Expanding the Scope of Reactions and Applications of Donor/Acceptor Metallocarbenes Open Access
Fu, Liangbing (2016)
Published
Abstract
The chemistry of rhodium-bound donor/acceptor carbenes has been extensively investigated and has given birth to a variety of useful transformations, among which C-H insertion reactions are of particular interest because it provides a unique strategy for the functionalization of unactivated C-H bonds. This dissertation is centered on expanding the scope of reactions and applications of donor/acceptor metallocarbenes by developing novel, efficient and selective transformations. The first part of this dissertation describes the role of ortho-substituents on the donor group in rhodium-catalyzed asymmetric synthesis of β-lactones by intramolecular C-H insertion reactions of aryldiazoacetates. A systematic optimization of the reaction conditions including catalyst, solvent, reaction temperature was first conducted, followed by exploration of the substrate scope of the transformation. It was demonstrated that a proper substituent at the 2-position of the aryldiazoacetates was critical to the β-lactone formation, especially for the insertion into the less reactive primary C-H bonds. The second part of the dissertation describes a rhodium(II)-catalyzed C-H functionalization of electron-deficient methyl groups. The combination of sterically demanding dirhodium triarylcyclopropane carboxylate catalysts and 2,2,2-trichloroethyl (TCE) aryldiazoacetates was shown to be critical to the success of the functionalizing challenging substrates such as ethyl crotonate. This reaction provides an alternative disconnection strategy for the asymmetric construction of 1,6-dicarbonyls. The third part of the dissertation describes the development of a novel approach for the synthesis of 2,2,2-trichloroethyl aryl- and vinyldiazoacetates by a palladium-catalyzed cross-coupling reaction. This method uses commercially readily available aryl iodides as the starting materials and circumvents the problems due to the requisite use of the more dangerous diazo transfer reagent o-nitrobenzenesulfonyl azide in diazo transfer reactions, and allows for rapid construction of a library of useful diazo compounds. The fourth part of the dissertation describes divergent reactions of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles for the efficient synthesis of polycyclic spiroindolines and tetrahydrocarbolines by rhodium(II)-catalyzed intramolecular annulations. It was shown that the product distribution of the reaction was highly dependent on the electronic and structural properties of the substrates. The last part first describes the exploration of vinylogous reactivity of ethyl (3E,5E)-2-diazo-6-phenylhexa-3,5-dienoate. The vinylogous O-H insertion reaction can be combined with an intramolecular Diels-Alder reaction to afford cyclic ether products. Efforts towards the formal total synthesis of ephedradine will then be described. A four-fold C-H functionalization strategy was designed and executed to afford the dihydrobenzofuran core structure of ephedradine A. Lastly, systematic optimization studies for the reaction of a trichloroethyl aryldiazoacetate and isopropyl acetate will be presented.
Table of Contents
Chapter 1 Introduction 1
1.1 Metallocarbene chemistry 1
1.2 Dirhodium catalysts for metallocarbene chemistry 3
1.3 Carbene induced C-H insertion reactions 8
1.4 Use of N-sulfonyl-1,2,3-triazoles as alternative carbene precursors 13
1.5 Conclusions 19
Chapter 2 Rhodium-catalyzed asymmetric synthesis of β-lactones by intramolecular C-H insertions of ortho-substituted aryldiazoacetates 20
2.1 Introduction 20
2.2 Results and discussion 26
2.3 Summary 38
Chapter 3 Rhodium(II)-catalyzed asymmetric C-H functionalization of electron-deficient methyl groups 40
3.1 Introduction 40
3.2. Results and discussion 48
3.3. Summary 56
3.3. Future directions 57
Chapter 4 Synthesis of 2,2,2-trichloroethyl aryl- and vinyldiazoacetates by palladium-catalyzed cross-coupling reactions 58
4.1 Introduction 58
4.2 Results and discussion 64
4.3 Summary 73
Chapter 5 Divergent reactions of indolyl- and pyrrolyl-tethered N-sulfonyl-1,2,3-triazoles: efficient synthesis of polycyclic spiroindolines and tetrahydrocarbolines by rhodium(II)-catalyzed intramolecular annulations 74
5.1 Introduction 74
5.2 Results and discussion 78
5.3 Summary 88
Chapter 6 Miscellaneous studies 90
6.1 Vinylogous reactivity of ethyl (3E,5E)-2-diazo-6-phenylhexa-3,5-dienoate 90
6.1.1 Introduction 90
6.1.2 Results and discussion 95
6.1.3 Summary 103
6.2 Efforts towards the formal total synthesis of ephedradine via sequential C-H functionalization strategy 103
6.2.1 Introduction 103
6.2.2 Results and discussion 108
6.2.3 Summary 112
6.2.4 Future directions 112
6.3 Exploration of the formation of a tertiary carbinol via a rhodium(II)-catalyzed reaction with isopropyl acetate 113
6.3.1 Introduction 113
6.3.2 Results and discussion 114
6.3.3 Summary 118
References 119
Experimental Section 133
General Methods 133
Experiment Section for Chapter 2 134
Experiment Section for Chapter 3 180
Experiment Section for Chapter 4 228
Experiment Section for Chapter 5 266
Experiment Section for Chapter 6.1 367
Experiment Section for Chapter 6.2 379
Experiment Section for Chapter 6.3 392
Appendix: X-ray crystallographic data 394
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