Palladium-catalyzed intramolecular aerobic C-H amination of enamines for the synthesis of 2-trifluoromethylindoles

Article abstract of DOI:10.1016/j.tet.2017.12.047

A new palladium-catalyzed C-H amination of aryl enamines for the synthesis of trifluoromethylated indoles is established. The attractive features of this transformation are the use of atom-economical O₂ as the oxidant and easily prepared enamines as substrates. A variety of pharmaceutically important 2-trifluoromethyl indoles can be targeted in moderate to good yields with good functional compatibility.

Full text of DOI:10.1016/j.tet.2017.12.047

Accepted Manuscript
Palladium-catalyzed intramolecular aerobic C-H amination of enamines for the
synthesis of 2-trifluoromethylindoles
Feng Wei, Xiao-Qin Shen, Jing-Jing Chu, Bo-Lun Hu, Xing-Guo Zhang
PII:
S0040-4020(17)31331-5
10.1016/j.tet.2017.12.047
TET 29203
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 November 2017
Revised Date: 16 December 2017
Accepted Date: 23 December 2017
Please cite this article as: Wei F, Shen X-Q, Chu J-J, Hu B-L, Zhang X-G, Palladium-catalyzed
intramolecular aerobic C-H amination of enamines for the synthesis of 2-trifluoromethylindoles,
Tetrahedron (2018), doi: 10.1016/j.tet.2017.12.047.
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Palladium-Catalyzed Intramolecular Aerobic C-H
Amination of Enamines for the Synthesis of
2-Trifluoromethylindoles
Leave this area blank for abstract info.
Feng Wei, Xiao-Qin Shen, Jing-Jing Chu, Bo-Lun Hu, Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China.

1
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Tetrahedron
journal homepage: www.elsevier.com
Palladium-Catalyzed Intramolecular Aerobic C-H Amination of Enamines for the
Synthesis of 2-Trifluoromethylindoles
Feng Wei, Xiao-Qin Shen, Jing-Jing Chu, Bo-Lun Hu, Xing-Guo Zhang
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new palladium-catalyzed C-H amination of aryl enamines for the synthesis of
trifluoromethylated indoles is established. The attractive features of this transformation are
the use of atom-economical O2 as the oxidant and easily prepared enamines as substrates.
A variety of pharmaceutically important 2-trifluoromethyl indoles can be targeted in
moderate to good yields with good functional compatibility.
Available online
Keywords:
C-H functionalization
oxidative amination
trifluoromethyl
indole
2009 Elsevier Ltd. All rights reserved.
enamine
1. Introduction
Herein, we report an intramolecular palladium-catalyzed C-H
oxidative amination of enamines using molecular oxygen as the
The indole scaffold is an essential structural motif in biologically
active compounds and natural products,1 and considerable efforts
have been devoted towards the development of efficient methods for
the preparation of their derivatives.2 Whereas the synthesis of
trifluoromethylated indoles was relatively less reported,3 although
the incorporation of a trifluoromethyl group into organic molecules
frequently enhances their biological activity and has become a
powerful and widely used strategy in drug discovery.4 For instance,
2-trifluoromethylindoles are widely used as core structures in many
pharmaceuticals, including general anesthesia inducer,5 tyrosine
kinase inhibitor6 and antitumor compounds.7 Traditionally, the direct
trifluoromethylation of indole with trifluoromethyl radical (such as
CF3SO2Na, CF3I) or electrophilic trifluoromethylating reagent
(Togni’s or Umemoto’s reagent) is the commonly used method,
which suffers poor regioselectivity or/and low yields (Scheme 1,
eq.1).8 Recently, some cyclization strategies have also been
developed for the preparation of 2-trifluoromethylindoles, which
involves the effective transformation of synthons bearing a CF3
group at the appropriate position.9 In 2016, Cramer group reported
the synthesis of 2-trifluoromethylindoles from palladium-catalyzed
cyclization of N-(o-toyl)-trifluoroacetimidoyl chlorides through
C(sp3)-H functionalization of toluene moiety (eq.2).10 Inspired by
some intramolecular aryl C-H amination reactions,11 we envisioned
whether CF3-containing enamine, a type of versatile building
terminal oxidant, affording 2-trifluoromethylindoles in moderate to
good yields (eq.3).
Scheme 1. The synthesis of 2-trifluoromethylindoles
2. Results and discussion
We initiated our study by testing the intramolecular C-H
amination of N-(3,3,3-trifluoro-1-phenylprop-1-en-2-yl)aniline 1a to
optimize the reaction conditions (Table 1). Firstly, substrate 1a was
treated with 10 mol% Pd(OAc)2 under oxygen atmosphere (1 atm) in
blocks,12 could participate in a similar aryl C-H amination reaction.
