Practical syntheses of 5-trifluoromethyl-1H-indoles

Article abstract of DOI:10.3987/com-01-9411

Short and convenient syntheses of 5-trifluoromethyltryptamine and 5-trifluoromethyltryptophole have been realized _via a regioselective, palladium catalyzed, coupling/annulation method involving functionalized alkynes and 2-iodo-4-trifluoromethylaniline. A new and improved approach for the preparation of 5-trifluoromethyl-1_H-indole is also described.

Full text of DOI:10.3987/com-01-9411

HETEROCYCLES, Vol. 57, No. 3, 2002, pp. 465 - 476, Received, 3rd December, 2001
PRACTICAL SYNTHESES OF 5-TRIFLUOROMETHYL-1H-INDOLES
Jean-Gilles Parmentier, Guillaume Poissonnet, and Solo Goldstein*
Chemistry Research Division A, Institut de Recherches Servier
11 rue des Moulineaux, 92150 Suresnes, France
e-mail: solo.goldstein@fr.netgrs.com
Abstract - Short and convenient syntheses of 5-trifluoromethyltryptamine and
5-trifluoromethyltryptophole have been realized via a regioselective, palladium
catalyzed, coupling/annulation method involving functionalized alkynes and 2-
iodo-4-trifluoromethylaniline. A new and improved approach for the preparation
of 5-trifluoromethyl-1H-indole is also described.
The indole nucleus is part of numerous natural compounds possessing biological activities.1 Substituted
indoles are used as starting materials for many such compounds and therefore it is important to have
access to these synthons in an easy and practical manner. Thus in the course of a project aiming to
prepare new ligands for the serotoninergic receptors,2 multigrams quantities of 5-trifluoromethyl-
tryptamine (1) and 5-trifluoromethyltryptophole (2) (Figure 1) were needed.
Figure 1
CF3
CF3
NH2
OH
N
H
1
N
H
2
CF3
N
H
3

However, it was rather surprising that such simple substituted indoles have not yet been prepared, the
5-trifluoromethyl-1H-indole (3) being the only compound of this type known in the literature.3,4
Two procedures have been employed for the preparation of 3. The first one, a three step synthesis starting
from commercially available 5-bromo-1H-indole, requires high temperatures and affords low yields of
end-product,3 while the second of these methods involves a multistep process including a Nordlander type
reaction.4 We first tried to apply these methodologies to our targets but in our hands both ways were not
satisfactory.
Despite limitations that were pointed out, these results prompted us to try the indole synthesis described
by Barluenga,5a which makes use of an ortho-substituted aniline intermediate.
Scheme 1
CF3
CF3
I
i
NH2
NH2
4
5
ii
SiMe3
CF3
iv
NH2
6
I
CF3
iii
N
H
7
v
CF3
N
H
3
i) BTMAICl2 / CaCO3 / MeOH / 95%
iii) CuI (1 equivalent) / DMF / 64%
v) 10% Pd/C / EtOH / 65%
ii) Pd(OAc)2 / Me3SiC≡CH / Et3N / 100%
iv) CuI (2 equivalents) / DMF / 80%

Thus, a palladium(II) acetate catalyzed Sonogashira coupling5b between 5 (itself obtained by ortho
iodation of 4)6 and trimethylsilylacetylene in the presence of CuI (one equivalent), in triethylamine
afforded 6 in good yield. Subsequently the ring closure of 6 using an additional equivalent of CuI in DMF
at 100°C afforded 3 in moderate yield.
Rather surprisingly, the strict application of Barluenga's conditions, using two or more equivalents of CuI
(vide infra), led to the exclusive formation of 3-iodo-5-trifluoromethylindole (7) in good yield. Despite its
relative instability this compound could be used to prepare 3 by treatment with palladium on charcoal
(Scheme 1).
Unfortunately, all attempts to introduce further functionality on the 3-position of the indole nucleus
resulted in recovery of starting materials only (Scheme 2).
Scheme 2
O
CF3
CF3
O
i, ii
N
H
OEt
N
H
3
i, iii
O
R
CF3
O
R
N
N
H
R = H, H or Bz, Bz
i) ClCOCOCl / Et2O; ii) EtOH; iii) R2NH
We therefore turned our attention to the synthesis of 3-substituted indoles via the palladium catalyzed
heteroannulation of difunctionalized alkynes described by Larock and Yum.7 This strategy, recently
improved and extended by Gronowitz,8 Ujjainwalla,9 Guillaumet10 and Cook11 is depicted for our target
molecules in Figure 2 (retrosynthetic scheme).

