Potassium tert-Butoxide Promoted Intramolecular Amination of 1-Aryl-2- (2-nitrobenzylidene)hydrazines: Efficient Synthesis of 1-Aryl-1H-indazoles

Abstract

1-Aryl-2-(2-nitrobenzylidene)hydrazines readily undergo intramolecular amination to afford 1-aryl-1H-indazole derivatives. The reaction was conducted in the presence of potassium tert-butoxide in N,N-dimethylformamide (DMF) at 100 °C and all products were obtained in good yields. Displacement of the nitro group was achieved in the absence of significant electron-withdrawing substituents such as nitro, cyanide, diazo, or carbonyl groups.

Key words

potassium tert-butoxide - indazoles - hydrazines - amination - nitro displacement

• References and Notes

• 1a Ali NA, Dar BA, Pradhan V, Farooqui M. Mini-Rev. Med. Chem. 2013; 13: 1792
• 1b Schmidt A, Beutler A, Snovydovych S. Eur. J. Org. Chem. 2008; 4073
• 2 Jiang R, Frackowiak B, Shin Y, Song X, Chen W, Lin L, Cameron MD, Duckett DR, Kamenecka TM. Bioorg. Med. Chem. Lett. 2013; 23: 2683
• 3 Corsi G, Palazzo G, Germani C, Barcellona PS, Silvestrini B. J. Med. Chem. 1976; 19: 778
• 4 Conway GA, Loeffler JL, Hall IH. J. Med. Chem. 1983; 26: 876
• 5 Lee F.-Y, Lien J.-C, Huang L.-J, Huang T.-M, Tsai S.-C, Teng C.-M, Wu C.-C, Cheng F.-C, Kuo S.-C. J. Med. Chem. 2001; 44: 3746
• 6 Li X, Chu S, Feher VA, Khalili M, Nie Z, Margosiak S, Nikulin V, Levin J, Sprankle KG, Tedder ME, Almassy R, Appelt K, Yager KM. J. Med. Chem. 2003; 46: 5663
• 7 Rooney L, Vidal A, D’Souza AM, Devereux N, Masick B, Boissel V, West R, Head V, Stringer R, Lao J, Petrus MJ, Patapoutian A, Nash M, Stoakley N, Panesar M, Verkuyl JM, Schumacher AM, Petrassi HM, Tully DC. J. Med. Chem. 2014; 57: 5129
• 8a Lebedev AY, Khartulyari AS, Voskoboynikov AZ. J. Org. Chem. 2005; 70: 596
• 8b Liu R, Zhu Y, Qin L, Ji S. Synth. Commun. 2008; 38: 249
• 8c Bae YK, Cho CS. Appl. Organomet. Chem. 2013; 27: 224
• 8d Gao M, Liu X, Wang X, Cai Q, Ding K. Chin. J. Chem. 2011; 29: 1199
• 9a Varughese DJ, Manhas MS, Bose AK. Tetrahedron Lett. 2006; 47: 6795
• 9b Creencia EC, Kosaka M, Muramatsu T, Kobayashi M, Iizuka T, Horaguchi T. J. Heterocycl. Chem. 2009; 46: 1309
• 10 Wray BC, Stambuli JP. Org. Lett. 2010; 12: 4576
• 11 Xiong X, Jiang Y, Ma D. Org. Lett. 2012; 14: 2552
• 12a Mahdavi M, Asadi M, Saeedi M, Rezaei Z, Moghbel H, Foroumadi A, Shafiee A. Synlett 2012; 23: 2521
• 12b Saeedi M, Mahdavi M, Foroumadi A, Shafiee A. Tetrahedron 2013; 69: 3506
• 12c Mahdavi M, Asadi M, Saeedi M, Ebrahimi M, Rasouli MA, Ranjbar PR, Foroumadi A, Shafiee A. Synthesis 2012; 44: 3649
• 13a Tamura R, Kamimura A, Ono N. Synthesis 1991; 423
• 13b Denney DB, Denney DZ, Perez AJ. Tetrahedron 1993; 49: 4463
• 14 Kislyi KA, Samet AV, Strelenko YA, Semenov VV. J. Org. Chem. 2008; 73: 2285
• 15 Filimonov SI, Chirkova ZV, Abramov IG, Firgang SI, Stashina GA, Strelenko YA, Khakimov DV, Pivina TS, Samet AV, Suponitsky KY. Tetrahedron 2012; 68: 5991
• 16 Farkas R, Törincsi M, Kolonits P, Fekete J, Alonso OJ, Novak L. Cent. Eur. J. Chem. 2010; 8: 300
