Electrochemical Radical δ-H Sulfonylation Reaction for the Synthesis of 4-((Aryl,Arylsul fonyl)methylene)-2,5-Cyclohexadiene Derivatives

Article abstract of DOI:10.1021/acs.joc.1c01213

A novel and efficient electrochemical radical δ-H sulfonylation reaction of para-quinone methides (p-QMs) and sodium sulfinates has been achieved under common laboratory conditions. In this strategy, a new C(sp2)-S bond was constructed for the synthesis of 4-((aryl,arylsulfonyl)methylene)-2,5-cyclohexadiene derivatives with a broad substrate scope, good functional group tolerance, and mild conditions. Further studies showed that the reaction had an excellent regional selectivity.

Full text of DOI:10.1021/acs.joc.1c01213

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Article
Electrochemical Radical δ‑H Sulfonylation Reaction for the Synthesis
of 4‑((Aryl,Arylsul fonyl)methylene)-2,5-Cyclohexadiene Derivatives
Lei Dai, Qiuyu Yu, Jinghang Zhang, Fan Wu, Chang Wang,* Jinpeng Zhang,* and Liangce Rong*
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sı Supporting Information
ABSTRACT: A novel and efficient electrochemical radical δ-H
sulfonylation reaction of para-quinone methides (p-QMs) and sodium
sulfinates has been achieved under common laboratory conditions. In
2
this strategy, a new C(sp )−S bond was constructed for the synthesis of
4
-((aryl,arylsulfonyl)methylene)-2,5-cyclohexadiene derivatives with a
broad substrate scope, good functional group tolerance, and mild
conditions. Further studies showed that the reaction had an excellent
regional selectivity.
INTRODUCTION
and these kinds of reactions are well developed (Scheme 1,
previous work a). Second, many examples have been reported
about p-QMs involving in 1,6-addition−dearomatization
■
Sulfone derivatives widely exist in a number of bioactive
natural products and pharmaceuticals with various activities.
For instance, intepirdine, PVT-101, could be used to treat
14
reactions (Scheme 1, previous work b). Third, the radical
1
mode 1,6-addition reactions of p-QMs were also reported by
Alzheimer’s disease. The indole skeleton containing a
15
a few research groups (Scheme 1, previous work c).
sulfone moiety (K103N−Y181C 150) is an important anti-
2
Recently, the reactions of p-QMs with some sulfonation
HIV drug. Vismodegib was a recently approved antitumor
16
17
18
3
reagents (ArSO
give corresponding products with a sulfone moiety (except
for CF SO Na) have been reported by the different
2 3 2 2 2
Na, CF SO Na, and ArSO NHNH ) to
drug. Bicalutamide is always used in treatment of prostate
4
cancer (Figure 1). Consequently, chemists have paid much
5
3
2
attention to the synthesis of sulfone compounds.
researchers; however, they were still the 1,6-conjugate
addition reaction.
In recent years, organic electrosynthesis has been widely
used in organic synthesis to give compounds with molecular
19
diversity. For instance, some vinyl sulfones derivatives were
2
0
availably obtained via electrochemical synthesis. As a part of
2
1
our current study on the reactions of p-QMs, herein, we
developed an electrochemical radical δ-H sulfonylation
reaction of p-QMs and sodium sulfinates to furnish 4-
(
(
(aryl,arylsulfonyl)methylene)-2,5-cyclohexadiene derivatives
Scheme 1, this work).
RESULTS AND DISCUSSION
■
In order to achieve our assumption, we commenced the study
by investigating the electrochemical reaction of 2,6-ditert-
butyl-4-(2-methylbenzylidene)cyclohexa-2,5-dien-1-one 1a
and sodium benzenesulfinate 2a (Table 1) in the presence
of platinum plate as a cathode, the reticulated vitreous carbon
Figure 1. Bioactive compounds with a sulfone moiety.
para-Quinone methide (p-QM) derivatives are the
significant structural motifs present in many naturally
6
occurring compounds with important biological activities,7
Received: May 24, 2021
Published: July 22, 2021
which were extensively used in lignin biosynthesis,
10
8
9
adrenergic receptors, enzyme inhibition, DNA alkylation,
11
and cross-linking reactions. In general , p-QMs are well
applied to organic synthesis with the three main approaches.
First, p-QMs, as versatile Michael acceptors, are unique
12
13
feedstocks for 1,6-addition and 1,6-addition cyclization,
©
2021 American Chemical Society
https://doi.org/10.1021/acs.joc.1c01213
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Scheme 1. Previous Work and the Current Reaction
(
RVC) as a anode, along with NaI (2 equiv) as a additive in
group. For instance, we clearly found that the yields of the p-
QMs with 2-Me or 2-MeO groups are better than that of 2-
Cl group (3a 89% and 3b 85% vs 3c 74%). The p-QMs with
para-substituents have the similar reaction results (3d, 3f, 3g
vs 3e, 3h). It also found when the number of electron-
donoring groups in p-QMs increased to 2 and 3, and the
yields of the reaction improved significantly (3i−3l). Next,
we studied the reactions of sodium 4-methylbenzenesulfinate
with p-QMs bearing different substituted groups, and
corresponding products (3m−3p) could be obtained with
good yields. In particular, the yields of the reaction increased
significantly when electron-donating groups were both
available on p-QMs and sodium sulfinate (3o, 3p).
Subsequently, other electron-donating groups (MeO, t-Bu)
on sodium phenyl sulfinate could give similar results of
sodium 4-methylbenzenesulfinate, in which both electron-
withdrawing and electron-donating groups of p-QMs were
well tolerated in the reaction condition to afford the
corresponding products (3q−3aa) with high yields. We
further investigated the reactions of sodium sulfinate with the
halogen atom group (F, Cl). It was found that the reactions
were worse than that of sodium benzensulfinate (3ab−3ah).
The sodium sulfinate with the strong electron-withdrawing
group (CF , NO ) could also be used in this synthesis
CH CN at room temperature under 10 mA current for 3 h.
Pleasurably, the desired product 3a was obtained in 26%
yield (Table 1, entry 1). Then, other additives, such as KI,
NH I, TBAI, and LiI, were tested in the reaction, but they all
showed poor performance (Table 1, entries 2−5). Addition-
ally, compared with CH CN, other aprotic solvents were not
suitable for this reaction (Table 1, entries 6−8). To our
delight, the reaction was significantly improved in the mixed
solvents of CH CN and H O (entry 9), which prompted us
to further investigate the reaction in different ratios of mixed
solvents (entries 10−15). The results showed that the highest
yield was obtained when the volume ratio of acetonitrile to
water was 4:0.25 (entry 14). The amounts of NaI, constant
current, and reaction time were all carefully screened (entries
3
4
3
3
2
1
6−23), which showed 2 equiv of NaI, a 5 mA current, and 3
h reaction time were sufficient to ensure the successful
completion of the reaction. In addition, it was found that,
when the reaction was carried out under a N condition
2
(Table 1, entry 24), the yield of the reaction did not change
much. The results were summarized in Table 1.
Under the optimized conditions, the reaction scope about
the p-QMs and the sodium sulfinates was examined carefully
(Table 2). At first, the reaction of various substituted p-QMs
3
2
and sodium benzensulfinate was tested under optimized
conditions. In general, the yields of the electron-donating
groups (Me, MeO) on the ortho-substituted phenol ring of p-
QMs were better than that of electron-withdrawing (Cl)
strategy (3ai, 3aj), and sodium 2-naphthalenesulfinate was
the efficient sulfonated reagent to give product 3ak with 83%
yield. As the isopropyl replaced the tertiary butyl in p-QMs,
the reactions were carried out smoothly to give correspond-
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a
Table 1. Screening of the Reaction Conditions
b
entry
additive
solvent
current (mA)
time (h)
yield (% )
1
2
3
4
5
6
7
8
9
NaI (2 equiv)
KI (2 equiv)
CH CN
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
5
20
5
5
5
0
5
5
5
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
4
5
4
26
15
10
trace
20
5
3
CH CN
3
NH I (2 equiv)
CH CN
4
3
TBAI (2 equiv)
LiI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (1 equiv)
NaI (3 equiv)
CH CN
3
CH CN
3
DMSO
THF
toluene
10
trace
38
41
53
60
71
80
52
89
60
42
87
CH CN/H O (1:1)
3
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH CN/H O (2:1)
3 2
CH CN/H O (3:1)
3
2
CH CN/H O (4:1)
3
2
CH CN/H O (4:0.5)
3
2
CH CN/H O (4:0.25)
3
2
CH CN/H O (4:0.1)
3
2
CH CN/H O (4:0.25)
3
2
CH CN/H O (4:0.25)
3
2
CH CN/H O (4:0.25)
3
2
CH CN/H O (4:0.25)
3
2
c
CH CN/H O (4:0.25)
NR
3
2
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
NaI (2 equiv)
CH CN/H O (4:0.25)
NR
88
3
2
CH CN/H O (4:0.25)
3
2
CH CN/H O (4:0.25)
87
85
3
2
d
CH CN/H O (4:0.25)
3
2
a
Undivided cell, RVC anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt cathode (1 cm × 1 cm), constant current at 5.0 mA, 1a (0.3 mmol), 2a (0.6
b
c
d
mmol), additive (2.0 equiv), solvent (4−4.25 mL), room temperature, under air. Isolated yield. No reaction. In N .
2
ing products (3al−3ap) with good yields. In addition, the
structure of product was confirmed by the X-crystal
diffraction analysis of 3l. The results were listed in Table 2.
In order to further study this synthesis, we designed
substrate 1′ to investigate the regioselectivity of the reaction.
It could be found that the reactions were still taken place at
the original alkene position, rather than the allyl (4a−4h)
and alkyne bond (4i, 4j), which indicated this electro-
chemical radical δ-H sulfonylation reaction had the high
regioselectivity. The obtained crystal structure 4a further
confirmed this result (Table 3).
Then, a series of control experiments was performed to
study the mechanism. Compounds 1b and 2a were carried
out under standard conditions with TEMPO (2 equiv), and
the trace 2b could be found. While BHT (2 equiv) was used
in the experiment, the reaction was completely inhibited, and
the radical capture product 5 was obtained, which confirmed
that this reaction was a radical pathway. In addition, the good
yield could still be obtained after the substrates were
elemental iodine and participated in the reaction cycle
again. Subsequently, B reacted with p-QMs 1 produce radical
intermediate C, which loses an electron to the current to give
intermediate D. Under the help of iodide, the desired product
+
+
3 could be obtained by elimination of a H , and then the H
participated in the reduction reaction on the cathode with
H O to release H .
