Copper-Catalyzed Radical Bis(trifluoromethylation) of Alkynes and 1,3-Enynes

Article abstract of DOI:10.1055/s-0039-1690187

The copper-catalyzed radical bis(trifluoromethylation) of alkynes and 1,3-enynes is described. With Cu(CH ₃ CN) ₄ BF ₄ as the catalyst, the reaction of arylalkynes with Togni reagent II and (bpy)Zn(CF ₃) ₂ at room temperature affords the corresponding 1,2-bis(trifluoromethylated) alkenes in good yields with excellent E-stereoselectivity. Under similar conditions, the reaction of 1,3-enynes provides the corresponding 1,4-bis(trifluoromethylated) allenes exclusively in satisfactory yields. The protocol exhibits broad substrate scope and excellent functional group compatibility.

Full text of DOI:10.1055/s-0039-1690187

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
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H. Shen et al.
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Copper-Catalyzed Radical Bis(trifluoromethylation) of Alkynes
and 1,3-Enynes
Haigen Shena
Hawen Xiaoa
Lin Zhu*a
CF3
via alkenyl radical
Ar
Ar
Cu(CH3CN)4BF4 (20 mol%)
CF3
or
or
R2
Togni II–CF3, (bpy)Zn(CF3)2
CH3CN, rt, 12 h
F3C
R1
R2
Chaozhong Li*a,b
R1
via allenyl radical
C
CF3
a Key Laboratory of Organofluorine Chemistry and Collaborative
Innovation Center of Chemistry for Life Sciences, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
zhulin@mail.ustc.edu.cn
highly chemo-, regio- and stereoselective
catalytic in copper
clig@mail.sioc.ac.cn
b School of Materials and Chemical Engineering, Ningbo Univer-
sity of Technology, No. 201 Fenghua Road, Ningbo 315211,
P. R. of China
Received: 12.07.2019
Accepted after revision: 05.08.2019
Published online: 15.08.2019
formations. Herein, we report the copper-catalyzed trifluo-
romethylation of alkenyl radicals, rendering the facile
bis(trifluoromethylation) of alkynes and 1,3-enynes under
mild conditions (Scheme 1, c).
DOI: 10.1055/s-0039-1690187; Art ID: st-2019-v0363-c
Abstract The copper-catalyzed radical bis(trifluoromethylation) of
alkynes and 1,3-enynes is described. With Cu(CH3CN)4BF4 as the cata-
lyst, the reaction of arylalkynes with Togni reagent II and
(bpy)Zn(CF3)2at room temperature affords the corresponding 1,2-
bis(trifluoromethylated) alkenes in good yields with excellent E-stereo-
selectivity. Under similar conditions, the reaction of 1,3-enynes pro-
vides the corresponding 1,4-bis(trifluoromethylated) allenes exclusively
in satisfactory yields. The protocol exhibits broad substrate scope and
excellent functional group compatibility.
CF3
CF3
F3C
H2N
F
O
O
F
O
Cl
O
Cl
CO2H
F
Vigabatrin
(aminotransferase
inhibitor)
F
Ph
Tefluthrin
(insecticide)
Bifenthrin
(insecticide)
Figure 1 Examples of Cvinyl–CF3-containing pharmaceuticals and agri-
cultural chemicals
Key words copper, trifluoromethylation, radicals, alkynes, 1,3-enynes
Trifluoromethylated molecules have found increasingly
important applications in pharmaceuticals and agrochemi-
cals.1 As a consequence, various trifluoromethylating re-
agents2 and trifluoromethylation methods3 have been de-
veloped in the past decades. In this aspect, a number of vi-
nylic CF3-containing compounds possess important
biological activities such as herbicides, insecticides, and
aminotransferase inhibitors. Representative examples are
shown in Figure 1. The construction of Cvinyl–CF3 bonds has
thus attracted a considerable attention, and several meth-
ods have been reported. A typical strategy is the trifluoro-
methylation of vinyl derivatives (e.g., vinyl halides, vinyl
carboxylic acids, or vinylboronates) with trifluoromethylat-
ing reagents in the presence of various transition metals
(Scheme 1, a).3e While this method allows the introduction
of CF3 groups in site-selective manner, it requires prefunc-
tionalized alkenes as substrates. An alternative strategy is
the addition of CF3 radicals to alkynes to give vinyl radicals,
which are then intercepted by various functionalities other
than CF3 groups (Scheme 1, b).4 However, the method typi-
cally provides products with CF3 as the end group. It is cer-
tainly desirable to develop new methods for Cvinyl–CF3 bond
(a) Trifluoromethylation of vinyl derivatives
Ir, Ru, Cu, Pd
(b) Addition of CF3 radicals to alkynes
CF3
FG
LG
CF3
CF3
CF3 reagent
LG = Br, I, H, CO2H,
B(OH)2, BF3K
FG = Hal, H, N3, Ar,
OTf, ArCO2, RO
(c) Trifluoromethylation of vinyl radicals (this work)
O
CF3
CF3
Cu (cat.)
