Synthesis of α-hydroxy-γ-butyrolactones from acrylates and 1,3-dioxolanes using N-hydroxyphthalimide (NHPI) as a key catalyst

Article abstract of DOI:10.1016/j.tetlet.2005.03.137

A new route to α-hydroxy-γ-butyrolactones through three-component radical coupling of 1,3-dioxoranes, acrylates, and molecular oxygen using N-hydroxyphthalimide (NHPI) as a key catalyst has been developed. For example, the addition of 1,3-dioxarane to methyl acrylate under dioxygen by NHPI followed by catalytic hydrogenation of the resulting adduct on Pd/C afforded α-hydroxy-γ-butyrolactone in good yield. This method provides a facile approach to α-hydroxy-γ-butyrolactones, which are difficult to synthesize by conventional methods.

Full text of DOI:10.1016/j.tetlet.2005.03.137

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3687–3689
Synthesis of a-hydroxy-c-butyrolactones from acrylates
and 1,3-dioxolanes using N-hydroxyphthalimide (NHPI)
as a key catalyst
Takashi Kagayama, Satoshi Sakaguchi and Yasutaka Ishii*
Department of Applied Chemistry, Faculty of Engineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan
Received 4 February 2005; revised 17 March 2005; accepted 22 March 2005
Available online 9 April 2005
Abstract—A new route to a-hydroxy-c-butyrolactones through three-component radical coupling of 1,3-dioxoranes, acrylates, and
molecular oxygen using N-hydroxyphthalimide (NHPI) as a key catalyst has been developed. For example, the addition of 1,3-
dioxarane to methyl acrylate under dioxygen by NHPI followed by catalytic hydrogenation of the resulting adduct on Pd/C afforded
a-hydroxy-c-butyrolactone in good yield. This method provides a facile approach to a-hydroxy-c-butyrolactones, which are difficult
to synthesize by conventional methods.
Ó 2005 Elsevier Ltd. All rights reserved.
a-Hydroxy-c-butyrolactone derivatives are important
starting materials in pharmaceutical synthesis and are
prepared by various methods. For instance, (S)-a-hy-
droxy-c-butyrolactone is prepared from ephedrine-de-
The adduct 3a is an interesting compound which can be
used as starting material for the synthesis of a-hydroxy-
c-butyrolactone (6a), since it is easily converted into the
2,5-dihydroxypentanoic acid (5a) through aldehyde 4a
by the deprotection of 3a with acid followed by hydro-
genation. The intramolecular cyclization of 5a would
provide 6a. The merit of the present method is that 3a
is very easily prepared by the use of cheap 1a and 2a,
which are manufactured in large scale as bulk chemicals.
Thus, we have tried to develop a new synthetic route to
a-hydroxy-c-butyrolactones from 1,3-dioxoranes and
acrylates by the use of NHPI as a key catalyst.
1
2
rived morpholinedione and homoserine. Malic acid is
used as the starting material for the synthesis of asym-
metric a-hydroxy-c-butyrolactone as a transient inter-
3
mediate for the synthesis of various pharmaceuticals.
Recently, we have reported that the concomitant cata-
lytic radical addition of 1,3-dioxolane (1a), synthetic
equivalent of formaldehyde, and molecular oxygen
to methyl acrylate (2a) leading to 2-hydroxy-4-(1,3-
dioxolan-2-yl)valerate (3a) is efficiently catalyzed by
4
N-hydroxyphthalimide (NHPI) (Eq. 1).
At first, 3a was prepared according to a previous report.
The reaction of 1a (15 mmol) with 2a (3 mmol) under O2
O
O
+
COOMe + O2
catalyzed by NHPI (0.15 mmol) and Co(OAc)
0.0015 mmol) without any solvent at room temperature
2
(
1
a
2a
(3 mmol)
1atm
for 3 h produced 3a in 82% isolated yield based on 2a
used. 1a was found to be recovered unchanged. But,
when the amount of 1a used was halved, 3a was difficult
to be obtained with satisfactory yield.
(
15 mmol)
OH
COOMe
cat.
ð1Þ
NHPI (5 mol%)
Co(OAc) (0.05 mol%)
2
O
O
Since the direct deprotection of 3a with dilute sulfuric
acid to aldehyde 4a was difficult to carry out, 3a was
treated in methanol in the presence of p-toluenesulfonic
acid (TsOH) followed by treatment of the resulting
r. t., 3 h
3a (82%)
0
dimethyl acetal 3a in aqueous acetic acid to give alde-
hyde 4a in quantitative yield. Representative results
for the conversion of adduct 3a into dimethyl acetal
Keywords: a-Hydroxy-c-butyrolactone; 1,3-Dioxoranes; Acrylates;
Dioxygen; N-Hydroxyphthalimide.
*
Corresponding author. Tel.: +81 6 6368 0793; fax: +81 6 6339
026; e-mail: ishii@ipcku.kansai-u.ac.jp
0
4
3a are shown in Table 1.
0
040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.137

