Silica sodium carbonate: the most efficient catalyst for the one-pot synthesis of indeno[1,2-b]quinoline and spiro[chromene-4,3′-indoline]-3-carbonitriles under solvent-free condition

Abstract

A new silica sodium carbonate-assisted convenient and efficient strategy for the synthesis of indeno[1,2-b]quinoline and spiro[chromene-4,3′-indoline]-3-carbonitriles derivatives in solvent-free media is described. The reactions can be performed at low catalyst loadings with excellent functional group tolerance. The catalyst can be easily recovered and reused for the next reaction for at least three runs without any significant impact on the yields of the products. The easy recovery of the catalyst and high yield of the products make the protocol attractive, sustainable, and economic.

Graphical abstract

Introduction

Heterocycles are ubiquitous in natural products, pharmaceuticals, organic materials, and numerous functional molecules. Therefore, the interest for developing new, versatile, and efficient synthesis of heterocycles has always been a challenge in the synthetic community [1]. Indeno[1,2-b]quinoline and its derivatives are very useful compounds in various fields of chemistry, including biological and pharmacological chemistry. Some of these compounds exhibit antimalarials [2], antitumor agents [3, 4], new potential topo I/II inhibitors [5, 6], steroid reductase inhibitors [7], acetylcholinesterase inhibitors [8], 5-HT-receptor binding [9], and anti-inflammatory activities [10]. In recent years, numerous protocols for preparation of indeno[1,2-b]quinoline have been developed in different ways by using acetic acid [11], p-toluenesulfonic acid [12] with microwave irradiations, ionic liquid [bmim][BF₄] [13], heteropolyacid H₁₄[NaP₅W₃₀O₁₁₀] [14], and TiO₂ [15, 16] as a catalyst. These reported methodologies produce good results in many instances. However, some of the synthetic strategies suffer with certain limitations such as expensive catalysts, low yields of products, long reaction times, tedious procedures for preparations of catalysts, tedious work-up conditions, and all are failed to show oxidized product. Hence, the development of efficient, simple, easy work-up, and environmentally benign protocol using a recyclable catalyst and solvent-free condition for the synthesis of indeno[1,2-b]quinoline derivatives is still desirable and in demand. In the recent years, heterogeneous catalysts have found increased application in organic synthesis as they are efficient, easily recovered and recycled [17, 18]. Although supported catalysts are available on different supports, including charcoal, alumina, silica, and polymer, silica has many other advantages such as no swelling, good mechanical and thermal stability, and ease of scalability. It is evident from the previous literature that silica-supported catalyst has invoked enormous interest as a potential green, heterogenous, and eco-friendly catalyst to construct carbon–carbon and carbon-heteroatom bonds in various organic transformations [19–21]. In this connection, silica sodium carbonate (SSC) has invoked tremendous attention as a green and heterogenous catalyst. The use of the SSC catalyst has several advantages over a conventional catalyst, such as its ease of handling (as a bench top catalyst), stable, inexpensive, recyclability, and reusability. Despite its great importance, few paper reported on its catalytic application in organic synthesis [22].

In continuation of our research in exploring new [23] and practical multicomponent reactions to synthesize useful heterocyclic compounds [24–26], we disclosed a novel methodology for synthesis of indeno[1,2-b]quinoline by condensation of 2,3-dihydro-1H-inden-5-amine with aromatic aldehydes and 2H-indene-1,3-dione in the presence of silica sodium carbonate under solvent-free condition at 50 °C (Scheme 1).

Results and discussion

To optimize the reaction condition, we began our examination of the reaction of 2,3-dihydro-1H-inden-5-amine, 4-methylbenzaldehyde, and 2H-indene-1,3-dione in the presence of different catalysts and solvents (Table 1). To establish the real effectiveness of the catalyst for the synthesis of indeno[1,2-b]quinoline derivatives, the test reaction was performed without catalyst in neat condition at 50 °C. It was found that only a 22 % amount of product was obtained in the absence of catalyst even after 8 h (Table 1, entry 1).

