Unusual Deoxidative Coupling Reaction of β-Sulfinyl Esters with Benzylic Trimethylammonium Salts

Article abstract of DOI:10.1021/acs.joc.1c00615

A KOH-promoted unusual deoxidative coupling reaction of β-sulfinyl esters with benzylic trimethylammonium salts to produce thioethers is discovered for the first time. If quaternary ammonium salts synthesized from enantiomerically enriched amines are adopted, highly enantiomerically enriched benzyl thioethers (>95-99% ee) with configurations opposite to those of the enantiomerically enriched amines are obtained.

Full text of DOI:10.1021/acs.joc.1c00615

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Unusual Deoxidative Coupling Reaction of β‑Sulfinyl Esters with
Benzylic Trimethylammonium Salts
Qiaoling Zhang, Hang Feng, Feng Chen, Ze He, and Qingle Zeng*
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ABSTRACT: A KOH-promoted unusual deoxidative coupling
reaction of β-sulfinyl esters with benzylic trimethylammonium salts
to produce thioethers is discovered for the first time. If quaternary
ammonium salts synthesized from enantiomerically enriched
amines are adopted, highly enantiomerically enriched benzyl
thioethers (>95−99% ee) with configurations opposite to those
of the enantiomerically enriched amines are obtained.
ith more and more new bioactive organosulfur
Wcompounds being discovered and used in the clinic,
organosulfur chemistry, especially chiral organosulfur chem-
class of new reactive organosulfur intermediates, have recently
displayed valuable applications in enantioselective reactions
and cross-coupling reactions.
anions (RSO−) and benzyl quaternary ammonium salts to
synthesize chiral benzylic sulfoxides under reaction conditions
similar to those of Bolm’s protocol and Poli’s method.6,7
However, we found that the products were not the expected
benzylic sulfoxides but instead thioethers, which is an
interesting unusual new reaction. In this context, we wish to
report the unusual deoxidative coupling reaction of β-sulfinyl
esters with benzylic trimethylammonium salts (Scheme 1).
First, 3-(toluene-4-sulfinyl)-propionic acid tert-butyl esters
and benzyl quaternary ammonium salts10−12 were used as
template substrates for a preliminary reactivity exploration and
condition optimization (Table 1). In the beginning, the
reaction in toluene with Cs2CO3 as the base went well, and the
target product was obtained with a yield of 60% (Table 1, entry
1). When exploring the effect of the catalyst on the reaction,
we found that the reaction with a transition-metal catalyst or
without a catalyst made little difference (Table 1, entries 2−4).
Then, the effects of various bases on the reaction were further
explored (Table 1, entries 1 and 5−7). The results show that
the reaction could proceed smoothly under weaker bases such
istry, is developing rapidly.1,2 Sulfinate anions (RSO−),3−5
a
Sulfinate anions (RSO−) could react with halogenated aryl
groups to form diaryl sulfoxides under the catalysis of
palladium (Scheme 1a).6 The transition-metal-free arylation
reaction of diaryliodonium salts and sulfenate anions generated
from β-sulfinyl esters was developed by Bolm’s group in 2018
(Scheme 1b).7 In this process, the diaryl sulfoxides were also
formed under mild reaction conditions.
As part of our ongoing research on organosulfur
chemistry,8,9 we tried to explore the reaction between sulfinate
Scheme 1. Reaction of Some Sulfinate Anions with
Electrophiles
t
as Cs2CO3 and K2CO3, but strong bases such as BuOK and
KOH gave higher yields (Table 1, entries 6 and 7 vs 1 and 5,
respectively). Solvent screening demonstrated that acetonitrile
achieved the best result under the reaction conditions (Table
1, entries 7−12). Increasing the temperature to 80 °C greatly
promoted the reaction, affording a highest yield of 90% (Table
1, entries 12−14). Since the boiling point of acetonitrile is 81.6
°C, no higher temperature was tested.
Received: March 15, 2021
Published: May 17, 2021
https://doi.org/10.1021/acs.joc.1c00615
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 7806−7812
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Note
a
outcomes of these transformations are shown in Table 2. The
various benzylic quaternary ammonium salts were tested with
different substituted groups, leading to a transformation into
the desired products in 85−90% yields (3a−3l). In addition,
compound 3j could be used in the synthesis of drug
intermediates and material intermediates 2-(4-chloro-3-meth-
yl-2-pyridylmethylthio)-1H-benzimidazole.
