G. Loriga et al. / Bioorg. Med. Chem. 14 (2006) 676–691
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4.1.18.3. 3-[30-(2-Chlorophenyl)-prop-20-en-10-yl]-3,6-
diazabicyclo[3.1.1]heptane (26c). Yield quantitative; Rf
0.14 (CHCl3/MeOH 9:1); IR: 1590, 1620, 3300; 1H
NMR (CDCl3) d 1.79–1.94 (m, 1H), 2.24 (br s, 1H),
2.59–2.67 (m, 1H), 2.75 (d, 2H, J = 11.2 Hz), 3.14 (d,
2H, J = 9.6 Hz), 3.41 (d, 2H, J = 6.6 Hz), 3.63–3.65
(m, 2H), 6.29 (dt, 1H, J = 6.4 and 15.6 Hz), 6.98 (d,
1H, J = 15.6 Hz), 7.12–7.37 (m, 4H). Anal. Calcd for
C14H17ClN2: C, 67.60; H, 6.89; Cl, 14.25; N, 11.26.
Found: C, 67.36; H, 6.86; Cl, 14.20; N, 11.22.
C15H18Cl2N2: C, 60.61; H, 6.10; Cl, 23.86; N, 9.43.
Found: C, 60.40; H, 6.08; Cl, 23.79; N, 9.40.
4.1.18.9. 3-(30-Phenyl-pent-20-en-10-yl)-3,6-diazabicyclo-
[3.1.1]heptane (26i). Yield quantitative; Rf 0.53 (CHCl3/
1
MeOH 7:3 + gtt Et3N); IR: 1590, 1620, 3300; H NMR
(CDCl3) d 0.97 (t, 3H, J = 7.8 Hz), 1.78–1.84 (m, 1H),
2.00–2.18 (m, 1H), 2.30–2.45 (q, 2H, J = 7.4 Hz), 2.69
(br s, 1H), 2.76–2.79 (m, 2H), 2.96 (d, 2H, J = 5.4 Hz),
3.13 (d, 2H, J = 7.6 Hz), 4.05–4.09 (m, 2H), 5.80 (t, 1H,
J = 6.4 Hz), 7.13–7.35 (m, 5H). Anal. Calcd for
C16H22N2: C, 79.29; H, 9.15; N, 11.56. Found: C, 79.02;
H, 9.12; N, 11.52.
4.1.18.4. 3-[30-(3-Chlorophenyl)-prop-20-en-10-yl]-3,6-
diazabicyclo[3.1.1]heptane (26d). Yield quantitative;
1
Rf 0.20 (CHCl3/MeOH 9:1); IR: 1590, 1620, 3300; H
NMR (CDCl3) d 1.79–1.94 (m, 1H), 2.26–2.36 (m,
1H), 2.60–2.68 (m, 2H), 2.98 (br s, 1H), 3.22 (d, 2H,
J = 14.2 Hz), 3.46 (d, 2H, J = 5.8 Hz), 4.19–4.25 (m,
2H), 6.25 (dt, 1H, J = 6.4 and 15.6 Hz), 6.58 (d, 1H,
J = 15.6 Hz), 7.16–7.37 (m, 4H). Anal. Calcd for
C14H17ClN2: C, 67.60; H, 6.89; Cl, 14.25; N, 11.26.
Found: C, 67.44; H, 6.85; Cl, 14.22; N, 11.24.
4.1.19. General procedure for the preparation of 3Aa–i.
To a solution of 26a–i (1.60 mmol) in CH2Cl2 (30 mL) at
0 °C was added a solution of propionic anhydride
(0.72 mL, 5.60 mmol) in CH2Cl2 (6 mL). When addition
was complete, the mixture was refluxed for 1 h. After
cooling at room temperature, the mixture was made
alkaline with 40% NaOH and stirred overnight. The
reaction mixture was extracted with CH2Cl2, the organic
layers were dried over Na2SO4, evaporated, and the res-
idue was purified by FC (eluent: CH2Cl2/acetone 7:3) to
afford the compounds 3Aa–i as oils. All final com-
pounds were converted into the HCl or HO2CCH@CH-
CO2H salts.
4.1.18.5. 3-[30-(4-Chlorophenyl)-prop-20-en-10-yl]-3,6-
diazabicyclo[3.1.1]heptane (26e). Yield quantitative;
Rf 0.43 (CHCl3/MeOH 9:1 + gtt Et3N); IR: 1590,
1620, 3300; 1H NMR (CDCl3) d 1.65–1.76 (m, 1H),
2.35–2.41 (m, 1H), 2.58 (d, 2H, J = 7.8 Hz), 2.82 (d,
2H, J = 11.4 Hz), 3.10 (br s, 1H), 3.31 (d, 2H,
J = 5.6 Hz), 4.00–4.10 (m, 2H), 6.25 (dt, 1H, J = 6.4
and 15.6 Hz), 6.51 (d, 1H, J = 15.6 Hz), 7.08–7.27 (m,
4H). Anal. Calcd for C14H17ClN2: C, 67.60; H, 6.89;
Cl, 14.25; N, 11.26. Found: C, 67.54; H, 6.90; Cl,
14.23; N, 11.20.
