CuBr-promoted tandem cyclization/trifluoromethylation of 2-alkynylanilines: Efficient synthesis of 3-trifluoromethylindoles

Article abstract of DOI:10.1002/cjoc.201400298

A new efficient strategy for the synthesis of 3-trifluoromethyl-indoles was developed through tandem cyclization/ trifluoromethylation of 2-alkynylanilines and Umemoto’s reagent under effect of CuBr. The reaction features the use of cheap copper salt, mil

Full text of DOI:10.1002/cjoc.201400298

FULL PAPER
DOI: 10.1002/cjoc.201400298
CuBr-Promoted Tandem Cyclization/Trifluoromethylation of
2-Alkynylanilines: Efficient Synthesis of
3-Trifluoromethylindoles†
Guangcun Ge,#,a Xiaojun Huang,#,a Changhua Ding,a Hao Li,a Shili Wan,a and Xuelong Hou*,a,b
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A new efficient strategy for the synthesis of 3-trifluoromethyl-indoles was developed through tandem cycliza-
tion/trifluoromethylation of 2-alkynylanilines and Umemoto's reagent under effect of CuBr. The reaction features
the use of cheap copper salt, mild reaction conditions and high yield of products. The preliminary mechanism study
indicates the solvent dimethylacetamide acts as the role of dealkylation.
Keywords copper, tandem reaction, trifluoromethylation, 2-alkynylaniline, 3-trifluoromethyl-indole
Introduction
provide rapid access to structurally diverse 3-trifluoro-
methyl indole derivatives.
The substituted indole nucleus is one of the most
abundant and important heterocycle-containing biologi-
cally significant natural compounds and synthetic
drugs.[1] The synthesis and functionalization of indoles
represents one of important fields in organic synthesis.
Many strategies have been developed to synthesize and
functionalize indoles.[2] The intramolecular cyclization
reaction of 2-alkynylanilines in the presence of transi-
tion metal or base is among the most powerful protocols
and allows a subsequent incorporation of functional
group such as halogen, alkynyl, aryl, carbonyl, boron,
stannane at the C-3 position of the indole ring.[3] How-
ever, 3-trifluoromethyl group could not be installed
through this strategy, in spite of the fact that
3-fluoromethyl indoles are considered as an important
subunit in the discovery of novel biomolecules and po-
tential therapeutic agents.[4] To date, the synthesis of
3-trifluoromethyl indoles has received the attention of
organic community in past decade. A number of proto-
cols have been developed, however, most of them rely
on the direct trifluoromethylation of the “preformed”
indole ring, affording 2-trifluoromethyl indoles or 2-
and 3-trifluoromethyl indoles mixture.[5] Very recently,
Liu and co-workers realized the 3-trifluoromethylation
of indoles using an in-situ generated PhI＋CF3 reagent
derived from PhI(OAc)2, Me3SiCF3 and KF.[5j] It is still
highly desirable to develop new efficient methods to
Results and Discussion
Our group has reported a CuBr-catalyzed domino
cyclization-trifluoromethylation reaction of homo-
propargylamines, providing 4-trifluoromethyl-2,3-
dihydro-pyrroliums in high yield.[6] On the basis of
these results, we envisioned that the synthesis of
3-trifluoromethyl-indole derivatives could be realized
by a copper promoted tandem cyclization/trifluoro-
methylation of 2-alkynylanilines.[7] With this idea in
mind, N,N-dimethyl-2-alkynylaniline 1a was chosen to
react with Umemoto’s reagent 2a in the presence of 1
equiv. of CuBr. The reaction proceeded smoothly and
the expected 3-trifluoromethyl-indole 3a was obtained
in 40% yield (Entry 1, Table 1). These results encour-
aged us to investigate the impact of various parameters
on the reaction. The solvent has a great effect on the
reaction. Toluene, dimethoxyethane (DME), dioxane,
and 1,2-dichloroethane (DCE) gave inferior results (En-
tries 2－5, Table 1). An increased yield was observed
using CH3CN or DMF as solvent (Entries 6 and 7, Table
1). Pleasingly, an excellent yield was achieved when the
reaction was run in dimethylacetamide (DMA) (Entry 8,
Table 1), which may attribute to its critical role in de-
methylation (vide infra). With DMA as solvent, several
commercially available trifluoromethylation reagents
*
E-mail: xlhou@sioc.ac.cn; Tel.: 0086-021-54925144
Received May 9, 2014; accepted June 16, 2014; published online July 20, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400298 or from the author.
