Synthesis of new trifluoromethylated indole derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.06.093

New indole trifluoromethyl derivatives have been synthesized using the reaction of indole derivatives with different 2,2,2-trifluoro-N-arylacetimidoyl chlorides in the presence of NaH as a base in acetonitrile at room temperature under an N₂ at

Full text of DOI:10.1016/j.tetlet.2013.06.093

Tetrahedron Letters 54 (2013) 4689–4692
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of new trifluoromethylated indole derivatives
⇑
Ali Darehkordi , Fariba Rahmani, Vahide Hashemi
Department of Chemistry, Faculty of Science, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 January 2013
Revised 8 June 2013
Accepted 21 June 2013
Available online 29 June 2013
New indole trifluoromethyl derivatives have been synthesized using the reaction of indole derivatives
with different 2,2,2-trifluoro-N-arylacetimidoyl chlorides in the presence of NaH as a base in acetonitrile
at room temperature under an N2 atmosphere. The FT-IR, 19F NMR, 1H NMR, 13C NMR, COSY and HMBC
spectra and elemental analysis confirm the structures of the products.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Trifluoromethylated indole
2,2,2-Trifluoro-N-arylacetimidoyl chloride
Indole
Heterocyclic compounds attract significant attention in the
chemical literature due to their abundance in natural products
and their diverse biological properties. A large variety of heterocy-
cles are known, and among these, indole and pyran ring systems
are of particular importance. A wide spectrum of biological activi-
ties have been linked to natural and unnatural compounds pos-
In view of the importance of di- and trifluoromethylated indole
derivatives, several methods for their synthesis have been reported
in the literature. Intermolecular coupling of a CF2Br group with the
2-position of indole (or pyrrole), via C–H bond activation with
tris(triphenylphosphine)rhodium(I) chloride (Wilkinson’s catalyst)
provides a useful method for the synthesis of difluoromethyl in-
dole (pyrrole) derivatives. This reaction represents a new way of
incorporating difluoromethyl groups into organic compounds.13
Friedel–Crafts reaction/C–H bond activation of indoles with
N-(2-iodophenyl)trifluoroacetimidoyl chlorides via addition–elim-
ination/arylation has been used for the synthesis of 6-trifluorome-
thylindolo[1,2-c]quinazolines.14
sessing
a substituted indole nucleus, making it a suitable
building block for many therapeutic agents.1,2
The indole nucleus is frequently found in natural products,
pharmaceuticals, functional materials, and agrochemicals.2 Indole
analogues constitute important therapeutic agents in medicinal
chemistry including anticancer,3 antioxidant,4 antirheumatoid,
and anti-HIV.5,6 Some indoles inhibit the growth of bladder cancer,
cell carcinoma, lung cancer, colon cancer, mammary tumors, pros-
tate cancer, and breast tumor cells.7 In addition, many indole deriv-
atives are potent scavengers of free radicals.8
One particularly important area of medicinal research is the
synthesis and application of organofluorine compounds.9 Organo-
fluorine chemistry represents an expanding and productive area
of research, as can be seen by the increasing number of recent pub-
lications, reviews, topics, and monographs in this area.10 Further-
more, organofluorine chemicals have found a wide range of
applications in the pharmaceutical industry, materials science,
and agriculture due, in part, to the unique biological properties im-
parted by the fluorine atom.9,11
In this research, to combine the interesting and remarkable bio-
logical activities of both indole and acetimidoyl groups, we re-
quired
a synthesis of the indole-annulated trifluoromethyl
derivative skeleton 4 (see Scheme 2). Therefore, N-aryltrifluoroace-
timidoyl chlorides were selected to form a link through carbon or
nitrogen to indole.
Trifluoromethylated compounds are of particular interest as the
strong electron-withdrawing effect of the CF3 group contributes to
a number of biologically important molecular properties. For
example, it results in a significant increase in the lipophilicity of
the molecule, which is a very important feature in drug delivery.
