新型順-1,3-二芳基螺[吡唑-4,2′-吡唑并[1,2-a]吡唑]衍生物的非對映選擇性合成

朱美軍, 張 瑜, 陸玉玲, 孫 晶, 顏朝國*

(1. 江海職業技術學院，江蘇 揚州 225101； 2. 揚州大學 化學化工學院，江蘇 揚州 225002)

新型順-1,3-二芳基螺[吡唑-4,2′-吡唑并[1,2-a]吡唑]衍生物的非對映選擇性合成

朱美軍1, 張 瑜2, 陸玉玲2, 孫 晶2, 顏朝國2*

(1. 江海職業技術學院，江蘇 揚州 225101； 2. 揚州大學 化學化工學院，江蘇 揚州 225002)

在三乙胺催化下，環偶氮甲亞胺與4-芳亞基-5-甲基-2-苯基吡唑-3-酮在乙腈中回流反應，經1,3-偶極環加成反應合成了13個新型的1,3-二芳基取代的螺[吡唑-4,2′-吡唑并[1,2-a]吡唑]衍生物(3a～3m)，其結構經1H NMR,13C NMR, IR和HR-MS(ESI)表征。采用X-射線單晶衍射研究了3d,3h,3j和3l的單晶結構。結果表明：3為特殊的順式-1,3-二芳基構型。

偶氮甲亞胺; 吡唑酮; 螺環化合物; 1,3-偶極環加成; 非對映選擇性合成

吡唑及其衍生物是多種天然產物和合成化合物的重要結構單元。吡唑類化合物大多具有良好的生物活性，在新藥和農藥開發中有諸多應用[1]。其中，吡唑并[1,2-a]吡唑是應用最為廣泛的吡唑類化合物之一[2-3]。如吡唑并[1,2-a]吡唑啉酮可用作除草劑，也可用作乙酰輔酶A羧化酶和肌醇(內肽)胞質Ca2+-ATPase的抑制劑[4-5]。此外，還對有氧和厭氧細菌有顯著的廣譜殺滅活性[6]。γ-內酰胺類抗生素是基于肽模擬物的吡唑并[1,2-α]吡唑啉酮類化合物[7]，藥理性質獨特，藥用價值較高，其合成方法的研究一直是該領域的熱點之一[8-9]。

Scheme1

1,3-偶極子偶氮甲亞胺和含雙鍵、三鍵的親偶極體的1,3-偶極環加成反應，由于具有底物多樣性，區域選擇性和立體選擇性，成為合成吡唑并[1,2-a]吡唑啉酮衍生物的高效方法之一[10-19]。本課題組持續開展了螺雜環化合物的高效合成方法的研究工作，取得諸多成果[20-23]。但使用環狀偶氮甲亞胺進行1,3-偶極環加成反應合成螺吡唑并[1,2-a]吡唑啉酮衍生物的報道較少[24-26]。最近，我們成功地通過環狀偶氮甲亞胺進行1,3-偶極環加成反應，合成了螺[茚-2,2′-吡唑并[1,2-a]吡唑]和螺[二氫吲哚-3,2′-吡唑并[1,2-a]吡唑]衍生物[27]。為進一步拓展環狀偶氮甲亞胺在1,3-偶極環加成反應中的應用范圍，我們繼續展開了環狀偶氮甲亞胺與4-亞芳基-5-甲基-2-苯基吡唑-3-酮的1,3-偶極環加成反應的研究。

本文在三乙胺催化下，環偶氮甲亞胺(1a,1b,1f,1i,1l)與4-芳亞基-5-甲基-2-苯基吡唑-3-酮(2a～2e,2j,2l,2m)在乙腈中回流反應，經1,3-偶極環加成反應合成了13個新型的1,3-二芳基取代的螺[吡唑-4,2′-吡唑并[1,2-a]吡唑]衍生物(3a～3m, Scheme 1)，其結構經1H NMR,13C NMR, IR和HR-MS(ESI)表征。采用X-射線單晶衍射研究了3d,3h,3j和3l的單晶結構。

