Catalyst-Free Synthesis of Spiropyrazolines from Chalcones and Cyclic Ketone N-Tosylhydrazones

Abstract

Treatment of cyclic ketone N-tosylhydrazones with chalcones in the presence of cesium carbonate at 110 °C affords spiropyrazolines with high selectivity and excellent yields. This protocol possesses many advantages such as readily available and stable starting materials, high selectivity, operational simplicity, and catalyst-free conditions.

Key words

spiropyrazolines - N-tosylhydrazones - chalcones - selective - catalyst-free

• References and Notes

• 1a Wang SQ, Wu QH, Wang HY, Zheng XX, Shen SL, Zhang YR, Miao JY, Zhao BX. Biosens. Bioelectron. 2014; 55: 386
• 1b Mysliwiec J, Szukalski A, Sznitko L, Miniewicz A, Haupa K, Zygadlo K, Matczyszyn K, Olesiak-Banska J, Samoc M. Dyes Pigments 2014; 102: 63
• 2a Lone IH, Khan KZ, Fozdar BI. Med. Chem. Res. 2014; 23: 363
• 2b Girisha KS, Kalluraya B, Narayana V Padmashree Eur. J. Med. Chem. 2010; 45: 4640
• 2c Shelke SN, Mhaske GR, Bonifácio VD. B, Gawande MB. Bioorg. Med. Chem. Lett. 2012; 22: 5727
• 2d Özkay ÜD, Can ÖD, Kplancıklı Z. A. Med. Chem. Res. 2012; 21: 1056
• 2e Ovais S, Pushpalatha H, Reddy GB, Rathore P, Bashir R, Yaseen S, Dheyaa A, Yaseen R, Tanwar O, Akthar M, Samim M, Javed K. Eur. J. Med. Chem. 2014; 80: 209
• 2f Hassan SY. Molecules 2013; 18: 2683
• 2g Hayat F, Salahuddin A, Umar S, Azam A. Eur. J. Med. Chem. 2010; 45: 4669
• 2h Monga V, Goyal K, Steindel M, Malhotra M, Rajani DP, Rajani SD. Med. Chem. Res. 2014; 23: 2019
• 2i Bhandari S, Tripathi AC, Saraf SK. Med. Chem. Res. 2013; 22: 5290
• 2j Evranos-Aksöz B, Yabanoğlu-Çiftçi S, Uçar G, Yelekçi K, Ertan R. Bioorg. Med. Chem. Lett. 2014; 24: 3278
• 2k Rizvi SU. F, Siddiqui HL, Johns M, Detorio M, Schinazi RF. Med. Chem. Res. 2012; 21: 3741
• 2l Li P, Tian Y, Zhai H, Deng F, Xie M, Zhang X. Med. Chem. Res. 2014; 23: 2869
• 3a Mish MR, Guerra FM, Carreira EM. J. Am. Chem. Soc. 1997; 119: 8379
• 3b Whitlock GA, Carreira EM. J. Org. Chem. 1997; 62: 7916
• 3c Kanemasa S, Kanai T. J. Am. Chem. Soc. 2000; 122: 10710
• 3d Guerra FM, Mish MR, Carreira EM. Org. Lett. 2000; 2: 4265
• 3e Whitlock GA, Carreira EM. Helv. Chim. Acta 2000; 83: 2007
