LiOH-catalyzed simple ring opening of epoxides under solvent-free conditions

Article abstract of DOI:10.1080/10426500903127573

LiOH has been found to be a very simple and selective catalyst for the rapid and mild synthesis of β-hydroxy sulfides and β-hydroxyl nitriles by ring opening of epoxides with aromatic, aliphatic, and heterocyclic thiols and trimethylsilyl cyanide at room temperature under solvent free conditions. All the reactions proceeded satisfactorily in short times and afforded the corresponding products in good to excellent yields with high regioselectivity and chemoselectivity under mild reaction conditions. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426500903127573

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Phosphorus, Sulfur, and Silicon and the
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LiOH-Catalyzed Simple Ring Opening of
Epoxides Under Solvent-Free Conditions
Najmedin Azizi a , Alireza Khajeh-Amiri a , Hossein Ghafuri a &
Mohammad Bolourtchian a
a Chemistry and Chemical Engineering Research Center of Iran,
Tehran, Iran
Published online: 02 Jul 2010.
To cite this article: Najmedin Azizi , Alireza Khajeh-Amiri , Hossein Ghafuri & Mohammad
Bolourtchian (2010): LiOH-Catalyzed Simple Ring Opening of Epoxides Under Solvent-Free Conditions,
Phosphorus, Sulfur, and Silicon and the Related Elements, 185:7, 1550-1557
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Phosphorus, Sulfur, and Silicon, 185:1550–1557, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500903127573
LiOH-CATALYZED SIMPLE RING OPENING OF EPOXIDES
UNDER SOLVENT-FREE CONDITIONS
Najmedin Azizi, Alireza Khajeh-Amiri, Hossein Ghafuri,
and Mohammad Bolourtchian
Chemistry and Chemical Engineering Research Center of Iran, Tehran, Iran
LiOH has been found to be a very simple and selective catalyst for the rapid and mild
synthesis of β-hydroxy sulfides and β-hydroxyl nitriles by ring opening of epoxides with
aromatic, aliphatic, and heterocyclic thiols and trimethylsilyl cyanide at room temperature
under solvent free conditions. All the reactions proceeded satisfactorily in short times and
afforded the corresponding products in good to excellent yields with high regioselectivity
and chemoselectivity under mild reaction conditions.
Keywords Epoxide; β-hydroxy nitriles; β-hydroxy sulfide; lithium hydroxide; solvent free
conditions; thiol
Epoxides have been recognized among the most versatile intermediates in organic
synthesis. They can be easily prepared and due to their ring strain, which enhances their
reactivity, and react with nucleophiles with high regioselectivity.1 In this context, reactions
with thionucleophiles play an important role, affording hydroxythio derivatives as useful
building blocks for the synthesis of cyclic sulfides,2,3 benzoxathiepines, benzothiazepines,
and thioketones,4 and as well as in organic chemistry, particularly in the pharmaceutical
and natural product fields.5
A direct and practical approach to β-hydroxy sulfides is the ring opening of 1,2-
disubstituted epoxides using thiols as the nucleophile.6 Thus, a variety of reagents and
catalysts have been developed to achieve this simple process, which is testimony to the
importance of this reaction,7 although these problems were overcome to some extent
by recently reported acid catalysts under solvent-free conditions.8 Unfortunately, these
processes turned out to involve stoichiometric or superstoichiometric amounts of toxic or
hazardous catalysts, long reaction times, low yields, the use of volatile organic solvents,
requirement of excess reagents or catalysts, and harsh reaction conditions. Furthermore,
almost all procedures for the preparation of β-hydroxy sulfides reported so far are restricted
to simple aromatic thiols.
Due to the growing concern for the influence of organic solvents on the environment
as well as on the human body, organic reactions without the use of conventional organic
solvents that employ a catalytic amount of an economic and readily available catalyst that
Received 7 April 2009; accepted 17 June 2009.
Financial support of this work by Chemistry and Chemical Research Center of Iran is gratefully appreciated.
Address correspondence to Najmedin Azizi, Chemistry and Chemical Engineering Research Center of Iran,
P.O. Box 14335-186, Tehran, Iran. E-mail: azizi@ccerci.ac.ir
1550

