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Synthesis of 2,3-dicyanopyrazine and ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylate derivatives from ethyl aroylpyruvates

  • Maryam Moloudi , Hassan Kabirifard ORCID logo EMAIL logo , Sohila Piri and Elham Naghizadeh
Published/Copyright: February 10, 2018
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Heterocyclic Communications
From the journal Heterocyclic Communications Volume 24 Issue 2

Abstract

Reactions of ethyl 4-aryl-2,4-dioxobutanoates 1a–c at ambient temperature with diaminomaleonitrile in glacial acetic acid and with malononitrile in ethanol/H2O (1:1) led to the formation of 5-(2-aryl-2-oxoethyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbontrile 2a–c and ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylate derivatives 3a–c, respectively.

Keywords: 5-amino-4,6-dicyanobiphenyl-3-carboxylate; 4-aryl-2,4-dioxobutanoate; diaminomaleonitrile; malononitrile; pyrazine-2,3-dicarbonitrile

Introduction

Pyrazines are important flavor components in food [1], and show diverse biological activities [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Diaminomaleonitrile (DAMN), a tetramer of hydrogen cyanide and a weakly basic diamine with similar reactivity to o-phenylenediamine, is an important synthetic precursor to pyrazine-2,3-dicarbonitriles [12]. DAMN can be condensed with α-diketones [12], glyoxal, α-keto aldehydes, α-keto oximes [13], α-keto thioesters [14], α-keto esters [15], [16], [17] and 4-acylfuran-2,3-diones [16], [17] to provide pyrazine-2,3-dicarbonitriles in good yields. On the other hand, malononitrile is an important starting material for the preparation of 2,6-dicyanoanilines [18] biphenyl-3-carboxylates [19] and 3-cyano-2-pyridinones [20]. In this paper we report simple procedures for synthesis of 2,3-dicyanopyrazine 2a–c and ethyl 4,6-dicyanobiphenyl-3-carboxylate derivatives 3a–c by reaction of ethyl 4-aryl-2,4-dioxobutanoates 1a–c with diaminomaleonitrile and malononitrile, respectively (Scheme 1).

Scheme 1 Synthesis of pyrazines 2a–c and ethyl biphenyl-3-carboxylates 3a–c.
Scheme 1

Synthesis of pyrazines 2a–c and ethyl biphenyl-3-carboxylates 3a–c.

Results and discussion

The reactions of ethyl aroylpyruvates 1a–c with diaminomaleonitrile in glacial acetic acid at room temperature for 12 h gave the pyrazine-2,3-dicarbonitriles 2a–c in moderate to good yields. On the other hand, treatment of compounds 1a–c with malononitrile under the neutral conditions in ethanol/H2O at room temperature for 3 h afforded the corresponding ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylates 3a–c in good to high yields (Scheme 1). The structures of products 2a–c and 3a–c were deduced from their elemental analyses, IR, 1H NMR, 13C NMR and mass spectra. In particular, analysis of 1H NMR and 13C NMR spectra revealed that compounds 2a–c exist in two tautomeric forms of iminoketone and enaminoketone in DMSO-d6 solution. For example, the 1H NMR spectrum of 2a shows four broad singlets at δ 4.64, 6.76, 10.49 and 13.62 for CH2, =CH, amidic NH and enaminic NH protons and multiplet signals integrated for 10 protons of two aromatic rings at δ 7.49–8.02. The 13C NMR spectrum of 2a shows carbon signals of CH2, =CH, four C≡N, amide C=O and ketone C=O at δ 43.5, 91.4, 111.3, 112.1, 113.3, 114.6, 176.9 and 195.0, respectively. The IR absorptions of NH, C≡N, amide C=O and ketone C=O groups are seen at 3442, 2224, 1711, 1697 and 1624 cm−1, respectively. The ratios of iminoketone tautomer to enaminoketone tautomer for compounds 2a–c from the proton integration values of CH2 and =CH signals are 0.48:0.52, 0.33:0.67 and 0.33:0.67, respectively. Thus, for halogen-substituted compounds 2b,c the enaminoketone form becomes two-fold predominant. In the IR and 13C NMR spectra of products 3a–c the absorptions of ketone carbonyl groups are absent. The 1H NMR spectra of 3a–c are also consistent with the given structures.

