Fluoroform-Derived CuCF3 for Trifluoromethylation of Terminal and TMS-Protected Alkynes

Article abstract of DOI:10.1021/acs.orglett.6b00999

An efficient trifluoromethylation reaction of alkynes using a fluoroform-derived CuCF₃ reagent is described. The CF₃ source is the inexpensive industrial waste fluoroform (CF₃H). The air-stable CuCF₃ reagent can be prepared in large quantities and is convenient to use. Synthetically useful trifluoromethylated alkynes containing a wide range of functional groups were successfully synthesized under mild conditions. Both terminal and TMS-protected alkynes gave the products in one step. The beneficial effect of a diamine ligand tetramethylethylenediamine (TMEDA) with the fluoroform-derived CuCF₃ reagent was also demonstrated.

Full text of DOI:10.1021/acs.orglett.6b00999

Letter
pubs.acs.org/OrgLett
Fluoroform-Derived CuCF3 for Trifluoromethylation of Terminal and
TMS-Protected Alkynes
Lisi He and Gavin Chit Tsui*
Department of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, China
S
* Supporting Information
ABSTRACT: An efficient trifluoromethylation reaction of alkynes using a
fluoroform-derived CuCF3 reagent is described. The CF3 source is the
inexpensive industrial waste fluoroform (CF3H). The air-stable CuCF3 reagent
can be prepared in large quantities and is convenient to use. Synthetically useful
trifluoromethylated alkynes containing a wide range of functional groups were
successfully synthesized under mild conditions. Both terminal and TMS-
protected alkynes gave the products in one step. The beneficial effect of a
diamine ligand tetramethylethylenediamine (TMEDA) with the fluoroform-
derived CuCF3 reagent was also demonstrated.
he introduction of a trifluoromethyl (CF3) group into
Torganic molecules can profoundly change their physical
and chemical properties.1 A great number of important
pharmaceutical compounds, including anti-HIV efavirenz
(Sustiva), antidepressant fluoxetine (Prozac), and anti-inflam-
matory celecoxib (Celebrex), contain the trifluoromethyl group.
Many drug properties, such as bioavailability, lipophilicity,
receptor-binding selectivity, and metabolic stability, can be
enhanced by the presence of the CF3 group. It is therefore not
surprising to witness the rapid development of new
trifluoromethylation methods in the past decades.2 Compared
to the advances achieved in trifluoromethylation of arenes and
heteroarenes, the formation of C(sp)−CF3 bonds by
trifluoromethylation of alkynes is still in its infancy, despite
the widespread use of trifluoromethylated acetylenes in
pharmaceutical, agrochemical and material science applica-
tions.3 Previous preparation of trifluoromethylated alkynes used
prefunctionalized alkynyl metals and electrophilic trifluorome-
thylating reagents, which often suffered from tedious
procedures and precautionary preparation of sensitive organo-
metallic reagents.2c The direct conversion of the C−H bond of
a terminal alkyne into the C−CF3 bond would be a much more
attractive solution. Indeed, copper-mediated/catalyzed trifluor-
omethylation of terminal alkynes with electrophilic trifluor-
omethylating reagents have been developed,4a−c as well as
photoredox catalytic trifluoromethylation of terminal alkynes
with CF3I.4d These methods circumvent the use of
prefunctionalized alkynes but at the same time are limited by
the prohibitively expensive trifluoromethylating reagents and
photoredox catalysts in large-scale syntheses. In search of
alternative low-cost CF3 sources and convenient operations,
Qing’s copper-mediated/catalyzed oxidative trifluoromethyla-
tion of terminal alkynes using nucleophilic TMSCF3 (Ruppert−
Prakash reagent) emerged as a useful method.5 Other CF3
sources such as trifluoromethyl ketones6a and sulfoxides6b have
been subsequently employed in analogous copper-mediated
processes by Mikami and Hu’s group, respectively. However,
the use of fluoroform (CF3H) as the ultimate CF3 source would
provide a highly atom-economical process and yet has not been
reported. We herein describe an efficient method for
synthesizing trifluoromethylated alkynes using a fluoroform-
derived CuCF3 reagent (Scheme 1).
