Exploring the Reactivity of (E)-3(5)-(2-Hydroxyphenyl)-5(3)-styryl-1H-pyrazoles as Dienes in the Diels–Alder Reaction: A New Synthesis of 1H-Indazoles

Abstract

The reactivity of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles as dienes in the Diels–Alder cycloaddition reaction was investigated. It is shown that di-tosylated derivatives react with N-methylmaleimide under microwave irradiation to afford the corresponding endo-tetrahydroindazoles, except in the case of strong electron-withdrawing substituents. Dehydrogenation of these tetrahydroindazoles with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave the expected 1H-indazoles in low to good yields.

The indazole nucleus is a common structural motif that is found in several biologically active molecules.[1] [2] Different aspects of pharmaceutical and other useful applications of indazoles have been extensively reviewed.[1–3] Among the several applications of indazoles, their use in medicinal chemistry as inhibitors of platelet aggregation,[4] of HIV protease[5] and nitric oxide synthase,[6] as 5-HT₄ receptor antagonists,[7] as antipyretic and anti-inflammatory (bendazac and benzidamine),[8] antitumor,[9] anticancer (lonidamine),[10] antimicrobial,[8b] [11] antidepressant, antiobesity,[12] and contraceptive agents, are the most commonly reported. Some indazoles also have analgesic activity and others are used in the treatment of CNS disorders (granisetron).[13]

Among the several synthetic routes to indazoles,[1] [14] [15] there are some examples that start from pyrazoles, namely those involving cycloaddition reactions of 1-phenyl-5-vinylpyrazole,[16] 1-acetyl-4-styrylpyrazoles,[17] 1-aryl-3-phenyl-1,6-dihydropyrano[2,3-c]pyrazoles,[18] or N-unsubstituted pyrazoles ortho-quinodimethanes with several dienophiles.[19]

Since there are very few examples of cycloadditions involving the pyrazole ring, and following our interest in the synthesis and transformation of styryl-1H-pyrazoles by Diels–Alder reactions to obtain novel indazole-type compounds,[17] we decided to study the reactivity of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles as dienes towards N-methylmaleimide. The oxidation of the obtained cycloadducts was also performed, thus developing a new method for the synthesis of 1H-indazoles.

The Diels–Alder cycloaddition is the most useful and widely employed method for the construction of six-membered rings and it is an elegant way to rapidly construct complex cyclic compounds.[20] However, it is well-known that vinylpyrazoles are very reluctant to participate as dienes in cycloaddition reactions involving the pyrazole ring due to the loss of its aromaticity in the reaction.[15] [16] Examples of this type of reaction are scarce and the products are usually obtained in very low yields.[15,16] In previous work, we showed that (E)- and (Z)-1-acetyl-3-(2-hydroxyphenyl)-4-styryl-1H-pyrazoles 1 (Figure [1]) are also reluctant to participate as dienes in cycloaddition reactions involving their pyrazole ring, but using reactive dienophiles, such as N-methylmaleimide, high temperature and high power microwave radiation (MW), the corresponding Diels–Alder adducts were obtained in moderate to good yields and with high selectivity.[17] Here, we report the results of our study on the reactivity of the isomeric (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 2 (Scheme [1]) as dienes under similar MW irradiation conditions. However, the reaction of (E)-1-acetyl-3-(2-acetyloxyphenyl)-5-styryl-1H-pyrazole (2e, R = H; Figure [1]) with N-methylmaleimide under our previous used MW irradiation conditions[17] was unsuccessful, even after 100 min reaction time in the presence of 9 equivalents of N-methylmaleimide. Only degradation was observed and 70% of starting material 2e (R = H) was recovered.

We then wanted to study the reactivity of these pyrazoles by replacing the acetyl groups with tosyl protecting groups. Reaction of pyrazoles 2a–d with p-toluenesulfonyl chloride in anhydrous pyridine at room temperature for 28–120 hours[21] gave (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazoles 4a–d in good isolated yields together with the corresponding mono-tosylated derivatives 3a–d as by-products (Table [1, ]Scheme [1]).[21] [22] [23] The tosylation of pyrazoles bearing strong electron-withdrawing groups (nitro group 2d) was difficult and led to substantial degradation; in this case, 4d was obtained in very low yield.

