WO2023109254A1 - [4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法 - Google Patents

[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法 Download PDF

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WO2023109254A1
WO2023109254A1 PCT/CN2022/123099 CN2022123099W WO2023109254A1 WO 2023109254 A1 WO2023109254 A1 WO 2023109254A1 CN 2022123099 W CN2022123099 W CN 2022123099W WO 2023109254 A1 WO2023109254 A1 WO 2023109254A1
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pyridine
nmr
phenyl
cdcl
acyl
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PCT/CN2022/123099
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French (fr)
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王强
缪成贵
姚侠
朱赟
赵王燕
刘皖湘
赵佩岚
方鑫
戴刚强
姚亦丹
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安徽科技学院
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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  • the present invention relates to a method for directly preparing 3-acyl imidazol[1,5-a]pyridine in one step by the secondary amination reaction of [4+1] ketomethyl, in particular to an electrochemically mediated [4+1]
  • the invention relates to a method for directly preparing 3-acyl imidazol[1,5-a]pyridine in one step through secondary amination reaction of ketomethyl, belonging to the technical field of chemical synthesis.
  • Imidazo[1,5-a]pyridines are characteristic fused N-heterocyclic compounds that have broad applications in medicinal chemistry for drug discovery.
  • the chemical community has developed several synthetic methods to construct these compounds, which greatly facilitated the study of drug structure-activity relationship (SAR) for this scaffold.
  • SAR drug structure-activity relationship
  • these methods have limitations in the synthesis of 3-acylimidazo[1,5-a]pyridines.
  • 3-Acylimidazo[1,5-a]pyridines are key pharmacophores widely used in bioactive compounds, such as cannabinoid receptor type 2 (CB 2 ) agonists (Figure 1, cmpd 1), for inflammatory pain and Monoiodate (MIA) Fibroblast Growth Factor Receptor (FGFR) Antagonist (Figure 1, cmpd 2) for Osteoarthritis Pain in Bladder Cancer and Retinoic Acid Receptor-Related Orphan Receptor in Autoimmune Disease Gamma c (RORc) agonist (Fig. 1, cmpd 3).
  • CB 2 cannabinoid receptor type 2
  • MIA Monoiodate
  • FGFR Fibroblast Growth Factor Receptor
  • Antagonist Figure 1, cmpd 2
  • Figure 1, cmpd 2 for Osteoarthritis Pain in Bladder Cancer
  • chemists reported the aggregation-induced emission (AIE) properties of 3-acylimidazo[1,5-a]pyridines and reported iodine-mediated activation of sp and sp hydrocarbons for the conversion of phenylacetylene (benzene Ethylene) and pyridine-2-phenyl (pyridin-2-yl) to directly synthesize methaneamine. Since most substituted phenylacetylenes and styrenes are expensive or even unavailable commercially, efficient and green methods for the direct functionalization of 3-acylimidazol[1,5-a]pyridines based on sp3 hydrocarbons are still urgently needed .
  • AIE aggregation-induced emission
  • the technical problem to be solved by the present invention is to provide a method for directly preparing 3-acylimidazol[1,5-a]pyridine in one step by secondary amination reaction of [4+1]ketomethyl, which uses cheap ketonemethyl
  • the two aminations of sp3 - based hydrocarbons well avoid the conventional multi-step reaction of 3-acylimidazo[1,5-a]pyridine synthesis.
  • the transformations of the present invention exhibit good substrate scope, functional group tolerance and moderate to good yields.
  • the application of this method can also be extended to the preparation of other active methyl large ⁇ systems.
  • the method for directly preparing 3-acyl imidazol[1,5-a]pyridine in one step by the secondary amination reaction of [4+1]ketomethyl comprises the following steps: under the condition of constant current of 10 ⁇ 25mA, in an electrolytic cell without a diaphragm , at 78-81°C, electrolyze 1 equivalent of R 1 -ethanone, 2 equivalents of pyridin-2-R 2 -formamide and 1.5 equivalents of NH 4 I for 16-20 hours to obtain the product 3-acyl imidazole[ 1,5-a]pyridine.
  • Solvents are DMSO or DMA.
  • the anode of the diaphragmless electrolyzer is a graphite rod, and the cathode is a platinum sheet.
  • the diameter of the graphite rod is 0.6-0.7 cm; the area of the platinum sheet is 1.0-1.2 cm 2 .
  • the R base includes phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4- Methoxyphenyl, 4-hydroxyphenyl, 4-fluorophenyl, 4-carboxymethylphenyl, 2-CF 3 -phenyl, 4-CF 3 -phenyl, 2-NO 2 -phenyl, 4-S(O) 2 Me-phenyl,
  • the R 2 group includes phenyl, methyl,
  • the R base -ethanone can be composed of heteroaryl replace.
  • the invention uses a redox mediator to carry out indirect electrocatalytic functionalization of sp 3 hydrocarbons, improves synthesis efficiency and shortens synthesis steps by using non-functionalized cheap starting materials.
  • the present invention has developed a highly efficient electrochemical synthesis method of 3-acyl imidazol[1,5-a]pyridine, in which the double amination of cheap ketomethyl sp 3 hydrocarbons well avoids the 3-acyl imidazol[1 , 5-a] pyridine synthesis of conventional multi-step reaction.
  • This transformation exhibited good substrate scope, functional group tolerance, and moderate to good yields.
  • the application of this method can also be extended to the preparation of other active methyl large ⁇ systems. Direct synthesis, inexpensive materials, simple metal-free system, no need for external electrolytes and oxidants, and scalability make this method a practical green method for the preparation of 3-acylimidazo[1,5-a]pyridines and large ⁇ -systems .
  • Fig. 1 is the bioactive substance containing 3-acyl imidazolium [1,5-a] pyridine in the prior art
  • Fig. 2 is the synthetic flow chart of 3-acyl imidazol[1,5-a]pyridine in the prior art
  • Fig. 3 is synthetic reaction figure of the present invention.
  • Fig. 4 is the applicability research figure of R group of the present invention.
  • Fig. 5 is a gram-level synthetic reaction diagram of the present invention.
  • Fig. 6 is a reaction mechanism diagram of the present invention.
  • Fig. 7 is the reaction diagram of electrochemical mediation of the present invention.
