C. G. Neochoritis, J. Stephanidou-Stephanatou, C. A. Tsoleridis
FULL PAPER
1-Acetyl-3-phenyl-3-azabicyclo[3.3.1]nonan-9-one
(3a):
Yield: ppm. 13C NMR (CDCl3): δ = 18.6 (Me), 20.2 (C-7), 20.7 (4Ј-Me),
0.231 g, 90% (93% in ethanol). Rf = 0.22 (PE/EtOAc, 10:1); oil.
1H NMR (CDCl3): δ = 1.62 (m, J = 13.1, 6.6, 5.8, 5.4, 2.8 Hz, 1 2), 63.2 (C-1), 119.9 (C-6Ј), 127.3 (C-5Ј),* 132.2 (C-3Ј),* 132.6 (C-
H, 7-Heq), 2.15–2.32 (m, 3 H, 6-CH2, 8-Heq), 2.28 (s, 3 H, COMe), 4Ј), 147.2 (C-1Ј), 207.2 (1-CO), 214.7 (C-9) ppm. * The assignments
28.0 (Me), 33.2 (C-6), 35.4 (C-8), 47.8 (C-5), 59.4 (C-4), 60.2 (C-
2.43 (m, J = 13.6, 11.6, 5.8, 2.3 Hz, 1 H, 8-Hax), 2.57 (m, J = 13.1, may be interchanged. IR (neat): ν = 1715, 1717 (C=O) cm–1. MS
˜
11.6, 11.5, 5.5, 4.5 Hz, 1 H, 7-Hax), 2.60 (m, J = 5.0, 4.2, 3.7,
2.5 Hz, 1 H, 5-Heq), 3.32 (ddd, J = 11.9, 3.7, 1.9 Hz, 1 H, 4-Hax),
3.52 (dd, J = 12.4, 2.0 Hz, 1 H, 2-Hax), 3.90 (ddd, J = 11.9, 2.5,
2.3 Hz, 1 H, 4-Heq), 3.96 (dd, J = 12.4, 2.3 Hz, 1 H, 2-Heq), 6.86
(tt, J = 7.3, 1.1 Hz, 1 H, 4Ј-H), 6.94 (m, J = 8.3, 1.75, 1.1, 0.5 Hz,
2 H, 2Ј-H, 6Ј-H), 7.27 (m, J = 8.3, 7.3, 2.6, 0.5 Hz, 2 H, 3Ј-H, 5Ј-
H) ppm. 13C NMR (CDCl3): δ = 19.9 (C-7), 28.0 (Me), 34.0 (C-6),
36.5 (C-8), 47.4 (C-5), 56.5 (C-4), 57.7 (C-2), 62.6 (C-1), 116.3 (C-
2Ј, C-6Ј), 119.8 (C-4Ј), 129.2 (C-3Ј, C-5Ј), 149.5 (C-1Ј), 206.9 (1-
(LCMS): m/z (%) = 308 (100) [M + Na]+·. C18H23NO2 (285.38):
calcd. C 75.76, H 8.12, N 4.91; found C 75.92, H 8.00, N 4.80.
