Nickel-Catalyzed Reductive Thiolation of Unactivated Alkyl Bromides and Arenesulfonyl Cyanides

Article abstract of DOI:10.1021/acs.joc.1c00903

The cross-electrophile coupling between unactivated alkyl bromides with arenesulfonyl cyanides catalyzed by Ni(acac)₂under reductive conditions to form unsymmetrical sulfides is developed. This approach for sulfide synthesis is practical, relies on available, unfunctionalized materials such as alkyl (pseudo)halides, and is scalable. This catalytic strategy provides a complementary method for the preparation of unsymmetrical alkyl-aryl sulfides under mild conditions with good functional group tolerance.

Full text of DOI:10.1021/acs.joc.1c00903

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Nickel-Catalyzed Reductive Thiolation of Unactivated Alkyl
Bromides and Arenesulfonyl Cyanides
Fei Wang, Weidong Rao, and Shun-Yi Wang*
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ABSTRACT: The cross-electrophile coupling between unactivated alkyl bromides with arenesulfonyl cyanides catalyzed by
Ni(acac)2 under reductive conditions to form unsymmetrical sulfides is developed. This approach for sulfide synthesis is practical,
relies on available, unfunctionalized materials such as alkyl (pseudo)halides, and is scalable. This catalytic strategy provides a
complementary method for the preparation of unsymmetrical alkyl−aryl sulfides under mild conditions with good functional group
tolerance.
such as low atomic economy and severe reaction conditions.
Therefore, it is important to find a more efficient sulfur reagent.
Sulfonyl cyanide compounds are widely used in various sulfone
and cyanation reactions as a type of bifunctional reagent.16
According to the related literature,17 sulfonyl groups are easily
reduced to sulfides in the presence of reducing agents.
Compared with thiols, the direct use of sulfonyl cyanide as a
sulfur source is more attractive in thiolation reactions.
Therefore, in combination with our previous work on Ni-
catalyzed reduction coupling, we describe the cross-electrophile
coupling reaction between unactivated alkyl bromides with p-
toluenesulfonyl cyanide under reductive conditions to form
unsymmetrical sulfides (Scheme 1c).
1. INTRODUCTION
Sulfide compounds widely exist in natural products and have a
wide range of applications in life sciences, materials chemistry,
and other fields.1 Many molecules containing a thioether
structure have been proved to have important application values
in the fields of medicine, materials, dyes, and so on.2 Because of
the synthetic versatility of sulfur compounds in organic
synthesis,3 chemists are continually looking for efficient
preparation strategies for multifunctional sulfide compounds.
The most classic synthesis method of alkyl sulfides is the two-
component reaction strategy of alkyl halides and mercaptan
under strong bases. Regrettably, this strategy needs a long
reaction time and high reaction temperature, and the use of
strong bases has a negative impact on yield and substrate
universality. It is still a challenge to develop a more mild and
efficient strategy to construct sulfides with a broad substrate
scope. Over the past few years, with the rapid development of
transition metal catalytic chemistry, transition metal-catalyzed
coupling reactions have become an important method for
building C−S bonds.4 Noble metals (Pd,5 Rh,6 Au,7 and Ag8)
are widely used in this strategy. On the other hand, inexpensive
metals (Fe,9 Cu,10 Co,11 Mn,12 and Ni13) are more desirable
(Scheme 1a). However, among the reported literatures, thiols
are usually used as thiolation agents. Due to the unpleasant odor
and high toxicity of mercaptans, it is very necessary to find a
cleaner sulfur reagent to replace mercaptan.
2. RESULTS AND DISCUSSION
This study was initiated by the reaction of 1-bromo-3-
phenylpropane 2b, 4-methylbenzenesulfonyl cyanide 1a, Ni-
(PPh3)2Cl2 (5 mol %), ligand (10 mol %), and Mn (1.5 equiv) in
dimethylformamide (DMF) at 40 °C for 24 h under dry
conditions and N2. To our delight, the reaction occurred
smoothly to give the target product (3-phenylpropyl)(p-
tolyl)sulfane 3d. As briefly illustrated in Table 1, different Ni
catalysts have been subjected to the reaction of 1a with 2b. It was
found that Ni(acac)2 is the more suitable catalyst and the
reaction afforded 3b in 73% yield (Table 1, entries 1−5). Next,
Recently, thiosulfonates have been successfully applied in the
reactions for the construction of sulfur-containing compounds
for their versatile reactivity.14 In recent years, we developed a
series of Ni-catalyzed coupling reactions of alkyl bromides and
cycloketone oxime esters with thiosulfonates to synthesize
highly functionalized sulfides, respectively (Scheme 1b).15
However, these developed strategies have some shortcomings
Received: April 19, 2021
Published: June 18, 2021
https://doi.org/10.1021/acs.joc.1c00903
© 2021 American Chemical Society
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Scheme 1. (a) Traditional Method of Preparing Asymmetric Sulfide; (b) Ni-Catalyzed C−S Bond Construction; and (c)
Reductive Ni-Catalyzed Cross Coupling Reaction between Unactivated Alkyl Bromides with Arenesulfonyl Cyanides
a
Table 1. Optimization of the Reaction Conditions
a
Reaction conditions: 1a (0.24 mmol, 1.2 equiv), 2b (0.20 mmol, 1.0 equiv), Ni(acac)2 (5.0 mol %), Mn (0.3 mmol, 1.5 equiv), ligand (10 mol %);
DMF (1 mL); N2 atmosphere; 40 °C; 24 h. Isolated yield.
we studied the effects of ligands. Different ligands such as a series
of bipyridine ligands and phenanthroline ligands have been
applied to the reaction. As a result, L1 provided inferior results
(Table 1, entries 6−12). Then, different dry solvents such as
DMF, DMA, dimethyl sulfoxide, and MeCN have been screened
for this reaction. DMF was crucial for the successful trans-
formation of 1a (Table 1, entries 13 and 14). When Zn was used
instead of Mn, the target product 3b could not be obtained
(Table 1, entry 15).
