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Chinese Journal of Organic Chemistry >

2025 , Vol. 45 >Issue 7: 2501 - 2508

DOI: https://doi.org/10.6023/cjoc202411013

ARTICLES

Rhodium Catalyzed Insertion Reaction of Diazothiooxindoles for Construction of Benzothiophene Derivatives

  • Xiaoyuan Cui , a, * ,
  • Fang Jin a ,
  • Xin Huang a ,
  • Tao Qin a ,
  • Congbin Ji , b, *
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  • a Department of Chemistry & Chemical Engineering, Jinzhong University, Jinzhong, Shanxi 030619
  • b School of Chemistry and Environmental Sciences, Shangrao Normal University, Shangrao, Jiangxi 334001
*E-mail: ;

Received date: 2024-11-14

  Revised date: 2025-01-04

  Online published: 2025-02-17

Supported by

Project supported by the Jinzhong University Research Funds for Doctor

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Abstract

Multi-substituted benzothiophene skeleton is an important synthetic intermediate, and the insertion reaction of diazo compounds catalyzed by transition metals provides a practical method for the synthesis of such compounds. This article uses Rhodium as catalyst to achieve the insertion reaction between diazothiooxindoles and pyridine carbonate compounds, providing a series of multi substituted benzothiophene compounds with good yield. This reaction has the characteristics of mild conditions and practical efficiency. At the same time, biological activity tests were conducted on several cell lines using the product, including NIH-3T3, B16-F10, 4T1 and HCT116.

Key words： multi-substituted benzothiophene; diazo compounds; metal catalysis

Cite this article

Xiaoyuan Cui , Fang Jin , Xin Huang , Tao Qin , Congbin Ji . Rhodium Catalyzed Insertion Reaction of Diazothiooxindoles for Construction of Benzothiophene Derivatives[J]. Chinese Journal of Organic Chemistry, 2025 , 45(7) : 2501 -2508 . DOI: 10.6023/cjoc202411013

苯并[b]噻吩, 尤其是多取代苯并噻吩骨架是一类重要的合成片段[1], 常作为许多生物活性化合物、药物分子及天然产物的核心成分, 如图1雷洛昔芬(Raloxifene)可以用于预防和治疗绝经后妇女的骨质疏松症, 有很强的抗雌激素的能力[2], 对真菌感染的病原菌有抗菌、杀菌作用的舍他康唑(Sertaconazole)[3]结构中也具有这类片段. Ibogaine可以作为抗毒瘾剂和抗抑郁症药物的关键原料[4]. 苯并[b]噻吩类衍生物还可以用于制备除草剂和杀虫剂[5]. 此外, 多取代苯并[b]噻吩衍生物在有机电子器件, 如发光二极管(OLEDs)和光伏(OPVs)等方面也具有重要应用[6]. 因此, 为了满足这些研究领域日益增长的需求, 开发有效的合成方法来制备多取代苯并[b]噻吩及其类似物已成为近年来有机合成化学的一个重要研究方向.
图1 苯并噻吩骨架在药物和光电材料中的应用

Figure 1 Application of benzothiophene skeleton in drugs and optoelectronic materials

尽管化学家们已经开发出许多苯并噻吩的合成方法[7], 例如过渡金属催化的反应, 但由于构建苯并噻吩骨架和引入取代基的方法有限, 多取代苯并噻吩的合成仍然困难[8]. 目前多取代苯并噻吩的合成主要有分子内环化[9]及分子间成环[10]两种策略, 如Scheme 1所示. 在环化策略中, 由于反应条件的限制, 适用范围相对受限, 对于其他杂环结构也没有很好地兼容性, 局限性较大. 成环策略为这类化合物的合成提供了另一种行之有效的方法, 但在成环策略中, 需要合成相应的环化前体或用吸电性炔烃或者烯烃底物, 反应实用性及底物适用性均有待提高.
图式1 铑催化硫代重氮氧化吲哚的插入反应

Scheme 1 Rhodium catalyzed insertion reaction of diazothiooxindoles

过渡金属催化的重氮化合物的插入反应在过去几十年中得到了飞速发展, 为多种类型的化合物提供了一种直接快速的构建方法[11]. 根据我们所知, 目前这类方法并没有应用于多取代苯并噻吩的高效构建中. 高原子利用率反应的开发研究一直是化学家们关注的焦点[12], 其中有不乏高效构建硫杂环的研究工作[13]. 因此, 发展重氮化合物的插入反应, 实用、高原子利用率地构建苯并噻吩骨架具有重要的研究价值. 本文采用硫代重氮氧化吲哚以及芳基羧酸2-吡啶酯作为原料, 在金属铑催化剂催化下实现了多取代苯并噻吩化合物的高效构建, 操作简单, 底物范围广泛, 为这类片段的构建提供了新型简单的方法.

