王夢佳　徐慧婷　陳　飛　謝佳慧　吳小雅　曲喜勝　吳春雷

(紹興文理學(xué)院　化學(xué)化工學(xué)院，浙江　紹興312000)

?

Yb(OTf)3促進(jìn)的螺環(huán)吲哚類衍生物合成研究

王夢佳徐慧婷陳飛謝佳慧吳小雅曲喜勝吳春雷

(紹興文理學(xué)院化學(xué)化工學(xué)院，浙江紹興312000)

以三氟甲磺酸鐿(Yb(OTf)3)為催化劑，PEG-400為溶劑，靛紅、β-環(huán)己二酮與丙二腈(或氰基乙酸乙酯)三組分于60℃反應(yīng)30 min合成一系列螺環(huán)吲哚類衍生物，收率為87%～95%，其結(jié)構(gòu)經(jīng)1H NMR和13C NMR確證.Yb(OTf)3/ PEG-400可回收套用五次.

靛紅；螺環(huán)吲哚；PEG-400；三氟甲磺酸鐿

吲哚是一類很重要的雜環(huán)化合物，也是組成很多藥物和天然化合物的核心結(jié)構(gòu)，而在吲哚的三號位形成螺環(huán)后能增強(qiáng)整個結(jié)構(gòu)的生物活性，如spirotryprostatins A、恩卡林堿和異恩卡林堿都表現(xiàn)出很好的調(diào)節(jié)毒蕈堿樣5-羥色胺受體的功能.[1]由于此類物質(zhì)極高的生物活性，因此有關(guān)它的合成也是研究的一大熱點，尤其是吲哚的三號位連接苯并吡喃所構(gòu)成的螺環(huán)吲哚類衍生物，其中NaCl(超聲),[2]HAuCl4·3H2O,[3]硬脂酸鈉,[4]InCl3,[5]NH4Cl,[6]三乙基芐銨,[7]L-脯氨酸[8]等物質(zhì)都已被用作催化劑來促進(jìn)此類物質(zhì)的合成，但綠色、高效的合成方法仍有待進(jìn)一步開發(fā).

三氟甲磺酸金屬鹽是一類高效的Lewis酸催化劑，已被廣泛應(yīng)用于各類有機(jī)反應(yīng)中.[9-11]近年來，聚乙二醇(PEG)由于具有無毒、溶解能力好、低蒸氣壓、易回收、易處理、環(huán)境友好和原料易得等優(yōu)點而成為很多有機(jī)反應(yīng)的綠色替代溶劑.[12-14]本文以三氟甲磺酸鐿為催化劑，PEG-400為溶劑，靛紅、環(huán)己二酮和丙二腈(或氰基乙酸乙酯)三組份一鍋法合成螺環(huán)吲哚類衍生物(4a～4n，Scheme 1)，其結(jié)構(gòu)經(jīng)1H NMR和13C NMR確證.

該方法具有反應(yīng)速度快、收率高和環(huán)境友好的特點，符合“綠色化學(xué)”的要求.

Scheme 1

1　實驗部分

1.1主要儀器與試劑

瑞士Buchi M-560型熔點儀(溫度計未經(jīng)校正)；Avance DMX Ⅲ 400 M 核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo)，瑞士Bruker公司)；反應(yīng)進(jìn)程用TLC跟蹤檢測.

所用試劑均為化學(xué)純或分析純.

1.2化合物4的合成通法

在圓底燒瓶中，加入5 mL PEG-400，再將靛紅(10 mmol)、β-環(huán)己二酮(10 mmol)和丙二腈(10 mmol)加入，開啟攪拌，加入催化劑Yb(OTf)3，60℃下反應(yīng)(TLC跟蹤).反應(yīng)結(jié)束后冷卻至室溫，過濾，濾餅用50%乙醇水溶液洗滌，濾液于80℃烘干至恒重回收PEG-400/Yb(OTf)3(套用).

