Job/Unit: O30770
/KAP1
Date: 29-07-13 11:34:02
Pages: 9
Generation of β-Carboline Analogs and Biological Study
Tryptamide (16): Tryptamine 6 (10 mmol, 1.6 g), was dissolved in
dry CH2Cl2 (20 mL). Succinic anhydride (1.1 equiv., 11 mmol,
1.1 g) was added slowly. The reaction was stirred at room temp. for
18 h. The resulting precipitate was filtered, washed with a small
amount of CH2Cl2 and dried to furnish tryptamide (16) (2.5 g,
98%), white crystalline powder; Rf = 0.3 (CH2Cl2/MeOH, 9:1);
25 °C): δ = 8.98 (br., 1 H, -NH), 8.51 (d, J = 5.2 Hz, 1 H, 2-H),
8.17 (d, J = 15.2 Hz, 1 H, 4-H), 8.11 (d, J = 8.0 Hz, 1 H, 11-H),
7.96 (d, J = 4.8 Hz, 1 H, 1-H), 7.56 (m, 2 H, 9-H, 8-H), 7.32 (t, J
= 7.6 Hz, 1 H, 10-H), 7.18 (d, J = 15.2 Hz, 1 H, 5-H), 3.84 (s, 3
H, -OMe) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 167.76
(6-C), 140.64 (7a-C), 139.75 (2-C), 138.77 (4-C), 136.24 (3b-C),
135.39 (3a-C), 130.86 (11b-C), 129.30 (8-C), 122.02 (11-C), 121.78
(5-C), 121.62 (11a-C), 120.86 (10-C), 116.06 (1-C), 111.90 (9-C),
m.p. 128–130 °C (CH Cl ). IR (film, CH Cl ): ν = 3394, 3271,
˜
max
2
2
2
2
2939, 1686, 1638, 1226, 1172, 833, 739, 669, 623 cm–1. 1H NMR
(400 MHz, CD3OD, 25 °C): δ = 7.54 (d, J = 8 Hz, 1 H, 4-H), 7.31 52.14 (-OMe) ppm. ESIMS m/z 253 [M + H]+. HRESIMS m/z
(d, J = 8 Hz, 1 H, 7-H), 7.10–7.07 (m, 2 H, 2-H, 6-H), 7.0–6.99
(dt, J = 8.0, 0.9 Hz, 1 H, 5-H), 3.45 (t, J = 7.3 Hz, 2 H, 9-H), 2.91
(t, J = 7.3 Hz, 2 H, 8-H), 2.56 (t, J = 6.9 Hz, 2 H, 13-H), 2.42 (t,
J = 6.9 Hz, 2 H, 12-H) ppm. 13C NMR (100 MHz, CD3OD, 25 °C):
δ = 174.2 (14-C), 171.1 (11-C), 136.6 (b-C), 127.6 (a-C), 122.9 (2-
C), 121.2 (6-C), 118.8 (5-C), 118.5 (4-C), 112.2 (3-C), 111.7 (7-C),
40.8 (9-C), 30.5 (12-C), 29.6 (13-C), 25.5 (8-C) ppm. ESIMS m/z
253.0976 (calcd. for C15H13N2 O2, 253.0972).
4,5-Dihydrocanthin-6-one (11): The preceeding crude mixture was
dissolved in CH2Cl2 (30 mL) and DBU (3 equiv., 2.73 mmol,
0.4 mL) was added, the solution was then stirred at room temp.
overnight. The reaction was quenched with a saturated NaHCO3
solution (10 mL), and the aqueous fraction was washed success-
ively with CH2Cl2 (2ϫ 30 mL), dried with Na2SO4 and concen-
trated under reduced pressure. The mixture was purified by flash
chromatography (cyclohexane/EtOAc, 6:4) to furnish 11 (126 mg,
61%). Alternatively, to a solution of 1 (0.09 mmol, 20 mg) in
283 [M
+
Na]+. HRESIMS m/z 283.1053 (calcd. for
C14H16N2O3Na, 283.1059).
