Total Synthesis of Rutaecarpine and Analogues by Tandem Azido Reductive Cyclization Assisted by Microwave Irradiation

Abstract

The total synthesis of rutaecarpine and several analogues has been developed by using an azido reductive cyclization process starting from substituted azido benzoic acids. The intramolecular azido reductive cyclization step was performed with triphenylphosphine or Ni₂B in HCl-MeOH (1 M) using microwave irradiation. This synthetic route is amenable for the generation of a library of quinazolinone compounds.

Key words

quinazolinones - β-carbolines - azido-reductive cyclization - Ni₂B - microwave irradiation

References and Notes

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29

Coupling reaction procedure for {2-azidophenyl)-(1-methylene-3,4-dihydro-1H-pyrido[3,4-b]indol-2 (9H)-yl}methanone (5a): To a stirred solution of 3 (0.250 g, 1.53 mmol) in CH₂Cl₂ (10 mL) was added Et₃N (0.22 mL, 1.63 mmol) dropwise at 0 ˚C over 10 min, then 2-azidobenzoyl chloride (0.295 g, 1.62 mmol) dissolved in CH₂Cl₂ (5 mL) was added at the same temperature. The reaction was brought to r.t. and stirred for another 2 h. After completion of the reaction, the solvent was evaporated and extracted with CH₂Cl₂ (3 × 20 mL), washed with aqueous NaHCO₃ followed by brine, separated, and dried over anhydrous Na₂SO₄. The combined organic extracts were evaporated under reduced pressure and further purified by column chromatography with EtOAc-hexane (1:1) as eluent to afford 5a in 84% yield as a white solid; mp 86-88 ˚C. IR (KBr): 3381, 2105, 1638, 1415 cm^-¹; ^¹H NMR (300 MHz, CDCl₃): δ = 8.12 (br s, 1 H), 7.53 (d, J = 7.55 Hz, 1 H), 7.36-7.43 (m, 2 H), 7.32 (d, J = 7.55 Hz, 1 H), 7.20-7.25 (m, 1 H), 7.11-7.16 (m, 3 H), 4.93 (s, 1 H), 4.07 (s, 1 H), 4.00 (t, J = 8.58, 9.09 Hz, 2 H), 3.24 (t, J = 8.08 Hz, 2 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 167.6, 136.9, 132.3, 132.1, 130.3, 129.1, 128.2, 126.7, 125.1, 124.7, 123.5, 119.9, 119.0, 118.4, 112.0, 111.1, 101.8, 41.1, 29.6; HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₉H₁₅N₅O: 352.1174; found: 352.1182.

30

Oxidation reaction procedure for 2-(2-azidobenzoyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-one (6a): To a stirred solution of 5a (0.400 g, 1.13 mmol) in anhydrous acetone (20 mL) was added KMnO₄ (0.264 g, 1. 70 mmol) at r.t. and the mixture was stirred for 12 h. The solvent was evaporated under reduced pressure and the reaction mixture was diluted with EtOAc (40 mL) and filtered through Celite. The organic layer was washed with aqueous NaHCO₃ followed by brine and dried over anhydrous Na₂SO₄. After filtration and evaporation, the crude product was purified by column chromatography, eluting with EtOAc-hexane (7:3) to afford 6a in 67% yield as a white solid; mp 87-90 ˚C. IR (KBr): 3421, 2111, 1697, 1634 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 8.18 (br s, 1 H), 7.84 (d, J = 7.84 Hz, 1 H), 7.63-7.59 (m, 2 H), 7.38-7.32 (m, 1 H), 7.23-7.20 (m, 2 H), 7.18 (d, J = 7.55 Hz, 1 H), 7.16-7.19 (m, 1 H), 4.43 (br, 2 H), 3.24 (t, J = 8.10 Hz, 2 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 167.9, 161.2, 142.6, 137.8, 132.6, 130.1, 129.5, 128.1, 126.5, 124.8, 124.6, 123.4, 119.8, 118.9, 118.0, 101.9, 41.9, 21.7; HRMS (ESI): m/z [M]⁺ calcd for C₁₈H₁₃N₅O₂Na: 354.3186; found: 354.3207.

