HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 2, 2014, pp. 413-425
Received, 25th November, 2013, Accepted, 18th December, 2013, Published online, 6th January, 2014.
DOI: 10.3987/COM-13-12899

■ Studies on the Chemical Transformations of Simple Condensates Derived from 3-Formylchromone under Nucleophilic Conditions

Magdy A. Ibrahim* and Nasser M. El-Gohary

Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo 11711, Egypt

Abstract

The chemical reactivity of the simple condensates 1 and 2, derived from 3-formylchromone, was studied towards some nucleophilic reactions. Reactions of compounds 1 and 2 with some nucleophilic reagents mainly proceed via nucleophilic addition at the exocyclic vinyl bond followed by either elimination or cyclization during the course of reactions. A variety of products were obtained depending on the substrate and the nucleophile used.

INTRODUCTION
Chromone derivatives have attracted attention from the point of view of both biological activity,1-3 and organic synthesis.4-6 The chemical reactivity of 3-substituted chromones towards nucleophilic reagents is widely different depending on the nature of the substituents at the 3-position and the reaction conditions. Several reports describe the action of different nucleophiles on various 3-substituted chromones, and a variety of heterocyclic systems were obtained.7-15 In continuation to our interest in the area of 3-substituted chromones,12-19 the present work aimed to study the chemical behavior of the simple condensates 1 and 2 (Figure 1) towards a variety of nitrogen and carbon nucleophiles.

RESULTS AND DISCUSSION
The simple condensates 1 and 2, derived from condensation reaction of 3-formylchromone with ethyl cyanoacetate and malononitrile, respectively (Figure 1), may be of interest in the synthesis of various heterocyclic systems due to the availability of diverse electron deficient sites. The present work aimed to study the effect of a variety of bifunctional nitrogen and carbon nucleophiles on the simple condensation products 1 and 2.
3-Substituted chromones underwent different transformations upon treatment with simple nucleophilic reagents.9,12,13 Thus, boiling ethyl ester 1 in 95% ethanol containing one drop of piperidine afforded the pyridine derivative 3 via partial hydrolysis of the cyano group in compound 1 to amide function which underwent intramolecular nucleophilic attack at the C­-2 position of chromone moiety with concomitant γ-pyrone ring opening to afford the target compound 3 (Scheme 1).17
On the other hand, treatment of compound 1 with aqueous 2% NaOH solution at 70 ­°C resulted in ring transformation to produce ethyl 3-amino-10-oxo-4aH,10H-pyrano[4,3-b]chromene-4-carboxylate (4) as shown in Scheme 1. The 1H NMR spectrum of compound 4 revealed the presence of two characteristic singlet signals at δ 5.89 and 8.14 ppm attributed to the H-4a and H-1, respectively, in addition to a triplet and quartet signals at δ 1.40 and 4.52 ppm assigned to the ethoxycarbonyl protons.

The chemical reactivity of ethyl ester 1 was studied towards some hydrazine derivatives. Thus, refluxing compound 1 with phenylhydrazine in absolute ethanol afforded the pyrazole derivative 5a, via nucleophilic addition at the exocyclic vinyl bond with elimination of ethyl cyanoacetate followed by nucleophilic attack of the NH group at C-2 position with concomitant γ-pyrone ring opening (Scheme 2). Structure of compound 5a was found to be identical with that previously obtained from the condensation of 3-formylchromone with phenylhydrazine as earlier published.21,22 Similarly, condensation of compound 1 with 7-chloro-4-hydrazinoquinoline in absolute ethanol gave the quinolinylpyrazole derivative 5b (Scheme 2). The IR and 1H NMR spectra showed the disappearance of the cyano and ethoxycarbonyl groups which confirm the elimination of ethyl cyanoacetate during the course of the reaction.

The same products 5a,b were obtained from reaction of compound 2 with phenylhydrazine and 7-chloro-4-hydrazinoquinoline, respectively, under the same reaction conditions (Scheme 2).
Out of the ordinary, hydrazine hydrate showed different behavior when reacted with ethyl ester 1. Refluxing compound 1 with hydrazine hydrate in absolute ethanol afforded a yellow crystalline product after 5 min (70% yield) which was identified as ethyl 2-amino-5-ethoxy-4-hydrazinyl-4H,5H-pyrano[3,2-c]chromene-3-carboxylate (6), the proposed mechanism for the formation of compound 6 is depicted in Scheme 3. The 1H NMR spectrum showed characteristic singlet signal at δ 6.35 ppm assigned to H-5 (as O-CH-O), in addition to characteristic doublet, exchanged singlet in D2O, at δ 5.85 ppm attributed to the H-4 proton.

