Electrochemical Synthesis Strategy for Cvinyl-CF3 Compounds through Decarboxylative Trifluoromethylation

Article abstract of DOI:10.1021/acs.joc.9b00766

An efficient decarboxylative trifluoromethylation of α,β-unsaturated carboxylic acids using the Langlois reagent as a trifluoromethyl precursor has been achieved by an electro-oxidative strategy. Under catalyst-free and external oxidant-free electrolysis

Full text of DOI:10.1021/acs.joc.9b00766

Note
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Electrochemical Synthesis Strategy for Cvinyl-CF3 Compounds
through Decarboxylative Trifluoromethylation
Huanliang Hong, Yibiao Li, Lu Chen, Bin Li, Zhongzhi Zhu, Xiuwen Chen, Ling Chen,
and Yubing Huang*
School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China
S
* Supporting Information
ABSTRACT: An efficient decarboxylative trifluoromethyla-
tion of α,β-unsaturated carboxylic acids using the Langlois
reagent as a trifluoromethyl precursor has been achieved by an
electro-oxidative strategy. Under catalyst-free and external
oxidant-free electrolysis conditions, a series of Cvinyl-CF3
compounds are obtained with a high regioselectivity in good
yields. The successful trapping of the CF3 radical by a
scavenger has confirmed that radical processes are involved in
this system.
he development of efficient and sustainable trifluorome-
thylation reactions to introduce a CF3 group into various
organic molecules has important research value in drug
development,1 new material synthesis, and life sciences, as a
CF3 group can dramatically change molecular characteristics,
such as stability, lipophilicity, bioavailability, etc.2 Cvinyl-CF3
has always been considered as an important moiety (Figure 1)
compounds through transition-metal-catalyzed or photocata-
lytic decarboxylation trifluoromethylations. For example, the
groups of Hu9 and Liu10 have shown the transition-metal-
catalyzed decarboxylative trifluoromethylations of α,β-unsatu-
rated carboxylic acids by using Togni’s reagent and the cheaper
Langlois reagent, respectively (Scheme 1a). Then, the group of
Zhu11 achieved a visible-light-induced decarboxylative trifluor-
omethylation at room temperature by using Togni’s reagent as
T
Scheme 1. Synthesis of Cvinyl-CF3 Compounds via
Decarboxylative Trifluoromethylations
Figure 1. Drugs and agents containing a Cvinyl-CF3 moiety.
in pharmaceutical reagents;3 among them, compounds
containing the Cvinyl-CF3 moiety are basically non-natural
and need to be constructed through a variety of organic
synthesis methodologies. Some effective strategies have been
reported to construct a Cvinyl-CF3 moiety by using
prefunctionalized olefins, such as vinyl boronic acids,4 vinyl
borates,5 vinyl halides,6 nitro olefins,7 and vinyl carboxylic
acids, which allow the reaction to exhibit a good reactivity and
specific regioselectivity. Among them, carboxylic acids are
ubiquitous compounds that are inexpensive and commercially
available in large quantities,8 Currently, α,β-unsaturated
carboxylic acids have been used to synthesize Cvinyl-CF3
Received: March 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00766
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a trifluoromethyl source (Scheme 1b). In order to improve the
methodology for decarboxylative trifluoromethylation, we have
been seeking milder conditions without the addition of a metal
catalyst to prepare Cvinyl-CF3 compounds by using a cheaper
trifluoromethylation reagent.
under a constant current electrolysis at 7 mA in a solvent
mixture DMSO/DCM (1.5:1) at room temperature, and the
desired product 3a was obtained in 59% yield (Table 1, entries
2). Subsequently, we explored the effect of solvent mixture
types and found that other types of solvent mixtures would
both lead to decreased reaction yields (Table 1, entries 6−8).
Moreover, replacing the solvent mixture with a single solvent
(DMSO) also hinders the progress of the reaction (Table 1,
entry 9). A reduced yield was obtained when decreasing the
amount of CF3SO2Na (Table 1, entry 10). We believed the
addition of a base can further increase the reaction yield, so we
investigated different types of bases, including organic bases
and inorganic bases, and found that potassium salts are
effective for this reaction. Then, we compared the effects of
different potassium salts and found that the yield of 3a reached
a maximum of 76% when using 0.5 equiv of KOtBu (Table 1,
entry 12) but did not increase with the increase of the amount
of KOtBu (Table 1, entry 14). The reaction yield decreased
when decreasing the constant current (Table 1, entry 15), and
further, no expected product was detected when the reaction
was conducted without electricity (Table 1, entry 16).
