J. W. Huffman, R. Mabon, M.-J. Wu, J. Lu, R. Hart, D. P. Hurst,
P. H. Reggio, J. L. Wiley and B. R. Martin, Bioorg. Med. Chem., 2003,
11, 539; (c) B. P. Smart, R. C. Oslund, L. A. Walsh and M. H. Gelb,
J. Med. Chem., 2006, 49, 2858; N-arylated indoles: (d) G. Spadoni,
C. Balsamini, A. Bedini, G. Diamantini, B. Di Giacomo, A. Tontini,
G. Tarzia, M. Mor, P. V. Plazzi, S. Rivara, R. Nonno, M. Pannacci,
V. Lucini, F. Frachini and B. M. Stankov, J. Med. Chem., 1998, 41,
3624; (e) K. Andersen, T. Liljefors, J. Hyttel and J. Perregaard, J. Med.
Chem., 1996, 39, 3723; (f) C. A. Harbert, J. J. Plattner and W. M. Welch,
J. Med. Chem., 1980, 23, 635.
3 J. A. Joule, in Science of Synthesis, ed. E. J. Thomas, Thieme, Stuttgart,
2000, vol. 10, ch. 13, p. 361.
4 L. M. Levy, G. M. Cabrera, J. E. Wright and A. M. Seldes,
Phytochemistry, 2000, 54, 941.
5 Y. Yamamoto, K. Nishiyama and N. Kiriyama, Chem. Pharm. Bull.,
1976, 24, 1853.
6 (a) G. D. Sala, D. Capozzo, I. Izzo, A. Giordano, A. Iommazzo and
A. Spinella, Tetrahedron Lett., 2002, 43, 8839; (b) F. Yokokawa,
H. Sugiyama, T. Aoyama and T. Shioiri, Synthesis, 2004, 1476; (c)
P. S. Baran, C. A. Guerrero and E. J. Corey, J. Am. Chem. Soc., 2003,
125, 5628; (d) J. M. Roe, R. A. B. Webster and A. Ganasan, Org. Lett.,
2003, 5, 2825; (e) D. B. Hansen, A. S. Lewis, S. J. Gavalas and
M. M. Joullie´, Tetrahedron: Asymmetry, 2006, 17, 15.
7 (a) M. C. Willis, G. N. Brace and I. P. Holmes, Angew. Chem., Int. Ed.,
2005, 44, 403; (b) M. C. Willis, G. N. Brace, T. J. K. Findlay and
I. P. Holmes, Adv. Synth. Catal., 2006, 348, 851.
8 For reviews of Pd-catalysed C–N and C–O cross-coupling of aryl
halides, see: (a) J. F. Hartwig, in Handbook of Organopalladium
Chemistry for Organic Synthesis, ed. E. I. Negishi, Wiley-Interscience,
New York, 2002, vol. 1, p. 1051; (b) J. F. Hartwig, in Handbook of
Organopalladium Chemistry for Organic Synthesis, ed. E. I. Negishi,
Wiley-Interscience, New York, 2002, vol. 1, p. 1097; (c) A. R. Muci and
S. L. Buchwald, Top. Curr. Chem., 2002, 219, 131; (d) D. Prim,
J.-M. Campagne, D. Joseph and B. Andrioletti, Tetrahedron, 2002, 58,
2041.
9 Amine 3 was prepared in multigram quantities by thermal [3,3]-
rearrangement of the corresponding trichloroacetimidate derivative,
followed by NaOH mediated hydrolysis. Based on the procedure of Itoh
et al.: H. Nagashima, H. Wakamatsu, N. Ozaki, T. Ishii, M. Watanabe,
T. Tajima and K. Itoh, J. Org. Chem., 1992, 57, 1682.
Scheme 3 Synthesis of demethylasterriquinone A1.
synthesis of demethylasterriquinone A1 (DAQ A1) was based on
achieving a direct nucleophilic addition of two molecules of indole
8 onto an activated quinone core. Although a number of literature
protocols for the addition of a variety N-H indoles to activated
quinones are known,15 examples featuring N-alkyl indoles are
scarce.16 In the event, addition of indole 8 to 2,5-dichloroquinone
could be promoted by HCl;17 subsequent treatment with DDQ
delivered the mono-substituted indole 9 in 65% yield. Attempts to
introduce a second indole unit using the same conditions were
unsuccessful, resulting in the return of both reaction partners.
