Novel atom-economic reaction: Comprehensive utilization of S-alkylisothiouronium salt in the synthesis of thioethers and guanidinium salts

Article abstract of DOI:10.1039/c3ra42503g

A novel atom-economic three-component one-pot reaction of a primary amine, an S-alkylisothiouronium salt and a Michael receptor is reported, which affords a guanidinium salt and thioether simultaneously. The guanidine moiety is involved in catalyzing the conjugated Michael addition of the mercaptan. The reaction proceeds under ambient conditions using a non-toxic EtOH-H₂O mixture as the solvent, and the two products can be very easily purified. Complete atom economy is achieved by fully utilizing the S-alkylisothiouronium salt and converting the previously wasted mercaptan by-product into the valuable thioether.

Full text of DOI:10.1039/c3ra42503g

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DOI: 10.1039/C3RA42503G
A novel atom economic three-component one-pot reaction of primary amine, S-alkylisothiouronium salt and
Michael receptor is reported, which affords guanidinium salt and thioether simultaneously. The guanidine moiety
is also involved in catalyzing the conjugated Michael addition of the mercaptan. The reaction proceeds under
ambient condition using the non-toxic EtOH/H2O mixture as the solvent, and the two products can be very easily
purified. Complete atom economy is achieved by fully utilizing S-alkylisothiouronium salt and converting the
previously wasted mercaptan by-product into the valuable thioether.

