LETTER
Synthesis of a New Mutagenic Benzoazepinoquinolinone Derivative
1783
NH2
NO2
I
N
N
a
b, c
d
13
70%
MeO2C
91%
93%
MeO2C
CO2Me
MeO
CO2Me
MeO
15
14
N
N
e, f
g
1
32%
38%
NHBoc
CO2Me
HN
HN
OMe
OMe
O
O
16
17
Scheme 3 Synthetic route of compound 1. Reagent and conditions: (a) ICl (5.6 equiv), NaHCO3 (3.0 equiv), MeCN, 40 °C; (b) Pd(PPh3)4 (0.2
equiv), HCO2H (3.0 equiv), Et3N (3.0 equiv), DMF, 50 °C; (c) Pd/C, H2, i-PrOH, 50–80 °C; (d) MsOH (0.3 equiv), 2-dichlorobenzene, 150 °C;
(e) 2 M KOH aq MeOH, r.t.; (f) DPPA (6.3 equiv), Et3N (9.5 equiv), t-BuOH, reflux; (g) BBr3 (8.7 equiv), CH2Cl2, –78 °C.
EtOAc. The organic layer was washed with brine, dried over
References and Notes
Na2SO4, and concentrated in vacuo. The residue was
(1) Nishigaki, R.; Watanabe, T.; Kajimoto, T.; Tada, A.;
purified by column chromatography on silica gel (hexane–
Takamura-Enya, T.; Enomoto, S.; Nukaya, H.; Terao, Y.;
EtOAc = 1:1.5) to afford deiodine compound (16.8 mg,
Muroyama, A.; Ozeki, M.; Node, M.; Hasei, T.; Totsuka, Y.;
98%). A suspension of the above compound (15.7 mg, 0.040
Wakabayashi, K. Chem. Res. Toxicol. 2009, submitted.
(2) (a) Skraup, Z. Ber. Dtsch. Chem. Ges. 1880, 2086.
mmol) and 10% Pd/C (3.1 mg) in 2-PrOH (1.0 mL) was
stirred for 0.5 h at 50 °C and for another 1 h at 80 °C under
a hydrogen atmosphere. The mixture was filtered with
Celite, and the filtrate was concentrated in vacuo to remove
the organic solvent. The residue was purified by column
chromatography on silica gel (hexane–EtOAc = 1:1.5) to
(b) Yamashkin, S. A.; Oreshkina, E. A. Chem. Heterocycl.
Compd. 2006, 42, 701. (c) Lown, J. W.; Sim, S.-K. Can. J.
Chem. 1976, 54, 2563.
(3) Hammen, P. D.; Braisted, A. C.; Northrup, D. L. Synth.
Commun. 1991, 21, 2157.
afford 15 (13.8 mg, 95%). Pale yellow crystals; mp 198–199
°C (hexane–EtOAc). 1H NMR (400 MHz, CDCl3): d = 8.96
(4) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org. Lett.
2005, 7, 763.
(d, J = 4.2 Hz, 1 H), 8.76 (s, 1 H), 7.39 (d, J = 4.2 Hz, 1 H),
7.24 (ddd, J = 8.1, 7.4, 1.3 Hz, 1 H), 6.99 (dd, J = 8.1, 1.3
Hz, 1 H), 6.84 (dt, J = 7.4, 1.3 Hz, 1 H), 6.80 (dd, J = 8.1,
(5) Chapoteau, E.; Chowdhary, M. S.; Czech, B. P.; Kumar, A.;
Zazulak, W. J. Org. Chem. 1992, 57, 2804.
(6) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc.
1972, 94, 6203.