2
2
CONCLUSION
■
In summary, a novel electrochemical radical δ-H sulfonylation
reaction of p-QMs and sodium arlysulfinate has been well
established with the assistance of NaI under mild conditions.
A wide range of substrates are tolerated in this trans-
formation, and various products can be obtained in moderate
to good yields. To the best of our knowledge, this is the first
example of a radical reaction about p-QMs and sodium
sulfinates.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents were
purchased from commercial suppliers without further purification.
All reactions were carried out under air conditions using IKA
■
increased 10-fold. The reactions were shown in Scheme 2.2
0
On the basis of the above results and reported literature,
the possible electrochemical pathways was given in Scheme 3.
Initially, iodine is oxidized at the anode to obtain elemental
iodine, which reacted with sodium sulfinate to form sulfonyl
iodide A. Then, radical B and iodine radical were generated
by the homolysis of A. The iodine radical generated
14,22
ElectraSyn 2.0 Pro with undivided cell. para-Quinone methides
23
and sodium sulfinates were synthesized according to known
literature procedures. Melting points were determined on an XT-5
microscopic melting point apparatus and were uncorrected. NMR
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a
Table 2. Substrate Scope of the p-QMs and Sodium Sulfinate
a
Reaction conditions: undivided cell, RVC anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt cathode (1 cm × 1 cm), constant current at 5.0 mA, 1a (0.3
b
mmol), 2a (0.6 mmol), NaI (2.0 equiv), CH CH/H O = 4:0.25 (4.25 mL), room temperature, 3−4 h (monitored by TLC), under air. Isolated
yield.
3
2
1
spectra were recorded on a Bruker 400 spectrometer ( H, 400 MHz;
mmol, 2 equiv), NaI (0.6 mmol, 2 equiv), and mixed solvents (4.25
mL, CH CN/H O = 4:0.25) were added in a reaction tube
13
C, 100 MHz). Chemical shifts were reported in ppm downfield
3
2
1
and referenced as follows: H, residual internal CDCl3 (δ 7.31
equipped with a reticulated vitreous carbon RVC (100 PPI, 1 cm ×
1 cm × 1.2 cm) anode and a platinum plate (1 cm × 1 cm)
cathode. The reaction was stirred at 5 mA under room temperature
about 3−4 h until TLC revealed the absence of the starting material.
Then the reaction was quenched by brine (10 mL), and the
resultant mixture was extracted with EtOAc (3 × 5 mL). The
combined extracts were washed sequentially with water (10 mL)
ppm); 13C, internal CDCl (δ 77.23 ppm). Coupling constants (J)
3
were quoted in hertz (Hz). The following abbreviations were used
to explain the multiplicities: s (singlet), d (doublet), t (triplet), q
quartet), m (multiplet). HRMS was obtained on a Bruker
micrOTOF-Q 134 instrument; X-ray diffractions were recorded on
a Siemens P4 or Simart-1000 diffractometer. All the reactions were
monitored by thin-layer chromatography (TLC). Flash chromatog-
raphy separations were performed on 300−400 mesh silica gel.
General Procedure for the Synthesis of 3 and 4. para-
Quinone methides 1 or 1′ (0.3 mmol), sodium sulfinates 2 (0.6
(
and brine (10 mL) and dried over NaSO . The extract was
4
concentrated under reduced pressure, and the residue was purified
by flash column chromatography (petroleum ether/EtOAc = 10:1−
40:1) to yield the corresponding product 3 and 4.
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a
Table 3. Substrate Scope of the Allyl p-QMs and Sodium Sulfinate
a
Reaction conditions: undivided cell, RVC anode (100 PPI, 1 cm × 1 cm × 1.2 cm), Pt cathode (1 cm × 1 cm), constant current at 5.0 mA, 1a (0.3
b
mmol), 2a (0.6 mmol), NaI (2.0 equiv), CH CH/H O = 4:0.25 (4.25 mL), room temperature, 3−4 h (monitored by TLC), under air. Isolated
yield.
3
2
1
General Procedure for Radical Trapping Reaction. para-
Quinone methide 1b (0.3 mmol), sodium sulfinates 2a (0.6 mmol),
sodium iodide (2 equiv, 90 mg), BHT (0.6 mmol, 132 mg), and
mixed solvent CH CN/H O (v/v = 4:0.25, 4.25 mL) were added in
152−153 °C; H NMR (400 MHz, CDCl ) (δ, ppm): 8.51 (d, J =
3
2.8 Hz, 1H), 7.75−7.71 (m, 2H), 7.55−7.51 (m, 1H), 7.43−7.38
(m, 2H), 7.38−7.34 (m, 1H), 7.21 (dd, J = 7.6 Hz, J = 1.6 Hz,
1
2
1H), 7.02−6.98 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.45 (d, J = 2.4
3
2
Hz, 1H), 3.53 (s, 3H), 1.33 (s, 9H), 1.06 (s, 9H). 1 C{ H} NMR
3
1
a reaction flask. The reaction flask was equipped with an RVC
3
electrode (1.0 × 1.0 × 1.2 cm ) as an anode and a Pt electrode as a
(100 MHz, CDCl ) (δ, ppm): 186.3, 157.4, 151.1, 150.6, 145.6,
140.8, 136.5, 133.3, 132.3, 131.6, 130.8, 128.5, 128.4, 126.5, 121.4,
3
2
cathode (1.0 × 1.0 cm ). The solution was stirred and electrolyzed
at a constant current (5 mA) without a reference electrode for 4 h
at room temperature, and the radical capture product 5 was
obtained.
120.4, 110.6, 55.3, 36.0, 35.5, 29.7, 29.3. HRMS (ESI-TOF): m/z
+
+
calcd for C H NaO S , 487.1919; found [M + Na] , 487.1923.
2
8
32
4
2,6-Di-tert-butyl-4-((2-chlorophenyl)(phenylsulfonyl)methylene)-
cyclohexa-2,5-dien-1-one (3c). Yellow solid. Isolated yield: 74%
2
,6-Di-tert-butyl-4-((phenylsulfonyl)(o-tolyl)methylene)-
cyclohexa-2,5-dien-1-one (3a). Yellow solid. Isolated yield: 89%
(104 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 137−138
1
(
120 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 130−131
°C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.62 (d, J = 2.4 Hz,
3
1
°C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.70 (d, J = 2.8 Hz,
1H), 7.74−7.71 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0
3
1
7
6
H), 7.70−7.66 (m, 2H), 7.61−7.55 (m, 1H), 7.47−7.41 (m, 2H),
Hz, 2H), 7.39−7.36 (m, 1H), 7.36−7.30 (m, 3H), 6.31 (d, J = 2.8
1
3
1
.31−7.27 (m, 1H), 7.18−7.12 (m, 2H), 6.97 (d, J = 6.8 Hz, 1H),
Hz, 1H), 1.36 (s, 9H), 1.06 (s, 9H). C{ H} NMR (100 MHz,
.32 (d, J = 2.4 Hz, 1H), 1.98 (s, 3H), 1.37 (s, 9H), 1.03 (s, 9H).
CDCl ) (δ, ppm): 186.1, 152.1, 151.5, 144.2, 139.9, 137.3, 135.2,
3
1
3
1
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.1, 151.9, 151.1,
133.8, 132.9, 131.6, 131.1, 130.1, 129.5, 128.9, 128.7, 126.6, 126.1,
3
1
1
47.2, 140CH CN:H O.0, 138.6, 136.5, 133.7, 132.1, 131.1, 130.2,
36.2, 35.6, 29.7, 29.3. HRMS (ESI-TOF): m/z calcd for
3
2
+
+
30.1, 129.8, 128.9, 128.7, 126.3, 125.4, 36.1, 35.5, 29.7, 29.3, 20.0.
C H ClNaO S , 491.1424; found [M + Na] , 491.1420.
27 29 3
+
HRMS (ESI-TOF): m/z calcd for C H NaO S , 471.1970; found
2,6-Di-tert-butyl-4-((phenylsulfonyl)(p-tolyl)methylene)-
cyclohexa-2,5-dien-1-one (3d). Yellow solid. Isolated yield: 85%
2
8
32
3
+
[
M + Na] , 471.1963.
2
,6-Di-tert-butyl-4-((2-methoxyphenyl)(phenylsulfonyl)-
(114 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 188−189
1
methylene)cyclohexa-2,5-dien-1-one (3b). Yellow solid. Isolated
°C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.67 (s, 1H), 7.66 (d, J
3
yield: 85% (118 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
= 7.6 Hz, 2H), 7.56 (t, J = 6.8 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H),
1
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Scheme 2. Radical Trapping, Control Reaction, and Scalability
Scheme 3. A Plausible Mechanism
(d, J = 2.8 Hz, 1H), 3.85 (s, 3H), 1.35 (s, 9H), 1.07 (s, 9H).
1
3
1
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 160.5, 151.2,
3
1
1
50.9, 147.5, 140.6, 136.6, 133.5, 133.2, 130.9, 129.0, 128.1, 126.7,
24.5, 113.5, 55.4, 36.1, 35.6, 29.7, 29.3. HRMS (ESI-TOF): m/z
+
+
calcd for C H NaO S , 487.1919; found [M + Na] , 487.1928.
2
8
32
4
2
,6-Di-tert-butyl-4-((4-(methylthio)phenyl)(phenylsulfonyl)-
methylene)cyclohexa-2,5-dien-1-one (3g). Yellow solid. Isolated
yield: 82% (118 mg) (eluent: petroleum ether/EtOAc = 40:1). Mp:
1
1
2
7
89−190 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.71 (d, J =
3
.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H),
.50 (t, J = 7.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.0
Hz, 2H), 6.56 (d, J = 2.4 Hz, 1H), 2.56 (s, 3H), 1.40 (s, 9H), 1.12
1
3
1
(
s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 151.5,
3
1
1
51.1, 147.2, 141.4, 140.5, 136.7, 133.7, 132.0, 130.7, 129.1, 128.8,
28.2, 126.7, 125.0, 36.2, 35.7, 29.7, 29.4, 15.1. HRMS (ESI-TOF):
+
+
m/z calcd for C H NaO S , 503.1691; found [M + Na] ,
2
8
32
3 2
5
03.1695.
-((4-Bromophenyl)(phenylsulfonyl)methylene)-2,6-di-tert-butyl-
cyclohexa-2,5-dien-1-one (3h). Yellow solid. Isolated yield: 78%
4
7
2
.14 (d, J = 7.2 Hz, 2H), 7.00 (d, J = 7.2 Hz, 2H), 6.50 (s, 1H),
.38 (s, 3H), 1.35 (s, 9H), 1.06 (s, 9H). C{ H} NMR (100 MHz,
1
3
1
(
120 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 140−141
CDCl ) (δ, ppm): 186.2, 151.3, 151.0, 147.9, 140.6, 139.7, 136.5,
1
3
°
C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.68 (d, J = 2.4 Hz,
3
1
2
4
33.5, 131.5, 130.9, 129.7, 129.0, 128.7, 128.3, 126.7, 36.2, 35.6,
9.8, 29.4, 21.5. HRMS (ESI-TOF): m/z calcd for C H NaO S ,
71.1970; found [M + Na] , 471.1975.
