2) by the reaction of butadiene 159 with enone 162. Despite much synthetic advancement, mechanistic details are very limited. A proposed mechanism by Langer and coworkers is presented in scheme 3.1.3. TiCl4 selectively activates one of the two electrophilic centers of the 1,3-dielectrophile by forming six membered chelation ring, which leads to the formation of exclusively one isomer and results in regioselective cyclization. Nature of the Lewis acid also affects the reaction pathway because specific functional groups are activated by specific Lewis acid.

Scheme 3.1.2 TiCl4 catalyzed regioselectivitive 3+3 cycloaddition of butadiene with enone

The proposed mechanism involves coordination of 202 with TiCl4 to give intermediate 203, which is then attacked by the terminal carbon atom of 159 to give intermediate 204. The 204 loses OSiMe3 moiety to deliver 205. Cyclization of 205 followed by aromatization in 206 deliver a functionalized arene (Scheme 3.1.3). The above mechanism allows to rationalize the regioselectivity of a particular formal [3+3] reaction, however, it is relatively silent regarding the different regioselectivities starting from two structurally similar substrates (Scheme 3.1.4, vide infra). Moreover,

52

the mechanism is based on a direct-conjugate addition of butadiene on dienophile. A competitive direct-direct 207, conjugate-direct 209 and conjugate-conjugate 210 addition (Figure 3.1.1) is not invoked in the mechanism.

Scheme 3.1.3 Proposed mechanism of TiCl4 catalyzed cycloaddition of butadiene with dienophile

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Figure 3.1.1 Four possible mechanisms of the titanium catalysis in cycloaddition of butadiene with dienophile

With the computational tools in hand, we became interested to investigate the mechanism of the formal [3+3] addition and the results are presented here. There appear no theoretical reports on the mechanism of the titanium catalyzed catalysis in cycloaddition of butadiene with dienophile.

DFT calculations are performed to gain mechanistic insight for the regioselectivity observed for the [3+3] cycloaddition of butadiene with enone (Scheme 3.1.4). An ortho phenyl substituted benzoate ester 164 is the dominant product from 162 (a methyl ketone) whereas para phenyl substituted benzoate ester 194 is the major product from 193. The regioselectivity is altered when methyl ketone is replaced with a trifluoromethyl ketone, 193.

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Scheme 3.1.4 Illustration of observed regioselectivities in catalysis in cycloaddition of butadiene with dienophile

A number of questions needs to be answered in order to logically investigate the mechanism; Is the silyl group in dielectrophiles 162 and 193 dynamic between the two oxygen atoms (162  162′ and 193  193′)? (Scheme 3.1.5) If yes, then which isomer is more stable? What is the stability order for these two isomers when they are bound to titanium? Is it a direct addition of 4 on 5, or a direct-conjugate or a conjugate-conjugate addition?

Scheme 3.1.5 Reversible silyl shifts between oxygens of enones 162 and 193

Therefore, in this study, we have attempted to address all these questions and the results are described below. However, to reduce the computational cost, SiMe3 group is replaced with SiH3. This simplification does not affect the results, (vide infra)

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3.1.1 Shift of the Silyl Group

α, β unsaturated ketones 162 and 193 can exist in isomeric species 162′ and 193′, respectively by the shift of the silyl group between two oxygen atoms (Scheme 3.1.6). The dynamic shift is studied both in the presence and absence of the transition metal (Ti) and it is observed that the shift of the silyl group both in fluorinated and non- fluorinated substrates, 193 and 162, respectively, is a kinetically favorable process even in the absence of the transition metal (titanium). A transition state for the silyl shift is found at activation energy of 2.91 kcal mol-1 from 162 (without titanium), the reaction is exothermic by 0.36 kcal mol-1. The low activation energy may be attributed to the close proximity of the silyl group to the keto oxygen in 162. The O1- Si bond (see Figure 3.1.2 for numbering) in the transition state slightly increases to 1.89Å compared to 1.73Å in 162. The O1-Si bond in the product 162′ is 2.27 Å. On the other hand, the O2-Si bond decreases to 1.88 Å in TS1 from 2.22 Å in 162, and finally to 1.74Å in 162′. The stronger bond of silicon with both oxygens may be another reason for low activation barrier

Figure 3.1.2 Numbering scheme for discussion and description of 1,2 and 1,4 addition

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Figure 3.1.3 Potential energy diagram for silyl shift between 162 and 162′. All values are relative to 162 at 0.0 kcal mol-1.

A similar behaviour is also observed for the fluorinated substrate 193. A transition state (Figure 3.1.4) for silyl shif is observed at a barrier of 4.06 kcal mol-1, and the reaction is exothermic by 0.9 kcal mol-1. A relatively higher activation barrier from 193 (compare 162162′) may be attributed to the trifloromethyl electron withdrawing effect which decreases the electron density on the keto oxygen. Therefore, the nucleophilic attack of the keto oxygen on the silyl group is relatively difficult. The shift of the silyl group in 162 and 193 is kinetically a favourable process even in the absence of transition metal.

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Figure 3.1.4 Potential energy diagram for silyl shift between 193 and 193′. All values are relative to 193 at 0.0 kcal mol-1.

3.1.2 Complexation with Titanium

Phenyl ketones 162′ and 193′ are more stable compared to their alkyl/trifluoroalkyl ketones 162 and 193, respectively, therefore, compounds 162′ and 193′ are anticipated as active species in the reaction. However, the situation is somewhat different after complexation with titanium. Although 162′ is more stable than 162; however, its titanium tetrachloride complex 211′ is relatively unstable by 2 kcal mol-1 compared to 211, a complex from 162. The greater stability of 211 relative to 211′ can be explained on the basis of attractive interaction between the hydrogens of CH3 with the chlorides of TiCl4. H—Cl bond distances are 2.89Å and 2.85Å (Figure 3.1.5).

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Figure 3.1.5 Potential energy diagram for complexation of 162 and 162′ with titanium to deliver 211 and 211′, respectively.

For 193, this reversal of stability on complexation with titanium is not observed. The complex of 193′ with titanium (214′) is still more stable than 214 by 0.38 kcal mol-1. The higher stability of 214′ over 214 is supportive to our hypothesis above that interaction of hydrogen of CH3 with the chlorides of TiCl4 is the main driving force for the higher stability of 211 over 211′. The attractive interactions (CH3---Cl) in 211 are replaced by repulsive interactions in 214 (CF3 with chlorides). These interactions are shown in Figure 3.1.6.

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Figure 3.1.6 Potential energy diagram for complexation of 193 and 193′ with titanium to deliver 214 and 214′, respectively.

In the next step of our mechanistic investigation, we analyzed the distribution of charges in 211, 211′, 214 and 214′ (shown in Figure 3.1.7) in order to predict the reactivity based on charge densities. In both 211 and 211′, the position of highest positive charge density is the carbon bearing the methyl group regardless of the fact whether this carbon is a keto carbon or silyloxy bearing carbon. In 211, C2 and C4 (see figure 3.1.2 for labelling) has 0.5 and 0.389 positive charges, respectively whereas in 211′, C2 and C4 bear 0.46 and 0.45 positive charges respectively. Since 211 is more stable and has higher positive charge on methyl ketone carbon therefore we believe that this isomer will be the active participating species in the reaction. For the fluorinated arene 214, the situation is quite opposite a high positive charge is observed on carbon bearing the phenyl ring (C4). In 214′, carbons 2 and 4 have 0.327 and 0.439 positive charges, respectively whereas in 214, carbons 2 and 4 bear 0.394 and 0.414 positive charges, respectively. Interestingly, both isomers (of any system) have similar sequence of charge distribution. Discussion in the subsequent section has been divided into fluorinated and methyl systems, and in each section, all possible routes for addition reaction are discussed in detail.

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Figure 3.1.7 Mulliken charges analyses on carbon 2 and 4 in 211, 211′, 214 and 214′

Fluorinated 1,3 dielectrophile explanation is given here:

3.1.3 Direct-Direct Addition of Fluorinated 1,3-Dielectrophile

The bis silyl ether 159 contains two oxygen atoms which are available for binding with titanium therefore, it is believed that the bis silyl ether binds to 214 before the reaction takes place. The titanium is penta coordinated in 214′ and the binding of 159 with titanium of 214 would generate an octahedral complex, 212. Coordination of oxygen with titanium is followed by loss of the silyl chloride. The literature reveals that octahedral complexes of titanium are well known and are quite stable. Complexation of 159 with 214′ generates an intermediate octahedral complex 212 where both oxygen atoms are in cis orientation. The distance between bond O1–Ti and O3–Ti are 2.12 and 2.38 Å. The large bond distance of siloxy-Ti may be due to steric reasons (Figure 3.1.8).

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Figure 3.1.8 Potential energy diagram for elimination of H3Si-Cl followed by C-C bond formation (212  216); All energies are relative to 212 at 0.0 kcal mol-1. Values in parenthesis correspond to trimethylsilyl substituted derivatives.

The chlorides–Ti bonds trans to oxy ligands are relatively short (2.24 Å) whereas other Ti–Cl bonds are somewhat elongated (2.29 and 2.32 Å, shown in Figure 3.1.8). The cis orientation of the oxy ligands is necessary for subsequent addition reaction. Any trans orientation of these groups will not be favorable for C–C bond formation. A chloride ligand on titanium in 212 is parallel to the silyl group at a distance of 3.29 Å. Activation energy 19.36 kcal mol-1 is required for the concomitant elimination of the silyl and chloride groups. The TS3 has the geometry very similar to 212 except the bond lengths change at the reaction site. The Ti–Cl bond elongates to 2.45 Åin TS3

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from 2.24 Å in 212. Cl–Si and O3–Si2 bond distances are 2.35 and 1.96 Å, respectively in the transition state. The reaction has low activation barrier, and easily accessible at room temperature. Moreover this step is also driven thermodynamically. The product of the reaction, 215 is 6.99 kcal mol-1 more stable than the starting material (212). The loss the silyl group generates an oxy ligands where both organic ligands are not well suited for C–C bond formation. Conformation changes are required to bring both organic fragments in proper orientation for C–C bond formation. This conformational change costs 7.66 kcal mol-1. The low activation energy 5.2 kcal mol-1 for the reaction may be attributed to relatively higher positive and negative charge densities on C4 and C6 carbons, respectively. The carbon-carbon bond being formed has 2.29 Å bond distance in the transition state. Some other bond lengths also change considerably during the C–C coupling reaction. The O3–Ti bond length increases from 1.78 Å in 215′ to 1.90 Å in the TS4 whereas the O1–Ti bond length decreases from 2.06 to 1.94 Å. Since we have replaced the trimethylsilyl group with SiH3 in order to reduce the computational cost, it was of interest whether this simplification affects the activation barriers, and may change the regioselectivities. Towards this end, activation barriers for the key step (1,2 or 1,4 (vide infra)) are studied with Si(CH3)3 groups as well, and the activation barriers are given in the parenthesis (see Figure 3.1.8). It is very obvious from Figure 3.1.8 that the activation barrier is not affected considerably by replacing trimethylsilyl (4.84 kcal mol-1) group -1 with SiH3 (5.20 kcal mol ). Moreover, the trends are unaffected.

Figure 3.1.9 Optimized geometries of 212, TS3 and 215

213 is believed to undergo an interesting rearrangement of OTiCl3 to the silyl group which subsequently delivers 217 by elimination of TiCl3(OSiH3). Although transition state for this oxy-titanium shift is located for methyl system (vide infra); however, no

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such transition state is located for fluorinated analogue. Rather, a true minimum 216 is observed in which oxytitanium is bound to both, silyl moiety and carbon 5. The O3–C5 and O3–Si1 bond distances are 2.66 Å and 3.04 Å, respectively. Thermodynamic cost for this shift is 16.42 kcal mol-1. 216 undergoes coordination of the 2nd silyloxy oxygen (O4) which is followed by elimination of another Si and Cl, very similar to the one observed in 212. The transition state for the elimination of silyl chloride (TS5) is not modelled here. The activation barrier for the elimination of silyl chloride is believed similar to the one observed in 212. The product of the silyl chloride elimination, 217 undergoes nucleophilic attack on the CF3–CO group. Kinetic barrier for the step is 26.56 kcal mol-1. The product (218) lies 18.7 kcal mol-1 lower in energy than 217 (Figure 3.1.10). The cyclized product is believed to undergo loss of a water molecule and finally tautomerization to deliver the product. The possibility of elimination of silyl chloride with concomitant cyclization to deliver the final product cannot be excluded safely.

Figure 3.1.10 Potential energy diagram for cyclization in 217 to generate 218. All energies are relative to 217 at 0.0 kcal mol-1.

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3.1.4 Direct-Conjugate Addition of Fluorinated 1,3-Dielectrophile

The competitive reaction for 215′ is direct-conjugate addition on enone fragment instead of a 1,2 addition. The activation barrier for C–C bond formation through 1,4 addition iss found higher compared to the 1,2 attack; 13.10 kcal mol-1 for 1,4 addition compared with 5.2 kcal mol-1 for the 1,2 attack. The higher activation barrier for 215′→219 (Figure 3.1.11) compared to 215–215′→213 may be due to steric crowding at the carbon bearing the siloxy and CF3 moieties, or may be due to electronic factors because of reduced charge density at keto carbon C2. The C6–C2 bond length is 2.39 Å in the TS7, compared to 2.29 Å in the transition state for the 1,2 attack, TS4. The titanium has trigonal bipyramidal geometry in TS7 where fluorine atoms of CF3 do not coordinate to the titanium. The reaction is thermodynamically favourable. The activation barrier for the similar reaction but involving Si(CH3)3 has a very similar activation barrier (12.37 kcal mol-1). These findings are consistent with those in Figure 3.1.7 that replacing a trimethylsilyl group with SiH3 does not change the activation barrier to alter the regioselectivities.

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Figure 3.1.11 Potential energy diagram for 1,4 addition in 215 to generated 218, followed by change in coordination to generate 219. Values in parenthesis correspond to trimethylsilyl substituted derivatives

218 undergoes elimination of O–SiH3 (next to CF3) and TiCl3 moiety to generate the species for the next step, 219. This process may be a direct one step process for the methyl ketone (vide infra) or may be a multistep process as in the case of trifluoro species. For the trifluoro species, first the silyl oxygen coordinates to titanium and a transition state TS8 has been located for this coordination. This is just an addition reaction because it does not involve elimination of any other group. The cyclic species undergoes cleavage of OSiH3 and TiCl3 to generate 220. In 220, a silyl group is parallel to a chloride on titanium, therefore elimination of silyl chloride generates the enolxy species 221. The geometry of 221 has some interesting features; C7 is coordinating with titanium at a distance of 2.34 Å, the carboxylate oxygen (O4) along with the ortho carbon C7 behave as bidentate ligand for titanium, the titanium in 221

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has distorted octahedral geometry. Nucleophilic attack of C7 on C4 in 221 generates the cyclic species 223. The reaction has kinetic demand of 33.20 kcal mol-1 (Figure 3.1.12). Although kinetically unfavorable, the reaction is highly favorable thermodynamically. The reaction is exothermic by 19.32 kcal mol-1. The high activation barrier is not possible to gain at room temperature which clearly illustrates that this is not the pathway which should be observed experimentally. The regioselectivity observed experimentally is in marked contradiction with the product obtained from 1,4 addition.

Figure 3.1.12 Potential energy diagram for intramolecular cyclization in 220 to generate 221, the energy values are relative to 220 at 0.0 kcal mol-1.

The 1,2 addition is a favorable pathway energetically, and it explains the right regioselectivity. Although the calculations above reveal that 1,2 attack of enol on the keto oxygen delivers the product which is observed experimentally yet there is another set of similar calculations but with CF3 ketone bound to titanium in the first

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step rather than a phenyl ketone. We have also considered this as a possible reaction in our study.

3.1.5 Direct-Direct Attack on CF3 Ketone

Calculations have been performed on a titanium bound complex starting from CF3 ketone, 222. Typically the nature and the number of steps are almost comparable to those for phenyl ketone regarding both 1,2 and 1,4 attack. We have repeated the same set of calculations for CF3 ketone to explore the associated kinetics and thermodynamics. The first step is elimination of silyl chloride from 222 for which activation energy of 19.67 kcal mol-1 is required from starting complex. The activation barrier is very comparable to the elimination of silyl chloride in 212 (19.36). Some of the important changes in bond distances on going to transition states are given in the table below (Table 3.1.1).

Table 3.1.1 Comparison of some important geometric parameters in 222 and TS10

Bond 222 TS10

Ti-Cl 2.24 2.45

Ti-O 2.36 2.00

O-Si 1.72 1.95

Si-Cl 3.31 2.35

Nucleophilic attack of enol on the C2 in 223′ is a kinetically favourable (Eact 6.22 kcal mol-1, see Figure 3.1.13) but this activation energy is slightly higher (1 kcal mol-1) - than activation energy for nucleophilic attack on phenyl ketone 215 (Eact 5.2 kcal mol 1). This difference in activation barrier may be attributed to the density of the positive charge of 214′ and 214 (vide supra). The important C6–C2 bond (being formed) has bond distance of 2.37 Å in the TS11 compared to 3.61 Å and 1.54 Å in 224 and 223′,

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respectively. The similar reaction using Si(CH3)3 group instead of SiH3 has the activation barrier of 6.63 kcal mol-1 (Figure 3.1.14).

Figure 3.1.13 Potential energy diagram of Ti catalyzed 1,2 addition of enol on CF3 ketone, All values are relative to 222 at 0.0 kcal mol-1.

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Figure 3.1.14 Comparison of potential energy diagram for 1,2 addition (223’  225) for SiH3 and SiMe3 (values in parenthesis) substituted systems, All energies are relative to 223’ at 0.0 kcal mol-1

The next key step in this pathway is the cyclization of 226 to 227, a reaction which generates the cyclic intermediate (227) from enol by nucleophilic attack (Figure 3.1.15). The calculated activation barrier for the cyclization is 20.60 kcal mol-1. This activation barrier is although high but still accessible under the reaction conditions. Although energetics associated with this pathway are not very high (may proceed under reaction conditions); however, its comparison with 1,2 attack on phenyl ketone (1,2 attack starting from 215) shows that this pathway is energetically less favorable. Moreover, the theoretical findings are consistent with the experimental regioselectivities (compare the structure of 227 and 218 with 217).

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Figure 3.1.15 Potential energy diagram for cylization in 226. All energies are relative to 226 at 0.0 kcal mol-1

3.1.6 Direct-Conjugate Attack on CF3 Ketone

The 1,4 attack on CF3 ketone is expected to be kinetically demanding, although it delivers the desired product. The 1,4 addition on CF3 ketone is also modeled, and found to have high activation barriers (see Figure 3.1.16 and 3.1.17). The first 1,4 attack has an activation barrier of 15.99 kcal mol-1. This high activation barrier is expected because this reaction not only involves 1,4 attack which is kinetically demanding but it involves intermediate 223′ on which attack is even more demanding kinetically.

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Figure 3.1.16 Potential energy diagram for 1,4 addition on 223’ (223’  228). All energies are relative to 223’ at 0.0 kcal mol-1.

Figure 3.1.17 Potential energy diagram for cyclization in 229 (229  218), All energies are relative to 229 at 0 kcal mol-1.

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3.1.7 Conjugate-Conjugate Attack on CF3 Ketone

The possibility of conjugate-conjugate addition have also been studied and found to have very high activation barrier. The activation energy for the first transition state (Figure 3.1.18) is calculated as 19.84 kcal mol-1(much higher than any of the above three mechanisms). This high activation barrier is not un-expected because the catalyst has indirect effect on active centers of the reaction. However, the reaction is favorable thermodynamically. The next key step of the reaction, such as cyclization reaction is even more energy demanding. The activation energy required for this step is 35.73 kcal mol-1 (Figure 3.1.19).

Figure 3.1.18 Potential energy diagram for conjugate-conjugate addition on 230 (230  231). All energies are relative to 230 at 0.0 kcal mol-1.

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Figure 3.1.19 Potential energy diagram for cyclization in 232 (232  218), All energies are relative to 232 at 0.0 kcal mol-1.

Analysis of the pathways, shown above, clearly indicates that the charge density shown in Figure 3.1.7 is a good tool to predict the regioselectivity. Moreover, pathways with 1,2 attack on ketone are energetically more favorable whereas conjugate addition is thermodynamically less favorable.

 Methyl system

From figure 3.1.7, it is apparent that the methyl ketone 211 has higher Mulliken charge density on C2; therefore, this structure is only considered for mechanistic studies. The phenyl ketone 211′ is not considered for all the possible routes such as direct-direct, direct-conjugate, and conjugate-conjugate attack because higher activation barriers are expected than 211 (vide supra). Moreover, the regioselectivity expected through a 1,2 attack is in contradiction to what is observed experimentally.

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3.1.8 Direct-Direct Addition on Methyl Ketone

The first step is typically cleavage of a chloride and a silyl group in 233. The titanium in 233 has an octahedral geometry where both oxygen ligands are cis to each other. The O3–Ti–O2 bond angle is 81.77 degrees. The O3–Ti and O2–Ti bond lengths are 2.40 and 2.06 Å, respectively. The Ti–Cl (trans to oxy ligands) bond lengths are in the range of 2.24–2.25 Å whereas the other chloride–titanium bond lengths are 2.30– 2.31 Å. One of the chlorides is bent towards silyl group primarily because of the dipole dipole interactions (Figure 3.1.20).