• 17 Gorvin JH, Whalley DP. J. Chem. Soc., Perkin Trans. 1 1979; 1364
• 18 Pearson DE, Buehler CA. Chem. Rev. 1974; 74: 45
• 19 Yanagisawa S, Ueda K, Taniguchi T, Itami K. Org. Lett. 2008; 10: 4673
• 20 Roman DS, Takahashi Y, Charette AB. Org. Lett. 2011; 13: 3242
• 21a Trofimov BA, Schmidt EY, Zorina NV, Ivanova EV, Ushakov IA. J. Org. Chem. 2012; 77: 6880
• 21b Trofimov BA, Schmidt EYu, Ushakov IA, Zorina NV, Skital’tseva EV, Protsuk NI, Mikhaleva AI. Chem. Eur. J. 2010; 16: 8516
• 22 Mahdavi M, Foroughi N, Saeedi M, Karimi M, Alinezhad H, Foroumadi A, Shafiee A, Akbarzadeh T. Synlett 2014; 25: 385
• 23a Starosotnikov AM, Lobach AV, Kachala VV, Shevelev SA. Russ. Chem. Bull., Int. Ed. 2004; 53: 584
• 23b Starosotnikov AM, Kachala VV, Lobach AV, Vinogradov VM, Shevelev SA. Russ. Chem. Bull., Int. Ed. 2003; 52: 1782
• 24 Synthesis of Indazole Derivatives 2; General Procedure: A mixture of 1-aryl-2-(2-nitrobenzylidene)hydrazine 1 (1 mmol) and t-BuOK (1 mmol) in DMF (5 mL) was stirred at 100 °C for 40–60 min. Upon completion (reaction monitored by TLC) the reaction mixture was poured into cold water and the precipitate was filtered off to obtain pure products 2 with no need for further purification. 1-Phenyl-1H-indazole (2a) Yield: 0.16 g (85%); off-white solid; mp 72–74 °C (Lit.^8a 76–78 °C). IR (KBr): 1598, 1504, 1465 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (t, J = 8.0 Hz, 1 H, H-4′), 7.39 (t, J = 7.6 Hz, 1 H, H-6), 7.46 (t, J = 7.6 Hz, 1 H, H-5), 7.57 (t, J = 8.0 Hz, 2 H, H-3′, H-5′), 7.76–7.78 (m, 3 H, H-4, H-2′, H-6′), 7.84 (d, J = 7.6 Hz, 1 H, H-7), 8.24 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 110.4, 121.3, 121.5, 122.8, 125.3, 126.6, 127.1, 129.5, 135.4, 138.8, 140.2. Anal. Calcd for C₁₃H₁₀N₂: C, 80.39; H, 5.19; N, 14.42. Found: C, 80.56; H, 5.33; N, 14.61. 1-(4-Fluorophenyl)-1H-indazole (2b) Yield: 0.18 g (85%); off-white solid; mp 84–86 °C (Lit.²⁵ 90 °C). IR (KBr): 1641, 1614, 1516 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.28 (m, 3 H, H-6, H-3′, H-5′), 7.46 (t, J = 8.0 Hz, 1 H, H-5), 7.69–73 (m, 3 H, H-4, H-2′, H-6′), 7.83 (d, J = 8.0 Hz, 1 H, H-7), 8.22 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 110.1, 116.3 (d, J _C–F = 22.8 Hz), 121.4, 121.6, 124.6 (d, J _C–F = 19.1 Hz), 125.2, 127.3, 135.4, 136.3, 138.9, 161.1 (d, J _C–F = 245 Hz). Anal. Calcd for C₁₃H₉FN₂: C, 73.57; H, 4.27; N, 13.20. Found: C, 73.69; H, 4.41; N, 13.38. 1-(4-Bromophenyl)-1H-indazole (2c) Yield: 0.24 g (90%); off-white solid; mp 85–87 °C (Lit.^8a 81–83 °C). IR (KBr): 1644, 1617, 1492 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.27 (t, J = 8.0 Hz, 1 H, H-6), 7.47 (t, J = 8.0 Hz, 1 H, H-5), 7.64–7.69 (m 4 H, H-2′, H-3′, H-5′, H-6′), 7.74 (d, J = 8.0 Hz, 1 H, H-4), 7.83 (d, J = 8.0 Hz, 1 H, H-7), 8.23 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 110.2, 119.8, 121.5, 121.8, 124.0, 125.5, 127.5, 132.5, 135.9, 138.6, 139.3. Anal. Calcd for C₁₃H₉BrN₂: C, 57.17; H, 3.32; N, 10.26. Found: C, 57.34; H, 3.18; N, 10.05. 5-Chloro-1-phenyl-1H-indazole (2d) Yield: 0.19 g (85%); off-white solid; mp 114–116 °C (Lit.