Free-Radical-Promoted Copper-Catalyzed Decarboxylative Alkylation of α,β-Unsaturated Carboxylic Acids with ICH2CF3 and Its Analogues

Article abstract of DOI:10.1021/acs.joc.7b01107

A novel and efficient free-radical-promoted copper-catalyzed decarboxylative alkylation of α,β-unsaturated carboxylic acids with ICH₂CF₃ and its analogues has been developed. This methodology provides a convenient access to the synthesis of allylic trifluoromethyl and β-CF₃ ketone containing compounds as well as other biologically useful fluorinated molecules and materials.

Full text of DOI:10.1021/acs.joc.7b01107

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Article
A Free Radical Promoted Copper-Catalyzed Decarboxylative Alkylation
of #,#-Unsaturated Carboxylic Acids with ICH2CF3 and its Analogues
Yan Zhu, Juwen Gong, and Yonghui Wang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 21 Jun 2017
Downloaded from http://pubs.acs.org on June 21, 2017
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A Free Radical Promoted Copper-Catalyzed Decarboxylative Alkylation of
α,β
-Unsaturated Carboxylic Acids with ICH2CF3 and its Analogues
Yan Zhu, Juwen Gong and Yonghui Wang*
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School of Pharmacy, Fudan University, 826 Zhangheng Road, Pudong, Shanghai 201203, China
yonghuiwang@fudan.edu.cn
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ABSTRACT: A novel and efficient free radical promoted copper-catalyzed decarboxylative alkylation of α,β-
unsaturated carboxylic acids with ICH2CF3 and its analogues has been developed. This methodology provides with a
convenient access to the synthesis of allylic trifluoromethyl and β-CF3 ketone containing compounds as well as other
biologically useful fluorinated molecules and materials.
Introduction
Due to its unique properties such as high electronegativity and acting as a bioisostere of the hydrogen atom,
fluorine is frequently found in some medicines and agrochemicals. About 20% of all marketed drugs, including a few
blockbuster drugs, contain fluorine.1 In particular, the trifluoromethyl group (CF3) has attracted substantial attention in
recent years and frequently found in certain pharmaceuticals and fluorocarbon-based compounds due to its unique
chemical and physiological stability and lipophilicity.2,3 For example, compound A (Figure 1) containing allylic
trifluoromethyl moiety is a potential indoleamine 2,3-dioxygenase (IDO) inhibitor for cancer immunotherapy,4 while
compound B containing β-CF3 ketone moiety is a potential herbicide which is extremely important in achieving high
crop efficiency.5 So far, tremendous progress has been acquired toward the incorporation of CF3 groups into aromatic
compounds.6 However, direct trifluoroethylation especially for synthesizing allylic trifluoromethanes and β-CF3
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ketones using inexpensive ICH2CF3 was seldom reported.
Figure 1. Biologically active compounds containing allylic trifluoromethane and β-CF3 ketone core structure
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Recently, there have been some reports for synthesizing allylic trifluoromethanes using copper-catalyzed
electrophilic allylic trifluoromethylation of terminal alkenes,8 nucleophilic allylic trifluoroethylation of allylic halides,9
and decarboxylative trifluoromethylation of allylic bromodifluoroacetate (Scheme 1).10 In 2012, Hu and his co-workers
reported palladium-catalyzed 2,2,2-trifluoroethylation of alkenyl boronic esters to synthesize allylic
trifluoromethanes.11 Later, Carreira reported the first example of cobalt-catalyzed Heck-type coupling reaction to
synthesize allylic trifluoromethanes using ICH2CF3 in a novel photochemical flow reactor.12 Very recently, Wu group
reported a copper-catalyzed decarboxylative trifluoroethylation of cinnamic acids.13 In 2015, Cho group reported
synthesis of β-trifluoromethlated ketones from propargylic alcohols by visible light photoredox catalysis.14 Later,
Margus and Xu reported an access to β-trifluoromethyl-substituted ketones via copper-catalyzed ring-opening
trifluoromethylation of substituted cyclopropanols.15 In the same year, a method of visible-light-induced photocatalysis
of 1,1,1-trifluoro-2-iodoethane with silyl enol ethers to prepare β-trifluoromethlated ketones was developed by Guo
and his co-workers.16 Xiang group recently reported copper/silver catalyzed oxidative coupling of vinylarenes with
ICH2CF3 or ICH2CHF2, leading to β-CF3/CHF2 substituted ketones.17 However, the reported methods of using
vinylarenes and ICH2CF3 to synthesize allylic trifluoromethanes and β-trifluoromethlated ketones are still limited. We
hope to develop a direct fluoroethylation method using inexpensive ICH2CF3 as well as its analogues such as
ICH2CHF2, ICH2CH2F and ICH2CH2CF3 to synthesize allylic trifluoromethanes, β-CF3 ketones and other fluorinated
compounds. We hypothesized that allylic trifluoromethanes and β-CF3 ketones could be achieved by using cinnamic
acids or 2-arylacrylic acids reacting with ICH2CF3 or its analogs through a free radical promoted process.
Scheme 1. Synthesis of allylic trifluoromethanes and β-CF3 ketones
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Synthesis of allylic trifluoromethanes:8-13
O
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is
]-c
atalys
R
[Cu
O
I
Buchwald's work
CF3
Cu salt or Cu metal (> 1 equiv)
Nishibayashi's work
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CF3SiMe3
O
R
X
[Cu]-catalysis
KF
R
O
CF2Br
Altman's work
R
CF3
O
B
[Pd]-catalysis
Hu's work
I
CF3
O
R
[Co]-catalysis
Blue LED
R
I
CF3
CF3
Carreira's work
[Cu] / [Ag]
Base
COOH
R
I
Wu's work
Synthesis of -CF3 ketones:14-17
OH
R
Photocatalyst
Cho's work
CF3I
[Cu]-catalysis
Togni reagent
Margus's work
R
OH
O
R
CF3
R
Photocatalyst
Guo's work
Si
O
I
CF3
[Cu]-catalysis
Xiang's work
R
I
CF3
This work:
O
O
R1
OH
R2
COOH
R1
CF3
Up to 85 %
I
CF3
R2
CF3
Cu / Ag salt,
Base, TBHP,
Microwave, 0.5 h
Cu / Ag salt,
Base, TBHP,
Microwave, 0.5 h
Up to 95 %
Results and Discussion
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Initially, 4-methoxycinnamic acid (1a) and 2,2,2-trifluoroethyl iodide (2a) were taken as representative reactants
to optimize the reaction conditions reported by Xiang.17 As depicted in entry 1 of Table 1, only 5% yield of the desired
product 3a was obtained with the first attempt. The yield of the product 3a rose to 29% when reaction was carried out
with 20% of Ag2SO4 as additive (Table 1, entry 2). Further attempts in the control experiments showed that the reaction
could hardly occur in absence of copper catalyst, base or oxidant (Table 1, entry 3-5). Next, different amounts of
Ag2SO4 were examined, and the results indicated that 100% of Ag2SO4 was superior to the other amounts (Table 1,
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entry 6-8), although the exact role of Ag2SO4 in promoting the reaction is not clear. However, to our great surprise and
delight, explorations on the reactants ratio of 1a and 2a indicated that the yield of 3a was able to be increased to 88%
(85% yield) when a ratio of 1a and 2a being 2:1 was applied (Table 1, entry 9-13). The optimized reaction conditions
(Table 1, entry 10) was then used for synthesizing allylic trifluoromethanes, β-trifluoromethlated ketones and other
fluorinated compounds.
