Studies on pyrazines. Part 34. Synthetic approach, stability and tautomerism of 2,6-dihydroxypyrazines

Article abstract of DOI:10.1039/a704415a

Demethylation of 2,6-dimethoxy-3,5-diphenylpyrazine with iodotrimethylsilane gives the corresponding 2,6-dihydroxy- and 2-hydroxy-6-methoxy-pyrazines, whilst the 3-methyl-5-phenyl analogue affords only monohydroxy compounds. In contrast, 2,6-dimethoxy-3,5-dimethylpyrazine decomposes completely under the demethylation conditions. Hydrolysis of 2,6-diacetoxypyrazines succeeds only in the formation of 2,6-dihydroxy-3,5-diphenylpyrazine. The stability of 2,6-dihydroxypyrazines is discussed on the basis of observations made in the synthetic approach. In addition, it has been established, on the basis of UV spectral analysis, that the 2-hydroxy-6-methoxypyrazines obtained in our work exist predominantly in the hydroxypyrazine form rather than as 1,2-dihydropyrazin-2-ones.

Full text of DOI:10.1039/a704415a

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Studies on pyrazines. Part 34.1 Synthetic approach, stability and
tautomerism of 2,6-dihydroxypyrazines
Nobuhiro Sato,* Kaori Matsumoto, Masayuki Takishima and
Katsura Mochizuki
Department of Chemistry, Yokohama City University, Yokohama 236, Japan
Demethylation of 2,6-dimethoxy-3,5-diphenylpyrazine with iodotrimethylsilane gives the corresponding
2,6-dihydroxy- and 2-hydroxy-6-methoxy-pyrazines, whilst the 3-methyl-5-phenyl analogue affords only
monohydroxy compounds. In contrast, 2,6-dimethoxy-3,5-dimethylpyrazine decomposes completely
under the demethylation conditions. Hydrolysis of 2,6-diacetoxypyrazines succeeds only in the formation
of 2,6-dihydroxy-3,5-diphenylpyrazine. The stability of 2,6-dihydroxypyrazines is discussed on the basis
of observations made in the synthetic approach. In addition, it has been established, on the basis of UV
spectral analysis, that the 2-hydroxy-6-methoxypyrazines obtained in our work exist predominantly in the
hydroxypyrazine form rather than as 1,2-dihydropyrazin-2-ones.
The stability and tautomerism of 2,6-dihydroxypyrazines have
a particular interest for us. To our best knowledge, 2,6-
dihydroxy-3,5-diphenylpyrazine2 is the only known compound
in this class, various efforts to prepare both the parent3 and
other alkyl or aryl derivatives2,4 having been unsuccessful. The
preparative failures are probably the result of the 2,6-di-
hydroxypyrazines having reduced stability. Previous reports5–7
from our laboratory and others have described that the stability
of related compounds, 2,5-dihydroxypyrazines, is strongly
affected by the presence of other substituents; i.e. 3,6-dimethyl
or 3,6-diphenyl derivatives were isolated with little difficulty,
whilst the parent and monomethyl or phenyl pyrazines have
resisted synthesis. Such a substituent effect is likely also to
characterize the stability of 2,6-dihydroxypyrazines. One of our
specific interests in this area is the tautomerism of 2,6-
dihydroxypyrazines and 2-hydroxy-6-methoxypyrazines. In
general, hydroxypyrazines in solution exist as their keto
tautomers, namely 1,2-dihydropyrazin-2-ones.8 A predominant
tautomer of 2,6-dihydroxy-3,5-diphenylpyrazine was claimed
to be the 6-hydroxy-1,2-dihydropyrazin-2-one2 by comparison
of its UV spectrum with that of 2,6-dimethoxy-3,5-diphenyl-
pyrazine. Conversely, 2-chloro-6-hydroxy-3,5-diphenylpyrazine
was shown to exist in the hydroxy form.2 We are currently
engaged in a program aimed at the synthesis of 3-methyl-5-
phenyl- and 3,5-dimethyl-substituted 2,6-dihydroxypyrazines
and 2-hydroxy-6-methoxypyrazines to elucidate their unusual
properties.
This procedure, however, was shown to be of no use for the
preparation of 2,6-dihydroxypyrazines possessing a 3- or 5-
methyl group since the methyl substituent of 2 is acetylated to
produce 2-acetoxy-3- or -5-acetoxymethylpyrazines.2 Since,
earlier, we had synthesized 3,6-disubstituted 2,5-dihydroxy-
pyrazines by demethylation of 2,5-dimethoxypyrazines with
iodotrimethylsilane,6 we attempted to synthesize 2,6-dihydroxy-
pyrazine 1a in a similar way (Scheme 2). 2,6-Dichloro-3,5-
R1
Cl
N
N
R2
Cl
R1
Cl
N
N
R2
R1
N
N
R2
i
+
OMe
MeO
OMe
4
6
5
1
ii, iii
R1
N
N
R2
+
HO
OMe
7
1, 4, 5, 6, 7 a R1 = R2 = Ph
b R1 = Ph, R2 = Me
c R1 = R2 = Me
The earlier synthesis of 2,6-dihydroxy-3,5-diphenylpyrazine
1a2 involves treatment of 1-hydroxy-3,5-diphenyl-1,2-dihydro-
pyrazin-2-one 2a with acetic anhydride–acetic acid followed by
hydrolysis of the resulting 2,6-diacetoxypyrazine 3a (Scheme 1).
Scheme 2 Reagents and conditions: i, NaOMe, MeOH; ii, Me3SiI,
MeCN; iii, H2O, room temp.
diphenylpyrazine 4a was conveniently prepared together with a
minor by-product, 2-chloro-6-hydroxypyrazine 8a, by treatment
of 1-hydroxy-1,2-dihydropyrazin-2-one 2a with phosphoryl
chloride at elevated temperature in a sealed reaction vessel.
Reaction of 4a with refluxing methanolic sodium methoxide
gave dimethoxypyrazine 5a and 2-chloro-6-methoxypyrazine
6a.4 Treatment of 5a with iodotrimethylsilane in refluxing
acetonitrile for 6 h, gave the desired 2,6-dihydroxypyrazine 1a
(39%) and partly dealkylated 2-hydroxy-6-methoxypyrazine 7a
(30%); 20% of the starting material was also recovered.
