Abstract View

Objectives: The β,β-difluoroamino moiety has become increasingly prevalent in biomolecules, however, their synthesis is often limited to substituted difluoroamines, with only a few protocols detailing the synthesis of primary difluoroamines that typically require custom precursors and multi-step synthesis utilizing harsh conditions.^1,2 Additionally, many of these established protocols are unapplicable towards the direct aminofluorination of olefins, thereby limiting the feasibility of aminofluorination in olefin-containing substrates in organic chemistry and subsequent hindered translation to radiopharmaceuticals. To address these challenges, our group recently developed an iron-catalyzed three-component amino(radio)fluorination of alkenes which addresses the aforementioned issues and enabled access to unprotected β-fluoroamines.³ Herein, we report a radiochemical protocol that uses iron phthalocyanine (FePc), [4-NO₂-Bz-NH₃][OTf], trifluoroacetic acid (TFA), triethylamine, and [¹⁸F]KF to achieve the direct aminoradiofluorination of α-fluoroalkenes to unprotected [18F]β,β-difluoroamines.4  

Methods: A solution containing the α-fluoroalkene substrate (0.025-0.05 mmol), dichloromethane (0.4 ml), TFA (0.5 equiv), Et₃N (0.8 equiv), and [18F]KF (ca. 3-5 mCi) was added to a reaction vial with FePc (0.1 equiv) and [4-NO₂-Bz-NH₃][OTf] (2.5 equiv) in air. The mixture was heated to 30^oC for 5 min. Afterwards, a solution with Boc₂O (0.2 ml) and Et₃N (0.3 ml) was added, and the reaction was allowed to stir for an additional 5 min. The product is filtered through a C(18) Sep-Pak before being eluted using a mixture of ammonium formate and CH₃CN. The crude reaction mixtures were characterized by radio-thin layer chromatograph (TLC) and/or radio-high-performance liquid chromatography (HPLC). Product isolation is confirmed through radio-HPLC. 

Results: The one-pot, two-step reaction described affords Boc-protected [¹⁸F]β,β-difluoroamines after extraction. A total of fifteen alkenes adjacent to electronically deficient, neutral, or rich aryl ring systems, including di- and tri-substituted and fused ring substrates were labeled under mild reaction conditions with moderate radiochemical conversions (5-69%). Six biologically relevant molecules were radiolabeled in similar conditions (RCC: 5-15%). 

Conclusions: We report the first one-step aminoradiodifluorination of α-fluoroalkenes to unprotected [¹⁸F] β,β-difluoroamines. This method presents opportunities for future applications in the development of β,β-(radio)difluoroamines, enabling the exploration of additional radiopharmaceuticals 

References:  

[1] Liang, S., Hammond, G. B. & Xu, B. Hydrogen bonding: regulator for nucleophilic fluorination. Chem. Eur. J. 2017, 23, 17850-17861. DOI: 10.1002/chem.201702664. 

[2] Lu, D.-F., Zhu, C.-L., Sears, J. D. & Xu, H. Iron(II)-catalyzed intermolecular aminofluorination of unfunctionalized olefins using fluoride ion. J. Am. Chem. Soc. 2016, 138, 11360-11367.DOI: 10.1021/jacs.6b07221.   

[3] Li, Y., Bortolus, M. R., Zhang, X., Wang, Z., Liu, D., Le, H., Esezobor, O. Z., Ni, J., Zhang, Q., Vasdev, N., Cheng, G.-J., Zheng, C., Fu, J. Iron-catalyzed three-component amino(radio)fluorination of alkenes to unprotected β-(radio)fluoroamines. Nat. Commun. 2025, 16, 10917. DOI: 10.1038/s41467-025-65880-z  

[4] Li, Y.#, Le, H.#, Wang, Z.#, Esezobor, O. Z., Zhang, X., Ma, D., Wang, Z., Zhang, Q., Vasdev, N., Zheng, C., Fu, J. Facile Synthesis of β,β-(radio)difluoroamines via amino(radio)fluorination of α‑Fluoroalkenes. ACS Catal. 2025, 15, 20123−20134. DOI: 10.1021/acscatal.5c05739.  

# contributed equally to this work