" On-water " thiolysis of epoxides promoted by PhSZnBr

Article abstract of DOI:10.1080/17415993.2013.781604

The synthesis of a new bench-stable and odorless zinc thiolate is here reported. The thiolysis of epoxides effected using this reagent showed a considerable rate acceleration of the reaction when effected in "on-water" conditions. In addition, the reactio

Full text of DOI:10.1080/17415993.2013.781604

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“On-water” thiolysis of epoxides
promoted by PhSZnBr
Simona Propersia, Caterina Tideia, Luana Bagnolia, Francesca
Marinia, Lorenzo Testaferria & Claudio Santia
a Department of Chimica e Tecnologia del Farmaco – Group of
Catalysis and Green Chemistry, University of Perugia, Via del Liceo
1 Perugia, Italy
Published online: 19 Apr 2013.
To cite this article: Simona Propersi, Caterina Tidei, Luana Bagnoli, Francesca Marini, Lorenzo
Testaferri & Claudio Santi (2013) “On-water” thiolysis of epoxides promoted by PhSZnBr, Journal of
Sulfur Chemistry, 34:6, 671-676, DOI: 10.1080/17415993.2013.781604
To link to this article: http://dx.doi.org/10.1080/17415993.2013.781604
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Journal of Sulfur Chemistry, 2013
Vol. 34, No. 6, 671–676, http://dx.doi.org/10.1080/17415993.2013.781604
SHORT COMMUNICATION
“On-water” thiolysis of epoxides promoted by PhSZnBr
Simona Propersi, Caterina Tidei, Luana Bagnoli, Francesca Marini, Lorenzo Testaferri
and Claudio Santi*
Department of Chimica e Tecnologia del Farmaco – Group of Catalysis and Green Chemistry,
University of Perugia, Via del Liceo 1 Perugia, Italy
(Received 25 January 2013; final version received 27 February 2013)
The synthesis of a new bench-stable and odorless zinc thiolate is here reported. The thiolysis of epoxides
effected using this reagent showed a considerable rate acceleration of the reaction when effected in “on-
water” conditions. In addition, the reactions evidenced a good regioselectivity combining the advantage
of the procedures effected in organic solvent with those effected using Lewis acid catalysis.
H
SPh
OH
O
PhSZnBr
WATER
Regioselective
Streospecific
R
R1
R1
β
R1
α
α
R
R
β
H
OH
SPh
Keywords: sulfur; zinc; thiolates; thiolysis; water
1. Introduction
The interest around organic sulfur compounds is continuously increasing in consideration of their
importance as intermediates in organic synthesis as well as biologically active molecules. For
these reasons, the development of new reagents and synthetic strategies to be able to combine
efficiency with respect to the environment is currently the objective of a number of studies.
Thiolysis of 1,2-epoxides represents an efficient strategy for the preparation of
β-hydroxysulfides that are generally considered useful intermediates in the synthesis of naturally
occurring derivatives (1), pharmaceuticals (2), allylic alcohols (3, 4), benzoxathiepines (5, 6), ben-
zotiazepines (7), α-thioketones (8) and β-hydroxysulfoxides (9). Moreover, β-hydroxysulfides
are also widely used in asymmetric synthesis (10, 11). A number of different conditions were
reported for the ring-opening reaction of epoxides, using organic solvents (THF, MeOH, CH2Cl2,
MeCN, benzene) in the presence of different catalysts or promoting agents (bases, Lewis acids,
heterogeneous catalysts, microwave irradiation, silica gel, alumina, Montmorillonite, polyethy-
lene glycol, tetrabutylammonium phenoxide). Recently some new ecofriendly protocols have
been also taken into consideration (12–20). However, despite their synthetic utilities, most of
the commonly used reaction conditions suffer from a number of drawbacks, which include the
use of smelling thiols, strong and non-selective acidic catalysts, expensive and toxic solvents or
*Corresponding author. Email: santi@unipg.it
Dedicated to the memory of Prof. Alessandro Degl’Innocenti
© 2013 Taylor & Francis