4a.1H NMR δ: 1.00 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.09 (d,J= 16.0 Hz, 1H, CHAHB), 2.13 (d,J= 16.0 Hz, 1H, CHAHB), 2.56 (s, 2H, CH2), 6.78 (d,J= 7.6 Hz, 1H, ArH), 6.88 (t,J= 7.4 Hz, 1H, ArH), 6.98 (d,J= 6.8 Hz, 1H, ArH), 7.14 (t,J= 8.2 Hz, 1H, ArH), 7.12 (s, 2H, NH2), 10.39 (s, 1H, NH);13C NMR δ: 27.5, 28.1, 32.4, 47.3, 50.4, 57.9, 109.7, 111.2, 117.8, 122.1, 123.5, 128.6, 134.9, 142.5, 159.2, 164.6, 178.5, 195.3.

4a～4n的實驗結(jié)果見表1,4b～4n的表征數(shù)據(jù)與Scheme l預(yù)期吻合.

表14a～4n的實驗結(jié)果

Product外 觀m.p.(lit)/℃收率a(%)4a白色固體290-292(290-292)5914b白色固體280-281(278-280)5924c白色固體279-280(278-280)5904d白色固體284-286(282-284)5894e白色固體293-295(294-296)5954f白色固體292-293(292-294)5914g白色固體290-291(291-293)7924h白色固體278-280934i黃色固體279-281874j白色固體296-297934k白色固體289-290914l白色固體292-293(291-294)20954m白色固體>300914n白色固體250-253(251-254)988

反應(yīng)條件同1.2

2　結(jié)果與討論

2．1反應(yīng)條件篩選

首先，以靛紅、丙二腈、1,3-環(huán)己二酮三組份合成4a為例，考察了不同催化劑、催化劑用量和不同的反應(yīng)溫度對收率的影響(見表2).

表2反應(yīng)條件的優(yōu)化

EntryCatalystMol%TempTime(min)Yielda%1--60180Trace2FeCl3.6H2O1060120473ZnCl21060120534MgBr21060120515Zn(OTf)2106030786Cu(OTf)2106030857Yb(OTf)356030838Yb(OTf)3106030919Yb(OTf)31560309010Yb(OTf)310r.t1208511Yb(OTf)310803089

由表2可知，不加催化劑時，只能檢測到微量的產(chǎn)物生成，而反應(yīng)在FeCl3.6H2O、ZnCl2和MgBr2的作用下能進(jìn)行，但即使延長反應(yīng)時間至120 min，收率仍然偏低，Zn(OTf)2、Cu(OTf)2和Yb(OTf)3等三氟甲磺酸鹽作催化劑時，反應(yīng)基本在30 min內(nèi)就能快速完成，并且收率良好，尤其是Yb(OTf)3較另外兩種鹽催化效果更好，因此選用Yb(OTf)3作為本反應(yīng)的催化劑.其次，催化劑用量也對反應(yīng)有著很大影響，由表2的Entry 7-9可以看出，Yb(OTf)3的用量為10 mol%較為合適.最后，實驗過程中還顯示溫度對該反應(yīng)的影響也較大，反應(yīng)在60℃下進(jìn)行較合適，反應(yīng)溫度過低需要延長反應(yīng)時間(Entry 10)，過高則反應(yīng)液顏色過深(Entry 11)，副產(chǎn)物較多.

在上述優(yōu)化條件下，以不同的取代靛紅、環(huán)己二酮和丙二腈(氰基乙酸乙酯)為底物合成了一系列螺環(huán)吲哚類衍生物，反應(yīng)在30min內(nèi)完成，且收率良好.靛紅上的不同取代基對反應(yīng)基本沒有影響，1,3-環(huán)己二酮上五位的二甲基取代以及丙二腈和氰基乙酸乙酯的變換也都能使反應(yīng)順利進(jìn)行.

2.2催化劑/溶劑體系回收套用

以合成4a為例，考察Yb(OTf)3/PEG-400的回收套用情況，結(jié)果見表3.從表3可見，Yb(OTf)3/PEG-400體系回收套用四次，其催化活性未見明顯降低.

表3Yb(OTf)3/PEG-400體系的回收使用結(jié)果

Round12345Isolatedyield/%9191919090

*Yb(OTf)310 mol%(以1計算)，于60℃反應(yīng)30 min，其余反應(yīng)條件同1.2.