———
Corresponding author. Tel./fax: +86 577 86689339; e-mail: zxg@wzu.edu.cn (X.-G. Zhang)

2
Tetrahedron
ACCEPTED MANUSCRIPT
DMSO at 100 °C, the desired product 2a was isolated in 26% yield
Unfortunately, our efforts to furnish N-alkyl and N-acryl enamines
(entry 1). To enhance the reaction yield, the solvent effect was
investigated. We found that toluene provided the similar yield (entry
2), but only trace amount of product were observed in DMF or DCE
(entries 3 and 4). To our delight, the combination of DMSO and
toluene as cosolvent afforded better results. A 68% yield was
obtained when the reaction was carried out in DMSO/toluene (2:1)
(entry 6). Subsequently, some oxidants were tested, including
Cu(OAc)2, K2S2O8, PhI(OAc)2 and Di-tert-butyl peroxide (DTBP),
but all gave low yields (entries 7-10). Considering that metal acetates
could promote some C-H activation reactions,13 we attempted to add
2 equiv of metal acetates, such as CsOAc, KOAc, NaOAc and
Zn(OAc)2 (entries 11-14). We were please to find that the reaction
afford product 2a in 84% yield in the presence of 2 equiv of
Zn(OAc)2 (entry 14). A lower yield was observed when the reaction
was conducted at 80 °C (entry 15).
failed, possibly due to their poor stability. Next, the substituent effect
of R group was examined. Similarly, methyl, ethyl and methoxyl
substituted in indoles 2m-2q in 52-83% yields. For substrate 1m and
1p, only 6-position C-H amination product 2m and 2p were isolated
owing to the steric hindrance of meta-substituents. 6-Fluoro and 6-
chloro indole 2r and 2s were obtained in 75% and 80% yields,
respectively. 2,6-ditrifluoromethyl indole 2t was obtained in 76%
yield. As expected, trifluoromethylated benzoindole 2u could also be
prepared in 72% yield by this palladium-catalyzed C-H amination.
Table 2. Exploration of substrate scope a
10 mol% Pd(OAc)2
2 equiv Zn(OAc)2
CF3
CF3
R1
R
o
HN
N
R'
4A MS, 1 atm O2
DMSO:Tol = 2:1, 100 oC, 12h
R'
2
1
CF3
CF3
CF3
CF3
N
CF3
a
N
N
Table 1. Screening of conditions
2a, 84%
2b, 73%
2c, 81%
CF3
N
CF3
F
N
N
Yield
Entry
Oxidant
Additive
Solvent
OCH3
(%)
26
2d, 51%
2e, 70%
2f, 53%
1
2
O2
O2
-
DMSO
CF3
N
CF3
Cl
N
N
-
Toluene
24
Cl
3
O2
-
DMF
Trace
Trace
48
F
Cl
4
O2
-
DCE
2g, 62%
2h, 53%
2i, 51%
5
O2
-
DMSO/Tol(1:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
DMSO/Tol(2:1)
CF3
CF3
CF3
N
N
Ph
N
6
O2
-
68
7
Cu(OAc)2
K2S2O8
PhI(OAc)2
DTBP
O2
-
21
CF3
8
-
-
24
2j, 80%
2k, 70%
2l, 72%
9
21
CF3
CF3
CF3
N
N
N
10
11
12
13
14
15b
-
23
H3CO
CsOAc
KOAc
NaOAc
23
2m, 73%
2n, 52%
2o, 61%
O2
20
H3CO
O2
70
CF3
CF3
CF3
N
N
F
N
O2
Zn(OAc)2 DMSO/Tol(2:1)
Zn(OAc)2 DMSO/Tol(2:1)
84
O2
55
2p, 83%
2q, 52%
2r, 75%
a Reaction conditions: 1a (0.2 mmol), 4Å MS (0.4 g), additive (2 equiv) in
solvent (3 mL) under O2 atmosphere (1 atm) at 100 °C for 12 h. Isolated
yields.
CF3
CF3
CF3
N
N
N
Cl
F3C
b At 80 °C
.
2s, 80%
2t, 76%
2u, 72%
With the optimal reaction conditions in hand, we began to
investigate substrate scope of the C-H amination and the results were
shown in Table 2. Initially, we tested a variety of N-aryl enamines,
and results demonstrated that the reaction conditions were
compatible with both electron-donating and electron-withdrawing
aryl moieties. For example, methyl, ethyl and methoxyl substituted
N-phenyl enamines afforded products 2b-2e in 51-81% yields.
Fluoro and chloro substituted N-phenyl enamines gave products 2f-
2i in 51-62% yields. Interestingly, the electron-deficient CF3-
containing enamine 1j was also suitable substrate to produce indole
2j in 80% yield. Moreover, N-biphenyl and N-naphthyl indole 2k
and 2l were obtained in 70% and 72% yields, respectively.
a
Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), 4Å MS (0.4 g)
and Zn(OAc)2 (0.4 mmol) in DMSO : Tol = 2 : 1 (3 mL) under 1 atm O2 at
100 °C for 12 h. Isolated yields.
