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J. Faist et al. / Bioorg. Med. Chem. 18 (2010) 6796–6804
catalytic amount of KI to form 7b [0.282 g, 62%]. IR (KBr): 3058,
5.2.2. General procedure for the synthesis of (7RS,8RS)-( )-2-(x-
3026, 2932, 2851, 2799, 1636, 1496, 1423, 1155, 1118, 749,
alkylamino)-5-dialkylamino-7,8-diphenyl-2-azabicyclo[3.2.2]-
nonanes (9a–9c,10a–10c)
699 cmꢂ1. UV (CH2Cl2, nm, (log
e
)): 257 (3.567), 230 (3.815). (E)-
1
7b: H NMR (CDCl3, 400 MHz) d (ppm) 1.27–1.36 (m, 2H, 400-H),
1.37–1.46 (m, 4H, 300-H, 500-H), 1.67–1.86 (m, 5H, 20-H, (CH2)2),
1.97–2.25 (m, 11H, 20-H, 200-H, 30-H, 4-H, 6-H, 600-H, 9-H), 2.26–
2.40 (m, 2H, 30-H, 6-H), 2.67–2.81 (m, 4H, N(CH2)2), 3.23–3.31 (m,
1H, 7-H), 3.32–3.40 (m, 1H, 3-H), 3.48 (td, J = 10.0, 2.5 Hz, 1H, 8-
H), 3.99 (d, J = 2.5 Hz, 1H, 1-H), 4.43–4.50 (m, 1H, 3-H), 7.13–7.37
(m, 10H, aromatic H). 13C NMR (CDCl3, 100 MHz) d (ppm) 23.51
((CH2)2), 24.14 (C-400), 25.72 (C-300, C-500), 30.61 (C-4), 30.91 (C-20),
34.40 (C-9), 38.09 (C-6), 40.58 (C-8), 40.62 (C-3), 45.25 (N(CH2)2),
46.73 (C-7), 54.16 (C-200, C-600), 54.58 (C-30), 56.17 (C-5), 61.33
(C-1), 126.88, 126.96, 127.05, 127.69, 128.86, 129.12 (aromatic C),
142.23, 144.32 (aromatic Cq), 171.39 (CO). (Z)-7b: 1H NMR (CDCl3,
400 MHz) d (ppm) 1.39–1.48 (m, 2H, 400-H), 1.54–1.62 (m, 4H,
300-H, 500-H), 1.76–1.86 (m, 4H, (CH2)2), 1.86–1.95 (m, 2H, 4-H),
2.10–2.22 (m, 2H, 6-H, 9-H), 2.26–2.33 (m, 1H, 6-H), 2.36–2.53
(m, 6H, 200-H, 30-H, 600-H, 9H), 2.54–2.62 (m, 3H, 20-H, 30-H),
2.67–2.81 (m, 4H, N(CH2)2), 3.13 (td, J = 13.1, 3.4 Hz, 1H, 3-H),
3.21–3.29 (m, 1H, 7-H), 3.31–3.39 (m, 1H, 8-H), 3.81 (br d,
J = 13.9 Hz, 1H, 3-H), 5.07 (d, J = 2.8 Hz, 1H, 1-H), 7.13–7.37 (m,
8H, aromatic H), 7.57 (d, J = 7.7 Hz, 2H, aromatic H). 13C NMR (CDCl3,
100 MHz) d (ppm) 23.51 ((CH2)2), 24.22 (C-400), 25.93 (C-300, C-500),
32.07 (C-20), 32.18 (C-4), 34.64 (C-8), 36.00 (C-6), 36.66 (C-9),
42.54 (C-3), 45.10 (C-7), 45.19 (N(CH2)2), 54.52 (C-200, C-600), 54.82
(C-30), 55.49 (C-1), 56.79 (C-5), 126.14, 126.43, 127.75, 128.38,
128.48 (aromatic C), 143.14, 143.61 (aromatic Cq), 171.39 (CO).
HRMS (EI+) calcd for C32H43N3O: 485.3406; found: 485.3403.
The corresponding acylnonane was suspended in dry diethyl
ether and cooled with an ice-bath. Under stirring LiAlH4 was added
in portions. After 1 h the ice-bath was removed and the reaction
batch was refluxed at 55 °C overnight, cooled to room temperature
and was cautiously quenched with ice water. Then it was alkalized
with 2 N aq NaOH and extracted five times with ether. The com-
bined organic layers were washed with water until the aqueous
phase reacted neutral, dried over anhydrous sodium sulfate and fil-
tered. Finally the solvent was removed in vacuo giving compound
9a–9c, 10a–10c.
5.2.2.1.
