Palladium-Catalyzed Tandem Carbocyclization and Hetroarylation for the Synthesis of 2-(Trifluoromethyl)indenylmethyleneindoles

Article abstract of DOI:10.1021/acs.joc.8b02781

A palladium-catalyzed tandem cyclization and cross-coupling reaction of o-(2-chlorovinyl)alkynylbenzenes with indoles/pyrroles is developed. The process proceeds via intramolecular carbocyclization and subsequent hetroarylation to afford previously unknown trifluoromethyl-containing indenylmethyleneindoles, which are potentially useful in drug design.

Full text of DOI:10.1021/acs.joc.8b02781

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Article
Palladium-Catalyzed Tandem Carbocyclization and Hetroarylation
for the synthesis of 2-(trifluoromethyl)indenylmethyleneindoles
Tao Zhang, Fan Chen, Xiao-Hong Zhang, Peng-Cheng Qian, and Xing-Guo Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02781 • Publication Date (Web): 07 Dec 2018
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Palladium-Catalyzed Tandem Carbocyclization and
Hetroarylation for the synthesis of
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9
2-(trifluoromethyl)indenylmethyleneindoles
Tao Zhang, Fan Chen,* Xiao-Hong Zhang, Peng-Cheng Qian, Xing-Guo Zhang*
College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou
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325035, China; Author to whom correspondence should be addressed; E-Mail:
fanchen@wzu.edu.cn; zxg@wzu.edu.cn
RECEIVED DATE (to be automatically inserted after your manuscript is
accepted if required according to the journal that you are submitting your paper
to)
Abstract
R1
CF3
CF3
R1
PdCl2, L1, t-BuONa
PCy2
R3
N
Cl
+
R2
Toluene, N2, 120 oC
N
R2
H
L1
R3
19 examples, yields up to 76 %
A palladium-catalyzed tandem cyclization and cross-coupling reaction of the
ortho-(2-chlorovinyl)-alkynylbenzenes with indoles/pyrroles is developed. The
process proceeds via intramolecular carbocyclization and subsequent hetroarylation to
afford previously unknown trifluoromethyl-containing indenylmethyleneindoles,
which are potentially useful in drug design.
INTRODUCTION
1
Both the indene and indole 2 are essential and important structural motifs found in
natural occurring products, pharmaceutical active compounds and functional materials.
For example, sulindac and indriline are clinically used as an efficient non-steroidal
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anti-inflammatory drug and an antidepressant agent. The pharmacologically active
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6
4
ergot alkaloids and the antitumor agent ellipticine contain the indole framework.
7
8
9
Therefore, the development of novel methods to construct these compounds is
important in synthetic organic and pharmaceutical fields. In the past decades, a large
number of attractive and valuable procedures have been reported for the synthesis of
indene 5 and indole skeletons, 6 including many CF3-substituted indenes 7 or indoles. 8
However, example for the synthesis of molecules bearing both indene and indole
moieties still remains unexplored. These polycyclics are previously unknown and
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potentially useful in the drug discovery process. As part of our continuing interest in
7b, 9
trifluoromethylated molecules,
we wish to develop some simple reactions to
construct polycyclic compounds with the introduction of trifluoromethyl group.10
Herein, we report a palladium-catalyzed cascade carbocyclization and hetroarylation
of ortho-(2-chlorovinyl)-alkynylbenzenes with indoles or pyrroles, leading to
CF3-containing indenylmethyleneindoles. .
RESULTS AND DISCUSSION
The model reaction of o-phenylethynyl-β-chloro-β-trifluoromethylstyrene (1a)
11
(Z/E = 97:3) with indole (2a) was chosen to screen reaction conditions, and the
results were summarized in Table 1. Based on our previous work, 7b the reaction was
firstly conducted in the presence of 10 mol% Pd(OAc)2, 0.2 eq. ligand L1, 2.0 eq.
o
t-BuONa in toluene at 120 C for 24 h. The desired product 3a was successfully
isolated in 67% yield (entry 1), and the structure of product 3a was confirmed by
X-ray crystallography. Encouraged by these results, various Pd catalysts were
investigated and PdCl2 was the most effective catalyst, affording the targeted product
3a in 72% yield (entries 2-5), whereas the reaction did not occur in the absence of the
palladium catalyst (entry 6). Subsequently, other phosphorus ligands were tested, but
all gave worse results than ligand L1 (entries 7-10). To further enhance the reaction
yield, different bases such as K2CO3, K3PO4, Cs2CO3 and Na2CO3 were investigated,
and t-BuONa was proved to be the best base for the tandem reaction (entries 11-14).
Other solvents including DMSO, DMF, and CH3CN were also examined, but all gave
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lower yields than toluene (entries 15-17). The elevated temperature did not enhance
the yield (entry 18).
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Table 1 Optimization of the Reaction Conditions a
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CF3
CF3
[Pd], L, Base
Solvent, N2
Cl
+
N
N
H
1a
2a
3a
PPh2
PCy2
OMe
Ph2P
P(t-Bu)2
PCy2
MeO
L4
P(o-Tol)3
L3
Base
L1
L2
L5
Entry
Catalyst
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
L
Solvent
Yieldb
67
1
2
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
L1
L1
L1
L1
L1
L1
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
K2CO3
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMSO
56
3
72
4
Pd(CH3CN)2Cl2
Pd(PPh3)4
-
70
5
61
6
NR
53
7
PdCl2
8
PdCl2
10
9
PdCl2
11
10
11
12
13
14
15
16
17
18
PdCl2
23
PdCl2
33
PdCl2
K3PO4
48
PdCl2
Cs2CO3
60
PdCl2
Na2CO3
t-BuONa
t-BuONa
t-BuONa
t-BuONa
53
PdCl2
Trace
Trace
45
PdCl2
DMF
PdCl2
CH3CN
Toluene
PdCl2
58 b
a
Reaction conditions: 1 (0.1 mmol), 2 (1.2 eq), [Pd] (0.1 eq), Ligand (0.2 eq), base (2.0 eq),
Solvent (1.0 mL), N2, 120 oC, 24 h. b At 140 oC.
