Introduction

The chemistry of pyrazoles and derivatives, one of the most valuable nitrogen containing heterocyclic compounds, has attracted much attention in recent years. They have been considered very important for pharmaceutical, chemical and agricultural industries [1,2,3]. Pyrazoles have been reported to possess antimicrobial, anticancer, antileukemic, antidepressant, antiinflammatory, antihelmintic, anticonvulsant, anti-tubercular, analgesic, antiproliferative agents, angiogenic, antioxidant, antipyretic, antioxidant or herbicidal properties [4,5,6,7,8]. In addition, fused pyrazoles possess a wide range of biological properties such as fungicidal [9], herbicidal [10], veridical [11] and insecticidal activity [12, 13] and have been used for the treatment of rheumatoid arthritis [14, 15].

Furans and their derivatives with substituent(s) at C-2 and/or C-3 have attracted strong interest due to their widespread in a large number of natural products and for their useful biological and pharmacological properties [16,17,18]. Among these compounds, pyrazole-fused ring derivatives such as furopyrazoles have demonstrated antitumour and antimicrobial activities [19]. Therefore, the preparation of furopyrazole derivatives is very important and challenging from a synthetic point of view. In recent years, despite a number of synthetic routs accessible for ring-fused pyrazoles such as dihydrofuro[2,3-c]pyrazole derivatives in the literature [20,21,22,23,24,25], synthesis of furo[2,3-c]pyrazole derivatives has received little attention and only few procedures have been reported. Among them, the majority has focused on the preparation of CF3-substituted furopyrazoles A based on Rh catalyzed [3 + 2] cycloaddition of CF3-substituted diazocarbonyl compound with aromatic alkynes [26], reaction of 4-bromo pyrazolone with malononitrile, cyanoacetamide and/or ethyl cyanoacetate to give furo[2,3-c]pyrazoles B using chitosan as a green basic catalyst by microwave irradiation technique [27] and synthesis of benzo-bis-furopyrazole C an important structural unit of cyanine dyes from p-chloranil and 3-methyl-1-phenyl-5-pyrazolone [28] (Fig. 1).

Fig. 1
figure 1

Fused furopyrazoles (a–c)

Full size image

With regard to the exploration of green chemistry, solvent selection is an imperative part of most chemical processes. Organic reactions in water as a solvent without use of any detrimental organic solvents are of immense interest. When water is used as a reaction medium, it leads to some specific interactions such as polarity, hydrogen bonding, hydrophobic effect and trans-phase interactions due to its exclusive structure and incredible physical and chemical assets [29, 30]. However, a clear-cut understanding on the role of water in accelerating organic reactions is yet to be made. Towards this direction various terminologies such as “on water,” in water,“in the presence of water” have been coined [31,32,33,34]. However, the insolubility of most organic reactants in water makes the reaction mixtures heterogeneous, which proves to be a major difficulty while using water as a solvent. But the effect of water on heterogeneous reactions is precisely opposite. Actually, depending on the nature of the reaction, water was observed to accelerate most reactions appreciably on its interface. The observed rate enhancement in water was explained by the hydrophobic effect [35,36,37,38]. In recent years, various reactions have been carried out in water, and mostly when the organic reactants are insoluble in the aqueous phase [39,40,41,42,43,44].

To the best of our knowledge, synthesis of 1H-furo[2,3-c]pyrazole-4-amines in aqueous medium is not yet reported. In continuation of our ongoing program for the development of sustainable processes the heterocyclic compounds [45,46,47,48,49,50,51], herein we wish to report our results for the uncatalyzed domino synthesis of novel highly substituted 1H-furo[2,3-c]pyrazole derivatives by a one-pot four-component condensation reaction between hydrazines, ethyl acetoacetate, aromatic amines and phenylglyoxal monohydrate in water.

