Novel synthesis of 4-arylsulfenyl-3-hydroxy-2-pyrone: One pot substitution-rearrangement-cyclization reaction of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester by sodium arylthiolate

Article abstract of DOI:10.3987/COM-05-S(K)60

-Treatment of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with sodium arylthiolate gave 4-arylsulfenyl-3-hydroxy-2-pyrone in excellent to good yields in one pot.

Full text of DOI:10.3987/COM-05-S(K)60

HETEROCYCLES, Vol. 66, 2005
503
HETEROCYCLES, Vol. 66, 2005, pp. 503 – 509. © The Japan Institute of Heterocyclic Chemistry
Received, 20th September, 2005, Accepted, 25th October, 2005, Published online, 28th October, 2005. COM-05-S(K)60
NOVEL SYNTHESIS OF 4-ARYLSULFENYL-3-HYDROXY-2-PYRONE:
ONE POT SUBSTITUTION-REARRANGEMENT-CYCLIZATION
REACTION OF ACETONIDE PROTECTED 4,5-DIHYDROXY-2-
CHLOROGLYCIDIC ESTER BY SODIUM ARYLTHIOLATE
Takuzo Komiyama, Yutaka Takaguchi, and Sadao Tsuboi*
Department of Material and Energy Science, The Graduate School of
Environmental Science, Okayama University, Okayama 700-8530, Japan
E-mail address : stsuboi6@cc.okayama-u.ac.jp
Abstract – Treatment of acetonide protected 4,5-dihydroxy-2-chloroglycidic
ester with sodium arylthiolate gave 4-arylsulfenyl-3-hydroxy-2-pyrone in
excellent to good yields in one pot.
The 2-pyrone moiety is an important component of large number of natural products which demonstrate a
wide range of biological activity.1 Recently, it has been discovered that phenyl-substituted 2-pyrone has
potent activity as HIV-1 protease inhibitors.2 In addition to biological activity, 2-pyrones have been used
for the syntheses of many useful molecules. For example, it is used as a diene component in Diels-Alder
reactions3 and as a precursor to other heterocyclic compounds.4 One group reported efficient asymmetric
base-catalyzed Diels-Alder reaction of 3-hydroxy-2-pyrone.5 As mentioned above, the 2-pyrone units are
very useful and have drawn much attention for their synthesis. There are various reported methods for the
synthesis of 2-pyrone.6 But concerning the synthesis of 3-hydroxy-2-pyrone, only a few methods are
reported.7 Moreover, there is no report about the synthesis of sulfur-substituted 3-hydroxy-2-pyrone so
far.
During some other researches in our group, we have unexpectedly discovered that 3-hydroxy-2-pyrone
(2) could be obtained in one pot by treating acetonide protected 4,5-dihydroxy-2-chloroglycidic ester (1)
with magnesium halide (Scheme 1).8 We carried out further investigation in this field and applied sodium
arylthiolate for this one pot cyclization reaction. And we found that the treatment of glycidic ester (1)
with sodium arylthiolate also gave 4-arylsulfenyl-3-hydroxy-2-pyrone (4) in good yield. As far as we
2-chloroglycidic ester by sodium thiolate. Furthermore, this reaction proceeds very smoothly under mild
This paper is dedicated to the memory of the Emeritus Professor Kenji Koga of Tokyo University.

