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

• excess NFSI, the heterobenzyl fluoride is obtained. In the case of product 3, the authors suggested that the absence of radical clock rearrangement products supported a polar mechanism. Conveniently, when both benzylic and heterobenzylic C–H bonds were present in a substrate, the reaction was selective

• for the heterobenzylic position, as shown by compound 4. In 2018, a subsequent publication by the same group detailed the use of increased lithium carbonate and NFSI loadings (conditions [B]) to access the difluorinated products [37]. This report also demonstrated a single example of 18F

• monofluorination radiolabelling using [18F]NFSI. Electrophilic fluorination of benzylic C–H bonds has been demonstrated as a powerful approach. However, these techniques can be constrained to defined substrate classes and the requirement of using strong bases. Palladium catalysis Palladium-catalysed chemistry is

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

• -Fluorinations of 1,3-diaryldiketone derivatives such as 1,3-diphenylpropane-1,3-dione (dibenzoylmethane, DBM, 1a) using electrophilic fluorinating reagents such as Selectfluor, NFSI, and NFOBS under a range of conditions have been described extensively [3][12][13][30][38][39][40][41][42][43]. We confirmed that

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• (Scheme 1b). Similarly, in the absence of metal catalysts, N-fluorobenzenesulfonimide (NFSI) was found to act as a mild fluorinating reagent for activated aromatics by mechanochemistry [5]. Such a collective effort to access halogenated substrates is understandable, owning the synthetic value of organic

Multi-faceted reactivity of N-fluorobenzenesulfonimide (NFSI) under mechanochemical conditions: fluorination, fluorodemethylation, sulfonylation, and amidation reactions

• José G. Hernández,
• Karen J. Ardila-Fierro,
• Dajana Barišić and
• Hervé Geneste

Beilstein J. Org. Chem. 2022, 18, 182–189, doi:10.3762/bjoc.18.20

• techniques, in this work we studied the reactivity of N-fluorobenzenesulfonimide (NFSI) by ball milling. We corroborated that, by mechanochemistry, NFSI can engage in a variety of reactions such as fluorinations, fluorodemethylations, sulfonylations, and amidations. In comparison to the protocols reported in

• solution, the mechanochemical reactions were accomplished in the absence of solvents, in short reaction times, and in yields comparable to or higher than their solvent-based counterparts. Keywords: amidation; ball mill; fluorination; in situ monitoring; mechanochemistry; NFSI; Raman monitoring

• stability under environments of mechanical stress, while at the same time enough reactivity to engage in chemical transformations. In the search for solid reagents compatible with mechanochemical techniques, we became interested in evaluating the behavior of N-fluorobenzenesulfonimide (NFSI) under ball

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• -fluorobenzenesulfonimide (NFSI) to provide amino-substituted nicotinate derivatives 8 in good to excellent yield (Scheme 4) [50]. The investigation showed that the electronic effect of the residue R on the substrates influences the results significantly. (E)-2-en-4-ynyl azides 1 bearing electron-donating groups had better

• -annulation reaction may undergo a free-radical addition pathway. Firstly, NFSI oxidizes Cu(I) to form bissulfonylamidyl radical 10. Secondly, intermolecular nitrogen free-radical addition to the alkyne provides the vinyl radical 11. Then, there may be two possible pathways. Path a: vinyl radical 11 is

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• disclosed the application of N-fluorobenzenesulfonimide (NFSI) and NBS (N-bromosuccinimide), respectively, as the halogen sources, with diazoacetamide under catalyst-free conditions via a carbene pathway, which constructed 3-fluorooxindoles and 3-bromooxindoles (Scheme 1, reaction 1) [20][21]. Then, the

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• full paper later published in 1995 [58]. 1-14. N-Fluorobenzenesulfonimide (NFSI) In 1991, N-fluorobenzenesulfonimide (NFSI, 14-2) was synthesized by Differding and co-worker [59]. It was prepared from benzenesulfonimide 14-1 in good yield by its reaction with 10% F2/N2 in acetonitrile at −40 °C (Scheme

•  30). NFSI is a stable and non-hygroscopic crystalline solid with a mp of 114–116 °C. NFSI was shown to fluorinate a variety of nucleophiles. As seen in Scheme 31, trimethylsilyl enol ethers, enolate anions of ketones and esters, and aryl- and vinyllithiums were fluorinated with NFSI in moderate to

