A. Thangamani / European Journal of Medicinal Chemistry 45 (2010) 6120e6126
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7.17e7.19 (m, 1H), 7.23 (d, 2H, J ¼ 8.0), 7.39 (d, 1H, J ¼ 15.6), 7.55 (d,
2H, J ¼ 8.0), 7.66e7.68 (m, 1H), 7.84 (d, 1H, J ¼ 16.0), 7.86e7.87 (m,
completion of the reaction as indicated by TLC. The solvent was
removed under reduced pressure and the crude product was
purified by column chromatography using benzene/ethyl acetate
(4.5/0.5) as eluent followed by recrystallization from methanol.
1H).13C NMR (CDCl3)
d: 21.66, 120.63, 128.36, 128.64, 129.82, 131.83,
132.02, 133.88, 141.28, 144.23, 145.76, 182.22. Anal. Calcd. for
C14H12O1S1: C, 73.65; H, 5.30; O, 7.01. Found: C, 73.58; H, 5.26; O,
7.0.
4.3.1. 10-(Phenyl)-20-(2-thienylcarbonyl)-spiro[3H-indole-3,30-[3H]
pyrrolizin]-2-one (4a)
4.2.4. (E)-3-(p-Fluorophenyl)-1-(thiophen-2-yl)prop-2-en-1-
one (1d)
Reaction time 15 min, yellow solid, mp 191e193 ꢁC, yield 89%
(0.37 g, 0.89 mmol). IR: nmax (KBr, cmꢀ1) 1654,1730. 1H NMR (CDCl3)
Yellow solid, mp 123e124 ꢁC, yield 97% (0.22 g, 0.97 mmol). IR:
d
: 1.67e2.06 (m, 4H), 2.62e2.76 (m, 2H), 3.93 (t, 1H, J ¼ 10.7),
4.23e4.27 (m, 1H), 4.79 (d, 1H, J ¼ 12.0), 6.69e6.70 (br d, 1H, J ¼ 6),
6.87(brs,1H), 7.03e7.56(m,10H), 8.23 (s,1H,NH).13CNMR(CDCl3)
nmax (KBr, cmꢀ1) 1647, 1588, 981. 1H NMR (CDCl3)
d: 7.07e7.12 (m,
2H), 7.16e7.18 (m, 1H), 7.33 (d, 1H, J ¼ 15.6), 7.60e7.64 (m, 2H),
d:
7.66e7.68 (m, 1H), 7.79 (d, 1H, J ¼ 15.6), 7.84e7.85 (m, 1H).13C NMR
27.28(C-6), 30.61 (C-5), 48.26(C-7), 52.90(C-4), 65.22(C-3), 71.97(C-
4a), 74.17 (C-2), 110.33, 122.47, 125.08, 127.01, 127.85, 128.08, 128.69,
129.46, 132.22, 134.41, 139.44, 140.35, 144.46, 181.06 (oxindole
carbon), 188.53 (thiophenyl carbon). Anal. Calcd. for C25H22N2O2S1:
C, 72.46; H, 5.31; N, 6.76. Found: C, 72.21; H, 5.25; N, 6.69.
(CDCl3)
d
: 116.32 (d, JCF ¼ 21.2),121.41, 128.48,130.55,130.65,132.05,
134.22, 142.94, 145.58, 164.24 (d, JCF ¼ 250.4), 182.03. Anal. Calcd. for
C13H9O1S1F: C, 67.22; H, 3.91; O, 6.89. Found: C, 67.16; H, 3.91; O, 6.89.
4.2.5. (E)-3-(p-Nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-
one (1e)
4.3.2. 10-(p-Chlorophenyl)-20-(2-thienylcarbonyl)-spiro[3H-indole-
3,30-[3H]pyrrolizin]-2-one (4b)
Yellow solid, mp 218e219 ꢁC, yield 99% (0.26 g, 0.99 mmol). IR:
nmax (KBr, cmꢀ1) 1649, 1597, 971. 1H NMR (CDCl3)
d:7.19e7.22 (m,
Reaction time 180 min, yellow solid, mp 198e200 ꢁC, yield 84%
1H), 7.50 (d, 1H, J ¼ 15.6), 7.72e7.74 (m, 1H), 7.77 (d, 2H, J ¼ 8.8),
(0.38 g, 0.84 mmol). IR: nmax (KBr, cmꢀ1) 1654, 1725. 1H NMR
7.84 (d, 1H, J ¼ 15.6), 7.88e7.89 (m, 1H), 8.27 (dd, 2H, J ¼ 2.0, 7.2).13C
(CDCl3)
d: 1.66e2.05 (m, 4H), 2.61e2.75 (m, 2H), 3.89 (t, 1H,
NMR (CDCl3)
d
: 123.99, 125.88, 129.11, 129.94, 134.53, 136.39,
J ¼ 10.5), 4.19e4.23 (m, 1H), 4.70 (d, 1H, J ¼ 12.0), 6.66 (d, 1H,
140.40, 141.03, 145.16, 148.14, 181.42. Anal. Calcd. for C13H9 N1 O1S1:
C, 60.22; H, 3.50; N, 5.40; O, 18.51. Found: C, 60.17; H, 3.51; N, 5.40;
O, 18.51.
