A domino synthetic approach for new, angular pyrazol- and isoxazol-heterocycles using [DBU][Ac] as an effective reaction medium

Abstract

O-Cinnamyloxy/geranyloxy/cyclohexenyloxy/cinnamoyloxy-acetophenones yielded pyrazol-heterocycles, all of which contained an angular methyl-attached pyranopyran unit with pyrazolones in the ionic liquid (IL), 1,8-diazabicyclo[5.4.0]undec-7-ene-8-ium acetate [DBU][Ac], via the domino/Knoevenagel-hetero-Diels–Alder (DKHDA) reaction. Besides, isoxazol yielded isoxazol-heterocycles possessing a framework to similar to O-allyloxy/prenyloxy-acetophenones, which did not involve chromatography to isolate the desired product. However, propargyl-substrates needed ZnO to promote the reaction. The heterosteroid-mimicking structure thus achieved may have different bioprofiles than the aldehyde-derived one. Moreover, the IL is recyclable and capable of promoting reaction effectively, which is indicative of an economical and greener way of achieving the interesting heterocycles. The stereochemistry of all the compounds was confirmed by ¹H NMR, ¹³C NMR, 2D NMR NOESY and the single crystal X-ray diffraction data.

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Introduction

The number and type of polycyclic compounds achievable via the DKHDA synthetic approach have increased dramatically in the past few decades, especially with the rate of polyheterocycles that contain pyran or pyran-fused carbocycles as well as heterocycles.¹ Pyran and pyrano-fused ring systems represent important molecular frameworks, which are found in a wide range of natural and synthetic bioactive molecules (Fig. 1) and have been known to display potential antimicrobial, insecticidal, anti-inflammatory, and molluscicidal activities.² Moreover, many photochromic materials having benzo-pyran frameworks have notable practical applications in data storage, optical filters, displays, sensor protection, waveguides, and ophthalmic plastic lenses.³

Fig. 1 Some bisoactive systems with angular pyran-based molecular frameworks.

In general involving participation from the aldehyde-substrate and an active methylene unit, the chemistry of DKHDA reaction allows the construction of many natural products, synthetic drugs⁴ and key skeletons existing therein, incorporating a variety of pyran-based heterocycles.⁵ Following Tietz's reports on salicylaldehyde derivatives,⁶ a flurry of reports appeared in literature that explored the chemistry of aldehyde-substrates,⁷ including quinoline, coumarin,⁸ salicylaldehyde and naphthaldehyde derivatives from our research group.⁹ Presently, synthetic chemists still seem to be continuing with this chemistry. Unlike the aldehyde-based substrate, the ketone-based substrate seems to be seldom selected for the protocol and is rarely studied even after two of our initial reports.¹⁰ These substrates formed typical heterocyclic molecular frameworks with angular methyl with pyrazolone, representing an important class of bioprofiles. Angularly fused polycyclic systems are known for their significant biological functions and so have useful applications in medicinal chemistry.¹¹ Biologically potential cannabicyclol, mahanimbine, steroids, and thyrsiferol are significant examples of naturally occurring compounds.¹² Analogs of thyrsiferol exhibit cytotoxic, antiviral, and antitumor activities.¹³ Heterosteroids, on the other hand, have improved biological function with angular methyl in their molecular framework.¹⁴ Further, pyripyropene E and phenylpyropene C belonging to this family are known to act as potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors. Another example is phenylpyropene C that inhibits both the JAK/STAT signal cascade in various cell lines and diacylglycerol acyltransferase.¹⁵

Therefore, it seems quite probable and interesting that the class of angular polycyclic compounds is desirable to be studied, developed and explored as new sources of biomaterials. We therefore studied the reactions between O-cinnamyloxy/geranyloxy/cyclohexenyloxy/cinnamoyloxy-acetophenones and pyrazolone; and between O-allyloxy/prenyloxy/propargyloxy-acetophenone and isoxazolone, as typical new combinations via the DKHDA strategy. These reactions were optimized in ionic liquid [DBU][Ac] as effective reaction medium. All new acetophenone-derived products displayed relatively improved antimetastatic property than the analogous salicylaldehyde-derived ones, when they were analysed and compared through the prediction of activity spectra for substances (PASS) online software.¹⁶

The translation of a conventional methodology into its favourable and environmentally friendly version has been one of the important aspects of study in modern synthetic organic chemistry, helping address not only environmental issues, but also economic and ecological issues. In literature a variety of catalysts and reaction conditions have been studied to promote the DKHDA reaction such as Lewis acids,¹⁷ EDDA,¹⁸ copper(I) iodine,¹⁹ bismuth(III)chloride,²⁰ indium(III) chloride,²¹ lithium perchlorate,²² triphenylphosphonium perchlorate,²³ zinc oxide,²⁴ D-proline,²⁵ pyridine,²⁶ water,²⁷ and solid-state melt reaction.^9b,28 Recently, the improved procedures of this protocol include reactions in zirconium oxide (NP)-[bmim][NO₃],²⁹ ionic liquid triethyl ammoniumactetate (TEAA)⁸ and tetrabutylammonium hydrogen sulfate (TBA-HS) medium.^9a It is to be noted that these reactions involved the chemistry of aldehyde substrates, which unfortunately could not favor the transformation of ketone-based substrates with a similar degree of efficiency. Although our earlier study using ketone-based substrates was made feasible with pyrazolone in TBA-HS^10a and TEAA^10b mediums, it required a higher temperature. We therefore studied [DBU][Ac] as an effective DHKDA reaction medium relatively at lower temperature. Today, ILs offer synthetic chemists with efficient green methodologies. As a reaction medium, [DBU][Ac] has so far promoted many useful reactions such as the aza-Michael addition,³⁰ Knoevenagel reaction³¹ multicomponent reaction³² and carbonylation.³³ To the best of our knowledge, it has not yet been tried in the DKHDA reaction in general, and in ketone-based DKHDA substrate in particular, as polycyclic compounds with angular methyl are difficult to synthesize.

Results and discussion

All ketone-substrates 2–5 employed in this work are new and have been prepared by the simple alkenylation of acetophenones 1a–c, suitably with cinnamyl bromide, geranyl bromide, and cyclohexenyl bromide and cinnamoyl chloride in presence of anhydrous K₂CO₃ in DMF (dimethylformamide). For initially designed substrates 6–8, on the other hand, we used allyl bromide, prenyl bromide and propargyl bromide, following the same method (Scheme 1).¹⁰ The ionic liquid, [DBU][Ac], was prepared by stirring equimolar amounts of DBU and acetic acid at room temperature for 24 h, as reported elsewhere.³⁰

Scheme 1 Synthesis of o-alkenylated/alkynylated acetophenons (2–8); reagents and conditions: (a) DMF, K₂CO₃, RT, 10–12 h.

