1, 3-dipolar cycloaddition reactions of benzonitrile oxide to 2(1II)-pyrazinone and its n- and o-methyl derivatives

Article abstract of DOI:10.3987/COM-99-8720

2(1H)-Pyrazinone, which is in equilibrium with 2-pyrazinol, reacts with benzonitrile oxide (BNO) affording the N-adducl with a 67% yield, while 2-methoxypyrazine gives two methoxypyrazinones (ca. 3%) and a biscycloadduct together with its degradation product, which derive from the two unisolable monocycloadducts to the C=N4 double bond. Af-Methylpyrazinone gives only the degradation product (3.4%) of the initial monocycloadduct of BNO to C=N4: double bond.

Full text of DOI:10.3987/COM-99-8720

HETEROCYCLES, Vol. 53, No. 1, 2000, p. 69 - 80, Received, 29th July, 1999
1,3-DIPOLAR CYCLOADDITION REACTIONS OF
BENZONITRILE OXIDE TO 2(1H)-PYRAZINONE AND ITS
N- AND O-METHYL DERIVATIVES
Antonino Corsaro,* Ugo Chiacchio, Venerando Pistarà, and Giancarlo Perrini
Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria 6, 95125 Catania, Italy
*Fax: +39 095 580138; E-mail: acorsaro@dipchi.unict.it
Abstract - 2(1H)-Pyrazinone, which is in equilibrium with 2-pyrazinol, reacts with benzonitrile
oxide (BNO) affording the N1-adduct with a 67% yield, while 2-methoxypyrazine gives two
methoxypyrazinones (ca. 3%) and a biscycloadduct together with its degradation product, which
derive from the two unisolable monocycloadducts to the C=N4 double bond. N-Methylpyrazinone
gives only the degradation product (3.4%) of the initial monocycloadduct of BNO to C=N4 double
bond.
Recently, we investigated the reactions of benzonitrile oxide (BNO) with aromatic diazines1 within a study
aimed at analysing the effect of the aza-substitution on the reactivity, regio- and stereochemistry of
pyridine nucleus, the dipolarophilic reactivity of which has been object of previous researches by us2-4
and others.5-8
Among the three diazines, we found that pyrazine (1) behaves like pyridine affording an unisolable
intermediate monocycloadduct (2), deriving from the addition of BNO in a concerted pseudopericyclic
cycloaddition,9 which in its turn originates the two stable cycloadducts (3) and (4), where a second molecule
of BNO is regio- and anti-stereospecifically added to the C=N or C=C double bond of 2 (Scheme 1). The
aza-substitution in the γ-position of the dienaminic system of monocycloadduct (2) increases the reactivity
of the γ,δ-double bond and reverses the regiochemistry of the γ,δ-attack with respect to pyridine,2 too.
Ph
N
O
N
H
H
N
O
N
N
H
H
N
N
Ph
O
BNO
3
O
Ph
N
N
H
N
N
H
H
Ph
1
2
N
O
H
N
Ph
4
Scheme 1

As extension of this line of research we have investigated the reactivity of 2(1H)-pyrazinone (5A) which
is in equilibrium with 2-pyrazinol (5B) and their N- (6) and O-methyl derivatives (7) towards BNO. The
study of these reactions appeared to us very interesting because they represent an unexplored route to the
synthesis of dihydroisoxazolo- or isoxazolo[4,5-b]pyrazine nucleosides which are analogous of the
naturally occurring purine nucleosides. In old works the construction of such heterocycles was carried out
starting from the rather unstable 4,5-diaminoisoxazole isolated as hydrochloride.10-12
To our best knowledge, the dipolarophilic reactivity of 2-pyrazinone (5) and its N- (6) and O-methyl
derivatives (7) has been neglected. Only 2,5- and 2,6-dihydroxypyrazines participate in a number of
interesting cycloaddition reactions, but as 1,3-dipoles.13-15
RESULTS AND DISCUSSION
Reactions were conducted by slowly adding three equivalents of a triethylamine solution in methanol to a
stirred, ice cooled, solution of pyrazine derivatives (5-7) and benzhydroximic acid chloride in the 1:3 ratio
in the same solvent. After heating to room temperature, the reaction mixture was allowed under stirring
for two days and then the solvent was removed and the residue was chromatographed. When ether,
chloroform or benzene were used as solvents, reaction mixtures afforded slightly different yields of the
same products and in some cases only a new N-addition product was isolated. Because of their
insolubility in the latter solvents, reactions of 5 and 6 were conducted in suspension and in these cases the
separated solid was filtered and then analyzed, while the filtrate was treated as above.
2(1H)-Pyrazinone
From literature data16-21 evidence exists that 2(1H)-pyrazinone (5A) is in equilibrium with 2-
hydroxypyrazine (5B), where the first is the dominant tautomer. We found that only 5A reacts with BNO
in methanol affording the N1-adduct (8) with a 67.6% yield, but 5B is probably involved in the addition of
BNO to the N1-nitrogen of 5. The presence of the hydroxy group in the 2-position favours the formation of a
hydrogen bonding with the oxygen of the 1,3-dipole and then the attack of the N1-nitrogen of 5 to the carbon
of the 1,3-dipole.
N
N
N
N
N
I2-KI
BNO
N
O
N
O
O
NaHCO3
THF/H2O
N
H
O
OH
HO
N
N
Ph
Ph
5B
5A
8
9
Scheme 2

