Odourless strategy for deep eutectic solvent-mediated ring opening of epoxides with in situ generated S -alkylisothiouronium salts

Article abstract of DOI:10.1055/s-0033-1341050

A general, straightforward and odourless ring-opening reaction allows the preparation of β-hydroxy sulfides from in situ generated S-alkylisothiouronium salts in urea-choline chloride-based deep eutectic solvent (DES). In addition, reaction of epoxides with thiourea in DES yields the corresponding thiiranes. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341050

LETTER
▌1085
letter
Odourless Strategy for Deep Eutectic Solvent-Mediated Ring Opening of
Epoxides with In Situ Generated S-Alkylisothiouronium Salts
Odourless Strategy for Ring Opening of Epoxides in Deep Eutectic Solvent
Najmedin Azizi,* Zahra Yadollahy, Amin Rahimzadeh-oskooee
Chemistry & Chemical Engineering Research Center of Iran, P.O. Box 14335-186, Tehran, Iran
Fax +98(21)44580762; E-mail: azizi@ccerci.ac.ir
Received: 06.01.2014; Accepted after revision: 02.03.2014
thiol equivalents such as S-alkylisothiouronium salts.
However, this reaction necessarily produces equivalent
amounts of urea, which needs to be separated from the
product.6 To the best of our knowledge, there is no report
of the thiolysis of epoxides using S-alkylisothiouronium
salts in DES.
Abstract: A general, straightforward and odourless ring-opening
reaction allows the preparation of β-hydroxy sulfides from in situ
generated S-alkylisothiouronium salts in urea–choline chloride-
based deep eutectic solvent (DES). In addition, reaction of epoxides
with thiourea in DES yields the corresponding thiiranes.
Key words: deep eutectic solvent, epoxide, odourless thiol chemis-
try
In the model reaction, it was found that, upon simple mix-
ing of benzyl chloride (1 mmol), thiourea (1 mmol),
NaOH (1.5 mmol) and phenyl 2,3-epoxypropyl ether (1
mmol), in choline chloride (ChCl)–urea-based DES (0.5
mL), the corresponding product was isolated in 75% yield
after simple workup (Scheme 1). In further optimisation
studies, we focused on varying the temperature, additives,
solvent and the order of addition of the reactants. Screen-
ing of different additives in DES revealed that 0.4 mL of
8 M aqueous sodium hydroxide solution was the most ef-
fective in terms of yield and time. In addition, it was found
that the order of the addition of reagents had a consider-
able effect on the yield. When the reaction was performed
with benzyl chloride (1.0 mmol) and thiourea (1.0 mmol)
in DES (0.5 mL) at 60 °C for 20 minutes, followed by co-
addition of 0.4 mL of a 8 M aqueous sodium hydroxide
and epoxide (in one portion with stirring for 40 minutes at
room temperature), product 4a was isolated in 95% isolat-
ed yield. With these optimised reaction conditions, we
further explored the scope and limitation of this protocol
by reaction of sterically, electronically and functionally
diverse epoxides and alkyl halides and the results are sum-
marised in Table 1.
Deep eutectic solvents (DES) have physiochemical prop-
erties similar to ionic liquids, such as negligible vapour
pressure, nonflammability, and high solvation capacity.
However, DES have many advantages over ionic liquids
such as ease of preparation, and disposal.1
Efficient ring opening of epoxides under the mild condi-
tions provides access to versatile intermediates for further
organic synthesis.2 Thiol-containing organic compounds
have found various applications as enzyme inhibitors, bi-
ologically active calcium antagonist, and antimicrobial
and cytotoxic activities.3 Therefore, there is a demand to
find efficient conditions for ring-opening reactions of ep-
oxides using thiol-based nucleophiles.4
Our interest in the development of new methodologies us-
ing green solvents5 prompted us to attempt an odourless
ring opening of epoxides with in situ generation of
S-alkylisothiouronium salts with the urea acting as one
component of the deep eutectic solvent.
S
The reaction was readily applicable to a range of epoxides
and alkyl halides. Primary, allylic and benzylic halides re-
acted with epoxides such as phenyl 2,3-epoxypropyl
ether, isopropyl 2,3-epoxypropyl ether, styrene oxide,
1,2-epoxybutane, cyclohexene oxide and allyl 2,3-epoxy-
propyl ether to give the corresponding β-hydroxy sulfides
in good to excellent yields. In general, complete and clean
reaction conversions were observed within two hours,
typically affording only one single product in high yield.
Furthermore, the reaction with unsymmetrical epoxides in
most cases was completely regioselective, with the only
products isolated being those resulting from the attack of
the nucleophile to the less hindered position of the epox-
ide, with the exception of styrene oxide. This may be at-
tributed to the large size of the thiolate nucleophile, such
that steric factors dominate electronic factors as common-
ly observed in epoxide ring opening in basic media.
Ph
Cl
+
PhO
+
H2N
NH2
O
2
1
3
urea–ChCl (0.5 mL)
NaOH, 60 °C to r.t.
OH
S
OPh
Ph
4
Scheme 1 The model reaction in DES
Odourless methodologies for ring opening of epoxides re-
mains scarce, with the only examples reported involving
SYNLETT 2014, 25, 1085–1088
Advanced online publication: 07.04.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1341050; Art ID: ST-2014-D0014-L
© Georg Thieme Verlag Stuttgart · New York