  • Fig. 8 is the 1 H NMR figure of the product 3-acyl imidazo [1,5-a] pyridine (3a) of the present invention.
  • Fig. 9 is the 13 C NMR figure of the product 3-acyl imidazol[1,5-a]pyridine (3a) of the present invention.
  • Fig. 10 is the 1 H NMR figure of product (5a) of the present invention.
  • Fig. 11 is a 13 C NMR chart of the product (5a) of the present invention.
  • the method for the direct preparation of 3-acyl imidazol[1,5-a]pyridine in one step by [4+1] ketomethyl secondary amination reaction comprises the following steps: under 10mA constant current condition, in the absence of Electrolysis of acetophenone (1a; 0.2mmol, 1eq), pyridine-2-phenyl(pyridin-2-yl) formamide (2a; 0.4mmol, 2eq) and NH 4 I (0.3mmol) in a diaphragm electrolyzer After 16 h, the product 3a was obtained in 76% yield (Table 1, entry 1). During the optimization process, reaction parameters such as redox media, solvent, and temperature were investigated.
  • the reaction was carried out at 80° C. under a constant flow of 10 mA for the indicated time, and the progress of the reaction was monitored by thin layer chromatography (TLC). Water (10 mL) was then added and the aqueous solution was extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane (5:1) to afford the product.
  • Substrate suitability research of the present invention investigated the substrate scope of the reaction under optimized conditions (Table 2).
  • Table 2 a variety of acetophenones ( R1 group) were investigated.
  • the results show that the solvent effect has a great influence on the phase transition.
  • the choice of DMA as the solvent for electron-deficient acetophenone derivatives can avoid unexpected side reactions in DMSO solvent, and the required reaction time for electron-deficient acetophenone derivatives is shorter.
  • the electron-withdrawing group chlorine provides higher yields than the electron-donating group methyl (Table 2, 3b-3d vs 3e-3g), and requires less reaction time, and in other acetophenone derivatives Similar electronic effects were found in (Table 2, 3h-3o).
  • the electrolytic system also exhibited good tolerance of functional groups, including methoxy (Table 2, 3h), hydroxyl (Table 2, 3i), fluorine (Table 2, 3j), ester (Table 2, 3k) , trifluoromethyl (Table 2, 3l and 3m), nitrile (Table 2, 3n), sulfonyl (Table 2, 3o). Multi-substituted acetophenones still yielded target products (Table 2, 3p-3q).
  • heteroaryl and unsaturated ketones are also suitable for this reaction (Table 2, 3r, 3s and 3t).
  • acetophenone (1a, 10mmol), phenyl(pyridin-2-yl)formamide (2a, 20mmol), NH 4 I (15mmol), (DMSO 50mL) were placed in 100mL
  • TLC thin layer chromatography
  • Analyzing the reaction mechanism of the present invention anodic oxidation of NH 4 I generates molecular iodine, and molecular iodine reacts with ketone to generate ⁇ -iodoketone 1aa. Nucleophilic substitution of ⁇ -iodoketone with an amine forms intermediate I, which undergoes anodic oxidative dehydrogenation to form intermediate II, intramolecular nucleophilic attack followed by anodic oxidative dehydrogenation to give product 3a.
  • Example 1 The difference between this example and Example 1 is that: the electrolysis reaction is carried out at 78° C., the diameter of the graphite rod is 0.7 cm; the area of the platinum sheet is 1.2 cm 2 .
  • 3-acylimidazo[1,5-a]pyridine is a characteristic drug moiety traditionally prepared through a three-step reaction, as shown in Figure 7, which can be used in the present invention