Since the CF3-containing enamines were prepared from the
palladium-catalyzed amination of β-chlorostyrenes with anilines, we
attempted to develop a one-pot method for this indole synthesis from
β-chlorostyrenes with anilines. However, direct combination of the
β-chlorostyrenes amination12a with the above C-H amination reaction
conditions did not work to afford indole. After a series of trials, we
found that indole 2a could be isolated in 39% yield by adding 2
equiv of HOAc to the cooled down mixture of β-chloro styrene

3
hertz. 19F NMR spectra were recorded on a 500MHz
amination, following with the optimal C-H amination (Scheme 2).
Thus, 2-trifluoromethyl indoles could be easily prepared through this
one-pot reaction of β-chlorostyrenes with anilines, albeit in a
moderate yield.
ACCEPTED MANUSCRIPT
spectrometer (470 MHz for 19F) and are reported relative to the
CDCl3 as the internal standard. High resolution mass spectra
were recorded on an ESI-Q-TOF mass spectrometry. All
reactions were conducted using standard Schlenk techniques.
Melting points were measured on an X4 melting point apparatus
and were uncorrected. Column chromatography was performed
using EM silica gel 60 (300-400 mesh).
Scheme 2. One-pot synthesis of 2-trifluoromethylindole
4.2. Typical experimental procedure for the synthesis of 1-
phenyl-2-(trifluoromethyl)-1H-indole derivatives 2a–2u
To a flame-dried Schlenk tube with a magnetic stirring bar was
charged 1 (52.7 mg, 0.2 mmol), Pd(OAc)2 (4.5 mg, 10 mol %),
Zn(OAc)2 (73.4 mg, 2 eq), 4 Å MS (400 mg ) in DMSO (2 mL)
and toluene (1 mL) under O2 atmosphere (equipped with O2
balloon). The reaction mixture was stirred at 100 °C for 12 hours.
After the reaction was finished, the mixture was poured into ethyl
acetate, which was washed with brine (2 x 15 mL). After the
aqueous layer was extracted with ethyl acetate, the combined
organic layers were dried over anhydrous MgSO4 and evaporated
under vacuum. The residue was purified by flash column
chromatography (petroleum ether/ethyl acetate) to afford the
desired products 2a - 2u.
Scheme 3. Possible mechanism
4.2.1 1-Phenyl-2-(trifluoromethyl)-1H-indole (2a):9f Pale yellow
solid, m.p. 54-56 °C; 1H NMR (500 MHz, CDCl3 ) δ 8.43 (s, 1H),
7.64 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 6.5 Hz, 2H), 7.47-7.33 (m,
5H), 7.20-7.17 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 135.0,
132.1, 130.0, 128.4, 127.6, 125.2, 121.7 (q, JC-F = 267.5 Hz),
121.3, 121.2 (q, JC-F = 37.5 Hz), 119.9, 118.7, 118.5, 111.7; 19F
NMR (470 MHz, CDCl3) δ -56.78 (3F); LRMS (EI, 70 ev) m/z
(%): 261 (M+, 100), 242 (11), 192 (32), 184 (24).
4.2.2 1-p-Tolyl-2-(trifluoromethyl)-1H-indole (2b):9f Pale yellow
oil; H NMR (500 MHz, CDCl3 ) δ 8.30 (s, 1H), 7.44 (d, J = 7.5
Base on the previously reported mechanism and our observed
results,14 a plausible mechanism for the Pd-catalyzed C-H amination
was proposed as outlined in Scheme 3. Firstly, with the coordination
of Pd(OAc)2 and N atom in substrate 1a, a divalent palladium
intermediate A is formed by removing an acetic acid. Then,
intramolecular elimination of another acetic acid produces
palladacycle B. Subsequent C-N reductive elimination affords the
indole product 2a and Pd(0) species, which undergo oxidation by O2
to regenerate catalytic Pd(OAc)2.
1
Hz, 2H ), 7.41-7.38 (m, 2H), 7.33-7.31 (m, 2H), 7.25 (d, J = 8.5
Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 2.34 (s, 3H); 13C NMR (125
MHz, CDCl3) δ 133.3, 132.3, 130.8, 130.0, 128.4, 127.53,
127.45, 126.9, 121.7 (q, JC-F = 267.5 Hz), 121.2 (q, JC-F = 37.6
Hz), 120.3, 119.3, 111.3, 21.4; 19F NMR (470 MHz, CDCl3) δ -
56.75 (3F); LRMS (EI, 70 ev) m/z (%): 275 (M+, 100), 254 (11),
206 (22), 178 (7).
4.2.3 1-(3,5-Dimethylphenyl)-2-(trifluoromethyl)-1H-indole (2c):
Yellow oil; 1H NMR (500 MHz, CDCl3 ) δ 8.24 (s, 1H), 7.30 (m,
5H), 6.98 (s, 1H), 6.66 (s, 1H), 2.35 (s, 3H), 1.93 (s, 3H); 13C
NMR (125 MHz, CDCl3) δ 135.4, 135.1, 134.0, 132.5, 130.8,
3. Conclusion
In summary, we have developed
a palladium-catalyzed
intramolecular C-H amination strategy for the synthesis of 2-
trifluoromethylindoles using O2 as oxidant. In the presence of
Pd(OAc)2, Zn(OAc)2 and 1 atm O2, a range of N-aryl enamines
underwent the palladium-catalyzed C-H amination to afford 2-
trifluoromethylindoles in moderate to good yields. It is
noteworthy that we also developed a one-pot reaction for the
synthesis 2-trifluoromethyl indoles from β-chlorostyrenes and
anilines, albeit in a moderate yield. The present process provided
a new optional method for the synthesis of trifluoromethyl-
containing indoles from simple starting materials.
