Novel and efficient synthesis of 2-aminooxazoles from pyrimidin-2(1H)-one

Article abstract of DOI:10.1055/s-2006-958941

Stepwise conversion of pyrimidin-2(1H)-one to 2-amino-5-aryloxazoles via oxazolo[3,2-a]pyrimidinium salts is reported. The sequence involves, (i) regioselective N-alkylation of pyrimidone by phenacyl bromides, (ii) cyclization of obtained 1-(2-aryl-2-oxoethyl)pyrimidin-2(1H)-ones into oxazolo[3,2-a] pyrimidinium salts under the action of fuming sulfuric (or triflic) acid, and (iii) reaction of the obtained salts with hydrazine leading to 2-amino-5-aryloxazoles. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958941

PAPER
263
Novel and Efficient Synthesis of 2-Aminooxazoles from Pyrimidin-2(1H)-one
Vadim L. Alifanov, Eugene V. Babaev*
Chemistry Department, Moscow State University, Moscow 119992, Russian Federation
Fax +7(495)9393020; E-mail: babaev@org.chem.msu.su
Received 21 August 2006; revised 18 October 2006
done 1. The overall sequence shown in Scheme 2 has
Abstract: Stepwise conversion of pyrimidin-2(1H)-one to 2-ami-
never been realized, although some related reactions have
been briefly discussed in the literature.
no-5-aryloxazoles via oxazolo[3,2-a]pyrimidinium salts is report-
ed. The sequence involves, (i) regioselective N-alkylation of
pyrimidone by phenacyl bromides, (ii) cyclization of obtained 1-(2-
aryl-2-oxoethyl)pyrimidin-2(1H)-ones into oxazolo[3,2-a]pyrimi-
dinium salts under the action of fuming sulfuric (or triflic) acid, and
(iii) reaction of the obtained salts with hydrazine leading to 2-ami-
N-Phenacylation of Pyrimidin-2(1H)-one (1)
no-5-aryloxazoles.
The reaction of 2-pyrimidone 1 and its derivatives with a-
Key words: fused ring systems, ring closure, ring opening, ox-
azoles, protecting groups
halogenocarbonyl compounds is poorly investigated in
the literature. There are only two examples of phenacyla-
tion in the 2-pyrimidone series, namely for 5-chloro-4-
phenyl-2-pyrimidone2 and the sterically hindered 4,6-
In our previous investigation1 we described a simple route
to 5-aryloxazoles IVa bearing a w-aminodienyl residue by
ring opening of bicyclic oxazolo[3,2-a]pyridinium salts
IIIa (Scheme 1), which in turn can easily be obtained
from 2-pyridone Ia via N-phenacyl-2-pyridones IIa. The
overall simplicity of this methodology to obtain a substi-
tuted five-membered azole (like IVa) from a six-mem-
bered azine Ia via bridgehead azolo-azine IIIa (rarely
used in heterocyclic synthesis) stimulated our interest to
expand this strategy to the related family of pyrimidine
derivatives. The retrosynthetic sequence of the suggested
conversions is shown on Scheme 2.
dimethyl-2-pyrimidone.3 Regarding the parent pyrimi-
done 1 only reactions with diethylacetal of bromo-
acetaldehyde4 and chloroacetic acid derivatives5 have
been studied. In all these cases exclusive formation of the
N-alkyl isomer was observed. Several 4-aryl-N-phenacyl-
2-pyrimidones were prepared from a-aminoketones by an
alternative strategy, not involving the alkylation step.6
Earlier examined alkylation reactions were carried out in
bipolar aprotic solvents with pyrimidone alkali salts. We
studied phenacylation of 1 in two different ways: using
K2CO3 as the base (Method A) and starting from the ini-
tially prepared sodium salt of 1 (Method B). Various
phenacyl bromides have been used (Scheme 3, Table 1),
and in all cases the N-phenacyl derivatives 2a–h were the
only products obtained in high yields.
One would expect that similar transformations starting
from pyrimidin-2(1H)-one (1, 2-pyrimidone) and involv-
ing N-phenacyl derivatives IIb and oxazolo[3,2-a]pyrim-
idinium salts IIIb may lead to unstable oxazolyl-
substituted aza-dienes IVb, which, therefore, could be
precursors of 2-aminooxazoles V. In this communication
we confirm this idea and report our first successful prepa-
ration of 5-aryl-2-aminoxazoles V starting from pyrimi-
In the IR spectra of 2a–h two types of bands for CO group
were observed, one for N–C=O fragment of pyrimidone
(~1660 cm–1) and another one for carbonyl group (~1700
cm–1), thus clearly confirming selective N-alkylation.
(Evidently, in the case of O-phenacylation one would ex-
O
H2SO4
O
ArCOCH2Br
O
NR2H
O
Ar
Ar
N+
N
O
N
N
Ar
H
IIa
IIIa
IVa
Ia
NR2
Scheme 1
N
O
N
N
O
H2N
O
N
O
O
Ar
Ar
Ar
N+
N
N
N
Ar
O
N
H
V
NR2
IIIb
IVb
IIb
1
Scheme 2
SYNTHESIS 2007, No. 2, pp 0263–0270
Advanced online publication: 14.12.2006
DOI: 10.1055/s-2006-958941; Art ID: Z16706SS
© Georg Thieme Verlag Stuttgart · New York

264
V. L. Alifanov, E. V. Babaev
PAPER
Cl
Ar
ArCOCH2Br
O
N
N
Ar
N
R2N+
O
Method A:
K2CO3/Me2CO, r.t., 2 d
Method B:
MeONa/MeOH; then
ArCOCH2Br, Me2CO, reflux, 2 h
R
R
N
H
O
NCH2COPh
N
O
O
NH
VI
KSCN,
NH2Ch2COPh
1
2a–h
Ar
Ac2O/HClO4
O
Scheme 3
Table 1 N-Phenacyl-2-pyrimidones 2a–h Prepared
S
Ar
N
N
Ar
MeI, py
Ph
NCH2COPh
N+
VIII
VII
Compound
Ar
Method
Yield (%)
Scheme 4
2a
2b
2c
2d
2e
2f
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-NO2C6H4
3-NO2C6H4
Ph
A
A
B
B
B
A
A
A
90
95
60
65
63
79
81
70
1
however, were not the desired bicyclic salts. In the H
NMR spectra of the products the singlet of NCH2-group
remained unchanged, and the general downfield shift of
all peaks confirmed that the products were protonated
starting materials 2 (Scheme 5). Bradsher had reported9
that sulfuric acid could be a suitable dehydration agent for
analogous cyclization in the pyridone series (IIa to IIIa).