Under the optimal reaction conditions, the substrate scope of various indoles was
initially investigated. As shown in Table 2, indoles with both electron-donating and
electron-withdrawing substituents underwent the tandem carbocyclization and
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hetroarylation smoothly, affording the products 3a-3i in moderate to good yields. For
example, 3, 5, 6 or 7-methyl indoles and 5-methoxyl indole provided
2-(trifluoromethyl)indenylmethyleneindoles 3a-3e in 58-74% yields with high
regioselectivity, while fluoro and chloro substituents 3f-3i were isolated in 61-76%
yields. Subsequently, various alkynes (R2 moiety) were tested to afford the methyl
and methoxyl equivalents 3j and 3k in good yields. Notably, aliphatic alkyne also
carried out the tandem reaction, giving product 3l in 36% yield. During the
examination of substitution effect on the phenyl group (R1 moiety), the results showed
that the tandem reaction seemed to be insensitive to the electronic effects of R1 group.
Methyl, methoxyl, 1,4-methylenedioxy and fluoro products 3m-3p were isolated in
good yields. And some heterocyclic groups, such as thiophene underwent the reaction
smoothly, giving product 3q in 59% yield. Moreover, the reaction conditions were
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also
applicable
to
pyrrole,
furnished
their
corresponding
2-(trifluoromethyl)indenylmethylenepyrroles 3r and 3s in 65% and 47% yields,
respectively.
Table 2. Substrate Scope a,b
R1
CF3
R2
CF3
R1
PdCl2, L1, t-BuONa
R3
Cl
+
PCy2
N
R2
N
Toluene, N2, 120 oC
H
L1
R3
1
2
3
CF3
CF3
CF3
Me
N
N
Ph
N
Ph
Ph
Me
Me
, 62% (98:2)
3b
3c
3d
, 68% (97:3)
, 74% (98:2)
CF3
CF3
CF3
N
N
N
Ph
Ph
Ph
Me
OMe
F
3e
3f
3g
, 61% (94:6)
, 58% (100:0)
, 74% (97:3)
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CF3
CF3
CF3
6
7
8
N
N
N
Ph
Ph
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Me
3j
Cl
Cl
3h
3i,
, 76% (97:3)
68%(100:0)
, 70%(100:0)
CF3
CF3
CF3
Me
N
N
N
Ph
MeO
3k
3l,
36%(93:7)
, 69%(99:1)
CF3
3m
, 57%(97:3)
MeO
O
O
CF3
CF3
F
N
N
N
Ph
Ph
Ph
3n,
3o,
3p,
67%(94:6)
CF3
74%(100:0)
52%(100:0)
CF3
S
CF3
N
N
N
Ph
Ph
Ph
Me
Me
O
3r
3s
, 47%(96:4)
, 65%(96:4)
3q,
59%(0:100)
a Reaction conditions: 1 (0.1 mmol), 2 (1.2 eq), PdCl2 (0.1 eq), L1 (0.2 eq), t-BuONa
(2.0 eq), Toluene (1.0 mL), N2, 120 oC, 24 h.
b
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The ratio of Z/E isomers is shown in parentheses and was determined by F NMR
spectroscopy.
On the basis of previous reports,7b a possible mechanism for this transformation
was proposed in Scheme 1. Firstly, the Pd(0) species is produced in situ from the
reduction of PdCl2 with phosphorus ligand. Then, oxidative addition of Pd(0) with
vinyl chloride 1a generates Pd(II) intermediate A. Intramolecular cis-addition of Pd(II)
to the carbon-carbon triple bond provides cis-isomer of vinylpalladium complex B.
Subsequently, ligand exchange with indole in the presence of t-BuONa gives
intermediate C. Finally, reductive elimination process delivers the target
indenylmethyleneindole 3a, and regenerates the Pd(0) species.
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CF3
Cl
CF3
PdCl
1a
Ph
PdCl2
Pd(0)
+ L1
9
A
Ph
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3a
cis-addition
CF3
N
CF3
H
t-BuONa
Pd N
Ph
PdCl
B
C
Ph
Scheme 1. Possible Mechanism.
CONCLUSIONS
In conclusion, we have developed a facile method for the synthesis of
CF3-containing
indenylmethyleneindoles.
A
variety
compatible
of
o-alkynyl-β-chloro-β-trifluoromethylstyrenes
were
to
the
palladium-catalyzed cascade carbocyclization and hetroarylation with various indoles
and pyrroles, affording the corresponding indenylmethylene-indoles/pyrroles in
moderate to good yields. This simple synthetic protocol provides new route to the
trifluoromethylated polycyclic molecules bearing indene and indole moieties, which
might be potentially useful in medicine chemistry.
