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J. Reniers et al. / Bioorg. Med. Chem. 19 (2011) 134–144
O–CH2), 6.89 (dd, 1H, J6–5 = 8.7 Hz, J6–8 = 2.3 Hz, H-6), 6.93 (d,
(CH3), 68.65 (O–CH2), 96.21 (C-8), 110.05 (C-6), 112.39 (C-4),
116.60 (Cq), 121.58 (C–ArH), 123.04 (C-5), 128.49 (Cq), 134.82
(Cq), 139.16 (C-3), 141.28 (Cq), 141.51 (Cq), 146.19 (Cq), 150.14
(C–ArH), 159.24 (Cq). MS: [M+H]+ 290.1. Anal. Calcd for
J8–6 = 2.1 Hz, 1H, H-8), 7.22–7.34 (m, 5H, ArH), 7.71 (d, J4–3
5.3 Hz, 1H, H-4), 7.94 (d, J5–6 = 8.5 Hz, 1H, H-5), 8.30 (d, J3–4
=
=
5.5 Hz, 1H, H-3), 8.89 (s, 1H, N–H). 13C NMR (CDCl3) d: 20.16
(CH3), 35.85 (CH2), 69.16 (O–CH2), 95.64 (C-8), 110.27 (C-6),
112.37 (C-4), 115.89 (Cq), 122.78 (C-5), 126.68 (C–ArH), 128.63
(C–ArH), 128.84 (Cq), 129.12 (C–ArH), 134.80 (Cq), 138.20 (Cq),
138.52 (C-3), 140.98 (Cq), 141.94 (Cq), 160.12 (Cq). MS: [M+H]+
303.1. Anal. Calcd for C20H18N2O: C, 79.44%; H, 6.00%; N, 9.26%.
Found: C, 78.33%; H, 5.94%; N, 8.88%. Purity by HPLC: 99%, mp
139.7 °C.
C18H15N3O + ½H2O: C, 72.47%; H, 5.41%; N, 14.08%. Found: C,
72.05%; H, 5.34%; N, 14.11%. Purity by HPLC: 99%, mp 232.5 °C.
4.2.2.12. 7-(Naphthalen-2-ylmethoxy)-1-methyl-b-carboline (3l). Com-
pound 3l was obtained from a solution of harmol (0.500 g,
1.592 mmol), cesium carbonate (1.555 g, 4.773 mmol) and 2-(bro-
momethyl)naphthalene (0.540 g, 2.442 mmol) in 10 mL of DMF.
The reaction mixture was stirred at room temperature for 6 h.
The crude product was purified by column chromatography
(dichloromethane/ethanol 95:5% v/v).
4.2.2.9. 7-(Pyridin-2-ylmethoxy)-1-methyl-b-carboline (3i). Com-
pound 3i was obtained from a solution of harmol (0.362 g,
1.153 mmol), cesium carbonate (1.771 g, 5.436 mmol) and 2-(bro-
momethyl)pyridine hydrobromide (0.363 g, 1.435 mmol) in 7 mL
of DMF. The reaction mixture was stirred at room temperature
for 24 h. The crude product was purified by column chromatogra-
phy (dichloromethane/ethanol 90:10% v/v).
Yield 82%, Rf = 0.70 (DCM/EtOH 8:2). 1H NMR (DMSO-d6) d: 2.67
(s, 3H, CH3), 5.38 (s, 2H, O–CH2), 6.94 (dd, J6–8 = 2.1 Hz, J6–5
=
8.5 Hz, 1H, H-6), 7.09 (d, J8–6 = 2.3 Hz, 1H, H-8), 7.47–7.53 (m, 2H,
ArH), 7.61 (dd, J = 1.6 Hz, J = 8.5 Hz, 1H, ArH), 7.77 (d, J4–3 = 5.3 Hz,
1H, H-4), 7.89–7.95 (m, 3H, ArH), 8.01 (s, 1H, ArH), 8.04 (d,
J5–6 = 8.7 Hz, 1H, H-5), 8.11 (d, J3–4 = 5.3 Hz, 1H, H-3), 11.38 (s, 1H,
N–H). 13C NMR (DMSO-d6) d: 20.86 (CH3), 70.19 (O–CH2), 96.49
(C-8), 110.24 (C-6), 112.49 (C-4), 115.61 (Cq), 123.22 (C-5), 126.18
(C–ArH), 126.68 (C–ArH), 126.72 (C–ArH), 126.90 (C–ArH), 127.67
(Cq), 128.17 (C–ArH), 128.33 (C–ArH), 128.66 (C–ArH), 133.09 (Cq),
