Diastereoselective synthesis of spiro[indene-2,2′-pyrazolo[1,2-a]pyrazoles] and spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] via 1,3-dipolar cycloaddition

Abstract

The 1,3-dipolar cycloaddition of cyclic azomethine imines with 2-arylideneindene-1,3-diones in refluxing acetonitrile afforded predominately cis-1,3-diaryl-substituted spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole] derivatives in good yields. Significantly, the similar cycloaddition reaction of cyclic azomethine imines with 3-phenacylideneoxindoles gave polysubstituted spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] in good yields and with high diastereoselectivity.

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Introduction

Among various nitrogen-containing heterocycles, pyrazolo[1,2-a]pyrazolone is a privileged heterocyclic ring system that is featured in a large number of medicinally relevant compounds exhibiting biological activities.^1–3 For example, Lilly's γ-lactam antibiotics LY 186826, LY 193239, and LY 255262 are pyrazolo[1,2-a]pyrazolone based peptidomimetics.^4a Pyrazolo[1,2-a]pyrazolones are also used as herbicides^5a and inhibitors of acetyl-CoA carboxylase^5b and sarco(endo)plasmic reticulum Ca²⁺–ATPase.^5c These potential properties have prompted many efforts toward the synthesis of various pyrazolo[1,2-a]pyrazolone derivatives.^6,7 1,3-Dipolar cycloaddition reaction has proved to be the most powerful protocol for various five-membered heterocyclic compounds.^8,9 Thus, the common method for the preparation of pyrazolo[1,2-a]pyrazolone derivatives was the 1,3-dipolar cycloaddition of cyclic azomethine imines to olefinic and acetylenic dipolarophiles.^10,11 For this purpose, many elegant synthetic methodologies and procedures have been developed for efficient and stereoselective synthesis of highly functionalized pyrazolo[1,2-a]pyrazolones.^12,13 Despite these extensive efforts, the application of cyclic azomethine imines for synthesis of spirocyclic pyrazolo[1,2-a]pyrazolone derivatives has rarely been reported in the literature.¹⁴ Against this situation and on the our continual aim to providing concise construction protocol for spiroheterocyclic system,^15,16 we proposed to design the 1,3-dipolar cycloaddition by using cyclic azomethine imines and cyclic dipolarophiles to synthesize spirocyclic pyrazolo[1,2-a]pyrazolones. Herein we wish to report the diastereoselective synthesis of polysubstituted spiro[indene-2,2′-pyrazolo[1,2-a]pyrazoles] and spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] via 1,3-dipolar cycloaddition.

Results and discussion

According to the previously reported 1,3-dipolar cycloaddition of cyclic azomethine imine for synthesis of functionalized pyrazolo[1,2-a]pyrazolones, the reaction conditions were examined by employing the 1,3-dipolar reaction of 2-benzylidene-5-oxopyrazolidiniumide and 2-(m-methoxybenzylidene)indene-1,3-dione as model reaction. When the reaction was carried out at room temperature in solvent such as methanol, ethanol and acetonitrile, the reaction proceeded very slowly and cannot be finished after 36 hours. If the reaction was carried out in refluxing methylene dichloride, toluene and acetonitrile, the expected product 1a can be obtained in about 27%, 34% and 70% yields, respectively. If methanol, ethanol and DMF were used as solvent, no expected product was obtained both at room temperature and at the elevated temperature. It is also observed that acidic catalyst such as p-toluenesulfonic acid, and Lewis acid copper chloride, copper acetate, etc., did not increase the yield of product. On the other hand, the reaction would be greatly hindered in the presences of the base such as triethylamine, piperidine and DBU. Finally, the reaction would cause formation of some byproducts in refluxing acetonitrile. It is better to carry the reaction in acetontrile at 70–75 °C, and the reaction would be finished in eight hours to give the expected product 1a in 75% yield. Thus, the best reaction condition is carrying out this 1,3-dipolar cycloaddition in the solvent of acetonitrile at 70–75 °C.

After obtaining the optimized reaction conditions, various cyclic azomethine imines and 2-arylidieneindene-1,3-diones were employed in the reaction. The results are summarized in Table 1 it can be seen that all reaction proceeded very smoothly to give the polysubstituted spiro[indene-2,2′-pyrazolo[1,2-a]pyrazoles] 1a–1q in satisfactory yields. The different aryl groups showed marginal effect on the yields of products. o-Hydroxyphenyl substituted azomethine imine also afforded the spiro product 1n in god yield.

Table 1 Synthesis of spiro[indene-2,2′-pyrazolo[1,2-a]pyrazoles] 1a–1q^a

Entry	Compd	Ar	Ar′	Yield^b (%)
a Reaction condition: cyclic azomethine imine (0.5 mmol), 2-arylideneindene-1,3-dione (0.5 mmol) CH3CN (15.0 mL), 70–75 °C 8 h.b Isolated yields.
1	1a	C6H5	m-CH3OC6H4	75
2	1b	C6H5	p-BrC6H4	67
3	1c	p-CH3C6H4	p-CH3C6H4	82
4	1d	p-CH3C6H4	m-CH3OC6H4	67
5	1e	p-CH3C6H4	p-ClC6H4	70
6	1f	p-CH3C6H4	p-BrC6H4	59
7	1g	p-CH3C6H4	m-NO2C6H4	86
8	1h	m-CH3C6H4	p-ClC6H4	73
9	1i	p-CH3OC6H4	m-CH3OC6H4	75
10	1j	p-CH3OC6H4	p-BrC6H4	60
11	1k	p-ClC6H4	m-CH3OC6H4	70
12	1l	p-ClC6H4	p-ClC6H4	69
13	1m	p-ClC6H4	p-BrC6H4	72
14	1n	p-BrC6H4	m-CH3OC6H4	65
15	1o	p-BrC6H4	p-BrC6H4	68
16	1p	m-NO2C6H4	p-ClC6H4	80
17	1q	o-HOC6H4	p-BrC6H4	55

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The structures of the obtained products 1a–1q were fully characterized by IR, HRMS, ¹H and ¹³C NMR spectroscopy. Because the two aryl groups can exist in cis/trans-configuration, the obtained products 1a–1q might have two diastereoisomers. The ¹H and ¹³C NMR spectra always display one set of typical absorptions for the characteristic groups in the molecules, which definitely indicated that the products 1a–1q existed in only one diastereoisomer. For an example, the compound 1a display two singlets at 5.72, and 4.38 ppm for the two CH units in newly-formed pyrazole ring and a singlet at 3.61 ppm for methoxy group in m-methoxyphenyl group. The two CH₂ units in original pyrazole ring show three mixed peaks with 1 : 2 : 1 integral. In order to confirm the configuration of the compounds 1a–1q, the single crystal structures of the compounds 1c (Fig. 1), 1e, 1k, 1m, 1n (Fig. 2) and 1o were successfully determined by X-ray diffraction method. As showed in Fig. 1, the two p-methylphenyl group exists in the cis-configuration. It also can be seen that the m-methoxyphenyl group and p-bromophenyl group also stand in cis-position (Fig. 2). The other four molecules also have cis-configuration (Fig. s1–s4). Thus, we could concluded that the obtained 1a–1q are cis-diastereoisomer, which also indicated that this 1,3-dipolar cycloaddition reaction is a regioselective and diastereoselective reaction.

