A new synthesis of substituted 2-trifluoromethylindoles

Article abstract of DOI:10.1016/j.mencom.2008.11.014

The one-pot synthesis of substituted 2-trifluoromethylindoles from β-halo-β-(trifluoromethyl)-(o-halostyrene) and primary amines is based on a CuI-catalysed double nucleophilic substitution reaction.

Full text of DOI:10.1016/j.mencom.2008.11.014

Mendeleev
Communications
Mendeleev Commun., 2008, 18, 327–328
A new synthesis of substituted 2-trifluoromethylindoles
Mikhail G. Mokrushin,a Aleksey V. Shastin,b Vasiliy M. Muzalevskiy,a
Elizabeth S. Balenkovaa and Valentine G. Nenajdenko*a
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
b Institute of Problems of Chemical Physics, Russian Academy of Sciences, 142432 Chernogolovka, Moscow
Region, Russian Federation
DOI: 10.1016/j.mencom.2008.11.014
The one-pot synthesis of substituted 2-trifluoromethylindoles from β-halo-β-(trifluoromethyl)-(o-halostyrene) and primary
amines is based on a CuI-catalysed double nucleophilic substitution reaction.
The replacement of a methyl group or chlorine atom with a tri-
fluoromethyl group in the molecules of pharmaceutical substances
NH2
N
O
X
N2H4·H2O
DMSO
CF3CX3
is widely used for a new drug development. Such change of
substance structure allows one, as a rule, to keep its primary
biological activity and to improve pharmacokinetical properties
due to the unique stability of trifluoromethyl group in vivo.1
Therefore, an elaboration of new selective methods of synthesis
of CF3-substituted products is an actual problem.2 There are
some recent examples of new perspective pharmacological sub-
stances containing 2-trifluoromethylindole fragments: chemokine
receptor 5 antagonist,3 general anesthesia inducer,4 tyrosine
kinase inhibitor5 and some perspective antineoplastic agents.6
Various methods of 2-trifluoromethylindoles synthesis were
elaborated last decades, they include the interaction of aromatic
nitrones with trifluoromethyl substituted alkynes; modified
Madelung reaction application;8 trifluoromethyl radicals addi-
tion to indole system;9 intramolecular reactions of trifluoroacetyl-
imidoyl radical with triple bond;10,11 reductive coupling of some
oxamides using titanium salts;12,13 catalytic thermolysis of some
2-N-trifluoroacetylaminobenzylmethyl esters;14 intramolecular
palladium-catalysed coupling of 2-iodophenyltrifluoroacetyl-
amides;15,16 Wittig and Heck reactions of some 2-halotrifluoro-
acetylanilides;17,18 synthesis using 2-halotrifluoroacetylanilides
and ketoesters19 and some examples of 2-trifluoromethylindole
containing molecules modification.20,21
CuCl, NH3
DMSO
Br
Br
Br
R
R
R
1
2
CF3
R'NH2, CuI, K2CO3
CF3
DMSO
N
R
R'
3
X = Cl, Br
Scheme 1
is devoted to the development of a new reaction scheme of
2-trifluoromethylindoles synthesis based on double nucleophilic
replacement of halogen atoms in trifluoromethyl-substituted
β-halo-(o-halostyrenes). A similar cyclization for nonfluorinated
indole synthesis was catalyzed by Pd2(dba)3 and a phosphine
ligand system.27
We have prepared a number of alkenes, β-halo-β-(trifluoro-
methyl)styrenes, from ortho-bromo substituted benzaldehydes23
and studied a model reaction with n-hexylamine using Pd(PPh3)4
or Pd·MeCN as a catalyst. If ButOK was used as the base, the
nucleophilic replacement of vinyl bromine by tert-butoxy group
took place.
Earlier, a new catalytic olefination reaction was discovered by
our research group.22 N-Unsubstituted hydrazones of aldehydes
or ketones can be transformed into various halogen-substituted
alkenes upon treatment with polyhaloalkanes in the presence
of a base and catalytic amounts of copper salts. Advantages of
this method are inexpensive starting compounds and simplicity
of products isolation. The β-halo-β-(trifluoromethyl)styrenes
can be easily obtained from corresponding benzaldehydes and
perhaloalkanes via catalytic olefination reaction.23 This reaction
does not require an inert atmosphere and an excess of organo-
metallic or organophosphorus compounds as, for example,
the Wittig-type reactions,24,25 or the aldol-type reaction of
benzaldehyde with fluoromethyl phenyl sulfone in the presence
We found that the reaction proceeds smoothly with various
