2,6-Diamino-3,5-diaryl-1,4-pyrazine derivatives as novel antioxidants

Article abstract of DOI:10.1055/s-2001-12764

The coupling of arylboronic acids with 2,6-diamino-3,5-dibromo-1,4-pyrazine (6) gave 2,6-diamino-3,5-diaryl-1,4-pyrazines (7). The reaction of 7 with methyl glyoxal in aqueous EtOH-HCl led to the N,N′-disubstituted products 8, instead of the expected bicy

Full text of DOI:10.1055/s-2001-12764

768
PAPER
2,6-Diamino-3,5-diaryl-1,4-pyrazine Derivatives as Novel Antioxidants
2
, 6-Diami
e
no-3,5-diar
a
yl-1,4-pyra
n
zine Derivati
-
ves as
N
F
ove
l
A
ntioxid
r
ants ançois Cavalier,a Maggi Burton,b Catherine De Tollenaere,a Frédérique Dussart,a Cécile Marchand,b
Jean-François Rees,b Jacqueline Marchand-Brynaert*a
g)
Unité de Chimie Organique et Médicinale, Université Catholique de Louvain, Bâtiment Lavoisier, place L. Pasteur 1,
1348 Louvain-la-Neuve, Belgium
h)
Unité de Biologie Animale, Université Catholique de Louvain, Bâtiment Carnoy, place Croix du Sud 4, 1348 Louvain-la-Neuve, Belgium
Fax +32(010)474168; E-mail: marchand@chor.ucl.ac.be
Received 18 September 2000; revised 3 January 2001
R3
O
Abstract: The coupling of arylboronic acids with 2,6-diamino-3,5-
2
dibromo-1,4-pyrazine (6) gave 2,6-diamino-3,5-diaryl-1,4-pyra-
zines (7). The reaction of 7 with methyl glyoxal in aqueous EtOH-
HCl led to the N,N'-disubstituted products 8, instead of the expected
bicyclic imidazolopyrazinones 1. The 2,6-bis[1-(ethoxycarbonyl)-
ethylamino]-3,5-diaryl-1,4-pyrazines 8 are powerful inhibitors of
the AAPH-induced linoleate peroxidation.
1
3
R4
R1
N
O
NH2
R2
R3
O
6
4
1
R4
R1
N
2
N
9
5
6
+
5
3
8
N
4
N
H
R2
3
7
2
1
Key words: 2,6-diamino-3,5-diaryl-1,4-pyrazine,
imidazolopy-
razinone, antioxidant, coelenterazine analogs
Scheme 1
Recently we became interested in the synthesis of imida- disubstituted pyrazine derivatives 8, displaying remark-
zolopyrazinone derivatives 1 (Scheme 1) as potential an- able antioxidative properties.
tioxidants useful in medicinal chemistry for the design of
2,6-Diaminopyrazine (5)7 (Scheme 2) prepared in two
drugs against injuries caused by oxidative stress.1,2 Coe-
steps from 2,6-dichloropyrazine,8 was treated with N-bro-
lenterazine (CLZ), a naturally occurring imidazolopyrazi-
mosuccinimide to give 2,6-diamino-3,5-dibromo-1,4-
none of marine origin (1: R1 = p-HO-Ph; R2 = PhCH2;
pyrazine (6) in moderate overall yield; in our hands, this
R3 = p-HO-PhCH2; R4 = H), is the luminescent substrate
method was more efficient than the synthesis of Y. C.