Table 1. Optimization of Reaction Conditions
temperature
yield
b
c
entry
catalyst
CuI
NiCl2
Pd(OAc)2
base
solvent
(°C)
(%)
To show that this protocol was applicable to a wider range of
substrates, various β-sulfinyl esters were evaluated (Table 3).
The transformation was performed and provided the
corresponding products in 85%−89% yields (3m−3w).
This deoxidative coupling reaction also provided an
excellent stereospecific synthesis of enantioenriched benzylic
thioethers with am inverse absolute configuration (Table 4).
Importantly, no racemization occurred during this coupling
reaction. The products 5a and 5b have nearly the same
enantiomeric purities as those of the starting (R)- and (S)-
benzylic amines 4a and 4b, respectively. By comparing our
corresponding products as well as the reported optical
rotation21 and HPLC elution order of the highly enantiomeri-
cally enriched product, the absolute configuration of our
product was determined. The obtained target product had a
configuration opposite to that of the highly enantiomerically
enriched benzyltrimethylammonium triflate, suggesting that
the reaction occurred through an SN2-type Walden inver-
sion.12−14
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
t-BuOK
KOH
KOH
KOH
KOH
KOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
THF
60
60
60
60
60
60
60
60
60
60
60
60
40
80
60
65
60
69
63
76
80
88
79
82
81
86
57
90
9
10
11
12
13
14
DMF
dioxane
MeCN
MeCN
MeCN
KOH
KOH
KOH
a
Unless otherwise specified, perform the reaction with 1a (1.0 mmol)
and 2a (1.2 mmol) under closed conditions in a test tube with a
sleeve rubber stopper. For entries 1−6, perform the reaction with
Cs2CO3, K2CO3, or t-BuOK (4 equiv). For entries 7−14, perform the
reaction with a KOH (50% aqueous, 20.0 equiv) and solvent (5 mL).
b
c
Isolated yield. Oil bath.
To check the effectiveness of the synthesis method, a gram-
scale reaction was carried out (Scheme 2). The 10 mmol scale
reaction gave the targeted product with a yield of 81%.
To explore the reaction mechanism, we conducted a few
control experiments (Scheme 3). First, experiments based on
With the optimized reaction conditions in hand, various
benzylic quaternary ammonium salts, 3-(toluene-4-sulfinyl)-
propionic acid, and tert-butyl ester were investigated. The
a
Table 2. Scope of Benzyl Quaternary Ammonium Salts
a
Reaction conditions are as follows: 1a (1 mmol), 2 (1.2 mmol, 1.2 equiv), and KOH (50% aqueous, 20.0 equiv) in MeCN (5 mL) at 80 °C under
air for 24 h.
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Note
a
Table 3. Scope of β-Sulfinyl Esters
a
Reaction conditions are as follows: 1 (1 mmol), 2a (1.2 mmol, 1.2 equiv), and KOH (50% aqueous, 20.0 equiv) in MeCN (5 mL) at 80 °C under
air for 24 h.
a
Table 4. Scope of the Reaction of Enantioenriched Benzylic Ammonium Salts with β-Sulfinyl Esters
b
entry
4
product 5
yield (%)
ee (%)
1
2
3
4
5
6
rac-4a
(R)-4a
(S)-4a
rac-4b
(R)-4b
(S)-4b
rac-5a
(S)-5a
(R)-5a
rac-5b
(S)-5b
(R)-5b
85
85
85
87
88
86
95
95
96
99
a
Reaction conditions are as follows: 1a (1 mmol), 4 (1.2 mmol, 1.2 equiv), and KOH (50% aqueous, 20.0 equiv) in MeCN (5 mL) at 80 °C under
b
air for 24 h. The enantiopurities of (R)- and (S)-1-phenylethylamine, (R)- and (S)-1-(4-bromophenyl)ethan-1-amine, the starting enantioenriched
benzylic amines for the preparation of enantioenriched benzylic ammonium salts (R)- and (S)-4a, and (R)- and (S)-4b are >95%, > 95%, > 96%,
and >99% ee, respectively.
