Highly E-Selective Synthesis of α-Fluoro-β-arylalkenyl Sulfones from gem-Difluoroalkenes with Sodium Sulfinates

Article abstract of DOI:10.1021/acs.joc.1c00490

The straightforward synthesis of α-fluoro-β-arylalkenyl sulfones under transition-metal-and base-free conditions has been described, which displays broad functional group compatibility and high stereoselectivity. In particular, the strategy is also applied to the late-stage modification of complex natural products and drugs.

Full text of DOI:10.1021/acs.joc.1c00490

pubs.acs.org/joc
Note
Highly E‑Selective Synthesis of α‑Fluoro-β-arylalkenyl Sulfones from
gem-Difluoroalkenes with Sodium Sulfinates
Yuxiu Li, Xiangqian Li, Xiaowei Li, and Dayong Shi*
Cite This: J. Org. Chem. 2021, 86, 6983−6993
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: The straightforward synthesis of α-fluoro-β-arylalkenyl
sulfones under transition-metal- and base-free conditions has been
described, which displays broad functional group compatibility and high
stereoselectivity. In particular, the strategy is also applied to the late-stage
modification of complex natural products and drugs.
onsidering the importance of vinyl sulfone compounds in
calculated that approximately 30−40% of new drugs approved
by the Food and Drug Administration contained fluorine in
2018 and 2019.4 Therefore, the rapidly growing demand for
the introduction of fluorine and fluorine-containing groups
into organic functional molecules has also inspired the
development of approaches to install and further diversify
fluorinated products. In recent years, the functionalization of
C−F bonds in polyfluorinated compounds offers an attractive
approach for building value-added fluorinated molecules.5 In
particular, selective cleavage and transformation of one C−F
bond gem-difluoroalkene provides an attractive alternative to
functionalized monofluoroalkenes that can be used as peptide
bond isosteres in drug discovery.6 The difluoromethylene
carbon of gem-difluoroalkenes is susceptible to nucleophilic
attack, such as various carbon-,7 oxygen-,8 nitrogen-,9 boron-,10
silicon-,11 sulfur-,12 and phosphine13-centered nucleophilic
intermediates. Very recently, we disclosed the visible-light-
promoted E-selective synthesis of α-fluoro-β-arylalkenyl
sulfides with gem-difluoroalkenes and sodium sulfinates via a
deoxygenation/isomerization process.14 Herein, we report a
simple method for installing highly E-selective α-fluoro-β-
arylalkenyl sulfones under transition-metal- and base-free
conditions from gem-difluoroalkenes and sodium sulfinates.
Initially, 2-(2,2-difluorovinyl)naphthalene 1a and sodium
benzenesulfinate 2a were chosen as the starting materials to
test this transformation (for more details about the
optimization of reaction conditions, see Tables S1−S4).
Fortunately, the desired product 3aa was isolated in 82%
yield with excellent stereoselectivity (>99/1 E/Z)2 at 100 °C
in DMSO.
C
organic chemistry, biology, and the pharmaceutical field,
numerous studies have been performed.1 α-Fluoro-vinyl
sulfones make up a valuable class of vinyl sulfones, and the
routes to these functional molecules have been studied by
many research groups (Scheme 1).2 Reactions such as
Scheme 1. Strategies for the Synthesis of α-Fluoro-vinyl
Sulfones
Horner−Wadsworth−Emmons reaction2a and Julia−Kocienski
olefination2b,f−h involve nucleophilic addition of RSO2CHR′F
to carbonyl compounds with the aid of bases. Olah et al.
utilized benzyl halides instead of carbonyl compounds to
achieve the Julia−Kocienski olefination.2d However, most of
them suffer from an excess of strong base, low temperatures,
moderate E/Z selectivity, or low atom economies. Con-
sequently, the development of useful measures to assemble
highly stereoselective α-fluoro-vinyl sulfones utilizing bench-
stable and easily accessible precursors under mild conditions is
still desirable and challenging.
Received: February 28, 2021
Published: April 14, 2021
Due to the distinct chemical and biological properties,
organofluorinated compounds are gaining prominence in
bioorganic and medicinal chemistry.3 For instance, it was
https://doi.org/10.1021/acs.joc.1c00490
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6983−6993
6983

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
With the optimized conditions in hand, we preliminarily
investigated the reaction scope of sodium sulfinates under the
optimal conditions. As depicted in Table 1, with gem-
Table 2. Substrate Scope of gem-Difluorostyrenes with
Sodium Sulfinate 2b
e
Table 1. Substrate Scope of Sodium Sulfinates with gem-
f
Difluorostyrene 1a
a
b
c
d
e
2b (4 equiv), 5 days. At 70 °C. For 3 days. At 120 °C. All
reactions were performed with 1 (0.10 mmol), 2b (3 equiv), and
DMSO (1.0 mL) at 100 °C for 48 h under N2 unless otherwise noted.
The E/Z ratio was determined by 19F NMR.
a
b
c
d
e
f
2 (4 equiv). For 48 h. For 3 days. At 40 °C. At 70 °C. All
reactions were performed with 1a (0.10 mmol), 2 (3 equiv), and
DMSO (1.0 mL) at 100 °C for 24 h under N2 unless otherwise noted.
The E/Z ratio was determined by 19F NMR.
Difluorostyrenes possessing various functional groups on the
aryl rings such as 3,4-dimethoxyl, p-tBu, p-CO2Me, p-Bnep, p-I,
etc., converted to the desired products in moderate yields and
outstanding E/Z ratios (3bb−fb). Moreover, polycyclic
aromatic gem-difluoroalkenes were amenable to this method,
leading to the corresponding products in 73−85% yields (3ib−
mb). Importantly, (hetero)aryl difluoroalkenes were also
screened, leading to quinolone (1n), benzothiophene (1o),
carbazole (1p), and indole (1q and 1r) heterocycles being
transformed into the expected products with satisfactory yields.
It is worth mentioning that under the influence of electronic
repulsion7,15 between F and the electron-rich aromatic ring,
products 3oo and 3qb had poor E/Z stereoselectivities.
To highlight the robustness and generality of the synthetic
utility of our method, we evaluated the protocol in the late-
stage modification of complex natural products and drugs
(Scheme 2). Small molecule drug mexiletine derivate was
coupled with sodium 4-methylbenzenesulfinate 2b to afford
desired product 4a in high yield (84%). gem-Difluoroalkenes
bearing cholesterol, menthol, estrone, and tocopherol, four
well-known bioactive natural alcohols, were readily adapted to
the target α-fluoro-vinyl sulfones 4b−e and 4h in synthetically
useful yields (45−82%) with excellent stereoselectivities. The
protocol could also be applied to saccharides, such as
ribofuranose and fructose derivatives, providing the corre-
sponding α-fluoro-vinyl sulfone derivatives (4f and 4g,
respectively).
difluoroalkene 1a as a representative difluoroalkene partner,
we were glad to find that a variety of sodium sulfinates
underwent defluorinative cross coupling to furnish the target
products in moderate to good yields with excellent stereo-
selectivities (3aa−av). Sodium arylsulfinates bearing electron-
donating groups (Me and OMe) or electron-withdrawing
groups (CF3, CN, and CO2Me) at the para position of the aryl
rings were quite compatible, furnishing the corresponding
products in 42−81% yields (3ab, 3ac, and 3af−ah). Generally,
electron-rich substrates afforded better product yields than
electron-deficient substrates, because the electron-rich sub-
strates were more susceptible to nucleophilic attack. Notably,
halogen-functionalized sodium arylsulfinates reacted smoothly
to give target products in moderate yields and excellent
stereoselectivities (3ad and 3aj), enabling latter availability for
additional treatment. Furthermore, an ortho-substituted sub-
strate participated in the reaction, albeit in poor yield (3ak and
3am), due to the steric hindrance effect. Gratifyingly, a variety
of sodium alkylsulfinates turned out to be efficient substrates,
leading to 3ao−av in 75−97% yields with excellent E/Z
selectivities.
Subsequently, we further explored the scope of gem-
difluoroalkenes, and various substituted gem-difluorostyrenes
were applied to the reaction with 2b (Table 2). gem-
6984
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
B2(OH)4-mediated Pd-catalyzed transfer hydrogenation.16
Treatment of 3ab with an alkyl radical precursor furnished
trisubstituted monofluoroalkene 5b in 46% yield with retention
of configuration.17 Meanwhile, nucleophilic substitution
reaction of 3ab with sodium 4-methylbenzenethiolate and
indole proceeded smoothly to give the corresponding products
5c and 5d9,18 in yields of 65% and 45%, respectively.
Impressively, a double-nucleophilic substitution event also
transpired in view of the good leaving capacity of F anionic and
Ts anionic (5e).
Scheme 2. Late-Stage Modification of Complex Natural
Products and Drugs
a
To gain further understanding of the cross-coupling
mechanism, we carried out a series of control experiments.
First, radical trapping experiments were performed. When
radical scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), 2,4-di-tert-butyl-4-methylphenol (BHT), and 1,1-
diphenylenthyiene were added to the reaction system (Scheme
4, eq 1), the reactions were not obviously inhibited, ruling out
Scheme 4. Control Experiments
a
All reactions were performed with the natural product or drug
derivative (0.10 mmol), 2 (3 equiv), and DMSO (1.0 mL) at 70 °C
for 48 h under N2 unless otherwise noted. The E/Z ratio was
determined by 19F NMR.
To our delight, the transformation was scaled up to 4 mmol
to provide desired product 3ab (1.02 g) without sacrificing
yield (Scheme 3), which opened up a simple and mild but
effective method for the synthesis of biologically active
compounds possessing α-fluoro-vinyl sulfone structural scaf-
folds on a larger scale. Furthermore, synthetic decoration of
formed product 3ab also proceeded well, leading to a series of
complex structures (Scheme 3). For example, α-fluorosulfone
5a could be conveniently prepared in 86% yield through
the radical process. The result of the competition experiment
showed that the electron-rich sodium sulfinates had a large
advantage in relative reactivities versus electron-deficient
substrates (Scheme 4, eq 2), strongly supporting the
nucleophilic substitution process. Alkyl sodium sulfinates
with gem-difluoroalkenes furnished better desired product
yields to reinforce this opinion (Table 1).
Scheme 3. Scale-up of the Reaction and Derivatization of
On the basis of experimental results and previous reports,6 a
plausible mechanism for the cross-coupling reaction of gem-
difluoroalkenes and sodium sulfinates to purvey α-fluoro-β-
arylalkenyl sulfones is illustrated in Scheme 5. First, the
a
Products
Scheme 5. A Proposal Mechanism
sulfonate anion resonates with intermediate I, following
nucleophilic addition to gem-difluoroalkene as a consequence
of the strong electron-withdrawing capability of fluorine atoms
and the repulsion effect from its lone-pair electrons to produce
intermediate II. On the basis of the observed diastereose-
lectivity, two conformational models (III and IV) are proposed
by rotation of key intermediate II. To weaken steric repulsion
a
Conditions: (i) Pd/C (10 mol %), B2(OH)4 (4 equiv), DCM/H2O,
50 °C; (ii) eosin Y (2 mol %), 1-cyclohexyl-2,4,6-triphenylpyridin-1-
ium tetrafluoroborate (3 equiv), iPr2NEt (4 equiv), 3/1 MeOH/DCE,
geen LED, rt; (iii) sodium 4-methylbenzenethiolate (1.5 equiv),
DMSO, rt; (iv) indole (1.2 equiv), K3PO4 (2 equiv), DMF, 60 °C;
(v) imidazole (2.5 equiv), K3PO4 (3 equiv), DMF, 100 °C.
6985
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
General Procedure for the Synthesis of α-Fluoro-β-
arylalkenyl Sulfones. A solution of gem-difluoroalkene 1 (0.1
mmol, 1 equiv) and sodium benzenesulfinate 2 (0.3 mmol, 3 equiv) in
degassed DMSO (1 mL) was stirred under a nitrogen atmosphere at
100 °C for 24 h. After completion of the reaction, 2 mL of water was
added to the reaction mixture and the aqueous solution was extracted
with ethyl acetate (3 × 4 mL). The combined organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The pure product
was obtained by flash column chromatography on silica gel (eluent,
20/1−5/1 petroleum ether/ethyl acetate) to afford desired product 3
or 4.
between the bulky sulfonate group and aryl group, the anti-β-F
elimination process will proceed via model transition state IV
preferentially to generate highly E-selective product.
In summary, we have presented a novel method for
acquiring various α-fluoro-vinyl sulfones in good yields and
stereoselectivities under transition-metal- and base-free con-
ditions. The reactions perform well under mild and green
conditions and are tolerant of wide varieties of functional
groups. Aryl and alkyl sulfinic acid sodium salts are both good
coupling partners. The strategy is also applied to the late-stage
modification of complex natural products and drugs. Further
application to pharmaceuticals is underway in our laboratory.
(E)-2-[2-Fluoro-2-(phenylsulfonyl)vinyl]naphthalene (3aa).2b,f,21
Purified by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 25.6 mg, 82% yield.
White solid. Mp: 105−106 °C. 1H NMR (600 MHz, CDCl3): δ
8.11−8.00 (m, 3H), 7.83 (t, J = 8.2 Hz, 3H), 7.73−7.65 (m, 2H),
7.61 (t, J = 7.8 Hz, 2H), 7.57−7.49 (m, 2H), 7.23 (d, J = 34.6 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3): δ 153.55 (d, J = 304.6 Hz),
137.4, 134.4, 133.8 (d, J = 1.9 Hz), 133.0, 131.1 (d, J = 7.2 Hz),
129.5, 128.7, 128.7, 128.6, 127.7, 127.6, 126.9 (d, J = 4.2 Hz), 126.8,
126.2 (d, J = 7.8 Hz), 115.7. 19F NMR (564 MHz, CDCl3): δ
−124.65 (d, J = 34.8 Hz). FTMS: (APCI) calcd for C18H12FO2S− [M
− H+] 311.0548, found 311.0542.