Fig. 1 Molecular structure of compound 1c.

Fig. 2 Molecular structure of compound 1n.

To further illustrate the synthetic value of 1,3-dipolar cycloaddition reaction for the synthesis of spiroheterocycles, 3-phenacylideneoxindoles were employed to react with cyclic azomethine imines under same reaction conditions. The results are summarized in Table 2. Various 3-phenacylideneoxindoles with different substituents afforded the expected spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] 2a–2j in high yields. It should be pointed out that 3-phenacylideneoxindoles without N-substituent also gave the spiro compound 2h in good yield. The structures of the spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] 2a–2j were also established by spectroscopy. The ¹H and ¹³C NMR spectra of compounds 2a–2j showed one set of typical absorptions for the characteristic groups in the molecules, which clearly indicated that only one diastereoisomer exists in the products 2a–2j. Single crystal structures of two representative compounds 2a and 2f displayed that the 1′-aryl group, 3-benzoyl group and the phenyl group of the oxindole moiety all exist in cis-configuration in the newly-formed pyrazole ring (Fig. 3 and 4). On the basis of ¹H NMR spectra and single crystal structures, it can be concluded that the 1,3-dipolar cycloaddition of cyclic azomethine imines with 3-phenacylideneoxindoles predominately produced the cis-diastereoisomer of the polysubstituted spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] 2a–2j. Recently, it has reported that Cu(OAc)₂ catalyzed 1,3-dipolar cycloaddition of cyclic azomethine imines with some 3-(ethoxycarbonylmethylene)oxindoles mainly afforded the trans-diastereoisomer of spiro[pyrazolidin-3,3′-oxindoles].¹⁴ Although the two reactions are similar 1,3-dipolar cycloaddition of cyclic azomethine imines with 3-methyleneoxindoles, the configuration of the product is different.

Table 2 Synthesis of spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles] 2a–2j^a

Entry	Compd	Ar	R	R′	Ar′	Yield^b (%)
a Reaction condition: cyclic azomethine imines (0.5 mmol), 3-phenacylideneoxindole (0.5 mmol) in CH3CN (15.0 mL), reflux, 7 h.b Isolated yields.
1	2a	C6H5	CH3	Bn	p-CH3C6H4	56
2	2b	C6H4	Cl	Bn	p-CH3C6H4	60
3	2c	p-CH3C6H4	Cl	Bn	p-CH3C6H4	68
4	2d	p-CH3OC6H4	CH3	Bn	p-CH3C6H4	70
5	2e	p-CH3OC6H4	Cl	Bn	p-CH3C6H4	55
6	2f	p-ClC6H4	Cl	Bn	p-CH3C6H4	65
7	2g	p-BrC6H4	CH3	Bn	p-CH3C6H4	62
8	2h	p-BrC6H4	CH3	H	p-ClC6H4	65
9	2i	p-BrC6H4	Cl	Bn	p-CH3C6H4	58
10	2j	p-BrC6H4	Cl	Bn	p-ClC6H4	69

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Fig. 3 Molecular structure of compound 2a.

Fig. 4 Molecular structure of compound 2f.

Conclusion

In summary, we have successfully developed concise protocol for the construction of spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole] and spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]. This method originated from the 1,3-dipolar cycloaddition reaction of cyclic azomethine imines with 2-arylideneindene-1,3-diones and 3-phenacyliceneoxindoles. It also provided new way to further exploiting 1,3-dipolar cycloaddition for the regioselective and diastereoselective synthesis of nitrogen-containing spiroheterocycles. This reaction also has the advantages of using readily variable substrates, simple reaction condition, without using catalyst, easiness of handling, satisfactory yields and wide variety of substrates.

Experimental section

1. General procedure for 1,3-dipolar cycloaddition reaction of cyclic azomethine imines with 2-arylideneindene-1,3-dione

A mixture of cyclic azomethine imines (0.5 mmol) and 2-arylideneindene-1,3-dione (0.5 mmol) in acetonitrile (15.0 mL) was heated to 70–75 °C for eight hours. After cooling, the resulting precipitate was collected by filtration to give crude product, which was subjected to column chromatography with light petroleum and ethyl acetate (v/v = 3 : 1) as elute to give pure product for analysis.

3′-(3-Methoxyphenyl)-1′-phenyl-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1a). White solid, 75%, mp 168–170 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J = 7.6 Hz, 1H, ArH), 7.71 (t, J = 7.6 Hz, 1H, ArH), 7.60 (t, J = 7.6 Hz, 1H, ArH), 7.43 (d, J = 8.0 Hz, 1H, ArH), 7.22–7.20 (m, 2H, ArH), 7.11–7.09 (m, 3H, ArH), 7.05 (t, J = 8.0 Hz, 1H, ArH), 6.67–6.62 (m, 3H, ArH), 5.77 (s, 1H, CH), 4.43–4.42 (m, 1H, CH), 3.88–3.84 (m, 1H, CH), 3.62 (s, 3H, OCH₃), 3.12–3.04 (m, 2H, CH), 2.93–2.88 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 198.2, 194.4, 172.6, 159.6, 143.1, 141.2, 136.7, 136.3, 135.5, 131.5, 129.5, 128.8, 128.5, 127.8, 123.2, 118.0, 113.6, 111.3, 72.0, 63.2, 55.1, 48.2, 32.6; IR (KBr) ν: 2958, 2838, 1740, 1708, 1646, 1597, 1489, 1464, 1432, 1338, 1260, 1235, 1176, 1125, 1098, 1072, 1037, 948, 889, 861, 790, 770, 746, 719, 698 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₃N₂O₄ ([M + H]⁺): 439.1652. Found: 439.1654.

