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TitleEXPLORATION AND DEVELOPMENT OF INDIUM-MEDIATED REACTIONS: SYNTHESIS OF DICHLOROINDIUM HYDRIDE, BORANE, AND THEIR APPLICATION TO VARIOUS REDUCTIONS

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AuthorSaavedra, Jaime Zendejas

Publication Date2012-01-01 Peer reviewed|Thesis/dissertation

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UNIVERSITY OF CALIFORNIA

SANTA CRUZ

EXPLORATION AND DEVELOPMENT OF INDIUM-MEDIATED

REACTIONS: SYNTHESIS OF DICHLOROINDIUM HYDRIDE, BORANE,

AND THEIR APPLICATION TO VARIOUS REDUCTIONS

A dissertation submitted in partial satisfaction

of the requirements for the degree of

DOCTOR OF PHILOSOPHY

in

CHEMISTRY AND BIOCHEMISTRY

by

Jaime Zendejas Saavedra

December 2012

The Dissertation of Jaime Z. Saavedra

is approved:

Professor Bakthan Singaram, Research Advisor

Professor Rebecca Braslau, Chair

Professor Roger G. Linington

____________________________________

Tyrus Miller

Vice Provost and Dean of Graduate Studies

Copyright by

Jaime Saavedra Zendejas

2012

iii

TABLE OF CONTENTS

LIST OF FIGURES....viii

LIST OF SCHEMES....ix

LIST OF TABLES......xiv

ABSTRACT.......xvi

DEDICATION AND ACKNOWLEDGEMENTS.......xix

CHAPTER 1. Introduction, Background, and Synthesis of Dichloroindium

Hydride.....1

1.1 Introduction.....2

1.2 Metal Hydrides....3

1.3 Use of NaBH4 with Metal Salts......7

1.3.1 Reductive Capabilities of NaBH4/AlCl3........7

1.3.2 Reductive Capabilities of NaBH4 and Platinum Salts..10

1.3.3 Reductions using NaBH4 and Cobalt Salts ......13

1.3.4 Reductions using NaBH4 and Nickel Salts ......17

1.4 Tin Hydrides .....21

1.5 Dichloroindium Hydride (HInCl2)....26

1.5.1 Appeal of Indium in Organic Synthesis...26

1.5.2 Generation of HInCl2 using Bu3SnH ......27

1.5.3 Generation of HInCl2 using DIBAL-H ......33

1.5.4 Generation of HInCl2 using Silanes ............................................35

1.5.5 Generation of HInCl2 using NaBH4....45

iv

1.6 Conclusions.......52

1.7 Thesis Outline...53

1.8 References.....55

CHAPTER 2. InCl3-NaBH4 Mediated Reduction of Aromatic and

Aliphatic Nitriles to Primary Amines......60

2.1 Introduction...61

2.1.1 Importance of Amines in Society...61

2.1.2 Amines Synthesis...62

2.1.3 Synthesis of Amines Via the Reduction of Nitriles Using

Aluminum Hydrides .......64

2.1.4 Synthesis of Amines via the Reduction of Nitriles Using

Borohydrides ..66

2.2 Background.......71

2.3 Results and Discussion..73

2.3.1 Preparation of HInCl2 from InCl3 and Lithium

Aminoborohydride(LAB) ......73

2.3.2 Re-evaluation of the InCl3/NaBH4 Reagent System ........77

2.3.3 Reduction of Nitriles using the InCl3/NaBH4/THF System .....84

2.4 Conclusions...90

2.5 Experimental..91

2.6 References.98

CHAPTER 3. Reductive Deoxygenation of Diaryl Ketones with

NaBH4/InCl3 ...102

3.1 Introduction.103

v

3.1.1 Deoxygenation of Carbonyls ...103

3.1.2 Traditional Methods: The Wolff-Kishner and Clemmensen

Reductions 103

3.1.3 Hydrogenation of Carbonyls ...106

3.1.4 Reduction of Carbonyls by Aluminum Hydrides....109

3.1.5 Deoxygenation of Aromatic Carbonyls and Alcohols using

Borohydrides ...112

3.1.6 Deoxygenation of Aromatic Carbonyls and Alcohols using

Hydrosilanes ...116

3.2 Background.126

3.3 Results and Discussion126

3.3.1 Exploration of Novel Reduction Systems ...126

3.3.2 Deoxygenation of Carbonyls Using HInCl2 ...132

3.4 Conclusions.....139

3.5 Experimental...140

3.6 References...145

CHAPTER 4. Re-exploration of the Reaction of NaBH4 with Metal Halides:

Alternative Methods for the Generation of Borane Complexes......149

4.1 Introduction....150

4.1.1 Borane .........150

4.1.2 Diborane ......151

4.1.3 Borane Complexes .......151

4.2 Background..156

vi

4.3 Results and Discussion159

4.3.1 Synthesis of Borane Coordination complexes .159

4.3.2 Borane Sulfide Synthesis......160

4.3.3 Synthesis of Borane-Dimethyl Sulfide (BMS) ....160

4.3.4 Synthesis of Borane -Dodecyl methyl sulfide (DodBMS).......164

4.3.5 Synthesis of Organoboranes.....................................................166

4.3.6 Synthesis of Amine Boranes.............167

4.3.7 Synthesis of Pyridine Borane (pyBH3)...........167

4.3.8 Synthesis and Exploration of

BH3N-Methylpyrrolidinone (BH3NMP) ................................................170

4.3.9 Catalytic Generation of Borane using the InCl3/NaBH4

System .......................................................................................174