Figure 2
A
CF3
CF3
R
R
N
H
SiR'3
N
H
B
CF3
I
R
+
NH2
SiR'3
C
CF3
OH
NH2
H
The regioselectivity of the reaction (step B) should be controlled by the size of the organosilyl substituent
while the R group represents a protected amino or hydroxyl group (Scheme 3).
Scheme 3
CF3
I
R
CF3
R
Pd(0)
L
+
Et3Si
NH2
SiEt3
N
H
Solvent
5
R=OSiEt3
R = NPht
9
R=OSiEt3
R=NPht
12
13
11
The preparation of the two propargyl derivatives (9) and (11) was first undertaken (Scheme 4).

Scheme 4
i
OSiEt3
OH
Et3Si
H
8
9
iv
ii
iii
O
OTos
N
Et3Si
Et3Si
O
10
11
i) nBuLi / THF / Et3SiCl (2 equivalents) / 96%
iii) nBuLi / THF / Et3SiCl (1 equivalent) / 79%
ii) TosCl / Et3N / CH2Cl2 (100%)
iv) DMF / Potassium Phthalimidate / 81%
It was found that the phthalimido and triethylsilyl ether fulfilled the requirement of stability and ease of
deprotection. The silyl ether (9) was obtained in a nearly quantitative yield by a one pot bis-silylation of
the propargyl alcohol (8) in THF at –78°C, using nBuLi and two equivalents of triethylsilyl chloride. On
the other hand, the phthalimido derivative (11) was synthesized by a three step sequence, namely
tosylation of the propargyl alcohol (8), followed by silylation of the terminal alkyne with triethylsilyl
chloride (nBuLi, THF, –78°C) to afford compound (10), and then reaction with potassium phthalimidate
in DMF to afford 11 in excellent yield.
Next the heteroannulation of 5 with 9 and 11 was investigated (Scheme 5, Table 1).
Scheme 5
CF3
I
R
R
CF3
i
Et3Si
NH2
SiEt3
N
H
5
R=OSiEt3
R = NPht
9
R=OSiEt3
R=NPht
12
13
11
i) PdCl2(dppf) 5% mol / DMF 100°C / LiCl (1 equivalent) / Na2CO3 (2 equivalents).

Table 1
Entry
R
Ratio Alkyne/5
Reaction Time (h)
Yield (%)
1
2
3
4
5
OSiEt3
OSiEt3
OSiEt3
NPht
1
2
3
2
1
18
14
12
18
20
44
43
40
83
78
NPht
As already indicated by Ujjainwalla,9 in our hands too, the use of PdCl2(dppf) proved to be far better than
Pd(OAc)2 and PPh3. We also found that an one or two ratio of 11/5 provided excellent yields of 13
(Entries 4 and 5, Table 1), while moderate yields of 12 (Entries 1-3, Table 1) were obtained with 9/5
ratios of one to three.
Scheme 6
CF3
OSiEt3
CF3
i
OH
N
H
SiEt3
N
H
12
2
O
N
CF3
NH2
ii
CF3
N
SiEt3
O
H
N
H
SiEt3
13
14
iii
CF3
NH2.HCl
N
H
1
i) 1N (nBu)4NF / THF /82%
iii) 1N (nBu)4NF / THF / Molecular sieves 3Å / 78%
ii) 98% NH2NH2.H2O / EtOH / HCl / 87%

