Oxidative Sulfonylation of Hydrazones Enabled by Synergistic Copper/Silver Catalysis

Article abstract of DOI:10.1021/acs.joc.0c02249

A copper/silver-cocatalyzed protocol for oxidative sulfonylation of hydrazones is demonstrated. A wide range of β-ketosulfones and N-acylsulfonamides are directly synthesized in moderate to good yields. Our work provides a viable method for scalable preparation of β-ketosulfone derivatives that have found wide applications in the pharmaceutical industry.

Full text of DOI:10.1021/acs.joc.0c02249

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Article
Oxidative Sulfonylation of Hydrazones Enabled by Synergistic
Copper/Silver Catalysis
Jun Xu, Chao Shen, Xian Qin, Jie Wu, Pengfei Zhang,* and Xiaogang Liu*
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ABSTRACT: A copper/silver-cocatalyzed protocol for oxidative sulfonylation of hydrazones is demonstrated. A wide range of β-
ketosulfones and N-acylsulfonamides are directly synthesized in moderate to good yields. Our work provides a viable method for
scalable preparation of β-ketosulfone derivatives that have found wide applications in the pharmaceutical industry.
structures for a variety of marketed pharmaceuticals.11 In sharp
INTRODUCTION
■
contrast to approaches for the synthesis of β-ketosulfones, the
Over the past decade, transition-metal-catalyzed C−H
formation of N-acylsulfonamides through oxo-sulfonylation of
functionalization has become a powerful synthetic strategy
hydrazones continues to be scarce, with recent progress
for the selective assembly of important organic compounds.1 In
achieved with the aid of an aerobic oxidative coupling
particular, synergistic catalysis has received much attention
strategy.12 Despite the progress achieved to date, each reported
from the organic community because of its ability to improve
catalytic system is applicable exclusively to a specific type of
the selectivity and efficacy of organic transformations.2
substrate, and the generation of different products using single
Synergistic catalysts consisting of two catalysts or one catalyst
catalytic systems remains challenging.13 A universal catalytic
with two or more active sites have been widely employed for
system for the synthesis of different products could
catalysis. The combination of multifunctional active species
significantly boost synthetic efficiency, benefiting the develop-
can facilitate many organic transformations that would
ment of mass-production techniques for practical applications.
otherwise not be possible with a single active species. For
Hydrazones are essential and versatile intermediates in
example, Loh et al. in 2015 reported a synergistic copper/
organic synthesis due to diverse reactivity profiles of the C
N−N structure. They are commonly employed as substrates
for functional group transformation, especially for the
functionalization of carbonyl compounds and nitrogen-
containing compounds.14 On the other hand, our previous
work demonstrates that the cheap copper salts are effective
catalysts for C−S cross-coupling since such metals have
multiple oxidation states, which can catalyze reactions via both
the oxidative addition/reductive elimination mechanism and
the single-electron-transfer process.15 In addition, the combi-
nation of catalytic silver salts and persulfates has proven
effective for the generation of sulfonyl radicals from sodium
cobalt-catalyzed direct coupling of sp3 α-carbon of alcohols
with alkenes and hydroperoxides.2e Recently, Li and co-
workers demonstrated a synergistic relay process involving
olefin isomerization and umpolung hydrazone addition, which
enabled redox-neutral α-alkylations of olefinic alcohols through
ruthenium(II) catalysis.2g
Sulfonyl compounds are important for organic synthesis and
biological medicine (Figure 1).3 For example, β-ketosulfones
are a prerequisite to the synthesis of heterocyclic or vinyl
sulfones, β-hydroxysulfones, polyfunctionalized 4H-pyrans,
quinoxalines, quinolines, allenes, and many others.4 Therefore,
considerable research efforts have been devoted to β-
ketosulfone synthesis via various pathways, including the
dehalogenative coupling of α-haloketones with sulfinates,5
reactions of diazo sulfones with aldehydes,6 oxidation of β-
hydroxysulfones or β-ketosulfides,7 oxidative difunctionaliza-
tion of alkenes or alkynes,8 and oxidative coupling of ketones
with sulfonylation reagents,9 as well as electrochemical
synthesis.10 In addition, N-acylsulfonamides also are the core
Received: September 18, 2020
Published: January 22, 2021
https://dx.doi.org/10.1021/acs.joc.0c02249
© 2021 American Chemical Society
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Figure 1. Examples of β-ketosulfone- or N-acylsulfonamide-based bioactive molecules.
sulfinates in the oxidative sulfonylation.16 In that regard, we
Table 1. Optimization of Oxidative Sulfonylation of
a b
,
reason that it is possible to achieve the oxidative sulfonylation
of hydrazones through synergistic copper/silver cocatalysis. In
this study, we demonstrate a one-pot protocol for the synthesis
of β-ketosulfone by employing ketone hydrazone and sodium
benzenesulfinate as starting materials. Moreover, this cocata-
lytic system also allows direct oxo-sulfonylation of aldehyde
hydrazones, giving the corresponding N-acylsulfonamides in
moderate to good yields (Scheme 1).
Acetophenone Hydrazones
b
entry
deviation from initial conditions
yield (%)
1
2
3
4
5
6
7
none
no Cu2O
85
0
Scheme 1. Copper/Silver-Cocatalyzed Oxidative
Sulfonylation of Hydrazones
no Ag2CO3
no K2S2O8
Cu2O was replaced with CuO
DCE was replaced with acetone
extended reaction time (12 h)
15
18
trace
73
83
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (2.0 equiv), DCE (1.0 mL), 80 °C,
b
3 h, air. Isolated yields. DCE = 1,2-dichloroethane.
1, entry 5), and changes in solvent and reaction time did not
improve the product yield (Table 1, entries 6 and 7).
With optimal reaction conditions in hand, we next explored
the substrate scope of ketone hydrazones for oxidative
sulfonylation. The sulfonylation of sodium benzenesulfinate
(2a) with acetophenone hydrazones, bearing substituent
groups at the ortho-, meta-, or para-position, both electron-
donating and electron-withdrawing groups, afforded the
corresponding β-ketosulfones (3a−n) in 62−85% yields
(Table 2). Since such transformations proceeded through a
single-electron-transfer pathway, we assumed that benzene π-
system would likely disperse the electron to stabilize the radical
intermediate, and the electronic effect of substituents on the
benzene ring has little influence on this process. The molecular
structure of β-ketosulfone 3g was confirmed by X-ray
crystallographic analysis (CCDC NO. 1902707). As the
fluorine atom has a great impact on the physical and biological
properties of organic compounds,17 we also tested acetophe-
none hydrazones containing several fluorine groups and
isolated corresponding products (3o−3q) in good yields. In
addition, heterocyclic ketone and α-substituted acetophenone
hydrazones were converted to corresponding products (3r−v)
RESULTS AND DISCUSSION
■
At the outset, the auxiliary groups for oxidative sulfonylation
were tested in MeCN using CuCl as the catalyst (Scheme S1).
Results reveal that acetophenone hydrazone (1a) gives the
highest yield. We thus selected N-aminomorpholine as the
auxiliary group for further investigation. Subsequently, reaction
conditions of oxidative sulfonylation of acetophenone
hydrazone (1a) with sodium benzenesulfinate (2a) were
optimized by changing metal catalysts, silver cocatalysts,
oxidants, solvents, reaction time, and temperatures (Table 1
and Tables S1−S6). The target product (3a) was obtained in
85% yield under standard reaction conditions (Table 1, entry
1). It should be noted that no corresponding product was
generated in the absence of Cu2O (Table 1, entry 2). Only
15% and 18% yields of the product were obtained without
Ag2CO3 or K2S2O8, respectively (Table 1, entries 3 and 4).
These results imply that the synergistic action of Ag2CO3 and
K2S2O8 determines organic transformation. Furthermore, no
reaction occurred when Cu2O was replaced with CuO (Table
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a b
,
a b
,
Table 2. Substrate Scope of Ketone Hydrazones
Table 3. Substrate Scope of Sodium Sulfinates
a
Reaction conditions: 1 (0.2 mmol), 2a (2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (2.0 equiv), DCE (1.0 mL), 80 °C,
a
Reaction conditions: 1a (0.2 mmol), 2 (2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (2.0 equiv), DCE (1.0 mL), 80 °C,
b
c
3 h, air. Isolated yields. Reaction was performed on a 1 mmol scale.
b
3 h, air. Isolated yields.
a b
,
in 63−78% yields. However, the current catalytic system does
not tolerate aliphatic ketone hydrazone (3w).
Table 4. Substrate Scope of Aldehyde Hydrazones
We next investigated a wide range of sodium sulfinates.
Functionalized sodium sulfinates are well compatible with our
catalytic system, affording corresponding products in moderate
to good yields (Table 3). Specifically, benzene sodium
sulfinates containing either electron-donating or electron-
withdrawing groups, at the ortho-, meta-, or para-position,
gave corresponding β-ketosulfones (3x−aq) in 51−83% yields.
Reactions of acetophenone hydrazones (1a) with both
aliphatic and heterocyclic sodium sulfinates proceeded
successfully as well, providing corresponding products (3ar−
aw) in 62−82% yields.
To expand the application scope, we applied the present
catalytic system to oxidative sulfonylation of aldehyde
hydrazones (4) with sodium benzenesulfinate (2a). A series
of substituted benzaldehyde hydrazones were tested, and the
corresponding products (5a−q) were obtained in 49−78%
yields (Table 4). Notably, aliphatic and heterocyclic aldehyde
hydrazones and functionalized benzene sodium sulfinates
could not undergo the reaction under standard conditions.
NMR data suggest that the morpholine moiety is retained, and
the sulfonylation of the aryl group does not occur. The product
likely comprises a carbonyl group. The molecular structure of
the product was further confirmed by infrared spectroscopy,
high-resolution mass spectroscopy, and the single-crystal X-ray
crystallographic analysis of 5n (CCDC no. 2032258).
To demonstrate the scalability of transformation, we carried
out gram-scale oxidative sulfonylation of hydrazones, with
yields of 79% and 68% for 3a and 5a, respectively (Scheme
2a). The potent and selective inhibitor of 11β-hydroxyster-
oiddehydrogenase type 1 (11β-HSD1) was also successfully
synthesized in 75% yield according to the copper/silver-
a
Reaction conditions: 4 (0.2 mmol), 2a (2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (2.0 equiv), DCE (1.0 mL), 80 °C,
b
c
3 h, air. Isolated yields. Reaction was performed on a 1 mmol scale.
cocatalyzed protocol (Scheme 2b).18 Since β-ketosulfones are
commonly employed as synthons in organic synthesis, further
transformations were performed (Scheme 2c). Several organic
compounds (7a−d) were obtained in good yields using β-
ketosulfone 3u as the starting material.
We next performed a series of control experiments in order
to understand reaction mechanisms. β-Ketosulfone could not
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Scheme 2. Gram-Scale Preparation and Further Synthetic Utilization
be obtained without the N-aminomorpholine group, indicating
the indispensable role of N-aminomorpholine in trans-
formation (Scheme 3a). According to literature methods,9a,19
N-aminomorpholine might act as an auxiliary group to
generation iminium ions, which is important for C−H
functionalization at the β-position of acetophenone derivatives.
When two equivalents of radical scavengers 2,2,6,6-tetrame-
thylpiperidine-1-oxyl were added to the catalytic system, the
oxidative sulfonylation reactions were inhibited (Scheme 3b).
Furthermore, the sulfonyl radical was captured in the presence
or absence of hydrazones using 1,1-diphenylethylene as the
radical collecting reagent (Scheme 3c). These results clearly
demonstrate that a radical pathway is involved in these two
reactions. The 18O-labeling experiments were performed by
adding H218O to the two reactions, and the only 18O-labeling
product of 3a was obtained. This result indicates that moisture
in the reaction may be responsible for the generation of
carbonyl of β-ketosulfone (Scheme S2). We further studied the
level of water content. The enamine (E) was isolated in 82%
yield for the reaction performed in super dry DCE. These two
reactions were further carried out under a nitrogen
atmosphere: product 3a was obtained in 81% yield, and
product 5a was not generated. These results imply that O2
participates in oxidative sulfonylation of aldehyde hydrazones
(Scheme S3). The 18O-labeling product of 5a was detected
when the reaction was performed under an 18O2 atmosphere,
confirming that the presence of O2 is responsible for the
generation of carbonyl groups. The reaction was also
monitored by electron paramagnetic resonance (EPR). When
the reaction was performed for 5 min, the EPR signal of Cu(II)
appears, suggesting its formation in the reaction mixture
(Figure S1).20
In light of control experiments and previous literature, we
proposed plausible mechanisms for these two reactions in
Scheme 4. For oxidative sulfonylation of ketone hydrazones,
starting with a single-electron-transfer process between ketone
hydrazone 1a and two molecules of Cu(I), a copper-imine
intermediate B is obtained with a Cu(II) species.9a,19a The
obtained Cu(II) species oxidizes sodium sulfinate 2a to
sulfonyl radical A with concomitant generation of a Cu(I)
species.19b Meanwhile, the copper-imine intermediate B is
transformed to enamine intermediate C. Synergistic action of
silver salt and oxidant generates main sulfonyl radical A, which
subsequently attacks the intermediate C to produce
intermediate D.16a Afterward, an intramolecular single-
electron-transfer process converts intermediate D to inter-
mediate E. Target product 3a can be obtained through
hydrolysis of intermediate E. For oxidative sulfonylation of
aldehyde hydrazones, a sulfonyl radical is first generated from
sodium benzenesulfinate (2a) in the presence of silver salts and
oxidants. The addition of the radical to the CN double bond
gives a carbon radical F, which interacts with O2 to give a
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Scheme 3. Control Experiments for Determination of the
Reaction Mechanism
CONCLUSIONS
■
In summary, we have developed a robust and efficient
approach for oxidative sulfonylation of hydrazones via
copper/silver synergistic catalysis. Control experiments
revealed that a radical pathway is involved in these reactions.
