P. B. Huleatt et al. / Tetrahedron Letters 49 (2008) 5309–5311
5311
the rapid preparation of gram quantities of each of the target com-
pounds 3–9. The bromoindoles described herein are being utilised
in our laboratories for the preparation of a variety of novel DHI and
DHICA derivatives. The results of these studies will be reported in
due course.
Br 2, AcOH
MeO
HO
MeO
HO
NO2
NO2
26
Br
25
K2CO3
(68%, 2 steps)
Me2SO4
Acknowledgement
MgBr
MeO
MeO
MeO
MeO
(4 equiv.)
This work was supported by the Science and Engineering Re-
search Council of A*STAR (Agency for Science, Technology and Re-
search), Singapore and by Johnson & Johnson Asia Pacific.
N
H
THF
NO2
(66%)
Br
4
Br
27
References and notes
NBS
(88%) TFA
H2SO4
1. (a) Higuchi, K.; Kawasaki, T. Nat. Prod. Rep. 2007, 24, 843–868; (b) Sundberg, R.
J. Indoles; Academic Press: London, 1996.
2. For examples see: (a) Alex, K.; Schwarz, N.; Khedkar, V.; Ali, S. I.; Tillack, A.;
´
Michalik, D.; Holenz, J.; Dıaz, J. L.; Beller, M. Org. Biomol. Chem. 2008, 6, 1802–
Br
Br
MgBr
1807; (b) Suzen, S. Top. Heterocycl. Chem. 2007, 11, 145–178; (c) Brancale, A.;
Silvestri, R. Med. Res. Rev. 2007, 27, 209–238; (d) Lambert, G. A. CNS Drug Rev.
2005, 11, 289–316; (e) Müller, D. Drug Discovery Today 2003, 8, 681–691.
3. (a) Meredith, P.; Sarna, T. Pigment Cell Res. 2006, 19, 572–594; (b) Prota, G.
Melanins and Melanogenesis; Academic: San Diego, 1992.
MeO
MeO
MeO
MeO
(4 equiv.)
N
H
THF
NO2
(38%)
Br
Br
4. Kujala, T.; Klika, K.; Ovcharenko, V.; Loponen, J.; Vienola, M.; Pihlaja, K. Z.
Naturforsch., C: Biosci. 2001, 56, 714–718.
5
28
5. Bunker, A. M.; Edmunds, J. J.; Berryman, K. A.; Walker, D. M.; Flynn, M. A.;
Welch, K. M.; Doherty, A. M. Bioorg. Med. Chem. Lett. 1996, 6, 1061–1066.
6. (a) Coowar, D.; Bouissac, J.; Hanbali, M.; Paschaki, M.; Mohier, E.; Luu, B. J. Med.
Chem. 2004, 47, 6270–6282; (b) Sechi, M.; Angotzi, G.; Dallocchio, R.; Dessi, A.;
Carta, F.; Sannia, L.; Mariani, A.; Fiori, S.; Sanchez, T.; Movsessian, L.; Plasencia,
C.; Neamati, N. Antiviral Chem. Chemother. 2004, 15, 67–81; (c) Reddy, M. S.;
Cook, J. M. Tetrahedron Lett. 1994, 35, 5413–5416.
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108.
Scheme 5.
N-bromosuccinimide is a powerful brominating agent and effec-
tively brominates deactivated aromatic systems.12 Gratifyingly,
when these conditions were employed, the conversion of 27 to
the dibromo intermediate 28 proceeded smoothly and in very good
yield. Finally, treatment of 28 with vinylmagnesium bromide as
previously outlined yielded the desired indole 5 in modest yield.
In summary, the syntheses of 3-, 4-, 7-bromo and 4,7-dibromi-
nated 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-car-
boxylic acid (DHICA) derivatives 3–9 have been described. The
syntheses are highlighted by their expediency and have led to
9. (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005,
44, 5188–5240; (b) Palacios, F.; Ochoa de Retana, A. M.; de Marigorta, E. M.; de
los Santos, J. M. Eur. J. Org. Chem. 2001, 2401–2414.
10. Knittel, D. Synthesis 1985, 186–188.
11. (a) Dalpozzo, R.; Bartoli, G. Curr. Org. Chem. 2005, 9, 163–178; (b) Bartoli, G.;
Palmieri, G.; Bosco, M.; Dalpozzo, R. Tetrahedron Lett. 1989, 30, 2129–2132.
12. Duan, J.; Zhang, L. H.; Dolbier, W. R., Jr. Synlett 1999, 1245–1246.