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Table 1. Screening of the reaction conditionsa
Yield
(%)b
Catalyst
(mol%)
Additive
(mol%)
Base/
Oxidant (1a : 2a)
Ratio
Entry
1
Et3N/
Cu(acac)2
(20)
-
1.25 : 1
TBHP
5
Cu(acac)2
(20)
Ag2SO4
(20)
Et3N/
2
1.25 : 1
TBHP
29
Ag2SO4
(20)
Et3N/
3
4
-
1.25 : 1
TBHP
trace
NR
Cu(acac)2
(20)
Ag2SO4
(20)
TBHP
Et3N
1.25 : 1
1.25 : 1
Cu(acac)2
(20)
Ag2SO4
(20)
5
6
NR
38
Cu(acac)2
(20)
Ag2SO4
(50)
Et3N/
1.25 : 1
TBHP
Cu(acac)2
(20)
Ag2SO4
(100)
Et3N/
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8
9
1.25 : 1
1.25 : 1
1.5 : 1
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64
TBHP
Cu(acac)2
(20)
Ag2SO4
(200)
Et3N/
TBHP
Cu(acac)2
(20)
Ag2SO4
(100)
Et3N/
TBHP
Cu(acac)2 Ag2SO4
Et3N/
88
10
2 : 1
(20)
(100)
TBHP
(85c)
Cu(acac)2
(20)
Ag2SO4
(100)
Et3N/
11
2.5 : 1
60
51
30
TBHP
Cu(acac)2
(20)
Ag2SO4
(100)
Et3N/
12
13
1 : 2
1 : 3
TBHP
Cu(acac)2
(20)
Ag2SO4
(100)
Et3N/
TBHP
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[a] Reaction conditions: 1a, 2a, catalyst, additive, Et3N (0.8 mmol), TBHP (1.2 mmol, 70% in water), CH3CN,
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microwave, 80 °C, 30 mins, air; [b] HPLC yield; [c] Yield based on ICH2CF3
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With the optimized reaction conditions, a wide range of acrylic acids bearing either electron-donating or electron-
withdrawing groups were subjected to the reactions with 2,2,2-trifluoroethyl iodide, as summarized in Table 2. The
presence of electron-donating groups such as methoxy groups on the aromatic ring was found to be beneficial to the
reaction and the formation of allylic trifluoromethanes 3 was in moderate to good yields (Table 2, 3b-j). For the
electron-withdrawing substituents such as flouro-(3k), chloro-(3l), bromo-(3m), cyano-(3n) on the para position of the
aromatic ring, allylic trifluoromethanes were produced only in moderate yields. However, when p-nitrocinnamic acid
with strong electron-withdrawing group was used, the reaction could hardly occur (Table 2, 3o). It is noteworthy that α-
methylcinnamic acid could not produce the desired product possibly due to a steric effect of the methyl group in α-
position (Table 2, 3p). Furthermore, heteroaryl-substituted acrylic acids were amenable to this reaction (Table 2, 3q
and 3r). To our delight, 9-fluorenylideneacetic acid and (2E, 4E)-5-phenylpenta-2,4-dienoic acid could also gave the
corresponding products in 62% (E:Z = 12.5:1) and 41% yields, respectively (Table 2, 3s and 3t). Most notably, indole
moiety was found to be well tolerated in this type of reaction without any protection (Table 2, 3u).
a, b
Table 2. Substrate scope for the reaction of cinnamic acids with ICH2CF3
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[a] Reaction conditions: 1 (0.8 mmol), 2a (0.4 mmol), Cu(acac)2 (0.08 mmol), Ag2SO4 (0.4 mmol), Et3N (0.8 mmol),
TBHP (1.2 mmol, 70% in water), CH3CN, microwave, 80 °C, 30 mins, air; [b] Yield based on ICH2CF3
With the promising results obtained in our studies on cinnamic acids, we continued our efforts toward exploring
the reactivity of various 2-arylacrylic acids with ICH2CF3 under the same optimized conditions (Table 3). It was shown
that 2-arylacrylic acids with either electron-donating or electron-withdrawing groups were all well-tolerated in the
reaction. The desired β-CF3 ketones (Table 3. 5a-5c) were isolated in yields of 68-81% with the electron-donating
methyl or methoxy groups. For electron-withdrawing groups such as F, Cl and Br on the aromatic ring, moderate to
excellent yields of the corresponding β-CF3 ketones were obtained under the optimized conditions. (Table 3. 5d-5f)
Noting that 2-phenylacrylic acid gave rise to the corresponding β-CF3 ketone in 72% yield under argon atmosphere
(Table 3, 5ac) which ruled out the possibility that the oxygen gas of air donating the oxygen atom to generate the
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ketone.
