Synthesis of a new class of pyrazole embedded spirocyclic scaffolds using magnetically separable Fe₃O₄@SiO₂–SO₃H nanoparticles as recyclable solid acid support

Abstract

An efficient, green and sustainable methodology for the synthesis of a new class of pyrazole embedded spirocyclic scaffolds has been developed. The method involves the condensation of a tetrone with a variety of arylhydrazones in the presence of Fe₃O₄@SiO₂–SO₃H magnetic nanoparticles (MNPs) as solid supported acid catalyst under solvent-free conditions. An interesting tandem rearrangement of the in situ generated adducts, derived from the acid catalyzed condensation of tetrone and arylhydrazones, leads to the formation of pyrazole embedded spirocyclic scaffolds. The significant advantages of this methodology are the use of solvent-free reaction conditions, employment of simple and easily available starting materials and reagents, good yields of the products with high atom-economy and operational simplicity of the reaction with the use of a magnetically separable and recyclable nano catalyst.

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Introduction

Fused pyrazole heterocycles serve as important synthetic targets in medicinal chemistry and the pharmaceutical industry.¹ Various derivatives of this class of compound are endowed with promising biological activities, as for example a pyrazole-fused steroid ring has been reported to enhance anti-inflammatory activity.² Similarly tricyclic pyrazoles have attracted considerable attention due to their applications as anticryptosporidial,³ anti-cancer,^4,5 selective cyclooxygenase-2 inhibitor,⁶ human dopamine D4 receptor⁷ and fungal enzyme inhibitor.⁸ Because of their immense biological activities, this class of compounds is considered as heterocycles of profound chemical and biological significance. Although various methods are available for the synthesis of fused pyrazole derivatives,⁹ the synthesis of spiro 1,3-indanedione fused tricyclic pyrazole derivatives has not been accomplished as yet. In light of their unique structural features and potential biological activities, the development of synthetic methodology for efficient construction of this type of new pyrazole embedded spirocyclic scaffolds with diverse functionalities remains desired.

The usages of heterogeneous acid catalysts in organic synthesis have drawn much attention for the development of green synthetic methodologies due to their operational simplicity, low cost, ease of isolation and recyclability.¹⁰ In this regard; nanostructured solid catalysts exhibit higher activity and selectivity than their corresponding bulk materials.¹¹ The nano-surface of the catalyst provides better surface area-to-volume ratio which allows greater contact between the reactants and the catalysts.¹² Among various solid acid systems, Fe₃O₄@SiO₂–SO₃H magnetic nanoparticles (MNPs) have gain enormous interest due to their inherent properties such as biocompatibility, thermal stability, reusability and separation by simple magnetic bar.¹³ The outer shell silica coating of this catalyst not only protects the inner magnetite core from oxidation but also stabilizes the MNPs against aggregation over a longer period. Thus in continuation of our research interest for the synthesis of bio-active compounds from ninhydrin¹⁴ and also in the development of green synthetic methodologies,¹⁵ we wish to report herein a simple and efficient green methodology for the synthesis of a new class of pyrazole embedded spirocyclic scaffolds such as spiro-1,3-diaryl-4-(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-ones employing nano-magnetite Fe₃O₄@SiO₂–SO₃H as heterogeneous acid catalyst under solvent-free conditions.

Results and discussion

Previously it has been reported that stirring a mixture of ninhydrin (1) and 1,3-indanedione (2) in acetic acid produces 2-hydroxy-2,2′-biindan-1,1′,3,3′-tetrone (3) in high yield.¹⁶ Further it has been demonstrated that this tetrone 3 can efficiently produce biologically important spiro dihydropyridine skeletons through the acid catalyzed condensation with various enamine nucleophilies.^17a With similarly anticipation, in the present study, the tetrone 3 was allowed to react with another nucleophile N-(4-methylbenzylidene)-N′-phenylhydrazone 4b (R₁ = p-methyl and R₂ = H) in p-TSA/EtOH medium under refluxing conditions. Interestingly, instead of the formation of the expected 1,3-diaryl-4-spiro(1′,3′-indanedione)-indeno[1,2-c]pyridazin-5-one 5,¹⁷ a new type of pyrazole embedded spirocyclic scaffold 1-phenyl-3-(4′-methylphenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one 6b (R₁ = p-methyl and R₂ = H) was formed in low yield through the acid catalyzed condensation and tandem rearrangement (Scheme 1).

Scheme 1 Synthesis of 1,3-diaryl-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-ones 6.