Figure 3.1.20 Optimized geometries of 233, TS17, 234 and TS18

The activation energy for a transition state for the cleavage of silyl chloride in 233 is calculated as 18.74 kcal mol-1 (from 233, see Figure 3.1.21). In the transition state TS17, Cl–Ti bond distance increases to 2.46 Å. The alkoxide–titanium bond distance decreases to 2.01 Å in TS17. The geometry around titanium also changes. The Cl–Ti– O3 (silyl) angle drops to 159.0 degrees in TS17 from 176.18 degrees in 233. This activation barrier for the cleavage of a silyl and a chloride is very comparable to the one observed for the tri- fluoro system (vide supra). These findings clearly illustrate that the cleavage is not significantly influenced by the structure of the complex. The reaction is exothermic by 6.5 kcal mol-1. The complex 234 has trigonal bipyramidal

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geometry around titanium. The two chlorides and alkoxide ligands do not make a perfect trigonal planar structure. O–Ti–Cl bond angle is 115 degrees, whereas Cl–Ti– Cl bond angle is 127.65 degrees. Two chlorides and the alkoxide ligands are in one plane (trigonal). The third chloride and keto oxygen atoms are in the perpendicular plane. The alkoxide–Ti and keto–titanium bond distances are 1.74 and 2.14 Å, respectively. The subsequent C–C bond formation in 234 has kinetic demand of 11.23 kcal mol-1 and the product is thermodynamically favourable by 12.03 kcal mol-1. In the TS18, the C2–C6 bond distance is 2.23 Å. Moreover, the O3–Ti and O3–C5 bond distances are 1.88 and 1.31 Å, respectively. The newly formed O2–Ti and C2–O2 bond distances are 1.94 and 1.30 Å, respectively. The 235, generated as a result of C– C bond formation, undergoes an interesting cleavage/shift of titanium oxy group on the silyl group. This shift is predicted to have a kinetic demand of 19.12 kcal mol-1. The O1–C2 bond length in transition state is 2.15 Å whereas the O2–Si1 bond distance is 3.17 Å. The titanium oxy groups interact very loosely with the silyl groups, as it is reflected with bond separation in the TS, and is remarkably different than what is observed for the trifluoromethyl analogue. In the case of trifluoromethyl system, this type of transition state is not observed rather an intermediate is observed in which titanium oxy species is located between carbon and silyl group (vide supra).

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Figure 3.1.21 Potential energy diagram for elimination of silyl chloride followed by 1,2 addition of enol to methyl ketone to generate 235. All energy values are relative to 233 at 0.0 kcal mol-1

It is believed that the 236 generated in the above step (Figure 3.1.22) soon loses

Cl3Ti–OSiH3 species and binds to TiCl4 to generate 237, as a precursor for the next step. Cleavage of a silyl and chloride in 238 generates an intermediate 239 ready for cyclization.

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Figure 3.1.22 Potential energy diagram for migration of OTiCl3 to silyl moiety in 236 to generate 237. All energy values are with respect to 236 at 0.0 kcal mol-1

Cyclization in 236 is a kinetically and thermodynamically favorable process (Figure 3.1.23). In the TS20, Ti gain trigonal bipyramidal geometry where two chlorides and an oxo ligand lie in the plane of trigon; however, the CH and chloride ligands are in the vertical axis. The CH–metal bond distance increases to 3.02 Å in the transition state from 2.22 Å in 236. Moreover, the CH and keto carbon bond distance is 2.87 Å which indicates a very early transition state. The calculated activation barrier for the cyclization is 19.54 kcal mol-1. Dehydration and tautomerization in 239 may deliver the final aromatic product.

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Figure 3.1.23 Potential energy diagram for cyclization in 238. All values are with respect to 238 at 0.0 kcal mol-1

3.1.9 Direct-Conjugate Addition on Methyl Ketone

Complex 234 generated by the loss of a silyl chloride molecule can also undergo a 1,4 addition on the α, β unsaturated ketone to deliver intermediate 240 which is thermodynamically more stable than the intermediate 234 by 3.03 kcal mol-1. The reaction has kinetic demand of 19.57 kcal mol-1 which is higher than the kinetic demand for the 1,2 addition in 234′ (11.23 kcal mol-1). These observations are also consistent with the theoretical calculations for the trifluoromethyl system (vide supra) where direct attack is more favorable than the 1,4 addition. From these calculations, one can infer that 1,2-addition is a more feasible pathway compared to 1,4-addition for these formal [3 + 3] addition reactions (1,4 addition). The difference in activation barrier for 1,2 and 1,4 attack is 8.34 kcal mol-1 for the methyl system whereas this difference is about 7.9 kcal mol-1 for the trifluoromethyl analogue. The subsequent cyclization has a calculated activation barrier of 19.72 kcal mol-1 which is not

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significantly different than the one calculated for the cyclization in 238 which clearly illustrates that the selectivity is governed at the first addition step of the formal [3 + 3] addition reaction. The 1,2 addition (1,2 addition), shown in Figure. 3.1.21 and 3.1.22, delivers the product with the experimentally observed regioselectivity. The 1,4 addition (shown in Figure 3.1.24) does not deliver the product with the correct regioselectivity. These findings are consistent with our the calculations that 1,2 addition is a favourable process with lower activation barriers compared to the 1,4 addition.

Figure 3.1.24 Potential energy diagram for Ti catalyzed 1,4 addition of enol to enone in 234. All values with respect to 234 at 0.0 kcal mol-1

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3.1.10 Conjugate-Conjugate Addition on Methyl Ketone

Conjugate-conjugate attack is also studied for the key steps of the reaction. Transition state for nucleophilic attack required activation energy 17.61 kcal mol-1 (Figure 3.1.25), barrier higher than for direct-direct attack but lower than direct-conjugate attack. The product of the reaction also did not show the desired regioselectivity. The second transition state is found at a very high barrier of 51 kcal mol-1 (Figure 3.1.26). The mechanism is also not favorable thermodynamically.

Figure 3.1.25 Potential energy diagram for conjugate-conjugate addition on 242 (242 → 243). All energies are with respect to 242 at 0 kcal mol-1

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Figure 3.1.26 Potential energy diagram for cyclization in 244 (244  245), All energies are relative to 244 at 0.0 kcal mol-1.

In summary, we have shown that the experimentally observed different regioselectivities for CH3 and CF3 enones can be explained by a common mechanism where 1,2 addition of silyl enol ethers on dielectrophiles is a more favorable pathway than the competing conjugate addition. The differences in regioselectivities originate from different isomeric structures of enones entering in the catalytic cycle. 3.2 Mechanistic Investigation of Zn(II) Catalysis in Alcohol Oxidation to form Aldehydes and Esters

Esters represent an important class of organic compounds and find applications in fine and bulk chemical industries, fragrances, essential oils, pheromones, pharmaceuticals, agrochemicals[146], plastics and textile industries. Conventional methods[147] of preparing esters generally involve tedious procedures and produce toxic wastes[148]. Over the time, several sophisticated strategies have appeared in the literature to build the ester bond, mainly through transition metal catalysis[149].

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Recently, palladium catalyzed direct oxidative cross esterification of benzylic and aliphatic alcohols was reported independently by Beller[150] and Lei[151]. In the direct oxidative cross reaction, oxygen was used as an oxidant and esters were prepared in good yields. The reaction involves the oxidation of alcohol to aldehyde, and the resulting aldehyde then reacts with another molecule of alcohol to form the hemiacetal, which on further oxidation delivers the ester product. The reaction is environmentally benign with high atom economy without the need for any activating agent. The concept of oxidation (dehydrogenation) of alcohols is more than 100 years old (Guerbet Chemistry)[152] but its elegant use in ester and amide formation has not been realized until recently. Several other late transition metals have been used for similar oxidation reactions[150,151,153].

Since the catalysts used in the oxidative transformation (mostly Pd, Ir, Ru, and Au) are expensive, therefore, the reactions are not economically viable, particularly on an industrial scale. An important factor in the large scale utilization of these reactions is the cost of the catalyst; therefore, recent study is more focused towards the exploration of cheap, non-toxic and environmentally benign catalysts, particularly those based on biorelevant metals such as iron, zinc, and copper. In this regard, Yefeng Zhu et al. have reported a copper metal based catalyst for the selective oxidation of alcohols to esters, and the selectivity was further extended to benzylic alcohols in DMF[87] More recently, alcohol oxidation to aldehyde and ester through zinc( II) catalyst has also been reported (Figure 3.2.1), where H2O2 is used as the terminal oxidant.

Zinc catalysis, in general, is not well explored, compared to other transition metal catalysis;[154] however, a shift in the trend has been observed recently. The importance of zinc catalysis has been demonstrated in several recent reports, including oxidative transformations. The oxidation of alcohols to aldehydes and esters is achieved with zinc bromide and H2O2 as catalyst and oxidant, respectively. In a similar approach, aromatic aldehydes have been converted to esters through zinc catalysis[155]. Zinc mediated oxidation of ether to aldehydes is also an interesting transformation[156]. Although experimental reports have started to emerge, the literature reveals only a handful number of theoretical mechanistic studies on zinc catalyzed reactions. In

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particular, there have been no theoretical reports on the mechanism of any Zn(II) mediated oxidation reactions. A computational study of the zinc(II) catalysis for oxidation of alcohols to form esters and aldehydes under H2O2 and pyridine-2- carboxylic acid ligand is presented here. The main interest behind this study is to compare the mechanism of the zinc catalyzed reaction with other metals.

Figure 3.2.1 Zinc catalyzed oxidation of alcohols to esters (ligand (L) = 79-83)

To find out the exact mechanism for the synthesis of 78 from 76 (Figure 3.2.1), DFT calculations have been performed at B3PW91 level of theory. Theoretical studies on oxidative esterification and amidation with other late transition metals (Ru, Pd, and Au) have already been reported. A key step in these oxidation processes is the transfer of hydrogen from alcohol to either metal or to some other recipient. Hydrogen transfer is a broad area of catalysis, and finds application in several transformations other than esterification and amidation of alcohols. Several mechanisms have been proposed and investigated for the hydrogen transfer; however, they can be broadly classified into inner sphere, outer sphere and intermediate sphere mechanisms[157]. A schematic presentation of inner, outer and intermediate sphere mechanisms for conversion of benzylic alcohol to benzaldehyde through zinc catalyst is given in Figure 3.2.2. In an inner sphere, mechanism, a coordinated alcohol delivers a β hydride to metal. In the

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outer sphere mechanism[158] , the alcohol delivers a hydride to the metal, but without being coordinated to the metal. Both inner sphere and outer sphere mechanisms involve the transfer of hydride to metal, however, there is another mechanism in which oxidation takes place by transferring of hydrogen to a hydrogen acceptor, instead of a metal. In the intermediate sphere mechanism, both hydrogen donor and acceptor coordinate to metal and exchange of hydrogen takes place. In this mechanism, metal acts only as a template to hold the hydrogen donor and hydrogen acceptor species. A classic example of the intermediate sphere mechanism is Meerwein Ponndorf Verley (MPV) reaction.

Eisenstein and coworkers have reported a theoretical study on the mechanism of Ru catalyzed dehydrogenative amide formation from alcohols. The catalytic cycle is shown in Figure 3.2.3. Both inner and outer sphere mechanisms are shown to operate. However, a bifunctional double hydrogen transfer mechanism is shown to operate for ruthenium dehydrogenation catalyst, originally discovered by Milstein. The most crucial step in the catalytic cycle is the β-hydride elimination from the coordinated alcohol to the transition metal. The two most important requirements of β-hydride elimination are; presence of a vacant coordination site and a d electron. Based on this, one would not expect any zinc species with more than three ligands to be an active catalyst because any such species will be 18e or higher species. Although the literature reveals up to 22 electron octahedral complexes of zinc, however, their catalytic role is not well established. A general numbering scheme for discussion of compounds in this manuscript is given in Figure 3.2.3.

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Figure 3.2.2 Zn catalyzed inner, intermediate and outer sphere mechanisms

Figure 3.2.3 Catalytic cycle for metal [Ru] catalyzed dehydrogenative ester formation.

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Figure 3.2.4 Numbering of the atoms of the structures under discussion

The experimental reaction conditions show that the oxidative esterification reaction may be carried out in ZnBr2 alone, without any added ligand, but the yields are low. Addition of ligands 79-83 significantly improves the conversion yields. Efficiencies of ligand 79 and 82 are much better than 80, 81 and 83. Because the efficiencies of ligands 79 and 82 are comparable, ligand 79 is used for this study to reduce the computational cost. In the study by Wu, H2O2 is used as the oxidant. In a similar report on oxidative amide formation from alcohol and amine, ZnI2 and TBHP are used as the catalyst and oxidant, respectively. In this study, mechanistic details of a ZnBr2 catalyzed reaction in the presence of TBHP oxidant are studied and the effects of ligand, oxidants (TBHP and H2O2) halides (Br2 and I2) and catalyst are also explored.

3.2.1 Inner Sphere Mechanism

Initially, we studied the inner sphere mechanism for zinc catalysed oxidation of alcohol to ester (Figure 3.2.5). The complex 253 is an eighteen electron complex and has a distorted tetrahedral geometry around the zinc atom. The complex 253 has another isomer 254, which is lower in energy than 253 by 19.01 kcal mol-1. A proton from carboxylic oxygen (O8) in 253 is shifted to O1 in complex 254. The complex 254 is occasionally obtained during the optimization of complex 253. The activation energy to gain a transition state TS28 for β-hydride elimination by zinc is calculated as 31.78 kcal mol-1 from 253. The considerably higher energy than the one reported for the ruthenium based catalyst (8.80 kcal mol-1). The high activation barrier is not unexpected because the ability of transition metals to abstract β-hydride decreases from left to right in the periodic table; moreover, it is expected to be small for zinc.

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There are certain marked differences in the transition states for Ru and Zn based species. The transition state for β-hydride elimination to ruthenium catalyst is a very early transition state with geometry very similar to the starting material, whereas the zinc based transition state is almost in the middle. The geometry around zinc in the transition state is close to distorted square pyramid. The C2–H6 bond is considerably elongated to 1.73 Å in the transition state from 1.10 Å in 253. Moreover, the Zn–H6 and O–Zn bond distances are 1.69 Å and 2.13 Å, respectively. A few important structural parameters are given in Table 3.2.1. The geometry around zinc in 11 is distorted tetrahedron. The aldehyde product is no longer in coordination with the metal centre and shows hydrogen bonding interaction with the carboxylic acid moiety of the ligand. N7–Zn–H6, O1–Zn–O8 and N7–Zn–O8 bond angles are 116.24°, 113.35° and 72.15°, respectively. The hydride shift on zinc is also thermodynamically uphill by 4.04 kcal mol-1 from 253.

Figure 3.2.5 Energy profile for oxidation of alcohol to aldehyde through β-hydride elimination (inner sphere mechanism) by zinc catalyst. All energy values are relative to 253 at 0.0 kcal mol-1.

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Table 3.2.1 Selected bond lengths of 253, 255 and TS28. All values are given in Angstroms

Bond 253 TS28 255

C-H 1.10 1.73 5.11

Zn-H 3.08 1.69 1.54

Zn-O 1.84 2.13 4.16

C-O 1.40 1.27 1.22

Effect of TBHP and H2O2 has also been investigated. Complex 256 is an 18 electron species with four coordinated groups such as bromide, oxygen of oxyligand and two oxygen atoms of TBHP with distorted tetrahedral geometry (Figure 3.2.6). Benzene ring shows some interaction with the metal through its π electrons. Complex 256 does not show any vacant space for hydride shift on metal due to the bending of benzene ring towards metal and coordination of two oxygen atoms of TBP. Rotation of benzene ring occurred in the transition state TS29 to promote hydride shift. In TS29, an alcohol delivers hydride to Zn center and is located at a barrier of 33.73 kcal mol-1. The bond distance of Zn-H9 reduces to 1.67 Å from 2.23 Å in the 256, and C2-H9 bond distance elongates to 1.67 from 1.01 Å. The The high activation barrier is attributed to many reasons such as; very congested space for hydride accommodation, increased number of ligands and electron count of Zn in TS29. The two most important requirements of β-hydride elimination are; presence of a vacant coordination site and a d electron. Based on this, one would not expect any zinc species with more than three ligands to be an active catalyst because any such species will be 18e or higher species. Although the literature reveals up to 22 electron

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octahedral complexes of zinc, however, their catalytic role is not well established. The reaction is thermodynamically favorable. Decoordination of alkoxy ligand, water molecule and aldehyde is expected in the next steps. Changing the oxidant to H2O2 decreases the activation barrier but the effect is not much significant. The activation energy for this step is calculated as 31.37 kcal mol-1 and energy of the reaction is calculated as -81.89 kcal mol-1.

Figure 3.2.6 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination in the presence of TBHP.

We have also compared the reaction in the absence of both oxidant and ligand. ZnBr2 (14 electron species) is used as a catalyst. The reaction starts with the exchange of bromine with oxyligand to generates ZnBr(OR) 258, an active species that enters into the catalytic cycle. Oxyligand increases the electron counts on metal center. The benzene ring also coordinates with the metal through the carbon bearing the hydroxymethyl substituent (C3) and shows interaction with the Zn through its π

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electrons. Zn–O1–C2–C3 dihedral angle is 0.16 degrees and C3–Zn bond distance is 2.82 Å. The complex is neither a perfect T-shaped structure nor a trigonal planar probably because of the weak coordination of benzene to zinc. The I–Zn–O1 bond angle is 169.35 degrees. The complex 258 changes its orientation to facilitate the hydride shift by minimizing the interaction of benzene with the metal center. Complex 258a shows the required compound in which the benzene ring is no longer interacting with the zinc atom. The Zn–O1–C2–C3 dihedral angle in 258a is 179.94 degrees and the I–Zn–O1 bond angle is 175.34 degrees. The hydride shift is not possible in 258 because of the non-availability of vacant site due to geometric constraints. Whereas in the 258a, enough vacant space is available for hydride occupation because benzene ring is now far away from metal center leaving the space for hydride (Figure 3.2.7).

Figure 3.2.7 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination, All energy values relative to 258 at 0.0 kcal mol-1

The hydride in 258a is aligned properly for transfer to zinc. The zinc species 258a lies 5.82 kcal mol-1 unstable compared to 258. A TS30 is found at activation barrier of 31.08 kcal mol-1 with respect to 258a, for the hydride elimination by zinc to generate

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the aldehyde coordinated species 259. The transition state is almost middle. C2–H and Zn–H bond distances are 1.62, and 1.68 Å. Moreover, bond length of O–C2 bond decreases to 1.30 Å in the transition state from 1.41 Å in 258a. I–Zn–O1 bond angle is 134.98 degrees. The total activation barrier from 258a to TS30 is very high and the reaction conditions (40°C, 16 h) are not expected to provide these thermodynamic requirements, therefore it is believed that the mechanism shown above (inner sphere) is not a plausible one. Moreover the reaction is thermodynamically uphill. The next step involves introduction of TBHP into the catalytic cycle, followed by hydride shift from metal center towards TBHP (Figure 3.2.8), decoordination of alkoxy ligand, aldehyde and water from the complex.

Figure 3.2.8 Removal of water molecule.

The generated aldehyde reacts with an alcohol to produce the hemiacetal. The reaction involves nucleophilic attack of the alcohol group on electrophilic center of aldehyde. The activation of aldehyde is attributed by the metal to facilitate the nucleophilic attack of oxygen. The reaction does not have any significant effect on activation energy, therefore their computational study is not required. Hemiacetal coordinates with the metal and undergoes dehydrogenation reaction in a similar fashion as observed in the first dehydrogenation step to give the product ester (Figure 3.2.9). Transition state TS31 is found at activation barrier of 29.11 kcal mol-1 which is slightly less than the one associated for 258 to 259 however yet unaccessible under reaction conditions. Moreover, the reaction is also thermodynamically not favorable.

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Figure 3.2.9 Energy profile for oxidation of hemiacetal to ester through β-hydride elimination by zinc catalyst. All energy values are relative to 262 at 0.0 kcal mol-1

Replacement of bromide with iodide did not show any significant effect. The kinetic demand for the first transition state using ligand is 29.78 kcal mol-1. TBHP presence -1 increases the energy to 34.59 kcal mol , while replacing TBHP with H2O2 decreases the activation barrier to 32.87 kcal mol-1. The activation barrier and trend of decreasing order is also comparable with the bromide. In the absence of ligand and oxidant, iodide based catalyst showed 33.09 kcal mol-1 activation energy and thermodynamically uphill process (5.96 kcal mol-1). Because the reaction is carried out experimentally at room temperature, the kinetic barrier for β-hydride elimination is very high to be accessible under the reaction conditions. Therefore, β-hydride elimination (inner sphere) is not believed to be a plausible mechanism.