(E)-2-(2-Fluoro-2-tosylvinyl)naphthalene (3ab). Purified by silica
gel column chromatography (eluent, 20/1−5/1 petroleum ether/
ethyl acetate). Isolated yield: 26.4 mg, 81% yield. White solid. Mp:
108−109 °C. 1H NMR (600 MHz, CDCl3): δ 8.03 (s, 1H), 7.92 (d, J
= 8.3 Hz, 2H), 7.86−7.79 (m, 3H), 7.66 (dd, J = 8.6, 1.5 Hz, 1H),
7.52 (pd, J = 6.8, 1.2 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.20 (d, J =
34.8 Hz, 1H), 2.46 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ
153.8 (d, J = 304.6 Hz), 145.7, 134.4, 133.7 (d, J = 1.9 Hz), 133.0,
131.0 (d, J = 7.4 Hz), 130.1, 128.7, 128.7, 128.6, 127.7, 127.6, 127.0
(d, J = 4.3 Hz), 126.8, 126.2 (d, J = 7.9 Hz), 115.2, 21.7. 19F NMR
(564 MHz, CDCl3): δ −124.65 (d, J = 34.9 Hz). FTMS: (APCI)
calcd for C19H16FO2S+ [M + H+] 327.0850, found 327.0843.
(E)-2-{2-Fluoro-2-[(4-methoxyphenyl)sulfonyl]vinyl}naphthalene
(3ac). Purified by silica gel column chromatography (eluent, 10/1−3/
1 petroleum ether/ethyl acetate). Isolated yield: 24.6 mg, 72% yield.
White solid. Mp: 80−81 °C. 1H NMR (600 MHz, CDCl3): δ 8.03 (s,
1H), 7.97 (d, J = 8.9 Hz, 2H), 7.87−7.79 (m, 3H), 7.67 (dd, J = 8.6,
1.2 Hz, 1H), 7.56−7.48 (m, 2H), 7.18 (d, J = 34.9 Hz, 1H), 7.05 (d, J
= 9.0 Hz, 2H), 3.89 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ
164.4, 154.0 (d, J = 304.1 Hz), 133.7 (d, J = 1.7 Hz), 133.0, 131.0,
130.9 (d, J = 7.3 Hz), 128.6, 128.6, 128.5, 127.6, 127.5, 127.1 (d, J =
4.1 Hz), 126.7, 126.2 (d, J = 7.9 Hz), 114.7, 55.8. 19F NMR (564
MHz, CDCl3): δ −124.61 (d, J = 34.9 Hz). FTMS: (APCI) calcd for
C19H16FO3S+ [M + H+] 343.0799, found 343.0798.
(E)-2-{2-[(4-Chlorophenyl)sulfonyl]-2-fluorovinyl}naphthalene
(3ad). Purified by silica gel column chromatography (eluent, 20/1−
5/1 petroleum ether/ethyl acetate). Isolated yield: 17.6 mg, 51%
yield. Yellow solid. Mp: 112−113 °C. 1H NMR (600 MHz, CDCl3): δ
8.04 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.84 (t, J = 8.8 Hz, 3H), 7.67
(dd, J = 8.6, 1.4 Hz, 1H), 7.60−7.49 (m, 4H), 7.22 (d, J = 34.8 Hz,
1H). 13C{1H} NMR (151 MHz, CDCl3): δ 153.15 (d, J = 304.3 Hz),
141.3, 135.9, 133.8 (d, J = 1.7 Hz), 131.2 (d, J = 7.3 Hz), 130.1,
129.8, 128.8, 128.6, 127.8, 127.7, 126.8, 126.8 (d, J = 4.3 Hz), 126.2
(d, J = 7.9 Hz), 116.1. 19F NMR (564 MHz, CDCl3): δ −125.10 (d, J
= 34.8 Hz). FTMS: (APCI) calcd for C18H13ClFO2S+ [M + H+]
347.0303, found 347.0298.
(E)-2-[2-([1,1′-Biphenyl]-4-ylsulfonyl)-2-fluorovinyl]naphthalene
(3ae). Purified by silica gel column chromatography (eluent, 20/1−5/
1 petroleum ether/ethyl acetate). Isolated yield: 26.6 mg, 69% yield.
White solid. Mp: 118−119 °C. 1H NMR (600 MHz, CDCl3): δ 8.10
(d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.82 (dd, J = 10.8, 7.3 Hz, 3H), 7.78
(d, J = 8.5 Hz, 2H), 7.68 (dd, J = 8.6, 1.5 Hz, 1H), 7.62−7.58 (m,
2H), 7.52 (ddd, J = 9.6, 7.3, 1.2 Hz, 2H), 7.49−7.45 (m, 2H), 7.42
(dd, J = 8.4, 6.2 Hz, 1H), 7.24 (d, J = 34.8 Hz, 1H). 13C{1H} NMR
(151 MHz, CDCl3): δ 153.8 (d, J = 304.3 Hz), 147.4, 139.0, 135.9,
133.8 (d, J = 1.4 Hz), 133.0, 131.1 (d, J = 7.0 Hz), 129.2, 129.1,
128.8, 128.7, 128.6, 128.1, 127.7, 127.6, 127.4, 127.0 (d, J = 4.2 Hz),
EXPERIMENTAL SECTION
■
General Information. All reactions including air- or moisture-
sensitive compounds were performed in the argon-filled glovebox or
by standard Schlenk techniques in oven-dried reaction vessels under
an argon atmosphere in a sealed tube. Unless otherwise noted, all of
the solvents and reagents were obtained from commercial suppliers
(Strem, Alfa, Aldrich, Adamas-beta, Innochem, Aladdin, Acros, TCI,
bidepharm, etc.) and used without further purification. All gem-
difluoroalkenes19 and sodium sulfonates20 were prepared following
literature procedures. Thin layer chromatography (TLC) employed
glass 0.25 mm silica gel plates. Chromatography columns were packed
with 200−300 mesh silica gel in petroleum ether (bp 60−90 °C). Gas
chromatographic analyses were performed on a Shimadzu GC 2030
gas chromatography instrument with a FID detector, and adamantane
1
was added as an internal standard. H, 13C{1H}, and 19F NMR data
were recorded with Bruker AVANCE NEO (600 MHz) and Agilent
DD2 600 (600 MHz) spectrometers with tetramethylsilane as an
internal standard. All chemical shifts (δ) are reported in parts per
million and coupling constants (J) in hertz. Singlet (s), doublet (d),
doublet of doublets (dd), triplet (t), doublet of triplets (dt), triplet of
doublets (td), quartet (q), multiplet (m), and doublet of doublets of
doublets (ddd) were used to express the signal. All chemical shifts
were reported relative to tetramethylsilane (0 ppm for 1H) and CDCl3
(77.0 ppm for 13C{1H}). High-resolution mass spectra (HRMS) were
recorded with a Thermo fisher Q-Exactive instrument, and accurate
masses are reported for the molecular ion.
Preparation for the Synthesis of gem-Difluoroalkene
Substrates.19 An oven-dried three-neck round-bottom flask
equipped with a PTFE-coated stir bar was charged with PPh3 (6.56
g, 25 mmol, 2.5 equiv), KI (3.32 g, 20 mmol, 2 equiv), and aldehyde
(10 mmol, 1 equiv). Under the inert nitrogen atmosphere, acetonitrile
(20 mL) was added to the vessel, and the temperature was increased
to 70 °C and allowed to stir for 30 min. Then methyl 2,2-difluoro-2-
(fluorosulfonyl)acetate (MDFA, 3.36 g, 17.5 mmol, 1.75 equiv) was
then added slowly over a period of 0.5 h. The resulting mixture was
stirred for 3 h, a nitrogen atmosphere being maintained until the end
of the reaction. Then the reaction was quenched with water (50 mL),
and the mixture extracted with ethyl acetate (3 × 30 mL). The
combined organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography to afford gem-difluoroalkenes 1.
Preparation for the Synthesis of Sodium Sulfinate
Substrates.20 A 25 mL round-bottom flask equipped with a
PTFE-coated stir bar was charged with Na2SO3 (20 mmol, 2.52 g,
2 equiv), NaHCO3 (20 mmol, 1.68 g, 2 equiv), and deionized H2O
(10 mL). After the mixture had been stirred for 5 min, the sulfonyl
chloride (10 mmol, 1 equiv) was added portionwise to the flask. The
mixture was heated to 80 °C in an oil bath for 12 h. After this time,
the reaction mixture was cooled to rt, and the solvent was removed in
vacuo by rotary evaporation, affording the crude sulfinate salt. The
impurities were triturated with EtOH and removed by filtration. The
solvent was removed from the filtrate in vacuo by rotary evaporation,
and the residue was washed three times with ethyl acetate to afford
pure sodium sulfonates 2.
6986
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
126.8, 126.2 (d, J = 7.7 Hz), 115.6. 19F NMR (564 MHz, CDCl3): δ
−124.61. FTMS: (APCI) calcd for C24H16FO2S− [M − H+]
387.0860, found 387.0857.
White solid. Mp: 119−120 °C. 1H NMR (600 MHz, CDCl3): δ 8.11
(dd, J = 7.9, 1.4 Hz, 1H), 8.07 (s, 1H), 7.85 (dd, J = 12.8, 8.1 Hz,
3H), 7.72 (dd, J = 8.6, 1.1 Hz, 1H), 7.67−7.62 (m, 1H), 7.57−7.49
(m, 2H), 7.28 (s, 0.49H), 7.22 (s, 0.5H), 7.16 (t, J = 7.7 Hz, 1H),
7.03 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 158.0, 153.7 (d, J = 304.3 Hz), 136.5, 133.7 (d, J = 1.6
Hz), 133.1, 131.7, 130.8 (d, J = 7.4 Hz), 128.7, 128.6, 127.7, 127.5,
126.8, 126.3 (d, J = 7.7 Hz), 124.8, 120.8, 116.5, 112.5, 56.3. 19F
NMR (564 MHz, CDCl3): δ −124.72. FTMS: (APCI) calcd for
C19H16FO3S+ [M + H+] 343.0799, found 343.0797.
(E)-2-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}naphthalene
(3al). Purified by silica gel column chromatography (eluent, 20/1−5/
1 petroleum ether/ethyl acetate). Isolated yield: 29.0 mg, 80% yield.
White solid. Mp: 102−103 °C. 1H NMR (600 MHz, CDCl3): δ 8.66
(s, 1H), 8.08−8.00 (m, 3H), 7.98 (dd, J = 8.7, 1.4 Hz, 1H), 7.94 (d, J
= 8.2 Hz, 1H), 7.86−7.79 (m, 3H), 7.74−7.62 (m, 3H), 7.57−7.46
(m, 2H), 7.34−7.23 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ
153.7 (d, J = 304.6 Hz), 135.7, 134.2, 133.8 (d, J = 1.8 Hz), 133.0,
132.2, 131.1 (d, J = 7.3 Hz), 131.0, 129.9, 129.7, 129.6, 128.8, 128.6,
128.0, 127.9, 127.7, 127.7, 127.0 (d, J = 4.1 Hz), 126.8, 126.3 (d, J =
7.9 Hz), 122.9, 115.8. 19F NMR (564 MHz, CDCl3): δ −124.53 (d, J
= 34.8 Hz). FTMS: (APCI) calcd for C22H16FO2S+ [M + H+]
363.0850, found 363.08444.
(E)-1-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}naphthalene
(3am). Purified by silica gel column chromatography (eluent, 20/1−
5/1 petroleum ether/ethyl acetate). Isolated yield: 11.5 mg, 32%
yield. Yellow oil. 1H NMR (600 MHz, CDCl3): δ 8.81 (d, J = 8.7 Hz,
1H), 8.51 (dd, J = 7.4, 1.1 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.05 (s,
1H), 7.96 (dd, J = 8.2, 0.5 Hz, 1H), 7.83−7.78 (m, 3H), 7.71−7.68
(m, 1H), 7.67−7.64 (m, 2H), 7.62−7.59 (m, 1H), 7.54−7.47 (m,
2H), 7.38 (d, J = 34.6 Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ
154.3 (d, J = 305.2 Hz), 136.3, 134.3, 133.8 (d, J = 1.7 Hz), 133.0,
132.3, 132.1, 131.1 (d, J = 7.0 Hz), 129.3, 129.0, 128.9, 128.7, 128.6,
127.7, 127.7, 127.2, 127.0 (d, J = 4.1 Hz), 126.8, 126.3 (d, J = 7.9
Hz), 124.6, 124.2, 116.0. 19F NMR (564 MHz, CDCl3): δ −123.74.
FTMS: (APCI) calcd for C22H16FO2S+ [M + H+] 363.0850, found
363.08445.