127.5, 124.6, 124.0, 121.7 (q, JC-F = 267.5 Hz), 121.3 (q, JC-F
=
36.3 Hz), 120.4, 118.5, 109.1, 21.6, 19.8; 19F NMR (470 MHz,
CDCl3) δ -57.00 (3F); LRMS (EI, 70 ev) m/z (%): 289 (M+, 100),
274 (14), 254 (7), 234 (4), 220 (17), 204 (15); HRMS (ESI)
Calcd for C17H15F3N+ ([M + H]+) 290.1151, Found: 290.1150.
4.2.4
1-(4-Ethylphenyl)-2-(trifluoromethyl)-1H-indole
(2d):
Yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.33 (s, 1H), 7.45 (d, J
= 7.5 Hz, 2H), 7.41-7.38 (m, 2H), 7.35-7.28 (m, 3H), 7.15 (d, J =
7.5 Hz, 1H), 2.64 (q, J = 7.5 Hz, 2H), 1.16 (t, J = 7.5 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 137.5, 133.5, 132.4, 130.0, 128.4,
127.6, 127.5, 125.9, 121.7 (q, JC-F = 267.5 Hz), 121.3 (q, JC-F
=
4. Experimental section
36.3 Hz), 119.6, 119.2, 111.5, 29.0, 16.3; 19F NMR (470 MHz,
CDCl3) δ -56.76 (3F); LRMS (EI, 70 ev) m/z (%): 289 (M+, 75),
275 (17), 274 (100), 254 (15), 234 (14); HRMS (ESI) Calcd for
C17H15F3N+ ([M + H]+) 290.1151, Found: 290.1156.
4.1. General
Chemicals were either purchased or purified by standard
1
techniques. H NMR and 13C NMR spectra were measured on a
500 MHz spectrometer (500 MHz for H, 125 MHz for 13C),
1
4.2.5 1-(4-Methoxyphenyl)-2-(trifluoromethyl)-1H-indole (2e):9f
Yellow solid, m.p. 99-102 °C; 1H NMR (500 MHz, CDCl3 ) δ
8.39 (s, 1H), 7.45-7.41 (m, 4H), 7.34 (d, J = 7.0 Hz, 1H), 7.27 (d,
J = 9.5 Hz, 1H), 6.96-6.95 (m, 2H), 3.72 (s, 3H); 13C NMR (125
using CDCl3 as the solvent with tetramethylsilane (TMS) as an
internal standard at room temperature. Chemical shifts are given
in δ relative to TMS, and the coupling constants J are given in

4
Tetrahedron
ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 155.3, 132.3, 130.1, 129.8, 128.4, 127.8, 127.5,
4.2.12 1-(Naphthalen-1-yl)-2-(trifluoromethyl)-1H-indole (2l):9f
1
121.6 (q, JC-F = 267.5 Hz), 121.8 (q, JC-F = 37.5 Hz), 119.5, 116.3,
112.6, 101.6, 55.8; 19F NMR (470 MHz, CDCl3) δ -56.79 (3F);
LRMS (EI, 70 ev) m/z (%): 291 (M+, 100), 276 (23), 156 (6), 249
(21), 228 (13), 208 (20).
Yellow oil; H NMR (500 MHz, CDCl3 ) δ 9.17 (s, 1H), 8.04 (d,
J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.59-7.54 (m, 2H),
7.53-7.48 (m, 3H), 7.47-7.41 (m, 3H), 7.37-7.34 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 132.2, 131.8, 130.3, 130.0, 129.0,
128.4, 127.6, 126.2, 125,5, 123.4, 122.4, 121.8 (q, JC-F = 267.5
Hz), 121.6, 121.5, 120.0, 119.8, 119.7, 119.2 (q, JC-F = 36.3 Hz),
118.3; 19F NMR (470 MHz, CDCl3) δ -56.02 (3F); LRMS (EI, 70
ev) m/z (%): 311 (M+, 100), 290 (19), 271 (22), 240 (10), 215
(11).