of enzymes (luciferases) producing light in the presence
Tong starting from tetrabromopyrazine.9 The following
of oxygen.3 Synthetic derivatives of coelenterazine can be
step was a double Suzuki coupling reaction10,11 with phe-
obtained by condensing 2-amino-1,4-pyrazine precursors
nylboronic acid and 4-methoxyphenylboronic acid to
2 with -keto-aldehydes 3 ( r the corresponding acetals)
yield respectively the 3,5-diaryl-2,6-diaminopyrazines 7a
and 7b. We used [1,4-bis(diphenylphosphino)butane]pal-
ladium(II) chloride as the catalyst, prepared in situ
in aqueous acidic medium (Scheme 1).4 Two routes have
been exploited for the synthesis of aminopyrazines 2
equipped with natural or non-natural substituents R1, R2,
from bis(benzonitrile)palladium(II) dichloride and 1,4-
and R4: (i) condensation of 1,2-propanedione-2-oxime de-
bis(diphenylphosphino)butane (dppb) in toluene.6 Depro-
rivatives with 2-amino-propionitrile compounds to form
tection of the methoxy group of 7b was realized with so-
the substituted heterocycles;5 (ii) functionalization of bro-
dium ethanethiolate in hot DMF,12 furnishing 7c in 67%
mo-aminopyrazine derivatives via a Suzuki coupling re-
yield. Reaction of 7 with methyl glyoxal 3a in aqueous
HCl–ethanol at 80°C, led to the double N,N’-alkylation
products 8 (Scheme 2); the expected bicyclic compounds
action with boronic acid derivatives.6 This last method
was exemplified in our group for the preparation of a se-
ries of 3,5-diaryl-2-amino-1,4-pyrazines 2 (R4 = H) and
1 could neither be isolated nor detected from the crude
the related 6,8-diaryl-imidazolopyrazinones 1 (R1 and
mixtures (NMR and UV analysis).
R2 = aryl; R4 = H) which reveal to be powerful antioxi-
This unusual result in the field of heterocyclic synthesis
could be explained as follows: under our experimental
conditions, methyl glyoxal would be transformed into the
corresponding diethyl -keto-acetal 3b, reacting on 2
preferentially with the ketone function to give a Schiff
base 9a in equilibrium with its enamine tautomer 9b
(Scheme 3).2 This intermediate could stabilize either by
cyclization into 1, or by hydrolysis into 8, depending on
the nature of the R4 substituent. The C-6 amino-substitut-
dants.1b
In this context, we examined the possibility of using 2,6-
diamino-1,4-pyrazine (5) (Scheme 2) as the starting mate-
rial for the synthesis of C-5 substituted imidazolopyrazi-
nones 1 (R4 = NH2) susceptible to be further derivatized,
for instance with lipophilic acyl chains (R4 = NHCO-
CnH2n+1). This led to the discovery of unexpected N,N’-
+
+
ed intermediates 9 (R4 = NH3 ; alkyl-NH2 ) conducted ex-
clusively to the monocyclic products 8, most probably for
steric and electronic reasons, while the C-6 unsubstituted
intermediates 9 (R4 = H) evolved mainly to the formation
Synthesis 2001, No. 5, 12 04 2001. Article Identifier:
1437-210X,E;2001,0,05,0768,0772,ftx,en;P06400SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

PAPER
2,6-Diamino-3,5-diaryl-1,4-pyrazine Derivatives as Novel Antioxidants
769
Cl
N
Cl
H2N
N
NH2
a, b
c
67%
59%
N
N
4
5
H2N
N
N
7
NH2
N
NH2
d
a R = H
b R = OMe
c R = OH
e, 67%
68–82%
N
Br
R
R
6
O
O
Me Me
N
EtO
OEt
O
O
a R = H
c R = OH
HN
NH
, f
Me
3
·2HCl
73%
N
R
R
8
Scheme 2 a) NaN3, DMSO, 65 ºC; b) H2, Pd–C 10%, DME, NH4OH; c) NBS, DMSO, H2O, 20 ºC; d) R–Ph–B(OH)2, PdCl2 (dppb) cat.,
toluene, reflux, 24 h; e) EtSNa, DMF, 100 ºC, 24 h; f) EtOH, 37% HCl, 80 ºC, 4 h.
of bicyclic products 1.2,4 Indeed, in a control experiment, Antioxidants (added at 5 mM) can at once delay the onset
starting from 2-amino-3,5-dibromo-1,4-pyrazine (10)13 of the oxidation process and reduce the rate of oxidation.
(Scheme 4), we prepared, in two steps, the corresponding The results are pictured in Figure 1. All the 3,5-diaryl-
3,5-bis(p-hydroxyphenyl) aminopyrazine 11c which was aminopyrazines behaved as excellent antioxidants, but the
further reacted with methyl glyoxal to furnish the imida- best compound clearly was 8c. Moreover, comparatively
zolopyrazinone 12c.
to vitamin E ( -tocopherol)17–19 and TroloxR,2 considered
as good references in the domain, on the one hand, and the
bicyclic derivative imidazolopyrazinone 12c,1b on the oth-
er hand, the monocyclic compound 8c was still the more
active one (Figure 2).
