Visible-light-promoted radical cyclisation of unactivated alkenes in benzimidazoles: synthesis of difluoromethyl- and aryldifluoromethyl-substituted polycyclic imidazoles

• Yujun Pang,
• Jinglan Yan,
• Nawaf Al-Maharik,
• Qian Zhang,
• Zeguo Fang and
• Dong Li

Beilstein J. Org. Chem. 2025, 21, 234–241, doi:10.3762/bjoc.21.15

• target products in good to excellent yields. Mechanistic studies revealed that the reaction proceeds via a radical pathway. Keywords: cyclization; difluoromethylation; hypervalent iodine; polycyclic imidazole; visible light; Introduction Organofluorine compounds continue to play important roles in

• groups have reported the direct difluoromethylation/cyclization reaction of benzimidazoles with alkenes for the syntheses of difluoromethylated tricyclic benzimidazoles to date. For example, in 2023, Chen and co-workers pioneered an electrochemical approach for the difluoromethylation and cyclization

• reaction of unactivated alkenes within benzimidazole molecules using CF2HSO2Na [18]. Subsequently, in 2024, Jin [19] and Yang [20] developed visible light-induced difluoromethylation strategies for unactivated alkenes within benzimidazoles using different CF2H sources (CF2HSO2Na and ([Ph3PCF2H]+Br

Mechanochemical difluoromethylations of ketones

• Jinbo Ke,
• Pit van Bonn and
• Carsten Bolm

Beilstein J. Org. Chem. 2024, 20, 2799–2805, doi:10.3762/bjoc.20.235

• the gas phase than in solution [32][33], it has remained a challenge to control such reactions. Our group has recently reported a mechanochemical difluoromethylation of primary, secondary, and tertiary alcohols [34], yielding products with difluoromethoxy groups, which are promising organofluorine

• by these findings, we now explored difluoromethylation reactions with compounds bearing less nucleophilic functional groups. Ketones caught our particular attention as they contain a weak nucleophilic carbonyl oxygen adjacent to an electrophilic carbonyl carbon. Previous studies have focused on

• subsequently oxidized to yield the corresponding aryl difluoromethyl ethers. Noteworthy, however, the latter study focused mostly on cyclic ketones, with only one reported example of a difluoromethylation reaction of an acyclic substrate. Against this background and seeing new synthetic opportunities, we

Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides

• Changdong Shao,
• Chen Ma,
• Li Li,
• Jingyi Liu,
• Yanan Shen,
• Chen Chen,
• Qionglin Yang,
• Tianyi Xu,
• Zhengsong Hu,
• Yuhe Kan and
• Tingting Zhang

Beilstein J. Org. Chem. 2024, 20, 155–161, doi:10.3762/bjoc.20.14

• -scale use. Therefore, novel bromination reagents and simple bromination approaches are still required to be established. Very recently, we reported a copper-catalyzed C5-bromination and difluoromethylation reaction of 8-aminoquinolines using ethyl bromodifluoroacetate as bifunctional reagent [30] and

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• . Keywords: acylhydrazones; difluoromethylation; dihydropyridazine; fluorinated building blocks; hydrazones; imidazolidines; pyrazoles; pyrazolidines; pyrazolines; trifluoromethylation; Introduction The introduction of fluorine into pharmaceuticals, agrochemicals, and materials can significantly enhance

• indispensable role in drug discovery and design since the hydrogen atom can act as lipophilic hydrogen-bond donor and act as a bioisostere for the alcohol moiety [81][82][83]. Thus, many effective difluoromethylation strategies have been developed in recent years. Difluoroacetohydrazonoyl bromides were chosen

Cathodic generation of reactive (phenylthio)difluoromethyl species and its reactions: mechanistic aspects and synthetic applications

• Sadanobu Iwase,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2022, 18, 872–880, doi:10.3762/bjoc.18.88

• resulted in much lower product yields. The detailed reaction mechanism was clarified based on the cathodic reduction of 1 in the presence of deuterated acetonitrile, CD3CN. Keywords: bis(phenylthio)difluoromethane; cathodic reduction; deuteration; o-phthalonitrile mediator; (phenylthio)difluoromethylation

• olefins in moderate yields [5]. Prakash et al. also achieved fluoride-induced nucleophilic (phenylthio)difluoromethylation of carbonyl compounds using PhSCF2SiMe3 [6]. Quite recently, Shen et al., developed various nucleophilic, electrophilic, and radical difluoromethylthiolating reagents [1]. However

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• , might serve better our need to produce the structure 1 (Scheme 1), rather than the literature example with electron-poor pentafluorophenol and chlorofluorocarbene [6]. Results and Discussion Synthesis of compound 4 Reports of bis(aryloxy)fluoromethanes as side products in difluoromethylation reactions

Copper-based fluorinated reagents for the synthesis of CF₂R-containing molecules (R ≠ F)

• Louise Ruyet and
• Tatiana Besset

Beilstein J. Org. Chem. 2020, 16, 1051–1065, doi:10.3762/bjoc.16.92

• molecules using copper-based fluorinated reagents will be given. Keywords: copper; difluoromethylation; fluorinated reagents; fluorine chemistry; synthetic methodologies; Introduction In a society in which fluorinated molecules are playing a pivotal role in pharmaceutical and agrochemical industries as

• reactivity of the complex was then studied in stoichiometric reactions with aryl iodides and iodonium salts. The difluoromethylation reaction was smoothly carried out at 90 °C with electron-rich and electron-poor aryl iodides. However, the reaction was more efficient with electron-poor aryl iodides (Scheme 1

