CN113214199A - 一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法 - Google Patents
一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法 Download PDFInfo
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- CN113214199A CN113214199A CN202110467354.7A CN202110467354A CN113214199A CN 113214199 A CN113214199 A CN 113214199A CN 202110467354 A CN202110467354 A CN 202110467354A CN 113214199 A CN113214199 A CN 113214199A
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- benzofuran
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Abstract
本发明公开了一种苯并呋喃‑3‑氧代羧酸酯类化合物的合成方法，该方法是将共轭烯基脒类化合物在
Description
技术领域
本发明涉及一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，特别涉及一种以共轭烯基脒类化合物为原料在
酸催化作用下经过重排-环化串联反应合成苯并呋喃-3-氧代羧酸酯类化合物的方法，属于苯并呋喃类生物活性分子合成技术领域。
背景技术
苯并呋喃为一种常见的杂环化合物，是许多具有生物活性的天然药物和合成化工原料的基本核心结构单元，苯并呋喃及其衍生物具有独特的抗癌、抗结核、抗糖尿病、抗菌、抗氧化、抗阿尔茨海默和抗炎等生物活性，其在药物分子以及天然产物的合成应用方面备受化学家和医学研究人员的关注。苯并呋喃结构广泛存在于天然药物分子以及抗菌、抗结核、抗癌药物分子中，充分证明苯并呋喃化合物的临床应用价值及其在开发新药中的重要潜力。如下几种已经商品化药物分子包含了苯并呋喃环结构，如Amiodarone常用于治疗心律不齐疾病；Angelicin、Nodekenetin和Xanthotoxin用于治疗银屑病、白癜风、特应性皮炎、牛皮癣等皮肤；Bergaten可结合其他药物用于改善癌症治疗；Usanic acid可用于抑制金黄色葡萄球菌、肠球菌和分枝杆菌等多重耐药菌株生长。
由于苯并呋喃衍生物具有独特的药用价值，其人工合成方法引起了化学家的极大兴趣，大量关于2-取代苯并呋喃衍生物或者2,3-取代苯并呋喃衍生物的合成方法已经被报道，但目前为止，仅有一例关于3-取代苯并呋喃衍生物制备的报道。2007年，Kozikowski课题组报道了以酚为原料制备苯并呋喃-3-羧酸酯的方法(US20100004308)。在Lewis酸作用下，苯酚发生F-C酰基化反应得到芳基酮产物2；芳基酮产物2在乙酸钠的甲醇溶液中于高温下环化，生成3-苯并呋喃酮3；3与(羧甲基)三苯基膦发生Witting反应得到1-苯并呋喃-3-乙酸乙酯产物，其可以在二氧化硒的作用下发生氧化反应得到苯并呋喃-3-氧代乙酸乙酯5。
但是上述方法操作复杂，部分反应条件苛刻，且底物适应范围有限。
发明内容
针对现有技术中合成3-取代苯并呋喃衍生物的方法存在操作繁琐、需要多步反应以及反应温度较高等技术缺陷；本发明的目的是在于提供一种以共轭烯基脒类化合物为原料在
酸作用下进行重排-环化串联反应得到苯并呋喃-3-氧代羧酸酯类化合物的方法，该方法操作简单，通过一锅反应实现，反应流程短，且无需过渡金属催化，底物普适性好，有利于大规模生产。
为了实现上述技术目的，本发明提供了一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，该方法是将共轭烯基脒类化合物在
酸作用下进行重排-环化串联反应，即得；
所述共轭烯基脒类化合物具有式1所示结构：