However, our attempts to use H2SO4 or PPA for cycliza-
tion of pyrimidones 2 also led to the salts of starting com-
pounds.
2g
2h
4-MeC6H4
4-MeOC6H4
NH+
O
(i) or (ii),(iii) or (iv),(iii)
pect no amide frequencies.) The structure of compound 2a
(and the regioselectivity of alkylation) was confirmed by
single crystal X-ray analysis (Figure 1).
Ar
N
O
N
O
(i) HClO4/Ac2O; (ii) H2SO4;
(iii) H2O/HClO4; (iv) PPA;
(v) H2SO4*SO3; (vi) CF3SO3H/P2O5
Ar
N
O
2a–h
(v),(iii) for 2a–h
(vi), (iii) for 3g–h
N
O
Ar
N+
3a–f for (v)
3f,g for (vi)
Scheme 5
Figure 1 X-ray crystal structure of the compound 2a
Nevertheless, fuming sulfuric acid (20–30 mass% of SO3)
turned out to be the reagent of choice, and its use resulted
in the formation of the desired salts 3a–e (Scheme 5) in
excellent yields (Table 2, Method A).
Cyclization of N-Phenacyl-2-pyrimidones 2 to
Oxazolo[3,2-a]pyrimidinium Salts 3
Table 2 2-Aryloxazolo[3,2-a]pyrimidinium Perchlorates 3a–g
Prepared
Aromatic oxazolo[3,2-a]pyrimidinium cation with
bridgehead nitrogen atom could be prepared by two dif-
ferent ways, either from oxazole or from pyrimidine, and
both strategies have been realized. The first approach is
illustrated by condensation of 4,5-disubstituted 2-amino-
oxazoles with acetylacetone7 leading to 5,7-dimethyl-
oxazolo[3,2-a]pyrimidinium salts. The alternative way
(Scheme 4) involved cyclization of hardly available N-
phenacyl-2-pyrimidones VI (by using somewhat unsafe
combination of Ac2O and HClO4) or their thione precur-
sors VII, leading to 2,7-diaryl-substututed salts VIII.6,8
Compound
Ar
Method
Yield (%)
3a
3b
3c
3d
3e
3f
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-NO2C6H4
3-NO2C6H4
Ph
A
A
A
A
A
A
B
B
90
85
83
80
87
55
79
75
We have tried to perform the cyclization of N-phenacyl-2-
pyrimidones 2 using the above protocol6 in a mixture of
Ac2O and HClO4. The isolated crystalline substances,
3f
Ph
3g
4-MeC6H4
Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aminooxazoles
265
The salts 3 could be easily isolated as perchlorates. The ter – the second nitrogen atom in the ring. As we have
singlet of CH2 group at 5.4 ppm (initially observed in par- seen, use of H2SO4, PPA or HClO4–Ac2O systems led
1
ent N-phenacyl-2-pyrimidones) disappeared in the H only to the salts of 2, whereas the use of stronger acids (su-
NMR spectra of the salts 3, and new downfield singlet of per acids) like H2SO4–SO3 or CF3SO3H resulted in suc-
formed oxazole ring appeared at 9.24–9.59 ppm. Respec- cessful cyclization. This may indicate that the real
tively, in the 13C spectra the signal for the methylene cyclization mechanism requires somewhat unusual as-
group observed for phenacyl derivatives 2 (at ~55 ppm) is sumption on the formation of dications IX as the reaction
changed to aromatic oxazole signal (at 110–115 ppm) for intermediates (Scheme 6).
3. Final confirmation of the structural change followed
from X-ray structure analysis of the crystal of compound
3
2
3b (Figure 2).
"usual"
acid
H2O
CF3SO3H
H
N+
H
N+
O
O
Ar
Ar
N+
N
O
double
protonation
super-
acid
IXc
dehydratation
H
N+
H
N+
O
OH
O
cyclization
Ar
Figure 2 X-ray crystal structure of the compound 3b
Ar
+
N+
H
N
OH
IXa
H
In the case of N-phenacyl-2-pyrimidones 2g,h with donor
groups (4-Me or 4-MeO) in the benzene ring, the obtained
products were insoluble in most solvents and had high
melting points, so it was difficult to prove their structures.
We suppose that in these cases SO3 caused sulfonation of
the benzene ring. (Analogous sulfonation was observed
during the attempts to prepare oxazolopyridinium salts
from electron rich phenacyl pyridones in sulfuric acid,9
that is even a weaker sulfonation media than oleum.) In
the case of N-phenacyl derivative 2f (unsubstituted at ben-
zene ring) partial sulfonation was also observed, however,
decrease of temperature and using DMSO for purification
has allowed us to obtain 2-phenyl derivative 3f pure.
IXb
Scheme 6
As an indirect proof of this hypothesis, one could consider
the changes in the color of reaction mixtures: usual acids
caused no changes, whereas super acids brought to solu-
tions bright (yellow to red) colors. The same colors ap-
peared when the final solid perchlorates 3 were dissolved
in triflic acid.