R1
N
R2
R1
N
N
R2
R1
N
N
R2
ii,iii
i
O
N
AcO
OAc
HO
OH
OH
3
1
2
1, 2, 3 a R1 = R2 = Ph
b R1 = Ph, R2 = Me
c R1 = R2 = Me
Our success in preparing dihydroxypyrazine 1a prompted us
to examine the synthesis of the 3-methyl-5-phenyl 1b and 3,5-
Scheme 1 Reagents and conditions: i, Ac2O, AcOH; ii, KHCO3,
MeOH; iii, HCl, room temp.
J. Chem. Soc., Perkin Trans. 1, 1997
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dimethyl derivatives 1c. Unlike dichloropyrazine 4a, prepar-
ation of the 3-methyl-5-phenyl derivative 4b was somewhat
troublesome, e.g. 2-chloro-6-hydroxy-3-methyl-5-phenylpyr-
azine 8b, prepared by controlled chlorination of readily acces-
R1
N
R2
Ph
N
Me
OH
HO
N
Cl
MeO
N
8
a R1 = R2 = Ph
b R1 = Ph, R2 = Me
9
sible 1-hydroxy-5-methyl-3-phenyl-1,2-dihydropyrazin-2-one
2b,2 failed to undergo further chlorination with phosphoryl
chloride at 175–185 ЊC and with recovery of only 25% of the
starting material. However, the required dichloropyrazine 4b
was successfully synthesized by the reaction sequence shown in
Scheme 3. Since the structure of 2-chloropyrazine 1-oxide 12b
Fig. 1 X-Ray structure of compound 12b
reflux, 44% of unchanged dimethoxypyrazine 5b was still
recovered; although two monohydroxy products 7b and 9 were
also obtained (ca. 20% each), the fully dealkylated product 1b
was absent. Under identical conditions, there was a 68%
recovery of dimethoxypyrazine 5c, none of the desired product
being obtained. A comparison of the amounts of dimethoxy-
pyrazines 5 recovered, suggests that the ability of the methoxy
group to undergo cleavage decreases in the order: 5a > 5b > 5c;
this too is the order for the stability of the dealkylated products
as judged by the product yields. Replacing iodotrimethylsilane
with boron tribromide–methyl sulfide complex, a useful reagent
for ether cleavage, failed to effect the necessary demethylation
and gave almost quantitative recovery of the dimethoxypyr-
azine 5b. To establish the structure of 2-hydroxy-6-methoxy-
pyrazine 7b, the compound was unambiguously synthesized
as shown in Scheme 4; in this deoxidative acetoxylation led to
R1
O
O
N
Me
O
N
Me
Cl
H2N
H2N
Me
O
R1
R1
i,ii
iii
+
N
H
N
10
11
iv
R1
N
N
Me
Cl
iii
4
O
12
4, 10, 11, 12
b R1 = Ph
c R1 = Me
R1
N
Me
R1
N
N
Me
iii, iv
i
ii
7
12
Scheme 3 Reagents and conditions: i, NaOH, MeOH, H2O, Ϫ30 ЊC to
room temp.; ii, HCl, room temp.; iii, POCl3; iv, K2S2O8, H2SO4, 10 ЊC to
room temp.
N
O
OMe
AcO
OMe
13
14
was confirmed by X-ray analysis (Fig. 1), the possible form-
ation of other isomers, arising from condensation and N-
oxidation processes, was excluded. Reaction of 12b with phos-
phoryl chloride at reflux smoothly proceeded to form, without
chlorination of the side chain, the dichloropyrazine 4b in
excellent yield. Similarly, the formation of 2,6-dichloro-3,5-
dimethylpyrazine 4c was effected; identification of the inter-
mediate chloropyrazine 11c was established by comparison with
the alternative, possible isomer, 2-chloro-3,6-dimethylpyrazine,
which was unequivocally synthesized from 3,6-dimethylpiper-
azine-2,5-dione.9
7, 12, 13, 14
b R1 = Ph
c R1 = Me
Scheme 4 Reagents and conditions: i, NaOMe, MeOH; ii, Ac2O; iii,
NaHCO3, MeOH; iv, HCl, room temp.
formation of acetoxymethylpyrazines as well as the desired
2-acetoxy-6-methoxypyrazines 14. An attempt to synthesize 7b
by treatment of 2-chloro-6-hydroxypyrazine 8b with methan-
olic sodium methoxide in a sealed vessel at 126–127 ЊC gave
recovery of starting material.
Methoxylation of dichloropyrazine 4b with methanolic
sodium methoxide at reflux for 3.5 h gave 2,6-dimethoxy-
pyrazine 5b4 in low yield (ca. 14%) together with the mono-
methoxylated products, 2-chloro-6-methoxypyrazine 6b (79%)
and 2-chloro-6-methoxy-3-methyl-5-phenylpyrazine (7%). The
best yield of 5b (85%) was obtained by heating the same
reagents in a sealed tube at 126–127 ЊC for 18 h, although 6b
(3%) was still a contaminant. Separation of 5b and 6b, by
recrystallization or Kugelrohr distillation proved difficult,
whilst three cycles of HPLC development were necessary. Simi-
larly, reaction of 2,6-dichloro-3,5-dimethylpyrazine 4c with
refluxing methanolic sodium methoxide for 6 h afforded mostly
the monosubstituted product 6c (68%), with little of the desired
dimethoxy compound 5c (5%). Interestingly, the desired substi-
tution proceeded well in a system consisting of a crown ether
and potassium methoxide to give the dimethoxypyrazine 5c
(78%) with little 6c (9%). This procedure, however, failed to
improve the yields of 5a and 5b.
Taken together, the results for the various attempts to
demethylate compound 5 suggest that the reaction conditions
needed for ether cleavage are so severe as to result in decom-
position, to a varying degree, of the initially formed 2,6-
dihydroxypyrazines or other monohydroxypyrazines. Accord-
ingly, we explored a synthetic method for the preparation of
dihydroxypyrazine 1 under much milder conditions, namely
deacetylation of 2,6-diacetoxypyrazines 3b and 3c; a successful
hydrolysis of 2-acetoxy-6-methoxypyrazine 14c had given 2-
hydroxy-6-methoxypyrazine 7c (Scheme 4), a compound not
accessible by treating dimethoxypyrazine 5b with iodotrime-
thylsilane. Although this procedure led to the preparation of
1a, a drawback to it was the difficulty in preparing methyl sub-
stituted diacetoxypyrazines. A variety of synthetic approaches
to 3 failed, e.g. by treating 2-acetoxy-6-chloro-3,5-dimethyl-
pyrazine 15, itself prepared by deoxidative acetoxylation of 2-
chloropyrazine 1-oxides 12c, with silver acetate or potassium
acetate–crown ether. Consequently, compounds
3 were
Demethylation of dimethoxypyrazine 5b with iodotrimethyl-
silane took longer than that of 5a; i.e. even after 48 h under
obtained, although in low yield (4–10%), by treating 1-hydroxy-
1,2-dihydropyrazin-2-ones 2 with refluxing acetic anhydride–
3168
J. Chem. Soc., Perkin Trans. 1, 1997

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Table 1 UV spectra of the hydroxypyrazines 1, 7, 9 and 2,6-dimethoxy-
pyrazines 5 in ethanol
R1
O
N
R2
Me
N
Me
Cl
Compd.
