1 Introduction
In the past few years, combinatorial methods using multi-component reactions (MCRs) have been closely examined as a fast and convenient solution for the synthesis of diverse classes of compounds [1]. MCRs, defined as one-pot reactions in which at least three molecule groups join through covalent bonds, have been steadily gaining importance in synthetic organic chemistry [1,2]. In the current work, we have elaborated a new MCR which gives wide access to annulated indenopyrazolopyridine joined to oxindole units through a spiro junction production.
Indole and indoline fragments are important moieties of a large number of natural biologically active compounds [3], and some indolines, spiro-annulated with heterocycles in the 3-position, have shown high biological activity [4]. The spirooxindole system is the core structure of many pharmacological agents and natural alkaloids [5]. For example, spirotryprostatin A and B, two natural alkaloids isolated from the fermentation broth of Aspergillus fumigatus, have been identified as novel inhibitors of microtubule assembly [5d], and pteropodine and isopteropodine have been shown to modulate the function of muscarinic serotonin receptors (Fig. 1) [5a]. Indenone-fused heterocycles represent important biological and medicinal scaffolds. The indenopyridine skeleton is present in the 4-azafluorenone group of alkaloids, represented by its simplest member onychnine (Fig. 1) [6]. Indenopyrazoles I and indenopyridazines II have been investigated as cyclin-dependent kinase [7] and selective monoamine oxidase B (MAO-B) [8] inhibitors, respectively. Indenopyridines III exhibit cytotoxic [9a], phosphodiesterase inhibitory [9b], adenosine A2A receptor antagonistic [9c], antiinflammatory/antiallergic [9d], coronary dilating [9e] and calcium modulating activities [9f]. These compounds have also been investigated for the treatment of hyperlipoproteinemia and arteriosclerosis [9g] as well as neurodegenerative diseases [9h].
Representatives of important spirooxindoles and indenone-fused heterocycles.
As part of our program aimed at developing new methodologies for the preparation of heterocyclic compounds [10], very recently, we have reported the synthesis of spiro[diindenopyridine indoline]triones [11]. Herein, we describe an efficient and catalyst-free synthetic approach to spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine indoline]diones and spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones based on a one-pot methodology.
2 Results and discussion
We found that a mixture of 1,3-indandione 1, pyrazol-5-amines 2 and isatins 3 in the absence of any catalyst in refluxing ethanol, afforded spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine indoline]diones 4 in good yields for 2 h (Scheme 1).
To obtain spirooxindole annulated indenopyrazolopyridine, we used four pyrazol-5-amines 2a-d and a wide diversity of isatins 3a-l, substituted both in aromatic nucleus and at N-1. In this method, twenty-four new compounds 4a-x were selectively synthesized by the one-pot, three-component condensation of 1,3-indandione 1, 1H-pyrazol-5-amines 2 and isatins 3 in good yields without using any catalyst. The results are summarized in Table 1.
Synthesis of spiro[indoline-pyrazolopyridopyrimidine] derivatives 4.