Addition of a second indole unit to quinone 9 could be achieved
under the action of Zn(OTf)2.18 Re-oxidation to the quinone
oxidation level was again achieved with DDQ, providing
bis(indole) 10 in 64% yield. Treatment of 10 with NaOH resulted
in hydrolysis of the two quinone chloro-substituents and delivered
demethylasterriquinone A1 in 98% yield.19 The stepwise addition
of the two indole units paves the way for the preparation of non-
symmetrical members of the asterriquinone family and related
structures.
10 S. D. Walker, T. E. Barder, J. R. Martinelli and S. L. Buchwald, Angew.
Chem., Int. Ed., 2004, 43, 1871; X. Huang, K. W. Anderson, D. Zim,
L. Jiang, A. Klapars and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
6653.
11 A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020;
M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295.
12 For an earlier synthesis of demethylasterriquinone A1, see:
M. C. Pirrung, Z. Li, K. Park and J. Zhu, J. Org. Chem., 2002, 67, 7919.
13 K. Arai and Y. Yamamoto, Chem. Pharm. Bull., 1990, 38, 2929.
14 A. Kaji, R. Saito, M. Nomura, K. Miyamoto and N. Kiriyama,
Anticancer Res., 1997, 17, 3675; B. Zhang, G. Salituro, D. Szalkowski,
Z. Li, Y. Zhang, I. Royo, D. Vilella, M. T. D´ıez, F. Pelaez, C. Ruby,
R. L. Kendall, X. Mao, P. Griffin, J. Calaycay, J. R. Zierath, J. V. Heck,
R. G. Smith and D. E. Moller, Science, 1999, 284, 974.
15 G. D. Harris, Jr., A. Nguyen, H. App, P. Hirth, G. McMahon and
C. Tang, Org. Lett., 1999, 1, 431; J. S. Yadav, B. V. S. Reddy and
T. Swamy, Tetrahedron Lett., 2003, 44, 9121; J. S. Yadav, B. V. S. Reddy
and T. Swamy, Synthesis, 2004, 106; H.-B. Zhang, L. Liu, Y.-J. Chen,
D. Wang and C.-J. Li, Eur. J. Org. Chem., 2006, 869.
In summary, we have demonstrated that indoles bearing
sterically demanding N-alkyl substituents can be conveniently
prepared using a tandem Pd-catalysed alkenyl-aryl-amination
approach. Significant variation in both the acyclic substrate and
amine are possible, allowing access to a variety of indole structures.
The utility of the method has been demonstrated in a short
synthesis of demethylasterriquinone A1.
The authors would like to thank the EPSRC for funding. The
EPSRC Mass Spectrometry Service at the University of Wales,
Swansea, is also thanked for its assistance. We thank Prof. Michael
Pirrung for advice concerning the synthesis of DAQ A1.
16 S. Koulouri, E. Malamidou-Xenikaki and S. Spyroudis, Tetrahedron,
2005, 61, 10894. Also see ref. 12.
17 M. C. Pirrung, K. Park and Z. Li, Org. Lett., 2001, 3, 365; M. C. Pirrung,
L. Deng, Z. Li and K. Park, J. Org. Chem., 2002, 67, 8374.
18 M. C. Pirrung, Y. Liu, L. Deng, D. K. Halstead, Z. Li, J. F. May,
M. Wedel, D. A. Austin and N. J. G. Webster, J. Am. Chem. Soc., 2005,
127, 4609; M. C. Pirrung, Z. Li, E. Hensley, Y. Liu, A. Tanksale, B. Lin,
A. Pai and N. J. G. Webster, J. Comb. Chem., 2007, DOI: 10.1021/
cc070062m.
Notes and references
1 Indole reviews: (a) R. J. Sundberg, Indoles, Academic Press, London,
1996; (b) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1, 2000, 1045.
2 Selected examples: N-alkyl indoles: (a) L. F. Kuyper, D. P. Baccanari,
M. L. Jones, R. N. Hunter, R. L. Tansik, S. S. Joyner, C. M. Boytos,
S. K. Rudolph, V. Knick, H. R. Wilson, J. M. Caddell, H. S. Friedman,
J. C. W. Comley and J. N. Stables, J. Med. Chem., 1996, 39, 892; (b)
19 M. C. Pirrung, K. Fujita and K. Park, J. Org. Chem., 2005, 70, 2537.
4766 | Chem. Commun., 2007, 4764–4766
This journal is ß The Royal Society of Chemistry 2007