3　結(jié)論

以三氟甲磺酸鐿為催化劑，PEG-400為溶劑，靛紅，β-環(huán)己二酮與丙二腈(或氰基乙酸乙酯)三組分于60℃反應(yīng)30 min合成了一系列螺環(huán)吲哚類衍生物，收率為87%～95%，其結(jié)構(gòu)經(jīng)1H NMR和13C NMR確證.Yb(OTf)3/ PEG-400可回收重復(fù)使用，收率幾乎不變.

[1]KANG T H, MATSUMOTO K, TOHDA M, et al. Pteropodine and isopteropodine positively modulate the function of rat muscarinic M1and 5-HT2receptors expressed in Xenopus oocyte.[J]. European Journal of Pharmacology, 2002, 444(1-2):39-45.

[2] ANSHU, ANUJ K J, DHARMENDRA. NaCl as a Novel and Green Catalyst for the Synthesis of Biodynamic Spiro Heterocycles in Water Under Sonication[J]. Synthetic Communications, 2011, 41(19):2905-2919.

[3] KIDWAI M, JAHAN A, MISHRA N K. Gold(III) chloride (HAuCl4.3H2O) in PEG: A new and efficient catalytic system for the synthesis of functionalized spirochromenes[J]. Applied Catalysis A General, 2012, s 425-426:35-43.

[4] WANG L M, JIAO N, QIU J, et al. Sodium stearate-catalyzed multicomponent reactions for efficient synthesis of spirooxindoles in aqueous micellar media [J]. Tetrahedron, 2010, 66： 339-343.

[5] SHANTHI G, SUBBULAKSHMI G, PERUMAL P T. A New InCl 3 -Catalyzed, Facile and Efficient Method for the Synthesis of Spirooxindoles under Conventional and Solvent-Free Microwave Conditions.[J]. Cheminform, 2007, 63(9):2057-2063.

[6] DABIRI M, BAHRAMNEJAD M, BAGHBANZADEH M. Ammonium salt catalyzed multicomponent transformation: simple route to functionalized spirochromenes and spiroacridines[J]. Cheminform, 2009, 65(45):9443-9447.

[7] ZHU S L, JI S J, ZHANG Y. A Simple and Clean Procedure for Three-Component Synthesis of Spirooxindoles in Aqueous Medium.[J]. Cheminform, 2007, 38(51):9365-9372.

[8] LI Y, HUI C, SHI C, et al. Efficient One-Pot Synthesis of Spirooxindole Derivatives Catalyzed by l-Proline in Aqueous Medium[J]. Journal of Combinatorial Chemistry, 2010, 12(2):231-237.

[9] ARASAMPATTU S N, BOREDDY S R R Efficient One-Pot Synthesis of Substituted Lactams via Three-Component Solvent-Free Reaction Catalyzed by Ytterbium Triflate[J]. Synthetic Communications, 2013, 43(9):1229-1236.

[10]HEO Y, CHO D H, MISHRA M K, et al. Erratum: Efficient one-pot synthesis of α-aminophosphonates from aldehydes and ketones catalyzed by ytterbium(III)triflate [J]. Tetrahedron Lett, 2013, 54(14)：1899-1899.

[11] ADRIANO M, SALVATORE G, FRANCESCO P，et al. Ytterbium triflate catalysed Meerwein-Ponndorf-Verley (MPV) reduction[J]. Tetrahedron Letters, 2012, 53(7):890-892.

[12]曹瑞偉,陳朝輝,吳春雷,等.CAN/PEG-400體系催化合成氧雜蒽二酮類衍生物[J].合成化學(xué),2012,20(4):511-514.

[13]RAGHU M, RAJASEKHAR M, REDDY B C O, et al. ChemInform Abstract: Polyethylene Glycol (PEG-400): A Mild and Efficient Reaction Medium for One-Pot Synthesis of 3-Hydroxy-3-(pyridin-2-ylmethyl)indolin-2-ones.[J]. Tetrahedron Letters, 2013, 54(27):3503-3506.

