B. A. Czeskis
2226. UV (EtOH, l max, nm): 271 (e 12197). MS (ES+): 257 (M + 1 + NH3). bisulfate (2 mL) and extracted with ethyl acetate (20 mL). The extract was
MS (ES-): 238 (M-1). Analysis calculated for: C13H5D9N2O2: C, 65.27; washed with brine, dried over sodium sulfate, and evaporated under vacuum.
H, 6.12; N, 11.71. Found: C, 65.44; H, 6.05; N, 11.61.
Biotage chromatography of the residue (12M column, eluting with hexanes/
ethyl acetate, 30:70), gave 2 (56 mg, 44%) as a white solid, identical (TLC, NMR)
to an authentic sample of 2. TLC: Rf 0.38 (hexanes/ethyl acetate 30:70).
1H-NMR (CDCl3): 1.37 (m, 2H), 1.60–1.90 (m, 9H), 2.15 (m, 2H), 3.18 (m, 1H),
3-Cyclopentyl indole, 3 (from nitrile 5)
A mixture of nitrile 5 (291 mg, 1.26 mmol), 10% palladium on carbon 3.35 (m, 4H), 4.00 (m, 2H), 6.15 (br.s, 1H), 7.30 (m, 3H), 7.56 (d, J=7.9 Hz, 1H),
(50 mg) and acetic acid (1.2 mL) in ethanol (5 mL) was vigorously stirred 7.79 (d, J=8.3 Hz, 2H), 7.92 (d, J=8.3 Hz, 2H), 8.00 (d, J=8.3 Hz, 1H). MS
under atmospheric pressure of hydrogen for 18 hours, then diluted with (ES+): 467 (M + 1). MS (ES-): 465 (M-1).
ethyl acetate (5 mL) and filtered. The filtrate was evaporated under
vacuum and subjected to Biotage chromatography on a 12M column.
Eluting with hexanes/ethyl acetate (85:15) gave 3-cyclopentyl indole (3)
1-(4-(Tetrahydropyran-4-ylmethylaminocarbonyl)
phenylsulfonyl)-3-nonadeuteriocyclopentyl indole, 2-d9
(126 mg, 54%) as a white solid. TLC: Rf 0.41 (hexanes/ethyl acetate
90:10). 1H-NMR (CDCl3): 1.76 (m, 4H), 1.85 (m, 2H), 2.21 (m, 2H), 3.31
In the same manner as described earlier, starting from deuteriocyclopentyl
(m, 1H), 7.01 (s, 1H), 7.14 (td, J = 7.9 and 0.9 Hz, 1H), 7.22 (td, J = 7.9 and
0.9 Hz, 1H), 7.38 (dd, J = 7.9 and 0.9 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.90
(br.s, 1H). IR (KBr, n, cm-1): 493, 575, 743, 810, 1011, 1100, 1230, 1340,
1422, 1457, 1484, 1622, 2861, 2955, 3055, 3403. UV (EtOH, lmax, nm):
223 (e 32567), 282 (e 5846). MS (ES+): 186 (M + 1). MS (ES-): 184 (M-1).
Analysis calculated for: C13H15N: C, 84.28; H, 8.16; N, 7.56. Found:
C, 84.06; H, 8.12; N, 7.61.
indole 3-d9 (73 mg, 0.376 mmol), potassium tert-butoxide (51 mg,
0.454 mmol) and sulfonyl chloride 4b (130 mg, 0.409 mmol) in tetrahydro-
furan (2.8 mL), 2-d9 (60 mg, 34%) was obtained as a white solid. TLC: the same
as the one for 2. 1H-NMR (CDCl3): 1.37 (m, 2H), 1.65 (m, 2H), 1.87 (m, 1H), 3.38
(m, 4H), 3.99 (m, 2H), 6.14 (br.s, 1H), 7.30 (m, 3H), 7.55 (d, J=7.9 Hz, 1H), 7.79
(d, J= 8.3 Hz, 2H), 7.93 (d, J= 8.3 Hz, 2H), 7.99 (d, J= 8.3 Hz, 1H). IR (KBr, n, cm-1):
569, 613, 745, 857, 980, 1011, 1093, 1128, 1179, 1302, 1373, 1447, 1541,
1646, 2105, 2223, 2843, 2928, 3428. UV (EtOH, l max, nm): 253. MS (ES+):
476 (M+ 1). MS (ES-): 474 (M-1). Analysis calculated for: C26H21D9N2O4S:
C, 65.66; H, 6.36; N, 5.89. Found: C, 65.36; H, 6.34; N, 5.70.
