A dramatic enhancing effect of InBr3 towards the oxidative Sonogashira cross-coupling reaction of 2-ethynylanilines

Article abstract of DOI:10.1039/c5ob02558c

The addition of InBr₃ to the oxidative Sonogashira cross-coupling reaction of 2-ethynylaniline with (E)-trimethyl(3,3,3-trifluoroprop-1-enyl)silane led to a dramatic increase in the reactivity to afford the corresponding 1,3-enynes bearing a trifluoromethyl group on their terminal sp² carbon. The subsequent cyclization of these 1,3-enynes under palladium catalysis provides access to the corresponding indoles bearing a 3,3,3-trifluoroprop-1-enyl group at their 2-position.

Full text of DOI:10.1039/c5ob02558c

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A dramatic enhancing effect of InBr3 towards the
oxidative Sonogashira cross-coupling reaction of
2-ethynylanilines†
Cite this: DOI: 10.1039/c5ob02558c
A. Ikeda, M. Omote, K. Kusumoto, M. Komori, A. Tarui, K. Sato and A. Ando*
The addition of InBr3 to the oxidative Sonogashira cross-coupling reaction of 2-ethynylaniline with (E)-tri-
methyl(3,3,3-trifluoroprop-1-enyl)silane led to a dramatic increase in the reactivity to afford the corres-
ponding 1,3-enynes bearing a trifluoromethyl group on their terminal sp2 carbon. The subsequent
cyclization of these 1,3-enynes under palladium catalysis provides access to the corresponding indoles
bearing a 3,3,3-trifluoroprop-1-enyl group at their 2-position.
Received 14th December 2015,
Accepted 11th January 2016
DOI: 10.1039/c5ob02558c
www.rsc.org/obc
Introduction
The Sonogashira cross-coupling reaction has been widely used
as an effective method for the formation of carbon–carbon
bonds in organic synthesis.1 The importance of this reaction is
exemplified by its regular use in agrochemical and pharma-
ceutical research, where it has featured as a key step in the Scheme 1 Remarkable increase in the yield of 1,3-enyne containing
the nitrogen atom. aNMR yield, which was calculated by the integration
of the 19F NMR signals relative to an ethyl trifluoroacetate standard.
construction of numerous natural products and biologically
active compounds.2–5 For example, the functionalized indole
scaffolds of many important medicinal agents, such as the anti-
cancer drug vinblastine and antiviral drug staurosporine,6–8 are
synthesized from functionalized 2-ethynylaniline derivatives,
which are prepared by Sonogashira cross-coupling
overcome these issues. After screening a variety of different
reaction conditions, we discovered that the addition of Ag2CO3
and InBr3 to the reaction mixture led to a dramatic increase in
the yield of the reaction (Scheme 1). Furthermore, the sub-
sequent cyclization of the 2-ethynylaniline derivatives prepared
in this way proceeded smoothly under palladium catalysis to
afford the corresponding indole rings bearing a variety of
different substituents. Herein, we describe the details of these
reactions as well as highlight the broad scope of this process.
a
reaction.9–11 Considerable research interest has therefore been
directed towards the development of efficient methods for the
Sonogashira cross-coupling reaction to provide facile access to a
broad range of enynes, which play a key role in the construction
of other complicated compounds.12–22
We recently reported the oxidative Sonogashira cross-coup-
ling reaction of (E)-trimethyl(3,3,3-trifluoroprop-1-enyl)silane
(1) as an effective trifluoropropenylation reagent for the facile
synthesis of 1,3-enynes bearing a trifluoromethyl group on
their terminal sp2 carbon.23,24 However, the scope of this reac-
tion was found to be limited in the sense that some substrates
bearing an electron-withdrawing group or an nitrogen atom on
their phenyl ring afforded poor yields of the corresponding
1,3-enynes. To successfully expand upon the scope of this
transformation we need to identify new reaction conditions to
Results and discussion
We initially examined the use of Ag2CO3 as a silver source
instead of AgF, which can act as an oxidant towards the palla-
dium catalyst (Table 1). Of the many different fluoride anion
sources evaluated in the current study, TBAF provided the
highest yield for the Sonogashira cross-coupling reaction of 2a
and 1, with 3a being isolated in 69% yield (Table 1, entries
2–4). Increasing the number of equivalents of TBAF added to
the reaction led to an increase in the yield of the product
(Table 1, entries 5 and 6). The use of Pd(OAc)2, which was used
as a catalyst in our previous report, led to a lower yield of the
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho,
Hirakata, Osaka 573-0101, Japan. E-mail: aando@pharm.setsunan.ac.jp
†Electronic supplementary information (ESI) available: Synthesis and character-
ization of compounds, copies of 1H NMR and 13C NMR spectra and HRMS data.
