Full Paper
cis-(2R*,3R*)-(9H-Fluoren-9-yl)methyl
idine-1-carboxylate and
methyl 2-Allyl-3-fluoropiperidine-1-carboxylate 5c: Under N2
2-Allyl-3-fluoropiper- (400 MHz, CDCl3): δ = 1.56–1.69 (2H, m, CH2), 1.81–1.89 (2H, m,
trans-(2S*,3R*)-(9H-Fluoren-9-yl)-
CH2), 2.41 (3H, s, CH3), 3.26–3.31 (2H, m, CH2), 4.94 (1H, dt, J = 8.5,
4.0 Hz, CH), 6.58 (1H, d, J = 8.5 Hz, CH), 7.25 (2H, d, J = 8.5 Hz, CH),
7.62 (2H, d, J = 8.5 Hz, ArH) ppm.
a
solution of 3c (trans/cis; 60:40–122 mg, 0.34 mmol, 1 equiv.) and
allyltrimethylsilane 4 (0.11 mL, 0.68 mmol, 2 equiv.) in dry DCM
(15 mL) was cooled to –84 °C (liquid N2/EtOAc). Then BF3·Et2O
(0.08 mL, 0.68 mmol, 2 equiv.) was added in a dropwise fashion at
–84 °C. The mixture was stirred for 1 h, during which period room
temperature was reached. The mixture was then stirred overnight
at r.t. for 19 h. DCM (20 mL) and sat. NaHCO3(aq) (20 mL) were added
and the resultant organic phase was further extracted with DCM
(2 × 20 mL). The combined organic extracts were dried with Na2SO4,
filtered and the solvent removed under reduced pressure to afford
the title compound 5c as an inseparable mixture of diastereomers
(cis/trans; 60:40 by VT NMR in [D6]DMSO). In this way 5c (95 mg,
77 %) was obtained as a pale-yellow oil. Rf = 0.50 (cHex/EtOAc; 3:1);
cis-(2S*,3R*)-3-Fluoro-2-methoxy-1-tosylpiperidine and trans-
(2R*,3R*)-3-Fluoro-2-methoxy-1-tosylpiperidine (3d): At room
temperature enamine 1d (173 mg, 0.73 mmol, 1 equiv.) in a 1:1
v/v MeCN-MeOH (16 mL) mixture was treated with Selectfluor® 2
(283 mg, 0.80 mmol, 1.1 equiv.). Stirring was continued for 17 h at
r.t. The reaction mixture was extracted with water (40 mL) and DCM
(3 × 40 mL). The organic extracts were dried with MgSO4, filtered
and the solvent removed under reduced pressure to give the title
compounds 3d (172 mg, 82 %) as a white solid. The mixture of
diastereomers (cis/trans; 60:40) proved to be chromatographically
inseparable. Rf = 0.55 (cHex/EtOAc; 3:1); IR (neat): νmax = 3032, 2951,
˜
2878, 2842, 1338, 1168, 1094, 1059, 962, 938, 816, 665, 585 cm–1
;
IR (neat): νmax = 3067, 2948, 1692, 1610, 1448, 1424, 1244, 1150,
HRMS (ES+) C13H18NO3SFNa (MNa+) calcd. 310.0889, found 310.0879
(–3.3 ppm); 1H NMR (400 MHz, CDCl3): δ = 1.20–1.28 (0.4H, m, CH2),
1.32–1.47 (1H, m, CH2), 1.61–1.68 (0.6H, m, CH2), 1.72–1.97 (2H, m,
CH2), 2.37–2.39 (3H, s, CH3), 2.86 (0.6H, dt, J = 3.0, 13.0 Hz, CH2),
3.07 (0.4H, dt, J = 3.0, 13.0 Hz, CH2), 3.29–3.42 (4H, m, CH2, CH3),
4.37 (0.6H, dddd, J = 3.5, 5.0, 12.0, 47.0 Hz, CH), 4.62 (0.4H, app. dq,
J = 2.5, 47.0 Hz, CH), 5.21 (0.4H, dd, J = 2.5, 7.0 Hz, CH), 5.27 (0.6H,
app. t, J = 3.0 Hz, CH), 7.23–7.29 (2H, m, ArH), 7.67 (1.2H, d, J =
8.5 Hz, ArH), 7.75 (0.8H, d, J = 8.5 Hz, ArH) ppm; 13C NMR (100 MHz,
CDCl3): δ = 18.1 (CH2), 21.4 (CH3), 23.3 (d, J = 10.0 Hz, CH2), 23.7 (d,
J = 20.0 Hz, CH2), 24.1 (d, J = 19.0 Hz, CH2), 39.25 (d, J = 1.5 Hz),
39.35 (CH2), 55.2 (CH3), 56.8 (d, J = 1.5 Hz, CH3), 83.8 (d, J = 31.0 Hz,
CH-trans), 84.1 (d, J = 24.5 Hz, CH-cis), 85.7 (d, J = 173.0 Hz, CH-
trans), 89.6 (d, J = 185.0 Hz, CH-cis), 127.0 (CH), 127.5 (d, J = 2.0 Hz,
CH), 129.4 (CH), 129.7 (CH), 137.3 (C), 137.5 (C), 143.3 (C), 143.7 (C)
ppm; 19F NMR (376 MHz, CDCl3): δ = –182.1 (0.6F, d, J = 47.0 Hz,
CF-cis), –188.4 to –188.8 (0.4F, m, CF-trans) ppm.
