Introduction

The xanthene derivatives attract much attention due to their diverse biological displays such as antioxidant [1, 2], antileukemic [3], antimicrobial [4, 5], insecticidal [6], antifungal [7], antimycobacterial [8], antiplasmodial [9,10,11], antitumor [9], apoptotic [12], antiproliferative [13], antimalarial [14], anticancer [15], antinociceptive [16], anti-inflammatory [17,18,19] and antiviral [20, 21] activities. Indigofera longeracemosa is a natural source of xanthene dye [22]. Several synthesis methods of xanthenes enhanced by various catalysts such as multiwalled carbon nanotubes anchored by ruthenium [23], homogeneous catalyst of ruthenium chloride hydrate [24], tetrachlorosilane [25], ceric ammonium nitrate supported HY-zeolite [26], ionic liquid [NMP]·H2PO4 [27], rice husk [28], succinimide-N-sulfonic acid [29], tetradecyltrimethylammonium bromide (TTAB) [30], Bronsted acidic ionic liquids [31], guanidine hydrochloride [32], nanoparticle silica-supported sulfuric acid (NPs SiO2-H2SO4) [33], tetrapropylammonium bromide [34], [CTA]Fe/MCM-41 [35], sulfated polyborate [36], cellulose sulfonic acid [37], ZrOCl2·8H2O [38], heterogeneous silica-bonded imidazolium–sulfonic acid chloride [39], basic ionic liquid from ethane-1,2-diyl bis (hydrogen sulfate), DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) [40] and Sncl4·5H2O [41] are well documented in the literature. The significance of supported iron oxide nanoparticles in various syntheses of organic compounds is shown in Table 1. Conversely, the potential efficacy of the above-mentioned catalysts for the synthesis of xanthenes possesses their own disadvantages, including stumpy yields of products, lengthy reaction times, far-reaching reaction conditions, monotonous work-up procedures or luxurious reagents. Moreover, in the majority of the reported techniques, the catalysts are not recyclable. However, in the present work, we have reported the one-pot synthesis of 9-substituted xanthene-1,8-diones by using iron oxide nanoparticles as a recyclable catalyst.

Table 1 Synthesis of xanthenes, diazepines, pyrimidines and pyridines by solid-supported iron nanocomposites
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Results and discussion

In this present work, efficient protocol for the synthesis of 9-substituted xanthene-1,8-diones (3a–j) was achieved by using iron oxide nanoparticles as a heterogeneous catalyst. Initially, various reaction conditions (as listed in Table 2) were tried for the synthesis of 9-substituted xanthene-1,8-diones (3a–j) from dimedone and substituted aldehydes. Among all, the iron oxide NPs’ catalytic reaction in ethanol was found to be more efficient based on the reaction yield. The catalyst, iron oxide NPs, was prepared by stirring a solution of 0.1 M ferric chloride with an aqueous extract of leaves of Raphanus sativa at room temperature for an hour [42]. The schematic representation of catalyst preparation is shown in Scheme 1. The optimization of iron oxide NPs catalyst required for better yield was also performed as given in Table 3. From the table, it was evident that 15 mol% of the catalyst in polar protic solvent resulted in considerably good yield. Also, the benefit of greener iron oxide (Fe2O3) was compared with other articles as shown in Table 4.

Table 2 Reaction condition optimization for the synthesis of xanthene-1,8-diones
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Scheme 1
scheme 1

Synthesis of iron oxide nanoparticles

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Table 3 Quantity of catalyst required
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Table 4 Comparison of Fe2O3 catalyst in the synthesis of xanthene-1,8-diones
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At the onset, the synthesis of xanthene-1,8-dione (Scheme 2) was carried out by the reaction of dimedone (2 equiv.) and various aldehydes (1 equiv.) in the presence of iron oxide nanoparticles in ethanol by stirring at room temperature. All the derivatives (Fig. 1) were purified through recrystallization in ethanol and were characterized by FTIR, 1H NMR, 13C NMR and HRMS spectral techniques.