See DOI: 10.1039/c5ob02558c
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optimized reactions to nitrogen-containing substrates failed to
afford similar increases in the yield. Further investigation is
therefore required for these substrates to fully expand the reac-
tion scope.
Table 1 Optimization of the reaction conditions using Ag2CO3 instead
of AgFa
As shown in Table 2, the reaction conditions with Ag2CO3
produced 3b in poor yield (Table 3, entry 1). Increasing the
temperature of the reaction led to the rapid decomposition of
the starting material (2b) to give a complex mixture (Table 3,
entry 2). It is noteworthy, however, that the addition of InBr3
(0.05 equivalents) led to the formation of 3b with an improved
yield of 48% (Table 3, entry 3). Further investigation of the
number of equivalents of InBr3 required for this reaction
revealed that the optimum results were obtained using a single
equivalent of this additive relative to 2b (Table 3, entries 4–6).
A variety of different Lewis acids were also examined under the
same conditions, including InCl3 and BF3·Et2O, but they were
all found to be ineffective for improving the yield of 3b com-
pared with InBr3 (Table 3, entries 7 and 8). This result suggests
that InBr3 would act as a soft Lewis acid in the reaction
mixture to accelerate the reaction, however, the reason for this
improvement is not clear yet. To further evaluate the scope
and limitations of this reaction, we selected the conditions
described in entry 5 of Table 3 as the optimum reaction
conditions.
Entry
Condition
Yieldb (%)
1c
2
AgF (5 eq.), 1 (4 eq.), Pd(OAc)2 (5 mol%)
CsF (6 eq.), 1 (4 eq.), Ag2CO3 (7.5 eq.)
[Pd(2-methylallyl)Cl]2 (4 mol%)
TASF (6 eq.), 1 (4 eq.), Ag2CO3 (7.5 eq.)
[Pd(2-methylallyl)Cl]2 (4 mol%)
TBAF (6 eq.), 1 (4 eq.), Ag2CO3 (7.5 eq.)
[Pd(2-methylallyl)Cl]2 (4 mol%)
TBAF (7 eq.), 1 (4 eq.), Ag2CO3 (7.5 eq.)
[Pd(2-methylallyl)Cl]2 (4 mol%)
TBAF (10 eq.), 1 (5 eq.), Ag2CO3 (5 eq.)
[Pd(2-methylallyl)Cl]2 (4 mol%)
TBAF (10 eq.), 1 (5 eq.), Ag2CO3 (5 eq.)
Pd(OAc)2 (4 mol%)
102 (93)d
0
3
4
5
6
7
24
69
89
109 (82)d
72
a These reactions were carried out in CH3CN at room temperature.
b NMR yields of 3a, which were calculated by the integration of the 19F
NMR signals of 3a relative to an ethyl trifluoroacetate standard.
c Reaction performed without the addition of H2O. d Isolated yield.
The scope and limitations of our newly developed Sono-
gashira cross-coupling reaction with InBr3 are summarized in
Scheme 2. The results show that substrates bearing an elec-
tron-withdrawing or electron-donating group on their phenyl
ring both reacted smoothly to give the desired 1,3-enynes
bearing a trifluoromethyl group on their terminal sp2 carbon
in moderate to good yields (3c–f, h–l and n). On the other
hand, substrates bearing a NO2 group were rapidly decom-
desired product compared with [Pd(2-methylallyl)Cl]2 (Table 1,
entry 7).
With the optimum reaction conditions in hand we pro-
ceeded to investigate the scope of this transformation towards
substrates bearing an electron-withdrawing group or aniline
on their phenyl ring, especially those that did not react under
our previously reported reaction conditions (Table 2). Pleas-
ingly, considerable improvements were observed in the yield of
3 compared with our previous report for electron-deficient sub-
strates, such as those bearing an acetyl or ester group (Table 2,
entries 1 and 2). Disappointingly, however, application of the
Table 3 Improvement of the reaction conditions in nitrogen-contain-
ing acetylenea
Table 2 The comparison with conditions of AgF and Ag2CO3
Entry
Additiveb (eq.)