EXPERIMENTAL SECTION
General Information
1
Chemicals were either purchased or purified by standard techniques. H NMR
and C NMR spectra were measured on a 500 MHz spectrometer (1H: 500 MHz,
13
13C{1H}: 125 MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as
an internal standard at room temperature. Chemical shifts are given in δ relative to
TMS, the coupling constants J are given in Hz. 19F NMR spectra were recorded on
a 500MHz spectrometer (19F at 470 MHz) and are reported relative to the CDCl3
as the internal standard. High resolution mass spectra were recorded on an
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ESI-Q-TOF mass spectrometry. All reactions under N2 atmosphere were
conducted using standard Schlenk techniques. Melting points were measured on
X4 melting point apparatus and uncorrected. Column chromatography was
performed using EM Silica gel 60 (300-400 mesh).
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General Procedure for the Synthesis of 1-bromo-2-(2-chloro-3,3,3-
trifluoroprop-1-en-1-yl)benzene
Zn (3923.4 mg, 60.0mmol), 2-bromobenzaldehyde (5550.6 mg, 30.0 mmol),
CF3CCl3 (8432.1 mg, 45.0 mmol) were added to DMF (20 mL) at room temperature
for 1 h. After stirring, the mixture was stirring at 50 °C for 24 hours. Then, Zn
(1961.7 mg, 30.0 mmol) and acetic anhydride (4.23 mL, 45.0 mmol) were added to
the mixture and the reaction was stirring for further 12 h. After the reaction was
complete, the reaction mixture was washed with saturated brine twice and extracted
with diethyl ether. The organic phase was dried over sodium sulfate and evaporated
under vacuum. The resulting oil was purified by column chromatography using
petroleum ether /EtOAc = 30:1 as the eluent on silica gel.
General Procedure for the Synthesis of 1-(2-chloro-3,3,3-trifluoroprop-1-
en-1-yl)-2-(phenylethynyl)benzene 11
Pd(Ph3P)2Cl2 (0.1 mmol, 70.2 mg), CuI (0.05 mmol, 9.6 mg),
1-bromo-2-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)benzene (5.0 mmol, 1427.4 mg)
were added to Et3N (20 mL) at room temperature. The flask was filled with nitrogen.
Ethynylbenzene (10.0 mmol, 1021.3 mg) was added dropwise to the mixture by a
syringe. After stirring at room temperature for 10 min, the mixture was stirred at 60
°C overnight. The reaction mixture was washed with saturated brine twice and
extracted with diethyl ether. The organic phase was dried over sodium sulfate and
evaporated under vacuum. The resulting oil was purified by column chromatography
using petroleum ether/EtOAc = 100:1 as the eluent on silica gel.
General Procedure for the Synthesis of 1-(phenyl(2-(trifluoromethyl)-
1H-inden-1-ylidene)methyl)-1H-indole derivatives 3a-3s
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To a flame-dried Schlenk tube with a magnetic stirring bar was charged with 1
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6
(0.1
mmol),
2
(0.12
mmol),
PdCl2
(1.8
mg,
0.01
mmol),
7
8
9
2-(dicyclohexylphosphino)biphenyl (0.02 mmol, 7.0 mg) and t-BuONa (19.2 mg, 0.2
mmol) in toluene (1 mL) under N2 atmosphere. The reaction mixture was stirred at
120 °C for 24 h. After the reaction was finished, the mixture was washed with ethyl
acetate and the combined organic layers were evaporated under vacuum. The residue
was purified by flash column chromatography using petroleum ether/EtOAc =
100:1-30:1 to afford the desired products 3a-3s.
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(Z)-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3a)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as a yellow solid (27.9 mg, 72% yield, Z/E =
98:2), m.p. 104-106 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.65 (d, J = 8.0 Hz, 1H),
7.50 (s, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.41-7.38 (m, 3H), 7.32-7.30 (m, 2H),
7.16-7.11 (m, 2H), 7.01-7.00 (m, 1H), 6.99-6.96 (m, 1H), 6.94-6.91 (m, 1H) ，
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6.74-6.72 (m, 2H), 6.01 (d, J = 7.5 Hz, 1H); C{1H} NMR (125 MHz, CDCl3) δ:
143.4, 138.0, 137.2, 136.8, 136.7, 136.5, 132.4, 132.0, 131.3, 130.6, 130.2, 129.3 (q,
JC-F = 33.75 Hz), 128.2, 127.8, 127.4, 123.6, 123.3, 123.0 (q, JC-F = 268.75 Hz), 122.7,
121.8, 121.3, 112.7, 106.7; 19F NMR (470 MHz, CDCl3) δ: -53.67 (s, 2.96 F), -57.52
(s, 0.04 F); LRMS (EI, 70 eV) m/z (%): 387 (M+, 39); HRMS (ESI) Calcd for
C25H17F3N+ ([M + H]+) 388.1308, Found: 388.1306.
(Z)-3-methyl-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3b) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 100:1, v/v) affords the title compound as an orange solid (27.3 mg, 68%
yield, Z/E = 97:3), m.p. 121-124 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.62 (d, J
= 8.0 Hz, 1H), 7.54-7.51 (m, 2H), 7.47-7.43 (m, 2H), 7.39-7.36 (m, 3H), 7.21-7.17 (m,
2H), 7.02-7.00 (m, 1H), 6.98-6.96 (m, 1H), 6.83 (s, 1H), 6.69 (d, J = 8.5 Hz, 1H),
13
6.15 (d, J = 8.5 Hz, 1H), 2.37 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ: 143.7,
137.9, 137.4, 137.1, 136.5, 135.9, 132.4, 131.2, 131.1, 129.3 (q, JC-F = 33.75 Hz),
128.2, 128.0, 127.6, 127.0, 126.1, 123.6, 123.3, 123.1 (q, JC-F = 268.75 Hz), 122.6,
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121.5, 119.3, 116.3, 112.8, 9.81; F NMR (470 MHz, CDCl3) δ: -53.64 (s, 2.90 F),
5
6
7
8
-57.44 (s, 0.10 F),; LRMS (EI, 70 eV) m/z (%): 401 (M+, 62); HRMS (ESI) Calcd for
C26H19F3N+ ([M + H]+) 402.1464, Found: 402.1455.
