基于异腈的多组分反应构建功能化杂环化合物骨架.doc

基于异腈的多组分反应构建功能化杂环化合物骨架郭思宇指导老师 徐小平 摘 要：利用异腈、丁炔二酸酯和氰基乙酰基吲哚通过三组分一锅化反应，构建了具有潜在生物活性的吲哚联吡喃类化合物。为具有联杂环骨架有机分子的合成提供了可选方法。 关键词：异腈 多组分反应 吲哚 吡喃一. 引言 多组分反应是指使用两种以上的起始原料反应生成一种终产物，这个终产物中包括起始原料的几乎所有的原子。因此，多组分反应具有两个主要优点：1、反应过程不需分离提纯中间产物，操作简单，并且产率可以得到保证；2、反应几乎利用原料中所有原子，具有较高的原子利用率。一般多组分反应对起始底物的衍生物也具有适用性，这使得终产物具有丰富的结构多样性。如基于异腈的经典多组分反应-Ugi反应1(图一)。对于Ugi反应底物中的醛酮、伯胺与羧酸都能够很容易买到，能使用数目约为1000种，而异腈能使用数目也数百种，这样能得到反应终产物数目是十分庞大的。图一 Ugi反应异腈是一类具有特殊强烈臭味的含氮有机化合物，在碱性条件下能稳定存在，遇酸易分解。虽然异腈具有不愉快气味，异腈在结构上却具有十分值得关注的特点。异腈基团经过热运动，共振后使得异腈基团中碳原子既具有一个空轨道又具有一对孤对电子（图二），这种结构类似于卡宾与一氧化碳，这种特殊结构使得异腈碳同时具有亲电性和亲核性，既能接受负电子体系进攻又能进攻缺电子基团。这种特性使得异腈的多组分反应成为一种构建杂环骨架的有效途径。图二 异腈亲电性与亲核性在查阅文献过程中，我们发现异腈容易与活泼共轭受体（如炔酯）发生反应生成1,3偶极子，继而可以与一些含有活泼氮氢2-4、氧氢 5-7、 碳氢8-10化合物反应生成杂环化合物（图三）。已经有许多文献报道异腈与炔酯反应，有效构建了一系列含有呋喃、吡喃、吡咯、吡啶杂环骨架的化合物（图四11）。其中的众多杂环化合物展示了优良的生物活性。图四 异腈与炔酯图三 异腈与活泼共轭受体的一般反应模式图四 异腈、炔酯参与的多组分反应构建杂环化合物在这些反应中，我们注意到：异腈、炔酯与具有烯醇式结构的化合物反应能生成吡喃类化合物（图五1213）。图五 异腈、炔酯与邻羰基活性碳氢化合物氰基乙酰基吲哚是我们实验室研究较多的一种能够形成烯醇结构的化合物，如果将其引入异腈、炔酯参与的多组分反应，是否可以构建一系列吲哚联吡喃类化合物呢？ 众所周知，吲哚与吡喃类骨架大多具有生物活性，如含有吲哚结构的吲哚美辛具有解热、缓解炎性疼痛作用，含有吡喃结构的黄酮是一种很强的抗氧剂，可有效清除体内的氧自由基（图五）。带此上面的疑问，我们进行了下面的研究工作。图五 吲哚美辛（左）与黄酮（右）二. 实验1 实验仪器化合物检测用红外光谱仪，核磁共振谱仪，熔点测定仪（微电脑温控型）等。本研究使用的仪器有一般常用的玻璃磨口仪器全套、循环水多用真空泵、旋转蒸发仪、冰箱、调压变压器、电子天平，、恒温磁力搅拌器，温度计、电动搅拌器、红外干燥灯、真空干燥器、层析柱等。(1) 红外光谱采用Varian 1000 FI-IR红外光谱仪。(2) 核磁采用Varian Inova 400 MHz，Varian NMR System 300 MHz核磁共振仪。(3) 薄层色谱(TLC)采用Merck 60 F254(0.2 mm thickness)的TLC板，检测反应进行的程度。(4) 熔点用X-T5A型熔点测定仪测定, 温度计未校正。2 实验试剂表一 实验药品试剂名纯度或规格厂家或来源无水乙醇AR上海凌峰化学试剂有限公司乙酸乙酯AR国药集团化学试剂有限公司丙酮AR上海凌峰化学试剂有限公司石油醚AR国药集团化学试剂有限公司叔丁胺CP中国医药（集团）上海试剂公司二氯甲烷99.5%国药集团化学试剂有限公司三氯甲烷99.0%上海凌峰化学试剂有限公司柱层析硅胶200300目国药集团化学试剂有限公司环己基异腈AR梯希爱（上海）化成工业发展有限公司乙酸酐AR国药集团化学试剂有限公司氢氧化钠AR国药集团化学试剂有限公司丁炔二酸二甲酯97%韶远化学科技（上海）有限公司丁炔二酸二乙酯99%安奈吉化学二甲亚砜AR国药集团化学试剂有限公司四氢呋喃AR国药集团化学试剂有限公司乙腈AR国药集团化学试剂有限公司氯化苄AR国药集团化学试剂有限公司碘化亚铜AR国药集团化学试剂有限公司对甲氧基碘苯AR国药集团化学试剂有限公司氯代正己烷AR国药集团化学试剂有限公司3 原料合成3.1 叔丁基异腈的制备14在装有磁力搅拌器、回流冷凝管和恒压滴液漏斗的250 mL的圆底烧瓶中，加入30.0 mL水，在搅拌下分批加入30.0 g氢氧化钠并使之溶解，在滴液漏斗中放置14.2 g ( 20.8 mL, 1.93 mol) 叔丁胺、11.8 g (8 mL) 三氯甲烷、0.20 g苄基三乙基氯化铵和30.0 mL二氯甲烷，混匀后在搅拌下于30 min内，将其滴加到45 C的氢氧化钠的溶液中，滴加开始反应物即开始回流，并在两小时后析出沉淀。继续搅拌1 h后加80.0 mL冰水稀释，分出有机层，水层用10.0 mL二氯甲烷萃取。将萃取液与有机层合并，依次用10.0 mL水和10 .0 mL浓度为5.00 %的氯化钠水溶液洗涤，加入无水硫酸镁干燥。