1086
N. Azizi et al.
LETTER
Styrene oxide reacted under these conditions with short
reaction times and excellent yields, in comparison with
other epoxides. However, lower regioselectivity was ob-
served for this substrate, and both regioisomers were
formed, although preferential attack at the less hindered
carbon atom of the epoxide was still consistent with an
SN2 mechanism (Table 1, entries 17 and 18).
Table 1 Ring Opening of Epoxides with In Situ Generated S-Alkyl-
isothiouronium Salts
R1X
+
1
OH
R2
4a–o
70–95%
urea–ChCl (0.5 mL)
R1S
NaOH, 60 °C to r.t.
60–120 min
S
H2N
R2
NH2
2
+
Thiiranes, the sulfur analogues of oxiranes, are important
and useful building blocks in organic synthesis.7 Several
methods have been developed for their synthesis with the
most general being the conversion of oxiranes into thi-
iranes.8 Having demonstrated the remarkable efficiency
of DES for selective ring opening of epoxides with in situ
generated thiols, we further examined the synthesis of thi-
iranes in DES. When a range of epoxides (1 mmol) was
mixed with thiourea (1.2 mmol) and 0.4 mL of 8 M aque-
ous sodium hydroxide in urea–choline chloride based
DES (0.5 mL) at 60 °C, the reaction was complete within
60 minutes and thiiranes 5 were obtained as the sole prod-
ucts (Table 2).
O
3
Entry Epoxide
Alkyl halide
Product Yield (%)a
1
2
4a
4a
95
92
Ph
Ph
Cl
Br
O
PhO
3
MeI
4b
80
Cl
Br
4
4c
78
Cl
Table 2 Reaction of Epoxides and Thiourea in DES
5
6
7
4d
4e
4f
78
76
84
S
S
O
urea–ChCl (0.5 mL)
60 °C, 80–120 min
Br
+
R
R
H2N
NH2
2
3
5
Ph
Ph
Cl
70–95%
O
Yield (%)a
O
Entry Epoxide 3
Thiirane 5
8
Br
4f
82
O
S
9
4g
4h
72
70
Br
1
95
Br
10
O
O
S
S
O
2
3
4
78
82
74
O
O
O
O
11
12
Ph
MeI
Ph
Cl
4i
88
82
85
78
4j
4k
4l
O
O
O
O
13
14
Cl
O
S
O
Br
O
S
O
O
O
15
16
Ph
Cl
4m
4n
86
80
5
95
Cl
S
6
7
88
70
Cl
O
O
S
90b
85:15
17
Ph
Ph
Cl
Br
4o
4o
O
S
8
76
88b
82:18
18
a GC yields.
a GC yields.
b A mixture of two isomers was obtained.
Based on these results, we postulate a mechanism which
probably begins with the electrophilic attack of benzyl
chloride 1 on thiourea to generate S-alkylisothiouronium
Synlett 2014, 25, 1085–1088
© Georg Thieme Verlag Stuttgart · New York