The structure of 8 was inferred from spectral and chemical data. Its IR spectrum shows two absorptions at
3447 br and 1675 cm-1; in its 1H-NMR spectrum signals of pyrazinone H5- and H6-protons are covered by
those of phenyl ring, while those of the H3 pyrazinone and amidoxime protons appear at 8.21 and 12.32
ppm; besides signals of carbons of phenyl group, its 13C-NMR spectrum contains signals at 130.31,
130.39, 144.26 and 153.03 ppm for C5-, C6-, C3- and C2-pyrazine carbons and at 150.51 ppm for
amidoxime carbon. By oxidation with iodine-potassium iodide in aqueous tetrahydrofuran in the presence
of sodium bicarbonate,22 8 afforded 3-phenyl-5H-[1,2,4]oxadiazolo[4,5-a]pyrazin-5-one (9), whose IR
1
13
and H-NMR spectra do not show the absorption of the hydroxy group and C-NMR spectrum exhibits
another quaternary carbon at 158.92 ppm.
1-Methyl-2(1H)-pyrazinone
1-Methyl-2(1H)-pyrazinone (6) is a very poor dipolarophile because of the deactivating effect of the
carbonyl and methylamino groups on the cyclic system. It reacts with BNO in methanol giving only a
3.4% yield of 1-methyl-3-hydroxypyrazin-2-one (11) deriving from the unisolable monocycloadduct (10)
of BNO to the C=N4 double bond of 6, which remains the most reactive site of the molecule.
Monocycloadduct (10) then undergoes the degradation process with the loss of benzonitrile because of
the autoxidation (Scheme 3).2, 3
1H- and 13C-NMR spectra of 11 support the assigned structure because, besides the signal of methyl
1
protons and carbon at 3.41 and 38.31 ppm, respectively, the H-NMR spectrum shows two doublets at
6.18 and 6.47 ppm for pyrazinone H6- and H5-protons and a broad singlet at 11.35 ppm for the hydroxy
proton, while the 13C-NMR shows signals at 119.59 and 129.14 ppm for olefinic C6- and C5-carbons and
at 154.40 and 155.72 ppm for carbonyl carbons. Furthermore the IR spectrum contains absorption bands
at 3260 br and 1670 cm-1 for hydroxy and carbonyl groups, respectively.
Ph
Ph
N
OH
O
N
N
N
OH
O
O
N
N
N
BNO
-PhCN
N
O
N
O
N
O
CH3
CH3
CH3
CH3
10
6
11
12
Scheme 3
Pyrazinedione (11) separates together with triethylamine hydrochloride as a precipitate when the reaction
is carried out in ether or benzene suspension with a yield of 2.8 and 1.9%, respectively. When chloroform
was used as a solvent, the chromatography eluted also another compound (12) (2.8% yield) which derives