• 3f Sasaki H, Carreira EM. Synthesis 2000; 135
• 3g Sibi MP, Stanley LM, Soeta T. Org. Lett. 2007; 9: 1553
• 3h Suga H, Furihata Y, Sakamoto A, Itoh K, Okumura Y, Tsuchida T, Kakehi A, Baba T. J. Org. Chem. 2011; 76: 7377
• 3i Alguacil R, Farifla F, Martin MV, Paredes MC. Tetrahedron 1999; 55: 229
• 3j Barluenga JA, Fernaández-Marí F, Viado AL, Aguilar E, Olano B, García-Granda S, Moya-Rubiera C. Chem. Eur. J. 1999; 5: 883
• 3k Novikov RA, Platonov DN, Dokichev VA, Tomilov YV, Nefedov OM. Russ. Chem. Bull. 2010; 59: 984
• 3l Ovchinnikov MY, Yangirov TA, Lobov AN, Sultanova RM, Khursan SL. Int. J. Chem. Kinet. 2013; 45: 449
• 3m Gao L, Hwang GS, Lee MY, Ryu DH. Chem. Commun. 2009; 5460
• 3n Kano T, Hashimoto T, Maruoka K. J. Am. Chem. Soc. 2006; 128: 2174
• 3o Galley G, Pätzel M, Jones PG. Tetrahedron 1995; 51: 1631
• 3p Sibi MP, Stanley LM, Jasperse CP. J. Am. Chem. Soc. 2005; 127: 8276 ; ref. 3o, to our knowledge, constitutes the only attempt to construct pyrazolines via cycloaddition of acryl ketones with diazo compounds
• 4a Padwa A, Weingarten MD. Chem. Rev. 1996; 96: 223
• 4b Kitagaki S, Anada M, Kataoka O, Matsuno K, Umeda C, Watanabe N, Hashimoto S. J. Am. Chem. Soc. 1999; 121: 1417
• 4c Hodgson DM, Stupple PA, Johnstone C. Chem. Commun. 1999; 2185
• 4d Zhou CY, Yu WY, Che CM. Org. Lett. 2002; 4: 3235
• 4e Mehta G, Muthusamy S. Tetrahedron 2002; 58: 9477
• 4f Hodgson DM, Angrish D, Labande AH. Chem. Commun. 2006; 627
• 4g Shimada N, Anada M, Nakamura S, Nambu H, Tsutsui H, Hashimoto S. Org. Lett. 2008; 10: 3603
• 4h England DB, Eagan JM, Merey G, Anac O, Padwa A. Tetrahedron 2008; 64: 988
• 4i Hodgson DM, Glen R, Redgrave AJ. Tetrahedron: Asymmetry 2009; 20: 754
• 4j Li H, Cheng B, Boonnak N, Padwa A. Tetrahedron 2011; 67: 9829
• 4k Hodgson DM, Labande AH, Muthusamy S. Cycloadditions of Carbonyl Ylides Derived from Diazocarbonyl Compounds. In Organic Reactions. Vol. 80. Denmark SE. John Wiley and Sons; Hoboken: 2013: 133-496
• 5a Gao L, Hwang GS, Ryu DH. J. Am. Chem. Soc. 2011; 133: 20708
• 5b Lee SI, Kang BC, Hwang GS, Ryu DH. Org. Lett. 2013; 15: 1428
• 6 Fulton JR, Aggarwal VK, de Vicente J. Eur. J. Org. Chem. 2005; 1479