Temp. (°C)
Time (h)
Yieldc (%)
1
2
3
4
5
6
7
8
—
—
rt
40
rt
rt
rt
rt
rt
rt
3
1
4
4
4
4
4
11
27
0
48
Yielda
InBr3 (0.05)
InBr3 (0.5)
InBr3 (1)
InBr3 (1.5)
InCl3 (1)
BF3·Et2O (1)
Entry
R =
Condition A
Condition B
76
90 (87)d
44
1b
2b
3
p-Ac
p-EtOCO
o-NH2
65
55
10
12
84
99
27
36
60
Trace
4
6-Quinoline
a The reaction was carried out with 2b (0.2 mmol), 1 (1.0 mmol), TBAF
Condition A: AgF (5 eq.), 1 (4 eq.), Pd(OAc)2 (5 mol%). Condition B: (2.0 mmol), Ag2CO3 (1.0 mmol) and [Pd(2-methylallyl)Cl]2 (4 mol%) in
Ag2CO3 (5 eq.), TBAF (10 eq.),
1
(5 eq.), [Pd(2-methylallyl)Cl]2 CH3CN and H2O. b The number of equivalents with respect to 2b
(4 mol%). a NMR yields of 3, which were calculated by integration of (0.2 mmol). c NMR yields of 3b, which were calculated by the
the 19F NMR signals of 3 relative to an ethyl trifluoroacetate standard. integration of the 19F NMR signals of 3b relative to an ethyl
b Isolated yields.
trifluoroacetate standard. d Isolated yield.
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Scheme 3 The scope and limitation of the cyclization reaction. aThese
reactions were carried out with 4 (0.1 mmol) and Pd(OAc)2 (10 mol%) in
PhMe at 110 °C.
Scheme 2 The oxidative Sonogashira cross-coupling reaction with
InBr3. aThese reactions were carried out with 2 (0.2 mmol), 1 (1.0 mmol),
TBAF (2.0 mmol), Ag2CO3 (1.0 mmol), InBr3 (0.2 mmol) and [Pd(2-
methylallyl)Cl]2 (4 mol%) in CH3CN and H2O at room temperature.
Cl]2. The results of these experiments revealed that Pd(OAc)2
gave the highest yield of 4b (Table 4, entries 4–6). We also
screened several other solvents, including DMF, TBC and
CH3CN, but they all failed to provide an improvement in the
yield of 4b compared with PhMe (Table 4, entries 7–9). When
the reaction was conducted at a lower concentration of 0.05 M,
we observed a considerable increase in the yield of the desired
product, albeit after a longer reaction time (Table 4, entry 10).
With the optimum reaction conditions in hand, we
explored the scope and limitations of this cyclization reaction
using the 1,3-enynes described above, which were prepared
using our newly developed Sonogashira cross-coupling reac-
tion (Scheme 3). The results revealed that the reaction pro-
ceeded well for substrates with an electron-withdrawing or
electron-donating substituent at their 5-position to afford the
posed (3g and m). Acetylenes bearing a variety of different
heterocycles, including a pyridine, indole or quinolone ring,
also reacted smoothly to give the corresponding products,
albeit after an extended reaction time (3o–p).
We then investigated the cyclization reaction of 3b to give
the corresponding indole ring bearing a 3,3,3-trifluoroprop-1-
enyl group at its 2-position (Table 4). A variety of different
additives were examined for this transformation, including
t
Cu(OAc)2, BuLi and InBr3, but they all provided low yields of
4b (Table 4, entries 1–3).25–28 The addition of Pd(PPh3)2Cl2 led
to an increase in the yield of indole 4b to 37% (Table 4, entry
4). Based on this result, we investigated several palladium cata-
lysts, including Pd(PPh3)2Cl2, Pd(OAc)2 and [Pd(2-methylallyl)-
corresponding indoles bearing
a 3,3,3-trifluoroprop-1-enyl
group at their 2-position in good yields (4c–h). In contrast,
substrates with a substituent at their 7-position afforded the
corresponding indole products in poor yields (4j–l, n). Sub-
strates bearing the electron-withdrawing groups (3j–k)
remained in the reaction mixture probably due to their steric
hindrance, regardless of longer reaction time. Notably, the
reaction of 3n bearing a methyl group failed to provide the
desired product 4n with decomposition of the starting
material.
Table 4 Optimization of the conditions for the cyclization reactiona
Entry
Additiveb (eq.)
Solv.
Yieldc (%)
Conclusions
1
2
3
4
5
6
7
8
Cu(Ac)2(1.0)
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
TBC
CH3CN
PhMe
16
0
tBuOLi (1.0)
In summary, we have found that the use of InBr3 is effective
for the oxidative Sonogashira cross-coupling reaction of 2-ethy-
nylanilines with (E)-trimethyl(3,3,3-trifluoroprop-1-enyl)silane
to provide improved yields of the corresponding 1,3-enyne
systems from substrates bearing electron-withdrawing and
nitrogen-containing groups. This work represents a significant
improvement over our previous study using AgF as an additive,
InBr3(1.0)
14
37
54
42
51
39
26
80e
Pd(PPh3)2Cl2 (0.1)
Pd(OAc)2 (0.1)
[Pd(2-methylallyl)Cl]2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
9
10d
a The reaction was carried out with 3b (0.1 mmol) at 110 °C for 24 h. which was limited in terms of its application to substrates
b The number of equivalents with respect to 3b (0.1 mmol). c NMR
with electron-donating substituents. Most notably, the
addition of InBr3 led to a dramatic increase in the yield of the
oxidative Sonogashira cross-coupling reaction with Ag2CO3,
yields of 4b, which were calculated by the integration of the 19F NMR
signals of 3b relative to an ethyl trifluoroacetate standard. d Reaction
carried out at a concentration of 0.05 M. e Isolated yield.
