Chlorotrifluoromethylthiolation of Sulfur Ylides for the Formation of Tetrasubstituted Trifluoromethylthiolated Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c02747

Tetrasubstituted trifluoromethylthiolated alkenes can be accomplished directly through the chlorotrifluoromethylthiolation of sulfur ylides utilizing nucleophilic halide reagent and electrophilic SCF3 reagent. This cascade reaction is mild, highly practical, easy to manipulate, uses catalyst-free conditions, and demonstrates a wide substrate range with excellent functional group tolerance, furnishing E-selective products in good to high yields. The synthetic utility of this approach is documented through gram-scale preparation and late-stage modification of pharmaceutically relevant compounds, making it suitable for drug discovery.

Full text of DOI:10.1021/acs.orglett.0c02747

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Letter
Chlorotrifluoromethylthiolation of Sulfur Ylides for the Formation of
Tetrasubstituted Trifluoromethylthiolated Alkenes
Na Wang,† Yimin Jia,† Hongmei Qin,† Zhong-xing Jiang, and Zhigang Yang*
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ABSTRACT: Tetrasubstituted trifluoromethylthiolated alkenes can be
accomplished directly through the chlorotrifluoromethylthiolation of
sulfur ylides utilizing nucleophilic halide reagent and electrophilic SCF3
reagent. This cascade reaction is mild, highly practical, easy to
manipulate, uses catalyst-free conditions, and demonstrates a wide
substrate range with excellent functional group tolerance, furnishing E-
selective products in good to high yields. The synthetic utility of this
approach is documented through gram-scale preparation and late-stage
modification of pharmaceutically relevant compounds, making it suitable
for drug discovery.
rganofluorine compounds are extensively utilized in
medicinal chemistry, agrochemistry, and materials
O
science owing to their special chemical, physical, and biological
properties.1,2 Among the various fluorine-containing moieties,
the trifluoromethylthio group (SCF3) is particularly interesting
because of its unique features of extremely strong electron-
withdrawing character, high lipophilicity (Hansch constant of
1.44), and metabolic stability.3 This may be beneficial in
improving the pharmacokinetics of drug molecules. Various
efforts have been devoted to the design of general and efficient
protocols for the selective incorporation of an SCF3 motif into
organic molecules over the past decades.4 However, there are
still relatively few efficient approaches to straightforwardly
access alkenes bearing a trifluoromethylthio group. Traditional
methods for the construction of the trifluoromethylthio
alkenes typically involve electrophilic substitution of alkenes,5
cross-coupling of vinyl boronic acids,6 vinyl halides,7 or vinyl
carboxylic acids,8 C−H bond activation of alkenes,9
nucleophilic substitution of enamines,10 and ring-opening of
methylenecyclopropanes11 by employing nucleophilic, electro-
philic, or radical SCF3 reagents (Figure 1a). Furthermore,
these molecules can also be formed through the difunction-
alization based on trifluoromethylthiolation of alkynes (Figure
1b).12 However, most of these methods required transition-
metal catalysts and/or excess bases.
Figure 1. Synthesis of trifluoromethylthioalkenes.
development of catalyst-free methodology that affords a
general and efficient tandem procedure for gram-scale
synthesis of multifunctionalized alkenes. The current trans-
formation provides a new route to access trifluoromethylthio-
lated alkenes (Figure 1c).
As the safer carbene precursors and readily available building
blocks, sulfur ylides13 have been broadly applied in the field of
organic synthetic chemistry. They are more stable and less
hazardous than diazo compounds, which are the most
commonly used carbene precursors. In addition, a strategy
based on multifunctionalization of carbonyl sulfur ylides to
establish trifluoromethylthioalkenes has not been reported.
