General and selective syn -carboxylation-trifluoromethylation of terminal alkynes: Application to the late-stage modification of dehydrocholic acid

Article abstract of DOI:10.1039/c9cc01173k

A general and selective method is developed that allows difunctionalization of terminal alkynes by a Cu(iii)-CF₃ complex and a carboxylic acid regioselectively and with unusual syn-stereochemistry. This method is broadly applicable to various carboxylic acids and terminal alkynes, producing a range of biologically active trifluoromethyl enol carboxylic esters. The synthetic potential of this method is further demonstrated by the late-stage functionalization of a complex pharmaceutical compound dehydrocholic acid.

Full text of DOI:10.1039/c9cc01173k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Zhang, C. Xiao,
H. Wan and X. Zhang, Chem. Commun., 2019, DOI: 10.1039/C9CC01173K.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
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
author guidelines.
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, outlined
in our author and reviewer resource centre, 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
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 5
View Article Online
DOI: 10.1039/C9CC01173K
Journal Name
COMMUNICATION
General and selective syn‐carboxylation‐trifluoromethylation of
terminal alkynes: Application to the late‐stage modification of
dehydrocholic acid†
Received 00th January 20xx,
Accepted 00th January 20xx
Song‐Lin Zhang*a, Chang Xiaoa, Hai‐Xing Wana and Xiao‐Ming Zhang*b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general and selective method is developed that allows
difunctionalization of terminal alkynes by a Cu(III)‐CF3
complex and a carboxylic acid regioselectively and with
unusual syn‐stereochemistry. This method is broadly
applicable to various carboxylic acids and terminal alkynes,
producing a range of biologically active trifluoromethyl enol
carboxylic esters. The synthetic potential of this method is
further demonstrated by the late‐stage tabbing of a complex
pharmaceutical compound dehydrocholic acid.
(a) Traditional sequential functionalization methods
X''
CF3
X'
cat. M
Ar-m
cat. M'
Nuꢀ
Nu
Ar
CF3
X'
X
R
cat. M'
RCO2H
O
H
Ar
CF3
O
Ar
CF3
(b) One-step anti-difunctionalization of alkynes
I
F3C
O
H
O
Cu catalyst
I
Ar
Ar
H
R
+
+
O
O
Ar
and
CF3
Szab
Sodeoka's studies
(refs 8a,b)
ó
The relevance of vicinal functionalized trifluoromethylated
alkenes has been well recognized in pharmaceuticals,
agrochemicals and materials.1‐2 Despite the broad interest,
there is currently no general methods for constructing such
trifluoromethylated alkene motif with a vicinal Nu group (Nu
denotes a nucleophilic group, such as an aryl, halo, oxy or
amino group). Traditionally, they are prepared by two major
kinds of methods (Scheme 1a): (i) sequential functionalization
of polyhalogenated olefins using cross‐coupling;3 and (ii)
photoredox
Ir catalyst
OTf
TfO
R
Ph2S-CF3
hv
Ar
CF3
Akita's method
(ref 8c)
anti-addition
(c) This study: one-step syn-carboxylation-trifluoromethylation
pyCuIII(CF3)3
RCO2
R
O
O
CF3
H
Ar
H
Ar
syn-addition
R: alkyl, vinyl, aryl, heteroaryl
functionalization of preformed Ar‐C≡
C‐CF3.4 However, these
methods suffer from a number of drawbacks, including low
atom‐ and step‐efficiency, limited substrate scope, and regio‐
and stereoselectivity issues. Recently, more straightforward
methods of trifluoromethylative difunctionalization of alkynes
are emerging that enable the synthesis of iodo‐
Scheme 1 Synthetic methods for vicinal Nu‐trifluoromethylated
alkenes.
Trifluoromethylated enol carboxylic esters are potentially
biologically active compounds that may share some analogous
properties to the trifluoromethylated enol phosphate esters.