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and allowed the scope of this reaction to be broadly expanded (47 mg, 81%) after column chromatography (AcOEt : hexane =
to nitrogen-containing substrates. The subsequent cyclization 10 : 90). δH (CDCl3, 400 MHz) 4.24 (2H, br s), 6.14 (1H, qd, J 6.9
of these products proceeded smoothly in the presence of a pal- Hz, 16.0 Hz), 6.52 (1H, qd, J 2.3 Hz, 16.0 Hz), 6.59 (1H, d, J 8.7
ladium catalyst to give the corresponding indoles bearing a Hz), 7.24 (1H, dd, J 2.3 Hz, 8.7 Hz), 7.4 (1H, d, J 2.3 Hz); δC
3,3,3-trifluoroprop-1-enyl group. A mechanistic study particu- (CDCl3, 400 MHz) 90.3, 91.7, 108.1, 109.0, 116.0, 118.4 (q, J 7.7
larly on the effect of InBr3 is now ongoing.
Hz), 122.4 (q, J 269.7 Hz), 127.2 (q, J 33.7 Hz), 1337, 134.5,
147.2; δF (CDCl3, 90 MHz) −65.73 (d, J 3.0 Hz); m/z (EI)
288.9705 (M+. C11H7BrF3N requires 288.9714).
(E)-4-Chloro-2-(5,5,5-trifluoropent-3-en-1-ynel)benzenamine
3d. The title product 3d was obtained as a light yellow oil
(44 mg, 89%) after column chromatography (AcOEt : hexane =
20 : 80). δH (CDCl3, 400 MHz) 4.23 (2H, br s), 6.14 (1H, qd, J 6.9
Hz, 16.0 Hz), 6.53 (1H, qd, J 2.3 Hz, 16.0 Hz), 6.64 (1H, d, J 8.7
Hz), 7.12 (1H, dd, J 2.3 Hz, 8.7 Hz), 7.26 (1H, d, J 2.7 Hz);
δC (CDCl3, 400 MHz) 91.2, 91.8, 107.5, 115.7, 118.4 (q, J 7.7
Hz), 122.3, 122.5 (q, J 269.7 Hz), 127.2 (q, J 33.7 Hz), 130.9,
131.6, 146.8; δF (CDCl3, 90 MHz) −65.39 (d, J 6.0 Hz); m/z (EI)
245.0214 (M+. C11H7ClF3N requires 245.0219).
Experimental
General information
All commercially available reagents were used as received.
Acetonitrile (CH3CN) and N,N-dimethylformamide (DMF) were
distilled over calcium hydride and stored in a bottle with acti-
vated molecular sieves (4 Å). The experiments of Sonogashira
cross-coupling reaction were carried out under an argon
atmosphere in a flame-dried glassware and used general inert
techniques for introducing agents and solvents unless other-
wise noted. The experiments of cyclization reaction were
carried out under air.
(E)-1-(4-Amino-3-(5,5,5-trifluoropent-3-en-1-ynel)phenyl)-
ethanone 3e. The title product 3e was obtained as a light
yellow solid (32 mg, 64%) after column chromatography
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded at room temperature on JNM-GX400 and
JNM-ECZ400S/L1 spectrometers. The 19F NMR spectrum was
recorded at room temperature on a Hitachi FT-NMR R-90H
spectrometer. Chemical shifts of 1H NMR and 13C NMR are
reported in parts per million (ppm) from an internal standard,
tetramethylsilane (TMS, 0.00 pm) and CHCl3 (77.0 ppm),
respectively. Chemical shifts of 19F NMR are reported in ppm
from CFCl3 (0.00 ppm) as an internal standard. All data are
reported as follows; chemical shifts relative integration value,
number of equivalent nuclei, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, br = broad, m = multiplet),
coupling constants J (Hz). High-resolution mass spectroscopy
(HRMS) experiments were performed with a double-focusing
mass spectrometer with EI ionization on a JEOL JMS-700 T
spectrometer. Melting points were measured on Yanagimoto
micro melting point apparatus MP-S3.
