Copper-mediated aerobic oxidative trifluoromethylation of terminal alkynes with Me3SiCF3

Article abstract of DOI:10.1021/ja102175w

An efficient copper-mediated trifluoromethylation of terminal alkynes with nucleophilic trifluoromethylating reagent (Me3SiCF3) was developed. Both aromatic alkynes and aliphatic alkynes were effective, and a variety of functionalities such as amino, -OMe, -CO2Et, -Br, and -NO2 were tolerated under the reaction conditions. This reaction provides a general, straightforward, and practically useful method to prepare trifluoromethylated acetylenes.

Full text of DOI:10.1021/ja102175w

Published on Web 05/07/2010
Copper-Mediated Aerobic Oxidative Trifluoromethylation of Terminal Alkynes
with Me3SiCF3
Lingling Chu† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Lu, Shanghai 200032, China and College of Chemistry, Chemical Engineering and
Biotechnology, Donghua UniVersity, 2999 North Renmin Lu, Shanghai 201620, China
Received March 15, 2010; E-mail: flq@mail.sioc.ac.cn
Trifluoromethylated compounds are of particular interest in the
fields of polymers, agrochemicals, and pharmaceuticals due to the
unique characteristics of the trifluoromethyl group (-CF3), such
as high electronegativity, electron density, steric hindrance, and
hydrophobicity.1 Hence, it has been of great synthetic interest to
develop an efficient method for incorporation of CF3 into organic
structures.2 The cross-coupling reactions between CuCF3 and
electrophiles, such as aromatic halides,3 and nucleophilic additions
and functional group compatible approach to a broad range of
trifluoromethylated acetylenes in moderate to good yields.
To test our hypothesis, initially, phenylacetylene 1a was chosen
as a model substrate for direct trifluoromethylation. When a mixture
of 1a, Me3SiCF3 (1.5 equiv), KF (1.5 equiv), and CuI (1.0 equiv)
in DMF was heated at 100 °C under air atmosphere, a diyne
byproduct 3a was formed in 98% yield instead of our desired
product 2a (Table 1, entry 1). We ascribed that this negative result
is presumably because the formation of Cu(alkynyl)(trifluoromethyl)
complex C via path I or path II was inhibited by the competitive
formation of bis-alkynyl-Cu complex D which will produce the
undesired diyne byproduct (Scheme 1). Thus, we assumed that using
a pregenerated CuCF3 to avoid the formation of complex B might
be possible to drive the reaction via path II to furnish 2a.
As expected, when 1a was added by using a syringe pump over
a period of 4 h to CuCF33a-h generated in situ by mixing Me3SiCF3,
KF, and CuI in DMF under air atmosphere, the desired product 2a
was formed in 16% yield, but the diyne 3a was still the major
product (78% yield) (entry 2). With this preliminary result in hand,
the improvement of the reaction efficiency was conducted by
screening of the diamine ligands as additive. To our delight, the
yield of 2a was improved to 51% and the byproduct 3a was reduced
to 43% in the presence of 1,10-phenanthroline (phen) (entries 3-5).
The beneficial effects of phen included stabilizing the reactive
Cu-CF3 by chelation3h and increasing the electron density on the
copper center by coordination and thus promoting the formation
of Cu(II)12 or Cu(III)13 complex C, which then undergoes reductive
elimination to deliver 2a (Scheme 1). However, the mechanism of
the formation of Cu(II) (or Cu(III)) complex from E (Scheme 1) was
not clear at the moment. The 19F NMR of the reaction mixture showed
that Me3SiCF3 was fully consumed, and it indicated the decomposition
of Me3SiCF3 took place under these reaction conditions, so the amount
of Me3SiCF3 was increased to 5 equiv and we were pleased to find
that the yield of 2a was enhanced to 93% (entry 6). Other Cu(I) salts
were less effective than CuI (entries 7-9). The screening of solvents
showed that DMF was the optimal solvent (entries 10-11). When
the loading of CuI was reduced to 0.5 equiv, the yield of 2a
