One-pot synthesis of alkyl styryl sulfides free from transition metal/ligand catalyst and thiols

Article abstract of DOI:10.1002/ejoc.201201163

A new protocol for the one-pot synthesis of styryl alkyl sulfides was developed. This methodology involves the in situ generation of thiolate anions by nucleophilic substitution between potassium thioacetate and alkyl halides followed by fragmentation. Further reactions of these thiolate anions with substituted (E,Z)-β-styryl halides gave the corresponding sulfides with retention of stereochemistry in good to excellent yields. This procedure does not require a metal catalyst, it proceeds under mild conditions and in short times, and it is free from malodorous and air-sensitive alkyl thiols. Copyright

Full text of DOI:10.1002/ejoc.201201163

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
FULL PAPER
DOI: 10.1002/ejoc.201201163
One-Pot Synthesis of Alkyl Styryl Sulfides Free from Transition Metal/Ligand
Catalyst and Thiols
Adrián A. Heredia[a] and Alicia B. Peñéñory*[a]
Keywords: Synthetic methods / Nucleophilic substitution / Sulfur / Vinyl sulfides
A new protocol for the one-pot synthesis of styryl alkyl sulf-
ides was developed. This methodology involves the in situ
generation of thiolate anions by nucleophilic substitution be-
tween potassium thioacetate and alkyl halides followed by
fragmentation. Further reactions of these thiolate anions with
substituted (E,Z)-β-styryl halides gave the corresponding
sulfides with retention of stereochemistry in good to excel-
lent yields. This procedure does not require a metal catalyst,
it proceeds under mild conditions and in short times, and it
is free from malodorous and air-sensitive alkyl thiols.
it has been used as a sulfur source in nucleophilic substitu-
Introduction
tion with alkyl[16] and aryl[17] halides by SN2 or SRN
1
Vinyl sulfides are important synthetic intermediates in
organic chemistry.[1] They are frequently used as enolate ion
equivalents,[2] Michael acceptors,[3] components of [2+2] cy-
cloadditions,[4] intermediates in the stereoselective synthesis
of functionalized alkenes[5] or heterocycles,[6] and substrates
in transition-metal-catalyzed carbon–carbon bond-forming
reactions.[7] Furthermore this functional group is a com-
mon feature in many natural products and compounds with
attractive biological activities.[8]
mechanisms, respectively, and in Pd-catalyzed arylation re-
actions.[18]
As part of our ongoing research into sulfur chemis-
try,[17a,19] in this paper, we report a simple and convenient
synthetic procedure for the preparation of alkyl arylvinyl
sulfides, using potassium thioacetate (1) as a sulfide surro-
gate.
Different processes have been reported for the synthesis
of vinyl sulfides.[9] Traditional methods involve the Wittig
reaction,[10] the use of thiols in the nucleophilic substitution
of activated vinyl halides by an addition–elimination
mechanism,[11] or the nucleophilic addition of thiols to al-
kynes.[12] Both of these last two processes can also occur
under transition metal catalysis. In the past few years, many
new protocols involving Pd, Ni, and Cu complexes or nano-
particles have been reported for the preparation of vinyl
sulfides.[13,14] Recently the iron-catalyzed cross-coupling re-
action of alkyl vinyl halides with thiols has also been re-
ported.[15] The main disadvantages of these methodologies
arise from the low availability and effectiveness of auxiliary
ligands, the air sensitivity of both catalysts and thiols, and
the high temperatures (80–140 °C) and long reaction times
(4–24 h) needed in the reactions.
Results and Discussion
We selected (E)-β-bromostyrene (2a) as a model sub-
strate and CuI (10 mol-%)/1,10-phenanthroline (20 mol-%)
in toluene as the initial conditions. After 24 h at 110 °C, the
reaction yielded only 25% of thioacetate derivative 3; see
Equation (1).
Changing the solvent to the polar aprotic DMSO, divinyl
sulfide (Ͻ 20%) was obtained under the same general con-
ditions. No reaction was observed after only 4 h either in
the presence or absence of CuI/1,10-phenanthroline when
either DMSO or DMF was used as solvent.
In view of the low reactivity of the thioacetate anion
towards the vinyl halide and, with the aim of synthesizing
vinyl alkyl sulfides, we envisioned the possibility of a one-
pot procedure by three consecutive reactions (Scheme 1).
The in situ generation of alkyl thiolate anion 4 by reaction
of 1 with the alkyl halide followed by fragmentation or hy-
On the other hand, potassium thioacetate is a versatile
reagent. It is commercially available and easy to handle, and
[a] INFIQC, Departamento de Química Orgánica, Facultad de
Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad
Universitaria,
5000 Córdoba, Argentina
Fax: +54-351-4333030
E-mail: penenory@fcq.unc.edu.ar
Homepage: www.fcq.unc.edu.ar
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201163.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
A. A. Heredia, A. B. Peñéñory
FULL PAPER
drolysis of the S-alkylthioacetate, and subsequent vinyla- Table 1. Optimization of the conditions for the one-pot synthesis
of benzyl (E)-styryl sulfide.[a]
tion with (E)-β-bromostyrene (2a) should afford the alkyl
vinyl sulfide (i.e., 5).
Scheme 1. One-pot synthesis of 5.
[b]
Entry
T, t, atm.
