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Search for "selective fluorination" in Full Text gives 25 result(s) in Beilstein Journal of Organic Chemistry.
Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis
- Stefan P. Schmid,
- Leon Schlosser,
- Frank Glorius and
- Kjell Jorner
Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196
Graphical Abstract
Figure 1: Schematic depiction of available data sources for predictive modelling, each with its advantages an...
Figure 2: Schematic depiction of different kinds of molecular representations for fluoronitroethane. Among th...
Figure 3: Depiction of the energy diagram of a generic enantioselective reaction. In the centre, catalyst and...
Figure 4: Hammett parameters are derived from the equilibrium constant of substituted benzoic acids (example ...
Figure 5: Selected examples of popular descriptors applied to model organocatalytic reactions. Descriptors en...
Figure 6: Example bromocyclization reaction from Toste and co-workers using a DABCOnium catalyst system and C...
Figure 7: Example from Neel et al. using a chiral ion pair catalyst for the selective fluorination of allylic...
Figure 8: Data set created by Denmark and co-workers for the CPA-catalysed thiol addition to N-acylimines [67]. T...
Figure 9: Selected examples of ML developments that used the dataset from Denmark and co-workers [67]. (A) Varnek...
Figure 10: Study from Reid and Sigman developing statistical models for CPA-catalysed nucleophilic addition re...
Figure 11: Selected examples of studies where mechanistic transferability was exploited to model multiple reac...
Figure 12: Generality approach by Denmark and co-workers [132] for the iodination of arylpyridines. From the releva...
Figure 13: Betinol et al. [133] clustered the relevant chemical space and then evaluated the average ee for every c...
Figure 14: Corminboeuf and co-workers [134] chose a representative subset of the reaction space (indicated by dark ...
Figure 15: Example for data-driven modelling to improve substrate and catalyst design. (A) C–N coupling cataly...
Figure 16: Example for utilising a genetic algorithm for catalyst design. (A) Morita–Baylis–Hillman reaction s...
Figure 17: Organocatalysed synthesis of spirooxindole analogues by Kondo et al. [171] (A) Reaction scheme of dienon...
Figure 18: Schematic depiction of required developments in order to overcome current limitations of ML for org...
Regio- and stereochemical stability induced by anomeric and gauche effects in difluorinated pyrrolidines
- Ana Flávia Candida Silva,
- Francisco A. Martins and
- Matheus P. Freitas
Beilstein J. Org. Chem. 2024, 20, 1572–1579, doi:10.3762/bjoc.20.140
- Ana Flavia Candida Silva Francisco A. Martins Matheus P. Freitas Department of Chemistry, Institute of Natural Sciences, Federal University of Lavras, 37200-900, Lavras, MG, Brazil Department of Chemistry, University of Houston, Houston, TX, USA 10.3762/bjoc.20.140 Abstract Selective fluorination
- stereochemical behavior. Consequently, various molecular properties, such as polarity, viscosity, and intra- and intermolecular interactions, are impacted by the C‒F bond. These features underlie the important role of selective fluorination in pharmaceuticals and agrochemicals development [1]. For instance
Graphical Abstract
Figure 1: a) Pseudoequatorial and pseudoaxial conformations of pyrrolidine. b) Cis- and trans-isomers of 3-fl...
Figure 2: Flat representations of 2,3-, 3,4-, and 2,4-difluoropyrrolidines. The potential effects resulting f...
Figure 3: MAE comparing the geometry parameters (bond length, bond angle, and dihedral angle) obtained from D...
Figure 4: Exhaustive illustration of all conformational, configurational, and constitutional isomers of diflu...
Figure 5: Stable difluorinated pyrrolidines derived from gas-phase calculations performed at the B3LYP-D3BJ/6...
Figure 6: σCH→σ*CF fluorine gauche interaction, which also occurred in 19, and anomeric interaction in isomer ...
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
- Alexander P. Atkins Alice C. Dean Alastair J. J. Lennox University of Bristol, School of Chemistry, Bristol, BS8 1TS, U.K. 10.3762/bjoc.20.137 Abstract The selective fluorination of C(sp3)–H bonds is an attractive target, particularly for pharmaceutical and agrochemical applications. Consequently
- is therefore not as concentrated in solution, allows for equilibration between benzylic radicals towards the more stable secondary radical. This switch in selectivity provides an interesting tool for selective fluorination in substrates with multiple benzylic sites. In 2017, Wu and co-workers
Graphical Abstract
Figure 1: A) Benzylic fluorides in bioactive compounds, with B) the relative BDEs of different benzylic C–H b...
Figure 2: Base-mediated benzylic fluorination with Selectfluor.
Figure 3: Sonochemical base-mediated benzylic fluorination with Selectfluor.
Figure 4: Mono- and difluorination of nitrogen-containing heteroaromatic benzylic substrates.
Figure 5: Palladium-catalysed benzylic C–H fluorination with N-fluoro-2,4,6-trimethylpyridinium tetrafluorobo...
Figure 6: Palladium-catalysed, PIP-directed benzylic C(sp3)–H fluorination of α-amino acids and proposed mech...
Figure 7: Palladium-catalysed monodentate-directed benzylic C(sp3)–H fluorination of α-amino acids.
Figure 8: Palladium-catalysed bidentate-directed benzylic C(sp3)–H fluorination.
Figure 9: Palladium-catalysed benzylic fluorination using a transient directing group approach. Ratio refers ...
Figure 10: Outline for benzylic C(sp3)–H fluorination via radical intermediates.
Figure 11: Iron(II)-catalysed radical benzylic C(sp3)–H fluorination using Selectfluor.
Figure 12: Silver and amino acid-mediated benzylic fluorination.
Figure 13: Copper-catalysed radical benzylic C(sp3)–H fluorination using NFSI.
Figure 14: Copper-catalysed C(sp3)–H fluorination of benzylic substrates with electrochemical catalyst regener...
Figure 15: Iron-catalysed intramolecular fluorine-atom-transfer from N–F amides.
Figure 16: Vanadium-catalysed benzylic fluorination with Selectfluor.
Figure 17: NDHPI-catalysed radical benzylic C(sp3)–H fluorination with Selectfluor.
Figure 18: Potassium persulfate-mediated radical benzylic C(sp3)–H fluorination with Selectfluor.
Figure 19: Benzylic fluorination using triethylborane as a radical chain initiator.
Figure 20: Heterobenzylic C(sp3)–H radical fluorination with Selectfluor.
Figure 21: Benzylic fluorination of phenylacetic acids via a charge-transfer complex. NMR yields in parenthese...
Figure 22: Oxidative radical photochemical benzylic C(sp3)–H strategies.
Figure 23: 9-Fluorenone-catalysed photochemical radical benzylic fluorination with Selectfluor.
Figure 24: Xanthone-photocatalysed radical benzylic fluorination with Selectfluor II.
Figure 25: 1,2,4,5-Tetracyanobenzene-photocatalysed radical benzylic fluorination with Selectfluor.
Figure 26: Xanthone-catalysed benzylic fluorination in continuous flow.
Figure 27: Photochemical phenylalanine fluorination in peptides.
Figure 28: Decatungstate-photocatalyzed versus AIBN-initiated selective benzylic fluorination.
Figure 29: Benzylic fluorination using organic dye Acr+-Mes and Selectfluor.
Figure 30: Palladium-catalysed benzylic C(sp3)–H fluorination with nucleophilic fluoride.
Figure 31: Manganese-catalysed benzylic C(sp3)–H fluorination with AgF and Et3N·3HF and proposed mechanism. 19...
Figure 32: Iridium-catalysed photocatalytic benzylic C(sp3)–H fluorination with nucleophilic fluoride and N-ac...
Figure 33: Iridium-catalysed photocatalytic benzylic C(sp3)–H fluorination with TBPB HAT reagent.
Figure 34: Silver-catalysed, amide-promoted benzylic fluorination via a radical-polar crossover pathway.
Figure 35: General mechanism for oxidative electrochemical benzylic C(sp3)–H fluorination.
