Organic Process Research & Development
Article
1140, 1127, 1119, 1100, 1088, 1077, 1065, 1029, 991, 970, 940,
911, 831, 814, 777, 745, 693, 618, 546, 514, 501, 441, 421, 405;
1H NMR (400 MHz, CDCl3) δH 1.72 (2H, m), 1.81 (2H, m),
1.90 (2H, t, J = 6.3), 2.56 (4H, m), 3.54 (2H, s), 3.63 (2H, s),
3.79 (3H, s), 3.86 (2H, t, J = 6.3), 6.84 (2H, m), 7.25 (3H, m),
7.29 to 7.32 (3H, m); 13C NMR (100 MHz, CDCl3) δC 31.05,
35.79, 55.24, 59.14, 63.08, 114.00, 127.00, 128.23, 129.13,
129.32, 130.06, 138.29, 158.67; MS (EI, 70 eV), m/z 372 (M +
H), 218, 211, 207, 188, 174, 160, 128, 121, 110, 98, 91, 56.
2-(1-Benzyl-4-((2,4,6-trimethylbenzyl)thio)piperidin-4-yl)-
ethanol, 18e. Reduction of 17e (free base) gave the title
compound as a cream-colored solid (98%). Mp 115−116 °C;
IR (Nujol) 3131, 2930, 1611, 1455, 1377, 1334, 1312, 1266,
1235, 1200, 1150, 1118, 1105, 1090, 1055, 1002, 977, 964, 921,
1458, 1417, 1377, 1348, 1307, 1252, 1213, 1153, 1074, 1038,
1003, 940, 930, 891, 844, 825, 816, 771, 752, 743, 711, 635,
583, 520, 482, 467; 1H NMR (400 MHz, CDCl3) δH 2.09 (6H,
m), 2.28 (3H, s), 3.67 (2H, s), 3.83 (6H, m), 5.00 (2H, s), 7.05
(2H, d, J = 7.9), 7.14 (2H, d, J = 8.0), 7.33 to 7.41 (3H, m),
7.61 (2H, m); 13C NMR (100 MHz, CDCl3) δC 21.00, 30.30,
31.55, 37.97, 54.36, 66.71, 127.16, 128.63, 129.10, 129.31,
130.43, 133.32, 133.90, 136.98; MS (EI, 70 eV), m/z 338 (M+),
233, 205, 172, 110, 105, 91.
1-Benzyl-4-((4-methoxybenzyl)thio)quinuclidin-1-ium
Chloride, 19d. Reaction of 18d gave the title compound as a
white solid (67%) after trituration with THF. Mp 121−123 °C;
IR (Nujol) 3575, 3339, 3266, 3033, 2924, 2853, 2099, 1902,
1655, 1608, 1582, 1513, 1491, 1461, 1446, 1424, 1380, 1344,
1305, 1253, 1242, 1218, 1181, 1136, 1101, 1070, 1036, 1014,
929, 839, 821, 777, 755, 736, 714, 700, 632, 600, 483, 523, 473,
429; 1H NMR (400 MHz, CDCl3) δH 2.09 (6H, m), 3.70 (2H,
s), 3.75 (3H, s), 3.86 (6H, m), 5.01 (2H, s), 6.78 (2H, m), 7.21
(2H, m), 7.37 (3H, m), 7.61 (2H, m); 13C NMR (100 MHz,
CDCl3) δC 30.29, 31.78, 37.93, 54.36, 55.22, 66.71, 114.05,
127.14, 128.82, 129.11, 129.87, 130.44, 133.31, 158.77; MS (EI,
70 eV), m/z 354 (M+), 233, 205, 172, 121, 110, 91.
1
853, 826, 777, 746, 709, 619, 576, 470; H NMR (400 MHz,
CDCl3) δH 1.78 (2H, m), 1.88 (2H, m), 1.96 (2H, t, J = 6.4),
2.24 (3H, s), 2.37 (6H, s), 2.59 (4H, m), 3.54 (2H, s), 3.63
(2H, s), 3.95 (2H, t, J = 6.4), 6.83 (2H, s), 7.25 to 7.32 (5H,
m); 13C NMR (100 MHz, CDCl3) δC 19.47, 20.87, 25.89,
35.73, 47.05, 49.08, 59.35, 63.16, 127.01, 128.20, 129.09,
129.63, 136.69, 136.99, 138.30; MS (EI, 70 eV), m/z 384 (M +
H), 252, 218, 207, 188, 174, 160, 133, 128, 116, 110, 91, 56.
General Method for the Preparation of 1-Benzyl-4-
(alkylthio)quinuclidin-1-ium Chlorides, 19. Methanesul-
fonyl chloride (6.0 mL, 79 mmol) was added dropwise to a
stirred solution of the alcohol 18 (70.4 mmol) and DIPEA
(15.4 mL, 88 mmol) in DCM (200 mL) under nitrogen at
ambient. The reaction mixture was heated to reflux and stirred
for 5 h. The reaction mixture was cooled to room temperature,
and brine (200 mL) was added. The organic phase was
separated, and the aqueous was washed with DCM (100 mL).
The combined organic phases were washed with brine (100
mL) and dried (Na2SO4), and the solvent was removed under
vacuum to give the crude title compound.