We investigated the scope of alkyl bromides under the
optimized reaction conditions. Primary alkyl bromides bearing
various functional groups were subjected to the reactions with 4-
methylbenzenesulfonyl cyanide 1a (Scheme 2). To our delight,
the carbon chain length has no effect on the reaction yields and
the desired sulfide products 3a−3f could be obtained in good
yields. The reaction of 3-(2-bromoethyl)-1H-indole 2g with 4-
methylbenzenesulfonyl cyanide 1a occurred well to afford 3g in
62% yield. On the other hand, the reaction of 1a with 2-(3-
bromopropyl)isoindoline-1,3-dione 2h afforded 3h in 65%
yield. Satisfactorily, a broad range of electron-donating func-
tional groups such as acetal, alcohol, silicon, and ether were well
tolerated under the identical reaction conditions. The desired
products 3i−3l were isolated in medium yields. To our delight,
different electron-withdrawing substituents, including ester,
cyano, halogen (Cl), were also well tolerated and 3m−3q
were observed in 45−79% yields, respectively. The reaction of 4-
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a
,b
Scheme 2. Substrate Scope
a
Reaction conditions: alkyl bromides bearing various functional groups 2 (0.20 mmol), substituted sulfonyl cyanide 1 (0.24 mmol), Ni(acac)2 (5.0
b
mol %); L1 (10 mol %), DMF (1 mL), Mn (0.3 mmol, 1.5 equiv), N2 atmosphere, 40 °C, 24 h. Isolated yields.
bromobut-1-ene 2r with 1a could also afford 3r in 56% yield.
Satisfactorily, when 1-bromobutane 2s and 1-bromotetradecane
2t were subjected to the reaction, 3s and 3t were isolated in
medium yields, respectively. It should be noted that 2-(4-
bromobutyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2u could
also undergo smoothly to give 3u in 40% yield. Surprisingly,
when tert-butyl (3-bromopropyl)carbamate 2v and methyl (R)-
3-bromo-2-[(tert-butoxycarbonyl)amino]propanoate 2w were
applied to the reactions with 1a under the optimized conditions,
3v and 3w were observed in medium to good yields, respectively.
2x reacted with 1a well to afford the desired product 3x in 60%
yield. Fortunately, the reaction of secondary bromide 3y also
took place well to give 3y in medium yield successfully.
However, the reaction of (3-bromobutyl)benzene 2z and 4-
methylbenzenesulfonyl cyanide 1a could not give the target
product 3z. Finally, we investigated the universality of sulfonyl
cyanide compounds. To our delight, the reaction of
benzenesulfonyl cyanide 1b and 1-bromo-3-phenylpropane 2b
could afford 4b in good yield. It should be noted that the
reaction of 4-methoxybenzenesulfonyl cyanide 1c with 2a could
also afford the cross-coupling product 4c in 83% yield. The
reaction 4-chlorobenzenesulfonyl cyanide 1d and 1-bromo-3-
phenylpropane 2b could give 4d in medium yield. Unfortu-
nately, the reaction of alkyl sulfonyl cyanide 1e with 2a failed to
afford 4e.
In order to explore the potential application of this reaction,
the reactions of 1a with 2b were carried out in 1 and 2 mmol
scales and 3b were observed in 60 and 65% yields, respectively
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Scheme 3. Related Derivative Reactions
(Scheme 3a). Sulfide 3b was easily oxidized to afford the
corresponding sulfoxide 5a and sulfone 5b in 90 and 95% yields,
respectively (Scheme 3b,c).18
II. Next, II is reduced to afford a NiI−SR complex III and 1,2-di-
p-tolyldisulfane 1a′. Intermediate 1a′ participates in the catalytic
cycle again. On the other hand, alkyl bromide 2 reacts with
complex III to furnish the alkyl radical and NiII−SR complex IV.
The complex IV reacts with an alkyl radical to form a NiIII(L)2
intermediate V. The sulfide 3 is generated by reductive
elimination and a NiI(L)2Br VI species is formed. Intermediate
VI can be further reduced to Ni0−Ln complex I to finish the
catalytic cycle.
In order to gain deeper insights into the reaction pathway,
further mechanistic studies were conducted (see Supporting
Information for more details). The reaction catalyzed by
Ni(acac)2 proceeded smoothly to give a mixture products of
2b and 1a′ after 16 h and product 3b could not be detected
(Scheme 4a) (see Supporting Information for more details).
Surprisingly, when we extended the reaction time to 24 h, a pure
product 3b could be obtained in 73% yield (Scheme 4b). The
reaction of 2b and 1a′ could afford the target product 3b in 70%
yield (Scheme 4c). These results indicated that product 1a′
might be a reaction intermediate. Next, we investigated the
conditions for the production of product 1a′, and it was found
that in this reaction system; the formation of product 1a′ is
mainly relied on the reduction of manganese powder (Scheme
4d). However, the efficiency of its generation is quite low
compared to the product yields (Scheme 4d). We speculated
that the byproducts, such as MnBr2, might promote the disulfide
formation. Therefore, we investigated the role of MnBr2. It was
found that when 0.1 equiv of MnBr2 was added, the yield of
product 1a′ was greatly improved. Increasing the amount of
MnBr2 could not further increase the yield of 1a′. These results
indicated that MnBr2 could promote the formation of product
1a′. Preliminary radical inhibition tests were conducted. When
TEMPO was added, the target product 3b could not be
obtained, and the product 6 could be detected by liquid
chromatography−mass spectrometry (LC−MS). Partial inhib-
ition was observed when ethene-1,1-diyldibenzene was added,
and the product 7 could be detected by LC−MS. These results
indicated that a single electron transfer process might be
involved in the reductive coupling.
