5010
N. Willand et al. / Tetrahedron Letters 48 (2007) 5007–5011
Desmond, R.; Dolling, Ulf-H.; Frey, L.; Karady, S.; Shi,
2H), 2.10 (m, 2H), 1.55 (m, 2H); 13C NMR (CD2Cl2):
209.67, 139.76, 128.44, 128.28, 126.97, 58.67, 55.05, 48.20,
Y.-J.; Verhoeven, T. R. J. Org. Chem. 1995, 60, 4324–
4330; (c) Faul, M. M.; Kobierski, M. E.; Kopach, M. E. J.
Org. Chem. 2003, 68, 5739–5741; (d) Wichmann, J.;
Adam, G.; Ro¨ver, S.; Cesura, A. M.; Dautzenberg, F.
M.; Jenck, F. Bioorg. Med. Chem. Lett. 1999, 9, 2343–
2348.
27.79.
Compound
(3e):
Hydrochloride
salt:
[(M+H)+] = 222 (100%); 1H NMR (DMSO-d6): 12.65
and 12.08 (br s, 1H), 7.71 (d, 1H, J = 5.07 Hz), 7.61 (d,
1H, J = 2.55 Hz), 7.15 (dd, 1H, J = 5.07 Hz, J = 2.55 Hz),
4.90 and 4.52 (m, 2H), 4.04 (m, 2H), 3.40–3.10 (m, 2H),
2.47 (m, 4H), 1.87 (m, 2H); 13C NMR (DMSO-d6): 204.47,
132.88, 131.58, 129.80, 128.06, 59.88, 48.04, 46.40, 25.60.
Compound (3f): Hydrochloride salt [(M+H)+] = 217
(100%); 1H NMR (DMSO-d6): 9.04 (m, 2H), 9.62 (m,
2H), 4.78 (m, 2H), 4.12 (m, 2H), 3.35 (m, 2H), 2.51–2.35
(m, 4H), 1.88 (m, 2H); 13C NMR (DMSO-d6): 203.98,
149.28, 143.15, 129.07, 66.81, 65.37, 61.00, 45.94, 25.87.
Compound (3g): Hydrochloride salt. [(M+H)+] = 164
(100%); 1H NMR (DMSO-d6): 12.81 (br s, 1H, NH),
4.30–4.00 (m, 4H), 3.85 (s, 1H), 3.50–3.20 (m, 2H), 2.50–
2.20 (m, 4H), 1.88 (m, 2H); 13C NMR (DMSO-d6): 204.09,
81.09, 74.56, 60.64, 46.39, 25.53. Compound (3h):
[(M+H)+] = 292 (40%); 1H NMR (CD2Cl2): 7.64–7.58
(m, 4H), 7.39–7.21 (m, 6H), 4.61 (s, 1H), 3.50 (m, 2H),
2.72 (dd, 2H, J = 16.10 Hz, J = 4.41 Hz), 2.15 (m, 4H),
1.60 (m, 2H); 13C NMR (CD2Cl2): 209.95, 143.88, 128.68,
127.28, 127.19, 68.49, 56.85, 48.08, 27.71. Compound (3i):
[(M+H)+] = 264 (100%); 1H NMR (CD2Cl2): 7.32–7.20
(m, 4H), 3.52 (m, 2H), 2.81 (m, 4H), 2.62 (dd, 2H,
J = 16.00 Hz, J = 4.41 Hz), 2.14 (d, 2H, J = 16.00 Hz),
2.00 (m, 2H), 1.60 (m, 2H); 13C NMR (CD2Cl2): 209.32,
139.24, 130.22, 128.27, 58.88, 52.13, 47.49, 35.24, 27.83.
