CN108383875B - 一种银催化的3-膦酰甲基吲哚啉及制备方法 - Google Patents
一种银催化的3-膦酰甲基吲哚啉及制备方法 Download PDFInfo
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- CN108383875B CN108383875B CN201810240791.3A CN201810240791A CN108383875B CN 108383875 B CN108383875 B CN 108383875B CN 201810240791 A CN201810240791 A CN 201810240791A CN 108383875 B CN108383875 B CN 108383875B
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
Abstract
本发明属于化学材料技术领域，公开了一种银催化的3‑膦酰甲基吲哚啉及制备方法，将N‑烯丙基作为新型自由基受体基团；通过新型自由基受体基团引发膦酰化‑芳基化反应，从而一步合成3‑膦酰甲基吲哚啉。本发明反应中非活化的碳碳双键作为新型自由基受体官能团，而H‑膦氧化物作为自由基前体；本发明显著的优点包括：操作简单、成本低、底物范围广、exo/endo选择性极好，和反应可轻易地放大以应用于工业生产。
Description
技术领域
本发明属于化学材料技术领域，尤其涉及一种银催化的3-膦酰甲基吲哚啉及制备方法。
背景技术
目前，业内常用的现有技术是这样的：
磷是生命的一个基本元素，有机磷化合物则在制药、农用化学品、材料科学、有机合成和配位化学领域都有广泛的应用。因此，人们投入大量努力将含磷官能团引入到各种有机体系中。其中，活化烯烃的膦酰化双官能团化反应在过去的十多年里已被证明是构建官能团化含磷分子的最有效策略之一。然而，非活化烯烃的膦酰化双官能团化反应不久前才实现。
吲哚骨架，包括氧化吲哚和吲哚啉，广泛存在于天然生物碱和临床药物分子中。将几种生物活性片段结合在同一分子中是药学研究和新药合成的一个主要基础，而组合吲哚和膦酰基团得到的活性分子则被大量用于抗癌、PET成像、抗艾滋、抗病毒、抗结核、精神病治疗、线粒体靶向治疗等领域。
这些成功持续激励化学工作者合成更多的含磷吲哚衍生物。例如，3-膦酰甲基氧化吲哚的合成已经被广泛研究。它们既可以通过衍生化靛红或简单氧化吲哚分子得到，也可以通过近年发展的N-芳基丙烯酰胺(反应式1a)或丙烯酰磺胺作为活化烯烃的芳化膦酰化反应合成。另一方面，Yang等人开发了一个2-烯丙基苯胺作为非活化烯烃的胺化膦酰化反应，通过该反应可以合成2-膦酰甲基-N-磺酰基吲哚啉(反应式1b)。然而，到目前为止3-膦酰烷基吲哚啉仍只能在激烈或剧毒的条件下通过复杂的实验步骤得到(反应式1c)。从易得的原料出发直接合成该目标产物尚未实现，亟待研究。
发明内容
针对现有技术存在的问题，本发明提供了一种银催化的3-膦酰甲基吲哚啉及制备方法，还涉及银催化的N-烯丙化苯胺的自由基环化反应方法。本发明的发明人长期从事生物活性分子的合成工作。受最近非活化烯烃双官能团化反应进展的启发，分析如果将N-烯丙基作为新型自由基受体基团，可能可以引发膦酰化-芳基化反应序列，从而一步合成3-膦酰甲基吲哚啉。成功实现了该合成设想，并开发了一个操作简单、底物范围广、exo选择、原料易得的3-膦酰甲基吲哚啉的便捷合成方法。此外，该方法可以放大到克级反应。
本发明是这样实现的，一种银催化的3-膦酰甲基吲哚啉制备方法，所述银催化的3-膦酰甲基吲哚啉制备方法包括以下步骤：
步骤一，将N-烯丙基作为新型自由基受体基团；
步骤二，通过新型自由基受体基团引发膦酰化-芳基化反应序列，一步合成3-膦酰甲基吲哚啉。
进一步，所述银催化的3-膦酰甲基吲哚啉制备方法的化学反应式为：
进一步，新型自由基受体基团引发膦酰化-芳基化反应方法包括：
开始时，H-膦氧化物与硝酸银反应，转化为膦酰自由基，所述自由基加成到烯丙基双键上形成新的C-P键并生成自由基中间体A；接着苯环对分子内的自由基进行捕获，生成关环的中间体B；随后从B到Ag+的单电子转移SET释放出吲哚啉产物3a1，以及Ag(0)和一个质子；Ag(0)被BPO氧化为Ag+，完成催化循环。
进一步，新型自由基受体基团引发膦酰化-芳基化反应的分子反应式为：
本发明的另一目的在于提供一种所述银催化的3-膦酰甲基吲哚啉制备方法制备的的3-膦酰烷基吲哚啉。
本发明的优点及积极效果为：
本发明通过银催化的N-烯丙化苯胺的自由基环化反应和一步合成3-膦酰烷基吲哚啉的方法。该反应中非活化的碳碳双键作为新型自由基受体官能团，而H-膦氧化物作为自由基前体。本发明显著的优点包括：操作简单、成本低、底物范围广、exo/endo选择性极好，和反应可轻易地放大以应用于工业生产。
本发明非活化的碳碳双键和H-膦氧化物分别充当自由基受体官能团和自由基前体。该反应操作简单，底物范围广，呈现exo选择性，且可以放大到克级以上。
附图说明
图1是本发明实施提供的银催化的3-膦酰甲基吲哚啉制备方法流程图。
图2是本发明实施提供的TEMPO实验中有机相用GC-MS进行检测曲线图。
图3是本发明实施提供的BHT实验中TEMPO实验中有机相用GC-MS进行检测曲线图
图4是本发明实施提供的31P NMR实验中蒸除有机溶剂后的残留物溶解在CDCl3中进行31P NMR测试图。
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。
下面结合附图对本发明的应用原理作进一步描述。
如图1所示，本发明实施例提供的银催化的3-膦酰甲基吲哚啉制备方法，包括以下步骤：
S101，将N-烯丙基作为新型自由基受体基团；
S102，通过新型自由基受体基团引发膦酰化-芳基化反应，从而一步合成3-膦酰甲基吲哚啉。
下面结合表1具体分析对本发明作进一步描述。
表1.反应条件优化a
a反应条件：1a(1.0mmol)，2a(2.0mmol)，催化剂(0.2mmol)，氧化剂(2.0mmol)，溶剂(5.0mL)，80℃，氩气保护。b分离产率。c1a回收。d5.0-6.0mol/L的癸烷溶液。e延长反应时间到12h。f加入K2CO3(1.0mmol)。g该反应使用5.3mmol的1a进行。
本发明的分析从N-(2-甲基烯丙基)-N-苯基乙酰胺1a的自由基环化反应开始(表1)。1a由乙酰苯胺和2-甲基烯丙基反应得到。当1a在80℃的乙腈中与2当量的亚磷酸二甲酯2a和20mol％的AgNO3反应时，膦酰化吲哚啉3a1仅以较低的产率生成(序号1)。氧气气氛不能使产率增加(未列出)。为了提高反应效率，本发明尝试加入氧化性引发剂。发现加入2当量无水过氧化叔丁醇(TBHP，序号2)时产率变得更低，而使用二叔丁基过氧化物(DTBP，序号3)或偶氮二异丁腈(AIBN，序号4)作为氧化剂时，该串联反应在6h内完成，且目标产物3a1以中等产率生成。接着本发明发现，使用过氧化苯甲酰(BPO，序号5)的反应3h便以64％的产率生成3a1，而延长反应时间并不能进一步提高产率。使用K2S2O8(序号6)，Oxone，PhI(OAc)2，或I2O5(未列出)作为氧化剂则导致底物1a迅速分解或聚合。使用AgNO3和BPO体系，当反应在其它溶剂中进行时，底物也严重损耗，吲哚啉3a1仅以0-24％的产率生成。这些被测试的不适宜溶剂包括1,2-二氯乙烷(DCE，序号7)，四氢呋喃(THF，序号8)，N,N-二甲基甲酰胺(DMF，序号9)，二甲亚砜(DMSO，序号10)，CH2Cl2，甲苯，MeNO2和丙酮(未列出)。银催化剂至关重要，去掉它时3a1仅有痕迹量生成(序号11)。AgOAc(entry12)和Ag2CO3(entry13)也可以作为该反应的高效催化剂，使用它们得到和AgNO3类似的结果。不过，Ag2O催化的反应进行地很慢，12h后也才以48％的产率生成产物3a1(entry14)。使用其它经常用于自由基反应的金属催化剂时，如CuI(entry15)，Cu(OAc)2和FeCl3(entry16)，没有目标产物生成。最后，通过仔细筛选各种类型的大量添加剂，本发明发现加入1当量的K2CO3可是使产率提高到73％，反应再现性也更好(序号17)。增加催化剂、膦氧化物或氧化剂的用量，以及升高反应温度到110℃，都不能进一步提高产率。50℃时，该芳化膦酰化反应不能发生，而降低催化剂或两个试剂的用量，都导致产率降低(未列出)。值得注意的是，这个3-膦酰甲基吲哚啉合成实用性强，因为它可以轻易地放大到克级规模而活性不降低(注释g)。