(E)-2-(2-Fluoro-2-{[4-(trifluoromethyl)phenyl]sulfonyl}vinyl)-
naphthalene (3af). Purified by silica gel column chromatography
(eluent, 20/1−5/1 petroleum ether/ethyl acetate). Isolated yield: 9.9
1
mg, 26% yield. White solid. Mp: 152−153 °C. H NMR (600 MHz,
CDCl3): δ 8.19 (d, J = 8.2 Hz, 2H), 8.06 (s, 1H), 7.91−7.82 (m, 5H),
7.68 (d, J = 8.6 Hz, 1H), 7.54 (dt, J = 15.8, 6.8 Hz, 2H), 7.29 (s,
0.54H), 7.23 (s, 0.48H). 13C{1H} NMR (151 MHz, CDCl3): δ 152.8
(d, J = 304.4 Hz), 141.2, 136.0 (q, J = 33.6 Hz), 134.0, 133.0, 131.5
(d, J = 7.0 Hz), 129.3, 128.9, 128.7, 127.9, 127.8, 126.7 (q, J = 3.7
Hz), 126.6, 126.2 (d, J = 8.0 Hz), 127.0, 123.0 (q, J = 273.3 Hz),
117.0. 19F NMR (564 MHz, CDCl3): δ −63.29, −125.31. FTMS:
(APCI) calcd for C19H11F4O2S− [M − H+] 379.0421, found
379.0415.
(E)-4-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}benzonitrile
(3ag). Purified by silica gel column chromatography (eluent, 10/1−
3/1 petroleum ether/ethyl acetate). Isolated yield: 15.7 mg, 46%
yield. White solid. Mp: 168−169 °C. 1H NMR (600 MHz, CDCl3): δ
8.16 (d, J = 8.4 Hz, 2H), 8.05 (s, 1H), 7.89 (d, J = 8.3 Hz, 2H), 7.84
(t, J = 9.4 Hz, 3H), 7.67 (d, J = 8.6 Hz, 1H), 7.61−7.51 (m, 2H), 7.29
(s, 0.51H), 7.23 (s, 0.48H). 13C{1H} NMR (151 MHz, CDCl3): δ
152.4 (d, J = 304.0 Hz), 141.8, 134.0 (d, J = 1.5 Hz), 133.2, 133.0,
131.6 (d, J = 7.5 Hz), 129.3, 128.9, 128.7, 128.0, 127.7, 127.0, 126.5
(d, J = 4.0 Hz), 126.1 (d, J = 7.7 Hz), 118.1, 117.5, 117.0. 19F NMR
(564 MHz, CDCl3): δ −125.59. FTMS: (APCI) calcd for
C19H13FNO2S+ [M + H+] 338.0646, found 338.0639.
Methyl (E)-4-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}-
benzoate (3ah). Purified by silica gel column chromatography
(eluent, 10/1−3/1 petroleum ether/ethyl acetate). Isolated yield:
15.6 mg, 42% yield. White solid. Mp: = 134−135 °C. 1H NMR (600
MHz, CDCl3): δ 8.27−8.22 (m, 2H), 8.12 (d, J = 8.5 Hz, 2H), 8.05
(s, 1H), 7.83 (t, J = 9.2 Hz, 3H), 7.67 (dd, J = 8.6, 1.6 Hz, 1H), 7.56−
7.49 (m, 2H), 7.25 (d, J = 34.7 Hz, 1H), 3.96 (s, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 165.3, 153.0 (d, J = 304.8 Hz), 141.4, 135.4,
133.9 (d, J = 1.5 Hz), 133.0, 131.3 (d, J = 7.4 Hz), 130.6, 128.8,
128.7, 128.6, 127.8, 127.7, 126.9, 126.7 (d, J = 4.3 Hz), 126.2 (d, J =
7.8 Hz), 116.7, 52.8. 19F NMR (564 MHz, CDCl3): δ −125.11.
FTMS: (APCI) calcd for C20H14FO4S− [M − H+] 369.0602, found
369.0601.
(E)-3-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}benzonitrile
(3ai). Purified by silica gel column chromatography (eluent, 10/1−3/
1 petroleum ether/ethyl acetate). Isolated yield: 10.1 mg, 30% yield.
Yellow solid. Mp: 138−139 °C. 1H NMR (600 MHz, CDCl3): δ 8.34
(s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.98 (d, J = 7.8 Hz,
1H), 7.86 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.77 (t, J = 7.9
Hz, 1H), 7.68 (dd, J = 8.6, 1.2 Hz, 1H), 7.55 (ddd, J = 15.1, 13.8, 6.8
Hz, 2H), 7.30 (s, 0.48H), 7.24 (s, 0.47H). 13C{1H} NMR (151 MHz,
CDCl3): δ 152.3 (d, J = 304.5 Hz), 139.4, 137.4, 134.0 (d, J = 1.9
Hz), 132.9, 132.6, 132.3, 131.6 (d, J = 7.3 Hz), 130.6, 128.9, 128.7,
128.0, 127.7, 127.0, 126.4 (d, J = 4.4 Hz), 126.1 (d, J = 7.9 Hz),
117.3, 116.7, 114.3. 19F NMR (564 MHz, CDCl3): δ −125.66 (d, J =
34.8 Hz). FTMS: (APCI) calcd for C19H12FNO2S+ [M+] 337.0567,
found 337.0562.
(E)-2-{2-[(3-Bromophenyl)sulfonyl]-2-fluorovinyl}naphthalene
(3aj). Purified by silica gel column chromatography (eluent, 20/1−5/
1 petroleum ether/ethyl acetate). Isolated yield: 16.4 mg, 42% yield.
Yellow solid. Mp: 100−101 °C. 1H NMR (600 MHz, CDCl3): δ 8.18
(s, 1H), 8.06 (s, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.87−7.81 (m, 4H),
7.69 (dd, J = 8.6, 1.3 Hz, 1H), 7.58−7.46 (m, 3H), 7.23 (d, J = 34.0
Hz, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ 152.9 (d, J = 304.2
Hz), 139.3, 137.5, 133.88 (d, J = 1.8 Hz), 133.0, 131.4, 131.4 (d, J =
7.3 Hz), 131.0, 128.8, 128.6, 127.8, 127.7, 127.3, 126.9, 126.7 (d, J =
4.4 Hz), 126.2 (d, J = 7.9 Hz), 123.4, 116.5. 19F NMR (564 MHz,
CDCl3): δ −125.04 (d, J = 34.7 Hz). FTMS: (APCI) calcd for
C18H12BrFO2S+ [M+] 389.9720, found 389.9719.
(E)-2-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}thiophene
(3an). Purified by silica gel column chromatography (eluent, 20/1−
5/1 petroleum ether/ethyl acetate). Isolated yield: 15.7 mg, 50%
yield. Yellow solid. Mp: 108−109 °C. 1H NMR (600 MHz, CDCl3): δ
8.06 (s, 1H), 7.87 (dd, J = 3.8, 0.8 Hz, 1H), 7.87−7.82 (m, 3H), 7.81
(dd, J = 4.9, 1.0 Hz, 1H), 7.70 (dd, J = 8.6, 1.2 Hz, 1H), 7.58−7.49
(m, 2H), 7.27−7.18 (m, 2H). 13C{1H} NMR (151 MHz, CDCl3): δ
153.6 (d, J = 303.9 Hz), 138.1, 135.8, 135.7, 133.8 (d, J = 1.8 Hz),
133.0, 131.2 (d, J = 7.4 Hz), 128.8, 128.6, 128.4, 127.7, 127.7, 126.9
(d, J = 4.3 Hz), 126.9, 126.3 (d, J = 7.9 Hz), 115.3. 19F NMR (564
MHz, CDCl3): δ −124.74 (d, J = 34.5 Hz). FTMS: (APCI) calcd for
+
C16H12FO2S2 [M + H+] 319.0257, found 319.0254.
(E)-2-[2-Fluoro-2-(methylsulfonyl)vinyl]naphthalene (3ao). Puri-
fied by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 23.8 mg, 95% yield.
White solid. Mp: 80−81 °C. 1H NMR (600 MHz, CDCl3): δ 8.06 (s,
1H), 7.91−7.81 (m, 3H), 7.72 (dd, J = 8.6, 1.0 Hz, 1H), 7.61−7.48
(m, 2H), 7.09 (d, J = 35.5 Hz, 1H), 3.16 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 153.2 (d, J = 304.6 Hz), 133.8 (d, J = 2.0 Hz), 133.0,
131.2 (d, J = 7.1 Hz), 128.8, 128.6, 127.8, 127.7, 126.9, 126.5 (d, J =
4.1 Hz), 126.2 (d, J = 7.9 Hz), 116.0, 40.6. 19F NMR (564 MHz,
CDCl3): δ −125.79 (d, J = 35.5 Hz). FTMS: (APCI) calcd for
C13H10FO2S− [M − H+] 249.0391, found 249.0390.
(E)-2-[2-(Ethylsulfonyl)-2-fluorovinyl]naphthalene (3ap). Purified
by silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 24.2 mg, 91% yield. White solid.
Mp: 56−57 °C. 1H NMR (600 MHz, CDCl3): δ 8.07 (s, 1H), 7.91−
7.83 (m, 3H), 7.73 (dd, J = 8.6, 1.5 Hz, 1H), 7.60−7.52 (m, 2H), 7.08
(d, J = 35.7 Hz, 1H), 3.26 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.5 Hz,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 151.7 (d, J = 305.1 Hz),
133.9 (d, J = 1.9 Hz), 133.0, 131.2 (d, J = 7.2 Hz), 128.9, 128.7,
127.8, 127.8, 126.9, 126.7 (d, J = 4.1 Hz), 126.2 (d, J = 7.8 Hz),
117.4, 47.0, 7.0. 19F NMR (564 MHz, CDCl3): δ −124.83 (d, J = 35.6
(E)-2-{2-Fluoro-2-[(2-methoxyphenyl)sulfonyl]vinyl}naphthalene
(3ak). Purified by silica gel column chromatography (eluent, 10/1−3/
1 petroleum ether/ethyl acetate). Isolated yield: 7.2 mg, 21% yield.
6987
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Hz). FTMS: (APCI) calcd for C14H12FO2S− [M − H+] 263.0546,
found 263.0544.
7.58−7.51 (m, 4H), 7.07 (d, J = 35.7 Hz, 1H), 4.21 (t, J = 6.3 Hz,
2H), 3.71 (t, J = 6.3 Hz, 2H). 13C{1H} NMR (151 MHz, CDCl3): δ
167.5, 151.3 (d, J = 304.2 Hz), 134.2, 133.8 (d, J = 1.8 Hz), 132.9,
131.5, 131.4 (d, J = 7.3 Hz), 128.7, 128.7, 127.8, 127.6, 126.8, 126.4
(d, J = 4.2 Hz), 126.1 (d, J = 7.8 Hz), 123.4, 118.3, 49.0, 31.8. 19F
NMR (564 MHz, CDCl3): δ −126.42 (d, J = 35.6 Hz). FTMS:
(APCI) calcd for C22H17FNO4S+ [M + H+] 410.0857, found
410.0859.
(E)-2-[2-Fluoro-2-(propylsulfonyl)vinyl]naphthalene (3aq). Puri-
fied by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 27.2 mg, 97% yield.
White solid. Mp: 74−75 °C. 1H NMR (600 MHz, CDCl3): δ 8.07 (s,
1H), 7.91−7.83 (m, 3H), 7.73 (dd, J = 8.6, 1.7 Hz, 1H), 7.59−7.52
(m, 2H), 7.07 (d, J = 35.7 Hz, 1H), 3.26−3.17 (m, 2H), 1.98−1.87
(m, 2H), 1.11 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 152.3 (d, J = 305.1 Hz), 133.8 (d, J = 1.7 Hz), 133.0, 131.1
(d, J = 7.2 Hz), 128.8, 128.6, 127.7, 127.7, 126.8, 126.7 (d, J = 4.0
Hz), 126.2 (d, J = 7.7 Hz), 117.0, 54.1, 16.1, 12.9. 19F NMR (564
MHz, CDCl3): δ −124.81 (d, J = 35.6 Hz). FTMS: (APCI) calcd for
C15H14FO2S− [M − H+] 277.0704, found 277.0699.
(E)-2-[2-Fluoro-2-(isopropylsulfonyl)vinyl]naphthalene (3ar). Pu-
rified by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 27.3 mg, 91% yield.
White solid. Mp: 76−77 °C. 1H NMR (600 MHz, CDCl3): δ 8.08 (s,
1H), 7.91−7.83 (m, 3H), 7.73 (dd, J = 8.6, 1.4 Hz, 1H), 7.59−7.51
(m, 2H), 7.06 (d, J = 35.7 Hz, 1H), 3.41 (hept, J = 6.9 Hz, 1H), 1.47
(d, J = 6.9 Hz, 6H). 13C{1H} NMR (151 MHz, CDCl3): δ 151.3 (d, J
= 306.1 Hz), 133.9 (d, J = 1.8 Hz), 133.0, 131.1 (d, J = 7.3 Hz),
128.8, 128.6, 127.8, 127.7, 126.9, 126.9 (d, J = 3.9 Hz), 126.3 (d, J =
7.9 Hz), 118.1, 53.0, 15.1. 19F NMR (564 MHz, CDCl3): δ −122.44
(d, J = 35.7 Hz). FTMS: (APCI) calcd for C15H14FO2S− [M − H+]
277.0704, found 277.0702.
(E)-1-(tert-Butyl)-4-(2-fluoro-2-tosylvinyl)benzene (3bb). Purified
by silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 20.3 mg, 77% yield. White solid.