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(Z)-5-methyl-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole (3c)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as an orange oil (29.7 mg, 74% yield, Z/E =
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98:2); H NMR (500 MHz, CDCl3, TMS) δ: 7.53 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H),
7.46-7.43 (m, 4H), 7.38-7.35 (m, 1H), 7.32-7.31 (m, 1H), 7.22-7.19 (m, 1H), 7.01 (d,
J = 3.0 Hz, 1H), 6.99-6.97 (m, 1H), 6.83 (d, J = 8.5 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H),
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6.60 (d, J = 8.5 Hz, 1H), 6.10 (d, J = 8.0 Hz, 1H), 2.43 (s, 3H); C{1H} NMR (125
MHz, CDCl3) δ: 143.7, 138.0, 137.2, 136.55, 136.48, 135.0, 132.6, 131.9, 131.3,
130.9, 130.6, 129.3 (q, JC-F = 33.75 Hz), 128.2, 127.7, 127.3, 126.8, 124.8, 123.6,
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123.0 (q, JC-F = 268.75 Hz), 122.7, 121.0, 112.5, 106.4, 21.5; F NMR (470 MHz,
CDCl3) δ: −53.67 (s, 2.94 F), −57.46 (s, 0.06 F); LRMS (EI, 70 eV) m/z (%): 401 (M+,
48); HRMS (ESI) Calcd for C26H19F3N+ ([M + H]+) 402.1464, Found: 402.1460.
(Z)-6-methyl-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3d) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 100:1, v/v) affords the title compound as a yellow solid (24.9 mg, 62% yield,
o
1
Z/E = 98:2), m.p. 118-121 C; H NMR (500 MHz, CDCl3, TMS) δ: 7.56 (s, 1H),
7.55-7.54 (m, 1H), 7.51 (d, J = 7.5 Hz, 1H), 7.46-7.44 (m, 3H), 7.38-7.35 (m, 1H),
7.32 (d, J = 7.5 Hz, 1H), 7.22-7.19 (m, 1H), 7.00-6.96 (m, 3H), 6.72 (d, J = 3.5 Hz,
13
1H), 6.52 (s, 1H), 6.07 (d, J = 3.5 Hz, 1H), 2.22 (s, 3H); C{1H} NMR (125 MHz,
CDCl3) δ: 143.7, 138.0, 137.3, 137.1, 136.7, 136.5, 133.1, 132.6, 131.9, 131.2, 130.1,
129.3 (q, JC-F = 33.75 Hz), 128.2, 128.0, 127.8, 127.3, 123.6, 123.5, 123.0 (q, JC-F
=
268.75 Hz), 122.7, 120.8, 112.7, 106.5, 21.9; 19F NMR (470 MHz, CDCl3) δ: −53.67
(s, 2.96 F), −57.57 (s, 0.04 F); LRMS (EI, 70 eV) m/z (%): 401 (M+, 94); HRMS (ESI)
Calcd for C26H19F3N+ ([M + H]+) 402.1464, Found: 402.1477.
(Z)-7-methyl-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole (3e)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as a yellow oil (23.3 mg, 58% yield, Z/E =
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100:0); 1H NMR (500 MHz, CDCl3, TMS) δ: 7.58 (d, J = 8.0 Hz , 1H), 7.56 (s, 1H),
7.52-7.48 (m, 1H), 7.41-7.40 (m, 5H), 7.18-7.15 (m, 1H), 7.13-7.10 (m, 1H), 6.90 (d,
J = 3.0 Hz, 2H), 6.87-6.84 (m, 1H), 6.77 (d, J = 3.0 Hz, 1H), 5.62 (d, J = 8.0 Hz, 1H),
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2.00 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ: 143.9, 138.8, 138.7, 138.0, 137.5,
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136.6, 136.2, 132.7, 131.2, 130.5, 130.3, 129.5, 128.8 (q, JC-F = 33.75 Hz), 128.2,
127.7, 126.4, 123.0 (q, JC-F = 267.5 Hz), 122.80, 122.77, 121.9, 119.4, 106.3, 19.9;
19F NMR (470 MHz, CDCl3) δ: −53.72 (s, 3.00 F); LRMS (EI, 70 eV) m/z (%): 401
(M+, 26); HRMS (ESI) Calcd for C26H18F3NaN+ ([M + Na]+) 424.1284, Found:
424.1278.
