CN109081800B - 含cf3吲哚啉和1,2,3,4-四氢异喹啉的合成方法 - Google Patents

含cf3吲哚啉和1,2,3,4-四氢异喹啉的合成方法 Download PDF

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CN109081800B
CN109081800B CN201810728158.9A CN201810728158A CN109081800B CN 109081800 B CN109081800 B CN 109081800B CN 201810728158 A CN201810728158 A CN 201810728158A CN 109081800 B CN109081800 B CN 109081800B
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梁德强
王宝玲
李维莉
马银海
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Abstract

本发明公开一种含CF3吲哚啉和1,2,3,4‑四氢异喹啉的合成方法，涉及化合物合成技术领域。所述含CF3吲哚啉和1,2,3,4‑四氢异喹啉的合成方法，基于非活化烯烃双键作为自由基受体的无金属三氟甲基化/环化自由基串联反应，利用该反应可以一步合成含CF3的吲哚啉和1,2,3,4‑四氢异喹啉，该合成方法具有条件温和、操作简单、成本低、底物范围广、和呈现exo选择性等显著优点。

Description

含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法
技术领域
本发明属于化合物合成技术领域，尤其涉及一种含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法。
背景技术
含CF3基团的化合物通常具有比对应C-H化合物更优异的生物、物理和化学性质，因而被广泛应用于医药、农用化学品和材料科学中。仅在医药领域，就有约30％的临床药物含有氟原子。因此，人们投入了大量努力开发将CF3引入到各种活性有机分子中的方法。该领域中，活化烯烃的三氟甲基化双官能团化反应已被证实是一步构筑复杂分子的强有力反应策略，但非活化烯烃的三氟甲基化反应研究则很少。
吲哚母核是大量天然生物碱和临床药物分子的核心结构，而在吲哚化学中，吲哚啉骨架比其它吲哚对应物(如氧化吲哚)难合成。如下从N-芳基丙烯酰胺合成含CF3氧化吲哚反应式：
Figure BDA0001720212620000011
含CF3的氧化吲哚既可以通过活化烯烃N-芳基丙烯酰胺或丙烯酰基磺酰胺的三氟甲基化/环化序列反应合成，也可以通过母体氧化吲哚的衍生化反应合成，而对应3-(2,2,2-三氟乙基)吲哚啉的合成却仍是一个巨大的挑战，原因可能是非活化烯烃在反应时容易发生聚合或双键转移。合成3-(2,2,2-三氟乙基)吲哚啉的报道非常少，且这些反应步骤繁琐、底物范围窄、成本高、条件苛刻或剧毒。现有的3-(2,2,2- 三氟乙基)吲哚啉合成方法如下列反应式：
Figure BDA0001720212620000021
合成方法a)合成步骤复杂，且仅有1例；合成方法b)试剂昂贵、底物范围窄；合成方法c)试剂昂贵、且使用过量铜；合成方法 d)用到有毒昂贵气体、条件苛刻；合成方法e)反应条件苛刻；另外，理论上氧化吲哚的还原反应也可以生成吲哚啉，但是该还原反应有严重的官能团不耐受问题。因此，开发一个通用、实用、且低成本的含CF3吲哚啉的合成方法十分必要。
发明内容
针对现有技术存在的问题，本发明提供了一种含CF3吲哚啉和 1,2,3,4-四氢异喹啉的合成方法，基于非活化烯烃双键作为自由基受体的无金属三氟甲基化/环化自由基串联反应，利用该反应可以一步合成含CF3的吲哚啉和1,2,3,4-四氢异喹啉，该合成方法具有条件温和、操作简单、成本低、底物范围广、和呈现exo选择性等显著优点。
一种含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法包括：
开发一个非活化烯烃的无金属三氟甲基化/芳基化反应，通过该串联反应可以从烯丙基胺衍生物出发合成含CF3的吲哚啉和四氢异喹啉。
进一步的，所述含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法包括以下步骤：
步骤一、合成底物烯丙基胺1，3和5
1)向一个放有磁力搅拌子的100mL圆底烧瓶中依次加入1.607 g，15.0mmol的甲苯胺、50.0mL的CH2Cl2和4.170mL，30.0mmol 的Et3N，最后加入1.273mL，18.0mmol的乙酰氯，反应混合液在室温用磁力搅拌器进行搅拌；
2)TLC显示原料对甲苯胺消耗完毕后，用100mL饱和NaHCO3溶液淬灭反应，然后用100.0mL的CH2Cl2萃取3次，合并的有机相用50mL食盐水洗涤2次，蒸除有机溶剂得到的固体用体积比5:1的石油醚/乙酸乙酯混合液洗涤，得到白色固体对甲基乙酰苯胺；
3)向保持搅拌的1.492g，10.0mmol的甲基乙酰苯胺和600mg， 15.0mmol的NaOH和30mL的DMF溶液中加入1.311mL，13.0mmol 的2-甲基-3-溴丙烯，得到的混合液用磁力搅拌器在室温搅拌反应；
4)TLC显示对甲基乙酰苯胺消耗完毕后，用食盐水淬灭反应并用CH2Cl2萃取3次，蒸除有机溶剂得到的残留物用硅胶进行柱层析，得到无色油状物N-(2-甲基烯丙基)-N-对甲苯基乙酰胺；
步骤二、含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成
1)向放有磁力搅拌子的35mL管状耐压管中依次加入312mg， 2.0mmol的CF3SO2Na、405mg，1.5mmol的K2S2O8、和189mg， 1.0mmol的N-(2-甲基烯丙基)乙酰苯胺，然后加入3.0mL溶剂DMSO 反应混合液在50℃搅拌24h后用2.0mL饱和Na2S2O3溶液和15.0mL 水淬灭，使用10.0mL的CH2Cl2萃取3次，然后蒸除有机溶剂，用硅胶进行柱层析，得到浅黄色油状物产物3-(2,2,2-三氟乙基)吲哚啉和含CF3四氢异喹啉。
进一步的，所述合成底物烯丙基胺1，3和5的反应式为：
Figure BDA0001720212620000041
进一步的，含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法的反应机理为：三氟甲基自由基对底物的非活化双键进行加成，生成烷基自由基中间体A，紧接着A的苯环对分子内的自由基进行捕获，从而实现关环，并生成去芳香化的芳基自由基中间体B，硫酸根负离子自由基攫取中间体B苯环饱和碳上的氢，生成产物吲哚啉和硫酸氢根负离子。
本发明的有益效果：本发明含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法，基于非活化烯烃双键作为自由基受体的无金属三氟甲基化/环化自由基串联反应，利用该反应可以一步合成含CF3的吲哚啉和1,2,3,4-四氢异喹啉，该合成方法具有条件温和、操作简单、成本低、底物范围广、和呈现exo选择性等显著优点。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
下面结合具体操作方法对本发明的应用原理作进一步描述。
化学试剂均来自商业购买，且未经特殊处理直接使用。化学反应通过薄层色谱(TLC)在F254玻璃硅胶板上进行监测。产物通过加压柱层析进行分离提纯，300-400目硅胶作为固定相。1H、13C、DEPT、19F和2D NMR测试在25℃使用BrukerAscendTM 400核磁共振仪进行，TMS作为内标。高分辨质谱(HRMS)在BrukermicroTOF II Focus 质谱仪(ESI)上进行。
一种含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法
步骤一、合成底物烯丙基胺1，3和5
