Magnesium chloride-catalyzed thiolysis of epoxides: Synthesis of β-hydroxy sulfides

Article abstract of DOI:10.1080/00397910903318625

A mild and convenient ring opening of epoxides with thiophenol and its derivatives takes place at room temperature in the presence of magnesium chloride as catalyst to afford the corresponding β-hydroxy sulfides along with minor amounts of 2-chlorocycloalkanols in good yields. When the crude reaction mixtures are treated with aqueous sodium hydroxide solution, pure 2-arlythiocycloalkanols are obtained in good yields.

Full text of DOI:10.1080/00397910903318625

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Magnesium Chloride–Catalyzed Thiolysis
of Epoxides: Synthesis of β-hydroxy
Sulfides
Rashmi Rani a , Shankha Pattanayak a , Jyoti Agarwal a & Rama
Krishna Peddinti a
a Department of Chemistry , Indian Institute of Technology Roorkee ,
Roorkee, Uttarakhand, India
Published online: 09 Aug 2010.
To cite this article: Rashmi Rani , Shankha Pattanayak , Jyoti Agarwal & Rama Krishna Peddinti
(2010) Magnesium Chloride–Catalyzed Thiolysis of Epoxides: Synthesis of β-hydroxy Sulfides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
40:18, 2658-2666, DOI: 10.1080/00397910903318625
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Synthetic Communications1, 40: 2658–2666, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318625
MAGNESIUM CHLORIDE–CATALYZED THIOLYSIS
OF EPOXIDES: SYNTHESIS OF b-HYDROXY SULFIDES
Rashmi Rani, Shankha Pattanayak, Jyoti Agarwal,
and Rama Krishna Peddinti
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee,
Uttarakhand, India
A mild and convenient ring opening of epoxides with thiophenol and its derivatives takes
place at room temperature in the presence of magnesium chloride as catalyst to afford
the corresponding b-hydroxy sulfides along with minor amounts of 2-chlorocycloalkanols
in good yields. When the crude reaction mixtures are treated with aqueous sodium
hydroxide solution, pure 2-arlythiocycloalkanols are obtained in good yields.
Keywords: Epoxides; b-hydroxy sulfides; ring opening; thiols
INTRODUCTION
The opening of oxirane ring with thiols is one of the important organic
transformations. The products, b-hydroxysulfides, are valuable synthons for
pharmaceuticals[1] and natural products, especially for the syntheses of leukotrienes
such as LTC4 and LTD4.[2–3] b-Hydroxysulfide moiety is a versatile unit for synthesiz-
ing benzoxathiepines,[4] benzotriazepines,[5] a-thioketones,[6] a-substituted a,b-
unsaturated enones,[7] and b-hydroxy sulfoxides.[8] Typically, b-keto esters are pre-
pared by thiolysis of epoxides with thiols under basic conditions or in the presence
of promoters or Lewis acids as catalysts under mild conditions in organic solvents.
These include LnCl3,[9] CoCl2,[10] ceric ammonium nitrate (CAN),[11] Triton B,[12]
InCl3,[13] LiClO4,[14] CaF–celite,[15] b-cyclodextrin,[16] AlPW12O40,[17] and hexafluoro-
isopropanol (HFIP)[18] under solvent-free conditions[19–22] and microwave
irradiation.[23] Though a variety of catalysts have been introduced for thiolysis of
epoxides, there is still demand for the alternate activators for this transformation.
RESULTS AND DISCUSSION
We herein report the remarkable catalytic activity of magnesium chloride in
the ring opening of oxiranes with thiols. The treatment of cyclohexene oxide with
Received May 29, 2009.
Address correspondence to Dr. Rama Krishna Peddinti, Department of Chemistry, Indian Institute
of Technology Roorkee, Roorkee 247 667, Uttarakhand, India. E-mail: rkpedfcy@iitr.ernet.in;
ramakpeddinti@rediffmail.com
2658