4.4 Conclusions..177

4.5 Experimental178

4.6 References185

CHAPTER 5. Synthesis of Dichloroindium Hydride and Exploration of its

Reactivity with Organic Functional Groups. Tandem, Selective and Partial

Reductions of Halo-Nitriles and Carbonyls...188

5.1 Introduction..189

5.1.1 Importance of Selectivity..189

5.1.2 Chemoselectivity ..190

5.1.3 Historical Selectivity in Reductions: LiAlH4 vs. NaBH4......191

vii

5.1.4 Chemoselective Reduction of Carbonyls ....191

5.1.5 Chemoselective Reduction of Nitriles .....198

5.1.6 Chemoselective Reductions of Nitriles Using Lithium

Aminoborohydrides ......201

5.1.7 Chemoselective Reduction of Halides ....204

5.1.8 Use of HInCl2 in Chemoselective Halide Reductions ....205

5.2 Background.....207

5.3 Results and Discussion211

5.3.1 Tandem, Selective and Partial Reduction of Nitriles and Halides

using HInCl2......211

5.3.2 Tandem Reductions Using HInCl2 and BH3THF .....212

5.3.3 Selective Reduction of Halides in the Presence of Nitriles.........214

5.3.4 Tandem, selective, and partial reduction of halo-nitriles using

DIBAL-H and InCl3.............217

5.3.5 Selective Reductions of Carbonyls using the InCl3/NaBH4 System...219

5.4 Conclusions..221

5.5 Experimental223

4.6 References234

Conclusions.......238

APPENDIX A: 11

B NMR AND 1

H NMR AND 13

C NMR SPECTROSCOPY ...241

CHAPTER 2. Spectra .......242

CHAPTER 3. Spectra .......273

CHAPTER 4. Spectra .......304

viii

CHAPTER 5. Spectra....320

Bibliography.....359

LIST OF FIGURES

Figure 2.1. Popular Amines in the Pharmaceutical Industry ....61

Figure 2.2. The InCl3/MeLAB System and the production of HInCl2 and In73

Figure 2.3. 11

B NMR Spectroscopy of the MeLAB/InCl3 System ...75

Figure 2.4. 11

B NMR Spectroscopy of the InCl3/NaBH4 System in

Different Solvents.......79

Figure 3.1. 11

B NMR of TiCl4/MeLAB ......129

Figure 4.1. From Little Acorns to Tall Oaks, From Boranes through Organoboranes

H. C. Brown, Nobel Lecture 1979......150

Figure 4.2. 11

B NMR Study of the Generation of (BH3)2TMEDA using

InCl3/NaBH4.158

Figure 4.3. 11

B NMR Study of the Generation of BH3DMS using

InCl3/NaBH4 ....162

Figure 4.4. 11

B NMR Study of the Generation of DodBMS using

InCl3/NaBH4.....165

Figure 4.5. 11

B NMR Study of the Generation of PyBH3 using

InCl3/NaBH4 ....169

Figure 4.6. 11

B NMR Studies of the of NaBH4 and NMP ....171

Figure 4.7. 11

B NMR Study of the Generation of BH3NMP using

InCl3/NaBH4 ....172

Figure 4.8. Generation of BH3NMP using Catalytic InCl3 and NaBH4

by 11

B NMR ....176

ix

Figure 4.9. Generation of Borane Complexes using InCl3/NaBH4 ....178

Figure 5.1. Possible Approaches to Crossing Mt. Chemoselectivity..189

Figure 5.2. Mechanism for the Reduction of Amide to a Tertiary Amine or

Alcohol .....202

Figure 5.3. Tandem, Selective and Partial Reductions of Halo-Nitriles Using

HInCl2.......223

LIST OF SCHEMES

Scheme 1.1. Reductive Capabilities of NaBH4.....5

Scheme 1.2. Reductive Capabilities of LiAlH4.6

Scheme 1.3. Addition of Metal Salts for Enhanced Reactivity of NaBH4....7

Scheme 1.4. Reduction of Various Esters using NaBH4/LiBr ......8

Scheme 1.5. Improved Reductive Capabilities of NaBH4 using AlCl3.....9

Scheme 1.6. Reduction of Alkenes and Alkynes using NaBH4, acetic acid

And Pd/C....13

Scheme 1.7. Satyanarayanas Proposed Generation of CoH2 and BH3....16

Scheme 1.8. Possible Generation of NiB Using NaBH4 and Ni(OAc)2..........17

Scheme 1.9. Generation of Di and Trialkyltin Hydrides using Ammonium

Chloride...........21

Scheme 1.10. Generation of Alkyl Tin Hydrides using LiAlH4....22

Scheme 1.11. Proposed Free-Radical Mechanism of Organotin Hydride Alkyl

Halide Reductions ..23

Scheme 1.12. Halide Reductions using Catalytic R3SnX and NaBH4..24

x

Scheme 1.13. Proposed Catalytic Cycle of the Transmetallation Between

Tin and Indium ...........25

Scheme 1.14. Selective Reductive Aldol Reactions of ,-unsaturated

Ketones ..29

Scheme 1.15. Proposed Catalytic Cycle for Acid Chloride Reductions....30

Scheme 1.16. Proposed Catalytic Cycle for the Dehalogenation of Organic

Halides ....32

Scheme 1.17. Hydroindation of a 1,3 Diene by HInCl2 and Reaction with

Carbonyl Various Compounds ...........32

Scheme 1.18. Proposed Catalytic Cycle of the Radical Cyclizations of Halo

Acetals.....34

Scheme 1.19. Reductive Deoxygenation of Various Ketones...36

Scheme 1.20. Reduction of Various Alcohols ......36

Scheme 1.21. Direct Chemoselective Reduction of Alcohols by

Ph2SiHCl/InCl3 ...............37

Scheme 1.22. Diastereoselective Aldol Reactions.38

Scheme 1.23. Proposed Mechanistic Cycle.......39

Scheme 1.24. Cyclization of Enynes ........40

Scheme 1.25. Intermolecular Radical Coupling .......41

Scheme 1.26. Proposed HInCl2 Mediated Azide Reduction................41

Scheme 1.27. Proposed Mechanism for the InCl3/Et3SiH/MeOH System-Promoted

Reductive Amination ..43

Scheme 1.28. Synthesis of primary alcohols from aliphatic carboxylic acids ..45

Scheme 1.29. Possible Pathways of Halide Reduction Using the InCl3/Bu3SnH

System ........47

Scheme 1.25. Intermolecular Radical Coupling .......41

xi

Scheme 1.30. InCl3/NaBH4 Mediated Stereoselective Generation of Alkenes

and Dimerization of an Alkyne.......................................51

Scheme 2.1. Mechanism of the Gabriel Amine Synthesis ......63

Scheme 2.2. Reduction of Nitriles using Triflouroacetoxyborohydride .68

Scheme 2.3. Reducitons of Functional Groups Using HInCl2.....72

Scheme 2.4. Solvent effects of the NaBH4/InCl3 System in the Reduction of

Halides. .......78

Scheme 2.5. Effects of Solvent on the NaBH4/InCl3 System in the Reduction of

Alkynylsilanes ....78

Scheme 2.6. InCl3/NaBH4 System in Acetonitrile ..83

Scheme 3.1. Wolff-Kishner Ketone Reduction Mechanism .....104

Scheme 3.2. Proposed Clemmensen Ketone Reduction Mechanism via Zwitterion

Intermediate ..105

Scheme 3.3. Proposed Carbenoid Clemmensen Ketone Reduction

Mechanism ....106

Scheme 3.4. Deoxygenation via Alcohol Intermediate and Direct

Hydrogenation ..108

Scheme 3.5. Proposed Mechanism for the Deoxygenation of Electron-Donating

Aromatic Carbonyls Using LiAlH4...110

Scheme 3.6. Proposed Mechanism for the Deoxygenation of Electron-Rich

Aromatic Carbonyls using NaBHX2/BF3OEt2....115

Scheme 3.7. Reduction of Aryl Alcohols Using (Ph3P+)2O/ NaBH4.118

Scheme 3.8. Deoxygenation of Diaryl Alcohols Using n-

BuLi/HBCl2...121

Scheme 3.9. Proposed Mechanism of the Reduction of Carbonyls Using

NH4F/Et3SiH ....123

xii

Scheme 3.10. Proposed Mechanism of the Deoxygenation of Aryl Carbonyls using

Ga(OTf)3/Me2SiHCl .....124

Scheme 3.11. Proposed Transition States for the Deoxygenation of Aryl

Carbonyls using Et3SiH/BF3OEt2...125

Scheme 3.12. Effects of Reaction Time and Temperature on the Deoxygenation

of 4-Bromobenzophenone ............136

Scheme 3.13. Proposed Mechanism for the Deoxygenation of Diaryl Ketones

using InCl3/NaBH4....139

Scheme 4.1. Hydroboration of Olefins Using NaBH4/ BF3OEt2 ...152

Scheme 4.2. Common Method for the Synthesis of Borane Complexes...160

Scheme 4.3. Competition Study between THF and DMS .163

Scheme 4.4. Generation of DodBMS using NaBH4/BF3OEt2.164

Scheme 4.5. Competition Study between NMP and Dod-S-Me...173

Scheme 4.6. Proposed Catalytic Cycle for the in situ Generation of Borane

using InCl3/NaBH4....175

Scheme 4.7. Generation of BH3NMP using Catalytic InCl3 and NaBH4 by 11

B

NMR .....176

Scheme 4.8. Generation of Borane Complexes using InCl3/NaBH4.....178

Scheme 5.1. Chemoselective Reduction of Ketones via the in situ Protection

of Aldehydes using tert-Butylamine and LiAlH(OtBu)3..196

Scheme 5.2. Chemoselective In Situ Protection of Aldehydes using

Ti(NR2)4 ....197

Scheme 5.3. Chemoselective Reduction of Ketones via the In Situ Protection of

Aldehydes using Et2AlSPh and DIBAL-H ...198

Scheme 5.4. Selective Reduction of Benzonitrile in the Presence of Capronitrile

Using LDBIPA .199

Scheme 5.5. Chemoselective Reduction of Nitriles using CoCl2/NaBH4 .....200

xiii

Scheme 5.6. Reduction of Amide to a Tertiary Amine or Alcohol .......201

Scheme 5.7. Nitrile Reduction OR Tandem Amination/Reduction of

Halobenzonitriles ......203

.

Scheme 5.8. The InCl3/MeLAB System and the Production of HInCl2 and In

Metal......208

Scheme 5.9. Carbon-Bromine Bond Reduction using InCl3/MeLAB ......209

Scheme 5.10. Reaction of InCl3/ NaBH4 in THF and MeCN .....210

Scheme 5.11. InCl3/NaBH4 Reduction of Aromatic, Heteroaromatic and

Aliphatic Nitriles to Primary Amines .......210

Scheme 5.12. Various methods of generating HInCl2.........211

Scheme 5.13. Generation of HInCl2 and BH3THF and their use in Tandem

Reductions.....212

Scheme 5.14. BH3THF/TMEDA Complex .......214

Scheme 5.15. Proposed Selective Reduction of Halides from the Generation of

HInCl2 with Lithium Dimethylaminoborohydride (MeLAB).......215

Scheme 5.16. Selective Reduction of Halides with Dichloroinidum Hydride........217

Scheme 5.17. Versatility of the InCl3/DIBAL-H System ......219

Scheme 5.18. Reducing Ability of the InCl3/NaBH4 System in the Reduction

of Alkyl Esters...................................................................................220

xiv

LIST OF TABLES

Table 1.1. Reaction of Ethyl Benzoate with NaBH4 and Metal Salts.......10

Table 1.2. Rates of hydrogenation of 1-Octene by NaBH4 and Various Metal

Salts .11

Table 1.3. Rates of hydrogenation of Various Olefins by NaBH4 and

H2PtCl6....12

Table 1.4. Reduction of Nitrogen Functional Groups Using NaBH4/CoCl2....14

Table 1.5. Reduction of Benzonitrile with NaBH4 and Various Metal Salts....15

Table 1.6. Reduction of Alkenes Using NaBH4/Ni(OAc)2......17

Table 1.7. Reduction of Nitriles to Primary Amines Using NaBH4/NiCl2 ..19

Table 1.8. Catalytic Reduction of Nitriles to Boc Amines Using NaBH4/NiCl2

and Boc2O ......20

Table 1.9. First Ionization Potential of Some Metals ..26

Table 1.10. Representative Reductions by HInCl2.28

Table 1.11. InCl3/Bu3SnH Reduction of Halides ......31

Table 1.12. Hydroindation of Alkynes Followed by Indolysis......33

Table 1.13. HInCl2 reduction of Azides to Primary Amines .....42

Table 1.14. Reduction of Amides to Amines ........44

Table 1.15. HInCl2 Reduction of Halides ..................................48

Table 1.16. Hydride Source and Solvent Effects on the Indium Catalyzed

Reduction of Halides...........49

Table 2.1. Percent Composition of BH3 THF and NaBH4 based on 11

B NMR ....81

Table 2.2. Effect of Solvent on the InCl3/NaBH4 System and the Reduction

of p-Tolunitrile.....84

xv

Table 2.3. Selected Solubilities of NaBH4 at Various Temperatures...86

Table 2.4. InCl3/NaBH4 Reduction of Benzonitriles to Primary Amines ...87

Table 2.5. InCl3/NaBH4 reduction of Benzyl and Aliphatic Nitriles to Primary

Amines............89

Table 3.1. Deoxygenation of Aromatic Carbonyls with Electron Donating

Groups ..114

Table 3.2. Deoxygenation of Aryl Carbonyls Using NaCNBH3/ZnI2 ..119

Table 3.3. 11

B-NMR Studies of MeLAB with Various Metal Salts ..127

Table 3.4. 11

B-NMR Studies of NaBH4 with Various Metal Salts.....131

Table 3.5. Reductive Capabilities of InCl3/NaBH4 with Various Carbonyls 133

Table 3.6. InCl3/NaBH4 Reduction of Benzopheneone.....134

Table 3.7. InCl3/NaBH4 Deoxygenation of Diaryl Ketones ......136

Table 4.1. Reductions of Various Compounds with Diborane ..153

Table 5.1. InCl3/Bu3SnH Reduction of Halides 205

Table 5.2. The InCl3/MeLAB System and the Production of HInCl2 and In ....208

xvi

EXPLORATION AND DEVELOPMENT OF INDIUM-MEDIATED

REACTIONS: SYNTHESIS OF DICHLOROINDIUM HYDRIDE, BORANE,

AND THEIR APPLICATION TO VARIOUS REDUCTIONS

Jaime Saavedra Zendejas

ABSTRACT

Metal hydrides, since their inception, have proven to be invaluable to the

organic chemist. As the complexity of chemical compounds has increased over time,

the need for finely tuned reducing agents has also increased and is responsible for the

development of other metal hydrides and reducing agents we have today. However, as

the specific requirements of metal hydrides continues to increase in the future, so too

will the need for hydrides with increased selectivity and ease of use. Dichloroindium

hydride, with its unique reactivity and ability to affect a variety of reactions sits

poised to become a prominent and widely used reagent. Among HInCl2s abilities, it

possesses the ability to behave as an ionic as well as radical reducing agent making it

useful to a variety of reactions that have in the past required less desirable reaction

conditions and reagents. Additionally, there are exist a variety of methods for the

generation of HInCl2, causing the reactivity and reducing ability to vary greatly

depending on the method and conditions used in the synthesis of HInCl2. This

versatility, allows for the tailoring of HInCl2. Thus, the generation of HInCl2 using a

variety of reaction conditions and hydride sources, such as: Bu3SnH, DIBAL-H,

Et3SiH, NaBH4, was comparatively reviewed.