3′-(4-Bromophenyl)-1′-phenyl-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1b). White solid, 67%, mp 164–166 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J = 8.0 Hz, 1H, ArH), 7.73 (t, J = 7.6 Hz, 1H, ArH), 7.61 (t, J = 7.6 Hz, 1H, ArH), 7.43 (d, J = 7.6 Hz, 1H, ArH), 7.30–7.28 (m, 2H, ArH), 7.18–7.16 (m, 2H, ArH), 7.11–7.10 (m, 3H, ArH), 6.98 (d, J = 8.4 Hz, 2H, ArH), 5.73 (s, 1H, CH), 4.40 (s, 1H, CH), 3.86–3.81 (m, 1H, CH), 3.11–3.05 (m, 2H, CH), 2.94–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 197.9, 194.5, 172.6, 142.9, 141.1, 136.5, 135.7, 134.4, 131.5, 131.3, 128.9, 128.5, 127.7, 127.6, 123.3, 121.9, 71.9, 62.6, 48.1, 32.4; IR (KBr) ν: 2957, 1711, 1491, 1413, 1343, 1274, 1231, 1174, 1078, 1012, 868, 811, 763 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₂₀BrN₂O₃ ([M + H]⁺): 487.0652. Found: 487.0653.

1′,3′-Di-p-tolyl-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1c). White solid, 82%, mp 168–170 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J = 7.6 Hz, 1H, ArH), 7.71 (t, J = 7.6 Hz, 1H, ArH), 7.59 (t, J = 7.6 Hz, 1H, ArH), 7.43 (d, J = 7.6 Hz, 1H, ArH), 7.08 (d, J = 8.0 Hz, 2H, ArH), 6.94–6.89 (m, 6H, ArH), 5.76 (s, 1H, CH), 4.39 (s, 1H, CH), 3.83–3.78 (m, 1H, CH), 3.11–3.02 (m, 2H, CH), 2.90–2.84 (m, 1H, CH), 2.19 (s, 3H, CH₃), 2.15 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 198.3, 194.8, 171.8, 143.1, 141.3, 138.6, 137.4, 136.2, 135.5, 132.0, 129.1, 129.1, 128.4, 127.7, 125.6, 123.2, 123.2, 72.0, 63.2, 48.5, 32.8, 21.1, 21.0; IR (KBr) ν: 3030, 2950, 1706, 1589, 1811, 1451, 1413, 1342, 1241, 1176, 1120, 1083, 1027, 964, 906, 864, 793, 748 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₅N₂O₃ ([M + H]⁺): 437.1860. Found: 437.1868.

3′-(3-Methoxyphenyl)-1′-(p-tolyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1d). White solid, 67%, mp 194–196 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J = 7.6 Hz, 1H, ArH), 7.71 (td, J₁ = 7.2 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.60 (td, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.44 (d, J = 7.6 Hz, 1H, ArH), 7.09–7.03 (m, 3H, ArH), 6.90 (d, J = 8 Hz, 2H, ArH), 6.66–6.63 (m, 2H, ArH), 6.59–6.58 (m, 1H, ArH), 5.75 (s, 1H, CH), 4.37 (s, 1H, CH), 3.82–3.78 (m, 1H, CH), 3.61 (s, 3H, OCH₃), 3.08–3.00 (m, 2H, CH), 2.91–2.86 (m, 1H, CH), 2015 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 198.3, 194.5, 172.5, 159.5, 143.2, 141.2, 138.7, 136.7, 136.2, 135.5, 131.7, 129.6, 129.5, 129.1, 128.4, 127.7, 123.2, 123.2, 118.0, 113.6, 111.2, 71.9, 63.3, 55.1, 48.2, 32.5, 21.0; IR (KBr) ν: 2960, 2837, 1741, 1707, 1597, 1513, 1490, 1466, 1433, 1351, 1278, 1260, 1236, 1178, 1095, 956, 921, 891, 862, 791, 746 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₄N₂NaO₄ ([M + Na]⁺): 475.1628. Found: 475.1631.

3′-(4-Chlorophenyl)-1′-(p-tolyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1e). White solid, 70%, mp 156–158 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J = 7.6 Hz, 1H, ArH), 7.73 (t, J = 7.6 Hz, 1H, ArH), 7.62 (t, J = 7.6 Hz, 1H, ArH), 7.46 (d, J = 8.0 Hz, 1H, ArH), 7.13 (d, J = 8.4 Hz, 2H, ArH), 7.08–7.03 (m, 4H, ArH), 6.91 (d, J = 8.4 Hz, 2H, ArH), 5.73 (s, 1H, CH), 4.39 (s, 1H, CH), 3.86–3.81 (m, 1H, CH), 3.10–3.03 (m, 2H, CH), 2.91–2.86 (m, 1H, CH), 2.16 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 198.0, 194.6, 172.5, 143.0, 141.2, 138.8, 136.4, 135.7, 133.8, 133.7, 129.2, 128.6, 128.1, 127.6, 127.3, 123.3, 123.3, 71.8, 62.7, 48.2, 32.4, 21.0; IR (KBr) ν: 2922, 2839, 1708, 1590, 1491, 1419, 1345, 1297, 1252, 1175, 1121, 1086, 1010, 868, 821, 788, 743 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₂ClN₂O₃ ([M + H]⁺): 457.1313. Found: 457.1318.

3′-(4-Bromophenyl)-1′-(p-tolyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1f). White solid, 59%, mp 158–160 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J = 7.6 Hz, 1H, ArH), 7.73 (t, J = 7.6 Hz, 1H, ArH), 7.62 (t, J = 7.2 Hz, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.29–7.28 (m, 2H, ArH), 7.06 (d, J = 8.0 Hz, 2H, ArH), 6.98 (d, J = 8.0 Hz, 2H, ArH), 6.90 (d, J = 7.6 Hz, 2H, ArH), 5.71 (s, 1H, CH), 4.37 (s, 1H, CH), 3.83–3.79 (m, 1H, CH), 3.09–3.02 (m, 2H, CH), 2.91–2.86 (m, 1H, CH), 2.15 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 198.0, 194.6, 172.5, 143.0, 141.2, 138.8, 136.4, 135.7, 134.4, 131.5, 129.2, 128.2, 127.6, 127.6, 127.6, 123.4, 123.3, 121.9, 71.8, 62.7, 48.1, 32.5, 21.0; IR (KBr) ν: 2950, 1705, 1489, 1407, 1340, 1231, 1176, 1118, 1080, 1008, 864, 782, 741 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₂BrN₂O₃ ([M + H]⁺): 501.0808. Found: 501.0807.