过滤，减压蒸馏，得6.00 g左右的叔丁基异腈。3.2 N-取代吲哚的制备3.2.1 N-苄基（正己基）吲哚制备 称取2.343 g（20 mmol）吲哚、适量TEBAC与20 mL DMSO于50 mL 圆底烧瓶中，称取8.4 g KOH 溶于14 mL 水中，在剧烈搅拌下加入圆底烧瓶中，将圆底烧瓶置于油浴中加热至100 oC,待体系温度稳定后缓慢加入3.0382 g (24 mmol)苄氯。反应一小时后，停止反应。待体系温度冷却后，水洗，分离有机层，无水硫酸镁干燥。旋干上柱，使用乙酸乙酯比石油醚1:50作为展开剂过柱分离。 N-正己基吲哚制备与N-苄基吲哚制备相同3.2.1 N-对甲氧基苯基吲哚制备 迅速称取2.343 g （20 mmol）吲哚、5.581 g（25 mmol）对甲氧基碘苯、16.291 g（50 mmol）碳酸铯、0.4761 g（2.5 mmol）碘化亚铜和7-8 mL 甲苯于50 mL 圆底烧瓶中，在氮气保护甲苯回流、磁力搅拌条件下反应24 h。抽滤后旋干上柱，石油醚淋洗。3.2 N-取代氰基乙酰基吲哚的制备 3 mL 醋酸酐与 0.3402 g 氰基乙酸置于50 mL 圆底烧瓶中，在50 oC 油浴中反应0.5 h ，然后加入 3 mmol N-取代基吲哚，将温度升高至 80 oC，继续反应0.5 h。反应结束后，抽滤、乙醇洗涤。4 吲哚联吡喃杂环骨架构建 将0.5 mmol N-取代氰基乙酰基吲哚、0.5 mmol 取代异腈、1 mmol 炔脂与2 mL 二氯甲烷置于25 mL 圆底烧瓶中。常温，磁力搅拌反应48 h，反应体系由无色变为棕红色。旋干上柱，使用丙:石油醚 115-1:10作为展开剂过柱分离。化合物表征数据：Dimethyl-2-(tert-butylamino)-5-cyano-6-(1-methyl-1H-indol-3-yl)-4H-pyran-3,4-dica-rboxylateMP162-165oC.1H NMR (DMSO, 400 MHz) 8.75 (s, 1H), 7.99 (s, 1H), 7.59-7.57 (m, 2H), 7.32-7.20 (m, 2H), 4.26 (s, 1H), 3.90 (s, 3H), 3.71 (s, 3H),3.60 (s, 3H), 1.31 (s, 9H).13C NMR (CDCl3, 75 MHz) 172.67, 169.43, 160.57, 157.24, 137.06, 131.88, 125.45, 123.31, 121.32, 118.33, 110.28, 106.02, 85.54, 71.64, 53.07, 52.96, 51.48, 40.19, 33.72, 30.81.IR (cm-1) 3247,3165,3118,2916,2212,1745,1680,1525,1442,1295,1205,1089.HRMS (ESI) m/z Calc. 423.1712 Found 423.1794Dimethyl-5-cyano-2-(cyclohexylamino)-6-(1-methyl-1H-indol-3-yl)-4H-pyran-3,4-di-carboxylateMP141-143 oC1H NMR (DMSO, 400 MHz) 8.60 (d, 1H, J = 8 Hz),8.17 (s, 1H), 7.73 (d, 1H, J = 8 Hz), 7.61 (d, 1H, J = 8 Hz), 7.33 (t, 1H, J = 8 Hz), 7.25 (t, 1H, J = 8 Hz), 4.24 (s, 1H), 3.91 (s, 3H), 3.72 (s, 3H),3.62 (s, 3H), 1.90-1.87 (m, 2H), 1.68-1.66 (m, 2H), 1.54-1.52 (m, 1H), 1.33-1.25 (m, 6H).13C NMR (DMSO, 75 MHz) 172.50, 168.54, 158.31, 157.15, 137.07, 134.00, 125.02, 123.26, 121.67, 120.55, 118.50, 111.58, 104.57, 81.48, 70.33, 53.05, 51.52, 50.05, 49.97, 33.65, 33.50, 25.16, 24.50.IR (cm-1) 3252,3173,2932,2203,1735,1630,1527,1447,1291,1185,1087 HRMS (ESI)m/z Calc. 449.1824 Found 449.1951Dimethyl-6-(1-benzyl-1H-indol-3-yl)-2-(tert-butylamino)-5-cyano-4H-pyran-3,4-dica-rboxylateMP 164.9-167.4 oC1H NMR (DMSO, 400 MHz) 8.19 (s, 1H), 7.64-7.61 (m, 2H), 7.33-7.20 (m, 7H), 5.56 (s, 2H),4.30 