On the other hand, the ring transformation of ethyl ester 1 was studied towards some 1,4-bifunctional nucleophiles. Thus, treatment of compound 1 with o-phenylenediamine in absolute ethanol afforded the benzodiazepine derivative 7 via nucleophilic addition at exocyclic vinyl carbon followed by elimination of ethyl cyanoacetate with concomitant intramolecular nucleophilic attack of the other amino group at C-2 position with γ-pyrone ring opening (Scheme 4). The IR and 1H NMR spectra of compound 7 revealed the absence of the nitrile and ethoxycarbonyl functions. 13C NMR spectrum of compound 7 showed characteristic signal assigned to C-3benzodiazepine at δ 88.2. Further, the mass spectrum of compound 7 showed the molecular ion peak at m/e 264 corresponding to the formula weight (264.29) and supports the identify of structure.
In another experiment, refluxing compound 1 with o-phenylenediamine for 6 h afforded 4-(1H-1,5-benzodiazepin-3-yl)coumarin-3-carbonitrile (8) (Scheme 4). In this reaction we found that the yellow crystalline product which formed after 15 min. was dissolved during the reaction and a new product 8 was obtained. Compound 8 obtained via the formation of benzodiazepine 7 which then reacted with ethyl cyanoacetate. The IR spectrum of compound 8 showed characteristic absorption band at 2222 cm-1 attributed to the nitile function. The 1H NMR spectrum of compound 8 showed the disappearance of OH proton which was appeared at δ 14.29 ppm in the 1H NMR spectrum of compound 7.

On the other hand, ethylenediamine showed different behavior and usually reacted with two equivalents of compound 1 to produce 1,2-bis[(chromon-3-yl)methyleneamino]ethane (9) (Scheme 5).23 The 1H NMR spectrum of compound 9 showed three characteristic singlet signals at δ 3.69, 8.02 and 8.17 ppm attributed to CH2, CH=N and H-2, respectively.

2-Aminothiophenol behaves similarly to o-phenylenediamine and produced the benzothiazepine derivative 10 when reacted with ethyl ester 1. Herein, we found that the same product 10 was obtained from the condensation reaction of compound 2 with 2-aminothiophenol under the same reaction conditions (the same mp, mmp and spectral data) (Scheme 6).

The chemical reactivity of compound 1 towards some carbon nucleophiles was studied. Thus, treating compound 1 with cyanoacetamide and cyanoacetohydrazide, in absolute ethanol containing few drops of piperidine, afforded the pyridone derivatives 11 and 12, respectively (Scheme 7).24

Next, the chemical reactivity of compound 2 under nucleophilic conditions was studied. Thus, refluxing compound 2 in 95% ethanol containing one drop of piperidine afforded 5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (13), via hydrolysis of one of the cyano groups to the amide group which underwent nucleophilic attack at C-2 position followed by γ-pyrone ring opening (Scheme 8).25 The IR spectrum of compound 13 showed characteristic absorption bands at 1688 and 1641 cm-1 assigned to the C=Ocyclic amide and C=Obenzoyl groups. The 1H NMR spectrum of compound 13 showed characteristic singlet signals at δ 8.05 and 8.42 ppm attributed to H-4 and H-6 of the pyridine nucleus, in addition to two exchangeable signals at δ 10.33 and 13.10 ppm attributed to NH and OH protons, respectively.
Ring transformation of compound 2 was achieved by hydrazine hydrate to produce the pyrazolylpyrazole derivative 14 as shown Scheme 8. The reaction proceeds via the formation of pyrazole intermediate A followed by nucleophilic attack of another molecule of hydrazine hydrate at C-2 position with γ-pyrone ring opening followed by cyclocondensation to afford the pyrazolylpyrazole derivative 14. The IR spectrum of compound 14 showed characteristic absorption band at 2221 cm-1 due to the nitrile function (C≡N). Its 1H NMR spectrum showed characteristic singlet at δ 7.64 ppm assigned to H-5pyrazole.

Reaction of compound 2 with ethylenediamine and o-phenylenediamine in absolute ethanol afforded diazepine 15 and benzodiazepine 16, respectively, via nucleophilic addition of one amino group at exocyclic vinyl carbon followed by cycloaddition of the other amino group onto the nitrile function with concomitant dehydrogenation (Scheme 9). The IR spectrum of compound 15 showed characteristic absorption bands at 3324 (NH2, NH), 2212 (C≡N) and 1645 cm-1 (C=Oγ-pyrone). Its 1H NMR spectrum showed two characteristic singlet signals at δ 3.83 (2CH2) and 8.88 ppm (H-2chromone). The 1H NMR spectrum of compound 16 showed characteristic singlet at δ 8.75 ppm assigned to H-2 of chromone moiety. 13C NMR spectrum of compound 16 showed characteristic signals attributed to C-3benzodiazepine and C≡N at δ 71.5 and 116.2, respectively. The mass spectrum of compound 16 showed the molecular ion peak at m/e 328 corresponding to the molecular formula (C19H12N4O2) and supports the structure.

