UC Irvine

Chapter 1. This chapter describes the importance and application of metalated heterocycles, specifically borylated and silylated heterocycles, in various fields. A general comparison of traditional preparation methods versus Lewis acid-cyclization routes and radical-cyclization routes is also described. In addition, the previous methods from both the Blum Laboratory and other laboratories that serve as precedents for the work presented this thesis are also summarized.

Chapter 2. An oxyboration reaction that employs B–O σ bonds as addition partners to C–C π bonds to form 4-borylated isochromenes has been developed. By nature of the mechanism, the reaction produces exclusively one borylated regioisomer, complementary to alternative routes that produce 3-borylated isochromenes via C–H activation. Access to the borylative heterocyclization route is demonstrated from alcohols directly or from a hydroboration–oxyboration sequence starting from the corresponding ketone, forming the heterocylic core and installing the boron in one synthetic step.

Chapter 3. In contrast to previously reported borylative heterocyclization methods, a reaction here proceeds without the need for air-free techniques, to access synthetically useful borylated thiophenes, benzothiophenes, and isocoumarins. A comparison of stability/decomposition rates in air of several catecholboronic ester (Bcat) compounds derived from different heterocycle cores showed a strong dependence on heterocycle structure. Lessons learned from this comparison were then harnessed for the development of borylative heterocyclization reactions under ambient-atmosphere conditions and with wet solvent. In contrast to literature reports suggesting general moisture sensitivity, a subset of Bcat products resulting from this technique were chromatography-stable and directly isolable, obviating the requirement for an extra synthetic transformation into more stable boron species, such as pinacolboronic esters (Bpin) for isolation. The isolated Bcat products were amenable to various downstream functionalization reactions, including reactions that were not accessible with their better-known Bpin counterparts, showing the complementarity of Bcat reaction partners and expanding their known chemistry. These results suggest the value of conceptual revisitation of substitution and solvent influence on stability and isolability of organo-Bcat compound classes, and lay groundwork for additional practical borylative methods development in air.

Chapter 4. A demethylative silyl radical cascade cyclization of 2-isocyanothioanisoles toward 2-silylated benzothiazole building blocks has been developed. The development of a “radical initiator–inhibitor symbiosis” system solves the challenge of otherwise dominant methyl-radical triggered side reactions brought about by kinetically unfavored generation of reactive silyl radical species. The products accessed in this protocol are amendable to various downstream functionalization reactions, including the quick construction of a topoisomerase II inhibitor via a Hiyama cross-coupling reaction and of an antiviral agent via a fluoride-/hydroxide-free nucleophilic substitution to acyl chloride.

Chapter 5. This chapter summarizes unpublished projects including: 1) Attempted borylative and silylative heterocyclization for synthesis of borylated and silylated furans; 2) Attempted intermolecular boration of benzynes; 3) Base-induced cyclative hydrosilylation toward benzoxasiloles. 4) Photoinduced radical route to borylative heterocyclization toward borylated benzosilolines; 5) Borylative radical cyclization for 2-borylated indoles; 6) 2-Silylative radical cyclization for 2-silylated indoles; 7) Indium-mediated group-transfer reaction. Among the aforementioned projects, some of them have obtained preliminary results, but efforts toward reaction optimization have failed, and/or the reproducibility of the targeted reaction is challenging. Outlooks and comments on potentials for these projects are also discussed in each individual section.