Chapter 1. This chapter introduces the concept of electrophilic-cyclization–group-transfer reactions and explains each expansion in methodology. Context is first provided for the initial discovery and development of this class of reactions by our research group. Subsequently, the chapter explains the logical progression from the initial borylative electrophilic-cyclization–group transfer reaction development to iodination–group-transfer reactions. Finally, the chapter discusses the logical conceptual leaps taken from these initial group transfer reactions that employed stoichiometric electrophiles, to the development of a thioarylation cyclization using gold(I)/(III) catalysis in place of stoichiometric electrophiles.

Chapter 2. A metal-free regio- and stereocontrolled group-transfer route toward the synthesis of trisubstituted alkenes is described. In this route, an electrophilic heterocyclization is followed by ring-opening group transfer. Specifically, a thioboration reaction transforms readily available alkynyl sulfide precursors into alkenyl boronates and alkenyl sulfides with defined regio- and stereochemistry in one synthetic step using commercially available B-chlorocatecholborane (ClBcat). Mechanistic studies identified the likely pathway as proceeding through zwitterionic rather than haloborated intermediates. The regio- and stereochemistry set in the initial cyclization step is preserved in the final acyclic alkene product, producing alkenes with up to four modifiable substituents with predictable regio- and stereochemistry. Downstream functionalization reactions showcase the versatility of the substitutions of the resulting alkenes. The mechanistic concept maps onto future reaction designs, given the abundance of known electrophiles and nucleophiles for electrophilic heterocyclization/dealkylation sequences. This chapter features work from Adena Issaian, a senior PhD-student member of the Blum Laboratory, who initiated this project based on a starting mechanistic hypothesis. She mentored me on my first sets of experiments on this project. After her graduation, I took the task of completing this scientific work. Our co-contributions were recognized with co-first author status on the published version of this report. Specific contributions are noted in the main body of the thesis chapter. Reprinted with permission from Kaplan, J. A.+; Issaian, A.+; Stang, M.; Gorial, D.; Blum, S. A. Repurposing π Electrophilic Cyclization/Dealkylation for Group Transfer. Angew. Chem., Int. Ed. 2021, 60, 25776–25780.

Chapter 3. The regio- and stereodefined synthesis of trisubstituted alkenes remains a significant synthetic challenge. Herein, a method is developed for producing regio- and stereodefined trisubstituted iodoalkenes by diverting intermediates from an iodination–electrophilic-cyclization mechanism. Specifically, cyclized sulfonium ion-pair intermediates are diverted to alkenes by ring-opening with nucleophilic iodide. Alternatively, scavenging of the iodide by AgOTf prevents ring-opening, enabling isolation of the sulfonium ion-pair intermediate. Isolation of the ion pair enables access to complementary reactivity, including ring-opening by alternative nucleophiles (i.e., amines), yielding trisubstituted acyclic alkenes and an example tetrasubstituted alkene. X-ray crystallographic determination of reaction intermediates and products confirm the initial electrophilic-cyclization step sets the stereo- and regiochemistry of the product. The products serve as synthetic building blocks by readily participating in downstream functionalization reactions, including oxidation, palladium-catalyzed cross-coupling, and nucleophilic displacement. Reprinted with permission from Kaplan, J. A.; Blum, S. A. Iodination–Group-Transfer Reactions to Generate Trisubstituted Iodoalkenes with Regio- and Stereochemical Control. J. Org. Chem. 2023, 88, 13236–13247.

Chapter 4. A thioarylation method is developed for the synthesis of 2,3-dihydrothiopheniums through an electrophilic-cyclization–cross-coupling mechanism, harnessing the gold(I)/(III) cycle of the recently developed MeDalPhosAuCl catalyst. Single-crystal X-ray crystal structural analysis of the dihydrothiophenium products characterized the anti-addition of the sulfur and Csp2 group to the alkyne and a preference for 5-endo dig cyclization. The dihydrothiophenium products are demonstrated as synthetic building blocks for stereodefined acyclic tetrasubstituted alkenes upon ring-opening reaction with amines. Intramolecular competition experiments show the favorability of Csp3 tether cyclizations over Csp2 tethers, preferentially generating dihydrothiopheniums over thiopheniums. Intermolecular competition experiments of alkyne aryl groups and an intermolecular aryl iodide competition suggest a rate-determining reductive elimination step in the gold(I)/gold(III) catalytic cycle. This rate-determining step is further supported by HRMS analysis of reaction intermediates that identify the catalyst resting state under turnover conditions. Catalyst poisoning experiments provide evidence of substrate inhibition, further consistent with these conclusions.