1 實驗部分

1.1 儀器與試劑

XT-4型顯微熔點儀(溫度未校正)；Agilent DD2 400 MHz型核磁共振儀(CDCl3為溶劑，TMS為內標);Bruker Tensor 27型紅外光譜儀(KBr壓片)；Bruker MaXis型超高分辨質譜儀；Bruker Smart APEX-2型X-射線單晶衍射儀。

1和2a～2m按文獻[14]方法合成；其余所用試劑和溶劑均為分析純。

1.2 3a～3m的合成通法

在反應瓶中依次加入10.5 mmol,20.5 mmol，三乙胺0.1 mmol和乙腈15.0 mL，回流反應6 h。旋蒸除溶，殘余物經硅膠柱層析(洗脫劑：石油醚/乙酸乙酯=1/1,V/V)純化得3a～3m。

3a: 白色固體,產率56%, m.p.160～162 ℃;1H NMRδ: 7.80～7.77(m, 2H, ArH), 7.44～7.39(m, 4H, ArH), 7.28～7.29(m, 2H, ArH), 7.26～7.25(m, 1H, ArH), 7.24～7.22(m, 3H, ArH), 7.04～7.02(m, 2H, ArH), 5.66(s, 1H, CH), 4.41(s, 1H, CH), 3.95～3.88(m, 1H, CH), 3.27～3.19(m, 1H, CH), 3.08～2.99(m, 1H, CH), 2.97～2.90(m, 1H, CH), 1.56(s, 3H, CH3);13C NMRδ: 173.9, 170.5, 159.1, 137.3, 134.5, 132.0, 131.6, 129.1, 129.0, 128.9, 126.0, 125.8, 122.2, 119.2, 77.3, 72.7, 63.5, 47.8, 31.8, 17.2; IRν: 2 871, 1 702, 1 494, 1 397, 1 320, 1 246, 1 125, 1 081, 1 007, 854, 806, 725 cm-1; HR-MS(ESI)m/z: Calcd for C27H24N4O2Br{[M+H]+}515.107 7, found 515.108 4。

3b: 白色固體,產率60%, m.p.198～200 ℃;1H NMRδ: 7.82～7.79(m, 2H, ArH), 7.41(t,J=8.0 Hz, 2H, ArH), 7.30～7.27(m, 2H, ArH), 7.26～7.22(m, 2H, ArH), 7.14～7.10(m, 4H, ArH), 7.07～7.05(m, 2H, ArH), 5.74(s, 1H, CH), 4.38(s, 1H, CH), 3.93～3.86(m, 1H, CH), 3.24～3.16(m, 1H, CH), 3.07～3.00(m, 1H, CH), 2.96～2.90(m, 1H, CH), 2.27(s, 3H, CH3), 1.57(s, 3H, CH3);13C NMRδ: 173.4, 170.9, 159.6, 138.9, 137.4, 135.3, 129.6, 128.9, 128.8, 128.6, 128.2, 125.9, 125.6, 125.0, 119.3, 77.4, 77.2, 72.9, 63.8, 47.9, 32.1, 21.1, 17.1; IRν: 3 020, 1 713, 1 594, 1 500, 1 455, 1 368, 1 327, 1 246, 1 187, 1 095, 1 016, 857, 816, 753 cm-1; HR-MS(ESI)m/z: Calcd for C28H27N4O2{[M+H]+}451.212 9, found 451.213 4。

3c: 白色固體,產率68%, m.p.184～186 ℃;1H NMRδ: 7.81～7.79(m, 2H, ArH), 7.41(t,J=8.0 Hz, 2H, ArH), 7.23(t,J=7.2 Hz, 1H, ArH), 7.13～7.05(m, 6H, ArH), 7.02～7.00(m, 2H, ArH), 5.70(s, 1H, CH), 4.37(s, 1H, CH), 3.93～3.87(m, 1H, CH), 3.22～3.15(m, 1H, CH), 3.08～3.02(m, 1H, CH), 2.95～2.88(m, 1H, CH), 2.28(s, 3H, CH3), 2.27(s, 3H, CH3), 1.56(s, 3H, CH3);13C NMRδ: 172.9, 170.9, 159.7, 138.8, 137.9, 137.4, 132.2, 129.6, 129.5, 128.9, 128.7, 125.9, 125.6, 124.8, 119.2, 77.3, 72.9, 63.7, 48.2, 32.4, 21.1, 21.0, 17.2; IRν: 1 714, 1 596, 1 502, 1 453, 1 365, 1 322, 1 242, 1 184, 1 090, 1 029, 859, 821, 755 cm-1; HR-MS (ESI)m/z: Calcd for C29H29N4O2{[M+H]+}465.228 5, found 465.229 3。

