Thia-Michael addition using cheap and odorless S-alkylisothiouronium salts as thiol equivalents in water

Article abstract of DOI:10.1055/s-2007-982530

S-Alkylisothiouronium salt has been found to be a non-toxic, odorless and simply operational alternative of thiol for the thia-Michael addition with electron-deficient olefins. The reactions were carried out under alkaline conditions in water at room temperature within 5-20 minutes to afford the expected products in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982530

LETTER
1529
Thia-Michael Addition Using Cheap and Odorless S-Alkylisothiouronium
Salts as Thiol Equivalents in Water
T
hia-Michael Add
a
ition Using
n
S
-Alkylisothiouron
Z
ium Salts hao,a Ze-Mei Ge,*a Tie-Ming Cheng,a Run-Tao Li*a,b
a
School of Pharmaceutical Sciences, Peking University, Beijing 100083, P. R. of China
b
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University,
Beijing 100083, P. R. of China
Fax +86(10)82716956; E-mail: zmge@bjmu.edu.cn
Received 2 February 2007
thia-Michael addition.11 However, most of these odorless
thiol reagents have some disadvantages, such as multi-
step process of preparation, high cost of catalysts, toxicity
of some precursors and solvents, and long reaction time,
Abstract: S-Alkylisothiouronium salt has been found to be a non-
toxic, odorless and simply operational alternative of thiol for the
thia-Michael addition with electron-deficient olefins. The reactions
were carried out under alkaline conditions in water at room temper-
ature within 5–20 minutes to afford the expected products in good which limit the practical application of those thiol equiv-
to excellent yields.
alents. Herein, we wish to report a kind of cheap, easily
available and odorless equivalent of thiols, S-alkylisothio-
uronium salts, which could react with various electron-de-
ficient olefins in water at room temperature to afford the
corresponding products in good to excellent yields.
Key words: thia-Michael addition, thiol equivalent, S-alkylisothio-
uronium salts, electron-deficient olefins, green chemistry
Sulfur-containing compounds are found in quite a number
of natural products and are also of particular importance
as pharmaceutically active substances.1 Thia-Michael
addition of thiols to various Michael acceptors is a very
important process in carbon–sulfur bond formation and is
widely applied in organic synthesis.2–7 Thus, a number of
methods have been developed for this reaction. Among
them, most efforts were focused on the discovery of new
catalysts.2–5
In our early research, we successfully prepared the
methylthioethers by using S-methylisothiouronium sul-
fate instead of methanethiol to react with different alkyl
reagents. Encouraged by this work, we attempted to
extend our work to the thia-Michael addition of S-alkyl-
isothiouronium salts to electron-deficient olefins.
According to the procedure described in literature,12
different S-alkylisothiouronium salts, including methyl-,
ethyl-, n-butyl-, cyclopentyl-, allyl- and benzylisothiouro-
nium salts, were prepared from the reaction of corre-
sponding alkylating reagents with thiourea in excellent
yields. The procedure is simple with all of the S-alkyl-
isothiouronium salts, which are odorless solids and per-
fectly stable in open air.
However, with the increase of environmental conscious-
ness in chemical research and industry, efficient, econom-
ic and clean procedure has received increased attention in
recent years. It has been reported that this type of reaction
could be carried out in solvent-free conditions,3 ionic
liquids4,6 or water.5,7 More recently, Chakraborti et al. de-
scribed the conjugate addition of thiols to a,b-unsaturated
carbonyl compounds in water at room temperature with-
out the use of any catalyst.7 Although these methods are
very effective, the use of the highly volatile and foul-
smelling thiols could lead to serious environmental and
safety problems. Therefore, some attempts have been
made to develop practically odorless and less volatile sub-
stitutes for thiols. Node and co-workers prepared a range
of odorless or faint-smelling thiols by increasing the alkyl
chain length or introducing a trimethylsiyl group onto a
benzene ring.8 Singh et al. employed the thioiminium salts
of the corresponding thiols to react with Michael accep-
tors giving the functionalized organic sulfides.9 Ranu and
co-workers reported thia-Michael addition of dialkyl dis-
ulfides to conjugated carbonyl compounds catalyzed by
indium iodide.10 Dong et al. used 4,4-bis(alkylthio)but-3-
en-2-ones as nonthiolic and odorless thiol equivalents in
O
NH2
NH
+
· HBr
S
S
H2O, r.t.
O
1a
2a
3a
Scheme 1 Thia-Michael addition of S-ethylisothiouronium hydro-
bromate with methyl vinyl ketone
Initially, the reaction of S-ethylisothiouronium hydrobro-
mate (1a, 1 mmol) with methyl vinyl ketone (2a, 1 mmol)
was carried out in aqueous sodium hydroxide (4 mmol
NaOH in 5 mL H2O) at room temperature (Scheme 1).
The reaction was performed within 10 minutes to give the
expected compound, 4-ethylthio-2-butanone (3a), in 80%
yield. It is worth mentioning that only a very faint odor of
ethanethiol was felt during both reaction and work-up pro-
cesses. Therefore, the S-alkylisothiouronium salts should
be developed into ideal thiol equivalents.
With this result in hand, we used the above reaction
shown in Scheme 1 as a model reaction to optimize the
reaction conditions in water at room temperature by TLC.
After examining the different bases, we found that weak
SYNLETT 2007, No. 10, pp 1529–1532
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982530; Art ID: W03507ST
© Georg Thieme Verlag Stuttgart · New York
1
8
.0
6
.2
0
0
7

