A simple and convenient synthesis of pyrazinones

Article abstract of DOI:10.1080/00397910600978499

Pyrazinones were synthesized by reacting mesoionic azlactone [2-aryl-4-methyl-Δ2-oxaxolin-5-one] and 1,4-diazabutadienes in good yields at room temperature. Copyright Taylor & Francis Group, LLC.

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A Simple and Convenient Synthesis of
Pyrazinones
Saikat Das Sharma a , Pranjal Gogoi a & Dilip Konwar a
a Synthetic Organic Chemistry Division , Regional Research Laboratory ,
Jorhat, Assam, India
Published online: 25 Jul 2007.
To cite this article: Saikat Das Sharma , Pranjal Gogoi & Dilip Konwar (2007) A Simple and Convenient
Synthesis of Pyrazinones, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:1, 107-111, DOI: 10.1080/00397910600978499
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Synthetic Communicationsw, 37: 107–111, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600978499
A Simple and Convenient Synthesis
of Pyrazinones
Saikat Das Sharma, Pranjal Gogoi, and Dilip Konwar
Synthetic Organic Chemistry Division, Regional Research Laboratory,
Jorhat, Assam, India
Abstract: Pyrazinones were synthesized by reacting mesoionic azlactone [2-aryl-4-
methyl-D2-oxaxolin-5-one] and 1,4-diazabutadienes in good yields at room
temperature.
Keywords: [4 þ 2]-cycloaddition, 1,4-diazabutadiene, mesoionic, pyrazinones
Pyrazines and their derivatives having impressive physiological activities are
important structural motifs in numerous natural products.[1] They are very rich
in medicinal aspects, such as antituberculant,[2] antiallergic,[3] antitumor,[4]
and anti-inflammatory[5] properties. Also, pyrazine derivatives are used
against Alzheimer’s disease, Parkinson’s disease, atherosclerosis, ischemia-
reperfusion injury including cerebral trauma and stroke,[6] and so on. They
are synthesized by condensation of 1,2-diketones with 1,2-diaminoketones,
a-amino acid amides, and 1,2-diamino acids; condensation of diamino maleo-
nitrile with b-ketosulphoxides and acyl cyanamides; and self-condensation of
a-amino acyl compounds from a-aminonitriles, a-oximinoketones, a-azido
ketones, and 2,5-dioxopiperazines.[1,6] These reported methods are not free
from limitations (e.g., long reaction sequence, low yield, involvement of
costly reagents).
Received in India May 10, 2006
Address correspondence to Dilip Konwar, Synthetic Organic Chemistry Division,
Regional Research Laboratory, Jorhat 785006, Assam, India. E-mail: dkonwar@
yahoo.co.uk
107

108
S. D. Sharma, P. Gogoi, and D. Konwar
Scheme 1.
The chemistry of 1,4-diazabutadiene (glyoxaldiimine)[7] is not fully
explored in organic chemistry.[8] It is frequently used as a bidentate ligand
in inorganic complexations.[9] It forms [2 þ 2]-cycloaddition product, that
is, b-lactams exclusively with ketenes,[10] but its behavior toward 1,3-
dipoles has not been studied until now. In continuation of our research
interest in mesoionic azlactones,[11] we first report here a simple and novel
synthetic method for pyrazine-5-one (6) derivatives from azlactones [2-aryl-
4-methyl-D2-oxaxolin-5-one] (3) with 1,4-diazabutadines (4) at room temp-
erature (Scheme 1) with high yields.
In a typical procedure, a suspension of 1 mmol of DL-a-benzoylalanine in
1 mmol of acetic anhydride was warmed in a oil bath at 508C under a nitrogen
atmosphere. A clear solution was obtained in about 15 min. Acetic acid and
excess of acetic anhydride were rapidly removed under reduced pressure.
The residue was dissolved in dry toluene (5 ml), and this was added to the
solution of 1 mmol of 1,4-diazabutadiene dissolved in a 1:1 mixture of
toluene and CH2Cl2; the mixture was stirred for a stipulated time at
25–308C. After workup, it produced corresponding pyrazinones with good
yields (Table 1).
Regarding the mechanism of the reaction, we propose that the reaction
perhaps occurred through 1,3-dipolar cycloaddition of azlactones (3) with
1,4-diazabutadiene (4). The involvement of a ketene intermidiate (5) was
ruled out because ketene generation requires higher temperature.[11a,12] In
addition, the mesoion did not form b-lactam (8) or criss-cross addition
product (7) with the 1,4-diazabutadiene system, which was confirmed by
the IR absorbtions at 1714 cm21 assignable for six-membered ring C55O
groups. On the other hand, the IR frequency of the C55O group of b-lactam
lies at 1745–1760 cm21 (Scheme 2).
In conclusion, we have discovered a new and simple method for the
synthesis of pyrazin-5-one by reacting azlactones and 1,4-diazabutadines
with very good yields at room temperature.