Table 1 Optimization of catalysts, solvents, and temperature in the synthesis of 4a

In search of effective, eco-friendly, and efficient, reusable catalytic system for this reaction, the same test reaction was performed with different supported metal Lewis acid catalysts such as Cu–Sn (200 mesh, 100 mg), FeCl₃·SiO₂, SiO₂, STA, BF₃·SiO₂ Zn(OTf)₂, SSC, Li(OTf), SnCl₂·2H₂O, and TiO₂·SiO₂. Among all screened catalysts, SSC gave the best result in view of yield and reaction time (Table 1, entry 8). In contrast, Cu–Sn (200 mesh, 100 mg), STA, SiO₂, Zn(OTf)₂, ZnCl₂, Li(OTf), and SnCl₂·2H₂O did not afford the desired product in good yields (Table 1, entries 2–6, 11, 12). SSC was shown to be more effective than STA in terms of yield and time for completion of the reaction (Table 1, entries 8 and 14).

To assess the effect of solvents on this reaction, we screened different solvents such as toluene, EtOH, ACN, DMF, ethylene glycol, methanol, water, and THF. It was observed that under solvent condition required longer times (2–4 h) to afford comparable yields (Table 1, entries 15–21). When the reaction was performed under solvent-free conditions, high yield of target product was obtained (Table 1, entry 8). Moreover, we found that the yields were affected by the amount of SSC loaded. When 10, 5, and 20 mol% of SSC were used, the yields were 94, 90, and 88 %, respectively (Table 1, entries 8, 22, 23). Therefore, 10 mol% of SSC was sufficient and optimal quantity for the completion of the reaction.

Thus, we selected the optimized reaction condition to examine the universality of this catalyst application with different electron-rich and -deficient substrates. It was gratifying to observe that most of the tested substrates exhibited satisfactory reactivity profiles, in all cases leading to a cyclization sequence that easily afforded the target structures (Table 2). Various substituted aldehydes undergo the reaction in the presence of catalytic amount of SSC (10 mol%) in neat condition at 50 °C. Compared with aromatic aldehydes, aliphatic aldehydes do not afford targeted product indeno[1,2-b]quinoline (Table 2, entry 11).

Table 2 Synthesis of indeno[1,2-b]quinoline catalyzed by SSC

On the other hand, to check the efficiency of the silica sodium carbonate, we used SSC catalyst for the synthesis of spiro[chromene-4,3′-indoline]-3-carbonitriles by one-pot condensation of isatin, malononitrile/ethyl cyanoacetate, and cyclic 1,3-dicarbonyl compounds (Scheme 2). Many methods have been developed for the construction of spiro[chromene-4,3′-indoline]-3-carbonitrile building blocks [27–35]. Although these methods insure good results in many instances, there is still a great demand for rapid and environment-friendly catalytic reaction conditions; for our best knowledge, nobody reported synthesis spiro[chromene-4,3′-indoline]-3-carbonitriles using silica sodium carbonate as a heterogeneous catalyst under solvent-free condition.

First, a mixture of isatin, dimedone, and malononitrile at 50 °C solvent-free condition was chosen as a model reaction to detect whether the use of SSC as catalyst was efficient and to investigate the optimized conditions. The results are summarized in Table 3.

Table 3 Detection of the reaction conditions

Increasing the amount of catalyst from 5 to 10 mol% could improve the reaction significantly. Inspired by the results, we changed the amount of the catalyst from 10 to 15 mol%, finding that 10 mol% of SSC was good enough (Table 3). The optimized conditions were used to construct a variety of spiro[chromene-4,3′-indoline]-3-carbonitrile derivatives. It was found that this method is effective with a variety of isatin, malononitrile/ethyl cyanoacetate, and 1,3-dicarbonyl compounds (Table 4). All the structures of synthesized compounds 4a–4j and 7a–7w have been ascertained on the basis of ¹H NMR, ¹³C NMR, and HRMS data.

Table 4 Synthesis of spiro[chromene-4,3′-indoline]-3-carbonitriles catalyzed by SSC

A possible mechanism for the indeno[1,2-b]quinoline cyclic ring formation is outlined in Scheme 3. The cyclization looks to proceed as a domino sequence of Knoevenagel condensation and Michael-type addition reaction using catalytic amount of SSC which in all step acted as an accelerator. The well-known reaction of 2H-indene-1,3-dione with benzaldehyde leads to the formation of the standard 2-benzylidene-2H-indene-1,3-dione adducts 8, which then could undergo Michael-type addition reaction with 1H-inden-5-amine 1 to form an adduct 9. The adduct 9 formed could then cyclized intramolecularly to give 10, which could then lose water, followed by air oxidation to afford indeno[1,2-b]quinoline ring systems 4.

