Rearrangement of 2-(2-aryl-2-oxoethyl)-1,2-dihydropyrido-[2,3-b]pyrazin- 3(4H)-ones [5]

Full text of DOI:10.1007/s10593-007-0208-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 10, 2007
REARRANGEMENT OF 2-(2-ARYL-
2-OXOETHYL)-1,2-DIHYDROPYRIDO-
[2,3-b]PYRAZIN-3(4H)-ONES
N. N. Kolos and L. Yu. Kovalenko
Keywords: 2-(2-aryl-2-oxoethyl)-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one, (2Z)-2-(3-arylpyrido-
[2,3-b]pyrazin-2-ylidene]acetic acids, rearrangement.
In previous work [1], we established that 3-(n-R-phenacyl)quinoxalin-2-ones undergo thermal
rearrangement to give 3-aryl-2-methylidenecarboxyquinoxalines upon heating in acetic acid. However, the
yields of the acids were low and 2-(2-aryl-2-oxoethyl)-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-ones (1) remain
unchanged under these conditions [2].
In the present work, we have shown that heating pyrido[2,3-b]pyrazin-3-ones 1a-c in DMF (or in
1-butanol) in the presence of molecular sulfur leads to acids 2a-c, which were isolated in satisfactory and high
yields. The rearrangement could not be carried out in the absence of sulfur. Our experimental data showed that
the yield of pyridopyrazines 2 is greater when the phenacyl fragment has an electron-withdrawing substituent.
Only pyrazine 1c undergoes rearrangement upon heating above the melting point though the yield of product 2c
does not exceed 20% under these conditions.
O
Ar
O
Ar
H
N
H
N
H
N
COOH
S
HOH
SH
SH
Ar
DMF
BuOH
N
N
H
O
N
N
H
O
N
NH2
or
O
A
1a-c
O
OH
H
N
COOH
SH
COOH
SH
H
NH2
N
–H2S
–
HOH
N
N
N
N
Ar
N
N
Ar
Ar
2a-c
B
1, 2 a Ar = Ph, b Ar = C6H4OMe-4, c Ar = C6H4Cl-4
__________________________________________________________________________________________
V. N. Karazin Kharkiv National University, Kharkiv 61077, Ukraine; e-mail: kolos@univer.kharkov.ua.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1588-1590, October, 2007. Original
article submitted June 6, 2007.
0009-3122/07/4310-1351©2007 Springer Science+Business Media, Inc.
1351

The first reaction step is presumably thiolation of the methylene group of the phenacyl moiety, which
occurs through an enolic form [3, 4]. Opening of the amide bond by the action of traces of moisture leads to
intermediate A, which undergoes cyclization to give a 1,5-benzodiazepine derivative. A subsequent
transformation of the seven-membered ring involves formation of intermediate B, which cyclizes to give
2-(3-arylpyrido[2,3-b]pyrazin-2-ylidene)acetic acids 2.
The configuration of 2a-c was established by 1H NMR spectroscopy using NOE. Saturation of the signal
of the vinylidene proton at 6.80 ppm in 2b leads to a response on the ortho protons of the aryl group, indicating
Z-configuration of the rearrangement product.
1
The H NMR spectra were taken on a Varian Mercury VX-200 spectrometer at 200 MHz in DMSO-d6
using TMS as the internal standard.
Pyrazinones 1b,c were obtained by the reaction of the corresponding β-aroylacrylic acids with
2,3-diaminopyridine by a procedure described in our previous work [2].
2-[2-(p-Methoxyphenyl)-2-oxoethyl]-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (1b). Yield 55%;
1
mp 210-211°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 3.48 (1H, d, J = 6.8, HA(CH2)); 3.75 (1H, dd,
J = 17.8, HB(CH2)); 3.83 (3H, s, OCH3); 4.39 (1H, t, J = 4.7, CH); 6.17 (1H, s, NH); 6.78 (1H, m, H-7); 6.97
(2H, d, J = 8.5, m-Ar); 7.03 (1H, d, J = 7.5, H-8); 7.54 (1H, d, J = 7.5, H-6); 7.96 (2H, d, J = 8.5, o-Ar); 10.75
(1H, s, NH). Found, %: N 14.43. C16H15N3O2. Calculated, %: N, 14.13.
2-[2-(p-Chlorophenyl)-2-oxoethyl]-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (1c). Yield 62%;
1
mp 239-240°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 3.39 (1H, d, J = 6.6, HA(CH2)); 3.55 (1H, dd,
J = 17.8, HB(CH2)); 4.42 (1H, t, J = 4.8, CH); 6.17 (1H, s, NH); 6.76 (1H, m, H-7); 6.96 (1H, d, J = 7.6, H-8);
7.54 (1H, d, J = 7.6, H-6); 7.58 (2H, d, J = 8.5, m-Ar); 7.99 (2H, d, J = 8.5, o-Ar); 10.74 (1H, s, NH). Found, %:
N 14.00. C15H12ClN3O2. Calculated, %: N 13.93.
Synthesis of Pyrido[2,3-b]pyrazines 2a,c (General Method). A solution of pyrido-2-pyrazinone 1
(1 mmol) and sulfur (0.064 g, 2 mmol) in DMF (10 ml) was heated at reflux for 6 h and cooled. The precipitate
formed was filtered off, washed with hot ethanol, and dried in the air.
(2Z)-2-(3-Phenylpyrido[2,3-b]pyrazin-2(1H)-ylidene)acetic Acid (2a). Yield 72%; mp 257-258°C
1
(ethanol). H NMR spectrum, δ, ppm (J, Hz): 6.85 (1H, s, =CH); 7.15 (1H, m, H-7); 7.56 (2H, m, m-C6H5,
p-C6H5); 7.99 (3H, d, J = 7.6, o-C6H5 + H-8); 8.08 (1H, d, J = 6.4, H-6); 12.45 (2H, s, NH, OH). Found, %:
N 15.48. C15H11N3O2. Calculated, %: N 15.84.
(2Z)-2-(3-p-Methoxyphenylpyrido[2,3-b]pyrazin-2(1H)-ylidene)acetic Acid (2b). Yield 45%;
1
mp 269-270°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 3.82 (3H, s, OCH3); 6.80 (1H, s, =CH); 7.05 (2H,
d, J = 8.6, m-Ar); 7.13 (1H, m, H-7); 7.91 (1H, d, J = 7.2, H-8); 7.97 (2H, d, J = 8.4, o-Ar); 8.04 (1H, d, J = 5.9,
H-6); 11.87 (1H, s, NH); 13.30 (1H, s, OH). Found, %: N 14.00. C16H13N3O2. Calculated, %: N 14.23.
(2Z)-2-(3-p-Chlorophenylpyrido[2,3-b]pyrazin-2(1H)-ylidene)acetic
Acid
(2c). Yield
89%;
1
mp 307-308°C (ethanol). H NMR spectrum, δ, ppm (J, Hz): 6.83 (1H, s, =CH); 7.58 (2H, d, J = 8.9, m-Ar);
7.16 (1H, m, H-7); 8.01 (3H, d, J = 8.9, H-8+o-Ar); 8.09 (1H, d, J = 5.8, H-6); 12.44 (1H, s, NH); 13.37 (1H, s,
OH). Found, %: N 13.85. C15H10ClN3O2. Calculated, %: N 14.02.
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