Chemistry ETDs

Publication Date

Fall 11-15-2018


This thesis is divided into two parts. The first part deals with the development of copper-catalyzed Suzuki-Miyaura coupling of alkylboron reagents for the first time. In the second part, we will discuss the development of novel nickel-catalyzed alkene dicarbofunctionalization reactions.

Part I. Cross-coupling reactions are versatile tools to form new carbon-carbon bonds and are widely used in the synthesis of various drug molecules, natural products and materials. However, these reactions are typically catalyzed by palladium, an expensive and rare metal which makes the reaction unsustainable in long-terms. Additionally, palladium-catalyzed cross-coupling reactions with alkylorganometallic reagents suffer from side reactions due to complications by β-hydride elimination and protodemetalation. The reactions also less tolerate to heteroarenes as these substrates generally deactivate the catalysts. These problems are largely addressed by using sterically hindered, expensive and difficult-to-make ligands. Recently, copper, a cheap and highly abundant metal, has emerged as an alternative catalyst, and has been utilized increasingly in cross-coupling reactions. The rising use of copper in cross-coupling can be attributed to lower tendency of alkylcopper intermediates for β-hydride elimination than those of analogous alkylpalladium species. Additionally, copper catalysts are also known to tolerate heteroarenes much better than palladium catalysts. In this thesis, we present our results on the development of a copper-catalyzed Suzuki-Miyaura cross-coupling reaction of alkylboron reagents with aryl and heteroaryl iodides. This novel reaction works well with alkylboron reagents without any complication form β-hydride elimination and tolerates heteroarenes without requiring sterically hindered and expensive ligands. We also conducted mechanistic studies of this reaction through independent synthesis of pertinent reaction intermediates such as anionic dialkylborate complexes, radical clock experiment and a Hammett plot. The experimental results with discrete alkylboron intermediates indicate that anionic alkyl(alkoxy)borate complexes, which are generally accepted as active transmetalating species, undergo disproportionation into anionic dialkylborate intermediates prior to transmetalation to copper catalyst. Radical clock experiment and the Hammett plot indicate that the reaction proceeds through non-radical pathway.

Part II. In this part, we discuss the development of nickel-catalyzed regioselective alkene dicarbofunctionalization reactions by using the imines as a coordination group. These reactions that simultaneously form two carbon-carbon bonds across alkenes will offer a highly effective strategy for providing modular, convergent, and expedient routes to generate complex bioactive molecules. However, the development of regioselective three-component dicarbofunctionalization of unactivated alkenes has remained a formidable challenge for more than three decades. These reactions are limited to difunctionalizing geometrically constrained norbornenes. Recent use of coordination approach brought some success in dicarbofunctionalization of unactivated alkenes. However, the current state of the coordination approach is also seriously limited as only alkenes proceeding via five-membered metallacycles or via stable and mostly planar six-membered metallacycles with vinylarenes can be utilized as substrates. Aliphatic γ, δ-alkenyl carbonyl compounds, which generate more challenging and less stable six-membered metallacycles, cannot be used as substrates. The use of these alkenes suffers from two key limitations: (1) formation of cross-coupling products caused by slow migratory insertion of alkenes due to weak binding, and (2) formation of Heck products caused by faster β-H elimination from metallacycles than competing transmetalation with organometallic reagents. These side reactions have seriously limited the generality of the coordination approach and the scope of alkene dicarbofunctionalization reactions. In this thesis, we will implement two novel strategies to difunctionalize unactivated alkenes regioselectively using organic halides and organometallic reagents. First, we will introduce a strategy of cationic catalysis, where cationic Ni(II) catalysts are generated in situ to address the key issues identified above. This process will enable us to perform regioselective γ, δ-difunctionalization of unactivated alkenes located at the γ, δ-position of carbonyl compounds. It is our observation that cationic Ni(II) promotes transmetalation faster than β-H elimination. This is unprecedented and will be of paramount fundamental significance in catalysis. Since this new cationic catalysis concept addresses two major issues that are common in alkene difunctionalization, we also anticipate that this discovery will be widely applicable for a general class of alkene substrates. In our second strategy, we introduce a novel concept of metallacycle contraction process, a reaction that harnesses the potential of alkylmetal intermediates to undergo β-H elimination to contract a six-membered metallacycle to a five-membered metallacycle, and difunctionalizes unactivated alkenes at the unusual 1,3-position rather than the usual 1,2-position of alkenes. This unprecedented reaction allows us to create two new carbon-carbon bonds at the β- and δ-positions of carbonyl compounds containing γ, δ-alkenes.




copper, cross-coupling, nickel, dicarbofunctionalization, cationic, catalysis

Document Type


Degree Name


Level of Degree


Department Name

Department of Chemistry and Chemical Biology

First Committee Member (Chair)

Ramesh Giri

Second Committee Member

Yang Qin

Third Committee Member

Mark Chalfant Walker

Fourth Committee Member

Changjian Feng