Mp: 93−94 °C. 1H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 8.2 Hz,
2H), 7.51 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.38 (d, J =
8.2 Hz, 2H), 7.03 (d, J = 35.1 Hz, 1H), 2.45 (s, 3H), 1.31 (s, 9H).
13C{1H} NMR (151 MHz, CDCl3): δ 153.9 (d, J = 2.4 Hz), 153.2 (d,
J = 302.9 Hz), 145.6, 134.5, 130.1, 130.0, 128.6, 126.8 (d, J = 3.9 Hz),
126.0, 115.1, 34.9, 31.1, 21.7. 19F NMR (564 MHz, CDCl3): δ
−125.72 (d, J = 35.1 Hz). FTMS: (APCI) calcd for C19H22FO2S+ [M
+ H+] 333.1319, found 333.1317.
Methyl (E)-4-(2-Fluoro-2-tosylvinyl)benzoate (3cb).2c Purified by
silica gel column chromatography (eluent, 10/1−3/1 petroleum
ether/ethyl acetate). Isolated yield: 16.4 mg, 50% yield. White solid.
1
Mp: 137−138 °C. H NMR (600 MHz, CDCl3): δ 8.05 (d, J = 8.4
Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.41 (d, J
= 8.1 Hz, 2H), 7.07 (d, J = 34.2 Hz, 1H), 3.93 (s, 3H), 2.47 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 166.2, 155.1 (d, J = 308.6 Hz),
(E)-2-[2-(Cyclopropylsulfonyl)-2-fluorovinyl]naphthalene (3as).
Purified by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 23.5 mg, 85% yield.
White solid. Mp: 69−70 °C. 1H NMR (600 MHz, CDCl3): δ 8.07 (s,
1H), 7.90−7.84 (m, 3H), 7.73 (dd, J = 8.6, 1.6 Hz, 1H), 7.55 (pd, J =
6.9, 1.3 Hz, 2H), 7.04 (d, J = 35.4 Hz, 1H), 2.65−2.56 (m, 1H),
1.45−1.40 (m, 2H), 1.21−1.15 (m, 2H). 13C{1H} NMR (151 MHz,
CDCl3): δ 153.4 (d, J = 304.7 Hz), 133.7 (d, J = 1.8 Hz), 133.0, 131.0
(d, J = 7.4 Hz), 128.7, 128.6, 127.7, 127.6, 126.9 (d, J = 4.1 Hz),
126.8, 126.2 (d, J = 7.8 Hz), 115.7, 29.5, 5.5. 19F NMR (564 MHz,
CDCl3): δ −124.21 (d, J = 35.4 Hz). FTMS: (APCI) calcd for
C15H12FO2S− [M − H+] 275.0548, found 275.0543.
(E)-2-[2-(Cyclohexylsulfonyl)-2-fluorovinyl]naphthalene (3at).
Purified by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 27.3 mg, 86% yield.
White solid. Mp: 97−98 °C. 1H NMR (600 MHz, CDCl3): δ 8.07 (s,
1H), 7.91−7.84 (m, 3H), 7.73 (dd, J = 8.6, 1.4 Hz, 1H), 7.59−7.51
(m, 2H), 7.04 (d, J = 35.7 Hz, 1H), 3.20−3.09 (m, 1H), 2.23 (d, J =
11.8 Hz, 2H), 1.99−1.90 (m, 2H), 1.78−1.70 (m, 1H), 1.64−1.56
(m, 2H), 1.38−1.28 (m, 2H), 1.24 (ddt, J = 16.2, 6.8, 3.1 Hz, 1H).
13C{1H} NMR (151 MHz, CDCl3): δ 151.5 (d, J = 306.0 Hz), 133.8
146.0, 133.9, 133.8 (d, J = 4.0 Hz), 131.2 (d, J = 2.2 Hz), 130.2,
130.0, 130.0, 128.9, 113.8, 52.4, 21.8. 19F NMR (564 MHz, CDCl3): δ
−121.17 (d, J = 34.2 Hz). FTMS: (APCI) calcd for C17H16FO4S+ [M
+ H+] 335.0748, found 335.0749.
(E)-1-{[1-Fluoro-2-(4-iodophenyl)vinyl]sulfonyl}-4-methylben-
zene (3db). Purified by silica gel column chromatography (eluent,
20/1−5/1 petroleum ether/ethyl acetate). Isolated yield: 18.5 mg,
46% yield. White solid. Mp: 166−167 °C. 1H NMR (600 MHz,
CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.39 (d,
J = 8.2 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 34.3 Hz, 1H),
2.46 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 154.5 (d, J =
306.2 Hz), 145.9, 138.2, 134.2, 131.5 (d, J = 7.4 Hz), 130.2, 129.0 (d,
J = 3.9 Hz), 128.8, 114.0, 96.8 (d, J = 3.3 Hz), 21.8. 19F NMR (564
MHz, CDCl3): δ −122.77. FTMS: (APCI) calcd for C15H11FIO2S−
[M − H+] 400.9514, found 400.9506.
(E)-2-[4-(2-Fluoro-2-tosylvinyl)phenyl]-5,5-dimethyl-1,3,2-dioxa-
borinane (3eb). Purified by silica gel column chromatography
(eluent, 10/1−2/1 petroleum ether/ethyl acetate). Isolated yield:
1
19.5 mg, 50% yield. White solid. Mp: 129−130 °C. H NMR (600
MHz, CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.1 Hz, 2H),
7.53 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.04 (d, J = 34.9
Hz, 1H), 3.76 (s, 4H), 2.46 (s, 3H), 1.02 (s, 6H). 13C{1H} NMR
(151 MHz, CDCl3): δ 154.0 (d, J = 305.3 Hz), 145.6, 134.4, 134.3,
131.4 (d, J = 4.0 Hz), 130.1, 129.2, 129.2, 128.7, 115.2, 72.3, 31.9,
21.9, 21.7. 19F NMR (564 MHz, CDCl3): δ −123.55. FTMS: (APCI)
calcd for C20H21FBO4S− [M − H+] 387.1243, found 387.1236.
(E)-4-(2-Fluoro-2-tosylvinyl)-1,2-dimethoxybenzene (3fb). Puri-
fied by silica gel column chromatography (eluent, 10/1−3/1
petroleum ether/ethyl acetate). Isolated yield: 24.6 mg, 72% yield.
Yellow oil. 1H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H),
7.38 (d, J = 8.2 Hz, 2H), 7.16−7.11 (m, 2H), 6.98 (d, J = 35.0 Hz,
1H), 6.86 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 2.45 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 152.3 (d, J = 300.5 Hz),
150.8 (d, J = 3.2 Hz), 148.9, 145.5, 134.6, 130.1, 128.6, 124.4 (d, J =
6.7 Hz), 122.3 (d, J = 3.9 Hz), 115.3, 112.2 (d, J = 8.9 Hz), 112.0,
55.9, 55.8, 21.8. 19F NMR (564 MHz, CDCl3): δ −128.11 (d, J = 35.0
Hz). FTMS: (APCI) calcd for C17H18FO4S+ [M + H+] 337.09043,
found 337.09030.
(d, J = 1.8 Hz), 133.0, 131.1 (d, J = 7.3 Hz), 128.8, 128.6, 127.7,
127.7, 126.9 (d, J = 4.0 Hz), 126.9, 126.3 (d, J = 7.9 Hz), 118.0, 60.7,
25.0, 24.9. 19F NMR (564 MHz, CDCl3): δ −122.31 (d, J = 35.7 Hz).
FTMS: (APCI) calcd for C18H18FO2S− [M − H+] 317.1017, found
317.1014.
(E)-2-[2-(Benzylsulfonyl)-2-fluorovinyl]naphthalene (3au). Puri-
fied by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 27.6 mg, 85% yield.
White solid. Mp: 141−142 °C. 1H NMR (600 MHz, CDCl3): δ 7.95
(s, 1H), 7.85 (dd, J = 9.7, 4.4 Hz, 3H), 7.63 (dd, J = 8.6, 1.5 Hz, 1H),
7.54 (tdd, J = 7.6, 7.0, 1.2 Hz, 2H), 7.42−7.34 (m, 5H), 6.79 (d, J =
35.7 Hz, 1H), 4.47 (s, 2H). 13C{1H} NMR (151 MHz, CDCl3): δ
151.1 (d, J = 304.8 Hz), 133.8 (d, J = 1.8 Hz), 132.9, 131.1 (d, J = 7.2
Hz), 130.8, 129.3, 129.0, 128.7, 128.6, 127.7, 127.7, 126.8, 126.7,
126.6 (d, J = 3.9 Hz), 126.1 (d, J = 7.8 Hz), 118.1, 59.0. 19F NMR
(564 MHz, CDCl3): δ −124.50 (d, J = 32.0 Hz). FTMS: (APCI)
calcd for C19H14FO2S− [M − H+] 325.0704, found 325.0701.
(E)-2-(2-{[1-Fluoro-2-(naphthalen-2-yl)vinyl]sulfonyl}ethyl)-
isoindoline-1,3-dione (3av). Purified by silica gel column chroma-
tography (eluent, 5/1−2/1 petroleum ether/ethyl acetate). Isolated
(E)-4-(2-Fluoro-2-tosylvinyl)-1,2-dimethylbenzene (3gb). Purified
by silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 15.3 mg, 50% yield. White solid.
Mp: 82−83 °C. 1H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 8.0 Hz,
2H), 7.37 (d, J = 8.1 Hz, 2H), 7.33 (s, 1H), 7.31 (d, J = 8.0 Hz, 1H),
7.14 (d, J = 7.9 Hz, 1H), 6.98 (d, J = 35.2 Hz, 1H), 2.45 (s, 3H), 2.27
1
yield: 30.6 mg, 75% yield. White solid. Mp: 127−128 °C. H NMR
(600 MHz, CDCl3): δ 7.98 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.80 (d,
J = 8.7 Hz, 1H), 7.74−7.69 (m, 2H), 7.61 (dd, J = 8.6, 1.5 Hz, 1H),
6988
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(s, 3H), 2.25 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 153.1 (d,
J = 302.7 Hz), 145.5, 139.6 (d, J = 2.7 Hz), 137.3, 134.7, 131.4 (d, J =
7.4 Hz), 130.2, 130.1, 128.7, 127.8 (d, J = 7.5 Hz), 127.2 (d, J = 3.9
Hz), 115.4, 21.7, 19.8, 19.7. 19F NMR (564 MHz, CDCl3): δ
−125.97. FTMS: (APCI) calcd for C17H18FO2S+ [M + H+] 305.1006,
found 305.1006.
(E)-1-(2-Fluoro-2-tosylvinyl)-2,4-dimethylbenzene (3hb). Purified
by silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 16.5 mg, 54% yield. White solid.
Mp: 90−91 °C. 1H NMR (600 MHz, CDCl3): δ 7.89 (d, J = 8.3 Hz,
2H), 7.53 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 2H), 7.22 (d, J =
34.5 Hz, 1H), 7.04 (s, 1H), 7.00 (d, J = 8.0 Hz, 1H), 2.46 (s, 3H),
2.38 (s, 3H), 2.31 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ
153.3 (d, J = 303.1 Hz), 145.5, 140.4 (d, J = 1.8 Hz), 137.8 (d, J = 1.4
Hz), 134.6, 131.4, 130.1, 129.6 (d, J = 11.9 Hz), 128.7, 127.1, 125.2
(d, J = 3.6 Hz), 112.2, 21.7, 21.3, 19.9. 19F NMR (564 MHz, CDCl3):
δ −126.87. FTMS: (APCI) calcd for C17H18FO2S+ [M + H+]
305.1006, found 305.1006.
(E)-2-(2-Fluoro-2-tosylvinyl)-6-methoxynaphthalene (3ib). Puri-
fied by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 31.8 mg, 89% yield.
White solid. Mp: 147−148 °C. 1H NMR (600 MHz, CDCl3): δ 7.96
(s, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.72 (t, J = 8.7 Hz, 2H), 7.63 (dd, J
= 8.6, 1.7 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.20−7.12 (m, 2H), 7.11
(d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 2.46 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 159.0, 153.2 (d, J = 302.7 Hz), 145.5, 135.2 (d, J =
2.0 Hz), 134.6, 130.8 (d, J = 7.3 Hz), 130.1, 130.1, 128.6, 128.4,
127.4,126.9 (d, J = 7.9 Hz), 124.8 (d, J = 4.2 Hz), 119.7, 115.5, 105.6,
55.4, 21.7. 19F NMR (564 MHz, CDCl3): δ −125.99 (d, J = 35.1 Hz).
FTMS: (APCI) calcd for C20H18FO3S+ [M + H+] 357.0955, found
357.0958.
acetate). Isolated yield: 31.2 mg, 78% yield. Yellow solid. Mp: 79−80
°C. 1H NMR (600 MHz, CDCl3): δ 8.29−8.25 (m, 2H), 8.21 (d, J =
7.5 Hz, 2H), 8.15 (d, J = 9.2 Hz, 1H), 8.11−7.96 (m, 7H), 7.43 (d, J
= 8.1 Hz, 2H), 2.47 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ
154.3 (d, J = 305.4 Hz), 145.7, 134.4, 132.4 (d, J = 1.5 Hz), 131.0,
130.4, 130.2, 129.7 (d, J = 1.4 Hz), 128.9, 128.8, 128.8, 127.2 (d, J =
2.3 Hz), 127.1, 126.3, 126.2, 126.0, 124.7, 124.6, 124.2, 122.4 (d, J =
4.4 Hz), 122.2, 111.7, 21.8. 19F NMR (564 MHz, CDCl3): δ −125.82
(d, J = 33.5 Hz). FTMS: (APCI) calcd for C25H18FO2S+ [M + H+]
401.1006, found 401.1010.
(E)-3-(2-Fluoro-2-tosylvinyl)quinoline (3nb). Purified by silica gel
column chromatography (eluent, 20/1−5/1 toluene/ethyl acetate).
