A simple two-step synthesis of indoles

Article abstract of DOI:10.1081/SCC-120021501

A two-step synthesis of indoles that is suitable for use on a large scale is described. The general applicability of this methodology has also been briefly explored.

Full text of DOI:10.1081/SCC-120021501

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A Simple Two-Step Synthesis of Indoles
Andrew Walkington a , Matthew Gray a , Frank Hossner a , John Kitteringham a & Martyn
Voyle a
a Synthetic Chemistry Department, GlaxoSmithKline, New Frontiers Science Park, Harlow,
Essex, UK
Version of record first published: 17 Aug 2006.
To cite this article: Andrew Walkington, Matthew Gray, Frank Hossner, John Kitteringham & Martyn Voyle (2003): A Simple
Two-Step Synthesis of Indoles, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 33:13, 2229-2233
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 13, pp. 2229–2233, 2003
A Simple Two-Step Synthesis of Indoles
*
Andrew Walkington, Matthew Gray, Frank Hossner,
John Kitteringham, and Martyn Voyle
SyntheticChemistry Department, GlaxoSmithKline,
New Frontiers Science Park, Harlow, Essex, UK
ABSTRACT
A two-step synthesis of indoles that is suitable for use on a large scale
is described. The general applicability of this methodology has also
been briefly explored.
Key Words: Indoles; Nucleophilic aromatic substitution; Hydro-
genation.
*Correspondence: Andrew Walkington, Synthetic Chemistry Department,
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road,
Stevenage, Hertfordshire SG1 2NY; E-mail: Andrew.J.Walkington@gsk.com.
2229
DOI: 10.1081/SCC-120021501
Copyright & 2003 by Marcel Dekker, Inc.
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2230
Walkington et al.
During the course of our recent work[1] we needed to prepare
multi-kilo quantities of 6-trifluoromethylindole (4). Unfortunately none
of the previously reported syntheses of this compound were suitable for
use on a large scale.[2–5] One of these methods[4] was used to prepare gram
quantities of the indole but it was not a viable process for pilot plant
operation because the starting material and both intermediates were
thermally unstable. However, we adapted this synthesis by changing
the key reagent from ethyl cyanoacetate to benzyl cyanoacetate (2) and
by adjusting the reaction conditions to give the safer two-step process
shown in Sch. 1. This process was subsequently used to prepare over
100 kg of 6-trifluoromethylindole.
The second step in the sequence involves several transformations
including reduction of the nitro-group, hydrogenolysis of the benzyl
ester and subsequent decarboxylation, cyclization, and elimination of
ammonia. The exact sequence of these events however is unknown.
In both steps the product was isolated by precipitation with water
and filtration (see Experimental). Impurities generated in the second step
(Sch. 2) remained in solution and the indole (4) was isolated with high
purity.
The general applicability of this methodology was then explored
and results from this investigation are presented in Table 1. The
conditions used for all of these reactions were the optimized conditions
developed specifically for the synthesis of 6-trifluoromethylindole
(4). Thus, the yield of product from the first step reflects the relative
susceptibility of the starting material to nucleophilic aromatic substi-
tution. Electron donating substituents, for example the methoxy group
in Entry 5, therefore lead to lower yields. The balance of material is
unreacted starting material and it is expected that yields could be
increased by using longer reaction times and more than the 1 equiv. of
benzyl cyanoacetate used in this instance.
The balance of material in the second step is made up by between 5
and 15% of the phenethylamines (5) in all reactions and varying amounts
of over-reduced products such as the indolines (6), and in the case of
Scheme 1.

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Two-Step Synthesis of Indoles
2231
Scheme 2.
Table 1.
Entry
R1
R2
Yielda (%)
Yielda (%)
1
2
3
4
5
6
H
CF3
H
97
96
88
88
87
74
73
CF3
H
H
97
75
H
CH3
OCH3
H
H
Cl
54
85 (þ6%
55 (R1 ¼R2 ¼H)
other isomer)
aSee experimental.
Entry 6, octahydroindole (7). Again it is anticipated that for individual
cases the yield of indole could be optimized by altering the conditions to
suit that particular substrate.
EXPERIMENTAL
General Procedure
Step 1
Benzyl cyanoacetate (2) (3.50 g, 0.02 mol) was added to a stirred
suspension of potassium carbonate (6.08 g, 0.044 mol) in DMF (5 mL)
and washed in with more DMF (2 mL). A solution of the substrate
(0.02 mol) in DMF (5 mL) was added and the resultant mixture was
stirred at 70ꢀC for 24 h. After cooling to RT the reaction mixture