(Z)-5-methoxy-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3f) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 50:1, v/v) affords the title compound as a red oil (30.9 mg, 74% yield, Z/E =
1
97:3); H NMR (500 MHz, CDCl3, TMS) δ: 7.53-7.50 (m, 2H), 7.45-7.40 (m, 3H),
7.36 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 1H), 7.22-7.19 (m, 1H), 7.12 (d, J = 2.0
Hz, 1H), 7.01 (d, J = 3.5 Hz, 1H), 6.99-6.97 (m, 1H), 6.70 (d, J = 3.5 Hz, 1H),
6.65-6.63 (m, 1H), 6.60-6.58 (m, 1H), 6.10 (d, J = 7.5 Hz, 1H), 3.84 (s, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ: 155.5, 143.7, 138.0, 137.2, 136.5, 136.4, 132.6, 132.0,
131.7, 131.4, 131.0, 129.3 (q, JC-F = 33.75 Hz), 128.2, 127.7, 127.2, 126.7, 123.6,
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123.0 (q, JC-F = 268.75 Hz), 122.7. 113.6, 112.9, 106.6, 103.2, 55.8; F NMR (470
MHz, CDCl3) δ: 19F NMR (470 MHz, CDCl3) δ: −53.72 (s, 2.93 F), −57.42 (s, 0.07 F);
LRMS (EI, 70 eV) m/z (%): 417 (M+, 46); HRMS (ESI) Calcd for C26H19F3NO+ ([M
+ H]+) 418.1413, Found: 418.1408.
(Z)-5-fluoro-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole (3g)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
75:1, v/v) affords the title compound as a yellow Solid (24.7 mg, 61% yield, Z/E =
94:6), m.p. 114-117 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.53-7.49 (m, 2H), 7.45
(d, J = 7.0 Hz, 2H), 7.41-7.38 (m, 2H), 7.31 (d, J = 9.0 Hz, 2H), 7.23-7.20 (m, 1H),
7.08 (s, 1H), 6.99-6.96 (m, 1H), 6.76-6.73 (m, 2H), 6.67-6.64 (m, 1H), 6.01 (d, J =
7.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3) δ: 158.9 (d, JC-F = 236.25 Hz), 143.1,
138.1, 137.14, 137.12, 136.4, 133.2, 132.3, 132.0, 131.4, 130.8 (d, JC-F = 10.0 Hz),
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129.3 (q, JC-F = 33.75 Hz), 128.3, 127.9, 127.7, 127.6, 123.5, 122.9 (q, JC-F = 268.75
Hz) , 122.8, 113.5 (d, JC-F = 10.0 Hz), 111.6 (d, JC-F = 26.25 Hz), 111.4, 106.5, 106.4
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(d, JC-F =26.25 Hz); F NMR (470 MHz, CDCl3) δ: −53.86 (s, 2.82 F), −57.64 (s,
9
0.18 F), −122.12 (s, 0.94 F), −122.94 (s, 0.06 F); LRMS (EI, 70 eV) m/z (%): 405
(M+, 21); HRMS (ESI) Calcd for C25H16F4N+ ([M + H]+) 406.1213, Found: 406.1239.
(Z)-5-chloro-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole (3h)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as a yellow solid (32.0 mg, 76% yield, Z/E =
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97:3) m.p. 117-119 C; H NMR (500 MHz, CDCl3, TMS) δ: 7.64 (s, 1H), 7.54 (s,
1H), 7.52 (d, J = 7.0 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.40-7.36 (m, 2H), 7.31 (d, J =
7.0 Hz, 1H), 7.23-7.20 (m, 1H), 7.07 (d, J = 3.0 Hz, 1H), 6.99-6.95 (m, 2H), 6.71 (d, J
= 3.0 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 5.99 (d, J = 8.0 Hz, 1H); 13C{1H} NMR (125
MHz, CDCl3) δ: 142.7, 138.1, 137.4, 136.9, 136.3, 132.3, 131.9, 131.8, 131.5, 131.2,
129.2 (q, JC-F = 33.75 Hz), 128.3, 128.0, 127.8, 127.7, 127.4, 123.6, 123.5, 122.91,
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122.88 (q, JC-F = 268.75 Hz), 120.8, 113.6, 106.0; F NMR (470 MHz, CDCl3) δ:
−53.86 (s, 2.92F), −57.64 (s, 0.08F); LRMS (EI, 70 eV) m/z (%): 421 (M+, 32);
HRMS (ESI) Calcd for C25H16F3ClN+ ([M + H]+) 422.0918, Found: 422.0941.
(Z)-6-chloro-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole (3i)
Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as a yellow solid (28.6 mg, 68% yield, Z/E =
o
1
100:0), m.p. 120-122 C; H NMR (500 MHz, CDCl3, TMS) δ: 7.59 (d, J = 7.5 Hz,
1H), 7.56 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.5 Hz, 2H), 7.41-7.37 (m,
2H), 7.32-7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.14 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 3.5
Hz, 1H), 6.98 (d, J = 7.5 Hz, 1H), 6.75 (d, J = 7.5 Hz, 2H), 5.99 (d, J = 7.5 Hz, 1H);
13C{1H} NMR (125 MHz, CDCl3) δ: 142.6, 138.2, 137.7, 137.0, 136.8, 136.2, 132.3,
131.7, 131.5, 131.2, 129.23, 129.22 (q, JC-F = 33.75 Hz), 128.6, 128.4, 128.0, 127.8,
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123.5, 123.0, 122.9 (q, JC-F = 268.75 Hz), 122.5, 122.1, 112.6, 106.4; F NMR (470
MHz, CDCl3) δ: −53.85 (s, 3.00 F); LRMS (EI, 70 eV) m/z (%): 421 (M+, 100);
HRMS (ESI) Calcd for C25H16F3ClN+ ([M + H]+) 422.0918, Found: 422.0931.
