Laboratory Learning Program 2024 - Photoredox-Catalyzed Cross Coupling of Alkyl Chlorides Via Silyl-Radical Mediated Chlorine Atom Abstraction (CHE-03)

Research Opportunity Number: CHE-03

Project Title: Photoredox-Catalyzed Cross Coupling of Alkyl Chlorides Via Silyl-Radical Mediated Chlorine Atom Abstraction

Project Summary: Over the past decade, there is a growing interest in the pharmaceutical industry to escape from C(sp2) rich compounds, which is the most commonly used molecular scaffold in drug-like molecules. Such rise in interest is due to a recent finding that higher C(sp3) content in drug molecules is correlated with higher clinical success, providing benefits of higher potency, better solubility, and improved metabolic profile. Therefore, it is highly desirable to develop methods that could form C(sp3) – C(sp3) bonds from easily accessible starting materials.(1) Generation of radicals from abundant functional groups plays an important role to generate key intermediates in organic synthesis. Alkyl chlorides are bench-stable feedstocks that remain underutilized due to the long-standing challenge of C(sp3)–Cl bond activation. In 2020, the MacMillan Group disclosed a strategy to generate alkyl radicals from alkyl chlorides using silane-mediated chloride abstraction with nickel and photoredox catalysis.(2) The development of a reaction with the ability to couple two separate molecular fragments, both bearing C(sp3)– Cl bonds, would greatly expedite the synthesis of complex, C(sp3)-rich molecules. To achieve this highly desirable transformation, this proposal seeks to utilize abundant alkyl chlorides to construct complex C(sp3)-rich molecules via silyl radical abstraction in combination with a transition metal to mediate the C(sp3)– C(sp3) cross coupling step. Work within the group has shown the feasibility of the coupling of tertiary chlorides with benzylic chlorides using an iron porphyrin catalyst. In order to expand upon this work, this project proposes the investigation of nickel catalysts to achieve a general C(sp3)– C(sp3) cross coupling. Researchers involved in this project will learn the (i) fundamentals of photoredox catalysis, (ii) fundamentals of transition metal catalysis, (iii) the typical set up for photoredox reactions, (iv) recrystallization, (v) how to purify compounds using column chromatography, and (vi) how to analyze chemical products using spectroscopic instrumentation such as Nuclear Magnetic Resonance (NMR) spectroscopy, Ultra High Performance Liquid Chromatography (UHPLC), and Gas chromatography–mass spectrometry (GC-MS). References: (1) Lovering, R.; Bikker, J.; Humblet. J. Med. Chem. 2009, 52, 21, 6752. (2) Sakai, H.; Liu, W.; Le, C.; MacMillan, D.W.C. J. Am. Chem. Soc. 2020, 142, 27, 11691– 11697

Student Roles and Responsibilities: Guided by the student’s supervisor and in-lab mentor, the student is expected to be fully responsible for this project, which includes but is not limited to: demonstrating the feasibility of the reaction, optimizing the reaction conditions, investigating the substrate scope of the reaction, and isolating the products.

Additional Considerations: 25 hours/week approximately

Department/Institute: Chemistry

Faculty Sponsor: David W.C. MacMillan

Participation Dates: 7/1/2024 to 7/31/2024

Stipend Offered: $0

Number of Internships Available: 0-2

Application Deadline: March 15, 2024, midnight eastern daylight time