10.1002/chem.201801140
Chemistry - A European Journal
FULL PAPER
overhead stirrer. The reaction mixture was vigorously stirred at 95 ºC for
12 h, then diluted with water (5 volumes), extracted with ethyl acetate (4
times). The combined organic layers were washed with brine (4 times),
dried over Na2SO4, filtered and concentrated under reduced pressure.
The desired compound was purified by flash chromatography (gradient,
hexane/methyl tert-butyl ether).
General procedure for chlorination. A solution of thioacetate
(0.10 mol) in a mixture of CH2Cl2 (300 mL) and water (300 mL) was
bubbled by pure chlorine gas at 0-5 ºC until complete saturation. The
organic layer was separated and washed with a saturated solution of
sodium thiosulfate until the complete neutralization of chlorine (Caution!
Exothermic!), washed with brine, dried over Na2SO4 and concentrated
under reduced pressure. The final compound was purified by flash
chromatography (gradient, hexane/methyl tert-butyl ether).
General procedure for synthesis of suflonyl fluorides. To a
solution of sulfonyl chloride (0.10 mol) in dry CH3CN (500 mL) was added
18-crawn-6 (0.03 mol), KF (0.20 mol) with rapid stirring. The reaction
mixture was stirred at rt until 1H NMR analysis showed complete
consumption of starting material (~ 16 h); the mixture was then filtered
and concentrated under reduced pressure. The residue was dissolved in
a mixture of ethyl acetate (500 mL) and water (500 mL). The organic
layer was separated, washed with brine (4 × 200 mL), dried over Na2SO4
and concentrated under reduced pressure to afford the pure desired
compound.
tert-Butyl 4-(acetylthio) piperidine-1-carboxylate (1c): yield
20.0 g, 80%, orange oil. 1Н NMR (400 MHz, CDCl3) : 3.75-3.85 (br s,
2H), 3.68 (m, 1H), 3.08 (m, 2H), 2.28 (s, 3H), 1.85 (m, 2H), 1.53-1.38 (m,
2H), 1.39 (s, 9H). 13С NMR (125 MHz, CDCl3) : 196.2, 154.7, 79.8, 43.9-
43.5, 40.3, 32.0, 31.9, 28.6. MS (APEI) m/z [M] calculated for
C12H21NO3S: 259.1; found: 259 (M, 98.64%). Anal. calcd. for
C12H21NO3S: C, 55.57; H, 8.16; N, 5.40; S, 12.36. Found: C, 55.40; H,
8.44; N, 5.50; S, 12.16.
was stirred 0.5 h and 2-fluoro-3-nitropyridine (0.42 g, 2.96 mmol, 0.9
equiv) was added in one portion. The mixture was left overnight at rt. The
solvent was removed under reduced pressure, and the resulting solid
residue was washed with water, dried to give the desired compound as a
1
yellow solid (0.82 g, 2.83 mmol, 96%), mp 96-97 ºC. H NMR (400 MHz,
CDCl3) δ: 8.37 (br s, 1H), 8.30 – 8.01 (m, 1H), 7.06 – 6.60 (m, 1H), 3.99
(d, J = 12.0 Hz, 2H), 3.69 – 3.49 (m, 1H), 3.11 (t, J = 12.1 Hz, 2H), 2.32
(d, J = 11.4 Hz, 2H), 2.22 – 2.05 (m, J = 11.4 Hz, 2H). 19F NMR (376
MHz, CDCl3) δ: 41.8. 13C NMR (101 MHz, CDCl3) δ: 152.7, 152.1, 135.9,
133.8, 115.0, 58.9 (d, J = 15.0 Hz), 47.1, 25.9. MS (APCI) m/z [M+H]+
calculated for C10H13FN3O4S: 290.1; found: 290.1 (M+H, 97%). Anal.
calcd. for C10H12FN3O4S: C, 41.52; H, 4.18; N, 14.53; S, 11.08. Found: C,
41.16; H, 4.33; N, 14.69; S, 10.86.
