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.

Key words

pyrazoles - Diels–Alder reaction - indazoles - microwave irradiation - dehydrogenation

• 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]⁺ .