Synthesis of trifluoromethylated acetylenes via copper-catalyzed trifluoromethylation of alkynyltrifluoroborates

Article abstract of DOI:10.1016/j.tetlet.2012.09.083

A new method for the synthesis of trifluoromethylated acetylenes is developed which involves the copper-catalyzed trifluoromethylation of alkynyltrifluoroborates with an electrophilic trifluoromethylating reagent. This method offers significant advantages such as efficiency and mild and base-free reaction conditions. A plausible mechanism is proposed.

Full text of DOI:10.1016/j.tetlet.2012.09.083

Tetrahedron Letters 53 (2012) 6646–6649
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of trifluoromethylated acetylenes via copper-catalyzed
trifluoromethylation of alkynyltrifluoroborates
Huidong Zheng a, Yuanyuan Huang a, Zhiwei Wang a, Huaifeng Li b, Kuo-Wei Huang b, , Yaofeng Yuan a,
⇑
Zhiqiang Weng a,
⇑
a College of Chemistry and Chemical Engineering, Fuzhou University, Fujian 350108, China
b KAUST Catalysis Centre and Division of Chemicals and Life Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2012
Revised 12 September 2012
Accepted 20 September 2012
Available online 27 September 2012
A new method for the synthesis of trifluoromethylated acetylenes is developed which involves the
copper-catalyzed trifluoromethylation of alkynyltrifluoroborates with an electrophilic trifluoromethylat-
ing reagent. This method offers significant advantages such as efficiency and mild and base-free reaction
conditions. A plausible mechanism is proposed.
Ó 2012 Published by Elsevier Ltd.
Keywords:
Copper catalysis
Trifluoromethylated acetylenes
Trifluoromethylation
Alkynyltrifluoroborates
Trifluoromethylated acetylenes (RC„CCF3) have found applica-
tions as building blocks in pharmaceuticals and as functional mate-
rials.1 As a result, the development of efficient methods for
preparing trifluoromethylated acetylenes has been a topic of
increasing importance in organic synthesis. Such molecules have
typically been synthesized through Pd-catalyzed cross-coupling
reactions of trifluoropropynyl metal reagents with aryl iodides,2
dehalogenation of trifluoromethylethenes,3 and trifluoromethyla-
tion of alkynyl lithium reagents4 or stannylacetylenes.5 However,
these methods present several disadvantages. For instance, tedious
reaction procedures are generally required and many alkynyl metal
reagents or substrates employed in the reactions are hazardous or
highly toxic.
Direct C–H bond trifluoromethylation of terminal alkynes has
been the subject of extensive research as it provides a straightfor-
ward method to synthesize trifluoromethylated acetylenes.6–8
Qing and co-workers reported the first example of Cu-mediated,
and later Cu-catalyzed oxidative trifluoromethylation of terminal
alkynes using (trifluoromethyl)trimethylsilane.6 Our group,7 and
Fu and Guo,8 have independently developed copper-catalyzed
trifluoromethylations of terminal alkynes using electrophilic
trifluoromethylating reagents (Togni’s and Umemoto’s reagents,
respectively). However, these methods suffered from individual
limitations, such as the requirement of using excess amounts of
base or oxidant and high reaction temperatures. As such, there re-
mains a need for further development of methods for the efficient
construction of such molecules.
Potassium organotrifluoroborates have advantages in cross-
coupling reactions compared to their boronic acid and boronic es-
ter counterparts in terms of easier preparation procedures and
greater nucleophilicity.9 Accordingly, organotrifluoroborates offer
a broader reaction scope to synthesize target molecules. Buchwald
and co-workers have developed an efficient iron(II)-catalyzed tri-
fluoromethylation of potassium vinyltrifluoroborates to produce
vinyl–CF3 containing products.10 In connection with our research
interest in metal-catalyzed trifluoromethylation chemistry,7,11 we
herein report an alternative method for the synthesis of trifluorom-
ethylated acetylenes via copper-catalyzed trifluoromethylation of
alkynyltrifluoroborates with an electrophilic trifluoromethylating
reagent.
Trifluoromethylation of p-tolylacetylenetrifluoroborate (1a)
with Togni’s reagent (2) to give the corresponding trifluoromethy-
lated product 3a was first attempted as a model reaction under var-
ious conditions (Table 1). We were pleased to find that treatment of
1a with 1.2 equiv of 2 in the presence of 30 mol % of CuSCN,
30 mol % of 2,20-bipyridine (L1), and 4 Å molecular sieves in
acetonitrile (MeCN) at room temperature for 16 hours afforded the
desired product 3a in 90% yield (entry 1). The presence of molecular
sieves was found to be important for efficient trifluoromethylation
to occur; in their absence a decreased yield was obtained (71%, entry
2). Under similar conditions, other nitrogen based ligands, such as
1,10-phenanthroline (L2), N,N,N0,N0-tetramethylethylenediamine
⇑
Corresponding authors.
E-mail addresses: hkw@kaust.edu.sa (K.-W. Huang), zweng@fzu.edu.cn (Z.
Weng).
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.09.083

