Synthesis of Quinuclidines
1
821 cm–1. H NMR (400 MHz, CDCl3): δ = 8.53 (d, J = 4.4 Hz, 2 CDCl3): δ = 8.33 (d, J = 8.8 Hz, 1 H), 7.85 (d, J = 8.4 Hz, 1 H),
H), 7.25 (d, J = 4.4 Hz, 2 H), 3.02–2.97 (m, 1 H), 2.91 (dd, J = 7.80 (d, J = 8.3 Hz, 1 H), 7.63 (dd, J = 7.1, 1.0 Hz, 1 H), 7.59–7.50
12.6, 5.4 Hz, 1 H), 2.73–2.69 (m, 2 H), 2.42 (dd, J = 8.5, 2.5 Hz, 2
(m, 2 H), 7.42 (dd, J = 8.2, 7.2 Hz, 1 H), 3.10–3.05 (m, 1 H), 2.98
H), 2.05–2.00 (m, 1 H), 1.80 (br., 1 H), 1.67–1.59 (m, 3 H), 1.46– (dd, J = 12.8, 5.6 Hz, 1 H), 2.82–2.76 (m, 2 H), 2.59 (dd, J = 10.8,
1.41 (m, 1 H), 1.39–1.28 (m, 1 H), 0.96 (t, J = 7.4 Hz, 3 H) ppm. 2.0 Hz, 2 H), 2.15 (m, 1 H), 1.80–1.70 (m, 3 H), 1.53–1.42 (m, 3
13C NMR (100 MHz, CDCl3): δ = 149.3, 131.8, 125.4, 94.3, 79.1, H), 1.00 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
47.6, 44.5, 39.3, 37.4, 28.5, 21.0, 18.7, 11.7 ppm. HRMS (ESI): δ = 133.3, 133.0, 128.3, 127.1, 126.4, 125.1, 124.2, 121.5, 93.8, 79.5,
calcd. for C15H21N2 [M + H]+ 229.1699; found 229.1710.
47.7, 44.7, 39.4, 37.9, 30.2, 28.7, 23.8, 21.4, 18.8, 11.9 ppm. HRMS
(ESI): calcd. for C20H24N [M + H]+ 278.1903; found 278.1924.
(3R,4R)-3-Ethyl-4-(3-phenylprop-2-yn-1-yl)piperidine (31): Accord-
ing to the general procedure for Sonogashira coupling, alkyne 15
(500 mg, 1.98 mmol) was treated with iodobenzene (0.33 mL,
(3R,4R)-3-Ethenyl-4-(3-phenylprop-2-yn-1-yl)piperidine (33): Ac-
cording to the general procedure for Sonogashira coupling, alkyne
2.97 mmol), PdCl2(PPh3)2 (69 mg, 0.1 mmol), and CuI (38 mg, 17 (328 mg, 1.32 mmol) was treated with iodobenzene (0.22 mL,
0.2 mmol) in THF/Et3N (20 mL). The product was purified by
flash chromatography (petroleum ether/EtOAc, 20:1) to give 24
(520 mg, 1.58 mmol, 80%) as an orange oil. [α]D = +24.6 (c = 0.39,
1.98 mmol), Pd(Cl)2(PPh3)2 (46 mg, 0.067 mmol), and CuI (25 mg,
0.13 mmol) in THF/Et3N (13 mL). The product was purified by
flash column chromatography (petroleum ether/EtOAc, 20:1) to
CH Cl ). IR (neat): ν = 2968, 2930, 2873, 1689, 1426, 1365, 1242, give 26 (394 mg, 1.21 mmol, 92%) as an orange oil. [α]D = +81.7
˜
2
2
1137, 756 cm–1. H NMR (400 MHz, CDCl3): δ = 7.40 (m, 2 H), (c = 0.43, CH Cl ). IR (neat): ν = 2975, 2926, 2858, 2231, 1688,
1
˜
2
2
1
7.33–7.21 (m, 3 H), 4.06–3.99 (m, 1 H), 3.76 (br., 1 H), 3.08 (br., 1
H), 2.90 (m, 1 H), 2.39 (d, J = 7.5 Hz, 2 H), 1.98 (br., 1 H), 1.71 2 H), 7.31 (m, 3 H), 5.82 (m, 1 H), 5.25 (dd, J = 17.2, 1.2 Hz, 1
(br., 1 H), 1.61–1.54 (br., 2 H), 1.48 (s, 9 H), 1.32–1.20 (m, 2 H), H), 5.19 (dd, J = 10.4, 1.2 Hz, 1 H), 4.12 (br., 1 H), 4.05 (d, J =
1.02 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 12.2 Hz, 1 H), 3.02 (dd, J = 13.2, 2.9 Hz, 1 H), 2.83 (br., 1 H), 2.56
1422, 1391, 1165 cm–1. H NMR (400 MHz, CDCl3): δ = 7.42 (m,
155.0, 131.4, 128.5, 127.5, 123.7, 88.3, 81.7, 79.1, 46.2, 42.9, 39.3,
39.1, 28.3, 27.1, 23.1, 16.7, 12.2 ppm. HRMS (FAB): calcd. for
C21H30NO2 [M + H]+ 328.2277; found 328.2273.
