Design, Synthesis, and Utilization of Iridium(III) Bis(oxazolinyl)phenyl and Iridium(III) Bis(imidazolinyl)phenyl Complexes for Catalytic Enantioselective Atom Transfer C-H Functionalization 公开

Owens, Clayton (2014)

Permanent URL: https://etd.library.emory.edu/concern/etds/cr56n107n?locale=zh
Published

Abstract

The science of organic chemistry has experienced significant advances in recent years due to the increase in efficient methodologies for the synthesis of complex molecules. Traditional synthetic methods have relied on functional groups for selective reactions to be achieved, but these functional groups often require independent preparation and may not be present in the target molecule. Thus, the consideration of carbon-hydrogen (C-H) bonds as functional groups represents a direct approach for overcoming this inherent limitation. C-H bonds were once perceived as being inert, but recent progression of technologies for their functionalization has allowed chemists to incorporate them in synthetic strategies. One such technology involves the design of transition metal complexes that generate a reactive metallocarbene or metallonitrene, which then selectively engages the desired C-H bond to be functionalized and forges a new C-C or C-N bond, respectively. Dirhodium(II) complexes have emerged as state of the art catalysts in metallocarbene and metallonitrene chemistry, but recent reports have revealed that iridium complexes offer reactivity which is unattainable under dirhodium catalysis. Our laboratory discovered that iridium(III) bis(oxazolinyl)phenyl complexes perform catalytic and highly chemo-, regio-, and enantioselective C-H insertion into cyclic dienes using donor/acceptor metallocarbenes. Further catalyst design has led to new iridium(III) bis(imidazolinyl)phenyl complexes which catalyze chemo- and enantioselective C-H functionalization of cyclic ethers using acceptor-only metallocarbenes. Computational analysis of the reactive intermediates has provided substantial insight into the controlling factors for the observed selectivity. Detailed analyses of our efforts to advance the technologies for C-H functionalization through catalyst design are described in this dissertation.

Table of Contents

1 Chapter One: C-H Functionalization by Metallocarbenes and Metallonitrenes: Background and Significance 1

1.1 Introduction................................................................................................. 1

1.2 Metallocarbenes............................................................................................. 4

1.2.1 Generation and Classification........................................................................ 4

1.2.2 C-H Insertion with donor/acceptor metallocarbenes......................................... 6

1.2.3 C-H Insertion with acceptor-only metallocarbenes........................................... 7

1.2.4 Conclusions and challenges......................................................................... 13

1.3 Metallonitrenes............................................................................................. 14

1.3.1 Introduction.............................................................................................. 14

1.3.2 Generation of metallonitrenes...................................................................... 14

1.3.3 Intramolecular C-H amination...................................................................... 16

1.3.4 Intermolecular C-H amination...................................................................... 16

1.3.5 Conclusions and challenges.......................................................................... 28

1.4 Conclusions.................................................................................................. 29

2 Chapter Two: Iridium Catalyzed Metallocarbene and Metallonitrene Atom-Transfer Reactions 30

2.1 Introduction................................................................................................. 30

2.2 Iridium(III) Salen Metallocarbene Atom-Transfer............................................... 30

2.2.1 Iridium(III) salen synthesis......................................................................... 30

2.2.2 Iridium(III) salen catalyzed cyclopropanation................................................. 32

2.2.3 Iridium(III) salen catalyzed cyclopropenation................................................. 35

2.2.4 Iridium(III) salen catalyzed C-H functionalization............................................ 37

2.2.5 Iridium(III) salen catalyzed Si-H insertion...................................................... 41

2.3 Iridium(III) Porphyrin Metallocarbene Atom-Transfer.......................................... 42

2.3.1 Iridium(III) porphyrin synthesis.................................................................... 42

2.3.2 Iridium(III) porphyrin catalyzed cyclopropanation........................................... 43

2.3.3 Iridium(III) porphyrin catalyzed C-H functionalization...................................... 46

2.3.4 Asymmetric intermolecular C-H functionalization by iridium(III) complexes of chiral Halterman porphyrin ligands..........48