1-Acetyl-3-(4-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(3e):
Yield: 0.263 g, 90% (92% in ethanol). Rf = 0.32 (PE/EtOAc, 10:1);
1
yellow solid, m.p. 79–80 °C. H NMR (CDCl3): δ = 1.60–1.70 (m,
1 H, 7-Heq), 2.15–2.35 (m, 3 H, 6-CH2, 8-Heq), 2.30 (s, 3 H, Me),
2.40–2.52 (m, 1 H, 8-Hax), 2.50–2.63 (m, 1 H, 7-Hax), 2.60–2.65 (m,
1 H, 5-Heq), 3.33 (dd, J = 11.9, 3.3 Hz, 1 H, 4-Hax), 3.52 (dd, J =
12.4, 1.9 Hz, 1 H, 2-Hax), 3.87 (ddd, J = 11.9, 2.4, 2.2 Hz, 1 H, 4-
Heq), 3.92 (ddd, J = 12.4, 2.4, 2.0 Hz, 1 H, 2-Heq), 6.87 (m, J =
8.60, 2.5, 2.0, 0.5 Hz, 2 H, 2Ј-H, 6Ј-H), 7.23 (m, J = 8.60, 2.5, 2.0,
0.5 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR (CDCl3): δ = 19.9 (C-7),
28.1 (Me), 34.1 (C-6), 36.5 (C-8), 47.2 (C-5), 56.5 (C-4), 57.6 (C-
2), 60.2 (C-1), 117.4 (C-2Ј, C-6Ј), 124.7 (C-4Ј), 129.1 (C-3Ј, C-5Ј),
CO), 213.9 (C-9) ppm. IR (neat): ν = 1712, 1718 (C=O) cm–1. MS
˜
(LCMS): m/z (%) = 312 (50) [M + MeOH + Na]+·, 280 (100) [M
+ Na]+·. C16H19NO2 (257.33): calcd. C 74.68, H 7.44, N 5.44; found
C 74.25, H 7.33, N 5.57.
1-Acetyl-3-(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one (3b):
148.0 (C-1Ј), 207.1 (C-1), 213.7 (C-9) ppm. IR (KBr): ν = 1710,
˜
Yield: 0.256 g, 89% (91% in ethanol). Rf = 0.24 (PE/EtOAc, 10:1);
1716 (C=O) cm–1. MS (LCMS): m/z (%) = 314/316 (100) [M +
Na]+·. C16H18ClNO2 (291.77): calcd. C 65.86, H 6.22, N 4.80;
found C 65.68, H 6.43, N 4.67.
1
oil. H NMR (CDCl3): δ = 1.65 (m, J = 13.1, 6.1, 4.5, 3.0, 3.0 Hz,
1 H, 7-Heq), 2.15–2.35 (m, 3 H, 6-CH2, 8-Heq), 2.29 (s, 3 H,
COMe), 2.44 (m, J = 13.7, 11.6, 6.1, 1.7 Hz, 1 H, 8-Hax), 2.60 (m,
J = 4.5, 3.5, 3.0, 3.0 Hz, 1 H, 5-Heq), 2.68 (m, J = 13.1, 11.6, 11.1,
6.0, 5.1 Hz, 1 H, 7-Hax), 3.30 (ddd, J = 11.5, 3.0, 1.2 Hz, 1 H, 4-
Hax), 3.48 (dd, J = 12.2, 1.7 Hz, 1 H, 2-Hax), 3.75 (ddd, J = 11.5,
3.0, 2.2 Hz, 1 H, 4-Heq), 3.77 (s, 3 H, OMe), 3.81 (dd, J = 12.2,
2.2 Hz, 1 H, 2-Heq), 6.86 (m, J = 8.8, 2.7, 2.4, 0.5 Hz, 2 H, 3Ј-H,
1-Acetyl-3-(4-bromophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(3f):
Yield: 0.303 g, 89% (91% in ethanol). Rf = 0.32 (PE/EtOAc, 10:1);
white crystals; m.p. 76–78 °C (diethyl ether/PE). 1H NMR (CDCl3):
δ = 1.60–1.70 (m, 1 H, 7-Heq), 2.17–2.29 (m, 3 H, 6-CH2, 8-Heq),
2.30 (s, 3 H, COMe), 2.40–2.58 (m, 2 H, 7-Hax, 8-Hax), 2.59–2.65
(m, 1 H, 5-Heq), 3.33 (ddd, J = 11.8, 3.3. 0.8 Hz, 1 H, 4-Hax), 3.52
(dd, J = 12.1, 2.0 Hz, 1 H, 2-Hax), 3.88 (ddd, J = 11.8, 2.2, 2.1 Hz,
1 H, 4-Heq), 3.93 (ddd, J = 12.1, 2.2, 2.0 Hz, 1 H, 2-Heq), 6.82 (m,
J = 8.7, 3.3, 2.4, 0.5 Hz, 2 H, 2Ј-H, 6Ј-H), 7.36 (m, J = 8.7, 3.3,
