3378 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 15
Velu et al.
141.1; IR (neat) 3407 cm-1; MS (ES) m/z 277 (M + H); Anal.
8-(5-Nitr o-1H-in d ol-1-yl)-1-octyl Nicotin a te (5g). Yield
69%; mp 67-68 °C, 1H NMR (CDCl3) δ 1.28-1.47 (m, 8H),
1.71-1.80 (m, 2H), 1.80-1.92 (m, 2H), 4.17 (t, 2H), 4.34 (t,
2H), 6.68 (d, 1H), 7.24-7.42 (m, 3H), 8.10 (dd, 1H), 8.29 (dt,
1H), 8.58 (d, 1H), 8.79 (dd, 1H), and 9.22 (d, 1H); 13C NMR
(CDCl3) δ 24.8, 25.7, 28.4, 28.9 (2C), 30.1, 46.8, 65.3, 103.8,
109.1, 117.0, 118.1, 123.2, 126.2, 127.6, 130.9, 136.9, 138.7,
141.3, 150.8, 153.3, and 166.2; IR (KBr) 1717 cm-1; MS (ES)
m/z 396 (M + H); Anal. (C22H25N3O4) C, H, N.
Gen er a l P r oced u r e for Qu a ter n iza tion . This procedure
is illustrated for the preparation of 2-(5-nitro-1H-indol-1-yl)-
ethyl N-methylnicotinate, iodide (6a ).
To a solution of the ester 5a (0.156 g, 0.502 mmol) in DME
(8 mL) was added iodomethane (0.32 mL, 5.1 mmol), and the
mixture was heated at 80 °C for 12 h. This was cooled to room
temperature, and the solvent was completely removed. The
residue was purified by column chromatography (10 × 2 cm)
using MeOH/CHCl3 (1:19) to obtain the pure pyridinium salt
6a (0.192 g, 84.0%).
(C15H20N2O3) C, H, N.
8-(5-Nitr o-1H-in d ol-1-yl)-1-octa n ol (4g). Yield 61%; mp
74-75 °C, 1H NMR (CDCl3) δ 1.25-1.36 (m, 8H), 1.41-1.60
(m, 3H including OH), 1.78-1.90 (m, 2H), 3.61 (t, 2H), 4.15
(t, 2H), 6.65 (d, 1H), 7.24 (d, 1H), 7.33 (d, 1H), 8.08 (dd, 1H),
and 8.56 (d, 1H); 13C NMR (CDCl3) δ 25.5, 26.7, 29.0, 29.1,
30.1, 32.5, 46.7, 62.7, 103.7, 109.1, 116.9, 118.1, 127.5, 130.9,
138.7, and 141.2; IR (neat) 3318 cm-1; MS (ES) m/z 291 (M +
H); Anal. (C16H22N2O3) C, H, N.
Gen er a l P r oced u r e for Ester ifica tion . This procedure
is illustrated for the preparation of [2-(5-nitro-1H-indol-1-yl)-
ethyl] nicotinate (5a ).
To a solution of alcohol 4a (0.20 g, 0.97 mmol) in CH2Cl2
(15 mL) were added nicotinic acid (0.143 g, 1.16 mmol), DCC
(0.221 g, 1.07 mmol), and DMAP (0.012 g, 0.099 mmol) and
stirred at room temperature for 24 h. Precipitation of a white
solid occurred. This was filtered and washed on the filter with
CH2Cl2 (15 mL). The combined filtrate was washed with water
(2 × 10 mL) and brine (2 × 10 mL). Removal of solvent from
the dried (Na2SO4) extract gave the crude product. It was
purified by flash column chromatography (20 × 3 cm) over
silica gel using acetone/hexanes (3:7) to afford the pure ester
5a (0.26 g, 87%).
