Synthesis of β-Arylethenesulfonyl Fluoride via Pd-Catalyzed Nondirected C-H Alkenylation

Article abstract of DOI:10.1021/acs.orglett.9b00165

A rapid synthesis of β-arylethenesulfonyl fluorides is realized using ligand-accelerated Pd(II)-catalyzed nondirected C-H alkenylation of simple arenes. The newly developed electron-deficient 2-pyridone ligand is crucial for this transformation with arenes as limiting reagent. This protocol features a broad substrate scope and good functional group tolerance. Late-stage functionalization of various pharmaceuticals and their further click manipulations demonstrate this procedure to be highly valuable.

Full text of DOI:10.1021/acs.orglett.9b00165

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of β‑Arylethenesulfonyl Fluoride via Pd-Catalyzed
Nondirected C−H Alkenylation
Xiao-Yue Chen,†,‡ Yichen Wu,† Jian Zhou,‡ Peng Wang,*,† and Jin-Quan Yu*,†,§
†State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Or-ganic
Chemistry, CAS 345 Lingling Road, Shanghai 200032, P.R. China
‡Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China Normal University, 3663N Zhongshan Road,
Shanghai 200062, P.R. China
§The Scripps Research Institute (TSRI), 10550 North Torrey Pines Road, La Jolla, California 92037, United States
S
* Supporting Information
ABSTRACT: A rapid synthesis of β-arylethenesulfonyl fluorides is
realized using ligand-accelerated Pd(II)-catalyzed nondirected C−H
alkenylation of simple arenes. The newly developed electron-deficient 2-
pyridone ligand is crucial for this transformation with arenes as limiting
reagent. This protocol features a broad substrate scope and good functional
group tolerance. Late-stage functionalization of various pharmaceuticals
and their further click manipulations demonstrate this procedure to be
highly valuable.
sized via sulfonylation of styrene derivatives7 or via Horner−
Wadsworth−Emmons approach from benzaldehyde.8 More
recently, the Sharpless group and the Arvidesson group have
adopted a Pd-catalyzed Heck-type alkenylation to access the
title compounds by using diazonium salts,6a aryl boronic
acids,6b or aryl iodides6c as starting materials (Scheme 1B).
Notably, Qin and Huetis recently reported several Rh(III)-
catalyzed directed C−H olefinations with vinyl sulfonyl
fluoride using different directing groups which provide a new
entry to β-arylethenesulfonyl fluorides (Scheme 1C).9 Taking
account of wide appearance of sulfur(VI) containing moieties
(sulfonate, sulfonamide, sulfone, etc.) in marketed drugs,10 we
became interested in developing a nondirected C−H
olefination reaction with vinyl sulfonyl fluorides. Herein, we
report a practical procedure to access β-arylethenesulfonyl
fluoride via ligand-accelerated Pd-catalyzed nondirected C−H
fluorosulfonylvinylation of simple arenes using arene as
limiting reagent (Scheme 1D). This direct C−H fluorosulfo-
nylvinylation of simple arenes substantially broadens the
diversity of β-arylethenesulfonyl fluorides that can be used to
access unique SuFEx precursors.
ondirected C(sp2)−H activation using arene as the
Nlimiting reagent remains a significant challenge: electron-
deficient arenes are significantly less reactive, and the diversity
and scope of transformation is rather limited.1,2 We have
recently developed a pyridone-based ligand that can enable C−
H olefination and carboxylation using 1 equiv of arenes.2a
However, extending this initial finding to broad synthetic
applications remains to be demonstrated. β-Arylethenesulfonyl
fluoride derivative, one irreplaceable scaffold in sulfur(VI)
fluoride exchange (SuFEx) chemistry,3,4 has been documented
as a unique bifunctional electrophile. Michael addition5 or
SuFEx chemistry3 could take place in a selective fashion
depending on suitable reaction conditions (Scheme 1A).
