Synthesis of pyrazine-2,3-dicarbonitrile and 1,2,4-triazine-5(4H)-one derivatives from furan-2,3-diones

Article abstract of DOI:10.1016/j.cclet.2013.08.001

The reaction of furan-2,3-diones with S-methylisothiosemicarbazide hydroiodide yielded novel 1,2,4-triazine-5(4H)-ones, and reaction of furan-2,3-diones with diaminomaleonitrile led to the formation of pyrazine-2,3-dicarbonitrile derivatives, and the hydr

Full text of DOI:10.1016/j.cclet.2013.08.001

Chinese Chemical Letters 24 (2013) 1130–1133
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Chinese Chemical Letters
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Original article
Synthesis of pyrazine-2,3-dicarbonitrile and 1,2,4-triazine-5(4H)-one
derivatives from furan-2,3-diones
¨
˙
*
S¸evket Hakan Ungo¨ren , Emine Dilekog˘lu, Irfan Koca
Department of Chemistry, Faculty of Arts and Sciences, Bozok University, Yozgat 66200, Turkey
A R T I C L E I N F O
A B S T R A C T
Article history:
The reaction of furan-2,3-diones with S-methylisothiosemicarbazide hydroiodide yielded novel 1,2,4-
triazine-5(4H)-ones, and reaction of furan-2,3-diones with diaminomaleonitrile led to the formation of
pyrazine-2,3-dicarbonitrile derivatives, and the hydrolysis of these products led to the formation of
more new pyrazine-2,3-dicarbonitrile derivatives. These compounds are potential herbicides and
pesticides.
Received 17 May 2013
Received in revised form 15 July 2013
Accepted 21 August 2013
Available online 5 October 2013
¨
ß 2013 S¸evket Hakan Ungo¨ren. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All
Keywords:
rights reserved.
Pyrazine-2,3-dicarbonitrile
1,2,4-Triazine-5(4H)-ones
Furan-2,3-diones
S-Methyl isothiosemicarbazide
Diaminomaleonitrile
1. Introduction
synthetic method for the preparation of some azine derivatives
from furan-2,3-diones.
Azines have many applications in all parts of chemical industry
and significantly impact on our daily lives as components of
medicines, agrochemicals, natural products and commodity
chemicals [1].
2. Experimental
Melting points were determined using an Electrothermal 9100
apparatus and are uncorrected. IR spectra (KBr) were measured on
a Shimadzu 8400 FTIR spectrometer. 1H NMR spectra were
recorded with a Bruker Avance 400 spectrometer using DMSO-
d6 solvents. Elemental analyses (C, H and N) were carried out with a
LECO-932 CHNS-O analyzer. The progress of the reactions was
Pyrazines are important flavor ingredients in food [2], and
exhibit interesting anticancer [2,3] and antituberculosis [2,4–6]
activities, and also pyrazine-2,3-dicarbonitriles show varying
degrees of herbicidal activity [7].
1,2,4-Triazine-5(4H)-ones constitute an important group of
herbicides with a wide range of uses. Most of them are used to
increase the efficiency of cultivated plants in the fight against
weeds. For example, Metribuzin (Fig. 1), which has excellent
selectivity, is a commercial herbicide produced by Bayer (Code No.
94337) and Du Pont (Code No. GPX-G2504) [8]. Some triazines are
inhibitors of electron transport in photosynthesis [9]. Also,
isomethiozin (Fig. 1), ethiozin, metamitron, and amibuzin show
similar activity. Moreover, 6-aza-20deoxy-isocytosine (3-amino-
1,2,4-triazin-5(2H)-one), is of great biological interest due to its
resistance to deaminase [10].
monitored by TLC using alumina silica gel Plates 60 F245
.
Furan-2,3-diones (1), the starting material, were synthesized by
the reaction of oxalyl chloride with 1,3-dicarbonyl compounds
following previously reported procedures [11–14]. S-Methyli-
sothiosemicarbazide hydroiodide was prepared according to the
literature [15].
2.1. General experimental procedure for the synthesis of triazines
(3a–d)
The purpose of this study was the synthesis of new molecules
bearing pyrazine-2,3-dicarbonitrile and 1,2,4-triazine-5(4H)-one
moieties as a potential herbicides. Herein, we report a simple
Equivalent amounts of furan-2,3-diones and S-methylisothio-
semicarbazide hydroiodide were reacted in MeCN at room
temperature (Scheme 1). Reactions were completed within a
few hours (1–2 h). White-colored products were separated by
filtration. Then, the crude products were purified with recrystalli-
zation from H2O or MeCN.
*
Corresponding author.
E-mail address: hungoren@erciyes.edu.tr (S¸.H. Ungo¨ren).
¨
¨
1001-8417/$ – see front matter ß 2013 S¸evket Hakan Ungo¨ren. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.08.001