Base
Yield of 5a [%][c]
Benzyl bromide was chosen as an alkylating agent, and
the polar DMSO as solvent to start with the screening for
optimized conditions (base, solvent, temperature, and time)
(Table 1). First, we screened a variety of bases in both the
presence and absence of copper/ligand and in both the pres-
ence and absence of a tiny amount of water to promote
hydrolysis. The reaction of bromide 2a with the thiolate
anion was not copper-catalyzed, and the one-pot reaction
only occurred in the presence of a base (Table 1, entries 1–
4). As expected, better results were obtained with the
stronger base, KOtBu, than with other weak bases such as
K3PO4, K2CO3, and KOH (Table 1, entries 4–7). When the
reaction was performed in the presence of CuI/1,10-phen-
anthroline and a base, the yield of sulfide 5a dropped by
about 10% compared to when the reaction was carried out
in the absence of copper and the ligand (Table 1, entries 3
and 4). Similar results were found for the combinations of
other bases and CuI/1,10-phenanthroline, probably due to
the formation of a complex between CuI and anion 4, which
would decrease its reactivity towards the vinyl bromide (re-
sults not shown). Surprisingly, when the reaction was per-
formed without adding water, the yield of 5a increased to
99%, suggesting that the alkyl thiolate anion is not formed
by hydrolysis during the reaction, but by a base-assisted
dethioacetylation (Table 1, entry 8, see below for further
mechanistic elucidation). Time, temperature, and atmo-
sphere were also optimized, and the reaction in DMSO with
KOtBu as a base also gave excellent results at 80 °C under
air after 1 h (Table 1, entries 10–14).
1
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 7 h, N2
110 °C, 1 h, N2
60 °C, 1 h, N2
r.t., 1 h, N2
–
–
–
–
2[d]
3[d]
4
KOH
KOH
39
49
27
28
87
99
99
99
74
62
72
82
5
6
K3PO4
K2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
7
8[e]
9[e,f]
10[e,f]
11[e,f]
12[e,f]
13[e,f]
14[e,f]
r.t., 1 h, air
60 °C, 1 h, air
80 °C, 1 h, air
[a] Reaction conditions unless otherwise stated: (E)-β-bromostyr-
ene (2a) (0.25 mmol), KSCOMe (1; 0.3 mmol), benzyl bromide
(0.3 mmol), in solvent (2 mL), in the presence of water (25 μL).
[b] Base: 0.35 mmol. [c] Determined by GC using the internal
method, error Ͻ 5%. Starting vinyl bromide 2a contained ca. 10%
of the (Z) isomer, and this led to ca. 10% of the (Z) isomer in the
product. [d] CuI (10 mol-%) and 1,10-phenanthroline (20 mol-%).
[e] Without the addition of water. [f] (E)-β-Bromostyrene 2a
(0.25 mmol), KSCOMe (1; 0.38 mmol), benzyl bromide
(0.38 mmol).
Table 2. Solvent screening for the one-pot synthesis of benzyl (E)-
styryl sulfide.[a]
We next examined different solvents in the model reac-
tion under these last-mentioned conditions (i.e., KOtBu,
80 °C, air, 1 h) (Table 2). Of the solvents screened, DMF
and acetonitrile gave good yields, but the yields were lower
than those obtained in DMSO (Table 2, entries 1–3). The
non-polar or polar protic solvents tested gave a product
yield of Ͻ 5% in the best case (Table 2, entries 4–9). We
selected DMF to continue this study due to its qualities as
a solvent for organic bases and other compounds, its lower
cost than DMSO and acetonitrile, and its intermediate boil-
ing point, all of which have made DMF a routine labora-
tory solvent. Finally, after the base:substrate ratio was in-
creased to 3:1 and the temperature was reduced to 50 °C,
the model reaction gave an excellent yield of sulfide 5a after
1 h in DMF (Table 2, entries 10–11). When the reaction was
performed starting with 6.5 mmol (1.20 g) of 2a in 25 mL
of DMF, 1.02 g of 5a (69% isolated yield) was obtained.
Having successfully obtained benzyl styryl sulfide (5a) in
a one-pot procedure, we next proceeded to explore the
Entry
Solvent
Yield of 5a [%][b]
1
2
3
4
5
6
7
8
DMSO
DMF
82
63
68
Ͻ 5
Ͻ 5
Ͻ 5
Ͻ 5
–
acetonitrile
ethanol
pyridine
PEG300
dioxane
THF
H2O
DMF
DMF
9
–
10[c]
11[c,d]
96
93 (76)[e]
[a] Reaction conditions unless otherwise stated: (E)-β-bromostyr-
ene 2a (0.25 mmol), KSCOMe (1; 0.38 mmol), benzyl bromide
(0.38 mmol), KOtBu (0.38 mmol), in solvent (2 mL) at 80 °C for
1 h under air. [b] Determined by GC using the internal method,
error Ͻ 5%. Starting vinyl bromide 2a contained ca. 10% of the
(Z) isomer, and this led to ca. 10% of the (Z) isomer in the product.
[c] Base: 0.75 mmol. [d] Reaction performed at 50 °C. [e] Isolated
scope and limitations of this methodology with a variety of yield.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
One-Pot Synthesis of Alkyl Styryl Sulfides
substituted styryl and alkyl halides (Tables 3 and 4). Com- unsubstituted styryl bromide (Table 3, entry 5), whereas
binations of (E)-styryl bromide or chloride with benzyl styryl bromides bearing electron-donating methyl and
bromide or chloride resulted in the formation of 5a in good methoxy substituents were less reactive and required longer
isolated yields (Table 3, entries 1–3). The (Z)-styryl bromide times and higher temperatures to obtain good yields of the
gave the corresponding (Z) isomer (i.e., Z5a) in 64% yield corresponding sulfides (Table 3, entries 6 and 7). The effect
(Table 3, entry 4). We also tested the effect of the substitu- of the substituents on the styryl halides, the stereochemical
ents on the styryl moiety. p-Chloro derivative 2c afforded outcome of the reaction (i.e., retention of configuration),
sulfide 5c in yields comparable to those obtained with the and the occurrence of the reaction without catalysis suggest
that the reaction of arylvinyl halides with thiolate anion 4
followed a classical vinylic nucleophilic substitution mecha-
Table 3. One-pot synthesis of arylvinyl benzyl sulfides.[a]
nism,[20] i.e., a concerted or stepwise addition–elimination
mechanism with retention of stereochemistry by a perpen-
dicular nucleophilic attack (Scheme 2).[11a,21]
Table 4. One-pot synthesis of alkyl (Z)-styryl sulfide.[a]
[a] Reaction conditions unless otherwise stated: (E)-β-bromostyr-
ene (2a) (0.25 mmol), KSCOMe (1; 0.38 mmol), alkyl halide
(0.38 mmol), KOtBu (0.75 mmol) in DMF (2 mL) at 50 °C for 1 h
under air. [b] Isolated yields. [c] The starting (E)-vinyl bromide 2a
contained ca. 10% of the (Z) isomer, and this led to ca. 10% of
the (Z) isomer in the product.