Electrochemical synthesis has emerged as an environ-
mentally friendly synthesis tool with the prospect of avoiding
the extensive use of chemical oxidants and reducing agents.12
Electrosynthesis provides an efficient alternative to conven-
tional chemical methods for redox transformations, through
the loss or acquisition of electrons at the electrode surface to
form highly reactive organic molecule intermediates, and is
applied to the reactions of radicals.13 As an easily available and
inexpensive trifluoromethylation reagent, the Langlois reagent
(CF3SO2Na), which releases a CF3 radical by a single-electron
oxidation process on the anode, has been shown to be useful as
a trifluoromethyl precursor for the electro-oxidation trifluor-
omethylation reactions.14 In order to develop convenient and
efficient trifluoromethylation reactions using the Langlois
reagent as a trifluoromethyl precursor and to further expand
the synthetic application of electrochemical oxidation, herein,
we propose an efficient electro-oxidative decarboxylative
trifluoromethylation between α,β-unsaturated carboxylic acids
and CF3SO2Na for the synthesis of diverse Cvinyl-CF3
compounds (Scheme 1c).
With the optimal reaction conditions in hand, we
subsequently examined a series of α,β-unsaturated carboxylic
acids for this electro-oxidative decarboxylative trifluoromethy-
lation (Table 2). Both electron-rich substituents (methyl-,
methoxy-, and benzyloxy-) and electron-poor substituents
Initially, we chose cinnamic acid (1a) as the model substrate to
react with CF3SO2Na 2 for the optimization of conditions for
electro-oxidative decarboxylative trifluoromethylation (Table
1). After different electrolytes were screened (Table 1, entries
Table 2. Substrate Scope of α,β-Unsaturated Carboxylic
a b
,
Acids
n
1−5), Bu4NBF4 was found to be suitable for the reaction
a
Table 1. Optimization of the Reaction Conditions
b
entry
electrolyte
base (equiv)
solvent
yield (%)
1
2
3
4
5
6
7
8
9
nBu4NBF4
nBu4NPF6
nBu4NOAc
nBu4NHSO4
Et4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
nBu4NPF6
none
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
MeCN/DCM
DMF/DCM
51
59
46
22
14
trace
nd
35
10
30
65
76
70
75
27
nd
none
none
none
none
none
none
none
DMSO/DCE
c
none
DMSO
d
10
none
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
DMSO/DCM
11
12
13
14
K2CO3 (0.5)
KOtBu (0.5)
KOAc (0.5)
KOtBu (1)
KOtBu (0.5)
KOtBu (0.5)
e
15
f
16
a
Reaction conditions: undivided cell, graphite rod (ϕ 6 mm) anode,
a
Pt plate (10 mm × 10 mm) cathode, constant current = 7 mA, 1a (0.1
Reaction conditions: graphite rod (ϕ 6 mm) anode, Pt plate (10 mm
× 10 mm) cathode, constant current = 7 mA, 1a (0.3 mmol),
CF3SO2Na 2 (0.9 mmol), nBu4NPF6 (0.5 equiv), KOtBu (0.5 equiv),
DMSO/DCM (1.5:1 v/v, 7.5 mL). The electrolysis was conducted in
mmol), CF3SO2Na 2 (0.3 mmol), electrolyte (0.5 equiv), base,
b
solvent (1.5:1 v/v, 2.5 mL), air, 3 h. Yield determined by GC
c
analysis with n-dodecane as the internal standard. DMSO (2 mL).
d
e
f
b
CF3SO2Na 2 (1 equiv). I = 3 mA. No electricity; nd = not
detected.
an undivided cell at room temperature under air for 3 h. Yields refer
c
d
to the isolated yields. Electrolysis for 6 h. Electrolysis for 7 h.
B
DOI: 10.1021/acs.joc.9b00766
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(halogen and nitro) at the para-position of the phenyl ring
scavengers15 to the reaction and carefully analyzing the
reaction results, we found that the addition of 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) and butylated hydrox-
ytoluene (BHT) could both inhibit the reaction (eqs a and b).