| Product 4 | Ar | X | R | Yield (%)a |
| a | C6H5 | H | H | 85 |
| b | C6H5 | Br | H | 87 |
| c | C6H5 | NO2 | H | 91 |
| d | C6H5 | Me | H | 80 |
| e | C6H5 | F | H | 92 |
| f | C6H5 | H | Me | 75 |
| g | C6H5 | H | Et | 76 |
| h | C6H5 | H | PhCH2 | 73 |
| i | C6H5 | Br | Me | 84 |
| j | C6H5 | Br | Et | 85 |
| k | C6H5 | NO2 | Me | 87 |
| l | C6H5 | NO2 | Et | 82 |
| m | 4-NO2-C6H4 | H | H | 91 |
| n | 4-NO2-C6H4 | Br | H | 93 |
| o | 4-NO2-C6H4 | NO2 | H | 94 |
| p | 4-NO2-C6H4 | H | Me | 89 |
| q | 4-NO2-C6H4 | H | Et | 87 |
| r | 4-MeO-C6H4 | H | H | 80 |
| s | 4-MeO-C6H4 | NO2 | H | 91 |
| t | 4-MeO-C6H4 | H | Et | 88 |
| u | 4-Br-C6H4 | H | H | 80 |
| v | 4-Br-C6H4 | Br | H | 82 |
| w | 4-Br-C6H4 | NO2 | H | 91 |
| x | 4-Br-C6H4 | H | Me | 88 |
a Isolated yields
Recently, we have reported several isatin based three components reactions for the synthesis of spirooxindole in the presence of p-TSA as a catalyst [12]. Herein, we used p-TSA as a catalyst in the reaction but we did not observe the significant effect of catalyst on the yields and reaction times. In the previous work the catalyst had a significant effect on the reaction but it must be emphasized that the substrate used was also different from the present work. Thus, meaningful comparison (structural etc.) is not straightforward. To the best of our knowledge, this new procedure provides the first example of a catalyst-free synthesis of spirooxindole annulated indenopyrazolopyridine. The reactions in ethanol under catalyst-free are considerably safe, nontoxic, environmentally friendly, and inexpensive. The absence of catalyst for the reaction allows avoiding the use of moisture-sensitive and heavy metal-containing Lewis acids. This method is simple and convenient and would be applicable for the synthesis of different types of spiroindoline-pyrazolopyridopyrimidine derivatives. In addition, the workup of these very clean reactions involves only a filtration and simple washing step with EtOH. Using this simple purification protocol the desired products are obtained in high purity.
As expected, when the isatin 3 was replaced by acenaphthylene-1,2-dione 5, 1′-aryl-3′-phenyl-1′H,2H-spiro[acenaphthylene-1,4′-indeno[1,2-b]pyrazolo[4,3-e]pyridine]-2,5′(10′H)diones 6 were obtained in good yields under the same reaction conditions (Scheme 2).
To further explore the potential of this protocol for spirooxindole synthesis, we investigated the reaction of 1,3-indandione 1 and isatin 3 with 2,6-diaminopyrimidin-4(3H)-one 7 and obtained 2-amino-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones 8a-j in 73–82% yields under the same reaction conditions (Scheme 3).
Compounds 4, 6 and 8 are stable solids whose structures were established by IR, 1H, and 13C NMR spectroscopy and elemental analysis.
3 Conclusions
In conclusion, we have described a facile, catalyst-free and three-component method for the synthesis of spiro[indenopyrazolopyridine indoline]diones, spiro[acenaphthylene-indenopyrazolopyridine]diones and spiro[indenopyridopyrimidine indoline]triones in ethanol using readily available starting materials. Prominent among the advantages of this new method are operational simplicity, good yields in short reaction times and easy work-up procedures employed.
4 Experimental
4.1 Materials and techniques
Melting points were measured on an Elecrtothermal 9100 apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13 and 75.47 MHz, respectively. 1H and 13C NMR spectra were obtained on solutions in DMSO-d6 using TMS as internal standard. Due to very low solubility of the products 4u-x, 8d,e and 8g-i we cannot report the 13C NMR data for these products. IR spectra were recorded using an FTIR apparatus. Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer.
The chemicals used in this work were obtained from Fluka and Merck and were used without purification.
4.2 General procedure for preparation of spiro[indenopyrazolopyridine indoline]diones(4), spiro[acenaphthylene-1,4′-indenopyrazolopyridine]diones (6) and spiro[indenopyridopyrimidine indoline]triones (7)
A mixture of 1,3-indandione 1 (1 mmol), 1,3-diphenyl-1H-pyrazol-5-amine 2 or 2,6-diaminopyrimidin-4(3H)-one 7 (1 mmol) and isatin 3 or acenaphthylene-1,2-dione 5 (1 mmol) in refluxing ethanol (5 mL) was stirred for 2 h. After completion of the reaction confirmed by TLC (eluent: EtOAc/n-hexane, 2:1), the reaction mixture was cooled to room temperature. Then, the precipitated product was filtered and washed with water (10 mL) and methanol (5 mL) to afford the pure product.