• high yields. Although aromatics such as anisole, toluene, and acetanilide could also be fluorinated by NFSI, these reactions required neat conditions and high temperatures, indicating that NFSI was not so powerful. 1-15. N-Fluorosaccharin and N-fluorophthalimide In 1991, Gakh et al. reported the

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

• and co-workers first synthesized the NFPYs [186]. Further synthesis of similar compounds resulted in the synthesis of N-fluorobis(phenyl)sulfonimide (NFSI) [187], N-fluorobis[(trifluoromethyl)sulfonyl]imide [188][189], N-fluoropyridinium salts [186], N-fluorosaccharinsultam and 4-nitro-substituted N

• = 50.3 kcal⋅mol−1) were most effective, affording 83% and 86% yield of the monofluorinated product 27a, respectively (Scheme 6). A range of electrophilic fluorine sources was evaluated (for example, NFSI and N-fluoropyridinium salts), but Selectfluor® was chosen for giving the highest yield of 27a

• Selectfluor® or Selectfluor® II was employed. Were mono- and difluorination to proceed via the same mechanism, one would expect to see traces of the monofluorinated product 27a unless the reaction of 27a was faster than the reaction of the starting material 26. Interestingly, NFSI gave exclusive

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• another enantiomer of 12a (Table 3, entries 13–18) with the QD-promoted reaction affording the best ee value (Table 3, entry 13). Additionally, we tested N-fluorobenzenesulfonimide (NFSI) as an alternative fluorinating agent in a combination with DHQ-Bn and QD with the outcome being indistinguishable with

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• formation [64]. 2.2. Stereoselective benzylic fluorination of N-(2-phenylacetyl)oxazolidin-2-one using NFSI Treatment of oxazolidinone 122 with N-fluorobenzenesulfonimide (NFSI) in the presence of NaHMDS afforded the fluorinated oxazolidinone derivative 123. The reductive removal of the chiral auxiliary

• . Selectfluor was found superior to other fluorination reagents such as fluoropyridinium tetrafluoroborate, 2,4,6-trimethylfluoropyridinium tetrafluoroborate, or NFSI. The fluorination process was explored with a broad range of substituted Phe derivatives. The removal of the PIP auxiliary group without

Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• enantioselective synthesis of valnoctamide, a commercialized mild tranquilizer. Finally, this methodology was extended to the sequential Michael/halogenation reaction using NFSI or NCS as electrophiles, with similar efficiency. Similarly, a cocatalyzed enantioselective β-functionalization of enals was developed by

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

• BINAP-derived palladium complex to perform the similar reaction with 4,4’-diF-NFSI as the fluorinating agent in higher enantioselectivities (Scheme 7b). In 2012 the group of Sanford [43] achieved the palladium-catalyzed C–H fluorination of 8-methylquinoline derivatives using AgF as the nucleophilic

• , Xu’s group [49] presented the palladium-catalyzed direct fluorination of unactivated C(sp3)–H bonds at the β-position of carboxylic acids with NFSI (Scheme 12). To achieve this transformation, an 8-aminoquinoline-derived auxiliary was developed as an effective directing group for the activation of the

• formed from A with Selectfluor or NFSI instead of an organometallic intermediate as usual. Then, the activated Pd(IV)–F electrophile B would be capable of electrophilic fluorination of weakly nucleophilic arenes. This unusual mechanism of catalysis may provide a new idea to the catalysis of C–H

Cobalt bis(acetylacetonate)–tert-butyl hydroperoxide–triethylsilane: a general reagent combination for the Markovnikov-selective hydrofunctionalization of alkenes by hydrogen atom transfer

• Xiaoshen Ma and
• Seth B. Herzon

Beilstein J. Org. Chem. 2018, 14, 2259–2265, doi:10.3762/bjoc.14.201

• ®, diethylaminosulfur trifluoride (DAST), or tosyl fluoride (see Supporting Information File 1, Table S1, entries 2–4), N-fluorobenzenesulfonimide (NFSI) provided the desired hydrofluorination product 4b in 36% yield (Table 1, entry 2). Carreira and co-workers reported the first hydrochlorination reaction via a cobalt