Scheme 2. Gram-Scale Reaction
radical trapping using 3 equiv of TEMPO were carried out to
suppress this transformation. The results showed that this
transformation did not undergo a free -adical-type reaction.
Second, benzyl chloride was investigated under the standard
conditions, giving the product 3a in an 80% yield. This work
showed that the benzyl quaternary ammonium salts did not
play any role in the deoxygenation reduction of this reaction.
Third, in the absence of benzyl quaternary ammonium salts, 1a
produced products 6 (10% yield) and 7 (90% yield) under the
standard conditions. Both 6 and 7 were isolated and
characterized by NMR (See the Supporting Information).
Based on the above experimental results, we propose a
plausible mechanism (Scheme 4). At the outset of the reaction,
the base KOH-mediated sulfinate 8 was formed via the retro-
Michael Aaddition of the deprotonated β-sulfinyl esters 1. The
oxygen-Michael addition of 8′, the tautomer 8 ,and tert-butyl
acrylate produced the oxygen-Michael addition product 6.15,16
Intermediate 6 aptly carried out disproportionation and turned
into diaryl disulfide 7 and the unstable intermediate 9, which
was decomposed by KOH. In the presence of KOH,
intermediate 7 produced RS− 10 and RSOH 11, which was
turned into 8′. The negatively charged RS− 10 attacked the
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https://doi.org/10.1021/acs.joc.1c00615
J. Org. Chem. 2021, 86, 7806−7812

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Note
Scheme 3. Control Experiments
General Procedure for the Preparation of β-Sulfinyl Esters.
β-Sulfinyl esters were prepared according to literature methods.17
General Procedure for the Deoxidative Coupling of β-
Sulfinyl Esters (3a−3w, 5a, and 5b). To an oven-dried 25 mL test
tube with a standard ground joint equipped with a stir bar were added
benzylic trimethylammonium triflate (enantioenriched benzylic
ammonium salts) (1.2 mmol, 1.2 equiv), β-sulfinyl esters (1 mmol,
1 equiv), KOH (50% aqueous, 20 mmol, 20 equvalents), and
acetonitrile (5.0 mL). The mixture was stirred at 80 °C for 24 h. After
cooling to room temperature, the reaction mixture was quenched by
the addition of a saturated NaCl solution (10 mL). The reaction
mixture was extracted with ethyl acetate (10 mL × 3). The combined
organic phase was dried over anhydrous MgSO4, filtered, and
concentrated in a vacuum on a rotary evaporator. The resulting
residue was purified by silica gel flash chromatography, eluting with
petroleum ether/EtOAc to afford the corresponding products as
either a colorless or yellowish oil or a white or yellowish solid.
Benzyl(4-tolyl)sulfide (3a).18 Colorless oil, 90% yield, 241.3 mg, Rf
= 0.3, in PE; 1H NMR (400 MHz, CDCl3) δ 7.19−7.08 (m, 7H), 6.96
(d, J = 7.9 Hz, 2H), 3.96 (s, 2H), 2.20 (s, 3H); 13C {1H} NMR (101
MHz, CDCl3) δ 137.82, 136.59, 132.50, 130.74, 129.63, 128.86,
128.45, 127.09, 39.82, 21.07; GCMS (EI) m/z (%) 214.00 (46) [M]+,
123.00 (5), 91.00 (100), 77.00 (5) 65 (20).
Scheme 4. A Plausible Mechanism
benzyl quaternary ammonium salt 4 via an SN2 nucleophilic
substitution to afford the desired highly enantiopure thioether
product 5 with the reverse configuration.
In summary, we have developed an unusual deoxidative
coupling reaction of β-sulfinyl esters with benzylic trimethy-
lammonium salts. This protocol achieves the products of
thioethers with excellent yields. In addition, when enantiomeri-
cally pure benzyl quaternary ammonium salts are used as
reactants, chiral benzyl thioethers with SN2-type reverse
configurations were obtained with extremely high enantiopur-
ities.
(2-Bromobenzyl)(4-tolyl)sulfide (3b).19 Yellowish oil, 87% yield,
255.1 mg, Rf = 0.33, in PE; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J
= 7.7 Hz, 1H), 7.18−7.05 (m, 4H), 7.04−6.96 (m, 3H), 4.08 (s, 2H),
2.23 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ 137.18, 137.05,
132.97, 131.86, 131.58, 130.78, 129.68, 128.71, 127.34, 124.54, 40.45,
21.11.