The chemistry involving the participation of a typical ketone-based substrate in DKHDA strategy at high temperatures, was revealed for the first time by our research group.^10a In order to optimize this reaction further to a larger degree, we screened all reaction conditions mentioned in Table 1 using the combination between O-geranylated acetophenone 3a and pyrazolone 9a as a model reaction before getting other products 10–13, 15–17. Initially, the effect of refluxing toluene and xylene was monitored for 24 h with (entries 1 and 2) and without the use of catalysts, EDDA (entry 3) and TBA-HS (entry 4). Since it gave traces of products in refluxing toluene and not more than 28% in other solvents, we avoided the use of solvent in the next attempt and examined the reaction at 140 °C (entry 5). Herein, though the reaction time was improved, the yields could not exceed 60%. In TBA-HS under solvent-free environment, the yields could be improved, but it required a higher temperature, i.e. 160 °C (entry 7), and the product was associated with traces of impurities, which may have been due to slight decomposition. We therefore employed the ionic liquid, TEAA, as reaction medium to reduce the temperature required. Herein, although the yield improved up to 55% at 120 °C (entry 8) and then to 77% at 150° C (entry 9), the association of decomposed matter with the desired products still continued and made the work up procedure tedious. Best results, however, could be seen when we employed ionic liquid, [DBU][Ac], as reaction medium, as 35% yields were attained at 80 °C (entry 10), which could be increased further to up to 58% at 110 °C (entry 11). Finally, a maximum 82% of desired products were achievable after 3.5 h at 130 °C (entry 12), showing good reactivities of reactants and much improved results. Other products 10–13 were obtained in the range of 70–92% (Scheme 2 and Table 2) using the same method. The scope of the reaction was extended further to isoxazolone as new active methylene unit used against O-allyloxy/prenyloxy/propargyloxy-acetophenones to obtain isoxazole-based heterocycles 15–17. In all cases, excellent yields were recorded, and no chromatography was required to isolate the desired products. Just recrystalizing the reaction mass in ethanol was enough to afford the pure product in the range of 78–86% (Scheme 3). Propargylated substrates (8a and b), however, required 25 mol% of ZnO additionally as catalyst to promote the reaction due to the unactivated dienophile propargyl moiety. Meldrum's acid and 1,3-cyclohexanedione as six membered cyclic active methylene units, surprisingly, revealed no reactivity against all ketone-substrates in the present study. Efforts to search for suitable conditions to cover them in the reaction are continued.

Table 1 Screening of various conditions to optimize DKHDA reaction

Entry	Catalyst	Solvent	Temp (°C)	Time [h]	Yield [%]
1	—	Toluene	RTflux	24	Trace
2	—	Xylene	Reflux	24	10
3	EDDA	Xylene	Reflux	24	22
4	TBA-HS	Xylene	Reflux	24	28
5	—	—	140	6.0	60
6	TBA-HS	—	120	6.0	48
7	TBA-HS	—	160	4.0	76
8	TEAA	—	120	6.0	50
9	TEAA	—	150	4.0	77
10	[DBU][Ac]	—	80	6.0	35
11	[DBU][Ac]	—	110	5.0	58
12	[DBU][Ac]	—	130	3.5	82

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Scheme 2 Synthesis of angular chromeno-fused pyrano[2,3-c]pyrazoles; (a) [DBU][Ac], 130 °C.

Scheme 3 Synthesis of angular chromeno-fused pyrano[2,3-c]isoxazole (a) [DBU][Ac], 130 °C and (b) 25 mol% ZnO in [DBU][Ac] at 130 °C.

Table 2 Synthesis of various angular chromeno-fused pyrano[2,3-c]pyrazole derivatives

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The spectroscopic data of all new heterocycles are in good agreement with their proposed structures. A ¹H NMR singlet at δ 1.18–1.98 ppm and a ¹³C NMR peak in the δ 22.72-33.72 ppm range is attributed to a central pyranopyranyl bridge-head carbon-attached angular methyl in all the compounds. On the other hand, bridge-head CH proton 5a/7b had varied splitting patterns in the δ 1.95–2.18 ppm range, depending on dienophile moiety used, except 17 which is lacks this proton due to the unsaturated pyran ring generation, and 13 in which a doublet due to this proton had shifted to ∼δ 3.42 ppm. The cis-orientation bridge-head methyl with respect to CH proton was also confirmed on the basis of single crystal X-ray diffraction data (Fig. 2) and 2D NMR NOESY (nuclear Overhauser effect spectroscopy) of 10f (Fig. 3), which is indicative of the endo-E-syn transition state exclusively, even though other pathways of reaction are possible. In addition, the single crystal X-ray data of 10f, 11e, 12a and 15b supported the same observation. The diastereotopic relationship between benzopyranyl methylene protons can be also confirmed from ¹H NMR peaks that appeared with different chemical shifts: one in the δ 3.54–4.65 ppm range as a doublet or doublet of doublets and the second one in the δ 4.34–5.17 ppm range as a doublet of doublets, except in 12 and 13. Cyclohexenyloxyacetophenone-derived 12 has only one proton, which gave a multiplate in the δ 4.64–4.91 ppm range. In all the pyrazol-heterocycles, a singlet in the δ 1.87–2.82 ppm range and a ¹³C NMR peak in the δ 14.10–16.78 ppm range conform the presence of the methyl group attached to pyrazol ring. Molecular ion peaks in the mass spectrometry data fully agree with the theoretically calculated molecular weights of the heterocycles.

Fig. 2 ORTEP of compounds 10f, 11e, 12a and 15b.

Fig. 3 ((NOESY of 10f)).

Conclusions

In conclusion, we have achieved and described the synthesis of new pyrazol- and isoxazol-based heterocycles through the reaction of O-alkenylated acetopheneones as typical and rarely studied DKHDA substrates with active methylene pyrazolone and isoxazolone, respectively, in an ionic liquid [DBU][Ac], effectively at 130 °C, via the domino Knoevenagel-hetero-Diels–Alder synthetic route. The DKHDA reaction of O-alkynylated acetopheones is also feasible with isoxazol but in the presence of ZnO as catalyst because it contains the unactivated dienophile moiety. This protocol is applicable to ketone-based substrates, which are an important source of biomolecules that contain a steroid-mimicking angular methyl framework. Besides, the use of recyclable ionic liquid in place of organic solvents in the present method offers both ecological and environmental benefits.

Experimental section

General procedure for the synthesis of O-alkenyloxy/alkynyloxy acetophenones (2–8)

A 2.0 mL solution of the respective alkenyl/alkynyl halide (0.013 mol) in DMF was added dropwise to a stirred solution of the corresponding O-hydroxyacetophenone 1a–c (0.01 mol) with the anhydrous K₂CO₃ (0.015 mol) suspended in DMF (10 mL). It was stirred further at room temperature until the completion of reaction as confirmed by TLC (10–12 h). The mixture was then poured into ice (100 g) with constant stirring. All the solid products, 2, 5, 6b and 8b, were filtered, washed with cold water (3 × 10 mL), and then dried at room temperature. In the case of the oily products, 3, 4, 6a, 7 and 8a, the emulsified content was extracted with three 25 mL diethyl ether portions, and the combined ether extracts collected were dried using anhydrous sodium sulfate. Pure oily products in the range of 94–98% were obtained upon the removal of ether.

General procedure for the preparation of ionic liquid [DBU][Ac]

A 50 mL three-necked flask was loaded with 6 mmol of DBU, and acetic acid (6 mmol) was then added dropwise at temperature ≤5 °C cooled by an ice bar. After dropwise addition, the ice bar was removed and the reaction mixture was stirred at room temperature for 24 h. The oil residue was vacuum-dried at 60 °C for 24 h to obtain [DBU][Ac] as a light yellow viscous liquid.

General procedure for the preparation of chromeno-fused pyrano[2,3-c]pyrazoles{10–13(a–f)}

In a 50 mL round-bottom flask, a mixture of o-alkenylated acetophenone (1 equiv.) and pyrazolones (1 equiv.) was made in the ionic liquid [DBU][Ac] (25 mol%) heated at 130 °C. The reaction was continuously monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate (3 × 10 mL) to separate the IL from the product. The combined solution of ethyl acetate was dried with Na₂SO₄ and then concentrated through the vacuum evaporation of ethyl acetate to give the crude product, which was further purified by column chromatography by using n-hexane/ethyl acetate (10% v/v) as mobile phase. The overall yields were in the range of 70–92%. The recovered IL [DBU][Ac] was vacuum-dried at 60 °C for 8 h and reused in the next reaction as the catalyst. It was noticed that the ionic liquid could be recycled at least four-times with unaltered efficiency.