-((3,5-Di-tert-butyl-4-oxocyclohexa-2,5-dien-1-ylidene)-
phenylsulfonyl)methyl)benzonitrile (3e). Yellow solid. Isolated
1
H), 7.66 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.51−7.44
+
2
8
32
3
(
(
m, 4H), 6.99 (d, J = 8.4 Hz, 2H), 6.42 (d, J = 2.8 Hz, 1H), 1.36
s, 9H), 1.07 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm):
+
13
1
3
4
1
1
86.1, 152.0, 151.5, 146.0, 140.2, 136.9, 133.9, 133.1, 131.7, 131.4,
(
30.2, 129.2, 128.2, 126.4, 124.3, 36.2, 35.8, 29.8, 29.4. HRMS (ESI-
yield: 75% (103 mg) (eluent: petroleum ether/EtOAc = 20:1).
Mp: 209−210 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.71 (d,
J = 2.4 Hz, 1H), 7.70 (d, J = 8.0 Hz, 4H), 7.65 (d, J = 8.0 Hz, 1H),
+
1
TOF): m/z calcd for C H BrNaO S , 535.0918; found [M +
Na] , 535.0905.
2
7
29
3
3
+
2
,6-Di-tert-butyl-4-((2,5-dimethoxyphenyl)(phenylsulfonyl)-
7
.53 (t, J = 7.6 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 6.33 (d, J = 2.8
1
3
1
methylene)cyclohexa-2,5-dien-1-one (3i). Yellow solid. Isolated
yield: 86% (128 mg) (eluent: petroleum ether/EtOAc = 10:1). Mp:
1
2.8 Hz, 1H), 7.79−7.74 (m, 2H), 7.56−7.51 (m, 1H), 7.44−7.39
(m, 2H), 6.91 (dd, J = 9.2 Hz, J = 3.2 Hz, 1H), 6.78 (d, J = 3.2
Hz, 1H), 1.42 (s, 9H), 1.09 (s, 9H). C{ H} NMR (100 MHz,
CDCl ) (δ, ppm): 185.9, 152.6, 152.1, 144.9, 139.9, 137.8, 137.2,
3
1
50−151 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.51 (d, J =
1
3
4
34.2, 132.3, 131.8, 129.6, 129.4, 128.2, 126.1, 118.1, 113.5, 36.3,
5.8, 29.7, 29.3. HRMS (ESI-TOF): m/z calcd for C H NNaO S ,
82.1766; found [M + Na] , 482.1771.
3
+
2
8
29
3
+
1
2
Hz, 1H), 6.67 (d, J = 9.2 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H), 3.77
2
,6-Di-tert-butyl-4-((4-methoxyphenyl)(phenylsulfonyl)-
(s, 3H), 3.48 (s, 3H), 1.33 (s, 9H), 1.07 (s, 9H). 1 C{ H} NMR
3
1
methylene)cyclohexa-2,5-dien-1-one (3f). Yellow solid. Isolated
yield: 84% (117 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
(100 MHz, CDCl ) (δ, ppm): 186.3, 153.1, 151.6, 151.3, 150.7,
145.0, 140.9, 136.7, 133.3, 130.8, 128.5, 126.5, 121.8, 117.3, 117.1,
111.6, 56.0, 55.7, 36.1, 35.6, 29.7, 29.4. HRMS (ESI-TOF): m/z
calcd for C H NaO S , 517.2025; found [M + Na] , 517.2010.
3
1
1
2
=
13−114 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.67 (d, J =
3
.8 Hz, 1H), 7.67−7.64 (m, 2H), 7.56 (t, J = 7.6 Hz, 1H), 7.44 (t, J
+
+
7.6 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.87−6.84 (m, 2H), 6.53
29 34 5
1
0573
https://doi.org/10.1021/acs.joc.1c01213
J. Org. Chem. 2021, 86, 10568−10579

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
4
-((5-Bromo-2-methoxyphenyl)(phenylsulfonyl)methylene)-2,6-
(145 mg) (eluent: petroleum ether/EtOAc = 10:1). Mp: 155−156
1
di-tert-butylcyclohexa-2,5-dien-1-one (3j). Yellow solid. Isolated
°C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.70 (d, J = 2.0 Hz,
3
yield: 81% (132 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
1H), 7.58 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.55 (d, J
1
1
2
78−179 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.48 (d, J =
= 2.0 Hz, 1H), 6.29 (s, 2H), 3.88 (s, 3H), 3.73 (s, 6H), 2.40 (s,
3
1
3
1
.4 Hz, 1H), 7.77−7.73 (m, 2H), 7.58−7.54 (m, 1H), 7.49−7.43
3H), 1.36 (s, 9H), 1.08 (s, 9H). C{ H} NMR (100 MHz, CDCl )
3
(
(
m, 3H), 7.32 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 8.8 Hz, 1H), 6.40
(δ, ppm): 186.2, 152.6, 151.3, 151.1, 147.7, 144.8, 138.9, 137.4,
d, J = 2.8 Hz, 1H), 3.54 (s, 3H), 1.32 (s, 9H), 1.08 (s, 9H).
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 156.6, 151.7,
51.1, 143.5, 140.7, 137.1, 134.6, 134.2, 133.5, 130.3, 128.7, 128.5,
26.3, 123.5, 112.5, 112.3, 55.7, 36.2, 35.6, 29.7, 29.4. HRMS (ESI-
TOF): m/z calcd for C H BrNaO S , 565.1024; found [M +
Na] , 565.1020.
136.1, 130.8, 129.5, 128.5, 127.9, 126.6, 109.1, 61.1, 56.3, 36.1, 35.6,
13
1
+
3
29.7, 29.4, 21.6. HRMS (ESI-TOF): m/z calcd for C H NaO S ,
561.2287; found [M + Na] , 561.2276.
31 38
6
+
1
1
2,6-Di-tert-butyl-4-((2-methoxyphenyl)((4-methoxyphenyl)-
sulfonyl)methylene)cyclohexa-2,5-dien-1-one (3q). Yellow solid.
+
2
8
31
4
+
Isolated yield: 83% (123 mg) (eluent: petroleum ether/EtOAc =
1
4
-(Benzo[d][1,3]dioxol-5-yl(phenylsulfonyl)methylene)-2,6-di-
15:1). Mp: 179−180 °C. H NMR (400 MHz, CDCl
3
) (δ, ppm):
tert-butylcyclohexa-2,5-dien-1-one (3k). Yellow solid. Isolated
8.57 (d, J = 2.4 Hz, 1H), 7.65−7.61 (m, 2H), 7.39−7.34 (m, 1H),
7.18 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 6.99 (td, J = 7.2 Hz, J
yield: 86% (123 mg) (eluent: petroleum ether/EtOAc = 15:1).
1
2
1
=
2
1
Mp: 148−149 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.64 (d,
0.8 Hz, 1H), 6.87−6.84 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 6.43 (d,
3
J = 2.4 Hz, 1H), 7.72−7.68 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.46
J = 2.4 Hz, 1H), 3.84 (s, 3H), 3.56 (s, 3H), 1.35 (s, 9H), 1.05 (s,
1
3
1
(
6
1
t, J = 7.6 Hz, 2H), 6.77−6.72 (m, 2H), 6.56 (d, J = 2.8 Hz, 1H),
9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.3, 163.5,
3
.47 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.04 (d, J = 8.0 Hz, 2H),
157.3, 150.9, 150.4, 146.2, 135.9, 132.3, 132.2, 131.5, 130.9, 130.8,
1
2
1
3
1
.35 (s, 9H), 1.09 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ,
ppm): 186.2, 151.4, 151.0, 148.8, 147.5, 147.1, 140.5, 136.8, 133.6,
30.7, 129.0, 128.1, 126.6, 126.2, 125.9, 111.8, 107.8, 101.7, 36.1,
5.6, 29.7, 29.4. HRMS (ESI-TOF): m/z calcd for C H NaO S ,
126.6, 121.7, 120.3, 113.6, 110.5, 55.7, 55.3, 36.0, 35.4, 29.7, 29.3.
3
+
HRMS (ESI-TOF): m/z calcd for C29
[M + Na] , 517.2036.
H
34NaO
S , 517.2025; found
5
+
1
3
5
+
2,6-Di-tert-butyl-4-((4-methoxyphenyl)((4-methoxyphenyl)-
sulfonyl)methylene)cyclohexa-2,5-dien-1-one (3r). Yellow solid.
2
8
30
5
+
01.1712; found [M + Na] , 501.1720.
Isolated yield: 81% (120 mg) (eluent: petroleum ether/EtOAc =
2
,6-Di-tert-butyl-4-((phenylsulfonyl)(3,4,5-trimethoxyphenyl)-
1
methylene)cyclohexa-2,5-dien-1-one (3l). Yellow solid. Isolated
20:1). Mp: 171−172 °C. H NMR (400 MHz, DMSO-d
6
) (δ, ppm)
yield: 88% (138 mg) (eluent: petroleum ether/EtOAc = 10:1). Mp:
8.61 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.11 (dd, J
8.8 Hz, J = 5.6 Hz, 4H), 6.99 (s, 1H), 6.96 (s, 1H) 6.52 (d, J = 2.4
Hz, 1H), 3.83 (s, 3H), 3.80 (s, 3H), 1.30 (s, 9H), 1.02 (s, 9H).
1
=
1
1
2
=
44−145 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.72 (d, J =
2
3
.8 Hz, 1H), 7.73−7.69 (m, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.46 (t, J
1
3
1
8.4 Hz, 2H), 6.56 (d, J = 2.4 Hz, 1H), 6.29 (s, 2H), 3.88 (s, 3H),
C{ H} NMR (100 MHz, DMSO-d ) (δ, ppm) 185.9, 164.0, 160.7,
6
1
3
.72 (s, 6H), 1.37 (s, 9H), 1.09 (s, 9H). 13C{ H} NMR (100 MHz,
150.4, 150.1, 150.0, 134.9, 133.4, 131.7, 131.5, 130.5, 127.1, 124.4,
115.4, 114.0, 56.5, 55.9, 36.2, 35.7, 29.9, 29.4. HRMS (ESI-TOF):
CDCl ) (δ, ppm): 186.2, 152.7, 151.5, 151.3, 147.2, 140.3, 139.0,
36.5, 133.7, 130.7, 129.0, 128.5, 127.7, 126.5, 109.2, 61.2, 56.3,
6.2, 35.7, 29.8, 29.4. HRMS (ESI-TOF): m/z calcd for
3
+
+
1
3
m/z calcd for C29H34NaO S , 517.2025; found [M + Na] ,
5
517.2020.
