Synthesis of thioesters through copper-catalyzed coupling of aldehydes with thiols in water

Article abstract of DOI:10.1039/c3gc40946e

Copper-catalyzed C-S bond formation between aldehydes and thiols in the presence of TBHP as an oxidant is described. Functional groups including chloro, trifluoromethyl, bromo, iodo, nitrile, ester and thiophene are all tolerated by the reaction condition

Full text of DOI:10.1039/c3gc40946e

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Synthesis of thioesters through copper-catalyzed
coupling of aldehydes with thiols in water†
Cite this: DOI: 10.1039/c3gc40946e
Chih-Lun Yi, Yu-Ting Huang and Chin-Fa Lee*
Copper-catalyzed C–S bond formation between aldehydes and thiols in the presence of TBHP as an
oxidant is described. Functional groups including chloro, trifluoromethyl, bromo, iodo, nitrile, ester and
thiophene are all tolerated by the reaction conditions employed. This reaction is performed in water
without the use of a surfactant. Both aryl and alkyl aldehydes couple suitably with aryl- and alkyl thiols,
affording the corresponding thioesters in moderate to good yields.
Received 21st May 2013,
Accepted 27th June 2013
DOI: 10.1039/c3gc40946e
www.rsc.org/greenchem
Moreover, the substrates are limited to aryl thiols.6 Water is
one of the most attractive media for chemical transform-
Introduction
Thioesters are important building blocks for organic syn- ations.7 Interestingly, Kita et al. reported the preparation of
thesis,1 and they have been utilized in acyl transfer reactions thioesters from aldehydes and dipentafluorophenyl disulfide
as the intermediates. Thioesters also play an important role in in water through a radical pathway.8 However, many limit-
biology.2 The traditional preparation of thioesters relied on the ations remained in this work. First, 1 equiv. of a water soluble
condensation reaction of carboxylic acids with thiols or metal initiator is necessary. Second, the scope of the substrate is
thiolates in the presence of an activating reagent.3 However, limited to dipentafluorophenyl disulfide and low yields were
some limitations remain regarding using this protocol. First, observed when simple phenyl disulfides were used; moreover,
some starting materials such as acyl chlorides are moisture- no alkyldisulfides were present in this system. Third, cetyltri-
sensitive and need to be prepared in situ. Second, this method methyl-ammonium bromide was required as a surfactant.
sometimes produces an equal amount of halide anion when Therefore, the development of a general method for preparing
acyl chlorides were used. As a result, the direct coupling of thioesters from aldehydes and thiols in water is highly desir-
aldehydes with thiol surrogates serves as an attractive route to able. Transition-metal-catalyzed C–H functionalization has
access thioesters. Since the discovery of this approach in 1976 emerged as an efficient strategy for introducing carbon–carbon
by Takagi et al., through a photo-induced reductive acylation and carbon–heteroatom bonds.9 Herein we report that the
of disulfides with aldehydes,4 several synthetic limitations catalytic amount of CuCl is an active catalyst for the coupling
have been observed using this approach. First, the reaction is of aldehydes with thiols in the presence of TBHP as an oxidant
not applicable to substituted aromatic aldehydes. Second, the in water without the need for a surfactant.
reaction needs a specific photo-reactor. Third, a diluted reac-
tion concentration is required. Recently, Takemoto et al.
reported the carbene-catalyzed coupling of aldehydes with
Results and discussion
thiols in THF;5 however, some drawbacks are observed in this
method, as well. First, the carbenes used in this work are
expensive. Second, alkyl aldehydes are less reactive than aro-
matic aldehydes, and more electron-rich carbenes are
required. Bandgar and co-workers described the Dess–Martin
periodinane-promoted synthesis of thioesters; however,
6 equiv. of Dess–Martin periodinane in combination with
6 equiv. of NaN3 are required to give the desired thioesters.
Initially, benzaldehyde and 1-dodecanethiol were selected as
the model substrates to determine the optimized reaction con-
ditions and the results are summarized in Table 1. We first
examined the source of the oxidant (Table 1, entries 1–5), and
TBHP was found to be superior to the others (Table 1, entry 1).
The effect of the solvent was then studied (Table 1, entries
6–9), and to our delight, water afforded the target in 50% iso-
lated yield (Table 1, entry 9). A 61% yield was obtained when
the reaction was performed at 100 °C (Table 1, entry 10);
however, a lower yield was determined at 110 °C (Table 1, entry
11). Interestingly, a similar result was obtained when the
copper salt was reduced to 2.5 mol% (Table 1, entry 12).
However, a low yield (51%) was observed when 1.0 mol% of
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402,
Republic of China. E-mail: cfalee@dragon.nchu.edu.tw; Fax: +886 4 2286-2547;
Tel: +886 4 2284-0411 ext. 810
†Electronic supplementary information (ESI) available: Experimental details,
spectral data for new products. See DOI: 10.1039/c3gc40946e
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Table 1 Optimize the reaction conditionsa
Table 2 Copper-catalyzed coupling reaction of aldehydes with alkyl
thiolsa
Entry “Cu” (mol%)
Oxidant (mmol) Temp. Solvent Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (14) TBHP (2.5)
80
80
80
80
80
80
80
80
80
100
110
100
100
100
100
100
100
100
100
100
100
100
100
100
Toluene 22
Toluene 12
Cu(OAc)2 (14) BPO (2.5)
Cu(OAc)2 (14) AcOOH (2.5)
Cu(OAc)2 (14) DTBP (2.5)
Cu(OAc)2 (14) H2O2 (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (14) TBHP (2.5)
Cu(OAc)2 (2.5) TBHP (2.5)
Toluene
Toluene
Toluene
3
—
—
CH3CN 29
THF
DCE
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
20
25
50
61
43
60
51
75
69
73
76
89
60
69
13
76
72
76
9
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
25e
Cu(OAc)2 (1)
TBHP (2.5)
Cu(OAc)2 (2.5) TBHP (1.0)
Cu(OTf)2 (2.5) TBHP (1.0)
CuO (2.5)
Cu2O (2.5)
CuCl (2.5)
CuBr (2.5)
CuI (2.5)
—
CuCl (2.5)
CuCl (2.5)
CuCl (2.5)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
a Reaction conditions: Cu source (0.0125 mmol, 2.5 mol%), oxidant
(1.0 mmol), thiol (0.5 mmol), benzaldehyde (2.5 mmol) under a
nitrogen atmosphere in the solvent (1.5 mL) for 1 h. b Isolated yield.
c Benzaldehyde (1.5 mmol). d Under an air atmosphere. e 30 min. TBHP
= tert-butyl hydroperoxide. BPO = benzoyl peroxide. AcOOH = peracetic
acid. DTBP = di-tert-butyl peroxide.
a Reaction conditions unless otherwise stated: CuCl (0.0125 mmol,
2.5 mol%), TBHP (1.0 mmol), thiol (0.5 mmol), and aldehyde
(2.5 mmol) under a nitrogen atmosphere in H2O (1.5 mL) for 1 h.
copper salt was used (Table 1, entry 13). Notably, a 75% yield b 5 mol% of CuCl was used.
was obtained when TBHP was decreased to 1 mmol (Table 1,
entry 13). We then examined the influence of copper sources
employed. Furthermore, sterically demanding substituted aryl
(Table 1, entries 15–20), and found that CuCl was superior to
Cu(OTf)2, CuO, Cu2O, CuBr and CuI. The control experiment
showed that the product was obtained with only a 13% yield
when the reaction was carried out in the absence of a copper
salt (Table 1, entry 21). When the aldehyde was reduced to
1.5 mmol, only 76% yield was obtained (Table 1, entry 22). A
72% yield resulted when the reaction was performed under an
air atmosphere (Table 1, entry 23). Shorter reaction times
reduced the product yield to 76% yield (Table 1, entry 24).
