One-pot preparation of oxazol-5(4H)-ones from amino acids in aqueous solvents

Article abstract of DOI:10.1248/cpb.c12-00291

A method for one-pot synthesis of oxazol-5(4H)-ones has been developed using 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), which is available for the activation of carboxylic acids in an aqueous solvent. The oxazolones were prepared by the TV-acylation of amino acids with carboxylic acids and the subsequent cyclodehydration of the resulting N-acylamino acids by the addition of N,N-diethylaniline. Since both these reactions proceed effectively with the same coupling reagent, DMT-MM, in aqueous solvents, the procedure is simplified and becomes easy to perform. In addition, 5-(triazinyloxy)oxazole derivatives have been synthesized by controlling the basicity of the reaction system.

Full text of DOI:10.1248/cpb.c12-00291

July 2012
Regular Article
Chem. Pharm. Bull. 60(7) 907–912 (2012)
907
One-Pot Preparation of Oxazol-5(4H)-ones from Amino Acids in
Aqueous Solvents
Hikaru Fujita and Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa
University; Kakuma-machi, Kanazawa 920–1192, Japan. Received April 2, 2012; accepted April 23, 2012
A method for one-pot synthesis of oxazol-5(4H)-ones has been developed using 4-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), which is available for the activation of carboxylic
acids in an aqueous solvent. The oxazolones were prepared by the N-acylation of amino acids with carboxylic
acids and the subsequent cyclodehydration of the resulting N-acylamino acids by the addition of N,N-dieth-
ylaniline. Since both these reactions proceed effectively with the same coupling reagent, DMT-MM, in aque-
ous solvents, the procedure is simplified and becomes easy to perform. In addition, 5-(triazinyloxy)oxazole
derivatives have been synthesized by controlling the basicity of the reaction system.
Key words oxazolone; oxazole; dehydrocondensation; cyclodehydration; aqueous solvent
Oxazol-5(4H)-ones (henceforth referred to as oxazolones) method, we first examined each reaction separately using L-
are useful precursors for the synthesis of substituted heterocy- leucine (2a) as a model compound.10,11) After several attempts,
clic compounds,1) natural products,2) and chiral amino acids.3,4) we succeeded in finding the optimum reaction conditions for
In general, the preparation of oxazolones from amino acids the first reaction. Benzoic acid (1) was treated with DMT-MM
is effected by two-step synthesis: N-acylation of the amino in the presence of N-methylmorpholine (NMM) in acetone–
group followed by cyclodehydration involving the activation H2O (3:1) at room temperature for 15min; then an aqueous
of the carboxy group. The N-acylation of amino acids can solution of 2a and NaOH was added (Chart 1). As a result,
be carried out in an aqueous solvent, typically using Schot- N-benzoyl-L-leucine (3a) was obtained in a satisfactory yield
ten–Baumann conditions,5) while the cyclodehydration of the (91%). The addition of NaOH as a base was found to be es-
resulting N-acylamino acids to form oxazolones is performed sential to complete the coupling reaction.
under anhydrous conditions with dehydrating reagents, such
The second reaction needs to follow the final conditions of
as carbodiimides and acid anhydrides. Thus, these reactions the former reaction to achieve a one-pot reaction. Thus, at first
must be performed in separate vessels. If the latter reaction 3a was treated with DMT-MM in acetone–H2O (1:1) at room
occurs in an aqueous solvent, both reactions can be con- temperature in the presence of NMM (1.0eq), which is gener-
ducted in the same vessel using water-soluble amino acids as ated in the first reaction (Chart 2). Unfortunately, the desired
a starting compound. Therefore, the procedure for preparing 4-isobutyl-2-phenyl-oxazol-5(4H)-one (4a) was produced in
oxazolones becomes simplified. In this study, we focused only 28% yield, along with the generation of 4-isobutyl-2-
on 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium phenyl-5-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)oxazole (5a) in
chloride (DMT-MM)6) as a dehydrocondensing reagent be- 33% yield as a by-product, which was probably formed by the
cause the chemoselective activation of carboxy groups using base-catalyzed coupling between DMT-MM and 4a (Table 1,
DMT-MM efficiently proceeds even in an aqueous solvent.7) Entry 1). When the reaction was conducted in the absence of
We report here a one-pot method for the synthesis of oxazo- NMM, 4a was formed in a low yield (4%) with the recovery
lones from amino acids. In this method, DMT-MM is utilized of 3a (96%), and 5a was not formed at all, indicating that a
successfully for both the N-acylation of amino acids with base is essential for the completion of cyclodehydration.12–15)
carboxylic acids and the subsequent cyclodehydration of the
On the basis of the assumption that the yield of oxazole de-
rivative 5a could be decreased by the separation of relatively
lipophilic 4a from water-soluble DMT-MM, we conducted the
reaction in a biphasic solvent system composed of CH2Cl2–
resulting N-acylamino acids.8,9)
Results and Discussion
To find the optimum reaction conditions for the one-pot acetone–H2O (1:1:1). As a result, the yield of 5a decreased
Chart 1. N-Benzoylation of L-Leucine (2a) in Acetone/H2O
The authors declare no conflict of interest.