# These authors contributed equally.
Dedicated to Professor Chengye Yuan and Professor Li-Xin Dai on the occasion of their 90th birthdays.
†
Chin. J. Chem. 2014, 32, 727—733
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
727

Ge et al.
FULL PAPER
were tested. Umemoto’s reagent 2b with tetrafluorobo-
rate as counterion gave product 3a in a slightly reduced
yield (Entry 9, Table 1), while the use of Togni’s re-
agent 2c led to a significant drop of yield (Entry 10,
Table 1) and no reaction occurred in the case of
Me3SiCF3 (2c) (Entry 11, Table 1). It can be seen that
some other copper salts such as CuI, CuCl, and CuBr2
could also promote the formation of 3-trifluoromethyl-
indole 3a albeit in less efficiency (Entries 12－14 vs.
Entry 8, Table 1). The presence of two alkyl groups on
the nitrogen atom of substrate 1 is important for the
success of this tandem cyclization/trifluoromethylation
reaction. No reaction took place when either the
N-methyl-2-alkynylaniline (1b) or the N-methyl-N-
tosyl-2-alkynylaniline (1c) was employed (Entries 15
and 16, Table 1). Lowering reaction temperature led to a
significant decrease of yield (Entries 17 and 18, Table
1). When the loading of CuBr was 10 mol%, the yield
of product 3a was only 12% (Entry 19, Table 1).
The substrate scope of the reaction was then inves-
tigated under the optimized reaction conditions (Table
2). The reaction proceeded very well in all cases, af-
fording 3-trifluoromethyl-indoles 3 in excellent yields
with the only exception of product 3n (vide infra). The
yield of the reaction was unanimously very high when
the R2 group on acetylene carbon of 2-alkynylaniline 1
was phenyl ring bearing either electron-withdrawing or
donating substituents (3b－3i) or even sterically hin-
dered 1-naphthalenyl substituent (3g). The reaction also
afforded the products in high yields if the R2 group in 1
was alkyl substituent such as hexyl and cyclopropyl (3j
－3l). In addition to the substrates with two methyl
groups on nitrogen of 2-alkynylaniline 1, N,N-diethyl-
or dibutyl-2-alkynylanilines 1 are also suitable for the
reaction, affording the corresponding 3-trifluoromethyl-
indole (3m) (97% yield) and 3n (67% yield) respec-
tively. The tandem cyclization/trifluoromethylation also
worked well for 2-alkynylaniline 1 bearing substitutents
at benzene ring of aniline subunit (3o and 3p).
Selective removal of ethyl group was found when
N-methyl-N-ethyl-2-alkynylaniline (1r) was subjected
to this tandem cyclization/trifluoromethylation with
Umemoto's reagent, giving the product 3a in 93% yield
(Eq. 1), which is in accordance with the previous re-
ports.[7b,7g] To reveal which reagent plays the role of
dealkylation as well as the fate of removed alkyl group,
2-alkynylaniline 1s was selected to react with
Umemoto's reagent (Eq. 2). The product 3r was ob-
tained in 44% yield, which indicated the dimethyl-
acetamide served as dealkylation reagent. This hy-
pothesis was further supported by the reaction of
N,N-diethyl-2-alkynylaniline 1m using N,N-dibutylaceta-
mide as solvent (Eq. 3). The GC-MS analysis of the
reaction mixtures clearly showed the formation of ethyl
acetate and dibutylamine. The reaction of N-methyl-
indole with Umemoto's reagent was performed under
optimized reaction conditions (Eq. 4). No reaction oc-
curred, which suggests the indole should not be the re-
action intermediate.
Table 1 Optimization of reaction conditions for copper-pro-
moted Tandem cyclization/trifluoromethylation of 2-alkynyl-
anilinesa
Ph
CF3
[Cu] (1.0 equiv.)