J ¼ 7.5), 6.89 (dd, 1H, J ¼ 4.5, 4.0), 7.01e7.59 (m, 9H), 7.91 (s, 1H,
NH).13C NMR(CDCl3)
d: 27.20 (C-6), 30.46 (C-5), 48.23 (C-7), 52.30
(C-4), 65.34 (C-3), 71.71 (C-4a), 73.98 (C-2), 110.00, 122.53, 124.90,
127.78, 127.92, 128.87, 129.44, 129.54, 129.72,132.29, 134.61, 137.96,
140.28, 144.30, 180.71 (oxindole carbon), 188.42 (thiophenyl
carbon). Anal .Calcd. for C25H21N2O2S1Cl: C, 66.96; H, 4.69; N, 6.25.
Found: C, 66.78; H, 4.61; N, 6.18.
4.2.6. (E)-3-(m-Bromophenyl)-1-(thiophen-2-yl)prop-2-en-1-
one (1f)
Yellow solid, mp 115e116 ꢁC, yield 95% (0.28 g, 0.95 mmol). IR:
nmax (KBr, cmꢀ1) 1645, 1600, 977. 1H NMR (CDCl3)
d: 7.19e7.22 (m,
1H), 7.27e7.32 (m, 1H), 7.40 (d, 1H, J ¼ 16.0), 7.53e7.55 (m, 2H),
4.3.3. 10-(p-Methylphenyl)-20-(2-thienylcarbonyl)-spiro[3H-indole-
3,30-[3H]pyrrolizin]-2-one (4c)
7.71e7.72 (m, 1H), 7.76 (d, 1H, J ¼ 16.0), 7.80 (s, 1H), 7.88e7.89 (m,
1H).13C NMR (CDCl3)
d: 122.99,123.30,127.58,128.58,130.71,131.01,
Reaction time 10 min, yellow solid, mp 188e190 ꢁC, yield 93%
132.33, 133.53, 134.56, 136.99, 142.47, 181.86. Anal. Calcd. for C13H9
O1S1Br: C, 53.26; H, 3.09; O, 5.46. Found: C, 53.21; H, 3.10; O, 5.46.
(0.40 g, 0.93 mmol). IR: nmax (KBr, cmꢀ1) 1656,1737. 1H NMR (CDCl3)
d: 1.72e2.04 (m, 4H), 2.28 (s, 3H), 2.61e2.74 (m, 2H), 3.90 (t, 1H,
J ¼ 10.7), 4.20e4.25 (m, 1H), 4.76 (d, 1H, J ¼ 12.0), 6.70 (d, 1H,
4.2.7. (E)-3-(p-N, N-Dimethylaminophenyl)-1-(thiophen-2-yl)
prop-2-en-1-one (1g)
J ¼ 7.5), 6.84 (dd, 1H, J ¼ 5.0, 4.0), 7.02e7.56 (m, 9H), 8.50 (s, 1H,
NH). 13C NMR (CDCl3)
d: 21.02, 27.29 (C-6), 30.61 (C-5), 48.29 (C-7),
Yellow solid, mp 122e123 ꢁC, yield 88% (0.23 g, 0.88 mmol). IR:
52.58 (C-4), 65.18 (C-3), 71.95 (C-4a), 74.26 (C-2), 110.12, 122.44,
125.12, 127.81, 127.82, 127.94, 129.40, 129.44, 132.20, 134.37, 136.34,
136.60, 140.45, 144.52, 181.26 (oxindole carbon), 188.55 (thiophenyl
carbon). Anal. Calcd. for C26H24N2O2S1: C, 72.90; H, 5.61; N, 6.54.