所述苯并呋喃-3-氧代羧酸酯类化合物具有式2所示结构：
其中，
R0和R1为非邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基；
R0和R1为邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基，或者，R0和R1构成闭合环状结构，环状结构由碳原子数为3～7的烷链构成，或由碳原子数为4～7的单烯烃链或共轭烯烃链构成，或由碳原子数为3～7的烷氧醚链构成；
R2为碳原子数为1～10的烷基、芳基甲基或对甲苯磺酰基；
所述芳基甲基具有式3所示结构：
其中，Ar选自苯基、萘基、取代苯基或联苯基，所述取代苯基为含有碳原子数为1～5的烷基、碳原子数为1～5的烷氧基、三氟甲基和卤素取代基中至少一种取代基的苯基。
本发明的苯并呋喃-3-氧代羧酸酯类化合物中R0、R1以及R2都是由共轭烯基脒类化合物原料引入的取代基团。R0和R1为苯环上任意位置取代的基团，R0和R1独立选自氢、碳原子数为1～10的烷基(烷基可以为直链烷基，或者为带支链的烷基，当碳原子数超过3的烷基还可以为环烷基或者为包含环烷结构的烷基，常见如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环己基等等)、碳原子数为1～10的烷氧基(常见如甲氧基、乙氧基、丙氧基、丁氧基等等)、苄氧基、烯丙氧基或卤素取代基(常见如氟取代基、氯取代基、溴取代基等)等取代基团。R0和R1为邻位取代基时，R0和R1还可以构成闭合环状结构，环状结构由碳原子数为3～7的烷链构成(常见如五元环、六元环等)，或由碳原子数为4～7的单烯烃链或共轭烯烃链构成(常见如碳源子数为4的共轭二烯)，或由碳原子数为3～7的烷氧醚链构成(常见如五元环氧醚)。R2为碳原子数为1～10的烷基(烷基可以为直链烷基，或者为带支链的烷基，当碳原子数超过3的烷基还可以为环烷基或者为包含环烷结构的烷基，常见如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、环己基、环己基甲基等等)、芳基甲基或对甲苯磺酰基。所述芳基甲基常见的为萘基甲基、联苯甲基、苄基或者是由苄基衍生出来的取代基，苄基衍生出来的取代基主要是苯环上含有一些常见的取代基，具体如含有碳原子数为1～5的烷基(常见如甲基、乙基、丙基、异丙基、丁基等等)、碳原子数为1～5的烷氧基(常见如甲氧基、乙氧基、丙氧基等等)、三氟甲基、卤素取代基(常见如氟取代基、氯取代基、溴取代基等)等等，这些取代基在苯环上的位置不受限制，且取代基数量也不受限制，常见为包含一个或两个取代基。R0、R1以及R2等取代基的种类及数目对合成苯并呋喃-3-氧代羧酸酯类化合物反应存在一定影响，但是选择不同取代基时，共轭烯基脒类化合物的重排-环化串联反应还是都能够顺利进行并得到苯并呋喃-3-氧代羧酸酯类化合物，只是选择不同取代基时，存在一定的电子效应和空间位阻效应，收率存在一定差异，这是本领域技术人员可以理解的。
作为一个优选的方案，所述
酸选自甲磺酸、樟脑磺酸、对甲苯磺酸和对甲苯磺酸一水合物中至少一种。更优选为樟脑磺酸、对甲苯磺酸、对甲苯磺酸一水合物中至少一种。虽然甲磺酸对共轭烯基脒类化合物的重排-环化串联反应具有一定的促进作用，但是效果远远差于樟脑磺酸、对甲苯磺酸、对甲苯磺酸一水合物等，此外，NH2SO3H、TfOH、H3BO3等路易斯酸对共轭烯基脒类化合物的重排-环化串联反应几乎没有促进作用。
作为一个优选的方案，所述
酸与共轭烯基脒类化合物的反应摩尔比为1.5～2.5:1。
酸的最佳用量为共轭烯基脒类化合物摩尔量的2倍，如果进一步增加
酸的用量，对共轭烯基脒类化合物的重排-环化串联反应的收率没有明显的提高，而降低
酸用量，则共轭烯基脒类化合物的重排-环化串联反应收率明显降低。
作为一个优选的方案，所述重排-环化串联反应采用乙腈、四氢呋喃、丙酮中至少一种作为反应溶剂。乙腈、1,4-二氧六环、DMF、DMSO、THF、DCM、丙酮、甲苯等作为反应介质都能够使得共轭烯基脒类化合物的重排-环化串联反应顺利进行，而在乙腈、THF、DCM、丙酮等反应介质中明显有利于共轭烯基脒类化合物的重排-环化串联反应，可以获得较高的收率，而反应介质为MeOH等质子溶剂时，反应几乎不能顺利进行。
