Abstract
The trifluoromethylation of aromatic and heteroaromatic cores has attracted considerable interest in recent years due to its pharmacological relevance. We studied the extension of a simple copper-catalyzed trifluoromethylation protocol to alkoxy-substituted iodopyridines and their benzologs. The trifluoromethylation proceeded smoothly in all cases, and the desired compounds were isolated and characterized. In the trifluoromethylation of 3-iodo-4-methoxyquinoline, we observed a concomitant O-N methyl migration, resulting in the trifluoromethylated quinolone as a product. Overall, the described procedure should facilitate the broader use of copper-catalyzed trifluoromethylation in medicinal chemistry.
Highlights
IntroductionThe most relevant examples include proton pump inhibitors, such as Ilaprazole and Omeprazole [1], the natural antibiotic Piericidin A [2], or a recently developed ERK inhibitor [3]
The methyl-methoxypyridine motif is present in several active pharmaceutical ingredients.The most relevant examples include proton pump inhibitors, such as Ilaprazole and Omeprazole [1], the natural antibiotic Piericidin A [2], or a recently developed ERK inhibitor [3]
Our objective was to systematically study the copper-catalyzed trifluoromethylation [24] of alkoxypyridine derivatives and their benzologs that could serve as useful building blocks in medicinal chemistry
Summary
The most relevant examples include proton pump inhibitors, such as Ilaprazole and Omeprazole [1], the natural antibiotic Piericidin A [2], or a recently developed ERK inhibitor [3]. The incorporation of fluorine into organic molecules typically leads to the improvement of their drug-like properties (i.e., metabolic stability, the crossing of biological barriers) [4,5,6]. This effect is more pronounced when a trifluoromethyl group is introduced, evidenced by the surge in the number of FDA-approved CF3 -group containing drugs in recent years [7,8,9]. Our objective was to systematically study the copper-catalyzed trifluoromethylation [24] of alkoxypyridine derivatives and their benzologs that could serve as useful building blocks in medicinal chemistry
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