The reusability of the SSC catalyst is one of the most important benefits and makes it useful for commercial applications as well. Thus, the recovery and reusability of the catalyst were investigated. The recyclability of the catalyst was checked with the model reaction (Table 5, entries 1–4). The catalyst was recovered after completion of the first fresh run, the reaction mixture cooled to room temperature, and then ethyl acetate was added. The product was dissolved in ethyl acetate and catalyst was separated by filtration. The recovered catalyst was dried at 70 °C for 12 h and tested in up to three more fresh substrates under the same conditions. The catalyst showed excellent recyclability in all these reactions (Table 5), as the reaction times and yield remained almost the same without having a loss of catalytic activity.

Table 5 Recycling and reuse of SSC on the synthesis of 4a

Conclusion

In this work, we have described a successful strategy for the efficient and convenient preparation of indeno[1,2-b]quinoline using silica sodium carbonate as catalyst in neat condition by intramolecular cyclization of 2,3-dihydro-1H-inden-5-amine, aldehyde, and 2H-indene-1,3-dione. It was suggested that silica sodium carbonate shows high catalytic activity. Moreover, silica sodium carbonate also used for the synthesis of spiro[chromene-4,3′-indoline]-3-carbonitriles, and can be easily recovered and reused for at least three runs without any significant impact on the yield of the products. The current strategy offers several advantages such as high yields and purity of products, low amount of catalyst, safe, cheap, and environmentally benign, and an easy experimental work-up procedure. Furthermore, we are trying our best to develop more reaction by using SSC as a catalyst in an environmental way and the related work is underway in our laboratory.

Experimental

Chemicals were purchased from Aldrich and Alfa Aesar Chemical Companies. NMR spectra were recorded in parts per million (ppm) in DMSO-d ₆ and CDCl₃ on a Jeol JNM ECP 400 NMR instrument using TMS as internal standard. Mass spectra were recorded on a Jeol JMS-700 mass spectrometer. All melting points were determined using open capillaries on an Electrothermal-9100 (Japan) instrument.

Two-step preparation of SSC

Silica sodium carbonate was prepared by adopting the literature [22].

Step 1: To a 250 cm³ round bottom flask equipped with a reflux condenser, in which the hose interface was connected to a pot of water, 10 g of silica gel 60 (63–200 μm) that was previously dried at 120 °C for 6 h was added. Then 40 cm³ of thionyl chloride was added dropwise to this flask which was perched in an ice bath (caution). After the addition of thionyl chloride, the reaction mixture was removed from the ice bath and stirred for 0.5 h in room temperature and 48 h under reflux conditions. Afterwards, the reaction mixture was filtrated to obtain silica chloride.

Step 2: To a stirred 250 cm³ round bottom flask containing 10 g of sodium bicarbonate and 25 cm³ of n-hexane under reflux conditions, 10 g of silica chloride (after drying at 120 °C for 6 h) was added. After 24 h, the reaction mixture was filtrated to separate the catalyst and the solid product was washed with 50 cm³ of distilled water ten times, using 5 cm³ each time until filtrate became quite neutral, to remove the remaining sodium bicarbonate. Finally, drying at 100 °C for 12 h afforded SSC.

General procedure for indeno[1,2-b]quinolines 4a–4j

A mixture of aldehyde (1 mmol), 2H-indene-1,3-dione (1 mmol), 2,3-dihydro-1H-inden-5-amine (1 mmol), and SSC (10 mol%) was stirred at 50 °C under solvent-free condition. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated, and the crude product was recrystallized from ethanol to afford the pure product. Used catalyst from different experiments was combined, washed with ethyl acetate, and dried overnight in a vacuum oven and reused.

General procedure for spiro[chromene-4,3′-indoline]-3-carbonitriles 7a–7w

A mixture of isatin (1 mmol), malononitrile/ethyl cyanoacetate (1 mmol), 1,3-dicarbonyl compounds (1 mmol), and SSC (10 mol%) was stirred at 50 °C under solvent-free condition. The reactions were followed by thin layer chromatography (TLC) using hexane/ethyl acetate as an eluent. After completion of the reaction, the mixture was washed with ethyl acetate and filtered to recover the catalyst. The filtrate was evaporated, and the crude product was recrystallized from ethanol to afford the pure product.

