Reactions of benzonitrile oxide with methoxypyrimidines and pyrimidones

Article abstract of DOI:10.3987/COM-05-10342

Methoxypyrimidines preferentially add to benzonitrile oxide to give cycloadducts to their C=N double bonds. These, however, lose benzonitrile affording the corresponding pyrimidones. Cycloadditions to their C=C double bonds take place to a very low extent, and products generally undergo a ring opening process which affords the corresponding oximes. Pyrimidones preferentially give addition products to their nitrogen atoms, and only in the case of 4-pyrimidone, the cycloadduct to its C=C double bond was isolated.

Full text of DOI:10.3987/COM-05-10342

HETEROCYCLES, Vol. 65, No. 5, 2005
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HETEROCYCLES, Vol. 65, No. 5, 2005, pp. 1079 - 1097
Received, 19th January, 2005, Accepted, 4th March, 2005, Published online, 4th March, 2005
REACTIONS OF BENZONITRILE OXIDE WITH METHOXYPYRIMIDI-
NES AND PYRIMIDONES
Antonino Corsaro,*a Venerando Pistarà,a Antonio Rescifina,a Maria A.
Chiacchio,a Anna Piperno,b and Giovanni Romeob
aDepartment of Chemical Science, Catania University, Viale Andrea Doria 6,
95125 Catania, Italy, E-mail: acorsaro@unict.it
bDepartment Pharmaceutical-Chemical, Messina University, Viale SS.
Annunziata, 90168 Messina, Italy
Abstract – Methoxypyrimidines preferentially add to benzonitrile oxide to give
cycloadducts to their C=N double bonds. These, however, lose benzonitrile
affording the corresponding pyrimidones. Cycloadditions to their C=C double
bonds take place to a very low extent, and products generally undergo a ring
opening process which affords the corresponding oximes. Pyrimidones
preferentially give addition products to their nitrogen atoms, and only in the case
of 4-pyrimidone, the cycloadduct to its C=C double bond was isolated.
INTRODUCTION
The 5,6-substituted pyrimidine nucleosides, enclosed those with a five- or six-membered heterocycle
fused to the pirimidine 5,6-double bond, have drawn the attention of several research groups because of
their biological activities, such as antitumor, anti-HIV, anti-HSV and spermicidal activities.1
Among the possible strategies for the construction of these unnatural nucleosides, cycloaddition reactions
of 1,3-dipoles2 to the pirimidine C5=C6 double bond appear to be the best direct method that involves a
small number of synthetic steps.
In connection with one of our research programs on modified nucleosides,3 we were interested to cover
the above synthetic route in order to obtain dihydroisoxazolopyrimidinone or -dione nucleosides by
1,3-dipolar cycloaddition reaction of benzonitrile oxide (1) (BNO) with 2-methoxypyrimidine (2a) and
4-methoxypyrimidine (2b) in the stoichiometric ratio of 1:2a,b = 4:1, since it appears from literature, that
1 is inert towards uracil,4 but 1 reacts with pyrimidine even if it affords products in low yields.5

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HETEROCYCLES, Vol. 65, No. 5, 2005
Based on our knowledges acquired within the 1,3-dipolar cycloaddition reactions of nitrile oxides with
pyridine6–8 and diazine systems,5 our synthetic strategy anticipated the formation of bis- and/or
tris-adducts through an initial pseudo-pericyclic process9 of the nitrile oxide addition to the C=N double
bond of pyrimidine derivatives, followed by the 1,3-dipole cycloaddition to their C=C double bond.5
These bis- and/or tris-adducts undergo, generally, upon exposure to the air and light at room temperature,
degradation processes with loss of benzonitrile to give the corresponding pyrimidones and/or -diones.5,6
Furthermore, these methoxy derivatives can undergo a very ease hydrolysis in acidic or, some times,
alkaline medium of the alkoxy group.10
However, we have also investigated the route of the reactions of 1 with pyrimid-2(1H)-one (3a) and
-4(3H or 1H)-one (3b) in the stoichiometric ratio of 1:3a,b = 6:1, considering that the addition of 1 to
pyrazinone11 as well as pyridone12 provides N- and/or O-addition products, of which the last ones are very
transient compounds since they spontaneously convert in the corresponding carbamates.12 Also these can
undergo the nitrile oxide cycloaddition to give bis- and/or tris-adducts and then our target molecules after
hydrolysis and degradation processes.
Against the availability of starting materials, these processes present the disadvantage of low yields; in
our case, however, methoxypyrimidines are expected to be more reactive with respect to the pyrimidine
owing to the greater nucleophilicity of their nitrogen atoms directly conjugated with the methoxyl
electron-donor group. In order to confirm this latter electronic effect, the work was completed by
performing the reaction of 1 with 5-methoxypyrimidine (2c), nitrogen atoms of which do not enjoyed the
effect of the methoxy group.
Really, the synthesis of this type of ring systems could be accomplished starting from an isoxazoline
derivative containing functional groups suitable for the ring closure to the pyrimidine, but this route
shows some difficulties and it is considerably longer.13
In this paper we report the results of the above investigations which the obtained adducts undergo a
further ring opening process of isoxazoline nucleus to give the corresponding oximes such as
dichlorobenzonitrile oxide adducts to uracil.4a
RESULTS AND DISCUSSION
Reactions were conducted by slowly adding triethylamine in anhydrous toluene or methanol to a stirred,
ice cooled, solution of pyrimidine derivatives (2a–c) and benzhydroximic acid chloride in the same
solvent over a period of 6 h. After that the room temperature was reached, the reaction mixture was
allowed under stirring for one day and then the solvent was removed. The residue was subjected to
column or flash chromatography in order to separate unreacted pyrimidine derivatives and nitrile oxide
dimers and then a centrifugally enhanced preparative thin layer chromatography (CEPTLC) was used for

HETEROCYCLES, Vol. 65, No. 5, 2005
1081
the separation of several different products contained in the remaining fractions. Because of their
insolubility in toluene, reactions of 1 with 3a,b were conducted only in methanol following the same
work-up.
2-Methoxypyrimidine (2a)
The greater nucleophilicity of 2a with respect to pyrimidine was disclosed by the greater reactivity of its
C=N double bond towards 1. Mainly 5-methoxy-3-phenyl-8aH-[1,2,4]oxadiazolo[4,5-c]pyrimidine (4)
(30%) was produced, which spontaneously degrades upon standing in toluene solution to the air and light
for two days at room temperature affording quantitatively the already known14 2-methoxypyrimidin-
4(3H)-one (5) (Scheme 1). Probably, this latter was also present in the reaction mixture, but in so small
amount that it was ignored. The oxadiazolo[4,5-c]pyrimidine (4) was characterized on the basis of its 1H
NMR spectrum which contains three double doublets at 5.59 (J = 1.7 and 3.6 Hz), 5.71 (J = 3.6 and 8.0
Hz) and 6.58 ppm (J = 1.7 and 8.0 Hz) for H-8a, H-8 and H-7 protons, respectively. The 13C NMR
spectrum contains signals at 81.29, 114.84, 131.68, 153.85 and 164.70 ppm, which are attributable to
C-8a, C-8, C-7, C-3 and C-5 carbons, respectively.
N
N
– PhCN
N
OCH3
O
N
Ph C N O
N
OCH3
O
H
1
Ph
4
5
+
N
O
Ph
N
Ph
N
N
OCH3
2a
N
N
Beckmann
OCH3
HN
Ph
N
O
OH
N
OCH3
N
N
OCH3
6
7
8
Scheme 1
Minor product was 2-methoxy-5-[(hydroxyimino)phenylmethyl]pyrimidine (7) (9%), which was
identified on the basis of a singlet at 8.34 ppm characteristic for H-4 and H-6 protons and a broad singlet
1
13
at 12.26 ppm for the oxime proton in the H NMR spectrum. The C NMR spectrum showed signals at
159.47 ppm for H-4 and H-6 carbons and 156.47 ppm for oxime carbon.
The structure of 7 was assigned and its syn stereochemistry confirmed by its Beckmann rearrangement,15
which gave 5-carboxamide derivative (8) (65%). Among its 1H NMR signals, that of the amide proton at
8.75 ppm was apparent, while that of the oxime proton at 12.26 ppm was disappeared. Its 13C NMR
spectrum was also diagnostic since this contained a new signal at 165.37 ppm for the amide carbon. Its IR
spectrum contained the absorption band of the amide carbonyl group at 1664 cm-1.
In the light of Ryu’s work,4a the oxime (7) could be generated from the initially formed 1,3-cycloadduct
(6), which spontaneously undergoes a ring opening process into 7. We tried to isolate or trap 6 by the

