Cu-catalyzed chlorotrifluoromethylation of alkenes with CF3SO2Cl

Article abstract of DOI:10.1016/j.jfluchem.2018.09.001

Although CF₃SO₂Cl is an efficient chlorotrifluoromethylation reagent, an expensive transition metal complex usually has to be used. We found that CuCl₂-catalyzed chlorotrifluoromethylation of alkenes with CF₃SO₂Cl occurred smoothly under mild conditions. A wide substrate scope and good functional group compatibility were observed.

Full text of DOI:10.1016/j.jfluchem.2018.09.001

Accepted Manuscript
Title: Cu-catalyzed Chlorotrifluoromethylation of Alkenes
with CF3SO2Cl
Authors: Wei Zhang, Jin-Hong Lin, Ji-Chang Xiao
PII:
S0022-1139(18)30290-2
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.09.001
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7-9-2018
7-9-2018
Please cite this article as: Zhang W, Lin J-Hong, Xiao J-Chang, Cu-catalyzed
Chlorotrifluoromethylation of Alkenes with CF3SO2Cl, Journal of Fluorine Chemistry
(2018), https://doi.org/10.1016/j.jfluchem.2018.09.001
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Cu-catalyzed Chlorotrifluoromethylation of Alkenes with CF3SO2Cl
Wei Zhang, Jin-Hong Lin,* and Ji-Chang Xiao*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University
of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China. Fax: +86-21-6416-6128; Tel: +86-21-5492-5340; Email: jlin@sioc.ac.cn,
jchxiao@sioc.ac.cn.
Graphical abstract
Chlorotrifluoromethylation of various alkenes, including aryl alkenes, α,β-unsaturated
alkenes and alkyl alkenes, with CF3SO2Cl catalyzed by a simple Cu complex is described.
Highlights

C
C
A
HLOROTRIFLUOROMETHYLATION WITH CF3SO2CL CATALYZED BY SIMPLE SYSTEM CONSISTING OF
U
C
L AND PYRIDINE WAS ACHIEVED
2
.

WIDE SUBSTRATE SCOPE AND GOOD FUNCTIONAL GROUP TOLERANCE WERE OBSERVED.

High yields were obtained under mild conditions.
Abstract: Although CF3SO2Cl is an efficient chlorotrifluoromethylation reagent, an expensive
transition metal complex usually has to be used. We found that CuCl2-catalyzed
chlorotrifluoromethylation of alkenes with CF3SO2Cl occurred smoothly under mild conditions. A
wide substrate scope and good functional group compatibility were observed.
Keywords: Chlorotrifluoromethylation, Alkenes, Catalysis, Copper, Fluorine
1. Introduction
Due to its strong electron-withdrawing nature (Hammett constants σp = 0.43, σm = 0.54) and
high lipophilicity (Hansch constant π = 0.88) [1, 2], trifluoromethyl group (CF3) has proven to be
a valuable functionality in medicinal chemistry and agrochemistry [3-6], and many CF3-containing
pharmaceuticals and agrochemicals have been developed, such as Fluoxetine, Efavirenz,
Pleconaril and Acifluorfen. The high demand for the biologically active CF3-molecules has
stimulated significant efforts to develop efficient methods for the installation of CF3 group [7-10].
Difunctionalization-type
trifluoromethylation
of
alkenes
[11,
12],
including
hydrotrifluoromethylation [13-15], oxtrifluoromethylation [16-18], carbotrifluoromethylation

[19-22], aminotrifluoromethylation [23-25], and halotrifluoromethylation [26-28], has emerged as
an important synthetic tool for CF3 incorporation. Halotrifluoromethylation is apparently an
attractive protocol as the presence of the halo substituent allows for further transformation. The
reaction could be achieved by the combined use of a trifluoromethylation reagent and a halogen
source [29-34], or by the use of a single halotrifluoromethylation reagent. Obviously, the use of a
single halotrifluoromethylation reagent is more straightforward and would therefore be highly
desirable.
The most commonly used halotrifluoromethylation reagents are CF3I and CF3SO2Cl. CF3I
(bp: -22 oC) is gaseous and the need to manipulate this gas may limit its applicability [35-38]. As
CF3SO2Cl could be easily reduced to generate active trifluoromethyl radical (CF3·) intermediate, it
has served a versatile reagent to achieve various trifluoromethylation reactions [39-48], such as
chlorotrifluoromethylation [39-43] and aminotrifluoromethylation [45, 46]. Compared with the
widely used trifluoromethylation reagents including Togni’s reagents and Umemoto reagent [9],
CF3SO2Cl is an easily available and inexpensive reagent. As CF3SO2Cl is usually reduced under
photocatalytic conditions, the use of an expensive transition metal complex as the photocatalyst is
usually required (Scheme 1, eq 1) [40-44, 48]. Recently, Liu found that CuI complex could also
reduce CF3SO2Cl and Cu-catalyzed radical aminotrifluoromethylation of alkenes was then
achieved [45, 46], but the stoichiometric use of a silver salt was required to suppress side reactions
(eq 2). We have been interested in the development of efficient methods for the incorporation of
fluoroalkyl groups [49-58]. We found that a simple catalyst system consisting of copper dichloride
(CuCl2) and pyridine could catalyze chlorotrifluoromethylation of alkenes with CF3SO2Cl (eq 3).
A series of alkenes including aryl alkenes, α,β-unsaturated alkenes and alkyl alkenes could all be
converted smoothly, demonstrating a wide substrate scope of this protocol. It is noteworthy that
general methods for chlorotrifluoromethylation of all of these alkenes are scarce.
Scheme 1. Difunctionalization of alkenes with CF3SO2Cl
2. Results and discussion
Although monovalent copper complex (CuI) is a good reducing reagent and Liu has shown that
CF3SO2Cl could be reduced by a CuI complex [45, 46], our initial attempts indicated that divalent