3. CONCLUSIONS
In conclusion, we have developed a cross-electrophile coupling
between unactivated alkyl bromides with arenesulfonyl cyanides
catalyzed by Ni(acac)2 under reductive conditions to form
unsymmetrical sulfides. The reaction occurred smoothly under
mild conditions with an excellent chemoselectivity. It provides a
complementary strategy for the construction of alkyl−aryl
sulfides. This strategy shows that sulfonyl cyanide compounds
have great research potential applications in the formation of C−
S bonds.
4. EXPERIMENTAL SECTION
General Experimental Information. Unless otherwise noted, all
commercially available compounds were directly used as purchased
without further purification. Solvents for chromatography were of
analytical grade, which were used without further purification.
Anhydrous DMF was provided from Beijing InnoChem Science &
Technology Co., Ltd. Analytical thin-layer chromatography was
performed on silica gel, visualized by irradiation with UV light. 300−
400 mesh silica gel was utilized for column chromatography. 1H NMR
and 13C{1H} NMR were recorded in CDCl3 on a BRUKER 400 MHz
spectrometer. Chemical shifts (δ) were reported referenced to an
internal tetramethylsilane standard or the CDCl3 residual peak (δ 7.26)
for 1H NMR. Chemical shifts of 13C{1H} NMR are reported relative to
CDCl3 (δ 77.16). Data are reported in the following order: chemical
shift (δ) in ppm; multiplicities are indicated s (singlet), bs (broad
singlet), d (doublet), t (triplet), and m (multiplet); and coupling
constants (J) are in hertz (Hz). IR spectra were recorded on a BRUKER
VERTEX 70 spectrophotometer and are reported in terms of frequency
of absorption (cm−1). High-resolution mass spectrometry (HRMS)
Combining the abovementioned experimental results with the
literature,15,19 a plausible reaction mechanism is proposed in
Scheme 5. The in situ reduction of NiII and 4-methylbenzene-
sulfonyl cyanide 1a by manganese affords Ni0(L)2 I and 1,2-di-p-
tolyldisulfane 1a′, respectively. The oxidative addition of
Ni0(L)2 I and 1,2-di-p-tolyldisulfane 1a′ furnishes intermediate
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Scheme 4. Control Experiments
spectra were observed by using a GCT Premier TOF-MS (CI source)
or BRUKER microTOF-Q III instrument (ESI source).
at room temperature. Next, CrO3 (20 mol %) was added to the reaction
and the mixture was stirred for another 5 min. Subsequently, aryl
thiocyanate (1 equiv) was added to the solution, which was stirred for 2
h at room temperature. Then, the reaction mixture was filtered through
a Celite and 60 mL ethyl acetate was added to wash the residue. The
General Preparation Method of Arylsulfonyl Cyanide.20 The
compounds were prepared following the reported procedure. H5IO6 (8
equiv) was dissolved in acetonitrile by vigorous stirring for half an hour
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Scheme 5. Plausible Mechanism
filtrate was further washed with iced water (3 × 60 mL) and iced brine
(60 mL). The organic layer was dried over MgSO4 and concentrated
under reduced pressure to afford the crude product. Recrystallization
from hexane/CH2Cl2 gave the product.
697, 488. 1H NMR (400 MHz, CDCl3): δ 7.30−7.21 (m, 4H), 7.20−
7.12 (m, 3H), 7.08 (d, J = 7.9 Hz, 2H), 2.91−2.84 (m, 2H), 2.73 (t, J =
7.6 Hz, 2H), 2.31 (s, 3H), 1.93−1.93 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3): δ 141.5, 136.2, 132.8, 130.2, 129.8, 128.6, 128.5, 126.1,
34.8, 33.8, 30.8, 21.1. HRMS (EI) m/z: calcd for C16H18S (M)+,
242.1129; found, 242.1130.
(4-Phenylbutyl)(p-tolyl)sulfane (3c). Yield: 60% (30.7 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2924, 1711, 1493, 1453, 1359,
1220, 1092, 803, 699, 490. 1H NMR (400 MHz, CDCl3): δ 7.29−7.23
(m, 3H), 7.22 (d, J = 2.0 Hz, 1H), 7.19−7.13 (m, 3H), 7.08 (d, J = 8.0
Hz, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H),
1.79−1.71 (m, 2H), 1.67 (tdd, J = 8.6, 5.9, 1.8 Hz, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 142.3, 136.1, 133.1, 130.1, 129.8, 128.5, 128.4,
125.9, 35.5, 34.4, 30.6, 28.9, 21.1. HRMS (EI) m/z: calcd for C17H20S
(M)+, 256.1286; found, 256.1284.
Representative Procedure Synthesis of (3-Phenylpropyl)(p-
tolyl)sulfane (3b). A screw-capped 8 mL vial (oven-dried) was
charged with (3-bromopropyl)benzene 2b (0.2 mmol, 1.0 equiv), 4-
methylbenzenesulfonyl cyanide 1a (0.24 mmol, 1.2 equiv), Ni(acac)2
(10 mol %), Mn (1.5 equiv), ligand (10 mol %), and DMF(dry) (2.0
mL) via a syringe. The reaction mixture was stirred for 1 day at 40 °C
(reaction module). After that, ethyl acetate (20 mL) was added to dilute
the reaction mixture, which was further washed with water (20 mL ×3).
The organic layer was dried over Na2SO4, filtered, and concentrated.
The crude compound was purified by flash chromatography to afford
pure 3b in 73% yield (35.3 mg).
