R. Saito et al. / Tetrahedron 65 (2009) 3019–3026
3023
using FT/IR-4100, FT/IR-460plus, or FT/IR-660plus spectrophoto-
meter (JASCO Co., Ltd., Japan). Fast-atom-bombardment (FAB) mass
spectra were taken on a JMS-600-H mass spectrometer (JEOL Ltd.,
Japan). Xenon was used as a bombardment gas, and all analyses
were carried out in positive mode with the ionization energy and
the accelerating voltage set at 70 eV and 3 kV, respectively.
141.0, 144.6, 149.2, 155.4, 163.5, 188.9. IR (KBr) nmax/cmꢁ1 1647
(n
C]O), 1024 (
n
C–O). MS (FABþ, DTT/TG¼1:2) m/z 323 [MþH]þ.
Anal. Calcd for C18H14N2O2S: C, 67.06; H, 4.38; N, 8.69. Found: C,
67.34; H, 4.46; N, 8.49.
4.2.4. 6-(4-Hydroxyphenyl)-2-(4-methoxyphenyl)carbonyl-
pyrazine (6e)
A mixture of dithiothreitol and a-thioglycerol (1:1 or 1:2) was used
as a liquid matrix. Absorption spectra were measured on a UV-240
spectrophotometer (SHIMADZU Co., Ltd., Japan), and combustion
analyses were performed on an MT-6 analyzer (Yanaco New
Science Inc., Japan). Column chromatography was carried out on
The reaction of 5 with (4-tert-butyldimethylsilyloxyphenyl)-
boronic acid afforded the deprotected compound 6e directly as an
yellow solid (198 mg, 63%); mp 182 ꢀC (decomp.). 1H NMR (CDCl3,
400 MHz)
8.00 (d, 2H, J¼8.8 Hz), 7.01 (d, 2H, J¼8.8 Hz), 6.98 (d, 2H, J¼8.8 Hz),
5.28 (s, 1H), 3.92 (s, 3H). 13C NMR (DMSO-d6, 100 MHz)
/ppm 55.7,
114.0 (ꢄ2), 116.1 (ꢄ2), 126.0, 128.1, 128.7 (ꢄ2), 133.3 (ꢄ2), 141.9,
143.1,149.1,149.9,159.8,163.7,190.7. IR (KBr) nmax/cmꢁ1 3323 (
OH),
d/ppm 9.14 (s, 1H), 9.05 (s, 1H), 8.22 (d, 2H, J¼8.8 Hz),
silica gel (63–210 mm particle size; Kanto Chemical Co.).
Botryllazine B (1) and its synthetic intermediates (4, 5, and 6a)
d
were prepared according to methods in the literature.18 Coe-
lenteramide (2) was synthesized by
a
previously reported
n
procedure.15,30
1638 (
n
C]O), 1164, 1012 (
n
C–O). FABMS (DTT/TG¼1:2) m/z 307
All conventional chemicals used in the present study are com-
mercially available, and were used as received. Recombinant
h-ALR2 was purchased from Wako Pure Chemical Industries, Ltd.
and used without further purification.
[MþH]þ. Anal. Calcd for C18H14N2O3: C, 70.58; H, 4.61; N, 9.15.
Found: C, 70.51; H, 4.71; N, 9.00.
4.2.5. 6-(4-Fluorophenyl)-2-(4-methoxyphenyl)carbonyl-
pyrazine (6f)
4.2. General procedure for Suzuki–Miyaura cross-coupling
reactions of chloropyrazines with phenylboronic acid
derivatives
Colorless solid (210 mg, 84%); mp 139–140 ꢀC. 1H NMR (CDCl3,
400 MHz)
d
/ppm 9.17 (s,1H), 9.10 (s, 1H), 8.21 (d, 2H, J¼8.8 Hz), 8.07
(dd, 2H, J¼8.4 and 5.5 Hz), 7.21 (t, 2H, J¼8.4 Hz), 7.01 (d, 1H,
J¼8.8 Hz), 3.92 (s, 3H). 13C NMR (CDCl3, 100 MHz)
d/ppm 56.0, 114.1
Tetrakis(triphenylphosphine)palladium (3 mol %), chloropyr-
azine (2.8 mmol), and a phenylboronic acid (phenylboronic acid
pinacol ester for 6b) (3.3 mmol) were successively dissolved in 1,4-
dioxane (10 mL) under an argon atmosphere. To the solution was
added 2 M K2CO3 (1.5 mL), and the mixture was refluxed for 5 h.