The symmetrically N,N’-disubstituted compounds 8 are
original products. However, related N-monosubstituted 2-
aminopyrazine compounds have already been mentioned
in the literature; they were prepared by reaction of 2-ami-
nopyrazines with -keto-acids in the presence of hydro-
gen and palladium on charcoal (reductive amination).14,15
Compounds 7, 8, and 11, bearing phenyl and p-methoxy-
phenyl substituents could be easily purified by column
chromatography. On the other hand, compounds 7c, 8c,
11c, and 12c, bearing p-hydroxyphenyl substituents (un-
protected phenols) were unstable under the usual chro-
matographic conditions, most probably due to their
sensitivity towards oxidation. They were roughly purified
by washing, and isolated as the hydrates and/or hydro-
chlorides, according to the elemental analysis. All the de-
Figure 1 Inhibition of AAPH-induced peroxidation of linoleic acid
by aminopyrazines. Measure of the absorbance at 234 nm as a
function of time. The compounds were tested at 5 M. 1 = AAPH
(control); 2 = 7a; 3 = 8a; 4 = 7c; 5 = 11c; 6 = 8c
rivatives were properly characterized by their 1H and 13
NMR data (see experimental section).
C
The ability of the synthesized compounds to inhibit lipid
peroxidation has been tested on the AAPH-induced oxida-
tion of linoleate.16 A micellar solution of linoleic acid
(1.6 mM) is incubated at 37 °C with AAPH [2 mM, 2,2’-
azobis(2-amidinopropane) dihydrochloride] as the free
radical generator, in a microplate-based spectrophotome-
ter. The production of conjugated dienes by the peroxida-
tion of linoleate is monitored continuously at 234 nm.
Solvents were dried prior to use. Reagents (Aldrich or Acros) were
used as purchased. Melting points (uncorrected) were determined
on an Electrothermal apparatus. 1H (200 MHz or 300 MHz) and 13
C
(50 MHz or 75 MHz) NMR spectra were recorded on Varian Gem-
ini 200 and 300 spectrometers. Chemical shifts are reported as val-
ues downfield from TMS. The mass spectra (FAB or EI modes)
Synthesis 2001, No. 5, 768–772 ISSN 0039-7881 © Thieme Stuttgart · New York

770
J.-F. Cavalier et al.
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R4
R1
N
NH2
R3
R3
O
O
OEt
OEt
+ 2 EtOH
+
N
R2
O
3a
3b
2
+
EtO
H
EtO
R3
NH
R3
EtO
EtO
N
Figure 2 Inhibition of AAPH-induced peroxidation of linoleic
acid by compound 8c comparatively to compound 12c, and refe-
rences. Measure of the absorbance at 234 nm as a function of time.
The compounds were tested at 5 µM. 1 = AAPH (control);
2 = TroloxR; 3 = Vitamin E; 4 =12c; 5 = 8c
R4
R1
N
R4
N
R2
R1
N
R2
N
(R4 = H)
9b
9a
(R4 = NH2)
H3O+
3b
Anal. Calcd for C4H4Br2N4: C, 17.93; H, 1.50; N, 20.91. Found: C,
18.10; H, 1.46; N, 20.70.
OEt EtO
H
R3
N
OEt
EtO
R3
NH
R3
RO
2,6-Diamino-3,5-diphenyl-1,4-pyrazine (7a)
A mixture of bis(benzonitrile)palladium (II) dichloride (72 mg, 0.1
equiv) and 1,4-bis(diphenylphosphino)butane (96 mg, 0.12 equiv)
in anhyd toluene (8 mL) was stirred at 20 °C under argon atmos-
phere for 30 min, until a creamy orange slurry of [1,4-bis(diphe-
nylphosphino)butane]palladium(II) chloride was formed. 2,6-Di-
amino-3,5-dibromo-1,4-pyrazine (5) (500 mg, 1.87 mmol, 1 equiv),
phenylboronic acid (475 mg, 2.1 equiv) in anhyd toluene (8 mL),
EtOH (1.6 mL) and aq Na2CO3 (1 M, 3.7 mL, 2 equiv) were added
to the preformed catalyst. The mixture was stirred under reflux for
24 h. After addition of H2O (75 mL), the mixture was extracted with
EtOAc (3 × 50 mL). The combined organic phases were washed
with brine (2 × 50 mL), filtered over celite and concentrated in vac-
uo. Purification by column chromatography on silica gel gave pure
7a (332 mg, 68% yield) as a yellow solid.