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HETEROCYCLES, Vol. 66, 2005
condition and gives desired product in good yield. Therefore, this reaction is not only unique but also
very effective protocol for the preparation of 4-arylsulfenyl-3-hydroxy-2-pyrone. In this paper we
demonstrate the novel synthesis of 4-arylsulfenyl-3-hydroxy-2-pyrone (4) by the reaction of acetonide
protected 4,5-dihydroxy-2-chloroglycidic ester (1) with sodium arylthiolate.
O
O
O
O
MgX2
X = Cl, Br
HO
X
HO
O
Cl
CO2Me
O
ArSNa
O
O
O
O
CO2Me
R
ArS
R
R
SAr
1
R
4
2
3
Scheme 1
Firstly, we optimized reaction conditions for the synthesis of 3-hydroxy-4-phenylsulfenyl-2-pyrone (4a)
(Table 1). The starting material, 2-chloroglycidic ester (1a) was prepared from acetonide protected
glyceraldehyde9 via Darzens condensation reaction with dichloroacetate.10 When 2-chloroglycidic ester
(1a) was treated with 1.5 equiv. of PhSNa at room temperature, the reaction proceeded cleanly but
became stagnant and the starting material was recovered (entry 1). However, all starting material was
consumed under refluxing condition and furnished 2-pyrone (4a) in excellent yield (entry 2). When
equivalent of PhSNa was reduced to 1.0, starting material was recovered again (entry 3).
Table 1. Optimization of reaction conditions for the synthesis of
3-hydroxy-4-phenylsulfenyl-2-pyrone (4a).
O
HO
O
O
Cl
CO2Me
PhSNa
O
O
PhS
1a
4a
entry
1
solvent
MeOH
PhSNa (equiv.)
1.5
temp.
rt
time (h)
3
yield (%)
75a)
95
2
3
MeOH
MeOH
1.5
1.0
reflux
reflux
0.5
3
83a)
a) Starting material (1a) was recovered: 22%, 16% yields (entries 1, 3), respectively.
Then we also tried to apply this reaction to the synthesis of various 4-arylsulfenyl-3-hydroxy-2-pyrone (4)
(Table 2). Treatment of glycidic esters (1a-e)8 with sodium arylthiolate in MeOH under refluxing
conditions provided 4-arylsulfenyl-3-hydroxy-2-pyrones (4b-j) in excellent to good yield after
purification by silica gel flash chromatography. On the other hand, treatment of 2-chloroglycidic ester
with sodium alkylthiolate gave 4-alkylsulfenyl-3-hydroxy- 2-pyrone in slightly low yield.11

HETEROCYCLES, Vol. 66, 2005
505
Table 2. Synthesis of various 4-arylsulfenyl-3-hydroxy-2-pyrone (4b-j).
O
HO
O
O
ArSNa (1.5 equiv.)
MeOH, reflux
Cl
CO2Me
O
O
S
R
Ar
R
4b-j
1a-e
entry substrate
R
H
H
Ar
4-MePh
4-ClPh
time (h)
product/ yield
1
2
1a
1a
0.5
1
4b/ 90
4c/ 72 (93)a)
4d/ 84 (93)a)
4e/ 96
3
1a
H
4-FPh
1
4
5
6
7
8
9
1a
1a
1b
1c
1d
1e
H
H
Me
Ph
3-MeOPh
2-naphtyl
1
1
1
1
1
1
4f/ 91
4g/ 96
4h/ 88
4i/ 84
4j/ 80
Ph
Ph
Ph
Ph
4-MeOPh
1-naphtyl
a) Based on consumed 1.
In order to further investigation of this reaction, we also carried out the next reaction concerning the
substitution-rearrangement product keto ester (3a) (Table 3). (This keto ester (3a) was prepared by the
procedure as shown in Scheme 2). When the keto ester (3a) was treated with 0.5 equiv. of PhSNa in
MeOH under refluxing condition, 2-pyrone (4a) was furnished smoothly in excellent yield (entry 1). On
the other hand, 2-pyrone (4a) was also obtained without PhSNa (entry 2). But in this case the starting
material remained even after 2 h. These results indicate that PhSNa plays a vital role not only in the
rearrangement of glycidic ester (1a) to keto ester (3a), but also in the conversion of keto ester (3a) to
2-pyrone (4a). Furthermore, the rearrangement product (3a) was converted to 2-pyrone (4a) in good yield
by our reported MgCl2 treatment method (entry 4).8
O
O
O
O
O
Cl
CO2Me
O
a
O
O
b
O
CO2Me
CO2Me
Br
SPh
3a
1a
5
.
Reagents and conditions: (a) MgBr2 6H2O (4.0 equiv.), THF, reflux, 4 h, 92%; (b) PhSNa (1.0 equiv.),
toluene, rt, 6 h, 40%.
Scheme 2
Plausible mechanism for the furnishing 2-pyrone (4a) from glycidic ester (1a) is shown in Scheme 3. The
first step of the reaction is a conversion of glycidic ester (1a) to keto ester (3a) resulted from the