These results show that DAMN undergoes cyclization by nucleophilic attack on the hydroxy ester fragment (C-1 and C-2) of compound 1 to produce pyrazine-2,3-dicarbonitrile derivatives 2 (Scheme 1) [21]. Nucleophilic attacks of two equivalents of CH2(CN)2 occur at carbonyl groups (C-2 and C-4) of the ethyl aroylpyruvate 1, followed by cyclization of the intermediate product 4 and then hydrolysis of the nitrile function to obtain the corresponding 5-amino-4,6-dicyanobiphenyl-3-carboxylate 3 (Scheme 1) [19].

Conclusion

Convenient synthetic routes to 5-(2-aryl-2-oxoethyl)-6-oxo-1,6-dihydropyrazine-2,3-dicarbontriles 2a–c and ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylates 3a–c starting from ethyl 4-aryl-2,4-dioxobutanoates 1a–c are described.

Experimental

The reagents were purchased from Merck and used without purification. Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Infrared spectra were measured using KBr disks on a Thermo Nicolet 8700 FT-IR spectrometer. 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-300 AVANCE instrument at 300 MHz or 500 MHz and 75 MHz or 125 MHz, respectively, using TMS as internal standard and DMSO-d6 or CDCl3 as solvent. Thin-layer chromatography was performed on Silufol-UV 254 plates. Mass spectra were obtained on an Agilent HP 5973 mass spectrometer operating at ionization potential of 70 eV. Ethyl 4-aryl-2,4-dioxobutanoates 1a-c were prepared from diethyl oxalate (10 mmol) and 4′-substituted acetophenone (10 mmol) in the presence of sodium ethoxide (10 mmol) in ethanol (30 mL) as previously reported [22].

General procedure for the synthesis of pyrazine-2,3-dicarbonitriles 2a–c

To a stirred solution of diaminomaleonitrile (1.0 mmol) in glacial acetic acid (10 mL) was added compound 1a–c (1.0 mmol) at room temperature and the mixture was then stirred for 12 h. The progress of the reaction was monitored by TLC (eluent AcOEt/hexane, 1:1). After removal of the solvent, the residue was crystallized from acetonitrile for 2a, 2-propanol for 2c and washed with chloroform for 2b.

6-Oxo-5-(2-oxo-2-phenylethyl)-1,6-dihydropyrazine-2,3-dicarbonitrile (2a)

Brown crystals; yield 0.18 g (68%); mp 242–244°C (ref. [16] mp 243°C); IR: ν 3442 (NH), 3064 (CH, aromatic), 2896 (CH, aliphatic), 2224 (C≡N), 1711 (C=O, amide), 1697, 1624 (C=O, ketone), 1597 (NH) cm−1; 1H NMR (DMSO-d6): δ 4.64 (2H, s, CH2), 6.76 (1H, s, =CH), 7.49–7.71 (6H, m, 2Ph), 7.94 (2H, d, 3J=7.1 Hz, 2CHortho of Ph), 8.02 (2H, d, 3J=7.4 Hz, 2CHortho of Ph), 10.49 (2H, br s, 2NH, amide), 13.62 (1H, br s, NH, enamine); 13C NMR (DMSO-d6): δ 43.5 (CH2), 91.4 (=CH), 111.3, 112.1, 113.3, 114.6 (4C≡N), 120.1, 126.7, 128.4, 128.7, 128.9, 129.0, 132.3, 133.9 (12C, 2Ph), 134.9, 135.9, 151.0, 151.5, 155.2, 159.2 (6C=N), 176.9 (2C=O, amide), 195.0 (2 C=O); EI-MS: m/z (%) 264 (M·+, 99), 235 (50), 186 (34), 159 (20), 131 (24), 105 (100), 77 (99), 51 (44). Anal. Calcd for C14H8N4O2 (264.24): C, 63.64; H, 3.05; N, 21.20. Found: C, 63.89; H, 3.34; N, 20.92.

5-[2-(4-Chlorophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyrazine-2,3-dicarbontrile (2b)