A broad range of β-ketosulfones and N-acylsulfonamides were
generated in good yields, which could be employed as useful
synthetic building blocks for the construction of value-added
fine chemicals.
EXPERIMENTAL SECTION
■
General Information. All reagents and deuterated solvents were
commercially available and used without further purification. All
sodium sulfinates [(2a, 2x, 2y, 2aa−ac, 2ai, 2ar, 2as),16c (2aj, 2au),16a
(2z, 2ak−am),24a (2ad, 2an, 2ap),27a (2ae−ah, 2ao, 2aq, 2at),27b
2av,27c and 2aw27d] are known compounds and prepared as
previously described. All aldehyde hydrazones [(4a−g, 4i, 4j, 4m,
4o),28a (4h, 4l, 4n, 4q),28c (4k, 4p),28b and (4sr, 4s)28d] are known
compounds and prepared as previously described. All products were
separated by silica gel (200−300 mesh) column chromatography with
petroleum ether (PE) (60−90 °C) and ethyl acetate (EA). H, 13C,
1
and 19F NMR spectra were recorded on a Bruker Advance 500
spectrometer at an ambient temperature with CDCl3 as a solvent and
tetramethylsilane (TMS) as the internal standard. Melting points were
determined on an X-5 Data microscopic melting point apparatus.
Analytical thin-layer chromatography (TLC) was performed on
Merck precoated TLC (silica gel 60 F254) plates. Compounds for
HRMS were analyzed by positive-mode electrospray ionization (ESI)
using an Agilent 6530 QTOF mass spectrometer. The crystal
structure analysis was performed on a Bruker Smart Apex II
diffractometer.
General Procedure for the Synthesis of Ketone Hydrazones
(1). A mixture of ketone (5.0 mmol, 1.0 equiv), 4-aminomorpholine
(5.5 mmol, 1.1 equiv), acetic acid (5.5 mmol, 1.1 equiv), and EtOH
(15.0 mL) in a 25 mL flask was stirred at room temperature for 1 h.
After completion of the reaction as indicated by TLC, purified water
was added to the mixture to form the precipitate. The precipitate was
washed with water and dried in vacuo to afford ketone hydrazone.
N-Morpholino-1-phenylethan-1-imine (1a): white solid (0.97 g,
95% yield), mp 70−71 °C; 1H NMR (CDCl3, 500 MHz) δ 7.75 (dd,
2H, J = 6.6, 2.7 Hz), 7.38 (dd, 3H, J = 4.9, 1.5 Hz), 3.88 (dd, 4H, J =
5.6, 3.9 Hz), 2.89 (dd, 4H, J = 5.6, 3.9 Hz), 2.39 (s, 3H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 159.9, 130.2 129.6, 128.3, 126.5, 66.3,
peroxy radical, G. Subsequent coordination of the peroxy
radical G with Cu(I) species affords intermediate H, which
undergoes an elimination process to provide final product 5a
and Cu(II) species.8b The obtained Cu(II) species oxidizes
sodium sulfinate 2a to sulfonyl radical A with concomitant
generation of a Cu(I) species.19b
Scheme 4. Plausible Mechanisms underlying Oxidative Sulfonylation
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55.2, 15.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H16N2O
205.1335, found 205.1356.
MHz) δ 7.92 (s, 1H), 7.66 (d, 1H, J = 7.8 Hz), 7.51 (d, 1H, J = 7.9
Hz), 7.26 (s, 1H), 3.89 (dd, 4H, J = 5.6, 3.9 Hz), 2.90 (dd, 4H, J =
5.6, 3.9 Hz), 2.37 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ
160.3, 136.0, 132.5, 129.8, 129.5, 125.1, 122.7, 66.2, 55.1, 15.7;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C12H15BrN2O 283.0441,
found 283.0439.
N-Morpholino-1-(p-tolyl)ethan-1-imine (1b): white solid (0.99 g,
1
91% yield), mp 74−75 °C; H NMR (CDCl3, 500 MHz) δ 7.65 (d,
2H, J = 8.2 Hz), 7.18 (d, 2H, J = 8.0 Hz), 3.87 (dd, 4H, J = 5.6, 3.9
Hz), 2.87 (dd, 4H, J = 5.6, 3.9 Hz), 2.36 (s, 6H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 163.3, 139.7, 135.9, 129.0, 126.4, 66.3, 55.2,
21.3, 15.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H18N2O
219.1492, found 219.1508.
N-Morpholino-1-(3-(trifluoromethyl)phenyl)ethan-1-imine (1l):
1
yellow solid (1.20 g, 88% yield), mp 87−88 °C; H NMR (CDCl3,
500 MHz) δ 8.02 (s, 1H), 7.94 (d, 1H, J = 7.9 Hz), 7.63 (d, 1H, J =
7.8 Hz), 7.49 (t, 1H, J = 7.8 Hz), 3.91−3.84 (m, 4H), 2.93−2.85 (m,
4H), 2.39 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 161.5, 139.5,
130.8 (q, JC−F = 32.8 Hz), 129.7, 128.8, 126.0 (q, JC−F = 3.8 Hz),
124.1 (q, JC−F = 273.4 Hz), 123.3 (q, JC−F = 3.8 Hz), 66.30, 55.14,
15.64; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H15F3N2O
273.1209, found 273.1215.
1-(4-Fluorophenyl)-N-morpholinoethan-1-imine (1c): white solid
1
(1.05 g, 95% yield), mp 65−66 °C; H NMR (CDCl3, 500 MHz) δ
7.75 (dd, 2H, J = 8.8, 5.5 Hz), 7.05 (t, 2H, J = 8.7 Hz), 3.87 (dd, 4H,
J = 5.6, 3.9 Hz), 2.87 (dd, 4H, J = 5.6, 3.9 Hz), 2.37 (s, 3H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 162.8 (d, JC−F = 243.2 Hz), 161.0, 134.9
(d, JC−F = 3.8 Hz), 128.4 (d, JC−F = 7.6 Hz), 115.2 (d, JC−F = 21.4
Hz), 66.3, 55.2, 15.7; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C12H15FN2O 223.1241, found 223.1261.
N-Morpholino-1-(o-tolyl)ethan-1-imine (1m): white solid (0.79 g,
72% yield), mp 90−91 °C; 1H NMR (CDCl3, 500 MHz) δ 7.22−7.16
(m, 4H), 3.99−3.78 (m, 4H), 2.99−2.82 (m, 4H), 2.32 (d, 6H, J =
22.1 Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 167.3, 139.9, 134.9,
130.8, 128.3, 127.5, 125.9, 66.4, 55.0, 25.8, 19.9; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C13H18N2O 219.1492, found 219.1493.
1-(2-Fluorophenyl)-N-morpholinoethan-1-imine (1n): white solid
1-(4-Chlorophenyl)-N-morpholinoethan-1-imine (1d): white
1
solid (0.91 g, 76% yield), mp 91−92 °C; H NMR (CDCl3, 500
MHz) δ 7.70 (d, 2H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.6 Hz), 3.88 (dd,
4H, J = 5.6, 3.9 Hz), 2.89 (dd, 4H, J = 5.6, 3.9 Hz), 2.37 (s, 3H);
13C{1H} NMR (CDCl3, 126 MHz) δ 160.8, 137.1, 131.5, 128.5,
127.8, 66.2, 55.2, 15.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C12H15ClN2O 239.0946, found 239.0953.
1
(0.89 g, 80% yield), mp 86−87 °C; H NMR (CDCl3, 500 MHz) δ
7.50 (ddd, 2H, J = 4.6, 2.4, 1.1 Hz,), 7.32 (dd, 1H, J = 8.1, 2.2 Hz),
7.06 (tdd, 1H, J = 8.3, 2.6, 0.9 Hz,), 3.87−3.85 (m, 4H), 2.88−2.86
(m, 4H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 162.8 (d,
1-(4-Bromophenyl)-N-morpholinoethan-1-imine (1e): white solid
1
(1.35 g, 96% yield), mp 94−95 °C; H NMR (CDCl3, 500 MHz) δ
J
C−F = 245.7 Hz), 161.9 (d, JC−F = 2.5 Hz), 141.5 (d, JC−F = 7.6 Hz),
7.70 (d, 2H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.6 Hz), 3.90−3.82 (m,
4H), 2.90−2.82 (m, 4H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz) δ 162.1, 137.1, 135.6, 128.5, 127.8, 66.3, 55.2, 15.5; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C12H15BrN2O 283.0441, found
283.0446.
129.8, (d, JC−F = 7.6 Hz), 122.1 (d, JC−F = 2.5 Hz), 116.4, (d, JC−F
=
21.4 Hz), 113.3 (d, JC−F = 21.4 Hz), 66.3, 55.1, 15.7; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C12H15FN2O 223.1241, found
223.1245.
1-(2,5-Difluorophenyl)-N-morpholinoethan-1-imine (1o): white
1-(4-Iodophenyl)-N-morpholinoethan-1-imine (1f): yellow solid
(1.43 g, 87% yield), mp 99−100 °C; 1H NMR (CDCl3, 500 MHz) δ
7.70 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H, J = 8.6 Hz), 3.91−3.83 (m,
4H), 2.91−2.82 (m, 4H), 2.33 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz) δ 162.2, 138.2, 137.4, 128.2, 95.9, 66.3, 55.1, 15.5; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C12H15IN2O 331.0302, found
331.0308.
N-Morpholino-1-(4-nitrophenyl)ethan-1-imine (1g). yellow solid
(1.21 g, 97% yield), mp 123−124 °C; 1H NMR (CDCl3, 500 MHz) δ
8.22 (d, 2H, J = 8.9 Hz), 7.93 (d, 2H, J = 8.9 Hz), 3.92−3.86 (m,
4H), 2.97−2.90 (m, 4H), 2.40 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz) δ 160.2, 148.3, 144.5, 127.2, 123.5, 66.2, 55.1, 15.9; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C12H15N3O3 250.1186, found
250.1191.
1
solid (0.87 g, 73% yield), mp 83−84 °C; H NMR (CDCl3, 500
MHz) δ 7.33−7.28 (m, 1H), 7.05−7.00 (m, 2H), 3.90−3.85 (m, 4H),
2.93−2.85 (m, 4H), 2.37 (d, 3H, J = 3.2 Hz,); 13C{1H} NMR
(CDCl3, 126 MHz) δ 160.9, 158.5 (d, JC−F = 243.2 Hz), 156.7 (d,
JC−F = 245.7 Hz), 128.8 (dd, JC−F = 7.6, 6.3 Hz), 117.3 (dd, JC−F
=
10.1, 7.6 Hz), 117.1 (dd, JC−F = 10.1, 7.6 Hz), 115.8 (dd, JC−F = 25.2,
3.8 Hz), 66.3, 54.9, 18.6 (d, JC−F = 6.3 Hz); HRMS (ESI-TOF) m/z
[M + H]+ calcd for C12H14F2N2O 241.1147, found 241.1159.
1-(3,5-Difluorophenyl)-N-morpholinoethan-1-imine (1p): white
1
solid (0.91 g, 76% yield), mp 92−93 °C; H NMR (CDCl3, 500
MHz) δ 7.30 (dd, 2H, J = 8.7, 2.0 Hz), 6.82 (tt, 1H, J = 8.6, 2.3 Hz),
3.92−3.83 (m, 4H), 2.93−2.83 (m, 4H), 2.33 (s, 3H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 163.0 (d, JC−F = 248.2 Hz), 162.9 (d, JC−F
248.2 Hz), 160.5, 109.4 (dd, JC−F = 20.2, 6.3 Hz), 104.7 (t, JC−F
=
=
N-Morpholino-1-(m-tolyl)ethan-1-imine (1h): white solid (0.89 g,
20.2 Hz), 66.24, 55.12, 15.63; HRMS (ESI-TOF) m/z [M + H]+
calcd for C12H14F2N2O 241.1147, found 241.1161.
1
82% yield), mp 81−82 °C; H NMR (CDCl3, 500 MHz) δ 7.57 (s,
1H), 7.51 (d, 1H, J = 7.7 Hz), 7.25 (d, 1H, J = 7.4 Hz), 7.19 (d, 1H, J
= 7.5 Hz), 3.90−3.85 (m, 4H), 2.92−2.82 (m, 4H), 2.38 (s, 3H), 2.37
(s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 163.8, 138.8, 138.0,
130.4, 128.2, 127.0, 123.7, 66.4, 55.2, 21.5, 15.9; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C13H18N2O 219.1492, found 219.1500.
1-(3-Fluorophenyl)-N-morpholinoethan-1-imine (1i): white solid
N-Morpholino-1-(3,4,5-trifluorophenyl)ethan-1-imine (1q): yel-
1
low solid (1.11 g, 86% yield), mp 101−102 °C; H NMR (CDCl3,
500 MHz) δ 7.43 (dd, 2H, J = 9.0, 6.7 Hz), 3.91−3.84 (m, 4H), 2.89
(s, 4H), 2.33 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 161.2
(m), 110.6 (m), 66.21, 55.15, 15.30; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C12H13F3N2O 259.1053, found 259.1053.