The chemical reactivity of compound 2 was studied towards some carbon nucleophiles. Thus, treating compound 2 with cyanoacetamide and cyanoacetohydrazide gave chromonylpyridine derivatives 17 and 18, respectively (Scheme 10). The 1H NMR spectra of compounds 17 and 18 showed characteristic singlets assigned to the H-2chromone at 9.26 and 9.38 ppm, respectively. Further, the mass spectrum of compound 18 showed the molecular ion peak at m/e 319 corresponding to the formula weight (319.28) and support the identify of structure.

EXPERIMENTAL
Melting points are uncorrected and were determined on a digital Stuart SMP3 apparatus. Infrared spectra were measured on FTIR Nicolet IS10 spectrophotometer (cm-1), using KBr disks. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were measured on Mercury-300BB, using DMSO-d6 as a solvent and tetramethylsilane as an internal standard. Mass spectra were measured using GC-MS qp 1000 ex Shimadzu mass spectrometer instrument (70 eV). Elemental microanalyses were performed on a Perkin-Elmer CHN-2400 analyzer at the Chemical War Department, Ministry of Defense, Egypt. Ethyl 2-cyano-3-(4-oxo-4H-chromen-3-yl)prop-2-enoate (1)21 and [(4-oxo-4H-chromen-3-yl)methylidene]propanedinitrile (2)26 were prepared according to the published methods.

