Compound 9
2,2,2-Trifluoro-1-(cis-3-fluoro-2-methylpiperidin-1-yl)ethan-1-one
From: The formation of all-cis-(multi)fluorinated piperidines by a dearomatization–hydrogenation process
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Compound data: 1H NMR Rotamer A
Compound data: 1H{19F} NMR Rotamer A
Compound data: 13C NMR Rotamer A
Compound data: 13C{19F} NMR Rotamer A
Compound data: 19F NMR
Compound data: 19F{1H} NMR
Compound data: 1H NMR Rotamer B
Compound data: 1H{19F} NMR Rotamer B
Compound data: 13C NMR Rotamer B
Compound data: 13C{19F} NMR Rotamer B
Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.
Compound 9 was prepared according to the general procedure outlined for compound 1 on 1 mmol scale, 0.5 mol% catalyst, 4 mmol HBpin, 1 M THF at 40 °C, purification with 0-5% EtOAc in pentane. The product was isolated as a colorless oil (164 mg, 0.769 mmol, 77% (volatile compound, 89% NMR yield), d.r. 95:5). The major diastereomer could be isolated by column chromatography. The product was present as a ~1.5:1 mixture of amide bond rotamers. Traces of defluorinated side-product were inseparable from the product. Rotamer A: 1H NMR (600 MHz, CDCl3, 299 K) δ 4.99 (h, J = 6.6 Hz, 1H), 4.59 (dtd, J = 47.0, 10.3, 5.7 Hz, 1H), 3.74 (d, J = 14.5 Hz, 1H), 3.15 (td, J = 13.8, 2.9 Hz, 1H), 2.08 – 1.96 (m, 1H), 1.90 – 1.81 (m, 2H), 1.64 – 1.44 (m, 1H), 1.24 (dd, J = 7.0, 1.9 Hz, 3H); 1H{19F} NMR (600 MHz, CDCl3, 299 K) δ 4.98 (p, J = 6.8 Hz, 1H), 4.58 (tt, J = 10.5, 5.7 Hz, 1H), 3.73 (d, J = 15.6 Hz, 1H), 3.14 (td, J = 13.8, 2.9 Hz, 1H), 2.06 – 1.96 (m, 1H), 1.89 – 1.79 (m, 2H), 1.60 – 1.46 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H); 13C NMR (151 MHz, CDCl3, 299 K) δ 156.17 (d, J = 35.9 Hz), 116.57 (q, J = 288.4 Hz), 88.01 (d, J = 181.1 Hz), 48.80 (d, J = 26.6 Hz), 39.54 (q, J = 3.6 Hz), 24.75 (d, J = 19.2 Hz), 23.37 (d, J = 9.8 Hz), 9.70 (d, J = 2.6 Hz); 13C{sel-19F at -69 and -181 ppm} NMR (151 MHz, CDCl3, 299 K) δ 156.17, 116.57, 88.01, 48.80, 39.54, 24.76, 23.37, 9.70; 19F NMR (564 MHz, CDCl3, 299 K) δ -69.05, -181.55 (d, J = 47.8 Hz); 19F{1H} NMR (564 MHz, CDCl3, 299 K) δ -69.05, -181.5. Rotamer B: 1H NMR (600 MHz, CDCl3, 299 K) δ 4.59 (dtd, J = 47.0, 10.3, 5.8 Hz, 1H), 4.43 (t, J = 6.2 Hz, 1H), 4.35 (d, J = 13.6 Hz, 1H), 2.82 (t, J = 12.5 Hz, 1H), 2.07 – 1.96 (m, 1H), 1.90 – 1.81 (m, 2H), 1.65 – 1.46 (m, 1H), 1.31 (dd, J = 6.7, 1.9 Hz, 3H); 1H{19F} NMR (600 MHz, CDCl3, 299 K) δ 4.58 (tt, J = 10.3, 5.8 Hz, 1H), 4.42 (t, J = 6.2 Hz, 1H), 4.34 (dd, J = 13.6, 4.7 Hz, 1H), 2.81 (t, J = 12.5 Hz, 1H), 2.07 – 1.96 (m, 1H), 1.89 – 1.80 (m, 2H), 1.65 – 1.46 (m, 1H), 1.30 (d, J = 6.7 Hz, 3H); 13C NMR (151 MHz, CDCl3, 299 K) δ 156.10 (d, J = 36.1 Hz), 116.73 (q, J = 287.9 Hz), 88.59 (d, J = 182.4 Hz), 51.54 (dd, J = 27.3, 3.5 Hz), 36.77, 24.80 (d, J = 19.2 Hz), 22.59 (d, J = 10.1 Hz), 10.91; 13C{sel-19F at -69 and -180 ppm} NMR (151 MHz, CDCl3, 299 K) δ 156.10, 116.73, 88.59, 51.54, 36.77, 24.80, 22.59, 10.91; 19F NMR (564 MHz, CDCl3, 299 K) δ -69.14, -179.53 (d, J = 48.5 Hz); 19F{1H} NMR (564 MHz, CDCl3, 299 K) δ -69.14, -179.5. ESI-MS: calculated [C8H11NOF4 +Na]+: 236.0674, found: 236.0682. IR ν = 2955 (w), 1681.9 (s), 1450.5 (m), 1381.1 (w), 1211.3 (s), 1188.2 (s), 1126.5 (s), 1057 (m), 1003 (m), 925.8 (m), 740.7 (m), 686.7 (m), 663.5 (m), 555.5 (m). In order to prove whether the fluorine atom is occupying an axial or equatorial position, we conducted a series of NMR studies that includes NOE and HF-HetNOE experiments. All those experiments showed unequivocally that the fluorine atom adopts equatorial orientation.
