All reactions were performed using flame-dried round-bottomed flasks or reaction vessels. Where appropriate, reactions were carried out under an inert atmosphere of nitrogen with dry solvents, unless otherwise stated. Yields refer to chromatographically and spectroscopically pure isolated yields. Reagents were purchased at the highest commercial quality and used without further purification. Reactions were monitored by thin-layer chromatography carried out on 0.25 mm E. Merck silica gel plates (60F-254
) using ultraviolet light as visualizing agent. NMR spectra were recorded on a Varian Inova 400 (Varian, Palo Alto, CA, USA) and were calibrated using residual undeuterated solvent as an internal reference (CDCl3
H-NMR = 7.26, 13
C-NMR = 77.16). The following abbreviations or combinations thereof were used to explain the multiplicities observed: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Liquid chromatography (LC) and high-resolution mass spectra (HRMS) were recorded on a ThermoFisher hybrid LTQ FT (ICR 7T) (ThermoFisher, Waltham, MA, USA). The University of Southampton (Southampton, UK) small molecule x-ray facility collected and analyzed all X-ray diffraction data (Supplementary Materials
6-Bromo-N-(3-(difluoromethyl)phenyl)quinolin-4-amine (8), 6-bromo-4-chloroquinoline (150 mg, 0.62 mmol, 1 eq) and 3-(difluoromethyl)aniline (97.3 mg, 0.68 mmol, 1.1 eq) were suspended in ethanol (10 mL) and refluxed for 18 h. This was followed by the addition of iPr2NEt (0.225 mL, 1.36 mmol, 2.2 eq.). The reaction mixture was concentrated in vacuo and extracted with ethyl acetate/saturated ammonium chloride. The title compound was then purified by flash chromatography using EtOAc: hexane followed by 1–5% methanol in EtOAc. The solvent was concentrated in vacuo and the product was obtained as a light beige solid (179 mg, 0.5134 mmol, 83%). MP 272–274 °C; 1H-NMR (400 MHz, DMSO-d6) δ 11.30 (s, 1H), 9.23 (d, J = 1.9 Hz, 1H), 8.56 (d, J = 6.9 Hz, 1H), 8.17 (dd, J = 9.0, 1.9 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 7.92–7.64 (m, 3H), 7.61 (dt, J = 6.4, 1.7 Hz, 1H), 7.14 (t, J = 55.7 Hz, 1H), 6.88 (d, J = 6.9 Hz, 1H). 13C-NMR (100 MHz, DMSO-d6) δ 153.9, 143.2, 137.7, 137.4, 136.6, 135.8 (t, J = 22.5 Hz), 130.6, 127.6 (t, J = 2.1 Hz), 126.4, 124.5 (t, J = 6.0 Hz), 123.0–121.8 (2C, m), 120.0, 118.8, 114.3 (t, J = 236.7 Hz), 100.5. HRMS m/z [M + H]+ calcd for C16H12N2BrF2: 349.0152, found 349.0140, LC tR = 3.78 min, >99% Purity.
Single colorless plate-shaped crystals of 8
were crystallized from EtOH/water and several drops of dioxane/HCL (4 M). A suitable crystal 0.16 × 0.10 × 0.02 mm3
was selected and mounted on a MITIGEN holder (MiTeGen, Ithaca, NY, USA) in perfluoroether oil on a Rigaku FRE+ equipped with VHF Varimax confocal mirrors and an AFC12 goniometer and HyPix 6000 detector. The crystal was kept at a steady T
= 100(2) K during data collection. The structure was solved with the ShelXT [30
] structure solution program using the using dual methods solution method and by using Olex2 [31
] as the graphical interface. The model was refined with version 2018/3 of ShelXL [32
] using full matrix least squares minimization on F2
minimization. All non-hydrogen atoms were refined anisotropically. Hydrogen atom positions were calculated geometrically and refined using the riding model except for those bonded to N-atoms which were located in the difference map and refined with a riding model. The difluoromethyl group was disordered over two positions (ca. 70:30). Thermal restraints and 1,2 and 1,3 equal distance geometric restraints applied to all equivalent atom pairs of disorder components. Equal distance geometric restraints were additionally applied to all C–F bonds.
Crystal Data for C16H12N2BrF2Cl (8H+Cl−), Mr = 385.64, orthorhombic, Pbca (No. 61), a = 7.54250(10) Å, b = 17.2573(4) Å, c = 23.3121(7) Å, a = b = g = 90°, V = 3034.38(12) Å3, T = 100(2) K, Z = 8, Z′ = 1, m(Mo Ka) = 2.903 mm−1, 26,395 reflections measured, 5342 unique (Rint = 0.0384) which were used in all calculations. The final wR2 was 0.0990 (all data) and R1 was 0.0539 (I ≥ 2 s(I)).