LiOH-CATALYZED RING OPENING OF EPOXIDES
1551
does not contain a metal would be of great interest. In this context, during our ongoing
studies of solvent-free conditions9 in the presence of lithium salts, in this article we report
a very mild, easy, and catalytic process for synthesizing β-hydroxysulfides under solvent-
free conditions. Our approach is based on a simple thiolysis of epoxides under very mild
conditions in the presence of a commercially available, catalytic amount of lithium hydrox-
ide. The combination of using a simple catalysis and solvent-free conditions gave excellent
yields of products and reduced the reaction times, which represents a highly ecofriendly
approach.
RESULTS AND DISCUSSION
To find the optimal conditions for the ring opening, initial studies were performed
by using LiOH as catalyst in the reaction of glycidyl phenyl ether with benzenethiol under
various conditions at room temperature (Scheme 1). The reaction was slow in the absence of
a catalyst, and reactions in solvents such as THF, CH2Cl2, acetone, DMF gave low yields
of the desired product even after prolonged reaction time. Next, we optimized the quantity
of the catalyst at room temperature under solvent-free conditions, and it was observed that
the use of just 20 mol% is sufficient to produce an excellent yield of the product.
LiOH (x mol%)
O
PhO
PhSH
+
PhO
SPh
rt, 5 min
OH
X=
Yields
200
97
100
97
50
97
20
97
10
80
5
1
50 10
Scheme 1
We further explored the scope and limitation of this simple process by reaction of
sterically, electronically, and functionally diverse epoxides and thiols under the optimized
condition, and the results are summarized in Table I. Aliphatic as well as aromatic thiols
reacted with different epoxides such as glycidyl phenyl ether, glycidyl isopropyl ether, 1,2-
epoxy butane, 1,2-epoxy propane, and allyl 2,3-epoxypropyl ether to give the corresponding
β-hydroxy sulfide in high to quantitative yield. Generally, aromatic thiols gave higher yields
in short reaction time when compared with the aliphatic thiols. In all cases reported, the
reactions proceeded smoothly at room temperature and typically afforded only one single
product in high yield. Furthermore, the reaction with unsymmetrical epoxides was in most
cases completely regioselective, since the only products isolated were those arriving from
the attack of the nucleophile to the less hindered position of the epoxide with the exception
of styrene oxide.
When styrene oxide was subjected to ring opening with the thiophenol, a mixture
of both regioisomers was obtained in the ratio of 90:10, the major product resulting from
the attack of nucleophile at the less-substituted carbon, which was confirmed by 1H NMR
analysis (Scheme 2).
The stereochemistry of the ring-opened products from bicyclic epoxides was found
to be trans from the coupling constants of the ring hydrogens, as has been observed in most
epoxide ring-opening reactions.

1552
N. AZIZI ET AL.
O
SPh
OH
LiOH, 20 mol %
+
PhSH
+
Ph
Ph
90 %
SFC,rt, 20 min
OH
10 %
SPh
90 %
Scheme 2
To establish the generality and scope of the present methodology, this study was
further extended to TMSCN, which is expected to produce the corresponding β-hydroxy
nitriles. β-hydroxy nitriles are useful synthetic intermediates in organic synthesis,10 and
it is a versatile moiety for the synthesis of 1,3-amino alcohols. The reaction of epoxides
with different cyanide sources, such as hydrogen cyanide, cyanides,11 and asymmetric ring
opening with TMSCN in organic solvent,12 or cyanide formed upon treatment of acetone
cyanohydrin with various bases, are among the most direct methods for the preparation
of these compounds.13 The reaction of epoxides with NaCN, KCN, or HCN usually re-
quires long reaction times, and protic and harmful solvents. They also lack appreciable
regioselectivty when dealing with sensitive and bulky epoxides.
No reaction was observed in the absence of the lithium hydroxide. Reactions in
solvents such as THF, CH2Cl2, acetone, and DMF gave lower yields of the desired product
after prolonged reaction time. The best reaction condition was found when we used 20
mol% of commercially available LiOH under solvent-free conditions. The reactions were
carried out with simple procedure by mixing directly the TMSCN (3.2 mmol), the epoxides
(3 mmol), and solid LiOH (20 mol%) at 0◦C to room temperature, under solvent-free
conditions (Scheme 3).
OSiMe3
TMSCN
O
H
R
R
LiOH (20 mol%), rt
CN
Scheme 3
To show the generality and the scope of the lithium hydroxide–promoted β-hydroxy
nitriles synthesis, the reaction was examined with various structurally diverse epoxides.
The results are shown in Table II. The data clearly show that all reactions proceed smoothly
under these conditions and afford the desired β-hydroxy nitriles in excellent yields with
high regioselectivity. The regioselectivity for the unsymmetrical epoxides is governed
1
by both steric and electronic effects. The regioselectivity was determined by H NMR
spectroscopy and by comparison with the known β-hydroxy nitriles.12 Unsymmetrical
oxiranes underwent cleavage by TMSCN with preferential attack at the less substituted
carbon atom except for styrene oxide.
Furthermore, it is noteworthy that, in some cases, the product obtained after the
routine workup was of sufficient purity for spectra analysis and did not require further
purification.
The simple procedure described here appears to be highly efficient and competitive
with the other methods reported in the literature. The ring-opening reaction of glycidyl
phenyl ether in the presence of different catalysts is compared in Table III.