1 结果与讨论

1.1 反应条件优化

首先, 选取重氮硫代氧化吲哚(1a)和4-甲基吡啶-2-苯甲酸酯(2a)作为模板底物进行条件优化, 实验结果见表1. 首先, 在氮气氛围中, 以二氯甲烷(DCM)为溶剂, 在50 ℃下对反应催化剂进行了初步筛选, 发现当使用Ph3PAuOTf和AgOTf为催化剂时, 反应仅能得到痕量的苯并噻吩类衍生物. 当使用Fe(OTf)3和Cu(OTf)2为催化剂时, 反应无法发生, 未检测到相应产物(表1, Entries 1~4). 基于本课题组[14]前期工作的启发, 我们猜测金属铑能够有效催化这类反应, 随后在反应中加入2.0 mol% Rh2(OAc)4作为催化剂时, 反应收率提高至68% (表1, Entry 5). 在对铑催化剂筛选时发现, 当使用Rh2(esp)2作为催化剂, 反应的收率能够进一步提高, 以75%的分离产率得到所需的产物3a(表1, Entry 6). 随后, 考察了不同溶剂对反应的影响, 发现1,2-二氯乙烷(DCE)作为溶剂时, 反应收率能够进一步提升至84%(表1, Entry 8). 采用甲苯、乙酸乙酯及四氢呋喃作为溶剂, 反应效果均不理想. 因此最终选择DCE作为反应溶剂. 基于上述优化结果, 确定了该反应的最佳反应条件: 2.0 mol%的Rh2(esp)2为催化剂, 1,2-二氯乙烷为溶剂, 在室温下于氮气氛围中反应2 h, 以84%的收率得到相应苯并噻吩类产物3a.
表1 反应条件的筛选和优化a

Table 1 Screening and optimization of reaction conditions

Entry Catalyst Solvent Temp./℃ Yielda/%
1 Ph3PAuOTf DCM 50 8
2 Fe(OTf)3 DCM 50 nr
3 AgOTf DCM 50 6
4 Cu(OTf)2 DCM 50 nr
5 Rh2(OAc)4 DCM 50 68
6 Rh2(esp)2 DCM 50 75
7 Rh2(esp)2 DCM 50 70
8 Rh2(esp)2 DCE 50 84
9 Rh2(esp)2 Toluene 50 22
10 Rh2(esp)2 EtOAc 50 30
11 Rh2(esp)2 THF 50 21
12 Rh2(esp)2 DCE 40 74
13 Rh2(esp)2 DCE 60 79

a Isolated yield; nr: no reaction.

1.2 底物扩展及克级规模制备

确定了最优反应条件后, 采用Rh2(esp)2为催化剂, 对重氮化转移反应的底物范围进行了拓展. 具体结果见表2. 首先对吡啶酮的底物范围进行了考察, 根据结果可以看出: 氟、氯、溴等卤素(3c~3i)基团均能兼容反应条件, 以70%~75%的收率得到目标产物. 值得一提的是, 卤素的引入为后续进一步官能团化反应提供了可能. 反应底物的位阻作用对于反应并没有影响, 当使用邻位溴取代的底物时, 反应能以67%的收率得到相应产物(3j).
表2 底物范围

Table 2 Scope of substrate

随后考察了酰基片段的适用性, 发现芳基氯仍旧可以兼容反应条件. 此外, 噻吩基(3p)也可以兼容, 但是反应收率有所降低. 最后, 对苯并噻吩骨架进行了考察, 发现烷基(3q, 3s~3t)、卤素(3r)、醚(3u)等取代的苯并噻吩均可以适用反应条件, 此外双烷基取代底物也能够以73%~81%的收率得到目标产物(3v~3x).
为了说明反应的实用性, 随后对反应进行了克级规模的研究, 如Scheme 2所示. 当把反应扩大至4.0 mmol时, 仍然能以80%的收率得到产物(1.2 g). 除了苯并噻吩骨架, 进一步将这个方法应用于多取代异色烯衍生物的合成, 使用3-异色酮类重氮底物4a, 在标准条件下反应仍能以63%的收率得到相应目标产物5a.
图式2 克级反应以及异色烯骨架的合成