from the addition of BNO to the N4-nitrogen of 11, this latter isolated with a 2.5% yield. Besides signals
relative to phenyl protons and carbons, the 1H-NMR spectrum contains an oxime proton at 12.45 ppm and
13C-NMR spectrum contains another signal of quaternary carbon at 158.18 ppm; the IR spectrum shows
the broad band of hydroxy group at 3398 cm-1.
2-Methoxypyrazine
The reaction mixture of 2-methoxypyrazine (7) with BNO in ether afforded the two methoxypyrazinones
(15) (3.0%) and (21) (2.8%) and a biscycloadduct (18) (9.6%), which latter derives from the addition of a
second molecule of BNO to the C=C double bond of 17, together with its degradation product (19)
(6.2%) (Scheme 4). As separately it was proven, the biscycloadduct (18) degrades into 19 and
benzonitrile upon standing in different solvents. Pyrazinones (15) and (21) are originated from
monocycloadducts (14) and (17) which are unstable to the autoxidation process leading to the loss of
1
benzonitrile2,3 in the reaction conditions. They have been well distinguished because in the H-NMR
spectra the signals of H3- and H6-protons of 15 appear as singlets at 8.14 and 7.97 ppm and those of H5-
and H6-protons of 21 appear as doublets at 6.94 and 7.00 ppm, respectively; in the 13C-NMR spectra
signals of C3- and C6-carbons of 15 are at 142.36 and 140.60 ppm, while those of C5- and C6-carbons of
21 are at 112.36 and 119.72 ppm.
In an attempt of acid hydrolysis by 20% hydrochloric acid methoxypyrazinones (15) and (21) afforded the
known pyrazinones (16)23 and (23).24
When the reaction mixture was conducted in methanol compound (22) was also isolated. It derives from
the addition of BNO to the N1-nitrogen of 21 and the structure of which has been inferred from spectral
data. Its IR spectrum is characterized by absorptions at 3430 br and 1660 cm-1 which are attributable to
1
the oximic hydroxy and carbonyl groups, respectively. Its H-NMR spectrum contains two doublets at
6.94 and 7.10 ppm for H5- and H6-protons and a broad singlet at 12.25 ppm for the oximic proton, while
its 13C-NMR spectrum contains the signal of another quaternary carbon at 156.57 ppm. Also structures of
18 and 19 rely upon their spectroscopic data and upon acid hydrolysis of 19, which afforded
1
dihydroisoxazole[4,5-b]-1,4-dihydropyrazine-2,3-dione (20). The H-NMR spectrum of 18 shows a
singlet at 5.73 ppm for the H5-oxadiazole proton and two doublets at 5.29 and 5.74 ppm with J = 8.2 Hz
for H4- and H5-isoxazole protons, besides the signal of methoxy proton at 3.78 ppm. The 13C-NMR
spectrum shows signals relative to the methoxy carbon at 53.71 ppm, the isoxazoline ring carbons at
60.63, 79.80 and 156.00 ppm and the oxadiazoline ring carbons at 81.72 and 150.00 ppm. The anti-
stereochemistry of 18 could not be deduced from its spectra, but it is proposed by analogy to pyridine,4
pyrimidine8 and pyridazine8 biscycloadducts, whose stereochemistry relies upon an X-Ray
crystallographic analysis.

Ph
N
O
N
N
N
N
BNO
OCH3
OCH3
7
13
Ph
Ph
N
N
O
N
N
O
N
N
OCH3
OCH3
17
14
-PhCN
-PhCN
BNO
Ph
N
HO
N
N
N
OH
O
N
N
O
OCH3
N
H
N
15
OCH3
H+, H2O
OCH3
Ph
21
18
H+, H2O
-PhCN
O
H
N
BNO
Ph
O
H
H
N
N
OH
O
O
N
O
O
O
N
N
N
16
OCH3
N
N
H
N
OCH3
Ph
19
H+, H2O
22
23
H
N
O
O
O
N
N
H
Ph
20
Scheme 4