¨
S¸.H. Ungo¨ren et al. / Chinese Chemical Letters 24 (2013) 1130–1133
1131
derivatives (3a–d) in 56%–82% yields as shown in Scheme 1. The
white-colored crude products precipitated in the form of hydro-
iodide salts could be crystallized from water or acetonitrile. The
compounds are stable for a few weeks in a dark environment after
being dried.
1H NMR and 13C NMR spectra revealed that compounds 3a–d
show tautomeric equilibriums in DMSO-d6 solutions (Table 1). The
13C NMR spectrum of 3a (tautomeric mixture) showed a methine
H N
2
CH
O
N
3
CH
O
N
N
3
H C
3
H C
3
NH
O
2
N
N
S
H C
N
3
H C
N
3
N
HO
N
N
S
OH
Metribuzin
Isomethiozin
6-Aza-2'deoxy-isocytidine
Fig. 1. Some structures of bioactive triazines.
carbon signal at
groups belonging to keto–enol tautomers at
and the carbon signal of a thiomethyl group at
the 1H NMR spectrum of 3a, a methine proton at
d
62.0, the carbon signals of Ph–C55O and Ph–C–OH
192.9 and 190.9,
16.5 and 14.2. In
6.56 and 6.47,
2.86 and 2.62 were
2.07 as a singlet was assigned to a proton
2.2. General experimental procedure for the synthesis of pyrazine-2,3-
d
d
d
d
dicarbonitrile (5a–d and 6a–c).
d
d
To a stirred solution of (1a–d) (0.01 mol) in benzene (50 mL),
diaminomaleonitrile (1.4 g, 0.01 mol) was added. The reaction
mixture was heated under reflux for 2 h (Scheme 2). It was cooled,
and the solid product was collected. The crude product was
purified with crystallization or column chromatography and dried
over P2O5.
Compound 5a–c (1 mmol) was refluxed for 1 min in 18 mL n-
butanol–water (5:1, v/v) mixture, and then the mixture was
allowed to cool to room temperature. The precipitated crude
product (6a–c) was filtered and recrystallized from acetonitrile.
NH proton
d 10.07 and 9.86, SCH3 protons d
observed. The signal at
d
of NR3ꢀHI. These NMR data of compounds 3a–d can be found in
Supporting information. The micro analyses of 3a–d also agree
with the proposed structures as shown Table 1.
The reactions of (1a–d) with 2.3-diaminomaleonitrile (4) run
via the same reaction mechanism to give pyrazine-2,3-dicarboni-
trile derivatives (5a–d) in benzene under reflux conditions for 2 h
(see Scheme 2). The products were obtained in moderate to
excellent yields as shown in Table 2.
Similar to 3a–d, compounds 5a–d show similar tautomeric
forms, such as the keto and enol forms, in DMSO-d6 solutions
(Table 2). In the 1H NMR spectra of 5a–d, OH protons of enol
3. Results and discussion
tautomers were clearly observed as a broad band in the range of
3.44–5.00, and the methine protons of keto tautomers in the range
d
Reaction of 1 with S-methylisothiosemicarbazide hydroiodide
in MeCN at room temperature gave the 1,2,4-triazine-5(4H)-one
O
R2
O
O
O
N
SMe
O
R1
R2
N
N
R1
R1
R2
N
SMe
. HI
N
H2N
NH2
+
. HI
. HI
O
NH2
MeS
N
H
3
O
O
O
O
1
2
Scheme 1. The reaction route of furan-2,3-diones with S-methylisothiosemicarbazide.
O
R2
O
O
O
H2N
H2N
CN
CN
NC
NC
N
R1
H2O/ H+
R1
R2
NC
NC
N
R1
+
O
N
H
O
O
N
H
O
O
6
5
1
4
Scheme 2. The synthesis of new pyrazine-2,3-dicarbonitrile derivatives from furan-2,3-diones.
Table 1
Some properties and data of synthesized compounds 3a–d.
O
R2
O
R2
O
R2
N
R1
OH . HI
N
N
N
R1
R1
N
HN
MeS
N
.
O
. HI
O
. HI
MeS
N
H
O
MeS
O
N
H
O
3
Entry
R1
R2
Mp (8C)
Mol. Formula (Mol. wt.)
Yields (%)
Elemental Analyses (%)
C
H
N
S
3a
3b
139
146
C19H16IN3O3S
493.3
82
65
Calcd.
Found
Calcd.
Found
46.26
46.32
45.58
45.42
3.27
8.52
8.69
7.59
7.39
6.50
6.41
5.79
5.96
3.19
3.64
3.68
C21H20IN3O5S
553.4
H3CO
H3CO
H3C
3c
144
149
C21H20IN3O3S
521.4
71
56
Calcd.
Found
48.38
48.16
3.87
3.86
8.06
8.21
6.15
6.20
H3C
3d
–OCH2CH3
C16H18IN3O5S
491.3
Calcd.
Found
39.11
39.21
3.69
3.57
8.55
8.30
6.53
6.46
H3CO