672 S. Propersi et al.
reagents, low yields, and long reaction times, sometimes associated to the formation of undesir-
able side products by the rearrangement of oxiranes or the oxidation of thiols. Water is rarely
used in organic reactions because of the insolubility of the majority of organic compounds, their
occasional decomposition as well as the incompatibility of some intermediates with this solvent.
However, aqueous medium has interesting advantages with respect to organic solvents: water
is inexpensive, abundant, readily available, non-toxic, and environmentally benign. Moreover, it
has been demonstrated that a number of reactions occur faster in water than in organic solvents.
This concept was first postulated by Sharpless and coworkers (21) to indicate a process in which
organic insoluble reactants are stirred in aqueous suspension reacting with a considerable rate
acceleration.
In continuation of our previous studies concerning the reactivity of zinc selenolates, we report
here the synthesis of a bench-stable (phenylsulfenyl)zinc bromide as an excellent reagent for the
thiolysis of epoxides in on-water conditions. During the last five years, we deeply investigated the
reaction of elemental zinc with organoselenium compounds in order to prepare new nucleophilic
chalcogenides. We demonstrated that, in a biphasic acidic system, it reduces diselenides affording
the formation of aliphatic and aromatic selenols that can be trapped, in situ, by electrophiles such
as epoxides, alkyl halides (22), and unprotected aziridines (23).
In a different way, elemental zinc reacts in refluxing THF with commercially available PhSeCl
and PhSeBr producing, through an oxidative metal insertion, the formation of the bench-stable
(phenylselenenyl)zinc halides (24). These reagents are characterized by extraordinary stability
under ordinary conditions and showed a strong reactivity toward a number of electrophiles. Nucle-
ophilic substitution of alkyl-, aryl-, vinyl-, and acyl- halides, ring-opening reactions (25) as well
as Michael-type addition reactions (26), and thiol oxidations (27) were successfully realized
resulting to be, in all the cases, accelerated when effected in on-water conditions.
2. Results and discussion
Benzenesulfenyl bromide 2 was easily prepared by bromination starting from the commercially
available disulfide 1. The product obtained after the under-vacuum evaporation of the organic
solvent was immediately used for the reaction with elemental zinc in refluxing THF. After 1 h,
the dissolution of the metal indicated the complete formation of the (phenylsulfenyl)zinc bromide
3 that was purified and isolated in 70% yield by crystallization from diethyl ether (Scheme 1).
The zinc thiolate 3 appeared as a white amorphous solid (m.p. 238–240◦C), air stable for several
weeks, and was fully characterized by 1H- and 13C- NMR spectroscopy and elemental analysis.
Zn, THF
reflux
S
S
S
Br2, CCl4
Br
ZnBr
S
1
2
3
Scheme 1. Synthesis of 3.
The nucleophilic properties of the zinc thiolate 3 were preliminarily investigated in the
ring-opening reaction of styrene oxide 4a. The reaction was performed in THF solution as well
as in water suspension and neat conditions, in order to verify the on-water rate acceleration
previously observed for the analogs of zinc selenolates (25). The results, summarized in Table 1
(Entries 9 and 11), clearly indicated that when water is the medium the reaction afforded in 15 min
quantitative yield of the β-hydroxysulfides 5a and 6a, whereas in THF solution, after 5 h, the yield