Scheme 2 Gram-scale reaction and synthesis of heterochromenes

1.3 可能机理

根据文献调研[15], 提出了反应的可能机理, 如Scheme 3所示. 硫代重氮氧化吲哚1在金属铑催化剂分解下产生铑卡宾, 接着与芳基羧酸2-吡啶酯2发生插入反应得到中间体I, 接着发生分子内去金属化反应得到两性离子中间体II, 最后进行分子内的1,6-酰基迁移, 即可得到苯并噻吩类衍生物3.
图式3 可能的反应机理

Scheme 3 Proposed reaction mechanism

1.4 生物活性研究

考虑到苯并噻吩衍生物在药学中的应用, 因此对其抗肿瘤活性进行了研究, 其中包括胚胎细胞、黑色素瘤细胞、乳腺癌细胞以及结肠癌细胞. 其中化合物3a在浓度为100 μg/mL的条件下, 作用时间为72 h, 利用噻唑蓝(MTT)检测法评估了化合物3a对癌细胞的增殖抑制作用. 该实验也有了一些初步的结果: 可以看到化合物3a对NIH-3T3、B16-F10、4T1和HCT116癌细胞均表现出一定的抑制作用, 其中对B16-F10细胞的抑制率最高可以达到60.82%, 该类化合物的生物活性研究还在进一步探索中.

2 结论

本文报道了铑催化硫代重氮氧化吲哚与芳基羧酸2-吡啶酯的插入反应, 在Rh2(esp)2的催化下均能够以中等到良好收率以及区域选择性得到目标产物, 并且对产物的抗肿瘤活性进行了初步筛选, 发现对B16-F10细胞有一定抑制效果. 该反应为苯并噻吩酮的多样性合成提供了一种简单、高效的方法.

3 实验部分

3.1 仪器与试剂

显微熔点仪(SGWX-4型); 质谱测定仪HRMS (ESI) (Bruker Daltonics Apex III); 红外光谱仪(SHIMADZU IRTracer-100型); 1H NMR和13C NMR在400 MHz核磁共振仪(Bruker DPX-400或500)上测定, CDCl3为溶剂, TMS为内标. 所用试剂均为分析纯或化学纯, 使用前未经纯化. NIH-3T3、B16-F10、4T1和HCT116细胞抑制率测试均由武汉华研生物科技有限公司测定.