(AcOEt : hexane
= 40 : 60). Mp 103–104 °C; δH (CDCl3,
400 MHz) 2.51 (3H, s), 4.71 (2H, br s), 6.17 (1H, qd, J 6.9 Hz,
16.0 Hz), 6.54 (1H, qd, J 1.8 Hz, 16.0 Hz), 6.71 (1H, d, J 8.7 Hz),
7.82 (1H, dd, J 1.8 Hz, 8.7 Hz), 7.95 (1H, d, J 1.8 Hz); δC (CDCl3,
400 MHz) 26.0, 89.8, 91.9, 105.3, 113.6, 118.4 (q, J 7.7 Hz),
122.5 (q, J 269.7 Hz), 127.3 (q, J 34.7 Hz), 127.6, 131.4, 134.2,
151.9, 195.6; δF (CDCl3, 90 MHz) −65.39 (d, J 6.0 Hz); m/z (EI)
253.0718 (M+. C13H10F3NO requires 253.0714).
(E)-Ethyl 4-amino-3-(5,5,5-trifluoropent-3-en-1-ynel)benzoate
3f. The title product 3f was obtained as a light yellow solid
(46 mg, 82%) after column chromatography (AcOEt : hexane =
30 : 70). Mp 111–112 °C; δH (CDCl3, 400 MHz) 1.37 (3H, t, J 7.3
Hz), 4.33 (2H, q, J 7.3 Hz), 4.63 (2H, br s), 6.16 (1H, qd, J 6.9
Hz, 16.0 Hz), 6.54 (1H, qd, J 2.3 Hz, 16.0 Hz), 6.69 (1H, d, J 8.7
Hz), 7.85 (1H, dd, J 2.3 Hz, 8.7 Hz), 8.02 (1H, d, J 1.8 Hz); δC
(CDCl3, 400 MHz) 14.4, 60.6, 89.7, 92.1, 105.5, 113.5, 118.5 (q,
J 7.7 Hz), 120.0, 122.5 (q, J 269.7 Hz), 127.1 (q, J 33.7 Hz),
132.5, 134.9, 151.6, 165.8; δF (CDCl3, 90 MHz) −65.41 (d, J 6.0
Hz); m/z (EI) 283.0823 (M+. C14H12F3NO2 requires 283.0820).
(E)-4-Methyl-2-(5,5,5-trifluoropent-3-en-1-ynel)benzenamine
Typical procedure for oxidative Sonogashira cross-coupling
reaction
Under an argon atmosphere, a mixture of Ag2CO3 (276 mg,
1.0 mmol), InBr3 (71 mg, 0.2 mmol) and [Pd(2-methylallyl)Cl]2 3h. The title product 3h was obtained as a light yellow solid
(3 mg, 4 mol%) in CH3CN (1.0 mL) was added to TBAF (35 mg, 77%) after column chromatography (AcOEt : hexane =
(2.0 mL, 2.0 mmol) at room temperature. After stirring for 10 : 90). Mp 45–46 °C; δH (CDCl3, 400 MHz) 2.21 (3H, s), 4.09
30 minutes at the same temperature, a solution of arylacetyl- (2H, br s), 6.10 (1H, qd, J 6.9 Hz, 16.0 Hz), 6.54 (1H, qd, J 2.3
enes 2 (0.2 mmol) and 1 (168 mg, 1.0 mmol) in CH3CN Hz, 16.0 Hz), 6.63 (1H, d, J 8.2 Hz), 6.99 (1H, d, J 8.2 Hz), 7.11
(1.0 mL) was added to the reaction mixture. The resulting (1H, s); δC (CDCl3, 400 MHz) 20.2, 89.3, 93.7, 106.3, 114.7,
mixture was filtered off to remove the silver salts with Celite, 118.9 (q, J 7.7 Hz), 122.6 (q, J 269.7 Hz), 126.3 (q, J 33.7 Hz),
and the filtrate was extracted with Et2O and the organic layer 127.3, 131.9, 132.5, 146.0; δF (CDCl3, 90 MHz) −65.24 (d, J 6.0
was dried over anhydrous MgSO4. After filtration of the solid, Hz); m/z (EI) 225.0769 (M+. C12H10F3N requires 225.0765).
the organic layer was concentrated under reduced pressure.
(E)-4-Methoxy-2-(5,5,5-trifluoropent-3-en-1-ynel)benzen-
The residue was purified by silica gel chromatography to amine 3i. The title product 3i was obtained as a light yellow
provide the corresponding 1,3-enynes 3 after a longer reaction oil (27 mg, 57%) after column chromatography (AcOEt : hexane
time (Table 4, entry 10).