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HETEROCYCLES, Vol. 65, No. 5, 2005
same benzonitrile oxide or other 1,3-dipoles or dienes, but without success. The sole evidence for the
1
initial formation of 6 was that deriving from H NMR spectral experiments conducted after 5 h on the
initial reaction mixture. These showed a very weak apparition of a double doublet at 4.45 ppm and a
doublet at 6.42 ppm for H-5 and H-4 protons, respetively.
When the reaction was conducted in methanol as solvent, somewhat lower yields of 4 (12%) and 7 (5%)
were obtained, together with a small amount of 5 (2%).
4-Methoxypyrimidine (2b)
The main product of the reaction between 1 and 2b was isoxazolo[4,5-e][1,2,4]oxadiazolo[4,5-a]-
pyrimidine (10, 26%), the structure of which was inferred by its 1H and 13C NMR spectra (Scheme 2). 1H
NMR signals were two doublets at 4.42 and 6.15 ppm with the characterictic coupling constant (J = 8.9
Hz) of cis isoxazolines16 and a singlet at 6.69 ppm for the H-5 oxadiazole proton. Three 13C NMR signals
at 45.62, 83.84, and 97.15 ppm were diagnostic of C-3a, C-9a, and C-5a carbons, respectively.
Minor products were the already known17 4-methoxypyrimidin-2(1H)-one (15, 8%) and
5-[(hydroxyimino)(phenyl)methyl]-4-methoxypyrimidin-2(1H)-one (13, 7%), the IR spectrum of which
1
shows the peculiar bands at 3478 (br) and 1672 cm-1. Its H NMR spectrum shows the H-6 proton as
singlet at 8.47 ppm together with the amide and oxime protons at 9.23 and 12.30 ppm as broad singlets,
13
respectively. Its C NMR spectrum showed signals at 153.93 and 160.02 ppm attributable to the oxime
and carbonyl carbons, respectively.
OCH3
Ph
N
N
OH
N
O
OCH3
OCH3
Ph
N
N
Ph
N
Ph
11
N
N
N
O
OH
N
O
O
H
OCH3
N
OCH3
N
OCH3
N
N
Ph
N
13
Ph
BNO
10
Beckmann
O
N
N
N
O
O
H
OCH3
N
N
2b
O
OCH3
N
Ph
12
9
HN
N
O
Ph
H
N
O
H
15
14
Scheme 2
The production of 10 was indicative of the initial formation of the non isolable cycloadduct (9), which
partly degrades into 15 by losing benzonitrile and partly undergoes a second cycloaddition of 1 to its C=C

HETEROCYCLES, Vol. 65, No. 5, 2005
1083
double bond affording 10. Also 10 undergoes the two degradation and ring opening of isoxazoline
nucleus processes to give 13, so as it was verified by means of the conversion of 10 into 13 keeping a
toluene solution of 10 at room temperature to the air and light for two days. Intermediates of these two
processes can be both 11 and 12. The structure and stereochemistry of 13 was assigned also by its
conversion into 14 (63%) by means of the Beckmann rearrangement15 (Scheme 2).
The distribution of reaction products in methanol was different, since only the oxime (13, 4%) and
pyrimidone (15, 12%) were isolated.
5-Methoxypyrimidine (2c)
Reaction mixture TLCs of 2c with 1 in the two used solvents presented, after ca. 7 h, two spots with Rf
lower than that of dimers. These, successively, turned yellow and then, after a day, disappeared. Our
attempts to isolate or trap, with different cycloaddition reactions, the compounds corresponding to these
two spots failed. From CEPTLC of the work-up reaction mixtures, oxadiazolo[4,5-a:4’,5’-c]pyrimidine
(16) and a mixture consisting of the two known isomer 5-methoxypyrimidin-2- (19)18 and -4-one (21)19 in
1
very low yields (16, 10%; 19, 8%; 21, 5%) was isolated. The structure of 16 was arisen from its H and
13C NMR spectral data and from its conversion into 5-methoxyuracil (17) by keeping 16 for two days to
1
the air and light in methanol solution at room temperature. The H NMR spectrum of 16 was
characterized by a singlet at 5.89 ppm for the H-5 proton, H-10a and H-6a protons being covered by
phenyl proton signals. 13C NMR signals were found at 79.86 and 94.36 ppm for C-6a and C-10a carbons,
at 110.22 ppm for the olefinic C-5 carbon and at 155.24 and 159.29 ppm for C-9 and C-3 carbons,
respectively.
N
O
O
CH3O
Ph
N
CH3O
CH3O
NH
– PhCN
– PhCN
– PhCN
N
O
N
N
H
17
O
Ph
16
CH3O
N
CH3O
N
N
BNO
N
O
N
H
O
N
N
Ph
2c
18
19
O
N
O
CH3O
CH3O
Ph
NH
N
N
N
20
21
Scheme 3

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HETEROCYCLES, Vol. 65, No. 5, 2005
The two methoxypyrimidones (19) and (21) were easily identified thorugh their 1H and 13C NMR spectral
data compared with those of authentical samples. They were generated from the two initially formed
cycloadducts (18) and (20), which successively fragment losing benzonitrile to give 19 and 21,
respectively, or add a second molecule of 1 to give the bisadduct (16) (Scheme 3).
Pyrimid-2(1H)-one (3a)
The exposure of 3a to 1 in methanol solution afforded the already known cycloadduct (22, 60%)5 which
was separated by flash chromatography, identified by comparison of its spectral data with those of an
authentical sample, and further confirmed by its spontaneous quantitative conversion into uracil (23) on
standing in the same solution at room temperature to the air and light for two days.
The CEPTLC of residual fractions allowed the separation of addition products (24, 9%) and (26, 4%) to
the N-1 nitrogen atom of 3a and uracil, respectively, and bicyclic product (28, 3%) (Scheme 4).
O
NH
– PhCN
N
H
O
N
O
23
Ph
N
N
O
O
O
N
O
H
Ph
N
22
NH
NH
1
– PhCN
Beckmann
N
O
N
O
N
O
OH
OH
Ph
Ph
N
Ph
N
O
N
H
BNO
N
25
26
27
N
O
3a
1
N
N
H
N
O
N
O
HClO4
Ph
O
Ph
O
OH
O
N
N
N
N
HN
Ph
Ph
28-I
28-II
N
O
OH
Ph
N
Ph
N
24
N
1
O
N
ClO4
29
Scheme 4
1
13
The structure of 24 was identified on the basis of its IR, H and C NMR spectra. Its IR spectrum is
characterized by absorptions bands at 3448 br and 1674 cm-1 which are attributable to the oxime hydroxy
1
and carbonyl groups, respectively. Its H NMR spectrum contains a triplet at 5.93 ppm (J = 8.3 Hz) for