  • Ammonium iodide was used as a redox mediator, and the inexpensive and readily available acetophenone and pyridylethylamine were synthesized in one step by electrochemical cascading sp 3 (CH) secondary amination reaction.

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  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明提供了一种[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，包括以下步骤：在10～25mA恒流条件下，在无隔膜电解槽中，电解1当量的R 1基-乙酮、2当量的吡啶-2-R 2基-甲酰胺和1.5当量的NH 4I 16～20h，得到产物。本发明开发了一种高效的3-酰基咪唑[1,5-a]吡啶的电化学合成方法，廉价酮甲基sp 3烃的两次胺化避免了3-酰基咪唑[1,5-a]吡啶合成的常规多步反应；直接合成法、廉价的材料、简单的无金属体系、无需外加电解质和氧化剂、可扩展性使该方法成为制备3-酰基咪唑[1,5-a]吡啶和大π-体系的实用绿色方法。

Description

[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法 技术领域
本发明涉及一种[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，尤其涉及一种电化学介导的[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，属于化学合成技术领域。
背景技术
咪唑并[1,5-a]吡啶是一种特征性的稠合N-杂环化合物，在药物发现的药物化学领域有着广泛的应用。近年来，化学界开发了若干合成方法来构建这些化合物，这大大促进了针对此骨架的药物构效关系的研究(SAR)。但是，这些方法在合成3-酰基咪唑[1,5-a]吡啶方面存在局限性。3-酰基咪唑[1,5-a]吡啶是广泛用于生物活性化合物的关键药效团，例如大麻素受体2型(CB 2)激动剂(图1，cmpd 1)、对于炎性疼痛和单碘酸钠(MIA)骨关节炎疼痛治疗膀胱癌的成纤维细胞生长因子受体(FGFR)拮抗剂(图1，cmpd 2)和治疗自身免疫性疾病的维甲酸受体相关孤儿受体γc(RORc)激动剂(图1，cmpd 3)。
3-酰基咪唑[1,5-a]吡啶衍生物采用常规方法合成必须通过多步反应实现，此外，在合成过程中，使用高腐蚀性试剂三氯磷酸盐似乎是不可避免的(图2)。显然，效率不令人满意，而且工艺对环境也有害。最近，化学家报道了3-酰基咪唑[1,5-a]吡啶的聚集诱导发光(AIE)特性，并报道了碘介导的sp和sp 2碳氢化合物活化，用于从苯乙炔(苯乙烯)和吡啶-2-苯基(吡啶-2-基)直接合成甲烷胺。由于大多数取代苯乙炔和苯乙烯价格昂贵，甚至在商业上无法购得，因此基于sp3碳氢化合物直接官能化的3-酰基咪唑[1,5-a]吡啶高效绿色方法仍然是迫切需求的。
发明内容
本发明所要解决的技术问题是，提供了一种[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，该法采用廉价酮甲基sp 3烃的两次胺化很好地避免了3-酰基咪唑[1,5-a]吡啶合成的常规多步反应。本发明的转化表现出良好的底物范围、官能团耐受性和中等至良好的产率。同时，该方法的应用也可推广到其它活性甲基大π体系的制备。直接合成 法、廉价的材料、简单的无金属体系、无需外加电化学试剂和氧化剂、可扩展性使该方法成为制备3-酰基咪唑并[1,5-a]吡啶和大π-体系的实用绿色方法。
为解决上述技术问题，本发明采用的技术方案为：
[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，包括以下步骤：在10～25mA恒流条件下，在无隔膜电解槽中，于78～81℃下，电解1当量的R 1基-乙酮、2当量的吡啶-2-R 2基-甲酰胺和1.5当量的NH 4I 16～20h，得到产物3-酰基咪唑[1,5-a]吡啶。
溶剂为DMSO或DMA。
所述无隔膜电解槽的阳极为石墨棒，阴极为铂片。
所述石墨棒的直径为0.6～0.7cm；所述铂片的面积为1.0～1.2cm 2。
电解反应结束后，加入水，水的加入量相当于溶剂体积的2～3.3倍，获得水溶液，再用乙酸乙酯萃取水溶液至少三次，每次乙酸乙酯的加入量为水的体积的1.5～5倍，合并萃取得到的有机相；再用饱和盐水洗涤合并的有机相，用无水Na 2SO 4干燥，减压下浓缩；残留物通过硅胶层析，用乙酸乙酯/己烷5:1洗脱，得到产物。
所述R 1基包括苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-甲氧基苯基、4-羟基苯基、4-氟苯基、4-羧甲基苯基、2-CF 3-苯基、4-CF 3-苯基、2-NO 2-苯基、4-S(O) 2Me-苯基、
Figure PCTCN2022123099-appb-000001
Figure PCTCN2022123099-appb-000002
所述R 2基包括苯基、甲基、
Figure PCTCN2022123099-appb-000003
所述R 1基-乙酮可由杂芳基
Figure PCTCN2022123099-appb-000004
替换。
所述杂芳基包括R＝H，Y＝CH、R＝Me，Y＝CH、R＝Cl，Y＝CH、R＝Br，Y＝CH或R＝H，Y＝N。
本发明的有益效果：
本发明使用氧化还原介体对sp 3碳氢化合物进行间接电催化官能化，通过使用非官能化廉价起始材料提高合成效率并缩短合成步骤。
本发明开发了一种高效的3-酰基咪唑[1,5-a]吡啶的电化学合成方法，其中廉价酮甲基 sp 3烃的两次胺化很好地避免了3-酰基咪唑[1,5-a]吡啶合成的常规多步反应。这种转化表现出良好的底物范围、官能团耐受性和中等至良好的产率。同时，该方法的应用也可推广到其它活性甲基大π体系的制备。直接合成法、廉价的材料、简单的无金属体系、无需外加电解质和氧化剂、可扩展性使该方法成为制备3-酰基咪唑并[1,5-a]吡啶和大π-体系的实用绿色方法。
附图说明
图1是现有技术中包含有3-酰基咪唑[1,5-a]吡啶的生物活性物质；
图2是现有技术中3-酰基咪唑[1,5-a]吡啶的合成流程图；
图3是本发明的合成反应图；
图4是本发明的R 2基团的适用性研究图；
图5是本发明的克级合成反应图；
图6是本发明的反应机理图；
图7是本发明的电化学介导的反应图；
图8是本发明的产物3-酰基咪唑[1,5-a]吡啶(3a)的 1H NMR图；
图9是本发明的产物3-酰基咪唑[1,5-a]吡啶(3a)的 13C NMR图；
图10是本发明的产物(5a)的 1H NMR图；
图11是本发明的产物(5a)的 13C NMR图。
具体实施方式
下面结合附图以及具体实施例对本发明[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法作进一步详细说明。
实施例1：
实验试剂及仪器：
本发明除非另有说明，所有反应均在空气气氛下进行，使用商业材料和溶剂，无需进一步纯化。在室温下，使用CDCl 3或DMSO-D 6作为溶剂测量 1H NMR(400MHz、500MHz或600MHz)和 13C NMR(101MHz、126MHz或151MHz)光谱。高分辨率质谱(HRMS)记录在BRUKER VPEXII光谱仪上，采用ESI模式。在200-300目硅胶上进行快速柱层析。