N-Aryltrifluoroacetimidoyl chlorides can be prepared by several
procedures.15,16 In this research, a one-pot synthesis of imidoyl ha-
lides is described which involves refluxing a mixture of trifluroace-
tic acid and a primary amine in carbon tetrachloride in the
presence of triethylamine and triphenylphosphine. Work-up and
distillation provided the desired imidoyl chlorides in good to excel-
lent yields16 (Scheme 1).
Also, substituted indoles are able to bind many receptors with
high affinity. Therefore, the synthesis and selective functionaliza-
tion of indoles have been the focus of much research.2,12
⇑
In an initial study, we examined the reaction of indole (1a) with
2a in presence of K2CO3 or NaH in toluene under reflux conditions.
Corresponding author. Tel.: +98 3913202440; fax: +98 3913202429.
E-mail
addresses:
adarehkordi@yahoo.com,
darehkordi@mail.vru.ac.ir
(A. Darehkordi).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.093

4690
A. Darehkordi et al. / Tetrahedron Letters 54 (2013) 4689–4692
CF3
Et3N/PPh3/CCl4
reflux
N C
ArNH2
CF3COOH
+
Ar
Cl
2a-e
2a
, Ar =
2e
, Ar =
2d
, Ar =
2b
, Ar =
2c
, Ar =
F3C
CF3
CF3
CH3
Cl
Scheme 1. Preparation of 2,2,2-trifluoroacetimidoyl chloride derivatives.
N
H
O
N
4a-c
1a
1b
1c
C
CF3
N
O
H
H
N
C
CF3
Ar
CF3
N
H
NaH, dry MeCN
N2, r.t
4d-g
Ar
N
C
N
H
Ar
Cl
O
OH
2a-e
O
O
N
H
4h-j
Ar
N
H
N
H
F3C
Scheme 2. Synthesis of new indole trifluoromethyl derivatives.
We faced problems when purifying the products, and the obtained
yields were very low. In addition, under these conditions, imidoyl
chlorides 2a–c reacted with indole 1a, to afford compounds 4a–c
in low yields (10–15%). Further attempts were made to improve
the yields. When the reaction was carried out in the presence of
NaH in acetonitrile at room temperature under an N2 atmosphere,
it afforded the corresponding products 4a–c in excellent yields
(78–89%) (Scheme 2). In this reaction the pyrrole nitrogen acts as
a nucleophile to displace chlorine.
CH, which were confirmed by 2D-NMR (COSY and HMBC). A dou-
blet at d 8.03, multiplets at d 7.18–7.20 and d 7.06–7.10 and a dou-
blet at d 6.92 corresponded to the aromatic protons present in the
molecule. The 13C NMR spectrum of 4e displayed a downfield sig-
nal at d 186.76 for the carbonyl group. The 19F NMR spectrum of 4e
showed a signal at d ꢀ70.61 corresponding to the CF3 group. The
above spectral data and elemental analysis results supported the
formation of compound 4e.17 The spectral data of compounds 4d,
4f, and 4g also supported their structures.
The IR spectrum of N-[2,2,2-trifluoro-1-(1H-indol-2-yl)ethyli-
dene]aniline (4a) showed an absorption band at 1623 cmꢀ1, which
corresponds to the C@N moiety. The 1H NMR spectrum of 4a exhib-
ited a doublet at d 7.52 (J = 7.0 Hz) and a doublet at d 6.88
(J = 6.9 Hz) due to the indole alkylene protons (HC@CH), and three
multiplets at d 7.58–7.60, d 7.01–7.03, and d 6.71–6.73, which cor-
respond to six aromatic protons, and a doublet at d 6.93 (J = 7.2 Hz)
which corresponds to two of the aromatic protons present in the
molecule. Also the 1H NMR spectrum of 4a showed a signal at d
2.09 corresponding to the CH3 group. The 19F NMR spectrum of
4a showed a signal at d ꢀ70.13 corresponding to the CF3 group.
