LiBr catalyzed solvent-free ring expansion of epoxides to 1,4-oxathian-2-ones with α-mercaptocarboxylic acids

Article abstract of DOI:10.1016/j.tetlet.2011.05.010

An efficient and rapid (10-20 min) one-pot synthesis of chemically and pharmaceutically interesting 1,4-oxathian-2-ones is reported. The protocol involves LiBr catalyzed regioselective ring-opening-ring-closing reaction cascade of terminal epoxides with α

Full text of DOI:10.1016/j.tetlet.2011.05.010

Tetrahedron Letters 52 (2011) 3614–3617
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
LiBr catalyzed solvent-free ring expansion of epoxides
to 1,4-oxathian-2-ones with
a-mercaptocarboxylic acids
⇑
Atul K. Singh, Ankita Rai, Lal Dhar S. Yadav
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and rapid (10–20 min) one-pot synthesis of chemically and pharmaceutically interesting
1,4-oxathian-2-ones is reported. The protocol involves LiBr catalyzed regioselective ring-opening–
Received 17 March 2011
Revised 27 April 2011
Accepted 4 May 2011
Available online 11 May 2011
ring-closing reaction cascade of terminal epoxides with
a-mercaptocarboxylic acids at rt under sol-
vent-free conditions. Recycling of the catalyst, atom economy, and formation of water as the only
by-product in the present synthesis are additional advantages relevant to green chemistry.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Epoxides
LiBr
Mercaptocarboxylic acids
Solvent-free
1,4-Oxathian-2-ones
Cascade reactions
1,4-Oxathiane nucleus is the key structural motif present in cer-
tain commercial systemic fungicides broadly used in agriculture.1
Organophosphorus derivatives of 1,4-oxathiane are insecticidal
and acaricidal.2 Some other 1,4-oxathiane derivatives have been
found to exhibit activity against tumor, HIV,3 candidosis, and
aspergillosis.4 Recently, 1,4-oxathiane nucleus has been reported
as a suitable substructure for muscarinic agonists.5
Epoxides are versatile intermediates in organic synthesis
mainly due to their susceptibility to a variety of nucleophiles6
and availability in optically pure forms.7 Nucleophilic ring opening
of epoxides has been extensively studied but little work has been
carried out on the epoxide ring expansion with nucleophiles,8
although it would offer useful synthetic methods for various het-
erocycles. For example, only a few attempts have been made for
the synthesis of 1,4-oxathian-2-ones via an epoxide ring-open-
ing–ring-closing reaction cascade and the results are not satisfac-
tory in terms of yields, reaction times, number of synthetic steps,
and environmental considerations. Kaufmann and Schickel9 have
synthesized 5-phenyl-1,4-oxathian-2-one in three steps starting
from styrene oxide and ethyl thioglycolate in the presence of
Amberlite IRA-400 (OH form). Under similar conditions, Black10
the presence of Amberlite IRA-400 (OH form) gave 1-(carboxym-
ethylthio)propan-2-ol which on distillation afforded 5-methyl-
1,4-oxathian-2-one.10 Orszulik11 also obtained a mixture of the
corresponding 1,4-oxathian-2-one (yield 9.5%) and hydroxyacetate
(yield 13.8%) on refluxing 2,3-epoxy-2-methylpentane with thio-
glycolic acid in chloroform for 66 h. The above points and our
ongoing efforts to develop one-pot synthetic processes12 prompted
us to devise an efficient protocol for the synthesis of 1,4-oxathian-
2-ones 3 via ring expansion of terminal epoxides 1 with
tocarboxylic acids 2 (Scheme 1).
a-mercap-
In general, the efficiency of a synthetic process can be enhanced
by increasing concentration of the reactants and using a suitable
catalyst. Thus, to accomplish our goal, we relied on the reaction un-
der solvent-free conditions using a Lewis acid, which would effi-
ciently catalyze both the steps of an epoxide ring-opening–ring-
closing cascade with an
a-mercaptocarboxylic acid. We focused
our initial efforts on the screening of a range of Lewis acid catalysts
for the synthesis of 1,4-oxathian-2-ones 3a using styrene oxide 1a
and thioglycolic acid 2a as model substrates under solvent-free
conditions (Table 1). Of the catalysts tested, LiBr was found to be
obtained
a mixture of 2-(carboxymethylthio)ethanol (yield
12.5%) and 1,4-oxathian-2-one (yield 10%) by the reaction of thio-
glycolic acid with ethylene oxide at 20 °C for 3 days fallowed by
distillation. Similarly, propylene oxide and thioglycolic acid in
HO
HS
O
O
O
LiBr (10 mol %)
neat, rt
O
R1
R1
S
R2
R2
1
3
2
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
Scheme 1. Synthesis of 1,4-oxathian-2-ones 3.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.010