1
(0.92 g, 83% yield), mp 69−70 °C; H NMR (CDCl3, 500 MHz) δ
N-Morpholino-1-(thiophen-3-yl)ethan-1-imine (1r): white solid
(0.75 g, 71% yield), mp 122−123 °C; 1H NMR (CDCl3, 500 MHz) δ
7.56 (d, 2H, J = 4.6 Hz,), 7.30−7.27 (m, 1H), 3.88−3.84 (m, 4H),
2.84 (s, 4H), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ
159.5, 141.8, 126.0, 125.7, 124.6, 66.3, 55.2, 16.0; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C10H14N2OS 211.0900, found 211.0912.
N-Morpholino-1-phenylpropan-1-imine (1s): white solid (0.92 g,
84% yield), mp 81−82 °C; 1H NMR (CDCl3, 500 MHz) δ 7.67 (dd,
2H, J = 6.4, 2.8 Hz), 7.40−7.36 (m, 3H), 3.88 (s, 4H), 2.94 (d, 2H, J
= 7.3 Hz), 2.85 (s, 4H), 1.08 (t, 3H, J = 7.6 Hz); 13C{1H} NMR
(CDCl3, 126 MHz) δ 171.1, 137.4, 129.6, 128.4, 127.1, 66.3, 55.8,
22.1, 12.0; HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H18N2O
219.1492, found 219.1490.
7.54−7.47 (m, 2H), 7.34 (dd, 1H, J = 8.1, 6.1 Hz), 7.07 (tdd, 1H, J =
8.2, 2.6, 0.8 Hz), 3.87 (dd, 4H, J = 5.6, 3.9 Hz), 2.87 (dd, 4H, J = 5.6,
3.9 Hz), 2.35 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 162.8 (d,
JC−F = 243.2 Hz), 161.9, 141.0 (d, JC−F = 7.6 Hz), 129.8 (d, JC−F = 7.6
Hz), 122.1 (d, JC−F = 3.8 Hz), 116.4 (d, JC−F = 21.4 Hz), 113.4 (d,
JC−F = 21.4 Hz), 66.32, 55.14, 15.69; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C12H15FN2O 223.1241, found 223.1243.
1-(3-Chlorophenyl)-N-morpholinoethan-1-imine (1j): white solid
1
(1.12 g, 94% yield), mp 98−99 °C; H NMR (CDCl3, 500 MHz) δ
7.76 (s, 1H), 7.61 (d, 1H, J = 7.7 Hz), 7.34 (d, 1H, J = 8.1 Hz), 7.29
(t, 1H, J = 7.8 Hz), 3.90−3.83 (m, 4H), 2.90−2.83 (m, 4H), 2.34 (s,
3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 160.5, 138.6, 133.5, 132.6,
130.2, 128.3, 125.6, 66.3, 55.1, 15.4; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C12H15ClN2O 239.0946, found 239.0946.
N-Morpholino-1-phenylbutan-1-imine (1t): white solid (0.83 g,
72% yield), mp 87−88 °C; 1H NMR (CDCl3, 500 MHz) δ 7.65 (dd,
2H, J = 6.5, 2.9 Hz), 7.40−7.33 (m, 3H), 3.92−3.81 (m, 4H), 2.91−
1-(3-Bromophenyl)-N-morpholinoethan-1-imine (1k): yellow
1
solid (1.29 g, 91% yield), mp 103−104 °C; H NMR (CDCl3, 500
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2.85 (m, 2H), 2.84−2.74 (m, 4H), 1.48 (dd, 2H, J = 15.3, 7.6 Hz),
0.93 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 170.1,
137.9, 129.4, 128.4, 127.1, 66.3, 55.7, 30.7, 20.7, 14.2; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C14H20N2O 233.1648, found
233.1656.
N-Morpholino-1-phenylpentan-1-imine (1u): white solid (1.10 g,
89% yield), mp 95−96 °C; 1H NMR (CDCl3, 500 MHz) δ 7.65 (dd,
2H, J = 6.6, 3.0 Hz), 7.40−7.34 (m, 3H), 3.91−3.81 (m, 4H), 2.93−
2.87 (m, 2H), 2.85−2.75 (m, 4H), 1.46−1.40 (m, 2H), 1.35 (dd, 2H,
J = 14.5, 7.3 Hz,), 0.90 (t, 3H, J = 7.2 Hz,); 13C{1H} NMR (CDCl3,
126 MHz) δ 170.3, 137.9, 129.4, 128.4, 127.1, 66.4, 55.7, 29.4, 28.4,
22.8, 13.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H22N2O
247.1805, found 247.1800.
1-(4-Fluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3c):8b puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (214 mg, 77% yield); H NMR (CDCl3,
500 MHz) δ 8.00 (dd, 2H, J = 8.8, 5.3 Hz), 7.93−7.85 (m, 2H), 7.68
(t, 1H, J = 7.5 Hz), 7.56 (t, 2H, J = 7.8 Hz), 7.16 (t, 2H, J = 8.5 Hz),
4.70 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 186.4, 166.5 (d,
JC−F = 258.3 Hz), 138.6, 134.4, 132.3 (d, JC−F = 10.1 Hz), 132.2,
129.3, 128.6, 116.2 (d, JC−F = 21.4 Hz), 63.6. 19F{1H} NMR (CDCl3,
471 MHz) δ −102.3.
1-(4-Chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (3d):8b puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (46 mg, 79% yield); 1H NMR (CDCl3, 500
MHz) δ 7.89 (dd, 4H, J = 13.9, 5.0 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.57
(t, 2H, J = 7.8 Hz), 7.47 (d, 2H, J = 8.6 Hz), 4.71 (s, 2H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 186.9, 141.2, 138.5, 134.4, 134.0, 130.8,
129.3, 129.3, 128.6, 63.6.
N-Morpholino-3,4-dihydronaphthalen-1(2H)-imine (1v): white
1
solid (0.99 g, 86% yield), mp 107−108 °C; H NMR (CDCl3, 500
MHz) δ 8.17 (d, 1H, J = 7.8 Hz), 7.30 (dd, 1H, J = 14.8, 7.4 Hz), 7.20
(t, 1H, J = 7.5 Hz), 7.13 (d, 1H, J = 7.5 Hz), 3.86 (s, 4H), 2.95−2.73
(m, 8H), 1.98−1.87 (m, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ
162.4, 144.5, 140.0, 133.4, 128.7, 126.3, 125.2, 66.4, 55.1, 39.2, 29.8,
22.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H18N2O
231.1492, found 231.1500.
1-(4-Bromophenyl)-2-(phenylsulfonyl)ethan-1-one (3e):8b puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (50 mg, 74% yield); 1H NMR (CDCl3, 500
MHz) δ 7.89 (t, 4H, J = 7.9 Hz), 7.68 (t, 1H, J = 7.5 Hz), 7.56 (t, 2H,
J = 7.8 Hz), 7.46 (d, 2H, J = 8.6 Hz), 4.71 (s, 2H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 186.9, 141.2, 138.6, 134.4, 134.1, 130.8, 129.3,
129.3, 128.6, 63.6.
General Procedure for Oxidative Sulfonylation of Ketone
Hydrazones. A mixture of ketone hydrazone (1) (0.2 mmol, 1.0
equiv), sodium sulfinate (2) (0.4 mmol, 2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (0.4 mmol, 2.0 equiv), and DCE
(1.0 mL) in a 15 mL tube was stirred at 80 °C in an oil bath for 3 h.
After completion of the reaction as indicated by TLC, a saturated
NaHCO3 solution was added to the residue. The mixture was then
extracted with DCM, and the collected organic layer was washed with
brine and dried with MgSO4. The solvent was removed in vacuo, and
the obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
General Procedure for the Synthesis of Product 3c on 1
mmol Scale. A mixture of ketone hydrazone (1h) (1.0 mmol, 1.0
equiv), sodium sulfinate (2) (2.0 mmol, 2.0 equiv), Cu2O (10 mol
%), Ag2CO3 (20 mol %), K2S2O8 (2.0 mmol, 2.0 equiv), and DCE
(5.0 mL) in a 15 mL tube was stirred at 80 °C in an oil bath for 3 h.
After completion of the reaction as indicated by TLC, a saturated
NaHCO3 solution was added to the residue. The mixture was then
extracted with DCM, and the collected organic layer was washed with
brine and dried with MgSO4. The solvent was removed in vacuo, and
the obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
1-(4-Iodophenyl)-2-(phenylsulfonyl)ethan-1-one (3f):8d purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
1
EA = 3:1), white solid (53 mg, 69% yield); H NMR (CDCl3, 500
MHz) δ 7.91−7.82 (m, 4H), 7.69−7.63 (m, 3H), 7.56 (t, 2H, J = 7.7
Hz), 4.70 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.5, 138.3,
134.9, 134.4, 131.5, 130.6, 129.3, 128.6, 103.2, 63.5.
1-(4-Nitrophenyl)-2-(phenylsulfonyl)ethan-1-one (3g):8c purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
1
EA = 3:1), white solid (38 mg, 62% yield); H NMR (CDCl3, 500
MHz) δ 8.33 (d, 2H, J = 8.6 Hz), 8.15 (d, 2H, J = 8.6 Hz), 7.89 (d,
2H, J = 7.6 Hz), 7.71 (t, 1H, J = 7.4 Hz), 7.59 (t, 2H, J = 7.7 Hz),
4.80 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 186.9, 150.9,
139.9, 138.3, 134.7, 130.5, 129.5, 128.5, 124.0, 63.9.
2-(Phenylsulfonyl)-1-(m-tolyl)ethan-1-one (3h):8b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (44 mg, 81% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.90 (d, 2H, J = 7.6 Hz), 7.73 (d, 2H, J = 11.2 Hz), 7.67 (t, 1H, J =
7.3 Hz), 7.55 (t, 2H, J = 7.7 Hz), 7.43 (d, 1H, J = 7.5 Hz), 7.37 (t,
1H, J = 7.6 Hz), 4.73 (s, 2H), 2.40 (s, 3H); 13C{1H} NMR (CDCl3,
126 MHz) δ 188.1, 138.8, 138.8, 135.8, 135.2, 134.2, 129.7, 129.2,
128.8, 128.6, 126.6, 63.5, 21.3.
1-(3-Fluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3i):19a puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (44 mg, 79% yield); 1H NMR (CDCl3, 500
MHz) δ 7.90 (dd, 2H, J = 8.4, 1.1 Hz), 7.77−7.73 (m, 1H), 7.68 (dd,
1H, J = 10.7, 4.3 Hz), 7.63−7.60 (m, 1H), 7.57 (t, 2H, J = 7.8 Hz),
7.48 (td, 1H, J = 8.0, 5.5 Hz), 7.33 (tdd, 1H, J = 8.2, 2.6, 0.7 Hz), 4.71
General Procedure for Gram-Scale Sulfonylation of
Acetophenone Hydrazone. A mixture of acetophenone phenyl-
hydrazone (1a) (5.0 mmol, 1.0 equiv), sodium benzenesulfinate (2a)
(10.0 mmol, 2.0 equiv), Cu2O (10 mol %), Ag2CO3 (20 mol %),
K2S2O8 (10.0 mmol, 2.0 equiv), and DCE (25 mL) was stirred in a
100 mL flask at 80 °C in an oil bath for 3 h. After completion of the
reaction as indicated by TLC, a saturated NaHCO3 solution was
added to the residue. The mixture was then extracted with DCM, and
the collected organic layer was washed with brine and dried with
MgSO4. The solvent was removed in vacuo, and the obtained residue
was further purified by silica gel column chromatography (200−300
mesh silica gel, PE/EA = 3:1).
(s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 186.9, 162.8 (d, JC−F
=
249.5 Hz), 138.6, 137.7 (d, JC−F = 6.3 Hz), 134.4, 130.6 (d, JC−F = 7.6
Hz), 129.3, 128.6, 125.3 (d, JC−F = 2.5 Hz), 121.6 (d, JC−F = 21.4 Hz),
115.8 (d, JC−F = 22.7 Hz), 63.6. 19F{1H} NMR (CDCl3, 471 MHz) δ
−110.9.
1-(3-Chlorophenyl)-2-(phenylsulfonyl)ethan-1-one (3j):19b puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (44 mg, 75% yield); 1H NMR (CDCl3, 500
MHz) δ 7.91−7.82 (m, 4H), 7.69 (t, 1H, J = 7.5 Hz), 7.60−7.55 (m,
3H), 7.44 (t, 1H, J = 7.9 Hz), 4.71 (s, 2H); 13C{1H} NMR (CDCl3,
126 MHz) δ 186.9, 138.5, 137.2, 135.3, 134.5, 134.4, 130.2, 129.4,
129.2, 128.6, 127.6, 63.5.
1-Phenyl-2-(phenylsulfonyl)ethan-1-one (3a):9a purified by silica
gel column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
white solid (44 mg, 85% yield); 1H NMR (CDCl3, 500 MHz) δ 7.94
(d, 2H, J = 8.2 Hz), 7.90 (d, 2H, J = 8.2 Hz), 7.66 (t, 1H, J = 7.5 Hz),
7.62 (t, 1H, J = 7.4 Hz), 7.55 (t, 2H, J = 7.7 Hz), 7.48 (t, 2H, J = 7.7
Hz), 4.74 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 188.0, 139.0,
135.7, 134.4, 134.3, 129.3, 129.2, 128.9, 128.6, 63.5.