2.4, 0.5 Hz, 2 H, 3Ј-H, 5Ј-H) ppm. 13C NMR (CDCl3): δ = 19.8
(C-7), 28.1 (Me), 34.0 (C-6), 36.5 (C-8), 47.2 (C-5), 56.3 (C-4), 57.4
(C-2), 62.3 (C-1), 111.9 (C-4Ј), 117.7 (C-2Ј, C-6Ј), 132.0 (C-3Ј, C-
5Ј-H), 6.92 (m, J = 8.8, 2.7, 2.4, 0.5 Hz, 2 H, 2Ј-H, 6Ј-H) ppm. 13
C
NMR (CDCl3): δ = 20.1 (C-7), 28.1 (Me), 34.0 (C-6), 36.4 (C-8),
47.5 (C-5), 55.6 (OMe), 58.0 (C-4), 59.1 (C-2), 62.7 (C-1), 114.6
(C-3Ј, C-5Ј), 118.6 (C-2Ј, C-6Ј), 143.8 (C-1Ј), 154.0 (C-4Ј), 207.2
(1-CO), 214.4 (C-9) ppm. IR (neat): ν = 1717, 1704 (C=O) cm–1.
˜
MS (LCMS): m/z (%) = 342 (80) [M + Na + MeOH]+·, 310 (100)
[M + Na]+·. C17H21NO3 (287.35): calcd. C 71.06, H 7.37, N 4.87;
found C 71.25, H 7.43, N 4.67.
5Ј), 148.4 (C-1Ј), 207.0 (1-CO), 213.6 (C-9) ppm. IR (KBr): ν =
˜
1700, 1714 (C=O) cm–1. MS (LCMS): m/z (%) = 358/360 (100) [M
+ Na]+·. C16H18BrNO2 (336.22): calcd. C 57.16, H 5.40, N 4.17;
found C 56.97, H 5.29, N 4.03.
1-Acetyl-3-(4-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(3c):
Yield: 0.239 g, 88% (91% in ethanol). Rf = 0.24 (PE/EtOAc, 9:1);
oil. 1H NMR (CDCl3): δ = 1.58–1.72 (m, 1 H, 7-Heq), 2.20–2.35
(m, 3 H, 6-CH2, 8-Heq), 2.28 (s, 3 H, Me), 2.30 (s, 3 H, Me), 2.39–
2.52 (m, 1 H, 8-Hax), 2.56–2.70 (m, 1 H, 7-Hax), 2.58–2.63 (m, 1
H, 5-Heq), 3.32 (dd, J = 11.8, 3.3 Hz, 1 H, 4-Hax), 3.50 (dd, J =
12.2, 1.9 Hz, 1 H, 2-Hax), 3.87 (ddd, J = 11.8, 2.3, 2.0 Hz, 1 H, 4-
Heq), 3.91 (dd, J = 12.2, 2.3 Hz, 1 H, 2-Heq), 6.88 (m, J = 8.2, 2.4,
1.9, 0.5 Hz, 2 H, 2Ј-H, 6Ј-H), 7.11 (m, J = 8.2, 2.4, 1.9, 0.5 Hz, 2
H, 3Ј-H, 5Ј-H) ppm. 13C NMR (CDCl3): δ = 20.0 (C-7), 20.4 (Me),
28.1 (Me), 34.1 (C-6), 36.5 (C-8), 47.5 (C-5), 57.0 (C-4), 58.1 (C-
2), 62.7 (C-1), 116.6 (C-2Ј, C-6Ј), 129.5 (C-4Ј), 129.8 (C-3Ј, C-5Ј),
Reaction of 4-Methoxyaniline, Formaldehyde and 2-Acetylcyclo-
hexanone: A formaldehyde solution (37% in water, 9 mmol) was
added to a solution of 4-methoxyaniline (2b, 1.0 mmol) in ethanol
(15 mL), and the mixture was warmed gently for 5 min to dissolve
all the reactants. 2-Acetylcyclohexanone (2.0 mmol) was added,
and the mixture was heated under reflux for 5 min and was then
stirred at room temperature overnight. The solvent was distilled
off, and the resulting residue was subjected to column chromatog-
raphy on silica gel with PE/EtOAc (10:1) as eluent to give, in elu-
tion order:
147.3 (C-1Ј), 207.3 (1-CO), 214.4 (C-9) ppm. IR (neat): ν = 1713,
˜
1718 (C=O) cm–1. MS (LCMS): m/z (%) = 326 (60) [M + Na +
MeOH]+·, 294 (100) [M + Na]+·. C17H21NO2 (271.35): calcd. C
75.25, H 7.80, N 5.16; found C 75.06, H 7.93, N 5.29.