2-(5-Nitr o-1H-in d ol-1-yl)eth yl Nicotin a te (5a ). Oil; 1H
NMR (CDCl3) δ 4.52 (t, 2H), 4.64 (t, 2H), 6.66 (d, 1H), 7.22-
7.38 (m, 3H), 8.02-8.09 (m, 2H), 8.53 (d, 1H), 8.71 (dd, 1H),
and 9.05 (d, 1H); 13C NMR (CDCl3) δ 45.2, 48.9, 104.6, 108.9,
117.2, 118.1, 123.3, 125.1, 127.6, 130.9, 137.0, 138.8, 141.5,
150.4, 153.4, and 164.5; MS (ES) m/z 312 (M + H).
3-(5-Nitr o-1H-in d ol-1-yl)-1-p r op yl Nicotin a te (5b). Yield
74%; mp 118-119 °C, 1H NMR (CDCl3) δ 2.29 (p, 2H), 4.28 (t,
2H), 4.31 (t, 2H), 6.62 (d, 1H), 7.19-7.34 (m, 3H), 8.10 (dd,
1H), 8.20 (dt, 1H), 8.57 (d, 1H), 8.81 (dd, 1H), and 9.18 (d, 1H);
13C NMR (CDCl3) δ 28.9, 43.4, 62.1, 104.1, 108.8, 117.0, 118.0,
123.1, 125.3, 127.5, 130.8, 136.7, 138.4, 141.2, 150.4, 153.4,
and 164.7; IR (neat) 1718 cm-1; MS (ES) m/z 326 (M + H);
Anal. (C17H15N3O4) C, H, N.
2-(5-Nitr o-1H-in d ol-1-yl)eth yl N-Meth yln icotin a te, Io-
d id e (6a ). Oil; 1H NMR (DMSO-d6) δ 4.41 (s, 3H), 4.74 (s, 4H),
6.73 (d, 1H), 7.79 (d, 1H), 7.83 (d, 1H), 8.00 (dd, 1H), 8.24 (dd,
1H), 8.53 (d, 1H), 8.83 (d, 1H), 9.19 (d, 1H), and 9.43 (s, 1H);
13C NMR (DMSO-d6) δ 44.8, 48.2, 65.4, 103.9, 110.3, 116.4,
117.4, 127.4, 127.8, 128.8, 132.8, 138.8, 140.8, 144.5, 146.6,
149.0, and 161.1; MS (ES) m/z 326 (M + H); Anal. (C17H16
IN3O4‚0.5H2O) C, H, N.
-
3-(5-Nitr o-1H-in d ol-1-yl)-1-p r op yl N-Meth yln icotin a te,
Iod id e (6b). Yield 88%; mp 182-183 °C, 1H NMR (DMSO-d6)
δ 2.29 (p, 2H), 4.34 (t, 2H), 4.43 (s, 3H), 4.52 (t, 2H), 6.76 (d,
1H), 7.72-7.78 (m, 2H), 7.99 (dd, 1H), 8.23 (dd, 1H), 8.53 (d,
1H), 8.83 (d, 1H), 9.19 (d, 1H), and 9.44 (s, 1H); 13C NMR
(DMSO-d6) δ 28.5, 43.0, 48.3, 63.9, 103.8, 110.4, 116.4, 117.5,
127.3, 127.7, 129.1, 132.6, 138.7, 140.6, 144.7, 146.5, 148.8,
and 161.5; IR (neat) 1735 cm-1; MS (ES) m/z 340 (M + H);
Anal. (C18H18IN3O4) C, H, N.
4-(5-Nitr o-1H-in d ol-1-yl)-1-bu tyl N-Meth yln icotin a te,
Iod id e (6c). Yield 60%; Oil; 1H NMR (CDCl3) δ 1.81-1.93 (m,
2H), 2.05-2.19 (m, 2H), 4.32 (t, 2H), 4.44 (t, 2H), 4.80 (s, 3H),
6.69 (d, 1H), 7.39 (d, 1H), 7.50 (d, 1H), 8.08 (dd, 1H), 8.21 (dd,
1H), 8.55 (d, 1H), 8.90 (d, 1H), 9.44 (d, 1H), and 9.67 (s, 1H);
13C NMR (CDCl3) δ 25.9, 26.9, 46.4, 50.2, 66.7, 104.1, 109.6,
117.1, 118.2, 127.7, 128.2, 130.5, 131.3, 138.7, 141.4, 145.3,
146.4, 148.4, and 160.7; MS (ES) m/z 354 (M + H); Anal.