But their synthesis is extremely challenging.8,9 Sodeoka and
Szabó recently independently employed Togni’s reagents as
both the CF3 and benzoate source for the difunctionalization of
terminal alkynes (Scheme 1b).8a,b Despite the novelty and the
excellent atom‐economy of this reaction, due to the inherent
limitation in scope of available and stable Togni’s reagents, the
reaction scope was rather limited, generating several ortho‐
iodobenzoate‐trifluoromethylated styrenes. Later, Akita and
co‐workers reported a similar strategy of using Yagupol’skii‐
Umemoto type reagent [Ph2SCF3]+OTf− as both CF3 and OTf
source to difunctionalize internal alkynes promoted by Ir(III)
photoredox catalyst/photo‐irradiation (Scheme 1b).8c The
reaction scope is greatly improved to tolerate a range of
internal alkynes, but is still limited to only OTf and OTs.
trifluoromethylated
alkenes,5
aryl‐trifluoromethylated
alkenes,6 and others.7 Despite the exciting initial success, such
difunctionalization reactions are still far from satisfying, and
challenges remain significant regarding particularly the
generality of the methods, the substrate scope and the
mildness of reaction conditions.
a Key Laboratory of Synthetic and Biological Colloids, Ministry of Education
of Chemical and Material Engineering, School of Food Science and Technology,
Jiangnan University, Wuxi 214122, Jiangsu Province, China. E‐mail:
slzhang@jiangnan.edu.cn; xmzhang@jiangnan.edu.cn.
,
School
b
†Electronic Supplementary Information (ESI) available: Experimental details,
additional results, characterization data and NMR spectra for all the products. See
DOI: 10.1039/x0xx00000x
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
ARTICLE
Journal Name
Table 1 Optimization of the reaction conditions a
Remarkably, in these reports anti‐addition of CF3 and
carboxylate/sulfonate across the triple bond of alkynes were
View Article Online
DOI: 10.1039/C9CC01173K
achieved. To our knowledge, selective one‐step syn
difunctionalization across the triple bond of alkynes by a CF3
and a carboxylate has thus far been unknown.
‐
O
CF3
CF3
O
H
CF3
Cu
H
N
CF3
Cl
Cl
base
solvent, time
N2, 100 o
In continuation of our recent interest in developing Cu(III)‐
CF3 chemistry,10‐12 we envisioned the possibility of achieving
carboxylation‐trifluoromethylation of alkynes using Cu(III)‐CF3
complexes as novel CF3 precursors and abundant carboxylic
acids as the ideal carboxylate source. The introduction of the
CF3 and carboxylate functionality from two independent
reagents allows free manipulation of both carboxylate and CF3
precursors. The ready availability and wide scope of carboxylic
acids could greatly enhance the generality and scope of the
reaction. To prove this hypothesis, we describe in this paper
the development of a general, efficient and selective
carboxylation‐trifluoromethylation of alkynes that is efficient
for a broad range of terminal alkynes and an almost full
spectrum of types of carboxylic acids (Scheme 1c). More,
unusual syn‐installation of a carboxylate and a CF3 across the
triple bond of alkynes is achieved that is complementary to
previous anti‐stereochemistry (Scheme 1c).
Cl
4a
5a
CF3
+
1
2a
+
O
C
O
H
HO
O
3a
CF3
Cl
4a'
yield (%)b
4a' 5a
entry
base
solvent
time
4a
1
2
3
4
5
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
KOtBu
DMF
4
54
67
72
0
11
6
28
16
12
0
DMF
8
DMF
12
8
0
toluene
NMP
0
8
54
5
0
6
7
DMF
DMF
8
8
trace
trace
-
-
-
-
KF
a
Reaction conditions: 1 (0.1 mmol), 2a (0.1 mmol), 3a (0.4 mmol), base (0.4
mmol), 4,4’‐difluorobiphenyl (0.1 mmol, internal standard) and solvent (3 mL)
Our study began by reaction of (py)CuIII(CF3)3
denotes pyridine),10c para‐chlorophenylacetylene (2a) and
(1) (py
stirred at 100 oC under N2. b 19F NMR yield based on 2a.
pivalic acid (3a) at 100oC under N2 (Table 1). When a strong Table 2 Substrate scope of terminal alkynes a
base NaO
produce a mixture of 4a
by 19F NMR spectroscopy (entry 1).13 When the reaction time
was extended to 8 hours, the byproducts 4a and 5a were
significantly reduced while the desired 4a increased to 67%
(entry 2). Further extending the time to 12 hours increased the
t
Bu was used in DMF, the reaction occurred to
O
,
4a′and 5a in 4 hours as determined
HO
CF3
Cu
(0.4 mmol)
Ar
3a
NaOtBu (0.4 mmol)
O
CF3
H
′
N
CF3
+
H
O
DMF (3 mL)
Ar
CF3
100 oC, N2, 12 h
(0.1 mmol)
2
4
1
(0.1 mmol)
yield to 72% while almost completely diminished 4a
(entry 3). The combinational use of NaO Bu and DMF is found
to be crucial to this reaction, which might be attributed to the
better solubility of the base in the reaction solution.