如图3所示，[4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，包括以下步骤：在10mA恒流条件下，在无隔膜电解槽中电解苯乙酮(1a；0.2mmol，1当量)、吡啶-2-苯基(吡啶-2-基)甲酰胺(2a；0.4mmol，2当量)和NH 4I(0.3mmol)16h，得到 产率为76％的产物3a(表1，条目1)。在优化过程中，考察了氧化还原介质、溶剂、温度等反应参数。至于其他氧化还原介质，KI、NaI和 nBu 4NI的产率都较低(表1，条目2-4)，NH 4Br仅给出微量3a(表1，条目5)。对于反应溶剂，DMA作为溶剂提供73％的产率(表1，条目6)，而DMF作为溶剂仅提供59％的产率(表1，条目7)。至于反应温度，将温度降低至70℃和升高至90℃均未能提高产率(表1，条目8和条目9)，并且在室温下电解后未检测到3a(表1，条目10)。用铂片阳极代替石墨棒阳极也会产生较低的产率(表1，条目11)，将电流降低到8mA并升高到12mA都会产生较低的产率(表1，条目12和13)。使用等量的I 2代替NH 4I以及电解仅产生18％的3a产率(表1，条目14)，DMA中的相同反应失败并产生微量3a(表1，条目15)，表明阳极氧化脱氢是该转化的关键因素。
本实施例溶剂为3mL DMSO，溶剂DMSO 3mL放入配备石墨棒阳极(直径＝0.6cm)和铂阴极(1.0cm 2)的20mL反应管中。在80℃下，10mA恒流下进行指定时间，通过薄层色谱(TLC)监测反应过程。然后加入水(10mL)，并用乙酸乙酯(3×50mL)萃取水溶液。用饱和盐水洗涤合并的有机相，并用无水Na 2SO 4干燥，减压下浓缩。残留物通过硅胶层析，用乙酸乙酯/己烷(5:1)洗脱，得到产物。
表1本发明的反应优化表
Figure PCTCN2022123099-appb-000005
本发明的底物适用性研究：本发明在优化的条件下，考察了反应的底物范围(表2)。首先，研究了多种苯乙酮(R 1组)。结果表明，溶剂效应对相变有很大影响。选择DMA作为缺电子苯乙酮衍生物的溶剂可以避免在DMSO溶剂中发生意外的副反应，而且缺电子苯乙酮衍生物所需的反应时间较短。具体而言，吸电子基团氯比给电子基团甲基(表2，3b-3d vs3e-3g)提供更高的产率，并且需要更少的反应时间，并且在其他苯乙酮衍生物(表2，3h-3o)中发现了类似的电子效应。此外，该电解体系还表现出良好的官能团耐受性，包括甲氧基(表2，3h)、羟基(表2，3i)、氟(表2，3j)、酯基(表2，3k)、三氟甲基(表2，3l和3m)、腈基(表2，3n)、磺酰基(表2，3o)。多取代苯乙酮仍然可获得目标产品(表2，3p-3q)。此外，杂芳酮和不饱和酮也适用于该反应(表2，3r、3s和3t)。对于其他底物胺(R 2基团)，杂芳基和烷基取代吡啶基胺均能与苯乙酮成功反应，并以中等产率获得相应的目标产物(表2，3u和3v-3y)。上述结果表明，该方法适用于多种酮类和吡啶甲胺类化合物，具有良好的底物适用性。此外，该方法还可以推广到其他活性甲基化合物的大π-体系的构建。结果表明， 在标准反应条件下，2-甲基喹啉和3-甲基喹啉均适用于该电解反应，并以令人满意的产率获得相应的产物(图4，5a-5e)。通过这种转换，可以有效地构建具有潜在荧光性质的大π-体系。
表2本发明的底物适用性研究表
Figure PCTCN2022123099-appb-000006
实施例2：
本实施例通过进行10mmol规模的反应来评估电化学方法。使用25mA恒流并反应20小时，可获得62％的3a产率(图5)。结果表明了该电化学合成咪唑[1,5-a]吡啶的潜力。
具体地，如图5所示，将苯乙酮(1a，10mmol)、苯基(吡啶-2-基)甲酰胺(2a，20mmol)、NH 4I(15mmol)、(DMSO 50mL)放置在100mL反应管中，该管配有石墨棒阳极(直径＝0.6cm)和铂阴极(1.0cm 2)。在80℃、25mA恒定电流下进行20小时，反应过程通过薄层色谱(TLC)监测。将系统倒入水中(100mL)并用乙酸乙酯(3×150mL)萃取。用饱和盐水洗涤合并的有机相，并用无水Na 2SO 4干燥，减压下浓缩。残留物通过硅胶层析，用乙酸乙酯/己烷(5:1)洗脱，得到产物3a(62％)。
分析本发明的反应机理：NH 4I的阳极氧化生成分子碘，分子碘与酮反应生成α-碘代酮1aa。α-碘酮与胺的亲核取代形成中间体I，中间体I经历阳极氧化脱氢形成中间体II，分子内亲核攻击随后阳极氧化脱氢，得到产物3a。
实施例3：
本实施例与实施例1的区别仅在于：于78℃下进行电解反应，石墨棒的直径为0.7cm；铂片的面积为1.2cm 2。
实施例4：
本实施例与实施例2的区别仅在于：于81℃下进行电解反应。
综上所述，现有技术中，3-酰基咪唑并[1,5-a]吡啶是传统上通过三步反应制备的具有特征性的药物部分，如图7所示，可本发明通过使用碘化铵作为氧化还原介质，将廉价且易于获得的苯乙酮与吡啶乙胺通过电化学串联sp 3(C-H)二次胺化反应一步获得。
产物的NMR谱图数据：
如图8～图9所示，phenyl(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3a) 1Yellow solid. 1H NMR(500MHz,CDCl 3)δ9.96(dd,J＝5.8,4.6Hz,1H),8.66–8.52(m,2H),8.10(dd,J＝8.4,3.7Hz,1H),8.07–7.96(m,2H),7.66–7.51(m,5H),7.47–7.38(m,1H),7.32–7.28(m,1H),7.09(d,J＝4.3Hz,1H). 13C NMR(126MHz,CDCl 3)δ182.19,138.20,134.68,133.99,132.09,131.22,130.98,128.83,128.01,127.61,127.32,125.09,118.41,116.42.HRMS(ESI)m/z[M+H +]calcd for C 20H 14N 2O 298.1106,found 298.1110。
(1-phenylimidazo[1,5-a]pyridin-3-yl)(o-tolyl)methanone(3b) 1Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.93(d,J＝3.6Hz,1H),8.07(d,J＝7.9Hz,1H),7.88(d,J＝3.9Hz,2H),7.81(d,J＝5.6Hz,1H),7.55–7.27(m,7H),7.10(s,1H),2.49(s,3H). 13C NMR(151MHz,CDCl 3)δ186.44,138.74,137.38,135.13,134.46,133.88,131.48,130.92,130.56,130.20,128.78,127.62,127.38,127.23,125.20,124.95,118.46,116.55,20.44.HRMS(ESI)m/z[M+H +]calcd for C 21H 16N 2O 312.1263,found 312.1259。
(1-phenylimidazo[1,5-a]pyridin-3-yl)(m-tolyl)methanone(3c)Yellow solid. 1H NMR(600 MHz,CDCl 3)δ9.91(d,J＝7.1Hz,1H),8.39(d,J＝7.3Hz,1H),8.29(s,1H),8.06(d,J＝9.0Hz,1H),7.96(d,J＝7.5Hz,2H),7.51(t,J＝7.7Hz,2H),7.41(tt,J＝15.0,7.4Hz,3H),7.28–7.24(m,1H),7.05(t,J＝6.8Hz,1H),2.49(s,3H). 13C NMR(151MHz,CDCl 3)δ182.48,138.18,137.62,134.55,134.09,134.01,132.87,131.21,131.15,128.80,128.40,127.85,127.54,127.28,124.99,118.36,116.33,21.51.HRMS(ESI)m/z[M+H +]calcd for C 21H 16N 2O 312.1263,found 312.1268。
