Efficient synthesis of β, β'-dihydroxy sulfides by ring opening of epoxides with mercaptoethanol catalyzed under solvent-free conditions

Article abstract of DOI:10.1080/17415993.2012.662685

A simple and highly efficient synthesis of β, β′-dihydroxy sulfides has been achieved by ring opening of epoxides with mercaptoethanol using catalytic amount of benzyltrimethylammonium hydroxide (Triton B) under solvent-free conditions. Excellent regioselectivity was found for aliphatic unsymmetrical epoxides, with nucleophilic attack at the less-hindered carbon atom of the epoxide. However, this regioselectivitywas not observed for styrene oxide and a mixture of two isomers was obtained. This process was also regio- and chemo-selective as illustrated using epichlorohydrin with two epoxide ring positions and mercaptoethanol with two functional groups (SH and OH). Figure Presented.

Full text of DOI:10.1080/17415993.2012.662685

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Efficient synthesis of β, β’-dihydroxy
sulfides by ring opening of epoxides
with mercaptoethanol catalyzed under
solvent-free conditions
Moufida Romdhani-Younes a & Mohamed Moncef Chaabouni a
a Laboratoire de Chimie Organique Structurale, Département de
Chimie, Faculté des Sciences de Tunis, Université Tunis El Manar,
2092, Tunis, Tunisia
Published online: 21 Mar 2012.
To cite this article: Moufida Romdhani-Younes & Mohamed Moncef Chaabouni (2012): Efficient
synthesis of β, β’-dihydroxy sulfides by ring opening of epoxides with mercaptoethanol catalyzed
under solvent-free conditions, Journal of Sulfur Chemistry, 33:2, 223-228
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Journal of Sulfur Chemistry
Vol. 33, No. 2, April 2012, 223–228
Efficient synthesis of β, β’-dihydroxy sulfides by ring opening
of epoxides with mercaptoethanol catalyzed under
solvent-free conditions
Moufida Romdhani-Younes* and Mohamed Moncef Chaabouni
Laboratoire de Chimie Organique Structurale, Département de Chimie, Faculté des Sciences de Tunis,
Université Tunis El Manar, 2092 Tunis, Tunisia
(Received 4 December 2011; final version received 28 January 2012)
A simple and highly efficient synthesis of β, β’-dihydroxy sulfides has been achieved by ring opening of
epoxides with mercaptoethanol using catalytic amount of benzyltrimethylammonium hydroxide (Triton B)
under solvent-free conditions. Excellent regioselectivity was found for aliphatic unsymmetrical epoxides,
with nucleophilic attack at the less-hindered carbon atom of the epoxide. However, this regioselectivity was
not observed for styrene oxide and a mixture of two isomers was obtained. This process was also regio- and
chemo-selective as illustrated using epichlorohydrin with two epoxide ring positions and mercaptoethanol
with two functional groups (SH and OH).
Keywords: Mercaptoethanol; epoxides; Triton B; solvent-free; hydroxy sulfides; regioselectivity
Introduction
Epoxides represent an important class of compounds in organic synthesis. For instance, their
nucleophilic opening leads to a large number of 1,2-difunctionalized systems (1–6). Their reac-
tions with different nucleophiles (e.g. amine, thiols, alcohol, and so on) have been the subject of
extensive studies (7–11). Ring opening of epoxides by thiols constitutes a convenient, practical
and widely employed method for the synthesis of β-hydroxysulfide moieties, which are useful as
intermediates in organic chemistry (12–15) especially in the preparation of important naturally
occurring products (16–19) and a variety of compounds with pharmacological and/or biological
activities (20–23).
*Corresponding author. Email: moufida.romdhani@gmail.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.662685
http://www.tandfonline.com