+
+
C H NaO S , 547.2130; found [M + Na] , 547.2132.
2,6-Di-tert-butyl-4-(((4-methoxyphenyl)sulfonyl)(3,4,5-
trimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3s). Yel-
3
0
2
36
6
,6-Di-tert-butyl-4-((2-chlorophenyl)(tosyl)methylene)-
cyclohexa-2,5-dien-1-one (3m). Yellow solid. Isolated yield: 80%
low solid. Isolated yield: 90% (150 mg) (eluent: petroleum ether/
1
(
°
1
116 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 156−157
C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.62 (d, J = 2.8 Hz,
EtOAc = 10:1). Mp: 144−145 °C. H NMR (400 MHz, CDCl
3
) (δ,
1
ppm): 8.73 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 6.90 (d, J
= 9.2 Hz, 2H), 6.54 (d, J = 2.8 Hz, 1H), 6.30 (s, 2H), 3.88 (s, 3H),
3.84 (s, 3H), 3.73 (s, 6H), 1.37 (s, 9H), 1.08 (s, 9H). C{ H}
NMR (100 MHz, CDCl ) (δ, ppm): 186.3, 163.8, 152.6, 151.3,
3
H), 7.60 (d, J = 8.4 Hz, 2H), 7.37−7.32 (m, 4H), 7.23 (d, J = 8.0
1
3
1
Hz, 2H), 6.31 (d, J = 2.8 Hz, 1H), 2.41 (s, 3H), 1.36 (s, 9H), 1.06
1
(
1
1
s, 9H). 13C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.1, 151.9,
3
3
51.4, 145.0, 144.6, 137.1, 137.0, 135.2, 132.9, 131.9, 131.1, 130.2,
29.6, 129.5, 128.8, 126.6, 126.2, 36.2, 35.6, 29.8, 29.3, 21.8. HRMS
ESI-TOF): m/z calcd for C H ClNaO S , 505.1580; found [M +
151.1, 147.9, 139.0, 135.8, 131.8, 130.9, 130.8, 128.1, 126.7, 114.2,
109.2, 61.2, 56.4, 55.8, 36.2, 35.6, 29.8, 29.4. HRMS (ESI-TOF): m/
+
+
+
(
z calcd for C31H38NaO S , 577.2236; found [M + Na] , 577.2243.
7
2
8
31
3
+
Na] , 505.1575.
,6-Di-tert-butyl-4-(p-tolyl(tosyl)methylene)cyclohexa-2,5-dien-
-one (3n). Yellow solid. Isolated yield: 82% (114 mg) (eluent:
2,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(2-
methoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3t). Yellow
2
1
solid. Isolated yield: 87% (136 mg) (eluent: petroleum ether/EtOAc
1
1
petroleum ether/EtOAc = 20:1). Mp: 188−189 °C. H NMR (400
MHz, CDCl ) (δ, ppm): 8.67 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 8.4
Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 7.6 Hz, 2H), 7.00
d, J = 8.0 Hz, 2H), 6.49 (d, J = 2.8 Hz, 1H), 2.40 (s, 3H), 2.39 (s,
H), 1.35 (s, 9H), 1.05 (s, 9H). C{ H} NMR (100 MHz, CDCl )
δ, ppm): 186.3, 151.1, 150.8, 148.3, 144.6, 139.6, 137.7, 136.2,
31.5, 131.0, 129.8, 129.7, 128.7, 128.3, 126.8, 36.1, 35.6, 29.8, 29.4,
1.8, 21.5. HRMS (ESI-TOF): m/z calcd for C H NaO S ,
= 20:1). Mp: 164−165 °C. H NMR (400 MHz, CDCl
) (δ, ppm):
3
8.48 (d, J = 2.4 Hz, 1H), 7.66−7.63 (m, 2H), 7.43−7.40 (m, 2H),
7.39−7.35 (m, 1H), 7.20 (dd, J = 7.6 Hz, J = 2.0 Hz, 1H), 7.00
(td, J = 7.6 Hz, J = 0.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.45 (d,
J = 2.4 Hz, 1H), 3.53 (s, 3H), 1.32 (s, 9H), 1.31 (s, 9H), 1.05 (s,
3
1
2
(
3
(
1
2
4
1
2
1
3
1
3
1
3
1
9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.4, 157.4,
3
157.2, 151.0, 150.5, 146.1, 137.9, 136.2, 132.3, 131.5, 130.9, 128.3,
+
126.7, 125.5, 121.6, 120.4, 110.5, 55.3, 36.0, 35.4, 35.2, 31.1, 29.7,
2
9
34
3
+
+
85.2126; found [M + Na] , 485.2135.
-((5-Bromo-2-methoxyphenyl)(tosyl)methylene)-2,6-di-tert-bu-
tylcyclohexa-2,5-dien-1-one (3o). Yellow solid; solated yield: 86%
29.3. HRMS (ESI-TOF): m/z calcd for C32
found [M + Na] , 543.2534.
H
40NaO
4
S , 543.2545;
+
4
2,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(p-tolyl)-
methylene)cyclohexa-2,5-dien-1-one (3u). Yellow solid. Isolated
(
°
=
(
(
1
1
2
143 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 207−208
C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.49 (s, 1H), 7.62 (d, J
7.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 7.29−7.22 (m, 3H), 6.68
d, J = 8.8 Hz, 1H), 6.40 (s, 1H), 3.57 (s, 3H), 2.40 (s, 3H), 1.33
s, 9H), 1.07 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm):
86.2, 156.7, 151.5, 150.9, 144.6, 144.0, 137.8, 136.8, 134.6, 134.1,
30.4, 129.3, 128.5, 126.4, 123.7, 112.4, 55.8, 36.1, 35.6, 29.7, 29.4,
1
yield: 83% (126 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
3
1
1
2
7
55−156 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.67 (d, J =
3
.8 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 8.8 Hz, 2H),
.19 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 2.4
1
3
1
3
Hz, 1H), 2.44 (s, 3H), 1.40 (s, 9H), 1.36 (s, 9H), 1.11 (s, 9H).
1
3
1
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.3, 157.6, 151.1,
3
+
1.7. HRMS (ESI-TOF): m/z calcd for C H BrNaO S , 579.1181;
150.8, 148.5, 139.6, 137.6, 136.1, 131.3, 131.0, 129.8, 128.7, 128.1,
126.9, 126.0, 36.1, 35.6, 35.3, 31.1, 29.7, 29.3, 21.5. HRMS (ESI-
2
9
33
4
+
found [M + Na] , 579.1172.
,6-Di-tert-butyl-4-(tosyl(3,4,5-trimethoxyphenyl)methylene)-
cyclohexa-2,5-dien-1-one (3p). Yellow solid. Isolated yield: 90%
+
+
2
TOF): m/z calcd for C32
H
40NaO
3
S , 527.2596; found [M + Na] ,
527.2587.
1
0574
https://doi.org/10.1021/acs.joc.1c01213
J. Org. Chem. 2021, 86, 10568−10579

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
+
+
2
,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(4-
TOF): m/z calcd for C H NaO S , 603.2756; found [M + Na] ,
34 44 6
603.2765.
methoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3v). Yellow
solid. Isolated yield: 88% (137 mg) (eluent: petroleum ether/EtOAc
2, 6-Di-tert-butyl-4-(((4-fluorophenyl)sulfonyl)(4-
methoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3ab). Yel-
low solid. Isolated yield: 75% (108 mg) (eluent: petroleum ether/
1
=
20:1). Mp: 140−141 °C. H NMR (400 MHz, DMSO-d ) (δ,
6
ppm) 8.42 (d, J = 2.8 Hz, 1H), 7.65−7.60 (m, 4H), 7.18−7.13 (m,
1
2
1
H), 7.01−6.97 (m, 2H), 6.56 (d, J = 2.4 Hz, 1H), 3.81 (s, 3H),
EtOAc = 20:1). Mp: 180−181 °C. H NMR (400 MHz, DMSO-d )
(δ, ppm) 8.57 (s, 1H), 7.71 (s, 2H), 7.44 (t, J = 8.4 Hz, 2H), 7.12
(d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.53 (s, 1H), 3.79 (s,
3H), 1.29 (s, 9H), 1.03 (s, 9H). C{ H} NMR (100 MHz, DMSO-
d6) (δ, ppm) 185.9, 165.6 (d, JC−F = 252.8 Hz), 160.8, 150.7, 150.4,
148.9, 136.5 (d, JC−F = 2.3 Hz), 135.6, 133.5, 131.5, 131.3 (d, JC−F
= 5.7 Hz), 126.8, 124.0, 117.4 (d, JC−F = 23.0 Hz), 114.1, 55.9,
36.2, 35.7, 29.8, 29.4. HRMS (ESI-TOF): m/z calcd for
6
1
3
1
.28 (s, 9H), 1.25 (s, 9H), 1.02 (s, 9H). C{ H} NMR (100 MHz,
DMSO-d ) (δ, ppm) 185.9, 160.7, 157.9, 150.5, 150.1, 149.9, 137.9,
35.2, 133.4, 131.3, 127.8, 127.0, 124.2, 114.0, 55.8, 36.1, 35.6, 35.5,
1.1, 29.7, 29.3. HRMS (ESI-TOF): m/z calcd for C H NaO S ,
6
1
3
1
1
3
5
+
3
2
40
4
+
43.2545; found [M + Na] , 543.2557.
-((4-Bromophenyl)((4-(tert-butyl)phenyl)sulfonyl)methylene)-
,6-di-tert-butylcyclohexa-2,5-dien-1-one (3w). Yellow solid. Iso-
4
2
+
+
lated yield: 80% (136 mg) (eluent: petroleum ether/EtOAc = 20:1).
C H FNaO S , 505.1825; found [M + Na] , 505.1834.
4-((5-Bromo-2-methoxyphenyl)((4-fluorophenyl)sulfonyl)-
methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3ac). Yel-
2
8
31
4
1
Mp: 150−151 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.63 (d,
3
J = 2.4 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.50−7.45 (m, 4H), 7.00
(
d, J = 8.4 Hz, 2H), 6.43 (d, J = 2.8 Hz, 1H), 1.35 (s, 9H), 1.32 (s,
low solid. Isolated yield: 75% (126 mg) (eluent: petroleum ether/
1
3
1
1
9
1
1
H), 1.07 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm):
86.1, 158.0, 151.7, 151.3, 146.7, 137.2, 136.5, 133.0, 131.8, 131.3,
30.3, 128.1, 126.5, 126.2, 124.2, 36.1, 35.7, 35.4, 31.1, 29.7, 29.3.
