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].

Pyrazines are important flavor ingredients in food ^[2],and exhibit interesting anticancer ^{[2, 3]} and antituberculosis ^{[2, 4, 5, 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-2'deoxy-isocytosine (3-amino- 1,2,4-triazin-5(2H)-one),is of great biological interest due to its resistance to deaminase ^[10].

Fig 1

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Fig 1 Some structures of bioactive triazines.

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 synthetic method for the preparation of some azine derivatives from furan-2,3-diones.

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 DMSOd₆ solvents. Elemental analyses (C,Hand N) were carried out with a LECO-932 CHNS-O analyzer. The progress of the reactions was 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, 12, 13, 14]}. S-Methylisothiosemicarbazide hydroiodide was prepared according to the literature ^[15].

Equivalent amounts of furan-2,3-diones and S-methylisothiosemicarbazide 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 recrystallization from H₂O or MeCN.

scheme 1

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scheme 1 The reaction route of furan-2,3-diones with S-methylisothiosemicarbazide.

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.

scheme 2

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scheme 2 The synthesis of new pyrazine-2,3-dicarbonitrile derivatives from furan-2,3-diones.

Compound 5a-c (1 mmol) was refluxed for 1 min in 18 mL nbutanol- 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.

Reaction of 1 with S-methylisothiosemicarbazide hydroiodide in MeCN at room temperature gave the 1,2,4-triazine-5(4H)-one derivatives (3a-d) in 56%-82% yields as shown in Scheme 1 The white-colored crude products precipitated in the form of hydroiodide 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 carbon signal at δ62.0,the carbon signals of Ph-C=O and Ph-C-OH groups belonging to keto-enol tautomers at δ192.9 and δ190.9, and the carbon signal of a thiomethyl group at δ16.5 and δ14.2. In the ¹H NMR spectrum of 3a,a methine proton at δ6.56 and δ6.47, NH proton δ10.07 and 9.86,SCH₃ protons δ2.86 and 2.62 were observed. The signal at δ2.07 as a singlet was assigned to a proton of NR₃·HI. 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.

Table 1

Table 1 Some properties and data of synthesized compounds 3a-d.

Table 1 Some properties and data of synthesized compounds 3a-d.

The reactions of (1a-d) with 2.3-diaminomaleonitrile (4) run via the same reaction mechanism to give pyrazine-2,3-dicarbonitrile 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.

Table 2

Table 2 Some properties and data of compounds 5a-d.

Table 2 Some properties and data of compounds 5a-d.

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 tautomers were clearly observed as a broad band in the range of δ3.44-5.00,and the methine protons of keto tautomers in the range of δ4.58-5.89 and NH protons of keto and enol forms in the range of δ12.15-13.15 as two singlet peaks were also observed. The absorptions of CN groups were observed at 2214 cm^-1. 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).

Table 3

Table 3 Some properties and synthesized compounds 6a-c.

Table 3 Some properties and synthesized compounds 6a-c.

In the ¹H NMR spectra of 6b,NH proton at δ13.83,aliphatic 55CH proton at δ6.71,CH₂ protons at δ4.57,OCH₃ protons at δ3.85 and δ3.83 were observed. The ₁₃C signals of=CH and CH₂ groups were detected at δ91.1 and 43.6,respectively. These NMR data of compounds 6a-c can be found in Supporting information.

We have easily synthesized new 1,2,4-triazine and pyrazine- 2,3-dicarbonitrile derivatives in moderate to good yields as potential herbicides. The synthesized compounds are similar derivatives of some commercial herbicides,and might contribute to the development of pesticides. For this purpose,performances of the compounds will be tested in future works.

This study was financially supported by the Center of Research Projects of Bozok University (No. IFE 2011/46).

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.