Ligand-free copper-catalyzed regio- And stereoselective 1,1-alkylmonofluoroalkylation of terminal alkynes

Article abstract of DOI:10.1039/d0cc05887d

The copper-catalyzed highly regio- and stereoselective 1,1-alkylmonofluoroalkylation of terminal alkynes with α-chloroacetamides and dialkyl 2-fluoromalonate or 2-fluoro-N,N-dialkyl-3-oxobutanamide without an external ligand has been realized. With this novel methodology, (E)-β-monofluoroalkyl-β,γ-unsaturated amides containing quaternary C-F centers can be easily constructed in good to excellent yields. This journal is

Full text of DOI:10.1039/d0cc05887d

View Article Online
View Journal
ChemComm
Chemical Communications
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Lv, W. Pu and X.
Wang, Chem. Commun., 2020, DOI: 10.1039/D0CC05887D.
Volume 54
This is an Accepted Manuscript, which has been through the
Number
January 2018
Pages 1-112
1
4
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Chemical Communications
rsc.li/chemcomm
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
S. J. Connon, M. O. Senge et al.
Conformational control of nonplanar free base porphyrins:
towards bifunctional catalysts of tunable basicity
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC05887D
ChemComm
COMMUNICATION
Ligand-free copper-catalyzed regio- and stereoselective 1,1-
alkylmonofluoroalkylation of terminal alkynes
Yunhe Lv,a* Weiya Pua and Xiaoxing Wanga
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The copper-catalyzed highly regio- and stereoselective 1,1- natural products, pharmaceuticals, and organic materials.8
alkylmonofluoroalkylation of terminal alkynes with α- Transition-metal-catalyzed difunctionalizations of terminal
chloroacetamides and dialkyl 2-fluoromalonate or 2-fluoro- alkynes have emerged as invaluable tools for accessing
N,N-dialkyl-3-oxobutanamide without an external ligand has multisubstituted olefins.9 In this context, significant
been realized. With this novel methodology, (E)-β- advancements have been made in the 1,2-difunctionalization
monofluoroalkyl-β,γ-unsaturated
amides
containing of alkynes (Scheme 1a). In contrast, reports on the 1,1-
quaternary C-F centers can be easily constructed in good to difunctionalization (gem-difunctionalization) of terminal
excellent yields.
alkynes are scarce (Scheme 1b).10 As part of our continuing
interest in Cu-catalyzed 1,1-difunctionalizations of alkynes,11
we envisaged that alkyl and monofluoroalkyl moieties can be
simultaneously installed into the terminal carbon atom of an
alkyne using an appropriate monofluoroalkylation reagent
with the strategic use of a available auxiliary group. According
to our previous reports,11a 8-aminoquinoline (AQ) was selected
as a bidentate auxiliary group to promote the in situ
generation of allenamide intermediate, followed by
nucleophilic addition of monofluoroalkylation reagent to
realize 1,1-alkylmonofluoroalkylations of alkynes. To the best
of our knowledge, 1,1-alkylmonofluoroalkylations of terminal
alkynes are unprecedented. Herein, we report the first
example of a copper-catalyzed regio- and stereoselective 1,1-
alkylmonofluoroalkylation of a terminal alkyne without an
external ligand (Scheme 1c).
As the incorporation of fluorine or fluorinated moieties into
organic molecules often leads to profound changes in their
physical, chemical, and biological properties, fluorine-
containing organic compounds have received increasing
attention in material science, pharmaceuticals and
agrochemicals.1 Therefore, the development of new synthetic
methods for the efficient incorporation of fluorine or
fluorinated moieties into organic molecules has important
implications in these fields. While a great number of methods
for fluorination,2 trifluoromethylation3 and difluoroalkylation4
for accessing fluorine-containing compounds have been well
developed in recent decades, there are very few reports of
monofluoroalkylation strategies. In this respect, Qing, Hu,
Zhang
and
Wang
independently
reported
monofluoroalkylations of arylsilanes, aryl halides and
arylboronic acids or esters with monofluoroalkyl halides by
palladium-, nickel-, or copper-catalyzed reactions.5 Gandelman
and coworker established a Suzuki cross-coupling reaction of
1-halo-1-fluoroalkanes with alkyl BBN for the efficient
synthesis of secondary alkyl fluorides.6 Although some
progress has been made in monofluoroalkylations, the
development of new monofluoroalkylation reactions is still
highly desirable.
