Synthesis of pyrazine-2,3-dicarbonitriles via the one-pot three-component reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione, diaminomaleonitrile, and functionalized alcohols in acetonitrile

Article abstract of DOI:10.1002/jhet.3761

An efficient one-pot three-component reaction of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-dione, diaminomaleonitrile, and alcohols with hetero-atom substituents or several hydroxyl groups in acetonitrile solvent under reflux led to the formation o

Full text of DOI:10.1002/jhet.3761

Received: 2 May 2019
DOI: 10.1002/jhet.3761
Revised: 31 August 2019
Accepted: 12 September 2019
A R T I C L E
Synthesis of pyrazine-2,3-dicarbonitriles via the one-pot
three-component reaction of 4-benzoyl-5-phenylamino-2,3-
dihydrothiophene-2,3-dione, diaminomaleonitrile, and
functionalized alcohols in acetonitrile
Roya Shahnaei | Hassan Kabirifard
| Parinaz Fathololoomi
Department of Chemistry, North Tehran
Abstract
Branch, Islamic Azad University, Tehran,
Iran
An efficient one-pot three-component reaction of 4-benzoyl-5-phenylamino-2,-
3-dihydrothiophene-2,3-dione, diaminomaleonitrile, and alcohols with hetero-
atom substituents or several hydroxyl groups in acetonitrile solvent under
reflux led to the formation of 5-(2-substituted ethoxy or propoxy-2-phenyl-1-N-
phenylthiocarbamoylethenyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile
derivatives in good yields.
Correspondence
Hassan Kabirifard, Department of
Chemistry, North Tehran Branch, Islamic
Azad University. Tehran, Iran.
Email: h_kabirifard@iau-tnb.ac.ir
1 | INTRODUCTION
derivatives exhibit varying degrees of biological
activity[34] such as fungicidal[35] and herbicidal
Heterocycles are considered as the largest category in
organic chemistry and have a special biological and
industrial significance. Pyrazines are important flavor
components in food[1] and show interesting
anticancer[1–4] and antituberculosis activities[1,5–8] and
apply in microbial metabolism[9] and also as μ-opioid
receptor antagonists.[10] Diaminomaleonitrile (DAMN) is
an important pioneer for the synthesis of heterocyclic
compounds.[11–13] Pyrazine-2,3-dicarbonitrile derivatives
are usually synthesized through DAMN condensation,
which usually have been synthesized through
condensation of DAMN with α-diketones,[14–16] glyoxal,
α-keto aldehydes, α-keto oximes,[11] α-keto thioester,[17]
α-keto esters,[18,19] and 4-acylfuran-2,3-diones.[20]
2,3-Dicyanopyrazines are very powerful electron
acceptors and are especially suitable building blocks for
the functional dyes and nonlinear optical materials
(NLOs).[21–23] In particular, 2,3-dicyanopyrazines can be
used as a convenient precursor for fluorescent dyes and
can be applied as an emitter for electro luminescence
devices.[24–28] Pyrazine-2,3-dicarbonitriles may be used as
precursors for tetrapyrazinoporphyrazines (TPyzPzs),
the heterocyclic aza analogs of the phthalocyanines
(AzaPcs).[29–33] Furthermore, pyrazine-2,3-dicarbonitrile
activities.[36] Earlier, we found that the reactions
of 4-benzoyl-5-phenylamino-2,3-dihydrothiophene-2,3-
dione (1) with DAMN in the presence of alcohols as
reactant and solvent at room temperature provided
1,6-dihydropyrazine-2,3-dicarbonitrile derivatives that
have N-phenylthiocarbamoyl group.[17] In part of our
studies on 2,3-dihydrothiophene-2,3-dione 1 associated
with the synthesis of the corresponding 1,6-dihydro
pyrazine-2,3-dicarbonitrile
derivatives,
we
have
now achieved the one-pot three-component reaction
of 2,3-dihydrothiophene-2,3-dione 1, DAMN, and
functionalized alcohols 2 with high boiling point or
expensive just as a reactant in acetonitrile solvent under
reflux has led to 1,6-dihydropyrazine-2,3-dicarbonitriles
3 (Schemes 1).