With these optimized reaction conditions in hand, the
scope of the substrates was then studied. The results are sum-
marized in Table 2. A variety of alkyl thiols were conducted
with aromatic- and alkyl aldehydes to afford the corresponding
thioesters in moderate to good yields. Aromatic aldehydes
bearing electron-donating and electron-withdrawing substitu-
ents are all suitable for catalysis. It is important to note that
this system shows good functional group tolerance; ester (Table 2,
products 3b, 3e, 3m and 3r), chloro (Table 2, products 3c, 3d and
3e), bromo (Table 2, products 3l and 3m), nitrile (Table 2,
product 3n), iodo (Table 2, product 3t) and trifluoromethyl
(Table 2, product 3s) are all tolerated by the reaction conditions
aldehydes also underwent the cross-coupling with thiols to afford
the desired products in 55–70% yields (Table 2, products 3i, 3j
and 3k). Alkyl thiols were also reacted with alkyl aldehydes to give
the corresponding thioesters (Table 2, products 3u and 3v).
Based on the promising results for alkyl thiols, we next
turned our attention to aryl thiols. Aryl thiols bearing electron-
donating and electron-withdrawing substituents underwent
cross-coupling with aryl- and alkyl (Table 3, products 4o, 4p
and 4q) aldehydes to provide the corresponding thioesters in
31–90% yields. Functional groups including chloro (Table 3,
products 4a, 4f, 4g, 4h, 4k and 4q), trifluoromethyl (Table 3,
product 4b), fluoro (Table 3, product 4c), bromo (Table 3, pro-
ducts 4d, 4e, 4i and 4l), nitrile (Table 3, products 4l and 4m),
ester (Table 3, product 4r) and thiophene (Table 3, product 4s)
are tolerated by the reaction conditions.
Conclusions
In conclusion, we have developed a general method for prepar-
ing thioesters by using 2.5 mol% of CuCl as a catalyst and
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(Hz). Standard abbreviations indicating multiplicity were used
as follows: s = singlet, d = doublet, t = triplet, dd = double
doublet, tt = triplet triplet, td = triplet doublet, dt = doublet
triplet, q = quartet, m = multiplet, and b = broad. Melting
points (m.p.) were determined using a Büchi 535 apparatus
and are reported uncorrected. High resolution mass spectra
(HRMS) were performed on an electron ionization time-of-
flight (EI-TOF) mass spectrometer or LCMS with an APCI
source by the services at the National Chung Hsing University.
Table 3 Copper-catalyzed synthesis of thioesters through the coupling of
aldehydes with aryl thiolsa
General procedure for Table 1
A Schlenk tube equipped with a magnetic stirrer bar was
charged with copper salt (0.0125 mmol) in a nitrogen-filled
glove box. The Schlenk tube was then covered with a rubber
septum and removed from the glove box. Under a nitrogen
atmosphere, 1-dodecanethiol (0.5 mmol), benzaldehyde
(2.5 mmol), oxidant (1.0 mmol), and solvent (1.5 mL) were
added via a syringe, and the Schlenk tube was connected to a
nitrogen-filled balloon and heated at 100 °C in an oil bath.
After stirring at this temperature for 1 h, the heterogeneous
mixture was cooled to room temperature and diluted with
ethyl acetate (20 mL). The resulting solution was directly fil-
tered through a pad of silica gel and then washed with ethyl
acetate (20 mL) and concentrated to give the crude material
which was then purified by column chromatography (SiO2,
hexane) to yield 3a.
Representative example of Table 1: S-dodecyl benzothioate
(entry 18, 3a).10 Following the general procedure for Table 1,
using CuCl (1.3 mg, 0.0125 mmol), benzaldehyde (0.26 mL,
2.5 mmol), 1-dodecanethiol (0.125 mL, 0.5 mmol) and TBHP
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
using column chromatography (SiO2, hexane) yielded 3a as a
yellow oil (136 mg, 89% yield). 1H NMR (400 MHz, CDCl3)
δ 0.88 (t, J = 6.6 Hz, 3 H), 1.26–1.44 (m, 18 H), 1.63–1.71 (m,
2 H), 3.06 (t, J = 7.4 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.55 (t, J =
7.4 Hz, 1 H), 7.97 (d, J = 4.0 Hz, 2 H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 22.7, 28.9, 29.0, 29.1, 29.3, 29.5, 29.5, 29.6, 29.6,
29.6, 31.9, 127.1, 128.5, 133.1, 137.2, 192.1.
a Reaction conditions unless otherwise stated: CuCl (0.0125 mmol,
2.5 mol%), TBHP (1.0 mmol), thiol (0.5 mmol), and aldehyde
(2.5 mmol) under a nitrogen atmosphere in H2O (1.5 mL) for 1 h.
b 5 mol% of CuCl was used.
TBHP as an oxidant. It is important to note that the reactions
were carried out in water without any surfactant. Aryl- and
alkyl aldehydes were coupled with aryl- and alkyl thiols, giving
the corresponding thioesters in 31–94% yields. This system
shows good functional group tolerance. Additionally, sterically
demanding substrates were also shown to have good activity
for catalysis. Mechanistic studies and applications of this cata-
lytic system are currently underway in our laboratory.
General procedure for Table 2
A Schlenk tube equipped with a magnetic stirrer bar was
charged with CuCl (1.3 mg, 0.0125 mmol) in a nitrogen-filled
glove box. The Schlenk tube was then covered with a rubber
septum and removed from the glove box. Under a nitrogen
atmosphere, thiol (0.5 mmol), aldehyde (2.5 mmol), TBHP
(0.14 mL, 1.0 mmol), and H2O (1.5 mL) were added via a
syringe, and the Schlenk tube was connected to a nitrogen-
filled balloon and heated at 100 °C in an oil bath. After stirring
at this temperature for 1 h, the heterogeneous mixture was
cooled to room temperature and diluted with ethyl acetate
Experimental
General information
All chemicals were purchased from commercial suppliers and (20 mL). The resulting solution was directly filtered through a
used without further purification. NMR spectra were recorded pad of silica gel and then washed with ethyl acetate (20 mL)
on a Varian Unity Inova-600 or a Varian Mercury-400 instru- and concentrated to give the crude material which was then
ment using CDCl3 as a solvent. Chemical shifts are reported in purified by column chromatography (SiO2, hexane) to yield 3.
parts per million (ppm) and referenced to the residual solvent
resonance. The coupling constants (J) are reported in hertz procedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol),
Ethyl 2-(benzoylthio)acetate (3b).3b Following the general
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benzaldehyde (0.26 mL, 2.5 mmol), ethyl 2-mercaptoacetate CDCl3) δ 14.1, 22.7, 28.9, 28.9, 29.1, 29.3, 29.5, 29.6, 29.6, 29.6,
(0.056 mL, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O 29.7, 31.9, 55.4, 113.6, 129.3, 130.1, 163.5, 190.6.