1-(3-Bromophenyl)-2-(phenylsulfonyl)ethan-1-one (3k):21c puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (51 mg, 76% yield); 1H NMR (CDCl3, 500
MHz) δ 8.03 (t, 1H, J = 1.8 Hz), 7.89 (d, 3H, J = 7.4 Hz), 7.74 (dd,
1H, J = 8.0, 0.9 Hz), 7.69 (t, 1H, J = 7.5 Hz), 7.57 (t, 2H, J = 7.9 Hz),
7.38 (t, 1H, J = 7.9 Hz), 4.70 (s, 2H); 13C{1H} NMR (CDCl3, 126
MHz) δ 186.8, 138.5, 137.4, 137.2, 134.5, 132.1, 130.4, 129.3, 128.6,
128.0, 123.3, 63.5.
2-(Phenylsulfonyl)-1-(p-tolyl)ethan-1-one (3b):8b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (45 mg, 82% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.82 (dd, 2H, J = 8.3, 1.1 Hz), 7.77 (d, 2H, J = 8.3 Hz), 7.59 (t, 1H,
J = 7.5 Hz,), 7.48 (t, 2H, J = 7.8 Hz,), 7.21 (d, 2H, J = 8.0 Hz), 4.64
(s, 2H), 2.36 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.5,
145.7, 138.77, 134.2, 133.3, 129.6, 129.5, 129.2, 128.6, 63.5, 21.8.
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2-(Phenylsulfonyl)-1-(3-(trifluoromethyl)phenyl)ethan-1-one
(3l). purified by silica gel column chromatography (200−300 mesh
silica gel, PE/EA = 3:1), white solid (53 mg, 81% yield), mp 110−111
MHz) δ 181.5, 141.1, 138.6, 135.6, 134.3, 129.3, 128.6, 127.2, 127.0,
65.2.
1-Phenyl-2-(phenylsulfonyl)propan-1-one (3s):8b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (41 mg, 75% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.97 (d, 2H, J = 7.5 Hz), 7.79 (d, 2H, J = 7.4 Hz), 7.65 (t, 1H, J =
7.5 Hz), 7.61 (t, 1H, J = 7.4 Hz), 7.52 (t, 2H, J = 7.8 Hz), 7.48 (t, 2H,
J = 7.8 Hz), 5.17 (q, 1H, J = 6.9 Hz), 1.58 (d, 3H, J = 6.9 Hz);
13C{1H} NMR (CDCl3, 126 MHz) δ 192.5, 136.2, 136.1, 134.2,
134.1, 129.8, 129.2, 128.9, 128.8, 65.0, 13.2.
1
°C; H NMR (CDCl3, 500 MHz) δ 8.17 (d, 2H, J = 9.2 Hz), 7.93−
7.85 (m, 3H), 7.71−7.63 (m, 2H), 7.57 (t, 2H, J = 7.8 Hz), 4.76 (s,
2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 186.9, 138.5, 136.2, 134.5,
132.6, 131.6 (q, JC−F = 32.8 Hz), 130.7 (q, JC−F = 3.8 Hz), 129.6,
129.4, 128.6, 126.0 (q, JC−F = 3.8 Hz), 123.4 (q, JC−F = 273.42 Hz),
63.6. 19F{1H} NMR (CDCl3, 471 MHz) δ −62.9; HRMS (ESI-TOF)
m/z [M + Na]+ calcd for C15H11F3O3S 351.0273, found 351.0264.
2-(Phenylsulfonyl)-1-(o-tolyl)ethan-1-one (3m):8b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (39 mg, 71% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.90 (d, 2H, J = 7.5 Hz), 7.73 (d, 2H, J = 11.2 Hz), 7.67 (t, 1H, J =
7.4 Hz), 7.55 (t, 2H, J = 7.8 Hz), 7.43 (d, 1H, J = 7.5 Hz), 7.36 (t,
1H, J = 7.6 Hz), 4.73 (s, 2H), 2.40 (s, 3H); 13C{1H} NMR (CDCl3,
126 MHz) δ 188.2, 138.8, 138.7, 135.7, 135.3, 134.3, 129.7, 129.2,
128.8, 128.6, 126.6, 63.4, 21.4.
1-Phenyl-2-(phenylsulfonyl)butan-1-one (3t):9b purified by silica
gel column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
1
white solid (41 mg, 71% yield); H NMR (CDCl3, 500 MHz) δ
7.90−7.86 (m, 2H), 7.73−7.68 (m, 2H), 7.54 (ddd, 2H, J = 15.1, 8.0,
1.1 Hz), 7.41 (dt, 4H, J = 15.7, 7.8 Hz), 4.94 (dd, 1H, J = 10.8, 3.7
Hz,), 2.14−2.05 (m, 1H), 2.04−1.95 (m, 1H), 0.81 (t, 3H, J = 7.4
Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 192.7, 137.4, 136.5, 134.2,
134.1, 129.8, 129.0, 128.9, 128.8, 71.4, 22.0, 11.5.
1-(2-Fluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3n):8d puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (36 mg, 65% yield); 1H NMR (CDCl3, 500
MHz) δ 7.91 (d, 2H, J = 7.5 Hz), 7.81 (td, 1H, J = 7.7, 1.7 Hz), 7.65
(t, 1H, J = 7.5 Hz), 7.55 (dt, 3H, J = 15.7, 7.9 Hz), 7.24 (d, 1H, J =
7.7 Hz), 7.11 (dd, 1H, J = 11.4, 8.4 Hz), 4.81 (s, 2H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 186.0 (d, JC−F = 2.5 Hz), 161.9 (d, JC−F = 255.8
Hz), 139.1, 136.2 (d, JC−F = 8.8 Hz), 134.2, 131.2 (d, JC−F = 1.3 Hz),
129.2, 128.6, 124.9 (d, JC−F = 2.5 Hz), 124.5 (d, JC−F = 11.3 Hz),
116.9 (d, JC−F = 23.9 Hz), 67.1 (d, JC−F = 8.8 Hz); 19F{1H} NMR
(CDCl3, 471 MHz) δ −109.2.
1-Phenyl-2-(phenylsulfonyl)pentan-1-one (3u): purified by silica
gel column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
white solid (47 mg, 78% yield), mp 132−133 °C; 1H NMR (CDCl3,
500 MHz) δ 7.88 (dd, 2H, J = 8.4, 1.2 Hz), 7.70 (dd, 2H, J = 8.4, 1.2
Hz), 7.58−7.54 (m, 1H), 7.53 (dd, 1H, J = 10.5, 4.3 Hz), 7.44 (t, 2H,
J = 7.8 Hz), 7.40 (t, 2H, J = 7.8 Hz), 5.02 (dd, 1H, J = 10.3, 4.2 Hz),
2.04−1.93 (m, 2H), 1.21−1.16 (m, 2H), 0.78 (t, 3H, J = 7.3 Hz);
13C{1H} NMR (CDCl3, 126 MHz) δ 192.7, 137.2, 136.5, 134.2,
134.1, 129.8, 128.94, 128.9, 128.8, 69.8, 30.3, 20.4, 13.8; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H18O3S 325.0869, found
325.0879.
1-(2,5-Difluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3o): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
2-(Phenylsulfonyl)-3,4-dihydronaphthalen-1(2H)-one (3v):9b pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (36 mg, 63% yield); 1H NMR (CDCl3, 500
1
PE/EA = 3:1), white solid (47 mg, 79% yield), mp 120−121 °C; H
NMR (CDCl3, 500 MHz) δ 7.91 (d, 2H, J = 7.4 Hz), 7.67 (t, 1H, J =
7.5 Hz), 7.56 (t, 2H, J = 7.8 Hz), 7.48 (ddd, 1H, J = 8.5, 5.5, 3.3 Hz),
7.28−7.24 (m, 1H), 7.15−7.09 (m, 1H), 4.80 (s, 2H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 184.9 (dd, JC−F = 3.4, 1.5 Hz), 158.7 (dd, JC−F
= 247.0, 2.5 Hz), 157.9 (dd, JC−F = 252.0, 2.5 Hz), 139.0, 134.3,
129.3, 128.6, 125.4 (dd, JC−F = 13.8, 6.7 Hz), 123.0 (dd, JC−F = 24.6,
9.8 Hz), 118.5 (dd, JC−F = 27.1, 8.0 Hz), 116.9 (dd, JC−F = 25.2, 2.5
Hz); 66.8 (d, JC−F = 9.1 Hz); 19F{1H} NMR (CDCl3, 471 MHz) δ
−114.5 (d, JF−F = 18.4 Hz), −116.5 (d, JF−F = 18.5 Hz); HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C14H10F2O3S 319.0211, found
319.0221.
1
MHz) δ H NMR (500 MHz, CDCl3) δ 7.91 (d, 1H, J = 7.9 Hz),
7.85 (dd, 2H, J = 8.5, 0.9 Hz), 7.60 (t, 1H, J = 7.5 Hz), 7.50 (t, 2H, J
= 7.8 Hz), 7.44 (t, 1H, J = 8.1 Hz), 7.24 (t, 1H, J = 7.6 Hz), 7.20 (d,
1H, J = 7.6 Hz), 4.05 (t, 1H, J = 5.7 Hz), 3.44 (ddd, 1H, J = 16.8, 9.6,
4.6 Hz), 2.92 (dt, 1H, J = 17.0, 5.5 Hz), 2.79 (ddd, 1H, J = 17.0, 10.9,
6.1 Hz), 2.59 (ddd, 1H, J = 14.7, 10.0, 5.1 Hz); 13C{1H} NMR
(CDCl3, 126 MHz) δ 188.7, 143.6, 139.0, 134.6, 134.0, 131.7, 129.12,
129.0, 129.0, 128.0, 127.1, 69.7, 26.6, 23.6.
1-Phenyl-2-tosylethan-1-one (3x):9a purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1), white solid
(44 mg, 81% yield); 1H NMR (CDCl3, 500 MHz) δ 7.95 (dd, 2H, J =
8.4, 1.1 Hz), 7.76 (d, 2H, J = 8.3 Hz), 7.62 (t, 1H, J = 7.4 Hz), 7.48
(dd, 2H, J = 8.0, 7.6 Hz), 7.33 (d, 2H, J = 8.0 Hz), 4.72 (s, 2H), 2.44
(s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 188.2, 145.4, 135.8,
135.7, 134.4, 129.9, 129.4, 128.9, 128.6, 63.6, 21.8.
1-(3,5-Difluorophenyl)-2-(phenylsulfonyl)ethan-1-one (3p):25c
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (43 mg, 73% yield); 1H NMR (CDCl3,
500 MHz) δ 7.82 (dd, 2H, J = 8.4, 1.1 Hz), 7.63 (dd, 1H, J = 10.7, 4.2
Hz), 7.51 (t, 2H, J = 7.8 Hz), 7.40 (dd, 2H, J = 7.6, 2.2 Hz), 7.01
(ddd, 1H, J = 8.3, 5.3, 2.3 Hz), 4.60 (s, 2H); 13C{1H} NMR (CDCl3,
2-((4-(tert-Butyl)phenyl)sulfonyl)-1-phenylethan-1-one (3y):22b
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (49 mg, 78% yield); 1H NMR (CDCl3,
500 MHz) δ 7.93 (dd, 2H, J = 8.3, 1.1 Hz), 7.81 (d, 2H, J = 8.6 Hz),
7.61 (t, 1H, J = 7.4 Hz), 7.53 (d, 2H, J = 8.6 Hz), 7.47 (t, 2H, J = 7.8
Hz), 4.72 (s, 2H), 1.34 (s, 9H); 13C{1H} NMR (CDCl3, 126 MHz) δ
188.1, 158.3, 135.9, 135.8, 134.3, 129.3, 128.8, 128.5, 126.2, 63.5,
35.3, 31.0.
126 MHz) δ 185.8, 163.1 (dd, JC−F = 252.0, 11.3 Hz), 138.4 (t, JC−F
=
7.7 Hz), 138.4, 134.6, 129.4, 128.6, 112.4 (dd, JC−F = 20.2, 6.6 Hz),
109.8 (t, JC−F = 25.2 Hz), 63.7. 19F{1H} NMR (CDCl3, 471 MHz) δ
−106.9.
2-(Phenylsulfonyl)-1-(3,4,5-trifluorophenyl)ethan-1-one (3q): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (42 mg, 67% yield), mp 124−125 °C; H
2-((4-Methoxyphenyl)sulfonyl)-1-phenylethan-1-one (3z):9a pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (46 mg, 80% yield); 1H NMR (CDCl3, 500
MHz) δ 7.95 (d, 2H, J = 8.3 Hz), 7.81 (dd, 2H, J = 8.8, 0.7 Hz), 7.62
(td, 1H, J = 7.6, 1.1 Hz), 7.49 (t, 2H, J = 7.5 Hz), 6.99 (dd, 2H, J =
8.8, 0.7 Hz), 4.72 (s, 2H), 3.88 (s, 3H); 13C{1H} NMR (CDCl3, 126
MHz) δ 188.3, 164.2, 135.8, 134.4, 130.9, 130.2, 129.4, 128.9, 114.4,
63.8, 55.7.