copper source was also an effective catalyst albeit with low efficiency (Table 1, entry 1). Further
brief survey revealed that the reaction solvent played a crucial role (entries 1-7) and a good yield
was obtained in 1,4-dioxane (entry 7). The concentration has an important effect on the reaction.
Increasing the concentration and decreasing the loadings of both the copper source and the
pyridine to 10 mol % gave the desired product in a high yield (entry 8). Slightly decreasing the
loading of CF3SO2Cl to 1.8 equiv did not lead to the decrease in the yield (entry 9 vs. entry 8).
The product was isolated in a lower yield (83%) due to its high volatility (entry 9). Other bases
such as Et3N (triethylamine) and DMAP (4-dimethylaminopyridine) are also quite effective
(entries 10-11), but the yield was dramatically decreased by using 4,4’-bpy (4,4’-bipyridine) as a
base (entry 12). Besides CuCl2, other copper sources such as Cu(OAc)2, Cu(OTf)2 and CuCl were
all good catalyst for this chlorotrifluoromethylation reaction (entries 12-15). Lowering the reaction
temperature from 100 oC to 90 oC decreased the yield significantly to 73% (entry 9 vs. entry 16).
The absence of the pyridine could still give the expected product in 45% yield (entry 17). No
chlorotrifluoromethylation was observed in the absence of the copper catalyst (entry 18).
Table 1. The optimization of reaction conditions a
entry
1
[Cu] (mol %)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (20)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
CuCl2 (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
CuCl (10)
base (mol %)
pyridine (60)
pyridine (60)
pyridine (60)
pyridine (60)
pyridine (60)
pyridine (60)
pyridine (60)
pyridine (10)
pyridine (10)
Et3N (10)
solvent
DMF
yield (%)b
7
46
2
MeCN
3
MeNO2
73
4
CHCl3
trace
73
5
DCE
6
THF
66
7
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
84
8c
96
9d
95 (83)e
10d
11d
12d
13d
14d
15d
16df
17d
81
DMAP (10)
4,4’-bpy (10)
pyridine (10)
pyridine (10)
pyridine (10)
pyridine (10)
-
95
22
88
89
91
CuCl2 (10)
CuCl2 (10)
73
45

18d
-
pyridine (10)
1,4-dioxane
ND
aReaction conditions: 1a (0.3 mmol), 2 (2.0 equiv), copper source, base, solvent (2.0 mL), under N2; DCE =
ClCH2CH2Cl; 4,4’-bpy = 4,4’-bipyridine; ND = not detected; bThe yields were determined by 19F NMR
spectroscopy; c0.5 mmol of 1a was used; d0.5 mmol of 1a and 1.8 equiv of 2 were used; eThe yield in parentheses
was an isolated yield; fThe reaction was performed at 90 oC.
With the optimized reaction conditions in hand (Table 1, entry 9), we then investigated the
substrate scope of this chlorotrifluoromethylation of alkenes. As shown in Scheme 2, a wide
substrate scope and a high level of functional group tolerance were observed. Electron-deficient,
-neutral, and –rich aryl alkenes could all be converted well into the expected products in moderate
to good yields (3b-3q). In the case of substrates containing a strong electron-donating group (3m),
the products are too unstable to be isolated, because benzyl cation would be easily formed by
elimination of a chloride anion. Radical halotrifluoromethylation of electron-deficient alkenes is
challenging, because the electrophilic nature of the radical intermediate formed by the addition of
trifluoromethyl radical to electron-deficient alkene would suppress the abstraction of a halogen
atom from electrophilic CF3X or CF3SO2Cl by the radical intermediate. To our delight,
chlorotrifluoromethylation of α,β-unsaturated amides (3r-3v), ester (3w) and ketone (3x)
proceeded smoothly under these conditions. Alkyl alkenes showed lower reactivity and low yields
were obtained (3y-4a). The protocol could also be applied to chloroperfluoroalkylation (4b-4d).
Scheme 2 Chlorotrifluoromethylation of alkenes.