31

Typical procedure for preparation of rutaecarpine (1a): A mixture of 6a (0.100 g, 0.302 mmol) in MeOH (2.0 mL) and Ni₂B (0.114 g, 0.906 mmol) and 1.0 M HCl (1.0 mL) in a glass tube was placed in a microwave reactor (CEM Discovery LabMate) and irradiated at 70 W for 2 min, during which time the temperature was kept at 52 ˚C with cooling. The reaction mixture was brought to ambient temperature and the solvent was evaporated, the residue was neutralized with saturated aqueous 5% NaHCO₃ solution, and then extracted with EtOAc (3 × 25 mL). The combined organic phases were washed with brine, dried over Na₂SO₄, filtered and evaporated under reduced pressure. The crude product thus obtained was purified by column chroma-tography on silica (60-120 mesh) to afford the final compound 1a (0.072 g, 90%); mp 254-255 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 9.25 (br s, 1 H), 8.33 (dd, J = 1.23, 7.85 Hz, 1 H), 7.62-7.74 (m, 3 H), 7.43-7.69 (m, 2 H), 7.35 (dt, J = 1.22, 6.85 Hz, 1 H), 7.20 (t, J = 8.44 Hz, 1 H), 4.57 (t, J = 6.96 Hz, 2 H), 3.25 (t, J = 6.95 Hz, 2 H); ^¹³C NMR (100 MHz, CDCl₃): δ = 161.6, 147.5, 144.9, 138.2, 134.3, 127.2, 126.6, 126.1, 125.6, 125.5, 121.3, 120.6, 120.1, 118.3, 112.1, 19.6, 41.1, 20.2; HRMS (ESI): m/z [M + H]^{+ ˙} calcd for C₁₈H₁₃N₃O: 287.1054; found: 287.1057.
Euxylophoricine A (1b): Yield: 0.043 g (82%); mp 293-295 ˚C; ^¹H NMR (300 MHz, CDCl₃): δ = 9.25 (br s, 1 H), 7.65 (s, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.44 (d, J = 8.1 Hz, 1 H), 7.35 (dd, J = 7.8, 8.1 Hz, 1 H), 7.20 (t, J = 7.8 Hz, 1 H), 7.06 (s, 1 H), 4.60 (t, J = 7.0 Hz, 2 H), 4.01 (s, 3 H), 3.99 (s, 3 H), 3.24 (t, J = 7.0 Hz, 2 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 161.1, 155.1, 148.7, 143.9, 143.6, 138.2, 127.3, 125.7, 125.3, 120.6, 119.9, 117.6, 114.5, 111.9, 107.1, 106.4, 56.3, 56.2, 41.1, 19.6; HRMS: m/z [M + H]^{+ ˙} calcd for C₂₀H₁₇N₃O₃: 347.1263; found: 347.1266.
Euxylophoricine C (1c): Yield: 0.041 g (80%); mp 307-309 ˚C; ^¹H NMR (300 MHz, CDCl₃): δ = 9.10 (br s, 1 H), 7.65 (s, 1 H), 7.64 (d, J = 6.95 Hz, 1 H), 7.44 (d, J = 6.92 Hz, 1 H), 7.36 (t, J = 6.95 Hz, 1 H), 7.20 (t, J = 6.9 Hz, 1 H), 7.06 (s, 1 H), 6.10 (s, 2 H), 4.57 (t, J = 6.9 Hz, 2 H), 3.27 (t, J = 6.9 Hz, 2 H); ^¹³C NMR (75 MHz, CDCl₃): δ = 160.9, 153.5, 147.1, 143.9, 143.8, 138.1, 127.2, 125.7, 125.4, 120.6, 120.0, 117.6, 116.1, 111.9, 105.9, 104.2, 102.5, 41.8, 19.8; HRMS: m/z [M + H]^{+ ˙} calcd for C₁₉H₁₃N₃O₃: 331.0955; found: 331.0961.