After having this interesting result we attempted to optimize the reaction conditions taking tetrone 3 and N-(4-methylbenzylidene)-N′-phenylhydrazone 4b (R₁ = p-methyl and R₂ = H) in 1 : 1 mole proportion and employing different solvents, catalysts and solid supports at varying temperatures (Scheme 2, Table 1). When the reaction was carried out in protic polar solvents such as water and ethanol without adding any catalyst, in both cases the reaction did not precede at all even after prolonged refluxing (Table 1, entry 1 and 2). Since the starting materials were soluble in ethanol, we selected ethanol as the reaction medium for further screening. Therefore subsequently, several acid catalysts (20 mol%) such as formic acid, lactic acid, acetic acid, p-TSA and silica sulphuric acid (SSA) were added to ethanol medium and the reactions were carried out under refluxing condition (Table 1, entries 3–7). In all the cases low to moderate yields of the product 6b were obtained. Interestingly, when SSA was used as solid acid support under solvent free conditions, some improvement in the yield of the product 6b was observed (Table 1, entry 8). This result encouraged us to perform the reaction in presence of several other solid catalysts (400 mg), such as melamine sulfonic acid (MSA), PEG-OSO₃H, nano Fe₃O_4, nano Fe₃O₄@SiO₂ and nano Fe₃O₄@SiO₂–SO₃H under solvent-free conditions (Table 1, entries 9–13). Gratifyingly, good yield of product 6b (∼71%) was obtained when the reaction was carried out on the solid surface of Fe₃O₄@SiO₂–SO₃H MNPs at 100 °C for 4 h under solvent-free conditions with continuous stirring (Table 1, entry 13). It is envisioned that, the adsorption of the reactant molecules on the large surface area of MNPs and simultaneous increase of the local concentration of the reactants around the active silica-SO₃H sites assist the reaction significantly. Since Fe₃O₄@SiO₂–SO₃H MNPs produce 6b in good yield at 100 °C (Table 1, entry 13), subsequently we varied several reaction parameters such as the amount of the nanocatalyst (200–600 mg), reaction time (2–6 h) and temperature (100–140 °C) to achieve best yield of the product (Table 1, entries 14–19). The experiments revealed that optimum yield of the product 6b (∼78%) can be obtained using 400 mg of Fe₃O₄@SiO₂–SO₃H nano catalyst under solvent-free conditions upon heating the solid reaction mixture at 120 °C for 4 h (Table 1, entry 14). To carry out the above solid state reactions initially the mixture of tetrone 3 and phenylhydrazone 4b, dissolved in minimum quantity of chloroform was soaked on the solid surface of the catalysts before heating and finally the product 6b was extracted with ethyl acetate for separation.

Scheme 2 Optimization of the reaction conditions.

Table 1 Optimization of reaction conditions for the synthesis of 6b

Entry	Solvent (10 mL)	Catalyst/solid support	Load	Time (h)	Temp.	Yield^a (%)
a Isolated yields.
1	H2O	—	—	12	Reflux	—
2	EtOH	—	—	12	Reflux	—
3	EtOH	Formic acid	20 mol%	10	Reflux	15
4	EtOH	Lactic acid	20 mol%	10	Reflux	18
5	EtOH	AcOH	20 mol%	10	Reflux	20
6	EtOH	p-TSA	20 mol%	10	Reflux	25
7	EtOH	Silica sulphuric acid (SSA)	20 mol%	10	Reflux	33
8	—	SSA	400 mg	4	100 °C	47
9	—	Melamine sulfonic acid (MSA)	400 mg	4	100 °C	21
10	—	PEG–OSO3H	400 mg	4	85 °C	25
11	—	Fe3O4	400 mg	4	100 °C	—
12	—	Fe3O4@SiO2	400 mg	4	100 °C	—
13	—	Fe3O4@SiO2–SO3H	400 mg	4	100 °C	71
14	—	Fe3O4@SiO2–SO3H	400 mg	4	120 °C	78
15	—	Fe3O4@SiO2–SO3H	400 mg	4	140 °C	73
16	—	Fe3O4@SiO2–SO3H	400 mg	6	120 °C	77
17	—	Fe3O4@SiO2–SO3H	400 mg	2	120 °C	57
18	—	Fe3O4@SiO2–SO3H	600 mg	4	120 °C	79
19	—	Fe3O4@SiO2–SO3H	200 mg	4	120 °C	55

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With the optimal reaction condition in hand (Table 1, entry 14), next the scope and generality of the reaction was assessed by employing various arylhydrazones (4a–s) with a variety of electron withdrawing and electron donating substituents under the similar reaction conditions (Scheme 3). The results summarized in Table 2 show that it is a very general reaction which produces the new spirocyclic scaffolds 6a–s with satisfactory yields. In all cases the products were fully characterized by ¹H NMR, ¹³C NMR and elemental analyses. Further determination of the X-ray crystal structures of compound 6e and 6o confirmed the product formation (Fig. 1).

Scheme 3 Synthesis of 1,3-diaryl-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-ones 6.