11-(p-Tolyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4a, C₂₆H₁₉NO)

R _f  = 0.33 (hexane/ethyl acetate 7:3); m.p.: 260–262 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.08–2.16 (m, 2H, CH₂), 2.50 (s, 3H, CH₃), 2.92 (t, J = 7.3 Hz, 2H, CH₂), 3.08 (t, J = 7.3 Hz, 2H, CH₂), 7.31 (d, J = 8.1 Hz, 2H, ArH), 7.37 (d, J = 8.1 Hz, 2H, ArH), 7.43 (t, J = 7.4 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.62 (t, J = 7.7 Hz, 1H, ArH), 7.66 (d, J = 7.3 Hz, 1H, ArH), 7.93 (s, 1H, ArH), 8.06 (d, 1H, J = 7.7 Hz, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 21.61, 25.98, 32.63. 33.07, 121.42, 122.16, 122.87, 123.67, 124.59, 126.94, 128.91, 129.45, 130.50, 131.15, 135.06, 137.64, 138.66, 143.54, 144.87, 148.02, 150.21, 150.32, 161.37, 190.67 ppm; HRMS (ESI): m/z calcd for C₂₆H₁₉NO 361.1466, found 361.1464.

11-(2-Chloro-6-fluorophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4b, C₂₅H₁₅ClFNO)

R _f  = 0.29 (hexane/ethyl acetate 7:3); m.p.: 190–192 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.12–2.19 (m, 2H, CH₂), 2.98 (t, J = 7.3 Hz, 2H, CH₂), 3.12 (t, J = 7.3 Hz, 2H, CH₂), 7.27 (s, 1H, ArH), 7.41 (d, J = 7.7 Hz, 1H, ArH), 7.46 (d, J = 8.1 Hz, 1H, ArH), 7.64 (d, 1H, ArH), 7.69 (t, J = 7.3 Hz, 1H, ArH), 7.82–7.84 (m, 1H, ArH), 7.95–7.98 (m, 1H, ArH), 8.00 (s, 1H, ArH), 8.11 (d, 1H, J = 7.7 Hz, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 25.95, 32.65, 33.18, 121.48, 121.68, 123.44, 123.96, 124.92, 125.26, 125.51, 125.91, 128.80, 130.93, 131.34, 135.40, 135.84, 137.61, 142.00, 143.88, 145.67, 150.41, 151.00, 161.12, 190.23 ppm; HRMS (ESI): m/z calcd for C₂₅H₁₅ClFNO 399.0826, found 399.0825.

11-(4-Fluorophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4c, C₂₅H₁₆FNO)

R _f  = 0.33 (hexane/ethyl acetate 7:3); m.p.: 246–248 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.11–2.18 (m, 2H, CH₂), 2.94 (t, J = 7.3 Hz, 2H, CH₂), 3.10 (t, J = 7.3 Hz, 2H, CH₂), 7.26 (d, J = 8.8 Hz, 2H, ArH), 7.38–7.43 (m, 3H, ArH), 7.46 (d, J = 7.3 Hz, 1H, ArH), 7.63 (d, J = 8.4 Hz, 1H, ArH), 7.67 (d, J = 7.7 Hz, 1H, ArH), 7.95 (s, 1H, ArH), 8.07 (d, J = 7.7 Hz, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 26.98, 32.67, 33.10, 115.28, 115.49, 121.52, 122.52, 123.77, 124.73, 126.76, 131.29, 131.38, 131.46, 135.24, 137.54, 143.53, 145.18, 146.63, 150.28, 150.58, 161.30, 190.66 ppm; HRMS (ESI): m/z calcd for C₂₅H₁₆FNO 365.1215, found 365.1217.