(C19H20IN3O4‚0.75H2O) C, H, N.
4-(5-Nitr o-1H-in d ol-1-yl)-1-bu tyl Nicotin a te (5c). Yield
1
100%; Oil; H NMR (CDCl3) δ 1.66-1.76 (m, 2H), 1.91-2.02
(m, 2H), 4.18 (t, 2H), 4.29 (t, 2H), 6.61 (d, 1H), 7.17-7.34 (m,
3H), 8.01 (dd, 1H), 8.17 (dt, 1H), 8.49 (d, 1H), 8.70 (dd, 1H),
and 9.10 (d, 1H); 13C NMR (CDCl3) δ 25.3, 25.9, 45.5, 63.8,
103.3, 108.5, 116.2, 117.3, 122.6, 125.2, 126.9, 130.4, 136.3,
137.9, 140.5, 149.7, 152.4, and 164.2; MS (ES) m/z 340 (M +
H).
5-(5-Nitr o-1H-in d ol-1-yl)-1-p en tyl N-Meth yln icotin a te,
1
Iod id e (6d ). Yield 74%; mp 107-108 °C; H NMR (CDCl3) δ
5-(5-Nitr o-1H-in d ol-1-yl)-1-p en tyl Nicotin a te (5d ). Yield
60%; mp 84-85 °C, 1H NMR (CDCl3) δ 1.42-1.52 (m, 2H),
1.78-1.87 (m, 2H), 1.91-1.99 (m, 2H), 4.21 (t, 2H), 4.34 (t,
2H), 6.68 (d, 1H), 7.25 (d, 1H), 7.36-7.41 (m, 2H), 8.10 (dd,
1H), 8.23 (dt, 1H), 8.58 (d, 1H), 8.87 (dd, 1H), and 9.19 (d, 1H);
13C NMR (CDCl3) δ 23.0, 27.9, 29.5, 46.3, 64.5, 103.7, 108.9,
116.8, 117.9, 123.0, 125.7, 127.4, 130.8, 136.6, 138.5, 141.1,
150.5, 153.1, and 164.9; IR (KBr) 1717 cm-1; MS (ES) m/z 354
(M + H); Anal. (C19H19N3O4‚0.3H2O) C, H, N.
1.40-1.58 (m, 2H), 1.80-2.0 (m, 4H), 4.28 (t, 2H), 4.42 (t, 2H),
4.82 (s, 3H), 6.67 (d, 1H), 7.34 (d, 1H), 7.47 (d, 1H), 8.05 (dd,
1H), 8.26 (t, 1H), 8.54 (d, 1H), 8.88 (d, 1H), 9.51 (s, 1H), and
9.55 (d, 1H); 13C NMR (MeOH-d4) δ 24.1, 29.2, 30.9, 47.4, 48.3,
67.7, 104.8, 111.1, 117.7, 118.8, 129.3, 129.4, 132.1, 133.2,
140.5, 142.6, 146.3, 148.2, 149.8, and 162.7; IR (KBr) 1729
cm-1; MS (ES) m/z 368 (M + H); Anal. (C20H22IN3O4) C, H, N.