3′-(3-Nitrophenyl)-1′-(p-tolyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1g). White solid, 86%, mp 196–198 °C; ¹H NMR (600 MHz, CDCl₃) δ: 8.02–7.98 (m, 3H, ArH), 7.75 (t, J = 7.2 Hz, 1H, ArH), 7.61 (t, J = 7.2 Hz, 1H, ArH), 7.45 (d, J = 7.2 Hz, 1H, ArH), 7.40–7.35 (m, 2H, ArH), 7.04 (d, J = 8.4 Hz, 2H, ArH), 6.90 (d, J = 7.2 Hz, 2H, ArH), 5.82 (s, 1H, CH), 4.37 (s, 1H, CH), 3.86–3.81 (m, 1H, CH), 3.12–3.07 (m, 1H, CH), 3.05–2.99 (m, 1H, CH); 2.93–2.87 (m, 1H, CH); 2.15 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 197.7, 194.5, 174.0, 148.2, 142.9, 141.1, 139.0, 138.2, 136.6, 136.0, 132.2, 129.4, 129.2, 128.1, 127.7, 123.5, 123.2, 122.9, 121.3, 77.7, 71.9, 62.3, 47.2, 31.6, 21.0; IR (KBr) ν: 3051, 1711, 1587, 1529, 1343, 1262, 1186, 1095, 956, 892, 834, 812, 758, 733 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁N₃NaO₅ ([M + Na]⁺): 490.1373. Found: 490.1383.

3′-(4-Chlorophenyl)-1′-(m-tolyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1h). White solid, 73%, mp 156–158 °C; ¹H NMR (600 MHz, CDCl₃) δ: 7.95 (d, J = 7.2 Hz, 1H, ArH), 7.72 (t, J = 7.2 Hz, 1H, ArH), 7.61 (t, J = 7.2 Hz, 1H, ArH), 7.43 (d, J = 7.2 Hz, 1H, ArH), 7.13 (d, J = 8.4 Hz, 2H, ArH), 7.04 (d, J = 7.2 Hz, 2H, ArH), 6.98–6.95 (m, 3H, ArH), 6.89 (d, J = 7.2 Hz, 1H, ArH), 5.74 (s, 1H, CH), 4.35 (s, 1H, CH), 3.83–3.82 (m, 1H, CH), 3.08–3.02 (m, 2H, CH), 2.91–2.85 (m, 1H, CH), 2.14 (s, 3H, CH₃); ¹³C NMR (150 MHz, CDCl₃) δ: 197.9, 194.5, 172.6, 143.1, 141.3, 138.3, 136.4, 135.6, 133.9, 133.7, 131.3, 129.7, 128.6, 128.4, 128.3, 127.3, 124.9, 123.3, 123.2, 77.5, 72.1, 62.6, 48.1, 32.4, 29.7, 21.1; IR (KBr) ν: 2919, 2849, 1740, 1710, 1588, 1543, 1491, 1338, 1256, 1188, 1091, 1042, 1013, 943, 866, 785, 701 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁ClN₂NaO₃ ([M + Na]⁺): 479.1133. Found: 479.1139.

3′-(3-Methoxyphenyl)-1′-(4-methoxyphenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1i). White solid, 75%, mp 184–186 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.95 (d, J = 7.2 Hz, 1H, ArH), 7.72 (t, J = 7.2 Hz, 1H, ArH), 7.64–7.60 (m, 1H, ArH), 7.47–7.45 (m, 1H, ArH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 7.05 (t, J = 7.6 Hz, 1H, ArH), 6.66–6.62 (m, 5H, ArH), 5.75 (s, 1H, CH), 4.37 (s, 1H, CH), 3.84–3.80 (m, 1H, CH), 3.66 (s, 3H, OCH₃), 3.62 (s, 3H, OCH₃) 3.11–3.01 (m, 2H, CH), 2.92–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 198.3, 194.7, 172.6, 159.8, 159.6, 143.2, 141.2, 136.8, 136.3, 135.5, 129.5, 129.1, 123.2, 129.2, 118.0, 113.8, 113.6, 111.2, 71.9, 63.2, 55.1, 48.1, 32.5; IR (KBr) ν: 3009, 2956, 2835, 1740, 1706, 1602, 1516, 1490, 1466, 1436, 1358, 1301, 1258, 1177, 1096, 1037, 959, 916, 893, 834, 789, 746 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₈H₂₄N₂NaO₅ ([M + Na]⁺): 491.1577. Found: 491.1579.

3′-(4-Bromophenyl)-1′-(4-methoxyphenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1j). White solid, 60%, mp 160–162 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (d, J = 7.6 Hz, 1H, ArH), 7.73 (t, J = 7.6 Hz, 1H, ArH), 7.64 (d, J = 7.2 Hz, 1H, ArH), 7.47 (d, J = 7.6 Hz, 1H, ArH), 7.29–7.27 (m, 2H, ArH), 7.21 (d, J = 8.4 Hz, 2H, ArH), 6.97 (d, J = 8.4 Hz, 2H, ArH), 6.62 (d, J = 8.4 Hz, 2H, ArH), 5.71 (s, 1H, CH), 4.34 (s, 1H, CH), 3.81–3.77 (m, 1H, CH), 3.66 (s, 3H, OCH₃), 3.08–3.01 (m, 2H, CH), 2.91–2.86 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 198.0, 194.8, 172.6, 159.8, 145.3, 143.0, 141.2, 136.5, 135.7, 135.6, 135.4, 134.4, 132.1, 131.5, 129.0, 127.5, 123.5, 123.3, 123.3, 122.9, 121.8, 113.9, 71.9, 62.6, 55.1, 48.0, 32.4; IR (KBr) ν: 2921, 2835, 1703, 1508, 1347, 1299, 1250, 1179, 1082, 1036, 808, 769 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₂BrN₂O₄([M + H]⁺): 517.0757. Found: 517.0754.