Ar
+
( bpy)Zn(CF3)2
+
O
Ar
via vinyl radicals
I
Ar
CF3
CF3
Scheme 1 Construction of Cvinyl–CF3 bonds
We recently introduced radical trifluoromethylation of
alkyl halides and proposed the mechanism of CF3 group
transfer from Cu(II)–CF3 intermediates to alkyl radicals.5
This concept was then successfully applied to a number of
reactions including decarboxylative trifluoromethylation of
aliphatic acids and C(sp3)–H trifluoromethylation by us6
and by the groups of Liu,7 Cook,8 Gong,9 and MacMillan.10
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Shen et al.
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We also developed the C(sp2)–H trifluoromethylation of al-
dehydes via acyl radicals.11 In the meantime, the trifluoro-
methylation of aryl C(sp2) radicals was also developed with
arene diazonium salts12 or aryl halides13 as aryl radical pre-
cursors. However, to date, there is no example of trifluoro-
methylation of alkenyl radicals. In continuation of our inter-
est in radical trifluoromethylation, we speculated that alke-
nyl radicals might also undergo trifluoromethylation via CF3
group transfer from Cu(II)–CF3 intermediates. This would
allow 1,2-bis(trifluoromethylation) of alkynes to occur.14 With
this idea in mind, we carried out the following investigations.
We commenced our study by using 4-(tert-butyl)phe-
nylacetylene (1a) as the model substrate. With Cu(OTf)2 as
the catalyst and 4,4′-dimethoxy-2,2′-bipyridine as the li-
gand, the reaction of 1a with a typical trifluoromethylating
reagent such as Ruppert–Prakash reagent (TMSCF3)2a or
Umemoto reagent2c in CH3CN at room temperature resulted
in either no reaction or a very low (<10%) yield of the ex-
pected product 2a. However, with the combination of
Umemoto reagent and Ruppert–Prakash reagent, the reac-
tion of 1a under similar conditions afforded the 1,2-bis(tri-
fluoromethylated) alkene 2a in 50% yield with a high E/Z ra-
tio (ca. 93:7 determined by 19F NMR spectroscopy). Encour-
aged by the result, we went on to optimize the reaction
conditions (see Tables S1–S4 in the Supporting Informa-
tion). We were pleased to find that the Cu(CH3CN)4BF4 (20
mol%) catalyzed reaction of 1a with the combination of
Togni reagent2e (1.7 equiv) and (bpy)Zn(CF3)2 (1.5 equiv,
bpy = 2,2′-bipyridine)15 at room temperature provided
product 2a in 81% isolated yield with excellent stereoselec-
tivity (E/Z > 95:5). No extra ligand was required.
With the optimized conditions in hand, we then exam-
ined the scope of the method. As shown in Scheme 2, a
wide range of arylacetylenes with either electron-donating
or electron-withdrawing substituents on the aromatic ring
were converted smoothly into the corresponding 1,2-
bis(trifluoromethylated) alkenes 2a–j in good to high yields.