合成底物烯丙基胺1，3和5的反应式为：
Figure BDA0001720212620000051
向一个放有磁力搅拌子的100mL圆底烧瓶中依次加入1.607g， 15.0mmol的甲苯胺、50.0mL的CH2Cl2和4.170mL，30.0mmol的 Et3N，最后加入1.273mL，18.0mmol的乙酰氯，反应混合液在室温用磁力搅拌器进行搅拌；
TLC显示原料对甲苯胺消耗完毕后，用100mL饱和NaHCO3溶液淬灭反应，然后用100.0mL的CH2Cl2萃取3次，合并的有机相用 50mL食盐水洗涤2次，蒸除有机溶剂得到的固体用体积比5:1的石油醚/乙酸乙酯混合液洗涤，得到白色固体对甲基乙酰苯胺；
向保持搅拌的1.492g，10.0mmol的甲基乙酰苯胺和600mg，15.0 mmol的NaOH和30mL的DMF溶液中加入1.311mL，13.0mmol 的2-甲基-3-溴丙烯，得到的混合液用磁力搅拌器在室温搅拌反应；
TLC显示对甲基乙酰苯胺消耗完毕后，用食盐水淬灭反应并用 CH2Cl2萃取3次，蒸除有机溶剂得到的残留物用硅胶进行柱层析，得到无色油状物N-(2-甲基烯丙基)-N-对甲苯基乙酰胺；
步骤二、含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成
从步骤一合成的底物N-(2-甲基丙酰基)乙酰苯胺1a1的三氟甲基化/芳基化反应开始本研究，如下反应式和表1：反应条件优化反应式：
Figure BDA0001720212620000061
表1反应条件a
Figure BDA0001720212620000062
a反应条件：1a1(1.0mmol)，CF3SO2Na(2.0mmol)，氧化剂(1.5mmol)，溶剂(3.0mL)，50℃，24h。b分离产率。c乙酰苯胺的分离产率。d底物1a1的回收率。e5.0-6.0mol/L的癸烷溶液。f 该反应在室温进行。
在50℃的二甲亚砜(DMSO，序号1)溶剂中，1a1与2当量的CF3SO2Na和1.5当量的K2S2O8顺利发生反应生成了目标分子 3-(2,2,2-三氟乙基)吲哚啉2a1，产率高达83％。使用N,N-二甲基甲酰胺(DMF，序号2)作为反应溶剂时，2a1也能以68％的产率生成，另外还有13％产率的乙酰苯胺生成。副产物乙酰苯胺来源于底物1a1 氮原子的氧化性脱保护。其它溶剂中的反应不能生成吲哚啉2a1，这些被测试的溶剂包括四氢呋喃(THF，序号3)，MeNO2，MeCN， CH2Cl2，甲苯和EtOH(序号4-8)。对一系列氧化剂的对比表明，过氧化叔丁醇(TBHP，序号10)在该自由基环合反应中的活性不如 K2S2O8，而其它的氧化剂，如Oxone(序号9)，过氧化二叔丁基(DTBP，序号11)，碘苯二乙酯(PIDA，序号12)和间氯过氧化苯甲酸(mCPBA，序号13)，则不能有效地引发该反应序列。在室温和其它完全相同的条件下，该串联反应不能发生，只观察到底物1a1的分解(序号 14)。
三氟甲基化吲哚啉2可以从各种烯丙基化的苯胺衍生物1合成得到(如下表2)；
苯环对位有甲基、溴原子或苯基的N-(2-甲基丙酰基)乙酰苯胺衍生物都顺利地与CF3SO2Na发生反应，以64-86％的产率生成5-位取代的吲哚啉2a2-4。丙酰基和辛酰基保护的吲哚啉2b1,2也可以由对应的酰基苯胺合成得到。磺酰基保护基(PGs)也可以被兼容，甲磺酰基、乙磺酰基、苯磺酰基、对甲苯磺酰基、邻甲苯磺酰基、对溴苯磺酰基、或N,N-二甲基氨磺酰保护的富电子、贫电子和电中性烯丙基化苯胺都可以发生该串联反应，并以中等到高的产率生成对应含 CF3的吲哚啉2c-h。苯环邻位有取代基的N-烯丙基乙酰苯胺是挑战性的底物，由于位阻效应，对应的7-甲基吲哚啉2i仅以31％的产率生成。有间位取代基的苯胺衍生物参与反应时则存在区域选择性问题， 4-位取代的吲哚啉2j-l和它们的区域异构体6-位取代的吲哚啉2j'-l' 同时生成。有趣的是，动力学不稳定的2j-l是主产物。现阶段该选择性尚不能被准确解释，但可能与反应中间体的热力学稳定性有关。
表2 3-(2,2,2-三氟乙基)吲哚啉合成a,b
Figure BDA0001720212620000081
a反应条件：1(1.0mmol)，CF3SO2Na(2.0mmol)，K2S2O8 (1.5mmol)，DMSO(3.0mL)，50℃，24h。b分离产率。
含CF3四氢异喹啉的合成
表3含CF3四氢异喹啉的合成a,b
Figure BDA0001720212620000091
a反应条件：1(1.0mmol)，CF3SO2Na(2.0mmol)，K2S2O8 (1.5mmol)，DMSO(3.0mL)，50℃，24h。b分离产率。
该反应策略可以拓展到N-烯丙基化的苄胺衍生物(表3)。例如， 4-(2,2,2-三氟乙基)-1,2,3,4-四氢异喹啉4a-d可以从苯磺酰基或邻苯磺酰基保护的N-烯丙基苄胺合成得到，产率41-65％。
根据Baldwin规则，6-endo-trig和6-exo-trig环化也都是容易发生的反应，为了避免潜在的生成六元环的竞争反应，本研究一开始聚焦在N-(2-甲基烯丙基)底物的三氟甲基化/环化反应。在以上所有反应中都实现了高度的exo选择性之后，我们尝试将反应进一步拓展到简单的N-烯丙基苯胺衍生物。令人高兴的是，在最优条件下N-烯丙基 -N-(4-溴苯基)甲磺酰胺5顺利发生该环合反应，并以91％的产率专一地生成5-exo-trig产物6的反应式如下：
简单N-烯丙基苯胺的exo选择性三氟甲基化/环合反应
Figure BDA0001720212620000092
为了验证该反应的自由基属性，我们实施了自由基捕获实验。加入4当量自由基捕获剂如2,2,6,6-四甲基哌啶氧化物(TEMPO)、2,6- 二叔丁基-4-甲基苯酚(BHT)、或1,1-二苯乙烯(DPE)后，最优条件下的模型反应几乎被完全抑制。此外，DPE实验中，DPE-CF3加合物7以32％的产率分离得到。根据以上结果和一些前期报道，我们提出了可能的反应机理。首先，CF3SO2Na与K2S2O8发生反应生成硫酸根阴离子、硫酸根负离子自由基、和三氟甲磺酰基自由基。三氟甲磺酰基自由基随后分解，释放出一分子SO2，转化为三氟甲基自由基。三氟甲基自由基对底物1a1的非活化双键进行加成，生成烷基自由基中间体A。紧接着A的苯环对分子内的自由基进行捕获，从而实现关环，并生成去芳香化的芳基自由基中间体B。最后，硫酸根负离子自由基攫取中间体B苯环饱和碳上的氢，生成产物吲哚啉2a1和硫酸氢根负离子。
自由基捕获实验和反应机理如下：
Figure BDA0001720212620000101
具体的含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成方法为：合成底物烯丙基胺1，3和5的反应式为：
Figure BDA0001720212620000102
以1a2的合成为例：参照上述反应式，向一个放有磁力搅拌子的 100mL圆底烧瓶中依次加入对甲苯胺(1.607g，15.0mmol)、CH2Cl2 (50.0mL)，和Et3N(4.170mL，30.0mmol)，最后加入乙酰氯(1.273 mL，18.0mmol)。反应混合液在室温用磁力搅拌器进行搅拌。TLC 显示原料对甲苯胺消耗完毕后，用饱和NaHCO3溶液(100mL)淬灭反应，然后用CH2Cl2(100.0mL)萃取3次。合并的有机相用食盐水 (50mL)洗涤2次。蒸除有机溶剂得到的固体用石油醚/乙酸乙酯(5： 1，体积比)混合液洗涤，得到白色固体对甲基乙酰苯胺(2.104g， 94％产率)。向保持搅拌的对甲基乙酰苯胺(1.492g，10.0mmol) 和NaOH(600mg，15.0mmol)的DMF(30mL)溶液中加入2-甲基-3-溴丙烯(1.311mL，13.0mmol)，得到的混合液用磁力搅拌器在室温搅拌反应。TLC显示对甲基乙酰苯胺消耗完毕后，用食盐水(60 mL)淬灭反应并用CH2Cl2(100.0mL)萃取3次。蒸除有机溶剂得到的残留物用硅胶进行柱层析(石油醚-乙酸乙酯＝20：1，体积比)，得到无色油状物N-(2-甲基烯丙基)-N-对甲苯基乙酰胺1a2(1.830g， 90％产率)。