R2
(a) general approach
Previous work
1,2-selectivity
very many examples
R
R1
R1-L
R2-L
R
R2
R1
(b) rare reaction patterns
R
1,1-selectivity
ref. 10, 11
(c) This work: 1,1-alkylmonofluoroalkylation of terminal alkynes
O
Multisubstituted olefins are not only a useful class of
synthetic intermediates, but also key structural units in
NH
AQ
O
7
[Cu]
AQ
X
R
+
+
HCF(EWG)2
AQ
X = Cl, Br
N
R
CF(EWG)2
◆ 1st three-component selective 1,1-alkylmonofluoroalkylation of alkynes
◆ ligand-free CuI catalytic system
◆ highly regio- and stereoselective
◆ excellent functional-group tolerance
◆ synthetic simplicity
a. College of Chemistry and Chemical Engineering, Anyang Normal University,
Anyang, 455000, P. R. China. luyh086@nenu.edu.cn; lvyunhe0217@163.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Difunctionalization of terminal alkynes.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 5
COMMUNICATION
Journal Name
Dimethyl 2-fluoromalonate derivatives are useful fluorinated products 4a-4n in good to excellent yields. The absolute
View Article Online
DOI: 10.1039/D0CC05887D
building blocks for monofluoroalkylations. Recently, various configuration of product 4k was determined by X-ray
alkylation, Mannich reaction, Michael addition and heterocycle crystallography (CCDC 1939449), and the structure was
formation processes using simple and inexpensive nucleophilic consistent with the product expected from 1,1-
monofluoroalkylation reagents for the synthesis of fluorinated alkylmonofluoroalkylation. Aryl alkynes bearing electron-
derivatives have been reported.12 Therefore, we first focused donating and electron-withdrawing groups in the meta and
on the copper-catalyzed 1,1-alkylmonofluoroalkylation of ortho positions were also well tolerated, affording the desired
ethynylbenzene (1a), 2-chloro-N-(quinolin-8-yl)acetamide (2a), products 4o-4w in 77–96% yields. The reaction also worked
and dimethyl 2-fluoromalonate (3a) according to our previous well with disubstituted alkynes (1x). In addition to aromatic
work. After screening of reaction conditions (see Table S1), alkynes, other alkynes, such as heteroaromatic alkynes, N-
optimum conditions were identified to be CuI (10 mol %), propargyl amides, aryl or alkyl propargyl ethers, conjugated
Cs2CO3 (1.2 equiv.), and THF under a N2 atmosphere at 80 °C enynes, and nonactivated aliphatic alkynes, were also
for 1.5 h (see Table S1, entry 6). With the optimized reaction examined. Heteroaromatic alkynes, 2- or 3-ethynylthiophene
conditions in hand, we investigated the scope of this copper- and 2-, 3- or 4-ethynylpyridine, were also effective, providing
catalyzed 1,1-alkylmonofluoroalkylation of alkynes 1. As shown 4y-4ac in 70-95% yields. N-Propargyl amides, such as 2-(prop-
in Table 1, we first investigated various aromatic alkynes. A 2-yn-1-yl)isoindoline-1,3-dione (1ad) and tert-butyl prop-2-yn-
series of para-substituted alkynes bearing F, Cl, Br, alkyl, 1-ylcarbamate
(1ae),
underwent
this
1,1-