The above spectral data and elemental analysis supported the for-
mation of compound 4a.17
In order to investigate the effect of the substitution on the pyr-
role ring on the nucleophilicity, indole-3-carbaldehyde (1b), which
has proved to be less reactive than indole, was selected. Reaction of
imidoyl halides 2a–d with 1b using sodium hydride as the base in
acetonitrile under an N2 atmosphere gave the corresponding tri-
fluoromethyl indole derivatives 4d–g in excellent yields. Spectro-
scopic data [IR, 1H NMR, 13C NMR, 19F NMR, 2D-NMR (COSY and
HMBC)] and a D2O exchange experiment showed that, in this reac-
tion, the carbon at the 2-position acted as the nucleophile.
The IR spectrum of 3-[2,2,2-trifluoro-1-(phenylimino)ethyl]-
3H-indole-3-carbaldehyde (4e) showed absorption bands at
1667 cmꢀ1 corresponding to carbonyl stretching and at
1453 cmꢀ1 corresponding to the C@N moiety. The 1H NMR spec-
trum of 4e exhibited a singlet at d 10.02 due to the indole NH
(D2O exchangeable) and a signal at d 8.65 assigned to the aldehyde
Of particular interest were the reactions of indole-3-carboxylic
acid 1c with various imidoyl chlorides, which gave the correspond-
ing derivatives 4h–j (Table 1). These products represent a little
known class of 1-(arylamino)-1-(trifluoromethyl)-4,9-dihydropyr-
ano[3,4-b]indol-3(1H)-ones, examples of which are difficult to pre-
pare using conventional procedures.
mechanism is illustrated in Scheme 3.
A
possible reaction
The IR spectrum of 2-(p-tolylamino)-2-(trifluoromethyl)-2H-
spiro[furan-3,30-indol]-5(4H)-one (4h) showed a strong absorption
at 3415 cmꢀ1 corresponding to the NH group. The absorption at
1673 cmꢀ1 corresponded to the carbonyl stretching, and the
absorptions at 1601 and 1094 cmꢀ1 to the C@N and C–O, respec-
tively. The 1H NMR spectrum of 4h exhibited a singlet at d 10.88
and at d 9.97 due to the NH protons. Doublets at d 7.57, d 7.45,
and d 7.32, multiplets at d 7.21–7.22 and d 7.01–7.05, and triplet
at d 6.94 correspond to eight aromatic protons present in the mol-
ecule. The signals at d 2.19 and d 3.67 were assigned to the methyl
and methylene protons, respectively. The 13C NMR spectrum of 4h
displayed a downfield signal at d 169.98 for the carbonyl and at d
34.25 and d 20.90 for the CH2 and methyl carbons, respectively.
The 19F NMR spectrum of 4 h showed a peak at d ꢀ73.86 for the
CF3 group. The above spectral and elemental analysis data, the ab-
sence of OH absorptions in the IR spectra and 1H NMR spectra sup-
port the formation of compound 4h.17 The spectral data of
compounds 4i and 4j also supported their structures.
A variety of acetymidoyl chloride and indoles were examined to
generate the desired coupled products under the optimized condi-
tions (Table 1).

A. Darehkordi et al. / Tetrahedron Letters 54 (2013) 4689–4692
4691
Table 1
Synthesis of 3-(1-nitroalkyl) indoles 4a–j by reaction of 2,2,2-trifluoro-N-arylacetimidoyl chloride derivatives 2a–d with indoles 1a–c
Entry
Indole
ArNC(CF3)Cl
Product
Time (h)
Isolated yield (%)
Cl
N
F3C
C
N
CH3
4a
21
89
87
C
N
N
F3C
H
CH3
Cl
F3C
C
N
N
4b
4c
20
22
C
N
N
F3C
H
CF3
Cl
C
N
CF3
C
F3C
F3C
N
N
78
91
F3C
N
H
CF3
CF3
Cl
C
O
O
H
N
CH3
H
N
CH3
4d
23
C
N
N
CF3
H
H
O
Cl
C
O
O
H
C
F3C
N
N
N
H
4e
4f
20
23
93
78
N
CF3
H
N
H
O
CF3
H
C
Cl
C
N
H
F3C
F3C
N
H
CF3
CF3
N
H
O
CF3
O
Cl
C
H
O
N
CF3
CF3
N
H
4g
4h
22
24
73
81
HN
N
H
CF3
CF3
Cl
C
O
O
F3C
N
CH3
O
OH
CF3
N
H
N
H
HN
CH3
O
Cl
C
O
F3C
F3C
N
O
OH
4i
4j
21
20
78
73
CF3
N
H
N
H
HN
O
Cl
C
O
N
Cl
O
OH
CF3
N
H
N
H
HN
Cl
Ar
O
O
N
C
CF3
NaH
OH
+
OH
Cl
N
H
N
- NaCl
O
O
O
H-shift
OH
N
H
OH
O
Ar
N
H
Ar
N
Ar
N
H
N
F3C
N
H
F3C
F3C
Scheme 3. A possible mechanism for the synthesis of 1-(arylamino)-1-(trifluoromethyl)-4,9-dihydropyrano[3,4-b]indol-3(1H)-ones 4h–j.

