In approaches to the unnamed indolo[2,3-a]carbazole (5,
Scheme 4) the antiviral and antitumor alkaloid isolated from
a blue-green alga Nostoc sphaericum,1 considerable, unsuc-
cessful effort was expended in Suzuki-Miyaura cross-
coupling reactions to establish the 2,2′-bisindolyl bond on
differentially N-protected 3-substituted indole coupling part-
ners. For example, cross-coupling between 3 and 2-bromo-
indolyl-3-acetonitrile failed presumably due to steric hin-
drance. As a result, we turned to the corresponding Stille
tactic by combining the easily prepared 2-bromoindole
carboxamide 129 with the 2-stannylated N-carboxyindole 1310
to provide the bisindolyl derivative 14 in good yield.
Treatment with Eschenmoser’s salt 14 gave gramine 15,
which upon sequential reaction with MeI and KCN/18-
crown-6 afforded the acetonitrile 16. LDA-mediated cycliza-
tion of 16 followed by immediate methylation of the
somewhat unstable phenol gave the natural product 5.11 The
synthesis of 5 from indole proceeded in eight steps and 42%
overall yield.
To conclude, an efficient and general protocol for the
synthesis of benzo[a]carbazoles 1 following a merged
directed ortho and remote metalation-Suzuki-Miyaura
cross-coupling strategy has been demonstrated and, with
variation to the Stille cross-coupling reaction, applied to the
synthesis of the indolo[2,3-a]carbazole alkaloid 5.12 Expan-
sion of the derived methodology for the construction of
similar heteroaromatics and more complex indolo[2,3-a]-
carbazole alkaloids2a,c may be anticipated and is in progress.
Acknowledgment. We are grateful to NSEC Canada for
financial support of our synthetic programs. We warmly
thank Glaucia Barbosa Candido Alves for preliminary results
and Simon Baxter, NSERC USRA, 2003, for enthusiastic
assistance.
Supporting Information Available: Complete experi-
mental details and characterization data of all new com-
pounds. This material is available free of charge via the
(7) To a solution of LDA (2.50 mmol, in THF (20 mL), prepared from
n-BuLi (1.0 mL, 2.50 M, 2.50 mmol), was added dropwise a solution of
8a (0.60 g, 2.42 mmol) in THF (5 mL) at 0 °C, and the reaction mixture
was stirred at rt for 30 min and quenched with a satd aq NH4Cl solution
(10 mL). The layers were separated, the aqueous layer was extracted with
Et2O (3 × 20 mL), and the combined organic phase was dried (Na2SO4)
and concentrated in vacuo. The residue was purified by flash column
chromatography (hexane) to afford 0.58 g (98%) of 1a: mp 120 °C dec;
IR (KBr) 3505 cm-1; 1H NMR (300 MHz, acetone-d6) δ 8.73 (d, 1H, J )
2.0 Hz), 8.48 (d, 1H, J ) 2.0 Hz), 7.69 (d, 1H, J ) 8.0 Hz), 7.47-7.35 (m,
3H), 4.4 (s, 3H), 2.99 (s, 1H); 13C NMR (75 MHz, acetone-d6) δ 127.5,
125.3, 124.5, 123.1, 122.7, 122.4, 119.8, 109.2, 101.5, 33. 8; MS EI m/z
(rel intensity) 247 (100), 218 (81), 201 (43), 91 (76); HRMS m/z calcd for
C17H13NO, 247.0997, found 247.0997.
OL049780X
(10) Hudkins, R. L.; Diebold, J. L.; Marsh, F. D. J. Org. Chem. 1995,
60, 6218.
(11) mp > 275 °C dec (lit.1 mp > 280 °C dec). IR and NMR are identical
to those reported. For details, see the Supporting Information.
(12) For previous syntheses, see: Hayashi, H.; Ohmoto, S.; Somei, M.
Heterocycles 1997, 45, 1647 (two routes from indigo in 13% (six steps)
and 5% (seven steps) overall yields respectively both of which involve a
terminal nonregioselective N-methylation): Hayashi, H.; Suzuki, Y.; Somei,
M. Heterocycles 1999, 51, 1233 (from indigo in 59% (six steps) overall
yield). All routes involve interesting key central-ring closures via potentially
electrocyclic processes, an anionic version of which for the cyclization of
15 may also be contemplated.
(8) For the preparation of enol triflates, see: Crisp, G. T.; Scott, W. J.
Synthesis 1985, 335.
(9) Prepared in 82% yield by NBS bromination of N,N-diethylindole-
3-carboxamide, see: Mistry, A. G.; Smith, K.; Bye, M. R. Tetrahedron
Lett. 1986, 27, 1051.
Org. Lett., Vol. 6, No. 14, 2004
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