Scheme 1. Trifluoromethylation of Alkynes with Different
CF3 Sources
Fluoroform (CF3H, trifluoromethane, HFC-23) is a large-
volume byproduct from Teflon manufacturing and a potent
greenhouse gas. It is readily available at low cost, nontoxic, and
ozone-friendly and, therefore, would be a very attractive CF3
source in synthesizing trifluoromethylated compounds. How-
ever, the activation of fluoroform is challenging due to its
chemical inertness, and only recently have synthetic methods
utilizing fluoroform emerged.7 In particular, the use of metals in
the direct metalation of CF3H to produce organometallic
trifluoromethylating reagents showed promising synthetic
applications.8 The pioneering work from Grushin’s group on
the direct cupration of fluoroform to prepare a CuCF3 reagent
Received: April 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00999
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Organic Letters
Letter
is one of the most useful and practical methods, which has been
successfully demonstrated in the trifluoromethylation of aryl/
vinyl halides, arenediazonium salts, α-haloketones and arylbor-
onic acids.8d−l However, to the best of our knowledge, there are
no examples of trifluoromethylation at the sp-hybridized carbon
centers using a fluoroform-derived organometallic reagent.
We initially tested the trifluoromethylation of 2-ethynylnaph-
thalene 1a with triethylamine trihydrofluoride (Et3N·3HF)-
stabilized CuCF3 reagent in dimethylformamide (DMF),
prepared by Grushin’s protocol using CuCl/t-BuOK/fluoro-
form,8d under an air atomosphere.8e The trifluoromethylated
product 2a was obtained only in 12% yield, and the undesired
byproduct diyne 3a was obtained in 85% yield (Table 1, entry
“ligandless” fluoroform-derived CuCF3 reagent has often been
more reactive in trifuoromethylation processes.8d−l Our results
showed that adding phosphine ligands such as triphenylphos-
phine (PPh3) and 1,2-bis(diphenylphosphino)ethane (dppe)
caused a drop in yield of 2a and increased the yield of 3a
(Table 1, entries 6 and 7, cf. entry 3). On the other hand,
adding a diamine ligand such as 1,10-phenanthroline (phen)
improved the yield of 2a significantly (Table 1, entry 8). The
highest yield (93%) was obtained with a cheap and
commercially available tetramethylethylenediamine TMEDA
(Table 1, entry 9).12 To prove that TMEDA acted as a ligand
instead of simply a base, we added Et3N and observed no
beneficial effects (Table 1, entry 10, cf. entry 3). We have also
found that reducing the equivalents of CuCF3/TMEDA and
increasing the concentration of the reaction gave poorer yields.
Finally, slowly oxidizing the Cu(I)CF3 in air in the presence of
TMEDA was not as efficient as using the preformed Cu(II)CF3
and TMEDA (Table 1, entry 11, cf. entry 9)13 albeit
significantly more efficient than the ligand-free case (cf. Table
1, entry 1).
Table 1. Optimization of Trifluoromethylation of 1a with
a
Fluoroform-Derived CuCF3
Terminal alkynes such as 1a are often obtained from the
TMS-protected alkynes by desilylation. The fluoroform-derived
CuCF3 reagent contains Et3N·3HF and KF, which are also
known for desilylation. Therefore, we envisioned that this
reagent can perform both desilylation and trifluoromethylation
of easily accessible and stable TMS-protected alkynes, saving
the extra steps for preparing and handling terminal alkynes,
especially for some volatile and unstable terminal alkynes.