Found: C, 72.68; H, 5.68; N, 6.60.
nmax (KBr, cmꢀ1) 1632, 1610, 980. 1H NMR (CDCl3)
d: 3.05 (s, 3H),
3.07 (s, 3H), 6.72 (d, 2H, J ¼ 8.8), 7.17e7.20 (m, 1H), 7.27e7.28 (m,
1H), 7.57 (d, 2H, J ¼ 8.4), 7.64e7.66 (m, 1H), 7.83e7.87 (m, 2H). 13C
NMR (CDCl3) d: 40.26, 111.92, 116.32, 122.49, 128.23, 130.63, 131.08,
133.03, 145.14, 146.48, 152.19, 182.30. Anal. Calcd. for C15H15 N1
O1S1: C, 70.01; H, 5.87; N, 5.44; O, 6.22. Found: C, 69.94; H, 5.89; N,
5.44; O, 6.22.
4.3.4. 10-(p-Fluorophenyl)-20-(2-thienylcarbonyl)-spiro[3H-indole-
3,30-[3H]pyrrolizin]-2-one (4d)
Reaction time 120 min, yellow solid, mp 182e184 ꢁC, yield 87%
4.2.8. (E)-3-(p-Methoxyphenyl)-1-(thiophen-2-yl)prop-2-en-1-
one (1h)
(0.38 g, 0.87 mmol). IR: nmax (KBr, cmꢀ1) 1652,1729. 1H NMR (CDCl3)
d
: 1.72e2.06 (m, 4H), 2.61e2.76 (m, 2H), 3.91 (t, 1H, J ¼ 10.7),
Yellow solid, mp 81e82 ꢁC, yield 90% (0.22 g, 0.90 mmol). IR: nmax
4.19e4.24 (m,1H), 4.70 (d,1H, J ¼ 11.5), 6.69 (d,1H, J ¼ 7.5), 6.86 (dd,
(KBr, cmꢀ1) 1646, 1591, 978. 1H NMR (CDCl3)
d: 3.84 (s, 3H), 6.82 (d,
1H, J ¼ 5.0, 4.5), 6.97e7.54 (m, 9H), 8.42 (s, 1H, NH).13C NMR(CDCl3)
2H, J ¼ 8.4), 7.15e7.17 (m, 1H), 7.29 (d, 1H, J ¼ 15.6), 7.59 (d, 2H,
d:27.20 (C-6), 30.49 (C-5), 48.25 (C-7), 52.17 (C-4), 65.39 (C-3), 71.81
J ¼ 8.8), 7.64 (d, 1H, J ¼ 4.8), 7.81 (d, 1H, J ¼ 16.0), 7.83e7.84 (m, 1H).
(C-4a), 74.09 (C-2), 110.12, 115.54 (d, J ¼ 21.2), 122.48, 124.97, 127.74,
127.88, 129.50, 129.52, 129.56, 132.25, 134.55, 135.09, 135.11, 140.46,
144.35, 161.90 (d, J ¼ 243.7), 181.06 (oxindole carbon), 188.52 (thi-
13C NMR (CDCl3)
d: 55.47, 114.47, 119.18, 127.40, 128.33, 130.18,
130.38, 131.64, 133.70, 143.83, 145.86, 161.76, 182.13. Anal. Calcd. for
C14H12O2S1: C, 73.65; H, 5.30; O, 7.01. Found: C, 73.58; H, 5.31; O, 7.0.
ophenyl carbon). 19F NMR (CDCl3/C6F6):
d 45.85e45.78 (m,1F). Anal.
Calcd. for C25H21N2O2S1F: C, 69.44; H, 4.86; N, 6.48. Found: C, 69.70;
H, 4.82; N, 6.56.
4.3. General procedure for the syntheses of thiophenyl based spiro
heterocycles 4ae4h
4.3.5. 10-(p-Nitrophenyl)-20-(2-thienylcarbonyl)-spiro[3H-indole-
3,30-[3H]pyrrolizin]-2-one (4e)
A
solution of (E)-3-aryl-1-(thiophen-2-yl)prop-2-en-1-ones
1ae1h (1 mmol), isatin (2) (1 mmol) and -proline (3) (1 mmol) in
methanol (20 mL)was refluxed by using a CaCl2 guard tube, until
L
Reaction time 70 min, yellow solid, mp 175e177 ꢁC, yield 90%
(0.41 g, 0.90 mmol). IR: nmax (KBr, cmꢀ1) 1655, 1721.1H NMR (CDCl3)