Isolated yield: 20.5 mg, 69% yield. White solid. Mp: 160−161 °C. 1H
NMR (600 MHz, CDCl3): δ 9.01 (d, J = 2.1 Hz, 1H), 8.38 (d, J = 1.6
Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.3 Hz, 2H), 7.81 (d, J
= 8.2 Hz, 1H), 7.76 (dd, J = 11.3, 4.0 Hz, 1H), 7.58 (t, J = 7.5 Hz,
1H), 7.41 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 34.7 Hz, 1H), 2.47 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 155.5 (d, J = 307.4 Hz), 150.6
(d, J = 6.5 Hz), 148.1, 146.0, 137.2 (d, J = 9.2 Hz), 134.0, 131.0,
130.2, 129.4, 128.8, 128.4, 127.5, 127.4, 123.0, 123.0, 111.9, 21.7. 19F
NMR (564 MHz, CDCl3): δ −120.89. FTMS: (APCI) calcd for
C18H15FNO2S+ [M + H+] 328.0802, found 328.0800.
(E)-3-(2-Fluoro-2-tosylvinyl)benzo[b]thiophene (3ob). Purified by
silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 23.8 mg, 30% yield. Yellow solid.
Mp: 153−154 °C. 1H NMR (600 MHz, CDCl3): δ 7.97 (s, 1H), 7.92
(d, J = 8.2 Hz, 3H), 7.89 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H),
7.46−7.36 (m, 4H), 2.47 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3):
δ 154.7 (d, J = 303.8 Hz), 145.7, 139.1, 137.5, 134.4, 130.6 (d, J =
14.0 Hz), 130.2, 128.7, 125.2, 125.0, 124.2 (d, J = 3.4 Hz), 122.8,
121.2, 106.6 (d, J = 3.0 Hz), 21.8. 19F NMR (564 MHz, CDCl3): δ
−122.44 (d, J = 33.8 Hz). FTMS: (APCI) calcd for C17H14FO2S2+ [M
+ H+] 333.0414, found 333.0411.
(E)-1-(2-Fluoro-2-tosylvinyl)naphthalene (3jb). Purified by silica
gel column chromatography (eluent, 20/1−5/1 petroleum ether/
ethyl acetate). Isolated yield: 22.6 mg, 73% yield. White solid. Mp:
3-[2-Fluoro-2-(methylsulfonyl)vinyl]benzo[b]thiophene (3oo).
Purified by silica gel column chromatography (eluent, 20/1−5/1
petroleum ether/ethyl acetate). Isolated yield: 17.6 mg, 65% yield.
The E/Z ratio of 9/1 by 19F NMR. Yellow solid. Mp: 97−98 °C. E
1
115−116 °C. H NMR (600 MHz, CDCl3): δ 8.08 (d, J = 8.5 Hz,
1H), 7.96 (d, J = 8.3 Hz, 2H), 7.88 (dd, J = 7.4, 6.0 Hz, 2H), 7.83 (d,
J = 7.3 Hz, 1H), 7.82 (d, J = 32.8 Hz, 1H), 7.61 (ddd, J = 8.3, 7.0, 1.2
Hz, 1H), 7.57−7.53 (m, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 8.2
Hz, 2H), 2.47 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 154.7
(d, J = 305.2 Hz), 145.8, 134.3, 133.6, 131.3, 130.7 (d, J = 1.5 Hz),
130.2, 128.9, 128.8, 128.5 (d, J = 10.7 Hz), 127.2, 126.4, 125.4 (d, J =
3.7 Hz), 125.3, 123.2, 111.5, 21.8. 19F NMR (564 MHz, CDCl3): δ
−124.85 (d, J = 32.8 Hz). FTMS: (APCI) calcd for C19H16FO2S+ [M
+ H+] 327.0850, found 327.0851.
1
isomer H NMR (600 MHz, CDCl3): δ 8.08 (s, 1H), 8.05 (s, 1H),
7.91 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.52−7.47 (m,
1H), 7.44 (t, J = 7.2 Hz, 1H), 7.30 (d, J = 34.5 Hz, 1H), 3.17 (s, 3H),
3.05 (d, J = 1.8 Hz, 1H). E isomer 13C{1H} NMR (151 MHz,
CDCl3): δ 154.1 (d, J = 303.8 Hz), 139.2, 137.4, 131.1 (d, J = 13.5
Hz), 125.3, 125.1, 123.8 (d, J = 3.2 Hz), 122.9, 121.1, 107.5 (d, J =
1.9 Hz), 40.8. E isomer 19F NMR (564 MHz, CDCl3): δ −123.55.
−
FTMS: (APCI) calcd for C11H8FO2S2 [M − H+] 254.9955, found
(E)-9-(2-Fluoro-2-tosylvinyl)phenanthrene (3kb). Purified by
silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 31.6 mg, 85% yield. White solid.
254.9949.
(E)-9-Ethyl-3-(2-fluoro-2-tosylvinyl)-9H-carbazole (3pb). Purified
by silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 22.7 mg, 58% yield. Yellow oil. 1H
NMR (600 MHz, CDCl3): δ 8.32 (d, J = 1.1 Hz, 1H), 8.06 (d, J = 7.7
Hz, 1H), 7.93 (d, J = 8.3 Hz, 2H), 7.67 (dd, J = 8.6, 1.5 Hz, 1H),
7.52−7.46 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 7.2 Hz,
3H), 7.27 (d, J = 6.8 Hz, 1H), 7.22 (d, J = 27.2 Hz, 1H), 4.34 (q, J =
7.2 Hz, 2H), 2.44 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H). 13C{1H} NMR
(151 MHz, CDCl3): δ 151.8 (d, J = 298.8 Hz), 145.3, 140.8 (d, J =
2.0 Hz), 140.4, 135.2, 130.1, 128.6, 128.1 (d, J = 6.9 Hz), 126.4,
123.4, 123.0 (d, J = 8.3 Hz), 122.7, 120.6, 120.3 (d, J = 3.8 Hz),
119.8, 116.7, 108.9, 108.8, 37.8, 21.7, 13.8. 19F NMR (564 MHz,
CDCl3): δ −129.32. FTMS: (APCI) calcd for C23H21FNO2S+ [M +
H+] 394.1272, found 394.1263.
1
Mp: 186−187 °C. H NMR (600 MHz, CDCl3): δ 8.76−8.71 (m,
1H), 8.66 (d, J = 8.3 Hz, 1H), 8.13−8.07 (m, 1H), 8.06 (s, 1H), 7.99
(d, J = 8.3 Hz, 2H), 7.82 (t, J = 20.8 Hz, 2H), 7.75−7.66 (m, 3H),
7.60 (t, J = 7.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 2H), 2.48 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 155.0 (d, J = 305.0 Hz), 145.8,
134.2, 130.8, 130.7, 130.4, 130.3, 130.2, 129.6, 129.3, 128.8, 128.1,
127.2, 127.1, 127.0, 124.0, 123.9 (d, J = 3.2 Hz), 123.2, 122.5, 112.0,
21.8. 19F NMR (564 MHz, CDCl3): δ −123.91 (d, J = 35.6 Hz).
FTMS: (APCI) calcd for C23H18FO2S+ [M + H+] 377.1006, found
377.1007.
(E)-9-(2-Fluoro-2-tosylvinyl)anthracene (3lb). Purified by silica
gel column chromatography (eluent, 20/1−5/1 petroleum ether/
ethyl acetate). Isolated yield: 27.5 mg, 73% yield. Yellow solid. Mp:
161−162 °C. 1H NMR (600 MHz, CDCl3): δ 8.48 (s, 1H), 8.05 (d, J
= 8.3 Hz, 2H), 8.02−7.95 (m, 3H), 7.90−7.84 (m, 2H), 7.53−7.47
(m, 4H), 7.46 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H). 13C{1H} NMR (151
MHz, CDCl3): δ 154.9 (d, J = 304.5 Hz), 146.0, 134.2, 131.0, 130.3,
129.3 (d, J = 1.0 Hz), 129.2, 128.9, 128.8, 126.8, 125.4, 124.7 (d, J =
1.2 Hz), 121.6, 112.6 (d, J = 5.9 Hz), 21.8. 19F NMR (564 MHz,
CDCl3): δ −116.70 (dt, J = 33.9, 2.9 Hz). FTMS: (APCI) calcd for
C23H18FO2S+ [M + H+] 377.1006, found 377.1008.
1-Benzyl-4-(2-fluoro-2-tosylvinyl)-1H-indole (3qb). Purified by
silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 22.2 mg, 55% yield. The E/Z ratio
1
is 7/1 by 19F NMR. Green solid. Mp: 107−111 °C. E isomer H
NMR (600 MHz, CDCl3): δ 7.92 (d, J = 8.3 Hz, 2H), 7.54 (s,
0.51H), 7.52 (s, 1H), 7.47 (s, 0.48H), 7.37 (d, J = 8.1 Hz, 2H), 7.33−
7.25 (m, 4H), 7.24 (d, J = 3.2 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 7.07
(d, J = 7.1 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.34 (s, 2H), 2.45 (s,
3H). E isomer 13C{1H} NMR (151 MHz, CDCl3): δ 153.6 (d, J =
303.9 Hz), 145.5, 137.0, 136.4, 134.8, 130.1, 129.6, 128.9, 128.7,
(E)-1-(2-Fluoro-2-tosylvinyl)pyrene (3mb). Purified by silica gel
column chromatography (eluent, 20/1−5/1 petroleum ether/ethyl
6989
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
127.8, 126.7, 121.9, 121.7, 121.6, 121.3 (d, J = 4.1 Hz), 112.8, 112.0
(d, J = 1.7 Hz), 100.0, 50.3, 21.8. E isomer 19F NMR (564 MHz,
CDCl3): δ −124.64. FTMS: (APCI) calcd for C24H21FNO2S+ [M +
H+] 406.1272, found 406.1264.
chromatography (eluent, 20/1−3/1 petroleum ether/ethyl acetate).
Isolated yield: 33.2 mg, 60% yield. White solid. Mp: 212−213 °C. 1H
NMR (600 MHz, CDCl3): δ 7.89 (d, J = 8.2 Hz, 2H), 7.52 (q, J = 8.4
Hz, 4H), 7.39 (d, J = 8.1 Hz, 2H), 7.33−7.27 (m, 3H), 7.02 (d, J =
34.6 Hz, 1H), 2.97−2.86 (m, 2H), 2.51 (dd, J = 19.0, 8.8 Hz, 1H),
2.46 (s, 3H), 2.45−2.39 (m, 1H), 2.32 (td, J = 10.9, 3.8 Hz, 1H),
2.20−2.11 (m, 1H), 2.10−2.00 (m, 2H), 2.00−1.95 (m, 1H), 1.65
(dd, J = 12.3, 9.0 Hz, 1H), 1.59−1.40 (m, 5H), 0.92 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 220.7, 154.2 (d, J = 305.9 Hz), 145.8,
140.8, 136.8, 134.4, 132.2, 132.0, 130.2, 130.1, 130.0, 129.1 (d, J = 3.8
Hz), 129.0, 128.8, 125.5, 120.1, 114.4, 92.1, 88.2, 50.5, 47.9, 44.5,
37.9, 35.8, 31.6, 29.1, 26.3, 25.6, 21.8, 21.6, 13.8. 19F NMR (564
MHz, CDCl3): δ −123.40. FTMS: (APCI) calcd for C35H34FO3S+ [M
+ H+] 553.2207, found 553.2197.
(E)-3-[2-Fluoro-2-(methylsulfonyl)vinyl]-1-tosyl-1H-indole (3ro).
Purified by silica gel column chromatography (eluent, 10/1−2/1
petroleum ether/ethyl acetate). Isolated yield: 28.7 mg, 73% yield.
White solid. Mp: 143−144 °C. 1H NMR (600 MHz, CDCl3): δ 8.08
(s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.64 (d, J =
7.9 Hz, 1H), 7.43−7.37 (m, 1H), 7.35−7.30 (m, 1H), 7.26 (d, J = 8.0
Hz, 2H), 7.14 (d, J = 35.3 Hz, 1H), 3.16 (s, 3H), 2.36 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 153.4 (d, J = 301.9 Hz), 145.8,
134.6, 134.4, 130.2, 128.6 (d, J = 3.0 Hz), 128.5, 127.1, 125.7, 124.1,
119.2, 113.7, 110.9, 107.0 (d, J = 3.9 Hz), 40.8, 21.6. 19F NMR (564
−
(8R,9S,13S,14S)-3-({4-[(E)-2-Fluoro-2-(methylsulfonyl)vinyl]-
phenyl}ethynyl)-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-
17H-cyclopenta[a]phenanthren-17-one (4e). Purified by silica gel
column chromatography (eluent, 20/1−3/1 petroleum ether/ethyl
acetate). Isolated yield: 37.8 mg, 79% yield. White solid. Mp: 233−
MHz, CDCl3): δ −120.47. FTMS: (APCI) calcd for C18H15FNO4S2
[M − H+] 392.0432, found 392.0425.
