Efficient Microwave-Assisted Synthesis of Tetrahydroindazoles and their Oxidation to Indazoles

Abstract

N-Acetyl-styrylpyrazoles undergo Diels-Alder cyclo­addition reactions with N-methylmaleimide under solvent-free conditions to give the corresponding tetrahydroindazoles in good yields and high selectivity. On heating, these reactions do not occur or ­afford only traces of the cycloadducts. The stereochemistry of ­obtained cycloadducts was assigned by NMR. Oxidation of the ­tetrahydroindazoles with DDQ gave the expected indazoles and was accompanied by N-deacylation.

Key words

4-styrylpyrazoles - Diels-Alder cycloadditions - microwave irradiation - N-methylmaleimide - indazoles - dehydrogenation

References and Notes

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16

Physical Data of ( E )-1-(1-Methyl-2,5-dioxo-3-pyrrol-idinyl)-5-styryl-3-(2-hydroxyphenyl)pyrazole ( 1d).
Mp 234-236 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.13 (s, 3 H, NCH ₃), 3.30 (dd, 1 H, J = 18.3, 9.1 Hz, 4′′′-CH ₂), 3.45 (dd, 1 H, J = 18.3, 5.2 Hz, 4′′′-CH ₂), 5.46 (dd, 1 H, J = 9.1, 5.2 Hz, 3′′′-CH), 6.90 (s, 1 H, H-4), 6.96 (ddd, 1 H, J = 7.7, 7.3, 1.2 Hz, H-5′), 7.00 (dd, 1 H, J = 8.4, 1.2 Hz, H-3′), 7.01 (d, 1 H, J = 15.8 Hz, H-α), 7.22-7.27 (m, 1 H, H-4′), 7.26 (d, 1 H, J = 15.8 Hz, H-β), 7.35-7.44 (m, 3 H, H-3′′,5′′,4′′), 7.53 (dd, 2 H, J = 8.1, 1.5 Hz, H-2′′,6′′), 7.59 (dd, 1 H, J = 7.7, 1.7 Hz, H-6′), 10.03 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 25.5 (NCH ₃), 34.8 (4′′′-CH₂), 55.6 (3′′′-CH), 100.8 (C-4), 112.6 (C-α), 115.8 (C-1′), 117.1 (C-3′), 119.5 (C-5′), 126.6 (C-6′), 126.9 (C-2′′,6′′), 128.9 (C-3′′,5′′), 129.1 (C-4′′), 129.9 (C-4′), 135.6 (C-1′′), 136.1 (C-β), 143.9 (C-5), 152.5 (C-3), 155.7 (C-2′), 173.3 (2′′′-C=O), 172.5 (5′′′-C=O). MS (EI): m/z (rel. int.) = 374 (30), 373 (100) [M^{+ •}], 372 (25), 262 (39), 261 (67), 231 (11), 202 (10), 155 (5), 128 (6), 115 (16), 91 (29), 77 (9), 65 (9).

17

Physical Data of ( E )-3-(2-Hydroxyphenyl)-1-methyl-5-styrylpyrazole ( 1b).
Mp 159-161 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.92 (s, 3 H, 1-CH₃), 6.81 (s, 1 H, H-4), 6.89 (ddd, 1 H, J = 7.9, 7.3, 1.1 Hz, H-5′), 6.91 (d, 1 H, J = 16.2 Hz, H-α), 7.02 (dd, 1 H, J = 8.0, 1.1 Hz, H-3′), 7.13 (d, 1 H, J = 16.2 Hz, H-β), 7.21 (ddd, 1 H, J = 8.0, 7.3, 1.6 Hz, H-4′), 7.32 (dd, 2 H, J = 7.6, 6.8 Hz, H-3′′,5′′), 7.39 (tt, 1 H, J = 7.6, 1.6 Hz, H-4′′), 7.51 (dd, 2 H, J = 6.8, 1.6 Hz, H-2′′,6′′), 7.57 (dd, 1 H, J = 7.9, 1.6 Hz, H-6′), 10.82 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 36.6 (1-CH₃), 98.9 (C-4), 113.7 (C-α), 116.5 (C-1′), 117.0 (C-3′), 119.2 (C-5′), 126.1 (C-6′), 126.7 (C-2′′,6′′), 128.6 (C-4′′), 128.8 (C-3′′,5′′), 129.0 (C-4′), 133.5 (C-β), 136.0 (C-1′′), 141.8 (C-5), 150.2 (C-3), 155.8 (C-2′). MS (EI): m/z (rel. int.) = 276 (100) [M^+• ], 275 (20), 231 (5), 202 (7), 185 (10), 144 (14), 128 (10), 115 (20), 102 (8), 91 (11), 77 (15). Anal. Calcd for C₁₈H₁₆N₂O: C, 78.24; H, 5.84; N, 10.14. Found:C, 77.84; H, 5.79; N, 10.02.