(Z)-1-(p-tolyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3j)
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Purification by column chromatography on silica gel (petroleum ether/ethyl acetate =
100:1, v/v) affords the title compound as an orange oil (28.1 mg, 70% yield, Z/E =
7
8
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100:0); H NMR (500 MHz, CDCl3, TMS) δ: 7.69 (d, J = 7.5 Hz, 1H), 7.54 (s, 1H),
9
7.46 (d, J = 7.5 Hz, 1H), 7.32-7.28 (m, 2H), 7.23-7.16 (m, 4H), 7.06 (d, J = 3.5 Hz,
1H), 7.04-7.01 (m, 1H), 6.98-6.95 (m, 1H), 6.78 (d, J = 3.5 Hz, 1H), 6.76 (d, J = 7.5
Hz, 1H), 6.02 (d, J = 7.5 Hz, 1H), 2.46 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ:
143.7, 142.0, 138.0, 136.8, 136.5, 136.3, 134.4, 132.5, 132.1, 130.7, 130.2, 129.3 (q,
JC-F = 33.75 Hz), 129.0, 127.6, 127.2, 123.5, 123.2, 123.1 (q, JC-F = 268.75 Hz), 122.7,
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121.8, 121.2, 112.8, 106.6, 21.8; F NMR (470 MHz, CDCl3) δ: −53.57 (s, 3.00 F);
LRMS (EI, 70 eV) m/z (%): 401 (M+, 46); HRMS (ESI) Calcd for C26H18F3NaN+ ([M
+ Na]+) 424.1284, Found: 424.1276.
(Z)-1-((4-methoxyphenyl)(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-indole
(3k) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 75:1, v/v) affords the title compound as a red oil (28.8 mg, 69% yield, Z/E =
1
99:1); H NMR (500 MHz, CDCl3, TMS) δ: 7.58 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H),
7.34 (d, J = 7.5 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.09-7.04
(m, 2H), 6.96 (d, J = 3.5 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 6.87-6.83 (m, 2H), 6.77 (d,
J = 7.5 Hz, 1H), 6.67 (d, J = 3.5 Hz, 1H), 6.62 (d, J = 8.0 Hz, 1H), 5.89 (d, J = 8.0 Hz,
13
1H), 3.78 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ: 162.5, 143.6, 137.9, 136.8,
136.6, 135.8, 134.4, 133.9, 130.8, 130.3, 129.3 (q, JC-F = 33.75 Hz), 127.5, 127.0,
125.8, 123.3, 123.22, 123.19 (q, JC-F = 268.75 Hz), 122.6, 121.8, 121.2, 113.8, 112.9,
19
106.6, 55.5; F NMR (470 MHz, CDCl3) δ: −53.56 (s, 2.98 F), −57.45 (s, 0.02 F);
LRMS (EI, 70 eV) m/z (%): 417 (M+, 100); HRMS (ESI) Calcd for C26H18F3NaNO+
([M + Na]+) 440.1233, Found: 440.1233.
(Z)-1-(1-(2-(trifluoromethyl)-1H-inden-1-ylidene)pentyl)-1H-indole (3l) Purification
by column chromatography on silica gel (petroleum ether/ethyl acetate = 100:1, v/v)
affords the title compound as a yellow solid (13.2 mg, 36% yield, Z/E = 93:7), m.p.
112-114 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.62 (d, J = 7.5 Hz, 1H), 7.41 (d, J
= 7.5 Hz, 1H), 7.24-7.18 (m, 3H), 7.14-7.11 (m, 2H), 7.05-7.02 (m, 1H), 6.72 (d, J =
7.5 Hz, 1H), 6.59 (s, 1H), 6.06 (d, J = 7.5 Hz, 1H), 3.77-3.72 (m, 2H), 2.17-2.12 (m,
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2H), 1.50-1.45(m, 2H), 0.89 (t, J = 7.5 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ:
145.3, 142.8, 141.4, 136.3, 132.4, 131.1 (q, JC-F = 33.75 Hz), 128.8, 128.2, 128.1,
127.4, 127.3, 124.1, 123.7 (q, JC-F = 268.75 Hz), 122.5, 121.7, 121.2, 120.3, 111.4,
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103.6, 38.1, 30.7, 22.4, 13.8; F NMR (470 MHz, CDCl3) δ: −56.26 (s, 2.79 F),
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−63.70 (s, 0.21 F); LRMS (EI, 70 eV) m/z (%): 367 (M+, 51); HRMS (ESI) Calcd for
C23H21F3N+ ([M + H]+) 368.1621, Found: 368.1612.
(Z)-1-((6-methyl-2-(trifluoromethyl)-1H-inden-1-ylidene)(phenyl)methyl)-1H-indole
(3m) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 100:1, v/v) affords the title compound as an orange oil (22.8 mg, 57% yield,
Z/E = 97:3); 1H NMR (500 MHz, CDCl3, TMS) δ: 7.67 (d, J = 7.5 Hz, 1H), 7.52-7.49
(m, 2H), 7.46-7.42 (m, 2H), 7.35 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.5 Hz, 2H),
7.16-7.13 (m, 1H), 7.04-6.99 (m, 3H), 6.77-6.73 (m, 2H), 5.81 (s, 1H), 2.03 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ: 142.9, 137.9, 137.3, 137.0, 136.8, 136.7, 135.6,
132.4, 131.2, 130.6, 130.2, 128.3, 128.19, 128.16 (q, JC-F = 33.75 Hz), 127.6, 124.5,
123.2, 123.1 (q, JC-F = 268.75 Hz), 122.4, 121.7, 121.2, 112.8, 106.4, 21.9; 19F NMR
(470 MHz, CDCl3) δ: −53.73 (s, 2.91 F), −57.59 (s, 0.09 F); LRMS (EI, 70 eV) m/z
(%): 401 (M+, 38); HRMS (ESI) Calcd for C26H19F3N+ ([M + H]+) 402.1464, Found:
402.1473.
