10.1002/cmdc.201900074
ChemMedChem
FULL PAPER
54.4, 54.1, 46.9, 45.5, 41.4. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C23H23N2O2 359.1760; Found 359.1760.
was stirred at 0 °C for 15 min and at room temperature for 1 h.
Ethanolamine (0.023 mL, 0.38 mmol) was added and the stirring was
continued at room temperature for 1.5 h. H2O (15 mL) was added to the
purple reaction mixture and it was extracted with EtOAc (30 mL). The
organic phase was washed with a 1 M aqueous solution of HCl (15 mL)
and a saturated aqueous solution of NaHCO3 (15 mL), dried over
anhydrous Na2SO4, filtered and evaporated to provide a purple oil. The
crude product was purified by flash chromatography (EtOAc/MeOH 1:0
19:1) to give 28 as a purple tar (0.045 g, 87%). 1H NMR (400 MHz, CDCl3)
δ 9.57 (d, J = 10.4 Hz, 1H), 8.42 (d, J = 10.0 Hz, 1H), 8.14 (d, J = 4.0 Hz,
1H), 7.88 (dd, J = 10.4, 1.6 Hz, 1H), 7.82 (d, J = 10.0, 1.6 Hz, 1H), 7.42–
7.35 (m, 3H), 7.27 (d, J = 4.0 Hz, 1H), 7.13–7.10 (m, 1H), 7.06 (t, J = 5.6
Hz, 1H), 3.91 (t, J = 5.0 Hz, 2H), 3.87 (s, 3H), 3.72–3.68 (m, 2H), 2.17 (s,
1H). 13C NMR (101 MHz, CDCl3) δ 192.8, 170.5, 159.7, 145.4, 144.7,
144.3, 142.2, 141.9, 138.0, 137.8, 129.3, 126.7, 125.9, 125.9, 122.4, 118.9,
117.9, 114.3, 62.1, 55.6, 43.5. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C21H20NO4 350.1392; Found 350.1391.
N-[2-(1H-Imidazol-5-yl)ethyl]-1-benzoylazulene-6-carboxamide (24):
Compound 20 (0.069 g, 0.25 mmol) and histamine (0.070 g, 0.63 mmol)
gave
a
dark green solid, which after flash chromatography
(EtOAc/EtOH/Et3N 74:24:2) gave 24 as a dark grey, amorphous solid
(0.045 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 9.59 (d, J
= 10.4 Hz, 1H), 8.94 (t, J = 5.6 Hz, 1H), 8.80 (d, J = 10.0 Hz, 1H), 8.13 (d,
J = 4.0 Hz, 1H), 8.04 (dd, J = 10.2, 1.4 Hz, 1H), 7.95 (dd, J = 10.4, 1.6 Hz,
1H), 7.80–7.77 (m, 2H), 7.67–7.63 (m, 1H), 7.59–7.55 (m, 3H), 7.49 (d, J
= 4.0 Hz, 1H), 6.88 (s, 1H), 3.57–3.52 (m, 2H), 2.82 (t, J = 7.4 Hz, 2H). 13
C
NMR (101 MHz, DMSO-d6) δ 191.5, 168.4, 145.7, 144.7, 143.3, 140.9,
140.5, 138.5, 137.5, 134.8, 131.5, 129.1, 128.4, 127.3, 126.5, 124.5, 118.6,
40.0. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C23H20N3O2 370.1555;
Found 370.1559.
N-[2-(1H-indol-3-yl)ethyl]-1-benzoylazulene-6-carboxamide
(25):
Methyl 1-benzoyl-1H-indole-5-carboxylate (31): Benzoyl chloride (0.12
mL, 1.0 mmol) and trimethylamine (0.14 mL, 1.0 mmol) were added to a
solution of methyl indole-5-carboxylate (0.18 g. 1.0 mmol) in anhydrous
DCM (1 mL) under argon. The resulting mixture was stirred at room
temperature for 23 h. The reaction mixture was diluted with DCM (30 mL)
and it was washed with a 1 M aqueous solution of HCl (15 mL), a saturated
solution of NaHCO3 (15 mL) and brine (15 mL), dried over anhydrous
Na2SO4, filtered and evaporated to provide a brownish solid. The crude
product was purified by flash chromatography (manual gradient of n-
hexane/EtOAc 9:1 1:3) to give 31 as a white, amorphous solid (0.17 g,
59%). 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 8.8 Hz, 1H), 8.34 (dd, J =
1.6, 0.8 Hz, 1H), 8.08 (dd, J = 8.8, 1.6 Hz, 1H), 7.77–7.74 (m, 2H), 7.65–
7.61 (m, 1H), 7.56–7.52 (m, 2H), 7.38 (d, J = 3.6 Hz, 1H), 6.69 (dd, J = 4.0,
0.8 Hz, 1H), 3.96 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 168.8, 167.5, 138.8,
134.2, 132.4, 130.7, 129.4, 128.9, 128.8, 126.3, 125.9, 123.3, 116.1, 108.9,
52.25. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for C17H14NO3 280.0974;
Found 280.0976.