Compound (3j): 3j was recrystallized in EtOH. Mp: 119.9–
121.3 ꢁC; [(M+H)+] = 269 (100%); 1H NMR (CD2Cl2):
8.19 (br s, 1H), 7.52 (d, 1H, J = 8.4 Hz), 7.29 (d, 7.9 Hz),
7.15–6.95 (m, 3H), 3.53 (m, 2H), 2.98–2.80 (m, 4H), 2.60
(dd, 2H, J = 16,00 Hz, J = 4.41 Hz), 2.08 (d, 2H,
J = 16.00 Hz), 1.98 (m, 2H), 1.53 (m, 2H); 13C NMR
(CD2Cl2): 209.94, 136.35, 127.64, 121.93, 119.25, 118.76,
114.41, 111.19, 58.92, 51.19, 47.50, 28.05, 25.35. Com-
pound (3k): Hydrochloride salt. [(M+H)+] = 290 (100%);
1H NMR (DMSO-d6): 12.31 and 11.85 (br s, 1H, NH),
7.0–6.80 (m, 3H), 4.30–4.10 (m, 2H), 3.76 (s, 3H), 3.72 (s,
3H), 3.62 (m, 1H), 3.45–3.00 (m, 5H), 2.50–2.20 (m, 4H),
1.88 (m, 2H); 13C NMR (DMSO-d6): 204.44, 149.28,
148.17, 129.94, 121.19, 113.11, 112.48, 61.05, 56.02, 52.64,
46.46, 30.47, 26.71, 25.61. Compound (3l): Hydrochloride
3. (a) Robinson, R. J. Chem. Soc. 1917, 111, 762–768; (b)
Scho¨pf, C. Angew. Chem. 1937, 50(41), 797–805.
4. Novelli, F.; Sparatore, F. Il Farmaco 2003, 57, 871–882.
5. Momose, T.; Toshima, M.; Toyooka, N.; Hirai, Y.;
Eugster, C. H. J. Chem. Soc., Perkin Trans. 1 1997, 9,
1307–1313.
6. Bradley, A. L.; Izenwasser, S.; Wade, D.; Klein-Stevens,
C.; Zhu, N.; Trudell, M. L. Bioorg. Med. Chem. Lett.
2002, 12, 2387–2390.
7. Nicolaou, K. C.; Montagnon, T.; Baran, P. S.; Zhong, Y.
L. J. Am. Chem. Soc. 2002, 124, 2245–2258.
8. General procedure for the synthesis of ‘IDABO’: 8,8-
Dimethyl-3-oxo-8-azonia-bicyclo[3.2.1]octane
iodide
‘IDABO’ (2): Tropinone (5.2 g, 37.4 mmol, 1 equiv) is
dissolved in 37 mL of acetone under stirring. Methyl
iodine (2.5 mL, 41.2 mmol, 1.1 equiv) is added dropwise
for 45 min. The reaction is stirred at room temperature for
a further 1 h. The precipitate is filtered and washed with
acetone and with pentane/ethyl acetate solution. The
resulting solid is dried on P2O5 to give 5.61 g (92%) of a
white powder. LCMS: [M+] = 154 (100%); 1H NMR
(DMSO-d6, 300 MHz): 4.17 (m, 2H), 3.39 (s, 3H), 3.19 (s,
3H), 2.50 (m, 2H), 1.95 (m, 2H); 13C NMR (DMSO-d6;
75 MHz): 202.80, 68.66, 50.90, 44.87, 44.53, 26.41.
9. Representative procedure for the synthesis of 3a–r: 8-
Pyridin-2-ylmethyl-8-aza-bicyclo[3.2.1]octan-3-one (3a):
2-(Aminomethyl)pyridine (1.7 mL, 16.2 mmol, 1 equiv) is
dissolved in 38 mL of ethanol, K2CO3 (4.6 g, 34.0 mmol,
2.1 equiv) dissolved in 12 mL distilled water is added. The
resulting solution is refluxed. A solution of 8,8-dimethyl-
3-oxo-8-azonia-bicyclo[3.2.1]octane
iodide
(5.0 g,
17.8 mmol, 1.1 equiv) in 25 mL distilled water is added
dropwise for 45 min. The reaction media is refluxed a
further 4 h. The heating is stopped, the solution is reduced
under vacuum and the organic layer is extracted with
DCM (3 · 25 mL), washed with brine (2 · 15 mL), dried
over MgSO4 and reduced under vacuo to give a brown oil.