Isolated yields. Reaction conditions: 1 (0.5 mol), 2 (1.8 eq.), CuCl2 (10 mol%), pyridine (10 mol%), 1,4-dioxane (2
mL), under N2 atmosphere. aThe yield of 3m was determined by 19F NMR spectroscopy; b3 equiv of 2 was used.
More experimental evidence was collected to gain more mechanistic insights into this process.
The chlorotrifluoromethylation was suppressed by the radical scavenger TEMPO
(2,2,6,6-tetramethylpiperidin-1-oxyl) and the TEMPO-CF3 product was detected by 19F NMR
spectroscopy (Scheme 3, eq 1). The conversion of vinylcyclopropane 5 with CF3SO2Cl under
optimal conditions gave ring-opening products 6 (eq 2). Without the presence of a substrate, the
CuCl2/pyridine catalyst system could lead to the complete conversion of CF3SO2Cl and CF3Cl was
observed (eq 3) (See Supporting Information). These results suggest that a radical mechanism may
be operative.
Scheme 3 Experimental evidences for radical mechanism.

aThe yields and the E/Z ratio were determined by 19F NMR spectroscopy.
On the basis of the above results, we propose that the reaction mechanism shown in Scheme
4 is plausible. CuII is a strong oxidant and would be easily reduced to CuI in the reaction system
[59]. CuI should be the real catalyst for the chlorotrifluoromethylation process [45, 46]. CF3SO2Cl
is activated by pyridine via forming pyridinum salt A. The redox reaction of salt A with CuI


produces CF3SO2 radical, CuIICl2 and pyridine. CF3SO2 radical would readily undergo

desulfonation to generate CF3 radical, which is trapped by alkenes to afford radical intermediate
B. The capture of radical B by CuCl2 gives CuIII species C, the reductive elimination of which
provides the final product and re-generates the catalyst CuI. Radical B and CuCl2 may also
undergo a single electron transfer process to form cation D and the catalyst CuI. The attack of a
chloride anion at cation D also furnishes the final product.
Scheme 4 The plausible reaction mechanism.
3. Conclusions
In summary, we have described Cu-catalyzed chlorotrifluoromethylation of various alkenes,
including aryl alkenes, α,β-unsaturated alkenes and alkyl alkenes, with CF3SO2Cl. A wide

substrate scope and good functional group compatibility were observed. This work represents the
first efficient protocol for chlorotrifluoromethylation with CF3SO2Cl catalyzed by a simple CuII
complex. The Cu/CF3SO2Cl system may find synthetic utility in other trifluoromethylation
chemistry.
4. Experimental section
4.1 General remark
1H, 13C and 19F NMR spectra were detected on a 400 MHz or 300 MHz NMR spectrometer.
1
Data for H NMR, 13C NMR and 19F NMR were recorded as follows: chemical shift (δ, ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, coupling constant (s) in
Hz). Mass spectra were obtained on GC-MS (EI) or LC-MS (ESI). High resolution mass data were
recorded on a high resolution mass spectrometer in the EI, ESI or DART mode.
4.2 General procedure for chlorotrifluoromethylation of alkenes:
CuCl2 (7 mg, 10 mol%), alkene (0.5 mmol), 1,4-dioxane (2 mL), CF3SO2Cl (152 mg, 1.8 eq.)
and pyridine (4 mg, 10 mol%) were added into a Schlenk tube under a N2 atmosphere. The
o
reaction mixture was stirred at 100 C for 1 h. After being cooled to room temperature, the solid
was removed by filtration and washed with DCM (30 mL). The combined organic solution was
evaporated, and the resulting crude product was purified by flash column chromatography to give
the products 3 or 4.
4.3 Compound data of chlorotrifluoromethylation products:
(3a) [31]: Colorless oil, 83% yield. 1H NMR (400 MHz, CDCl3) δ 7.38-7.32 (m, 5H), 5.10 (t, J
= 7.0 Hz, 1H ), 3.15-2.80 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -64.1 (t, J = 11.3 Hz, 3F). 13C
NMR (100 MHz, CDCl3) δ 139.7, 129.0, 128.9, 126.8, 124.7 (q, J = 276.5 Hz), 54.8 (q, J = 3.4
Hz), 43.7 (q, J = 28.2 Hz). GC-MS (EI): Calculated for C9H8ClF3 [M]: 208.0; Found: 208.0.
(3b) [31]: White solid, 93% yield. 1H NMR (400 MHz, CDCl3) δ 7.56-7.53 (m ,4H), 7.42-7.39
(m, 4H), 7.35-7.31 (m, 1H), 5.12 (t, J = 7.0 Hz, 1H ), 3.05-2.79 (m, 2H). 19F NMR (376 MHz,
CDCl3) δ -63.8 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 141.9, 140.1, 138.6, 128.8,
127.7, 127.6, 127.2, 127.1, 124.8 (q, J = 276.3 Hz), 54.5 (q, J = 3.4 Hz), 43.6 (q, J = 28.2 Hz).
GC-MS(EI): Calculated for C15H12ClF3 [M]: 284.1; Found: 284.1.
(3c) [31]: Yellow oil, 63% yield. 1H NMR (400 MHz, CDCl3) δ 8.26 (d, J = 8.8 Hz, 2H), 7.61
(d, J = 8.8 Hz, 2H), 5.20 (t, J = 7.0 Hz, 1H), 3.11-2.85 (m, 2H). 19F NMR (376 MHz, CDCl3) δ
-63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 148.0, 146.2, 128.0, 124.3 (q, J = 276.3
Hz), 124.2, 53.2 (q, J = 3.4 Hz), 43.4 (q, J = 28.5 Hz). GC-MS (EI): Calculated for
C9H7ClF3NO2[M]: 253.0; Found: 253.0.
(3d) [31]: Colorless oil, 88% yield. 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.4 Hz, 2H),
7.54 (d, J = 8.4 Hz, 2H), 5.14 (t, J = 7.2 Hz, 1H), 3.08-2.82 (m, 2H). 19F NMR (376 MHz, CDCl3)
δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 144.3, 132.7, 127.7, 124.3 (q, J =
276.3 Hz), 118.0, 112.9, 53.5 (q, J = 3.4 Hz), 43.3 (q, J = 28.6 Hz). GC-MS (EI): Calculated for

