Synthesis of new 3-(Trifluoromethyl)-1H-indoles by reduction of trifluoromethyloxoindoles

Article abstract of DOI:10.1002/jhet.5570450404

(Chemical Equation Presented) This work describes the synthesis of new 3-trifluoromethylindoles. Different isatins were trifluoromethylated using (trifluoromethyl)trimethylsilane (Me₃SiCF₃) as a nucleophilic agent giving new 3-hydroxy-3-(trifluoromethyl)indolin-2-one. Different "one-step" procedures to transform the latter compounds into the reduced indoles were attempted, but failed. For the synthesis of the new trifluoromethylindoles the corresponding 2-oxo-3-(trifluoromethyl)indoles were reduced using borane/THF complex to furnish 3-(trifluoromethyl)indolin-3-ol that additionally were dehydrated using thionyl chloride in pyridine to give excellent yields of the desired products.

Full text of DOI:10.1002/jhet.5570450404

Jul-Aug 2008
969
Synthesis of new 3-(Trifluoromethyl)-1H-indoles by Reduction of
Trifluoromethyloxoindoles
Mônica M. Bastos,a,b Lúcia M. U. Mayer,a Elza C. S. Figueiraa, Marcio Soaresa, Warner
B. Koverb and Núbia Boechat*a
a Departamento de Pesquisa e Desenvolvimento de Fármacos, Instituto de Tecnologia em Fármacos, Far-
manguinhos/FIOCRUZ, Rua Sizenando Nabuco, 100, Manguinhos, Rio de Janeiro 21041-250 Brazil
b Instituto de Química, Universidade Federal do Rio de Janeiro, UFRJ, Centro de Tecnologia, Bloco A, 6º
andar, Ilha do Fundão, Rio de Janeiro 21949-900
Received February 28, 2007
HO
CF3
HO
CF3
O
CF3
R1
R1
R1
BH3.THF
SOCl2
N
N
N
pyridine
THF
CH3
CH3
CH3
24 h, r.t.
24 h, 0°C-r.t.
R1=H, Br, Cl, CH3, NO2
R1=H, Br, Cl, CH3, NO2
R1=H, Br, Cl, CH3, NO2
This work describes the synthesis of new 3-trifluoromethylindoles. Different isatins were
trifluoromethylated using (trifluoromethyl)trimethylsilane (Me3SiCF3) as a nucleophilic agent giving new
3-hydroxy-3-(trifluoromethyl)indolin-2-one. Different “one-step” procedures to transform the latter
compounds into the reduced indoles were attempted, but failed. For the synthesis of the new
trifluoromethylindoles the corresponding 2-oxo-3-(trifluoromethyl)indoles were reduced using borane/THF
complex to furnish 3-(trifluoromethyl)indolin-3-ol that additionally were dehydrated using thionyl
chloride in pyridine to give excellent yields of the desired products.
J. Heterocyclic Chem., 45, 969 (2008).
INTRODUCTION
proceed by formation of the 3,3-difluoroindolines which
subsequently, eliminated HF. The presence of electron
withdrawing groups on the aromatic nucleus retarded
elimination of HF, resulting in 3,3-difluoroindolines as
the major products [19].
Indoles are present in numerous natural and bioactive
compounds, but are often prone to instability due to a
great sensitivity to oxidizing conditions [20], in particular
at the position C-3. The presence of the electron-
withdrawing trifluoromethyl substituent at this site could
disfavor electrophilic processes.
To obtain indoles, many synthetic methodologies have
been devised and continue to be developed, reflecting the
importance of their skeletal structure [20]. We have been
interested in obtaining trifluoromethylindoles as part of
our program for the discovery of new drugs for neglected
diseases [21].
The introduction of fluorine atoms, particularly in the
form of trifluoromethyl group, into an organic
compound can bring remarkable changes in the physical,
chemical and biological properties, making them suitable
for different applications in the areas of materials science,
agrochemicals and pharmaceuticals [1-5].
While a wide variety of methodologies have been
developed for introducing trifluoromethyl groups into
organic compounds [6], the use of (trifluoromethyl)-
trimethylsilane (Me3SiCF3) as a nucleophilic trifluoro-
methylating agent has rapidly become the method of
choice for reaction with ketones and aldehydes [7].