λmax/nm (ε)
AcO
N
N
OMe
Me
1a
5a
7a
5b
7b
9
227.0 (21 000), 274.5 (18 600), 349.5 (18 600), 416.5 (6100)
230.5 (24 500), 276.0 (20 300), 343.0 (23 000)
228.5 (19 700), 275.5 (15 800), 346.5 (18 400)
258.0 (22 500), 326.5 (26 500)
257.5 (13 900), 328.0 (17 100)
258.5 (13 900), 327.5 (16 900)
a R1 = R2 = Ph
b R1 = Ph, R2 = Me
c R1 = R2 = Me
15
16
acetic acid (Scheme 1). In addition to diacetoxypyrazine 3b, 2-
acetoxy-5-acetoxymethyl-3-phenylpyrazine and 2-acetoxy-5-
methyl-3-phenylpyrazine were generated in modest yields.
Formation of the latter compound was quite unexpected, in
that it occurred as a result of deacetylation of the initially
formed 1-acetoxy-1,2-dihydropyrazin-2-one, and subsequent
acetylation of the resulting 1,2-dihydropyrazin-2-one, rather
than by formation and successive deoxygenation of 2-
acetoxypyrazine 1-oxide.
When diacetoxypyrazine 3b was treated with potassium
hydrogencarbonate in methanol at room temperature, it was
completely consumed after 5 h, with the solution becoming
dark greenish brown. As expected, the reaction yielded only
tarry material upon work-up, the dihydroxypyrazine 1b being
neither isolated nor detected. On attempted deacetoxylation of
3c under identical conditions, no product was detected nor
starting material recovered, although the reaction mixture
remained colourless. An attempt to hydrolyse 3c with acidic
ion-resin failed completely. In conclusion, since the 2,6-
dihydroxypyrazines 1b and 1c could not be prepared, it is clear
that the 2,6-dihydroxy isomer is far less stable than the 2,5-
dihydroxy isomer, neither the dimethyl or methyl, phenyl sub-
stitutents having an effect on the stabilization. Since 2,5-
dihydroxy-3,6-dimethylpyrazine decomposed even when car-
bon dioxide bubbled through an aqueous suspension,7 it is
likely that the instability described is a result of extreme sus-
ceptibility to acid or base.
5c
7c
224.0 (14 900), 311.0 (14 900)
222.0 (11 800), 312.5 (12 300)
absorption >400 nm has been observed for pyrazine com-
pounds excepting 1,2-dihydropyrazine-2-thiones;10 further, the
longest wavelength band in the spectrum of N-methylpyr-
azinone 16a should appear in the 360–380 nm region, esti-
mated on the basis of the absorption maxima for compounds 7
and 9 and 2-chloro-6-hydroxypyrazine derivatives.2 With time,
the UV spectrum of 1a altered, the bands converging at 247,
305 and 413 nm. In view of the similarity of the three shorter
wavelength bands in the spectrum of 1a to those of dimethoxy-
pyrazine 5a, it seems most likely that 2,6-dihydroxypyrazine 1a
initially exists in the hydroxy form, but is gradually transformed
into another compound whose structure as yet remains
unidentified.
Experimental
Melting points were determined using a Büchi 535 apparatus
and are uncorrected. Boiling points were oven temperatures for
Kugelrohr distillation and are uncorrected. UV spectra were
recorded on a Shimadzu UV-2100 spectrometer. NMR spectra
1
were obtained with a JEOL JNM EX270 (270 MHz H, 67.8
MHz 13C) instrument with solutions in CDCl3, unless otherwise
noted, containing Me4Si as internal standard. J Values are given
in Hz. Column chromatography and preparative HPLC separ-
ation were performed using Silica Gel 60 and 10 µm SiO2
(2.2 × 30 cm), respectively. Drying refers to drying over MgSO4.
Evaporation refers to evaporation under reduced pressure.
A convenient method for the elucidation of hydroxypyr-
azine–pyrazinone tautomerism is by UV spectral analysis. For
the purposes of comparison in studying 2,6-dihydroxy- and 2-
hydroxy-6-methoxypyrazines, 2,6-dimethoxypyrazine
5 was
needed as a proton-fixed tautomer, whilst 1-methyl-6-hydroxy-
1,2-dihydropyrazin-2-one 16 was needed as the alternative type
of structure. Treatment of 2-hydroxy-6-methoxypyrazine 7a
with ethereal diazomethane, however, afforded not the N-
methylpyrazinone 16a but only dimethoxypyrazine 5a (24%),
together with starting material 7a. Similarly, compounds 16b
and 16c were not accessible by treating the corresponding
hydroxypyrazines 7 with diazomethane although a good deal of
the starting material was consumed. Difficulties in preparing
compounds 16 had been expected from the earlier lack of suc-
cess in synthesizing 16a,2 i.e. 6-chloro-1-methyl-3,5-diphenyl-
1,2-dihydropyrazin-2-one underwent facile displacement of the
halogen with methoxide but further hydrolysis with hydro-
chloric acid upon work-up furnished 2-hydroxy-1-methyl-1,2-
dihydropyrazin-2-one.
As shown in Table 1, the UV spectra of 2-hydroxy-6-
methoxypyrazines 7 and 9 are closely similar to those of 2,6-
dimethoxypyrazines 5. Despite lack of the other pair of com-
pounds 16 for comparison, it can, nevertheless, be concluded
that in ethanol the hydroxy tautomers predominate: the spectra
of proton-fixed tautomers 16 would be quite different from
those of 5 as illustrated by published spectral data for O- and
N-methylated derivatives of 2-chloro-6-hydroxypyrazines.2 This
conclusion is further supported by the spectra of 7b and 9
which show absorption with almost identical maxima; this only
occurs for compounds existing together in the hydroxy form.