4.2.6
5,7-Dimethoxy-3-phenyl-2-((trifluoromethyl)thio)-1H-
inden-1-one (2f): Pale yellow oil; 1H NMR (500 MHz, CDCl3 ) δ
8.60 (s, 1H), 7.44-7.39 (m, 4H), 7.35-7.32 (m, 2H), 7.04-6.98 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 149.5 (d, JC-F = 243.8 Hz),
131.6, 130.81, 130.77, 129.8, 128.5, 127.8, 123.8 (d, JC-F = 15.0
Hz), 122.1 (q, JC-F = 36.3 Hz), 121.6, 121.5, 121.3 (q, JC-F
=
4.2.13 5-Methyl-1-phenyl-2-(trifluoromethyl)-1H-indole (2m):
Pale yellow oil; 1H NMR (500 MHz, CDCl3 ) δ 8.36 (s, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.29-7.24 (m, 4H),
7.14-7.10 (m, 2H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ
137.9, 135.0, 132.0, 130.6, 128.3, 127.4, 127.0, 125.1, 121.7 (q,
JC-F = 267.5 Hz), 121.2, 121.1 (q, JC-F = 36.3 Hz), 120.0, 111.6,
21.5; 19F NMR (470 MHz, CDCl3) δ -56.77 (3F); LRMS (EI, 70
ev) m/z (%): 275 (M+, 100), 274 (7), 254 (6), 240 (24); HRMS
(ESI) Calcd for C16H12F3NNa+ ([M + Na]+) 298.0814, Found:
298.0809.
267.5 Hz), 120.6, 109.6 (d, JC-F = 15.0 Hz), 116.9; 19F NMR (470
MHz, CDCl3) δ -57.06 (3F), -134.50 (1F); LRMS (EI, 70 ev) m/z
(%): 279 (M+, 100), 258 (24), 239 (33), 208 (13), 183 (16);
HRMS (ESI) Calcd for C15H10F4N+ ([M + H]+) 280.0744, Found:
280.0743.
4.2.7 1-(4-Fluorophenyl)-2-(trifluoromethyl)-1H-indole (2g):9f
Yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.41-7.38
(m, 4H), 7.33-7.29 (m, 2H), 7.20 (d, J = 9.5 Hz, 1H), 7.06-7.02
(m 1H); 13C NMR (125 MHz, CDCl3) δ 158.7 (d, JC-F = 235.0
Hz), 131.7, 131.4, 129.7, 128.5, 127.81, 127.76, 121.6 (q, JC-F
=
4.2.14 6-Methyl-1-phenyl-2-(trifluoromethyl)-1H-indole (2n):
Pale yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.39 (s, 1H), 7.58
(d, J = 8.0 Hz, 1H), 7.38-7.34 (m, 3H), 7.29-7.26 (m, 1H), 7.21
(d, J = 7.5 Hz, 2H), 7.13-7.10 (m, 1H), 2.35 (s, 3H); 13C NMR
(125 MHz, CDCl3) δ 137.3, 134.9, 129.7, 129.1, 129.0, 127.4,
36.3 Hz), 121.4 (q, JC-F = 267.5 Hz), 119.9, 114.2 (d, JC-F = 26.3
Hz), 112.7, 105.8 (d, JC-F = 11.3 Hz); 19F NMR (470 MHz,
CDCl3) δ -57.08 (3F), -121.89 (1F); LRMS (EI, 70 ev) m/z (%):
279 (M+, 100), 258 (24), 239 (33), 208 (13), 183 (16).
125.1, 121.7 (q, JC-F = 267.5 Hz), 121.66, 121.1, 121.0 (q, JC-F
=
4.2.8 1-(4-Chlorophenyl)-2-(trifluoromethyl)-1H-indole (2h):9f
Yellow oil; 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 7.53 (d, J
= 8.5 Hz, 1H), 7.42-7.41 (m, 4H), 7.32 (d, J = 8.5 Hz, 2H), 7.25-
7.23 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 133.2, 131.4,
36.3 Hz), 119.9, 111.6, 21.3; 19F NMR (470 MHz, CDCl3) δ -
56.78 (3F); LRMS (EI, 70 ev) m/z (%): 275 (M+, 100), 274 (7),
254 (6), 240 (24); HRMS (ESI) Calcd for C16H12F3NNa+ ([M +
Na]+) 298.0814, Found: 298.0810.
129.8, 129.5, 128.5, 128.4, 127.9, 127.2, 125.7, 122.4 (q, JC-F
=
37.5 Hz), 121.3 (q, JC-F = 267.5 Hz), 120.5, 112.8; 19F NMR (470
MHz, CDCl3) δ -57.08 (3F); LRMS (EI, 70 ev) m/z (%): 295
(M+,100), 274 (7), 256 (10), 234 (14).
4.2.15 6-Methoxy-1-phenyl-2-(trifluoromethyl)-1H-indole (2o):
°
1
White solid, m.p. 151-153 C; H NMR (500 MHz, CDCl3 ) δ
8.41(s, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.38-7.37 (m, 3H), 7.29-
7.26 (m, 1H), 7.12-7.10 (m, 1H), 6.94 (d, J = 8.0 Hz, 2H), 3.80 (s,
3H); 13C NMR (125 MHz, CDCl3) δ 159.2, 135.0, 131.0, 127.6,
125.1, 124.4, 121.8 (q, JC-F = 267.5 Hz), 121.2, 121.1, 120.7 (q,
JC-F = 37.5 Hz), 119.7, 114.0, 111.6, 55.3; 19F NMR (470 MHz,
CDCl3) δ -56.89 (3F); LRMS (EI, 70 ev) m/z (%): 291 (M+, 100),
272 (4), 208 (12); HRMS (ESI) Calcd for C16H13F3NO+ ([M +
H]+) 292.0944, Found: 292.0956.