H. Zheng et al. / Tetrahedron Letters 53 (2012) 6646–6649
6647
Table 1
Optimization of the Cu-catalyzed trifluoromethylation of alkynyltrifluoroboratesa
F3C
I
O
BF3K
[Cu] (30 mol%)
CF3
ligand (30 mol%)
+
4 Å MS
solvent, r.t., 16 h
1a
2
3a
Solvent
Entry
[Cu]
Ligand
Yieldb (%)
1
2
3
4
5
6
7
8
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuSCN
CuI
L1
L1
L2
L3
L4
—
L1
L1
L1
L1
L1
L1
L1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Diglyme
DMAC
CH2Cl2
90
71c
27
12
18
15
16
30
49
73
85
33
24
CuCl
9
Cu(OTf)2
Cu(TFA)2
CuSCN
CuSCN
CuSCN
10
11
12
13
N
N
N
N
N
N
L3
N
L4
L1
L2
a
b
c
Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), solvent (1.0 mL), 4 Å MS (200 mg/mmol), r.t., 16 h, Ar atmosphere.
Yields were determined by GC analysis of the crude reaction mixture with nonane as the internal standard.
Without addition of molecular sieves.
Table 2
(L3), and 2,4,6-trimethylpyridine (L4) showed much poorer
performances (entries 3–5), as was also the case under ligand-free
conditions (entry 6). A subsequent screen of copper sources, using
2,20-bipyridine as the ligand, indicated that CuI and CuCl led to low-
er yields (entries 7 and 8), whereas Cu(OTf)2 and Cu(TFA)2 gave only
modest yields (entries 9 and 10). The results indicated that CuSCN,
which also served as an effective pre-catalyst in a recent example of
oxidative trifluoromethylthiolation of an arylboronic acid,12 gave
the best result. Evaluation of various solvents showed that the
trifluoromethylation proceeded with comparable efficiency in dig-
lyme (entry 11). When the reaction was performed in dimethylacet-
amide (DMAC) or CH2Cl2, inferior results were obtained (entries 12
and 13).
Copper-catalyzed trifluoromethylation of alkynyltrifluoroboratesa
F3C
I
O
CuSCN (30 mol%)
L1 (30 mol%)
R
CF3
R
BF3K
+
4 Å MS
MeCN, r.t., 16 h
3
1
2
Entry Alkynyltrifluoroborate
Product
Yieldb (%)
BF3K
CF3
1
75
1a
3a
BF3K
CF3
Having optimized the conditions, we next explored the
substrate scope of the copper-catalyzed trifluoromethylation of
alkynyltrifluoroborates (Table 2). A broad range of alkynyltrifluo-
roborates was successfully employed for the trifluoromethylation
reaction. Variation of the 4-alkyl-substituted phenyl alkynyltriflu-
oroborates afforded a useful range of products (3a, 3c–g) in good
isolated yields (75–88%; entries 1 and 3–7). Phenyl alkynyltrifluo-
roborate also reacted efficiently to produce 3b in 75% yield as
determined by 19F NMR spectroscopy with an internal standard
(entry 2). Biphenyl alkynyltrifluoroborate underwent the trifluo-
romethylation very smoothly to afford 3h in a good yield (83%,
entry 8). Notably, halogen-substituted phenyl alkynyltrifluorobo-
rates proved to be suitable substrates as the 4-fluoro- and 3,4-di-
chloro-phenyl alkynyltrifluoroborates produced the corresponding
trifluoromethylated acetylenes 3i and 3j in yields of 47% and
68%, respectively (entries 9 and 10). An electron-donating group
such as p-methoxy was well-tolerated, affording product 3k in
70% yield (entry 11). To investigate the compatibility of non-
aromatic alkynyltrifluoroborates, hept-1-ynyltrifluoroborate was
used as the substrate. Gratifyingly, under these reaction conditions,
product 3l was formed in a good yield of 75% (entry 12).
2
75c
78
1b
3b
BF3K
CF3
3
4
5
6
7
1c
3c
Et
Et
BF3K
CF3
79
85
81
88
3d
CF3
1d
BF3K
n-Pr
n-Bu
t-Bu
n-Pr
n-Bu
t-Bu
n-Am
3e
CF3
1e
BF3K
3f
CF3
1f
BF3K
A plausible mechanism for the copper-catalyzed trifluoromethy-
lation of alkynyltrifluoroborates with the electrophilic trifluorome-
thylating reagent 2 is shown in Scheme 1. Initial complexation of
3g
(continued on next page)
1g
n-Am