(4-tert-Butylbenzyl)(4-methylphenyl)sulfide (3c).20 White solid,
85% yield, 229.9 mg, Rf = 0.35, in PE, mp 57−65 °C. ; 1H NMR (400
MHz, CDCl3) δ 7.18 (dt, J = 8.3, 5.9 Hz, 6H), 6.99 (d, J = 8.0 Hz,
2H), 3.99 (s, 2H), 2.23 (s, 3H), 1.22 (s, 9H); 13C {1H} NMR (101
MHz, CDCl3) δ 150.07, 136.32, 134.60, 133.06, 130.23, 129.62,
128.51, 125.44, 39.24, 34.51, 31.37, 21.06.
EXPERIMENTAL SECTION
■
General Information. The test tube used was dried in an electric
oven at 110 °C. Chemicals were purchased from Aladdin, Adamas,
Aldrich, Alfa Aesar, and Kelong Chemical Co. and used as received
unless other mentioned. Petroleum ether (PE) refers to the fraction
that boils in the 60−90 °C range. Unless otherwise stated, there was
no further purification of the commercial supplier’s products. 1H
NMR spectra were recorded on a Bruker Avance III 400 MHz
(2-Fluorobenzyl)(4-tolyl)sulfide (3d).21 Yellowish oil, 89% yield,
206.8 mg, Rf = 0.33, in PE; 1H NMR (400 MHz, CDCl3) δ 7.27−7.17
(m, 4H), 7.11−6.99 (m, 4H), 4.10 (s, 2H), 2.33 (s, 3H); 13C {1H}
NMR (101 MHz, CDCl3) δ 160.77 (d, J = 247.0 Hz), 136.99, 131.85,
131.39, 130.88 (d, J = 3.9 Hz), 129.65, 128.83 (d, J = 8.2 Hz), 125.17
(d, J = 14.8 Hz), 123.97 (d, J = 3.8 Hz), 115.36 (d, J = 21.8 Hz),
32.93 (d, J = 3.1 Hz), 21.09.
1
instrument. H NMR data are reported in δ units (ppm) and were
measured relative to the signals for either residual chloroform (7.26
ppm) or residual acetone (2.05 ppm) in the deuterated solvent unless
otherwise stated. 13C {1H} NMR spectra are reported in (ppm)
relative to deuterated chloroform (77.2 ppm) unless otherwise stated,
(2-Chlorobenzyl)(4-tolyl)sulfide (3e).19 Yellowish oil, 89% yield,
221.4 mg, Rf = 0.29, in PE; 1H NMR (400 MHz, CDCl3) δ 7.30−7.25
(m, 1H), 7.17−6.96 (m, 7H), 4.08 (s, 2H), 2.23 (s, 3H); 13C {1H}
NMR (101 MHz, CDCl3) δ 137.03, 135.55, 134.05, 131.90, 131.55,
130.75, 129.67, 129.64, 128.49, 126.69, 37.73, 21.10.
1
and all were obtained with H decoupling. Mass spectral data of the
products were collected by a GC-MS analysis with a QP-2010 SE
instrument. All chiral HPLC analyses were performed on an LC3000
I-type high-performance liquid chromatograph (Beijing Gangchen
Technology Co., Ltd.) with Daicel Chiralcel OD-H, Chiralcel OJ-H,
Chiralpak AD-H, and Chiralpak AS-H chiral columns (4.6 mm × 250
mm × 5 μm) using n-hexane/isopropanol as the mobile phase, and
the UV detection was monitored at 254 nm. Optical rotations were
measured on a Autopol IV polarimeter with a sodium lamp at λ = 589
nm and reported as [α]DT (c in grams per 100 mL, solvent).
Quaternary ammonium triflates and β-sulfinyl esters were prepared
according to literature methods.14,17
(3-Methylbenzyl)(4-tolyl)sulfide (3f).22 Colorless oil, 90% yield,
205.5 mg, Rf = 0.24, in PE; 1H NMR (400 MHz, CDCl3) δ 7.16−7.04
(m, 3H), 7.04−6.92 (m, 5H), 3.95 (s, 2H), 2.22 (s, 6H); 13C {1H}
NMR (101 MHz, CDCl3) δ 138.11, 137.60, 136.48, 132.77, 130.56,
129.62, 128.35, 127.89, 125.90, 39.76, 21.38, 21.07.