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HETEROCYCLES, Vol. 66, 2005
regioselective nucleophilic attack of thiophenoxide anion to the epoxide ring. Then, acetone was
eliminated via base catalyzed keto-enol tautomer (3a’), which thereby converted into intermediate
compound (6). Then the nucleophilic attack toward the ester carbonyl carbon would furnish the
3-hydroxy-4-phenylsulfenyl-2-pyrone (4a) after elimination of MeOH and tautomerization.
Table 3. Synthesis of 4-phenylsulfenyl-3-hydroxy-2-pyrone (4a) from 3-phenylsulfenyl-2-keto ester (3a)
O
O
O
HO
O
O
CO2Me
PhS
SPh
3a
4a
entry
1
2
additive (equiv.)
PhSNa (0.5)
----
solvent
MeOH
MeOH
temp.
reflux
reflux
time (h)
yield (%)
95
0.5
2
70 (93)a)
0b)
92
3
----
THF
THF
reflux
reflux
3
3
4
MgCl2 (1.0)
a) Based on consumed 3a
b) Starting material was recovered quantitatively.
(PhSH)
MeOH
base catalyzed
keto-enol
H
O
O
O
O
Cl
CO2Me
tautomerism
O
O
O
O
CO2Me
O
CO2Me
SPh
1a
H
SPh
3a'
PhS-
PhS-
3a
OH
O
O
keto-enol
tautomerism
HO
O
HO
O
O
O
O
O
OMe
- acetone
- MeOH
CO2Me
PhS
PhS
H
SPh O
SPh
4a
6
Scheme 3
In conclusion, we have developed an efficient and novel protocol for the synthesis of 4-arylsulfenyl-
3-hydroxy-2-pyrones by the reaction of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with
sodium arylthiolate in excellent to good yields. And we have found that sodium arylthiolate plays a vital
role not only in the rearrangement of glycidic ester, but also in cyclization step in this reaction.

HETEROCYCLES, Vol. 66, 2005
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EXPERIMENTAL
NMR spectra were recorded on JEOL JNM-AL300 instrument and calibrated using residual undeuterated
solvent as an internal reference. IR spectra were recorded on a Thermo Nicolet Avatar 360T2 infrared
spectrophotometer. Elemental analyses were performed on Perkin-Elmer 2400 series Ⅱ CHNS/O
analyzer. For thin layer chromatography aluminum sheets Merk silica gel coated 60 F254 plates were
used and the plates were visualized with UV light and phosphomolybdic acid (5% in EtOH). Merck silica
gel 60 N (spherical, neutral) (40-50 μm) was used for the flash chromatography. Melting points were
obtained in open capillary tubes on a Mel-Temp-II hot stage microscope. THF was distilled from sodium
wire/ benzophenone before use. All other chemicals were used as received.
General procedure for the synthesis of 4a-j (synthesis of 4a from 1a): To a stirred solution of
2-chloroglycidic ester (1a) (50 mg, 0.21 mmol) in MeOH (5 mL) was added PhSNa (42 mg, 0.32 mmol),
and the reaction mixture was stirred at refluxing condition for 30 min. Then the reaction mixture was
allowed to cool to rt. After evaporation of MeOH, the resulting solution was diluted with EtOAc and
saturated NH4Cl solution (0.3 mL) was added. Then the organic layer was extracted three times with
EtOAc. The combined organic layer was dried over MgSO4 and concentrated. The crude product was
purified by column-chromatography (hexane/EtOAc 10:1 to 1: 1) to give 3-hydroxy-4-phenylsulfenyl-2-
pyrone (4a) (44 mg, 95 %).
o
1
3-Hydroxy-4-phenylsulfenyl-2-pyrone (4a). Pale yellow crystal; mp 159-161 C (toluene); H NMR
(300 MHz, CDCl3) δ 5.68 (d, J=5.7 Hz, 1H), 6.34 (br, 1H), 6.96 (d, J=5.7 Hz, 1H), 7.43-7.47 (m, 3H),
7.53-7.56 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 106.3, 128.4, 129.4, 129.8, 129.9, 135.2, 135.7, 141.2,
158.9; IR (neat): 3295, 1671, 1345, 1176, 1107, 752. Anal. Calcd for C11H8O3S: C, 59.99; H, 3.66. Found
C, 59.74; H, 3.59.
3-Hydroxy-4-(4-tolylsulfenyl)-2-pyrone (4b). Pale yellow crystal; mp 180-183 oC (Et2O); 1H NMR (300
MHz, CDCl3) δ 2.41 (s, 3H), 5.66 (d, J=5.7 Hz, 1H), 6.30 (br, 1H), 6.94 (d, J=5.7 Hz, 1H), 7.25 (d, J=8.1
Hz, 2H), 7.43 (d, J=8.1 Hz, 2H); IR (neat): 3304, 1671, 1344, 1177, 1107, 816. Anal. Calcd for
C12H10O3S: C, 61.52; H, 4.30. Found C, 61.89; H, 4.27.
4-(4-Chlorophenylsulfenyl)-3-hydroxy-2-pyrone (4c). White crystal; mp 159-160 oC (Hexane/ EtOAc);
1H NMR (300 MHz, CDCl3) δ 5.69 (d, J=5.4 Hz, 1H), 6.34 (br, 1H), 6.99 (d, J=5.4 Hz, 1H), 7.41 (d,
J=8.7 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H); IR (neat): 3274, 1662, 1345, 1177, 1106, 829. Anal. Calcd for
C11H7O3ClS: C, 51.87; H, 2.77. Found C, 51.75; H, 2.57.
4-(4-Fluorophenylsulfenyl)-3-hydroxy-2-pyrone (4d). White crystal; mp 180-181 oC (Hexane/ EtOAc);
1H NMR (300 MHz, CDCl3) δ 5.64 (d, J=5.7 Hz, 1H), 6.28 (br, 1H), 6.98 (d, J=5.7 Hz, 1H), 7.12-7.18 (m,