Methyl Ester 17: Tryptamide 16 (7.6 mmol, 2 g), was dissolved in
MeOH (60 mL). Catalytic Amberlyst H-15® (20% w/w, 200 mg) EtOAc (2 mL) was added 5% Pd/C (1 mg). The reaction mixture
was added and the solution was heated under reflux for 18 h. The
solution was then filtered and the solvent was removed under re-
duced pressure. The crude product was crystallized from di-
isopropyl ether to furnish 17 (2.0 g, 98%), white crystalline powder;
m.p. 101–102 °C (CH2Cl2); Rf = 0.6 (CH2Cl2/MeOH, 9:1). IR (film,
was stirred under an atmosphere of H2. An additional amount of
5% Pd/C (1 mg) was added to the reaction mixture every hour until
completion of the reaction as determined by TLC; 4 additions were
needed). The reaction mixture was filtered thought a plug of silica
gel and concentrated under reduced pressure. The crude material
CH Cl ): ν = 3336, 3282, 2862, 1721, 1651, 1538, 1258, 1221, was column chromatographed (cyclohexane/EtOAc, 6:4) to yield
˜
max
2
2
1188, 936, 800 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 8.30
11 (18 mg, 90%), pale yellow crystalline powder; m.p. 161–163 °C
(br., 1 H, -NH), 7.58 (d, J = 7.8 Hz, 1 H, 4-H), 7.35 (d, J = 7.8 Hz,
1 H, 7-H), 7.18 (t, J = 7.8 Hz, 1 H, 6-H), 7.10 (t, J = 7.8 Hz, 1 H,
5-H), 7.04 (s, 1 H, 2-H), 5.30 (s, 1 H, -NH), 3.64 (s, 3 H, -OMe),
3.57 (t, J = 6.5 Hz, 2 H, 9-H), 2.95 (t, J = 6.5 Hz, 2 H, 8-H), 2.63
(CH2Cl2); Rf = 0.4 (Cyclohexane/EtOAc, 7:3). IR (film, CH2Cl2):
1
ν
˜
= 1673, 1434, 1141, 841, 793, 746 cm–1. H NMR (400 MHz,
max
CDCl3, 25 °C): δ = 8.52 (m, 2 H, 8-H, 2-H), 8.05 (d, J = 7.6 Hz, 1
H, 11-H), 7.73 (d, J = 5.6 Hz,1 H, 1-H), 7.66 (t, J = 8.4 Hz, 1 H,
(t, J = 6.8 Hz, 2 H, 13-H), 2.39 (t, J = 6.8 Hz, 2 H, 12-H) ppm. 9-H), 7.48 (t, J = 7.6 Hz, 1 H, 10-H), 3.49 (t, J = 7.6 Hz, 2 H, 4-
13C NMR (100 MHz, CDCl3, 25 °C): δ = 173.4 (14-C), 172.7 (11-
C), 136.6 (b-C), 127.3 (a-C), 122.1 (2-C), 121.8 (6-C), 120.8 (5-C),
117.8 (4-C), 111.7 (3-C), 110.7 (7-C), 57.0 (-OMe), 40.0 (9-C), 29.9
(12-C), 28.7 (13-C), 24.7 (8-C) ppm. ESIMS m/z 297 [M + Na]+.
HRESIMS m/z 297.1216 (calcd. for C15H18N2 O3Na, 297.1215).
H), 3.22 (t, J = 7.6 Hz, 2 H, 5-H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 166.85 (6-C), 144.03 (2-C), 142.74 (3b-C),
137.89 (7a-C), 135.41 (11b-C), 130.25 (9-C), 129.67 (3a-C), 124.707
(10-C), 124.51 (11a-C), 122.17 (11-C), 116.81 (8-C), 113.40 (1-C),
33.33 (5-C), 27.65 (4-C) ppm. ESIMS m/z 223 [M + H]+. HRES-
IMS m/z 223.0869 (calcd. for C14H11N2 O, 223.0866).
Infractine (10) and 4,5-Dehydroinfractine (14): Trifluoromethane-
sulfonic anhydride (1.5 equiv., 1.37 mmol, 0.23 mL) was added over
1 min to a stirred mixture of 17 (0.91 mmol, 250 mg) and 2-chloro-
pyridine (1.5 equiv., 1.37 mmol, 0.13 mL) in CH2Cl2 (10 mL) at
–78 °C. After 5 min, the reaction mixture was brought to 0 °C for
5 min and then to room temp. After 3 h, the reaction was quenched
with a saturated NaHCO3 solution (10 mL), and the aqueous frac-
tion was washed successively with dichloromethane (2ϫ 30 mL),
dried with Na2SO4 and concentrated under reduced pressure. The
crude reaction mixture was either used in the next reaction without
further purification or purified by flash chromatography (cyclohex-
ane/EtOAc, 6:4) to furnish 10 (142 mg, 60%) and 14 (57 mg, 24%).