dramatically dropped to 43% (entry 12). Surprisingly, when air was
replaced with O2, the reaction was completely inhibited and only 3a
was generated (entry 13). We surmised that the reactive CuCF3 was
quenched by the high concentration of oxygen.3a
of CF3 to carbonyls4 or imines5 provide a number of powerful
-
methods to access these valuable compounds. However, to the best
of our knowledge, no example relating direct cross-coupling of
CuCF3 with nucleophiles has ever been reported so far, albeit this
alternative strategy may open up a new viewpoint to prepare
trifluoromethylated compounds. Recently, metal-catalyzed oxidative
coupling reactions via functionalization of C-H bonds have
received a great deal of interest and attention due to their atom
and step economy.6 Among these impressive research, significant
progress has also been made in the arena of metal-catalyzed
oxidative cross-coupling of terminal alkynes with nucleophiles,7
which inspired us to hypothesize that the direct cross-coupling of
terminal alkynes with CuCF3 may be possible (Scheme 1).
Scheme 1. Plausible Reaction Pathways for Trifluoromethylation
On the other hand, as versatile building blocks, trifluoromethy-
lated acetylenes have found widespread use in medicinal, agro-
chemical, and material science.8 Usually, they can be prepared by
Pd(0) catalyzed cross-coupling reactions of trifluoro-propynyl metal
reagents with aryl iodides or dehalogenation of trifluoromethyl-
ethenes.9 Electrophilic trifluoromethylation of alkynyl metal re-
agents have also been reported.10 However, this “prefunctional-
ization” process suffers from tedious procedures and great caution
for preparation of alkynyl metal reagents or using toxic substrates,
thus the formation of alkynyl-CF3 bonds remains an elusive goal.
Herein, we described the first example of a copper-mediated protocol
3
for Csp-Csp oxidative trifluoromethylation of terminal alkynes with
nucleophilic (trifluoromethyl)trimethylsilane (Ruppert-Prakash re-
agent, Me3SiCF3) (eq 1).11 This reaction represents a straightforward
The scope with respect to terminal alkynes is presented in Table
2. Aromatic alkynes (1a-1p) as well as aliphatic alkynes (1q-1r)
afforded the corresponding trifluoromethylated products in moderate
to good yields. Both electron-rich (1a-1b, 1e, 1j, 1p) and electron-
† Shanghai Institute of Organic Chemistry.
‡ Donghua University.
9
7262 J. AM. CHEM. SOC. 2010, 132, 7262–7263
10.1021/ja102175w  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Initial Studies for Copper-Mediated Trifluoromethylation of
fluoromethylating reagent (Me3SiCF3). This reaction provides a
general, straightforward, and practically useful method to prepare
trifluoromethylated acetylenes.
Terminal Alkynesa
Acknowledgment. National Natural Science Foundation of
China (20832008) is gratefully acknowledged for funding this work.
% yield
2a (3a)b
entry
CuX (equiv)
ligand (equiv)
solvent
Supporting Information Available: Detailed experimental proce-
dures and spectral data for all new compounds are provided. This
material is available free of charge via the Internet at http://pubs.acs.org.
1c d
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuI (1.0)
CuCl (1.0)
CuBr (1.0)
CuCN (1.0)
CuI (1.0)
CuI (1.0)
CuI (0.5)
CuI (1.0)
/
/
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
CH3CN
DMF
DMF
0 (98)
16 (78)
8 (71)
25 (69)
51 (43)
93 (2)
77 (16)
65 (23)
49 (44)
24 (54)
35 (49)
43 (49)
<5 (92)
,
2d
3d
4d
5d
6
TMEDA (1.0)
Bipy (1.0)
phen (1.0)
phen (1.0)
phen (1.0)
phen (1.0)
phen (1.0)
phen (1.0)
phen (1.0)
phen (0.5)
phen (1.0)
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In conclusion, we have developed an efficient copper-mediated
trifluoromethylation of terminal alkynes with a nucleophilic tri-
JA102175W
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J. AM. CHEM. SOC. VOL. 132, NO. 21, 2010 7263