Indeed, the TMS-protected alkyne 1b′ was trifluoromethylated
smoothly under the optimized conditions in 90% yield
(Scheme 2). This one-pot/one-step protocol is more
preparation method of
temp
yield of 2a
b
entry
CuCF3
ligand
none
(°C)
(%)
c
e
1
A
A
B
B
B
B
B
B
B
B
A
23
23
23
45
65
23
23
23
23
23
23
12
d
e
2
none
52
c
e
3
none
65
c
e
4
none
46
c
e
5
none
18
c
e
6
PPh3
18
c
e
7
dppe
28
c
e
8
phen
81
c
e
f
9
TMEDA
Et3N
95 (93 )
c
e
10
65
Scheme 2. One-Pot Trifluoromethylation of a TMS-
Protected Alkyne with Fluoroform-Derived CuCF3
c
e
11
TMEDA
75
a
Conditions: CuCF3 (in DMF solution, 3.0 equiv, stabilized by Et3N·
b
3HF), ligand (3.0 equiv), 1a (0.1 mmol in 1 mL of DMF). The
CuCF3 solution was prepared from CuCl/t-BuOK/fluoroform by the
procedure in ref 8d (method A). A modification of the procedure used
air to bubble through the CuCF3 solution for 1 h before addition of
the alkyne substrate (method B). The reaction vessel was open to air.
Air was bubbled through the reaction mixture for 2 h, and then the
c
d
e
reaction vessel was open to air for the remaining time. Yield was
determined by 19F NMR analysis using benzotrifluoride as the internal
f
standard. Isolated yield.
1). Bubbling air through the reaction mixture increased the
yield of 2a significantly but still generated a large amount of 3a
(Table 1, entry 2). In the trifluoromethylation of aryl boronic
acids with the same fluoroform-derived CuCF3 reagent,8e air
was proposed to oxidize the air-sensitive Cu(I)CF3 to a much
more electrophilic Cu(II)CF3 species for the transmetalation
process. In our case, the oxidation process is competing with
the formation of diyne 3a, which is known to occur at a Cu(I)
center.5a We therefore decided to preform the Cu(II)CF3
species by bubbling air through the initially prepared Cu(I)CF3
solution for 1 h before adding the alkyne substrate9 and let the
reaction proceed in open air.10 The result showed a drastic
improvement in yield (Table 1, entry 3, cf. entry 1). At elevated
temperatures, we observed a decrease in yield of 2a
accompanied by an increase in yield of 3a (Table 1, entries 4
and 5). It has been shown that the use of ligand helped to
stabilize the reactive Cu−CF3 by chelation and increase the
electron density on the Cu center.5a,11 In contrast, the
convenient and efficient than the separate desilylation and
trifluoromethylation sequence. The study of shorter reaction
time (1.5 h) under the one-pot condition revealed a mixture of
1b (79%) and 2b (21%) suggesting the actual intermediate
toward the trifluoromethylated product is the terminal alkyne
1b. We have also studied the nature of the silyl protecting
group, including TMS, TES, TBS, TIPS, and DMPS groups,
and the yield of the trifluoromethylated product parallels the
ease of desilylation.14 The TMS-protected alkynes gave the
highest yields.
The scope of the reaction was subsequently explored using
both terminal and TMS-protected alkynes (Scheme 3). All
reactions were conveniently run in air and at room temperature.
The fluoroform-derived CuCF3 reagent was easy to handle,
prepared on a large scale (15 mmol), and stable in air for
days.14 Under the optimized conditions, trifluoromethylated
alkyne products 2 were obtained in moderate to excellent yields
with good functional group compatibilities. In general, electron-
B
DOI: 10.1021/acs.orglett.6b00999
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Organic Letters
Letter
TMS-protected alkynes in the one-pot desilylation/trifluor-
omethylation was advantageous. The volatility of some
products made the isolation difficult; therefore, NMR yields
were given in these cases to describe more accurate yields of the
reaction. The bis-trifluoromethylated product 2r was success-
fully obtained using a larger excess of the reagent. The reaction
was not only limited to aromatic alkynes; alkyl-substituted
products 2s,t were also formed in good yields albeit in longer
reaction times.