phenyl, methoxy, methoxycarbonyl and aldehyde groups alkylmonofluoroalkylation reaction to provide corresponding
afforded the desired
products 4ad and 4ae in 88% and 91% yields, respectively. Aryl
or alkyl propargyl ethers, such as 1af-1aj also provided desired
1,1- alkylmonofluoroalkylation product 4af-4aj in good yields. 2-
Phenylbut-3-yn-2-ol (1ak) was also well tolerated. Remarkably,
alkynes containing free hydroxy groups (1aj and 1ak) were also
suitable coupling partners, which demonstrated the excellent
Table
1
The
scope
of
alkynes
in
the
alkylmonofluoroalkylationa
O
O
O
O
CuI (10 mol%)
AQ
R
R
+
+
Cl
MeO
OMe
AQ
R
Cs2CO3 (1.2 equiv)
CF(COOMe)2
4
F
3a
THF, 80 o
C
functional group tolerance of our method and the synthetic
potential offered for further transformations. In addition, the
present conditions are also suitable for conjugated enynes and
nonactivated aliphatic alkynes. Starting from 2-methylbut-1-
en-3-yne (1al) and hept-1-yne (1am), 4al and 4am were
obtained in 70% and 46% yields, respectively. To our delight,
α-2-bromo-N-(quinolin-8-yl)acetamide 2b was also tolerated in
this reaction (4a and 4z). However, 2-chloroacetamide 2c and
2-chloro-N-propylacetamide 2d were not effective for this 1,1-
alkylmonofluoroalkylation reaction.
1
2a
R
O
O
O
AQ
AQ
CF(COOMe)2
AQ
CF(COOMe)2
CF(COOMe)2
4a, R = H, 94%, 88%b
R
4r, R = F, 96%
4o, R = F, 90%
4p, R = Cl, 91%
4q, R = OMe, 77%
4b, R = F, 95%
4s, R = Cl, 92%
4c, R = Cl, 85%
4d, R = Br, 89%
4e, R = Me, 80%
4f, R = Et, 91%
4g, R = nPr, 92%
4h, R = nBu, 90%
4i, R = tBu, 91%
4t, R = Br, 92%
4u, R = Me, 85%
4v, R = NHCOOtBu, 88%
4w, R = NO2, 90%
O
4j, R = n-amyl, 90%
4k, R = Ph, 91%
To further demonstrate the scope of the reaction with
respect to monofluoroalkylation reagents, we next examined
various monofluoroalkylation reagents in this reaction system
(Table 2). When we used diethyl 2-fluoromalonate as the
monofluoroalkylation reagent, the desired product 5b was
obtained in 96% yield. To our delight, when 2-fluoro-N,N-
AQ
4l, R = OMe, 78%
4m, R = COOMe, 92%
CF(COOMe)2
4x, 74%
4k
X-ray
4n, R = CHO, 80%
O
O
O
N
AQ
AQ
AQ
S
N
S
CF(COOMe)2
O
CF(COOMe)2
CF(COOMe)2
4z, 91%, 85%b
4y, 95%
4aa, 70%
O
O
dimethyl-3-oxobutanamide,
N,N-diethyl-2-fluoro-3-
AQ
O
N
AQ
AQ
oxobutanamide, and 2-fluoro-1-morpholinobutane-1,3-dione
were subjected to the optimized reaction conditions, desired
1,1-alkylmonofluoroalkylation products 5c-5e in excellent
yields. Not surprisingly, these novel monofluoroalkylation
reagents were well tolerated in this reaction with different
CF(COOMe)2
N
CF(COOMe)2
CF(COOMe)2
4ab, 78%
4ad, 88%
4ac, 79%
O
O
O
O
O
AQ
AQ
AQ
Ph
O
N
CF(COOMe)2
AQ
O
CF(COOMe)2
O
CF(COOMe)2
H
4ag, 71%
4ae, 91%
4af, 52%
O
O
O
alkynes,
such
as
halogenated
aromatic
alkynes,
AQ
O
O
AQ
HO
heteroaromatic alkynes, N-propargyl amides, alkyl propargyl
ethers, and conjugated enynes, and led to 5f-5k in 70-91%
yields when using 2-fluoro-1-morpholinobutane-1,3-dione as a
representative monofluoroalkylation reagent.
