Site-selective and Stereoselective Functionalization of Non-Activated C–H Bond Open Access

Liao, Kuangbiao (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/xd07gs69t?locale=en
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Abstract

The major challenge for C–H functionalization remains to be selectivity; although considerable progress has been achieved, the established approaches to develop selective transformation rely on the use of substrate control, which inevitably possesses inherent limitation. A more versatile but challenging approach would be catalyst control, in which the sophisticated catalyst can distinguish one C–H bond from others by recognizing the subtle steric and electronic differences. The approach in the Davies group is to develop a rhodium carbene toolbox to control the selectivity at will.

 

Catalyst Synthesis. In general, systematic study and further catalyst structural modification are required to discover the optimal catalyst. However, current catalyst synthesis has limitations in structural diversification and accessibility. Therefore, a high-throughput Suzuki coupling process was developed to enable rational design and systematic study. So far, three catalyst libraries have been effectively established from three corresponding preformed bromo-containing dirhodium catalyst through a four-, eight- and twelve-fold palladium catalyzed Suzuki coupling reaction.

 

Catalyst Design. The catalyst design philosophy was inspired by highly selective enzymatic catalysis, in which each enzyme pocket will allow only one specific substrate to fit. Therefore, if a series of sophisticated catalyst pockets can be designed to recognize the unique steric and electronic character of the target C–H bonds, a similar type of selective catalysis could also be viable. The hypothesis is trying to develop a catalyst 1 with a “small” pocket that only 1° C–H bond can fit; a catalyst 2 with “medium” pocket that 2° C–H bond will be sterically preferred over 3° C–H bond and electronically preferred over primary C–H bond; a catalyst 3 with “large” pocket so that tertiary C–H bond will be electronically preferred over other C–H bonds.

 

 

This thesis will discuss efforts toward developing three dirhodium catalysts, Rh2[tris(p-tBuC6H4)TPCP]4, Rh2[3,5-di(p-tBu)C6H4TPCP]4, and Rh2(TCPTAD)4, to achieve site- and stereoselective C–H functionalization at the most accessible primary, secondary, and tertiary non-activated C–H bonds, respectively. The reaction scope is ranging from alkanes, alkyl halides, alkyl ester, protected alcohols, alkyl silanes to natural products, including steroids, vitamin and phytol derivatives. These three catalysts demonstrated strong catalyst control capability to recognize the target C–H bonds to achieve extremely high site-, diastereo- and enantioselectivity.

Table of Contents

Chapter 1 Introduction .................................................................................................................. 1

1. C–H Functionalization ........................................................................................................... 1

2. Grand Challenge of C–H Functionalization ........................................................................ 6

Chapter 2 Catalyst Design and Synthesis .................................................................................. 15

1. Catalyst Design Philosophy ................................................................................................. 15

2. Catalyst Development .......................................................................................................... 18

Chapter 3 Alkane Reactions ....................................................................................................... 39

1. Introduction .......................................................................................................................... 39

1.1. C–H Borylation ............................................................................................................... 40

1.2. C–H Amination and Azidation ....................................................................................... 42

1.3. Carbene Insertion ............................................................................................................ 47

2. Initial Exploration of Pentane Functionalization .............................................................. 54

3. Initial exploration of linear and branched TPCP catalysts .............................................. 59

4. Optimum Catalyst for Selective Functionalization at the Most Accessible Secondary C–

H Bond ...................................................................................................................................... 63

5. Optimum Catalyst for Selective Functionalization at the Most Accessible Primary C–H

Bond .......................................................................................................................................... 68

6. Optimum Catalyst for Selective Functionalization at the Most Accessible Tertiary C–H

Bond .......................................................................................................................................... 71

7. Conclusion ............................................................................................................................ 74

Chapter 4 Selective Functionalization of the Most Accessible Secondary C–H bond ........... 76

1. Catalyst Structure Analysis ................................................................................................ 76

2. Substrate Scope .................................................................................................................... 78

3. Conclusion ............................................................................................................................ 85

Chapter 5 Selective Functionalization of the Most Accessible Primary C–H bond ............... 86

1. Introduction .......................................................................................................................... 86

2. Catalyst Structure Analysis ................................................................................................ 87

3. Substrate Scope .................................................................................................................... 92

