Allylic C-H Arylation, Enantioselective Catalyst Development, and Enantioselective Allylic C-H Amidation Open Access

Farr, Caitlin (Summer 2020)

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The allylic substitution reaction, developed by Tsuiji and Trost, was an important advancement in natural product synthesis and drug molecule design which proceeds via a π-allyl intermediate. The Tsuiji-Trost reaction allowed for a disconnection that provided the opportunity for the convergent synthesis of natural products like strychnine. Instead of utilizing an allylic leaving group in the olefin substrate to access the π-alllyl intermediate, our group developed allylic C–H functionalization of internal and terminal olefins with rhodium(III) and iridium(III) pentamethylcyclopentadienyl catalysts. This methodology provided a class of reactions that were efficient and highly useful. We have previously described the successful development of a rhodium catalyst system capable of activating unsymmetrical 1,2- disubstituted olefins for regioselective allylic C–H amination and etherification, and described the mechanistic investigations in detail. Herein, we will disclose the development of a rhodium catalyzed regioselecitve allylic C–H arylation and amidation to enable access to motifs present in natural products and drug molecules. Also, we expand on the regioselective allylic amidation and describe the development of a planar chiral rhodium(III) catalyst for the enantioselective allylic amination of unactivated terminal and internal olefins.

Table of Contents

1. Metal catalyzed functionalization of olefins via π-allyl intermediates

1.1 Introduction to Allylic Substitution 1

1.2 Allylic C–H Functionalization of terminal olefins 4

1.3 Rhodium(III) catalyzed Allylic C–H Functionalization 6

1.4 Development of rhodium(III) catalyzed Allylic C–H Functionalization of unsymmetrical 1,2-disubstituted olefins 8

1.5 Conclusions 12

1.6 References 13

2. Development and progress towards the regioselective allylic C­­–H arylation of 1,2-disubstituted allyl benzene derivatives

2.1 Introduction to allylic C–H arylation 19

2.2 Reaction discovery: allylic C–H arylation 20

2.3 Reaction discovery: benzylic site selective allylic C–H arylation 25 

2.4 Rhodium(III) catalyzed allylic C–H functionalization mechanism and kinetic studies 30

2.5 Conclusion 36

2.6 Experimental Procedures 38

2.7 Spectral Data 48

2.8 References 55

3. Development of a Novel Chiral Indenyl Catalyst for Regio- and Enantioselective C–H Amidation of Unactivated Olefins

3.1 Introduction: Allylic C–H Amidation 56

3.2 Chiral group IX catalysts for allylic C–H amidation 58

3.3 Development of Catalyst for enantioselective allylic C–H amidation 63

3.4 Determining Catalyst and Substrate Stereochemistry 69

3.5 Reaction development: rhodium(III) indenyl catalyzed allylic C–H amidation 71

3.6 Reaction Mechanism and Stoichiometric Studies 77

3.7 Conclusion and Future Directions 81

3.8 Experimental Procedures 82

3.9 Spectral Data 119

3.10 References 175

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