A. K. Singh et al. / Tetrahedron Letters 52 (2011) 3614–3617
3615
Table 1
activates oxygen-containing electrophiles for nucleophilic
attack.13–15 LiBr could be easily recovered and reused in subse-
quent runs without any loss of efficiency. The lesser catalytic effi-
ciency of LiCl than LiBr (Table 1, entries 1 and 2) is probably due to
its less solubility in organic media. The lower yield of 3a in the case
of LiI may be attributed to the formation of 2-iodo-2-phenyletha-
nol as a side-product due to the strong nucleophilicity of IÀ (Table
1, entry 3). No appreciable amount of 3a was formed from 1a and
2a in the absence of LiBr; the starting materials were recovered
unchanged.
The optimum catalyst loading for LiBr was found to be 10 mol %.
When the amount of the catalyst was decreased to 5 mol %, the
yield of the product 3a was reduced considerably but with
15 mol % loading of the catalyst no further improvement of the
yield was observed. The reaction was also performed in different
solvents using LiBr as the catalyst but a significantly lower yield
of 3a was obtained in a longer reaction time (15 h). It was found
that among H2O, EtOH, CH2Cl2, THF, and MeCN, the best solvent
in terms of yield was CH2Cl2 (80% yield of 3a). With these optimal
conditions established, the present solvent-free one-pot procedure
was applied to the synthesis of various 1,4-oxathian-2-ones 3
(Table 2).16 The general utility of the protocol was demonstrated
Optimization of catalyst for the synthesis of 1,4-oxathian-2-ones 3aa
HO
HS
O
O
S
O
catalyst (10 mol %)
neat, rt
O
Ph
Ph
2a
1a
3a
Entry
Catalyst
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
LiCl
LiBr
LiI
NaBr
KBr
FeCl3
FeBr3
CuCl2
CuBr2
ZnCl2
ZnBr2
20
10
15
45
45
45
45
45
45
45
45
58
89
60c
26
17
44
49
33
35
24
28
10
11
a
b
c
For experimental procedure, see Ref. 16.
Isolated yield of purified product 3a.
In addition to 60% of 3a, 2-iodo-2-phenylethanol was isolated in 21% yield.
across a range of terminal epoxides 1 using two
a-mercaptocar-
the best for the epoxide ring expansion to afford 3a (Table 1, entry
boxylic acids 2 and the results are summarized in Table 2. In gen-
eral, styrene oxides (Table 2 entries 1–10) afford better yields of 3
2). This is in accordance with the strong oxophilicity of Li+ which
Table 2
Synthesis of 1,4-oxathian-2-one 3 via ring expansion of epoxides 1a
HO
HS
O
O
O
LiBr (10 mol %)
neat, rt
O
R1
R1
S
R2
R2
2
1
3
Entry
1
Epoxide 1
2, R2
Time (min)
Product 3
Yieldb,c (%)
89
O
O
O
H
10
3a
3b
3c
3d
3e
3f
Ph
Ph
S
O
O
O
O
O
2
3
4
5
6
7
8
H
10
15
10
15
15
15
20
84
79
93
80
85
81
p-ClC6H4
o-ClC6H4
p-ClC6H4
o-ClC6H4
S
O
H
S
O
O
O
H
p-MeOC6H4
p-O2NC6H4
p-MeOC6H4
S
O
O
O
H
p-O2NC6H4
O
S
O
O
Me
Me
Me
Ph
Ph
S
Me
O
O
O
3g
3h
p-ClC6H4
o-ClC6H4
p-ClC6H4
o-ClC6H4
S
O
Me
O
O
77
S
Me
(continued on next page)