Ethyl 5-(2-hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (3).
A mixture of compound 1 (0.54 g, 2 mmol) in 95% EtOH (15 mL) containing one drop of piperidine was heated under reflux for 30 min. The solid obtained after cooling was filtered off and crystallized from aqueous EtOH to give compound 3 as white crystals, yield (0.32 g, 59%), mp 176−177 °C (lit., mp 177 °C).20 IR (KBr, cm-1): 3579, 3502 (OH, NH), 3065 (CHarom.), 2991, 2846, 2805 (CHaliph.), 1720 (C=Oester and C=Opyridone), 1628 (C=Ohydrogen bonded), 1601 (C=N), 1560 (C=C).
Ethyl 3-amino-10-oxo-4aH,10H-pyrano[4,3-b]chromene-4-carboxylate (4).
A mixture of compound 1 (0.54 g, 2 mmol) and aqueous sodium hydroxide solution (2%, 20 mL), was stirred at 70 °C for 2 h. After cooling, the reaction mixture was neutralized with dilute HCl. The precipitated solid was filtered off and crystallized from EtOH to give compound 4 as yellow crystals, yield (0.28 g, 52%), mp 211 °C. IR (KBr, cm-1): 3422 (NH2), 3065 (CHarom.), 2978, 2933 (CHaliph.), 1740 (C=Oester), 1643 (C=Oγ-pyrone), 1608 (C=C). 1H NMR (DMSO-d6, δ): 1.40 (t, 3H, CH3, J = 7.4 Hz), 4.06 (bs, 2H, NH2 exchangeable with D2O), 4.52 (q, 2H, CH2, J = 7.0 Hz), 5.89 (s, 1H, H-4a), 6.99 (d, 1H, H-6, J = 7.6 Hz), 7.16 (t, 1H, H-8, J = 7.2 Hz), 7.51 (t, 1H, H-7, J = 7.8 Hz), 7.76 (d, 1H, H-9, J = 7.6 Hz), 8.14 (s, 1H, H-1). Anal. Calcd for C15H13NO5­­ (287.27): C, 62.72; H, 4.56; N, 4.88%. Found: C, 62.54; H, 4.27; N, 4.60%.
4-(2-Hydroxybenzoyl)-1-phenyl-1H-pyrazole (5a).
A mixture of compound 1 or 2 (2 mmol) and phenylhydrazine (0.22 mL, 2 mmol), in absolute EtOH was heated under reflux for 1 h. The solid obtained after cooling was filtered off and recrystallized from MeOH to give compound 5a as white crystals, yield (37−39%), mp 115 °C (lit., mp 115 °C,21 113 °C 22).
4-(2-Hydroxybenzoyl)-1-(7-chloroquinolin-4-yl)-1H-pyrazole (5b).
A mixture of compound 1 or 2 (2 mmol) and 7-chloro-4-hydrazinoquinoline (0.38 g, 2 mmol) in absolute EtOH (25 mL) was heated under reflux 1 h. After cooling, the solid so formed was filtered off and crystallized from DMF/H2O to give compound 5b as white crystals, yield (51−54%), mp 291 °C. IR (KBr, cm-1): 3301 (OH), 3060 (CHarom.), 1628 (C=O), 1609 (C=N), 1594 (C=C). 1H NMR (DMSO-d6, δ): 6.90 (d, 1H, Ar-H), 6.96−7.05 (m, 1H, Ar-H), 7.51 (t, 1H, Ar-H, J = 7.5 Hz), 7.76−7.80 (m, 1H, Ar-H), 7.88 (d, 1H, Ar-H), 8.18 (s, 1H, H-8quinoline), 8.25 (d, 1H, Ar-H), 8.41 (s, 1H, H-5pyrazole), 8.52 (d, 1H, H-3quinoline), 9.04 (s, 1H, H-3pyrazole), 9.10 (d, 1H, H-2quinoline), 11.06 (bs, 1H, OH exchangeable with D2O). Anal. Calcd for C19H12N3O2Cl (349.78): C, 65.24; H, 3.46; N, 12.01%. Found: C, 65.28; H, 3.28; N, 11.54%.
Ethyl 2-amino-5-ethoxy-4-hydrazinyl-4H,5H-pyrano[3,2-c]chromene-3-carboxylate (6).
A mixture of compound 1 (0.54 g, 2 mmol) and hydrazine hydrate (0.1 mL, 2 mmol) in absolute EtOH (25 mL) was heated under reflux for 5 min. The solid obtained during heating was filtered off and crystallized from DMF/EtOH to give compound 6 as yellow crystals, yield (0.38 g, 70%), mp 241 °C. IR (KBr, cm-1): 3410, 3241, 3283, 3215 (2NH2, NH), 2978, 2905 (CHaliph.), 1663 (C=Oester), 1615 (C=C). 1H NMR (DMSO-d6, δ): 1.11 (t, 3H, CH3, J = 7.2 Hz), 1.24 (t, 3H, CH3, J = 7.2 Hz), 4.05 (q, 2H, CH2, J = 7.2 Hz), 4.11 (q, 2H, CH2, J = 7.8 Hz), 5.23 (s, 1H, NH exchangeable with D2O), 5.85 (d, 1H, H-4 exchanged to singlet with D2O, J = 8.4 Hz), 6.35 (s, 1H, H-5 as O-CH-O), 6.40 (d, 1H, NH exchangeable with D2O), 6.89 (t, 1H, H-8, J = 8.4 Hz), 7.13 (t, 1H, H-7), 7.29 (t, 1H, H-9), 7.79 (d, 1H, H-10), 8.84 (bs, 2H, NH2 exchangeable with D2O), 9.84 (bs, 1H, NH exchangeable with D2O). M/z (I %): 301 (M-EtOH, 10), 286 (58), 239 (11), 224 (10), 196 (10), 166 (100), 147 (22), 121 (72), 120 (66), 94 (52), 77 (10), 65 (54). Anal. Calcd for C17H21N3O5 (347.37): C, 58.78; H, 6.09; N, 12.10%. Found: C, 58.95; H, 6.31; N, 12.18%.