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a, b
Table 3. Substrate scope for the reaction of 2-arylacrylic acids with ICH2CF3
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[a] Reaction conditions: 4 (0.8 mmol), 2a (0.4 mmol), Cu(acac)2 (0.08 mmol), Ag2SO4 (0.4 mmol), Et3N (0.8 mmol),
TBHP (1.2 mmol, 70% in water), CH3CN, microwave, 80 °C, 30 mins, air.; [b] Yield based on ICH2CF3; [c] In Ar
Encouraged by the results of reactions using 2,2,2-trifluoroethyl iodide, the decarboxylative alkenylation strategy
was subsequently applied to a variety of other fluorinated reagents. Like 2,2,2-trifluoroethyl iodide, 1,1-difluoro- 2-
iodoethane performed well to give the corresponding allylic difluoromethane in 84% yield (Table 4, 6a). When 1-
fluoro-2- iodoethane, 1,1,1-trifluoro-3-iodopropane and 2-iodoacetonitrile were employed as substrates to react with
1a, lower yields of the corresponding products were obtained (Table 4, 6b, 6c and 6d). Gratefully, β-CHF2 ketone, γ-F
ketone, γ-CF3 ketone and β-CN ketone core structures could be easily obtained under the optimized conditions (Table
4, 7a-7d).
a, b
Table 4. Substrate scope for the reactions of α, β-unsaturated acids with analogues of ICH2CF3
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[a] Reaction conditions: 1a or 4f (0.8 mmol), 2 (0.4 mmol), Cu(acac)2 (0.08 mmol), Ag2SO4 (0.4 mmol), Et3N (0.8
mmol), TBHP (1.2 mmol, 70% in water), CH3CN, microwave, 80 °C, 30 mins, air; [b] Yield based on 2
To study the reaction mechanism, some experiments were designed and performed. Firstly, isotope labelling
experiment (TBHP in decane and H2O18, instead of TBHP in water) was performed, and the product 5a was
detected by HRMS and then isolated in 82% yield. No isotope product O18-5a’ was identified (Scheme 2, C)
. This
indicates that the oxygen atom in product 5a was not originally from water. Then the reaction of ICH2CF3 and 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) was attempted under the optimized conditions, and the expected product
TEMPO-CH2CF3 was detected by HRMS, and the yield was 74% based on 19F NMR data (Scheme 2, D). When
TEMPO was added to the reaction of 4-methoxycinnamic acid with ICH2CF3 or 2-arylacrylic acid with ICH2CF3 under
the optimized conditions, the corresponding products 3a and 5a were not detected by LC-MS and 19F NMR, but
TEMPO−CH2CF3 were formed in 47% and 43% yield, respectively (Scheme 2, E and F). These experimental results
indicated that the reaction proceeded through a free radical process.
Scheme 2. Mechanism study
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A proposed mechanism based on the literature precedent and experimental data is shown in Scheme 3. Initially,
reaction of cinnamic acid with copper catalyst would produce a salt of Cu (II) carboxylate (I) in the presence of base
and TBHP. A free radical CH2CF3 was generated under copper/silver catalyst and TBHP. Addition of CH2CF3 to the
α-position of double bond in cupric cinnamate gave radical J. An elimination of Cu (I) carbon dioxide then occurred,
generating product K.18 Oxidation of Cu (I) by the oxidant in the presence of cinnamic acid would regenerate the
cupric cinnamate. However, there is also a possibility that the decarboxylation occurred first and then
α–CF3
alkylcopper species formed.19 Similarly, radical N was generated after addition of CH2CF3 to Cu (II) carboxylate (N),
which then combined with tBuOO to afford intermediate P. Finally Pwas converted into product β-CF3 ketone in the
presence of base by releasing Cu (I), carbon dioxide and one molecule of tert-butanol. 20
Scheme 3. Proposed mechanism
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R2
COOH
Base
ICH2CF3
Cu / Ag
L
COOH
R1
G
H
[O]
COO
Cu (II)
R1
Cu (II)
COO
Base
COO
R2
2
9
2
CF3CH2
I
R2
COO
N
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R1
M
Cu (II)
COO
O
COO
J
Cu (II)
CF3
Cu (II)
2
2
R1
CF3
[O]
Cu (II)
R2
CO2
Cu (I)
[O]
TBHP
t-BuOH + CO2
Cu (I)
O
O
COO Cu (II)
2
O
R1
CF3
R2
CF3
K
P
R2
CF3
Q
Conclusions
In conclusion, we have developed a simple approach to the synthesis of allylic trifluoromethyl and β-CF3 ketone
compounds by a free radical promoted copper-catalyzed decarboxylative alkylation. This strategy provides an efficient
and convenient access to the synthesis of fluorinated biologically active molecules and materials. Further investigations
toward detailed mechanistic studies and synthetic applications are currently underway.
Experimental Section
General Information: All commercially available reagents were used without further purification unless otherwise
stated. All of the microwave-assisted reactions were performed in an Initiator microwave system at the specified
temperature which was monitored by external surface sensor using the standard mode of operation. The reactions were
monitored by thin-layer chromatography (TLC analysis. Silica gel (200-300 mesh) was used for column
chromatography. High-resolution MS (HRMS) were recorded on a commercial apparatus; the ion source is
electrospray ionization (ESI). 1H, 19F NMR spectra were recorded on 400 MHz instrument and C NMR spectra was
13
recorded on 600 MHz instrument. Chemical shifts in 1H NMR spectra are reported in parts per million (ppm) on the δ
scale from an internal standard of CDCl3 (7.26 ppm). Data are reported as follows: chemical shift (δ ppm), multiplicity
(s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constant in hertz (Hz), and
integration. Chemical shifts of 13C NMR spectra are reported in ppm from the central peak of CDCl3 (77.0 ppm) on the
δ scale.
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General procedure for the synthesis of arylacrylic acids 21
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Typical procedure (i): HCHO solution 37% (28 mmol, 2.8 equiv, 2.27 g), nBu4NI (0.5 mmol, 0.05 equiv, 184.7
mg), and K2CO3 (30 mmol, 3 equiv, 4.15 g) were added to a solution of methyl 2-arylacetate (10 mmol, 1 equiv) in
toluene (13 mL) at room temperature. The resulting mixture was stirred for 12 h at 50 °C. After cooling to room
temperature, water (10 mL) was added and the aqueous phase was extracted with ethyl acetate (3x20 mL). The
collected organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give the
corresponding methylene ester, which was purified by flash chromatography. (ii) An aqueous solution of 1 N sodium
hydroxide (10 mL) was added to different ethyl acrylate (5 mmol), and then the reaction mixture was refluxed for 1 h.
After cooling down to room temperature, the resulting mixture was extracted with diethyl ether three times (3x20 mL).
