Synlett 2006(9): 1369-1373  
DOI: 10.1055/s-2006-939715
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Vera L. M. Silva, Artur M. S. Silva*, Diana C. G. A. Pinto, José A. S. Cavaleiro
Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
Fax: +351(234)370084; e-Mail: arturs@dq.ua.pt;
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Publikationsverlauf

Received 10 February 2006
Publikationsdatum:
22. Mai 2006 (online)

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.

    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).