+
HN
N
N
N
R1
N
R2
R1
R2
H3O+
(R = Et, H)
H+
R3
N
H
O
8
N
Mp 157–158°C; Rf 0.23 (EtOAc–cyclohexane, 3:5).
1
1H NMR (200 MHz, CDCl3): = 7.70 (dd, J = 8.0, 1.5 Hz, 4H), 7.40
(m, 4H), 7.31 (dd, J = 7.3, 1.5 Hz, 2H), 4.65 (s, 4H, NH2).
R1
N
R2
13C NMR (50 MHz, CDCl3): = 149.9 (C-2), 138.2, 129.8 (C-3),
128.9, 128.3, 127.8.
Scheme 3
MS (EI, 70 eV): m/z = 262 (M).
were obtained on a Finnigan MAT TSQ–70 instrument. TLC were
carried out using silica gel 60 F254 plates (0.2 nm, Merck) and the
spots were visualized using UV light (254 nm). Column chromatog-
raphy was performed on Merck silical gel 60 (70–230 mesh). Ele-
mental analyses were obtained at the University College of London.
Anal. Calcd for C16H14N4.0.2 H2O: C, 72.26; H, 5.41; N, 21.07.
Found: C, 72.31; H, 5.33; N, 20.93.
2,6-Diamino-3,5-di(p-methoxyphenyl)-1,4-pyrazine (7b)
7b was prepared as described for 7a, by using 98.6 mg (0.1 equiv)
of bis(benzonitrile)palladium(II) dichloride, 131.5 mg (0.12 equiv)
of 1,4-bis(diphenylphosphino)butane, 689 mg (2.57 mmol, 1 equiv)
of 2,6-diamino-3,5-dibromopyrazine (5), 860 mg (2.2 equiv) of 4-
methoxyphenylboronic acid, 2.28 mL of EtOH, 5.2 mL (2 equiv) of
1 M aq Na2CO3, and 2 × 10 mL of toluene. Column chromatography
on silica gel gave 678 mg (82% yield) of 7b as a yellow solid.
2,6-Diamino-3,5-dibromo-1,4-pyrazine (5)
To a solution of 2,6-diamino-1,4-pyrazine8 (966 mg, 8.78 mmol) in
DMSO (30 mL) and H2O (1.22 mL, 5.56 equiv) was added N-bro-
mosuccinimide in small portions (3.44 g, 2.2 equiv). The mixture
was stirred for 4 h at 20 °C, then diluted with H2O (100 mL) and ex-
tracted with EtOAc (3 × 100 mL). The combined organic phases
were washed with 5% aq Na2CO3 (2 × 150 mL) and brine (2 × 100
mL), then dried over MgSO4 and concentrated in vacuo. Recrystal-
lization from CHCl3 gave 5 (1.63 g, 69% yield) as a brown solid.
Mp 152.3°C; Rf 0.11 (EtOAc–cyclohexane, 3:5).
1H NMR (200 MHz, CDCl3): = 7.65 (d, J = 8.8 Hz, 4H), 6.98 (d,
J = 8.8 Hz, 4H), 4.54 (s, 4H, NH2), 3.84 (s, 6H, OCH3).
13C NMR (50 MHz, CDCl3): = 159.3, 149.4 (C-2), 130.7, 129.8
(C-3), 129.6, 114.4, 55.6.
Mp 183.7° C.
1H NMR (300 MHz, DMSO-d6): = 6.29 (s, NH2).
13C NMR (75 MHz, DMSO-d6): = 151.5 (C-2), 150.1 (C-3).
MS (EI, 70 eV): m/z = 270 (M + 2), 268 (M), 266 (M – 2).
MS (EI, 70 eV): m/z = 322 (M), 307 (M-CH3).