Procedure Scale-Up Synthesis of (3-Phenylpropyl)(p-tolyl)-
sulfane (3b). A screw-capped 50 mL vial (oven-dried) equipped with a
magnetic stir bar was charged with (3-bromopropyl)benzene 2b (1
mmol, 1.0 equiv), 4-methylbenzenesulfonyl cyanide 1a (1.2 mmol, 1.2
equiv), Ni(acac)2 (10 mol %), Mn (1.5 equiv), ligand (10 mol %), and
DMF(dry) (5.0 mL) via a syringe. The reaction mixture was stirred for
2 days at 40 °C (reaction module). After that, ethyl acetate (20 mL) was
added to dilute the reaction mixture, which was further washed with
water (20 mL ×3). The organic layer was dried over Na2SO4, filtered,
and concentrated. The residue was purified by flash chromatography to
afford a pure product 3b in 60% yield (145.3 mg).
Phenethyl(p-tolyl)sulfane (3a). Yield: 60% (27.4 mg) (PE). Yellow
oil. IR (neat, ν, cm−1): 2922, 2853, 1493, 1453, 1092, 802, 697, 489. 1H
NMR (400 MHz, CDCl3): δ 7.33−7.26 (m, 4H), 7.25−7.21 (m, 1H),
7.20−7.16 (m, 2H), 7.11 (d, J = 7.9 Hz, 2H), 3.17−3.06 (m, 2H), 2.90
(dd, J = 9.4, 6.4 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 140.3, 136.2, 132.5, 130.1, 129.7, 128.5, 128.5, 126.4, 35.9,
35.8, 21.0. HRMS (EI) m/z: calcd for C15H16S (M)+, 228.0973; found,
228.0973.
(5-Phenylpentyl)(p-tolyl)sulfane (3d). Yield: 60% (32.4 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2926, 1492, 1452, 1091, 800, 745,
697, 488. 1H NMR (400 MHz, CDCl3): δ 7.25 (m, J = 9.6, 7.7 Hz, 4H),
7.19−7.13 (m, 3H), 7.08 (d, J = 7.8 Hz, 2H), 2.89−2.83 (m, 2H), 2.59
(t, J = 7.7 Hz, 2H), 2.31 (s, 3H), 1.68−1.58 (m, 4H), 1.45 (qd, J = 7.3,
3.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 142.6, 136.0, 133.1,
130.0, 129.8, 128.5, 128.4, 125.8, 35.9, 34.4, 31.1, 29.3, 28.6, 21.1.
HRMS (EI) m/z: calcd for C18H22S (M)+, 270.1442; found, 270.1440.
(2-Phenoxyethyl)(p-tolyl)sulfane (3e). Yield: 70% (34.2 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2973, 1380, 1087, 1045, 879. 1H
NMR (400 MHz, CDCl3): δ 7.36−7.30 (m, 2H), 7.28−7.23 (m, 2H),
7.11 (d, J = 7.9 Hz, 2H), 6.97−6.90 (m, 1H), 6.88−6.78 (m, 2H), 4.11
(t, J = 7.1 Hz, 2H), 3.24 (t, J = 7.1 Hz, 2H), 2.32 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 158.4, 136.8, 131.6, 130.8, 129.8, 129.5, 121.0,
114.6, 66.6, 33.5, 21.1. HRMS (EI) m/z: calcd for C13H16OS (M)+,
244.0922; found, 244.0922.
(4-Methoxyphenethyl)(p-tolyl)sulfane (3f). Yield: 45% (23.2 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2922, 1736, 1511, 1492, 1242,
1176, 1035, 802, 490. 1H NMR (400 MHz, CDCl3): δ 7.34−7.29 (m,
2H), 7.18−7.10 (m, 4H), 6.89−6.84 (m, 2H), 3.82 (s, 3H), 3.16−3.09
(m, 2H), 2.88 (dd, J = 9.1, 6.6 Hz, 2H), 2.36 (s, 3H). 13C{1H} NMR
(3-Phenylpropyl)(p-tolyl)sulfane (3b). Yield: 73% (35.3 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2920, 1492, 1453, 1091, 801, 743,
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(100 MHz, CDCl3): δ 158.3, 136.3, 132.7, 132.6, 130.2, 129.8, 129.6,
114.0, 55.4, 36.2, 35.0, 21.2. HRMS (EI) m/z: calcd for C16H18OS
(M)+, 258.1078; found, 258.1081.
4-(p-Tolylthio)butanenitrile (3o). Yield: 45% (17.2 mg). (EA/PE =
1:20). Yellow oil. IR (neat, ν, cm−1): 2921, 2246, 1492, 1423, 1091, 803,
490. 1H NMR (400 MHz, CDCl3): δ 7.27 (d, J = 7.9 Hz, 2H), 7.11 (d, J
= 7.9 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 2.49 (t, J = 7.1 Hz, 2H), 2.32 (s,
3H), 1.91 (p, J = 7.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
137.2, 131.1, 131.0, 130.0, 119.2, 33.4, 24.9, 21.1, 15.9. HRMS (EI) m/
z: calcd for C11H13NS (M)+, 191.0769; found, 191.0773.
(6-Chlorohexyl)(p-tolyl)sulfane (3p). Yield: 60% (30.7 mg). (PE).
Yellow oil. IR (neat, ν, cm−1):2927, 1492, 1092, 801, 726, 650, 488. 1H
NMR (400 MHz, CDCl3): δ 7.23−7.14 (m, 2H), 7.02 (d, J = 8.0 Hz,
2H), 3.44 (t, J = 6.7 Hz, 2H), 2.86−2.74 (m, 2H), 2.24 (s, 3H), 1.76−
1.62 (m, 2H), 1.60−1.52 (m, 2H), 1.37 (dq, J = 7.3, 3.4 Hz, 4H).