NMR (CDCl3, 500 MHz) δ 7.88 (d, 2H, J = 7.5 Hz), 7.71 (t, 1H, J =
7.5 Hz), 7.64 (t, 2H, J = 7.0 Hz), 7.59 (t, 2H, J = 7.8 Hz), 4.66 (s,
2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 184.9, 151.3 (ddd, JC−F
=
254.8, 21.4, 3.2 Hz), 144.0 (dt, JC−F = 283.5, 15.1 Hz), 138.2, 134.7,
131.3 (dd, JC−F = 10.3, 6.0 Hz), 129.5, 128.5, 114.2 (dd, JC−F = 16.9,
5.5 Hz), 63.6. 19F{1H} NMR (CDCl3, 471 MHz) δ −131.0 (d, JF−F
=
18.8 Hz), −149.4; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C14H9F3O3S 337.0117, found 337.0102.
2-(Phenylsulfonyl)-1-(thiophen-3-yl)ethan-1-one (3r):22a purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
1-Phenyl-2-((4-(trifluoromethoxy)phenyl)sulfonyl)ethan-1-one
(3aa):22c purified by silica gel column chromatography (200−300
1
1
mesh silica gel, PE/EA = 3:1), white solid (58 mg, 82% yield); H
EA = 3:1), white solid (38 mg, 72% yield); H NMR (CDCl3, 500
NMR (CDCl3, 500 MHz) δ 7.96 (d, 2H, J = 8.9 Hz), 7.94−7.90 (m,
2H), 7.64 (t, 1H, J = 7.4 Hz), 7.49 (t, 2H, J = 7.8 Hz), 7.36 (d, 2H, J
= 8.2 Hz), 4.76 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.9,
MHz) δ 8.22−8.16 (m, 1H), 7.89 (d, 2H, J = 7.4 Hz), 7.67 (t, 1H, J =
7.5 Hz), 7.55 (t, 2H, J = 7.8 Hz), 7.52 (dd, 1H, J = 5.1, 1.1 Hz), 7.33
(dd, 1H, J = 5.1, 2.8 Hz), 4.62 (s, 2H); 13C{1H} NMR (CDCl3, 126
3713
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J. Org. Chem. 2021, 86, 3706−3720

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pubs.acs.org/joc
Article
153.4, 136.8, 135.6, 134.6, 131.1, 129.2, 129.0, 120.8, 120.2 (q, JC−F
260.8 Hz), 63.3; 19F{1H} NMR (CDCl3, 471 MHz) δ −57.6.
=
MHz) δ 8.76 (t, 1H, J = 1.9 Hz), 8.53 (dd, 1H, J = 8.2, 1.2 Hz), 8.26
(d, 1H, J = 7.8 Hz), 7.97−7.92 (m, 2H), 7.80 (t, 1H, J = 8.0 Hz), 7.66
(t, 1H, J = 7.4 Hz), 7.52 (t, 2H, J = 7.8 Hz), 4.83 (s, 2H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 187.7, 148.3, 140.7, 135.4, 134.9, 134.5,
130.6, 129.2, 129.1, 128.7, 124.2, 62.9.
2-((4-Chlorophenyl)sulfonyl)-1-phenylethan-1-one (3ab):9a puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (46 mg, 79% yield); 1H NMR (CDCl3, 500
MHz) δ 7.94 (d, 2H, J = 7.4 Hz,), 7.84 (d, 2H, J = 8.6 Hz), 7.65 (t,
1H, J = 7.4 Hz), 7.51 (dd, 4H, J = 16.0, 8.1 Hz), 4.75 (s, 2H);
13C{1H} NMR (CDCl3, 126 MHz) δ 187.9, 141.2, 137.0, 135.6,
134.6, 130.2, 129.6, 129.3, 129.0, 63.3.
1-Phenyl-2-(o-tolylsulfonyl)ethan-1-one (3ak):22a purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (38 mg, 70% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.99−7.93 (m, 2H), 7.89 (d, 1H, J = 7.9 Hz), 7.62 (t, 1H, J = 7.4
Hz), 7.52 (t, 1H, J = 7.0 Hz), 7.48 (t, 2H, J = 7.8 Hz), 7.33 (dd, 2H, J
= 14.5, 7.4 Hz), 4.76 (s, 2H), 2.73 (s, 3H); 13C{1H} NMR (CDCl3,
126 MHz) δ 188.0, 138.4, 137.0, 135.9, 134.4, 134.3, 132.8, 130.6,
129.4, 128.9, 126.6, 63.0, 20.6.
2-((4-Bromophenyl)sulfonyl)-1-phenylethan-1-one (3ac):9a puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (54 mg, 80% yield); 1H NMR (CDCl3, 500
MHz) δ 7.94 (d, 2H, J = 7.5 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.70 (d,
2H, J = 8.6 Hz), 7.65 (t, 1H, J = 7.4 Hz), 7.50 (t, 2H, J = 7.8 Hz),
4.74 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.9, 137.6,
135.6, 134.6, 132.6, 130.3, 129.8, 129.3, 120.0, 63.3.
2-((2-Fluorophenyl)sulfonyl)-1-phenylethan-1-one (3al):24a puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (36 mg, 65% yield); 1H NMR (CDCl3, 500
MHz) δ 7.96 (d, 2H, J = 7.5 Hz), 7.88 (t, 1H, J = 7.4 Hz), 7.73−7.61
(m, 2H), 7.50 (t, 2H, J = 7.7 Hz), 7.33 (t, 1H, J = 7.6 Hz), 7.26 (s,
1H), 4.93 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.8, 159.7
(d, JC−F = 255.8 Hz), 136.7 (d, JC−F = 8.8 Hz), 135.7, 134.6, 130.8,
129.2, 129.0, 126.7 (d, JC−F = 15.1 Hz), 124.8 (d, JC−F = 3.8 Hz),
117.2 (d, JC−F = 21.4 Hz), 62.2 (d, JC−F = 2.5 Hz); 19F{1H} NMR
(CDCl3, 471 MHz) δ −107.7.
Ethyl 4-((2-Oxo-2-phenylethyl)sulfonyl)benzoate (3ad):26a puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (48 mg, 72% yield); 1H NMR (CDCl3, 500
MHz) δ 8.21 (d, 2H, J = 8.4 Hz), 7.98 (d, 2H, J = 8.4 Hz), 7.94 (dd,
2H, J = 8.3, 1.0 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.50 (t, 2H, J = 7.8 Hz),
4.77 (s, 2H), 4.43 (q, 2H, J = 7.1 Hz), 1.42 (t, 3H, J = 7.1 Hz);
13C{1H} NMR (CDCl3, 126 MHz) δ 187.8, 164.9, 142.2, 135.6,
135.6, 134.6, 130.3, 129.3, 129.0, 128.8, 63.3, 61.9, 14.3.
2-((2-Bromophenyl)sulfonyl)-1-phenylethan-1-one (3am):21b pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (45 mg, 66% yield); 1H NMR (CDCl3, 500
MHz) δ 8.09 (dd, 1H, J = 6.1, 3.5 Hz), 7.97−7.92 (m, 2H), 7.79 (dd,
1H, J = 5.5, 3.6 Hz), 7.62 (dd, 1H, J = 10.8, 4.1 Hz), 7.49 (dt, 4H, J =
11.6, 4.4 Hz), 5.09 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ
187.8, 138.2, 135.8, 135.4, 135.1, 134.5, 132.5, 129.2, 128.9, 128.1,
120.9, 60.5.
1-Phenyl-2-(m-tolylsulfonyl)ethan-1-one (3ae):23a purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (45 mg, 83% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.94 (dd, 2H, J = 8.3, 1.0 Hz), 7.69 (d, 2H, J = 1.6 Hz), 7.62 (t, 1H,
J = 7.4 Hz), 7.51−7.42 (m, 4H), 4.73 (s, 2H), 2.42 (s, 3H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 188.0, 139.6, 138.6, 135.8, 135.1, 134.4,
129.3, 129.1, 128.9, 128.8, 125.7, 63.6, 21.3.
2-((3-Fluorophenyl)sulfonyl)-1-phenylethan-1-one (3af):9c puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (42 mg, 75% yield); 1H NMR (CDCl3, 500
MHz) δ 7.98−7.88 (m, 2H), 7.71 (d, 1H, J = 7.8 Hz), 7.63 (dd, 2H, J
= 15.7, 8.1 Hz), 7.58−7.53 (m, 1H), 7.51 (dd, 2H, J = 14.7, 6.6 Hz),
7.37 (td, 1H, J = 8.2, 2.1 Hz), 4.75 (s, 2H); 13C{1H} NMR (CDCl3,
126 MHz) δ 187.7, 162.3 (d, JC−F = 238.1 Hz), 135.6, 134.6, 131.1 (d,
1-Phenyl-2-((2-(trifluoromethyl)phenyl)sulfonyl)ethan-1-one
(3an):22c purified by silica gel column chromatography (200−300
1
mesh silica gel, PE/EA = 3:1), white solid (33 mg, 51% yield); H
NMR (CDCl3, 500 MHz) δ 8.18 (d, 1H, J = 7.8 Hz), 7.94 (d, 3H, J =
8.3 Hz), 7.80 (t, 1H, J = 7.6 Hz), 7.74 (t, 1H, J = 7.6 Hz), 7.64 (t, 1H,
J = 7.4 Hz), 7.50 (t, 2H, J = 7.8 Hz), 4.91 (s, 2H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 187.9, 153.1, 137.5 (q, JC−F = 31.5 Hz), 135.7,
134.6, 134.3, 133.8, 132.5, 129.2, 129.0, 128.5 (q, JC−F = 6.3 Hz),
122.8 (q, JC−F = 273.4 Hz), 63.3. 19F{1H} NMR (CDCl3, 471 MHz) δ
−56.7.
J
C−F = 7.6 Hz), 129.3, 120.0, 124.5 (d, JC−F = 2.5 Hz), 121.6 (d, JC−F
= 21.4 Hz), 116.1 (d, JC−F = 25.2 Hz), 100.1 (d, JC−F = 13.8 Hz),
63.3. 19F{1H} NMR (CDCl3, 471 MHz) δ −108.9.
2-((3,5-Difluorophenyl)sulfonyl)-1-phenylethan-1-one (3ao):24b
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (41 mg, 70% yield); 1H NMR (CDCl3,
500 MHz) δ 7.97−7.90 (m, 2H), 7.66 (t, 1H, J = 7.0 Hz), 7.51 (t, 2H,
J = 7.7 Hz), 7.49−7.41 (m, 2H), 7.14−7.09 (m, 1H), 4.77 (s, 2H);
13C{1H} NMR (CDCl3, 126 MHz) δ 187.5, 162.8 (dd, JC−F = 255.8,
11.3 Hz), 141.8, 135.4, 134.8, 129.2, 129.1, 112.8 (dd, JC−F = 21.4, 7.6
Hz), 110.0 (t, JC−F = 25.2 Hz), 63.0. 19F{1H} NMR (CDCl3, 471
MHz) δ −104.8.
2-((3-Chlorophenyl)sulfonyl)-1-phenylethan-1-one (3ag):22c pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (44 mg, 75% yield); 1H NMR (CDCl3, 500
MHz) δ 7.94 (d, 2H, J = 7.5 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J = 7.8
Hz), 7.65 (t, 2H, J = 7.5 Hz), 7.51 (t, 3H, J = 7.8 Hz), 4.76 (s, 2H);
13C{1H} NMR (CDCl3, 126 MHz) δ 187.7, 140.3, 135.6, 135.5,
134.6, 134.5, 130.5, 129.3, 129.0, 128.7, 126.9, 63.3.
2-((3-Bromophenyl)sulfonyl)-1-phenylethan-1-one (3ah):23b pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (52 mg, 77% yield); 1H NMR (CDCl3, 500
MHz) δ 8.04 (t, 1H, J = 1.8 Hz), 7.93 (dd, 2H, J = 8.3, 1.1 Hz), 7.84
(d, 1H, J = 7.9 Hz), 7.78 (d, 1H, J = 8.0 Hz), 7.64 (t, 1H, J = 7.4 Hz),
7.50 (t, 2H, J = 7.8 Hz), 7.43 (t, 1H, J = 7.9 Hz), 4.75 (s, 2H);
13C{1H} NMR (CDCl3, 126 MHz) δ 187.7, 140.5, 137.3, 135.6,
2-((3,4-Difluorophenyl)sulfonyl)-1-phenylethan-1-one (3ap): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (43 mg, 72% yield), mp 127−128 °C; 1H
NMR (CDCl3, 500 MHz) δ 7.96−7.91 (m, 2H), 7.76 (ddd, 1H, J =
9.2, 7.2, 2.2 Hz), 7.72−7.68 (m, 1H), 7.67−7.62 (m, 1H), 7.51 (t,
2H, J = 7.8 Hz), 7.35 (td, 1H, J = 9.0, 7.3 Hz), 4.76 (s, 2H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 187.8, 154.3 (dd, JC−F = 260.8, 12.6 Hz),
150.2 (dd, JC−F = 255.8, 13.9 Hz), 135.5, 135.3 (t, JC−F = 3.8 Hz),
134.6, 131.5, 130.7, 129.3, 129.0, 127.3, 123.2, 63.3.
1-Phenyl-2-((3-(trifluoromethyl)phenyl)sulfonyl)ethan-1-one
(3ai): purified by silica gel column chromatography (200−300 mesh
silica gel, PE/EA = 3:1), white solid (47 mg, 71% yield), mp 115−116
°C; 1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 8.12 (d, 1H, J = 7.9
Hz), 7.94−7.89 (m, 3H), 7.71 (t, 1H, J = 7.9 Hz), 7.64 (t, 1H, J = 7.4
Hz), 7.49 (t, 2H, J = 7.8 Hz), 4.79 (s, 2H); 13C{1H} NMR (CDCl3,
126 MHz) δ 187.7, 139.9, 135.5, 134.7, 132.2, 131.9 (q, JC−F = 34.0
Hz), 130.9 (q, JC−F = 3.8 Hz), 130.0, 129.2, 129.0, 125.9 (q, JC−F = 3.8
Hz), 123.0 (q, JC−F = 273.4 Hz), 63.2. 19F{1H} NMR (CDCl3, 471
MHz) δ −62.8; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C15H11F3O3S 329.0454, found 329.0444.