Compound 20 (0.036 g, 0.13 mmol) and tryptamine (0.053 g, 0.33 mmol)
gave a purple oil, which after flash chromatography (EtOAc) gave 25 as a
1
dark grey, amorphous solid (0.044g, 81%). H NMR (400 MHz, DMSO-d6)
δ 10.85 (s, 1H), 9.59 (d, J = 10.4 Hz, 1H), 8.99 (t, J = 5.6 Hz, 1H), 8.79 (d,
J = 10.0 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 8.03 (d, J = 10.4 Hz, 1H), 7.96
(d, J = 10.0 Hz, 1H), 7.80–7.77 (m, 2H), 7.66–7.55 (m, 4H), 7.49 (d, J =
4.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H). 7.24 (s, 1H), 7.08 (t, J = 7.4 Hz, 1H),
7.00 (t, J = 7.4 Hz, 1H), 3.64–3.59 (m, 2H), 3.03 (t, J = 7.4 Hz, 2H). 13C
NMR (101 MHz, DMSO-d6) δ 191.5, 168.4, 145.7, 144.7, 143.3, 140.9,
140.5, 138.4, 137.5, 136.3, 131.5, 129.1, 128.4, 127.4, 127.3, 126.5, 124.5,
122.8, 121.0, 118.6, 118.3, 111.7, 111.4, 40.9, 24.95. HRMS (ESI-QTOF)
m/z: [M + H]+ Calcd for C28H23N2O2 419.1760; Found 419.1756.
1-Benzoyl-N-(pyridin-3-ylmethyl)azulene-6-carboxamide
Compound 20 (0.069 g, 0.25 mmol) and 3-picolylamine (0.064 mL, 0.63
mmol) gave green solid, which after flash chromatography
(26):
a
(EtOAc/MeOH 49:1) gave 26 as a green, amorphous solid (0.074 g, 80%).
1H NMR (400 MHz, DMSO-d6) δ 9.60 (d, J = 10.4 Hz, 1H), 9.48 (t, J = 5.8
Hz, 1H), 8.81 (d, J = 10.4 Hz, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.50 (dd, J =
4.8, 1.6 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 8.11 (dd, J = 10.4, 1.6 Hz, 1H),
8.01 (dd, J = 10.2, 1.4 Hz, 1H), 7.83–7.77 (m, 3H), 7.66–7.62 (m, 1H),
7.59–7.54 (m, 2H), 7.50 (d, J = 4.0 Hz, 1H), 7.40 (dd, J = 8.0, 4.8 Hz, 1H),
4.57 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 191.5, 168.7,
148.9, 148.3, 145.0, 144.7, 143.4, 141.0, 140.5, 138.5, 137.5, 135.3, 134.6,
131.5, 129.1, 128.4, 127.4, 126.4, 124.6, 123.6, 118.7, 41.1. HRMS (ESI-
QTOF) m/z: [M + H]+ Calcd for C24H19N2O2 367.1447; Found 367.1446.
Methyl 1-benzoyl-1H-indole-6-carboxylate (32): The same procedure
as described above was repeated with methyl indole-6-carboxylate (0.18
g, 1.0 mmol) to give 32 as a white, amorphous solid (0.060 g, 22%). 1H
NMR (400 MHz, CDCl3) δ 9.08 (m, 1H), 8.03 (dd, J = 8.2, 1.4 Hz, 1H),
7.77–7.74 (m, 2H), 7.66–7.61 (m, 2H), 7.57–7.53 (m, 2H), 7.46 (d, J = 4.0
Hz, 1H), 6.66 (d, J = 4.0, 0.8 Hz, 1H), 3.95 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 168.6, 167.7, 135.6, 134.6, 134.2, 132.4, 130.6, 129.4, 128.9,
126.9, 125.3, 120.7, 118.3, 108.4, 52.27. HRMS (ESI-QTOF) m/z: [M + H]+
Calcd for C17H14NO3 280.0974; Found 280.0974.