13C{1H} NMR (100 MHz, CDCl3): δ 136.1, 133.0, 130.0, 129.8, 45.1,
34.4, 32.6, 29.2, 29.2, 28.1, 26.6, 21.1. HRMS (EI) m/z: calcd for
C14H21ClS (M)+, 242.0896; found, 242.0896.
(3-Chloropropyl)(p-tolyl)sulfane (3q). Yield: 45% (18.0 mg). (PE).
Yellow oil. IR (neat, ν, cm−1): 2922, 1492, 1437, 1267, 1091, 802, 490.
1H NMR (400 MHz, CDCl3): δ 7.32−7.24 (m, 2H), 7.10 (d, J = 7.9 Hz,
2H), 3.64 (t, J = 6.3 Hz, 2H), 3.02 (t, J = 6.9 Hz, 2H), 2.32 (s, 3H), 2.03
(p, J = 6.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 136.6, 131.9,
130.6, 129.9, 43.5, 31.9, 31.6, 21.1. HRMS (EI) m/z: calcd for
C10H13ClS (M)+, 200.0426; found, 200.0424.
But-3-en-1-yl(p-tolyl)sulfane (3r). Yield: 56% (19.9 mg). (PE).
Yellow oil. IR (neat, ν, cm−1): 2922, 1710, 1492, 1359, 1220, 1092, 915,
802, 529. 1H NMR (400 MHz, CDCl3): δ 7.27−7.24 (m, 2H), 7.10 (d,
J = 7.9 Hz, 2H), 5.84 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.13−4.98 (m,
2H), 2.99−2.86 (m, 2H), 2.40−2.33 (m, 2H), 2.32 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 136.7, 136.3, 132.7, 130.4, 129.8, 116.2,
34.0, 33.6, 21.1. HRMS (EI) m/z: calcd for C11H14S (M)+, 178.0816;
found, 178.0817.
3-(2-(p-Tolylthio)ethyl)-1H-indole (3g). Yield: 62% (33.1 mg).
(EA/PE = 1:20). Yellow oil. IR (neat, ν, cm−1): 3412, 2919, 1708, 1491,
1355, 1355, 1220, 1091, 802, 740,489. 1H NMR (400 MHz, CDCl3): δ
7.91 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.31 (dd, J = 10.5, 8.0 Hz, 3H),
7.20−7.16 (m, 1H), 7.13−7.08 (m, 3H), 6.99 (d, J = 2.2 Hz, 1H), 3.20
(dd, J = 8.9, 6.5 Hz, 2H), 3.06 (dd, J = 8.9, 6.5 Hz, 2H), 2.32 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 136.3, 136.2, 1329, 130.1, 129.8,
127.3, 122.2, 121.8, 119.5, 118.8, 114.9, 111.3, 35.0, 25.6, 21.1. HRMS
(EI) m/z: calcd for C17H17NS (M)+, 267.1082; found, 267.1084.
2-(3-(p-Tolylthio)propyl)isoindoline-1,3-dione (3h). Yield: 57%
(35.5 mg). (EA/PE = 1:20). Yellow oil. IR (neat, ν, cm−1): 1736,
1711, 1371, 1236, 1044, 720, 530. 1H NMR (400 MHz, CDCl3): δ 7.83
(m, J = 5.4, 3.0 Hz, 2H), 7.70 (m, J = 5.5, 3.0 Hz, 2H), 7.28−7.25 (m,
2H), 7.08 (d, J = 7.9 Hz, 2H), 3.80 (t, J = 7.0 Hz, 2H), 2.92−2.84 (m,
2H), 2.30 (s, 3H), 1.97 (p, J = 7.1 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 168.4, 136.6, 134.0, 132.2, 132.0, 130.9, 129.8, 123.3, 37.1,
32.3, 28.3, 21.1. HRMS (EI) m/z: calcd for C18H17NO2S (M)+,
311.0980; found, 311.0979.
3-(p-Tolylthio)propan-1-ol (3i). Yield: 65% (23.7 mg). (EA/PE =
1:50). Yellow oil. IR (neat, ν, cm−1): 2922, 1492, 1263, 1042, 905, 802,
487. 1H NMR (400 MHz, CDCl3): δ 7.30−7.24 (m, 2H), 7.10 (d, J =
8.0 Hz, 2H), 3.75 (t, J = 6.1 Hz, 2H), 2.99 (t, J = 7.1 Hz, 2H), 2.31 (s,
3H), 1.91−1.81 (m, 2H), 1.64 (s, 1H). 13C{1H} NMR (100 MHz,
CDCl3): δ 136.4, 132.4, 130.3, 129.8, 61.6, 31.9, 31.2, 21.1. HRMS (EI)
m/z: calcd for C10H14OS (M)+, 182.0765; found, 182.0764.
2-(2-(p-Tolylthio)ethyl)-1,3-dioxolane (3j). Yield: 45% (20.2 mg).
(PE). Yellow oil. IR (neat, ν, cm−1): 2880, 1493, 1398, 1129, 1016, 943,
1
876, 802, 489. H NMR (400 MHz, CDCl3): δ 7.28−7.22 (m, 2H),
Butyl(p-tolyl)sulfane (3s). Yield: 40% (14.4 mg). (PE). Yellow oil.
IR (neat, ν, cm−1): 2957, 1492, 1463, 1093, 801, 489. 1H NMR (400
MHz, CDCl3): δ 7.28 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 2.91
(t, J = 7.4 Hz, 2H), 2.35 (s, 3H), 1.65 (q, J = 7.3 Hz, 2H), 1.45 (dt, J =
14.7, 7.4 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 135.9, 133.3, 129.9, 129.7, 34.2, 31.5, 22.1, 21.1, 13.8.
HRMS (EI) m/z: calcd for C11H16S (M)+, 180.0973; found, 180.0973.