(3-Methoxybenzyl)(4-tolyl)sulfide (3g).21 Yellowish oil, 88% yield,
1
215.1 mg, Rf = 0.3, 5% ethyl acetate, in PE; H NMR (400 MHz,
CDCl3) δ 7.17−7.07 (m, 3H), 6.98 (d, J = 7.9 Hz, 2H), 6.72 (ddd, J =
7809
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Note
13.9, 10.6, 5.0 Hz, 3H), 3.96 (s, 2H), 3.67 (s, 3H), 2.22 (s, 3H); 13
C
2-(Benzylthio)benzo[d]thiazole (3s).29 Yellowish oil, 85% yield,
218.8 mg, Rf = 0.4, 5% ethyl acetate, in PE; H NMR (400 MHz,
1
{1H} NMR (101 MHz, CDCl3) δ 159.65, 139.39, 136.60, 132.53,
130.74, 129.65, 129.44, 121.22, 114.19, 112.91, 55.18, 39.84, 21.07.
(4-Trifluoromethyl)(4-tolyl)sulfide (3h).23 White solid, 86% yield,
CDCl3) δ 7.82 (d, J = 8.1 Hz, 1H), 7.69−7.62 (m, 1H), 7.42−7.13
(m, 7H), 4.52 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3) δ 166.44,
153.18, 136.20, 135.36, 129.17, 128.74, 127.79, 126.09, 124.32,
121.59, 121.04, 37.75.
1
242.8 mg, Rf = 0.35, in PE, mp 77−82 °C; H NMR (400 MHz,
CDCl3) δ 7.43 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.18−
7.07 (m, 2H), 6.99 (d, J = 8.0 Hz, 2H), 3.99 (s, 2H), 2.23 (s, 3H);
13C {1H} NMR (101 MHz, CDCl3) δ 142.18 (d, J = 1.3 Hz), 137.20,
131.45, 131.30, 129.77, 129.28 (d, J = 32.7 Hz), 129.09, 125.36 (q, J =
3.8 Hz), 124.17 (d, J = 272.1 Hz), 39.56, 21.07.
2-(Benzylthio)benzo[d]oxazole (3t).30 White solid, 86% yield,
207.5 mg, Rf = 0.3, 5% ethyl acetate, in PE, mp 42−47 °C; 1H NMR
(400 MHz, CDCl3) δ 7.56−7.52 (m, 1H), 7.40−7.33 (m, 3H), 7.28−
7.13 (m, 5H), 4.48 (s, 2H); 13C {1H} NMR (101 MHz, CDCl3) δ
164.56, 151.91, 141.95, 135.87, 129.11, 128.80, 127.95, 124.34,
123.97, 118.51, 109.93, 36.60.
(4-Cyanobenzyl)(4-methylphenyl)sulfide (3i).24 Yellowish solid,
85% yield, 203.4 mg, Rf = 0.18, 5% ethyl acetate, in PE, mp 65−71
3-(Benzylthio)pyridine (3u).24 Yellowish oil, 85% yield, 171.1 mg,
1
°C; H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 8.3 Hz, 2H), 7.13
1
(dd, J = 73.0, 20.1 Hz, 6H), 3.96 (s, 2H), 2.23 (s, 3H); 13C {1H}
NMR (101 MHz, CDCl3) δ 143.76, 137.56, 132.20, 131.74, 130.81,
129.83, 129.52, 118.82, 110.85, 39.90, 21.09.
Rf = 0.18, 5% ethyl acetate, in PE; H NMR (400 MHz, CDCl3) δ
8.37 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.41−7.27 (m, 3H), 7.26−7.03
(m, 4H), 6.89 (ddd, J = 7.4, 4.9, 1.0 Hz, 1H), 4.36 (s, 2H); 13C {1H}
NMR (101 MHz, CDCl3) δ 158.85, 149.44, 138.01, 135.99, 129.00,
128.52, 127.12, 122.11, 119.62, 34.46.
