Palladium-Catalyzed Fluoroalkylation via C(sp3)-S Bond Cleavage of Vinylsulfonium Salts

Article abstract of DOI:10.1021/acs.orglett.1c02172

An interrupted Pummerer/palladium-catalyzed fluoro-alkylation strategy was developed for alkenyl C-H fluoroalkylthiolation. Palladium-catalyzed ring-opening fluoroalkylation via aliphatic C-S bond cleavage of the vinylsulfonium salts efficiently afforded

Full text of DOI:10.1021/acs.orglett.1c02172

pubs.acs.org/OrgLett
Letter
Palladium-Catalyzed Fluoroalkylation via C(sp3)−S Bond Cleavage of
Vinylsulfonium Salts
Yuan He, Zilong Huang, Juan Ma, Fei Huang, Jie Lin, Hongmei Wang,* Bao-Hua Xu, Yong-Gui Zhou,*
and Zhengkun Yu*
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ABSTRACT: An interrupted Pummerer/palladium-catalyzed flu-
oro-alkylation strategy was developed for alkenyl C−H fluoroal-
kylthiolation. Palladium-catalyzed ring-opening fluoroalkylation via
aliphatic C−S bond cleavage of the vinylsulfonium salts efficiently
afforded fluoroalkylthiolated alkene derivatives from readily
available alkene substrates and CsF. The protocol features broad
substrate scopes and good functional group tolerance under an air
atmosphere. The practicability of the synthetic method was
demonstrated by transforming the multisubstituted alkene products to diverse fluoroalkylthiolated N-heterocycles.
luorine has been known to exist in many important
vinylsulfonium salts have been paid much less attention due
F
chemicals.1 By incorporating a fluorine atom or a
to the multiple reactivities of alkenyl moieties compared with
their aryl analogs.20
fluoroalkyl group at a specific position in the candidate
molecules, it is possible to fine-tune the pharmacological and
pharmacokinetic properties of the drug candidates. Among the
documented fluoroalkyl groups, fluoroalkylthio groups have
been paid considerable attention due to their tunable
lipophilicity, binding affinity, metabolic stability, and specific
electronic properties.2 Biologically active fluoroalkylthio motifs
can be used as the key structural units for the construction of
pharmaceutical agents such as M2 muscarinic receptor
agonist,3 5-HT2c receptor,4 and the inhibitor of cartilage
matrix degradation.5 In the early days, harsh fluorinating
reagents were used to prepare fluoroalkylated compounds.6
Because these reagents are potentially explosive, highly
moisture-sensitive, and toxic, continuous efforts have been
made to develop simple and green fluorination methods.7 A
few fluorination methods have been reported for directly
functionalizing aliphatic C−H bonds.8 In this regard, benzylic
C−H9 and those positioned α to a carbonyl group10 can be
fluorinated under relatively mild conditions. Decarboxylative
fluorination has also been applied to construct a C(sp3)−F
bond under radical or transition-metal catalysis conditions.11
Recently, the difunctionalization of alkenes by fluorinating
reagents has been paid much attention to access fluoroalky-
lated compounds.12 The ring-opening fluorination of carbo-
cycles has opened another route for the same purpose.13−16
Arylsulfonium salts have recently been employed as useful
coupling partners not only in light of their accessibility from
simple arenes but also due to their versatility for many
carbon−carbon and carbon−heteroatom bond formation
reactions.17,18 Notably, aryl thianthrenium and dibenzothio-
phene sulfonium salts have been successfully used for the site-
selective fluorination of arenes (Scheme 1a);19 however,
During the ongoing investigation of polar alkenes, we
became interested in the regio- and stereoselective con-
Scheme 1. Fluoroalkylation Strategies
Received: June 30, 2021
Published: July 20, 2021
https://doi.org/10.1021/acs.orglett.1c02172
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6110−6114
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struction of multifunctionalized alkenes. In an attempt to
conduct the vinylic C−H fluorination of α-alkenoyl ketene
N,S-acetal 1Aa with N-fluorobenzenesulfonimide (NFSI),21 we
found that the vinylic C−H bond could be formally
difluorinated to form 1Ba (73%) (Scheme 1b). The use of
α-aroyl analogs of 1Aa led to similar results (see the
Supporting Information (SI) for details), but its di-
(methylthio)-substituted S,S-acetal analog did not react
under the same conditions. Thus we envisioned that vinylic
C−H fluorination might be realized via vinylsulfonium salts in
a fashion similar to that of arylsulfonium salts.19 Unexpectedly,
the reaction of a vinylsulfonium salt with CsF under palladium
catalysis did not form the desired vinylic C−F bond through
the cleavage of the vinylic C−S bond; instead, it underwent a
fluoroalkylation process by cleavage of an aliphatic C−S bond.