Figure 36: Electrochemical benzylic C(sp3)–H fluorination with HF·amine reagents.
Figure 37: Electrochemical benzylic C(sp3)–H fluorination with 1-ethyl-3-methylimidazolium trifluoromethanesul...
Figure 38: Electrochemical benzylic C(sp3)–H fluorination of phenylacetic acid esters with HF·amine reagents.
Figure 39: Electrochemical benzylic C(sp3)–H fluorination of triphenylmethane with PEG and CsF.
Figure 40: Electrochemical benzylic C(sp3)–H fluorination with caesium fluoride and fluorinated alcohol HFIP.
Figure 41: Electrochemical secondary and tertiary benzylic C(sp3)–H fluorination. GF = graphite felt. DCE = 1,...
Figure 42: Electrochemical primary benzylic C(sp3)–H fluorination of electron-poor toluene derivatives. Ring f...
Figure 43: Electrochemical primary benzylic C(sp3)–H fluorination utilizing pulsed current electrolysis.
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
- from an aspect of green chemistry [7][8][9][10]. In this context, we have developed various electrochemical methodologies for efficient selective fluorination [11][12] and molecular conversion of organofluorine compounds to date [13][14][15][16][17][18]. We have also achieved the gem-difluorination of
Graphical Abstract
Scheme 1: Electrochemical gem-difluorination of sulfides bearing α-electron-withdrawing groups.
Scheme 2: Electrochemical gem-difluorodesulfurization of dithioacetals.
Scheme 3: Electrochemical gem-difluorodesulfurization of dithiocarbonate.
Scheme 4: Cathodic reduction of 1.
Figure 1: Cyclic voltammograms of (a) PhSCF2Br (1, 8 mM) in 0.1 M n-Bu4NClO4/MeCN; (b) o-phthalonitrile (4 mM...
Scheme 5: Indirect cathodic reduction of 1 using o-phthalonitrile as mediator.
Scheme 6: Mechanism for the formation of product 3.
Scheme 7: Reaction of compound 1 with PhS anions.
Scheme 8: Cathodic reduction of compound 1 in the presence of α-methylstyrene at a high current density.
Scheme 9: Indirect cathodic reduction of compound 1 in CD3CN.
Scheme 10: Indirect cathodic reduction of compound 1 in the presence of 1,1-diphenylethylene.
Scheme 11: Reaction mechanism.
Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs
- Jongwoo Son
Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122
- [24]. This manganese porphyrin catalytic system was also effective in the direct site-selective fluorination of complex steroid scaffold 3, containing 28 unactivated C–H bonds. Based on the authors’ analysis of steric and electronic factors, it was suggested that the methylene units at C2 and C3 of
Graphical Abstract
Scheme 1: Mn-catalyzed late-stage fluorination of sclareolide (1) and complex steroid 3.
Figure 1: Proposed reaction mechanism of C–H fluorination by a manganese porphyrin catalyst.
Scheme 2: Late-stage radiofluorination of biologically active complex molecules.
Figure 2: Proposed mechanism of C–H radiofluorination.
Scheme 3: Late-stage C–H azidation of bioactive molecules. a1.5 mol % of Mn(TMP)Cl (5) was used. bMethyl acet...
Figure 3: Proposed reaction mechanism of manganese-catalyzed C–H azidation.
Scheme 4: Mn-catalyzed late-stage C–H azidation of bioactive molecules via electrophotocatalysis. a2.5 mol % ...
Figure 4: Proposed reaction mechanism of electrophotocatalytic azidation.
Scheme 5: Manganaelectro-catalyzed late-stage azidation of bioactive molecules.
Figure 5: Proposed reaction pathway of manganaelectro-catalyzed late-stage C–H azidation.
Scheme 6: Mn-catalyzed late-stage amination of bioactive molecules. a3 Å MS were used. Protonation with HBF4⋅...
Figure 6: Proposed mechanism of manganese-catalyzed C–H amination.
Scheme 7: Mn-catalyzed C–H methylation of heterocyclic scaffolds commonly found in small-molecule drugs. aDAS...
Scheme 8: Examples of late-stage C–H methylation of bioactive molecules. aDAST activation. bFor insoluble sub...
Scheme 9: A) Mn-catalyzed late-stage C–H alkynylation of peptides. B) Intramolecular late-stage alkynylative ...
Figure 7: Proposed reaction mechanism of Mn(I)-catalyzed C–H alkynylation.
Scheme 10: Late-stage Mn-catalyzed C–H allylation of peptides and bioactive motifs.
Scheme 11: Intramolecular C–H allylative cyclic peptide formation.
Scheme 12: Late-stage C–H glycosylation of tryptophan analogues.
Scheme 13: Late-stage C–H glycosylation of tryptophan-containing peptides.
Scheme 14: Late-stage C–H alkenylation of tryptophan-containing peptides.
Scheme 15: A) Late-stage C–H macrocyclization of tryptophan-containing peptides and B) traceless removal of py...
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
- [201], due to the instability of the primary radical (Figure 10). The selective fluorination of C2 over C3 may be rationalized by steric effects (rather than polarity matching), which are reported for quinuclidinium radical cations [203]. A similar selectivity for the most hydridic C(sp3)–H bond was
Graphical Abstract
Figure 1: Fluorine-containing drugs.
Figure 2: Fluorinated agrochemicals.
Scheme 1: Selectivity of fluorination reactions.
Scheme 2: Different mechanisms of photocatalytic activation. Sub = substrate.
Figure 3: Jablonski diagram showing visible-light-induced energy transfer pathways: a) absorption, b) IC, c) ...
Figure 4: Schematic illustration of TTET.
Figure 5: Organic triplet PSCats.
Figure 6: Additional organic triplet PSCats.
Figure 7: A) Further organic triplet PSCats and B) transition metal triplet PSCats.
Figure 8: Different fluorination reagents grouped by generation.
Scheme 3: Synthesis of Selectfluor®.
Scheme 4: General mechanism of PS TTET C(sp3)–H fluorination.
Scheme 5: Selective benzylic mono- and difluorination using 9-fluorenone and xanthone PSCats, respectively.
Scheme 6: Chen’s photosensitized monofluorination: reaction scope.
Scheme 7: Chen’s photosensitized benzylic difluorination reaction scope.
Scheme 8: Photosensitized monofluorination of ethylbenzene on a gram scale.
Scheme 9: Substrate scope of Tan’s AQN-photosensitized C(sp3)–H fluorination.
Scheme 10: AQN-photosensitized C–H fluorination reaction on a gram scale.
Scheme 11: Reaction mechanism of the AQN-assisted fluorination.
Figure 9: 3D structures of the singlet ground and triplet excited states of Selectfluor®.
Scheme 12: Associated transitions for the activation of acetophenone by violet light.
Scheme 13: Ethylbenzene C–H fluorination with various PSCats and conditions.
Scheme 14: Effect of different PSCats on the C(sp3)–H fluorination of cyclohexane (39).
Scheme 15: Reaction scope of Chen’s acetophenone-photosensitized C(sp3)–H fluorination reaction.
Figure 10: a) Site-selectivity of Chen’s acetophenone-photosensitized C–H fluorination reaction [201]. b) Site-sele...
Scheme 16: Formation of the AQN–Selectfluor® exciplex Int1.
Scheme 17: Generation of the C3 2° pentane radical and the Selectfluor® N-radical cation from the exciplex.
Scheme 18: Hydrogen atom abstraction by the Selectfluor® N-radical cation from pentane to give the C3 2° penta...
Scheme 19: Fluorine atom transfer from Selectfluor® to the C3 2° pentane radical to yield 3-fluoropentane and ...
Scheme 20: Barrierless fluorine atom transfer from Int1 to the C3 2° pentane radical to yield 3-fluoropentane,...
Scheme 21: Ketone-directed C(sp3)–H fluorination.
Scheme 22: Ketone-directed fluorination through a 5- and a 6-membered transition state, respectively.
Scheme 23: Effect of different PSCats on the photosensitized C(sp3)–H fluorination of 47.
Scheme 24: Substrate scope of benzil-photoassisted C(sp3)–H fluorinations.