224 M. Romdhani-Younes and M. M. Chaabouni
While there are a few examples utilizing water or solvent-free conditions (6,24,25), most
thiolysis of epoxides is realized in organic solvents using thiols under basic conditions (26–28)
or Lewis acid catalysts (29–32), such as InCl3, ZnCl2 or BF3 · OEt2. However, these methods
usually suffer from limitations such as the use of toxic and expensive reagents, non-selective
catalysts, long reaction times or elevated temperatures (33–35). Therefore, it is of significant
interest to selectively synthesize β-hydroxysulfides and it still remains a highly desired goal in
organic synthesis.
In our research, we have previously shown the specific role of Triton B as a catalyst in the
synthesis of dihydroxy dithiacrown ethers (36) by ring opening of diglycidic ethers with dimer-
captoethane using this catalyst. In continuation with our work on the application of Triton B for
various organic transformations as an easily available catalyst, we report here a simple, efficient
and practical procedure using this catalyst as an environmental-friendly and commercially avail-
able cheap catalyst for the synthesis of a new series of β, β’-dihydroxysulfides under solvent-free
conditions.
Results and discussion
We investigated the ring opening of various epoxides with mercaptoethanol and our successful
results are reported in Table 1. As shown in Scheme 1, the ring opening of epoxides was initiated
by thiolate ion produced by the reaction of mercaptoethanol with Triton B. The method provides
high yields of versatile β, β’-dihydroxy sulfides.
The ring-opening reactions were carried out in a simple manner by adding mercapthoethanol
dropwise over a 10-min period to a stirred solution of epoxide and Triton B at room tem-
perature without solvent. The best result was obtained using 2.5% of Triton B and a reactive
mercapthoethanol:epoxide molar ratio of 1:1.
As shown in Table 1, excellent regioselectivity was observed for all aliphatic epoxides 1a–d.
Selective nucleophilic attack by the thiolate anion occurs at the less-substituted carbon atom.
The 1H NMR spectra of crude products 2a–d showed particularly a triplet in the range of 3.75–
−
−
3.85 ppm assigned to CH2OH protons and multiplets centered at 3.90 ppm for CHROH. No
RCHS-protonsignalsaround2.75 ppmexpectedfortheotherisomerwereobserved, whichimplies
that the absence of the attack on the (β)-carbon of the epoxide. For instance, the 1H NMR spectrum
of 2a showed signals at δ = 1.25 (d, 3H, J = 6 Hz, CH3); 2.53–2.65 (m, 2H, CHCH2S); 2.74 (t,
2H, J = 6 Hz, SCH2CH2); 3.75 (t, 2H, J = 6 Hz, CH2OH); 3.89 (m, 1H, CPhHOH); 4.25 (broad
s, 2H, OH), indicating the absence of the signal related to RCHS-proton of the other isomer. In
addition, only five distinct signals were observed in the 13C NMR spectrum of 2a, in agreement
with the proposed structure. This regiospecificity was not observed in the case of styrene oxide,
as is usually observed in the literature (37), which led to a mixture of two regioisomers (60:40
α/β). In this case, the nucleophilic attack takes place predominantly on the less-substituted carbon
(path α Scheme 1). The regioselectivity and the ratio of the two regioisomers were determined
by H and 13C NMR spectroscopy. The H NMR spectrum of the mixture of the two isomers
2e1 and 2e2 showed two multiplets at 3.93 and 4.70 ppm due to the CHPh protons in the 2e1
and 2e2 isomers, respectively. The 13C NMR spectra showed, in addition to the peaks related to
the aromatic carbon, the existence of eight different peaks corresponding to the eight aliphatic
carbons of the two isomers 2e1 and 2e2.
1
1
Under similar conditions, treatment of cyclohexeneoxide 1f with mercaptoethanol gave a very
good yield of the corresponding expected trans-β, β’-dihydroxy sulfide (Scheme 2).
The reaction of epichlorohydrin 1d provides an excellent example of a chemo- and regiose-
lective reaction. Reaction of mercaptoethanol with epichlorohydrin in the presence of Triton B
gave the corresponding β, β’-dihydroxy sulfide by nucleophilic attack at the terminal carbon of

Journal of Sulfur Chemistry 225
Table 1. Ring opening of epoxides by mercaptoethanol.
Epoxide
Thioetherdiolsa
Boiling point (◦C)/Torr
Yield (%)
97
Ratio α/β
H3C
H3C
S
102/0.4
100:0
O
OH
OH
OH
1a
2a
H3C
S
H3C
110/0.4
98
100:0
O
OH
1b
2b
Ph
Ph
O
O
S
130/0.1
Oil
97
92
100:0
100:0
O
OH
OH
1c
2c
Cl
S
Cl
O
1d
OH
OH
2d
Ph
S
159/0.1b
60 %
OH
OH
2e1
Ph
Ph
S
98c
96
60:40
40 %
OH
OH
OH
O
2e2
1e
S
O
136/0.4
–
OH
1f
2f
Notes: aThe ratios were determined by 1H NMR.
bBoiling point of mixture of two isomers.
cTotal yield of two isomers.
Scheme 1.
the epoxide moiety. No product from nucleophilic substitution of the chloride atom was observed
(1H and 13C NMR).
The above process was also chemoselective as illustrated using mercaptoethanol with two
potential reactive nucleophilic functional groups (thiol and alcohol). The reaction of mercap-
toethanol with all of the epoxides in the presence of Triton B takes place chemoselectively with
exclusive attack of the thiolate anion on less-hindered carbon atom of the epoxide. No significant
amount of the product was observed from the attack of alcoholate anion. This may be due to the
higher acidic and nucleophilic character of thiol when compared with alcohol.