Based on our continued interest in the preparation of
organofluorine compounds,14 we herein present the successful
Received: August 17, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02747
© XXXX American Chemical Society
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A

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As the precursor of sulfur ylides, sulfonium salts are very
stable solids and can readily be synthesized from commercially
available and inexpensive haloalkanes and thioethers. It can be
easily converted into sulfur ylide under basic conditions. Thus,
we initiated our investigation on this sequential trifluorome-
thylthiolation using the carbonyl-substituted sulfonium salt 1a
as a model substrate to identify the reaction conditions. When
1a was reacted with Munavalli’s15b SCF3 reagent 2a and AcCl
using DIPEA as base in DMF, the expected chlorotrifluor-
omethylthiolated enolate 3a′ was observed in 33% yield (Table
1, entry 1). To our delight, upon addition of 4 Å MS
With the above-optimized conditions in hand, the substrate
generality and functional group compatibility of the trifluor-
omethylthiolation were evaluated with respect to different
sulfonium salts (Scheme 1). A variety of sulfonium salts were
Scheme 1. Substrate Scope of Trifluoromethylthiolation of
a−c
Sulfur Ylides with BzCl
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
2
R
solvent
yield (%)
E/Z
d
1
2a
2a
2b
2c
2d
2a
2a
2a
2a
2a
2a
2a
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
DMF
DMF
DMF
DMF
DMF
THF
DCM
toluene
MeCN
DMAC
DMSO
DMF
33
60
17
58
ND
12
20
trace
30
56
ND
93
8:1
2
3
4
5
6
7
8
9
8:1
4:1
7:1
ND
6:1
10:1
ND
10:1
8:1
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), BzCl (1.0
10
11
12
mmol), DIPEA (0.5 mmol), and 4 Å M.S. (200 mg) in DMF (5.0
b
ND
>20:1
mL) at room temperature for 12 h. Reported yields are of isolated
c
products for E-configured products. The E/Z ratio is given in
1
parentheses and was determined by H NMR and 19F NMR analysis
a
Reaction conditions: 1a (0.1 mmol), 2a (0.1 mmol), AcCl or BzCl
of a crude reaction mixture.
(0.2 mmol), DIPEA (0.1 mmol), and 4 Å M.S. (40 mg) in solvent
b
(1.0 mL) at room temperature for 12 h. Yields were determined by
c
19F NMR analysis using PhCF3 as an internal standard. The E/Z
converted to the chlorotrifluoromethylthiolated adducts in
good to excellent yields. Substrates bearing both electron-
donating groups (Me, OMe, OTs) and electron-withdrawing
groups (Cl, Br, CF3, NO2) on the para position of the phenyl
ring all proceeded smoothly to give the desired products 3b−h
in 75−90% yield. Excellent results were generally furnished by
using meta-substituted aryls regardless of the electronic
properties of substituents (3i−j). The sterically hindered
ortho-substituted aryls were well tolerated with the reaction
conditions, delivering the expected products 3k−m with 75−
92% yields and good stereoselectivity (>10:1, E/Z). Notably,
substrates having two substituents (such as 3,4-dichloro, 3,4-
dimethoxy, and 2-fluoro-4-methoxy) on the aromatic ring
could be extended to the protocol, and the desired product
3n−p were detected in excellent yields. Interestingly, the
heteroaromatic moieties could also well contained in substrates
1q−r, as shown by the formation of the resulting 2-furyl and 2-
thienyl derivatives 3q−r in 84% and 62% yields, respectively.
Finally, when fused ring substituted substrate 1s (Ar = 2-
naphthyl) was subjected to this process, the corresponding
trifluoromethylthiolated alkene was achieved in a satisfactory
yield and high stereoselectivity.
ratio was determined by H NMR and 19F NMR analysis of a crude
1
d
reaction mixture. Without 4 Å molecular sieves. ND = not detected.
(molecular sieves) to the reaction system, the yield of product
3a′ was increased to 60% (Table 1, entry 2). The role of 4 Å
MS may be to remove traces of water in the reaction. In
contrast, other electrophilic SCF3 sources were also examined.
A 17% yield was achieved when Shen’s reagent (2b)15c was
investigated (Table 1, entry 3). Haas’ (2c)15a reagent could
give the desired product 3a′ in reasonable yield, whereas the
use of Billard’s reagent (2d)12a led to no reaction (Table 1,
entry 5). Further study of several solvents, such as THF, DCM,
toluene, MeCN, and DMAC (N,N-dimethylacetamide),
indicated the yield of 3a′ was not improved (Table 1, entries
6−10). These results demonstrate that an amide solvent such
as DMF or DMAC may be able to stabilize acid chloride to
give better reactivities.16 Surprisingly, when DMSO was used
as solvent, the expected reaction did not occur (Table 1, entry
11). Importantly, the employment of benzoyl chloride (BzCl)
as a substrate could provide the corresponding adduct 3a in
93% yield with excellent stereoselectivity (E/Z > 20:1, Table 1,
entry 12).