3d: 白色固體,產率70%, m.p.178～180 ℃;1H NMRδ: 7.80(d,J=8.0 Hz, 2H, ArH), 7.41 (t,J=8.0 Hz, 2H, ArH), 7.23(t,J=7.2 Hz, 1H, ArH), 7.13～7.11(m, 2H, ArH), 7.07～7.00(m, 4H, ArH), 6.82～6.80(m, 2H, ArH), 5.69(s, 1H, CH), 4.37(s, 1H, CH), 3.93～3.87(m, 1H, CH), 3.76(s, 3H, OCH3), 3.22～3.15(m, 1H, CH), 3.08～3.01(m, 1H, CH), 2.95～2.89(m, 1H, CH), 2.27(s, 3H, CH3), 1.57(s, 3H, CH3);13C NMRδ: 172.9, 170.9, 159.8, 159.3, 138.8, 137.4, 129.6, 128.9, 128.7, 127.2, 126.2, 125.9, 125.6, 119.2, 114.2, 77.2, 73.0, 63.5, 55.2, 48.2, 32.3, 21.1, 17.2; IRν: 3 003, 2 834, 1 713, 1 599, 1 505, 1 455, 1 363, 1 318, 1 249, 1 184, 1 122, 1 087, 1 030, 923, 829, 758 cm-1; HR-MS(ESI)m/z: Calcd for C29H29N4O3{[M+H]+}481.223 4, found 481.224 0。

3e: 白色固體,產率75%, m.p.190～192 ℃;1H NMRδ: 7.81～7.79(m, 2H, ArH), 7.44～7.40(m, 4H, ArH), 7.24(t,J=7.6 Hz, 1H, ArH), 7.11～7.01(m, 6H, ArH), 5.65(s, 1H, CH), 4.38(s, 1H, CH), 3.93～3.86(m, 1H, CH), 3.25～3.17(m, 1H, CH), 3.08～2.99(m, 1H, CH), 2.96～2.89(m, 1H, CH), 2.27(s, 3H, CH3), 1.57(s, 3H, CH3);13C NMRδ: 173.8, 170.6, 159.2, 139.0, 137.3, 134.6, 132.0, 129.6, 129.0, 128.4, 126.8, 125.9, 125.7, 122.1, 119.2, 77.3, 72.7, 63.4, 47.9, 31.9, 21.1, 17.3; IRν: 3 037, 2 936, 2 886, 1 709, 1 598, 1 497, 1 406, 1 369, 1 335, 1 290, 1 235, 1 181, 1 083, 1 008, 859, 819, 754 cm-1; HR-MS(ESI)m/z: Calcd for C28H26N4O2Br{[M+H]+}529.123 4, found 529.123 2。

3f: 白色固體,產率68%, m.p.154～156 ℃;1H NMRδ: 7.79～7.78(m, 2H, ArH), 7.43～7.39(m, 2H, ArH), 7.24～7.22(m, 1H, ArH), 7.19～7.11(m, 3H, ArH), 7.06～7.02(m, 1H, ArH), 6.98～6.87(m, 2H, ArH), 6.83～6.78(m, 2H, ArH), 5.69(s, 1H, CH), 4.35(s, 1H, CH), 3.92～3.86(m, 1H, CH), 3.74(s, 3H, OCH3), 3.22～3.15(m, 1H,CH), 3.08～3.00(m, 1H, CH), 2.96～2.89(m, 1H, CH), 2.27(s, 3H, CH3), 1.55(s, 3H, CH3);13C NMRδ: 170.9, 159.8, 159.6, 138.4, 137.4, 135.2, 128.9, 128.8, 128.7, 127.2, 125.6, 125.5, 123.4, 122.0, 119.3, 114.2, 72.8, 63.7, 55.1, 47.8, 32.0, 21.4, 17.2; IRν: 2 945, 2 836, 1 714, 1 601, 1 504, 1 455, 1 362, 1 299, 1 246, 1 176, 1 124, 1 086, 1 030, 847, 757 cm-1; HR-MS(ESI)m/z: Calcd for C29H28N4O3Na{[M+Na]+}503.205 9, found 503.205 7。