amines in the presence of K2CO3 and copper iodide as a catalyst
(Scheme 1, Table 1).† As a result, corresponding 2-trifluoro-
indoles 3 can be prepared in reasonable yields in two steps
starting from ortho-bromobenzaldehydes 1. Variation of amine
component permits variation of substituents at indole nitrogen.
Table 1 Synthesis of 2-trifluoromethylindoles 3a–l.
Yield
of 3 (%)
Compound
R
R'
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
5-MeO
H
H
H
H
H
H
n-C6H13
n-C6H13
2-phenylethyl
2-methoxyethyl
60
40
58
49
48
53
39
50
65
54
55
74
26
of n-butyl lithium and subsequent dehydration.
3-methoxypropyl
We proposed that β-halo-β-(trifluoromethyl)styrenes with a
halogen atom in the ortho-position can be used as precursors for
2-trifluoromethylindoles synthesis. Simultaneous nucleophilic
substitution of vinyl and aryl halogen atoms by primary amines
can open simple way to 2-trifluoromethylindoles bearing sub-
stituents at the 1-position and in the aromatic ring. This work
2-(3,4-diethoxyphenyl)ethyl
Pri
Et
Et
Et
5-MeO
5-EtO
3j
3k
3l
5,6,7-(MeO)3 Et
2-(3,4-dimethoxyphenyl)ethyl
H
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© 2008 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2008, 18, 327–328
4
(a) M. T. Baker and M. N. Attala, Patent WO03070177; (b) M. A.
Akanmu, C. Songkram, H. Kagechika and K. Honda, Neurosci. Lett.,
2004, 364,199.
Note that only aliphatic amines, which are good nucleophiles,
can participate in the transformation. No reaction takes place in
the case of anilines and tert-butylamine. We have found that 2
bearing both Br and Cl atoms at the double bond can be
involved into reaction. No reaction is observed in the case
of 1-(2-bromo-3,3,3-trifluoroprop-1-enyl)-2,4-dichlorobenzene
giving tar products only.
Thus, we have elaborated a new effective approach to 2-tri-
fluoromethylindoles, which allows preparation of the target product
with variation of substituents at benzene ring and nitrogen atom.
5
6
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This study was supported by the Russian Foundation for
Basic Research (project nos. 08-03-00736-a and RFBR-DFG
07-03-91562-NNIO_a).
7
8
9
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2008.11.014.
10 Y. Ueda, H. Watanabe, J. Uemura and K. Uneyama, Tetrahedron Lett.,
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†
IR spectra were recorded on a UR 20 spectrophotometer (Nujol), all
indoles have the signals of CF3 group in the 1300–1100 cm–1 area.
1H and 13C NMR spectra were recorded on a Bruker AMX 400 spectro-
meter (400 and 100 MHz, respectively) in CDCl3 with TMS as the
internal standard. TLC was carried out with Merck 60 F254 plates;
Merck silica gel (63–200) mesh was used for column chromatography.
General procedure for the synthesis of 2-trifluoromethylindoles. 1 mmol
of corresponding β-halo-β-(trifluoromethyl)-(o-halostyrene), 1.2 mmol of
primary amine, 0.019 g (10 mol%) of CuI, 0.414 g (3 mmol) of K2CO3
and 2 ml of DMSO were placed to a sealed reactor. The reaction mixture
was heated to 90–100 °C and was stirred at this temperature for 18 h.
After that it was placed to 50 ml of water, the reaction products were
extracted with CH2Cl2 (3×20 ml). Organic layer was washed twice by
water, brine and dried over Na2SO4. The solvent was evaporated and the
residue was purified by flash chromatography on SiO2 using 1:1 hexane–
CH2Cl2 as an eluent.
1-Hexyl-2-(trifluoromethyl)-1H-indole 3a: yellowish oil. 1H NMR (CDCl3)
d: 1.01 (t, 3H, hexyl, H-6, 3J 7.0 Hz), 1.39–1.46 (m, 4H, hexyl, H-4,5),
1.48–1.53 (m, 2H, hexyl, H-3), 1.88–1.95 (m, 2H, hexyl, H-2), 4.29 (t,
2H, hexyl, H-1, 3J 8.1 Hz), 7.02 (s, 1H, H-3), 7.27 (t, 1H, H-5, 3J 7.3 Hz),
7.42–7.48 (m, 2H, H-6,7), 7.76 (d, 1H, H-4, 3J 8.1 Hz). 13C NMR
(CDCl3) d: 14.02, 22.62, 26.70, 30.03, 31.46, 45.09 (Chexyl), 104.46 (q,
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3
C=C–CF3, J 3.7 Hz), 110.35 (Carom.), 120.64 (Carom.), 121.73 (q, CF3,
1J 268.1 Hz), 122.39, 124.33, 125.95, 126.84 (q, C–CF3, 2J 37.3 Hz), 137.88
(Carom.). Found (%): C, 65.74; H, 7.27. Calc. for C15H18F3N·0.25H2O
(%): C, 65.80; H, 6.81.
Other spectral data are given in the Online Supplementary Materials.
Received: 10th June 2008; Com. 08/3154
– 328 –