11-(4-Chlorophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4d, C₂₅H₁₆ClNO)

R _f  = 0.30 (hexane/ethyl acetate 7:3); m.p.: 274–276 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.09–2.17 (m, 2H, CH₂), 2.92 (t, J = 7.3 Hz, 2H, CH₂), 3.08 (t, J = 7.3 Hz, 2H, CH₂), 7.36 (d, J = 8.4 Hz, 2H, ArH), 7.38 (s, 1H, ArH), 7.44 (t, J = 7.3 Hz, 1H, ArH), 7.53 (d, J = 8.4 Hz, 2H, ArH), 7.61–7.67 (m, 2H, ArH), 7.93 (s, 1H, ArH), 8.06 (d, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 25.99, 32.67, 33.12, 121.51, 122.44, 123.80, 124.79, 126.53, 128.57, 130.94, 131.31, 131.97, 134.98, 135.27, 137.53, 143.59, 145.24, 146.26, 150.32, 150.63, 161.27, 190.59 ppm; HRMS (ESI): m/z calcd for C₂₅H₁₆ClNO 381.0920, found 381.0920.

11-(4-Bromophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4e, C₂₅H₁₆BrNO)

R _f  = 0.32 (hexane/ethyl acetate 7:3); m.p.: 286–288 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.12–2.15 (m, 2H, CH₂), 2.93 (t, J = 7.3 Hz, 2H, CH₂), 3.09 (t, J = 7.3 Hz, 2H, CH₂), 7.30 (d, J = 7.3 Hz, 2H, ArH), 7.39 (s, 1H, ArH), 7.46 (t, J = 7.7 Hz, 1H, ArH), 7.62–7.70 (m, 4H, ArH), 7.94 (s, 1H, ArH), 8.06 (d, 1H, J = 7.7 Hz, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 25.93, 32.62, 33.08, 121.48, 122.03, 122.39, 123.22, 123.74, 124.75, 126.39, 131.20, 131.26, 131.47, 132.44, 135.22, 137.47, 143.52, 145.20, 146.15, 150.23, 150.58, 161.18, 190.50 ppm; HRMS (ESI): m/z calcd for C₂₅H₁₆BrNO 425.0415, found 425.0414.

11-(2-Bromophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4f, C₂₅H₁₆BrNO)

R _f  = 0.31 (hexane/ethyl acetate 7:3); m.p.: 220–222 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.11–2.17 (m, 2H, CH₂), 2.94 (t, J = 7.3 Hz, 2H, CH₂), 3.10 (t, J = 7.7 Hz, 2H, CH₂), 7.24 (d, 2H, J = 9.5 Hz, ArH), 7.38–7.50 (m, 3H, ArH), 7.62–7.68 (m, 2H, ArH), 7.77 (d, J = 7.7 Hz, 1H, ArH), 7.98 (s, 1H, ArH), 8.09 (d, J = 7.7 Hz, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 25.96, 32.65, 33.17, 121.58, 122.21, 1213.90, 124.77, 126.18, 127.35, 130.19, 130.39, 131.30, 132.87, 135.26, 137.55, 143.85, 145.35, 145.53, 150.41, 150.78, 161.18, 190.29. ppm; HRMS (ESI): m/z calcd for C₂₅H₁₆BrNO 425.0415, found 425.0412.

11-(2-Nitrophenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4 g, C₂₅H₁₆N₂O₃)

R _f  = 0.30 (hexane/ethyl acetate 7:3); m.p.: 278–280 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.10–2.17 (m, 2H, CH₂), 2.92 (t, J = 7.3 Hz, 2H, CH₂), 3.10 (t, J = 7.3 Hz, 2H, CH₂), 7.18 (s, 1H, ArH), 7.39 (d, J = 8.4 Hz, 1H, ArH), 7.44 (t, J = 7.3 Hz, 1H, ArH), 7.64 (d, J = 7.3 Hz, 2H, ArH), 7.73 (t, J = 7.3 Hz, 1H, ArH), 7.80 (t, J = 7.3 Hz, 1H, ArH), 7.99 (s, 1H, ArH), 8.09 (d, J = 7.3 Hz, 1H, ArH), 8.37 (d, J = 9.2 Hz, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 26.79, 33.47, 33.99, 122.39, 122.51, 124.75, 125.83, 126.73, 130.74, 130.94, 132.17, 132.54, 134.38, 136.25, 144.71, 146.39, 149.29, 151.28, 151.74, 161.84, 190.76. ppm; HRMS (ESI): m/z calcd for C₂₅H₁₆N₂O₃ 392.1160, found 392.1162.

