ORDER
REPRINTS
Modified Leimgruber–Batcho Reaction to Prepare Indole
2299
The above reaction could be repeated using 498 g of the starting aniline 3
to give the crude product (705 g) in quantitative yield.
Preparation of 3-chloro-4-fluoro-6-methylnitrobenzene 5. A solution
of sodium nitrite (7.6 g, 0.11 mol) in water (20 mL) was added dropwise over
30 min at 08C to a stirred suspension of 2-fluoro-4-methyl-5-nitroaniline 4
(
17 g, 0.1 mol) in concentrated hydrochloric acid (200 mL). The mixture
was stirred at 08C for 20 min then transferred to a dropping funnel and
added dropwise over 30 min to a stirred suspension of copper(I) chloride
(16 g) in concentrated hydrochloric acid (150 mL) at 08C. The mixture was
allowed to warm to rt and stirred for 16 hr, then poured onto ice-water
(
extracts were washed with brine, dried (MgSO ), filtered, and concentrated in
1.5 L) and extracted with ethyl acetate (3 Â 250 mL). The combined organic
4
vacuo to leave a crude oil. The oil was purified by column chromatography
on silica gel using heptane as eluent to give the product (14.2 g, 75%) as a
yellow solid. A sample was recrystallised (heptane) to give a white solid mp
[
6]
5
7
7–588C (lit. 57–58 8C); d (400 MHz; CDCl ) 8.03 (1H, d, J ¼ 7.2 Hz),
H
3
.13 (1H, d, J ¼ 9.1 Hz), 2.6 (3H, s).
The above reaction could be repeated using 200 g of the starting aniline 4
to give the product (147 g) in 60% yield.
Preparation of [2-(4-Chloro-5-fluoro-2-nitro-phenyl)-vinyl]-dimethyl-
amine 6. A mixture of 3-chloro-4-fluoro-6-methylnitrobenzene 5 (230g, 1.2
mol), N,N-dimethylformamide di-iso-propylacetal (305mL, 1.5 mol), and
N,N-dimethylformamide (700mL) were heated to 1308C and stirred for 2 hr.
The mixture was cooled to 808C and the solvent was evaporated (the water
bath temperature was maintained at 808C) to leave a crude oil. Methanol
(
500mL) was added to the crude oil and the mixture was cooled in an ice
bath. The emerging precipitate was filtered to give a purple solid (290g)
containing solvent. A sample was dried further to provide the following data.
dH (400MHz; CDCl ) 8.02 (1H, d, J ¼ 8.1 Hz), 7.14 (1H, d, J ¼ 11.2Hz),
3
6
.96 (1H, d, J ¼ 13.3Hz), 5.92 (1H, dd, J ¼ 13.3, 1.7 Hz), 2.95 (6H, s).
Preparation of 6-chloro-5-fluoroindole 2. Raney nickel (5 spatula full)
was added to a stirred solution of [2-(4-chloro-5-fluoro-2-nitro-phenyl)-
vinyl]-dimethylamine 6 (290 g, wet with DMF–MeOH) in tetrahydrofuran
(
1.5 L) and methanol (1.5 L) at ?8C. Hydrazine hydrate (100 mL) was added
over 1 hr keeping the internal temperature below 40 8C by the use of ice
cooling. The mixture was then stirred at rt for 16 hr then filtered through a
c
c
Sometimes the presence of an intermediate (assumed to be the N-hydroxyindole) was
noted at this stage by thin layer chromatography. If such an intermediate was noted,
addition of further hydrazine hydrate and reaction for 30 min ensured complete for-
mation of the indole 2.