3688
T. Kagayama et al. / Tetrahedron Letters 46 (2005) 3687–3689
0
Table 1. Deprotection of adduct 3a to dimethyl acetal 3a under
a
several conditions
Table 2. One-pot synthesis of 6a upon treatment of reactant derived
a
from 1a and 2a with H on Pd/C
2
Run
MeOH/mL
TsOH/mol%
Temp/°C
Yield/%
Run
Cat. (wt%)
H
2
(MPa)
6a/%
1
2
3
1.5
1.5
5
0.5
0.5
2.0
40
Reflux
Reflux
28
75
1
2
3
5% Pd/C (5)
5% Pd/C (5)
10% Pd/C (10)
8
8
8
0
86
93
Quant.
a
a
Adduct 3a (1 mmol) was reacted in MeOH in the presence of TsOH
for 3 h.
See text.
From a practical synthetic viewpoint, the one-pot syn-
thesis of 6a without isolation of 3a is more attractive
in large-scale synthesis. Thus, a reaction mixture ob-
tained by the reaction of 1a with 2a under the condition
The reaction of 3a (1 mmol) in methanol (5 mL) in the
presence of TsOH (2 mol%) under reflux afforded
0
dimethyl acetal 3a in quantitative yield (run 3). When
the quantities of methanol and TsOH were reduced, 3a
of Eq. 1 was hydrogenated with H (8 MPa) on 10%Pd/
2
0
was difficult to be transformed to 3a completely (runs
0
C (5 wt%), but 6a was not obtained at all (Table 2, run
1
1
and 2). The deprotection of 3a to aldehyde 4a was
successfully achieved by treating with a mixed solvent
). To reveal the reason for unsuccessful performance of
the hydrogenation, the iodometry of the resulting prod-
ucts was examined, and it was found that small amounts
of certain peroxides are involved in the reaction prod-
ucts probably because of the reaction of 1a with 2a at
room temperature without solvent. These peroxides
are thought to deactivate the Pd/C catalyst. Hence, the
reaction mixture was evaporated under reduced pressure
to remove the unreacted 1a and was treated in 2-propa-
nol in the presence of TsOH at 70 °C for 6 h followed by
of acetic acid (5 mL) and water (1 mL) at 40 °C for 7 h
(
Eq. 2).
cat.
OMe OH
TsOH (2 mol%)
MeOH, rf., 3 h
3a
MeO
COOMe
3
a'
ð2Þ
OH
H
COOH
hydrogenation on 5%Pd/C (5 wt%) under H (8 MPa) at
AcOH/H2O (5/1)
2
O
o
4a
60 °C for 6 h to afford 6a in 86% yield (run 2). When
4
0 C, 7 h
1
9
0%Pd/C (10 wt%) was employed, 6a was obtained in
3% yield (run 3). These results show that the peroxides
We next tried the conversion of 4a to hydroxyl lactone
a. When 4a was treated with NaBH in methanol fol-
containing in the crude products are decomposed in
-propanol by heating at 70 °C.
6
4
2
lowed by aq HCl, it was found that the reduction of
a and the intramolecular cyclization of the resulting
alcohol 5a simultaneously take place in one-pot to give
a in 80% yield (Eq. 3).
4
The success of the one-pot synthesis of 6a, which is an
important raw material in pharmaceutical synthesis,
from cheap bulk chemicals, 1a and 2a, provides a very
convenient method for large-scale synthesis.
6
i) NaBH4 /MeOH
O
(
1 mmol / 5 mL)
r. t., 1 h
HO
O
ð3Þ
We next examined the reaction of 2-methyl-1,3-dioxol-
ane (1b) (15 mmol) with 2a (3 mmol) in the presence of
NHPI and Co(OAc) without any solvent at room tem-
2
4
a
ii) 36% HCl (0.1 mmol)
r. t., 2 h
6
a (80%)
(
1 mmol)
perature for 3 h to lead to 2-hydroxy-4-methyl-4-(1,3-
dioxolan-2-yl)valerate (3b) in 81% yield based on 2a
Although it was found that 6a can be synthesized from
cheap starting materials, this strategy consisting of four-
step transformations is troublesome and not suited for
large-scale synthesis. Thus, the direct conversion of 3a
into 6a by the reductive deprotection of dioxorane moi-
ety by H on Ru/C or Pd/C was examined under several
2
conditions. After isolation of 3a from the reaction mix-
ture, the 3a (1 mmol) was hydrogenated in 2-propanol
(Eq. 5).
O
O
+
2a
+
O2
1
b
1atm
(
15 mmol)
(3 mmol)
ð5Þ
cat.
OH
(
acid (TsOH) (75 mg) under H (2 MPa) on 5%Ru/C
1.5 mL) and H O (1.5 mL) involving p-toluenesulfonic
NHPI (5 mol%)
2
2
Co(OAc) (0.05 mol%)
2
COOMe
O
O
(1 wt%) at 60 °C for 6 h to afford a-hydroxy-c-butyro-
lactone 6a in quantitative yield (Eq. 4).
r. t., 3 h
3
b (81%)
cat.
TsOH (2 mol%)
5
% Ru / C (1 wt%)
The treatment of 3b with TsOH afforded a deprotected
product, methyl 2-hydroxy-5-oxahexanoate (4b), in
quantitative yield (Eq. 6).
ð4Þ
3
a
6a
quantitative
-PrOH/H O, 60 oC, 6 h
2
2
H2 (2 MPa)
It was found that the hydrocyclization of 4b to 4-
methyl-2-hydroxy-c-butyrolactone (6b) is important to
carry out in basic media. Table 3 shows the hydrocycli-
The same result was obtained by the use of 10%Pd/C
1 wt%) in the place of 5%Ru/C.
(