含CF3吲哚啉和1,2,3,4-四氢异喹啉的合成步骤
以2a1的合成为例：向放有磁力搅拌子的35mL管状耐压管中依次加入CF3SO2Na(312mg，2.0mmol)、K2S2O8(405mg，1.5mmol)、和N-(2-甲基烯丙基)乙酰苯胺1a1(189mg，1.0mmol)，然后加入溶剂DMSO(3.0mL)。反应混合液在50℃搅拌24h后用饱和Na2S2O3溶液(2.0mL)和水(15.0mL)淬灭。使用CH2Cl2(10.0mL)萃取 3次，然后蒸除有机溶剂，用硅胶进行柱层析(石油醚-乙酸乙酯＝30： 1，体积比)，得到浅黄色油状物产物2a1(214mg，83％产率)。
产物的光谱数据
Figure BDA0001720212620000111
2a1,1-(3-methyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)ethan-1-one,白色固体:mp 73-74℃.1H NMR(400MHz,DMSO-d6)δ＝1.37(s,3H),2.16(s,3H),2.63-2.76(m,1H),2.81-2.93(m,1H),3.90(d,J＝10.8Hz,1H),4.14(d,J＝10.8Hz,1H),7.04 (ddd,J＝0.7,7.4,7.4Hz,1H),7.20(ddd,J＝0.9,7.4,7.4Hz,1H),7.36(d,J＝7.4 Hz,1H),8.03(d,J＝7.4Hz,1H)；13C NMR(100MHz,DMSO-d6)δ＝169.10, 141.81,138.21,128.44,127.34(q,1J(C–F)＝277.1Hz),123.88,123.55,116.34,60.66, 42.06(q,2J(C–F)＝25.4Hz),40.92(q,3J(C–F)＝1.3Hz),27.29,24.43；19F NMR(376 MHz,DMSO-d6)δ＝-59.18(t,J(H–F)＝11.9,3F)；HRMS(ESI-TOF)Calcd for C13H15F3NO+([M+H]+)258.1100.Found 258.1103.
Figure BDA0001720212620000121
2a2,1-(3,5-dimethyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)ethan-1-one,无色油状物. 1H NMR(400MHz,CDCl3)δ＝1.46(s,3H),2.23(s,3H),2.33(s,3H),2.37-2.61(m, 2H),3.81(d,J＝10.8Hz,1H),4.09(d,J＝10.8Hz,1H),6.91(s,1H),7.05(dd,J＝1.0,8.2Hz,1H),8.07(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.35, 138.99,137.71,133.78,129.21,126.30(q,1J(C–F)＝276.9Hz),122.50,117.03,61.13 (q,4J(C–F)＝2.0Hz),43.17(q,2J(C–F)＝26.7Hz),41.02(q,3J(C–F)＝1.4Hz),25.98(q, 4J(C–F)＝0.9Hz),24.12,21.11；19F NMR(376MHz,CDCl3)δ＝-60.43(t,J(H–F)＝10.9, 3F)；HRMS(ESI-TOF)Calcd forC14H17F3NO+([M+H]+)272.1257.Found 272.1272.
Figure BDA0001720212620000122
2a3,1-(5-bromo-3-methyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)ethan-1-one,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.47(s,3H),2.23(s,3H),2.39-2.60(m,2H),3.83(d,J＝10.8Hz,1H),4.13(d,J＝10.8Hz,1H),7.23(d,J＝1.8Hz,1H),7.35(dd, J＝2.0,8.6Hz,1H),8.09(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝ 168.69,140.47,139.67,131.63,125.31,126.05(q,1J(C–F)＝277.0Hz),118.73,116.29, 60.99(q,4J(C–F)＝1.8Hz),42.91(q,2J(C–F)＝26.9Hz),41.08(q,3J(C–F)＝1.1Hz), 26.12,24.11；19F NMR(376MHz,CDCl3)δ＝-60.41(t,J(H–F)＝11.2,3F)；HRMS (ESI-TOF)Calcd for C13H14BrF3NO+([M+H]+)336.0205.Found 336.0209.
Figure BDA0001720212620000131
2a4,1-(3-methyl-5-phenyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)ethan-1-one,白色晶体:mp 165-166℃.1H NMR(400MHz,CDCl3)δ＝1.53(s,3H),2.27(s,3H),2.47-2.68(m,2H),3.87(d,J＝10.8Hz,1H),4.16(d,J＝10.8Hz,1H),7.32-7.35(m, 2H),7.43(dd,J＝7.8,7.4Hz,2H),7.49(dd,J＝1.7,8.4Hz,1H),7.54-7.56(m,2H), 8.26(d,J＝8.4Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.59,140.71,140.67, 138.23,137.40,128.83,127.74,127.18,126.89,126.25(q,1J(C–F)＝277.0Hz),120.66, 117.49,61.28(q,4J(C–F)＝1.4Hz),43.26(q,2J(C–F)＝26.7Hz),41.16,26.12,24.18；19F NMR(376MHz,CDCl3)δ＝-60.35(t,J(H–F)＝11.2,3F)；HRMS(ESI-TOF) Calcd for C19H19F3NO+([M+H]+)334.1413.Found334.1413.
Figure BDA0001720212620000132
2b1,1-(5-bromo-3-methyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)propan-1-one,白色固体:mp 69-70℃.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.3Hz,3H),1.46(s,3H),2.38-2.59(m,4H),3.82(d,J＝10.8Hz,1H),4.11(d,J＝10.8Hz,1H),7.22(s, 1H),7.36(dd,J＝1.3,8.6Hz,1H),8.13(d,J＝8.6Hz,1H)；13C NMR(100MHz, CDCl3)δ＝172.08,140.70,139.56,131.67,126.06(q,1J(C–F)＝277.1Hz),125.26, 118.70,116.13,60.08(q,4J(C–F)＝1.1Hz),43.06(q,2J(C–F)＝26.9Hz),41.11,29.17, 26.08,8.59；19F NMR(376MHz,CDCl3)δ＝-60.40(t,J(H–F)＝12.0,3F)；HRMS (ESI-TOF)Calcd for C14H16BrF3NO+([M+H]+)350.0362.Found 350.0364.