作为一个优选的方案，所述重排-环化串联反应的条件为：温度为80～110℃，时间为6～12h。反应温度在80～110℃范围内，能够保证共轭烯基脒类化合物的重排-环化串联反应顺利进行，而反应温度在90～100℃的范围内，能获得较高的收率，而降低反应温度至80℃以下，则共轭烯基脒类化合物的重排-环化串联反应收率明显降低，如果反应温度高于100℃，而容易产生副反应而导致降低反应收率。
本发明的共轭烯基脒类化合物的重排-环化串联反应完成后，直接减压浓缩得到粗产物，其经柱色谱分离纯化即得苯并呋喃-3-氧代羧酸酯类化合物。
本发明的共轭烯基脒类化合物的重排-环化串联反应可以空气气氛中进行反应。
本发明的共轭烯基脒类化合物的重排-环化串联反应的具体反应如下：
本发明的共轭烯基脒类化合物的重排-环化串联反应的反应机理如下(以(二甲基氨基)亚甲基)氨基)-3-(2-羟基苯基)丙烯酸乙酯在对甲苯磺酸作用下的重排-环化串联反应为例进行具体说明)：(二甲基氨基)亚甲基)氨基)-3-(2-羟基苯基)丙烯酸乙酯在对甲苯磺酸作用下发生质子化得到季铵盐中间体I，中间体I经过分子内环化得到1,3-苯并噁嗪七元环中间体II；然后，中间体II经水合和开环重排后形成两性离子中间体V，中间体IV发生分子环化得到二氢苯并呋喃五元环中间体V，中间体V在酸性条件芳构化发生脱水反应得到苯并呋喃中间体VI，中间体VI进一步发生分子内亲核加成得到中间体VII，中间体VII进而脱去一分子NH3得到苯并呋喃-3-羧酸酯衍生物。
与现有技术相比，本发明技术的具有以下优势：
1)本发明提供的苯并呋喃-3-氧代羧酸酯的合成方法不需使用过渡金属类或贵金属类催化剂以及氧化剂，生产成本低，且有利于环保。
2)本发明提供的苯并呋喃-3-氧代羧酸酯的合成方法操作简单，流程短，可以通过一锅法完成，且反应条件温和，可以在空气条件及相对较低温度条件下进行。
3)本发明提供的苯并呋喃-3-氧代羧酸酯的合成方法反应体系干净，副产物少，产率中等至良好。
4)本发明提供的苯并呋喃-3-氧代羧酸酯的合成方法底物普适性好，官能团耐受性好。
5)本发明提供的苯并呋喃-3-氧代羧酸酯的合成方法可用于糖原合成酶激酶GSK-3β，为苯并呋喃衍生物用于天然药物分子的合成提供了一种新原料来源。
附图说明
图1为化合物3的单晶结构图示。
图2为化合物3的1H NMR。
图3为化合物3的13C NMR。
具体实施方式
以下具体实施例旨在进一步详细说明本发明技术方案内容，而不是限制本发明权利要求的保护范围。
以下实施例中的反应原料无特殊说明，均是来源于商品原料。
以下实施例中涉及的共轭烯基脒类化合物通过以下方法合成：将氟化钾(0.046g,4.0equiv)和18-冠醚-6(0.052g，1.0equiv)依次加入洁净干燥的Schlenk管中，双排气管抽真空并鼓入氮气置换三次，在氮气氛围下加入异腈化合物(1.0equiv)、Kobayashi芳炔前体衍生物(1.5equiv)和DMF(1.0mL)，混合物在室温(25℃)下搅拌5h，取样检测，TLC监测反应原料完全消失。反应体系中加入1M H2O稀释并用乙酸乙酯萃取三次，合并有机相，饱和食盐水洗涤后用无水硫酸钠干燥有机相，抽滤，减压浓缩，柱色谱(PE:EA＝10:1)分离纯化得到纯的共轭烯基脒产物；经过替换不同的异腈化合物和Kobayashi芳炔前体衍生物，可以获得相应的共轭烯基脒产物。具体的Kobayashi芳炔前体衍生物结构如下：
具体的异腈化合物结构如下：
从而得到本发明涉及的共轭烯基脒类化合物：
其中，上述化合物中R0和R1为非邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基；R0和R1为邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基，或者，R0和R1构成闭合环状结构，环状结构由碳原子数为3～7的烷链构成，或由碳原子数为4～7的单烯烃链或共轭烯烃链构成，或由碳原子数为3～7的烷氧醚链构成；R2为碳原子数为1～10的烷基、芳基甲基或对甲苯磺酰基；所述芳基甲基结构如下：