Meanwhile, the CF3 radical formed in the reaction by BHT
was trapped, a 14% yield of the trapping product 4 was
were tolerated in this conversion, and the corresponding Cvinyl
-
CF3 products (3b−3d and 3f−3h) were given in good to
excellent yields. When the para-substituted group was
hydroxyl, the reaction gave the desired product 3e with a
lower yield, 40% isolated yield. The position of the substituent
on the aromatic ring had a slight effect on the reaction.
Compared to the products containing a para-substituent, the
isolated yields of products containing a meta- or ortho-
substituent were slightly reduced (3i−3o); among them,
unsaturated carboxylic acid substrates with methoxy and
halogen were transformed into the corresponding products
(3j−3l and 3o) smoothly in good yields. The substrates
containing multiple substituents, especially multiple methoxy
groups, could be well applied to the reactions, and the
corresponding products (3p−3r) were delivered in moderate
to excellent yields. It should be noted that heterocyclic
(benzo[d][1,3]dioxole and pyridine) substrates underwent the
transformations smoothly, affording the desired products 3s
and 3t in 72% and 57% yields, respectively. In addition, when
(E)-2-methyl-3-phenylacrylic acid was used as a reaction
substrate, no desired product (3u) was detected.
detected (eq b), where trapping product 4 ([M + H]+
=
289.1765) had been confirmed by HRMS. Subsequently, we
also tested other olefin substrates, such as styrene, styrylbor-
onic acid, and nitrovinylbenzene and found that they could not
be applied to the reaction (eq c).
In order to analyze the reaction process in depth, we
implemented cyclic voltammetry (CV) experiments and
recorded cyclic voltammetry (CV) diagrams for different
systems (Figure 2). With electrolyte solution as a test
background, the oxidative peak of cinnamic acid (1a) was
recorded at 1.01 V vs SCE in the presence of KOtBu, and
CF3SO2Na (2) had a close oxidative peak recorded at 0.95 V
vs SCE (Figure 2a−c). As expected, the oxidative peak was
recorded at 1.00 V vs SCE when KOtBu was absent in the
reaction system, while the recorded oxidative peak decreased
to 0.77 vs SCE when KOtBu was added in the reaction system,
which indicated that KOtBu played a key role in this
transformation (Figure 2d,e).
The practical utility of this electrochemical synthesis strategy
was demonstrated by scale-up experiments (Scheme 2). When
On the basis of the above experimental results, a tentative
mechanism for this electro-oxidative decarboxylative trifluor-
omethylation was proposed in Scheme 4. Initially, CF3SO2Na
produced a CF3 radical on the anode via the single-electron
transfer (SET) oxidation process, while releasing SO2.14
Subsequently, the attack of the CF3 radical onto α,β-
unsaturated carboxylic acid 1 generated radical intermediate
B, which would be further oxidized to release CO2 and
converted to the desired product 3.
Scheme 2. Scale-Up Experiments
In summary, we have discovered an efficient electro-oxidative
strategy using α,β-unsaturated carboxylic acids and CF3SO2Na
for an operationally simple decarboxylative trifluoromethyla-
tion. The reaction is conducted under catalyst-free and external
oxidant-free electrolysis conditions to deliver a series of Cvinyl
-
CF3 compounds in good yields. Mechanistic studies have
confirmed the formation of the CF3 radical, which is provided
by CF3SO2Na on the anode via the single-electron transfer
(SET) oxidation process. Furthermore, simple and mild
electrolysis conditions, inexpensive and readily available
substrates, and a high regioselectivity provide a great advantage
for the transformation. We anticipate that the protocol will not
only enrich the content of the trifluoromethylations but also
promote the innovation and development in sustainable
chemistry. Further synthetic applications of this novel protocol
are ongoing in our laboratory.
conducting the reactions at a 5 mmol scale, the desired
products 3c and 3g were delivered smoothly in isolated yields
of 69% and 64%, respectively. The experimental results
exhibited the potential application of an electrochemical
strategy in the actual synthesis.