Interestingly, an excellent chemoselectivity was observed in
the reaction of 1j bearing two triple bonds, and 1,2-bis(tri-
fluoromethylation) occurred exclusively at the aryl-conju-
gated triple bond to produce 2j while the internal triple
bond remained intact. Heterocyclic arylacetylenes were
also suitable substrates for the transformation, as exempli-
fied by the synthesis of 2k and 2l in satisfactory yields. A
variety of functional groups were well tolerated, including
ethers, ketones, esters, and nitriles. The wide functional
group compatibility enabled late-stage modification of
complex molecules. For example, alkynyl-containing ste-
roids, carbohydrates, and vitamin E derivatives underwent
bis(trifluoromethylation) to provide the corresponding
products 2n–q in acceptable yields. In all cases, an excellent
E-stereoselectivity (E/Z > 95:5 determined by crude 19F
NMR spectroscopy) was observed. Nevertheless, the exten-
sion of the method to alkyl-substituted alkynes resulted in
CF3
O
Cu(CH3CN)4BF4 (20 mol%)
CH3CN, rt, 12 h
O
(bpy)Zn(CF3)2
+
+
Ar
CF3
I
Ar
2, yielda,b
CF3
1
CF3
CF3
CF3
CF3
CF3
2a, 81%
CF3
tBu
Ph
MeO
2b, 71%
2c, 84%
OMe
CF3
CF3
CF3
CF3
2d, 79%
CF3
O
CF3
NC
2e, 79%
3
MeO
2f, 71%
CF3
CF3
CF3
CF3
O
CF3
O
CF3
2g, 68%
O
2h, 78%
2i, 77%
Me
CF3
CF3
CF3
S
N
CF3
O
O
CF3
CF3
N
2l, 61%
2j, 78%
2k, 76%
CF3
CF3
CF3
H
H
O
CF3
CF3
CF3
O
H
O
O
O
2m, 80%
O
2o, 77%
O
2n, 67%
O
O
O
O
CF3
O
O
H
H
O
CF3
CF3
CF3
H
2p, 58%
H
O
O
2q, 70%c
CF3
PhthN
CF3
2
2r, 17% (E/Z = 1.1:1)
Scheme 2 1,2-Bis(trifluoromethylation) of alkynes. a Conditions: 1
(0.30 mmol), Togni (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol),
Cu(CH3CN)4BF4(0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield
based on 1. c DCM (6.0 mL) was used in place of CH3CN as the solvent.
a low efficiency and poor stereoselectivity, as evidenced by
the synthesis of 1,2-bis(trifluoromethylated) alkene 2r in
17% yield with almost no stereoselectivity. Instead, a signif-
icant amount (ca. 50%) of the hydrotrifluoromethylated by-
product was obtained.
The above method can be extended to the 1,2-bis(trifluo-
romethylation) of unactivated alkenes.16 For example, the
reaction of alkene 3 under the above optimized conditions
furnished the corresponding product 4 in 78% yield
(Scheme 3).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

C
H. Shen et al.
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To gain more insight into the mechanism of the bis(tri-
fluoromethylation) of alkynes and 1,3-enynes, the radical
capture experiment was conducted. When a stoichiometric
amount of 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO)
was added into the reaction of arylalkyne 1h under the stan-
dard conditions, the yield of the desired product 2h decreased
to 27% while TEMPO–CF3 was obtained in 80% yield. This result
indicated that a CF3 radical was involved in the reaction.
On the basis of the above results and literature re-
ports,5,6,14 a plausible mechanism is proposed (Scheme 5).
Transmetalation of the CF3 anion from (bpy)Zn(CF3)2 to the
Cu catalyst generates a Cu(I)–CF3 species that undergoes
single-electron transfer with the Togni reagent to form a CF3
radical and a Cu(II)–CF3 intermediate. The addition of the
CF3 radical to the alkyne or 1,3-enynes gives the corre-
sponding alkenyl radical A or propargyl radical B. Radical B
is in equilibrium with its tautomer allenyl radical C. Finally,
radical A or C is intercepted by Cu(II)–CF3 to afford the cor-
responding bis(trifluoromethylation) product 2 or 6 and re-
generate the Cu(I) catalyst. The formation of allene 6 seems
to indicate that allenyl radical C is more reactive than prop-
argyl radical B towards the Cu(II)–CF3 intermediate. More
mechanistic studies are certainly required to have a clear
understanding on the mechanism.