To further probe the efficacy of current method, we next
turned our attention to building dichlorinated trifluorome-
B
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thylthiolated alkenes. As depicted in Scheme 2, when
dichloride reagent PhPOCl2 (phenylphosphonic dichloride)
on the aryl ring were suitable substrates (4i−j). Noticeably, the
transformation was also workable when a six-membered
episulfide was combined on the sulfonium salt (4k).
To highlight the applicability of this protocol further, we
evaluated the chlorotrifluoromethylthiolation method with
biologically active compounds and natural products. Poly-
ethylene glycols (PEGs), water-soluble, nontoxic, and bio-
compatible polymers, could be readily chlorotrifluoromethylth-
iolated from their derived esters with acceptable yields (4l,m).
Sulfonium salts derived from commercially available nature
products, such as coumarin and malic acid, were also suitable
substrates, delivering the corresponding tetrasubstituted
trifluoromethylthiolated alkenes 4n,o as the sole adducts in
57% and 60% yields, respectively. These results show that this
reaction can be utilized in the late-stage modification of
complex compounds. The geometric configuration of trifluor-
omethylthiolated alkene was established on the basis of single
crystal X-ray diffraction analysis of 4d (Figure 2).
Scheme 2. Substrate Scope of Trifluoromethylthiolation of
Sulfur Ylides with PhPOCl2
a−c
Figure 2. X-ray crystallography of 4d.
This reaction system is readily scalable as illustrated by the
gram-scale preparation, demonstrating a potential opportunity
of practical applications. When 1a was performed on a 3.5
mmol (1.0 g) preparative scale, the resulting trifluoromethylth-
iolated alkene 3a could be achieved without loss of reactivity
while still maintaining a 84% isolated yield, matching the result
observed in the small-scale reaction (Figure 3a).
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), PhPOCl2 (1.0
mmol), DIPEA (0.5 mmol), and 4 Å M.S. (200 mg) in DMF (5.0
b
mL) at room temperature for 12 h. Reported yields are of isolated
c
products for E-configured products. The E/Z ratio is given in
parentheses and it was determined by 1H NMR and 19F NMR analysis
of a crude reaction mixture.
was employed as a chlorine source instead of BzCl, the
resulting E-configured product 4a was observed in 58%
isolated yield, together with the Z-configured product in
about 39% yield. Other nucleophilic chlorine reagents, such as
TMSCl, PhSO2Cl, PCl3, and SOCl2, were also examined; no
better results were obtained (see the SI for details).
Subsequently, the scope of the process was investigated. A
variety of carbonyl sulfonium salts proceeded smoothly with
Munavalli’s SCF3 reagent 2a and PhPOCl2 to give the
corresponding trifluoromethylthiolated alkenes in good yields.
The electronic and steric properties of the substituents on the
phenyl ring moderately interfered with the reactivity. For
example, the substrates with electron-donating groups (Me,
OMe, and OTs) and electron-withdrawing groups (Cl and
CF3) at the para position of the phenyl ring were found to be
tolerant under the standard conditions, providing the desired
products 4b−f in 61−71% yields. Similarly, good yields were
generally furnished in the presence of meta-substituted aryls
(4g−h). Interestingly, sulfonium salts bearing disubstituents
Figure 3. Gram-scale experiment and synthetic applications.
Moreover, the synthetic utility of the current process is
illustrated via chemical transformation of trifluoromethylthio-
lated alkenes. Treatment of adduct 3a with sodium hydroxide
in the mixture solvent of methanol and water (3:1) gave
disubstituted ylide 5 with excellent yield (Figure 3b, upper).
Notably, the nucleophilic substitution at carbon could be
readily achieved by the reaction of trifluoromethylthiolated
compound 3b with potassium thiocyanate to generate
thiocyanate 6 in 65% yield (Figure 3b, bottom).
C
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To probe the mechanism of the current protocol, additional
experiments were conducted to examine the possibility of the
pathway (Figure 4). First, when sulfonium salt 1a was treated
Figure 5. Plausible mechanism.