Scheme 25: A) Benzil-photoassisted enone-directed C(sp3)–H fluorination. B) Classification of the reaction mod...
Scheme 26: A) Xanthone-photoassisted ketal-directed C(sp3)–H fluorination. B) Substrate scope. C) C–H fluorina...
Scheme 27: Rationale for the selective HAT at the C2 C–H bond of galactose acetonide.
Scheme 28: Photosensitized C(sp3)–H benzylic fluorination of a peptide using different PSCats.
Scheme 29: Peptide scope of 5-benzosuberenone-photoassisted C(sp3)–H fluorinations.
Scheme 30: Continuous flow PS TTET monofluorination of 72.
Scheme 31: Photosensitized C–H fluorination of N-butylphthalimide as a PSX.
Scheme 32: Substrate scope and limitations of the PSX C(sp3)–H monofluorination.
Scheme 33: Substrate crossover monofluorination experiment.
Scheme 34: PS TTET mechanism proposed by Hamashima and co-workers.
Scheme 35: Photosensitized TFM of 78 to afford α-trifluoromethylated ketone 80.
Scheme 36: Substrate scope for photosensitized styrene TFM to give α-trifluoromethylated ketones.
Scheme 37: Control reactions for photosensitized TFM of styrenes.
Scheme 38: Reaction mechanism for photosensitized TFM of styrenes to afford α-trifluoromethylated ketones.
Scheme 39: Reaction conditions for TFMs to yield the cis- and the trans-product, respectively.
Scheme 40: Substrate scope of trifluoromethylated (E)-styrenes.
Scheme 41: Strategies toward trifluoromethylated (Z)-styrenes.
Scheme 42: Substrate scope of trifluoromethylated (Z)-styrenes.
Scheme 43: Reaction mechanism for photosensitized TFM of styrenes to afford E- or Z-products.
Synthesis of new fluorescent molecules having an aggregation-induced emission property derived from 4-fluoroisoxazoles
- Kazuyuki Sato,
- Akira Kawasaki,
- Yukiko Karuo,
- Atsushi Tarui,
- Kentaro Kawai and
- Masaaki Omote
Beilstein J. Org. Chem. 2020, 16, 1411–1417, doi:10.3762/bjoc.16.117
- heteroaromatic systems, especially those comprising two heteroatoms such as pyrazoles [28][29], isoxazoles [30], and thiazoles [31][32]. Recently, we reported the selective fluorination of isoxazoles, to give monofluorinated isoxazoles 3 or trifluorinated isoxazolines 4 in moderate to good yields (Scheme 1) [33
- fluorinated diketone, 2-fluoro-1,3-diphenylpropane-1,3-dione (7a), the corresponding enaminoketone 8a was obtained in only low yield (Scheme 4, entry 4) and we did not attempt the conversion of 8a towards the α-fluorinated boron ketoiminate 9a. Next, we attempted the selective fluorination of 6b to obtain the
- desired fluorinated analog 9b. However, in the synthesis of F-BKIs through the selective fluorination of the corresponding BKIs, the use of 1 equiv of Selectfluor did not give any product and performing the reaction with excess amounts of Selectfluor gave rise to the corresponding α,α-difluorinated
Graphical Abstract
Scheme 1: Selective fluorination of isoxazoles and one-pot synthesis of 4-fluoroisoxazoles.
Scheme 2: One-pot reaction for the synthesis of 3,5-disubstituted 4-fluoroisoxazoles 3. aIsolated yield. bIso...
Figure 1: UV–vis and fluorescence (FL) spectra of compounds 3b and 3c.
Scheme 3: Synthesis of BKIs 6 either from 1,3-diketones 1 or from isoxazoles 2.
Scheme 4: Synthesis of enaminoketones 5 and 8 and their conversion to BKIs (yields refer to isolated yields; a...
Scheme 5: Attempted selective fluorination of BKI 6b.
Scheme 6: Ring-opening reaction of 4-fluoroisoxazoles 3 and their conversion into F-BKIs 9 (yields refer to i...
Figure 2: Photochemical properties comparisons of BKIs and F-BKIs. (a–c) BKI 6b: photograph (a), UV–vis (b), ...
SnCl4-catalyzed solvent-free acetolysis of 2,7-anhydrosialic acid derivatives
- Kesatebrhan Haile Asressu and
- Cheng-Chung Wang
Beilstein J. Org. Chem. 2019, 15, 2990–2999, doi:10.3762/bjoc.15.295
- destabilizing electron-withdrawing carboxy group flanking atom C-2 and the lack of a participating auxiliary in position C-3 of 5. Glycal 24 is widely used for α-sialylation by utilizing neighboring group participation and site-selective fluorination at C-3 [12][13][14][41]. Moreover, it is the main precursor
Graphical Abstract
Figure 1: Representative structures of bacterial glycans containing sialic acid.
Scheme 1: Concise synthesis of 2,7-anhydrosialic acid derivatives 2–6. Conditions for the preparation of 2 an...
Figure 2: a) ORTEP diagram of compound 4. Thermal ellipsoids indicate 50% probability. b) HMBC spectrum of 6.
Scheme 2: N- and C-1-functionalization of 2.
Scheme 3: Mechanism of the SnCl4-catalyzed acetolysis of 2,7-anhydro derivatives 15. R = Me, Bn, PG = electro...
Scheme 4: Synthesis and acetolysis of 2,7-anhydro derivatives 21 and 25.
Figure 3: HMBC spectrum of carbohydrate 22.
Scheme 5: Attempted acetolysis of 2,7-anhydro-NeuN3-based disaccharides 29, 33, and 37.
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
- -selective fluorination of α-bromocarbonyl compounds using a copper/CsF catalyst system (Scheme 32). Tertiary alkyl fluorides could be generated by this fluorination through the assistance of an amide group. From the results, the catalytic cycle of this reaction includes: 1) copper salt induced generation of
- transformation is proposed in Scheme 33 below. Notably, Cu acts as both a mediator and an oxidizer in this reaction. In the same year, Daugulis et al. [78] presented a Cu-catalyzed selective fluorination of benzoic acid derivatives and benzylamine derivatives assisted by an aminoquinoline auxiliary. With a CuI
- orchestrated redox process, an alkoxyl radical-guided strategy for the site-selective fluorination of unactivated methylene and methine C–H bonds was published by Liu and co-workers in 2018 (Scheme 44) [91]. The fluorination of various primary, secondary, and tertiary hydroperoxides was achieved in moderate to
Graphical Abstract
Scheme 1: The main three strategies of fluorination: nucleophilic, electrophilic and radical fluorination.
Scheme 2: Doyle’s Pd-catalyzed fluorination of allylic chlorides.
Scheme 3: Allylic fluorination of 2- and 3-substituted propenyl esters.
Scheme 4: Regioselective allylic fluorination of cinnamyl phosphorothioate esters.
Scheme 5: Palladium-catalyzed aliphatic C–H fluorination reported by Doyle.
Scheme 6: Pd-catalyzed enantioselective fluorination of α-ketoesters followed by stereoselective reduction to...
Scheme 7: Pd-catalyzed C(sp3)–H fluorination of oxindoles.
Scheme 8: C–H fluorination of 8-methylquinoline derivatives with F− reagents.
Scheme 9: Fluorination of α-cyano acetates reported by van Leeuwen.
Scheme 10: The catalytic enantioselective electrophilic C–H fluorination of α-chloro-β-keto phosphonates.
Scheme 11: Fluorination of unactivated C(sp3)–H bonds directed by the bidentate PIP auxiliary.
Scheme 12: Fluorination of C(sp3)–H bonds at the β-position of carboxylic acids.
Scheme 13: Enantioselective benzylic C–H fluorination with a chiral transient directing group.
Scheme 14: Microwave-heated Pd-catalyzed fluorination of aryl alcohols.
Scheme 15: Fluorination of aryl potassium trifluoroborates.
Scheme 16: C(sp2)–F bond formation using precatalyst [L·Pd]2(cod).