4.2.9 1-(3,4-Dichlorophenyl)-2-(trifluoromethyl)-1H-indole (2i):
Pale yellow oil; 1H NMR (500 MHz, CDCl3 ) δ 8.52 (s, 1H), 7.70
(s, 1H), 7.58-7.55 (m, 1H), 7.50-7.43 (m, 5H); 13C NMR (125
MHz, CDCl3) δ 133.5, 130.9, 129.7, 129.4, 128.6, 128.1, 127.0,
125.9, 122.9 (q, JC-F = 36.3 Hz), 121.7, 121.4, 121.1 (q, JC-F
=
267.5 Hz), 120.9, 119.6, 113.2; 19F NMR (470 MHz, CDCl3) δ -
57.25 (3F); LRMS (EI, 70 ev) m/z (%): 328 (M+, 48), 311 (41),
294 (8), 292 (26); HRMS (ESI) Calcd for C15H8Cl2F3NNa+ ([M +
Na]+) 351.9878, Found: 351.9881.
4.2.16 5-Methoxy-1-phenyl-2-(trifluoromethyl)-1H-indole (2p):
Pale yellow oil; 1H NMR (500 MHz, CDCl3 ) δ 8.45 (s, 1H), 7.59
(d, J = 9.0 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.30-7.27 (m, 2H),
7.13-7.10 (m, 1H), 7.04-7.01 (m, 2H), 6.88 (d, J = 9 Hz, 1H),
3.77 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.6, 134.9, 133.4,
129.4, 127.3, 125.2, 122.5, 121.7 (q, JC-F = 267.5 Hz), 121.3,
121.2 (q, JC-F = 36.3 Hz), 115.5, 113.3, 111.7, 55.3; 19F NMR
(470 MHz, CDCl3) δ -56.76 (3F); LRMS (EI, 70 ev) m/z (%):
291 (M+, 100), 272 (4), 208 (12), 176 (5); HRMS (ESI) Calcd for
C16H13F3NO+ ([M + H]+) 292.0944, Found: 292.0941.
4.2.10
2-(Trifluoromethyl)-1-(4-(trifluoromethyl)phenyl)-1H-
1
indole (2j):9f Yellow oil; H NMR (500 MHz, CDCl3 ) δ 8.62 (s,
1H), 7.84 (s, 1H), 7.49 (d, J = 9.0 Hz, 1H), 7.43-7.40 (m, 5H),
7.36-7.34 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 136.2, 131.1,
129.8, 128.7, 128.1, 126.0, 124.0 (q, JC-F = 32.5 Hz), 123.8, 123.3
(q, JC-F = 255.0 Hz), 122.9 (q, JC-F = 37.5 Hz), 121.8, 121.3 (q, JC-
= 267.5 Hz), 119.1, 112.3; 19F NMR (470 MHz, CDCl3) δ -
F
57.14 (3F), -60.70 (3F); LRMS (EI, 70 ev) m/z (%): 329 (M+,
100), 310 (12), 208 (13), 289 (20), 240 (18).
4.2.17 6-Ethyl-1-phenyl-2-(trifluoromethyl)-1H-indole (2q): Pale
yellow oil; 1H NMR (500 MHz, CDCl3 ) δ 8.38 (s, 1H), 7.59 (d, J
= 8.0 Hz, 1H), 7.37-7.36 (m, 3H), 7.29-7.26 (m, 1H), 7.23-7.22
(m, 2H), 7.13-7.10 (m, 1H), 2.65 (q, J = 7.5 Hz, 2H), 1.23 (t, J =
7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 143.5, 135.0, 129.8,
129.3 127.9, 127.4, 125.1, 121.7 (q, JC-F = 267.5 Hz), 121.2,
120.7 (q, JC-F = 36.2 Hz), 120.0, 119.9, 111.6, 28.6, 15.3; 19F
NMR (470 MHz, CDCl3) δ -56.77 (3F); LRMS (EI, 70 ev) m/z
(%): 289 (M+, 100), 275 (17), 274 (96), 234 (8), 204 (15), 137
(10); HRMS (ESI) Calcd for C17H15F3N+ ([M + H]+) 290.1151,
Found: 290.1159.
4.2.11 1-(Biphenyl-2-yl)-2-(trifluoromethyl)-1H-indole (2k): Pale
°
1
yellow solid, m.p. 79-81 C; H NMR (500 MHz, CDCl3) δ 8.64
(s, 1H), 7.65-7.56 (m, 7H), 7.49-7.37 (m, 5H), 7.29-7.28 (m, 1H);
13C NMR (125 MHz, CDCl3) δ 138.1, 133.0, 132.1, 129.9, 129.7,
129.5, 129.2, 128.4, 128.2, 128.0, 127.8, 127.6, 127.3, 126.4,
124.9, 121.9, 121.6 (q, JC-F = 267.5 Hz), 121.5 (q, JC-F = 37.5 Hz),
120.3; 19F NMR (470 MHz, CDCl3) δ -57.00 (3F); LRMS (EI, 70
ev) m/z (%): 337 (M+, 100), 216 (9), 296 (18), 267 (10), 240 (12);
HRMS (ESI) Calcd for C21H15F3N+ ([M + H]+) 338.1151, Found:
338.1156.