The spectrum of 2,6-dihydroxypyrazine 1a shows four maximal
absorptions, in which the shortest wavelength band was missed
in the former study, and the longest one which was the evidence
cited for the compounds being in the keto form.2 However, no
3-Methyl-5-phenyl-1,2-dihydropyrazin-2-one 10b
This compound was prepared by the procedure of Jones,11 as
needles, yield 33%; mp 225–226 ЊC (decomp.) (EtOAc) (lit.,11
212–213 ЊC) (Found: C, 71.0; H, 5.4; N, 15.0. C11H10N2O
requires C, 71.0; H, 5.4; N, 15.0%); δH 2.59 (3H, s), 7.34–7.46
(3H, m), 7.61 (1H, s) and 7.77–7.80 (2H, m); δC 20.6, 119.8,
125.1, 128.0, 128.9, 134.4, 135.8, 156.9 and 157.5.
2-Chloro-3-methyl-5-phenylpyrazine 11b
A mixture of the pyrazinone 10b (4.66 g, 25 mmol) and phos-
phoryl chloride (33 cm3) in a sealed tube was heated at 170–
175 ЊC for 18 h. The mixture was concentrated under reduced
pressure, and the residue was poured into ice–water and
extracted with CHCl3 (3 × 150 cm3). The combined extracts
were washed with aqueous NaHCO3 and then water, dried and
evaporated. The residue was sublimed at 75–80 ЊC/1–2 mmHg
giving the chloropyrazine 11b (4.70 g, 92%) as needles; mp
77 ЊC (EtOH) (lit.,4 74–75 ЊC) (Found: C, 64.3; H, 4.5; N, 13.7.
C11H9N2Cl requires C, 64.6; H, 4.4; N, 13.7%); δH 2.73 (3H, s),
7.48–7.51 (3H, m), 7.97–8.00 (2H, m) and 8.62 (1H, s); δC 22.4,
126.9, 129.1, 129.9, 135.5, 138.2, 147.1, 150.3 and 152.2.
Preparation of the 2-chloropyrazine 1-oxides 12
2-Chloro-3-methyl-5-phenylpyrazine 1-oxide 12b. Potassium
persulfate (2.34 g, 8.65 mmol) was added to a mixture of chloro-
pyrazine 11b (1.59 g, 7.8 mmol) in concentrated sulfuric acid
(15 cm3) at <10 ЊC, and the mixture was stirred at room tem-
perature for 24 h. It was then poured into ice–water and
extracted with CHCl3 (3 × 50 cm3). The combined extracts were
washed with aqueous NaHCO3 and then water, dried and evap-
J. Chem. Soc., Perkin Trans. 1, 1997
3169

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orated. The residue was chromatographed on silica (60 g;
hexane–EtOAc, 4:1) to give recovery of the starting chloro-
pyrazine (1.01 g, 63%). The following fraction afforded the N-
oxide 12b (0.386 g, 23%) as pale yellow needles; mp 142.5–
143 ЊC (EtOH) (lit.,4 153–154 ЊC) (Found: C, 60.0; H, 4.1; N,
12.7. C11H9N2OCl requires C, 59.9; H, 4.1; N, 12.7%); δH 2.75
(3H, s), 7.50–7.52 (3H, m), 7.90–7.94 (2H, m) and 8.55 (1H, s);
δC 22.9, 126.7, 129.1, 129.3, 130.7, 134.1, 152.0 and 155.4.
The melting point of the isomeric N-oxide, 3-chloro-2-
methyl-6-phenylpyrazine 1-oxide, was reported as 141–142 ЊC.4
X-Ray crystallography. Single-crystal X-ray diffraction
experiment on 12b, prepared by recrystallization (20% v/v
EtOAc–hexane) was carried out on a MAC Science MXC3k
four-circle diffractometer with graphite-monochromatized Mo-
Kα radiation (λ = 0.710 73 Å) and a ω–2θ scan technique. The
structure was solved by direct methods (SIR 92) and refined on F
by the full-matrix least-squares method. All the non-hydrogen
atoms were refined with anisotropic thermal parameters.
Hydrogen atoms found from the difference Fourier syntheses
were included in the final refinement with the isotropic thermal
parameters. The final R indices were R = 0.043 and Rw = 0.047
(weighting scheme, ω = exp(10 sin2 θ/λ2)/[σ2(F) ϩ 0.0001F2].
The calculations were carried out using a SUN SPARK 10
work station (Crystan-GM program system provided by MAC
Science).
(2H, m), 8.14–8.17 (2H, m) and 13.0 (1H, br s); δC[(CD3)2SO]
128.0, 128.1, 128.5, 128.6, 129.1, 129.2, 134.9, 136.3 and 155.5.
2,6-Dichloro-3-methyl-5-phenylpyrazine 4b. A mixture of 2-
chloropyrazine 1-oxide 12b (0.663 g, 3.0 mmol) in phosphoryl
chloride (9 cm3) was stirred and heated at 80 ЊC (bath temper-
ature) for 30 min. After being cooled, the mixture was poured
into ice–water, neutralized with NaHCO3 and extracted with
CHCl3 (3 × 30 cm3). The combined extracts were washed with
water, dried and evaporated. Kugelrohr distillation at 140–
150 ЊC/30 mmHg of the residue gave an oil (0.665 g, 93%),
which crystallized with time, mp 59–60 ЊC (lit.,4 58–59 ЊC); δH
2.70 (3H, s), 7.48–7.50 (3H, m), 7.76–7.78 (2H, m); δC 21.4,
128.3, 129.4, 129.7, 135.4, 142.4, 144.7, 150.3 and 150.7.
2,6-Dichloro-3,5-dimethylpyrazine 4c. A mixture of the N-
oxide 12c (0.951 g, 6.0 mmol) in phosphoryl chloride (10 cm3)
was gently heated and stirred until complete dissolution and
then refluxed for 1.5 h. After this, the solution was concentrated
under reduced pressure and the residual oil was poured into
ice–water. The resulting precipitate was filtered off, and the
filtrate and washings were neutralized with NaHCO3 and
extracted with CHCl3 (4 × 30 cm3). The combined extracts were
washed with water, dried and evaporated. The residue was
purified by chromatography on silica (20 g; hexane–EtOAc,
2:1). The combined products were distilled to give an oil (0.869
g, 82%); bp 68 ЊC/40 mmHg; δH 2.60 (6H, s); δC 21.1, 143.7 and
149.9.