3-Nonadeuteriocyclopentyl indole, 3-d9
In the same manner as described earlier, starting from nitrile (5-d9)
(193 mg, 0.81 mmol), 10% palladium on carbon (30 mg) and acetic acid
(0.8 mL) in ethanol (3 mL), deuteriocyclopentyl indole 3-d9 (89 mg, 57%)
was obtained as a colorless solid. TLC: the same as the one for 3.
1H-NMR (CDCl3): 7.01 (s, 1H), 7.14 (td, J = 7.9 and 0.9 Hz, 1H), 7.22 (td,
J = 7.9 and 0.9 Hz, 1H), 7.38 (dd, J = 7.9 and 0.9 Hz, 1H), 7.70 (d, J = 7.9
Hz, 1H), 7.90 (br.s, 1H). IR (KBr, n, cm-1): 493, 575, 743, 816, 1011, 1099,
1247, 1333, 1417, 1456, 2100, 2222, 3403. UV (EtOH, l max, nm): 223
(e 22415), 282 (e 5828), 290 (e 5138). MS (ES+): 195 (M + 1). MS (ES-):
193 (M-1). Analysis calculated for: C13H6D9N: C, 80.39; H, 7.78; N, 7.21.
Found: C, 79.72; H, 7.85; N, 7.20.
N-Formyl-2-(cyclopentylcarbonyl)aniline, 12
To
a
solution of 3-cyclopentyl indole
3 (370 mg, 2.0 mmol) in
methanol (40 mL),
a
solution of sodium periodate (1.70 g,
7.95 mmol) in water (17 mL) was added. The reaction mixture was
stirred at room temperature for 16 hours and evaporated under
vacuum at room temperature to remove methanol. The residue
was diluted with saturated aqueous sodium bicarbonate (5 mL) and
water (5 mL), extracted with ethyl acetate (20 mL), and filtered. The
organic layer was separated and washed with brine (3 mL). The
combined aqueous layers were re-extracted with ethyl acetate
(10 mL). The combined organic extracts were dried over sodium sulfate
and evaporated under vacuum. Biotage (40S) chromatography (eluting
with hexane/ethyl acetate 85:15) gave ketone 12 (328 mg, 75%) as a
4-(Tetrahydropyran-4-ylmethylaminocarbonyl)
phenylsulfonyl chloride, 4b
1
yellow oil. TLC: Rf 0.37 (hexanes/ethyl acetate 80:20). H-NMR (CDCl3): 1.7
To
a solution of 4-aminomethyltetrahydropyran (300 mg, 2.6mmol),
(m, 4H), 1.9 (m, 4H), 3.78 (quint, J= 7.5 Hz, 1H), 7.17 (t, J = 7.9 Hz, 1H), 7.55
(t, J= 7.5 Hz, 1H), 7.96 (d, J = 7.9 Hz, 1H), 8.48 (s, 1H), 8.73 (d, J = 8.4 Hz, 1H),
11.67 (s, 1H). IR (KBr, n, cm-1): 750, 992, 1210, 1295, 1452, 1513, 1579,
1652, 1700, 2863, 2953, 3245. UV (EtOH, lmax, nm): 230 (e 25086), 260
(e 11695), 319 (e 4684). HRMS (AP+) calculated for C13H15NO2: 217.1103.