[a] Reaction conditions unless otherwise stated: (E)-vinyl halide
(0.25 mmol), KSCOMe (1; 0.38 mmol), alkyl halide (0.38 mmol),
KOtBu (0.75 mmol) in DMF (2 mL) at 50 °C for 1 h under air.
[b] Isolated yields. [c] The starting (E)-vinyl halide contained ca.
10% of the (Z) isomer, and this led to ca. 10% of the (Z) isomer
in the product. [d] Benzyl chloride as alkylating reagent. [e] (Z)-
styryl bromide. [f] The starting (Z)-vinyl halide contained ca. 10%
of the (E) isomer, this led to ca. 10% of the (E) isomer in the
product. [g] Reaction time: 2 h. [h] Reaction mixture was heated at
100 °C for 2 h.
Scheme 2. Concerted vinylic nucleophilic substitution.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
A. A. Heredia, A. B. Peñéñory
FULL PAPER
Finally, other alkyl bromides were tested (Table 4). As in the reaction media. This implies deprotonation of the
expected for an SN2 reaction, the primary methyl, n-butyl, methyl group α to the carbonyl, followed by elimination of
and cinnamyl bromides gave, together with the benzyl a ketene with the concomitant generation of anion 4. Evi-
bromides, the best yields of the corresponding sulfides dence for the formation of phenylketene comes from the
(Table 4, entries 1–4). However, the sterically hindered cy- observation of a product 8a or 8b arising from phenylketene
clohexylmethyl bromide and the secondary cyclopentyl dimerization[22] after methylation, and the methyl 2-phenyl-
bromide gave moderate yields (Table 4, entries 5 and 6, acetate from hydration of phenylketene[23] during work-up
respectively). The tertiary tert-butyl chloride and cyclohexyl or by traces of water present in DMF; see Equation (3).[24]
bromide failed to form the respective alkyl thiolate anions,
as an E2 elimination competed effectively with the nucleo-
philic substitution, and this represents the only limitation
of this methodology.
We also investigated the mechanism for the generation of
thiolate anion 4 from the S-alkyl thioacetate. When a mix-
ture of S-benzyl benzothioate (6), KOtBu, and MeI was
Scheme 4. Suggested mechanism for the generation of thiolate
stirred for 1 h at 50 °C in DMF, benzyl methyl sulfide was
not obtained, and unreacted 6 was recovered quantitatively;
see Equation (2). Under the same conditions, S-benzyl-2-
phenylethanethioate (7a), a compound with an acidic hy-
drogen α to the carbonyl group, was alkylated at the α posi-
tion (Scheme 3, path a). Furthermore, the reaction of 7a
with KOtBu and (E)-β-bromostyrene (2a) in DMF gave a
94% yield of (E)-styryl benzyl sulfide (5a, Scheme 3, path
b). Finally, when the reactions of S-benzyl-2-phenylethane-
thioate (7a, n = 1) and S-phenyl-2-phenylethanethioate (7b,
n = 0) were performed in two steps, i.e, deprotonation by
the base and subsequent addition of MeI – see Equa-
tion (3) – benzyl methyl sulfide and phenyl methyl sulfide,
respectively, were obtained as a major products (25%) to-
gether with (in both cases) methyl benzoate (28%), methyl
2-phenylacetate (30%), and a product of [M]+ = 250, whose
structure could be 8a or 8b (17%), as detected by GC-MS
(yields determined by GC).
anion 4.
Conclusions
In summary, we have developed a new one-pot method-
ology for the synthesis of alkyl arylvinyl sulfides in good to
excellent yields, free of any metal/ligand systems and from
malodorous and air-sensitive alkyl thiols. This procedure
uses the commercially available potassium thioacetate, low
temperatures, and short reaction times.
Experimental Section
General Information: KSCOMe, and alkyl and benzyl halides were
all high purity commercially available compounds, and were used
without further purification. (E) and (Z)-β-bromostyrenes were
prepared from cinnamic acids following literature procedures.[25]
Thioesters 6 and 7a,b were prepared by standard procedures.[26]
The commercially available CuI (Ͼ 98%) was used as received.
DMF, acetonitrile, and DMSO absolute grade were stored over
molecular sieves (4 Å) and used without further purification. Tolu-
ene, dioxane, THF, and pyridine were distilled by standard pro-
cedures and stored over molecular sieves (4 Å). PEG300 and eth-
anol were used without further purification. All the reaction prod-
ucts were isolated by radial chromatography (silica gel, petroleum/
diethyl ether) from the reaction mixture and characterized by 1H
and 13C NMR spectroscopy and mass spectrometry. 1H and 13C
NMR spectra were recorded at 400.16 and 100.62 MHz, respec-
tively, with a Bruker 400 spectrometer, and all spectra were re-
ported in δ (ppm) relative to Me4Si, with CDCl3 as solvent. Gas
chromatographic analyses were performed with an Agilent 5890
device with a flame-ionization detector, using a 30 m capillary col-
umn of 0.32 mmϫ0.25 μm film thickness, with a 5% phenyl-
polysiloxane phase. GS-MS analyses were performed with an
Agilent 7890 device using a 30 mϫ0.25 mmϫ0.25 μm with a 5%
phenylpolysiloxane phase column. HRMS spectra were recorded
Scheme 3. Reactions of S-benzyl 2-phenylethanethioate (7a).