3.2.2 Intermediate Sphere Mechanism

The kinetic barrier of the inner sphere mechanism is very high to be accessible under the experimental reaction conditions; therefore, the intermediate sphere mechanism is envisaged. In the intermediate sphere mechanism, the hydrogen acceptor (TBHP in this case) also coordinates to the metal. Complex 264 is an active species that enters into a catalytic cycle with 20 electrons and a distorted square pyramid type structure (Figure 3.2.10). The alkoxide oxygen (O1) is strongly coordinated to zinc at the distance of 1.94 Å. An oxygen atom of TBHP (O9) is weakly coordinated to zinc

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(2.45 Å), and the other OH (O10) proton interacts with the bromide ligand. Complex 265 is an isomer of 264 that is structurally similar to 264 except that a proton from O8 is shifted to O1 and is more stable than the complex 264. The kinetic barrier (23.06 kcal mol-1) is remarkably low and easily accessible under the reaction conditions than the kinetic barrier in the absence of a ligand. In the transition state, C2–H6 and O9– O10 bonds are elongated to 1.25 and 1.85 Å, respectively. An ortho hydrogen of the pyridine moiety also shows interaction with O10 of TBHP (2.10 Å). The reaction is thermodynamically favorable by 68.56 kcal mol-1 from 264. The high energy of reactions may be due to the factors as follows: the weak O9–O10 bond in the starting complex 264 is replaced by the strong O–H bond, and the OH moiety generated during the reaction is also coordinated to the metal.

Figure 3.2.10 Energy profile for the oxidation of alcohol to aldehyde through intermediate sphere mechanism. All energy values are relative to 265 at 0.0 kcal mol-1

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The next step is the reaction of generated aldehyde with another alcohol to generate hemiacetal followed by the exchange of a proton with a hydroxyl ligand to form an alkoxy ligand. The reaction is same as mentioned in ligandless ZnBr2 catalyzed reaction and is kinetically less demanding step. Next, we studied the ester formation process that is very similar to the transformation of 264 to 266. Complex 267 is the active specie for this reaction (Figure 3.2.11). The kinetic demand for the reaction is calculated as 18.75 kcal mol-1 . The structural features of TS33 are very similar to that of TS20-22, however activation barrier and energy of reaction are considerably low compared to TS32.

Figure 3.2.11 Energy profile for the oxidation of hemiacetal to ester through intermediate sphere mechanism. All energy values are relative to 267 at 0.0 kcal mol-1

Next, we have studied the reaction coordinates in the absence of a ligand. Complex 269 is an 18 electron complex with a distorted tetrahedral geometry around the zinc atom (Figure 3.2.12). The oxygen of alkoxide (O1) is in strong coordination with the metal (1.85 Å) compared to the oxygens of TBHP (O9 and O10) shows weak coordination (2.91 and 2.18 Å). TBHP also interacts with the oxygen of benzyloxy ligand through hydrogen bonding. Benzene ring is bended towards metal in the complex 269 but changes its orientation in the transition state (TS34) to avoid its

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interaction with the zinc atom. This change in orientation is necessary to facilitate the hydride shift. The hydride in TS34 is aligned properly for transfer to TBHP. The Zn– O1–C2–C3 dihedral angle in 25 is -42.92 degrees and the I–Zn–O1 bond angle is

155.44 degrees. The kinetic demand for the transition state TS34 for the hydrogen shift to TBHP and O9-O10 bond breakage is 28.50 kcal mol-1. H6 is between O9 and C2 with a bond distance of 1.51 and 1.21 Å respectively. The O9-O10 bond is considerably elongated (1.82 Å compared to 1.44 Å in 269). The overall reaction is highly exothermic. The high exothermicity may be attributed to several factors. A weak O6–O7 bond is broken and replaced with metal–oxygen bond, and an OH bond. Moreover the water produced in this reaction is in hydrogen bonding with the oxygen of the butyloxy ligand.

Figure 3.2.12 Energy profile for the oxidation of alcohol to aldehyde through intermediate sphere mechanism. All energy values are relative to 269 at 0.0 kcal mol-1

The zinc species 270 undergoes a ligand exchange with hemiacetal (generated by reaction of aldehyde with alcohol) to generate the species 271 for the next transformation. The zinc atom in 271 has four ligands (Br, OH and two OR)

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coordinated to it, and the geometry is distorted tetrahedral (Figure 3.2.13). The transition state (TS35) is unsymmetrical and O–H bond distances are 1.22 and 1.19 Å respectively. An exchange of oxy ligands between 271 and 272 is a kinetically and -1 thermodynamically highly favorable process (Eact = 1.19 kcal mol only) (Energy of the reaction = -1.24 kcal mol-1). The low energies of reaction and activation may be attributed to the very similar nature of both ligands involved in the reaction (geometry details).

Figure 3.2.13 Energy profile for the exchange of hydrogen shift between ligands, All energy values are relative to 271 at 0.0 kcal mol-1

Complex 272 undergoes decoordination of butanol followed by coordination of TBHP to generate the active species 273 for the subsequent hydrogen shift to TBHP. The O1–Zn and O9–Zn bond distances are 1.93 and 2.26 Å, respectively. The kinetic demand for the reaction is 26.37 kcal mol-1 for hydrogen transfer to TBHP and concomitant breakage of O6–O7 bond (Figure 3.2.14). The activation barrier is lower than the barrier associated with the transformation of 261 to 262. Bond lengths in the transition state TS36 are not very different from TS36. The C1–H6 and O9–H6 bond lengths are 1.23 and 1.50 Å respectively.

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Figure 3.2.14 Energy profile for the oxidation of hemiacetal to ester through intermediate sphere mechanism. All energy values are relative to 273 at 0.0 kcal mol-1

Changing the oxidant with H2O2 decreases the activation barrier. Transition state for oxidation of alcohol to aldehyde is obtained at activation energy of 22.63 kcal mol-1 in the presence of a ligand. Second oxidation reaction is found at activation barrier of 21.99 kcal mol-1. Replacement of bromide with iodide decreases the activation barrier for dehydrogenation of alcohol to aldehyde (18.75 kcal mol-1) but increases the activation barrier of ester formation (21.53 kcal mol-1). Ligandless mechanism with iodide showed the same activation barrier for alcohol dehydrogenation step as ZnBr2 catalyzed reaction (28.50 kcal mol-1). However, activation barrier for ester formation -1 step is high (30.13 kcal mol ) compared to ZnBr2 catalyzed ester formation.

3.2.3 Outer Sphere Mechanism

Although the activation barrier associated with intermediate sphere mechanism is marginally accessible but we have also explored the outer sphere mechanism in order to search for more plausible mechanism under the reaction conditions. Outer sphere mechanism involves hydride shifts to metal vacant site without coordination of alcohol with Zn. The mechanism operates by proton abstraction of tert-butyl peroxide

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(TBP) ligand by iodide. Complex 275 is an active specie in which Zn is coordinated with five atoms, two oxygen atoms of TBP, one oxygen and one nitrogen of the ligand and one bromide. O1 is at a distance of 4.25 Å from the metal which shows that alcohol is not coordinated with the metal. The kinetic demand for the concerted transition state (simultaneous proton and hydride shift to TBP and Zn) TS37 is 28.50 kcal mol-1 (Figure 3.2.15). The Zn-H6 bond length shortens to 1.64 Å in TS37 from 4.28 Å in 275. The O1–H12 and C2-H6 bond length increases to 1.45 and 1.60 Å in TS37 from 0.97 and 1.09 Å in 275, which shows the transfer of proton from O1 towards O10 and hydride from C2 towards Zinc. The high activation energy may be attributed to steric effect due to the presence of the ligand. The product 376 shows interaction of O1-H12 having 1.72 Å bond distance and is not stable due to the generation of a weak Zn-H bond.

Figure 3.2.15 Energy profile for the oxidation of alcohol to aldehyde through outer sphere mechanism. All energy values are relative to 275 at 0.0 kcal mol-1

The activation energy for oxidation of alcohol is lower for intermediate sphere mechanism (Br = 23.06, I = 18.36) than outer sphere mechanism. Figure 3.2.16 shows geometries of ZnBr system catalyzed reaction which clarifies the difference between two mechanisms. In outer sphere mechanism, the presence of a ligand decreases the

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open space for hydride shift towards the metal. In complex 269, no vacant space is required for hydride shift which is the reason for its lower activation barrier. Moreover, the benzene ring in 269 is properly oriented for hydrogen shift.

Figure 3.2.16 Optimized geometries and related structural parameters for 269, TS34, 275 and TS37.

The complex 276, loses its aldehyde moiety and transfers the hydride towards. The oxidation of hemiacetal to ester through outer sphere mechanism is then studied in the next step. Complex 277 has TBP and ligand coordinated with the metal (Figure 3.2.17). The activation energy for the reaction is 25.96 kcal mol-1. The O9-H12 and Zn-H6 bond length decreases to 1.06 and 1.67 in the transition state TS38 from 1.61 and 4.20 in 277. The reaction is endothermic by 7.78 kcal mol-1.

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Figure 3.2.17 Energy profile for the oxidation of hemiacetal to ester through outer sphere mechanism. All energy values are relative to 277 at 0.0 kcal mol-1

Next, we have studied the mechanism in the absence of a ligand. Complex 279 enters into the catalytic cycle in which an alcohol can give proton and hydride to TBP and Zn, respectively, without being coordinated to zinc (Figure 3.2.18). Both oxygen atoms of TBP coordinate with Zn in 279, and block the vacant site for alcohol (hydrogen donor) coordination. The kinetic demand for the reaction is 28.17 kcal mol- 1 for outer sphere mechanism where both hydrogen and hydride simultaneously shift to TBHP and Zinc, respectively. The TS39 shows concerted mechanism, having proton transfer from O1 to TBP and hydride shift from C2 to Zn in a single transition state. The Zn–H6 bond length shortens to 1.66 Å in TS39 from 3.03 Å in 279, while C2–H bond length increases to 1.53 Å in TS39 from 1.09 Å in 279. The change in bond length shows the bond breakage of C2–H and concomitant bond formation of Zn–H. The O1–H bond length also increases to 1.26 Å in TS39 from 0.97 Å in 279, which also confirms the transfer of proton from O1 towards O6. The Br–Zn–O10 bond angle is 158.38 degrees in 279.

The structure is not linear due to the presence of benzene ring in front of the bromide moiety. The Br–Zn–O10 bond angle is 127.45 degrees in TS39 because three groups are in coordination with Zn having distorted trigonal geometry. The reaction is

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endergonic by 10.39 kcal mol-1. The complex 36 is the product of the reaction where aldehyde is not in coordination with metal but hydride and TBHP are in coordination with the metal. The aldehyde moiety is held in this complex through hydrogen bonding acceptor interaction with TBHP. In complex 280, the oxygen of the resulting aldehyde (O1) interacts with the proton of TBHP ligand at a distance of 1.68 Å. The oxygen of TBHP coordinates with zinc at a distance of 2.17 Å. ZnI catalyzed reaction is next studied. There were no remarkable differences between ZnBr and ZnI catalyzed oxidation of alcohol and activation energy is also in the same range i.e., 28.31 kcal mol-1.

Figure 3.2.18 Energy profile for the oxidation of alcohol to aldehyde through outer sphere mechanism. All energy values are relative to 279 at 0.0 kcal mol-1

-1 Activation energy found for ZnI2 catalyzed same reaction is 27.75 kcal mol . The activation energy is also comparable with intermediate sphere mechanism for both I- and Br- . The complex 280 loses the aldehyde moiety to generate complex 281 and proceed directly to the next step where a hydride from the metal shifts to TBHP ligand, and causes the reduction of latter (Figure 3.2.19). The shift of a hydride from Zn to TBHP has a kinetic demand of 26.24 kcal mol-1 however; the reaction is highly

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favorable thermodynamically (by 64.20 kcal mol-1). The large amount of energy released may be consumed to decoordinate the water and aldehyde to generate the catalyst species for the next step. This reduction of TBHP through hydride transfer from zinc is very crucial for the regeneration of an active catalyst for the next oxidation cycle where hemiacetal is converted to ester. The activation barrier for this step is very comparable to the rate determining oxidation of alcohol to aldehyde.

Figure 3.2.19 Energy profile for hydride shift to TBHP to regenerate the catalyst. All energy values are relative to 281 at 0.0 kcal mol-1

As mentioned earlier, aldehyde generated after the first oxidation step, is converted to hemiacetal by reaction with alcohol. The oxidation of hemiacetal to ester is then studied through outer sphere mechanism with an active catalyst 283 (Figure 3.2.20) which is analogous to catalysts 279. The oxygen of TBP ligand acts as hydrogen bond acceptor for coordinating hemiacetal at a distance of 1.19 Å. The C–H of hemiacetal is also weakly coordinated to Zinc. This geometric parameter is different than that of 279 where no such coordination is observed. In brief, the structure of the starting complex 283 resembles very much with the TS41 which results in very low activation barrier, 9.95 kcal mol-1. Br–Zn–O bond angles in 283 and TS41 are 172.41 and 130.88 degrees, respectively. Transition state is distorted trigonal in structure, quite similar to TS39. In TS41, H6–Zn and C2–H6 bond distances are 1.67 Å and 1.45 Å. The trend of decreasing and increasing bond lengths in TS41 are also

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consistent with the changes in the TS39. The reaction is also considerably exothermic by 15.60 kcal mol-1.

Figure 3.2.20 Energy profile for the oxidation of hemiacetal to ester through outer sphere mechanism. All energy values are relative to 283 at 0.0 kcal mol-1

Bromide replacement with iodide gave activation energy in the same range, first oxidation step transition state demands 28.31 kcal mol-1 activation energy and second oxidation step activation energy is 25.65 kcal mol-1. Activation energy found for -1 ligandless ZnI2 catalyzed alcohol oxidation is 27.75 kcal mol , second oxidation -1 reaction showed 10.39 kcal mol Which are not very different from ZnBr2 system catalyzed reaction.

The activation energy of outer sphere mechanism for ester oxidation in the presence of a ligand is also higher than intermediate sphere mechanism (Br = 18.75, I = 21.53 vs 25.96 and 25.65 kcal mol-1). The structural differences are same as described for alcohol oxidation step (vide supra). The overall comparison of both mechanisms for aldehyde and ester formation is given in table 3.2.2.

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Table 3.2.2 Comparison of intermediate and outer sphere mechanism. All energy values are Gibbs free energy in kcal mol-1

Geometries Intermediate Outer Sphere Sphere

Br in presence of L 23.06 28.50

Aldehyde I in presence of L 18.36 28.31 Oxidation

Br 28.50 28.17

I 28.58 27.75

Br in presence of L 18.75 25.97

Ester I in presence of L 21.53 25.65 Oxidation

Br 27.36 9.95

I 30.13 10.39

3.3 Mechanistic Investigation of Zn(II) Catalysis in Oxidative Amidation of Alcohols and Amines

The amide functional group is an important structural motif of natural and synthetic compounds. In nature, the amide bond is primarily present in proteins[159] which may have structural role, or may function as enzymes[160] for various biological processes. Synthetically, nylon is an example of a polymer which contains amide linkages. The

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amide bond also plays significant role in the pharmaceutical industry since many nitrogen containing compounds play key role in medicines for the treatment of various bacterial and fungal diseases[161]. Penicillin[162] and lysergic acid diethylamide[163] are the most famous example of amide containing drugs. Moreover, twenty-five percent of all synthetic pharmaceutical drugs are assessed to contain an amide bond. The role of the amide bond in chemistry and biology has been extensively studied in the last century, and reviewed in several books and articles[164]. The formation of amide bond is, therefore, a fundamental reaction in chemical synthesis[165]. Conventionally, an amide bond is formed by (a) the reaction of carboxylic acid (acid halides and esters) derivatives with amines (b) coupling of alkyl/aryl halides with amides[166] (c) acid or base catalyzed rearrangement reaction. A few important named reactions for the synthesis of the amide bond are Schmidt[167], Ritter[168], Beckman[169] and Ugi[170] reactions. Most of the conventional methods involve tedious procedures, and produce toxic wastes[171]. Moreover the yields are not very promising. However, over the time, several sophisticated strategies have appeared to build the amide bond, mainly through transition metal catalysis. Murahashi and co-workers[172] have reported ruthenium catalysis for amides synthesis from nitriles. Transition metal catalyzed amines acylation using oxidants and base is also known[173]. Amide synthesis by oxidation reaction using terminal alkynes is also reported. More recently, direct oxidative amidation of alcohols with amines is reported where an alcohol is dehydrogenated to an aldehyde, and the resulting aldehyde then reacts with amines to form hemiaminal which after another dehydrogenation delivers the amide product[174]. The reaction is environmentally benign with high atom economy without the need of any activating agent. The concept of dehydrogenation of alcohols is more than 100 years old (Guerbet Chemistry)[152] but its elegant use in amide and ester formation has not been realized until recently. The oxidative amidation of alcohols with amines is relatively underdeveloped compared to the ester counterpart, mainly because of the competing N-alkylation. In some of these reactions, hydrogen molecules are liberated (dehydrogenative) whereas in some reaction hydrogen acceptor molecules are used to thermodynamically facilitate the reaction. The original report of Milstein and co- workers involves ruthenium pincer complex; however, several other catalyst have

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been reported in this regard. Leitner and co-workers have recently reported a rhenium triphos catalyst for the dehydrogenative formation of esters and amides from primary alcohols[175]. Most of the catalysts reported for the oxidative amidation involve the use of expensive metals, such as ruthenium or rhodium or heterogeneous catalysts, such as alumina-supported silver clusters, Au/ TiO2 systems, Au/HT systems and Au/DNA nanohybrids. Since most of these transformations require expensive catalysts, therefore, they are economically not viable. An important factor in the large scale utilization of these reactions is the cost of the catalyst; therefore research is more focused towards exploration of cheap, non-toxic and environmentally benign metals in these protocols. In this regard, an inexpensive iron metal based catalyst in dehydrogenative amidation of benzylic alcohols with mono and di-substituted amines is reported[176]. A copper catalyzed version of the reaction is also reported[177]. Towards this end, we have recently reported the use of zinc halide for the oxidative amidation of alcohols at room temperature using tert butyl hydrogen peroxide (TBHP) as the oxidant[178]. Benzylic alcohol (76) is converted to N-alkyl benzamide

(196) using ZnI2 as catalyst and TBHP as an oxidant at 40 °C over a period of 16 h (Figure 3.3.1).

Figure 3.3.1 Oxidative amidation of benzylic alcohol with TBHP using ZnI2 catalyst.

The zinc catalysis, in general, is not well explored compared to other transition metal catalysis; however, a shift in the trend has been observed recently. Importance of zinc catalysis has been demonstrated recently in several reports. Although experimental reports have started to emerge but the theoretical reports are very limited. More specifically, there appears no theoretical reports on the mechanism of the zinc catalyzed oxidative amidation (or esterification) of alcohols. We became interested in investigating the mechanism of the zinc catalyzed oxidative amidation and the results

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are presented here. We were also interested to find whether the mechanism of the zinc catalyzed reaction is similar to the ruthenium (and other related metals) or not.

To understand the mechanism for the generation of 196 from 76 and 195 (Figure 3.3.1), DFT calculations have been performed at B3PW91 level of theory. The reaction has already been reported to proceed with the aid of Ru, Ir, Pd and Au catalysts. The metal catalyzed oxidative transformation of alcohols to amides has also been subject of theoretical studies. A key step in these oxidation processes is the transfer of hydrogen from alcohol to either metal or to some other recipient. Hydrogen transfer is a broad area of catalysis and finds application in several transformations other than esterification and amidation of alcohols. Several mechanisms have been proposed and investigated for the hydrogen transfer; however, they can be broadly classified into inner sphere, outer sphere and intermediate sphere mechanisms.

Figure 3.3.2 Numbering of atoms of structures under discussion

3.3.1 Inner Sphere Mechanism

ZnI2 is a 14 electron species which upon replacement of an iodide with an oxy ligand generates ZnI(OR) which enters into the catalytic cycle. Complex 246 is therefore considered as the active species entering in the catalytic cycle. The oxy ligand species 246 in its most stable geometry is more than 14 electron complex. The benzene ring of the alcohol is bent towards zinc and it coordinates to zinc through its p electrons, but only through the carbon bearing the hydroxymethyl substituent (C3). Zn–O1–C2– C3 dihedral angle is 0.16 degrees and C3–Zn distance is 2.82 Å. The complex is neither a perfect T-shaped structure nor a trigonal planar probably because of the weak coordination of benzene to zinc. The I–Zn– O1 bond angle is 169.35 degrees.

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Before the hydride shifts to the zinc, the complex 246 is believed to change its orientation to 246a in which the benzene ring is no longer interacting with the zinc atom. The Zn–O1–C2–C3 dihedral angle in 246a is 179.94 degrees and the I–Zn–O1 bond angle is 175.34 degrees. This change in orientation is necessary, not because for creating a vacant site but to facilitate the hydride shift. The hydride shift is not possible in 246 because of the geometric constraints (Figure 3.3.3).

Figure 3.3.3 Energy profile for zinc mediated oxidation of alcohol to aldehyde through β-hydride elimination, at B3PW91/6-311G(d,p) with pseudopotential for Zn and I (SDDALL). All values are relative to 246a at 0.0 kcal mol-1.