• active (IPr)CuCF2H, starting from (IPr)CuCl [38]. In situ-generated copper-based difluoromethylating reagents Although the review focused on the 2014–2019 period, a brief overview of seminal major advances should be given. In 2012, Hartwig and co-worker studied the difluoromethylation reaction of aryl

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

• for the difluoromethylation of aryl-substituted acrylic acids was also achieved by Liu and co-workers. The HCF2-substituted E-alkenes were finally obtained with iron catalysis and zinc difluoromethanesulfinate ((CF2HSO2)2Zn, Baran reagent). Also, the authors proved that the formation of the Cvinyl–CF3

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

Photocatalytic formation of carbon–sulfur bonds

• Alexander Wimmer and
• Burkhard König

Beilstein J. Org. Chem. 2018, 14, 54–83, doi:10.3762/bjoc.14.4

• photocatalytically generated thiyl radical to give the C–S cross-coupling product. The same group reported on a photoredox-catalyzed approach for the difluoromethylation of thiophenols, again applying [fac-Ir(ppy)3] as photocatalyst (Scheme 20) [51]. Herein, they describe a single-electron photoreduction of readily

• resulting aryl thiol anion reacts with the difluorocarbene to deliver the coupled difluoromethylated aryl sulfide. This method provides a facile synthetic procedure for the selective difluoromethylation of aryl thiols with different functional groups in excellent yields. A very different approach for the

Deoxygenative gem-difluoroolefination of carbonyl compounds with (chlorodifluoromethyl)trimethylsilane and triphenylphosphine

• Fei Wang,
• Lingchun Li,
• Chuanfa Ni and
• Jinbo Hu

Beilstein J. Org. Chem. 2014, 10, 344–351, doi:10.3762/bjoc.10.32

• , we have developed a relatively environmentally benign method to prepare TMSCF2Br, which can be used as a general carbene source for the difluoromethylenation of alkynes and alkenes and difluoromethylation of heteroatom nucleophiles [34]. In this paper, the novel preparation of TMSCF2Cl from TMSCF2Br

• scale in a pressure tube. aYield was determined by 19F NMR spectroscopy using PhCF3 as an internal standard. bIsolated yield. Various procedures for the generation of difluoromethylene phosphonium ylide [19][20][21][22][23][24][25]. Difluoromethylenation of alkenes and alkynes and difluoromethylation of

• . Condition screening of gem-difluoroolefination with TMSCF2X. Supporting Information Full experimental details (difluoromethylation of O, S, and N-nucleophiles and gem-difluoroolefination of carbonyl compounds with TMSCF2Cl) and compound characterization data are given. Supporting Information File 70

Recent advances in transition metal-catalyzed Csp²-monofluoro-, difluoro-, perfluoromethylation and trifluoromethylthiolation

• Grégory Landelle,
• Armen Panossian,
• Sergiy Pazenok,
• Jean-Pierre Vors and
• Frédéric R. Leroux

Beilstein J. Org. Chem. 2013, 9, 2476–2536, doi:10.3762/bjoc.9.287

• ² carbon atoms. Transformations are discussed according to the reaction-type and the metal employed. The review will not extend to conventional non-transition metal methods to these fluorinated groups. Keywords: catalysis; cross-coupling; difluoromethylation; fluorine; monofluoromethylation; organo

• fluorine, its hydration and thus reduced nucleophilicity [21]. The importance of this developing research field is reflected by the various review articles which have been published dealing with transition metal mediated or catalyzed fluorination [22][23][24], difluoromethylation [24], and

• Catalytic difluoromethylation The synthesis of difluoromethylated aromatics attracted considerable interest in recent years due to their potential pharmacological and agrochemical activity [42][50][51][52][53][54][55][56]. 2.1 Copper catalysis In contrast to widely used stoichiometric copper-mediated

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide

• Yuzo Nakamura,
• Motohiro Fujiu,
• Tatsuya Murase,
• Yoshimitsu Itoh,
• Hiroki Serizawa,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2013, 9, 2404–2409, doi:10.3762/bjoc.9.277

• 1,10-phenanthroline. Further studies on highly efficient trifluoromethylation and difluoromethylation reactions with trifluoromethylzinc reagents are under way. Experimental Typical procedure for copper-catalyzed trifluoromethylation of aryl iodide To the suspension of zinc powder (without activation

Enantioselective nucleophilic difluoromethylation of aromatic aldehydes with Me₃SiCF₂SO₂Ph and PhSO₂CF₂H reagents catalyzed by chiral quaternary ammonium salts

• Chuanfa Ni,
• Fang Wang and
• Jinbo Hu

Beilstein J. Org. Chem. 2008, 4, No. 21, doi:10.3762/bjoc.4.21

• Chuanfa Ni Fang Wang Jinbo Hu Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China 10.3762/bjoc.4.21 Abstract Background Although the nucleophilic difluoromethylation of aldehydes, ketones, and

• imines has been realized with PhSO2CF2H and related reagents, there are still no reports on the enantioselective nucleophilic reactions. Results With a chiral quaternary ammonium salt as the catalyst and KOH as the base, we describe the first enantioselective difluoromethylation of aromatic aldehydes

• with PhSO2CF2H or Me3SiCF2SO2Ph. The enantioselectivity is substrate-dependent and for 2-chlorinated benzaldehyde an ee up to 64% was obtained. Conclusion These results provide some insights into the enantioselective nucleophilic difluoromethylation chemistry, which will stimulate further progress in