The lack of reaction in the absence of a base, the en-
hancement of the yield with increasing basicity of the base
(Table 1, entries 1, 2, 4–8), and the requirement of an acidic
hydrogen α to the carbonyl group support the mechanism
suggested in Scheme 4 for the formation of thiolate anion 4 with a GCT Premie orthogonal acceleration time-of-flight (oa-
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
One-Pot Synthesis of Alkyl Styryl Sulfides
TOF) GC mass spectrometer. Ionization was achieved by electron
impact (70 eV), and detection was in positive mode.
ter (7a or 7b, 0.38 mmol) and KOtBu (0.75 mmol) were added, and
the mixture was stirred at 50 °C for 1 h. The reaction mixture was
allowed to cool to room temperature, and methyl iodide (excess)
was added. After then, diethyl ether (15 mL) and water (15 mL)
were added, and the mixture was stirred. The organic phase was
separated, and the aqueous phase was extracted with diethyl ether
(2ϫ 15 mL). The combined organic extracts were dried with anhy-
drous Na2SO4. The products have been quantified by integration
of a GC trace, and their identities were confirmed by EI MS.
General Procedure for the Reactions of (E)-β-Bromostyrene (2a) with
Potassium Thioacetate (1): See Equation (1). The reactions were
carried out in a 10 mL three-necked Schlenk tube, equipped with
a nitrogen gas inlet, a condenser, and a magnetic stirrer bar. The
tube was dried under vacuum, and filled with nitrogen, and then
the dried solvent (2.0 mL) was added. (E)-β-Bromostyrene
(45.7 mg, 0.25 mmol), CuI (4.7 mg, 0.025 mmol, 10 mol-%), 1,10-
phenanthroline (9.9 mg, 0.055 mmol, 20 mol-%), and finally potas-
sium thioacetate (57.1 mg, 0.5 mmol) were added to the degassed
solvent under nitrogen, and the mixture was stirred at 110 °C for
24 h. The reaction mixture was then allowed to cool to room tem-
perature. Diethyl ether (15 mL) and water (15 mL) were added, and
the mixture was stirred. The organic phase was separated, and the
aqueous phase was extracted with diethyl ether (2ϫ 15 mL). The
combined organic extracts were dried with anhydrous Na2SO4, and
the product was isolated by radial chromatography (hexane) to give
3 (11.1 mg, 25%) as a pale yellow oil. The identity of the product,
(E)-S-styryl ethanethioate (3),[27] was confirmed by 1H and 13C
NMR spectroscopy and EI-MS: 1H NMR (400.16 MHz, CDCl3,
(E)-Benzyl(4-methylstyryl)sulfane (5d): Following the general pro-
cedure for Table 3, using potassium thioacetate (1; 43.4 mg,
0.38 mmol), benzyl bromide (45 μL, 0.38 mmol), (Z)-1-(2-bromo-
vinyl)-4-methylbenzene (2d, 49.3 mg, 0.25 mmol), and potassium
tert-butoxide (84.2 mg, 0.75 mmol) for 2 h at 50 °C, and then puri-
fication by radial chromatography (hexane) gave 5d (39.7 mg, 66%)
as a white solid. m.p. 74–75 °C. 1H NMR (400.16 MHz, CDCl3,
30 °C): δ = 2.30 (s, 3 H), 3.98 (s, 2 H), 6.51 (d, J = 15.6 Hz, 1 H),
6.64 (d, J = 15.6 Hz, 1 H), 7.08 (d, J = 8.1 Hz, 2 H), 7.14 (d, J =
8.1 Hz, 2 H), 7.32–7.35 (m, 5 H) ppm. 13C NMR (100.62 MHz,
CDCl3, 30 °C): δ = 21.2, 37.5, 123.1, 125.6, 127.3, 128.4, 128.7,
128.9, 129.3, 134.2, 136.9, 137.4 ppm. MS (EI): m/z (%) = 240 (41)
30 °C): δ = 2.41 (s, 3 H), 6.71 (d, J = 16.3 Hz, 1 H), 7.22 (d, J = [M]+, 149 (27), 148 (12), 134 (23), 91 (100), 65 (15). HRMS (GC-
16.3 Hz, 1 H), 7.26 (d, J = 7.3 Hz, 1 H), 7.33 (t, J = 7.2 Hz, 2 H),
7.39 (d, J = 7.2 Hz, 2 H) ppm. 13C NMR (100.62 MHz, CDCl3,
30 °C): δ = 30.55, 117.17, 126.40, 128.14, 128.72, 131.64, 136.03,
192.70 ppm. MS (EI): m/z (%) = 178 (18) [M]+, 137 (12), 136 (100),
135 (71), 134 (13), 91 (38), 43 (47).
MS, EI): calcd. for C16H16S [M]+ 240.0973; found 240.0972.
(E)-Cinnamyl(styryl)sulfane (5h): Following the general procedure
for Table 4, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
cinnamyl bromide (74.9 mg, 0.38 mmol), (E)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
General Procedure for the One-pot Synthesis of Alkyl Vinyl Sulfides: 0.75 mmol), and then purification by radial chromatography (hex-
1
See Table 3 and Table 4. The reactions were carried out in a 10 mL
three-necked Schlenk tube, equipped with a magnetic stirrer bar.