The reductive capabilities of the InCl3/NaBH4 system and its dependence on the

solvent used for reduction were explored. Investigation by 11

B NMR spectroscopic

xvii

analyses indicates that the reaction of InCl3 with NaBH4 in THF generates HInCl2

along with boranetetrahydrofuran (BH3THF) in situ. Nitriles undergo reduction to

primary amines under optimized conditions at 25 C using one equivalent of

anhydrous InCl3 with three equivalents of NaBH4 in THF. A variety of aromatic,

heteroaromatic, and aliphatic nitriles are reduced to their corresponding primary

amines in 7099% isolated yields.

Continued exploration of various applications of HInCl2, the InCl3/NaBH4

system was used in selective reductive deoxygenation of diaryl carbonyls to the

corresponding methylene hydrocarbons in good to excellent yields using a simple and

convenient procedure. In addition, the generation of borane using the InCl3/NaBH4

system, as well as the synthesis of various known and novel borane complexes using

a simple and reliable method under mild reaction conditions.

Lastly, novel methods of preparing HInCl2 via the in situ reduction of InCl3

using lithium amino borohydride (LAB) were developed. The generation of HInCl2

from the reduction of InCl3 by NaBH4 was used for comparison. The formation of

HInCl2 from the InCl3/NaBH4 system also generates borane that is trapped as BH3-

tetrahydrofuran (THF). Both reducing agents were used to control the reactivity of the

system. This allowed for the selective, tandem, and/or partial reduction of multi-

functionalized compounds containing nitriles and halogens. The InCl3/NaBH4 system

in THF was found to efficiently reduce both nitriles and carbon-halogen bonds in a

tandem fashion utilizing both HInCl2 and BH3THF. In comparison, the

InCl3/NaBH4/MeCN system scavenges the in situ generated borane and affords the

xviii

selective reduction of the carbon-halogen bond in halo nitriles. Similarly, the

InCl3/MeLAB and the InCl3/DIBAL-H systems were also found to selectively reduce

the carbon-halogen bond in halo nitriles, while DIBAL-H alone selectively reduced

halo nitriles to the corresponding halo aldehyde. The sequential addition of two

equivalents of DIBAL-H followed by the addition of an equivalent of InCl3 allows

the partial reduction of halo nitriles to halo imines; subsequent reduction of the

carbon-halogen bond affords the corresponding aldehyde in a one-pot procedure.

xix

I dedicate this dissertation

to:

Dios, Familia,

y

Mxico.

xx

ACKNOWLEDGMENTS

The Dearly Departed: While there are many people that have helped and

contributed to the completion of this objective in my life, I would first like to

recognize and acknowledge those that were not able to see the completed objective

and who I can no longer thank in person. Jos Guadalupe Saavedra, Ruben Zendejas,

Maria de Jesus Zendejas, Leopoldo Saavedra Garcia, Felipe Saavedra, Antonia

Sanchez, Kenny Ikei, Until we meet again, Rest In Peace.

My dissertation committee: Bakthan, thank you, I am forever grateful. I

learned many things from you in chemistry and in life. Rebecca, thank you for being

my chair and for all of your advice and input over the years, it has made me a better

scientist. Roger, we both began our careers at UC Santa Cruz back in the fall of 2007,

I am glad to see that your lab has flourished into a UCSC powerhouse. I appreciated

your advice and friendship over the years, thank you.

Ted, we had some great conversations and

To my labmates: Rauwr. To the ones that came before me: I learned what I

know now in the lab from you, thank you. To the ones that came after: try not to burn

the place down. Angel, hold down the fort.

Dios: El es el Maestro de mi alma y Capitn de mi destino. El Seor es mi luz

y mi Salvador. El es la defensa de mi vida.

xxi

Famila: Sin el apoyo moral, financiero, entrenamiento de alto rendimiento y

refuerzo cuando se necesit, no se hubiera podido cumplir el objetivo, gracias.

Mexico: Por la Patria Todo. Un soldado ms ingresa a las filas en la lucha por

una nacin prospera y soberana.

Friends: A los Jaguares: los nombres salen sobrando, Rauwr.

Fellow Grad Gtudents: Nate, Mike, Eric Evans, Eric Mejia, Eric Shultz,

Brandon, Chad, Gabriel Navarro: Rauwr

1

CHAPTER 1

Introduction, Background, and Synthesis of Dichloroindium Hydride

2

1.1 Introduction

The use of metals in reactions have played an important role in the development

and advancement of organic chemistry with far reaching effects spanning novel

laboratory techniques to vital industrial applications. Today the use of metals spans

the full range of chemistry applications and stands as a testament to their importance

in the field. Early applications of metals in chemistry were focused on perhaps the

most important fundamental functional group transformation of all: the reduction.

These methods utilized metals in non-hydridic procedures to reduce carbonyl

functional groups such as ketones and aldehydes. For instance, diaryl ketones were

found to be reduced to the corresponding secondary alcohols using zinc along with

sodium hydroxide (NaOH) in ethanol (eq. 1).1

(1)

Similarly, aliphatic aldehydes were reduced to the corresponding primary alcohol

using iron metal in acetic acid (eq. 2).2

(2)

While these early applications of metals demonstrated their ability to reduce

carbonyls, their use was limited in part due to the relatively harsh reaction conditions

employed. Although there still exist some notable reductions that employ non-

3

hydridic methods, such as the MeerwienPonndorf-Verley reaction, most reductions

of carbonyls now call for more modern methods.3

Sometime later, metal hydride reductions of various functional groups were

developed and today remain among the most common and useful chemical

transformations in modern organic chemistry (eq. 3).

(3)

1.2 Metal Hydrides

The first large scale use of metal hydrides in organic chemistry is due in large

part to Professors H. C. Brown and H. I. Schlesingers discovery of a novel method of

generating diborane.4 They found that diborane could be generated by reacting boron

trifluoride etherate (BF3:OEt2) with lithium hydride (LiH) (eq. 4).4

(4)

The resulting diborane was then used in the production of LiBH4, which was first

generated by reaction with LiH (eq. 5).5

(5)

Interestingly, LiBH4 was found to be of great utility during the Manhattan Project in

the search for volatile compounds of uranium. These compounds could then be used

4

for the diffusion separation of uranium to concentrate fissionable isotopes that could

ultimately be employed to make an atomic bomb (eq. 6).6

(6)

Subsequent metal borohydrides have included a variety of metals including sodium

borohydride (NaBH4) which today forms an integral part of the organic chemists

toolset. Professors H.C. Brown and H.I. Schlesinger discovered that reacting sodium

hydride (NaH) with methylborate at elevated temperatures also generated NaBH4 (eq.

7).7

(7)

Upon further examination and separation of the two products, Brown and Schlesinger

found that in the presence of acetone, NaBH4 reacted in a highly exothermic fashion

and resulted in four equivalents of isopropyl alcohol (eq. 8).7

(8)

Interestingly, much of this early work on borohydrides was not published until 1953,

as it was considered classified information during the war years. Sodium borohydride

remains a mild and inexpensive reducing agent toward various functional groups

including ketones and aldehydes (Scheme 1.1).8

5

NaBH4

R R'

O

R H

O

R H

OH

R R'

OH

R OR'

OR H

OH

O

O

HOOH

O

R

R'

R

R'

HO

R N

O

R'

R"

R OH

O

NR

NR

RR'

NR

NR

R-NO2

slow reaction

slowreaction

slowreaction

R-CN

NR

Scheme 1.1. Reductive Capabilities of NaBH48

As Scheme 1.1 points out, NaBH4 has limited ability to reduce some functional

groups including nitriles, amides, esters and carboxylic acids.9 The mild reductive

ability of NaBH4 allows for the selective reduction of ketones and aldehydes in the

presence of other functional groups. In addition to its limited reducing powers, pure

NaBH4 tends to be quite insoluble in some organic solvents, establishing the need for

more powerful and soluble reducing agents.

Fortunately, Schlesinger and Finholt developed a significantly more powerful

reducing agent, lithium aluminum hydride (LiAlH4), when reacting LiH with AlCl3

(eq. 9).10

(9)

6

This novel metal hydride, unlike NaBH4, was found to be very powerful and capable

of reducing most organic functional groups (Scheme 1.2).