226 M. Romdhani-Younes and M. M. Chaabouni
Scheme 2.
Table 2. Comparison of catalytic activity of Triton B with CsF-celite (28).
Epoxide
Catalyst (mol%)
T
Solvent
Time (min)
Yield (%)
Ph
O
CsF-celite(100%)
Triton B (2.5%)
Reflux
R.T.
CH3CN
60
10
78
98
O
Solvent-free
1c
Ph
CsF-celite(100%)
Triton B (2.5%)
Reflux
R.T.
CH3CN
60
10
84
97
O
Solvent-free
1e
The procedure described here appears to be highly efficient and competitive with other methods
reported in the literature (28). The ring-opening reaction of phenoxymethyl oxide 1c and styrene
oxide 1e with mercaptoethanol in the presence of the CsF-celiteas, a catalyst, is compared in
Table 2.
In conclusion, we have reported the thiolysis of alkyl and aryl-1,2-epoxides with mercap-
toethanol under solvent-free conditions catalyzed by Triton B (2.5%) at room temperature. This
protocol is novel in terms of high regio- and chemoselectivity in comparison with other methods
reported in the literature. The additional advantage is that these reactions were carried out at room
temperature in short reaction times under solvent-free conditions with small amounts of catalyst
in high yields. This, together with the use of an inexpensive easy to handle and stable catalysts
makes this new methodology environmental-friendly and useful for the synthesis of chemically
and pharmaceutically interesting β, β’-dihydroxy sulfides.
Experimental
1
1
The products were characterized by H and 13C NMR spectroscopy and HRMS. The H and
13C NMR spectra were recorded in CDCl3 as solvent on a Bruker AC 300 spectrometer. The
chemical shifts were reported in δ-values relative to TMS (internal reference). For the 1H NMR,
the multiplicities of signals are indicated by the following abbreviations: s: singlet, d: doublet, t:
triplet, m: multiplet. HRMS spectra were obtained using MAT 95 SBE instrument.
General procedure for the synthesis of β, β’-dihydroxy sulfides: mercaptoethanol (10 mmol)
was added dropwise over a 10-min period to a stirred solution of epoxide 1a–f (10 mmol) and
Triton B (0.25 mmol) at room temperature. The consumption of the epoxide was monitored by thin
layer chromatography. The mixture obtained was purified by distillation except the product 2d
which was isolated by column chromatography (Silica Gel 60 F254, acetone/ethyl acetate 1:1).
3-Thiahexan-1,5-diol (2a). 1H NMR(300 MHz, CDCl3): 1.25 (d, 3H, J = 6 Hz, CH3); 2.53–2.65
(m, 2H, J = 6 Hz, J = 12 Hz, CHCH2S CHCH2S); 2.74 (t, 2H, J = 6 Hz, SCH2CH2); 3.75 (t, 2H,
J = 6 Hz, CH2OH); 3.89 (m, 1H, CHOH); 4.25 (broad s, 2H, OH). 13C NMR (75 MHz, CDCl3):
22.1 (C, CH3); 34.5 (C, SCH2CH2); 40.2 (C, CHCH2S); 61.2 (C, CH2OH); 66.3 (C, CHOH).
HRMS: calculated 159.0450 for (C5H12O2SNa), found 159.0455 (M + Na)+.

