Iron Carbene-Mediated Methylation of Carboxylic Acids
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Date
2025-05
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The Ohio State University
Abstract
Carboxylic acids are the 9th most common functional group found in drug molecules and are found in many natural products including amino acids, steroids, and fatty acids. Functionalization of carboxylic acids is very important, as esters are the 15th most common functional group found in drug molecules. The two most common methods used to methylate carboxylic acids to make esters include (i) Fischer esterification, utilizing strong acid and methanol, and (ii) diazomethane, utilizing a high energy (and often explosive) diazo intermediate. These harsh methods leave little room for functional group tolerance and selectivity. Additionally, these methods require significant safety precautions if done on scale. We have developed an iron mediated methylation of carboxylic acids using dibromomethane as a carbene precursor. Our method shows excellent functional group tolerance while using mild and inexpensive reagents. Methylation can be done on a wide range of carboxylic acids to form ester products with alkyl, benzyl, allyl, halide, and heteroatom substituents, as well as on common drug molecules and amino acid motifs. Robustness exploration, mechanistic studies, and initial rate experiments were also done to further explore the system. In conclusion, we developed a robust, mild, and cost-effective methylation of carboxylic acids with high functional group tolerance.
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organic chemistry methodology