6648
H. Zheng et al. / Tetrahedron Letters 53 (2012) 6646–6649
Togni’s reagent. The results show that the catalytic reactions pro-
Table 2 (continued)
ceed smoothly at room temperature without addition of a base
or oxidant. A variety of functional groups, such as alkyl, alkoxy,
and halides were tolerated. Further studies to develop related tri-
fluoromethylation processes under copper catalysis and to eluci-
date the roles of the ligands are currently underway in our
laboratories.
Entry Alkynyltrifluoroborate
Product
Yieldb (%)
83
CF3
BF3K
8
3h
CF3
1h
Ph
Ph
BF3K
Acknowledgements
9
47
68
1i
3i
CF3
F
F
We acknowledge financial support from the National Natural
Science Foundation of China (21072030) and the Fuzhou Univer-
sity (022318) to Z.W. and the King Abdullah University of Science
and Technology to K.-W.H.
BF3K
Cl
Cl
Cl
Cl
10
1j
3j
BF3K
CF3
Supplementary data
11
12
70
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
09.083.
1k
3k
MeO
MeO
75c
BF3K
CF3
1l
3l
References and notes
a
Reaction conditions: alkynyltrifluoroborate (0.1 mmol), 2 (0.12 mmol), CuSCN
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b
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c
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Subsequent transmetallation of A with the alkynyltrifluoroborate
generates copper(I)-acetylide species B as the key intermediate.
Nucleophilic attack of the alkynyl group of B at the CF3 moiety is as-
sumed to occur next to generate the desired trifluoromethylated
acetylene product, along with Cu-alkoxide complex C. This under-
goes further reaction with the alkynyltrifluoroborate to regenerate
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In conclusion, we have developed an effective copper catalyst
system for the trifluoromethylation of alkynyltrifluoroborates with
N
N
Cu SCN
A
R
BF3K
KSCN
N
Cu
R
N
KF3B
B
O
I
O
CF3
I
N
N
R
BF3K
R
CF3
Cu
O
I
C
Scheme 1. A possible mechanism for the copper-catalyzed trifluoromethylation of alkynyltrifluoroborates.

H. Zheng et al. / Tetrahedron Letters 53 (2012) 6646–6649
6649
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