Spectroscopic data of compounds

(5R,5aS,11bR)-1,11b-Dimethyl-3,5-diphenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10a). Yield 92%, mp 218–220 °C, IR (ν_max, cm⁻¹): 2975, 2920, 1596, 1519, 1485, 1446, 1231, 1083, 1046, 852, 756, 692; ¹H NMR (400 MHz, CDCl₃): δ 1.79 (s, 3H, angular CH₃), 2.37 (m, 1H, H_5a), 2.64 (s, 3H, py-CH₃), 3.54 (dd, J = 12.0, 1.6 Hz, 1H, H₆), 4.37 (dd, J = 12.0, 2.0 Hz, 1H, H_6′), 5.07 (d, J = 10.8, 1H, H_5′), 6.83–7.63 (m, 14H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.60 (py-CH₃), 30.33 (angular CH₃), 35.23 (C-11b), 44.20 (C-5a), 61.84 (C-6), 80.92 (C-5), 103.20, 117.13, 120.35, 121.34, 125.47, 127.39, 127.90, 128.79, 128.91, 129.48, 129.99, 138.27, 138.48, 146.42, 148.98, 151.52 (Ar-C). ESI-MS: m/z: 408.20 (M)⁺, anal. calcd for C₂₇H₂₄N₂O₂: C, 79.39; H, 5.92; N, 6.86; found: C, 79.16; H, 5.87; N, 6.96.

(5R,5aS,11bR)-3-(2,5-Dichlorophenyl)-1,11b-dimethyl-5-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10b). Yield 88%, mp 122–124 °C, IR (ν_max, cm⁻¹): 2987, 2920, 1580, 1519, 1486, 1415, 1250, 1089, 1045, 859, 814, 786, 663; ¹H NMR (400 MHz, CDCl₃): δ 1.87 (s, 3H, angular CH₃), 2.05 (m, 1H, H_5a), 2.74 (s, 3H, py-CH₃), 3.76 (dd, J = 12.0, 1.6 Hz, 1H, H₆), 4.37 (dd, J = 12.0, 2.4 Hz, 1H, H_6′), 5.13 (d, J = 10.4, 1H, H_5′), 6.88–7.51 (m, 12H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.57 (py-CH₃), 30.25 (angular CH₃), 35.75 (C-11b), 43.92 (C-5a), 62.75 (C-6), 80.64 (C-5), 101.12, 113.02, 118.05, 123.71, 126.32, 126.85, 127.39, 128.86, 129.46, 129.91, 130.55, 131.21, 133.12, 138.02, 142.27, 147.58, 157.24 (Ar-C). ESI-MS: m/z: 477.10 (M)⁺, anal. calcd for C₂₇H₂₂Cl₂N₂O₂: C, 67.93; H, 4.65; N, 5.87; found: C, 67.49; H, 4.81; N, 5.65.

(5R,5aS,11bR)-10-Chloro-1,11b-dimethyl-3,5-diphenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10c). Yield 89%, mp 226–228 °C, IR (ν_max, cm⁻¹): 2983, 2924, 1596, 1517, 1483, 1405, 1262, 1233, 1080, 1045, 864, 820, 757, 672; ¹H NMR (400 MHz, CDCl₃): δ 1.85 (s, 3H, angular CH₃), 2.06 (m, 1H, H_5a), 2.74 (s, 3H, py-CH₃), 3.78 (dd, J = 12.0, 1.6 Hz, 1H, H₆), 4.34 (dd, J = 12.0, 2.4 Hz, 1H, H_6′), 5.14 (d, J = 10.4, 1H, H_5′), 6.81–7.75 (m, 13H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.56 (py-CH₃), 30.21 (angular CH₃), 35.63 (C-11b), 44.64 (C-5a), 62.84 (C-6), 80.85 (C-5), 103.25, 116.89, 120.22, 122.04, 125.57, 127.45, 127.93, 128.65, 128.92, 129.28, 129.91, 138.25, 138.56, 146.25, 148.72, 151.56 (Ar-C). ESI-MS: m/z: 443.00 (M)⁺, anal. calcd for C₂₇H₂₃ClN₂O₂: C, 73.21; H, 5.23; N, 6.32; found: C, 73.16; H, 5.46; N, 6.28.

(5R,5aS,11bR)-10-Chloro-3-(2,5-dichlorophenyl)-1,11b-dimethyl-5-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10d). Yield 89%, mp 176–178 °C, IR (ν_max, cm⁻¹): 2989, 2928, 1596, 1532, 1487, 1464, 1222, 1096, 1049, 867, 814, 756, 663; ¹H NMR (400 MHz, CDCl₃): δ 1.89 (s, 3H, angular CH₃), 2.06 (m, 1H, H_5a), 2.79 (s, 3H, Py-CH₃), 3.78 (dd, J = 12.0, 1.6 Hz, 1H, H₆), 4.38 (dd, J = 12.0, 2.4 Hz, 1H, H_6′), 5.16 (d, J = 10.8, 1H, H_5′), 6.81–7.69 (m, 11H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.58 (Py-CH₃), 30.22 (angular CH₃), 35.58 (C-11b), 43.99 (C-5a), 62.90 (C-6), 80.90 (C-5), 101.06, 113.14, 117.98, 120.26, 123.89, 126.45, 126.80, 127.42, 128.90, 129.60, 129.80, 130.70, 131.12, 133.03, 137.26, 142.29, 147.52, 157.26 (Ar-C). ESI-MS: m/z: 511.83 (M)⁺, anal. calcd for C₂₇H₂₁Cl₃N₂O₂: C, 63.36; H, 4.14; N, 5.47; found: C, 63.49; H, 4.20; N, 5.28.

(5R,5aS,11bR)-1,11b-Bimethyl-10-nitro-3,5-diphenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10e). Yield 91%, mp 270–273 °C, IR (ν_max, cm⁻¹): 2982, 2926, 1595, 1516, 1486, 1453, 1326, 1262, 1245, 1098, 1044, 831, 755, 749, 687; ¹H NMR (400 MHz, CDCl₃): δ 1.89 (s, 3H, angular CH₃), 2.17 (m, 1H, H_5a), 2.82 (s, 3H, Py-CH₃), 3.91 (dd, J = 12.4, 2.0 Hz, 1H, H₆), 4.43 (dd, J = 12.0, 1.2 Hz, 1H, H_6′), 5.06 (d, J = 10.4, 1H, H_5′), 6.96–8.48 (m, 13H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.57 (angular CH₃), 30.34 (Py-CH₃), 35.26 (C-11b), 44.23 (C-5a), 61.69 (C-6), 80.95 (C-5), 103.21, 117.18, 120.34, 121.38, 125.48, 127.40, 127.96, 128.80, 128.95, 129.50, 130.03, 138.33, 138.52, 146.45, 149.03, 151.57 (Ar-C). ESI-MS: m/z: 454.20 (M)⁺, anal. calcd for C₂₇H₂₃N₃O₄: C, 71.51; H, 5.11; N, 9.27; found: C, 71.49; H, 5.09; N, 9.32.

(5R,5aS,11bR)-3-(2,5-Dichlorophenyl)-1,11b-dimethyl-10-nitro-5-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (10f). Yield 88%, mp 220–222 °C, IR (ν_max, cm⁻¹): 2991, 2925, 1594, 1526, 1478, 1414, 1341, 1256, 1246, 1091, 1041, 845, 755, 745, 635; ¹H NMR (400 MHz, CDCl₃): 1.90 (s, 3H, angular CH₃), 2.15 (m, 1H, H_5a), 2.81 (s, 3H, Py-CH₃), 3.89 (dd, J = 12.0, 1.6 Hz, 1H, H₆), 4.42 (dd, J = 14.8, 2.4 Hz, 1H, H_6′), 5.00 (d, J = 10.8, 1H, H_5′), 6.96–8.49 (m, 11H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.56 (Py-CH₃), 30.12 (angular CH₃), 35.57 (C-11b), 43.98 (C-5a), 62.93 (C-6), 80.87 (C-5), 101.01, 113.12, 117.95, 123.91, 126.42, 126.74, 127.43, 128.93, 129.56, 129.88, 130.75, 131.07, 133.01, 137.22, 142.17, 147.51, 157.04 (Ar-C). ESI-MS: m/z: 523.30 (M)⁺, anal. calcd for C₂₇H₂₁Cl₂N₃O₄: C, 62.08; H, 4.05; N, 8.04; found: C, 62.19; H, 4.11; N, 8.16.