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S¸.H. Ungo¨ren et al. / Chinese Chemical Letters 24 (2013) 1130–1133
1132
Table 2
Some properties and data of compounds 5a-d.
O
R2
HO
R2
NC
NC
NC
NC
N
N
R1
R1
.
O
O
N
H
N
H
O
O
5
Entry
R1
R2
Mp (8C)
Mol. Formula (Mol. wt.)
Yields (%)
Elemental Analyses (%)
C
H
N
5a
5b
106
143
C21H12N4O3
368.3
88
85
Calcd.
Found
Calcd.
Found
68.48
68.61
62.69
62.76
3.28
3.21
4.68
4.68
15.21
15.11
10.85
10.96
aC23H16N4O5.C4H8O2
516.5
H3CO
H3CO
H3C
5c
163
84
C23H16N4O3
396.4
89
63
Calcd.
Found
69.69
69.42
4.07
4.26
14.13
14.35
H3C
5d
–OCH2CH3
C18H14N4O5
366.3
Calcd.
Found
59.02
59.19
3.85
3.91
15.29
15.19
H3CO
a
This compound was purified using ethyl acetate as eluent from column chromatography.
Table 3
Some properties and synthesized compounds 6a-c.
H
NC
NC
N
NC
NC
N
R1
R1
.
O
O
N
H
O
N
H
O
6
Entry
R1
Mp (8C)
Mol. Formula (Mol. wt.)
Yields (%)
Elemental Analyses (%)
C
H
N
6aa
6b
243
266
C14H8N4O2
264.2
44
56
Calcd.
Found
Calcd.
Found
63.64
63.69
61.22
60.98
3.05
3.01
3.43
3.35
21.20
21.31
19.04
19.13
C15H10N4O3
294.3
H3CO
H3C
6ca
267
C15H10N4O3
278.3
34
Calcd.
Found
64.74
64.89
3.62
3.71
20.13
19.98
a
This compounds were synthesized earlier with different method [16].
Appendix A. Supplementary data
of
of
d
d
4.58–5.89 and NH protons of keto and enol forms in the range
12.15–13.15 as two singlet peaks were also observed. The
absorptions of CN groups were observed at 2214 cmꢁ1. These NMR
data of compounds 5a–d can be found in Supporting information.
Simply heating an n-butanol/water solution (5:1) of 5a–c led to
the formation of new pyrazine-2,3-dicarbonitrile derivatives (6a–
c). On cooling of the solution, the orange crude products
precipitated in moderate yields and a highly pure state (Table 3).
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.cclet.2013.
08.001.
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In the 1H NMR spectra of 6b, NH proton at
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and
3.83 were observed. The 13C signals of 55CH and CH2 groups
were detected at 91.1 and 43.6, respectively. These NMR data of
d
13.83, aliphatic
3.85
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Acknowledgment
This study was financially supported by the Center of Research
Projects of Bozok University (No. IFE 2011/46).

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