Homologated amino acids with three vicinal fluorines positioned along the backbone: development of a stereoselective synthesis

• Raju Cheerlavancha,
• Ahmed Ahmed,
• Yun Cheuk Leung,
• Aggie Lawer,
• Qing-Quan Liu,
• Marina Cagnes,
• Hee-Chan Jang,
• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2017, 13, 2316–2325, doi:10.3762/bjoc.13.228

• the electrophilic fluorination reagent NFSI (compared with nucleophilic fluorination reagents such as DeoxoFluor). Accordingly, two aldehyde substrates (7a and 7b) were prepared [21][22], containing either a phthalimide or a Boc protecting group. Electrophilic fluorination was attempted according to

• β-fluorinated carbonyl compounds besides 9. Thus, β-fluoroaldehyde 17 which was synthesized by an independent method (see Supporting Information File 1) was treated with NFSI and catalyst 10 according to Jørgensen’s fluorination protocol [20] (Table 1, entry 1). However, this resulted in a complex

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• nucleophiles dates back to 2002, when Kim and Park described the first use of cinchona alkaloid-based quaternary ammonium salts A (i.e., derivative A1) for the enantioselective α-fluorination of β-ketoesters 1 by using N-fluorobenzenesulfonimide (NFSI, 2) as the fluoride-transfer reagent [73] (Scheme 2). By

• asymmetric α-heterofunctionalization reactions [79][80]. Hereby they also reported the fluorination of 3-substituted benzofuranones 4 by using NFSI (2) as the electrophilic F-transfer reagent [80]. The reaction could be carried out in excellent yields and with modest enantioselectivities for a rather broad

• anions can control Pd-catalysed α-fluorinations [84]). Very interestingly, however, the authors clearly proved that the nature of the F-transfer reagent is crucial to obtain high selectivities. While NFSI or SelectfluorTM did not give reasonable enantioselectivities [81], the pyridinium salt 6 turned out

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• derivatives 123 via the Nazarov cyclization followed by electrophilic fluorination, has been described in 2007 by Ma et al. [65]. This reaction was catalyzed by Cu(II) triflate and proceeded in the presence of N-fluorobenzenesulfonimide (NFSI) 122 as a fluorinating reagent (Scheme 39). Scientists are

Copper-catalyzed aminooxygenation of styrenes with N-fluorobenzenesulfonimide and N-hydroxyphthalimide derivatives

• Yan Li,
• Xue Zhou,
• Guangfan Zheng and
• Qian Zhang

Beilstein J. Org. Chem. 2015, 11, 2721–2726, doi:10.3762/bjoc.11.293

• addition and a nucleophilic oxygen attack [35]. Very recently, Studer and co-workers presented an aminooxygenation of alkenes with N-fluorobenzenesulfonimide (NFSI) and sodium 2,2,6,6-tetramethylpiperidine-1-olate (TEMPONa) via nitrogen-centred radical addition to the alkene followed by trapping of 2,2,6,6

• -tetramethylpiperidine-N-oxyl (TEMPO) [36]. NFSI is a very interesting reagent. Besides classic electrophilic fluorination reagent [37], it has been used not only as fluoride-atom transfer reagent [38][39][40] but also as nucleophilic/radical amination reagent [41]. We are highly interested in the multiple reaction

• modes of NFSI [37][38][39][40][41], especially as a nitrogen-centred radical. In this context, we have realized copper-catalyzed benzylic sp3 C–H amination [42], aminative multiple functionalization of alkynes [43], diamination, aminocyanation [44] and aminofluorination of alkenes [45], as well as

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• 134a,b with ephedrine yielded a separable mixture of diastereomeric phosphonamides, trans-135a,b and cis-136a,b. The fluorination with N-fluorobenzenesulfonimide (NFSI) of either trans-135a or cis-136a was found to be strongly dependant on the base used to generate the phosphonamidate anion. The best

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• -chloroaldehydes, a type of α-branched aldehyde, mediated by the Jørgensen–Hayashi catalyst 1 [8]. The reaction yielded the desired α-chloro-α-fluoroaldehydes with high enantioselectivity when the starting aldehyde was used in excess over N-fluorobenzenesulfonimide (NFSI) in the reaction. However, when an excess