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Novel Atom Economic Reaction: Comprehensive Utilization of S-
Alkylisothiouronium Salt in the Synthesis of Thioether and Guanidini-
um Salt
Pengchao Gao, Penglin Leng, Qi Sun, Xin Wang, Zemei Ge* and Runtao Li*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A novel atom economic three-component one-pot reaction of primary amine, S-alkylisothiouronium salt and Michael receptor is reported,
which affords guanidinium salt and thioether simultaneously. The guanidine moiety is also involved in catalyzing the conjugated Michael
addition of the mercaptan. The reaction proceeds under ambient condition using the non-toxic EtOH/H2O mixture as the solvent, and the
10 two products can be very easily purified. Complete atom economy is achieved by fully utilizing S-alkylisothiouronium salt and convert-
ing the previously wasted mercaptan by-product into the valuable thioether.
Interestingly, guanidinum salts are most often prepared through
Introduction
the reaction of S-alkylisothiouronium salt with primary amine
45 (Scheme 1, eq 2)6,7. In this reaction, only the amidine segment of
S-alkylisothiouronium salt is used, and the malodorous mercaptan
is released as waste, which can seriously contaminate the envi-
ronment.
The technology in organic synthesis has become so sophisticated
15 that, given enough intellectual and economic input, almost all
molecules can sooner or later be accessible in some way. Howev-
er, such finesse often comes at a price that sacrifices the efficien-
cy in material use. Although in “The Twelve Principles of Green
Chemistry”, "atom economy" has been advocated to maximize
20 the utilization of materials, to date there are still limited organic
reactions that can live up to such standard1 and most reactions
always involve the formation of by-products or waste. The chem-
ical industry produces considerable amount of waste every year2,
and for chemists in the 21st century, the problem of waste reduc-
25 tion or even utilization is now of paramount importance.
Both thioethers8 and guanidines9,10 have interesting potentials in
50 medicinal applications. Thioethers are known to have anti-fungal9
and anti-hepatitis activities, whereas guanidines are known to
have antifibrinolytic11, anti-cancer12, anti-HIV13, anti-viral14, anti-
adipogenic15 activities, etc. Inspired by Tian’s concept of atom-
economic reaction in green chemistry, we envisioned that the S-
55 alkylisothiouronium salts can be used efficiently if the above two
reactions can be combined into one reaction (Scheme 1, eq 3). In
this way, two valuable products, thioether and guanidine, are
obtained in one pot in a way that much better meets the require-
ment of green chemistry.
In order to solve this problem, many efforts have been focused on
the reutilization of by-products3. Tian4 has created the concept of
"atom-economic reaction", which not only efficiently uses the
reactants but also converts the by-products into useful products in
30 situ. However, due to practical difficulties, this attractive idea is
seldom practised. Here we report a novel three-component one-
pot reaction of primary amine, S-alkylisothiouronium salt and
Michael receptor to simultaneously afford two valuable products,
thioether and guanidinum salt, with complete atom economy.
35 In our previous work, S-alkylisothiouronium salt has been suc-
cessfully used to replace thiol in the thia-Michael addition to
afford various thioethers (Scheme 1, eq 1).5 The foul smell and
toxicity of thiols are thus effectively avoided. However, this
method is not atom economic because the amidine segment of the
40 S-alkylisothiouronium salt is abandoned as by-product.
60 Thus, we initially examined the reaction of S-benzylisothiourea
with benzylamine and methyl acrylate as the model to explore
this possible consecutive reaction under a variety of conditions.
a State Key Laboratory of Natural and Biomimetic Drugs, School of
Pharmeceutical Sciences, Peking University, Beijing 100191, P. R. of
China
E-mail: zmge@bjmu.edu.cn; lirt@bjmu.edu.cn
Fax: 86 10 82716956; Tel: 86 82801504
†Electronic Supplementary Information (ESI) available: see
Scheme 1. The design of the atom-economic reaction.
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Table 1. Exploration of the atom-economic reaction.
Entrya
Solvent
Base
Temp/°C
Time/h
Yield of
4a (%)b
Trace
58
35
65
Trace
Trace
Trace
Trace
Trace
17
39
31
48
53
63
68
63
36
57
65
61
0
66
68
57
35
68
62
73
73
Yield of
5a (%)b
0
38
31
43
0
Trace
<10
0
0
21
17
40
34
41
53
53
47
21
50
48
48
0
46
42
50
33
51
45
54
51
1
2
3
4
5
6
7
8
DMSO
H2O
EtOH
EtOH/H2O(1:1)
Acetone
i-PrOH
DMF
Ethyl Acetate
CH2Cl2
CH3OH
CH3OH/H2O(1:1)
EtOH/H2O(1:2)
EtOH/H2O(2:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
EtOH/H2O(1:1)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1 equiv)
TEA(0.1equiv)
NaOAc(0.1 equiv)
DIEA(0.1 equiv)
DBU(0.1 equiv)
NaOH(0.1 equiv)
No base
TEA(0.5 equiv)
TEA(1.0 equiv)
TEA(2.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
TEA(1.0 equiv)
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
0
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
1
6
12
6
6
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29c
30d
50
70
90
30
30
30
30
30
a
b
c
d
The molar ratio 1a/2a/3a = 1:1:1 and without illustration. Isolated yield. The mol ratio 1a/2a/3a = 1.1:1:1 The mol ratio
1a/2a/3a = 1.5:1:1
The reaction was first carried out at 30 °C using triethyl amine
(TEA) as the catalyst to screen a variety of solvents, including
polar solvents, apolar solvents, polar aprotic solvents and mixture
tion. Firstly, various S-alkylisothiouronium salts were reacted
with benzyl amine and three kinds of Michael receptors. As
shown in Table 2, all reactions proceeded smoothly to afford the
5
solvents. It can be seen that polar solvents are more favorable for 30 corresponding thia-Michael addition products (4) and benzyl-
the reaction than apolar solvents, and the mixture solvent 1:1
EtOH/H2O is the best, which provides the desired products ben-
guanidinium salts (5) in 59%–83% yield and 44%–75% yield,