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2232
Walkington et al.
was quenched by the careful addition of 5 N HCl (12.5 mL). The mixture
was partitioned between diethyl ether (100 mL) and water (50 mL), the
aqueous was re-extracted with diethyl ether (25 mL) and the combined
organicextracts washed with water (25 mL), dried (anhydrous sodium
sulfate), filtered, and evaporated. The product was purified by chromatog-
raphy on silica gel (200 g) with 1:1 dichloromethane–hexane as eluent.
Step 2
A mixture of the substrate (0.013 mol), 5% Pd/C powder (0.84 g),
glacial acetic acid (4 mL), water (4 mL), and ethanol (40 mL) was hydro-
genated at 50 psig for 18 h at 25ꢀC. The catalyst was removed by filtration
through Celite and the filter bed washed with ethanol (20 mL). The com-
bined filtrate was evaporated and the product purified by chromatog-
raphy on silica gel (50 g) with 2:1 dichloromethane–hexane as eluent.
Preparation of Benzyl 2-Cyano-2-(2-nitro-4-trifluoromethylphenyl)ethano-
ate (3). A solution of benzyl cyanoacetate (2) (23.4 kg, 133.8 mol) in
DMF (11 L) was added to a stirred suspension of potassium carbonate
(37.4 kg, 271.0 mol) in DMF (33 L) at RT over 10 min. 4-Chloro-3-nitro-
benzotrifluoride (1)[6] (30.4 kg, 134.8 mol) was added over 52 min
maintaining the temperature between 20–27ꢀC. After rinsing in with
DMF (7 L) the reaction mixture was stirred for 30 min and then heated
to 48–51ꢀC for 22 h. The mixture was cooled to 20ꢀC and aqueous hydro-
chloric acid made from conc. hydrochloric acid (48 L) and water (48 L)
was added over 1 h maintaining the temperature at 16–22ꢀC. Water
(136 L) was added over 15 min and the mixture stirred at 15ꢀC for
30 min. The product was collected by filtration and washed on the filter
bed with water (100 L) and dried as much as possible on the filter to give
64.52 kg (132%) as a damp solid which was used directly in the next
1
stage. H NMR (of dried sample) (400 MHz, CDCl3): ꢀ (8.48 (1H, s,
Ar-H), 8.01 (1H, dd, J 8.4, 1.3, Ar-H), 7.95 (1H, d, J 8.4, Ar-H),
7.33–7.42 (5H, m, Ar-H), 5.77 (1H, s, Ar-CH-CN), {[5.25 (d, J 12.0),
5.27, (d, J 12.0)], 2H, O-CH2-Ph}. 13C NMR (100 MHz, CDCl3): ꢀ
162.8, 147.5, 133.9, 133.4 (q, J 34.5), 132.5, 131.0 (q, J 3.2), 129.0,
128.8, 128.5, 123.4 (q, J 3.2), 122.3 (q, J 273.1), 113.7, 69.7, 41.2. m/z
(EIMS) Found: Mþ 364.06709. C17H11F3N2O4 requires M, 364.0671.
Preparation of 6-Trifluoromethylindole (4). Five percent palladium on
charcoal catalyst paste (6.18 kg containing 52.8% water, 2.92 kg) and
benzyl 2-cyano-2-(2-nitro-4-trifluoromethylphenyl)ethanoate (26.78 kg

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Two-Step Synthesis of Indoles
2233
@ 77.5%, 57.0 mol) were charged to a hydrogenation vessel. Ethanol
(159 L), glacial acetic acid (16 L), and water (15 L) were added and the
reaction mixture stirred vigorously under an atmosphere of hydrogen at
26–42 psig between 19–36ꢀC for 23 h. The catalyst was removed by filtra-
tion through Celite (2 kg) and the filter bed washed with ethanol (50 L).
The combined filtrate was concentrated in vacuo at 22–33ꢀC over 2 h to a
volume of 165 L and water (330 L) was added over 20 min. The suspen-
sion was stirred at 20ꢀC for 30 min and the product collected by filtration.
The product was washed with water (40 L) and then dried under vacuum
to give 8.36 kg (79%) yield. M.p. 111–113ꢀC (aq. IMS), (Lit.[4] m.p.
109–110ꢀC. H NMR (400 MHz, CDCl3): ꢀ 8.20 (1H, br s, N-H), {[7.70
1
(1H, d, J 8.4), 7.61 (1H, s), 7.35 (1H, d, J 8.7), 7.38 (1H, app t, J 2.8),
6.56–6.61 (1H, m)], Ar-H}. 13C NMR (100 MHz, CDCl3): ꢀ 134.6, 130.2,
126.8, 128.4, (q, J 271.7), 124.5 (q, J 31.3), 121.1, 116.5 (q, J 4.0), 108.6
(q, J 4.0), 102.9. m/z (EIMS) Found: Mþ 185.0453. C9H6F3N requires M,
185.0452.
REFERENCES
1. Andrews, I.P.; Faruk, E.A.; Gray, M.; Hossner, F.; Kitteringham, J.;
Paknoham, S.J.; Voyle, M. PCT Int. Appl. 1999, WO 9943650.
2. Raucher, S.; Koolpe, G.A. Synthesis of substituted indoles via
Meerwein arylation. J. Org. Chem. 1983, 48, 2066–2069.
3. Tischler, A.N.; Lanza, T.J. 6-Substituted indoles from o-halonitro-
benzenes. Tetrahedron Letters 1986, 27, 1653–1656.
4. Kalir, A.; Pelah, Z. 6-Trifluoro-methylindole. Israel J. Chem. 1966, 4,
155–159.
´
5. Belley, M.; Scheigetz, J.; Dube, P.; Dolman, S. Synthesis of N-
aminoindole ureas from ethyl 1-amino-6-(trifluoromethyl)-1H-
indole-3-carboxylate. Synlett. 2001, 222–225.
6. Commercially available in bulk from a number of suppliers, e.g.,
Sigma-Aldrich.
Received in the UK June 21, 2002

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