A mixture of (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazole (4a), N-methylmaleimide (6 equiv) and a few drops of 1,2,4-trichlorobenzene (1,2,4-TCB) was irradiated with MW at 800 W for one hour (Scheme [1]).[24] After this period, thin-layer chromatography revealed the presence of starting material together with a new product; therefore, three additional equivalents of N-methylmaleimide were added and the mixture was irradiated for a further 40 minutes. After this treatment and purification of the reaction mixture, the cycloadduct was isolated in 40% yield and 58% of the starting material was recovered. Since the increase of reaction time and amount of N-methylmaleimide did not contribute to the complete consumption of the starting material, we performed the cycloaddition reaction of (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazoles 4b–d with N-methylmaleimide under similar conditions. The expected cycloadducts 5b and 5c were obtained in low isolated yields, thus confirming the poor reactivity of these pyrazoles (Table [2]).[24] [25] In the case of pyrazole 4d, no cycloadduct was formed, with only extensive degradation of the starting material being observed. To improve the yields of the Diels–Alder reaction, we performed the reaction under pressure using sealed vials and different solvents (DMF and NMP) but the desired cycloadducts were not obtained.

The NMR spectroscopic data are consistent with the structure proposed for cycloadducts 5a–c, particularly with regard to:[25] (i) the absence of the signals due to the resonance of the pyrazole and vinylic protons; (ii) the presence of the two tosyl groups indicated by signals corresponding to the resonance of the methyl groups (δ_H = 2.40–2.48 ppm, δ_C 21.7–21.8 ppm) and by those of the aromatic rings of the two tosyl groups; (iii) the presence of an N-methyl group (δ_H = 2.37 ppm, δ_C = 24.1 ppm) and the carbonyl groups of the N-methylmaleimide moiety (δ_C = 174.9, 176.3 ppm); and (iv) the presence of several signals in the aliphatic region due to the newly formed cyclohexene ring. The cis-configuration of protons H-3a with H-7 and of H-3b with H-6a was confirmed by NOE cross-peeks observed in the NOESY spectrum and by the coupling constants of some of the protons (J _H3a–H7 ≈ 5.4 Hz, J _H3b–H6a ≈ 7.9 Hz); no coupling constants were observed between H-3a and H-3b or between H-6a and H-7. These data indicate that the reaction selectively afforded the endo-adduct. No traces of the exo-adduct were detected.

To evaluate the scope of this reaction and its utility as a new synthetic methodology with which to obtain novel indazole-type compounds, we performed the cycloadduct oxidation using DDQ as oxidant in 1,2,4-trichlorobenzene at 170 °C (Scheme [1], step c).[26] [27] Under these conditions the expected 7-aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo[3,4-e]indazoles 6a–c were obtained in good (54–63%, 6a,b) or low (28%, 6c) yields.

In summary, we have shown the reactivity as dienes of tosylated 5-styrylpyrazoles 4a–d with N-methylmaleimide leading to the formation of novel indazole-type compounds 5a–c. The yields, although low, are comparatively good when one considers that the Diels–Alder reaction involves the very unreactive pyrazole ring and that it is possible to recover and reuse the starting material for successive transformation. The presence of a strong electron-withdrawing substituent at the para-position of the styryl group decreases the reactivity of the di-tosylated pyrazole and no cycloadduct was isolated in the case of derivative 4d.

The Diels–Alder cycloadditions of 4a–c with N-methylmaleimide described herein were stereoselective and gave the expected endo-cycloadducts, and their oxidation with DDQ in 1,2,4-trichlorobenzene gave new indazole-type compounds 6a–c.

Acknowledgment

Thanks are due to the University of Aveiro, ‘Fundação para a Ciência e a Tecnologia’ (FCT, Portugal), EU, QREN, FEDER and COMPETE for funding the Organic Chemistry Research Unit (project PEst-C/QUI/UI0062/2013; FCOMP-01-0124-FEDER-037296), the Portuguese National NMR Network, and project FCOMP-01-0124-FEDER-010840:PTDC/QUI-QUI/102454/2008. In addition, V.L.M.S. acknowledges the project New Strategies Applied to Neuropathological Disorders (CENTRO-07-ST24-FEDER-002034), co-funded by QREN, ‘Mais Centro-Programa Operacional Regional do Centro’, and EU, FEDER for her Assistant Researcher position.