*To whom correspondence should be addressed. e-mail: kunisima@p.kanazawa-u.ac.jp
© 2012 The Pharmaceutical Society of Japan

908
Vol. 60, No. 7
The reaction products in the parentheses are eliminated from the following reaction balances.
Chart 2. Reaction Balances for the Reactants and the Products in Every Step of the Reactions
to 15%, and the desired 4a was obtained in 68% yield (En- completion of the N-acylation of 2a (rt, 4.5h), CH2Cl2 and
try 2). Furthermore, the yield of 4a increased and that of 5a DEA hydrochloride (DEA·HCl, 1.3eq) were added to the
decreased by employing organic bases weaker than NMM reaction mixture. Then, the second reaction was started by
(pKa=7.41).16–19) The best result was obtained with N,N-dieth- the addition of DMT-MM (1.1eq) to the resulting biphasic
ylaniline (DEA; pKa=6.56) giving 4a in 78% and 5a in 1% mixture. The desired 4a was obtained in 71% yield along with
yields (Entry 4). Interestingly, the reaction was not improved a small amount of 5a (2% yield). As illustrated in Chart 2, the
by the use of an inorganic base, NaHCO3, despite having the addition of DEA·HCl was intended to recreate the conditions
lowest pKa value (6.37) among the bases examined (Entry 5). corresponding to those of Table 1, Entry 4, by replacing the
Compared with yields in the biphasic solvent system, when N-methylmorpholinium ion, which is the counter cation of the
the reaction using DEA was performed in the monophasic sol- carboxylate anion of 3a, with the N,N-diethylanilinium ion. In
vent of acetone–H2O (1:1), the yield of 4a decreased slightly addition, the free NMM that arises from the reaction of DMT-
and that of 5a increased slightly (Entry 4 vs. 6). Consequently, MM and the carboxylate anion of 3a can be converted into
we employed the reaction conditions of Entry 4 for the sec- NMM·HCl by the liberation of the free DEA. The resulting
ond reaction, where DEA was used as a base in the biphasic NMM·HCl can no longer act as a base to deprotonate from
CH2Cl2–acetone–H2O (1:1:1).
Next, we attempted to prepare oxazolone 4a directly
4a.
We succeeded in preparing various oxazolones 4 from ami-
from amino acid 2a by utilizing the one-pot method under no acids under the described optimum conditions. As shown
the optimum reaction conditions described above. After the in Table 2, oxazolones (4a–4f) with a lipophilic substituent
Table 1. Cyclodehydration of 3a under Various Conditions
Entry
Base (pKa)
Solvent
Reaction time (h)
Yield of 4aa) (%)
Yield of 5aa) (%)
1
2
NMM (7.41)16)
NMM (7.41)16)
Acetone–H2O (1:1)
2
5
28
68
33
15
CH2Cl2–acetone–H2O
(1:1:1)b)
3
4
5
6
2,6-Lutidine (6.96)17)
DEA (6.56)18)
CH2Cl2–acetone–H2O
(1:1:1)b)
5
5
5
2
77
78
66
71
8
1
CH2Cl2–acetone–H2O
(1:1:1)b)
NaHCO3 (6.37)19)
CH2Cl2–acetone–H2O
(1:1:1)b)
16
6
DEA (6.56)18)
Acetone–H2O (1:1)
1
a) The yields were determined by H-NMR using (E)-N,N-dimethylcinnamamide as an internal standard. b) Biphasic solvent system.