= 10 : 90). δH (CDCl3, 400 MHz) 3.74 (3H, s), 3.96 (2H, br s),
(E)-4-Bromo-2-(5,5,5-trifluoropent-3-en-1-ynel)benzenamine 6.14 (1H, qd, J 6.8 Hz, 15.9 Hz), 6.54 (1H, qd, J 2.3 Hz, 15.9
3c. The title product 3c was obtained as a light yellow oil Hz), 6.64–6.68 (1H, m), 6.80–6.83 (2H, m); δC (CDCl3,
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400 MHz) 55.8, 89.4, 93.3, 106.8, 115.8, 116.1, 118.7 (q, J 7.8
(E)-2-(5,5,5-Trifluoropent-3-en-1-ynel)-1H-indole
3p. The
Hz), 118.8, 122.6 (q, J 268.8 Hz), 126.5 (q, J 33.9 Hz), 142.5, title product 3p was obtained as a light yellow solid (37 mg,
151.8; δF (CDCl3, 90 MHz) −65.31 (d, J 5.0 Hz); m/z (EI) 79%) after column chromatography (AcOEt : hexane = 20 : 80).
241.0713 (M+. C12H10F3NO requires 241.0714).
Mp 128–129 °C; δH (CDCl3, 400 MHz) 6.12 (1H, qd, J 6.8 Hz,
(E)-2-Bromo-6-(5,5,5-trifluoropent-3-en-1-ynel)benzenamine 15.6 Hz), 6.53 (1H, qd, J 2.3 Hz, 15.6 Hz), 6.56–6.57 (1H, m),
3j. The title product 3j was obtained as a light yellow solid 7.26–7.37 (3H, m), 7.82 (1H, s), 8.25 (1H, br s); δC (CDCl3,
(49 mg, 84%) after column chromatography (AcOEt : hexane = 400 MHz) 82.3, 98.6, 103.2, 111.2, 113.0, 119.4 (q, J 8.0 Hz),
10 : 90). Mp 38–39 °C; δH (CDCl3, 400 MHz) 4.35 (2H, br s), 122.8 (q, J 268.5 Hz), 125.3, 125.3, 125.7, 125.8 (q, J 33.8 Hz),
6.07 (1H, qd, J 6.9 Hz, 15.7 Hz), 6.56 (1H, qd, J 2.3 Hz, 15.7 127.8, 136.0; δF (CDCl3, 90 MHz) −65.11 (d, J 4.0 Hz); m/z (EI)
Hz), 6.69 (1H, d, J 8.3 Hz), 7.22 (1H, dd, J 2.0 Hz, 8.3 Hz), 7.56 235.0608 (M+. C13H8F3N requires 235.0609).
(1H, d, J 1.9 Hz); δC (CDCl3, 400 MHz) 83.3, 96.0, 108.3, 112.2,
Cyclization reaction into indole ring29
115.0, 119.1 (q, J 7.5 Hz), 122.8 (q, J 269.2 Hz), 126.2 (q, J 33.9
Hz), 132.4, 136.2, 145.4; δF (CDCl3, 90 MHz) −65.22 (d, J 5.0 A mixture of 1,3-enynes 3 (0.1 mmol) and Pd(OAc)2 (2.2 mg,
Hz); m/z (EI) 288.9708 (M+. C11H7BrF3N requires 288.9714).
10 mol%) in PhMe (2.0 mL) was stirred at 110 °C until starting
(E)-1-(2-Amino-3-(5,5,5-trifluoropent-3-en-1-ynel)phenyl)- materials disappeared. The reaction was quenched by the
ethanone 3k. The title product 3k was obtained as a yellow addition of water and the whole mixture was extracted with
solid (43 mg, 84%) after column chromatography (AcOEt : Et2O. The organic layer was dried over anhydrous MgSO4 and
hexane = 10 : 90). Mp 128–129 °C; δH (CDCl3, 400 MHz) 2.58 the solid was filtered off. The filtrate was concentrated under
(3H, s), 6.09 (1H, qd, J 6.8 Hz, 15.9 Hz), 6.48 (1H, qd, J 2.3 Hz, reduced pressure and the residue was purified by silica gel
15.9 Hz), 6.57 (2H, br s), 6.61 (1H, d, J 8.8 Hz), 7.34 (1H, qd, chromatography to provide the indoles 4.
J 1.9 Hz, 8.8 Hz), 7.88 (1H, d, J 2.0 Hz); δC (CDCl3, 400 MHz)
27.7, 82.6, 96.9, 108.6, 117.5, 117.9, 119.1 (q, J 7.5 Hz), 122.8 product 4b was obtained as a white solid (17 mg, 80%) after
(q, J 269.2 Hz), 126.2 (q, J 34.2 Hz), 136.6, 137.2, 151.0, 200.3; column chromatography (AcOEt : hexane 10 : 90). Mp
δF (CDCl3, 90 MHz) −65.15 (d, J 6.0 Hz); m/z (EI) 253.0709 133–134 °C; δH (CDCl3, 400 MHz) 5.97 (1H, qd, J 6.9 Hz,
(M+. C13H10F3NO requires 253.0714).