19

Typical Experimental Procedure.
Acetyl chloride (1 mol equiv) was added to a stirred solution of (E)-3-(2-hydroxyphenyl)-5-styrylpyrazole (1a) in dry pyridine. The mixture was stirred at r.t. and under nitrogen atmosphere until complete disappearance of the starting 5-styrylpyrazole 1a. After that period the reaction mixture was poured over ice and H₂O, and acidified at pH 2 with a 10% solution of HCl. The resulting mixture was extracted with CHCl₃ and dried over anhyd Na₂SO₄. The solvent was evaporated to dryness and the residue purified by thin layer chromatography with CH₂Cl₂ as eluent giving the expected (E)-1-acetyl-3-(2-hydroxyphenyl)-5-styrylpyrazole (1c) in moderate yield (44%). Mp 124.4-126.2 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.77 (s, 3 H, 1-COCH ₃), 6.98 (ddd, 1 H, J = 7.7, 7.5, 1.1 Hz, H-5′), 7.06 (s, 1 H, H-4), 7.07 (dd, 1 H, J = 8.3, 1.1 Hz, H-3′), 7.22 (d, 1 H, J = 16.5 Hz, H-β), 7.30-7.43 (m, 4 H, H-4′,3′′,4′′,5′′), 7.57 (d, 2 H, J = 7.7 Hz, H-2′′,6′′), 7.63 (dd, 1 H, J = 7.7, 1.6 Hz, H-6′), 7.93 (d, 1 H, J = 16.5 Hz, H-α), 10.38 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 24.0 (1-COCH₃), 104.0 (C-4), 114.8 (C-1′), 116.4 (C-α), 117.3 (C-3′), 119.6 (C-5′), 127.2 (C-2′′,6′′), 127.4 (C-6′), 128.8 (C-3′′,5′′), 129.0 (C-4′′), 131.0 (C-4′), 135.6 (C-β), 136.0 (C-1′′), 145.8 (C-5), 153.9 (C-3), 156.5 (C-2′), 170.8 (1-COCH₃). MS (EI): m/z (rel. int.) = 304 (80) [M^+•], 262 (73) [M - C₂H₂O]⁺, 245 (5), 233 (5), 216 (4), 202 (6) [M - C₈H₆]⁺, 191 (2), 185 (21) [M - C₇H₅NO]⁺, 178 (4), 171 (100), 155 (3), 140 (4), 128 (5), 115 (23), 102 (6), 89 (5), 77 (8) [C₆H₅ ⁺], 65 (4). Anal. Calcd for C₁₉H₁₆N₂O₂: C, 74.98; H, 5.30; N, 9.20. Found: C, 75.01; H, 5.26; N, 9.05.

