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1.89 (dtd, J=13.0, 9.0, 8.6, 3.5 Hz, 1H), 1.79–1.64 (m, 2H), 1.61–1.38
(m, 2H), 1.40 ppm (dd, J=24.6, 6.2, 1.8, 3H); 13C NMR (101 MHz,
CDCl3): d=171.68, 135.23, 133.76, 128.45, 127.24, 93.91 (dd, J=
176.1, 25.0 Hz), 88.97 (dd, J=171.0, 26.1 Hz), 67.15, 56.46 (dd, J=
20.4, 5.0 Hz), 52.82 (d, J=2.8 Hz), 28.62, 24.02, 22.95, 18.92,
16.32 ppm (dd, J=22.4, 5.0 Hz); 19F NMR (377 MHz, CDCl3, decou-
pled): d=ꢀ183.47 (d, J=14.4 Hz, 1F), ꢀ191.82 ppm (d, J=14.4 Hz,
1F); 19F NMR (377 MHz, CDCl3, not decoupled): d=ꢀ183.20–
ꢀ183.74 (m, 1F), ꢀ191.52–ꢀ192.08 ppm (m, 1F); IR (neat): n˜ =
3189, 2928, 2854, 1645, 1526, 1473, 1232, 1069, 991, 958, 771, 720,
656 cmꢀ1; HRMS (ESI+) m/z: exact mass calculated for C18H27F2N2O
[M+H]+: 325.2086; found: 325.2088; ½aꢄD25 =ꢀ41.0 (c=1.0, CHCl3).
13C NMR (101 MHz, CDCl3): d=172.23, 135.93, 133.83, 128.41,
127.37, 90.50 (dd, J=180.1, 20.2 Hz), 89.03 (dd, J=174.6, 20.2 Hz),
68.58, 57.81 (dd, J=20.2, 5.7 Hz), 52.48, 31.11, 24.94, 23.52, 18.94,
16.50 ppm (dd, J=23.2, 5.8 Hz); 19F NMR (377 MHz, CDCl3, decou-
pled): d=ꢀ190.00 (d, J=10.0 Hz, 1F), ꢀ199.89 ppm (d, J=
10.0 Hz,1F); 19F NMR (377 MHz, CDCl3, not decoupled): d=ꢀ189.73
- ꢀ190.27 (m, 1F), ꢀ199.67 - ꢀ200.17 ppm (m, 1F); IR (neat): n˜ =
3261, 2937, 2857, 1663, 1493, 1041, 990, 787 cmꢀ1; HRMS (ESI+)
m/z: exact mass calculated for C18H27F2N2O [M+H]+: 325.2086;
found: 325.2087; ½aꢄ2D5 =ꢀ95.2 (c=0.5, CHCl3).
(S)-1-((S)-3,4-Difluorobutyl)-N-(2,6-dimethylphenyl)piperidine-2-
carboxamide (18): To a stirring solution of (S)-3,4-difluorobutyl 4-
nitrobenzenesulfonate (60) (0.45 g, 1.5 mmol, 1.0 equiv) in 6 mL
MeCN was added to a stirring solution of carboxamide 22 (0.42 g,
1.8 mmol, 1.2 equiv) and sodium carbonate (0.35 g, 3.3 mmol,
2.2 equiv) in 6 mL MeCN. The reaction mixture was stirred at 808C
for 14 h and then allowed to cool to room temperature. The reac-
tion was quenched with saturated NaHCO3 (30 mL) and the mix-
ture extracted with EtOAc (3ꢂ20 mL). The collected organic layers
were dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (2:1 to 1:2
hexane/EtOAc) to afford vicinal difluoride 18 (0.37 g, 1.1 mmol,
74%) as a white solid. 100% purity by analytical HPLC (Reprosil
Chiral-NR). TLC: Rf =0.31 (3:2 hexane/EtOAc; UV, KMnO4); mp: 128–
1298C; 1H NMR (400 MHz, CDCl3): d=7.96 (s, 1H), 7.12–7.05 (m,
3H), 4.95–4.71 (m, 1H), 4.64–4.35 (m, 2H), 3.20–3.10 (m, 1H), 3.08
(dt, J=12.6, 8.4 Hz, 1H), 2.94 (dd, J=10.1, 3.6 Hz, 1H), 2.56–2.42
(m, 1H), 2.24 (s, 6H), 2.18–1.69 (m, 7H), 1.64–1.45 (m, 1H), 1.46–
1.30 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=172.46, 135.59,
133.74, 128.49, 127.36, 89.83 (dd, J=173.2, 19.9 Hz), 84.19 (dd, J=
174.4, 23.3 Hz), 68.84, 52.21 (d, J=3.1 Hz), 51.41, 30.91, 27.77 (dd,
J=20.6, 5.9 Hz), 24.87, 23.64, 18.88 ppm (d, J=1.2 Hz); 19F NMR
(377 MHz, CDCl3, decoupled): d=ꢀ190.86 (dd, J=13.5, 1.7 Hz, 1F),
ꢀ229.72 ppm (d, J=13.5 Hz, 1F); 19F NMR (377 MHz, CDCl3, not de-
coupled): d=ꢀ190.62–ꢀ191.11 (m, 1F), ꢀ229.72 ppm (tdd, J=
47.5, 21.0, 13.5 Hz, 1F); IR (neat): n˜ =3290, 2949, 1651, 1488, 1091,
1044, 989, 768 cmꢀ1; HRMS (ESI+) m/z: exact mass calculated for
C18H27F2N2O [M+H]+: 325.2086; found: 325.2087; ½aꢄ2D5 =ꢀ82.1 (c=
0.5, CHCl3).