16.0 Hz), 6.75 (1H, s), 7.13 (1H, td, J 0.9 Hz, 6.9 Hz), 7.16 (1H,
(E)-2-(3,3,3-Trifluoroprop-1-enyl)-1H-indole 4b. The title
=
(E)-Ethyl 2-amino-3-(5,5,5-trifluoropent-3-en-1-ynel)benzoate qd, J 1.8 Hz, 16.0 Hz), 7.26 (1H, ddd, J 0.9 Hz, 1.4 Hz, 8.2 Hz),
3l. The title product 3l was obtained as a light yellow solid 7.36 (1H, dd, J 0.9 Hz, 8.2 Hz), 7.61 (1H, d, J 8.2 Hz), 8.12 (1H,
(45 mg, 80%) after column chromatography (AcOEt : hexane = br s); δC (CDCl3, 400 MHz) 107.9, 111.0, 113.3 (q, J 34.5 Hz),
10 : 90). Mp 50–51 °C; δH (CDCl3, 400 MHz) 1.40 (3H, t, J 7.3 120.7, 121.4, 123.5 (q, J 267.9 Hz), 124.4, 128.0 (q, J 6.9 Hz),
Hz), 4.34 (2H, q, J 7.3 Hz), 6.03 (2H, br s), 6.07 (1H, qd, J 6.9 128.2, 131.9, 137.4; δF (CDCl3, 90 MHz) −65.72 (d, J 6.0 Hz);
Hz, 15.6 Hz), 6.47 (1H, qd, J 2.3 Hz, 15.6 Hz), 6.61 (1H, d, J 8.2 m/z (EI) 211.0614 (M+. C11H8F3N requires 211.0609).
Hz), 7.33 (1H, dd, J 2.3 Hz, 8.2 Hz), 8.03 (1H, d, J 2.3 Hz); δC
(E)-5-Bromo-2-(3,3,3-trifluoroprop-1-enyl)-1H-indole 4c. The
(CDCl3, 400 MHz) 60.7, 82.6, 97.0, 109.0, 110.8, 116.7, 119.2 (q, title product 4c was obtained as a light yellow solid (19 mg,
J 7.7 Hz), 122.8 (q, J 269.7 Hz), 125.8 (q, J 33.7 Hz), 135.8, 64%) after column chromatography (AcOEt : hexane = 10 : 90).
136.9, 151.0, 167.3; δF (CDCl3, 90 MHz) −65.13 (d, J 2.3 Hz); Mp 92–93 °C; δH (CDCl3, 400 MHz) 6.01 (1H, qd, J 6.4 Hz, 16.0
m/z (EI) 283.0819 (M+. C14H12F3NO2 requires 283.0820).
Hz), 7.14 (1H, qd, J 1.8 Hz, 16.0 Hz), 7.23 (1H, d, J 8.7 Hz), 7.34
(E)-2-Methyl-2-(5,5,5-trifluoropent-3-en-1-ynel)benzenamine (1H, dd, J 1.8 Hz, 8.7 Hz), 7.74 (1H, d, J 1.8 Hz), 8.18 (1H, br s);
3n. The title product 3n was obtained as a light yellow solid δC (CDCl3, 400 MHz) 106.9, 112.5, 113.9, 114.4 (q, J 34.7 Hz),
(18 mg, 41%) after column chromatography (AcOEt : hexane = 123.3 (q, J 268.8), 123.9, 127.3, 127.6 (q, J 6.7 Hz), 129.9, 133.0,
10 : 90). Mp 52–53 °C; δH (CDCl3, 400 MHz) 2.14 (3H, s), 3.85 135.9; δF (CDCl3, 90 MHz) −63.95 (d, J 5.0 Hz); m/z (EI)
(2H, br s), 6.04 (1H, qd, J 6.9 Hz, 15.6 Hz), 6.47 (1H, qd, J 2.3 288.9712 (M+. C11H7BrF3N requires 288.9714).
Hz, 15.6 Hz), 6.60 (1H, d, J 8.2 Hz), 7.15–7.18 (2H, m); δC
(E)-5-Chloro-2-(3,3,3-trifluoroprop-1-enyl)-1H-indole 4d. The
(CDCl3, 400 MHz) 17.1, 82.5, 98.1, 110.9, 114.4, 119.4 (q, J 7.7 title product 4d was obtained as a light yellow solid (18 mg,
Hz), 121.9, 122.9 (q, J 269.7 Hz), 125.3 (q, J 33.7 Hz), 131.2, 73%) after column chromatography (AcOEt : hexane = 10 : 90).
134.2, 146.0; δF (CDCl3, 90 MHz) −65.02 (d, J 6.0 Hz); m/z (EI) Mp 84–86 °C; δH (CDCl3, 400 MHz) 6.02 (1H, qd, J 6.4 Hz, 16.0
225.0770 (M+. C12H10F3N requires 225.0765).