C10H7ClF3N[M]: 233.0; Found: 233.1.
(3e) [31]: Colorless oil, 80% yield. 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.4 Hz, 2H),
7.47 (d, J = 8.4 Hz, 2H), 5.14 (t, J = 7.0 Hz, 1H), 3.92 (s, 3H), 3.07-2.82 (m, 2H). 19F NMR (376
MHz, CDCl3) δ -64.0 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 166.2, 144.1, 130.7,
130.2, 126.9, 124.5 (q, J = 276.2 Hz), 53.92 (q, J = 3.4 Hz), 52.2, 43.4 (q, J = 28.4 Hz). GC-MS
(EI): Calculated for C11H10ClF3O2 [M]: 266.0; Found: 266.1.
(3f) [32]: Colorless oil, 87% yield. 1H NMR (400 MHz, CDCl3) δ 7.82-7.77 (m, 4H), 7.59 (t, J
= 7.4 Hz, 1H), 7.52-7.45 (m, 4H), 5.17 (t, J = 7.0 Hz, 1H), 3.09-2.85 (m, 2H). 19F NMR (376 MHz,
CDCl3) δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 195.7, 143.6, 138.0, 137.1,
132.6, 130.5, 129.9, 128.3, 126.8, 124.5 (q, J = 276.3 Hz), 53.95 (q, J = 3.5 Hz), 43.4 (q, J = 28.4
Hz). GC-MS (EI): Calculated for C16H12ClF3O [M]: 312.1; Found: 312.1.
(3g): Colorless oil, 76% yield. 1H NMR (400 MHz, CDCl3) δ 10.0 (s, 1H), 7.94 (s, 1H), 7.87 (d,
J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.58 (t, J = 7.6 Hz, 1H), 5.20 (t, J = 7.0 Hz, 1H),
3.11-2.86 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz,
CDCl3) δ 191.4, 140.8, 136.9, 132.7, 130.5, 129.7, 127.5, 124.5 (q, J = 276.3 Hz), 53.8 (q, J = 3.4
Hz), 43.5 (q, J = 28.4 Hz). HRMS (EI): Calculated for C10H8ClF3O[M]: 236.0216; Found:
236.0219. IR: 3446, 1701, 1607, 1427, 1386, 1264, 1141, 1111, 1047, 910, 847, 799, 758, 698,
640, 589 cm-1.
(3h) [39]: Pale yellow oil, 91 % yield. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 8.23 (d, J =
8.0 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 8.0 Hz, 1H), 5.22 (t, J = 7.2 Hz, 1H), 3.13-2.88
(m, 2H). 19F NMR (376 MHz, CDCl3) δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ
148.4, 141.5, 132.9, 130.1, 124.4 (q, J = 276.2 Hz), 123.9, 122.0, 53.3 (q, J = 3.4 Hz), 43.5 (q, J =
28.5 Hz). GC-MS (EI): Calculated for C9H7ClF3NO2 [M]: 253.0; Found: 253.0
(3i) [32]: Yellow oil, 77% yield. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 1H), 7.87
(d, J = 8.0 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 5.87 (dd, J1 = 8.4 Hz, J2 =
4.8 Hz, 1H), 3.08-2.88 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -64.0 (t, J = 11.3 Hz, 3F). 13C
NMR (100 MHz, CDCl3) δ 147.4, 134.4, 133.8, 129.8, 129.7, 124.7, 124.5 (q, J = 276.3 Hz),
49.085 (q, J = 3.5 Hz), 43.43 (q, J = 28.9 Hz).
(3j): Pale yellow oil, 77% yield. 1H NMR (400 MHz, CDCl3) δ 7.71-7.65 (m, 3H), 7.51-7.46
(m, 1H), 5.51 (t, J = 7.2 Hz, 1H), 3.15-2.94 (m, 2H). 19F NMR (376 MHz, CDCl3) δ -64.0 (t, J =
11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 142.4, 133.5, 133.3, 129.5, 128.0, 124.3 (q, J = 276.3
Hz), 116.4, 111.1, 51.4 (q, J = 3.4 Hz), 42.74 (q, J = 28.7 Hz). HRMS (EI): Calculated for
C10H7ClF3N [M]: 233.0219; Found: 233.0223. IR: 3446, 2228, 1634, 1601, 1489, 1451, 1430,
1381, 1334, 1303, 1262, 1146, 1089, 1041, 935, 859, 762, 642, 597, 555, 505 cm-1.
1
(3k): Colorless oil, 91% yield. H NMR (400 MHz, CDCl3) 7.72-7.67 (m, 4H), 3.17-3.0 (m,
2H), 2.15 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -63.2 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz,