1
Besides the broad signal at 7.33 ppm relative to the amide proton, the H-NMR spectrum of 19 contains
signals of methoxy and H4- and H5-isoxazoline protons at 3.76, 5.45 and 5.93 ppm. This latter appears as
double doublet25 and confirms the assigned regiochemistry. Its 13C-NMR spectrum contains another
quaternary carbon at 152.80 ppm and its IR spectrum shows an absorption at 1660 cm-1. The
disappearance of the signal relative to the methoxy protons and carbon in their 1H- and 13C-NMR spectra
and the appearance of another carbonyl carbon at 156.15 ppm characterize the 13C-NMR spectrum of 20.
These results are in line with our previous mechanistic hypothesis on the reactivity of pyridine towards
BNO,2 which involves a mechanism of pesudopericyclic reaction.9 Monocycloadducts (14) and (17) are
viewed as secondary products which derive from the electrocyclic closure of the initial adduct 13 of BNO
to the N4-nitrogen of 7. The oxygen atom of the dipole then cyclizes on the C3- or C5-carbons affording
the two corresponding unstable monocycloadducts, which undergo either the autoxidation process2,3 or
the addition of second molecule of BNO to the C=C double bond of 7 to give the biscycloadduct (18).
In contrast with the reaction of BNO with 5, where the presence of the hydroxy group in the 2-position
directs the attack to the N1-nitrogen to the 1,3-dipole carbon, in this case of 7 only the N4-nitrogen is
reactive towards BNO because of the presence of the methoxy group which is unfavourable to the attack
of BNO to the N1-nitrogen to give the zwitterion (24) (Scheme 5). Indeed, the electrocyclization of 24 on
the C2-carbon would lead to the reversible formation of the ketal (25), while that one on C6-carbon to give
26 does not take place because of the steric hindrance of the 1,3-dipole phenyl ring with the methoxy
group.
N
OCH3
N
O
N
N
N
BNO
Ph
25
N
OCH3
O
N
OCH3
N
N
X
Ph
N
7
OCH3
O
24
N
26
Ph
Scheme 5
We have searched for one of our target reaction products (28) or (30), which should be obtained by
elimination of methanol from cycloadducts (27) or (29), but without success (Scheme 6). Probably these
latter, which are also favoured by the electron donor effect of methoxy group, as well as other
conceivable products are formed in our reaction conditions, but their yields are so low that they escape
their isolation from the reaction mixture.

Ph
Ph
Ph
N
N
Ph
N
N
H
Ph
N
BNO
O
O
N
N
-CH3OH
N
O
N
N
X
O
N
OCH3
O
OCH3
14
28
27
-PhCN
H
N
H
Ph
H
H
Ph
N
O
O
N
BNO
O
N
-CH3OH
X
N
O
OCH3
N
OCH3
N
O
N
15
29
30
Scheme 6
In conclusion, the results of these reactions examined by us show that only the route for
dihydroisoxazolopyrazine heterocycles through a 1,3-dipolar cycloaddition process of 7 with BNO,
followed by an acid hydrolysis can be useful, even if the yield remains modest.
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-NMR spectra were recorded on a
Varian 200 spectrometer using tetramethylsilane as internal standard and deuterochloroform or DMSO-d6
as solvents. IR spectra were recorded on a Perkin Elmer Paragon 500 FT IR spectrophotometer using
potassium bromide discs and MS on a VG ZAB-2SE spectrometer operating at 70 eV. Thin layer
chromatography were performed on aluminium plates pre-coated with Merck silica gel 60-F254.
Preparative chromatographic separations of reaction mixtures were performed by means of gravity or
flash chromatography using Merck silica gel 60 and in some cases by means of centrifugally enhanced
preparative thin layer chromatography using Merck silica gel 60 PF254. Mixtures of cyclohexane-ethyl
acetate were used as eluents.
Starting materials.
Benzhydroximic acid chloride was obtained by treatment of benzaldoxime with sodium hypochlorite;26
2(1H)-pyrazinone,27 1-methyl-2(1H)-pyrazinone28 and 2-methoxypyrazine27 were prepared from 2-
chloropyrazine following literature procedures. Benzaldoxime and 2-chloropyrazine are commercial