3g: 白色固體,產率64%, m.p.156～158 ℃;1H NMRδ: 7.78(d,J=7.6 Hz, 2H, ArH), 7.43～7.40(t,J=6.4 Hz, 2H, ArH), 7.23～7.22(m, 2H, ArH), 7.21～7.17(m, 2H, ArH), 7.16～7.13(m, 2H, ArH), 6.92～6.90(m, 1H, ArH), 6.80～6.78(m, 2H, ArH), 5.66(s, 1H, CH), 4.35(s, 1H, CH), 3.90～3.88(m, 1H, CH), 3.74(s, 3H, OCH3), 3.23～3.20(m, 1H, CH), 2.99～2.94(m, 2H, CH), 1.67～1.60(m, 1H, CH), 1.56(s, 3H, CH3);13C NMRδ: 174.4, 170.6, 159.9, 159.1, 137.7, 134.9, 130.2, 128.9, 128.3, 127.2, 125.7, 125.3, 123.2, 123.2, 119.3, 114.3, 72.6, 63.2, 55.2, 47.3, 31.5, 17.2; IRν: 3 063, 2 995, 2 944, 2 830, 1 713, 1 601, 1 505, 1 460, 1 412, 1 364, 1 302, 1 246, 1 182, 1 089, 1 032, 907, 848, 758 cm-1; HR-MS(ESI)m/z: Calcd for C28H25N4O3ClNa{[M+Na]+} 523.151 3, found 523.151 8。

3h: 白色固體,產率65%, m.p.200～202 ℃;1H NMRδ: 7.81～7.79(m, 2H, ArH), 7.43～7.39(m, 4H, ArH), 7.25～7.22(m, 1H, ArH), 7.16～7.13(m, 2H, ArH), 7.03～7.01(m, 2H, ArH), 6.80～6.77(m, 2H, ArH), 5.64(s, 1H, CH), 4.36(s, 1H, CH), 3.93～3.86(m, 1H, CH), 3.74(s, 3H, OCH3), 3.24～3.17(m, 1H, CH), 3.06～3.00(m, 1H, CH), 2.96～2.89(m, 1H, CH), 1.58(s, 3H, CH3);13C NMRδ: 173.9, 170.6, 160.0, 159.2, 137.3, 134.6, 132.0, 129.0, 127.2, 126.8, 125.7, 123.2, 122.1, 119.1, 114.3, 77.3, 72.7, 63.3, 55.2, 47.8, 31.9, 17.3; IRν: 2 945, 1 707, 1 607, 1 503, 1 408, 1 370, 1 303, 1 248, 1 178, 1 086, 1 041, 826, 771 cm-1; HR-MS(ESI)m/z: Calcd for C28H26N4O3Br{[M+H]+}545.118 3, found 545.118 6。

3i: 白色固體,產率60%, m.p.168～170 ℃;1H NMRδ: 7.81～7.79(m, 2H, ArH), 7.44～7.40(m, 2H, ArH), 7.29～7.27(m, 4H, ArH), 7.25～7.23(m, 2H, ArH), 7.18～7.16(m, 2H, ArH), 7.14～7.12(m, 2H, ArH), 5.74(s, 1H, CH), 4.37(s, 1H, CH), 3.94～3.87(m, 1H, CH), 3.22～3.15(m, 1H, CH), 3.07～3.01(m, 1H, CH), 2.97～2.89(m, 1H, CH), 1.58(s, 3H, CH3);13C NMRδ: 173.5, 170.6, 159.2, 137.3, 135.2, 134.9, 130.4, 129.2, 129.0, 128.9, 128.3, 127.4, 125.8, 125.0, 119.2, 76.8, 72.8, 63.9, 47.9, 31.9, 17.1; IRν: 2 928, 2 843, 1 706, 1 598, 1 496, 1 366, 1 319, 1 245, 1 179, 1 096, 1 017, 847, 782, 708 cm-1; HR-MS(ESI)m/z: Calcd for C27H24N4O2Cl{[M+H]+}471.158 2, found 471.158 6。