2.3.5 Intramolecular C-H functionalization by iridium(III) porphyrin complexes........... 54

2.4 Iridium(I) Catalyzed Metallocarbene Atom-Transfer........................................... 56

2.5 Iridium (III) Catalyzed Metallonitrene Atom-Transfer......................................... 57

2.5.1 Iridium(III) salen catalyzed intramolecular C-H amination of sulfonyl azides........57

2.5.2 Intermolecular C-H amidation using acyl azides.............................................. 59

2.6 Iridium (I) Catalyzed Metallonitrene Atom-Transfer............................................ 60

2.7 Conclusions.................................................................................................. 62

3 Chapter Three: Development of Iridium NCN Pincer Catalysts for Enantioselective Metallocarbene C-H Functionalization..........63

3.1 Bis(oxazolinyl)phenyl (phebox) complexes........................................................ 65

3.1.1 Palladium(II) phebox complexes developed by Denmark.................................. 65

3.1.2 Rhodium(III) phebox complexes................................................................... 66

3.1.3 Stoichiometric Reactions at the Rhodium(III) Phebox Metal Center.................... 68

3.1.4 Rhodium(III) phebox complexes in asymmetric catalysis.................................. 70

3.1.5 Phebox complexes with metals other than rhodium.......................................... 72

3.2 Iridium(III) Phebox Complexes........................................................................ 73

3.2.1 Synthesis of iridium phebox complexes.......................................................... 73

3.2.2 Stoichiometric and catalytic C-H functionalization using iridium(III) phebox complexes..........75

3.3 Design and Synthesis of New Iridium(III) Phebox Complexes.............................. 79

3.3.1 Synthesis of iridium(III) phebox complex 174................................................ 79

3.3.2 Proof of principle for iridium(III) phebox catalyzed atom transfer using a donor/acceptor metallocarbene......81

3.3.3 Design concept and synthesis of new iridium(III) phebox complexes.................. 83

3.3.4 X-ray structure analysis of [(R,R)-tBuPhebox-Bn]IrCl2(OH2) 216....................... 85

3.4 Iridium(III) Phebox Catalyzed C-H Insertion of Donor/Acceptor Diazoesters........... 86

3.4.1 Initial optimization of catalyst and reaction conditions...................................... 86

3.4.2 Scope of aryl diazoesters for C-H insertion into cyclic 1,4 dienes........................ 92

3.4.3 Confirmation of the absolute stereochemistry for iridium(III) phebox catalyzed C-H insertion of methyl phenyldiazoacetate into 1,4-cyclohexadiene.............................................................................................. 95

3.4.4 C-H functionalization of substituted cyclic 1,4-dienes........................................ 97

3.4.5 Iridium(III) phebox catalyzed C-H insertion into 1,3,5-cycloheptatriene............ 102

3.4.6 Iridium(III) phebox catalyzed C-H insertion into tetrahydrofuran..................... 103

3.4.7 Reactions of iridium(III) phebox complexes with alpha-alkyl diazoesters........... 104

3.4.8 Evaluation of non-ester donor/acceptor carbene precursors for iridium(III) phebox catalyzed C-H functionalization of 1,4-cyclohexadiene..........105

3.5 Computational Studies for Iridium(III) Phebox Catalyzed Donor/Acceptor C-H Insertion into 1,4-cyclohexadiene..........109

3.5.1 DFT Analysis of the reactive carbene intermediate.......................................... 110

3.5.2 Attempts to experimentally validate the computation...................................... 118

3.6 Structural Studies Performed by the Berry Group.............................................. 120

3.6.1 Introduction.............................................................................................. 120

3.6.2 Variable temperature 13C NMR studies.......................................................... 121

3.6.3 UV-Vis studies on the reaction of iridium(III) phebox 213 mediated decomposition of methyl p-methoxyphenyldiazoacetate 264........124

3.7 Conclusions................................................................................................. 125

4 Chapter Four: Iridium(III) Phebox and Iridium(III) Phebim Catalyzed Acceptor-only Metallocarbene C-H Functionalization..........127

4.1 Introduction................................................................................................ 127

4.2 Iridium(III) Phebox Catalyzed Acceptor-only Atom Transfer............................... 128

4.2.1 Insertion of ethyl diazoacetate into 1,4-cyclohexadiene.................................. 128

4.2.2 Insertion of ethyl diazoacetate into tetrahydrofuran....................................... 130

4.2.3 Evaluation of other acceptor-only metallocarbene precursors for C-H insertion into THF........134

4.2.4 Iridium(III) phebox catalyzed enantioselective C-H functionalization of phthalan.................137

4.2.5 Iridium(III) phebox catalyzed enantioselective C-H functionalization of tetrahydrofuran and 2,5-dihydrofuran..........141