Scheme 17: Pd-catalyzed fluorination of (hetero)aryl triflates and bromides.
Scheme 18: The Pd-catalyzed C–H fluorination of arenes with Selectfluor/NFSI.
Scheme 19: Pd(II)-catalyzed ortho-monofluorination protocol for benzoic acids.
Scheme 20: Pd-catalyzed C(sp2)–H bond fluorination of 2-arylbenzothiazoles.
Scheme 21: Nitrate-promoted fluorination of aromatic and olefinic C(sp2)–H bonds and proposed mechanism.
Scheme 22: Fluorination of oxalyl amide-protected benzylamine derivatives.
Scheme 23: C–H fluorination of benzaldehydes with orthanilic acids as transient directing group.
Scheme 24: Pd(II)-catalyzed aryl C–H fluorination with various directing groups.
Scheme 25: Cu-catalyzed aliphatic, allylic, and benzylic fluorination.
Scheme 26: Cu-catalyzed SN2 fluorination of primary and secondary alkyl bromides.
Scheme 27: Copper-catalyzed fluorination of alkyl triflates.
Scheme 28: Cu-catalyzed fluorination of allylic bromides and chlorides.
Scheme 29: Synthetic strategy for the fluorination of active methylene compounds.
Scheme 30: Fluorination of β-ketoesters using a tartrate-derived bidentate bisoxazoline-Cu(II) complex.
Scheme 31: Highly enantioselective fluorination of β-ketoesters and N-Boc-oxindoles.
Scheme 32: Amide group-assisted site-selective fluorination of α-bromocarbonyl compounds.
Scheme 33: Cu-mediated aryl fluorination reported by Sanford [77].
Scheme 34: Mono- or difluorination reactions of benzoic acid derivatives.
Scheme 35: Cu-catalyzed fluorination of diaryliodonium salts with KF.
Scheme 36: Copper(I)-catalyzed cross-coupling of 2-pyridylaryl bromides.
Scheme 37: AgNO3-catalyzed decarboxylative fluorination of aliphatic carboxylic acids.
Scheme 38: The Mn-catalyzed aliphatic and benzylic C–H fluorination.
Scheme 39: Iron(II)-promoted C–H fluorination of benzylic substrates.
Scheme 40: Ag-catalyzed fluorodecarboxylation of carboxylic acids.
Scheme 41: Vanadium-catalyzed C(sp3)–H fluorination.
Scheme 42: AgNO3-catalyzed radical deboronofluorination of alkylboronates and boronic acids.
Scheme 43: Selective heterobenzylic C–H fluorination with Selectfluor reported by Van Humbeck.
Scheme 44: Fe(II)-catalyzed site-selective fluorination guided by an alkoxyl radical.
Scheme 45: Fluorination of allylic trichloroacetimidates reported by Nguyen et al.
Scheme 46: Iridium-catalyzed fluorination of allylic carbonates with TBAF(t-BuOH)4.
Scheme 47: Iridium-catalyzed asymmetric fluorination of allylic trichloroacetimidates.
Scheme 48: Cobalt-catalyzed α-fluorination of β-ketoesters.
Scheme 49: Nickel-catalyzed α-fluorination of various α-chloro-β-ketoesters.
Scheme 50: Ni(II)-catalyzed enantioselective fluorination of oxindoles and β-ketoesters.
Scheme 51: Scandium(III)-catalyzed asymmetric C–H fluorination of unprotected 3-substituted oxindoles.
Scheme 52: Iron-catalyzed directed C–H fluorination.
Scheme 53: Electrophilic silver-catalyzed Ar–F bond-forming reaction from arylstannanes.
Figure 1: Nucleophilic, electrophilic and radical CF3 sources.
Scheme 54: Cu(I)-catalyzed allylic trifluoromethylation of unactivated terminal olefins.
Scheme 55: Direct copper-catalyzed trifluoromethylation of allylsilanes.
Scheme 56: Cupper-catalyzed enantioselective trifluoromethylation of five and six-membered ring β-ketoesters.
Scheme 57: Cu-catalyzed highly stereoselective trifluoromethylation of secondary propargyl sulfonates.
Scheme 58: Remote C(sp3)–H trifluoromethylation of carboxamides and sulfonamides.
Scheme 59: Trifluoromethylation of allylsilanes with photoredox catalysis.
Scheme 60: Ag-catalyzed decarboxylative trifluoromethylation of aliphatic carboxylic acids in aqueous CH3CN.
Scheme 61: Decarboxylative trifluoromethylation of aliphatic carboxylic acids via combined photoredox and copp...
Scheme 62: Palladium-catalyzed Ar–CF3 bond-forming reaction.
Scheme 63: Palladium-catalyzed trifluoromethylation of arenes with diverse heterocyclic directing groups.
Scheme 64: Pd-catalyzed trifluoromethylation of indoles as reported by Liu.
Scheme 65: Pd-catalyzed trifluoromethylation of vinyl triflates and vinyl nonaflates.
Scheme 66: Pd(II)-catalyzed ortho-trifluoromethylation of aromatic C–H bonds.
Scheme 67: Visible-light-induced Pd(OAc)2-catalyzed ortho-trifluoromethylation of acetanilides with CF3SO2Na.
Scheme 68: CuI-catalyzed trifluoromethylation of aryl- and alkenylboronic acids.
Scheme 69: Cu-catalyzed trifluoromethylation of aryl- and vinylboronic acids.
Scheme 70: Copper-catalyzed trifluoromethylation of α,β-unsaturated carboxylic acids.
Scheme 71: Formation of C(sp2)–CF3 bond catalyzed by copper(I) complex.
Scheme 72: Loh’s Cu(I)-catalyzed trifluoromethylation of enamides and electron-deficient alkenes.
Scheme 73: Copper and iron-catalyzed decarboxylative tri- and difluoromethylation.
Scheme 74: Cu-catalyzed trifluoromethylation of hydrazones developed by Bouyssi.
Scheme 75: Cu(I)-catalyzed trifluoromethylation of terminal alkenes.
Scheme 76: Cu/Ag-catalyzed decarboxylative trifluoromethylation of cinnamic acids.
Scheme 77: Copper-catalyzed direct alkenyl C–H trifluoromethylation.
Scheme 78: Copper(I/II)-catalyzed direct trifluoromethylation of styrene derivatives.
Scheme 79: Regioselective trifluoromethylation of pivalamido arenes and heteroarenes.
Scheme 80: Synthesis of trifluoromethylquinones in the presence of copper(I).
Scheme 81: Oxidative trifluoromethylation of imidazoheterocycles in ionic liquid/water.
Scheme 82: A mild and fast continuous-flow trifluoromethylation of coumarins using a CuI/CF3SO2Na/TBHP system.
Scheme 83: Copper-catalyzed oxidative trifluoromethylation of various 8-aminoquinolines.
Scheme 84: PA-directed copper-catalyzed trifluoromethylation of anilines.
Scheme 85: Trifluoromethylation of potassium vinyltrifluoroborates catalyzed by Fe(II).
Scheme 86: Alkenyl trifluoromethylation catalyzed by Ru(phen)3Cl2 as photocatalyst.
Scheme 87: Ru-catalyzed trifluoromethylation of alkenes by Akita’s group.
Scheme 88: Ir-catalyzed Cvinyl–CF3 bond formation of α,β-unsaturated carboxylic acids.
Scheme 89: Ag(I)-catalyzed denitrative trifluoromethylation of β-nitrostyrenes.
Scheme 90: Photocatalyzed direct trifluoromethylation of aryl and heteroaryl C–H bonds.
Scheme 91: Rhenium (MTO)-catalyzed direct trifluoromethylation of aromatic substrates.
Scheme 92: Trifluoromethylation of unprotected anilines under [Ir(ppy)3] catalyst.
Scheme 93: Oxidative trifluoromethylation of imidazopyridines and imidazoheterocycles.
Scheme 94: Ruthenium-catalyzed trifluoromethylation of (hetero)arenes with trifluoroacetic anhydride.
Scheme 95: Phosphovanadomolybdic acid-catalyzed direct C–H trifluoromethylation.
