May-Jun 2003
Synthesis and Isolation of Chloro-β-carbolines
425
136.08 (9a-C), 135.17 (8a-C), 126.77 (7-C), 126.66 (4b-C),
123.83 (4a-C), 123.62 (6-C), 120.37 (5-C), 117.14 (8-C), 113.11
Anal. Calcd. for C H N OCl: C, 61.94; H, 3.90; N, 12.04; O,
12 9 2
6.88; Cl, 15.24. Found: C, 61.96; H, 3.90; N, 12.03; Cl, 15.26.
37
37
+
(4-C) and 20.75 ppm (CH ); ms: m/z 254 ( Cl Cl, M , 12),
3
8-Chloro-harmol (4b).
37
35
+
35
35
+
252 ( Cl Cl, M , 65), 250 ( Cl Cl, M , 100), 222(2), 217
(6), 215 (20), 195 (6), 179 (10), 151 (7), 125 (10), 107 (8).
Anal. Calcd. for C H N Cl : C, 57.39; H, 3.21; N, 11.16; Cl,
1
Compound 4b has mp 268-270° (d) (isopropyl alcohol);
H
nmr (dimethylsulfoxide-d ): δ 11.31 (bs, 1 H, NH), 8.12 (d, 1H,
6
12
8
2
2
3-H, J = 5.1), 7.95 (d, 1H, 5-H, J = 8.4 Hz), 7.80 (d, 1H, 4-H, J =
28.24. Found: C, 57.38; H, 3.20; N, 11.17; Cl, 28.25.
5.1 Hz), 6.93 (d, 1H, 6-H, J = 8.4) and 2.79 ppm (s, 3H, CH );
3
6-Chloro-harmine (3a).
13
C nmr (dimethylsulfoxide-d ): δ 153.54 (7-C), 142.12 (1-C),
6
1
139.44 (9a-C), 138.31 (3-C), 134.58 (8a-C), 128.13 (4b-C),
120.50 (5-C), 115.17 (4a-C), 111.80 (4-C), 110.01 (6-C), 94.61
Compound 3a has mp 251-253° (isopropyl alcohol); H nmr
(dimethylsulfoxide-d ): δ 11.05 (bs, 1 H, NH), 8.13 (d, 1H, 3-H,
6
37
+
(8-C) and 20.66 ppm (CH ); ms: m/z 234 ( Cl, M , 33), 232
J = 5.5 Hz), 8.06 (s, 1H, 5-H), 7.74 (d, 1H, 4-H, J = 5.5 Hz), 7.12
3
35
+
13
(
Cl, M , 100), 204 (20), 197 (17), 170 (22).
Anal. Calcd. for C H N OCl: C, 61.94; H, 3.90; N, 12.04; O,
(s, 1H, 8-H), 4.01 (s, 3H, CH O) and 2.79 ppm (s, 3H, CH );
C
3
3
nmr (dimethylsulfoxide-d ): δ 154.70 (7-C), 141.53 (1-C),
12
9 2
6
6.88; Cl, 15.24. Found: C, 61.95; H, 3.90; N, 12.05; Cl, 15.23.
140.23 (9a-C), 137.93 (3-C), 134.52 (8a-C), 126.52 (4b-C and
5-C), 114.73 (6-C), 114.14 (4a-C), 112.21 (4-C), 94.93 (8-C),
6-Chloro-7-acetylharmol (5a).
37
+
56.11 (CH O ) and 20.23 ppm (CH ); ms: m/z 248 ( Cl, M ,
3
3
1
35
+
Compound 5a has mp 213-215° (d) (benzene-ethanol); H nmr
33), 246 ( Cl, M , 100), 233 (10), 231 (30), 217 (1), 205 (13),
203 (40), 168 (10), 140 (7), 123 (9).
