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

• generate a fluoride ion that facilitates limiting enolization processes, and an electrophilic N–F fluorinating agent that is reactive towards neutral enol species. Keywords: difluorination; difluoromethylene; direct fluorination; electrophilic fluorination; organofluorine; Introduction Fluorine is

• ][31][32]. Since profit margins in the life science industries are always under constant pressure, less expensive methods of introducing fluorine selectively into active intermediates for manufacture on the industrial scale are required and, as a relatively inexpensive strategy, direct fluorination of

• techniques [34][35][36]. Difluorination occurs very slowly in comparison to monofluorination, although some difluorinated by-products are, in general, formed upon fluorination of dicarbonyl substrates and difluorinated products can be readily separated from monofluorinated systems [34]. Direct fluorination

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

• by direct fluorination (10% F2/N2) of the pyridine in acetonitrile and in the presence of a suitable salt at low temperature (method B in Scheme 10). This one-step process was successfully applied to many other pyridine derivatives (method B in Figure 2). It was finally shown that the stable N

• active N-F fluorinating agents, chiral N-fluorosultams, were synthesized by Lang and co-worker [52]. A camphor-derived imine was reduced or methylated, followed by direct fluorination (10% F2/N2) to give optically active N-F reagents 9-1 and 9-2 in 75% and 80% yield, respectively (Scheme 21). These N

• (Scheme 23) [53]. A direct fluorination using 10% F2/N2 at −40 °C gave N-F reagent 10-2 in 74% yield. Another method, via the N-trimethylsilylation, was also reported but in low efficiency. This N-F reagent is a colorless, thermally stable (<200 °C) solid with a mp of 114–116 °C. The reagent 10-2 having

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

• photocatalytic direct fluorination of unactivated C(sp3)–H bonds by employing Selectfluor® and anthraquinone (AQN, T1 = 61.9 kcal⋅mol−1) as a photosensitizer. Control experiments showed that, under their conditions, both light and AQN were necessary for the reaction to proceed. A variety of different compounds

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• ]. Remarkable advances in the direct fluorination (F2/N2) of carbonyl compounds by Sandford and co-workers [14][15] are noteworthy in this regard, and mitigate the expense and poor atom economy associated with stoichiometric approaches. Moreover, this substructure provides a versatile entry point for subsequent

• )/I(III) catalysis [35][36][37]. Moreover, elegant studies by Hara and co-workers have demonstrated that α-fluoroketones could be prepared by exposing silyl enol ethers to stoichiometric p-ToIIF2, in the presence of BF3·OEt2 and NEt3/HF 1:2 [38]. A report by Kitamura and co-workers in which the direct

• fluorination of acetophenone derivatives was achieved using iodosylarenes and commercially available NEt3/HF 1:5 to generate the ArIF2 species in situ is also highly pertinent [39][40] (Figure 1A). Elegant reports describing the conversion of internal alkynes to α-fluoroketones via π-acid catalysis were also

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

• -phenylalanine (70) was prepared by direct fluorination of 4-borono-ʟ-phenylalanine (BPA, 69) with [18F]AcOF or [18F]F2. The reaction was followed by a HPLC separation using a Delta-Pak Cl8 cartridge 0.1% acetic acid as the mobile phase at a flow rate of 10 mL/min. The product was isolated in radiochemical

• hand, Wade et al. reported that ester 138b (R = iPr) afforded the isopropyl 3-fluorophenylalaninate (139b) as racemate in 45–50% yield [70] under similar reaction conditions (Scheme 31). 2.6. Fluorination and reductive amination of phenylpyruvate A direct fluorination of the ester derivatives of

• diastereoisomeric purity (dr > 99:1) (Scheme 38). 2.9. Direct fluorination of β-methylene C(sp3)−H The direct fluorination of β-methylene C(sp3)−H bonds of Phe derivatives 157a–v having installed the bidentate auxiliary, 2-(pyridine-2-yl)isopropylamine (PIP-amine) 158, was attempted using Selectfluor in the

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

• , 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

Palladium-catalyzed Heck-type reaction of secondary trifluoromethylated alkyl bromides

• Tao Fan,
• Wei-Dong Meng and
• Xingang Zhang

Beilstein J. Org. Chem. 2017, 13, 2610–2616, doi:10.3762/bjoc.13.258

• past decade, investigations mainly focused on direct fluorination or fluoroalkylation of aromatics [1][2][3][4][5]. Fluoroalkylated alkenes are a kind of important fluorinated structural motifs and have wide applications in medicinal chemistry and advanced functional materials [6][7][8][9]. However

Organofluorine chemistry: Difluoromethylene motifs spaced 1,3 to each other imparts facial polarity to a cyclohexane ring

• Mathew J. Jones,
• Ricardo Callejo,
• Alexandra M. Z. Slawin,
• Michael Bühl and
• David O'Hagan

Beilstein J. Org. Chem. 2016, 12, 2823–2827, doi:10.3762/bjoc.12.281

• byproducts. The reaction of ketones 5a–c with 1,2-ethanedithiol in the presence of catalytic BF3·OEt2 afforded the corresponding bis-dithianes 6a–c in moderate to good yields [26] (Scheme 2). The reaction of diketone 5c also afforded the monoderivatised ketone 9 as a minor product. Direct fluorination of