HRMS (ESI-TOF): m/z calcd for C H BrNaO S , 591.1544;
found [M + Na] , 591.1534.
2
dimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3x). Yel-
low solid. Isolated yield: 86% (142 mg) (eluent: petroleum ether/
EtOAc = 10:1). Mp: 170−161 °C. H NMR (400 MHz, CDCl ) (δ,
ppm): 8.48 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.42 (d, J
8.4 Hz, 2H), 6.91 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H), 6.76 (d, J =
.2 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H),
.76 (s, 3H), 3.48 (s, 3H), 1.32 (s, 9H), 1.31 (s, 9H), 1.07 (s, 9H).
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.4, 157.3, 153.0,
51.7, 151.2, 150.6, 145.7, 137.9, 136.4, 130.9, 128.4, 126.6, 125.5,
22.0, 117.3, 117.0, 111.5, 56.0, 55.7, 36.1, 35.5, 35.3, 31.1, 29.7,
9.4. HRMS (ESI-TOF): m/z calcd for C H NaO S , 573.2651;
found [M + Na] , 573.2653.
4
methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3y). Yellow
EtOAc = 20:1). Mp: 189−190 °C. H NMR (400 MHz, CDCl ) (δ,
3
3
ppm): 8.50 (d, J = 2.8 Hz, 1H), 7.76−7.70 (m, 2H), 7.48 (dd, J =
1
8.8 Hz, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.10 (t, J = 8.4
2
+
3
1
37
3
Hz, 2H), 6.65 (d, J = 9.2 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 3.54
(s, 3H), 1.34 (s, 9H), 1.08 (s, 9H). C{ H} NMR (100 MHz,
CDCl ) (δ, ppm): 186.1, 156.5, 151.9, 151.3, 142.8, 137.2, 136.5(d,
JC−F = 2.7 Hz), 134.8, 134.4, 131.4 (d, JC−F = 9.6 Hz), 130.2, 126.1,
23.4, 115.9 (d, JC−F = 22.6 Hz), 112.6, 112.3, 55.7, 36.2, 35.6, 29.7,
29.4. HRMS (ESI-TOF): m/z calcd for C H BrFNaO S ,
83.0930; found [M + Na] , 583.0919.
4-(Benzo[d][1,3]dioxol-5-yl((4-fluorophenyl)sulfonyl)methylene)-
2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3ad). Yellow solid.
Isolated yield: 80% (119 mg) (eluent: petroleum ether/EtOAc =
+
13
1
,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(2,5-
3
1
1
+
3
28 30 4
+
5
=
3
1 2
3
13
1
1
3
15:1). Mp: 174−175 °C. H NMR (400 MHz, CDCl ) (δ, ppm):
3
1
1
2
8.71 (d, J = 2.4 Hz, 1H), 7.76−7.71 (m, 2H), 7.18 (t, J = 8.8 Hz,
2H), 6.80 (d, J = 2.0 Hz, 1H), 6.78 (d, J = 4.0 Hz, 1H), 6.59 (d, J
= 2.4 Hz, 1H), 6.50 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.09 (d, J =
+
3
3
42
5
1
2
+
13
1
6.4 Hz, 2H), 1.41 (s, 9H), 1.14 (s, 9H). C{ H} NMR (100 MHz,
CDCl ) (δ, ppm): 186.1, 165.7 (d, J = 255.6 Hz), 151.6, 151.3,
-((5-Bromo-2-methoxyphenyl)((4-(tert-butyl)phenyl)sulfonyl)-
3
C−F
1
9
48.9, 147.6, 146.6, 136.9, 136.4(d, JC−F = 2.8 Hz), 131.1 (d, JC−F
.6 Hz), 130.6, 126.4, 126.2, 125.8, 116.4 (d, JC−F = 22.4 Hz),
111.8, 107.9, 101.8, 36.2, 35.7, 29.8, 29.4. HRMS (ESI-TOF): m/z
calcd for C H FNaO S , 519.1617; found [M + Na] , 519.1612.
,6-Di-tert-butyl-4-(((4-fluorophenyl)sulfonyl)(3,4,5-
trimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3ae). Yel-
low solid. Isolated yield: 83% (135 mg) (eluent: petroleum ether/
EtOAc = 10:1). Mp: 162−163 °C. H NMR (400 MHz, CDCl ) (δ,
ppm): 8.71 (d, J = 2.8 Hz, 1H), 7.73−7.67 (m, 2H), 7.12 (t, J = 8.4
Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 6.30 (s, 2H), 3.88 (s, 3H), 3.74
=
solid. Isolated yield: 84% (151 mg) (eluent: petroleum ether/EtOAc
1
=
20:1). Mp: 120−121 °C. H NMR (400 MHz, CDCl ) (δ, ppm):
3
+
+
8
3
1
.47 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.48−7.44 (m,
2
8
29
5
H), 7.26 (s, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 2.8 Hz,
2
H), 3.55 (s, 3H), 1.32 (s, 9H), 1.31 (s, 9H), 1.08 (s, 9H).
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 157.6, 156.7,
51.6, 150.9, 144.0, 137.6, 136.7, 134.6, 134.1, 130.4, 128.4, 126.4,
25.7, 123.7, 112.4, 112.3, 55.7, 36.1, 35.6, 35.4, 31.1, 29.7, 29.4.
HRMS (ESI-TOF): m/z calcd for C H BrNaO S , 621.1650;
found [M + Na] , 621.1646.
13
1
3
1
1
1
3
+
3
2
39
4
+
13
1
(s, 6H), 1.37 (s, 9H), 1.09 (s, 9H). C{ H} NMR (100 MHz,
CDCl ) (δ, ppm): 186.1, 165.7 (d, J = 255.8 Hz), 152.7, 151.7,
4
-(Benzo[d][1,3]dioxol-5-yl((4-(tert-butyl)phenyl)sulfonyl)-
3
C−F
methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3z). Yellow
151.5, 146.7, 139.1, 136.5, 136.2 (d, JC−F = 3.1 Hz), 131.3 (d, JC−F
= 9.5 Hz), 130.6, 127.5, 126.3, 116.2 (d, JC−F = 22.5 Hz), 109.2,
61.1, 56.3, 36.1, 35.6, 29.7, 29.4. HRMS (ESI-TOF): m/z calcd for
C H FNaO S, 565.2036; found [M + Na] , 565.2028.
2,6-Di-tert-butyl-4-(((4-chlorophenyl)sulfonyl)(2,5-
dimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3af). Yel-
low solid. Isolated yield: 80% (127 mg) (eluent: petroleum ether/
EtOAc = 10:1). Mp: 186−187 °C. H NMR (400 MHz, CDCl ) (δ,
ppm): 8.51 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.37 (d, J
solid. Isolated yield: 87% (139 mg) (eluent: petroleum ether/EtOAc
15:1). Mp: 165−166 °C. H NMR (400 MHz, CDCl ) (δ, ppm):
.60 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.8
Hz, 2H), 6.75 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 1.6 Hz, 1H), 6.57
d, J = 2.4 Hz, 1H), 6.50 (dd, J = 8.0 Hz, J = 1.6 Hz, 1H), 6.03
d, J = 12.4 Hz, 2H), 1.34 (s, 9H), 1.32 (s, 9H), 1.09 (s, 9H).
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 157.7, 151.2,
50.9, 148.8, 147.8, 147.5, 137.6, 136.5, 130.9, 128.1, 126.8, 126.2,
26.1, 111.8, 107.8, 101.7, 36.2, 35.7, 35.4, 31.1, 29.8, 29.4. HRMS
ESI-TOF): m/z calcd for C H NaO S , 557.2338; found [M +
Na] , 557.2331.
1
=
8
3
+
3
0
35
6
(
(
1
2
13
1
1
3
3
1
1
(
= 8.8 Hz, 2H), 6.92 (dd, J
= 9.2 Hz, J = 3.2 Hz, 1H), 6.80 (d, J =
1 2
+
2.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 2.8 Hz, 1H),
3.78 (s, 3H), 3.48 (s, 3H), 1.34 (s, 9H), 1.07 (s, 9H). C{ H}
NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 153.2, 151.5, 151.4,
151.0, 144.1, 140.1, 139.1, 137.0, 130.7, 130.0, 128.7, 126.3, 121.6,
117.4, 117.2, 111.5, 56.0, 55.6, 36.1, 35.6, 29.7, 29.4. HRMS (ESI-
TOF): m/z calcd for C H ClNaO S , 551.1635; found [M +
3
2
38
5
+
13
1
2
,6-Di-tert-butyl-4-(((4-(tert-butyl)phenyl)sulfonyl)(3,4,5-
3
rimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3aa). Yel-
low solid. Isolated yield: 89% (155 mg) (eluent: petroleum ether/
1
+
EtOAc = 10:1). Mp: 170−171 °C. H NMR (400 MHz, CDCl ) (δ,
3
29 33
5
+
ppm): 8.71 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.47−
Na] , 551.1627.
7
3
.43 (m, 2H), 6.55 (d, J = 2.4 Hz, 1H), 6.27 (s, 2H), 3.87 (s, 3H),
4-((5-Bromo-2-methoxyphenyl)((4-chlorophenyl)sulfonyl)-
methylene)-2,6-di-tert-butylcyclohexa-2,5-dien-1-one (3ag). Yel-
1
3
1
.71 (s, 6H), 1.36 (s, 9H), 1.31 (s, 9H), 1.08 (s, 9H). C{ H}
NMR (100 MHz, CDCl ) (δ, ppm): 186.3, 157.8, 152.6, 151.4,
low solid. Isolated yield: 81% (140 mg) (eluent: petroleum ether/
3
1
1
1
51.1, 147.7, 138.9, 137.2, 136.0, 130.8, 128.4, 127.9, 126.6, 125.9,
09.0, 61.1, 56.2, 36.1, 35.6, 35.3, 31.1, 29.7, 29.4. HRMS (ESI-
EtOAc = 15:1). Mp: 175−176 °C. H NMR (400 MHz, CDCl ) (δ,
3
ppm): 8.48 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 8.4 Hz, 2H), 7.49 (dd,
1
0575
https://doi.org/10.1021/acs.joc.1c01213
J. Org. Chem. 2021, 86, 10568−10579

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
J = 8.8 Hz, J = 2.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.35 (d, J =
1H), 7.61 (d, J = 8.0 Hz, 2H), 7.41−7.37 (m, 1H), 7.23−7.17 (m,
3H), 7.01 (t, J = 7.2 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.40 (d, J =
2.8 Hz, 1H), 3.55 (s, 3H), 3.18−3.11 (m, 1H), 3.03−2.93 (m, 1H),
2.39 (s, 3H), 1.19 (dd, J = 7.2, 4.8 Hz, 6H), 0.88 (dd, J = 6.8, 1.6
1
2
2
3
.4 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H),
.54 (s, 3H), 1.33 (s, 9H), 1.08 (s, 9H). C{ H} NMR (100 MHz,
1
3
1
CDCl ) (δ, ppm): 186.1, 156.5, 151.9, 151.4, 142.6, 139.0, 137.4,
3
1
3
1
1
3
34.7, 134.4, 130.2, 130.0, 128.9, 126.0, 123.2, 112.6, 112.3, 55.7,
Hz, 6H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 185.2,
3
6.2, 35.7, 29.7, 29.4. HRMS (ESI-TOF): m/z calcd for
157.5, 148.9, 148.4, 146.3, 144.4, 138.0, 136.2, 132.3, 131.7, 130.8,
129.2, 128.6, 126.5, 121.6, 120.4, 110.7, 55.4, 27.5, 27.1, 23.6, 22.2,
21.9, 21.7. HRMS (ESI-TOF): m/z calcd for C H NaO S,
+
+
C H BrClNaO S , 599.0634; found [M + Na] , 599.0646.