Results and discussion

For our initial study, the reaction of ethyl acetoacetate (1, 1.0 mmol), hydrazine hydrate (2a, 1.0 mmol), 2-aminopyridine (3a, 1.0 mmol) and phenylglyoxal monohydrate (4, 1.0 mmol) was chosen as a model reaction (Table 1). This combination in the absence of any catalyst and solvent-free condition at 90 °C provided four-component product 5a after 60 min in 54% yield (Table 1, entry 1). Next, the same reaction mixture stirred at reflux temperature in water for 40 min gave the desired product 5a in 88% yield (Table 1, entry 2). Interestingly, the model reaction in water and in the presence of a catalytic amount of guanidine hydrochloride or formic acid was examined. The results indicated that using of the catalyst did not improve the yield of the product. In order to study the solvent effect, the model reaction was carried out in the presence of various polar protic and polar aprotic solvents. It was found that polar protic solvents (EtOH and MeOH) and low boiling aprotic solvents (CH3CN and THF) under reflux conditions afforded the moderate yields of the product 5a after 2 h (Table 1, entries 3–6).

Table 1 Optimization of the reaction conditionsa
figure a
Full size table

With the optimized reaction conditions for the synthesis of amine substituted ring-fused furopyrazoles, we explored the generality of this reaction. Our attention was focused on the use of commercially available aromatic amines such as 2-amino-4-methylpyridine (3b), 4-chloroaniline (3c), 2-amino-5-nitropyridine (3d) and 2-amino-5-bromopyridine (3e). The reaction with 3b gave the corresponding product 5b in high yield (84%) after 40 min. Interestingly, under similar reaction conditions, the other amines 3c-e with ethyl acetoacetate, hydrazine hydrate and phenylglyoxal monohydrate gave the corresponding 2,2′-bis(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1-phenylethanone (6a) instead of the desired ring-fused furopyrazoles. It is suggested that 3-methyl-1H-pyrazol-5-ol (7a) generated in situ from the condensation of hydrazine hydrate (2a) and ethyl acetoacetate (1) is more nucleophilic than amine containing electron-withdrawing group (3c–e) and reacts with intermediate 8a to afford product 6a (Scheme 1).

Scheme 1
scheme 1

Synthesis of furopyrazole 5a–b and bis (pyrazole-5-ols) (6a)

Full size image

Thus, encouraged by the results, we further explored the scope and limitation of the current method. With the optimal conditions in hand, one-pot, two-step domino reaction of phenyl hydrazine (2b, 1.0 mmol), ethyl acetoacetate (1, 1.0 mmol), 2-aminopyridine (3a, 1.0 mmol) and phenylglyoxal monohydrate (4, 1.0 mmol) was investigated. Initially, the reaction of phenyl hydrazine (2b, 1.0 mmol) and ethyl acetoacetate (1, 1.0 mmol) in the presence of a catalytic amount of guanidine hydrochloride (10 mol%) as organocatalyst in water at reflux condition was studied. The reaction gave 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) in high yield (90%) after 90 min (Scheme 2). We also evaluated the amount of catalyst required for this reaction. It was found that when we increased the amount of catalyst from 10 mol% to 15 mol% and 20 mol%, the yield did not improve. Moreover, by decreasing the amount of catalyst from 10 mol % to 5 mol%, the yield decreased from 90 to 75%. Also, under the identical condition, the yield of the reaction was not affected in the presence of 10 mol% catalyst after different time intervals (90 min, 120 min and 150 min). Thus, 10 mol% guanidine hydrochloride was chosen as a quantitative catalyst for this reaction and 90 min was chosen as the reaction time. After determining the optimum reaction condition, to established the synthesis of 7b, phenylglyoxal monohydrate (4, 1.0 mmol) and various aryl amines (1.0 mmol) were added to the reaction mixture for the synthesis of a series of novel furopyrazoles 5c–f (Scheme 2).

Scheme 2
scheme 2

One-pot synthesis of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) and furopyrazole 5c–f

Full size image

As indicated in Fig. 2, the various aromatic amines such as 2-aminopyridine, 2-amino-4-methylpyridine, 2-amino-5-bromopyridine and 2-amino-3-methylpyridine (3f), afforded the corresponding furopyrazole 5c–f within 50–60 min in high yields (75–85%).

Fig. 2
figure 2

One-pot, two-step synthesis of furopyrazole 5c–f

Full size image

However, when the reaction was performed with 4-chloroaniline (3c) or 2-amino-5-nitropyridine (3d), 2,2′-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenylethanone (6b) was obtained instead of the expected furopyrazole derivatives. Accordingly, the reaction occurred via initial formation of intermediate 8b from the reaction of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b) and phenylglyoxal monohydrate followed by Michael addition of 7b to 8b to give product 6b because of the higher nucleophilicity of 7b than amines bearing strong electron-withdrawing group (3c–d) (Scheme 3).