compounds and have been purchased from the Aldrich Co. Eluents used in chromatography were reagent
grade. Solvents were dried following literature procedures.29
The identification of samples deriving from different experiments was secured by mixed melting points
and IR spectra.
General procedure for reactions of BNO with pyrazine derivatives (5-7).
To a stirred, ice cooled, solution of benzhydroximic acid chloride (0.3 mol) and pyrazine derivative (0.1
mol) in anhydrous methanol (100 mL) 0.3 mol of triethylamine in the same solvent (30 mL) were added
over a period of 0.5 h. After having warmed the reaction mixture to rt, it was allowed under stirring for
two days and then the solvent was removed and the residue was chromatographed. The same reactions
were repeated in solution or suspension because of the insolubility of pyrazinones, in ether, benzene and
chloroform. In these cases a solid separated which was filtered and then analysed, while the filtrate was
worked up as above.
1-[(Hydroxyimino)(phenyl)methyl]pyrazin-2(1H)-one (8): 67.6% yield, mp 190-191 °C, pale yellow
crystals from ethyl acetate (Anal. Calcd for C11H9N3O2: C, 61.39; H, 4.22; N, 19.53. Found: C, 61.42; H,
4.19; N, 19.49); νmax (KBr): 3447 br, 1675 cm-1; δH (DMSO-d6): 7.43-7.56 (7H, m, phenyl H, pyrazinone
H5 and H6), 8.21 (1H, s, pyrazinone H3), 12.32 (1H, br s, hydroxy H); δC (DMSO-d6): 123.09, 125.46,
128.79, 128.88, 128.92, 128.96 (phenyl C), 130.31(pyrazinone C6), 130.39 (pyrazinone C5), 144.26
(pyrazinone C3), 152.51 (pyrazinone C2), 155.03 (amidoxime C); MS: m/z 215 (M+).
Conversion of 8 into 9 by iodine-potassium iodide oxidation.
To a stirred solution of 8 (430 mg, 2 mmol) in tetrahydrofuran (40 mL) was added a solution of sodium
bicarbonate (680 mg, 8.1 mmol) in water (50 mL). The reaction mixture was protected from light, and a
solution of potassium iodide (1,175 g, 7.0 mmol) and iodine (541 mg, 2.1 mmol) in water (100 mL) was
added to it. After refluxing for 4 h, the mixture was diluted with concentrated sodium bisulfide solution
(150 mL), extracted with ether, dried over sodium sulfate and then evaporated at reduced pressure. The
crystallization of the residue gave 350 mg of 3-phenyl-5H-[1,2,4]oxadiazolo[4,5-a]pyrazin-5-one (9):
85.1% yield, mp 152-154 °C, colourless crystals from ethanol (Anal. Calcd for C11H7N3O2: C, 62.00; H,
3.28; N, 19.75. Found: C, 61.97; H, 3.31; N, 19.71); νmax (KBr): 1672 cm-1; δH (CDCl3): 7.15 (1H, s,
pyrazinone H-3) 7.48-7.52 (3H, m, phenyl H), 7.59-7.62 (2H, m, phenyl H), 8.12 (1H, s, pyrazinone H-
5); δC (CDCl3): 122.40, 130.90, 131.06, 131.43, (phenyl C), 134.60 (pyrazinone C-3), 150.92 (pyrazinone
C-5), 152.36 (pyrazinone C-6), 154.21 (oxadiazole C-3), 158.92 (oxadiazole C-5); MS: m/z 213 (M+).