4.3 Spectral data
1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo [4,3-e]pyridine-4,3′-indoline]-2′,5(10H) -dione (4a): orange powder (yield 85%). m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3435, 3164, 1680, 1669.1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.70–7.84 (18H, m, H-Ar), 10.32 (1H, s, NH), 11.22 (1H, s, NH).13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.8, 103.1, 106.9, 109.7, 120.7, 121.1, 122.2, 124.9, 126.0, 128.1, 128.5, 128.7, 130.1, 130.9, 132.2, 133.0, 134.1, 136.6, 136.7, 138.2, 139.4, 142.4, 150.2, 156.7, 178.8, 189.5. Anal. Calcd for C32H20N4O2: C, 78.03; H, 4.09; N, 11.38%. Found: C, 77.92; H, 4.01; N, 11.30%.
5′-Bromo-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline] -2′,5(10H)-dione (4b). Orange powder (yield 87%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3461, 3195, 1701, 1674. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.61–7.84 (17H, m, H-Ar), 10.46 (1H, s, NH), 11.30 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.9, 102.5, 106.1, 111.6, 113.9, 120.8, 121.2, 125.0, 127.6, 128.2, 128.5, 128.6, 128.7, 130.0, 131.0, 131.4, 132.2, 132.9, 134.1, 136.6, 138.2, 138.8, 139.5, 141.7, 150.1, 157.0, 178.6, 189.4. Anal. Calcd for C32H19BrN4O2: C, 67.26; H, 3.35; N, 9.80. Found: C, 67.25; H, 3.44; N, 9.72.
5′-Nitro-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4c). Orange powder (yield 91%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3482, 3153, 1680, 1627. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.81–8.08 (17H, m, H-Ar), 11.06 (1H, s, NH), 11.44 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.7, 102.1, 105.3, 109.7, 120.5, 120.9, 121.5, 125.1, 126.1, 128.2, 128.5, 128.7, 130.0, 131.1, 132.3, 132.7, 134.0, 136.5, 137.1, 138.1, 139.6, 142.9, 148.9, 150.1, 157.4, 179.6, 189.4. Anal. Calcd for C32H19N5O4: C, 71.50; H, 3.56; N, 13.03% Found: C, 71.59; H, 3.49; N, 12.96.
5′-Methyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline] -2′,5(10H)-dione (4d). Orange powder (yield 80%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3540, 3148, 1695, 1680. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.19 (3H, s, CH3), 6.58–7.81 (17H, m, H-Ar), 10.21 (1H, s, NH), 11.20 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 21.1, 47.8, 103.1, 107.1, 109.5, 120.7, 121.0, 124.9, 125.3, 128.0, 128.5, 129.0, 130.1, 131.1, 132.2, 133.1, 134.1, 136.6, 136.9, 138.2, 139.4, 139.4, 140.0, 150.1, 156.6, 178.7, 189.5. Anal. Calcd for C33H22N4O2: C, 78.25; H, 4.38; N, 11.06% Found: C, 78.11; H, 4.32; N, 10.96.
5′-Fluoro-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline] -2′,5(10H)-dione (4e). Orange powder (yield 92%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3420, 3231, 1721, 1701. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.63–7.85 (17H, m, H-Ar), 10.32 (1H, s, NH), 11.25 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 48.3, 102.7, 106.2, 110.3, 120.8, 121.2, 124.9, 128.1, 128.5, 128.6, 130.1, 130.9, 132.2, 132.9, 134.1, 136.6, 138.0, 138.2, 138.6, 139.5, 150.1, 157.0, 179.0, 189.4. Anal. Calcd for C32H19FN4O2: C, 75.28; H, 3.75; N, 10.97% Found: C, 75.15; H, 3.82; N, 11.04.
1′-Methyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline] -2′,5(10H)-dione (4f). Orange powder (yield 75%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3164, 1685, 1622. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.87 (3H, s, NCH3), 6.72–7.83 (18H, m, H-Ar), 11.30 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 26.4, 47.2, 103.3, 106.5, 108.5, 120.7, 121.2, 123.0, 124.5, 124.9, 128.0, 128.4, 128.6, 128.8, 130.1, 130.9, 132.2, 132.8, 134.1, 135.7, 136.7, 138.2, 139.3, 143.4, 150.1, 157.0, 177.2, 189.4. Anal. Calcd for C33H22N4O2: C, 78.25; H, 4.38; N, 11.06% Found: C, 78.15; H, 4.30; N, 10.96.