134.7, 129.2, 129.0, 126.2 (dd, JC−F = 7.9, 4.1 Hz), 118.9 (dd, JC−F
=
20.0, 2.0 Hz), 118.4 (d, JC−F = 18.6 Hz), 63.2. 19F{1H} NMR (CDCl3,
471 MHz) δ −126.6 (d, JF−F = 23.6 Hz), −132.9 (d, JF−F = 18.8 Hz);
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C14H10F2O3S 319.0211,
found 319.0199.
2-((4-Bromo-2-fluorophenyl)sulfonyl)-1-phenylethan-1-one
(3aq): purified by silica gel column chromatography (200−300 mesh
silica gel, PE/EA = 3:1), white solid (46 mg, 65% yield), mp 134−135
1
°C; H NMR (CDCl3, 500 MHz) δ 7.94 (dd, 2H, J = 8.4, 1.1 Hz),
2-((3-Nitrophenyl)sulfonyl)-1-phenylethan-1-one (3aj):23c puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (49 mg, 81% yield); 1H NMR (CDCl3, 500
7.76−7.71 (m, 1H), 7.67−7.62 (m, 1H), 7.53−7.45 (m, 4H), 4.90 (s,
2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.7, 159.2 (d, JC−F
=
260.8 Hz), 135.5, 134.7, 131.8, 130.5 (d, JC−F = 8.8 Hz), 129.2, 129.0,
3714
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J. Org. Chem. 2021, 86, 3706−3720

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
128.4 (d, JC−F = 3.8 Hz), 125.9 (d, JC−F = 13.9 Hz), 120.9 (d, JC−F
=
General Procedure for the Synthesis of Product 5m on a 1
mmol Scale. A mixture of aldehyde hydrazone (4m) (1.0 mmol, 1.0
equiv), sodium benzenesulfinate (2a) (2.0 mmol, 2.0 equiv), Cu2O
(10 mol %), Ag2CO3 (20 mol %), K2S2O8 (2.0 mmol, 2.0 equiv), and
DCE (5.0 mL) was stirred in a 15 mL tube at 80 °C in an oil bath for
3 h. After completion of the reaction as indicated by TLC, a saturated
NaHCO3 solution was added to the residue. The mixture was then
extracted with DCM, and the collected organic layer was washed with
brine, dried with MgSO4. The solvent was removed in vacuo, and the
obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
General Procedure for Gram-Scale Sulfonylation of
Benzaldehyde Hydrazone. A mixture of benzaldehyde hydrazone
(4a) (5.0 mmol, 1.0 equiv), sodium benzenesulfinate (2a) (10.0
mmol, 2.0 equiv), Cu2O (10 mol %), Ag2CO3 (20 mol %), K2S2O8
(10.0 mmol, 2.0 equiv), and DCE (25 mL) was stirred in a 100 mL
flask at 80 °C in an oil bath for 3 h. After completion of the reaction
as indicated by TLC, a saturated NaHCO3 solution was added to the
residue. The mixture was then extracted with DCM, and the collected
organic layer was washed with brine and dried with MgSO4. The
solvent was removed in vacuo, and the obtained residue was further
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1).
25.2 Hz), 62.1. 19F{1H} NMR (CDCl3, 471 MHz) δ −106.6; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C14H10BrFO3S 378.9410, found
378.9415.
2-(Cyclopropylsulfonyl)-1-phenylethan-1-one (3ar):9a purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA =
3:1), white solid (35 mg, 79% yield); 1H NMR (CDCl3, 500 MHz) δ
8.03 (dd, 2H, J = 8.4, 1.2 Hz), 7.68−7.63 (m, 1H), 7.53 (t, 2H, J = 7.8
Hz), 4.64 (s, 2H), 2.76 (tt, 1H, J = 8.0, 4.8 Hz), 1.29−1.27 (m, 2H),
1.12−1.08 (m, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 188.9,
135.8, 134.6, 129.3, 129.0, 61.1, 30.9, 5.5.
2-(Ethylsulfonyl)-1-phenylethan-1-one (3as):9a purified by silica
gel column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
1
white solid (35 mg, 82% yield); H NMR (CDCl3, 500 MHz) δ
8.06−7.99 (m, 2H), 7.66 (t, 1H, J = 7.4 Hz), 7.53 (t, 2H, J = 7.8 Hz,),
4.57 (s, 2H), 3.29 (q, 2H, J = 7.4 Hz), 1.47 (t, 3H, J = 7.5 Hz);
13C{1H} NMR (CDCl3, 126 MHz) δ 189.3, 135.8, 134.7, 129.3,
129.0, 58.8, 48.2, 6.7.
1-Phenyl-2-(propylsulfonyl)ethan-1-one (3at):24b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
= 3:1), white solid (35 mg, 78% yield); 1H NMR (CDCl3, 500 MHz)
δ 7.98−7.92 (m, 2H), 7.59 (t, 1H, J = 7.4 Hz), 7.46 (t, 2H, J = 7.8
Hz), 4.49 (s, 2H), 3.20−3.13 (m, 2H), 1.88 (dq, 2H, J = 15.1, 7.5
Hz), 1.05 (t, 3H, J = 7.4 Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ
189.3, 135.8, 134.7, 129.3, 129.0, 59.6, 55.4, 15.8, 13.1.
N-Morpholino-N-(phenylsulfonyl)benzamide (5a): purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
1-Phenyl-2-(thiophen-2-ylsulfonyl)ethan-1-one (3au):21a purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
1
= 3:1), white solid (49 mg, 75% yield), mp 129−130 °C; H NMR
(CDCl3, 500 MHz) δ 8.04 (d, 2H, J = 7.6 Hz), 7.59 (t, 1H, J = 7.4
Hz), 7.50 (t, 2H, J = 7.7 Hz), 7.44−7.38 (m, 3H), 7.35−7.29 (m,
2H), 3.64−3.03 (m, 8H); 13C{1H} NMR (CDCl3, 126 MHz) δ 169.4,
136.7, 133.0, 131.9, 129.3, 127.3, 126.7, 125.8, 125.3, 65.2, 51.5; IR
(KBr) 2957, 2858, 1682, 1351, 1163 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C17H18N2O4S 369.0879, found 369.0878.
4-Methyl-N-morpholino-N-(phenylsulfonyl)benzamide (5b): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (54 mg, 78% yield), mp 136−137 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.11 (d, 2H, J = 8.0 Hz), 7.65 (t, 1H, J =
7.0 Hz), 7.57 (t, 2H, J = 7.6 Hz), 7.44 (d, 2H, J = 7.7 Hz), 7.20 (d,
2H, J = 7.7 Hz), 3.59−3.45 (m, 8H), 2.40 (s, 3H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 171.3, 142.1, 138.9, 133.9, 131.9, 129.4, 128.7,
128.5, 128.0, 67.3, 53.6, 21.6; IR (KBr) 2962, 2856, 1681, 1350, 1108
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C18H20N2O4S
383.1036, found 383.1046.
1
EA = 3:1), white solid (33 mg, 62% yield); H NMR (CDCl3, 500
MHz) δ 7.97−7.92 (m, 2H), 7.73 (dd, 1H, J = 4.9, 1.1 Hz), 7.69 (dd,
1H, J = 3.8, 1.1 Hz), 7.63 (dd, 1H, J = 10.7, 4.2 Hz), 7.49 (t, 2H, J =
7.6 Hz), 7.13 (dd, 1H, J = 4.9, 3.9 Hz), 4.82 (s, 2H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 187.8, 139.4, 135.7, 135.5, 135.0, 134.5, 129.3,
128.9, 128.0, 64.4.
2-((5-Chlorothiophen-2-yl)sulfonyl)-1-phenylethan-1-one (3av):
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (41 mg, 69% yield); mp 132−133 °C;
1H NMR (CDCl3, 500 MHz) δ 7.86 (d, 2H, J = 7.3 Hz), 7.56 (t, 1H,
J = 7.4 Hz), 7.42 (dd, 3H, J = 9.8, 5.9 Hz), 6.88 (d, 1H, J = 4.1 Hz),
4.75 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.8, 140.7,
137.2, 135.5, 135.2, 134.6, 129.2, 129.0, 127.4, 64.0; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C12H9ClO3S2 322.9574, found
322.9574.
2-((3,5-Dimethylisoxazol-4-yl)sulfonyl)-1-phenylethan-1-one
(3aw): purified by silica gel column chromatography (200−300 mesh
silica gel, PE/EA = 3:1), white solid (45 mg, 80% yield), mp 138−139
°C; 1H NMR (CDCl3, 500 MHz) δ 8.03−7.89 (m, 2H), 7.67 (t, 1H, J
= 7.4 Hz), 7.53 (t, 2H, J = 7.8 Hz), 4.70 (s, 2H), 2.56 (s, 3H), 2.39 (s,
3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 188.0, 176.0, 158.1, 135.4,
134.8, 129.2, 129.1, 115.0, 63.4, 12.7, 10.9; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C13H13NO4S 280.0638, found 280.0628.
2-(Phenylsulfonyl)-1-(4-(trifluoromethyl)phenyl)ethan-1-one
(3ax):18 purified by silica gel column chromatography (200−300
4-Chloro-N-morpholino-N-(phenylsulfonyl)benzamide (5c): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (52 mg, 71% yield), mp 142−143 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.13−8.06 (m, 2H), 7.67 (t, 1H, J = 7.4
Hz), 7.58 (t, 2H, J = 7.8 Hz), 7.46 (d, 2H, J = 8.6 Hz), 7.38 (d, 2H, J
= 8.6 Hz), 3.59−3.43 (m, 8H); 13C{1H} NMR (CDCl3, 126 MHz) δ
170.3, 138.6, 137.7, 134.1, 133.3, 129.4, 129.1, 128.8, 128.2, 67.2,
53.6; IR (KBr) 2963, 2856, 1683, 1351, 1167 cm−1; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C17H17ClN2O4S 403.0490, found
403.0486.
1
mesh silica gel, PE/EA = 3:1), white solid (50 mg, 76% yield); H
4-Bromo-N-morpholino-N-(phenylsulfonyl)benzamide (5d): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (57 mg, 70% yield), mp 156−157 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.5 Hz), 7.67 (t, 1H, J =
7.4 Hz), 7.58 (t, 2H, J = 7.8 Hz), 7.54 (d, 2H, J = 8.3 Hz), 7.38 (d,
2H, J = 8.4 Hz), 3.60−3.45 (m, 8H); 13C{1H} NMR (CDCl3, 126
MHz) δ 170.4, 138.6, 134.1, 133.7, 131.2, 129.4, 129.2, 128.8, 126.0,
67.2, 53.6; IR (KBr) 2962, 2852, 1680, 1351, 1109 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H18BrN2O4S 448.0063,
found 448.0075.
4-Cyano-N-morpholino-N-(phenylsulfonyl)benzamide (5e): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (49 mg, 69% yield), mp 138−139 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.13−8.06 (m, 2H), 7.70 (t, 3H, J = 8.1
Hz), 7.60 (t, 2H, J = 7.8 Hz), 7.55 (d, 2H, J = 8.4 Hz), 3.43 (dd, 8H, J
= 190.8, 45.0 Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 169.6, 139.5,
138.2, 134.4, 131.8, 129.4, 128.9, 127.5, 117.8, 114.7, 67.2, 53.4; IR
NMR (CDCl3, 500 MHz) δ 8.06 (d, 2H, J = 8.2 Hz), 7.97−7.90 (m,
2H), 7.83 (d, 2H, J = 8.3 Hz), 7.65 (t, 1H, J = 7.4 Hz), 7.51 (t, 2H, J
= 7.8 Hz), 4.78 (s, 2H); 13C{1H} NMR (CDCl3, 126 MHz) δ 187.7,
142.0, 135.9 (q, JC−F = 32.8 Hz), 135.5, 134.7, 129.4, 129.2, 129.0,
126.4 (q, JC−F = 3.8 Hz), 123.0 (q, JC−F = 273.4 Hz), 63.1. 19F{1H}
NMR (CDCl3, 471 MHz) δ −63.2.
General Procedure for Oxidative Sulfonylation of Aldehyde
Hydrazones. A mixture of aldehyde hydrazone (4) (0.2 mmol, 1.0
equiv), sodium benzenesulfinate (2a) (0.4 mmol, 2.0 equiv), Cu2O
(10 mol %), Ag2CO3 (20 mol %), K2S2O8 (0.4 mmol, 2.0 equiv), and
DCE (1.0 mL) was stirred in a 15 mL tube at 80 °C in an oil bath for
3 h. After completion of the reaction as indicated by TLC, a saturated
NaHCO3 solution was added to the residue. The mixture was then
extracted with DCM, and the collected organic layer was washed with
brine and dried with MgSO4. The solvent was removed in vacuo, and
the obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
3715
https://dx.doi.org/10.1021/acs.joc.0c02249
J. Org. Chem. 2021, 86, 3706−3720

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(KBr) 2966, 2853, 1690, 1352, 1162 cm−1; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C18H17N3O4S 394.0832, found 394.0822.