For reviews, please see:
• 7a Barluenga J, Valdés C. Angew. Chem. Int. Ed. 2011; 50: 7486
• 7b Shao Z, Zhang H. Chem. Soc. Rev. 2012; 41: 560
• 8 Barluenga J, Quinones N, Tomás-Gamasa M, Cabal MP. Eur. J. Org. Chem. 2012; 2312
• 9a Wu YC, Liu L, Li HJ, Wang D, Chen YJ. J. Org. Chem. 2006; 71: 6592
• 9b Wu YC, Liu L, Liu YL, Wang D, Chen YJ. J. Org. Chem. 2007; 72: 9383
• 9c Wu YC, Li HJ, Liu L, Wang D, Yang HZ, Chen YJ. J. Fluoresc. 2008; 18: 357
• 9d Wu YC, Liron M, Zhu JP. J. Am. Chem. Soc. 2008; 130: 7148
• 9e Wu YC, Zhu JP. Org. Lett. 2009; 11: 5558
• 9f Wu YC, Li HJ, Yang HZ. Org. Biomol. Chem. 2010; 8: 3394
• 9g Wu YC, Li HJ, Liu L, Liu Z, Wang D, Chen YJ. Org. Biomol. Chem. 2011; 9: 2868
• 9h Wu YC, Li HJ, Liu L, Demoulin N, Liu Z, Wang D, Chen YJ. Synlett 2011; 1573
• 9i Wu YC, Li HJ, Liu L, Demoulin N, Liu Z, Wang D, Chen YJ. Adv. Synth. Catal. 2011; 353: 907
• 9j Li HJ, Luo DH, Wu QX, Dai CY, Shen ZL, Wu YC. Chin. Chem. Lett. 2014; 25: 1235
• 9k Li HJ, Deng K, Luo DH, Liu DH, Wang JL, Lin CH, Wu YC. RSC Adv. 2014; 4: 26316
• 10 Synthetic Procedure for Spiropyrazolines 3 A mixture of cyclohexanone (4a, 21 μL, 0.2 mmol) and N-tosylhydrazide (38.0 mg, 0.2 mmol) in MeOH (mL) was stirred at r.t. for 3 h, and then the solvent was removed in vacuo to give cyclohexanone tosylhydrazone (2a, 63.6 mg) in 100% yield. Subsequently, the mixture of the resulting cyclohexanone N-tosylhydrazone (2a, 63.6 mg, 0.2 mmol), Cs₂CO₃ (66.5 mg, 0.2 mmol) and chalcone (1a, 20.8 mg, 0.1 mmol) in MeCN (1.0 mL) was stirred at 110 °C (screw-capped vial) for 2 h under argon, cooled to r.t., and H₂O (10 mL) and EtOAc (10 mL) were added. The two layers were separated, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed by brine, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (100–200 mesh) to afford the desired spiropyrazoline 3a (30.0 mg) in 88% yield. Spiropyrazoline 3a: pale yellow solid; mp 180–181 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 7.3 Hz, 2 H), 7.52–7.05 (m, 9 H), 4.24 (s, 1 H), 1.72–1.24 (m, 10 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.5, 153.1, 137.5, 136.1, 132.1, 129.9, 128.6, 128.4, 127.9, 127.1, 67.1, 57.7, 37.3, 31.6, 25.2, 23.4, 22.4. FTIR (film): 3315, 2930, 2855, 1625, 1449, 1423, 1226, 870, 718, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₁H₂₂N₂NaO [M + Na]⁺: 341.1624; found: 341.1619. Spiropyrazoline 3b: pale yellow solid; mp 174–175 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.4 Hz, 2 H), 7.54–7.07 (m, 8 H), 6.77 (s, br, 1 H), 4.16 (s, 1 H), 2.03–1.03 (m, 9 H), 0.90 (d, J = 5.8 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.6, 152.9, 137.5, 136.2, 132.1, 129.9, 128.4, 128.3, 127.9, 127.1, 68.7, 59.2, 37.3, 31.8 (d), 31.4, 31.1, 22.0. FTIR (film): 33327, 2949, 2924, 2867, 1708, 1673, 1624, 1598, 1449, 1422, 1221, 857, 717, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₂H₂₅N₂ [M + H]⁺: 333.1961; found: 333.1960. Spiropyrazoline 3c: pale yellow solid; mp 169–170 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.19 (d, J = 6.3 Hz, 2 H), 7.56–7.13 (m, 8 H), 5.99 (s, br, 1 H), 4.21 (s, 1 H), 2.06–0.87 (m, 14 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.4, 152.7, 137.4, 136.1, 132.0, 129.9, 128.5, 128.3, 127.9, 127.0, 69.0, 59.2, 38.0, 31.7, 29.3, 29.1, 28.6, 11.3. FTIR (film): 3306, 2956, 2924, 2856, 1610, 1574, 1531, 1447, 1425, 1219, 860, 717, 698 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₂₇N₂O [M + H]⁺: 347.2118; found: 347.2149. Spiropyrazoline 3d: pale yellow solid; mp 163–164 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.15 (d, J = 7.1 Hz, 2 H), 7.55–7.07 (m, 8 H), 5.65 (s, br, 1 H), 4.16 (s, 1 H), 2.10–0.90 (m, 9 H), 0.84 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.4, 152.8, 137.4, 136.1, 132.0, 129.9, 128.3, 128.2, 127.9, 127.0, 68.7, 59.4, 46.9, 38.0, 32.5, 32.2, 27.3, 24.0, 23.4. FTIR (film): 3313, 2948, 2866, 1611, 1447, 1426, 1223, 1120, 860, 697 