(7) Compound 14
1.3 Hz, 1 H), 4.01 (s, 3 H), 3.89 (s, 3 H), 3.53 (br, 2 H), 3.27
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 166.5, 165.1,
154.6, 150.4, 145.5, 144.5, 144.3, 136.4, 131.1, 129.9,
NaHCO3 (859.8 mg, 10.23 mmol) and ICl (1.0 mL, 19.09
mmol) were added to a soln of 13 (1.35 g, 3.40 mmol) in
127.3, 126.9, 126.5, 126.1, 122.7, 117.9, 115.8, 64.2, 52.7,
52.2. IR (KBr): 3436, 3381, 2950, 1728, 1643, 1606, 1487,
1448, 1248, 1224, 1149 cm–1. MS (70 eV): m/z (%) = 366
(44) [M+], 306 (100), 291 (67), 275 (52), 259 (85), 219 (56),
203 (43), 102 (34), 77 (16). HRMS: m/z calcd for
MeCN (15 mL) at r.t., and the mixture was stirred at 40 °C
for 25.5 h. The reaction mixture was quenched with a sat. aq
soln of Na2S2O3, and diluted with a sat. aq soln of NaHCO3
and extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on
silica gel (hexane–EtOAc = 2:1) to afford 14 (1.25 g, 70%).
Yellow crystals; mp 194–195 °C (hexane–EtOAc). 1H NMR
(400 MHz, CDCl3): d = 9.25 (s, 1 H), 8.75 (s, 1 H), 8.41 (dd,
J = 8.0, 1.3 Hz, 1 H), 7.82 (dt, J = 8.0, 1.3 Hz, 1 H), 7.75 (dt,
J = 8.0, 1.7 Hz, 1 H), 7.28 (br d, J = 8.0 Hz, 1 H), 4.00 (s, 3
H), 3.81 (s, 3 H), 3.23 (s, 3 H). 13C NMR (100 MHz, CDCl3):
d = 166.5, 164.7, 156.8, 155.3, 147.9, 143.5, 136.6, 135.2,
133.9, 133.2, 130.7, 127.2, 126.0, 125.8, 124.8, 101.3, 70.9,
64.1, 52.8, 52.2. IR (KBr): 1730, 1608, 1525, 1471, 1438,
1344, 1248, 1213, 1168 cm–1. MS (70 eV): m/z (%) = 522
(100) [M+], 491 (16), 400(12), 335 (37), 275 (32). HRMS:
m/z calcd for C20H15IN2O7 [M+]: 521.9924; found: 521.9931.
(8) Compound 15
C20H18N2O5 [M+]: 366.1215; found: 366.1207.
(9) Compound 16
A soln of 15 (66.8 mg, 0.182 mmol) and MsOH (3.5 mL,
0.055 mmol) in o-dichlorobenzene (2.0 mL) was stirred at
150 °C for 2 h. The reaction mixture was poured into a sat.
aq soln of NaHCO3 and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane–EtOAc = 1:2) to
afford 16 (55.6 mg, 91%). Yellow crystals; mp 190–191 °C
(hexane–EtOAc). 1H NMR (400 MHz, CDCl3): d = 8.89 (d,
J = 4.5 Hz, 1 H), 8.50 (s, 1 H), 8.03 (s, 1 H), 7.60 (d, J = 4.5
Hz, 1 H), 7.45 (ddd, J = 7.9, 7.1, 1.3 Hz, 1 H), 7.33 (dd, J =
7.9, 1.3 Hz, 1 H), 7.27 (ddd, J = 8.4, 7.1, 1.3 Hz, 1 H), 7.13
(dd, J = 8.4, 1.3 Hz, 1 H), 4.13 (s, 3 H), 3.98 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 166.8, 165.7, 162.9, 149.6,
142.6, 142.1, 136.8, 135.0, 132.1, 131.8, 130.7, 130.2,
129.0, 125.9, 121.6, 121.4, 116.3, 63.9, 52.7. IR (KBr):
3058, 2950, 1735, 1660, 1591, 1475, 1286, 1195, 1120
cm–1. MS (70 eV): m/z (%) = 334 (100) [M+], 317 (96), 305
(46), 277 (29), 246 (27), 218 (31), 203 (49), 102 (44).
Tetrakis(triphenylphosphine) palladium (5.0 mg, 0.004
mmol), Et3N (12 mL, 0.087 mmol), and formic acid (2.7 mL,
0.065 mmol) were added to a soln of 14 (22.7 mg, 0.043
mmol) in N,N-dimethylformamide (1 mL) at r.t., and the
mixture was stirred at 50 °C for 3 h. The reaction mixture
was poured into a sat. aq soln of NaHCO3 and extracted with
Synlett 2009, No. 11, 1781–1784 © Thieme Stuttgart · New York