4-Nitro-N-morpholino-N-(phenylsulfonyl)benzamide (5f): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
7.62 (dt, 3H, J = 13.8, 6.8 Hz), 3.47 (dd, 8H, J = 158.1, 82.2 Hz);
13C{1H} NMR (CDCl3, 126 MHz) δ 168.5, 147.3, 138.3, 136.2,
134.4, 133.6, 129.4, 129.3, 129.0, 125.8, 122.7, 67.2, 53.6; IR (KBr)
2966, 2862, 1683, 1352, 1166 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C17H17N3O6S 414.0730, found 414.0740.
1
PE/EA = 3:1), white solid (46 mg, 62% yield), mp 168−169 °C; H
NMR (CDCl3, 500 MHz) δ 8.27 (d, 2H, J = 8.8 Hz), 8.10 (dd, 2H, J
= 8.4, 1.0 Hz), 7.71 (t, 1H, J = 7.5 Hz), 7.61 (dt, 4H, J = 7.7, 3.4 Hz),
3.65−3.62 (m, 4H), 3.30−3.21 (m, 4H); 13C{1H} NMR (CDCl3, 126
MHz) δ 169.4, 148.9, 141.3, 138.1, 134.5, 129.4, 129.0, 127.8, 123.3,
67.2, 53.4; IR (KBr) 2962, 2856, 1706, 1502, 1327, 1146 cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H17N3O6S 414.0730,
found 414.0741.
2-Fluoro-N-morpholino-N-(phenylsulfonyl)benzamide (5m): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (181 mg, 52% yield), mp 134−135 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.11 (dd, 2H, J = 8.4, 1.1 Hz), 7.67 (t,
1H, J = 7.5 Hz), 7.59 (dd, 2H, J = 11.1, 4.4 Hz), 7.42 (dd, 1H, J =
13.8, 5.5 Hz), 7.28−7.25 (m, 1H), 7.17 (td, 1H, J = 7.5, 0.9 Hz),
7.11−7.05 (m, 1H), 3.65 (d, 4H, J = 4.3 Hz), 3.23−3.09 (m, 4H);
13C{1H} NMR (CDCl3, 126 MHz) δ 167.9, 158.5 (d, JC−F = 248.2
Hz), 138.5, 134.1, 131.8 (d, JC−F = 7.6 Hz), 129.2, 128.8, 127.8 (d,
JC−F = 3.8 Hz), 124.8 (d, JC−F = 17.6 Hz), 124.2 (d, JC−F = 2.5 Hz),
115.2 (d, JC−F = 21.4 Hz), 67.4, 53.6. 19F{1H} NMR (CDCl3, 471
MHz) δ −101.3; IR (KBr) 3060, 2851, 1673, 1326, 1145 cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H17FN2O4S
387.0785, found 387.0767.
2-Nitro-N-morpholino-N-(phenylsulfonyl)benzamide (5n): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
PE/EA = 3:1), white solid (40 mg, 53% yield), mp 179−180 °C; 1H
NMR (CDCl3, 500 MHz) δ 8.15 (d, 1H, J = 7.9 Hz), 8.00 (d, 2H, J =
7.7 Hz), 7.68 (t, 1H, J = 7.0 Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.59−7.49
(m, 3H), 7.34 (dd, 1H, J = 7.6, 1.1 Hz), 3.47−3.06 (m, 8H); 13C{1H}
NMR (CDCl3, 126 MHz) δ 169.2, 138.6, 138.2, 134.2, 132.5, 130.5,
129.3, 128.8, 127.0, 125.9, 117.7, 67.4, 53.3; IR (KBr) 2959, 2851,
1722, 1346, 1160 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C17H17N3O6S 414.0730, found 414.0737.
3-Methyl-N-morpholino-N-(phenylsulfonyl)benzamide (5g): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (49 mg, 71% yield), mp 139−140 °C; H
NMR (CDCl3, 500 MHz) δ 8.15−8.04 (m, 2H), 7.69−7.63 (m, 1H),
7.57 (t, 2H, J = 7.7 Hz), 7.33−7.27 (m, 4H), 3.52 (dd, 8H, J = 41.7,
21.9 Hz), 2.37 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 171.5,
138.9, 137.7, 134.9, 133.9, 132.1, 129.4, 128.7, 128.1, 127.7, 124.6,
67.3, 53.6, 21.3; IR (KBr) 2958, 2854, 1694, 1352, 1168 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C18H20N2O4S 383.1036, found
383.1023.
3-Fluoro-N-morpholino-N-(phenylsulfonyl)benzamide (5h): pu-
rified by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (47 mg, 67% yield), mp 128−129 °C; H
NMR (CDCl3, 500 MHz) δ 8.11 (d, 2H, J = 7.3 Hz), 7.67 (t, 1H, J =
7.4 Hz), 7.58 (t, 2H, J = 7.8 Hz), 7.38 (td, 1H, J = 7.9, 5.5 Hz), 7.27
(d, 1H, J = 6.7 Hz), 7.18 (ddd, 2H, J = 7.9, 6.7, 2.0 Hz), 3.85−3.15
(m, 8H); 13C{1H} NMR (CDCl3, 126 MHz) δ 169.9, 161.9 (d, JC−F
= 248.2 Hz), 138.6, 137.0 (d, JC−F = 6.3 Hz), 134.2, 129.7 (d, JC−F
=
3,4-Dimethyl-N-morpholino-N-(phenylsulfonyl)benzamide (5o):
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (52 mg, 73% yield), mp 154−155 °C;
1H NMR (CDCl3, 500 MHz) δ 8.11 (dd, 2H, J = 8.3, 0.9 Hz), 7.65 (t,
1H, J = 7.4 Hz), 7.56 (t, 2H, J = 7.7 Hz), 7.32−7.27 (m, 2H), 7.15 (d,
1H, J = 7.7 Hz), 3.54−3.33 (m, 8H), 2.30 (s, 3H), 2.27 (s, 3H);
13C{1H} NMR (CDCl3, 126 MHz) δ 171.4, 140.9, 139.0, 136.2,
133.8, 132.3, 129.4, 129.2, 129.0, 128.7, 125.6, 67.3, 53.6, 19.9, 19.7;
IR (KBr) 2958, 2854, 1683, 1352, 1168 cm−1; HRMS (ESI-TOF) m/
z [M + Na]+ calcd for C19H22N2O4S 397.1192, found 397.1183.
3,4-Dichloro-N-morpholino-N-(phenylsulfonyl)benzamide (5p):
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (56 mg, 71% yield), mp 171−172 °C;
1H NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.6 Hz), 7.68 (t, 1H,
J = 7.4 Hz), 7.59 (dd, 3H, J = 8.8, 6.7 Hz), 7.49 (d, 1H, J = 8.3 Hz),
7.37 (dd, 1H, J = 8.3, 2.0 Hz), 3.66−3.20 (dd, 8H, J = 133.9, 96.4
Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 168.8, 138.5, 135.8, 134.4,
134.3, 132.3, 130.0, 129.7, 129.4, 128.9, 127.0, 67.2, 53.6; IR (KBr)
2941, 2847, 1687, 1360, 1166 cm−1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C17H16Cl2N2O4S 437.0100, found 437.0110.
2,4-Dichloro-N-morpholino-N-(phenylsulfonyl)benzamide (5q):
purified by silica gel column chromatography (200−300 mesh silica
gel, PE/EA = 3:1), white solid (39 mg, 49% yield), mp 182−183 °C;
1H NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.5 Hz), 7.69 (t, 1H,
J = 7.4 Hz), 7.59 (t, 2H, J = 7.8 Hz), 7.41 (d, 1H, J = 1.8 Hz), 7.30
(dd, 1H, J = 8.2, 1.8 Hz), 7.14 (d, 1H, J = 8.2 Hz), 3.55 (dd, 4H, J =
67.7, 9.5 Hz), 3.27−3.15 (m, 4H); 13C{1H} NMR (CDCl3, 126
MHz) δ 167.8, 138.0, 135.8, 135.0, 134.3, 130.5, 129.3, 129.3, 128.9,
127.0, 126.9, 67.4, 53.2; IR (KBr) 2960, 2855, 1694, 1354, 1167
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H16Cl2N2O4S
437.0100, found 437.0080.
7.6 Hz), 129.4, 128.8, 123.0 (d, JC−F = 2.5 Hz), 118.2 (d, JC−F = 21.4
Hz), 114.5 (d, JC−F = 23.4 Hz), 67.2, 53.6. 19F{1H} NMR (CDCl3,
471 MHz) δ −107.1; IR (KBr) 2959, 2855, 1694, 1354, 1171 cm−1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H17FN2O4S
387.0785, found 387.0774.
3-Chloro-N-morpholino-N-(phenylsulfonyl)benzamide (5i): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (49 mg, 68% yield), mp 150−151 °C; H
NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.5 Hz), 7.68 (t, 1H, J =
7.4 Hz), 7.58 (t, 2H, J = 7.8 Hz), 7.48−7.43 (m, 2H), 7.39−7.31 (m,
2H), 3.79−3.08 (m, 8H); 13C{1H} NMR (CDCl3, 126 MHz) δ 169.8,
138.6, 136.5, 134.2, 133.9, 131.2, 129.4, 129.3, 128.9, 127.5, 125.5,
67.2, 53.6; IR (KBr) 2957, 2853, 1694, 1354, 1167 cm−1; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C17H17ClN2O4S 403.0490,
found 403.0474.
3-Bromo-N-morpholino-N-(phenylsulfonyl)benzamide (5j): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (57 mg, 70% yield), mp 160−161 °C; H
NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.3 Hz), 7.68 (t, 1H, J =
7.4 Hz), 7.59 (dt, 4H, J = 11.0, 8.2 Hz), 7.43 (d, 1H, J = 7.8 Hz), 7.28
(t, 1H, J = 8.7 Hz), 3.82−3.05 (m, 8H); 13C{1H} NMR (CDCl3, 126
MHz) δ 169.6, 138.6, 136.7, 134.2, 130.4, 129.7, 129.5, 129.4, 128.9,
126.0, 121.7, 67.2, 53.6; IR (KBr) 2959, 2854, 1694, 1354, 1166
cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for C17H17BrN2O4S
446.9985, Found 446.9965.
3-Cyano-N-morpholino-N-(phenylsulfonyl)benzamide (5k): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (39 mg, 55% yield), mp 142−143 °C; H
NMR (CDCl3, 500 MHz) δ 8.10 (d, 2H, J = 7.5 Hz), 7.75 (dd, 3H, J
= 19.3, 9.4 Hz), 7.70 (t, 1H, J = 7.5 Hz), 7.60 (t, 2H, J = 7.8 Hz), 7.55
(t, 1H, J = 7.8 Hz), 3.80−3.02 (m, 8H); 13C{1H} NMR (CDCl3, 126
MHz) δ 169.0, 138.2, 136.3, 134.4, 134.3, 131.4, 130.9, 129.4, 129.0,
128.9, 117.7, 112.4, 67.2, 53.5; IR (KBr) 2960, 2854, 1694, 1355,
1168 cm−1; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C18H17N3O4S 394.0832, found 394.0818.
General Procedure for the Synthesis of Sulphone 7a. K2CO3
(3.0 mmol, 3.0 equiv) was added to a solution of 3u (1.0 mmol, 1.0
equiv) in acetone (10 mL) at room temperature. The reaction
mixture was stirred for 10 min. Afterward, propargyl bromide (1.05
mmol, 1.05 equiv) was added to the reaction mixture and stirred at
reflux in an oil bath for 8 h. After completion of the reaction as
indicated by TLC, the residue was quenched with water and extracted
with DCM, and the collected organic layers were washed with brine
and dried with MgSO4. The solvent was removed in vacuo, and the
3-Nitro-N-morpholino-N-(phenylsulfonyl)benzamide (5l): puri-
fied by silica gel column chromatography (200−300 mesh silica gel,
1
PE/EA = 3:1), white solid (37 mg, 50% yield), mp 175−176 °C; H
NMR (CDCl3, 500 MHz) δ 8.36 (dd, 2H, J = 8.3, 4.8 Hz), 8.12 (d,
2H, J = 7.5 Hz), 7.87 (d, 1H, J = 7.7 Hz), 7.70 (t, 1H, J = 7.5 Hz),
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obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 5:1) to afford
intermediate 6a. Bi(OTf)3 (2 mol %) and molecular sieves (4 Å, 50
mg) were added to a solution of intermediate 6a (0.5 mmol, 1.0
equiv) in dry MeNO2 (2 mL) at room temperature. The reaction
mixture was stirred for 3 h. After completion of the reaction as
indicated by TLC, the residue was quenched with water and extracted
with DCM, and collected organic layers were washed with brine and
dried with MgSO4. The solvent was removed in vacuo, and the
obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
General Procedure for the Synthesis of Sulphone 7b. K2CO3
(2.0 mmol, 2.0 equiv) was added to a solution of 3u (1.0 mmol, 1.0
equiv) in acetone (10 mL) at room temperature. The reaction
mixture was stirred for 10 min, at which time allyl bromide (1.1
mmol, 1.1 equiv) was added to the reaction mixture. The reaction
mixture was further stirred at reflux in an oil bath for 16 h. After
completion of the reaction as indicated by TLC, the residue was
quenched with water and extracted with DCM. The collected organic
layers were washed with brine and dried with MgSO4. The solvent
was removed in vacuo, and the obtained residue was further purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
EA = 5:1) to afford intermediate 6b. PdCl2 (10 mmol %) and CuCl2
(0.75 mmol, 1.5 equiv) were added to a mixed solution of THF and
MeOH (10 mL; v/v = 9:1) containing intermediate 6b (0.5 mmol,
1.0 equiv) at room temperature. Oxygen was then bubbled into the
mixture for 2 h while stirring for 8 h. After completion of the reaction
as indicated by TLC, the residue was quenched with water and
extracted with DCM. The collected organic layers were washed with
brine and dried with MgSO4. The solvent was removed in vacuo, and
the obtained residue was further purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1).
in vacuo, and the obtained residue was further purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 6:1).