4.2.6 Kinetic isotope effect for the C-H insertion of ethyl diazoacetate into tetrahydrofuran...........143

4.2.7 Attempts to perform C-H functionalization into other cyclic ethers.....................145

4.2.8 Attempts to perform acceptor-only C-H funtionalization into acyclic ethers.........147

4.2.9 Conclusions...............................................................................................149

4.3 Computational Studies for Iridium(III) Phebox Catalyzed Acceptor-only C-H Insertion into THF and Phthalan.................150

4.3.1 DFT analysis of the geometry of the reactive acceptor-only carbene intermediate derived from ethyl diazoacetate....150

4.3.2 Calculated transition state and intrinsic reaction coordinate for iridium(III) phebox catalyzed C-H insertion of ethyl diazoacetate into THF............152

4.3.3 Factors controlling the enantioselectivity for C-H insertion of ethyl diazoacetate into THF via TSHT-eq....154

4.3.4 Factors controlling the enantioselectivity for C-H insertion of ethyl diazoacetate into phthalan................156

4.4 Bis(imidazolinyl)phenyl (phebim) Iridium(III) Complexes.................................. 158

4.4.1 Introduction............................................................................................. 158

4.4.2 Synthesis of phebim ligands and rhodium(III) complexes thereof.................... 159

4.4.3 Synthesis of phebim ligand 295 and its iridium(III) phebim complex 296........ 162

4.4.4 Enantioselective intermolecular C-H insertion of ethyl diazoacetate into phthalan catalyzed by iridium(III) phebim complex 296...............164

4.4.5 Synthesis of electronically varied iridium(III) phebim ligands 295, 297-300 and their iridium(III) phebim complexes 296, 301-304.......165

4.4.6 Catalytic activity of electronically varied iridium(III) phebim complexes 301-304 for C-H insertion of ethyl diazoacetate into phthalan.......166

4.4.7 Synthesis of iridium(III) bromo phebox complexes 305 and 306 and their reactivity towards C-H insertion of ethyl diazoacetate into phthalan........168

4.4.8 Synthesis of sec-butyl, cyclohexyl, iso-butyl, and CH2-cyclohexyl iridium(III) chloro phebox complexes 311-314........................169

4.4.9 Catalytic activity of sec-butyl, cyclohexyl, iso-butyl, and CH2-cyclohexyl iridium(III) chloro phebox complexes 315-318...............173

4.4.10 C-H insertion of ethyl diazoacetate into 2,5-dihydrofuran and THF............................ 174

4.4.11 Iridium(III) phebim catalyzed C-H insertion of ethyl diazoacetate into isochroman.......177

4.5 Conclusions............................................................................................................180

5 Chapter Five: Iridium(III) Phebox Catalyzed C-H Amination.................................. 182

5.1 Iridium(III) Phebox Catalyzed C-H Amination............................................................. 182

5.1.1 Iridium(III) phebox catalyzed intramolecular C-H amination using aryl azides...............183

5.1.2 Iridium(III) phebox catalyzed intramolecular C-H amination using sulfamate esters.......185

5.2 Conclusions........................................................................................................... 187

6 Experimentals........................................................................................................ 188

6.1 General Information............................................................................................... 188

6.2 Chapter 3 Procedures and Characterization................................................................ 190

6.2.1 Synthesis of 4,6-dimethylisophthaloyl dichloride 196............................................... 190

6.2.2 Synthesis of phebox ligands and iridium(III) phebox complexes................................ 192

6.2.3 Synthesis of triphenylphosphine iridium(III) phebox complexes 262 and 263 and their NMR spectra..........211

6.2.4 Procedures and characterization data for C-H insertion reactions using donor/acceptor carbenes................215

6.2.5 X-ray Crystallographic Data for [(R,R)-tBuPhebox-Bn]IrCl2(H2O) 216......... 248

6.3 Chapter 4 Procedures and Characterization................................................ 253

6.3.1 Iridium(III) phebox catalyzed enantioselective C-H insertion of acceptor-only metallocarbenes................. 253

6.3.2 Synthesis of amides 274, 307-310....................................................... 262

6.3.3 Synthesis of phebim ligands 295, 297-300, 311-314............................. 267

6.3.4 Synthesis of iridium(III) phebim complexes 296, 301-306, 299, 315-317, trans-318, cis-318.............276

6.4 Chapter 5 Procedures and Characterization. .............................................. 288

7 Appendix -List of Synthesized Compounds............................................. 291

References................................................................................................299

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