(E)-N-[1-(2,6-Dimethylphenoxy)propan-2-yl]-4-(2-fluoro-2-
tosylvinyl)benzamide (4a). Purified by silica gel column chromatog-
raphy (eluent, 10/1−3/1 petroleum ether/ethyl acetate). Isolated
yield: 40.4 mg, 84% yield. White solid. Mp: 93−94 °C. 1H NMR (600
MHz, CDCl3): δ 7.81 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.4 Hz, 2H),
7.54 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 34.3
Hz, 1H), 6.91 (d, J = 7.4 Hz, 2H), 6.87−6.82 (m, 1H), 6.72−6.63 (m,
1H), 4.53−4.38 (m, 1H), 3.84 (dd, J = 9.1, 3.9 Hz, 1H), 3.73 (dd, J =
9.2, 3.1 Hz, 1H), 2.38 (s, 3H), 2.17 (s, 6H), 1.44 (d, J = 6.9 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 165.9, 154.9 (d, J = 307.7 Hz),
1
234 °C. H NMR (600 MHz, CDCl3): δ 7.57 (q, J = 8.5 Hz, 4H),
7.33−7.27 (m, 3H), 6.92 (d, J = 35.3 Hz, 1H), 3.13 (s, 3H), 2.96−
2.87 (m, 2H), 2.51 (dd, J = 18.9, 8.7 Hz, 1H), 2.46−2.38 (m, 1H),
2.32 (d, J = 3.8 Hz, 1H), 2.20−2.11 (m, 1H), 2.10−2.01 (m, 2H),
2.00−1.94 (m, 1H), 1.68−1.56 (m, 3H), 1.54−1.42 (m, 3H), 0.92 (s,
3H). 13C{1H} NMR (151 MHz, CDCl3): δ 220.6, 153.5 (d, J = 305.4
Hz), 140.9, 136.8, 132.2, 132.1, 130.2 (d, J = 7.4 Hz), 129.0, 128.6 (d,
J = 3.6 Hz), 125.8 (d, J = 2.4 Hz), 125.5, 120.0, 115.2, 92.3, 88.2,
50.5, 47.9, 44.5, 40.6, 37.9, 35.8, 31.5, 29.1, 26.3, 25.6, 21.6, 13.8. 19F
NMR (564 MHz, CDCl3): δ −124.55. FTMS: (APCI) calcd for
C29H30FO3S+ [M + H+] 477.1894, found 477.1882.
154.8, 146.0, 135.8 (d, J = 1.8 Hz), 134.1, 132.5 (d, J = 4.1 Hz),
130.7, 130.3 (d, J = 7.6 Hz), 130.2, 129.1, 128.8, 127.5, 124.2, 113.9,
73.8, 46.1, 21.8, 17.8, 16.2. 19F NMR (564 MHz, CDCl3): δ −121.91.
FTMS: (APCI) calcd for C27H29FNO4S+ [M + H+] 482.1796, found
482.1789.
[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d]-
[1,3]dioxol-4-yl]methyl 4-[(E)-2-Fluoro-2-tosylvinyl]benzoate (4f).
Purified by silica gel column chromatography (eluent, 5/1−2/1
petroleum ether/ethyl acetate). Isolated yield: 26.5 mg, 52% yield.
White solid. Mp: 115−116 °C. 1H NMR (600 MHz, CDCl3): δ 8.08
(d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H),
7.41 (d, J = 8.0 Hz, 2H), 7.07 (d, J = 34.2 Hz, 1H), 5.02 (s, 1H), 4.76
(d, J = 5.9 Hz, 1H), 4.65 (d, J = 5.9 Hz, 1H), 4.52 (t, J = 6.8 Hz, 1H),
4.36 (ddd, J = 24.9, 11.3, 6.8 Hz, 2H), 3.33 (s, 3H), 2.47 (s, 3H), 1.50
(s, 3H), 1.34 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 165.3,
155.3 (d, J = 308.9 Hz), 146.0, 134.1 (d, J = 4.1 Hz), 134.0, 130.9 (d,
J = 1.9 Hz), 130.2, 130.2, 130.1 (d, J = 7.4 Hz), 128.9, 113.7, 112.7,
109.5, 85.3, 84.3, 81.9, 65.4, 55.0, 26.5, 25.0, 21.8. 19F NMR (564
MHz, CDCl3): δ −120.94. FTMS: (APCI) calcd for C25H27FO8S−
[M−] 506.1416, found 506.1407.
[(3aS,5aR,8aR,8bS)-2,2,7,7-Tetramethyltetrahydro-3aH-bis([1,3]-
dioxolo)[4,5-b:4′,5′-d]pyran-3a-yl]methyl 4-[(E)-2-Fluoro-2-
tosylvinyl]benzoate (4g). Purified by silica gel column chromatog-
raphy (eluent, 5/1−2/1 petroleum ether/ethyl acetate). Isolated
yield: 20.2 mg, 36% yield. Colorless oil. 1H NMR (600 MHz,
CDCl3): δ 8.08 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.63 (d,
J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 34.2 Hz, 1H),
4.69 (d, J = 11.8 Hz, 1H), 4.64 (dd, J = 7.9, 2.6 Hz, 1H), 4.44 (d, J =
2.6 Hz, 1H), 4.33 (d, J = 11.8 Hz, 1H), 4.26 (dd, J = 7.9, 1.2 Hz, 1H),
3.95 (dd, J = 13.0, 1.9 Hz, 1H), 3.80 (d, J = 13.0 Hz, 1H), 2.47 (s,
3H), 1.54 (s, 3H), 1.45 (s, 3H), 1.34 (s, 6H). 13C{1H} NMR (151
MHz, CDCl3): δ 165.1, 155.3 (d, J = 309.2 Hz), 146.1, 134.0 (d, J =
4.4 Hz), 131.1 (d, J = 2.0 Hz), 130.2, 130.0 (d, J = 7.5 Hz), 128.9,
113.7, 109.2, 108.9, 101.6, 70.8, 70.6, 70.1, 65.6, 61.4, 26.5, 25.9, 25.9,
24.0, 21.8. 19F NMR (564 MHz, CDCl3): δ −120.91. FTMS: (APCI)
calcd for C28H31FO9S− [M−] 562.1678, found 562.1669.
(3S,8S,9S,10R,13R,14S,17R)-10,13-Dimethyl-17-[(R)-6-methyl-
heptan-2-yl]-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-
1H-cyclopenta[a]phenanthren-3-yl 4-[(E)-2-Fluoro-2-tosylvinyl]-
benzoate (4b). Purified by silica gel column chromatography (eluent,
20/20/1−20/20/7 petroleum ether/dichloromethane/ethyl acetate).
Isolated yield: 56.3 mg, 82% yield. White solid. Mp: 198−199 °C. 1H
NMR (600 MHz, CDCl3): δ 7.97 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.3
Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.1 Hz, 2H), 6.99 (d, J
= 34.3 Hz, 1H), 5.34 (d, J = 3.9 Hz, 1H), 4.92−4.50 (m, 1H), 2.43−
2.31 (m, 5H), 1.98−1.87 (m, 3H), 1.84 (dt, J = 13.2, 3.3 Hz, 1H),
1.80−1.72 (m, 1H), 1.70−1.61 (m, 1H), 1.52−1.34 (m, 6H), 1.34−
1.22 (m, 3H), 1.21−1.01 (m, 8H), 0.99 (s, 3H), 0.96−0.88 (m, 3H),
0.85 (d, J = 6.5 Hz, 3H), 0.80 (d, J = 2.7 Hz, 3H), 0.79 (d, J = 2.7 Hz,
3H), 0.61 (s, 3H). 13C{1H} NMR (151 MHz, CDCl3): δ 165.1, 155.1
(d, J = 308.0 Hz), 146.0, 139.5, 134.1, 133.6 (d, J = 4.0 Hz), 132.0 (d,
J = 1.9 Hz), 130.2, 130.0, 130.0 (d, J = 7.5 Hz), 128.9, 122.9, 113.9,
75.0, 56.7, 56.2, 50.0, 42.3, 39.8, 39.5, 38.2, 37.0, 36.7, 36.2, 35.8,
32.0, 31.9, 28.2, 28.0, 27.9, 24.3, 23.9, 22.8, 22.6, 21.8, 21.1, 19.4,
18.7, 11.9. 19F NMR (564 MHz, CDCl3): δ −121.37. FTMS: (APCI)
calcd for C43H57FO4S− [M−] 688.3962, found 688.3956.
(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4-[(E)-2-Fluoro-2-
tosylvinyl]benzoate (4c). Purified by silica gel column chromatog-
raphy (eluent, 20/1−5/1 petroleum ether/ethyl acetate). Isolated
1
yield: 20.8 mg, 45% yield. White solid. Mp: 103−104 °C. H NMR
(600 MHz, CDCl3): δ 8.04 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.3 Hz,
2H), 7.62 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.07 (d, J =
34.3 Hz, 1H), 4.93 (td, J = 10.9, 4.4 Hz, 1H), 2.47 (s, 3H), 2.15−2.07
(m, 1H), 1.92 (heptd, J = 6.9, 2.7 Hz, 1H), 1.73 (dt, J = 5.4, 3.0 Hz,
2H), 1.55 (tdd, J = 14.1, 7.3, 3.3 Hz, 2H), 1.18−1.05 (m, 2H), 0.93
(d, J = 6.6 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 165.3, 155.1 (d, J = 308.4 Hz),
(R)-2,8-Dimethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]chroman-6-
yl 4-[(E)-2-Fluoro-2-(phenylsulfonyl)vinyl]benzoate (4h). Purified by
silica gel column chromatography (eluent, 20/1−5/1 petroleum
ether/ethyl acetate). Isolated yield: 56.6 mg, 82% yield. White solid.
Mp: 80−81 °C. 1H NMR (600 MHz, CDCl3): δ 8.18 (d, J = 8.5 Hz,
2H), 8.07−8.00 (m, 2H), 7.76−7.70 (m, 1H), 7.68 (d, J = 8.5 Hz,
2H), 7.65−7.59 (m, 2H), 7.12 (d, J = 34.1 Hz, 1H), 6.79 (d, J = 2.5
Hz, 1H), 6.74 (d, J = 2.6 Hz, 1H), 2.81−2.69 (m, 2H), 2.17 (s, 3H),
1.82 (dt, J = 13.8, 6.9 Hz, 1H), 1.75 (dt, J = 13.3, 6.4 Hz, 1H), 1.59−
146.0, 134.1, 133.6 (d, J = 4.0 Hz), 132.0 (d, J = 1.8 Hz), 130.2,
130.0, 130.0 (d, J = 7.6 Hz), 128.9, 113.9, 75.3, 47.2, 40.9, 34.3, 31.4,
26.6, 23.6, 22.0, 21.8, 20.7, 16.5. 19F NMR (564 MHz, CDCl3): δ
−121.43. FTMS: (APCI) calcd for C26H31FO4S− [M]− 458.19326,
found 458.19244.
(8R,9S,13S,14S)-3-({4-[(E)-2-Fluoro-2-tosylvinyl]phenyl}ethynyl)-
13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta-
[a]phenanthren-17-one (4d). Purified by silica gel column
6990
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
1.32 (m, 8H), 1.31−1.23 (m, 9H), 1.21−1.16 (m, 1H), 1.16−1.10
(m, 3H), 1.09−1.02 (m, 3H), 0.85 (dd, J = 10.0, 6.6 Hz, 12H).
13C{1H} NMR (151 MHz, CDCl3): δ 165.0, 155.1 (d, J = 308.9 Hz),
150.0, 142.5, 137.1, 134.7, 134.1 (d, J = 4.0 Hz), 131.2 (d, J = 1.9
Hz), 130.6, 130.2, 130.1, 129.6, 128.9, 127.5, 121.1, 121.1, 119.0,
114.2, 76.2, 40.2, 39.4, 37.5, 37.4, 37.3, 32.8, 32.7, 31.0, 28.0, 24.8,
24.5, 24.3, 22.7, 22.6, 22.5, 21.0, 19.8, 19.7, 16.2. 19F NMR (564
MHz, CDCl3): δ −120.87. FTMS: (APCI) calcd for C42H55FO5S+
[M+] 690.3749, found 690.3746.
Gram-Scale Experiment. A solution of 1a (4.0 mmol, 760 mg, 1
equiv) and 2b (12 mmol, 2.14 g, 3 equiv) in degassed DMSO (40
mL) was stirred under a nitrogen atmosphere at 100 °C for 24 h.
After completion of the reaction, 100 mL of water was added to the
reaction mixture and the aqueous solution was extracted with ethyl
acetate (5 × 40 mL). The combined organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The pure product was
obtained by flash column chromatography on silica gel (eluent, 20/
1−5/1 petroleum ether/ethyl acetate) to obtain desired product 3ab
in 78% yield (1.02 g).