3616
A. K. Singh et al. / Tetrahedron Letters 52 (2011) 3614–3617
Table 2 (continued)
Entry
Epoxide 1
2, R2
Time (min)
10
Product 3
Yieldb,c (%)
90
O
O
S
O
9
10
11
12
13
14
15
Me
3i
p-MeOC6H4
p-MeOC6H4
Me
O
O
O
Me
H
20
20
20
15
20
15
20
3j
78
81
78
87
84
85
81
p-O2NC6H4
p-O2NC6H4
O
S
Me
O
O
O
3k
3l
Me
Me
Me
S
O
O
Me
H
Me
S
Me
O
O
O
3m
3n
3o
3p
S
O
O
O
O
Me
H
S
O
Me
O
S
O
O
O
16
Me
S
Me
a
For experimental procedure, see Ref. 16.
b
c
Isolated yield of purified product 3.
All compounds gave C, H and N analyses within 0.37% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Lithium bromide activates epoxides 1 through coordinating with
oxygen, which facilitates the regioselective nucleophilic epoxide
opening with the –SH group of mercaptocarboxylic acids 2 to form
4. Intramolecular dehydrative cyclization of the intermediate 4 af-
fords 1,4-oxathian-2-ones 3 and liberates LiBr to complete the cat-
alytic cycle (Scheme 2).
O
S
O
O
R1
R2
-H2O
R1
1
3
LiBr
In summary, we have developed a convenient and efficient one-
pot synthesis of 1,4-oxathian-2-ones via LiBr catalyzed regioselec-
tive epoxide ring-opening-ring-closing reaction cascade with
a-
R1
Li
Br
mercaptocarboxylic acids. This rapid (10–20 min) synthesis is per-
formed at rt under solvent-free conditions. Recycling and economic
viability of the catalyst, atom-economy, and formation of water as
the only by-product are additional advantages of the present meth-
odology relevant to green chemistry.
O
O
OH2
OLi
S
R1
R2
HS
HO
R2
O
R1
OH
O
Acknowledgment
2
S
OH
Li
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra.
R2
Br
4
References and notes
Scheme 2. A plausible mechanism for the formation of 1,4-oxathian-2-ones 3.
1. Cook, M. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Eds.; Pergamon Press: Oxford, 1984; Vol. 3.
2. Haubein, A. H. J. Am. Chem. Soc. 1959, 81, 144.
3. Borkow, G.; Barnard, J.; Nguyen, T. M.; Belmonte, A.; Wainberg, M. A.; Parniak,
M. A. J. Virol. 1997, 71, 3023.
4. Miyauchi, H.; Tanio, T.; Ohashi, N. Bioorg. Med. Chem. Lett. 1996, 6, 2377.
5. Piergentili, A.; Quaglia, W.; Giannella, M.; Bello, F. D.; Bruni, B.; Buccioni, M.;
Carrieric, A.; Ciattini, S. Bioorg. Med. Chem. 2007, 15, 886.
6. (a) Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737; (b) Buchanan, J. G.; Sable,
H. Z. In Selective Organic Transformations; Thyagarajan, B. S., Ed.; Wiley, 1972;
(c) Rao, A. S.; Paknikar, S. K.; Kirtane, J. G. Tetrahedron 1983, 39, 2323; (d) Smith,
J. G. Synthesis 1984, 629.
than the alkene and cycloalkene oxides (Table 2 entries 11–16).
Another important feature of this procedure is the compatibility
with a variety of functional groups such as ether, nitro, and halides
under the reaction conditions. The larger nucleophile
a-mercapto-
propionic acid gives slightly lower yields than
acid.
a-mercaptoacetic
On the basis of the experimental results, a plausible mechanism
for the formation of 1,4-oxathian-2-ones 3 is depicted in Scheme 2.