Crystal data and structure refinement for 12b.—Empirical
formula = C11H9N2OCl, formula weight = 220.50, T = 298 K,
triclinic, P1, a = 7.056(4) Å, b = 7.170(8) Å, c = 11.032(5) Å,
¯
Preparation of the 2,6-dimethoxypyrazines 5
α = 76.24(6)Њ, β = 83.48(4)Њ, γ = 72.16(6)Њ, V = 515.6(7) Å3, Z = 2,
dc = 1.417 Mg mϪ3, absorption coefficient = 0.340 mmϪ1, crys-
tal size = 0.35 × 0.20 × 0.20 mm, θmax for data collected =
26.47Њ, index ranges = Ϫ9 р h р 8, Ϫ9 р k р 0, Ϫ14 р l р 13,
reflections collected = 2627, independent reflections = 2331,
refinement method = full-matrix least-squares on F, data/
parameters = 1458/172, goodness of fit on F = 1.586, final R
indices [I > 3.00σ(I)] R 0.043, Rw 0.047, largest diff. peak and
2,6-Dimethoxy-3,5-diphenylpyrazine 5a. A mixture of the
dichloropyrazine 4a (0.151 g, 0.50 mmol) in methanolic sodium
methoxide, prepared from Na (0.058 g, 2.5 mmol) in dry MeOH
(3 cm3), was stirred and refluxed for 5 h. The solution was evap-
orated to dryness, and the residue was extracted with ether
(3 × 30 cm3). The combined extracts were dried and concen-
trated under reduced pressure. Chromatography of the residue
on Florisil (hexane–EtOAc, 2:1) and, successively, HPLC
(hexane–EtOAc 9:1) gave 2-chloro-6-methoxypyrazine 6a
(0.042 g, 29%) as needles; mp 79–80 ЊC (hexane) (lit.,2 95–
96 ЊC); δH 4.12 (3H, s), 7.44–7.49 (6H, m), 7.84–7.88 (2H, m)
and 8.12–8.15 (2H, m); δC 54.6, 128.1, 128.2, 128.7, 129.1,
129.5, 134.8, 136.6, 140.2, 140.5, 143.5 and 155.3.
hole = 0.25 and Ϫ0.25 e ÅϪ3
.
2-Chloro-3,5-dimethylpyrazine 1-oxide 12c. A mixture of
chloropyrazine 11c12 (2.00 g, 14.0 mmol) in concentrated sul-
furic acid (14 cm3) was treated with potassium persulfate (4.0 g,
15 mmol) in the above manner. Chloroform extracts were evap-
orated, and the residue was recrystallized to give the N-oxide
12c (1.69 g, 76%) as small prisms; mp 82–85 ЊC (hexane)
(Found: C, 45.6; H, 4.5; N, 17.6. C6H7N2OCl requires C, 45.4;
H, 4.5; N, 17.7%); δH 2.48 (3H, s), 2.65 (s) and 8.24 (1H, s); δC
21.1, 22.6, 131.2, 152.6 and 155.0.
The second fraction furnished the dimethoxypyrazine 5a
(0.097 g, 66%) as needles, mp 98–99 ЊC (MeOH) (lit.,2 98–
99 ЊC); δH 4.10 (6H, s), 7.54–7.48 (6H, m) and 8.12–8.16 (4H,
m); δC 53.8, 127.9, 128.1, 128.5, 132.2, 136.2 and 154.8.
2,6-Dimethoxy-3-methyl-5-phenylpyrazine 5b. A mixture of
the dichloropyrazine 4b (0.560 g, 2.34 mmol) and methanolic
sodium methoxide, prepared from Na (0.567 g, 25 mmol) and
dry MeOH (20 cm3), in a sealed tube was heated at 126–127 ЊC
(bath temperature) for 18 h, after which the mixture was con-
centrated under reduced pressure. The residue was diluted with
water and the solution was extracted with EtOAc (3 × 50 cm3).
The combined extracts were washed with water, dried and
evaporated. After chromatography of the residue on Florisil
(hexane–EtOAc, 9:1), HPLC was performed using hexane–
EtOAc (49:1); the development was repeated twice more. The
less polar fraction was identified as the dimethoxypyrazine 5b
(0.457 g, 85%) and formed needles, mp 60–61 ЊC (MeOH)
(Found: C, 68.1; H, 6.2; N, 12.2. C13H14N2O2 requires C, 67.8;
H, 6.1; N, 12.2%); δH 2.45 (3H, s), 4.01 (6H, s), 7.29–7.35 (3H,
m), 7.40–7.45 (2H, m) and 7.95–7.99 (2H, m); δC 17.9, 53.4,
53.6, 127.6, 128.0, 128.4, 131.2, 132.9, 136.4, 154.4 and 155.3.
The more polar fraction was 2-chloro-6-methoxypyrazine 6b
(0.014 g, 3%) and formed prisms, mp 79–80 ЊC (hexane) (lit.,4
81–82 ЊC); δH 2.51 (3H, s), 4.04 (3H, s), 7.40–7.46 (3H, m) and
7.70–7.74 (2H, m).
Preparation of the 2,6-dichloropyrazines 4
2,6-Dichloro-3,5-diphenylpyrazine 4a.
A mixture of 1-
hydroxy-1,2-dihydropyrazin-2-one 2a (5.28 g, 20 mmol) and
phosphoryl chloride (30 cm3) in a sealed tube was heated at
160–170 ЊC (bath temperature) for 20 h. The mixture was con-
centrated under reduced pressure, and the residual oil was
poured into ice–water to which ether (100 cm3) was then added.
Undissolved material was filtered off and the filtrate was
extracted with ether (3 × 200 cm3). The combined extracts were
washed with water, dried and evaporated to give dichloropyr-
azine 4a (3.65 g, 56%). The mother liquor and the above undis-
solved material were combined and extracted with CHCl3
(3 × 100 cm3). The extract was washed with aqueous Na2CO3,
and then water, dried and evaporated. The residue was chrom-
atographed on silica (45 g:hexane–EtOAc, 4:1) to give 4a
(0.350 g) from the first elution. The combined products were
sublimed at 120–140 ЊC/1–3 mmHg to afford colourless crystals
(3.62 g, 60%), mp 95–97 ЊC (lit.,4 100–101 ЊC); δH 7.49–7.51
(6H, m) and 7.86–7.90 (4H, m); δC 128.3, 129.6, 129.9, 135.2,
142.8 and 150.4.
