Selective lithiation of 2,3-dibromo-1-methylindole. A synthesis of 2,3-disubstituted indoles

Article abstract of DOI:10.1016/S0040-4039(02)01710-0

Indole (1) can be converted to 2,3-dibromo-1-methylindole (3) in two operations (92% yield). Treatment of 3 with tert-butyllithium effects clean monolithiation to 3-bromo-2-lithio-1-methylindole (4), which can be trapped with various electrophiles to afford the 3-bromo-2-substituted indoles (5-8) in 85-99% yield. A second bromine-lithium exchange reaction and quenching with electrophiles yields the 2,3-disubstituted indoles (9-10) in 88-95% yield.

Full text of DOI:10.1016/S0040-4039(02)01710-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7135–7137
Selective lithiation of 2,3-dibromo-1-methylindole. A synthesis of
2,3-disubstituted indoles
Yanbing Liu and Gordon W. Gribble*
Department of Chemistry, Dartmouth College, Hanover, NH 03755, USA
Received 18 July 2002; revised 14 August 2002; accepted 15 August 2002
Abstract—Indole (1) can be converted to 2,3-dibromo-1-methylindole (3) in two operations (92% yield). Treatment of 3 with
tert-butyllithium effects clean monolithiation to 3-bromo-2-lithio-1-methylindole (4), which can be trapped with various
electrophiles to afford the 3-bromo-2-substituted indoles (5–8) in 85–99% yield. A second bromine–lithium exchange reaction and
quenching with electrophiles yields the 2,3-disubstituted indoles (9–10) in 88–95% yield. © 2002 Published by Elsevier Science Ltd.
Although polyhalogenated indoles are ubiquitous in
nature,1 only recently have these compounds been
employed in synthesis. For example, we have employed
2,3-diiodoindoles, which are readily synthesized from
indole,2 in bis-Suzuki reactions,3 to generate and trap
2,3-dilithio-1-methylindole,4 to effect (inadvertently) an
unusual indole ring fragmentation;5 and in a synthesis
of isatins.6 Others have recently used monohaloindoles
in synthesis.7 We recently described a highly efficient
preparation of 2,3-dibromo-1-methylindole (3) from
indole (1) en route to syntheses of the naturally occur-
ring 2,3,6-tribromo-1-methylindole and 2,3,5,6-tetra-
bromo-1-methylindole.8 This sequence makes use of the
excellent Katritzky indole C-2 lithiation protocol9 fol-
lowed by Bergman’s indole C-2 bromination method to
give 2-bromoindole (2).10 Subsequent bromination and
Scheme 1.
Keywords: 2,3-dibromo-1-methylindole; 2,3-disubstituted indoles; lithiation; lithioindoles.
* Corresponding author. Tel.: +1-603-646-3118; fax: +1-603-646-3946; e-mail: grib@dartmouth.edu
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)01710-0

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Y. Liu, G. W. Gribble / Tetrahedron Letters 43 (2002) 7135–7137
methylation of 2 in one-pot affords 2,3-dibromo-1-
methylindole (3) in excellent overall yield (92% from
indole).
Petroleum Research Fund (PRF), administered by the
American Chemical Society. We also thank Wyeth for
their support.
Whereas our earlier attempts to effect selective mono-
lithiation of 2,3-diiodoindoles and 2,3-bromoiodoin-
doles were unsuccessful,11 we now report that selective
monolithiation of 2,3-dibromo-1-methylindole (3) at
−78°C is a clean process, even with a large excess of
tert-butyllithium, to generate the relatively stable 3-
bromo-2-lithio-1-methylindole (4).12 Subsequent reac-
References
1. More than 300 halogenated indoles occur naturally,
found mostly in marine plants and animals. For reviews,
see: (a) Gribble, G. W. Acc. Chem. Res. 1998, 31, 141–
152; (b) Gribble, G. W. Chem. Soc. Rev. 1999, 28,
335–346; (c) Gribble, G. W. Environ. Sci. Pollut. Res.