10: brown oil; Rf = 0.6 (cyclohexane/EtOAc, 7:3). IR (film,
Canthin-6-one (1): Trifluoromethanesulfonic anhydride (4 equiv.,
3.64 mmol, 0.62 mL) was added over 1 min to a stirred mixture of
17 (0.91 mmol, 250 mg) and of 2-chloropyridine (4 equiv.,
3.64 mmol, 0.34 mL) in CH2Cl2 (10 mL) at –78 °C with air bub-
bling in the reaction vessel. After 5 min, the reaction mixture was
brought to 0 °C for 5 min and then to room temp. After 5 h, the
reaction was diluted with an aqueous saturated solution of
NaHCO3 (10 mL) and the aqueous layer was extracted with
CH2Cl2 (2ϫ 30 mL), then dried with Na2SO4 and concentrated
under reduced pressure. The crude reaction was dissolved in tolu-
ene (30 mL) and DMAP (3 equiv., 2.73 mmol, 333.5 mg) was
added. The solution was then stirred with air bubbling, at room
temp. for 1 d. The reaction was diluted with an aqueous saturated
CH Cl ): νmax = 2850, 1698, 1632, 1182, 1040, 748 cm–1. 1H NMR
˜
2
2
(400 MHz, CDCl3, 25 °C): δ = 9.25 (br., 1 H, -NH), 8.4 (d, J = solution of NaHCO3 (10 mL), the aqueous layer was extracted with
5.2 Hz, 1 H, 2-H), 8.13 (d, J = 8.0 Hz, 1 H, 11-H), 7.85 (d, J = CH2Cl2 (2ϫ 30 mL), dried with Na2SO4 and concentrated under
5.2 Hz, 1 H, 1-H), 7.57 (m, 2 H, 8-H, 9-H), 7.30 (m, 1 H, 10-H),
3.68 (s, 3 H, -OMe), 3.47 (t, J = 6.8 Hz, 2 H, 4-H), 3.03 (t, J =
6.4 Hz, 2 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
174.98 (6-C), 143.93 (3b-C), 140.50 (7a-C), 138.76 (2-C), 134.63
reduced pressure. The crude mixture was then purified by flash
chromatography (cyclohexane/EtOAc, 7:3) to furnish 1 (150 mg,
73%). Alternatively, to a solution of 11 (0.09 mmol, 20 mg) in tolu-
ene (2 mL) DDQ was added (0.09 mmol, 20.5 mg). The reaction
(3a-C), 129.02 (11b-C), 128.29 (8-C), 122.01 (11a-C), 121.72 (11- mixture was stirred 1 d at room temp., filtered through a plug of
C), 119.99 (10-C), 113.25 (1-C), 111.85 (9-C), 52.0 (-OMe), 32.70
(5-C), 28.85 (4-C) ppm. ESIMS m/z 255 [M + H]+. HRESIMS m/z
255.1123 (calcd. for C15H15N2 O2Na, 255.1123). 14: brown oil; Rf
silica gel and purified by flash chromatography (cyclohexane/
EtOAc, 7:3) to furnish 1 (11 mg, 55%), white crystalline powder;
m.p. 161–163 °C (CH2Cl2); Rf = 0.6 (CH2Cl2/MeOH, 9:1). IR (film,
= 0.7 (cyclohexane/EtOAc, 7:3). IR (film, CH Cl ): ν
= 2850,
CH Cl ): ν
= 1673, 1434, 1141, 841, 793, 746 cm–1. 1H NMR
˜
˜
2
2
max
2
2
max
1698, 1632, 1182, 1040, 748 cm–1. 1H NMR (400 MHz, CDCl3, (400 MHz, CDCl3, 25 °C): δ = 8.78 (d, J = 5.0 Hz, 1 H, 2-H), 8.63
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