LiAlH4

R R'

O

R H

O

R H

OH

R R'

OH

R OR'

O

O

O

HOOH

O

R

R'

R

R'

HO

R N

O

R'

R"

R OH

O

Mixture

RR'

NRR-NO2

R-CN

R H

OH

R H

OH

R NH2

R NH2

Scheme 1.2. Reductive Capabilities of LiAlH410

Perhaps even more importantly, the ease of preparation and stability of LiAlH4 made

it a particularly attractive reducing agent. Indeed, shortly after this discovery, LiAlH4

was made commercially available. Although LiAlH4 is an excellent reducing agent, it

is not very amenable to selective reductions and its lack of selectivity diminishes its

application where multifunctional molecules are involved. Additionally, handling

LiAlH4 requires extreme care due to its exceptional pyrophoric qualities

7

1.3 Use of NaBH4 with Metal Salts

Both NaBH4 and LiAlH4 are used extensively, despite NaBH4 being limited

by its mild reductive character and the unselective nature of LiAlH4. One way to

further bridge the reductive capabilities gap between these two reducing agents is to

enhance the reactivity of NaBH4 by inclusion of additives such as metal salts. One

such example developed by Schlesinger, Brown and Hyde is the in situ generation of

LiBH4 (eq. 10).11

(10)

Kollontisch and coworkers later expanded this method to demonstrate that LiCl,

CaCl2, or LiI could be used in conjunction with NaBH4 in order to enhance NaBH4s

reducing abilities (Scheme 1.3).12

Scheme 1.3. Addition of Metal Salts for Enhanced Reactivity of NaBH4

Specifically, they were able to show that the reduction of p-nitrobenzoate utilizing a

NaBH4/LiI mixture afforded the corresponding alcohol in 80% yield (eq. 11).12

8

(11)

Brown and coworkers continued their work with lithium salts and found that

LiBr in conjunction with NaBH4 in diglyme proved highly effective in the reduction

of esters (Scheme 1.4).13

Scheme 1.4. Reduction of Various Esters using NaBH4/LiBr13

1.3.1 Reductive Capabilities of NaBH4/AlCl3

Brown and coworkers later expanded their focus beyond lithium based salts

and found that the addition of aluminum chloride (AlCl3) to a reaction containing

NaBH4 significantly increased its reductive capabilities.14

They found that reacting an

equivalent of AlCl3 with three equivalents of NaBH4 in diglyme allowed for the

reduction of many more functional groups than with NaBH4 alone (Scheme 1.5).14

9

AlCl3/NaBH4

R R'

O

R H

O

R H

OH

R R'

OH

R OR'

OR H

OH

O

O

HOOH

O

R

R'

R

R'

HO

R N

O

R'

R"

R OH

O

NR

RR'

R-NO2

R-CN

R H

OH

R NH2

R N

R'

R"

RR'

Scheme 1.5. Improved Reductive Capabilities of NaBH4 using AlCl314

Notably, esters, alkenes, and carboxylic acids are readily reduced with the mixed

NaBH4/AlCl3 system; in contrast they are reduced only very slowly or not at all at

room temperature using NaBH4 alone. Disubstituted amides also undergo reduction

with the AlCl3/NaBH4 system, but unlike LiAlH4, the compounds retain the nitrogen

substituent to afford tertiary amines. In addition to exploring the increased reductive

capabilities of the AlCl3/NaBH4 system, Brown and coworkers also explored other

metal salts (Table 1.1).14

10

Table 1.1. Reaction of Ethyl Benzoate with NaBH4 and Metal Salts14

Entry NaBH4 (equiv.)

Metal Salt

(equiv.)

Temp.

(C)

Time

(h)

% Yield

1 5 GaCl3 (1.7)

75 1 92

2 5 TiCl4 (1.25)

75 2 99

3 5 SnCl4 (1.25)

75 1 50

4 5 ZnCl2 (2.5)

75 1 0

By using the reduction of ethyl benzoate as a measure of increased reductive

capability of NaBH4, it became clear that the addition of some metal salts greatly

increase the reactivity of NaBH4.

1.3.2. Reductive Capabilities of NaBH4 and Platinum Salts

Further studies on metal salt additives were undertaken using aqueous

solutions of NaBH4 to develop its potential as a hydrogenation catalyst for alkenes,

such as 1-octene (Table 1.2).15

11

Table 1.2. Rates of hydrogenation of 1-Octene by NaBH4 and Various Metal Salts15

Entry NaBH4 (equiv.)

Metal Salt

(equiv.)

50% Conv.

Time (min.)

100% Conv.

Time (min.)

1 5 RuCl3 (0.2)

70 170a

2 5 RhCl3 (0.2)

7 20

3 5 PdCl2 (0.2)

16 90a

4 5 OsO4 (0.2)

45 110a

5 5 IrCl4 (0.2)

32 80a

6 5 H2PtCl6 (0.2)

9 17

7 5 PtO2

(0.2)

14 27

a Estimated times for full conversion.

Interestingly, all of the metal salt additives facilitated the hydrogenation of 1-octene

which is not observed with NaBH4 alone. Continued work in this area by H. C.

Brown and C. A. Brown found that reacting NaBH4 with chloroplatinic acid

(H2PtCl6) produced an active catalyst for the hydrogenation of a variety of olefins

(Table 1.3).16

12

Table 1.3. Rates of hydrogenation of Various Olefins by NaBH4 and H2PtCl616

Entry Compound

50% Conv.

Time (min.)

100% Conv.

Time (min.)

1 5 10

2 6 14

3

35 100a

4

6.5 15

5

25 80a

6

11 23

7

9 19

8

26 62

9

6 13

10

5 13

11

- NDb

a Estimated times for full conversion.

b Not determined.

As Table 1.3 demonstrates, a variety of olefins underwent hydrogenation with ease,

but hydrogenation was considerably slower when reducing highly hindered olefins

such as 2,4,4-trimethyl-2-pentene (Table 1.3, entry 3).16

Substituted cyclohexenes

followed a similar trend. The ready reduction of multiple bonds was also

13

demonstrated using this system with the reduction of 4-vinylcyclohexene and 3-

hexyne (Table 1.3, entries 9 and 10 respectively).16

Interestingly, the reduction of

benzene was also investigated and was found to proceed slowly: only 20% reduction

was observed after one hour (Table 1.3, entry 11). Recently, Cordes and coworkers

have expanded Browns original work to a wide variety of alkenes and alkynes using

NaBH4 and palladium on carbon (Pd/C) in the presence of acetic acid and isopropyl

alcohol (IPA) (Scheme 1.6).17

Scheme 1.6. Reduction of Alkenes and Alkynes using NaBH4, acetic acid and Pd/C

1.3.3 Reductions using NaBH4 and Cobalt Salts

As the search for enhanced reactivity of NaBH4 through the addition of metal

salts intensified, Suzuki and coworkers also undertook the exploration of NaBH4 with

metal salts with a particular focus on cobaltous chloride (CoCl2).18

They

demonstrated that the CoCl2/NaBH4 system was able to reduce a variety of nitrile,

nitro, and amides to their corresponding primary amines (Table 1.4).18

14

Table 1.4. Reduction of Nitrogen Functional Groups Using NaBH4/CoCl218

Entry Reagent Product Temp.

(C) Solvent

% Yield

1

20 MeOH 72

2

-10 MeOH 60

3

40 MeOH 50

4

101 Dioxane 38

5

101 Dioxane 30

6

20 MeOH 80

7

20 MeOH 70

As shown in Table 1.4, nitrile compounds including aromatic (entries 1-3) as well as

aliphatic nitriles (entries 6, 7) are readily reduced to their corresponding primary

amines. Nitro groups are also reduced at elevated temperatures (entry 3), allowing for

selective reductions of nitriles in the presence of nitro groups at lower temperatures

(entry 2). Nitro compounds containing sulfonic acids (entry 4) and amides were partly

reduced at elevated temperatures (101 C).18

In addition to the exploration of the

15

CoCl2/NaBH4 system, Suzuki and coworkers also explored the reductive capabilities

of other metal salts using benzonitrile as a substrate (Table 1.5).18

Table 1.5. Reduction of Benzonitrile with NaBH4 and Various Metal Salts18

Entry Compound

50% Conv.

Time (min.)

1 NiCl2 75

2 Cobalt (II)

Benzoate

50

3 OsCl4 78

4 IrCl3 75

5 PtCl2 80

Attempts were later made to try to elucidate the mechanism of the CoCl2/NaBH4

system, including development of a homogenous cobalt hydrogenation catalysis19

and

the generation of soluble cobalt borohydride complexes.20

Later studies suggest the

intermediate formation of a cobalt boride catalyzes the reduction by NaBH4.21

Sometime later, Satyanarayana and coworkers seemed to contradict these reports,

positing that the mixture of NaBH4 and CoCl2 behaved like CoH2 and BH3 due to

their reported ability to hydroborate or hydrocobaltate alkenes (Scheme 1.7).22

16

Scheme 1.7. Satyanarayanas Proposed Generation of CoH2 and BH322

They asserted that this allows either for the selective hydrocobaltation or

hydroboration based on the method of reaction. The alkane products were obtained by

reacting CoCl2 with NaBH4 at 0 C, which presumably prevents the generated cobalt

hydride from decomposing, and allows for the reduction of the alkene. Conversely,

reaction of CoCl2 with NaBH4 affords alcohol products at room temperature, which

presumably destroys the generated cobalt hydride, leaving only cobalt metal and

borane for the hydroboration-oxidation of the alkene to the corresponding alcohol.22

However, 11

B NMR studies were never conducted to corroborate this proposition.

Indeed, it is now generally believed that cobalt boride is formed in these types of

reactions.21

17

1.3.4 Reductions using NaBH4 and Nickel Salts

In 1970 C. A. Brown began using nickel salts in conjunction with NaBH4 to

produce active hydrogenation nickel catalysts.23

Reaction of NaBH4 with aqueous

solutions of nickel salts produced P-1 nickel, an active catalyst for atmospheric

pressure hydrogenations (Scheme 1.8).23

Scheme 1.8. Possible Generation of NiB Using NaBH4 and Ni(OAc)2

Chemical analysis and theoretical calculations allowed for the deduction of

stoichiometry in the reaction in Scheme 1.8, however, the boron content varies with

the ratio of reactants used in the preparation.23

P-1 nickel was then used to reduce a

variety of alkenes. Partial reduction of some dienes was also reported using this

catalyst (Table 1.6).23

Table 1.6. Reduction of Alkenes Using NaBH4/Ni(OAc)223

Entry Compound

50% Conv.

Time (min.)

100% Conv.

Time (min.)