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• 21 Tosylation of (E)-3(5)-(2-Hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 2a–d; General Procedure: The requisite amount of TsCl (see Table 1) was added to a stirred solution of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazole 2a–d (1.0 to 4.4 mmol, Table 1) in anhydrous pyridine (10–45 mL). The mixture was stirred at room temperature under nitrogen until complete consumption of the starting material. The reaction mixture was then poured onto ice-water and acidified to pH 3–4 with hydrochloric acid (20%). The resulting mixture was extracted with chloroform and dried with anhydrous Na₂SO₄. After filtration, the solvent was evaporated and the residue was dissolved in CH₂Cl₂ and purified by thin-layer chromatography using CH₂Cl₂ as eluent. Two products were isolated; the one with the higher R_f corresponded to (E)-3-(2-hydroxyphenyl)-5-styryl-1-tosyl-1H-pyrazoles (3a, 427.3 mg, 38%; 3b, 58.0 mg, 5%; 3c, 306.6 mg, 20%; 3d, 14.8 mg, 2%) and the other to (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazoles (4a, 631.7 mg, 41%; 4b, 812.2 mg, 52%; 4c, 1.64 g, 80%; 4d, 157.6 mg, 16%).
• 22 (E)-3-(2-Hydroxyphenyl)-5-[2-(4-methoxyphenyl)vinyl]-1-tosyl-1H-pyrazole (3b): White solid (recrystallized from ethanol); mp 145–146 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.38 (s, 3 H, 4′′′-CH ₃), 3.87 (s, 3 H, 4′′-OCH ₃), 6.88 (s, 1 H, H-4), 6.88–6.93 (m, 1 H, H-5′), 6.96 (d, J = 8.8 Hz, 2 H, H-3′′,5′′), 7.02 (dd, J = 8.3, 1.0 Hz, 1 H, H-3′), 7.12 (d, J = 16.3 Hz, 1 H, H-β), 7.23–7.26 (m, 1 H, H-4′), 7.29 (d, J = 8.5 Hz, 2 H, H-3′′′,5′′′), 7.49–7.51 (m, 1 H, H-6′), 7.53 (d, J =8.8 Hz, 2 H, H-2′′,6′′), 7.64 (d, J = 16.3 Hz, 1 H, H-α), 7.86 (d, J = 8.5 Hz, 2 H, H-2′′′,6′′′), 10.30 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃), 55.4 (4′′-OCH₃), 102.9 (C-4), 111.9 (C-α), 114.4 (C-3′′,5′′), 114.8 (C-1′), 117.5 (C-3′), 119.4 (C-5′), 127.1 (C-6′), 127.8 (C-2′′′,6′′′), 128.5 (C-1′′), 128.7 (C-2′′,6′′), 130.1 (C-3′′′,5′′′), 130.9 (C-4′), 134.2 (C-1′′′), 135.6 (C-β), 146.0 (C-4′′′), 146.9 (C-5), 155.2 (C-3), 156.6 (C-2′), 160.5 (C-4′′). MS (EI): m/z (%) = 446 (45) [M]^+· , 445 (3) [M – H]⁺, 291 (100) [M – Ts]⁺, 264 (4), 248 (7), 219 (4), 202 (3), 189 (4), 172 (4), 165 (3), 156 (5), 145 (3), 139 (4), 130 (2), 121 (6), 115 (3), 107 (2), 102 (5), 91 (22), 77 (4), 65 (8). Anal. Calcd. for C₂₅H₂₂N₂O₄S: (446.5): C, 67.25; H, 4.97; N, 6.27; S, 7.18; found: C, 66.98; H, 4.90; N, 6.16; S, 6.82.