O
Cu(CH3CN)4BF4
(20 mol%)
CF3
CF3
+
+ (bpy)Zn(CF3)3
O
TsO
I
CH3CN, rt, 12 h
OTs
4, 78%
CF3
3
Scheme 3
Encouraged by the successful 1,2-bis(trifluoromethyla-
tion) of arylalkynes and unactivated alkenes, we went on to
examine the behaviors of 1,3-enynes. We anticipated that
1,3-enynes would undergo alkene 1,2-bis(trifluoromethyla-
tion), given that (1) CF3 radicals are electrophilic in nature
and thus alkenes are more reactive than alkynes towards
CF3 radical addition, and (2) the resulting propargyl radicals
are more stable than their resonant structures as short-
lived allenyl radicals. Indeed, only a few examples17 of 1,4-
radical addition of 1,3-enynes have been reported. To our
surprise, the reaction of 1,3-enynes 5 under the above opti-
mized conditions led to the exclusive formations of the cor-
responding allenes 6 while no 1,2-addition products could
be detected. As summarized in Scheme 4, the method was
applicable not only to aryl-substituted 1,3-enynes (to give
6a–f) but also to alkyl-substituted 1,3-enynes (to give 6g–i).
The protocol was efficient and exhibited good functional
group tolerance. It is worth mentioning that previous
methods for the synthesis of trifluoromethylated allenes
typically require the use of propargyl halides, esters, or to-
sylates as the substrates and often suffer from the genera-
tion of 3-CF3-substituted 1-alkynes as the byproducts.18
Thus, the above 1,4-bis(trifluoromethylation) of easily
available 1,3-enynes offers a nice complement to the litera-
ture methods.
CF3
F3C
R2
C
or
Ar
R1
CF3
R2
CF3
CF3
2
6
Cu(I)
R2
CF3
R1
C
or
Ar
CF3
R1
CF3
A
B
C
Cu(II)–CF3
Cu(I)–CF3
Ar
R2
or
R1
Cu(CH3CN)4BF4
(20 mol%)
O
O
R2
F3C
R1
R2
CF3
C
(bpy)Zn(CF3)2
+
O
+
O
CF3
CF3
I
CH3CN
rt, 12 h
R1
I
6, yielda,b
5
CF3
CF3
F3C
H
C
Scheme 5 Proposed mechanism of bis(trifluoromethylation)
F3C
H
F3C
C
H
C
CF3
CF3
In summary, we have successfully developed a copper-
catalyzed 1,2-bis(trifluoromethylation) of alkynes, provid-
ing a practical and efficient approach to 1,2-bis(trifluoro-
methylated) alkenes with excellent E-stereoselectivity. This
reaction can be extended to 1,3-enynes, leading to the effi-
cient synthesis of 1,4-bis(trifluoromethylated) allenes. The
protocol exhibits broad substrate scope and excellent func-
tional group compatibility. As the procedure is catalytic in
copper and operationally simple,19,20 the method should
find important applications in the synthesis of trifluoro-
methylated molecules.
6b, 65%
6a, 78%
6c, 85%
MeO2C
Cl
Br
O
F3C
H
F3C
H
F3C
C
C
C
CF3
CF3
CF3
O
6d, 71%
6f, 58%
6e, 46%
MeO
O
F3C
F3C
H
C
F3C
H
C
C
CF3
CF3
CF3
2
BzO
BsO
PhthN
6g, 83%
6i, 69%
6h, 93%
Scheme 4 Bis(trifluoromethylation) of 1,3-enynes. a Conditions: 5
(0.30 mmol), Togni reagent (0.51 mmol), (bpy)Cu(CF3)3 (0.45 mmol),
Cu(CH3CN)4BF4 (0.06 mmol), CH3CN (6.0 mL), rt, 12 h. b Isolated yield
based on 5.