Performing the reaction in toluene or NMP led to either no
′and 5a
t
O
CF3
O
CF3
O
CF3
O
CF3
O
O
O
O
H
H
H
H
Cl
O
OHC
product or much lower yield of 4a (entries 4,5). Using KO
KF led to neglectable formation of 4a (entries 6,7). Noteworthy,
the Cu(III)‐CF3 complex is optimal for this reaction; using
tBu or
NC
4a, 72%(59%)
Me
O
4b, 94%(67%)
4d, 82%(53%)
4c, 80%(54%)
1
O
CF3
O
(phen)CuIII(CF3)3 (phen denotes phenanthroline)10b led to the
decomposition of 4a and the formation of acyl fluorides as
shown by 19F NMR spectroscopy.14 The stoichiometry of 4
equivalents of carboxylic acids is also crucial to the efficient
generation of 4a because reducing 3a to 2 equivalents led to
trace amount of 4a due to the decomposition to acyl fluorides
although the reasons are currently not well understood.
CF3
O
O
CF3
O
O
CF3
O
H
H
H
H
F3C
F
Br
4g (65%)
4e, 69%(45%)
4f, 70%(63%)
4h (61%)
O
CF3
O
CF3
O
O
CF3
O
O
N
O
CF3
O
A range of terminal arylalkynes15 were found to react
efficiently under the optimal conditions (Table 1, entry 3),
tolerating various functional groups on the aryl ring, including
fluoro, chloro, bromo, trifluoromethyl, alkyl, cyano, keto, nitro
and even aldehyde (Table 2). Heteroaryl, e.g., 3‐
pyridylacetytlene (2j) also reacted smoothly with pivalic acid
H
H
H
H
O2N
4j, 72%(51%)
4i, 75%(53%)
4k, 38%
4l, 43%
O
O
O
O
H
O
CF3
H
O
CF3
O
O
H
+
+
H
and complex
1
to give the syn‐addition product 4j in a good
CF3
CF3
yield of 72%. In the case of para‐methyl and ‐methoxy
phenylacetylenes 2m and 2n, in addition to the major
formation of 4m and 4n in 72% and 66% yields, the
H3CO
4n, 66%(50%)
H3C
4m, 72%(63%) 4m', 20%(14%)
H3C
H3CO
4n', 27%(13%)
a Both 19F NMR and isolated yields (in parentheses) are provided if available.
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 5
Journal Name
ARTICLE
carboxylic acids, benzyl carboxylic acids, acrylic acids, benzoic
Table 3 Substrate scope of carboxylic acids a,b
View Article Online
acids and heteroaryl carboxylic acids.DOGIe: n10e.1r0a3ll9y/,C9tChCe01s1y73nK
‐
O
addition products were selectively obtained without significant
formation of regio‐ or stereoisomers except the case of
R
HO
CF3
Cu
(0.4 mmol)
R
O
3
NaOtBu (4 equiv)
O
CF3
H
adamantyl and isopentenyl carboxylic acids wherein anti
‐
CF3
N
+
Ar
H
DMF (3 mL)
Ar
addition products 4s′ and 4w′ could also be generated in
minor amounts.
CF3
100 oC, N2, 12 h
(0.1 mmol)
2
4
1
(0.1 mmol)
The reactions can be easily scaled up. For example for the
preparation of 4a, when the reaction was scaled up to 60
mmol level, 4a was isolated in 0.96 g (52% yield), only slightly
lower than the isolated yield of 59% at a 0.1 mmol scale
(Scheme 2, eq 1). To show the potential usefulness of the
aliphatic carboxylic acids
O
O
CF3
O
CF3
O
CF3
O
CF3
O
O
O
H
H
H
H
products
solvent in the presence of K2CO3 led to the formation of
benzoyl acetate in a 50% isolated yield (eq 2). Possibly, the
methanol abstracts the acyl group to give ‐CF3 enolate that
4, alcolysis of the 4a by excess methanol as the
Cl
Cl
Cl
Cl
4o (51%)
4p (50%)
4r, 14%
4q, 50%(32%)
7
cyclic carboxylic acids
benzylic carboxylic acids
α
undergoes further alcolysis of the CF3 group.