The aqueous layer was then acidified with 3N aqueous HCl solutions (pH < 1.0 by litmus paper test), and extracted
with ethyl ether (3x20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated.
The crude acrylic acids were separated on a silica gel column with petroleum ether (60-90 °C), ethyl acetate and HOAc
(5‰) as eluent to afford the desired product (For detailed structure information please see Supporting Information
Scheme S1 on page S2).
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General procedure for the synthesis of 3, 5, 6 and 7. To a sealed microwave reaction vial were added acrylic acid
(0.8 mmol), ICH2CF3 (0.4 mmol, 84.0 mg), Cu(acac)2 (0.08 mmol, 20.9 mg), Ag2SO4 (0.4 mmol, 124.5 mg), Et3N (0.8
mmol, 81.6 mg), TBHP (1.2 mmol, 154.4 mg, 70% in water) and MeCN (2 mL). Then the reaction mixture was stirred
at 80 °C for 30 minutes in microwave reactor. After completion of the reaction, the resulting mixture was diluted with
ethyl acetate (EA) and washed with water. The separated aqueous phase was washed with EA. The combined organic
layers were dried over MgSO4, filtered, and concentrated under vacuo. The crude mixture was purified by column
chromatography on silica gel (petroleum: ethyl acetate = 20:1~9:1) to afford the desired product 3a-3u.
To a sealed microwave reaction vial were added 2-arylacrylic acid (0.8 mmol), ICH2CF3 (0.4 mmol, 84.0 mg),
Cu(acac)2 (0.08 mmol, 20.9 mg), Ag2SO4 (0.4 mmol, 124.5 mg), Et3N (0.8 mmol, 81.6 mg), TBHP (1.2 mmol, 154.4
mg, 70% in water) and MeCN (2 mL). Then the reaction mixture was stirred at 80 °C for 30 minutes in microwave
reactor. After completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and washed with
water. The separated aqueous phase was washed with EA. The combined organic layers were dried over MgSO4,
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filtered, and concentrated under vacuo. The crude mixture was purified by column chromatography on silica gel
(petroleum: ethyl acetate = 10:1~5:1) to afford the desired product 5a-5f.
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To a sealed microwave reaction vial were added (E)-3-(4-methoxyphenyl)acrylic acid (0.8 mmol, 142.5 mg), 2
(0.4 mmol), Cu(acac)2 (0.08 mmol, 20.9 mg), Ag2SO4 (0.4 mmol, 124.5 mg), Et3N (0.8 mmol, 81.6 mg), TBHP (1.2
mmol, 154.4 mg, 70% in water) and MeCN (2 mL). Then the reaction mixture was stirred at 80 °C for 30 minutes in
microwave reactor. After completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and
washed with water. The separated aqueous phase was washed with EA. The combined organic layers were dried over
MgSO4, filtered, and concentrated under vacuo. The crude mixture was purified by column chromatography on silica
gel (petroleum: ethyl acetate = 20:1~9:1) to afford the desired product 6a-6d.
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To a sealed microwave reaction vial were added 2-(4-bromophenyl)acrylic acid (0.8 mmol, 181.6 mg), 2 (0.4
mmol), Cu(acac)2 (0.08 mmol, 20.9 mg), Ag2SO4 (0.4 mmol, 124.5 mg), Et3N (0.8 mmol, 81.6 mg), TBHP (1.2 mmol,
154.4 mg, 70% in water) and MeCN (2 mL). Then the reaction mixture was stirred at 80 °C for 30 minutes in
microwave reactor. After completion of the reaction, the resulting mixture was diluted with ethyl acetate (EA) and
washed with water. The separated aqueous phase was washed with EA. The combined organic layers were dried over
MgSO4, filtered, and concentrated under vacuo. The crude mixture was purified by column chromatography on silica
gel (petroleum: ethyl acetate = 10:1~5:1) to afford the desired product 7a-7d.
(E)-1-methoxy-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3a) 22 73.5 mg, 85% yield; Colorless oil; 1H NMR (400 MHz,
CDCl3) δ 7.36 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.57 (d, J = 15.8 Hz, 1H), 6.01 (dt, J = 14.8, 7.3 Hz, 1H),
3.83 (s, 3H), 3.06 – 2.93 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 159.6, 136.0, 129.0, 127.6, 126.1 (q, J = 276.0
Hz), 114.7, 114.0, 55.1, 37.5 (q, J = 29.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.40 (t, J = 10.6 Hz, 3F); MS
(ESI) m/z 217.2 [M + H]+.
(E)-1-methoxy-3-(4,4,4-trifluorobut-1-en-1-yl)benzene (3b) 39.8 mg, 46% yield; Pale yellow oil; 1H NMR (400 MHz,
CDCl3) δ 7.25 (dd, J = 9.5, 6.3 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 6.84 (dd, J = 8.2, 1.8 Hz, 1H), 6.58 (d,
J = 15.8 Hz, 1H), 6.18 – 6.04 (m, 1H), 3.82 (s, 3H), 3.06 – 2.91 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 159.9,
137.6, 136.6, 129.6, 125.9 (q, J = 274.5 Hz), 119.1, 117.5, 113.7, 111.8, 55.2, 37.6 (q, J = 29.9 Hz); 19F {1H} NMR
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(376 MHz, CDCl3) δ -66.19 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C11H12F3O: 217.0835, found:
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217.0836.
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(E)-1-methoxy-2-(4,4,4-trifluorobut-1-en-1-yl)benzene (3c)
45.0 mg, 52% yield; Pale yellow oil; H NMR (400
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MHz, CDCl3) δ 7.45 (d, J = 7.6 Hz, 1H), 7.27 (dd, J = 13.2, 4.9 Hz, 1H), 7.02 – 6.93 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H),
6.16 (dt, J = 15.9, 7.2 Hz, 1H), 3.86 (s, 3H), 3.09 – 2.94 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 156.7, 131.6,
129.1, 128.8, 127.3, 126.0 (q, J = 274.5 Hz), 123.3, 120.7, 117.7, 110.9, 38.1 (q, J = 29.7 Hz); 19F {1H} NMR (376
MHz, CDCl3) δ -66.21 (t, J = 10.7 Hz, 3F); MS (ESI) m/z 217.2 [M + H]+.