3j: 白色固體,產率78%, m.p.204～206 ℃;1H NMRδ: 7.81～7.79(m, 2H, ArH), 7.43(t,J=8.0 Hz, 2H, ArH), 7.28～7.27(m, 3H, ArH), 7.25～7.23(m, 2H, ArH), 7.18～7.16(m, 2H, ArH), 7.09～7.07(m, 2H, ArH), 5.68(s, 1H, CH), 4.36(s, 1H, CH), 3.93～3.86(m, 1H, CH), 3.23～3.16(m, 1H, CH), 3.08～3.02(m, 1H, CH), 2.97～2.90(m, 1H, CH), 1.55(s, 3H, CH3);13C NMRδ: 173.9, 170.3, 158.8, 137.2, 135.0, 134.2, 133.8, 130.1, 129.3, 129.1, 129.0, 127.3, 126.4, 125.9, 119.1, 72.7, 63.4, 47.8, 31.8, 17.2; IRν: 2 942, 2 885, 1 704, 1 494, 1 407, 1 370, 1 336, 1 285, 1 234, 1 184, 1 092, 1 009, 824, 762, 733, 701 cm-1; HR-MS(ESI)m/z: Calcd for C27H23N4O2Cl2{[M+H]+}505.119 3, found 505.119 8。

3k: 白色固體,產率75%, m.p.210～212 ℃;1H NMRδ: 7.79 (d,J=8.0 Hz, 2H, ArH), 7.44～7.40(m, 6H, ArH), 7.25～7.23(m, 1H, ArH), 7.10(d,J=8.0 Hz, 2H, ArH), 7.01(d,J=8.0 Hz, 2H, ArH), 5.65(s, 1H, CH), 4.34(s, 1H, CH), 3.93～3.86(m, 1H, CH), 3.22～3.15(m, 1H, CH), 3.09～2.99(m, 1H, CH), 2.96～2.89(m, 1H, CH), 1.55(s, 3H, CH3);13C NMRδ: 173.9, 170.3, 158.8, 137.1, 134.1, 132.2, 132.0, 130.7, 129.0, 127.6, 126.7, 125.9, 123.2, 122.3, 119.9, 72.5, 63.5, 47.8, 31.8, 17.2; IRν: 2 942, 1 740, 1 655, 1 600, 1 494, 1 406, 1 369, 1 336, 1 288, 1 238, 1 184, 1 082, 1 008, 823, 759 cm-1; HR-MS(ESI)m/z: Calcd for C27H23N4O2Br2{[M+H]+}593.018 2, found 593.018 1。

3l: 白色固體,產率78%, m.p.193～195 ℃;1H NMRδ: 8.19～8.14(m, 2H, ArH), 7.78(d,J=7.2 Hz, 2H, ArH), 7.48～7.42(m, 5H, ArH), 7.34～7.25(m, 2H, ArH), 7.12(d,J=7.6 Hz, 2H, ArH), 5.75(s, 1H, CH), 4.39(s, 1H, CH), 3.99～3.92(m, 1H, CH), 3.28～3.21(m, 1H, CH), 3.07～2.93(m, 2H, CH), 1.51(s, 3H, CH3);13C NMRδ: 175.3, 170.1, 158.2, 148.4, 137.9, 136.9, 132.2, 131.1, 130.4, 130.1, 129.0, 127.6, 126.1, 123.3, 120.3, 119.3, 72.3, 63.4, 47.2, 31.1, 17.2; IRν: 3 072, 2 930, 1 712, 1 596, 1 534, 1 494, 1 403, 1 354, 1 240, 1 180, 1 088, 1 006, 822, 761, 718 cm-1; HR-MS(ESI)m/z: Calcd for C27H22N5O4BrNa{[M+Na]+}582.075 3, found 582.074 7。