Table 2 Synthesis of 1,3-diaryl-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-ones 6a–s^a

a Isolated yields.

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Fig. 1 ORTEP diagram of X-ray crystal structure of 6e and 6o with atom numbering scheme. Thermal ellipsoids are shown at 50% probability (CCDC no. 1412850 and 1434717).†

The synthesized Fe₃O₄@SiO₂–SO₃H nanoparticles^13a were characterized by scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), EDX with elemental analysis and powder X-ray diffraction (XRD) analysis. The elemental analyses of the nanoparticles were performed using EDX equipped onto TEM. The silicon and sulphur peak in the quantitative EDX analysis of Fe₃O₄@SiO₂–SO₃H indicate the incorporation of the SiO₂ and –SO₃H group on the surface of the solid support (Fig. 2a). SEM image of Fe₃O₄@SiO₂–SO₃H nanocomposites clearly indicates the formation of nearly spherical shaped particles within the diameter range of 150 to 180 nm (Fig. 2b). The morphology of the MNPs was further investigated with high-resolution transmission electron microscopy (HRTEM) at an accelerating voltage of 200 kV (Fig. 2c). The figure clearly shows the formation of nearly spherical shaped Fe₃O₄@SiO₂–SO₃H nanoparticles with size within the range of 30 to 40 nm. The TEM images of the MNPs, before (Fig. 2c) and after five times applications (Fig. 2d) indicate the unaltered morphology. The X-ray diffraction study was carried out to confirm the crystalline nature of as-synthesized Fe₃O₄@SiO₂–SO₃H MNPs (Fig. 3). The position and relative intensities of all peaks corroborate well with the standard XRD pattern of the nanoparticles indicating the formation of the crystalline cubic spinel structured MNPs.^13a

Fig. 2 (a) TEM-EDX of Fe₃O₄@SiO₂–SO₃H MNPs; (b) SEM image of Fe₃O₄@SiO₂–SO₃H MNPs; and TEM images of Fe₃O₄@SiO₂–SO₃H MNPs (c) before use in reaction and (d) after five times applications.

Fig. 3 X-ray diffraction patterns of Fe₃O₄@SiO₂–SO₃H MNPs (a) before use and (b) after five times usages.

A probable mechanism for the formation of pyrazole embedded spirocyclic scaffolds 6 has been explicated in Scheme 4. The protonation of the hydroxy group of tetrone 3 by the sulfonic group of Fe₃O₄@SiO₂–SO₃H MNPs generates the intermediate 7 which then loses a molecule of water to form the electron deficient olefinic intermediate 8. Then a Michael type addition between arylhydrazones 4 and intermediate 8 generates the adduct 9. Subsequently, intramolecular nucleophilic attack of the –NH group to the adjacent carbonyl carbon of 9 produces hemiaminal 10. One such intermediate 10 (10q, Ar = Ar′ = p-Br–C₆H₅–) has been isolated under the reaction condition after 1 h and the crystal structure has been determined (Fig. 4). The intermediate 10 tautomerizes to enolic form 11 for the intramolecular nucleophilic attack of the 1,3-indanedione moiety to the adjacent carbonyl carbon to generate a [3.1.0] bicyclic intermediate 12. This unstable intermediate 12 produces the spirocyclic scaffolds 6 through the breaking of the central C–C bond with simultaneous elimination of water. From mechanistic point of view the acid catalyzed tandem rearrangement of intermediate 10 to product 6 with the formation of an unusual intermediate 12 is quite new and interesting.

Scheme 4 Plausible mechanism for the formation of compound 6.

Fig. 4 ORTEP diagram of X-ray crystal structure of intermediate 10q (Ar = Ar′ = p-Br–C₆H₅–) with atom numbering scheme. Thermal ellipsoids are shown at 50% probability (CCDC no. 1415047).†

The recovering and reusability test of the Fe₃O₄@SiO₂–SO₃H MNPs catalyst was also investigated for the formation of compound 6b from tetrone 3 and N-(4-methylbenzylidene)-N′-phenylhydrazone 4b under the optimized reaction conditions (Table 1, entry 14). After the completion of the reaction, the reaction mixture was ultrasonicated with ethyl acetate to isolate the product 6b from the surface of the solid support. The suspended Fe₃O₄@SiO₂–SO₃H MNPs were separated easily from the mixture using an external magnetic bar without performing any filtration. After that, Fe₃O₄@SiO₂–SO₃H MNPs were washed three times with ethyl acetate (3 × 5 mL), followed by washing with ethanol. Then the catalyst was air dried and used for the next cycles. The catalyst worked well up to five catalytic runs and the yield of the product 6b varied from 78% to 69% (Fig. 5).

Fig. 5 Reusability test of the MNPs catalyst for the synthesis of compound 6b.