1′-Ethyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4 g). Orange powder (yield 76%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1685, 1622. 1HNMR (300 MHz, DMSO-d6): δH (ppm) 0.87 (3H, t, 3JHH = 6.9 Hz, CH3), 3.42–3.52 (2H, m, CH2), 6.70–7.85 (18H, m, H-Ar), 11.27 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 12.3, 34.7, 47.3, 103.0, 106.7, 108.6, 120.8, 121.1, 122.8, 124.8, 124.9, 128.1, 128.5, 128.6, 128.9, 130.1, 130.9, 132.2, 133.0, 134.1, 136.1, 136.6, 138.2, 139.4, 142.9, 150.1, 156.8, 176.6, 189.4. Anal. Calcd for C34H24N4O2: C, 78.44; H, 4.65; N, 10.76% Found: C, 78.35; H, 4.59; N, 10.69.
1′-Benzyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline] -2′,5(10H)-dione (4 h). Orange powder (yield 73%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1701, 1690. 1H NMR (300 MHz, DMSO-d6): δH (ppm), 4.18 and 4.90 (2H, ABq, 2JHH = 15.2 Hz, CH2), 6.47–7.85 (24H, m, H-Ar), 11.36 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 44.0, 47.4, 103.2, 106.3, 109.2, 120.9, 121.2, 123.1, 124.7, 124.9, 127.4, 127.5, 128.1, 128.5, 128.9, 130.1, 132.3, 132.7, 134.1, 135.7, 136.3, 136.6, 138.2, 142.7, 150.2, 157.2, 177.6, 189.6. Anal. Calcd for C39H26N4O2: C, 80.39; H, 4.50; N, 9.62% Found: C, 80.50; H, 4.58; N, 9.55.
5′-Bromo-1′-methyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4i). Orange powder (yield 84%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3169, 1695, 1622. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.87 (3H, s, NCH3), 6.76–7.87 (17H, m, H-Ar) 11.37 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 26.6, 47.3, 102.7, 105.7, 110.4, 114.7, 120.8, 121.4, 125.0, 127.3, 128.1, 128.4, 128.7, 130.0, 131.0, 131.5, 132.3, 132.7, 134.1, 136.6, 137.7, 138.1, 139.4, 142.8, 150.0, 157.3, 176.9, 189.4. Anal. Calcd for C33H21BrN4O2: C, 67.70; H, 3.62; N, 9.57% Found: C, 67.61; H, 3.56; N, 9.50.
5′-Bromo-1′-ethyl-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4j). Orange powder (yield 85%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3169, 1715, 1685. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 0.86 (3H, t, 3JHH = 6.9 Hz, CH3), 3.42–3.52 (2H, m, CH2), 6.74–7.84 (17H, m, H-Ar) 11.35 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 12.2, 34.8, 47.4, 102.3, 105.9, 110.6, 114.5, 120.8, 121.3, 125.0, 127.6, 128.2, 128.4, 128.6, 128.7, 130.0, 131.0, 131.6, 132.3, 132.8, 134.0, 136.6, 138.2, 139.6, 142.2, 150.0, 157.1, 176.3, 189.4. Anal. Calcd for C34H23BrN4O2: C, 68.12; H, 3.87; N, 9.35% Found: C, 68.23; H, 3.79; N, 9.46.
1′-Methyl-5′-nitro-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4k). Orange powder (yield 87%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1701, 1685. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.98 (3H, s, NCH3), 6.76–7.14 (17H, m, H-Ar) 11.51 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 26.9, 47.0, 102.2, 108.7, 120.1, 120.9, 121.6, 125.1, 126.1, 128.2, 128.5, 128.7, 130.0, 131.1, 132.5, 136.2, 136.6, 138.1, 143.4, 149.3, 150.1, 178.1. Anal. Calcd for C33H21N5O4: C, 71.86; H, 3.84; N, 12.70% Found: C, 71.94; H, 3.76; N, 12.62.
1′-Ethyl-5′-nitro-1,3-diphenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4l). Orange powder (yield 82%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1695, 1664. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 0.91 (3H, bs, CH3), 3.48–3.61 (2H, m, CH2), 6.74–8.21 (17H, m, H-Ar) 11.48 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 12.2, 35.3, 47.2, 101.9, 105.2, 108.8, 120.3, 120.9, 121.6, 125.1, 126.2, 128.3, 128.5, 128.7, 130.0, 131.1, 132.3, 132.6, 134.0, 136.6, 138.1, 139.7, 143.3, 148.9, 150.1, 157.4, 177.6, 189.4. Anal. Calcd for C34H23N5O4: C, 72.20; H, 4.10; N, 12.38% Found: C, 72.09; H, 4.03; N, 12.49.