3-(2-Hydroxybenzoyl)-1H-1,5-benzodiazepine (7).
A mixture of compound 1 (0.54 g, 2 mmol) and o-phenylendiamine (0.22 g, 2 mmol) in absolute EtOH (30 mL) was heated under reflux for 15 min. The yellow crystals obtained during heating was filtered off and crystallized from EtOH to give compound 7 as yellow crystals, yield (0.44 g, 82%), mp 220 °C. IR (KBr, cm-1): 3090 (NH), 1637 (C=O), 1611 (C=N), 1570 (C=C). 1H NMR (DMSO-d6, δ): 6.92−6.98 (m, 3H, Ar-H), 7.16−7.19 (m, 1H, Ar-H), 7.31−7.40 (m, 4H, Ar-H), 8.56 (d, 2H, H-2diazepine and H-4diazepine), 10.19 (s, 1H, NH exchangeable with D2O), 14.29 (s, 1H, OH exchangeable with D2O). 13C NMR (DMSO-d6, δ): 88.2, 117.3, 120.0, 121.7, 122.2, 123.0, 123.9, 126.9, 133.1, 133.8, 134.8, 136.4, 139.5, 152.8, 155.2, 159.6. M/z (I %): 264 (16), 210 (14), 206 (27), 185 (14), 131 (22), 108 (38), 91 (24), 77 (24), 65 (27), 60 (100). Anal. Calcd for C16H12N2O2 (264.29): C, 72.72; H, 4.58; N, 10.60%. Found: C, 72.50; H, 4.65; N, 10.84%.
4-(1H-1,5-Benzodiazepin-3-yl)coumarin-3-carbonitrile (8).
A mixture of compound 1 (0.54 g, 2 mmol) and o-phenylendiamine (0.22 g, 2 mmol) in absolute EtOH (30 mL) was heated under reflux for 6 h. The solid obtained after cooling was filtered off and crystallized from DMF to give compound 8 as yellow crystals, yield (0.24 g, 45%), mp > 300 °C. IR (KBr, cm-1): 3133 (NH), 2222 (C≡N), 1663 (C=O), 1623 (C=N), 1592 (C=C). 1H NMR (DMSO-d6, δ): 6.80−7.20 (m, 2H, Ar-H), 7.35−7.55 (m, 4H, Ar-H), 7.78−7.92 (m, 2H, Ar-H), 8.60 (bs, 2H, Ar-H). M/z (I %): 312 (M-1, 21), 311 (M-2, 32), 188 (32), 138 (26), 121 (47), 93 (37), 57 (100). Anal. Calcd for C19H11N3O2 (313.32): C, 72.81; H, 3.54; N, 13.41%. Found: C, 72.73; H, 3.41; N, 13.08%.
1,2-Bis[(chromon-3-yl)methyleneamino]ethane (9).
A mixture of compound 1 (0.54 g, 2 mmol) and ethylenediamine (0.12 mL, 2 mmol) in absolute EtOH (20 mL) was heated under reflux for 2 h. After cooling, the resulting precipitate was filtered off and crystallized from DMF to give compound 9 as yellow crystals, yield (0.41 g, 55%), mp 200−201 °C (lit., mp 200 ºC).23 IR (KBr, cm-1): 3067 (CHarom.), 2931, 2861 (CHaliph.), 1679 (C=O), 1610 (C=N), 1604 (C=C). 1H NMR (DMSO-d6, δ): 3.69 (s, 4H, 2CH2), 6.69−6.92 (m, 4H, Ar-H), 7.28−7.50 (m, 4H, Ar-H), 8.02 (s, 2H, 2CH=N), 8.17 (s, 2H, H-2chromone).
3-(2-Hydroxybenzoyl)-1,5-benzothiazepine (10).
A mixture of compound 1 or 2 (2 mmol) and 2-aminothiophenol (0.26 g, 2 mmol) in absolute EtOH (20 mL) was heated under reflux for 3 h. After cooling, the pale yellow precipitate was filtered off and crystallized from EtOH to give compound 10 as pale yellow crystals, yield (32−34%), mp 145 °C. IR (KBr, cm-1): 3057 (CHarom.), 1622 (C=Ohydrogen bonded), 1589 (C=N), 1558 (C=C). 1HNMR (DMSO-d6, δ): 6.99−7.10 (m, 3H, Ar-H), 7.39−7.44 (m, 3H, Ar-H), 7.54 (t, 1H, Ar-H), 8.06 (d, 1H, Ar-H), 8.17−8.19 (m, 2H, Ar-H), 11.58 (s, 1H, OH, exchangeable with D2O). Anal. Calcd for C16H11NO2S (281.34): C, 68.31; H, 3.94; N, 4.98; S, 11.40%. Found: C, 68.15; H, 3.63; N, 4.80; S, 11.21%.