• NFSI with respect to the starting aldehyde was used, poor asymmetric induction was observed. In this paper, we describe the determination of the absolute stereochemistry of a resulting α-chloro-α-fluoroaldehyde using this methodology and discuss the possible reaction mechanism that involves kinetic

• resolution. Results and Discussion In our previous study [8], enantioselective fluorination of racemic 2-chloro-3-phenylpropanal (2a) was carried out with 3 equiv of NFSI in the presence of organocatalyst (S)-1 to yield the corresponding α-chloro-α-fluoroaldehyde 3a in good conversion. Isolation of the

Flow microreactor synthesis in organo-fluorine chemistry

• Hideki Amii,
• Aiichiro Nagaki and
• Jun-ichi Yoshida

Beilstein J. Org. Chem. 2013, 9, 2793–2802, doi:10.3762/bjoc.9.314

• and Nagaki reported the reactions of aryllithiums with electrophilic fluorinating agents such as NFSI and N-fluorosultam (Scheme 6) [54]. The present flow microreactor method showed a high level of functional group compatibility; a wide repertoire of aryl fluorides possessing electron-withdrawing

Development of the titanium–TADDOLate-catalyzed asymmetric fluorination of β-ketoesters

• Lukas Hintermann,
• Mauro Perseghini and
• Antonio Togni

Beilstein J. Org. Chem. 2011, 7, 1421–1435, doi:10.3762/bjoc.7.166

• up to 91% enantiomeric excess, with either F–TEDA (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)) in acetonitrile solution or NFSI (N-fluorobenzenesulfonimide) in dichloromethane solution as fluorinating reagents. The effects of various reaction parameters and of the

• (Table 3). Results for either fluorination (→6-F) with F–TEDA or the more soluble reagent NFSI (N-fluorobenzenesulfonimide) and NCS (N-chlorosuccinimide) for chlorination [43] (→6-Cl) are displayed in Table 3. Above ambient temperature, increasing temperatures give lower selectivity (Table 3, entries 1–3

• fluorination by choosing NFSI (N-fluorobenzenesulfonimide) as the reagent with better solubility. Reaction with NFSI in dichloroethane gave 1-F with 24% ee (5 mol % K1, 40 °C, 3 d, 66% conversion), which is close to the enantiomeric excess observed with F–TEDA in acetonitrile at the same temperature (Table 2

DBFOX- Ph/metal complexes: Evaluation as catalysts for enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones

• Takehisa Ishimaru,
• Norio Shibata,
• Dhande Sudhakar Reddy,
• Takao Horikawa,
• Shuichi Nakamura and
• Takeshi Toru

Beilstein J. Org. Chem. 2008, 4, No. 16, doi:10.3762/bjoc.4.16

• enantioselective fluorination of 3-(2-arylacetyl)-2-thiazolidinones 1 with N-fluorobenzenesulfonimide (NFSI) by DBFOX-Ph/metal complexes under a variety of conditions. After optimization of the metal salts, solvents and additives, we found that the fluoro-2-thiazolidinones 2 were obtained in good to high yields

• -thiazolidinones with N-fluorobenzenesulfonimide (NFSI) (Figure 1). Results and Discussion Our previous studies of the DBFOX-Ph/Ni(II)-catalyzed enantioselective fluorination of β-keto esters have shown that the optimal reaction conditions require NFSI as the fluorine source and a catalytic amount of Ni(ClO4)2

• a water molecule for DBFOX-Ph/Ni(II)/1 as shown in Scheme 1. In the complex, the Si face is shielded by one of the phenyl groups of DBFOX-Ph so that NFSI approaches from the Re face of the substrates (Scheme 1). Since a major difference in ee values of 2 was not observed for the fluorination

Single and double stereoselective fluorination of (E)-allylsilanes

• Marcin Sawicki,
• Angela Kwok,
• Matthew Tredwell and
• Véronique Gouverneur

Beilstein J. Org. Chem. 2007, 3, No. 34, doi:10.1186/1860-5397-3-34

• -fluorobenzenesulfonimide [34] (NFSI). The d.r. for this first fluorination was excellent (>20:1). The subsequent electrophilic fluorodesilylation of the resulting fluorinated silane 6 delivered 3 in excellent yield with no trace of side-products. In comparison with allylsilanes 1a-i, the fluorodesilylation of 6 was more