下面结合表2对本发明作进一步描述。
表2.N-芳基和烯丙基的范围a,b
a反应条件：1b-h(2.0mmol)，2a(4.0mmol)，AgNO3(0.4mmol)，BPO(4.0mmol)，K2CO3(2.0mmol)，MeCN(10.0mL)，氩气保护，80℃，3h。b分离产率。
得到最优反应条件后，一系列3-膦酰烷基吲哚啉可以从带有不同N-芳基基团的烯丙基化酰基苯胺一步合成得到(表2)。例如，N-(2-甲基烯丙基)-N-苯基丙酰胺与亚磷酸二甲酯2a反应生成对应的膦氧化物3b，产率68％。在N-芳基对位带有甲基、溴原子、或氯原子的N-(2-甲基烯丙基)酰基苯胺也可以顺利地反应，以中等到较高产率生成5-位取代的吲哚啉3c1-3。邻位取代的酰基苯胺是挑战性的底物，因为对应的产物7-甲基和7-氯吲哚啉3d1,2仅以较低的产率生成。类似的位阻效应也存在于由2,4-二甲基苯胺、2-氯-4-溴苯胺、和5-氯-2-溴苯胺合成得到的烯丙化酰基苯胺的反应中，对应的二取代产物3e1-3仅以很低到中等产率生成。N-芳基环上有3-氯基团时，存在区域选择性问题，产物4-氯吲哚啉3f和它的区域异构体6-氯吲哚啉3f'分别以45％和36％的产率生成。值得注意的是，从4-氨基吡啶合成得到的底物，也能顺利与亚磷酸二甲酯2a反应，目标产物3-膦酰甲基杂环化合物3g以58％的产率生成。使用烯丙基溴代替2-甲基烯丙基溴与乙酰苯胺反应得到的N-烯丙基乙酰苯胺，仅以5-exo-trig的方式进行反应，对应的吲哚啉3h以47％的产率生成，另外还有9％产率的膦酰化吲哚3h'生成。3h'可能由最初生成的吲哚啉3h氧化得到。上面所有反应中(包括涉及3h和3h'的反应)，exo/endo选择性都极好，没有检测到形式上的6-endo-trig产物。
下面结合表3对本发明作进一步描述。
表3.N-PGs和H-膦氧化物的范围a,b
a反应条件：1(2.0mmol)，2a(4.0mmol)，AgNO3(0.4mmol)，BPO(4.0mmol)，K2CO3(2.0mmol)，MeCN(10.0mL)，氩气保护，80℃，3h。b分离产率。
接下来本发明分析了吸电子N-保护基团(PG)的范围(表3)。本发明发现，乙酰基保护的带有电中性、富电子和贫电子N-芳基基团的N-(2-甲基烯丙基)苯胺都能顺利地和亚磷酸二甲酯2a反应，目标产物3-膦酰烷基吲哚啉3a1-3以56-83％的产率生成。辛酰基保护的吲哚啉3i也可以高产率地生成。对一系列的磺酰基保护基的评估表明，甲磺酰基和乙磺酰基等烷基磺酰基，以及包括苯磺酰基、对甲苯磺酰基、邻甲苯磺酰基、和对氯苯磺酰基在内的芳基磺酰基，在该反应中都可以被兼容，对应的产物3j-o以37％-91％的产率生成。其中，5-苯基-1-甲磺酰基吲哚啉3j2的产率超过90％，而4-溴苯磺酰基保护的吲哚啉3o产率较低。被N,N-二甲基氨磺酰基保护的烯丙化4-氨基吡啶也是一个高活性底物，对应的氨磺酰吲哚啉3p以65％的产率生成。随后，本发明将该自由基环化反应拓展到其它H-膦氧化物。亚磷酸二乙酯2a与带有不同N-保护基和不同电性N-芳基基团的各种2-甲基烯丙基苯胺顺利反应，中等到高产率地生成目标产物3q1-4。二苯基磷氧也可以作为磷源反应，中等产率生成吲哚啉3r1,2。不幸的是，苯甲酰基、2,4-二氯苯甲酰基，或噻吩-2-磺酰基保护的烯丙基苯胺的反应体系过于混乱。
本发明开展了一些对照实验用于探明反应机理(反应式2a)。和预期一样，在加入2当量的2,2,6,6-四甲基哌啶氧化物(TEMPO)或1.2当量的2,6-二叔丁基-4-甲基苯酚(BHT)作为自由基捕获剂后，标准条件下的模型反应被完全抑制。
此外，膦酰基-TEMPO和膦酰基-BHT加合物，以及苯基-BHT加合物，都在气相色谱-质谱联用分析法(GC-MS)对反应混合液的检测中被发现。基于以上发现和前期报道，本发明提出了一个可能的反应机理(反应式2b)。一开始，H-膦氧化物2a与硝酸银反应，转化为膦酰自由基，该自由基加成到烯丙基双键上形成一个新的C-P键并生成自由基中间体A。紧接着苯环对分子内的自由基进行捕获，生成关环的中间体B。随后从B到Ag+的单电子转移(SET)释放出吲哚啉产物3a1，以及Ag(0)和一个质子。Ag(0)被BPO氧化为Ag+，从而完成催化循环。
本发明开发了一个银催化的N-烯丙化苯胺的自由基环化反应和一步合成3-膦酰烷基吲哚啉的方法。该反应中非活化的碳碳双键作为新型自由基受体官能团，而H-膦氧化物作为自由基前体。本方法显著的优点包括：操作简单、成本低、底物范围广、exo/endo选择性极好，和反应可轻易地放大以应用于工业生产。
下面结合具体分析对本发明作进一步描述。
商业购买的化学试剂均未经特殊处理直接使用。反应过程通过薄层色谱(TLC)在F254玻璃硅胶板上进行监测。产物通过加压柱层析使用300-400目硅胶进行分离提纯。1H、13C、DEPT、31P、和2D NMR使用布鲁克AscendTM 400核磁共振仪在25℃进行测试，TMS作为内标。高分辨质谱(HRMS)在布鲁克microTOF II Focus质谱仪(ESI)上进行。使用安捷伦7890A/5975C气相色谱质谱联用仪(GC-MS)对部分反应混合液进行分析。
II.3-膦酰甲基吲哚啉的合成
合成3-膦酰甲基吲哚啉的方法(以3a1为例)：
在装有磁力搅拌子的35-mL耐压管中，加入亚磷酸二甲酯2a(440mg，4.0mmol)、过氧化苯甲酰(BPO，969mg，4.0mmol)，K2CO3(276mg，2.0mmol)，AgNO3(68mg，0.4mmol)，和底物1a(379mg，2.0mmol)，最后加入MeCN(10.0mL)。混合液在氩气保护下80℃反应3h，然后用饱和Na2S2O3(5.0mL)和水(30.0mL)淬灭反应。得到的混合液用CH2Cl2(20.0mL×3)萃取，蒸干有机溶剂得到的残留物用硅胶为固定相、乙酸乙酯为展开剂进行柱层析得到浅黄色油状物3a1(434mg，73％产率)。
产物的光谱表征：
3a1,dimethyl((1-acetyl-3-methylindolin-3-yl)methyl)phosphonate,paleyellow oil.1H NMR(400MHz,CDCl3)δ＝1.52(s,3H),2.06-2.24(m,2H),2.26(s,3H),3.60(d,J＝10.9Hz,3H),3.70(d,J＝11.0Hz,3H),3.81(d,J＝10.8Hz,1H),4.40(d,J＝10.8Hz,1H),7.06(ddd,J＝0.9,7.4,7.4Hz,1H),7.14(dd,J＝0.8,7.4Hz,1H),7.21-7.25(m,1H),8.19(d,J＝8.1Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.99,141.42,138.83(d,3J(C–P)＝14.4Hz),128.34,123.88,121.92,117.13,60.95(d,3J(C–P)＝2.0Hz),52.35(d,2J(C–P)＝6.6Hz),52.08(d,2J(C–P)＝6.8Hz),41.12(d,2J(C–P)＝3.2Hz),35.89(d,1J(C–P)＝136.6Hz),27.50(d,3J(C–P)＝6.7Hz),24.24；31P NMR(162MHz,CDCl3)δ＝30.03；HRMS(ESI-TOF)Calcdfor C14H21NO4P+([M+H]+)298.1203.Found 298.1205.