Found: 217.1120. Analysis calculated for C13H15NO2: C, 71.87; H, 6.96;
N, 6.45. Found: C, 71.76; H, 6.69; N, 6.23.
triethylamine (400 mL, 2.87 mmol) and 4-dimethylaminopyridine
(15 mg. 0.12 mmol) in tetrahydrofuran (4 mL) at À78ꢀC, a solution of
4-chloroformylphenylsulfonyl chloride (623 mg, 2.6 mmol) in tetrahy-
drofuran (5 mL) dropwise was added. The reaction mixture was
allowed to reach 0ꢀC, stirred for 3 hours at this temperature, then
diluted with 1 N-hydrochloric acid (2 mL) and extracted with ethyl
acetate (10 mL). The extract was washed with brine, dried over
sodium sulfate, and evaporated under vacuum to give phenylsulfonyl
chloride 4b (760 mg, 92%) as a white solid (used in the next step
without further purification). 1H-NMR (CDCl3): 1.43 (m, 2H), 1.70
(m, 2H), 1.95 (m, 1H), 3.43 (m, 4H), 4.03 (m, 2H), 6.35 (br.s, 1H),
7.69 (d, J = 8.3 Hz, 0.5H), 7.78 (d, J = 8.3 Hz, 0.5H), 7.90 (d, J = 8.3 Hz,
0.5H), 8.01 (d, J = 8.3 Hz, 1H), 8.07 (d, J = 8.3 Hz, 0.5H), 8.14
(d, J = 8.3 Hz, 1H). IR (KBr, n, cm-1): 564, 558, 625, 692, 807, 855,
904, 984, 1012, 1046, 1092, 1116, 1143, 1173, 1239, 1292, 1378,
3-Cyclopentyl indole, 3 (from ketone 12)
(a) With isolation of amino alcohol 13:
To a solution of ketone 12 (221 mg, 1.02 mmol) in 95% ethanol (3 mL),
a solution of potassium cyanide (66 mg, 1.01 mmol) in water (0.25 mL)
1445, 1487, 1546, 1600, 1648, 1727, 1799, 2693, 2717, 2761, 2846, and ethanol (2.5 mL) was added. The reaction mixture was stirred at
2930, 3092, 3339. UV (EtOH, l max, nm): 230 (e 14962). MS (ES+): 318
(M+ 1). MS (ES-): 316 (M-1). Analysis calculated for: C13H16ClNO4S: C, 49.13;
H, 5.07; N, 4.41. Found: C, 50.10; H, 5.20; N, 4.33.
room temperature for 4 hours and evaporated under vacuum to leave
amino alcohol 13 as a white solid. TLC: Rf 0.50 (dichlomethane/
methanol/ammonium hydroxide 85:15:1.5). 1H-NMR (CD3OD): 0.72
(m, 1H), 1.3–1.6 (m, 5H), 1.84 (q, J = 7.2 Hz, 2H), 2.38 (quint, J = 8.5 Hz,
1H), 6.88 (td, J = 7.5 and 0.9 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 7.16 (td,
J = 7.5 and 1.3 Hz, 1H), 7.28 (d, J = 7.5 Hz, 1H), 8.55 (s, 1H). MS (ES+):
217 (M + 1). MS (ES-): 215 (M-1).To a solution of amino alcohol 13 in
tetrahydrofuran (3 mL) and acetic acid (3 mL) at 0–5ꢀC (ice bath),
sodium borohydride (190 mg, 5.0 mmol) in portions over the period of
10 minutes was added. The reaction mixture was stirred for 2 hours
and treated at 0–5ꢀC (ice bath) by slow addition of 2N-hydrochloric
1-(4-(Tetrahydropyran-4-ylmethylaminocarbonyl)
phenylsulfonyl)-3-cyclopentyl indole, 2
To a solution of 3-cyclopentyl indole (3) (50 mg, 0.27 mmol) and potassium
tert-butoxide (37 mg, 0.33 mmol) in tetrahydrofuran (2 mL) at 0–5ꢀC (ice bath),
a solution of sulfonyl chloride 4b (94 mg, 0.3 mmol) in tetrahydrofuran
(0.5 mL) was added. The reaction mixture was allowed to reach room
temperature, stirred for 16 hours, then diluted with aqueous 10% sodium
J. Label Compd. Radiopharm 2012, 55 171–176
Copyright © 2012 John Wiley & Sons, Ltd.