July 2012
909
at the 4-position (R2) were obtained in fairly good yields synthesis of 2,4-disubstituted-5-(4,6-dimethoxy-1,3,5-triazin-2-
(71–79%, Entries 1–6). On the other hand, reactions of rela- yloxy)oxazoles 5 by modifying the present one-pot method.
tively high water-soluble alanine and glycine were found to af- As described above, the conversion of oxazolones 4 to oxa-
ford low yields (4g: 37%, 4i: 35%; Entries 7 and 10). The yield zoles 5 could be promoted by the deprotonation of 4 or their
of 4g was improved to 54% by shortening the reaction time in enol form with a strong base. Thus, we conducted the second
the second reaction (Entry 7 vs. 8). The yield of 4i increased reaction without the addition of DEA·HCl using two or more
moderately by the use of 2.5eq of DMT-MM coupled with a equivalents of DMT-MM. As shown in Chart 3, oxazole de-
lesser reaction time (Entry 10 vs. 11). In addition, the yield of rivatives 5b and 5c were successfully obtained in 80% and
4-methyloxazolone (4g) was improved by replacing the 2-phe- 57% yields, respectively. Thus, DMT-MM plays three roles
nyl group with a more lipophilic 1-naphthyl group (4h, Entry in the synthesis of 5. Although similar reactions giving oxa-
7 vs. 9). In view of these results, the low yields of 4g and 4i zoles possessing the tert-butoxycarbonyloxy,25) diphenylphos-
can be attributed to the hydrolysis of the intermediates arising phoryloxy, or N,N,N′,N′-tetramethylamidiniooxy26) group at
from them because of their relatively high water-solubility.
the 5-position have been reported in the cyclodehydration of
Because oxazol-5(4H)-ones bearing a hydrogen at the 4-po- N-acylamino acids with (Boc)2O, diphenyl chlorophosphate
sition readily undergo tautomerization to the corresponding (DPCP), or chloro-N,N,N′,N′-tetramethylformamidinium chlo-
oxazoles,20,21) 4-monosubstituted oxazolones are generally ride, respectively, these reactions did not occur in aqueous sol-
obtained as a racemic mixture even though they are prepared vents. The reaction for the synthesis of O-Boc-oxazoles could
from optically active amino acids. In most cases, however, not be stopped at the oxazolones forming stage. In marked
such racemic mixtures can be utilized in subsequent reac- contrast, our present synthesis enables the selective formation
tions.1–4,21) In our case, 4b was obtained as a diastereomeric of either oxazolones or oxazoles.
1
mixture (d.r.=1:1, determined by H-NMR), which is con-
sistent with the general tendency of oxazolones to racemize,
and thus, other oxazolones were probably also produced as
racemic mixtures.
Conclusion
In conclusion, we have succeeded in developing a one-
pot method for the synthesis of oxazolones or oxazoles from
Finally, because oxazoles are also an important class of amino acids using DMT-MM. This method is applicable to
heterocyclic compounds,22–24) we attempted the preferential various kinds of amino acids and provides convenient access
Table 2. One-Pot Synthesis of the Oxazolones 4 Using DMT-MM in Aqueous Solvents
Reaction time (h)
Time 1a) Time 2b)
4.5
Yield (%)c)
Oxazole
Entry
Product number
R1
Ph
Ph
Ph
Ph
Amino acid
L-Leucine
R2
Oxazolone
derivative
1
2
3
4
4a
4b
4c
4d
5
4
4
6
71
2
L-Isoleucine
L-Valine
10
79d)
76
nd
nd
3
7.5
8
L-Phenylalanine
75
5
6
4e
4f
Ph
Ph
L-Methionine
L-Tryptophan
6.5
3
4.5
8
73
71
nd
4
7
8
4g
Ph
L-Alanine
L-Alanine
L-Alanine
Glycine
–Me
–Me
–Me
–H
12.5
30
8
37
54
53
35
41
2
3
1
2
5
4ge)
4h
4i
Ph
1-Naphthyl
Ph
2
9
109
6
10
11
25
9
6
4ie)
Ph
Glycine
–H
2.5
a) The reaction time for the first reaction (N-acylation). b) The reaction time for the second reaction (cyclodehydration). c) Yields were determined by 1H-NMR. All the
crude reaction mixtures found to contain an activated triazinyl ester of starting carboxylic acids in a range of 4% (Entry 10) to 11% (Entry 1). d) A mixture of the diastereo-
meric isomers (d.r.=1:1). e) An excess (2.5eq) of DMT-MM was used for the cyclodehydration.

