Abstract
AbstractThe 2,2,2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a rapid and transition metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CF3CH2OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these transformations translate easily to fluoroform that has been labeled with either carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.8 min), so allowing the appendage of complex molecules with a no-carrier-added 11C- or 18F- 2,2,2-trifluoroethoxy group. This provides scope to create candidate PET tracers with radioactive and metabolically stable 2,2,2-trifluoroethoxy moieties. We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling which can be of further benefit for drug discovery and development.
Funder
U.S. Department of Health & Human Services | National Institutes of Health
Intramural Research Program of the National Institutes of Health
Publisher
Springer Science and Business Media LLC
Reference53 articles.
1. Li, H. P., He, X. H., Peng, C., Li, J. L. & Han, B. A straightforward access to trifluoromethylated natural products through late-stage functionalization. Nat. Prod. Rep. 40, 988–1021 (2023).
2. Charpentier, J., Früh, N. & Togni, A. Electrophilic trifluoromethylation by use of hypervalent iodine reagents. Chem. Rev. 115, 650–682 (2015).
3. Liu, X., Xu, C., Wang, M. & Liu, Q. Trifluoromethyltrimethylsilane: Nucleophilic trifluoromethylation and beyond. Chem. Rev. 115, 683–730 (2015).
4. Xiao, H. W., Zhang, Z. Z., Fang, Y. W., Zhu, L. & Li, C. Z. Radical trifluoromethylation. Chem. Soc. Rev. 50, 6308–6319 (2021).
5. Rozen, S. & Hagooly, A. in e-EROS Encyclopedia of Reagents for Organic Synthesis 1‒3 (John Wiley & Sons, Ltd., 2001).