Scheme 2
scheme 2

Synthesis of 9-substituted xanthene-1,8-diones 3a–j

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Fig. 1
figure 1

Reaction time, percentage yield and melting point of xanthene-1,8-diones (3a–j) and 6

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The structure of the xanthene derivative 3h was also confirmed by single-crystal XRD analysis. The diffraction intensity data were collected for the space group P21/n of the crystallized title compound through Bruker AXS area detector. The random structure obtained by direct methods with reliable index value was 0.18 for 27 surviving atoms and refined with F2 by full-matrix least square methods. All hydrogen atoms were allowed to fix by geometrically corresponding to parent carbon atoms. The refined R value received at the end of refinement cycle was 7.9%, and Ortep plot drawn at 30% probability of crystal structure is displayed in Fig. 2. The outer rings A & C adopted envelope conformation which is confirmed by the total puckering amplitudes and (Cremer & Pople, 1975) [QT = 0.4470 Å and 0.4688 Å for rings A & C, respectively]. In the central ring B, C1 had slight deviation appeared by − 0.091(1)Å, which is confirmed from least-square plane calculation value (Nardelli et al. 1965). The crystal packing was stabilized by van der Waals interaction, and the molecule exhibited intramolecular C–H⋯π interaction between C15 and ring C [C14–C19] through H15 atom with 2.68 Å by 104° angle.

Fig. 2
figure 2

ORTEP diagram of compound 3h

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After the synthesis of 4-nitrosubstituted xanthene-1,8-dione, nitroreduction was carried out in the presence of Zn/Cacl2 in ethanol under reflux. Further, the synthesized 4-aminophenyl-xanthene-1,8-dione was coupled with different aldehydes in ethanol using sodium acetate (20 mol%) as a catalyst (Scheme 3).

Scheme 3
scheme 3

Synthesis of 9-(4-(((2-hydroxynaphthalen-1-yl)methylene)amino)phenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione 6

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The plausible mechanism for the synthesis of xanthenes in the presence of iron oxide nanoparticles can be visualized as shown in Fig. 3. Initial activation of the carbonyl group of aldehyde 2 by Fe produced an intermediate I. Then, two nucleophilic attacks by dimedone 1 with loss of two molecules of water successively formed an intermediate II, which underwent dehydration to afford the desired product 3. The heterogeneous reaction phase of iron oxide catalyst used in the synthesis of 9-substituted xanthenes-1,8-diones was easy to use for another cycle, and the catalyst recyclability is shown in Fig. 4. In view of reactivity, xanthene containing electron-withdrawing moiety comparatively formed higher yield than the compounds having electron-donating moiety.

Fig. 3
figure 3

Plausible mechanistic pathway of 9-substituted xanthene-1,8-diones (3a–n)

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Fig. 4
figure 4

Catalyst recyclability chart for 3d, 3i and 3j

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Experimental

Preparation of iron oxide nanoparticles

Radish (Raphanus sativus) leaves extract (2 equiv.) was stirred with 0.1 M FeCl3 (1 equiv.) solution under room temperature for an hour. Then, the reaction mixture was dried at 300 °C for 3 h to get iron oxide nanoparticles [53].

A general procedure for the production of xanthene-1,8-dione compounds 3(a–j)

A mixture of aldehyde (1 mmol), dimedone (2 mmol) and iron oxide nanoparticles (0.1 mmol) as a catalyst was stirred at room temperature for 2 h in ethanol (20 mL). The forward movement of the reaction was monitored by TLC. After completion of the reaction, the catalyst was removed by using Whatman filter paper, and in some cases, the suspended nanoparticle was removed by centrifugation method. Then, the crude product was recrystallized from ethanol to form a pure crystal of the 9-substituted xanthene-1,8-diones (3a–j). The catalyst used in the reaction was reusable for up to 5 cycles (as shown in Fig. 4).

A general procedure for the production of 9-(4-(((2-hydroxynaphthalen-1-yl)methylene)amino)phenyl-xanthene-1,8(2H)-dione 6

Compound 3j was reduced by using Zn and Cacl2 using ethanol as a solvent under reflux for 8 h. The reaction progress was monitored by TLC. Then, the reaction mixture was filtered (for removing Zn and ZnO) and poured into ice-cold water to get 9-(4-aminophenyl)-xanthene-1,8-dione. Further, it was condensed with 2-hydroxy naphthaldehyde to get xanthene Schiff base.