其中，Ar选自苯基、萘基、取代苯基或联苯基，所述取代苯基为含有碳原子数为1～5的烷基、碳原子数为1～5的烷氧基、三氟甲基至少一种取代基的苯基。
条件优化实验：
以(二甲基氨基)亚甲基)氨基)-3-(2-羟基苯基)丙烯酸乙酯为底物，在最佳反应条件下进行的反应作为标准反应，具体反应式如下：
具体操作步骤为：将共轭烯基脒(二甲基氨基)亚甲基)氨基)-3-(2-羟基苯基)丙烯酸乙酯(0.052g,1.0equiv)和对甲苯磺酸一水合物(0.076g,2.0equiv.)加入Schlenck管，随后加入2mL乙腈溶剂，在100℃搅拌8h。TLC检测原料完全转化，直接减压浓缩得到粗产物，以PE：EA＝100：1的混合溶液为洗脱剂经SiO2柱色谱分离纯化得到苯并呋喃-3-乙酸乙酯产物。
以下实验组1～26是以上述标准反应作为参考，进行对比说明：
上表中实验组1～9考察了反应溶剂对共轭烯基脒类化合物的重排-环化串联反应的影响，通过实验表明采用乙腈、1,4-二氧六环、DMF、DMSO、THF、DCM、丙酮、甲苯等作为反应介质都能够使得共轭烯基脒类化合物的重排-环化串联反应顺利进行，收率在32％以上，而在乙腈、THF、DCM、丙酮等反应介质中明显有利于共轭烯基脒类化合物的重排-环化串联反应，可以获得70％以上收率，而反应介质为MeOH等质子溶剂时，反应几乎不能顺利进行。
上表中实验组1、10～20考察了
酸对共轭烯基脒类化合物的重排-环化串联反应的影响，在所选择的
酸中，樟脑磺酸、对甲苯磺酸、对甲苯磺酸一水合物能明显促进反应获得较高的收率，目标产物收率在70％以上。而虽然甲磺酸对共轭烯基脒类化合物的重排-环化串联反应具有一定的促进作用，但是效果较差，只能获得26％的目标产物收率，此外，NH2SO3H、TfOH、H3BO3等路易斯酸对共轭烯基脒类化合物的重排-环化串联反应几乎没有促进作用。
上表中实验组1、21～23考察了反应温度对共轭烯基脒类化合物的重排-环化串联反应的影响，反应温度在80～110℃范围内，能够保证共轭烯基脒类化合物的重排-环化串联反应顺利进行，目标产物收率能够保持在56％以上，而反应温度在90～100℃的范围内，能获得较高的收率，目标产物收率保持在68％以上，而降低反应温度至80℃以下，则共轭烯基脒类化合物的重排-环化串联反应收率明显降低，如果反应温度高于100℃，而溶液产生少量副反应而导致稍微降低反应收率。
上表中实验组1、24～25考察了
酸添加量对共轭烯基脒类化合物的重排-环化串联反应的影响，
酸的最佳用量为共轭烯基脒类化合物摩尔量的2倍，如果进一步增加
酸的用量，对共轭烯基脒类化合物的重排-环化串联反应的收率没有明显的提高，而降低
酸用量，则共轭烯基脒类化合物的重排-环化串联反应收率明显降低。
实施例1～22
以下实施例1～22均在最优反应条件下反应，具体反应方程式如下，主要是考察不同底物在最优条件反应的收率情况：
具体操作步骤为：将共轭烯基脒类化合物(0.052g,1.0equiv)和对甲苯磺酸一水合物(0.076g,2.0equiv.)加入Schlenck管，随后加入2mL乙腈溶剂，在100℃搅拌8h。TLC检测原料完全转化，直接减压浓缩得到粗产物，以PE：EA＝100：1的混合溶液为洗脱剂经SiO2柱色谱分离纯化得到苯并呋喃-3-乙酸乙酯产物。
实施例1
化合物1：收率为82％。
1H NMR(400MHz,CDCl3-d)δ8.90(s,1H),8.28(ddd,J＝6.6,3.3,2.0Hz,1H),7.56(ddd,J＝8.2,3.2,1.7Hz,1H),7.47–7.36(m,2H),4.44(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3-d)δ178.6,161.2,156.1,155.2,126.4,125.2,124.3,123.0,118.8,111.7,62.9,14.2；HRMS(ESI)m/z calcd for C12H10O4Na+[M+Na]+241.0471,found 241.0472.