˜
1053, 957, 757, 738, 674 cm–1; HRMS (ES+) C23H24NO2FNa (MNa+)
calcd. 388.1689, found 388.1695 (+1.6 ppm); 1H NMR (500 MHz,
85 °C, [D6]DMSO): δ = 1.22–1.37 (1H, m, CH2), 1.39–1.48 (1H, m,
CH2), 1.53–1.91 (2H, m, CH2), 2.17–2.24 (1.4H, m, CH2), 2.31–2.43
(0.6H, m, CH2), 2.70 (0.6H, td, J = 3.0, 13.5 Hz, CH2), 2.86 (0.4H, td,
J = 3.0, 13.5 Hz, CH2), 3.66 (0.6H, d, J = 13.5 Hz, CH2), 3.86 (0.4H, d,
J = 13.5 Hz, CH2), 4.21–4.53 (3.6H, m, CH-cis, CH, CH2), 4.26 (1H, t,
J = 6.0 Hz, CH), 4.63 (0.4H, dd, J = 2.5, 47.0 Hz, CH-trans), 4.92 (0.6H,
d, J = 10.0 Hz, CH2), 4.99 (0.4H, d, J = 10.0 Hz, CH2), 5.03 (0.6H, d,
J = 17.0 Hz, CH2), 5.06 (0.4H, d, J = 16.5 Hz, CH2), 5.46–5.65 (1H, m,
CH), 7.28–7.35 (2H, m, ArH), 7.41 (2H, t, J = 7.5 Hz, ArH), 7.59–7.65
(2H, m, ArH), 7.85 (2H, d, J = 7.5 Hz, ArH) ppm; 13C NMR (125 MHz,
85 °C, [D6]DMSO): δ = 18.4 (CH2), 22.3 (d, J = 9.5 Hz, CH2), 23.6 (d,
J = 21.5 Hz, CH2), 24.4 (d, J = 18.5 Hz, CH2), 27.7 (CH2), 31.7 (d, J =
9.5 Hz, CH2), 36.8 (CH2), 37.7 (CH2), 46.6 (CH), 46.7 (CH), 52.6 (d, J =
24.5 Hz, CH), 54.0 (d, J = 21.0 Hz, CH), 65.9 (CH2), 66.0 (CH2), 87.9
(d, J = 172.0 Hz, CH), 88.1 (d, J = 179.5 Hz, CH), 116.3 (CH2), 116.7
(CH2), 119.4 (CH), 119.45 (CH), 124.25 (CH), 124.27 (CH), 124.3 (CH),
124.35 (CH), 126.5 (CH), 127.0 (CH), 133.6 (CH), 133.9 (CH), 140.41
(C), 140.43 (C), 140.5 (C), 143.5 (C), 143.55 (C), 154.3 (CO), 154.6 (CO)
