Copper-catalyzed synthesis of α-trifluoromethylthio-substituted ketones

Article abstract of DOI:10.1021/ol501290p

The CF₃S-substituted moiety serves as an important structural element in many bioactive molecules. A versatile copper catalyst that allowed for trifluoromethylthiolation of primary and secondary α-bromoketones is described. The reaction with readily available elemental sulfur and CF ₃SiMe₃ afforded a broad scope and moderate to good yields of α-trifluoromethylthio-substituted ketones. This procedure represents a very operationally simple yet powerful strategy for the synthesis of α-trifluoromethylthio-substituted ketones, a useful and versatile class of synthetic synthons.

Full text of DOI:10.1021/ol501290p

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Synthesis of α‑Trifluoromethylthio-Substituted
Ketones
Yangjie Huang,† Xing He,† Xiaoxi Lin, Mingguang Rong, and Zhiqiang Weng*
Department of Chemistry, Fuzhou University, Fuzhou 350108, China
S
* Supporting Information
ABSTRACT: The CF3S-substituted moiety serves as an important
structural element in many bioactive molecules. A versatile copper
catalyst that allowed for trifluoromethylthiolation of primary and
secondary α-bromoketones is described. The reaction with readily
available elemental sulfur and CF3SiMe3 afforded a broad scope and
moderate to good yields of α-trifluoromethylthio-substituted ketones.
This procedure represents a very operationally simple yet powerful strategy for the synthesis of α-trifluoromethylthio-substituted
ketones, a useful and versatile class of synthetic synthons.
α-Trifluoromethyl-substituted carbonyl compounds are valua-
ble synthons for the preparation of numerous derivatives
containing the CF3 group that are of increasing interest in
pharmaceutical, agricultural, and material sciences.1 With their
broad application considered, the development of novel and
more efficient synthetic methods for α-CF3-substituted carbon-
yl compounds has been the focus of extensive research
interest.2,3
However, whereas efficient methods for synthesis of α-CF3-
substituted carbonyl compounds have been reported,4 the
development of preparation of α-CF3S-substituted analogues is
much less explored (Scheme 1). Compared to other fluorinated
reactions of ketone or benzoylacetic ethyl ester with
trifluoromethylsulfenyl chloride to give the α-CF3S-substituted
ketones.11,12 Recently, the Shen and the Rueping groups
independently described the electrophilic trifluoromethylthio-
lation of β-ketoesters to afford the corresponding α-
trifluoromethylthiolated carbonyl compounds.6,13 Most re-
cently, Li and Zard reported trifluoromethylthiolation of α-
bromoketones with O-octadecyl-S-trifluorothiolcarbonate.14
However, some of these methods show modest substrate
scope and require extremely toxic and corrosive CF3SCl or
electrophilic-type trifluoromethylthiolation reagent and are
limited in their functional group compatibility.
Nonetheless, elegant work from the Qing group on copper-
catalyzed oxidative trifluoromethylthiolation of aryl boronic
acids with CF3SiMe3 and elemental sulfur10a,15 has raised
anticipation that efficient trifluoromethylthiolation could be
realized by using readily available and inexpensive catalysts and
fluorinated reagents.
Scheme 1. Methods for Synthesis of α-CF3S-Substituted
Ketones
As part of our ongoing interest in the development of
efficient methods for trifluoromethylthiolation16 and trifluor-
omethylselenolation,17 we herein report copper-catalyzed
trifluoromethylthiolation of α-bromoketones with elemental
sulfur and CF3SiMe3 to synthesize α-trifluoromethylthio-
substituted ketones.
Our initial investigation commenced with the treatment of 2-
bromo-1-p-tolylethanone 1a, elemental sulfur, and CF3SiMe3
and KF with CuI (20 mol %)/phen (20 mol %) as catalyst in
CH2Cl2 as the solvent at 40 °C (Table 1). The reaction
occurred leading to the formation of the trifluoromethylthio-
lated ketone 2a in 25% yield (entry 1).
To determine the efficient copper catalyst for this one-pot
synthesis, we then examined a variety of copper salts. When
CuSCN was used as a catalyst, a small improvement in the yield
(39%) was observed (entry 2). When Cu(MeCN)4PF6, CuF2,
alkyl groups (SF5−, πx = 1.23; CF3O−, πx = 1.04; CF3−, πx =
0.88), the CF3S− group shows the highest lipophilicity value
(πx = 1.44).5,6 It is well-known that the introduction of
trifluoromethylthio group into organic molecules such as
pharmaceuticals and agrochemicals greatly enhances their
bioavailability.7−10
Therefore, new methods for incorporation of CF3S−
substituents into carbonyl compounds would be broadly useful
in synthetic chemistry. Haas and Kolasa initially reported the
Received: May 6, 2014
Published: June 4, 2014
© 2014 American Chemical Society
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Letter
reducing the reaction time to 8 h resulted in incomplete
conversion (entry 21).
