April 2012
437
Chart 4. Synthesis of 3,6-Substituted β-Carboline Compounds 3 and 4
°
acid in the presence of polyphosphoric acid (PPA) in 180 C carboline (4) 3-Amino-β-carboline (3d) was prepared
for 6h in 45% yield.30) Subsequently, we treated 2e with by a Curtius-Rearrangement reaction starting with ethyl
FeSO4 and H2O2 in different reagents (including formamide β-carboline-3-carboxylate (2c). Thus, refluxing of 2c with
°
or N-methylformamide), under mild conditions (10–15 C) via 85% hydrazine hydrate in MeOH gave the hydrazide 3b
Minisci-Reaction, giving the expected products 1-carbamoyl- which, after treatment with sodium nitrite, yielded the azide
3-(1H-benzo[d]imidazol-2-yl)-β-carboline (2f) in 55% yield 3c.27) When 3c was refluxed for several minutes in HCl
(Chart 3).31–36) The title compound 2 was achieved from 2f solution, rearrangement to the amine 3d occurred in good
by the method analogus with 1f prepared from 1d mentioned yield.27) Treatment of 3d with methanol (or cyclohexylmetha-
above.
nol) and H2SO4 in the presence of isoamyl nitrite provided
Yield 60%. mp 321–323 C (MeOH). 1H-NMR (300MHz, 4e.27) Subsequently, we treated 4e with FeSO4 and H2O2 in
DMSO-d6) δ: 13.12 (1H, s, benzimidazole), 12.27 (1H, s, the presence of H2SO4 in formamide under mild conditions
°
°
indole), 9.34 (1H, s, ArH), 9.06 (1H, s, ArH), 8.95 (1H, d, (10–15 C) via Minisci-Reaction, giving the expected products
J=7.7Hz, ArH), 8.07 (1H, d, J=7.7Hz, ArH), 7.59–7.74 (2H, 1-carbamoyl-3-cyclohexylmethoxy-β-carboline (4f).37) The key
m, –CONH2), 7.30 (2H, s, –SO2NH2), 7.29–7.24 (4H, m, ArH). intermediate 4f was converted into the target molecules 4 in
13C-NMR (300MHz, DMSO-d6) δ: 167.2 (s), 151.4 (s), 144.2 45–80% yields through both the chlorosulfonylation in dry
(s), 143.4 (s), 137.1 (s), 136.2 (s), 135.4 (s), 134.6 (s), 132.3 (s), chlorosulfonic acid and subsequent aminolysis with amine
131.7 (d), 126.5 (d), 122.8 (d), 121.7 (d), 120.6 (d), 119.5 (s), solution (Chart 4).
1
119.1 (d), 115.6 (d), 113.5 (d), 111.3 (s). IR (KBr) cm−1: 3415,
Yield 65%. mp 304–306 C (MeOH). H-NMR (300MHz,
°
3280, 3124, 3111, 1725. MS m/z: 408 (M+1)+. Anal. Calcd for DMSO-d6) δ: 11.64 (1H, s, indole), 8.70 (1H, s, ArH), 8.07
C19H14N6O3S: C, 56.15; H, 3.47; N, 20.68; Found: C, 56.18; H, (1H, s, ArH), 7.97 (1H, d, J=7.9Hz, ArH), 7.89 (1H, m, ArH),
3.36; N, 20.70.
7.69–7.81 (2H, m, –CONH2), 7.22 (2H, s, –SO2NH2), 4.23 (2H,
6-Aminosulfonyl-1-carbamoyl-3-methoxy-β-carboline (3) d, J=5.2Hz, –CH2O), 1.0–2.0 (11H, m, cyclohexyl). 13C-NMR
For compound 3, the same method with compound 4 as fol- (300MHz, DMSO-d6) δ: 167.3 (s), 155.6 (s), 144.4 (s), 135.1
low is used, only the cyclohexanol group was introduced from (s), 134.9 (s), 132.1 (d), 128.2 (s), 126.6 (d), 120.6 (d), 118.8 (s),
intermedium 3d.27)
112.8 (d), 104.1 (s), 71.3 (t), 37.2 (d), 29.4 (t), 26.1 (t), 25.3 (t).
Yield 57%. mp 165–167 C (MeOH). 1H-NMR (300MHz, IR (KBr) cm−1: 3465, 3346, 3319, 1672. MS m/z: 402 (M+1)+.
DMSO-d6) δ: 11.68 (1H, s, indole), 8.72 (1H, s, ArH), 8.12 (1H, Anal. Calcd for C19H22N4O4S: C, 56.70; H, 5.51; N, 13.92;
s, ArH), 7.96 (1H, d, J=7.8Hz, ArH), 7.8 (2H, m, –CONH2), Found: C, 56.67; H, 5.55; N, 13.90.
°
7.23 (2H, s, –SO2NH2), 7.1 (1H, d, J=7.8Hz, ArH), 4.02 (3H,
6-Aminosulfonyl-1-N-methylcarbamoyl-β-carboline (5)
s, –OCH3). 13C-NMR (300MHz, DMSO-d6) δ: 167.2 (s), 155.6 Compound 5 was obtained by the similar process as com-
(s), 144.5 (s), 135.2 (s), 134.9 (s), 132.2 (d), 128.1 (s), 126.6 pound 1 mentioned above via 5d and 5e37) (Chart 2).
1
°
(d), 120.7 (d), 118.8 (s), 112.8 (d), 104.1 (s), 53.8 (q). IR (KBr)
Yield 68%. mp 256–257 C (MeOH). H-NMR (300MHz,
cm−1: 3470, 3350, 3304, 1672. MS m/z: 321 (M+1)+. Anal. DMSO-d6) δ: 12.09 (1H, s, indole), 8.90 (1H, d, J=4.8Hz,
Calcd for C13H12N4O4S: C, 48.74; H, 3.78; N, 17.49; Found: C, ArH), 8.78 (1H, s, ArH), 8.50 (1H, m, ArH), 8.00 (1H,
48.70; H, 3.84; N, 17.51.
m, ArH), 7.90 (1H, d, J=8.4Hz, –CONH–), 7.20 (2H, s,
6-Aminosulfonyl-1-carbamoyl-3-cyclohexylmethoxy-β- –SO2NH–), 2.90 (3H, d, J=4.8Hz, –CONCH3). 13C-NMR