2000, 7, 37–49.
2. For syntheses of 2,3-dihaloindoles, see: (a) Erickson, K.
L.; Brennan, M. R.; Namnum, P. A. Synth. Commun.
1981, 11, 253–259; (b) Saulnier, M. G.; Gribble, G. W. J.
Org. Chem. 1982, 47, 757–761; (c) Harrington, P. J.;
Hegedus, L. S. J. Org. Chem. 1984, 49, 2657–2662; (d)
Brennan, M. R.; Erickson, K. L.; Szmalc, F. S.; Tansey,
M. J.; Thornton, J. M. Heterocycles 1986, 24, 2879–2885
and references cited therein; (e) Conway, S. C.; Gribble,
G. W. Heterocycles 1990, 30, 627–633; (f) Conway, S. C.;
Gribble, G. W. Heterocycles 1992, 34, 2095–2108; (g)
Gribble, G. W.; Allison, B. D.; Conway, S. C.; Saulnier,
M. G. Org. Prep. Proc. Int. 1992, 24, 649–654.
3. Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41,
8717–8721.
tion of
4 with various electrophiles affords the
corresponding 3-bromo-2-substituted indoles (5–8) in
85–99% yield as summarized in Scheme 1. Presumably,
the inductive electron withdrawing effect of the indole
nitrogen is responsible for the observed selective
bromine–lithium exchange at C-2. Also, the greater
electron density at C-3 may destabilize an anion at this
position. These new 3-bromoindoles (5–8) exhibited
satisfactory spectral and elemental analytical data,13
and a general procedure is given.14
In a one-pot operation we have also found that both
bromines of 3 can be sequentially replaced by elec-
trophiles. Thus, treatment of 3 with tert-butyllithium
followed by methyl iodide affords 7, which, without
isolation, is further treated with tert-butyllithium and
then DMF to afford 1,2-dimethyl-3-formylindole
(9)15,16 in 88% yield. A similar protocol with carbon
dioxide and ammonium chloride as the two elec-
trophiles gave 2-carboxy-1-methylindole (10)17,18 in 95%
yield. Both 9 and 10 are known compounds, and the
synthesis of 9 is representative of our procedure.19 For
the synthesis of 10 it is necessary to remove the excess
carbon dioxide in vacuo before adding the second
equivalent of tert-butyllithium.
4. Liu, Y.; Gribble, G. W. Tetrahedron Lett. 2001, 42,
2949–2951.
5. Gribble, G. W.; Saulnier, M. G. J. Org. Chem. 1983, 48,
607–609.
6. Gribble, G. W.; Liu, Y. Org. Prep. Proc. Int. 2001, 33,
615–619.
7. (a) Amat, M.; Seffar, F.; Llor, N.; Bosch, J. Synthesis
2001, 267–275; (b) Brown, M. A.; Kerr, M. A. Tetra-
hedron Lett. 2001, 42, 983–985; (c) Gribble, G. W.;
Fraser, H. L.; Badenock, J. C. Chem. Commun. 2001,
805–806; (d) Katayama, S.; Ae, N.; Nagata, R. J. Org.
Chem. 2001, 66, 3474–3483; (e) Zhang, H.; Larock, R. C.
Org. Lett. 2001, 3, 3083–3086; (f) Abbiati, G.; Beccalli, E.
M.; Marchesini, A.; Rossi, E. Synthesis 2001, 2477–2483;
(g) Chauder, B.; Larkin, A.; Snieckus, V. Org. Lett. 2002,
4, 815–817.
8. Liu, Y.; Gribble, G. W. J. Nat. Prod. 2002, 65, 748–749.
9. Katritzky, A. R.; Akutagava, K. Tetrahedron Lett. 1985,
26, 5935–5938.
10. Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57,
2495–2497.
In summary, we have shown that 2,3-dibromo-1-
methylindole (3) can be selectively converted to 3-
bromo-2-lithio-1-methylindole (4) by bromine-lithium
exchange with tert-butyllithium at −78°C. The resulting
species 4 can be trapped with electrophiles to give 5–8.
