Rapid 18F‐ and 19F‐Difluoromethylation through Desulfurative Fluorination of Transient N‐, O‐, and C‐Linked Dithioles. Issue 5 (8th December 2022)

• Record Type: Journal Article
• Authors: Newton, Josiah J.; Engüdar, Gökçe; Brooke, Alan J.; Nodwell, Matthew B.; Horngren‐Rhodes, Holly; Martin, Rainer E.; Schaffer, Paul; Britton, Robert; Friesen, Chadron M.
• Is Part Of: Chemistry. Volume 29:Issue 5(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-08
• Subjects: difluoromethyl -- desulfurative fluorination -- heterocycles -- medicinal chemistry -- radiochemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202202862
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: The difluoromethyl group plays an important role in modern medicinal and agrochemistry. While several difluoromethylation reagents have been reported, these typically rely on difluoromethyl carbenes or anions, or target specific processes. Here, we describe a conceptually unique and general process for O−H, N−H and C−H difluoromethylation that involves the formation of a transient dithiole followed by facile desulfurative fluorination using silver(I) fluoride. We also introduce the 5, 6‐dimethoxy‐1, 3‐benzodithiole (DMBDT) function, which undergoes sufficiently rapid desulfurative fluorination to additionally support 18 F‐difluoromethylation. This new process is compatible with the wide range of functional groups typically encountered in medicinal chemistry campaigns, and the use of Ag 18 F is demonstrated in the production of 18 F‐labeled derivatives of testosterone, perphenazine, and melatonin, 58.0±2.2, 20.4±0.3 and 32.2±3.6 MBq μmol −1, respectively. We expect that the DMBDT group and this 18 F/ 19 F‐difluoromethylation process will inspire and support new efforts in medicinal chemistry, agrochemistry and radiotracer production. Abstract : New opportunities for radiochemists : The AgF‐promoted desulfurative fluorination of dithioles can lead to difluoromethylation. DMBDT‐BF4 and DMBDT‐OMe were identified as readily available and versatile reagents for the functionalization of alcohols and heterocycles during which DMBDT undergoes rapid desulfurative fluorination. Furthermore, Ag 18 F can be used to incorporate radioactive groups into structurally complex and pharmaceutically relevant molecules.