Copper-mediated trifluoromethylation of propargyl acetates leading to trifluoromethyl-allenes

Article abstract of DOI:10.1039/c3ob42575d

A copper-mediated trifluoromethylation of propargyl acetates with S-(trifluoromethyl)diphenylsulfonium triflate leading to trifluoromethylated allenes in moderate to excellent yields is described. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ob42575d

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Copper-mediated trifluoromethylation of
propargyl acetates leading to trifluoromethyl-
allenes†
Cite this: DOI: 10.1039/c3ob42575d
Yun-Long Ji,a Jun-Jie Kong,a Jin-Hong Lin,*a Ji-Chang Xiao*a and Yu-Cheng Gub
Received 24th December 2013,
Accepted 18th February 2014
DOI: 10.1039/c3ob42575d
A copper-mediated trifluoromethylation of propargyl acetates with S-(trifluoromethyl)diphenylsulfonium
triflate leading to trifluoromethylated allenes in moderate to excellent yields is described.
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The introduction of a trifluoromethyl group into an organic
molecule usually results in a profound effect on its physical,
chemical and biological properties.1 Due to the versatility of
this moiety, determined searches have been undertaken to
find efficient and general methods for transition metal-pro-
moted trifluoromethylation of a wide range of substrates.2
However, despite the significance of functionalized allenes,3
transition metal-mediated trifluoromethylation leading to
allene derivatives has been largely ignored.4 We firstly reported
the copper-mediated trifluoromethylation of aromatic and
hetero-aromatic iodides by using electrophilic trifluoromethy-
lating reagents.5 Shortly afterwards, we extended our studies to
the trifluoromethylation of arylboronic acids,6 alkenes7 and
alkynes.8 As part of our continuing research interest in this
area of chemistry, we have now investigated the copper-
mediated trifluoromethylation of propargyl acetates with
S-(trifluoromethyl)diphenylsulfonium triflate leading to tri-
fluoromethyl-allenes, compounds which couldn’t previously be
easily obtained via late stage trifluoromethylation.9
Scheme 1 Trifluoromethylation of propargyl esters and chlorides
leading to allenes.
Propargyl alcohol derivatives and halides have proved to be
valuable building blocks in the synthesis of allenes.10 Trifluoro-
methylation of these compounds resulting in trifluoromethyl-
allenes has been reported by employing a [CuCF3] reagent pre-
pared in advance or generated in situ from nucleophilic tri-
fluoromethyl sources. An early approach described by Burton
et al. requires the use of a toxic [CdCF3] reagent to get [CuCF3]
(eqn (1), Scheme 1).4a Recently, Szabó and coworkers found
that the stable and easily accessible [(Ph3P)3CuCF3] reagent is
also applicable for this transformation, but the process usually
works only with terminal alkynes as substrates or only results
in disubstituted allenes (eqn (2)).4c Another approach develo-
ped by the group of Nishibayashi can yield trisubstituted
allenes, but the substrates are limited to 1-methyl-substituted
alkynes (eqn (3)).4d In this communication, we report that the
electrophilic trifluoromethylating reagent S-(trifluoromethyl)-
diphenylsulfonium triflate converts a variety of propargyl acet-
ates into trisubstituted trifluoromethyl-allenes (eqn (4)).
Previously, we reported that S-(trifluoromethyl)diphenylsul-
fonium triflate, [Ph2SCF3]+[OTf]− (1), can be reduced by copper
powder in DMF to give a [CuCF3] intermediate. Under the
same conditions, trifluoromethylation of propargyl acetates 2a
proceeded, but the yield was very low (22%). 19F NMR analysis
of the reaction mixture showed that CuCF3 was not completely
consumed over a period of 2 h (δ = −33.9 ppm relative to
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: jlin@sioc.ac.cn, jchxiao@sioc.ac.cn; Fax: (+86) 21-6416-6128;
Tel: (+86) 21-5492-5380
bSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42
6EY, UK
†Electronic supplementary information (ESI) available: Experimental pro-
cedures, characterization data for all compounds. See DOI: 10.1039/c3ob42575d
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Table 1 Trifluoromethylation of 2a by [Ph2SCF3]+[OTf]−a
Table 2 Cu(0)-mediated trifluoromethylation of propargyl acetatesa
Entry
1
Substrate
Product
3, Yieldb (%)
3a, 94
Entry Solvent
Temp (°C) Time (h) Ligandb
Yieldc (%)
1
2
3
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
CH3CN
60
60
70
80
80
80
70
70
70
2
9
2
2
9
9
2
2
2
2
2
2
2
2
—
—
—
—
—
—
—
—
—
—
22
35
53
50
N.D.
N.D.
10
24
N.D.
N.D.
4
2
3
4
5
3b, 90
3c, 92
3d, 90
3e, 86
5d
6e
7
8
9
10
11
12
13f
14f,g
1,4-Dioxane 70
DMF
DMF
DMF
DMF
70
70
70
70
1,10-Phen 50
PPh3
—
49
80
—
99 (94)h
a Reaction conditions: 2a (0.1 mmol, 1.0 equiv.), 1 (2 equiv.), Cu (3
equiv.) in a solvent (2 mL). b 1 equiv. of ligand was used. c Determined
by 19F NMR. d CuI (1 equiv.) was used instead of Cu. N.D. = not
detected. e Cu(OAc)2 (1 equiv.) was used instead of Cu. f 0.5 mL DMF
was used. g 4 equiv. of 1 and 6 equiv. of Cu were used. h Isolated yield.
6
7
3f, 85
3g, 76
CFCl3) (entry 1, Table 1). On increasing the reaction time to
9 hours, the intermediate [CuCF3] disappeared, and the yield