2 | RESULTS AND DISCUSSION
The aim of this study was to introduce acetonitrile as a
convenient solvent for one-pot three-component reaction
of
4-benzoyl-5-phenylamino-2,3-dihydrothiophene-
2,3-dione (1), DAMN, and functionalized alcohols 2 under
reflux conditions (Scheme 1). In order to further optimize
J Heterocyclic Chem. 2019;1–6.
wileyonlinelibrary.com/journal/jhet
© 2019 Wiley Periodicals, Inc.
1

2
SHAHNAEI ET AL.
functionalized alcohols 2 in acetonitrile solvent under
reflux conditions for 2 to 3 hours in good yields (Table 2).
Compounds 3a-g are explained by elemental analyses,
IR, 1H NMR, 13C NMR spectroscopy, and mass spectrom-
etry. The mass spectra of some products exhibited fairly
weak molecular ion peaks. Structural comparison of 3a-g
can easily be seen through the IR and 13C NMR spectra.
The IR spectra of 3a-g showed the characteristic absorp-
tion bands of C≡N, amide C─O, thioamide C─N, NH,
C─S, and ether C─O─C (asy and sy) groups at 2250 to
2240, 1747 to 1728, 1545 to 1538, 1375 to 1359, 1184 to
1164, 1219 to 1207, and 1125 to 1078 cm−1, respectively.
Their 13C NMR spectra also showed signals at δ 59.62 to
74.33, 118.72 to 122.91, 146.81 to 147.23, 162.63 to 163.25,
and 188.00 to 188.24 ppm due to the carbons of the ether
C─O, 2C≡N, C5─N, amide C─O, and thioamide C─S. In
SCHEME 1 One-pot three-component reaction of 4-benzoyl-
5-phenylamino-2,3-dihydrothiophene-2,3-dione (1),
diaminomaleonitrile and functionalized alcohols 2
the reaction conditions, the model reaction was carried
out using 2,3-dihydrothiophene-2,3-dione 1, DAMN, and
2,2,2-trifluoroethanol (2a) under various conditions
(Table 1). The reaction conditions were optimized based
on the solvent and temperature used for the synthesis of
the
corresponding
1,6-dihydropyrazine-
1
2,3-dicarbonitrile 3a.
the H NMR spectra of 3a-g, we have two sets of multi-
To identify the best solvent and temperature in this
reaction, the model reaction was performed with differ-
ent solvents such as n-hexane, CH3Cl, THF, acetone,
CH3CN, DMF, and solvent-free under room temperature
and reflux conditions (Table 1). Acetonitrile under reflux
condition exhibited the best performance in the reaction
(84% yield). The yield gradually increased as we shifted
from less polar to more polar solvents. The refluxing
plays a main role in product yield and reaction time.
To show the generality of this new method, the reac-
tions were performed using 4-benzoyl-5-phenylamino-2,-
plet signals for aliphatic and aromatic protons and two
broad singlets at δ 12.08 to 12.14 and 13.77 to 13.89 ppm
for the amidic and thioamidic NH protons, respectively.
The high deshilding of the thioamidic NH proton is prob-
ably the result of the amino group participation in the
intramolecular hydrogen bonding with the oxygen of
ether fragment.
Carbon atoms C-2, C-3, and C-5 in compound 1 are
electrophilic sites that can display different reactivities
depending on the structures of the nucleophiles and reac-
tion conditions.[37] DAMN cyclizes by nucleophilic attack
on the α-ketothioesteric fragment (C-2 and C-3) of 1, then
3-dihydrothiophene-2,3-dione
(1),
DAMN,
and
TABLE 1 Optimization of one-pot three-component reaction conditions for the synthesis of
5-(2-(20,20,20-trifluoroethoxy)-2-phenyl-1-N-phenylthiocarbamoylethenyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile (3a)a
Entry
Solvent
n-hexane
n-hexane
CHCl3
Time (h)
T (ꢀC)
r.t.
Yield (%)b
1
4
3
4
3
4
3
4
3
3
2
3
2
4
3
3
11
18
29
40
34
46
45
57
72
84
70
79
31
46
42
2
Reflux
r.t.
3
4
CHCl3
Reflux
r.t.
5
THF
6
THF
Reflux
r.t.