(1-phenylimidazo[1,5-a]pyridin-3-yl)(p-tolyl)methanone(3d) 1Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.91(d,J＝7.1Hz,1H),8.39(d,J＝7.3Hz,1H),8.29(s,1H),8.06(d,J＝9.0Hz,1H),7.96(d,J＝7.5Hz,2H),7.51(t,J＝7.7Hz,2H),7.41(tt,J＝15.0,7.4Hz,3H),7.25(d,J＝8.8Hz,1H),7.05(t,J＝6.8Hz,1H),2.49(s,3H). 13C NMR(151MHz,CDCl 3)δ186.44,138.74,137.38,135.13,134.46,133.88,131.48,130.92,130.56,130.20,128.78,127.62,127.38,127.23,125.20,124.95,118.46,116.55,20.44.HRMS(ESI)m/z[M+H +]calcd for C 21H 16N 2O 312.1263,found 312.1266。
(2-chlorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3e) 7Yellow solid. 1H NMR(600 MHz,CDCl 3)δ9.92(d,J＝7.0Hz,1H),8.06(d,J＝9.0Hz,1H),7.85(d,J＝7.6Hz,2H),7.72(d,J＝7.4Hz,1H),7.51–7.31(m,7H),7.13(t,J＝6.8Hz,1H). 13C NMR(151MHz,CDCl 3)δ182.95,138.52,135.86,133.66,132.18,131.96,130.91,130.81,130.11,128.79,127.77,127.43,127.26,126.12,125.74,118.50,116.94.HRMS(ESI)m/z[M+H +]calcd for C 21H 15ClN 2O332.0716,found 332.0720。
(3-chlorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3f)Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.93(d,J＝4.4Hz,1H),8.64–8.38(m,2H),8.10(d,J＝7.4Hz,1H),7.96(d,J＝4.9Hz,2H),7.63–7.29(m,6H),7.11(s,1H). 13C NMR(151MHz,CDCl 3)δ182.95,138.52,135.86,133.85,133.66,132.18,131.96,130.91,130.81,130.11,128.79,127.77,127.43,127.26,126.12,125.74,118.50,116.94.HRMS(ESI)m/z[M+H +]calcd for C 21H 15ClN 2O332.0716,found332.0721。
(4-chlorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3g) 1Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.92(d,J＝5.7Hz,1H),8.54(d,J＝7.2Hz,2H),8.08(d,J＝8.3Hz,1H),7.95(d,J＝6.1Hz,2H),7.51(s,4H),7.40(s,1H),7.30(s,1H),7.09(s,1H). 13C NMR(151MHz,CDCl 3)δ180.55,138.49,136.51,134.91,133.83,132.41,131.40,128.89,128.29,127.76,127.38,127.31,125.37,118.49,116.66.HRMS(ESI)m/z[M+H +]calcd for C 21H 15ClN 2O332.0716,found 332.0720。
(4-methoxyphenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3h) 1Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.90(d,J＝7.2Hz,1H),8.64(d,J＝8.8Hz,2H),8.05(d,J＝9.0Hz,1H),7.97(d,J＝7.3Hz,2H),7.51(t,J＝7.7Hz,2H),7.38(t,J＝7.4Hz,1H),7.24(dd,J＝8.5,7.0Hz, 1H),7.02(dd,J＝11.3,8.0Hz,3H),3.91(s,3H). 13C NMR(151MHz,CDCl 3)δ180.83,162.98,134.18,134.13,133.29,130.89,130.55,128.81,127.49,127.31,127.28,124.71,118.35,116.11,113.64,113.37,55.42.HRMS(ESI)m/z[M+H +]calcd for C 21H 16N 2O 2328.1212,found 328.1208。
(4-hydroxyphenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3i)Yellow solid. 1H NMR(400MHz,DMSO-D6)δ10.36(s,1H),9.77(d,J＝7.0Hz,1H),8.45(d,J＝8.4Hz,2H),8.28(d,J＝9.1Hz,1H),8.01(d,J＝7.4Hz,2H),7.54(t,J＝7.6Hz,2H),7.43(dd,J＝15.4,7.7Hz,2H),7.27(d,J＝6.2Hz,1H),6.94(d,J＝8.6Hz,2H). 13C NMR(151MHz,DMSO-d6)δ179.81,161.75,133.76,133.64,133.33,132.78,130.44,129.07,128.94,127.53,126.93,126.77,125.90,118.64,117.01,115.02.HRMS(ESI)m/z[M+H +]calcd for C 20H 14N 2O 2314.1055,found 314.1051。
(4-fluorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3j) 1Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.92(s,1H),8.64(s,2H),8.08(d,J＝4.3Hz,1H),7.96(s,2H),7.52(s,2H),7.40(s,1H),7.30(s,1H),7.21(s,2H),7.09(s,1H). 13C NMR(151MHz,CDCl 3)δ180.46,165.32(d,JC-F＝252Hz),134.79,134.38,133.87,133.56(d,JC-F＝9.1Hz),131.30,128.90,127.74,127.37,127.34,125.24,118.49,116.58,115.11(d,JC-F＝21.1Hz).HRMS(ESI)m/z[M+H +]calcd for C 20H 13FN 2O 316.1012,found 316.1008。
methyl 4-(1-phenylimidazo[1,5-a]pyridine-3-carbonyl)benzoate(3k)Yellow solid. 1H NMR(500MHz,CDCl 3)δ9.92(d,J＝6.8Hz,1H),8.56(d,J＝7.7Hz,2H),8.18(d,J＝7.8Hz,2H),8.08(d,J＝8.9Hz,1H),7.94(d,J＝7.1Hz,2H),7.51(t,J＝7.0Hz,2H),7.39(d,J＝7.1Hz,1H),7.35–7.27(m,1H),7.10(d,J＝6.3Hz,1H),3.97(s,3H). 13C NMR(151MHz,CDCl 3)δ186.44,138.74,137.38,135.13,134.46,133.88,131.48,130.92,130.56,130.20,128.78,127.62,127.38,127.23,125.20,124.95,118.46,116.55,20.44.HRMS(ESI)m/z[M+H +]calcd for C 22H 16N 2O 3356.1161,found 356.1165。