1-Methyl-3-hydroxypyrazine-2-one (11): 3.4% yield, mp 229-231 °C (lit.,30 mp 230-232 °C) colourless
crystals from ethanol (Anal. Calcd for C5H6N2O2: C, 47.6; H, 4.8; N, 21.20. Found: C, 47.9; H, 5.1; N,
22.0); νmax (KBr): 1692, 1670 cm-1; δH (DMSO-d6): 3.40 (3H, s, methyl H), 6.18 (1H, d, J = 5.2 Hz,
pyrazine H-6), 6.40 (1H, d, J = 5.2 Hz, pyrazine H-5), 11.35 (1H, br s, hydroxy H); δC (DMSO-d6): 38.31
(methyl C), 119.78 (pyrazine C-5), 129.27 (pyrazine C-6), 154.40 (pyrazine C-3), 155.72 (pyrazine C-2);
MS: m/z 126 (M+).
1-[(Hydroxyimino)(phenyl)methyl]-4-methyl-1,4-dihydropyrazine-2,3-dione (12): 2.8% yield, mp 189-
191 °C, colourless crystals from ethyl acetate (Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13.
Found: C, 58.84; H, 4.55; N, 17.18); νmax (KBr): 3496 br, 1672 cm-1; δH (DMSO-d6): 3.59 (3H, s, methyl
H), 6.53 (1H, d, J = 5.8 Hz, pyrazine H-6), 6.80 (1H, d, J = 5.8 Hz, pyrazine H-5), 7.58-7.64 (3H, m,
phenyl H), 7.80-7.88 (2H, m, phenyl H), 12.41 (1H, br s, hydroxy H); δC (DMSO-d6): 37.18 (methyl C),
113.13 (pyrazine C-5), 116.54 (pyrazine C-6), 128.02, 130.80, 132.21, 139.82 (phenyl C), 150.75
(pyrazine C-3), 153.80 (pyrazine C-2), 158.18 (amidoxime C); MS: m/z 245 (M+).
2-Hydroxy-5-methoxypyrazine (15): 3.0% yield, mp 168-170 °C, colourless crystals from ethanol (Anal.
Calcd for C5H6N2O2: C, 47.62; H, 4.80; N, 22.21. Found: C, 47.59; H, 4.82; N, 22.19); νmax (KBr): 3258
br cm-1; δH (DMSO-d6): 3.98 (3H, s, methoxy H), 7.97 (1H, s, pyrazine H-6), 8.14 (1H, s, pyrazine H-3),
11.23 (1H, br s, hydroxy H); δC (DMSO-d6): 54.90 (methoxy C), 140.60 (pyrazine C-6), 142.36 (pyrazine
C-3), 148.50 (pyrazine C-5), 153.23 (pyrazine C-2); MS: m/z 126 (M+).
5-Methoxy-3,8-diphenyl-3a,9a-dihydro-5aH-isoxazolo[4',5':5,6]pyrazino[1,2-d][1,2,4]oxadiazole (18):
9.6% yield, mp 174-176 °C, pale yellow crystals from ethyl acetate (Anal. Calcd for C19H16N4O3: C,
65.51; H, 4.63; N, 16.08. Found: C, 65.57; H, 4.58; N, 16.18); νmax (KBr): 1600, 1570, cm-1; δH (CDCl3):
3.78 (3H, s, methoxy H), 5.29 (1H, d, J = 8.2 Hz, dihydroisoxazole H-4), 5.73 (1H, s, dihydroxadiazole
H-5), 5.74 (1H, d, J = 8.2 Hz, dihydroisoxazole H-5), 7.41-7.97 (10H, m, phenyl H); δC (CDCl3): 53.71
(methoxy C), 60.63 (dihydroisoxazole C-5), 79.80 (dihydroisoxazole C-4), 81.72 (dihydroxadiazole C-5),
127.29, 128.17, 128.63, 129.34, 130.60,131.90, 132.11, 140.32 (phenyl C), 156.00 (dihydroisoxazole C-
3), 158.38 (dihydroxadiazole C-3), 159.69 (pyrazine C-2); MS: m/z 348 (M+).
5-Methoxy-3-phenyl-7,7a-dihydroisoxazolo[4,5-b]pyrazin-6(3aH)-one (19): 6.2% yield, mp 196-198 °C,
pale yellow crystals from ethyl acetate (Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found:
C, 58.87; H, 4.58; N, 17.18); νmax (KBr): 1660 cm-1; δH (CDCl3): 3.76 (3H, s, methoxy H), 5.45 (1H, d, J
= 7.8 Hz, dihydroisoxazole H-4), 5.83 (1H, dd, J1 = 7.8 Hz, J2 = 4.2 Hz, dihydroisoxazole H-5), 7.33 (1H,