Deprotection of 12 occurred smoothly upon treatment with 1N (nBu)4NF in THF to afford 2 in 82% yield
(Scheme 6). However removal of the C-2 triethylsilyl group in compound (13) proved to be unexpectedly
problematic. Thus while regeneration of the amino group was easily achieved using the common Gabriel
conditions to give 14, no standard C-desilylating agents (e.g. HCl/MeOH, AlCl3/dichloromethane,
aqueous 2N KOH, 1N (nBu)4NF) succeeded in producing the desired target (1).
This transformation was finally achieved by treatment in THF with a stoichiometric amount of 1N
(nBu)4NF, in the presence of molecular sieves 3Å (48 h at room temperature), affording after addition of
ethanolic HCl, the hydrochloride salt of 1.
In conclusion, the synthetic approaches described above allowed the first preparation of
5-trifluoromethyltryptamine (1) and 5-trifluoromethyltryptophole (2) which are important pharmaceutical
intermediates. In addition a new and improved approach for the preparation of 5-trifluoromethyl-1H-
indole was also described. These syntheses can be readily scaled up to multigram quantities and are
therefore practical ways for preparing 5-trifluoromethyl-1H-indoles.
EXPERIMENTAL
1
13
Melting Points were measured on a Tottoli Büchi 535 apparatus and are uncorrected. H and C NMR
were recorded on Bruker 300 MHz or 500 MHz spectrometers. The chemical shifts are reported in ppm (δ
value) downfield from tetramethylsilane (TMS), which was used as an internal standard. FT-IR spectra
were measured on Fourrier Transform Bruker IFS 48 and IFS 28. MS spectra were recorded on a
NERMAG R.10-10 C mass spectrometer (EI and HRMS (m/z)). Reagents and solvents were purchased
from Aldrich-Sigma, Riedel-de-Haen, Baker or Acros. Analytical TLC was carried out on precoated
plates (silicagel 60 F 254). Flash column chromatography was performed on Kieselgel 60 (230-400 mesh)
silica gel (Merck). Solvent mixtures were reported as volume to volume ratios. The elemental analyses
were established using Carlo Erba EAS 1108, EAS 1106 or Perkin Elmer 240B apparatuses for carbon,
hydrogen, nitrogen and sulfur and a Mettler apparatus for halogens.
5-Trifluoromethyltryptamine (1)
10 mL of a 1N TBAF solution in THF were added to a solution of 14 (3 g, 8.7 mmol) followed by stirring
for 72 h with 1 g of molecular sieves 3Å. The THF was removed under vacuum and the residue was
dissolved in 100 mL of a 1N HCl solution. The solution was washed three times with 50 mL of ether then
brought to basic pH using 2N NaOH and extracted twice with dichloromethane. The organic phases were
dried over Na2SO4 and evaporated. Treatment with ethanolic HCl afforded the corresponding
hydrochloride salt of 1 (2.25 g, 78%) whose crystals were collected and dried: mp > 250°C (ethanol); IR
+
1
(Nujol) ν: 3298 (NH), 3007 (NH3 ), 1340-1090 (C-F) cm-1. H-NMR (DMSO-d6) δ: 3.08 (4H, s), 7.38