910
Vol. 60, No. 7
The oxazolones were purified by column chromatography
for analysis, with some losses.
1
IR, MS, and H-NMR spectra of all oxazolones were con-
sistent with the literature.
4-Isobutyl-2-phenyloxazol-5(4H)-one (4a)5,6,20,27): Colorless
1
°
crystals. mp 55–57 C. H-NMR (CDCl3) δ: 8.02–7.98 (2H, m),
7.61–7.46 (3H, m), 4.42 (1H, dd, J=5.5, 9.0Hz), 2.07 (1H, m),
1.89–1.80 (1H, m), 1.73–1.64 (1H, m), 1.04 (3H, d, J=6.5Hz),
1.01 (3H, d, J=6.5Hz). IR (CHCl3) cm−1: 1824, 1655. High
resolution (HR)-MS (EI) m/z: 217.1111 [Calcd for C13H15NO2:
217.1097 (M+)].
4-[(1S)-1-Methylpropyl]-2-phenyl-oxazol-5(4H)-one (4b)5):
Colorless oil (a mixture of diastereomers, whose ratio was
found to be changed from 1:1 to 9:10 [=(SS):(RS)], after
1
purification by silica-gel column chromatography). H-NMR
(CDCl3) for the SS isomer: δ: 8.03–7.99 (2H, m), 7.60–7.55
(1H, m), 7.52–7.46 (2H, m), 4.37 (1H, d, J=4.7Hz), 2.20–2.09
(1H, m), 1.62–1.52 (1H, m), 1.44–1.34 (1H, m), 1.07 (3H, d,
1
J=6.9Hz), 0.97 (3H, t, J=7.4Hz). H-NMR (CDCl3) for the
a) i) DMT-MM (1.05eq), N-methylmorpholine (0.20eq), acetone/H2O (3:1),
RS isomer δ: 8.03–7.99 (2H, m), 7.60–7.55 (1H, m), 7.52–7.46
(2H, m), 4.42 (1H, d, J=4.0Hz), 2.20–2.09 (1H, m), 1.75–1.64
(1H, m), 1.52–1.40 (1H, m), 1.02 (3H, t, J=7.3Hz), 0.91 (3H,
d, J=6.9Hz). IR (CHCl3) cm−1: 1820, 1653. HR-MS (EI) m/z:
217.1107 [Calcd for C13H15NO2: 217.1103 (M+)].
rt, 15min; ii) L-alanine (1.1eq), NaOH (1.1eq), acetone/H2O (1:1), rt, 13h; iii)
DMT-MM (3.5eq), N-methylmorpholine (2.0eq), CH2Cl2/acetone/H2O (1:1:1),
rt, 6h, 80%. b) i) DMT-MM (1.05eq), N-methylmorpholine (0.20eq), acetone/
H2O (3:1), rt, 15min; ii) DL-2-phenylglycine (1.1eq), NaOH (1.1eq), acetone/H2O
(1:1), rt, 60h; iii) DMT-MM (2.1eq), CH2Cl2/acetone/H2O (1:1:1), rt, 2h, 57%.
Chart 3. One-Pot Synthesis of Oxazole Derivatives
4-Isopropyl-2-phenyloxazol-5(4H)-one (4c)5,6,20,27)
:
Color-
°
to synthetically useful oxazolones.
less crystals. mp 49–52 C. 1H-NMR (CDCl3) δ: 8.04–8.00
(2H, m), 7.61–7.55 (1H, m), 7.52–7.47 (2H, m), 4.30 (1H, d,
J=4.7Hz), 2.46–2.33 (1H, m), 1.15 (3H, d, J=7.0Hz), 1.03 (3H,
Experimental
General Methods 1H-NMR spectra were recorded on a d, J=7.0Hz). IR (CHCl3) cm−1: 1820, 1655. HR-MS (EI) m/z:
JEOL JNM-ECS400 and a JNM-ECS600 spectrometer. 13C- 203.0943 [Calcd for C12H13NO2: 203.094 (M+)].