Tetradecyl(p-tolyl)sulfane (3t). Yield: 50% (32.0 mg). (PE). Yellow
7.09 (d, J = 7.9 Hz, 2H), 4.97 (t, J = 4.5 Hz, 1H), 3.98−3.80 (m, 4H),
3.05−2.92 (m, 2H), 2.31 (s, 3H), 2.01−1.92 (m, 2H). 13C{1H} NMR
(100 MHz, CDCl3): δ 136.3, 132.5, 130.2, 129.8, 103.2, 65.1, 33.8, 28.7,
21.1. HRMS (EI) m/z: calcd for C12H16O2S (M)+, 224.0871; found,
224.0867.
tert-Butyldimethyl(2-(p-tolylthio)ethoxy)silane (3k). Yield: 40%
(22.6 mg). (PE). Yellow oil. IR (neat, ν, cm−1): 2927, 1493, 1471, 1254,
1
1
oil. IR (neat, ν, cm−1): 2922, 2852, 1465, 798. H NMR (400 MHz,
1085, 834, 774, 661. H NMR (400 MHz, CDCl3): δ 7.41−7.34 (m,
2H), 7.19 (d, J = 7.9 Hz, 2H), 3.88 (t, J = 7.2 Hz, 2H), 3.12 (t, J = 7.2
Hz, 2H), 2.42 (s, 3H), 0.99 (s, 9H), 0.15 (s, 6H). 13C{1H} NMR (100
MHz, CDCl3): δ 136.2, 132.6, 130.1, 129.8, 62.6, 36.7, 26.0, 21.1, 18.5,
−5.1. HRMS (EI) m/z: calcd for C15H26SiOS (M)+, 282.1474; found,
282.1473.
(3-Methoxypropyl)(p-tolyl)sulfane (3l). Yield: 42% (16.5 mg).
(PE). Yellow oil. IR (neat, ν, cm−1):2922, 1492, 1115, 1092, 802, 489.
1H NMR (400 MHz, CDCl3): δ 7.30−7.21 (m, 2H), 7.09 (d, J = 7.9 Hz,
2H), 3.46 (t, J = 6.1 Hz, 2H), 3.31 (d, J = 0.6 Hz, 3H), 2.96 (t, J = 7.2
Hz, 2H), 2.31 (s, 3H), 1.92−1.82 (m, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 136.1, 132.7, 130.1, 129.8, 71.1, 58.7, 31.1, 29.5, 21.1.
HRMS (EI) m/z: calcd for C11H16OS (M)+, 196.0922; found,
196.0919.
Ethyl 6-(p-Tolylthio)hexanoate (3m). Yield: 79% (42.4 mg). (EA/
PE = 1:30). Yellow oil. IR (neat, ν, cm−1): 2923, 1733, 1493, 1460,
1178, 801, 489. 1H NMR (400 MHz, CDCl3): δ 7.26−7.21 (m, 2H),
7.08 (d, J = 7.9 Hz, 2H), 4.11 (q, J = 7.1 Hz, 2H), 2.91−2.82 (m, 2H),
2.31 (s, 3H), 2.28 (t, J = 7.5 Hz, 2H), 1.67−1.59 (m, 4H), 1.48−1.42
(m, 2H), 1.24 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3):
δ 173.7, 136.1, 132.9, 130.0, 129.7, 60.3, 34.3, 29.8, 29.0, 28.3, 24.6,
21.1, 14.4. HRMS (EI) m/z: calcd for C15H22O2S (M)+, 266.1341;
found, 266.1340.
Ethyl 4-(p-Tolylthio)butanoate (3n). Yield: 47% (22.4 mg). (EA/
PE = 1:30). Yellow oil. IR (neat, ν, cm−1): 1729, 1493, 1373, 1202,
1177, 1018, 803, 489. 1H NMR (400 MHz, CDCl3): δ 7.28−7.23 (m,
2H), 7.13−7.05 (m, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.91 (t, J = 7.2 Hz,
2H), 2.44 (t, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.92 (p, J = 7.2 Hz, 2H), 1.24
(t, J = 7.1 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.1, 136.4,
132.3, 130.4, 129.8, 60.5, 33.8, 33.0, 24.6, 21.1, 14.3. HRMS (EI) m/z:
calcd for C13H18O2S (M)+, 238.1028; found, 238.1031.
CDCl3): δ 7.27 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 2.95−2.83
(m, 2H), 2.34 (s, 3H), 1.65 (t, J = 7.5 Hz, 2H), 1.46−1.41 (m, 2H), 1.29
(d, J = 3.4 Hz, 20H), 0.91 (t, J = 6.7 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 135.8, 133.2, 129.7, 129.6, 34.4, 32.0, 29.7, 29.7, 29.7, 29.6,
29.5, 29.4, 29.3, 29.2, 28.8(3), 28.8(0), 22.7, 21.0, 14.1. HRMS (EI) m/
z: calcd for C21H36S (M)+, 320.2538; found, 320.2537.