(Z)-1-((5-methoxy-2-(trifluoromethyl)-1H-inden-1-ylidene)(phenyl)methyl)-1H-indole
(3n) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 100:1, v/v) affords the title compound as a yellow oil (27.9 mg, 67% yield,
Z/E = 94:6); 1H NMR (500 MHz, CDCl3, TMS) δ: 7.67 (d, J = 7.5 Hz, 1H), 7.49-7.47
(m, 2H), 7.46 (s, 1H), 7.41-7.33 (m, 4H), 7.16-7.13 (m, 1H), 7.03-6.99 (m, 2H), 6.95
(s, 1H), 6.77 (d, J = 8.5 Hz, 1H), 6.73 (s, 1H), 6.49 (d, J = 8.5 Hz, 1H), 5.90 (d, J =
13
7.5 Hz, 1H), 3.78 (s, 3H); C{1H} NMR (125 MHz, CDCl3) δ: 159.6, 141.7, 139.6,
137.4, 136.8, 136.7, 131.9, 131.0, 130.4, 130.2, 130.0, 129.6 (q, JC-F = 33.75 Hz),
128.2, 127.6, 124.8, 123.2, 122.9 (q, JC-F = 268.75 Hz), 121.7, 121.2, 114.0, 112.7,
107.8, 106.3, 55.6; 19F NMR (470 MHz, CDCl3) δ: −53.86 (s, 2.83 F), −57.80 (s, 0.17
F); LRMS (EI, 70 eV) m/z (%): 417 (M+, 37); HRMS (ESI) Calcd for C26H19F3NO+
([M + H]+) 418.1413, Found: 418.1438.
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(Z)-1-(phenyl(6-(trifluoromethyl)-5H-indeno[5,6-d][1,3]dioxol-5-ylidene)methyl)-1H-
indole (3o) Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate = 100:1, v/v) affords the title compound as a yellow solid (31.9 mg,
74% yield, Z/E = 100:0), m.p. 123-125 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.66
(d, J = 7.5 Hz, 1H), 7.52-7.49 (m, 1H), 7.44-7.41 (m, 1H), 7.38-7.36 (m, 2H), 7.34 (d,
J = 7.5 Hz, 1H), 7.30 (d, J = 7.5 Hz, 1H), 7.17-7.14 (m, 1H), 7.04-7.01 (m, 2H), 6.86
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(s, 1H), 6.77-6.75 (m, 2H), 5.86 (s, 1H), 5.83 (s, 1H), 5.45 (s, 1H); C{1H} NMR
(125 MHz, CDCl3) δ: 148.2, 147.5, 142.9, 137.2, 136.64, 136.61, 132.8, 132.4, 132.1,
131.3, 131.2, 130.4, 130.2, 128.2, 127.5 (q, JC-F = 33.75 Hz), 123.3, 122.9 (q, JC-F
=
19
268.75 Hz), 121.9, 121.4, 112.6, 106.8, 104.7, 102.9, 101.3; F NMR (470 MHz,
CDCl3) δ: −53.33 (s, 3.00 F); LRMS (EI, 70 eV) m/z (%): 431 (M+, 76); HRMS (ESI)
+
Calcd for C26H17F3NO2 ([M + H]+) 432.1206, Found: 432.1228.
(Z)-1-((6-fluoro-2-(trifluoromethyl)-1H-inden-1-ylidene)(phenyl)methyl)-1H-indole
(3p) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 75:1, v/v) affords the title compound as a yellow solid (21.0 mg, 52% yield,
Z/E = 100:0), m.p. 121-123 oC; 1H NMR (500 MHz, CDCl3, TMS) δ: 7.69 (d, J = 7.5
Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.49 (s, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.41-7.36 (m,
3H), 7.34 (d, J = 7.5 Hz, 1H), 7.19-7.16 (m, 1H), 7.04-7.01 (m, 2H), 6.93-6.89 (m,
13
1H), 6.81 (d, J = 7.5 Hz, 1H), 6.73 (d, J = 7.5 Hz, 1H), 5.74-5.72 (m, 1H); C{1H}
NMR (125 MHz, CDCl3) δ: 163.2 (d, JC-F = 243.75 Hz), 144.6, 138.2 (d, JC-F = 8.75
Hz), 136.9, 136.6, 135.8, 134.1, 132.5, 132.1, 131.8, 131.6, 130.4, 129.2 (q, JC-F
=
33.75 Hz), 128.3, 123.6 (d, JC-F = 8.75 Hz), 123.5, 122.8 (q, JC-F = 268.75 Hz), 122.1,
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121.5, 114.6 (d, JC-F = 23.75 Hz), 112.6, 111.0 (d, JC-F = 26.25 Hz), 107.3; F NMR
(470 MHz, CDCl3) δ: −53.88 (s, 3.00 F), -113.31 (s, 1.00 F); LRMS (EI, 70 eV) m/z
(%): 405 (M+, 49); HRMS (ESI) Calcd for C25H16F4N+ ([M + H]+) 406.1213, Found:
406.1234.