(1.5 mL), followed by purification using column chromato-
S-(2-Methyl-1-butyl) 4-methoxybenzothioate (3g). Following
graphy (SiO2, hexane–EtOAc, 100 : 1) yielded 3b as a colorless the general procedure for Table 2, using CuCl (1.3 mg,
oil (99 mg, 88% yield). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, J = 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol),
7.2 Hz, 3 H), 3.88 (s, 2 H), 4.23 (q, J = 7.2 Hz, 3 H), 7.46 (t, J = 2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP
7.8 Hz, 2 H), 7.59 (t, J = 7.4 Hz, 1 H), 7.97 (d, J = 4.2 Hz, 2 H); (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
13C NMR (100 MHz, CDCl3) δ 14.0, 31.3, 61.8, 127.3, 128.6, using column chromatography (SiO2, hexane–EtOAc, 100 : 1)
133.7, 136.0, 168.7, 190.0.
yielded 3g as a yellow oil (112 mg, 94% yield). 1H NMR
S-Dodecyl 4-chlorobenzothioate (3c).10 Following the (400 MHz, CDCl3) δ 0.93 (t, J = 7.4 Hz, 3 H), 1.00 (d, J = 6.8 Hz,
general procedure for Table 2, using CuCl (1.3 mg, 3 H), 1.23–1.30 (m, 1 H), 1.47–1.54 (m, 1 H), 1.64–1.69 (m,
0.0125 mmol), 4-chlorobenzaldehyde (359 mg, 2.5 mmol), 1 H), 2.93 (dd, J = 7.2, 12.8 Hz, 1 H), 3.11 (dd, J = 6.0, 13.2 Hz,
1-dodecanethiol (0.125 mL, 0.5 mmol) and TBHP (0.14 mL, 1 H), 3.86 (s, 3 H), 6.90–6.94 (m, 2 H), 7.95–7.99 (m, 2 H);
1.0 mmol) in H2O (1.5 mL), followed by purification using 13C NMR (100 MHz, CDCl3) δ 11.4, 18.8, 28.7, 35.1, 35.4, 55.5,
column chromatography (SiO2, hexane) yielded 3c as a yellow 113.6, 129.3, 130.1, 163.6, 190.6; HRMS-EI calcd for
1
oil (130 mg, 76% yield). H NMR (400 MHz, CDCl3) δ 0.88 (t, C13H18O2S: 238.1028, found: 238.1035.
J = 6.8 Hz, 3 H), 1.26–1.43 (m, 18 H), 1.63–1.70 (m, 2 H), 3.06
S-Benzyl 4-methoxybenzothioate (3h).5 Following the
(t, J = 7.4 Hz, 2 H), 7.40–7.43 (m, 2 H), 7.89–7.92 (m, 2 H); 13C general procedure for Table 2, using CuCl (1.3 mg,
NMR (100 MHz, CDCl3) δ 14.1, 22.7, 28.9, 29.1, 29.2, 29.3, 29.5, 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol),
29.5, 29.6, 29.6, 29.6, 31.9, 128.5, 128.8, 135.6, 139.5, 191.0.
phenylmethanethiol (0.060 mL, 0.5 mmol) and TBHP
S-(2-Methyl-1-butyl) 4-chlorobenzothioate (3d). Following (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
the general procedure for Table 2, using CuCl (1.3 mg, using column chromatography (SiO2, hexane–EtOAc, 100 : 1)
0.0125 mmol), 4-chlorobenzaldehyde (359 mg, 2.5 mmol), yielded 3h as a yellow solid (86 mg, 66% yield). M.p.: 50–51 °C
2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP (lit.5 m.p.: 51–52 °C). 1H NMR (400 MHz, CDCl3) δ 3.83 (s,
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification 3 H), 4.29 (s, 2 H), 6.90 (dd, J = 2.0, 6.8 Hz, 2 H), 7.23–7.38 (m,
using column chromatography (SiO2, hexane) yielded 3d as a 5 H), 7.94 (dd, J = 2.0, 6.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3)
yellow oil (105 mg, 86% yield). 1H NMR (400 MHz, CDCl3) δ 33.1, 55.4, 113.7, 127.2, 128.6, 128.9, 129.4, 129.5, 137.7,
δ 0.94 (t, J = 7.4 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.24–1.31 163.7, 189.7.
(m, 1 H), 1.47–1.54 (m, 1 H), 1.67–1.72 (m, 1 H), 2.95 (dd,
S-Dodecyl 2-methylbenzothioate (3i).10 Following the
J = 7.2, 12.8 Hz, 1 H), 3.13 (dd, J = 5.6, 12.8 Hz, 1 H), 7.40–7.44 general procedure for Table 2, using CuCl (1.3 mg,
(m, 2 H), 7.91–7.94 (m, 2 H); 13C NMR (100 MHz, CDCl3) 0.0125 mmol), 2-methylbenzaldehyde (0.30 mL, 2.5 mmol),
δ 11.4, 18.8, 28.7, 34.9, 35.7, 128.5, 128.8, 135.6, 139.5, 1-dodecanethiol (0.125 mL, 0.5 mmol) and TBHP (0.14 mL,
190.9; HRMS-EI calcd for
242.0541.
C
12H15ClOS: 242.0532, found: 1.0 mmol) in H2O (1.5 mL), followed by purification using
column chromatography (SiO2, hexane) yielded 3i as a color-
1
Ethyl 2-((4-chlorobenzoyl)thio)acetate (3e). Following the less oil (107 mg, 67% yield). H NMR (400 MHz, CDCl3) δ 0.88
general procedure for Table 2, using CuCl (1.3 mg, (t, J = 6.8 Hz, 3 H), 1.26–1.44 (m, 18 H), 1.63–1.70 (m, 2 H),
0.0125 mmol), 4-chlorobenzaldehyde (359 mg, 2.5 mmol), 2.48 (s, 3 H), 3.03 (t, J = 7.2 Hz, 2 H), 7.22–7.26 (m, 2 H),
ethyl 2-mercaptoacetate (0.056 mL, 0.5 mmol) and TBHP 7.35–7.39 (m, 1 H), 7.76 (dd, J = 1.6, 8.4 Hz, 1 H); 13C NMR
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification (100 MHz, CDCl3) δ 14.1, 20.5, 22.7, 28.9, 29.2, 29.3, 29.5, 29.6,
using column chromatography (SiO2, hexane–EtOAc, 100 : 1) 29.6, 29.6, 29.6, 31.9, 125.7, 128.3, 131.4, 131.5, 136.6, 137.8,
yielded 3e as a white solid (90 mg, 70% yield). M.p.: 55–56 °C. 194.6.