Conclusions

In summary, an efficient, green and sustainable methodology for the synthesis of a new class of biologically important pyrazole embedded spirocyclic scaffolds has been developed. The method involves the condensation of a tetrone with a variety of arylhydrazones in presence of Fe₃O₄@SiO₂–SO₃H MNPs as solid supported acid catalyst under solvent-free condition. An interesting tandem rearrangement of the in situ generated adducts, derived from the acid catalyzed condensation of tetrone and arylhydrazones, leads to the formation of pyrazole embedded spirocyclic scaffolds. The significant advantages of this methodology are the use of solvent-free reaction conditions, employment of simple and easily available starting materials and reagents, good yields of the products with high atom-economy and operational simplicity of the reaction with the use of a magnetically separable and recyclable nano catalyst. In addition, the employment of iron oxides as acid catalysts compared to other transition metal catalysts is safer in terms of toxicity and also more environmental acceptability.

Experimental section

General methods

Starting materials and solvents were purchased from commercial suppliers and used without further purification. Melting points were determined in open capillary tubes. IR spectra were recorded with a Perkin-Elmer 782 spectrophotometer. ¹H (300 MHz) and ¹³C (75 MHz) NMR spectra were recorded with a Bruker 300 MHz instrument in CDCl₃ and DMSO-d₆. Elemental analyses (C, H, and N) were performed with a Perkin-Elmer 240C elemental analyzer. The X-ray diffraction data for crystallized compounds were collected with Mo-Kα radiation at 296 K using a Bruker APEX-II CCD system. The crystals were positioned at 50 mm from the CCD. Frames were measured with a counting time of 5 s. Data analysis was carried out with the Bruker APEX2 and Bruker SAINT program. The structures were solved by direct methods with the Shelxs97 program (Sheldrick, 2008). The morphological analysis of the nanoparticles was confirmed by TEM, monitored on a HRTEM, JEOL JEM 2010 at an accelerating voltage of 200 kV and fitted with a CCD camera. The crystallinity of synthesized nanoparticles was determined by XRD analysis. The diffractogram was documented from PANalytical, XPERT-PRO diffractometer using Cu_α (λ = 1.54060) as X-ray source. ZEISS EVO-MA Field Emission Scanning Electron Microscope operating voltage 5.0 kV is used for SEM.

Preparation of the catalyst^13a

Preparation of the magnetic Fe₃O₄ nanoparticles^13a. Fe₃O₄ nanoparticles were synthesized using a chemical co-precipitation method. 20 mmol of FeCl₃·6H₂O and 10 mmol of FeCl₂·4H₂O were dissolved in 75 mL of distilled water in a three-necked round bottomed flask under nitrogen atmosphere for 30 min. Then, 10 mL of NaOH (10 M) was added into the solution for 30 min with vigorous stirring. The stirring was further continued for 1 h. After that the mixture was heated at 85 °C for 1 h. The black precipitate formed was isolated by magnetic separation, washed with double distilled water and ethanol until neutrality and then dried under vacuum.

Preparation of Fe₃O₄@SiO₂ (ref. 13a). 0.50 g of the freshly made Fe₃O₄ nanoparticles was homogeneously dispersed in a mixture of 50 mL of ethanol, 9 mL of deionized water, and 1.0 mL of concentrated aqueous ammonia solution. Then 0.50 mL of TEOS was added to the mixture. The mixture was stirred at room temperature for 16 h under nitrogen atmosphere. After that the magnetic nanocomposites Fe₃O₄@SiO₂ were isolated by magnetic decantation to remove the unbounded silica particles, washed with de-ionized water and ethanol and dried under vacuum.

Preparation of Fe₃O₄@SiO₂– SO₃H MNPs^13a. A flask was charged with 500 mg of Fe₃O₄@SiO₂ nanocomposites and 10 mL of dry CH₂Cl₂. Then, chlorosulfonic acid (0.4 mL) was added dropwise to the solution of Fe₃O₄@SiO₂ over a period of 1 h, upon which HCl gas evolved from the reaction vessel immediately. After the addition was completed, the mixture was further stirred for 2 h. After the completion of the reaction, Fe₃O₄@SiO₂–SO₃H MNPs was collected using a normal magnet and washed with CH₂Cl₂ and ethanol and dried under vacuum.