was increased slightly to 35% (entry 2). On elevating the reac-
tion temperature to 70 °C, the reaction was completed in 2 h
and gave the desired product in 53% yield (entry 3). Further
increasing the temperature led to the formation of a penta-
fluoroethylated by-product due to decomposition of [CuCF3]
(entry 4). Cu(I) and Cu(II) were also investigated, but neither of
them could promote the desired conversion (entries 5 and 6).
An examination of the effect of the solvent suggested that DMF
is suitable for this transformation (entry 3 vs. entries 7–10).
It has been reported that the addition of a ligand improves
trifluoromethylation,11 but in our case, no positive effect was
found (entries 11 and 12). Interestingly, the concentration of
the reactants had a significant effect on the reaction. When
the concentration was increased from 0.05 M to 0.2 M, the
desired product was obtained in good yield (entry 13). With
the use of 4 equiv. of the triflate 1, the conversion proceeded
very well to give the expected product in quantitative yield, and
almost none of the pentafluoroethylated by-product was
detected by 19F NMR (entry 14).
With the optimized reaction conditions in hand (entry 14,
Table 1), we explored the scope of this trifluoromethylation. As
shown in Table 2, the reaction conditions could tolerate
various functional groups and gave corresponding trifluoro-
methylation products with moderate to excellent yields in
most cases. The desired transformation proceeded very well
even for the substrates substituted by bulky alkyl groups, such
as i-Bu and t-Bu (entries 3 and 4). In the case of the cyclohexyl-
substituted substrate, the reaction afforded the desired
product in lower yield, as well as 5% of the pentafluoroethy-
8
3h, 96
3i, 96
9
10
11
12
13
14
3j, 97
3k, 80
3l, 79
3m, 16c
3n, 76
a Propargyl acetate (0.1 mmol, 1.0 equiv.) and 1 (4 equiv.), Cu (6 equiv.)
in DMF (0.5 ml) at 70 °C. b Isolated yields. c The yield was determined
by 19F NMR.
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acetate to the important intermediate [CuCF3], which is gener-
ated from the reaction of S-(trifluoromethyl)diphenylsulfo-
nium triflate with copper powder (Scheme 3). Propargyl acetate
acts as a bidentate ligand and the coordination to [CuCF3]
favors oxidative addition to give intermediate A. The reductive
elimination of intermediate A gives the final product.
Scheme 2 Attempts for the trifluoromethylation of propargyl acetate
by previously described methods.
Conclusions
In conclusion, we have described the copper-mediated trifluoro-
methylation of propargyl acetates with S-(trifluoromethyl)-
diphenylsulfonium triflate under mild conditions leading to
trifluoromethyl-allenes in moderate to excellent yields. Trisub-
stituted allenes are potential intermediates in the synthesis of
important drug candidates. The application of our trifluoro-
methylation system composed of copper powder and S-(tri-
fluoromethyl)diphenylsulfonium triflate for tandem reactions
is currently under investigation.
lated by-product (entry 7). An examination of the effect of
phenyl substituents suggested that those that are electron-rich
are favorable for the reaction (entries 8–11). The substrate sub-
stituted with a weak electron-withdrawing group still could be
converted to the expected product in good yield (entry 12). But
a strong electron-withdrawing group greatly suppressed the
desired conversion (entry 13). The transformation is also appli-
cable for a 2-naphthyl substrate, even though the yield was
lower (entry 14).
The groups of Szabό and Nishibayashi have independently
reported the trifluoromethylation of propargyl trifluoroacetates
and chlorides. In Szabό’s case, [(Ph3P)3CuCF3] was used to
obtain the desired trifluoromethylated allenes in reactions per-
Acknowledgements
We thank the National Natural Science Foundation (21032006,
formed at 22 °C. They found that heating the reaction system 21172240), the 973 Program of China (2012CBA01200), the
Chinese Academy of Sciences and the Syngenta PhD Student-
ship Award for financial support. We thank Dr John Clough of
to 50 °C resulted in the rearrangement of the allenes to form
trifluoromethylated alkynes. In sharp contrast, no trifluoro-
methylated alkynes were detected under our reaction con- Syngenta at Jealott’s Hill International Research Centre for
proofreading the manuscript.
ditions, even when the reactions were performed at a higher
temperature (70 °C). Furthermore, we found that Szabό’s reac-
tion system doesn’t work for the trifluoromethylation of pro-
pargyl acetates (Scheme 2). Nishibayashi’s reaction conditions
(CuTc, KF and Me3SiCF3) were not effective with propargyl
acetates either. Even with a stoichiometric amount of CuTc,
only 19% yield of the desired product could be detected using
19F NMR, with trifluoromethylbenzene as an internal standard
(Scheme 2). These results indicated that different reaction con-
ditions should be applied to different kinds of substrates. The
three simple protocols are complementary for the trifluoro-
methylation of propargyl (trifluoro)acetates and chlorides
leading to trifluoromethylated allenes.
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