R1
+
Ph
solvent, temp
S
N
R
N
R2
CF3
1a, R1 = R2 = Me
3a
2a, R = OTf
2b, R = BF4
1b, R1 = H; R2 = Me
1c, R1 = Ts; R2 = Me
＋
CF3 reagent [Cu] Solvent Temp/℃ 3ab/%
Entry
1
1
CuBr DMSO 80
CuBr toluene 80
40
7
1a 2a
1a 2a
1a 2a
1a 2a
1a 2a
1a 2a
1a 2a
1a 2a
1a 2b
1a
2
3
CuBr DME
CuBr dioxane 80
CuBr DCE 80
CuBr CH3CN 80
80
3
4
23
39
46
60
95c
90
26
nre
87
67
59
nr
5
6
7
CuBr DMF
CuBr DMA
CuBr DMA
CuBr DMA
CuBr DMA
CuCl DMA
80
80
80
80
80
80
80
80
80
80
50
rt
8
9
10
11
12
13
14
15
16
17
18
19f
2cd
TMSCF3
1a
1a 2a
1a 2a
1a 2a
1b 2a
1c 2a
1a 2a
1a 2a
1a 2a
On the basis of the above experimental results and
literatures, a plausible reaction mechanism was pro-
posed (Scheme 1).[6,8] Coordination of CuBr with triple
bond of 2-alkynylaniline 1r followed by an intra-
molecular cyclization produces intermediate Int-A with
a C－Cu bond.[8] The reaction of Int-A with the
Umemoto's reagent yields Int-B.[8f] Subsequently, the
N-methyl group of Int-B was attacked by the dimethyl-
acetamide to afford product 3. The hydrolysis of ac-
companying formation Int-C releases dimethylamine
and methyl acetate. The stoichiometric amount of CuBr
was needed as dimethylamine generated in the reaction
may deactivate CuBr by forming the complex with it.
CuI
DMA
CuBr2 DMA
CuBr DMA
CuBr DMA
CuBr DMA
CuBr DMA
CuBr DMA
nr
87
72
12
80
a Mol ratio: 1/2/[Cu] = 1.0/1.2/1.0. b Determined by 19F NMR using
c
para-chloro-trifluoromethylbenzene as inter standard. Isolated
yield. d 2c＝1-trifluoromethyl-1,2-benziodoxol-3(1H)-one. e nr＝
no reaction. f 0.1 equiv. CuBr used.
728
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© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 727—733

Efficient Synthesis of 3-Trifluoromethylindoles
Table 2 Substrate scope of CuBr-promoted tandem cyclization/trifluoromethylation of 2-alkynylanilines with Umemoto’s reagenta
R2
CF3
CuBr (1.0 equiv.)
+
R1
R2
R1
R3
DMA, 80 οC
S
N
N
R3
OTf
R3
CF3
2a
1
3
CF3
CF3
CF3
CF3
Ph
N
N
N
N
3a, 98%
CF3
3b, 95%
3c, 94%
3d, 95%
CF3
CF3
N
CF3
OMe
Cl
Et
N
N
N
3e, 91%
3f, 94%
3g, 92%
3h, 96%
OMe
CF3
CF3
CF3
CF3
Ph
Br
N
N
N
N
4
3i, 92%
3j, 83%
3k, 82%
3l, 93%
CF3
CF3
CF3
CF3
Cl
N
Et
N
n-Bu
N
N
Cl
3m, 97%
3n, 67%
3o, 97%
3p, 97%
a Molar ratio: 1/2a/CuBr＝1.0/1.2/1.0; isolated yield.
Ph
CF3
CuBr (1.0 equiv.)
+
(1)
(2)
DMA, 80 oC
S
N
N
OTf
CF3
93%
3a
1r
2a
CF3
Ph
CuBr (1.0 equiv.)
2a
+
N
DMA, 80 o
44%
C
N
O
O
3r
1s
Ph
CF3
CuBr (1.0 equiv.)
80 oC
O
(3)
2a
+
OEt
+
Ph
O
Et
N
1.2 equiv.
N
n-Bu2NH
Et
Nn-Bu2
Et
1m
3m, 79% (19F NMR)
CuBr (1.0 equiv.)
DMA, 80 oC
2a
no reaction
+
(4)
N
Chin. J. Chem. 2014, 32, 727—733
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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729

Ge et al.
FULL PAPER
Scheme 1 Proposed reaction mechanism
L
R
Cu
CF3
Umemoto's
CF3
CuBr
OMe
NMe2
Int-C
Reagent (2a)
R
R
O
R
+
N
NMe2
N
N
N
1
Int-A
Int-B
3
Conclusions
fied by silica gel chromatography with petroleum ether
as the eluent to afford 3.
In conclusion, we developed a new efficient strategy
for the synthesis of 3-trifluoromethyl-indoles through
domino reaction of cyclization-trifluoromethylation of
2-alkynylanilines and Umemoto's reagent under effect
of CuBr. The reaction features the use of cheap copper
salt, mild reaction conditions and high yield of products.
The preliminary mechanism study indicates the solvent
dimethylacetamide acts as the role of dealkylation. Fur-
ther exploration on the reaction mechanism and the ex-
tension of this cyclization-trapping protocol are cur-
rently underway in our lab.