O
O
CF(COOMe)2
CF(COOMe)2
CF(COOMe)2
O
4ah, 86%
4ai, 88%
4aj, 58%
O
O
O
AQ
AQ
AQ
OH
Ph
CF(COOMe)2
CF(COOMe)2
4ak, 65%
CF(COOMe)2
4al, 70%
4am, 46%
We further demonstrated both the potential pharmaceutical
relevance and the functional group tolerance of this method
by a late-stage 1,1-alkylmonofluoroalkylation in the synthesis
of complex bioactive molecules. As shown in Scheme 2,
ethynyl estradiol 6, the first orally active progestin,13 smoothly
underwent 1,1-alkylmonofluoroalkylation to yield the desired
a
Reactions were carried out with 1 (0.33 mmol), 2a (0.3 mmol),
3a (0.45 mmol), CuI (10 mol %), and Cs2CO3 (0.36 mmol) in THF
(0.9 mL) under a N2 atmosphere at 80 °C for 1.5 h. Yield of the
b
isolated product. 2-Bromo-N-(quinolin-8-yl)acetamide 2b was
used.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 5
ChemComm
Please do not adjust margins
Journal Name
product 7 in 62% yield (Scheme 2a). Citronellol-derived alkyne
COMMUNICATION
To elucidate the reaction mechanism, a series of control
View Article Online
DOI: 10.1039/D0CC05887D
8
also reacted smoothly, affording monofluoroalkylated experiments were then carried out (see the ESI). When 2.0
compound 9 in a good yield (Scheme 2b). Thus, this type of equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO)
late-stage modification of complex bioactive molecules has were added under the standard conditions, 4a was isolated in
great potential in drug discovery and development for the 80% yield. In the presence of other radical scavengers, such as
synthesis of analogues with quaternary C-F centers.14 In 2,6-di-tertbutyl-4-methylphenol (BHT, 2.0 equiv.), product 4a
addition, a 5.0 mmol scale reaction was successfully carried was isolated in similar yields, implying that a radical pathway is
out to give 4a in 60% yield (Scheme 2c). The methyl ester not involved in this reaction system. To further clarify the
group of 4a was selectively removed by treatment with LiCl in reaction mechanism, some probable intermediates were
DMF to generate α-fluorinated ester 10 (Scheme 2d).15 4a examined under the standard conditions. To our excitement,
could be readily converted to primary amide 11 with the 4-phenyl-N-(quinolin-8-yl)but-3-ynamide 13 reacted with 3a to
treatment of 2-iodoxybenzoic acid (IBX) in a mixed solvent of give product 4a in 81% yield, which demonstrated that 13
H2O and HFIP at 60 °C. Moreover, further treatment of 11 with might serve as a key intermediate in the catalytic cycle. To gain
tert-butyl nitrite (TBN) in AcOH led to carboxylic acid 12 more insight into the transformation from 13 and 3a to
(Scheme 2e).16
product 4a, further mechanistic experiments have been
conducted. When 4-phenyl-N-(quinolin-8-yl)buta-2,3-
Table 2 The scope of monofluoroalkylation reagents in the 1,1- dienamide 14, readily generated in situ from 13 by a
alkylmonofluoroalkylationa
rearrangement in the presence of Cs2CO3, was treated with 3a
in THF at 80 °C for 1.5 h, product 4a was efficiently generated
in 89% yield. Therefore, compound 14 is also highly likely to be
a reaction intermediate.
