Copper(I)-mediated direct trifluoromethylthiolation of allylic halides with elemental sulfur and (trifluoromethyl)trimethylsilane

Article abstract of DOI:10.1002/ejoc.201500384

Abstract A new method has been developed for the copper-mediated trifluoromethylthiolation of allylic halides by using potassium fluoride, elemental sulfur, and (trifluoromethyl)trimethylsilane in anhydrous N,N-dimethylformamide. This protocol provides facile access to a variety of allylic trifluoromethyl thioethers in moderate to good yields under mild, ligand-free reaction conditions.

Full text of DOI:10.1002/ejoc.201500384

FULL PAPER
DOI: 10.1002/ejoc.201500384
Copper(I)-Mediated Direct Trifluoromethylthiolation of Allylic Halides with
Elemental Sulfur and (Trifluoromethyl)trimethylsilane
Jue Li,[a] Peiqiang Wang,[a] Fei-Fei Xie,[a] Xi-Gang Yang,[a] Xiao-Nan Song,[a]
Wei-Dong Chen,[b] Jiangmeng Ren,*[a] and Bu-Bing Zeng*[a,c]
Keywords: Synthetic methods / Allylic compounds / Copper / Fluorine / Sulfur / Reaction mechanisms
A new method has been developed for the copper-mediated
trifluoromethylthiolation of allylic halides by using potassium
fluoride, elemental sulfur, and (trifluoromethyl)trimethylsil-
ane in anhydrous N,N-dimethylformamide. This protocol
provides facile access to a variety of allylic trifluoromethyl
thioethers in moderate to good yields under mild, ligand-free
reaction conditions.
(SCF3) (bpy = 2,2Ј-bipyridine).[8] Trifluoromethylthiolation
can also be achieved in situ by using elemental sulfur and
(trifluoromethyl)trimethylsilane in the absence or presence
of transition-metal salts and ligands.[9]
Introduction
The trifluoromethylthio group (SCF3) is an active struc-
tural fragment that is found in a broad range of pharmaceu-
tical and agrochemical agents. Because of its strong elec-
tron-withdrawing effect and extremely high lipophilicity, the
introduction of a trifluoromethylthio group can lead to an
increase in the permeability and bioavailability of the
parent compound.[1] The development of new synthetic
methods for the introduction of trifluoromethylthio groups
into organic molecules has therefore attracted considerable
attention from organic and medicinal chemists. During the
past two decades, significant research efforts have been de-
voted to the development of straightforward, efficient, high-
yielding, and economical processes for the preparation of
trifluoromethylthio-containing organic molecules in both
academic and industrial laboratories.[2]
Several methods have been reported to introduce a tri-
fluoromethylthio group into a small organic molecule,
including halogen/fluorine exchange reactions of poly-
halogenomethyl thioethers[3] and the use of trifluoromethyl-
thiolation reagents such as trifluoromethylsulfenyl chloride
(CF3SCl),[4] bis(trifluoromethyl) disulfide (CF3SSCF3),[5]
trifluoromethylthiolated hypervalent iodine reagent A,[6] tri-
fluoromethanesulfenamide B,[7] (Figure 1) and (bpy)Cu-
Figure 1. Different trifluoromethylthiolation reagents.
Allylic functional groups, which are common building
blocks in organic chemistry, can be converted into a variety
of useful compounds. The trifluoromethylthiolation reac-
tions of allylsilanes, allylic bromides, and alkyl halides have
recently been reported.[8–10] However, previous reports of
the trifluoromethylthiolation of allylic halides describe the
reaction taking place in the presence of a ligand, and those
reactions with allylic chlorides resulted in low yields. In this
current study, we have developed a ligand-free direct ap-
proach for the trifluoromethylthiolation of allylic chlorides
and bromides in the presence of copper thiocyanate, potas-
sium fluoride, elemental sulfur, and (trifluoromethyl)tri-
[a] Shanghai Key Laboratory of New Drug Design, East China methylsilane to give allylic trifluoromethyl thioethers in
University of Science and Technology,
moderate to excellent yields.
130 Meilong Road, Shanghai 200237, P. R. China
E-mail: renjm@ecust.edu.cn
zengbb@ecust.edu.cn
http://pharmacy.ecust.edu.cn/
[b] Shanghai Key Laboratory of Chemical Biology, East China
University of Science and Technology,
130 Meilong Road, Shanghai 200237, P. R. China
Results and Discussion
[c] Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences,
Cinnamyl chloride (1a) was selected as the model sub-
strate and was combined with TMSCF3 (TMS = trimethyl-
silyl) and elemental sulfur to optimize the reaction condi-
345 Lingling Road, Shanghai 200032, P. R. China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500384.
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Copper(I)-Mediated Direct Trifluoromethylthiolation of Allylic Halides
tions and provide the trifluoromethylthio-containing spe- methylformamide (DMF), and acetonitrile, and N,N-di-
cies. Several copper salts were screened, including CuI, methylformamide gave the best result (Table 1, Entries 14–
CuBr, CuCl, CuSCN, CuCN, Cu, CuCl2, and Cu(OAc)2. 16). Finally, increasing the temperature to 45 °C provided
The results of these reactions reveal that CuSCN was the the optimum yield of 2a (Table 1, Entry 17).
optimal copper salt for the trifluoromethylthiolation reac-
With the optimal conditions in hand, we proceeded to
tion to give the desired product 2a in 62.3% yield. Several investigate the scope of the reaction with a variety of dif-
bases were also screened in this reaction, and KF gave the ferent allylic compounds. Cinnamyl chloride derivatives
best results (see Supporting Information for further details). with an electron-withdrawing substituent at the ortho or
Following these preliminary results, we then examined the para position of the aromatic ring gave moderate yields un-
optimal number of equivalents for the combination of S8 der the optimized conditions. Unfortunately, the cinnamyl
and TMSCF3 with respect to 1a (Table 1, Entries 1–4) and chloride with an ortho-nitro group on the aromatic ring per-
found that decreasing the number to 3 equiv. each did not formed poorly and afforded 2i in 23% yield. Pleasingly, cin-
have an adverse impact on the yield of 2a (Table 1, Entry 2). namyl chlorides that contain electron-donating substi-