[14] FIROUZABADI H, IRANPOOR N, KAZEMI F, et al. Palladium nano-particles supported on agarose as efficient catalyst and bioorganic ligand for C C bond formation via solventless Mizoroki-Heck reaction and Sonogashira-Hagihara reaction in polyethylene glycol (PEG 400)[J]. Journal of Molecular Catalysis A Chemical, 2012, 357:154-161.

附錄：氫譜 4b:1H NMR δ: 0.79 (t,J= 6.8 Hz, 3H, CH3), 0.94 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.00 (d,J= 16.0 Hz, 1H, CHAHB), 2.14 (d,J= 16.0 Hz, 1H, CHAHB), 2.52 (m, 2H, CH2), 3.69 (q,J= 6.8 Hz, 2H, CH2), 6.66 (d,J= 7.6 Hz, 1H, ArH), 6.75 (t,J= 7.2 Hz, 1H, ArH), 6.82 (d,J= 7.2 Hz, 1H, ArH), 7.03 (t,J= 7.2 Hz, 1H, ArH), 7.84 (s, 2H, NH2), 10.12 (s, 1H, NH);13C NMR δ: 13.6, 27.1, 28.2, 32.0, 47.1, 51.1, 59.3, 76.8, 108.6, 113.6, 121.0, 122.7, 127.6, 136.4, 144.5, 159.6, 162.8, 168.1, 180.2, 195.1. 4c:1H NMR δ: 1.00 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.12 (m, 2H, CH2), 2.19 (s, 3H, Ar-CH3), 2.55 (m, 2H, CH2), 6.67 (d,J= 7.2 Hz, 1H, ArH), 6.78 (s, 1H, ArH), 6.93 (d,J= 8.4 Hz, 1H, ArH), 7.19 (s, 2H, NH2), 10.27 (s, 1H, NH).13C NMR δ: 21.1, 27.7, 27.9, 32.4, 47.3, 50.5, 58.2, 109.4, 111.3, 117.8, 124.1, 128.9, 130.9, 135.0, 140.1, 159.2, 164.5, 178.4, 195.3. 4d.1H NMR δ: 0.82 (t,J= 7.2 Hz, 3H, CH3), 0.96 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.03 (d,J= 15.6 Hz, 1H, CHAHB), 2.13 (d,J= 15.6 Hz, 1H, CHAHB), 2.15 (s, 3H, CH3), 2.48-2.54 (m, 2H, CH2), 3.70 (q,J= 7.2 Hz, 2H, CH2), 6.55 (d,J= 8.0 Hz, 1H, ArH), 6.64 (s, 1H, ArH), 6.84 (d,J= 7.6 Hz, 1H, ArH), 7.84 (s, 2H, NH2), 10.02 (s, 1H, NH).13C NMR δ: 13.5, 21.1, 27.3, 28.1, 32.0, 47.1, 51.1, 59.3, 76.9, 108.3, 113.6, 123.4, 127.9, 129.5, 136.5, 142.1, 159.5, 162.7, 168.2, 180.2, 195.1. 4e.1H NMR δ: 1.00 (s, 3H, CH3), 1.01 (s, 3H, CH3), 2.14 (s, 2H, CH2), 2.49-2.56 (m, 2H, CH2), 6.78 (d,J= 8.0 Hz, 1H, ArH), 7.08 (s, 1H, ArH), 7.17 (d,J= 5.6 Hz,1H, ArH), 7.29 (s, 2H, NH2), 10.51 (s, 1H, NH).13C NMR δ: 27.7, 27.9, 32.4, 47.5, 50.4, 57.1, 110.6, 111.1, 117.7, 123.7, 126.1, 128.5, 136.9, 141.5, 159.3, 165.1, 178.3, 195.6. 