11-Phenyl-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4 h, C₂₅H₁₇NO)

R _f  = 0.33 (hexane/ethyl acetate 7:3); m.p.: 238–240 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.08–2.15 (m, 2H, CH₂), 2.91 (t, J = 7.3 Hz, 2H, CH₂), 3.07 (t, J = 7.3 Hz, 2H, CH₂), 7.41–7.44 (m, 4H, ArH), 7.55–7.57 (m, 3H, ArH), 7.60–7.66 (m, 2H, ArH), 7.93 (s, 1H, ArH), 8.06 (d, 1H, J = 7.0 Hz, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 25.97, 32.64, 33.08, 121.42, 122.14, 122.79, 123.69, 124.66, 126.79, 128.17, 128.77, 129.45, 131.17, 133.62, 135.08, 137.61, 143.59, 144.95, 147.66, 150.26, 150.37, 161.31, 190.59 ppm; HRMS (ESI): m/z calcd for C₂₅H₁₇NO 347.1310, found 347.1311.

11-(o-Tolyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4i, C₂₆H₁₉NO)

R _f  = 0.34 (hexane/ethyl acetate 7:3); m.p.: 266–268 °C; ¹H NMR (400 MHz, CDCl₃): δ = 2.02 (s, 3H, CH₃), 2.09–2.14 (m, 2H, CH₂), 2.91 (t, J = 7.0 Hz, 2H, CH₂), 3.09 (t, J = 7.0 Hz, 2H, CH₂), 7.16 (d, J = 7.3 Hz, 1H, ArH), 7.24 (s, 1H, ArH), 7.33–7.43 (m, 4H, ArH), 7.61–7.67 (m, 2H, ArH), 7.96 (s, 1H, ArH), 8.08 (d, J = 7.3 Hz, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 19.81, 25.97, 32.61, 33.13, 120.52, 121.48, 122.52, 123.74, 124.70, 125.69, 126.86, 128.72, 130.09, 131.20, 133.78, 135.11, 135.95, 137.61, 143.77, 145.12, 147.26, 150.29, 150.58, 161.34, 190.68 ppm; HRMS (ESI): m/z calcd for C₂₆H₁₉NO 361.1466, found 361.1466.

11-(4-Isopropylphenyl)-2,3-dihydrocyclopenta[g]indeno[1,2-b]quinolin-10(1H)-one (4j, C₂₈H₂₃NO)

R _f  = 0.32 (hexane/ethyl acetate 7:3); m.p.: 264–266 °C; ¹H NMR (400 MHz, CDCl₃): δ = 1.37 (d, 6H, 2CH₃), 2.07–2.15 (m, 2H, CH₂), 2.91 (t, J = 7.4 Hz, 2H, CH₂), 3.01–3.08 (m, 3H, CH₂, CH), 7.35 (d, J = 8.4 Hz, 2H, ArH), 7.40–7.44 (m, 3H, ArH), 7.50 (s, 1H, ArH), 7.06 (t, J = 7.3 Hz, 1H, ArH), 7.64 (d, J = 7.3 Hz, 1H, ArH), 7.91 (s, 1H, ArH), 8.04 (d, J = 7.7 Hz, 1H, ArH) ppm; ¹³C NMR (100 MHz, CDCl₃): δ = 24.08, 26.01, 32.67, 33.09, 34.13, 121.43, 122.13, 122.99, 123.65, 124.66, 126.22, 126.96, 128.21, 129.60, 130.76, 131.16, 135.06, 137.66, 143.61, 144.84, 148.12, 149.43, 150.29, 161.40, 190.74 ppm; HRMS (ESI): m/z calcd for C₂₈H₂₃NO 389.1779, found 389.1780.

2-Amino-5′-fluoro-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (7d, C₁₉H₁₆FN₃O₃)

R _f  = 0.27 (hexane/ethyl acetate 6:4); m.p.: 288–290 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.01 (s, 3H, CH₃), 1.02 (s, 3H, CH₃), 2.14 (s, 2H, CH₂), 2.54 (s, 2H, CH₂), 6.75–6.78 (m, 1H, ArH), 6.95 (d, J = 8.8 Hz, 2H, ArH), 7.29 (s, 2H, NH₂), 10.42 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 27.32, 27.37, 31.92, 47.32, 49.95, 56.91, 109.82, 109.90, 110.31, 114.24, 117.21, 138.28, 158.85, 164.45, 178.05, 194.98 ppm; HRMS (ESI): m/z calcd for C₁₉H₁₆FN₃O₃ 353.1175, found 353.1177.

