Organic Syntheses, Vol. 79, pp. 244-250
[4-Oxazolecarboxylic acid, 2-methyl-, methyl ester]
Submitted by James D. White, Christian L. Kranemann, and Punlop Kuntiyong
1.
Checked by Mitsuru Kitamura and Koichi Narasaka.
1. Procedure
A. Methyl α-[(methoxyethylidene)amino]acetate (
1). A
flame-dried,
500-mL, two-necked, round-bottomed flask is equipped with a
stir
bar,
rubber septum, and an
argon inlet.
The flask is charged with
methyl acetimidate hydrochloride
(10.0 g, 91 mmol) (Note
1)
and
dry dichloromethane (140
mL) (Note
2). The stirred suspension is cooled
to 0°C and solid
methyl glycinate hydrochloride
(11.5 g, 91 mmol, Note 1)
is added in one portion with a
powder funnel under a stream
of Ar. After the mixture is stirred for 45 min at 0°C, a solution of
dry triethylamine (12.7 mL, 91
mmol) (Note
2) in
dry
dichloromethane (11 mL) is added
via
syringe pump during 2.5 hr. Stirring is continued for 5
hr while the mixture is allowed to warm slowly to room temperature (Note
3).
Water (30 mL, pH 7 buffered) is added, giving a clear biphasic mixture (Note
4).
The phases are separated in a
250-mL separatory funnel, and
the aqueous phase is extracted with
dichloromethane
(2 × 15 mL). The combined organic phases are washed
with pH 7 buffered water (1 × 17 mL) and
brine (1
× 17 mL). After the organic solution is dried over
anhydrous magnesium sulfate, it is
filtered and concentrated under reduced pressure, leaving
11.50 g of the crude product as a colorless solid. Distillation
of this material (41 mm, 135°C) gives
10.10
g (
76%) of pure
methyl α-[(methoxyethylidene)amino]acetate
(1, Note 5).
B. Potassium
methyl α-[(methoxyethylidene)amino]-β-hydroxyacrylate (
2). A
flame-dried,
2-L, three-necked, round-bottomed flask is equipped with a
stir
bar,
rubber septum, and an
argon inlet.
The flask is charged with a solution of
potassium
tert-butoxide
(7.81 g, 70 mmol) (Note
1)
in
dry tetrahydrofuran (THF, 200
mL) (Note
2), and the solution is stirred
at −10°C for 15 min. A solution of
methyl
α-[(methoxyethylidene)amino]acetate (10.10 g, 70
mmol) and
methyl formate (5.0 mL,
84 mmol) (Note
1) in
dry
THF (50 mL) is added via a
syringe pump
during 20 min. After a further 5 min at −10°C,
dry
diethyl ether (750 mL) (Note
2)
is added via a
cannula, resulting in the formation of a yellowish
precipitate. Stirring is continued for 2 hr at 0°C and the cold solution is filtered
through a
Schlenk tube (Note
6) under
argon. The pale yellow filter cake is washed under
argon
with
dry diethyl ether (3 ×
40 mL), and the cake is dried under an
argon
stream and then under reduced pressure. The solid is transferred from the
Schlenk
tube to a
wide mouthed vessel under an
argon
atmosphere. The resultant crude
potassium
methyl α-[(methoxyethylidene)amino-β-hydroxyacrylate
(
2) is used directly for the next step (Note
7).
C. 4-Methoxycarbonyl-2-methyl-1,3-oxazole
(
3). A
flame-dried, 50-mL, two-necked, round-bottomed flask
is equipped with a
stir bar,
reflux condenser,
rubber septum, and an
argon inlet. The
flask is charged with
glacial acetic acid
(15 mL) which is heated to reflux. To this is added crude
potassium methyl α-[(methoxyethylidene)-amino]-β-hydroxyacrylate,
prepared above, in one portion with a
powder funnel. Material
which adheres to the wall of the funnel and the flask is washed into the mixture with
a stream of
acetic anhydride.
The mixture is stirred at reflux for 1.5 hr, then allowed to cool and carefully poured
into a
250-mL Erlenmeyer flask containing a saturated
aqueous solution of sodium bicarbonate (50
mL) (Note
7). The pH of the solution is adjusted
to 8 by further addition of solid
sodium bicarbonate
(Note
8). The solution is extracted with
dichloromethane
(4 × 30 mL), and the organic extract is dried over
anhydrous sodium sulfate,
filtered and concentrated under reduced pressure to give
4.48 g of crude product. This is purified by distillation
(41 mm, 150°C) to afford
3.74 g
(
38% from 1; Note
9) of
4-methoxycarbonyl-2-methyl-1,3-oxazole
(
3, Note
10).