(5aS,11bR)-1,5,11b-Trimethyl-5-(4-methylpent-3-en-1-yl)-3-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c] pyrazole (11a). Yield 82%, mp 120–122 °C, IR (ν_max, cm⁻¹): 3064, 2977, 2907, 1944, 1728, 1597, 1512, 1487, 1216, 1086, 1042, 755, 691; 1H NMR (400 MHz, CDCl₃): δ 1.06 (S, 3H, 5-CH₃), 1.66 (S, 3H, 11b-CH₃), 1.73 (S, 3H, 5d′-CH₃), 1.77 (S, 3H, 5d′-CH₃), 1.90–1.94 (m, 2H, H_5b′), 2.06 (d, J = 3.6 Hz, 1H, H_5a), 2.22 (m, 2H, H_5a′), 2.71 (S, 3H, Py-CH₃), 4.40 (d, J = 11.6 Hz, 1H, H₆), 4.70 (dd, J = 12.8, 4.4 Hz, 1H, H_6′), 5.19 (t, J = 7.2 Hz, 1H, H_5C′), 6.75–7.78 (m, 9H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.75 (Me-5), 17.67 (Me-5e′), 21.25 (Me-5e′′), 21.66 (C-5b′), 25.71 (Me-5), 32.29 (Me-11b), 33.62 (C-11b), 40.82 (C-5a′), 44.45 (C-5a), 61.70 (C-6), 84.14 (C-5), 101.13, 116.16, 120.45, 123.37, 123.64, 125.43, 127.54, 128.04, 128.90, 129.60, 132.52, 138.83, 146.82, 148.22, 152.82 (Ar-C). ESI-MS: m/z: 428.30 (M)⁺, anal. calcd for C₂₈H₃₂N₂O₂: C, 78.47; H, 7.53; N, 6.54; found: C, 78.35; H, 7.47; N, 6.61.

(5aS,11bR)-3-(2,5-Dichlorophenyl)-1,5,11b-trimethyl-5-(4-methylpent-3-en-1-yl)-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (11b). Yield 80%, mp 114–116 °C, IR (ν_max, cm⁻¹): 3069, 2982, 2926, 1953, 1721, 1592, 1520, 1486, 1382, 1222, 1094, 1052, 755, 704; ¹H NMR (400 MHz, CDCl3): δ 1.03 (S, 3H, 5-CH₃), 1.55 (S, 3H, 11b-CH₃), 1.67 (S, 3H, 5d′-CH₃), 1.76 (S, 3H, 5d′′-CH₃), 1.82 (m, 2H, H_5b′), 2.01 (d, J = 3.6 Hz, 1H, H-5a), 2.10 (m, 2H, H_5a′), 2.67 (s, 3H, Py-CH₃), 4.37 (dd, J = 12.8, 1.2 Hz, 1H, H₆), 4.68 (dd, J = 12.2, 4.4 Hz, 1H, H_6′), 5.09 (t, J = 7.2 Hz, 1H, H_5C′), 7.10–7.49 (m, 7H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.22 (Me-5), 17.61 (Me-5e′), 21.23 (Me-5e′′), 21.63 (C-5b′), 25.31 (Me-5), 30.49 (Me-11b), 32.95 (C-11b), 40.74 (C-5a′), 44.06 (C-5a), 64.32 (C-6), 83.51 (C-5), 101.04, 116.93, 120.45, 123.32, 124.12, 125.42, 25.86, 128.12, 128.91, 129.95, 130.28, 133.72, 138.06, 141.65, 146.36, 148.12, 154.17. ESI-MS: m/z: 496.90 (M)⁺, anal. calcd for C₂₈H₃₀Cl₂N₂O₂: C, 67.60; H, 6.08; N, 5.63; found: C, 67.55; H, 6.14; N, 5.61.

(5aS,11bR)-10-Chloro-1,5,11b-trimethyl-5-(4-methylpent-3-en-1-yl)-3-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (11c). Yield 84%, mp 130–132 °C, IR (ν_max, cm⁻¹): 3062, 2972, 2906, 1889, 1745, 1602, 1498, 1387, 1235, 1014, 978, 815, 708; ¹H NMR (400 MHz, CDCl₃): δ 1.07 (S, 3H, 5-CH₃), 1.58 (S, 3H, 11b-CH₃), 1.66 (S, 3H, 5d′–CH₃), 1.78 (S, 3H, 5d′-CH₃), 1.82 (m, 2H, H_5b′), 2.01 (d, J = 4.0 Hz, 1H, H_5a), 2.11 (m, 2H, H_5a′), 2.69 (S, 3H, Py-CH₃), 4.35 (d, J = 12.8 Hz, 1H, H₆), 4.62 (dd, J = 13.2, 4.4 Hz, 1H, H_6′), 5.12 (t, J = 6.4 Hz, 1H, H_5C′), 6.62–7.48 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.71 (Me-5), 17.63 (Me-5e′), 21.31 (Me-5e′′), 21.69 (C-5b′), 25.82 (Me-5), 31.85 (Me-11b), 33.82 (C-11b), 41.03 (C-5a′), 43.82 (C-5a), 63.05 (C-6), 83.59 (C-5), 101.05, 116.57, 120.21, 123.28, 123.52, 124.12, 126.51, 128.71, 128.72, 129.68, 132.58, 133.64, 134.18, 136.87, 146.12, 148.78, 153.16 (Ar-C). ESI-MS: m/z: 462.21 (M)⁺, anal. calcd for C₂₈H₃₁ClN₂O₂: C, 72.63; H, 6.75; N, 6.05; found: C, 72.69; H, 6.68; N, 6.12.

(5aS,11bR)-10-Chloro-3-(2,5-dichlorophenyl)-1,5,11b-trimethyl-5-(4-methylpent-3-en-1-yl)-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (11d). Yield 81%, mp 126–128 °C, IR (ν_max, cm⁻¹): 2985, 2914, 1887, 1742, 1595, 1496, 1388, 1237, 1083, 1043, 817, 758, 709; ¹H NMR (400 MHz, CDCl₃): δ 1.06 (S, 3H, 5-CH₃), 1.57 (S, 3H, 11b-CH₃), 1.68 (S, 3H, 5d′-CH₃), 1.76 (S, 3H, 5d′-CH₃), 1.81 (m, 2H, H_5b′), 1.99 (d, J = 4.4 Hz, 1H, H_5a), 2.10 (m, 2H, H_5a′), 2.71 (S, 3H, Py-CH₃), 4.34 (d, J = 12.4 Hz, 1H, H₆), 4.64 (dd, J = 12.4, 4.4 Hz, 1H, H_6′), 5.10 (t, J = 6.4 Hz, 1H, H_5C′), 6.66–7.53 (m, 6H, Ar-H); ¹³C NMR (100 MHz, CDCl3): δ 16.74 (Me-5), 17.68 (Me-5e′), 21.26 (Me-5e′′), 21.68 (C-5b′), 25.75 (Me-5), 32.30 (Me-11b), 33.62 (C-11b), 40.73 (C-5a′), 43.86 (C-5a), 62.91 (C-6), 83.72 (C-5), 101.07, 116.72, 120.43, 123.20, 123.20, 126.49, 128.59, 128.81, 129.63, 131.63, 132.51, 133.73, 134.10, 137.07, 146.17, 148.99, 152.86 (Ar-C). ESI-MS: m/z: 530.20 (M)⁺, anal. calcd for C₂₈H₂₉Cl₃N₂O₂: C, 63.23; H, 5.50; N, 5.27; found: C, 63.29; H, 5.42; N, 5.21.