cm^–1. ESI-HRMS: m/z calcd for C₂₅H₃₁N₂O [M + H]⁺: 375.2431; found: 375.2437. Spiropyrazoline 3e: pale yellow solid; mp 153–154 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 6.6 Hz, 2 H), 7.54–7.05 (m, 8 H), 6.08 (s, br, 1 H), 4.16 (s, 1 H), 3.72 (s, br, 1 H), 2.06–1.13 (m, 12 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.5, 169.8, 1152.2, 137.4, 135.8, 132.2, 129.8, 128.5, 128.2, 128.0, 127.3, 68.0, 58.6, 47.1, 35.7, 30.3, 29.0, 28.3, 23.1. FTIR (film): 3286, 2928, 2854, 1629, 1539, 1471, 1448, 1431, 1369, 1221, 1143, 1125, 860, 719, 700 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₂₆N₃O₂ [M + H]⁺: 376.2020; found: 375.2015. Spiropyrazoline 3f: white solid; mp 185–186 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (d, J = 7.3 Hz, 2 H), 7.56–7.16 (m, 8 H), 6.59 (s, br, 1 H), 4.37 (s, 1 H), 3.83 (dd, J = 28.5, 4.1 Hz, 2 H), 3.54 (s, 2 H), 1.88–1.42 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.3, 153.3, 137.2, 135.2, 132.4, 129.9, 128.7, 128.6, 128.0, 127.5, 66.9, 65.5, 64.0, 57.2, 37.6, 31.7. FTIR (film): 3300, 2957, 2924, 2852, 1626, 1575, 1535, 1448, 1429, 1384, 1225, 1105, 861, 718, 700 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₂₁N₂O₂ [M + H]⁺: 321.1598; found: 321.1596. Spiropyrazoline 3g: yellow solid; mp 155–156 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.12 (d, J = 7.3 Hz, 2 H), 7.53–7.11 (m, 8 H), 6.78 (s, br, 1 H), 4.28 (s, 1 H), 2.67–2.18 (m, 7 H), 1.87–1.44 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.3, 152.9, 137.3, 135.5, 132.2, 129.9 (d), 128.5, 127.9, 127.3, 66.9, 53.0, 51.8, 45.8, 36.7, 31.0, 29.6. FTIR (film): 3304, 2924, 2853, 1625, 1449, 1431, 1378, 1226, 1131, 860, 718, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₁H₂₄N₃O [M + H]⁺: 334.1914; found: 334.1916. Spiropyrazoline 3h: yellow foam; mp 67–68 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 7.6 Hz, 2 H), 7.52–7.11 (m, 9 H), 4.31 (s, 1 H), 3.64–3.18 (m, 4 H), 1.74–1.33 (m, 13 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.2, 154.5, 152.6, 137.2, 135.3, 132.2, 129.8, 128.6, 128.4, 127.9, 127.4, 79.8, 67.7, 56.9, 41.0, 39.7, 36.3, 30.9, 28.3. FTIR (film): 3300, 1692, 1671, 1630, 1449, 1422, 1366, 1265, 1247, 1164, 860, 700 cm^–1. ESI-HRMS: m/z calcd for C₂₅H₃₀N₃O₃ [M + H]⁺: 420.2282; found: 420.2283. Spiropyrazoline 3i: yellow foam; mp 61–62 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.14 (d, J = 8.6 Hz, 2 H), 7.57–7.14 (m, 13 H), 6.70 (s, br, 1 H), 4.32 (s, 1 H), 2.86–1.52 (m, 12 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.3, 153.1, 139.7, 137.3, 135.5, 132.3, 129.9, 128.8, 128.6, 128.4, 128.3, 128.0, 127.4, 126.2, 67.4, 60.1, 57.2, 51.0, 49.8, 36.6, 33.4, 30.9. FTIR (film): 3309, 2926, 1624, 1575, 1536, 1494, 1449, 1428, 1375, 1225, 1128, 860, 749, 718, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₈H₃₀N₃O [M + H]⁺: 424.2383; found: 424.2389. Spiropyrazoline 3j: yellow solid; mp 141–142 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.11 (d, J = 7.8 Hz, 2 H), 7.52–7.12 (m, 8 H), 6.48 (s, br, 1 H), 4.24 (s, 1 H), 1.91–1.37 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.3, 152.9, 137.6, 137.5, 132.1, 129.9, 128.6, 128.0, 127.9, 127.1, 78.5, 57.2, 41.0, 31.7, 22.9, 22.7. FTIR (film): 3304, 2957, 2873, 1673, 1598, 1575, 1526, 1494, 1448, 1423, 1229, 1156, 717, 699 cm^–1. ESI-HRMS: m/z calcd for C₂₀H₂₁N₂O [M + H]⁺: 305.1648; found: 305.1648. Spiropyrazoline 3n: pale yellow solid; mp 157–158 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.04 (m, 10 H), 6.56 (s, br, 1 H), 4.07 (s, 1 H), 2.86–2.31 (m, 11 H), 1.88–1.44 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.8, 153.4, 139.8, 135.3, 128.7, 128.6, 128.5, 128.4, 127.3, 126.1, 68.0, 60.2, 56.1, 50.9, 49.8, 36.5, 33.5, 31.0, 25.5. FTIR (film): 3300, 2926, 2812, 1655, 1541, 1496, 1455, 1432, 1376, 1345, 1191, 1128, 1079, 889, 749, 701 cm^–1. ESI-HRMS: m/z calcd for C₂₃H₂₈N₃O [M + H]⁺: 362.2227; found: 362.2220.