2. Notes
3. After 2 hr the
ice-bath is no longer refilled
with fresh ice, allowing the mixture to warm to room temperature during the remaining
3 hr.
4. Stirring for 2 to 3 min is required for complete dissolution of
all precipitate.
5. The product is characterized by NMR spectroscopy:
1H NMR (400 MHz, CDCl
3) δ:
1.86 (s, 3 H), 3.66 (s, 3 H), 3.71 (s, 3 H),
4.03 (s, 2 H);
13C
NMR (100 MHz, CDCl
3) δ: 14.5, 50.6, 51.4,
52.2, 164.8, 171.1.
6. Compound
2 is very hygroscopic.
1H NMR (500 MHz, DMSO-d
6) δ:
1.60 (s, 3 H), 3.36 (s, 3 H), 3.49 (s, 3 H),
8.57 (s, 1 H).
8. Water (50 mL) is added to keep all inorganic salts dissolved.
9. The submitters found that the yield of
3 can be increased
to
58% if crude
2, obtained
in step B by rotary evaporation of the solvent (rather than filtration through a
Schlenk
tube followed by washing with
ether),
is taken directly into hot
glacial acetic acid
in step C. This procedure minimizes exposure of hygroscopic
2 to moisture.
These changes were not checked.
10. The product is characterized by NMR-spectroscopy:
1H NMR (400 MHz, (CDCl
3) δ:
2.31 (s, 3 H), 3.70 (s, 3 H), 7.97 (s, 1 H);
13C NMR (100
MHz, CDCl
3) δ: 13.5, 51.8, 133.0,
143.6, 161.4, 162.2.
3. Discussion
The method described for the preparation of
4-methoxycarbonyl-2-methyl-1,3-oxazole
is that of Cornforth,
2 and is widely
applicable to the synthesis of 2-substituted 1,3-oxazole-4-carboxylates.
3 The
appropriate imidate hydrochloride required for step A is obtained from the reaction
of a nitrile with an alcohol in the presence of
hydrochloric
acid (eq. 1).
4 A different
synthesis of 2-substituted 1,3-oxazole-4-carboxylates employing
rhodium-catalyzed
heterocycloaddition of a diazomalonate to a nitrile has been described in
Organic
Syntheses by Helquist,
5 but
appears to be less general than the present route.

New methods for the synthesis of 2,4-disubstitued oxazoles are summarized in a
recent review.
6 2-Alkyl-1,3-oxazoles bearing alkyl, aryl, or acyl
substitution at C4 are common substructures in natural products.
7 Examples
include macrolides such as
rhizoxin
(4),
8 hennoxazole A
(5),
9 and
phorboxazole
A (6),
10
as well as many cyclic peptides that incorporate an oxazole subunit presumably derived
from serine.
11
4-Methoxycarbonyl-2-methyl-1,3-oxazole
(3) is metalated exclusively at C5 with
n-butyllithium.
3 Selective functionalization at the methyl group of
3 can
be achieved with
N-bromosuccinimide
to yield the 2-bromomethyl derivative
8. The latter affords a route to 2,4-disubstituted
oxazoles that are not immediately accessible through the Cornforth synthesis. Thus,
8 undergoes displacement with
sodium phenylsulfinate
to give sulfone
9, which can then be transformed to aldehyde
10.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
4-Methoxycarbonyl-2-methyl-1,3-oxazole: 4-Oxazolecarboxylic
acid, 2-methyl-, methyl ester (11); (85806-67-3)
Methyl α-[(methoxyethylidene)amino]acetate: Glycine,
N-(1-methoxyethylidene)-, methyl ester (10); (64991-38-4)
Methyl acetimidate hydrochloride: Acetimidic
acid, methyl ester, hydrochloride (8); Ethanimidic acid, methyl
ester, hydrochloride (9); (14777-27-6)
Methyl glycinate hydrochloride: ALDRICH: Glycine
methyl ester hydrochloride: Glycine, methyl ester, hydrochloride
(8,9); (5680-79-5)
Triethylamine (8); Ethanamine, N,N-diethyl-
(9); (121-44-8)
Potassium methyl α-[(methoxyethylidene)amino]-β-hydroxyacrylate:
Propanoic acid, 2-[(1-methoxyethylidene)amino]-3-oxo-, methyl ester, ion(1−),
potassium (11); (105205-36-5)
Potassium tert-butoxide: tert-Butyl alcohol,
potassium salt (8); 2-Propanol, 2-methyl-, potassium salt
(9); (865-47-4)
Methyl formate: Formic acid, methyl ester
(8,9); (107-31-3)
Acetic acid (8,9); (64-19-7)
Acetic anhydride (8); Acetic acid, anhydride
(9); (108-24-7)
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