Novel synthesis of 4-chloro-3-hydroxy-2-pyrone by the reaction of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with magnesium chloride

Article abstract of DOI:10.1016/j.tetlet.2004.06.101

Treatment of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with magnesium chloride gave 4-chloro-3-hydroxy-2-pyrone in excellent to good yields. Treatment of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with magnesium chloride gave 4-chloro-3-hydroxy-2-pyrone in excellent to good yields.

Full text of DOI:10.1016/j.tetlet.2004.06.101

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6299–6301
Novel synthesis of 4-chloro-3-hydroxy-2-pyrone by the reaction of
acetonide protected 4,5-dihydroxy-2-chloroglycidic ester
with magnesium chloride
Takuzo Komiyama, Yutaka Takaguchi and Sadao Tsuboi*
Department of Environmental Chemistry and Materials, Faculty of Environmental Science and Technology,
Okayama University, Tsushima, Okayama 700-8530, Japan
Received 24 May 2004; revised 14 June 2004; accepted 18 June 2004
Abstract—Treatment of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester with magnesium chloride gave 4-chloro-3-hydroxy-
2-pyrone in excellent to good yields.
Ó 2004 Elsevier Ltd. All rights reserved.
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 syn-
theses 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 its synthesis. There are vari-
ous reported methods for the synthesis of 2-pyrone.6
But concerning with the synthesis of 3-hydroxy-2-py-
rone, only a few methods are reported.7 Moreover, there
is no report about synthesis of 6-substituted 4-halo-3-
hydroxy-2-pyrone so far. Here, in this paper we demon-
strate the novel synthesis of 4-chloro-3-hydroxy-2-py-
rones by the reaction of acetonide protected 4,5-
dihydroxy-2-chloroglycidic ester with magnesium chlo-
ride.
tion reaction of aldehyde 4 with dichloroacetate by our
original procedure as shown in Scheme 1. Aldehyde,
substituted with electron donating aromatic group such
as 4c, is directly converted to 3-chloro-2-keto ester 5c by
Darzens condensation reaction with dichloroacetate.8
The reaction of aliphatic aldehydes with dichloroacetate
gives 2-chloroglycidates, which were transformed to
3-bromo-2-keto esters 5b by the treatment with MgBr2Æ
Et2O.9 Ester 5 was converted to the corresponding pro-
tected diol 6 in three steps via substitution of halogen by
hydroxyl group with K2CO3 in the H2O/acetone, fol-
lowed by NaBH4 reduction and acetonide protection
of hydroxyl groups. Dihydroxylation of a,b-unsaturated
esters can also be used for the preparation of this pro-
tected diols.10 Treating of the ester 6 with DIBAL-H
in ether at À78 °C afforded the corresponding aldehyde,
and again Darzens condensation reaction with methyl
dichloroacetate furnished glycidic esters 1. With this
procedure, variety of glycidic esters 1 can be prepared
from various commercially available or synthesized
aldehydes.
In the presence of magnesium chloride, 2-chloroglycidic
ester 1a–c11 was converted to corresponding 4-halo-3-
hydroxy-2-pyrones 2a–c in excellent to good yields12,13
(Table 1). Treatment of glycidic ester 1a with 4 equiv
of magnesium chloride in THF under refluxing condi-
tion for 2 h provided 4-chloro-3-hydroxy-2-pyrone (2a)
in 97% yield after purification by silica gel flash chroma-
tography (Table 1, entry 1). When EtOAc was used as a
solvent, the yield became moderate (entry 2) and, the
The starting material of this pyrone synthesis, 2-chloro-
glycidic ester 1, was prepared by the Darzens condensa-
Keywords: 2-Pyrone; Magnesium chloride; Darzens condensation;
Dichloroacetate; Cyclization.
*
Corresponding author. Tel./fax: +81-86-251-8898; e-mail: stsuboi6@
cc.okayama-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.101