1 6 72

2

8.5 56

3

13 36

18

4

2 ~360

5

8 56

6

12 43

7

7.5 63

8

6 80

9

* a

10

* b

a4-ethylcyclohexene was obtained.

b2-methyl-1-hexene

was obtained.

The effects of ring size were minor as evidenced by Table 1.6 entries 5 and 6.

Increasing substitution of the alkene was found to significantly slow reaction rates

(Table 1.6, entry 4). Selective hydrogenation utilizing 4-vinylcyclohexene and 2-

methyl-1,5-hexadiene resulted in selective reduction of the less substituted alkene in

excellent yields (Table 1.6, entries 9, 10).

Khurana and coworkers later set out to expand on these initial studies. They

found nickel salts in conjunction with NaBH4 were capable of reducing a variety of

nitriles to their corresponding primary amines.18,24

This was achieved through the in

situ formation of nickel boride in anhydrous ethanol under ambient conditions (Table

1.7).24

19

Table 1.7. Reduction of Nitriles to Primary Amines Using NaBH4/NiCl224

Entry Reagent Product % Yield

1

82

2

72

3

72

4

85

5

64

6

81

7

81

From the substrates shown in Table 1.7, the reduction is chemoselective:

halogen, methoxy and olefinic groups were unreactive under these conditions.

Caddick and coworkers further extended this work, using nickel boride generated

form NaBH4 and nickel salts to prepare Boc protected amines (Table 1.8).25

20

Table 1.8. Catalytic Reduction of Nitriles to Boc Amines Using NaBH4/NiCl2 and

Boc2O25

Entry Reagent Product % Yield

1

80

2

74

3

65

4

52

5

59

6

81

7

57

8

59

Nitro groups are cleanly converted to the corresponding Boc protected amine (Table

1.8, entry 5). Amides and ester functional groups are tolerated using this system

(Table 1.8, entries 6, 7), but isolated double bonds are hydrogenated (Table 1.8, entry

8).

21

As discussed above, the use of metal salts to increase the reductive capabilities of

NaBH4 has proved to be an attractive strategy to fill the reactivity gap between

LiAlH4 and NaBH4. However, other alternatives have also been developed to safely

and selectively reduce avariety functional groups26

Among these alternatives, a

variety of Group 13 metal hydride derivatives have been developed over the years,

some of which are utilized extensively.27

1.4 Tin Hydrides

While aluminum and boron hydrides were among the first to be discovered and

used as reducing agents, other metal hydrides including tin hydrides were also

developed. In 1918, Paneth and coworkers first developed tin hydrides;28

by the mid

1920s they had developed a reliable method for generating gaseous tin hydride

though the cathodic reduction of tin sulfate using lead electrodes.29

This method,

however, was highly inefficient as evidenced by the observation that eight electrolytic

cells operating for over a week produced only a few cubic centimeters of gaseous tin

hydride.

During that same time period, Kraus and coworkers developed a method for

synthesizing tin hydride using organotinsodium compounds with ammonium chloride

or bromide in liquid ammonia (Scheme 1.9).30

22

Scheme 1.9. Generation of Di and Trialkyltin Hydrides using Ammonium Chloride

This novel method allowed for the generation of both dialkyl and trialkyl tin hydrides,

and remained the predominant method of generating tin hydrides for some time.

Interestingly, Schlesinger, Finhold, and coworkers also began to study the capabilities

of tin based hydrides. With the advent of LiAlH4, Schlesinger developed a novel

method of generating alkyl tin hydrides through the reduction of organotin halides

with LiAlH4 (Scheme 1.10).31

Scheme 1.10. Generation of Alkyl Tin Hydrides using LiAlH4

This novel method allowed for generation of a variety of tin hydrides including SnH4,

RSnH3, R2SnH2, and R3SnH.31

This method with only slight variations became the

standard method of synthesis for exploring the properties and reactivity of tin

23

hydrides.32

These explorations found that SnH4 is very unstable, but, progressive

substitution of alkyl or aryl groups significantly increases its stability.33,34,35

Following reports of the success of organotin hydride replacing alkyl,36,37

aryl,36

and acyl halides38

with hydrogen, Kuivila and coworkers began to explore the

mechanism of the reduction of alkyl halides by organotin hydrides (eq. 12).39

(12)

In 1964 Kuivila proposed that the reduction by R3SnH proceeds via a free radical

mechanism (Scheme 1.11).40

Scheme 1.11. Proposed Free-Radical Mechanism of Organotin Hydride Alkyl Halide

Reductions40

24

They proposed that initiation step 1, is brought about by the abstraction of a hydrogen

atom from the organotin hydride by a free radical, Q. Propagation proceeds via

catalytic cycle 2.40

The investigators reasoned their results supported a chain reaction

type mechanism because such a small amount of catalyst has a large effect on the

over-all reaction rate.40

Subsequently, the use of organotin hydrides in radical

reactions continued to expand in the areas of dehalogenations, deoxygenations,

decarboxylations, carbon-nitrogen bond scission, additions to carbon-carbon double

and triple bonds, as well as additions to carbonyls.41,42

The rise of organotin hydrides as versatile reagents also brought the

drawbacks associated with their inherent toxicity.35

In addition, many encountered

difficulty completely removing toxic tin byproducts that were generated in

stoichiometric amounts during the reactions. These drawbacks significantly limited

the use of organotin hydride mediated radical reactions in the pharmaceutical

industry.43

Considerable efforts were made to find alternative reagents capable of

achieving the same result but under more benign conditions.

One of the early alternatives developed for limiting the use of organotin

hydride was reported by Corey and coworkers who found that NaBH4 could be used

along with only catalytic amounts of tin to reduce halides (Scheme 1.12).44

Scheme 1.12. Halide Reductions using Catalytic R3SnX and NaBH4

25

Coreys procedure employs catalytic trialkyltin chloride dissolved in ethanol to form

an ethanolic NaBH4 solution which is quickly added at or below room temperature to

generate the trialkyltin hydride in situ.44

Sometime later, Marshall and Baba independently found that transmetallation

between tin and indium was possible while exploring the versatility of organotin

compounds in the generation of reactive organometallic intermediates(Scheme

1.13).45,46

InCl3

Bu3SnCl

R1 H

O

R SnBu3

R InCl2

R

R1

OInCl2

R

R1

OSiMe3

Me3SiCl

Scheme 1.13. Proposed Catalytic Cycle of the Transmetallation Between Tin and

Indium45,46

The use of InCl3 to catalyze the addition of alkynyltins and allyltins with aldehydes

prompted the further exploration of indium in organometallic reactions. It is here that

indium hydride first emerged as a possible alternative to organotin hydride reagents.

26

1.5 Dichloroindium Hydride (HInCl2)

1.5.1 Appeal of Indium in Organic Synthesis

Currently, the predominant use of indium is in the manufacturing of semiconductors

and other relevant materials.47

However, indium has also garnered attention in metal

mediated reactions due in part to the relatively low oxidation potential of the most

common oxidation states of indium, In+ (0.14 V) and In

3+ (0.44 V).

48 Because indium

has a relatively low oxidation potential, it tends to allow favorable reaction conditions

for the synthesis of organoindium compounds under ambient conditions.

Additionally, indium has a relatively low ionization potential compared to other

metals commonly used in organic synthesis (Table 1.9).49

Table 1.9. First Ionization Potential of Some Metals49

Metal Potential

(eV)

Sodium 5.12

Lithium 5.39

Indium 5.79

Aluminum 5.98

Tin 7.43

Magnesium 7.65

Zinc 9.39

The unique properties of indium also prove favorable in the area of metal

hydrides. Indium hydride reagents (LiInH4, LiPhInH3, and LiPh2InH2) were first

prepared from InCl3 and LiH by Wiberg and Schmidt. They found that indium

trihydride had no appreciable reducing properties.50

They did, however, find that

27

LiInH4 has some reducing abilities, and was found to reduce acetamide, acetonitrile,

butyric acid and quinine.50

Indium hydrides were later explored by Butsugan and

coworkers demonstrating the ability to reduce a variety of functional groups including

aldehydes, ketones, esters, and halides.51

The use of indium as a metal hydride

reducing agent was not extensively used due to the instability and low reactivity of

some species. Subsequently, other indium hydride reagents have been developed. The

following section summarizes the generation of dichloroindium hydride (HInCl2) and

its application to various reductions in organic synthesis.

1.5.2 Generation of HInCl2 using Bu3SnH

Dichloroindium hydride was first prepared by Baba and coworkers while

exploring indium hydride species. They noted that a monometallic indium hydride

having only one attached hydride had not previously been described in the

literature.52

Meanwhile, they had begun exploring the transmetallation of organotin

compounds for the generation of versatile organometallic intermediates, including

organoindium compounds.46

It is from here that Baba and coworkers set out to

explore the generation of an indium monometallic single hydride by the reaction of

InCl3 and tributylstannane hydride (Bu3SnH), which they envisioned could reduce

InCl3 and generate dichloroindium hydride (HInCl2) (eq. 13).52

(13)

28

The in situ generated HInCl2 arising from the reduction of InCl3 with Bu3SnH was in

fact attained, and reduction of a variety of functionalities including, aldehydes,

ketones and alkyl halides was demonstrated (Table 1.10).52

Table 1.10. Representative Reductions by HInCl252

Entry Substrate Product % Yield

1

O

H

93

2

78

3

99

4

76

5

96

6

93

7 77 a Yields determined by GLC, HInCl2/THF solution was stirred

for 1hr prior to addition of substrate.

29

Interestingly, the InCl3/Bu3SnH system was also found to effect stereoselective

reductive Aldol reactions, affording both syn and anti selectivity depending on the

solvent used (Scheme 1.14).53

Scheme 1.14. Selective Reductive Aldol Reactions of ,-unsaturated Ketones53

The use of anhydrous THF favors formation of the anti product (syn:anti 5:95) as the

lack of protons favors a thermodynamic transformation via retro-Aldol to from

intermediate 1. Alternatively, the use of methanol or H2O/THF favors the syn

derivatives (syn:anti 99:1 and 95:5 respectively) due to the immediate protonation of

intermediate 2 .