• 23 (E)-5-[2-(4-Methoxyphenyl)vinyl]-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazole (4b): White solid (recrystallized from ethanol); mp 129–131 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.39 (s, 6 H, 4′′′-CH ₃ and 4′′′′-CH ₃), 3.88 (s, 3 H, 4′′-OCH ₃), 6.72 (s, 1 H, H-4), 6.91 (d, J = 16.2 Hz, 1 H, H-β), 6.97 (d, J = 8.8 Hz, 2 H, H-3′′,5′′), 7.09 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.27–7.32 (m, 1 H, H-5′), 7.29 (d, J = 8.3 Hz, 2 H, H-3′′′′,5′′′′), 7.38–7.41 (m, 1 H, H-3′), 7.40 (d, J = 8.3 Hz, 2 H, H-2′′′′,6′′′′), 7.51–7.54 (m, 1 H, H-4′), 7.52 (d, J = 8.8 Hz, 2 H, H-2′′,6′′), 7.54 (d, J = 16.2 Hz, 1 H, H-α), 7.70 (dd, J = 7.5, 1.6 Hz, 1 H, H-6′), 7.86 (d, J = 8.3 Hz, 2 H, H-2′′′,6′′′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃ and 4′′′′-CH₃), 55.4 (4′′-OCH₃), 106.9 (C-4), 112.1 (C-α), 114.4 (C-3′′,5′′), 123.8 (C-3′), 125.5 (C-1′), 127.3 (C-5′), 127.8 (C-2′′′,6′′′), 128.2 (C-2′′′′,6′′′′), 128.5 (C-2′′,6′′), 128.7 (C-1′′), 129.4 (C-3′′′,5′′′), 129.97 (C-4′,3′′′′,5′′′′), 130.0 (C-6′), 130.2 (C-1′′′′), 131.8 (C-1′′′), 134.5 (C-β), 145.6 (C-4′′′), 145.8 (C-4′′′′), 146.1 (C-5), 147.2 (C-2′), 150.8 (C-3), 160.4 (C-4′′). MS (EI): m/z (%) = 600 (54) [M]^+· , 446 (14) [M – Ts]⁺, 445 (10) [M – H – Ts]⁺, 292 (37), 291 (47) [M – 2Ts]⁺, 290 (100) [M – H – 2Ts]⁺, 262 (8), 247 (10), 218 (6), 188 (12), 156 (5), 121 (6), 91 (21). HRMS (EI): m/z [M^+· ] calcd. for C₃₂H₂₈N₂O₆S₂: 600.1389; found: 600.1410.
• 24 Synthesis of endo-7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxy­phenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]-indazoles 5a–c; General Procedure: A mixture of the appropriate (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazole 4a–c (0.18 mmol), N-methylmaleimide (1.08–2.16 mmol, Table 2) and a few drops of 1,2,4-TCB was irradiated at atmospheric pressure in an Ethos SYNTH microwave (Milestone Inc.) at 800 W for 40 min to 100 min (Table 2). The crude product was dissolved in a small volume of chloroform and purified by column chromatography. Light petroleum was first used as eluent to remove the 1,2,4-TCB and then elution was performed with light petroleum–ethyl acetate (2:3). In some cases the cycloadduct was isolated after thin-layer chromatography using light petroleum–ethyl acetate (2:3) as eluent. The cycloadducts 5a–c were obtained in low to moderate yields (5a, 49.1 mg, 40%; 5b, 33.3 mg, 26%; 5c, 29.6 mg, 23%).
• 25 rel-(3aS,3bS,6aR,7S)-7-(4-methoxyphenyl)-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]indazole (5b): White solid; mp 114–124 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.37 (s, 3 H, NCH ₃), 2.40 (s, 3 H, CH ₃), 2.48 (s, 3 H, CH ₃), 3.33 (d, J = 5.4 Hz, 1 H, H-3a), 3.50 (d, J = 7.9 Hz, 1 H, H-3b), 3.56 (d, J = 5.4 Hz, 1 H, H-7), 3.72 (s, 3 H, 4′′-OCH ₃), 4.40 (d, J = 7.9 Hz, 1 H, H-6a), 6.57 (d, J = 8.4 Hz, 2 H, H-3′′,5′′), 6.69 (d, J = 8.4 Hz, 2 H, H-2′′,6′′), 7.20 (d, J = 8.1 Hz, 2 H, H-3′′′′,5′′′′), 7.24 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.36 (d, J = 8.1 Hz, 2 H, H-2′′′′,6′′′′), 7.34–7.40 (m, 3 H, H-3′,5′, H-8), 7.46 (dt, J = 7.2, 1.6 Hz, 1 H, H-4′), 7.59 (dd, J = 7.5, 1.6 Hz, 1 H, H-6′), 7.77 (d, J = 8.3 Hz, 2 H, H-2′′′, 6′′′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (CH₃), 21.8 (CH₃), 24.1 (NCH₃), 26.9 (C-3a), 38.3 and 38.5 (C-6a,7), 44.9 (C-3b), 55.1 (4′′-OCH₃), 113.7 (C-3′′,5′′), 123.4 (C-3′), 126.6 (C-1′), 127.6 (C-5′), 127.7 and 127.8 (C-2′′′,6′′′ and C-2′′′′,6′′′′), 128.7 (C-2′′,6′′), 129.6 (C-3′′′′,5′′′′), 130.1 (C-3′′′,5′′′, C-8), 130.5 (C-4′), 130.9 (C-1′′), 131.6 (C-6′, C-1′′′′), 134.6 (C-1′′′), 141.9 (C-8a), 145.9 (C-4′′′), 146.2 (C-4′′′′), 147.1 (C-2′), 150.9 (C-3), 158.6 (4′′-OCH₃), 174.9 (C=O), 176.3 (C=O). MS (ESI⁺): m/z (%) = 712 (100) [M + H]⁺, 734 (25) [M + Na]⁺. HRMS-ESI⁺: m/z [M + H]⁺ calcd for C₃₇H₃₄N₃O₈S₂: 712.17818; found: 712.17738.
• 26 Synthesis of 7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo[3,4-e]indazoles 6a–c; General Procedure: A mixture of the appropriate endo-7-aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]indazole 5a–c (0.10 mmol) and DDQ (68.10 mg, 0.30 mmol) in 1,2,4-TCB (5–10 mL) was heated at 170 °C until consumption of the starting material was observed. The crude product was purified by column chromatography, with light petroleum as eluent to remove the 1,2,4-TCB, followed by elution with a mixture of light petroleum–ethyl acetate (2:3) to remove the reaction product, which in some cases was further purified by thin-layer chromatography with the same mixture of light petroleum–ethyl acetate (2:3) as eluent. 7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo-[3,4-e]indazoles 6a–c were obtained in good to low yields [6a, 42.7 mg, 63%; 6b, 38.2 mg, 54%; 6c, 19.9 mg, 28%].
• 27 7-(4-Methoxyphenyl)-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo[3,4-e]indazole (6b): Yellow solid; mp 97–99 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.28 (s, 3 H, 4′′′′-CH ₃), 2.38 (s, 3 H, 4′′′-CH ₃), 3.02 (s, 3 H, NCH ₃), 3.93 (s, 3 H, 4′′-OCH ₃), 6.90 (d, J = 8.4 Hz, 2 H, H-3′′′′,5′′′′), 6.96 (d, J = 8.4 Hz, 2 H, H-2′′′′,6′′′′), 7.09 (d, J = 8.7 Hz, 2 H, H-3′′,5′′), 7.34 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.38–7.43 (m, 2 H, H-4′, H-5′), 7.47 (dd, J = 8.3, 0.9 Hz, 1 H, H-3′), 7.54–7.59 (m, 1 H, H-6′), 7.56 (d, J = 8.7 Hz, 2 H, H-2′′,6′′), 7.95 (d, J = 8.3 Hz, 2 H, H-2′′′,6′′′), 8.35 (s, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃ and 4′′′′-CH₃), 23.9 (NCH₃), 55.4 (4′′-OCH₃), 113.6 (C-3′′,5′′), 118.5 (C-8), 118.7 (C-3a), 123.5 (C-3′), 125.4 (C-1′), 125.5 (C-3b,6a), 126.6 (C-5′), 127.5 (C-2′′′′,6′′′′), 127.7 (C-2′′′, 6′′′), 128.0 (C-1′′), 129.2 (C-3′′′′, 5′′′′), 130.3 (C-3′′′, 5′′′), 131.1 (C-2′′,6′′), 131.3 and 131.5 (C-4′ and C-6′), 131.5 (C-4′), 132.1 (C-1′′′′), 133.9 (C-1′′′), 140.6 (C-7), 143.7 (C-3), 145.3 (C-4′′′′), 146.4 (C-4′′′), 146.9 (C-8a), 148.3 (C-2′), 160.4 (C-4′′), 165.6 (C=O), 167.6 (C=O). MS (ESI⁺): m/z (%) = 708 (100) [M + H]⁺, 730 (60) [M + Na]⁺, 746 (20) [M + K]⁺ .