4. Conclusion ............................................................................................................................ 98

Chapter 6 Selective Functionalization of the Most Accessible Tertiary C–H bond ............... 99

1. Introduction .......................................................................................................................... 99

2. Catalyst Structure Analysis .............................................................................................. 101

3. Substrate Scope .................................................................................................................. 104

4. Conclusion .......................................................................................................................... 112

Chapter 7 Catalyst Symmetry & Quantitative Model ............................................................ 114

1. Introduction ........................................................................................................................ 114

2. Catalyst Symmetry ............................................................................................................. 117

3. Quantitative Model ............................................................................................................ 120

4. Conclusion .......................................................................................................................... 126

References ................................................................................................................................... 127

Supporting Information ............................................................................................................ 135

SI‐Chapter 2 ............................................................................................................................. 137

1. Catalyst Synthesis............................................................................................................. 137

2. High Resolution Mass Spectrometry (HRMS) spectra of catalysts .................................. 206

SI‐Chapter 3 ............................................................................................................................. 290

1. Characterization of Pentane Functionalization Products ................................................ 290

1.5 NMR Spectra .................................................................................................................. 303

2. Characterization of 2‐Methylpentane Functionalization Products ................................. 327

3. Catalyst Screen for Secondary Selective Catalyst ............................................................ 352

4. Catalyst Screen for Primary Selective Catalyst ................................................................ 410

5. Catalyst Screen for Tertiary Selective Catalyst ................................................................ 488

6. X‐Ray Crystallographic Data ............................................................................................. 535

7. Computational Study ....................................................................................................... 631

SI‐Chapter 4 ............................................................................................................................. 779

1. General Considerations .................................................................................................... 779

2. C–H Functionalization Reactions...................................................................................... 782

3. General Procedure for Enantiomeric Excess (e.e.) Determination on HPLC ................... 784

4. Substrate Screen .............................................................................................................. 787

4.2 NMR Spectra for Product Characterization .................................................................. 801

SI‐Chapter 5 Selective Functionalization of the Most Accessible Primary C‐H bond .............. 849

1. General Considerations .................................................................................................... 849

2. General Procedures for C–H Functionalization Reactions ............................................... 852

3. General Procedure for Data Analysis ............................................................................... 853

4. Absolute Stereochemistry Determination ....................................................................... 855

5. Diazo Compounds Preparation ........................................................................................ 856

6. Characterization of C–H Functionalization Products ....................................................... 862

7. Crude 1H NMR Spectra for C–H Functionalization Products 5‐29 .................................... 885

8. NMR Spectra for C–H Functionalization Products ........................................................... 907

9. HPLC for C–H Functionalization Products ........................................................................ 971

10. X‐Ray Crystallographic Data of Product 5.3.7 ................................................................ 990

SI‐Chapter 6 ........................................................................................................................... 1003

1. General Considerations .................................................................................................. 1003

2. General Procedures for C–H Functionalization Reactions ............................................. 1006

3. General Procedure of Data Analysis .............................................................................. 1007

4. Determination of the Absolute Stereochemistry........................................................... 1009

5. Preparation of Diazo Compounds .................................................................................. 1010

6. Characterization of C–H Functionalization Products ..................................................... 1023

7. Crude 1H NMR Spectra ................................................................................................... 1057

8. NMR Spectra .................................................................................................................. 1089

9. HPLC ............................................................................................................................... 1133

10. X‐Ray Crystallographic Data for 6.3.16 ........................................................................ 1177

SI‐Chapter 7 ........................................................................................................................... 1192

1. General Considerations .................................................................................................. 1192

2. Acquisition and Preparation of Substrates .................................................................... 1193

3. C‐H Functionalization Reactions .................................................................................... 1194

4. NMR Spectra for Characterizations ............................................................................... 1203

5. Crude 1H NMR Spectra for the Ratio Determination ..................................................... 1213

6. HPLC Spectra for C–H Functionalization Reactions ........................................................ 1230

7. X‐Ray Crystallographic Data for Rh2(S‐p‐PhTPCP)4......................................................... 1241

8. Predictive Model: Carboxylic Acid Surrogate Calculation .............................................. 1280

SI‐References: ........................................................................................................................ 1291

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