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2,6-Diamino-3,5-diaryl-1,4-pyrazine Derivatives as Novel Antioxidants
771
N
N
NH2
N
NH2
Br
a
b R = OMe
c R = OH
b, 80%
69%
Br
N
R
R
10
11
Me
N
O
N
O
Me
O
3
N
H
c, 67%
HO
OH
12c
Scheme 4 a) R–Ph–B(OH)2, PdCl2 (dppb) cat., toluene, reflux, 24 h; b) EtSNa, DMF, 100°C, 24 h; c) EtOH, 37 % HCl, 80°C, 4 h.
Anal. Calcd for C18H18N4O2: C, 67.10; H, 5.60; N, 17.40. Found: C,
66.94; H, 5.45; N, 17.21.
2,6-Bis(1-ethoxycarbonylethylamino)-3,5-bis(p-hydroxy-
phenyl)-1,4-pyrazine (8c)
8c was prepared as described for 8a, by using 2,6-diaminopyrazine
7c (165 mg, 0.58 mmol, 1 equiv), methyl glyoxal (0.2 mL, 40% in
H2O, 2.2 equiv), 37% aq HCl (0.17 mL, 3.6 equiv), and EtOH (4.5
mL). Compound 8c (dihydrochloride, 231 mg, 73% yield) is a red
solid.
2,6-Diamino-3,5-di(p-hydroxyphenyl)-1,4-pyrazine (7c)
A stirred solution of pyrazine 7b (360 mg, 1.12 mmol, 1 equiv) and
sodium ethanethiolate (790 mg, 8 equiv) in DMF (6 mL) was heated
under argon atmosphere at 100 °C for 24 h. EtOAc (30 mL) and aq
NH4Cl (25 mL, saturated solution) were added. The aqueous phase
was extracted with EtOAc (4 × 25 mL). The combined organic lay-
ers were washed with brine (2 × 25 mL), dried over MgSO4 and con-
centrated in vacuo. Recrystallization from CHCl3 gave 7c
(monohydrate, 236 mg, 67% yield) as a red solid.
Mp 174–176°C (dec.).
1H NMR (300 MHz, DMSO-d6): = 7.45 (d, J = 8.6 Hz, 4H), 6.94
(d, J = 8.6 Hz, 4H), 4.51 (q, J = 7.3 Hz, 2H), 4.02 (q, J = 7.1 Hz, 4H),
1.32 (d, J = 7.3 Hz, 6H), 1.18 (t, J = 7.1 Hz, 6H).
13C NMR (75 MHz, DMSO-d6): = 172.9, 158.2, 149.7 (C-2),
132.3, 130.5, 129.6 (C-3), 115.7, 60.6, 59.5, 17.0, 14.0.
Mp 88–90°C.
1H NMR (300 MHz, DMSO-d6): = 9.45 (s, 2H, OH), 7.47 (d,
J = 7.5 Hz, 4H), 6.82 (d, J = 7.5 Hz, 4H), 5.49 (s, 4H, NH2).
MS (FAB+): m/z = 495 (M + 1).
13C NMR (75 MHz, DMSO-d6): = 156.3, 149.5 (C-2), 129.4,
128.9, 127.1 (C-3), 115.1.
Anal. Calcd for C26H30N4O6 1.7HCl 0.5H2O (565.51): C, 55.22; H,
5.78; Cl, 10.66; N, 9.91. Found: C, 55.16; H, 5.62; Cl, 11.02; N,
9.93.
MS (EI, 70 eV): m/z = 294 (M).
Anal. Calcd for C16H16N4O3 (312.3): C, 61.48; H, 5.12; N, 17.93.
Found: C, 61.13; H, 5.12; N, 17.71.
2-Amino-3,5-bis(p-methoxyphenyl)-1,4-pyrazine (11b)
11b was prepared as described for 7a, by using bis(benzonitrile)pal-
ladium(II) dichloride (306.3 mg, 0.1 equiv), 1,4-bis(diphenylphos-
2,6-Bis(1-ethoxycarbonylethylamino)-3,5-diphenyl-1,4-
pyrazine (8a)
phino)butane
(408.3
mg,
0.12
equiv),
2-amino-3,5-
dibromopyrazine (10)13 (2.02 g, 8 mmol, 1 equiv), 4-methoxyphe-
nylboronic acid (2.55 g, 2.1 equiv), 1 M aq Na2CO3 (16 mL, 2
equiv), EtOH (6.8 mL), and toluene (2 × 20 mL). Column chroma-
tography on silica gel gave 1.6 g (69% yield) of 11b as a yellow sol-
id.
