W. Liu et al. / European Journal of Medicinal Chemistry 46 (2011) 907e913
911
column chromatography with mixture eluent of petroleum ether
and ethyl acetate to give the product.
6.95e7.38 (m, 9H, AreH). Anal. Calcd. for C25H24ClNO3: C, 71.17; H,
5.73; N, 3.32%; found C, 69.92; H, 5.89; N, 3.54%.
5.1.2.1. 1-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)ethanone (8a). Yield 43.2%; mp 152e154 ꢀC; MS (ESI,
m/z): [M þ H]þ 364.1, [M þ Na]þ 386.1; IR (KBr, cmꢃ1): 2959, 2914,
5.1.3.3. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl propionate (8g). Yield 95.1%; mp
159e160 ꢀC; MS (ESI, m/z): [M þ H]þ 436; IR (KBr, cmꢃ1): 2969, 2939,
2844, 1645, 1455, 843, 753, 694; 1H NMR (CDCl3, 300 MHz):
d
1.29 (s,
2879, 1744, 1645, 1540, 972, 699; 1H NMR (CDCl3, 300 MHz):
d 1.15 (t,
6H, 2-CH3), 1.87 (s, 3H, eCH3), 2.81 (s, 2H, eCH2e), 4.20 (s, 2H,
eCH2e), 6.95e7.3 3 (m, 9H, AreH). Anal. calcd for C23H22ClNO: C,
75.92; H, 6.09; N, 3.85%; found C, 75.71; H, 6.35; N, 4.03%.
3H, eCH3, J ¼ 7.8 Hz)1.30 (s, 6H, 2-CH3), 2.43 (q, 2H, eCH2e,
J ¼ 7.8 Hz), 2.83 (s, 2H, eCH2e), 4.21 (s, 2H, eCH2e), 4.37 (s, 2H,
eCH2e), 6.95e7.38 (m, 9H, AreH). Anal. Calcd. for C26H26ClNO3: C,
71.63; H, 6.01; N, 3.21%; found C, 71.52; H, 6.01; N, 3.45%.
5.1.2.2. 1-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)propan-1- one (8b). Yield 73.2%; mp 143e145 ꢀC; MS
(ESI, m/z): [M þ H]þ 378.2, [M þ Na]þ 400.2; IR (KBr, cmꢃ1): 3452,
2959, 2929, 2869, 1595, 1505, 948, 848, 694; 1H NMR (CDCl3,
5.1.3.4. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 4-chlorobenzoate (8h). Yield 70.3%; mp
224e226 ꢀC; MS (ESI, m/z): [M þ H]þ 518; IR (KBr, cmꢃ1): 2964, 2919,
300 MHz):
d
0.935 (t, 3H, J ¼ 7.2 Hz, eCH3), 1.30 (s, 6H, 2-CH3), 2.14 (q,
2854,1729, 1650, 1600, 953, 743; 1H NMR (CDCl3, 300 MHz):
d 1.29 (s,
2H, J ¼ 7.2 Hz, eCH2e), 2.82 (s, 2H, eCH2e), 4.22 (s, 2H, eCH2e),
6.95e7.34 (m, 9H, AreH). Anal. calcd for C24H24ClNO: C, 76.28; H,
6.40; N, 3.71%; found C, 76.52; H, 6.39; N, 3.35%.
6H, 2-CH3), 2.84 (s, 2H, eCH2e), 4.21 (s, 2H, eCH2e), 4.60 (s, 2H,
eCH2e), 6.97e8.00 (m, 13H, AreH). Anal. Calcd. for C30H25Cl2NO3: C,
69.50; H, 4.86; N, 2.70%; found C, 69.07; H, 4.91; N, 3.10%.