Scheme 3
scheme 3

Synthesis of bis (pyrazole-5-ols) (6b)

Full size image

It should be noted that the purification of the title compounds is very easy. After cooling the reaction mixture to room temperature, the solid that separated out was filtered. The crude product was stirred for 5 min in boiling CH3CN and the resulting precipitate was filtered to give the pure product. In another study, one-pot three-component reaction of 3-methyl-1-phenyl-1H-pyrazol-5-ol (7b), phenylglyoxal monohydrate (4) and aromatic amines 3a–f in the absence of catalyst in water under reflux conditions was examined (Scheme 4). In this process, the same products 5c–f and 6b as well as yields were obtained after 50–60 min. As a result, guanidine hydrochloride as catalyst in the synthesis of compounds 5c–f and 6b is only effective for the first step of the reaction, in which phenyl hydrazine reacts with ethyl acetoacetate, and has no effect on the second step.

Scheme 4
scheme 4

One-pot three-component synthesis of compounds 5c–f and 6b

Full size image

In order to expand the scope of the current method, the reaction of hydrazine hydrate (2a, 1.0 mmol), ethyl acetoacetate (1, 1.0 mmol), 2-aminopyridine (3a, 1.0 mmol) and benzaldehyde (1.0 mmol) was examined to synthesize 3-methyl-4-(phenyl(pyridin-2-ylamino)methyl)-1H-pyrazol-5-ol (9). Unfortunately, the attempt to replace phenylglyoxal monohydrate with benzaldehyde failed and 4,4′-(phenylmethylene)bis(3-methyl-1H-pyrazol-5-ol) (10) was obtained instead of compound 9. Therefore, it might be concluded that 4-benzylidene-3-methyl-1H-pyrazol-5(4H)-one (8) is initially formed as an intermediate. Then, the intermediate is attacked by 3-methyl-1H-pyrazol-5(4H)-one to give the product 10, which might be due to the higher nucleophilicity of the 3-methyl-1H-pyrazol-5(4H)-one than 2-aminopyridine (Scheme 5). Also, we examined the reaction of 2-aminopyridine and benzaldehyde in the presence of guanidine hydrochloride under solvent-free condition at 90 °C for 20 min. Then, 3-methyl-1H-pyrazol-5-ol (7a) was added to the reaction mixture and stirred at 90 °C for 15 min. As a result, compound 10 obtained instead of the desired product 9.

Scheme 5
scheme 5

Proposal mechanism for the synthesis of compound 10

Full size image

The plausible reaction mechanism of formation of compounds 5a–f is described in Scheme 6. The reaction proceeds through the in situ formation of 1H-pyrazol-5-ol 7 by the condensation of hydrazine 2 and ethyl acetoacetate 1. The last one reacts with the phenylglyoxal monohydrate with loss of a water molecule leading to the formation of intermediate 11. Next, the Michael addition of amine to intermediates 11 provide to intermediate 12 and subsequent intramolecular cyclization and dehydration, to afford final the corresponding furopyrazole 5.

Scheme 6
scheme 6

Proposed mechanism pathway for the formation of 5a–f

Full size image

Conclusion

In summary, we have developed a protocol for the facile preparation of novel fused 1H-furo[2,3-c]pyrazole-4-amines in high yields by a one-pot four-component domino protocol involving Knoevenagel condensation, Michael addition, cyclization and dehydration sequences in an aqueous medium under reflux conditions. In this process, the replacement of the amine bearing electron-donating group or weak electron-withdrawing group moiety with amine bearing strong electron-withdrawing group led to the formation of bis(pyrazole-5-ol) compounds. The advantages of this method include environmental acceptability, easy work-up, easy product separation and purification, short reaction time, no additive catalyst, and finally compliance with green chemistry protocols. Moreover, our products are expected to be of pharmacological interest and may act as potential drug candidates similar to the pyrazoles. To the best of our knowledge, this is the first report on the synthesis of novel 1H-furo[2,3-c]pyrazole-4-amine derivatives.