DMF (2.0 mL) was added to the tube, then potassium thioacetate
ane) gave 5h (38.5 mg, 61%) as a yellow solid. m.p. 93–95 °C. H
NMR (400.16 MHz, CDCl3, 30 °C): δ = 3.59 (dd, J = 7.2 and
1.2 Hz, 2 H), 6.27 (dt, J = 15.6 and 7.2 Hz, 1 H), 6.57 (d, J =
(0.38 mmol), alkyl halide (0.38 mmol), and β-halostyrene 15.6 Hz, 2 H), 6.73 (d, J = 15.6 Hz, 1 H), 7.26–7.38 (m, 10 H) ppm.
(0.25 mmol) were added, and the mixture was stirred for some min-
utes at room temperature. Finally, base (0.75 mmol) was added,
and the mixture was stirred at 50 °C for 1 h. The reaction mixture
was then allowed to cool to room temperature. Diethyl ether
(15 mL) and water (15 mL) were added, and the mixture was
stirred. The organic phase was separated, and the aqueous phase
was extracted with diethyl ether (2ϫ 15 mL). The combined or-
ganic extracts were dried with anhydrous Na2SO4, and the products
were isolated by radial chromatography from the crude reaction
mixture or quantified by GC using the internal standard method
(see Tables 3 and 4). The identities of all the products were con-
13C NMR (100.62 MHz, CDCl3, 30 °C): δ = 35.6, 124.0, 125.0,
125.7, 126.5, 127.1 and 127.8, 128.3, 128.6, 128.7, 133.0, 136.6,
137.0 ppm. MS (EI): m/z (%) = 117 (100) [M – 135]+, 116 (11), 115
(39), 91 (23). HRMS (GC-MS, EI): calcd. for C17H16S [M]+
252.0973; found 252.0963.
(E)-(Cyclohexylmethyl)(styryl)sulfane (5i): Following the general
procedure for Table 4, using potassium thioacetate (1; 43.4 mg,
0.38 mmol), (bromomethyl)cyclohexane (53 μL, 0.38 mmol), (E)-β-
bromostyrene (2a, 45.7 mg, 0.25 mmol), and potassium tert-butox-
ide (84.2 mg, 0.75 mmol), and then purification by radial
chromatography (hexane) gave 5i (31.9 mg, 55%) as a colorless oil.
1H NMR (400.16 MHz, CDCl3, 30 °C): δ = 0.98–1.28 (m, 5 H),
1.65–1.90 (m, 6 H), 2.69 (d, J = 6.8 Hz, 2 H), 6.44 (d, J = 15.6 Hz,
1 H), 6.72 (d, J = 15.6 Hz, 1 H), 7.15–7.29 (m, 5 H) ppm. 13C
NMR (100.62 MHz, CDCl3, 30 °C): δ = 26.1, 26.3, 32.8, 37.9, 40.2,
125.4, 126.2, 126.3, 126.7, 128.6, 137.2 ppm. MS (EI): m/z (%) =
232 (62) [M]+, 137 (13), 136 (100), 135 (54), 134 (10), 97 (17), 91
(30), 55 (54), 41 (19). HRMS (GC-MS, EI): calcd. for C15H20S
[M]+ 232.1286; found 232.1322.
1
firmed by H and 13C NMR spectroscopy and EI-MS.
General Procedure for the Reactions Between Thioesters and KOtBu:
See Equation (2) and Scheme 3. The reactions were carried out in
a 10 mL three-necked Schlenk tube, equipped with a magnetic stir-
rer bar. DMF (2.0 mL) was added to the tube. Thioester (6 or 7a,
0.38 mmol), methyl iodide (0.38 mmol) or β-halostyrene
(0.25 mmol), and KOtBu (0.75 mmol) were added, and the mixture
was stirred at 50 °C for 1 h. The reaction mixture was then allowed
to cool to room temperature. Diethyl ether (15 mL) and water
(15 mL) were added, and the mixture was stirred. The organic
phase was separated, and the aqueous phase was extracted with
diethyl ether (2ϫ 15 mL). The combined organic extracts were
dried with anhydrous Na2SO4. The products were quantified by
integration of a GC trace, and their identities were confirmed by
EI-MS.
(E)-Cyclopentyl(styryl)sulfane (5j): Following the general procedure
for Table 4, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
1-bromocyclopentane (53 μL, 0.38 mmol), (E)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
0.75 mmol), and then purification by radial chromatography (hex-
ane) gave 5j (24.5 mg, 48%) as
a
colorless oil. 1H NMR
(400.16 MHz, CDCl3, 30 °C): δ = 1.61–2.1 (m, 8 H), 3.42–3.49 (m,
1 H), 6.50 (d, J = 15.6 Hz, 1 H), 6.77 (d, J = 15.6 Hz, 1 H), 7.16–
7.21 (m, 1 H), 7.28–7.29 (m, 4 H) ppm. 13C NMR (100.62 MHz,
CDCl3, 30 °C): δ = 24.9, 33.6, 44.7, 125.2, 125.5, 126.8, 127.6,
128.6, 137.3 ppm. MS (EI): m/z (%) = 204 (58) [M]+, 137 (13), 136
General Procedure for the Reactions Between Thioesters and KOtBu
Performed in Two Steps: See Equation (3). The reactions were car-
ried out in a 10 mL three-necked Schlenk tube, equipped with a
magnetic stirrer bar. DMF (2.0 mL) was added to the tube. Thioes-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
A. A. Heredia, A. B. Peñéñory
FULL PAPER
(100), 135 (92), 91 (35), 69 (10), 41 (25). HRMS (GC-MS, EI):
calcd. for C13H16S [M]+ 204.0973; found 204.0978.