HETEROCYCLES, Vol. 65, No. 5, 2005
1085
the H-5 proton, two double doublets at 8.02 and 9.48 ppm (J = 8.3 and 1.7 Hz) for H-6 and H-4 protons,
respectively, and a broad singlet at 12.07 ppm for the oxime proton. In its 13C NMR spectrum, the signal
of an oxime carbon at 154.20 ppm in addition to that of carbonyl group at 169.16 ppm are evident.
Furthermore, its structure was assigned based on its easy conversion into the corresponding
isoxazolopyrimidinium salt (29) by treatment with perchloric acid. The salt was identified through the
disappearance of the signal of carbonyl carbon in the 13C NMR spectrum and that of the oxime proton in
the 1H NMR spectrum. The shift to lower fields of the three pyrimidine protons were also apparent.
The bicyclic compound (28) derives from the cycloaddition of a second molecule of 1 to the C=N double
bond of 24, and it exists as mixture of two isomers (28-I) and (28-II) in the ratio of 28-I:28-II = 65:35, so
1
13
as it appears from its H and C NMR spectra. Indeed, the first shows two broad singlets at 10.22 and
10.69 ppm for the hydroxy and oxadiazole protons and the second shows two signals for the oxadiazole
C-5 carbons at 93.83 and 99.79 ppm and C-3 carbons at 144.88 and 156.63 ppm.
The pyrimidin-2,4(1H,3H)-dione oxime (26) was identified through its 1H NMR spectrum where a broad
signal at 11.14 for the N-H proton was evident; the appearance of two signals at 166.20 and 168.24 ppm
for C-4 and C-2 carbonyl carbons, respectively, was in the 13C NMR spectrum, and the IR spectrum
contains two absorption bands attributable to carbonyl groups at 1676 and 1680 cm-1. Furthermore, its
structure and stereochemistry was realized by means of its conversion into the amide 27 by the Beckmann
rearrangement.15
The oxime (26) originated, as it was verified, by addition of a second molecule of 1 to the N-1 nitrogen
atom of 23 or by loss of benzonitrile from the non isolable 25. The oxime (25) in its turn can be
originated by addition of a second molecule of 1 to the N-1 nitrogen atom of 22 or to the C=N double
bond of 24.
Pyrimid-4(3H)- or pyrimid-4(1H)-one (3b)
The two lactam forms, pyrimidin-4(1H)-one (3b-I) and pyrimidin-4(3H)-one (3b-II) exist in equilibrium
with 4-hydroxypyrimidine (3b-III). The first two compounds are known to be favored in the crystalline
state and solutions,20 whereas the contribution of 3b-III to the equilibrium should become comparable to
that of the keto forms in the gaseous phase.20a From previous estimations based on ultraviolet,21 IR and
1
Raman22 and H and 13C NMR23 spectroscopy it is concluded that the main species (more than 80%)
present in aqueous solutions is 3b-II and, furthermore, because this percentage is naturally dependent on
the dielectric constant of solvent, it is expected that it is progressively shifted toward the isomer (3b-II) in
water-ethanol solutions as the ethanol content is increased23a (Scheme 5).
These observations were confirmed by our results based on its chemical reactivity.
Upon reaction of 3b with 1 the initial flash chromatography afforded adduct (30, 40%) to the N-3
nitrogen atom along with small amounts of adduct (31, 6%) to the N-1 nitrogen atom. Successively,

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HETEROCYCLES, Vol. 65, No. 5, 2005
CEPTLC has allowed to isolate isoxazolo[5,4-d]pyrimid-4-one (32) in very low yield (5%) together with
other amounts of adducts (30, 5%) and (31, 2%) (Scheme 5).
1
Oximes (30) and (31) were characterized by the oxime proton in the range 12.36–12.40 ppm in the H
NMR spectra and by oxime and carbonyl carbon atoms in the range 154.20–155.71 ppm and
13
164.46–164.85 ppm, respectively, in the C NMR spectra. The oxime (30) was differentiated starting
from 31 by the obtainment of 35 upon treatment of 30 with perchloric acid. The obtained salt (35) was
identified by two doublets at 7.71 (J = 7.6 Hz) and 9.54 ppm (J = 0.9 Hz) for H-8 and H-5 protons,
1
respectively, and a double doublet at 9.01 (J = 0.9 and 7.6 Hz) for the H-7 proton in the H NMR
spectrum.
The dihydroisoxazole[5,4-d]pyrimid-4-one (32) was identified on the basis of its 1H and 13C NMR spectra.
The first contains three doublets at 5.00, 6.96, and 9.06 ppm (J = 8.2 Hz) for H-3a, H-7a, and H-6 protons,
respectively, and a broad doublet at 11.05 ppm for the N-H proton. The second confirms the assigned
structure containing signals at 59.84 and 91.41 ppm for C-3a and C-7a carbons, 153.73 and 166.84 ppm
for the oxime C-3 and carbonyl C-9 carbons, respectively.
HO
N
O
O
O
N
Ph
HClO4
N
N
N
Ph
ClO4
N
N
H
N
30
35
3b-I
O
O
N
BNO
NH
N
N
OH
NH
Ph
N
3b-II
31
O
O
O
N
OH
Ph
N
Ph
O
Beckmann
NH
NH
N
N
OH
HN
O
Ph
34
N
N
N
3b-III
32
33
Scheme 5
On standing in methanol solution 32 undergoes the ring opening process of isoxazoline nucleus to give
1
the oxime (33) easily identifiable by H NMR signals at 8.43 and 12.18 ppm for H-6 and oxime protons
13
and the C NMR signal at 154.76 ppm for the C-6 carbon. Its structure and stereochemistry was further
realized by means of its conversion by the Beckmann reaction15 into the amide (34) identified through its

HETEROCYCLES, Vol. 65, No. 5, 2005
1087
13C NMR signal at 164.11 ppm of the new amide carbon atom and its IR absorption bands at 3346, 1680,
1636 cm-1.
O
N
O
H
O
O
N
N
H
N
N
N
N
N
H
HO
OH
OH
N
H
Ph
OH
Ph
Ph
31
36
37
Ph
Ph
O
O
O
O
NH
NH
H
NH2
39-I
N
N
N
H
O
O
38-I
H2O, OH
– HCO2H
Ph
Ph
HN
O
O
N
N
H
NH2
39-II
N
H
HN
O
O
38-II
Scheme 6
Probably, owing to the use of not dried solvents and/or silica gels, the first attempt of CEPTLC afforded
8% of the oxime (30) and 9% (global yield) of N-formyl-2-(3-phenyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)-
acetamide (38-I) in equilibrium with its 2,5-dihydro isomer (38-II), which are originated from the
hydration24 of 31 into 36. This latter undergoes an opening ring process to give 37, which, finally,
recloses into the oxadiazoline nucleus (Scheme 6).
There were NMR spectral evidences for the mixture of two inseparable forms (38-I) and (38-II) in the
equilibrium ratio of 89:11. Besides the two doublets at 9.08 and 10.17 ppm of formyl and imidic proton,
respectively, 1H NMR signals in deuterated acetone were at 2.60 (dd, methylene Ha), 2.69 (dd, methylene
Hb), 5.97 (m, oxadiazole H-5) and 6.62 (br s, N-H) ppm for 38-I, while those of 38-II were at 2.92 (dd,
methylene Ha), 2.98 (dd, methylene Hb), 6.12 (m, oxadiazole H-5) and 6.74 (br s, N-H) ppm. 13C NMR
signals at 42.64 and 43.94 ppm were attributable to the two methylenic carbons, those at 90.27 and 91.30
ppm to the two C-5 oxadiazole carbons. The IR spectrum shows one broad intense bands at 3440 cm-1,
and two bands at 1640 and 1628 cm-1. This amide was furthermore characterized by selective hydrolysis
of the N-formyl group to afford the primary amide (39, 92%) as shown by the disappearance of the formyl
proton and carbonyl carbon atom in 1H NMR and 13C NMR spectra, respectively.
Probably, in spite of what happens in the reaction of pyrimidine with 1, the steric congestion of the
transition state owing to the 2-methoxy group, prevents the formation of bis-adducts in the reaction of 2a
with 1 and therefore the sole reaction products are 4 and 7, which derives from the non isolable 6. The