Experimental section

General information

All commercially available chemicals and reagents were used without further purification. Melting points were determined with an Electrothermal model 9100 apparatus and are uncorrected. IR spectra were recorded on a Shimadzu 4300 spectrophotometer. The 1H and 13C NMR spectra were recorded in DMSO-d6 on Bruker DRX-300 Avance spectrometers. Chemical shifts (δ) are reported in parts per million and are referenced to the NMR solvent. Mass spectra of the products were obtained with an HP (Agilent technologies) 5973 mass selective detector. Elemental analyses were carried out by a CHN–O–Rapid Heraeus elemental analyzer (Wellesley, MA).

General procedure for the synthesis of compounds 5a–b and 6a

Hydrazine hydrate (1.0 mmol), ethylacetoacetate (1.0 mmol), aromatic amine (1.0 mmol), phenylglyoxal monohydrate (1.0 mmol) and 5 mL of H2O were placed in a 50 mL round bottom flask over a magnetic stirrer and the contents were refluxed for appropriate times (40–55 min). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was allowed to cool at room temperature and the resulting solid (crude product) filtered and dried. The crude product was stirred for 5 min in boiling CH3CN and the resulting precipitate was filtered. The products 5a, 5b and 6a thus obtained were found to be pure upon 1H and 13C-NMR, mass spectra, elemental analyses, and TLC examination.

General procedure for the synthesis of compounds 5c–f and 6b

Phenyl hydrazine (1.0 mmol), ethylacetoacetate (1.0 mmol), guanidine hydrochloride (10% mol) and 5 mL of H2O were placed in a 50 mL round bottom flask over a magnetic stirrer and the contents were refluxed for 90 min (the progress of the reaction was monitored by TLC). Then, aromatic amine (1.0 mmol), phenylglyoxal monohydrate (1.0 mmol) were added to the reaction mixture and the contents were refluxed for appropriate times (50–60 min). The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was allowed to cool at room temperature and the resulting solid (crude product) filtered and dried. The crude product was stirred for 5 min in boiling CH3CN and the resulting precipitate was filtered. The products 5c–f and 6b thus obtained were found to be pure upon 1H and 13C-NMR, mass spectra, elemental analyses, and TLC examination.

3-Methyl-5-phenyl-N-(pyridin-2-yl)-1H-furo[2,3-c]pyrazol-4-amine (5a)

Light pink powder; m.p. = 324–325 °C; IR (KBr, cm−1): 3417, 3113, 3030, 2885, 1636, 1617, 1578, 1530, 1505, 1450, 1384, 1340, 1276, 1244, 1154, 1112, 1059; 1H NMR (300 MHz, DMSO-d6): δ = 1.50 (s, 3H, CH3), 6.62 (t, 1H, J = 6.6 Hz, Ar–H), 7.00–7.11 (m, 4H, Ar–H), 7.35 (d, 1H, J = 9.0 Hz, Ar–H), 7.52 (d, 2H, J = 7.8 Hz, Ar–H), 7.59 (d, 1H, J = 6.6 Hz, Ar–H), 9.92 (br, 1H, NH), 11.55 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ = 10.87, 91.28, 95.45, 112.45, 112.93, 117.12, 125.11, 125.24, 127.02, 127.65, 128.77, 135.37, 142.33, 160.10, 164.61; MS m/z (%): 291 (M + 1) (100), 290 (M)+, 289, 275, 233, 218, 205, 154, 128, 103, 78; Anal. calcd. for C17H14N4O: C, 70.34; H, 4.82; N, 19.31. Found: C, 70.43; H, 4.75; N, 19.37.

3-Methyl-N-(4-methylpyridin-2-yl)-5-phenyl-1H-furo[2,3-c]pyrazol-4-amine (5b)

White powder; m.p. = 332–334 °C; IR (KBr, cm−1): 3219, 3169, 3055, 2913, 1644, 1623, 1561, 1524, 1498, 1382, 1346, 1270, 1243, 1220, 1166, 1112, 1058; 1H NMR (300 MHz, DMSO-d6): δ = 1.49 (s, 3H, CH3), 2.10 (s, 3H, CH3), 6.45–6.47 (dd, 1H, J = 1.2, 7.2 Hz, Ar–H), 6.95–7.11 (m, 4H, Ar–H), 7.45–7.51 (m, 3H, Ar–H), 9.93 (br, 1H, NH), 11.47 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ = 10.86, 21.23, 91.44, 112.30, 114.88, 115.37, 124.36, 126.90, 127.46, 128.70, 135.52, 135.64, 140.20, 141.96, 145.08, 164.71; MS m/z (%): 304 (M)+ (100), 289, 275, 247, 232, 219, 205, 169, 152, 128, 115, 92, 78, 65; Anal. calcd. for C18H16N4O: C, 71.05; H, 5.26; N, 18.42. Found: C, 70.97; H, 5.30; N, 18.54.