Isatins (1H-indole-2,3-diones) are synthetically
versatile substrates, which can be used for the synthesis of
a large variety of heterocyclic compounds, such as indoles
and quinolines, and thus as raw material for drug
synthesis. The use of isatins as organic starting materials
has greatly advanced during the last twenty-five years due
to their importance as pharmacologically active
compounds [8].
a
RESULTS AND DISCUSSION
In this present study, we have investigated the
reduction
of
3-hydroxy-1-methyl-3-(trifluoromethyl)-
Many specific methods have been used for the
reduction of isatins [9-18] but none of these can be
generally applied. Garden and our group have described
the ready conversion of isatins to 3-fluoroindoles in a
two-step process, which involves an initial reaction with
diethylaminosulfur trifluoride (DAST) to yield the 3,3-
difluoro-2-oxindole derivative, and subsequent reduction
using borane/THF. The reaction course was shown to
indolin-2-one derivatives (6-10) under various conditions.
Compounds 6-10 were obtained by trifluoromethylation
reactions using (trifluoromethyl)trimethylsilane as
a
nucleophilic agent with different isatins in the presence of
catalytic CsF. A 2:1 ratio of reagent: starting material and
room temperature were found to be the best conditions.
After 24 hours of reaction time the corresponding
trifluoromethylated products were obtained (Scheme 1).

970
M. M. Bastos, L. M. U. Mayer, E. C. S. Figueira, M. Soares, W. B. Kover and N. Boechat
Vol 45
Although tertiary trifluoromethyl alcohols are stable
even in acidic conditions, benzylic ones are more often
susceptible to elimination or substitution [24]. However
compounds 11-15 do not undergo elimination of H2O.
According to the literature, reduction of various
3-hydroxy-2-oxoindoles resulted in the consumption of
the starting material and the formation of the
corresponding indole over the period of a couple of hours
[25]. It is well established that introduction of fluorine
atoms, with their small size, very high electronegativity
and strong bond energies, induce important modifications
in the chemical properties of vicinal groups [2]. In our
case, the presence of the trifluoromethyl group in the
oxoindole nucleus could disfavor the subsequent
dehydration into corresponding indoles.
Thus we searched for good conditions for indolinol
dehydration. There are only few reported trifluoroalkyl-
indoles in the literature, and most of the described
approaches are not regioselective and gave rise to a mixture
of products [26]. Bonnet-Delpon and co-workers have
shown that 3-(trifluoromethyl)indolin-3-ol derivatives can
be dehydrated using thionyl chloride (SOCl2) in pyridine
[26]. During ongoing investigations from our laboratory,
the dehydration of compounds 11-15 using this
methodology has proven to be a versatile method for the
synthesis of new indole derivatives 16-20 (Scheme 3).
All these compounds were obtained in high purity and
characterized by NMR spectra.
Scheme 1
O
HO
CF3
O
R1
R1
Me3SiCF3
O
N
N
CsF
24 h, r.t.
CH3
CH3
(1) R1=H
(2) R1=Br
(3) R1=Cl
(4) R1=CH3
(6) R1=H (90%)
(7) R1=Br (52%)
(8) R1=Cl (96%)
(9) R1=CH3 (71%)
(10) R1=NO2 (72%)
(5) R1=NO2
LiAlH4 and THF were initially used to reduce 3-
hydroxy-trifluoromethylindolin-2-one derivatives (6-10),
at room temperature, but the starting materials were
completely recovered, even in the presence of an excess
of LiAlH4.
Reduction of derivatives 6-10 with 3 equiv. of
BH3.THF for 24 hours at room temperature, afforded
products of reduction of the carbonyl group at position
C-2, namely 3-(trifluoromethyl)indolin-3-ol compounds
(11-15), but not the expected dehydrated indoles (16-20)
(Scheme 2). Compounds 11-15 have not been previously
described in the literature. They were obtained in high
purity and characterized by NMR analysis.
Scheme 3
HO
CF3
Scheme 2
CF3
R1
R1
HO
SOCl2, Py
24 h, r.t.
HO
CF3
O
CF3
R1
R1
N
N
BH3.THF
CH3
CH3
N
N
THF
(11) R1=H
(12) R1=Br
(13) R1=Cl
(14) R1=CH3
(15) R1=NO2
(16) R1=H (98%)
(17) R1=Br (98%)
(18) R1=Cl (90%)
(19) R1=CH3 (93%)
(20) R1=NO2 (82%)
CH3
CH3
24 h, r.t.
