DOI: 10.3109/14756366.2014.963072
Fluorinated pyrrolidines and piperidines
5
was magnetically stirred at the same temperature for 1 h, then were added. The mixture was magnetically stirred at room
neutralized with water/ice/Na2CO3 up to pH 10 and extracted with temperature overnight, then water was added and extracted with
ethyl acetate (ꢁ3). The combined organic phases were dried over ethyl acetate (ꢁ3). The combined organic phases were dried over
magnesium sulfate, filtered and concentrated in vacuo. The magnesium sulfate, filtered and concentrated in vacuo, thereby
reaction crude was purified over silica gel with the eluent diethyl obtaining compound 15 without further purification (575 mg,
ether/pentane/diethylamine: 20/79/1, thereby obtaining com- 87%). Aspect: yellow solid. Mp: 177.2 ꢀC. 1H NMR (CD3OD,
pounds 11 and 12 (3/2) as a racemic mixture of their enantiomers 400 MHz, ppm) ꢀ: 8.44 (d, 2H, J ¼ 9.0 Hz), 8.03 (d, 2H,
1
(84 mg, 71%). Aspect: brown oil. H NMR (CDCl3, 400 MHz, J ¼ 9.0 Hz), 3.66 (m, 1H), 3.40 (m, 2H), 2.88 (ddd, 2H,
ppm) ꢀ: 8.39 (d, 2H, J ¼ 8.8 Hz), 8.04 (d, 2H, J ¼ 8.8 Hz), 4.67 J ¼ 12.0 Hz, J ¼ 8.8 Hz, J ¼ 3.4 Hz), 1.88 (m, 2H), 1.57 (m, 2H).
(ddt, 1H, J ¼ 46.4 Hz, J ¼ 7.6 Hz, J ¼ 3.7 Hz), 4.10 (ddt, 1H, 13C NMR (CDCl3, 100 MHz, ppm) ꢀ: 150.3, 142.7, 128.9, 124.5,
J ¼ 21.7 Hz, J ¼ 9.0 Hz, J ¼ 3.1 Hz), 3.89 (ddd, 1H, J ¼ 26.7 Hz, 65.3, 43.0, 33.2.
J ¼ 12.3 Hz, J ¼ 3.9 Hz), 3.76 (ddd, 1H, J ¼ 14.9 Hz, J ¼ 12.3 Hz,
J ¼ 7.7 Hz), 3.41 (m, 2H), 1.93 (m, 1H), 1.93 (m, 1H), 1.70 (m, 1-(4-nosyl)-4-methanesulfonatepiperidine (16)
1H), 1.56 (m, 1H). 13C NMR (CDCl3, 100 MHz, ppm) ꢀ: 150.3,
Into a round-bottom flask, compound 15 (400 mg, 1.4 mmol) was
143.4, 128.8, 124.5, 94.6 (d, J ¼ 182.7 Hz), 60.3 (d, J ¼ 21.2 Hz),
solubilized in acetonitrile (5 mL), triethylamine (0.38 mL,
49.8, 43.1 (d, J ¼ 25.2 Hz), 28.2, 24.5. 19F {1H} NMR (CDCl3,
2.8 mmol) and mesyl chloride (0.16 mL, 2.1 mmol) were added.
376 MHz, ppm) ꢀ: ꢂ192.0. HRMS (Q-TOF 2, ES+, MeOH): m/z
The mixture was magnetically stirred at 80 ꢀC overnight, then
calc. for [M+Na]+: C12H14ClFN2NaO4S 359.0239 found:
water and an aqueous solution of NaOH 2M were added. The
359.0239.