(br., 1 H), 2.23 (d, J = 7.6 Hz, 2 H), 1.95 (m, 1 H), 1.63 (m, 1 H),
1.50 (s, 10 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 155.0, 134.7,
131.4, 128.1, 127.5, 123.7, 117.5, 88.3, 81.8, 79.3, 42.9, 42.0, 39.4,
39.0, 28.3, 27.2, 23.5 ppm.
According to the general procedure for Boc deprotection, 24
(484 mg, 1.48 mmol) was dissolved in CH2Cl2 (15 mL), and TFA According to the general procedure for Boc deprotection, 26
(1.5 mL) was added. After workup, 31 (326 mg, 1.43 mmol, 97%)
was obtained as an orange oil. [α]D = +11.3 (c = 0.56, CH2Cl2). IR
(240 mg, 0.74 mmol) was dissolved in CH2Cl2 (7 mL), and TFA
(0.7 mL) was added. After workup, free amine 33 (152 mg,
(neat): ν = 3279, 2957, 2922, 2872, 2227, 1571, 1490, 1462, 1263, 0.67 mmol, 91%) was obtained as an orange oil. [α]D = +80.5 (c =
˜
755, 719 cm–1. H NMR (400 MHz, CDCl3): δ = 7.43–7.39 (m, 2 0.76, CH Cl ). IR (neat): ν = 3293, 2920, 2225, 1689, 1490, 1441,
1
˜
2
2
H), 7.33–7.28 (m, 3 H), 3.00 (dd, J = 12.1, 4.0 Hz, 1 H), 2.94 (dd,
J = 12.1, 4.2 Hz, 1 H), 2.71 (dd, J = 12.3, 3.2 Hz, 2 H), 2.40 (dd,
J = 8.5, 3.0 Hz, 2 H), 2.02 (m, 1 H), 1.69–1.61 (m, 4 H), 1.46–1.35
756, 692 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.40 (m, 2 H),
7.30 (m, 3 H), 6.11 (ddd, J = 19.5, 17.1, 9.2 Hz, 1 H), 5.20 (m, 2
H), 3.15 (dt, J = 12.4, 5.0 Hz, 1 H), 3.06 (dd, J = 12.4, 3.2 Hz, 1
(m, 2 H), 0.96 (t, J = 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, H), 2.92 (dd, J = 12.4, 3.2 Hz, 1 H), 2.85 (br., 1 H), 2.75 (m, 1 H),
CDCl3): δ = 131.3, 128.0, 127.3, 123.8, 88.8, 81.4, 47.8, 44.7, 39.6,
37.8, 23.3, 21.1, 18.8, 11.9 ppm. HRMS (ESI): calcd. for C16H22N
[M + H]+ 228.1752; found 228.1750.
2.54 (m, 1 H), 2.32 (d, J = 8.0 Hz, 2 H), 1.97 (m, 1 H), 1.72 (m, 1
H), 1.53 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.0,
131.3, 128.0, 127.4, 123.7, 117.0, 88.5, 81.6, 50.9, 45.8, 42.2, 38.4,
28.2, 23.5 ppm. HRMS (ESI): calcd. for C16H20N [M + H]+
226.1590; found 226.1600.