O
CF3
O
CF3
O
O
CF3
O
O
CF3
O
(1)
O
H
O
HO
CF3
O
O
H
+
H
H
(24 mmol)
Ar
3a
H
NaOtBu (4 equiv)
CF3
O
CF3
H
N
Cu
CF3
+
H
O
X
DMF
Cl
Ar
Cl
100oC, N2, 6 h
CF3
Cl
4s, 71%(62%)
4a
Cl
2a (6 mmol)
4u, 86%(62%) 4v, 77%(60%)
4s', 14%(13%)
4t, 87%(50%)
1
(6 mmol)
0.96 g, 52% yield
(X = Cl)
(54%) (X=F)
acrylic carboxylic acids
(2)
H
H
O
O
O
O
O
CF3
K2CO3, MeOH
RT, 6 h
OCH3
OCH3
O
CF3
O
H
O
O
CF3
O
CF3
O
O
CF3
O
Ar
H
O
Cl
Cl
O
O
4a
7 , 50%
H
CF3
+
H
H
H
keto/enol = 2.5:1
(3)
Cl
Cl
4w' (16%)
Cl
Cl
Cl
F3C
4x, 65%(43%)
4w (49%)
4y, 44%
OH
O
4z, 39%
H
aromatic carboxylic acids
O
O
H
R
O
O
H
H3C
H3CO
Standard
conditions
Cl
pyCu(CF3)3
Cl
+
H
H
O
O
CF3
O
O
O
CF3
O
CF3
H
H
O
dehydrocholic acid
O
O
O
6, 51%(33%)
H
4aa, 56%(43%), R = H;
4ab, 22%, R = Br;
4ac, 23%, R = tBu;
4ad, 30%, R = NMe2;
4ae, 67%(56%), R = Me
H
H
Scheme 2 Scale‐up study and synthetic applications.
Cl
F
F
4af, 53%(46%)
4ag, 65%
As a further demonstration of the synthetic potential, it was
applied to the functionalization of dehydrocholic acid, a
pharmaceutical that can treat cholic diseases. Thus, the
terminal carboxylic group is converted to the fluorinated enol
ester in an acceptable yield (Scheme 2, eq 3). This tabbing may
have a significant influence on the basic properties (in
particular, metabolic stability and cell permeability) of the
resulting compound, which is potentially valuable to the in
vivo delivery and metabolic stability of pharmaceuticals.
Based on some mechanistic studies and the experimental
observations,16 a plausible mechanism profile is proposed to
involve the initial generation of intermediate of type 5a
(Scheme 3), which then undergoes rate‐limiting carboxylation
with the assistance of bulky Cu complexes to give the desired
products. The coordination of bulky Cu complex is believed to
be important to achieve high syn‐stereoselectivity. Further
efforts are required to fully clarify the details of each reaction
step.
heteroaromatic carboxylic acids
N
S
O
O
CF3
O
O
CF3
H
H
Cl
4ah, 21%(16%) 4ai, 56%(42%)
Cl
a
Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), 3 (0.4 mmol), NaOtBu (0.4
mmol), 4,4’‐difluorobiphenyl (0.1 mmol, internal standard) and solvent (3 mL)
stirred at 100 oC under N2. b Both 19F NMR and isolated yields (in parentheses) are
provided if available.
stereoisomeric (E)‐products 4m′ and 4n′ arising from anti‐
addition of pivalate and CF3 were also isolated in minor 20%
and 27% yields.
Additionally, a broad range of carboxylic acids can
participate in the syn‐carboxylation‐trifluoromethylation of
alkynes (Table 3), including cyclic and acyclic aliphatic
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
ARTICLE
Journal Name
CF3
B. Kobychev, V. M. Muzalevskiy and V. G. NVeienwajAdrteicnlekOon,linJe.
Fluorine Chem., 2016, 188, 157;DO(eI:)10g.1e0r3m9/yCl9aCtiCo0n1:173SK.