2-Amino-5′-fluoro-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (7i, C₁₇H₁₂FN₃O₃)

R _f  = 0.29 (hexane/ethyl acetate 6:4); m.p.: 307–310 °C; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 1.92 (t, J = 6.1 Hz, 2H, CH₂), 2.19–2.24 (m, 2H, CH₂), 2.64 (t, J = 5.9 Hz, 2H, CH₂), 6.76 (d, J = 7.8 Hz, 1H, ArH), 6.91–6.98 (m, 2H, ArH), 7.28 (s, 2H, NH₂), 10.42 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.72, 26.78, 36.31, 47.40, 57.00, 109.74, 109.82, 111.00, 111.39, 114.44, 117.25, 138.20, 158.71, 166.40, 178.18, 195.13 ppm; HRMS (ESI): m/z calcd for C₁₇H₁₂FN₃O₃ 325.0863, found 325.0864.

2-Amino-5′-chloro-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (7 l, C₁₇H₁₂ClN₃O₃)

R _f  = 0.30 (hexane/ethyl acetate 6:4); m.p.: 291–293 °C; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 1.87–1.98 (m, 2H, CH₂), 2.24 (t, J = 6.6 Hz, 2H, CH₂), 2.64 (t, J = 5.9 Hz, 2H, CH₂), 6.79 (d, J = 8.1 Hz, 1H, ArH), 7.14 (d, J = 2.2 Hz, 1H, ArH), 7.18 (dd, J = 2.2, 8.1 Hz, 1H, ArH), 7.31 (s, 2H, NH₂), 10.54 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 19.69, 26.77, 36.28, 47.17, 56.82, 110.54, 111.26, 117.23, 123.46, 125.61, 128.02, 136.57, 140.94, 158.73, 166.56, 177.91, 195.21 ppm; HRMS (ESI): m/z calcd for C₁₇H₁₂ClN₃O₃ 341.0567, found 341.0568.

7′-Amino-5-nitro-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carbonitrile (7o, C₁₅H₈N₆O₆)

R _f  = 0.31 (hexane/ethyl acetate 6:4); m.p.: 291–293 °C;¹H NMR (400 MHz, DMSO-d ₆ ): δ = 7.01 (d, J = 8.4 Hz, 1H, ArH), 8.15 (dd, J = 2.2, 8.4 Hz, 1H, ArH), 8.24 (d, J = 2.2 Hz, 1H, ArH), 7.55 (s, 2H, NH₂), 11.18 (s, 1H, NH), 11.22 (s, 1H, NH), 12.34 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 46.85, 56.20, 85.82, 109.43, 116.75, 120.00, 125.90, 134.64, 142.58, 148.63, 149.27, 153.90, 158.66, 161.66, 178.39 ppm; HRMS (ESI): m/z calcd for C₁₅H₈N₆O₆ 368.0505, found 368.0506.

7′-Amino-5-chloro-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carbonitrile (7p, C₁₅H₈ClN₅O₄)

R _f  = 0.28 (hexane/ethyl acetate 6:4); m.p.: 289–290 °C; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 6.79 (d, J = 8.4 Hz, 1H, ArH), 7.20 (dd, J = 2.2, 8.4 Hz, 1H, ArH), 7.33 (d, J = 2.2 Hz, 1H, ArH), 7.44 (s, 2H, NH₂), 10.61 (s, 1H, NH), 11.15 (s, 1H, NH), 12.31 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 46.95, 57.08, 86.28, 110.63, 116.86, 124.15, 125.82, 128.28, 135.61, 141.06, 149.27, 153.59, 158.40, 161.53, 177.51 ppm; HRMS (ESI): m/z calcd for C₁₅H₈ClN₅O₄ 357.0264, found 357.0265.

7′-Amino-5-fluoro-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carbonitrile (7q, C₁₅H₈FN₅O₄)

R _f  = 0.29 (hexane/ethyl acetate 6:4); m.p.: 287–289 °C; ¹H NMR (400 MHz, DMSO-d ₆ ): δ = 6.75–6.78 (m, 1H, ArH), 6.98 (t, J = 8.1 Hz, 1H, ArH), 7.16 (dd, J = 1.8, 8.1 H, ArH), 7.42 (s, 2H, NH₂), 10.49 (s, 1H, NH), 11.14 (s, 1H, NH), 12.32 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 47.13, 57.23, 86.36, 109.87, 111.60, 111.84, 114.47, 114.70, 116.83, 138.29, 149.25, 153.50, 158.34, 161.47, 177.71 ppm; HRMS (ESI): m/z calcd for C₁₅H₈FN₅O₄ 341.0560, found 341.0561.