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(E)-2,4-dimethoxy-1-(4,4,4-trifluorobut-1-en-1-yl)benzene (3d) 79.7 mg, 81% yield; Colorless oil; H NMR (400
MHz, CDCl3) δ 7.36 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 15.9 Hz, 1H), 6.54 – 6.42 (m, 2H), 6.03 (dt, J = 15.8, 7.2 Hz,
1H), 3.84 (s, 3H), 3.82 (s, 3H), 3.08 – 2.90 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 160.8, 157.9, 131.2, 130.0,
126.1 (q, J = 274.5 Hz), 118.3, 115.3, 104.8, 98.4, 55.3, 55.2, 38.1 (q, J = 29.6 Hz); 19F {1H} NMR (376 MHz, CDCl3)
δ -66.33 (t, J = 10.8 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C12H14F3O2: 247.0940, found: 247.0953.
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(E)-1,2-dimethoxy-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3e) 24 79.7 mg, 81% yield; Colorless oil; H NMR (400
MHz, CDCl3) δ 6.90 (d, J = 9.5 Hz, 2H), 6.80 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 15.8 Hz, 1H), 6.02 – 5.90 (m, 1H), 3.89
(s, 3H), 3.86 (s, 3H), 3.02 – 2.89 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 149.2, 149.0, 136.2, 129.2, 125.9 (q, J
= 274.5 Hz), 119.7, 115.0, 111.0, 108.7, 55.8, 55.7, 37.5 (q, J = 29.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.76
(t, J = 10.7 Hz, 3F); MS (ESI) m/z 247.2 [M + H]+.
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(E)-5-(4,4,4-trifluorobut-1-en-1-yl)benzo[d][1,3]dioxole (3f) 51.5 mg, 56% yield; Colorless oil; H NMR (400 MHz,
CDCl3) δ 6.93 (s, 1H), 6.79 (dd, J = 19.9, 8.0 Hz, 2H), 6.51 (d, J = 15.8 Hz, 1H), 5.98 – 5.90 (m, 1H), 5.96 (s, 2H),
3.03 – 2.89 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 148.1, 147.6, 136.2, 130. 7, 128.7, 125.9 (q, J = 274.5 Hz),
115.3, 108.3, 105.7, 101.1, 37.5 (q, J = 29.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.31 (t, J = 10.7 Hz, 3F);
HRMS (ESI): m/z [M + H]+ calcd for C11H10F3O2: 231.0627, found: 231.0633.
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(E)-1-methyl-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3g) 33.4 mg, 42% yield; Colorless oil; H NMR (400 MHz,
CDCl3) δ 7.30 (t, J = 13.9 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.60 (d, J = 15.8 Hz, 1H), 6.10 (dt, J = 14.9, 7.3 Hz, 1H),
3.10 – 2.89 (m, 2H), 2.38 (s, 3H); 13C {1H} NMR (150 MHz, CDCl3) δ 138.0, 136.5, 133.5, 129.3, 126.3, 126.0 (q, J =
274.5 Hz), 116.1, 37.7 (q, J = 29.9 Hz), 21.1; 19F {1H} NMR (376 MHz, CDCl3) δ -66.25 (t, J = 10.7 Hz, 3F); MS
(ESI) m/z 200.1 [M + H]+.
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(E)-1,2,3-trimethoxy-5-(4,4,4-trifluorobut-1-en-1-yl)benzene (3h) 91.7 mg, 83% yield; Colorless oil; H NMR (400
MHz, CDCl3) δ 6.64 – 6.56 (m, 2H), 6.51 (d, J = 15.8 Hz, 1H), 6.08 – 5.90 (m, 1H), 3.86 (s, 6H), 3.83 (s, 3H), 3.04 –
2.89 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 153.3, 138.2, 136.5, 131.8, 125.8 (q, J = 274.5 Hz), 116.5, 103.5,
60.8, 56.0, 37.4 (q, J = 29.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -65.92 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z
[M + H]+ calcd for C13H16F3O3: 277.1046, found: 277.0973.
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(E)-4-(4,4,4-trifluorobut-1-en-1-yl)-1,1'-biphenyl (3i) 70.2 mg, 67% yield; White solid, mp: 114.7-116.9 °C; 1H NMR
(400 MHz, CDCl3) δ 7.60 (dd, J = 13.6, 5.0 Hz, 4H), 7.54 – 7.41 (m, 4H), 7.36 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 15.8
Hz, 1H), 6.16 (dt, J = 15.8, 7.3 Hz, 1H), 3.13 – 2.92 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 140.9, 140.6, 136.2,
135.2, 128.8, 128.7, 127.4, 127.3, 127.0, 125.9 (q, J = 283.5 Hz), 117.2, 37.7 (q, J = 30.0 Hz); 19F {1H} NMR (376
MHz, CDCl3) δ -66.15 (td, J = 10.6, 3.5 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C16H14F3: 263.1042, found:
263.1049.
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(E)-1-(benzyloxy)-2-methoxy-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3j) 104.4 mg, 81% yield; Pale yellow oil; H
NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.3 Hz, 2H), 7.39 (t, J = 7.3 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 6.98 (s, 1H),
6.93 – 6.81 (m, 2H), 6.54 (d, J = 15.8 Hz, 1H), 6.00 (dt, J = 14.8, 7.3 Hz, 1H), 5.18 (s, 2H), 3.93 (s, 3H), 3.06 – 2.89
(m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 149.7, 148.3, 136.9, 136.2, 129.7, 128.6, 128.5, 127.8, 125.9 (q, J =
274.5 Hz), 119.5, 115.2, 113.9, 109.4, 70.9, 55.9, 37.5 (q, J = 29.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.18 (t,
J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C18H18F3O2: 323.1253, found: 323.1260.
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(E)-1-fluoro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3k) 28.6 mg, 35% yield; Colorless oil; H NMR (400 MHz,
CDCl3) δ 7.25 - 7.08 (m, 2 H), 6.83 (t, J = 8.4 Hz, 2 H), 6.37 (d, J = 15.8 Hz, 1 H), 5.92 – 5.75 (m, 1 H), 2.88 – 2.63
(m, 2 H); 13C {1H} NMR (150 MHz, CDCl3) δ 162.6 (d, J = 247.5 Hz), 135.5, 132.4 (d, J = 2.7 Hz), 128.0 (d, J = 8.0
Hz), 125.9 (q, J = 274.5 Hz), 117.0, 115.6 (d, J = 21.7 Hz), 37.6 (q, J = 30.0 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ
-66.47 (t, J = 10.6 Hz, 3F), -113.91; MS (ESI) m/z 205.1 [M + H]+.