It has been known that S-alkyl tetrahydro-1H-thiophen-1-ium
salts and analogs can undergo ring-opening reactions with
nucleophiles such as thiolates, azide, halogens, amines, and so
on.22 Herein we disclose an interrupted Pummerer/palladium-
catalyzed fluoroalkylation strategy for vinylic C−H fluoro-
alkylthiolation via vinylsulfonium salts (Scheme 1b).
Scheme 2. Scope of Sulfonium Salts of Ketene Dithioacetals
(1)
a
Initially, the reaction of 1-(1,1-bis(methylthio)-3-oxo-3-
phenyl-prop-1-en-2-yl)tetrahydro-1H-thiophen-1-ium trifluor-
omethanesulfonate (1a) with CsF was conducted to optimize
the reaction conditions for the formation of 2-((4-fluoro-
butyl)thio)-3,3-bis(methylthio)-1-phenylprop-2-en-1-one
(2a). Vinylsulfonium salt 1a was conveniently prepared from
the readily available alkene by the interrupted Pummerer
reaction.18−20 (See the SI for details.) The reaction conditions
were optimized to 1a/CsF 1:2 (molar ratio), 5 mol %
Pd(OAc)2 as the catalyst, 1,4-dioxane as the solvent, 100 °C,
12 h under an air atmosphere, giving the desired product 2a in
85% isolated yield. The use of pyridine·HF and NFSI soluble
in organic solvents could not result in 2a. The phase-transfer
catalysts TEBAC (triethyl benzyl ammonium chloride) and 18-
crown-6 remarkably diminished the reaction efficiency in the
absence of the palladium catalyst, suggesting that the reaction
does not merely proceed via a fluoride-promoted nucleophilic
ring-opening pathway and the palladium catalysis plays a
crucial role (Table S1). It is noteworthy that alkenyl fluoride
2a′ was not detected in the reaction mixture by 19F NMR
analysis.
Under the optimal conditions, the scope of vinylsulfonium
salts 1 generated from di(alkylthio)-substituted alkenes, that is,
ketene dithioacetals, was explored (Scheme 2). They could
exhibit diverse reactivity to form the fluoroalkylation products
of type 2 in good to excellent yields. An obvious steric effect
was observed for ortho-methyl-substituted α-benzoyl vinyl-
sulfonium salts (1b−1d), and their reaction with CsF afforded
products 2b−2d (56−75%). Somehow, the α-(4-methoxy)-
benzoy-substituted substrate did not react to form the desired
product 2e. Halogens (F, Cl, and Br) and a CF3 group on the
α-benzoyl moiety did not show an obvious substituent effect,
and the reaction formed products 2f−2k in 81−87% yields. α-
(2-Naphthoyl) and α-heteroaroyl (2-furoyl or 2-thienoyl)-
substituted vinylsulfonium salts also reacted well to produce
2l−2n in 82−87% yields. Di(ethylthio)-substituted vinyl-
sulfonium salt (1o) reacted with CsF less efficiently than its
di(methylthio) analog 1a, yielding 2o in 75% yield. In a similar
fashion, cyclic five-membered alkyldithio-substituted vinyl-
sulfonium salts 1p−1r, 1t, and 1u reacted to give the
corresponding products 2p−2r, 2t, and 2u (57−70%), whereas
the 4-F substituent on the α-benzoyl moiety of 1s obviously
a
Conditions: 1 (0.30 mmol), CsF (0.60 mmol), Pd(OAc)2 (0.015
mmol), dioxane (2 mL), air, 100 °C, 12 h. Yields refer to isolated
products.