(E)-Butyl(styryl)sulfane (5g):[32] Following the general procedure
for Table 4, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
1-bromobutane (41 μL, 0.38 mmol), (E)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
0.75 mmol), and then purification by radial chromatography (hex-
ane) gave 5g (44.7 mg, 93%) as a colorless oil. 1H NMR
(400.16 MHz, CDCl3, 30 °C): δ = 0.94 (t, J = 7.2 Hz, 3 H), 1.45
(sex, J = 7.6 Hz, 2 H), 1.68 (q, J = 7.2 Hz, 2 H), 2.80 (t, J = 7.2 Hz,
2 H), 6.46 (d, J = 15.6 Hz, 1 H), 6.72 (d, J = 15.6 Hz, 1 H), 7.17–
7.29 (m, 5 H) ppm. 13C NMR (100.62 MHz, CDCl3, 30 °C): δ =
13.7, 22.0, 31.6, 32.3, 125.4, 125.5, 126.6, 126.8, 128.6, 137.2 ppm.
MS (EI): m/z (%) = 192 (83) [M]+, 137 (10), 136 (66), 135 (100),
134 (15), 115 (12), 91 (45), 41 (12).
(E)-Benzyl(styryl)sulfane (5a):[28] Following the general procedure
for Table 3, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
benzyl bromide (45 μL, 0.38 mmol), (E)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
0.75 mmol), and then purification by radial chromatography (hex-
ane) gave 5a (43.0 mg, 76%) as
a
white solid. 1H NMR
(400.16 MHz, CDCl3, 30 °C): δ = 4.00 (s, 2 H), 6.51 (d, J = 15.6 Hz,
1 H), 6.70 (d, J = 15.6 Hz, 1 H), 7.24–7.35 (m, 10 H) ppm. 13C
NMR (100.62 MHz, CDCl3, 30 °C): δ = 37.4, 124.4, 125.6, 127.0,
127.4, 128.0, 128.66, 128.71, 128.9, 137.0, 137.3 ppm. MS (EI): m/z
(%) = 226 (27) [M]+, 135 (14), 134 (11), 91 (100), 65 (13).
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra (1H and 13C) for all the products (3, 5a, Z5a,
and 5c–j).
(Z)-Benzyl(styryl)sulfane (Z5a):[29] Following the general procedure
for Table 3, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
benzyl bromide (45 μL, 0.38 mmol), (Z)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
0.75 mmol), and then purification by radial chromatography (hex-
ane) gave Z5a (36.2 mg, 64%) as a colorless oil. 1H NMR
(400.16 MHz, CDCl3, 30 °C): δ = 3.99 (s, 2 H), 6.24 (d, J = 10.8 Hz,
1 H), 6.41 (d, J = 10.8 Hz, 1 H), 7.19–7.46 (m, 10 H) ppm. 13C
NMR (100.62 MHz, CDCl3, 30 °C): δ = 39.6, 125.9, 126.0, 126.8,
127.4, 128.3, 128.7 and 128.7, 129.0, 136.9, 137.4 ppm. MS (EI):
m/z (%) = 260 (21) [M]+, 91 (100), 65 (12).
Acknowledgments
This work was partly supported by Consejo Nacional de Investiga-
ciones Científicas y Técnicas (CONICET) and Fondo de Ciencia y
Tecnología (FONCYT), Argentina. A. A. H. gratefully acknowl-
edges the receipt of a fellowship from CONICET.
(E)-Benzyl(4-chlorostyryl)sulfane (5c):[30] Following the general pro-
cedure for Table 3, using potassium thioacetate (1; 43.4 mg,
0.38 mmol), benzyl bromide (45 μL, 0.38 mmol), (Z)-1-(2-bromo-
vinyl)-4-chlorobenzene (2c, 54.3 mg, 0.25 mmol) and potassium
tert-butoxide (84.2 mg, 0.75 mmol), and then purification by radial
chromatography (hexane) gave 5c (50.2 mg, 77%) as a white solid.
1H NMR (400.16 MHz, CDCl3, 30 °C): δ = 4.01 (s, 2 H), 6.45 (d,
J = 15.6 Hz, 1 H), 6.69 (d, J = 15.6 Hz, 1 H), 7.15 (d, J = 8.4 Hz,
2 H), 7.23 (d, J = 8.4 Hz, 2 H), 7.25–7.35 (m, 5 H) ppm. 13C NMR
(100.62 MHz, CDCl3, 30 °C): δ = 37.3, 125.3, 126.4, 126.7, 127.4,
128.7, 128.8, 128.9, 132.5, 135.5, 137.0 ppm. MS (EI): m/z (%) =
260 (21) [M]+, 91 (100), 65 (11).
[1] a) S. Oae, Organic Sulfur Chemistry: Structure and Mechanism,
CRC Press, Boca Raton, FL, 1991; b) R. J. Cremlyn, An Intro-
duction to Organosulfur Chemistry, Wiley & Sons, New York,
1996; c) C. A. Woodland, G. C. Crawley, R. C. Hartley, Tetra-
hedron Lett. 2004, 45, 1227–1231.
[2] B. M. Trost, A. C. Lavoie, J. Am. Chem. Soc. 1983, 105, 5075–
5090.
[3] a) V. Aucagne, C. Lorin, A. Tatibouët, P. Rollin, Tetrahedron
Lett. 2005, 46, 4349–4352; b) R. D. Miller, R. Hassig, Tetrahe-
dron Lett. 1985, 26, 2395–2398.
[4] K. Narasaka, Y. Hayashi, H. Shimadzu, S. Niihata, J. Am.
Chem. Soc. 1992, 114, 8869–8885.
[5] J. V. Comasseto, J. Organomet. Chem. 1983, 253, 131–181.