6-Hydroxy-2-oxo-4-(4-oxo-4H-chromen-3-yl)-1,2-dihydropyridine-3,5-dicarbonitrile (11).
A mixture of compound 1 (0.54 g, 2 mmol) and cyanoacetamide (0.17 g, 2 mmol) in absolute EtOH (30 mL) containing two drops of piperidine was heated under reflux for 3 h. The formed precipitate during heating was filtered off and crystallized from DMF/H2O to give compound 11 as yellow crystals, yield (0.21 g, 34%), mp 212 °C. IR (KBr, cm-1): 3408 (OH), 3188 (NH), 3025 (CHarom.), 2271, 2228 (2 C≡N), 1686 (C=Opyridone), 1630 (C=Oγ-pyrone), 1617 (C=C). 1H NMR (DMSO-d6, δ): 6.92 (t, 1H, H-6chromone, J = 7.6 Hz), 7.32 (d, 1H, H-8chromone, J = 6.8 Hz), 7.40 (t, 1H, H-7chromone, J = 6.8 Hz), 7.62 (d, 1H, H-5chromone), 8.02 (s, 1H, NH), 8.37 (s, 1H, H-2chromone), 10.31 (s, 1H, OH exchangeable with D2O). M/z (I %): 305 (M+, 4), 289 (5), 265 (6), 240 (46), 222 (8), 194 (11), 147 (14), 120 (100), 105 (7), 92 (39), 80 (86), 77 (11), 64 (77). Anal. Calcd for C16H7N3O4 (305.25): C, 62.96; H, 2.31; N, 13.77%. Found: C, 62.75; H, 2.24; N, 13.54%.
Ethyl 1,2-diamino-5-cyano-6-oxo-4-(4-oxo-4H-chromen-3-yl)-1,6-dihydropyridine-3-carboxylate (12).
A mixture of compound 1 (0.54 g, 2 mmol) and cyanoacetohydrazide (0.2 g, 2 mmol), in absolute EtOH (30 mL) containing two drops of piperidine, was heated under reflux for 30 min. The pale yellow precipitate obtained during heating was filtered off and crystallized from EtOH to give compound 12 as white crystals, yield (0.26 g, 48%), mp 195 °C. IR (KBr, cm-1): 3280 (2NH2), 3060 (CHarom.), 2983, 2920 (CHaliph.), 2263 (C≡N), 1720 (C=Oester), 1680 (C=Opyridone), 1625 (C=Oγ-pyrone), 1605 (C=C). 1HNMR (DMSO-d6, δ): 1.35 (t, 3H, CH3, J = 7.5 Hz), 4.44 (q, 2H, CH2, J = 7.5 Hz), 4.56 (s, 2H, NH2 exchangeable with D2O), 6.97-7.04 (m, 2H, Ar-H), 7.49−7.53 (m, 2H, Ar-H), 8.49 (s, 1H, 1H of C-NH2 exchangeable with D2O), 9.43 (s, 1H, H-2chromone), 10.48 (s, 1H, 1H of C-NH2 exchangeable with D2O). 13C NMR (DMSO-d6, δ): 14.1, 61.7, 95.6, 114.0, 116.1, 116.5, 119.5, 123.7, 124.4, 130.8, 133.4, 134.2, 135.8, 149.9, 156.8, 160.7, 162.3, 192.0. M/z (I %): 350 (M-NH2, 97), 321 (100), 303 (27), 275 (84), 249 (27), 210 (26), 171 (86), 121 (78), 93 (35), 77 (22), 65 (76). Anal. Calcd for C18H14N4O5 (366.34); C, 59.02; H, 3.85; N, 15.29%. Found: C, 59.15; H, 3.82; N, 15.06%.
5-(2-Hydroxybenzoyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (13).
A mixture of compound 2 (0.67, 3 mmol) in 95% EtOH (25 mL) containing one drop of piperidine was heated under reflux for 2 h. The solid obtained after cooling was filtered off and crystallized from EtOH to give compound 13 as white crystals, yield (0.31 g, 43%), mp 270 °C (lit., mp 266−267 °C).25 IR (KBr, cm-1): 3182, 3078 (OH, NH), 3002 (CHarom.), 2228 (C≡N), 1688 (C=Ocyclic amide), 1641 (C=Obenzoyl), 1617 (C=C). 1H NMR (DMSO-d6, δ): 6.92−7.98 (m, 2H, Ar-H), 7.35 (d, 1H, Ar-H, J = 6.0 Hz), 7.42 (t, 1H, Ar-H, J = 7.5 Hz), 8.05 (s, 1H, H-4pyridine), 8.42 (s, 1H, H-6pyridine), 10.33 (bs, 1H, NH exchangeable with D2O), 13.10 (bs, 1H, OH exchangeable with D2O).
5-Amino-3-[(2-hydroxyphenyl)-1H-pyrazol-4-yl]-1H-pyrazole-4-carbonitrile (14).
A mixture of compound 2 (0.67 g, 3 mmol) and hydrazine hydrate (0.15 mL, 3 mmol) in absolute EtOH (25 mL) was heated under reflux for 30 min. The solid obtained during heating was filtered off and crystallized from DMF/EtOH to give compound 14 as yellow crystals, yield (0.32 g, 60%), mp 255 °C. IR (KBr, cm-1): 3335 (br, NH2, 2NH, OH), 2221 (C≡N), 1624 (C=N), 1602 (C=C). 1HNMR (DMSO-d6, δ): 6.95-6.99 (m, 3H, 3Ar-H), 7.31 (d, 1H, Ar-H, J = 8.7 Hz), 7.47 (bs, 2H, NH2 exchangeable with D2O), 7.64 (s, 1H, H-5pyrazole), 10.20 (bs, 3H, 2NH and OH exchangeable with D2O). M/z (I %): 241 (M-CN, 46), 93 (39), 83 (54), 64 (100). Anal. Calcd for C13H10N6O (266.26); C, 58.64; H, 3.76; N, 31.56%. Found: C, 58.33; H, 3.54; N, 31.67%.
5-Amino-7-(4-oxo-4H-chromen-3-yl)-2,3-dihydro-1H-1,4-diazepine-6-carbonitrile (15).