The residue is purified by flash chromatography on silica
gel using a mixture of cyclohexane/ethyl acetate (1/1) as
eluent to give a yellow oil (2.2 g, 68%). [(M+H)+] = 217
(100%); 1H NMR (CDCl3): 8.45 (d, 1H, J = 5.49 Hz), 7.62
(td, 1H, J = 7.55 Hz, J = 1.77 Hz), 7.51 (d, 1H,
J = 7.55 Hz), 7.12 (t, 1H, J = 5.49 Hz), 3.82 (s, 2H), 3.44
(m, 2H), 2.66 (dd, 2H, J = 16.01 Hz, J = 4.32 Hz), 2.13 (d,
2H, J = 16.01 Hz), 2.09 (m, 2H), 1.55 (m, 2H); 13C NMR
(CDCl3): 209.02, 158.30, 147.92, 135.63, 121.54, 121.04,
1
salt. LCMS: [(M+H)+] = 248 (100%); H NMR (DMSO-
d6): 12.35 and 11.95 (br s, 1H), 7.37 (m, 2H), 7.17 (m, 2H),
4.40–4.10 (m, 2H), 3.70–3.54 (m, 1H), 3.45–3.00 (m, 5H),
2.50–2.25 (m, 4H), 1.85 (m, 2H); 13C NMR (DMSO-d6):
204.41, 133.79, 131.20, 131.09, 115.94, 115.66, 61.01,
58.01, 52.33, 46.46, 42.49, 29.97, 26.72, 25.59. Compound
(3m): Hydrochloride salt. [(M+H)+] = 230 (100%); 1H
NMR (DMSO-d6): 12.35 and 11.95 (br s, 1H), 7.37–7.21
(m, 5H), 4.40–4.10 (m, 2H), 3.70–3.54 (m, 1H), 3.45–3.00
(m, 5H), 2.50–2.25 (m, 4H), 1.85 (m, 2H); 13C NMR
(DMSO-d6): 204.42, 137.62, 129.25, 129.07, 127.25, 61.00,
58.04, 52.36, 46.49, 42.48, 30.80, 25.59. Compound (3n):
Hydrochloride salt. [(M+H)+] = 236 (100%); 1H NMR
(DMSO-d6): 12.35 and 11.95 (br s, 1H), 7.48–7.35 (m, 1H),
7.10–6.95 (m, 2H), 4.40–4.10 (m, 2H), 3.80–3.00 (m, 6H),
2.50–2.25 (m, 4H), 1.85 (m, 2H); 13C NMR (DMSO-d6):
204.38, 139.19, 127.69, 126.47, 125.25, 61.12, 58.14, 52.14,
46.44, 42.51, 26.69, 25.61, 25.15. Compound (3o):
57.98,
55.96,
47.08,
26.79.
Compound
(3b):
[(M+H)+] = 217 (100%); 1H NMR (CD2Cl2): 8.54 (s,
1H), 8.43 (d, 1H, J = 3.83 Hz), 7.71 (d, 1H, J = 7.67 Hz),
7.21 (dd, 1H, J = 7.67 Hz, J = 4.67 Hz), 3.65 (s, 2H), 3.39
(m, 2H), 2.60 (dd, 2H, J = 16.01 Hz, J = 4.32 Hz), 2.13 (d,
2H, J = 16.01 Hz), 2.09 (m, 2H), 1.57 (m, 2H); 13C NMR
(CD2Cl2): 208.79, 148.85, 147.68, 135.21, 133.83, 122.48,
25
57.68, 51.74, 47.31, 26.73. Compound (3c): ½aꢀD ꢁ30.5
(MeOH); [(M+H)+] = 230 (100%); 1H NMR (CD2Cl2):
7.34–7.13 (m, 5H), 3.69 (q, 1H, J = 6.4 Hz), 3.54 (m, 1H),
3.39 (m, 1H), 2.56 (m, 2H), 2.02–1.89 (m, 4H), 1.47 (m,
2H), 1.34 (d, 3H, J = 6.4 Hz); 13C NMR (CD2Cl2): 209.76,
145.87, 128.46, 127.01, 56.68, 56.15, 56.03, 46.39, 28.39,
28.06, 23.10. Compound (3d): [(M+H)+] = 216 (100%); 1H
NMR (CD2Cl2): 7.50–7.25 (m, 5H), 3.70 (s, 2H), 3.50 (m,
2H), 2.70 (dd, 2H, J = 16.01 Hz, J = 4.32 Hz), 2.15 (m,
1
[(M+H)+] = 184 (100%); H NMR (DMSO-d6): 3.52 (m,
4H), 3.26 (s, 3H), 2.74 (t, 2H, J = 5.76 Hz), 2.60 (dd, 2H,
J = 16.11 Hz, J = 4.50 Hz), 2.01 (d, 2H, J = 16.11 Hz),
1.91 (m, 2H), 1.42 (m, 2H); 13C NMR (DMSO-d6): 209.53,
72.42, 59.16, 58.59, 48.99, 47.08, 28.20. Compound (3p):
[(M+H)+] = 306 (100%); 1H NMR (CD2Cl2): 7.30–7.10
(m, 8H), 6.91–6.84 (m, 2H), 3.88 (dd, 1H, J = 9.9 Hz,