• References and Notes

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• 21 Tosylation of (E)-3(5)-(2-Hydroxyphenyl)-5(3)-styryl-1H-pyrazoles 2a–d; General Procedure: The requisite amount of TsCl (see Table 1) was added to a stirred solution of (E)-3(5)-(2-hydroxyphenyl)-5(3)-styryl-1H-pyrazole 2a–d (1.0 to 4.4 mmol, Table 1) in anhydrous pyridine (10–45 mL). The mixture was stirred at room temperature under nitrogen until complete consumption of the starting material. The reaction mixture was then poured onto ice-water and acidified to pH 3–4 with hydrochloric acid (20%). The resulting mixture was extracted with chloroform and dried with anhydrous Na₂SO₄. After filtration, the solvent was evaporated and the residue was dissolved in CH₂Cl₂ and purified by thin-layer chromatography using CH₂Cl₂ as eluent. Two products were isolated; the one with the higher R_f corresponded to (E)-3-(2-hydroxyphenyl)-5-styryl-1-tosyl-1H-pyrazoles (3a, 427.3 mg, 38%; 3b, 58.0 mg, 5%; 3c, 306.6 mg, 20%; 3d, 14.8 mg, 2%) and the other to (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazoles (4a, 631.7 mg, 41%; 4b, 812.2 mg, 52%; 4c, 1.64 g, 80%; 4d, 157.6 mg, 16%).
• 22 (E)-3-(2-Hydroxyphenyl)-5-[2-(4-methoxyphenyl)vinyl]-1-tosyl-1H-pyrazole (3b): White solid (recrystallized from ethanol); mp 145–146 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.38 (s, 3 H, 4′′′-CH ₃), 3.87 (s, 3 H, 4′′-OCH ₃), 6.88 (s, 1 H, H-4), 6.88–6.93 (m, 1 H, H-5′), 6.96 (d, J = 8.8 Hz, 2 H, H-3′′,5′′), 7.02 (dd, J = 8.3, 1.0 Hz, 1 H, H-3′), 7.12 (d, J = 16.3 Hz, 1 H, H-β), 7.23–7.26 (m, 1 H, H-4′), 7.29 (d, J = 8.5 Hz, 2 H, H-3′′′,5′′′), 7.49–7.51 (m, 1 H, H-6′), 7.53 (d, J =8.8 Hz, 2 H, H-2′′,6′′), 7.64 (d, J = 16.3 Hz, 1 H, H-α), 7.86 (d, J = 8.5 Hz, 2 H, H-2′′′,6′′′), 10.30 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃), 55.4 (4′′-OCH₃), 102.9 (C-4), 111.9 (C-α), 114.4 (C-3′′,5′′), 114.8 (C-1′), 117.5 (C-3′), 119.4 (C-5′), 127.1 (C-6′), 127.8 (C-2′′′,6′′′), 128.5 (C-1′′), 128.7 (C-2′′,6′′), 130.1 (C-3′′′,5′′′), 130.9 (C-4′), 134.2 (C-1′′′), 135.6 (C-β), 146.0 (C-4′′′), 146.9 (C-5), 155.2 (C-3), 156.6 (C-2′), 160.5 (C-4′′). MS (EI): m/z (%) = 446 (45) [M]^+· , 445 (3) [M – H]⁺, 291 (100) [M – Ts]⁺, 264 (4), 248 (7), 219 (4), 202 (3), 189 (4), 172 (4), 165 (3), 156 (5), 145 (3), 139 (4), 130 (2), 121 (6), 115 (3), 107 (2), 102 (5), 91 (22), 77 (4), 65 (8). Anal. Calcd. for C₂₅H₂₂N₂O₄S: (446.5): C, 67.25; H, 4.97; N, 6.27; S, 7.18; found: C, 66.98; H, 4.90; N, 6.16; S, 6.82.