(1H, dd, J = 5.5 and 1.2 HZ), 7.47 (1H, d, J = 1.2 HZ), 7.58 (1H, d, J = 5.5 HZ), 8.00 (1H, s), 8.19 (3H, s
large, exchangeable), 11.55 (1H, s, exchangeable). Anal. Calcd for C11H11N2F3HCl: C, 49.92; H, 4.57; N,
10.58; Cl, 13.39. Found: C, 49.66; H, 4.87; N, 10.64; Cl, 13.38.
5-Trifluoromethyltryptophole (2)
10 mL of a 1N TBAF solution in THF were added via a syringe and under argon to a solution of 12
(4.5 g, 10 mmol) in 100 mL of THF, followed by stirring for 24 h. The solvent was evaporated and the
residue was purified by flash chromatography (eluent: dichloromethane/ethyl acetate, 98/2). Compound
(2) (1.87 g, 82%) was obtained as a yellow solid: mp 65-67°C (ethyl acetate); IR (Nujol) ν: 3544, 3313,
3263 (NH,OH), 1328, 1105 (C-F) cm-1; 1H-NMR (DMSO-d6) δ: 2.90 (2H, t, J = 4.9 HZ), 3.68 (2H, td, J =
4.9 and 3.7 HZ), 4.66 (1H, t, J = 3.7 HZ, exchangeable), 7.35 (2H, dd and s, J = 5.5 and 1.2 HZ), 7.52 (1H,
d, J = 5.5 HZ), 7.92 (1H, d, J = 1.2 HZ), 11.28 (1H, s, exchangeable). Anal. Calcd for C11H10NOF3: C,
57.64; H, 4.40; N, 6.11. Found: C, 57.86; H, 4.52; N, 6.11.
5-Trifluoromethyl-1H-indole (3)
Compound (6) (5.2 g, 20 mmol), calcium carbonate (2.4 g, 20 mmol) and CuI (1.9 g, 10 mmol) were
heated at 120°C in 100 mL of DMF for 2 h. The solvent was removed under vacuum and the residue was
flash chromatographed (eluent: dichloromethane/heptane, 50/50) to afford 3 (2.4 g, 64%). Alternately, a
suspension of 7 (3 g, 8 mmol) and 10% Pd on charcoal (0.3 g) in 50 mL of ethanol was hydrogenated
under hydrogen pressure (5 bars). The catalyst was filtered off then the solvent was concentrated under
vacuum and the residue was flash chromatographed (eluent: dichloromethane/heptane, 50/50) to afford 3
(1.78 g, 65%): mp 67-68°C (heptane) (lit.,2: 67-68°C); IR (Nujol) ν: 3433 (NH), 1332, 1162 (C-F) cm-1;
1H-NMR (DMSO-d6) δ: 7.93 (1H, s), 7.59 (1H, d, J = 5.5 HZ), 7.53 (1H, d, J = 1.2 HZ), 7.36 (1H, dd, J =
5.5 and 1.2 HZ), 6.60 (1H, s), 11.53 (1H, s, exchangeable). Anal. Calcd for C9H6NF3: C, 58.39; H, 3.27; N,
7.57. Found: C, 58.20; H, 3.45; N, 7.71.
2-Iodo-5-trifluoromethylaniline (5)
Benzyltrimethylammonium dichloroiodate (12.9 g, 37 mmol) was added portionwise to a suspension of
4-trifluoromethylaniline (4) (5.63 g, 35 mmol) and calcium carbonate (3.7 g, 37 mmol) in 50 mL of
dichloromethane and 150 mL of methanol. The mixture was stirred for 2 h at rt, filtered and concentrated
under vacuum. The brown oil was flash chromatographed (eluent: dichloromethane) to afford 5 (10 g,
100%) as a light sensitive oil: IR (Neat) ν: 3404, 3287, 3193 (NH2) cm-1; 1H-NMR (CDCl3) δ: 5.00 (2H, s,
exchangeable), 6.82 (1H, d, J = 5.5 HZ), 7.38 (1H, dd, J = 5.5 and 1.3 HZ), 7.79 (1H, d, J = 1.3 HZ).

