Synthesis of a New Mutagenic Benzoazepinoquinolinone Derivative

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

References and Notes

• 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 

1

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.

8

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.

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): 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.

10

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.

11

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.