CDCl3) δ 147.8, 132.1, 126.8, 124.1 (q, J = 277.3 Hz), 118.1, 112.1, 65.4 (q, J = 2.2 Hz), 49.0 (q,
J = 27.6 Hz), 30.3 (q, J = 1.5 Hz). HRMS (EI): Calculated for C11H9ClF3N [M]: 247.0376; Found:
247.0378. IR: 3413, 2995, 2232, 1610, 1506, 1364, 1310, 1259, 1235, 1149, 1122, 1064, 1035,
842, 750, 710, 624, 560 cm-1.
(3l): White solid, 73% yield, m.p. 59-62 oC. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.07
(d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.54 (d, J =
8.8 Hz, 1H), 5.28 (t, J = 7.0 Hz, 1H), 3.96 (s, 3H), 3.14-2.90 (m, 2H). 19F NMR (376 MHz, CDCl3)
δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 166.8, 139.1, 135.0, 132.4, 130.6,
130.4, 128.3, 126.1, 125.9, 124.66, 124.65 (q, J = 276.3 Hz), 54.7 (q, J = 3.4 Hz), 52.2, 43.4 (q, J
= 28.3 Hz). HRMS (EI): Calculated for C15H12ClF3O2 [M]: 316.0478; Found: 316.0470. IR (KBr):
3412, 3075, 3025, 3970, 1716, 1633, 1439, 1384, 1348, 1282, 1256, 1226, 1205, 1130, 1109, 1047,
989, 920, 895, 855, 818, 752, 683, 670, 574, 486 cm-1.
(3n) [31]: White solid, 92% yield. 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 8.8 Hz, 2H), 7.10
(d, J = 8.8 Hz, 2 H), 5.10 (dd, J1 = 7.4 Hz, J2 = 6.6 Hz, 1H), 3.03-2.76 (m, 2H), 2.27 (s, 3H). 19F
NMR (376 MHz, CDCl3) δ -64.0 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 169.1, 150.9,
137.1, 127.9, 124.7 (q, J = 276.2 Hz), 122.1, 54.0 (q, J = 3.5 Hz), 43.7 (q, J = 28.4 Hz), 20.9.
GC-MS (EI): Calculated for C11H10ClF3O2 [M]: 266.0; Found: 266.0.
(3o): White solid, 82% yield, m.p. 124-126 oC. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.8
Hz, 1H), 7.37-7.36 (m, 2H), 6.31 (s, 1H), 5.18 (t, J = 7.0 Hz, 1H), 3.11-2.87 (m, 2H), 2.45 (s, 3H).
19F NMR (376 MHz, CDCl3) δ -63.87 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 160.1,
153.4, 151.7, 143.3, 125.3, 124.4 (q, J = 276.3 Hz), 122.5, 120.3, 115.5, 115.3, 53.5 (q, J = 3.4
Hz), 43.2 (q, J = 28.5 Hz), 18.4. HRMS (EI): Calculated for C13H10ClF3O [M]: 290.0321; Found:
290.0324. IR (KBr): 3093, 2993, 1727, 1622, 1560, 1510, 1421, 1386, 1257, 1135, 1104, 1070,
1048, 1017, 982, 913, 885, 864, 740, 709, 672, 656, 582, 522, 463, 438 cm-1.
(3p) [31]: White solid, 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.2 Hz, 2H), 7.47
(t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.18 (d, J = 8.0 Hz, 2H),
6.88 (d, J = 6.8 Hz, 1H), 5.09-5.02 (m, 2H), 4.18 (q, J = 7.2 Hz, 2H), 3.31-3.19 (m, 2H), 3.02-2.77
(m, 2H), 1.23 (t, J = 7.0 Hz, 3H). 19F NMR (376 MHz, CDCl3) δ -63.8 (t, J = 11.3 Hz, 3F). 13C
NMR (100 MHz, CDCl3) δ 171.4, 166.8, 138.3, 137.1, 133.7, 131.6, 129.8, 128.4, 126.9, 126.8,
124.6 (q, J = 276.3 Hz), 61.5, 54.3 (q, J = 3.4 Hz), 53.4 (d, J = 2.1 Hz), 43.4 (q, J = 28.2 Hz), 37.4,
13.9. MS (ESI+): Calculated for C21H22ClF3NO3+ [M+H]+: 428.1; Found: 428.0.
(3q) [31]: 1:1 stereoisomers were obtained. Colorless oil, 85% yield. 1H NMR (400 MHz,
CDCl3) δ 7.30 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 7.11 (s, 1H), 5.07 (t, J = 7.0 Hz, 1H),
3.05-2.79 (m, 4H), 2.53-2.46 (m, 1H), 2.44-2.39 (m, 1H), 2.32-2.26 (m, 1H), 2.18-1.93 (m, 4H),
1.68-1.39 (m, 6H), 0.90 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -64.0 (t, J = 11.3 Hz, 3F). 13C
NMR (100 MHz, CDCl3) δ 220.4, 140.70, 140.69, 137.13, 137.12, 137.06, 137.04, 127.2, 127.1,
125.9, 125.8, 124.7 (q, J = 276.2 Hz), 123.91, 123.86, 54.6-54.5 (m), 50.3, 47.7, 44.2, 43.40 (q, J