(6) R1=H
(7) R1=Br
(8) R1=Cl
(9) R1=CH3
(10) R1=NO2
(11) R1=H (81%)
(12) R1=Br (87%)
(13) R1=Cl (89%)
(14) R1=CH3 (88%)
(15) R1=NO2 (79%)
HPLC analysis were performed with a Shim-pack CLC-
C8 column (250mm x 4.6mm i.d.), injection volume 20
μL, using acetonitrile: water at 30 °C and a gradient of
these solvents varying between 30-90% in 40 minutes,
flow rate between 0.7-1.0 mL/min, and run time of 60
minutes. The spectral data were acquired between 190-
800 nm and the effluent was monitored at 215 nm.
The above-described method was modified to allow for
scaling up to a semi preparative separation of products 18,
19 and 20 from starting materials. The semi preparative
HPLC was performed with a Shim-pack PREP-C8
column (250mm x 20mm i.d.). The mobile phase was
acetonitrile:water at 30 °C with an average gradient of 10
to 90% during 50 minutes, flow rate between 5 and 7
mL/min, with an average run time of 60 minutes. The
injection volume was 400 μL of concentrated product.
Compounds 18, 19 and 20 were obtained in 75, 78, 70%
The formation of a more reactive BH3-carbonyl
complex than the one with LiAlH4, could explain these
results. THF is a weaker base than H- and the AlH3
concentration at equilibrium in the reactional medium is
very low. Nerverthless, the BH3 concentration is high and
a significant concentration of the BH3-carbonyl complex
exists [22].
It has been observed that the reduced compounds 11-15
are thermally unstable [23] when warmed on a water bath,
during removal of solvent. This decomposition is
consistent with previous observations on the reduction of
3,3-difluoro-2-oxoindoles [20]. In order to circumvent the
thermal instability problem, the solvent was removed
without warming and the products were obtained in good
yields.

Jul-Aug 2008
Synthesis of new 3-(trifluoromethyl)-1-H-indoles by reduction of trifluoromethyloxoindoles
971
7,48-7.52 (m, 2H); 13C NMR (acetone-d6) ꢀ 26.63, 75.72 (q, J=
30 Hz), 110.06, 121.21, 123.48, 123.93, 124.69, 125.74, 126.38,
128.00, 132.46, 145.69, 171.09; 19F NMR (acetone-d6) ꢀ - 79.86;
MS (GC) m/z 231 (M+). Anal. Calcd. for C10H8F3NO2: C, 51.96;
H, 3.49; N, 6.06. Found: C, 52.25; H, 3.74; N, 5.95.
yields, respectively with 98% purity. All other compounds
were obtained in high purity and characterized, so no
further purification was necessary.
In conclusion, we have found that the use of BH3.THF
solutions for the reduction of 3-trifluoromethyloxoindoles
derivatives is a useful method for the synthesis of
3-(trifluoromethyl)indolin-3-ol compounds. The reduced
compounds can be converted into corresponding
3-trifluoromethylindoles using thionyl chloride (SOCl2) in
pyridine. This new approach is a particularly efficient and
concise method for the conversion into desired indoles.
The synthesis provided analytically pure compounds (11-
20) in overall yields of 70-98%, in three steps, from isatin
derivatives. Ten new compounds were obtained in this
study.
5-Bromo-3-hydroxy-1-methyl-2-oxo-3-trifluoromethylind-
1
ole (7). m.p. 196-198 °C; Yield 52%; H NMR (acetone-d6) ꢀ
3.24 (s, 3H), 6.78 (s, 1H), 7.11 (d, 1H, J= 8.5 Hz), 7.64 (s, 1H),
7.68 (d, 1H, J= 8.0 Hz); 13C NMR (acetone-d6) ꢀ 26.84, 75.61
(q, J= 30 Hz), 112.16, 115.78, 120.93, 123.18, 125.45, 126.72,
127.70, 129.27, 135.33, 145.02, 170.54; 19F NMR (acetone-d6)
ꢀ - 79.81; MS (GC) m/z 309 (M+). Anal. Calcd. for
C10H7BrF3NO2: C, 38.74; H, 2.28; N, 4.52. Found: C, 38.52; H,
2.19; N, 4.26.
5-Chloro-3-hydroxy-1-methyl-2-oxo-3-trifluoromethylind-
1
ole (8). m.p. 192-194 °C; Yield 96%; H NMR (CDCl3) ꢀ 3.22
(s, 3H), 6.83 (d, 1H, J= 8.0 Hz), 7.42 (dd, 1H, J= 2.0 Hz, 8.0
Hz), 7.52 (s, 1H); 13C NMR (CDCl3) ꢀ 27.51, 110.70, 114.50,
120.54, 124.67, 126.22, 127.34, 130.03, 132.41, 143.74, 171.49;
19F NMR (CDCl3) ꢀ - 80. 15; MS (GC) m/z 265 (M+). MS (EIS)
Calcd. m/z 265.616 (MH+). Found: m/z 265.616 (MH+).