2,6-Dimethoxy-3,5-dimethylpyrazine 5c. A mixture of di-
chloropyrazine 4c (0.354 g, 2.0 mmol) and dicyclohexano-18-
crown-6 (1.864 g, 5.0 mmol) under argon was treated with
0.1 mol dmϪ3 potassium methoxide solution (MeOH–C6H6,
The second fraction provided 2-chloro-6-hydroxypyrazine 8a
(0.171 g, 3%) as pale yellow needles, mp 249–250 ЊC (EtOH)
(lit.,2 244–246 ЊC); δH[(CD3)2SO] 7.47–7.54 (6H, m), 7.78–7.81
3170
J. Chem. Soc., Perkin Trans. 1, 1997

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1:9) (50 cm3, 5.0 mmol), added via a syringe. The mixture was
stirred under reflux for 8 h and then evaporated. The residue
was treated with water (80 cm3) after which it was extracted
with ether (4 × 30 cm3). The extracts were worked up in the
manner described above. Florisil chromatography (hexane–
EtOAc, 3:1) of the residue and then HPLC (hexane–EtOAc,
9:1) gave 2-chloro-6-methoxypyrazine 6c (0.031 g, 9%), bp 85–
90 ЊC/45 mmHg, which crystallized with time; mp 54–55.5 ЊC
(Found: C, 48.6; H, 5.3; N, 16.1. C7H9N2OCl requires C, 48.7;
H, 5.3; N, 16.2%); δH 2.42 (3H, s), 2.51 (3H, s) and 3.96 (3H, s);
δC 18.4, 20.5, 54.1, 141.0, 141.2, 141.3 and 156.1.
The dimethoxypyrazine 5c (0.263 g, 78%) was obtained from
the second fraction; bp 98–100 ЊC/46 mmHg, which crystallized
with time; mp 76–77 ЊC (Found: C, 57.3; H, 7.3; N, 16.7.
C8H12N2O2 requires C, 57.1; H, 7.2; N, 16.7%); δH 2.35 (6H, s)
and 3.94 (3H, s); δC 17.5, 53.3, 131.2 and 154.8.
Preparation of the 2-methoxypyrazine 1-oxides 13
2-Methoxy-3-methyl-5-phenylpyrazine 1-oxide 13b. A mixture
of the chloropyrazine N-oxide 12b (0.086 g, 0.39 mmol) in
methanolic sodium methoxide, prepared from Na (0.057 g, 2.5
mmol) and dry MeOH (65 cm3), was stirred and heated at 50–
65 ЊC (bath temperature) for 2.5 h, and then concentrated under
reduced pressure. Water was added to the residue, and the result-
ing solution was extracted with EtOAc (3 × 30 cm3). The com-
bined extracts were washed with water, dried and evaporated.
The residue was subjected to chromatography on silica (14 g;
hexane–EtOAc, 2:1) to give starting material (0.018 g, 21%)
from the first fraction. The second fraction afforded 13b (0.065
g, 77%) as needles, mp 142 ЊC (MeOH) (Found: C, 66.7; H, 5.6;
N, 12.9. C12H12N2O2 requires C, 66.65; H, 5.6; N, 12.95%); δH
2.61 (3H, s), 4.18 (3H, s), 7.47–7.49 (2H, m), 7.86–7.89 (3H, m)
and 8.39 (1H, s); δC 19.4, 59.7, 126.6, 129.1, 129.5, 130.1, 134.9,
149.6 and 152.3.
Demethylation of the dimethoxypyrazines 5
2-Methoxy-3,5-dimethylpyrazine 1-oxide 13c. A mixture of
the chloropyrazine N-oxide 12c (0.317 g, 2.0 mmol) in meth-
anolic sodium methoxide, prepared from Na (0.064 g, 2.8
mmol) and dry MeOH (5 cm3), was refluxed and stirred for 2.5
h, after which it was worked up as described above. Evaporation
of the extracts gave a crude product, which was recrystallized to
afford needles (0.207 g, 67%), mp 88–91 ЊC (hexane) (Found: C,
54.8; H, 6.6; N, 18.2. C7H10N2O2 requires C, 54.5; H, 6.5; N,
18.2%); δH 2.42 (3H, s), 2.51 (3H, s), 4.10 (3H, s) and 7.85 (1H,
s); δC 19.0, 20.9, 59.3, 131.2, 149.0, 149.7 and 151.7.
2,6-Dihydroxy-3,5-diphenylpyrazine 1a and 2-hydroxy-6-
methoxy-3,5-diphenylpyrazine 7a. The dimethoxypyrazine 5a
(0.292 g, 1.0 mmol) under argon was treated with MeCN (4
cm3) and iodotrimethylsilane (0.341 cm3, 2.4 mmol), added via
a syringe. The mixture was stirred and refluxed for 6 h after
which it was diluted with water (0.72 cm3) and stirred for 30
min. The precipitate was filtered off and identified as the 2,6-
dihydroxypyrazine 1a by spectral comparison with an authentic
sample. The filtrate was concentrated under reduced pressure,
and a small amount of EtOAc was added to the residue. After
refrigeration overnight, a second crop as small orange coloured
needles, was filtered off (total 0.103 g, 39%), mp 238 ЊC
(decomp.) (nitromethane) [lit.,2 258–259 ЊC (decomp.)];
δH[(CD3)2SO] 7.33–7.36 (2H, m), 7.42–7.48 (4H, m) and 8.12–
8.14 (4H, d); δC[(CD3)2SO] 127.2, 127.7, 127.9, 129.1, 136.5 and
154.5.
The above filtrate was treated with EtOAc after which it was
washed with aqueous NaHSO3, aqueous NaHCO3 and brine,
and then dried and evaporated. Florisil chromatography
(hexane–EtOAc, 4:1) of the residue followed by HPLC
(hexane–EtOAc, 4:1) afforded the starting dimethoxypyrazine
5a (0.060 g, 21%). A second fraction provided 2-hydroxy-6-
methoxypyrazine 7a (0.084 g, 30%) as yellow prisms, mp 149–
150 ЊC (hexane) (Found: C, 73.4; H, 5.1; N, 9.75. C17H14N2O2
requires C, 73.4; H, 5.1; N, 10.1%); δH 4.02 (3H, s), 6.58 (1H,
br s), 7.34–7.49 (6H, m) and 8.10–8.18 (4H, m); δC 54.2,
128.1, 128.2, 128.3, 128.7, 130.4, 134.4, 135.8, 135.9, 152.4 and
154.8.