LETTER
Odourless Strategy for Ring Opening of Epoxides in Deep Eutectic Solvent
1087
2740. (c) Schneider, C. Synthesis 2006, 3919.
(d) Nandakumar, M. V.; Tschöp, A.; Krautscheid, H.;
salts 2 in DES (Scheme 2). DES plays a triple role, as an
ionic reaction medium for the fast generation of salts 2,
activating the epoxide by hydrogen bonding and capture
of the in situ generated urea. Hydrolysis of 2 with NaOH
generates the thiolate that subsequently adds to the acti-
vated epoxide 4 to yield β-hydroxy sulfide product.
Schneider, C. Chem. Commun. 2007, 2756. (e) Mai, E.;
Schneider, C. Synlett 2007, 2136. (f) Fringuelli, F.; Pizzo,
F.; Tortoioli, S.; Vaccaro, L. Adv. Synth. Catal. 2002, 344,
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S
NH2
R
X
NH2X–
H2N
NH2
+
R
S
2
1
–OH
R
S
OH
O
Cl–
H
N
N
H
H2N
H2N
N
H
O
HO
H
R
(5) (a) Azizi, N.; Batebi, E. Catal. Sci. Technol. 2012, 2, 2445.
(b) Azizi, N.; Gholibeglo, E. RSC Adv. 2012, 2, 7413.
(c) Azizi, N.; Batebi, E.; Bagherpour, S.; Ghafuri, H. RSC
Adv. 2012, 2, 2289.
O
R
S–
3
R
4
(6) Zhu, J.; Li, R.; Ge, Z.; Cheng, T.; Li, R. Chin. J. Chem. 2009,
27, 791.
Scheme 2 Postulated mechanism
(7) Thiiranes and Thiirenes, In Comprehensive Heterocyclic
Chemistry; Vol. 7; Ditter, D. C.; Katritzky, A. R.; Rees, C.
W., Eds.; Pergamon: Elmsford NY, 1984, 132–182.
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In conclusion, we have devised a convenient, quick and
odourless protocol for thiolysis of 1,2-epoxides with in
situ generated S-alkylisothiouronium salts, efficient
equivalents of alkylthiols in urea–choline chloride-based
deep eutectic solvent.9 This provides an efficient and con-
venient one-pot synthesis of β-hydroxy sulfides by a sim-
ple reaction of alkyl halides, epoxides and thiourea in
good to excellent yields. Additionally, a simple and effi-
cient procedure for the synthesis of thiiranes from oxi-
ranes by treatment with thiourea in DES has been
developed.10,11
Acknowledgment
Financial support for this work by the Chemistry and Chemical
Engineering Research Center of Iran is gratefully appreciated.
(9) Deep Eutectic Solvent Preparation: The choline chloride–
urea-based deep eutectic solvent was prepared according to
the literature (see ref. 1). Urea (200 mmol) and choline
chloride (100 mmol) were mixed, stirred and heated until a
clear liquid was formed. This was used without any further
purification.
References and Notes
(1) (a) Abbott, A. P.; Capper, G.; Davies, D. L.; Rasheedand, R.
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Jarag, K. J.; Pandit, A. B.; Shankarling, G. S. Ultra
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Gutiérrez, M. C.; Ferrer, M. L.; del Monte, F. Chem. Soc.
Rev. 2012, 41, 4996.
(2) (a) Corey, E. J.; Clark, D. A.; Goto, G.; Marfat, A.;
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Renaud, P. Chem. Soc. Rev. 2013, 7, 7900. (c) Yin, C.; Huo,
F.; Zhang, J.; Martínez-Máñez, R.; Yang, Y. L. H.; Li, S.
Chem. Soc. Rev. 2013, 42, 6032.
(3) (a) Luly, J. R.; Yi, N.; Soderquist, J.; Stein, H.; Cohen, J.;
Perun, T. J.; Plattner, J. J. J. Med. Chem. 1987, 30, 1609.
(b) Kesavan, V.; Bonnet-Delpon, D.; Bégué, J. P.
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(10) General Procedure for Ring Opening of Epoxides with In
Situ Generated Thiol in DES: A test tube, equipped with a
magnetic stir bar, was charged with alkyl halide (1.0 mmol),
thiourea (1.0 mmol), and the DES (0.5 mL), and the mixture
was heated at 60 °C until the reaction was complete
(monitored by TLC, or GC; usually 20 min). Next, epoxide
(1.0 mmol), and aq NaOH (8 M, 0.4 mL) were added and the
reaction was stirred at r.t. for 60–120 min. The crude
reaction mixture was then diluted with EtOAc (10 mL),
washed with aq NH4Cl and H2O to remove DES. The
organic layer was dried over Na2SO4, filtered and evaporated
under reduced pressure. The crude reaction products were
purified by flash chromatography on silica gel column to
afford the corresponding pure materials. All the products
gave analytical data identical with those in the literature
reports.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1085–1088

1088
N. Azizi et al.
LETTER
extracted with Et2O (10 mL). After drying over Na2SO4,
filtering and evaporation of the solvent, the crude product
was purified by silica gel column chromatography, eluting
with EtOAc–n-hexane (1:10) to give the pure product.
(11) General Procedure for Conversion of Epoxides to
Thiiranes: A mixture of epoxide (1.0 mmol) and thiourea
(1.2 mmol), in DES (0.5 mL), was stirred at 60 °C for 80–
120 min and, after completion of the reaction as indicated by
GC, the reaction mixture was diluted with H2O (5 mL) and
Synlett 2014, 25, 1085–1088
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