reduced the yield of 2s to 34%. Cycloalkyldithio-substituted α-
(2-aphthoyl) (1v) and α-acetyl (1w) vinylsulfonium salts also
smoothly underwent the reaction with CsF, leading to 2v and
2w (68−72%). However, the six-membered cycloalkyldithio-
substituted α-benzoyl vinylsulfonium salt 1x enabled the
formation of only 2x in 45% yield, exhibiting a lower reactivity
than its five-membered cycloalkyldithio-substituted analog 1a.
It should be noted that the molecular structure of compound
2l was confirmed by the X-ray single-crystal crystallographic
determination. (See the SI for details.)
The substituent and size effects from the cycloalkyl-
sulfonium ring in 1 were then explored (Scheme 3a−c). The
reaction of the vinylsulfonium salts derived from 2-methylte-
trahydro-1H-thiophene, that is, vinylsulfonium salts 1y and 1z,
with CsF gave a mixture of two inseparable fluoroalkylation
products 2y/2y′ (51%, 10:3) and 2z/2z′ (39%, 2:1) via
different aliphatic C−S bond cleavages of the cycloalkylsulfo-
nium ring, which reveals that the sterically hindered C(sp3)−S
bond is much easier to cleave. The vinylsulfonium salt of
thietane 1z1 was decomposed quickly under the standard
conditions. To our delight, the vinylsulfonium salts of
tetrahydro-2H-thiopyran 1z2−1z4 efficiently reacted with
CsF to produce the target products 2z2−2z4 (57−78%)
bearing a C5-fluoroalkylthio functionality, whereas products
2a−2z contain a C4-fluoroalkylthio chain. Unfortunately,
further extension of the fluoroalkylthio chain failed because
the vinylsulfonium salts corresponding to large aliphatic cyclic
sulfoxides CnH2nSO (n ≥ 6) could not be successfully
prepared by the known methods. It is noteworthy that
dibenzothiophene sulfonium salts of ketene dithioacetals 1
were not successfully prepared either due to the increased
steric interaction in the interrupted Pummerer reaction.
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bonds in 3b/3c, no fluoroalkylation occurred through the
cleavage of these long-chain alkyl−S bonds, and the Ph−S
bond is much easier to cleave than the Me−S bond in 3d
without the occurrence of fluoroarylation. In the case of using
Scheme 3. Diversity of the Fluoroalkylation
−
other counteranions such as BF4 , the chemoselectivities were
not obviously affected, but the yields of 4a−4c and 1A were
slightly decreased.
Next, the protocol generality was explored by performing the
reaction of styryl sulfonium salts 5 with CsF (Scheme 4). In
a
Scheme 4. Scope of Styryl Sulfonium Salts (5)
a
Conditions: 5 (0.30 mmol), CsF (0.60 mmol), Pd(OAc)2 (0.015
b
mmol), dioxane (2 mL), air, 100 °C, 12 h. Pd(OAc)2 (0.03 mmol),
c
24 h. Isomer ratio was determined by 1H NMR analysis. Yields refer
to isolated products.