Acid chlorides have been partially reduced to the corresponding aldehyde in

the presence of triphenylphosphine (PPh3) when reduced with HInCl2 generated using

a catalytic amount of InCl3 and one equivalent of Bu3SnH (Scheme 1.15).54

30

Scheme 1.15. Proposed Catalytic Cycle for Acid Chloride Reductions54

The catalytic cycle proposed by Baba and coworkers proceeds via the coordination of

PPh3 to InCl3 followed by a hydride transfer from the Bu3SnH to the InCl3 to generate

HInCl2, which then partially reduces the acid chloride to the corresponding aldehyde

and regenerates the InCl3.54

Baba suggests that coordination of PPh3 to HInCl2

increases the nucleophilicity of the hydride anion and decreases the acidity of the

indium center, causing the selective interaction with the more reactive acid chloride

and not the generated aldehyde.

Much like Bu3SnH, dichloroindium hydride was also found to be an efficient

hydrogen donor to organic radicals in the reduction of organic halides via a free

radical mechanism (Table 1.11).55

31

Table 1.11. InCl3/Bu3SnH Reduction of Halides55

Entry Halide Time

(h)

Yield

(%)

1 1-bromododecane 2.0 83

2

2.0 79

3

2.5 12

4a

5 90

5b

I

O

5 61

aInCl3 0.1 mmol, Bu3SnH 1 mmol, RX 1mmol, THF 2 ml,

rt. bBu3SnH (3 mmol) was used.

The proposed catalytic cycle for the reduction of organic halides suggests a radical

dehalogenation mechanism, whereby the In-H bond is cleaved to allow formation of

the indium radical which then reacts with organic halides (Scheme 1.16).55

32

Scheme 1.16. Proposed Catalytic Cycle for the Dehalogenation of Organic Halides55

Recently, this system has been effectively used in the generation of allylic

indium through the hydroindation of 1,3-dienes, which are then reacted with carbonyl

or imine compounds in a one-pot reaction system.56

For example, 1,4-diphenyl-1,3-

butadiene undergoes hydroindation. Uupon the addition of the aliphatic aldehyde 3-

phenylpropanal, the allylated product is afforded in 88% yield (Scheme 1.17).56

Scheme 1.17. Hydroindation of a 1,3 Diene by HInCl2 and Reaction with Carbonyl

Various Compounds56

33

While the InCl3/Bu3SnH system generates HInCl2 effectively, the toxicity and

reactivity of Bu3SnH make it less than an ideal system. This has lead to the

exploration and development of alternative methods of generating HInCl2.

1.5.3. Generation of HInCl2 using DIBAL-H

Oshima and coworkers developed an alternate method of generating HInCl2

using diisobutyl-aluminum hydride (DIBAL-H) as the hydride source to reduce InCl3

(eq. 14).57

(14)

Dichloroindium hydride was produced and was used along with triethylborane (Et3B)

to carry out the hydroindation of a variety of alkynes to the corresponding (Z)-alkenes

(Table 1.12).57

Table 1.12. Hydroindation of Alkynes Followed by Indolysisa57

Entry R Yield

(%)

E/Zb

1 PhCH2O(CH2)3 79 1/99

2 EtOOC(CH2)6 99

34

Oshima suggested that the addition of Et3B promotes the reaction by acting as

a radical initiator, facilitating the radical addition of HInCl2 across the carbon-carbon

triple bond. Subsequent studies by Oshima and coworkers expanded on the radical

nature of HInCl2 and found that HInCl2 and Et3B in the presence of dioxygen

promoted radical cyclizations of halo acetals via the generation of an ethyl radical.58

The proposed mechanism begins with the generation of an ethyl radical from the

reaction of Et3B with a trace amount of O2, which then abstracts a hydrogen from

HInCl2 to generate an indium radical (InCl2) (Scheme 1.18).58

R2

R1O O

R5

R4

R3

I

InCl2I

InCl2

HInCl2

R2

R1O O

R5

R4

R3

R5

R4

R3OR1O

R2

R5

R4

R3OR1O

R2

1

23

4

Et3B O2 Et2BOO Et

Et-HEt HInCl2

Initiation

Scheme 1.18. Proposed Catalytic Cycle of the Radical Cyclizations of Halo Acetals58

35

The InCl2 generated then reacts with alkyl iodide 1 to form a carbon radical

intermediate 2 which undergoes a 5-exo-trig cyclization to afford intermediate 3.

Lastly, hydride abstraction from HInCl2 regenerates InCl2 and afford final product 4.

Chemoselective reductions of alkyl bromides and carbonyl functionalities

using HInCl2 were also explored.58

Interestingly, alkyl bromides were found to

undergo exclusive reduction in the presence of ester and ketone functionalities, but

aldehydes were found to undergo reduction faster than alkyl bromides.58

As

demonstrated above, the generation of HInCl2 by DIBAL-H has proven to be a viable

alternative to the original synthesis of HInCl2 using Bu3SnH. However, continued

exploration of alternative hydride sources has led to other novel methods of

generating HInCl2.

1.5.4 Generation of HInCl2 using Silanes

Mixtures of silanes and InCl3 have been used to carry out a variety of

reductions in organic synthesis. The combination of chlorodimethylsilane and InCl3

was first used to catalyze the reductive Friedel-Crafts alkylation of various aromatics

with carbonyl compounds (eq. 15).59

(15)

Additionally, the reductive deoxygentation of aryl ketones was achieved using

chlorodimethylsilane and InCl3 (Scheme 1.19).60

36

Scheme 1.19. Reductive Deoxygenation of Various Ketones60

Interestingly, this system was unable to reduce p-cyanoacetophenone to the

corresponding hydrocarbon. The mixture of chlorodiphenylsilane and InCl3 has also

allowed analogous reductive deoxygenations of a variety of secondary and tertiary

alcohols (Scheme 1.20).61

Scheme 1.20. Reduction of Various Alcohols61

Additionally, this system was found to afford high chemoselectivity for

benzylic hydroxyl groups in the presence of other functional groups such as esters, as

exemplified by the selective deoxygenation of hydroxyl esters (Scheme 1.21).61

37

Scheme 1.21. Direct Chemoselective Reduction of Alcohols by Ph2SiHCl/InCl361

It is proposed that InCl3 acts as a Lewis acid that loosely coordinates to oxygen to

accelerate the deoxygenation of the resulting intermediate by promoting a hydride

transfer from silane.61

While the generation of HInCl2 was not reported in these

earlier studies, the in situ formation of HInCl2 may also explain the observed

reductions. Later studies of InCl3 with other silanes, including triethylsilane (Et3SiH),

have led to the proposal that the in situ generation of HInCl2 is the key reactive

species (Scheme 1.22).62

38

Scheme 1.22. Diastereoselective Aldol Reactions62

InBr3 was also found to undergo a similar reduction in the presence of Et3SiH

to generate HInBr2, which was used in a variety of diastereoselective reductive Aldol

reductions.62

Mechanistically, it is suggested that X2InH is generated by the slow

transmetallation of InX3 with Et3SiH, which then undergoes a 1,4 addition with the

enone to afford the indium enolate 1 (Scheme 1.23). Subsequent reaction of 1 with

the aldehyde via a Zimmerman-Traxler six-membered cyclic transition state 2,

ultimately affords product 4.62

39

Scheme 1.23. Proposed Mechanistic Cycle62

Further exploration of the InCl3/Et3SiH system revealed its ability to reduce

alkyl bromides in addition to the intramolecular cyclization of enynes via the

hydroindation of alkynes.63

The proposed mechanism precedes via the formation of a

vinyl radical which cyclizes to the alkene product. For example,

allylpropargylmalonate afforded the cyclized exo-methylene compound in a 53 %

yield (Scheme 1.24).63

40

Scheme 1.24. Cyclization of Enynes63

Baba and coworkers have also demonstrated the inter- and intramolecular

radical coupling of ene-ynes and halo-alkenes using the InCl3/MeONa/Ph2SiH2

system.64

For example, phenyl iodide and acrylonitrile afforded the coupled 3-

phenylpropanenitrile product in a 60% yield (Scheme 1.25).64

41

Et3B (Cat.)

HInCl2

InCl3 Ph2SiH2

ICN

NaOMe

CN

60%

(1 equiv.) (2equiv.)

(1equiv.)

CN

InCl2

CNH InCl2

Scheme 1.25. Intermolecular Radical Coupling64

Due to the versatility of the InCl3/Et3SiH system to generate HInCl2, this

system has also been extended to the reduction of organic azides to the corresponding

amines in a highly chemoselective fashion.65

Nanni and coworkers sought to replace

tin analogues in use at the time with a greener reagent. They first set out to verify

whether HInCl2 could act as an effective, mild reducing agent capable of converting

organic azides to the corresponding amines (Scheme 1.26).65

Scheme 1.26. Proposed HInCl2 Mediated Azide Reduction65

Nanni and coworkers demonstrated that azides, in fact, undergo reduction in the

presence of HInCl2 and explored the substrate scope (Table 1.13).65

42

Table 1.13. HInCl2 reduction of Azides to Primary Amines65

Entry Substrate Product % Yielda

1

96

2

97

3

95

4

70

5

83

6

80

a Yields determined for pure amines isolated after workup and/or

chromatography.

