10170
A. Avenoza et al. / Tetrahedron 58 (2002) 10167–10171
4.2.2. (N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)phenyl-
ketone (4a). The residue was chromatographed on a silica
gel column, eluting with hexane/ethyl acetate (7:3), to yield
97% of compound 4a as white solid. Mp: 155–1578C.
ESIþ(m/z)¼306.5. Anal. calcd for C20H19NO2; C, 78.66; H,
30.1 (C2, C3, C5, C6); 62.7 (C4); 73.1 (C1); 123.6, 128.3,
128.4, 131.8, 135.8 142.2, 149.4, 152.6, 159.9 (Arom.);
194.9 (CO).
4.2.7. Methyl N-benzyl-7-azabicyclo[2.2.1]heptane-1-
carboxylate (6). Acetyl chloride (107 mL, 1.5 mmol) was
added dropwise to methanol (10 mL) at 08C. The mixture
was stirred for 10 min and amino acid hydrochloride 5
(200 mg, 1.03 mmol) was added. The resulting solution was
stirred at 608C for 12 h. The solvent was removed, the
residual oil suspended in diethyl ether (20 mL) and the
solvent evaporated again. The solvent addition/evaporation
was repeated twice more and the methyl ester was obtained
1
6.27; N, 4.59; found C, 78.98; H, 6.15; N, 4.71. H NMR
(CDCl3): d 1.60–1.72 (m, 2H); 1.86–2.20 (m, 4H); 2.42–
2.58 (m, 2H); 4.40–4.47 (m, 1H, H4); 7.35–7.50 (m, 6H,
Arom.); 7.64–7.72 (m, 2H, Arom.); 8.20–8.27 (m, 2H,
Arom.). 13C NMR (CDCl3): d 30.0, 32.7 (C2, C3, C5, C6);
62.7 (C4); 73.0 (C1); 128.1, 128.2, 128.3, 128.4, 131.5,
132.3, 134.6, 135.7 (Arom.); 172.9 (CON); 196.1 (CO).
1
4.2.3. 1-(N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)-sec-
butylketone (4b). The residue was chromatographed on a
silica gel column, eluting with hexane/ethyl acetate (6:4), to
as a pure, colourless oil. H NMR (CD3OD) d 1.79–1.86
(m, 2H); 2.05–2.13 (m, 6H); 4.16–4.20 (m, 1H, H4); 3.79
(s, 3H, CO2CH3); 13C NMR (CD3OD) d 30.7, 31.6 (C2, C3,
C5, C6); 55.8, 62.7 (CO2CH3, C4); 74.8 (C1); 172.1
(CO2CH3). The methyl ester hydrochloride was dissolved
in dry acetonitrile (25 mL) under an argon atmosphere and
BnBr (178 mL, 1.5 mmol) and DIEA (434 mL, 2.5 mmol)
were added to the mixture. The reaction mixture was stirred
at 508C for 24 h. The solvent was removed and the residual
solid was dissolved in CH2Cl2. The resulting suspension
was washed with saturated aqueous NaHCO3 (2£30 mL)
and brine (30 mL), dried and the solvent was evaporated to
give an oil, which was purified by column chromatography
(hexane/ethyl acetate, 1:1) to give 6 (96 mg, 78%) as a
colourless oil. ESIþ(m/z)¼246.6. Anal. calcd for
C15H19NO2; C, 73.44; H, 7.81; N, 5.71; found C, 73.61;
yield 51% of compound 4b as
a colourless oil.
ESIþ(m/z)¼286.6. Anal. calcd for C18H23NO2; C, 75.76;
H, 8.12; N, 4.91; found C, 75.57; H, 8.01; N, 4.85. 1H NMR
(CDCl3): d 0.93 (t, 3H, J¼7.5 Hz); 1.19 (d, 3H, J¼6.6 Hz);
1.30–1.62 (m, 3H); 1.66–2.05 (m, 5H); 2.30–2.41 (m, 2H);
2.86–2.96 (m, 1H); 4.20–4.27 (m, 1H, H4); 7.36–7.50 (m,
3H, Arom.); 7.64–7.71 (m, 2H, Arom.). 13C NMR (CDCl3):
d 11.6, 16.7, 26.9, 30.5, 30.6, 31.5, 31.9, 43.8 (2CH3, CH,
CH2, C2, C3, C5, C6); 62.2 (C4); 73.2 (C1); 128.3, 128.5,
131.4, 134.7 (Arom.); 173.0 (CON); 211.3 (CO).
4.2.4. 1-(N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)-tert-
butylketone (4c). The residue was chromatographed on a
silica gel column, eluting with hexane/ethyl acetate (8:2), to
yield 99% of compound 4c as white solid. Mp: 150–1548C.
ESIþ(m/z)¼286.6. Anal. calcd for C18H23NO2; C, 75.76; H,
1
H, 7.74; N, 5.82. H NMR (CDCl3): d 1.33–1.45 (m, 2H);
1.66–1.79 (m, 2H); 1.84–1.96 (m, 2H); 2.09–2.19 (m, 2H);
3.24–3.32 (m, 1H, H4); 3.56 (br s, 2H, CH2Ph); 3.68 (s, 3H,
CO2CH3); 7.21–7.41 (m, 5H, Arom.). 13C NMR (CDCl3): d
28.0, 32.7 (C2, C3, C5, C6); 50.2, 51.8, 59.6 (CH2Ph,
CO2CH3, C4); 71.0 (C1); 126.7, 128.1, 128.8, 139.6
(Arom.); 173.6 (CO2CH3).