Scheme 96: Picolinamide-assisted ortho-trifluoromethylation of arylamines.
Scheme 97: A nickel-catalyzed C–H trifluoromethylation of free anilines.
Scheme 98: Cu-mediated trifluoromethylation of terminal alkynes reported by Qing.
Scheme 99: Huang’s C(sp)–H trifluoromethylation using Togni’s reagent.
Scheme 100: Cu-catalyzed methods for trifluoromethylation with Umemoto’s reagent.
Scheme 101: The synthesis of alkynyl-CF3 compounds in the presence of fac-[Ir(ppy)3] under visible-light irradi...
Scheme 102: Pd-catalyzed Heck reaction reported by Reutrakul.
Scheme 103: Difluoromethylation of enamides and ene-carbamates.
Scheme 104: Difluoromethylation of α,β-unsaturated carboxylic acids.
Scheme 105: Copper-catalyzed direct C(sp2)–H difluoroacetylation reported by Pannecoucke and co-workers.
Scheme 106: Difluoroalkylation of aldehyde-derived hydrazones with functionalized difluoromethyl bromides.
Scheme 107: Photoredox-catalyzed C–H difluoroalkylation of aldehyde-derived hydrazones.
Scheme 108: Synergistic ruthenium(II)-catalyzed C–H difluoromethylation reported by Ackermann.
Scheme 109: Visible-light photocatalytic decarboxylation of α,β-unsaturated carboxylic acids.
Scheme 110: Synthesis of difluorinated ketones via S-alkyl dithiocarbamates obtained from acyl chlorides and po...
Scheme 111: Synthesis of aryl and heteroaryl difluoromethylated phosphonates.
Scheme 112: Difluoroalkylation of secondary propargyl sulfonates using Cu as the catalyst.
Scheme 113: Ru(II)-mediated para-selective difluoromethylation of anilides and their derivatives.
Scheme 114: Bulky diamine ligand promoted cross-coupling of difluoroalkyl bromides.
Scheme 115: Copper-catalyzed C3–H difluoroacetylation of quinoxalinones.
Scheme 116: Copper(I) chloride-catalyzed trifluoromethylthiolation of enamines, indoles and β-ketoesters.
Scheme 117: Copper-boxmi-catalyzed asymmetric trifluoromethylthiolation of β-ketoesters.
Scheme 118: Direct Cu-catalyzed trifluoromethylthiolation of boronic acids and alkynes.
Scheme 119: Cu-catalyzed synthesis of α-trifluoromethylthio-substituted ketones.
Scheme 120: Trifluoromethylthiolation reactions promoted by diazotriflone and copper.
Scheme 121: Halide activation of N-(trifluoromethylthio)phthalimide.
Scheme 122: The visible light-promoted trifluoromethylthiolation reported by Glorius.
Scheme 123: Synthesis of α-trifluoromethylthioesters via Goossen’s approach.
Scheme 124: Photoinduced trifluoromethylthiolation of diazonium salts.
Scheme 125: Ag-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids.
Scheme 126: Catalytic (hetero)aryl C–H trifluoromethoxylation under visible light.
Scheme 127: Photoinduced C–H-bond trifluromethoxylation of (hetero)arenes.
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
- either be guided, e.g., selective fluorination of a molecule or can also follow an unselective approach, e.g., fluorination in various positions, but in either case the goal is exploration of SAR directly on a lead structure and easy diversification. In addition, LSF can explore the addition of small
Graphical Abstract
Figure 1: Depiction of the energy levels of a typical organic molecule and the photophysical processes it can...
Figure 2: General catalytic cycle of a photocatalyst in a photoredox organocatalysed reaction. [cat] – photoc...
Figure 3: Structures and names of the most common photocatalysts encountered in the reviewed literature.
Figure 4: General example of a reductive quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocata...
Figure 5: General example of an oxidative quenching catalytic cycle. [cat] – photocatalyst, [cat]* – photocat...
Scheme 1: Oxidative coupling of aldehydes and amines to amides using acridinium salt photocatalysis.
Figure 6: Biologically active molecules containing a benzamide linkage.
Scheme 2: The photocatalytic reduction of amino acids to produce the corresponding free or protected amines.
Scheme 3: The organocatalysed photoredox base-mediated oxidation of thiols to disulfides.
Scheme 4: C-Terminal modification of peptides and proteins using organophotoredox catalysis.
Scheme 5: The reduction and aryl coupling of aryl halides using a doubly excited photocatalyst (PDI).
Figure 7: Mechanism for the coupling of aryl halides using PDI, which is excited sequentially by two photons.
Scheme 6: The arylation of five-membered heteroarenes using arenediazonium salts under organophotoredox condi...
Scheme 7: The C–H (hetero)arylation of five-membered heterocycles under Eosin Y photocatalysis.
Scheme 8: The C–H sulfurisation of imidazoheterocycles using Eosin B-catalyzed photochemical methods.
Scheme 9: The introduction of the thiocyanate group using Eosin Y photocatalysis.
Scheme 10: Sulfonamidation of pyrroles using oxygen as the terminal oxidant.
Scheme 11: DDQ-catalysed C–H amination of arenes and heteroarenes.
Scheme 12: Photoredox-promoted radical Michael addition reactions of allylic or benzylic carbons.
Figure 8: Proposed mechanistic rationale for the observed chemoselectivities.
Scheme 13: The photocatalytic manipulation of C–H bonds adjacent to amine groups.
Scheme 14: The perylene-catalysed organophotoredox tandem difluoromethylation–acetamidation of styrene-type al...
Figure 9: Examples of biologically active molecules containing highly functionalised five membered heterocycl...
Scheme 15: The [3 + 2]-cycloaddition leading to the formation of pyrroles, through the reaction of 2H-azirines...
Figure 10: Proposed intermediate that determines the regioselectivity of the reaction.
Figure 11: Comparison of possible pathways of reaction and various intermediates involved.
Scheme 16: The acridinium salt-catalysed formation of oxazoles from aldehydes and 2H-azirines.
Scheme 17: The synthesis of oxazolines and thiazolines from amides and thioamides using organocatalysed photor...
Figure 12: Biologically active molecules on the market containing 1,3,4-oxadiazole moieties.
Scheme 18: The synthesis of 1,3,4-oxadiazoles from aldehyde semicarbazones using Eosin Y organophotocatalysis.
Scheme 19: The dimerization of primary thioamides to 1,2,4-thiadiazoles catalysed by the presence of Eosin Y a...
Scheme 20: The radical cycloaddition of o-methylthioarenediazonium salts and substituted alkynes towards the f...
Scheme 21: The dehydrogenative cascade reaction for the synthesis of 5,6-benzofused heterocyclic systems.
Figure 13: Trifluoromethylated version of compounds which have known biological activities.
Scheme 22: Eosin Y-catalysed photoredox formation of 3-substituted benzimidazoles.
Scheme 23: Oxidation of dihydropyrimidines by atmospheric oxygen using photoredox catalysis.
Scheme 24: Photoredox-organocatalysed transformation of 2-substituted phenolic imines to benzoxazoles.
Scheme 25: Visible light-driven oxidative annulation of arylamidines.
Scheme 26: Methylene blue-photocatalysed direct C–H trifluoromethylation of heterocycles.
Scheme 27: Photoredox hydrotrifluoromethylation of terminal alkenes and alkynes.
Scheme 28: Trifluoromethylation and perfluoroalkylation of aromatics and heteroaromatics.
Scheme 29: The cooperative asymmetric and photoredox catalysis towards the functionalisation of α-amino sp3 C–...
Scheme 30: Organophotoredox-catalysed direct C–H amidation of aromatics.
Scheme 31: Direct C–H alkylation of heterocycles using BF3K salts. CFL – compact fluorescent lamp.
Figure 14: The modification of camptothecin, demonstrating the use of the Molander protocol in LSF.
Scheme 32: Direct C–H amination of aromatics using acridinium salts.
Scheme 33: Photoredox-catalysed nucleophilic aromatic substitution of nucleophiles onto methoxybenzene derivat...
