The Synthesis and Application of a Series of C4-Symmetric Dirhodium Catalysts Derived from 1-(2-Chlorophenyl)-2,2-Diphenylcyclopropanecarboxylate Ligands Open Access
Liu, Wenbin (Fall 2019)
Abstract
Rhodium-bound donor/acceptor carbenes have been developed as an influential tool for selective C–H functionalization, in which the donor moiety attenuates the reactivity. Additionally, the selectivity can be further altered by using different dirhodium catalysts with specially designed ligands and therefore, catalyst-controlled site-selective C–H functionalization can be achieved. The first chapter gives an overview about the rhodium carbene chemistry, dirhodium tetracarboxylate catalysts, and site-selective C–H functionalization.
The second chapter describes the development of Rh2(S-2-Cl-5-BrTPCP)4, which is a sterically encumbered catalyst that induces high site-selectivity for functionalization at terminal unactivated methylene C–H bonds, even in the presence of electronically activated benzylic C–H bonds that are typically favored by previously established dirhodium catalysts. Rh2(S-2-Cl-5-BrTPCP)4 and its derivatives, which contain different substituents on the 2-chlorophenyl groups in the (S)-1-(2-chlorophenyl)-2,2-diphenylcyclopropanecarboxylate ligand scaffold, have similar selectivity profiles and all adopt a C4-symmetry geometry with an additional M-axial chirality between the 2-chlorophenyl and cyclopropane moieties. Computational studies on Rh2(S-2-Cl-5-BrTPCP)4 suggest the same conformation is favored in dichloromethane and it is rigid without alteration when the carbene binds.
The third chapter demonstrates the ability of the rhodium donor/acceptor carbene chemistry in the synthesis of positional analogs for methylphenidate. Using the right dirhodium catalysts and protecting groups, 2- and 4-susbstituted analogs are accessed as single regioisomer with high stereoselectivity via C–H insertion on piperidines. The 3-substituted analogs can be prepared indirectly by cyclopropanation followed by reductive ring-opening.
The fourth chapter describes the immobilization of dirhodium triarylcyclopropanecarboxylate catalysts for site- and stereoselectivity C–H insertion reactions in flow. Systematic studies on the effect of anchor sites suggest the aryl ring trans to the carboxylate group, which points to the periphery of the catalyst, is the optimal site for linking to the solid support covalently. Moreover, Rh2(S-2-Cl-5-BrTPCP)4 is derivatized to Rh2(S-2-Cl-5-CF3TPCP)4 for catalyst immobilization.
The fifth chapter introduces a new method for accessing diazo compounds via copper-catalyzed dehydrogenation of hydrazones using oxygen as the terminal oxidant, which is effective for the preparation of diazoesters, diazoketones and diazoamides in high yields.
Table of Contents
Chapter 1. Introduction to Selective C–H Functionalization via Rhodium Carbenes .................1
1.1. Site-selective C–H Functionalization................................................................................ 1
1.2. Rhodium Carbene Chemistry ........................................................................................... 2
1.3. Dirhodium Tetracarboxylate Catalysts ........................................................................... 4
Chapter 2. Synthesis and Development of the Sterically Demanding C4-Symmetric Catalysts, the Rh2(o-ClTPCP)4 Series, for Overcoming Electronic Preference ..........................................11
2.1. Introduction ...................................................................................................................... 11
2.1.1 Symmetry of Dirhodium (II) Carboxylate Catalysts .............................................. 11
2.1.2. Site- and Stereoselective Functionalization of Electronically Activated and Unactivated Methylene C–H Bonds .................................................................................. 16
2.2. Results and Discussion ..................................................................................................... 19
2.2.1. Synthesis and Initial Examination of Rh2(S-o-ClTPCP)4 Catalyst ...................... 19
2.2.2. C–H Insertion of 4,5-Substituted 1,3-Dioxolane .................................................... 26
2.2.3. Development of Rh2(2-Cl-4-BrTPCP)4 and Rh2(2-Cl-5-BrTPCP)4 ...................... 29
2.2.5. Catalyst-Controlled Selective Functionalization of Unactivated C−H Bonds in the Presence of Electronically Activated C−H Bonds ...................................................... 43
2.2.6. Extension in Rh2(S-o-ClTPCP)4 Catalysts Family ................................................. 57
2.2.7. Computational Studies for Structural Understanding of the Complex and Carbene ................................................................................................................................ 60
2.3. Conclusion ........................................................................................................................ 63
Chapter 3. Catalyst-controlled Site-selective Functionalization of Piperidines for Methylphenidate Analogs .............................................................................................................64
3.1. Introduction ...................................................................................................................... 64
3.2. Results and Discussion ..................................................................................................... 68
3.2.1. C–H Functionalization of Piperidines at C2 Sites .................................................. 68
3.2.2. C–H Functionalization of Piperidines at C4 Sites .................................................. 75
3.2.3. C3 Analog Generation .............................................................................................. 78
3.3. Conclusion ........................................................................................................................ 81
Chapter 4. Efforts Towards Immobilization of Rh2(TPCP)4 for Asymmetric C–H Insertion in Flow ...............................................................................................................................................82
4.1 Introduction ....................................................................................................................... 82
4.1.1 Continuous Flow Chemistry ..................................................................................... 82
4.1.2 Immobilization of Dirhodium (II) Catalysts and Application in Flow ................. 83
4.2 Results and Discussion ...................................................................................................... 94
4.2.1 Immobilization of Rh2(S-p-BrTPCP)4 ...................................................................... 94
4.2.2 Exploration of Influence of Anchor Site on Rh2(S-o-ClTPCP)4 ............................ 97
4.2.3 Development of immobilized Rh2(S-2-Cl-5-CF3TPCP)4 for Flow Reaction in Cartridge ............................................................................................................................ 105
4.3 Conclusion ....................................................................................................................... 113
Chapter 5. Oxidation of Hydrazones for Diazo Synthesis with Oxygen as Terminal Oxidant 114
5.1 Introduction ..................................................................................................................... 114
5.1.1 Overview of Diazo Synthesis ................................................................................... 114
5.1.2 Hydrazone Oxidation for Diazo Synthesis ............................................................. 115
5.2 Results and Discussion .................................................................................................... 118
5.3 Conclusion ....................................................................................................................... 125
Experimental Part .......................................................................................................................127
6.1 General Considerations and Reagents .......................................................................... 127
6.2 Experimental Part for Chapter 2 .................................................................................. 131
6.3 Experimental Part for Chapter 3 .................................................................................. 227
6.4 Experimental Part for Chapter 4 .................................................................................. 262
6.5 Experimental Part for Chapter 5 .................................................................................. 292
References ...................................................................................................................................303
Appendix: X-Ray Crystallographic Data ...................................................................................311
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The Synthesis and Application of a Series of C4-Symmetric Dirhodium Catalysts Derived from 1-(2-Chlorophenyl)-2,2-Diphenylcyclopropanecarboxylate Ligands () | 2019-11-05 13:34:29 -0500 |
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