3a2,dimethyl((1-acetyl-3,5-dimethylindolin-3-yl)methyl)phosphonate,pale yellow oil.1H NMR(400MHz,CDCl3)δ＝1.50(s,3H),2.05-2.23(m,2H),2.24(s,3H),2.32(s,3H),3.61(d,J＝10.9Hz,3H),3.71(d,J＝11.0Hz,3H),3.79(d,J＝10.8Hz,1H),4.38(d,J＝10.8Hz,1H),6.93(s,1H),7.03(dd,J＝0.9,8.2Hz,1H),8.05(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.69,139.12,139.02(d,3J(C–P)＝14.8Hz),133.54,128.83,122.46,116.92,61.14(d,3J(C–P)＝2.0Hz),52.36(d,2J(C–P)＝6.6Hz),52.09(d,2J(C–P)＝6.8Hz),41.10(d,2J(C–P)＝3.2Hz),35.87(d,1J(C–P)＝136.4Hz),27.34(d,3J(C–P)＝6.3Hz),24.11,21.09；31P NMR(162MHz,CDCl3)δ＝30.17；HRMS(ESI-TOF)Calcd for C15H23NO4P+([M+H]+)312.1359.Found 312.1358.
3a3,dimethyl((1-acetyl-5-bromo-3-methylindolin-3-yl)methyl)phosphonate,pale yellow oil.1H NMR(400MHz,CDCl3)δ＝1.51(s,3H),2.04-2.20(m,2H),2.24(s,3H),3.61(d,J＝11.0Hz,3H),3.72(d,J＝11.0Hz,3H),3.81(d,J＝10.8Hz,1H),4.42(d,J＝10.8Hz,1H),7.23(d,J＝2.0Hz,1H),7.33(dd,J＝2.0,8.6Hz,1H),8.08(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝169.04,141.06(d,3J(C–P)＝14.4Hz),140.65,131.25,125.29,118.67,116.10,61.06(d,3J(C–P)＝2.1Hz),52.45(d,2J(C–P)＝6.7Hz),52.17(d,2J(C–P)＝6.8Hz),41.24(d,2J(C–P)＝3.0Hz),35.83(d,1J(C–P)＝137.3Hz),27.46(d,3J(C–P)＝6.7Hz),24.19；31P NMR(162MHz,CDCl3)δ＝29.40；HRMS(ESI-TOF)Calcd for C14H20BrNO4P+([M+H]+)376.0308.Found 376.0310.
3b,dimethyl((3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,paleyellow oil.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.4Hz,3H),1.51(s,3H),2.05-2.22(m,2H),2.41-2.58(m,2H),3.59(d,J＝10.9Hz,3H),3.70(d,J＝10.9Hz,3H),3.78(d,J＝10.8Hz,1H),4.40(d,J＝10.8Hz,1H),7.05(ddd,J＝0.9,7.5,7.4Hz,1H),7.13(d,J＝7.2Hz,1H),7.21-7.25(m,1H),8.22(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.34,141.70,138.78(d,3J(C–P)＝14.5Hz),128.41,123.74,121.87,117.16,60.04(d,3J(C–P)＝1.2Hz),52.36(d,2J(C–P)＝6.6Hz),52.09(d,2J(C–P)＝6.8Hz),41.18(d,2J(C–P)＝2.7Hz),35.93(d,1J(C–P)＝136.5Hz),29.23,27.42(d,3J(C–P)＝6.4Hz),8.70；31P NMR(162MHz,CDCl3)δ＝30.08；HRMS(ESI-TOF)Calcd for C15H23NO4P+([M+H]+)312.1359.Found 312.1375.
3c1,dimethyl((3,5-dimethyl-1-propionylindolin-3-yl)methyl)phosphonate,white solid:mp 90-91℃.1H NMR(400MHz,CDCl3)δ＝1.22(t,J＝7.4Hz,3H),1.50(s,3H),2.03-2.21(m,2H),2.32(s,3H),2.39-2.57(m,2H),3.61(d,J＝10.9Hz,3H),3.71(d,J＝11.0Hz,3H),3.77(d,J＝10.8Hz,1H),4.38(d,J＝10.8Hz,1H),6.92(s,1H),7.03(d,J＝8.2Hz,1H),8.09(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.00,139.39,138.96(d,3J(C–P)＝15.2Hz),133.36,128.88,122.42,116.90,60.20(d,3J(C–P)＝1.7Hz),52.34(d,2J(C–P)＝6.5Hz),52.06(d,2J(C–P)＝6.8Hz),41.14(d,2J(C–P)＝3.0Hz),35.87(d,1J(C–P)＝136.1Hz),29.12,27.25(d,3J(C–P)＝5.8Hz),21.10,8.73；31P NMR(162MHz,CDCl3)δ＝30.20；HRMS(ESI-TOF)Calcd for C16H25NO4P+([M+H]+)326.1516.Found 326.1514.
3c2,dimethyl((5-bromo-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,white solid:mp 98-99℃.1H NMR(400MHz,CDCl3)δ＝1.22(t,J＝7.4Hz,3H),1.51(s,3H),2.03-2.19(m,2H),2.38-2.57(m,2H),3.61(d,J＝10.9Hz,3H),3.72(d,J＝11.0Hz,3H),3.79(d,J＝10.8Hz,1H),4.42(d,J＝10.8Hz,1H),7.23(d,J＝1.8Hz,1H),7.34(dd,J＝2.1,8.6Hz,1H),8.12(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.40,140.95(d,3J(C–P)＝16.2Hz),140.87,131.25,125.25,118.59,115.91,60.11(d,3J(C–P)＝1.6Hz),52.43(d,2J(C–P)＝6.6Hz),52.15(d,2J(C–P)＝6.8Hz),41.24(d,2J(C–P)＝2.8Hz),35.79(d,1J(C–P)＝137.3Hz),29.15,27.38(d,3J(C–P)＝6.5Hz),8.59；31P NMR(162MHz,CDCl3)δ＝29.42；HRMS(ESI-TOF)Calcd for C15H22BrNO4P+([M+H]+)390.0464.Found 390.0446.