Scheme 34: The direct C–H cyanation of aromatics with a focus on its use for LSF.
The selective electrochemical fluorination of S-alkyl benzothioate and its derivatives
- Shunsuke Kuribayashi,
- Tomoyuki Kurioka,
- Shinsuke Inagi,
- Ho-Jung Lu,
- Biing-Jiun Uang and
- Toshio Fuchigami
Beilstein J. Org. Chem. 2018, 14, 389–396, doi:10.3762/bjoc.14.27
- ; electrosynthesis; fluorobenzothiophenone; selective fluorination; Introduction Due to the interesting properties of fluorine atoms and carbon–fluorine bonds, organofluorine compounds are widely used in various fields like pharmaceutical chemistry, agrochemistry, and materials sciences [1][2]. Therefore, the
- selective fluorination of organic compounds is highly useful for the development of novel organofluorine compounds. Although a number of fluorination reagents have been developed so far, they have still some problems, i.e., they are costly, difficult to handle, and explosive [3][4]. On the other hand
Graphical Abstract
Figure 1: Cyclic voltammograms of 0.1 M Bu4NBF4/MeCN with a Pt disk working electrode in the absence (brown l...
Figure 2: Calculated HOMO diagram of 1a.
Figure 3: Calculated HOMO diagrams of 1h, 1i and 1j.
Scheme 1: Plausible reaction paths of the anodic oxidation of 1i in Et4NF·4HF/CH2Cl2.
Scheme 2: Anodic fluorination of 1k.
Scheme 3: Anodic fluorination of cyclic derivative 1l.
Scheme 4: Anodic oxidation of 1m and 1n in Et4NF·4HF/CH2Cl2.
Scheme 5: General reaction mechanism for the anodic fluorination of 1.
Scheme 6: Reaction mechanism for the anodic oxidation of carboxylic acids 1m and 1n in the presence of a fluo...
Fluorination of some highly functionalized cycloalkanes: chemoselectivity and substrate dependence
- Attila Márió Remete,
- Melinda Nonn,
- Santos Fustero,
- Matti Haukka,
- Ferenc Fülöp and
- Loránd Kiss
Beilstein J. Org. Chem. 2017, 13, 2364–2371, doi:10.3762/bjoc.13.233
- -amino ester stereo- and regioisomers, derived from unsaturated cyclic β-amino acids is described. The nucleophilic fluorinations involving hydroxy–fluorine exchange of some highly functionalized alicyclic diol derivatives have been carried out in view of selective fluorination, investigating substrate
Graphical Abstract
Scheme 1: Fluorination of diol derivative (±)-1.
Scheme 2: Fluorination of diol derivative (±)-4.
Figure 1: X-ray structure of fluorohydrine derivative (±)-5.
Scheme 3: Fluorination of diol derivative (±)-6.
Scheme 4: Fluorination of cyclohexane-derived diol (±)-8.
Scheme 5: Proposed route for the formation of compounds (±)-10 and (±)-11.
Scheme 6: Fluorination of diol derivative (±)-12.
Scheme 7: Fluorination of diol derivative (±)-14.
Scheme 8: Proposed route for the formation of compounds (±)-15, (±)-16 and (±)-17.
Scheme 9: Fluorination of N-Cbz-protected diol derivative (±)-18.
Scheme 10: Fluorination of diol derivative (±)-20.
Scheme 11: Fluorination of meso diol derivative 24.
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
- also rendered fluorine containing compounds important in the development of organic materials such as liquid crystals [8][9]. Strategic fluorination can add polarity to a molecule, however, such compounds do not generally increase in their hydrophilic capacity, thus selective fluorination leads to
Graphical Abstract
Figure 1: Selected fluorinated polar alicyclic scaffolds.
Scheme 1: Retrosynthetic plan to the preparation of 1,1,3,3-tetrafluorocyclohexane structures.
Scheme 2: Preparation of starting materials 5c and 6a–c.
Scheme 3: Deoxofluorination of diketones 5. Reagents and conditions: a) DAST, DCM, rt, overnight, 4a (traces)...
Scheme 4: Fluorodesulfurisation of bis-dithianes 6. Reagents and conditions: a) NIS, HF·Py, DCM, −78 °C to rt...
Figure 2: X-ray structure of compound 4c. The image shows two molecules stacked with the non-fluorine face po...
Figure 3: 1H NMR spectra of 4c. A) shows the spectrum in [2H8]-toluene, and B) shows the spectrum in chlorofo...
Figure 4: Electrostatic potential map for 4c calculated at the B3LYP/6-311G(d,p) level for an optimised struc...
Carbon–carbon bond cleavage for Cu-mediated aromatic trifluoromethylations and pentafluoroethylations
- Tsuyuka Sugiishi,
- Hideki Amii,
- Kohsuke Aikawa and
- Koichi Mikami
Beilstein J. Org. Chem. 2015, 11, 2661–2670, doi:10.3762/bjoc.11.286
- , the research activity on selective fluorination and trifluoromethylation has reached a mature state. The progress in fluoroalkylation of organic compounds could be accelerated by the use of fluoroalkylating reagents, which are inexpensive and easy to handle. Perfluoroalkyl carboxylic acid derivatives
Graphical Abstract
Scheme 1: Trifluoromethylation using trifluoroacetate.
Scheme 2: Decarboxylative pentafluoroethylation and its application.
Scheme 3: Trifluoromethyation with trifluoroacetate in a flow system.
Scheme 4: Trifluoromethylation of 4-bromotoluene by [(NHC)Cu(TFA)].
Scheme 5: Trifluoromethylation of aryl iodides with small amounts of Cu and Ag2O. aThe yield was determined b...
Scheme 6: C–H trifluoromethylation of arenes using trifluoroacetic acid.
Scheme 7: CF3Cu generated from chlorofluoroacetate and CuI.
Scheme 8: [18F]Trifluoromethyation with difluorocarbenes for PET. aRadiochemical yield determined by HPLC.
Scheme 9: Trifluoromethylation with trifluoroacetate and copper iodide.
Scheme 10: Preparation of trifluoromethylcopper from trifluoromethyl ketone.
Scheme 11: Trifluoromethylation of aryl iodides. aIsolated yield. b1 equivalent each of CF3Cu reagent and 1,10...
Scheme 12: Pentafluoroethylation of aryl bromides. aYield was determined by 19F NMR analysis using benzotriflu...
Scheme 13: Perfluoroalkylation reactions of arylboronic acids. aIsolated yield. bDMF was used instead of tolue...
Scheme 14: Trifluoromethylation with silylated hemiaminal of fluoral.
Scheme 15: Catalytic trifluoromethylation with a fluoral derivative.
Scheme 16: The scope of Cu-catalyzed aromatic trifluoromethylation. The yield was determined by 19F NMR analys...
Scheme 17: Plausible mechanism of Cu-catalyzed aromatic trifluoromethylation [53].
C–H bond halogenation catalyzed or mediated by copper: an overview
- Wenyan Hao and
- Yunyun Liu
Beilstein J. Org. Chem. 2015, 11, 2132–2144, doi:10.3762/bjoc.11.230
- a catalytic system consisting of (BPMED)CuI (copper(I) bisimine complex), N-hydroxyphthalimide (NHPI), KB(C6F5)4 and KI. The protocol allowed the selective fluorination of various substrates, including cycloalkanes and benzylic compounds using commercially available Selectfluor as fluorine source
Graphical Abstract
Scheme 1: Copper-catalyzed C–H bond halogenation of 2-arylpyridine.
Scheme 2: ortho-Chlorination of 2-arylpridines with acyl chlorides.
Scheme 3: Copper-catalyzed chlorination of 2-arylpyridines using LiCl.
Scheme 4: Copper-catalyzed C–H halogenation of 2-arylpyridines using LiX.
Scheme 5: Copper-mediated selective C–H halogenations of 2-arylpyridine.
Scheme 6: Copper-catalyzed C–H o-halogenation using removable DG.
Scheme 7: Copper-catalyzed C–H halogenations using PIP as DG.