(1-phenylimidazo[1,5-a]pyridin-3-yl)(2-(trifluoromethyl)phenyl)methanone(3l)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.89(d,J＝7.1Hz,1H),8.06(d,J＝31.6Hz,1H),7.87–7.75(m,4H),7.69–7.58(m,2H),7.45(t,J＝7.6Hz,2H),7.34(dd,J＝9.0,6.9Hz,2H),7.17–7.11(m,1H). 13C NMR(101MHz,CDCl 3)δ183.58,138.29,135.80,133.80,133.55,132.01,130.99,130.16,129.72,128.79,128.43(q,JC-F＝32.3Hz),127.80,127.42,127.23,126.95(q,JC-F＝4.8Hz),125.83,123.93(q,JC-F＝274Hz),118.51,117.05.HRMS(ESI)m/z[M+H +]calcd for C 21H 13F 3N 2O366.0980,found 366.0985。
(1-phenylimidazo[1,5-a]pyridin-3-yl)(4-(trifluoromethyl)phenyl)methanone(3m)Yellow solid. 1H NMR(600MHz,CDCl 3)δ9.94(d,J＝7.1Hz,1H),8.63(d,J＝8.1Hz,2H),8.09(d,J＝9.0Hz,1H),8.00–7.92(m,2H),7.79(d,J＝8.2Hz,2H),7.52(t,J＝7.7Hz,2H),7.40(t,J＝7.4Hz,1H),7.33(ddd,J＝8.9,6.7,0.8Hz,1H),7.12(td,J＝7.1,1.0Hz,1H). 13C NMR(151MHz,CDCl 3)δ180.53,141.22,135.37,133.76,133.67,133.7(q,JC-F＝21.2Hz),131.67,131.18,128.91,127.88, 127.41,127.32,125.73,124.92(q,JC-F＝3.7Hz),124.01(q,JC-F＝272Hz),118.55,116.93.HRMS(ESI)m/z[M+H +]calcd for C 21H 13F 3N 2O366.0980,found 366.0984。
(2-nitrophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3n)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.81(d,J＝7.1Hz,1H),8.16–8.11(m,1H),8.01(d,J＝9.1Hz,1H),7.80–7.71(m,4H),7.67–7.62(m,1H),7.43(t,J＝7.6Hz,2H),7.30(dt,J＝6.8,4.2Hz,2H),7.11(td,J＝7.0,1.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ181.01,148.79,135.76,135.33,133.40,133.29,131.91,130.64,130.15,128.77,127.79,127.29,126.86,125.71,123.80,118.59,117.06.HRMS(ESI)m/z[M+H +]calcd for C 20H 13N 3O 3343.0957,found 343.0953。
(4-(methylsulfonyl)phenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3o)Yellow solid. 1H NMR(400MHz,DMSO-D6)δ9.84(d,J＝6.7Hz,1H),8.55(d,J＝7.9Hz,2H),8.37(d,J＝9.0Hz,1H),8.13(d,J＝7.8Hz,2H),8.00(d,J＝7.3Hz,2H),7.55(dd,J＝17.9,11.2Hz,3H),7.41(s,2H),2.50(s,3H). 13C NMR(101MHz,DMSO-D6)δ179.50,143.15,142.17,134.21,133.16,133.09,131.41,131.22,128.95,127.78,127.20,126.93,126.64,118.72,117.97,43.33.HRMS(ESI)m/z[M+H +]calcd for C 21H 16N 2O 3S376.0882,found 376.0886。
(3,4-difluorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3p)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.90(d,J＝7.1Hz,1H),8.56(ddd,J＝11.5,8.0,2.0Hz,1H),8.50–8.39(m,1H),8.08(d,J＝9.0Hz,1H),7.95(d,J＝7.2Hz,2H),7.53(t,J＝7.6Hz,2H),7.40(t,J＝7.4Hz,1H),7.35–7.28(m,2H),7.09(t,J＝6.5Hz,1H). 13C NMR(101MHz,CDCl 3)δ178.64,152.99(dd,JC-F＝257Hz,13.1Hz),149.75(dd,JC-F＝249Hz,12.1Hz),135.10,134.96(dd,JC-F＝13.9Hz,8.8Hz),133.67,133.61,131.49,128.93,128.18–127.72(m),127.41,127.31,125.56,120.45(d,JC-F＝20.2Hz),118.53,116.82(t,JC-F＝8.8Hz).HRMS(ESI)m/z[M+H +]calcd for C 20H 12F 2N 2O334.0918,found 334.0914。
(2,4-dichlorophenyl)(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3q)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.89(d,J＝7.1Hz,1H),8.08(d,J＝9.0Hz,1H),7.89–7.82(m,2H),7.69(d,J＝8.3Hz,1H),7.52(d,J＝1.9Hz,1H),7.47(t,J＝7.6Hz,2H),7.36(td,J＝8.3,2.0Hz,3H),7.18–7.12(m,1H). 13C NMR(101MHz,CDCl 3)δ181.61,136.88,136.36,136.09,133.65,133.50,133.27,132.15,131.87,130.04,128.85,127.92,127.41,127.27,126.52,126.00,118.58,117.15.HRMS(ESI)m/z[M+H +]calcd for C 20H 12C l2N 2O366.0327,found 366.0331。