O
O
CuI (10 mol%)
AQ
CF(EWG)2
R
+
+
HCF(EWG)2
Cl
AQ
R
Cs2CO3 (1.2 equiv)
THF, 80 o
C
1
2a
3
5
O
O
O
(COOMe)2CF
O
O
CuI
QA
Ph
O
QA
Ph
O
Cs2CO3
Ph
not favorable
Ph
AQ
QA
Ph
O
AQ
H
H
Ph
O
F
F
Ph
Cs2CO3
Cs2CO3
F
CF(COOEt)2
14
favorable
H
L =
CF(COOMe)2
O
HCF(COOMe)2
O
N
O
N
O
AQ
O
O
N
13
5b, 96%
5c, 90%
5d, 82%
5e, 90%
AQ
Ph
CuL
O
O
O
Ph
H
not favorable
QA
AQ
O
AQ
NH
(COOMe)2CF
O
O
O
O
Cl
S
N
AQ
N
Cu
Cl
2a
CF(COOMe)2
Cl
F
A
F
Ph
protonolysis
F
4a
O
N
O
O
N
O
O
N
Ph
O
5f, 90%
5g, 88%
5h, 84%
B
O
AQ
O
O
F
O
N
Scheme 3 Plausible mechanistic pathway.
O
QA
O
O
O
O
O
F
F
O
N
N
O
N
O
AQ
QA
5k, 91%
Based on the above results and previous reports, a possible
mechanism is proposed (Scheme 3). Initially, a Sonogashira
coupling between ethynylbenzene and 2a in the presence of
CuI, Cs2CO3 and a bidentate 8-aminoquinoline auxiliary occurs
to generate intermediate 13.17 Then, the rearrangement of 13
to afford intermediate 14 in the presence of Cs2CO3.18
Subsequently, the carbonyl-substituted double bond of
intermediate 14 undergoes nucleophilic addition by the
carbanion species generated from 3a to afford intermediate B,
which undergoes protonolysis to afford product 4a. The steric
interaction shown in 14 and carbanion may explain the
observed regioselectivity and stereoselectivity. Despite the
mechanism not requiring an extra ligand, tetrahydrofuran may
serve as a ligand in this transformation.
In summary, we have described a regio- and stereoselective
ligand-free copper-catalyzed 1,1-alkylmonofluoroalkylation of
terminal alkynes with α-chloroacetamides and dialkyl 2-
fluoromalonate or 2-fluoro-N,N-dialkyl-3-oxobutanamide using
bidentate 8-aminoquinoline auxiliary groups. This novel 1,1-
alkylmonofluoroalkylation of alkynes provides a powerful
approach for the construction of (E)-β-monofluoroalkyl-β,γ-
unsaturated amides containing quaternary C-F centers in good
to excellent yields directly from readily available and
O
O
5j, 70%
5i, 82%
O
a Reactions were carried out with 1 (0.33 mmol), 2a (0.3 mmol), 3
(0.45 mmol), CuI (10 mol %), and Cs2CO3 (0.36 mmol) in THF
(0.9 mL) under a N2 atmosphere at 80 °C for 1.5 h. Yield of the
isolated product.
O
QA
CF(COOMe)2
HO
HO
O
O
O
CuI (10 mol%)
H
(a)
O
+
+
7, 62%
Cl
H
MeO
MeO
OMe
OMe
AQ
Cs2CO3 (1.2 equiv)
H
H
F
THF, 80 o
C
H
6
H
O
O
CF(COOMe)2
O
O
O
CuI (10 mol%)
(b)
+
+
Cl
O
AQ
O
AQ
Cs2CO3 (1.2 equiv)
THF, 80 o
F
8
C
9, 80%
O
O
O
O
CuI (10 mol%)
AQ
(c)
Ph
+
+
Cl
MeO
OMe
AQ
2a, 5 mmol
Cs2CO3 (1.2 equiv) Ph
THF, 80 oC, 4 h
4a, 1.31g, 60%
CF(COOMe)2
F
1a, 5.5 mm
3a, 7.5mmol
O
Ph
O
O
LiCl (1.0 equiv)
AQ
(d)
(e)
Ph
DMF, 100 oC, 4 h
QA
O
CF(COOMe)2
10, 75%
F
4a
O
O
O
IBX (2.0 equiv)
H2O/HFIP, 60 o
TBN (3.0 equiv)
AcOH, 75 o
AQ
NH2
OH
Ph
Ph
Ph
C
C
CF(COOMe)2
CF(COOMe)2
11, 71%
CF(COOMe)2
12, 73%
4a
Scheme 2 Synthetic applications of this reaction.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 5
COMMUNICATION
Journal Name
8
9
(a) D. W. Robertson, J. A. Katzenellenbogen, J. R. Hayes and B.