(E)-1-chloro-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3l) 25 33.5 mg, 38% yield; Colorless oil; H NMR (400 MHz,
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CDCl3) δ 7.31 (s, 4H), 6.57 (d, J = 15.9 Hz, 1H), 6.10 (dt, J = 15.4, 7.2 Hz, 1H), 3.08 – 2.91 (m, 2H); 13C {1H} NMR
(150 MHz, CDCl3) δ 135.4, 134.7, 133.8, 128.8, 127.6, 125.8 (q, J = 276.0 Hz), 117.9, 37.6 (q, J = 30.0 Hz); 19F {1H}
NMR (376 MHz, CDCl3) δ -66.17 (t, J = 10.6 Hz, 3F); MS (ESI) m/z 221.1 [M + H]+.
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(E)-1-bromo-4-(4,4,4-trifluorobut-1-en-1-yl)benzene (3m) 35.0 mg, 33% yield; Colorless oil; H NMR (400 MHz,
CDCl3) δ 7.44 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 8.3 Hz, 2H), 6.53 (d, J = 15.9 Hz, 1H), 6.18 – 6.01 (m, 1H), 3.07 – 2.84
(m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 135.5, 135.1, 131.8, 127.9, 125.7 (q, J = 274.1 5Hz), 122.0, 118.0, 37.6
(q, J = 30.0 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.14 (t, J = 10.6 Hz, 3F); MS (ESI) m/z 265.1 and 267.1 [M +
H]+.
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(E)-4-(4,4,4-trifluorobut-1-en-1-yl)benzonitrile (3n) 32.1 mg, 38% yield; Pale yellow oil; 1H NMR (400 MHz, CDCl3)
δ 7.56 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 6.56 (d, J = 15.9 Hz, 1H), 6.18 (dt, J = 15.8, 7.2 Hz, 1H), 3.07 –
2.88 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 140.5, 135.0, 132.4, 126.9 125.6 (q, J = 274.5 Hz), 121.3, 118.7,
111.4, 37.6 (q, J = 30.2 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -65.96 (t, J = 10.5 Hz, 3F); HRMS (ESI): m/z [M +
H]+ calcd for C11H9F3N: 212.0682, found: 212.0688.
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(E)-3-(4,4,4-trifluorobut-1-en-1-yl)pyridine (3q) 38.9 mg, 52% yield; Pale yellow oil; H NMR (400 MHz, CDCl3) δ
8.49 (d, J = 37.1 Hz, 2H), 7.65 (d, J = 7.7 Hz, 1H), 7.20 (s, 1H), 6.53 (d, J = 15.9 Hz, 1H), 6.21 – 6.00 (m, 1H), 3.06 –
2.83 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 149.1, 148.2, 133.2, 132.9, 131.8, 125.6 (q, J = 276.0 Hz), 123.5,
119.7, 37.7 (q, J = 30.2 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.25 (t, J = 10.6 Hz, 3F); HRMS (ESI): m/z [M +
H]+ calcd for C9H9F3N: 188.0682, found: 188.0695.
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(E)-2-(4,4,4-trifluorobut-1-en-1-yl)thiophene (3r) 30.0 mg, 39% yield; Colorless oil; H NMR (400 MHz, CDCl3) δ
7.19 (d, J = 4.4 Hz, 1H), 6.98 (d, J = 4.6 Hz, 2H), 6.73 (d, J = 15.7 Hz, 1H), 5.94 (dt, J = 14.9, 7.3 Hz, 1H), 3.07 –
2.87 (m, 2H); C {1H} NMR (150 MHz, CDCl3) δ 141.0, 129.6, 128.5, 127.4, 126.3,125.7 (q, J = 280.5 Hz), 116.6,
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37.5 (q, J = 30.1 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.23 (t, J = 10.6 Hz, 3F); HRMS (ESI): m/z [M + H]+
calcd for C8H8F3S: 193.0221, found:193.0220.
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((1E, 3E)-6,6,6-trifluorohexa-1,3-dien-1-yl)benzene (3s)
(E:Z = 12.5:1): 52.6 mg, 62% yield; Colorless oil; H
NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 14.8, 7.6 Hz, 2H), 7.31 (q, J = 7.5 Hz, 2H), 7.23 (d, J = 7.3 Hz, 0.78H), 7.20
(d, J = 6.0 Hz, 0.16H), 6.91 (dd, J = 15.5, 11.2 Hz, 0.08H), 6.74 (dd, J = 15.7, 10.4 Hz, 0.95H), 6.63 (d, J = 15.5 Hz,
0.09H), 6.53 (d, J = 15.7 Hz, 0.94H), 6.42 – 6.30 (m, 1H), 5.67 (dt, J = 15.0, 7.4 Hz, 0.84H), 5.45 (q, J = 7.7 Hz,
0.04H), 3.14 – 2.98 (m, 0.16H), 2.96 – 2.79 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 136.9, 136.8, 135.4, 134.3,
133.5, 128.7, 128.6, 128.5, 127.8, 127.6, 126.6, 126.5, 125.9 (q, J = 274.5 Hz), 120.7 (q, J = 3.0 Hz), 37.4 (q, J = 29.9
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Hz), 32.8 (q, J = 30.0 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -65.99 (t, J = 10.7 Hz), -66.24 (t, J = 10.6 Hz, 3F); MS
(ESI) m/z 213.2 [M + H]+.
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9-(3,3,3-trifluoropropylidene)-9H-fluorene (3t) 42.7 mg, 41% yield; White solid; mp: 64.2-65.7 °C; 1H NMR (400
MHz, CDCl3) δ 7.81 – 7.63 (m, 4H), 7.37 (dq, J = 23.5, 7.4 Hz, 4H), 6.60 (t, J = 6.9 Hz, 1H), 3.70 - 3.61 (m, 2H); 13C
{1H} NMR (150 MHz, CDCl3) δ 141.5, 139.8, 139.1, 138.5, 136.4, 128.9, 128.6, 127.3, 127.2, 125.9 (q, J = 273.0 Hz),
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124.6, 120.2, 120.1, 119.6, 114.9, 34.3 (q, J = 30.1 Hz); F {1H} NMR (376 MHz, CDCl3) δ -65.92 (t, J = 10.6 Hz,
3F); HRMS (ESI): m/z [M + H]+ calcd for C16H12F3: 261.0886, found: 261.0890.