Figure BDA0001720212620000133
2b2,1-(5-bromo-3-methyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)octan-1-one,白色晶体:mp 92-93℃.1H NMR(400MHz,CDCl3)δ＝0.89(t,J＝7.0Hz,3H),1.25-1.42(m,8H),1.46(s,3H),1.72(tt,J＝7.6,7.4Hz,2H),2.37-2.58(m,4H),3.82(d,J＝ 10.8Hz,1H),4.12(d,J＝10.8Hz,1H),7.22(d,J＝1.4Hz,1H),7.36(dd,J＝2.0, 8.6Hz,1H),8.13(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝171.55, 140.71,139.61,131.65,126.06(q,1J(C–F)＝277.0Hz),125.24,118.80,116.15,60.25 (q,4J(C–F)＝2.0Hz),43.06(q,2J(C–F)＝26.9Hz),41.09,35.93,31.70,29.29,29.12, 26.02,24.49,22.63,14.08；19F NMR(376MHz,CDCl3)δ＝-60.38(t,J(H–F)＝10.9, 3F)；HRMS(ESI-TOF)Calcd for C19H26BrF3NO+([M+H]+)420.1144.Found 420.1143.
Figure BDA0001720212620000141
2c1,3,5-dimethyl-1-(methylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,无色油状物. 1H NMR(400MHz,CDCl3)δ＝1.47(d,J＝0.8Hz,3H),2.33(s,3H),2.39-2.62(m,2H),2.90(s,3H),3.74(d,J＝10.4Hz,1H),3.95(d,J＝10.4Hz,1H),6.95(s,1H), 7.05-7.07(m,1H),7.29(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝138.16, 137.41,133.72,129.60,126.12(q,1J(C–F)＝277.0Hz),123.60,113.28,62.03(q,4J(C–F)＝2.1Hz),42.64(q,2J(C–F)＝27.0Hz),40.97(q,3J(C–F)＝1.7Hz),34.38,25.62(q, 4J(C–F)＝1.5Hz),20.95；19FNMR(376MHz,CDCl3)δ＝-60.27(t,J(H–F)＝11.2,3F)； HRMS(ESI-TOF)Calcd forC13H17F3NO2S+([M+H]+)308.0927.Found 308.0923.
Figure BDA0001720212620000142
2c2,5-bromo-3-methyl-1-(methylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.48(s,3H),2.42-2.62(m,2H),2.93(s,3H), 3.77(d,J＝10.5Hz,1H),3.99(d,J＝10.5Hz,1H),7.27(d,J＝1.9Hz,1H),7.29(d, J＝8.6Hz,1H),7.37(dd,J＝2.0,8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝139.75,139.37,132.01,126.43,125.90(q,1J(C–F)＝276.9Hz),116.38,114.95,61.89 (q,4J(C–F)＝2.1Hz),42.50(q,2J(C–F)＝27.2Hz),41.04(q,3J(C–F)＝1.7Hz),35.03, 25.78(q,4J(C–F)＝1.5Hz)；19FNMR(376MHz,CDCl3)δ＝-60.21(t,J(H–F)＝10.8, 3F)；HRMS(ESI-TOF)Calcd forC12H14BrF3NO2S+([M+H]+)371.9875.Found 371.9877.
Figure BDA0001720212620000143
2c3,3-methyl-1-(methylsulfonyl)-5-phenyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.53(s,3H),2.46-2.69(m,2H),2.95(s,3H), 3.81(d,J＝10.5Hz,1H),4.03(d,J＝10.5Hz,1H),7.32-7.36(m,2H),7.41-7.45(m,2H),7.47-7.48(m,2H),7.51-7.54(m,2H)；13C NMR(100MHz,CDCl3)δ＝140.34, 139.89,137.93,137.47,128.93,128.10,127.40,126.91,126.13(q,1J(C–F)＝277.0Hz), 121.88,113.66,62.16(q,4J(C–F)＝2.1Hz),42.68(q,2J(C–F)＝27.0Hz),41.10(q,3J(C–F)＝1.7Hz),34.87,25.76(q,4J(C–F)＝1.4Hz)；19F NMR(376MHz,CDCl3)δ＝-60.14 (t,J(H–F)＝11.1,3F)；HRMS(ESI-TOF)Calcd for C18H19F3NO2S+([M+H]+)370.1083. Found 370.1084.
Figure BDA0001720212620000151
2d1,1-(ethylsulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.42(t,J＝7.4Hz,3H),1.47(d,J＝0.8Hz,3H), 2.41-2.62(m,2H),3.15(q,J＝7.4Hz,2H),3.82(d,J＝10.5Hz,1H),4.05(d,J＝ 10.5Hz,1H),7.05(ddd,J＝0.9,7.5,7.5Hz,1H),7.14(dd,J＝0.9,7.5Hz,1H),7.23 (ddd,J＝1.3,7.4,7.4Hz,1H),7.37(d,J＝8.1Hz,1H)；13C NMR(100MHz,CDCl3) δ＝140.73,137.02,128.95,126.13(q,1J(C–F)＝277.0Hz),123.47,122.98,113.36, 61.83(q,4J(C–F)＝2.1Hz),44.37,42.67(q,2J(C–F)＝27.0Hz),41.06(q,3J(C–F)＝1.7 Hz),25.70(q,4J(C–F)＝1.5Hz),7.72；19FNMR(376MHz,CDCl3)δ＝-60.28(t,J(H–F)＝11.2,3F)；HRMS(ESI-TOF)Calcd for C13H17F3NO2S+([M+H]+)308.0927.Found 308.0926.
Figure BDA0001720212620000152
2d2,5-bromo-1-(ethylsulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline,浅黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.42(t,J＝7.4Hz,3H),1.47(d,J＝0.6Hz, 3H),2.40-2.60(m,2H),3.14(q,J＝7.4Hz,2H),3.82(d,J＝10.6Hz,1H),4.05(d,J＝10.6Hz,1H),7.24(d,J＝1.9Hz,1H),7.26(d,J＝8.6Hz,1H),7.34(dd,J＝2.0, 8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.05,139.17,131.85,126.30,125.91 (q,1J(C–F)＝276.9Hz),115.87,114.95,61.88(q,4J(C–F)＝2.1Hz),44.72,42.57(q, 2J(C–F)＝27.2Hz),41.14(q,3J(C–F)＝1.7Hz),25.79(q,4J(C–F)＝1.5Hz),7.72；19F NMR(376MHz,CDCl3)δ＝-60.27(t,J(H–F)＝11.1,3F)；HRMS(ESI-TOF)Calcd for C13H16BrF3NO2S+([M+H]+)386.0032.Found 386.0032.