Scheme 8: Copper-catalyzed quinoline C–H chlorination.
Scheme 9: Copper-catalyzed arene C–H fluorination of benzamides.
Scheme 10: Copper-catalyzed arene C–H iodination of 1,3-azoles.
Scheme 11: Copper-catalyzed C–H halogenations of phenols.
Scheme 12: Proposed mechanism for the C–H halogenation of phenols.
Scheme 13: Copper-catalyzed halogenation of electron enriched arenes.
Scheme 14: Copper-catalyzed C–H bromination of arenes.
Scheme 15: CuI-mediated synthesis of iododibenzo[b,d]furans via C–H functionalization.
Scheme 16: Cu-Mn spinel oxide-catalyzed phenol and heteroarene halogenation.
Scheme 17: Copper-catalyzed halogenations of 2-amino-1,3thiazoles.
Scheme 18: Copper-mediated chlorination and bromination of indolizines.
Scheme 19: Copper-catalyzed three-component synthesis of bromoindolizines.
Scheme 20: Copper-mediated C–H halogenation of azacalix[1]arene[3]pyridines.
Scheme 21: Copper-mediated cascade synthesis of halogenated pyrrolones.
Scheme 22: Copper-mediated alkene C–H chlorination in spirothienooxindole.
Scheme 23: Copper-catalyzed remote C–H chlorination of alkyl hydroperoxides.
Scheme 24: Copper-catalyzed C–H fluorination of alkanes.
Scheme 25: Copper-catalyzed or mediated C–H halogenations of active C(sp3)-bonds.
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
- ][17][18][19][20]. More than 20 years ago, we reported the first successful example of the electrochemical selective fluorination of heteroatom-containing compounds such as α-(phenylthio)ester and its analogues as shown in Scheme 1 [21][22]. Furthermore, anodic fluorodesulfurization of dithioacetals
Graphical Abstract
Scheme 1: Anodic fluorination of sulfides having an electron-withdrawing group.
Scheme 2: Anodic fluorination of dithioacetals.
Figure 1: Dependency of fluorinated product selectivity on a series of fluoride salts (a) Et3N·nHF (n = 3–5) ...
Scheme 3: Plausible reaction mechanism for anodic fluorination of 1b, 1d, and 1f.
Scheme 4: Mechanism for suppression of the elimination of HF (deprotonation) and preferable desulfurization o...
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
- processes. Keywords: fluorinated building blocks; fluoroarylacetic acid; fluoromalonate; fluorooxindole; organo-fluorine; selective fluorination; Introduction Since 1954, when Fried and Sabo observed that the incorporation of a fluorine atom into a corticosteroid derivative led to valuable enhanced
Graphical Abstract
Scheme 1: SNAr reaction of 2-fluoronitrobenzene (2a) with diethyl 2-fluoromalonate (1).
Figure 1: Molecular structure of 3.
Scheme 2: Synthesis of benzyl fluoride derivative 5.
Figure 2: Molecular structure of methyl ester 6a.
Scheme 3: Synthesis of pyridyl fluoride 7.
Figure 3: Molecular structure of 7.
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
- flow microreactor system, selective fluorination reactions were accomplished. For instance, fluorination of β-dicarbonyl compounds proceeds with high efficiency, whereas the use of conventional macrobatch systems suffered from low conversion [27][28]. Since then, direct fluorination processes using
Graphical Abstract
Scheme 1: Direct fluorination using microreactor systems.
Scheme 2: Use of DAST in continuous-flow reactors.
Scheme 3: Flow microreactor synthesis of fluorinated epoxides.
Scheme 4: Highly controlled isomerization of gem-difluoroalkenes.
Scheme 5: Flow system for catalytic aromatic fluorination.
Scheme 6: Continuous-flow reactor for electrophilic aromatic fluorination.
Scheme 7: Examples of [18F]-radiolabeled molecular imaging probes.
Scheme 8: Flow microreactor synthesis of dipeptides.
Scheme 9: Flow synthesis involving SNAr reactions.
Scheme 10: Flow synthesis of fluoroquinolone antibiotics.
Scheme 11: Highly controlled formation of PFPMgBr.
Scheme 12: Selective flow synthesis of photochromic diarylethenes.
Scheme 13: Flow microreactor system for perfluoroalkylation by generation of perfluoroalkyllithiums in the pre...
Scheme 14: Integrated flow microreactor system for perfluoroalkylation by generation of perfluoroalkyllithiums...
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
- enantiomer of β-lactam 4b remained intact. The net result was that a fluorinated stereocentre was rapidly constructed, with defined absolute configuration, within a nitrogen heterocycle. Conclusion When the concept of selective fluorination is applied in the context of N-heterocycles, the resulting molecules
Graphical Abstract
Figure 1: Fluorination alters the reactivity of aziridines.
Scheme 1: Fluorination makes β-lactam derivatives more reactive towards lipase-catalysed methanolysis.
Figure 2: The ring pucker in azetidine derivatives can be influenced by a C–F…N+ charge–dipole interaction.
Figure 3: Fluorination ridifies the pyrrolidine rings of ligand 10, with several consequences for its G-quadr...
Figure 4: Proline 11 readily undergoes a ring-flip process, but (4R)-fluoroproline 12 is more rigid because o...
Scheme 2: Hyperconjugation rigidifies the ring pucker of a fluorinated organocatalyst 14, leading to higher e...
Figure 5: Fluorinated piperidines prefer the axial conformation, due to stabilising C–F…N+ interactions.
Figure 6: Fluorination can rigidify a substituted azepane, but only if it acts in synergy with the other subs...
Figure 7: The eight-membered N-heterocycle 24 prefers an axial orientation of the fluorine substituent, givin...
Figure 8: Some iminosugars are “privileged structures” that serve as valuable drug leads.
Figure 9: Fluorinated iminosugar analogues 32–34 illuminate the binding interactions of the α-glycosidase inh...
Figure 10: Fluorinated miglitol analogues, and their inhibitory activity towards yeast α-glycosidase.
Figure 11: Analogues of isofagomine (31) have different pKaH values, and therefore exhibit maximal β-glucosida...
Scheme 3: General strategy for the synthesis of fluorinated N-heterocycles via deoxyfluorination.
Figure 12: Late stage deoxyfluorination in the synthesis of multifunctional N-heterocycles.
Scheme 4: During the deoxyfluorination of N-heterocycles, neighbouring group participation can sometimes lead...
Scheme 5: A building block approach for the synthesis of fluorinated aziridines 2 and 3.
Scheme 6: Building block approach for the synthesis of a difluorinated analogue of calystegine B (63).
Scheme 7: Synthesis of fluorinated analogues of brevianamide E (65) and gypsetin (68) via electrophilic fluor...
Scheme 8: Organocatalysed enantioselective fluorocyclisation.
Scheme 9: Synthesis of 3-fluoroazetidine 73 via radical fluorination.
Scheme 10: Synthesis of 3,3-difluoropyrrolidine 78 via a radical cyclisation.
Scheme 11: Chemoenzymatic synthesis of fluorinated β-lactam 4b.
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
- d-chloroform/diisopropyl tartrate showed distinct baseline separated signals for different enantiomers. Keywords: asymmetric; dihydroxylation; ee determination; fluorination; fluorosugars; organo-fluorine; Introduction Selective fluorination can be used to make subtle but decisive modifications of
Graphical Abstract
Scheme 1: Key steps from the synthesis of 6-fluoro-D-olivose (6) from D-glucose (1).
Scheme 2: De novo asymmetric syntheses of 6-deoxy-6-fluorohexoses [13].
Scheme 3: Fluorobutenoate building block 14, and related species 16 and 19 from the literature [14-16].
Scheme 4: Fluorobutenoate building blocks 25 and 26 prepared from crotonic acid.
Figure 1: Side product 27 isolated from attempted fluorination.
Figure 2: The ligand panel used in the asymmetric dihydroxylation studies. The bold oxygen shows the point of...
Scheme 5: Typical AD procedure; see Table 1 for outcomes.