7
Acetone
Acetone
CH3CN
CH3CN
DMF
8
Reflux
r.t.
9
10
11
12
13
14
15
Reflux
r.t.
DMF
Reflux
r.t.
Solvent free
Solvent free
Solvent free
50
60
aReaction conditions: 2,3-dihydrothiophene-2,3-dione 1 (1.0 mmol), diaminomaleonitrile (1.0 mmol), 2,2,2-trifluoroethanol (2a, 1.0 mmol) and solvent (10 mL).
bIsolated yields.

SHAHNAEI ET AL.
3
TABLE 2 Synthesis of 5-(2-substituted ethoxy or
propoxy-2-phenyl-1-N-phenylthiocarbamoylethenyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile derivatives (3a-g)a
Entry
R
Product
Time (h)
Yield (%)b
1
2
3
4
5
6
7
CF3
3a
3b
3c
3d
3e
3f
2
2
3
3
3
3
2
84
80
75
74
77
78
81
CCl3
MeOCH2
HSCH2
HOCH2CH2SCH2
HOCH2
HOCH2CH(oh)
3 g
aReaction conditions: 2,3-dihydrothiophene-2,3-dione 1 (1.0 mmol), diaminomaleonitrile (1.0 mmol), functionalized alcohol 2 (1.0 mmol) and acetonitrile
(10 mL).
bIsolated yields.
the nucleophilic attack of the alcohols on the ketonic car-
bonyl group of intermediate 4 form 1,6-dihydropyrazine-
2,3-dicarbonitrile derivatives 3 (Scheme 2).[17] In the case
of phenol in order to attack the intermediate 4, the elec-
trons of the phenol oxygen atom are involved in the reso-
nance with aromatic ring and to some extent they have
sp2 properties, thus phenol is not suitable as a nucleo-
phile and does not participate in the reaction.
The significant degree of selectivity that occurs in
electrophile-nucleophile interactions is predicted by
Pearson's hard and soft acids and bases (HSAB) the-
ory.[38] Therefore, compound 3d shows that nucleophilic
attack of 2-mercaptoethanol from the hydroxy group
(OH) as hard nucleophile occur at ketonic carbonyl
group as hard electrophile of intermediate 4 and the thiol
group (SH) as soft nucleophile does not take part in the
nucleophilic attack.
propoxy-2-phenyl-1-N-phenylthiocarbamoylethenyl)-
6-oxo-1,6-dihydropyrazine-2,3-dicarbonitriles (3a-g) is
reported from the reaction of 4-benzoyl-5-phenylamino-
2,3-dihydrothiophene-2,3-dione
(1),
DAMN,
and
functionalized alcohols 2a-g in acetonitrile solvent
under reflux conditions. This procedure provides
multiple advantages over previous report,[17] such as
simpler evaporation of acetonitrile than evaporation of
alcohols with high boiling point, low cost of acetonitrile
than some functionalized alcohols, and good isolated
yields.
4 | EXPERIMENTAL
4.1 | General
The chemicals were purchased from Merck in high
purity and used without further purification. All melt-
ing points are uncorrected and were determined in
capillary tube on Electrothermal 9100 apparatus. The
elemental analyses (C, H, and N) were obtained from
a Heraeus CHN-O-Rapid analyzer. These results agree
favorably with the calculated values. FT-IR spectra
were recorded from KBr disk using a Thermo Nico-
let 8700 spectrometer and frequencies were reported in
cm−1.
3 | CONCLUSIONS
An proficient method and one-pot three-component cou-
pling for the synthesis of 5-(2-substituted ethoxy or
1H NMR and 13C NMR spectra were obtained on a
Bruker DRX-300 AVANCE at 300 and 75 MHz instru-
ment with DMSO-d6 as solvent and using TMS as an
internal standard. Chemical shifts and coupling con-
stants were reported in ppm and Hz, respectively.
Thin-layer chromatography was carried out on silica
gel 254 analytical sheets obtained from Fluka. Mass
spectra were recorded on an Agilent HP 5973 mass
spectrometer operating at an ionization potential of
70 eV.
SCHEME 2 Proposed mechanism for the one-pot three-
component synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile 3

4
SHAHNAEI ET AL.