2-Trimethylsilylethynyl-4-trifluoromethylaniline (6)
A solution of 5 (10 g, 35 mmol) in 10 mL of triethylamine was slowly added at 0°C, to a suspension of
CuI (0.6 g, 35 mmol), bis(triphenylphosphine)dichloropalladium (200 mg, 0.4 mmol), and trimethyl-
silylacetylene (5.7 mL, 40 mmol) in 90 mL of triethylamine. The mixture was stirred for 20 h at rt and
concentrated under vacuum. Water (100 mL) and dichloromethane (100 mL) were added to the residue
followed by filtering on a celite bed. The organic layer was separated, dried over Na2SO4 and evaporated
under reduced pressure. The residue was flash chromatographed (eluent: dichloromethane/heptane, 1/1) to
afford 6 (9g, 100%) as an orange oil: IR (Neat) ν: 2154, 2067 (C≡C), 1625 (NH2), 1509 (C≡C) cm-1; 1H-
NMR (CDCl3) δ: 0.27 (9H, s,), 4.54 (2H, s, exchangeable), 6.70 (1H, d, J = 5.5 HZ), 7.31 (1H, dd, J = 5.5
and 1.2 HZ), 7.54 (1H, d, J = 1.2 HZ).
3-Iodo-5-trifluoromethyl-1H-indole (7)
A suspension of 6 (2.57 g, 10 mmol) and CuI (3.8 g, 20 mmol) in 80 mL of DMF was heated for 2 h at
100°C. The solvent was distilled off under reduced pressure and the residue purified by flash
chromatography (eluent: dichloromethane) to afford 7 (2.5 g, 80%) as an unstable, light sensitive brown
oil: IR (Neat) ν: 1627 (NH), 1329-1115 (C-F) cm-1; 1H-NMR (DMSO-d6) δ: 7.47 (1H, dd, J = 5.6 and 1.2
HZ), 7.60 (1H, d, J = 5.6 HZ), 7.63 (1H, d, J = 1.2 HZ), 7.78 (1H, s), 12.00 (1H, s, exchangeable).
1-Triethylsilanyl-4-(triethylsilanyloxy)but-1-yne (9)
139 mL of a 1.6 N nBuLi solution in hexane was introduced via syringe under argon into a flask
containing 8 (7.6 mL, 0.1 mol) and 100 mL of THF, followed by cooling to -78°C. The solution was
stirred for 1 h and then triethylsilyl chloride (35 mL, 0.21 mol) was added dropwise. The solution was
allowed to reach rt and stirring was continued for 24 h. The reaction mixture was poured onto 1 L of
ice/water and extracted twice with 500 mL of ether. The combined organic phases were dried over
Na2SO4 and evaporated to dryness affording 9 (28.5 g, 96%) as a colorless oil: IR (Neat) ν: 2475 (C≡C)
1
cm-1; H-NMR (CDCl3) δ: 0.50-0.90 (30H, m), 2.48 (2H, t, J = 4.3 HZ), 3.70 (2H, t, J = 4.9 HZ). Anal.
Calcd for C16H34OSi2: C, 64.36; H, 11.48. Found: C, 64.94; H, 11.52.
4-(Triethylsilanyl)but-3-ynyl-4-methylbenzenesulfonate (10)
A solution of tosyl chloride (104 g, 0.55 mol) in 200 mL of dichloromethane was added dropwise at 0°C
to a flask containing 8 (38 mL, 0.5 mol), triethylamine (140 mL, 1mol) and 500 mL of dichloromethane.
The reaction mixture was stirred for 2 h, added to 1 L of water followed by separation of phases. The
organic layer was dried over Na2SO4 and evaporated to dryness affording, after flash chromatography
(eluent: dichloromethane/heptane, 1/1), the tosylate (89 g) as a pale yellow oil. This oil was then added to

300 mL of THF in a flask, under argon atmosphere, followed by cooling to -78°C. 250 mL of a
1.6 N nBuLi solution in hexane was added via syringe, during 15 min. The mixture was stirred for 1 h
and then triethylsilyl chloride (85 mL, 0.5 mol) was added and the reaction mixture allowed to reach rt.
Water (200 mL) was added forming two phases that were separated. The organic layer was dried over
Na2SO4, filtered and the solvent removed under vacuum to afford 10 (109 g, 79%) as a pale yellow oil; IR
1
(Neat) ν: 2179 (C≡C) cm-1; H-NMR (CDCl3) δ: 0.60-1.00 (15H, m), 2.50 (3H, s), 2.65 (2H, t, J = 6.7
HZ), 4.10 (2H, t, J = 7.3 HZ), 7.20 (2H, d, J = 7.9 HZ), 7.80 (2H, d, J = 7.9 HZ). Anal. Calcd for
C17H26O3SSi: C, 60.31; H, 7.74; S, 9.47. Found: C, 60.19; H, 8.05; S, 9.15.
2-(4-Triethylsilanylbut-3-ynyl)isoindole-1,3-dione (11)
A solution of 10 (109 g, 0.32 mol) and potassium phtalimidate (72 g, 0.35 mol) in 500 mL of anhydrous
DMF was heated at 60°C in a round bottomed flask for 4 h. The DMF was removed under reduced
pressure and the residue taken up in 300 mL of water and 500 mL of dichloromethane. After separation,
the organic phase was dried over Na2SO4, quickly filtered on 200 g of silica gel and evaporated under
reduced pressure affording 11 (79 g, 81%) as a colorless oil; IR (Neat) ν : 2177 (C≡C), 1775, 1718 (C=O)
cm-1; 1H-NMR (DMSO-d6) δ: 0.45-0.85 (15H, m), 2.65 (2H, t, J = 4.3 HZ), 3.88 (2H, t, J = 4.3 HZ), 7.72
(2H, m), 7.85 (2H, m). Anal. Calcd for C18H23NO2Si: C, 68.97; H, 7.40; N, 4.47. Found: C, 69.15; H,
7.58; N, 4.42.
2-Triethylsilanyl-3-(2-triethylsilanyloxyethyl)-5-trifluoromethyl-1H-indole (12)
A suspension of 4 (3.4 g, 20 mmol), 9 (6 g, 20 mmol), PdCl2(dppf) (0.25 g, 0.3 mmol), LiCl (0.85 g, 20
mmol), Na2CO3 (4.24 g, 40 mmol) in 200 mL of DMF was placed in a round bottomed flask under argon
and heated at 100°C during 10 h. The DMF was distilled off, the residue was taken up in
dichloromethane, filtered on celite and finally purified by flash chromatography (eluent: heptane)
1
affording 12 (4.1 g, 44%) as a colourless oil: IR (Neat) ν: 3479 (NH); 1330, 1116 (C-F) cm-1; H-NMR
(CDCl3) δ: 0.41-1.00 (30H, m), 3.00 (2H, t, J = 4.9 HZ), 3.74 (2H, t, J = 4.9 HZ), 7.40 (2H, s), 7.88 (1H,
broad), 8.20 (1H, s, exchangeable). Anal. Calcd for C23H38NOF3Si2: C, 60.35; H, 8.37; N, 3.10. Found: C,
61.13; H, 8.43; N, 3.10.
2-[2-(2-Triethylsilanyl-5-trifluoromethyl-1H-indol-3-yl)ethyl]isoindole-1,3-dione (13)
A suspension of 4 (7.2 g, 25 mmol), 11 (16 g, 50 mmol), PdCl2(dppf) (0.4 g, 0.5 mmol), LiCl (1.08 g, 25
mmol), Na2CO3 (5.4 g, 50 mmol) in 100 mL of DMF was placed in a round bottomed flask and heated
under argon at 100°C for 20 h. The DMF was distilled under vacuum, the residue was taken up in
dichloromethane, filtered on celite and finally purified by flash chromatography (eluent:

dichloromethane/heptane, 1/1) to afford 13 (10 g, 83%) as a light yellow oil: IR (Neat) ν: 3470 and
1
3400 (NH), 1722, 1706 (C=O), 1520 (NH) cm-1; H-NMR (DMSO-d6) δ: 0.94 (15H, s), 3.12 (2H, t, J =
5.0 HZ), 3.77 (2H, t, J = 4.9 HZ), 7.35 (1H, dd, J = 6.1 and 1.2 HZ), 7.55 (1H, d, J = 6.1 HZ), 7.84 (4H, m),
7.92 (1H, d, J = 1.2 HZ), 10.97 (1H, s, exchangeable). Anal. Calcd for C25H27N2O2F3Si: C, 63.54; H, 5.76;
N, 5.93. Found: C, 63.77; H, 5.96; N, 5.93.
2-(2-Triethylsilanyl-5-trifluoromethyl-1H-indol-3-yl)ethylamine (14)
A solution of 13 (4.7 g, 10 mmol), 98% hydrazine hydrate (3.4 mL, 100 mmol) and 150 mL of ethanol
was refluxed for 3 h followed by addition of 20 mL of 1N HCl solution and the mixture was further reflux
for 1 h. Water (100 mL) was added and basic pH was reached by addition of a 5% Na2CO3 solution. The
mixture was extracted twice with 50 mL of dichloromethane. The combined organic layers were dried
over Na2SO4 and evaporated to dryness. The residue was crystallised from ethanol affording 14 (3 g,
87%) as yellow crystals: mp 56-57°C (ethanol); IR (Neat) ν: 3150 (NH); 1330-1110 (C-F) cm-1. 1H-NMR
(DMSO-d6) δ: 0.90 (15H, m), 2.70-36.00 (2H, large exchangeable), 2.72 (2H, m), 2.87 (2H, m), 7.33 (1H,
dd, J = 6.1 and 1.2 HZ), 7.53 (1H, d, J = 6.1 HZ), 7.92 (1H, d, J = 1.2 HZ), 10.88 (1H, s). Anal. Calcd for
C17H25N2F3Si: C, 59.62; H, 7.36; N, 8.18. Found: C, 59.04; H, 7.08; N, 8.06.
ACKNOWLEDGEMENTS
We are grateful to Dr Jean-Paul Volland and his team for analytical support and to Mrs Florence
Chevereau for the skillful typing of the manuscript.
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