[1′-(4-Chlorophenyl)-3′-(3-methoxyphenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1k). White solid, 70%, mp 200–202 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 7.6 Hz, 1H, ArH), 7.75 (td, J₁ = 7.2 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.64 (td, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.17 (d, J = 8.8 Hz, 2H, ArH), 7.09 (d, J = 8.4 Hz, 2H, ArH), 7.04 (t, J = 8.0 Hz, 1H, ArH), 6.67–6.58 (m, 3H, ArH), 5.72 (s, 1H, CH), 4.39 (s, 1H, CH), 3.84–3.79 (m, 1H, CH), 3.61 (s, 3H, OCH₃), 3.08–3.03 (m, 2H, CH), 2.92–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 198.1, 194.3, 172.7, 159.6, 143.1, 141.1, 136.5, 136.5, 135.7, 134.7, 130.3, 129.5, 129.2, 128.7, 123.3, 123.3, 118.0, 113.7, 111.4, 76.3, 71.7, 63.5, 55.1, 48.0, 32.3; IR (KBr) ν: 3087, 2960, 2904, 2834, 1740, 1707, 1597, 1489, 1466, 1433, 1379, 1340, 1307, 1279, 1260, 1235, 1176, 1091, 1040, 1015, 955, 921, 890, 849, 821, 789, 755, 730 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁ClN₂NaO₄ ([M + Na]⁺): 495.1082. Found: 495.1084.

1′,3′-Bis(4-chlorophenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1l). White solid, 69%, mp 170–172 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 7.6 Hz, 1H, ArH), 7.77 (t, J = 7.6 Hz, 1H, ArH), 7.67 (t, J = 7.6 Hz, 1H, ArH), 7.47 (d, J = 7.6 Hz, 1H, ArH), 7.16–7.09 (m, 6H, ArH), 7.02 (d, J = 8.4 Hz, 2H, ArH), 5.71 (s, 1H, CH), 4.37 (s, 1H, CH), 3.82–3.78 (m, 1H, CH), 3.06–3.01 (m, 2H, CH), 2.92–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 197.8, 194.4, 172.8, 142.9, 141.0, 136.7, 136.0, 134.8, 133.8, 133.6, 130.0, 129.1, 128.8, 128.6, 127.3, 123.4, 123.4, 76.4, 71.6, 62.9, 48.0, 32.2; IR (KBr) ν: 2952, 2842, 1708, 1591, 1489, 1408, 1343, 1232, 1179, 1088, 1009, 964, 904, 804, 740 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₁₉Cl₂N₂O₃ ([M + H]⁺): 477.0767. Found: 477.0772.

3′-(4-Bromophenyl)-1′-(4-chlorophenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1m). White solid, 72%, mp 174–176 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 7.6 Hz, 1H, ArH), 7.77 (t, J = 7.2 Hz, 1H, ArH), 7.67 (t, J = 7.6 Hz, 1H, ArH), 7.47 (d, J = 7.6 Hz, 1H, ArH), 7.29–7.27 (m, 2H, ArH), 7.15 (d, J = 8.4 Hz, 2H, ArH), 7.10 (d, J = 8.4 Hz, 2H, ArH), 6.82 (d, J = 8.4 Hz, 2H, ArH), 5.69 (s, 1H, CH), 4.38 (s, 1H, CH), 3.84–3.78 (m, 1H, CH), 3.08–3.01 (m, 2H, CH), 2.94–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 197.7, 194.4, 172.8, 142.9, 141.0, 136.8, 136.0, 134.8, 132.2, 131.6, 130.0, 129.1, 128.8, 127.6, 123.4, 123.4, 122.0, 76.4, 71.6, 62.9, 47.9, 32.1; IR (KBr) ν: 2950, 1707, 1487, 1407, 1342, 1230, 1179, 1081, 1006, 904, 804, 739 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₁₉BrClN₂O₃ ([M + H]⁺): 521.0262. Found: 521.0258.

1′-(4-Bromophenyl)-3′-(3-methoxyphenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1n). White solid, 65%, mp 206–208 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 7.6 Hz, 1H, ArH), 7.75 (td, J₁ = 7.2 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.65 (td, J₁ = 7.6 Hz, J₂ = 0.8 Hz, 1H, ArH), 7.46 (d, J = 7.6 Hz, 1H, ArH), 7.24–7.23 (m, 2H, ArH), 7.11 (d, J = 8.4 Hz, 2H, ArH), 7.04 (t, J = 8.0 Hz, 1H, ArH), 6.67–6.58 (m, 3H, ArH), 5.72 (s, 1H, CH), 4.38 (s, 1H, CH), 3.84–3.79 (m, 1H, CH), 3.61 (s, 3H, OCH₃), 3.08–3.00 (m, 2H, CH), 2.92–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 198.1, 194.2, 172.7, 159.6, 143.1, 141.1, 136.6, 136.5, 135.8, 131.7, 130.8, 129.5, 123.4, 123.0, 118.1, 113.7, 111.4, 76.3, 71.6, 63.6, 55.1, 48.0, 32.3; IR (KBr) ν: 3088, 2960, 2903, 2835, 1741, 1706, 1597, 1488, 1466, 1432, 1352, 1260, 1235, 1177, 1094, 1040, 1012, 956, 921, 890, 847, 822, 789, 752, 728 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁BrN₂NaO₄ ([M + Na]⁺): 539.0577. Found: 539.0575.

1′,3′-Bis(4-bromophenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1o). White solid, 68%, mp 180–182 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.97 (d, J = 7.6 Hz, 1H, ArH), 7.77 (t, J = 7.6 Hz, 1H, ArH), 7.67 (t, J = 7.6 Hz, 1H, ArH), 7.48 (d, J = 7.6 Hz, 1H, ArH), 7.29–7.27 (m, 4H, ArH), 7.09 (d, J = 8.4 Hz, 2H, ArH), 6.95 (d, J = 8.0 Hz, 2H, ArH), 5.67 (s, 1H, CH), 4.37 (s, 1H, CH), 3.82–3.78 (m, 1H, CH), 3.10–3.01 (m, 2H, CH), 2.94–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 197.7, 194.3, 172.7, 142.9, 141.0, 136.8, 136.0, 134.1, 131.8, 131.6, 130.6, 129.4, 127.6, 123.5, 123.4, 123.1, 122.0, 76.4, 71.5, 63.0, 48.0, 32.2; IR (KBr) ν: 2950, 1707, 1589, 1483, 1406, 1342, 1229, 1178, 1115, 1076, 1005, 904, 802, 738 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₁₉Br₂N₂O₃ ([M + H]⁺): 564.9757. Found: 564.9754.