4.2 | Material
(481.45): C, 57.38%; H, 2.93%; N, 14.55%; found: C,
57.60%; H, 3.18%; N, 14.76%.
Ethyl 2,4-dioxo-4-phenylbutanoate was prepared from
diethyl oxalate (6.0 mmol) and acetophenone (4.0 mmol)
in the presence of sodium ethoxide (8.4 mmol) in abso-
lute ethanol (30 mL) under N2 atmosphere.[39] 4-Benzoyl-
5-phenylamino-2,3-dihydrothiophene-2,3-dione (1) was
obtained by careful addition of phenyl isothiocyanate
(10 mmol) to ethyl 2,4-dioxo-4-phenylbutanoate
(10 mmol) in KOH (10 mmol) and DMF (20 mL) with
stirring for 24 hours at room temperature.[37]
4.5 | 5-(2-(20,20,20-Trichloroethoxy)-2-
phenyl-1-N-phenylthiocarbamoylethenyl)-
6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile
(3b)
Brown powder; yield: 0.43 g (80%); mp 248 to 250ꢀC. IR
−
(KBr): ν 3255 (NH), 3036 (CH, aromatic), 2249 (CN),
1747 (C─O, amide), 1601 (C─C), 1560 (NH), 1541, 1361,
1164 (C─N, NH, C─S, thioamide), 1210, 1118 (C─O─C)
1
4.3 | General procedure for the synthesis
of 1,6-dihydropyrazine-2,3-dicarbonitriles
(3a-g)
cm−1; H NMR (DMSO-d6): δ 5.26 (2H, s, CH2O), 7.28
(1H, t, 3J 7.5 Hz, CHpara of Ph-NH), 7.44 (2H, t, 3J
7.5 Hz, 2CHmeta of Ph─NH), 7.49–7.95 (7H, m, 2Ph),
12.13, 13.87 (2H, 2br s, 2NH); 13C NMR (DMSO-d6): δ
74.33 (CH2O), 95.03 (CCl3), 114.29 (─C), 118.79, 121.66
(2CN), 123.09, 126.41, 126.97, 128.68, 128.79, 129.23
(10C, 2Ph), 130.71 (Cipso of Ph─C─C), 139.43 (Cipso of
Ph-NH), 147.23 (C5), 148.38 (C3), 149.90 (C2), 161.26
(O─C─), 163.25 (C─O, amide), 188.06 (C─S) ppm. EI-
MS: m/z (%) 534 (M++4, 1), 532 (M++2, 9), 530 (M+,
26), 496 (23), 396 (5), 352 (15), 321 (12), 295 (15),
261 (10), 244 (22), 177 (16), 165 (17), 145 (13), 109 (23),
93 (81), 77 (100), 51 (36). Anal. Calcd for
C23H14Cl3N5O2S (530.81): C, 52.04%; H, 2.66%; N,
13.19%; found: C, 52.23%; H, 2.84%; N, 12.95%.
A
mixture
of
4-benzoyl-5-phenylamino-2,-
3-dihydrothiophene-2,3-dione (1, 0.309 g, 1.0 mmol),
DAMN (0.108 g, 1.0 mmol), and functionalized alcohols
2a-g (1.0 mmol) in the acetonitrile (10 mL) was refluxed
for 2 to 3 hours. The progress of the reaction was moni-
tored by TLC (eluent AcOEt/hexane 4:1). The solvent
was evaporated, the residue was recrystallized from etha-
nol for 3a, 3c-e, and methanol:hexane (9:1) for 3b. For
derivatives 3f,g, the solution was poured into H2O
(10 mL), a precipitate formed, which was filtered and
crystallized from ethanol: H2O (4:1).