3c3,dimethyl((5-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,white solid:mp 106-107℃.1H NMR(400MHz,CDCl3)δ＝1.22(t,J＝7.4Hz,3H),1.51(s,3H),2.03-2.19(m,2H),2.39-2.57(m,2H),3.61(d,J＝10.9Hz,3H),3.72(d,J＝11.0Hz,3H),3.79(d,J＝10.8Hz,1H),4.43(d,J＝10.8Hz,1H),7.08(d,J＝1.8Hz,1H),7.19(dd,J＝2.2,8.6Hz,1H),8.16(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.33,140.61(d,3J(C–P)＝14.6Hz),140.39,128.49,128.33,122.34,118.13,60.18(d,3J(C–P)＝1.6Hz),52.42(d,2J(C–P)＝6.6Hz),52.14(d,2J(C–P)＝6.8Hz),41.26(d,2J(C–P)＝2.9Hz),35.78(d,1J(C–P)＝137.3Hz),29.12,27.34(d,3J(C–P)＝6.6Hz),8.61；31P NMR(162MHz,CDCl3)δ＝29.44；HRMS(ESI-TOF)Calcd for C15H22ClNO4P+([M+H]+)346.0969.Found 346.0972.
3d1,dimethyl((3,7-dimethyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.26(t,J＝7.5Hz,3H),1.46(s,3H),1.93-2.15(m,2H),2.26(s,3H),2.51-2.67(m,2H),3.66(d,J＝10.9Hz,3H),3.73(d,J＝11.0Hz,3H),3.80(d,J＝11.0Hz,1H),4.40(d,J＝10.8Hz,1H),6.95-6.99(m,1H),7.04-7.08(m,2H)；13C NMR(100MHz,CDCl3)δ＝172.85(br),142.26(d,3J(C–P)＝16.7Hz),140.53,130.47,129.43(br),125.41,118.80,61.76(br),52.31(d,2J(C–P)＝6.5Hz),52.15(d,2J(C–P)＝6.9Hz),42.45(d,2J(C–P)＝2.9Hz),33.84(d,1J(C–P)＝135.6Hz),29.18(br),24.29(d,3J(C–P)＝3.4Hz),20.51,9.91；31P NMR(162MHz,CDCl3)δ＝30.39；HRMS(ESI-TOF)Calcd forC16H25NO4P+([M+H]+)326.1516.Found 326.1531.
3d2,dimethyl((7-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.26(t,J＝7.4Hz,3H),1.47(s,3H),1.94-2.15(m,2H),2.52-2.67(m,2H),3.68(d,J＝10.9Hz,3H),3.72(d,J＝11.0Hz,3H),3.87(d,J＝11.1Hz,1H),4.40(d,J＝11.1Hz,1H),7.07(s,1H),7.08(d,J＝1.4Hz,1H),7.23-7.25(m,1H)；13C NMR(100MHz,CDCl3)δ＝173.21,144.97(d,3J(C–P)＝16.2Hz),139.48,129.69,126.29,124.73,120.31,62.36(d,3J(C–P)＝3.4Hz),52.35(d,2J(C–P)＝6.6Hz),52.24(d,2J(C–P)＝6.9Hz),43.01(d,2J(C–P)＝2.8Hz),33.81(d,1J(C–P)＝137.0Hz),28.95,24.32(d,3J(C–P)＝3.6Hz),9.79；31P NMR(162MHz,CDCl3)δ＝29.82；HRMS(ESI-TOF)Calcd forC15H22ClNO4P+([M+H]+)346.0969.Found 346.0973.
3e1,dimethyl((3,5,7-trimethyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.25(t,J＝7.4Hz,3H),1.45(s,3H),1.91-2.14(m,2H),2.23(s,3H),2.30(s,3H),2.49-2.65(m,2H),3.67(d,J＝10.9Hz,3H),3.73(d,J＝10.9Hz,3H),3.78(d,J＝11.0Hz,1H),4.37(d,J＝11.0Hz,1H),6.77(s,1H),6.88(s,1H)；13C NMR(100MHz,CDCl3)δ＝172.75(br),142.40(brd,3J(C–P)＝17.0Hz),138.17,135.12,131.01,129.03(br),119.48,61.92(br),52.28(d,2J(C–P)＝6.5Hz),52.13(d,2J(C–P)＝6.9Hz),42.38(d,2J(C–P)＝2.8Hz),33.77(d,1J(C–P)＝135.4Hz),29.09(br),24.15(d,3J(C–P)＝3.1Hz),21.06,20.37,9.93；31P NMR(162MHz,CDCl3)δ＝30.50；HRMS(ESI-TOF)Calcd for C17H27NO4P+([M+H]+)340.1672.Found 340.1672.
3e2,dimethyl((5-bromo-7-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,colorlessoil.1H NMR(400MHz,CDCl3)δ＝1.25(t,J＝7.4Hz,3H),1.47(s,3H),1.92-2.12(m,2H),2.49-2.65(m,2H),3.68(d,J＝11.0Hz,3H),3.73(d,J＝11.0Hz,3H),3.85(d,J＝11.2Hz,1H),4.42(d,J＝11.2Hz,1H),7.19(d,J＝1.8Hz,1H),7.41(d,J＝1.8Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.89,146.43(d,3J(C–P)＝16.2Hz),138.92,132.05,125.70,123.85,117.93,62.22(d,3J(C–P)＝3.4Hz),52.43(d,2J(C–P)＝6.6Hz),52.29(d,2J(C–P)＝6.9Hz),43.26(d,2J(C–P)＝2.6Hz),33.71(d,1J(C–P)＝137.6Hz),28.94,24.29(d,3J(C–P)＝3.8Hz),9.66；31P NMR(162MHz,CDCl3)δ＝29.14；HRMS(ESI-TOF)Calcd forC15H21BrClNO4P+([M+H]+)424.0075.Found 424.0076.
3e3,dimethyl((7-bromo-4-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,colorlessoil.1H NMR(400MHz,CDCl3)δ＝1.26(t,J＝7.4Hz,3H),1.61(s,3H),2.09(dd,J＝15.7,17.7Hz,1H),2.49-2.67(m,3H),3.65(d,J＝10.9Hz,3H),3.75(d,J＝11.0Hz,3H),3.83(d,J＝11.2Hz,1H),4.58(d,J＝11.2Hz,1H),6.94(d,J＝8.6Hz,1H),7.36(d,J＝8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.75,143.26,139.90(d,3J(C–P)＝16.0Hz),133.75,128.74,127.61,112.00,61.18(d,3J(C–P)＝1.0Hz),52.43(d,2J(C–P)＝6.6Hz),52.31(d,2J(C–P)＝6.9Hz),44.99(d,2J(C–P)＝2.5Hz),31.24(d,1J(C–P)＝136.6Hz),29.25,23.37(d,3J(C–P)＝5.5Hz),9.64；31P NMR(162MHz,CDCl3)δ＝29.63；HRMS(ESI-TOF)Calcd for C15H21BrClNO4P+([M+H]+)424.0075.Found 424.0072.