Furthermore, in one-pot sequential bromine–lithium
exchange reactions, 3 can be converted to 2,3-disubsti-
tuted indoles, e.g. 9, 10.
Acknowledgements
This work was supported by the National Institutes of
Health (GM58601), and in part by the Donors of the
11. Unpublished results from our laboratory.

Y. Liu, G. W. Gribble / Tetrahedron Letters 43 (2002) 7135–7137
7137
12. For example, allowing 4 to warm to room temperature in
the presence of 2,5-dimethylfuran (to trap 1-methyl-2,3-
indolyne, if formed) for 3 days returned only 3-bromo-1-
methylindole (5) upon workup. In a similar experiment (in
the absence of 2,5-dimethylfuran), although the THF
solution of 4 changed from bright yellow to bluish upon
warming to room temperature, upon workup with water
5 was obtained in 89% yield. In one reaction with a large
excess of tert-butyllithium and quenching with DMF, some
2,3-diformyl and 3-formyl products were detected by NMR
in the crude product, but 8 was the major product.
matography (silica gel; EtOAc/hexanes) gave 5–8.13 Except
for 6, these new 3-bromoindoles were too labile to obtain
elemental analyses but correct HRMS data were obtained.
In general one must use 2 equiv. of tert-butyllithium for
each bromine in order to decompose the so-formed tert-
butyl bromide; and normally we use the electrophile in
excess of the tert-butyllithium. For example, even with a
12-fold excess of tert-butyllithium and quenching 4 with
12.5 equiv. of DMF the yield of 8 is 72%, along with 16%
of 2,3-diformyl-1-methylindole and 12% of 3-formyl-1-
methylindole.
1
13. 3-Bromo-1-methylindole (5) (99%): yellow oil; H NMR
15. 1,2-Dimethyl-3-formylindole (9) (88%): mp 129–130°C
1
(white solid) (lit.16 mp 131–132°C); H NMR (DMSO-d6)
(CDCl3) l 7.58 (m, 1H), 7.34–7.27 (m, 2H), 7.23–7.19 (m,
1H), 7.09 (s, 1H), 3.80 (s, 3H); MS m/z 211, 209 (M+, 100%),
131, 130, 115, 103, 88, 77. HRMS m/z calcd for C9H8NBr
(M+) 208.9840, found 208.9840. 3-Bromo-2-carboxy-1-
methylindole (6) (85%): mp 180°C (dec.) (recrystallized
from aqueous acetone to afford a colorless solid); 1H NMR
(DMSO-d6) l 7.61 (d, 1H, J=8.5 Hz), 7.53 (d, 1H, J=8.0
Hz), 7.39 (t, 1H, J=8.0 Hz), 7.22 (t, 1H, J=8.0 Hz), 3.99
(s, 3H); MS m/z 255, 253 (M+, 100%), 221, 208, 194, 167,
146, 128, 115, 102, 91, 77. HRMS m/z calcd for
C10H8NO2Br (M+) 252.9738, found 252.9737. Anal. calcd
for C10H8NO2Br: C, 47.44; H, 3.19; N, 5.54. Found: C,
47.27; H, 3.25; N, 5.36%. 3-Bromo-1,2-dimethylindole (7)
(97%): mp 60°C (dec.) (off-white solid); 1H NMR (CDCl3)
l 7.50 (m, 1H), 7.27 (m, 1H), 7.23–7.15 (m, 2H), 3.72 (s,
3H), 2.46 (s, 3H); MS m/z 225, 223 (M+), 144 (100%), 128,
115, 102, 89, 77. HRMS m/z calcd for C10H10NBr (M+)
222.9997, found 222.9997. 3-Bromo-2-formyl-1-methylin-
dole (8) (86%): mp 91–92°C (dec.) (yellowish solid); 1H
NMR (DMSO-d6) l 10.05 (s, 1H), 7.70 (d, 1H, J=8.5 Hz),
7.65 (d, 1H, J=8.0 Hz), 7.54–7.51 (m, 1H), 7.30–7.27 (m,
1H), 4.04 (s, 3H); 13C NMR (CDCl3) l 182.3, 138.9, 129.8,
128.0, 125.3, 121.9, 120.7, 111.7, 103.7, 31.8; MS m/z 239,
237 (M+, 100%), 210, 208, 196, 194, 169, 167, 144, 130, 115,
103, 89, 77, 63. HRMS m/z calcd for C10H8NOBr (M+)
236.9789, found 236.9789.
