Synthesis of benzyl fluorides

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Visible light activates diarylketone catalysts to abstract a benzylic hydrogen atom selectively, which enables an operationally simple direct fluorination of benzylic C-H groups in the presence of a fluorine radical donor. 9-Fluorenone catalyzes benzylic C-H monofluorination, while xanthone catalyzes benzylic C-H difluorination.
J.-B. Xia, C. Zhu, C. Chen, J. Am. Chem. Soc., 2013, 135, 17494-17500.

A Cu-catalyzed C-H fluorination with N-fluorobenzenesulfonimide (NFSI), followed by substitution of the resulting fluoride with various nucleophiles, enables a site-selective transformation of benzylic C-H bonds into diverse functional groups.
A. Vasilopoulos, D. L. Golden, J. A. Buss, S. S. Stahl, Org. Lett., 2020, 22, 5746-5748.

A mild C-F functionalization of benzylic sp³ C-H bonds allows the synthesis of monofluorinated benzylic substrates in the presence of commercially available iron(II) acetylacetonate and Selectfluor in very good yields and selectivity. A convenient route to β-fluorinated products of 3-aryl ketones provides a synthetic equivalent to the difficult to accomplish conjugate addition of fluoride to α,β-unsaturated ketones.
S. Bloom C. R. Pitts, R. Woltornist, A. Griswold, M. G. Holl, T. Lectka, Org. Lett., 2013, 15, 1722-1724.

In a direct fluorination of C(sp³)-H bonds, a catalytic N-oxyl radical generated from N,N-dihydroxypyromellitimide abstracts the hydrogen followed by trapping of the resulting carbon radical by Selectfluor. This simple metal-free protocol enables the chemoselective introduction of a fluorine atom into various aromatic and aliphatic compounds and serves as a powerful tool for the efficient synthesis of fluorinated molecules.
Y. Amaoka, M. Nagamoto, M. Inoue, Org. Lett., 2013, 15, 2160-2163.

Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor reagent) is a new deoxofluorinating agent that is much more thermally stable than DAST (C₂H₅)₂NSF₃. It is effective for the conversion of alcohols to alkyl fluorides, aldehydes and ketones to the corresponding gem-difluorides, and carboxylic acids to the trifluoromethyl derivatives with, in some cases, superior performance compared to DAST.
G. S. Lal, G. P. Pez, R. J. Pesaresi, F. M. Prozonic, H. Cheng, J. Org. Chem., 1999, 7048-7054.

[IPrH][F(HF)₂] is a highly selective and soluble reagent for a microwave-assisted fluorination of various organic substrates. The scope of substrates includes benzyl bromides, iodides, chlorides, aliphatic halides, tosylates, mesylates, α-haloketones, a silyl chloride, acyl and sulfuryl chlorides, and a nitroarene. The reagent can be regenerated using hydrofluoric acid without organic solvents.
B. Alič, J. Petrovčič, J. Jelen, G. Tavčar, J. Iskra, J. Org. Chem., 2022, 87, 5987-5993.

A nucleophilic fluorination of triflates by weakly basic tetrabutylammonium bifluoride provides excellent yields with minimal formation of elimination-derived side products. Most primary and secondary hydroxyl groups are excellent substrates, but benzylic and aldol-type secondary hydroxyl groups give poor yields as a result of the instability of their triflates.
K.-Y. Kim, B. C. Kim, H. B. Lee, H. Shin, J. Org. Chem., 2008, 73, 8106-8108.

PyFluor is an inexpensive and thermally stable deoxyfluorination reagent that fluorinates a broad range of alcohols with only minor formation of elimination side products. The reagents combines selectivity, safety, and economic viability.
M. K. Nielsen, C. R. Ugaz, W. Li, A. G. Doyle, J. Am. Chem. Soc., 2015, 137, 9571-9574.

AlkylFluor, a salt analogue of PhenoFluor, enables a practical, high-yielding deoxyfluorination of various primary and secondary alcohols. AlkylFluor is readily prepared on multigram scale and is stable to long-term storage in air and exposure to water.
N. W. Goldberg, X. Shen, J. Li, T. Ritter, Org. Lett., 2016, 18, 6102-6104.

In situ generation of highly active CF₃SO₂F enables a deoxyfluorination of alcohols with KF as the fluorine source. This mild and fast reaction tolerates diverse functionalities, including halogen, nitro, ketone, ester, alkene, and alkyne.
J. Xu, C. Peng, B. Yao, H.-J. Xu, Q. Xie, J. Org. Chem., 2022, 87, 6471-6478.

The solid, air-stable peptide coupling reagent TFFH (tetramethylfluoroformamidinium hexafluorophosphate) activates various alcohols towards deoxofluorination under mild conditions, that are even compatible with carbonyl functional groups.
G. Bellavance, P. Dubé, B. Nguyen, Synlett, 2012, 23, 569-572.