1-(4-Nitrophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4m). Orange powder (yield 91%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3409, 3137, 1711, 1706. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.66–8.49 (17H, m, H-Ar), 10.37 (1H, s, NH), 11.30 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.8, 94.6, 104.1, 107.1, 109.8, 120.9, 122.3, 125.0, 125.5, 128.1, 128.5, 128.8, 131.0, 132.3, 132.4, 132.8, 136.4, 136.5, 140.0, 142.3, 143.1, 146.5, 151.7, 156.7, 178.7, 189.5. Anal. Calcd for C32H19N5O4: C, 71.50; H, 3.56; N, 13.03% Found: C, 71.63; H, 3.64; N, 13.11.
5′-Bromo-1-(4-nitrophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4n). Orange powder (yield 93%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3425, 3174, 1706, 1674. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.61–8.51 (16H, m, H-Ar), 10.53 (1H, s, NH), 11.40 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.9, 103.5, 106.4, 111.6, 113.9, 121.0, 125.2, 125.5, 127.8, 128.2, 128.4, 128.9, 131.1, 131.6, 132.3, 133.9, 136.5, 138.5, 140.2, 141.6, 143.1, 146.6, 151.5, 157.0, 178.4. Anal. Calcd for C32H18BrN5O4: C, 62.35; H, 2.94; N, 11.36% Found: C, 62.21; H, 2.83; N, 11.43.
5′-Nitro-1-(4-nitrophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4o). Orange powder (yield 94%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3331, 2918, 2840, 1701, 1685. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.81–8.52 (16H, m, H-Ar), 11.09 (1H, s, NH), 11.51 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.7, 103.1, 109.8, 120.7, 121.1, 121.3, 125.4, 125.5, 126.2, 128.3, 128.5, 129.0, 131.2, 132.2, 132.5, 136.5, 136.8, 142.9, 143.1, 146.7, 148.8, 151.5, 179.4. Anal. Calcd for C32H18N6O6: C, 65.98; H, 3.11; N, 14.43% Found: C, 65.90; H, 3.05; N, 14.38.
1′-Methyl-1-(4-nitrophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine -4,3′-indoline]-2′,5(10H)-dione (4p). Orange powder (yield 89%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3143, 1680, 1612. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.87 (3H, s, CH3), 6.73–8.51 (17H, m, H-Ar), 11.38 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 26.5, 47.1, 104.3, 106.7, 108.5, 120.9, 121.0, 123.0, 124.5, 125.0, 125.5, 128.1, 128.4, 128.8, 129.0, 131.0, 132.2, 132.4, 133.8, 135.3, 136.6, 143.1, 143.4, 146.5, 151.6, 177.0. Anal. Calcd for C33H21N5O4: C, 71.86; H, 3.84; N, 12.70% Found: C, 71.73; H, 3.75; N, 12.60.
1′-Ethyl-1-(4-nitrophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-
4,3′-indoline]-2′,5(10H)-dione (4q). Orange powder (yield 87%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3153, 1695, 1690. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 0.87 (3H,t, 3JHH = 6.3 Hz, CH3), 3.41–3.54 (2H, m, CH2), 6.70–8.51 (17H, m, H-Ar), 11.35 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 12.2, 34.7, 47.3, 103.9, 107.0, 108.7, 121.0, 122.9, 124.8, 125.0, 125.5, 128.2, 128.4, 128.8, 129.0, 131.0, 132.4, 133.8, 135.7, 136.5, 140.1, 142.8, 143.1, 146.5, 151.6, 156.8, 176.5, 189.5. Anal. Calcd for C34H23N5O4: C, 72.20; H, 4.10; N, 12.38% Found: C, 72.10; H, 4.17; N, 12.31.