28
30
4
2
,6-Di-tert-butyl-4-(((4-chlorophenyl)sulfonyl)(3,4,5-
2
7
30
4
+
trimethoxyphenyl)methylene)cyclohexa-2,5-dien-1-one (3ah). Yel-
473.1762; found [M + Na] , 473.1755.
low solid. Isolated yield: 85% (142 mg) (eluent: petroleum ether/
4-(((4-Chlorophenyl)sulfonyl)(2-methoxyphenyl)methylene)-2,6-
diisopropylcyclohexa-2,5-dien-1-one (3an). Yellow solid. Isolated
1
EtOAc = 10:1). Mp: 147−148 °C. H NMR (400 MHz, CDCl ) (δ,
3
ppm): 8.68 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.42 (d, J
yield: 75% (106 mg) (eluent: petroleum ether/EtOAc = 30:1). Mp:
1
=
3
8.4 Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 6.29 (s, 2H), 3.89 (s, 3H),
183−184 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.51 (d, J =
3
.74 (s, 6H), 1.37 (s, 9H), 1.09 (s, 9H). 13C{ H} NMR (100 MHz,
1
2.4 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.43−7.34 (m, 3H), 7.24
(dd, J = 7.2, 1.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.75 (d, J = 8.4
Hz, 1H), 6.38 (d, J = 2.8 Hz, 1H), 3.52 (s, 3H), 3.20−3.12 (m,
1H), 3.03−2.95 (m, 1H), 1.20 (t, J = 6.4 Hz, 6H), 0.88 (dd, J = 6.8,
CDCl ) (δ, ppm): 186.1, 152.7, 151.7, 151.5, 146.5, 140.5, 139.2,
3
1
3
38.7, 136.7, 130.5, 129.9, 129.2, 127.4, 126.3, 109.2, 61.1, 56.3,
6.2, 35.6, 29.7, 29.4. HRMS (ESI-TOF): m/z calcd for
+
+
13
1
C H ClNaO S , 581.1741; found [M + Na] , 581.1726.
2.0 Hz, 6H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 185.1,
30
35
6
3
2
,6-Di-tert-butyl-4-((4-methoxyphenyl)((4-trifluoromethyl)-
157.3, 149.3, 148.8, 144.9, 140.1, 139.1, 136.7, 132.5, 132.0, 130.5,
130.1, 128.7, 126.1, 121.1, 120.6, 110.6, 55.3, 27.5, 27.1, 22.2, 21.9,
21.7. HRMS (ESI-TOF): m/z calcd for C H ClNaO S, 493.1216;
found [M + Na] , 493.1218.
2,6-Diisopropyl-4-((2-methoxyphenyl)((4-methoxyphenyl)-
sulfonyl)methylene)cyclohexa-2,5-dien-1-one (3ao). Yellow solid.
phenyl)sulfonyl)methylene)cyclohexa-2,5-dien-1-one (3ai). Yellow
solid. Isolated yield: 70% (112 mg) (eluent: petroleum ether/EtOAc
20:1). Mp: 147−148 °C. H NMR (400 MHz, CDCl ) (δ, ppm):
.70 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.4
2
6
27
4
1
+
=
8
3
Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.58
(
d, J = 2.4 Hz, 1H), 3.90 (s, 3H), 1.41 (s, 9H), 1.12 (s, 9H).
Isolated yield: 85% (119 mg) (eluent: petroleum ether/EtOAc =
1
3
1
1
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 160.8, 151.8,
30:1). Mp: 170−171 °C. H NMR (400 MHz, CDCl
3
) (δ, ppm):
3
1
=
3
5
51.5, 146.1, 144.1, 137.5, 133.3, 130.7, 128.7, 126.3, 126.1 (d, JC−F
8.56 (d, J = 2.8 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.38 (t, J = 7.2
Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.2 Hz, 1H), 6.85 (d,
J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 1H), 6.39 (d, J = 2.8 Hz, 1H),
3.83 (s, 3H), 3.54 (s, 3H), 3.20−3.12 (m, 1H), 3.02−2.94 (m, 1H),
3.0 Hz), 125.7 (q, JC−F = 195.2 Hz)124.1, 113.7, 55.5, 36.2, 35.7,
+
0.4, 29.7, 29.4. HRMS (ESI-TOF): m/z calcd for C H F NaO S ,
55.1793; found [M + Na] , 555.1780.
29 31 3 4
+
1
3
1
2
,6-Di-tert-butyl-4-((4-methoxyphenyl)((4-nitrophenyl)sulfonyl)-
1.20 (t, J = 6.4 Hz, 6H), 0.88 (d, J = 6.8 Hz, 6H). C{ H} NMR
(100 MHz, CDCl ) (δ, ppm): 185.2, 163.6, 157.4, 148.9, 148.3,
methylene)cyclohexa-2,5-dien-1-one (3aj). Yellow solid. Isolated
3
yield: 73% (112 mg) (eluent: petroleum ether/EtOAc = 10:1). Mp:
146.5, 135.8, 132.3, 132.2, 131.6, 130.9, 130.8, 126.5, 121.7, 120.4,
113.7, 110.6, 55.8, 55.4, 27.5, 27.1, 22.2, 22.0, 21.7. HRMS (ESI-
TOF): m/z calcd for C27H30NaO S, 489.1712; found [M + Na],
5
489.1710.
4-(((4-(tert-Butyl)phenyl)sulfonyl)(2-methoxyphenyl)methylene)-
2,6-diisopropylcyclohexa-2,5-dien-1-one (3ap). Yellow solid. Iso-
1
1
2
7
39−140 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.72 (d, J =
3
.4 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H),
.11 (d, J = 8.4 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 6.58 (d, J = 2.8
1
3
1
Hz, 1H), 3.90 (s, 3H), 1.42 (s, 9H), 1.13 (s, 9H). C{ H} NMR
(
1
3
100 MHz, CDCl ) (δ, ppm): 186.1, 160.9, 152.1, 151.8, 146.1,
45.3, 138.0, 133.4, 130.5, 129.5, 126.1, 124.1, 123.7, 113.9, 55.5,
3
lated yield: 82% (121 mg) (eluent: petroleum ether/EtOAc = 30:1).
1
Mp: 173−174 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.52 (d,
6.3, 35.8, 29.8, 29.4. HRMS (ESI-TOF): m/z calcd for
3
+
+
C H NNaO S , 532.1770; found [M + Na] , 532.1753.
J = 2.4 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.48−7.42 (m, 3H), 7.26
(dd, J = 7.2, 1.2 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 6.80 (d, J = 8.0
Hz, 1H), 6.45 (d, J = 2.4 Hz, 1H), 3.56 (s, 3H), 3.22−3.15 (m,
1H), 3.06−2.99 (m, 1H), 1.35 (s, 9H), 1.22 (d, J = 3.2 Hz, 3H),
1.21 (d, J = 3.2 Hz, 3H), 0.93 (d, J = 2.4 Hz, 3H), 0.92 (d, J = 2.4
28
31
6
2
,6-Di-tert-butyl-4-((4-methoxyphenyl)(naphthalen-2-
ylsulfonyl)methylene)cyclohexa-2,5-dien-1-one (3ak). Yellow solid.
Isolated yield: 83% (128 mg) (eluent: petroleum ether/EtOAc =
1
2
8
0:1). Mp: 189−190 °C. H NMR (400 MHz, CDCl ) (δ, ppm):
3
1
3
1
.81 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H), 7.96−7.91 (m, 3H), 7.71 (t,
J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H),
Hz, 3H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 185.2,
3
157.5, 157.4, 148.9, 148.4, 146.4, 137.9, 136.1, 132.4, 131.6, 130.8,
128.4, 126.6, 125.5, 121.6, 120.4, 110.6, 55.3, 35.3, 31.1, 27.4, 27.1,
6
1
.89 (d, J = 8.8 Hz, 2H), 6.59 (d, J = 2.4 Hz, 1H), 3.88 (s, 3H),
1
3
1
.42 (s, 9H), 1.11 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ,
22.2, 22.0, 21.7. HRMS (ESI-TOF): m/z calcd for C30
515.2232; found [M + Na] , 515.2236.
H36NaO
4
S,
3
+
ppm): 186.3, 160.7, 151.3, 151.0, 147.7, 137.6, 136.7, 135.2, 133.3,
1
1
32.1, 131.0, 130.0, 129.5, 129.4, 129.3, 128.1, 127.8, 126.9, 124.7,
4-((2-(Allyloxy)phenyl)(phenylsulfonyl)methylene)-2,6-di-tert-bu-
tylcyclohexa-2,5-dien-1-one (4a). Yellow solid. Isolated yield: 86%
23.0, 113.6, 55.4, 36.2, 35.7, 29.8, 29.4. HRMS (ESI-TOF): m/z
+
+
(
127 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 94−95 °C.
calcd for C H NaO S , 537.2075; found [M + Na] , 537.2078.