1-Methyl-2-phenyl-3-(trifluoromethyl)-1H-indole
(3a)[5f] Pale yellow solid, 54 mg, 98% yield; 1H NMR
(400 MHz, CDCl3) δ: 3.58 (s, 3H), 7.30－7.56 (m, 8H),
7.88－7.90 (m, 1H); 13C NMR (100 MHz, CDCl3) δ:
30.8, 104.0 (q, JC F＝35 Hz), 110.1, 119.8 (q, JC
＝
－
F
－
1.5 Hz), 121.6, 123.0, 124.5 (q, JC F＝1.8 Hz), 124.9 (q,
－
JC F＝266 Hz), 128.4, 129.4, 130.2, 130.5 (q, JC F＝1.2
－
－
Hz), 136.4, 140.9 (q, JC F＝3.8 Hz); 19F NMR (376
－
MHz, CDCl3) δ: −52.62.
1-Methyl-2-(o-tolyl)-3-(trifluoromethyl)-1H-in-
dole (3b) Brown liquid, 55 mg, 95% yield; 1H NMR
(400 MHz, CDCl3) δ: 2.15 (s, 3H), 3.48 (s, 3H), 7.32－
7.46 (m, 7H), 7.88－7.91 (m, 1H); 13C NMR (100 MHz,
Experimental
CDCl3) δ: 19.7, 30.1, 103.9 (q, JC F＝35 Hz), 110.0,
－
General information
119.8 (q, JC F＝1.2 Hz), 121.5, 122.9, 124.5 (q, JC
＝
－
F
－
Commercially available reagents were used without
further purification. Solvents were purified prior to use
according to the standard methods. Unless otherwise
noted, all reactions were carried out under an atmos-
phere of argon and flame-dried glassware with standard
vacuum-line techniques. NMR spectra are recorded at
room temperature on 400 MHz Varian-400, 400 MHz
Agilent-400 or 300 MHz Bruker AM-300 NMR spec-
trometers. The chemical shifts for 1H NMR are reported
from tetramethylsilane (TMS) with the solvent reso-
nance as the internal standard (δ 7.26 for CHCl3). Data
are reported as follows: chemical shift, multiplicity (s＝
singlet, d＝doublet, t＝triplet, q＝quartet, sep＝septet,
bs＝broad singlet, m＝multiplet), coupling constants
(Hz), and integration. Chemical shifts are reported from
tetramethylsilane with the solvent resonance as the in-
ternal standard (CDCl3: δ 77.15). HRMS data were ob-
tained on Bruker APEXIII mass spectrometer and MS
data were performed on HP 5989A mass spectrometer
with or without internal standard. Melting point was
measured on XT-4 micro-melting point apparatus.
2.0 Hz), 124.8 (q, JC F＝260 Hz), 125.8, 129.8, 129.9,
－
130.1, 130.8 (q, JC F＝1.3 Hz), 136.4, 138.2 140.3 (q,
－
JC F＝4.0 Hz); 19F NMR (376 MHz, CDCl3) δ: −54.14;
－
MS (EI) m/z (rel): 289 (M＋, 100), 288 (22), 290 (18),
204 (12), 219 (10), 205 (9), 108 (6.9), 220 (6.6); IR
(KBr) ν: 2945, 2924, 1591, 1561, 1407, 1240, 1187,
1088, 958, 744, 727 cm−1; HRMS for C17H14NF3: calcd
289.1078; found 289.1076.
1-Methyl-2-(m-tolyl)-3-(trifluoromethyl)-1H-
indole (3c) White solid, 55 mg, 94% yield; m.p. 59－
61 ℃; 1H NMR (400 MHz, CDCl3) δ: 2.41 (s, 3H), 3.51
(s, 3H), 7.18－7.37 (m, 7H), 7.82 (d, J＝7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 21.5, 30.8, 103.8 (q,
JC F＝35 Hz), 110.0, 119.8 (q, JC F＝1.6 Hz), 121.6,
－
－
123.0, 124.5 (q, JC F＝1.9 Hz), 124.9 (q, JC F＝265
－
－
Hz), 127.6 (q, JC F＝1.1 Hz), 128.3, 130.1, 130.2, 131.1
－
(q, JC F＝1.1 Hz), 136.4, 138.1, 141.1 (q, JC F＝3.8
－
－
Hz); 19F NMR (376 MHz, CDCl3) δ: −52.67; MS (EI)
m/z (rel): 289 (M＋, 100), 288 (23), 290 (22), 204 (15),
219 (11), 205 (11), 274 (10), 134 (9); IR (KBr) ν: 2971,
2921, 1555, 1468, 1213, 1172, 1078, 956, 744, 698 cm−1;
HRMS for C17H14NF3: calcd 289.1078; found 289.1080.