4,4,5,5-Tetramethyl-2-(4-(p-tolylthio)butyl)-1,3,2-dioxaborolane
(3u). Yield: 40% (23.4 mg). (PE). Yellow oil. IR (neat, ν, cm−1): 1711,
1359, 1220, 1145, 1092, 529. 1H NMR (400 MHz, CDCl3): δ 7.29−
7.25 (m, 2H), 7.12−7.08 (m, 2H), 2.96−2.88 (m, 2H), 2.33 (s, 3H),
1.81−1.73 (m, 2H), 1.26 (s, 12H), 0.94 (d, J = 7.8 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3): δ 135.7, 133.4, 129.7, 129.6, 83.2, 36.5, 29.8,
25.0, 24.1, 21.1. HRMS (EI) m/z: calcd for C16H25O2BS (M)+,
292.1668; found, 292.1664.
tert-Butyl (3-(p-Tolylthio)propyl)carbamate (3v). Yield: 73% (41.4
mg). (EA/PE = 1:20). Yellow oil. IR (neat, ν, cm−1): 2916, 1672, 1490,
1296, 1117, 1076, 811, 485. 1H NMR (400 MHz, CDCl3): δ 7.27−7.23
(m, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.67 (s, 1H), 3.43 (t, J = 6.5 Hz, 1H),
2.89 (t, J = 7.2 Hz, 2H), 2.31 (s, 3H), 2.10−1.99 (m, 1H), 1.78 (p, J =
6.9 Hz, 2H), 1.44 (d, J = 3.5 Hz, 12H). 13C{1H} NMR (100 MHz,
CDCl3): δ 156.0, 136.4, 132.3, 130.3, 129.8, 79.3, 39.5, 31.8, 29.6, 28.6,
21.1. HRMS (EI) m/z: calcd for C15H23O2NS (M)+, 281.1449; found,
281.1446.
Methyl N-(tert-Butoxycarbonyl)-S-(p-tolyl)-D-cysteinate (3w).
Yield: 48% (31.2 mg). (EA/PE = 1:20). Yellow oil. IR (neat, ν,
cm−1): 1747, 1708, 1493, 1363, 1219, 1162, 1016, 808, 491. 1H NMR
(400 MHz, CDCl3): δ 7.34−7.29 (m, 2H), 7.09 (d, J = 7.9 Hz, 2H),
5.35 (d, J = 8.2 Hz, 1H), 4.54 (dd, J = 8.4, 4.5 Hz, 1H), 3.54 (s, 3H),
3.32 (d, J = 5.0 Hz, 2H), 2.31 (s, 3H), 1.42 (s, 9H). 13C{1H} NMR (100
MHz, CDCl3): δ 171.2, 155.0, 137.3, 131.8, 131.0, 129.9, 80.1, 53.4,
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Article
52.4, 37.9, 28.3, 21.1. HRMS (EI m/z: calcd for C16H23NO4S (M)+,
325.1348; found, 325.1345.
cooled to 0 °C. A solution of m-CPBA (purity: 85%, 207.1 mg, 1.2
mmol) in CH2Cl2 (10.0 mL) was added dropwise, and the mixture was
stirred at 25 °C. After disappearance of the sulfide, the reaction mixture
was quenched by adding H2O (20 mL), extracted with EtOAc (3 × 10
mL). The organic layer was dried over Na2SO4, filtered, and
concentrated. The product was purified by column chromatography
on silica gel (10 → 20% ethyl acetate/petroleum ether). Yield: 95%
(77.9 mg). (EA/PE = 1:10). White solid. IR (neat, ν, cm−1): 2970,
2921, 1650, 1437, 1296, 1196, 1017, 738. 1H NMR (400 MHz,
CDCl3): δ 7.79−7.72 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.25 (ddd, J =
7.6, 6.2, 1.5 Hz, 2H), 7.21−7.15 (m, 1H), 7.12−7.05 (m, 2H), 3.10−
3.00 (m, 2H), 2.68 (t, J = 7.5 Hz, 2H), 2.43 (s, 3H), 2.02 (tt, J = 8.2, 6.3
Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 144.7, 140.0, 136.2,
129.9, 128.6, 128.4, 128.1, 126.4, 55.6, 34.1, 24.3, 21.6. HRMS (EI) m/
z: calcd for C16H18O2S (M)+, 274.1028; found, 274.1023.
(8S,9R,13R,14R)-13-Methyl-3-(3-(p-tolylthio)propoxy)-
6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]-
phenanthren-17-one (3x). Yield: 60% (52.1 mg). (EA/PE = 1:10).
Yellow oil. IR (neat, ν, cm−1): 2924, 1736, 1712, 1608, 1495, 1358,
1055, 1036, 808, 529. 1H NMR (400 MHz, CDCl3): δ 7.26 (d, J = 7.9
Hz, 2H), 7.18 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 7.8 Hz, 2H), 6.70 (m, J =
9.5, 8.7, 2.8 Hz, 1H), 6.64 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (dt, J = 16.8,
5.9 Hz, 2H), 3.05 (t, J = 7.1 Hz, 2H), 2.88 (q, J = 5.3, 4.7 Hz, 2H), 2.49
(dd, J = 18.8, 8.6 Hz, 1H), 2.43−2.36 (m, 1H), 2.31 (s, 3H), 2.19−2.11
(m, 1H), 2.09−2.00 (m, 4H), 1.96 (td, J = 10.1, 9.5, 2.8 Hz, 2H), 1.59
(dd, J = 11.8, 9.2 Hz, 2H), 1.55−1.45 (m, 4H), 1.44−1.38 (m, 1H),
0.90 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 221.1, 157.0, 137.8,
136.3, 132.4, 132.2, 130.2, 129.8, 126.4, 114.7, 112.3, 66.1, 50.5, 48.1,
44.1, 38.5, 36.0, 31.7, 31.1, 29.8, 29.1, 26.7, 26.0, 21.7, 21.1, 14.0.
HRMS (EI) m/z: calcd for C28H34O2S (M)+, 434.2280; found,
434.2279.
tert-Butyl 4-(p-Tolylthio)piperidine-1-carboxylate (3y). Yield: 45%
(27.6 mg). (EA/PE = 1:20). Yellow oil. IR (neat, ν, cm−1): 1711, 1420,
1359, 1220, 1167, 529. 1H NMR (400 MHz, CDCl3): δ 7.35−7.31 (m,
2H), 7.11 (d, J = 7.8 Hz, 2H), 3.96 (d, J = 13.5 Hz, 2H), 3.12 (tt, J =
10.3, 3.9 Hz, 1H), 2.89 (ddd, J = 13.9, 10.8, 3.0 Hz, 2H), 2.33 (s, 3H),
1.88 (dt, J = 11.9, 3.5 Hz, 2H), 1.44 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3): δ 154.8, 137.7, 133.6, 130.0, 129.8, 79.7, 49.6, 45.1, 32.2, 28.5,
21.2. HRMS (EI) m/z: calcd for C17H25O2SN (M)+, 307.1606; found,
307.1606.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00903.