mixture is stirred 5 min and extracted with ethyl acetate (ꢁ3). The
combined organic phases were dried over magnesium sulfate,
filtered and concentrated in vacuo, thereby obtaining compound
15 without further purification (504 mg, 99%). Aspect: yellow
solid. 1H NMR (CD3OD, 400 MHz, ppm) ꢀ: 8.38 (d, 2H,
(2S)-1-(4-nosyl)-2-(2-chloro-(1S)-fluoroethyl)pyrrolidine and
(2R)-1-(4-nosyl)-2-(2-chloro-(1R)-fluoroethyl)pyrrolidine (12)
1
Aspect: brown oil. H NMR (CDCl3, 400 MHz, ppm) ꢀ: 8.41 (d,
J ¼ 9.0 Hz), 7.98 (d, 2H, J ¼ 9.0 Hz), 4.70 (m, 1H), 3.24–3.05
(m, 4H), 2.97 (s, 3H), 2.03 (m, 2H), 1.88 (m, 2H). 13C NMR
(CD3OD, 100 MHz, ppm) ꢀ: 151.5, 143.1, 129.9, 125.5, 77.0,
43.6, 38.7, 31.7. HRMS (Q-TOF 2, ES+, MeOH): m/z calc. for
[M+H]+: C12H17N2O7S2 365.0471 found 365.0473.
2H, J ¼ 9.0 Hz), 8.04 (d, 2H, J ¼ 9.0 Hz), 4.92 (dm, 1H,
J ¼ 47.8 Hz), 3.95 (dm, 1H, J ¼ 20.6 Hz), 3.77 (ddd, 1H, J ¼
16.3 Hz, J ¼ 12.1 Hz, J ¼ 6.3 Hz), 3.71 (ddd, 1H, J ¼ 16.1 Hz,
J ¼ 12.1 Hz, J ¼ 5.5 Hz), 3.48 (ddd, 1H, J ¼ 10.3 Hz, J ¼ 7.2 Hz,
J ¼ 4.5 Hz), 3.26 (dt, 1H, J ¼ 10.2 Hz, J ¼ 7.2 Hz), 2.02 (m, 1H),
1.93 (m, 1H), 1.62 (m, 1H), 1.59 (m, 1H). 13C NMR (CDCl3,
100 MHz, ppm) ꢀ: 150.3, 143.1, 128.8, 124.5, 92.7 (d,
J ¼ 182.8 Hz), 60.4 (d, J ¼ 22.9 Hz), 49.4, 42.8 (d, J ¼ 25.6 Hz),
26.0 (d, J ¼ 4.7 Hz), 24.5. 19F {1H} NMR (CDCl3, 376 MHz,
ppm) ꢀ: ꢂ193.8.
1-(4-nosyl)-1,2,5,6-tetrahydropyridine (17)
Into a round-bottom flask, compound 16 (300 mg, 0.82 mmol)
was solubilized in DBU (5 mL). The mixture was magnetically
stirred at 80 ꢀC for 2 h, then water was added and extracted with
ethyl acetate (ꢁ3). The combined organic phases were washed
with an aqueous solution of HCl 0.5 M and brine, dried over
magnesium sulfate, filtered and concentrated in vacuo. The
reaction crude was purified over silica gel with the eluent ethyl
acetate/petroleum ether: 30/70 thereby obtaining compound 17
(86 mg, 39%). Aspect: yellow solid. Mp: 134.3 ꢀC. 1H NMR
(CDCl3, 400 MHz, ppm) ꢀ: 8.37 (d, 2H, J ¼ 9.0 Hz), 7.98 (d, 2H,
J ¼ 9.0 Hz), 5.78 (dm, 1H, J ¼ 10.2 Hz), 5.63 (dm, 1H,
J ¼ 10.2 Hz), 3.67 (m, 2H), 3.28 (t, 2H, J ¼ 5.7 Hz), 2.21 (m,
2H). 13C NMR (CDCl3, 100 MHz, ppm) ꢀ: 150.3, 143.2, 128.8,
125.4, 124.4, 122.5, 44.8, 42.7, 25.2. HRMS (Q-TOF 2, ES+,
MeOH): m/z calc. for [M+H]+: C11H13N2O4S 269.0590 found
269.0593.
(2S)-1-(4-nosyl)-2-((1R)-chloro-2-fluoroethyl)pyrrolidine and
(2R)-1-(4-nosyl)-2-((1S)-chloro-2-fluoroethyl)pyrrolidine (13)
To a HF/SbF5 mixture (2 mL, 12.2 mol% SbF5) was added NCS
(208 mg, 1.56 mmol). After 1 min of stirring at ꢂ20 ꢀC, the
substrate 4 (122 mg, 0.52 mmol) was slowly added. The mixture
was magnetically stirred at the same temperature for 10 min, then
neutralized with water/ice/Na2CO3 up to pH 10 and extracted with
ethyl acetate (ꢁ3). The combined organic phases were dried over
magnesium sulfate, filtered and concentrated in vacuo. The
reaction crude was purified over silica gel with the eluent diethyl
ether/pentane/diethylamine: 20/79/1, thereby obtaining com-
pounds 13 and 130 (7/3) as a racemic mixture of their enantiomers
(154 mg, 88%), 130 could not be isolated. Aspect: yellow solid.