2-Hydroxy-6-methoxy-5-methyl-3-phenylpyrazine 7b and 2-
hydroxy-6-methoxy-3-methyl-5-phenylpyrazine 9. A mixture of
the dimethoxypyrazine 5b (0.115 g, 0.50 mmol) in MeCN (2
cm3) was treated with iodotrimethylsilane (0.36 cm3, 2.5 mmol)
as described above except that the reaction was run for 48 h.
After being quenched with water, the mixture was evaporated
and the residue was diluted with EtOAc. The resulting solution
was washed with aqueous NaHSO3, aqueous NaHCO3 and
brine and then dried and evaporated. The residue was purified
by Florisil chromatography (hexane–EtOAc, 4:1) and then
subjected to HPLC (hexane–EtOAc, 4:1) to afford starting
material (0.050 g, 44%) as the first fraction. The second fraction
gave the hydroxypyrazine 7b (19 mg, 18%) as prisms, mp 191.5–
192 ЊC (hexane–propan-2-ol) (Found: C, 66.75; H, 5.6; N, 12.9.
C12H12N2O2 requires C, 66.65; H, 5.6; N, 12.95%); δH 2.46 (3H,
s), 3.94 (3H, s), 7.33–7.46 (3H, m) and 8.00–8.01 (2H, m); δC
18.0, 53.9, 127.8, 128.2, 128.3, 129.2, 135.3, 136.1, 152.0 and
155.5.
Preparation of the 2-acetoxy-6-methoxypyrazines 14
2-Acetoxy-6-methoxy-5-methyl-3-phenylpyrazine 14b. A mix-
ture of the N-oxide 13b (0.059 g, 0.27 mmol) in Ac2O (1.0 cm3)
was refluxed and stirred for 1 h, and then concentrated under
reduced pressure. Water was added to the residue, and the
resulting solution was neutralized with NaHCO3 and extracted
with EtOAc (3 × 20 cm3). The combined extracts were washed
with water, dried and evaporated. The residue was purified by
chromatography on silica (6 g, hexane–EtOAc, 4:1) to give
acetate 14b (0.047 g, 67%) as powder, mp 66–67 ЊC (Found: C,
65.2; H, 5.5; N, 10.75. C14H14N2O3 requires C, 65.1; H, 5.5; N,
10.85%); δH 2.23 (3H, s), 2.53 (3H, s), 3.99 (3H, s), 7.36–7.46
(3H, m) and 7.70–7.74 (2H, m); δC 18.7, 21.1, 54.3, 128.3,
128.39, 128.44, 135.7, 136.5, 142.1, 147.2, 156.4 and 168.6.
2-Acetoxy-6-methoxy-3,5-dimethylpyrazine 14c. A mixture of
the N-oxide 13c (0.284 g, 1.8 mmol) in Ac2O (3.2 cm3) was
stirred and heated at 120 ЊC (bath temperature) for 2 h, and
then worked up as described above. Evaporation of extracts
gave a crude product, which was purified by Florisil chrom-
atography (hexane–EtOAc, 3:1) and successively HPLC
(hexane–EtOAc, 5:1) to provide 14c (0.178 g, 50%), which
crystallized with time, bp 130–133 ЊC/53 mmHg, mp 56–57 ЊC
(Found: C, 55.3; H, 6.2; N, 14.2. C9H12N2O3 requires C, 55.1; H,
6.2; N, 14.3%); δH 2.33 (3H, s), 2.36 (3H, s), 2.44 (3H, s) and
3.92 (3H, s); δC 17.6, 18.5, 20.8, 54.0, 134.9, 141.3, 147.8, 155.8
and 168.5.
The second fraction afforded 2-acetoxymethyl-5-methoxy-6-
methylpyrazine (0.134 g, 38%), bp 100 ЊC/30 mmHg, which
crystallized with time, mp 50.5–51 ЊC (Found: C, 55.1; H, 6.2;
N, 14.25. C9H12N2O3 requires C, 55.1; H, 6.2; N, 14.3%); δH 2.11
(3H, s), 2.48 (3H, s), 3.98 (3H, s), 5.12 (2H, s) and 7.99 (1H, s);
δC 19.2, 20.8, 53.7, 64.6, 137.6, 141.1, 144.4, 158.5 and 170.6.
2-Acetoxy-6-chloro-3,5-dimethylpyrazine 15. A mixture of
the chloropyrazine N-oxide 12c (0.476 g, 3.0 mmol) in Ac2O
(4.5 cm3) was stirred and heated at 120 ЊC (bath temperature)
for 2.5 h, and then evaporated. Water was added to the residue,
after which the mixture was neutralized with Na2CO3 and
extracted with EtOAc (3 × 10 cm3). The combined extracts were
washed with water, dried, evaporated and Kugelrohr distilled to
give the acetoxypyrazine 15 (0.436 g, 72%), which crystallized
with time as pale yellow prisms; bp 85 ЊC/32 mmHg, mp 38–
41 ЊC (Found: C, 47.7; H, 4.5; N, 13.8. C8H9N2O2Cl requires C,
The more polar portion furnished the alternative hydroxy-
pyrazine 9 (24 mg, 22%) as small prisms; mp 126–127 ЊC (hex-
ane) (Found: C, 66.6; H, 5.7; N, 12.8. C12H12N2O2 requires C,
66.65; H, 5.6; N, 12.95%); δH 2.44 (3H, s), 3.92 (3H, s), 6.94 (1H,
br s), 7.33–7.44 (3H, m) and 7.92–7.94 (2H, m); δC 17.7, 53.9,
127.9, 128.1, 128.2, 128.6, 131.2, 136.0, 153.4 and 154.4.
J. Chem. Soc., Perkin Trans. 1, 1997
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47.9; H, 4.5; N, 14.0%); δH 2.37 (3H, s), 2.43 (3H, s) and 2.63
(3H, s); δC 18.4, 20.7, 21.3, 142.7, 144.6, 149.4, 150.1 and 168.1.
(lit.,2 186–187 ЊC); δH 2.18 (3H, s), 2.26 (3H, s), 5.34 (2H, s),
7.47–7.49 (3H, m), 7.81–7.85 (2H, m) and 8.40 (1H, s).