2-(2-Fluoro-2-tosylethyl)naphthalene (5a). The preparation fol-
lowed literature methods.18 An oven-dried vial equipped with a
PTFE-coated stir bar was charged with tetrahydroxydiboron
[B2(OH)4] (0.4 mmol, 36 mg, 4 equiv) and Pd/C (5 wt %, 0.01
mmol, 21.2 mg). The vial was capped with a septum, degassed, and
backfilled with argon. The vial was charged with 2.0 mL of
dichloromethane followed by 3ab (0.10 mmol, 32.6 mg, 1 equiv)
and 50 μL of water. The mixture was heated at 50 °C for 12 h
(monitored by TLC). The solution was then filtered through a Celite
plug and washed with DCM. The crude product was purified by
column chromatography on silica gel, eluting with ethyl 1/5 (v/v)
acetate/petroleum ether to afford hydrogenated product 5a in 86%
yield (28.2 mg). White solid. Mp: 102−103 °C. 1H NMR (600 MHz,
CDCl3): δ 7.88 (d, J = 8.2 Hz, 2H), 7.83−7.75 (m, 3H), 7.71 (s, 1H),
7.51−7.44 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.4 Hz,
1H), 5.32 (ddd, J = 48.5, 10.5, 2.1 Hz, 1H), 3.67 (ddd, J = 40.1, 15.0,
1.8 Hz, 1H), 3.30 (td, J = 15.6, 10.5 Hz, 1H), 2.47 (s, 3H). 13C{1H}
NMR (151 MHz, CDCl3): δ 146.0, 133.5, 132.6, 132.2, 131.3, 130.1,
129.7, 128.6, 128.4, 127.7, 127.7, 127.1, 126.4, 126.1, 102.8 (d, J =
221.5 Hz), 34.2 (d, J = 19.6 Hz), 21.8. 19F NMR (565 MHz, CDCl3):
δ −177.28. FTMS: (APCI) calcd for C19H16FO2S− [M − H+]
327.0860, found 327.0852.
backfilled with argon, and the reaction mixture was stirred at rt for 16
h (monitored by TLC). After this amount of time, 4 mL of water was
added to the reaction mixture and the aqueous solution was extracted
with ethyl acetate (3 × 4 mL). The combined organic layer was dried
over Na2SO4, filtered, and concentrated in vacuo. The pure product
was obtained by flash column chromatography on silica gel (eluent,
20/1−5/1 petroleum ether/ethyl acetate) to afford desired product
1
5c in 65% yield (28 mg). Yellow solid. Mp: 106−107 °C. H NMR
(600 MHz, CDCl3): δ 8.66 (s, 1H), 8.33 (s, 1H), 8.15 (dd, J = 8.7,
1.6 Hz, 1H), 7.85−7.78 (m, 4H), 7.76 (d, J = 8.7 Hz, 1H), 7.54−7.50
(m, 1H), 7.50−7.47 (m, 1H), 7.21 (d, J = 8.3 Hz, 2H), 6.97 (d, J =
8.2 Hz, 2H), 6.87 (d, J = 8.3 Hz, 2H), 2.36 (s, 3H), 2.19 (s, 3H).
13C{1H} NMR (151 MHz, CDCl3): δ 147.2, 144.3, 136.6, 135.6,
134.47, 134.0, 133.2, 132.8, 130.0, 130.0, 129.7, 129.4, 129.1, 129.0,
128.3, 128.0, 127.9, 127.6, 126.6, 126.4, 21.6, 20.9. FTMS: (APCI)
−
calcd for C26H21O2S2 [M − H+] 429.0988, found 429.0980.
(E)-1-[2-(Naphthalen-2-yl)-1-tosylvinyl]-1H-indole (5d). The
preparation followed literature methods.18 An oven-dried vial
equipped with a PTFE-coated stir bar was charged with 3ab (0.10
mmol, 32.6 mg, 1 equiv), indole (0.12 mmol, 14 mg, 1.2 equiv),
K3PO4 (0.2 mmol, 42.5 mg, 2 equiv), and DMF (2 mL). Then the
reaction mixture was stirred at 60 °C until the reaction was complete
(monitored by TLC). After this time, 4 mL of water was added to the
reaction mixture and the aqueous solution was extracted with ethyl
acetate (3 × 4 mL). The combined organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The pure product was
obtained by flash column chromatography on silica gel (eluent, 10/
1−5/1 petroleum ether/ethyl acetate) to afford desired product 5d in
45% yield (19 mg). Yellow semisolid. 1H NMR (600 MHz, CDCl3): δ
8.29 (s, 1H), 7.63 (dd, J = 12.3, 8.1 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H),
7.47 (d, J = 8.3 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.42−7.39 (m,
1H), 7.08 (d, J = 3.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 2H), 6.99 (dd, J =
11.1, 3.9 Hz, 1H), 6.79 (dd, J = 11.3, 4.0 Hz, 1H), 6.72 (d, J = 2.9 Hz,
1H), 6.59−6.52 (m, 2H), 2.28 (s, 3H). 13C{1H} NMR (151 MHz,
CDCl3): δ 144.8, 136.4, 135.6, 135.5, 134.6, 134.2, 132.8, 132.6,
129.6, 128.8, 128.7, 128.5, 128.5, 128.1, 127.9, 127.8, 127.5, 126.6,
124.9, 122.7, 120.8, 120.7, 110.3, 105.6, 21.5. FTMS: (APCI) calcd
for C27H22NO2S+ [M + H+] 424.1366, found 424.1358.
1,1′-[2-(Naphthalen-2-yl)ethene-1,1-diyl]bis(1H-imidazole) (5e).
The preparation followed literature methods.18 An oven-dried vial
equipped with a PTFE-coated stir bar was charged with 3ab (0.10
mmol, 32.6 mg, 1 equiv), imidazole (0.25 mmol, 17 mg, 2.5 equiv),
K3PO4 (0.3 mmol, 63.7 mg, 3 equiv), and DMF (2 mL). Then the
reaction mixture was stirred at 100 °C until the reaction was complete
(monitored by TLC). After this time, 4 mL of water was added to the
reaction mixture and the aqueous solution was extracted with ethyl
acetate (3 × 4 mL). The combined organic layer was dried over
Na2SO4, filtered, and concentrated in vacuo. The pure product was
obtained by flash column chromatography on silica gel (eluent, 10/
1−3/1 petroleum ether/ethyl acetate) to afford desired product 5e in
(Z)-2-(2-Cyclohexyl-2-fluorovinyl)naphthalene (5b).22 The prep-
aration followed literature methods.17 An oven-dried vial equipped
with a PTFE-coated stir bar was charged with 3ab (0.10 mmol, 32.6
mg, 1 equiv), eosin Y (2.0 mol %, 1.4 mg), and 1-cyclohexyl-2,4,6-
triphenylpyridin-1-ium tetrafluoroborate (0.30 mmol, 143.2 mg, 3
equiv). MeOH (3 mL) and DCE (1 mL) were added, and then the
resulting mixture was degassed by three freeze−thaw cycles and
backfilled with argon. Subsequently, DIPEA (4 equiv) was added, and
the reaction mixture was warmed to room temperature and irradiated
with a green LED for 40 h. After this time, the mixture was diluted
with DCM (15 mL), transferred to a round-bottom flask, and
concentrated in vacuo. A crude product was purified by column
chromatography on silica gel, eluting with petroleum ether to afford
radical-substituted product 5b in 46% yield (11.7 mg). Colorless oil.
1H NMR (600 MHz, CDCl3): δ 7.89 (s, 1H), 7.82−7.75 (m, 3H),
7.64 (dd, J = 8.5, 1.3 Hz, 1H), 7.42 (pd, J = 6.8, 1.2 Hz, 2H), 5.59 (d,
J = 40.7 Hz, 1H), 2.34−2.23 (m, 1H), 2.04−1.96 (m, 2H), 1.88−1.81
(m, 2H), 1.76−1.69 (m, 1H), 1.43−1.36 (m, 2H), 1.35−1.29 (m,
2H), 1.25−1.20 (m, 1H). 13C{1H} NMR (151 MHz, CDCl3): δ 165.5
(d, J = 268.6 Hz), 133.5, 132.2, 131.6 (d, J = 1.7 Hz), 127.9, 127.8,
127.5, 127.0 (d, J = 7.4 Hz), 126.7 (d, J = 7.6 Hz), 126.0, 125.6, 103.7
(d, J = 8.8 Hz), 41.6 (d, J = 24.3 Hz), 30.1 (d, J = 1.7 Hz), 26.0, 25.9.
19F NMR (565 MHz, CDCl3): δ −104.60. FTMS: (APCI) calcd for
C18H18F− [M − H+] 253.1398, found 253.1393.
1
71% yield (20.3 mg). Yellow oil. H NMR (600 MHz, CDCl3): δ
7.91−7.83 (m, 2H), 7.80 (dd, J = 5.9, 2.5 Hz, 1H), 7.59 (s, 1H),
7.57−7.51 (m, 3H), 7.44 (s, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.35 (s,
1H), 7.03 (s, 1H), 6.97 (s, 1H), 6.31 (s, 1H). 13C{1H} NMR (151
MHz, CDCl3): δ 137.8, 137.5, 133.7, 133.1, 131.8, 131.2, 130.9,
129.2, 128.4, 127.8, 127.4, 127.2, 126.6, 125.6, 122.4, 119.7, 118.5,
+
117.6. FTMS: (APCI) calcd for C18H15N4 [M + H+] 287.1291,
found 287.1287.
Procedure for Control Experiments (Scheme 4, eq 1). A
solution of gem-difluoroalkene 1a (0.1 mmol, 19 mg, 1 equiv), sodium
benzenesulfinate 2b (0.3 mmol, 53.5 mg, 3 equiv), and additive (2
equiv) in degassed DMSO (1.0 mL) was stirred under a nitrogen
atmosphere at 100 °C for 24 h. After completion of the reaction, 2 mL
of water was added to the reaction mixture and the aqueous solution
was extracted with ethyl acetate (3 × 4 mL). The combined organic
layer was dried over Na2SO4, filtered, and concentrated in vacuo. The
pure product was obtained by flash column chromatography on silica
gel (eluent, 20/1−5/1 petroleum ether/ethyl acetate) to afford
desired product 3ab.
(E)-[2-(Naphthalen-2-yl)-1-tosylvinyl](p-tolyl)sulfane (5c). An
oven-dried vial equipped with a PTFE-coated stir bar was charged
with 3ab (0.10 mmol, 32.6 mg, 1 equiv) and sodium 4-
methylbenzenethiolate (0.20 mmol, 29.2 mg, 2 equiv). DMSO (1
mL) was added; then the resulting mixture was degassed and
6991
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Procedure for the Competition Experiment (Scheme 4, eq
2). A solution of gem-difluoroalkene 1a (0.1 mmol, 19 mg, 1 equiv),
sodium benzenesulfinate 2c (0.15 mmol, 29.1 mg, 1.5 equiv), and 2h
(0.15 mmol, 33.3 mg, 1.5 equiv) in degassed DMSO (1.0 mL) was
stirred under a nitrogen atmosphere at 100 °C for 3 h. After
completion of the reaction, 2 mL of water was added to the reaction
mixture and the aqueous solution was extracted with ethyl acetate (3
× 4 mL). The combined organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo. The pure product was obtained by
flash column chromatography on silica gel (eluent, 10/1−3/1
petroleum ether/ethyl acetate) to afford desired products 3ac and
3ah.
also appreciated. Haiyan Sui and Xiaoju Li from Shangdong
University Core Facilities for Life and Environmental Sciences
are thanked for their help with the NMR experiments. The
authors thank Dr. Zemin Wang, Dr. Zhong Zhang, Dr. Ruihua
Liu, Dr. Ping Chen, and Xiaoling Shi for kind suggestions.
REFERENCES
■
(1) (a) Palmer, J. T.; Rasnick, D.; Klaus, J. L.; Bromme, D. Vinyl
sulfones as mechanism-based cysteine protease inhibitors. J. Med.
Chem. 1995, 38, 3193−3196. (b) Kondo, T.; Mitsudo, T.-a. Metal-
catalyzed carbon-sulfur bond formation. Chem. Rev. 2000, 100, 3205−
3220. (c) Meadows, D. C.; Gervay-Hague, J. Vinyl sulfones: synthetic
preparations and medicinal chemistry applications. Med. Res. Rev.
2006, 26, 793−814. (d) Kisselev, A. F.; van der Linden, W. A.;
Overkleeft, H. S. Proteasome inhibitors: an expanding army attacking
a unique target. Chem. Biol. 2012, 19, 99−115. (e) Frankel, B. A.;
Bentley, M.; Kruger, R. G.; McCafferty, D. G. Vinyl sulfones:
inhibitors of SrtA, a transpeptidase required for cell wall protein
anchoring and virulence in Staphylococcus aureus. J. Am. Chem. Soc.
2004, 126, 3404−3405.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00490.
■
sı
Detailed optimization of reaction conditions, some of
1
the mechanistic studies, and copies of H, 13C{1H}, and
19F NMR spectra for new compounds (PDF)
(2) (a) McCarthy, J. R.; Matthews, D. P.; Edwards, M. L.; Stemerick,
D. M.; Jarvi, E. T. A new route to vinyl fluorides. Tetrahedron Lett.
1990, 31, 5449−5452. (b) He, M.; Ghosh, A. K.; Zajc, B. Julia
Olefination as a General Route to Phenyl (α-Fluoro)vinyl Sulfones.
Synlett 2008, 19, 999−1004. (c) Shastin, A. V.; Nenajdenko, V. G.;
Muzalevskiy, V. M.; Balenkova, E. S.; Fröhlich, R.; Haufe, G. New
synthetic approach to α-fluoro-β-arylvinyl sulfones and their
application in Diels−Alder reactions. Tetrahedron 2008, 64, 9725−
9732. (d) Prakash, G. K.; Chacko, S.; Vaghoo, H.; Shao, N.; Gurung,
L.; Mathew, T.; Olah, G. A. Efficient nucleophilic fluoromethylation
and subsequent transformation of alkyl and benzyl halides using
fluorobis(phenylsulfonyl)methane. Org. Lett. 2009, 11, 1127−1130.
(e) Yamada, S.; Shimoji, K.; Takahashi, T.; Konno, T.; Ishihara, T. An
effective preparation of sulfonyl- or sulfinyl-substituted fluorinated
alkenes and their stereoselective addition-elimination reactions with
organocuprates. Chem. - Asian J. 2010, 5, 1846−1853. (f) Zhu, L.; Ni,
C.; Zhao, Y.; Hu, J. 1-tert-Butyl-1H-tetrazol-5-yl fluoromethyl sulfone
(TBTSO2CH2F): a versatile fluoromethylidene synthon and its use in
the synthesis of monofluorinated alkenes via Julia−Kocienski
olefination. Tetrahedron 2010, 66, 5089−5100. (g) Li, W.; Yin, Y.;
Yao, H.; Shuai, W.; Sun, H.; Xu, S.; Liu, J.; Yao, H.; Zhu, Z.; Xu, J.