(dimethylsulfoxide-d ): δ 11.81 (s, 1 H, NH), 8.48 (s, 1H, 5-H),
6
8.25 (d, 1H, 3-H, J = 5.2 Hz), 7.50 (s, 1H, 8-H), 7.98 (d, 1H, 4-H,
Anal. Calcd. for C H N OCl: C, 63.29; H, 4.49; N, 11.36; O,
13 11
2
13
J = 5.2), 2.77 (s, 3H, CH ) and 2.39 (s, 3H, CH CO); C nmr
6.49; Cl, 14.37. Found: C, 63.27; H, 4.49; N, 11.37; Cl, 14.38.
3
3
(dimethylsulfoxide-d ): δ 168.57 (CO), 145.89 (7-C), 142.43
6
8-Chloro-harmine (3b).
(1-C), 139.03 (9a-C), 137.73 (3-C), 135.25 (8a-C), 125.92
(4b-C), 122.52 (5-C), 119.89 (4a-C), 117.27 (6-C), 112.83 (4-C),
107.06 (8-C), 20.47 (CH ) and 20.36 ppm (CH CO); ms: m/z
1
Compound 3b has mp 210-212° (isopropyl alcohol); H nmr
(dimethylsulfoxide-d ): δ 11.05 (bs, 1 H, NH), 8.22 (d, 1H, 3-H,
3
3
6
37
+
35
+
276 ( Cl, M , 33), 274 ( Cl, M , 100), 234 (33), 232 (100), 207
(18), 191 (5), 165 (3),133 (3), 114 (2).
J = 5.5 Hz), 8.20 (d, 1H, 5-H, J = 8.4 Hz), 7.89 (d, 1H, 4-H, J =
5.5 Hz), 7.13 (d, 1H, 6-H, J = 8.4 Hz), 3.97 (s, 3H, CH O) and
3
13
Anal. Calcd. for C H N O Cl: C, 61.21; H, 4.04; N, 10.20;
2.80 ppm (s, 3H, CH ); C nmr (dimethylsulfoxide-d ): δ
14 11
2 2
3
6
O, 11.65; Cl, 12.80. Found: C, 61.23; H, 4.04; N, 10.19; Cl,
12.79.
154.80 (7-C), 142.33 (1-C), 139.20 (9a-C), 138.22 (3-C), 134.93
(8a-C), 128.00 (4b-C), 120.92 (4a-C), 116.81 (5-C), 112.31
(4-C), 105.92 (6-C), 103.30 (8-C), 56.81 (CH O) and 20.52 ppm
3
8-Chloro-7-acetylharmol (5b).
37
+
35
+
(CH ); ms: m/z 248 ( Cl, M , 33), 246 ( Cl, M , 100), 233 (8),
3
1
Compound 5b has mp 238-240° (d) (benzene-ethanol); H nmr
231 (25), 215 (1), 205 (20), 203 (60), 168 (8), 140 (8), 123 (9).
(dimethylsulfoxide-d ): δ 11.78 (s, 1 H, NH), 8.28 (d, 1H, 3-H,
J = 5.2 Hz), 8.22 (d, 1H, 5-H, J = 8.5 Hz), 7.98 (d, 1H, 4-H, J =
5.2 Hz), 7.17 (d, 1H, 6-H, J = 8.5), 2.84 (s, 3H, CH ) and 2.40 (s,
3H, CH CO); C nmr (dimethylsulfoxide-d ): δ 179.29 (CO),
Anal. Calcd. for C H N OCl: C, 63.29; H, 4.49; N, 11.36; O,
6
13 11
2
6.49; Cl, 14.37. Found: C, 63.30; H, 4.49; N, 11.35; Cl, 14.36.
3
6,8-Dichloro-harmine (3c).
