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Publication Date

2024-5

First Advisor

David Gorin

Second Advisor

Michael Kinsinger

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Engineering

Keywords

organometallic catalysis, Chan-Evans-Lam, cyclopropane, benzyl, C-H activation, copper-catalyzed reactions

Abstract

Late stage functionalization (LSF) is a prevalent strategy for drug development and improvement. Utilizing LSF methods, complicated molecules can be synthesized and, at the last step, functionalized. This allows for simpler syntheses and the quick development of diverse molecular libraries. Activating C-H bonds on arenes is of particular interest for LSF due to the widespread presence of aromatic rings in drug molecules. This study aims to design a method for arene C-H cyclopropylation and benzylation. Both cyclopropanes and benzyl groups are found throughout medicinal chemistry. The installation of cyclopropanes in drug molecules has been found to increase a host of desirable biological properties such as metabolic stability and solubility. Similarly, the diaryl moiety produced by benzylating an aromatic ring acts as a pharmacophore, facilitating interaction with the active sites in enzymes. However, methods for C-H cyclopropylation and benzylation can often exhibit limitations. To our knowledge, there is no successful C-H activation that installs an unsubstituted cyclopropane and there are only limited examples of substituted cyclopropane installation. C-H benzylations are more established, however, many have been demonstrated only on unsubstituted benzene rings. This limits their applicability to large drug molecules with multi-substituted aromatic cores. Thus, exploration of C-H benzylation/cyclopropylation strategies and development of reactions that are not substrate-specific is essential. This study utilized the Chan-Evans-Lam, which is a copper-catalyzed nucleophile-nucleophile cross-coupling. Though primarily used for heteroatom arylations, both substrate and substituent scope have been expanded in recent years. Published conditions for successful C-O cyclopropylation and C-H activation were used as a starting point for reaction design and product formation was determined from 1 H nuclear magnetic resonance and mass spectroscopy. Evidence of C-H activation and alkylation was seen on two electron rich aromatic substrates: 1,3,5-trimethoxybenzene and N-methylindole. Preliminary characterization indicates successful benzylation on both substrates with catalytic amounts of copper but undetermined yield. Preliminary attempts at cyclopropylation, though also successful at forging a C-C bond, were performed with stoichiometric copper and produced allyl products. This indicates an intermediate ring-opening of the cyclopropane, hypothesized to occur through radical chemistry. Overall, evidence has been found that C(sp 2 )-C(sp 3 ) bonds can be made from C-H activations with the Chan-Evans-Lam. However, future studies will need to confirm characterization of products, obtain yields, and alter conditions to retain the cyclopropane.

Rights

©2025 Danielle Joubran. Access limited to the Smith College community and other researchers while on campus. Smith College community members also may access from off-campus using a Smith College log-in. Other off-campus researchers may request a copy through Interlibrary Loan for personal use.

Language

English

Comments

78 pages: color illustrations, charts. Includes bibliographical references (pages 61-66).

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