4.1.19.1. 3-Cinnamyl-6-propionyl-3,6-diazabicyclo[3.1.1]-
heptane (3Aa). Yield 75%; Rf 0.32 (CH2Cl2/acetone 7:3);
mp 191–193 °C (as hydrochloride); IR: 1590, 1620, 1690;
1H NMR (CDCl3) d 1.14 (t, 3H, J = 7.6 Hz), 1.97–3.15
(m, 8H), 3.32 (d, 2H, J = 6.6 Hz), 4.20–4.30 (m, 1H),
4.30–4.40 (m, 1H), 6.25 (dt, 1H, J = 6.4 and 15.6 Hz),
6.54 (d, 1H, J = 15.6 Hz), 7.17–7.39 (m, 5H); 13C NMR
(CDCl3) d 9.26, 25.68, 27.87, 52.17, 54.41, 58.21, 58.53,
61.30, 126.19, 126.32, 127.39, 128.45, 132.55, 136.74,
173.26. Anal. Calcd for C17H22N2O: C, 75.52; H, 8.20; N,
10.36. Found: C, 75.44; H, 8.16; N, 10.30.
4.1.18.6. 3-(30-Phenyl-but-20-en-10-yl)-3,6-diazabicyclo-
[3.1.1]heptane (26f). Yield quantitative; Rf 0.37
(CHCl3/MeOH 9:1); IR: 1590, 1620, 3300; 1H NMR
(CDCl3) d 1.56 (br s, 1H), 1.81–1.89 (m, 1H), 2.11 (s,
3H), 2.41–2.48 (m, 1H), 2.73 (d, 2H, J = 7.8 Hz), 3.14
(d, 2H, J = 10.2 Hz), 3.40 (d, 2H, J = 6.8 Hz), 3.58–3.63
(m, 2H), 5.98 (t, 1H, J = 6.4 Hz), 7.18–7.40 (m, 5H).
Anal. Calcd for C15H20N2: C, 78.90; H, 8.83; N, 12.27.
Found: C, 78.67; H, 8.80; N, 12.23.
4.1.19.2. 3-[30-(4-Nitrophenyl)-prop-20-en-10-yl]-6-pro-
pionyl-3,6-diazabicyclo[3.1.1]heptane (3Ab). Yield 74%;
Rf 0.24 (CH2Cl2/acetone 7:3); mp 170–172 °C (as fuma-
rate); IR: 1590, 1620, 1650; 1H NMR (CDCl3) d 1.15 (t,
3H, J = 7.0 Hz), 2.06–2.19 (m, 2H), 2.25–2.38 (m, 2H),
2.80–3.18 (m, 4H), 3.38 (d, 2H, J = 6.0 Hz), 4.30–4.42
(m, 2H), 6.40 (dt, 1H, J = 6.6 and 15.8 Hz), 6.62 (d,
1H, J = 15.8 Hz), 7.47–8.20 (m, 4H); 13C NMR (CDCl3)
d 9.33, 25.79, 29.69, 52.20, 54.63, 58.52, 61.95, 124.00,
126.77, 128.82, 130.39, 130.89, 131.95, 173.57. Anal.
Calcd for C17H21N3O3: C, 64.74; H, 6.71; N, 13.32.
Found: C, 64.66; H, 6.69; N, 13.30.
4.1.18.7.
3-[30-(4-Chlorophenyl)-but-20-en-10-yl]-3,6-
diazabicyclo[3.1.1]heptane (26g). Yield quantitative; Rf
0.28 (CHCl3/MeOH 9:1); IR: 1590, 1620, 3300; 1H
NMR (CDCl3) d 1.84–1.86 (m, 1H), 2.07 (s, 3H),
2.37–2.40 (m, 1H), 2.73 (d, 2H, J = 7.8 Hz), 3.07 (br
s, 1H), 3.14 (d, 2H, J = 10.2 Hz), 3.40 (d, 2H,
J = 6.8 Hz), 3.63–3.66 (m, 2H), 5.96 (t, 1H,
J = 6.4 Hz), 7.11–7.31 (m, 4H). Anal. Calcd for
C15H19ClN2: C, 68.56; H, 7.29; Cl, 13.49; N, 10.66.
Found: C, 68.32; H, 7.26; Cl, 13.44; N, 10.62.
4.1.19.3. 3-[30-(2-Chlorophenyl)-prop-20-en-10-yl]-6-pro-
pionyl-3,6-diazabicyclo[3.1.1]heptane (3Ac). Yield 60%; Rf
0.30 (CH2Cl2/acetone 7:3); mp 149–151 °C (as hydrochlo-
4.1.18.8. 3-[30-(3,4-Dichlorophenyl)-but-20-en-10-yl]-
3,6-diazabicyclo[3.1.1]heptane (26h). Yield quantitative;
Rf 0.53 (CHCl3/MeOH 9:1 + gtt Et3N); IR: 1590,
1620, 3300; 1H NMR (CDCl3) d 1.85–1.90 (m, 1H),
2.06 (s, 3H), 2.54–2.65 (m, 1H), 2.76 (d, 2H,
J = 10.6 Hz), 3.03 (br s, 1H), 3.08 (d, 2H, J = 8.2 Hz),
3.40 (d, 2H, J = 6.8 Hz), 3.60–3.69 (m, 2H), 5.98 (t,
1H, J = 6.4 Hz), 7.21–7.50 (m, 3H). Anal. Calcd for
1
ride); IR: 1590, 1620, 1650; H NMR (CDCl3) d 1.13 (t,
3H, J = 7.6 Hz), 1.90–3.19 (m, 8H), 3.36 (d, 2H,
J = 7.8 Hz), 4.20–4.40 (m, 2H), 6.21 (dt, 1H, J = 6.6 and
15.8 Hz), 6.92 (d, 1H, J = 15.8 Hz), 7.10–7.51 (m, 4H);
13C NMR (CDCl3) d 9.13, 25.57, 27.89, 51.97, 54.18,
57.89, 58.41, 61.17, 126.64, 126.68, 128.29, 128.56,
129.25, 129.42, 132.60, 134.81, 173.20. Anal. Calcd for