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HETEROCYCLES, Vol. 65, No. 5, 2005
monocycloadduct (4), too, is converted into 5, but this process is slower than the ring-opening process of
6. All our attempts made in order to isolate or trap 6 failed.
Besides a low yield (8%) of 15, 4-methoxypyrimidine (2b) affords a modest yield (26%) of bis-adduct
(10), which spontaneously undergoes the two process of isoxazole ring-opening and loss of benzonitrile
to give 13 without allowing the isolation of dihydroisoxazolopyrimidindione (12), which was another
molecular target.
For these reasons, dihydroisoxazolopyrimidines can not be obtained by cycloadditions of 2a,b with 1, but
only the oximes, which can be useful intermediates for the synthesis of a variety of other compounds such
as for example isoxazolopyrimidinium salts.25 As it was expected, 5-methoxypyrimidine (2c) affords
monoadducts (18) and (20) and the bis-adduct (16) in very low yield. These, however, lose benzonitrile to
give the corresponding pyrimidones (19) and (21) and pyrimidindione (17).
In addition to the already known 22 obtained with a satisfactory yield, the reaction of 3a with 1 has not
permitted the obtainment of addition products to the C5=C6 double bond of pyrimid-2-one.
On the contrary, the reaction of 3b with 1 was the unique one that has led to an isolated
dihydroisoxazolopyrimidone, even if in very low yield, together with the expected N-adducts (30) and
(31). The bicyclic compound (32) presents a greater stability with respect to 6, but, however, it is easily
susceptible of opening its isoxazole ring.
CONCLUSION
In conclusion, pyrimidine derivatives under investigation preferentially add benzonitrile oxide to give
cycloadducts to their C=N double bonds with exception of 3b which affords only addition products to its
nitrogen atoms. Cycloadducts to their C=C double bonds are very weak compounds, and therefore, the
synthetic route followed by us for dihydro- and isoxazolopyrimidinones or diones discloses its
limitations.
EXPERIMENTAL
All melting points were determined on a Kofler hot-stage apparatus and are uncorrected. Elemental
1
analyses were performed on a Carlo Erba 1106 elemental analyzer. H and 13C NMR spectra were
recorded on a Varian Unity Inova (500 MHz for the proton and 125 MHz for the carbon spectra)
spectrometers using tetramethylsilane as internal standard and CDCl3 or DMSO-d6 as solvents. All proton
and carbon signals were full assigned by 2D homo- and heteronuclear correlation spectroscopy (gCOSY
and gHSQC). IR spectra were obtained on a Perkin Elmer Paragon 500 FT IR spectrophotometer by using
potassium bromide discs or nujol mulls and mass spectra were registered on a VG ZAB-2SE spectrometer
operating at 70 eV. Thin layer chromatography were performed on aluminium plates pre-coated with

HETEROCYCLES, Vol. 65, No. 5, 2005
1089
Merck silica gel 60-F254. Preparative chromatographic separations of reaction mixtures were performed
by means of gravity or flash chromatography26 using Merck silica gel 60 and centrifugally enhanced
preparative thin layer chromatography (CEPTLC) using Merck silica gel 60 PF254. Mixtures of
cyclohexane-toluene, toluene-ethyl acetate and ethyl acetate-methanol were used as eluents with a rising
gradient towards the most polar eluent.
Starting materials
Benzhydroximic acid chloride27 (2a,28 2b,29 and 2c30) were prepared following established literature
procedures. Pyrimidone (3a) as its hydrochloride and 3b are commercial compounds and have been
purchased from the Aldrich Co. Solvents and eluents for the chromatography were dried following
literature procedures.31 The identification of samples deriving from different experiments was secured by
mixed melting points and IR and 1H NMR spectra.
General procedure for reactions of 1 with pyrimidine derivatives (2a–c) and (3a,b)
To a stirred, ice cooled, solution of benzhydroximic acid chloride (5 g, 32 mmol) and
methoxypyrimidines (2a–c) (0.9 g, 8 mmol) in anhydrous toluene (100 mL), triethylamine (4.5 mL, 32
mmol) in the same solvent (20 mL) was added over a period of 1 h and then the reaction mixture was
allowed to reach rt. After one day of stirring, the solvent was removed and the residue was subjected to
gravity or flash chromatography with which unreacted 2a–c and dimers of 1 were generally separated as
predominant compounds. Residues of remaining fractions were then cromatograpfed by CEPTLC.
These reactions were then repeated in anhydrous CH3OH solution under the same conditions. Because of
their insolubility in toluene, reactions of 3a,b with 1 under the stoichiometric ratio of 1:3a,b = 6:1 were
conducted only in anhydrous CH3OH under the same conditions.
Reactions of 1 with 2a
By CEPTLC of the residue of fractions not containing unreacted 2a and dimers of 1,
oxadiazolo[4,5-c]pyrimidine (4), and pyrimid-2-one oxime (7) were isolated together with other products
in so small amounts that they were ignored.
5-Methoxy-3-phenyl-8aH-[1,2,4]oxadiazolo[4,5-c]pyrimidine (4). 30% yield, mp 142–143 °C, from
ethyl acetate. Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.71; H, 4.82; N,
18.40. 1H NMR (DMSO-d6): δ 3.86 (3H, s, methoxyl H), 5.59 (1H, dd, J = 1.7, 3.6 Hz, H-8a), 5.71 (1H,
dd, J = 3.6, 8.0 Hz, H-8), 6.58 (1H, dd, J = 1.7, 8.0 Hz, H-7), 7.32–7.58 (3 H, m, phenyl H), 7.66–8.04
13
(2H, m, phenyl H). C NMR (DMSO-d6): δ 54.76 (methoxyl C), 81.29 (C-8a), 114.84 (C-8), 128.87,
130.45, 131.36, 131.68, 133.53 (C-7 and phenyl C), 153.85 (C-3), 164.70 (C-5). MS (EI): m/z 229, (M+).
2-Methoxy-5-[(Z)-(hydroxyimino)(phenyl)methyl]pyrimidine (7). 9% yield, mp 129–130 °C, from
ethyl acetate. Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 62.69; H, 4.83; N,
18.37. IR (KBr): νmax 3444 br cm-1. 1H NMR (DMSO-d6): δ 3.92 (3H, s, methoxyl H), 7.38–7.58 (3H, m,

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phenyl H), 7.62–7.75 (2H, m, phenyl H), 8.34 (2H, s, H-4 and H-6), 12.26 (1H, br s, oxime H, D2O
exchangeable). 13C NMR (DMSO-d6): δ 54.48 (methoxyl C), 129.92, 131.38, 132.14, 149.65 (phenyl C),
156.47 (oxime C), 159.47 (C-4 and C-6), 163.96 (C-2). MS (EI): m/z 229, (M+).
The same product distribution was observed in CH3OH, but with somewhat lower little yields for 4 (12%)
and 7 (5%). Also 5 was isolated in trace amounts.
Reactions of 1 with 2b
The CEPTLC has allowed to isolate the following products in the stated yields in this order:
4-Methoxypyrimidin-2(1H)-one (15). 26% yield, identical in mp, IR and 1H NMR spectra with those of
a sample prepared according to the literature.17
3,8-Diphenyl-4-methoxy-3a,9a-dihydro-5aH-isozazolo[4,5-e][1,2,4]oxadiazolo[4,5-a]pyrimidine (10).
8% yield, mp 176–178 °C, from ethyl acetate. Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08.
Found: C, 62.29; H, 4.62; N, 16.12. 1H NMR (CDCl3): δ 3.78 (3H, s, methoxy H), 4.42 (1H, d, J = 8.9 Hz,
H-7a), 6.15 (1H, s, H-4a), 6.69 (1H, d, J = 8.9 Hz, H-9a), 7.42–7.78 (10H, m, phenyl H). 13C NMR
(CDCl3): δ 45.62 (C-3a), 54.26 (methoxy C), 83.84 (C-7a), 97.15 (C-9a), 127.48, 128.48, 128.76, 129.12,
131.04, 131.32, 132.01, 134.86 (phenyl C), 153.39 (C-7), 155.78 (C-3), 164.90 (C-8). MS (EI): m/z 348,
(M+).
5-[(Hydroxyimino)(phenyl)methyl]-4-methoxypyrimidin-2(1H)-one (13). 7% yield, mp 135–137 °C,
from ethyl acetate. Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.96; H, 4.53; N,
1
17.11. IR (KBr): νmax 3478 br, 1672 cm-1. H NMR (DMSO-d6): δ 4.04 (3H, s, methoxyl H), 7.44–7.49
(2H, m, phenyl H), 7.66–7.88 (3H, m, phenyl H), 8.47 (1H, d, J = 6.0 Hz, H-6), 9.23 (1H, d, J = 6.0 Hz,
N1-H, D2O-exchangeable), 12.30 (1H, br s, oxime H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 54.98
(methoxyl C), 116.64 (C-5), 127.45, 128.82, 130.69, 134.90 (phenyl C), 149.82 (C-6), 153.93 (oxime C),
158.02 (C-4), 160.02 (C-2). MS (EI): m/z 245, (M+).
From the reaction mixture conducted in CH3OH only 13 (4%) and 15 (12%) were isolated.
Reaction of 1 with 2c
The flash chromatography has allowed to isolate bisadduct (16) and a mixture consisting of
5-methoxypyrimidin-4(3H)-one (19)19, (5% yield) and 5-methoxypyrimidin-2(1H)-one (21)18 (8% yield),
1
which were separated by CEPTLC and then easily identified by comparison of their mps, IR, H NMR
spectrum with those of samples prepared according to the literature.
6-Methoxy-3,9-diphenyl-6aH-bis[1,2,4]oxadiazolo[4,5-a:4’,5’-c]pyrimidine (16). 10% yield, mp
170–172 °C, from ethyl acetate. Anal. Calcd for C19H16N4O3: C, 65.51; H, 4.63; N, 16.08. Found: C,
1
65.41; H, 4.62; N, 16.11. H NMR (CDCl3): δ 3.96 (3H, s, methoxyl H), 5.89 (1H, s, H-6a), 7.04–7.58
(8H, m, H-5, H-10a, and phenyl H), 7.64–7.82 (4H, m, phenyl H). 13C NMR (CDCl3): δ 54.65 (methoxyl
C), 79.86 (C-6a), 94.36 (C-10a), 112.22 (C-5), 124.43, 126.34, 129.74, 129.92, 130.35, 130.79, 132.25,