Hydride in 246a is aligned properly for transfer to zinc. The zinc species 246a is2.49 kcal mol-1 unstable compared to 246. Kinetic demand for the reaction is 33.08 kcal mol-1 with respect to 246, for the hydride elimination by zinc to generate the aldehyde coordinated species 286. This activation barrier is considerably higher than the one reported for the ruthenium based catalyst (8.80 kcal mol-1). There are certain marked differences in the transition states for Ru and zinc based species. The ruthenium transition state is a very early transition state with geometry very similar to the starting material[20] whereas the zinc based transition state is almost middle. C2–H and Zn–H bond distances are 1.62 and 1.68 Å. Moreover, bond distance of O–C2 bond decreases to 1.30 Å in the transition state from 1.41 Å in 246a. I–Zn–O1 bond

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angle is 134.98 degrees. The total activation barrier from 4 to TS42 is very high, but the reaction conditions (40°C, 16 h) are not expected to provide these thermodynamic requirements, therefore it is believed that the mechanism shown above (inner sphere) is not a plausible one. Moreover the reaction is thermodynamically uphill. The product of this step, 286 lies 5.96 kcal mol-1 higher in energy than 246. Effect of oxidants such as H2O2 and CH3OOH has also been investigated. The mechanism is same for different oxidants and there is no significant effect on activation barrier. For -1 H2O2, activation energy is found as 32.87 kcal mol and for CH3OOH, 33.55 kcal mol-1 activation energy is calculated. Next, we have studied the effect of halide when changes from iodide to bromide in the presence of same three oxidants. Changing halides also does not show any significant change on activation energy and mechanism is same as that for ZnI. In case of bromide, TBHP gave 33.73 kcal mol-1, -1 -1 H2O2 = 31.38 kcal mol and CH3OOH = 33.97 kcal mol .

3.3.2 Intermediate Sphere Mechanism

Since the activation barriers associated with the inner sphere mechanism (shown in Figure 3.3.3) are very high therefore alternative mechanism have also been searched for. Intermediate sphere mechanism (shown above) is next studied where alcohol (hydrogen donor) and tert-butyl hydrogen peroxide (TBHP) (a hydrogen acceptor) both are coordinated to zinc. In the first step of the mechanism, TBHP coordinates with 246 to form 287 which may be an 18 electron species. TBHP also interacts with the oxygen of benzyloxy ligand through hydrogen bonding. The benzene moiety in the complex 248 also coordinates to zinc but the interacting atom is the ortho carbon (C4), and because of this the dihedral angle Zn–O1–C2–C3 is 45.30 degrees. Zn–C3 and Zn–C4 bond distances are 3.23 and 3.33 Å respectively. Although this mechanism does not require creation of a vacant site on zinc (no hydride abstraction by zinc); however, the geometry of the benzylic CH2 with respect to TBHP in 248 does not allow transfer of hydrogen to TBHP. Therefore, it is believed that the benzene ring in 248 undergoes a rotation similar to the one observed for the conversion of 246 to 246a. A transition state is located for a hydrogen shift to TBHP with concomitant breakage of O–O bond at a total barrier of 28.61 kcal mol-1 (Figure 3.3.4).

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Figure 3.3.4 Energy profile for oxidation of alcohol to aldehyde through TBHP coordinated to zinc catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential for Zn and I. All energy values are with respect to 248a at 0 kcal mol-1.

In the transition state, C2–H9 and H9–O6 bond distances are 1.21 and 1.52 Å. The O6 O7 bond of TBHP is considerably elongated (1.81 Å compared to 1.44 Å. in 248a). The transition state is of much lower energy compared to the one for hydride shift to the transition metal (zinc) and the overall reaction is highly exothermic. The low activation barrier may be due to the generation of metal oxygen bond in the transition state compared to relatively unstable M–H bond in the TS4-5. Moreover, the water molecule generated as a result of hydrogen shift also coordinates with the zinc atom although this oxygen atom is quite away from zinc in the starting material 248a (compare 2.30 Å in TS with 2.92 Å in 248a). The high exothermicity may be attributed to several factors. A weak O6–O7 bond is broken and replaced with metal– oxygen bond, and an OH bond. Moreover the water produced in this reaction is in hydrogen bonding with the oxygen of the butyloxy ligand. The kinetic barrier predicted through this mechanism is in nice agreement with the experiment which suggests that this mechanism may be a plausible one. The zinc species 287 undergoes

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a ligand exchange with hemiaminal (generated by reaction of aldehyde with amine) to generate the species 285 for the next transformation. The zinc atom in 285 has four ligands (I, OR, OH and NH) coordinated to it, and the geometry is distorted tetrahedral (Figure 3.3.5).

Figure 3.3.5 Energy profile for proton exchange between oxy ligands to generate 288, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All values are with respect to 285 at 0.0 kcal mol-1.

The transition state (TS44) is unsymmetrical and bond distances of O–H are 1.18 and 1.25 Å. An exchange of oxy ligands between 285 and 288 is a kinetically highly -1 favorable process (Eact = 3.40 kcal mol only) however the reaction is slightly endothermic (0.35 kcal mol-1). The low energies of reaction and activation may be attributed to the very similar nature of both ligands involved in the reaction (geometry details). Complex 288 undergoes decoordination of butanol followed by coordination of TBHP to generate the active species 289 for the subsequent hydrogen shift to TBHP. The O6–Zn and O7–Zn bond distances are 2.21 and 3.20 Å, respectively. The kinetic demand for a transition state is 20.56 kcal mol-1 for hydrogen transfer to TBHP and concomitant breakage of O6–O7 bond (Figure 3.3.6). The activation barrier is considerably lower than the barrier associated with the transformation of

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248a to 287. Bond lengths in the transition state TS45 are not very different from TS43. The C1–H and O–H bond distances are 1.20 and 1.54 Å respectively.

Figure 3.3.6 Energy profile for oxidation of hemiaminal to amide through TBHP coordinated to zinc catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All values are relative to 289 at 0.0 kcal mol-1

Comparison of different oxidants, such as H2O2 and CH3OOH and halides, such as bromide have also been performed for both oxidation of alcohol and hemiaminal. ZnI catalyzed oxidation of alcohol reaction, in all the three oxidants does not show any -1 significant change in activation energy (H2O2 = 30.08, CH3OOH = 29.45 kcal mol ). There is a change of about 7 kcl mol-1 activation energy in ZnI catalyzed oxidation of hemiaminal in the presence of H2O2 and CH3OOH.

Changing the iodide with bromide also showed the results similar to iodide system. In presence of different oxidants, the alcohol oxidation is not effecting a lot but hemiaminal showed a significant effect of about 8 kcal mol-1.

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3.3.3 Outer Sphere Mechanism

Although the activation barrier associated with intermediate sphere mechanism is marginally accessible but we have also explored the outer sphere mechanism in order to search for more plausible mechanism under the reaction conditions. Outer sphere mechanism involves hydride shifts to metal vacant site without coordination of alcohol with Zn. The mechanism operates by proton abstraction of tert-butyl peroxide (TBP) ligand by iodide. Complex 291 enters into the catalytic cycle in which an alcohol can give proton and hydride to TBP and Zn, respectively, without being coordinated to zinc. Both oxygen atoms of TBP coordinate with Zn in 291, and block the vacant site for alcohol (hydrogen donor) coordination. Kinetic demand for the outer sphere mechanism is 26.86 kcal mol-1 where both hydrogen and hydride simultaneously shift to TBHP and Zinc, respectively. The TS46 shows concerted mechanism, having proton transfer from O1 to TBP and hydride shift from C2 to Zn in a single transition state. The Zn–H9 bond length shortens to 1.66 Å in TS46 from 3.57 Å in 291, while C2–H bond length increases to 1.52 Å in TS46 from 1.09 Å in 12. The change in bond length shows the bond breakage of C2–H and concomitant bond formation of Zn–H. The O1–H bond length also increases to 1.28 Å in TS46 from 0.97 Å in 291, which also confirms the transfer of proton from O1 towards O6. The I–Zn–O6 bond angle is 158.71 degrees in 291. The structure is not linear due to the presence of benzene ring in front of the iodide moiety. The I–Zn–O6 bond angle is 127.03 degrees in TS46 because three groups are in coordination with Zn having distorted trigonal geometry. The transition state is found at the barrier of 26.86 kcal mol-1. (Figure 3.3.7), which is of lower energy compared to inner sphere and intermediate sphere mechanism (including the energy of conformational change, Figure 3.3.3).

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Figure 3.3.7 Energy profile for oxidation of alcohol to aldehyde through outer sphere mechanism in complex 291, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All energy values are with respect to 291 at 0.0 kcal mol-1

The reaction is unstable by 10.08 kcal mol-1. The lower activation barrier (compared to inner and intermediate sphere mechanisms) may be attributed due to the early nature of the transition state TS46 with geometry very similar to the starting material. The complex 292 is the product of the reaction where aldehyde is not in coordination with metal but hydride and TBHP are in coordination with the metal. The aldehyde moiety is held in this complex through hydrogen bonding acceptor interaction with TBHP. In complex 292, the oxygen of the resulting aldehyde (O1) interacts with the proton of TBHP ligand at a distance of 1.68 Å. The oxygen of TBHP coordinates with zinc at a distance of 2.17 Å. In the outer sphere mechanism, we also considered complex 293 as possible active catalyst for the oxidation of alcohol to aldehyde. The complex 293 differs from 291 regarding the proton acceptor ligand. The complex 14 may be obtained by interaction (hydrogen bonding) of alcohol 76 with complex 246a (Figure 3.3.3). Surprisingly, the activation barrier for oxidation through outer sphere mechanism in complex 293 is 24.4 kcal mol-1 (Figure 3.3.8), which is 2.46 kcal mol-1 lower compared to the outer sphere mechanism shown in Figure 3.3.7.

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Figure 3.3.8 Energy profile for oxidation of alcohol to aldehyde through outer sphere mechanism in complex 293, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I. All energy values are with respect to 293 at 0.0 kcal mol-1.

The lower activation barrier for oxidation in complex 293 is probably attributed to comparatively more early nature of the transition state TS47 compared to TS46. In TS47, the C2–H9 and Zn– H9 bond lengths are 1.46 Å and 1.48 Å, compared to 1.51 Å and 1.66 Å in TS46. The activation barrier associated with this mechanism is very easily accessible under the reaction conditions. Moreover, the oxidation of aldehyde in complex 293 is less endergonic compared to that in complex 291. The complex 13 (Figure 3.3.7) loses the aldehyde moiety to generate complex 295 and proceed directly to the next step where a hydride from the metal shifts to TBHP ligand, and causes the reduction of latter (Figure 3.3.9).

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Figure 3.3.9 Energy profile for hydride shift to TBHP to regenerate the catalyst, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I.

However, the complex 294 does not have any such ligand where a hydride from the metal may be shifted. Therefore, it is believed that benzylic alcohol in ligand 294 gets replaced with TBHP to generate 294 which is subsequently converted to 295 by the loss of benzaldehyde molecule. Such type of ligand exchange takes place with very small activation barrier (see Figure 3.3.5). The shift of a hydride from Zn to TBHP has a kinetic demand of 24.24 kcal mol-1; however, the reaction is highly favorable thermodynamically (by 75.43 kcal mol-1). The large amount of energy released may be consumed to decoordinate the water and aldehyde to generate the catalyst species for the next step. This reduction of TBHP through hydride transfer from zinc is very crucial for the regeneration of an active catalyst for the next oxidation cycle where hemiaminal is converted to amide. The activation barrier for this step is very comparable to the rate determining oxidation of alcohol to aldehyde. As mentioned earlier, aldehyde generated after the first oxidation step, is converted to hemiaminal by reaction with alkylamines. The oxidation of hemiaminal to amide is then studied through outer sphere mechanism with two different catalysts 287 and 298, which are analogous to catalysts 291 and 293, respectively. The complex 287 can be converted to complexes 287 and 298 merely by ligand exchange. The complex 18 has a TBP

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ligand attached to the central zinc atom. The oxygen of TBP ligand acts as hydrogen bond acceptor for coordinating hemiaminal at a distance of 1.82 Å. The C–H of hemiaminal is also weakly coordinated to Zinc. This geometric parameter is different than that of 291 where no such coordination is observed. In brief, the structure of the starting complex 287 (Figure 3.3.10) resembles very much with the TS49 which results in very low activation barrier, 7.88 kcal mol-1.

Figure 3.3.10 Energy profile for oxidation of hemiaminal to amide through outer sphere mechanism in complex 297, calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I.

I–Zn–O bond angles in 297 and TS 18-19 are 168.71 and 132.70 degrees, respectively. Transition state is distorted trigonal in structure, quite similar to TS46. In TS49, H9–Zn and O6–H9 bond lengths are 1.67 Å and 1.37 Å. The trend of decreasing and increasing bond lengths in TS49 are also consistent with the changes in the TS46. The reaction is also considerably exothermic by 17.82 kcal mol-1.

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Oxidation of hemiaminal with complex 298 is also studied but the activation barrier is slightly higher (9.35 kcal mol-1) than what is observed with complex 297. For both intermediate sphere and outer sphere mechanisms, the oxidation of hemiaminal to amide is more feasible than the oxidation of alcohol to aldehyde, therefore, it was of interest to explore the activation barrier for oxidation of hemiaminal to amide through inner sphere mechanism. For this purpose, a structure is taken from 285 with TBHP decoordinated from zinc. A transition state is located (TS50) for hydride shift to zinc at a barrier of 28.22 kcal mol-1 (Figure 3.3.11).

Figure 3.3.11 Energy profile for oxidation of hemiaminal to amide through β-hydride elimination by zinc catalyst calculated at B3PW91/6-311G(d,p) with pseudopotential (SDDALL) for Zn and I.

This activation barrier is slightly less than the one associated for 246a to 286 however yet inaccessible therefore, we believe that in this whole catalytic cycle, β-hydride elimination by zinc has no significant contribution to the product formation, particularly at higher concentrations of TBHP.

Outer sphere mechanism showed lowest activation barrier even in the presence of different oxidants such as H2O2 and CH3OOH both with ZnI and ZnBr. The ZnI catalyzed transition state for oxidation of alcohol to aldehyde is located at a barrier of

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-1 30.05 for H2O2 and 28.60 kcal mol for CH3OOH. The activation energy is significantly decreases in second oxidation step ( H2O2 = 18.11 and CH3OOH = 16.75 -1 kcal mol respectively). ZnBr also showed same results, first oxidation step for H2O2 -1 = 21.80 and CH3OOH = 28.76 kcal mol is calculated. Oxidation of hemiaminal showed lowest activation energy for all the three oxidants, (H2O2 = 9.85 and -1 CH3OOH = 8.11 kcal mol respectively). Comparison of different oxidants and halides are shown in table 3.3.1 and 3.3.2. Based on the calculation the most plausible mechanism and catalytic cycle are shown in Figure 3.3.12 and 3.3.13, respectively.

Table 3.3.1 Effect of different oxidants on ZnI2 catalyzed reaction

Steps (I) TBHP H2O2 CH3OOH

Inner sphere 34.59 32.87 33.55

Intermediate 28.60 30.08 29.45 (1st step)

Intermediate 20.56 28.13 27.51 (2nd step)

Outer (1st step) 27.75 30.05 28.60

Outer (2ndstep) 9.28 18.11 16.75

Table 3.3.2 Effect of different oxidants on ZnBr2 catalyzed reaction

Steps (Br) TBHP H2O2 CH3OOH

Inner sphere 33.73 31.38 33.97

Intermediate (1st step) 28.50 30.13 29.29

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Intermediate (2nd step) 22.26 28.12 27.30

Outer (1st step) 28.17 21.80 28.76

Outer (2nd step) 8.10 9.85 8.11

Figure 3.3.12 Reaction profile for the oxidative transformation of alcohol to amides through TBHP and ZnI2 (outer sphere mechanism).

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Figure 3.3.13 Catalytic cycle for zinc catalyzed oxidative amidation of benzylic alcohol.

3.4 Zn Catalyzed Oxidation of Thioacetal to Thioester & Oxidation of Benzylamine to Benzaldimine & Guanidine

Thioesters have been utilized as important building blocks in essential biological and organic synthesis and are also considered as possible precursors to life[179]. Thioesters

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are obligatory intermediates in many reactions that involve either utilization or regeneration of ATP. The most typical method for synthesis of thioester involves the reaction of an acid chloride with an alkali metal salt of a thiol or by the displacement of halides by the alkali metal salt of a thiocarboxylic acid. Conventionally, thioesters were prepared from alcohols by the Mitsunobu reaction[180]. Carbonylation of alkynes and alkenes in the presence of thiols also delivers thioester[181].

Guanidine is a nitrogen containing organic base or catalyst, that has been mostly used in heterocyclic compounds synthesis [182]. The essential amino acid arginine contains this moiety that plays a significant role in the interaction with enzymes or receptors through hydrogen bonding and/or electrostatic interactions[183]. Guanidine containing compounds are biologically very active antimicrobial[184], antiviral[185] or antifungal agents. They participate in synthesis of various natural products, drugs, agrochemicals, and explosives etc and can acts as ancillary ligands, anion hosts, ionic liquids, fluorescent molecular probes, and molecular transporters[186].Guanidine can be obtained from natural sources or can be synthesized. Common methods involve the reaction of a guanylating agent with primary or secondary amines[187]. They are also obtained from thioureas via desulfurization reactions[188]. Due to the importance of thiourea and guanidines, several synthetic methods have been developed and described in the literature. Utilizing the knowledge from Zn (II) catalysis in the alcohol oxidation to form aldehyde, ester and amide, we aimed to predict that, the oxidation reaction is also possible for generation of thioesters, benzaldimine, and guanidine. We have performed same set of calculations for the three products generation and results are presented here:

 Zn catalyzed oxidation of thioacetal to thioester To find out the exact mechanism for the generation of 198 from 301 (Figure 3.4.1), DFT calculations have been performed at B3PW91 level of theory. A general numbering scheme for discussion of compounds in this manuscript is given in Figure 3.4.2.

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Figure 3.4.1 Zn catalyzed oxidation of thioacetal to thioester

Figure 3.4.2 Numbering of atoms of structures under discussion

All the three possible mechanisms, such as inner sphere, intermediate sphere and outer sphere mechanisms (vide supra) have been analyzed in the presence and absence of pyridine-2-carboxylic acid (ligand). The first step for thioester formation is similar to ester and amide formation, i.e. generation of aldehyde from alcohol. Therefore, we have performed calculations for second step such as oxidation of thioacetal to thioester. Inner sphere mechanism is omitted because from our previous studies it is investigated that inner sphere is not favorable for oxidation of alcohol. We then, focused on intermediate and outer sphere mechanisms.

3.4.1 Intermediate Sphere Mechanism

We have studied the mechanism of second oxidation reaction (oxidation of thioacetal) for intermediate and outer sphere mechanism because first step, i.e. oxidation of alcohol is same as for ester and amide. Figure 3.4.3 shows ZnBr2 catalyzed thioacetal oxidation in the presence of a ligand.

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Figure 3.4.3 Energy profile for the oxidation of thioacetal to thioester through intermediate sphere mechanism. All energy values are relative to 302 at 0.0 kcal mol-1

Complex 302 is the active specie for this reaction. The alkoxide oxygen (O1) is strongly coordinated to zinc at the distance of 1.88 Å. An oxygen atom of TBHP (O9) is weakly coordinated to zinc (2.39 Å), and the other OH (O10) proton interacts with the bromide ligand. The transition state TS51 involves transfer of hydrogen atom from O1 towards O9 of TBHP and concomitant bond breakage of O9-O10. The kinetic energy calculated for the reaction is 22.97 kcal mol-1 and reaction is highly exothermic. The high exothermicity may be attributed to several factors. A weak O6– O7 bond is broken and replaced with metal–oxygen bond, and an OH bond. Moreover the water produced in this reaction is in hydrogen bonding with the oxygen of the butyloxy ligand. In the transition state, C2–H6 and O9–O10 bonds are elongated to 1.22 and 1.81 Å, respectively. An ortho hydrogen of the pyridine moiety also shows interaction with O10 of TBHP (2.08 Å).

Next, we have studied the mechanism with iodide. The activation energy does not show significant change, and the transition state is located at 23.57 kcal mol-1 energy. We have also studied the mechanism in the absence of a ligand with both iodide and

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bromide. Ligandless mechanism with bromide showed higher activation energy (30.69 kcal mol-1) for the mechanism compared to the energy in the presence of a ligand. The same situation is observed for iodide case, the kinetic demand is 30.48 kcal mol-1. The trend of energies both in the presence and absence of a ligand is similar to oxidation of hemiacetal to generate ester.

3.4.2 Outer Sphere Mechanism

Outer sphere mechanism involves hydride shifts to metal vacant site without coordination of alcohol with Zn. The mechanism operates by proton abstraction of tert-butyl peroxide (TBP) ligand by iodide. Complex 305 is an active specie in which Zn is coordinated with five atoms, two oxygen atoms of TBP, one oxygen and one nitrogen of the ligand and one bromide. O1 is at a distance of 4.51 Å from the metal which shows that alcohol is not coordinated with the metal. The concerted transition state (simultaneous proton and hydride shift to TBP and Zn) TS52 is found at energy of 29.22 kcal mol-1 (Figure 6.4). The Zn-H6 bond length shortens to 1.65 Å in TS52 from 4.29 Å in 305. The O1–H12 and C2-H6 bond length increases to 1.46 and 1.61 Å in TS52 from 0.98 and 1.10 Å in 305, which shows the transfer of proton from O1 towards O10 and hydride from C2 towards Zinc. The reaction is endergonic by 12.71 kcal mol-1. The high activation energy may be attributed to steric effect due to the presence of the ligand. The product 306 shows interaction of O1-H12 having 1.73 Å bond distance and is not stable due to the generation of a weak Zn-H bond. Table

3.4.1 shows comparison of ZnBr2 and ZnI2 catalyzed intermediate and outer sphere activation energy in the presence and absence of a ligand.