1
Copies of H and 13C{1H} spectra of the products and
control experiments (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Phenyl(3-phenylpropyl)sulfane (4b). Yield: 83% (37.9 mg). (PE).
Shun-Yi Wang − Key Laboratory of Organic Synthesis of
Jiangsu Province, College of Chemistry, Chemical Engineering
and Materials Science, Collaborative Innovation Center of
Suzhou Nano Science and Technology, Soochow University,
Suzhou 215123, P. R. China; orcid.org/0000-0002-8985-
8753; Email: shunyi@suda.edu.cn; Fax: 86-512-65880307
Yellow oil. IR (neat, ν, cm−1): 1710, 1583, 1480, 1438, 1358, 1220,
1
1091, 737, 691, 529. H NMR (400 MHz, CDCl3): δ 7.32−7.22 (m,
6H), 7.21−7.11 (m, 4H), 2.91 (t, J = 7.3 Hz, 2H), 2.75 (t, J = 7.5 Hz,
2H), 1.96 (m, J = 7.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ
141.4, 136.7, 129.3, 129.0, 128.6, 128.5, 126.1, 126.0, 34.8, 33.1, 30.8.
HRMS (EI) m/z: calcd for C15H16S (M)+, 228.0973; found, 228.0970.
(4-Methoxyphenyl)(3-phenylpropyl)sulfane (4c). Yield: 90% (46.5
mg). (PE). Yellow oil. IR (neat, ν, cm−1): 1736, 1611, 1511, 1493, 1242,
1176, 1090, 1035, 802, 490. 1H NMR (400 MHz, CDCl3): δ 7.37−7.29
(m, 2H), 7.26 (t, J = 7.4 Hz, 2H), 7.19−7.09 (m, 3H), 6.87−6.76 (m,
2H), 3.77 (s, 3H), 2.81 (t, J = 7.3 Hz, 2H), 2.71 (t, J = 7.6 Hz, 2H), 1.88
(m, J = 7.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3): δ 158.9, 141.5,
133.3, 128.6, 128.5, 126.6, 126.0, 114.6, 55.4, 35.2, 34.7, 30.9. HRMS
(EI) m/z: calcd for C16H18OS (M)+, 258.1078; found, 258.1081.
(4-Chlorophenyl)(3-phenylpropyl)sulfane (4d). Yield: 59% (30.7
mg). (PE). Yellow oil. IR (neat, ν, cm−1): 1475, 1453, 1094, 1010, 809,
698, 487. 1H NMR (400 MHz, CDCl3): δ 7.31−7.26 (m, 2H), 7.25−
7.18 (m, 5H), 7.16 (dd, J = 8.0, 1.4 Hz, 2H), 2.92−2.85 (m, 2H), 2.74
(t, J = 7.5 Hz, 2H), 1.94 (m, J = 7.4 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3): δ 141.2, 135.2, 131.9, 130.6, 129.1, 128.6, 128.6, 126.2, 34.7,
33.2, 30.6. HRMS (EI) m/z: calcd for C15H15ClS (M)+, 262.0583;
found, 262.0583.
Authors
Fei Wang − Key Laboratory of Organic Synthesis of Jiangsu
Province, College of Chemistry, Chemical Engineering and
Materials Science, Collaborative Innovation Center of Suzhou
Nano Science and Technology, Soochow University, Suzhou
215123, P. R. China
Weidong Rao − Key Laboratory of Biomass-based Green Fuels
and Chemicals, College of Chemical Engineering, Nanjing
Forestry University, Nanjing 210037, China; orcid.org/
0000-0002-6088-7278
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00903
Notes
Methyl-4-((3-phenylpropyl)sulfinyl)benzene (5a). In a round-
bottomed flask (10 mL) equipped with a stir bar, a solution of 2b
(72.6 mg, 0.30 mmol) in CH3CN (2 mL) was prepared. Aqueous 30%
H2O2 (0.6 mmol, 0.8 mL) and Me3SiCl (0.30 mmol, 38 μL) were
added, and the mixture was stirred at 25 °C for 10 min. After
disappearance of the sulfide, the reaction mixture was quenched by
adding H2O (20 mL), which was extracted with EtOAc (3 × 10 mL).
The organic layer was dried over Na2SO4, filtered, and concentrated.
The product was purified by column chromatography on silica gel (20
→ 100% ethyl acetate/petroleum ether). Yield: 90% (70.0 mg). (EA/
PE = 1:1). White solid. IR (neat, ν, cm−1): 1720, 1532, 1333, 1201,
1136, 1016, 937, 742, 689. 1H NMR (400 MHz, CDCl3): δ 7.50−7.44
(m, 2H), 7.33−7.22 (m, 4H), 7.20−7.15 (m, 1H), 7.14−7.09 (m, 2H),
2.82−2.68 (m, 4H), 2.39 (s, 3H), 2.13−2.01 (m, 1H), 2.00−1.88 (m,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 141.4, 140.6, 140.5, 129.9,
128.5, 128.4, 126.3, 124.1, 56.4, 34.6, 23.6, 21.4. HRMS (EI) m/z: calcd
for C16H18OS (M)+, 258.1078; found, 258.1078.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (nos. 21971174 and 21772137), PAPD,
Cyrus Tang (Zhongying) scholar and Soochow University for
financial support.
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