[6] a) M. Yar, S. P. Fritz, P. J. Gates, E. M. McGarrigle, V. K. Ag-
garwal, Eur. J. Org. Chem. 2012, 160–166; b) C. Quinet, L.
Sampoux, I. E. Markó, Eur. J. Org. Chem. 2009, 1806–1811.
[7] a) S. R. Dubbaka, P. Vogel, Angew. Chem. 2005, 117, 7848–
7859; Angew. Chem. Int. Ed. 2005; 44, 7674–7684; b) H. Lin,
X. Dong, Y. Li, Q. Shen, L. Lu, Eur. J. Org. Chem. 2012, 4675–
4679.
[8] a) N. Muraoka, M. Mineno, K. Itami, J. I. Yoshida, J. Org.
Chem. 2005, 70, 6933–6936; b) H. S. Sader, D. M. Johnson,
R. N. Jones, Antimicrob. Agents Chemother. 2004, 48, 53–62; c)
M. Ceruti, G. Balliano, F. Rocco, P. Milla, S. Arpicco, L. Cat-
tel, F. Viola, Lipids 2001, 36, 629–636; d) P. Johannesson, G.
Lindeberg, A. Johansson, G. V. Nikiforovich, A. Gogoll, B.
Synnergren, M. Le Greves, F. Nyberg, A. Karlén, A. Hallberg,
J. Med. Chem. 2002, 45, 1767–1777; e) E. Marcantoni, M.
Massaccesi, M. Petrini, G. Bartoli, M. C. Bellucci, M. Bosco,
L. Sambri, J. Org. Chem. 2000, 65, 4553–4559.
(E)-Benzyl(4-methoxystyryl)sulfane (5e):[31] Following the general
procedure for Table 3, using potassium thioacetate (1; 43.4 mg,
0.38 mmol), benzyl bromide (45 μL, 0.38 mmol), (Z)-1-(2-bromo-
vinyl)-4-methoxybenzene (2e, 53.3 mg, 0.25 mmol), and potassium
tert-butoxide (84.2 mg, 0.75 mmol) for 2 h at 100 °C, and then puri-
fication by radial chromatography (hexane) gave 5e (46.2 mg, 72%)
1
as a white solid. H NMR (400.16 MHz, CDCl3, 30 °C): δ = 3.79
(s, 3 H), 3.98 (s, 2 H), 6.49 and 6.54 (d, J = 15.2 and 15.6 Hz, 2
H), 6.81 (d, J = 8.8 Hz, 2 H), 7.18 (d, J = 8.8 Hz, 2 H), 7.24–7.35
(m, 5 H) ppm. 13C NMR (100.62 MHz, CDCl3, 30 °C): δ = 37.7,
55.3, 114.1, 121.5, 126.9, 127.3, 128.5, 128.6, 128.8, 129.9, 137.5,
158.9 ppm. MS (EI): m/z (%) = 257 (23), 256 (90) [M]+, 165 (77),
151 (21), 150 (87), 121 (24), 91 (100), 65 (35).
(E)-Methyl(styryl)sulfane (5f):[21] Following the general procedure
for Table 4, using potassium thioacetate (1; 43.4 mg, 0.38 mmol),
iodomethane (24 μL, 0.38 mmol), (E)-β-bromostyrene (2a,
45.7 mg, 0.25 mmol), and potassium tert-butoxide (84.2 mg,
0.75 mmol), and then purification by radial chromatography (hex-
[9] N. V. Zyk, E. K. Beloglazkina, M. A. Belova, N. S. Dubinina,
Russ. Chem. Rev. 2003, 72, 769–786.
[10] V. Aucagne, A. Tatibouët, P. Rollin, Tetrahedron 2004, 60,
1817–1826.
[11] a) C. F. Bernasconi, Z. Rappoport, Acc. Chem. Res. 2009, 42,
993–1003; b) M.-Y. Lei, Y.-J. Xiao, W.-M. Liu, K. Fukamizu,
S. Chiba, K. Ando, K. Narasaka, Tetrahedron 2009, 65, 6888–
6902.
[12] a) J. R. Cabrera-Antonino, A. Leyva-Pérez, A. Corma, Adv.
Synth. Catal. 2012, 354, 678–687; b) C. J. Weiss, T. J. Marks, J.
Am. Chem. Soc. 2010, 132, 10533–10546; c) M. S. Silva, R. G.
Lara, J. M. Marczewski, R. G. Jacob, E. J. Lenardao, G. Perin,
ane) gave 5f (35.6 mg, 95%) as
a
colorless oil. 1H NMR
(400.16 MHz, CDCl3, 30 °C): δ = 2.38 (s, 3 H), 6.31 (d, J = 15.4 Hz,
1 H), 6.79 (d, J = 15.4 Hz, 1 H), 7.18 (m, 1 H), 7.28–7.29 (m, 4 H)
ppm. 13C NMR (100.62 MHz, CDCl3, 30 °C): δ = 14.85, 124.75,
125.41, 125.82, 126.69, 128.67, 137.16 ppm. MS (EI): m/z (%) =
150 (100) [M]+, 135 (83), 134 (25), 102 (11), 91 (68), 77 (12), 51
(10).
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
One-Pot Synthesis of Alkyl Styryl Sulfides
Tetrahedron Lett. 2008, 49, 1927–1930; d) V. P. Ananikov, N. V.
Orlov, I. P. Beletskaya, Organometallics 2006, 25, 1970–1977; e)
A. Kondoh, K. Takami, H. Yorimitsu, K. Oshima, J. Org.
Chem. 2005, 70, 6468–6473; f) O. Arjona, R. Medel, J. Rojas,
A. M. Costa, J. Vilarrasa, Tetrahedron Lett. 2003, 44, 6369–
6373; g) M. Beller, J. Seayad, A. Tillack, H. Jiao, Angew. Chem.