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HETEROCYCLES, Vol. 66, 2005
2H), 7.52-7.53 (m, 2H); IR (neat): 3293, 1671, 1346, 1180, 1108, 838. Anal. Calcd for C11H7O3FS: C,
55.46; H, 2.96. Found C, 55.54; H, 2.84.
o
3-Hydroxy-4-(3-methoxyphenylsulfenyl)-2-pyrone (4e). White crystal; mp 116-117 C (Hexane/
EtOAc); 1H NMR (300 MHz, CDCl3) δ 3.83 (s, 3H), 5.74 (d, J=5.7 Hz, 1H), 6.37 (br, 1H), 6.97 (d, J=5.7
Hz, 1H), 6.97-7.14 (m, 3H), 7.33-7.38 (m, 1H); IR (neat): 3303, 1679, 1348, 1180, 1102, 762. Anal.
Calcd for C12H10O4S: C, 57.59; H, 4.03. Found C, 57.45; H, 3.98.
o
1
3-Hydroxy-4-(2-naphthylsulfenyl)-2-pyrone (4f). White crystal; mp 126-129 C (Hexane/ EtOAc); H
NMR (300 MHz, CDCl3) δ 5.70 (d, J=5.7 Hz, 1H), 6.39 (br, 1H), 6.93 (d, J=5.7 Hz, 1H), 7.51-7.60 (m,
3H), 7.84-7.91 (m, 3H), 8.11 (s, 1H); IR (neat): 3288, 1663, 1347, 1180, 1103, 817. Anal. Calcd for
C15H10O3S: C, 66.65; H, 3.73. Found C, 66.79; H, 3.61.
3-Hydroxy-6-methyl-4-phenylsulfenyl-2-pyrone (4g). White crystal; mp 186-187 oC (Hexane/ EtOAc);
1H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 5.40 (s, 1H), 6.11 (br, 1H), 7.26-7.47 (m, 3H), 7.51-7.55 (m,
2H); IR (neat): 3266, 1668, 1392, 1360, 1210, 1153, 859. Anal. Calcd for C12H10O3S: C, 61.52; H, 4.30.
Found C, 61.46; H, 4.22.
o
3-Hydroxy-6-phenyl-4-phenylsulfenyl-2-pyrone (4h). Pale yellow crystal; mp 207-208 C (Hexane/
EtOAc); 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), 6.42 (br, 1H), 7.33-7.36 (m, 3H), 7.45-7.50 (m, 5H),
7.58-7.61 (m, 2H); IR (neat): 3270, 1672, 1373, 1182, 750. Anal. Calcd for C17H12O3S: C, 68.90; H, 4.08.
Found C, 68.66; H, 4.04.
o
3-Hydroxy-6-(4-methoxyphenyl)-4-phenylsulfenyl-2-pyrone (4i). Pale yellow crystal; mp 145-146 C
(Hexane/ EtOAc); 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 3H), 5.98 (s, 1H), 6.22 (br, 1H), 6.85 (d, J=9.0
Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 7.45-7.50 (m, 3H), 7.57-7.61 (m, 2H); IR (neat): 3283, 1676, 1623, 1511,
1372, 1251, 1169. Anal. Calcd for C18H14O4S: C, 66.24; H, 4.32. Found C, 65.94; H, 4.17.
o
3-Hydroxy-6-(1-naphthyl)-4-phenylsulfenyl-2-pyrone (4j). Yellow crystal; mp 200-202 C (Hexane/
EtOAc); 1H NMR (300 MHz, CDCl3) δ 5.98 (s, 1H), 6.44 (br, 1H), 7.42-7.53 (m, 7H), 7.60-7.63 (m, 2H),
7.83-7.93 (m, 3H); IR (neat): 3261, 1664, 1367, 1176. Anal. Calcd for C21H14O3S: C, 72.81; H, 4.07.
Found C, 72.86; H, 4.09.
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