NMR spectra were recorded on a JEOL JNM-ECS400 spec-
4-Benzyl-2-phenyloxazol-5(4H)-one (4d)5,6,14,20,27)
:
White
1
°
trometer. Chemical shifts are reported as δ values relative to solid. mp 72–74 C. H-NMR (CDCl3) δ: 7.94–7.90 (2H, m),
tetramethylsilane as internal standard. Infrared spectra were 7.57–7.52 (1H, m), 7.48–7.42 (2H, m), 7.29–7.17 (5H, m), 4.69
recorded on a HORIBA FT-720 FREEXACT-II spectrom- (1H, dd, J=5.0, 7.0Hz), 3.37 (1H, dd, J=5.0, 14.0Hz), 3.19
eter. Mass spectra were measured on a JEOL JMS-SX102A (1H, dd, J=7.0, 14.0Hz). IR (CHCl3) cm−1: 1821, 1657. HR-MS
(electron ionization (EI)-MS and FAB-MS) spectrometer. El- (EI) m/z: 251.0949 [Calcd for C16H13NO2: 251.0941 (M+)].
emental analyses were carried out with a Yanaco CHN Corder
MT-5 instrument.
4-[2-(Methylsulfanyl)ethyl]-2-phenyloxazol-5(4H)-one
1
(4e)5,20): Colorless oil. H-NMR (CDCl3) δ: 8.02–7.98 (2H, m),
DMT-MM was prepared from 2-chloro-4,6-dimethoxy- 7.61–7.56 (1H, m), 7.52–7.46 (2H, m), 4.61 (1H, dd, J=6.0,
1,3,5-triazine (CDMT) and N-methylmorpholine according to 7.5Hz), 2.74 (2H, t, J=7.1Hz), 2.37–2.27 (1H, m), 2.20–2.09
the literature procedure.6) N,N-Diethylaniline hydrochloride (1H, m), 2.12 (3H, s). IR (CHCl3) cm−1: 1828, 1653. HR-MS
was prepared from N,N-diethylaniline and concentrated HCl. (EI) m/z: 235.0661 [Calcd for C12H13NO2: 235.0662 (M+)].
Other chemicals were obtained from commercial sources and
used as received unless otherwise noted.
4-[(1H-Indol-3-yl)methyl]-2-phenyloxazol-5(4H)-one (4f)5):
1
°
Colorless crystals. mp 148–149 C. H-NMR (CDCl3) δ: 8.01
General Procedure for Preparation of Oxazolones (1H, brs), 7.91–7.86 (2H, m), 7.74–7.70 (1H, m), 7.55–7.49 (1H,
DMT-MM (0.525mmol) was added to a solution of carbox- m), 7.45–7.39 (2H, m), 7.32–7.28 (1H, m), 7.18–7.09 (3H, m),
ylic acid (0.500mmol) and N-methylmorpholine (0.10mmol) 4.76 (1H, dd, J=5.0, 6.1Hz), 3.53 (1H, dd, J=5.0, 14.8Hz),
in acetone/H2O (1.67mL:0.56mL) at room temperature. After 3.41 (1H, dd, J=6.1, 14.8Hz). IR (CHCl3) cm−1: 1817, 1655.
stirring 15–30min, a solution of amino acid (0.550mmol) and HR-MS (EI) m/z: 290.1057 [Calcd for C18H14N2O2: 290.1050
sodium hydroxide (0.55mmol) in water (1.11mL) was added, (M+)].
and the mixture was stirred at room temperature. After the
4-Methyl-2-phenyloxazol-5(4H)-one (4g)5,6,14,20,27)
:
White
reaction was completed (monitored by TLC), dichloromethane solid. mp 44 C. 1H-NMR (CDCl3) δ: 8.03–7.98 (2H, m),
(1.67mL), N,N-diethylaniline hydrochloride (0.650mmol) and 7.61–7.56 (1H, m), 7.53–7.47 (2H, m), 4.46 (1H, q, J=7.6Hz),
DMT-MM (0.550mmol) were added in order, and the mixture 1.60 (3H, d, J=7.6Hz). IR (CHCl3) cm−1: 1817, 1655. HR-MS
was stirred for 2–8h at room temperature. The reaction mix- (EI) m/z: 175.0635 [Calcd for C10H9NO2: 175.0628 (M+)].
