Download PDF
Synlett 2011(1): 61-64  
DOI: 10.1055/s-0030-1259095
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Ahmed Kamal*a, M. Kashi Reddya, T. Srinivasa Reddyb, Leonardo Silva Santosc, Nagula Shankaraiah*b
a Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 607, India
Fax: +91(40)27193189; e-Mail: ahmedkamal@iict.res.in;
b National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India
c Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
Fax: +56(71)200448; e-Mail: lssantos@utalca.cl;
Further Information

Publication History

Received 13 August 2010
Publication Date:
10 December 2010 (online)

   Permissions and Reprints All articles of this category
Preview

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

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.