Ph3P+CF2CO2 ? as an F? and :CF2 source for trifluoromethylthiolation of alkyl halides

Article abstract of DOI:10.1016/j.cclet.2018.11.013

As trifluoromethylthiolation has received increasing attention recently, many CF₃S-reagents and trifluoromethylthiolation methods have been developed. Herein we describe trifluoromethylthiolation of alkyl halides by using Ph₃P⁺CF₂CO₂ ^? as a fluoride and difluorocarbene source. Difluorocarbene is a versatile intermediate, but its side reactions are usually ignored and the by-products would therefore be discarded. In this work, a side reaction of difluorocarbene, the generation of a fluoride anion from difluorocarbene, was developed into a synthetic tool. Although the trifluoromethylthiolation reaction involved multi-sequential steps, the cleavage of C–F bond, the formation of CF₂=S bond, F-C(S)F₂ bond, and C-SCF₃ bond, the conversion proceeded fast and was completed within 10 min.

Full text of DOI:10.1016/j.cclet.2018.11.013

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CCLET 4717 No. of Pages 3
Chinese Chemical Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Ph3P+CF2CO2À as an FÀ and :CF2 source for trifluoromethylthiolation of
alkyl halides
a,
b,
Zhuo Liua,b, Jin Longa,b, Xuan Xiaoa,b, Jin-Hong Linb, , Xing Zheng , Ji-Chang Xiao
,
*
*
*
Yu-Cai Caoc
a
Institute of Pharmacy and Pharmacology, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China,
Hengyang 421001, China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
b
Sciences, Shanghai 200032, China
c
Shanghai Research Institute of Chemical industry, Shanghai 200062, China
A R T I C L E I N F O
A B S T R A C T
Article history:
As trifluoromethylthiolation has received increasing attention recently, many CF3S-reagents and
trifluoromethylthiolation methods have been developed. Herein we describe trifluoromethylthiolation of
Received 9 October 2018
Received in revised form 27 October 2018
Accepted 12 November 2018
Available online xxx
À
alkyl halides by using Ph3P+CF2CO2 as a fluoride and difluorocarbene source. Difluorocarbene is a
versatile intermediate, but its side reactions are usually ignored and the by-products would therefore be
discarded. In this work, a side reaction of difluorocarbene, the generation of a fluoride anion from
difluorocarbene, was developed into a synthetic tool. Although the trifluoromethylthiolation reaction
involved multi-sequential steps, the cleavage of C–F bond, the formation of CF2=S bond, F-C(S)F2 bond,
and C-SCF3 bond, the conversion proceeded fast and was completed within 10 min.
© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Difluorocarbene
Trifluoromethylthiolation
Alkyl halides
Thiocarbonyl fluoride
Fluorine
Due to its strong electron-withdrawing effects (Hammett
constants sp = 0.50, sm = 0.40) and high lipophilicity (Hansch
the trifluoromethylation reagent is quite volatile. Apparently, the
development of effective trifluoromethylthiolation protocols by
using easily handled reagents is highly desirable.
parameter
p= 1.44) [1–3], trifluoromethylthio group (CF3S) has
been of increasing importance in drug design and development.
CF3S-containing pharmaceuticals such as Tiflorex, Cefazaflur and
Toltrazuril have been continuously developed [4]. Therefore,
significant efforts have been directed towards the development
of efficient methods for the incorporation of a CF3S group into
organic molecules [4–14]. Compared with traditional methods
such as halogen-fluorine exchange [15,16] and trifluoromethyla-
tion of sulfur compounds [17,18], direct trifluoromethylthiolation
is obviously an efficient and straightforward strategy for CF3S
incorporation [4]. A variety of direct trifluoromethylthiolation
approaches have been developed, including electrophilic, radical
and nucleophilic trifluoromethylthiolation (Scheme 1, Eq. (1)) [19–
25]. In these approaches, the synthesis of CF3S-containing reagents
is usually required, and the reagents may be expensive, sensitive to
air or difficult to prepare. Interestingly, the classic trifluorome-
thylation reagent, TMSCF3, could also enable the trifluorome-
thylthiolation in the presence of a sulfur source Eq. (1) [26–28]. But
As a versatile intermediate, difluorocarbene has found wide-
spread application in a wide range of reactions, such as [2 + 1]
cyclization and X-H insertion (X = N, O, S, etc.) [29,30]. Difluor-
ocarbene is quite electrophilic and thus would be readily trapped
by surrounding nucleophiles to generate unavoidable by-products.
The side reactions are usually ignored and the by-products would
therefore be discarded. However, the development of these
unwanted processes into synthetic tools may provide a foundation
for the exploration of difluorocarbene chemistry.
Ph3P+CF2CO2 (PDFA), a reagent which was developed by our
À
group [31–40] and was also used by other groups [41–46], could be
easily prepared via a reaction of Ph3P with BrCF2CO2K. Pure
product could be obtained simply by washing, and the reagent is
bench-stable and easy to handle. We have previously found that
PDFA could act as an efficient difluorocarbene reagent to realize
trifluoromethylthiolation (Scheme 1, Eq. (2)) [36,38]. Since an
external fluoride anion was used to install the CF3S moiety and the
trifluoromethylthiolation reaction occurred very rapidly (5 min or
20 min), 18F-trifluoromethylthiolation was examined and success-
fully achieved [36,38]. Based on our previous observation that side
reaction of difluorocarbene would produce a fluoride anion [34],
we have now investigated trifluoromethylthiolation by using this
* Corresponding authors.
E-mail addresses: jlin@sioc.ac.cn (J.-H. Lin), zhengxing9166@sohu.com
(X. Zheng), jchxiao@sioc.ac.cn (J.-C. Xiao).
https://doi.org/10.1016/j.cclet.2018.11.013
1001-8417/© 2018 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Z. Liu, et al., Ph3P+CF2CO2À as an FÀ and :CF2 source for trifluoromethylthiolation of alkyl halides, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.11.013

