Introduction

In recent years, interest in green chemistry [1,2,3] has developed, and reducing the use of organic solvents and toxic reagents for facile, efficient, and nonpolluting synthetic procedures has become a major challenge for organic chemists. In this area, use of natural materials as a promising catalyst in organic reactions has received a considerable attention due to their green credentials [4, 5]. Furthermore, the combination of multi-component reactions (MCRs) and solvent-free conditions leads to a significant reduction in reaction times, enhancements in conversions, improved selectivity, with several advantages of the eco-friendly approach such as energy savings, waste reduction, easy work‐ups, and the avoidance of hazardous organic solvents [6, 7].

So, the design of novel MCRs using solvent-free conditions for the synthesis of simple and complex bioactive heterocycles has remained as a significant topic in the drug discovery process, and analysis of drugs [8, 9]. Among these bioactive heterocycles, pyran ring systems are an important category of oxygen-containing heterocycles. Also, they have broad existence in a variety of important natural compounds, including carbohydrates, alkaloids, polyether antibiotics, pheromones, and iridoids [10]. Pyran-based compounds are widely applied as cosmetics, pigments [11], and potential biodegradable agrochemicals [12]. These compounds display a variety of biological functions including anti-leishmanial [13], anti-HIV [14], antioxidant [15], anti-tumor [16], and central nervous system (CNS) activities and effects [17]; they are also used for the treatment of Alzheimer’s disease [18] and schizophrenia [19].

Moreover, spiroheterocycle compounds containing one sp 3 carbon atom common to two rings are found in a number of natural or synthetic molecules [20, 21] and have plenty inimitable virtues [22, 23]. For example, this type of framework has been found as a core structure of many bioactive natural alkaloids such as spirotryprostatins, gelsemine, mitraphylline, horsfiline, chitosenine (Fig. 1) [24]. Molecules with spirocyclic structures are exclusively attractive because the conformational restriction associated with the structural rigidity affects significantly their biological and pharmaceutical activity [25, 26].

Fig. 1
figure 1

Some biologically active alkaloids

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Furthermore, EDTA (ethylenediaminetetraacetic acid) and its salts are substituted diamines and are used in foods, cosmetic formulations, pharmaceutical products, and manufacturing. Moreover, they are used to treat heavy metal poisoning and to reduce blood cholesterol [27]. Among these salts, we used the ethylenediaminetetraacetic acid disodium salt dehydrate (organic salt Na2EDTA, Fig. 2) as a solid acid–base bifunctional catalyst for organic synthesis.

Fig. 2
figure 2

Structure of Na2EDTA

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Considering the significant potential of spirocyclic compounds, especially when fused to pyran derivatives as a source of valuable drug candidates and with our continued interest in multi-component reactions and our ongoing program for the synthesis of heterocyclic systems based on green chemistry protocols [28,29,30,31,32], herein, we report a green and efficient procedure for the synthesis of spiro-2-amino-4H-pyrans, spiroacenaphthylenes, and spirooxindoles 4/5/6 through a single-pot, three-component condensation reaction between isatin/acenaphthoquinone/ninhydrin 1, malononitrile 2, and CH-acids 3 in the presence of the catalytic amount of Na2EDTA as an efficient, eco-friendly, and reusable catalyst under solvent-free conditions at 70 °C (Scheme 1).

Scheme 1
scheme 1

One-pot, three-component synthesis of spiro-4H-pyran derivatives, catalyzed by Na2EDTA

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Experimental

General

Melting points and IR spectra of all compounds were determined by using an Electro thermal 9100 apparatus and JASCO FT/IR-460 plus spectrometer. The 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-300 and 400 Avanve instrument with deuterated dimethyl sulfoxide (DMSO-d 6) as solvent and using TMS as internal reference at 300, 400, 75, and 100 MHz, respectively. Thin-layer chromatography (TLC) was performed on silica-gel Polygram SILG/UV 254 plates. All chemicals were received from chemical producer Merck (Darmstadt, Germany) and Fluka (Buchs, Switzerland) and used without further purification.

General procedure for the synthesis of spirooxindoles, spiroacenaphthylenes, and spiro-2-amino-4H-pyrans (4–6)

A mixture of isatin/acenaphthoquinone/ninhydrin)1 mmol) 1a-c, malononitrile 2 (1 mmol), CH-acid 3a-g (1 mmol), and 15 mol % of Na2EDTA was heated under solvent-free conditions at 70 °C for the mentioned time shown in tables. The progress of the reaction was monitored by TLC using EtOAc/n-hexane (1:3) as an eluent. Upon completion, the reaction mixture was allowed to cool to room temperature. Then, 5 mL of water was then added to the reaction mixture, the resulting solid was collected by filtration and washed twice with water (2 × 5 mL), and then the pure solid products 4/5/6 were recrystallized from ethanol. Selected spectroscopic data of selected and known products are given below:

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

Mp 292–294 °C; IR (KBr): ν max = 3375, 3310, 3143, 2960, 2191, 1725, 1656, 1603, 1465, 1352, 1222, 1178, 1052, 907 cm−1; 1H NMR (400 MHz, DMSO-d 6): δ 1.01 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.08–2.20 (m, 2H, CH2), 2.53 (s, 2H, CH2), 6.80 (d, 1H, J = 7.6 Hz, ArH), 6.90 (t, 1H, J = 7.6 Hz, ArH), 6.98 (d, 1H, J = 7.2 Hz, ArH), 7.14 (t, 1H, J = 7.6 Hz, ArH), 7.22 (s, 2H, NH2), 10.40 (s, 1H, NH).