1
8.12; N, 4.91; found C, 75.94; H, 8.23; N, 4.83. H NMR
(CDCl3): d 1.30 (s, 9H); 1.49–1.56 (m, 2H); 1.65–2.08 (m,
4H); 2.30–2.47 (m, 2H); 4.21–4.28 (m, 1H, H4); 7.35–7.50
(m, 3H, Arom.); 7.58–7.65 (m, 2H, Arom.). 13C NMR
(CDCl3): d 28.2 [C(CH3)3]; 29.9, 32.1 (C2, C3, C5, C6); 44.6
[C(CH3)3]; 61.9 (C4); 73.3 (C1); 128.1, 128.4, 131.3, 134.9
(Arom.); 173.3 (CON); 212.0 (CO).
4.2.8. (N-Benzyl-7-azabicyclo[2.2.1]hept-1-yl)-diphenyl-
methanol (7) and (N-benzyl-7-azabicyclo[2.2.1]hept-1-
yl)-phenylketone (8). The reaction was carried out follow-
ing the general procedure (Method B) for acylation of the
organolithium. The mixture was purified by column
chromatography (hexane/ethyl acetate, 1:1) to give 7 as an
oil and 8 as a mixture with compound 7. Data for compound
7: ESIþ(m/z)¼370.5. Anal. calcd for C26H27NO; C, 84.51;
H, 7.37; N, 3.79; found C, 84.72; H, 7.23; N, 3.68. 1H NMR
(CDCl3): d 1.22–1.44 (m, 4H); 1.78–1.86 (m, 2H); 2.30–
2.42 (m, 2H); 3.10–3.17 (m, 1H, H4); 3.58 (br s, 2H,
CH2Ph); 7.16–7.34 (m, 12H, Arom.); 7.74–7.80 (m, 3H,
Arom.). 13C NMR (CDCl3): d 28.1, 32.3 (C2, C3, C5, C6);
50.1, 58.8 (CH2Ph, C4); 74.7, 79.6 (COH, C1); 126.6, 126.7,
127.5, 128.0, 128.1, 128.2, 128.6, 129.9, 140.4, 147.1
(Arom.). Extracted data for compound 8 from the mixture of
7 and 8: ESIþ(m/z)¼292.4. Signal of ketone 13C NMR
(CDCl3): d 201.5 (CO).
4.2.5. 1-(N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)-
methylketone (4d). The residue was chromatographed on
a silica gel column, eluting with hexane/ethyl acetate (8:2),
to yield 99% of compound 4d as a solid. Mp: 143–1458C.
ESIþ(m/z)¼244.3. Anal. calcd for C15H17NO2; C, 74.05; H,
1
7.04; N, 5.76; found C, 73.89; H, 7.18; N, 5.66. H NMR
(CDCl3): d 1.52–1.62 (m, 2H); 1.64–1.77 (m, 2H); 1.88–
1.94 (m, 2H); 2.13–2.25 (m, 2H); 2.30 (s, 3H); 4.22–4.31
(m, 1H, H4); 7.35–7.50 (m, 3H, Arom.); 7.62–7.70 (m, 2H,
Arom.). 13C NMR (CDCl3): d 25.6 (CH3); 30.5, 30.9 (C2,
C3, C5, C6); 62.3 (C4); 73.8 (C1); 128.3, 128.4, 131.5, 134.5
(Arom.); 173.0 (CON); 205.0 (CO).
4.2.6. (N-Benzoyl-7-azabicyclo[2.2.1]hept-1-yl)pyridin-
3-ylketone (4e). The residue was chromatographed on a
silica gel column, eluting with hexane/ethyl acetate (8:2), to
give 81% of compound 4e as an oil. ESIþ(m/z)¼307.3.
Anal. calcd for C19H18N2O2; C, 74.49; H, 5.92; N, 9.14;
found C, 74.29; H, 5.84; N, 9.26. 1H NMR (CDCl3): d 1.66–
1.73 (m, 2H); 1.85–2.10 (m, 4H); 2.47–2.55 (m, 2H);
4.42–4.50 (m, 1H, H4); 7.32–7.54 (m, 4H, Arom.); 7.62–
7.70 (m, 2H, Arom.); 8.42–8.50 (m, 1H, Arom.); 8.63–8.69
(m, 1H, Arom.); 9.49 (s, 1H, Arom.). 13C NMR (CDCl3): d
4.2.9. Methyl N-benzoylpyrrolidine-2-carboxylate (9).
Acetyl chloride (558 mL, 7.8 mmol) was added dropwise to
methanol (10 mL) at 08C. The mixture was stirred for
10 min and the proline (300 mg, 2.6 mmol) was added. The
resulting solution was stirred at 608C for 12 h. The solvent
was removed, the residual oil suspended in diethyl ether
(20 mL) and the solvent evaporated again. The solvent