br s, amide H), 7.93-7.98 (5H, m, phenyl H); δC (CDCl3): 54.26 (methoxy C), 62.41 (dihydroisoxazole C-
4), 84.16 (dihydroisoxazole C-5), 127.35, 127.63, 128.01, 128.80, 130.75 (phenyl C), 152.25 (pyrazine C-
3), 152.80 (dihydroisoxazole C-3), 157.63 (pyrazine C-2); MS: m/z 245 (M+).
2-Hydroxy-3-methoxypyrazine (21): 2.8% yield, mp 201-203 °C (lit.,31 mp 205 °C), colourless crystals
from ethanol (Anal. Calcd for C5H6N2O2: C, 47.62; H, 4.80; N, 22.21. Found: C, 47.67; H, 4.88; N,
22.18); νmax (KBr): 3420 br cm-1; δH (DMSO-d6): 4.01 (3H, s, methoxy H), 6.91 (1H, d, J = 4.2 Hz,
pyrazine H-6), 7.00 (1H, d, J = 4.2 Hz, pyrazine H-5), 12.64 (1H, br s, hydroxy H); δC (DMSO-d6): 53.50
(methoxy C), 112.36 (pyrazine C-5), 119.72 (pyrazine C-6), 152.54 (pyrazine C-2), 158.28 (pyrazine C-
3); MS: m/z 126 (M+).
1-[(Hydroxyimino)(phenyl)methyl]-3-methoxypyrazin-2(1H)-one (22): 2.1% yield, mp 190-192 °C,
colourless crystals from ethanol (Anal. Calcd for C12H11N3O3: C, 58.77; H, 4.52; N, 17.13. Found: C,
58.87; H, 4.48; N, 17.21); νmax (KBr): 3430 br, 1660 cm-1; δH (DMSO-d6): 3.88 (3H, s, methoxy), 6.94
(1H, d, J = 4.5 Hz, pyrazine H-5), 7.09 (1H, d, J = 4.5 Hz, pyrazine H-6), 7.43-7.52 (5H, m, phenyl H),
12.25 (1H, s, hydroxy H); δC (DMSO-d6): 54.10 (methoxy C), 118.57, 122.10, 125.43 (phenyl C), 130.23
(pyrazine C-5), 130.40 (pyrazine C-6), 154.24 (pyrazine C-2), 158.34 (pyrazine C-3), 156.57 (amidoxime
C); MS: m/z 245 (M+).
Acid hydrolysis of adducts (15, 19 and 21).
A solution of 15, 19 or 21 (4 mmol) in ethanol (10 mL) containing 20% hydrochloric acid (2 mL) was
refluxed for 6 h. After cooling the mixture was poured on ice and extracted with chloroform. The
combined extracts were washed with 5% sodium hydroxide and dried on anhydrous sodium sulphate. The
solvent was evaporated to give products (16),23 (20) or (23),24 of which 16 and 23 were identical with
authentic samples prepared following literature methods.
1,6-Dihydropyrazine-2,5-dione (16):23 95% yield, mp > 320 °C, colourless crystals from ethanol (Anal.
Calcd for C4H4N2O2: C, 42.86; H, 3.60; N, 24.99. Found: C, 42.81; H, 3.62; N, 25.03); νmax (KBr): 3286
br cm-1; δH (DMSO-d6): 8.12 (1H, s, pyrazine H-6), 8.32 (1H, s, pyrazine H-3), 11.34 (2H, br s, hydroxy
H); δC (DMSO-d6): 140.98 (pyrazine C-6), 145.77 (pyrazine C-3), 154.42 (pyrazine C-2), 154.67
(pyrazine C-5); MS: m/z 112 (M+).
3-Phenyl-3a,4,7,7a-tetrahydroisoxazolo[4,5-b]pyrazine-5,6-dione (20): 88% yield, mp 171-172 °C, pale
yellow crystals from ethyl acetate (Anal. Calcd for C11H9N3O3: C, 57.14; H, 3.92; N, 18.17. Found: C,