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

Mp 294–295 °C; IR (KBr): ν max = 3360, 3150, 2955, 2192, 1722, 1677, 1648, 1590, 1473, 1347, 1220, 1033, 806, 552 cm−1; 1H NMR (300 MHz, DMSO-d 6): δ 1.03 (s, 6H, 2CH3), 2.16 (s, 2H, CH2), 2.50–2.58 (m, 2H, CH2), 6.81 (d, 1H, J = 8.1 Hz, ArH), 7.11 (s, 1H, ArH), 7.21 (dd, 1H, J = 8.1 Hz, J = 2.1 Hz, ArH), 7.36 (s, 2H, NH2), 10.58 (s, 1H, NH); 13C NMR (300 MHz, DMSO-d 6): δ 27.6, 27.9, 32.4, 47.5, 50.3, 57.1, 110.6, 111.1, 117.7, 123.7, 126.1, 128.5, 136.9, 141.3, 141.4, 159.3, 165.1, 178.3, 195.6 ppm.

2′- Amino- 7′,7′- dimethyl- 2,5′-dioxo-5′,6′,7′,8′- tetrahydro-2H-spiro[acenaphthylene- 1,4′- chromene]- 3′- carbonitrile ( 5a )

Mp 271–273 °C; IR (KBr): ν max = 3351, 3274, 3187, 2942, 2194, 1735, 1657, 1461, 1342, 1213, 1154, 1022, 901 cm−1; 1H NMR (400 MHz, DMSO-d 6): δ 1.03 (s, 3H, CH3), 1.05 (s, 3H, CH3), 2.04–2.14 (m, 2H, CH2), 2.64 (s, 2H, H2), 7.32 (s, 2H, NH2), 7.40 (d, 1H, J = 6.8 Hz, ArH), 7.66 (t, 1H, J = 6.8 Hz, ArH), 7.83 (t, 1H, J = 8.0 Hz, ArH), 7.92–7.95 (m, 2H, ArH), 8.27 (d, 1H, J = 7.6 Hz, ArH).

2′- Amino- 2,5′- dioxo-2H,5′H- spiro[acenaphthylene- 1,4′- pyrano[3,2- c]chromene]- 3′- carbonitrile ( 5b )

Mp 295–297 °C; IR (KBr): ν max = 3385, 3280, 3157, 2936, 2192, 1717, 1685, 1652, 1474, 1331, 1226, 1172, 1020, 914 cm−1; 1H NMR (300 MHz, DMSO-d 6): δ 7.50 (d, 1H, J = 8.1 Hz, ArH), 7.57 (t, 1H, J = 7.5 Hz, ArH), 7.64–7.81 (m, 5H, ArH, NH2), 7.89 (t, 1H, J = 7.8 Hz, ArH), 7.99–8.07 (m, 3H, ArH), 8.36 (d, 1H, J = 7.8 Hz, ArH); 13C NMR (300 MHz, DMSO-d 6): δ 52.01, 58.2, 102.6, 112.9, 117.2, 117.6, 121.6, 122.6, 123.2, 125.6, 129.18, 129.5, 130.3, 131.7, 132.7, 134.1, 141,6, 142.1, 152.5, 155.8, 158.8, 158.9, 159.4, 203.6 ppm.

2- Amino- 7,7- dimethyl- 1′,3′,5- trioxo- 1′,3′,5,6,7,8-hexahydrospiro[chromene- 4,2′- indene]- 3- carbonitrile ( 6a )

Mp 288–290 °C; IR (KBr): ν max = 3370, 3240, 2955, 2190, 1743, 1712, 1683, 1656, 1592, 1347, 1258, 1161, 1050, 791 cm−1; 1H NMR (300 MHz, DMSO-d 6): δ 1.04 (s, 6H, 2CH3), 2.21 (s, 2H, CH2), 2.63 (s, 2H, CH2), 7.71 (s, 2H, NH2), 8.00–8.07 (m, 4H, ArH); 13C NMR (300 MHz, DMSO-d 6): δ 27.6, 32.9, 49.3, 52.2, 53.5, 110.4, 117.3, 123.6, 137.1, 141, 160.3, 160.3, 160.35, 166.9, 196.5, 200.2 ppm.