(i)
1-Acetyl-3-(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(3b): Yield 0.014 g (73%).
(ii) 1-Acetyl-3-(4-methoxyphenyl)-5-{[(4-methoxyphenyl)amino]-
1-Acetyl-3-(2,4-dimethylphenyl)-3-azabicyclo[3.3.1]nonan-9-one (3d): methyl}-3-azabicyclo[3.3.1]nonan-9-one (4b): Yield: 0.093 g, 22%. Rf
Yield: 0.254 g, 89% (91% in ethanol). Rf = 0.30 (PE/EtOAc, 10:1);
= 0.11 (PE/EtOAc, 10:1); oil. 1H NMR (CDCl3): δ = 1.62–1.72 (m,
oil. 1H NMR (CDCl3): δ = 1.62–1.75 (m, 1 H, 7-Heq), 2.08–2.17 1 H, 7-Heq), 2.12–2.23 (m, 2 H, 6-CH2), 2.24–2.32 (m, 1 H, 8-Heq),
(m, 1 H, 6-H), 2.17–2.25 (m, 2 H, 6-H, 8-Heq), 2.27 (s, 3 H, Me), 2.30 (s, 3 H, COMe), 2.40–2.51 (m, 1 H, 8-Hax), 2.65–2.80 (m, 1
2.28 (s, 3 H, Me), 2.41 (s, 3 H, 2Ј-Me), 2.33–2.45 (m, 1 H, 8-Hax),
H, 7-Hax), 3.12 (d, J = 13.1 Hz, 1 H, NCH), 3.15 (d, J = 13.1 Hz,
2.59–2.65 (m, 1 H, 5-Heq), 2.85–3.05 (m, 1 H, 7-Hax), 3.27 (ddd, J 1 H, NCH), 3.31 (dd, J = 11.5, 1.0 Hz, 1 H, 4-Hax), 3.55 (dd, J =
= 11.5, 3.8, 0.8 Hz, 1 H, 4-Hax), 3.36 (ddd, J = 12.5, 2.4, 1.2 Hz, 1
H, 2-Hax), 3.43 (dd, J = 11.5, 1.0 Hz, 1 H, 4-Heq), 3.45 (dd, J =
11.5, 1.0 Hz, 1 H, 2-Hax), 3.64 (dd, J = 11.5, 2.1 Hz, 1 H, 4-Heq),
3.74–3.79 (m, masked by OMe signals, 2 H, 2-Heq, NH), 3.75 (s, 3
12.5, 1.0 Hz, 1 H, 2-Heq), 7.01 (dd, J = 9.0, 1.8 Hz, 1 H, 5Ј-H), H, OMe), 3.77 (s, 3 H, OMe), 6.61 (m, J = 8.4, 3.2, 2.4, 0.5 Hz, 2
7.01 (d, J = 9.0 Hz, 1 H, 6Ј-H), 7.03 (d, J = 1.8 Hz, 1 H, 3Ј-H) H, 2ЈЈ-H, 6ЈЈ-H), 6.78 (d, J = 8.4, 3.2, 2.4, 0.5 Hz, 2 H, 3ЈЈ-H, 5ЈЈ-
5342
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 5336–5346