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DOI: 10.1055/s-0029-1217358
Synthesis of a New Mutagenic Benzoazepinoquinolinone Derivative
Publication History
Publication Date:
12 June 2009 (online)
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Abstract
A novel mutagenic compound 1, isolated as a Maillard product from tryptophan and glucose, was synthesized using Larock’s quinoline formation, where addition of iodonium cation to an acetylene moiety of N-propargylaniline triggers subsequent intramolecular electrophilic aromatic substitution to afford quinolines. The key synthetic intermediate 14 was obtained in a good yield when iodonium chloride was employed as an initiator of Larock’s method. Conversion of 14 with another six steps, including annulation of a lactam ring and Curtius rearrangement, furnished the target molecule 1. The synthesized and isolated 1 were identical in comparison of physical and spectral data.
Key words
Larock’s quinoline formation - Curtius rearrangement - benzoazepinoquinolinone derivative
-
2a
Skraup Z. Ber. Dtsch. Chem. Ges. 1880, 2086 -
2b
Yamashkin SA.Oreshkina EA. Chem. Heterocycl. Compd. 2006, 42: 701 -
2c
Lown JW.Sim S.-K. Can. J. Chem. 1976, 54: 2563 - 3
Hammen PD.Braisted AC.Northrup DL. Synth. Commun. 1991, 21: 2157 - 4
Zhang X.Campo MA.Yao T.Larock RC. Org. Lett. 2005, 7: 763 - 5
Chapoteau E.Chowdhary MS.Czech BP.Kumar A.Zazulak W. J. Org. Chem. 1992, 57: 2804 - 6
Shioiri T.Ninomiya K.Yamada S. J. Am. Chem. Soc. 1972, 94: 6203
References and Notes
Nishigaki, R.; Watanabe, T.; Kajimoto, T.; Tada, A.; Takamura-Enya, T.; Enomoto, S.; Nukaya, H.; Terao, Y.; Muroyama, A.; Ozeki, M.; Node, M.; Hasei, T.; Totsuka, Y.; Wakabayashi, K. Chem. Res. Toxicol. 2009, submitted.
7
Compound 14
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 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): δ = 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): δ = 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.
Compound 15
Tetrakis(triphenylphosphine)
palladium (5.0 mg, 0.004 mmol), Et3N (12 µL,
0.087 mmol), and formic acid (2.7 µL, 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 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 = 1:1.5)
to afford deiodine compound (16.8 mg, 98%). A suspension
of the above compound (15.7 mg, 0.040 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 afford 15 (13.8 mg, 95%). Pale
yellow crystals; mp 198-199 ˚C (hexane-EtOAc). ¹H
NMR (400 MHz, CDCl3): δ = 8.96 (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,
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): δ = 166.5,
165.1, 154.6, 150.4, 145.5, 144.5, 144.3, 136.4, 131.1, 129.9, 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 C20H18N2O5 [M+]:
366.1215; found: 366.1207.
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): δ = 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). ¹³C NMR
(100 MHz, CDCl3): δ = 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). HRMS: m/z calcd for C19H14N2O4 [M+]:
334.0953; found: 334.0947.
Compound 17
An
aq soln of KOH (2 M, 1.0 mL) was added to a soln of 16 (89.3
mg, 0.267 mmol) in MeOH (0.4 mL), and the mixture was stirred at
r.t. for 8.5 h. The reaction mixture was concentrated in vacuo to
remove the solvent. The residue was dissolved in H2O,
and the pH was adjusted to 6 with an aq soln of 2 M HCl. The mixture
was extracted with CHCl3 and EtOAc. The combined organic
layer was washed with brine, dried over Na2SO4,
and concentrated in vacuo. The residue was purified by column chromatography
on silica gel (CHCl3-MeOH = 2:1)
to afford a carboxylic acid derivative (62.2 mg, 73%).
Diphenyl phosphoryl azide (0.8 ml, 3.76 mmol) and Et3N
(0.8 ml, 5.74 mmol) were added to a soln of the above compound (192.5
mg, 0.601 mmol) in t-BuOH (3.0 mL) at
r.t., and the mixture was refluxed for 27.5 h. The solvent was removed
in vacuo, and the residue was purified by column chromatography
on silica gel (hexane-EtOAc = 1:1)
to afford 17 (103.7 mg, 44%).
Pale yellow crystals; mp 108-109 ˚C (EtOAc). ¹H
NMR (400 MHz, CDCl3): δ = 8.84 (s,
1 H), 8.81 (d, J = 4.6
Hz, 1 H), 8.49 (s, 1 H), 7.51 (s, 1 H), 7.44 (d, J = 4.6
Hz, 1 H), 7.42 (ddd, J = 8.0,
7.2, 1.2 Hz, 1 H), 7.35 (dd, J = 7.6,
1.2 Hz, 1 H), 7.26 (ddd, J = 7.6,
7.2, 1.2 Hz, 1 H), 7.14 (dd, J = 8.0,
1.2 Hz, 1 H), 4.16 (s, 3 H), 1.56 (s, 9 H). ¹³C
NMR (100 MHz, CDCl3): δ = 167.5, 156.0,
152.1, 148.9, 144.4, 141.4, 135.0, 133.6, 132.0, 130.8, 130.2, 125.7,
125.5, 121.3, 120.1, 119.0, 112.9, 81.3, 63.4, 28.3 (3 C). IR (KBr):
3433, 2978, 1732, 1657, 1591, 1523, 1479, 1353, 1336, 1234, 1155
cm-¹. MS (70 eV): m/z (%) = 391
(5 [M+], 335 (11), 291 (27),
274 (13), 262 (27), 57 (100), 41 (52). HRMS: m/z calcd
for C22H21N3O4 [M+]:
391.1532; found: 391.1538.
Compound 1 A soln of BBr3 in CH2Cl2 (1 M, 170 µL, 0.170 mmol) was added to a soln of 17 (13.4 mg, 0.034 mmol) in CH2Cl2 (0.4 mL) at -78 ˚C, and the mixture was stirred at -78 ˚C for 2 h. The mixture was poured into a sat. aq soln of NaHCO3 and extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was roughly purified with preparative thin-layer chromatography (hexane-EtOAc = 1:5) and the powder obtained was further purified by washing with CHCl3 and MeOH to afford 1 (3.5 mg, 38%). Ocher powder; mp (dec.). ¹H NMR (600 MHz, DMSO-d 6): δ = 15.23 (s, 1 H), 10.42 (s, 1 H), 8.51 (d, J = 4.6 Hz, 1 H), 7.43 (dd, J = 1.5, 8.0 Hz, 1 H), 7.41 (dd, J = 1.5, 8.0 Hz, 1 H), 7.30 (d, J = 4.6 Hz, 1 H), 7.29 (dd, J = 1.5, 6.9 Hz, 1 H), 7.24 (dt, J = 1.5, 8.0 Hz, 1 H), 7.20 (s, 1 H), 5.82 (s, 2 H). ¹³C NMR (125 MHz, DMSO-d 6): δ = 176.1, 157.5, 147.3, 144.9, 141.4, 140.6, 137.1, 131.7, 130.2, 128.0, 125.6, 120.7, 120.3, 117.9, 111.8, 104.5. IR (KBr): 3469, 3298, 3193, 1637, 1593, 1521, 1469, 1409, 1353, 1313, 1286, 1259 cm-¹. MS (70 eV): m/z (%) = 277 (100) [M+], 259 (63), 231 (40), 204 (32), 177 (18), 102 (11), 77 (7). HRMS: m/z calcd for C16H11N3O2 [M+]: 277.0851; found: 277.0856.