3f,dimethyl((4-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.22(t,J＝7.4Hz,3H),1.67(s,3H),2.32-2.61(m,4H),3.52(d,J＝10.9Hz,3H),3.71(d,J＝11.0Hz,3H),3.77(d,J＝10.8Hz,1H),4.55(d,J＝10.8Hz,1H),6.97(dd,J＝0.8,8.0Hz,1H),7.17(dd,J＝8.1,8.1Hz,1H),8.23(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.42,144.06,133.56(d,3J(C–P)＝12.3Hz),129.94,129.81,125.03,115.75,60.21(d,3J(C–P)＝1.0Hz),52.35(d,2J(C–P)＝6.7Hz),52.11(d,2J(C–P)＝6.8Hz),42.53,33.19(d,1J(C–P)＝137.0Hz),29.34,26.20(d,3J(C–P)＝9.4Hz),8.56；31P NMR(162MHz,CDCl3)δ＝29.92；HRMS(ESI-TOF)Calcd forC15H22ClNO4P+([M+H]+)346.0969.Found 346.0964.
3f',dimethyl((6-chloro-3-methyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.4Hz,3H),1.50(s,3H),2.02-2.19(m,2H),2.39-2.57(m,2H),3.61(d,J＝10.9Hz,3H),3.71(d,J＝11.0Hz,3H),3.79(d,J＝10.8Hz,1H),4.43(d,J＝10.8Hz,1H),7.00-7.05(m,2H),8.28(s,1H)；13CNMR(100MHz,CDCl3)δ＝172.49,142.74,137.19(d,3J(C–P)＝13.9Hz),134.00,123.64,122.68,117.46,60.37,52.39(d,2J(C–P)＝6.6Hz),52.13(d,2J(C–P)＝6.8Hz),40.96(d,2J(C–P)＝1.8Hz),35.90(d,1J(C–P)＝137.1Hz),29.19,27.52(d,3J(C–P)＝6.6Hz),8.57；31P NMR(162MHz,CDCl3)δ＝29.60；HRMS(ESI-TOF)Calcd for C15H22ClNO4P+([M+H]+)346.0969.Found 346.0974.
3g,dimethyl((3-methyl-1-propionyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.23(t,J＝7.3Hz,3H),1.56(s,3H),2.11-2.28(m,2H),2.42-2.60(m,2H),3.58(d,J＝11.0Hz,3H),3.72(d,J＝11.0Hz,3H),3.82(d,J＝10.8Hz,1H),4.46(d,J＝10.8Hz,1H),8.04(brs,unexchangeable,1H),8.35(s,1H),8.42(d,J＝5.5Hz,1H)；13C NMR(100MHz,CDCl3)δ＝173.33,150.26,148.40(br),144.07,134.00(brd,3J(C–P)＝13.3Hz),111.42,60.26,52.43(d,2J(C–P)＝6.7Hz),52.19(d,2J(C–P)＝6.8Hz),40.47(br),36.01(d,1J(C–P)＝137.8Hz),29.40,28.08(d,3J(C–P)＝7.7Hz),8.36；31P NMR(162MHz,CDCl3)δ＝29.12；HRMS(ESI-TOF)Calcd for C14H22N2O4P+([M+H]+)313.1312.Found 313.1316.
3h,dimethyl((1-acetylindolin-3-yl)methyl)phosphonate,colorless oil.1HNMR(400MHz,CDCl3)δ＝1.92-2.03(m,1H),2.25-2.34(m,4H),3.76-3.82(m,7H),3.95-4.00(m,1H),4.24-4.29(m,1H),7.05(dd,J＝7.4,7.4Hz,1H),7.17(d,J＝7.4Hz,1H),7.24(dd,J＝7.9,7.6Hz,1H),8.20(d,J＝8.1Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.80,142.32,133.71(d,3J(C–P)＝17.9Hz),128.48,123.85,123.41,117.10,54.98(d,3J(C–P)＝1.6Hz),52.60(d,2J(C–P)＝6.9Hz),52.52(d,2J(C–P)＝6.9Hz),34.90(d,2J(C–P)＝4.1Hz),30.32(d,1J(C–P)＝138.4Hz),24.22；31P NMR(162MHz,CDCl3)δ＝31.24；HRMS(ESI-TOF)Calcd forC13H19NO4P+([M+H]+)284.1046.Found 284.1045.
3h',dimethyl((1-acetyl-1H-indol-3-yl)methyl)phosphonate,whitesemisolid.1H NMR(400MHz,CDCl3)δ＝2.63(s,3H),3.22(d,J＝1.0Hz,1H),3.27(d,J＝1.0Hz,1H),3.69(s,3H),3.72(s,3H),7.31(ddd,J＝1.1,7.4,7.7Hz,1H),7.37(ddd,J＝1.4,7.0,7.4Hz,1H),7.48(d,J＝4.0Hz,1H),7.55-7.57(m,1H),8.44(d,J＝8.0Hz,1H)；13CNMR(100MHz,CDCl3)δ＝168.48,135.63,130.10(d,3J(C–P)＝6.2Hz),125.54,124.24(d,3J(C–P)＝8.8Hz),123.68,118.80,116.69,111.93(d,2J(C–P)＝9.7Hz),52.96(d,2J(C–P)＝6.8Hz),24.01,22.02(d,1J(C–P)＝143.2Hz)；31P NMR(162MHz,CDCl3)δ＝28.60；HRMS(ESI-TOF)Calcd for C13H17NO4P+([M+H]+)282.0890.Found 282.0890.
3i,dimethyl((3,5-dimethyl-1-octanoylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝0.88(t,J＝7.0Hz,3H),1.22-1.42(m,8H),1.50(s,3H),1.69-1.76(m,2H),2.03-2.22(m,2H),2.32(s,3H),2.37-2.50(m,2H),3.62(d,J＝10.9Hz,3H),3.71(d,J＝11.0Hz,3H),3.78(d,J＝10.8Hz,1H),4.37(d,J＝10.8Hz,1H),6.92(s,1H),7.03(dd,J＝0.9,8.2Hz,1H),8.09(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝171.47,139.37,139.02(d,3J(C–P)＝15.2Hz),133.36,128.86,122.40,116.98,60.40(d,3J(C–P)＝1.8Hz),52.33(d,2J(C–P)＝6.6Hz),52.08(d,2J(C–P)＝6.8Hz),41.13(d,2J(C–P)＝3.1Hz),35.94,35.82(d,1J(C–P)＝136.1Hz),31.75,29.36,29.19,27.19(d,3J(C–P)＝5.5Hz),24.62,22.65,21.10,14.10；31P NMR(162MHz,CDCl3)δ＝30.25；HRMS(ESI-TOF)Calcd forC21H35NO4P+([M+H]+)396.2298.Found 396.2294.
3j1,dimethyl((3,5-dimethyl-1-(methylsulfonyl)indolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.50(s,3H),2.11-2.26(m,2H),2.32(s,3H),2.93(s,3H),3.60(d,J＝10.9Hz,3H),3.68(d,J＝11.0Hz,3H),3.71(d,J＝11.0Hz,1H),4.19(d,J＝10.3Hz,1H),6.99(s,1H),7.03(d,J＝8.2Hz,1H),7.29(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝138.40,138.37(d,3J(C–P)＝13.2Hz),133.34,129.23,123.79,113.12,62.15(d,3J(C–P)＝3.2Hz),52.29(d,2J(C–P)＝6.6Hz),52.12(d,2J(C–P)＝6.7Hz),41.11(d,2J(C–P)＝3.2Hz),35.17(d,1J(C–P)＝137.8Hz),34.33,27.63(d,3J(C–P)＝7.3Hz),20.93；31P NMR(162MHz,CDCl3)δ＝29.70；HRMS(ESI-TOF)Calcd forC14H23NO5PS+([M+H]+)348.1029.Found 348.1030.