4.4 | 5-(2-(20,20,20-Trifluoroethoxy)-2-
phenyl-1-N-phenylthiocarbamoylethenyl)-
6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile
(3a)
4.6 | 5-(2-(20-Methoxyethoxy)-2-phenyl-1-
N-phenylthiocarbamoylethenyl)-6-oxo-1,6-
dihydropyrazine-2,3-dicarbonitrile (3c)
Brown powder; yield: 0.34 g (75%); mp 178 to 18ꢀC. IR
−
Orange powder; yield: 0.40 g (84%); mp 218 to 22ꢀC. IR
(KBr): ν 3297 (NH), 2240 (CN), 1742 (C─O, amide),
−
(KBr): ν 3257 (NH), 3034 (CH, aromatic), 2248 (CN),
1613 (C─C), 1567 (NH), 1538, 1359, 1172 (C─N, NH,
1
1740 (C─O, amide), 1603 (C─C), 1573 (NH), 1540, 1362,
1179 (C─N, NH, C─S, thioamide), 1269 (C─F), 1216,
1122 (C─O─C) cm−1; 1H NMR (DMSO-d6): δ 5.11 (2H, q,
C─S, thioamide), 1207, 1117, 1098 (C─O─C) cm−1; H
NMR (DMSO-d6): δ 3.29 (3H, s, CH3O), 3.68, 4.49 (4H,
3
2br t, 2CH2O), 7.28 (1H, t, J 7.5 Hz, CHpara of Ph─NH),
3
3
3JHF 9.0 Hz, CH2O), 7.28 (1H, t, J 7.6 Hz, CHpara of Ph-
7.45 (2H, t, J 7.5 Hz, 2CHmeta of Ph─NH), 7.52 to 7.93
3
NH), 7.44 (2H, t, J 7.6 Hz, 2CHmeta of Ph-NH), 7.49 to
(7H, m, 2Ph), 12.14, 13.77 (2H, 2br s, 2NH); 13C NMR
(DMSO-d6): δ 58.13 (CH3O), 64.91, 69.60 (2CH2O),
114.26 (─C), 118.73, 121.46 (2CN), 122.91, 126.35,
126.98, 128.67, 128.75, 129.15 (10C, 2Ph), 130.62 (Cipso of
Ph─C─C), 139.46 (Cipso of Ph-NH), 147.17 (C5), 148.43
(C3), 149.86 (C2), 161.66 (O─C─), 162.78 (C─O, amide),
188.17 (C─S) ppm. EI-MS: m/z (%) 457 (M+, 27),
424 (33), 354 (8), 322 (5), 295 (12), 261 (5), 244 (11),
220 (20), 165 (13), 135 (25), 109 (13), 93 (100), 77 (79),
45 (80). Anal. Calcd for C24H19N5O3S (457.50): C,
63.01%; H, 4.19%; N, 15.31%; found: C, 62.84%; H,
3.98%; N, 15.09%.
7.95 (7H, m, 2Ph), 12.10, 13.86 (2H, 2br s, 2NH); 13C
2
NMR (DMSO-d6): δ 60.46, 60.93, 61.40, 61.92 (q, JCF
1
36.4 Hz, CH2O), 117.86, 121.62, 125.38, 129.14 (q, JCF
282 Hz, CF3), 114.27 (─C), 118.83, 122.91 (2CN), 123.04,
126.46, 127.22, 128.71, 128.82, 129.21 (10C, 2Ph), 130.75
(Cipso of Ph─C─C), 139.47 (Cipso of Ph─NH), 147.07 (C5),
147.52 (C3), 149.92 (C2), 161.27 (O─C─), 162.83 (C─O,
amide), 188.08 (C─S) ppm. EI-MS: m/z (%) 480 (M+ − 1,
16), 448 (26), 426 (30), 394 (32), 352 (8), 322 (6), 295 (8),
261 (6), 244 (15), 177 (24), 165 (16), 145 (10), 109 (15),
93 (36), 77 (100), 51 (29). Anal. Calcd for C23H14F3N5O2S

SHAHNAEI ET AL.
5
4.7 | 5-(2-(20-Mercaptoethoxy)-2-phenyl-
1-N-phenylthiocarbamoylethenyl)-6-oxo-
1,6-dihydropyrazine-2,3-dicarbonitrile (3d)
4.9 | 5-(2-(20-Hydroxyethoxy)-2-phenyl-1-
N-phenylthiocarbamoylethenyl)-6-oxo-1,6-
dihydropyrazine-2,3-dicarbonitrile (3f)
Green powder; yield: 0.34 g (74%); mp 201 to 203ꢀC.
IR (KBr): ν 3263 (NH), 3140 (CH, aromatic), 2925
Orange crystals; yield: 0.35 g (78%); mp 258 to 260ꢀC
−
(Moloudi et al[17] yield: 0.30 g (68%); mp 257–259ꢀC).
