Triol-promoted activation of C–F bonds: Amination of benzylic fluorides under highly concentrated conditions mediated by 1,1,1-tris(hydroxymethyl)propane

Activation of the C–F bond of benzylic fluorides was achieved using 1,1,1-tris(hydroxymethyl)propane (2) as a hydrogen bond-donating agent. Investigations demonstrated that hydrogen bond-donating solvents are promoting the activation and hydrogen bond-accepting ones are hindering it. However, the reaction is best run under highly concentrated conditions, where solvents cannot interfere with the interaction between the organofluorine compound and the triol. Various benzylic fluorides react with secondary amines or anilines to form benzylic amines in good yields.


General information
Unless otherwise noted, all commercial reagents were used without further purification.
Dichloromethane, toluene, ether, tetrahydrofuran and acetonitrile were purified using a Vacuum Atmospheres Inc. Solvant Purification System. Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using Silicyle silica gel 60 Å F254 TLC plates, and visualized under UV or by staining with iodine. Flash column chromatography was carried out on Silicycle Silica Gel 60 Å, 230 × 400 mesh. Highresolution mass spectra were obtained on a LC/MS-TOF Agilent 6210 using either electrospray ionization (ESI) or atmospheric pressure photoionization (APPI). Nuclear magnetic resonance (NMR) spectra were recorded using Agilent DD2 500 and Varian Inova 400 spectrometers. 1 H and 13 C chemical shifts are reported in ppm downfield of tetramethylsilane and referenced to tetramethylsilane ( = 0 ppm) or residual chloroform peak ( = 7.26 ppm). For 19 F NMR, CFCl 3 is used as the external standard. Coupling constants (J) are measured in hertz (Hz). Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad resonance. Infrared spectra were recorded using a Thermo Scientific Nicolet 380 FTIR spectrometer. Melting points were recorded on a Stanford ResearchSystem OptiMelt capillary melting point apparatus and are uncorrected.

1-(4-Chlorophenyl)ethanol (SM-1).
In a round-bottomed flask, commercially available 4-chloroacetophenone (1.00 g, 6.47 mmol, 1 equiv) was diluted in absolute ethanol (3 mL), then a suspension of sodium borohydride (162 mg, 4.27 mmol, 0.66 equiv) in 7 mL of absolute EtOH was added. The reaction mixture was allowed to stir for 2.5 hours, upon which the reaction appeared completed by TLC analysis. The reaction mixture was quenched with aq. 10% NaOH and stirred until the solution was homogeneous. Water was added and ethanol was evaporated under reduced pressure. The aqueous mixture was extracted with 3 × CH 2 Cl 2 and the combined organic extracts were washed with NaHCO 3 (aq. 5%), then water. The solution was dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuo, affording the pure title compound (1.04 g, 100%) as a clear liquid. Spectral data were identical to those previously reported.

S5
CH 2 Cl 2 was cooled to −78 °C, upon which 4-(trimethylsilyl)morpholine (935 μL, 5.26 mmol, 1.65 equiv) was added. The mixture was allowed to heat to room temperature and stirred for 2.5 hours. This solution was cooled again to −78 °C and a solution of 1-(4chlorophenyl)ethanol (SM-1) (500 mg, 3.19 mmol, 1 equiv) in 10 mL CH 2 Cl 2 was added dropwise. The mixture was again allowed to reach room temperature and was stirred for 16 hours, at which point it was quenched by slowly adding 1 mL MeOH, then a saturated aqueous NaHCO 3 solution. The aqueous mixture was extracted with 3 × CH 2 Cl 2 and the combined organic extracts were dried over anhydrous MgSO 4 , filtered and concentrated.
After silica-gel chromatography using 100% hexanes, product-containing fractions were filtered over cotton wool prior to evaporation into a polypropylene tube. The title compound (274 mg, 54%) was obtained as a colorless oil. Spectral data were identical to those previously reported.

Substitution reactions
General procedure: All amination reactions of the article were run using the following procedure. In the initial screening and fine-tuning sections, solvent (0.5 M concentration) was used and reaction conditions were modified from the described procedure below.
In a Biotage microwave vial (which serves as a general borosilicate glass vessel) equipped with a magnetic stir bar, the benzylic fluoride (1 equiv) was weighted and then freshly ground 1,1,1-tris(hydroxymethyl)propane (2) (1.1 equiv) was added. The amine (2 equiv) was added through a syringe and finally, the vial was capped and purged with argon. The reaction was placed in an oil bath and stirred at 100 °C for 24 hours. At the end of the heating period, an aqueous Na 2 CO 3 (1 M) solution was added (on the typical scale, 1 mL was used) and the reaction mixture was stirred to loosen up its pasty form.
This mixture was then extracted with 3 × Et 2 O and the combined organic extracts were washed with brine, dried on anhydrous MgSO 4 , filtered and evaporated in vacuo. At this point, conversion was measured by 1 H NMR. Silica gel column chromatography followed when necessary.
Spectral data were identical to those previously reported. 8

Other attempted reactions
This reaction was attempted by following the general procedure for substitution reactions on a 0.16 mmol (25 mg) scale of 1-chloro-4-(1-fluoroethyl)benzene (SM-2) and using freshly distilled morpholine (28 μL, 0.32 mmol). However, after work-up, only 3 mg of crude was obtained and 1 H NMR analysis did not allow to identify any of the products formed. It is probable in these conditions that the starting fluoride (SM-2) decomposed and polymerized, hindering its isolation.
This reaction was attempted by following the general procedure for substitution reactions on a 0.16 mmol (30 mg) scale of 4-(fluoromethyl)-1,1'-biphenyl (1) and using freshly distilled n-butylamine (32 μL, 0.32 mmol). After work-up, 69% of conversion was measured by 1 H NMR, but two different products (SM-3 and possibly SM-4) were formed in a 2:1 mixture. The purification was attempted by column chromatography using hexanes/EtOAc (96/4) but the products of mono-and dibenzylation could not be separated.       Figure S22: 1 H NMR spectrum of compound 16.