To investigate the mechanism of the electro-oxidative
decarboxylative trifluoromethylation, several control experi-
ments were conducted (Scheme 3). By adding radical
Scheme 3. Control Experiments
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all of the
chemicals were purchased commercially and used without further
purification. Technical grade petroleum ether (40−60 °C bp) and
ethyl acetate were used for column chromatography. 1H, 13C, and 19
F
NMR spectra were recorded on a Bruker Advance III 500
spectrometer using CDCl3 as the solvent with TMS as the internal
standard. The chemical shifts are referenced to signals at 7.26 and
77.0 ppm, respectively. Chemical shifts (δ) and coupling constants (J)
are given in ppm and in hertz, respectively. The peak patterns are
indicated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m,
multiplet. Electrolysis reactions were conducted using a Model MCH-
K-300D (36 V) power supply purchased from Meichuang Instru-
ments (Shenzhen) Co., Ltd. Cyclic voltammetry (CV) analysis was
C
DOI: 10.1021/acs.joc.9b00766
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The Journal of Organic Chemistry
Note
Figure 2. Cyclic voltammograms of 0.02 M nBu4NPF6 solution in DMSO/DCM (1.5:1) at room temperature: (a) none; (b) after the addition of
cinnamic acid 1a (0.04 M) and KOtBu(0.02 M); (c) after the addition of CF3SO2Na 2 (0.12 M); (d) after the addition of cinnamic acid 1a (0.04
M) and CF3SO2Na 2 (0.12 M); (e) after the addition of cinnamic acid 1a (0.04 M), CF3SO2Na 2 (0.12 M), and KOtBu(0.02 M). The
voltammogram was obtained at a scan rate of 0.8 V/s with Pt electrode as an auxiliary electrode and a saturate calomel electrode (SCE) as a
reference electrode.
(E)-(3,3,3-Trifluoroprop-1-en-1-yl)benzene (3a):3b 33 mg (65%
yield), colorless oil; H NMR (500 MHz, CDCl3, ppm) δ 7.49 (m,
Scheme 4. Proposed Mechanism
1
2H), 7.42 (m, 3H), 7.18 (dd, J = 16.1, 2.1 Hz, 1H), 6.24 (dq, J = 16.1,
6.5 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ 137.7 (q, J =
6.8 Hz), 133.4, 130.0, 129.0, 127.6, 123.6 (q, J = 269.6 Hz), 115.8 (q,
J = 33.7 Hz); 19F NMR (471 MHz, CDCl3, ppm) δ −63.32; IR (KBr,
cm−1) ν 2928, 2861, 1731, 1459; HRMS (ESI) calcd for C9H7F3 [M
+ H]+ 173.0573, found 173.0568.
(E)-1-Methyl-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3b):3b 39
1
mg (70% yield), colorless oil; H NMR (500 MHz, CDCl3, ppm) δ
7.38 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.9 Hz, 2H), 7.17−7.12 (m,
1H), 6.18 (dq, J = 16.1, 6.6 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3, ppm) δ 140.3, 137.5 (q, J = 6.6 Hz), 130.6, 129.6,
127.5, 123.8 (q, J = 269.6 Hz), 114.7 (q, J = 33.7 Hz), 29.7, 21.4; 19F
NMR (471 MHz, CDCl3, ppm) δ −63.09; IR (KBr, cm−1) ν 2921,
2854, 1728, 1460; HRMS (ESI) calcd for C10H10F3 [M + H]+
187.0729, found 187.0724.
(E)-1-Methoxy-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3c):3b
1
51 mg (84% yield), purple oil; H NMR (500 MHz, CDCl3, ppm)
δ 7.42 (d, J = 8.7 Hz, 2H), 7.12 (dd, J = 16.1, 2.0 Hz, 1H), 6.94 (d, J
= 8.7 Hz, 2H), 6.09 (dq, J = 16.0, 6.6 Hz, 1H), 3.86 (s, 3H); 13C{1H}
NMR (126 MHz, CDCl3, ppm) δ 161.0, 137.1 (q, J = 6.6 Hz), 129.1,
126.05, 124.0 (q, J = 268.4 Hz), 114.3, 113.4 (q, J = 33.6 Hz), 55.4;
19F NMR (471 MHz, CDCl3, ppm) δ −62.83; IR (KBr, cm−1) ν 2924,
performed on a Princeton PARSTAT4000 electrochemical work-
2850, 1663, 1514, 1259, 1119; HRMS (ESI) calcd for C10H10F3O [M
station, using a platinum electrode as a working electrode, a graphite
rod as a counter electrode, and a saturated calomel electrode (SCE) as
a reference electrode. Cyclic voltammograms were recorded at a scan
rate of 0.8 V/s. IR spectra were obtained either as potassium bromide
pellets or as liquid films between two potassium bromide pellets with
a Bruker VERTEX 70 spectrometer. Mass spectra were recorded on a
Shimadzu GCMS-QP2020 gas chromatograph−mass spectrometer.