A further decrease in the molar equivalency of S8 and tutents afforded good yields of the corresponding trifluoro-
TMSCF3 led to a significant reduction in the yield. When methylthiolated products. A naphthyl-containing substrate
the reaction was conducted in the absence of a copper salt, also underwent the reaction smoothly under the optimized
the product was formed in a much lower yield (Table 1, En- conditions to give the desired product 2m in 82.9% yield
try 5). Moreover, none of the desired product was formed (Table 2, Entry 12). The optimized conditions were then
when the reaction was conducted in the absence of potas- applied to an alkyl-substituted allylic chloride, which gave
sium fluoride (Table 1, Entry 6). In combination, these re- the corresponding trifluoromethylthiolated product 2n in
sults highlight the importance of the copper salt and base moderate yield (Table 2, Entry 13). A terminal alkene suc-
for the success of the reaction. The amount of CuSCN was cessfully underwent the reaction by employing the same
also examined in the presence of 2.0 equiv. of KF. Surpris- conditions to give product 2o in 65.3% yield (Table 2, En-
ingly, the use of 0.5 equiv. of CuSCN afforded the desired try 14). Geranyl bromide, which does not contain an aro-
product in 59.6% yield (Table 1, Entry 9). However, increas- matic ring or a conjugated system, also afforded the corre-
ing the loading of CuSCN gave a lower yield of 2a and also sponding allylic trifluoromethyl thioether 2p in high yield.
resulted in an increase in the yield of byproduct 3a (Table 1, Allylic chlorides that contained a substituted heteroarom-
Entries 7 and 8). These results, therefore, confirm that the atic ring underwent the trifluoromethylthiolation reaction
loading amount of the copper salt affected the trifluorome- as well to give the corresponding products in moderate
thylthiolation reaction. An investigation of the amount of yields. Interestingly, both branched and linear allylic chlor-
KF revealed that the addition of 4.0 equiv. of KF afforded ides gave the corresponding stable linear allylic trifluorome-
the best result (Table 1, Entries 10–13). Several solvents thyl thioether 2q (Table 2, Entry 16), which indicates that a
were investigated under these new conditions, including rearrangement reaction takes place during the trifluorome-
tetrahydrofuran (THF), dichloromethane (DCM), N,N-di- thylthiolation process.
Table 1. Optimization of the trifluoromethylthiolation of cinnamyl chloride (1a).
Entry
Cu salt (equiv.)
Base (equiv.)
S8/TMSCF3 (equiv.)
Solvent
Temp. [°C]
Yield [%] of 2a/3a[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuSCN (2.0)
CuSCN (2.0)
CuSCN (2.0)
CuSCN (2.0)
–
CuSCN (2.0)
CuSCN (1.5)
CuSCN (1.0)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
CuSCN (0.5)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
KF (2.0)
–
KF (2.0)
KF (2.0)
KF (2.0)
KF (1.0)
KF (3.0)
KF (4.0)
KF (5.0)
KF (4.0)
KF (4.0)
KF (4.0)
KF (4.0)
4.0:4.0
3.0:3.0
2.0:2.0
1.0:1.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
3.0:3.0
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
45
60.3:0
62.3:0
47.9:0
23.0:0
22.0:0
n.r.[b]
38.8:32.0
19.2:50.2
59.6:0
35.5:0
60.0:0
70.0:0
65.2:0
n.r.[b]
DCM
MeCN
DMF
n.r.[b]
33.2:0
85.2:0
[a] Isolated yield. [b] n.r. = no reaction.
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J. Ren, B.-B. Zeng et al.
FULL PAPER
Table 2. Scope of trifluoromethylthiolation of allylic compounds.[a] anion was captured by elemental S8 followed by trapping
of the resulting S2– anion with DMF (Scheme 1a). In con-
trast, no reaction was observed by 19F NMR spectroscopy
when a mixture of 1a, CuSCN, KF, and S8 was stirred at
45 °C (Scheme 1b). To determine whether CF3SSCF3 was
the active trifluoromethylthiolating agent in the reaction, a
mixture of 1a, TMSCF3, CuSCN, KF, and S8 was stirred
at 45 °C for 90 min, and the reaction was monitored by 19
F
NMR spectroscopy (Scheme 1c). A signal at δ = –16.0 ppm
in the 19F NMR spectrum might be an active substance,
which we hypothesized to be a copper complex (see the
Supporting Information for further details). Notably, pre-
vious work in this area suggests that the CS2 generated dur-
ing this reaction was derived from CO2 and DMF.[9b] To
further explore the direct detectable evidence during the
current study and to exclude the possibility of the CS2 being
derived from CO2, we performed an additional control ex-
periment. Thus, a mixture of TMSCF3, CuSCN, KF, and
S8 was stirred in DCM at room temperature under CO2.
GC–MS analysis revealed that no CS2 was generated under
these conditions (Scheme 1d).
[a] Reagents and conditions: 1 (2.0 mmol), CuSCN (1.0 mmol), KF
(8.0 mmol), S8 (6.0 mmol), and TMSCF3 (6.0 mmol) in DMF
(12 mL) under N2. [b] Isolated yield.
Scheme 1. Mechanistic experiment.
On the basis of the obtained results, we propose a mecha-
nism for the trifluoromethylthiolation reaction (Scheme 2).
–
Several additional experiments were conducted to TMSCF3 is initially converted into the active SCF3 anion
investigate the mechanism of the reaction and develop a in the presence of S8, KF, and DMF. The SCF3– anion then
deeper understanding of the role of each reactant in this undergoes a reaction with CuSCN to give copper(I) com-
transformation (Scheme 1).
A mixture of TMSCF3, plex C, which then proceeds to react with 1a to give cop-
CuSCN, KF, and S8 in DMF was stirred at 45 °C under per(III) complex D (which would promote the chloride
nitrogen. The progress of the reaction was monitored anion to leave and, therefore, accelerate the SN1 process).
periodically by a combination of GC–MS and 19F NMR Complex D would then provide product 2a along with cop-
spectroscopy. CF3SCF3, CF3SSCF3, N,N-dimethylmeth- per(I) complex C to complete the catalytic cycle. Further
anethioamide (4a), and CS2 were detected in the solution studies to determine the exact mechanism of this reaction
–
by GC–MS, which suggests that the in situ generated CF3
are currently underway in our laboratory.
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Eur. J. Org. Chem. 2015, 3568–3571