4f.1H NMR δ: 0.82 (t,J= 6.2 Hz, 3H, CH3), 0.95 (s, 3H, CH3), 0.98 (s, 3H, CH3), 2.07-2.13 (m, 2H, CH2), 2.48-2.55 (m, 2H, CH2), 3.70 (q,J= 6.0 Hz, 2H, CH2), 6.66 (d,J= 8.8 Hz, 1H, ArH), 6.88 (s, 1H, ArH), 7.10 (d,J= 8.0 Hz, 1H, ArH), 7.91 (s, 2H, NH2), 10.29 (s, 1H, NH).13C NMR δ: 13.6, 27.5, 27.9, 32.0, 47.4, 51.0, 59.4, 76.1, 109.8, 112.9, 122.9, 124.8, 127.5, 138.6, 143.6, 159.7, 163.4, 167.9, 180.0, 195.3. 4g.1H NMR δ: 0.99 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.10 (d,J=16.0 Hz, 1H, CHAHB), 2.18 (d,J=16.0 Hz, 1H, CHAHB), 2.49-2.62 (m, 2H, CH2), 6.92 (t,J= 8.0 Hz, 1H, ArH), 6.98 (d,J= 6.8 Hz, 1H, ArH), 7.21 (m, 1H, ArH), 7.32 (s, 2H, NH2), 10.84 (s, 1H, NH).13C NMR δ: 27.5, 28.0, 32.4, 48.1, 50.3, 57.3, 110.9, 114.0, 117.6, 122.2, 123.5, 128.7, 136.6, 140.3, 159.3, 164.9, 178.4, 195.5. 4h.1H NMR δ: 0.83 (t,J= 7.2 Hz, 3H, CH3), 0.95 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.03 (d,J=15.6 Hz, 1H, CHAHB), 2.18 (d,J=15.0 Hz, 1H, CHAHB), 2.47-2.62 (m, 2H, CH2), 3.64-3.78 (m, 2H, CH2), 6.79 (t,J= 7.6 Hz, 1H, ArH), 6.83 (d,J= 6.4 Hz, 1H, ArH), 7.10 (m, 1H, ArH), 7.92 (s, 2H, NH2), 10.55 (s, 1H, NH).13C NMR δ: 13.4, 27.2, 28.2, 32.0, 47.9, 51.0, 59.4, 76.3, 113.1, 121.3, 122.3, 127.6, 138.3, 142.2, 159.6, 163.2, 167.9, 180.2, 195.3. 4i.1H NMR δ: 1.01 (s, 3H, CH3), 1.04 (s, 3H, CH3), 2.13 (d,J=16.0 Hz, 1H, CHAHB), 2.19 (d,J=16.0 Hz, 1H, CHAHB), 2.50-2.60 (m, 2H, CH2), 7.13 (d,J= 7.2 Hz, 1H, ArH), 7.52 (d,J= 7.2 Hz, 1H, ArH), 7.99 (d,J= 8.4 Hz, 1H, ArH), 7.47 (s, 2H, NH2), 11.27 (s, 1H, NH).13C NMR δ: 27.7, 27.8, 32.5, 46.5, 50.2, 56.4, 110.4, 117.4, 122.6, 123.7, 130.0, 130.9, 138.4, 139.1, 159.5, 165.6, 179.0, 195.7. 4j.1H NMR δ: 0.99 (s, 3H, CH3), 1.03 (s, 3H, CH3), 2.07 (d,J=16.0 Hz, 1H, CHAHB), 2.18 (d,J= 16.0 Hz, 1H, CHAHB), 2.21 (s, 3H, CH3), 2.50-2.61 (m, 2H, CH2), 6.79 (t,J= 6.8 Hz, 1H, ArH), 6.82 (s, 1H, ArH), 6.95 (d,J= 6.8 Hz, 1H, ArH), 7.21 (s, 2H, NH2), 10.44 (s, 1H, NH).13C NMR δ: 16.8, 27.4, 28.1, 32.4, 47.5, 50.5, 58.3, 111.4, 117.8, 118.7, 120.8, 122.0, 130.0, 134.6, 141.1, 159.2, 164.4, 178.9, 195.2. 4k.1H NMR δ: 0.79 (t,J= 7.2 Hz, 3H, CH3), 0.94 (s, 3H, CH3), 1.02 (s, 3H, CH3), 2.00 (d,J= 15.6 Hz, 1H, CHAHB), 2.15 (d,J=15.0 Hz, 1H, CHAHB), 2.17 (s, 3H, CH3), 2.45-2.61 (m, 2H, CH2), 3.63-3.74 (m, 2H, CH2), 6.65 (d,J= 6.4 Hz, 1H, ArH), 6.68 (t,J= 7.2 Hz, 1H, ArH), 6.86 (d,J= 6.8 Hz, 1H, ArH), 7.84 (s, 2H, NH2), 10.17 (s, 1H, NH).13C NMR δ: 13.3, 16.8, 27.0, 28.3, 32.0, 47.3, 51.1, 59.3, 77.0, 113.7, 117.5, 120.2, 121.0, 128.9, 136.0, 142.9, 159.5, 162.7, 168.2, 180.7, 195.0. 