1-(4-Methoxyphenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4r). Orange powder (yield 80%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3430, 3148, 1690, 1674. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.87 (3H, s, OCH3), 6.68–7.84 (17H, m, H-Ar), 10.32 (1H, s, NH), 11.12 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.9, 56.1, 102.6, 106.8, 109.7, 115.1, 120.7, 121.0, 122.2, 124.8, 126.8, 128.0, 128.4, 128.5, 128.7, 130.8, 131.1, 132.1, 133.2, 134.2, 136.6, 136.8, 139.5, 142.4, 149.6, 156.7, 159.6, 178.9, 189.4. Anal. Calcd for C33H22N4O3: C, 75.85; H, 4.24; N, 10.72% Found: C, 75.77; H, 4.16; N, 10.84.
1-(4-Methoxyphenyl)-5′-nitro-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4s). Orange powder (yield 91%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3420, 3263, 1690, 1680. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.88 (3H, s, OCH3), 6.81–8.08 (16H, m, H-Ar), 11.05 (1H, s, NH), 11.34 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.8, 56.1, 101.6, 105.2, 109.7, 115.1, 120.5, 120.9, 121.4, 126.1, 127.0, 128.2, 128.5, 128.6, 131.0, 131.1, 132.3, 132.8, 134.1, 136.5, 137.2, 139.7, 142.9, 148.9, 149.6, 157.4, 159.7, 179.7, 18.4. Anal. Calcd for C33H21N5O5: C, 69.84; H, 3.73; N, 12.34% Found: C, 69.71; H, 3.67; N, 12.25.
1′-Ethyl-1-(4-methoxyphenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e] pyridine-4,3′-indoline]-2′,5(10H)-dione (4t). Orange powder (yield 88%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1674, 1612. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 0.86 (3H, t, 3JHH = 6.9 Hz, CH3), 3.44–3.57 (2H, m, CH2), 3.87 (3H, s, OCH3), 6.68–7.91 (17H, m, H-Ar), 11.17 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 12.3, 34.6, 47.3, 56.1, 102.4, 106.6, 108.6, 115.1, 120.7, 121.1, 122.7, 123.1, 124.7, 126.8, 128.1, 128.3, 128.4, 128.8, 130.8, 131.1, 132.1, 133.1, 134.1, 136.1, 136.6, 139.5, 142.9, 149.5, 156.7, 159.6, 174.1, 176.6, 189.4. Anal. Calcd for C35H26N4O3: C, 76.35; H, 4.76; N, 10.18% Found: C, 76.22; H, 4.69; N, 10.25.
1-(4-Bromophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine-4,3′-indoline]-2′,5(10H)-dione (4u). Orange powder (yield 80%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3440, 3143, 1691, 1621. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.66–7.83 (17H, m, H-Ar), 10.13 (1H, s, NH), 10.91 (1H, s, NH). Anal. Calcd for C32H19BrN4O2: C, 67.26; H, 3.35; N, 9.80;% Found: C, 67.35; H, 3.28; N, 9.74.
5′-Bromo-1-(4-bromophenyl)-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine -4,3′-indoline]-2′,5(10H)-dione (4v). Orange Powder (yield 82%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3425, 3130, 1687, 1629. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.68–7.98 (16H, m, H-Ar), 11.02 (1H, s, NH), 11.30 (1H, s, NH). Anal. Calcd for C32H18Br2N4O2: C, 59.10; H, 2.79; N, 8.62;% Found: C, 59.18; H, 2.70; N, 8.68
1-(4-Bromophenyl)-5′-nitro-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e]pyridine -4,3′-indoline]-2′,5(10H)-dione (4w). Orange Powder (yield 91%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3430, 3137, 1685, 1627. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.69–8.01 (16H, m, H-Ar), 11.07 (1H, s, NH), 11.35 (1H, s, NH). Anal. Calcd for C32H18BrN5O4: C, 62.35; H, 2.94; N, 11.36;% Found: C, 62.44; H, 2.99; N, 11.31.
1-(4-Bromophenyl)-1′-methyl-3-phenyl-1H-spiro[indeno[1,2-b]pyrazolo[4,3-e] pyridine-4,3′-indoline]-2′,5(10H)-dione (4x). Orange Powder (yield 88%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3420, 1711, 1695. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 2.87 (3H, s, CH3), 6.72–7.91 (17H, m, H-Ar), 11.12 (1H, s, NH). Anal. Calcd for C33H21BrN4O2: C, 67.70; H, 3.62; N, 9.57% Found: C, 67.56; H, 3.53; N, 9.50.