3j2,dimethyl((3-methyl-1-(methylsulfonyl)-5-phenylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.57(s,3H),2.19-2.33(m,2H),3.00(s,3H),3.56(d,J＝10.9Hz,3H),3.67(d,J＝11.0Hz,3H),3.79(d,J＝10.3Hz,1H),4.29(d,J＝10.3Hz,1H),7.34(dddd,J＝1.2,1.2,7.4,7.3Hz,1H),7.40-7.49(m,5H),7.53-7.56(m,2H)；13C NMR(100MHz,CDCl3)δ＝140.46,140.24,138.68(d,3J(C–P)＝12.2Hz),137.00,128.90,127.70,127.26,126.79,122.14,113.48,62.26(d,3J(C–P)＝3.3Hz),52.34(d,2J(C–P)＝6.7Hz),52.14(d,2J(C–P)＝6.7Hz),41.22(d,2J(C–P)＝3.2Hz),35.29(d,1J(C–P)＝138.3Hz),34.84,28.05(d,3J(C–P)＝8.3Hz)；31P NMR(162MHz,CDCl3)δ＝29.50；HRMS(ESI-TOF)Calcd for C19H25NO5PS+([M+H]+)410.1186.Found 410.1188.
3k,dimethyl((5-bromo-1-(ethylsulfonyl)-3-methylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.42(t,J＝7.4Hz,3H),1.50(s,3H),2.10-2.23(m,2H),3.10-3.24(m,2H),3.61(d,J＝11.0Hz,3H),3.70(d,J＝11.0Hz,3H),3.78(d,J＝10.4Hz,1H),4.27(d,J＝10.4Hz,1H),7.25-7.27(m,2H),7.31(dd,J＝1.9,8.6Hz,1H)；13C NMR(100MHz,CDCl3)δ＝140.30,140.16(d,3J(C–P)＝13.0Hz),131.41,126.53,115.54,114.80,62.03(d,3J(C–P)＝3.3Hz),52.38(d,2J(C–P)＝6.7Hz),52.21(d,2J(C–P)＝6.7Hz),44.35,41.30(d,2J(C–P)＝3.2Hz),35.08(d,1J(C–P)＝138.5Hz),27.71(d,3J(C–P)＝7.6Hz),7.70；31P NMR(162MHz,CDCl3)δ＝29.04；HRMS(ESI-TOF)Calcd forC14H22BrNO5PS+([M+H]+)426.0134.Found 426.0133.
3l1,dimethyl((3-methyl-1-(phenylsulfonyl)indolin-3-yl)methyl)phosphonate,pale yellow oil.1H NMR(400MHz,CDCl3)δ＝1.28(s,3H),1.82(dd,J＝15.6,17.4Hz,1H),2.04(dd,J＝15.5,18.6Hz,1H),3.63(d,J＝10.9Hz,3H),3.64(d,J＝10.9Hz,3H),3.67(d,J＝10.9Hz,1H),4.13(d,J＝10.9Hz,1H),7.00-7.08(m,2H),7.23(ddd,J＝1.6,7.2,7.2Hz,1H),7.44-7.49(m,2H),7.56(dddd,J＝1.2,1.3,7.5,7.4Hz,1H),7.67(d,J＝8.1Hz,1H),7.85-7.87(m,2H)；13C NMR(100MHz,CDCl3)δ＝140.29,139.24(d,3J(C–P)＝15.9Hz),136.95,133.28,129.12,128.56,127.32,123.92,122.77,114.62,61.66(d,3J(C–P)＝3.4Hz),52.23(d,2J(C–P)＝6.7Hz),41.21(d,2J(C–P)＝3.2Hz),35.27(d,1J(C–P)＝136.7Hz),26.51(d,3J(C–P)＝4.0Hz)；31P NMR(162MHz,CDCl3)δ＝29.72；HRMS(ESI-TOF)Calcd forC18H23NO5PS+([M+H]+)396.1029.Found 396.1031.
3l2,dimethyl((3,5-dimethyl-1-(phenylsulfonyl)indolin-3-yl)methyl)phosphonate,pale yellow oil.1H NMR(400MHz,CDCl3)δ＝1.25(s,3H),1.77(dd,J＝16.5,17.4Hz,1H),2.01(dd,J＝15.6,18.5Hz,1H),2.28(s,3H),3.64(d,J＝10.9Hz,3H),3.65(d,J＝10.9Hz,3H),3.66(d,J＝10.9Hz,1H),4.11(d,J＝11.0Hz,1H),6.85(s,1H),7.03(d,J＝8.2Hz,1H),7.46(dd,J＝7.8,7.4Hz,2H),7.53-7.57(m,2H),7.84(d,J＝7.8Hz,2H)；13C NMR(100MHz,CDCl3)δ＝139.45(d,3J(C–P)＝16.2Hz),137.93,136.94,133.68,133.16,129.09,129.06,127.34,123.31,114.55,61.83(d,3J(C–P)＝3.3Hz),52.20(d,2J(C–P)＝6.9Hz),52.19(d,2J(C–P)＝6.9Hz),41.21(d,2J(C–P)＝3.2Hz),35.31(d,1J(C–P)＝136.4Hz),26.41(d,3J(C–P)＝3.7Hz),20.98；31P NMR(162MHz,CDCl3)δ＝29.81；HRMS(ESI-TOF)Calcd for C19H25NO5PS+([M+H]+)410.1186.Found 410.1197.
3l3,dimethyl((5-bromo-3-methyl-1-(phenylsulfonyl)indolin-3-yl)methyl)phosphonate,pale yellow oil.1H NMR(400MHz,CDCl3)δ＝1.26(s,3H),1.78(dd,J＝16.0,17.2Hz,1H),2.00(dd,J＝15.6,18.8Hz,1H),3.63-3.68(m,7H),4.14(d,J＝11.0Hz,1H),7.17(s,1H),7.34(d,J＝8.6Hz,1H),7.49(dd,J＝7.6,7.6Hz,2H),7.54-7.60(m,2H),7.83(d,J＝7.8Hz,2H)；13C NMR(100MHz,CDCl3)δ＝141.46(d,3J(C–P)＝15.8Hz),139.58,136.67,133.51,131.44,129.24,127.26,126.20,116.42,116.17,61.84(d,3J(C–P)＝3.7Hz),52.30(d,2J(C–P)＝6.8Hz),52.25(d,2J(C–P)＝6.6Hz),41.31(d,2J(C–P)＝3.0Hz),35.13(d,1J(C–P)＝137.5Hz),26.42(d,3J(C–P)＝4.0Hz)；31P NMR(162MHz,CDCl3)δ＝29.06；HRMS(ESI-TOF)Calcd for C18H22BrNO5PS+([M+H]+)474.0134.Found 474.0132.
3m,dimethyl((3-methyl-1-tosylindolin-3-yl)methyl)phosphonate,paleyellow oil.1H NMR(400MHz,CDCl3)δ＝1.30(s,3H),1.82(dd,J＝14.5,17.2Hz,1H),2.04(dd,J＝15.5,18.6Hz,1H),2.37(s,3H),3.64(d,J＝11.0Hz,3H),3.65(d,J＝10.8Hz,1H),3.66(d,J＝10.9Hz,3H),4.11(d,J＝10.9Hz,1H),7.01(ddd,J＝0.9,7.5,7.4Hz,1H),7.06(dd,J＝1.2,7.5Hz,1H),7.20-7.22(m,1H),7.25(d,J＝8.1Hz,2H),7.65(d,J＝8.1Hz,1H),7.73(ddd,J＝1.7,1.7,8.3Hz,2H)；13C NMR(100MHz,CDCl3)δ＝144.16,140.42,139.25(d,3J(C–P)＝15.9Hz),133.99,129.71,128.50,127.38,123.78,122.72,114.62,61.71(d,3J(C–P)＝3.5Hz),52.20(d,2J(C–P)＝6.7Hz),52.19(d,2J(C–P)＝6.6Hz),41.18(d,2J(C–P)＝3.2Hz),35.29(d,1J(C–P)＝136.7Hz),26.40(d,3J(C–P)＝3.8Hz),21.53；31P NMR(162MHz,CDCl3)δ＝29.76；HRMS(ESI-TOF)Calcd for C19H25NO5PS+([M+H]+)410.1186.Found 410.1189.