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 1.32 (s, 9H).13C NMR (DMSO, 75 MHz) 172.32, 168.73, 159.88, 156.43, 137.37, 136.24, 132.81, 129.08, 128.17, 127.79, 125.10, 123.23, 121.43, 120.73, 117.73, 111.94, 105.24, 85.67, 71.43, 53.13, 52.95, 52.87, 51.65, 49.98, 30.48.IR(cm-1) 3269,3170,2954,2203,1740,1658,1544,1447,1384,1302,1165,1079.HRMS (ESI) m/z Calc. 449.2107 Found 449.2007.Dimethyl-6-(1-benzyl-1H-indol-3-yl)-5-cyano-2-(cyclohexylamino)-4H-pyran-3,4-di-carboxylate MP 163-163 oC1H NMR (DMSO, 400 MHz) 8.60 (d, 1H, J = 8 Hz), 8.39 (s, 1H), 7.73 (d, 1H, J = 8 Hz), 7.65 (d, 1H, J = 8 Hz), 7.34-7.21 (m, 7H), 5.57 (s, 2H) , 4.27 (s, 1H), 3.73 (s, 3H), 3.63 (s, 3H), 1.91-1.88 (m, 2H), 1.69-1.67 (m, 2H), 1.55-1.53 (m, 1H), 1.38-1.20 (m, 6H).13C NMR (DMSO, 75 MHz) 172.46, 168.59, 158.35, 157.02, 137.35, 136.32, 133.58, 129.11, 128.20, 127.84, 125.31, 123.40, 121.79, 120.70, 118.41, 112.07, 105.23, 82.23, 70.36, 53.08, 51.54, 50.10, 33.72, 33.57, 25.17, 24.52.IR(cm-1) 3260,3130,3027,2931,2200,1739,1668,1525,1448,1373,1290,1181,1081.HRMS (ESI) m/z Calc. 525.2264 Found 525.2140.Dimethyl-2-(tert-butylamino)-5-cyano-6-(1-hexyl-1H-indol-3-yl)-4H-pyran-3,4-dicar-boxylateMP 122.0-124.2 oC1H NMR (DMSO, 400 MHz) 8.76 (s, 1H), 8.03 (s, 1H), 7.63 (dd, 2H, J = 8,8 Hz), 7.31-7.21 (m, 2H) , 4.31 (t, 2H, J = 8 Hz),4.29 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 1.79-1.76 (m, 2H), 1.33 (s, 9H), 1.22-1.20 (m, 6H), 0.80 (t, 3H, J = 8 Hz).13C NMR (DMSO, 75 MHz) 172.32, 168.78, 159.94, 156.56, 136.18, 132.57, 124.95, 123.01, 121.17, 120.67, 117.73, 111.55, 104.64, 85.37, 71.43, 53.08, 52.89, 51.60, 46.49, 31.17, 30.48, 29.77, 27.52, 26.12, 22.40, 14.20. IR(cm-1) 3259,3176,3114,2937,2212,1750,1656,1520,1445,1382,1299,1171,1085 HRMS (ESI) m/z Calc. 493.2577 Found493.2497.Dimethyl-5-cyano-2-(cyclohexylamino)-6-(1-hexyl-1H-indol-3-yl)-4H-pyran-3,4-dica-rboxylateMP 128.7-129.8 oC1H NMR (DMSO, 400 MHz) 8.59 (d, 1H, J = 8 Hz), 8.19 (s, 1H), 7.69 (dd, 2H, J = 4 , 8 Hz), 7.32-7.21 (m, 2H) , 4.30 (t, 2H , J = 8 Hz),4.24 (s, 1H), 3.71 (s, 3H), 3.62 (s, 3H), 1.90-1.87 (m, 2H), 1.79-1.75 (m, 2H), 1.68-1.64 (m, 2H), 1.54-1.50 (m, 1H), 1.35-1.25 (m, 12H), 0.83-0.81 (m, 3H).13C NMR (DMSO, 75 MHz) 172.46, 168.57, 158.35, 157.14, 136.30, 133.31, 125.11, 123.20, 121.58, 120.65, 118.46, 111.64, 104.64, 81.71, 70.34, 53.04, 51.51, 50.08, 46.57, 33.70, 33.55, 31.18, 29.84, 26.14, 25.16, 24.54, 22.40, 14.22.IR(cm-1) 3244,3132,2940,2202,1739,1685,1525,1445,1074 HRMS (ESI) m/z Calc. 519.2733 Found 519.2654.Dimethyl-2-(tert-butylamino)-5-cyano-6-(1-(4-methoxyphenyl)-1H-indol-3-yl)-4H-py-ran-3,4-dicarboxylateMP 84.1-87.1 oC1H NMR (DMSO, 300 MHz) 8.79 (s, 1H), 8.18 (s, 1H), 7.72-7.71 (m, 1H), 7.53 (t, 3H, J = 9 Hz), 7.33-7.32 (m, 2H) , 7.18 (d, 2H, J = 9 Hz), 4.33 (s, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 3.62 (s, 3H), 1.34 (s, 9H).13C NMR (DMSO, 100 MHz) 177.15, 173.77, 164.88, 164.12, 161.09, 141.29, 137.17, 135.85, 131.52, 130.19, 129.08, 127.01, 125.89, 122.62, 120.50, 116.78, 111.88, 91.64, 76.40, 60.94, 58.13, 57.99, 56.65, 35.53.IR(cm-1) 3261,3175,2947,2212,1743,1654,1524,1445,1301,1176,1074HRMS (ESI) m/z Calc. 515.2056. Found 515.2020.Dimethyl-5-cyano-2-(cyclohexylamino)-6-(1-(4-methoxyphenyl)-1H-indol-3-yl)-4H-pyran-3,4-dicarboxylateMP 162.8-163.8 oC 1H NMR (DMSO, 400 MHz) 8.61 (d, 1H, J = 8 Hz), 8.28 (s, 1H), 7.81 (d, 1H, J = 4 Hz), 7.54 (d, 2H, J = 8 Hz), 7.49 (d, 1H, J = 8 Hz), 7.35-7.29 (m, 2H) , 7.18 (d, 2H, J = 8 Hz), 4.27 (s, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.63 (s, 3H), 1.92-1.87 (m, 2H), 1.69-1.64 (m, 2H), 1.54-1.50 (m, 1H), 1.36-1.22 (m, 6H).13C NMR (DMSO, 75 MHz) 172.29, 168.57, 159.23, 158.28, 156.68, 136.41, 132.80, 130.80, 126.53, 125.35, 124.18, 122.32, 120.91, 118.31, 115.50, 111.83, 106.82, 83.16, 70.24, 55.94, 53.07, 51.52, 50.09, 33.66, 33.59, 25.17, 24.54.I.R.( cm-1) 3257,3179,3119,2932,2208,1739,1675,1523,1466,1286,1226,1071.HRMS (ESI) m/z Calc. 541.2213 Found 541.2135.Dimethyl-6-(1-benzyl-5-methoxy-1H-indol-3-yl)-2-(tert-butylamino)-5-cyano-4H-pyr-an-3,4-dicarboxylateMP 210.1-212.4 oC1H NMR (DMSO, 400 MHz) 8.78 (s, 1H), 8.15 (s, 1H), 7.52 (d, 1H, J = 12 Hz), 7.33-7.25 (m, 5H) , 7.07 (s, 1H),6.89 (d, 1H, J = 8 Hz),5.52 (s, 2H), 4.31 (s, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.62 (s, 3H), 1.33 (s, 9H).13C NMR (DMSO, 75 MHz) 172.33, 168.81, 159.96, 156.56, 155.06, 137.45, 133.08, 131.26, 129.06, 128.13, 127.74, 125.75, 117.84, 113.42, 112.80, 104.87, 102.53, 85.24, 71.43, 55.68, 53.09, 52.93, 51.63, 50.13, 30.54.I.R.