3.2 实验方法

3.2.1 化合物3的合成

氮气氛围下, 在预先干燥的10 mL Schlenk管中依次加入Rh2(esp)2 (0.004 mmol)、硫代重氮氧化吲哚衍生物1 (0.2 mmol)、吡啶类苯甲酸酯衍生物2 (0.2 mmol)和无水1,2-二氯乙烷(2.0 mL). 50 ℃反应2 h, 用TLC监测原料反应完毕, 柱层析硅胶柱中纯化[淋洗剂: V(石油醚)∶V(乙酸乙酯)=3∶1~1.5∶1], 减压浓缩纯化得到目标产物3.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3a): 60.6 mg, 黄色固体, 产率84%. m.p. 173~178 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.06 (m, 2H), 7.80~7.78 (m, 1H), 7.50~7.38 (m, 5H), 7.26~7.24 (m, 1H), 6.58~6.57 (m, 1H), 6.16~6.14 (m, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.5, 161.8, 152.2, 146.3, 137.3, 134.5, 132.6, 131.6, 130.5, 128.9, 127.5, 125.3, 125.1, 122.6, 120.7, 120.2, 119.0, 109.0, 21.6; IR (ATR) ν: 1744, 1373, 1250, 1103, 1049, 856, 756 cm－1; HRMS (ESI) calcd for C21H16NO3S [M＋H]＋ 362.0851, found 362.0854.
3-[2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3b): 58.3 mg, 黄色固体, 产率79%. m.p. 156~158 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.06 (d, J=6.4 Hz, 2H), 7.82~7.80 (m, 1H), 7.66~7.63 (m, 1H), 7.53~7.26 (m, 7H), 6.82 (d, J=7.2 Hz, 1H), 6.33 (t, J=5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.4, 161.8, 146.3, 140.4, 138.7, 134.6, 132.6, 131.4, 130.5, 128.9, 127.5, 125.4, 125.2, 122.7, 122.2, 120.6, 119.4, 106.3; IR (ATR) ν: 1744, 1389, 1250, 1111, 1018, 910, 756 cm－1; HRMS (ESI) calcd for C20H13NO3SNa [M＋Na]＋ 370.0514, found 370.0517.
3-[4-氯-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3c): 57.2 mg, 黄色固体, 产率75%. m.p. 174~175 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.06 (m, 2H), 7.82~7.80 (m, 1H), 7.68~7.64 (m, 1H), 7.53~7.49 (m, 2H), 7.43~7.39 (m, 3H), 7.34~7.32 (m, 1H), 6.84~6.83 (m, 1H), 6.37~6.34 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.4, 160.4, 147.6, 146.7, 138.6, 134.7, 132.6, 131.2, 130.5, 129.0, 127.3, 125.5, 125.3, 122.7, 120.5, 120.4, 118.0, 108.3; IR (ATR) ν: 1744, 1674, 1597, 1304, 1134, 756, 702 cm－1; HRMS (ESI) calcd for C20H13Cl- NO3S [M＋H]＋ 382.0305, found 382.0296.
3-[4-溴-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3d): 64.6 mg, 黄色固体, 产率76%. m.p. 169~172 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.05 (m, 2H), 7.81~7.79 (m, 1H), 7.68~7.64 (m, 1H), 7.52~7.49 (m, 2H), 7.42~7.39 (m, 3H), 7.26~7.24 (m, 1H), 7.033~7.028 (m, 1H), 6.48~6.46 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.4, 160.2, 146.7, 138.3, 136.5, 134.7, 132.6, 131.1, 130.5, 129.0, 127.3, 125.5, 124.1, 122.7, 120.4, 118.0, 110.7; IR (ATR) ν: 1744, 1667, 1520, 1196, 1080, 1049, 702 cm－1; HRMS (ESI) calcd for C20H13BrNO3S [M＋H]＋ 425.9800, found 425.9805.
3-[5-溴-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3e): 62.8 mg, 黄色固体, 产率74%. m.p. 169~171 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.06 (m, 2H), 7.82~7.79 (m, 1H), 7.68~7.64 (m, 1H), 7.55~7.48 (m, 4H), 7.45~7.40 (m, 3H), 6.72~6.70 (m, 1H); 13C NMR (125 MHz, CDCl3) δ: 162.2, 160.2, 146.6, 143.5, 138.2, 134.7, 132.5, 130.8, 130.5, 129.0, 127.3, 125.6, 125.3, 123.2, 122.7, 120.4, 117.8, 98.3; IR (ATR) ν: 1744, 1674, 1597, 1304, 1134, 756, 702 cm－1; HRMS (ESI) calcd for C20H13BrNO3S [M＋H]＋ 425.9800, found 425.9793.