1H NMR (400 MHz, CDCl3) δ 1.30 (t, J = 7.0 Hz, 3 H), 3.89 (s,
S-(2-Methyl-1-butyl) 2-methylbenzothioate (3j). Following
2 H), 4.23 (q, J = 7.1 Hz, 2 H), 7.44 (dd, J = 2.0, 6.8 Hz, 2 H), the general procedure for Table 2, using CuCl (1.3 mg,
7.92 (dd, J = 2.0, 6.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) 0.0125 mmol), 2-methylbenzaldehyde (0.30 mL, 2.5 mmol),
δ 14.1, 31.4, 61.9, 128.7, 129.0, 134.4, 140.1, 168.5, 188.9; 2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP
HRMS-EI calcd for C11H11ClO3S: 258.0117, found: 258.0115.
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
S-Dodecyl 4-methoxybenzothioate (3f).10 Following the using column chromatography (SiO2, hexane) yielded 3j as a
general procedure for Table 2, using CuCl (1.3 mg, yellow oil (77 mg, 70% yield). 1H NMR (400 MHz, CDCl3)
0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol), δ 0.94 (t, J = 7.6 Hz, 3 H), 1.01 (d, J = 6.4 Hz, 3 H), 1.24–1.31
1-dodecanethiol (0.125 mL, 0.5 mmol) and TBHP (0.14 mL, (m, 1 H), 1.48–1.55 (m, 1 H), 1.67–1.72 (m, 1 H), 2.47 (s, 3 H),
1.0 mmol) in H2O (1.5 mL), followed by purification using 2.93 (dd, J = 7.2, 13.2 Hz, 1 H), 3.09 (dd, J = 6.0, 13.2 Hz, 1 H),
column chromatography (SiO2, hexane–EtOAc, 100 : 1) yielded 7.23 (t, J = 7.4 Hz, 2 H), 7.33–7.39 (m, 1 H), 7.78 (dd, J = 1.6,
3f as a yellow oil (147 mg, 87% yield). 1H NMR (400 MHz, 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 11.4, 18.8,
CDCl3) δ 0.88 (t, J = 7.0 Hz, 3 H), 1.26–1.43 (m, 18 H), 1.64–1.67 20.5, 28.7, 35.0, 36.0, 125.6, 128.3, 131.4, 131.4, 136.5,
(m, 2 H), 3.04 (t, J = 7.4 Hz, 2 H), 3.85 (s, 3 H), 6.9 (dd, J = 2.0, 137.9, 194.6; HRMS-EI calcd for
6.8 Hz, 2 H), 7.95 (dd, J = 2.0, 6.8 Hz, 2 H); 13C NMR (100 MHz, found: 222.1072.
C13H18OS: 222.1078,
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S-Benzyl 2-methylbenzothioate (3k).3b Following the general yield). 1H NMR (400 MHz, CDCl3) δ 0.89 (t, J = 7.0 Hz, 3 H),
procedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol), 1.25–1.44 (m, 6 H), 1.62–1.68 (m, 2 H), 2.40 (s, 3 H), 3.05 (t, J =
2-methylbenzaldehyde (0.30 mL, 2.5 mmol), phenylmethane- 7.4 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 2 H), 7.87 (dd, J = 1.6, 6.4 Hz,
thiol (0.060 mL, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in 2 H); 13C NMR (100 MHz, CDCl3) δ 14.0, 21.6, 22.5, 28.6, 28.9,
H2O (1.5 mL), followed by purification using column chrom- 29.5, 31.3, 127.2, 129.2, 134.7, 144.0, 191.7; HRMS-EI calcd for
atography (SiO2, hexane) yielded 3k as a yellow oil (67 mg, 55% C14H20OS: 236.1235, found: 236.1228.
1
yield). H NMR (400 MHz, CDCl3) δ 2.50 (s, 3 H), 4.28 (s, 2 H),
S-(2-Methyl-1-butyl) 4-methylbenzothioate (3p). Following
7.22–7.27 (m, 3 H), 7.30–7.39 (m, 5 H), 7.76 (d, J = 8.0 Hz, 1 H); the general procedure for Table 2, using CuCl (1.3 mg,
13C NMR (100 MHz, CDCl3) δ 20.6, 33.9, 125.7, 127.2, 128.5, 0.0125 mmol), 4-methylbenzaldehyde (0.30 mL, 2.5 mmol),
128.6, 128.9, 131.6, 131.7, 136.9, 137.1, 137.6, 193.5.
2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP
S-Dodecyl 4-bromobenzothioate (3l). Following the general (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
procedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol), using column chromatography (SiO2, hexane) yielded 3p as a
4-bromobenzaldehyde (467 mg, 2.5 mmol), 1-dodecanethiol yellow oil (86 mg, 78% yield). 1H NMR (400 MHz, CDCl3)
(0.125 mL, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O δ 0.94 (t, J = 7.4 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.24–1.31
(1.5 mL), followed by purification using column chromato- (m, 1 H), 1.48–1.54 (m, 1 H), 1.66–1.71 (m, 1 H), 2.41 (s, 3 H),
graphy (SiO2, hexane) yielded 3l as a white solid (152 mg, 79% 2.94 (dd, J = 7.2, 13.6 Hz, 1 H), 3.11 (dd, J = 5.6, 13.2 Hz, 1 H),
1
yield). M.p.: 31–32 °C. H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 7.22–7.26 (m, 2 H), 7.87–7.90 (m, 2 H); 13C NMR (100 MHz,
6.8 Hz, 3 H), 1.25–1.43 (m, 18 H), 1.64–1.68 (m, 2 H), 3.06 (t, CDCl3) δ 11.4, 18.8, 21.6, 28.8, 35.0, 35.4, 127.2, 129.2, 134.7,
J = 7.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.82 (d, J = 8.4 Hz, 144.0, 191.8; HRMS-EI calcd for C13H18OS: 222.1078, found:
2 H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.7, 28.9, 29.1, 29.1, 222.1085.
29.3, 29.4, 29.5, 29.5, 29.6, 29.6, 31.9, 128.2, 128.6, 131.8,
135.9, 191.0; HRMS-EI calcd for C19H29BrOS: 384.1122, found: the general procedure for Table 2, using CuCl (1.3 mg,
384.1115. 0.0125 mmol), 3-methylbenzaldehyde (0.30 mL, 2.5 mmol),
S-(2-Methyl-1-butyl) 3-methylbenzothioate (3q). Following
Ethyl 2-((4-bromobenzoyl)thio)acetate (3m). Following the 2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP
general procedure for Table 2, using CuCl (1.3 mg, (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
0.0125 mmol), 4-bromobenzaldehyde (467 mg, 2.5 mmol), using column chromatography (SiO2, hexane) yielded 3q as a
ethyl 2-mercaptoacetate (0.056 mL, 0.5 mmol) and TBHP yellow oil (99 mg, 89% yield). 1H NMR (400 MHz, CDCl3)
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification δ 0.94 (t, J = 7.4 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H), 1.24–1.31
using column chromatography (SiO2, hexane–EtOAc, 100 : 1) (m, 1 H), 1.44–1.54 (m, 1 H), 1.68–1.70 (m, 1 H), 2.94 (dd, J =
yielded 3m as a yellow solid (135 mg, 89% yield). M.p.: 7.6, 13.6 Hz, 1 H), 3.13 (dd, J = 6.0, 13.6 Hz, 1 H), 7.30–7.38 (m,
41–42 °C. 1H NMR (400 MHz, CDCl3) δ 1.21 (t, J = 7.2 Hz, 3 H), 2 H), 7.78–7.79 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 11.4,
3.80 (s, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 7.51 (dd, J = 1.6, 6.8 Hz, 18.8, 21.3, 28.7, 35.0, 35.5, 124.4, 127.6, 128.4, 133.9, 137.3,
2 H), 7.74 (dd, J = 1.6, 6.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3) 138.4, 192.2; HRMS-EI calcd for C13H18OS: 222.1078, found:
δ 14.0, 31.4, 61.9, 128.7, 128.8, 131.9, 134.7, 168.4, 189.0; 222.1072.