(5aS,11bR)-1,5,11b-Trimethyl-5-(4-methylpent-3-en-1-yl)-10-nitro-3-phenyl-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (11e). Yield 78%, mp 136–1138 °C, IR (ν_max, cm⁻¹): 3061, 2979, 1617, 1594, 1491, 1389, 1258, 1082, 1039, 828, 737, 691; ¹H NMR (400 MHz, CDCl₃): δ 1.04 (S, 3H, 5-CH₃), 1.66 (S, 3H, 11b-CH₃), 1.73 (S, 3H, 5d′-CH₃), 1.80 (S, 3H, 5d′-CH₃), 1.93 (m, 2H, H_5b′), 2.12 (d, J = 4 Hz, 1H, H_5a), 2.23 (m, 2H, H_5a′), 2.79 (S, 3H, Py-CH₃), 4.55 (d, J = 13.2, Hz, 1H, H₆), 4.75 (dd, J = 13.2, 4.4 Hz, 1H, H_6′), 5.19 (t, J = 7.2 Hz, 1H, H_5C′), 6.84–8.49 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.78 (Me-5), 17.64 (Me-5e′), 21.23 (Me-5e′′), 21.63 (C-5b′), 25.70 (Me-5), 32.23 (Me-11b), 33.68 (C-11b), 40.74 (C-5a′), 43.70 (C-5a), 62.51 (C-6), 83.64 (C-5), 99.84, 116.89, 120.69, 123.13, 123.65, 123.80, 124.06, 124.12, 125.66, 128.87, 130.17, 132.72, 138.49, 141.71, 146.40, 148.04, 158.19 (Ar-C). ESI-MS: m/z: 473.20 (M)⁺, anal. calcd for C₂₈H₃₁N₃O₄: C, 71.01; H, 6.60; N, 8.87; found: C, 71.08; H, 6.68; N, 8.82.

(5aS,11bR)-3-(2,5-Dichlorophenyl)-1,5,11b-trimethyl-5-(4-methylpent-3-en-1-yl)-10-nitro-5,5a,6,11b-tetrahydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazole (11f). Yield 76%, mp 170–172 °C, IR (ν_max, cm⁻¹): 3065, 2981, 1689, 1621, 1588, 1502, 1390, 1251, 1086, 1035, 835, 729, 696; ¹H NMR (400 MHz, CDCl₃): δ 1.05 (S, 3H, 5-CH₃), 1.68 (S, 3H, 11b-CH₃), 1.71 (S, 3H, 5d′-CH₃), 1.83 (S, 3H, 5d′-CH₃), 1.91 (m, 2H, H_5b′), 2.10 (d, J = 4 Hz, 1H, H_5a), 2.24 (m, 2H, H_5a′), 2.78 (S, 3H, Py-CH₃), 4.53 (d, J = 13.6 Hz, 1H, H₆), 4.78 (dd, J = 12.8, 4.4 Hz, 1H, H_6′), 5.18 (t, J = 7.2 Hz, 1H, H_5C′), 6.88–8.38 (m, 6H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.75 (Me-5), 17.66 (Me-5e′), 21.28 (Me-5e′′), 21.68 (C-5b′), 25.64 (Me-5), 32.31 (Me-11b), 33.72 (C-11b), 41.05 (C-5a′), 43.64 (C-5a), 63.11 (C-6), 84.04 (C-5), 99.89, 116.84, 120.71, 123.17, 123.68, 123.88, 124.15, 125.68, 129.07, 131.18, 130.22, 132.62, 139.04, 141.54, 146.52, 148.09, 158.15 (Ar-C); ESI-MS: m/z: 541.15 (M)⁺, anal. calcd for C₂₈H₂₉Cl₂N₃O₄: C, 62.00; H, 5.39; N, 7.75; found: C, 62.08; H, 5.48; N, 7.68.

1,12b-Dimethyl-3-phenyl-3,4a,4a1,5,6,7,7a,12b-octahydro-chromeno[4′,3′,2′:4,5]chromeno[2,3-c]pyrazole (12a). Yield 79%, mp 200–202 °C, IR (ν_max, cm⁻¹): 3061, 2946, 2872, 1937, 1736, 1601, 1515, 1486, 1250, 1125, 1069, 1002, 757, 690; ¹H NMR (400 MHz, CDCl₃): δ 1.62 (m, 1H, 1H of H₆), 1.72 (S, 3H, 12b-CH₃), 1.78 (m, 2H, 1H of H₆ and 1H of H₅), 1.87 (m, 1H, 1H of H₇), 1.97 (m, 1H, H_7b), 2.23 (s, 3H, Py-CH₃), 2.33 (m, 2H, 1H of H₅ and 1H of H₇), 4.12 (m, 1H, H_4a), 4.91 (m, 1H, H_7a), 6.82–7.74 (m, 9H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.22 (Py-CH₃), 18.61 (C-6), 29.31 (12b-CH3), 30.49 (C-5), 32.15 (C-7), 33.66 (C-12b), 44.86 (C-7b), 69.97 (C-4a), 74.32 (C-7a), 100.13, 116.93, 120.45, 125.42, 125.82, 128.12, 128.91, 129.95, 130.65, 132.45, 138.65, 146.36 (Ar); ESI-MS: m/z: 372.35 (M)⁺, anal. calcd for C₂₄H₂₄N₂O₂: C, 77.39; H, 6.49; N, 7.52; found: C, 77.32; H, 6.54; N, 7.61.

3-(2,5-Dichlorophenyl)-1,12b-dimethyl-3,4a,4a1,5,6,7,7a,12b-octahydrochromeno[4′,3′,2′:4,5]chromeno[2,3-c]pyrazole (12b). Yield 77%, mp 222–224 °C, IR (ν_max, cm⁻¹): 3033, 2950, 2864, 1897, 1737, 1608, 1515, 1436, 1390, 1327, 1105, 1061, 1005, 765, 662; ¹H NMR (400 MHz, CDCl₃): δ 1.47 (m, 1H, 1H of H₆), 1.87 (m, 7H, 1H of H₆, 3H of 12b-CH₃, 3H of Py-CH₃), 1.94 (m, 2H, 1H of H₅ and 1H of H₇), 2.04 (m, 1H, H_7b), 2.21 (m, 2H, 1H of H₅ and 1H of H₇), 3.94 (m, 1H, H_4a), 4.64 (m, 1H, H_7a), 6.87–7.61 (m, 7H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 14.10 (Py-CH₃), 15.61 (C-6), 26.69 (12b-CH₃), 27.23 (C-5), 27.83 (C-7), 34.09 (C-12b), 47.28 (C-7b), 75.64 (C-4a), 77.05 (C-7a), 102.35, 117.63, 121.57, 126.15, 127.42, 129.18, 129.51, 129.65, 130.87, 132.75, 133.72, 136.67, 147.17, 151.30, 158.01 (Ar); ESI-MS: m/z: 440.20 (M)⁺, anal. calcd for C₂₄H₂₂Cl₂N₂O₂: C, 65.31; H, 5.02; N, 6.35; found: C, 65.24; H, 5.08; N, 6.41.

11-Chloro-1,12b-dimethyl-3-phenyl-3,4a,4a1,5,6,7,7a,12b-octahydrochromeno[4′,3′,2′:4,5]chromeno[2,3-c]pyrazole (12c). Yield 80%, mp 214–216 °C, IR (ν_max, cm⁻¹): 3319, 2947, 2864, 1929, 1702, 1621, 1511, 1392, 1336, 1248, 1106, 1003, 851, 766, 687; ¹H NMR (400 MHz, CDCl₃): δ 1.71 (s, 3H, 12b-CH₃), 1.78 (m, 2H, 2H of H₆), 1.82 (m, 2H, 1H of H₅ and 1H of H₇), 1.95 (m, 1H, 1H of H_7b), 2.21 (s, 3H, Py-CH₃), 2.29 (m, 2H, 1H of H₅ and 1H of H₇), 4.11 (m, 1H, H_4a), 4.89 (m, 1H, H_7a), 6.81–7.73 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 13.82 (C-6), 16.21 (Py-CH₃), 24.54 (12b-CH₃), 25.77 (C-5), 27.37 (C-7), 28.99 (C-12b), 40.14 (C-7b), 65.19 (C-4a), 69.45 (C-7a), 97.87, 112.15, 114.54, 115.80, 120.99, 123.31, 124.69, 125.19, 130.41, 131.40, 141.26, 142.86, 148.12 (Ar). ESI-MS: m/z: 406.10 (M)⁺, anal. calcd for C₂₄H₂₃ClN₂O₂: C, 70.84; H, 5.70; N, 6.88; found: C, 70.72; H, 5.64; N, 6.92.