respectively.
10 zylthioether (4a) and benzylguanidine (5a) in 65% and 43% yield
(calculated based on the amine), respectively (Table 1, entries 1–
13). The use of different bases was then examined by carrying out
the reaction in 1:1 EtOH/H2O at 30 °C (Table 1, entries 14–18).
The inorganic bases and the organic bases give similar results.
15 Since the use of organic base is more convenient for the separa-
tion of products (see Experimental), we selected TEA as the base
because it is cheap and easy to handle, although using DBU as
the base gives slightly higher yield than using TEA. Using 1.0
equiv TEA gives more satisfying yield than using other stoichi-
20 ometries (Table 1, entries 19–21). Afterwards, the reaction tem-
perature and the reaction time were examined (Table 1, entries
23–25). The reaction is best carried out at 30 °C for 6 h. Finally,
we found that the best result could be obtained when the molar
ratio of the reactants is 1a/2a/3a = 1.1:1:1.
Subsequently, we treated glycin and 2-(azepan-1-yl)ethanamine
respectively with different S-alkylisothiouronium salts and Mi-
35 chael receptors to examine whether our method could simultane-
ously deliver the thia-Michael addition products and other kinds
of valuable guanidines, such as glucocyamine16, a new food addi-
tive for animals and an anti-myasthenia agent, and guanethidine17
(also known as Ismelin), a potent anti-hypertension drug. As
40 expected, glucocyamine and Ismelin can be obtained in moderate
yield along with the formation of the thia-Michael addition prod-
ucts in good yield (Table 3).
Encouraged by the above results, we further explored the possi-
bility of carrying out this atom-economic reaction to afford a
45 single functionalized molecule. Thus, we designed and synthe-
sized the substrate 1118 (Scheme 2), which contains not only the
Michael receptor but also a primary amine moiety. The reaction
of equi-molar 11 and S-benzylisothiourea hydrochloride
25 With the optimized reaction conditions (Table 1, entry 29) in
hand, we then investigated the scope of this atom-economic reac
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Table 2. Atom-economic reactions of substituted S-alkylisothiouronium salts (1) and Michael receptors (2).
Entry
1
2
4 (yield, %)
5 (yield, %)
1
4a
5a
(73)
(54)
2a
2
4b
5a
(82)
(64)
2b
1a
3
4
4c
(80)
5a
(68)
2c
2a
4d
(62)
5b(65)
5
2b
4e
5b
(73)
(62)
1b
2c
2a
4f
(59)
5b
(57)
6
7
4g
5c
(68a)
(58)
4h
5c
8
2b
(81)
(63)
1c
4i
5c
9
2c
2a
(77)
(67)
10
4j
5c
(68)
(54)
11
2b
4k
5c
(76)
(61)
1d
4l
5c
12
13
2c
2a
(65)
(56)
O
O
4m
5c
(51)
S
(71a)
14
2b
4n
5c
(83)
(57)
1e
4o
5c
15
16
2c
2a
(66)
(44)
4p
5c
(78)
(75)
17
18
2b
2c
4q
(72)
5c
(68)
1f
4r
(63)
5c
(70)
a
Performed without TEA
5
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Table 3. Utilization of the atom-economic reaction to synthesize glucocyamine and Ismelin.
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Entry
S-Alkylisothiouronium salt
Michael receptor
Amine (3)
Product 4 (yield%)
Product 5 (yield%)
4a
(74)
5d
(57)
1
2a
3b
4c
5d
2c
(83)
(59)
2
3
1a
4d
(69)
5e
Ismelin
(66)
2a
2b
4e
(75)
Ismelin
(54)
4
5
1b
3c
4f
(73)
Ismelin
(53)
2c
2b
4h
(75)
3b
5d
(64)
6
7
1c
O
4j
(64)
5d
(55)
2a
2b
3b
S
O
1d
4l
(55)
5d
(60)
8
5
proceeded well under the optimized reaction conditions to afford
the desired product 12 in 42.1% yield. This result excellently
demonstrates the atom economy of the developed truly atom-
economic reaction (Scheme 3).
Based on the experimental observations, the possible mechanistic
10 pathway for this atom-economic reaction is proposed in Scheme
4. S-Alkylisothiouronium (1’) is firstly released from its salt (1)
in the presence of TEA. Then, the reaction of 1’ with the primary
amine (3) simultaneously affords the guanidine (5’) and the thio-
late anion, which attacks the Michael receptor (2) to form the
15 thioether (4). The strongly basic guanidine (5’) captures the HX
from the TEA salt to form the stable guanidinium salt (5), which
releases TEA to participate again in the next catalytic cycle.
Scheme 3. Single molecule atom-economic reaction of 11 with S-
benzylisothiourea hydrochloride.
30
20
35 Scheme 4. Possible pathway of the atom-economic reaction
Scheme 2. Synthesis of ethyl 3-(4-aminomethylphenyl) acrylate
(11)
25
4
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Conclusions
DOI: 10.1039/C3RA42503G
In conclusion, we have developed a novel atom economic three-
component one-pot reaction of primary amine, S-alkyliso-
thiouronium salt and Michael receptor to obtain both thioether
and guanidinium salt in one-pot. And the two products can be
easily separated by simply extraction of ethyl acetate and water.
Furthermore, we realized the utilization of S-alkyliso-
thiouronium salt with complete atom economy.
60
65
70
5
10 Experimental section
Compounds 1a-f5, 2a-c19, 3a-c10,17, 4a-r19-26, 5a-e15-18, 628, 729,
829, 930, 1031, 1132 are known. 12 is a new compound. Characteri-
zation data (1H NMR, 13C NMR, Mp, ESI-MS) are reported in
Electronic Supplementary Information (ESI).
15 Representative experimental procedure
To the mixed solvent (10 mL, H2O/EtOH = 1:1) was added the S-
Alkylisothiouronium salt (4.4 mmol), the amine (4.0 mmol) the
Michael receptor (4.0 mmol) and TEA (4.0 mmol). The mixture
was stirred at 30 °C for 6 h, then 5 mL H2O was added and the
20 mixture was extracted with EtOAc (15 mL × 3). The remaining
aqueous layer was concentrated under reduced pressure using a
rotary evaporator and the resulting solid was washed with a small
amount of ethanol, then recrystallized from hot water to give the
corresponding guanidinium salt (5). The combined organic layer
25 was dried over anhydrous Na2SO4 and concentrated under re-
duced pressure, and the residue was purified by column chroma-
tography (Petroleum ether/Ethyl acetate) to afford the corre-
sponding thia-Michael addition product (4).
27 A. Porcheddu, G. Giacomelli, A. Chighine, S. Masala, Org. Lett.,
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28 S. Chowdhury, Y. T. Chen, X. Fang, W. Grant, J. Pocas, M. D.
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