3n,dimethyl((3,5-dimethyl-1-(o-tolylsulfonyl)indolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.38(s,3H),1.95(dd,J＝15.6,17.2Hz,1H),2.09(dd,J＝15.5,18.6Hz,1H),2.29(s,3H),2.62(s,3H),3.64(s,3H),3.67(s,3H),3.70(d,J＝10.8Hz,1H),4.14(d,J＝10.8Hz,1H),6.91(s,1H),6.96-6.99(m,1H),7.28-7.32(m,3H),7.44(ddd,J＝1.3,7.7,7.5Hz,1H),7.97(dd,J＝1.0,8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝139.29(d,3J(C–P)＝16.4Hz),138.64,138.16,137.36,133.36,133.00,132.87,129.49,128.91,126.30,123.28,114.59,61.57(d,3J(C–P)＝3.3Hz),52.21(d,2J(C–P)＝6.6Hz),52.18(d,2J(C–P)＝6.8Hz),41.41(d,2J(C–P)＝3.2Hz),35.18(d,1J(C–P)＝136.3Hz),26.19(d,3J(C–P)＝3.5Hz),20.98,20.88；31P NMR(162MHz,CDCl3)δ＝29.93；HRMS(ESI-TOF)Calcd for C20H27NO5PS+([M+H]+)424.1342.Found 424.1357.
3o,dimethyl((1-((4-bromophenyl)sulfonyl)-3-methylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.32(s,3H),1.77(dd,J＝15.6,17.4Hz,1H),2.03(dd,J＝15.5,18.7Hz,1H),3.64(d,J＝10.9Hz,3H),3.65(d,J＝10.9Hz,3H),3.66(d,J＝11.0Hz,1H),4.15(d,J＝11.0Hz,1H),7.01-7.09(m,2H),7.23(ddd,J＝1.6,7.2,8.1Hz,1H),7.59-7.63(m,3H),7.72(ddd,J＝2.3,2.0,8.7Hz,2H)；13C NMR(100MHz,CDCl3)δ＝139.99,139.33(d,3J(C–P)＝16.1Hz),135.96,132.41,128.78,128.62,128.38,124.19,122.86,114.57,61.60(d,3J(C–P)＝3.2Hz),52.23(d,2J(C–P)＝6.7Hz),41.25(d,2J(C–P)＝3.1Hz),35.33(d,1J(C–P)＝136.8Hz),26.48(d,3J(C–P)＝4.0Hz)；31P NMR(162MHz,CDCl3)δ＝29.49；HRMS(ESI-TOF)Calcd for C18H22BrNO5PS+([M+H]+)474.0134.Found474.0138.
3p,dimethyl((1-(N,N-dimethylsulfamoyl)-3-methyl-5-phenylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.57(s,3H),2.16-2.30(m,2H),2.96(s,6H),3.66(d,J＝10.9Hz,3H),3.70(d,J＝11.0Hz,3H),3.78(d,J＝10.2Hz,1H),4.27(d,J＝10.2Hz,1H),7.32(dddd,J＝2.0,1.9,7.4,7.3Hz,1H),7.35(dd,J＝1.2,1.1Hz,1H),7.40-7.44(m,4H),7.52-7.55(m,2H)；13C NMR(100MHz,CDCl3)δ＝141.21,140.70,138.80(d,3J(C–P)＝15.0Hz),136.33,128.82,127.40,127.05,126.79,121.43,114.09,62.49(d,3J(C–P)＝3.3Hz),52.33(d,2J(C–P)＝6.6Hz),52.17(d,2J(C–P)＝6.8Hz),41.41(d,2J(C–P)＝3.2Hz),38.30,35.28(d,1J(C–P)＝136.9Hz),26.79(d,3J(C–P)＝5.2Hz)；31PNMR(162MHz,CDCl3)δ＝29.90；HRMS(ESI-TOF)Calcd for C20H28N2O5PS+([M+H]+)439.1451.Found 439.1452.
3q1,diethyl((1-acetyl-3-methylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.24(t,J＝7.1Hz,3H),1.31(t,J＝7.1Hz,3H),1.52(s,3H),2.05-2.23(m,2H),2.25(s,3H),3.80(d,J＝10.8Hz,1H),3.90-4.12(m,4H),4.44(d,J＝10.8Hz,1H),7.05(ddd,J＝0.9,7.4,7.4Hz,1H),7.13(d,J＝6.8Hz,1H),7.20-7.25(m,1H),8.19(d,J＝8.0Hz,1H)；13C NMR(100MHz,CDCl3)δ＝168.97,141.45,139.14(d,3J(C–P)＝14.5Hz),128.31,123.86,121.93,117.18,61.70(d,2J(C–P)＝6.6Hz),61.54(d,2J(C–P)＝6.7Hz),61.01(d,3J(C–P)＝1.8Hz),41.29(d,2J(C–P)＝3.2Hz),36.84(d,1J(C–P)＝136.6Hz),27.60(d,3J(C–P)＝6.3Hz),24.26,16.41(d,3J(C–P)＝6.1Hz),16.37(d,3J(C–P)＝6.1Hz)；31P NMR(162MHz,CDCl3)δ＝27.36；HRMS(ESI-TOF)Calcd for C16H25NO4P+([M+H]+)326.1516.Found 326.1520.
3q2,diethyl((3,5-dimethyl-1-propionylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.22(t,J＝7.4Hz,3H),1.25(t,J＝7.1Hz,3H),1.32(t,J＝7.0Hz,3H),1.51(s,3H),2.07(dd,J＝15.5,17.3Hz,1H),2.17(dd,J＝15.6,18.2Hz,1H),2.32(s,3H),2.39-2.56(m,2H),3.77(d,J＝10.8Hz,1H),3.91-4.13(m,4H),4.41(d,J＝10.8Hz,1H),6.93(s,1H),7.02(d,J＝8.1Hz,1H),8.09(d,J＝8.2Hz,1H)；13CNMR(100MHz,CDCl3)δ＝171.97,139.32,139.17(d,3J(C–P)＝15.1Hz),133.29,128.76,122.49,116.82,61.66(d,2J(C–P)＝6.6Hz),61.49(d,2J(C–P)＝6.7Hz),60.20(d,3J(C–P)＝1.7Hz),41.24(d,2J(C–P)＝3.2Hz),36.69(d,1J(C–P)＝136.2Hz),29.08,27.37(d,3J(C–P)＝5.8Hz),21.09,16.40(d,3J(C–P)＝6.2Hz),16.37(d,3J(C–P)＝6.1Hz),8.72；31P NMR(162MHz,CDCl3)δ＝27.51；HRMS(ESI-TOF)Calcd for C18H29NO4P+([M+H]+)354.1829.Found354.1828.