实施例2
化合物2：收率为75％。
1H NMR(400MHz,CDCl3-d)δ8.91(s,1H),8.31–8.26(m,1H),7.61–7.53(m,1H),7.47–7.37(m,2H),3.99(s,3H)；13C NMR(100MHz,CDCl3-d)δ178.1,161.6,156.3,155.2,126.4,125.2,124.2,123.0,118.8,111.7,53.4；HRMS(ESI)m/z calcd for C11H8O4Na+[M+Na]+227.0315,found 227.0315.
实施例3
化合物3：产率为82％。
1H NMR(400MHz,CDCl3-d)δ8.79(s,1H),8.06(s,1H),7.37(s,1H),4.43(q,J＝7.1Hz,2H),3.17–2.88(m,4H),2.15(p,J＝7.4Hz,2H),1.45(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3-d)δ178.7,161.4,155.9,154.9,143.7,141.9,122.8,118.8,117.7,107.4,62.8,33.2,32.6,26.6,14.2；HRMS(ESI)m/z calcd for C15H14O4Na+[M+Na]+281.0784,found 281.0809.
实施例4
化合物4：收率为64％。
1H NMR(400MHz,CDCl3-d)δ8.84(s,1H),8.31–8.23(m,1H),7.58–7.53(m,1H),7.50–7.46(m,2H),7.44–7.37(m,5H),5.41(s,2H)；13C NMR(100MHz,CDCl3-d)δ178.1,161.0,156.1,155.2,134.6,129.0,128.9(2C),128.8(2C),126.4,125.2,124.2,122.9,118.8,111.7,68.3；HRMS(ESI)m/z calcd for C16H12O4Na+[M+Na]+303.0628,found303.0657.
实施例5
化合物5：收率为70％。
1H NMR(400MHz,CDCl3-d)δ8.45(s,1H),7.50(d,J＝7.5Hz,2H),7.37(t,J＝7.5Hz,2H),7.33–7.28(m,1H),7.24(d,J＝2.0Hz,1H),7.16(d,J＝8.3Hz,1H),6.79(d,J＝8.0Hz,1H),5.22(s,2H),4.19(q,J＝7.1Hz,2H),1.29(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3-d)δ179.9,162.7,157.2,153.5,153.1,136.6,128.7(2C),128.0,127.4(2C),127.1,119.9,114.0,107.4,105.2,70.9,62.5,14.1；HRMS(ESI)m/z calcd for C19H16O5Na+[M+Na]+347.0890,found 347.0891.
实施例6
化合物6：收率为63％。
1H NMR(400MHz,CDCl3-d)δ8.86(s,1H),8.33–8.23(m,1H),7.97–7.93(m,1H),7.91–7.83(m,3H),7.59–7.49(m,4H),7.44–7.37(m,2H),5.57(s,2H)；13CNMR(100MHz,CDCl3-d)δ178.1,161.0,156.1,155.2,133.5,133.3,132.0,128.8,128.2,127.9,126.7,126.6,126.4,126.0,125.2,124.2,122.9,118.8,111.7,68.5；HRMS(ESI)m/z calcd forC21H14O4Na+[M+Na]+353.0784,found 353.0785.
实施例7
化合物7：收率为64％。
1H NMR(400MHz,CDCl3-d)δ8.42(s,1H),7.29(dt,J＝10.4,7.8Hz,3H),7.17(dd,J＝8.2,3.6Hz,3H),6.77(d,J＝8.1Hz,1H),6.10(ddt,J＝17.3,10.5,5.2Hz,1H),5.52(dq,J＝17.3,1.7Hz,1H),5.36–5.28(m,3H),4.63(dt,J＝5.2,1.7Hz,2H),2.35(s,3H)；13C NMR(100MHz,CDCl3-d)δ179.7,162.5,157.1,153.5,153.1,138.7,132.9,131.7,129.5(2C),128.8(2C),127.1,119.9,118.1,113.8,107.0,105.1,69.9,68.0,21.4；HRMS(ESI)m/zcalcd for C21H18O5Na+[M+Na]+373.1046,found373.1044.