(E)-1-(phenyl(5-(trifluoromethyl)-4H-cyclopenta[b]thiophen-4-ylidene)methyl)-1H-in
dole (3q) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 50:1, v/v) affords the title compound as a red oil (23.2 mg, 59% yield, Z/E =
0:100); 1H NMR (500 MHz, CDCl3, TMS) δ: 7.66 (d, J = 7.5 Hz, 1H), 7.55-7.51 (m,
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1H), 7.42-7.38 (m, 5H), 7.17-7.14 (m, 1H), 7.11 (d, 3.5 Hz, 1H), 7.03-7.00 (m, 2H),
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6.76-6.74 (m, 2H), 5.65 (d, J = 3.5 Hz, 1H); C{1H} NMR (125 MHz, CDCl3) δ:
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144.7, 143.0, 138.8, 137.2, 136.4, 132.4, 131.6, 131.1, 130.9, 130.2, 128.7, 128.3,
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126.9 (q, JC-F = 33.75 Hz), 124.7, 123.3, 122.7 (q, JC-F = 268.75 Hz), 122.4, 121.9,
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121.3, 112.8, 106.6; F NMR (470 MHz, CDCl3) δ: −52.56 (s, 3.00 F); LRMS (EI,
70 eV) m/z (%): 393 (M+, 43); HRMS (ESI) Calcd for C23H15F3NS+ ([M + H]+)
394.0872, Found: 394.0882.
(Z)-3-methyl-1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-pyrrole
(3r) Purification by column chromatography on silica gel (petroleum ether/ethyl
acetate = 100:1, v/v) affords the title compound as an orange oil (22.8 mg, 65% yield,
1
Z/E = 96:4); H NMR (500 MHz, CDCl3, TMS) δ: 7.52-7.50 (m, 1H), 7.46 (s, 1H),
7.44 (d, J = 7.5 Hz, 1H), 7.42-7.39 (m, 2H), 7.36-7.33 (m, 2H), 7.26-7.23 (m, 1H),
7.17-7.14 (m, 1H), 6.60-6.59 (m, 1H), 6.44-6.42 (m, 2H), 6.22 (s, 1H), 2.14 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ: 145.7, 137.9, 137.4, 137.1, 136.0, 132.6, 132.4,
131.2, 129.5 (q, JC-F = 33.75 Hz), 127.9, 127.5, 127.1, 124.4, 123.5, 123.0 (q, JC-F
=
268.75 Hz), 122.7, 122.5, 121.6, 113.7, 12.1; 19F NMR (470 MHz, CDCl3) δ: −53.93
(s, 2.89 F), -56.55 (s, 0.11 F); LRMS (EI, 70 eV) m/z (%): 351 (M+, 68); HRMS (ESI)
Calcd for C22H17F3N+ ([M + H]+) 352.1308, Found: 352.1308.
(Z)-1-(1-(phenyl(2-(trifluoromethyl)-1H-inden-1-ylidene)methyl)-1H-pyrrol-3-yl)etha
n-1-one (3s) Purification by column chromatography on silica gel (petroleum
ether/ethyl acetate = 30:1, v/v) affords the title compound as a red solid (17.8 mg,
o
1
47% yield, Z/E = 96:4) m.p. 113-115 C; H NMR (500 MHz, CDCl3, TMS) δ:
7.54-7.52 (m, 2H), 7.45-7.41 (m, 3H), 7.34-7.32 (m, 3H), 7.28 (d, J = 7.5 Hz, 1H),
7.15-7.12 (m, 1H), 6.81 (s, 1H), 6.70 (s, 1H), 6.23 (d, J = 7.5 Hz, 1H), 2.40 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ: 193.5, 143.5, 138.6, 138.3, 136.6, 136.3, 132.0,
131.6, 129.4 (q, JC-F = 33.75 Hz), 128.5, 128.32, 128.30, 128.25, 125.4, 123.4, 123.1,
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122.6 (q, JC-F = 268.75 Hz), 111.2, 27.4; F NMR (470 MHz, CDCl3) δ: −54.39 (s,
2.88 F), −56.95 (s, 0.12 F); LRMS (EI, 70 eV) m/z (%): 379 (M+, 47); HRMS (ESI)
Calcd for C23H16F3NaNO+ ([M + Na]+) 402.1076, Found: 402.1098.
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SUPPLEMENTARY INFORMATION
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Copies of H and 13C NMR spectra for products 3a-3s and X-ray data for
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compound 3a. This material is available free of charge via the Internet at
http://pubs.acs.org.
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Supplementary crystallographic data was deposited at the Cambridge
Crystallographic Data Centre (CCDC) under the number CCDC-1881771 (3a) and
can be obtained free of charge from via www.ccdc.cam.ac.uk/data_request.cif.
ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China (No. 21272177), Natural
Science Foundation of Zhejiang Province (No. LR15B020002) and Project of
Wenzhou Science and Technology Bureau (W20170003) for financial supports.
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(11) These compounds were prepared by the reaction of 2-bromobenzaldehyde with
CF3CCl3, followed by a Sonogashira reaction with phenylacetylene. The detailed
reaction process with the measured spectroscopic data can be seen in our reported ref:
Shi, S.; Sun, L-L.; Liao, Z-Y.; Zhang, X-G. Copper-Catalyzed Thiolation Cyclization
of 1-Chloro-1,5-enynes with Sodium Hydrosulfide: Synthesis of CF3-Containing
1H-Isothiochromenes. Synthesis 2012, 44, 966-972.
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