In contrast to alkenes and alkynes, sulfur ylides displayed
unique reactivity toward carbon nucleophilic and electrophilic
properties. This protocol provides a general, expeditious, and
mild pathway to access tetrasubstituted trifluoromethylthio-
lated alkenes and shows good functional-group compatibility.
The employment of the current transformation as a late-stage
derivatization tool has been developed via the successful
chlorotrifluoromethylthiolation of biologically relevant com-
pounds. Further efforts are devoted to develop new
applications of sulfur ylide derived fluoroalkylation.
Figure 4. Mechanistic studies.
under the standard reaction conditions in the absence of SCF3
reagent 2a, the reaction proceeded efficiently to afford the
stabilized carbonyl sulfur ylide 1a′ in 96% yield (Figure 4a).
Subsequently, the corresponding product 3a was detected with
83% yield when 1a′ was used as a substrate instead of 1a
subjected to the chlorotrifluoromethylthiolation reaction under
the same reaction conditions (Figure 4b). In addition, when
1a′ was treated with only BzCl in the absence of electrophilic
SCF3 reagent 2a, an O,S-functionalized alkene 7 was observed
in 95% yield. It then was employed as a substrate under the
above reaction conditions; no desired tetrasubstituted
trifluoromethylthiolated alkene 3a was detected, and the
alkene 7 was recovered almost quantitatively (Figure 4c).
These results clearly indicate that the intermediate 7 is not
involved in the reaction process. Finally, the reaction was
carried out in the absence of 4 Å MS; when 2.0 equiv of water
was used as an additive, only a trace amount of the expected
enolate 3a was detected and accompanied by the formation of
the ketone 3aa as a side product (Figure 4d). This data might
reveal that molecular sieves play an important role in
accelerating the enolization of ketone moiety and preventing
undesirable hydrolysis of the ester group on the product.
In light of the above experimental results, a plausible
reaction pathway for the chlorotrifluoromethylthiolation of
sulfur ylides was depicted (Figure 5). The sulfonium salt 1a
would easily suffer deprotonation under basic conditions to
generate sulfur ylide species 1a′. Subsequently, the SCF3-
substituted sulfonium vinyl benzoate A or vinyl phosphinate B
could be formed in the presence of BzCl or PhPOCl2,
proceeding through electrophilic trifluoromethylthiolation and
alcoholysis processes. The thienyl ring of the species A
underwent a nucleophilic attack by a chloride anion
concerning the ring-opening of cyclic thioether to deliver the
SCF3-substituted chloro benzoate 3a. Similarly, nucleophilic
attack by chloride anions on the thienyl ring and the enol
carbon of the species B would result in the formation of
dichlorinated product 4a.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Experimental procedures, screening of reaction con-
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ditions, characterization data, and copies of H, 13C, 19F
NMR (PDF)
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CCDC 2021741 contains the supplementary crystallographic
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AUTHOR INFORMATION
Corresponding Author
■
Zhigang Yang − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan 430071,
China; orcid.org/0000-0002-4857-4850; Email: zgyang@
whu.edu.cn
Authors
Na Wang − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan 430071,
China
Yimin Jia − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
Pharmaceutical Sciences, Wuhan University, Wuhan 430071,
China
In conclusion, we have illustrated an unprecedented example
of catalyst-free chlorotrifluoromethylthiolation of sulfur ylides.
Hongmei Qin − Hubei Province Engineering and Technology
Research Center for Fluorinated Pharmaceuticals, School of
D
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Pharmaceutical Sciences, Wuhan University, Wuhan 430071,
China
Zhong-xing Jiang − Hubei Province Engineering and
Technology Research Center for Fluorinated Pharmaceuticals,
School of Pharmaceutical Sciences, Wuhan University, Wuhan
430071, China; orcid.org/0000-0003-2601-4366
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Complete contact information is available at:
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Author Contributions
†N.W., Y.J., and H.Q. contributed equally.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for financial support from the National Key
Research and Development Program of China (Grant Nos.
2016YFC1304704 and 2018YFA0704000) and the Key
Research Program of Frontier Sciences, CAS (QYZDY-SSW-
SLH018).
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