1530
Y. Zhao et al.
LETTER
bases, such as Na2CO3, NaHCO3, K3PO4, were unfavor- plored in a range of 1–4 equivalents and the best result
able for the reaction and NaOH was the most suitable was obtained in the presence of 2.5 equivalents of NaOH.
base. Furthermore, the amount of NaOH was also ex-
Table 1 Thia-Michael Addition of S-Alkylisothiouronium Salts to Electron-Deficient Olefins under Alkaline Conditions in Water
R1
S
NH
NaOH (2.5 equiv)
H2O, r.t.
EWG
R1
S
· HX
+
R2
EWG
R2
NH2
1
2
3
71–93%
Entry
1
S-Alkylisothiouronium salts
Electron-deficient olefins Products
Time (min)
10
Yield (%)a
73
O
S
NH
C
· HBr
S
NH2
O
3a7
1a
2a
S
O
O
2
10
81
3b7
3c7
2b
2c
S
CO2Me
CN
3
4
10
5
81
80
CO2Me
CN
S
3d13a
2d
2b
O
NH2
S
S
· HBr
n-Bu
n-Bu
5
10
90
NH
3e13b
1b
S
6
7
2c
10
5
90
93
CO2Me
CN
n-Bu
3f6b
n-Bu
2d
S
3g6b
NH
S
S
· 0.5 H2SO4
C
8
2a
15
74
NH2
O
3h13c
1c
O
S
9
2b
2d
10
5
74 (87,b 96c)
89
3i13d
CN
10
S
3j14
Ph
S
NH2
NH
C
11
12
2a
2b
20
15
83
84
· HCl
Ph
S
O
3k7
Ph
1d
S
O
3l7
S
Ph
13
14
2c
15
15
73 (84,b 93c)
87
CO2Me
CN
3m7
2d
Ph
S
3n13e
S
NH2
NH
C
15
2a
15
79
· HCl
S
O
3o13f
1e
Synlett 2007, No. 10, 1529–1532 © Thieme Stuttgart · New York

