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Publication Date

2018-05-14

First Advisor

David J. Gorin

Document Type

Honors Project

Degree Name

Bachelor of Arts

Department

Chemistry

Keywords

Methylation, Phenol, Anisole, Synthesis, Chan-Lam, Cross-coupling, Nucleophile, Alkylation, Oxygen, Heteroatom, Methyl ether-Synthesis, Nucleophilic reaction, Heterocyclic chemistry

Abstract

Aryl methyl ethers are common in consumer products including pharmaceutical compounds that treat conditions from Alzheimer’s to cancer to HIV.1 However current methodology focuses predominantly on electrophilic sources of methyl, using reagents such as diazomethane, TMS-diazomethane, methyl iodide, and dimethyl sulfate. While highly efficient, electrophiles are inherently toxic to humans, causing the death of multiple chemists since 2008, thereby signaling the need for an alternative, safe, regioselective methylating reagent to perform such reactions.2,3 Our attention turned to nucleophilic sources of methyl that could be cross-coupled with atmospheric oxygen to avoid the inherent toxicity of electrophiles. The Chan-Evans Lam reaction pairs a nucleophile with a boronic acid (most commonly an arylboronic acid) using a copper catalyst and an oxidant. There is limited precedent for alkylation, including only two examples of methylation to our knowledge, one using carboxylic acids, published by the Gorin lab, and one on nitrogen nucleophiles. After screening conditions of successful Chan-Lam alkylations, we were able to successfully methylate 4 fluorophenol. Optimization studies were performed using 19F NMR quantification. The optimized conditions were tested on a variety of substrates to obtain isolated yields. Para-substituted electron-withdrawing groups (EWGs) underwent conversion most successfully, with isolated yields as high as 99%. We were able to successfully methylate ortho-substituted EWGs using the same conditions. When using weaker withdrawing groups or donating groups, the temperature and/or copper and ligand equivalents were increased to encourage conversion. However, a number of phenols still resist methylation. Further investigation should target expansion of the substrate scope, as well as further mechanistic studies.

Rights

2018 Mairead Elizabeth Bartlett. 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

91 pages : illustrations. Includes bibliographical references (pages 67-72)

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