3′-(4-Chlorophenyl)-1′-(3-nitrophenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1p). White solid, 80%, mp 184–186 °C; ¹H NMR (600 MHz, CDCl₃) δ: 8.08–8.01 (m, 3H, ArH), 7.80 (s, 1H, ArH), 7.66–7.61 (m, 2H, ArH), 7.43–7.35 (m, 2H, ArH), 7.14 (m, 2H, ArH), 7.03 (m, 2H, ArH), 5.70 (s, 1H, CH), 4.53 (s, 1H, CH), 3.86 (s, 1H, CH), 3.72 (s, 1H, CH), 3.07–3.05 (m, 2H, CH); ¹³C NMR (150 MHz, CDCl₃) δ: 197.5, 194.0, 173.1, 148.2, 142.9, 141.0, 136.9, 136.2, 134.4, 134.0, 129.7, 128.7, 127.6, 123.9, 123.7, 123.4, 123.0, 75.3, 71.5, 63.4, 47.8, 31.8, 29.7; IR (KBr) ν: 2920, 1741, 1707, 1585, 1532, 1492, 1406, 1351, 1260, 1236, 1181, 1088, 1013, 867, 815, 755, 727 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₁₈N₃ClNaO₅ ([M + Na]⁺): 510.0827. Found: 510.0829.

3′-(4-Bromophenyl)-1′-(2-hydroxyphenyl)-6′,7′-dihydro-1′H-spiro[indene-2,2′-pyrazolo[1,2-a]pyrazole]-1,3,5′(3′H)-trione (1q). White solid, 55%, mp 176–178 °C; ¹H NMR (400 MHz, CDCl₃) δ: 8.00 (d, J = 7.6 Hz, 1H, ArH), 7.77 (t, J = 7.6 Hz, 1H, ArH), 7.68–7.64 (m, 1H, ArH), 7.50 (d, J = 7.6 Hz, 1H, ArH), 7.29–7.27 (m, 3H, ArH), 7.01–6.94 (m, 3H, ArH), 6.73 (d, J = 8.4 Hz, 1H, ArH), 6.61–6.60 (m, 1H, ArH), 6.47 (d, J = 7.2 Hz, 1H, ArH), 5.67 (s, 1H, CH), 4.53 (s, 1H, CH), 3.97–3.90 (m, 1H, CH), 3.28–3.20 (m, 1H, CH), 3.14–3.05 (m, 1H, CH), 2.97–2.90 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 197.4, 194.5, 172.7, 155.9, 145.3, 142.7, 141.5, 136.7, 136.0, 135.4, 133.6, 132.1, 131.6, 130.4, 128.4, 127.7, 123.5, 123.5, 123.5, 122.1, 119.5, 117.9, 110.0, 71.7, 62.8, 48.6, 32.0; IR (KBr) ν: 3853, 3730, 3452, 2862, 1708, 1654, 1491, 1453, 1410, 1348, 1246, 1182, 1119, 1078, 1005, 817, 758, 722 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₆H₂₀BrN₂O₄ ([M + H]⁺): 503.0601. Found: 503.0597.

2. General procedure for 1,3-dipolar cycloaddition reaction of cyclic azomethine imines with 3-phenacylideneoxindoles

A mixture of cyclic azomethine imine (0.5 mmol) and 3-phenacylideneoxindole (0.5 mmol) in acetonitrile (15.0 mL) was refluxed for seven hours. In most cases, the resulting precipitate was collected by filtration and washed with little cold alcohol to give pure product. In few case, the obtained solid was subjected to column chromatography with light petroleum and ethyl acetate (v/v = 1 : 1) as elute to give pure product for analysis.

1-Benzyl-5-methyl-3′-(4-methylbenzoyl)-1′-phenyl-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2a). White solid, 56%, mp 180–182 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.33 (s, 1H, ArH), 7.30 (s, 1H, ArH), 7.28–7.16 (m, 4H, ArH), 7.11–7.02 (m, 5H, ArH), 6.97 (d, J = 8 Hz, 2H, ArH), 6.85 (d, J = 7.2 Hz, 2H, ArH), 6.61 (d, J = 8 Hz, 1H, ArH), 6.03 (s, 1H, ArH), 5.87 (d, J = 8 Hz, 1H, CH), 4.91 (d, J = 16 Hz, 1H, CH), 4.40 (s, 1H, CH), 4.15 (d, J = 16 Hz, 1H, CH), 3.90–3.86 (m, 1H, CH), 3.14–3.09 (m, 2H, CH), 2.94–2.92 (m, 1H, CH), 2.30 (s, 3H, CH₃), 2.25 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.7, 174.0, 143.6, 139.5, 134.8, 132.8, 131.8, 131.6, 128.9, 128.8, 128.7, 128.5, 128.4, 127.9, 127.8, 127.4, 126.9, 123.6, 108.0, 78.2, 65.6, 64.7, 47.7, 43.9, 32.6, 21.6, 20.9; IR (KBr) ν: 2963, 1706, 1640, 1555, 1495, 1421, 1363, 1245, 1191, 1119, 978, 819, 784, 734 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₅H₃₁N₃NaO₃ ([M + Na]⁺): 564.2258. Found: 564.2277.

1-Benzyl-5-chloro-3′-(4-methylbenzoyl)-1′-phenyl-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2b). White solid, 60%, mp 200–202 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.49 (s, 1H, ArH), 7.32 (d, J = 7.6 Hz, 2H, ArH), 7.22–7.16 (m, 3H, ArH), 7.10–7.05 (m, 5H, ArH), 6.98–6.96 (m, 2H, ArH), 6.82–6.76 (m, 3H, ArH), 6.01 (s, 1H, ArH), 5.88 (d, J = 8.4 Hz, 1H, CH), 4.87 (d, J = 16 Hz, 1H, CH), 4.37 (s, 1H, CH), 4.16 (d, J = 16 Hz, 1H, CH), 3.88–3.81 (m, 1H, CH), 3.15–3.02 (m, 2H, CH), 2.96–2.89 (m, 1H, CH), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.4, 173.8, 172.6, 144.0, 140.4, 134.2, 132.6, 131.1, 129.0, 128.7, 128.6, 128.2, 128.1, 127.9, 127.8, 127.7, 127.6, 126.9, 125.5, 109.3, 78.0, 65.5, 64.7, 47.3, 44.1, 32.2, 21.7; IR (KBr) ν: 2918, 2865, 1716, 1607, 1483, 1422, 1350, 1302, 1255, 1217, 1176, 1129, 1067, 1018, 972, 895, 821, 778, 735 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₄H₂₈ClN₃NaO ([M + Na]⁺): 584.1711. Found: 584.1714.