Schweizer, C. Tresse, P. Bisseret, J. Lalevée, G. Evano and N.
Blanchard, Org. Lett., 2015, 17, 1794.
(a) N. Iqbal, J. Jung, S. Park and E. J. Cho, Angew. Chem., Int.
Ed., 2014, 53, 539; (b) Z. Hang, Z. Li and Z.‐Q. Liu, Org. Lett.,
2014, 16, 3648; (c) T. Xu, C. W. Cheung and X. Hu, Angew.
Chem., Int. Ed., 2014, 53, 4910; (d) M. P. Jennings, E. A. Cork
and P. V. Ramachandran, J. Org. Chem., 2000, 65, 8763; (e)
C.‐J. Wallentin, J. D. Nguyen, P. Finkbeiner and C. R. J.
Stephenson, J. Am. Chem. Soc., 2012, 134, 8875.
R
O
Py CuIII CF3
O
RCO2
CF3
1
Ar
CF3
CF3
Ar
5a
LnCu-X
+
LnCuX
TScarboxylation
Ar
H
5
slow
rate-determining
R
O
R
O
CF3
H+
O
CF3
H
O
Ar
LnCuX
Ar
A
4
LnCu-X
Scheme 3 A plausible mechanism.
In conclusion, syn‐carboxylation‐trifluoromethylation
6
7
(a) Z. Li, A. Garcia‐Dominguez and C. Nevado, J. Am. Chem.
Soc., 2015, 137, 11610; (b) see also ref 11c.
Amino‐trifluoromethylation: (a) Y. Xiang, Y. Kuang and J. Wu,
a
reaction across the triple bond of terminal alkynes is
developed to produce regio‐ and stereoselectively
trifluoromethylated enol esters. This reaction uses a key
Cu(III)‐CF3 complex as the CF3 source and carboxylic acids as
the carboxylate source to difunctionalize terminal alkynes with
high regio‐ and stereoselectivity. It is applicable to a broad
range of carboxylic acids and alkynes, can be easily scaled up
to gram scale, and has be applied to the late‐stage
functionalization of dehydrocholic acid.
Org. Chem. Front., 2016, 3, 901; (b) G.‐C. Ge, X.‐J. Huang, C.‐
H. Ding, S.‐L. Wan, L.‐X. Dai and X.‐L. Hou, Chem. Commun.,
2014, 50, 3048; (c) F. Wang, N. Zhu, P. Chen, J. Ye and G. Liu,
Angew. Chem., Int. Ed., 2015, 54, 9356.
Carboxyl‐trifluoromethylation of alkynes: (a) P. G. Janson, I.
Gaoneim, N. O. Ilchenko and K. J. Szabó, Org. Lett., 2012, 14
2882; (b) H. Egami, R. Shimizu, S. Kawamura and M.
Sodeoka, Tetrahedron Lett., 2012, 53, 5503; (c) R. Tomita, T.
Koike and M. Akita, Angew. Chem., Int. Ed., 2015, 54, 12923.
For a related perfluoroalkyl‐carboxylation of alkynes, see: X.
Wang and A. Studer, Org. Lett., 2017, 19, 2977.
8
9
,
This study was supported by the National Natural Science
Foundation of China (No. 21472068).
Conflicts of interest
There are no conflicts of interest to declare.
10 (a) S.‐L. Zhang and W.‐F. Bie, Dalton Trans., 2016, 45, 17588;
(b) S.‐L. Zhang and W.‐F. Bie, RSC Adv., 2016, , 70902; (c)
6
S.‐L. Zhang, C. Xiao and H.‐X. Wan, Dalton Trans., 2018, 47
4779; (d) C. Xiao and S.‐L. Zhang, Dalton Trans., 2019, 48
848.
,
,
Notes and references
11 (a) S.‐L. Zhang, H.‐X. Wan and W.‐F. Bie, Org. Lett., 2017, 19
6372; (b) S.‐L. Zhang and C. Xiao, J. Org. Chem., 2018, 83
,
,
1
2
3
4
(a) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley‐VCH,
Weinheim, Germany, 2004; (b) K. Uneyama, Organofluorine
Chemistry, Blackwell, Oxford, U.K., 2006; (c) S. Purser, P. R.
Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev.,
2008, 37, 320; (d) Y. Jiang, H. Yu, Y. Fu and L. Liu, Sci. China:
Chem., 2015, 58, 673.