Synthesis of arylhydrazones 4

Arylhydrazones 4 were prepared according to the literature procedure by refluxing aromatic aldehydes and arylhydrazines in toluene medium using Dean–Stark apparatus.¹⁸

General procedure for the synthesis of compounds 6

A mixture of tetrone 3 (0.5 mmol) and arylhydrazones 4 (0.5 mmol) was dissolved in minimum quantity of chloroform (3.0 mL) in a 100 mL round bottom flask. Then the mixture was soaked on Fe₃O₄@SiO₂–SO₃H nanoparticles (400 mg) by stirring for 10 min and the solvent was removed under reduced pressure. The thoroughly mixed reaction mixture was heated around 120 °C on an oil bath for 4 h with continuous stirring. Upon completion of the reaction, the solid mass was cooled to room temperature, ethyl acetate was added to the mixture and the product was extracted from the solid support by ultrasonication. The finely dispersed nanoparticles were separated from the solution by using an external magnetic bar and the separated organic phase was collected in another round bottom flask. The extract was concentrated under reduced pressure to get the crude product which was purified by column chromatography (ethyl acetate/hexanes) (v/v = 1 : 3) to afford pure compounds 6a–s.

Characterization data of 6a–s.
1,3-Diphenyl-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6a). Yellow amorphous solid, m.p. 236–238 °C; IR (KBr): 1520, 1692, 1735 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.03–7.90 (m, 3H), 7.84–7.80 (m, 2H), 7.66–7.62 (m, 2H), 7.60–7.57 (m, 3H), 7.42–7.29 (m, 2H), 7.09–7.00 (m, 4H), 6.97–6.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.7, 191.9, 150.2, 143.8, 140.6, 136.8, 135.7, 134.8, 131.7, 129.9, 129.6, 129.4, 128.7, 128.6, 128.5, 128.3, 128.0, 127.8, 127.2, 124.2, 123.3, 112.9, 70.5; C₃₁H₁₈N₂O₃ (466.48): C, 79.82; H, 3.89; N, 6.01; found C, 79.65; H, 3.83; N, 5.93.
1-Phenyl-3-(4′-methylphenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6b). Yellow amorphous solid, m.p. 214–216 °C; IR (KBr): 1514, 1687, 1733 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.95–7.92 (m, 3H), 7.84–7.81 (m, 2H), 7.64–7.56 (m, 5H), 7.41–7.30 (m, 2H), 7.03–6.95 (m, 3H), 6.76–6.73 (m, 2H), 2.12 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.4, 191.7, 149.9, 143.4, 140.3, 137.7, 136.4, 135.3, 134.5, 129.6, 129.3, 129.2, 129.1, 128.4, 128.2, 128.1, 127.6, 126.8, 126.7, 123.9, 123.0, 112.6, 70.3, 20.7; C₃₂H₂₀N₂O₃ (480.51): C, 79.99; H, 4.20; N, 5.83; found C, 79.83; H, 4.14; N, 5.76.
1-Phenyl-3-(4′-chlorophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6c). Yellow amorphous solid, m.p. 198–200 °C; IR (KBr): 1539, 1680, 1704 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.05–7.92 (m, 2H), 7.86–7.85 (m, 2H), 7.64–7.57 (m, 6H), 7.48–7.32 (m, 2H), 7.04–7.00 (m, 3H), 6.95–6.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.5, 191.6, 148.9, 143.6, 140.4, 137.0, 136.0, 134.9, 134.5, 130.2, 130.0, 129.7, 129.6, 128.6, 128.1, 127.9, 127.4, 127.0, 126.5, 124.3, 123.4, 112.8, 70.5; C₃₁H₁₇N₂O₃Cl (500.93): C, 74.33; H, 3.42; N, 5.59; found C, 74.13; H, 3.35; N, 5.50.
1-Phenyl-3-(3′-chlorophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6d). Yellow amorphous solid, m.p. 158–160 °C; IR (KBr): 1595, 1671, 1717 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.03–7.98 (m, 3H), 7.90–7.87 (m, 2H), 7.65–7.59 (m, 5H), 7.42–7.39 (m, 2H), 7.08–7.00 (m, 5H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.5, 191.7, 148.7, 143.6, 140.4, 137.2, 136.1, 134.9, 133.9, 133.6, 129.7, 129.5, 129.3, 128.7, 128.6, 128.4, 127.9, 127.0, 126.8, 124.4, 123.4, 112.6, 70.5; C₃₁H₁₇N₂O₃Cl (500.93): C, 74.33; H, 3.42; N, 5.59; found C, 74.15; H, 3.36; N, 5.51.