A. K. Singh et al. / Tetrahedron Letters 52 (2011) 3614–3617
3617
7. (a) Sharpless, K. B. Chem. Br. 1986, 22, 38; (b) Pfenninger, A. Synthesis 1986, 89;
(c) Hanson, R. M. Chem. Rev. 1991, 91, 437.
8. (a) Patel, R.; Srivastava, V. P.; Yadav, L. D. S. Synlett 2010, 1797; (b) Park, H. S.;
Kwon, D. W.; Lee, K.; Kim, Y. H. Tetrahedron Lett. 2008, 49, 1616; (c) Antoniotti,
S.; Dunach, E. Tetrahedron Lett. 2009, 50, 2536.
9. Kaufmann, H. P.; Schickel, R. Fette Seifen Anstrichmittel 1963, 65, 851.
10. Black, D. K. J. Chem. Soc. (C) 1966, 1708.
11. Orszulik, S. T. Tetrahedron Lett. 1986, 27, 3781.
12. (a) Rai, A.; Singh, A. K.; Singh, S.; Yadav, L. D. S. Synlett 2011, 335; (b) Rai, A.;
Singh, A. K.; Singh, P.; Yadav, L. D. S. Tetrahedron Lett. 2011, 52, 1354; (c) Yadav,
L. D. S.; Singh, S.; Rai, V. K. Green Chem. 2009, 11, 878; (d) Yadav, L. D. S.; Patel,
R.; Rai, V. K.; Srivastava, V. P. Tetrahedron Lett. 2007, 48, 7793; (e) Yadav, L. D.
S.; Patel, R.; Srivastava, V. P. Synlett 2008, 583; (f) Yadav, L. D. S.; Singh, S.; Rai,
V. K. Tetrahedron Lett. 2009, 50, 2208.
13. Chakraborti, A. K.; Rudrawar, S.; Kondaskar, A. Eur. J. Org. Chem. 2004, 3597.
14. Basak, A. (ne´e Nandi); Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett. 1998,
39, 4883.
Et2O (2 Â 5 mL) to remove any organic impurity and dried under reduced
pressure to afford LiBr, which was used in subsequent runs without further
purification.
Characterization data of representative compounds.
Compound 3a: Yellowish oil, yield 89%. IR (KBr) mmax 2992, 2874, 1750, 1609,
1585, 1455, 750, 705 cmÀ1 1H NMR (400 MHz; CDCl3): d: 3.34 (d, 1H,
.
J = 15.0 Hz), 3.45 (d, 1H, J = 15.0 Hz), 3.92 (dd, 1H, J = 12.2, 5.6 Hz), 4.08 (dd,
1H, J = 12.2, 8.0 Hz), 5.06 (dd, 1H, J = 8.0, 5.6 Hz), 7.20–7.41 (m, 5H). 13C NMR
(100 MHz, CDCl3) d: 23.5, 46.9, 77.1, 126.8, 127.9, 129.0, 139.4, 168.5. EIMS (m/
z) 194 (M+). Anal. Calcd for C10H10O2S: C, 61.83; H, 5.19. Found: C, 61.46; H,
5.01. Compound 3f: Yellowish oil, yield 85%. IR (KBr) mmax 3024, 2998, 2876,
1745, 1602, 1583, 1458, 755, 700 cmÀ1 1H NMR (400 MHz; CDCl3): d: 1.46 (d,
.
3H, J = 7.1 Hz), 3.53 (q, 1H, 7.1 Hz), 3.91 (dd, 1H, J = 12.2, 5.6 Hz), 4.06 (dd, 1H,
J = 12.2, 8.0 Hz), 5.07 (dd, 1H, J = 8.0, 5.6 Hz), 7.23–7.46 (m, 5H). 13C NMR
(100 MHz, CDCl3) d: 19.8, 44.3, 45.1, 77.5, 126.5, 127.8, 128.9, 139.4, 172.2.
EIMS (m/z) 208 (M+). Anal. Calcd for C11H12O2S: C, 63.43; H, 5.81. Found: C,
63.69; H, 5.45. Compound 3k: Yellowish oil, yield 81%. IR (KBr) mmax 2945,
15. Chakraborti, A. K.; Basak, A. (born Nandi); Grover, V. J. Org. Chem. 1999, 64,
8014.
2894, 1740, 1120 cmÀ1 1H NMR (400 MHz; CDCl3): d: 1.30 (d, 3H J = 7.0 Hz),
.
3.02–3.61 (m, 1H), 3.29 (d, 1H, J = 15.0 Hz), 3.40 (d, 1H, J = 15.0 Hz), 3.92 (dd,
1H, J = 12.2, 5.5 Hz), 4.51 (dd, 1H, J = 12.2, 7.9). 13C NMR (100 MHz, CDCl3) d:
17.9, 23.5, 40.1, 77.6, 168.2. EIMS (m/z) 132 (M+). Anal. Calcd for C5H8O2S: C,
45.43; H, 6.10. Found: C, 45.67; H, 6.46. Compound 3m: Yellowish oil, yield
16. General procedure for the synthesis of compounds 3:
A mixture of a-
mercaptocarboxylic acid (1 mmol), epoxide (1 mmol), and LiBr
2
1
(0.1 mmol) was stirred under neat condition at room temperature for 10–
20 min (Table 2). After completion of the reaction (monitored by TLC), water
(5 mL) was added, and the mixture was extracted with EtOAc (3 Â 5 mL). The
combined organic phase was dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The resulting crude product was
purified by silica gel column chromatography using a mixture of EtOAc–
hexane (3:7) as eluent to afford an analytically pure sample of 3. After isolation
of the product, the remaining aqueous layer containing LiBr was washed with
87%. IR (KBr) m .
max 2964, 2850, 1745, 1125 cmÀ1 1H NMR (400 MHz; CDCl3): d:
1.40–1.48 (m, 4H), 1.56–1.88 (m, 4H), 3.06 (ddd, 1H, J = 11.4, 11.1, 3.5 Hz), 3.30
(d, 1H, J = 15.1 Hz), 3.42 (d, 1H, J = 15.1 Hz), 4.18 (ddd, 1H, J = 11.4, 11.0,
3.3 Hz). 13C NMR (100 MHz, CDCl3) d: 21.8, 23.7, 24.8, 28.0, 29.6, 52.0, 77.4,
168.3. EIMS (m/z) 172 (M+). Anal. Calcd for C8H12O2S: C, 55.78; H, 7.02. Found:
C, 55.65; H, 7.22.