( cm-1) 3256,3163,2951,2213,1745,1662,1445,1297,1108,1078.HRMS (ESI) m/z Calc. 529.2213 Found 529.2175.Dimethyl-6-(1-benzyl-5-methoxy-1H-indol-3-yl)-5-cyano-2-(cyclohexylamino)-4H-p-yran-3,4-dicarboxylateMP 148.6-153.5 oC1H NMR (DMSO, 400 MHz) 8.63 (d, 1H, J = 8 Hz), 8.30 (s, 1H), 7.52 (d, 1H, J = 12 Hz), 7.33-7.25 (m, 5H) , 7.17 (s, 1H),6.91 (d, 1H, J = 8 Hz),5.51 (s, 2H), 4.26 (s, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 3.62 (s, 3H), 1.87-1.81(m, 2H),1.64-1.59 (m, 2H),1.51-1.45 (m, 1H),1.35-1.24 (m, 6H).13C NMR (DMSO, 75 MHz) 172.47, 168.63, 158.41, 157.10, 155.38, 137.40, 133.74, 131.39, 129.08, 128.17, 127.81, 125.97, 118.41, 113.18, 112.83, 104.82, 102.99, 82.25, 70.37, 55.90, 53.06, 51.54, 50.22, 49.91, 33.42, 25.17, 24.26.IR(cm-1) 3268,3114,2935,2853,2210,1743,1675,1532,1453,1380,1298,1212,1082.HRMS (ESI) m/z Calc. 555.2369 Found 555.2353.Dimethyl-6-(1-benzyl-5-bromo-1H-indol-3-yl)-2-(tert-butylamino)-5-cyano-4H-pyran-3,4-dicarboxylateMP 184.4-187.9 oC1H NMR (DMSO, 400 MHz) 8.75 (s, 1H), 8.28 (s, 1H), 7.82 (s, 1H), 7.62(d, 1H, J = 8 Hz), 7.39 (d, 1H, J = 8 Hz) , 7.32-7.27 (m, 5H),5.57 (s, 2H), 4.31 (s, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 1.31 (s, 9H).13C NMR (DMSO, 75 MHz) 172.20, 168.79, 159.83, 155.79, 137.15, 135.02, 134.18, 129.13, 128.26, 127.74, 126.74, 125.83, 123.16, 117.64, 114.21, 114.06, 104.85, 86.28, 71.49, 53.14, 52.98, 51.68, 50.15, 30.49IR(cm-1) 3255,3165,2962,2204,1740,1658,1527,1445,1360,1294,1179,1069.HRMS (ESI) m/z Calc. 577.1212 Found 577.1192.Dimethyl-6-(1-benzyl-5-bromo-1H-indol-3-yl)-5-cyano-2-(cyclohexylamino)-4H-pyr-an-3,4-dicarboxylateMP 128.6-136.7 oC1H NMR (DMSO, 400 MHz) 8.61 (d, 1H, J = 8 Hz), 8.45 (s, 1H), 7.89 (s, 1H), 7.61(d, 1H,J = 8 Hz), 7.40 (d, 1H, J = 8 Hz) , 7.31-7.28 (m, 5H), 5.56 (s, 2H), 4.25 (s, 1H), 3.71 (s, 3H), 3.62 (s, 3H),1.90-1.85(m, 2H),1.67-1.62 (m, 2H),1.53-1.50 (m, 1H),1.35-1.19 (m, 6H).13C NMR (DMSO, 75 MHz) 175.15, 171.42, 161.06, 159.28, 139.89, 137.91, 137.62, 131.96, 131.10, 130.64, 