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134.48, 136.58 (phenyl C), 155.24 (C-9), 159.29 (C-3), 164.28 (C-6). MS (EI): m/z 348, (M+).
Reaction of 1 with 3a
The flash chromatography of the reaction mixture conducted in CH3OH afforded the cycloadduct (22,
60%) identical to that previously obtained by the same reaction conducted in CH2Cl2.5 This, on standing
one day in CH3OH solution in the presence of air and light at rt, quantitatively degrades into benzonitrile
and uracil, identical with authentical samples.
The residual mixture of products was furthermore separated by means of CEPTLC to give mainly oximes
(24) and (26), and bisadduct (28).
1-[(Z)-(Hydroxyimino)(phenyl)methyl)]pyrimidin-2(1H)-one, (24). 9% yield, mp 128–130 °C, from
ethyl acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.30; H, 4.22; N,
1
19.57). IR (KBr): νmax 3448 br, 1674 cm-1. H NMR (DMSO-d6): δ 5.93 (1H, t, J = 8.3 Hz, H-5),
7.47–7.52 (3H, m, phenyl H), 7.85–7.98 (2H, m, phenyl H), 8.02 (1H, dd, J = 1.7, 8.3 Hz, H-6), 9.48 (1H,
dd, J = 1.7, 8.3 Hz, H-4), 12.07 (1H, br s, oxime H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 106.21
(C-5), 128.86, 129.15, 131.57, 134.90 (phenyl C), 154.20 (oxime C), 156.93 (C-4), 166.24 (C-6), 169.16
(C-2). MS (EI): m/z 215, (M+).
1-(4-Hydroxy-3,5-diphenyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)pyrimidin-2(1H)-one (28-I) in mixture
with
1-(4-oxido-3,5-diphenyl-2,5-dihydro-1,2,4-oxadiazol-5-yl)pyrimidin-2(1H)-one
(28-II).
(28-I:28-II = 65:35): 3% global yield, mp 144–148 °C, from ethyl acetate. Anal. Calcd for C18H14N4O3: C,
64.66; H, 4.22; N, 16.76. Found: C, 61.89; H, 4.23; N, 16.74. IR (KBr): νmax 3260 br, 1668 cm-1. 1H NMR
(DMSO-d6): δ 5.94 (1H, t, J = 5.5 Hz, pyrimidone H-5), 7.10 (1H, d, J = 5.5 Hz, pyrimidone H-4),
7.36–7.48 (6H, m, phenyl H), 7.89–8.14 (5H, m, phenyl H, pyrimidone H-6), 10.22 (1H, br s, hydroxyl H,
D2O-exchangeable) 10.69 (1H, br s, N-H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 93.83 (28-I oxad.
C-5), 99.72 (28-II oxad. C-5), 102.42 (pyrimidone C-5), 124.73, 126.36, 128.66, 129.45, 130.31, (phenyl
C), 133.77 (pyrimidone C-4), 148.88 (28-I oxad. C-3), 156.62 (28-II oxad. C-3 ), 162.80 (pyrimidone
C-6), 164.34 (pyrimidone C-2). MS (EI): m/z 334, (M+).
1-[(Z)-(Hydroxyimino)(phenyl)methyl]pyrimidine-2,4(1H,3H)-dione (26). 4% yield, mp 134–136 °C,
from ethyl acetate. Anal. Calcd for C11H9N3O3: C, 57.14; H, 3.92; N, 18.17. Found: C, 57.32; H, 3.93; N,
18.12). IR (KBr): νmax 3478 br, 1676, 1680 cm-1. 1H NMR (DMSO-d6): δ 6.26 (1H, d, J = 7.8 Hz, H-5),
7.33–7.50 (3H, m, phenyl H), 7.55–8.02 (2H, m, phenyl H), 7.86 (1H,d, J = 7.8 Hz, H-6), 11.14 (1H, br s,
amide N-H, D2O-exchangeable), 12.46 (1H, br s, oxime H, D2O-exchangeable). 13C NMR (DMSO-d6): δ
102.28 (C-5), 127.76, 128.74, 130.40, 133.89 (phenyl C), 155.18 (oxime C), 158.29 (C-6 ), 166.20 (C-4),
168.24 (C-2). MS (EI): m/z 231, (M+).
Reaction of 1 with 3b
The flash chromatography of the reaction mixture afforded amidoxime (30) together with minor amount