2-(4-Methylphenyl)thiomethyl-pyridine (3j).25 Brown oil, 85%
1
yield, 182.8 mg, Rf = 0.13, 10% ethyl acetate, in PE; H NMR (400
Benzyl(cyclopentyl)sulfide (3v).31 Yellowish oil, 86% yield, 173.1
MHz, CDCl3) δ 8.45 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.50 (td, J = 7.7,
1.8 Hz, 1H), 7.23−7.12 (m, 3H), 7.09−6.93 (m, 3H), 4.14 (s, 2H),
2.21(s, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ 157.95, 149.35,
136.60, 136.56, 131.95, 130.53, 129.67, 123.01, 121.98, 41.29, 21.04.
(Naphthalen-2-ylmethyl)(4-tolyl)thioether (3k).26 Yellowish oil,
86% yield, 227.4 mg, Rf = 0.23, in PE; 1H NMR (400 MHz, CDCl3) δ
8.06 (d, J = 8.5 Hz, 1H), 7.78 (dd, J = 8.3, 1.0 Hz, 1H), 7.67 (d, J =
8.0 Hz, 1H), 7.44 (dddd, J = 20.3, 8.0, 6.8, 1.3 Hz, 2H), 7.28−7.11
(m, 4H), 6.99 (d, J = 7.9 Hz, 2H), 4.43 (s, 2H), 2.23 (s, 3H); 13C
{1H} NMR (101 MHz, CDCl3) δ 136.79, 133.99, 133.13, 132.85,
131.50, 131.13, 129.68, 128.81, 128.20, 127.33, 126.21, 125.82,
125.27, 124.00, 37.98, 21.11.
1
mg, Rf = 0.37, in PE; H NMR (400 MHz, CDCl3) δ 7.29−7.09 (m,
5H), 3.66 (s, 2H), 2.93−2.83 (m, 1H), 1.93−1.32 (m, 8H); 13C {1H}
NMR (101 MHz, CDCl3) δ 138.94, 128.79, 128.45, 126.80, 43.06,
36.47, 33.56, 24.94.
Benzyl(butyl)sulfide (3w).32 Colorless oil, 86% yield, 155.1 mg, Rf
1
= 0.35, in PE; H NMR (400 MHz, CDCl3) δ 7.26−7.08 (m, 5H),
3.60 (s, 2H), 2.38−2.23 (m, 2H), 1.51−1.39 (m, 2H), 1.34−1.19 (m,
2H), 0.79 (t, J = 7.3 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ
138.70, 128.84, 128.45, 126.87, 36.31, 31.34, 31.08, 22.01, 13.70.
(1-Phenylethyl)(4-tolyl)sulfide (rac-5a).13 Yellowish oil, 85% yield,
194.1 mg, Rf = 0.25, in PE; 1H NMR (400 MHz, CDCl3) δ 7.24−7.07
(m, 7H), 6.95 (d, J = 7.9 Hz, 2H), 4.19 (q, J = 7.0 Hz, 1H), 2.21 (s,
3H), 1.53 (d, J = 7.0 Hz, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ
143.39, 137.38, 133.23, 131.30, 129.48, 128.36, 127.33, 127.07, 48.40,
22.21, 21.13; HPLC Chiralcel OJ-H column, λ= 254 nm, hexane/
isopropanol = 90:10, 1.0 mL/min flow rate, tR(major) = 8.14 min,
tR(major) = 16.69 min.
1,2,3,4-Tetrahydro-1-(4-methylphenylthio)naphthalene (3l).13
1
Colorless oil, 86% yield, 230.6 mg, Rf = 0.25, in PE; H NMR (400
MHz, CDCl3) δ 7.36−7.26 (m, 3H), 7.08−6.95 (m, 5H), 4.40 (t, J =
4.1 Hz, 1H), 2.81−2.57 (m, 2H), 2.26 (s, 3H), 2.20−2.06 (m, 1H),
1.98−1.78 (m, 2H), 1.71−1.59 (m, 1H); 13C {1H} NMR (101 MHz,
CDCl3) δ 137.60, 137.32, 135.76, 132.82, 132.38, 130.58, 129.78,
129.28, 127.05, 125.72, 48.27, 29.21, 28.49, 21.20, 18.62.