The reactivity of open-chain vinylsulfonium salts of type 3
was comparatively investigated (Scheme 3d−f). Treatment of
vinylsulfonium salt 3a derived from α-benzoyl ketene
di(methylthio)acetal (1A) and dimethylsulfoxide (DMSO)
with CsF under the standard conditions gave methylthiolated
alkene 4a in 91% isolated yield with methyl fluoride formed as
the major byproduct. The parent alkene 1A was generated in
6% yield from the decomposition of the starting vinylsulfonium
salt, which might be promoted by moisture in air or by water
present in the sulfonium salt during its preparation. In the case
of the vinylsulfonium salt of methyl decyl thioether (3b), two
kinds of C(sp3)−S bond cleavages occurred to form 4a (16%)
and 4b (34%) by cleavage of the decyl−S and methyl−S
bonds, respectively, as well as 1A (31%). Notably, decyl
fluoride was not detected in the reaction mixture by 19F NMR
analysis, but MeF and methyl decyl thioether (RSMe) in both
the gas and liquid phases were detected by GC-MS analysis.
(See the SI for details.) Decyl triflate was presumably formed
during the reaction because the corresponding molecular ion
peak of decanal generated from the triflate byproduct was
detected by GC-MS analysis. Compound 3c behaved in a
fashion similar to that of 3b. Interestingly, the vinylsulfonium
salt of methyl phenyl thioether (3d) predominantly underwent
the decomposition reaction to form 1A (52%) and 4a (41%)
with the release of PhSMe and PhOTf without phenyl fluoride
formed in the reaction mixture. These results have suggested
that the Me−S bond is easier to cleave than decyl/dodecyl−S
contrast with the multisubstituted vinylsulfonium salts of type
1, the sulfonium salt of styrene, that is, (E)-1-styryl-tetrahydro-
1H-thiophen-1-ium trifluoromethanesulfonate (5a), reacted
with CsF less efficiently, giving the target product 6a in 12%
yield. The yield was enhanced to 35% by increasing the catalyst
loading to 10 mol % and extending the reaction time to 24 h.
1,1-Diaryl-substituted vinylsulfonium salts 5b−5h underwent
the reaction smoothly, efficiently yielding products 6b−6h
(61−79%). In the cases of vinylsulfonium salts 5c and 5e
derived from 4-Me- and 3,4-Me2-substituted 1,1-diaryl alkenes,
isomeric products 6c (61%, E/Z = 1:1) and 6e (72%, E/Z =
9:5) were obtained, respectively. The use of 2-bromo-
substituted 1,1-diaryl vinylsulfonium salt (E)-(5d) led to
(E)-6d (64%), showing only one configuration. It is note-
worthy that the sulfonium salt of 2-methylstyrene (5i) did not
undergo the same type of fluoroalkylation reaction. The
sulfonium salts of 1,2-stilbenes also reacted well with CsF,
resulting in 6j and 6k (45−47%), exhibiting an obvious
negative steric impact on the reaction efficiency. The reactivity
difference is rationalized as follows. Styrylsulfonium salt 5a was
readily decomposed under the standard conditions, which led
to 6a in a low yield. An additional aryl at the one-position gives
extra stabilization to 1,1-diarylvinylsulfonium salts 5b−5h due
to the conjugation effect, which reacted with CsF to afford the
target products in decent yields. However, a negative steric
impact exists in the sulfonium salts of 1,2-stilbenes (5j and 5k),
deteriorating the reaction efficiency. Interestingly, the 1,1-
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diphenyl vinylsulfonium salt (5l) of tetrahydro-2H-thiopyran
underwent ring-opening fluoroalkylation to afford the desired
product 6l (55%) bearing a C5-fluoroalkylthio chain.
The gram-scale preparation of compound 2a was performed
on a 5 mmol scale of 1a to give 2a in 79% yield (1.3 g). In the
presence of the K2CO3 base, the condensation of 2a with
guanidine nitrate formed 5-((4-fluorobutyl)thio)-4-(methyl-
thio)-6-phe-nylpyrimidin-2-amine (7) in 75% yield (Scheme
5a). The treatment of 2a with an excess of hydrazine hydrate
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02172.