1-Chloro-3-(2,5-dichlorophenyl)-1,12b-dimethyl-3,4a,4a1,5,6,7,7a,12b-octahydrochromeno[4′,3′,2′:4,5]chromeno[2,3-c] pyrazole (12d). Yield 76%, mp 232–234 °C, IR (ν_max, cm⁻¹): 3321, 2954, 2859, 1931, 1712, 1625, 1518, 1492, 1389, 1231, 1115, 1008, 849, 768, 682, 598; ¹H NMR (400 MHz, CDCl₃): δ 1.69 (m, 1H, 1H of H₆), 1.72 (S, 3H, 12b-CH₃), 1.77 (m, 1H, 1H of H₆), 1.84 (m, 2H, 1H of H₅ and 1H of H₇), 1.96 (m, 1H, 1H of H_7b), 2.20 (s, 3H, Py-CH₃), 2.26 (m, 2H, 1H of H₅ and 1H of H₇), 4.14 (m, 1H, H_4a), 4.91 (m, 1H, H_7a), 6.78–7.71 (m, 6H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 14.72 (C-6), 16.24 (Py-CH₃), 24.51 (12b-CH₃), 25.69 (C-5), 27.41 (C-7), 30.09 (C-12b), 41.17 (C-7b), 64.24 (C-4a), 69.28 (C-7a), 99.67, 111.08, 113.84, 115.62, 121.12, 123.35, 125.38, 130.22, 131.38, 132.68, 140.86, 142.56, 148.06 (Ar); ESI-MS: m/z: 475.79 (M)⁺, anal. calcd for C₂₄H₂₁Cl₃N₂O₂: C, 60.58; H, 4.45; N, 5.89; found: C, 60.64; H, 4.54; N, 5.79.

1,12b-Dimethyl-11-nitro-3-phenyl-3,4a,4a1,5,6,7,7a,12b-octahydrochromeno[4′,3′,2′:4,5]chromeno[2,3-c]pyrazole (12e). Yield 72%, mp 224–226 °C, IR (ν_max, cm⁻¹): 3070, 2923, 2858, 1737, 1605, 1512, 1391, 1247, 1092, 1039, 870, 771, 656; ¹H NMR (400 MHz, CDCl₃): 1.54 (m, 1H, 1H of H₆), 1.74 (m, 1H, 1H of H₆), 1.84 (m, 1H, 1H of H₅), 1.95 (m, 7H, 3H of 12b-CH₃, 3H of Py-CH₃, 1H of H_7b), 2.12 (m, 1H, 1H of H₇), 2.26 (m, 2H, 1H of H₅ and 1H of H₇), 4.01 (m, 1H, H_4a), 4.82 (m, 1H, H_7a), 6.93–8.33 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.21 (Py-CH₃), 19.06 (C-6), 29.35 (12b-CH₃), 30.42 (C-5), 31.87 (C-7), 34.16 (C-12b), 42.96 (C-7b), 68.77 (C-4a), 73.21 (C-7a), 101.03, 115.83, 121.05, 125.52, 128.02, 128.88, 129.65, 130.58, 132.45, 136.65, 141.45, 142.26, 146.36 (Ar); ESI-MS: m/z: 416.80 (M)⁺, anal. calcd for C₂₄H₂₃N₃O₄: C, 69.05; H, 5.55; N, 10.07; found: C, 69.12; H, 5.44; N, 9.98.

3-(2,5-Dichlorophenyl)-1,12b-dimethyl-11-nitro-3,4a,4a1,-5,6,-7,7a,12b-octahydrochromeno[4′,3′,2′:4,5]chromeno[2,3-c]pyrazole (12f). Yield 70%, mp 236–238 °C, IR (ν_max, cm⁻¹): 3068, 2919, 2861, 1742, 1621, 1556, 1402, 1289, 1098, 1041, 869, 775, 661, 614; ¹H NMR (400 MHz, CDCl₃): δ 1.56 (m, 1H, 1H of H₆), 1.72 (m, 1H, 1H of H₆), 1.81 (m, 1H, 1H of H₅), 1.98 (m, 7H, 3H of 12b-CH₃, 3H of Py-CH₃, 1H of H_7b), 2.25 (m, 3H, 1H of H₅ and 2H of H₇), 4.05 (m, 1H, H_4a), 4.89 (m, 1H, H_7a), 6.89–8.27 (m, 6H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 15.98 (Py-CH₃), 19.26 (C-6), 29.38 (12b-CH₃), 30.29 (C-5), 31.68 (C-7), 34.26 (C-12b), 43.36 (C-7b), 68.57 (C-4a), 74.25 (C-7a), 100.22, 114.93, 120.85, 124.72, 127.12, 128.87, 129.54, 130.45, 133.68, 136.78, 141.49, 143.16, 147.26 (Ar); ESI-MS: m/z: 485.09 (M)⁺, anal. calcd for C₂₄H₂₁Cl₂N₃O₄: C, 59.27; H, 4.35; N, 8.64; found: C, 59.34; H, 4.42; N, 8.72.

(5R,5aR,11bR)-1,11b-Dimethyl-3,5-diphenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13a). Yield 78%, mp 202–204 °C, IR (ν_max, cm⁻¹): 3059, 2946, 2860, 1950, 1712, 1648, 1598, 1510, 1390, 1174, 1072, 749, 610; ¹H NMR (400 MHz, CDCl₃): δ 1.79 (s, 3H, 11b-Me), 2.64 (s, 3H, Py-Me), 3.42 (d, J = 10.4 Hz, 1H, H_5a), 4.66 (d, J = 11.6 Hz, 1H, H₅), 7.11–7.51 (m, 14H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.28 (Py-Me), 29.35 (11b-Me), 49.26 (C-11b), 54.23 (C-5a), 78.43 (C-5), 103.37, 117.28, 120.02, 121.50, 126.88, 127.54, 127.93, 128.42, 128.88, 129.37, 130.22, 132.17, 136.46, 138.51, 142.42, 145.60, 147.21 (Ar-C), 168.56 (–C=O); ESI-MS: m/z: 422.20 (M)⁺, anal. calcd for C₂₇H₂₂N₂O₃: C, 76.76; H, 5.25; N, 6.63; found: C, 76.68; H, 5.33; N, 6.66.

(5R,5aR,11bR)-3-(2,5-Dichlorophenyl)-1,11b-dimethyl-5-phenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13b). Yield 76%, mp 184–186 °C, IR (ν_max, cm⁻¹): 3034, 2921, 2858, 1901, 1711, 1605, 1581, 1517, 1391, 1173, 1136, 1074, 779, 597; ¹H NMR (400 MHz, CDCl₃): δ 1.80 (s, 3H, 11b-Me), 2.66 (s, 3H, Py-Me), 3.43 (d, J = 11.2 Hz, 1H, H_5a), 4.67 (d, J = 11.2 Hz, 1H, H₅), 6.89–7.51 (m, 12H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.31 (Py-Me), 29.37 (11b-Me), 49.29 (C-11b), 54.21 (C-5a), 78.43 (C-5), 103.41, 117.30, 120.04, 121.49, 126.85, 127.37, 127.58, 128.03, 128.40, 128.87, 129.39, 130.02, 132.46, 135, 97, 136.56, 138.50, 143.12, 145.68, 147.03 (Ar-C), 168.61 (–C=O); ESI-MS: m/z: 490.40 (M)⁺, anal. calcd for C₂₇H₂₀Cl₂N₂O₃: C, 66.00; H, 4.10; N, 5.70; found: C, 66.08; H, 4.03; N, 5.76.