Figure BDA0001720212620000161
2d3,1-(ethylsulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline-5-carbonitrile,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.44(t,J＝7.4Hz,3H),1.50(s,3H),2.43-2.63(m,2H),3.20(q,J＝7.4Hz,2H),3.90(d,J＝10.3Hz,1H),4.13(d,J＝ 10.6Hz,1H),7.40(d,J＝1.5Hz,1H),7.47(dd,J＝0.3,8.4Hz,1H),7.55(dd,J＝ 1.6,8.5Hz,1H)；13CNMR(100MHz,CDCl3)δ＝144.81,137.78,133.90,127.02, 125.69(q,1J(C–F)＝277.0Hz),118.62,113.60,106.51,61.83(q,4J(C–F)＝2.1Hz), 45.70,42.65(q,2J(C–F)＝27.3Hz),40.94(q,3J(C–F)＝1.7Hz),26.27(q,4J(C–F)＝1.3 Hz),7.71；19F NMR(376MHz,CDCl3)δ＝-60.24(t,J(H–F)＝11.5,3F)；HRMS (ESI-TOF)Calcd for C14H16F3N2O2S+([M+H]+)333.0879.Found 333.0882.
Figure BDA0001720212620000162
2d4,1-(ethylsulfonyl)-3-methyl-5-phenyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.45(t,J＝7.4Hz,3H),1.52(s,3H),2.46-2.68 (m,2H),3.18(q,J＝7.4Hz,2H),3.87(d,J＝10.5Hz,1H),4.10(d,J＝10.5Hz,1H), 7.32-7.36(m,2H),7.41-7.47(m,4H),7.51-7.54(m,2H)；13C NMR(100MHz, CDCl3)δ＝140.41,140.14,137.73,137.03,128.89,127.95,127.30,126.87,126.13(q, 1J(C–F)＝277.0Hz),121.77,113.62,62.14(q,4J(C–F)＝2.1Hz),44.53,42.75(q,2J(C–F)＝27.0Hz),41.18(q,3J(C–F)＝1.6Hz),25.78(q,4J(C–F)＝1.4Hz),7.78；19F NMR(376 MHz,CDCl3)δ＝-60.20(t,J(H–F)＝10.9,3F)；HRMS(ESI-TOF)Calcd for C19H21F3NO2S+([M+H]+)384.1240.Found 384.1241.
Figure BDA0001720212620000163
2e1,3-methyl-1-(phenylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,白色固体:mp 121-122℃.1H NMR(400MHz,CDCl3)δ＝1.22(d,J＝0.8Hz,3H),1.97-2.09(m, 1H),2.25-2.37(m,1H),3.71(d,J＝11.0Hz,1H),3.96(d,J＝11.0Hz,1H), 7.00-7.06(m,2H),7.24-7.29(m,1H),7.45-7.49(m,2H),7.57(dddd,J＝1.2,1.2,6.8, 6.6Hz,1H),7.69(d,J＝8.2Hz,1H),7.82-7.85(m,2H)；13C NMR(100MHz,CDCl3) δ＝140.33,137.91,136.89,133.43,129.20,128.92,127.21,125.96(q,1J(C–F)＝277.1 Hz),124.13,122.74,114.98,61.29(q,4J(C–F)＝2.2Hz),42.72(q,2J(C–F)＝26.9Hz), 41.03(q,3J(C–F)＝1.7Hz),25.21(q,4J(C–F)＝1.6Hz)；19F NMR(376MHz,CDCl3)δ＝ -60.38(t,J(H–F)＝11.2,3F)；HRMS(ESI-TOF)Calcd for C17H17F3NO2S+([M+H]+) 356.0927.Found 356.0928.
Figure BDA0001720212620000171
2e2,5-bromo-3-methyl-1-(phenylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,白色固体:mp 135-136℃.1H NMR(400MHz,CDCl3)δ＝1.21(d,J＝0.6Hz,3H),1.96-2.08(m,1H),2.22-2.34(m,1H),3.70(d,J＝11.1Hz,1H),3.96(d,J＝11.1Hz, 1H),7.13(d,J＝2.0Hz,1H),7.37(dd,J＝2.0,8.6Hz,1H),7.48-7.51(m,2H), 7.57-7.62(m,2H),7.80-7.83(m,2H)；13C NMR(100MHz,CDCl3)δ＝140.07, 139.60,136.56,133.70,131.87,129.34,127.16,126.13,125.75(q,1J(C–F)＝277.1Hz), 116.67,116.49,61.37(q,4J(C–F)＝2.2Hz),42.55(q,2J(C–F)＝27.1Hz),41.11(q,3J(C–F)＝1.7Hz),25.24(q,4J(C–F)＝1.5Hz)；19F NMR(376MHz,CDCl3)δ＝-60.34(t,J(H–F)＝10.8,3F)；HRMS(ESI-TOF)Calcd forC17H16BrF3NO2S+([M+H]+)434.0032. Found434.0035.
Figure BDA0001720212620000172
2f1,3-methyl-1-tosyl-3-(2,2,2-trifluoroethyl)indoline,白色晶体:mp128-129℃.1H NMR(400MHz,CDCl3)δ＝1.24(d,J＝0.9Hz,3H),1.96-2.09(m,1H),2.22-2.34(m,1H),2.38(s,3H),3.69(d,J＝11.0Hz,1H),3.94(d,J＝11.1Hz,1H),7.00-7.05 (m,2H),7.24-7.28(m,3H),7.68(d,J＝8.1Hz,1H),7.72(ddd,J＝1.6,1.6,8.3Hz, 2H)；13C NMR(100MHz,CDCl3)δ＝144.40,140.43,137.90,133.82,129.79,128.86, 127.27,125.98(q,1J(C–F)＝277.0Hz),123.99,122.68,114.95,61.29(q,4J(C–F)＝2.1 Hz),42.68(q,2J(C–F)＝26.9Hz),40.99(q,3J(C–F)＝1.6Hz),25.12(q,4J(C–F)＝1.5Hz), 21.53；19F NMR(376MHz,CDCl3)δ＝-60.39(t,J(H–F)＝10.9,3F)；HRMS(ESI-TOF) Calcd for C18H19F3NO2S+([M+H]+)370.1083.Found 370.1082.
Figure BDA0001720212620000181
2f2,1-((4-bromophenyl)sulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline,白色晶体:mp 121-122℃.1H NMR(400MHz,CDCl3)δ＝1.26(d,J＝0.8Hz,3H),2.06-2.18(m,1H),2.32-2.44(m,1H),3.69(d,J＝10.9Hz,1H),3.93(d,J＝10.9Hz, 1H),7.03-7.08(m,2H),7.24-7.29(m,1H),7.60-7.66(m,3H),7.70(ddd,J＝2.2,2.0, 8.7Hz,2H)；13C NMR(100MHz,CDCl3)δ＝139.99,137.84,135.77,132.51,129.00, 128.68,128.62,125.96(q,1J(C–F)＝276.9Hz),124.34,122.86,114.70,61.35(q,4J(C–F)＝2.2Hz),42.71(q,2J(C–F)＝26.9Hz),41.04(q,3J(C–F)＝1.6Hz),25.37(q,4J(C–F)＝ 1.6Hz)；19F NMR(376MHz,CDCl3)δ＝-60.35(t,J(H–F)＝11.1,3F)；HRMS (ESI-TOF)Calcd for C17H16BrF3NO2S+([M+H]+)434.0032.Found 434.0048.