HRMS-EI calcd for C11H11BrO3S: 301.9612, found: 301.9604.
Ethyl 2-((3-methylbenzoyl)thio)acetate (3r).3b Following the
S-(2-Methyl-1-butyl) 3-cyanobenzothioate (3n). Following general procedure for Table 2, using CuCl (1.3 mg,
the general procedure for Table 2, using CuCl (2.5 mg, 0.0125 mmol), 3-methylbenzaldehyde (0.30 mL, 2.5 mmol),
0.025 mmol), 3-formylbenzonitrile (331 mg, 2.5 mmol), ethyl 2-mercaptoacetate (0.056 mL, 0.5 mmol) and TBHP
2-methyl-1-butanethiol (0.065 mL, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification using column chromatography (SiO2, hexane) yielded 3r as a
using column chromatography (SiO2, hexane–EtOAc, 100 : 1) yellow oil (101 mg, 85% yield). 1H NMR (400 MHz, CDCl3)
yielded 3n as a yellow oil (52 mg, 44% yield). 1H NMR δ 1.29 (t, J = 7.2 Hz, 3 H), 2.40 (s, 3 H), 3.87 (s, 2 H), 4.22 (q, J =
(400 MHz, CDCl3) δ 0.95 (t, J = 7.4 Hz, 3 H), 1.01 (t, J = 6.4 Hz, 7.2 Hz, 2 H), 7.31–7.40 (m, 2 H), 7.76–7.78 (m, 2 H); 13C NMR
3 H), 1.24–1.35 (m, 1 H), 1.47–1.69 (m, 1 H), 1.70–1.74 (m, (100 MHz, CDCl3) δ 14.0, 21.1, 31.3, 61.7, 124.5, 127.7, 128.5,
1 H), 3.00 (dd, J = 7.2, 13.2 Hz, 1 H), 3.17 (dd, J = 6.0, 13.6 Hz, 134.4, 136.0, 138.5, 168.7, 190.1.
1 H), 7.58–7.62 (m, 1 H), 7.83–7.86 (m, 1 H), 8.18–8.21 (m,
S-Hexyl 4-(trifluoromethyl)benzothioate (3s). Following the
1 H), 8.26–8.27 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 11.3, general procedure for Table 2, using CuCl (2.5 mg,
18.8, 28.7, 34.8, 35.9, 113.0, 117.8, 129.6, 130.8, 131.1, 136.0, 0.025 mmol), 4-(trifluoromethyl)benzaldehyde (0.35 mL,
138.0, 190.2; HRMS-EI calcd for C13H15NOS: 233.0874, found: 2.5 mmol), 1-hexanethiol (0.0725 mL, 0.5 mmol) and TBHP
233.0879.
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
S-Hexyl 4-methylbenzothioate (3o). Following the general using column chromatography (SiO2, hexane) yielded 3s as a
procedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol), colorless oil (72 mg, 49% yield). 1H NMR (600 MHz, CDCl3)
4-methylbenzaldehyde (0.30 mL, 2.5 mmol), 1-hexanethiol δ 0.90 (t, J = 6.9 Hz, 3 H), 1.31–1.34 (m, 4 H), 1.41–1.46 (m,
(0.0725 mL, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O 2 H), 1.66–1.71 (m, 2 H), 3.10 (t, J = 7.2 Hz, 2 H), 7.72 (d, J =
(1.5 mL), followed by purification using column chromato- 8.4 Hz, 2 H), 8.07 (d, J = 8.4 Hz, 2 H); 13C NMR (150 MHz,
graphy (SiO2, hexane) yielded 3o as a yellow oil (105 mg, 89% CDCl3) δ 14.0, 22.5, 28.6, 29.3, 29.7, 31.3, 123.5 (q, J =
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271.1 Hz), 125.6, 125.6, 127.5, 134.5 (q, J = 32.4 Hz), 139.9, and concentrated to give the crude material which was then
191.2; 19F NMR (376 MHz, CDCl3) δ −64.7 (s); HRMS-EI calcd purified by column chromatography (SiO2, hexane) to yield 4.
for C14H17F3OS: 290.0952, found: 290.0954.
S-(4-Chlorophenyl) 4-methoxybenzothioate (4a).11 Following
S-Decyl 3-iodobenzothioate (3t). Following the general pro- the general procedure for Table 3, using CuCl (1.3 mg,
cedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol), 3-iodo- 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol),
benzaldehyde (592 mg, 2.5 mmol), 1-decanethiol (0.1075 mL, 4-chlorobenzenethiol (0.074 g, 0.5 mmol) and TBHP (0.14 mL,
0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), 1.0 mmol) in H2O (1.5 mL), followed by purification using
followed by purification using column chromatography (SiO2, column chromatography (SiO2, hexane–EtOAc, 100 : 1) yielded
hexane) yielded 3t as a white solid (99 mg, 49% yield). M.p.: 4a as a white solid (93 mg, 67% yield). M.p.: 96–97 °C (lit.11
44–45 °C. 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3 H), m.p.: 98–101 °C). 1H NMR (400 MHz, CDCl3) δ 3.86 (s, 3 H),
1.26–1.43 (m, 14 H), 1.62–1.70 (m, 2 H), 3.06 (t, J = 7.4 Hz, 6.94 (d, J = 9.2 Hz, 2 H), 7.41 (t, J = 1.0 Hz, 4 H), 7.98 (d, J = 8.8
2 H), 7.17 (t, J = 7.8 Hz, 1 H), 7.86–7.93 (m, 2 H), 8.27 (t, J = Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 55.5, 113.9, 126.1,
1.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 14.1, 22.6, 28.9, 128.9, 129.3, 129.7, 135.7, 136.3, 164.0, 187.9.
29.1, 29.2, 29.3, 29.4, 29.5, 29.5, 31.8, 94.2, 126.3, 130.1, 135.9,
138.8, 141.8, 190.6; HRMS-APCI calcd for C17H26OIS[M + H]+: Following the general procedure for Table 3, using CuCl
405.07436, found: 405.07428. (1.3 mg, 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL,
S-(4-(Trifluoromethyl)phenyl) 4-methoxybenzothioate (4b).