Pyrazinone Synthesis
109
Table 1. Synthesis of pyrazinones 6(a–l)
Sl. no.
R1
R2
Time (h)
Yield (%)a
6a
6b
6c
6d
6e
6f
C6H5
p-CH3O-C6H4
p-CH3O-C6H4
p-CH3O-C6H4
p-CH3O-C6H4
p-CH3-C6H4
p-CH3-C6H4
p-CH3-C6H4
p-CH3-C6H4
p-HO-C6H4
p-HO-C6H4
p-HO-C6H4
p-HO-C6H4
1
78
75
72
65
69
71
67
74
69
65
69
67
p-CH3-C6H4
p-Cl-C6H4
o-Cl-C6H4
C6H5
1.2
0.55
1.25
1.1
1
p-CH3-C6H4
p-Cl-C6H4
o-Cl-C6H4
C6H5
6g
6h
6i
1.15
1.05
1.1
1.2
1.1
1.1
6j
p-CH3-C6H4
p-Cl-C6H4
o-Cl-C6H4
6k
6l
aIsolated yield.
bReaction temperature was at 25–308C.
cAll the compounds were characterized by IR, NMR, mass spectra and elemental
analyses.
EXPERIMENTAL
1H NMR spectra were recorded at 60 MHz. Chemical shifts are expressed in d
units relative to the tetramethylsilane (TMS) signal as internal reference in
CDCl3. Fourier transform IR spectroscopy (FTIR) spectra were recorded in
CHCl3. Imines and benzoyl alanines were prepared following standard
literature procedures. Column chromatography was performed on silica gel
(60–120 mesh) using ethyl acetate and hexane as eluent.
Scheme 2. Plausible mechanism for the formation of pyrazinones.

110
S. D. Sharma, P. Gogoi, and D. Konwar
General Procedure for the Synthesis of Pyrazinone
A suspension of 1 mmol of DL-a-benzoylalanine and 1 mmol of acetic
anhydride were warmed in an oil bath at 508C under a nitrogen atmosphere.
A clear solution was obtained in 15 min, and acetic acid and acetic
anhydride were removed under reduced pressure. The residue was dissolved
in dry toluene (5 ml) and added to the solution of 1 mmol of 1,4-diazabuta-
diene dissolved in a 1:1 mixture of toluene and CH2Cl2. The mixture was
stirred for stipulated time at 25–308C. After completion of the reaction, the
products were separated and purified by column chromatography on silica
gel (60–120 mesh) using ethyl acetate/hexane mixture as eluent.
Data
6a: White solid, yield 0.345 g (78%). Mp 1028C; 1H NMR (CDCl3, 60 MHz):
d 1.3 (s, 3H), 3.7 (s, 6H), 6.4 (d, 1H), 6.8 (d, 1H), 7.0–7.7 (m, 13H), 7.9
(s, 1H); FTIR (CHCl3, cm–1): 1181.4, 1662.6, 1714.3, 3280.1; MS (m/z):
443.41 (Mþ). Anal. calcd. for C26H25O4N3: C, 70.41; H, 5.68; N, 9.47.
Found: C, 70.35; H, 5.61; N, 9.39.
6c: White solid, yield 0.343 g (72%). Mp 1138C; 1H NMR (CDCl3, 60 MHz):
d 1.3 (s, 3H), 3.7 (s, 6H), 6.5 (d, 1H), 6.8 (d, 1H), 7.1–7.6 (m, 12H), 7.8
(s, 1H); FTIR (CHCl3, cm–1): 1180.9, 1662.4, 1714.8, 3281.2; MS (m/z):
477.98 (Mþ). Anal. calcd. for C26H24O4N3Cl: C, 65.34; H, 5.06; N, 8.79.
Found: C, 65.41; H, 5.10; N, 8.71.
6f: White solid, yield 0.301 g (71%). Mp 988C; 1H NMR (CDCl3, 60 MHz): d
1.3 (s, 3H), 2.33 (s, 9H), 6.5 (d, 1H), 6.7 (d, 1H), 6.5–7.3 (m, 12H), 7.7 (s, 1H);
FTIR (CHCl3, cm–1): 1658.9, 1714.8, 3285.2; MS (m/z): 425.58 (Mþ). Anal.
calcd. for C27H27N3O2: C, 76.21; H, 6.40; N, 9.87. Found: C, 76.13; H, 6.29;
N, 9.77.
6h: White solid, yield 0.330 g (74%). Mp 1198C; 1H NMR (CDCl3, 60 MHz):
d 1.3 (s, 3H), 2.3 (s, 6H), 6.5 (d, 1H), 6.7 (d, 1H), 7.2–7.7 (m, 12H), 7.8
(s, 1H); FTIR (CHCl3, cm–1): 1662.7, 1714.1, 3283.2; MS (m/z): 446.01
(Mþ). Anal. calcd. for C26H24N3O2Cl: C, 70.03; H, 5.42; N, 9.42. Found:
C, 70.14; H, 5.31; N, 9.30.
6i: White solid, yield 0.286 g (69%). Mp 1238C; 1H NMR (CDCl3, 60 MHz):
d 1.3 (s, 3H), 5.4 (s, 2H), 6.4 (d, 1H), 6.7 (d, 1H), 7.1–7.6 (m, 13H), 7.7
(s, 1H); FTIR (CHCl3, cm–1): 1663.1, 1714.3, 3283.2, 3416.2; MS (m/z):
415.49 (Mþ). Anal. calcd. for C24H21O4N3: C, 69.39; H, 5.10; N, 10.11.
Found: C, 69.47; H, 5.02; N, 10.18.

Pyrazinone Synthesis
111
6j: Yellow solid, yield 0.279 g (65%). Mp 1318C; 1H NMR (CDCl3, 60 MHz):
d 1.3 (s, 3H), 2.3 (s, 3H), 5.4 (s, 2H), 6.5 (d, 1H), 6.8 (d, 1H), 7.2–7.6
(m, 12H), 7.7 (s, 1H); FTIR (CHCl3, cm–1): 1663.4, 1714.5, 3280.2,
3419.7; MS (m/z): 429.56 (Mþ). Anal. calcd. for C25H23O4N3: C, 69.92; H,
5.40; N, 9.78. Found: C, 69.84; H, 5.31; N, 9.73.
ACKNOWLEDGMENT
The authors thank the director, R. R. L. Jorhat, head of the Synthetic Organic
Chemistry Division, the analytical chemistry division of this laboratory. Also,
S. D. S. and P. G. thank Council of Scientific and Industrial Research (CSIR)
for their fellowships.
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