LiOH-CATALYZED RING OPENING OF EPOXIDES
1553
Table I Ring opening of epoxide with thiols
Entry
Products
Yields (%)a
Time (mm)
Ref.
OH
1
2
97
95
5
20
8c
8q
X = H
O
S
X = Me
X = Br
X = Cl
X = Et
3
4
5
92
88
97
40
40
20
8p
8q
8m
X
6
82
88
80
90
90
100
100
120
120
120
8e
8s
8p
8p
8q
7
8
9
10
OH
11
12
97
95
20
30
8c
8r
O
S
X = H
X = Br
X = Me
13
90
20
8r
X
14
15
95
90
10
50
8c
8p
OH
O
S
X = H
X = Br
X = Me
16
92
30
8p
X
17
85
120
8q
OH
18
19
20
97
93
90
20
15
60
8c
8q
8q
O
S
X = H
X = Me
X= Br
X
X = H
X = Me
X = Br
OH
21
22
23
82
80
78
80
60
8c
8q
8s
S
100
X
(Continued on next page)

1554
N. AZIZI ET AL.
Table I Ring opening of epoxide with thiols (Continued)
Entry
Products
Yields (%)a
Time (mm)
Ref.
24
25
84
76
100
85
8m
8m
OH
X = H
X = Me
S
X
26
27
70
76
180
200
8q
8c
28
29
78
80
200
200
8c
8q
30
31
86
78
120
120
8q
8m
aNMR yields.
In summary, we have developed an efficient and very simple methodology for the
ring opening of epoxides with aromatic and aliphatic thiols and TMSCN that provides
access to useful and synthetically challenging β-hydroxy sulfides and β-hydroxy nitriles.
The use of inexpensive and readily available reagents, chemical efficiency, water tolerance
of the catalyst, operational simplicity, simple workup, and high regioselectivity make this
process particularly attractive. Additionally, the most important advantage was that when
pure reactants were used, the products were always obtained in quantitative yields and a
workup was not required in most cases. Consequently, these reactions were completely
solvent-free, atom economic, and sustainable, and no waste was produced.
EXPERIMENTAL
All chemicals were purchased and used without any further purification. NMR spectra
were recorded at 500 MHz for proton and at 125.7 MHz for carbon nuclei in (CDCl3/CCl4)
or (CDCl3). The products were purified by column chromatography carried out on silica
gel by using ethyl acetate/petroleum ether mixtures if necessary. All the epoxides used are
known, and products obtained are known compounds.

LiOH-CATALYZED RING OPENING OF EPOXIDES
1555
Table II LiOH catalyzed reactions of epoxides with TMSCN under solvent free-conditions
OH
20 mol% LiOH
O
H
+
TMSCN
R
R
SFC, rt
CN
75 -95 %
Product
Entry
1
Expoxide
Yields (%)a Time (min) Ref.
80
5
11e
2
90
120
11c
X
3
4
80
75
100
120
11d
11d
X= Cl
X= Br
NC
OH
5
6
92
95
80
40
11c
11c
7
95
20
11d
8
9
80
78
80
11c
11e
180
aNMR yields.
General Procedure for Aqueous Ring Opening of Epoxides with Thiols
Catalyzed by LiOH
To a stirred solution of epoxide (5 mmol) and LiOH (20 mol%) in a test tube, thiols
(5 mmol) were added, and the resulting mixture was stirred at room temperature for 5–200
min. Then water (5 mL) was added, and the organic materials were extracted with diethyl
ether (2 × 10 mL). The organic layer was separated and dried over anhydrous Na2SO4,

1556
N. AZIZI ET AL.
Table III Comparison of the catalytic activity of LiOH with other methods in the literature
SH
OH
O
O
O
S
+
Entry
Catalyst (mol%)
Solvent
Time (min)
Yields (%)
Ref.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
InCl3 (1)
SFC
SFC
SFC
SFC
Water
SFC
MeOH
CH3CN
SFC
Water
SFC
SFC
10
1080
120
1200
20
85
73
95
95
100
98
99
99
98
90
98
80
98
97
8a
8a
8a
8a
8f
8d
7h
7h
8c
8j
8b
8i
8q
p-TsOH (5)
K2CO3 (5)
n-Bu3P (5)
ZnCl2 (10)
TBAF (10)
Et3N (100)
MgClO4 (75)
LiClO4 (12)
Borax (20)
ZnClO4 (5)
In(OTf)3 (1)
Ga(OTf)3 (1)
LiOH (20)
30
240
150
20
540
60
20
30
5
SFC
SFC
This work
and the solvent was removed under reduce pressure to give the pure product. Evaporation
of the solvent afforded the desired pure product in most cases. In a few cases, the crude
product was further purified by flash column chromatography to provide the corresponding
pure product. All compounds were characterized on the basis of their spectroscopic data
(IR, NMR) and by comparison with those reported in the literature.
General Procedure for the Preparation of β-Hydroxy Nitriles
To mixture of epoxide (3 mmol) and LiOH (20 mol%) in a test tube, TMSCN
(3.1 mmol) was added, and the mixture was stirred at 0◦C for few min and then at room
temperature for 20–180 min. The reaction was monitored with TLC or GC. Then water
(5 mL) was added, and the organic materials were extracted with diethyl ether (2 × 10 mL).
The organic layer was separated and dried over anhydrous MgSO4, and the solvent was
removed to give the β-hydroxy nitriles in the pure product.
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