A mixture of compound 2 (0.67 g, 3 mmol) and ethylenediamine (0.2 mL, 3 mmol), in absolute EtOH (20 mL) was heated under reflux for 2 h. After cooling, the solid obtained was filtered off and crystallized from DMF/H2O to give compound 15 as yellow crystals, yield (0.47 g, 70%), mp 283 °C. IR (KBr, cm-1): 3324 (NH2, NH), 3050 (CHarom.), 2929, 2867 (CHaliph.), 2212 (C≡N), 1645 (C=Oγ-pyrone), 1601 (C=N), 1585 (C=C). 1H NMR (DMSO-d6, δ): 3.83 (s, 4H, 2CH2), 5.83 (bs, 2H, NH2 exchangeable with D2O), 6.91−6.99 (m, 2H, Ar-H), 7.18−7.46 (m, 1H, Ar-H), 8.06 (d, 1H, H-5), 8.88 (s, 1H, H-2), 9.91 (bs, 1H, NH exchangeable with D2O). M/z (I %): 279 (M-1, 24), 182 (23), 140 (29), 94 (41), 64 (82), 55 (100). Anal. Calcd for C15H12N4O2 (280.29); C, 64.28; H, 4.32; N, 19.99%. Found: C, 64.68; H, 4.60; N, 19.32%.
4-Amino-2-(4-oxo-4H-chromen-3-yl)-1H-1,5-benzodiazepine-3-carbonitrile (16).
A mixture of compound 2 (0.67 g, 3 mmol) and o-phenylendiamine (0.32 g, 3 mmol) in absolute EtOH (25 mL) was heated under reflux for 2 h. The solid obtained during heating was filtered off and crystallized from DMF/EtOH to give compound 16 as yellow crystals, yield (0.42 g, 63%), mp 292 °C. IR (KBr, cm-1): 3319 (NH2, NH), 3052 (CHarom.), 2210 (C≡N), 1633 (C=Oγ-pyrone), 1615 (C=N), 1582 (C=C). 1HNMR (DMSO-d6, δ): 6.89-6.98 (m, 3H, Ar-H), 7.44-7.58 (m, 4H, Ar-H), 7.69 (bs, 2H, NH2 exchangeable with D2O), 7.80 (d, 1H, H-5chromone), 8.30 (bs, 1H, NH exchangeable with D2O), 8.75 (s, 1H, H-2chromone). 13C NMR (DMSO-d6, δ): 71.5, 116.2, 116.7, 117.3, 119.1, 122.6, 124.3, 126.2, 127.6, 130.8, 133.2, 140.1, 146.1, 151.6, 152.8, 156.8, 183.4. M/z (I %): 328 (M, 88), 311 (69), 299 (63), 256 (25), 208 (100), 152 (25), 121 (63), 93 (38), 65 (75). Anal. Calcd for C19H12N4O2 (328.33); C, 69.51; H, 3.68; N, 17.06%. Found: C, 69.64; H, 3.33; N, 17.00%.
6-Amino-2-oxo-4-(4-oxo-4H-chromen-3-yl)-1,2-dihydropyridine-3,5-dicarbonitrile (17).
A mixture of compound 2 (0.44 g, 2 mmol) and cyanoacetamide (0.17 g, 2 mmol) in absolute EtOH (20 mL) containing two drops of piperidine was heated under reflux for 2 h. The yellow crystals obtained during heating was filtered off and crystallized from DMF/EtOH to give compound 17 as pale yellow crystals, yield (0.20 g, 45%), mp > 300 °C. IR (KBr, cm-1): 3385, 3320, 3195 (br, NH2, NH), 3050 (CHarom.), 2217 (2C≡N), 1684 (C=Opyridone), 1663 (C=Oγ-pyrone), 1622 (C= N). 1HNMR (DMSO-d6, δ): 7.51 (t, 1H, H-6chromone, J = 7.8 Hz), 7.62 (d, 1H, H-8chromone, J = 8.7 Hz), 7.77 (t, 1H, H-7chromone, J = 7.8 Hz), 7.88 (d, 1H, H-5chromone, J = 8.4 Hz), 8.25 (s, 1H, NH), 8.56 (s, 1H, NH), 8.97 (s, 1H, NH), 9.26 (s, 1H, H-2chromone). M/z (I %): 304 (M+, 13), 288 (10), 275 (9), 262 (10), 250 (14), 235 (10), 214 (15), 185 (9), 172 (13), 131 (12), 121 (13), 94 (11), 80 (100), 77 (9), 64 (42). Anal. Calcd for C16H8N4O3 (304.27); C, 63.16; H, 2.65; N, 18.41%. Found: C, 62.89; H, 2.51; N, 18.16%.
1,6-Diamino-2-oxo-4-(4-oxo-4H-chromen-3-yl)-1,2-dihydropyridine-3,5-dicarbonitrile (18).
A mixture of compound 2 (0.44 g, 2 mmol) and cyanoacetohydrazide, (0.2 g, 2 mmol), in absolute EtOH (50 mL) containing two drops of piperidine, was heated under reflux for 30 min. The pale yellow precipitate obtained during heating was filtered off and crystallized from DMF/MeOH to give compound 18 as yellow crystals, yield (0.27 g, 61%), mp 289 °C. IR (KBr, cm-1): 3183, 3085 (2NH2), 2999 (CHarom.), 2225 (2C≡N), 1689 (C=Opyridone), 1644 (C=Oγ-pyrone), 1624 (C=C). 1HNMR (DMSO-d6, δ): 4.55 (s, 2H, N-NH2 exchangeable with D2O), 6.98-7.04 (d, 2H, Ar-H), 7.38-7.58 (m, 2H, Ar-H), 8.80 (s, 2H, C-NH2 exchangeable with D2O), 9.38 (s, 1H, H-2chromone). M/z (I %): 319 (M+, 17), 304 (18), 273 (18), 225 (19), 217 (17), 167 (20), 144 (17), 115 (16), 92 (17), 77 (12), 65 (100). Anal. Calcd for C16H9N5O3 (319.28): C, 60.19; H, 2.84; N, 21.93%. Found: C, 60.23; H, 2.86; N, 21.74%.