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Mp: 125.4 ꢀC. H NMR (CDCl3, 400 MHz, ppm) ꢀ: 8.40 (d, 2H,
(3S,4S)-1-(4-nosyl)-4-chloro-3-fluoropiperidine and
(3R,4R)-1-(4-nosyl)-4-chloro-3-fluoropiperidine (18)
J ¼ 9.0 Hz), 8.04 (d, 2H, J ¼ 9.0 Hz), 4.64 (ddd, 1H, J ¼ 47.5 Hz,
J ¼ 5.2 Hz, J ¼ 8.9 Hz), 4.64 (m, 1H), 4.51 (ddd, 1H, J ¼ 47.5 Hz,
J ¼ 9.6 Hz, J ¼ 6.6 Hz), 4.06 (ddd, 1H, J ¼ 4.0 Hz, J ¼ 5.0 Hz,
J ¼ 8.5 Hz), 3.42 (dt, 1H, J ¼ 10.6 Hz, J ¼ 6.9 Hz), 3.36 (ddd, 1H,
J ¼ 10.6 Hz, J ¼ 7.3 Hz, J ¼ 5.7 Hz), 2.08 (m, 1H), 1.96 (m, 1H),
1.76 (m, 1H), 1.52 (dtt, 1H, J ¼ 12.5 Hz, J ¼ 7.3 Hz, J ¼ 7.2 Hz).
13C NMR (CDCl3, 100 MHz, ppm) ꢀ: 150.3, 143.3, 128.7, 124.5,
83.1 (d, J ¼ 176.6 Hz), 60.9 (d, J ¼ 19.8 Hz), 60.8 (d, J ¼ 3.1 Hz),
49.6, 26.7, 24.7. 19F {1H} NMR (CDCl3, 376 MHz, ppm) ꢀ:
ꢂ219.2. HRMS (Q-TOF 2, ES+, MeOH): m/z calc. for [M+Na]+:
C12H14ClFN2NaO4S 359.0239 found: 359.0239.
To a HF/SbF5 mixture (1 mL, 12.2 mol% SbF5) was added NCS
(72 mg, 0.54 mmol). After 1 min of stirring at ꢂ20 ꢀC, compound
17 (50 mg, 0.18 mmol) was slowly added. The mixture was
magnetically stirred at the same temperature for 10 min, then
neutralized with water/ice/Na2CO3 up to pH 10 and extracted with
ethyl acetate (ꢁ3). The combined organic phases were dried over
magnesium sulfate, filtered and concentrated in vacuo. The
reaction crude was purified over silica gel with the eluent
petroleum ether/ethyl acetate: 90/10, thereby obtaining compound
18 (30 mg, 50%) and 19 (4 mg, 6%) as a racemic mixture of
enantiomers. Aspect: white solid. Mp: 157.1 ꢀC. 1H NMR
(CDCl3, 400 MHz, ppm) ꢀ: 8.39 (d, 2H, J ¼ 8.9 Hz), 7.98 (d,
2H, J ¼ 8.9 Hz), 4.63 (dm, 1H, J ¼ 45.9 Hz), 4.09 (m, 1H), 3.58
1-(4-nosyl)piperidine-4-ol (15)
In a round-bottom flask, 4-nosyl chloride (512 mg, 2.3 mmol) was
solubilized in dichloromethane (8 mL), 4-hydroxypiperidine
(404 mg, 4.0 mmol) and triethylamine (0.4 mL, 3.0 mmol)
(
broaddd, 1H, J ¼ 13.7Hz, J ¼ 4.7 Hz), 3.50 (ddd, 1H, J ¼ 27.3 Hz,
J ¼ 13.5 Hz, J ¼ 2.5 Hz), 3.38 (m, 1H), 3.26 (m, 1H), 2.30 (m,