T. Kagayama et al. / Tetrahedron Letters 46 (2005) 3687–3689
3689
a
Table 3. Hydrocyclization of 4b under several conditions
The hydrocyclization of 4b proceeds smoothly on Ru
and Pd supported on basic oxides like Al O and CaCO
3
Run
Cat. (wt%)
6b/% (syn/anti)
2
3
(
runs 4 and 5). Therefore, inherent basic Raney Ni
1
5% Ru/C (1)
5% Ru/C (1)
5% Ru/C (1)
68 (53/47)
43 (40/60)
95 (46/54)
99 (42/58)
95 (42/58)
93 (47/53)
b
catalyst was also effective for the present reaction
(run 6).
2
c
3
4
5
6
5% Ru/Al
2
O
3
(1)
(1)
5% Pd/CaCO
Raney Ni (5)
3
In conclusion, we have developed the one-pot synthetic
method of a-hydroxy-c-butyrolactone 6a from cheap
starting materials, 1,3-dioxorane 1a and methyl acrylate
a
Compound 4b (1 mmol) was treated with H
2
(4 MPa) in 3-propanol/
2
a, which are easily available from commercial source,
H
2
O (3/3 mL) at 60 °C for 6 h.
b
c
Aq HCl (0.1 mL) was added.
KOH (0.01 mmol) was added.
using NHPI as a key catalyst. This method was success-
fully extended for the synthesis of methyl substituted
a-hydroxy-c-butyrolactone 6b from 2-methyl-1,3-dioxo-
lane 1b and 2a.
cat.
OH
Acknowledgements
TsOH (2 mol%)
COOMe
3
b
ð6Þ
acetone, 40 oC, 5 h
O
This work was partially supported by a Grant-in-Aid for
Scientific Research (S) from the Ministry of Education,
Culture, Sports and Technology (MEXT), Japan.
4
b (97%)
zation of 4b in several catalysts varying media. When 4b
was allowed to react with H (4 MPa) on Ru/C in basic
2
2
-propanol containing in a small amount of KOH,
References and notes
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