= 28.2 Hz), 43.35 (q, J = 28.1 Hz), 37.8, 35.6, 31.4, 29.18, 29.16, 26.2, 25.5, 21.4, 13.7.
(3r) [42]: White solid, 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.50 (d, J = 7.6
Hz, 2H), 7.34 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 4.64 (dd, J1 = 8.8 Hz, J2 = 3.6 Hz, 1H),
3.31-3.19 (m, 1H), 2.82-2.69 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -64.1 (t, J = 11.3 Hz, 3F).
13C NMR (100 MHz, CDCl3) δ 164.5, 136.4, 129.1, 125.6, 122.1 (q, J =275.6 Hz), 120.4, 52.2 (q,
J = 3.0 Hz), 38.9 (q, J = 29.7 Hz). GC-MS (EI): Calculated for C10H9ClF3NO [M]: 251.0; Found:
251.0.
1
(3s) [42]: Colorless oil, 44% yield. H NMR (400 MHz, CDCl3) δ 7.51-7.42 (m, 3H),
7.29-7.27 (m, 2H), 4.33 (dd, J1 = 9.0 Hz, J2 = 4.6 Hz, 1H), 3.33 (s, 3H), 3.28-3.14 (m, 1H),
2.63-2.51 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -64.7 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz,
CDCl3) δ 166.9, 142.1, 130.1, 128.8, 127.1, 124.7 (q, J =276.1 Hz), 45.8 (q, J = 3.2 Hz), 38.9 (q, J
= 28.8 Hz), 38.0. GC-MS (EI): Calculated for C11H11ClF3NO [M]: 265.0; Found: 265.0.
(3t): White solid, 43% yield, m.p. 80-81 oC. 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 5H),
7.06 (s, 1H), 4.52 (dd, J1 = 8.8 Hz, J2 = 3.6 Hz, 1H), 4.45 (d, J = 4 Hz, 2H), 3.25-3.13 (m, 1H),
2.74-2.61 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -64.1 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz,
CDCl3) δ 166.4, 136.9, 128.8, 127.9, 127.7, 125.1 (q, J = 275.7 Hz), 51.9 (q, J = 3.1 Hz), 44.2,
39.0 (q, J = 29.6 Hz). HRMS (EI): Calculated for C11H11ClF3NO [M]: 265.0481; Found: 265.0478.
IR (KBr): 3293, 3071, 2993, 2945, 1655, 1557, 1456, 1424, 1402, 1367, 1340, 1298, 1266,
1232,1143, 1070, 1042, 858, 749, 698, 658, 623, 579, 511, 468 cm-1.
(3u): White solid, 46% yield, m.p. 113-115 oC. 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0
Hz, 1H), 7.24-7.20 (m, 2H), 7.09 (t, J = 8.0 Hz, 1H), 4.64 (t, J = 6.8 Hz, 1H), 4.40-4.33 (m, 1H),
4.14-4.07 (m, 1H), 3.32-3.18 (m, 3H), 2.89-2.76 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -64.1 (t,
J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 164.0, 142.2, 131.5, 127.7, 125.1 (q, J = 275.8
Hz), 124.9, 124.7, 117.5, 48.3 (q, J = 3.1 Hz), 47.8, 38.3 (q, J = 29.2 Hz), 28.0. HRMS (EI):
Calculated for C12H11ClF3NO [M]: 277.0481; Found: 277.0479. IR (KBr): 3027, 2935, 2864, 1652,
1597, 1484, 1464, 1429, 1385, 1285, 1243, 1221, 1204, 1143, 1068, 937, 857, 760, 648, 591, 546,
492, 424 cm-1.
1
(3v) [42]: Colorless oil, 47% yield. H NMR (400 MHz, CDCl3) δ 7.45-7.32 (m ,5H), 3.34 (s,
3H), 3.19-3.07 (m, 1H), 2.78-2.67 (m, 1H), 1.63 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -60.3 (t, J
= 10.5 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 168.0, 143.8, 129.4, 128.39, 128.37, 124.6 (q, J =
277.1 Hz), 63.4 (q, J = 2.5 Hz), 46.7 (q, J = 28.0 Hz), 42.0, 29.0. GC-MS (EI): Calculated for
C12H13ClF3NO [M]: 279.1; Found: 279.1.
1
(3w) [42]: Colorless oil, 49% yield. H NMR (300 MHz, CDCl3) δ 7.42 (t, J = 7.7 Hz, 2H),
7.29 (t, J = 7.5 Hz, 1H), 7.13 (d, J = 7.8 Hz, 2H), 4.70 (t, J = 6.9 Hz, 1H), 3.25-3.08 (m, 1H),
2.93-2.76 (m, 1H). 19F NMR (282 MHz, CDCl3) δ -64.9 (t, J = 9.9 Hz, 3F). 13C NMR (100 MHz,
CDCl3) δ 166.3, 150.1, 129.7, 126.7, 124.6 (q, J = 275.8 Hz), 120.9, 48.8 (q, J = 3.3 Hz), 39.1 (q,
J = 29.7 Hz). GC-MS (EI): Calculated for C10H8ClF3O2 [M]: 252.0; Found: 252.0.