7′-Amino-1-benzyl-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carbonitrile (7r, C₂₂H₁₅N₅O₄)

R _f  = 0.27 (hexane/ethyl acetate 6:4); m.p.: 291–293 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 4.88 (d, J = 16.1 Hz, 1H, CH₂), 4.95 (d, J = 16.1 Hz, 1H, CH₂), 6.69 (d, J = 7.7 Hz, 1H, ArH), 6.97 (t, J = 7.3 Hz, 1H, ArH), 7.14 (t, J = 7.7, 1H, ArH), 7.23–7.30 (m, 5H, ArH), 7.46–7.47 (m, 4H, NH₂, NH, ArH), 11.21 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 43.30, 46.41, 57.54, 86.58, 108.83, 116.93, 122.56, 123.63, 126.99, 127.11, 128.29, 128.46, 132.74, 136.01, 142.62, 149.18, 153.50, 158.37, 161.52, 176.31 ppm; HRMS (ESI): m/z calcd for C₂₂H₁₅N₅O₄ 413.1124, found 413.1125.

Ethyl 7′-amino-5-chloro-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carboxylate (7 s, C₁₇H₁₃ClN₄O₆)

R _f  = 0.27 (hexane/ethyl acetate 6:4); m.p.: 298–300 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.79 (t, J = 7.3 Hz, 3H, CH₃), 3.73 (q, J = 7.3 Hz, 2H, CH₂), 6.88 (d, J = 8.8 Hz, 1H, ArH), 8.00 (d, J = 2.2, 1H, ArH), 8.08–8.10 (m, 3H, NH₂, ArH), 10.02 (s, 1H, NH), 11.03 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 12.95, 46.35, 59.09, 75.48, 88.49, 109.24, 122.96, 124.45, 126.98, 137.32, 142.92, 148.97, 152.31, 158.61, 161.15, 167.16, 176.02 ppm; HRMS (ESI): m/z calcd for C₁₇H₁₃ClN₄O₆ 404.0523, found 404.0525.

Ethyl 7′-amino-5-nitro-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carboxylate (7t, C₁₇H₁₃N₅O₈)

R _f  = 0.30 (hexane/ethyl acetate 6:4); m.p.: 295–298 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.79 (t, J = 7.3 Hz, 3H, CH₃), 3.72 (q, J = 7.3 Hz, 2H, CH₂), 6.66 (d, J = 6.2 Hz, 1H, ArH), 7.09 (br s, 2H, ArH), 7.99 (s, 2H, NH₂), 10.36 (s, 1H, NH), 10.99 (s, 1H, NH), 12.18 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.12, 46.31, 59.39, 75.01, 88.11, 108.17, 118.73, 125.20, 136.58, 141.77, 149.15, 150.81, 152.83, 159.01, 161.51, 167.04, 180.18 ppm; HRMS (ESI): m/z calcd for C₁₇H₁₃N₅O₈ 415.0764, found 415.0765.

7′-Amino-5-methyl-2,2′,4′-trioxo-1,1′,2,2′,3′,4′-hexahydrospiro[3H-indole-3,5′-[5H]pyrano[2,3-d]pyrimidine]-6′-carbonitrile (7u, C₁₆H₁₁N₅O₄)

R _f  = 0.31 (hexane/ethyl acetate 6:4); m.p.: 288–291 °C; ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.21 (s, 3H, CH₃), 6.66 (d, J = 8.4 Hz, 1H, ArH), 6.94–6.96 (m, 2H, ArH), 7.34 (s, 2H, NH₂), 10.36 (s, 1H, NH), 11.10 (s, 1H, NH) ppm; ¹³C NMR (100 MHz, DMSO-d ₆): δ = 20.61, 46.66, 58.02, 86.88, 108.99, 116.96, 124.28, 128.64, 130.58, 133.58, 139.65, 149.23, 153.27, 158.18, 161.39, 177.57 ppm; HRMS (ESI): m/z calcd for C₁₆H₁₁N₅O₄ 337.0811, found 337.0811.