Additionally, -azidonitriles were shown to undergo cyclizations to afford pyrrolidin-

2-imines (eq. 16).65

(16)

43

The authors propose the -azidonitriles undergo a similar radical cyclization as the

previously mentioned cyclization of enynes. More recently, the chemoselective

reductive amination of carbonyl compounds has been demonstrated by Yang and

coworkers using the InCl3/Et3SiH system (eq. 17).66

(17)

In addition, the system can be applied to a variety of cyclic, acyclic, aromatic and

aliphatic amines in the presence of functionalities like esters, hydroxyls, carboxylic

acids and olefins. NMR and ESI-MS were used to help elucidate a mechanism for the

generation of indium hydride and postulated that a stable methanol-coordinated

indium (III) species is responsible for the ionic hydride transfer to the imine carbon

(Scheme 1.27).66

InCl2(MeOH)x-1Cl2 In

Et3SiH

Et3SiOMe + HCl

[InCl2(MeOH)x]+Cl-

InCl3

MeOH

R1

O

R2

NH

R4R3

ClR1

N R2

R4

R3

+Cl-

H2O

R1

N

R2

R4R3

InClCl

(MeOH)x-1

+ Cl-

R1

N

R2

R4R3

H

H

44

Scheme 1.27. Proposed Mechanism for the InCl3/Et3SiH/MeOH System-Promoted

Reductive Amination66

Sakai and coworkers have further explored the scope of the reducing

capabilities of indium hydride with various carbonyl compounds. Tertiary amides

were directly reduced to the corresponding tertiary amines using the InBr3/Et3SiH

reducing system (Table 1.14).67

Table 1.14. Reduction of Amides to Amines 67

Entry Substrate Product % Yielda

1

90

2

97

3

95

4

70

5

Br

Et2N

83

a Yields determined from the isolated amines.

45

Interestingly, the reduction of carboxylic acids to primary alcohols, using a

similar system, has recently been reported.68

Sakai and coworkers describe an

efficient method for directly converting carboxylic acids to the corresponding primary

alcohol using InBr3 and tetramethyldisiloxane (TMDS) (Scheme 1.28).68

Ph OHOH

Ph

OH

OH

I

OH

OH

84% 95% 63%

68% ND 51%

PhS

OH

55%

CHCl3, 60 CHO

O

R HO R

H HInBr3/TMDS

Scheme 1.28. Synthesis of primary alcohols from aliphatic carboxylic acids68

As the previous examples demonstrate, the use of silanes to generate HInCl2

eliminates the need for tin hydride sources to generate HInCl2 and allows for a less

toxic alternative.

1.5.5 Generation of HInCl2 using NaBH4

46

Although HInCl2 has great potential as a mild reducing agent, some of the

methods previously used for its synthesis utilize less than ideal conditions and

reagents. Akio Baba, the first to synthesize HInCl2 from Bu3SnH, would later express

doubt if indeed the generated HInCl2 was responsible for the observed reactivity, or if

it merely promoted the reactivity of the Bu3SnH (Scheme 1.29).69

47

Scheme 1.29. Possible Pathways of Halide Reduction Using the InCl3/Bu3SnH

System69

To further probe the role of HInCl2 in the reduction of halides, Baba and

coworkers set out find a hydride source (M-H) that has no ability to reduce halides on

its own and would therefore necessarily require HInCl2 to effect the reduction.

Sodium borohydride was deemed a good candidate as it satisfied these requirements,

in addition to being a mild, inexpensive and easily handled hydride.52

The use of

NaBH4 in the generation of HInCl2 was first demonstrated by Baba and coworkers

when exploring the reduction of halides (Table 1.15).69

48

Table 1.15. HInCl2 Reduction of Halides69

Entry Substrate % Yielda

1

90

2 95

3 0

4 93

5

83

6

1

a InCl3 0.1 mmol, NaBH4 1.5 mmol, RX 1 mmol,

MeCN 2 mL, rt, 2 h.

This new system was also used in a representative intramolecular cyclization: 1-

allyloxy-2 iodobenzene afforded 3-methyl-2,3-dihydrobenzofuran in 62 % yield (eq.

18). 69

(18)

Representative InCl3/NaBH4 intermolecular radical additions were also demonstrated

using iodobenzene and electron-deficient olefins (eq. 19).69

(19)

49

Since these initial studies by Baba and coworkers, the InCl3/NaBH4 reagent system

has received significant attention due to the simple and convenient in situ preparation

of HInCl2.

Although a considerable number of subsequent studies have examined the

InCl3/NaBH4 system, few studies have reported on the significant influence solvent

can have on reaction rates and yields.69,70

For example, Baba and coworkers report

that alkyl halides are reduced efficiently (up to 78% reduction) using a catalytic

amount of InCl3 along with a stoichiometric amount of NaBH4 in MeCN (Table 1.16,

entry 4). However, the same reaction is low yielding in THF (only 15% reduction)

under the same reaction conditions (Table 1.16, entry 5).69

Others observed similar

solvent effects when working with HInCl2.70

Table 1.16. Hydride Source and Solvent Effects on the Indium Catalyzed Reduction

of Halidesa69

Entry Metal hydride Solvent Yield (%)

1 Bu3SnH THF 82

2 LiH THF trace

3 BH3-THF THF trace

4 NaBH4 MeCN 78

50

5 NaBH4 THF 15

6 NaBH4 MeCN 90b

aInCl3 (0.1 mmol), metal hydride (1 mmol), halide (1

mmol), solvent (2 mL). b1.5 mmol of NaBH4 was used.

Although the importance of the solvent is readily apparent, it has not been

satisfactorily explored. In subsequent work, Ranu and coworkers used the

InCl3/NaBH4 system to generate HInCl2 to chemoselectively reduce conjugated

alkenes such as, ,-dicyano olefins, ,-unsaturated nitriles, cyanoesters,

cyanophosphonate and dicarboxylic esters (eq. 20).71,72

(20)

Interestingly, the attempted reduction of chalcones produced a mixture of saturated

ketones and alcohols when quenched with H2O, whereas the system gave exclusively

saturated alcohols when quenched with MeOH.71

Similarly, Ranu and coworkers

found that the InCl3/NaBH4 system selectively reduces the ,-carbon-carbon double

bond in ,,,-unsaturated diaryl ketones, dicarboxylic esters, cyano esters and

dicyano compounds (eq. 21).73

(21)

51

Ranu and coworkers have demonstrated the InCl3/NaBH4 systems ability to

synthesize (E)-alkenes through the stereoselective reduction of vicinal dibromides

(Scheme 1.30, eq. 1),74

as well as the selective reduction of 2,3-epoxybromides to the

corresponding allylic alcohols (Scheme 1.30, eq. 2).75

Interesting reactions using

alkynes have also been developed using the InCl3/NaBH4 system including the

dimerization of terminal alkynes to enynes (Scheme 1.30, eq. 3).76

Scheme 1.30. InCl3/NaBH4 Mediated Stereoselective Generation of Alkenes and

Dimerization of an Alkyne76

Others have since continued exploration of the InCl3/NaBH4 system in its

reaction with alkynes. For example, Pan and coworkers have been able to

stereoselectively synthesize (E)-2-arylvinylphosphonates through the hydroindation

and subsequent hydrolysis of arylalkylphosphonates (eq. 22).

52

(22)

Pan and coworkers were able to expand this methodology to the coupling of terminal

alkynes with aryl halides to give disubstituted (E)-alkenes.77

1.6. Conclusion

In summary, since their inception, metal hydrides have proven to be

invaluable to the organic chemist. As the complexity of chemical compounds has

increased over time, the need for finely tuned reducing agents has also increased and

is responsible for the development of many modern day metal hydrides and reducing

agents. However, as the specific requirements for metal hydrides continues to

increase, so too will the need for hydrides with increased selectivity and ease of use.

Dichloroindium hydride, with its unique reactivity and ability to effect a variety of

reactions, sits poised to become a prominent and widely used reagent. As the previous

discussion implies, HInCl2 has the ability to behave as an ionic and/or radical

reducing agent. However, it remains unclear as to the cause or the conditions that

favor either a radical or ionic reducing agent. Having the ability to reliably control

this reactivity would greatly improve the utility of HInCl2 and help widen its scope to

a variety of reactions. Depending on the conditions used in the synthesis of HInCl2,

the reactivity and reducing ability can be fine-tuned. This versatility allows for the

tailoring of applications involving HInCl2. The generation of HInCl2 using a variety

53

of reaction conditions and hydride sources, such as Bu3SnH, DIBAL-H, Et3SiH,

NaBH4, has been reviewed. The following chapters describe advances toward

understanding the InCl3/NaBH4 system, and a broadening of the synthetic scope of

HInCl2.

1.7. Thesis Outline

The following chapters describe advances in the understanding of chemistry

employing HInCl2 and its application to a variety of reductions. The second chapter

discusses the reductive capabilities of the InCl3/NaBH4 system and its dependence on

the solvent used for the reduction. Investigation by 11

B NMR spectroscopic analyses

indicates that the reaction of InCl3 with NaBH4 in THF generates HInCl2 along with

boranetetrahydrofuran (BH3THF) in situ. Nitriles undergo reduction to primary

amines under optimized conditions at 25 C using one equivalent of anhydrous InCl3

with three equivalents of NaBH4 in THF.78

A variety of aromatic, heteroaromatic, and

aliphatic nitriles are reduced to their corresponding primary amines in 7099%

isolated yields.

The third chapter describes the continued exploration of various applications

of HInCl2, generated using the InCl3/NaBH4 system, including the selective reductive

deoxygenation of diaryl carbonyls to the corresponding methylene hydrocarbons in

good to excellent yields using a simple and convenient procedure.

54

The fourth chapter explores the generation of borane using the InCl3/NaBH4

system, as well as the synthesis of various known and novel borane complexes using

a simple and reliable method under mild reaction conditions.

The fifth and final chapter deals with additional novel methods of preparing

HInCl2 via the in situ reduction of InCl3 using lithium amino borohydride (LAB). The

generation of HInCl2 from the reduction of InCl3 by NaBH4 was used for comparison.

The formation of HInCl2 from the InCl3/NaBH4 system also generates borane that is

trapped as BH3-tetrahydrofuran (THF). Both reducing agents were used to control the

reactivity of the system. This allowed for the selective, tandem, and/or partial reduction

of multi-functionalized compounds containing nitriles and halogens. The InCl3/NaBH4

system in THF was found to efficiently reduce both nitriles and carbon-halogen bonds

in a tandem fashion utilizing both HInCl2 and BH3THF. In comparison, the

InCl3/NaBH4/MeCN system scavenges the in situ generated borane and affords the

selective reduction of the carbon-halogen bond in halo nitriles. Similarly, the

InCl3/MeLAB and the InCl3/DIBAL-H systems were also found to selectively reduce

the carbon-halogen bond in halo nitriles, while DIBAL-H alone selectively reduced

halo nitriles to the corresponding halo aldehyde. The sequential addition of two

equivalents of DIBAL-H followed by the addition of an equivalent of InCl3 allows

the partial reduction of halo nitriles to halo imines; subsequent reduction of the

carbon-halogen bond affords the corresponding aldehyde in a one-pot procedure.79

55

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24 Khurana, J. M.; Kukreja, G. Synth. Commun. 2002, 32, 1265-1269.