1-Benzyl-4-((2,4,6-trimethylbenzyl)thio)quinuclidin-1-ium
Chloride, 19e. Reaction of 18e gave the title compound as a
white solid (92%) after trituration with THF. Mp 239−242 °C;
IR (Nujol) 3380, 2925, 2725, 1612, 1582, 1461, 1377, 1342,
1
1213, 1158, 1076, 1038, 932, 851, 765, 709, 633, 561, 495; H
NMR (400 MHz, DMSO) δH 2.18 (9H, m), 2.29 (6H, s), 3.70
(2H, s), 3.55 (6H, m), 3.75 (2H, s), 4.52 (2H, s), 6.80 (2H, s),
7.54 (5H, bs); 13C NMR (100 MHz, CDCl3) δC 18.86, 25.71,
29.28, 37.76, 54.12, 65.97, 127.63, 128.67, 128.92, 129.25,
130.17, 133.00, 135.98, 136.52; MS (EI, 70 eV), m/z 366 (M+),
233, 205, 172, 148, 133, 110, 91.
General Method for the Preparation of 1-Benzyl-4-
(alkylthio)quinuclidines, 20. A suspension of the quinucli-
dinium salt 19 (56.8 mmol) in 20% sodium hydroxide (50 mL)
and thiophenol (11.5 mL, 115 mmol) was heated to 90−100
°C and stirred until reaction was complete (6 h). The reaction
mixture was cooled to ambient, diluted with water (200 mL),
and extracted with ethyl acetate (2 × 200 mL). The combined
organic extracts were washed with water (150 mL) followed by
1 M hydrochloric acid (2 × 120 mL). The organic phase was
discarded, the acidic aqueous phase was basified with 1 M
sodium hydroxide (300 mL) and extracted with ethyl acetate (2
× 200 mL). The combined organic extracts were dried
(Na2SO4), and the solvent was removed under vacuum to
afford the crude product 20.
The following compounds were prepared according to this
procedure.
1-Benzyl-4-(cyclohexylthio)quinuclidin-1-ium Chloride,
19a. Reaction of 18a gave the title compound as a white
solid (87%) after column chromatography (40% MeOH in
DCM). Mp 78−81 °C; IR (Nujol) 2926, 2850, 1494, 1457,
1376, 1345, 1263, 1215, 1073, 1039, 1000, 928, 884, 842, 817,
771, 709, 631, 475; 1H NMR (400 MHz, CDCl3) δH 1.17 (1H,
m), 1.27 (4H, m), 1.51 (1H, m), 1.66 (2H, m), 1.83 (2H, m),
2.10 (6H, m), 2.65 (1H, m), 3.83 (6H, m), 4.98 (2H, s), 7.33−
7.41 (3H, m), 7.61 (2H, m); 13C NMR (100 MHz, CDCl3) δC
25.21, 26.01, 30.90, 35.88, 37.99, 40.69, 54.37, 66.73, 127.19,
129.25, 130.76. 133.31; MS (EI, 70 eV), m/z 316 (M+), 234,
200, 110, 91.
The following compounds were prepared according to this
procedure.
1-Benzyl-4-(phenylthio)quinuclidin-1-ium Chloride, 19b.
Reaction of 18b gave the title compound as a white solid
(67%) after triturating with THF. IR (Nujol) 3384, 3324, 3229,
2924, 2856, 1619, 1584, 1571, 1499, 1464, 1410, 1376, 1343,
1306, 1066, 1053, 1032, 1004, 974, 919, 842, 774, 758, 710,
704, 696, 651, 632, 582, 546, 507, 466, 424, 412; 1H NMR (400
MHz, CDCl3) δH 2.05 (6H, m), 3.83 (6H, m), 5.06 (2H, s),
7.31−7.42 (8H, m), 7.60 (2H, m); 13C NMR (100 MHz,
CDCl3) δC 30.40, 40.22, 54.54, 66.74, 127.13, 128.20, 129.15,
129.28, 130.05, 130.51, 133.36, 137.58; MS (EI, 70 eV), m/z
310 (M+), 110, 91, 56.
4-(Cyclohexylthio)quinuclidine, 20a. Reaction of 19a gave
the title compound as a pale-green oil (55%) which crystallised
on standing. Mp 49−52 °C; IR (Nujol) 2901, 1451, 1377,
1350, 1312, 1259, 1198, 1171, 1118, 1052, 1009, 997, 971, 924,
1
883, 855, 825, 818, 763, 743, 698, 647, 517; H NMR (400
MHz, CDCl3) δH 1.22 (1H, m), 1.33 (4H, m), 1.54 (1H, m),
1.71 (8H, m), 1.89 (2H, m), 2.76 (1H, m), 2.91 (6H, m); 13C
NMR (100 MHz, CDCl3) δC 25.46, 26.28, 33.36, 36.28, 39.08,
40.51, 48.66; MS (EI, 70 eV), m/z 226 (M + 1), 144, 115, 87.
4-(Phenylthio)quinuclidine, 20b. Reaction of 19b gave the
title compound as a white solid (64%). Mp 75−76 °C, IR
(Nujol) 3073, 3057, 2938, 2866, 1581, 1571, 1472, 1452, 1436,
1377, 1353, 1313, 1259, 1168, 1150, 1064, 1053, 1024, 1007,
998, 970, 922, 826, 784, 758, 705, 696, 648, 513, 435; 1H NMR
1-Benzyl-4-((4-methylbenzyl)thio)quinuclidin-1-ium Chlor-
ide, 19c. Reaction of 18c gave the title compound as a pale
brown solid (90%) after trituration with toluene. Mp 213−218
°C; IR (Nujol) 3472, 3387, 2928, 2855, 1614, 1515, 1496,
K
dx.doi.org/10.1021/op300263w | Org. Process Res. Dev. XXXX, XXX, XXX−XXX