−
(CH, aliphatic), 2249 (CN), 1736 (C─O, amide), 1545,
1375, 1182 (C─N, NH, C═S, thioamide), 1215, 1012
IR (KBr): ν 3450 (NH), 3250 (OH), 2965 (CH, ali-
phatic), 2240 (CN), 1740 (C─O, amide), 1607 (C─C),
1573 (NH), 1542, 1363, 1184 (C─N, NH, C─S, thio-
1
(C─O─C) cm−1; H NMR (DMSO-d6): δ 1.22 (1H, br s,
SH), 3.11 (2H, t, 3J 6.5 Hz, CH2SH), 3.59 (2H, t, 3J
6.5 Hz, CH2O), 7.29 (1H, t, 3J 7.6 Hz, CHpara of
Ph─NH), 7.45 (2H, t, 3J 7.6 Hz, 2CHmeta of Ph-NH),
7.52 to 7.94 (7H, m, 2Ph), 12.08, 13.89 (2H, 2br s,
2NH); 13C NMR (DMSO-d6): δ 31.69 (CH2SH), 59.62
(CH2O), 114.21 (─C), 118.99, 121.31 (2CN), 123.03,
126.41, 127.28, 128.71, 128.81, 129.16 (10C, 2Ph),
130.75 (Cipso of Ph─C─C), 139.43 (Cipso of Ph─NH),
147.16 (C5), 149.69 (C3), 151.34 (C2), 162.16 (O─C─),
164.609 (C─O, amide), 188.00 (C═S) ppm. EI-MS: m/z
(%) 459 (M+, 5), 426 (23), 388 (3), 354 (7), 322 (27),
246 (6), 165 (14), 109 (27), 93 (100), 77 (93), 51 (70).
Anal. Calcd for C23H17N5O2S2 (459.54): C, 60.11%; H,
3.73%; N, 15.24%; found: C, 60.27%; H, 3.53%; N,
15.02%.
amide), 1218, 1078 (C─O─C), 1032 (C─OH) cm−1; H
1
3
NMR (DMSO-d6): δ 3.73 (2H, br t, J 4.9 Hz, CH2OH),
4.38 (2H, t, 3J 4.9 Hz, CH2-O), 4.95 (1H, br t, OH),
3
7.28 (1H, t, J 7.6 Hz, CHpara of Ph-NH), 7.44 (2H, t,
3J 7.6 Hz, 2CHmeta of Ph-NH), 7.56 to 7.93 (7H, m,
2Ph), 12.13, 13.81 (2H, 2br s, 2NH); 13C NMR (DMSO-
d6): δ 62.65 (CH2OH), 67.50 (CH2O), 114.23 (─C),
118.73, 121.39 (2CN), 122.95, 126.33, 126.79, 128.62,
128.74, 129.11 (10C, 2Ph), 130.64 (Cipso of Ph-C─C),
139.41 (Cipso of Ph─NH), 146.86 (C5), 148.70 (C3),
149.82 (C2), 160.32 (O─C─), 162.89 (C─O, amide),
188.16 (C─S) ppm. EI-MS: m/z (%) 443 (M+, 1),
322 (6), 220 (15), 165 (9), 93 (93), 77 (51), 44 (100).
Anal. Calcd for C23H17N5O3S (443.48): C, 62.29%; H,
3.86%; N, 15.79%; found: C, 62.05%; H, 4.08%; N,
15.48%.
4.8 | 5-(2-(20-(200-Hydroxyethylthio)
ethoxy)-2-phenyl-1-N-
phenylthiocarbamoylethenyl)-6-oxo-1,6-
dihydropyrazine-2,3-dicarbonitrile (3e)
4.10 | 5-(2-(20,30-Dihydroxypropoxy)-2-
phenyl-1-N-phenylthiocarbamoylethenyl)-
6-oxo-1,6-dihydropyrazine-2,3-dicarbonitrile
(3 g)
Olive powder; yield: 0.39 g (77%); mp 208 to 210ꢀC. IR
−
(KBr): ν 3511 (NH), 3112 (CH, aromatic), 2243 (CN),
Dark red crystals; yield: 0.38 g (81%); mp 192 to 194ꢀC.