3-[3-溴-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3f): 61.1 mg, 黄色固体, 产率72%. m.p. 170~172 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.06~8.03 (m, 2H), 7.92~7.89 (m, 1H), 7.81~7.79 (m, 1H), 7.65~7.63 (m, 1H), 7.51~7.47 (m, 2H), 7.42~7.39 (m, 4H), 6.24~6.21 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.3, 157.9, 146.5, 142.2, 138.2, 134.6, 132.5, 131.0, 130.5, 128.9, 127.3, 125.5, 125.2, 122.7, 120.5, 118.7, 117.8, 106.1; IR (ATR) ν: 1744, 1667, 1543, 1520, 1250, 795, 702 cm－1; HRMS (ESI) calcd for C20H13BrNO3S [M＋H]＋ 425.9800, found 425.9807.
3-[5-氯-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3g) 55.6 mg, 黄色固体, 产率73%. m.p. 131~133 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.05 (m, 2H), 7.82~7.79 (m, 1H), 7.67~7.63 (m, 1H), 7.52~7.39 (m, 7H), 6.77~6.75 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.2, 160.1, 146.7, 141.5, 135.9, 134.7, 132.6, 130.9, 130.5, 129.0, 127.3, 125.5, 125.3, 122.8, 122.7, 120.3, 117.9, 112.8; IR (ATR) ν: 1744, 1311, 1242, 1018, 957, 795, 702 cm－1; HRMS (ESI) calcd for C20H13ClNO3S [M＋H]＋ 382.0305, found 382.0298.
3-[5-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3h): 57.8 mg, 黄色固体, 产率80%. m.p. 162~164 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.06 (m, 2H), 7.81~7.78 (m, 1H), 7.66~7.62 (m, 1H), 7.45~7.34 (m, 6H), 7.14~7.13 (m, 1H), 6.73 (d, J=9.2 Hz, 1H), 2.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.4, 161.2, 146.2, 143.2, 135.6, 134.5, 132.7, 131.5, 130.5, 128.9, 127.6, 125.3, 125.1, 122.6, 121.7, 120.6, 119.1, 115.2, 17.0; IR (ATR) ν: 1744, 1389, 1204, 1080, 825, 756, 702 cm－1; HRMS (ESI) calcd for C21H16NO3S [M＋H]＋ 362.0851, found 362.0852.
3-[3-氟-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3i): 51.1 mg, 黄色固体, 产率70%. m.p. 168~171 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.04 (m, 2H), 7.82~7.80 (m, 1H), 7.67~7.63 (m, 1H), 7.51~7.40 (m, 5H), 7.28~7.20 (m, 2H), 6.27~6.23 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.3, 155.6 (d, JC-F=21.0 Hz), 153.0 (d, JC-F=200.0 Hz), 146.7, 134.7, 134.0 (d, JC-F=4.0 Hz), 132.6, 131.0, 130.5, 128.9, 127.3, 125.5, 125.3, 122.7, 120.6 (d, JC-F=13.0 Hz), 120.4, 117.8 (d, JC-F=1.0 Hz), 104.1 (d, JC-F=5.0 Hz); 19F NMR (376 MHz, CDCl3): δ: －128.27; IR (ATR) ν: 1744, 1620, 1242, 1180, 1080, 748, 702 cm－1; HRMS (ESI) calcd for C20H13FNO3S [M＋H]＋ 366.0600, found 366.0604.
3-[5-甲基-6-溴-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3j): 58.7 mg, 黄色固体, 产率67%. m.p. 181~183 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.10~8.07 (m, 2H), 7.81~7.78 (m, 1H), 7.67~7.63 (m, 1H), 7.57 (s, 1H), 7.52~7.48 (m, 2H), 7.45~7.39 (m, 3H), 6.70~6.69 (m, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.3, 160.5, 151.6, 146.6, 137.6, 134.6, 132.5, 131.1, 130.5, 128.9, 127.4, 125.5, 125.2, 122.7, 121.1, 120.5, 117.7, 102.6, 22.9; IR (ATR) ν: 1744, 1597, 1204, 1080, 856, 756, 702 cm－1; HRMS (ESI) calcd for C21H15BrNO3S [M＋H]＋ 439.9956, found 439.9958.