32
34
4
1
H NMR (400 MHz, CDCl ) (δ, ppm): 8.55 (d, J = 2.4 Hz, 1H),
2
,6-Diisopropyl-4-((2-methoxyphenyl)(phenylsulfonyl)-
3
methylene)cyclohexa-2,5-dien-1-one (3al). Yellow solid. Isolated
7.79 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.59−7.54 (m,
1H), 7.43 (d, J = 8.4 Hz, 2H), 7.41−7.37 (m, 1H), 7.33−7.30 (m,
1H), 7.06 (td, J = 7.6 Hz, J = 0.8 Hz, 1H), 6.78 (d, J = 8.4 Hz,
yield: 80% (105 mg) (eluent: petroleum ether/EtOAc = 30:1). Mp:
1
1
1
7
1
3
6
81−182 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.51 (d, J =
3
1
2
.6 Hz, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H),
.44−7.35 (m, 3H), 7.22 (d, J = 7.2 Hz, 1H), 7.01 (t, J = 7.2 Hz,
H), 6.74 (d, J = 8.4 Hz, 1H), 6.40 (d, J = 2.4 Hz, 1H), 3.52 (s,
H), 3.18−3.10 (m, 1H), 3.03−2.94 (m, 1H), 1.18 (t, J = 6.0 Hz,
1H), 6.52 (d, J = 2.4 Hz, 1H), 5.93−5.80 (m, 1H), 5.27−5.22 (m,
1H), 5.22−5.19 (m, 1H), 4.41−4.34 (m, 1H), 4.28−4.21 (m, 1H),
1
3
1
1.38 (s, 9H), 1.10 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ,
3
ppm): 186.3, 156.3, 151.0, 150.6, 145.1, 141.0, 136.7, 133.2, 132.6,
132.4, 131.5, 130.9, 128.5, 128.4, 126.5, 121.6, 120.5, 117.1, 111.7,
68.6, 36.0, 35.5, 29.7, 29.3. HRMS (ESI-TOF): m/z calcd for
1
3
1
H), 0.88 (dd, J = 6.8, 2.0 Hz, 6H). C{ H} NMR (100 MHz,
CDCl ) (δ, ppm): 185.2, 157.5, 149.1, 148.5, 145.8, 140.9, 136.4,
3
+
+
1
5
33.3, 132.4, 131.7, 130.7, 128.6, 128.5, 126.4, 121.4, 120.5, 110.6,
C H NaO S , 513.2075; found [M + Na] , 513.2087.
30 34 4
5.3, 27.5, 27.1, 22.1, 21.9, 21.7. HRMS (ESI-TOF): m/z calcd for
4-((2-(Allyloxy)phenyl)(tosyl)methylene)-2,6-di-tert-butylcyclo-
+
C H NaO S, 459.1606; found [M + Na] , 459.1608.
hexa-2,5-dien-1-one (4b). Yellow solid. Isolated yield: 85% (129
26
28
4
1
2
,6-Diisopropyl-4-((2-methoxyphenyl)(tosyl)methylene)-
mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 137−138 °C. H
cyclohexa-2,5-dien-1-one (3am). Yellow solid. Isolated yield: 82%
NMR (400 MHz, CDCl ) (δ, ppm): 8.56 (d, J = 2.4 Hz, 1H), 7.66
3
111 mg) (eluent: petroleum ether/EtOAc = 30:1). Mp: 175−176
(d, J = 8.0 Hz, 2H), 7.43−7.38 (m, 1H), 7.28 (dd, J = 7.6 Hz, J =
1
2
1
1.6 Hz, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.06 (t, J = 7.2 Hz, 1H),
3
1
0576
https://doi.org/10.1021/acs.joc.1c01213
J. Org. Chem. 2021, 86, 10568−10579

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
6
1
4
1
1
1
3
.81 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 5.92−5.82 (m,
8.4 Hz, J = 2.0 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.11−7.05 (m,
2
H), 5.24 (dd, J = 11.2 Hz, J = 1.6 Hz, 1H), 5.22−5.19 (m, 1H),
2H), 6.66 (d, J = 8.4 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 5.88−5.79
(m, 1H), 5.22 (s, 1H), 5.20−5.16 (m, 1H), 4.36−4.30 (m, 1H),
4.23−4.17 (m, 1H), 2.37 (s, 3H), 1.38 (s, 9H), 1.11 (s, 9H).
1
2
.43−4.37 (m, 1H), 4.31−4.25 (m, 1H), 2.43 (s, 3H), 1.38 (s, 9H),
.10 (s, 9H). 13C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.3,
1
3
1
3
1
56.4, 150.9, 150.4, 145.6, 144.2, 138.1, 136.4, 132.6, 132.3, 131.4,
31.0, 129.1, 128.4, 126.6, 121.8, 120.5, 117.0, 111.8, 68.7, 36.0,
5.4, 29.7, 29.3, 21.6. HRMS (ESI-TOF): m/z calcd for
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 165.5 (d, J
3 C−F
= 253.5 Hz), 154.0, 151.1, 150.8, 144.7, 136.7, 132.8, 132.7, 132.1,
131.4 (d, JC−F = 9.4 Hz), 131.0, 130.0, 126.4, 121.1, 117.0, 115.6 (d,
JC−F = 22.4 Hz), 111.5, 68.6, 36.1, 35.5, 29.7, 29.4, 20.5. HRMS
+
+
C H NaO S , 527.2232; found [M + Na] , 527.2220.
31
36
4
+
4
-((2-(Allyloxy)phenyl)((4-fluorophenyl)sulfonyl)methylene)-2,6-
(ESI-TOF): m/z calcd for C H FNaO S , 545.2138; found [M +
Na] , 545.2127.
3
1
35
4
+
di-tert-butylcyclohexa-2,5-dien-1-one (4c). Yellow solid. Isolated
yield: 81% (124 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
4-((2-(Allyloxy)-5-chlorophenyl)(tosyl)methylene)-2,6-di-tert-bu-
tylcyclohexa-2,5-dien-1-one (4h). Yellow solid. Isolated yield: 73%
1
1
2
7
1
07−108 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.59 (d, J =
3
.4 Hz, 1H), 7.78−7.23 (m, 2H), 7.42−7.38 (m, 1H), 7.33 (dd, J =
(118 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 152−153
1
1
.6 Hz, J = 1.6 Hz, 1H), 7.11−7.05 (m, 3H), 6.77 (d, J = 8.0 Hz,
°C. H NMR (400 MHz, CDCl
3
) (δ, ppm): 8.54 (d, J = 2.4 Hz,
2
H), 6.49 (d, J = 2.4 Hz, 1H), 5.91−5.81 (m, 1H), 5.24 (dd, J = 4
1H), 7.70−7.64 (m, 2H), 7.36 (dd, J
7.29−7.24 (m, 3H), 6.76 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz,
1H), 5.88−5.78 (m, 1H), 5.23 (dd, J = 3.6 Hz, J = 1.6 Hz, 1H),
5.22−5.18 (m, 1H), 4.41−4.35 (m, 1H), 4.31−4.25 (m, 1H), 2.44
= 8.8 Hz, J = 2.8 Hz, 1H),
1 2
1
Hz, J = 1.6 Hz, 1H), 5.21 (dd, J = 3.2 Hz, J = 1.6 Hz, 1H),
2
1
2
4
.40−4.34 (m, 1H), 4.26−4.21 (m, 1H), 1.39 (s, 9H), 1.10 (s, 9H).
1
2
1
3
1
C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.2, 156.1, 151.2,
3
1
3
1
(
s, 3H), 1.37 (s, 9H), 1.12 (s, 9H). C{ H} NMR (100 MHz,
1
50.8, 144.5, 136.7, 132.4 (d, JC−F = 2.1 Hz), 131.4 (d, JC−F = 9.5
CDCl ) (δ, ppm): 186.2, 155.1, 151.4, 150.9, 144.6, 143.7, 137.9,
Hz), 131.3, 130.8, 126.3, 121.4, 120.6, 117.2, 115.6 (d, JC−F = 22.4
3
1
36.9, 132.2, 131.9, 131.1, 130.5, 129.4, 128.5, 126.4, 125.5, 123.4,
Hz), 111.6, 68.5, 36.1, 35.5, 29.7, 29.3. HRMS (ESI-TOF): m/z
calcd for C H FNaO S , 531.1981; found [M + Na] , 531.1969.
+
+
117.4, 113.1, 69.2, 36.1, 35.6, 29.7, 29.4, 21.7. HRMS (ESI-TOF):
m/z calcd for C H ClNaO S , 561.1842; found [M + Na] ,
30
33
4
+
+
4
-((2-(Allyloxy)phenyl)((4-chlorophenyl)sulfonyl)methylene)-2,6-
31 35
4
di-tert-butylcyclohexa-2,5-dien-1-one (4d). Yellow solid. Isolated
yield: 78% (123 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
561.1830.
2,6-Di-tert-butyl-4-((2-(phenylethynyl)phenyl)(phenylsulfonyl)-
methylene)cyclohexa-2,5-dien-1-one (4i). Yellow solid. Isolated
1
9
0−91 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.57 (d, J = 2.4
3
yield: 76% (122 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
Hz, 1H), 7.70−7.65 (m, 2H), 7.44−7.36 (m, 3H), 7.33 (dd, J = 7.6
Hz, J = 1.6 Hz, 1H), 7.07 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 8.4 Hz,
1
1
1
2
7
40−141 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.76 (d, J =
3
2
.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 7.6 Hz, 1H),
.50−7.42 (m, 4H), 7.33 (s, 1H), 7.31−7.28 (m, 2H), 7.25 (t, J =
7.6 Hz, 2H), 7.07 (d, J = 7.2 Hz, 2H), 6.58 (d, J = 2.4 Hz, 1H),
1
5
4
H), 6.50 (d, J = 2.4 Hz, 1H), 5.90−5.80 (m, 1H), 5.24 (s, 1H),
.21 (dd, J = 6.4 Hz, J = 1.6 Hz, 1H), 4.40−4.34 (m, 1H), 4.26−
1
2
1
3
1
.20 (m, 1H), 1.39 (s, 9H), 1.10 (s, 9H). C{ H} NMR (100
1
3
1
1
.43 (s, 9H), 1.06 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ,
MHz, CDCl ) (δ, ppm): 186.2, 156.1, 151.3, 150.9, 144.2, 140.0,
3
3
ppm): 186.2, 151.5, 151.4, 145.6, 140.4, 137.6, 135.0, 133.6, 131.9,
31.4, 131.3, 129.8, 128.8, 128.7, 128.4, 128.3, 128.0, 126.6, 125.3,
122.5, 94.4, 87.4, 36.3, 35.6, 29.8, 29.3. HRMS (ESI-TOF): m/z
1
39.2, 137.0, 132.5, 132.4, 131.7, 130.8, 129.9, 128.7, 126.3, 121.3,
1
120.6, 117.2, 111.6, 68.6, 36.1, 35.5, 29.7, 29.3. HRMS (ESI-TOF):
+
+
m/z calcd for C H ClNaO S , 547.1686; found [M + Na] ,
3
0
33
4
+
+
calcd for C H NaO S , 557.2126; found [M + Na] , 557.2139.