The most polar fraction gave 2-acetoxy-5-methyl-3-phenyl-
pyrazine (0.685 g, 30%), mp 110–112 ЊC (hexane–propan-2-ol,
5:1) (Found: C, 68.5; H, 5.3; N, 12.2. C13H12N2O2 requires C,
68.4; H, 5.3; N, 12.3%); δH 2.38 (3H, s), 2.41 (3H, s), 7.08 (1H,
s), 7.43–7.45 (3H, m) and 8.30–8.34 (2H, m); δC 17.8, 19.8,
122.5, 128.0, 129.0, 130.3, 130.8, 135.4, 149.4, 154.6 and 165.7.
2,6-Diacetoxy-3,5-dimethylpyrazine 3c. A mixture of the 1-
hydroxy-1,2-dihydropyrazin-2-one 2c (1.401 g, 0.010 mol) in a
mixture of Ac2O (2.5 cm3) and AcOH (7 cm3) was stirred and
heated at 90 ЊC (bath temperature) for 12.5 h. The mixture was
worked up in the above described manner to give the crude
diacetoxypyrazine 3c which was purified by chromatography on
Florisil (hexane–EtOAc, 1:1) followed by HPLC (hexane–
EtOAc 2:1) to afford pale yellow needles (0.230 g, 10%),
mp 91.5–94.5 ЊC (hexane) (Found: C, 53.6; H, 5.4; N, 12.5.
C10H12N2O4 requires C, 53.6; H, 5.4; N, 12.5%); δH 2.36 (6H, s)
and 2.45 (6H, s); δC 18.4, 20.7, 144.4, 148.6 and 168.0.
Hydrolysis of the acetoxypyrazines 14
2-Hydroxy-6-methoxy-5-methyl-3-phenylpyrazine 7b. A mix-
ture of the acetoxypyrazine 14b (0.014 g, 0.05 mmol) in MeOH
(1 cm3) containing NaHCO3 (7 mg) was refluxed and stirred for
30 min. After being cooled, the mixture was acidified to pH 3
with 1 mol dmϪ3 hydrochloric acid and evaporated. Water was
added to the residue, and the solution was extracted with CHCl3
(3 × 5 cm3). The combined extracts were washed with water,
dried and evaporated to give the hydroxypyrazine 7b (12 mg,
100%), which was identical with the compound obtained by
demethylation of 5b on the basis of spectral evidence.
2-Hydroxy-6-methoxy-3,5-dimethylpyrazine 7c. A mixture of
the acetoxypyrazine 14c (0.196 g, 1.0 mmol) in MeOH (20 cm3)
containing NaHCO3 (0.134 g, 1.6 mmol) was stirred under
reflux for 30 min, and worked up as described above. Evapor-
ation of the extracts gave a crude product, which was recrystal-
lized from hexane containing a trace of propan-2-ol to provide
7c (0.136 g, 88%) as a powder, mp 165–168 ЊC (decomp.)
(Found: C, 54.8; H, 6.6; N, 18.1. C7H10N2O2 requires C, 54.5; H,
6.5, N, 18.2%); δH 2.37 (3H, s), 2.41 (3H, s), 3.85 (3H, s) and
7.28 (1H, br s); δC 17.3, 17.6, 53.7, 129.2, 133.3, 152.9 and 155.0.
Later fractions furnished a mixture of unidentified products.
References
1 Part 33: N. Sato and H. Mizuno, J. Chem. Res. (S), 1997, 250.
2 G. W. H. Cheeseman and R. A. Godwin, J. Chem. Soc. C, 1971,
2977.
Preparation of the 2,6-diacetoxypyrazines 3
3 G. W. H. Cheeseman and E. S. G. Törzs, J. Chem. Soc., 1965, 6681.
4 A. Ohta, A. Imazeki, Y. Itoigawa, H. Yamada, C. Suga, C. Takagai,
H. Sano and T. Watanabe, J. Heterocycl. Chem., 1983, 20, 311.
5 J. Adachi and N. Sato, J. Heterocycl. Chem., 1986, 23, 871.
6 N. Sato and Y. Kato, J. Heterocycl. Chem., 1986, 23, 1677.
7 G. Karmas and P. E. Spoerri, J. Am. Chem. Soc., 1957, 79, 680.
8 N. Sato, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon, Oxford, 2nd
edn., 1996, vol. 6, p. 241 and references cited therein.
2,6-Diacetoxy-3-methyl-5-phenylpyrazine 3b. A mixture of 1-
hydroxy-1,2-dihydropyrazin-2-one 2b (2.026 g, 0.010 mol) in a
mixture of Ac2O (30 cm3) and AcOH (6 cm3) was refluxed and
stirred for 2 h, and then evaporated. Water was added to the
residue and the mixture was extracted with EtOAc (3 × 20 cm3).
The combined extracts were washed with aqueous NaHCO3
and water, dried and evaporated. The residue was chromato-
graphed on silica (100 g; hexane–EtOAc, 1:5) to provide the
diacetate 3b (0.121 g, 4%) as the least polar fraction; mp 106–
106.5 ЊC (hexane–propan-2-ol, 7:1) (Found: C, 63.0; H, 4.9; N,
9.7. C15H14N2O4 requires C, 62.9; H, 4.9; N, 9.8%); δH 2.22 (3H,
s), 2.39 (3H, s), 2.55 (3H, s), 7.43–7.49 (3H, m) and 7.77–7.81
(2H, m); δC 18.7, 20.8, 21.0, 128.6, 129.5, 134.8, 144.7, 145.1,
147.7, 149.1, 167.9 and 168.0.
9 K. W. Blake and P. G. Sammes, J. Chem. Soc. C, 1970, 1070.
10 W. L. F. Armarego, in Physical Methods in Heterocyclic Chemistry,
ed. A. R. Katritzky, Academic Press, New York, 1971, vol. 3, p. 67.
11 R. G. Jones, J. Am. Chem. Soc., 1949, 71, 78.
12 G. Karmas and P. E. Spoerri, J. Am. Chem. Soc., 1952, 74, 1580.
Paper 7/04415A
Received 23rd June 1997
Accepted 15th July 1997
The second polar fraction afforded 2-acetoxy-5-acetoxy-
methyl-3-phenylpyrazine (0.687 g, 24%), mp 187 ЊC (toluene)
3172
J. Chem. Soc., Perkin Trans. 1, 1997