Hz), 6.68 (1H, s), 7.12–7.29 (3H, m), 7.58 (1H, s), 8.23 (1H, br
(E)-2-(5,5,5-Trifluoropent-3-en-1-ynel)pyridine 3o. The title s); δC (CDCl3, 400 MHz) 107.0, 112.1, 114.3 (q, J 34.7 Hz),
product 3o was obtained as a light yellow oil (39 mg, 99%) 120.7, 123.3 (d, J 268.8 Hz), 124.8, 126.4, 127.7 (d, J 6.7 Hz),
after column chromatography (AcOEt : hexane = 30 : 70). δH 129.3, 133.1, 135.7; δF (CDCl3, 90 MHz) −63.98 (d, J 6.0 Hz);
(CDCl3, 400 MHz) 6.27 (1H, qd, J 6.6 Hz, 16.0 Hz), 6.53 (1H, m/z (EI) 247.0215 (M+. C11H7ClF3N requires 245.0219).
qd, J 2.3 Hz, 16.0 Hz). 7.28–7.31 (1H, m), 7.49 (1H, d, J 7.8 Hz),
(E)-1-(2-(3,3,3-Trifluoroprop-1-enyl)-1H-indol-5-yl)ethanone
7.68–7.72 (1H, m), 8.64 (1H, d, J 4.4 Hz); δC (CDCl3, 400 MHz) 4e. The title product 4e was obtained as a light yellow solid
83.2, 94.9, 118.1 (q, J 7.8 Hz), 122.2 (q, J 269.1 Hz), 123.6, (16 mg, 65%) after column chromatography (AcOEt : hexane =
127.4, 129.0 (q, J 34.2 Hz), 136.2, 142.0, 150.3; δF (CDCl3, 10 : 90). Mp 219–220 °C; δH (CDCl3, 400 MHz) 2.67 (3H, s), 6.07
90 MHz) −65.47 (d, J 4.0 Hz); m/z (EI) 197.0448 (M+. C10H6F3N (1H, qd, J 6.4 Hz, 16.0 Hz), 6.86 (1H, s), 7.19 (1H, qd, J 1.8 Hz,
requires 197.0452).
16.0 Hz), 7.40 (1H, d, J 8.7 Hz), 7.94 (1H, dd, J 1.4 Hz, 8.7 Hz),
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8.29 (1H, d, J 1.8 Hz), 8.49 (1H, br s); δC (CDCl3, 400 MHz)
26.2, 108.1, 111.1, 114.4 (q, J 33.7 Hz), 123.2, 123.4, 123.6 (q,
J 268.8 Hz), 127.7 (q, J 6.7 Hz), 127.3, 129.7, 134.1, 140.4,
197.8; δF (CDCl3, 90 MHz) −63.64 (d, J 8.0 Hz); m/z (EI)
253.0714 (M+. C13H10F3NO requires 253.0714).
(E)-Ethyl 2-(3,3,3-trifluoroprop-1-enyl)-1H-indol-5-carboxylate
4f. The title product 4f was obtained as a light yellow solid
(16 mg, 56%) after column chromatography (AcOEt : hexane =
10 : 90). Mp 225–226 °C; δH (CDCl3, 400 MHz) 1.44 (3H, t, J 7.3
Hz), 4.42 (2H, q, J 7.3 Hz), 6.06 (1H, qd, J 6.4 Hz, 16.0 Hz), 6.85
(1H, s), 7.20 (1H, qd, J 1.8 Hz, 16.0 Hz), 7.39 (1H, d, J 8.7 Hz),
7.99 (1H, dd, J 1.4 Hz, 8.7 Hz), 8.40 (1H, s), 8.44 (1H, br s);
δC (CDCl3, 400 MHz) 14.2, 60.3, 107.9, 110.8, 114.3 (q, J 33.7
Hz), 122.0, 123.6 (q, J 268.8 Hz), 123.8, 124.5, 127.3, 127.8 (q,
J 6.7 Hz), 133.9, 140.2, 167.2; δF (CDCl3, 90 MHz) −63.60 (d,
J 6.0 Hz); m/z (EI) 283.0815 (M+. C14H12F3NO2 requires
283.0820).
Notes and references
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Mp 153–155 °C; δH (CDCl3, 400 MHz) 2.43 (3H, s), 5.95 (1H,
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The title product 4i was obtained as a white solid (16 mg, 67%)
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133–134 °C; δH (CDCl3, 400 MHz) 3.85 (3H, s), 5.96 (1H, qd,
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Acknowledgements
We are grateful to the Central Glass Co., Ltd and Tosoh F-Tech,
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