After cooling to room temperature, 25 ml of water was added to the
reaction mixture and organic materials were extracted with
dichloromethane (40 mLꢄ3). The resulting organic layer was dried
over anhydrous magnesium sulfate, and the solvent was evapo-
rated. The obtained residues were purified by column chromatog-
raphy on silica gel to obtain 6.
(ꢄ2), 116.6, 116.9, 128.9, 129.4, 129.5, 132.2, 134.0 (ꢄ2), 143.4, 144.1,
149.9, 150.1, 163.5, 164.5, 190.9. IR (KBr) nmax/cmꢁ1 1655 (
nC]O),
1235 (
n
C–F), 1014 (
n
C–O). FABMS (DTT/TG¼1:2) m/z 309 [MþH]þ.
Anal. Calcd for C18H13FN2O2$0.1hexane: C, 70.42; H, 4.48; N, 8.83.
Found: C, 70.58; H, 4.34; N, 8.70.
4.2.6. 6-(4-Biphenylyl)-2-(4-methoxyphenyl)carbonylpyrazine (6g)
Colorless solid (271 mg, 90%); mp 135–136 ꢀC. 1H NMR (DMSO-
d6, 400 MHz)
d
/ppm 9.56 (s, 1H), 9.06 (s, 1H), 8.27 (d, 2H, J¼8.4 Hz),
8.12 (d, 2H, J¼8.8 Hz), 7.88 (d, 2H, J¼8.8 Hz), 7.77 (d, 2H, J¼7.7 Hz),
7.51 (t, 2H, J¼7.7 Hz), 7.42 (t, 1H, J¼7.7 Hz), 7.15 (d, 2H, J¼8.8 Hz),
3.90 (s, 3H). 13C NMR (DMSO-d6, 100 MHz)
d/ppm 55.7, 114.0 (ꢄ2),
4.2.1. 6-(4-Aminophenyl)-2-(4-methoxyphenyl)carbonyl-
pyrazine (6b)
126.8 (ꢄ2), 127.4 (ꢄ3), 127.6 (ꢄ2), 128.0, 129.1 (ꢄ2), 133.3 (ꢄ2),
134.2, 139.2, 141.9, 143.2, 143.9, 149.2, 149.3, 163.8, 190.5. IR (KBr)
Yellow solid (2.84 g, 93%); mp 174 ꢀC (decomp.). 1H NMR
nmax/cmꢁ1 1651 (
n
C]O), 1020 (
n
C–O). FABMS (DTT/TG¼1:2) m/z
(DMSO-d6, 400 MHz)
d/ppm 9.28 (s, 1H), 8.80 (s, 1H), 8.08 (d, 2H,
367 [MþH]þ. Anal. Calcd for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65.
J¼8.8 Hz), 7.87 (d, 2H, J¼8.8 Hz), 7.13 (d, 2H, J¼8.8 Hz), 6.67 (d, 2H,
Found: C, 78.95; H, 5.04; N, 7.56.
J¼8.8 Hz), 5.73 (s, 2H), 3.88 (s, 3H). 13C NMR (DMSO-d6, 100 MHz)
d
/ppm 55.7, 113.9 (ꢄ2), 114.0 (ꢄ2), 122.0, 128.2, 128.2 (ꢄ2), 133.2
4.2.7. 6-(3-Hydroxyphenyl)-2-(4-methoxyphenyl)carbonyl-
pyrazine (6h)
(ꢄ2),140.7,142.4, 149.0,150.4,151.3,163.7,190.8. IR (KBr) nmax/cmꢁ1
3397, 3318 (
n
NH), 1637 (
n
C]O), 1024 (
n
C–O). FABMS (DTT/TG¼1:2)
Pale yellow solid (212 mg, 86%); mp 152–153 ꢀC. 1H NMR (DMSO-
m/z 306 [MþH]þ. Anal. Calcd for C18H13N3O2$0.1H2O: C, 70.39; H,
d6, 400 MHz) d/ppm 9.76 (s,1H), 9.42 (s, 1H), 9.02 (s, 1H), 8.09 (d, 2H,
4.96; N, 13.68. Found: C, 70.41; H, 5.00; N, 13.50.