(3R,4R)-3-Ethyl-4-[3-(1-naphthyl)prop-2-yn-1-yl]piperidine (32): Ac-
cording to the general procedure for Sonogashira coupling, alkyne
15 (500 mg, 1.98 mmol) was treated with 1-iodonaphthalene
(0.43 mL, 2.97 mmol), Pd(Cl)2(PPh3)2 (69 mg, 0.1 mmol), and CuI
(38 mg, 0.2 mmol) in THF/Et3N (20 mL). The product was purified
by flash column chromatography (petroleum ether/EtOAc, 20:1) to
4-[3-(Piperidin-4-yl)prop-1-yn-1-yl]-6-methoxyquinoline (34): Ac-
cording to the general procedure for Sonogashira coupling, alkyne
21 (283 mg, 1.27 mmol) was treated with 4-bromo-6-methoxyquin-
oline (450 mg, 1.91 mmol), Pd(Cl)2(PPh3)2 (35 mg, 0.064 mmol),
and CuI (25 mg, 0.13 mmol) in THF/Et3N (13 mL). The product
was purified by flash column chromatography (petroleum ether/
give 25 (654 mg, 1.73 mmol, 88%) as a viscous, orange oil. [α]D
=
+25.6 (c = 0.41, CH Cl ). IR (neat): ν = 2969, 2930, 2872, 1688,
˜
2
2
1426, 1325, 1166, 829, 799 cm–1. H NMR (400 MHz, CDCl3): δ = EtOAc, 4:1) to give 27 (0.45 g, 1.2 mmol, 95%) as an orange oil.
1
8.32 (dd, J = 8.1, 0.7 Hz, 1 H), 7.86 (d, J = 7.3 Hz, 1 H), 7.81 (d,
IR (neat): ν = 2974, 2928, 2851, 2223, 1688, 1618, 1580, 1423, 1365,
˜
J = 8.2 Hz, 1 H), 7.62 (dd, J = 7.1, 1.0 Hz, 1 H), 7.58 (m, 1 H), 1243, 1226, 1164, 848 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.71
7.54 (m, 1 H), 7.43 (dd, J = 8.2, 7.2 Hz, 1 H), 4.15–4.04 (m, 1 H), (d, J = 4.0 Hz, 1 H), 8.01 (d, J = 9.2 Hz, 1 H), 7.51 (d, J = 2.8 Hz,
3.86 (br., 1 H), 3.12 (br., 1 H), 3.01–2.87 (m, 1 H), 2.56 (d, J =
7.9 Hz, 2 H), 2.08 (m, 1 H), 1.81 (m, 1 H), 1.66–1.55 (m, 2 H), 1.49
(s, 9 H), 1.47–1.40 (m, 1 H), 1.33–1.26 (m, 1 H), 1.06 (t, J = 7.3 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 154.8, 133.2, 132.9,
129.9, 128.0, 127.8, 127.4, 126.0, 125.9, 125.0, 121.3, 93.2, 79.6,
78.9, 53.6, 46.0, 42.9, 39.2, 28.2, 27.1, 22.9, 16.5, 12.1 ppm. HRMS
(FAB): calcd. for C25H32NO2 [M + H]+ 378.244; found 378.2433.
1 H), 7.42–7.38 (m, 2 H), 4.17 (br., 2 H), 3.97 (s, 3 H), 2.77 (t, J =
11.6 Hz, 2 H), 2.59 (d, J = 6.4 Hz, 2 H), 1.92 (d, J = 11.5 Hz, 2
H), 1.85 (m, 1 H), 1.48 (s, 9 H), 1.44–1.31 (m, 2 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 158.2, 154.7, 146.9, 144.0, 131.1, 129.1,
128.6, 123.7, 122.3, 103.4, 97.7, 79.3, 78.3, 55.3, 35.6, 31.4, 28.3,
26.6 (carbons next to NBoc were not observed) ppm. HRMS
(FAB): calcd. for C23H29N2O3 [M + H]+ 381.2178; found 381.2175.
According to the general procedure for Boc deprotection, 25
According to the general procedure for Boc deprotection, 27
(130 mg, 0.34 mmol) was dissolved in CH2Cl2 (3 mL), and TFA (166 mg, 0.44 mmol) was dissolved in CH2Cl2 (4 mL), and TFA
(0.3 mL) was added. After workup, free amine 32 (90 mg,
0.32 mmol, 95%) was obtained as an orange oil. [α]D = +9.1 (c =
(0.4 mL) was added. After workup, free amine 34 (93 mg,
0.33 mmol, 75%) was obtained as an orange oil. IR (neat): ν =
˜
0.33, CH Cl ). IR (neat): ν = 3057, 2957, 2924, 2871, 1688, 1460,
3314, 2924, 2580, 2237, 1618, 1581, 1503, 1472, 1446, 1268, 1254,
˜
2
2
1439, 1200, 1175, 1135, 799, 774 cm–1. 1H NMR (400 MHz, 1228, 848 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.67 (d, J =
Eur. J. Org. Chem. 2014, 7413–7425
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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