Conversion of Oxazolo[3,2-a]pyrimidinium Salts 3 to
In order to avoid the sulfonation problem, we have tried to
perform cyclization of SO3-sensitive compounds 2f–h in
a mixture of triflic acid and P2O5 (Scheme 5). In this case
the desired salts 3f,g were obtained in good yields
(Table 2, Method B), whereas the compound 2h decom-
posed completely.
2-Amino-5-aryloxazoles 4
Although the structures of the type 3 are known for de-
cades, there are no examples of their reactions with nu-
cleophiles. We found that in reactions with hydrazine
bicyclic salts 3a–g underwent selective cleavage of the
pyrimidine fragment leading with excellent yields to 2-
amino-5-aryloxazoles 4a–g (Scheme 7, Table 3). Al-
though hydrazinolysis of structurally related oxazolopyri-
dinium salt IIIa led to the cleavage and transformation of
oxazole part,11 in the case of the salts 3 there is no evi-
dence for ambident properties of the bicycle.
Melting points and 1H NMR spectral data of the aminoox-
azoles 4a,b,d,f,g correspond to literature data, and for pre-
viously unknown compound 4c,e we obtained satisfactory
data of elementary analysis. Structure of most oxazoles 4
was confirmed by 13C NMR spectra and mass spectra
(which are absent in the literature), and the structure 4b
was proved by X-ray analysis (Figure 3).
Cyclization Mechanism
The formation of fused oxazoles 3 from 2 resembles clo-
sure of N-acyl-a-aminocarbonyl compounds to oxazoles
(known as Robinson–Gabriel cyclization in the case of
monocycles). The influence of the nature of acid on the re-
sults of the cyclization of 2 to 3 may bring some light to
the mechanism of this conversion. Clearly, the oxygen in
the bicycles 3 originates from the amide group in pyrimi-
dones 2; this mechanism was proved by isotope label for
monocyclic case,10 and there is no evidence for its change
in the case of bicyclic analogs. Therefore, protonation of
the ketone oxygen in phenacyl derivatives 2 is required.
However, 2-pyrimidones 2 have the concurrent basic cen-
Derivatives of 2-aminoxazole possess various types of bi-
ological activities; the parent scaffold is present in some
Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York

266
V. L. Alifanov, E. V. Babaev
PAPER
N
compounds 4 it would be necessary to start from hardly
available 2-halogen derivatives of arylacetic aldehydes.
O
O
Ar
H2N
Ar
N+
N
The are only few alternative methodologies to prepare 2-
amino-5-aryloxazoles: Curtius rearrangement of ox-
azolyl-2-carboxylic acids hydrazides,17 multistep synthe-
sis starting from N-(tosylmethyl)-N¢-tritylcarbodiimide,18
and condensation of a-bromoketones with N-cyanourea.19
Hence the strategy proposed in this communication, in-
volving simple sequence with high yields and requiring
cheap materials, may serve as a competitive complemen-
tary route to the class of compounds 4.
3a–g
4a–g
N2H4*H2O
N
H
N
O
O
Ar
Ar
N
N
NNH2
NHNH2
Scheme 7
Table 3 2-Amino-5-aryloxazoles Prepared
Closer inspection of the suggested strategy may clarify,
that actual use of 2-pyrimidone as the source of NCO frag-
ment of 2-aminoxazole is nothing else but applying the
idea of protecting group. Indeed, reaction of urea with a-
bromoketones proceeds in a complex manner without
clear regioselectivity (in contrast to thiourea). Pyrimidone
may be considered as a sort of ‘protected’ urea that may
be selectively N-phenacylated. Here the protecting group
is the fragment of malonaldehyde, which is safely re-
moved by hydrazinolysis at the final step. The role of ma-
lonaldehyde as protecting group is not only envisaged: in
fact, most common way to obtain 2-pyrimidone is the con-
densation of urea with malonaldehyde derivatives. Hence,
the overall sequence of ‘protection and deprotection’ of
urea in the synthesis of 2-aminoxazoles can be described
as shown in Scheme 8.
Compound
Ar
Yield (%)
4a
4b
4c
4d
4e
4f
4-ClC6H4
4-BrC6H4
2,4-Cl2C6H3
4-NO2C6H4
3-NO2C6H4
Ph
95
96
88
93
88
90
82
4g
4-MeC6H4
OR
OR
H2N
N
NH2
NH
N2H4
O
+
OR
RO
N
N+
H2N
O
N
O
O
R
R
regioselective
formation of
2-aminooxazole
protection
of urea
deprotection
Scheme 8
Figure 3 X-ray crystal structure of the compound 4b
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on AM 400 Bruker spectrometer for 1H at 360 MHz and for
13C at 90 or 100 MHz. Chemical shifts are reported in ppm refer-
enced to residual protons in the deuterated solvent. IR spectra were
obtained on UR-20 spectrometer in Nujol. Mass spectra were deter-
mined on Kratos MS-30 mass spectrometer (EI 70 eV). TLC was
performed with Silufol UV-254 (Merck). The experimental intensi-
ties of diffraction reflections for single crystals of compounds 2a,20
3b,21 and 4b22 were measured on a CAD4 automated diffractometer
common drugs: antiseptic sulfamoxole and sulfaguanole,
anti-asthmatic isamoxole, hypotensive azepexole, and
anti-inflammatory ditazole. Many simple N-acyl- and N-
alkyl derivatives of this family display anti-
inflammatory12 and antiviral13 activities, and very recently
N-substituted 2-aminoxazoles have been found as a novel
class of VEGFR2 kinase inhibitors.14 Therefore, develop-
ment of flexible routes to this family remains an actual
task. It should be mentioned that common methods lead- (MoKaradiation, graphite monochromator, w scan mode) at r.t. All
subsequent calculations were carried out with the SHELX97 pro-
gram package.