°
ture was poured into an organic solvent (hexane, EtOAc, or
4-Methyl-2-(naphthalen-1-yl)oxazol-5(4H)-one (4h)5): White
hexane/EtOAc) (30mL), successively washed with water twice solid. mp 87–88 C. 1H-NMR (CDCl3) δ: 9.26 (1H, d,
(30, 10mL), aqueous 1M HCl twice (30, 10mL), water (10mL), J=8.8Hz), 8.17 (1H, dd, J=1.2, 8.1Hz), 8.05 (1H, d, J=8.1Hz),
saturated aqueous NaCl (10mL). The organic layer was dried 7.92 (1H, d, J=8.0Hz), 7.69–7.64 (1H, m), 7.61–7.54 (2H, m),
over MgSO4, filtered, and the solvent was evaporated under 4.62 (1H, q, J=7.5Hz), 1.69 (3H, d, J=7.9Hz). IR (CHCl3)
°
reduced pressure to give oxazolone 4a–i.
cm−1: 1817, 1647. HR-MS (EI) m/z: 225.0789 [Calcd for

July 2012
911
C14H11NO2: 225.0790 (M+)].
After stirring 15min,
a
solution of DL-2-phenylglycine
2-Phenyloxazol-5(4H)-one (4i)14,27): Colorless crystals. mp (83.1mg, 0.550mmol) and sodium hydroxide (0.55mmol) in
1
°
89–90 C. H-NMR (CDCl3) δ: 8.02–7.98 (2H, m), 7.62–7.56 water (1.11mL) was added, and the mixture was stirred for
(1H, m), 7.53–7.47 (2H, m), 4.43 (2H, s). IR (CHCl3) cm−1: 60h at room temperature. Dichloromethane (1.67mL) and
1826, 1655. HR-MS (EI) m/z: 161.0479 [Calcd for C9H7NO2: DMT-MM (290.6mg, 1.05mmol) were added in order, and the
161.0477 (M+)].
Synthesis
mixture was stirred for 2h at room temperature. The reac-
of
N-Benzoyl-leucine
(3a)5) DMT-MM tion mixture was poured into hexane–EtOAc (15mL:15mL),
(145.2mg, 0.525mmol) was added to a solution of benzoic acid successively washed with water twice (30, 10mL), aqueous
1a (61.1mg, 0.500mmol) and N-methylmorpholine (10.1mg, 1M HCl (30mL), water (10mL), saturated aqueous NaHCO3
0.10mmol) in acetone/H2O (1.67mL:0.56mL) at room temper- (30mL), water (10mL), saturated aqueous NaCl (10mL). The
ature. After stirring 15min, a solution of L-leucine (72.3mg, organic layer was dried over MgSO4, filtered, and the solvent
0.551mmol) and sodium hydroxide (0.55mmol) in water was evaporated under reduced pressure. The residue was puri-
(1.11mL) was added, and the mixture was stirred for 12h at fied by column chromatography (silica gel, hexane–EtOAc=
room temperature. EtOAc (30mL) was added to the reaction 9:1) to give oxazole derivative 5c (106.6mg, 57%) as color-
1
°
mixture and extracted with saturated aqueous NaHCO3 four less crystals. mp 125 C. H-NMR (CDCl3) δ: 8.09–8.02 (2H,
times. The combined aqueous phase was acidified with 6M m), 7.85–7.81 (2H, m), 7.50–7.45 (3H, m), 7.43–7.37 (2H, m),
aqueous HCl to pH 1–2, and extracted with CHCl3 (10mL) 7.32–7.27 (1H, m), 4.00 (6H, s). 13C-NMR (CDCl3) δ: 174.0,
six times. The combined organic layer was washed with 172.4, 155.1, 145.7, 130.4, 129.9, 128.7, 128.6, 127.8, 127.1,
saturated aqueous NaCl (10mL), dried over MgSO4, filtered, 126.1, 125.8, 123.8, 55.9. IR (CHCl3) cm−1: 1601, 1556. HR-
and the solvent was evaporated under reduced pressure. The MS (FAB) m/z: 377.1254 {(Calcd for C20H17N4O4+: 377.1244
resultant solid was recrystallized from hexane–CHCl3 to give [(M+H)+]}. Anal. Calcd for C20H16N4O4: C, 63.82; H, 4.28; N,
1
3a (107.4mg, 91%) as colorless crystals. H-NMR (DMSO- 14.89. Found: C, 63.72; H, 4.30; N, 14.85.