EXPERIMENTAL
All solvents and reagents were used as obtained from
commercial sources, unless otherwise indicated. Dry
tetrahydrofuran was purchased from Vetec and used after
redistillation. All reactions were monitored by thin-layer
chromatography over precoated Merck Silica gel 60 F254 plates
and visualized by UV irradiation. Melting points were measured
on a Büchi B-545 instrument. The GC-MS spectra were
obtained on a Hewlett Packard 5960 MS connected to a Hewlett
Packard 5890 gas chromatograph. NMR spectra were recorded
on a Bruker Avance 500 spectrometer. Chemical shifts were
reported as ꢀ values (ppm) downfield from internal Me4Si in the
solvent shown. Coupling constants (J) are expressed in Hertz
(Hz). The following NMR abbreviations are used: s (singlet), d
(doublet), dd (double-doublet), t (triplet), q (quartet), m
(multiplet). Infrared (IR) spectra were recorded on KBr pellets
with a Nicolet 670 FT-IR spectrometer. HPLC were carried out
using a Merck-Hitachi LaChrom model equipped with a 7100
pump and a 7455 photodiode array detector. All analytical
assays and semipreparative chromatography were performed
under the conditions given previously. The abbreviation THF
refers to tetrahydrofuran.
1,5-Dimethyl-3-hydroxy-2-oxo-3-trifluoromethylindole (9).
1
m.p. 166-168 °C; Yield 71%; H NMR (acetone-d6) ꢀ 2.35 (s,
3H), 3.19 (s, 3H), 6.49 (s, 1H), 6.98 (d, 1H, J= 8.0 Hz), 7.30 (dd,
1H, J= 1.0 Hz, J= 8.0 Hz), 7.35 (s, 1H); 13C NMR (acetone-d6) ꢀ
20.92, 26.64, 75.83 (q, J= 30 Hz), 109.80, 121.26, 123.51,
124.70, 125.78, 127.05, 128.03, 132.60, 133.53, 143.29, 171.05;
19F NMR (acetone-d6) ꢀ - 79.79; MS (GC) m/z 245 (M+). Anal.
Calcd. for C11H10F3NO2: C, 53.88; H, 4.11; N, 5.71. Found: C,
53.62; H, 4.49; N, 5.91.
5-Nitro-3-hydroxy-1-methyl-2-oxo-3-trifluoromethylindole
1
(10). m.p. 149-151 °C; Yield 72%; H NMR (DMSO-d6) ꢀ 3.26
(s, 3H), 7.40 (d, 1H, J= 9.0 Hz), 8.14 (s, 1H), 8.21 (d, 1H, J= 2.0
Hz), 8.45 (dd, 1H, J= 2.5 Hz); 13C NMR (DMSO-d6) ꢀ 26.94,
74.01 (q, J= 30 Hz), 110.27, 118.72, 120.60, 121.56, 124.39,
124.48, 128.51, 143.08, 149.93, 170.50; 19F NMR (DMSO-d6)
ꢀ - 78.12; MS (GC) m/z 276 (M+).
General procedure for the synthesis of compounds (11-15).
The trifluoromethyl derivatives 6-10 (1 mol equiv.) were
dissolved in dry THF (10 mL) under a nitrogen atmosphere. To
the solution was added a solution of BH3.THF (1 M, 3 mol
equiv.). The reaction mixture was stirred at room temperature
for 24 hours. Aqueous HCl (3 M) was added dropwise and the
mixture was subsequently neutralized with aqueous NaOH (2.5
M). Saturated aqueous NaCl (10 mL) was added and the mixture
extracted with CH2Cl2 (3 x 15 mL). The organic phase was
further washed with water (2 x 15 mL), dried over Na2SO4,
filtered and evaporated at reduced pressure at room temperature.
1-Methyl-3-(trifluoromethyl)indolin-3-ol (11). Oil. Yield
Isatins derivatives 1-5 were prepared from their
corresponding isatins by reaction of each starting material with
CaH2 in DMF [27] in the presence of iodomethane. The reaction
mixture was heated to 100 °C for 4 hours. After treatment with
0.5 M hydrochloric acid, the isatins were obtained in 90%, 85%,
92%, 88% and 54% yields [27-28]. N-Methylisatins were
characterized by GC-MS, NMR and melting point
measurements.