133.35 (Cq), 135.10 (Cq), 135.33 (Cq), 138.29 (C-3), 141.85 (Cq),
142.30 (Cq), 159.60 (Cq). MS: [M+H]+ 339.2. Anal. Calcd for
Yield 90%, Rf = 0.56 (DCM/EtOH 8:2). 1H NMR (CDCl3) d: 2.76 (s,
3H, CH3), 5.29 (s, 2H, O–CH2), 6.97–7.00 (m, 2H, H-6 + H-8), 7.23
(dd, J = 5.5 Hz, J = 7.1 Hz, 1H, ArH), 7.55 (d, J = 8.0 Hz, 1H, ArH),
7.69–7.73 (m, 2H, H-4 + ArH), 7.97 (d, J5–6 = 9.2 Hz, 1H, H-5), 8.31
(d, J3–4 = 5.5 Hz, 1H, H-3), 8.59 (d, J = 4.8 Hz, 1H, ArH), 8.94 (s, 1H,
N–H). 13C NMR (CDCl3) d: 20.33 (CH3), 71.01 (O–CH2), 96.01 (C-
8), 110.36 (C-6), 112.36 (C-4), 116.26 (Cq), 121.56 (C–ArH),
122.87 (C–ArH), 122.90 (C-5), 128.58 (Cq), 134.88 (Cq), 137.09
(C–ArH), 138.83 (C-3), 141.24 (Cq), 141.74 (Cq), 149.29 (C–ArH),
157.12 (Cq), 159.46 (Cq). MS: [M+H]+ 290.1. Anal. Calcd for
C23H18N2O: C, 81.63%; H, 5.36%; N, 8.28%. Found: C, 81.50%; H,
5.29%; N, 7.99%. Purity by HPLC: 99%, mp 238.6 °C.
C
18H15N3O: C, 74.72%; H, 5.23%; N, 14.52%. Found: C, 74.23%; H,
4.2.3. 7-(N,N-Dimethylaminoethyloxy)-1-methyl-b-carboline
(3m)
5.23%; N, 14.22%. Purity by HPLC: 99%, mp 187.5 °C.
Compound 3m was obtained from a solution of harmol (0.440 g,
1.401 mmol), cesium carbonate (2.060 g, 6.322 mmol) and 2-
chloro-N,N-dimethylethylamine hydrochloride (0.330 g, 2.291
mmol) in 10 mL of DMF. The reaction mixture was heated at
110 °C for 7 h. The crude product was purified by column chroma-
tography (dichloromethane/ethanol/triethylamine 80:20:2% v/v/
v).
4.2.2.10. 7-(Pyridin-3-ylmethoxy)-1-methyl-b-carboline (3j). Com-
pound 3j was obtained from a solution of harmol (0.355 g,
1.131 mmol), cesium carbonate (1.550 g, 4.757 mmol) and 3-(bro-
momethyl)pyridine hydrobromide (0.342 g, 1.352 mmol) in 7 mL
of DMF. The reaction mixture was stirred at room temperature
for 24 h. The crude product was purified by column chromatogra-
phy (dichloromethane/ethanol 90:10% v/v).
Yield 44%, Rf = 0.26 (DCM/EtOH/NEt3 8:2:0.2). 1H NMR (CDCl3)
d: 2.35 (s, 6H, 2CH3), 2.77 (t, J = 5.7 Hz, 2H, O–CH2–CH2), 2.78 (s,
3H, CH3), 4.12 (t, J = 5.7 Hz, 2H, O–CH2), 6.90 (dd, J6–5 = 8.5 Hz,
J6–8 = 2.1 Hz, 1H, H-6), 6.94 (d, J8–6 = 2.1 Hz, 1H, H-8), 7.71 (d,
J4–3 = 5.5 Hz, 1H, H-4), 7.94 (d, J5–6 = 8.7 Hz, 1H, H-5), 8.31 (d,
J3–4 = 5.3 Hz, 1H, H-3), 8.94 (s, 1H, N–H). 13C NMR (CDCl3) d:
20.34 (CH3), 46.06 (2CH3), 58.39 (O–CH2–CH2), 66.43 (O–CH2),
95.65 (C-8), 110.11 (C-6), 112.34 (C-4), 115.96 (Cq), 122.69 (C-5),
128.69 (Cq), 134.87 (Cq), 138.79 (C-3), 141.16 (Cq), 141.85 (Cq),
160.05 (Cq). MS: [M+H]+ 270.1. Anal. Calcd for C16H19N3O + ½H2O:
C, 69.04%; H, 7.24%; N, 15.10%. Found: C, 68.95%; H, 6.79%; N,
14.50%. Purity by HPLC: 99%, mp 218.3 °C.