■
sı
Experimental materials and procedures, NMR of
compounds, and X-ray crystallographic analysis for
compounds 1Ba, 2l, and 7−9 (PDF)
Accession Codes
CCDC 2035272, 2073867, 2073869, 2077381, and 2091625
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/data_request/cif, or by emailing data_request@ccdc.
cam.ac.uk, or by contacting The Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
Scheme 5. Gram-Scale Experiment and Product
Derivatization
a
AUTHOR INFORMATION
Corresponding Authors
■
Zhengkun Yu − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China;
Innovation Academy for Green Manufacture, Chinese
Academy of Sciences, Beijing 100190, P. R. China; State Key
Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China; orcid.org/0000-0002-
9908-0017; Email: zkyu@dicp.ac.cn
Hongmei Wang − State Key Laboratory of NBC Protection
for Civilian, Beijing 102205, P. R. China; orcid.org/
0000-0003-1057-334X; Email: wanghongmei@dicp.ac.cn
Yong-Gui Zhou − Dalian Institute of Chemical Physics,
Chinese Academy of Sciences, Dalian 116023, P. R. China;
orcid.org/0000-0002-3321-5521; Email: ygzhou@
dicp.ac.cn
a
Reagents and conditions: (a) guanidine nitrate (2 equiv), K2CO3 (2
equiv), MeCN (2 mL), air, 100 °C, 36 h. (b) Hydrazine hydrate (10
equiv), EtOH (2 mL), air, 80 °C, 12 h. (c) Phenylhydrazine (2
equiv), EtOH (2 mL), air, 80 °C, 24 h. (d) Hydroxylamine
hydrochloride (10 equiv), K2CO3 (10 equiv), EtOH (2 mL), air, 80
°C, 12 h.
or phenyl-hydrazine in refluxing ethanol afforded 4-fluoroalkyl-
thiopyrazoles 8 and 9 in 90 and 81% yields, respectively
(Scheme 5b,c). 4-((4-Fluorobutyl)thio)-3-(methylthio)-5-phe-
nylisoxazole (10) was also efficiently synthesized (84%) by the
reaction of 2a and hydroxylamine (Scheme 5d). The molecular
structures of compounds 7−9 were further confirmed by the
X-ray single-crystal crystallographic determinations. (See the SI
for details.)
Authors
Yuan He − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R.
China; orcid.org/0000-0001-6600-8433
Control experiments were conducted to probe into the
reaction mechanism. The reaction of 1a with CsF was carried
out in the presence of 3.0 equiv of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenyl
(BHT) under the standard conditions. These radical-trapping
reagents could not inhibit the ring-opening fluoroalkylation
reaction, leading to 2a in 37−55% yield, which excludes a
radical pathway in the catalytic cycle. A palladium-catalyzed
fluoroalkylation mechanism via aliphatic the C−S bond
cleavage of vinylsulfonium salts is proposed. Because a small
amount of the target product 2a (11−15%) could be formed in
the absence of the catalyst (Table S1), nucleophilic ring-
opening fluorination cannot be excluded, but palladium-
catalyzed ring-opening fluorination is predominant.
In conclusion, we have developed a C−H fluoroalkyl-
thiolation strategy of alkenes via the palladium-catalyzed
fluoroalkylation of vinylsulfonium salts under an air atmos-
phere. Multisubstituted fluoroalkylthiolated alkenes can be
accessed by means of the ring-opening fluoroalkylation of the
vinylsulfonium salts. The synthetic protocol has been shown to
have potential for the synthesis of diverse fluoroalkylthiolated
N-heterocycles.
Zilong Huang − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R.
China; orcid.org/0000-0001-5350-8308
Juan Ma − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Fei Huang − School of Food Science and Pharmaceutical
Engineering, Nanjing Normal University, Nanjing 210023, P.
R. China; orcid.org/0000-0002-5290-2490
Jie Lin − Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China; University
of Chinese Academy of Sciences, Beijing 100049, P. R. China
Bao-Hua Xu − Innovation Academy for Green Manufacture,
Chinese Academy of Sciences, Beijing 100190, P. R. China;
orcid.org/0000-0002-7222-4383
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02172
Notes
The authors declare no competing financial interest.
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Letter
phosis: Conversion of An Aromatic Skeleton into A Different Ring
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21871253) for the support of our research.
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