Yellow powder; yield 0.15 g (50%); mp 262–264°C; IR: ν 3434 (NH), 3082 (CH, aromatic), 2914 (CH, aliphatic), 2236, 2223 (C≡N), 1700 (C=O, amide), 1624 (C=O, ketone), 1590 (NH) cm−1; 1H NMR (DMSO-d6): δ 4.62 (2H, s, CH2), 6.70 (1H, s, =CH), 7.56 (2H, d, 3J=8.5 Hz, 2CHortho of Ph-Cl), 7.62 (2H, d, 3J=8.5 Hz, 2CHortho of Ph-Cl), 7.95 (2H, d, 3J=8.5 Hz, 2CHmeta of Ph-Cl), 8.03 (2H, d, 3J=8.5 Hz, 2CHmeta of Ph-Cl), 13.81 (1H, br s, NH, enamine), amidic NH protons signals are missing; 13C NMR (DMSO-d6): δ 43.5 (CH2), 92.6 (=CH), 112.7, 113.4, 113.7, 114.8 (4C≡N), 119.0, 128.4, 128.9, 129.0, 129.1, 130.2, 134.1 (11C, 2Ph), 134.7, 136.5 (2C=N), 138.7 (Cipso of Ph-Cl), 150.9, 151.4, 156.6, 159.5 (4C=N), 173.3 (2C=O, amide), 194.2 (2C=O); EI-MS: m/z (%) 300 (M·++2, 9), 298 (M·+, 27), 269 (11), 186 (16), 139 (100), 111 (51), 75 (31), 43 (28). Anal. Calcd for C14H7ClN4O2 (298.68): C, 56.30; H, 2.36; N, 18.76. Found: C, 56.58; H, 2.58; N, 18.49.

5-[2-(4-Bromophenyl)-2-oxoethyl]-6-oxo-1,6-dihydropyrazine-2,3-dicarbontrile (2c)

Yellow powder; yield 0.15 g (44%); mp 270–272°C; IR: ν 3439 (NH), 3080 (CH, aromatic), 2911 (CH, aliphatic), 2235, 2224 (C≡N), 1701 (C=O, amide), 1624 (C=O, ketone), 1588 (NH) cm−1; 1H NMR (DMSO-d6): δ 4.62 (2H, s, CH2), 6.71 (1H, s, =CH), 7.70 (2H, d, 3J=8.5 Hz, 2CHmeta of Ph-Br), 7.77 (2H, d, 3J=8.4 Hz, 2CHmeta of Ph-Br), 7.87 (2H, d, 3J=8.5 Hz, 2CHortho of Ph-Br), 7.95 (2H, d, 3J=8.4 Hz, 2CHortho of Ph-Br), 13.80 (1H, br s, NH, enamine); 13C NMR (DMSO-d6): δ 43.4 (CH2), 91.7 (=CH), 112.2, 113.2, 113.3, 114.6 (4C≡N), 119.9, 125.9, 128.0, 128.6, 128.7, 130.3, 131.9, 132.1 (12C, 2Ph), 134.1, 134.9, 150.8, 151.3, 155.5, 159.1 (6C=N), 175.0 (2C=O, amide), 194.3 (2C=O); EI-MS: m/z (%) 344 (M·++2, 43), 342 (M·+, 44), 315 (14), 183 (100), 157 (50), 131 (16), 104 (13), 76 (30), 50 (11). Anal. Calcd for C14H7BrN4O2 (343.13): C, 49.00; H, 2.06; N, 16.33. Found: C, 49.28; H, 2.31; N, 16.05.

General procedure for the synthesis of ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylates 3a–c

To a stirred solution of malononitrile (1.0 mmol) in EtOH/H2O (1:1, 10 mL) was added compound 1a–c (1.0 mmol) at room temperature and the mixture was then stirred for 3 h. The progress of the reaction was monitored by TLC (eluent AcOEt/hexane, 1:1). The resulting solid was filtered, washed with EtOH/H2O (1:1) and then crystallized from ethanol.

Ethyl 5-amino-4,6-dicyanobiphenyl-3-carboxylate (3a)

Yellow cotton-like solid; yield 0.12 g (82%); mp 196–198°C; IR: ν 3459, 3330, 3235 (NH), 2973 (CH, aliphatic), 2229, 2214 (C≡N), 1739 (C=O, ester), 1643 (C=C), 1580 (NH), 1250 (C-O) cm−1; 1H NMR (CDCl3): δ 1.47 (3H, t, 3J=7.2 Hz, CH3), 4.50 (2H, q, 3J=7.2 Hz, CH2), 5.52 (2H, br s, NH2), 7.51 (1H, s, CH), 7.53–7.62 (5H, m, Ph); 13C NMR (CDCl3): δ 13.8 (CH3), 62.3 (CH2), 93.8 (C4), 98.6 (C6), 114.6, 115.3 (2C≡N), 118.2 (C2), 128.4, 128.8, 129.7 (5C, Ph), 136.7 (Cipso of Ph), 136.9 (C3), 150.0 (C1), 154.1 (C5), 163.3 (C=O, ester); EI-MS: m/z (%) 291 (M·+, 100), 263 (50), 245 (36), 219 (34), 191 (51), 164 (44), 77 (9). Anal. Calcd for C17H13N3O2 (291.30): C, 70.09; H, 4.50; N, 14.42. Found: C, 70.27; H, 4.39; N, 14.65.