Copper(I)-Mediated Direct Trifluoromethylthiolation of Allylic Halides
Supporting Information (see footnote on the first page of this arti-
cle): General experimental methods, characterization data for com-
pound 2, and NMR spectra.
Acknowledgments
We thank the National Natural Science Foundation of China
(21302053) for the generous financial support. We are also grateful
for the financial support from the Fundamental Research Funds
for the Central University (WY111307).
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Scheme 2. Proposed mechanism for the trifluoromethylthiolation
reaction.
Conclusions
An efficient and convenient method has been developed
for the preparation of allylic trifluoromethyl thioethers.
This reaction proceeds under mild conditions to give the
products in moderate to good yields. Both electron-deficient
and electron-rich substrates were well tolerated under the
optimized reaction conditions. Notably, all of the required
materials for this reaction are inexpensive and nontoxic.
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Experimental Section
General Procedure for the Trifluoromethylthiolation of 2a–2s: Into
an oven-dried reaction tube were placed CuSCN (0.5 equiv.), KF
(4.0 equiv.), and S8 (3.0 equiv.), and the tube was then evacuated
and backfilled with nitrogen. A solution of the substrate (2 mmol)
in DMF (12 mL) and then TMSCF3 (3.0 equiv.) were added suc-
cessively by a syringe. Then the reaction mixture was stirred at
45 °C for 12 h. Water was added, and the mixture was filtered
through Celite. The resulting mixture was extracted with ethyl acet-
ate (3 ϫ 15 mL), and the combined organic layers were washed with
water and dried with anhydrous sodium sulfate. The solvent was
removed by rotary evaporation, and the residue was purified by
column chromatography on silica gel (petroleum ether and ethyl
acetate).
Received: March 23, 2015
Published Online: April 22, 2015
Eur. J. Org. Chem. 2015, 3568–3571
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