1
(3x) [42]: Colorless oil, 58% yield. H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.6 Hz, 2H),
7.64 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.8 Hz, 2H), 5.32 (t, J = 6.4 Hz, 1H), 3.27-3.14 (m, 1H),
2.89-2.75 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -64.0 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz,
CDCl3) δ 190.6, 134.3, 133.2, 129.4, 129.1, 125.3 (q, J = 275.5 Hz), 48.3 (q, J = 2.9 Hz), 37.4 (q,
J = 29.2 Hz). GC-MS (EI): Calculated for C10H8ClF3O [M]: 236.0; Found: 236.0.
(3y): Pale yellow oil, 41% yiled. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.8 Hz, 2H), 6.99
(d, J = 8.8 Hz, 2H), 4.46-4.40 (m, 1H), 4.28 (dd, J1 = 10.0 Hz, J2 = 4.8 Hz, 1H), 4.18 (dd, J1 =
10.0 Hz, J2 = 6.0 Hz, 1H), 2.99-2.86 (m, 1H), 2.75-2.62 (m, 1H). 19F NMR (376 MHz, CDCl3) δ
-63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 160.1, 134.1, 125.1 (q, J = 275.6 Hz),
118.7, 115.3, 105.2, 70.4, 50.0 (q, J = 3.2 Hz), 38.8 (q, J = 29.2 Hz). HRMS (EI): Calculated for
C11H9ClF3NO [M]: 263.0325; Found: 263.0328. IR: 3429, 2952, 2227, 1607, 1577, 1509, 1462,
1430, 1394, 1254, 1154, 1090, 1042, 945, 835, 737, 679, 636, 549, 512, 431 cm-1.
(3z): White solid, 41% yield, m.p. 96-98 oC. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz,
1H), 7.12-7.07 (m, 2H), 6.27 (s, 1H), 4.32-4.25 (m, 1H), 2.97-2.83 (m, 2H), 2.79-2.56 (m, 2H),
2.44 (s, 3H), 2.42-2.34 (m, 1H), 2.16-2.06 (m, 1H). 19F NMR (376 MHz, CDCl3) δ -63.7 (t, J =
11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 170.2, 160.3, 154.0, 152.7, 151.9, 125.4, 124.9 (q, J
= 275.9 Hz), 117.9, 117.8, 114.5, 110.2, 53.0 (q, J = 3.2 Hz), 42.4 (q, J = 28.5 Hz), 32.6, 30.7,
18.6. HRMS (ESI): Calculated for C16H15ClF3O4+ [M+H]+: 363.0605; Found:363.0601. IR (KBr):
3081, 2923, 1739, 1615, 1574, 1389, 1265, 1137, 1018, 982, 929, 883, 866, 821, 797, 741, 707,
662, 633, 562, 525, 476, 453, 413 cm-1.
(4a): White solid, m.p.: decomposes before melting as determined by DSC measurements, 33%
yield. 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 6.64 (s,
1H), 4.20-4.16 (m, 1H), 3.97 (s, 2H), 2.95-2.72 (m, 2H), 2.72-2.46 (m, 3H), 2.43-2.31 (m, 1H),
2.29-2.21 (m, 1H), 2.18-1.82 (m, 8H), 1.67-1.37 (m, 6H), 0.90 (s, 3H). 19F NMR (376 MHz,
CDCl3) δ -63.9 (t, J = 11.3 Hz, 3F). 13C NMR (100 MHz, CDCl3) δ 220.7, 156.7, 137.7, 132.2,
126.3, 125.2 (q, J = 276.0 Hz), 114.4, 112.0, 66.7, 53.8 (q, J = 3.1 Hz), 50.3, 47.9, 43.9, 42.4 (q, J
= 28.3 Hz), 38.3, 35.8, 34.8, 31.5, 29.6, 26.5, 25.9, 25.8, 21.5, 13.8. HRMS (EI): Calculated for
C24H30ClF3O2 [M]: 442.1886; Found: 442.1893. IR (KBr): 3454, 2934, 2866, 1735, 1610, 1571,
1500, 1390, 1342, 1243. 1187, 1150, 1063, 1006, 959, 879, 823, 787, 732, 628, 879, 439 cm-1.
1
(4b): Colorless oil, 80% yield. H NMR (400 MHz, CDCl3) δ 7.73-7.68 (m, 4 H), 3.23-2.97
(m, 2H), 2.22 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -81.3--81.4 (m, 3F), -110.8--112.6 (m, 2F),
-124.77--124.79 (m, 2F), -126.0--126.1 (m, 2F). 13C NMR (100 MHz, CDCl3) δ 148.0, 132.2,
126.7, 118.1, 112.3, 121.8-105.3 (m), 66.0, 45.2 (t, J = 19.5 Hz), 30.8. HRMS (EI): Calculated for
C14H9ClF9N [M]: 397.0280; Found: 397.0285. IR: 3080, 2995, 2953, 2233, 1610, 1506, 1410,
1353, 1227, 1135, 1079, 1053, 1019, 939, 873, 846, 745, 723, 694, 591, 571, 532 cm-1.
1
(4c): Colorless oil, 52% yield. H NMR (400 MHz, CDCl3) δ 7.51-7.42 (m, 3H), 7.29 (d, J =
8.4 Hz, 2H), 4.44 (dd, J1 = 9.2 Hz, J2 = 3.6 Hz, 1H), 3.41-3.25 (m, 4 H), 2.58-2.44 (m, 1H). 19F

