Development of Enantioselective C–N Bond Forming Reactions using Planar Chiral Rh(III) Indenyl Catalysts Pubblico
Gross, Patrick (Spring 2024)
Abstract
As drug designs exhibit increased three-dimensional complexity, the stereoselective formation of C–N bonds has become increasingly important in synthetic organic chemistry. To enable the rapid synthesis of chiral C–N containing motifs, the Blakey group developed a planar chiral Rh(III) indenyl catalyst to render a redox-neutral allylic C–H amidation enantioselective. Herein we report the application of this chiral catalyst platform to the development of two enantioselective methods for the synthesis of chiral aziridines and 2-aminotetralins. The enantioselective aziridination method uses a sulfonyl protected hydroxylamine nitrogen sources and demonstrates a previously unseen level of exclusive selectivity for unactivated alkenes. This transformation is proposed to operate via a migratory insertion mechanism and not via the more common metal nitrene intermediate typically reported for transition metal-catalyzed aziridinations of alkenes. Exchanging the sulfonyl protecting group of the hydroxylamine for a carbamate enabled the 1,2‑arylamination of 4-phenylbutenes to form 2-aminotetralins, a drug scaffold of longstanding pharmaceutical interest. This transformation is a new example of a Group IX piano stool catalyzed activation of an electrophilic nitrogen source towards indirect nucleophilic attack. Optimization studies revealed the indenyl scaffold to be privileged, making our planar chiral catalysts ideal choice to render this transformation enantioselective. During our investigation of the scope of this method, competing 6-endo and 5-endo cyclization modes were observed leading to the formation of 2-aminotetralin regioisomers. The formation of a spirocyclic intermediate in the 5-endo pathway was confirmed through isolation; intentional trapping of this intermediate expanding the scope of this 1,2-arylamntion to include a variety amine-substituted [4.5]‑ and [5.5]‑carbospirocycles. Mechanistic investigations revealed an electrophilic aromatic substitution mechanism to be operative for the C–C bond formation. We propose a migratory insertion mechanism leading to the formation of an electrophilic four membered aza-metallocycle which is subjected to nucleophilic attack from the aromatic ring.
Table of Contents
Chapter 1: Strategies for the Enantioselective Synthesis of Aziridines
1.1 Introduction to Aziridines
1
1.2 Enantioselective Synthesis of Aziridines
3
1.2.1 Overview of Aziridine Synthetic Strategies
3
1.2.2 Enantioselective Synthesis of Aziridines via Intramolecular Condensation
4
1.2.3 Enantioselective Synthesis of Aziridines via Carbon Addition to Imines
5
1.2.4 Enantioselective Synthesis of Aziridines via Nitrogen Addition to Alkenes
8
1.3 Transition Metal Catalyzed Enantioselective Aziridination of Unactivated Alkenes
13
1.4 Conclusion
15
1.5 References
16
Chapter 2: Development of an Enantioselective Unactivated Alkene Aziridination Method using Planar Chiral Rh(III) Indenyl Catalysts and the Synthesis of Electron Rich Planar Chiral Indenyl Scaffolds
2.1 Introduction to Chiral Cyclopentadienyl Catalysts
25
2.1.1 Overview of Chiral Cyclopentadienyl Transition Metal Catalysts
25
2.1.2 Chiral Cp Ligands of C2-Symmetry
26
2.1.3 Planar Chiral Cp Transition Metal Complexes
28
2.2 Development of Group IX Transition Metal Catalyzed Allylic C–H Functionalization Strategies in the Blakey Group
29
2.2.1 Development of Group IX Catalyzed Oxidative Allylic C–H Functionalization Methods
30
2.2.2 Development of Group IX Catalyzed Redox Neutral Allylic C–H Functionalization Methods
32
2.2.3 Development of a Planar Chiral Rh(III) Indenyl Catalyst for Enantioselective C–H Amidation
33
2.3 Enantioselective Aziridination of Unactivated Alkenes Using A Planar Chiral Rh(III) Indenyl Catalyst
38
2.3.1 Evaluation of Catalytic Activity of First- and Second-Generation Planar Chiral Catalysts
39
2.3.2 Synthesis of Third-Generation Electron Rich Planar Chiral Catalysts
40
2.3.3 Optimization of Reaction Conditions
45
2.3.4 Reaction Scope
47
2.3.5 Mechanistic Investigation
51
2.4 Conclusion
53
2.5 References
55
2.6 Supporting Information
63
2.6.1 General Information
63
2.6.2 Experimental Procedures and Tabulated Data
64
2.6.3 Supporting Information References
125
2.6.4 NMR and HPLC Data
128
Chapter 3: Group IX Transition Metal Catalyzed Activation of Electrophilic Nitrogen Reagents Towards Direct and Indirect Nucleophilic Attack
3.1 Introduction to Transition Metal Catalyzed Activation of Electrophilic Nitrogen Reagents
259
3.2 Direct Nucleophilic Attack
261
3.3 Indirect Nucleophilic Attack
265
3.4 Conclusion
271
3.5 References
272
Chapter 4: Enantioselective 1,2-Arylamination: Synthesis of 2-Aminotetralins and 2‑ Amino Carbospirocycles
4.1 Introduction to 2-Aminotetralins
276
4.1.1 2-Aminotetralins in Medicinal Chemistry
276
4.1.2 Enantioselective Synthesis of 2-Aminotetralins
278
4.2 Development of an Enantioselective 1,2-Arylamination
280
4.2.1 Reaction Discovery and Optimization
280
4.2.2 Regioselectivity and Scope of the Enantioselective 1,2-Arylamination
286
4.2.3 Mechanistic Investigations
290
4.3 Conclusion
293
4.4 References
295
4.5 Supporting Information
302
4.5.1 General Information
302
4.5.2 Experimental Procedures and Tabulated Data
304
4.5.3 Supporting Information References
338
4.5.4 NMR, HPLC and SFC Data
341
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