ing to 2-aminooxazoles are frequently multistep reactions
that require complicated reagents or the processes are ac-
2-Pyrimidone hydrochloride was prepared by reaction of urea with
malonaldehyde bis(dimethyl acetal) (1,1,3,3-tetramethoxypropane)
by a method described in the literature20 [yield: 71%; yellow solid;
mp 203–207 °C; (Lit.23 mp 210 °C)].
companied by side reactions. The ‘handbook’ strategy to
2-aminooxazoles – reaction of cyanamide with a-hydrox-
ycarbonyl compounds15 – is difficult to apply for the syn-
thesis of 5-aryl substituted 2-aminooxazoles 4, since the
starting materials would be poorly available a-hydroxy
derivatives of phenylacetic aldehyde. Another old strate-
gy is cyclocondensation of urea with a-halogencarbonyl
compounds;16 this process is complicated by concurrent
formation of imidazolones.15b Again, for the synthesis of
1-(2-Aryl-2-oxoethyl)pyrimidin-2(1H)-ones 2a,b,f–h; 1-[(2-(4-
Chlorophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2a); Typical
Procedure; Method A
K2CO3 (55.2 g, 0.4 mol) was added under stirring to a suspension of
2-pyrimidone hydrochloride (26.5 g, 0.2 mol) in anhyd acetone
Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aminooxazoles
267
(500 mL). A solution of 4-chlorophenacyl bromide (23.3 g, 0.1 mol)
in acetone (100 mL) was added, and the mixture was stirred for 2
days at r.t. Acetone was evaporated in vacuum, and the residue was
washed with H2O, then with EtOAc. The product was isolated by
suction and recrystallized from MeCN to afford 2a; yield: 22.3 g
(90%).
13C NMR (90 MHz, DMSO-d6): d = 56.6 (CH2), 103.9 (C-5), 124.1
(C-3¢, Ar), 129.5 (C-2¢, Ar), 138.9 (C-1¢, Ar), 150.4 (C-4¢, Ar),
150.5 [C-4 (6)], 155.5 (C-2), 166.9 [C-6 (4)], 192.0 (C=O).
Anal. Calcd for C12H9N3O4: C, 55.60; H, 3.50; N, 16.21. Found: C,
55.69; H, 3.39; N, 16.49.
1-[(2-(3-Nitrophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2e)
Yield: 63%; white solid; mp 162–164 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
IR (Nujol): 1710, 1670 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 5.55 (s, 2 H, CH2), 6.45 (m, 1
H, H-5), 7.86 (m, 1 H, H-5¢-Ar), 8.12 (m, 1 H, H-4), 8.48 (m, 2 H,
H-4¢-Ar, H-6¢-Ar), 8.59 (m, 1 H, H-6), 8.76 (m, 1 H, H-2¢-Ar).
13C NMR (90 MHz, DMSO-d6): d = 56.5 (CH2), 103.9 (C-5), 122.3
(C-2¢, Ar), 128.2 (C-4¢, Ar), 130.8 (C-5¢, Ar), 134.1 (C-6¢, Ar),
135.6 (C-1¢, Ar), 148.1 (C-3¢, Ar), 150.4 [C-4 (6)], 155.5 (C-2),
166.9 [C-6 (4)], 191.4 (C=O).
1-(2-Aryl-2-oxoethyl)pyrimidin-2(1H)-ones 2c–e; 1-[(2-(2,4-
Dichlorophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2c); Typical
Procedure; Method B
2-Pyrimidone hydrochloride (26.5 g, 0.2 mol) was added to a fresh-
ly prepared solution of NaOMe obtained by reaction of Na (9.2 g,
0.4 mol) with absolute MeOH (400 mL). The mixture was stirred
for 30 min, and MeOH was evaporated under reduced pressure. The
residue was suspended in anhyd acetone (400 mL), and a solution
of 2,4-dichlorophenacyl bromide (26.8 g, 0.1 mol) in acetone (200
mL) was added with stirring. The mixture was refluxed for 2 h and
treated as described in Method A to give 2c; yield: 17.0 g (60%).
Anal. Calcd for C12H9N3O4: C, 55.60; H, 3.50; N, 16.21. Found: C,
55.58; H, 3.42; N, 16.19.
1-[(2-(4-Chlorophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2a)
Yield: 90%; white solid; mp 230–231 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
1-(2-Oxo-2-phenylethyl)pyrimidin-2(1H)-one (2f)
Yield: 79%; white solid; mp 184–186 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
IR (Nujol): 1710, 1650 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 5.50 (s, 2 H, CH2), 6.51 (m, 1
H, H-5), 7.60 (m, 2 H, H-3¢-Ar), 7.73 (m, 1 H, H-4¢-Ar), 8.06 (m, 2
H, H-2¢-Ar), 8.15 (m, 1 H, H-4), 8.63 (m, 1 H, H-6).
13C NMR (90 MHz, DMSO-d6): d = 56.2 (CH2), 103.7 (C-5), 127.9
(C-2¢, Ar), 128.9 (C-3¢, Ar), 134.1 (C-4¢, Ar), 134.3 (C-1¢, Ar),
150.6 [C-4 (6)], 155.5 (C-2), 166.7 [C-6 (4)], 192.4 (C=O).
IR (Nujol): 1695, 1615 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 5.48 (s, 2 H, CH2), 6.51 (m, 1
H, H-5), 7.68 (m, 2 H, Ar-H, BB¢), 8.07 (m, 2 H, Ar-H, AA¢), 8.13
(m, 1 H, H-4), 8.62 (m, 1 H, H-6).
13C NMR (90 MHz, DMSO-d6): d = 56.1 (CH2), 103.8 (C-5), 129.1
(C-3¢, Ar), 129.8 (C-2¢, Ar), 133.0 (C-1¢, Ar), 139.0 (C-4¢, Ar),
150.5 [C-4 (6)], 155.5 (C-2), 166.7 [C-6 (4)], 191.6 (C=O).