(S)-1-((2R,3R)-2,3-Difluorobutyl)-N-(2,6-dimethylphenyl)piperi-
dine-2-carboxamide (16): To a stirring solution of (2R,3R)-2,3-di-
fluorobutyl 4-nitrobenzenesulfonate (87) (0.19 g, 0.66 mmol,
1.0 equiv) in 3 mL MeCN was added carboxamide 22 (0.18 g,
0.79 mmol, 1.2 equiv) and Na2CO3 (0.15 g, 1.4 mmol, 2.2 equiv). The
reaction mixture was stirred at 808C for 48 h and then allowed to
cool to room temperature. The reaction was quenched with satu-
rated NaHCO3 (30 mL) and the mixture extracted with EtOAc (3ꢂ
20 mL). The collected organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (4:1 to 3:2 hexane/EtOAc) to afford a mix-
ture of 91% 16 and 9% 17, together (0.18 g, 0.56 mmol, 85%). Fur-
ther purification by preparative HPLC (Reprosil Chiral-NR, heptane/
EtOH=70:30) provided the product 16 as a white solid of 100%
purity. TLC: Rf =0.25 (7:3 hexane/EtOAc; UV, KMnO4); mp: 145–
1
1468C; H NMR (400 MHz, CDCl3): d=8.07 (brs, 1H), 7.12–7.05 (m,
3H), 4.90–4.51 (m, 2H), 3.24–3.04 (m, 3H), 2.88 (app td, J=14.1,
7.5 Hz, 1H), 2.44–2.34 (m, 1H), 2.24 (s, 6H), 2.09–1.99 (m, 1H),
1.94–1.81 (m, 1H), 1.79–1.65 (m, 2H), 1.61–1.41 (m, 2H), 1.42 ppm
(ddd, J=24.0, 6.6, 1.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): d=
135.42, 133.80, 128.47, 127.31, 92.82 (dd, J=178.7, 20.1 Hz), 88.81
(dd, J=174.3, 21.7 Hz), 67.36, 56.12 (dd, J=23.4, 4.5 Hz), 52.73,
28.87, 24.16–23.89 (m), 23.08, 18.92, 16.22 ppm (dd, J=23.2,
5.8 Hz); 19F NMR (377 MHz, CDCl3, decoupled): d=ꢀ191.12 (d, J=
9.5 Hz, 1F), ꢀ199.73 ppm (d, J=9.5 Hz, 1F); 19F NMR (377 MHz,
CDCl3, not decoupled): d=ꢀ191.12 (dpd, J=47.8, 24.0, 9.4 Hz, 1F),
ꢀ199.51–ꢀ199.96 ppm (m, 1F); IR (neat): n˜ =3328, 2945, 2855,
1651, 1495, 1106, 996, 831, 766, 696 cmꢀ1; HRMS (ESI+) m/z: exact
mass calculated for C18H27F2N2O [M+H]+: 325.2086; found:
325.2087; ½aꢄ2D5 =ꢀ58.9 (c=0.5, CHCl3).