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of its isomer (31) and a mixture of isoxazolo[5,4-d]pyrimidone (32) and the corresponding oxime (34),
which were separated by CEPTLC.
3-[(Z)-(Hydroxyimino)(phenyl)methyl]pyrimidin-4(3H)-one (30). 45% yield, mp 169–171 °C, from
ethyl acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.31; H, 4.20; N, 19.57.
IR (KBr): νmax 3446 br, 1670 cm-1. 1H NMR (DMSO-d6): δ 6.58 (1H, d, J = 6.7 Hz, H-5), 7.44–7.50 (3H,
m, phenyl H), 7.58–7.63 (2H, m, phenyl H), 8.05 (1H, d, J = 6.7 Hz, H-6), 8.36 (1H, s, H-2), 12.40 (1H,
br s, oxime H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 102.28 (C-5), 127.76, 128.74, 130.40,
133.89 (phenyl C), 152.18 (C-2 ), 155.71 (oxime C ), 158.96 (C-6), 164.85 (C-4). MS (EI): m/z 215,
(M+).
1-[(Z)-(Hydroxyimino)(phenyl)methyl]pyrimidin-4(1H)-one (31). 6% yield, mp 142–144 °C, from
ethyl acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.50; H, 4.20; N, 19.45.
IR (KBr): νmax 3432 br, 1664 cm-1. 1H NMR (DMSO-d6): δ 5.87 (d, 1H, J = 7.4 Hz, H-5), 7.73 (1H, d, J =
7.4 Hz, H-6), 7.45–7.58 (3H, m, phenyl H), 7.84–8.02 (2H, m, phenyl H), 8.12 (1H, s, H-2), 12.36 (1H, br
13
s, oxime H, D2O-exchangeable). C NMR (DMSO-d6): δ 105.41 (C-5), 130.09, 130.41, 132.21, 139.34
(phenyl C), 154.20 (oxime C), 154.66 (C-6), 158.89 (C-2), 164.46 (C-4). MS (EI): m/z 215, (M+).
3-Phenyl-5,7a-dihydroisoxazolo[5,4-d]pyrimidin-4(3aH)-one (32). 5% yield, mp 137–139 °C, from
ethyl acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.29; H, 4.22; N, 19.47.
IR (KBr): νmax 3438 br, 1674 cm-1. 1H NMR (DMSO-d6): δ 5.00 (1H, d, J = 8.2 Hz, H-3a), 6.96 (1H, d, J
= 8.2 Hz, H-7a), 7.12–7.29 (m, 2H, phenyl H), 7.46–7.50 (m, 3H, phenyl H), 9.06 (1H, s, H-6), 11.05 (br
13
d, 1H, N5-H, D2O-exchangeable). C NMR (DMSO-d6): δ 59.84 (C-3a), 91.41 (C-7a), 127.32, 128.36,
130.26, 131.30, 153.96 (C-3), 157.68 (C-6), 166.34 (C-4). MS (EI): m/z 215, (M+).
5[(Z)-(Hydroximimo)(phenyl)methyl]pyrimidin-4(3H)-one (33). 3% yield, mp 163–165 °C, from ethyl
acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.62; H, 4.23; N, 19.50. IR
(KBr): νmax 3412 br, 1668 cm-1. 1H NMR (DMSO-d6): δ 7.17–7.58 (3H, m, phenyl H) 7.86–8.09 (2H, m,
phenyl H), 8.43 (1H, s, H-6), 8.85 (1H, H-2), 10.19 (1H, br s, N-H, D2O-exchangeable), 12.18 (1H, br s,
oxime H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 101.98 (C-5), 128.72, 130.81, 131.37, 136.09
(phenyl C), 150.64 (C-6), 152.54 (C-2), 154.76 (oxime C), 162.84 (C-4); MS (EI): m/z 215, (M+).
Owing to the use of not dried eluents and/or silica, the first tentative of CEPTLC of the residue of
fractions not containing unreacted 3b and dimers of 1 afforded, in addition to the two oximes (30, 38%)
and (33, 4%), N-formyl acetamide (38) consisting of inseparable two isomers (38-I) and (38-II) as shown
by its 1H and 13C NMR spectra.
N-Formyl-2-(3-phenyl-4,5-dihydro-1,2,4-oxadiazol-5-yl)acetamide (38-I) in mixture with
N-Formyl-2-(3-phenyl-2,5-dihydro-1,2,4-oxadiazol-5-yl)acetamide (38-II). (38-I:38-II = 7:13): 9%
global yield, mp 137–141 °C, from ethyl acetate. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N,

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1
18.02. Found: C, 56.85; H, 4.79; N, 17.95). IR (KBr): νmax 3440 br, 1640, 1628 cm-1. H NMR
(DMSO-d6): δ 2.60 (dd, 1H, J = 6.5, 14.5 Hz, 2H-oxad. H-a), 2.92 (1H, dd, J = 5.5, 15.5 Hz, 4H-oxad.
H-a), 2.69 (1H, dd, J = 4.5, 14.5 Hz, 2H-oxad. H-b), 2.98 (1H, dd, J = 5.0, 15.5 Hz, 4H-oxad. H-b), 5.97
(1H, m, 2H-oxad. H-5), 6.12 (1H, m, 4H-oxad. H-5), 6.62 (1H, br s, 2H-oxad. N-H, D2O-exchangeable),
6.74 (1H, br s, 4H-oxad. N-H, D2O-exchangeable), 7.43–7.73 (3H, m, phenyl H), 7.74–7.76 (2H, m,
phenyl H), 10.17 (1H, br s, N-H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 42.64 (2H-oxad.
methylene C), 43.94 (4H-oxad. methylene C), 90.26 (2H-oxad. C-5), 101.29 (4H-oxad. C-5), 126.92,
127.34, 129.56, 131.38, 131.53 (phenyl C), 160.52 (2H-oxad. C-3), 162.76 (4H-oxad. C-3), 167.47
(formyl C), 171.43 (amide C). MS (EI): m/z 233, (M+).
Alkaline hydrolysis of N-formyl acetamide (38)
N-Formyl amide (38) (100 mg, 1 mmol) was dissolved in 1M NaOH/dioxane (1:1 mixture, 5 mL) and
stirred for 2 h at 60 °C. After cooling the reaction mixture was neutralized with 1M HCl (5 mL) and
extracted with chloroform (2 × 5 mL). The combined organic extracts, dried on anhydrous Na2SO4, were
concentrated in vacuum to give the crude amide (39), which was then recrystallized.
2-(3-Phenyl-4,5-dihydro-1,2,4-oxadiazolol-5-yl)acetamide (39-I) in mixture with 2-(3-phenyl-2,5-
dihydro-1,2,4-oxadiazol-5-yl)acetamide (39-II). (39-I:39-II = 77:13): 92% global yield, mp
129–133 °C, from ethyl acetate. Anal. Calcd for C10H11N3O2: C, 58.53; H, 5.40; N, 20.48. Found: C,
58.67; H, 5.39; N, 20.56. IR (KBr): νmax 3444, 3410 br, 1642 cm-1. 1H NMR (DMSO-d6): δ 2.62 (1H, dd,
J = 6.0, 15.3 Hz, 39-I H-a), 2.89 (1H, dd, J = 5.9, 15.8 Hz, 39-II H-a), 2.69 (1H, dd, J = 5.5, 15.3 Hz,
39-I H-b), 2.98 (1H, dd, J = 5.9, 15.8 Hz, 39-II H-b), 5.96 (1H, m, 39-I H-5), 5.97 (1H, m, 39-II H-5),
7.33–7.63 (3H, m, phenyl H), 7.67 (2H, br s, 39-I N-H, D2O-exchangeable), 7.74 (2H, br s, 39-II, N-H,
13
D2O-exchangeable), 7.78–7.86 (2H, m, phenyl H). C NMR (DMSO-d6): δ 39.68 (39-I methylene C),
41.82 (39-II methylene C), 87.95 (39-I oxad. C-5), 99.97 (39-II oxad. C-5), 127.86, 127.92, 128.06,
128.45, 129.44, 130.23, 130.99, (phenyl C), 162.32 (39-I oxad.C-3), 164.56 (39-II oxad. C-3), 167.47
(formyl C). MS (EI): m/z 205, (M+).
Transformation of 10 and 32 into 13 and 33
A sample of 10 or 32 (0.5 mmol), allowed to stand in solution of CH3OH (5 mL) in the presence of air
and light at rt, quantitatively isomerize within two days into 13 or 33, which were identified by
comparison of their mps, IR, 1H NMR spectrum with those of authentical samples.
Conversion of 4 and 16 into 5 and 17
Upon standing in solution of CH3OH in the presence of air and light at room temperature, cycloadducts
(4) or (16) quantitatively degrade within two days into benzonitrile and pyrimidone (5)14 or
pyrimidindione (17)32 which were separated by CEPTLC and then identified by comparison of their mps,
IR, 1H NMR spectrum with those of authentical samples.