1-Methyl-2-(p-tolyl)-3-(trifluoromethyl)-1H-
indole (3d) Brown solid, 55 mg, 95% yield; m.p. 99－
General experimental procedure for Table 2
To a flame dried Schlenk tube was added sequen-
tially CuBr (28.6 mg, 0.2 mmol, 98% in purity), 2-alky-
nylaniline 1 (0.2 mmol) and Umemoto’s reagent 2 (96.5
mg, 0.24 mmol) and 1 mL DMA. The resulting mixture
was allowed to stir until the disappearance of 2-alkynyl-
aniline 1 as monitored by TLC at 80 ℃. The reaction
mixture was added water and extracted with diethyl
ether for three times. The combined organic layers were
concentrated under vacuum. Then the residue was puri-
1
101 ℃; H NMR (400 MHz, CDCl3) δ: 2.49 (s, 3H),
3.58 (s, 3H), 7.31－7.43 (m, 7H), 7.87－7.89 (m, 1H);
13C NMR (100 MHz, CDCl3) δ: 21.5, 30.7, 103.9 (q,
JC F＝27 Hz), 110.0, 119.8 (q, JC F＝1.5 Hz), 121.6,
－
－
122.9, 124.6 (q, JC F＝1.9 Hz), 125.0 (q, JC F＝266
－
－
Hz), 127.2, 129.1, 130.4 (q, JC F＝1.2 Hz), 136.5, 139.4,
－
141.1 (q, JC F＝3.7 Hz); 19F NMR (376 MHz, CDCl3) δ:
－
−52.66; MS (EI) m/z (rel): 289 (M＋, 100), 288 (22), 290
730
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Chin. J. Chem. 2014, 32, 727—733

Efficient Synthesis of 3-Trifluoromethylindoles
(18), 204 (12), 219 (10), 205 (9), 108 (6.9), 220 (6.6);
IR (KBr) ν: 2959, 2922, 1505, 1467, 1409, 1129, 1081,
956, 743 cm−1; HRMS for C17H14NF3: calcd 289.1078;
found 289.1077.
310 (20), 205 (16), 127 (13), 308 (12), 273 (12); IR
(KBr) ν: 2924, 2853, 1487, 1435, 1132, 1088, 956, 830,
746 cm−1; HRMS for C16H11NClF3: calcd 309.0532;
found 309.0531.
1-Methyl-2-(4-ethylphenyl)-3-(trifluoromethyl)-
1H-indole (3e) Brown solid, 55 mg, 91% yield; m.p.
81－84; H NMR (400 MHz, CDCl3) δ: 1.20 (t, J＝7.6
1-Methyl-2-(4-bromophenyl)-3-(trifluoromethyl)-
1H-indole (3l) Colorless solid, 65 mg, 92% yield; m.p.
116－118 ℃; H NMR (400 MHz, CDCl3) δ: 3.42 (s,
1
1
Hz, 3H), 2.63 (q, J＝7.6 Hz, 2H), 3.42 (s, 3H), 7.16－
3H), 7.16－7.26 (m, 5H), 7.52 (d, J＝8.4 Hz, 1H), 7.72
7.27 (m, 7H), 7.72 (d, J＝7.6 Hz, 1H); 13C NMR (100
(d, J＝8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ:
MHz, CDCl3) δ: 15.4, 28.8, 30.7, 103.8 (q, JC F＝35
30.8, 104.3 (q, JC F＝34 Hz), 110.1, 119.9 (q, JC ＝
F
－
－
－
Hz), 110.0, 119.8 (q, JC F＝1.5 Hz), 121.5, 122.9, 124.6
1.4 Hz), 121.8, 123.3, 124.0, 124.4 (q, JC F＝1.9 Hz),
－
－
(q, JC F＝1.9 Hz), 125.0 (q, JC F＝266 Hz), 127.3,
124.7 (q, JC F＝267 Hz), 129.1, 131.7, 132.1 (q, JC ＝
－
－
－
－
F
127.9, 130.4 (q, JC F＝1.1 Hz), 136.4, 141.1 (q, JC
＝
F
1.1 Hz), 136.5, 139.4 (q, JC F＝3.7 Hz);19F NMR (376
－
－
－
3.7 Hz), 145.6; 19F NMR (376 MHz, CDCl3) δ: −53.01;
MS (EI) m/z (rel): 303 (M＋, 100), 288 (44), 304 (19),
144 (13), 289 (8), 302 (7), 253 (7), 204 (7); IR (KBr) ν:
2969, 2927, 1464, 1408, 1132, 1087, 957, 833, 746 cm−1;
HRMS for C18H16NF3: calcd 303.1235; found 303.1238.