• 23 (E)-5-[2-(4-Methoxyphenyl)vinyl]-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazole (4b): White solid (recrystallized from ethanol); mp 129–131 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.39 (s, 6 H, 4′′′-CH ₃ and 4′′′′-CH ₃), 3.88 (s, 3 H, 4′′-OCH ₃), 6.72 (s, 1 H, H-4), 6.91 (d, J = 16.2 Hz, 1 H, H-β), 6.97 (d, J = 8.8 Hz, 2 H, H-3′′,5′′), 7.09 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.27–7.32 (m, 1 H, H-5′), 7.29 (d, J = 8.3 Hz, 2 H, H-3′′′′,5′′′′), 7.38–7.41 (m, 1 H, H-3′), 7.40 (d, J = 8.3 Hz, 2 H, H-2′′′′,6′′′′), 7.51–7.54 (m, 1 H, H-4′), 7.52 (d, J = 8.8 Hz, 2 H, H-2′′,6′′), 7.54 (d, J = 16.2 Hz, 1 H, H-α), 7.70 (dd, J = 7.5, 1.6 Hz, 1 H, H-6′), 7.86 (d, J = 8.3 Hz, 2 H, H-2′′′,6′′′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃ and 4′′′′-CH₃), 55.4 (4′′-OCH₃), 106.9 (C-4), 112.1 (C-α), 114.4 (C-3′′,5′′), 123.8 (C-3′), 125.5 (C-1′), 127.3 (C-5′), 127.8 (C-2′′′,6′′′), 128.2 (C-2′′′′,6′′′′), 128.5 (C-2′′,6′′), 128.7 (C-1′′), 129.4 (C-3′′′,5′′′), 129.97 (C-4′,3′′′′,5′′′′), 130.0 (C-6′), 130.2 (C-1′′′′), 131.8 (C-1′′′), 134.5 (C-β), 145.6 (C-4′′′), 145.8 (C-4′′′′), 146.1 (C-5), 147.2 (C-2′), 150.8 (C-3), 160.4 (C-4′′). MS (EI): m/z (%) = 600 (54) [M]^+· , 446 (14) [M – Ts]⁺, 445 (10) [M – H – Ts]⁺, 292 (37), 291 (47) [M – 2Ts]⁺, 290 (100) [M – H – 2Ts]⁺, 262 (8), 247 (10), 218 (6), 188 (12), 156 (5), 121 (6), 91 (21). HRMS (EI): m/z [M^+· ] calcd. for C₃₂H₂₈N₂O₆S₂: 600.1389; found: 600.1410.
• 24 Synthesis of endo-7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxy­phenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]-indazoles 5a–c; General Procedure: A mixture of the appropriate (E)-5-styryl-1-tosyl-3-(2-tosyloxyphenyl)-1H-pyrazole 4a–c (0.18 mmol), N-methylmaleimide (1.08–2.16 mmol, Table 2) and a few drops of 1,2,4-TCB was irradiated at atmospheric pressure in an Ethos SYNTH microwave (Milestone Inc.) at 800 W for 40 min to 100 min (Table 2). The crude product was dissolved in a small volume of chloroform and purified by column chromatography. Light petroleum was first used as eluent to remove the 1,2,4-TCB and then elution was performed with light petroleum–ethyl acetate (2:3). In some cases the cycloadduct was isolated after thin-layer chromatography using light petroleum–ethyl acetate (2:3) as eluent. The cycloadducts 5a–c were obtained in low to moderate yields (5a, 49.1 mg, 40%; 5b, 33.3 mg, 26%; 5c, 29.6 mg, 23%).
• 25 rel-(3aS,3bS,6aR,7S)-7-(4-methoxyphenyl)-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]indazole (5b): White solid; mp 114–124 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.37 (s, 3 H, NCH ₃), 2.40 (s, 3 H, CH ₃), 2.48 (s, 3 H, CH ₃), 3.33 (d, J = 5.4 Hz, 1 H, H-3a), 3.50 (d, J = 7.9 Hz, 1 H, H-3b), 3.56 (d, J = 5.4 Hz, 1 H, H-7), 3.72 (s, 3 H, 4′′-OCH ₃), 4.40 (d, J = 7.9 Hz, 1 H, H-6a), 6.57 (d, J = 8.4 Hz, 2 H, H-3′′,5′′), 6.69 (d, J = 8.4 Hz, 2 H, H-2′′,6′′), 7.20 (d, J = 8.1 Hz, 2 H, H-3′′′′,5′′′′), 7.24 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.36 (d, J = 8.1 Hz, 2 H, H-2′′′′,6′′′′), 7.34–7.40 (m, 3 H, H-3′,5′, H-8), 7.46 (dt, J = 7.2, 1.6 Hz, 1 H, H-4′), 7.59 (dd, J = 7.5, 1.6 Hz, 1 H, H-6′), 7.77 (d, J = 8.3 Hz, 2 H, H-2′′′, 6′′′). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (CH₃), 21.8 (CH₃), 24.1 (NCH₃), 26.9 (C-3a), 38.3 and 38.5 (C-6a,7), 44.9 (C-3b), 55.1 (4′′-OCH₃), 113.7 (C-3′′,5′′), 123.4 (C-3′), 126.6 (C-1′), 127.6 (C-5′), 127.7 and 127.8 (C-2′′′,6′′′ and C-2′′′′,6′′′′), 128.7 (C-2′′,6′′), 129.6 (C-3′′′′,5′′′′), 130.1 (C-3′′′,5′′′, C-8), 130.5 (C-4′), 130.9 (C-1′′), 131.6 (C-6′, C-1′′′′), 134.6 (C-1′′′), 141.9 (C-8a), 145.9 (C-4′′′), 146.2 (C-4′′′′), 147.1 (C-2′), 150.9 (C-3), 158.6 (4′′-OCH₃), 174.9 (C=O), 176.3 (C=O). MS (ESI⁺): m/z (%) = 712 (100) [M + H]⁺, 734 (25) [M + Na]⁺. HRMS-ESI⁺: m/z [M + H]⁺ calcd for C₃₇H₃₄N₃O₈S₂: 712.17818; found: 712.17738.
• 26 Synthesis of 7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo[3,4-e]indazoles 6a–c; General Procedure: A mixture of the appropriate endo-7-aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-3a,3b,6a,7-tetrahydro-1H-pyrrolo[3,4-e]indazole 5a–c (0.10 mmol) and DDQ (68.10 mg, 0.30 mmol) in 1,2,4-TCB (5–10 mL) was heated at 170 °C until consumption of the starting material was observed. The crude product was purified by column chromatography, with light petroleum as eluent to remove the 1,2,4-TCB, followed by elution with a mixture of light petroleum–ethyl acetate (2:3) to remove the reaction product, which in some cases was further purified by thin-layer chromatography with the same mixture of light petroleum–ethyl acetate (2:3) as eluent. 7-Aryl-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo-[3,4-e]indazoles 6a–c were obtained in good to low yields [6a, 42.7 mg, 63%; 6b, 38.2 mg, 54%; 6c, 19.9 mg, 28%].
• 27 7-(4-Methoxyphenyl)-5-methyl-1-tosyl-3-(2-tosyloxyphenyl)-4,6-dioxo-1H-pyrrolo[3,4-e]indazole (6b): Yellow solid; mp 97–99 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.28 (s, 3 H, 4′′′′-CH ₃), 2.38 (s, 3 H, 4′′′-CH ₃), 3.02 (s, 3 H, NCH ₃), 3.93 (s, 3 H, 4′′-OCH ₃), 6.90 (d, J = 8.4 Hz, 2 H, H-3′′′′,5′′′′), 6.96 (d, J = 8.4 Hz, 2 H, H-2′′′′,6′′′′), 7.09 (d, J = 8.7 Hz, 2 H, H-3′′,5′′), 7.34 (d, J = 8.3 Hz, 2 H, H-3′′′,5′′′), 7.38–7.43 (m, 2 H, H-4′, H-5′), 7.47 (dd, J = 8.3, 0.9 Hz, 1 H, H-3′), 7.54–7.59 (m, 1 H, H-6′), 7.56 (d, J = 8.7 Hz, 2 H, H-2′′,6′′), 7.95 (d, J = 8.3 Hz, 2 H, H-2′′′,6′′′), 8.35 (s, 1 H, H-8). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.7 (4′′′-CH₃ and 4′′′′-CH₃), 23.9 (NCH₃), 55.4 (4′′-OCH₃), 113.6 (C-3′′,5′′), 118.5 (C-8), 118.7 (C-3a), 123.5 (C-3′), 125.4 (C-1′), 125.5 (C-3b,6a), 126.6 (C-5′), 127.5 (C-2′′′′,6′′′′), 127.7 (C-2′′′, 6′′′), 128.0 (C-1′′), 129.2 (C-3′′′′, 5′′′′), 130.3 (C-3′′′, 5′′′), 131.1 (C-2′′,6′′), 131.3 and 131.5 (C-4′ and C-6′), 131.5 (C-4′), 132.1 (C-1′′′′), 133.9 (C-1′′′), 140.6 (C-7), 143.7 (C-3), 145.3 (C-4′′′′), 146.4 (C-4′′′), 146.9 (C-8a), 148.3 (C-2′), 160.4 (C-4′′), 165.6 (C=O), 167.6 (C=O). MS (ESI⁺): m/z (%) = 708 (100) [M + H]⁺, 730 (60) [M + Na]⁺, 746 (20) [M + K]⁺ .