I found this article pretty interesting. The authors report a selective method to add a trifluoromethyl group on heterocycles via radical formation. A really large amount of compounds are trifluoromethyl substituted, this functional group is especially found in bioactive molecules. The reactions are run in aqueous media at room temperature, there is no need for an inert atmosphere or purified solvents and a lot of functional groups are tolerated. Also, by switching the solvent from DCM to DMSO, the selectivity of the reaction can be modified.Thursday, September 1, 2011
Innate C-H trifluoromethylation of heterocycles
I found this article pretty interesting. The authors report a selective method to add a trifluoromethyl group on heterocycles via radical formation. A really large amount of compounds are trifluoromethyl substituted, this functional group is especially found in bioactive molecules. The reactions are run in aqueous media at room temperature, there is no need for an inert atmosphere or purified solvents and a lot of functional groups are tolerated. Also, by switching the solvent from DCM to DMSO, the selectivity of the reaction can be modified.
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Why is there such an abundance of CF3 groups found in drugs and other biologically active molecules? What are the specific properties of a CF3 group that make it so beneficial to have in a molecule? Anybody any ideas?
ReplyDeleteI was also wondering about drug fluorination recently. Here's some stuff I found.
ReplyDelete"Fluorine substitution has proven useful for improving the therapeutic index of medicinal agents. While the first examples may have been serendipitous, nevertheless, roughly one-fifth of the pharmaceuticals on the market contain fluorine. Introduction of fluorine into small molecules often results in increased hydrophobicity and metabolic stability, eventually leading to improved bioactivity and bioavailability, as evidenced in the case of the anti-hyperglycemic sitagliptin and the anti-depressant fluoxetine."
from "Influence of Selective Fluorination on the Biological Activity and Proteolytic Stability of Glucagon-like Peptide-1" published in the Journal of Medicinal Chemistry in November 2008.
Also, from the Fluorotronics, Inc. website (probably not the most unbiased source):
"Fluorination (introduction of fluorine atoms) into a drug or drug-like molecule offers beneficial physical and biological properties related to conformation, basicity, binding affinity, metabolic stability, solubility, steric effects, lipophilicity (especially seen with aromatic fluorination), and other properties important for life sciences and pharmaceutical industries. "
Thanks John!! There must be some review articles out there on the subject... one would think...
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