1
81%; H NMR (acetone-d6): 2.77 (3H, s), 3.32-3.34 (1H, m),
General procedure for the synthesis of compounds (6-10).
Isatin derivatives (1 mmol) were dissolved in THF (10 mL).
(Trifluoromethyl)trimethylsilane (2 mmol) and catalytic
amounts of cesium fluoride (CsF) were added. The reaction
mixture was stirred at room temperature. After 24 hours, the
solution was extracted with cold water (20 mL), and the aqueous
phase was subsequently re-extracted with CH2Cl2 (3 x 15 mL).
The combined organic phases were dried over anhydrous
sodium sulfate, filtered and evaporated under reduced pressure.
3-Hydroxy-1-methyl-2-oxo-3-trifluoromethylindole (6).
3.61 (1H, d, J= 11 Hz), 6.64-6.72 (2H, m), 6.80 (1H, s), 7.13-
7.25 (2H, m); 13C NMR (DMSO-d6): 34.8, 62.7, 78.1, 107.9,
117.3, 124.2, 124.6, 125.4, 127.0, 130.7, 153.2; 19F NMR
.
(acetone-d 6): -80.9; MS (GC) m/z (%): 217 (M+ ).
5-Bromo-1-methyl-3-(trifluoromethyl)indolin-3-ol (12). Oil.
1
Yield 87%; H NMR (acetone-d6): 2.84 (3H, s), 3.47-3.51 (1H,
m), 3.75 (1H, d, J= 11 Hz), 5.90 (1H, s), 6.60 (1H, d, J= 8 Hz),
7.35-7.38 (1H, m), 7.38 (1H, s); 13C NMR (acetone-d6): 34.9, 63.9,
79.4, 108.9, 110.5, 125.1, 127.9, 128.4, 128.6, 134.6, 153.6; 19F
.
NMR (acetone-d6): -80.9; MS (GC) m/z (%): 295 (M+ ).
5-Chloro-1-methyl-3-(trifluoromethyl)indolin-3-ol (13).
1
m.p. 173-175 °C; Yield 90%; H NMR (acetone-d6) ꢀ 3.22 (s,
1H), 6.55 (s, 1H), 7.10 (d, 1H, J= 8.0 Hz), 7.16-7.19 (m, 1H),
1
Oil. Yield 89%; H NMR (acetone-d6): 2.86 (3H, s), 3.49-3.53

972
M. M. Bastos, L. M. U. Mayer, E. C. S. Figueira, M. Soares, W. B. Kover and N. Boechat
Vol 45
Biomedical Frontiers of Fluorine Chemistry, ACS Symposium Series -
American Chemical Society, Washington, DC, 1996, 639; (c) Filler, R.
Organic Chemistry in Medicinal Chemistry and Biomedical
Applications, Elsevier, Amsterdam, 1993; (d) Welch, J. T.;
Eswaraksrishnan, S. Fluorine in Bioorganic Chemistry, Wiley, New
York, NY, 1991; (e) Filler, R.; Kirk, K.; Hudlicky, M.; Pavlath, A. E.
Biological properties of fluorinated compounds. In Chemistry of
Organic Fluorine Compounds II: A Critical Review, ACS Monograph
187: American Chemical Society, Washington, DC, 1995.
[2] (a) Elliot, A. J. Fluorinated pharmaceuticals. In Chemistry of
Organic Fluorine Compounds II, ACS Monograph 187: American
Chemical Society, Washington, DC, 1995; (b) Sholoshonok, V. A.
Enantiocontrolled Synthesis of Organo-Fluorine Compounds:
Stereochemical Challenge and Biomedical Targets, Wiley, New York,
NY, 1999.
[3] (a) Cartwright, D.; Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Recent Developments in Fluorine-Containing Agrochemicals. In
Organofluorine Chemistry: Principles and Commercial Applications,
Plenum, New York, NY, 1994; (b) Lang, R. W. Fluorinated
agrochemicals. In Chemistry of Organic Fluorine Compounds II, ACS
Monograph 187: American Chemical Society, Washington, DC, 1995.
[4] Smart, B. E.; Banks, R. E.; Smart, B. E.; Tatlow, J. C.
Characteristics of C-F systems. In Organofluorine Chemistry: Principles
and Commercial Applications, Plenum, New York, NY, 1994.
[5] (a) O'Hagan, D. O.; Rzepa, H. S. J. Chem. Soc. Chem.