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(E)-3-(4,4,4-trifluorobut-1-en-1-yl)-1H-indole (3u) 58.5 mg, 65% yield; Yellow solid; mp: 91.8-93.0 °C; H NMR
(400 MHz, CDCl3) δ 8.11 (s, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.21 (p, J = 7.1 Hz, 3H), 6.76 (d,
J = 16.0 Hz, 1H), 6.20 – 5.96 (m, 1H), 3.12 – 2.88 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 136.7, 129.3, 126.2
(q, J = 274.5 Hz), 125.4, 123.7, 122.7, 120.5, 119.9, 114.4, 113.7, 111.4, 38.3 (q, J = 29.7 Hz); 19F {1H} NMR (376
MHz, CDCl3) δ -66.45 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C12H11F3N: 226.0838, found:
226.0840.
4,4,4-trifluoro-1-phenylbutan-1-one (5a) 26 60.6 mg, 75% yield; White solid; mp: 59.3-60.2 °C; 1H NMR (400 MHz,
CDCl3) δ 8.04 – 7.90 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 3.32 – 3.19 (m, 2H), 2.68 – 2.49 (m,
2H); 13C {1H} NMR (150 MHz, CDCl3) δ 196.2, 136.1, 133.5, 129.9, 128.7, 127.2 (q, J = 273.0 Hz), 31.1 (d, J = 1.6
Hz), 28.3 (q, J = 29.7 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.85 (t, J = 10.9 Hz, 3F); MS (ESI) m/z 203.1 [M +
H]+.
4,4,4-trifluoro-1-(p-tolyl)butan-1-one (5b) 26 70.0 mg, 81% yield; White solid; mp: 79.3-81.8 °C; 1H NMR (400 MHz,
CDCl3) δ 7.96 – 7.77 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H), 3.23 (dd, J = 10.7, 4.8 Hz, 2H), 2.67 – 2.49 (m, 2H), 2.42 (s,
3H); 13C {1H} NMR (150 MHz, CDCl3) δ 195.9, 144.5, 133.7, 129.4, 128.1, 125.4 (q, J = 274.5 Hz), 31.0, 28.4 (q, J =
29.7 Hz), 21.6; 19F {1H} NMR (376 MHz, CDCl3) δ -66.42 (t, J = 12.0 Hz, 3F); MS (ESI) m/z 217.1 [M + H]+.
4,4,4-trifluoro-1-(4-methoxyphenyl)butan-1-one (5c) 26 63.1 mg, 68% yield; White solid; mp: 60.9-62.6 °C; 1H NMR
(400 MHz, CDCl3) δ 7.94 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.5 Hz, 2H), 3.87 (s, 3H), 3.30 – 3.11 (m, 2H), 2.68 – 2.45
(m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 194.8, 163.8, 130.3, 129.2, 127.2 (q, J = 274.5 Hz), 113.9, 55.5, 30.8,
28.4 (q, J = 29.6 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.42 (t, J = 10.9 Hz, 3F); MS (ESI) m/z 233.1 [M + H]+.
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4,4,4-trifluoro-1-(4-fluorophenyl)butan-1-one (5d) 26 57.2 mg, 65% yield; Colorless oil; 1H NMR (400 MHz, CDCl3)
δ 8.10 – 7.91 (m, 2H), 7.15 (t, J = 8.6 Hz, 2H), 3.23 (dd, J = 9.9, 5.6 Hz, 2H), 2.68 – 2.48 (m, 2H); 13C {1H} NMR
(150 MHz, CDCl3) δ 194.7, 166.0 (d, J = 255.6 Hz), 132.6, 130.7 (d, J = 9.4 Hz), 127.1 (q, J = 274.5 Hz), 115.9 (d, J
= 22.0 Hz), 31.1, 28.3 (q, J = 29.8 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.49 (t, J = 10.8 Hz, 3F), -104.29 (ddd,
J = 13.2, 6.6, 4.3 Hz, 1F); MS (ESI) m/z 221.1 [M + H]+.
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1-(4-chlorophenyl)-4,4,4-trifluorobutan-1-one (5e) 86.9 mg, 92% yield; White solid; mp: 66.9-68.1 °C; H NMR
(400 MHz, CDCl3) δ 7.89 (d, J = 7.4 Hz, 2H), 7.43 (d, J = 7.4 Hz, 2H), 3.47 – 3.07 (m, 2H), 2.73 – 2.39 (m, 2H); 13C
{1H} NMR (150 MHz, CDCl3) δ 195.0, 140.1, 134.4, 129.4, 129.1, 127.0 (q, J = 274.5 Hz), 31.1, 28.2 (q, J = 29.8 Hz);
19F {1H} NMR (376 MHz, CDCl3) δ -66.58 (t, J = 10.8 Hz, 3F); MS (ESI) m/z 237.1 [M + H]+.
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1-(4-bromophenyl)-4,4,4trifluorobutan-1-one (5f) 106.8 mg, 95% yield; White solid; mp: 78.6-80.1 °C; H NMR
(400 MHz, CDCl3) δ 7.81 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 3.27 – 3.13 (m, 2H), 2.67 – 2.45 (m, 2H); 13C
{1H} NMR (150 MHz, CDCl3) δ 195.2, 134.8, 132.0, 129.4, 128.7, 127.0 (q, J = 273.0 Hz), 31.1, 28.2 (q, J = 29.8 Hz);
19F {1H} NMR (376 MHz, CDCl3) δ -66.44 (t, J = 10.8 Hz, 3F); MS (ESI) m/z 281.1 and 283.1 [M + H]+.