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Figure 3.4.4 Energy profile for the oxidation of thioacetal to thioester through outer sphere mechanism. All energy values are relative to 305 at 0.0 kcal mol-1

Table 3.4.1 Comparison of ZnBr2 and ZnI2 catalyzed intermediate and outer sphere activation energy

Intermediate Outer sphere Sphere mechanism -1 mechanism (kcal mol ) -1 (kcal mol )

Br in presence of 22.97 29.21 L

I in presence of L 23.57 15.40

Br 26.29 15.68

I 30.49 14.84

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 Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine

Our second newly predicted reaction is Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine (Figure 3.4.5).

Figure 3.4.5 Zn catalyzed oxidation of benzylamine to benzaldimine and guanidine

Two oxidation steps such as oxidation of benzylamine to benzaldimine and then oxidation of diamine to guanidine are studied. All the three possible mechanisms such as inner sphere, intermediate sphere and outer sphere mechanisms in the presence and absence of a ligand with ZnBr2 nd ZnI2 are studied and results are presented here:

3.4.3 Inner Sphere Mechanism

Initially, we studied the inner sphere mechanism for zinc catalyzed oxidation of benzylamine to benzaldimine (Figure 3.4.6). The complex 307 is an eighteen electron complex and has a distorted tetrahedral geometry around the zinc atom. The complex 307 has another isomer 308, which is lower in energy than 307 by 19.05 kcal mol-1. A proton from carboxylic oxygen (O8) in 307 is shifted to O1 in complex 308. The complex 308 is occasionally obtained during the optimization of complex 307. A transition state TS53 for β-hydride elimination by zinc is calculated as 50.01 kcal mol- 1 from 307. The very high activation energy may be attributed to middle transition state. The geometry around zinc in the transition state is close to distorted square pyramid. The C2–H6 bond is considerably elongated to 1.72 Å in the transition state from 1.09 Å in 307. Moreover, the Zn–H6 and O–Zn bond distances are 1.68 Å and 2.12 Å, respectively.

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Figure 3.4.6 Energy profile for oxidation of benzylamine to benzaldimine through β- hydride elimination (inner sphere mechanism) by zinc catalyst. All energy values are relative to 307 at 0.0 kcal mol-1

The benzaldimine product is no longer in coordination with the metal center and shows hydrogen bonding interaction with the carboxylic acid moiety of the ligand. The hydride shift on zinc is also thermodynamically uphill by 22.50 kcal mol-1 from 307. Changing the bromide with iodide does not show significant change in activation energy. The transition state is located at a barrier of 50.71 kcal mol-1. The activation demand of inner sphere reaction suggested that the mechanism is not favorable.

3.4.4 Intermediate Sphere Mechanism

In the intermediate sphere mechanism, the hydrogen acceptor (TBHP in this case) also coordinates to the metal. Complex 310 is an active species that enters into a catalytic cycle with 20 electrons and a distorted square pyramid type structure (Figure 3.4.7). The nitrogen (N12) is strongly coordinated to zinc at the distance of 1.90 Å.

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An oxygen atom of TBHP (O9) is weakly coordinated to zinc (2.45 Å), and the other OH (O10) proton interacts with the bromide ligand. A transition state is located at a barrier of 28.00 kcal mol-1. The kinetic barrier is remarkably low. In the transition state, C2–H6 and O9–O10 bonds are elongated to 1.29 and 1.88 Å, respectively. An ortho hydrogen of the pyridine moiety also shows interaction with O10 of TBHP (2.13 Å). The reaction is thermodynamically favorable by 72.54 kcal mol-1.

Figure 3.4.7 Energy profile for the oxidation of benzylamine to benzaldimine through intermediate sphere mechanism. All energy values are relative to 310 at 0.0 kcal mol-1.

The next step is the reaction of generated benzaldimine with amine to generate guanidine followed by the exchange of a proton with a hydroxyl ligand to form an alkoxy ligand. The reaction is same as mentioned in ester and amide case, and is kinetically less demanding step. Next, we studied the oxidation of diamine to guanidine through intermediate sphere mechanism that is very similar to the transformation of 310 to 311. Complex 312 is the active specie for this reaction (Figure 3.4.8). The kinetic demand for the reaction is 25.15 kcal mol-1 .The structural

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features of TS55 are very similar to that of TS54, however activation barrier and energy of reaction are considerably low compared to TS54.

Figure 3.4.8 Energy profile for the oxidation of diamine to guanidine through intermediate sphere mechanism. All energy values are relative to 312 at 0.0 kcal mol-1

3.4.5 Outer Sphere Mechanism

Outer sphere mechanism involves hydride shifts to metal vacant site without coordination of alcohol with Zn. The mechanism operates by proton abstraction of tert-butyl peroxide (TBP) ligand by iodide. Complex 314 is an active specie in which Zn is coordinated with five atoms, two oxygen atoms of TBP, one nitrogen of diamine and one nitrogen of the ligand and one bromide. N12 is at a distance of 4.28 Å from the metal which shows that alcohol is not coordinated with the metal. The concerted transition state (simultaneous proton and hydride shift to TBP and Zn) TS56 is located at a barrier of 45.38 kcal mol-1 (Figure 3.4.9). The Zn-H6 bond length shortens to 1.62 Å in TS56 from 4.28 Å in 314. The N12–H12 and C2-H6 bond length increases to 1.11 and 2.02 Å in TS56 from 1.02 and 1.09 Å in 314, which shows the transfer of proton from N12 towards O10 and hydride from C2 towards Zinc. The

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reaction is endergonic by 31.27 kcal mol-1. The high activation energy may be attributed to steric effect due to the presence of the ligand. The product 315 shows interaction of N12-H12 having 1.72 Å bond distance and is not stable due to the generation of a weak Zn-H bond.

Figure 3.4.9 Energy profile for the oxidation of banzylamine to banzaldimine through outer sphere mechanism. All energy values are relative to 314 at 0.0 kcal mol-1

Complex 315, loses its benzaldimine moiety and transfers the hydride towards alkoxide ligand. The oxidation of diamine to guanidine through outer sphere mechanism is then studied in the next step. The reaction mechanism and transition state are similar to that of complex 18 transformations into 315. The kinetic demand for the reaction is 14.44 kcal mol-1 that is remarkably lower than transformation of 314 to 315. The O9-H12 and Zn-H6 bond length decreases to 1.06 and 1.67 in the transition state TS57 from 1.61 and 4.20 in 316 (Figure 3.4.10). We have also studied the mechanism in the absence of a ligand. Table 3.4.2 shows activation energy for

ZnBr2 and ZnI2 catalyzed reaction both in the presence and in the absence of a ligand.

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Figure 3.4.10 Energy profile for the oxidation of diamine to guanidine through outer sphere mechanism. All energy values are relative to 316 at 0.0 kcal mol-1

Table 3.4.2 Activation energy for ZnBr2 and ZnI2 catalyzed oxidation of banzylamine

Geometries Inner Intermediate Outer Sphere Sphere Sphere Br in 28.01 45.39 benzylamine presence of L Oxidation I in presence 28.57 45.19 of L Br 50.01 29.12 42.49 I 50.71 28.83 40.03 Br in 25.15 14.42 benzaldimine presence of L Oxidation I in presence 26.39 14.10

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of L Br 26.29 13.51 I 26.62 13.42

3.5 Mechanism of Zn(OTf)2 Catalyzed Hydroamination- Hydrogenation of Alkynes to Amines: Insight from Theory

Amines and their derivatives are highly valuable organic compounds in biological systems[189], materials science[190], agrochemicals[191] and in chemical industry[192]. Biologically important amines are used as neurotransmitters, antidepressants and antihistamines. Examples include venlafaxine (antidepressant and for anxiety disorder treatment), tripelennamine (for prevention of asthma, rhinitis and urticarial) and chlorpheniramine (for treatment of allergic conditions). Industrial applications of amines include their use as solvents, bactericides, additives for pharmaceuticals, chiral auxiliaries, corrosion inhibitors, detergents, cosmetics, fine chemicals and azo dyes. Amines also play an outstanding role as building blocks for organic synthesis, ligands for catalysis, polymers and pharmacological agents. Therefore, the development of efficient synthetic protocols for the synthesis of amines and their derivatives attract considerable interest.

Conventionally, amines are prepared by (a) reaction of ketone, aldehyde, alcohol, carboxylic acid or haloalkane with ammonia or amines[193] (b) hydrogenation of amide, azide or nitrile[194]. A few named reactions for the synthesis of amines[195] are Schmidt reaction, Schotten-Baumann reaction, Ugi reaction, Gabriel synthesis, Curtius rearrangement, Delepine reaction, Mitsunobu reaction, Staudinger reaction, Eschweiler-Clarke reaction. A drawback of using alkyl halides for alkylation of ammonia or amines is overalkylation that leads to mixtures of primary, secondary, tertiary amines and quaternary ammonium salts[196]. The disadvantage of overalkylation is tedious purification of the desired product which significantly affects the manufacturing cost. Most of the common methods for amines synthesis are cumbersome, non-stoichiometric, multistep and also produce side products[197].

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Hydroamination is an important sustainable alternative atom efficient synthetic strategy for amine formation[198]. The reaction involves addition of an N-H bond across unsaturated carbon-carbon bonds. Alkynes are superior to alkenes for hydroamination reaction due to their greater reactivity. An uncatalyzed hydroamination reaction suffers from high activation barrier due to electrostatic repulsions between an electron rich unactivated multiple bond and lone pair of a nitrogen atom. A catalyst overcomes the high activation energy by decreasing electrostatic repulsion. In this regard, a variety of catalytic methods have been reported in the literature.

Pioneering work on metal catalyzed hydroamination reaction was carried out with mercury and thallium but the major drawback is the high toxicity of metals[199]. The first example of alkyne hydroamination reaction using lanthanides as a catalyst was reported by Marks et al. Lanthanides (Sm, Lu,Nd)[200], early transition metals (Ti, Zr) and actinide (U, Th)[201] are highly reactive catalysts for this transformation, but these catalysts are highly sensitive towards air and moisture[202]. Moreover, they are also oxophilic and show a limited tolerance towards polar functional groups[203]. Late transition metals are more tolerant towards moisture and air, and they also show a wider tolerance towards functional groups. These reasons have spurred scientists to investigate late transition metals as potential candidates for hydroamination catalyzed reactions of unsaturated system. However, most of the late transition metals that act as a catalyst rely on expensive metals (palladium, platinium, rhodium, ruthenium, gold, and iridium). Moreover, most of the late transition metal shows limited scope for unactivated substrates, sluggish reaction rates and modest selectivity[204]. Therefore, the reactions are economically not viable, and methods involving cheap, non-toxic and environmentally benign catalysts such as iron, copper and zinc are thus eagerly sought. In this regard, Yang et al.[205] and Hannedouche have reported iron metal based catalyst for the cyclohydroamination of aminoalkenes. The Marc Taillefer[241], Lalic, Miura, and Buchwald groups reported hydroamination of unsaturated systems by copper based catalyst using efficient methods in terms of reactivity and proceeds the reaction at room temperature[206]. However, most of the Cu catalyzed hydroamination reactions are intramolecular to generate N-heterocycles. Only a few

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examples have been reported for intermolecular reaction, but are mostly based on heterogeneous Cu catalyst system. The pre functionalization of the amines is another major issue in most of the Cu catalyzed hydroamination reactions.

The zinc catalysis, in general, is underdeveloped compared to other transition metal catalysis; however, situation has changed in the recent past[114]. Importance of zinc catalysis has been exhaustively explored in several recent reports[114] including hydroamination reaction[207]. The groups of Roesky and Blechert reported zinc catalyzed hydroamination of alkenes to synthesize functionalized amines[208]. Reduction of imines is demonstrated by various research groups[209]. However, reductive amination is considerably less developed. More recently, hydroamination- hydrogenation of alkynes with amines through Zn(OTf)2 catalyst has been reported by Beller and coworkers (Scheme 3.5.1) using environmentally benign, cheap and [209] readily available H2 as the reductant . Although experimental reports have started to emerge; however, the literature reveals only a handful number of theoretical mechanistic studies on zinc catalyzed reactions. More particularly, there appears no theoretical reports on the mechanism of any Zn(II) mediated hydroamination- hydrogenation of alkynes to amines.

Scheme 3.5.1 Zn(OTf)2 catalyzed hydroamination-hydrogenation of alkynes with amines

3.5.1 Hydroamination-Hydrogenation Reaction

To explore possible reaction mechanisms for the formation of 108 from 106 and 107, DFT calculations have been performed using B3LYP basis set. The key steps of the reaction are (a) nucleophilic attack of nitrogen on electrophilic carbon (b) hydrogenation reaction. For other transition metals, several mechanisms have been proposed and investigated for hydroamination-hydrogenation of unsaturated system to

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amines. Hydroamination reaction can be broadly classified into two approaches. (1) Inner sphere and (2) outer sphere mechanism. A schematic presentation of inner sphere and outer sphere mechanism for hydroamination of alkyne through zinc catalyst is given in Figure 3.5.1.

Figure 3.5.1 Hydroamination reaction by inner sphere and outer sphere mechanism

In inner sphere mechanism, amine and alkyne coordinate with Zn. The mechanism operates by the replacement of one of the ligand from the metal center. The proton of amine is abstracted by ligand, and the resulting amine attacks the alkyne (Figure 3.5.1a). In outer sphere mechanism, one of the substrate is not coordinated with Zn (Figure 3.5.1 b). Amine activation through inner sphere mechanism is reported for Ruthenium catalyzed hydroamination reaction. The mechanism involves oxidative addition of amines to the ruthenium centre, followed by coordination of alkyne to Ru[210]. Recently, Alkyne activation, followed by oxidative addition of amine and its nucleophilic attack on alkyne through inner sphere mechanism is theoretically reported by Sven Tobisch for CuH-catalyzed hydroamination of arylalkynes with hydroxylamine esters.

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The hydroamination of alkyne catalyzed by Zn(OTf)2 (Figure 3.5.1) involves three different components; the alkyne and amine as reactants, and the Zn catalyst. The reaction involves hydroamination and hydrogenation processes. Both inner sphere and outer sphere mechanisms (vide supra) are studied for hydroamination reaction. Four different approaches are studied for hydrogenation reaction. Utilizing the knowledge from literature, all the possible routes are studied, and presented here in two sections; hydroamination reaction and hydrogenation reaction. Numbering of atoms of structures under discussion is given in Figure 3.5.2.

Figure 3.5.2 Numbering of atoms under discussion

 Hydroamination reaction

3.5.2 Inner Sphere Mechanism

Inner sphere mechanism operates by amine coordination with metal center by replacing one of the triflate ligand. Complex 318 is a zinc catalyst with +2 oxidation state and 18 electrons. Each triflate ligand coordinate with metal through its two oxygen atoms with the average distance of 2.2 Å from the metal center. The amine adduct 323 having 20 electrons Zn species with distorted trigonal bipyramidal geometry is 26.59 kcal mol-1 more stable compared to 318. The benzene ring of amine is slightly bent towards triflate ligand in 323, and coordinates with triflate oxygen with its hydrogen atoms. Before proton shifts to triflate, the benzene ring changes its orientation, and is no longer interacting with the triflate group to proceed easy shifting of proton, as shown in TS58 (Figure 3.5.3). The kinetic demand for the TS58 is 33.19 kcal mol-1 from 318 and 6.60 kcal mol-1 with respect to 323. In TS58, the proton (H5) is abstracted by one of the triflate ligands. Complex 323 shows that amine group is in coordination with metal. Moreover, the N4-H5 bond distance is 1.02 Å in 323 but increases to 2.34 Å in the TS58 which shows its bond breakage from the nitrogen. In TS58 the hydrogen is close to the triflate group at a distance of 0.99 Å, compared to

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2.63 Å in the 323. The TS58 is a very late transition state with geometry very similar to the product. The energy of reaction is found 30.45 kcal mol-1 (an endothermic reaction). The high energy of reaction may be attributed to the loosening of more stable Zn-O bond relative to Zn-N bond.

Elimination of TfOH group is followed by alkyne coordination with the Zn center (324). The formation of the complex 324 from 319 is also an endothermic process. Although hydrogenation mechanism is discussed separately in a later section but we have also included some discussion here to give complete picture of reaction mechanism. Transition state TS59 shows concerted mechanism, that involves the nucleophilic attack of nitrogen to the electrophilic carbon of the coordinated alkyne and heterolytic hydrogen cleavage simultaneously in a single transition state. The N4- C1 bond distance decreases from 2.64 Å in the TS59 to 1.45 Å in 325. In the TS59, hydrogen molecule cleaves heterolytically in which hydride shifts towards the metal center and proton shifts towards the nucleophilic carbon of alkyne (C2). The Zn-H- bond distance is shortened from 1.68 Å in the TS59 to 1.54 Å in 325. A Similar trend is observed for H5-C2, which is 1.35 Å in TS59 from 1.08 Å in 325. The overall energy required for this step is very high (48.21 kcal mol-1) and the reaction is not very favorable. In complex 325, nitrogen is in enamine form, and is still coordinated with metal center. Moreover, hydrogen atoms of enamine show hydrogen bonding with oxygen atoms of triflate ligand which keeps the enamine moiety close to the catalyst. The bond distance of Zn-N increases to 2.14 Å in 8 from 1.89 Å in TS59. Hydride shift occurs from metal center towards C1 in the next step. The activation energy for the TS60 is calculated as 20.58 kcal mol-1 from 325.The bond distance of hydride from Zn and C1 are 1.70 Å and 1.61 Å respectively.

Tautomerization of enamine-imine is next expected to generate the imine moiety. Nitrogen is bonded with metal in complex 326. The TfOH group re-enters into the catalytic cycle, nucleophilic nitrogen abstracts the proton while the triflate anion shifts towards metal center. Mechanism of the reaction is shown in scheme 3.5.2 and potential energy diagram is shown in Figure 3.5.3. Activation energies of hydroamination and hydrogenation steps are high enough to be available at reaction

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conditions (120oC, 24h). Moreover the reaction is also thermodynamically uphill. Therefore, another mechanism is investigated.

Scheme 3.5.2 Schematic presentation for inner sphere hydroamination- hydrogenation reaction.

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Figure 3.5.3 Potential energy diagram for inner sphere hydroamination- hydrogenation reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1

3.5.3 Outer Sphere Mechanism

Next, we focused on outer sphere mechanism, which is possible when one of the substrate is not coordinated with the metal center. The discussion is divided in two subsections. (1) Outer sphere mechanism in amine adduct (2) Outer sphere mechanism in alkyne adduct.

In the mechanism of amine adduct, amine is coordinated with the metal center and undergoes a nucleophilic attack on non-coordinated alkyne. The mechanism starts with the complex 326, as shown in inner sphere mechanism. Complex 328 is

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generated by the addition of alkyne group in the complex 326. The alkyne group is at the distance of 4.50 Å from metal, suggesting that it is not in coordination with the catalyst. In the transition state TS61, a proton is abstracted by nucleophilic carbon of unactivated alkyne, and C-N bond is formed by nucleophilic attack of nitrogen on electrophilic carbon simultaneously. TS61 shows concerted proton abstraction by nucleophilic carbon C2 and C-N bond formation (Figure 3.5.4). The N4-H5 bond is considerably elongated to 2.17 Å in the TS61 from 1.02 Å in 328. A few important structural parameters are given in table 3.5.1.

Table 3.5.1 Selected bond lengths of 328, 329 and TS61. All values are given in Angstroms

Bond 11 TS61 12

N4-H5 1.02 2.17 2.65

N4-C1 3.58 3.01 1.47

C2-H5 3.34 1.11 1.08

C1-C2 1.21 1.28 1.33

The TS61 is obtained at activation barrier of 48.85 kcal mol-1 from 328 but the energy of TS61 with respect to 318 is not very high (16.32 kcal mol-1) and can be accessible. The reaction is also thermodynamically favorable, as the energy of reaction is -21.39 kcal mol-1. The high activation barrier is expected because alkyne in this study is unactivated and repulsion between nucleophilic nitrogen and π electrons occurs. Complex 329 is the enamine intermediate of the reaction, and nitrogen is still in coordination with the metal (Zn-N bond distance is 2.04 Å) without affecting its oxidation state. The next step of the mechanism is related to tautomerization reaction involving the proton shift of nitrogen to terminal nucleophilic carbon. The kinetic demand for the reaction is 55.07 kcal mol-1 from 329 (01.15 with respect to 318 ). The

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C2-H5 and C2-N4 bond distances in the TS62 are 1.43 Å and 1.39 Å, which confirm its transfer from N4 to C2. The high activation barrier may be attributed to 1,3- sigmatropic shift reaction. In an alternate way, the proton can shift intermolecularly where triflate ligand may abstract a proton from nitrogen and deliver it to the carbon. The complex 330 is a reactive imine which is ready for reduction process to yield amine (vide infra). In 330, imine is η1-coordinated via the nitrogen lone pair to a Zn center and is 72.06 kcal mol-1 lower in energy than 318.

Figure 3.5.4 Potential energy diagram for hydroamination and hydrogen transfer reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1.