1-Methyl-2-(4-methoxylphenyl)-3-(trifluorometh-
yl)-1H-indole (3f) White solid, 60 mg, 94% yield;
m.p. 186－188 ℃; 1H NMR (400 MHz, CDCl3) δ: 3.57
(s, 3H), 3.90 (s, 3H), 7.03－7.41 (m, 7H), 7.86 (d, J＝
7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 30.7, 55.4,
MHz, CDCl3) δ: −52.80; MS (EI) m/z (rel): 353 (M＋,
100), 355 (96), 204 (37), 205 (27), 354 (23), 127 (19),
102 (16), 356 (15); IR (KBr) ν: 2919, 2850, 1466, 1433,
1151, 1085, 957, 826, 746 cm−1; HRMS for C16H11-
NBrF3: calcd 353.0027; found 353.0031.
1-Methyl-2-hexyl-3-(trifluoromethyl)-1H-indole
(3j) Colorless liquid, 47 mg, 83% yield; 1H NMR (400
MHz, CDCl3) δ: 0.81 (brs, 3H), 1.23－1.35 (m, 6H),
1.47－1.55 (m, 2H), 2.78 (t, J＝8.0 Hz, 3H), 3.57 (s,
3H), 7.08－7.21 (m, 3H), 7.63 (d, J＝7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ: 14.1, 22.7, 25.2, 29.3, 29.6,
103.9 (q, JC F＝35 Hz), 110.0, 113.9, 119.8 (q, JC
＝
F
－
－
1.5 Hz), 121.5, 122.2, 122.9, 124.5 (q, JC F＝2.0 Hz),
30.0, 31.6, 102.2 (q, JC F＝35 Hz), 109.4, 119.3 (d,
－
－
125.0 (q, JC F＝266 Hz), 131.8 (q, JC F＝1.1 Hz),
JC F＝1.4 Hz), 121.2, 122.1, 124.6 (q, JC F＝2 Hz),
－
－
－
－
136.4, 140.8－140.9 (m, 1C), 160.4; 19F NMR (376
MHz, CDCl3) δ: −52.67; MS (EI) m/z (rel): 305 (M＋,
100), 290 (19), 306 (18), 304 (12), 153 (9), 193 (6), 242
(5), 235 (5); IR (KBr) ν: 2923, 1613, 1504, 1468, 1408,
1245, 1978, 956, 837, 763 cm−1; HRMS for C17H14-
NOF3: calcd 305.1027; found 305.1031.
125.7 (d, JC F＝265 Hz), 136.3, 141.8－142.0 (m, 1C);
－
19F NMR (376 MHz, CDCl3) δ: −53.51; MS (EI) m/z
(rel): 283 (M＋, 37), 213 (100), 212 (65), 144 (35), 226
(33), 214 (12), 284 (6.7), 145 (6.5); IR (KBr) ν: 2956,
2928, 1561, 1472, 1412, 1283, 1224, 1085, 955, 742
cm−1; HRMS for C16H20NF3: calcd 283.1548; found
283.1551.
1-Methyl-2-(6-methoxylnaphthalen-1-yl)-3-(tri-
fluoromethyl)-1H-indole (3g) White solid, 65 mg,
1-Methyl-2-cyclopropyl-3-(trifluoromethyl)-1H-
indole (3k) White solid, 39 mg, 82% yield; m.p. 65－
1
92% yield; m.p. 114－115 ℃; H NMR (400 MHz,
1
CDCl3) δ: 3.42 (s, 3H), 3.82 (s, 3H), 7.08－7.33 (m,
67 ℃; H NMR (400 MHz, CDCl3) δ: 0.84－0.85 (m,
6H), 7.65－7.76 (m, 4H); 13C NMR (100 MHz, CDCl3)
2H), 1.10－1.13 (m, 2H), 1.84 (s, 1H), 3.79 (s, 3H),
δ: 30.8, 55.5, 104.1 (q, JC F＝35 Hz), 105.8, 110.0,
7.15－7.28 (m, 3H), 7.71－7.13 (m, 1H); 13C NMR
－
119.78, 119.8 (q, JC F＝1.5 Hz), 121.6, 123.0, 124.6 (q,
(100 MHz, CDCl3) δ: 6.5, 6.7 (q, JC F＝2.5 Hz), 30.4,
－
－
JC F＝2.0 Hz), 125.0 (q, JC F＝268 Hz), 125.2, 126.9,
104.0 (q, JC F＝36 Hz), 109.4, 119.6 (q, JC F＝2.0 Hz),
－
－
－
－
128.0 (d, JC F＝1.5 Hz), 128.3, 129.9, 130.0 (q, JC
＝
121.2, 122.5, 124.4 (q, JC F＝2.0 Hz), 125.4 (q, JC ＝
－
－
－
－
F
F
1.5 Hz), 134.8, 136.5, 141.0 (q, JC F＝4.2 Hz), 158.7;
268 Hz), 135.9, 141.6－141.7 (m, 1C); 19F NMR (376
MHz, CDCl3) δ: −52.17; MS (EI) m/z (rel): 339 (M＋,
100), 170 (60), 224 (50), 212 (37), 240 (17), 97 (14),
168 (12), 128 (11); IR (KBr) ν: 2923, 2853, 1556, 1469,
1414, 1228, 1076, 955, 746, 652 cm−1; HRMS for
C13H12NF3: calcd 239.0922; found 239.0925.