1-Benzyl-5-chloro-3′-(4-methylbenzoyl)-1′-(p-tolyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2c). White solid, 68%, mp 202–204 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.51–7.50 (m, 1H, ArH), 7.32 (d, J = 8 Hz, 2H, ArH), 7.23–7.20 (m, 1H, ArH), 7.16–7.12 (m, 2H, ArH), 6.98–6.93 (m, 4H, ArH), 6.88–6.86 (m, 2H, ArH), 6.78 (d, J = 7.6 Hz, 3H, ArH), 6.00 (s, 1H, ArH), 5.87 (d, J = 8.4 Hz, 1H, CH), 4.89 (d, J = 16 Hz, 1H, CH), 4.33 (s, 1H, CH), 4.14 (d, J = 16 Hz, 1H, CH), 3.85–3.81 (m, 1H, CH), 3.10–3.04 (m, 2H, CH), 2.90 (s, 1H, CH), 2.30 (s, 3H, CH₃), 2.19 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.4, 173.8, 172.5, 143.9, 140.5, 138.5, 134.2, 132.7, 128.9, 128.9, 128.6, 128.5, 128.2, 127.9, 127.8, 127.6, 126.9, 125.7, 109.3, 78.1, 65.5, 64.7, 47.3, 44.0, 32.2, 21.6, 21.1; IR (KBr) ν: 2920, 2860, 1715, 1606, 1562, 1480, 1422, 1349, 1300, 1254, 1217, 1175, 1127, 1061, 972, 896, 818, 769, 729 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₅H₃₀ClN₃NaO₃ ([M + Na]⁺): 598.1868. Found: 598.1871.

1-Benzyl-1′-(4-methoxyphenyl)-5-methyl-3′-(4-methylbenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2d). White solid, 70%, mp 188–189 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.30 (s, 1H, ArH), 7.25 (s, 2H, ArH), 7.19–7.14 (m, 3H, ArH), 6.97–6.93 (m, 4H, ArH), 6.81–6.80 (m, 2H, ArH), 6.61–6.60 (m, 1H, ArH), 6.55–6.53 (m, 2H, ArH), 5.99 (s, 1H, ArH), 5.86 (d, J = 8 Hz, 1H, CH), 4.89 (d, J = 16 Hz, 1H, CH), 4.30 (s, 1H, CH), 4.10 (d, J = 16 Hz, 1H, CH), 3.80–3.78 (m, 1H, CH), 3.67 (s, 3H, OCH₃), 3.10–3.03 (m, 2H, CH), 2.91–2.86 (m, 1H, CH), 2.29 (s, 3H, CH₃), 2.24 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.7, 174.1, 172.0, 159.5, 143.6, 139.6, 134.8, 132.8, 131.8, 129.1, 128.9, 128.8, 128.6, 128.4, 127.8, 127.4, 126.9, 123.8, 123.3, 113.3, 108.1, 78.0, 65.6, 64.7, 55.1, 47.7, 43.8, 32.6, 21.6, 21.0; IR (KBr) ν: 2917, 2865, 1711, 1610, 1502, 1420, 1358, 1303, 1251, 1183, 1140, 1028, 979, 898, 841, 775, 733 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₆H₃₃N₃NaO₄ ([M + Na]⁺): 594.2363. Found: 594.2380.

1-Benzyl-5-chloro-1′-(4-methoxyphenyl)-3′-(4-methylbenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2e). White solid, 55%, mp 219–221 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.50–7.49 (m, 1H, ArH), 7.33 (d, J = 7.6 Hz, 2H, ArH), 7.23–7.20 (m, 1H, ArH), 7.17–7.14 (m, 2H, ArH), 6.99–6.95 (m, 4H, ArH), 6.80 (d, J = 7.2 Hz, 3H, ArH), 6.58 (d, J = 4.4 Hz, 2H, ArH), 6.00 (s, 1H, ArH), 5.90 (d, J = 8.4 Hz, 1H, CH), 4.88 (d, J = 16 Hz, 1H, CH), 4.31 (s, 1H, CH), 4.15 (d, J = 16 Hz, 1H, CH), 3.84–3.80 (m, 1H, CH), 3.68 (s, 3H, OCH₃), 3.08–3.04 (m, 2H, CH), 2.90 (s, 1H, CH), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.5, 173.9, 172.6, 159.8, 144.1, 140.6, 134.3, 132.8, 129.1, 129.0, 128.8, 128.7, 128.1, 127.9, 127.7, 127.0, 125.8, 122.9, 113.7, 109.4, 78.0, 65.6, 64.8, 55.2, 55.2, 47.3, 44.1, 32.3, 21.8; IR (KBr) ν: 2919, 2858, 1715, 1609, 1566, 1513, 1479, 1423, 1349, 1302, 1252, 1217, 1175, 1134, 1025, 977, 897, 824, 772, 732 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₅H₃₀ClN₃NaO₄ ([M + Na]⁺): 614.1817. Found: 614.1833.

1-Benzyl-5-chloro-1′-(4-chlorophenyl)-3′-(4-methylbenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2f). White solid, 65%, mp 222–224 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.48–7.47 (m, 1H, ArH), 7.32 (d, J = 8 Hz, 2H, ArH), 7.24 (d, J = 7.2 Hz, 1H, ArH), 7.20–7.17 (m, 2H, ArH), 7.04–7.02 (m, 2H, ArH), 6.99–6.96 (m, 4H, ArH), 6.84–6.81 (m, 1H, ArH), 6.80–6.78 (m, 2H, ArH), 6.00 (s, 1H, ArH), 5.95 (d, J = 8.4 Hz, 1H, CH), 4.86 (d, J = 16 Hz, 1H, CH), 4.32 (s, 1H, CH), 4.17 (d, J = 16 Hz, 1H, CH), 3.83–3.79 (m, 1H, CH), 3.10–3.03 (m, 2H, CH), 2.92–2.87 (m, 1H, CH), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.2, 173.5, 172.5, 144.1, 140.4, 134.6, 134.1, 132.5, 129.6, 129.0, 129.0, 128.6, 128.4, 128.1, 128.0, 127.9, 127.8, 126.9, 125.2, 109.5, 109.5, 77.4, 65.4, 65.4, 64.6, 47.3, 44.0, 32.1, 21.7, 21.7; IR (KBr) ν: 2994, 2919, 2862, 1861, 1714, 1605, 1483, 1420, 1350, 1301, 1255, 1217, 1176, 1128, 1091, 1016, 972, 894, 822, 772, 729 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₄H₂₇Cl₂N₃NaO₃ ([M + Na]⁺): 618.1322. Found: 618.1338.