4.2.18 6-Fluoro-1-phenyl-2-(trifluoromethyl)-1H-indole (2r):
°
Yellow solid, m.p. 89-91 C; 1H NMR (500 MHz, CDCl3) δ 8.41

5
(s, 1H), 7.49 (s, 1H), 7.38-7.27 (m, 4H), 7.12-7.06 (m, 3H); 13C
NMR (125 MHz, CDCl3) δ 162.4 (d, JC-F = 245.0 Hz) ,134.9,
317, 1881; (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
ACCEPTED MANUSCRIPT
Chem. Soc. Rev. 2008, 37, 320; (d) Hagmann, W. K. J. Med. Chem.
2008, 51, 4359; (e) Liang, T.; Neumann, C. N.; Ritter, T. Angew. Chem.,
Int. Ed. 2013, 52, 8214.
131.6, 128.2 (d, JC-F = 21.3 Hz), 127.3, 125.2, 121.6 (q, JC-F
=
267.5 Hz), 121.4, 121.3 (q, JC-F = 37.5 Hz), 120.8, 118.8, 115.4
(d, JC-F = 22.5 Hz), 111.7; 19F NMR (470 MHz, CDCl3) δ -56.85
(3F), -114.62 (1F); LRMS (EI, 70 ev) m/z (%): 279 (M+, 100),
258 (21), 239 (30), 232 (8), 208 (13); HRMS (ESI) Calcd for
C15H10F4N+ ([M + H]+) 280.0744, Found: 280.0752.
5. (a) Baker, M. T.; Attala, M. N. PCT Int. Appl. WO 2003070177, 2003; (b)
Akanmu, M. A.; Songkram, C.; Kagechika, H.; Honda, K. Neurosci.
Lett. 2004, 364, 199.
6. Romines, W. H.; Kania, R. S.; Lou, J.; Collins, M. R.; Cripps, S. J.; He,
M.; Zhou, R.; Palmer, C. L.; Deal, J. G. PCT Int. Appl. WO
2003106462, 2003.
4.2.19 6-Chloro-1-phenyl-2-(trifluoromethyl)-1H-indole (2s):
7. (a) Fukuda, Y.; Furuta, H.; Kusama, Y.; Ebisu, H.; Oomori, Y.;
Terashima, S. J. Med. Chem. 1999, 42, 1448; (b) Fukuda, Y.; Furuta, H.;
Shiga, F.; Oomori, Y.; Kusama, Y.; Ebisu, H.; Terashima, S. Bioorg.
Med. Chem. Lett. 1997, 7, 1683.
°
1
Pale yellow solid, m.p. 76-78 C; H NMR (500 MHz, CDCl3) δ
8.52 (s, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.46-7.44 (m, 5H), 7.39-
7.36 (m, 1H), 7.23-7.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
8. (a) Iqbal, N.; Choi, S.; Ko, E.; Cho, E. J. Tetrahedron Lett. 2012, 53,
2005; (b) Fennewald, J. C.; Lipshutz, B. H. Green Chem. 2014, 16,
1097; (c) He, R.-Y.; Zeng, H.-T.; Huang, J.-M. Eur. J. Org. Chem. 2014,
4258; (d) Straathof, N. J. W.; Gemoets, H. P. L.; Wang, X.; Schouten, J.
C.; Hessel, V.; Noël, T. ChemSusChem 2014, 7, 1612; (e) Shimizu, R.;
Egami, H.; Nagi, T.; Chae, J.; Hamashima, Y.; Sodeoka, M.
Tetrahedron Lett. 2010, 51, 5947; (f) Wiehn, M. S.; Vinogradova, E. V.;
Togni, A. J. Fluorine Chem. 2010, 131, 951; (g) Cheng, Y.-Z.; Yuan, X.;
Ma, J.; Yu, S. Chem. Eur. J. 2015, 21, 8355; (h) Monteiro, J. L.;
Carneiro, P. J.; Elsner, P.; Roberge, D. M.; Wuts, P. G. M.; Kurjan, K.
C.; Gutmann, B.; Kappe, C. O. Chem. Eur. J. 2017, 23, 176.
134.9, 133.6, 131.2, 130.6, 128.7, 127.1, 125.3, 121.6 (q, JC-F
=
267.5 Hz), 121.3 (q, JC-F = 36.3 Hz), 120.8, 118.5, 118.3, 111.8;
19F NMR (470 MHz, CDCl3) δ -56.81 (3F); LRMS (EI, 70 ev)
m/z (%): 295 (M+, 100), 241 (12), 240 (59), 183 (6); HRMS
(ESI) Calcd for C15H10ClF3N+ ([M + H]+) 296.0488, Found:
296.0487.