Journal of Sulfur Chemistry 673
Table 1. Comparison of different reaction conditions for the thiolysis of styrene oxide (4a).
SPh
OH
O
α
conditions
β
α
β
OH
SPh
4a
5a
t(min)
43200
43200
10
20
180
40
5
20
15
300
60
6a
Yield (%)
Entry
Conditions
PhSH, H2O, 20◦C
5a/6a
Reference
1
2
3
4
5
6
41
98
90
98
98
86
91
100
100
41
0
80/20
85/15
72/28
83/17
80/20
97/3
(12, 13)
(12)
(15)
(16)
(17)
(18)
PhSH, DABCO (1%), H2O, 25◦C
PhSH, [Emim] BF4, 50◦C
PhSH, LiClO4 (12.5 mol), 25◦C
PhSH, Borax (10%), H2O, 25◦C
PhSH, Ga(OTf)3 (1%), 25◦C
PhSH, InCl3 (10%), H2O, 30◦C
PhSH, ZnCl2 (10%), H2O, 30◦C
PhSZnBr, H2O, 20◦C
7
8
9
10
11
97/3
(19)
(20)
84/16
89/11
89/11
PhSZnBr, THF, 20◦C
PhSZnBr, neat, 20◦C
was only moderate. The nucleophilic attack was driven predominantly at the benzylic α-carbon
by electronic effects with a good regioselectivity (89:11) for both the applied conditions.
In Table 1, the results obtained from the thiolysis of 4a mediated by (phenylsulfenyl)zinc
bromide 3 are compared with those reported in the literature for the same reaction effected using
benzenethiol as the nucleophile in different reaction conditions: using alternative solvents (water,
ionic liquids), in solvent-free conditions, and in the presence or absence of catalysts.
The reaction of PhSH with 4a at room temperature in water and in the absence of catalysts is
particularly slow (Entry 1) (12, 13) and afforded the couple of β-hydroxysulfides 5a and 6a in
moderate yield and regioselectivity (14).1 Slightly better yields can be obtained with additives
such as DABCO (Entry 2) (12) and borax (Entry 5) (17), whereas the use of ionic liquids (Entry 3)
(15) or solvent-free conditions (Entry 4) (16) are much more effective in reducing the reaction time
increasing the yields. Better results were reported for the process catalyzed by Lewis acids (Entries
6–8) (18–20). In these cases, good yields were associated with very short reaction times and also
the regioselectivity was usually enhanced, probably as a consequence of the acidic activation of
the oxirane. In this context, the use of PhSZnBr 3 appears to be superior to all the reactions effected
in water showing most of the advantages of the Lewis-acid-catalyzed reactions (rate acceleration,
highyields, andhighregioselectivity). Inaddition, zincthiolateisacompletelyodorlesscompound
offering a valuable advantage with respect to the use of the smelling benzenethiol.
In order to investigate the scope of the reaction, the conditions described in Table 1 (Entries 9
and 10), were applied to the thiolysis of a number of variously substituted epoxides. The results
are summarized in Table 2 and indicate that, in all the cases, the process is accelerated when
carried out in water suspension. For the epoxides 4e and 4f, in THF, it was not possible to isolate
the desired β-hydroxysulfides and a mixture of non-identified products and the starting material
was recovered.
Concerning the regiochemistry, it is interesting to observe that the ring-opening reaction of the
epoxide 4b is completely selective on the α-position (5b), whereas in the case of the methyloxirane
4c, the steric effects in the absence of a stabilizing aromatic ring lead exclusively to the product
deriving from an SN2 attack occurring on the less hindered β-carbon (6c). Only in the case of the
phenylcyclohexene oxide 4e the thiolysis proceeded with poor regioselectivity affording 5e and
6e in a ratio of 65:35.
The attempt to effect the thiolysis of the functionalized epoxide 7 with PhSZnBr (3) in water
suspension failed leading to the corresponding hydroxylactone 8 (Scheme 2).This result suggested