5.1.2.3. 1-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)hexan-1- one (8c). Yield 56.3%; mp 137e140 ꢀC; MS
(ESI, m/z): [M þ H]þ 420.1, [M þ Na]þ 442.3; IR (KBr, cmꢃ1): 2949,
2919, 2854, 1640, 1595, 967, 843, 694; 1H NMR (CDCl3, 300 MHz):
5.1.3.5. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 4-methoxybenzoate (8i). Yield 56.0%; mp
230e240 ꢀC; MS (ESI, m/z): [M þ H]þ 514, [M þ Na]þ 536; IR (KBr,
cmꢃ1): 2955, 2914, 2854, 1719, 1729, 1600, 1510, 963, 768, 748; 1H
d
0.82 (t, 3H, J ¼ 7.2 Hz, eCH3), 1.01 (m, 2H, J ¼ 7.2 Hz, eCH2e), 1.03
NMR (CDCl3, 300 MHz): d 1.28 (s, 6H, 2-CH3), 2.83 (s, 2H, eCH2e),
(m, 2H, eCH2e), 1.15 (s, 6H, 2-CH3), 1.44 (m, 2H, eCH2e), 2.11 (t, 2H,
eCH2e), 2.81 (s, 2H, eCH2e), 4.22 (s, 2H, eCH2e), 6.95e7.34 (m, 9H,
AreH). Anal. calcd. for C27H30ClNO$H2O: C, 74.04; H, 7.36; N, 3.20%;
found C, 74.22; H, 7.18; N, 3.13%.
3.84 (s, 3H, eCH3), 4.21 (s, 2H, eCH2e), 4.57 (s, 2H, eCH2e),
6.87e8.01 (m, 13H, AreH). Anal. Calcd. for C31H28ClNO4: C, 72.44; H,
5.49; N, 2.72%; found C, 72.07; H, 5.61; N, 3.11%.
5.1.3.6. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 4-methylbenzoate (8j). Yield 60.1%; mp
246e248 ꢀC; MS (ESI, m/z): [M þ H]þ 498, [M þ Na]þ 520; IR (KBr,
cmꢃ1): 2954, 1724, 1645, 1276, 958, 753, 694, 639; 1H NMR (CDCl3,
5.1.2.4. 2-Chloro-1-(2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-
dihydro-5H-pyrrolizin-3-yl)ethanone
(8d). Yield
59.3%;
mp
157e159 ꢀC; MS (ESI, m/z): [M þ H]þ 398.2, [M þ Na]þ 420.2; IR (KBr,
cmꢃ1): 2919, 2839, 1645, 1595, 1450, 1012, 748, 704; 1H NMR (CDCl3,
300 MHz): d 1.29 (s, 6H, 2-CH3), 2.40 (s, 3H, eCH3), 2.84 (s, 2H,
300 MHz):
d
1.31 (s, 6H, 2-CH3), 2.84 (s, 2H, eCH2e), 3.85 (s, 2H,
eCH2e), 4.22 (s, 2H, eCH2e), 4.59 (s, 2H, eCH2e), 6.97e7.95 (m,13H,
AreH). Anal. Calcd. for C31H28ClNO3: C, 74.76; H, 5.67; N, 2.81%;
found C, 74.29; H, 5.78; N, 3.22%.
eCH2e), 4.24 (s, 2H, eCH2e), 6.95e7.38 (m, 9H, AreH). Anal. calcd.
for C23H21Cl2NO: C, 69.35; H, 5.31; N, 3.52%; found C, 69.07; H, 5.41;
N, 3.71%.
5.1.3.7. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 4-nitrobenzoate (8k). Yield 75.8%; mp
104e107 ꢀC; MS (ESI, m/z): [M þ H]þ 529; IR (KBr, cmꢃ1): 2929, 2849,
5.1.3. General procedures for the synthesis of the target compounds
8eeu
The flask was charged with 10 mL of absolute acetone, 1mmol of
triethylamine, 0.8 mmol of corresponding substituted aromatic and
alkyl acid, after stirred for 15 min, 0.5 mmol of 2-chloro-1-(2-(4-
chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-
3-yl)ethanone (8d) was added. The resulting solution was stirred at
room temperature for over 24 h. Then the solvent was distilled off
to give the crude product, which was then purified by flash column
chromatography with mixture eluent of petroleum ether and ethyl
acetate to give the product, followed by recrystallization from
acetone.