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Although the activation barrier associated with outer sphere hydroamination mechanism in amine adduct is marginally accessible at reaction conditions; but we have also explored the outer sphere mechanism in alkyne adduct in order to search for more plausible mechanism both kinetically and thermodynamically. In this route, alkyne first coordinates to the zinc metal without changing its oxidation state (Figure 3.5.5). In reactant 331, Zn is coordinated with six atoms, i.e.; two alkyne carbons and four oxygen atoms (of both triflate ligands). Alkyne coordinates via π electrons in a η2-manner. The transition state TS63 shows nucleophilic attack of amine in an outer sphere fashion. The kinetic demand is 0.85 kcal mol-1 from 331 and -14.96 kcal mol-1 from 318. The low activation barrier is not unexpected, alkyne activation reduces the repulsion between nucleophilic nitrogen and π system of alkyne. This increases the electrophilicity of carbon for the amine. TS63 is a very early transition state with geometry very similar to 331. Moreover, both hydrogen atoms of amine show hydrogen bonding with the oxygen atoms of triflate ligands in TS63. The C1-N4 bond distance is shortened from 2.55 Å in TS63 to 1.53 Å in the intermediate 332. These geometric changes clearly indicate the bond formation between both atoms. Zn is coordinated with five atoms in the transition state, only C2 shows η1-coordination with the metal center. Transformation of 332 into 333 proceeds through transition state TS64, located at 35.91 kcal mol-1 activation barrier. The reaction involves shifting of H5 towards C2. The high activation barrier may be attributed to 1,3- sigmatropic shift reaction. In an alternate way, the proton can shift intermolecularly where triflate ligand may abstract a proton from nitrogen and deliver it to carbon. Intermediate 333 shows enamine coordinated with Zn in a η1-fashion. In 333, the alkyne unit is suitably oriented towards the metal center, such that the amine deprotonation does not lead major structural reorganization. Finally, enamine undergoes tautomerization reaction to yield the reactive product imine.

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Figure 3.5.5 Potential energy diagram for hydroamination reaction through outer sphere mechanism and hydrogen transfer reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1

The kinetic barrier associated with mechanism suggests that the mechanism may be a plausible one. On the basis of these observations, we may argue that outer sphere nucleophilic attack of non-coordinated nitrogen on electrophilic coordinated carbon is a plausible mechanism. The plausible mechanism of zinc catalyzed hydroamination reaction of alkyne is then compared with other late transition metals catalyzed hydroamination reaction and it is found that the mechanism is in contradiction with other late transition metals such as Ru[210], Pd, Pt, and Au[211]. Inner sphere nucleophilic attack is found preferred in these metals. Zn catalyzed alkyne coordination followed by outer sphere mechanism for nucleophilic attack is an interesting aspect for further exploration in the area.

 Hydrogenation Reaction:

Hydrogenation reaction through hydrogen activation is also of particular interest for theoretical chemist and a large extend of research is under process to thoroughly

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elucidate the exact mechanism. The catalyst facilitates the reaction to proceed with a very low activation barriers but most of the hydrogenation catalysts are based on precious metals such as Pd, Au, Pt, Ir, Ru, and Rh. Role of non precious metals such as Zn is quite unusual and interesting in this regard. First example of Zn catalyzed hydrogenation reaction using hydrogen molecule is reported recently for reduction of imines. Utilizing the knowledge from literature about other metals catalyzed reaction, the mechanism can be broadly classified into four different approaches: (1) hydrogenation through dihydride route[212] (which was proposed originally by James, Bianchini, Oro and their research teams for hydrogenation of imine). In the mechanism, both hydrogen atoms first coordinate with metal center, followed by proton transfer to nitrogen and hydride towards electrophilic center. The sequence of hydrogen transfer may change or it may occur simultaneously. (2) Heterolytic cleavage of molecular hydrogen in which proton shifts towards ligand and hydride shift towards electrophilic centre. The mechanism is proposed by Stephan Enthaler for synthesis of secondary amines by zinc catalyzed reductive amination (PMHS was used as hydrogen source and Zn(OTf)2 as a catalyst, scheme 3.5.3).

Scheme 3.5.3 Zinc catalyzed hydrogenation of imines

(3) hydrogenation reaction operates from hydrogen cleavage in such away that proton shifts towards nitrogen and hydride towards zinc[213]. The mechanism is proposed by Preston. A et al, for Lewis acid catalyzed hydrogenation of imines and nitriles with hydrogen molecule. (4) proton transfer towards triflate ligand and hydride towards Zn center[214]. The mechanism is theoretically proposed by David Balcells et.al, for iridium catalyzed alkylation of amines with alcohol (Scheme 3.5.4). Mechanism 2-4 differs regarding the fate of proton and hydride, generated from heterolytic cleavage of H2 molecule.

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Scheme 3.5.4 Iridium catalyzed hydrogenation of imines

Hydrogenation of the hydroamination product (imine) have been investigated by four different approaches (vide supra). All the routes discussed are:

3.5.4 Hydrogen Cleavage on Zinc and Nitrogen

A number of attempts have been made to locate the transition state for dihydride route of hydrogen to metal center but all of them met with failure. The reason for this failure can be attributed to unstable (+4) oxidation state for zinc, generated after oxidative addition of H2 molecule on Zn center. Therefore, we focused on the other pathways, involving the heterolytic hydrogen cleavage in which proton shifts towards nitrogen and hydride towards zinc (Figure 3.5.6). Complex 333 changes its orientation to more stable 341 in which nitrogen is coordinated with the metal center. The kinetic demand for the reaction is 38.98 kcal mol-1. The high activation energy may be attributed to the low activating power of nitrogen for hydrogen cleavage. Intermediate 342 is 18.96 kcal mol-1 higher in energy than 341. The TS65 shows penta-coordinated zinc with two triflate ligands and one hydrogen, imine is not coordinated with Zn, the N4-H+ bond distance is 1.89 Å and Zn-H- is 1.90 Å, indicating the hydrogen shifting towards these both groups.

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Figure 3.5.6 Potential energy diagram for hydrogen activation on Zn and nitrogen calculated at B3LYP/6-31G(d). All energies are relative to 318 at 0.0 kcal mol-1.

3.5.5 Hydrogen Activation on Triflate and Electrophilic Carbon

Next, we studied heterolytic cleavage of molecular hydrogen to deliver proton to triflate and hydride to electrophilic carbon (Figure 3.5.7). The kinetic demand for the reaction is 42.42 kcal mol-1. The reason for such higher activation energy is low activating power of carbon for hydrogen activation. However, overall energy of the reaction is minimum (-31.54 kcal mol-1), which is accessible at reaction condition. The intermediate 343 is also 21.22 kcal mol-1 higher in energy than the 341 due to the bond loosening of stable Zn-O for generation of unstable Zn-N bond.

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Figure 3.5.7 Potential energy diagram for hydrogen activation on triflate and carbon calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1

3.5.6 Hydrogen Cleavage on Zinc and Triflate

Next we analyzed heterolytic hydrogen cleavage involving proton transfer towards triflate ligand and hydride towards Zn center (Figure 3.5.8). The transition state TS67 is found at activation barrier of 33.88 kcal mol-1 from 341. In TS67, Zn is coordinated with four atoms, i.e. two oxygens of triflate ligand, one nitrogen and one hydride. The geometry is distorted tetrahedral. The Zn-H and O-H bond distances are 1.68 Å and 1.35 Å respectively. The low activation barrier is attributed to the high power of metal and ligand for hydrogen activation. Here the catalyst acts like Lewis pair, containing Lewis acidic nature of Zn (II) and Lewis basic nature of triflate ligand. Acid attracts the hydride, while base attracts the proton, resulting in bond cleavage of hydrogen molecule. The intermediate 344 is 16.34 kcal mol-1 higher in energy than the 341. The high energy is attributed to the Zn-N bond formation which is less stable than Zn-O bond.

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Figure 3.5.8 Potential energy diagram for hydrogen activation reaction calculated at B3LYP/6-31G(d,p). All energies are relative to 318 at 0.0 kcal mol-1.

The final step of hydride shift from metal center to the electrophilic carbon have low energy barrier of 15.26 kcal mol-1 from 344.Transition state TS68 shows hydride between zinc and C1 with the bond distance of 1.56 Å and 2.1 Å respectively. Finally, TfOH re-enters and participates in the catalytic cycle. Product 345 is amine and -1 Zn(OTf)2. The reaction is also exothermic by 83.00 kcal mol .The activation energy and energy of reaction suggested that the mechanism is favorable kinetically and thermodynamically.

3.6 Conclusions

Density functional theory calculations have been performed to gain mechanistic insight of the cycloaddition, oxidation and hydroamination reactions catalyzed by titanium and zinc catalysis. The silyl moieties in 1,3 dielectrophiles are dynamic even in the absence of a metal catalyst (Eact < 5 kcal mol-1). The isomeric dielectrophiles (for example 162 and 162′) differ in their reactivity in formal [3 + 3] addition, and it

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depends on the strength of the positive charge (Mulliken charges) on the electrophilic carbon atom. Calculations reveal that a single mechanism can justify the experimentally observed different regioselectivities for 162 and 193 depending on the isomeric species entering in the catalytic cycle (211 and 214′). Direct-direct, direct- conjugate and conjugate-conjugate addition mechanisms have been studied for both isomeric forms of each dielectrophile. The calculations reveal that 1,2 addition of 1,3- bis(silyl enol ethers) on 1,3-dielectrophile is a favorable process over the conjugate addition. For the methyl analogue, the difference in the activation barriers for the direct and conjugate addition is even more pronounced in the favor of 1,2 addition (about 8.34 kcal mol-1). The trends in the activation barrier for 1,2 and 1,4 addition for both dielectrophiles can be correlated to Mulliken charges at the electrophilic centers. For zinc catalyzed oxidation of benzylic alcohols to esters, inner sphere, intermediate sphere, and outer sphere mechanisms are analyzed in the presence and absence of pyridine-2-carboxylic acid (ligand). Effect of halides (Br2 and I2), and oxidants

(TBHP and H2O2) have also been investigated. The inner sphere mechanism, which involves a hydride transfer to the transition metal, is found to be kinetically more demanding than the competitive intermediate sphere and outer sphere mechanism. In the presence of the ligand, the calculated activation barrier for β-hydride elimination (inner sphere) is 31.78 kcal mol-1. Intermediate sphere mechanism for oxidation of alcohol through ZnI2 in the presence of a ligand showed lowest activation energy among all catalyst systems (18.36 kcal mol-1). First oxidation step (alcohol oxidation) is found most favorable in the presence of a ligand through intermediate sphere mechanism. Ester oxidation reaction showed opposite effect than alcohol oxidation and is found at low activation barrier in the absence of a ligand. ZnBr2 catalyzed reaction is calculated at a lowest activation barrier (9.95 kcal mol-1). The reaction is -1 also favorable for ZnI2 catalyst (10.39 kcal mol ). In case of the mechanism of zinc catalyzed oxidative amidation, the inner sphere mechanism is kinetically more demanding (Ea = 30.59 kcal mol-1). The activation barrier associated with outer sphere mechanism is 24.4 kcal mol-1, which can be easily surpassed under the reaction conditions. Therefore, the more plausible mechanism is outer sphere mechanism. The oxidation of hemiaminal to amide is also kinetically highly favorable with Ea = 7.88 kcal mol-1 (outer sphere mechanism). The intermediate sphere mechanism involving

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transfer of hydrogen to tert-butyl hydrogen peroxide (TBHP) has activation barrier of 25.98 kcal mol-1, and therefore, cannot be excluded safely. The striking difference for the zinc catalyzed reaction from other metals (Ru, Ir, Pd) is the preference for outer sphere mechanism over inner and intermediate sphere mechanism. The mechanism of the zinc (II) catalyzed hydroamination-hydrogenation through molecular hydrogen as a reductant is also investigated by density functional theory methods, and the mechanistic outcomes are compared with those of other late transition metals. For hydroamination reaction, inner and outer sphere mechanisms for nucleophilic attack of nitrogen on electrophilic centre have been analyzed. The inner sphere mechanism is kinetically more demanding. Outer sphere route for nucleophilic attack of non- coordinated amine on coordinated alkyne is found most plausible. The overall energy of outer sphere mechanism in amine adduct also can be surpassed under the reaction conditions, therefore cannot be excluded safely. The plausible mechanism of zinc catalyzed hydroamination reaction of alkyne showed differences from the mechanism of the same reaction with other late transition metals. In Pd, Pt, Ru and Au, inner sphere mechanism operates. Hydrogenation of imine with four different pathways is investigated in the next studies. For hydrogenation reaction, heterolytic hydrogen cleavage involving proton shift on triflate ligand and hydride to metal is found most plausible over the competitive heterolytic H2 cleavage reactions. However, heterolytic hydrogen cleavage involving proton shift to nitrogen and hydride towards metal also cannot be excluded safely. Hydrogenation reaction is similar to some extend with iridium catalyzed hydrogenation reaction of imines, but the mechanism is in contradiction with other late transition metal catalyzed hydrogenation of imines.

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Chapter 4

4 References

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1. Halpern, J., (1968). General introduction-homogeneous catalysis of hydrogenation, oxidation and related reactions. Discussions of the Faraday Society, 46, 7-19. 2. Ma, J., Sun, N., Zhang, X., Zhao, N., Xiao, F., Wei, W. and Sun, Y., (2009). A

short review of catalysis for CO2 conversion. Catalysis Today, 148(3), 221- 231. 3. Kwong, F. Y., & Buchwald, S. L., (2002). A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides and thiols. Organic letters, 4(20), 3517-3520. 4. Ermakova, M., Ermakov, D. Y., Kuvshinov, G., (2000). Applied Catalysis A: General, 201, 61-70. 5. Gates, B.C., (1995). Supported metal clusters: synthesis, structure, and catalysis. Chemical reviews, 95(3), pp.511-522. 6. Nguyen, S. T., Grubbs, R. H., & Ziller, J. W. (1993). Synthesis and activities of new single-component, ruthenium-based olefin metathesis catalysts. Journal of the American Chemical Society, 115(21), 9858-9859. 7. Filippou, D., & Hudon, G., (2009). Iron removal and recovery in the titanium dioxide feedstock and pigment industries. Journal of the Minerals, metals, and Materials Society, 61(10), 36. 8. Fu, G.C., (2008). The development of versatile methods for palladium- catalyzed coupling reactions of aryl electrophiles through the use of P (t-Bu)3 and PCy3 as ligands. Accounts of chemical research, 41(11),1555-1564. 9. Stauffer, S. R., Lee, S., Stambuli, J. P., Hauck, S. I., & Hartwig, J. F. (2000). High turnover number and rapid, room-temperature amination of chloroarenes using saturated carbene ligands. Organic letters, 2(10), 1423-1426. 10. Lin, Y., & Finke, R. G. (1994). A More General Approach to Distinguishing" Homogeneous" from" Heterogeneous" Catalysis: Discovery of Polyoxoanion- + and Bu4N -Stabilized, Isolable and Redissolvable, High-Reactivity. Nanocluster Catalysts. Inorganic Chemistry, 33(22), 4891-4910. 11. Ciriminna, R., Carraro, M. L., Campestrini, S., & Pagliaro, M. (2008). Heterogeneous catalysis for fine chemicals in dense phase carbon dioxide. Advanced Synthesis & Catalysis, 350(2), 221-226. 12. Marnellos, G., & Stoukides, M. (1998). Ammonia synthesis at atmospheric pressure. Science, 282(5386), 98-100. 13. Cmolik, J., & Pokorny, J. (2000). Physical refining of edible oils. European Journal of Lipid Science and Technology, 102(7), 472-486. 14. Riisager, A., Eriksen, K. M., Wasserscheid, P., & Fehrmann, R. (2003). Propene and 1-octene hydroformylation with silica-supported, ionic liquid- phase (SILP) Rh-phosphine catalysts in continuous fixed-bed mode. Catalysis Letters, 90(3), 149-153.

154

15. Widegren, J. A., & Finke, R. G. (2003). A review of the problem of distinguishing true homogeneous catalysis from soluble or other metal-particle heterogeneous catalysis under reducing conditions. Journal of Molecular Catalysis A: Chemical, 198(1), 317-341. 16. Schroder, D., & Schwarz, H. (2008). Gas-phase activation of methane by ligated transition-metal cations. Proceedings of the National Academy of Sciences, 105(47), 18114-18119. 17. Zahmakıran, M., & Ozkar, S. (2011). Metal nanoparticles in liquid phase catalysis; from recent advances to future goals. Nanoscale, 3(9), 3462-3481. 18. Yates, K., & McClelland, R. A. (1967). Mechanisms of ester hydrolysis in aqueous sulfuric acids. Journal of the American Chemical Society, 89(11), 2686-2692. 19. Trost, B. M. (1995). Atom economy, a challenge for organic synthesis: homogeneous catalysis leads the way. Angewandte Chemie International Edition, 34(3), 259-281. 20. Pape, A. R., Kaliappan, K. P., & Kundig, E. P. (2000). Transition-metal- mediated dearomatization reactions. Chemical reviews, 100(8), 2917-2940. 21. Hagen, J. (2006). Homogeneously catalyzed industrial processes. Industrial Catalysis: A Practical Approach, Second Edition, 59-82. 22. Halpern, J. (1970). Oxidative-addition reactions of transition metal complexes. Accounts of Chemical Research, 3(11), 386-392. 23. Jones, W. D., & Feher, F. J. (1989). Comparative reactivities of hydrocarbon carbon-hydrogen bonds with a transition-metal complex. Accounts of Chemical Research, 22(3), 91-100. 24. Cavallo, L., Correa, A., Costabile, C., & Jacobsen, H. (2005). Steric and electronic effects in the bonding of N-heterocyclic ligands to transition metals. Journal of organometallic chemistry, 690(24), 5407-5413. 25. Yasuda, H., Nagasuna, K., Akita, M., Lee, K., & Nakamura, A. (1984). Zirconocene-. eta. 4-1, 3-pentadiene complex and its higher homologs. A new synthetic method involving. sigma.-. pi. rearrangement of the hydrido-2, 4- pentadienylzirconium species. Organometallics, 3(10), 1470-1478. 26. Bryndza, H. E., & Tam, W. (1988). Monomeric metal hydroxides, alkoxides, and amides of the late transition metals: synthesis, reactions, and thermochemistry. Chemical Reviews, 88(7), 1163-1188. 27. Nisa, R. U., Mahmood, T., Ludwig, R., & Ayub, K. (2016). Theoretical mechanistic investigation of zinc (II) catalyzed oxidation of alcohols to aldehydes and esters. RSC Advances, 6(38), 31876-31883. 28. Fleischer, M. (1954). The abundance and distribution of the chemical elements in the earth's crust. J. chem. Educ, 31(9), 446. 29. Enthaler, S. (2014). Zinc‐Catalyzed Depolymerization of End‐of‐Life Polysiloxanes. Angewandte Chemie, 126(10), 2754-2759.

155

30. Jensen, W. B. (2003). The place of zinc, cadmium, and mercury in the periodic table. Journal of Chemical Education, 80(8), 952. 31. Oshino, H., Nakamura, E., & Kuwajima, I. (1985). Catalytic homo- Reformatskii reaction. Ambident chemical reactivities of the zinc homoenolate of propionate. The Journal of Organic Chemistry, 50(15), 2802-2804. 32. Sase, S., Jaric, M., Metzger, A., Malakhov, V., & Knochel, P. (2008). One-pot Negishi cross-coupling reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates. The Journal of organic chemistry, 73(18), 7380-7382. 33. Trost, B. M., Yeh, V. S., Ito, H., & Bremeyer, N. (2002). Effect of ligand structure on the zinc-catalyzed henry reaction. asymmetric syntheses of (−)- denopamine and (−)-arbutamine. Organic letters, 4(16), 2621-2623. 34. Trost, B. M., Ito, H., & Silcoff, E. R. (2001). Asymmetric Aldol reaction via a dinuclear zinc catalyst: α-hydroxyketones as donors. Journal of the American Chemical Society, 123(14), 3367-3368. 35. Shimizu, T., & Seki, M. (2001). Palladium on charcoal-catalyzed Fukuyama coupling reaction. Tetrahedron Letters, 42(3), 429-432. 36. Li, T., Schulz, S., & Roesky, P. W. (2012). Synthesis, reactivity and applications of zinc–zinc bonded complexes. Chemical Society Reviews, 41(10), 3759-3771. 37. (a) Aresta, M., & Dibenedetto, A. (2007). Utilisation of CO2 as a chemical feedstock: opportunities and challenges. Dalton Transactions, (28), 2975- 2992.; (b) Kember, M. R., Buchard, A., & Williams, C. K. (2011). Catalysts for CO2/epoxide copolymerisation. Chemical Communications, 47(1), 141- 163. 38. Eberhardt, R., Allmendinger, M., Zintl, M., Troll, C.,Luinstras, A. G., & Rieger, B., (2004) New dicarboxylate catalysts for the CO2/propylene oxide copolymerization reaction. 205(1),42-47. 39. Kissling, S., Altenbuchner, P. T., Niemi, T., Repo, T., & Rieger, B. (2015). Zinc‐Catalyzed Transformation of Carbon Dioxide. Zinc Catalysis: Applications in Organic Synthesis, 179-206. 40. Kim, J. G., Cowman, C. D., LaPointe, A. M., Wiesner, U., & Coates, G. W. (2011). Tailored living block copolymerization: multiblock poly (cyclohexene carbonate) s with sequence control. Macromolecules, 44(5), 1110-1113. 41. Barnes, D. K., Galgani, F., Thompson, R. C., & Barlaz, M. (2009). Accumulation and fragmentation of plastic debris in global environments. Philosophical Transactions of the Royal Society of London B: Biological Sciences, 364(1526), 1985-1998.