－
19F NMR (376 MHz, CDCl3) δ: −52.53; MS (EI) m/z
(rel): 355 (M＋, 100), 356 (22), 312 (15), 178 (12), 242
(10), 340 (8), 243 (8), 354 (7); IR (KBr) ν: 2964, 2920,
1547, 1392, 1088, 1031, 954, 853, 810, 751 cm−1;
HRMS for C21H16NOF3: calcd 355.1184; found
355.1180.
1-Methyl-2-phenethyl-3-(trifluoromethyl)-1H-
1
1-Methyl-2-(4-chlorophenyl)-3-(trifluoromethyl)-
1H-indole (3h) White solid, 59 mg, 96% yield; m.p.
indole (3l) Pale yellow liquid, 56 mg, 93% yield; H
NMR (400 MHz, CDCl3) δ: 2.98－3.02 (m, 2H), 3.26 (t,
J＝8.0 Hz, 2H), 3.52 (s, 3H), 7.22－7.37 (m, 8H), 7.82
－7.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 27.5 (d,
JC F＝1.2 Hz), 29.4, 36.5 (q, JC F＝0.7 Hz), 102.4 (q,
1
117－119 ℃; H NMR (400 MHz, CDCl3) δ: 3.57 (s,
3H), 7.31－7.52 (m, 7H), 7.86－7.88 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ: 30.8, 104.4 (q, JC F＝35
－
－
－
Hz), 110.1, 119.9 (q, JC F＝1.5 Hz), 121.8, 123.3, 124.4
JC F＝35 Hz), 109.6, 119.3 (q, JC F＝1.5 Hz), 121.3,
－
－
－
(q, JC F＝1.8 Hz), 124.7 (q, JC F＝268 Hz), 128.6,
122.3, 124.5 (q, JC F＝2.0 Hz), 125.7 (q, JC F＝266
－
－
－
－
128.8, 131.9 (q, JC F＝1.1 Hz), 135.7, 136.5, 139.4 (q,
－
MS (EI) m/z (rel): 309 (M＋, 100), 311 (31), 204 (21),
Hz), 126.6, 128.5, 128.8, 136.3, 140.5, 140.6 (q, JC ＝
－
JC F＝3.8 Hz); 19F NMR (376 MHz, CDCl3) δ: −52.66;
－
F
3.8 Hz); 19F NMR (376 MHz, CDCl3) δ: −53.61; MS (EI)
m/z (rel): 303 (M＋, 28), 212 (100), 213 (12),91 (6), 304
Chin. J. Chem. 2014, 32, 727—733
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
731

Ge et al.
FULL PAPER
cm−1; HRMS for C16H11NClF3: calcd 309.0532; found
309.0536.
4-(2-Phenyl-3-(trifluoromethyl)-1H-indol-1-yl)-
butyl acetate (3r) White solid, 33 mg, 44% yield; m.p.
(6), 115 (4), 65 (3), 192 (2);IR (KBr) ν: 3027, 2944,
1557, 1472, 1411, 1225, 1127, 1083, 954, 742, 698 cm−1;
HRMS for C18H16NF3: calcd 303.1235; found 303.1234.
