Notes
J ournal of Natural Products, 2002, Vol. 65, No. 5 749
and with stirring at 0 °C and was treated with a solution of
bromine (0.54 mL, 10.5 mmol) in DMF (10 mL). The resulting
solution was warmed to room temperature, treated with KOH
(2.24 g, 40.0 mmol) and methyl iodide (2.49 mL, 40.0 mmol),
and stirred at room temperature for 3 h. The mixture was
poured into water and extracted with ether (3 × 50 mL). The
organic layer was washed with water (5 × 50 mL), dried
(MgSO4), and concentrated in vacuo to give 2.66 g (92%) of 5
as an off-white solid: mp 38.5-40 °C (lit.10 mp 39-40 °C); 1H
NMR (DMSO-d6, 500 MHz) δ 7.57 (1H, m, H-4), 7.41 (1H, m,
H-7), 7.27 (1H, m, H-6), 7.18 (1H, m, H-5), 3.82 (3H, s, NCH3);
13C NMR (DMSO-d6, 125 MHz) δ 136.1 (C-7a), 126.0 (C-3a),
122.9 (C-4), 120.9 (C-5), 117.9 (C-6), 115.3 (C-2), 110.8 (C-7),
91.3 (C-3), 32.4 (CH3). This material was used directly in the
next steps.
crude solid after removal of solvent was recrystallized from
hexane to give 0.100 g (65%) of 2 as white needles: mp 170-
1
171 °C (lit.2 mp 171.5-172 °C); H NMR (CDCl3, 500 MHz) δ
7.77 (1H, s, H-4), 7.60 (1H, s, H-7), 3.77 (3H, s, NCH3); 13C
NMR (DMSO-d6, 125 MHz) δ 135.7 (C-7a), 126.7 (C-3a), 121.9
(C-4), 118.5 (C-6), 117.4 (C-2), 116.1 (C-7), 115.4 (C-5), 90.6
(C-3), 32.9 (CH3); HREIMS m/z 442.7148 (calcd for C9H5NBr4,
442.7155). Unfortunately, samples and spectra of this com-
pound2 were unavailable for direct comparison.
2,3,5,6-Tetr a br om o-1-m eth ylin d ole (2) fr om 1. To a
stirred solution of 1 (0.100 g, 0.271 mmol) in a mixture of
formic acid and acetic acid (1:1, 10 mL) cooled in an ice bath
was added a solution of bromine (0.0430 g, 0.271 mmol) in
formic acid and acetic acid (1:1, 1 mL). The mixture was stirred
in the ice bath for an additional 2 h. The resulting mixture
was poured into water (50 mL) and extracted with ethyl
acetate (2 × 20 mL). The organic layer was washed with water
(2 × 50 mL), saturated aqueous sodium bicarbonate solution
(20 mL), and water (50 mL) and dried (MgSO4). The crude solid
after removal of solvent was recrystallized from hexane to give
0.081 g (67%) of 2 as white needles, identical with that
obtained above.
2,3,6-Tr ibr om o-1-m eth ylin d ole (1). To a stirred solution
of 5 (0.200 g, 0.692 mmol) in chloroform (15 mL) at room
temperature was added dropwise with stirring under N2
a
solution of bromine (0.111 g, 0.694 mmol) in chloroform (5 mL).
The resulting solution was heated at reflux for 2 h, allowed to
cool to room temperature, and poured into saturated aqueous
sodium sulfite solution. The organic layer was washed with
water (3 × 50 mL), dried (MgSO4), and concentrated in vacuo.
The resulting residue was purified by flash chromatography
over silica gel (hexane/ether, 4:1) to give 0.198 g (78%) of 1 as
Ack n ow led gm en t. This research was supported by the
National Institutes of Health (GM58601), for which we are
grateful.
1
white crystals: mp 89-90 °C (lit.2 mp 90.5-91 °C); H NMR
(CDCl3, 300 MHz) δ 7.47 (1H, d, J ) 1.5 Hz, H-7), 7.38 (1H, d,
J ) 8.4 Hz, H-4), 7.29 (1H, dd, J ) 8.4, 1.5 Hz, H-5), 3.78 (3H,
Refer en ces a n d Notes
1
s, NCH3); H NMR (DMSO-d6, 500 MHz) δ 7.90 (1H, d, J )
(1) (a) Gribble, G. W. Chem. Soc. Rev. 1999, 28, 335-346. (b) Gribble.
G. W. Environ. Sci., Pollut. Res. 2000, 7, 37-49. (c) Gribble, G. W.
Unpublished compilation.
(2) Carter, G. T.; Rinehart J r., K. L.; Li, L. H.; Kuentzel, S. L.; Connor,
J . L. Tetrahedron Lett. 1978, 4479-4482.
(3) Ooi, T.; Utsumi, K.; Kusumi, T. Heterocycles 2001, 54, 577-579.
(4) Settimo, A. D.; Nannipieri, E. J . Org. Chem. 1970, 35, 2546-2551.
(5) For example, the crude polyhaloindole extract from the red alga
Rhodophyllis membranacea exhibits strong antifungal activity: Bren-
nan, M. R.; Erickson, K. L. Tetrahedron Lett. 1978, 1637-1640. 3,6-
Dibromoindole from the Palauan ascidian Distaplia regina shows
antibacterial activity: Qureshi, A.; Faulkner, D. J . Nat. Prod. Lett.
1999, 13, 59-62.
(6) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2001, 42, 2949-2951.
(7) Bergman, J .; Venemalm, L. J . Org. Chem. 1992, 57, 2495-2497.
(8) Bocchi, V.; Palla, G. Synthesis 1982, 1096-1097.
(9) (a) Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41, 8717-8721.
(b) Gribble, G. W.; Liu, Y. Org. Prep. Proc. Int. 2001, 33, 615-619.
(10) Zajc, B.; Zupan, M. Tetrahedron 1989, 45, 7869-7878.
1.5 Hz, H-7), 7.35 (1H, d, J ) 8.5 Hz, H-4), 7.30 (1H, dd, J )
8.5, 1.5 Hz, H-5), 3.80 (3H, s, NCH3); 13C NMR (DMSO-d6, 125
MHz) δ 136.8 (C-7a), 125.1 (C-3a), 123.9 (C-4), 119.7 (C-5),
116.6 (C-6), 115.8 (C-2), 113.7 (C-7), 91.6 (C-3), 32.7 (CH3);
HREIMS m/z 364.8046 (calcd for C9H6NBr3, 364.8050). Un-
fortunately, samples and spectra of this compound2 were
unavailable for direct comparison.
2,3,5,6-Tetr a br om o-1-m eth ylin d ole (2) fr om 5. To a
stirred solution of 5 (0.100 g, 0.346 mmol) in a mixture of
formic acid and acetic acid (1:1, 10 mL) cooled in an ice bath
was added dropwise a solution of bromine (0.111 g, 0.694
mmol) in formic acid and acetic acid (1:1, 1 mL). The mixture
was stirred in the ice bath for an additional 2 h. The resulting
mixture was poured into water (50 mL) and extracted with
ethyl acetate (2 × 20 mL). The organic layer was washed with
water (2 × 50 mL), saturated aqueous sodium bicarbonate
solution (20 mL), and water (50 mL) and dried (MgSO4). The
NP010610S