(a) M. Schlosser, Angew. Chem., Int. Ed., 2006, 45, 5432; (b)
J.‐A. Ma and D. Cahard, Chem. Rev., 2008, 108, PR1; (c) V. V.
Grushin, Acc. Chem. Res., 2010, 43, 160; (d) T. Furuya, A. S.
Kamlet and T. Ritter, Nature, 2011, 473, 470; (e) T. Liang, C.
10908; (c) C. Xiao, H.‐X. Wan and S.‐L. Zhang, Asian J. Org.
Chem., 2019, DOI: 10.1002/ajoc.201800432.
12 For related Cu(III)‐CF3 complexes, see: (a) M. A. Willert‐
Porada, D. J. Burton and N. C. Baenziger, J. Chem. Soc. Chem.
Commun. 1989, 1633; (b) D. Naumann, T. Roy, K.‐F. Tebbe
and W. Crump, Angew. Chem. Int. Ed. Engl., 1993, 32, 1482;
(c) A. M. Romine, N. Nebra, A. I. Konovalov, E. Martin, J.
Benet‐Buchholz and V. V. Grushin, Angew. Chem., Int. Ed.,
2015, 54, 2745; (d) X. Tan, Z. Liu, H. Shen, P. Zhang, Z. Zhang
and C. Li, J. Am. Chem. Soc., 2017, 139, 12430.
N. Neumann and T. Ritter, Angew. Chem., Int. Ed., 2013, 52
8214.
,
13 4a
ppm. Some byproducts
characterized as shown in Tables 2 and 3. The major NMR
differences are summarized for and 4’ in Figure S1 in ESI
,
4a′
and 5a feature 19F signals at ca. ‐58.5, ‐55.5 and ‐50.0
were isolated and fully
Cascade cross‐coupling: (a) J.‐P. Begue, D. Bonnet‐Delpon, D.
Bouvet and M. H. Rock, J. Chem. Soc. Perkin Trans. 1, 1998,
1797; (b) A. A. Goldberg, V. M. Muzalevskiy, A. V. Shastin, E.
S. Balenkova and V. G. Nenajdenko, J. Fluorine Chem., 2010,
131, 384; (c) Y. Zhao, Y. Zhou, J. Liu, D. Yang, L. Tao, Y. Liu, X.
Dong, J. Liu and J. Qu, J. Org. Chem., 2016, 81, 4797.
4′
4
†.
14 19F NMR detected an upfield shifted signal at ca +17.5 ppm,
assigned to the formation of acyl fluorides. See: T. Scattolin,
K. Deckers and F. Shoenebeck, Org. Lett., 2017, 19, 5740.
15 Aliphatic alkynes (e.g. 5‐chloropentyne) gave complex
mixtures while internal alkynes (e.g., diphenylacetylene)
were completely inactive under the reaction conditions.
More, ortho‐chlorophenylacetylene was found to give the
desired product in a 33% NMR yield, but the major product
For a review of functionalization of Ar‐C≡C‐CF3, see: (a) T.
Konno, Synlett, 2014, 25, 1350. For a related example to the
current study: (b) M. Kawatsura, J. Namioka, K. Kajita, M.
Yamamoto, H. Tsuji and T. Itoh, Org. Lett., 2011, 13, 3285;
For other examples, see: (c) arylation: Y. Yamamoto, E.
Ohkubo and M. Shibuya, Green Chem., 2016, 18, 4628; (d)
amination: B. A. Trofimov, L. V. Andriyankova, L. P. Nikitina,
K. V. Belyaeva, A. G. Mal’kina, A. V. Afonin, I. A. Ushiakov, V.
is the Ar‐C≡C‐CF3 in a yield of 48%.
16 For some mechanistic studies, see ESI† for more details.
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/C9CC01173K
pyCuIII(CF3)3
RCO2
R
O
O
CF3
H
Ar
H
Ar
single isomer
(R: alkyl, benzyl, vinyl, aryl, heteroaryl)
36 examples
A general and selective syn-carboxylation-trifluoromethylation across the triple bond of terminal
alkynes is developed by virtue of a reactive Cu(III)-CF3 complex, which produces a broad range
of biologically active trifluoromethylated enol esters with excellent regio- and stereoselectivity.