Anal. Calcd for C12H9ClN2O2: C, 57.96; H, 3.65; N, 11.27. Found:
C, 57.67; H, 3.41; N, 11.29.
Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N, 13.08. Found: C,
66.99; H, 4.86; N, 13.24.
1-[(2-(4-Bromophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2b)
Yield: 95%; white solid; mp 237–239 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
1-[(2-(4-Methylphenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2g)
Yield: 81%; white solid; mp 197–199 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
IR (Nujol): 1690, 1660 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 3.29 (s, 3 H, CH3), 5.45 (s, 2
H, CH2), 6.50 (m, 1 H, H-5), 7.40 (m, 2 H, Ar-H, BB¢), 7.95 (m, 2
H, Ar-H, AA¢), 8.14 (m, 1 H, H-4), 8.62 (m, 1 H, H-6).
IR (Nujol): 1700, 1660 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 5.43 (s, 2 H, CH2), 6.41 (m, 1
H, H-5), 7.72 (m, 2 H, Ar-H, BB¢), 7.99 (m, 2 H, Ar-H, AA¢), 8.08
(m, 1 H, H-4), 8.57 (m, 1 H, H-6).
Anal. Calcd for C12H9BrN2O2: C, 49.17; H, 3.09; N, 9.56. Found: C,
48.75; H, 2.89; N, 9.36.
13C NMR (90 MHz, DMSO-d6): d = 21.2 (CH3), 56.0 (CH2), 103.6
(C-5), 128.0 (C-2¢, Ar), 129.4 (C-3¢, Ar), 131.9 (C-1¢, Ar), 144.6 (C-
4¢, Ar), 150.6 [C-4 (6)], 155.5 (C-2), 166.6 [C-6 (4)], 191.9 (C=O).
1-[(2-(2,4-Dichlorophenyl)-2-oxoethyl]pyrimidin-2(1H)-one
(2c)
Yield: 60%; white solid; mp 205–207 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
Anal. Calcd for C13H12N2O2: C, 68.41; H, 5.30; N, 12.27. Found: C,
68.65; H, 5.49; N, 12.38.
IR (Nujol): 1710, 1680 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 5.27 (s, 2 H, CH2), 6.42 (m, 1
H, H-5), 7.51 (d, J5¢,6¢ = 8.2 Hz, 1 H, H-5¢-Ar), 7.57 (s, 1 H, H-3¢-
Ar), 7.91 (d, J6¢,5¢ = 8.2 Hz, 1 H, H-6¢-Ar), 8.19 (m, 1 H, H-4), 8.57
(m, 1 H, H-6).
1-[(2-(4-Methoxyphenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2h)
Yield: 70%; white solid; mp 173–175 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
IR (Nujol): 1700, 1640 cm–1.
1H NMR (360 MHz, DMSO-d6): d = 3.90 (s, 3 H, OCH3), 5.40 (s, 2
H, CH2), 6.41 (m, 1 H, H-5), 7.05 (m, 2 H, Ar-H, BB¢), 8.01 (m, 2
H, Ar-H, AA¢), 8.08 (m, 1 H, H-4), 8.56 (m, 1 H, H-6).
Anal. Calcd for C12H8Cl2N2O2: C, 50.91; H, 2.85; N, 9.89. Found:
C, 50.74; H, 2.83; N, 9.75.
1-[(2-(4-Nitrophenyl)-2-oxoethyl]pyrimidin-2(1H)-one (2d)
Yield: 65%; pale yellow solid; mp 215–217 °C; Rf = 0.15 (CHCl3–
MeOH, 10:1).
IR (Nujol): 1695, 1655 cm–1.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C,
63.88; H, 4.88; N, 11.56.
Attempted Cyclization of 2a
1H NMR (360 MHz, DMSO-d6): d = 5.55 (s, 2 H, CH2), 6.54 (m, 1
H, H-5), 8.16 (m, 1 H, H-4), 8.28 (m, 2 H, Ar-H, BB¢), 8.41 (m, 2
H, Ar-H, AA¢), 8.65 (m, 1 H, H-6).
HClO4 (0.3 mL) was carefully added under good cooling to Ac2O
(10 mL). Pyrimidone 2a (0.746 g, 0.003 mol) was added, the color-
less mixture was stirred for 30 min, and then kept for 24 h at r.t. The
obtained precipitate was filtered, dried and recrystallized from
Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York

268
V. L. Alifanov, E. V. Babaev
PAPER
EtOH to afford the perchlorate of 2a; yield: 1.00 g (96%); white sol-
id; mp 325–327 °C.
Anal. Calcd for C12H7Cl3N2O5: C, 39.43; H, 1.93; N, 7.66. Found:
C, 39.14; H, 1.91; N, 7.75.
1H NMR (360 MHz, DMSO-d6): d = 5.73 (s, 2 H, CH2), 6.98 (m, 1
H, H-5), 7.59 (m, 2 H, Ar-H, BB¢), 8.09 (m, 2 H, Ar-H, AA¢), 8.86
(m, 1 H, H-4), 8.91 (m, 1 H, H-6).
2-(4-Nitrophenyl)oxazolo[3,2-a]pyrimidinium Perchlorate (3d)
Yield: 80%; pale yellow solid; mp 271–273 °C.
1H NMR (360 MHz, DMSO-d6): d = 8.17 (dd, J6,7 = 4.5 Hz,
J6,5 = 6.3 Hz, 1 H, H-6), 7.36 (m, 2 H, Ar-H, BB¢), 8.46 (m, 2 H, Ar-
H, AA¢), 9.41 (dd, J7,6 = 4.5 Hz, J7,5 = 1.8 Hz, 1 H, H-7), 9.50 (s, 1
H, H-3), 9.73 (dd, J5,6 = 6.3 Hz, J5,7 = 1.8 Hz, 1 H, H-5).