Funding Information
This project was supported by the Natural Science Foundation of
Shanghai (Grant Number 16ZR1443700), by the National Natural Sci-
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D

D
H. Shen et al.
Cluster
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ence Foundation of China (Grant Numbers 21421002, 21532008,
21602239, and 21871285), by the Strategic Priority Research Program
of the Chinese Academy of Sciences (Grant Number XDB20020000),
and by the Shanghai Scientific and Technological Innovation Project
(12) (a) Dai, J.; Fang, C.; Xiao, B.; Yi, J.; Xu, J.; Liu, Z. J.; Lu, X.; Liu, L.;
Fu, Y. J. Am. Chem. Soc. 2013, 135, 8436. (b) Danoun, G.;
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(Grant Number 18JC1410600).
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(13) Le, C.; Chen, T. Q.; Liang, T.; Zhang, P.; MacMillan, D. W. C.
Science 2018, 360, 1010.
Supporting Information
(14) During the preparation of this manuscript, the Cook group
reported the 1,2-bis(trifluoromethylation) of alkynes with
bpyCu(CF3)3 as the CF3source. See: Guo, S.; AbuSalim, D.; Cook,
S. Angew. Chem. Int. Ed. 2019, 58, in press; DOI:
10.1002/anie.201905247.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690187.
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(19) Typical Procedure for the 1,2-Bis(trifluoromethylation) of
Alkynes
To a 25 mL sealed tube were added Cu(CH3CN)4BF4 (19 mg, 20
mol%), Togni reagent II (161 mg, 0.51 mmol), and bpyZn(CF3)2
(162 mg, 0.45 mmol). The mixture was evacuated and backfilled
with argon (3×). Alkyne 1a (54 L, 0.3 mmol) and anhydrous
CH3CN (6.0 mL) were then added successively. The reaction
mixture was stirred at room temperature for 12 h. The resulting
mixture was diluted with DCM and filtered through a pad of
Celite. After the removal of solvent under reduced pressure, the
crude product was purified by column chromatography on
silica gel with petroleum ether as the eluent to give the (E)-1,2-
bis(trifluoromethylated) product 2a as a colorless oil; yield 72
mg (81%).
(20) (E)-1-(tert-Butyl)-4-(1,1,1,4,4,4-hexafluorobut-2-en-2-
yl)benzene (2a)
1H NMR (400 MHz, CDCl3):  = 7.43 (d, J = 7.6 Hz, 2 H), 7.22 (d,
J = 8.4 Hz, 2 H), 6.47 (q, J = 7.2 Hz, 1 H), 1.34 (s, 9 H). 13C NMR
(100 MHz, CDCl3):  = 153.0, 141.4 (qq, J = 30.7, 4.5 Hz), 128.4,
125.9, 125.3, 122.5 (qq, J = 35.2, 6.3 Hz), 122.0 (q, J = 273.5 Hz),
121.6 (q, J = 270.9 Hz), 34.7, 31.2. 19F NMR (376 MHz, CDCl3):  =
–58.00 (d, J = 6.8 Hz, 3 F), –68.25 (s, 3 F). IR (neat):  = 2964,
2927, 2872, 1270, 1185, 1147, 1023, 832, 646 cm-1. EIMS: m/z
(rel. intensity) = 296 (20) [M+], 281 (100), 253. HRMS: m/z calcd
for C14H14F6 [M]: 296.1000; found: 296.0999.
(7) Paeth, M.; Carson, W.; Luo, J.; Tierney, D.; Cao, Z.; Cheng, M.;
Liu, W. Chem. Eur. J. 2018, 24, 11559.
(8) Guo, S.; AbuSalim, D. I.; Cook, S. P. J. Am. Chem. Soc. 2018, 140,
12378.
(9) Chen, Y.; Ma, G.; Gong, H. Org. Lett. 2018, 20, 4677.
(10) (a) Kautzky, J. A.; Wang, T.; Evans, R. W.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2018, 140, 6522. (b) Kornfilt, D. J. P.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2019, 141, 6853.
(11) Zhang, P.; Shen, H.; Zhu, L.; Li, C. Org. Lett. 2018, 20, 7062.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–D