naphthalen-1-yl(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3r)Yellow solid. 1H NMR(600MHz,CDCl 3)δ10.05(s,1H),8.35(s,1H),8.23–7.97(m,3H),7.89(m,3H),7.48(m,7H),7.17(s,1H). 13C NMR(151MHz,CDCl 3)δ185.27,135.24,134.83,133.93,131.70,131.37,131.25,128.80,128.41,127.80,127.46,127.31,126.95,126.03,125.57,125.45,124.42,118.55,116.81.HRMS(ESI)m/z[M+H +]calcd for C 24H 16N 2O348.1263,found 348.1267。
furan-2-yl(1-phenylimidazo[1,5-a]pyridin-3-yl)methanone(3s)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.88(d,J＝6.6Hz,1H),8.36(s,1H),8.01(dd,J＝31.0,7.9Hz,3H),7.75(s,1H),7.52(t,J＝6.9Hz,2H),7.44–7.23(m,2H),7.04(t,J＝6.1Hz,1H),6.65(s,1H). 13C NMR(101MHz,CDCl 3)δ169.31,151.51,146.87,134.64,133.96,132.85,131.29,128.87,127.66,127.21,127.06,124.94,122.06,118.51,116.47,112.35.HRMS(ESI)m/z[M+H +]calcd for C 18H 12N 2O 2288.0899,found 288.0898。
(E)-3-phenyl-1-(1-phenylimidazo[1,5-a]pyridin-3-yl)prop-2-en-1-one(3t)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.91(d,J＝7.1Hz,1H),8.36(d,J＝16.0Hz,1H),8.04(d,J＝9.1Hz,1H),8.01–7.95(m,2H),7.91(d,J＝16.0Hz,1H),7.76(dd,J＝7.7,1.4Hz,2H),7.53(t,J＝7.7Hz,2H),7.46–7.37(m,4H),7.28-7.24(m,1H),7.06(td,J＝7.1,1.0Hz,1H). 13C NMR(101MHz,CDCl 3)δ178.76,141.98,135.32,134.69,133.87,131.63,130.10,128.88,128.78,128.65,127.70,127.33,127.21,125.02,123.65,118.46,116.41.HRMS(ESI)m/z[M+H +]calcd for C 22H 16N 2O324.1263,found 324.1267。
phenyl(1-(pyridin-2-yl)imidazo[1,5-a]pyridin-3-yl)methanone(3u)Yellow solid. 1H NMR(400MHz,CDCl 3)δ9.91(d,J＝7.1Hz,1H),9.00(d,J＝9.0Hz,1H),8.67(s,1H),8.53(d,J＝7.3Hz,2H),8.29(d,J＝7.6Hz,1H),7.77(t,J＝7.7Hz,1H),7.65–7.49(m,3H),7.41–7.33(m,1H),7.20(s,1H),7.11(t,J＝6.5Hz,1H). 13C NMR(101MHz,CDCl 3)δ182.25,153.96,148.80,138.17,136.52,133.78,133.19,132.70,132.15,130.99,128.01,127.11,126.15,121.63,121.42,120.68,117.05.HRMS(ESI)m/z[M+H +]calcd for C 19H 13N 3O299.1059,found 299.1056。
(1-methylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone(3v)Yellow solid. 1H NMR(600MHz,DMSO-D6)δ9.70(d,J＝6.3Hz,1H),8.28(d,J＝6.5Hz,2H),7.98(d,J＝8.6Hz,1H),7.57(m,3H),7.41–7.32(m,1H),7.29–7.21(m,1H),2.56(s,3H). 13C NMR(101MHz,DMSO-D6)δ179.69,137.60,131.88,131.23,129.70,127.40,125.62,123.83,117.51,116.69,12.19.HRMS(ESI)m/z[M+H +]calcd for C 15H 12N 2O,236.0950,found 236.0954。
(1-isobutylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone(3w)Yellow solid. 1H NMR(400MHz,DMSO-D6)δ9.72(d,J＝5.7Hz,1H),8.32(d,J＝5.4Hz,2H),7.99(d,J＝7.5Hz,1H),7.57(dd,J＝21.1,4.9Hz,3H),7.42–7.15(m,2H),2.82(s,2H),2.07(s,1H),0.94(s,6H). 13C NMR(101MHz,DMSO-D6)δ180.26,138.08,135.87,132.26,131.79,130.29,127.91,126.10,124.43,117.97,117.12,109.61,35.44,28.74,22.22.HRMS(ESI)m/z[M+H +]calcd for C 18H 18N 2O,278.1419,found 278.1416。
(1-cyclopropylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone(3x) 1H NMR(400MHz,DMSO-D6)δ9.68(d,J＝5.5Hz,1H),8.27(d,J＝6.5Hz,2H),8.08(d,J＝7.9Hz,1H),7.54(dd,J＝20.9,5.8Hz,3H),7.32(d,J＝4.9Hz,1H),7.20(s,1H),2.39(s,1H),1.08–0.80(m,4H).13C NMR(101MHz,DMSO-D6)δ179.00,137.20,136.99,131.36,130.98,130.86,129.51,127.09, 125.39,123.50,117.04,116.58,7.35,6.84.HRMS(ESI)m/z[M+H +]calcd for C 17H 14N 2O,262.1106,found 262.1110。
(1-isopropylimidazo[1,5-a]pyridin-3-yl)(phenyl)methanone(3y)Yellow solid. 1H NMR(400MHz,DMSO-D6)δ9.71(d,J＝6.3Hz,1H),8.35(d,J＝6.9Hz,2H),8.02(d,J＝8.5Hz,1H),7.56(dd,J＝18.6,6.7Hz,3H),7.32(d,J＝7.5Hz,1H),7.21(s,1H),3.43(dd,J＝12.7,6.3Hz,1H),1.34(s,3H),1.33(s,3H). 13C NMR(151MHz,DMSO-d6)δ180.06,141.81,138.02,132.21,131.81,130.49,130.27,127.93,126.13,124.30,117.96,117.23,26.30,22.33.HRMS(ESI)m/z[M+H +]calcd for C 17H 16N 2O,264.1263,found 264.1266。