1-Phenyl-3-(4′-bromophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6e). Brown amorphous solid, m.p. 220–222 °C; IR (KBr): 1518, 1697, 1723 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.99–7.94 (m, 3H), 7.90–7.87 (m, 2H), 7.62–7.58 (m, 5H), 7.43–7.33 (m, 2H), 7.10–7.07 (m, 2H), 7.02–6.94 (m, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.5, 191.6, 149.0, 143.7, 140.5, 137.1, 136.0, 134.9, 131.0, 130.8, 130.3, 129.7, 129.5, 128.6, 128.0, 127.1, 124.3, 123.4, 122.7, 116.2, 112.8, 70.5; C₃₁H₁₇N₂O₃Br (545.38): C, 68.27; H, 3.14; N, 5.14; found C, 68.08; H, 3.07; N, 5.05.
1-Phenyl-3-(3′-bromophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6f). Brown amorphous solid, m.p. 152–154 °C; IR (KBr): 1527, 1691, 1727 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.02–7.87 (m, 4H), 7.62–7.58 (m, 6H), 7.47–7.36 (m, 2H), 7.33–7.20 (m, 3H), 7.16–6.99 (m, 1H), 6.96–6.89 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.5, 191.6, 148.5, 143.5, 140.4, 137.2, 136.1, 134.9, 133.8, 131.3, 131.0, 129.7, 129.6, 129.5, 129.2, 128.6, 127.9, 127.2, 127.0, 124.5, 123.4, 122.0, 120.7, 112.5, 70.5; C₃₁H₁₇N₂O₃Br (545.38): C, 68.27; H, 3.14; N, 5.14; found C, 68.06; H, 3.06; N, 5.03.
1-Phenyl-3-(4′-fluorophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6g). Yellow amorphous solid, m.p. 176–178 °C; IR (KBr): 1525, 1691, 1739 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.99–7.86 (m, 4H), 7.67–7.60 (m, 6H), 7.45–7.35 (m, 2H), 7.11–7.05 (m, 3H), 6.81–6.65 (m, 2H); ¹³C NMR (75 MHz, CDCl₃, F coupled) δ_C 194.7, 191.7, 164.3, 161.0, 149.2, 143.7, 140.6, 137.0, 135.9, 134.9, 130.7, 129.7, 129.5, 128.6, 128.0, 127.9, 127.1, 124.3, 123.4, 115.0, 114.7, 113.1, 70.3; C₃₁H₁₇N₂O₃F (484.47): C, 76.85; H, 3.54; N, 5.78, found C, 76.64; H, 3.46; N, 5.69.
1-Phenyl-3-(4′-cyanophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6h). Yellow amorphous solid, m.p. 246–248 °C; IR (KBr): 1516, 1694, 1742, 2235 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.99–7.93 (m, 5H), 7.68–7.62 (m, 4H), 7.42–7.37 (m, 2H), 7.29–7.21 (m, 5H), 7.00 (d, J = 7.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C 193.9, 190.8, 147.8, 143.2, 140.0, 137.2, 136.3, 135.9, 134.6, 131.3, 129.6, 129.5, 129.2, 128.9, 128.5, 127.5, 126.6, 124.1, 123.1, 117.9, 112.2, 111.8, 70.3; C₃₂H₁₇N₃O₃ (491.49): C, 78.20; H, 3.49; N, 8.55; found C, 78.02; H, 3.42; N, 8.47.
1-Phenyl-3-(3′-nitrophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6i). Brown amorphous solid, m.p. 190–192 °C; IR (KBr): 1534, 1665, 1714 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.93–7.80 (m, 5H), 7.67–7.55 (m, 8H), 7.35–7.18 (m, 3H), 6.93 (d, J = 7.5 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.2, 191.2, 147.5, 147.3, 143.4, 140.3, 137.6, 136.3, 134.9, 134.6, 133.7, 129.9, 129.5, 129.3, 128.8, 127.9, 127.3, 127.0, 126.6, 124.5, 123.4, 123.1, 122.9, 112.4, 70.7; C₃₁H₁₇N₃O₅ (511.48): C, 72.79; H, 3.35; N, 8.22; found C, 72.58; H, 3.27; N, 8.11.
1-Phenyl-3-(4′-methoxyphenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6j). Yellow amorphous solid, m.p. 204–206 °C; IR (KBr): 1525, 1696, 1744 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.96–7.95 (m, 3H), 7.87–7.83 (m, 2H), 7.68–7.58 (m, 5H), 7.44–7.35 (m, 2H), 7.05–7.01 (m, 3H), 6.51–6.48 (m, 2H), 3.64 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.4, 191.7, 159.2, 149.6, 143.4, 140.3, 136.4, 135.4, 134.5, 129.7, 129.3, 129.2, 129.1, 128.1, 127.6, 127.5, 127.1, 126.7, 123.9, 123.7, 123.0, 113.8, 70.2, 54.7; C₃₂H₂₀N₂O₄ (496.51): C, 77.41; H, 4.06; N, 5.64; found C, 77.24; H, 3.99; N, 5.56.