3q3,diethyl((5-bromo-3-methyl-1-(phenylsulfonyl)indolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.25-1.29(m,9H),1.79(dd,J＝15.5,17.7Hz,1H),1.99(dd,J＝15.4,18.8Hz,1H),3.67(d,J＝10.9Hz,1H),3.92-4.09(m,4H),4.16(d,J＝10.9Hz,1H),7.17(d,J＝2.0Hz,1H),7.33(dd,J＝2.0,8.6Hz,1H),7.45-7.51(m,2H),7.54(d,J＝8.9Hz,1H),7.58(dddd,J＝2.0,2.0,7.5,7.4Hz,1H),7.82-7.85(m,2H)；13C NMR(100MHz,CDCl3)δ＝141.61(d,3J(C–P)＝15.4Hz),139.59,136.71,133.46,131.34,129.22,127.30,126.25,116.37,116.11,61.87(d,3J(C–P)＝3.7Hz),61.73(d,2J(C–P)＝6.4Hz),61.67(d,2J(C–P)＝6.5Hz),41.44(d,2J(C–P)＝3.2Hz),36.03(d,1J(C–P)＝137.7Hz),26.67(d,3J(C–P)＝4.4Hz),16.37(d,3J(C–P)＝6.2Hz)；31P NMR(162MHz,CDCl3)δ＝26.33；HRMS(ESI-TOF)Calcd for C20H26BrNO5PS+([M+H]+)502.0447.Found 502.0448.
3q4,diethyl((3-methyl-1-tosylindolin-3-yl)methyl)phosphonate,colorless oil.1H NMR(400MHz,CDCl3)δ＝1.25-1.31(m,9H),1.82(dd,J＝15.5,17.6Hz,1H),2.04(dd,J＝15.5,18.6Hz,1H),2.37(s,3H),3.67(d,J＝10.8Hz,1H),3.96-4.05(m,4H),4.13(d,J＝10.8Hz,1H),7.00(ddd,J＝0.9,7.5,7.4Hz,1H),7.06(dd,J＝1.1,7.5Hz,1H),7.19-7.22(m,1H),7.24(d,J＝7.9Hz,2H),7.64(d,J＝8.1Hz,1H),7.73(ddd,J＝1.6,1.6,8.3Hz,1H)；13C NMR(100MHz,CDCl3)δ＝144.10,140.40,139.46(d,3J(C–P)＝15.9Hz),134.01,129.69,128.41,127.40,123.72,122.74,114.54,61.70(d,3J(C–P)＝3.4Hz),61.61(d,2J(C–P)＝6.6Hz),61.58(d,2J(C–P)＝6.7Hz),41.29(d,2J(C–P)＝3.4Hz),36.18(d,1J(C–P)＝136.9Hz),26.59(d,3J(C–P)＝3.9Hz),21.53,16.40(d,3J(C–P)＝6.1Hz),16.38(d,3J(C–P)＝6.1Hz)；31P NMR(162MHz,CDCl3)δ＝27.09；HRMS(ESI-TOF)Calcd for C21H29NO5PS+([M+H]+)438.1499.Found 438.1499.
3r1,1-(3-((diphenylphosphoryl)methyl)-3,5-dimethylindolin-1-yl)propan-1-one,white semisolid.1H NMR(400MHz,CDCl3)δ＝1.17(t,J＝7.4Hz,3H),1.42(s,3H),2.23(s,3H),2.32-2.38(m,2H),2.59-2.71(m,2H),3.72(d,J＝10.9Hz,1H),4.56(d,J＝10.9Hz,1H),6.84(s,1H),6.93(d,J＝8.2Hz,1H),7.35-7.55(m,6H),7.58-7.63(m,2H),7.77-7.82(m,2H),7.99(d,J＝8.2Hz,1H)；13C NMR(100MHz,CDCl3)δ＝172.09,139.39,139.20(d,3J(C–P)＝10.9Hz),134.08(d,1J(C–P)＝97.2Hz),133.89(d,1J(C–P)＝97.8Hz),133.15,131.72(d,4J(C–P)＝2.6Hz),131.60(d,4J(C–P)＝2.7Hz),130.45(d,J(C–P)＝9.1Hz),130.28(d,J(C–P)＝9.3Hz),128.82,128.76(d,J(C–P)＝11.9Hz),128.62(d,J(C–P)＝11.7Hz),122.44,116.85,60.17(d,3J(C–P)＝2.3Hz),42.90(d,2J(C–P)＝4.1Hz),40.13(d,1J(C–P)＝67.2Hz),28.96,27.17(d,3J(C–P)＝4.1Hz),21.03,8.65；31P NMR(162MHz,CDCl3)δ＝27.62；HRMS(ESI-TOF)Calcd for C26H29NO2P+([M+H]+)418.1930.Found 418.1927.
3r2,((3-methyl-1-tosylindolin-3-yl)methyl)diphenylphosphine oxide,white solid:mp 144-145℃.1H NMR(400MHz,CDCl3)δ＝1.30(s,3H),2.28(s,3H),2.30(dd,J＝11.4,15.2Hz,1H),2.58(dd,J＝8.9,15.2Hz,1H),3.58(d,J＝10.9Hz,1H),4.21(d,J＝10.8Hz,1H),6.84(ddd,J＝0.9,7.5,7.5Hz,1H),7.03(dd,J＝0.8,7.6Hz,1H),7.10-7.15(m,3H),7.38-7.51(m,6H),7.59-7.70(m,7H)；13C NMR(100MHz,CDCl3)δ＝144.01,140.38,139.34(d,3J(C–P)＝11.2Hz),134.57(d,1J(C–P)＝97.9Hz),133.98,133.89(d,1J(C–P)＝97.3Hz),131.66(d,4J(C–P)＝2.6Hz),131.53(d,4J(C–P)＝2.7Hz),130.41(d,J(C–P)＝9.1Hz),130.30(d,J(C–P)＝9.3Hz),129.65,128.71(d,J(C–P)＝11.6Hz),128.65(d,J(C–P)＝11.6Hz),128.39,127.43,123.63,123.13,114.50,62.39(d,3J(C–P)＝4.4Hz),42.99(d,2J(C–P)＝3.9Hz),39.47(d,1J(C–P)＝67.7Hz),26.01(d,3J(C–P)＝2.0Hz),21.52；31P NMR(162MHz,CDCl3)δ＝26.70；HRMS(ESI-TOF)Calcd for C29H29NO3PS+([M+H]+)502.1600.Found502.1605.
下面结合实验对本发明作进一步描述。
GC-MS和13P NMR实验
1.GC-MS实验
1)TEMPO实验
最优条件下的模型反应中加入1.2当量2,2,6,6-四甲基哌啶氧化物(TEMPO)。混合液反应3h，然后用饱和Na2S2O3(5.0mL)和水(30.0mL)淬灭，CH2Cl2(20.0mL)萃取3次。有机相用GC-MS进行检测。如图2。
2)BHT
最优条件下的模型反应中加入0.3当量2,6-二叔丁基-4-甲基苯酚(BHT)。混合液反应3h，然后用饱和Na2S2O3(5.0mL)和水(30.0mL)淬灭，CH2Cl2(20.0mL)萃取3次。有机相用GC-MS进行检测，如图3。
2.13P NMR
最优条件下的模型反应中加入2.0当量TEMPO。混合液反应3h，然后用饱和Na2S2O3(5.0mL)和水(30.0mL)淬灭，CH2Cl2(20.0mL)萃取3次。蒸除有机溶剂后的残留物溶解在CDCl3中进行31P NMR测试。
产物3a1(δ＝30.03)和亚磷酸二甲酯的特征峰(δ＝10.45)都消失，一个新的主峰在6.06。如图4。
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)
1.一种银催化的3-膦酰甲基吲哚啉制备方法，其特征在于，所述银催化的3-膦酰甲基吲哚啉制备方法包括以下步骤：
步骤一，将N-烯丙基作为自由基受体基团；
步骤二，通过自由基受体基团引发膦酰化-芳基化反应序列，一步合成3-膦酰甲基吲哚啉；
所述银催化的3-膦酰甲基吲哚啉制备方法的化学反应式为：
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