3-Methyl-1,5-diphenyl-N-(pyridin-2-yl)-1H-furo[2,3-c]pyrazol-4-amine (5c)

Light pink powder; m.p. = 310–312 °C; IR (KBr, cm−1): 3430, 3062, 2920, 1595, 1500, 1445, 1389, 1359, 1309,1231, 1029; 1H NMR (300 MHz, DMSO-d6): δ = 1.52 (s, 3H, CH3), 6.65 (t, 1H, J = 6.6 Hz, Ar–H), 6.99–7.26 (m, 9H, Ar–H, NH), 7.39 (d, 1H, J = 12.0 Hz, Ar–H), 7.57–7.60 (m, 3H, Ar–H), 7.75 (d, 1H, J = 6.9 Hz, Ar–H); 1H NMR (300 MHz, DMSO-d6 +D2O): δ = 1.65 (s, 3H, CH3), 6.86 (t, 1H, J = 6.6 Hz, Ar–H), 7.15–7.41 (m, 8H, Ar–H), 7.54 (d, 1H, J = 8.7 Hz, Ar–H), 7.66–7.69 (m, 3H, Ar–H), 7.90 (d, 1H, J = 6.9 Hz, Ar–H); 13C NMR (75 MHz, DMSO-d6): δ = 23.25, 112.72, 117.05, 120.48, 120.93, 125.70, 125.89, 125.91, 127.05, 127.88, 128.94, 129.43, 135.14, 138.86, 140.41, 142.71, 144.85, 145.74, 148.62; MS m/z (%): 366 (M)+ (100), 346, 292, 261, 233, 231, 218, 205, 187, 185, 155, 128, 105, 91, 77; Anal. calcd. for C23H18N4O: C, 75.41; H, 4.91; N, 15.30. Found: C, 75.34; H, 4.99; N, 15.33.

3-Methyl-N-(3-methylpyridin-2-yl)-1,5-diphenyl-1H-furo[2,3-c]pyrazol-4-amine (5d)

Pink powder; m.p. = 330–331 °C; IR (KBr, cm−1): 3413, 3061, 2948, 2917, 1597, 1548, 1500, 1449, 1347, 1309, 1255, 1031; 1H NMR (300 MHz, DMSO-d6): δ = 1.52 (s, 3H, CH3), 2.32 (s, 3H, CH3), 6.56 (t, 1H, J = 6.6, Ar–H), 6.87 (d, 1H, J = 6.6 Hz, Ar–H), 6.95–7.25 (m, 7H, Ar–H, NH); 7.57–7.60 (m, 5H, Ar–H); 13C NMR (75 MHz, DMSO-d6): δ = 13.01, 16.99, 112.68, 112.75, 120.86, 123.19, 124.21, 125.84, 126.53, 127.14, 127.74, 128.86, 129.40, 135.26, 138.80, 142.30, 145.19, 145.77, 148.62, 148.64; MS m/z (%): 380 (M)+ (100), 351, 310, 275, 260, 247, 245, 231, 219, 208, 190, 168, 128, 105, 92, 77; Anal. calcd. for C24H20N4O: C, 75.79; H, 5.26; N, 14.73. Found: C, 75.84; H, 5.15; N, 14.77.

3-Methyl-N-(4-methylpyridin-2-yl)-1,5-diphenyl-1H-furo[2,3-c]pyrazol-4-amine (5e)

Yellowish powder; m.p. = 270–272 °C; IR (KBr, cm−1): 3444, 3069, 2979, 2910, 1596, 1503, 1452, 1359, 1216, 1027; 1H NMR (300 MHz, DMSO-d6): δ = 1.50 (s, 3H, CH3), 2.12 (s, 3H, CH3), 6.50 (d, 1H, J = 6.9 Hz, Ar–H), 6.98–7.25 (m, 8H, Ar–H, NH), 7.55–7.64 (m, 5H, Ar–H); 13C NMR (75 MHz, DMSO-d6): δ = 13.03, 21.27, 112.11, 114.99, 115.38, 116.65, 117.31, 118.91, 120.74, 124.78, 124.87, 125.69, 126.95, 127.81, 128.88, 129.38, 134.83, 136.71, 144.90, 148.56; MS m/z (%): 380 (M)+ (100), 351, 310, 275, 260, 247, 245, 232, 219, 190, 169, 119, 105, 92, 77; Anal. calcd. for C24H20N4O: C, 75.79; H, 5.26; N, 14.73. Found: C, 75.68; H, 5.20; N, 14.80.