SYNTHESIS OF b-HYDROXY SULFIDES
2659
thiophenol (2a) in the presence of 20 mol% of MgCl2 in CH2Cl2 at room temperature
furnished a single compound (by thin-layer chromatography, TLC) after column
1
chromatography (method A; see the Experimental section). However, the H NMR
analysis of this material revealed that it is a 92:8 mixture of 2-phenylthiocyclohexa-
nol (3a) and 2-chlorocyclohexanol (5). We then extended MgCl2-catalyzed thiolysis
of cyclohexene oxide with 4-substituted thiophenols 2b–f and naphthalene-1-thiol
(2 g) and found that 2-arlythiocyclohexanols 3b–g contain 7–13% of 2-chlorocyclo-
hexanol (5) (Scheme 1, Table 1). When the reaction of cyclopentene oxide was
carried out with thiophenols in the presence of MgCl2, the corresponding 2-arlythio-
cyclopentanols 4a–g were obtained along with 2–17% of 2-chlorocyclopentanol (6).
To obtain pure 2-arylthiocycloalkanols, we treated the crude mixture of
2-arylthiocycloalkanol and 2-chlorocycloalkanol with 1 N NaOH solution for an
hour (method B; see the Experimental section). As expected, after the usual workup
and column chromatography 2-arylthiocycloalkanols were obtained in good yields
(Scheme 2, Table 1). The 1H NMR analysis of the products disclosed that these com-
pounds are pure and free from 2-chlorocycloalkanol. Several examples illustrating
this protocol are summarized in Table 1.
The structures of b-hydroxy sulfides 3a–g and 4a–g were assigned on the
basis of their infrared (IR), 1H NMR (500 MHz), and 13C NMR (125 MHz)
spectral analysis. The trans stereochemistry of the products was deduced from
the coupling constants of the protons on carbons 1 and 2. For example, in the
1H NMR (500-MHz) spectrum of 2-(4-bromophenylthio)cyclohexan-1-ol (3d),
1
two H signals appeared at d 2.77 (ddd, J ¼ 13.5, 10.0, 3.5 Hz) and d 3.33 (ddd,
J ¼ 14.5, 10.0, 4.0 Hz) for the CHS and CHOH protons, respectively, which are
indicative of trans stereochemistry. When the reaction of thiophenol and cyclohex-
ene oxide in the CH2Cl2 was carried out in the absence of MgCl2, no product was
noticed. The formation of 2-chlorocycloalkanols in these reactions (Scheme 1)
clearly indicates that the attack of chloride ion from MgCl2 took place. At the
same time, part of MgCl2 participated in the catalysis of thiolysis reaction. As
shown in Scheme 3, the transformation of chlorohydrins 5 and 6 into the corre-
sponding epoxides takes place in the presence of sodium hydroxide, and then these
epoxides further produce b-hydroxy sulfides 3 and 4 (through path a with arylsul-
fide ion as nucleophile) and cycloalkane-1,2-diols 7 and 8 (through path b with
hydroxide ion as nucleophile). The diols, being soluble in water, are separated
during workup.
Scheme 1. Thiolysis of epoxides mediated by MgCl2.

2660

2661

2662

SYNTHESIS OF b-HYDROXY SULFIDES
2663
Scheme 2. Synthesis of b-hydroxysulfides.
EXPERIMENTAL
General Procedure
Method a. A mixture of epoxide (2 mmol), aromatic thiol (2 mmol), and
anhydrous MgCl2 (Aldrich, 20 mol%) in dry dichloromethane (DCM) was stirred at
ambient temperature in a nitrogen atmosphere for the time mentioned in Table 1. After
completion of the reaction as indicated by TLC, the volatile materials were removed
under reduced pressure. The resultant residue was purified by column chromatography
on silica gel using 5–25% ethyl acetate in hexane as eluent to furnish the corresponding
product. The products 3 or 4 contain 2–17% of trans-2-chlorocyclo-hexanol=pentanol
(5 or 6), which was not separable by column chromatography.
Method b. After the reaction was over as described in method A, 2 ml of 1 N
NaOH solution were added to the reaction mixture and stirred for another 1 h. The
reaction mixture was diluted by CH2Cl2 and filtered off. The filtrate was washed
thoroughly with water, dried over anhydrous Na2SO4, and concentrated. The
residue was purified by column chromatography (silica gel, hexane=ethyl acetate)
to furnish pure trans-2-arylthiocycloalkanol 3 or 4.
Selected Spectral Data
trans-2-(4-Chlorophenylthio)cyclohexanol (3c). IR (KBr) nmax: 3413 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 7.39 (dt, J ¼ 3.0, 9.5 Hz, 2H), 7.27 (dt, J ¼ 2.5, 9.0 Hz,
Scheme 3. Conversion of chlorohydrins into b-hydroxysulfides.