129.81, 128.83, 125.88, 121.10, 117.46, 116.94, 107.71, 85.66, 73.13, 55.92, 54.38, 53.09, 36.52, 28.02, 27.49, 27.46.IR(cm-1) 3258,3126,2855,2203,1739,1643,1525,1449,1371,1277,1186,1077.HRMS (ESI) m/z Calc. 603.1369 Found 603.1350.Dimethyl-2-(tert-butylamino)-5-cyano-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-3-yl)-4H-pyran-3,4-dicarboxylateMP 79.3-82.2 oC1H NMR (DMSO, 300 MHz) 8.77 (s, 1H), 8.25 (s, 1H), 7.72-7.61 (m, 4H), 7.47(d, 2H, J = 6 Hz), 7.27-7.23 (m, 2H) , 5.70 (s, 2H), 4.32 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H),1.31 (s, 9H).13C NMR (DMSO, 100 MHz) 177.27, 173.76, 164.88, 161.31, 147.24, 141.22, 137.85, 133.35, 131.01, 130.97, 130.09, 128.39, 126.54, 125.79, 122.67, 116.79, 110.60, 90.91, 76.40, 58.08, 57.91, 56.59, 54.37, 35.45, 32.49.IR(cm-1) 3260,3177,2965,2213,1742,1679,1537,1442,1321,1177,1129,1070.HRMS (ESI) m/z Calc. 567.1981 Found 567.1857.Dimethyl-5-cyano-2-(cyclohexylamino)-6-(1-(4-(trifluoromethyl)benzyl)-1H-indol-3-yl)-4H-pyran-3,4-dicarboxylateMP 175.1-176.5 oC1H NMR (DMSO, 400 MHz) 8.60 (d, 1H, J = 8 Hz), 8.43 (s, 1H), 7.73(d, 1H, J = 8 Hz), 7.70 (d, 2H, J = 8 Hz) , 7.61(d, 1H, J = 8 Hz), 7.48 (d, 2H, J = 8 Hz) ,7.29-7.21 (m, 2H), 5.69 (s, 2H), 4.26 (s, 1H), 3.72 (s, 3H), 3.62 (s, 3H),1.88-1.86(m, 2H),1.67-1.63 (m, 2H),1.51-1.49 (m, 1H),1.36-1.17 (m, 6H).13C NMR (DMSO, 75 MHz) 175.27, 171.42, 161.15, 159.77, 145.03, 139.15, 136.49, 131.23, 128.88, 128.84, 128.15, 126.40, 124.74, 123.61, 121.21, 114.76, 108.42, 85.26, 73.17, 55.90, 54.35, 52.91, 52.32, 36.55, 36.39, 27.98, 27.34.IR(cm-1) 3255,3168,2934,2209,1744,1634,1538,1448, 1305,1176,1072.HRMS (ESI) m/z Calc. 593.2138 Found 593.2120.Dimethyl-6-(1-(3-bromobenzyl)-1H-indol-3-yl)-2-(tert-butylamino)-5-cyano-4H-pyra-n-3,4-dicarboxylateMP 141.5-144.6 oC1H NMR (DMSO, 400 MHz) 8.75 (s, 1H), 8.24 (s, 1H), 7.64 (dd, 2H, J = 8,8 Hz), 7.50-7.47 (m, 2H), 7.31-7.21 (m, 4H),5.85 (s, 2H), 4.31 (s, 1H), 3.73 (s, 3H), 3.62 (s, 3H), 1.32 (s, 9H).13C NMR (DMSO, 100 MHz) 177.26, 173.76, 164.88, 161.29, 145.21, 141.13, 137.73, 136.24, 136.05, 135.45, 131.86, 130.08, 128.36, 127.34, 126.52, 125.76, 122.63, 116.83, 110.52, 90.97, 76.38, 58.11, 57.92, 56.62, 54.13, 