The high-resolution mass spectra were recorded by a Thermo
Scientific Q Exactive hybrid quadrupole-Orbitrap mass spectrometer
(ESI-FTMS). TLC was performed by using commercially prepared
100−400 mesh silica gel plates, and visualization was affected at 254
nm.
+ H]+ 203.0678, found 203.0673.
(E)-1-(Benzyloxy)-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene
(3d):16 67 mg (80% yield), colorless oil; 1H NMR (500 MHz, CDCl3,
ppm) δ 7.45 (m, 6H), 7.38 (t, J = 7.0 Hz, 1H), 7.12 (dd, J = 16.1, 2.0
Hz, 1H), 7.02 (d, J = 8.7 Hz, 2H), 6.10 (dq, J = 16.0, 6.6 Hz, 1H),
5.13 (s, 2H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ 160.2, 137.1
(q, J = 6.8 Hz), 136.5, 129.1, 128.7, 128.2, 127.5, 126.3, 123.9 (q, J =
268.6 Hz), 115.2, 113.6 (q, J = 33.6 Hz), 70.1; 19F NMR (471 MHz,
CDCl3, ppm) δ −62.82; IR (KBr, cm−1) ν 2922, 2856, 1662, 1275,
1105; HRMS (ESI) calcd for C16H13F3O [M + H]+ 279.0991, found
279.0988.
(E)-4-(3,3,3-Trifluoroprop-1-en-1-yl)phenol (3e):3b 22 mg (40%
General Procedure for the Synthesis of Cvinyl-CF3 Compounds 3.
1
n
yield), yellow oil; H NMR (500 MHz, CDCl3, ppm) δ 7.38 (d, J =
A mixture of 1a (0.3 mmol), CF3SO2Na 2 (0.9 mmol), Bu4NPF6
(0.5 equiv), and KOtBu (0.5 equiv) in 7.5 mL of the solvent (DMSO/
DCM = 1.5:1) was added to a round-bottomed flask (10 mL). The
reaction flask was equipped with a graphite rod (ϕ 6 mm) as an anode
and a Pt plate (10 mm × 10 mm) as a cathode. The solution was
electrolyzed in an undivided cell at an ambient temperature under a
constant current (7 mA) for 3−7 h. After electrolysis, the mixture was
poured into water and extracted with ethyl acetate twice. The
combined organic layer was washed with brine (10 mL) and dried
over MgSO4, filtered, and concentrated. The resulting mixture was
purified by silica gel column chromatography to afford 3.
8.6 Hz, 2H), 7.09 (dd, J = 16.1, 2.1 Hz, 1H), 6.87 (m, 2H), 6.08 (dq,
J = 16.1, 6.6 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ
157.6, 137.1 (q, J = 7.0 Hz), 129.3, 125.9, 124.0 (q, J = 268.6 Hz),
115.9, 113.2 (q, J = 33.5 Hz); 19F NMR (471 MHz, CDCl3, ppm) δ
−62.85; IR (KBr, cm−1) ν 3370, 2930, 2860, 1604, 1265, 1117;
HRMS (ESI) calcd for C9H7F3O [M + H]+ 189.0522, found
189.0521.
(E)-1-Chloro-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3f):3b 45
mg (73% yield), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 7.30
(t, J = 6.4 Hz, 4H), 7.03 (dd, J = 16.1, 2.1 Hz, 1H), 6.11 (dq, J = 16.1,
D
DOI: 10.1021/acs.joc.9b00766
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The Journal of Organic Chemistry
Note
6.5 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ 136.4 (q, J =
6.8 Hz), 136.0, 131.9, 129.2, 128.8, 123.4 (q, J = 269.0 Hz), 116.4 (q,
J = 34.0 Hz); 19F NMR (471 MHz, CDCl3, ppm) δ −63.43; IR (KBr,
cm−1) ν 2922, 2854, 2354, 1726, 1266, 1030; HRMS (ESI) calcd for
C9H7ClF3 [M + H]+ 207.0182, found 207.0179.