S-Dodecyl heptanethioate (3u). Following the general pro- 2.5 mmol), 4-(trifluoromethyl)benzenethiol (0.071 mL,
cedure for Table 2, using CuCl (1.3 mg, 0.0125 mmol), hept- 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL),
aldehyde (0.37 mL, 2.5 mmol), 1-dodecanethiol (0.125 mL, followed by purification using column chromatography (SiO2,
0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), hexane–EtOAc, 100 : 1) yielded 4b as a white solid (134 mg,
followed by purification using column chromatography (SiO2, 86% yield). M.p.: 105–106 °C. 1H NMR (600 MHz, CDCl3)
hexane) yielded 3u as a colorless oil (116 mg, 74% yield). δ 3.86 (s, 3 H), 6.95 (dd, J = 2.4, 7.2 Hz, 2 H), 7.63 (d, J = 7.8 Hz,
1H NMR (400 MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 3 H), 1.26–1.34 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.99 (dd, J = 2.4, 7.2 Hz, 2 H);
(m, 24 H), 1.54–1.57 (m, 2 H), 1.63–1.67 (m, 2 H), 2.53 (t, J = 13C NMR (150 MHz, CDCl3) δ 55.5, 114.0, 123.8 (q, J = 270.9
7.6 Hz, 2 H), 2.86 (t, J = 7.4 Hz, 2 H); 13C NMR (100 MHz, Hz), 125.8, 125.8, 128.8, 129.8, 131.1 (q, J = 32.6 Hz), 132.5,
CDCl3) δ 14.0, 14.1, 22.4, 22.7, 25.7, 28.6, 28.8, 28.8, 29.1, 29.3, 135.2, 164.2, 187.2; 19F NMR (376 MHz, CDCl3) δ −64.3 (s);
29.5, 29.6, 29.6, 29.6, 29.6, 31.4, 31.9, 44.1, 199.8; HRMS-APCI HRMS-APCI calcd for C15H12O2F3S[M + H]+: 313.0505, found:
calcd for C19H39OS[M + H]+: 315.2716, found: 315.2724.
313.0513.
S-(2-Methyl-1-butyl) heptanethioate (3v). Following the
S-(4-Fluorophenyl) 4-methoxybenzothioate (4c). Following
general procedure for Table 2, using CuCl (1.3 mg, the general procedure for Table 3, using CuCl (1.3 mg,
0.0125 mmol), heptaldehyde (0.37 mL, 2.5 mmol), 2-methyl- 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol),
1-butanethiol (0.065 mL, 0.5 mmol) and TBHP (0.14 mL, 4-fluorobenzenethiol (0.054 mL, 0.5 mmol) and TBHP
1.0 mmol) in H2O (1.5 mL), followed by purification using (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification
column chromatography (SiO2, hexane) yielded 3v as a color- using column chromatography (SiO2, hexane–EtOAc, 100 : 1)
less oil (84 mg, 78% yield). 1H NMR (400 MHz, CDCl3) yielded 4c as a white solid (81 mg, 62% yield). M.p.: 89–90 °C.
δ 0.86–0.94 (m, 9 H), 1.17–1.34 (m, 7 H), 1.39–1.46 (m, 1 H), 1H NMR (600 MHz, CDCl3) δ 3.86 (s, 3 H), 6.95 (dd, J = 2.4,
1.55–1.67 (m, 3 H), 2.55 (t, J = 7.4 Hz, 2 H), 2.75 (dd, J = 7.2, 7.2 Hz, 2 H), 7.12–7.15 (m, 2 H), 7.46–7.48 (m, 2 H), 7.99 (dd,
12.4 Hz, 1 H), 2.92 (dd, J = 6.0, 12.8 Hz, 1 H); 13C NMR J = 2.4, 7.2 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δ 55.5, 113.9,
(100 MHz, CDCl3) δ 11.3, 14.0, 18.7, 22.4, 25.7, 28.6, 28.6, 31.4, 116.3, 116.4, 122.8, 122.8, 129.0, 129.6, 137.1, 137.2, 162.6,
35.0, 35.3, 44.2, 199.8; HRMS-APCI calcd for C12H25OS[M + H]+: 164.0, 164.3, 188.5; 19F NMR (376 MHz, CDCl3) δ −112.9 (s);
217.16206, found: 217.16198.
HRMS-APCI calcd for C14H12O2FS[M + H]+: 263.0537, found:
263.0544.
S-(4-Bromophenyl) 4-methoxybenzothioate (4d). Following
the general procedure for Table 3, using CuCl (1.3 mg,
General procedure for Table 3
A Schlenk tube equipped with a magnetic stirrer bar was 0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol),
charged with CuCl (1.3 mg, 0.0125 mmol) in a nitrogen-filled 4-bromobenzenethiol (0.099 g, 0.5 mmol) and TBHP (0.14 mL,
glove box. The Schlenk tube was then covered with a rubber 1.0 mmol) in H2O (1.5 mL), followed by purification using
septum and removed from the glove box. Under a nitrogen column chromatography (SiO2, hexane–EtOAc, 100 : 1) yielded
atmosphere, thiol (0.5 mmol), aldehyde (2.5 mmol), TBHP 4d as a white solid (107 mg, 66% yield). M.p.: 103–104 °C.
(0.14 mL, 1.0 mmol), and H2O (1.5 mL) were added via a 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3 H), 6.94 (d, J = 9.2 Hz, 2
syringe, and the Schlenk tube was connected to a nitrogen- H), 7.35 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.97 (d, J =
filled balloon and heated at 100 °C in an oil bath. After stirring 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 55.5, 113.9, 124.0,
at this temperature for 1 h, the heterogeneous mixture was 126.7, 128.9, 129.7, 132.2, 136.5, 164.0, 187.7; HRMS-APCI
cooled to room temperature and diluted with ethyl acetate calcd for C14H12O2BrS[M + H]+: 322.9736, found: 322.9748.
(20 mL). The resulting solution was directly filtered through a
S-(2-Bromophenyl) 4-methoxybenzothioate (4e). Following
pad of silica gel and then washed with ethyl acetate (20 mL) the general procedure for Table 3, using CuCl (1.3 mg,
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0.0125 mmol), 4-methoxybenzaldehyde (0.31 mL, 2.5 mmol), solid (103 mg, 67% yield). M.p.: 66–67 °C. H NMR (400 MHz,
2-bromobenzenethiol (0.062 mL, 0.5 mmol) and TBHP CDCl3) δ 2.42 (s, 3 H), 7.34–7.42 (m, 4 H), 7.55–7.58 (m, 2 H),
(0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purification 7.79–7.82 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.3, 124.1,
using column chromatography (SiO2, hexane–EtOAc, 100 : 1) 124.7, 126.5, 127.9, 128.6, 132.4, 134.6, 136.3, 136.5, 138.7,
yielded 4e as a white solid (120 mg, 74% yield). M.p.: 189.5; HRMS-APCI calcd for C14H12OBrS[M + H]+: 306.9787,
1
79–80 °C. H NMR (400 MHz, CDCl3) δ 3.86 (s, 3 H), 6.95 (dd, found: 306.9795.