Typically, β-arylethenesulfonyl fluoride motifs can be synthe-
Scheme 1. Synthesis of β-Arylethenesulfonyl Fluoride
Our efforts to develop the C−H alkenylation with vinyl
sulfonyl fluorides is based on our recent finding that 2-
pyridone ligand can accelerate Pd(II)-catalyzed nondirected
C−H functionalization of simple arenes with high efficency.2a
A series of inert simple arenes, heterocycles, and functional
molecules can be tolerated with our procedure relying on the
development of 2-pyridone ligand. Taking account of the step-
economy of C−H activation reactions, it will be highly desired
if the nondirected C−H fluorosulfonylvinylation can be
Received: January 14, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00165
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
realized in this regard. However, this hypothesis faces several
challenges according to the known literature. First, the direct
Friedel−Crafts reaction of simple arene with ESF (ethene-
sulfonyl fluoride) might occur under acidic conditions.6a
Second, ESF is less reactive than normal ethyl acrylate under
Pd-catalyzed Heck-type reaction conditions,3b although ESF is
a superior Michael acceptor.5c
We chose the less active 1,2-dichlorobenzene (1q) substrate
to test our previous ligand-accelerated Pd-catalyzed non-
directed C−H functionalization conditions. Gratifyingly, 60%
yield of desired olefinated products (3q) with a selectivity of
1.4/1.0 (β/α) was obtained. After systematic evaluation of
different reaction parameters, such as palladium sources,
solvents, oxidants, and 2-pyridone-type ligands, 3,5-bistrifluor-
omethyl-2-pyridone L1 still served as the best ligand
employing HFIP as solvent and AgOAc as oxidant. We then
turned our attention to develop more efficient 2-pyridone
ligands (Scheme 2). We were pleased to find that a slightly
ester (3l), and NO2 (3v) were all compatible with this
procedure. When high active arenes were employed, a small
amount of dialkenylated products were also observed (see the
Supporting Information). For instance, benzene gave the
monoproduct 3a in 65% yield and diolefinated products in
about 10% yield using HFIP as solvent. It is noteworthy that
the major alkenylation reaction for electron-rich monosub-
stituted arenes occurred at the meta position in good yields
(3b−f). This observation is inconsistent with the previous
system employing ethyl acrylate as coupling partner for Pd-
catalyzed nondirected C−H functionalization in which the
para position product predominates as the major isomer.
Primary study indicates the selectivity difference is caused by
the unique properties of ESF, although the detailed reason is
unclear so far (see control experiments in the Supporting
Information). Not surprisingly, less reactive electron-deficient
arenes were alkenylated using this catalytic system to afford the
corresponding products in moderate to good yields with
synthetically useful meta selectivity (3g−l). Moreover,
naphthalene also provided the mono-olefinated product
(3m) in 61% yield with a 14.0/1.0 (β/α) selectivity ratio by
steric control. Disubstituted and trisubstituted aromatics were
then examined. Generally, the selectivity of symmetric 1,2-
disubstituted arenes was primarily governed by steric (3n−q),
whereas substrates with less sterically hindered substituents
such as 1,2-difluorobenzene (3p) and 1,2-dichlorobenzene
(3q) provided a mixture of α- and β-olefinated products with
the latter one as the major isomer. Fluorosulfonylvinylation of
m-xylene led to the β isomer selectively (3r), but the 1,3-
dichlorobenzene (3s) gave the α isomer as the major products
probably due to the electronics. Symmetric 1,4-disubstituted
aromatics (3t) and 4-substituted anisoles (3u,v) were also
suitable substrates for this reaction and generally underwent
monofunctionalization in high yield and selectivity. 1,3,5- and
1,2,3-trisubstituted arenes also reacted smoothly, providing the
desired products in high yields (3w,x). We then investigated
heterocyclic aromatics using this catalytic system. Hetero-
cycles, including indoline (1y), 1,2,3,4-tetrahydroquinoline
(1z), thiophene (1aa), furan (1ab), (benzo)thiophene (1ac),
and 1,3-dimethyluracil (1ad), underwent this nondirected C−
H fluorosulfonylvinylation reaction efficiently to give the
corresponding heteroarylethenesulfonyl fluorides in moderate
to good yields (3y−ad). However, electron-deficient hetero-
cyclic aromatics, like pyridine and quinoline, cannot tolerate
the current conditions.
a
Scheme 2. Ligand Evaluation
a
The yield was determined by 1H NMR using CH2Br2 as the internal
b
standard. The reaction was conducted on a 0.2 mmol scale, HFIP
(0.25 mL). 73% isolated yield, β/α = 2.0/1.0.
c
more electron-deficient ligand L2 gave us improved yield and
selectivity (76% yield, β/α = 1.8/1.0), in which C5-CF3 was
replaced by electron-withdrawing C2F5 group. Neither placing
the C2F5 at the C3 position in the ligand scaffold (L3) nor 3,5-
di-C2F5 substituted ligand L4 gave promising yields. Other
modifications with long-chain perfluoroalkyl groups at the C5
position (L5,6) were also investigated, providing lower yields.