l 10.08 (s, 1H), 8.10 (m, 1H), 7.55 (d, 1H, J=8.1 Hz),
7.29–7.18 (m, 2H), 3.75 (s, 3H), 2.71 (s, 3H); MS m/z 173
(M+), 172 (100%), 144, 128, 115, 102, 77. HRMS m/z calcd
for C11H11NO (M+) 173.0841, found 173.0842. Anal. calcd
for C11H11NO: C, 76.26; H, 6.41; N, 8.09. Found: C, 76.28;
H, 6.42; N, 8.10.%
16. Leete, E. J. Am. Chem. Soc. 1959, 81, 6023–6026.
17. 2-Carboxy-1-methylindole (10) (96%): mp 209–210°C
(recrystallized from aqueous acetone to give a colorless
1
solid) (lit.18 mp 209–210°C); H NMR (DMSO-d6) l 12.9
(bs, 1H), 7.67 (d, 1H, J=8.0 Hz), 7.56 (d, 1H, J=8.0 Hz),
7.33 (m, 1H), 7.21 (s, 1H), 7.12 (t, 1H, J=7.5 Hz), 4.02
(s, 3H); MS m/z 175 (M+, 100%), 158, 144, 130, 102, 89,
75, 63. HRMS m/z calcd for C10H9NO2 (M+) 175.0633,
found 175.0631. Anal. calcd for C10H9NO2: C, 68.55; H,
5.18; N, 8.00. Found: C, 68.11; H, 5.21; N, 7.86.
18. Johnson, J. R.; Hasbrouck, R. B.; Dutcher, J. D.; Bruce,
W. F. J. Am. Chem. Soc. 1945, 67, 423–430.
19. 1,2-Dimethyl-3-formylindole (9). To a solution of 2,3-
dibromo-1-methylindole (3) (0.100 g, 0.346 mmol) in THF
(10 mL) cooled to −78°C under N2 was added tert-butyl-
lithium (0.450 mL, 0.765 mmol, 1.7 M solution in hexanes).
The resulting yellow solution was stirred for 5 min and then
treated at −78°C with methyl iodide (50 mL, 0.796 mmol).
The solution was warmed to rt, stirred at rt for 10 min, and
recooled to −78°C. A second batch of tert-butyllithium
(0.610mL, 1.04mmol, 1.7Msolutioninhexanes)wasadded
and, after 5 min of stirring, DMF (100 mL, 1.3 mmol) was
added. The reaction mixture was allowed to warm to rt,
poured into water, and extracted with ethyl acetate (2×10
mL). The organic extract was washed with water (3×20 mL),
dried (MgSO4), and concentrated in vacuo. The crude
product was flash chromatographed on silica gel (EtOAc/
hexane, 1:1) to give 52 mg (88%) of 9 as a colorless solid.15
14. General procedure: To a solution of 2,3-dibromo-1-
methylindole (3) (0.100 g, 0.346 mmol) in THF (10 mL)
cooled to −78°C under N2 was added tert-butyllithium (0.45
mL, 0.765 mmol, 1.7 M solution in hexanes). The resulting
yellow solution was stirred at −78°C for 5 min and then
treated with an electrophile. The reaction mixture was
allowed to warm to rt, poured into water, and extracted
with ethyl acetate (2×10 mL). The organic extract was
washed with water (3×20 mL), dried (MgSO4), and concen-
trated in vacuo to afford the crude product. Flash chro-