57.21; H, 3.89; N, 17.22); νmax (KBr): 1692, 1674 cm-1; δH (CDCl3): 5.42 (1H, dd, J1 = 7.9 Hz, J2 = 4.3
Hz, dihydroisoxazole H-4), 5.96 (1H, dd, J1 = 7.9 Hz, J2 = 4.0 Hz, dihydroisoxazole H-5), 7.30 (2H, br s
amide H), 7.27-7.71 (5H, m, phenyl H), δC (CDCl3): 63.78 (dihydroisoxazole C-4), 85.94
(dihydroisoxazole C-5), 127.42, 127.87, 128.34, 130.56 (phenyl C), 155.36 (pyrazindione C-3), 156.12
(pyrazindione C-2) 157.14 (dihydroisoxazole C-3); MS: m/z 231 (M+).
1,4-Dihydropyrazine-2,3-dione (23):24 92% yield, mp >330 °C, pale yellow crystals from ethanol (Anal.
Calcd for C4H4N2O2: C, 42.86; H, 3.60; N, 24.99. Found: C, 42.91; H, 3.58; N, 25.03); νmax (KBr): 3420
br cm-1; δH (DMSO-d6): 6.64 (2H, s, pyrazine H-5 and H-6), 11.42 (2H, br s, hydroxy H); δC (DMSO-d6):
119.34 (pyrazine C-4 and C-5), 153.86 (pyrazine C-2 and C-3); MS: m/z 112 (M+).
ACKNOWLEDGEMENTS
Authors are grateful to the Italian M.U.R.S.T. for partial financial support.
REFERENCES AND NOTES
1.
2.
3.
4.
5.
6.
A. Corsaro, G. Perrini, V. Pistarà, P. Quadrelli, A. Gamba Invernizzi, and P. Caramella,
Tetrahedron, 1996, 52, 6421.
A. Corsaro, G. Perrini, P. Caramella, F. Marinoni Albini, and T. Bandiera, Tetrahedron Lett., 1986,
27, 1517.
P. Caramella, T. Bandiera, F. Marinoni Albini, A. Gamba Invernizzi, A. Corsaro, and G. Perrini,
Tetrahedron, 1988, 44, 4917.
F. Marinoni Albini, R. De Franco, T. Bandiera, P. Caramella, A. Corsaro, and G. Perrini, J.
Heterocycl. Chem., 1989, 26, 757.
P. Caramella, V. Bertolasi, S. Forte, R. De Franco, T. Bandiera, and F. Marinoni Albini, J. Chem.
Res. 1989, (S) 308; (M) 2364.
F. Marinoni Albini, R. De Franco, T. Bandiera, P. Grünanger, and P. Caramella, Gazz. Chim. Ital.,
1990, 120, 1.
7.
8.
9.
G. Grassi, F. Risitano, and F. Foti, Tetrahedron, 1995, 43, 11855.
G. Grassi, F. Risitano, G. Bruno, and F. Nicolò, J. Chem. Res. 1996, (S) 220; (M) 1173.
J. A. Ross, R. P. Seiders, and D. M. Lemal, J. Am. Chem. Soc., 1976, 98, 4325.
10. E. Abushanabe, D. Y. Lee, and L. Goodman, J. Heterocycl. Chem., 1973, 10, 181.
11. G. De Simoni and G. Minoli, Tetrahedron, 1968, 24, 4907.

12. G. De Simoni and G. Minoli, Tetrahedron, 1970, 26, 1393.
13. A. E. A. Porter and P. G. Sammers, Chem. Comm., 1970, 1103.
14. J. L. Markham and P. G. Sammes, J. Chem. Soc., Perkin Trans. 1, 1979, 1885.
15. M. E. K. Cartoon, G. W. H. Cheeseman, H. Dowlatshai, and P. Sharma, J. Chem. Soc., Perkin
Trans. 1, 1980, 1603.
16. G. W. H. Cheeseman, A. R. Katrizky, and S. Øksne, J. Chem. Soc., 1961, 3893.
17. G. W. H. Cheeseman, J. Chem. Soc., 1960, 242.
18. J. C. Mac Donald, G. C. Bishop, and M. Mazurek, Tetrahedron, 1976, 655.
19. S. Tobias and H. Günther, Tetrahedron Lett., 1982, 23, 4785.
20. L. Lapinski, M. J. Nowak, J. Fulara, A. Leš, and L. Adamowic, J. Phys. Chem., 1992, 96, 6250.
21. R. H. Cox and A. A. Bothner-By, J. Phys. Chem., 1968, 72, 1646.
22. G. Büchi and J. C. Vederas, J. Am. Chem. Soc., 1972, 94, 9128.
23. O. J. Mieden and C. Von Sonntag, Z. Naturforsch., Teil B 1989, 44, 959 (Chem. Abstr., 1990, 112,
179842g).
24. J. Adachi and N. Sato, J. Org. Chem., 1972, 37, 221.
25. The double doublet changes in a doublet (J = 7.8 Hz) by treatment with deuterium oxide.
26. A. Corsico Coda and G. Tacconi, Gazz. Chim. Ital., 1984, 114, 131
27. A. Albert and J. N. Phillips, J. Chem. Soc., 1956, 1294.
28. K. Eichenberger, R. Rometsch, and J. Druey, Helv. Chim. Acta, 1956, 39, 1765.
29. D. D. Perrin, W. L. F. Armarego, and D. R. Perrin, ‘Purification of Laboratory Chemicals’; 2nd Edn.
Pergamon Press, New York, 1980.
30. G. W. H. Cheeseman and E. S. G. Törzs, J. Chem. Soc., 1965, 6681.
31. N. Sato, N. Miwa, H. Suzuki, and T. Sakakibara, J. Heterocycl. Chem., 1994, 31, 1229.