如图10～图11所示，2-(1-phenylimidazo[1,5-a]pyridin-3-yl)quinoline(5a)Yellow solid. 1H NMR(400MHz,CDCl 3)δ10.48(d,J＝7.1Hz,1H),8.73(d,J＝8.2Hz,1H),8.23(d,J＝8.6Hz,1H),8.16(d,J＝8.2Hz,1H),7.99(dd,J＝20.2,8.1Hz,3H),7.82(d,J＝7.9Hz,1H),7.73(t,J＝7.2Hz,1H),7.52(t,J＝7.1Hz,3H),7.36(t,J＝7.1Hz,1H),7.10–7.01(m,1H),6.93(d,J＝6.5Hz,1H). 13C NMR(101MHz,CDCl 3)δ150.69,147.36,136.01,134.90,134.78,132.72,129.81,129.55,128.97,128.81,127.70,127.08,126.95,126.90,126.13,121.68,120.71,118.38,114.18.HRMS(ESI)m/z[M+H +]calcd for C 22H 15N 3321.1266,found 321.1262。
6-methyl-2-(1-phenylimidazo[1,5-a]pyridin-3-yl)quinoline(5b)Yellow solid. 1H NMR(400MHz,CDCl 3)δ10.44(d,J＝6.5Hz,1H),8.61(d,J＝8.5Hz,1H),8.12(d,J＝8.3Hz,1H),8.08–7.92(m,4H),7.59–7.48(m,4H),7.35(d,J＝6.9Hz,1H),7.03–6.95(m,1H),6.87(t,J＝5.9Hz,1H),2.55(s,3H). 13C NMR(101MHz,CDCl 3)δ149.92,145.74,135.96,135.31,135.02,134.88,132.48,131.67,129.57,128.72,128.58,128.47,126.91,126.82,126.70,126.61,121.42,120.56,118.24,113.92,21.54.HRMS(ESI)m/z[M+H +]calcd for C 23H 17N 3335.1422,found 335.1425。
6-chloro-2-(1-phenylimidazo[1,5-a]pyridin-3-yl)quinolone(5c)Yellow solid. 1H NMR(400MHz,CDCl 3)δ10.35(d,J＝6.8Hz,1H),8.64(d,J＝8.6Hz,1H),8.08-7.93(m,5H),7.75(s,1H),7.62(d,J＝8.5Hz,1H),7.51(t,J＝7.2Hz,2H),7.36(d,J＝6.8Hz,1H),7.05–6.98(m,1H),6.88(d,J＝6.4Hz,1H). 13C NMR(101MHz,CDCl 3)δ150.83,145.65,134.93,134.67,134.50,132.97,131.53,130.35,130.32,129.94,128.78,127.45,126.98,126.91,126.81,126.37,121.80,121.45,118.37,114.28.HRMS(ESI)m/z[M+H +]calcd for C 22H 14ClN 3355.0876,found 355.0872。
6-bromo-2-(1-phenylimidazo[1,5-a]pyridin-3-yl)quinoline(5d)Yellow solid. 1H NMR(400MHz,CDCl 3)δ10.32(d,J＝7.3Hz,1H),8.61(d,J＝8.8Hz,1H),8.05–7.97(m,3H),7.95–7.87(m,3H),7.73(dd,J＝8.9,2.2Hz,1H),7.51(t,J＝7.7Hz,2H),7.36(d,J＝7.4Hz,1H),7.03–6.96(m,1H),6.89–6.81(m,1H). 13C NMR(101MHz,CDCl 3)161.53,150.96,145.90,134.83,132.89,130.52,129.73,128.91,128.84,127.41,127.07,127.02,126.96,126.15,122.70,121.87, 121.45,118.37,115.17,114.31.HRMS(ESI)m/z[M+H +]calcd for C 22H 14BrN 3399.0371,found399.0376。
2-(1-phenylimidazo[1,5-a]pyridin-3-yl)quinoxaline(5e)Yellow Solid. 1H NMR(400MHz,CDCl 3)δ10.32(d,J＝7.3Hz,1H),8.61(d,J＝8.8Hz,1H),8.05–7.97(m,3H),7.95–7.87(m,3H),7.73(dd,J＝8.9,2.2Hz,1H),7.51(t,J＝7.7Hz,2H),7.36(d,J＝7.4Hz,1H),7.03–6.96(m,1H),6.89–6.81(m,1H). 13C NMR(101MHz,CDCl 3)δ161.53,133.94,132.19,130.25,129.10,128.91,128.22,127.41,127.07,126.15,122.70,118.37,115.17.HRMS(ESI)m/z[M+H +]calcd for C 21H 14N 4 322.1218,found 322.1222。
尽管根据有限数量的实施例描述了本发明，但是受益于上面的描述，本技术领域内的技术人员明白，在由此描述的本发明的范围内，可以设想其它实施例。此外，应当注意，本说明书中使用的语言主要是为了可读性和教导的目的而选择的，而不是为了解释或者限定本发明的主题而选择的。因此，在不偏离所附权利要求书的范围和精神的情况下，对于本技术领域的普通技术人员来说许多修改和变更都是显而易见的。对于本发明的范围，对本发明所做的公开是说明性的，而非限制性的，本发明的范围由所附权利要求书限定。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (5)

  1. [4+1]酮甲基二次胺化反应一步直接制备3-酰基咪唑[1,5-a]吡啶的方法，其特征在于，包括以下步骤：在10～25mA恒流条件下，在无隔膜电解槽中，于78～81℃下，电解1当量的
    Figure PCTCN2022123099-appb-100001
    2当量的
    Figure PCTCN2022123099-appb-100002
    和1.5当量的NH 4I 16～20h，得到产物3-酰基咪唑[1,5-a]吡啶；
    所述R 1基选自苯基、2-甲基苯基、3-甲基苯基、4-甲基苯基、2-氯苯基、3-氯苯基、4-氯苯基、4-甲氧基苯基、4-羟基苯基、4-氟苯基、4-羧甲基苯基、2-CF 3-苯基、4-CF 3-苯基、2-NO 2-苯基、4-S(O) 2Me-苯基、
    Figure PCTCN2022123099-appb-100003
    Figure PCTCN2022123099-appb-100004
    所述R 2基选自苯基、甲基、
    Figure PCTCN2022123099-appb-100005
  2. 根据权利要求1所述的方法，其特征在于，溶剂为DMSO或DMA。
  3. 根据权利要求1所述的方法，其特征在于，所述无隔膜电解槽的阳极为石墨棒，阴极为铂片。
  4. 根据权利要求3所述的方法，其特征在于，所述石墨棒的直径为0.6～0.7cm；所述铂片的面积为1.0～1.2cm 2。
  5. 根据权利要求2所述的方法，其特征在于，电解反应结束后，加入水，水的加入量相当 于溶剂体积的2～3.3倍，获得水溶液，再用乙酸乙酯萃取水溶液至少三次，每次乙酸乙酯的加入量为水的体积的1.5～5倍，合并萃取得到的有机相；再用饱和盐水洗涤合并的有机相，用无水Na 2SO 4干燥，减压下浓缩；残留物通过硅胶层析，用乙酸乙酯/己烷5:1洗脱，得到产物。
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