4692
A. Darehkordi et al. / Tetrahedron Letters 54 (2013) 4689–4692
11. (a) Resnati, G.; Soloshonok, V. A. Tetrahedron. 1996, 52, 319–330; (b) Banks, R.
The yields of these reactions were generally excellent. It is
E.; Tatlow, J. C.; Smart, B. E. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum Press: New York, 1994; (c) Prakash, G. K. S.; Yudin, A. K.
Chem. Rev. 1997, 97, 757–786.
important to note that the presence of an electron-withdrawing
group had no effect on the yield. Under the optimized conditions,
various indoles with electron-donating or electron-withdrawing
groups reacted to give the corresponding trifluoromethylated in-
dole products in excellent yields, but in somewhat longer reaction
times (20–24 h).
In conclusion, we have successfully synthesized a series of new
indole trifluoromethyl derivatives using different 2,2,2-trifluoro-N-
arylacetimidoyl chlorides under mild conditions via functionaliza-
tion of indoles. In addition to its efficiency, simplicity, and mild
reaction conditions, this method provides high yields of trifluo-
romethylated indole. Therefore this protocol is efficient and may
open up a new area for the functionalization of indoles. Further
studies including the pharmacological activities in this area are
being carried out in our laboratory.
12. Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68, 2109–2114.
13. Yajun, L.; Jiangtao, Z.; Haibo, X.; Shan, L.; Dongjie, P.; Zhengke, L.; Yongming,
W.; Yuefa, G. Chem. Commun. 2012, 3136–3138.
14. Jiangtao, Z.; Haibo, X.; Zixian, C.; Shan, L.; Yongming, W. Chem. Commun. 2011,
1512–1514.
15. Tamura, K.; Uneyama, K.; Mizukami, H.; Maeda, K.; Watanabe, H. J. Org. Chem.
1993, 58, 32–35.
16. Darehkordi, A.; Khabazzadeh, H.; Saidi, K. J. Fluorine Chem. 2005, 126, 1140–
1143.
17. Preparation of 4-methyl-N-[2,2,2-trifluoro-1-(1H-indol-1-yl)ethylidene]aniline
(4a) In a typical experimental procedure, a dry, two-necked, 50 mL round-
bottomed flask equipped with a nitrogen inlet was charged with 5 mL of dry
MeCN, 0.117 g (1.0 mmol) of indole and 0.24 g (1.0 mmol) of NaH. The solution
was stirred under a nitrogen atmosphere at room temperature for 30 min, then
a solution of 2a (1.0 mmol in 2 mL of dry MeCN) was added dropwise via a
syringe. The mixture was stirred at room temperature for 20 h under an N2
atmosphere and then filtered. After removing the solvent under reduced
pressure, the crude product was purified by preparative thin-layer
chromatography on silica gel [eluent: n-hexane/EtOAC, 4:1] to give the
product 4a. The products obtained from indole-3-carbaldehyde were purified
by recrystallization from EtOH (twice). Yield = 89%, yellow oil, FT-IR (neat)
Acknowledgment
m
max = 1623 cmꢀ1 1H NMR (DMSO-d6, 500 MHz) d = 7.58–7.60 (m, 1H), 7.52 (d,
,
We gratefully acknowledge, the Vail-e-Asr University of Rafsan-
jan Faculty Research Grant for financial support.