Having identified these optimal conditions, we next
examined the substrate scope for this new reaction. A variety
of aromatic α-bromoketones were surveyed to synthesize
different trifluoromethylthiolated ketones (Scheme 2).
Table 1. Optimization of Copper-Catalyzed
Trifluoromethylthiolation of 2-Bromo-4′-
a
methylacetophenone
Scheme 2. Copper-Catalyzed Trifluoromethylthiolation of α-
Bromoketones
b
temp
(°C)
time yield
a
entry
[Cu]
ligand
solvent
(h)
(%)
1
CuI
phen
phen
phen
phen
phen
phen
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
CH3OH
DMF
40
40
40
40
40
40
40
40
40
40
40
40
40
40
80
40
40
40
30
50
40
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
8
25
39
63
68
63
92
2
2
CuSCN
3
Cu(MeCN)4PF6
CuF2
4
5
Cu(TFA)2
Cu(OTf)2
6
7
8
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
bpy
58
0
9
tmeda
dmcda
Me3py
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
10
11
12
13
14
15
16
17
18
19
20
21
9
1
5
0
1
DMF
1
DMSO
THF
1
9
toluene
CH2Cl2
CH2Cl2
CH2Cl2
0
57
74
48
a
Reaction conditions: Cu(OTf)2 (0.050 mmol), phen (0.050 mmol),
α-bromoketones (0.25 mmol), CF3SiMe3 (1.0 mmol), S8 (1.0 mmol),
a
Reaction conditions: [Cu] (0.010 mmol), ligand (0.010 mmol), 2-
bromo-4′-methylacetophenone (0.050 mmol), CF3SiMe3 (0.20
mmol), S8 (0.20 mmol), KF (0.20 mmol), solvent (1.0 mL), N2;
phen = 1,10-phenanthroline, bpy = 2,2′-bipyridine, tmeda =
N,N,N′,N′-tetramethylethylenediamine, dmcda = trans-N,N′-dimeth-
KF (1.0 mmol), CH2Cl2 (1.0 mL), N2. Yields of isolated products are
b
shown. The yield was determined by 19F NMR spectroscopy with
PhOCF3 as internal standard.
b
yl-1,2-cyclohexanediamine, Me3py = 2,4,6-trimethylpyridine. The
α-Bromoketones bearing methyl, dimethyl, and phenyl
substitutions at the aromatic rings reacted with S8 and
CF3SiMe3 to give the products 2a−c, respectively, in 68−
87% yields. The unfunctionalized aromatic α-bromoketones, 2-
bromo-1-phenylethanone, and 2-bromo-1-(naphthalen-2-yl)-
ethanone also underwent trifluoromethylthiolation to afforded
the desired products 2d and 2e in good yields (72% and 75%,
respectively).
Variation of electronic properties of the aryl substitutents in
the aromatic α-bromoketones had a dramatic effect on the
reaction efficiency. α-Bromoketone substrates with a methoxy
substituent at the ortho-, meta-, or para-position of the aromatic
rings provided the corresponding products 2f−h in good yields
(80%, 78% and 88%, respectively). Furthermore, α-bromoke-
tone possessing a dimethylamino substituent in the para-
position of the aryl groups also provided the desired product 2i,
exclusively (70% yield). Additionally, α-bromoketone having
nitro or nitrile substituents at the meta- or para-position of the
aryl groups could also be transferred through this protocol,
although reduced yields of the corresponding products 2j,k
were observed (17% and 13%, respectively), with the
trifluoromethylated alcohol resulting from the addition of
CF3 to the carbonyl group as side product. Notably, substrates
bearing halogenated arenes were also accommodated and
furnished the desired products 2l−n in moderate yields (20−
69%), thereby providing possibilities for subsequent chemical
transformations. Heteroaryl groups, such as coumarin group,
could also be tolerated to give the trifluoromethylthiolated
yield was determined by 19F NMR spectroscopy with PhOCF3 as
internal standard.
and Cu(TFA)2 (with phen as ligands) were employed, a
moderate yield of product was obtained (entries 3−5). Notably,
the use of Cu(OTf)2 with phen as ligand produced the best
results (92% yield; entry 6). It is also noteworthy that the
products derived from the addition of the CF3 to the carbonyl
group1a,18 were not detected by using these conditions.
Cu(OTf)2 was therefore established as the preferred Cu source
for the copper-catalyzed trifluoromethylthiolation. Only a trace
amount of product was formed in the absence of a copper
source and ligand (entry 7). The result clearly demonstrated
the importance of both the catalyst and ligands in this
transformation.