156

42. Sato, O., Arai, K., & Shirai, M. (2005). Decomposition behavior of poly (ethylene-2, 6-naphthalene dicarboxylate) in high temperature water. Fluid phase equilibria, 228, 523-525. 43. (a) Bhar, S., & Ranu, B. C. (1995). Zinc-promoted selective cleavage of ethers in presence of acyl chloride. The Journal of Organic Chemistry, 60(3), 745- 747.; (b) Enthaler, S., & Weidauer, M. (2012). Synthesis of δ-and ε- Cyanoesters by Zinc-Catalyzed Ring-Opening of Cyclic Ethers with Acid Chlorides and Subsequent Cyanation. Catalysis letters, 142(2), 168-175. 44. Liu, Y., Wang, M., & Pan, Z. (2012). Catalytic depolymerization of polyethylene terephthalate in hot compressed water. The Journal of Supercritical Fluids, 62, 226-231. 45. Prakash, G. S., Iyer, P. S., Arvanaghi, M., & Olah, G. A. (1983). Zinc iodide catalyzed preparation of aroyl azides from aroyl chlorides and trimethylsilyl azide. The Journal of Organic Chemistry, 48(19), 3358-3359. 46. Lebel, H., & Leogane, O. (2005). Boc-protected amines via a mild and efficient one-pot Curtius rearrangement. Organic letters, 7(19), 4107-4110. 47. Demko, Z. P., & Sharpless, K. B. (2001). Preparation of 5-substituted 1 H- tetrazoles from nitriles in water. The Journal of organic chemistry, 66(24), 7945-7950. 48. Dong, H., Shen, M., Redford, J. E., Stokes, B. J., Pumphrey, A. L., & Driver, T. G. (2007). Transition metal-catalyzed synthesis of pyrroles from dienyl azides. Organic letters, 9(25), 5191-5194. 49. Hajra, S., Sinha, D., & Bhowmick, M. (2006). Metal triflate catalyzed highly regio-and stereoselective 1, 2-bromoazidation of alkenes using NBS and TMSN 3 as the bromine and azide sources. Tetrahedron letters, 47(39), 7017- 7019. 50. Kalita, B., Lamar, A. A., & Nicholas, K. M. (2008). Hydrous zinc halide- catalyzed aminosulfonation of hydrocarbons. Chemical Communications, (36), 4291-4293. 51. Yu, J., Liu, S. S., Cui, J., Hou, X. S., & Zhang, C. (2012). A Mild and Efficient Direct α-Amination of β-Dicarbonyl Compounds Using Iodosobenzene and p-Toluenesulfonamide Catalyzed by Perchlorate Zinc Hexahydrate. Organic letters, 14(3), 832-835. 52. Lebold, T. P., Leduc, A. B., & Kerr, M. A. (2009). Zn (II)-catalyzed synthesis of piperidines from propargyl amines and cyclopropanes. Organic letters, 11(16), 3770-3772. 53. Shivani, Pujala, B., & Chakraborti, A. K. (2007). Zinc (II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils. The Journal of organic chemistry, 72(10), 3713-3722.

157

54. Enthaler, S., & Wu, X. F. (Eds.). (2015). Zinc catalysis: applications in organic synthesis. John Wiley & Sons. 119-148. 55. Simmons, H. E., & Smith, R. D. (1958). A new synthesis of cyclopropanes from olefins. Journal of the American Chemical Society, 80(19), 5323-5324. 56. Reformatsky, S. (1887). Neue Synthese zweiatomiger einbasischer Sauren aus den Ketonen. European Journal of Inorganic Chemistry, 20(1), 1210-1211. 57. Baba, S., & Negishi, E. (1976). A novel stereospecific alkenyl-alkenyl cross- coupling by a palladium-or nickel-catalyzed reaction of alkenylalanes with alkenyl halides. Journal of the American Chemical Society, 98(21), 6729- 6731. 58. Irie, K., & Watanabe, K. I. (1980). Aldol condensations with metal (II) complex catalysts. Bulletin of the Chemical Society of Japan, 53(5), 1366- 1371. 59. Trost, B. M., & Ito, H. (2000). A direct catalytic enantioselective aldol reaction via a novel catalyst design. Journal of the American Chemical Society, 122(48), 12003-12004. 60. Liu, Y., Zhang, Y., Jee, N., & Doyle, M. P. (2008). Construction of highly functionalized diazoacetoacetates via catalytic Mukaiyama− Michael reactions. Organic letters, 10(8), 1605-1608. 61. Harada, S., Kumagai, N., Kinoshita, T., Matsunaga, S., & Shibasaki, M. (2003). Direct catalytic asymmetric Michael reaction of hydroxyketones: asymmetric Zn catalysis with a Et2Zn/linked-BINOL complex. Journal of the American Chemical Society, 125(9), 2582-2590. 62. Zhong, Y. W., Tian, P., & Lin, G. Q. (2004). New β-amino alcohols with a bicyclo [3.3. 0] octane scaffold in an asymmetric Henry reaction. Tetrahedron: Asymmetry, 15(5), 771-776. 63. Salter, M. M., Kobayashi, J., Shimizu, Y., & Kobayashi, S. (2006). Direct- type catalytic three-component mannich reactions leading to an efficient synthesis of α, β-diamino acid derivatives. Organic letters, 8(16), 3533-3536. 64. Takacs, J. M., Lawson, E. C., Reno, J. M., Youngman, M. A., & Quincy, D. A. (1997). Enantioselective Diels-Alder reactions: room temperature bis (oxazoline)-zinc,-magnesium, and-copper triflate catalysts. Tetrahedron: Asymmetry, 8(18), 3073-3078. 65. Hatano, M., Suzuki, S., & Ishihara, K. (2006). Highly efficient alkylation to ketones and aldimines with Grignard reagents catalyzed by zinc (II) chloride. Journal of the American Chemical Society, 128(31), 9998-9999. 66. Cozzi, P. G., Orioli, P., Tagliavini, E., & Umani-Ronchi, A. (1997). Enantioselective allylation of aldehydes promoted by chiral zinc bis (oxazoline) complexes. Tetrahedron letters, 38(1), 145-148. 67. Reber, S., Knopfel, T. F., & Carreira, E. M. (2003). Enantioselective total synthesis of (R)-strongylodiols A and B. Tetrahedron, 59(35), 6813-6817.

158

68. Yamamoto, Y., Onuki, S., Yumoto, M., & Asao, N. (1994). Zinc Chloride as a Radical Initiator as well as a Chelating Agent. Journal of the American Chemical Society, 116(1), 421-422. 69. Nakamura, M., Liang, C., & Nakamura, E. (2004). Zn (II)/amine-catalyzed coupling reaction of alkylidenemalonates with propargyl alcohol: a one-pot synthesis of methylenetetrahydrofurans. Organic letters, 6(12), 2015-2017. 70. Furukawa, J., Kawabata, N., & Nishimura, J. (1966). A novel route to cyclopropanes from olefins. Tetrahedron Letters, 7(28), 3353-3354. 71. Sniady, A., Durham, A., Morreale, M. S., Wheeler, K. A., & Dembinski, R. (2007). Room temperature zinc chloride-catalyzed cycloisomerization of alk- 3-yn-1-ones: synthesis of substituted furans. Organic letters, 9(7), 1175-1178. 72. Witte, H., & Seeliger, W. (1972). Simple Synthesis of 2‐Substituted 2‐ Oxazolines and 5, 6‐Dihydro‐4H‐1, 3‐oxazines. Angewandte Chemie International Edition, 11(4), 287-288. 73. Chen, W., Cai, Y., Fu, X., Liu, X., Lin, L., & Feng, X. (2011). Enantioselective one-pot synthesis of 2-amino-4-(indol-3-yl)-4 H- chromenes. Organic letters, 13(18), 4910-4913. 74. Sarvari, M. H., & Sharghi, H. (2004). Reactions on a Solid Surface. A Simple, Economical and Efficient Friedel− Crafts Acylation Reaction over Zinc Oxide (ZnO) as a New Catalyst. The Journal of organic chemistry, 69(20), 6953- 6956. 75. Singh, P. K., & Singh, V. K. (2009). Enantioselective Friedel− Crafts Alkylation of Pyrroles Catalyzed by PYBOX-DIPH-Zn (II) Complexes. Organic letters, 12(1), 80-83. 76. Trost, B. M., & Yeh, V. S. (2002). Stereocontrolled synthesis of (+)- boronolide. Organic letters, 4(20), 3513-3516. 77. Yuan, Z. L., Lei, Z. Y., & Shi, M. (2008). BINAM and H 8-BINAM-based chiral imines and Zn (OTf)2-catalyzed enantioselective Friedel–Crafts alkylation of indoles with nitroalkenes. Tetrahedron: Asymmetry, 19(11), 1339-1346. 78. Zhao, Y., Wang, H., Hou, X., Hu, Y., Lei, A., Zhang, H., & Zhu, L. (2006). Oxidative cross-coupling through double transmetallation: surprisingly high selectivity for palladium-catalyzed cross-coupling of alkylzinc and alkynylstannanes. Journal of the American Chemical Society, 128(47), 15048- 15049. 79. Negishi, E. (1982). Palladium-or nickel-catalyzed cross coupling. A new selective method for carbon-carbon bond formation. Accounts of Chemical Research, 15(11), 340-348. 80. Backvall, J.-E., Modern oxidation methods, John Wiley & Sons, (2011), 112- 130.

159

81. Hill, C. L. (2004). Stable, Self‐Assembling, Equilibrating Catalysts for Green Chemistry. Angewandte Chemie International Edition, 43(4), 402-404. 82. Frei, B., England, L., & Ames, B. N. (1989). Ascorbate is an outstanding antioxidant in human blood plasma. Proceedings of the National Academy of Sciences, 86(16), 6377-6381. 83. Yu, H. B., Zheng, X. F., Lin, Z. M., Hu, Q. S., Huang, W. S., & Pu, L. (1999). Asymmetric Epoxidation of α, β-Unsaturated Ketones Catalyzed by Chiral Polybinaphthyl Zinc Complexes: Greatly Enhanced Enantioselectivity by a Cooperation of the Catalytic Sites in a Polymer Chain. The Journal of organic chemistry, 64(22), 8149-8155. 84. Cao, H. T., & Gree, R. (2009). DEAD-(cat) ZnBr2 an efficient system for the oxidation of alcohols to carbonyl compounds. Tetrahedron Letters, 50(13), 1493-1494. 85. Wang, P., Cai, J., Yang, J., Sun, C., Li, L., Hu, H., & Ji, M. (2013). Zinc (II)- catalyzed oxidation of alcohols to carbonyl compounds with chloramine- T. Tetrahedron Letters, 54(6), 533-535. 86. Muthupandi, P., & Sekar, G. (2011). Zinc-catalyzed aerobic oxidation of benzoins and its extension to enantioselective oxidation. Tetrahedron letters, 52(6), 692-695. 87. Wu, X. F. (2012). A General and Efficient Zinc‐Catalyzed Oxidation of Benzyl Alcohols to Aldehydes and Esters. Chemistry-A European Journal, 18(29), 8912-8915. 88. Wu, X. F. (2012). A General and Efficient Zinc‐Catalyzed Oxidation of Benzyl Alcohols to Aldehydes and Esters. Chemistry-A European Journal, 18(29), 8912-8915. 89. Allen, C. L., Burel, C., & Williams, J. M. (2010). Cost efficient synthesis of amides from oximes with indium or zinc catalysts. Tetrahedron Letters, 51(20), 2724-2726. 90. Wu, X. F., Sharif, M., Pews‐Davtyan, A., Langer, P., Ayub, K., & Beller, M. (2013). The First ZnII‐Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines under Solvent‐Free Conditions. European Journal of Organic Chemistry, 2013(14), 2783-2787. 91. Haskel, A., Straub, T., & Eisen, M. S. (1996). Organoactinide-catalyzed intermolecular hydroamination of terminal alkynes. Organometallics, 15(18), 3773-3775. 92. Zhang, Z., Bender, C. F., & Widenhoefer, R. A. (2007). Gold (I)-catalyzed enantioselective hydroamination of N-allenyl carbamates. Organic letters, 9(15), 2887-2889. 93. Müller, T. E., & Pleier, A. K. (1999). Intramolecular hydroamination of alkynes catalysed by late transition metals. Journal of the Chemical Society, Dalton Transactions, 4, 583-588.

160

94. Jenter, J., Lühl, A., Roesky, P. W., & Blechert, S. (2011). Aminotroponiminate zinc complexes as catalysts for the intramolecular hydroamination. Journal of Organometallic Chemistry, 696(1), 406-418. 95. Zulys, A., Dochnahl, M., Hollmann, D., Löhnwitz, K., Herrmann, J. S., Roesky, P. W., & Blechert, S. (2005). Intramolecular hydroamination of functionalized alkenes and alkynes with a homogenous zinc catalyst. Angewandte Chemie International Edition, 44(47), 7794-7798. 96. Dochnahl, M., Lohnwitz, K., Pissarek, J. W., Biyikal, M., Schulz, S. R., Schoen, S., & Blechert, S. (2007). Intramolecular Hydroamination with Homogeneous Zinc Catalysts: Evaluation of Substituent Effects in N, N′‐ Disubstituted Aminotroponiminate Zinc Complexes. Chemistry-A European Journal, 13(23), 6654-6666. 97. Biyikal, M., Lohnwitz, K., Roesky, P. W., & Blechert, S. (2008). Preparation and catalytic performance of novel dimeric tetranuclear zinc complexes in hydroamination of alkenes at room temperature. Synlett, 2008(20), 3106-3110. 98. Pissarek, J. W., Schlesiger, D., Roesky, P. W., & Blechert, S. (2009). Diethylzinc: a simple and efficient catalyst for the swift hydroamination at room temperature. Advanced Synthesis & Catalysis, 351(13), 2081-2085. 99. Shanbhag, G. V., & Halligudi, S. B. (2004). Intermolecular hydroamination of alkynes catalyzed by zinc-exchanged montmorillonite clay. Journal of Molecular Catalysis A: Chemical, 222(1), 223-228. 100. Alex, K., Tillack, A., Schwarz, N., & Beller, M. (2008). General Zinc‐ Catalyzed Intermolecular Hydroamination of Terminal Alkynes. ChemSusChem, 1(4), 333-338. 101. Alex, K., Tillack, A., Schwarz, N., & Beller, M. (2008). Zinc‐Promoted Hydrohydrazination of Terminal Alkynes: An Efficient Domino Synthesis of Indoles. Angewandte Chemie International Edition, 47(12), 2304-2307. 102. Pews-Davtyan, A., & Beller, M. (2011). A novel Zn-catalyzed hydroamination of propargylamides: a general synthesis of di-and tri-substituted imidazoles. Chemical Communications, 47(7), 2152-2154. 103. Prior, A. M., & Robinson, R. S. (2008). An assessment of late transition metals as hydroamination catalysts in the cyclization of C-propargyl vinylogous amides into pyrroles. Tetrahedron Letters, 49(3), 411-414. 104. Tsuchimoto, T., Aoki, K., Wagatsuma, T., & Suzuki, Y. (2008). Lewis Acid Catalyzed Addition of Pyrazoles to Alkynes: Selective Synthesis of Double and Single Addition Products. European Journal of Organic Chemistry, 2008(23), 4035-4040. 105. Okuma, K., Seto, J. I., Sakaguchi, K. I., Ozaki, S., Nagahora, N., & Shioji, K. (2009). Palladium-free zinc-mediated hydroamination of alkynes: efficient synthesis of indoles from 2-akynylaniline derivatives. Tetrahedron Letters, 50(24), 2943-2945.

161

106. Patil, N. T., & Singh, V. (2011). Synthesis of 1, 3, 5-trisubstituted pyrazolines via Zn(II) catalyzed double hydroamination of enynes with aryl hydrazines. Chemical Communications, 47(39), 11116-11118. 107. (a) Riant, O., Mostefai, N., & Courmarcel, J. (2004). Recent advances in the asymmetric hydrosilylation of ketones, imines and electrophilic double bonds. Synthesis, 2004(18), 2943-2958.; (b) Selke, R., & Pracejus, H. (1986). Phosphinites of carbohydrates as chiral ligands for asymmetric synthesis catalyzed by complexes. Journal of molecular catalysis, 37, 213-225. 108. Mimoun, H. (1999). Selective reduction of carbonyl compounds by polymethylhydrosiloxane in the presence of metal hydride catalysts. The Journal of organic chemistry, 64(7), 2582-2589. 109. Sakai, N., Nonomura, Y., Ikeda, R., & Konakahara, T. (2013). Zinc-catalyzed Reduction of Aldehydes with a Hydrosilane Leading to Symmetric Ethers and Silyl Ethers. Chemistry Letters, 42(5), 489-491. 110. Andersson, P. G., & Munslow, I. J. (Eds.). (2008). Modern reduction methods. John Wiley & Sons, 104-120 111. Lawrence, N. J., Drew, M. D., & Bushell, S. M. (1999). Polymethylhydrosiloxane: a versatile reducing agent for organic synthesis. Journal of the Chemical Society, Perkin Transactions, 23, 3381- 3391. 112. Bette, V., Mortreux, A., Savoia, D., & Carpentier, J. F. (2004). New developments in zinc-catalyzed asymmetric hydrosilylation of ketones with PMHS. Tetrahedron, 60(12), 2837-2842. 113. Enthaler, S. (2011). A straightforward zinc-catalysed reduction of sulfoxides to sulfides. Catalysis Science & Technology, 1(1), 104-110. 114. Wu, X. F., & Neumann, H. (2012). Zinc Catalyzed Organic Synthesis: C-C, C- N, C- O Bond Formation Reactions. Advanced Synthesis & Catalysis, 354(17), 3141-3160. 115. Werkmeister, S., Fleischer, S., Junge, K., & Beller, M. (2012). Towards a Zinc Catalyzed Asymmetric Hydrogenation/Transfer Hydrogenation of Imines. Chemistry–An Asian Journal, 7(11), 2562-2568. 116. Jochmann, P., & Stephan, D. W. (2013). H2 Cleavage, Hydride Formation, and Catalytic Hydrogenation of Imines with Zinc Complexes of C5Me5 and N- Heterocyclic Carbenes. Angewandte Chemie International Edition, 52(37), 9831-9835. 117. Bonaga, L. V., Zhang, H. C., Moretto, A. F., Ye, H., Gauthier, D. A., Li, J., & Maryanoff, B. E. (2005). Synthesis of macrocycles via cobalt-mediated [2+ 2+ 2] cycloadditions. Journal of the American Chemical Society, 127(10), 3473-3485. 118. Ramesha, S., Bhojya Naik, H. S., & Harish Kumar, H. N. (2007). Titanium trichloride-catalysed cyclocondensation: synthesis of 2-mercaptoquinoline

162

substituted 1, 2, 3, 4-tetrahydropyrimidinones. Journal of Sulfur Chemistry, 28(6), 573-579. 119. Aaron L. O. (2004) New C-N and C-C bond forming reactions catalyzed by titanium complexes. Dalton Trans, 2005, 225-233 120. Bandini, M., Cozzi, P. G., Morganti, S., & Umani-Ronchi, A. (1999). Highly diastereoselective pinacol coupling of aldehydes catalyzed by titanium-Schiff base complexes. Tetrahedron letters, 40(10), 1997-2000. 121. Narasaka, K., Bald, E., & Mukaiyama, T. (1975). The Claisen rearrangement promoted by titanium tetrachloride. Chemistry Letters, 4(10), 1041-1044. 122. Gennari, C., Bernardi, A., Colombo, L., & Scolastico, C. (1985). Enantioselective synthesis of anti-. alpha.-methyl-. beta.-hydroxy esters through titanium tetrachloride-mediated aldol condensation. Journal of the American Chemical Society, 107(20), 5812-5813. 123. Chan, T. H., & Brownbridge, P. (1979). Reaction of electrophiles with 1, 3-bis (trimethylsiloxy)-1-methoxybuta-1, 3-diene, a dianion equivalent of methyl acetoacetate. Journal of the Chemical Society, Chemical Communications, (13), 578-579. 124. Martin, S., Ulrich, P., and Gernot, F. (1997). On the Mechanism of McMurry reaction. Angewandte Chemie International Edition Engl.,36, 2234-2237 125. Gaussian 09, Revision C.01, Frisch, M. J., Trucks, G. W., Schlegel, H. B., Scuseria, G. E., Robb, M. A., J. R. Cheeseman, G. Scalmani, V. Barone, G. A. Petersson, H. Nakatsuji, X. Li, M. Caricato, A. Marenich, J. Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P. Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D. Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B. Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G. Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K. Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R. Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O. Farkas, J. B. Foresman, and D. J. Fox, Gaussian, Inc., Wallingford CT, (2010). 126. Specowius, V., Bendrath, F., Winterberg, M., Ayub, K., & Langer, P. (2012). Synthesis of Functionalized Indolizines by Lewis Acid Mediated Cyclocondensation of 3(Pyridin2yl) propiolates with Enones. Advanced Synthesis & Catalysis, 354(6), 1163-1169. 127. Hariharan, P. C., & Pople, J. A. (1973). The influence of polarization functions on molecular orbital hydrogenation energies. Theoretical Chemistry Accounts: Theory, Computation, and Modeling (Theoretica Chimica Acta), 28(3), 213-222.