(7RS,8RS)-( )-5-Dimethylamino-2-(4-ethylpiperazin-
The
1-yl)ethyl-7,8-diphenyl-2-azabicyclo[3.2.2]nonane (9a).
reaction of compound 6a [0.620 g, 1.27 mmol] and LiAlH4
[0.193 g, 4.93 mmol] in 45 mL dry diethyl ether gave after work-
up a residue 9a [0.547 g, 93%]. A small amount was purified for
analytical purposes by CC over aluminum oxide eluting with
CH2Cl2/MeOH (49:1). IR (KBr): 3083, 3024, 2941, 2808, 1653,
1600, 1494, 1450, 1269, 1165, 1128, 1033, 939, 757, 699 cmꢂ1
.
UV (CH2Cl2, nm, (log e
)): 234 (3.906). 1H NMR (CDCl3, 400 MHz)
d (ppm) 1.04 (t, J = 7.2 Hz, 3H, CH2–CH3), 1.84–1.90 (m, 2H, 4-H),
1.93 (dd, J = 13.4, 9.0 Hz, 1H, 6-H), 2.01–2.14 (m, 3H, 20-H, 9-H),
2.15–2.40 (m, 10H, 200-H, 300-H, 500-H, 6-H, 600-H, 9-H), 2.30 (s, 6H,
N(CH3)2), 2.35 (q, J = 7.2 Hz, 2H, CH2-CH3), 2.55 (t, J = 7.2 Hz, 2H,
10-H), 2.88 (ddd, J = 12.5, 6.5, 5.8 Hz, 1H, 3-H), 2.90 (d, J = 2.9 Hz,
1H, 1-H), 2.96 (ddd, J = 12.5, 6.4, 5.9 Hz, 1H, 3-H), 3.13 (td, J = 9.7,
2.5 Hz, 1H, 8-H), 3.48 (t, J = 9.0 Hz, 1H, 7-H), 7.11–7.38 (m, 10H,
aromatic H). 13C NMR (CDCl3, 100 MHz) d (ppm) 11.88 (CH2–
CH3), 31.34 (C-4), 35.06 (C-6), 37.38 (C-9), 37.95 (N(CH3)2), 38.07
(C-8), 40.27 (C-7), 48.00 (C-3), 52.20 (CH2-CH3), 52. 64 (C-300,
C-500), 53.37 (C-200, C-600), 55.01 (C-10), 57.00 (C-20), 57.44 (C-5),
68.50 (C-1), 125.78, 125.96, 127.49, 127.71, 128.48, 128.70 (aro-
matic C), 144.78, 145.87 (aromatic Cq). HRMS (EI+) calcd for
5.2.1.6. (7RS,8RS)-( )-1-(7,8-Diphenyl-5-piperidino-2-azabicy-
clo[3.2.2]non-2-yl)-3-piperidinopropan-1-one (7c). Compound
3c [0.457 g, 1.29 mmol] and triethylamine [0.196 g, 1.94 mmol] in
20 mL dry CH2Cl2 gave with chloropropionyl chloride [0.246 g,
1.94 mmol] the 3-chloropropionamide [0.358 g, 0.793 mmol, 61%]
which reacted with excess piperidine [1.35 g, 15.9 mmol] and a cat-
alytic amount of KI to form 7c [0.283 g, 71%]. IR (KBr): 3058, 3026,
2931, 2851, 2797, 1637, 1496, 1438, 1153, 1110, 758, 699 cmꢂ1. UV
C30H44N4: 460.3566; found: 460.3567.
(CH2Cl2, nm, (log
e
)): 259 (3.480), 230 (3.764). (E)-7c: 1H NMR
5.2.2.2. (7RS,8RS)-( )-2-(4-Ethylpiperazin-1-yl)ethyl-7,8-diphe-
nyl-5-pyrrolidino-2-azabicyclo[3.2.2]nonane (9b). The reac-
(CDCl3, 400 MHz) d (ppm) 1.28–1.36 (m, 2H, 400-H), 1.37–1.49 (m,
10H, 300-H, 500-H, 3CH2), 1.72–1.79 (m, 2H, 20-H), 1.83–1.90 (m, 1H,
6-H), 1.92–1.99 (m, 1H, 4-H), 1.99–2.10 (m, 4H, 200-H, 600-H), 2.10–
2.17 (m, 4H, 30H, 4-H, 9-H), 2.23–2.29 (m, 1H, 6-H), 2.32–2.40 (m,
1H, 30-H), 2.49–2.68 (m, 4H, N(CH2)2), 3.19–3.28 (m, 1H, 7-H),
3.29–3.38 (m, 1H, 3-H), 3.43 (td, J = 9.9, 2.5 Hz, 1H, 8-H), 3.99 (d,
J = 2.4 Hz, 1H, 1-H), 4.45–4.53 (m, 1H, 3-H), 7.13–7.36 (m, 10H, aro-
tion of compound 6b [0.840 g, 1.63 mmol] and LiAlH4 [0.168 g,
4.43 mmol] in 40 mL dry diethyl ether gave after work-up a residue
9b [0.700 g, 88%]. A small amount was purified for analytical pur-
poses by CC over aluminum oxide eluting with CH2Cl2/MeOH
(79:1). IR (KBr): 3058, 3024, 2936, 2806, 1600, 1493, 1449, 1165,
1031, 943, 756, 699 cmꢂ1. UV (CH2Cl2, nm, (log
e)): 233 (3.958).