inexpensive coupling reagents. This novel protocol can be used
for the late-stage 1,1-alkylmonofluoroalkylation of biologically
relevant moieties and gram-scale reactions. Low costs, mild
reaction conditions, no requirement of an extra ligand,
synthetic simplicity, broad substrate scope, excellent
functional group tolerance and high regio- and
chemoselectivity make this 1,1-alkylmonofluoroalkylation
system very attractive. Further studies on the mechanism and
gem-difunctionalization of other types of alkynes are currently
underway in our laboratory.
We gratefully acknowledge the National Natural Science
Foundation of China (21801008), the Science & Technology
Foundation of Anyang City, ASJY-2019-CYB-013 and the Henan
Key Laboratory of New Optoelectronic Functional Materials for
their financial support.
S. Katzenellenbogen, J. Med. Chem., 1982, 25, V1ie6w7A;rt(icble) OCn.linSe.
DOI: 10.1039/D0CC05887D
Higman, J. A. M. Lummiss and D. E. Fogg, Angew. Chem., Int.
Ed., 2016, 55, 3552; (c) A. S. Levenson and V. C. Jordan, Eur. J.
Cancer 1999, 35, 1628; (d) S. Bhatt, J. D. Stender, S. Joshi, G.
Wu and B. S. Katzenellenbogen, Oncogene 2016, 35, 5722.
(a) Z. Li, A. García-Domínguez and C. Nevado, Angew. Chem.
Int. Ed., 2016, 55, 6938; (b) Z. Li, A. García-Domínguez and C.
Nevado, J. Am. Chem. Soc., 2015, 137, 11610; (c) S. Domański
and W. Chaładaj, ACS Catal., 2016, 6, 3452; (d) G. D. Kortman
and K. L. Hull, ACS Catal., 2017, 7, 6220; (e) Z. Liu, J. Derosa
and K. M. Engle, J. Am. Chem. Soc., 2016, 138, 13076; (f) T.
Xu and X. Hu, Angew.Chem. Int. Ed., 2015, 54, 1307; (g) L.
Guo, F. Song, S. Zhu, H. Li and L. Chu, Nat. Commun., 2018, 9,
4543; (h) Y. Ning, Q. Ji, P. Liao, E. A. Anderson and X. Bi,
Angew.Chem. Int. Ed., 2017, 56, 13805; (i) Y.-T. He, L.-H. Li, Q.
Wang, W. Wu and Y.-M. Liang, Org. Lett., 2016, 18, 5158.
10 (a) H. Kusama, H. Yamabe, Y. Onizawa, T. Hoshino and N.
Iwasawa, Angew. Chem. Int. Ed., 2005, 44, 468; (b) M. Murai,
E. Uemura, S. Hori and K. Takai, Angew. Chem. Int. Ed., 2017,
56, 5862; (c) S. Tong, C. Piemontesi, Q. Wang, M.-X. Wang
and J. Zhu, Angew.Chem. Int. Ed., 2017, 56, 7958; (d) S.
Krautwald, M. J. Bezdek and P. J. Chirik, J. Am. Chem. Soc.,
2017, 139, 3868; (e) A. Morinaga, K. Nagao, H. Ohmiya and
M. Sawamura, Angew. Chem. Int. Ed., 2015, 54, 15859; (f) L.
Liu, K. Sun, L. Su, J. Dong, L. Cheng, X. Zhu, C.-T. Au, Y. Zhou
and S.-F. Yin, Org. Lett., 2018, 20, 4023; (g) Q. Sun, L. Li, L. Liu,
Q. Guan, Y. Yang, Z. Zha and Z. Wang, Org. Lett., 2018, 20,
5592; (h) Q. Sun, L. Li, L. Liu, Y. Yang, Z. Zha and Z. Wang,
Science China Chemistry, 2019, 62, 904; (i) N.-N. Wang, L.-R.