1′,3′-diphenyl-1′H,2H-spiro[acenaphthylene-1,4′-indeno[1,2-b]pyrazolo[4,3-e]pyridine]-2,5′(10′H)-dione (6a). Orange Powder (yield 88%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3174, 1714, 1690. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.36–8.17 (20H, m, H-Ar), 11.36 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 52.5, 104.7, 108.2, 120.7, 121.2, 121.4, 121.9, 124.9, 127.3, 128.0, 128.2, 128.6, 128.8, 129.4, 130.0, 130.1, 131.8, 132.3, 133.3, 136.8, 138.2, 141.4, 145.0, 150.3, 157.1, 189.8, 205.2. Anal. Calcd for C36H21N3O2: C, 81.96; H, 4.01; N, 7.96% Found: C, 81.85; H, 4.07; N, 7.89.
1′-(4-nitrophenyl)-3′-phenyl-1′H,2H-spiro[acenaphthylene-1,4′-indeno[1,2-b]pyrazolo[4,3-e]pyridine]-2,5′(10′H)-dione (6b). Orange Powder (yield 89; m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3190, 1685, 1648. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.36–8.52 (19H, m, H-Ar), 11.42 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 52.4, 105.7, 108.5, 121.1, 121.6, 12.0, 125.0, 127.4, 128.2, 128.3, 128.8, 129.4, 130.1, 131.0, 131.7, 131.8, 133.2, 136.7, 141.4, 143.2, 143.2, 144.7, 146.5, 151.7, 204.9. Anal. Calcd for C36H20N4O4: C, 75.52; H, 3.52; N, 9.79% Found: C, 75.40; H, 3.44; N, 9.71.
2-Amino-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8a). Light orange powder (yield 82%); m.p. 268–270 °C. IR (KBr) (νmax/cm−1): 3461, 3336, 3195, 1701, 1648, 1627. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.50–7.77 (10H, m, H-Ar, NH2), 10.23 (1H, s, NH), 10.56 (1H, s, NH), 10.92 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 47.7, 93.1, 106.5, 108.8, 120.4, 120.6, 121.4, 123.6, 127.7, 128.6, 130.8, 132.2, 133.6, 136.4, 136.5, 143.0, 154.8, 155.6, 156.1, 161.1, 179.5, 189.6. Anal. Calcd for C21H13N5O3: C, 65.79; H, 3.42; N, 18.27%. Found: C, 65.70; H, 3.37; N, 18.19.
2-Amino-5′-bromo-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8b). Light orange Powder (yield 77%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3456, 3184, 1706, 1648, 1633. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.57–7.82 (9H, m, H-Ar, NH2), 10.41 (1H, s, NH), 10.62 (1H, s, NH), 11.01 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 48.0, 92.6, 105.6, 110.8, 113.1, 120.8, 126.3, 130.5, 131.0, 132.3, 133.6, 136.3, 138.9, 142.5, 154.9, 155.7, 156.5, 161.1, 179.2, 189.6. Anal. Calcd for C21H12BrN5O3: C, 54.56; H, 2.62; N, 15.15%;. Found: C, 54.46; H, 2.68; N, 15.09.
2-Amino-5′-nitro-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8c). Orange Powder (yield 81%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3649, 3435, 3326, 1716, 1690, 1643. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.64–8.11 (9H, m, H-Ar, NH2), 10.69 (1H, s, NH), 11.05 (1H, s, NH), 11.16 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) Anal. 47.8, 92.0, 104.9, 108.9, 119.0, 120.9, 125.6, 131.1, 132.4, 133.5, 136.3, 137.4, 142.4, 149.8, 155.1, 156.0, 157.0, 161.3, 180.2, 189.6. Calcd for C21H12N6O5: C, 58.88; H, 2.82; N, 19.62% Found: C, 58.76; H, 2.90; N, 19.53.
2-Amino-5′-methyl-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8d). Light orange Powder (yield 79%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3602, 3430, 3383, 1695, 1648, 1627. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.14 (3H, s, CH3), 6.56–7.81 (9H, m, H-Ar, NH2), 10.49 (1H, s, NH), 11.00 (1H, s, NH). Anal. Calcd for C22H15N5O3: C, 66.49; H, 3.80; N, 17.62% Found: C, 66.38; H, 3.73; N, 17.54.