A mixture of 2,6-diaminopyrazine (7a) (150 mg, 0.57 mmol, 1
equiv), methyl glyoxal (132 mL, 40% solution in H2O, 2.2 equiv)
and 37% aq HCl (171 mL, 3.6 equiv) in EtOH (5 mL) was heated
under argon atmosphere at 80°C during 4 h. After concentration in
vacuo, the crude solid was washed with Et2O to afford 8a (hydro-
chloride monohydrate, 79 mg, 27% yield) as a yellow solid.
Mp 136.6°C; Rf 0.21 (EtOAc–cyclohexane, 3:5).
1H NMR (300 MHz, DMSO-d6): = 8.42 (s, 1H, H-6), 7.90 (d,
J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H),
6.98 (d, J = 8.7 Hz, 2H), 6.11 (s, 2H, NH2), 3.78 (s, 3H), 3.81 (s,
3H).
13C NMR (75 MHz, DMSO-d6): = 159.5, 159.0, 151.4 (C-2),
139.8 (C-5), 137.7 (C-3), 136.4 (C-6), 129.9, 129.6, 129.5, 126.2,
114.0 (br), 55.2, 52.1.
Mp 133–136°C (dec.).
1H NMR (300 MHz, DMSO-d6): = 7.43 (d, J = 8.6 Hz, 4H), 6.95
(m, 6H), 4.55 (q, J = 7.1 Hz, 2H), 4.08 (q, J = 6.9 Hz, 4H), 1.38 (d,
J = 7.1 Hz, 6H), 1.20 (t, J = 6.9 Hz, 6H).
13C NMR (75 MHz, DMSO-d6): = 172.0, 151.0 (C-2), 136.5,
129.0, 128.5, 127.5 (C-3), 127.0, 60.6, 59.5, 16.7, 13.6.
MS (FAB+): m/z = 462 (M + 1).
MS (EI, 70 eV): m/z = 307 (M).
Anal. Calcd for C26H30N4O4 1.1HCl. 0.8 H2O (517.03): C, 60.39;
H, 6.32; Cl, 7.75; N, 10.83. Found: C, 60.00; H, 6.62; Cl, 7.30; N,
10.95.
Anal. calcd for C18H17N3O2: C, 70.34; H, 5.57; N, 13.67. Found:
C, 70.16; H, 5.56; N, 13.53.
2-Amino-3,5-bis(p-hydroxyphenyl)-1,4-pyrazine (11c)
11c was prepared as described for 7c, by using 2-amino-3,5-bis(p–
methoxyphenyl)pyrazine (11b) (1.6 g, 5.21 mmol, 1 equiv) and so-
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J.-F. Cavalier et al.
PAPER
dium ethanethiolate (3.5 g, 8 equiv) in DMF (25 mL). The crude
solid was washed with EtOAc–Et2O (1:1, v/v) to give 11c (1.28 g,
80% yield) as a yellow solid (hygroscopic material).
References
(1) (a) Dubuisson, M.; Trouet, A.; Rees, J.-F. Belg. Patent WO
98/43641, 1998. (b) Marchand-Brynaert, J.; de Tollenaere,
C.; Cavalier, J.-F.; Burton, M.; Rees, J.-F. Eur. Patent,
submitted 00 87 0107.0, 2000. (c) Rees, J.-F.; de
Wergifosse, B.; Noiset, O.; Dubuisson, M.; Janssens, B.;
Thompson, E. M. J. Exp. Biol. 1998, 201, 1211.
(d) Dubuisson, M.; de Wergifosse, B.; Trouet, A.; Baguet,
F.; Marchand-Brynaert, J.; Rees, J.-F. Biochem. Pharmacol.
2000, 60, 471.
Mp 250–252°C.
1H NMR (300 MHz, DMSO-d6): = 9.64 (s, 2H, OH), 8.35 (s, 1H,
H-6), 7.79 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 6.88 (d,
J = 8.6 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 5.99 (s, 2H, NH2).