Journal of Sulfur Chemistry 227
3-Thiaheptan-1,5-diol (2b). 1H NMR (300 MHz, CDCl3): 0.94 (t, 3H, J = 6 Hz, CH3) ; 1.53 (m,
2H, CH2CH3); 2.50–2.59 (m, 2H, CHCH2S); 2.73 (t, 2H, J = 6 Hz, SCH2CH2); 3.62 (m, 1H,
CHOH); 3.73 (t, 2H, J = 6 Hz, CH2OH); 3.96–4.19 (broad s, 2H, OH). 13C NMR (75 MHz,
CDCl3):11.1 (C1, CH3); 28.8 (C2, CH2CH3); 35.5 (C6, SCH2CH2); 38.0 (C4, CHCH2S); 60.8
(C7, CH2OH); 70.7 (C3, CHOH). HRMS: calculated 173.0612 for (C6H14O2SNa), found
173.0619 (M + Na)+.
7-Phenoxy-3-thiahexan-1,5-diol (2c). 1H NMR (300 MHz, CDCl3): 2.70 (t, 2H, J = 6 Hz, SCH2);
2.80–2.86 (m, CHCH2S); 3.7 (t, 2H, J = 6 Hz, CH2OH); 3.83 (broad s, 2H, OH); 3.97 (m,
2H, CH2OPh); 4.10 (m, 1H, CHOH); 6.86–7.24 (m, 5H, Ph). 13C NMR(75 MHz, CDCl3): 35.9
(C, CH2OPh); 41.1 (C, CHCH2S); 61.2 (C, CH2OH); 68.6 (C, CHOH); 72.0 (C, CH2OPh); 114.5;
120.7; 129.8; 158.0 (aromatic). HRMS: calculated 251.0712 for (C11H16O3SNa), found 251.0727
(M + Na)+.
6-Chloro-3-thiahexan-1,5-diol (2d). 1H NMR (300 MHz, CDCl3): 2.63 (t, 2H, SCH2); 2.46–2.70
(m, 2H, CH2CH); 3.4–3.70 (m, 2H, ClCH2CH); 3.80 (m, 1H, CHOH); 3.90 (t, 2H, CH2OH);
4.40 (broad s, 2H, OH). 13C NMR (75 MHz, CDCl3): 34.5 (C, SCH2); 42.5 (C, CH2CH);
47.8 (C, ClCH2CH); 61.2 (C, CH2OH); 70.8 (C, CHOH). HRMS: calculated 193.0060 for
(C5H11O2ClSNa), found 193.0056 (M + Na)+.
1-Phenyl-3-thiapentan-1,5-diol (2e1). 1H NMR (300 MHz, CDCl3): 2.43–2.63 (m, 2H,
SCH2CH2OH); 2.72–2.80 (m, 2H, CHCH2S); 3.52–3.63 (m, 2H, CH2CH2OH); 4.10–4.25 (broad
s, 2H, OH); 4.70 (m, 1H, PhCHOH); 7.25–7.29 (m, 5H, aromatic). 13C NMR (75 MHz, CDCl3):
34.5 (C, SCH2CH2); 42.5 (C, CHCH2S); 61.1 (C, CH2OH); 72.9 (C, PhCHOH); 127.2; 127.7;
129.0; 140.7 (aromatic).
2-Phenyl-3-thiapentan-1, 5-diol (2e2). 1H NMR (300 MHz, CDCl3): 2.43–2.63 (m, 2H,
SCH2CH2OH): 3.52–3.63 (m, 2H, CH2CH2OH); 3.76 (m, 2H, SCHCH2OH); 3.93 (SCHPh);
4.107–4.25 (broad s, 2H, OH); 7.10–7.29 (m, 5H, aromatic). 13C NMR (75 MHz, CDCl3): 33.79
(C, SCH2CH2OH); 52.28 (C, SCHPh); 60.87 (C, SCH2CH2OH); 65.76 (C, SCHCH2OH); 127.2;
128.7; 128.7; 139.0 (aromatic). HRMS: calculated 221.0606 for (C10H14O2SNa), found 221.0600
(M + Na)+.
2-(2-Hydroxyethylthio)cyclohexanol (2f). 1H NMR (300 MHz, CDCl3): 1.24–1.46 (m, 4H,
(CH2)2); 1.73 (m, 2H, CH2CHS); 2.07 (m, 2H, CH2CHOH); 2.48 (ddd, 1H, J = 12 Hz, 9 Hz,
3 Hz, CHS); 2.80 (t, 2H, J = 6 Hz, SCH2); 3.35 (ddd, 1H, J = 11 Hz, 9.8 Hz, 4.5 Hz, CHOH);
3.75 (t, 2H, CH2OH); 3.95 (broad s, 2H, OH). 13C NMR (75 MHz, CDCl3): 24.3, 26. (CH2)2; 31.5
(CH2CHS); 33.2 (CH2CH2OH); 33.7 (CH2CHOH); 52.7 (CHS); 60.2 (CH2OH); 72.2 (CHOH).
HRMS: calculated 199.0763 for (C8H16O2SNa), found 199.0769 (M + Na)+.
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