3,4,6,7-Tetrahydro-9-(4-methoxyphenyl)-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H,9H)-dione 3a

Pale yellow crystals; IR (KBr, cm−1) vmax: 2968 (–CH), 1668 (–C=O), 1464 (C=C), 1183 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.99 and 1.09 (2 s, 12H, gem-dimethyl), 2.18–2.20 (2d, 4H, C4 and C5 –CH2, J = 6.9 Hz), 2.45 (s, 4H, C2 and C7 –CH2) 3.72 (s, 3H, –OCH3), 4.69 (s, 1H, C9–H), 6.75 (d, 2H, ArH, J =  8.7 Hz), 7.2 (d, 2H, ArH, J =  8.7 Hz); 13C NMR (75 MHz,CDCl3): δ 196.51, 162.09, 157.96, 136.49, 129.31, 115.79, 113.47, 55.10, 50.77, 40.86, 32.19, 30.96, 29.27, 27.34; DEPT-135: 129.31, 113.46, 55.11, 30.96, 29.28, 27.34 (CH↑,CH3↑); 50.77, 40.86 (CH2↓); HRMS (EI+): Calcd. for C24H28O4 m/z 380.1987[M+]; found m/z 380.1983[M+].

9-(4-Chlorophenyl)-3,4,6,7-tetrahydro-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H,9H)-dione 3b

White powder; IR (KBr, cm−1) vmax: 2954 (–CH), 1654 (–C=O), 1457 (C=C), 1190 (–C–O); 1H NMR (400 MHz, CDCl3): δ 0.97 and 1.09 (2 s, 12H, gem-dimethyl), 2.13–2.24 (2d, 4H, C4 and C5 –CH2, J = 12 Hz), 2.45 (s, 4H, C2 and C7 –CH2), 4.69 (s, 1H, C9–H), 7.16 (d, 2H, ArH, J =  6 Hz), 7.23 (d, 2H, ArH, J =  6 Hz); 13C NMR (75 MHz, CDCl3): δ 196.35, 162.45, 142.70, 132.03, 129.77, 128.21, 115.28, 50.70, 40.86, 32.19, 31.47, 29.26, 27.29; DEPT-135: 129.77, 128.21, 31.46, 29.27, 27.29 (CH↓,CH3↓); 40.85, 50.69(CH2↑); HRMS (EI+): Calcd. for C23H25ClO3 m/z 384. 1492[M+]; found m/z 384.1483[M+].

3,4,6,7-Tetrahydro-3,3,6,6,9-pentamethyl-2H-xanthene-1,8(5H,9H)-dione 3c

Half white shining powder; IR (KBr, cm−1) vmax: 2962 (–CH), 1654 (–C=O), 1457 (C=C), 1211 (–C–O); 1H NMR (300 MHz, CDCl3): δ 1.08 and 1.10 (2 s, 12H, gem-dimethyl), 2.27 and 2.35 (2 s, 8H, C4, C5 and C2, C7 –CH2), 3.64 (s, 3H, –CH3), δ 7.27 (s, 1H, C9–H); 13C NMR (75 MHz, CDCl3): δ 197.08, 162.72, 116.75, 50.96, 40.84, 32.07, 29.25, 27.21, 21.74, 20.86; DEPT-135: 32.03, 29.25, 27.21, 21.74, 20.86 (CH↓,CH3↓); 50.95, 40.83 (CH2↑); HRMS (EI+): Calcd. for C18H24O3m/z 288.1725[M+]; found m/z 288.1711 [M+].

3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-phenyl-2H-xanthene-1,8(5H,9H)-dione 3d

White powder; IR (KBr, cm−1) vmax: 2954 (–CH), 1654 (–C=O), 1549 (C=C), 1288 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.98 and 1.09 (2 s, 12H, gem-dimethyl), 2.17 (2d, 4H, C4 and C5 –CH2, J =  13.8 Hz), 2.46 (s, 4H, C2 and C7 –CH2), 4.75 (s, 1H, C9–H), 7.09–7.29 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3): δ 196.40, 162.26, 144.07, 128.38, 128.03, 126.36, 115.69, 50.75, 40.89, 32.19, 31.83, 29.25, 27.33; DEPT-135: 126.38, 31.83, 29.27, 27.34 (CH↓,CH3↓); 50.74, 40.89 (CH2↑); HRMS (EI+): Calcd. for C23H26O3m/z 350.1881[M+]; found m/z 350.1871[M+].