(S)-(1-Phenylethyl) (p-tolyl) sulfide ((S)-5a).13 Yellowish oil, 85%
yield, 194.1 mg, Rf = 0.25, in PE; [α]D28 = −34.7 (c = 0.03, EtOAc);
HPLC Chiralcel OJ-H column, λ= 254 nm, hexane/isopropanol =
90:10; 1.0 mL/min flow rate, tR(major) = 8.22 min, tR(minor) =
17.13 min.
Benzyl(3-tolyl)sulfide (3m).27 Yellowish oil, 89% yield, 190.8 mg,
Rf = 0.25, in PE; 1H NMR (400 MHz, CDCl3) δ 7.26−6.98 (m, 8H),
6.91 (s, 1H), 4.02 (s, 2H), 2.20 (s, 3H); 13C {1H} NMR (101 MHz,
CDCl3) δ 138.61, 137.56, 136.19, 130.42, 128.88, 128.71, 128.49,
127.20, 127.17, 126.70, 39.03, 21.34.
(R)-(1-Phenylethyl) (p-tolyl) sulfide ((R)-5a).13 Yellowish oil, 85%
28
yield, 194.1 mg, Rf = 0.28, in PE; [α]D = +39.4 (c = 0.03, EtOAc);
Benzyl(4-bromophenyl)sulfide (3n).18 White solid, 89% yield,
248.4 mg, Rf = 0.38, in PE, 53−60 °C; 1H NMR (400 MHz, CDCl3)
δ 7.31−7.12 (m, 7H), 7.06 (d, J = 8.5 Hz, 2H), 4.00 (s, 2H); 13C
{1H} NMR (101 MHz, CDCl3) δ 137.06, 135.45, 131.88, 131.51,
128.81, 128.59, 127.36, 120.35, 39.11.
HPLC, Chiralcel OJ-H column, λ= 254 nm, hexane/isopropanol =
90:10, 1.0 mL/min flow rate, tR(minor) = 8.23 min, tR(major) = 17.07
min.
(1-(4-Bromophenyl)ethane)(4-methylphenyl) sulfide (rac-5b).
1
Colorless oil, 87% yield, 224.6 mg, Rf = 0.35, in PE; H NMR (400
Benzyl(2-tolyl)sulfide (3o).28 Colorless oil, 87% yield, 186.5 mg, Rf
MHz, CDCl3) δ 7.40−7.35 (m, 2H), 7.18−7.10 (m, 4H), 7.06- 7.01
(m, 2H), 4.21 (q, J = 7.0 Hz, 1H), 2.30 (s, 3H), 1.58 (d, J = 7.0 Hz,
3H); 13C {1H} NMR (101 MHz, CDCl3) δ 142.58, 137.70, 133.41,
131.40, 130.69, 129.57, 129.02, 120.72, 47.85, 22.03, 21.14. GCMS
(EI) m/z (%) 306.00 (10) [M]+, 183.00 (80), 123.03 (10), 104
(100), 91 (10), 77 (25); HRMS (ESI-TOF) m/z [M + Na]+ Calcd
for C15H15BrNaS+ 328.9970, found 328.9970; HPLC Chiralcel OJ-H
column, λ= 254 nm, hexane/isopropanol = 99.5:0.5; 0.8 mL/min flow
rate; tR(major) = 14.20 min, tR(major) = 15.88 min.
(S)-(1- (4-Bromophenyl)ethane)(4-methylphenyl) sulfide ((S)-5b).
White solid, 88% yield, 227.1 mg, Rf = 0.35, in PE, mp 49−57 °C;
HPLC Chiralcel OJ-H column, λ= 254 nm, hexane/isopropanol =
99.5:0.5, 0.8 mL/min flow rate, tR(minor) = 13.95 min, tR(major) =
15.54 min.
(R)-(1-(4-Bromophenyl)ethane)(4-methylphenyl) sulfide ((R)-5b).
White solid, 86% yield, 222.0 mg, Rf = 0.38, in PE, mp 45−55 °C;
HPLC Chiralcel OJ-H column, λ= 254 nm, hexane/isopropanol =
99.5:0.5, 0.8 mL/min flow rate, tR(major) = 13.87 min, tR(minor) =
15.57 min.