Scheme 6: Conversion of enantiomerically-enriched diols to dibenzoates for HPLC analysis.
Figure 3: Diisopropyl L-tartrate (30) used as a chiral modifier for NMR determination of ee.
Figure 4: Partial 19F{1H} NMR spectra (376 MHz, L-(+)-DIPT/CDCl3, 300 K) spectra of (a) racemate 28c, (b) dio...
Figure 5: Partial 19F{1H} NMR (400 MHz, L-(+)-DIPT/CDCl3, 300 K) spectra of 28b and 28a using optimised condi...
Scheme 7: Applying cyclic sulfate methodology to gain access to anti-diastereoisomers (transformations were d...
Scheme 8: Protecting and chain extending the educts of asymmetric dihydroxylation.
Synthesis and crystallographic analysis of meso-2,3-difluoro-1,4-butanediol and meso-1,4-dibenzyloxy-2,3-difluorobutane
- Bruno Linclau,
- Leo Leung,
- Jean Nonnenmacher and
- Graham Tizzard
Beilstein J. Org. Chem. 2010, 6, No. 62, doi:10.3762/bjoc.6.62
- ; epoxide opening; gauche effect; organofluorine; vicinal difluoride; Introduction Selective fluorination of bioactive compounds is a widely employed strategy for the modification of their properties [1]. Fluorine atoms can be introduced to modulate the pKa of adjacent acidic and basic functional groups as
Graphical Abstract
Figure 1: Vicinal difluoride containing building blocks.
Scheme 1: Synthesis of meso-2,3-difluoro-1,4-butanediol.
Scheme 2: Monoprotection of 3, and activation of the remaining alcohol.
Scheme 3: Reaction of 12 leading to defluorinated products.
Figure 2: Molecular overlay of both conformers of 7.
Figure 3: Crystal packing of 7 viewed along the b axis. Short contacts (see text) are shown in light blue.
Figure 4: Crystal structure of 3.
Figure 5: Crystal packing of 3 viewed along the c axis. H-bonds are shown in light blue.
The C–F bond as a conformational tool in organic and biological chemistry
- Luke Hunter
Beilstein J. Org. Chem. 2010, 6, No. 38, doi:10.3762/bjoc.6.38
- properties of functional molecules to be optimised through selective fluorination chemistry. This concept has been demonstrated in diverse areas including medicine, catalysis, materials science and biotechnology. It is hoped that the examples highlighted in this review have persuaded the reader of the great
Graphical Abstract
Figure 1: Conformational effects associated with C–F bonds.
Figure 2: HIV protease inhibitor Indinavir (17) and fluorinated analogues 18 and 19. In analogue 18 the gauche...
Figure 3: Cholesteryl ester transfer protein inhibitors 20 and 21. In the fluorinated analogue 21, nO→σ*CF hy...
Figure 4: HIV reverse transcriptase inhibitor 22 and acid-stable fluorinated analogues 23–25. The F–C–C–O gau...
Figure 5: Dihydroquinidine (26) and fluorinated analogues 27 and 28. Newman projections along the C9–C8 bonds...
Figure 6: The neurotransmitter GABA (29) and fluorinated analogues (R)-30 and (S)-30. Newman projections of (R...
Figure 7: The insect pheromone 31 and fluorinated analogues (S)-32 and (R)-32. The proposed bioactive conform...
Figure 8: Capsaicin (33) and fluorinated analogues (R)-34 and (S)-34.
Figure 9: Asymmetric epoxidation reaction catalysed by pyrrolidine 35. Inset: the geometry of the activated i...
Figure 10: The asymmetric transannular aldol reaction catalysed by trans-4-fluoroproline (41), and its applica...
Figure 11: The asymmetric Stetter reaction catalysed by chiral NHC catalysts 49–52. The ring conformations of ...
Figure 12: A multi-vicinal fluoroalkane.
Figure 13: X-ray crystal structures of diastereoisomeric multi-vicinal fluoroalkanes 55 and 56. The different ...
Figure 14: Examples of fluorinated liquid crystal molecules. Arrows indicate the orientation of the molecular ...
Figure 15: Di-, tri- and tetra-fluoro liquid crystal molecules 60–62.
Figure 16: Collagen mimics of general formula (Pro-Yaa-Gly)10 where Yaa is either 4(R)-hydroxyproline (63) or ...
Figure 17: Enkephalin-related peptide 64 and the fluorinated analogue 65. The electron-withdrawing trifluorome...
Figure 18: The C–F bond influences the conformation of β-peptides. β-Heptapeptide 66 adopts a helical conforma...
Figure 19: The conformations of pseudopeptides 69 and 70 are influenced by the α-fluoroamide effect and the fl...
Three step synthesis of single diastereoisomers of the vicinal trifluoro motif
- Vincent A. Brunet,
- Alexandra M. Z. Slawin and
- David O'Hagan
Beilstein J. Org. Chem. 2009, 5, No. 61, doi:10.3762/bjoc.5.61
- diastereoisomeric series of this motif. The route is a significant improvement on an earlier six step strategy. Keywords: C–F bond; organo–fluorine chemistry; stereospecific fluorination; vicinal trifluoro motif; Introduction Selective fluorination is an important strategy for the design of performance molecules
Graphical Abstract
Scheme 1: Previous six step route to the vicinal all-syn-trifluoro motif.
Scheme 2: Novel three step successive fluorination strategy from α,β-epoxy alcohols to different diastereoiso...
Scheme 3: Synthesis approach to the requisite α,β-epoxy alcohols 6b and 7b.
Figure 1: X-ray structure (CCDC 750307) and stereochemistry of α,β-epoxy alcohol 7b.
Figure 2: X-ray structure (CCDC 750306) and stereochemistry of α,β-epoxy alcohol 7a.
Scheme 4: Three step sequential fluorination from α,β-epoxy alcohols to eg. the vicinyltrifluoro tosylate 11.
Scheme 5: Unexpected cyclisation of 9b to furan 14 with HF·pyridine. An X-ray structure of 14 (CCDC 750309) r...
Scheme 6: Epoxide ring opening of 9b with 3HF·Et3N required forcing conditions. The structure and stereochemi...
Scheme 7: Three step sequential fluorination from α,β-epoxy alcohol 7b to vicinal trifluoro tosylate 17b.
Scheme 8: Epoxide ring opening with 3HF∙Et3N and synthesis of the all-syn vicinal trifluoro tosylate 17a.
Themed series in organo- fluorine chemistry
- David O'Hagan
Beilstein J. Org. Chem. 2008, 4, No. 11, doi:10.3762/bjoc.4.11
- practiced particularly when tuning the properties of molecules for specialist functions. Of particular prominence is the role fluorine substitution finds in pharmaceutical development [1], and selective fluorination has made a major contribution to the bioactivity of a wide range of agrochemical products [2
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
- -actives of pharmaceutical interest.[15] It is well known too that selective fluorination can improve pharmacokinetics and the fluorine substituent can often modify bio-activity in an advantageous manner.[16] For example in the structural series relevant to this study the α-fluorinated-γ-lactone 5 is a key
Graphical Abstract
Scheme 1: Reagents: i N3CH2C(O)F, AlMe3
Scheme 2: Reagents: i KF, DMF, 73%; ii NaOH, EtOH then aqHCl, 44%; iii (CO)2Cl2, 90%.
Scheme 3: Reagents: i iPr2EtN, Yb(OTf)3, 9, DCM, 92%; ii I2, THF/ H2O, Na2S2O3, 82%.
Scheme 4: Reagents i. I2, THF/H2O.
Scheme 5: Reagents: (a) I2, THF/H2O, Na2S2O3.
Scheme 6: Reagents: i iPr2EtN, Yb(OTf)3, 9 or PhCHFCOCl, DCM, 92%.
Scheme 7: Reagents: i. LiAlH4, THF, 99%; ii. HCl-Et2O.
Figure 1: ORTEP drawing of (2S, 2'S)-28 showing two crystallographically independent molecules within the uni...
Scheme 8: Reagents: (a) I2, THF/H2O, Na2S2O3.