Huang, W.-J. Hao, T.-S. Zhang, G. Li, S.-J. Tu and B. Jiang, Org.
Lett., 2016, 18, 1298; (j) Z. Kuang, H. Chen, J. Yan, K. Yang, Y.
Lan and Q. Song, Org. Lett., 2018, 20, 5153; (k) X. Liu, W.
Ming, X. Luo, A. Friedrich, J. Maier, U. Radius, W. L. Santos
and T. B. Marder, Eur. J. Org. Chem., 2020, 2020, 1941; (l) Y.
Gu, Y. Duan, Y. Shen and R. Martin, Angew. Chem. Int. Ed.,
2020, 59, 2061; (m) Y. Gao, Z.-Q. Wu and K. M. Engle, Org.
Lett., 2020, 22, 5235.
11 (a) Y. Lv, W. Pu and L. Shi, Org. Lett., 2019, 21, 6034; (b) Y. Lv,
W. Pu, X. Liu, J. Sun and M. Cui, Chem. Commun., 2019, 55,
13446; (c) Y. Lv, Y. Wang, W. Pu, X. Zhu, N. Wu and Y. Zhao,
Org. Chem. Front., 2020, 7, 2752.
12 (a) J. Dubois, C. Foures, S. Bory, S. Falcou, M. Gaudry and A.
Marquet, Tetrahedron 1991, 47, 1001; (b) K. Kwon, S. M. Kim
and D. Y. Kim, J. Fluorine Chem., 2009, 130, 759; (c) E. Lisse
and G. Sandford, J. Fluorine Chem., 2018, 206, 117; (d) A.
Harsanyi and G. Sandford, Green Chem., 2015, 17, 3000; (e)
A. Harsanyi and G. Sandford, Org. Process Res. Dev., 2014, 18,
981.
Conflicts of interest
The authors declare no conflict of interest.
Notes and references
1
(a) K. Müller, C. Faeh and F. Diederich, Science 2007, 317,
1881; (b) S. Purser, P. R. Moore, S. Swallow and V.
Gouverneur, Chem. Soc. Rev., 2008, 37, 320; (c) Y. Zhou, J.
Wang, Z. Gu, S. Wang, W. Zhu, J. L. Aceña, V. A. Soloshonok,
K. Izawa and H. Liu, Chem. Rev., 2016, 116, 422.
2
3
(a) T. Liang, C. Neumann and T. Ritter, Angew. Chem., Int. Ed.,
2013, 52, 8214; (b) P. A. Champagne, J. Desroches, J.-D.
Hamel, M. Vandamme and J.-F. Paquin, Chem. Rev., 2015,
115, 9073.
For selected reviews of trifluoromethylation, see: (a) T.
Furuya, A. S. Kamlet and T. Ritter, Nature 2011, 473, 470; (b)
J. Charpentier, N. Früh and A. Togni, Chem. Rev., 2015, 115,
650; (c) X. Yang, T. Wu, R. J. Phipps and F. D. Toste, Chem.
Rev., 2015, 115, 826.
4
5
(a) C. Ni, M. Hu and J. Hu, Chem. Rev., 2015, 115, 765; (b) W.
Miao, Y. Zhao, C. Ni, B. Gao, W. Zhang and J. Hu, J. Am. Chem.
Soc., 2018, 140, 880; (c) K. Hori, H. Motohashi, D. Saito and K.
Mikami, ACS Catal., 2019, 9, 417; (d) Z. Feng, Y.-L. Xiao and X.
Zhang, Acc. Chem. Res., 2018, 51, 2264.