Anal. Calcd for C12H10Cl2N2O6: C, 45.80; H, 3.52; N, 8.90. Found:
C, 45.69; H, 3.43; N, 8.80.
Treatment of 2a with concd H2SO4 and PPA led to the same per-
chlorate. In the case of TiCl4 or POCl3 no identifiable products were
isolated.
Anal. Calcd for C12H8ClN3O7: C, 42.18; H, 2.36; N, 12.30. Found:
C, 42.36; H, 2.48; N, 12.43.
2-Aryloxazolo[3,2-a]pyrimidinium Perchlorates 3a–f; 2-(4-
Chlorophenyl)oxazolo[3,2-a]pyrimidinium Perchlorate (3a);
Typical Procedure; Method A
2-(3-Nitrophenyl)oxazolo[3,2-a]pyrimidinium Perchlorate (3e)
Yield: 87%; white solid; mp 248–250 °C.
Dried 4-chlorohenacylpyrimidone (2a; 4.28 g, 0.02 mol) was care-
fully added to a stirred mixture of fuming H2SO4 [32 mL; prepared
by mixing of H2SO4 (25 mL, d = 1.84) and commercial (60 mass%
of SO3) fuming H2SO4 (17 mL, 34 g)]. [For 2c–e fuming sulfuric
acid (40 mL) with 30 mass% of SO3 was used for mixing]. The tem-
perature was kept in the range –5 to 0 °C. The mixture (orange to
red) was stirred below 0 °C until the compound 2a completely dis-
solved and then kept for 5 h under r.t. (For 2c the mixture was kept
for 24 h, and for 2d,e, 72 h at r.t.). After that the mixture was care-
fully poured into crushed ice (500 g). Then HClO4 (10 mL, 65%)
was added. The product was isolated by suction filtration, washed
with H2O, then with EtOH and Et2O, and dried in vacuum over P2O5
to afford 3a; yield: 5.23 g (79%); white solid; mp 268–270 °C.
1H NMR (360 MHz, DMSO-d6): d = 7.64 (m, 2 H, Ar-H, BB¢), 8.06
(m, 2 H, Ar-H, AA¢), 8.14 (dd, J6,7 = 4.5 Hz, J6,5 = 6.3 Hz, 1 H, H-
6), 9.31 (s, 1 H, H-3), 9.34 (dd, J7,6 = 4.5 Hz, J7,5 = 1.7 Hz, 1 H, H-
7), 9.66 (dd, J5,6 = 6.3 Hz, J5,7 = 1.7 Hz, 1 H, H-5).
13C NMR (100 MHz, DMSO-d6): d = 111.8 (C-3), 118.6 (C-6),
122.6 (C-1¢, Ar), 127.7 (C-2¢, Ar), 130.1 (C-3¢, Ar), 137.1 (C-4¢,
Ar), 142.4 [C-7 (5)], 150.8 (C-2), 153.2 (C-9), 162.6 [C-5 (7)].
1H NMR (360 MHz, CF3CO2D): d = 8.66 (m, 1 H, H-3¢-Ar), 8.83
(m, 1 H, H-6), 9.13 (m, 1 H, H-2¢-Ar), 9.32 (m, 1 H, H-4¢-Ar), 9.67
(m, 2 H, H-3-Ar + H-5¢-Ar), 10.13 (m, 1 H, H-7), 10.19 (m, 1 H, H-
5).
13C NMR (90 MHz, DMSO-d6): d = 113.3 (C-3), 118.6 (C-6), 120.7
(C-2¢, Ar), 125.2 (C-1¢, Ar), 126.5 (C-6¢, Ar), 131.6 (C-4¢, Ar),
131.8 (C-5¢, Ar), 142.7 [C-7 (5)], 148.6 (C-3¢, Ar), 149.6 (C-2),
153.3 (C-9), 163.3 [C-5 (7)].
Anal. Calcd for C12H8ClN3O7: C, 42.18; H, 2.36; N, 12.30. Found:
C, 42.25; H, 2.22; N, 12.36.
2-Phenyloxazolo[3,2-a]pyrimidinium Perchlorate (3f)
Method A: To the precipitate, obtained after cyclization and addi-
tion of H2O and HClO4, was added DMSO (50 mL), the mixture
was thoroughly suspended, and the insoluble part was filtered off.
The filtrate was partially evaporated in vacuum and diluted with
Et2O (50 mL). The precipitate was filtered, washed with Et2O and
EtOH, and dried in vacuum over P2O5 to afford the 3f; yield: 55%;
white solid; mp 261–263 °C.
1H NMR (360 MHz, CF3CO2D): d = 8.84 (m, 3 H, H-6-Ar + H-3¢-
Ar), 9.19 (m, 3 H, H-2¢,4¢-Ar), 9.81 (s, 1 H, H-3), 10.49 (m, 1 H, H-
7), 10.56 (m, 1 H, H-5).
Anal. Calcd for C12H8Cl2N2O5: C, 43.53; H, 2.44; N, 8.46. Found:
C, 43.33; H, 2.40; N, 8.53.
13C NMR (90 MHz, DMSO-d6): d = 111.2 (C-3), 118.4 (C-6), 123.6
(C-1¢, Ar), 125.9 (C-2¢, Ar), 129.8 (C-3¢, Ar), 132.3 (C-4¢, Ar),
142.2 [C-7 (5)], 151.8 (C-2), 153.2 (C-9), 162.4 [C-5 (7)].
2-(4-Bromophenyl)oxazolo[3,2-a]pyrimidinium Perchlorate
(3b)
Yield: 85%; white solid; mp 279–281 °C.
Anal. Calcd for C12H9ClN2O5: C, 48.58; H, 3.06; N, 9.44. Found: C,
48.65; H, 2.91; N, 9.38.