d6) δ: 12.57 (1H, brs), 8.60 (1H, d, J=8.0Hz), 7.91–7.86 (2H,
2-(4-Isobutyl-2-phenyloxazol-5-yloxy)-4,6-dimethoxy-
m), 7.58–7.52 (1H, m), 7.51–7.44 (2H, m), 4.48–4.40 (1H, m), 1,3,5-triazine (5a) Colorless oil. 1H-NMR (CDCl3) δ:
1.83–1.62 (2H, m), 1.62–1.54 (1H, m), 0.92 (3H, d, J=6.5Hz), 7.98–7.93 (2H, m), 7.46–7.40 (3H, m), 4.02 (6H, s), 2.36 (2H,
0.87 (3H, d, J=6.5Hz). IR (CHCl3) cm−1: 3440, 1726, 1660, d, J=7.4Hz), 2.06 (1H, m), 0.94 (6H, d, J=6.9Hz). IR (CHCl3)
1518. HR-MS (FAB) m/z: 236.1298 {Calcd for C13H18NO3+: cm−1: 1599, 1558. HR-MS (FAB) m/z: 357.1565 {Calcd for
236.1281 [(M+H)+]}. Consistent with data reported in the lit- C18H21N4O4+: 357.1557 [(M+H)+]}.
erature. The optical purity of the product was not confirmed.
Synthesis of 2-(4-Methyl-2-phenyloxazol-5-yloxy)-4,6-
Acknowledgement This work was supported partially by
dimethoxy-1,3,5-triazine (5b) DMT-MM (145.2mg, a Grant-in-Aid for Scientific Research (No. 20390007) from
0.525mmol) was added to a solution of benzoic acid 1a Japan Society for the Promotion of Science (JSPS).
(61.1mg, 0.500mmol) and N-methylmorpholine (10.1mg,
0.10mmol) in acetone–H2O (1.67mL:0.56mL) at room
temperature. After stirring 15min, a solution of L-alanine
(49.0mg, 0.550mmol) and sodium hydroxide (0.55mmol)
in water (1.11mL) was added, and the mixture was stirred
for 13h at room temperature. Dichloromethane (1.67mL),
N-methylmorpholine (110µL, 1.00mmol) and DMT-MM
(484.2mg, 1.75mmol) were added in order, and the mixture
was stirred for 6h at room temperature. The reaction mix-
ture was poured into EtOAc (30mL), successively washed
with water twice (30, 10mL), aqueous 1M HCl (30mL), water
(10mL), saturated aqueous NaHCO3 (30mL), water (10mL),
saturated aqueous NaCl (10mL). The organic layer was dried
over MgSO4, filtered, and the solvent was evaporated under
reduced pressure. The residue was purified by column chro-
matography (silica gel, hexane–EtOAc=4:1) to give oxazole
References and Notes
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°
derivative 5b (125.8mg, 80%) as a white solid. mp 101–103 C.
1H-NMR (CDCl3) δ: 7.98–7.92 (2H, m), 7.47–7.40 (3H, m),
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Synthesis of 2-(2,4-Diphenyloxazol-5-yloxy)-4,6-dime-
thoxy-1,3,5-triazine (5c) DMT-MM (145.3mg, 0.525mmol)
was added to a solution of benzoic acid 1a (61.1mg,
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1

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Vol. 60, No. 7
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