References

1. D. A. Horton, G. T. Bourne, and M. L. Smyth, Chem. Rev., 2003, 103, 893. CrossRef
2. K. Kralova, F. Sersen, M. Lacova, and H. Stankovicova, Biol. Plant., 1995, 38, 397. CrossRef
3. J. Nawrot-Modranka, E. Nawrot-Modranka, and J. Graczyk, Eur. J. Med. Chem., 2006, 41, 1301. CrossRef
4. A. S. Plaskon, O. O. Grygorenko, and S. V. Ryabukhin, Tetrahedron, 2012, 68, 2743. CrossRef
5. M. A. Ibrahim, M. A. Abdel-Hamed, and N. M. El-Gohary, J. Braz. Chem. Soc., 2011, 22, 1130. CrossRef
6. R. Gašparová and M. Lácová, Molecules, 2005, 10, 937. CrossRef
7. A. S. Plaskon, S. V. Ryabukhin, D. M. Volochnyuk, A. N. Shivanyuk, and A. A. Tolmachev, Tetrahedron, 2008, 64, 5933. CrossRef
8. S. Klutchko, J. Shavel, and M. V. von Strandtmann, J. Org. Chem., 1974, 39, 2436. CrossRef
9. U. Petersen and H. Heitzer, Liebigs. Ann. Chem., 1976, 9, 1659. CrossRef
10. R. B. Gammill, S. A. Nash, and S. A. Mizsak, Tetrahedron Lett., 1983, 24, 3435. CrossRef
11. W. Huang, M.-Z. Liu, Y. Li, Y. Tan, and G.-I. Yang, Bioorg. Med. Chem., 2007, 15, 5191. CrossRef
12. M. A. Ibrahim, ARKIVOC, 2008, xvii, 192.
13. M. A. Ibrahim, Tetrahedron, 2009, 65, 7687. CrossRef
14. M. A. Ibrahim, Synth. Commun., 2009, 39, 3527. CrossRef
15. M. A. Ibrahim, T. E. Ali, N. M. El-Gohary, and A. M. El-Kazak, Eur. J. Chem., 2013, 4, 311. CrossRef
16. M. Abdel-megid, M. A. Ibrahim, Y. Gabr, N. M. El-Gohary, and E. A. Mohamed, J. Heterocycl. Chem., 2013, 50, 615. CrossRef
17. M. A. Ibrahim, Tetrahedron, 2013, 69, 6861. CrossRef
18. M. A. Ibrahim, J. Braz. Chem. Soc., 2013, 24, 1754. CrossRef
19. M. A. Ibrahim, T. E. Ali, A. M. El-Kazak, and A. M. Mohamed, Heterocycles, 2013, 87, 1075. CrossRef
20. C. K. Ghosh, S. Sahana, and C. Bandyopadhyay, Indian J. Chem., 1993, 32B, 624.
21. D. L. M. Coutinho and P. S. Fernandes, Indian J. Chem., 1992, 31B, 573.
22. C. K. Ghosh and K. K. Mukhopadhyay, J. Indian Chem. Soc., 1978, 55, 52.
23. C. K. Ghosh and S. Khan, Synthesis, 1980, 701. CrossRef
24. T. E. Ali and M. A. Ibrahim, J. Braz. Chem. Soc., 2010, 21, 1007. CrossRef
25. A. Nohara, T. Ishiguro, and Y. Sanno, Tetrahedron Lett., 1974, 15, 1183. CrossRef
26. R. V. Hangarge, S. A. Sonwane, D. V. Jarikote, and M. S. Shingare, Green Chem., 2001, 3, 310. CrossRef