1-Benzylpiperidine-4-sulfonyl fluoride (17). 8e (0.50 g, 2.46
mmol, 1 equiv) was suspended in CH2Cl2 (30 mL) and DIPEA (0.40 mL,
2.48 mmol, 1 equiv) was added followed by benzyl chloride (3.8 g, 2.48
mmol, 1 equiv) at rt. The resulting mixture was stirred 0.5 h and
NaBH(OAc)3 (0.90 g, 4.24 mmol, 1.7 equiv) was added in portions. The
mixture was stirred overnight at rt. The mixture was diluted with water
and partitioned. The organic layer was additionally washed with brine,
dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by flash chromatography (gradient,
CHCl3/MTBE) to afford the desired compound as a yellow oil (0.50 g,
1.94 mmol, 79%). 1H NMR (400 MHz, CDCl3) δ: 7.57 – 6.90 (m, 5H),
3.52 (s, 2H), 3.34 – 3.22 (m, 2H), 3.09 – 2.98 (m, 1H), 2.22 – 2.13 (m,
2H), 2.10 – 1.93 (m, 4H). 19F NMR (376 MHz, CDCl3) δ: 41.4. 13C NMR
(101 MHz, CDCl3) δ: 137.8, 129.0, 128.5, 127.4, 62.6, 59.2 (d, J = 14.1
Hz), 51.7, 26.3. MS (APEI) m/z [M] calculated for C12H16FNO2S: 257.1;
found: 257.1 (M, 100%). Anal. calcd. for C12H16FNO2S: C, 56.01; H, 6.27;
N, 5.44; S, 12.46. Found: C, 56.21; H, 6.15; N, 5.69; S, 12.71.
1-(p-Tolylcarbamoyl)azetidine-3-sulfonyl fluoride (18). 2f (0.50
g, 2.80 mmol,
1 equiv) was suspended in CH2Cl2 (30 mL) and
triethylamine (0.72 g, 7.13 mmol, 2.5 equiv), p-methylbenzenesulfonyl
chloride (0.54 g, 2.80 mmol, 1 equiv) were added at rt. The reaction
solution was stirred overnight. The resulting mixture was partitioned
between CH2Cl2-H2O, the organic layer was additionally washed with
brine, dried over Na2SO4, filtered and concentrated under reduced
pressure to give the title compound as a white solid (0.70 g, 2.39 mmol,
83%), mp 146-148 ºC. 1H NMR (500 MHz, CDCl3) δ: 7.74 (d, J = 7.8 Hz,
2H), 7.41 (d, J = 7.9 Hz, 2H), 4.25 (m, 3H), 4.18 – 4.07 (m, 2H), 2.48 (s,
3H). 19F NMR (376 MHz, CDCl3) δ: 46.4. 13C NMR (125 MHz, CDCl3) δ:
145.4, 130.9, 130.3, 128.5, 51.4, 47.1 (d, J = 22.2 Hz), 21.8. MS (APCI)
m/z [M-H]- calculated for C10H11FNO4S2: 292.0; found: 292 (M-H, 100%).
Anal. calcd. for C10H12FNO4S2: C, 40.95; H, 4.12; N, 4.78; S, 21.86.
Found: C, 41.15; H, 4.22; N, 4.91; S, 22.68.
(9H-fluoren-9-yl) methyl 4-((fluorosulfonyl) methyl) piperidine-
1-carboxylate (20). 4-((Fluorosulfonyl)methyl)piperidine hydrochloride
(6f) (0.50 g, 2.30 mmol, 1 equiv) and NaHCO3 (0.20 g, 2.30 mmol, 1
equiv) were suspended in a mixture of 20 mL of acetone and 20 mL of
water. Fmoc-OSu (0.78 g, 2.30 mmol, 1 equiv) was added slowly with
stirring, and the resulting mixture was stirred at rt overnight. The organic
phrase was separated, washed with brine, dried over Na2SO4, and
evaporated to dryness to give a white solid (0.92 g, 98%), mp 85-86 ºC.
1H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.9 Hz, 2H), 7.56 (d, J = 7.9
Hz, 2H), 7.41 (t, J = 7.2 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 4.48 (br s, 2H),
4.21 (t, J = 6.4 Hz, 2H), 4.02 (br s, 1H), 3.25 (s, 2H), 2.76 (t, J = 12.3 Hz,
2H), 2.30 – 2.09 (m, 1H), 1.90 (d, J = 12.8 Hz, 2H), 1.16 (br s, 2H). 19F
NMR (376 MHz, CDCl3) : 59.1. 13C NMR (101 MHz, CDCl3) δ: 155.1,
144.1, 141.5, 127.8, 127.2, 125.1, 120.1, 67.2, 56.6 (d, J = 14.3 Hz),
47.6, 43.5, 32.1, 31.0. Anal. calcd. for C21H22FNO4S: C, 62.52; H, 5.50;
N, 3.47; S, 7.95. Found: C, 62.73; H, 5.34; N, 3.65; S, 8.15.