(5R,5aR,11bR)-10-Chloro-1,11b-dimethyl-3,5-diphenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13c). Yield 79%, mp 216–218 °C, IR (ν_max, cm⁻¹): 3062, 2976, 2908, 1939, 1721, 1639, 1592, 1508, 1492, 1190, 1256, 1087, 1045, 756, 689; ¹H NMR (400 MHz, CDCl₃): δ 1.79 (s, 3H, 11b-Me), 2.68 (s, 3H, Py-Me), 3.41 (d, J = 11.2 Hz, 1H, H_5a), 4.66 (d, J = 11.6 Hz, 1H, H₅), 6.92–7.75 (m, 13H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.36 (Py-Me), 29.41 (11b-Me), 49.29 (C-11b), 54.23 (C-5a), 78.32 (C-5), 103.52, 117.12, 120.46, 121.32, 127.28, 127.95, 128.02, 128.65, 128.89, 129.35, 130.15, 132.39, 136.19, 138.36, 142.27, 145.92, 147.13 (Ar-C), 168.53 (–C=O); ESI-MS: m/z: 456.12 (M)⁺, anal. calcd for C₂₇H₂₁Cl₁N₂O₃: C, 70.97; H, 4.63; N, 6.13; found: C, 70.88; H, 4.68; N, 6.08.

(5R,5aR,11bR)-10-Chloro-3-(2,5-dichlorophenyl)-1,11b-dimethyl-5-phenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13d). Yield 76%, mp 212–214 °C, IR (ν_max, cm⁻¹): 3052, 2931, 2856, 1950, 1714, 1646, 1596, 1509, 1386, 1136, 1070, 1025, 752, 691, 616; ¹H NMR (400 MHz, CDCl₃): δ 1.78 (s, 3H, 11b-Me), 2.67 (s, 3H, Py-Me), 3.43 (d, J = 10.8 Hz, 1H, H_5a), 4.67 (d, J = 11.2 Hz, 1H, H₅), 6.81–7.76 (m, 11H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.38 (Py-Me), 29.36 (11b-Me), 49.32 (C-11b), 54.19 (C-5a), 78.38 (C-5), 103.38, 117.08, 120.41, 121.30, 127.39, 127.84, 127.92, 128.74, 128.87, 129.42, 129.53, 130.11, 132.36, 135, 16, 136.19, 138.36, 142.27, 145.92, 147.13 (Ar-C), 168.53 (–C=O); ESI-MS: m/z: 524.10 (M)⁺, anal. calcd for C₂₇H₁₉Cl₃N₂O₃: C, 61.67; H, 3.64; N, 5.33; found: C, 61.74; H, 3.68; N, 5.26.

(5R,5aR,11bR)-1,11b-Dimethyl-10-nitro-3,5-diphenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13e). Yield 74%, mp 230–232 °C, IR (ν_max, cm⁻¹): 3060, 2935, 2867, 1972, 1619, 1599, 1522, 1391, 1231, 1176, 1059, 821, 761, 611; ¹H NMR (400 MHz, CDCl₃): δ 1.80 (s, 3H, 11b-Me), 2.67 (s, 3H, Py-Me), 3.45 (d, J = 10.4 Hz, 1H, H_5a), 4.72 (d, J = 10.8 Hz, 1H, H₅), 6.86–8.49 (m, 13H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.43 (Py-Me), 29.38 (11b-Me), 49.33 (C-11b), 54.17 (C-5a), 78.40 (C-5), 103.40, 117.26, 120.01, 121.51, 126.56, 126.88, 127.43, 128.93, 129.42, 129.74, 130.75, 131.07, 133.01, 137.31, 143.57, 145.75, 147.26 (Ar-C), 168.56 (–C=O); ESI-MS: m/z: 467.10 (M)⁺, anal. calcd for C₂₇H₂₁N₃O₅: C, 69.37; H, 4.53; N, 8.99; found: C, 69.43; H, 4.61; N, 8.89.

(5R,5aR,11bR)-3-(2,5-Dichlorophenyl)-1,11b-dimethyl-10-nitro-5-phenyl-5,5a-dihydro-3H-chromeno[4′,3′:4,5]pyrano[2,3-c]pyrazol-6 (11bH)-one (13f). Yield 70%, mp 224–226 °C, IR (ν_max, cm⁻¹): 3062, 2941, 2865, 1970, 1935, 1621, 1602, 1524, 1395, 1234, 1169, 1061, 819, 759, 609; ¹H NMR (400 MHz, CDCl₃): δ 1.81 (s, 3H, Me), 2.69 (s, 3H, Py-Me), 3.46 (d, J = 10.8 Hz, 1H, H_5a), 4.71 (d, J = 11.2 Hz, 1H, H₅), 6.78–8.51 (m, 11H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 16.41 (Py-Me), 29.41 (Me), 49.36 (C-11b), 54.21 (C-5a), 78.42 (C-5), 103.38, 117.31, 120.06, 121.48, 126.62, 126.96, 127.52, 128.35, 128.95, 129.51, 129.76, 130.68, 131.11, 133.06, 135.42, 137.32, 143.54, 145.81, 147.21 (Ar-C), 168.61 (–C=O); ESI-MS: m/z: 535.07 (M)⁺, anal. calcd for C₂₇H₁₉Cl₂N₃O₅: C, 60.46; H, 3.57; N, 7.83; found: C, 60.43; H, 3.61; N, 7.89.

General procedure for the preparation of chromeno-fused pyrano[2,3-c]isoxazoles{15–17(a–b)}

In a 50 mL round-bottom flask, a mixture of o-alkenylated/alkynylated acetophenone (1 equiv.) and isoxazolone (1 equiv.) was taken in ionic liquid [DBU][Ac](25 mol%) for substrate (6 and 7), and for substrate 8 ZnO (25 mol%) was added to activate the inactive dienophile along with[DBU][Ac](25 mol%) and heated at 130 °C. The reaction was continuously monitored by TLC. After completion, the reaction mixture was extracted with ethyl acetate three times to separate the IL from the product. The combined solution of ethyl acetate was dried with Na₂SO₄ and then concentrated through vacuum evaporation to give the crude product, which was further purified by crystallization in ethanol. The overall yields were in the range of 78–86%. The recovered IL was vacuum-dried at 60 °C for 8 h and reused in the next reaction as the catalyst.

(5aS,11bR)-5,5,11b-Trimethyl-1-phenyl-5,5a,6,11b-tetrahydro chromeno[4′,3′:4,5]pyrano[3,2-d]isoxazole (15a). Yield 86%, mp 204–206 °C, IR (ν_max, cm⁻¹): 3315, 3048, 2954, 2869, 1912, 1609, 1631, 1523, 1428, 1336, 1140, 996, 813, 756, 621; ¹H NMR (400 MHz, CDCl₃): δ 1.18 (s, 3H, 11b-CH3), 1.68 (s, 3H, 5-CH₃), 1.69 (s, 3H, 5-CH₃), 2.01 (d, J = 2.8 Hz, 1H, H-_5a), 4.40 (dd, J = 12.8, 1.6 Hz, 1H, H-₆), 4.61 (dd, J = 12.6, 4.0 Hz, 1H, H-_6′), 6.66–7.70 (m, 9H, Ar-H); ¹³C NMR (100 MHz, CDCl3): δ 22.72 (C-11b), 28.15 (Me-5), 34.20 (Me-5′), 34.48 (C-11b), 47.61 (C-5a), 61.47 (C-6), 85.53 (C-5), 93.48, 116.13, 127.51, 128.33, 128.40, 128.52, 129.51, 130.12, 130.40, 132.02, 150.33, 164.49, 167.64 (Ar-C); ESI-MS: m/z: 347.20 (M)⁺, anal. calcd for C₂₂H₂₁NO₃: C, 76.06; H, 6.09; N, 4.03; found: C, 76.12; H, 6.04; N, 4.09.