NMR (376 MHz, CDCl3) δ -81.2--81.3 (m, 3F), -112.4--114.6 (m, 2F), -124.70--124.73 (m, 2F),
-126.1--126.2 (m, 2F). 13C NMR (100 MHz, CDCl3) δ 167.0, 142.1, 130.1, 128.9, 127.18,
121.9-105.3 (m), 45.18 (t, J = 2.7 Hz), 38.0, 36.1 (t, J = 20.3 Hz). HRMS (EI): Calculated for
C14H11ClF9NO [M]: 415.0385; Found: 415.0378. IR: 3340, 3066, 2962, 1679, 1597, 1497, 1432,
1354, 1236, 1135, 1075, 1037, 880, 848, 774, 700, 670, 564, 530, 483, 411 cm-1.
(4d): 1:1 stereoisomers were obtained. White solid, m.p.: decomposes before melting as
determined by DSC measurements, 66% yield. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.0 Hz,
1H), 7.19 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 5.20 (t, J = 6.8 Hz, 1H), 3.07-2.81 (m, 4H), 2.54-2.27
(m, 3 H), 2.19-1.96 (m, 4H), 1.69-1.41 (m, 6H), 0.91 (s, 3H). 19F NMR (376 MHz, CDCl3) δ -81.2
(t, J = 11.3 Hz, 3F), -113.7--114.0 (m, 2F), -124.61--124.64 (m, 2F), -125.98--126.04 (m, 2F). 13
C
NMR (100 MHz, CDCl3) δ 220.4, 140.81, 140.80, 137.6, 137.3, 127.21, 127.15, 126.0, 123.93,
123.88, 121.9-105.4 (m), 53.69-53.64 (m), 50.4, 47.8, 44.3, 40.31 (t, J = 20.3 Hz), 40.28 (t, J =
20.4 Hz), 37.9, 35.7, 31.5, 29.3, 29.2, 26.3, 25.5, 21.5, 13.7. HRMS (EI): Calculated for
C24H24ClF9O [M]: 534.1372; Found: 534.1361. IR (KBr): 3460, 2933, 2863, 1740, 1500, 1456,
1355, 1233, 1134, 1102, 1053, 1013, 881, 850, 824, 747, 713, 678, 591, 527 cm-1.
(6) [60]: Colorless oil, 57% isolated yield. 1H NMR: (400 MHz, CDCl3) δ 7.32-7.27 (m, 10H),
5.73-5.61 (m, 1H), 5.46-5.36 (m, 1H), 5.21-5.10 (m, 4H), 3.00 (d, J = 7.2, Hz, 2H), 2.75-2.62 (m,
2H); 19F NMR: (376 MHz, CDCl3) δ -66.4 (t, J = 10.5 Hz, 3F) (E configuration); HRMS (DART):
Calculated for C22H21ClF3O4+ [M+H]+:441.1075; Found: 441.1073.
Acknowledgements
The authors thank National Basic Research Program of China (2015CB931903), the National
Natural Science Foundation (21421002, 21472222, 21502214, 21672242), the Chinese Academy
of Sciences (XDA02020105, XDA02020106), Key Research Program of Frontier Sciences (CAS)
(QYZDJSSW-SLH049), and Shanghai Research Institute of Chemical industry CO., LTD
(SKL-LCTP-201802) for financial support.
Appendix A. Supplementary data
Supplementary data associated with this article can be found in the online version.
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