1H NMR (360 MHz, DMSO-d6): d = 7.81 (m, 2 H, Ar-H, BB¢), 8.02
(m, 2 H, Ar-H, AA¢), 8.14 (dd, J6,7 = 4.6 Hz, J6,5 = 6.3 Hz, 1 H, H-
6), 9.31 (s, 1 H, H-3), 9.36 (dd, J7,6 = 4.6 Hz, J7,5 = 1.8 Hz, 1 H, H-
7), 9.68 (dd, J5,6 = 6.3 Hz, J5,7 = 1.8 Hz, 1 H, H-5).
13C NMR (90 MHz, DMSO-d6): d = 111.8 (C-3), 118.5 (C-6), 122.9
(C-1¢, Ar), 125.9 (C-4¢, Ar), 127.8 (C-2¢, Ar), 132.8 (C-3¢, Ar),
142.3 [C-7 (5)], 150.8 (C-2), 153.2 (C-9), 162.6 [C-5 (7)].
Method B: N-Phenacyl-2-pyrimidone 2f (0.37 g, 0.0016 mol) was
mixed with P2O5 (0.65 g, 0.0046 mol) and freshly distilled triflic
acid (5 mL) was added to the mixture. The dark-red mixture ob-
tained was refluxed for 3 h at 85–90 °C. The mixture was cooled and
carefully poured into crushed ice (100 g). HClO4 (3 mL) was added,
and the precipitate was filtered, washed with H2O, EtOH and Et2O,
and dried in vacuum over P2O5 to afford the 3f; yield: 0.375 g
(79%); white solid; mp 261–263 °C, identical to the sample ob-
tained by Method A.
Anal. Calcd for C12H8Br2N2O5: C, 38.38; H, 2.15; N, 7.46. Found:
C, 38.24; H, 1.99; N, 7.46.
2-(2,4-Dichlorophenyl)oxazolo[3,2-a]pyrimidiniumPerchlorate
(3c)
Yield: 83%; white solid; mp 315–317 °C.
1H NMR (360 MHz, DMSO-d6): d = 7.69 (m, 3 H, H-6-Ar + H-3¢-
Ar), 8.11 (m, 3 H, H-2¢,4¢-Ar), 9.28 (s, 1 H, H-3), 9.40 (m, 1 H, H-
7), 9.67 (m, 1 H, H-5).
1H NMR (360 MHz, DMSO-d6): d = 7.69 (dd, J5¢,6 = 8.9 Hz,
J5¢,3¢ = 1.8 Hz, 1 H, H-5¢-Ar), 7.82 (d, J3¢,5¢ = 1.8 Hz, 1 H, H-3¢-Ar),
2-(4-Methylphenyl)oxazolo[3,2-a]pyrimidinium Perchlorate
(3g)
Method B; yield 75%; white solid; mp 239–241 °C.
1H NMR (360 MHz, DMSO-d6): d = 7.50 (m, 2 H, Ar-H, BB¢), 7.98
(m, 2 H, Ar-H, AA¢), 8.13 (m, 1 H, H-6), 9.20 (s, 1 H, H-3), 9.37
(m, 1 H, H-7), 9.64 (m, 1 H, H-5).
13C NMR (90 MHz, DMSO-d6): d = 21.2 (CH3), 110.5 (C-3), 118.4
(C-6), 120.9 (C-1¢, Ar), 125.8 (C-2¢, Ar), 130.4 (C-3¢, Ar), 142.1 [C-
7 (5)], 142.8 (C-4¢, Ar), 152.0 (C-2), 153.1 (C-9), 162.0 [C-5 (7)].
8.16 (m, 2 H, H-5-Ar + H-6¢-Ar), 9.41 (dd, J7,6 = 4.4 Hz, J7,5 = 1.8
Hz, 1 H, H-7), 9.45 (s, 1 H, H-3), 9.61 (dd, J5,6 = 6.2 Hz, J5,7 = 1.8
Hz, 1 H, H-5).
13C NMR (90 MHz, DMSO-d6): d = 115.2 (C-3), 118.8 (C-6), 121.4
(C-1¢, Ar), 128.9 (C-3¢, Ar), 130.7 (C-6¢, Ar), 131.0 (C-5¢, Ar),
132.2 (C-2¢, Ar), 137.4 (C-4¢, Ar), 142.4 [C-7 (5)], 147.2 (C-2),
152.8 (C-9), 163.6 [C-5 (7)].
Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aminooxazoles
269
Anal. Calcd for C13H11ClN2O5: C, 50.26; H, 3.57; N, 11.41. Found:
C, 50.40; H, 3.41; N, 11.32.
Anal. Calcd for C9H7N3O3: C, 52.69; H, 3.44; N, 20.48. Found: C,
52.72; H, 3.32; N, 20.37.
2-Amino-5-aryloxazoles 4a–g; 5-(4-Chlorophenyl)-1,3-oxazol-
2-amine (4a); Typical Procedure
5-Phenyl-1,3-oxazol-2-amine (4f)
Yield: 90%; white solid; mp 215–216 °C (Lit.19b mp 215–216 °C);
Rf = 0.4 (CHCl3–MeOH, 10:1).
Perchlorate 3a (3.3 g, 0.01 mol)) was suspended in anhyd MeCN
(50 mL), and hydrazine hydrate (5 mL) was added with stirring. The
mixture turned orange, and was refluxed for 20 min (until decolori-
zation). The solution was cooled to r.t. and poured into cold H2O
(100 mL). The product was isolated by suction filtration and recrys-
tallized from EtOH to afford 4a; yield: 1.65 g (95%); white solid;
mp 220–221 °C (Lit.18a mp 220–222 °C); Rf = 0.4 (CHCl3–MeOH,
10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.48 (br s, 2 H, NH2), 6.96 (s,
1 H, H-4), 7.12 (m, 1 H, H-4¢-Ar), 7.30 (m, 2 H, H-3¢-Ar), 7.42 (m,
2 H, H-2¢-Ar).
13C NMR (100 MHz, DMSO-d6): d = 121.9 (C-2¢, Ar), 123.0 (C-4),
126.2 (C-1¢, Ar), 128.7 (C-4¢, Ar), 128.8 (C-3¢, Ar), 143.1 (C-5),
161.4 (C-2).