(E)-1-Methyl-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3n): 37
mg (66% yield), colorless oil; H NMR (500 MHz, CDCl3, ppm) δ
1
7.49 (d, J = 7.6 Hz, 1H), 7.44 (dd, J = 16.0, 2.1 Hz, 1H), 7.31 (d, J =
7.4 Hz, 1H), 7.25 (dd, J = 11.3, 7.5 Hz, 2H), 6.14 (dq, J = 15.9, 6.5
Hz, 1H), 2.42 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ
137.0, 135.5 (q, J = 6.9 Hz), 132.6, 130.8, 129.8, 126.4, 126.2, 123.6
(q, J = 269.1 Hz), 117.0 (q, J = 33.6 Hz), 19.7; 19F NMR (471 MHz,
CDCl3, ppm) δ −63.30; IR (KBr, cm−1) ν 2923, 2857, 2356, 1732,
1263, 1094; HRMS (ESI) calcd for C10H10F3 [M + H]+ 187.0729,
found 187.0725.
(E)-1-Bromo-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3g):3b 65
1
mg (80% yield), yellow oil; H NMR (500 MHz, CDCl3, ppm) δ
7.58−7.51 (m, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.12 (dd, J = 16.1, 2.1
Hz, 1H), 6.23 (dq, J = 16.1, 6.4 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3, ppm) δ 136.5 (q, J = 6.6 Hz), 132.3, 132.2, 129.0, 124.3,
123.4 (q, J = 269.6 Hz), 116.5 (q, J = 34.0 Hz); 19F NMR (471 MHz,
CDCl3, ppm) δ −63.46; IR (KBr, cm−1) ν 2921, 2854, 2356, 1657,
1275, 1126; HRMS (ESI) calcd for C9H6BrF3Na [M + Na]+
272.9497, found 272.9500.
(E)-1-Chloro-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3o): 44
1
mg (72% yield), yellow oil; H NMR (500 MHz, CDCl3, ppm) δ
7.59 (m, 2H), 7.45 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (tt, J = 6.9, 3.5 Hz,
2H), 6.24 (dq, J = 16.1, 6.4 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3, ppm) δ 134.4, 134.0 (q, J = 6.8 Hz), 131.8, 131.0, 130.2,
(E)-1-Nitro-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3h):3b 44
1
mg (68% yield), yellow oil; H NMR (500 MHz, CDCl3, ppm) δ
8.29 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.7 Hz, 2H), 7.25 (dd, J = 16.2,
2.0 Hz, 1H), 6.39 (dq, J = 16.2, 6.3 Hz, 1H); 13C{1H} NMR (126
MHz, CDCl3, ppm) δ 148.5, 139.5, 135.4 (q, J = 6.8 Hz), 128.4,
124.3, 122.9 (q, J = 269.7 Hz), 120.0 (q, J = 34.5 Hz); 19F NMR (471
MHz, CDCl3, ppm) δ −63.95; IR (KBr, cm−1) ν 2924, 2357, 1521,
1344, 1121; HRMS (ESI) calcd for C9H7F3NO2 [M + H]+ 218.0423,
found 218.0420.
127.4, 127.2, 123.2 (q, J = 269.6 Hz), 118.4 (q, J = 34.1 Hz, 1H); 19
F
NMR (471 MHz, CDCl3, ppm) δ −63.61; IR (KBr, cm−1) ν 2924,
2855, 1662, 1319, 1130; HRMS (ESI) calcd for C9H6ClF3 [M + H]+
207.0183, found 207.0185.
(E)-1,2-Dimethoxy-4-(3,3,3-trifluoroprop-1-en-1-yl)benzene
(3p):11 57 mg (82% yield), yellow oil; H NMR (500 MHz, CDCl3,
1
ppm) δ 7.09 (dd, J = 16.1, 2.0 Hz, 1H), 7.04 (dd, J = 8.2, 1.7 Hz, 1H),
6.98 (d, J = 1.8 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.09 (dq, J = 16.0,
6.6 Hz, 1H), 3.93 (s, 3H), 3.93 (s, 3H); 13C{1H} NMR (126 MHz,
CDCl3, ppm) δ 150.7, 149.2, 137.4 (q, J = 6.9 Hz), 126.3, 123.9 (q, J
= 268.6 Hz), 121.7, 113.6 (q, J = 33.6 Hz), 111.0, 109.2, 55.9, 55.9;
19F NMR (471 MHz, CDCl3, ppm) δ −62.80; IR (KBr, cm−1) ν 2944,
2846, 1662, 1517, 1263, 1121; HRMS (ESI) calcd for C11H11F3O2
[M + H]+ 233.0784, found 233.0778.