Synthesis and nucleophilic aromatic substitution of 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzene

• Javier Ajenjo,
• Martin Greenhall,
• Camillo Zarantonello and
• Petr Beier

Beilstein J. Org. Chem. 2016, 12, 192–197, doi:10.3762/bjoc.12.21

• Abstract 3-Fluoro-5-nitro-1-(pentafluorosulfanyl)benzene was prepared by three different ways: as a byproduct of direct fluorination of 1,2-bis(3-nitrophenyl)disulfane, by direct fluorination of 4-nitro-1-(pentafluorosulfanyl)benzene, and by fluorodenitration of 3,5-dinitro-1-(pentafluorosulfanyl)benzene

• nitrogen nucleophiles provided 3-fluoro-5-nitro-1-(pentafluorosulfanyl)benzenes substituted in position four. Keywords: direct fluorination; fluorine; nucleophilic aromatic substitution; pentafluorosulfanyl group; vicarious nucleophilic substitution; Introduction Organic compounds with a

• converted to arylsulfur chlorotetrafluorides [11][12]. Fluorination in the second step affords arylsulfur pentafluorides [11][13]. Umemoto’s synthesis does not require handling the elemental fluorine, gives better yields, and displays a wider substrate scope than the direct fluorination method. However

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• elemental fluorine for the key construction of the carbon–fluorine bond by complementary direct selective direct fluorination [41][42][43][44], continuous flow [45][46][47][48][49] and building block [50] strategies, in this paper, we describe nucleophilic aromatic substitution reactions of carbanions

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

• microreactor technology to overcome long-standing problems in synthetic organofluorine chemistry are showcased. Reactions using hazardous fluorinating reagents Direct fluorination employing elemental fluorine (F2) is one of the most straightforward methods to make fluorine-containing molecules with high atom

• economy. However, handling F2 needs special care and there are a lot of practical difficulties associated with direct fluorination. Elemental fluorine is a poisonous pale yellow gas at room temperature (bp −188 °C). Reactions of organic substances with elemental fluorine are typically strongly exothermic

• and extremely fast, frequently explosive. So it is difficult to control direct fluorination reactions with F2 gas in conventional batch reactors. In 1999, the pioneering work using flow microreactor technology for direct fluorination was reported by Chambers and Spink (Scheme 1) [26]. Utilizing the

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

• to be successfully achieved. One such reagent, PhenoFluor (45, Figure 12), was originally developed by Ritter and co-workers for the direct fluorination of phenols [56]. Recent work showed that 45 can also be used to effect late-stage fluorination of hydroxy groups within complex molecular

• enantioselectivity. 6.5 Radical reactions Examples of direct fluorination of C–H bonds with fluorine-containing radicals are rare in the literature, especially if stereoselective versions of such reactions are sought. However, this transformation can be a very effective and concise method for synthesising

Multigramme synthesis and asymmetric dihydroxylation of a 4-fluorobut-2E-enoate

• James A. B. Laurenson,
• John A. Parkinson,
• Jonathan M. Percy,
• Giuseppe Rinaudo and
• Ricard Roig

Beilstein J. Org. Chem. 2013, 9, 2660–2668, doi:10.3762/bjoc.9.301

• literature (Scheme 3); silver mediated fluorination of butenoyl bromide 15 is known [14] delivering 16 in moderate yield but via a slow and expensive reaction. Wittig reaction, following in situ reduction of ethyl fluoroacetate (17) has been reported [15], while Purrington [16] prepared 19 by direct

• fluorination of silylketene acetal 18 with elemental fluorine. We decided to explore a halogen exchange approach from crotonic acid (20) which is commercially available cheaply, and in high diastereoisomeric purity (>98%). Diastereomeric purity is particularly important as the de novo syntheses must deliver

Synthesis of SF₅-containing benzisoxazoles, quinolines, and quinazolines by the Davis reaction of nitro-(pentafluorosulfanyl)benzenes

• Petr Beier and
• Tereza Pastýříková

Beilstein J. Org. Chem. 2013, 9, 411–416, doi:10.3762/bjoc.9.43

• of SF5 organics is their limited availability. In SF5-aromatics, para- and meta-nitro-(pentafluorosulfanyl)benzenes (3 and 4) (Figure 1) are available by the direct fluorination of the corresponding bis(nitrophenyl)disulfides [18][19][20], and several other SF5-benzenes are available through

Recyclable fluorous cinchona alkaloid ester as a chiral promoter for asymmetric fluorination of β-ketoesters

• Wen-Bin Yi,
• Xin Huang,
• Zijuan Zhang,
• Dian-Rong Zhu,
• Chun Cai and
• Wei Zhang

Beilstein J. Org. Chem. 2012, 8, 1233–1240, doi:10.3762/bjoc.8.138

• significantly reduced the ee of the product (Table 1, entries 7 and 8). A control reaction without C-1 gave 2a in 35% yield as a racemic product (Table 1, entry 9). The results suggest that a stoichiometric amount of C-1 is required to minimize the formation of achiral fluorination product by direct

