Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Ellman, Jonathan
Abstract
Sequential, multicomponent C–H bond functionalization is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. The first chapter reviews existing literature in this area. The second and third chapters describe multicomponent carboamidations of bridged bicyclic alkenes and terminal alkenes, respectively, to provide pharmaceutically relevant α-branched amine products. The fourth chapter details in progress work for the synthesis of challenging β-amino quaternary centers from C−H bond substrates, internally-substituted dienes, and formyl imine surrogates. Finally, the fifth chapter presents a concise and general method for the synthesis of N-acylsulfenamides, which have application in the preparation of high oxidation state sulfur compounds.Chapter 1 comprehensively reviews the examples of sequential, multicomponent C–H bond addition that have been published in the literature. This class of reaction is a powerful approach for the rapid, modular generation of molecular complexity in a single reaction. In this approach, C–H bonds are typically added across π-bonds or π-bond isosteres, followed by subsequent coupling to another type of functionality, thereby forming two σ-bonds in a single reaction sequence. Such sequential C–H bond addition reactions include additions across both conjugated and isolated π-systems followed by coupling with reactants such as carbonyl compounds, cyanating reagents, aminating reagents, halogenating reagents, oxygenating reagents, and alkylating reagents. These atom-economical reactions transform ubiquitous C–H bonds under mild conditions to more complex structures with a high level of regiochemical and stereochemical control. Surprising connectivities and diverse mechanisms have been elucidated in the development of these reactions. Chapter 2 describes a method for the three-component coupling of C–H bond substrates, bridged bicyclic alkenes, and dioxazolones to provide syn-1,2-carboamidated bridged bicyclic compounds. Broad scope was developed across C−H bond substrates, [2.2.1]- and [3.2.1]-bridged bicyclic alkenes, and aliphatic and aromatic dioxazolones. The use of a chiral Cp-derived Rh(III) catalyst enables the asymmetric synthesis of products. Chapter 3 details the efficient syntheses of α-branched amines by three- and four-component C−H functionalization employing a diversifiable hydrazone directing group. The hydrazone in the α-branched amine products has been readily converted to multiple desirable functionalities such as a nitrile, a carboxylic acid, alkenes, and heterocycles using diverse heterolytic chemistry and homolytic transition metal- or photoredox-catalyzed processes. This study represents the first example of a four-component reaction including C−H functionalization. Chapter 4 describes progress towards the three-component preparation of β-amino quaternary centers from C−H bond substrates, internally-substituted dienes, and formyl imine surrogates. Under Rh(III)-catalyzed conditions, this reaction demonstrated broad scope for a variety of C−H bond substrates and different diene substitution patterns. Formyl imine surrogates bearing various nitrogen protecting groups including Ts, Cbz, and Boc were explored. A 1,3-addition of the C−H bond and formyl imine was observed across the diene substrates, consistent with previously reported Co-catalyzed sequential C−H bond additions to dienes and carbonyl compounds. Chapter 5 provides a robust and general method for the preparation of N- acylsulfenamides, which are central inputs for the asymmetric synthesis of high oxidation state sulfur compounds. This straightforward transformation proceeds by reaction of primary amides, carbamates, sulfonamides, sulfinamides, and ureas with stable N-thiosuccinimides or N-thiophthalimides, which in turn are prepared in a single step from commercial thiols. The use of stable N-thiosuccinimide and N-thiophthalimide reactants is desirable because it obviates the use of highly reactive sulfenyl chlorides.
Recommended Citation
Brandes, Daniel Solomon, "New Developments in Sequential, Multicomponent C–H Functionalization" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1119.
https://elischolar.library.yale.edu/gsas_dissertations/1119