G Model
CCLET 4717 No. of Pages 3
2
Z. Liu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
14 vs. 12). This may be because difluorocarbene would be trapped
rapidly by elemental sulfur [38,39] and the generation of fluoride
from difluorocarbene would be slightly suppressed. The yield was
also decreased by either decreasing or increasing the loading of
Ph3P+CF2CO2 alone (entries À15 and 16 vs. 12). Increasing the
À
loadings of both Ph3P+CF2CO2 and S8 increased the yield to 84%
(entry 17).
With the optimized reaction conditions in hand (Table 1, entry
17), we then explored the substrate sÀcope of the trifluorome-
thylthiolation by using Ph3P+CF2CO2 as the fluoride and
difluorocarbene source (Scheme 2). Electron-rich, -neutral, and
–deficient benzyl bromides could all be well converted into the
desired products in moderate to good yields (3a-3m). These
conditions could be applied to the conversion of secondary
bromides (3c). A low isolated yield of 3c was because of its high
volatility (60% 19F NMR yield was obtained before isolation).
Besides benzyl bromides, allyl bromides (3n) and alkyl bromides
(3o-3p) also showed good reactivity towards this trifluorome-
thylthiolation. As shown in Scheme 2, a wide range of functional
group could be tolerated, such as aryl halides, cyanide, ester,
alkene, and heteroarene. Although the electrophilicity of benzyl
chlorides is apparently lower than benzyl bromides, trifluorome-
thylthiolation of benzyl chlorides proceeded smoothly.
Scheme 1. Trifluoromethylthiolation strategies.
difluorocarbene reagent without the presence of an external
fluoride anion (Scheme 1, Eq. (3)). The generation of fluoride anion
from difluorocarbene, a process which has always been considered
as a side reaction, was an important chemical step in this protocol.
Interestingly, although the trifluoromethylthiolation reaction
involved multi-sequential steps, the cleavage of C–F bond, the
formation of CF2=S bond, F-C(S)F2 bond, and C-SCF3 bond, the
conversion proceeded fast and was completed within 10 min.
As our previous work has shown that DBU [1,8-diazabicyclo
[5.4.0]undec-7-ene] could well promote the generation of fluoride
anion from difluorocarbene in DMF [34], we then firstly examined
the DBU-promoted trifluoromethylthiolation of benzylÀbromide
(1a) with the difluorocarbene reagent Ph3P+CF2CO2 in the
presence of elemental sulfur (S8) (Table 1, entry 1). The desired
product was obtained albeit in a low yield, suggesting that
Ph3P+CF2CO2À can successfully act as the F- and :CF2 source. A brief
survey of the reaction solvents (entries 1–4) revealed that DMA
was a superior solvent (entry 2). Besides DBU, various other bases
were also screened and some bases were found to be ineffective
(entries 5–12). To our delight, 62% yield was obtained by using
Cs2CO3 as a base (entry 12). Increasing the loading of elemental
sulfur alone led to a slight decrease in the yield (entries 13 and
In this trifluoromethylthiolation process, only -CF2- source and
S source were present, and thus the question arose as to how the
CF3S moiety was formed in the absence of an external fluoride. It
was found that trifluoromethane (HCF3) was rapidly generated as
the major product by stirring the mixture of Ph3P+CF2CO2 and
À
Cs2CO3 in DMA (Scheme 3) (details can be found Supporting
information). The low yield (22%) should be because of its low
boiling point (À82 ꢀC). No HCF3 was detected by simply heating
À
Ph3P+CF2CO2 in DMA without the presence of Cs2CO3. The
observation of HCF3 meant that the reaction of Ph3P+CF2CO2À with
Cs2CO3 produced
a fluoride anion, which was trapped by
difluorocarbene to form CF3À anion. Although it has been reported
À
that CF3 anion could react with an electrophilic sulfur source to
generate CF3SÀ anion [27,47], the formation of CF3 anion might
À
not be the predominant path in our reactions. Evidence has been
collected in our previous work to reveal that the capture of
Table 1
The optimization of the reaction conditionsa.
Entry
Ratiob
Solvent
Base
Yield (%)c
1
2
3
4
5
6
7
8
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:0.75:1
1:3:1:1
DMF
DMA
DME
MeCN
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DBU
DBU
DBU
DBU
24
33
14
28
ND
15
tBuONa
tBuOK
Na2HPO4
HCO2Na
Na2CO3
Li2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7
18
9
trace
trace
52
62
57
53
45
53
84
10
11
12
13
14
15
16
17
1:3:1.25:1
1:2:0.75:1
1:4:0.75:1
1:4:1.25:1
a
Reaction conditions: substrate 1a (0.2 mmol), Ph3P+CF2CO2À, S8, base, and
solvent (3 mL) at 70 ꢀC for 10 min; DME = 1,2-dimethoxyethane.
Scheme 2. Substrate scope of trifluoromethylthiolation. Isolated yields. Reaction
conditions: substrate 1 (0.2 mmol), Ph3P+CF2CO2À (4 equiv.), S8 (1.25 equiv.), Cs2CO3
(1 equiv.), and DMA (3 mL) at 70 ꢀC for 10 min.
b
Molar ratio of 1a:2:S8:base.
c
The yields were determined by 19F NMR spectroscopy.
Please cite this article in press as: Z. Liu, et al., Ph3P+CF2CO2À as an FÀ and :CF2 source for trifluoromethylthiolation of alkyl halides, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.11.013