Procedure for synthesis of compound 6 and 7. To an oven-
dried 25 mL test tube with standard ground joint equipped with a stir
bar were added β-sulfinyl esters (1 mmol, 1 equiv), KOH (50%
1
= 0.25, in PE; H NMR (400 MHz, CDCl3) δ 7.24−6.96 (m, 9H),
3.99 (s, 2H), 2.23 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ
137.97, 137.31, 135.79, 130.08, 129.01, 128.90, 128.52, 127.22,
126.44, 126.15, 38.36, 20.33.
Benzyl(4-chlorophenyl)sulfide (3p).18 White solid, 89% yield,
1
208.9 mg, Rf = 0.35, in PE, mp 45−48 °C; H NMR (400 MHz,
CDCl3) δ 7.24−7.10 (m, 9H), 4.00 (s, 2H); 13C {1H} NMR (101
MHz, CDCl3) δ 137.14, 134.69, 132.50, 131.45, 128.97, 128.82,
128.57, 127.33, 39.34.
Benzyl(2-fluorophenyl)sulfide (3q).24 Yellowish oil, 88% yield,
192.1 mg, Rf = 0.35, in PE; 1H NMR (400 MHz, CDCl3) δ 7.23−7.07
(m, 7H), 6.95 (ddd, J = 7.9, 7.5, 4.8 Hz, 2H), 4.02 (s, 2H); 13C {1H}
NMR (101 MHz, CDCl3) δ 161.72 (d, J = 245.6 Hz), 137.23, 133.05
(d, J = 1.8 Hz), 128.86, 128.80, 128.48, 127.27, 124.35 (d, J = 3.8
Hz), 122.76 (d, J = 17.8 Hz), 115.62 (d, J = 22.6 Hz), 38.43 (d, J =
2.9 Hz).
Benzyl(4-methoxyphenyl)sulfide (3r).18 White solid, 89% yield,
204.9 mg, Rf = 0.4, 5% ethyl acetate, in PE, mp 42−45 °C; 1H NMR
(400 MHz, CDCl3) δ 7.24−7.05 (m, 7H), 6.75−6.66 (m, 2H), 3.90
(s, 2H), 3.69 (s, 3H); 13C {1H} NMR (101 MHz, CDCl3) δ 159.23,
138.15, 134.10, 128.91, 128.38, 127.00, 126.10, 114.45, 55.32, 41.25.
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Note
aqueous, 20 mmol, 20 equiv), and acetonitrile (5.0 mL). The mixture
was stirred at 80 °C for 24 h. After cooling to room temperature, the
reaction mixture was quenched by the addition of a saturated NaCl
solution (10 mL). The reaction mixture was extracted with ethyl
acetate (10 mL × 3). The combined organic phase was dried over
anhydrous MgSO4, filtered, and concentrated in a vacuum on a rotary
evaporator. The resulting residue was purified by silica gel flash
chromatography, eluting with petroleum ether/EtOAc to afford the
corresponding products.
ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (no. 21372034) and the State
Key Laboratory of Geohazard Prevention and Geoenviron-
ment Protection (no. SKLGP2020Z003).
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ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00615.
Chiral HPLC traces of products 5a and 5b; H and 13C
NMR spectra for compounds 3, 5, 6, and 7; and HRMS
spectra for compounds 5b and 6 (PDF)
1
AUTHOR INFORMATION
■
Corresponding Author
Qingle Zeng − State Key Laboratory of Geohazard Prevention
and Geoenvironment Protection, College of Materials,
Chemistry & Chemical Engineering, Chengdu University of
Technology, Chengdu 610059, China; orcid.org/0000-
0003-0750-540X; Email: qlzeng@cdut.edu.cn,
qinglezeng@hotmail.com
Authors
Qiaoling Zhang − State Key Laboratory of Geohazard
Prevention and Geoenvironment Protection, College of
Materials, Chemistry & Chemical Engineering, Chengdu
University of Technology, Chengdu 610059, China
Hang Feng − State Key Laboratory of Geohazard Prevention
and Geoenvironment Protection, College of Materials,
Chemistry & Chemical Engineering, Chengdu University of
Technology, Chengdu 610059, China
Feng Chen − State Key Laboratory of Geohazard Prevention
and Geoenvironment Protection, College of Materials,
Chemistry & Chemical Engineering, Chengdu University of
Technology, Chengdu 610059, China
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00615
Notes
The authors declare no competing financial interest.
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