Commun. 1997, 645; (b) Dunitz, J. D.; Taylor, R. Chem. Eur. J. 1997, 3,
89; (c) Howard, J. A. K.; Hoy, V. J.; O'Hagan, D. O.; Smith, G. T.
Tetrahedron. 1996, 52, 12613.
[6] (a) Olah, G. A.; Prakash, G. K. S.; Chambers, R. D. Synthetic
Fluorine Chemistry, Wiley, New York, NY, 1992; (b) Furin, G. G.
Synthetic Aspects of the Fluorination of Organic Compounds, Harward
Academic, London, 1991; (c) McClinton, M. A.; McClinton, D. A.
Tetrahedron. 1992, 48, 6555; (d) Rozen, S. Acc. Chem. Res. 2005, 38,
803.
[7] Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757;
(b) Pedrosa, R.; Sayleri, S.; Vicente, M.; Maestro, A.; J. Org. Chem.
2006, 71, 2177.
[8] (a) Silva, J. F. M.; Garden, S. J.; Pinto, A. C. J. Braz. Chem.
Soc. 2001, 12(3), 273; (b) Nair, V.; Ros, S; Jayan, C. N.; Viji, S. 2003,
Synthesis-Stuttgart, 2452; (c) Alcaide, B.; Almendros, P.; Rodriguez-
Acebes, R. J. Org. Chem. 2006, 71, 2346.
[9] Hewlins, M. J. E.; Jacson, A. H.; Oliveira-Campos, A. M.;
Shannon, P. V. R. J. Chem. Soc. Perkin Trans. 1. 1981, 2906.
[10] Katz, A. H.; Demerson, C. A.; Humber, L. G. US 4 670 462,
CA 107:P96704j, 1987.
(1H, m), 3.77 (1H, d, J= 8 Hz), 6.65 (1H, d, J= 8 Hz), 7.24 (1H,
d), 7.26-7.27 (1H, m); 13C NMR (acetone-d6): 34.1, 63.0, 78.4,
109.0, 121.2, 124.1, 124.6, 126.9, 127.2, 130.7, 152.3; 19F NMR
.
(acetone-d6): -80.9; MS (GC) m/z (%): 251 (M+ ).
1,5-Dimethyl-3-(trifluoromethyl)indolin-3-ol (14). Oil.
1
Yield 88%; H NMR (acetone-d6): 2.23 (3H, s), 2.78 (3H, s),
3.38-3.40 (1H, m), 3.64 (1H, d, J= 12 Hz), 5.64 (1H, s), 6.55
(1H, d, J= 8 Hz), 7.05-7.07 (1H, m), 7.13 (1H, s); 13C NMR
(acetone-d6): 20.7, 35.8, 64.4, 79.9, 109.0, 123.4, 125.6, 126.0,
126.7, 127.6, 127.9, 130.1, 132.4, 152.7; 19F NMR (acetone-d6):
.
-80.6. MS (GC) m/z (%): 231 (M+ ).
5-Nitro-1-methyl-3-(trifluoromethyl)indolin-3-ol (15). Oil.
1
Yield 79%; H NMR (acetone-d6): 3.09 (3H, s), 3.77-3.81 (1H,
m), 4.06 (1H, d, J= 12 Hz), 6.70 (1H, d, J= 9 Hz), 8.16 (1H, s),
8.19 (1H, dd, J= 2.5 Hz); 13C NMR (acetone-d6): 33.4, 63.4,
78.6, 106.4, 122.5, 124.8, 126.2, 127.6, 129.7, 138.6, 157.9; 19
F
.
NMR (acetone-d6): -80.7. MS (GC) m/z (%): 262 (M+ ).
General procedure for the synthesis of compounds (16-20).
To a solution of an indolinol derivative (11-15) (1 mol equiv.)
in freshly distilled pyridine (5 mL) was added thionyl chloride
(1.5 mol equiv.), at 0 °C, under a nitrogen atmosphere. After 24
hours at room temperature, an aqueous solution 3 M of HCl (19
mL) was added to the mixture. After extraction with
dichloromethane (3 x 30 mL), the combined organic phases were
washed with brine, dried (MgSO4) and concentrated.
1-Methyl-3-(trifluoromethyl)-1H-indole (16). m.p. 55-57 °C;
1
Yield 98%; H NMR (DMSO-d6): 3.85 (s, 3H), 7.22 (t, J= 7.2
Hz), 7.31 (t, J= 7.2 Hz), 7.57–7.61 (m, 2H); 13C NMR (DMSO-
d6): 32.8, 102.9 (q, J= 36 Hz), 110.9, 118.3, 120.6, 123.3, 125.9,
128.6 (q, J= 265 Hz), 121.1, 122.7, 123.2, 130.2, 136.5; 19 F NMR
.