3m: 白色固體,產率74%, m.p.158～160 ℃;1H NMRδ: 8.18～8.15(m, 2H, ArH), 7.80～7.78(m, 2H, ArH), 7.42～7.32(m, 7H, ArH), 7.09(d,J=7.6 Hz, 2H, ArH), 5.74(s, 1H, CH), 4.37(s, 1H, CH), 3.94～3.89(m, 1H, CH), 3.25～3.19(m, 1H, CH), 3.01～2.95(m, 2H, CH), 1.25(s, 3H, CH3);13C NMRδ: 174.7, 169.9, 158.1, 147.7, 142.6, 137.0, 132.2, 130.3, 129.1, 127.6, 126.2, 126.0, 124.1, 123.3, 119.0, 72.4, 63.5, 47.5, 31.3, 29.6, 17.2; IRν: 3 072, 2 925, 2 854, 1 714, 1 599, 1 521, 1 495, 1 402, 1 344, 1 241, 1 181, 1 114, 1 011, 846, 757, 719 cm-1; HR-MS(ESI)m/z: Calcd for C27H22N5O4BrNa{[M+Na]+}582.075 3, found 582.075 6。

2 結果與討論

2.1 合成

[27]方法合成3b，反應不完全，產率僅30%左右。延長反應時間，仍然有部分原料不能反應。加入酸(或堿)催化劑可以改善反應結果。當加入催化量的三乙胺時，反應可快速完成，順利的合成3b，產率大幅提高(約60%)。在此反應條件下，可以中等至良好的產率合成預期產物。初步的構效分析表明，兩種反應底物上的取代基對產率影響較小。

2.2 表征

(1)1H NMR

由于產物的吡唑環中存在3個手性碳原子，反應中可能形成多種非對映異構體?；衔锏?H NMR譜圖中僅顯示一組特征吸收峰，這表明產物中僅存在一種非對映異構體。如3d在δ3.76處的特征峰為甲氧基的單峰，δ2.27和δ1.57處出現了兩個甲基的單峰，δ5.89和δ4.33處單峰為吡咯環C—H的特征吸收峰，δ3.93～2.89處的多重峰為吡唑啉酮環中相鄰的兩個亞甲基由于非對映特性而出現的4個H的吸收峰。

(2) X-射線單晶衍射

圖1～圖4為3d,3h,3j和3l的單晶結構圖。由圖1～圖4可見，4個分子具有相同的相對構型。兩個芳基在新形成的吡唑環中均位于順式位置。5-甲基-2-苯基吡唑-3-酮單元中的羰基位于兩個芳基的反式位置，甲基伸向兩個芳基的同一側。結合1H NMR的分析，我們確定3a～3m均具有該相對構型，中間吡唑環中位于1,3-位上的兩個芳基以順式構型存在,這與文獻[24]報道不同。值得注意的是，我們之前合成的螺[茚-2,2′-吡唑并[1,2-a]吡唑]和螺[二氫吲哚-3,2′-吡唑并[1,2-a]吡唑]也具有順式1,3-二芳基的相對構型[27]。

綜上可知，環狀偶氮甲亞胺與環狀親1,3-偶極子的環環加成反應具有非常高的非對映選擇性。

圖1 3d(CCDC: 1538806)的單晶分子結構

圖23h(CCDC: 1538807)的單晶分子結構

Figure2Single crystal structure of3h

圖3 3j(CCDC: 1538808)的單晶分子結構

圖4 3l(CCDC: 1544352)的單晶分子結構

3 結論

通過環狀偶氮甲亞胺與4-亞芳基-5-甲基-2-苯基吡唑-3-酮的1,3-偶極環加成反應合成了一系列順-1,3-二芳基取代的螺[吡唑-4,2′-吡唑并[1,2-a]吡唑]。該多環體系由3個吡唑環分別以并環和螺環方式連接，結構新穎。該反應具有反應條件簡單、底物普適性強、反應產率高，非對映選擇性好等優點。合成的新化合物在藥物研發中具有潛在的應用價值。

參考文獻

[1] LALEU B, GAGGINI F, ORCHARD M,etal. First in class,potent,and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis[J].J Med Chem,2010,53:7715-7730.