Figure BDA0001720212620000182
2g1,3-methyl-1-(o-tolylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,白色固体:mp 114-115℃.1H NMR(400MHz,CDCl3)δ＝1.34(d,J＝0.7Hz,3H),2.18-2.31(m,1H),2.36-2.48(m,1H),2.61(s,3H),3.76(d,J＝10.9Hz,1H),4.01(d,J＝10.9Hz, 1H),7.04(ddd,J＝0.9,7.6,7.3Hz,1H),7.09(dd,J＝1.3,7.5Hz,1H),7.21(ddd,J＝ 1.6,7.3,7.2Hz,1H),7.33(dd,J＝7.5,8.2Hz,2H),7.44(d,J＝8.1Hz,1H),7.48 (ddd,J＝1.2,7.6,7.5Hz,1H),7.98(d,J＝8.1Hz,1H)；13C NMR(100MHz,CDCl3) δ＝140.95,138.08,137.57,137.07,133.26,132.98,129.44,128.73,126.39,126.01 (q,1J(C–F)＝277.0Hz),123.75,122.69,114.82,61.07(q,4J(C–F)＝2.1Hz),42.59(q, 2J(C–F)＝26.9Hz),41.11(q,3J(C–F)＝1.7Hz),25.14(q,4J(C–F)＝1.5Hz),20.82；19F NMR(376MHz,CDCl3)δ＝-60.42(t,J(H–F)＝11.3,3F)；HRMS(ESI-TOF)Calcd for C18H19F3NO2S+([M+H]+)370.1083.Found 370.1081.
Figure BDA0001720212620000183
2g2,5-chloro-3-methyl-1-(o-tolylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.32(s,3H),2.17-2.29(m,1H),2.32-2.44(m, 1H),2.60(s,3H),3.73(d,J＝10.9Hz,1H),3.99(d,J＝10.9Hz,1H),7.04(d,J＝2.1 Hz,1H),7.17(dd,J＝2.1,8.6Hz,1H),7.33(dd,J＝7.4,7.2Hz,2H),7.40(d,J＝8.6Hz,1H),7.48(ddd,J＝1.2,7.5,7.5Hz,1H),7.94-7.96(m,1H)；13C NMR(100MHz, CDCl3)δ＝139.74,139.37,138.09,136.70,133.48,133.08,129.48,128.93,128.79, 126.50,125.80(q,1J(C–F)＝277.0Hz),123.16,115.93,61.20(q,4J(C–F)＝2.2Hz), 42.46(q,2J(C–F)＝27.2Hz),41.23(q,3J(C–F)＝1.7Hz),25.14(q,4J(C–F)＝1.4Hz), 20.84；19F NMR(376MHz,CDCl3)δ＝-60.41(t,J(H–F)＝11.1,3F)；HRMS(ESI-TOF) Calcd for C18H18ClF3NO2S+([M+H]+)404.0693.Found 404.0675.
Figure BDA0001720212620000191
2h1,N,N,3,5-tetramethyl-3-(2,2,2-trifluoroethyl)indoline-1-sulfonamide,浅黄色油状物.1H NMR(400MHz,CDCl3)δ＝1.45(d,J＝0.9Hz,3H),2.31(s,3H), 2.38-2.60(m,2H),2.90(s,6H),3.74(d,J＝10.4Hz,1H),3.99(d,J＝10.4Hz,1H),6.91(s,1H),7.00-7.03(m,1H),7.24(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3) δ＝139.21,137.11,132.84,129.25,126.26(q,1J(C–F)＝277.0Hz),123.16,113.80, 62.24(q,4J(C–F)＝2.1Hz),42.70(q,2J(C–F)＝26.8Hz),41.06(q,3J(C–F)＝1.7Hz), 38.24,25.38(q,4J(C–F)＝1.5Hz),20.91；19F NMR(376MHz,CDCl3)δ＝-60.34(t, J(H–F)＝11.0,3F)；HRMS(ESI-TOF)Calcd for C14H20F3N2O2S+([M+H]+)337.1192. Found 337.1195.
Figure BDA0001720212620000192
2h2,5-bromo-N,N,3-trimethyl-3-(2,2,2-trifluoroethyl)indoline-1-sulfonamide,白色固体:mp 82-83℃.1H NMR(400MHz,CDCl3)δ＝1.47(d,J＝0.9Hz,3H),2.39-2.58(m,2H),2.91(s,6H),3.75(d,J＝10.4Hz,1H),4.00(d,J＝10.4Hz,1H), 7.20(d,J＝2.0Hz,1H),7.24(d,J＝8.6Hz,1H),7.33(dd,J＝2.0,8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.89,139.01,131.67,125.98(q,1J(C–F)＝276.9Hz), 125.87,115.52,115.48,62.15(q,4J(C–F)＝2.1Hz),42.64(q,2J(C–F)＝27.1Hz),41.12 (q,3J(C–F)＝1.7Hz),38.22,25.54(q,4J(C–F)＝1.4Hz)；19F NMR(376MHz,CDCl3)δ＝-60.33(t,J(H–F)＝11.8,3F)；HRMS(ESI-TOF)Calcd for C13H17BrF3N2O2S+ ([M+H]+)401.0141.Found 401.0144.
Figure BDA0001720212620000201
2h3,N,N,3-trimethyl-5-phenyl-3-(2,2,2-trifluoroethyl)indoline-1-sulfonamide,白色固体:mp 93-94℃.1H NMR(400MHz,CDCl3)δ＝1.52(s,3H),2.46-2.67(m,2H), 2.94(s,6H),3.82(d,J＝10.3Hz,1H),4.06(d,J＝10.3Hz,1H),7.30(d,J＝1.4Hz,1H),7.33(dddd,J＝1.2,1.2,7.3,7.3Hz,1H),7.41-7.47(m,4H),7.52-7.54(m,2H)；13C NMR(100MHz,CDCl3)δ＝140.98,140.57,137.53,136.62,128.84,127.78, 127.16,126.85,126.18(q,1J(C–F)＝277.1Hz),121.36,114.13,62.40(q,4J(C–F)＝2.1 Hz),42.79(q,2J(C–F)＝26.9Hz),41.14(q,3J(C–F)＝1.6Hz),38.27,25.53(q,4J(C–F)＝ 1.3Hz)；19F NMR(376MHz,CDCl3)δ＝-60.27(t,J(H–F)＝11.1,3F)；HRMS (ESI-TOF)Calcd for C19H22F3N2O2S+([M+H]+)399.1349.Found 399.1368.
Figure BDA0001720212620000202
2i,1-(3,7-dimethyl-3-(2,2,2-trifluoroethyl)indolin-1-yl)ethan-1-one,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.41(d,J＝0.8Hz,3H),2.26-2.38(m,7H),2.44-2.57 (m,1H),3.85(brd,J＝9.8Hz,1H),4.11(d,J＝11.1Hz,1H),6.94-6.98(m,1H), 7.07-7.12(m,2H)；13C NMR(100MHz,CDCl3)δ＝168.87(br),140.99(br),140.28 (br),130.82,129.63(br),126.35(q,1J(C–F)＝276.9Hz),125.75,118.96(br),62.35 (br),42.21(br),41.55(q,2J(C–F)＝27.0Hz),23.57(br),23.38(br),20.40(br)；19F NMR(376MHz,CDCl3)δ＝-60.41(t,J(H–F)＝11.1,3F)；HRMS(ESI-TOF)Calcd for C14H17F3NO+([M+H]+)272.1257.Found272.1260.