2664
R. RANI ET AL.
2H), 3.32 (dt, J ¼ 4.5, 10.0 Hz, 1H), 2.79–2.72 (m, 1H), 2.18–2.02 (m, 2H), 2.81–2.62
(m, 2H), 1.42–1.18 (m, 4H). 13C NMR (CDCl3, 125 MHz): d 134.8, 133.8, 131.0,
129.1, 71.9, 56.4, 33.7, 32.4, 25.9, 24.1
trans-2-(4-Methylphenylthio)cyclohexanol (3e). IR (KBr) nmax: 3444 cmꢀ1
;
1H NMR (CDCl3, 500MHz): d 7.37 (d, J¼ 8 Hz, 2H), 7.12 (d, J ¼ 8Hz, 2H), 3.28
(dt, J ¼ 4.0, 10.0 Hz, 1H), 2.68 (dt, J ¼ 3.5, 11.0 Hz, 1H), 2.34 (s, 3H), 2.15–2.03
(m, 2H), 1.74–1.63 (m, 2H), 1.36–1.16 (m, 4H). 13C NMR (CDCl3, 125 MHz): d
138.1, 134.6, 129.7, 128.3, 71.8, 56.6, 33.7, 32.5, 26.1, 24.3, 21.1
trans-2-(4-Bromophenylthio)cyclopentanol (4d). IR (KBr)nmax: 3373 cmꢀ1
;
1H NMR (CDCl3, 500MHz): d 7.37 (d, J¼ 8.0 Hz, 2H), 7.23 (d, J ¼ 8.5 Hz, 2H), 4.06
(dd, J ¼ 5.0, 10.5 Hz, 1H), 3.34 (dd, J ¼ 7.0, 11.5 Hz 1H), 2.28–2.18 (m, 1H),
2.17–1.98 (m, 1H), 1.82–1.66 (m, 2H), 1.63–1.51 (m, 2H). 13C NMR (CDCl3,
125MHz): d 134.9, 131.8, 131.7, 120.2, 78.3, 53.7, 33.2, 30.7, 21.7
trans-2-(1-Naphthenylthio)cyclopentanol (4g). IR (KBr) nmax: 3363 cmꢀ1
;
1H NMR (CDCl3, 500 MHz): d 7.86 (d, J ¼ 1.5 Hz, 1H), 7.77 (dd, J ¼ 13.0, 17.5 Hz,
3H), 7.51–7.42 (m, 3H), 4.17 (dt, J ¼ 4.5, 6.5 Hz, 1H), 3.53 (dt, J ¼ 4.5, 7.5 Hz, 1H),
2.32–2.22 (m, 1H), 2.16–2.02 (m, 1H), 1.84–1.69 (m, 2H), 1.67–1.58 (m, 2H).
13C NMR (CDCl3, 125 MHz): d 133.7, 133.3, 131.8, 128.4, 128.3, 128.2, 127.6,
127.1, 126.5, 125.7, 78.3, 53.6, 33.3, 30.9, 21.9.
CONCLUSION
In conclusion, we have demonstrated a mild and efficient method for the prep-
aration of b-hydroxy sulfides using MgCl2 as a catalyst. In addition, the advantages
such as availability, nontoxicity, stability, low cost of catalyst, and simplicity give new
synthetic applications for MgCl2 in organic synthesis. To the best of our knowledge,
magnesium chloride is not known to catalyze thiolysis of epoxides with thiophenol
and its derivatives.
ACKNOWLEDGMENTS
We thank the Department of Science and Technology (DST), New Delhi, for
providing financial assistance. R. R. thanks the DST and J. A. thanks the University
Grants Commission, New Delhi, for the fellowship awards.
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