2004, 116, 3448–3479; Angew. Chem. Int. Ed. 2004, 43, 3368–
3398; h) F. Alonso, I. P. Beletskaya, M. Yus, Chem. Rev. 2004,
104, 3079–3159; i) I. P. Beletskaya, V. P. Ananikov, Eur. J. Org.
Chem. 2007, 3431–3444.
Peñéñory, Org. Lett. 2003, 5, 4133–4136; c) J. E. Argüello, L. C.
Schmidt, A. B. Peñéñory, J. Org. Chem. 2007, 72, 2936–2944.
[20] While we were working on this manuscript, a paper was pub-
lished with the same observation, see: H.-L. Kao, C.-F. Lee,
Org. Lett. 2011, 13, 5204–5207.
[21] X. Chen, Z. Rappoport, J. Org. Chem. 1998, 63, 5684–5686.
[22] The base-catalyzed rearrangement of a neutral phenylketene
dimer of the lactone type (corresponding to 8a) to its acidic
isomer (corresponding to 8b) has been reported, see: J. E. Bal-
dwin, J. D. Roberts, J. Am. Chem. Soc. 1963, 85, 2444–2445.
[23] Y. Chiang, A. V. Fedorov, A. J. Kresge, I. Onyido, T. T. Tidwell,
J. Am. Chem. Soc. 2004, 126, 9382–9386.
[24] The origin of the methyl benzoate is not clear. All the control
experiments of reagents and products did not afford methyl
benzoate, as judged by analysis by GC-MS.
[25] a) S. Chowdhury, S. Roy, J. Org. Chem. 1997, 62, 199–200; b)
C. Kuang, H. Senboku, M. Tokuda, Tetrahedron Lett. 2001,
42, 3893–3896.
[26] M. B. Smith, J. March, March’s Advanced Organic Chemistry,
6th ed., John Wiley & Sons, New Jersey, 2007, p. 1425.
[27] J. H. Wang, Q. Xu, X. Huang, Chin. Chem. Lett. 2000, 11, 1–
2.
[13] a) I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011, 111, 1596–
1636; b) T. Kondo, T. Mitsudo, Chem. Rev. 2000, 100, 3205–
3220.
[14] For examples of the copper-catalyzed synthesis of vinyl sulfides
from alkenyl halides, see: a) M. S. Kabir, M. Lorenz, M. L.
Van Linn, O. A. Namjoshi, S. Ara, J. M. Cook, J. Org. Chem.
2010, 75, 3626–3343; b) M. S. Kabir, M. L. Van Linn, A.
Monte, J. M. Cook, Org. Lett. 2008, 10, 3363–3366; c) W. Bao,
Y. Liu, X. Lv, Synthesis 2008, 1911–1917; d) Z. Wang, H. Mo,
W. B a o, Synlett 2007, 91–94; e) C. G. Bates, P. Saejueng, M. Q.
Doherty, D. Venkataraman, Org. Lett. 2004, 6, 5005–5008.
[15] Y.-Y. Lin, Y.-J. Wang, C.-H. Lin, J.-H. Cheng, C.-F. Lee, J. Org.
Chem. 2012, 77, 6100–6106.
[28] Y. Yatsuminji, O. Okada, A. Tsubouchi, T. Takeda, Tetrahedron
2006, 62, 9981–9987.
[29] S. Ranjit, Z. Duan, P. Zhang, X. Liu, Org. Lett. 2010, 12, 4134–
4136.
[16] T.-C. Zheng, M. Burkart, D. E. Richardson, Tetrahedron Lett.
1999, 40, 603–606.
[17] a) L. C. Schmidt, V. Rey, A. B. Peñéñory, Eur. J. Org. Chem.
2006, 2210–2214; b) G. Petrillo, M. Novi, G. Garbarino, M. [30] M. V. R. Reddy, E. P. Reddy, S. C. Bell, WO2006US06698,
Filiberti, Tetrahedron 1989, 45, 7411–7420; c) S. M. Soria-Cas-
tro, Synlett 2012, 2997–2998, and references therein.
[18] a) C. Lai, B. J. Backes, Tetrahedron Lett. 2007, 48, 3033–3037;
b) N. Park, K. Park, M. Jang, S. Lee, J. Org. Chem. 2011, 76,
4371–4378.
[19] a) J. E. Argüello, L. C. Schmidt, A. B. Peñéñory, ARKIVOC
2003, 411–419; b) J. E. Argüello, L. C. Schmidt, A. B.
2006.
[31] S. Shoai, P. Bichler, B. Kang, H. Buckley, J. A. Love, Organo-
metallics 2007, 26, 5778–5781.
[32] C. G. Bates, P. Saejueng, M. Q. Doherty, D. Venkataraman,
Org. Lett. 2004, 6, 5005–5008.
Received: August 29, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O21163
/KAP1
Date: 18-12-12 19:11:15
Pages: 8
A. A. Heredia, A. B. Peñéñory
FULL PAPER
Thioether Formation
A. A. Heredia, A. B. Peñéñory* ........ 1–8
One-Pot Synthesis of Alkyl Styryl Sulfides
Free from Transition Metal/Ligand Cata-
lyst and Thiols
We have developed a one-pot methodology
for the synthesis of alkyl arylvinyl sulfides
in good to excellent yields, free of any me-
tal/ligand systems and from malodorous
and air-sensitive alkyl thiols. This pro-
cedure uses commercially available potass-
ium thioacetate, low temperatures, and
short reaction times.
Keywords: Synthetic methods / Nucleo-
philic substitution / Sulfur / Vinyl sulfides
8
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0