1-(3-Methoxybenzoyl)azulene-6-carboxylic acid (27): Compound
6
General procedure for the synthesis of compounds 33–36:
Appropriate indole derivative was dissolved in anhydrous 1,4-dioxane (2.5
mL) under argon. N,N-Dimethylbenzamide (4.3 equiv for 33, 35, 36 or 1.0
equiv for 34) and POCl3 (4.3 equiv for 33, 35, 36 or 1.0 equiv for 34) were
added. The resulting solution was heated under microwave irradiation at
100 °C for 1–3 h. The red reaction mixture was poured into 1 M aqueous
solution of NaOH (40 mL) on ice bath and extracted with DCM (25 + 15
mL). The organic phases were combined, washed with water (20 mL),
dried over anhydrous Na2SO4, filtered, and evaporated to provide a crude
product, which was purified by flash chromatography.
(0.11 g, 0.34 mmol) was dissolved in THF (3 mL) and MeOH (0.5 mL). A 2
M aqueous solution of NaOH (0.5 mL) was added to the blue solution and
the resulting mixture was stirred at room temperature for 30 min. A 1 M
aqueous solution of HCl (5 mL) was added to the purple reaction mixture
on ice bath and then the mixture was extracted with EtOAc (40 mL). The
organic phase was washed with a 1 M aqueous solution of HCl (2 × 20
mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and
evaporated to provide a green solid. The crude product was purified by
flash chromatography (manual gradient of EtOAc/AcOH 99:1) to give 27
as a green, amorphous solid (0.10 g, 98%). 1H NMR (400 MHz, DMSO-d6)
δ 9.61 (d, J = 10.4 Hz, 1H), 8.82 (d, J = 10.4 Hz, 1H), 8.44 (dd, J = 10.4,
1.6 Hz, 1H), 8.33 (dd, J = 10.4, 1.6 Hz, 1H), 8.21 (d, J = 4.4 Hz, 1H), 7.52
(d, J = 4.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 7.34–7.32 (m, 1H), 7.30–7.29
(m, 1H), 7.23–7.20 (m, 1H), 3.83 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
δ 191.2, 168.3, 159.1, 145.4, 144.4, 141.8, 141.7, 139.5, 138.0, 137.0,
129.5, 128.9, 127.6, 124.7, 121.6, 118.8, 117.5, 113.9, 55.3. HRMS (ESI-
QTOF) m/z: [M - H]- Calcd for C19H13O4 305.0814; Found 305.0813.
Methyl 3-benzoyl-1H-indole-5-carboxylate (33): Methyl indole-5-
carboxylate (0.18 g, 1.0 mmol) with 1 h heating gave an orange oil, which
after flash chromatography (manual gradient of n-hexane/EtOAc 9:1
EtOAc) gave a yellow solid. The solid was washed a small amount of
acetone to give 33 as a white, amorphous solid (0.009 g, 3%). 1H NMR
(400 MHz, DMSO-d6) δ 12.39 (s, 1H), 8.96 (dd, J = 1.6, 0.8 Hz, 1H), 8.10
(s, 1H), 7.89 (dd, J = 8.6, 1.8 Hz, 1H), 7.84–7.81 (m, 2H), 7.66–7.61 (m,
2H), 7.58–7.54 (m, 2H), 3.89 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
189.9, 167.0, 140.0, 139.4, 137.5, 131.4, 128.5, 128.5, 125.9, 124.1, 123.8,
123.3, 115.6, 112.4, 51.9. HRMS (ESI-QTOF) m/z: [M + H]+ Calcd for
C17H14NO3 280.0974; Found 280.0977.
N-(2-Hydroxyethyl)-1-(3-methoxybenzoyl)azulene-6-carboxamide
(28): Compound 27 (0.046 g, 0.15 mmol) was dissolved in DMF (1 mL).
The blue solution was cooled to 0 °C and EDC-HCl (0.032 g, 0.17 mmol)
and HOBt-H2O (0.025 g, 0.17 mmol) were added. The reaction mixture
13
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