−
1728 (C─O, amide), 1602 (C─C), 1574 (NH), 1544,
1364, 1183 (C─N, NH, C─S, thioamide), 1219, 1125
IR (KBr): ν 3243 (NH), 3055 (CH, aromatic), 2250
(CN), 1734 (C─O, amide), 1599 (C─C), 1559 (NH),
1540, 1363, 1176 (C─N, NH, C═S, thioamide), 1213,
1119 (C─O─C) cm−1; 1H NMR (DMSO-d6): δ 3.45,
3.66, 3.84 (3H, m, CH2OH, CHOH), 4.28, 4.41 (2H, m,
1
3
(C─O─C) cm−1; H NMR (DMSO-d6): δ 2.68 (2H, t, J
3
6.6 Hz, CH2S), 2.92 (2H, t, J 6.8 Hz, CH2S), 3.56 (2H,
t, 3J 6.6 Hz, CH2OH), 4.50 (2H, t, 3J 6.8 Hz, CH2O),
3
3
7.28 (1H, t, J 7.5 Hz, CHpara of Ph─NH), 7.45 (2H, t,
CH2O), 7.28 (1H, t, J 7.6 Hz, CHpara of Ph─NH), 7.45
3J 7.5 Hz, 2CHmeta of Ph─NH), 7.50 to 7.94 (7H, m,
2Ph), 12.12, 13.82 (2H, 2br s, 2NH), OH proton is miss-
ing in spectrum; 13C NMR (DMSO-d6): δ 29.77, 34.31
(2CH2S), 60.94 (CH2OH), 65.21 (CH2O), 114.28 (─C),
118.84, 121.49 (2CN), 122.94, 126.42, 126.99, 128.73,
128.83, 129.14 (10C, 2Ph), 130.69 (Cipso of Ph─C─C),
139.47 (Cipso of Ph─NH), 146.90 (C5), 148.36 (C3),
149.93 (C2), 160.01 (O─C─), 162.63 (C─O, amide),
188.24 (C─S) ppm. EI-MS: m/z (%) 503 (M+, 1), 460 (2),
426 (38), 394 (38), 352 (7), 322 (16), 295 (10), 244 (12),
220 (30), 165 (19), 109 (20), 93 (100), 77 (85), 44 (29).
Anal. Calcd for C25H21N5O3S2 (503.60): C, 59.62%; H,
4.20%; N, 13.91%; found: C, 59.46%; H, 4.41%; N,
14.13%.
(2H, t, 3J 7.6 Hz, 2CHmeta of Ph─NH), 7.52 to 7.94
(7H, m, 2Ph), 12.12, 13.81 (2H, 2br s, 2NH), 2OH pro-
tons are missing in spectrum; 13C NMR (DMSO-d6): δ
62.64 (CH2OH), 67.46 (CHOH), 69.23 (CH2O), 114.22
(─C), 118.72, 121.38 (2CN), 122.96, 126.34, 126.80,
128.67, 128.75, 129.11 (10C, 2Ph), 130.62 (Cipso of
Ph─C─C), 139.40 (Cipso of Ph─NH), 146.87 (C5), 148.71
(C3), 149.81 (C2), 160.31 (O─C─), 162.88 (C─O, amide),
188.16 (C─S) ppm. EI-MS: m/z (%) 473 (M+, 1),
388 (2), 373 (38), 354 (38), 322 (16), 295 (10), 220 (12),
195 (30), 165 (19), 135 (0), 93 (100), 77 (85), 44 (29).
Anal. Calcd for C24H19N5O4S (473.50): C, 60.88%; H,
4.04%; N, 14.79%; found: C, 60.59%; H, 3.86%; N,
15.03%.

6
SHAHNAEI ET AL.
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Hassan Kabirifard https://orcid.org/0000-0003-2680-
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
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How to cite this article: Shahnaei R,
Kabirifard H, Fathololoomi P. Synthesis of
pyrazine-2,3-dicarbonitriles via the one-pot three-
component reaction of 4-benzoyl-5-phenylamino-
2,3-dihydrothiophene-2,3-dione,
diaminomaleonitrile, and functionalized alcohols
in acetonitrile. J Heterocyclic Chem. 2019;1–6.
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