J = 2.0, 6.8 Hz, 2 H), 7.29 (td, J = 1.6, 8.0 Hz, 1 H), 7.37 (td, J =
S-(3-(Trifluoromethyl)phenyl) 4-methylbenzothioate (4j).
1.6, 7.6 Hz, 1 H), 7.61 (dd, J = 2.0, 7.6 Hz, 1 H), 7.72 (dd, J = Following the general procedure for Table 3, using CuCl
1.6, 8.0 Hz, 1 H), 8.01 (dd, J = 2.0, 6.8 Hz, 2 H); 13C NMR (1.3 mg, 0.0125 mmol), 4-methylbenzaldehyde (0.30 mL,
(100 MHz, CDCl3) δ 55.5, 113.9, 127.9, 129.0, 129.4, 129.8, 2.5 mmol), 3-(trifluoromethyl)benzenethiol (0.070 mL,
130.0, 131.1, 133.5, 137.6, 164.1, 186.7; HRMS-APCI calcd for 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL),
C14H12O2BrS[M + H]+: 322.9736, found: 322.9750.
followed by purification using column chromatography (SiO2,
S-(4-Chlorophenyl) 4-chlorobenzothioate (4f).12 Following hexane) yielded 4j as a yellow solid (134 mg, 90% yield). M.p.:
1
the general procedure for Table 3, using CuCl (2.5 mg, 62–63 °C. H NMR (600 MHz, CDCl3) δ 2.42 (s, 3 H), 7.28 (d,
0.025 mmol), 4-chlorobenzaldehyde (359 mg, 2.5 mmol), J = 7.8 Hz, 2 H), 7.56 (t, J = 9.6 Hz, 1 H), 7.69 (d, J = 7.8 Hz,
4-chlorobenzenethiol (74 mg, 0.5 mmol) and TBHP (0.14 mL, 2 H), 7.78 (s, 1 H), 7.91 (d, J = 7.8 Hz, 2 H); 13C NMR (150 MHz,
1.0 mmol) in H2O (1.5 mL), followed by purification using CDCl3) δ 21.7, 123.6 (q, J = 271.1 Hz), 126.1 (q, J = 3.5 Hz),
column chromatography (SiO2, hexane) yielded 4f as a white 127.6, 129.0, 129.3, 129.3, 129.5, 129.7, 131.5 (q, J = 32.4 Hz),
solid (72 mg, 51% yield). M.p.: 136–137 °C (lit.12 m.p.: 131.7 (q, J = 3.9 Hz), 133.5, 138.5, 145.1, 188.6; 19F NMR
1
136–138 °C). H NMR (400 MHz, CDCl3) δ 7.43 (s, 4 H), 7.46 (376 MHz, CDCl3)
δ −64.2 (s); HRMS-APCI calcd for
(d, J = 8.4 Hz, 2 H), 7.94 (d, J = 8.4 Hz, 2 H); 13C NMR C15H12OF3S[M + H]+: 297.0555, found: 297.0563.
(100 MHz, CDCl3) δ 125.3, 128.8, 129.1, 129.6, 134.6, 136.1,
S-(4-Chlorophenyl) 4-bromobenzothioate (4k).13 Following
136.2, 140.3, 188.5.
the general procedure for Table 3, using CuCl (1.3 mg,
S-(3-(Trifluoromethyl)phenyl) 4-chlorobenzothioate (4g). 0.0125 mmol), 4-bromobenzaldehyde (467 mg, 2.5 mmol),
Following the general procedure for Table 3, using CuCl 4-chlorobenzenethiol (74 mg, 0.5 mmol) and TBHP (0.14 mL,
(2.5 mg, 0.025 mmol), 4-chlorobenzaldehyde (359 mg, 1.0 mmol) in H2O (1.5 mL), followed by purification using
2.5 mmol), 3-(trifluoromethyl)benzenethiol (0.070 mL, column chromatography (SiO2, hexane) yielded 4k as a white
0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), solid (106 mg, 64% yield). M.p.: 144–145 °C (lit.13 m.p.:
1
followed by purification using column chromatography (SiO2, 145–146 °C). H NMR (400 MHz, CDCl3) δ 7.42 (s, 4 H), 7.62
hexane) yielded 4g as a yellow solid (114 mg, 72% yield). M.p.: (d, J = 8.4 Hz, 2 H), 7.86 (d, J = 8.4 Hz, 2 H); 13C NMR
51–52 °C. 1H NMR (600 MHz, CDCl3) δ 7.48 (dt, J = 2.4, 9.0 Hz, (100 MHz, CDCl3) δ 125.2, 128.9, 128.9, 129.5, 132.1, 135.0,
2 H), 7.59 (t, J = 7.8 Hz, 1 H), 7.70 (dd, J = 7.8, 13.8 Hz, 2 H), 136.1, 136.2, 188.7.
7.78 (s, 1 H), 7.96 (dt, J = 2.4, 8.4 Hz, 2 H); 13C NMR (150 MHz,
S-(4-Bromophenyl) 3-cyanobenzothioate (4l). Following the
CDCl3) δ 123.5 (q, J = 271.1 Hz), 126.4 (q, J = 3.6 Hz), 128.3, general procedure for Table 3, using CuCl (2.5 mg,
128.8, 128.9, 129.0, 129.1, 129.2, 129.7, 131.7 (q, J = 32.6 Hz), 0.025 mmol), 3-formylbenzonitrile (331 mg, 2.5 mmol), 4-bromo-
131.7 (q, J = 3.9 Hz), 134.4, 138.4, 140.5, 187.9; 19F NMR benzenethiol (99 mg, 0.5 mmol) and TBHP (0.14 mL,
(376 MHz, CDCl3)
δ
−64.2 (s); HRMS-APCI calcd for 1.0 mmol) in H2O (1.5 mL), followed by purification using
column chromatography (SiO2, hexane–EtOAc, 100 : 1) yielded
C14H9OClF3S[M + H]+: 317.00092, found: 317.00103.
S-(4-Chlorophenyl) 2-methylbenzothioate (4h). Following 4l as a white solid (108 mg, 68% yield). M.p.: 150–151 °C.
the general procedure for Table 3, using CuCl (1.3 mg, 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.4 Hz, 2 H), 7.60–7.67
0.0125 mmol), 2-methylbenzaldehyde (0.30 mL, 2.5 mmol), (m, 3 H), 7.90 (d, J = 7.6 Hz, 1 H), 8.22 (d, J = 8.0 Hz, 1 H),
4-chlorobenzenethiol (74 mg, 0.5 mmol) and TBHP (0.14 mL, 8.28 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 113.3, 117.5,
1.0 mmol) in H2O (1.5 mL), followed by purification using 124.7, 125.1, 129.8, 131.0, 131.3, 132.6, 136.3, 136.6, 137.1,
column chromatography (SiO2, hexane) yielded 4h as a white 187.8; HRMS-EI calcd for C14H8BrNOS: 316.9510, found:
1
solid (94 mg, 71% yield). M.p.: 90–91 °C. H NMR (400 MHz, 316.9518.