2-Amino-5′-fluoro-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8e). Red Powder (yield 80%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3639, 3514, 3378, 3158, 1789, 1721, 1638. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 6.55–7.79 (9H, m, H-Ar, NH2), 10.27 (1H, s, NH), 10.60 (1H, s, NH), 10.99 (1H, s, NH). Anal. Calcd for C21H12FN5O3: C, 62.84; H, 3.01; N, 17.45% Found: C, 62.70; H, 3.08; N, 17.53.
2-Amino-1′-methyl-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8f). Orange Powder (yield 78%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3382, 3174, 1704, 1648, 1630. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.13 (3H, s, CH3). 6.55–7.80 (9H, m, H-Ar, NH2), 10.48 (1H, s, NH), 10.99 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 26.7, 47.2, 107.7, 120.5, 120.6, 122.1, 123.3, 128.0, 130.9, 132.3, 133.5, 135.7, 136.4, 154.9, 155.6, 156.2, 178.0, 189.5. Anal. Calcd for C22H15N5O3: C, 66.49; H, 3.80; N, 17.62% Found: C, 66.56; H, 3.85; N, 17.51.
2-Amino-1′-ethyl-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8 g). Orange Powder (yield 77%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3446, 3336, 1701, 1680, 1648. 1HNMR (300 MHz, DMSO-d6): δH (ppm) 1.23 (3H, bs, CH3), 3.65–3.78 (2H, m, CH2), 6.57–7.81 (10H, m, H-Ar, NH2), 10.49 (1H, s, NH), 10.99 (1H, s, NH). Anal. Calcd for C23H17N5O3: C, 67.15; H, 4.16; N, 17.02% Found: C, 67.01; H, 4.07; N, 16.91.
2-Amino-5′-bromo-1′-methyl-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine -5,3′-indoline]-2′,4,6(11H)-triones (8 h). Light orange Powder (yield 78%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3479, 3382, 17014, 1648, 1630, 1603. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.12 (3H, s, CH3), 6.61–7.81 (9H, m, H-Ar, NH2), 10.53 (1H, s, NH), 11.07 (1H, s, NH). Anal. Calcd for C22H14BrN5O3: C, 55.48; H, 2.96; N, 14.70% Found: C, 55.40; H, 3.02; N, 14.77.
2-Amino-5′-bromo-1′-ethyl-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine -5,3′-indoline]-2′,4,6(11H)-triones (8i). Yellow Powder (yield 73%); m.p. > 300 °C. IR (KBr) (νmax/cm−1): 3446, 3336, 1701, 1680, 1648. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 1.19 (3H, bs, CH3), 3.70 (2H, bs, CH2), 6.61–7.81 (9H, m, H-Ar, NH2), 10.51 (1H, s, NH), 11.04 (1H, s, NH). Anal. Calcd for C23H16BrN5O3: C, 56.34; H, 3.29; N, 14.28% Found: C, 56.23; H, 3.21; N, 14.22.
2-Amino-1′-methyl-5′-nitro-1H-spiro[indeno[1,2-b]pyrido[2,3-d]pyrimidine-5,3′-indoline]-2′,4,6(11H)-triones (8j). Orange Powder (yield 76%); m.p. 270–272 °C. IR (KBr) (νmax/cm−1): 3566, 3346, 3211, 1701, 1669, 1643. 1H NMR (300 MHz, DMSO-d6): δH (ppm) 3.25(3H, s, CH3), 6.68–8.19 (10H, m, H-Ar, NH2), 10.65 (1H, s, NH), 11.22 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): δC (ppm) 27.32, 47.2, 91.8, 104.7, 107.9, 118.7, 120.9, 121.0, 125.7, 131.2, 132.5, 133.4, 136.2, 136.6, 142.9, 150.7, 155.1, 156.1, 157.1, 161.2, 178.9, 189.6. Anal. Calcd for C22H14N6O5: C, 59.73; H, 3.19; N, 19.00% Found: C, 59.92; H, 3.11; N, 19.09.
Acknowledgements
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University.