(S)-1-((R)-3,4-Difluorobutyl)-N-(2,6-dimethylphenyl)piperidine-2-
carboxamide (19): To a stirring solution of (R)-3,4-difluorobutyl 4-
nitrobenzenesulfonate (59) (0.45 g, 1.5 mmol, 1.0 equiv) in 6 mL
MeCN was added to a stirring solution of carboxamide 22 (0.42 g,
1.8 mmol, 1.2 equiv) and sodium carbonate (0.35 g, 3.3 mmol,
2.2 equiv) in 6 mL MeCN. The reaction mixture was stirred at 808C
for 11 h and then allowed to cool to room temperature. The reac-
tion was quenched with saturated NaHCO3 (30 mL) and the mix-
ture extracted with EtOAc (3ꢂ20 mL). The collected organic layers
were dried over Na2SO4 and concentrated in vacuo. The crude
product was purified by flash column chromatography (2:1 to 1:2
hexane/EtOAc) to afford vicinal difluoride 19 (0.43 g, 1.3 mmol,
86%) as a white solid. 99.9% purity by analytical HPLC (Reprosil
Chiral-NR). TLC: Rf =0.31 (3:2 hexane/EtOAc; UV, KMnO4); mp: 110–
111 8C; 1H NMR (400 MHz, CDCl3): d=8.02 (s, 1H), 7.12–7.04 (m,
3H), 4.82–4.34 (m, 3H), 3.22–3.16 (m, 1H), 3.11 (ddd, J=12.7, 9.8,
7.1 Hz, 1H), 2.96 (dd, J=9.9, 3.7 Hz, 1H), 2.47–2.39 (m, 1H), 2.25 (s,
6H), 2.18–2.06 (m, 2H), 2.02–1.85 (m, 2H), 1.84–1.68 (m, 3H), 1.61–
1.47 (m, 1H), 1.43–1.30 ppm (m, 1H); 13C NMR (101 MHz, CDCl3):
d=172.46, 135.44, 133.67, 128.50, 127.30, 90.49 (dd, J=173.8,
19.8 Hz), 84.06 (dd, J=174.5, 23.3 Hz), 68.46, 53.28 (d, J=4.0 Hz),
51.85, 30.57, 28.49 (dd, J=20.9, 5.9 Hz), 24.86, 23.50, 18.90 ppm (d,
J=1.1 Hz); 19F NMR (377 MHz, CDCl3, decoupled): d=ꢀ189.58 (d,
(S)-1-((2S,3S)-2,3-Difluorobutyl)-N-(2,6-dimethylphenyl)piperi-
dine-2-carboxamide (17): To a stirring solution of (2S,3S)-2,3-di-
fluorobutyl 4-nitrobenzenesulfonate (88) (0.35 g, 1.2 mmol,
1.0 equiv) in 6 mL MeCN was added carboxamide 22 (0.33 g,
1.4 mmol, 1.2 equiv) and Na2CO3 (0.28 g, 2.6 mmol, 2.2 equiv). The
reaction mixture was stirred at 808C for 19 h and then allowed to
cool to room temperature. The reaction was quenched with satu-
rated NaHCO3 (30 mL) and the mixture extracted with EtOAc (3ꢂ
20 mL). The collected organic layers were dried over Na2SO4 and
concentrated in vacuo. The crude product was purified by flash
column chromatography (4:1 to 3:2 hexane/EtOAc) to afford a mix-
ture of 92% 17 and 8% 16, together (0.33 g, 1.0 mmol, 87%). Fur-
ther purification by preparative HPLC (Reprosil Chiral-NR, heptane/
EtOH=70:30) provided the product 17 as a white solid of 99.9%
purity. TLC: Rf =0.25 (7:3 hexane/EtOAc; UV, KMnO4); mp: 116–
1
117 8C8C; H NMR (400 MHz, CDCl3): d=8.12 (brs, 1H), 7.11–7.04 (m,
3H), 4.78–4.52 (m, 2H), 3.34 (td, J=14.4, 10.1 Hz, 1H), 3.23 (app dt,
J=11.1, 4.0 Hz, 1H), 3.01 (app dd, J=10.2, 3.6 Hz, 1H), 2.56–2.38
(m, 1H), 2.25 (s, 6H), 2.23–2.12 (m, 2H), 1.86–1.70 (m, 3H), 1.66–
1.53 (m, 1H), 1.42 (dd, J=23.0, 6.5 Hz, 3H) 1.45–1.31 ppm (m, 1H);
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ChemMedChem 2016, 11, 1 – 25
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ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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