13
3
6
146.29 (7-C), 143.09 (1-C), 138.42 (3-C), 138.21 (9a-C), 135.21
(8a-C), 127.33 (4b-C), 120.84 (5-C), 115.37 (6-C), 120.76
Compound 3c has mp 222-224° (benzene-isopropyl alcohol;
1
H nmr (dimethylsulfoxide-d ): δ 11.25 (bs, 1 H, NH), 8.17 (d,
6
(4a-C), 112.75 (4-C), 109.35 (8-C), 20.65 (CH ) and 20.38 ppm
1H, 3-H, J = 5.5 Hz), 7.93 (s, 1H, 5-H), 7.64 (d, 1H, 4-H, J = 5.5
3
37
+
35
+
13
(CH CO); ms: m/z 276 ( Cl, M , 3), 274 ( Cl, M , 10), 234
Hz), 3.93 (s, 3H, CH O) and 2.76 ppm (s, 3H, CH ); C nmr
3
3
3
(33), 232 (100), 207 (3), 197 (5), 165 (3),140 (3), 114 (2).
(dimethylsulfoxide-d ): δ 150.90 (7-C), 143.13 (1-C), 137.10
6
Anal. Calcd. for C H N O Cl: C, 61.21; H, 4.04; N, 10.20;
O, 11.65; Cl, 12.80. Found: C, 61.22; H, 4.04; N, 10.21; Cl,
12.79.
(9a-C), 138.62 (3-C), 135.20 (8a-C), 126.72 (4b-C), 121.20
(5-C), 119.41 (4a-C), 118.90 (6-C), 112.72 (4-C), 111.30 (8-C),
14 11
2 2
37
37
60.91 (CH O ) and 20.72 ppm (CH ); ms: m/z 284 ( Cl Cl,
3
3
+
37
35
+
35
35
+
M , 10), 282 ( Cl Cl, M , 75), 280 ( Cl Cl, M , 100), 267
(25), 265 (75), 253 (2), 239 (30), 237 (90), 202 (5).
6,8-Dichloro-7-acetylharmol (5c).
Compound 5c was obtained as trace in the chlorination of
compound 5 in solution (see Table I, method (ii)). H nmr
Anal. Calcd. for C
5.69; Cl, 25.22. Found: C, 55.55; H, 3.59; N, 9.98; Cl, 25.24.
H N OCl : C, 55.54; H, 3.59; N, 9.96; O,
13 10 2 2
1
(dimethylsulfoxide-d ): δ 11.78 (s, 1 H, NH), 8.26 (d, 1H, 3-H,
6
6-Chloro-harmol (4a).
J = 5.2 Hz), 8.50 (s, 1H, 5-H), 7.97 (d, 1H, 4-H, J = 5.2 Hz), 2.85
37
+
Compound 4a was obtained by hydrolysis of 6-chloro-7-
acetylharmol (5a). mp 260-262° (d) (benzene-ethanol); H nmr
(s, 3H, CH ) and 2.43 (s, 3H, CH CO); ms: m/z 310 ( Cl, M ,
3), 308 ( Cl, M , 10), 268 (70), 266 (100), 231 (8).
3
3
1
35
+
(dimethylsulfoxide-d ): δ 11.30 (bs, 1 H, NH), 8.10 (s, 1H,
6
General Procedure for the Chlorination Reaction of β-Carbolines
(1-5) in Solid State with N-Chlorosuccinimide (NCS) (Table I,
method (iii)).
5-H), 8.03 (d, 1H, 3-H, J = 5.1), 7.90 (d, 1H, 4-H, J = 5.1 Hz),
13
7.50 (s, 1H, 8-H) and 2.79 ppm (s, 3H, CH ); C nmr
3
(dimethylsulfoxide-d ): δ 154.44 (7-C), 141.02 (1-C), 139.23
6
(9a-C), 137.83 (3-C), 135.55 (8a-C), 127.11 (4b-C), 121.50
(5-C), 115.11 (4a-C), 114.15 (6-C), 110.80 (4-C), 96.66 (8-C)
The substrate (~1.0 g) and freshly powdered NCS (1:1.2 molar
equivalents) were mixed very gently in a mortar, at room tempera-
ture. Aliquots were taken at different reaction times, dissolved in
ethanol and the fresh solution was immediately monitored: (a) by tlc
37
+
35
and 22.57 ppm (CH ); ms: m/z 234 ( Cl, M , 33), 232 ( Cl,
3
+
M , 100), 204 (10), 197 (25), 170 (13).