1H, J = 7.0 Hz), 7.01–7.03 (m, 2H), 6.93 (d, 2H, J = 7.2 Hz), 6.88 (d, 1H,
J = 6.9 Hz), 6.71–6.73 (m, 3H), 2.09 (s, 3H, CH3) ppm. 19F NMR (DMSO-d6,
475 MHz) d = ꢀ70.13 ppm. Anal. Calcd for C17H13F3N2 (302.29): C, 67.54; H,
4.33; N, 9.27. Found: C, 67.24; H, 4.11; N, 9.36. Preparation of 2-[2,2,2-trifluoro-
1-(phenylimino)ethyl]-1H-indole-3-carbaldehyde (4e): Similarly, 4e was
prepared from 0.145 g (1.0 mmol) of indole-3-carbaldehyde, 0.24 g
(1.0 mmol) of NaH in 5 mL of dry MeCN, and 1.0 mmol of 2b. This compound
References and note
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was obtained as
m
a
white solid. Mp = 114–115 °C, Yield = 93%, FT-IR (KBr)
.
max = 1453, 1667 cmꢀ1
1H NMR (DMSO-d6, 500 MHz) d = 10.02 (s, 1H), 8.65 (s,
1H), 8.03 (d, 1H, J = 7.3 Hz), 7.18–7.20 (m, 4H), 7.06–7.10 (m, 2H), 6.92 (d, 2H,
J = 7.4 Hz) ppm.19
(DMSO-d6, 100.6 MHz);
F
NMR (DMSO-d6, 475 MHz) d = ꢀ70.61 ppm. 13C NMR
d (ppm): 112.03, 120.88, 121.23, 121.86, 124.19,
124.44, 125.64, 128.15, 129.68, 135.39, 137.68, 138.06, 139.53, 143.59, 186.76.
Anal. Calcd for C17H11F3N2O (316.28): C, 64.56; H, 3.51; N, 8.86. Found: C,
64.28; H, 3.34; N, 8.88.
Preparation of 2-(p-tolylamino)-2-(trifluoromethyl)-2H-spiro[furan-3,30-indol]-
5(4H)-one (4h): Similarly, 4h was prepared from 0.175 g (1.0 mmol) of
indole-3-acetic acid, 0.48 g (2.0 mmol) of NaH in 5 mL of dry MeCN, and
1.0 mmol of 2a. This compound was obtained as a white solid. Mp = 184 °C,
8. Chyan, Y. J.; Poeggler, B.; Omar, R. A.; Chain, D. G.; Frangione, B.; Ghiso, J.;
Pappolla, M. A. J. Biol. Chem. 1999, 274, 21937–21942.
Yield = 81%, FT-IR (KBr) m ,
max = 3415, 1673, 1601, 1094 cmꢀ1 1H NMR (DMSO-
d6, 500 MHz) d = 10.88 Hz (s, 1H), 9.97 (s, 1H), 7.57 (d, 1H, J = 7.9 Hz), 7.45 (d,
2H, J = 8.3 Hz), 7.32 (d, 1H, J = 8.1 Hz), 7.21–7.22 (m, 1H), 7.01–7.05 (m, 2H),
6.94 (t, 1H, J = 7.5, 7.2 Hz), 3.67 (s, 2H), 2.19 (s, 3H) ppm. 19F NMR (DMSO-d6,
475 MHz) d = ꢀ73.86. 13C NMR (DMSO-d6, 100.6 MHz); d (ppm): 20.90, 34.25,
109.13, 111.84, 118.84, 119.19, 119.55, 121.44, 124.35, 127.71, 129.51, 132.35,
136.59, 137.40, 169.98. Anal. Calcd for C19H15F3N2O2 (360.33): C, 63.33; H,
4.20; N, 7.77. Found: C, 63.28; H, 4.23; N, 7.71.
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Eds.; Wiley: New York, 1992; (b) Ojima, I.; McCarthy, J. R.; Welch, J. T.
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