163

128. Roos, B. O., Fülscher, M., Malmqvist, P. Å., Merchan, M., & Serrano-Andres, L. (1995). Theoretical studies of the electronic spectra of organic molecules. Quantum Mechanical Electronic Structure Calculations with Chemical Accuracy, 357-438. 129. Waghmare, U. V., Kim, H., Park, I. J., Modine, N., Maragakis, P., & Kaxiras, E. (2001). HARES: an efficient method for first-principles electronic structure calculations of complex systems. Computer physics communications, 137(3), 341-360. 130. Nova, A., Balcells, D., Schley, N. D., Dobereiner, G. E., Crabtree, R. H., & Eisenstein, O. (2010). An Experimental− Theoretical Study of the Factors That Affect the Switch between Ruthenium-Catalyzed Dehydrogenative Amide Formation versus Amine Alkylation. Organometallics, 29(23), 6548- 6558. 131. Wang, Z. J., Benitez, D., Tkatchouk, E., Goddard III, W. A., & Toste, F. D. (2010). Mechanistic Study of Gold (I)-Catalyzed Intermolecular Hydroamination of Allenes. Journal of the American Chemical Society, 132(37), 13064-13071. 132. Nijveldt, R. J., Van Nood, E. L. S., Van Hoorn, D. E., Boelens, P. G., Van Norren, K., & Van Leeuwen, P. A. (2001). Flavonoids: a review of probable mechanisms of action and potential applications. The American journal of clinical nutrition, 74(4), 418-425. 133. Brunsveld, L., Folmer, B. J. B., Meijer, E. W., & Sijbesma, R. P. (2001). Supramolecular polymers. Chemical Reviews, 101(12), 4071-4098. 134. Rappoport, Z., The Chemistry of Phenols, John Wiley & Sons, (2004). 135. Chupakhin, O. N., Charushin, V. N., & Van der Plas, H. C. (2012). Nucleophilic aromatic substitution of hydrogen. Academic Press.300-320. 136. Langenaeker, W., Demel, K., & Geerlings, P. (1991). Electrophilic substitution on mono-substituted benzenes. Journal of Molecular Structure: THEOCHEM, 234, 329-342., and reference herein. 137. Miyaura, N., & Suzuki, A. (1995). Palladium-catalyzed cross-coupling reactions of organoboron compounds. Chemical reviews, 95(7), 2457-2483. 138. Karapetyan, G., T Dang, T., Sher, M., V Ghochikyan, T., Saghyan, A., & Langer, P. (2012). Diversity-oriented synthesis of functionalized phenols by regioselective [3+ 3] cyclocondensations of 1, 3-bis (silyloxy)-1, 3-butadienes with 3-alkoxy-2-en-1-ones and related substrates. Current Organic Chemistry, 16(5), 557-565. 139. Shkoor, G., M.Sc. Thesis, University of Rostock, (2010), 8-10. 140. Dötz, K. H., & Tomuschat, P. (1999). Annulation reactions of chromium carbene complexes: scope, selectivity and recent developments. Chemical Society Reviews, 28(3), 187-198.

164

141. Danheiser, R. L., Brisbois, R. G., Kowalczyk, J. J., & Miller, R. F. (1990). An annulation method for the synthesis of highly substituted polycyclic aromatic and heteroaromatic compounds. Journal of the American Chemical Society, 112(8), 3093-3100. 142. Serra, S., Fuganti, C., & Moro, A. (2001). Regiospecific Synthesis of Heterosubstituted Phenols from 3-Alkoxycarbonyl-3, 5-dienoic Acids via Benzannulation Reaction. The Journal of organic chemistry, 66(23), 7883- 7888. 143. Feist, H., & Langer, P. (2007). One pot synthesis of functionalized carbacycles by formal [3+3] cyclizations of 1,3-bis(silyl enol ethers) with 1,3- dielectrophiles. Synthesis, 2007(03), 327-347. 144. Mukaiyama, T. (1977). Titanium tetrachloride in organic synthesis. Angewandte Chemie International Edition, 16(12), 817-826. 145. Ramesha, S., Bhojya Naik, H. S., & Harish Kumar, H. N. (2007). Titanium trichloride-catalysed cyclocondensation: synthesis of 2-mercaptoquinoline substituted 1, 2, 3, 4-tetrahydropyrimidinones. Journal of Sulfur Chemistry, 28(6), 573-579. 146. Ali, A. H., Dembitsky M.V., & Srebnik, M., (1985), Esters and Agrochemicals. 1985(6), 357-395. 147. Larock, R. C. R. C., Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley-VCH, New York, USA, 2nd edn, (1999),362-367. 148. Liu, K, S., (1994) Preparation of fatty acids methyl esters for gas chromatographic analysis of lipids in biological materials. Journal of the American Oil Chemists Society, 71(11),1179-1187. 149. (a) Brennfuhrer, A., Neumann, H., & Beller, M. (2009). Palladium‐Catalyzed Carbonylation Reactions of Aryl Halides and Related Compounds. Angewandte Chemie International Edition, 48(23), 4114-4133. (b) Rout, S. K., Guin, S., Ghara, K. K., Banerjee, A., & Patel, B. K. (2012). Copper catalyzed oxidative esterification of aldehydes with alkylbenzenes via cross dehydrogenative coupling. Organic letters, 14(15), 3982-3985. 150. Gowrisankar, S., Neumann, H., & Beller, M. (2011). General and Selective Palladium‐Catalyzed Oxidative Esterification of Alcohols. Angewandte Chemie International Edition, 50(22), 5139-5143. 151. Liu, C., Wang, J., Meng, L., Deng, Y., Li, Y., & Lei, A. (2011). Palladium‐ Catalyzed Aerobic Oxidative Direct Esterification of Alcohols. Angewandte Chemie, 123(22), 5250-5254. 152. Lenick, J., Dacula, S, L,(2001)Guerbert Chemistry, Journal of Surfactants and Dtergents, 4(3), 311-315. 153. Bai, X. F., Ye, F., Zheng, L. S., Lai, G. Q., Xia, C. G., & Xu, L. W. (2012). Hydrosilane and bismuth-accelerated palladium catalyzed aerobic oxidative

165

esterification of benzylic alcohols with air. Chemical Communications, 48(68), 8592-8594. 154. (a) Liu, C., Tang, S., & Lei, A. (2013). Oxidant controlled Pd-catalysed selective oxidation of primary alcohols. Chemical Communications, 49(13), 1324-1326. (b) Oliveira, R. L., Kiyohara, P. K., & Rossi, L. M. (2009). Clean preparation of methyl esters in one-step oxidative esterification of primary alcohols catalyzed by supported gold nanoparticles. Green Chemistry, 11(9), 1366-1370. (c) Miyamura, H., Yasukawa, T., & Kobayashi, S. (2010). Aerobic oxidative esterification of alcohols catalyzed by polymer-incarcerated gold nanoclusters under ambient conditions. Green Chemistry, 12(5), 776-778. 155. Wu, X. F. (2012). Zinc-catalyzed oxidative esterification of aromatic aldehydes. Tetrahedron Letters, 53(26), 3397-3399. 156. Song, Z. Z., Gong, J. L., Zhang, M., & Wu, X. F. (2012). Zinc‐ Catalyzed Oxidative Transformation of Benzylic Ethers: A General Procedure for Aldehyde Synthesis. Asian Journal of Organic Chemistry, 1(3), 214-217. 157. (a) Zassinovich, G., Mestroni, G., & Gladiali, S. (1992). Asymmetric hydrogen transfer reactions promoted by homogeneous transition metal catalysts. Chemical Reviews, 92(5), 1051-1069. (b) Samec, J. S., Backvall, J. E., Andersson, P. G., & Brandt, P. (2006). Mechanistic aspects of transition metal-catalyzed hydrogen transfer reactions. Chemical Society Reviews, 35(3), 237-248. 158. Noyori, R., & Ohkuma, T. (2001). Asymmetric Catalysis by Architectural and Functional Molecular Engineering: Practical Chemo and Stereoselective Hydrogenation of Ketones. Angewandte Chemie International Edition, 40(1), 40-73. 159. Dunn, B. M., Ploegh, H. L., Speicher, D. W., & Wingfield, P. T. (2000). Current protocols in protein science, 1-2. 160. Kung, P. P., Huang, B., Zhang, G., Zhou, J. Z., Wang, J., Digits, J. A., & Elleraas, J. (2009). Dihydroxyphenylisoindoline amides as orally bioavailable inhibitors of the heat shock protein 90 (hsp90) molecular chaperone. Journal of medicinal chemistry, 53(1), 499-503. 161. Glomb, M. A., & Pfahler, C. (2001). Amides are novel protein modifications formed by physiological sugars. Journal of Biological Chemistry, 276(45), 41638-41647. 162. Garrod, L. P. (1960). The relative antibacterial activity of four penicillins. British Medical Journal, 2(5214), 1695. 163. Passie, T., Halpern, J. H., Stichtenoth, D. O., Emrich, H. M., & Hintzen, A. (2008). The pharmacology of lysergic acid diethylamide: a review. CNS Neuroscience & Therapeutics, 14(4), 295-314. 164. Sewald, N., & Jakubke, H. D. (2002). Application of Peptides and Proteins. Peptides: Chemistry and Biology, 403-428.

166

165. Bray, B. L. (2003). Large-scale manufacture of peptide therapeutics by chemical synthesis. Nature reviews. Drug discovery, 2(7), 587. 166. Braese, S., & Meijere, A. D. (2004). Cross-Coupling of Organyl Halides with Alkenes: the Heck Reaction. Metal-Catalyzed Cross-Coupling Reactions, Second Edition, 217-315. 167. Aube, J., & Milligan, G. L. (1991). Intramolecular Schmidt reaction of alkyl azides. Journal of the American Chemical Society, 113(23), 8965-8966. 168. Ritter, J. J., & Minieri, P. P. (1948). A new reaction of nitriles. I. Amides from alkenes and mononitriles. Journal of the American Chemical Society, 70(12), 4045-4048. 169. (a) Beckmann, E. (1886). Zur Kenntniss der Isonitrosoverbindungen. European Journal of Inorganic Chemistry, 19(1), 988-993. (b) Horning, E. C., Stromberg, V. L., & Lloyd, H. A. (1952). Beckmann rearrangements. An investigation of special cases. Journal of the American Chemical Society, 74(20), 5153-5155. 170. Ugi, I., & Steinbrückner, C. (1960). Uber ein neues Kondensations Prinzip. Angewandte Chemie, 72(78), 267-268. 171. Pattabiraman, V. R., & Bode, J. W. (2011). Rethinking amide bond synthesis. Nature, 480(7378), 471-480. 172. Murahashi, S., Naota, T., & Saito, E. (1986). Ruthenium-catalyzed amidation of nitriles with amines. A novel, facile route to amides and polyamides. Journal of the American Chemical Society, 108(24), 7846-7847. 173. Tamaru, Y., Yamada, Y., & Yoshida, Z. I. (1983). Direct oxidative transformation of aldehydes to amides by palladium catalysis. Synthesis, 1983(06), 474-476. 174. Gunanathan, C., Ben-David, Y., & Milstein, D. (2007). Direct synthesis of amides from alcohols and amines with liberation of H2. Science, 317(5839), 790-792. 175. Schleker, P. P. M., Honeker, R., Klankermayer, J., & Leitner, W. (2013). Catalytic Dehydrogenative Amide and Ester Formation with Rhenium– Triphos Complexes. ChemCatChem, 5(7), 1762-1764. 176. Gaspa, S., Porcheddu, A., & De Luca, L. (2013). Iron-catalysed oxidative amidation of alcohols with amines. Organic & biomolecular chemistry, 11(23), 3803-3807. 177. Bantreil, X., Fleith, C., Martinez, J., & Lamaty, F. (2012). Copper Catalyzed Direct Synthesis of Benzamides from Alcohols and Amines. ChemCatChem, 4(12), 1922-1925. 178. Wu, X. F., Sharif, M., Pews. Davtyan, A., Langer, P., Ayub, K., & Beller, M. (2013). The First ZnII Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines under Solvent Free Conditions. European Journal of Organic Chemistry, 2013(14), 2783-2787.

167

179. De Duve, C. (1995). The beginnings of life on earth. American Scientist, 83(5), 428-437. 180. Volante, R. P. (1981). A new, highly efficient method for the conversion of alcohols to thiolesters and thiols. Tetrahedron Letters, 22(33), 3119-3122. 181. Beller, M., Cornils, B., Frohning, C. D., & Kohlpaintner, C. W. (1995). Progress in hydroformylation and carbonylation. Journal of Molecular Catalysis A: Chemical, 104(1), 17-85. 182. Costa, M. V., de Sequeira Aguiar, L. C., Malta, L. F. B., Viana, G. M., & Costa, B. B. (2016). Simple and efficient methodology to prepare guanidines from 1, 3-disubstituted thioureas. Tetrahedron Letters, 57(14), 1585-1588. and references therein 183. Peterlin-Masic L., & Kikelj, D. (2001). Arginine mimetics. Tetrahedron, 57(33), 7073-7105. 184. Katla, V. R., Syed, R., Kuruva, C. S., Kuntrapakam, H. K., & Chamarthi, N. R. (2013). Synthesis of novel phosphorylated guanidine derivatives from cyanamide and their anti-inflammatory activity. Chemical and Pharmaceutical Bulletin, 61(1), 25-32. 185. Magano, J. (2009). Synthetic approaches to the neuraminidase inhibitors zanamivir (Relenza) and oseltamivir phosphate (Tamiflu) for the treatment of influenza. Chemical reviews, 109(9), 4398-4438. 186. Berlinck, R. G., Burtoloso, A. C. B., & Kossuga, M. H. (2008). The chemistry and biology of organic guanidine derivatives. Natural product reports, 25(5), 919-954. 187. Alonso-Moreno, C., Antinolo, A., Carrillo-Hermosilla, F., & Otero, A. (2014). Guanidines: from classical approaches to efficient catalytic syntheses. Chemical Society Reviews, 43(10), 3406-3425. 188. Viana, G. M., de Sequeira Aguiar, L. C., de Araújo Ferrão, J., Simas, A. B. C., & Vasconcelos, M. G. (2013). The use of aqueous potassium dichloroiodate for the synthesis of ureas. Tetrahedron Letters, 54(8), 936-940. 189. Lawrence, S. A., (2004), Amines: synthesis, properties and applications. Cambridge University Press, UK, 8-10. 190. Gunanathan, C., Ben-David Y., and Milstein, D., (2007), Synthesis of Amides from Alcohols and Amines with Liberation of H2 ,Science 80(317), 790–792. 191. Bytschkov, I., & Doye, S. (2001). Microwave Assisted Catalytic Intermolecular Hydroamination of Alkynes. European Journal of Organic Chemistry, 2001(23), 4411-4418. 192. Nisa, R. U., & Ayub, K. (2017). Mechanism of Zn(OTf)2 Catalyzed Hydroamination-Hydrogenation of Alkynes with Amines: Insight from Theory. New Journal of Chemistry. 41(12), 5082-5090.

168

193. Vorbruggen, H., & Krolikiewicz, K. (1984). Amination, Trimethylsilanol as Leaving Group, Silylation—Amination of Hydroxy N-Heterocycles. European Journal of Inorganic Chemistry, 117(4), 1523-1541. 194. Balaraman, E., Gnanaprakasam, B., Shimon, L. J., & Milstein, D. (2010). Direct hydrogenation of amides to alcohols and amines under mild conditions. Journal of the American Chemical Society, 132(47), 16756-16758. 195. Li, J. J., Springer Sci. Bus. Media, (2010), Name reactions: a collection of detailed mechanisms and synthetic applications. Springer Science & Business Media.1-10. 196. Salvatore, R. N., Yoon, C. H., & Jung, K. W. (2001). Synthesis of secondary amines. Tetrahedron, 57(37), 7785-7811. 197. Beller, M., H. Trauthwein, M. Eichberger, C. Breindl, Herwig, T. E. Müller, O. R. Thiel, Chemistry. A European Journal., 1999(5), 1306–1319. 198. Senn, H. M., Blöchl, P. E., & Togni, A. (2000). Toward an alkene hydroamination catalyst: static and dynamic ab initio DFT studies. Journal of the American Chemical Society, 122(17), 4098-4107. 199. Pohlki, F., & Doye, S. (2003). The catalytic hydroamination of alkynes. Chemical Society Reviews, 32(2), 104-114. 200. Gagne, M. R., & Marks, T. J. (1989). Organolanthanide-catalyzed hydroamination. Facile, regiospecific cyclization of unprotected amino olefins. Journal of the American Chemical Society, 111(11), 4108-4109. 201. Haskel, A., Straub, T., & Eisen, M. S. (1996). Organoactinide-catalyzed intermolecular hydroamination of terminal alkynes. Organometallics, 15(18), 3773-3775. 202. Muller, T. E., Hultzsch, K. C., Yus, M., Foubelo, F., & Tada, M. (2008). Hydroamination: direct addition of amines to alkenes and alkynes. Chemical Reviews, 108(9), 3795-3892. 203. Hultzsch, K. C. (2005). Catalytic asymmetric hydroamination of non-activated olefins. Organic & Biomolecular chemistry, 3(10), 1819-1824. 204. Zhang, Z., Bender, C. F., & Widenhoefer, R. A. (2007). Gold (I)-catalyzed enantioselective hydroamination of N-allenyl carbamates. Organic Letters, 9(15), 2887-2889. 205. Huehls, C. B., Lin, A., & Yang, J. (2014). Iron-Catalyzed Intermolecular Hydroamination of Styrenes. Organic Letters, 16(14), 3620-3623. 206. (a) Blieck, R., Bahri, J., Taillefer, M., & Monnier, F. (2016). Copper- catalyzed hydroamination of terminal allenes. Organic letters, 18(6), 1482- 1485. (b) Rucker, R. P., Whittaker, A. M., Dang, H., & Lalic, G. (2012). Synthesis of tertiary alkyl amines from terminal alkenes: copper-catalyzed amination of alkyl boranes. Journal of the American Chemical Society, 134(15), 6571-6574. (c) Miki, Y., Hirano, K., Satoh, T., & Miura, M. (2013). Copper Catalyzed Intermolecular Regioselective Hydroamination of

169

Styrenes with Polymethylhydrosiloxane and Hydroxylamines. Angewandte Chemie International Edition, 52(41), 10830-10834. (d) Martín, R., Rodríguez Rivero, M., & Buchwald, S. L. (2006). Domino Cu Catalyzed C- N Coupling/Hydroamidation: A Highly Efficient Synthesis of Nitrogen Heterocycles. Angewandte Chemie International Edition, 45(42), 7079-7082. (b) Shi, S. L., & Buchwald, S. L. (2015). Copper-catalyzed selective hydroamination reactions of alkynes. Nature chemistry, 7(1), 38. 207. Zhang, M., & Wu, X. F. (2013). Zinc (II)-catalyzed oxidative amidation of arylaldehydes with alkylamines under solvent-free conditions. Tetrahedron Letters, 54(9), 1059-1062. 208. Meyer, N., Löhnwitz, K., Zulys, A., Roesky, P. W., Dochnahl, M., & Blechert, S. (2006). Aminotroponate zinc complexes as catalysts for the intramolecular hydroamination of alkenes and alkynes. Organometallics, 25(15), 3730-3734. 209. Werkmeister, S., Fleischer, S., Zhou, S., Junge, K., & Beller, M. (2012). Development of new hydrogenations of imines and benign reductive hydroaminations: zinc triflate as a catalyst. ChemSusChem, 5(4), 777-782. 210. Uchimaru, Y. (1999). N–H activation vs. C–H activation: ruthenium-catalysed regioselective hydroamination of alkynes and hydroarylation of an alkene with N-methylaniline. Chemical Communications, 12, 1133-1134. 211. (a) Rekhroukh, F., Blons, C., Estevez, L., Mallet-Ladeira, S., Miqueu, K., Amgoune, A., & Bourissou, D. (2017). Gold (III)–arene complexes by insertion of olefins into gold–aryl bonds. Chemical Science.(b) Nobis, M., and Drieben-Holscher, B., (2001), Recent Developments in Transition Metal Catalyzed Intermolecular Hydroamination Reactions—A Breakthrough? Angewandte. Chemie International Edition., 40, 3983-3985. 212. Fabrello, A., Bachelier, A., Urrutigoïty, M., and Kalck, P., (2010), Mechanistic analysis of the transition metal-catalyzed hydrogenation of imines and functionalized enamines. Coordination Chemistry Review, 254, 273–287. 213. Chase, P. A., Jurca, T., and Stephan, D. W., (2008), Lewis acid-catalyzed

hydrogenation: B(C6F5)3-mediated reduction of imines and nitriles with H2 Chemical. Communication.,2008(14), 1701-1703. 214. Balcells, D., Nova, A., Clot, E., Gnanamgari, D., Crabtree, R. H., and Eisenstein, O., (2008), Mechanism of Homogeneous Iridium-Catalyzed Alkylation of Amines with Alcohols from a DFT Study, Organometallics, 27, 2529–2535.

170