21

Physical Data of ( E )-1-Acetyl-4-(4-chlorostyryl)-3-(2-hydroxyphenyl)pyrazole ( 5b).
Mp 169.1-169.9 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.76 (s, 3 H, 1-COCH ₃), 6.94 (AB, 1 H, J = 16.1 Hz, H-β), 6.99 (dd, 1 H, J = 7.5, 6.9 Hz, H-5′), 7.04 (AB, 1 H, J = 16.1 Hz, H-α), 7.12 (dd, 1 H, J = 8.3, 1.1 Hz, H-3′), 7.33-7.36 (m, 1 H, H-4′), 7.36 (d, 2 H, J = 8.6 Hz, H-3′′5′′), 7.42 (d, 2 H, J = 8.6 Hz, H-2′′,6′′), 7.62 (dd, 1 H, J = 7.5, 1.6 Hz, H-6′), 8.47 (dd, 1 H, J = 0.7 Hz, H-5), 9.82 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.6 (1-COCH₃), 115.9 (C-1′), 117.4 (C-3′), 117.9 (C-α), 119.8 (C-5′), 122.9 (C-4), 126.2 (C-5), 127.8 (C-2′′,6′′), 128.9 (C-6′), 129.0 (C-3′′,5′′), 130.9 (C-4′), 131.3 (C-β), 133.9 (C-4′′), 135.0 (C-1′′), 152.4 (C-3), 156.0 (C-2′), 168.1 (1-COCH₃). MS (EI): m/z (rel. int.) = 340 (36) [M^+• , ³⁷Cl], 338 (81) [M^+• , ³⁵Cl], 298 (35), 296 (81), 281 (5), 267 (4), 260 (8), 242 (4), 231 (6), 202 (8), 185 (20), 171 (100), 149 (5), 115 (14), 102 (6), 77 (4). Anal. Calcd for C₁₉H₁₅ClN₂O₂: C, 67.36; H, 4.46; N, 8.27. Found: C, 67.48; H, 4.73; N, 8.30.

22

Physical Data of ( Z )-1-Acetyl-4-(4-chlorostyryl)-3-(2-hydroxyphenyl)pyrazole ( 6b).
Mp 141.8-143.6 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.72 (s, 3 H, 1-COCH ₃), 6.50 (dd, 1 H, J = 11.9, 1.1Hz, H-α), 6.75 (d, 1 H, J = 11.9 Hz, H-β), 6.95 (ddd, 1 H, J = 7.2, 7.9, 1.2 Hz, H-5′), 7.09 (dd, 1 H, J = 8.3, 1.2 Hz, H-3′), 7.17-7.23 (m, 4 H, H-2′′,3′′,5′′,6′′), 7.33 (ddd, 1 H, J = 7.2, 8.3, 1.6 Hz, H-4′), 7.87 (dd, 1 H, J = 7.9, 1.6 Hz, H-6′), 8.00 (d, 1 H, J = 1.1 Hz, H-5), 10.23 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 21.6 (1-COCH₃), 115.7 (C-1′), 117.3 (C-3′), 119.6 (C-5′), 119.9 (C-α), 120.0 (C-4), 127.6 (C-5), 128.5 (C-6′), 128.7 (C-2′′,6′′), 129.8 (C-3′′,5′′), 131.0 (C-4′), 132.4 (C-β), 133.5 (C-4′′), 134.4 (C-1′′), 153.1 (C-3), 156.3 (C-2′), 167.8 (C=O). MS (EI): m/z (rel. int.) = 340 (31) [M^+• , ³⁷Cl], 338 (69) [M^+• , ³⁵Cl], 298 (32), 296 (71), 281 (5), 260 (8), 231 (7), 202 (8), 185 (22), 171 (100), 149 (6), 115 (17), 102 (8), 89 (5), 77 (7). Anal. Calcd for C₁₉H₁₅ClN₂O₂: C, 67.36; H, 4.46; N, 8.27. Found: C, 67.15; H, 4.37; N, 7.98.

23

Optimised Experimental Procedure.
A mixture of (E or Z)-1-acetyl-3-(2-hydroxyphenyl)-4-styrylpyrazoles 5a-d or 6a-c and N-methylmaleimide (1:6 mole ratio) was irradiated at atmospheric pressure in an Ethos SYNTH microwave (Milestone Inc.), at 800 W for 40 min. The crude product was dissolved in CHCl₃ and purified by thin layer chromatography with a 8:2 mixture of CHCl₃-EtOAc as eluent. The residue was crystallised from EtOH to give the expected 1-acetyl-3-(2-hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxopyrrolo[3,4-g]-5,5a,8a,8b-tetrahydro-indazoles (7a, 88%; 7b, 68%; 7c, 95%; 7d, 95%; 8a, 32%; 8b, 54%; 8c, 54%).