Figure BDA0001720212620000203
2j,4-chloro-1-(ethylsulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物. 1H NMR(400MHz,CDCl3)δ＝1.42(t,J＝7.4Hz,3H),1.62(s,3H),2.66-2.78(m, 1H),2.86-2.98(m,1H),3.13-3.19(m,2H),3.83(d,J＝10.7Hz,1H),4.16(d,J＝ 10.7Hz,1H),6.98(dd,J＝0.8,8.0Hz,1H),7.17(dd,J＝8.1,8.1Hz,1H),7.32(dd, J＝0.8,8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝143.02,131.89,131.01,130.31, 126.09(q,1J(C–F)＝277.0Hz),124.91,111.85,61.31(q,4J(C–F)＝2.3Hz),44.73,42.40 (q,3J(C–F)＝1.8Hz),40.37(q,2J(C–F)＝26.7Hz),24.74(q,4J(C–F)＝1.3Hz),7.69；19F NMR(376MHz,CDCl3)δ＝-60.35(t,J(H–F)＝10.9,3F)；HRMS(ESI-TOF)Calcd for C13H16ClF3NO2S+([M+H]+)342.0537.Found 342.0539.
Figure BDA0001720212620000211
2j',6-chloro-1-(ethylsulfonyl)-3-methyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物. 1H NMR(400MHz,CDCl3)δ＝1.44(t,J＝7.4Hz,3H),1.46(s,3H),2.39-2.59(m, 2H),3.16(q,J＝7.4Hz,2H),3.84(d,J＝10.5Hz,1H),4.06(d,J＝10.5Hz,1H), 7.01(dd,J＝1.6,8.1Hz,1H),7.04(d,J＝7.9Hz,1H),7.39(dd,J＝0.4,1.6Hz,1H)；13CNMR(100MHz,CDCl3)δ＝141.94,135.37,134.80,125.93(q,1J(C–F)＝277.0 Hz),123.86,123.49,113.77,62.12(q,4J(C–F)＝2.1Hz),44.81,42.64(q,2J(C–F)＝27.1 Hz),40.79(q,3J(C–F)＝1.7Hz),25.91(q,4J(C–F)＝1.5Hz),7.73；19F NMR(376MHz, CDCl3)δ＝-60.29(t,J(H–F)＝11.0,3F)；HRMS(ESI-TOF)Calcd for C13H16ClF3NO2S+([M+H]+)342.0537.Found342.0533.
Figure BDA0001720212620000212
2k,5-bromo-1-(ethylsulfonyl)-3,4-dimethyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.42(t,J＝7.4Hz,3H),1.58(s,3H),2.42(s, 3H),2.59(q,J(H–F)＝11.2Hz,2H),3.13(q,J＝7.5Hz,2H),3.72(d,J＝10.6Hz,1H),4.15(d,J＝10.6Hz,1H),7.14(d,J＝8.6Hz,1H),7.43(d,J＝8.6Hz,1H)；13C NMR (100MHz,CDCl3)δ＝140.92,135.00,134.53,133.06,125.90(q,1J(C–F)＝277.2Hz), 120.44,112.46,61.71(q,4J(C–F)＝2.2Hz),44.36,42.31(q,3J(C–F)＝1.7Hz),41.07(q, 2J(C–F)＝26.5Hz),24.94(q,4J(C–F)＝1.3Hz),19.15,7.68；19F NMR(376MHz,CDCl3) δ＝-60.31(t,J(H–F)＝10.8,3F)；HRMS(ESI-TOF)Calcd for C14H18BrF3NO2S+ ([M+H]+)400.0188.Found 400.0189.
Figure BDA0001720212620000221
2k',5-bromo-1-(ethylsulfonyl)-3,6-dimethyl-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.43(t,J＝7.4Hz,3H),1.45(d,J＝0.6Hz,3H), 2.37(s,3H),2.41-2.59(m,2H),3.14(q,J＝7.4Hz,2H),3.81(d,J＝10.5Hz,1H), 4.04(d,J＝10.5Hz,1H),7.257(s,1H),7.265(s,1H)；13C NMR(100MHz,CDCl3)δ＝140.22,138.70,136.54,126.74,125.94(q,1J(C–F)＝276.9Hz),118.36,115.43, 62.09(q,4J(C–F)＝2.1Hz),44.54,42.67(q,2J(C–F)＝27.1Hz),40.84(q,3J(C–F)＝1.7 Hz),25.85(q,4J(C–F)＝1.4Hz),23.35,7.72；19F NMR(376MHz,CDCl3)δ＝-60.31(t, J(H–F)＝11.2,3F)；HRMS(ESI-TOF)Calcd for C14H18BrF3NO2S+([M+H]+)400.0188. Found400.0189.
Figure BDA0001720212620000222
2l,5-bromo-3,4-dimethyl-1-(methylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.59(d,J＝0.8Hz,3H),2.42(s,3H),2.60(q, J(H–F)＝11.0Hz,2H),2.92(s,3H),3.64(d,J＝10.6Hz,1H),4.10(d,J＝10.6Hz, 1H),7.18(d,J＝8.6Hz,1H),7.46(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3) δ＝140.66,135.15,134.68,133.22,125.86(q,1J(C–F)＝277.1Hz),120.92,112.43, 61.66(q,4J(C–F)＝2.2Hz),42.20(q,3J(C–F)＝1.7Hz),41.05(q,2J(C–F)＝26.6Hz), 34.72,24.99(q,4J(C–F)＝1.3Hz),19.14；19F NMR(376MHz,CDCl3)δ＝-60.28(t, J(H–F)＝10.8,3F)；HRMS(ESI-TOF)Calcd for C13H16BrF3NO2S+([M+H]+)386.0032. Found 386.0031.
Figure BDA0001720212620000223
2l',5-bromo-3,6-dimethyl-1-(methylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,无色油状物.1H NMR(400MHz,CDCl3)δ＝1.46(s,3H),2.39(s,3H),2.42-2.60(m,2H), 2.93(s,3H),3.76(d,J＝10.5Hz,1H),3.97(d,J＝10.5Hz,1H),7.28(s,1H),7.31(s,1H)；13C NMR(100MHz,CDCl3)δ＝139.93,138.94,136.68,126.85,125.91(q, 1J(C–F)＝277.0Hz),118.88,115.48,62.10(q,4J(C–F)＝2.0Hz),42.63(q,2J(C–F)＝27.1 Hz),40.76(q,3J(C–F)＝1.7Hz),34.90,25.86(q,4J(C–F)＝1.4Hz),23.39；19F NMR (376MHz,CDCl3)δ＝-60.27(t,J(H–F)＝11.2,3F)；HRMS(ESI-TOF)Calcd for C13H16BrF3NO2S+([M+H]+)386.0032.Found 386.0030.
Figure BDA0001720212620000231
4a,4-methyl-2-(phenylsulfonyl)-4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline, 白色固体:mp 133-134℃.1H NMR(400MHz,CDCl3)δ＝1.47(d,J＝1.0Hz,3H), 2.46-2.71(m,2H),2.79(d,J＝12.0Hz,1H),3.62(d,J＝12.0Hz,1H),4.03(d,J＝ 14.8Hz,1H),4.46(d,J＝14.8Hz,1H),7.01-7.04(m,1H),7.16-7.24(m,2H),7.31(d,J＝7.6Hz,1H),7.56-7.66(m,3H),7.86-7.89(m,2H)；13C NMR(100MHz, CDCl3)δ＝139.75,135.83,133.12,130.51,129.26,127.77,127.36,127.08,126.53, 126.39,126.26(q,1J(C–F)＝277.1Hz),53.64(q,4J(C–F)＝1.6Hz),48.27,42.67(q, 2J(C–F)＝26.6Hz),36.52(q,3J(C–F)＝1.4Hz),24.45(q,4J(C–F)＝1.2Hz)；19F NMR (376MHz,CDCl3)δ＝-59.21(t,J(H–F)＝11.6,3F)；HRMS(ESI-TOF)Calcd for C18H19F3NO2S+([M+H]+)370.1083.Found 370.1086.