(a) C. Guo, X. Yue and F.-L. Qing, Synthesis 2010, 2010, 1837;
(b) C. Guo, R.-W. Wang, Y. Guo and F.-L. Qing, J. Fluorine
Chem., 2012, 133, 86; (c) Y. Zhao, B. Gao, C. Ni and J. Hu, Org.
Lett., 2012, 14, 6080; (d) Y. Zhao, C. Ni, F. Jiang, B. Gao, X.
Shen and J. Hu, ACS Catal., 2013, 3, 631; (e) J. Hu, B. Gao, L.
Li, C. Ni and J. Hu, Org. Lett., 2015, 17, 3086; (f) L. An, Y.-L.
Xiao, Q.-Q. Min and X. Zhang, Angew. Chem. Int. Ed., 2015,
54, 9079; (g) Y. Wu, H.-R. Zhang, Y.-X. Cao, Q. Lan and X.-S.
Wang, Org. Lett., 2016, 18, 5564; (h) J. Sheng, H.-Q. Ni, G. Liu,
Y. Li and X.-S. Wang, Org. Lett., 2017, 19, 4480; (i) J. Sheng, H.-
Q. Ni, H.-R. Zhang, K.-F. Zhang, Y.-N. Wang and X.-S. Wang,
Angew. Chem., Int. Ed., 2018, 57, 7634.
13 (a) A. B. Forinash and S. L. Evans, Pharmacotherapy 2003, 23,
1573; (b) P. M. Levine, K. Imberg, M. J. Garabedian and K.
Kirshenbaum, J. Am. Chem. Soc., 2012, 134, 6912.
14 Y. Zhu, J. Han, J. Wang, N. Shibata, M. Sodeoka, V. A.
Soloshonok, J. A. S. Coelho and F. D. Toste, Chem. Rev., 2018,
118, 3887.
15 F. Zhu, P.-W. Xu, F. Zhou, C.-H. Wang and J. Zhou, Org. Lett.,
2015, 17, 972.
16 (a) Z. Zhang, X. Li, M. Song, Y. Wan, D. Zheng, G. Zhang and G.
Chen, J. Org. Chem., 2019, 84, 12792; (b) P. Chaudhary, S.
Gupta, N. Muniyappan, S. Sabiah and J. Kandasamy, Green
Chem., 2016, 18, 2323.
6
7
X. Jiang, S. Sakthivel, K. Kulbitski, G. Nisnevich and M.
Gandelman, J. Am. Chem. Soc., 2014, 136, 9548.
(a) C. Oger, L. Balas, T. Durand and J. M. Galano, Chem. Rev.,
2013, 113, 1313; (b) R. Manikandan and M. Jeganmohan,
Chem. Commun., 2017, 53, 8931; (c) R. Kumar, V. Dwivedi
and M. S. Reddy, Adv. Synth. Catal., 2017, 359, 2847.
17 (a) Y. Yamane, N. Miwa and T. Nishikata, ACS Catal., 2017, 7,
6872; (b) F.-X. Luo, X. Xu, D. Wang, Z.-C. Cao, Y.-F. Zhang and
Z.-J. Shi, Org. Lett., 2016, 18, 2040.
18 J. Li, D. Ding, L. Liu and J. Sun, RSC Adv., 2013, 3, 21260.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
ChemComm
View Article Online
DOI: 10.1039/D0CC05887D
Table of contents entry
O
AQ
N
NH
O
CuI, Cs2CO3
X
+
AQ
R
+ HCF(EWG)2
AQ
X = Cl, Br
THF, N2
80 oC, 1.5 h
R
CF(EWG)2
51 examples, up to 96% yield
◆ low cost
◆ ligand-free CuI catalytic system
◆ highly regio- and stereoselective
◆ excellent functional-group tolerance
◆ synthetic simplicity
◆ mild reaction conditions
◆ 1st three-component selective 1,1-alkylmonofluoroalkylation of alkynes
A novel copper-catalyzed highly regio- and stereoselective 1,1-alkylmonofluoroalkylation of
terminal alkynes without an external ligand has been developed.