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(E)-1-(4,4-difluorobut-1-en-1-yl)-4-methoxybenzene (6a) 66.6 mg, 84% yield; Colorless oil; H NMR (400 MHz,
CDCl3) δ 7.33 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 6.51 (d, J = 15.9 Hz, 1H), 6.00 (dt, J = 15.7, 7.3 Hz, 1H),
5.86 (t, J = 4.4 Hz, 0.41H), 5.72 (t, J = 4.4 Hz, 0.16H), 3.82 (s, 3H), 2.84 – 2.64 (m, 2H); 13C {1H} NMR (150 MHz,
CDCl3) δ 159.3, 134.6, 129.5, 127.4, 117.2 (t, J = 238.5 Hz), 117.1 (t, J = 6.6 Hz), 114.0, 55.2, 38.0 (t, J = 21.9 Hz);
19F {1H} NMR (376 MHz, CDCl3) δ -115.53 (dtd, J = 56.7, 17.3, 2.4 Hz, 2F); HRMS (ESI): m/z [M + H]+ calcd for
C11H13F2O: 199.0929, found: 199.0935.
(E)-1-(4-fluorobut-1-en-1-yl)-4-methoxybenzene (6b) 18.0 mg, 25% yield; Colorless oil; 1H NMR (400 MHz, CDCl3)
δ 7.30 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 15.9 Hz, 1H), 6.15 – 5.98 (m, 1H), 4.53 (dt, J = 47.2,
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6.3 Hz, 2H), 3.79 (s, 3H), 2.59 (dq, J = 23.7, 6.5 Hz, 2H); C {1H} NMR (150 MHz, CDCl3) δ 158.9, 132.1, 129.9,
127.1, 126.2, 113.8, 83.1 (d, J = 167.7 Hz), 55.0, 33.9 (d, J = 20.5 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -217.02
(ttd, J = 47.4, 23.7, 2.7 Hz, 1F); HRMS (ESI): m/z [M + H]+ calcd for C11H14FO: 181.1023, found: 181.1022.
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(E)-1-methoxy-4-(5,5,5-trifluoropent-1-en-1-yl)benzene (6c) 17.5 mg, 19% yield; Pale yellow oil; H NMR (400
MHz, CDCl3) δ 7.29 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 6.40 (d, J = 15.8 Hz, 1H), 6.10 – 5.95 (m, 1H), 3.80
(s, 3H), 2.46 (dd, J = 15.4, 7.1 Hz, 2H), 2.33 – 2.15 (m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 159.1, 131.0, 130.3,
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129.8, 126.9 (q, J = 276.0 Hz), 124.5, 123.4, 114.0, 55.1, 33.7 (q, J = 28.1 Hz), 25.4; 19F {1H} NMR (376 MHz,
CDCl3) δ -66.27 (t, J = 10.7 Hz, 3F); HRMS (ESI): m/z [M + H]+ calcd for C12H14F3O: 231.0991, found: 231.0995.
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(E)-4-(4-methoxyphenyl)but-3-enenitrile (6d) 2712.5 mg, 18% yield; Pale yellow solid; mp: 74.9-76.2 °C; H NMR
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(400 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 15.8 Hz, 1H), 5.91 (dt, J = 15.8,
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5.7 Hz, 1H), 3.81 (s, 3H), 3.27 (d, J = 5.7 Hz, 2H); C {1H} NMR (150 MHz, CDCl3) δ 159.7, 134.1, 128.4, 127.7,
117.5, 114.4, 114.1, 55.3, 20.7; MS (ESI) m/z 174.2 [M + H]+.
1-(4-bromophenyl)-4,4-difluorobutan-1-one (7a) 26 89.5 mg, 85% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 8.5 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 6.00 (tt, J = 56.9, 4.1 Hz, 1H), 3.13 (t, J = 7.2 Hz, 2H), 2.38 – 2.18
(m, 2H); 13C {1H} NMR (150 MHz, CDCl3) δ 196.6, 135.0, 131.9, 129.4, 128.5, 116.3 (t, J = 238.7 Hz), 30.7 (t, J =
4.9 Hz), 28.2 (t, J = 21.9 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -117.13 (dt, J = 56.8, 17.8 Hz, 2F); MS (ESI) m/z
263.1 and 265.1 [M + H]+.
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1-(4-bromophenyl)-4-fluorobutan-1-one (7b) 28 50.0 mg, 51% yield; Yellow oil; H NMR (400 MHz, CDCl3) δ 7.84
(d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 4.56 (dt, J = 47.2, 5.7 Hz, 2H), 3.12 (t, J = 7.1 Hz, 2H), 2.25 – 2.06 (m,
13
2H); C {1H} NMR (150 MHz, CDCl3) δ 198.0, 135.5, 131.9, 129.5, 128.3, 83.1 (d, J = 164.7 Hz), 33.9 (d, J = 3.8
Hz), 24.7 (d, J = 20.0 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ 45.44 (tt, J = 47.7, 27.5 Hz, 1F); MS (ESI) m/z 245.1
and 247.1 [M + H]+.
1-(4-bromophenyl)-5,5,5-trifluoropentan-1-one (7c) 87.0 mg, 74% yield; Colorless oil; 1H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.34 – 2.12 (m, 2H), 2.12 – 1.92 (m, 2H);
13C {1H} NMR (150 MHz, CDCl3) δ 197.5, 135.3, 132.0, 129.4, 128.4, 127.0 (q, J = 274.5 Hz), 36.7, 32.9 (q, J = 28.7
Hz), 16.3 (d, J = 2.4 Hz); 19F {1H} NMR (376 MHz, CDCl3) δ -66.11 (t, J = 10.8 Hz, 3F); HRMS (ESI): m/z [M + H]+
calcd for C11H11BrF3O: 294.9940, found: 294.9943.
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4-(4-bromophenyl)-4-oxobutanenitrile (7d) 46.7 mg, 49% yield; White solid; mp: 87.1-88.8 °C; H NMR (400
MHz, CDCl3) δ 7.81 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 3.34 (d, J = 6.7 Hz, 2H), 2.76 (d, J = 6.7 Hz, 2H);
13C {1H} NMR (150 MHz, CDCl3) δ 194.3, 134.3, 132.2, 129.4, 129.2, 119.0, 34.2, 11.7; MS (ESI) m/z 238.1 and
240.1 [M + H]+.
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Author Information
Corresponding Author
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*E-mail for Y. Wang: yonghuiwang@fudan.edu.cn
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Notes
The authors declare no competing financial interest.
Acknowledgments
This work was supported by Grant 81573276 from the National Science Foundation of China and Grant 15431900300
from Shanghai Bio-pharmaceutical Science and Technology Supporting Plan.
Supporting Information
Segmental experiment data, mechanism studies, 1H, 13C and 19F NMR data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
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ACS Paragon Plus Environment
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