4l.1H NMR δ: 1.92 (t,J= 6.4 Hz, 2H, CH2), 2.21-2.25 (m, 2H, CH2), 2.23 (s, 3H, CH3), 2.65 (t,J= 6.0 Hz, 2H, CH2), 6.66 (d,J= 8.0 Hz, 1H, ArH), 6.81 (s, 1H, ArH), 6.93 (d,J= 7.6 Hz, 1H, ArH), 7.17 (s, 2H, NH2), 10.26 (s, 1H, NH).13C NMR δ: 20.2, 21.1, 27.2, 36.9, 47.4, 58.2, 109.3, 112.4, 117.9, 124.2, 128.9, 130.9, 135.1, 140.0, 159.0, 166.4, 178.5, 195.4. 4m.1H NMR δ: 1.93 (t,J= 6.0 Hz, 2H, CH2), 2.17-2.29 (m, 2H, CH2), 2.62-2.68 (m, 2H, CH2), 6.92 (t,J= 8.0 Hz, 1H, ArH), 7.01 (d,J= 7.2 Hz, 1H, ArH), 7.21 (d,J= 8.0 Hz, 1H, ArH), 7.31 (s, 2H, NH2), 10.83 (s, 1H, NH).13C NMR δ: 20.2, 27.2, 36.7, 48.2, 57.4, 112.0, 113.9, 117.0, 122.4, 123.4, 128.7, 136.7, 140.2, 159.2, 166.8, 178.6, 195.6. 4n.1H NMR δ: 1.92 (t,J= 6.0 Hz, 2H, CH2), 2.16-2.29 (m, 2H, CH2), 2.50-2.67 (m, 2H, CH2), 6.77 (d,J= 7.6 Hz, 1H, ArH), 6.88 (t,J= 7.6 Hz, 1H, ArH), 7.00 (d,J= 7.2 Hz, 1H, ArH), 7.13 (t,J= 7.6 Hz, 1H, ArH),, 7.18 (s, 2H, NH2), 10.37 (s, 1H, NH).13C NMR δ: 20.2, 27.2, 36.8, 47.3, 58.0, 109.6, 112.3, 117.8, 122.1, 123.6, 128.6, 135.0, 142.4, 159.1, 166.5, 178.6, 195.5.

(責(zé)任編輯王海雷)

Synthesis of Spiro[4H-pyran-oxindole] Derivatives Catalyzed by Ytterbium Triflate

Wang Mengjia Xu Huiting Chen Fei Xie Jiahui Wu Xiaoya Qu Xisheng Wu Chunlei

(School of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing, Zhejiang 312000)

A series of spiro[4H-pyran-oxindole] derivatives in yield of 87% ～ 95% was synthesized by the reaction of isatins, malononitrile or ethyl cyano-acetate, and 1,3-dicarbonyl compounds in the presence of catalytic amount of Yb(OTf)3using PEG-400 as the solvent at 60℃ for 30 min．The structures were confirmed by1H NMR and13C NMR. It is proven that Yb(OTf)3/ PEG-400 can be recycled for five times．

isatins; spiro[4H-pyran-oxindole]; PEG-400; Yb(OTf)3

2016-03-31

浙江省教育廳科研項目(編號：Y201431839)；紹興文理學(xué)院學(xué)生科技創(chuàng)新重點項目。

王夢佳(1994-)，女，浙江杭州人，主要研究方向為藥物及中間體合成.

10.16169/j.issn.1008-293x.k.2016.08.17

O626.13

A

1008-293X(2016)08-0093-05