CDCl3) δ 2.48 (s, 3 H), 7.25–7.31 (m, 2 H), 7.40–7.44 (m, 5 H),
S-p-Tolyl 3-cyanobenzothioate (4m). Following the general
7.92 (dd, J = 1.6, 8.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) procedure for Table 3, using CuCl (2.5 mg, 0.025 mmol), 3-for-
δ 20.8, 125.9, 126.6, 128.6, 129.4, 131.8, 132.2, 135.8, 136.1, mylbenzonitrile (331 mg, 2.5 mmol), 4-methylbenzenethiol
136.2, 137.5, 191.4; HRMS-APCI calcd for C14H12OClS[M + H]+: (63 mg, 0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O
263.0292, found: 263.0294.
(1.5 mL), followed by purification using column chromato-
S-(4-Bromophenyl) 3-methylbenzothioate (4i). Following the graphy (SiO2, hexane–EtOAc, 100 : 1) yielded 4m as a white
general procedure for Table 3, using CuCl (1.3 mg, solid (65 mg, 51% yield). M.p.: 100–101 °C. 1H NMR (400 MHz,
0.0125 mmol), 3-methylbenzaldehyde (0.30 mL, 2.5 mmol), CDCl3) δ 2.41 (s, 3 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.38 (d, J =
4-bromobenzenethiol (99 mg, 0.5 mmol) and TBHP (0.14 mL, 8.0 Hz, 2 H), 7.62 (t, J = 8.0 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H),
1.0 mmol) in H2O (1.5 mL), followed by purification using 8.22 (d, J = 8.0 Hz, 1 H), 8.28 (s, 1 H); 13C NMR (100 MHz,
column chromatography (SiO2, hexane) yielded 4i as a yellow CDCl3) δ 21.3, 113.2, 117.6, 122.4, 129.7, 130.2, 130.9, 131.3,
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134.8, 136.3, 137.4, 140.3, 188.9; HRMS-EI calcd for column chromatography (SiO2, hexane–EtOAc, 100 : 1) yielded
C15H11NOS: 253.0561, found: 253.0566.
4r as a white solid (45 mg, 32% yield). M.p.: 113–114 °C. 1H
S-(4-Methoxyphenyl) 4-(tert-butyl)benzothioate (4n). Follow- NMR (400 MHz, CDCl3) δ 2.41 (s, 3 H), 3.95 (s, 3 H), 7.28 (d, J =
ing the general procedure for Table 3, using CuCl (1.3 mg, 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 8.06 (d, J = 8.4 Hz, 2 H),
0.0125
mmol),
4-(tert-butyl)benzaldehyde
(0.44
mL, 8.14 (d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.3,
2.5 mmol),4-methoxybenzenethiol (0.063 mL, 0.5 mmol) and 52.5, 123.1, 127.3, 129.9, 130.2, 134.2, 134.8, 139.9, 140.0,
TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purifi- 166.0, 190.1; HRMS-EI calcd for C16H14O3S: 286.0664, found:
cation using column chromatography (SiO2, hexane–EtOAc, 286.0667.
100 : 1) yielded 4n as a white solid (85 mg, 57% yield). M.p.:
S-p-Tolyl thiophene-2-carbothioate (4s). Following the
1
88–89 °C. H NMR (400 MHz, CDCl3) δ 1.34 (s, 9 H), 3.82 (s, general procedure for Table 3, using CuCl (1.3 mg,
3 H), 6.97 (d, J = 8.8 Hz, 2 H), 7.41 (d, J = 9.2 Hz, 2 H), 7.48 (d, 0.0125 mmol), 2-thiophenecarboxaldehyde (0.24 mL,
J = 8.4 Hz, 2 H), 7.96 (d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, 2.5 mmol), 4-methylbenzenethiol (63 mg, 0.5 mmol) and
CDCl3) δ 31.0, 35.1, 55.3, 114.8, 118.0, 125.6, 127.3, 133.9, TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), followed by purifi-
136.6, 157.3, 160.6, 190.5; HRMS-EI calcd for C18H20O2S: cation using column chromatography (SiO2, hexane) yielded 4s
300.1184, found: 300.1177.
as a yellow oil (37 mg, 31% yield). 1H NMR (400 MHz, CDCl3) δ
S-p-Tolyl heptanethioate (4o). Following the general pro- 2.39 (s, 3 H), 7.14 (t, J = 4.4 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H),
cedure for Table 3, using CuCl (1.3 mg, 0.0125 mmol), hept- 7.40 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 4.8 Hz, 1 H), 7.89 (d, J = 3.6
aldehyde (0.37 mL, 2.5 mmol), 4-methylbenzenethiol (63 mg, Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 21.3, 123.3, 127.9,
0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL), 130.1, 131.5, 133.1, 135.0, 139.9, 141.4, 182.5; HRMS-EI calcd
followed by purification using column chromatography (SiO2, for C12H10OS2: 234.0173, found: 234.0165.
1
hexane) yielded 4o as a yellow oil (84 mg, 71% yield). H NMR
(400 MHz, CDCl3) δ 0.89 (t, J = 6.8 Hz, 3 H), 1.26–1.37 (m, 6 H),
1.67–1.71 (m, 2 H), 2.35 (s, 3 H), 2.62 (t, J = 7.6 Hz, 2 H), 7.20
(d, J = 8.4 Hz, 2 H), 7.28 (dd, J = 2.0, 6.4 Hz, 2 H); 13C NMR
(100 MHz, CDCl3) δ 13.9, 21.2, 22.4, 25.5, 28.5, 31.4, 43.5,
124.3, 129.9, 134.3, 139.4, 197.9; HRMS-APCI calcd for
C14H21OS [M + H]+: 237.1308, found: 237.1313.
Acknowledgements
The National Science Council, Taiwan (NSC 101-2113-M-005-
008-MY3), the National Chung Hsing University and the
Center of Nanoscience and Nanotechnology (NCHU) are grate-
fully acknowledged for financial support. We also thank Prof.
Fung-E Hong (NCHU) for sharing his GC-MS instruments.
C.F.L. is a Golden-Jade Fellow of Kenda Foundation, Taiwan.
S-o-Tolyl heptanethioate (4p). Following the general pro-
cedure for Table 3, using CuCl (1.3 mg, 0.0125 mmol), hept-
aldehyde (0.37 mL, 2.5 mmol), 2-methylbenzenethiol (0.06 mL,
0.5 mmol) and TBHP (0.14 mL, 1.0 mmol) in H2O (1.5 mL),
followed by purification using column chromatography (SiO2,
1
hexane) yielded 4p as a yellow oil (85 mg, 72% yield). H NMR
(400 MHz, CDCl3) δ 0.89 (t, J = 6.8 Hz, 3 H), 1.26–1.40 (m, 6 H),
1.67–1.74 (m, 2 H), 2.33 (s, 3 H), 2.64 (t, J = 7.4 Hz, 2 H),
7.17–7.21 (m, 1 H), 7.28–7.30 (m, 2 H), 7.38 (d, J = 8.0 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 13.9, 20.6, 22.4, 25.6, 28.5, 31.4,
43.6, 126.4, 127.3, 129.9, 130.6, 135.8, 141.8, 197.1; HRMS-EI
calcd for C14H20OS: 236.1235, found: 236.1239.
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