[2] INDELICATO J M, PASINI C E. The acylating potential ofγ-lactam antibacterials:Base hydrolysis of bicyclic pyrazolidinones[J].J Med Chem,1988,31:1227-1230.

[3] TERNANSKY R J, DRAHEIM S E. The chemistry of substituted pyrazolidinones:Applications to the synthesis of bicyclic derivatives[J].Tetrahedron,1992,48:777-796.

[4] MICHEL M, MANFRED B, FREDRIK C,etal. Aryldiones incorporating a [1,4,5]oxadiazepane ring. Part I:Discovery of the novel cereal herbicide pinoxaden[J].Bioorg Med Chem,2009,17:4241-4256.

[5] KAMATA M, YAMASHITA T, KINA A,etal. Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors[J].Bioorg Med Chem Lett,2012,22:4769-4772.

[6] SHENG Y, DANIEL G, KATHARINA W,etal. Synthesis and SERCA activities of structurally simplified cyclopiazonic acid analogues[J].Bioorg Med Chem,2011,19:4669-4678.

[7] BOYD D B. Application of the hypersurface iterative projection method to bicyclic pyrazolidinone antibacterial agents[J].J Med Chem,1993,36:1443-1449.

[8] COLDHAM I, HUFTON R. Intramolecular dipolar cycloaddition reactions of azomethine ylides[J].Chem Rev,2005,105:2765-2810.

[9] XU X F, DOYLE M P. The [3+3]-cycloaddition alternative for heterocycle syntheses:Catalytically generated metalloenolcarbenes as dipolar adducts[J].Acc Chem Res,2014,47:1396-1405.

[10] NA R S, JING C F, XU Q H,etal. Phosphine-catalyzed annulations of azomethine imines:Allene-dependent [3+2],[3+3],[4+3],and [3+2+3] pathways[J].J Am Chem Soc,2011,133:13337-13348.

[11] Imaizumi T, Yamashita Y, Kobayashi S. Group 11 metal amide-catalyzed asymmetric cycloaddition reactions of azomethine imines with terminal alkynes[J].J Am Chem Soc,2012,134:20049-20052.

[12] ZHU R Y, WANG C S, ZHENG J.etal. Organocatalytic asymmetric inverse-electron-demand 1,3-dipolar cycloaddition ofN,N′-cyclic azomethine imines[J].J Org Chem,2014,79:9305-9312.

[13] PEZDIRC L, BEVK D, GROSELJ U.etal. Combinatorial solution-phase synthesis of alkyl (1S*,2S*,3R*,5R*,6R*)-1-alkyl-3-aryl-6-benzoylamino-1-hydroxy-7-oxo-5-phenylhexahydropyrazolo[1,2-a]- pyrazole-2-carboxylates[J].J Comb Chem,2007,9:717-723.

[14] NA R S, LIU H L, LI Z,etal. Thermal [3+2] cycloaddition reaction of azomethine imines with allenoates for dinitrogen-fused heterocycles[J].Tetrahedron,2012,68:2349-2356.

[15] NOVAK A, TESTEN A, BEZENSEK J,etal. Synthesis of pyrazolo[1,2-a]pyrazole-based peptide mimetics[J].Tetrahedron,2013,69:6648-6665.

[16] CHEN W, DU W, DUAN Y Z,etal. Enantioselective 1,3-dipolar cycloaddition of cyclic enones catalyzed by multifunctional primary amines:Beneficial effects of hydrogen bonding[J].Angew Chem Int Ed,2007,46:7667-7670.

[17] HONG L, KAI M, WU C Y,etal. Enantioselective 1,3-dipolar cycloaddition of methyleneindolinones andN,N′-cyclic azomethine imines[J].Chem Commun,2013,49:6713-6715.

[18] LI Z, YU H, LIU L H,etal. Phosphine-catalyzed [3+2] cycloaddition reactions of azomethine imines with electron-deficient alkenes:A facile access to dinitrogen-fused heterocycles[J].Chem Eur J,2014,20:1731-1736.

