Construction of CF₂ moieties in FDA-approved drugs (2016–2025): industrial routes, mechanisms, and scale-up considerations

• Wenyan Yao,
• Huanhuan Zhang,
• Xiaolong Yang and
• Feng Liu

Beilstein J. Org. Chem. 2026, 22, 1122–1150, doi:10.3762/bjoc.22.91

• traditional fluorination methods. For heteroaryl-CF2 groups, metal-catalyzed direct introduction of the CF2 unit still faces challenges for industrial application, whereas the difluorocarbene route for ArO-CF2 has been validated. This review provides a reference for process development of new CF2-containing

• drugs, from strategic design to scale-up evaluation. Keywords: difluoromethylene group (-CF2-); difluoromethyl group (-CF2H); FDA-approved drugs; fluorination methods; process scale-up; Introduction In recent years, the CF2 group has demonstrated unique advantages in drug discovery and clinical

Origami with small molecules: exploiting the C–F bond as a conformational tool

• Patrick Ryan,
• Ramsha Iftikhar and
• Luke Hunter

Beilstein J. Org. Chem. 2025, 21, 680–716, doi:10.3762/bjoc.21.54

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• incorporate fluorine into compounds of interest, with regio and site selectivity pre-determined by the nature of the functionalised carbon. However, the development of C(sp3)–H fluorination methods represents a more sustainable and versatile approach, as there is no requirement to pre-functionalise the

• demonstrate stereospecificity, again on predefined substrate classes. Radical fluorination methods offer an expansion to substrate scopes and rely on the use of more expensive fluorine-atom-transfer reagents. Finally, oxidative benzylic activation methods, often in tandem with enabling technologies, such as

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• difluoromethylene units. To meet the demands of synthetic chemists within the life science discovery and manufacturing arenas, many fluorination methods have been developed over the years to introduce difluoromethylene groups into organic systems. Approaches using nucleophilic fluorination include halogen exchange

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• physicochemical properties of a compound, thus affecting its pharmacodynamic and pharmacokinetic profile. Consequently, fluorination methods are particularly useful in the synthesis of bioactive substances, including marketed drugs (24 and 25) (Scheme 10A) [93]. In addition to oxygen insertion, vanadium use has

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• fluorination methods, of which direct C–H fluorination is among the most powerful. Despite the challenges and limitations associated with the direct fluorination of unactivated C–H bonds, appreciable advancements in manipulating the selectivity and reactivity have been made, especially via transition metal

• fluorine (I = 1/2) allows the coupling with nearby carbon and hydrogen atoms to be resolved [27]. 1.1.2 Relevance of direct C–H fluorination methods: Remarkable developments in synthetic chemistry over the last several decades have allowed the transformation of almost every organic functional group into

• (especially C(sp3)–H) bonds into other functional groups would not only enormously expand the synthetic maneuverability but would also intensify the use of hydrocarbon feedstocks in organic synthesis. In this context, the advantage of direct C–H fluorination over traditional fluorination methods is that it

Recent advances in transition-metal-catalyzed incorporation of fluorine-containing groups

• Xiaowei Li,
• Xiaolin Shi,
• Xiangqian Li and
• Dayong Shi

Beilstein J. Org. Chem. 2019, 15, 2213–2270, doi:10.3762/bjoc.15.218

• fluorination methods to these building blocks, such as Friedel–Crafts-type electrophilic halogenation [10][11], Sandmeyer-type reactions of diazonium salts [12], and halogenations of preformed organometallic reagents [13], commonly involve multiple steps, harsh reaction conditions, and the use of

Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

• Bin Yin,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2015, 11, 85–91, doi:10.3762/bjoc.11.12

• , selective fluorination of organic compounds is becoming significantly important. Although the selective fluorination has been extensively studied, highly efficient and safe fluorination methods are still demanded [7][8]. With these facts in mind, we have developed a selective electrochemical fluorination

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• ]. However, with the advent of stereoselective fluorination methods [10][11] it seems clear that the subset of stereoselectively fluorinated N-heterocycles [12] offers particularly rich possibilities. We therefore felt that it would be worthwhile to examine in a brief review some of the unique features of

• cost and ready availability of perfluorinated building blocks. It should be noted, however, that access to enantiopure targets is not straightforward via the building block approach. Such targets may be better obtained through diastereoselective or enantioselective fluorination methods, and examples of