Scheme 3. Scope of Terminal and TMS-Protected Alkynes in
Trifluoromethylation with Fluoroform-Derived CuCF3
a
Although the mechanism of copper-mediated oxidative
trifluoromethylation is not fully understood,5a,8e,15 particularly
with the fluoroform-derived CuCF3 reagent, we have proposed
a plausible reaction pathway as the following (Scheme 4): the
Scheme 4. Proposed Mechanism
[Cu(I)CF3] reagent generated from fluoroform is air-sensitive
and most likely is oxidized by air to a [Cu(II)CF3] species.8d,e
Our NMR studies clearly showed the disappearance of
[Cu(I)CF3] peak after bubbling air through it for 1 h.14 The
diamine TMEDA acts as a ligand to stabilize the Cu-CF3 by
chelation and increase the electron density on the copper
center.5a,11 In the presence of alkyne 1 and air, the Cu(II)/
Cu(III) complex 4 is possibly formed,16 which undergoes
reductive elimination to deliver product 2. However, the
mechanism for the formation of 4 and its nature is not clear at
the moment. In contrast, the [Cu(I)CF3] reagent facilitated the
formation of the diyne product 3 via an oxidative
homocoupling pathway.5
In conclusion, we have discovered a new application of
fluoroform-derived CuCF3 reagent in the oxidative trifluor-
omethylation of terminal and TMS-protected alkynes. A wide
array of trifluoromethylated alkynes containing diverse func-
tional groups was successfully synthesized from easily accessible
substrates. By modifying the literature procedure, we were able
to prepare a “Cu(II)CF3” reagent from fluoroform in large
quantities which is air-stable and convenient to use. The
compatibility and utility of this reagent in the presence of a
diamine ligand TMEDA was also demonstrated. Currently, we
are investigating the potential of this reagent in other efficient
C−CF3 bond forming processes and their mechanisms.
a
Conditions: CuCF3 (0.5 M in DMF, 1.2 mL, 3.0 equiv, stabilized by
Et3N·3HF), TMEDA (3.0 equiv), alkyne 1 (0.2 mmol in 2 mL of
b
c
DMF), isolated yields. 2.0 mmol scale. Yield was determined by 19
F
d
NMR analysis using benzotrifluoride as the internal standard. 6.0
equiv of CuCF3 and TMEDA. 36 h reaction time.
e
rich aromatic alkynes 2b gave higher yields than electron-poor
ones 2e,f. Substituent groups were tolerated at the ortho 2m−o,
meta 2l, and para 2b−j positions on the aromatic ring. Aryl
halides including bromide and even iodide gave high yields of
the monotrifluoromethylated alkynes 2h,i. This chemoselectiv-
ity is remarkable since aryl iodides are very reactive toward the
fluoroform-derived Cu(I)CF3 reagent in aromatic trifluorome-
thylations.8d,h It is also noteworthy that chemoselective
desilylation/trifluoromethylation took place only at the alkyne
terminus of the bis-silylated substrate 1j′ leaving the aryl TMS
group intact in the product 2j. The unprotected amino group
was compatible, and alkyne 2o was obtained in good yield.
However, a hydroxyl group at the para or ortho position was
not tolerated, and a complicated mixture of products was
obtained. Heteroaromatic alkynes containing thienyl 2p and
pyridyl 2q groups were also tolerated. TMS-protected alkynes
generally gave comparable yields as terminal alkynes, except
when the substrates are volatile 1d,f,g, in which case using
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00999.
Experimental procedures and characterization data for all
new compounds (PDF)
C
DOI: 10.1021/acs.orglett.6b00999
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Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: gctsui@cuhk.edu.hk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Chinese University of
Hong Kong Start-up Fund and the Direct Grant for Research
(Project Code 4053142).
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