Ethyl 5-amino-4,6-dicyano-4′-chlorobiphenyl-3-carboxylate (3b)

Yellow cotton-like solid; yield 0.14 g (86%); mp 212–214°C; IR: ν 3327, 3350, 3252 (NH), 2980 (CH, aliphatic), 2221 (C≡N), 1738 (C=O, ester), 1634 (C=C), 1579 (NH), 1257 (C-O) cm−1; 1H NMR (CDCl3): δ 1.45 (3H, t, 3J=7.1 Hz, CH3), 4.48 (2H, q, 3J=7.1 Hz, CH2), 5.57 (2H, br s, NH2), 7.44 (1H, s, CH), 7.51 (4H, m, Ph-Cl); 13C NMR (CDCl3): δ 14.0 (CH3), 63.0 (CH2), 95.4 (C4), 99.1 (C6), 114.7, 115.1 (2C≡N), 120.0 (C2), 129.4, 129.7 (4C, Ph), 135.0 (Cipso of Ph-Cl), 136.5 (Cpara of Ph-Cl), 136.6 (C3), 148.8 (C1), 153.2 (C5), 163.2 (C=O, ester); EI-MS: m/z (%) 327 (M·++2, 39), 325 (M·+, 100), 297 (52), 275 (30), 253 (28), 217 (53), 189 (23), 163 (12). Anal. Calcd for C17H12ClN3O2 (325.75): C, 62.68; H, 3.71; N, 12.90. Found: C, 62.92; H, 3.89; N, 12.58.

Ethyl 5-amino-4,6-dicyano-4′-bromobiphenyl-3-carboxylate (3c)

Yellow cotton-like solid; yield 0.14 g (76%); mp 230–232°C; IR: ν 3428, 3350, 3251 (NH), 2979 (CH, aliphatic), 2220 (C≡N), 1737 (C=O, ester), 1634 (C=C), 1577 (NH), 1257 (C-O) cm−1; 1H NMR (CDCl3): δ 1.45 (3H, t, 3J=7.1 Hz, CH3), 4.48 (2H, q, 3J=7.1 Hz, CH2), 5.55 (2H, br s, NH2), 7.44 (1H, s, CH), 7.45 (2H, d, 3J=8.3 Hz, 2CHmeta of Ph-Br), 7.67 (2H, d, 3J=8.3 Hz, 2CHortho of Ph-Br); 13C NMR (CDCl3): δ 14.0 (CH3), 63.0 (CH2), 95.5 (C4), 99.1 (C6), 114.7, 115.1 (2C≡N), 120.0 (C2), 124.8 (Cipso of Ph-Br), 130.0, 132.3 (4C, Ph), 135.5 (Cpara of Ph-Br), 136.6 (C3), 148.8 (C1), 153.2 (C5), 163.2 (C=O, ester); EI-MS: m/z (%) 371 (M·++2, 99), 369 (M·+, 100), 341 (41), 326 (24), 297 (20), 217 (75), 189 (39), 163 (29). Anal. Calcd for C17H12BrN3O2 (370.20): C, 55.15; H, 3.27; N, 11.35. Found: C, 54.91; H, 3.08; N, 11.52.

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Received: 2017-8-26
Accepted: 2018-1-2
Published Online: 2018-2-10
Published in Print: 2018-4-25

©2018 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/hc-2017-0190
Keywords for this article
5-amino-4,6-dicyanobiphenyl-3-carboxylate; 4-aryl-2,4-dioxobutanoate; diaminomaleonitrile; malononitrile; pyrazine-2,3-dicarbonitrile
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  11. Baker’s yeast catalyzed one-pot synthesis of bioactive 2-[benzylidene(or pyrazol-4-ylmethylene)hydrazono]-1,3-thiazolidin-4-one-5-yl-acetic acids
  12. Design, synthesis and anticancer activity evaluation of aziridine-1,2,3-triazole hybrid derivatives
  13. Synthesis and antimicrobial activity of 3,4-dihydropyrimidin-2(1H)-one derivatives containing a hydrazone moiety
  14. Synthesis and antiproliferative activity of flavonoid triazolyl glycosides
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