1-Benzyl-1′-(4-bromophenyl)-5-methyl-3′-(4-methylbenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2g). White solid, 62%, mp 218–220 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.28 (s, 2H, ArH), 7.24–7.23 (m, 2H, ArH), 7.21–7.17 (m, 2H, ArH), 7.15–7.12 (m, 2H, ArH), 6.95 (s, 1H, ArH), 6.93–6.92 (m, 2H, ArH), 6.90 (s, 1H, ArH), 6.80 (d, J = 7.2 Hz, 2H, ArH), 6.64 (d, J = 8 Hz, 1H, ArH), 5.98 (s, 1H, ArH), 5.91 (d, J = 8 Hz, 1H, CH), 4.87 (d, J = 16 Hz, 1H, CH), 4.29 (s, 1H, CH), 4.13 (d, J = 16 Hz, 1H, CH), 3.81–3.78 (m, 1H, CH), 3.11–3.03 (m, 2H, CH), 2.92–2.87 (m, 1H, CH), 2.29 (s, 3H, CH₃), 2.24 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.5, 173.7, 143.8, 139.5, 134.7, 132.7, 132.0, 131.2, 130.6, 129.4, 129.2, 128.8, 128.6, 128.5, 127.8, 127.6, 126.9, 123.3, 122.5, 108.3, 77.7, 65.5, 64.6, 47.7, 43.8, 32.6, 21.6, 21.0; IR (KBr) ν: 2913, 2856, 1705, 1553, 1493, 1423, 1362, 1302, 1250, 1188, 1068, 976, 902, 820, 776, 733 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₅H₃₀BrN₃NaO₃ ([M + Na]⁺): 642.1363. Found: 642.1375.

1′-(4-Bromophenyl)-3′-(4-chlorobenzoyl)-5-methyl-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2h). White solid, 65%, mp 241–242 °C; ¹H NMR (400 MHz, DMSO-d₆) δ: 10.48 (s, 1H, NH), 7.40–7.38 (m, 2H, ArH), 7.32–7.29 (m, 4H, ArH), 6.97–6.95 (m, 3H, ArH), 6.67 (d, J = 8 Hz, 1H, ArH), 6.11 (d, J = 8 Hz, 1H, CH), 5.69 (s, 1H, CH), 4.28 (s, 1H, CH), 3.72–3.67 (m, 1H, CH), 3.07–3.02 (m, 1H, CH), 2.93–2.87 (m, 2H, CH), 2.15 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ:191.7, 174.8, 174.4, 138.7, 138.0, 133.5, 131.6, 130.7, 129.9, 129.3, 129.0, 128.8, 128.6, 127.6, 123.8, 121.1, 108.7, 75.9, 65.8, 64.0, 45.8, 30.6, 20.5; IR (KBr) ν: 2821, 1720, 1660, 1542, 1486, 1409, 1320, 1250, 1208, 1091, 979, 830, 787, 734 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₂₇H₂₁BrClN₃NaO₃ ([M + Na]⁺): 572.0347. Found: 572.0352.

1-Benzyl-1′-(4-bromophenyl)-5-chloro-3′-(4-methylbenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2i). White solid, 58%, mp 221–223 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.48 (s, 1H, ArH), 7.32 (d, J = 7.6 Hz, 2H, ArH), 7.25–7.23 (m, 1H, ArH), 7.21–7.17 (m, 4H, ArH), 6.98 (d, J = 8 Hz, 2H, ArH), 6.91 (d, J = 8 Hz, 2H, ArH), 6.84–6.82 (m, 1H, ArH), 6.80–6.78 (m, 2H, ArH), 6.00 (s, 1H, ArH), 5.95 (d, J = 8.4 Hz, 1H, CH), 4.87 (d, J = 16 Hz, 1H, CH), 4.30 (s, 1H, CH), 4.16 (d, J = 16 Hz, 1H, CH), 3.83–3.79 (m, 1H, CH), 3.07–3.04 (m, 2H, CH), 2.91 (s, 1H, CH), 2.30 (s, 3H, CH₃); ¹³C NMR (100 MHz, CDCl₃) δ: 191.2, 173.5, 172.5, 144.2, 140.4, 134.1, 132.5, 131.4, 130.2, 129.3, 129.0, 129.0, 128.7, 128.0, 128.0, 127.9, 127.8, 126.9, 125.2, 122.9, 109.6, 77.48, 65.4, 64.6, 47.3, 44.0, 32.2, 21.7; IR (KBr) ν: 2989, 2912, 2875, 1714, 1609, 1482, 1423, 1349, 1298, 1253, 1217, 1176, 1134, 1065, 968, 901, 820, 771, 728 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₄H₂₇BrClN₃Na ([M + Na]⁺): 662.0817. Found: 662.0815.

1-Benzyl-1′-(4-bromophenyl)-5-chloro-3′-(4-chlorobenzoyl)-6′,7′-dihydro-1′H-spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazole]-2,5′(3′H)-dione (2j). White solid, 69%, mp 202–204 °C; ¹H NMR (400 MHz, CDCl₃) δ: 7.46–7.45 (m, 1H, ArH), 7.34 (d, J = 8.4 Hz, 2H, ArH), 7.24–7.18 (m, 5H, ArH), 7.14 (d, J = 8.8 Hz, 2H, ArH), 6.91–6.86 (m, 3H, ArH), 6.81 (d, J = 7.2 Hz, 2H, ArH), 6.03 (d, J = 8.4 Hz, 1H, CH), 5.95 (s, 1H, ArH), 4.84 (d, J = 16 Hz, 1H, CH), 4.30 (s, 1H, CH), 4.24 (d, J = 16 Hz, 1H, CH), 3.86–3.82 (m, 1H, CH), 3.11–3.04 (m, 2H, CH), 2.94–2.87 (m, 1H, CH); ¹³C NMR (100 MHz, CDCl₃) δ: 190.7, 173.3, 140.4, 139.7, 133.9, 133.4, 131.5, 129.9, 129.2, 129.2, 129.1, 128.7, 128.7, 128.1, 128.0, 127.0, 125.0, 123.0, 109.7, 77.5, 65.5, 64.4, 47.1, 44.1, 31.9; IR (KBr) ν: 2916, 2387, 1709, 1647, 1485, 1422, 1349, 1241, 1215, 1177, 1187, 1000, 980, 955, 900, 820, 773, 736, 701 cm⁻¹; MS (m/z): HRMS (ESI) calcd for C₃₃H₂₄BrCl₂N₃NaO₃ ([M + Na]⁺): 682.0270. Found: 682.0277.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (Grant No. 21272200) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Grant BK2013016). We also thank Analysis and Test Center of Yangzhou University providing all analytical instruments.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and detailed spectroscopic data of all new compounds. CCDC 1418868–1418875. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra02358d

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