3,4,6,7-Tetrahydro-9-(4-hydroxy-3-methoxyphenyl)-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H,9H)-dione 3e

Light brown powder; IR (KBr, cm−1) vmax: 3390 (–OH), 2962 (–CH), 1654 (–C=O), 1521 (C=C), 1358 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.99 and 1.09 (2 s, 12H, gem-dimethyl), 2.19 (2d, 4H, C4 and C5 –CH2, J = 15 Hz), 2.44 (s, 4H, C2 and C7 –CH2), 3.88 (s, 3H, –OCH3), 4.74 (bs, 1H, –OH), 5.45 (s, 1H, C9–H), 6.56 (d,1H, ArH, J =  6 Hz), 6.715 (d, 1H, ArH, J =  9 Hz), 6.99 (s, 1H, ArH); 13C NMR (75 MHz, CDCl3): δ 196.64, 162.10, 145.89, 136.47, 115.92, 55.89, 40.87, 32.81, 31.32, 29.23, 27.29; HRMS (EI+): Calcd. for C24H28O5m/z 396.1936 [M+]; found m/z 396.1925 [M+].

3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-(thiophen-2-yl)-2H-xanthene-1,8(5H,9H)-dione 3f

Black powder; IR (KBr, cm−1) vmax: 2962 (–CH), 1661 (–C=O), 1619(C=C), 1190 (–C–O); 1H NMR (300 MHz, CDCl3): δ 1.05 and 1.10 (2 s, 12H, gem-dimethyl), 2.25 and 2.45 (2 s, 8H, C4, C5 and C2, C7 –CH2), 5.14 (s, 1H, C9–H), 6.8–7.26 (m, 3H, ArH); 13C NMR (75 MHz, CDCl3): δ 196.30, 162.70, 148.12, 126.75, 125.32, 123.37, 115.27, 50.74, 40.85, 32.13, 29.35, 27.35, 26.37; DEPT-135: 126.76, 125.32, 123.39, 29.36, 28.57, 27.35, 26.36 (CH↓,CH3↓); 50.73, 40.84 (CH2↑); HRMS (EI+): Calcd. for C21H24O3S m/z 356.1446 [M+]; found m/z 356.1435 [M+].

3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-(2-nitrophenyl)-2H-xanthene-1,8(5H,9H)-dione 3g

Brownish orange powder; IR (KBr, cm−1) vmax: 2954 (–CH), 1661 (–C=O, 1558 (-N–O−), 1521 (C=C), 1211 (–C–O); 1H NMR (300 MHz, CDCl3): δ 1.00 and 1.09 (2 s, 12H, gem-dimethyl), 2.21 (2d, 4H, C4 and C5 –CH2, J = 16.2), 2.47 (s, 4H, C2 and C7 –CH2), 5.52 (s, 1H, C9–H), 7.00–7.77 (m, 4H, ArH); 13C NMR (75 MHz, CDCl3): δ 196.40, 163.05, 149.87, 137.94, 131.95, 131.17, 127.21, 124.63, 114.17, 50.61, 40.86, 32.06, 28.92, 27.61; DEPT-135: 131.97, 131.16, 127.22, 124.63, 28.93, 27.61 (CH↓,CH3↓); 50.61, 40.85 (CH2↑); HRMS (EI+): Calcd. for C23H25NO5m/z 395.1732 [M+]; found m/z 395.1745 [M+].

3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-p-tolyl-2H-xanthene-1,8(5H,9H)-dione 3h

White powder; IR (KBr, cm−1) vmax: 2962 (–CH), 1661 (–C=O, 1499 (C=C), 1197 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.99 and 1.09 (2 s, 12H, gem-dimethyl), 2.2 (2d, 4H, C4 and C5 –CH2, J =  6.7 Hz), 2.45 (s, 4H, C2 and C7 –CH2), 2.23 (s, 3H,–CH3), 4.70 (s, 1H, C9–H), 7 (d, 2H, ArH, J = 7.5), 7.16 (d, 2H, ArH, J = 7.5); 13C NMR (75 MHz, CDCl3): δ 196.41, 162.10, 141.19, 135.77, 128.78, 128.24, 115.79, 50.78, 40.89, 32.19, 31.44, 29.25, 27.38, 21.04; DEPT-135: 128.78, 128.25, 31.44, 29.25, 27.38, 21.04 (CH↓,CH3↓); 50.78, 40.89 (CH2↑); HRMS (EI+): Calcd. for C24H28O3m/z 364.2038 [M+]; found m/z 364.2033 [M+].