6300
T. Komiyama et al. / Tetrahedron Letters 45 (2004) 6299–6301
O
O
O
Cl
CO2Me
R
vi , vii
i or i , ii
iii - v
O
RCHO
CO2Et
O
O
CO2Et
4b,c
X
R
R
b: R = n-Pr
5b: X = Br
5c: X = Cl
1b,c
c: R = p-MeOC6H4
6b,c
Scheme 1. Reagents and conditions: (i) t-BuOK (1.2 equiv), CHCl2CO2Et (1.0 equiv), THF, 5c (72%); (ii) MgBr2ÆEt2O (2.0 equiv), Et2O, reflux, 5b
(80%, two steps); (iii) K2CO3, H2O–acetone; (iv) NaBH4, THF–MeOH, 0 °C; (v) DMP, PTSA (cat.), acetone, rt, 6b (51%, three steps), 6c (71%, three
steps); (vi) DIBAL-H (1.5 equiv), Et2O, À78 °C; (vii) t-BuOK, CHCl2CO2Me (1.0 equiv), THF, 1b (76%, three steps), 1c (71%, two steps).
Table 1. Synthesis of 4-chloro-3-hydroxy-2-pyrone 2 by the reaction of acetonide protected 4,5-dihydroxy-2-chloroglycidic ester 1 with magnesium
chloride
O
O
O
O
Cl
CO2Me
HO
Cl
MgCl2
O
O
O
O
+
CO2Me
R
Cl
R
1a-c
2a-c
3
a: R = H
b: R = n-Pr
c: R = p-MeOC6H4
Entry
Substratea
Conditions
MgCl2 (4.0 equiv), THF, reflux, 2 h
Product/yield (%)
1
2
3
4
5
6
7
1a
1a
1a
1a
1a
1b
1c
2a/97
MgCl2 (4.0 equiv), EtOAc, 60 °C, 3 h
MgCl2 (4.0 equiv), toluene, reflux, 23 h
MgCl2 (1.0 equiv), THF, reflux, 5 h
MgCl2 (0.2 equiv), THF, reflux, 29 h
MgCl2 (4.0 equiv), THF, reflux, 68 h
MgCl2 (4.0 equiv), THF, reflux, 20 h
2a/81, 3/7
2a/49, 3/26b
2a/97
2a/91
2b/92b,c
2c/92
a A mixture of two stereoisomers was used as a substrate (ratio is 1.9:1 for entries 1–5). Major isomers, which were obtained from Scheme 1 were used
as a substrate (entries 6 and 7).
b Starting material was also recovered in 20% and 25% yields, respectively (entries 3 and 6).
c Based on consumed 1b.
reaction was not completed even after 23 h, and the
reaction in toluene gave the product in 49% yield (entry
3). In entries 2 and 3, 3-chloro-2-keto ester 3 was also
obtained. To optimize the effect of magnesium chloride,
its concentration was reduced to 1.0 and 0.2 equiv,
respectively (entries 4 and 5). In these cases it was found
to take longer reaction time to complete the reaction.
But the yield of 2a was almost same as that of entry 1.
These result shows that the reaction proceeds with cata-
lytic amount of magnesium chloride. Furthermore,
treatment of 5-substituted glycidic esters 1b,c with mag-
nesium chloride also gave the desired products 2b,c in
good yields (entries 6 and 7), but reaction was not com-
pleted in case of entry 6. This is because some steric hin-
drance may prevent magnesium chloride to approach
the substrate.
Plausible mechanism for furnishing pyrone 2a from
glycidic ester 1a is shown in Scheme 2. At first, as re-
ported,9 2-chloroglycidic ester 1a was transformed to
3-chloro-2-keto ester 3 in the presence of magnesium
chloride. Then acetonide group was deprotected, fol-
lowed by nucleophilic addition of hydroxyl group to
ester carbonyl carbon. Finally, elimination of water
O
OH
O
O
O
Cl
CO2Me
O
HO
deprotection
MgCl2
OMe
O
O
CO2Me
Cl
Cl
O
1a
3
- MeOH
O
O
O
HO
Cl
O
O
-H2O
O
O
O
H
Cl
H
Cl
2a
OH
Scheme 2.

T. Komiyama et al. / Tetrahedron Letters 45 (2004) 6299–6301
6301
Synth. Commun. 1975, 5, 457–460; (c) Kumashiro, I.
Nippon Kagaku Zasshi 1961, 82, 932–934.
and tautomerization furnished 4-chloro-3-hydroxy-2-
pyrone (2a).
8. (a) Takeda, A.; Tsuboi, S.; Wada, S.; Kata, H. Bull. Chem.
Soc. Jpn. 1972, 45, 1217–1220; (b) Takeda, A.; Tsuboi, S.;
Nakashima, I. Bull. Chem. Soc. Jpn. 1975, 48, 1067–1098;
(c) Tsuboi, S.; Furutani, H.; Takeda, A.; Kawazoe, K.;
Sato, S. Bull. Chem. Soc. Jpn. 1987, 60, 2475–2479.
9. Coutrot, P.; Grison, C.; Tabyaoui, M.; Czernecki, S.;
Valery, J. M. J. Chem. Soc., Chem. Commun. 1988,
1515–1516.
10. (a) Milas, N. A.; Sussman, S.; Mason, H. S. J. Am. Chem.
Soc. 1939, 61, 1844–1847; (b) Danishefsky, S. J.; De-
Ninno, M. P. J. Org. Chem. 1986, 51, 2615–2617.
11. Compound 1a was prepared from acetonide protected
D-glyceraldehyde via Darzens condensation reaction with
dichloroacetate. For preparation of acetonide protected D-
glyceraldehyde see: Schmid, C. R.; Bryant, J. D.; Dowla-
tzedah, M.; Phillips, J. L.; Prather, D. E.; Schantz, R. D.;
Sear, N. L.; Vianco, C. S. J. Org. Chem. 1991, 56,
4056–4058.
12. Typical procedure (synthesis of 2a from 1a): To a stirred
solution of a-chloroglycidic ester 1a (50 mg, 0.21 mmol) in
THF (2 mL) was added magnesium chloride (80 mg,
0.84 mmol), and the reaction mixture was heated to reflux
for 2 h. Then the reaction mixture was allowed to cool to
room temperature. Distilled water (2 mL) was added and
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 5:1 to 2:1) to give
4-chloro-3-hydroxy-2-pyrone (2a) in 97% yield.
In conclusion, we have developed an efficient and novel
protocol for the synthesis of 4-chloro-3-hydroxy-2-py-
rone by the reaction of acetonide protected 4,5-dihydr-
oxy-2-chloroglycidic ester with magnesium chloride in
excellent to good yields. And a variety of 6-substituted
4-chloro-3-hydroxy-2-pyrones can also be prepared
from commercially available or synthesized aldehydes
by this method. Further investigation and a more
detailed study of this methodology are in progress and
will be reported in the future.
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