(5aS,11bR)-10-Chloro-5,5,11b-trimethyl-1-phenyl-5,5a,6,-11b-tetrahydrochromeno[4′,3′:4,5]pyrano[3,2-d]isoxazole (15b). Yield 84%, mp 212–214 °C, IR (ν_max, cm⁻¹): 3363, 3069, 2864, 2094, 1627, 1601, 1546, 1416, 1378, 1142, 934, 820, 760, 619; ¹H NMR (400 MHz, CDCl₃): δ 1.21 (s, 3H, 11b-CH₃), 1.68 (s, 3H, 5-CH₃), 1.70 (s, 3H, 5-CH₃), 1.99 (d, J = 2.4 Hz, 1H, H_5a), 4.41 (dd, J = 12.8, 1.6 Hz, 1H, H₆), 4.55 (dd, J = 13.2, 3.6 Hz, 1H, H_6′), 6.62–7.69 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl3): δ 22.75 (C-11b), 28.64 (Me-5), 34.03 (Me-5′), 34.61 (C-11b), 47.02 (C-5a), 61.68 (C-6), 85.31 (C-5), 92.90, 117.76, 125.74, 127.84, 127.91, 128.54, 129.42, 129.74, 130.36, 131.35, 151.05, 164.23, 167.70 (Ar-C); ESI-MS: m/z: 381.30 (M)⁺, anal. calcd for C₂₂H₂₀ClNO₃: C, 69.20; H, 5.28; N, 3.67; found: C, 69.15; H, 5.24; N, 3.71.

(5aS,11bR)-11b-Methyl-1-phenyl-5,5a,6,11b-tetrahydro-chromeno[4′,3′:4,5]pyrano[3,2-d]isoxazole (16a). Yield 84%, mp 180–182 °C, IR (ν_max, cm⁻¹): 3296, 3065, 2955, 2869, 1895, 1626, 1578, 1491, 1380, 1242, 1146, 1032, 824, 770, 686; ¹H NMR (400 MHz, CDCl₃): δ 1.81 (s, 3H, 11b-CH₃), 2.18 (m, 1H, H_5a), 4.27 (dd, J = 12, 3.2 Hz, 1H, H₆), 4.31 (d, J = 10.8 Hz, H₅), 4.54 (dd, J = 11.2, 3.2 Hz, 1H, H_6′), 4.58 (dd, J = 12, 3.2 Hz, 1H, H_5′), 6.80–7.72 (m, 9H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 29.69 (Me-11b), 34.02 (C-5a), 37.84 (C-11b), 62.84 (C-6), 69.07 (C-5), 103.13, 117.05, 120.69, 121.07, 125.62, 127.87, 128.91, 129.08, 129.59, 138.42, 149.54, 162.58, 166.11 (Ar-C); ESI-MS: m/z: 319.10 (M)⁺, anal. calcd for C₂₀H₁₇NO₃: C, 75.22; H, 5.37; N, 4.39; found: C, 75.17; H, 5.25; N, 4.42.

(5aS,11bR)-10-Chloro-11b-methyl-1-phenyl-5,5a,6,11b-tetrahydrochromeno[4′,3′:4,5]pyrano[3,2-d]isoxazole (16b). Yield 82%, mp 166–1168 °C, IR (ν_max, cm⁻¹): 3298, 3059, 2958, 2871, 1902, 1628, 1572, 1489, 1388, 1239, 1149, 1031, 829, 772, 682; ¹H NMR (400 MHz, CDCl₃): δ 1.79 (s, 3H, 11b-CH₃), 2.13 (m, 1H, H_5a), 4.25 (dd, J = 12.6, 3.6 Hz, 1H, H₆), 4.33 (d, J = 10.4 Hz, 1H, H₅), 4.52 (dd, J = 11.6, 3.2 Hz, 1H, H_6′), 4.59 (dd, J = 12.2, 3.6 Hz, 1H, H_5′), 6.78–7.69 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 29.71 (Me-11b), 34.25 (C-5a), 37.64 (C-11b), 62.69 (C-6), 69.19 (C-5), 102.83, 116.95, 121.06, 121.12, 126.22, 127.89, 128.78, 129.06, 129.63, 137.84, 150.04, 162.72, 166.16 (Ar-C) ESI-MS: m/z: 381.30 (M)⁺, anal. calcd for C₂₀H₁₆ClNO₃: C, 67.90; H, 4.56; N, 3.96; found: C, 67.86; H, 4.85; N, 4.02.

11b-Methyl-1-phenyl-6,11b-dihydrochromeno[4′,3′:4,5]pyrano[3,2-d]isoxazole (17a). Yield 80%, mp 186–188 °C, IR (ν_max, cm⁻¹): 3061, 2946, 2872, 1882, 1601, 1515, 1486, 1392, 1250, 1125, 1036, 833, 757, 690; ¹H NMR (400 MHz, CDCl₃): δ 1.87 (s, 3H, 11b-CH₃), 4.65 (d, J = 12.8 Hz, 1H, H₆), 5.17 (dd, J = 11.6, 2.0 Hz, 1H, H_6′), 6.56 (d, J = 1.2 Hz, 1H, H₅), 6.87–7.72 (m, 9H, Ar-H); ¹³C NMR (100 MHz, CDCl₃): δ 27.54 (Me-11b), 36.03 (C-11b), 64.89 (C-6), 100.64, 115.68, 117.68, 119.51, 120.81, 122.17, 124.98, 128.19, 129.69, 130.67, 133.14, 133.75, 152.72, 159.36, 163.33 (Ar-C); ESI-MS: m/z: 317.20 (M)⁺, anal. calcd for C₂₀H₁₅NO₃: C, 75.70; H, 4.76; N, 4.41; found: C, 75.66; H, 4.85; N, 4.32.

10-Chloro-11b-methyl-1-phenyl-6,11b-dihydrochromeno [4′,3′:4,5]pyrano[3,2-d]isoxazole (17b). Yield 78%, mp 178–180 °C, IR (ν_max, cm⁻¹): 3059, 2951, 2869, 1871, 1642, 1521, 1489, 1402, 1321, 1250, 1128, 1038, 837, 751, 689; ¹H NMR (400 MHz, CDCl₃): δ 1.85 (s, 3H, 11b-CH₃), 4.61 (d, J = 12.6 Hz, 1H, H-₆), 5.13 (dd, J = 12.2, 1.6 Hz, 1H, H-_6′), 6.54 (d, J = 1.6 Hz, 1H, H-₅), 6.85–7.69 (m, 8H, Ar-H); ¹³C NMR (100 MHz, CDCl3): δ 27.75 (Me-11b), 36.13 (C-11b), 65.02 (C-6), 100.68, 115.46, 117.72, 119.62, 121.03, 122.20, 126.08, 128.13, 129.53, 131.12, 133.42, 133.87, 151.95, 160.06, 163.36 (Ar-C) ESI-MS: m/z: 351.07 (M)⁺, anal. calcd for C₂₀H₁₄ClNO₃: C, 68.28; H, 4.01; N, 3.98; found: C, 68.34; H, 4.12; N, 3.92.

Acknowledgements

We sincerely express our thanks to the Head, Department of Chemistry, Sardar Patel University, for providing necessary research facilities for the study. Authors TRS, BML and BDP specially thank the UGC, New Delhi, India for its financial assistance under the UGC Scheme of RFSMS. We also thank DST, New Delhi, in general, and PURSE central facility for mass analysis (vide sanction letter DO. no. SR/59/Z-23/2010/43 dated 16th march 2011).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 978637, 989312, 1025475 and 1024805. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra00493d

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