J¼8.8 Hz), 7.61 (d,1H, J¼7.7 Hz), 7.54 (s,1H), 7.36 (t,1H, J¼7.7 Hz), 7.14
(d, 2H, J¼8.8 Hz), 6.93 (d,1H, J¼7.7 Hz), 3.89 (s, 3H). 13C NMR (DMSO-
4.2.2. 2-(4-Methoxyphenyl)carbonyl-6-phenylpyrazine (6c)
d6, 100 MHz)
d
/ppm 55.7, 113.6, 114.0 (ꢄ2), 117.5, 117.8, 128.0, 130.3,
Colorless solid (368 mg, 92%); mp 114–115 ꢀC. 1H NMR (CDCl3,
133.3 (ꢄ2),136.5,143.2,143.8,149.2,149.6,158.1,163.7,190.5. IR (KBr)
400 MHz)
(dd, 2H, J¼7.9 and 2.2 Hz), 7.51–7.56 (m, 3H), 7.02 (d, 2H, J¼8.8 Hz),
3.92 (s, 3H). 13C NMR (CDCl3, 100 MHz)
/ppm 55.7,113.8 (ꢄ2), 127.2
(ꢄ2), 128.7, 129.3 (ꢄ2), 130.5, 133.8 (ꢄ2), 135.7, 143.5, 143.9, 149.8,
d/ppm 9.21 (s,1H), 9.13 (s,1H), 8.25 (d, 2H, J¼8.8 Hz), 8.08
nmax/cmꢁ1 3306 (
nOH), 1652 (nC]O), 1161, 1016 (nC–O). FABMS (DTT/
TG¼1:2) m/z 307 [MþH]þ. Anal. Calcd for C18H14N2O3$0.1hexane: C,
d
70.86; H, 4.83; N, 8.89. Found: C, 70.86; H, 4.66; N, 8.69.
150.5, 164.1, 190.7. IR (KBr) nmax/cmꢁ1 1657 (
n
C]O), 1026 (
n
C–O).
4.2.8. 6-(3,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)-
carbonylpyrazine (6i)
FABMS (DTT/TG¼1:2) m/z 291 [MþH]þ. Anal. Calcd for C18H14N2O2:
C, 74.47; H, 4.86; N, 9.65. Found: C, 74.73; H, 4.91; N, 9.53.
Pale yellow solid (278 mg, 98%); mp 127–128 ꢀC. 1H NMR (CDCl3,
400 MHz)
7.65–7.69 (m, 2H), 7.01 (d, 1H, J¼8.4 Hz), 7.00 (d, 2H, J¼8.8 Hz), 3.97
(s, 3H), 3.96 (s, 3H), 3.91 (s, 3H). 13C NMR (CDCl3, 100 MHz)
/ppm
d
/ppm 9.17 (s, 1H), 9.06 (s, 1H), 8.26 (d, 2H, J¼8.8 Hz),
4.2.3. 6-(4-Mercaptophenyl)-2-(4-methoxyphenyl)-
carbonylpyrazine (6d)
d
Pale yellow solid (140 mg, 43%); mp 101–102 ꢀC. 1H NMR (CDCl3,
55.7, 56.1, 56.2, 109.9, 111.5, 113.7 (ꢄ2), 120.0, 128.5, 128.8, 133.8
400 MHz)
d
/ppm 8.88 (s, 1H), 8.41 (s, 1H), 8.03 (d, 2H, J¼8.8 Hz),
(ꢄ2), 142.9, 143.1, 149.5, 149.8, 150.2, 151.3, 164.1, 190.7. IR (KBr)
7.66 (dd, 2H, J¼7.3 and 1.9 Hz), 7.46–7.52 (m, 3H), 6.84 (d, 2H,
nmax/cmꢁ1 1653 (
n
C]O), 1026 (
n
C–O). FABMS (DTT/TG¼1:2) m/z
J¼8.8 Hz), 3.89 (s, 3H). 13C NMR (DMSO-d6, 100 MHz)
d/ppm 55.6,
351 [MþH]þ. Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00.
113.7 (ꢄ2), 127.6, 128.0, 129.8, 130.0 (ꢄ2), 133.2 (ꢄ2), 135.1 (ꢄ2),
Found: C, 68.40; H, 5.16; N, 7.83.