(DMSO-d6): -54.8. MS (GC) m/z (%): 199 (M+ ).
5-Bromo-1-methyl-3-(trifluoromethyl)-1H-indole (17). m.p.
1
58-60 °C; Yield 98%; H NMR (DMSO-d6): 3.85 (s, 3H), 7.44
(dd, 1H, J= 2,0 Hz e J= 6,8 Hz), 7.58 (d, 1H, J= 8,8 Hz), 7.71
(s, 1H), 8.06 (s, 1H); 13C NMR (DMSO-d6): 33.1, 102.6 (q, J=
36,8 Hz), 113.2, 113.8, 120.2, 122.8, 125.5, 128.1 (q, J= 265
Hz), 120.3, 124.8, 125.3, 131.7, 135.3; 19F NMR (DMSO-d6): -
.
55.0. MS (GC) m/z (%): 277 (M+ ).
5-Chloro-1-methyl-3-(trifluoromethyl)-1H-indole (18).
1
m.p. 59-61 °C; Yield 75%; H NMR (DMSO-d6): 3.85 (s, 3H),
7.33 (dd, 1H, J= 2,0 Hz e J= 6,8 Hz), 7.57 (s, 1H), 7.63 (d, 1H,
J= 8,8 Hz), 8.08 (s, 1H); 13C NMR (DMSO-d6): 33.1, 102.7 (q,
J= 36,6 Hz), 112.8, 117.3, 120.2, 122.8, 125.5, 128.1 (q, J= 264
[11] Katz, A. H.; Demerson, C. A.; Humber, L. G. Eur. Pat. Appl.
EP 238,226, Chem. Abstr. 1987, 109, P6494e.
[12] Katz, A. H.; Demerson, C. A.; Shaw, C. C.; Asselin, A. A.;
Humber, L. G.; Conway, K. M.; Gavin, G.; Guinosso, C.; Jensen, N. P.;
Mobilio, D.; Noureldin, R.; Schmid, J.; Shah, U.; Engen, D. V.; Chau, T.
T.; Weichman, B. M. J. Med. Chem. 1988, 31, 1244.
[13] Demerson, C. A.; Humber, L. G.; Philipp, A. H.; Martel, R.
R. J. Med. Chem. 1976, 19, 391.
[14] Soll, R. M.; Guinosso, C.; Asselin, A. J. Org. Chem. 1988,
53, 2844.
[15] Mirand, C.; Massiot, G.; Lévy, J. J. Org. Chem. 1982, 47,
4169.
[16] Jiang, B.; Smallheer, J. M.; Amaral-Ly, G.; Wuonola, M. A.
J. Org. Chem. 1994, 59, 6823.
[17] Wierenga, W.; Griffin, J.; Warpehoski, M. A. Tetrahedron
Lett. 1983, 24, 2437.
[18] Pinto, A. C.; Silva, F. S. Q.; Silva, R. B. Tetrahedron Lett.
1994, 35, 8923.
Hz), 122.8, 124.1, 125.9, 131.9, 135.1; 19F NMR (DMSO-d6: -
.
55,0. MS (GC) m/z (%): 233 (M+ ).
1,5-Dimethyl-3-(trifluoromethyl)-1H-indole (19). Yield
.
78%. MS (GC) m/z (%): 213 (M+ ).
5-Nitro-1-methyl-3-(trifluoromethyl)-1H-indole (20). m.p.
1
155-156 °C; Yield 70%; H NMR (DMSO-d6): 3.93 (s, 3H),
7.81 (d, 1H, J= 9,5 Hz), 8.17 (dd, 1H, J= 2,0 Hz e 7,0 Hz), 8.30
(s, 1H), 8.42 (s, 1H); 13C NMR (DMSO-d6): 33.4, 105.4, (q, J=
36,7 Hz), 112.0, 114.6, 117.8, 122.2, 122.7, 124.8, 126.9 (q, J=
265 Hz), 134.3, 139.3, 142.1; 19F NMR (DMSO-d6): -55.2. MS
.
(GC) m/z (%): 244 (M+ ).
Acknowledgment. The authors gratefully thank Dr. Solange
M. S. V. Wardell for manuscript revising.
[19] Torres, J. C.; Garden, S. J.; Pinto, A. C.; Silva, F. S. Q.;
Boechat, N. Tetrahedron. 1999, 55, 1881.