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General procedure for the formation of perchlorates (29) and (35) from 24 and 30
After addition of 70% HClO4 (10 mL) to a stirred solution of oximes (24) and (30) (1 mmol) in CHCl3
(10 mL), a vigorous stirring was maintained for other 2 h and then the HClO4 phase was separated and
allowed to stand overnight in an ice bath. From inorganic solution, isoxazolopyrimidinium perchlorates
separated as yellow powders which were recrystallized from acetic acid.
3-Phenyl[1,2,4]oxadiazolo[4,5-a]pyrimidin-4-ium perchlorate (29). 89% yield, mp 208–210 °C, from
ethyl acetate. Anal. Calcd for C11H8N3O5Cl: C, 44.39; H, 2.71; N, 14.12. Found: C, 44.26; H, 2,71; N,
1
14.10. H NMR (DMSO-d6): δ 7.74 (1H, dd, J = 5.8, 7.8 Hz, H-6), 7.68–7.89 (m, 3H, phenyl H),
7.92–7.98 (m, 2H, phenyl H), 8.98 (1H, dd, J = 1.2, 7.8 Hz, H-5), 9.04 (1H, dd, J = 1.2, 5.8 Hz, H-7). 13C
NMR (DMSO-d6): δ 115.09 (C-6), 126.82, 129.35, 130.96, 132.41 (phenyl C), 156.80 (C-5), 159.22 (C 7),
159.63 (C-3), 164.26 (C-7a). MS (EI): m/z 297, (M+).
3-Phenyl[1,2,4]oxadiazolo[4,5-c]pyrimidin-4-ium perchlorate (35). 84% yield, mp 202–204 °C, from
ethyl acetate. Anal. Calcd for C11H8N3O5Cl: C, 44.39; H, 2.71; N, 14.12 Found: C, 44.48; H, 2,70; N,
1
14.13. H NMR (DMSO-d6): δ 7.71 (1H, dd, J = 7.6 Hz, H-8), 7.67–7.82 (m, 3H, phenyl H), 7.92–7.98
(m, 2H, phenyl H), 9.01 (1H, dd, J = 0.9, 7.6 Hz, H-7), 9.54 (1H, d, J = 0.9 Hz, H-5). 13C NMR
(DMSO-d6): δ 106.43 (C-8), 125.33, 129.75, 132.47, 134.12 (phenyl C), 154.13 (C-3), 160.17 (C-7),
164.21 (C-5), 164.77 (C-8a). MS (EI): m/z 297, (M+).
General procedure for the Beckmann rearrangement of Z-oximes (7), (13), (26), and (33) into 8, 14,
27, and 34
To a stirred ice-cooled solution of oximes (7), (13), (26), and (33) (1.0 mmol) in dry dioxane (15 mL) was
added, droopwise, SOCl2 (0.50 mL, 6.6 mmol) over a period of 10 min and then the reaction mixture was
allowed to reach the rt. After having stirred for 10 h, the reaction mixture was poured into cold water (50
mL) and extracted with EtOAc (2 × 30 mL). The organic layers were combined and washed with water (2
× 30 mL), dried with anhydrous Na2SO4 and evaporated under vacuum. Flash chromatography of the
residue afforded amides (8), (14), (27), and (34).
2-Methoxy-N-phenylpyrimidine-5-carboxamide (8). 62% yield, mp 199–201 °C, from ethyl acetate.
Anal. Calcd for C12H11N3O2: C, 62.87; H, 4.84; N, 18.33. Found: C, 61.67; H, 4.86; N, 18.36. IR (KBr):
ν
max 3340 br, 1664 cm-1. 1H NMR (DMSO-d6): δ 3.89 (3H, s, methoxyl H), 7.02–7.35 (3H, m, phenyl H),
7.62–7.87 (2H, m, phenyl H), 8.75 (1H, br s, amide N-H, D2O-exchangeable), 9.14 (2H, s, H-4 and H-6).
13C NMR (DMSO-d6): δ 54.42 (methoxyl C), 119.54 (C-5), 123.48, 124.32, 128.81, 138.90 (phenyl C),
159.59 (C-4, C-6), 165.37 (amide C); 170.30 (C-2). MS (EI): m/z 229, (M+).
4-Methoxy-2-oxo-N-phenyl-1,2-dihydropyrimidine-5-carboxamide (14). 61% yield, mp 218–220 °C,
from ethyl acetate. Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C, 58.90; H, 4.50; N,
1
17.26. IR (KBr): νmax 3344 br, 1666, 1628 cm-1. H NMR (DMSO-d6): δ 3.99 (3H, s, methoxyl H),

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7.06–7.49 (3H, m, phenyl H), 7.64–7.78 (2H, m, phenyl H), 9.4 (1H, d, J = 5.4 Hz, H-6), 11.73 (1H, bd,
N-H, D2O-exchangeable), 9.85 (1H, br s, amide N-H, D2O-exchangeable). 13C NMR (DMSO-d6): δ 53.92
(methoxyl C), 104.72 (C-5), 121.87, 123.59, 129.42, 138.80 (phenyl C), 158.10 (C-6), 158.74 (C-4),
164.41 (C-2), 164.33 (amide C). MS (EI): m/z 245, (M+).
2,4-Dioxo-N-phenyl-3,4-dihydropyrimidine-1(2H)-carboxamide (27). 66% yield, mp 238–240 °C,
from ethyl acetate. Anal. Calcd for C11H9N3O3: C, 57.14; H, 3.92; N, 18.17. Found: C, 57.03; H, 3.92; N,
1
18.22. IR (KBr): νmax 3328 br, 1678, 1668, 1644 cm-1. H NMR (DMSO-d6): δ 6.01 (1H, d, J = 7.6 Hz,
H-5), 7.01–7.28 (3H, m, phenyl H), 7.48–7.66 (2H, m, phenyl H), 8.55 (1H, d, J = 7.6 Hz, H-6), 11.21
(1H, br d, N-H, D2O-exchangeable), 8.7 (1H, br s, amide N-H, D2O-exchangeable). 13C NMR
(DMSO-d6): δ 100.82 (C-5), 119.69, 123.28, 128.75, 138.80 (phenyl C), 148.54(C-6), 159.25 (C-2),
162.27 (amide C), 162.91 (C-4). MS (EI): m/z 231, (M+).
6-Oxo-N-phenyl-1,6-dihydropyrimidine-5-carboxamide (34). 62% yield, mp 224–226 °C, from ethyl
acetate. Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.19; H, 4.28; N, 19.47. IR
1
(KBr): νmax 3346 br, 1680, 1636 cm-1. H NMR (DMSO-d6): δ 7.05–7.19 (3H, m, phenyl H), 7.61–7.78
(2H, m, phenyl H), 8.33 (1H, s, H-6), 7.87 (1H, d, J = 9.2 Hz, H-2), 9.69 (1H, br s, amide N-H,
13
D2O-exchangeable), 10.45 (1H, br d, N3-H, D2O-exchangeable). C NMR (DMSO-d6): δ 118.38 (C-5),
118.35, 124.23, 128.96, 139.44 (phenyl C), 152.43 (C-6), 160.19 (C-2), 162.21 (C-4), 164.11 (amide C).
MS (EI): m/z 215, (M+).
ACKNOWLEDGEMENTS
This work was supported by M.I.U.R. (project P.R.I.N. 2002 and F.I.R.B.).
REFERENCES
1. (a) G. Turk, G. Moroni, S. Pampuro, M. C. Brinon, and H. Salomon, Int. J. Antimic. Agents, 2002, 20,
282; (b) R. Kumar, J. Enz. Inhib. Med. Chem., 2003, 18, 273; (c) R. Kumar, B. Agrawal, D. Tyrrell,
and J. Lorne, PCT Int. Appl. 2002, WO2002094844; (d) S.-T. Jan, M.-J. Shih, T. K. Venkatachalam,
O. J. D’Cruz, C.-L. Chen, and F. M. Uckun, Ant. Chem. Chemoth., 1999, 10, 39; (e) L. I. Wiebe, E. E.
Knaus, A. M. Cheraghali, R. Kumar, K. W. Morin, and L. Wang, Nucleosides Nucleotides Nucleic
Acids, 1995, 14, 501; (f) G. Negron, G. Calderon, F. Vazquez, L. Lomas, J. Cardenas, C. Marquez,
and R. Gavino, Synth. Commun., 2002, 32, 1977; (g) A. F. Sayed Ahmed and E. El Kafrawi, Egypt. J.
Pharm. Sci., 1996, 37, 285.
2. (a) P. Caramella and P. Grünangher, ‘1,3-Dipolar Cycloaddition Chemistry,’ ed. by A. Padwa, Wiley,
New York, 1984; (b) D. P. Curran, ‘Adv. Cycloaddition,’ Vol. 1, 1988, p. 129; (c) W. Carruthers,
‘Cycloaddition Reactions in Organic Synthesis,’ Pergamon Press, Oxford, 1990; (d) P. Grünangher