1H NMR (360 MHz, DMSO-d6): d = 6.57 (br s, 2 H, NH2), 7.01 (s,
1 H, H-4), 7.26 (m, 2 H, Ar-H, BB¢), 7.41 (m, 2 H, Ar-H, AA¢).
13C NMR (90 MHz, DMSO-d6): d = 123.4 (C-2¢, Ar), 123.9 (C-4),
127.5 (C-1¢, Ar), 128.8 (C-3¢, Ar), 130.2 (C-4¢, Ar), 142.0 (C-5),
161,5 (C-2).
MS (EI, 70 eV): m/z (%) = 105 (70), 160 (100).
5-(4-Methylphenyl)-1,3-oxazol-2-amine (4g)
Yield: 82%; white solid; mp 218–220 (Lit.18a mp 218–220 °C);
Rf = 0.4 (CHCl3–MeOH, 10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.74 (br s, 2 H, NH2), 7.09 (s,
1 H, H-4), 7.17 (m, 2 H, Ar-H, BB¢), 7.32 (m, 2 H, Ar-H, AA¢).
MS (EI, 70 eV): m/z (%) = 138 (100), 194 (76).
13C NMR (90 MHz, DMSO-d6): d = 21.1 (CH3), 121.9 (C-2¢, Ar),
122.0 (C-4), 126.0 (C-1¢, Ar), 129.3 (C-3¢, Ar), 135.5 (C-4¢, Ar),
143.2 (C-5), 161.0 (C-2).
5-(4-Bromophenyl)-1,3-oxazol-2-amine (4b)
Yield: 96%; white solid; mp 220–221 °C (Lit 19b mp 220–222 °C);
Rf = 0.4 (CHCl3–MeOH, 10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.61 (br s, 2 H, NH2), 7.04 (s,
1 H, H-4), 7.35 (m, 2 H, Ar-H, BB¢), 7.44 (m, 2 H, Ar-H, AA¢).
Acknowledgment
MS (EI, 70 eV): m/z (%) = 183 (100), 238 (100).
This work was supported by the Russian Foundation of Basic
Research (RFBR Grant no. 05-03-39022-GFEN_a).
5-(2,4-Dichlorophenyl)-1,3-oxazol-2-amine (4c)
Yield: 88%; white solid; mp 202–204 °C; Rf = 0.4 (CHCl3–MeOH,
10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.24 (br s, 2 H, NH2), 7.23 (dd,
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J
5¢,6¢ = 8.6 Hz, J5¢,3¢ = 2 Hz, 1 H, H-5¢-Ar), 7.35 (s, 1 H, H-4), 7.38
(d, J3¢,5¢ = 2 Hz, 1 H, H-3¢-Ar), 7.58 (d, J6¢,5¢ = 8.6 Hz, 1 H, H-6¢-Ar).
13C NMR (100 MHz, DMSO-d6): d = 125.9 (C-1¢, Ar), 126.3 (C-6¢,
Ar), 127.7 (C-4), 128.2 (C-2¢, Ar), 128.7 (C-5¢, Ar), 129.8 (C-3¢,
Ar), 130.4 (C-4¢, Ar), 138.8 (C-5), 161.5 (C-2).
MS (EI, 70 eV): m/z (%) = 173 (64), 228 (100).
Anal. Calcd for C9H6Cl2N2O: C, 47.19; H, 2.64; N, 12.23. Found:
C, 47.22; H, 2.68; N, 12.37.
5-(4-Nitrophenyl)-1,3-oxazol-2-amine (4d)
Yield: 93%; orange solid; mp 235–237 (Lit.18a 235–237 °C);
Rf = 0.4 (CHCl3–MeOH, 10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.99 (br s, 2 H, NH2), 7.39 (s,
1 H, H-4), 7.60 (m, 2 H, Ar-H, BB¢), 8.16 (m, 2 H, Ar-H, AA¢).
13C NMR (100 MHz, DMSO-d6): d = 121.9 (C-2¢, Ar), 124.6 (C-3¢,
Ar), 128.9 (C-4), 134.6 (C-1¢, Ar), 141.5 (C-5), 144.5 (C-4¢, Ar),
162.9 (C-2).
MS (EI, 70 eV): m/z (%) = 175 (47), 205 (100).
5-(3-Nitrophenyl)-1,3-oxazol-2-amine (4e)
Yield: 88%; orange solid; mp 201–203 °C; Rf = 0.4 (CHCl3–
MeOH, 10:1).
1H NMR (360 MHz, DMSO-d6): d = 6.81 (br s, 2 H, NH2), 7.27 (s,
1 H, H-4), 7.53 (m, 1 H, H-5¢-Ar), 7.83 (m, 1 H, H-6¢-Ar), 7.95 (m,
1 H, H-4¢-Ar), 8.21 (m, 1 H, H-2¢-Ar).
13C NMR (100 MHz, DMSO-d6): d = 115.7 (C-2¢, Ar), 120.3 (C-4¢,
Ar), 126.1 (C-4), 127.8 (C-6¢, Ar), 130.2 (C-1¢, Ar), 130.5 (C-5¢,
Ar), 141.0 (C-5), 148.4 (C-3¢, Ar), 162.1 (C-2).
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Veal, J. M.; Nolte, R. T.; Wang, L.; Liu, W.; Crosby, R. M.;
MS (EI, 70 eV): m/z (%) = 175 (17), 205 (100).
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V. L. Alifanov, E. V. Babaev
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Synthesis 2007, No. 2, 263–270 © Thieme Stuttgart · New York