(E)-1-Methyl-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3i):3b 34
mg (62% yield), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 7.29
(m, 3H), 7.23 (m, 1H), 7.14 (m, 1H), 6.22 (dq, J = 16.1, 6.6 Hz, 1H),
2.40 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ 138.6, 137.8
(q, J = 6.7 Hz), 133.3, 130.8, 128.8, 128.2, 124.7, 121.6 (q, J = 269.6
Hz), 115.6 (q, J = 33.8 Hz), 21.3; 19F NMR (471 MHz, CDCl3, ppm)
δ −63.26; IR (KBr, cm−1) ν 2925, 2359, 1737, 1520, 1263; HRMS
(ESI) calcd for C10H9F3 [M + H]+ 187.0729, found 187.0724.
(E)-1-Methoxy-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3j):3b 46
mg (76% yield), purple oil; 1H NMR (500 MHz, CDCl3, ppm) δ 7.33
(t, J = 7.9 Hz, 1H), 7.16−7.12 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H),
7.00−6.99 (m, 1H), 6.96 (dd, J = 8.2, 2.4 Hz, 1H), 6.22 (dq, J = 16.1,
6.5 Hz, 1H), 3.86 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ
159.9, 137.6 (q, J = 6.5 Hz), 134.8, 130.0, 123.6 (q, J = 269.0 Hz),
120.1, 116.1 (q, J = 34.02 Hz), 115.7, 112.7, 55.3; 19F NMR (471
MHz, CDCl3, ppm) δ −63.32; IR (KBr, cm−1) ν 2952, 2855, 2356,
1594, 1267, 1120; HRMS (ESI) calcd for C10H10F3O [M + H]+
203.0678, found 203.0674.
(E)-1,3-Dichloro-2-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3q):11
1
52 mg (73% yield), colorless oil; H NMR (500 MHz, CDCl3, ppm)
δ 7.39 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 2.6 Hz, 1H), 7.25−7.24 (m,
1H), 6.42 (dq, J = 16.4, 6.3 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3, ppm) δ 134.7, 131.5 (q, J = 7.3 Hz), 130.9, 130.0, 128.8,
124.5 (q, J = 33.9 Hz), 122.8 (q, J = 270.9 Hz,); 19F NMR (471 MHz,
CDCl3, ppm) δ −64.71, −64.72; IR (KBr, cm−1) ν 2926, 2856, 1673,
1434, 1310, 1131; HRMS (ESI) calcd for C9H5Cl2F3 [M + H]+
240.9793, found 240.9796.
(E)-1,2,3-Trimethoxy-5-(3,3,3-trifluoroprop-1-en-1-yl)benzene
(E)-1-Chloro-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3k):3b 43
1
(3r): 69 mg (88% yield), yellow oil; H NMR (500 MHz, CDCl3,
1
mg (69% yield), colorless oil; H NMR (500 MHz, CDCl3, ppm) δ
ppm) δ 7.1 (m, 1H), 6.7 (s, 2H), 6.1 (dq, J = 16.0, 6.5 Hz, 1H), 3.9
(s, 6H), 3.9 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ
153.5, 139.7, 137.6 (q, J = 6.9 Hz), 129.0, 123.6 (q, J = 269.6 Hz),
115.2 (q, J = 33.7 Hz), 104.6, 61.0, 56.2; 19F NMR (471 MHz,
CDCl3, ppm) δ −63.07; IR (KBr, cm−1) ν 2937, 2846, 1586, 1284,
1123; HRMS (ESI) calcd for C12H13F3O3 [M + H]+ 263.0889, found
263.0885.
7.48 (s, 1H), 7.39−7.35 (m, 3H), 7.12 (dd, J = 16.1, 2.1 Hz, 1H),
6.25 (dq, J = 16.1, 6.4 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3,
ppm) δ 136.3 (q, J = 6.7 Hz), 135.2, 135.0, 130.2, 130.0, 127.4, 125.8,
123.3 (q, J = 269.6 Hz), 117.3 (q, J = 34.0 Hz); 19F NMR (471 MHz,
CDCl3, ppm) δ −63.58; IR (KBr, cm−1) ν 2921, 2854, 2360, 1726,
1530, 1269, 1126; HRMS (ESI) calcd for C9H7ClF3 [M + H]+
207.0182, found 207.0181.