N-(5-Bromopyridin-2-yl)-3-methyl-1,5-diphenyl-1H-furo[2,3-c]pyrazol-4-amine (5f)

White powder; m.p. = 313–315 °C; IR (KBr, cm−1): 3430, 3065, 2918, 1594, 1531, 1492, 1440, 1405, 1326, 1223, 1102, 1052; 1H NMR (300 MHz, DMSO-d6): δ = 1.52 (s, 3H, CH3), 7.02–7.26 (m, 8H, Ar–H), 7.39 (d, 1H, J = 9.6 Hz, Ar–H), 7.56–7.61 (m, 4H, Ar–H), 7.95 (br, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ = 15.13, 106.65, 113.05, 118.35, 121.18, 122.47, 124.77, 125.93, 127.08, 128.16, 128.48, 129.02, 129.42, 134.73, 143.44, 143.67, 150.83, 152.87, 161.31; MS m/z (%): 446 (M + 2)+ (100), 444 (M)+, 380, 365, 339, 313, 311, 283, 285, 260, 247, 231, 218, 204, 185, 158, 156, 128, 105, 92, 77; Anal. calcd. for C23H17BrN4O: C, 62.02; H, 3.82; N, 12.58. Found: C, 62.08; H, 3.75; N, 12.64.

2,2-Bis(5-hydroxy-3-methyl-1H-pyrazol-4-yl)-1-phenylethanone (6a)

Yellowish powder; m.p. = 260–262 °C; IR (KBr, cm−1): 3371, 3023, 2896, 1691, 1600, 1529, 1446, 1364, 1291, 1241, 1172, 1076; 1H NMR (300 MHz, DMSO-d6): δ = 1.73 (s, 6H, 2 × CH3), 3.11 (2 × OH exchanged with water of DMSO-d6), 5.13 (s, 1H, methine-H), 7.15–7.25 (m, 3H, Ar–H), 7.56 (d, 2H, J = 7.5 Hz, Ar–H), 10.55 (br, 2H, 2 × NH); 13C NMR (75 MHz, DMSO-d6): δ = 10.77, 38.08, 100.40, 128.56, 128.73, 132.70, 137.17, 138.93, 160.56, 197.35; MS m/z (%): 312 (M)+, 311, 310, 293, 281, 216, 207, 185, 175, 157, 128, 112, 105 (100), 98, 91, 77; Anal. calcd. for C16H16N4O3: C, 61.53; H, 5.12; N, 17.94. Found: C, 61.59; H, 5.22; N, 18.01.

2,2-Bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazol-4-yl)-1-phenylethanone (6b)

Pink powder; m.p. = 273–275 °C; IR (KBr, cm−1): 3417, 3062, 2907, 2865, 2782, 1679, 1621, 1566, 1498, 1406, 1368, 1312, 1204, 1136, 1010; 1H NMR (300 MHz, DMSO-d6): δ = 1.94 (s, 6H, 2 × CH3), 5.24 (s, 1H, methine-H), 6.88 (t, 1H, J = 7.2 Hz, Ar–H), 7.08–7.35 (m, 11H, Ar–H), 7.81–7.86 (m, 3H, Ar–H), 10.91 (br, 2H, 2 × OH); 13C NMR (75 MHz, DMSO-d6): δ = 11.72, 32.09, 118.75, 125.07, 128.60, 129.21, 129.35, 133.89, 135.95, 136.28, 137.33, 148.06, 163.39, 207.86; MS m/z (%): 368, 292, 290, 261, 236, 213, 187 (100), 185, 173, 157, 141, 128, 115, 105, 91, 77; Anal. calcd. for C28H24N4O3: C, 72.41; H, 5.17; N, 12.06. Found: C, 72.33; H, 5.19; N, 12.11.