1-(4′-Bromophenyl)-3-phenyl-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6k). Brown amorphous solid, m.p. 228–230 °C; IR (KBr): 1521, 1693, 1737 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.95–7.91 (m, 3H), 7.86–7.82 (m, 2H), 7.75–7.72 (m, 2H), 7.56–7.53 (m, 2H), 7.50–7.47 (m, 1H), 7.45–7.38 (m, 1H), 7.10–7.06 (m, 4H), 6.98–6.93 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.1, 191.4, 150.3, 143.4, 139.2, 136.6, 135.5, 134.5, 132.5, 131.1, 129.2, 128.3, 128.1, 127.7, 127.5, 123.9, 123.2, 122.9, 113.0, 70.5; C₃₁H₁₇N₂O₃Br (545.38): C, 68.27; H, 3.14; N, 5.14; found C, 68.10; H, 3.08; N, 5.06.
1-(4′-Bromophenyl)-3-(4′-methylphenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6l). Brown amorphous solid, m.p. 234–236 °C; IR (KBr): 1519, 1694, 1728 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.94–7.87 (m, 3H), 7.86–7.84 (m, 2H), 7.75–7.72 (m, 2H), 7.56–7.50 (m, 2H), 7.48–7.36 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.97–6.94 (m, 2H), 6.78–6.75 (m, 2H), 2.15 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.5, 191.8, 150.7, 143.7, 139.6, 138.2, 136.9, 135.7, 134.9, 132.8, 129.7, 129.6, 128.7, 128.6, 128.5, 128.0, 124.3, 123.4, 123.3, 113.3, 70.6, 21.0; C₃₂H₁₉N₂O₃Br (559.40): C, 68.71; H, 3.42; N, 5.01; found C, 68.50; H, 3.35; N, 4.93.
1-(4′-Bromophenyl)-3-(2′-chlorophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6m). Brown amorphous solid, m.p. 224–226 °C; IR (KBr): 1600, 1660, 1720 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.02–7.86 (m, 1H), 7.85–7.82 (m, 2H), 7.77–7.72 (m, 4H), 7.61–7.32 (m, 5H), 7.15–7.02 (m, 2H), 7.01–6.92 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 193.9, 192.1, 147.6, 143.4, 139.4, 136.5, 135.6, 134.8, 134.3, 132.9, 132.8, 132.1, 130.3, 130.0, 129.5, 128.8, 128.5, 128.3, 125.9, 123.9, 123.5, 123.2, 114.6, 69.4; C₃₁H₁₆N₂O₃BrCl (579.82): C, 64.21; H, 2.78; N, 4.83; found C, 64.02; H, 2.71; N, 4.73.
1-(4′-Bromophenyl)-3-(3′-chlorophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6n). Yellow amorphous solid, m.p. 230–232 °C; IR (KBr): 1564, 1695, 1722 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.94–7.92 (m, 3H), 7.91–7.79 (m, 2H), 7.68–7.62 (m, 2H), 7.46–7.37 (m, 3H), 7.34–7.29 (m, 1H), 7.00–6.91 (m, 3H), 6.90–6.86 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.4, 191.5, 149.1, 143.6, 139.5, 137.3, 136.1, 135.0, 134.0, 133.3, 133.0, 129.6, 129.4, 128.9, 128.6, 128.0, 126.8, 124.5, 123.7, 123.3, 70.5; C₃₁H₁₆N₂O₃BrCl (579.82): C, 64.21; H, 2.78; N, 4.83; found C, 64.03; H, 2.73; N, 4.74.
1-(4′-Bromophenyl)-3-(2′-bromophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6o). Yellow amorphous solid, m.p. 252–254 °C; IR (KBr): 1595, 1671, 1707 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.00–7.99 (m, 1H), 7.85–7.81 (m, 2H), 7.75–7.71 (m, 4H), 7.56–7.41 (m, 4H), 7.23–7.21 (m, 1H), 7.15–7.12 (m, 1H), 7.06–7.04 (m, 1H), 6.95–6.89 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.0, 192.2, 149.0, 143.4, 139.4, 136.5, 135.6, 134.9, 132.8, 132.2, 132.1, 130.2, 129.5, 129.4, 128.9, 128.5, 128.3, 126.4, 124.4, 124.0, 123.6, 123.2, 114.4, 69.2; C₃₁H₁₆N₂O₃Br₂ (624.27): C, 59.64; H, 2.58; N, 4.49; found C, 59.46; H, 2.51; N, 4.40.
1-(4′-Bromophenyl)-3-(3′-bromophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6p). Yellow amorphous solid, m.p. 232–234 °C; IR (KBr): 1592, 1655, 1703 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.02–7.87 (m, 5H), 7.75–7.72 (m, 2H), 7.53–7.38 (m, 4H), 7.21 (d, J = 7.8 Hz, 1H), 7.14–7.11 (m, 3H), 7.07–6.92 (m, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.3, 191.4, 148.9, 143.5, 139.4, 137.3, 136.1, 134.9, 133.6, 132.9, 131.4, 131.3, 129.6, 129.4, 128.8, 128.5, 127.9, 127.1, 124.5, 123.7, 123.2, 122.0, 70.5; C₃₁H₁₆N₂O₃Br₂ (624.27): C, 59.64; H, 2.58; N, 4.49, found C, 59.43; H, 2.50; N, 4.39.