4.2.20 1-Phenyl-2,6-bis(trifluoromethyl)-1H-indole (2t): Yellow
1
oil; H NMR (500 MHz, CDCl3 ) δ 8.43 (s, 1H), 7.60 (d, J = 8.0
Hz, 2H), 7.52-7.49 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.28-7.25
(m, 1H), 7.12-7.08 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
136.0, 135.0, 130.2, 129.7 (q, JC-F = 32.5 Hz), 127.0, 125.5,
125.4, 125.3, 124.3 (q, JC-F = 270.0 Hz), 122.2 (q, JC-F = 37.5
Hz), 121.5 (q, JC-F = 267.5 Hz), 120.7, 118.3, 111.9; 19F NMR
(470 MHz, CDCl3) δ -56.80 (3F), -62.42 (3F); LRMS (EI, 70 ev)
m/z (%): 329 (M+, 100), 310 (13), 389 (7), 240 (60); HRMS
(ESI) Calcd for C16H10F6N+ ([M + H]+) 330.0712, Found:
330.0717.
9. (a) Jiang, H.; Wang, Y.; Wan, W.; Hao, J. Tetrahedron 2010, 66, 2746;
(b) Usachev, B. I.; Obydennov, D. L.; Sosnovskikh, V. Y. J. Fluorine
Chem. 2012, 135, 278; (c) Shmatova, O. I.; Shevchenko, N. E.;
Nenajdenko, V. G. Eur. J. Org. Chem. 2015, 6479; (d) Kino, T.; Nagase,
Y.; Horino, Y.; Yamakawa, T. J. Mol. Catal. A: Chem. 2008, 282, 34; (e)
Chen, Z.; Zhu, J.; Xie, H.; Li, S; Wu, Y.; Gong, Y. Synlett. 2010, 9,
1418; (f) Dong, S.-X.; Zhang, X.-G.; Liu, Q.; Tang, R.-Y.; Zhong, P.; Li,
J.-H. Synthesis 2010, 9, 1521; (g) Chen, Z.; Zhu, J.; Xie, H.; Li, S.; Wu,
Y.; Gong, Y. Adv. Synth. Catal. 2011, 353, 325; (h) Cao, L.; Shen, D.;
Wei, J.; Chen, J.; Deng, H.; Shao, M.; Shi, J.; Zhang, H.; Cao, W. Eur. J.
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W.-G. Synthesis 2014, 46, 3309; (j) Dong, X.; Hu, Y.; Xiao, T.; Zhou, L.
RSC Adv. 2015, 5, 39625; (k) Shen, D.; Han, J.; Chen, J.; Deng, H.;
Shao, M.; Zhang, H.; Cao, W. Org. Lett. 2015, 17, 3283; (l) Dan-oh, Y.;
Matta, H.; Uemura, J.; Watanabe, H.; Uneyama, K. Bull. Chem. Soc.
Jpn. 1995, 68, 1497; (m) Wang, Z.-X.; Ge, F.-L.; Wan, W.; Jiang, H.-Z.;
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Ishihara, T.; Yamanaka, H. J. Org. Chem. 2004, 69, 8258.
4.2.21 1-Phenyl-2-(trifluoromethyl)-1H-benzo[f]indole (2u): Pale
yellow solid, m.p. 99-101 °C; 1H NMR (500 MHz, CDCl3) δ 8.55
(s, 1H), 7.92-7.91 (m, 2H), 7.61-7.48 (m, 5H), 7.38-7.35 (m, 2H),
7.21 (d, J = 7.5 Hz, 1H), 7.11-7.08 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 134.9, 133.6, 132.9, 129.6, 128.7, 128.5, 128.2, 126.2,
126.0, 125.8, 125.3, 125.1, 122.8 (q, JC-F = 35.0 Hz), 121.6 (q, JC-
F = 267.5 Hz), 121.59, 121.2, 111.7; 19F NMR (470 MHz, CDCl3)
δ -57.75 (3F); LRMS (EI, 70 ev) m/z (%): 311 (M+, 100), 310
(16), 290 (8), 272 (10), 241 (66), 120 (24); HRMS (ESI) Calcd
for C19H13F3N+ ([M + H]+) 312.0995, Found: 312.1002.
10. Pedroni, J.; Cramer, N. Org. Lett. 2016, 18, 1932.
11. (a) Clagg, K.; Hou, H.; Weinstein, A. B.; Russell, D.; Stahl, S. S.;
Koenig, S. G. Org. Lett. 2016, 18, 3586; (b) Bedford, R. B.; Bowen, J.
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A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 16184; (e) Chng, L. L.; Yang, J.; Wei, Y.; Ying,
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2011, 76, 8690.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 21272177) and Natural Science Foundation of Zhejiang
Province (No. LR15B020002) for financial support.
References and notes
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Tetrahedron
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