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C. Larraya et al. / European Journal of Medicinal Chemistry 39 (2004) 515–526
1
IR (KBr): m 2942 (CH) cm–1; H-NMR (CDCl3): d 3.94 (s,
3H, OCH3), 6.70 (d, 1H, J = 9.1 Hz, H6), 6.72 (d, 1H,
J = 3.8 Hz, H3), 7.44 (t, 2H, J = 7.2 Hz, Harom), 7.55 (t, 1H,
J = 7.2 Hz, Harom), 7.66 (d, 1H, J = 3.8 Hz, H2), 7.84 (d, 2H,
J = 7.2 Hz, Harom), 8.15 (d, 1H, J = 9.1 Hz, H7); 13C-NMR
(CDCl3): d 53.5 (OCH3), 108.0 (C6), 109.1 (C3), 123.6 (Cq),
124.1 (C7), 126.8 (2 × CH), 128.5 (C2), 129.4 (2 × CH),
134.1 (CH), 138.0 (Cq), 145.9 (Cq), 162.0 (Cq); MS (IS)
m/z = 289 (M + 1).
124.5 (C7 + Cq), 127.1 (2 × CH), 128.9 (CH), 129.8 (2 ×
CH), 134.5 (CH), 138.4 (Cq), 146.3 (Cq), 162.1 (Cq); MS
(IS) m/z = 409 (M + 1 for 79Br), m/z = 411 (M + 1 for 81Br).
6.1.5.2. 1-Benzenesulfonyl-5-(5-bromopentyloxy)pyrrolo
[3,2-b]pyridine (6). Green oil (54%); IR (film): m 2951 (CH),
1
1374 (SO2) cm–1; H-NMR (CDCl3): d 1.46–1.93 (m, 6H,
CH2CH2CH2CH2O), 3.36 (t, 2H, J = 6.7 Hz, CH2Br), 4.26
(t, 2H, J = 6.2 Hz, CH2O), 6.65 (d, 1H, J = 3.2 Hz, H3), 6.66
(d, 1H, J = 8.9 Hz, H6), 7.33–7.41 (m, 3H, Harom), 7.64 (d,
1H, J = 3.2 Hz, H2), 7.80 (d, 2H, J = 7.0 Hz, Harom), 8.13 (d,
1H, J = 8.9 Hz, H7). 13C-NMR (CDCl3): d 25.4 (CH2), 28.7
(CH2), 33.0 (CH2), 34.4 (CH2), 66.3 (OCH2), 108.7 (C3),
110.5 (CH), 124.4 (Cq), 124.7 (C7), 127.1 (2 × CH), 128.9
(CH), 129.8 (2 × CH), 134.5 (CH), 138.3 (Cq), 146.3 (Cq),
162.2 (Cq). MS (IS) m/z = 423 (M + 1 for 79Br), m/z = 425 (M
+ 1 for 81Br).
6.1.4. 1-Benzenesulfonylpyrrolo[3,2-b]pyridin-5-one (4)
Under an inert atmosphere, aluminum chloride (9.91 g,
74.30 mmol) was added to a solution of 1-benzenesulfonyl-
5-methoxypyrrolo[3,2-b]pyridine (3) (2.14 g, 7.43 mmol) in
dichloromethane (100 ml) at room temperature. The reaction
was heated at reflux for 18 h. The mixture was cooled at 0 °C,
neutralized to pH 8 using saturated aqueous sodium hydro-
gen carbonate and extracted with dichloromethane. The com-
bined extracts were dried over anhydrous MgSO4 and the
solvent was removed in vacuo. The crude residue was chro-
matographed over silica gel (eluent: ethyl acetate) to afford 4
(1.62 g, 81%) as a white solid; m.p. 209–210 °C (pentane);
6.1.5.3. 1-Benzenesulfonyl-5-(6-bromohexyloxy)pyrrolo[3,2-
b]pyridine (7). White solid (53%); m.p. 90–91 °C; IR (Kbr):
m 2941 (CH) cm–1; 1H-NMR (CDCl3): d 1.42 (sb, 4H,
CH2CH2CH2CH2O), 1.78–1.80 (m, 4H, CH2CH2CH2CH2
CH2O ) 3.33 (t, 2H, J = 6.7 Hz, CH2Br), 4.25 (t, 2H,
J = 6.4 Hz, CH2O), 6.65 (m, 2H, H6), 7.26–7.51 (m, 3H,
IR (KBr): m 3442 (NH), 1651 (CO), 1377 (SO2) cm–1; H-
1
NMR (CDCl3): d 6.46 (d, 1H, J = 3.9 Hz, H3), 6.47 (d, 1H,
J = 5.7 Hz, Harom), 7.44–7.52 (m, 3H, Harom), 7.60 (t, 1H,
J = 7.2 Hz, Harom), 7.83 (d, 1H, J = 3.9 Hz, H2), 7.82 (d, 1H,
J = 9.7 Hz, H6), 8.10 (d, 1H, J = 9.7 Hz, H7); 13C-NMR
(CDCl3): d 103.6 (C3), 119.0 (Cq), 126.3 (CH), 127.1 (2 ×
CH), 128.0 (CH), 129.2 (CH), 130.0 (2 × CH), 134.8 (C6),
136.0 (Cq), 138.2 (Cq), 165.0 (CO); MS (IS) m/z = 275 (M +
1).