1-(4′-Bromophenyl)-3-(4′-bromophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6q). Brown amorphous solid, m.p. 160–162 °C; IR (KBr): 1517, 1696, 1744 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.99–7.88 (m, 5H), 7.79–7.73 (m, 2H), 7.55–7.37 (m, 4H), 7.12–7.06 (m, 3H), 6.99–6.93 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.0, 191.1, 149.0, 143.3, 139.1, 136.8, 135.1, 135.7, 134.6, 132.6, 132.3, 130.7, 129.9, 129.3, 128.5, 128.2, 127.6, 124.0, 123.3, 122.9, 122.6, 117.3, 70.1; C₃₁H₁₆N₂O₃Br₂ (624.27): C, 59.64; H, 2.58; N, 4.49; found C, 59.44; H, 2.51; N, 4.39.
1-(4′-Bromophenyl)-3-(3′-nitrophenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6r). Brown amorphous solid, m.p. 150–152 °C; IR (KBr): 1537, 1670, 1725 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 8.02–7.93 (m, 4H), 7.91–7.87 (m, 2H), 7.77–7.70 (m, 3H), 7.67–7.64 (m, 1H), 7.54–7.47 (m, 3H), 7.44–7.34 (m, 1H), 7.32–7.26 (m, 1H), 7.07 (d, J = 7.2 Hz, 1H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.1, 191.1, 148.0, 147.3, 143.4, 139.3, 137.8, 136.4, 135.0, 134.6, 133.4, 133.1, 129.7, 129.5, 129.2, 129.1, 128.5, 127.9, 124.6, 124.0, 123.4, 123.3, 122.9, 112.7, 70.5; C₃₁H₁₆N₃O₅Br (590.37): C, 63.07; H, 2.73; N, 7.12; found C, 62.86; H, 2.66; N, 7.02.
1-(4′-Bromophenyl)-3-(4′-methoxyphenyl)-4-spiro(1′,3′-indanedione)-1,4-dihydrobenzo[g]indazol-5-one (6s). Brown amorphous solid, m.p. 218–220 °C; IR (KBr): 1521, 1692, 1731 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ_H 7.90–7.87 (m, 3H), 7.79–7.76 (m, 2H), 7.67–7.64 (m, 2H), 7.48–7.45 (m, 2H), 7.39 (t, J = 7.8 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.93–6.90 (m, 2H), 6.43–6.40 (m, 2H); 3.57 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ_C 194.6, 191.8, 159.6, 150.4, 143.7, 139.6, 136.8, 135.8, 134.9, 132.8, 130.0, 129.7, 129.6, 128.6, 128.0, 124.3, 123.7, 123.5, 123.3, 113.3, 70.5, 55.1; C₃₂H₁₉N₂O₄Br (575.40): C, 66.79; H, 3.33; N, 4.87; found C, 66.60; H, 3.26; N, 4.80.
Intermediate 10q. Yellow amorphous solid, m.p. 214–216 °C; IR (KBr): 1701, 1721, 3340 cm⁻¹. ¹H NMR (300 MHz, DMSO-d₆) δ_H 8.45 (s, 1H), 8.10–8.07 (m, 2H), 7.97–7.78 (m, 5H), 7.72–7.52 (m, 6H), 7.49–7.37 (m, 3H), 5.06 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ_C 197.1, 196.5, 195.6, 148.1, 141.5, 141.0, 140.9, 140.8, 136.0, 135.5, 135.4, 135.0, 131.6, 131.4, 131.2, 130.6, 129.1, 125.1, 123.8, 122.7, 122.6, 121.9, 119.7, 113.9, 99.5, 73.4, 53.3; C₃₁H₁₈N₂O₄Br₂ (642.29): C, 57.97; H, 2.82; N, 4.36; found C, 57.76; H, 2.75; N, 4.26.

Acknowledgements

A. K. and S. M. thank UGC, New Delhi, India for offering Senior Research Fellowship (SRF) and Junior Research Fellowship (JRF) respectively. The financial assistance of CSIR, New Delhi is gratefully acknowledged [Major Research Project, No. 02(0007)/11/EMR-II]. Crystallography was performed at the DST-FIST, India-funded single crystal diffractometer facility at the Department of Chemistry, University of Calcutta. We also acknowledge Center for Research in Nanoscience and Nanotechnology (CRNN), University of Calcutta for instrumental facilities.

References

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Footnote

† Electronic supplementary information (ESI) available: Supplementary data (¹H and ¹³C data of the synthesized compounds). CCDC 1412850, 1415047 and 1434717. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra23599e

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