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CCLET 4717 No. of Pages 3
Z. Liu et al. / Chinese Chemical Letters xxx (2018) xxx–xxx
3
the Key Research Program of Frontier Sciences (CAS) (No.
QYZDJSSW-SLH049), the Key Project of Hunan Provincial Educa-
tion Department (No. 17A190), the Zhengxiang Scholar Program of
the University of South China, Hunan Provincial Hengyang City
Joint Fund (No. 2017JJ4050), Hunan Graduate Science and
Technology Innovation Projects (No. 2018-400), Program for
Innovative Talent Team of Hengyang (No. 2017-1), the Key Project
of Hengyang Science and Technology Department (No. 2017KJ166),
and Shanghai Research Institute of Chemical Industry Co., LTD. (No.
SKL-LCTP-201802) for financial support.
Scheme 3. The evidence for the generation of a fluoride anion from difluor-
ocarbene. aThe yield was determined by 19F NMR spectroscopy.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2018.11.013.
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In summary, we have described the trifluoromethylthiolation of
alkyl halides by using Ph3P+CF2CO2 as a fluoride and difluor-
À
ocarbene source. The development of a side reaction of difluor-
ocarbene, a process which is usually ignored in organic synthesis,
into a synthetic tool may provide foundation for the exploration of
difluorocarbene chemistry. The trifluoromethylthiolation process
occurred rapidly even though the reaction involved multi-
sequential steps, the cleavage of C–F bond, the formation of
CF2=S bond, F-C(S)F2 bond, and C-SCF3 bond. As the difluorocar-
bene reagent, Ph3P+CF2CO2À, could be easily prepared and is easy
to handle, this trifluoromethylthiolation protocol may find
application in the synthesis of CF3S-containing biologically active
molecules.
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Please cite this article in press as: Z. Liu, et al., Ph3P+CF2CO2À as an FÀ and :CF2 source for trifluoromethylthiolation of alkyl halides, Chin. Chem.
Lett. (2018), https://doi.org/10.1016/j.cclet.2018.11.013