Discovery of novel vinyl sulfone derivatives as anti-tumor agents with
microtubule polymerization inhibitory and vascular disrupting
activities. Eur. J. Med. Chem. 2018, 157, 1068−1080. (h) Fang, X.;
Zhou, J.; Wang, W.; Yang, X.; Wu, F. Highly stereoselective
monofluoroolefination: Facile access to (E)-α-fluorinated arylvinyl
sulfones from trifluoromethyl α-fluorinated arylsulfonyl gem-diols.
Tetrahedron Lett. 2020, 61, 151964.
AUTHOR INFORMATION
Corresponding Author
■
Dayong Shi − State Key Laboratory of Microbial Technology
and Marine Biotechnology Research Center, Shandong
University, Qingdao 266237, Shandong, P. R. China;
Laboratory for Marine Biology and Biotechnology, Pilot
National Laboratory for Marine Science and Technology,
Qingdao 266237, Shandong, P. R. China;
Email: shidayong@sdu.edu.cn
Authors
Yuxiu Li − State Key Laboratory of Microbial Technology and
Marine Biotechnology Research Center, Shandong University,
Qingdao 266237, Shandong, P. R. China; orcid.org/
0000-0002-5185-7501
Xiangqian Li − State Key Laboratory of Microbial Technology
and Marine Biotechnology Research Center, Shandong
University, Qingdao 266237, Shandong, P. R. China
Xiaowei Li − State Key Laboratory of Microbial Technology
and Marine Biotechnology Research Center, Shandong
University, Qingdao 266237, Shandong, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00490
Author Contributions
(3) (a) Muller, K.; Faeh, C.; Diederich, F. Fluorine in
Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317,
1881−1886. (b) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur,
V. Fluorine in medicinal chemistry. Chem. Soc. Rev. 2008, 37, 320−
330. (c) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;
Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in
pharmaceutical industry: fluorine-containing drugs introduced to the
market in the last decade (2001−2011). Chem. Rev. 2014, 114, 2432−
2506. (d) Preshlock, S.; Tredwell, M.; Gouverneur, V. 18F-Labeling of
Arenes and Heteroarenes for Applications in Positron Emission
Tomography. Chem. Rev. 2016, 116, 719−766. (e) Meanwell, N. A.
Fluorine and Fluorinated Motifs in the Design and Application of
Bioisosteres for Drug Design. J. Med. Chem. 2018, 61, 5822−5880.
(f) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok,
V. A.; Coelho, J. A. S.; Toste, F. D. Modern Approaches for
Asymmetric Construction of Carbon-Fluorine Quaternary Stereo-
genic Centers: Synthetic Challenges and Pharmaceutical Needs.
Chem. Rev. 2018, 118, 3887−3964. (g) Johnson, B. M.; Shu, Y. Z.;
Zhuo, X.; Meanwell, N. A. Metabolic and Pharmaceutical Aspects of
Fluorinated Compounds. J. Med. Chem. 2020, 63, 6315−6386.
Y.L. and D.S. conceived the project. Y.L., X.W.L., and X.Q.L.
performed the experiments, analyzed the data, and discussed
the results. Y.L. and D.S. wrote the paper. Y.L., X.W.L., and
X.Q.L. wrote the Supporting Information and contributed
other related materials.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by the National Program for Support of
Top-notch Young Professionals, the Fund of Taishan scholar
project, the Shandong Provincial Natural Science Foundation
for Distinguished Young Scholars (JQ201722), the Qingdao
Science and Technology Benefit People Demonstration Guide
Special Project (20-3-4-20 nsh), and the Fundamental
Research Funds of Shandong University (2020GN033). The
Postdoctoral Science Foundation of China (2019M662377) is
6992
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(4) (a) Mei, H.; Han, J.; Fustero, S.; Medio-Simon, M.; Sedgwick, D.
M.; Santi, C.; Ruzziconi, R.; Soloshonok, V. A. Fluorine-Containing
Drugs Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25,
11797−11819. (b) Mullard, A. 2018 FDA drug approvals. Nat. Rev.
Drug Discovery 2019, 18, 85−89. (c) Mei, H.; Remete, A. M.; Zou, Y.;
Moriwaki, H.; Fustero, S.; Kiss, L.; Soloshonok, V. A.; Han, J.
Fluorine-containing drugs approved by the FDA in 2019. Chin. Chem.
Lett. 2020, 31, 2401−2413.
(5) (a) Amii, H.; Uneyama, K. C-F bond activation in organic
synthesis. Chem. Rev. 2009, 109, 2119−2183. (b) Clot, E.; Eisenstein,
O.; Jasim, N.; Macgregor, S. A.; McGrady, J. E.; Perutz, R. N. C−F
and C−H Bond Activation of Fluorobenzenes and Fluoropyridines at
Transition Metal Centers: How Fluorine Tips the Scales. Acc. Chem.
Res. 2011, 44, 333−348. (c) Stahl, T.; Klare, H. F. T.; Oestreich, M.
Main-Group Lewis Acids for C−F Bond Activation. ACS Catal. 2013,
3, 1578−1587. (d) Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T.
Functionalization of fluorinated molecules by transition-metal-
mediated C-F bond activation to access fluorinated building blocks.
Chem. Rev. 2015, 115, 931−972. (e) Eisenstein, O.; Milani, J.; Perutz,
R. N. Selectivity of C-H Activation and Competition between C-H
and C-F Bond Activation at Fluorocarbons. Chem. Rev. 2017, 117,
8710−8753. (f) Coates, G.; Rekhroukh, F.; Crimmin, M. R. Breaking
Carbon−Fluorine Bonds with Main Group Nucleophiles. Synlett
2019, 30, 2233−2246.
(6) (a) Landelle, G.; Bergeron, M.; Turcotte-Savard, M. O.; Paquin,
J. F. Synthetic approaches to monofluoroalkenes. Chem. Soc. Rev.
2011, 40, 2867−2908. (b) Chelucci, G. Synthesis and metal-catalyzed
reactions of gem-dihalovinyl systems. Chem. Rev. 2012, 112, 1344−
1462. (c) Kuehnel, M. F.; Lentz, D.; Braun, T. Synthesis of
fluorinated building blocks by transition-metal-mediated hydro-
defluorination reactions. Angew. Chem., Int. Ed. 2013, 52, 3328−
3348. (d) Liu, Q.; Ni, C.; Hu, J. China’s flourishing synthetic
organofluorine chemistry: innovations in the new millennium. Natl.
Sci. Rev. 2017, 4, 303−325. (e) Orsi, D. L.; Altman, R. A. Exploiting
the unusual effects of fluorine in methodology. Chem. Commun. 2017,
53, 7168−7181. (f) Zhang, X.; Cao, S. Recent advances in the
synthesis and CF functionalization of gem-difluoroalkenes. Tetrahe-
dron Lett. 2017, 58, 375−392. (g) Fujita, T.; Fuchibe, K.; Ichikawa, J.
Transition-Metal-Mediated and -Catalyzed C-F Bond Activation by
Fluorine Elimination. Angew. Chem., Int. Ed. 2019, 58, 390−402.
(7) Jiang, L.-F.; Ren, B.-T.; Li, B.; Zhang, G.-Y.; Peng, Y.; Guan, Z.-
Y.; Deng, Q.-H. Nucleophilic Substitution of gem-Difluoroalkenes
with TMSNu Promoted by Catalytic Amounts of Cs2CO3. J. Org.
Chem. 2019, 84, 6557−6564.
(15) (a) Koch, H. F.; Kielbania, A. J. Nucleophilic reactions of
fluoroolefins. Evidence for a carbanion intermediate in vinyl and allyl
displacement reactions. J. Am. Chem. Soc. 1970, 92, 729−730.
(b) Kim, M. S.; Jeong, I. H. A highly stereoselective preparation of
CF3-substituted 1-aryl-1,2-diphenylethenes: application to the syn-
thesis of panomifene. Tetrahedron Lett. 2005, 46, 3545−3548.
(c) Zhang, J.; Xu, C.; Wu, W.; Cao, S. Mild and Copper-Free
Stereoselective Cyanation of gem-Difluoroalkenes by Using Benzyl
Nitrile as a Cyanating Reagent. Chem. - Eur. J. 2016, 22, 9902−9908.
(16) Cummings, S. P.; Le, T. N.; Fernandez, G. E.; Quiambao, L. G.;
Stokes, B. J. Tetrahydroxydiboron-Mediated Palladium-Catalyzed
Transfer Hydrogenation and Deuteriation of Alkenes and Alkynes
Using Water as the Stoichiometric H or D Atom Donor. J. Am. Chem.
Soc. 2016, 138, 6107−6110.
(17) Ociepa, M.; Turkowska, J.; Gryko, D. Redox-Activated Amines
in C(sp3)−C(sp) and C(sp3)−C(sp2) Bond Formation Enabled by
Metal-Free Photoredox Catalysis. ACS Catal. 2018, 8, 11362−11367.
(18) Ma, T.; Chen, Y.; Li, Y.; Ping, Y.; Kong, W. Nickel-Catalyzed
Enantioselective Reductive Aryl Fluoroalkenylation of Alkenes. ACS
Catal. 2019, 9, 9127−9133.
(19) (a) Hu, J.; Han, X.; Yuan, Y.; Shi, Z. Stereoselective Synthesis
of Z Fluoroalkenes through Copper-Catalyzed Hydrodefluorination of
gem-Difluoroalkenes with Water. Angew. Chem., Int. Ed. 2017, 56,
13342−13346. (b) Krishnamoorthy, S.; Kothandaraman, J.; Saldana,
J.; Prakash, G. K. S. Direct Difluoromethylenation of Carbonyl
Compounds by Using TMSCF3: The Right Conditions. Eur. J. Org.
Chem. 2016, 2016, 4965−4969. (c) Thomoson, C. S.; Martinez, H.;
Dolbier, W. R. The use of methyl 2,2-difluoro-2-(fluorosulfonyl)-
acetate as the difluorocarbene source to generate an in situ source of
difluoromethylene triphenylphosphonium ylide. J. Fluorine Chem.
2013, 150, 53−59.
(20) Cabrera-Afonso, M. J.; Lu, Z. P.; Kelly, C. B.; Lang, S. B.;
Dykstra, R.; Gutierrez, O.; Molander, G. A. Engaging sulfinate salts via
Ni/photoredox dual catalysis enables facile Csp2-SO2R coupling.
Chem. Sci. 2018, 9, 3186−3191.
(21) Frost, A. B.; Brambilla, M.; Exner, R. M.; Tredwell, M.
Synthesis and Derivatization of 1,1-[18F]Difluorinated Alkenes.
Angew. Chem., Int. Ed. 2019, 58, 472−476.
(22) Zhao, Y.; Jiang, F.; Hu, J. Spontaneous resolution of Julia-
Kocienski intermediates facilitates phase separation to produce Z- and
E-monofluoroalkenes. J. Am. Chem. Soc. 2015, 137, 5199−5203.
(8) Wang, M.; Liang, F.; Xiong, Y.; Cao, S. Synthesis of fluorovinyl
aryl ethers by a three-component reaction of gem-difluoroalkenes with
arylboronic acids and oxygen. RSC Adv. 2015, 5, 11996−11999.
(9) Xiong, Y.; Zhang, X.; Huang, T.; Cao, S. Synthesis of N-(α-
fluorovinyl)azoles by the reaction of difluoroalkenes with azoles. J.
Org. Chem. 2014, 79, 6395−6402.
(10) Sakaguchi, H.; Uetake, Y.; Ohashi, M.; Niwa, T.; Ogoshi, S.;
Hosoya, T. Copper-Catalyzed Regioselective Monodefluoroborylation
of Polyfluoroalkenes en Route to Diverse Fluoroalkenes. J. Am. Chem.
Soc. 2017, 139, 12855−12862.
(11) Tan, D.-H.; Lin, E.; Ji, W.-W.; Zeng, Y.-F.; Fan, W.-X.; Li, Q.;
Gao, H.; Wang, H. Copper-Catalyzed Stereoselective Defluorinative
Borylation and Silylation of gem-Difluoroalkenes. Adv. Synth. Catal.
2018, 360, 1032−1037.
(12) Cong, Z. S.; Li, Y. G.; Chen, L.; Xing, F.; Du, G. F.; Gu, C. Z.;
He, L. N-Heterocyclic carbene-catalyzed stereoselective construction
of olefinic carbon-sulfur bonds via cross-coupling reaction of gem-
difluoroalkenes and thiols. Org. Biomol. Chem. 2017, 15, 3863−3868.
(13) Peng, Y.; Zhang, X.; Qi, X.; He, Q.; Zhang, B.; Hao, J.; Yang, C.
Metal-Free Access to (E/Z)-α-Fluorovinyl Phosphorus Compounds
from gem-Difluorostyrenes. Eur. J. Org. Chem. 2019, 2019, 1170−
1177.
(14) Li, Y.; Li, X.; Li, X.; Shi, D. Visible-light-promoted E-selective
synthesis of alpha-fluoro-beta-arylalkenyl sulfides via the deoxygena-
tion/isomerization process. Chem. Commun. 2021, 57, 2152−2155.
6993
https://doi.org/10.1021/acs.joc.1c00490
J. Org. Chem. 2021, 86, 6983−6993