Figure BDA0001720212620000232
4b,4-methyl-2-(o-tolylsulfonyl)-4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline, 白色固体:mp 127-128℃.1H NMR(400MHz,CDCl3)δ＝1.41(d,J＝1.1Hz,3H), 2.33-2.55(m,2H),2.67(s,3H),3.02(d,J＝12.5Hz,1H),3.63(dd,J＝0.9,12.5Hz, 1H),4.29(d,J＝15.1Hz,1H),4.56(d,J＝15.0Hz,1H),7.05-7.07(m,1H), 7.18-7.25(m,2H),7.29-7.39(m,3H),7.49(ddd,J＝1.4,7.5,7.5Hz,1H),7.98(dd,J ＝1.3,7.9Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.02,138.09,135.27,133.25, 132.97,130.78,130.43,127.44,127.07,126.66,126.37,126.31,126.06(q,1J(C–F)＝ 277.2Hz),53.08(q,4J(C–F)＝1.7Hz),47.43,42.41(q,2J(C–F)＝26.6Hz),36.46(q, 3J(C–F)＝1.4Hz),24.28(q,4J(C–F)＝1.3Hz),20.88；19F NMR(376MHz,CDCl3)δ＝ -59.50(t,J(H–F)＝11.3,3F)；HRMS(ESI-TOF)Calcd for C19H21F3NO2S+([M+H]+) 384.1240.Found 384.1253.
Figure BDA0001720212620000241
4c,4,6-dimethyl-2-(o-tolylsulfonyl)-4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline, 无色油状物.1H NMR(400MHz,CDCl3)δ＝1.39(d,J＝0.6Hz,3H),2.31(s,3H), 2.35-2.51(m,2H),2.66(s,3H),3.00(d,J＝12.5Hz,1H),3.61(d,J＝12.4Hz,1H), 4.24(d,J＝14.8Hz,1H),4.50(d,J＝14.8Hz,1H),6.94(d,J＝7.9Hz,1H),7.01(dd, J＝0.8,7.9Hz,1H),7.09(s,1H),7.31-7.37(m,2H),7.48(ddd,J＝1.2,7.5,7.5Hz, 1H),7.97(dd,J＝1.1,8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.00,138.10, 137.10,135.38,133.22,132.96,130.43,128.00,127.74,126.73,126.55,126.30, 126.13(q,1J(C–F)＝277.3Hz),53.08(q,4J(C–F)＝1.7Hz),47.31,42.39(q,2J(C–F)＝ 26.5Hz),36.43(q,3J(C–F)＝1.4Hz),24.26(q,4J(C–F)＝1.1Hz),21.26,20.87；19F NMR(376MHz,CDCl3)δ＝-59.48(t,J(H–F)＝11.4,3F)；HRMS(ESI-TOF)Calcd for C20H23F3NO2S+([M+H]+)398.1396.Found 398.1394.
Figure BDA0001720212620000242
4d,6-chloro-4-methyl-2-(o-tolylsulfonyl)-4-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline, 无色油状物.1H NMR(400MHz,CDCl3)δ＝1.40(d,J＝0.6Hz,3H),2.31-2.54(m, 2H),2.66(s,3H),3.00(d,J＝12.6Hz,1H),3.62(d,J＝12.6Hz,1H),4.24(d,J＝ 15.2Hz,1H),4.51(d,J＝15.2Hz,1H),7.01(d,J＝8.3Hz,1H),7.18(dd,J＝2.1, 8.3Hz,1H),7.28(d,J＝2.0Hz,1H),7.33-7.39(m,2H),7.50(ddd,J＝1.3,7.5,7.5Hz,1H),7.97(dd,J＝1.1,7.9Hz,1H)；13C NMR(100MHz,CDCl3)δ＝141.95, 138.06,135.19,133.37,133.18,133.03,130.41,129.34,128.10,127.45,126.58, 126.39,125.89(q,1J(C–F)＝277.2Hz),52.80(q,4J(C–F)＝1.7Hz),47.05,42.81(q, 2J(C–F)＝26.8Hz),36.65(q,3J(C–F)＝1.4Hz),24.29(q,4J(C–F)＝1.2Hz),20.86；19F NMR(376MHz,CDCl3)δ＝-59.45(t,J(H–F)＝11.6,3F)；HRMS(ESI-TOF)Calcd for C19H20ClF3NO2S+([M+H]+)418.0850.Found418.0832.
Figure BDA0001720212620000251
6,5-bromo-1-(methylsulfonyl)-3-(2,2,2-trifluoroethyl)indoline,白色固体:mp 100-101℃.1H NMR(400MHz,CDCl3)δ＝2.31-2.45(m,1H),2.56-2.69(m,1H), 2.91(s,3H),3.67-3.74(m,1H),3.77(dd,J＝7.6,10.5Hz,1H),4.20(dd,J＝9.1,9.9 Hz,1H),7.31(d,J＝8.6Hz,1H),7.33(s,1H),7.39(ddd,J＝0.5,1.9,8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.86,134.08,132.17,127.67,125.94(q,1J(C–F)＝ 275.8Hz),116.59,115.25,56.07(q,4J(C–F)＝1.4Hz),38.26(q,2J(C–F)＝28.3Hz), 35.05,34.45(q,3J(C–F)＝2.8Hz)；19FNMR(376MHz,CDCl3)δ＝-64.64(t,J(H–F)＝ 10.5,3F)；HRMS(ESI-TOF)Calcd forC11H12BrF3NO2S+([M+H]+)357.9719.Found 357.9722.
Figure BDA0001720212620000252
7,(3,3,3-trifluoroprop-1-ene-1,1-diyl)dibenzene,无色油状物.1H NMR(400MHz, CDCl3)δ＝6.13(q,J(H–F)＝8.2Hz,1H),7.23-7.26(m,4H),7.30-7.41(m,6H)；13CNMR(100MHz,CDCl3)δ＝152.45(q,3J(C–F)＝5.6Hz),140.12,137.25,129.39, 129.10(q,4J(C–F)＝1.8Hz),128.48,128.47,128.03,127.96,123.08(q,1J(C–F)＝269.0 Hz),115.44(q,2J(C–F)＝33.6Hz)；19F NMR(376MHz,CDCl3)δ＝-55.60(d,J(H–F)＝ 8.3,3F)；HRMS(ESI-TOF)Calcd for C15H12F3 +([M+H]+)249.0886.Found 249.0887.
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (1)

1.一种含CF3的吲哚啉的合成方法，其特征在于：
包括开发一个非活化烯烃的无金属三氟甲基化/芳基化反应，通过该串联反应可以从烯丙基胺衍生物出发合成含CF3的吲哚啉；
所述合成方法包括以下步骤：
向放有磁力搅拌子的35 mL管状耐压管中依次加入312 mg，2.0 mmol的CF3SO2Na、405mg，1.5 mmol的K2S2O8、和189 mg，1.0 mmol的N-(2-甲基烯丙基)乙酰苯胺，然后加入3.0 mL溶剂DMSO反应混合液在50°C搅拌24 h后用2.0 mL饱和Na2S2O3溶液和15.0 mL水淬灭，使用10.0 mL的CH2Cl2萃取3次，然后蒸除有机溶剂，用硅胶进行柱层析，得到浅黄色油状物产物1-(3-甲基-3-(2,2,2-三氟乙基)吲哚啉-1-基)乙基-1-酮。
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