(E)-5-(3,3,3-Trifluoroprop-1-en-1-yl)benzo[d][1,3]dioxole (3s): 47
mg (72% yield), colorless oil; H NMR (500 MHz, CDCl3, ppm) δ
(E)-1-Bromo-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3l). 58 mg
(71% yield), purple oil; 1H NMR (500 MHz, CDCl3, ppm)) δ 7.63 (t,
J = 1.7 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H),
7.29 (t, J = 3.9 Hz, 1H), 7.14−7.08 (m, 1H), 6.27−6.20 (m, 1H);
13C{1H} NMR (126 MHz, CDCl3, ppm) δ 136.2 (q, J = 6.7 Hz),
135.4, 132.9, 130.5, 130.3, 126.2, 123.3 (q, J = 269.2 Hz), 123.1,
117.3 (q, J = 34.1 Hz); 19F NMR (471 MHz, CDCl3, ppm) δ −63.60;
IR (KBr, cm−1) ν 2926, 2854, 2361, 1734, 1524; HRMS (ESI) calcd
for C9H6BrF3Na [M + Na]+ 272.9497, found 272.9498.
1
7.28 (s, 1H), 7.07 (dd, J = 16.1, 2.1 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H),
6.95−6.93 (m, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.03 (s, 2H); 13C{1H}
NMR (126 MHz, CDCl3, ppm) δ 149.3, 148.4, 137.2 (q, J = 6.9 Hz),
127.7, 123.8 (q, J = 268.7 Hz), 123.5, 113.8 (q, J = 33.7 Hz), 108.5,
106.2, 101.6; 19F NMR (471 MHz, CDCl3, ppm) δ −62.88; IR (KBr,
cm−1) ν 3830, 2922, 2356, 1501, 1258, 1114; HRMS (ESI) calcd for
C10H8F3O2 [M + H]+ 217.0470, found 217.0465.
(E)-1-Nitro-3-(3,3,3-trifluoroprop-1-en-1-yl)benzene (3m): 44 mg
(67% yield), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 8.36 (t,
J = 1.8 Hz, 1H), 8.27 (dd, J = 8.2, 1.4 Hz, 1H), 7.81 (d, J = 7.7 Hz,
1H), 7.63 (t, J = 8.0 Hz, 1H), 7.25 (ddd, J = 16.1, 4.1, 2.0 Hz, 1H),
6.39 (dq, J = 16.1, 6.3 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3,
ppm) δ 148.7, 135.1, 135.4 (q, J = 6.8 Hz), 133.2, 130.1, 124.5, 123.0
(q, J = 269.2 Hz), 122.2, 119.1 (q, J = 34.6 Hz); 19F NMR (471 MHz,
CDCl3, ppm) δ −63.86; IR (KBr, cm−1) ν 3088, 2926, 2858, 1671,
1538, 1127; HRMS (ESI) calcd for C9H6F3NO2 [M + H]+ 218.0423,
found 218.0418.
(E)-3-(3,3,3-Trifluoroprop-1-en-1-yl)pyridine (3t):5b 29 mg (57%
yield), yellow oil; 1H NMR (500 MHz, CDCl3, ppm) δ 8.72 (s, 1H),
8.65 (d, J = 3.3 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.38 (dd, J = 7.8,
4.9 Hz, 1H), 7.19 (dd, J = 16.2, 1.7 Hz, 1H), 6.32 (dq, J = 16.2, 6.3
Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3, ppm) δ 150.8, 149.1,
134.3 (q, J = 6.5 Hz), 134.0, 129.3, 123.9, 123.1 (q, J = 269.3 Hz),
118.2 (q, J = 34.1 Hz); 19F NMR (471 MHz, CDCl3, ppm) δ −63.82;
IR (KBr, cm−1) ν 2925, 2858, 1732, 1424, 1126; HRMS (ESI) calcd
for C8H6F3N [M + H]+ 174.0525, found 174.0524.
E
DOI: 10.1021/acs.joc.9b00766
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3,3,3-trifluoropropenyl derivatives. Org. Biomol. Chem. 2017, 15,
5693−5700.
ASSOCIATED CONTENT
■
S
* Supporting Information
̈
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The Supporting Information is available free of charge via the
Internet at The Supporting Information is available free of
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acs.joc.9b00766.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wyuchemhyb@126.com.
ORCID
Yibiao Li: 0000-0001-8249-5630
Lu Chen: 0000-0002-9601-4241
Yubing Huang: 0000-0002-3025-8366
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Foundation of the
Department of Education of Guangdong Province
(2017KZDXM085), Chemical Industry Collaborative Innova-
tion Center of Yueshan Town 2017 (368), and the Foundation
for Young Talents (construction of N-biheteroarenes by the
hydrogen transfer strategy and its antitumor activity).
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