674 S. Propersi et al.
Table 2. Scope of the reaction.
Epoxide
Products ( 5/6)
Solvent
t (min)
Yielda(%)
99, 41
5/ 6b
H2O, THF
15, 300
89/11, 89/11
4a
H2O, THF
H2O, THF
15, 60
82, 51
70, 44
4b
5b
15, 240
4c
6c
H2O, THF
H2O, THF
15, 120
30, 600
73, 46
49, –
4d
5d
65/35, –
4e
5e/6e
OH
SPh
5f
H2O, THF
60, 600
52, –
4f
Notes: aThe yields are referred to the amount of product obtained after purification.
bThe regioisomeric ratios were calculated by the 1H-NMR of the crude.
that zinc reasonably acts as a Lewis acid activating the oxirane ring that is preferentially trapped
by the internal nucleophile. However, it is interesting to underline that a similar competition has
never been observed for the water.
In conclusion, a new zinc thiolate for the nucleophilic ring opening of epoxide is reported
here. The reaction, using on-water conditions, is very fast and proceeds in good yield and good
regioselectivity affording the corresponding β-hydroxysulfides. Further investigation devoted to
the synthesis of other zinc thiolates is currently ongoing.
OH
O
3, H2O, r.t.
O
O
OH
O
8
7
Scheme 2. Reaction of PhSZnBr with epoxide 7.

Journal of Sulfur Chemistry 675
3. Experimental
Epoxides 4a–d are commercial compounds (Aldrich). Epoxides 4e and 4f and 7 have been
prepared from the corresponding commercial olefins by oxidation with m-CPBA according to
the procedure described in the literature (28). Intermediates have been purified by flash chro-
matography on silica gel column (eluant dichloromethane). 5a, 5b, 5d, 5e, 5f and 6a, 6c and 6e
have spectral properties identical to those previously described (29–34), and the diasteroisomeric
couples 5a/6a and 5e/6e were not separated and analyzed as mixture.
1
All the new compounds were fully characterized by NMR and elemental analysis. H- and
13C-NMR spectra were recorded at 400 and 100.62 MHz, respectively, on a Bruker Avance-DRX
400 instrument. Elemental analyses were carried out on a Carlo Erba 1106 elemental analyzer.
3.1. Preparation of PhSZnBr 3
Three hundred milligrams of diphenyl disulfide (1.37 mmol) was dissolved in diethyl ether (8 ml)
and a solution of bromine (1.0 M in CCl4, 1.37 mmol) was added at 0◦C. After 30 min, the organic
solvent was removed under reduced pressure affording a red solid (PhSBr, 380 mg). The solid
was dissolved in fresh distilled THF and the resulting solution heated at reflux. After that the
elemental zinc (65.4 mg, 2.21 mmol) was added and the reaction mixture was vigorously stirred
at reflux until complete discoloration. The colorless solution was filtered in order to remove
the unreacted elemental zinc and zinc thiolate 3 was purified by crystallization from diethyl
ether.
3.2. Phenylthiozinc(II) bromide (3)
1
White solid, m.p. 238–240◦C. H-NMR (DMSO-d6): δg.32–7.25 ppm (m, 2H), 7.02–6.95 (m,
2H), 6.9–6.8 (m, 1H). 13C-NMR δg33.2, 128.6, 122.8, 102.6. Anal. Calcd for C6H5BrSZn: C,
28.32; H, 1.98. Found: C, 28.08; H, 1.87.
3.3. Thiolysis in on water conditions: general procedure
To a suspension of 50 mg of PhSZnBr (0.2 mmol) in 2 ml of water, 0.2 mmol of epoxides 4a–f was
added at room temperature and the mixture was maintained under vigorous stirring for the time
reported in Table 2. After that the reaction mixture was extracted with ethyl acetate (3 × 3 ml),
the organic layer dried over sodium sulfate and the crude purified by flash chromatography on a
silica gel column (eluant diethyl ether 30%–petroleum ether 70%).
Acknowledgements
Financial support from Fondazione Cassa di Risparmio: Project “Processi ecosostenibili per la produzione e l’analisi
di molecole di interesse farmaceutico”, 2012.0114.021, and Consorzio CINMPIS, Bari (Consorzio Interuniversitario
Nazionale di Metodologie e Processi Innovativi di Sintesi), are gratefully acknowledged.
Note
1. Our attempts to reproduce the yields and the regioselectivity reported for the synthesis of 5a and 6a failed,
confirming, in all the cases, the results reported in references (12) and (13).

676 S. Propersi et al.
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