H
H
arom), 7.62 (d, 1H, J = 3.6 Hz, H2), 7.84 (d, 2H, J = 7.9 Hz,
arom), 8.14 (d, 1H, J = 9.1 Hz, H7); 13C-NMR (CDCl3): d
25.7 (CH2), 28.3 (CH2), 29.2 (CH2), 34.3 (CH2Br), 66.3
(OCH2), 108.7 (C3), 110.3 (CH), 124.4 (Cq), 124.5 (C7),
127.1 (2 × CH), 128.9 (CH), 129.8 (2 × CH), 134.5 (CH),
138.3 (Cq), 146.3 (Cq), 162.3 (Cq). MS (IS) m/z = 437 (M +
1 for 79Br), m/z = 439 (M + 1 for 81Br).
6.1.5.4. 1-Benzenesulfonyl-4-(4′-bromobutyl)pyrrolo[3,2-b]
pyridone (8). Yellow oil (23%); IR (film): m 1645 (CO), 1374
(SO2) cm–1; 1H-NMR (CDCl3): d 1.77–2.01 (m, 4H,
CH2CH2CH2N), 3.43 (t, 2H, J = 6.0 Hz, CH2Br), 4.07 (t, 2H,
J = 6.2 Hz, CH2N), 6.37 (dd, 1H, J = 3.7 Hz, J = 0.6 Hz, H3),
6.46 (d, 1H, J = 9.7 Hz, H6), 7.46–7.69 (m, 4H, Harom),
7.82–7.90 (m, 2H, Harom), 7.98 (dd, 1H, J = 9.7 Hz,
J = 0.6 Hz, H7); 13C-NMR (CDCl3): d 26.9 (CH2), 30.0
(CH2), 33.5 (CH2Br), 44.00 (NCH2), 102.2 (C3), 117.2
(CH), 117.9 (Cq), 127.1 (2 × CH + CH), 127.2 (CH), 130.0
(2 × CH), 134.9 (CH), 136.6 (Cq), 138.2 (Cq), 161.8 (CO);
MS (IS) m/z = 409 (M + 1 for 79Br), m/z = 411 (M + 1 for
81Br).
6.1.5. General procedure for compounds 5–7 and 8–10
Under an inert atmosphere, potassium carbonate (0.20 g,
1.46 mmol) was added to a stirred solution of 1-benzene-
sulfonylpyrrolo[3,2-b]pyridin-5-one (4) (0.10 g, 0.36 mmol)
in N,N-dimethylformamide (15 ml) at room temperature.
Alkyl-dibromide (0.17 ml, 1.46 mmol) was added dropwise
and the mixture was stirred an additional time (12 h) at room
temperature. The solvent was removed under reduced pres-
sure and the crude was taken up in water and extracted with
ethyl acetate. The combined extracts were dried over anhy-
drous MgSO4. The solvent was evaporated and the products
5–7 and 8–10 were purified by column chromatography
(eluent: light petroleum/ethyl acetate: 8:2).
6.1.5.5. 1-Benzenesulfonyl-4-(4′-bromopentyl)pyrrolo[3,2-b
]
6.1.5.1. 1-Benzenesulfonyl-5-(4-bromobutoxyloxy)pyrrolo
[3,2-b]pyridine (5). Colorless oil (54%); IR (KBr): m 2939
(CH), 1373 (SO2) cm–1; 1H-NMR (CDCl3): d 1.89–2.07 (m,
4H, CH2CH2CH2O), 3.47 (t, 2H, J = 6.6 Hz, CH2Br), 4.33 (t,
2H, J = 6.2 Hz, CH2O), 6.68 (d, 1H, J = 9.1 Hz, H6), 6.68 (d,
1H, J = 9.1 Hz, H6), 6.69 (dd, 1H, J = 3.7 Hz, J = 0.6 Hz, H3),
7.41–7.58 (m, 3H, Harom), 7.66 (d, 1H, J = 3.7 Hz, H2), 7.84
(d, 2H, J = 7.2 Hz, Harom), 8.15 (dd, 1H, J = 9.1 Hz,
J = 0.6 Hz, H7); 13C-NMR (CDCl3): d 28.1 (CH2), 29.9
(CH2), 33.9 (CH2Br), 65.4 (OCH2), 108.4 (C3), 110.3 (CH),
pyridone (9). Yellow oil (24%); IR (film): m 1642 (CO) cm–1;
1H-NMR (CDCl3): d 1.77–2.05 (m, 6H, CH2CH2CH2CH2),
3.43 (t, 2H, J = 6.0 Hz, CH2Br), 4.07 (t, 2H, J = 6.2 Hz,
CH2N), 6.37 (dd, 1H, J = 3.2 Hz, J = 0.6 Hz, H3), 6.46 (d, 1H,
J = 9.5 Hz, H6), 7.46–7.69 (m, 4H, Harom), 7.82–7.90 (m, 2H,
H
arom), 7.98 (dd, 1H, J = 9.5 Hz, J = 0.6 Hz, H7). 13C-NMR
(CDCl3): d 25.9 (CH2), 26.9 (CH2), 30.0 (CH2), 33.5 (CH2),
44.0 (NCH2), 102.2 (C3), 117.2 (CH), 117.9 (Cq), 127.1 (2 ×
CH + CH), 127.2 (CH), 130.0 (2 × CH), 134.9 (CH), 136.6