Although bipyridine has been shown previously to be a
powerful ligand for copper-mediated trifluoromethylthiolation
with aryl halides,16a bpy was not so efficient as a ligand in this
case, affording a less satisfactory yield (entry 8). Changing to
other nitrogen ligands, such as tmeda, dmcyda, or Me3py, only
retarded the reaction (entries 9−11). Additionally, the choice
of solvent influenced the yield. The use of other solvents, e.g.,
CH3CN, CH3OH, DMF, DMSO, THF, or toluene (entries
12−18), was found to be detrimental. The effect of temperature
was also investigated. Reactions performed either at lower
temperatures (30 °C) or elevated temperature (50 °C)
produced lower yields (entries 19 and 20). Furthermore,
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Letter
product 2o in 30% yield (19F NMR). Interestingly, the
trifluoromethylthiolation of an aliphatic α-bromoketone was
possible and proceeded in excellent yield (2p, 85%), thus
enhancing the scope of our reaction.
Scheme 5. Synthetic Utility of 2a
The scope was then extended to the use of secondary
bromides (Scheme 3). The reaction with 2-bromopropiophe-
Scheme 3. Copper-Catalyzed Trifluoromethylthiolation of
a
Secondary α-Bromoketones
the reaction under the optimized conditions (Scheme 6).
Suprisingly, the reaction produced the desired product 2a in
Scheme 6. Inhibition Experiment with TEMPO
a
Reaction conditions: Cu(OTf)2 (0.075 mmol), phen (0.075 mmol),
α-bromoketones (0.25 mmol), CF3SiMe3 (1.0 mmol), S8 (1.0 mmol),
KF (1.0 mmol), CH2Cl2 (1.0 mL), N2. Yields of isolated products are
shown.
none, 4′-(benzyloxy)-2-bromopropiophenone, and 2-bromo-1-
(3-chlorophenyl)-1-propanone led to the formation of desired
products 2q−s in good yields (77%, 80%, and 64%,
respectively), albeit with the higher catalyst loading of CuI
(30 mol %)/phen (30 mol %). Moreover, 2-bromo-1-(4-
bromophenyl)-1-propanone smoothly underwent trifluorome-
thylthiolation to afford product 2t in 71% yield with remarkable
chemoselectivity, leaving the C(sp2)−Br bond untouched.
To prove the practicality of this protocol for large-scale
synthesis, we prepared 2a on a gram scale under the optimized
reaction conditions (Scheme 4). The trifluoromethylthiolation
of 1a took place satisfactorily, affording the expected product
2a in 72% yield.
only 19% yield together with the TEMPO−CF3 adduct 6 in
56% yield by 19F NMR analysis. This observation indicated that
a CF3 radical intermediate might be involved in the reactions.
In summary, a new approach to the direct construction of α-
trifluoromethylthio-substituted ketones from readily available
α-bromoketones, elemental sulfur, and CF3SiMe3 has been
achieved using copper catalysis. This method provides a broad
scope and moderate to good yields of the trifluoromethylth-
iolated products, and a variety of functional groups are
compatible with these reaction conditions. The present
reaction, therefore, is anticipated to be a powerful protocol
for the synthesis of α-trifluoromethylthio-substituted ketones,
which are important synthons for the preparation of numerous
derivatives containing the CF3S− group. Further studies of this
and related copper-catalyzed chemistry are in progress.
Scheme 4. Gram-Scale Synthesis of α-Trifluoromethylthio-
Substituted Ketones
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for products and
mechanistic study experiments. This material is available free of
charge via the Internet at http://pubs.acs.org.
In a synthetic application of the present reaction, we
attempted to prepare alcohol and pyrazole derivatives, and
the results are summarized in Scheme 5. The trifluoromethylth-
iolated ketone 2a was treated with NaBH4 to deliver alcohol 3
in 90% yield or alternatively reacted with PhMgBr to generate
tertiary alcohol 4 in 72% yield.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zweng@fzu.edu.cn.
Author Contributions
†These authors contributed equally.
Notes
The utility of the reaction is further illustrated by the
synthesis of trifluoromethylthio-substituted pyrazoles, which is
of great interest in medicinal chemistry.4b,19 Reaction of 2a with
dimethylformamide acetal followed by hydrazine gave the
desired trifluoromethylthio-substituted pyrazole 5 in 88%
overall yield, thus demonstrated herein that this new protocol
provides a convenient methodology to access these biologically
interesting scaffolds (Scheme 5).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Natural Science
Foundation of China (21072030), Research Fund for the
Doctoral Program of Higher Education of China (No.
20123514110003), the SRF for ROCS, SEM, China (2012-
1707), and Fuzhou University (022318, 022494).
In an attempt to find out whether any radical intermediates
are formed in trifluoromethylthiolation, a radical scavenger,
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), was added to
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Letter
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Weng, Z. Tetrahedron 2014, 70, 672−677.
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