6-(5-Nitr o-1H-in d ol-1-yl)-1-h exyl N-Meth yln icotin a te,
1
Iod id e (6e). Yield 64%; mp 127-128 °C, H NMR (CDCl3) δ
6-(5-Nitr o-1H-in d ol-1-yl)-1-h exyl Nicotin a te (5e). Yield
90%; mp 64-65 °C, 1H NMR (CDCl3) δ 1.32-1.52 (m, 4H),
1.70-1.81 (m, 2H), 1.82-1.93 (m, 2H), 4.17 (t, 2H) 4.31 (t, 2H),
6.65 (d, 1H), 7.23-7.41 (m, 3H), 8.07 (dd, 1H), 8.26 (dt, 1H),
8.55 (d, 1H), 8.76 (dd, 1H), and 9.19 (d, 1H); 13C NMR (CDCl3)
δ 25.5, 26.4, 28.4, 30.0, 46.6, 65.1, 103.8, 109.1, 117.0, 118.1,
123.2, 126.1, 127.5, 130.8, 136.8, 138.6, 141.3, 150.7, 153.3,
and 165.1; IR (KBr) 1721 cm-1; MS (ES) m/z 368 (M + H);
Anal. (C20H21N3O4) C, H, N.
7-(5-Nitr o-1H-in d ol-1-yl)-1-h ep tyl Nicotin a te (5f). Yield
73%; mp 78-79 °C, 1H NMR (CDCl3) δ 1.28-1.49 (m, 6H),
1.71-1.80 (m, 2H), 1.82-1.92 (m, 2H), 4.17 (t, 2H), 4.33 (t,
2H), 6.68 (d, 1H), 7.25 (d, 1H), 7.33-7.61 (m, 2H), 8.11 (dd,
1H), 8.29 (dt, 1H), 8.59 (d, 1H), 8.78 (dd, 1H), and 9.22 (d, 1H);
13C NMR (CDCl3) δ 25.8, 26.7, 28.5, 28.7, 30.1, 46.8, 65.2, 103.9,
109.1, 117.1, 118.3, 123.3, 126.2, 127.7, 130.9, 137.0, 138.8,
141.5, 150.8, 153.4, and 165.3; IR (neat) 1720 cm-1; MS (ES)
m/z 382 (M + H); Anal. (C21H23N3O4) C, H, N.
21.31-1.55 (m, 4H), 1.74-1.83 (m, 2H), 1.83-1.97 (m, 2H),
4.21 (t, 2H), 4.39 (t, 2H), 4.78 (s, 3H), 6.67 (d, 1H), 7.40 (d,
1H), 7.47 (d, 1H), 8.05 (dd, 1H), 8.29 (dd, 1H), 8.54 (d, 1H),
8.89 (d, 1H), 9.44 (s, 1H), and 9.64 (d, 1H); 13C NMR (CDCl3)
δ 25.5, 26.4, 28.3, 30.0, 46.8, 50.3, 67.2, 103.8, 109.4, 117.1,
118.1, 127.6, 128.5, 130.4, 131.1, 138.7, 141.2, 145.1, 146.1,
148.8, and 160.8; IR (KBr) 1721 cm-1; MS (ES) m/z 382 (M +
H); Anal. (C21H24IN3O4) C, H, N.
7-(5-Nitr o-1H-in d ol-1-yl)-1-h ep tyl N-Meth yln icotin a te,
Iod id e (6f). Yield 82%; mp 97-98 °C, 1H NMR (CDCl3) δ
1.30-1.45 (m, 6H), 1.73-1.80 (m, 2H), 1.81-1.90 (m, 2H), 4.16
(t, 2H), 4.38 (t, 2H), 4.78 (s, 3H), 6.66 (d, 1H), 7.24 (d, 1H),
7.36 (d, 1H), 8.08 (dd, 1H), 8.31 (t, 1H), 8.56 (d, 1H), 8.91(d,
1H), 9.04 (s, 1H), and 9.70 (d, 1H); 13C NMR (CDCl3) δ 25.6,
26.6, 28.3, 28.6, 30.1, 46.8, 50.4, 67.4, 103.9, 109.3, 117.1, 118.2,
127.6, 128.5, 130.6, 131.1, 138.8, 141.4, 145.1, 146.0, 148.9,
and 160.8; MS (ES) m/z 396 (M + H); Anal. (C22H26IN3O4) C,
H, N.