[19] PLESHCHEV M I, DAS GUPTA N V, KUZNETSOV V V,etal. An-mediated new,regioselective one-pot access to bicyclic cationic structures with 2,3-dihydro-1H-pyrazolo[1,2-a]pyrazol-4-ium core[J].Tetrahedron,2015,71:9012-9021.

[20] HAN Y, SHENG Y J, YAN C G. Convenient synthesis of triphenylphosphanylidene spiro[cyclopentane-1,3′-indolines] and spiro[cyclopent[2]ene-1,3′-indolines]viathree-component reactions[J].Org Lett,2014,16:2654-2657.

[21] GAO H, SUN J, YAN C G. Selective synthesis of functionalized spiro[indoline-3,2′-pyridines] and spiro[indoline-3,4′-pyridines] by Lewis acid catalyzed reactions of acetylenedicarboxylate,arylamines,and isatins[J].J Org Chem,2014,79:4131-4136.

[22] YANG F, SUN J, GAO H,etal. Unprecedented formation of spiro[indoline-3,7′-pyrrolo[1,2-a]azepine] from multicomponent reaction of L-proline,isatin and but-2-ynedioate[J].RSC Adv,2015,5:32786-32794.

[23] WU P, GAO H, SUN J,etal. 1,3-Dipolar cycloaddition reaction for diastereoselective synthesis of functionalized dihydrospiro[indoline-3,2′-pyrroles][J].Chin Chem Lett,2017,28:329-332.

[24] ZHANG D, ZHANG D M, XU G Y,etal. Copper-catalyzed 1,3-dipolar cycloaddition of methyleneindolinones andN,N′-cyclic azomethine imines[J].Chin Chem Lett,2015,26:301-303.

[25] KOPTELOV Y B, MOLCHANOV A P, KOSTIKOV R R. Regio- and diastereoselective cycloaddition of stable cyclic azomethine imines toN-arylitaconimides[J].Russ J Org Chem,2015,51:1134-1143.

[26] DUAN J D, CHENG J, CHENG Y Y,etal. Synthesis of dinitrogen-fused spirocyclic heterocyclesviaorganocatalytic 1,3-dipolar cycloaddition of 2-arylidene-1,3-indandiones and an azomethine imine[J]Asian J Org Chem,2016,5:477-480.

[27] LU Y L, SUN J, JIANG Y H,etal. Diastereoselective synthesis of spiro[indene-2,2′-pyrazolo[1,2-a]pyrazoles] and spiro[indoline-3,2′-pyrazolo[1,2-a]pyrazoles]via1,3-dipolar cycloaddition[J].RSC adv,2016,6:50471-50748.

DiastereoselectiveSynthesisofNovelcis-1,3-Diarylspiro[pyrazole-4,2′-pyrazolo[1,2-a]pyrazoles]

ZHU Mei-jun1, ZHANG Yu2, LU Yu-ling2, SUN Jing2, YAN Chao-guo2*

(1. Jianghai Polytechnic College, Yangzhou 225101, China; 2. College of Chemistry amp; Chemical Engineering, Yangzhou University, Yangzhou 225002, China)

Thirteen novel 1,3-diaryl-substituted spiro[pyrazole-4,2′-pyrazolo[1,2-a]pyrazoles] derivatives(3a～3m) were synthesized by triethylamine catalyzed 1,3-dipolar cycloaddition of cyclic azomethine imines with 4-arylidene-5-methyl-2-phenylpyrazol-3-ones in refluxing acetonitrile. The structures were characterized by1H NMR,13C NMR, IR and HR-MS(ESI). The single crystal structures of3d,3h,3jand3lwere investigated by X-ray single diffraction. The results indicated that3have unusualcis-1,3-diaryl-configuration.

azomethine imine; prazol-3-one; spiro compound; 1,3-dipolar cycloaddition; diastereoselective synthesis

2017-09-07;

2017-11-07

國家自然科學基金資助項目(21572196)

朱美軍(1975-)，女，漢族，江蘇揚州人，碩士，主要從事有機合成的研究。 E-mail: happyfengjunyang@126.com

顏朝國，教授, E-mail: cgyan@yzu.edu.cn

O626.2

A

10.15952/j.cnki.cjsc.1005-1511.2017.12.17214