13C NMR (75 MHz, DMSO-d6): = 157.8, 157.3, 151.1 (C-2),
140.3 (C-5), 138.0 (C-3), 135.8 (C-6), 129.5, 128.4, 128.2, 126.3,
115.5, 115.4.
(2) Devillers, I.; de Wergifosse, B.; Bruneau, M.-P.; Tinant, B.;
Declercq, J.-P.; Touillaux, R.; Rees, J.-F.; Marchand-
Brynaert, J. J. Chem. Soc., Perkin Trans. 2 1999, 1481.
(3) (a) de Wergifosse, B.; Noiset, O.; Dubuisson, M.;
Marchand-Brynaert, J.; Baguet, F.; Rees, J.-F. In
Bioluminescence and Chemiluminescence Roda, A.; Kricka,
L.; Stanley, P. Eds.; Wiley and Son: NY, 1999, 396.
(b) Ohmiya, Y.; Hirano, T. Chem. Biol. 1996, 3, 337.
(c) Jones, K.; Hibbert, F.; Keenan, M. Trends Biotechnol.
1999, 17, 477.
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Jones, K.; Hibbert, F. Chem. Commun. 1997, 323.
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Biochem. 1996, 240, 308.
MS (EI, 70 eV): m/z = 279 (M).
Anal. Calcd for C16H13N3O2 H2O (297.29): C, 64.63; H, 5.04; N,
14.13. Found: C, 64.96; H, 5.30; N, 13.91.
2-Methyl-6,8-bis(p-hydroxyphenyl)-3,7-dihydroimidazolo[1,2-
a]pyrazin-3-one (12c)
A mixture of 11b (600 mg, 2.15 mmol, 1 equiv), methyl glyoxal
(0.5 mL, 40% in H2O, 1.5 equiv), and 37% aq HCl (0.62 mL, 3.6
equiv) in EtOH (20 mL) was heated under argon atmosphere at
80°C during 4 h. After concentration in vacuo, the solid residue was
washed with EtOAc–EtOH (1:1, v/v) to afford 12c (hydrochloride
monohydrate, 731 mg, 67% yield) as a red solid.
Mp 167–169°C.
1H NMR (300 MHz, DMSO-d6): = 8.67 (s, 1H, H-5), 8.01 (m,
4H), 7.05 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 2.46 (s, 3H).
(5) Kishi, Y.; Tinano, H.; Goto, T. Tetrahedron Lett. 1972, 27,
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1973, 606.
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Chem. 1980, 17, 11.
13C NMR (75 MHz, DMSO-d6): = 160.6, 158.8, 143.9 (C-8),
136.9 (C-9), 130.9, 129.7, 127.9, 126.4 (C-6), 125.2, 124.7 (C-3),
123.9 (C-2), 115.7, 115.6, 107.9 (C-5), 9.7.
MS (FAB+): m/z = 334 (M + 1), 306, 291.
(9) Tong, Y. C. J. Heterocl. Chem. 1975, 12, 1127.
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(11) (a) Gong, Y.; Pauls, H. W. Synlett 2000, 829.
(b) Nakamura, H.; Aizawa, M.; Takeuchi, D.; Murai, A.;
Shimoura, O. Tetrahedron Lett. 2000, 41, 2185.
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1731.
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64, 6969.
Anal. Calcd for C19H15N3O3 1.1HCl 1.3H2O (396.83): C, 57.45 H,
4.75; Cl, 9.85; N, 10.50. Found: C, 57.64; H, 5.26; Cl, 9.57; N, 9.93.
Acknowledgement
This work was supported by the Fonds National de la Recherche
Scientifique (F.N.R.S., Belgium), and the Walloon Government
(convention no. 9713664).
(18) Barclay, L. R. C.; Edwards, C. E.; Vinqvist, M. R. J. Am.
Chem. Soc. 1999, 121, 6226.
(19) Zhou, B.; Jia, Z.-S.; Chen, Z.-H.; Yang, L.; Wu, L.-M.; Liu,
Z.-L. J. Chem. Soc., Perkin Trans. 2 2000, 785.
Synthesis 2001, No. 5, 768–772 ISSN 0039-7881 © Thieme Stuttgart · New York