3
5
34
3
547.1675.
2
,6-Di-tert-butyl-4-((2-((4-chlorophenyl)ethynyl)phenyl)-
phenylsulfonyl)methylene)cyclohexa-2,5-dien-1-one (4j). Yellow
solid. Isolated yield: 72% (123 mg) (eluent: petroleum ether/EtOAc
4
-((2-(Allyloxy)-5-methylphenyl)(phenylsulfonyl)methylene)-2,6-
(
di-tert-butylcyclohexa-2,5-dien-1-one (4e). Yellow solid. Isolated
yield: 84% (127 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp:
1
1
= 20:1). Mp: 149−150 °C. H NMR (400 MHz, CDCl
3
) (δ, ppm):
8
8−89 °C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.52 (d, J = 2.8
3
8
.74 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 7.6
Hz, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.44 (t,
Hz, 1H), 7.52−7.43 (m, 4H), 7.35−7.31 (m, 2H), 7.23 (d, J = 8.0
J = 8.0 Hz, 2H), 7.18 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 7.13 (d, J
=
1
2
Hz, 2H), 7.00 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 2.4 Hz, 1H), 1.43
1.8 Hz, 1H), 6.68 (d, J = 8.4 Hz, 1H), 6.54 (d, J = 2.0 Hz, 1H),
1
3
1
(
s, 9H), 1.06 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm):
3
5
.90−5.80 (m, 1H), 5.21 (dd, J = 9.6 Hz, J = 1.6 Hz, 1H), 5.18
1
2
1
1
86.2, 151.5, 151.4, 145.6, 140.5, 137.6, 135.0, 134.8, 133.6, 132.6,
31.9, 131.5, 131.2, 129.8, 128.9, 128.7, 128.4, 128.3, 126.5, 125.0,
(
(
(
d, J = 1.2 Hz, 1H), 4.34 (dd, J = 13.6 Hz, J = 4.8 Hz, 1H), 4.22
dd, J = 13.2 Hz, J = 4.4 Hz, 1H), 2.36 (s, 3H), 1.36 (s, 9H), 1.11
s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm): 186.4, 154.2,
1 2
1
2
13
1
121.0, 93.0, 88.3, 36.3, 35.6, 29.9, 29.3. HRMS (ESI-TOF): m/z
calcd for C H ClNaO S , 591.1737; found [M + Na] , 591.1729.
3
+
+
3
5
33
3
1
1
50.6, 141.2, 133.2, 132.9, 131.9, 131.1, 129.8, 128.5, 126.7, 121.3,
17.0, 111.6, 68.7, 36.1, 35.5, 29.8, 29.4, 20.5. HRMS (ESI-TOF):
2
,6-Di-tert-butyl-4-((phenylsulfonyl)methyl)phenol (5). White
1
+
+
solid. Mp: 110−112 °C. H NMR (400 MHz, CDCl
.63 (d, J = 8.0 Hz, 3H), 7.48 (t, J = 7.6 Hz, 2H), 6.80 (s, 2H),
.31 (s, 1H), 4.27 (s, 2H), 1.37 (s, 18H). C{ H} NMR (100
) (δ, ppm):
3
m/z calcd for C H NaO S , 527.2232; found [M + Na] ,
3
1
36
4
7
5
5
27.2218.
-((2-(Allyloxy)-5-methylphenyl)(tosyl)methylene)-2,6-di-tert-bu-
tylcyclohexa-2,5-dien-1-one (4f). Yellow solid. Isolated yield: 86%
13
1
4
MHz, CDCl ) (δ, ppm): 154.3, 137.9, 136.1, 133.4, 128.9, 128.7,
3
127.7, 118.8, 63.2, 34.2, 30.1.
(
134 mg) (eluent: petroleum ether/EtOAc = 20:1). Mp: 145−146
1
°C. H NMR (400 MHz, CDCl ) (δ, ppm): 8.53 (d, J = 2.8 Hz,
3
1
H), 7.68 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.19 (dd, J1
ASSOCIATED CONTENT
■
=
8.4 Hz, J = 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.70 (d, J =
2
sı
*
Supporting Information
8
.4 Hz, 1H), 6.54 (d, J = 2.8 Hz, 1H), 5.90−5.80 (m, 1H), 5.21
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01213.
(
dd, J = 9.2 Hz, J = 1.6 Hz, 1H), 5.17 (d, J = 1.2 Hz, 1H), 4.39−
1
2
4
.33 (m, 1H), 4.27−4.22 (m, 1H), 2.43 (s, 3H), 2.36 (s, 3H), 1.37
13 1
(s, 9H), 1.11 (s, 9H). C{ H} NMR (100 MHz, CDCl ) (δ, ppm):
1H and 13C{1H} NMR spectra for all products and X-
ray crystallographic data (PDF)
3
1
1
3
86.3, 154.3, 150.8, 150.4, 145.8, 144.2, 138.4, 136.4, 132.9, 132.8,
31.8, 131.2, 129.7, 129.1, 128.5, 126.7, 121.5, 116.9, 111.7, 68.8,
6.1, 35.5, 29.8, 29.4, 21.7, 20.5. HRMS (ESI-TOF): m/z calcd for
Accession Codes
+
+
C H NaO S , 541.2389; found [M + Na] , 541.2373.
32
38
4
CCDC 1980583−1980584 contain the supplementary
crystallographic data for this paper. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_-
request/cif, or by emailing data_request@ccdc.cam.ac.uk, or
by contacting The Cambridge Crystallographic Data Centre,
4
-((2-(Allyloxy)-5-methylphenyl)((4-fluorophenyl)sulfonyl)-
methylene)-2,6-di-tert-utylcyclohexa-2,5-dien-1-one (4g). Yellow
solid. Isolated yield: 79% (124 mg) (eluent: petroleum ether/
EtOAc = 20:1). Mp: 108−109 °C. H NMR (400 MHz, CDCl ) (δ,
ppm): 8.56 (d, J = 2.4 Hz, 1H), 7.81−7.74 (m, 2H), 7.19 (dd, J =
1
3
1
1
0577
https://doi.org/10.1021/acs.joc.1c01213
J. Org. Chem. 2021, 86, 10568−10579

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
3
2 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
36033.
Impurity Control Strategy of the Hedgehog Pathway Inhibitor
Vismodegib. Org. Process Res. Dev. 2016, 20, 1509.
(4) Parent, E. E.; Dence, C. S.; Jenks, C.; Sharp, T. L.; Welch, M.
J.; Katzenellenbogen, J. A. Katzenellenbogen, Synthesis and
Biological Evaluation of [18F]Bicalutamide, 4-[76Br]-
Bromobicalutamide, and 4-[ Br]Bromo-thiobicalutamide as Non-
AUTHOR INFORMATION
Corresponding Authors
Liangce Rong − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry
and Materials Science, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China; orcid.org/
■
76
Steroidal Androgens for Prostate Cancer Imaging. J. Med. Chem.
2
(
007, 50, 1028.
5) (a) Jiang, Y.; Loh, T.-P. Catalytic and direct methyl
sulfonylation of alkenes and alkynes using a methyl sulfonyl radical
generated from a DMSO, dioxygen and copper system. Chem. Sci.
2014, 5, 4939. (b) Xu, Y.-H.; Wang, M.; Lu, P.; Loh, T.-P.
Palladium-catalyzed alkenyl CeH bond sulfonylation reaction
usingorganosulfonyl chlorides. Tetrahedron 2013, 69, 4403. (c) Mee-
sin, J.; Katrun, P.; Pareseecharoen, C.; Pohmakotr, M.; Reutrakul,
V.; Soorukram, D.; Kuhakarn, C. Iodine-catalyzed Sulfonylation of
Arylacetylenic Acids and Arylacetylenes with Sodium Sulfinates:
Synthesis of Arylacetylenic Sulfones. J. Org. Chem. 2016, 81, 2744.
0
000-0003-0561-1137; Email: lcrong@jsnu.edu.cn
Jinpeng Zhang − Key Lab of Environment and Health,
School of Public Health, Xuzhou Medical University,
Xuzhou, Jiangsu 221004, People’s Republic of China;
Email: xiaopangpeng@126.com
Chang Wang − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry
and Materials Science, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China;
(d) Wang, K.; Wang, G.; Duan, G.; Xia, C. Cobalt(II)-catalyzed
remote C5-selective C−H sulfonylation of quinolines via insertion of
sulfur dioxide. RSC Adv. 2017, 7, 51313. (e) Zheng, D.; Mao, R.; Li,
Z.; Wu, J. A copper(I)-catalyzed three-component reaction of
triethoxysilanes, sulfur dioxide, and alkyl halides. Org. Chem. Front.
Email: wangchangacdm@jsnu.edu.cn
Authors
Lei Dai − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry
and Materials Science, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
Qiuyu Yu − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry
and Materials Science, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
Jinghang Zhang − Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, School of
Chemistry and Materials Science, Jiangsu Normal
University, Xuzhou, Jiangsu 221116, People’s Republic of
China
Fan Wu − Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, School of Chemistry
and Materials Science, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, People’s Republic of China
2
(
016, 3, 359.
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Kessler, W.; Kirschning, A.; Muller, R. Elansolid A3, a Unique p-
Quinone Methide Antibiotic from Chitinophaga sancti. Chem. - Eur.
J. 2011, 17, 7739. (c) Yuan, Y.; Men, H.; Lee, C. Total Synthesis of
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Evolution of a Total Synthesis of (−)-Kendomycin Exploiting a
Petasis-Ferrier Rearrangement/Ring-Closing Olefin Metathesis Strat-
egy. J. Am. Chem. Soc. 2006, 128, 5292. (e) Kupchan, S. M.; Karim,
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two novel diterpenoid quinone methide tumor inhibitors from
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9) (a) Hamels, D.; Dansette, P. M.; Hillard, E. A.; Top, S.;
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01213
(
(
Notes
Vessieres, A.; Herson, P.; Jaouen, G.; Mansuy, D. Ferrocenyl
Quinone Methides as Strong Antiprolife rative Agents: Formation by
Metabolic and Chemical Oxidation of Ferrocenyl Phenols. Angew.
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation
of China (NSFC) (81872647) and the Natural Science
Foundation of the Jiangsu Higher Education Institutions of
China (18KJA150004), and this work was also sponsored by
TAPP.
(10) Zhou, Q.; Qu, Y.; Mangrum, J. B.; Wang, X. DNA Alkylation
with N-Methylquinolinium Quinone Methide to N2-dG Adducts
Resulting in Extensive Stops in Primer Extension with DNA
Polymerases and Subsequent Suppression of GFP Expression in
A549 Cells. Chem. Res. Toxicol. 2011, 24, 402.
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