1-Ethyl-2-phenyl-3-(trifluoromethyl)-1H-indole
(3m) Brown solid, 56 mg, 97% yield; m.p. 104－106
1
40－42 ℃; H NMR (400 MHz, CDCl3) δ: 1.45－1.52
1
℃; H NMR (400 MHz, CDCl3) δ: 1.29 (t, J＝7.2 Hz,
(m, 2H), 1.84－1.76 (m, 2H), 2.00 (s, 3H), 3.92 (t, J＝
6.4 Hz, 2H), 4.01 (t, J＝7.2 Hz, 2H), 7.26－7.52 (m,
8H), 7.85 (d, J＝8.0 Hz, 1H); 13C NMR (100 MHz,
3H), 4.04 (q, J＝7.2 Hz, 2H), 7.29－7.54 (m, 8H), 7.87
－7.90 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 15.4,
38.8, 104.2 (q, JC F＝4.9 Hz), 110.2, 120.0 (q, JC
＝
F
－
－
CDCl3) δ: 21.0, 25.8, 26.5, 43.4, 63.6, 104.5 (q, JC ＝
－
F
1.5 Hz), 121.5, 123.0, 124.7 (q, JC F＝1.9 Hz), 124.9 (q,
－
35 Hz), 110.2, 120.0 (q, JC F＝1.4 Hz), 121.6, 123.1,
－
JC F＝268 Hz), 128.4, 129.4, 130.4 (q, JC F＝1.1 Hz),
－
－
124.6－124.7 (m, 1C), 124.8 (q, JC F＝265 Hz), 128.4,
－
130.4, 135.2, 140.4 (q, JC F＝3.8 Hz); 19F NMR (376
－
129.5, 130.3, 135.5, 130.5 (d, JC F＝1.1 Hz), 140.5 (q,
－
MHz, CDCl3) δ: −52.77; MS (EI) m/z (rel): 289 (M＋,
100), 274 (73), 205 (42), 204 (26), 290 (18), 275 (13),
254 (13), 206 (7); IR (KBr) ν: 2981, 2933, 1560, 1458,
1420, 1257, 1127, 1087, 974, 939, 749, 700 cm−1;
HRMS for C17H14NF3: calcd 289.1078; found 289.1077.
1-Butyl-2-phenyl-3-(trifluoromethyl)-1H-indole
(3n) Brown solid, 42 mg, 67% yield; m.p. 48－50 ℃;
1H NMR (400 MHz, CDCl3) δ: 0.82 (t, J＝7.6 Hz, 3H),
1.18－1.24 (m, 2H), 1.62－1.68 (m, 2H), 3.98 (t, J＝8.0
Hz, 2H), 7.29－7.54 (m, 8H), 7.88 (d, J＝8.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ: 13.6, 20.0, 32.0, 43.7,
104.1 (q, JC F＝35 Hz), 110.4, 119.9 (q, JC F＝1.5 Hz),
JC F＝2.8 Hz), 171.1; 19F NMR (376 MHz, CDCl3) δ:
－
−52.87; MS (EI) m/z (rel): 375 (M＋, 91), 274 (100), 205
(32), 43 (27), 204 (24), 376 (21), 275 (18), 254(12); IR
(KBr) ν: 2959, 2934, 1734, 1611, 1418, 1234, 1093, 961,
754, 699 cm−1; HRMS for C21H20NO2F3: calcd
375.1446; found 375.1450.
Acknowledgement
Financially supported by the Major Basic Research
Development Program (No. 2011CB808706), National
Natural Science Foundation of China (Nos. 21272251,
21121062 and 21032007), Chinese Academy of Sci-
ences, the Technology Commission of Shanghai Mu-
nicipality, and the Croucher Foundation of Hong Kong.
－
－
121.5, 122.9, 124.6 (q, JC F＝1.5 Hz), 124.9 (q, JC
＝
F
－
－
267 Hz), 128.4, 129.4, 130.4, 130.5 (d, JC F＝0.7 Hz),
－
135.6, 140.6 (q, JC F＝4.2 Hz); 19F NMR (376 MHz,
－
CDCl3) δ: −52.70; MS (EI) m/z (rel): 317 (M＋, 80), 274
(100), 205 (35), 204 (25), 275 (19), 318 (16), 254 (12),
206 (6); IR (KBr) ν: 2964, 2933, 1558, 1458, 1416,
1146, 1091, 965, 746, 699 cm−1; HRMS for C19H18NF3:
calcd 317.1391; found 317.1390.
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－
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1
138－140 ℃; H NMR (400 MHz, CDCl3) δ: 3.40 (s,
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－
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www.cjc.wiley-vch.de
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2014, 32, 727—733

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Chin. J. Chem. 2014, 32, 727—733
© 2014 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
733