ppm; 19F NMR (470 MHz, 85 °C, [D6]DMSO): δ = –179.1 (0.6F, d, J =
47.5 Hz, CF-cis), –179.6 (0.4F, t, J = 44.0 Hz, CF-trans) ppm.
cis-(2R*,3R*)-2-Allyl-3-fluoro-1-tosylpiperidine
and
trans-
(2S*,3R*)-2-Allyl-3-fluoro-1-tosylpiperidine (5d): Under N2 a solu-
tion of 3d (cis/trans; 60:40–129 mg, 0.45 mmol, 1 equiv.) and allyltri-
methylsilane 4 (0.14 mL, 0.90 mmol, 2 equiv.) in dry DCM (20 mL)
was cooled to –78 °C (CO2(s)-acetone). Then TiCl4 (0.14 mL,
0.90 mmol, 2 equiv.) was added in a dropwise fashion. The mixture
was stirred for 18 h, during which period room temperature was
reached. DCM (15 mL) and sat. NaHCO3(aq) (15 mL) were added and
the resultant organic phase was further extracted with DCM (2 ×
15 mL). The combined organic extracts were dried with MgSO4,
filtered and the solvent removed under reduced pressure to afford
a crude mixture of the title compounds (cis/trans; 60:40) as a yellow
oil. The crude adducts were then further purified by flash column
chromatography (cHex/EtOAc; 5:1) to obtain the cis-5d (61 mg,
46 %) and then trans-5d (43 mg, 32 %) as white solids. Data for cis-
N-(5-Hydroxypentyl)-4-methylbenzenesulfonamide (7d):[20]
A
solution of 5-aminopentanol 6 (475 mg, 4.60 mmol, 1 equiv.) in
DCM (20 mL) was cooled to 0 °C (ice-water) and then treated se-
quentially with TsCl (877 mg, 4.60 mmol, 1 equiv.) and TEA (0.96 mL,
6.90 mmol, 1.5 equiv.). Stirring was continued at 0 °C for 1 h then at
room temperature for 17 h. TLC analysis (cHex/EtOAc; 1:1) indicated
consumption of the sulfonyl chloride. 1
M HCl (30 mL) was added
and the resultant aqueous layer was extracted with DCM (30 mL).
The combined organic layers were washed with water (50 mL) and
the organic phase was dried with MgSO4. The residue was purified
by flash column chromatography (cHex/EtOAc; 3:1) to give 7d
(978 mg, 83 %) as an off-white solid. Rf = 0.10 (cHex/EtOAc; 1:1); 1H
NMR (400 MHz, CDCl3): δ = 1.31–1.37 (2H, m, CH2), 1.44–1.53 (4H,
m, CH2), 2.43 (3H, s, CH3), 2.90 (2H, q, J = 7.0 Hz, CH2), 3.63 (2H, t,
J = 6.5 Hz, CH2), 4.76 (1H, s(br), NH), 7.31 (2H, d, J = 8.0 Hz, ArH),
7.75 (2H, d, J = 8.0 Hz, ArH) ppm.
5d: Rf = 0.55 (cHex/EtOAc; 3:1); IR (neat): νmax = 3076, 2953, 2928,
˜
2875, 1643, 1598, 1494, 1467, 1382, 1150, 1090, 1052, 952, 813, 719,
653 cm–1; HRMS (ES+) C15H20NO2SFNa (MNa+) calcd. 320.1096,
found 320.1083 (–4.2 ppm); 1H NMR (400 MHz, CDCl3): δ = 1.39–
1.53 (1H, m, CH2), 1.57–1.80 (2H, m, CH2), 1.82–1.97 (1H, m, CH2),
2.23–2.39 (2H, m, CH2), 2.42 (3H, s, CH3), 2.79–2.93 (1H, m, CH2),
3.70 (1H, d, J = 14.5 Hz, CH2), 4.28–4.37 (1H, m, CH), 4.38–4.63 (1H,
m, CH), 4.92–4.98 (1H, m, CH2), 5.02 (1H, ddd, J = 1.5, 3.0, 17.0, CH2),
1-Tosyl-1,2,3,4-tetrahydropyridine (1d):[20] At room temperature
a solution of 7d (329 mg, 1.28 mmol, 1 equiv.) in DCM (20 mL) was 5.56–5.70 (1H, m, CH), 7.27 (2H, d, J = 8.5 Hz ArH), 7.70 (2H, d, J =
treated with Celite (0.5 g) and PCC (552 mg, 2.56 mmol, 2 equiv.).
Stirring was maintained for 18 h. The mixture was then filtered
through silica and washed with DCM (2 × 20 mL). The solvent was
removed under reduced pressure before the residue was purified
by flash column chromatography (cHex/EtOAc; 3:1). This gave 1d
(159 mg, 52 %) as a white solid. Rf = 0.60 (cHex/EtOAc; 1:1); 1H NMR
8.5 Hz, ArH) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.6 (CH3), 23.7
(d, J = 9.5 Hz, CH2), 25.3 (d, J = 19.0 Hz, CH2), 28.6 (d, J = 1.0 Hz,
CH2), 39.3 (d, J = 2.0 Hz, CH2), 55.3 (d, J = 24.0 Hz, CH), 88.8 (1H, d,
J = 182.5 Hz, CH), 117.9 (CH2), 127.1 (CH), 129.6 (CH), 134.1 (CH),
138.2 (C), 143.3 (C) ppm; 19F NMR (376 MHz, CDCl3): δ = –179.2 (d,
J = 47.5 Hz, CF) ppm. Data for trans-5d: Rf = 0.45 (cHex/EtOAc; 3:1);
Eur. J. Org. Chem. 0000, 0–0
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