Results and discussion

Considering the importance of spiro-4H-pyrans, we were willing to find a practical and general method for their synthesis in high yields and purities and also, because the development of efficient and environmentally friendly synthetic procedures is always desirable, we decided to peruse whether those compounds could be prepared by condensation of isatin/acenaphthoquinone/ninhydrin, malononitrile, and CH-acids through Knoevenagel–Michael–annulation sequence in the absence of any hazardous or toxic catalysts and organic solvents. For this purpose, the condensation reaction between isatin 1a (1 mmol), malononitrile 2 (1 mmol), and dimedone 3a (1 mmol) was selected as a model reaction in the presence of different amounts of Na2EDTA as a catalyst (10, 15 and 20 mol %) at various temperatures (25, 50, 60, 70 and 80 °C). As can be seen in Table 1, the best result was obtained when the reaction was carried out in the presence of 15 mol% of Na2EDTA at 70 °C in solvent-free conditions, which afforded the corresponding 2-amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile 4a in 10 min with 94% of yield (Table 1, entry 6).

Table 1 Optimization of the amount of catalyst (Na2EDTA) and temperature in a one-pot synthesis of the model reaction
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To explore the scope of the reaction further, the present study is extended to various cyclic ketones and different activated CH-acids using these optimized conditions. All the reactions were complete in 10–15 min and resulted in the formation of the target structures in high yields without the formation of any side products. This one-pot reaction was efficiently promoted using isatin with reduced reaction times and increased yields rather than other cyclic ketones and dimedone reacted rapidly and gave higher yields in comparison with other activated CH-acids (Table 2, entries 1–17).

Table 2 Solvent-free synthesis of spiro-4H-pyran derivatives in the presence of Na2EDTA (15 mol%) as a catalyst at 70 °C
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Recovery of the catalysts is a significant feature in green organic synthesis. Thus, for recyclability of the catalyst, we also investigated the recycling of Na2EDTA under solvent-free conditions at 70 °C using a selected model reaction of isatin, malononitrile, and dimedone in the presence of Na2EDTA as a homogeneous catalyst. After the completion of the reaction, 5 mL of water was added to the mixture. The Na2EDTA was dissolved in water and filtered for the separation of the crude product. The separated product was washed twice with water (2 × 5 mL). The resulting product was subsequently recrystallized from ethanol to give the pure solid. In order to recover the catalyst, since Na2EDTA is soluble in water, the filtrate was extracted with diethyl ether. The aqueous layer was separated, its solvent was evaporated under reduced pressure, and Na2EDTA was recovered and reused (Fig. 3).

Fig. 3
figure 3

Results of recycling over five consecutive recycling experiments

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As shown in Fig. 3, the catalytic system worked well up to five catalytic runs and slightly reduced the product yield, which may be due to little weight loss of catalyst during each recovery process.

The probable mechanism for the formation of the products using Na2EDTA, which act as an acid–base bifunctional catalyst in all steps, is outlined in Scheme 2. On the basis of this suggested mechanism, the synthesis of spiro-4H-pyrans 4-6 could be achieved through two ways. In two paths, Na2EDTA is an efficient catalyst to form the olefin I, which readily prepares in situ from Knoevenagel condensation of carbonyl group of cyclic ketone 1a–c with malononitrile 2 (path A) or C–H activated 3a-g (path B). In continue, Michael addition of C–H activated 3a–g (path A) or malononitrile 2 (path B) with olefin I in the presence of Na2EDTA finally give intermediate II. At the end, intermediate II through an intramolecular cyclization by nucleophilic attack of the hydroxyl group on the cyano group producing the desired products 4–6.

Scheme 2
scheme 2

Proposed mechanism for the formation of spiro-4H-pyran derivatives in the presence of Na2EDTA

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On this mechanism, we suggest that the Na2EDTA plays a dual role: first, to electrophilically activate the cyclic ketone carbonyl via H-bond formation between one H-atom of Na2EDTA and the O-atom of the C=O group, and second, to enhance the nucleophilicity of the C–H activated or malononitrile through deprotonation of the Cα-H by Na2EDTA.

In order to assess the efficiency and generality of this methodology, the obtained result from the reaction of isatin and malononitrile with dimedone by this method has been compared with those of the previously reported methods (Table 3). It was found that the present method is convincingly superior to the reported methods with respect to reaction time and exhibits broad applicability in terms of yields.

Table 3 Comparison of the efficiency of Na2EDTA with other reported catalysts in the literature for the synthesis of 4a
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Conclusions

In this work, we have demonstrated a simple single-pot, three-component synthesis of spiro-4H-pyran derivatives in excellent yields and purities with very short reaction times, from readily available starting materials by using catalytic amount of Na2EDTA as an environmentally benign solid acid–base bifunctional catalyst, under solvent-free conditions. This green and efficient procedure has a number of advantages such as operational simplicity, easy work-up, use of inexpensive, non-toxic, reusable, easy to handle catalyst without any byproduct, avoidance of hazardous organic solvents, and it may find a wide range of applications in diversity-oriented synthesis, and drug discovery, which make the methodology more attractive than the other conventional methods for the synthesis of these biologically important heterocycles.