1096
HETEROCYCLES, Vol. 65, No. 5, 2005
and P. Vta-Finzi, ‘Isoxazoles: The Chemistry of Heterocyclic Compounds,’ Wiley, New York, 1991.
3. (a) U. Chiacchio, A. Corsaro, D. Iannazzo, A. Piperno, V. Pistarà, A. Rescifina, R. Romeo, G.
Sindona, and G. Romeo, Tetrahedron: Asymmetry, 2003, 14, 2717; (b) U. Chiacchio, A. Corsaro, D.
Iannazzo, A. Piperno, V. Pistarà, A. Rescifina, R. Romeo, V. Valveri, A. Mastino, and G. Romeo, J.
Med. Chem., 2003, 46, 3696; (c) M. G. Saita, U. Chiacchio, D. Iannazzo, A. Corsaro, P. Merino, A.
Piperno, T. Previtera, A. Rescifina, G. Romeo, and R. Romeo, Nucleosides Nucleotides Nucleic
Acids, 2003, 22, 749; (d) U. Chiacchio, A. Corsaro, J. Mates, P. Merino, A. Piperno, A. Rescifina, G.
Romeo, R. Romeo, and T. Tejero, Tetrahedron, 2003, 59, 4733; (e) U. Chiacchio, A. Corsaro, D.
Iannazzo, A. Piperno, V. Pistarà, A. Procopio, A. Rescifina, G. Romeo, R. Romeo, M. C. R.
Siciliano, and E. Valveri, Arkivoc, 2002, 11, 159; (f) U. Chiacchio, A. Corsaro, V. Pistarà, A.
Rescifina, D. Iannazzo, A. Piperno, G. Romeo, R. Romeo, and G. Grassi, Eur. J. Org. Chem., 2002,
1206; (g) U. Chiacchio, A. Corsaro, D. Iannazzo, A. Piperno, A. Procopio, A. Rescifina, G. Romeo,
and R. Romeo, Eur. J. Org. Chem., 2001, 1893; (h) U. Chiacchio, A. Corsaro, D. Iannazzo, A.
Piperno, A. Rescifina, R. Romeo, and G. Romeo, Tetrahedron Lett., 2001, 42, 1777; (i) U.
Chiacchio, A. Rescifina, A. Corsaro, V. Pistarà, G. Romeo, and R. Romeo, Tethrahedron:
Asymmetry, 2000, 11, 2045; (j) U. Chiacchio, A. Corsaro, G. Gumina, A. Rescifina D. Iannazzo, A.
Piperno, G. Romeo, and R. Romeo, J. Org. Chem., 1999, 64, 9321.
4. (a) J. N. Kim and E. K. Ryu, J. Org. Chem., 1992, 57, 1088; (b) J. N. Kim and E. K. Ryu,
Heterocycles, 1992, 34, 1423.
5. A. Corsaro, G. Perrini, V. Pistarà, P. Quadrelli, A. Gamba Invernizzi, and P. Caramella, Tetrahedron,
1996, 52, 6421.
6. A. Corsaro, G. Perrini, P. Caramella, F. Marinone Albini, and T. Bandiera, Tetrahedron Lett., 1986,
27, 1517.
7. P. Caramella, T. Bandiera, F. Marinone Albini, A. Gamba Invernizzi, A. Corsaro, and G. Perrini,
Tetrahedron, 1998, 44, 4917.
8. F. Marinone Albini, R. De Franco, T. Bandiera, P. Caramella, A. Corsaro, and G. Perrini, J.
Heterocycl. Chem., 1988, 26, 757.
9. J. A. Ross, R. P. Seiders, and D. M. Lemal, J. Am. Chem. Soc., 1976, 98, 4325.
10. D. J. Brown, ‘Comprehensive Heterocyclic Chemistry,’ Vol. 3, Part 2B, ed. by A. R. Katritzky, W.
R. Charles, A. J. Boulton, and A. McKillop, Pergamon Press, Oxford, 1984.
11. A. Corsaro, U. Chiacchio, V. Pistarà, and G. Perrini, Heterocycles, 2000, 53, 69.
12. P. Caramella, A. Gamba Invernizzi, and P. Quadrelli, ‘Atti del XXI Convegno Nazionale della
Divisione di Chimica Organica,’ Terrasini (Palermo), Italy, 28 settembre–2 ottobre 1993.
13. (a) W. J. Tuman and L. Bauer, J. Org. Chem., 1972, 37, 2983; (b) E. C. Taylor and E. E. Garcia, J.

HETEROCYCLES, Vol. 65, No. 5, 2005
1097
Org. Chem., 1964, 29, 2116; (c) G. Desimomi, P. Grünanger, and P. Vita Finzi, Tetrahedron, 1967,
23, 675 and 681; (d) Jpn. Kokai, 1979, 7944696; (e) D. Van Tinh and W. Stadlbauer, J. Heterocyclic
Chem., 1996, 33, 1025; (f) G. Renzi, V. D. Piaz, and C. Musante, Gaz. Chim. Ital., 1973, 103, 219.
14. J. L. Wong and D. S. Fuchs, J. Org. Chem., 1970, 35, 3786.
15. R. E. Gawley, Org. React., 1988, 35, 1.
16. G. Bianchi, C. De Micheli, R. Gandolfi, P. Grünangher, P. Vita Finzi, and O. Vajna de Pava, J.
Chem. Soc., Perkin Trans. 1, 1973, 1148.
17. M. Prystas, Collect. Czech. Chem. Comm., 1975, 40, 1786.
18. T. J. Kress, J. Org. Chem., 1985, 50, 3073.
19. (a) J. F. W. Mc Comie and A. B. Turner, J. Chem. Soc., 1963, 5590; (b) S. A. Jacobsen, S.
Rodbotten, and T. Benneche, J. Chem. Soc., Perkin Trans. 1, 1999, 3265.
20. (a) J. Elguero, C. Marzin, A. R. Katritzky, and P. Linda, ‘Advaces in Heterocyclic Chemistry,’
Supplement 1, Academic Press, New York, 1976, pp. 127–129; (b) P. Cieplak, P. Bash, C. Singh,
and P. A. Kollman, J. Am. Chem. Soc., 1987, 109, 6283; (c) K. Pihlaja, P. Oksman, G. Stajer, and G.
Bernàth, Org. Mass Spectrometry, 1990, 25, 115; (d) S. F. Mason, J. Chem. Soc., 1957, 4874.
21. D. J. Brown, E. Hoerger, and S. F. Mason, J. Chem. Soc., 1955, 211.
22. A. Albert and E. Spinner, J. Org. Chem., 1960, 31, 1221.
23. (a) Y. Inoue, N. Furutachi, and K. Nakanishi, J. Org. Chem., 1966, 31, 175; (b) L. Bauer, G. E.
Wright, B. A. Mikrut, and C. L. Bell, J. Heterocycl. Chem., 1965, 2, 447; (c) G. W. H. Cheeseman,
C. J. Turner, and D. J. Brown, Org. Magn. Reson., 1979, 12, 212; (d) G. B. Barlin and M. D. Fenn,
Heterocycles, 1986, 24, 1301.
24. (a) T. J. Delia, J. Org. Chem., 1984, 49, 2065; (b) R. S. Sodum, R. S. Klein, and B. A. Otter, J.
Heterocycl. Chem., 1986, 23, 1239.
25. (a) E. Abele, R. Abele, and E. Lukevics, Chem. Het. Comp., 2003, 39, 825; (b) J. P. Adams, J. Chem.
Soc., Perkin Trans. 1, 2000, 125. (c) J. P. Adams, Cont. Org. Synth., 1997, 4, 517.
26. W. C. Still, M. Kahn, and A. Mitra, J. Org. Chem., 1978, 43, 2923.
27. G. Bianchetti, D. Pocar, and P. Dalla Croce, Gazz. Chim. Ital., 1963, 93, 1714.
28. D. J. Brown and R. V. Foster, J. Chem. Soc., 1965, 4911.
29. D. J. Brown and L. N. Short, J. Chem. Soc., 1953, 331.
30. L. Valgimigli, G. Brigati, G. Pedulli, G. A. Di Labio, M. Mastragostino, C. Arbizzani, and D. A.
Pratt, Chem. Eur. J., 2003, 9, 4997.
31. W. L. F. Armarego and D. D. Perrin, ‘Purification of Laboratory Chemicals,’ 4th ed.,
Butterworth-Heinemann, Oxford, 1996.
32. S. A. Jacobsen, S. Rodbotten, and T. Benneche, J. Chem. Soc., Perkin Trans. 1, 1999, 3265.