A continuous-flow protocol for the light-induced fluorination of benzylic compounds in very good isolated yields in residence times below 30 min uses Selectfluor as the fluorine source and xanthone as an inexpensive and commercially available photoorganocatalyst. The flow photoreactor is based on transparent fluorinated ethylene propylene tubing and a household compact fluorescent lamp with black-light irradiation.
D. Cantillo, O. de Frutos, J. A. Rincón, C. Mateos, C. O. Kappe, J. Org. Chem., 2014, 79, 8486-8490.

The merger of palladium catalysis with electrooxidation enables the hydrofluorination of aryl-substituted alkenes ranging from styrenes to more challenging α,β-unsaturated carbonyl derivatives to the corresponding benzylic fluorides. This method can also be applied to the late-stage modification of pharmaceutical derivatives.
A. Mandal, J. Jang, B. Yang, H. Kim, K. Shin, Org. Lett., 2023, 25, 195-199.

A light-induced, Ru-catalyzed three-component alkyl-fluorination of olefins under mild reaction conditions provides a wide range of fluorinated products with good functional group tolerance. A key advantage of this photoredox reaction is the use of generic alkyl groups and nucleophilic fluoride.
W. Deng, W. Feng, Y. Li, H. Bao, Org. Lett., 2018, 20, 4245-4249.

The combination of sulfuryl fluoride and Me₄NF enables a room temperature deoxyfluorination of a broad range of benzaldehydes and α-ketoesters.
P. R. Melvin, D. M. Ferguson, S. D. Schimler, D. C. Bland, M. S. Sanford, Org. Lett., 2019, 21, 1350-1353.

A desulfurizing difluorination reaction of benzyl sulfides having an electron-withdrawing group such as an ester, a ketone, a nitrile, or an amide in the presence of IF5 gave gem-difluoro compounds in good yield.
T. Fukuhara, S. Hara, Synlett, 2009, 198-200.

A general strategy for the 1,3-oxidation of cyclopropanes using aryl iodine(I-III) catalysis enables the synthesis of 1,3-difluorides, 1,3-fluoroacetoxylated products, 1,3-diols, 1,3-amino alcohols, and 1,3-diamines. These reactions make use of practical, commercially available reagents and can engage a variety of substituted cyclopropane substrates.
S. M. Banik, K. M. Mennie, E. N. Jacobsen, J. Am. Chem. Soc., 2017, 139, 9152-9155.

In a highly regioselective, direct visible-light-mediated aminofluorination of styrenes, a shelf-stable N-Ts-protected 1-aminopyridine salt serves as the nitrogen-radical precursor, and the commercially available hydrogen fluoride-pyridine was used as the nucleophilic fluoride source.
J.-N. Mo, W.-L. Yu, J.-Q. Chen, X.-Q. Hu, P.-F. Xu, Org. Lett., 2018, 20, 4471-4474.

Related

A palladium-catalyzed direct monofluoromethylation of arylboronic esters produces monofluoromethyl arenes at room temperature within 4 h with a good functional group tolerance. The monofluoromethylating agent, CH₂FI, can readily be prepared via a halogen-exchange process.
J. Hu, B. Gao, L. Li, C. Ni, J. Hu, Org. Lett., 2015, 17, 3086-3089.

A cobalt complex catalyzes an asymmetric cross-coupling of α-bromo-α-fluorotoluene derivatives with a variety of aryl zincates derived from lithium aryl n-butyl pinacol boronates and ZnBr₂ under mild reaction conditions. The reaction tolerates various common functional groups such as fluoride, chloride, bromide, cyano, or ester groups.
W. Huang, X. Wan, Q. Shen, Org. Lett., 2020, 22, 4327-4332.

A nickel-catalyzed cross-coupling between arylboronic acids and unactived 1-fluoro-1-iodoalkanes offers high efficiency, mild conditions, and excellent functional-group compatibility. Readily available nitrogen and phosphine ligands generated a variety of easily tunable catalysts to promote the fluoroalkylation for a broad range of both coupling partners.
J. Sheng, H.-Q. Ni, G. Liu, Y. Li, X.-S. Wang, Org. Lett., 2017, 19, 4440-4443.

A Pd-catalyzed gem-difluoroallylation of organoborons using 3-bromo-3,3-difluoropropene (BDFP) proceeds in high efficiency with high α/γ-substitution regioselectivity. The reaction offers low catalyst loading (0.8 to 0.01 mol %), broad substrate scope, and excellent functional group compatibility, thus providing a facile route for practical application in drug discovery and development.
Q.-Q. Min, Z. Yin, Z. Feng, W.-H. Guo, X. Zhang, J. Am. Chem. Soc., 2014, 136, 1230-1233.