The yield was further improved to 81% NMR yield (73%
isolated yield) with a selectivity of 2.0/1.0 (β/α) by
concentrating the reaction system in the presence of optimal
ligand L2. Notably, the newly developed ligand L2 is crucial
for this ligand-accelerated Pd-catalyzed nondirected C−H
fluorosulfonylvinylation of simple arenes. The kinetic study
using L1 and L2 under the standard conditions showed that
the initial reaction rate with L2 is 1.6 times faster than that
with L1 (see the Supporting Information). According to our
previous study,2a the ligand might be capable of accelerating
the C−H cleavage step as an inner base and stabilizing the
active palladium catalyst.
Under the optimal conditions, the scope of simple arenes
was systematically examined employing L2 as ligand. As
summarized in Scheme 3, both electron-rich and electron-
deficient aromatics were tolerated with this procedure,
providing the monofluorosulfonylvinylated products in mod-
erate to excellent yields (3a−l). In addition, this protocol
features good functional group tolerance. Alkyl (3b−d), MeO
(3e), F (3g), Cl (3h), CF3 (3i), aldehyde (3j), ketone (3k),
Taking advantage of this novel protocol, several amino acid
derivatives and drugs were evaluated under the ligand-
accelerated Pd-catalyzed nondirected C−H fluorosulfonylviny-
lation conditions (5a−f). Both phenylalanine derivative 5a and
O-methyltyrosine derivative 5b delivered the corresponding
olefinated products in 76% and 60% yields, respectively.
Pharmaceuticals and their derivatives, such as clofibrate (5c),
praziquantel (5d), metalaxyl (5e), and estrone (5f), were
compatible with this protocol, providing corresponding
products in moderate to good yields (Scheme 4). Notably,
gram-scale reaction with praziquantel gave the desired
olefinated products 5d in 70% yield. The late-stage
fluorosulfonylvinylation of those complex structures demon-
strated the versatility of this reaction.
The unique reactivity of β-arylethenesulfonyl fluoride were
tested choosing fluorosulfonylvinylated O-methyltyrosine
derivative 5b. Amidation of 5b with morpholine provided
the desired product sulfonamide 6 in 81% yield. Vinylsulfone 7
B
DOI: 10.1021/acs.orglett.9b00165
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
Scheme 3. Substrates Scope of Simple Arenes
a
b
c
For detailed reaction conditions, see the Supporting Information. Isolated yield; the regioselectivity was determined by 1H NMR. CHCl3 (0.25
d
e
mL) was used instead of HFIP. Pd(OAc)2 (20 mol %), L2 (60 mol %), and ESF (4.0 equiv) were used. L1 (13.9 mg, 30 mol %) and CHCl3
(0.25 mL), 10 h. Ag2CO3 (1.5 equiv) was used instead of AgOAc, 16 h.
f
a
Scheme 4. Late-Stage Functionalization
Scheme 5. Applications of β-Arylethenesulfonyl Fluoride
a
Isolated yield; the regioselectivity was determined by 1H NMR.
b
Pd(OAc)2 (20 mol %), L1 (60 mol %), ESF (4.0 equiv), and CHCl3
(0.25 mL) were used.
was obtained in 90% yield under the typical Friedel−Crafts
reaction conditions. More importantly, two bioactive frag-
ments can be easily assembled to one complex functional
molecule via SuFEx chemistry. As summarized in Scheme 5c,
TBS-protected (+)-δ-tocopherol 8 can be easily installed on
fluorosulfonylvinylated praziquantel 5d-a in 83% yield under
the standard SuFEx conditions. Assembly of fluorosulfonylvi-
nylated metalaxyl (5e) and 5d-a by a bisphenol A linkage led
to the desired product 12 in 65% total yield after two
sequential manipulations.
In summary, practical and rapid synthesis β-arylethenesul-
fonyl fluoride has been achieved using ligand-accelerated Pd-
catalyzed nondirected C−H alkenylation for the first time. The
key to the success of this protocol is the development of an
electron-deficient 2-pyridone ligand. Moreover, this protocol
features broad substrate scope and functional group tolerance.
The late-stage fluorosulfonylvinylation of several amino acid
derivatives and drugs demonstrates the versatility of this
procedure and will open a new avenue for drug discovery via
SuFEx click chemistry.
C
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00165.
■
S
Experimental procedures, complete characterization
1
data, and H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: pengwang@sioc.ac.cn.
*E-mail: yu200@scripps.edu.
ORCID
Jian Zhou: 0000-0003-0679-6735
Peng Wang: 0000-0002-6442-3008
Jin-Quan Yu: 0000-0003-3560-5774
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge “Thousand Youth Talents Plan”,
Shanghai Institute of Organic Chemistry, State Key Laboratory
of Organometallic Chemistry, and The Scripps Research
Institute for financial support.
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