1734, 1660, 1276, 748; 1H NMR (CDCl3, 300 MHz):
d 1.30 (s, 6H, 2-
CH3), 2.85 (s, 2H, eCH2e), 4.21 (s, 2H, eCH2e), 4.65 (s, 2H, eCH2e),
6.98e8.30 (m, 13H, AreH). Anal. Calcd. for C30H25ClN2O5: C, 68.12; H,
4.76; N, 5.30%; found C, 67.97; H, 5.15; N, 5.42%.
5.1.3.8. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 3-chlorobenzoate (8l). Yield 75.4%; mp
199e200 ꢀC; MS (ESI, m/z): [M þ Na]þ 540.1; IR (KBr, cmꢃ1): 2954,
2859,1724,1650, 958, 778, 748; 1H NMR (CDCl3, 300 MHz):
d 1.29 (s,
6H, 2-CH3), 2.83 (s, 2H, eCH2e), 4.20 (s, 2H, eCH2e), 4.60 (s, 2H,
eCH2e), 6.97e8.03 (m,13H, AreH). Anal. Calcd. for C30H25Cl2NO3: C,
69.50; H, 4.86; N, 2.70%; found C, 69.21; H, 5.24; N, 2.48%.
5.1.3.1. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl formate (8e). Yield 85.1%; mp 164e168 ꢀC;
MS (ESI, m/z): [M þ H]þ 406.2; IR (KBr, cmꢃ1): 3457, 2949, 1729, 1640,
5.1.3.9. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl 3-methylbenzoate (8m). Yield 60.8%; mp
102e108 ꢀC; MS (ESI, m/z): [M þ H]þ 498, [M þ Na]þ 520; IR (KBr,
cmꢃ1): 2954, 2934, 2879, 1729, 1645, 967, 763, 704; 1H NMR (CDCl3,
958, 928, 694; 1H NMR (CDCl3, 300 MHz):
d 1.33 (s, 6H, 2-CH3), 2.84
(s, 2H, eCH2e), 4.21 (s, 2H, eCH2e), 4.45 (s, 2H, eCH2e), 6.95e7.39
(m, 9H, AreH), 8.11 (s, 1H, eCH). Anal. Calcd. for C24H22ClNO3: C,
70.64; H, 5.44; N, 3.43%; found C, 70.17; H, 5.31; N, 3.78%.
300 MHz):
d 1.18 (s, 6H, 2-CH3), 2.51 (s, 3H, eCH3), 2.76 (s, 2H,
eCH2e), 4.15 (s, 2H, eCH2e), 4.51 (s, 2H, eCH2e), 6.89e7.92 (m, 13H,
AreH). Anal. Calcd. for C31H28ClNO3: C, 74.76; H, 5.67; N, 2.81%;
found C, 74.98; H, 5.34; N, 2.62%.
5.1.3.2. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-5H-
pyrrolizin-3-yl)-2-oxoethyl acetate (8f). Yield 86.7%; mp 186e188 ꢀC;
MS (ESI, m/z): [M þ H]þ 422; IR (KBr, cmꢃ1): 2954, 2924, 2869, 1744,
1645, 704; 1H NMR (CDCl3, 300 MHz):
d
1.30 (s, 6H, 2-CH3), 2.18 (s, 3H,
5.1.3.10. 2-(2-(4-Chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-dihydro-
eCH3), 2.83 (s, 2H, eCH2e), 4.21 (s, 2H, eCH2e), 4.36 (s, 2H, eCH2e),
5H-pyrrolizin-3-yl)-2-oxoethyl 2-chlorobenzoate (8n). Yield 80.1%;