tert-Butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (1d): yield
25.3 g, 89%, white solid, mp 83-84 ºC. 1Н NMR (400 MHz, CDCl3) : 4.25
(br s, 2H), 3.63 (m, 1H), 2.75 (br s, 2H), 2.38 (m, 2H), 1.85 (m, 2H), 1.45
(s, 9H). 13С NMR (125 MHz, CDCl3) : 184.3, 80.7, 72.9, 42.8-42.4, 28.4,
26.7. MS (APCI) m/z [M-H]- calculated for C10H18NO5S: 264.1; found: 264
(the sulfonic acid is registered, M-H, 100%). Anal. calcd. for
C10H18ClNO4S: C, 42.33; H, 6.39; Cl, 12.49; N, 4.94; S, 11.30. Found: C,
42.52; H, 6.11; Cl, 12.29; N, 4.78; S, 11.15.
tert-Butyl 4-(fluorosulfonyl)piperidine-1-carboxylate (1e): yield
24.3 g, 91%, white solid, mp 69-70 ºC. 1Н NMR (400 MHz, CDCl3) : 4.28
(br s, 2H), 3.48 (m, 1H), 2.79 (br s, 2H), 2.19 (m, 2H), 1.87 (m, 2H), 1.46
(s, 9H). 19F NMR (376 MHz, CDCl3) : 41.6. 13С NMR (125 MHz, CDCl3)
: 154.1, 80.5, 59.0 (d, J = 14.8 Hz), 42.5-41.7, 28.3, 25.9. MS (APCI)
m/z [M+H]+ calculated for C10H20NO5S: 266.1; found: 266 (the sulfonic
acid is registered, M+H, 100%). Anal. calcd. for C10H18FNO4S: C, 44.93;
H, 6.79; N, 5.24; S, 11.99. Found: C, 44.84; H, 6.89; N, 5.09; S, 12.11.
Piperidine-4-sulfonyl fluoride hydrochloride (1f): yield 19.1 g,
94%, white solid, mp 186-187 ºC (dec.). 1H NMR (400 MHz, D2O) δ: 4.27
– 4.17 (m, 1H), 3.67 (d, J = 13.3 Hz, 2H), 3.20 (t, J = 12.9 Hz, 2H), 2.58
(d, J = 14.3 Hz, 2H), 2.18-2.21 (m, 2H). 19F NMR (376 MHz, D2O) : 41.2.
13С NMR (101 MHz, D2O) : 55.5 (d, J = 14.0 Hz), 42.2, 22.7. MS Anal.
calcd. for C5H11ClFNO2S: C, 29.49; H, 5.44; Cl, 17.41; N, 6.88; S, 15.74.
Found: C, 29.37; H, 5.69; Cl, 17.70; N, 6.78; S, 15.48.
1-(2-(1H-indol-1-yl)propanoyl)piperidine-4-sulfonyl
fluoride
(15). Piperidine-4-sulfonyl fluoride hydrochloride (0.54 g, 2.65 mmol, 1
equiv) was suspended in CH2Cl2 (40 mL) and Et3N (1 mL, 7.16 mmol, 2.7
equiv) was added at rt. The resulting mixture was stirred 0.5 h and 2-(1H-
indol-1-yl) propanoic acid (0.50 g, 2.65 mmol, 1 equiv) and BOP (1 g,
2.26 mmol, 0.85 equiv) were added. The mixture was stirred overnight at
rt. The mixture was concentrated to dryness and used for the next step.
1-(3-Nitropyridin-2-yl)piperidine-4-sulfonyl fluoride (16). 1f
(0.66 g, 3.24 mmol, 1 equiv) was suspended in CH3CN (40 mL) and
DIPEA (1 mL, 6.12 mmol, 2 equiv) was added at rt. The resulting mixture
2-(1H-indol-1-yl)-1-(4-(pyrrolidin-1-ylsulfonyl)piperidin-1-
yl)propan-1-one (25). 1f (0.54 g, 2.65 mmol, 1 equiv) was suspended in
CH2Cl2 (40 mL) and Et3N (1 mL, 7.16 mmol, 2.7 equiv) was added at rt.
The resulting mixture was stirred 0.5 h and 2-(1H-indol-1-yl) propanoic
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