Yield 91%, Rf = 0.44 (DCM/EtOH 8:2). 1H NMR (CDCl3) d: 2.78 (s,
3H, CH3), 5.15 (s, 2H, O–CH2), 6.96 (dd, J6–5 = 8.7 Hz, J6–8 = 2.1 Hz,
1H, H-6), 6.99 (d, J8–6 = 2.1 Hz, 1H, H-8), 7.33 (dd, J = 4.8 Hz,
J = 7.8 Hz, 1H, ArH), 7.73 (d, 1H, J4–3 = 5.5 Hz, 1H, H-4), 7.80 (dt,
J = 1.8 Hz, J = 8.0 Hz, 1H, ArH), 7.99 (d, J5–6 = 8.7 Hz, 1H, H-5), 8.32
(d, J3–4 = 5.3 Hz, 1H, H-3), 8.59 (dd, J = 1.4 Hz, J = 4.6 Hz, 1H, ArH),
8.71 (d, J = 1.6 Hz, 1H, ArH), 9.22 (s, 1H, N–H). 13C NMR (CDCl3)
d: 20.29 (CH3), 68.00 (O–CH2), 96.25 (C-8), 110.08 (C-6), 112.41
(C-4), 116.47 (Cq), 122.96 (C-5), 123.74 (C–ArH), 128.61 (Cq),
132.53 (Cq), 134.96 (Cq), 135.49 (C–ArH), 138.78 (C-3), 141.28
(Cq), 141.81 (Cq), 149.02 (C–ArH), 149.56 (C–ArH), 159.47 (Cq).
MS: [M+H]+ 290.1. Anal. Calcd for C18H15N3O + ½H2O: C, 72.47%;
H, 5.41%; N, 14.08%. Found: C, 72.66%; H, 5.32%; N, 14.01%. Purity
by HPLC: 99%, mp 226.6 °C.
4.2.4. 7-(N,N-Dimethylaminopropyloxy)-1-methyl-b-carboline
(3n)
Compound 3n was obtained from a solution of harmol (0.400 g,
1.274 mmol), cesium carbonate (1.450 g, 4.450 mmol) and
3-chloro-N,N-dimethylpropylamine hydrochloride (0.440 g, 2.784
mmol) in 10 mL of DMF. The reaction mixture was heated at 110 °C
for 7 h. The crude product was purified by column chromatography
(dichloromethane/ethanol/triethylamine 80:20:2% v/v/v).
Yield 52%, Rf = 0.22 (DCM/EtOH/NEt3 8:2:0.2). 1H NMR (CDCl3)
d: 2.00–2.07 (m, 2H, O–CH2–CH2), 2.30 (s, 6H, 2CH3), 2.53 (t, J =
7.2 Hz, 2H, O–CH2–CH2–CH2), 2.79 (s, 3H, CH3), 4.12 (t, J = 6.4 Hz,
2H, O–CH2), 6.89 (dd, J6–5 = 8.6 Hz, J6–8 = 2.1 Hz, 1H, H-6), 6.96 (d,
J8–6 = 2.0 Hz, 1H, H-8), 7.70 (d, J4–3 = 5.5 Hz, 1H, H-4), 7.94 (d,
J5–6 = 8.7 Hz, 1H, H-5), 8.12 (s, 1H, N–H), 8.31 (d, J3–4 = 5.3 Hz, 1H,
4.2.2.11. 7-(Pyridin-4-ylmethoxy)-1-methyl-b-carboline (3k). Com-
pound 3k was obtained from a solution of harmol (0.355 g,
1.131 mmol), cesium carbonate (1.695 g, 5.202 mmol) and 4-(bro-
momethyl)pyridine hydrobromide (0.378 g, 1.494 mmol) in 7 mL
of DMF. The reaction mixture was stirred at room temperature
for 24 h. The crude product was purified by column chromatogra-
phy (dichloromethane/ethanol 90:10% v/v).
Yield 62%, Rf = 0.39 (DCM/EtOH 8:2). 1H NMR (CDCl3) d: 2.77 (s,
3H, CH3), 5.20 (s, 2H, O–CH2), 6.95–6.99 (m, 2H, H-6 + H-8), 7.39
(d, J = 5.5 Hz, 2H, ArH), 7.72 (d, J4–3 = 5.3 Hz, 1H, H-4), 8.00 (d,
J5–6 = 9.2 Hz, 1H, H-5), 8.32 (d, J3–4 = 5.5 Hz, 1H, H-3), 8.48 (s, 1H,
N–H), 8.62 (d, J = 5.7 Hz, 2H, ArH). 13C NMR (CDCl3) d: 20.34