35.50, 32.53.IR( cm-1) 3248,3166,3116,2963,2208,1754,1677,1531,1444,1387,1300,1176,1085.HRMS (ESI) m/z . Calc. 577.1212Dimethyl-6-(1-(3-bromobenzyl)-1H-indol-3-yl)-5-cyano-2-(cyclohexylamino)-4H-pyr-an-3,4-dicarboxylateMP 149.7-150.5 oC1H NMR (DMSO, 400 MHz) 8.59 (d, 1H, J = 8 Hz), 8.41 (s, 1H), 7.72 (d, 1H, J = 8 Hz), 7.65 (d, 1H, J = 8 Hz), 7.57 (s, 1H),7.48-7.45 (m, 1H), 7.32-7.20 (m, 4H),5.57 (s, 2H), 4.26 (s, 1H), 3.72 (s, 3H), 3.62 (s, 3H), 1.88-1.85 (m, 2H), 1.66-1.62 (m, 2H), 1.52-1.49 (m, 1H), 1.35-1.15 (m, 6H).13C NMR (DMSO, 75 MHz) 172.42, 168.57, 158.30, 156.91, 140.09, 136.22, 133.52, 131.25, 131.09, 130.59, 126.87, 125.27, 123.51, 122.35, 121.86, 120.72, 118.35, 111.93, 105.47, 82.46, 70.31, 53.07, 51.52, 50.07, 49.27, 33.70, 33.55, 25.15, 24.51.IR (cm-1) 3250,3130,2934,2856,2200,1740,1675,1525,1447, 1289,1182,1082.HRMS (ESI) m/z Calc. 603.1369 Found 603.1354.Diethyl-2-(tert-butylamino)-5-cyano-6-(1-methyl-1H-indol-3-yl)-4H-pyran-3,4-dicarb-oxylateMP 119-121 oC1H NMR (DMSO, 400 MHz) 8.77 (s, 1H), 8.00 (s, 1H), 7.61-7.58 (m, 2H), 7.31 (t, 1H, J = 8 Hz), 7.24 (t, 1H, J = 8 Hz), 4.24 (s, 1H), 4.20 -4.03 (m, 4H), 3.91 (s, 3H),1.32 (s, 9H),1.23 (t, 3H, J = 6 Hz), 1.16(t, 3H, J = 6 Hz).13C NMR (DMSO, 100 MHz) 176.97, 173.40, 164.83, 161.40, 141.98, 138.11, 129.87, 128.05, 126.22, 125.51, 122.72, 116.48, 109.64, 90.26, 76.56, 66.56, 64.85, 57.85, 38.54, 35.53, 32.51, 19.62, 19.53.IR(cm-1) 3269,3118,2973,2209,1740,1674,1529,1434, 1380,1211,1041.HRMS (ESI) m/z Calc. 451.2107 Found 451.2095.Diethyl-5-cyano-2-(cyclohexylamino)-6-(1-methyl-1H-indol-3-yl)-4H-pyran-3,4-dica-rboxylateMP 119-123 oC1H NMR (DMSO, 400 MHz) 8.61 (d, 1H, J = 8 Hz), 8.16 (s, 1H), 7.73 (d, 1H, J = 8 Hz), 7.60 (d, 1H, J = 8 Hz), 7.33 (t, 1H, J = 6 Hz), 7.24 (t, 1H, J = 6 Hz), 4.21-4.02 (m, 5H), 3.91 (s, 3H), 1.89-1.87 (m, 2H), 1.68-1.66 (m, 2H), 1.53-1.51 (m, 1H), 1.35-1.16 (m, 12H).13C NMR (DMSO, 75 MHz) 172.11, 168.22, 158.22, 156.98, 137.06, 133.91, 125.05, 123.20, 121.61, 120.53, 118.42, 111.55, 104.62, 81.50, 70.41, 61.51, 59.72, 50.00, 33.69, 33.63, 33.54, 25.16, 24.51, 14.66, 14.55.IR( cm-1) 3249,3162,2931,2860,2203,1750,1631,1527,1449, 1364,1171,1088.HRMS (ESI) m/z