13
matic H). C NMR (CDCl3, 100 MHz) d (ppm) 24.16 (C-400), 24.99
1H NMR (CDCl3, 400 MHz) d (ppm) 1.04 (t, J = 7.2 Hz, 3H, CH2–
CH3), 1.73–1.81 (m, 4H, (CH2)2), 1.97 (t, J = 6.0 Hz, 2H, 4-H), 2.00–
2.13 (m, 3H, 2-H, 6-H), 2.15–2.43 (m, 11H, 200-H, 300-H, 500-H, 6-H,
600-H, 9-H), 2.35 (q, J = 7.2 Hz, 2H, CH2–CH3), 2.55 (t, J = 7.2 Hz,
2H, 10-H), 2.71–2.79 (m, 4H, N(CH2)2), 2.90 (d, J = 2.8 Hz, 1H,
1-H), 2.89–3.00 (m, 2H, 3-H), 3.15 (td, J = 9.6, 2.4 Hz, 1H, 8-H),
3.50 (t, J = 9.2 Hz, 1H, 7-H), 7.11–7.39 (m, 10H, aromatic H). 13C
NMR (CDCl3, 100 MHz) d (ppm) 11.91 (CH2–CH3), 23.64 ((CH2)2),
33.77 (C-4), 35.77 (C-6), 37.17 (C-9), 38.06 (C-8), 40.01 (C-7),
45.20 (N(CH2)2), 48.04 (C-3), 52.24 (CH2-CH3), 52.66 (C-300, C-500),
53.41 (C-200, C-600), 55.07 (C-10), 57.00 (C-20, C-5), 68.65 (C-1),
125.81, 125.98, 127.56, 127.74, 128.51, 128.75 (aromatic C),
144.76, 145.92 (aromatic Cq). HRMS (EI+) calcd for C32H46N4:
486.3723; found: 486.3730.
(CH2), 25.75 (C-300, C-500), 26.71 (2CH2), 30.63 (C-4), 30.95 (C-20),
33.52 (C-9), 37.27 (C-6), 40.99 (C-3), 41.14 (C-8), 46.41 (N(CH2)2),
46.85 (C-7), 54.17 (C-2000, C-600), 54.60 (C-30), 57.77 (C-5), 61.16 (C-
1), 126.81, 126.99, 127.03, 127.70, 128.89, 129.12 (aromatic C),
142.31, 144.38 (aromatic Cq), 171.38 (CO). (Z)-7c: 1H NMR (CDCl3,
400 MHz) d (ppm) 1.40–1.49 (m, 4H, 400-H, CH2), 1.54–1.67 (m,
8H, 300-H, 500-H, 2CH2), 1.77–1.87 (m, 1H, 4-H), 1.93–2.08 (m, 2H,
4-H, 6-H), 2.09–2.13 (m, 1H, 9-H), 2.30–2.47 (m, 7H, 200-H, 30-H,
6-H, 600-H, 9-H), 2.49–2.71 (m, 7H, 20-H, 30-H, N(CH2)2), 3.11 (td,
J = 13.6, 3.4 Hz, 1H, 3-H), 3.16–3.23 (m, 1H, 7-H), 3.30–3.38 (m,
1H, 8-H), 3.80 (br d, J = 13.6 Hz, 1H, 3-H), 5.10 (d, J = 3.2 Hz, 1H,
1-H), 7.13–7.36 (m, 8H, aromatic H), 7.55 (d, J = 7.7 Hz, 2H, aromatic
13
H). C NMR (CDCl3, 100 MHz) d (ppm) 24.26 (C-400), 24.99 (CH2),
25.98 (C-300, C-500), 26.81 (2CH2), 31.86 (C-4), 32.15 (C-20), 35.03
(C-6), 35.29 (C-8), 36.18 (C-9), 42.72 (C-3), 45.41 (C-7), 46.32
(N(CH2)2), 54.55 (C-200, C-600), 54.86 (C-30), 55.30 (C-1), 58.27 (C-5),
126.18, 126.43, 126.51, 127.70, 128.41, 128.47 (aromatic C),
143.24, 143.62 (aromatic Cq), 170.52 (CO). HRMS (EI+) calcd for
5.2.2.3. (7RS,8RS)-( )-2-(4-Ethylpiperazin-1-yl)ethyl-7,8-diphe-
nyl-5-piperidino-2-azabicyclo[3.2.2]nonane (9c).
The reaction
of compound 6c [0.401 g, 0.758 mmol] and LiAlH4 [0.168 g,
4.43 mmol] in 40 mL dry diethyl ether gave after work-up pure
9c [0.348 g, 92%]. IR (KBr): 3058, 3024, 2929, 2806, 1600, 1494,
C33H45N3O: 499.3563; found: 499.3575.