LETTER
Thia-Michael Addition Using S-Alkylisothiouronium Salts
1531
Table 1 Thia-Michael Addition of S-Alkylisothiouronium Salts to Electron-Deficient Olefins under Alkaline Conditions in Water (continued)
R1
S
NH
NaOH (2.5 equiv)
H2O, r.t.
EWG
R1
S
· HX
+
R2
EWG
R2
NH2
1
2
3
71–93%
Entry
16
S-Alkylisothiouronium salts
Electron-deficient olefins Products
Time (min)
15
Yield (%)a
80
S
O
2b
2d
3p3f
CN
17
18
10
15
85
80
S
3q13g
O
NH2
S
C
2a
2c
2b
2d
· HBr
NH
S
S
1f
3r
3s
3t
19
20
21
22d
15
15
71 (81,b 90c)
CO2Me
O
S
81
88
73
10
CN
S
3u
Ph
3v
SCH2Ph
CN
NH2
NH
CN
C
180
· HCl
Ph
Ph
S
2e
1d
a Isolated yields of pure product after silica gel column chromatography.
b The molar ratio of S-alkylisothiouronium salt and electron-deficient olefin was 2:1.
c The molar ratio of S-alkylisothiouronium salt and electron-deficient olefin was 4:1.
d The reaction was performed under reflux condition.
Under the optimized reaction conditions, the thia-Michael panenitrile (3v)16 in 73% yield (entry 22). Finally, it is
additions of various S-alkylisothiouronium salts to differ- noteworthy that the ester group, nitrile group, carbonyl
ent electron-deficient olefins were performed and the re- group and C=C double bond in electron-deficient olefins
sults are summarized in Table 1.15,16 Except for entry 22, or S-alkylisothiouronium salts were stable in all cases ow-
all the reactions were completed within 20 minutes in ing to the short reaction time and mild reaction conditions.
good to excellent yields (71–93%). Much to our delight,
the S-methylisothiouronium sulfate (1c), as the equivalent
of methanethiol with a very strong foul smell, gave satis-
In summary, we have demonstrated that S-alkylisothiou-
ronium salts are the efficient equivalents of alkylthiols for
the thia-Michael additions with various electron-deficient
fying results (entries 8–10, 74–89%). To the best of our
olefins in water at room temperature. The advantages of
knowledge, there are only a few reports on the thia-
this procedure include: 1) avoiding the foul smell and tox-
Michael addition of methanethiol or its equivalent to elec-
icity of thiols, especially methanethiol; 2) the use of water
tron-deficient olefins and the results were not satisfacto-
as solvent; 3) inexpensive and simple process for prepara-
ry.11a,13 Meanwhile, the S-cyclopentylisothiouronium
tion of the S-alkylisothiouronium salts; 4) a broad range of
reaction substrates and, 5) short reaction time and high
yields.
hydrobromate (1f) with high steric hindrance also reacted
smoothly with various electron-deficient olefins affording
the corresponding addition products in 71–88% yields.
However, when the S-benzylisothiouronium hydro-
Acknowledgment
chloride (1d) reacted with 3-phenylacrylonitrile (2e), only
a small amount of the product was observed. Fortunately,
this reaction could be carried out at refluxing temperature
within three hours to give 3-phenyl-3-benzylthiopro-
This work is supported by the Natural Science Foundation of China
(NSFC 20672009).
Synlett 2007, No. 10, 1529–1532 © Thieme Stuttgart · New York

1532
Y. Zhao et al.
LETTER
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(15) Typical Procedure for the Thia-Michael Addition of S-
Alkylisothiouronium Salts to Electron-Deficient Olefins:
To a magnetically stirred solution of an S-alkylisothio-
uronium salt (3 mmol) and an electron-deficient olefin (3
mmol) in H2O (5 mL) was slowly added an aq NaOH
solution (7.5 mmol NaOH in 2 mL H2O), and then the
mixture was stirred at r.t. for the indicated time in Table 1.
Then, the reaction mixture was extracted with EtOAc (3 × 10
mL). The combined organic extracts were dried over Na2SO4
and concentrated under reduced pressure. The residue was
purified by column chromatography over silica gel using
EtOAc–PE as eluent to afford the corresponding product. All
the new compounds were characterized on the basis of 1H
NMR and elemental analysis and the structures of the known
compounds were confirmed by 1H NMR spectra, which were
consistent with literature data.
(16) Spectroscopic data of the selected compound:
3-Methylthiopropanenitrile14 (3j; Table 1, entry 10):
colorless liquid. 1H NMR (300 MHz, CDCl3): d = 2.20 (s, 3
H), 2.67 (t, J = 6.9 Hz, 2 H), 2.78 (t, J = 6.9 Hz, 2 H).
3-Cyclopentylthiopropanenitrile (3u; Table 1, entry 21):
colorless liquid. 1H NMR (300 MHz, CDCl3): d = 1.48–1.62
(m, 4 H), 1.73–1.77 (m, 2 H), 1.97–2.05 (m, 2 H), 2.64 (t,
J = 7.2 Hz, 2 H), 2.81 (t, J = 7.2 Hz, 2 H), 3.13–3.23 (m,
1 H). Anal. Calcd for C8H13NS: C, 61.89; H, 8.44; N, 9.02.
Found: C, 61.92; H, 8.274; N, 8.902.
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3-Phenyl-3-benzylthiopropanenitrile (3v; Table 1; entry
22): colorless oil. 1H NMR (300 MHz, CDCl3): d = 2.80 (dd,
J = 2.5, 7.5 Hz, 2 H), 3.52 (d, J = 13.8 Hz), 3.66 (d, J = 13.8
Hz, 1 H), 3.90 (t, J = 7.2 Hz, 1 H), 7.21–7.41 (m, 10 H).
Anal. Calcd for C16H15NS: C, 75.8; H, 5.91; N, 5.53. Found:
C, 75.70; H, 6.04; N, 5.41.
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