24

Physical Data of 1-Acetyl-5-(4-ethoxyphenyl)-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4- g ]-5,5a,8a,8b-tetrahydroindazole ( 7c).
Mp 236-237 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.44 (t, 3 H, J = 7.0 Hz, 4′′-OCH₂CH ₃), 2.54 (s, 3 H, 1-COCH ₃), 2.76 (s, 3 H, 7-CH ₃), 3.37 (dd, 1 H, J = 8.5, 7.4 Hz, H-5a), 3.54 (br dd, 1 H, J = 7.4, 4.5 Hz, H-5), 4.07 (dq, 2 H, J = 7.0, 1.9 Hz, 4′′-OCH ₂CH₃), 4.46 (dd, 1 H, J = 8.5, 7.1 Hz, H-8a), 4.97 (br dd, 1 H, J = 7.1, 3.6 Hz, H-8b), 6.94 (dd, 1 H, J = 4.5, 3.6 Hz, H-4), 6.96 (d, 2 H, J = 8.6 Hz, H-3′′,5′′), 6.97 (ddd, 1 H, J = 8.6, 7.2, 0.9 Hz, H-5′), 7.10 (dd, 1 H, J = 8.0, 0.9 Hz, H-3′), 7.21 (d, 2 H, J = 8.6 Hz, H-2′′,6′′), 7.38 (ddd, 1 H, J = 8.0, 7.2, 1.4 Hz, H-4′), 7.66 (dd, 1 H, J = 8.6, 1.4 Hz, H-6′), 9.85 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 14.9 (4′′-OCH₂ CH₃), 21.5 (1-COCH₃), 25.0 (7-CH₃), 40.6 (C-8a), 42.1 (C-5a), 44.5 (C-5), 57.5 (C-8b), 63.5 (4′′-OCH₂CH₃), 114.4 (C-1′), 114.5 (C-3′′,5′′), 117.7 (C-3′), 119.7 (C-5′), 126.2 (C-4), 127.5 (C-6′;), 129.0 (C-1′′), 129.8 (C-2′′,6′′), 131.9 (C-4′), 137.8 (C-3a), 149.3 (C-3), 157.1 (C-2′), 158.5 (C-4′′), 168.6 (1-COCH₃), 173.4 (C-6), 174.5 (C-8). MS (EI): m/z (rel. int.) = 459 (52) [M^+• ], 417 (28), 348 (100), 306 (70), 277 (18), 257 (10), 171 (35), 160 (7), 91 (10). Anal. Calcd for C₂₉H₂₅N₃O₅: C, 67.96; H, 5.48; N, 9.14. Found: C, 67.80; H, 5.49; N, 8.76.