^8d 116–117 °C). IR (KBr): 1620, 1507, 1459 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.43 (m, 2 H, H-6, H-4′), 7.57 (t, J = 8.0 Hz, 2 H, H-3′, H-5′), 7.67–7.72 (m, 3 H, H-7, H-2′, H-6′), 7.84 (d, J = 1.6 Hz, 1 H, H-4), 8.16 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 111.5, 120.5, 122.8, 126.1, 127.0, 127.1, 127.8, 129.6, 134.6, 137.3, 139.8. Anal. Calcd for C₁₃H₉ClN₂: C, 68.28; H, 3.97; N, 12.25. Found: C, 68.11; H, 4.15; N, 12.38. 5-Chloro-1-(4-fluorophenyl)-1H-indazole (2e) Yield: 0.20 g (83%); off-white solid; mp 84–86 °C. IR (KBr): 1638, 1522, 1410 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.23–7.28 (m, 2 H, H-2′, H-6′), 7.39 (dd, J = 8.8, 2.0 Hz, 1 H, H-6), 7.59 (d, J = 8.8 Hz, 1 H, H-7), 7.66 (dd, J = 8.8, 4.8 Hz, 2 H, H-3′, H-5′), 7.84 (d, J = 2.0 Hz, 1 H, H-4), 8.14 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 111.2, 116.4 (d, J _C–F = 22.9 Hz), 120.5, 124.6 (d, J _C–F = 8.3 Hz), 126.0, 127.2, 135.4, 134.6, 135.9 (d, J _C–F = 2.9 Hz), 137.4, 161.4 (d, J _C–F = 245 Hz). Anal. Calcd for C₁₃H₈ClFN₂: C, 63.30; H, 3.27; N, 11.36. Found: C, 63.12; H, 3.42; N, 11.51. 1-(4-Bromophenyl)-5-chloro-1H-indazole (2f) Yield: 0.26 g (85%); off-white solid; mp 115–116 °C. IR (KBr): 1638, 1589, 1504 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.40 (dd, J = 8.8 Hz, 1 H, H-6), 7.60 (d, J = 9.0 Hz, 2 H, H-3′, H-5′), 7.64 (d, J = 8.8 Hz, 1 H, H-7), 7.67 (d, J = 9.0 Hz, 2 H, H-2′, H-6′), 7.85 (d, J = 1.2 Hz, 1 H, H-4), 8.16 (s, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 111.3, 120.3, 120.6, 124.0, 126.3, 127.4, 128.0, 132.7, 135.1, 137.1, 138.8. Anal. Calcd for C₁₃H₈BrClN₂: C, 50.77; H, 2.62; N, 9.11. Found: C, 50.59; H, 2.81; N, 8.91. 5-Chloro-1-(4-methoxyphenyl)-1H-indazole (2g) Yield: 0.22 g (85%); off-white solid; mp 96–98 °C. IR (KBr): 1638, 1617, 1522 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.91 (s, 3 H, OMe), 7.08 (d, J = 8.8 Hz, 2 H, H-3′, H-5′), 7.37 (dd, J = 9.0, 2.0 Hz, 1 H, H-6), 7.57 (d, J = 9.0 Hz, 1 H, H-7), 7.59 (d, J = 8.8 Hz, 2 H, H-2′, H-6′), 7.78 (dd, J = 2.0, 0.8 Hz, 1 H, H-4), 8.16 (d, J = 0.8 Hz, 1 H, H-3). ¹³C NMR (100 MHz, CDCl₃): δ = 55.6, 111.3, 114.7, 120.3, 124.6, 125.7, 126.9, 127.5, 132.9, 134.0, 137.5, 158.7. Anal. Calcd for C₁₄H₁₁ClN₂O: C, 65.00; H, 4.29; N, 10.83. Found: C, 65.23; H, 4.51; N, 10.67. 5-Chloro-1-(4-nitrophenyl)-1H-indazole (2h) Yield: 0.24 g (88%); off-white solid; mp 229–231 °C. IR (KBr): 1641, 1623, 1592, 1504, 1334 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.50 (dd, J = 8.8, 2.0 Hz, 1 H, H-6), 7.80 (d, J = 8.8 Hz, 1 H, H-7), 7.84 (dd, J = 2.0, 0.4 Hz, 1 H, H-4),7.97 (d, J = 9.2 Hz, 2 H, H-2′, H-6′), 8.25 (d, J = 0.4 Hz, 1 H, H-3), 8.45 (d, J = 9.2 Hz, 2 H, H-3′, H-5′). ¹³C NMR (100 MHz, CDCl₃): δ = 111.6, 121.1, 121.6, 125.4, 127.2, 128.3, 128.8, 136.8, 137.1, 144.9, 145.4. Anal. Calcd for C₁₃H₈ClN₃O₂: C, 57.05; H, 2.95; N, 15.35. Found: C, 56.88; H, 3.20; N, 15.57.
• 25 Elguero J, Estopa C, Ilavsky D. J. Chem. Res. 1981; 4237