3-[3,5-二氯-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3k): 54.0 mg, 黄色固体, 产率65%. m.p. 136~139 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.09~8.05 (m, 2H), 7.82~7.79 (m, 1H), 7.68~7.64 (m, 1H), 7.55~7.39 (m, 6H), 6.73~6.70 (m, 1H); 13C NMR (100 MHz, CDCl3) δ: 162.2, 160.1, 146.6, 143.4, 138.2, 134.7, 132.5, 130.9, 130.5, 129.0, 127.3, 125.5, 125.3, 123.2, 122.7, 120.4, 117.8, 98.2; IR (ATR) ν: 1744, 1674, 1520, 1203, 1080, 1049, 702 cm－1; HRMS (ESI) calcd for C20H12Cl2- NO3S [M＋H]＋ 415.9915, found 415.9919.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-4-甲基苯甲酸酯(3l): 63.8 mg, 黄色固体, 产率85%. m.p. 142~144 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.96~7.94 (m, 2H), 7.79~7.77 (m, 1H), 7.44~7.37 (m, 3H), 7.29~7.23 (m, 3H), 6.56~6.55 (m, 1H), 6.15~6.13 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.6, 161.8, 152.1, 146.3, 138.7, 137.4, 135.3, 132.6, 131.6, 131.1, 128.7, 127.6, 127.4, 125.3, 125.1, 122.6, 120.7, 120.2, 119.2, 108.8, 21.6, 21.3; IR (ATR) ν: 1744, 1674, 1373, 1172, 1049, 1018, 740 cm－1; HRMS (ESI) calcd for C22H18NO3S [M＋H]＋ 376.1007, found 376.1015.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-4-氯苯甲酸酯(3m): 63.2 mg, 黄色固体, 产率80%. m.p. 204~205 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01~7.98 (m, 2H), 7.80~7.77 (m, 1H), 7.48~7.38 (m, 5H), 7.24~7.22 (m, 1H), 6.56~6.55 (m, 1H), 6.16~6.14 (m, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 161.7, 161.6, 152.2, 146.0, 141.2, 137.2, 132.6, 131.8, 131.5, 129.3, 126.0, 125.4, 125.2, 122.6, 120.7, 120.2, 119.1, 109.0, 21.6; IR (ATR) ν: 1744, 1667, 1589, 1373, 1080, 725, 679 cm－1; HRMS (ESI) calcd for C21H15ClNO3S [M＋H]＋ 396.0461, found 396.0471.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-2-甲基苯甲酸酯(3n): 57.8 mg, 黄色固体, 产率77%. m.p. 165~167 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.02~7.99 (m, 1H), 7.81~7.78 (m, 1H), 7.50~7.46 (m, 1H), 7.44~7.381 (m, 3H), 7.374~7.23 (m, 3H), 6.57~6.56 (m, 1H), 6.16~6.14 (m, 1H), 2.61 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 162.8, 161.9, 152.2, 146.4, 142.1, 137.4, 133.7, 132.6, 132.1, 131.7, 131.6, 126.4, 126.2, 125.3, 125.0, 122.6, 120.5, 120.2, 118.7, 109.0, 22.0, 21.6; IR (ATR) ν: 1744, 1674, 1597, 1304, 1134, 756, 702 cm－1; HRMS (ESI) calcd for C22H18NO3S [M＋H]＋ 376.1007, found 376.1017.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-3-甲基苯甲酸酯(3o): 56.3 mg, 黄色固体, 产率75%. m.p. 131~133 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.88~7.84 (m, 2H), 7.80~7.77 (m, 1H), 7.45~7.34 (m, 5H), 7.26~7.24 (m, 1H), 6.57~6.56 (m, 1H), 6.16~6.14 (m, 2H), 2.40 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.3, 161.8, 152.1, 146.3, 138.7, 137.4, 135.3, 132.6, 131.6, 131.1, 128.8, 127.6, 127.4, 125.3, 125.1, 122.6, 120.7, 120.2, 119.2, 108.9, 21.6, 21.3; IR (ATR) ν: 1744, 1674, 1265, 1180, 1003, 887, 756 cm－1; HRMS (ESI) calcd for C22H18NO3S [M＋H]＋ 376.1007, found 376.1008.