25

Physical Data of 1-Acetyl-5-(4-ethoxyphenyl)-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4- g ]-5,5a,8a,8b-tetrahydroindazole ( 8c).
Mp 244-245 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.42 (t, 3 H, J = 7.0 Hz, 4′′-OCH₂CH ₃), 2.46 (s, 3 H, 1-COCH ₃), 2.89 (s, 3 H, 7-CH ₃), 3.56 (br d, 1 H, J = 8.6 Hz, H-5a), 4.70 (br d, 1 H, J = 7.6 Hz, H-5), 4.02 (dq, 2 H, J = 7.0 Hz, 4′′-OCH ₂CH₃), 4.42 (dd, 1 H, J = 8.6, 8.0 Hz, H-8a), 4.80 (dd, 1 H, J = 8.0, 3.8 Hz, H-8b), 6.96 (dd, 1 H, J = 7.6, 3.8 Hz, H-4), 6.88 (d, 2 H, J = 8.7 Hz, H-3′′,5′′), 6.98 (ddd, 1 H, J = 7.6, 7.4, 1.0 Hz, H-5′), 7.09 (dd, 1 H, J = 8.2, 1.0 Hz, H-3′), 7.23 (d, 2 H, J = 8.7 Hz, H-2′′,6′′), 7.37 (ddd, 1 H, J = 8.2, 7.4, 1.5 Hz, H-4′), 7.70 (dd, 1 H, J = 7.6, 1.5 Hz, H-6′), 9.81 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 14.8 (4′′-OCH₂ CH₃), 21.5 (1-COCH₃), 25.3 (7-CH₃), 41.5 (C-8a), 41.8 (C-5), 43.0 (C-5a), 55.7 (C-8b), 63.6 (4′′-OCH₂CH₃), 114.3 (C-1′), 115.2 (C-3′′,5′′), 117.6 (C-3′), 119.7 (C-5′), 125.9 (C-4), 127.6 (C-6′), 127.9 (C-2′′,6′′), 128.2 (C-1′′), 131.8 (C-4′), 138.2 (C-3a), 149.6 (C-3), 157.0 (C-2′), 158.3 (C-4′′), 168.4 (1-COCH₃), 173.9 (C-6), 177.7 (C-8). MS (EI): m/z (rel. int.) = 459 (46) [M^+• ], 417 (29), 348 (14), 306 (42), 295 (100), 282 (14), 210 (21), 171 (36), 135 (16), 77 (5). Anal. Calcd for C₂₉H₂₅N₃O₅: C, 67.96; H, 5.48; N, 9.14. Found: C, 67.91; H, 5.45; N, 9.16.

26

Optimised Experimental Procedure.
A mixture of each of the appropriate 1-acetyl-3-(2-hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxopyrrolo[3,4-g]-5,5a,8a,8b-tetrahydroindazoles 7a,b,d or 8c and DDQ (1:3 mol ratio) in 1,2,4-trichlorobenzene was irradiated at atmospheric pressure in an Ethos SYNTH microwave (Milestone Inc.), at 800 W for 30 min. The crude product was purified by column chromatography, using light PE as eluent, to remove the 1,2,4-trichlorobenzene, followed by EtOAc to remove the reaction product, which was further purified by TLC with a 9:1 mixture of CHCl₃-EtOAc as eluent. The residue was recrystallised from EtOH to give 5-aryl-3-(2-hydroxyphenyl)-7-methyl-6,8-dioxopyrrolo[3,4-g]indazoles (9a from 7a, 85%; 9b from 7b, 32%; 9c from 8c, 31%; 9d from 7d, 34%).

27

Physical Data of 3-(2-Hydroxyphenyl)-7-methyl-5-phenyl-6,8-dioxopyrrolo[3,4- g ]indazole ( 9a).
Mp >275 °C. ¹H NMR (300.13 MHz, CDCl₃): δ = 3.21 (s, 3 H, NCH ₃), 7.05 (ddd, 1 H, J = 7.7, 7.6, 1.2 Hz, H-5′), 7.16 (dd, 1 H, J = 8.1, 1.2 Hz, H-3′), 7.36 (ddd, 1 H, J = 7.6, 8.1, 1.6 Hz, H-4′), 7.48-7.61 (m, 4 H, H-2′′,3′′,5′′,6′′), 8.02 (dd, 1 H, J = 7.7, 1.6 Hz, H-6′), 8.44 (s, 1 H, H-4), 10.47 (s, 1 H, NH), 11.27 (s, 1 H, 2′-OH). ¹³C NMR (75.47 MHz, CDCl₃): δ = 24.0 (NCH₃), 116.2 (C-1′), 117.7 (C-3′), 119.8 (C-5′), 130.2 (C-4), 127.3 (C-6′), 128.2 (C-2′′,6′′), 129.7 (C-3′′,5′′), 130.5 (C-4′), 128.5 (C-4′′), 133.1 (C-8b), 136.6 (C-5,1′′), 145.7 (C-3), 156.3 (C-2′), 133.4 (C-3a), 128.2 (C-5a), 116.5 (C-8a), 167.9 (C-6,8). MS (EI): m/z (rel. int.) = 369 (100) [M^+• ], 326 (3), 311 (3), 284 (5), 255 (5), 226 (4), 164 (3), 91 (2).