• fluorination. Solvent screening indicated that using 1:1 CH3CN/CH2Cl2 gave product 2a in 51% yield and 70% ee (Table 1, entry 15), which is better than using CH3CN alone. Other single or binary solvent systems containing toluene, THF, H2O, and CF3C6H5 did not afford better results (Table 1, entries 10–14). It

Highly selective synthesis of (E)-alkenyl-(pentafluorosulfanyl)benzenes through Horner–Wadsworth–Emmons reaction

• George Iakobson and
• Petr Beier

Beilstein J. Org. Chem. 2012, 8, 1185–1190, doi:10.3762/bjoc.8.131

• aromatic meta- and para-nitro-(pentafluorosufanyl)benzenes (1 and 2) are made by direct fluorination of the corresponding bis(nitrophenyl)disulfides [10][11][12]. A recent report also described a two step synthesis of SF5-benzenes from diaryl disulfides avoiding the use of elemental fluorine [13]. While

Combination of gold catalysis and Selectfluor for the synthesis of fluorinated nitrogen heterocycles

• Antoine Simonneau,
• Pierre Garcia,
• Jean-Philippe Goddard,
• Virginie Mouriès-Mansuy,
• Max Malacria and
• Louis Fensterbank

Beilstein J. Org. Chem. 2011, 7, 1379–1386, doi:10.3762/bjoc.7.162

• explained either by direct fluorination of the enamine resulting from the gold-promoted alkyne hydroamination or by oxidation of the intermediate vinyl gold(I) complex by Selectfluor into a gold(III) fluoride species followed by a reductive elimination. Moreover, the formation of C(sp2)–F bonds, either by

Continuous gas/liquid–liquid/liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination

• Jessica R. Breen,
• Graham Sandford,
• Dmitrii S. Yufit,
• Judith A. K. Howard,
• Jonathan Fray and
• Bhairavi Patel

Beilstein J. Org. Chem. 2011, 7, 1048–1054, doi:10.3762/bjoc.7.120

• : continuous flow reactions; fluorine; fluoropyrazole; gas-liquid flow reactor; selective direct fluorination; Introduction Organic systems which bear fluorine atoms are used in an ever widening range of applications in the life sciences. Many commercially significant pharmaceutical and agrochemical products

• [15] and heterocyclic [16][17] systems have been established and scaled-up by our industrial collaborators for use in the synthesis of commercially important pharmaceutical intermediates [18]. As part of our studies, aimed at further control of the direct fluorination procedures for larger scale

• established that, in both batch and continuous flow processes, 1,3-dicarbonyl derivatives are not equally reactive towards fluorine gas [12] and that the ease of selective direct fluorination depends on the nature and proximity of other functional groups. Substrates that have a high initial equilibrium enol

Shelf-stable electrophilic trifluoromethylating reagents: A brief historical perspective

• Norio Shibata,
• Andrej Matsnev and
• Dominique Cahard

Beilstein J. Org. Chem. 2010, 6, No. 65, doi:10.3762/bjoc.6.65

• (or selenides) with m-chloroperbenzoic acid followed by cyclization of the corresponding sulfoxides (or selenoxides) either with triflic anhydride or by direct fluorination with 10% F2/N2 in the presence of one equivalent of triflic acid or HBF4 (Scheme 2). The tellurophenium salt 7 was synthesized in

The vicinal difluoro motif: The synthesis and conformation of erythro- and threo- diastereoisomers of 1,2-difluorodiphenylethanes, 2,3-difluorosuccinic acids and their derivatives

• David O'Hagan,
• Henry S. Rzepa,
• Martin Schüler and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2006, 2, No. 19, doi:10.1186/1860-5397-2-19

• . Early synthetic methods to vicinal difluoro compounds have involved direct fluorination of alkenes with for eg. elemental fluorine (F2) [4] or XeF2 [5]. Such methods however are either difficult to carry out in a standard laboratory environment or they suffer from very poor stereoselectivity. The direct

• -difluorosuccinic acids 19. The preparation of stereoisomers of 2,3-difluorosuccinic acids, has involved conversions of tartaric acids (esters) [6][7], as described above in Scheme 1. Other approaches have involved the direct fluorination of fumaric acid [16] and the catalytic hydrogenation of 2,3-difluoromaleic

Stereoselective α-fluoroamide and α-fluoro- γ-lactone synthesis by an asymmetric zwitterionic aza-Claisen rearrangement

• Kenny Tenza,
• Julian S. Northen,
• David O'Hagan and
• Alexandra M. Z. Slawin

Beilstein J. Org. Chem. 2005, 1, No. 13, doi:10.1186/1860-5397-1-13

• Background Asymmetric introduction of fluorine α-to a carbonyl has become popular recently, largely because the direct fluorination of enolates by asymmetric electrophilic fluorinating reagents has improved, and as a result such compounds are becoming attractive synthons. We have sought an alternative but