3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-1-噻吩基甲酸酯(3p): 40.4 mg, 黄色固体, 产率 55%. m.p. 197~199 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.91~7.90 (m, 1H), 7.79~7.77 (m, 1H), 7.71~7.69 (m, 1H), 7.45~7.36 (m, 3H), 7.25~7.23 (m, 1H), 7.17~7.14 (m, 1H), 6.56~6.55 (m, 1H), 6.17~6.15 (m, 1H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 161.8, 157.8, 152.1, 145.9, 137.4 136.1, 135.2, 132.5, 131.5, 130.4, 128.4 125.3, 125.1, 122.6, 120.8, 120.2, 119.1, 108.9, 21.6; IR (ATR) ν: 1736, 1667, 1520, 1412, 1150, 725, 656 cm－1; HRMS (ESI) calcd for C19H14NO3S2 [M＋H]＋ 368.0415, found 368.0421.
5-甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩- 2-基-苯甲酸酯(3q): 61.5 mg, 黄色固体, 产率82%. m.p. 165~167 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.05 (m, 2H), 7.76~7.61 (m, 2H), 7.50~7.45 (m, 2H), 7.24~7.19 (m, 3H), 6.57~6.56 (m, 1H), 6.16~6.14 (m, 1H), 2.42 (s, 3H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.5, 161.8, 152.1, 146.4, 137.4, 135.3, 134.4, 131.8, 130.5, 129.8, 128.8, 127.6, 126.8, 122.3, 120.6, 120.2, 118.9, 108.9, 21.61, 21.59; IR (ATR) ν: 1744, 1535, 1250, 1173, 1018, 795, 702 cm－1; HRMS (ESI) calcd for C22H18- NO3S [M＋H]＋ 376.1007, found 376.1003.
5-氯-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3r): 61.6 mg, 黄色固体, 产率78%. m.p. 179~181 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.04 (m, 2H), 7.72~7.70 (m, 1H), 7.67~7.63 (m, 1H), 7.51~7.47 (m, 2H), 7.413~7.408 (m, 1H), 7.36~7.33 (m, 1H), 7.23~7.22 (m, 1H), 6.60~6.59 (m, 1H), 6.20~6.17 (m, 1H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.3, 161.6, 152.3, 147.6, 137.1, 134.7, 132.8, 131.8, 130.6, 130.5, 128.9, 127.3, 125.6, 123.8, 120.4, 120.3, 118.3, 109.1, 21.7; IR (ATR) ν: 1744, 1581, 1242, 1049, 964, 802, 702 cm－1; HRMS (ESI) calcd for C21H15ClNO3S [M＋H]＋ 396.0461, found 396.0464.
6-甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩- 2-基-苯甲酸酯(3s): 60.8 mg, 黄色固体, 产率81%. m.p. 178~180 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.08~8.05 (m, 2H), 7.63~7.62 (m, 1H), 7.59~7.58 (m, 1H), 7.50~7.46 (m, 2H), 7.33~7.31 (m, 1H), 7.25~7.19 (m, 2H), 6.56~6.55 (m, 1H), 6.15~6.13 (m, 1H), 2.47 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.5, 161.8, 152.2, 146.3, 137.3, 134.5, 132.6, 131.6, 130.5, 128.9, 127.5, 125.3, 125.1, 122.6, 120.7, 120.2, 119.0, 109.0, 21.67, 21.59; IR (ATR) ν: 1744, 1605, 1219, 1103, 1018, 810, 702 cm－1; HRMS (ESI) calcd for C22H18NO3S [M＋H]＋ 376.1007, found 376.1009.
7-甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩- 2-基-苯甲酸酯(3t): 63.0 mg, 黄色固体, 产率84%. m.p. 155~157 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.09~8.06 (m, 2H), 7.66~7.62 (m, 1H), 7.50~7.46 (m, 2H), 7.34~7.18 (m, 4H), 6.56~6.55 (m, 1H), 6.15~6.13 (m, 2H), 2.56 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.6, 161.7, 152.1, 146.1, 137.3, 134.5, 132.5, 132.1, 131.5, 130.5 128.8, 127.6, 125.6, 125.5, 120.2, 119.8, 118.4, 108.3, 21.6, 19.5; IR (ATR) ν: 1744, 1597, 1242, 1118, 972, 779, 702 cm－1; HRMS (ESI) calcd for C22H18- NO3S [M＋H]＋ 376.1007 found 376.1009.