REFERENCES
[20] (a) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25, 1;
(b) Gribble, G. W. Contemp. Org. Syn. 1994, 1, 145; (c) Furstner, A.;
Bogdanovic, B. Angew. Chem. Int. Ed. Engl. 1996, 35, 2442; (d)
Sundberg, R. J. lndoles, Academic Press, San Diego, 1996; (e)
[1] (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemistry: Principles and Commercial Applications, Plenum, New
York, NY, 1994, 2; (b) Ojima, I.; McCarthy, J. R.; Welch, J. T.

Jul-Aug 2008
Synthesis of new 3-(trifluoromethyl)-1-H-indoles by reduction of trifluoromethyloxoindoles
973
Sundberg, R. J. Indoles, Academic Press, London, 1996; (f) Saito, I.;
Nakagawa, H.; Kuo, Y. H. J. Am. Chem. Soc. 1985, 107, 5279; (g)
Amsterdamsky, C.; Rigaudy, J. Tetrahedron Lett. 1980, 21, 3187.
[21] (a) Boechat, N.; Carvalho, A. S.; Pinto, A. C.; Gibaldi, D.;
Bozza, M. Lett.Drug Design Discov. 2006, 3(2), 98; (b) Boechat, N.;
Valverde, A. L.; Nora, V. M.; Krettli, A. U. PI04011074, 2004; (c)
Krettli, A.; Boechat, N.; Nora, V. M.; Vasconcelos, T. R. A.; Freitas, I.
O.; Andrade, A. A.; Varotti, F. P. Int. J. Aantimicrob. Agents. 2006, 28,
271; (d) Boechat, N.; Costa, M. S.; Lourenço, M. C. S.; Genestra, M. S.;
Ferreira, I. N.; Junior, I. N., PI 0503681-0, 2005; (e) Costa, M. S.;
Boechat, N.; Rangel, E. A.; Silva, F. C.; Souza, A. M. T.; Rodrigues, C.
R.; Castro, H. C.; Junior, I. N.; Lourenço, M. C. S.; Wardell, S. M. S. V.;
Ferreira, V. F. Bioorg. Med. Chem. 2006, 14, 24, 8644; (f) Boechat, N.;
Pinto, A. C. USA Patent, 6,034,266, 2000.
395; (d) Brennan, M. R.; Erickson, K. L.; Szmalo, F. S.; Tansey, M. J.;
Thornton, J. M. Heterocycles. 1986, 24, 2879.
[24] (a) Bonnet-Delpon, D.; Charpentier-Morize, M.; Jacquot, R.
J. Org. Chem. 1988, 53, 759; (b) Aubert, C.; Bégue, J. P.; Bonnet-
Delpon, D.; Mesureur, D. J. Chem. Soc. Perkin Trans. 1 1989, 395; (c)
Okada, E.; Tsukushi, N. Heterocycles, 2000, 53, 127.
[25] Garden, S. J.; Silva, R. B.; Pinto, A. C. Tetrahedron. 2002,
58, 8399.
[26] Rodrigues, I.; Bonnet-Delpon, D.; Bégué, J. P. J. Org. Chem.
2001, 66, 2098.
[27] Garden, S. J.; Torres, J. C.; Silva, L. E.; Pinto, A. C. Synth.
Commun. 1998, 28, 1679.
[28] (a) Maginnity, P. M.; Gaulin, C. A. J. Am. Chem. Soc. 1951,
73, 3579; (b) Sumpter, W. C.; Jones, W. F. J. Am. Chem. Soc. 1943, 65,
1802; (c) Holt, J. S.; Kellie, A. E.; O’Sulivan, D. G.; Sadler, P. W. J.
Chem. Soc. 1958, 1217; (d) Huntress, E. H.; Bornstein, J. J. Am. Chem.
Soc. 1949, 71, 745; (e) Giovannini, E.; Potmann, P.; Jëhl, A.; Schnyder,
K.; Knecht, B.; Zen-Ruflinen, H. P. Helv. Chim. Acta. 1957, 249.
[22] McEvoy, F. J.; Allen Jr., G. J. J. Org. Chem. 1973, 38, 3350.
[23] (a) Bergman, J.; Venemalm, L. J. Org. Chem. 1992, 57, 2495;
(b) Piers, K.; Meimaroglou, C.; Jardine, R. V.; Brown, R. K. Can. J. Chem.
1963, 41, 2399; (c) Higa, T.; Scheuer, P. J. Naturwissenschaften, 1975, 62,