3,4,6,7-Tetrahydro-9-(4-hydroxyphenyl)-3,3,6,6-tetramethyl-2H-xanthene-1,8(5H,9H)-dione 3i

Brown solid; IR (KBr, cm−1) vmax: 3425(–OH), 2954 (–CH), 1626 (–C=O, 1464 (C=C), 1232 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.99 and 1.08 (2 s, 12H, gem-dimethyl), δ 2.19 (2d, 4H, C4 and C5 –CH2,J = 4.5 Hz), δ 2.44 (s, 4H, C2 and C7 –CH2), δ 4.67 (s, 1H, C9-H), δ 6.56 (d, 2H, ArH, J = 1.8 Hz), δ 7.07 (d, 2H, ArH, J =  2.1 Hz); 13C NMR (75 MHz,CDCl3): δ 196.74, 162.21, 154.55, 135.90, 129.36, 115.96, 115.17, 50.83, 40.94, 32.15, 30.98, 29.09, 27.37; DEPT-135: 50.83, 40.94 (CH2↑); 129.36, 115.96, 30.98, 29.09, 27.37(CH↓, CH3↓); HRMS (EI+): Calcd. for C23H26O4m/z 366.1831 [M+]; found m/z 366.1830 [M+].

3,4,6,7-Tetrahydro-3,3,6,6-tetramethyl-9-(4-nitrophenyl)-2H-xanthene-1,8(5H,9H)-dione 3j

Pale yellow powder; IR (KBr, cm−1) vmax: 2968 (–CH), 1661 (–C=O, 1466 (C=C), 1197 (–C–O); 1H NMR (300 MHz, CDCl3): δ 0.99 and 1.11 (2 s, 12H, gem-dimethyl), δ 2.20 (2d, 4H, C4 and C5 –CH2, J =  11.7 Hz), δ 2.49 (s, 4H, C2 and C7 –CH2), δ 4.83 (s, 1H, C9-H), δ 7.46 (d, 2H, ArH, J =  8.7 Hz), δ 8.07 (d, 2H, ArH, J =  8.7 Hz); 13C NMR (75 MHz, CDCl3): δ 195.94, 162.82, 151.40, 146.63, 129.31, 123.33, 114.63, 50.65, 40.92, 32.36, 32.14, 29.12, 27.29; DEPT-135: 129.31, 123.33, 32.36, 29.12, 27.29 (CH↓,CH3↓); 50.65, 40.92(CH2↑); HRMS (EI+): Calcd. for C23H25NO5m/z 395.1732 [M+]; found m/z 395.1749 [M+].

(E)-9-(4-(((2-hydroxynaphthalen-1-yl)methylene)amino)phenyl)-3,3,6,6-tetramethyl-3,4,5,6,7,9-hexahydro-1H-xanthene-1,8(2H)-dione (6)

Brick red solid; IR (KBr, cm−1) vmax: 3416 (–OH), 1635 (–C=O, 1373 (C=N), 1120 (–C–O); 1H NMR (400 MHz, CDCl3): δ 0.99 and 1.10 (2 s, 12H, gem-dimethyl), 2.14–2.26 (2d, 4H, C4 and C5 –CH2, J = 16.4), 2.48 (s, 4H, C2 and C7 –CH2), 4.81 (s, 1H, C9-H), 6.9–7.8 (m, 6H, ArH), 8.01 (s, 1H,–CH); 13C NMR (75 MHz,CDCl3): δ 196.46, 171.22, 162.43, 153.95, 142.99, 136.71, 133.36, 129.73, 128.08, 127.17, 123.42, 119.96, 115.37, 108.69, 50.76, 40.90, 32.24, 31.93, 29.69, 27.36, 14.11; HRMS (EI+): Calcd. for C34H33NO4m/z 519.2410 [M+]; found m/z 519.2398 [M+].

Conclusion

In summary, we have reported a simple method of synthesis of xanthene-1,8-diones by treating dimedone and aldehyde in the presence of iron oxide nanoparticle catalyst using ethanol as a solvent. In this context, we have found a green method for the synthesis of xanthene-1,8-dione derivatives, and the advantages of this procedure include high yields, operational simplicity and environmentally friendly procedure.