6-甲氧基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻 吩-2-基-苯甲酸酯(3u): 60.2 mg, 黄色固体, 产率77%. m.p. 149~151 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.04 (m, 2H), 7.65~7.61 (m, 1H), 7.50~7.45 (m, 2H), 7.33~7.31 (m, 1H), 7.26~7.23 (m, 2H), 7.02~6.99 (m, 1H), 6.55~6.54 (m, 1H), 6.14~6.12 (m, 1H), 3.87 (s, 3H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.5, 161.8, 152.1, 146.4, 145.6, 137.4, 132.6, 131.6, 130.6, 129.6, 125.2, 125.0, 124.7, 122.6, 120.7, 120.2, 118.9, 108.9, 21.9, 21.6; IR (ATR) ν: 1744, 1667, 1366, 1103, 1018, 810, 702 cm－1; HRMS (ESI) calcd for C22H18NO4S [M＋H]＋ 392.0957, found 392.0964.
5,7-二甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3v): 63.0 mg, 黄色固体, 产率81%. m.p. 155~158 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.07~8.05 (m, 2H), 7.64~7.61 (m, 1H), 7.49~7.45 (m, 2H), 7.24~7.22 (m, 1H), 7.06~7.03 (m, 2H), 6.57~6.56 (m, 1H), 6.15~6.13 (m, 1H), 2.51 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 162.7, 161.8, 152.1, 146.2, 137.4, 135.6, 134.4, 131.8, 131.6, 130.5, 129.7, 128.8, 127.7, 127.4, 120.2, 119.7, 118.2, 108.8, 21.6, 21.5, 19.3; IR (ATR) ν: 1744, 1535, 1450, 1172, 1018, 848, 748 cm－1; HRMS (ESI) calcd for C23H19NO3S [M＋H]＋ 390.1164, found 390.1165.
4,7-二甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯3w): 56.8 mg, 黄色固体, 产率73%. m.p. 168~170 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.04~8.01 (m, 2H), 7.65~7.62 (m, 1H), 7.49~7.45 (m, 2H), 7.23~7.21 (m, 1H), 7.09~7.04 (m, 2H), 6.54~6.53 (m, 1H), 6.15~6.12 (m, 1H), 2.52 (s, 3H), 2.29 (s, 3H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) δ: 163.0, 162.8, 152.4, 146.7, 137.8, 134.4, 133.1, 130.4, 129.7, 129.6, 128.8, 127.9, 127.6, 125.2, 121.0, 120.0, 108.6, 21.7, 19.2, 18.1; IR (ATR) ν: 1744, 1674, 1597, 1304, 1134, 756, 702 cm－1; HRMS (ESI) calcd for C23H20NO3S [M＋H]＋ 390.1164, found 390.1178.
5,6-二甲基-3-[4-甲基-2-氧代吡啶-1(2H)-基]苯并噻吩-2-基-苯甲酸酯(3x): 62.7 mg, 黄色固体, 产率78%. m.p. 215~216 ℃; 1H NMR (400 MHz, CDCl3) δ: 8.01~7.99 (m, 2H), 7.64~7.60 (m, 1H), 7.48~7.42 (m, 3H), 7.23~7.21 (m, 1H), 6.95 (s, 1H), 6.55 (s, 1H), 6.15~6.13 (m, 1H), 2.42 (s, 3H), 2.22 (s, 3H); 13C NMR (125 MHz, CDCl3) δ: 163.1, 162.7, 152.6, 145.8, 137.9, 134.9, 134.4, 133.5, 131.7, 130.4, 130.0, 129.4, 128.8, 128.3, 127.6, 120.2, 120.0, 108.9, 21.7, 21.4, 18.4; IR (ATR) ν: 1744, 1674, 1597, 1304, 1134, 756, 702 cm－1; HRMS (ESI) calcd for C23H20NO3S [M＋H]＋ 404.0124, found 404.0150.
4-[2-氧代吡啶-1(2H)-基]-1H-异色烯-3-基苯甲酸酯(5a): 43.5 mg, 白色固体, 产率63%. m.p. 104~105 ℃; 1H NMR (400 MHz, CDCl3) δ: 7.86~7.83 (m, 2H), 7.50~7.32 (m, 4H), 7.28~7.26 (m, 4H), 7.05 (d, J=7.6 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 6.36~6.32 (m, 1H), 5.38~5.28 (m, 2H); 13C NMR (100 MHz, CDCl3) δ: 183.7, 165.8, 163.4, 140.6, 136.6, 135.4, 133.0, 132.7, 130.4, 129.3, 129.0, 128.9, 128.2, 127.0, 125.1, 120.8, 107.4, 70.4; IR (ATR) ν: 1744, 1311, 1242, 1018, 957, 795, 702 cm－1; HRMS (ESI) calcd for C21H15NO4Na [M＋Na]＋ 368.0899, found 368.0903.
辅助材料(Supporting Information) 化合物3a~3x以及5a的1H NMR、13C NMR谱图, 和产物3i的19F NMR谱图. 这些材料可以免费从本刊网站(http://sioc-journal.cn/)上下载.
(Cheng, F.)

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