Calc. 477.2264 Found 477.2202.Diethyl-6-(1-benzyl-1H-indol-3-yl)-2-(tert-butylamino)-5-cyano-4H-pyran-3,4-dicarboxylateMP 150.2-154.0 oC1H NMR (DMSO, 400 MHz) 8.76 (s, 1H), 8.20 (s, 1H), 7.63 (d, 1H, J = 8 Hz),7.34-7.20 (m, 7H), 5.56 (s, 2H),4.27 (s, 1H), 4.21-4.01 (m, 4H), 1.31 (s, 9H),1.23 (t, 3H, J = 6 Hz), 1.17(t, 3H, J = 6 Hz).13C NMR (DMSO, 75 MHz) 174.80, 171.25, 162.64, 159.14, 140.24, 139.10, 135.64, 131.91, 130.99, 130.64, 127.99, 126.04, 124.22, 123.54, 120.54, 114.78, 108.16, 88.50, 74.41, 64.45, 62.72, 55.71, 52.82, 33.36, 30.38, 17.48, 17.40.IR(cm-1)3259,3163,2977,2207,1739,1667,1524,1447, 1377,1288,1186,1078.HRMS (ESI) m/z Calc. 527.2488 Found 527.2488.Diethyl-6-(1-benzyl-1H-indol-3-yl)-5-cyano-2-(cyclohexylamino)-4H-pyran-3,4-dicar-boxylateMP 166.1-167.5 oC1H NMR (DMSO, 400 MHz) 8.60 (d, 1H, J = 8 Hz), 8.38 (s, 1H), 7.71 (d, 1H, J = 8 Hz), 7.63 (d, 1H, J = 8 Hz), 7.33-7.19 (m, 7H), 5.56 (s, 2H),4.22 (s, 1H), 4.19-4.01 (m, 4H), 1.89-1.87 (m, 2H), 1.67-1.65 (m, 2H), 1.53-1.51 (m, 1H), 1.35-1.15 (m, 12H).13C NMR (DMSO, 75 MHz) 174.96, 171.08, 161.04, 159.71, 140.19, 139.14, 136.35, 131.93, 131.01, 130.67, 128.17, 126.20, 124.59, 123.51, 121.18, 114.89, 108.10, 85.04, 73.26, 64.41, 62.59, 52.90, 36.59, 36.42, 28.01, 27.37, 17.52, 17.41.IR(cm-1) 3283,3104,2931,2206,1744,1675,1529,1449, 1383,1283,1177,1078.HRMS (ESI) m/z Calc. 553.2559 Found 553.2559.Diethyl-2-(tert-butylamino)-5-cyano-6-(1-hexyl-1H-indol-3-yl)-4H-pyran-3,4-dicarbo-xylateMP 42.5-47.3 oC1H NMR (DMSO, 300 MHz) 8.76 (s, 1H), 8.03 (s, 1H), 7.66-7.59 (m, 2H), 7.30-7.22 (m, 2H), 4.31 (t, 2H, J = 6 Hz), 4.25 (s, 1H), 4.18-4.03 (m, 4H), 1.33 (s, 9H), 1.23-1.15(m, 14H),0.80 (t, 3H, J = 6 Hz).13C NMR (DMSO, 100 MHz) 176.93, 173.36, 164.77, 161.38, 141.15, 137.52, 129.93, 127.97, 126.12, 125.60, 122.65, 116.55, 109.66, 90.32, 76.50, 66.55, 64.84, 57.81, 51.46, 36.16, 35.49, 34.76, 31.11, 27.39, 19.62, 19.52, 19.20.IR( cm-1) 3262,3177,2956,2212,1740,1678,1531,1443,1381,1287,1197,1078. HRMS (ESI) m/z Calc. 521.2890Diethyl-5-cyano-2-(cyclohexylamino)-6-(1-hexyl-1H-indol-3-yl)-4H-pyran-3,4-dicar-boxylateMP 122.4-125.0 oC1H NMR (DMSO, 400 MHz) 8.60 (d, 1H, J = 8 Hz), 8.18 (s, 1H), 7.71 (d,