1-Phenyl-2-tosylpent-4-yn-1-one (6a):4b purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 5:1),
1
white solid (265 mg, 85% yield); H NMR (CDCl3, 500 MHz) δ
8.00−7.94 (m, 2H), 7.62 (t, 3H, J = 7.8 Hz), 7.48 (t, 2H, J = 7.8 Hz),
7.30 (d, 2H, J = 8.0 Hz), 5.26 (dd, 1H, J = 8.4, 6.3 Hz), 2.97 (t, 1H, J
= 2.4 Hz), 2.95 (d, 1H, J = 2.6 Hz), 2.43 (s, 3H), 1.89 (t, 1H, J = 2.6
Hz); 13C{1H} NMR (CDCl3, 126 MHz) δ 190.9, 145.9, 136.9, 134.1,
132.8, 129.8, 129.7, 129.2, 128.8, 78.2, 71.2, 68.2, 21.7, 18.3.
1-Phenyl-2-tosylpent-4-en-1-one (6b):24c purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 5:1),
white solid (252 mg, 80% yield); 1H NMR (CDCl3, 500 MHz) δ 7.94
(d, 2H, J = 7.2 Hz), 7.65 (d, 2H, J = 8.3 Hz), 7.60 (t, 1H, J = 7.4 Hz),
7.47 (t, 2H, J = 7.8 Hz), 7.31 (d, 2H, J = 8.1 Hz), 5.58 (ddt, 1H, J =
17.0, 10.1, 6.8 Hz), 5.12 (dd, 1H, J = 10.9, 3.7 Hz), 5.03 (dd, 1H, J =
17.0, 1.4 Hz), 4.97 (dd, 1H, J = 10.2, 1.1 Hz), 2.89−2.73 (m, 2H),
2.43 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 192.0, 145.5,
137.2, 134.0, 133.2, 132.0, 129.9, 129.6, 129.1, 128.8, 119.0, 69.3,
32.5, 21.7.
5-Methyl-1-phenyl-2-tosylhex-4-en-1-one (6c):25a purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA
1
= 5:1), white solid (270 mg, 79% yield); H NMR (CDCl3, 500
MHz) δ 7.90 (dd, 2H, J = 8.3, 1.1 Hz), 7.66 (d, 2H, J = 8.3 Hz),
7.61−7.56 (m, 1H), 7.46 (t, 2H, J = 7.8 Hz), 7.30 (d, 2H, J = 8.0 Hz),
5.02 (dd, 1H, J = 10.2, 4.4 Hz), 4.87 (t, 1H, J = 7.4 Hz), 2.82−2.69
(m, 2H), 2.43 (s, 3H), 1.55 (s, 3H), 1.53 (s, 3H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 192.6, 145.3, 137.4, 136.5, 133.8, 133.6, 129.8,
129.5, 129.0, 128.7, 117.5, 69.7, 27.3, 25.6, 21.7, 17.8.
3-(Methylsulfonyl)-1-phenyl-2-tosylpropan-1-one (6d):4c purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
1
EA = 4:1), white solid (300 mg, 82% yield); H NMR (CDCl3, 500
General Procedure for the Synthesis of Substituted
Diphenyl 7c. K2CO3 (3.0 mmol, 3.0 equiv) was added to a solution
of 3u (1.0 mmol, 1.0 equiv) in acetone (10 mL) at room temperature.
The reaction mixture was stirred for 10 min, at which time 1,1-
dimethyl allyl bromide (1.05 mmol, 1.05 equiv) was added to the
reaction mixture. The reaction mixture was further stirred at reflux in
an oil bath for 8 h. After completion of the reaction as indicated by
TLC, the residue was quenched with water and extracted with DCM.
The collected organic layers were washed with brine and dried with
MgSO4. The solvent was removed in vacuo, and the obtained residue
was further purified by silica gel column chromatography (200−300
mesh silica gel, PE/EA = 5:1) to afford intermediate 6c. Bi(OTf)3 (2
mol %) and molecular sieves (4 Å, 50 mg) were added to
intermediate 6c (0.5 mmol, 1.0 equiv) in dry MeNO2 (2 mL) at
room temperature. The reaction mixture was stirred for 3 h. After
completion of the reaction as indicated by TLC, the residue was
quenched with water and extracted with DCM. The collected organic
layers were washed with brine and dried with MgSO4. The solvent
was removed in vacuo, and the obtained residue was further purified
by silica gel column chromatography (200−300 mesh silica gel, PE/
EA = 3:1).
General Procedure for the Synthesis of Substituted
Quinoxaline 7d. NH2OH−HCl (1.1 mmol, 1.1 equiv) was added
to a stirred solution of 3u (1.0 mmol, 1.0 equiv) in dimethyl sulfoxide
(2 mL) at room temperature and kept for 10 min. Then, the reaction
mixture was heated at 100 °C in an oil bath for 10 h. After completion
of the reaction as indicated by TLC, the residue was quenched with
water and extracted with DCM. The collected organic layers were
washed with brine and dried with MgSO4. The solvent was removed
in vacuo, and the obtained residue was further purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 4:1) to
afford intermediate 6d. Compound 1,2-diaminobenzene (0.55 mmol,
1.1 equiv) was added to intermediate 6d (0.5 mmol, 1.0 equiv) in 1,4-
dioxane (15 mL) at room temperature. The reaction mixture was
further stirred at 100 °C in an oil bath for 10 h. After completion of
the reaction as indicated by TLC, the residue was quenched with
water and extracted with DCM. The collected organic layers were
washed with brine and dried with MgSO4. The solvent was removed
MHz) δ 7.93−7.89 (m, 2H), 7.58 (dd, 3H, J = 10.1, 7.9 Hz), 7.44 (t,
2H, J = 7.9 Hz), 7.28 (s, 2H), 5.61 (dd, 1H, J = 11.2, 2.0 Hz), 4.11
(dd, 1H, J = 13.9, 11.2 Hz), 3.76 (dd, 1H, J = 14.0, 1.3 Hz), 2.87 (s,
3H), 2.42 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 190.1, 146.5,
136.0, 134.5, 132.8, 130.0, 129.5, 129.4, 128.8, 64.7, 52.3, 42.7, 21.7.
5-Methyl-2-phenyl-3-tosylfuran (7a):4b purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
white solid (126 mg, 81% yield); 1H NMR (CDCl3, 500 MHz) δ 7.84
(dd, 2H, J = 7.3, 2.2 Hz), 7.68 (d, 2H, J = 8.2 Hz), 7.45−7.34 (m,
3H), 7.19 (d, 2H, J = 8.2 Hz), 6.41 (s, 1H), 2.35 (s, 3H), 2.32 (s,
3H); 13C{1H} NMR (CDCl3, 126 MHz) δ 153.4, 151.6, 144.0, 139.3,
129.6, 129.6, 128.6, 128.5, 128.2, 127.1, 124.5, 108.4, 21.6, 13.4.
1-Phenyl-2-tosylpentane-1,4-dione (7b):24c purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 3:1),
yellowish liquid (139 mg, 84% yield); 1H NMR (CDCl3, 500 MHz) δ
7.91 (dd, 2H, J = 8.3, 1.1 Hz), 7.56 (dd, 3H, J = 9.8, 7.9 Hz), 7.41
(dd, 2H, J = 8.1, 7.6 Hz), 7.25 (d, 2H, J = 8.0 Hz), 5.51 (dd, 1H, J =
10.8, 2.9 Hz), 3.49 (dd, 1H, J = 18.1, 10.9 Hz), 3.29 (dd, 1H, J = 18.1,
2.9 Hz), 2.40 (s, 3H), 2.16 (s, 3H).
3-Methyl-1,1′-biphenyl (7c):25a purified by silica gel column
chromatography (200−300 mesh silica gel, PE/EA = 3:1), colorless
1
liquid (66 mg, 79% yield); H NMR (CDCl3, 500 MHz) δ 7.55 (dd,
2H, J = 8.0, 0.9 Hz), 7.37 (dd, 4H, J = 14.0, 6.2 Hz), 7.28 (t, 2H, J =
7.5 Hz), 7.12 (d, 1H, J = 7.5 Hz), 2.37 (s, 3H); 13C{1H} NMR
(CDCl3, 126 MHz) δ 141.6, 141.4, 138.5, 128.9, 128.8, 128.2, 128.1,
127.4, 127.3, 124.5, 21.7.
2-Methyl-3-phenylquinoxaline (7d):4c purified by silica gel
column chromatography (200−300 mesh silica gel, PE/EA = 6:1),
1
white solid (86 mg, 78% yield); H NMR (CDCl3, 500 MHz) δ
8.13−8.08 (m, 1H), 8.05 (dd, 1H, J = 8.2, 1.5 Hz), 7.70 (pd, 2H, J =
7.0, 1.7 Hz), 7.65 (dd, 2H, J = 8.1, 1.3 Hz), 7.49 (ddd, 3H, J = 8.5,
7.8, 6.3 Hz), 2.77 (s, 3H); 13C{1H} NMR (CDCl3, 126 MHz) δ
154.9, 152.5, 141.2, 141.0, 139.1, 129.7, 129.2, 129.2, 129.0, 128.9,
128.5, 128.3, 24.4.
(2-(Phenylsulfonyl)ethene-1,1-diyl)dibenzene (8):25b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA =
20:1), yellow liquid (56 mg, 35% yield); 1H NMR (CDCl3, 500
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MHz) δ 7.53−7.48 (m, 2H), 7.41 (t, 1H, J = 7.4 Hz), 7.32−7.18 (m,
9H), 7.14 (d, 2H, J = 7.3 Hz), 7.00 (d, 2H, J = 7.1 Hz).
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02249
(Z)-1-Phenyl-2-(phenylsulfonyl)ethen-1-amine (E):26b purified by
silica gel column chromatography (200−300 mesh silica gel, PE/EA =
3:1), yellow solid (46 mg, 82% yield); 1H NMR (CDCl3, 500 MHz) δ
7.94 (d, 2H, J = 7.4 Hz), 7.53 (t, 1H, J = 7.3 Hz), 7.48 (t, 2H, J = 7.6
Hz), 7.45 (d, 2H, J = 7.2 Hz), 7.41 (d, 1H, J = 7.1 Hz), 7.36 (t, 2H, J
= 7.4 Hz), 5.06 (s, 1H); 13C{1H} NMR (CDCl3, 126 MHz) δ 156.7,
144.5, 136.8, 132.4, 130.9, 129.0, 128.9, 126.4, 125.9, 91.4.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the by the NUS NANONASH program jointly
funded by NUS Yong Loo Lin School of Medicine, Faculty of
Engineering and Faculty of Science (NUHSRO/2020/002/
NanoNash/LOA; R-143-000-B43-114), the Agency for
Science, Technology and Research (A*STAR) (A1883c0011
and A1983c0038), National Research Foundation, the Prime
Minister’s Office of Singapore under its NRF Investigatorship
Program (NRF-NRFI05-2019-0003), the National Natural
Science Foundation of China (21771135 and 21871071), the
Key Industrial Technology Innovation Project of Suzhou
(SYG201919), and the Major Scientific and Technological
Innovation Project of Zhejiang (2019C01081) for financial
support.
General Procedure for Sample Preparation and Crystal
Measurement. Single crystals of products 3g and 5n were prepared
by volatilization using a mixture of dichloromethane and diethyl ether
as the solvent. Then, a suitable crystal was selected and placed on a
CCD area detector diffractometer. The crystal was kept at 296.15 K
during data collection. The structure was solved with the Olex2.Solve
structure solution program using Charge Flipping and refined with the
ShelXL refinement package using Least Squares minimization.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge on the
ACS Publications Web site. The Supporting Information is
available free of charge at https://pubs.acs.org/doi/10.1021/
acs.joc.0c02249.
REFERENCES
■
Optimization of reaction conditions, mechanism inves-
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NMR and HRMS spectra of products (PDF)
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CCDC 1902707 and 2032258 contain the supplementary
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AUTHOR INFORMATION
Corresponding Authors
■
Pengfei Zhang − College of Material Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China; Email: pfzhang@hznu.edu.cn
Xiaogang Liu − Department of Chemistry and the N.1
Institute for Health, National University of Singapore,
Singapore 117543, Singapore; Center for Functional
Materials, National University of Singapore Suzhou Research
Institute, Suzhou 215123, China; orcid.org/0000-0003-
2517-5790; Email: chmlx@nus.edu.sg
Authors
Jun Xu − Department of Chemistry and the N.1 Institute for
Health, National University of Singapore, Singapore 117543,
Singapore; Center for Functional Materials, National
University of Singapore Suzhou Research Institute, Suzhou
215123, China
Chao Shen − College of Material Chemistry and Chemical
Engineering, Hangzhou Normal University, Hangzhou
311121, China
Xian Qin − Department of Chemistry and the N.1 Institute for
Health, National University of Singapore, Singapore 117543,
Singapore
Jie Wu − Department of Chemistry and the N.1 Institute for
Health, National University of Singapore, Singapore 117543,
Singapore; Center for Functional Materials, National
University of Singapore Suzhou Research Institute, Suzhou
215123, China; orcid.org/0000-0002-9865-180X
3718
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