25 Caddick, S.; Judd, D. B.; Lewis, A. K. D.; Reich, M. T.; Williams, M. R. V.

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29 Paneth, F.; Rabinowitsch, E. Ber.Chem. 1924, 57, 1877-1890.

30 Kraus, C. A.; Greer, W. N. J. Am. Chem. Soc. 1922, 44, 2629-2633.

31 Finholt, A. E.; Bond, A. C.; Wilzbach, K. E.; Schlesinger, H. I. J. Am. Chem. Soc.

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32 Anderson, H. H. J. Am. Chem. Soc. 1957, 79, 4913-4915.

33 Dillard, C. R.; McNeill, E. H.; Simmons, D. E.; Yeldell, J. B. J. Am. Chem. Soc.

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34 Kuivila, H. G.; Beumel, O. F. J. Am. Chem. Soc. 1958, 80, 3798-3798.

35 Ingham, R. K.; Rosenberg, S. D.; Gilman, H. Chem. Rev. 1960, 60, 459-539.

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57

37 Kupchik, E. J.; Connolly, R. E. J. Org. Chem. 1961, 26, 4747.

38 Kuivila, H. G. J. Org. Chem. 1960, 25, 284-285.

39 Kuivila, H. G.; Menapace, L. W.; Warner, C. R. J. Am. Chem. Soc. 1962, 84,

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40 Menapace, L. W.; Kuivila, H. G. J. Am. Chem. Soc. 1964, 86, 3047.

41 Strunk, R. J.; Digiacom.Pm; Aso, K.; Kuivila, H. G. J. Am. Chem. Soc. 1970, 92,

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42 Neumann, W. P. Synthesis-Stuttgart 1987, 8, 665-683.

43 Studer, A.; Amrein, S. Synthesis-Stuttgart 2002, 7, 835-849.

44 Corey, E. J.; Suggs, J. W. J. Org. Chem. 1975, 40, 2555.

45 Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1995, 60, 1920-1921.

46 Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H.

Tetrahedron Lett. 1995, 36, 9497-9500.

47 Cintas, P. Synlett 1995, 11, 1087.

48 Vaysek, P. Handbook of Chemistry and Physics: 91st Ed.; Lide, D.R. Taylor &

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49 Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis-Stuttgart 2007, 12, 1739-1764.

50 Wiberg, E.; Schmidt, M. Naturforsch, 1957, 12b, 54-58.

51 (a)Yamada, M.; Tanaka, K.; Araki, S.; Butsugan, Y. Tetrahedron Lett. 1995, 36,

3169-3172. (b) Yamada, M.; Tanaka, K.; Butsugan, Y.; Kawai, M.; Yamamura,

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52 Miyai, T.; Inoue, K.; Yasuda, M.; Shibata, I.; Baba, A. Tetrahedron Lett. 1998, 39,

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53 Inoue, K.; Ishida, T.; Shibata, I.; Baba A. Adv. Synth. Catal. 2002, 344, 283-287.

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58

55 Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. Tetrahedron Lett. 2001, 42, 4661-

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56 Hayashi, N.; Honda, H.; Yasuda, M.; Shibata, I.; Baba, A. Org. Lett. 2006, 8,

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57 (a) Takami, K.; Yorimitsu, H.; Oshima, K., Org. Lett. 2002, 4, 2993-2995. (b)

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58 Takami, K.; Mikami, S.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Tetrahedron

2003, 59, 6627-6635.

59 (a) Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron Lett. 1998, 39, 6291-6294. (b)

Miyai, T.; Onishi, Y.; Baba, A. Tetrahedron 1999, 55, 1017-1026.

60 Miyai, T.; Ueba, M.; Baba, A., Synlett 1999, 2, 182-184.

61 Yasuda, M.; Onishi, Y.; Ueba, M.; Miyai, T.; Baba, A. J. Org. Chem. 2001, 66,

7741-7744.

62 Shibata, I.; Kato, H.; Ishida, T.; Yasuda, M.; Baba, A. Angew. Chem., Int. Ed.

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64 Hayashi, N.; Shibata, I.; Baba, A. Org. Lett. 2005, 7, 3093-3096.

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67 Sakai, N.; Fujii, K.; Konakahara, T. Tetrahedron Lett. 2008, 49, 6873-6875.

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69 Inoue, K.; Sawada, A.; Shibata, I.; Baba, A. J. Am. Chem. Soc. 2002, 124, 906-

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59

71 Ranu, B. C.; Samanta, S., Tetrahedron Lett. 2002, 43, 7405-7407.

72 Ranu, B. C.; Samanta, S., Tetrahedron 2003, 59, 7901-7906.

73 Ranu, B. C.; Samanta, S., J. Org. Chem. 2003, 68, 7130-7132.

74 Ranu, B. C.; Das, A.; Hajra, A., Synthesis 2003, 7, 1012-1014.

75 Ranu, B. C.; Banerjee, S.; Das, A., Tetrahedron Lett. 2004, 45, 8579-8581.

76 Wang, C. Y.; Su, H.; Yang, D. Y., Synlett 2004, 3, 561-563.

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60

CHAPTER 2

InCl3-NaBH4 Mediated Reduction of

Aromatic and Aliphatic Nitriles to Primary Amines

61

2.1 Introduction

2.1.1 Importance of Amines in Society

The prevalence and extensive use of amines as starting materials for plastics,

agrochemicals and dyes in industry make it an important functional group in organic

chemistry.1 Amines play important roles in biological processes and in many

pharmaceuticals widely used today.1 Many amines have been found to be particularly

active as central nervous system (CNS) drugs as evidenced by the many

pharmaceuticals that employ amines.2

Figure 2.1. Popular Amines in the Pharmaceutical Industry2

Amine containing drugs are used to treat a variety of ailments including depression,

which affects an estimated one in ten Americans today, according to the Center for

62

Disease Control (CDC).3 Thus, the growing interest and use of amines has

necessitated novel and efficient methods for their synthesis.4 Consequently, a variety

of methods for amine synthesis have been developed.1

2.1.2 Amine Synthesis

One method of synthesizing amines includes the incorporation of ammonia,

usually through a transition metal catalyst including rhodium, iridium, ruthenium,

gold, copper, or palladium.5 Although a copper catalyzed method has been known for

some time, it is limited in its scope and can require high catalyst and ligand loadings.

The palladium-catalyzed coupling of ammonia with aryl halides to produce primary

aryl amines has emerged as a promising method of synthesizing aryl amines (eq. 1).5

(1)

These catalysts were found to be highly selective for coupling of ammonia and are an

effective method of generating aryl amines. However, this method is limited to the

synthesis of aryl amines and requires elevated temperature and pressure.

Another method of synthesizing amines is through the Gabriel amine

synthesis (eq. 2).6

(2)

63

Mechanistically, this reaction begins via the alkylation of a potassium salt of

phthalimide using a primary alkyl halide.7 This produces the corresponding N-

alkylphthalimide, which upon workup with hydrazine undergoes transamination to

afford the primary amine as a salt (Scheme 2.1).7

Scheme 2.1. Mechanism of the Gabriel Amine Synthesis7

An interesting modification of the Gabriel synthesis involves the use of

primary and secondary alcohols to synthesize allylic amines.8 Alcohols in THF

underwent reaction at room temperature in the presence of 1.5 equivalents of

triphenylphosphine (PPh3), diisopropyl azodicaroboxylate (DIAD) and phthalimide

followed by treatment with hydrazine to afford the corresponding primary amine (eq.

3).8

64

(3)

2.1.3 Synthesis of Amines Via the Reduction of Nitriles Using Aluminum

Hydrides

Many of the above mentioned methods of generating amines require harsh

reaction conditions and often suffer from poor reaction yields. Among the many

procedures used to synthesize amines, the reduction of nitriles has been shown to be

an attractive method due to the ready availability of nitriles and the high atom

efficiency of these reductions.4

Among the most commonly utilized methodologies

for the conversion of nitriles to primary amines is the hydrogenation of nitriles in the

presence of a transition metal at elevated temperature and pressure.4,9,10,11

While there

are many transition metal catalysts for the hydrogenation of nitriles, palladium,

platinum, and nickel are the most popular (eq. 4).12

(4)

65

For example, Beller and coworkers recently demonstrated that easily accessible

ruthenium catalysts along with N-heterocyclic carbene ligands can readily

hydrogenate various nitriles to the corresponding primary amines (eq. 5).13

(5)

While the hydrogenation of nitriles to afford the corresponding primary

amines is an efficient method, the elevated temperature and pressures required have

left a need for milder alternatives. One of the early alternatives dates back to the late

1940s and involves the use of hydrides in the reduction of nitriles. As described in

the previous chapter, the historical reactivity gap between LiAlH4 and NaBH4 has

led to the development of hydrides with intermediary reactivity and selectivity. The

nitrile functional group is an interesting functional group to probe this reactivity

gap, as it is not reduced with NaBH4, but is readily reduced with LiAlH4. Nystrom

and coworkers first explored the reduction of nitriles by LiAlH4 in 1948, shortly after

the development of LiAlH4 itself (eq. 6).14

(6)

66

However, reaction conditions were not ideal, requiring refluxing in ether for over six

hours. The scope and reaction conditions were further explored and optimized by

Nelson and coworkers.15

However, it was H.C. Brown and coworkers who found that

reacting LiAlH4 with sulfuric acid (H2SO4) in tetrahydrofuran (THF) generated

aluminum hydride (AlH3) (eq. 7), which could reduce nitriles at room temperature

(eq. 8).16