实施例8
化合物8：收率为68％。
1H NMR(400MHz,CDCl3-d)δ8.75(s,1H),7.63(s,1H),7.01(s,1H),6.03(s,2H),4.42(q,J＝7.1Hz,2H),1.44(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3-d)δ178.6,161.2,155.2,150.6,147.6,146.5,119.2,117.8,102.0,101.2,93.6,62.8,14.2；HRMS(ESI)m/zcalcd for C13H10O6Na+[M+Na]+285.0370,found 285.0397.
实施例9
化合物9：收率为66％。
1H NMR(400MHz,CDCl3-d)δ8.82(d,J＝4.0Hz,1H),8.07(d,J＝3.9Hz,1H),7.38(d,J＝4.1Hz,1H),3.98(d,J＝3.9Hz,3H),3.01(t,J＝7.8Hz,5H),2.16(ddt,J＝14.7,10.9,5.5Hz,2H)；13C NMR(100MHz,CDCl3-d)δ178.2,161.8,156.0,154.9,143.8,141.9,122.7,118.8,117.7,107.4,53.3,33.2,32.6,26.6；HRMS(ESI)m/z calcd for C14H12O4Na+[M+Na]+267.0628,found 267.0655.
实施例10
化合物10：收率为66％。
1H NMR(400MHz,CDCl3-d)δ8.92(s,1H),8.06(dd,J＝9.8,7.9Hz,1H),7.40(dd,J＝9.3,6.2Hz,1H),4.44(q,J＝7.1Hz,2H),1.45(t,J＝7.1Hz,3H)；19F{1H}NMR(376MHz,CDCl3-d)δ-136.19(dt,J＝20.0,8.6Hz),-139.78(ddd,J＝20.0,9.7,6.2Hz)；19F NMR(376MHz,CDCl3-d)δ-136.19(d,J＝20.0Hz),-139.79(d,J＝19.8Hz)；13C NMR(100MHz,CDCl3-d)δ178.1,160.8,157.1(d,J＝3.6Hz),151.1(d,J＝16.4Hz),150.0(d,J＝10.9Hz),148.7,120.1(d,J＝9.5Hz),118.8,110.1(d,J＝21.7Hz),101.2(d,J＝22.6Hz),63.1,14.2；HRMS(ESI)m/z calcd for C12H8F2O4Na+[M+Na]+277.0283,found 277.0284.
实施例11
化合物11：收率为68％。
1H NMR(400MHz,CDCl3-d)δ8.77(s,1H),8.01(s,1H),7.33(s,1H),4.43(q,J＝7.1Hz,2H),2.38(s,7H),1.45(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3-d)δ178.7,161.4,155.6,154.3,135.7,134.1,122.8,122.0,118.7,112.0,62.8,20.7,20.2,14.2；HRMS(ESI)m/z calcd for C14H14O4Na+[M+Na]+269.0784,found 269.0808.
实施例12
化合物12：收率为70％。
1H NMR(400MHz,CDCl3-d)δ8.46(s,1H),7.33(t,J＝8.2Hz,1H),7.18(d,J＝8.2Hz,1H),6.78(d,J＝8.0Hz,1H),4.40(q,J＝7.2Hz,2H),3.93(s,3H),1.40(t,J＝7.2Hz,3H)；13CNMR(100MHz,CDCl3-d)δ180.3,162.8,157.0,154.5,152.8,127.2,119.8,113.6,105.7,105.0,62.5,56.0,14.2；HRMS(ESI)m/z calcd for C13H12O5Na+[M+Na]+271.0577,found271.0577.
实施例13
化合物13：收率为83％。
1H NMR(400MHz,CDCl3-d)δ8.47(s,1H),7.30(t,J＝8.2Hz,1H),7.18(dd,J＝8.3,0.7Hz,1H),6.78(d,J＝8.1Hz,1H),6.12(ddt,J＝17.3,10.4,5.1Hz,1H),5.53(dq,J＝17.3,1.6Hz,1H),5.32(dq,J＝10.6,1.5Hz,1H),4.67(dt,J＝5.2,1.6Hz,2H),4.38(q,J＝7.2Hz,2H),1.38(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3-d)δ179.9,162.6,157.1,153.5,153.1,132.9,127.1,119.9,118.0,113.9,107.0,105.1,70.0,62.6,14.1；HRMS(ESI)m/zcalcd for C15H14O5Na+[M+Na]+297.0733,found297.0736.
实施例14
化合物14：收率为72％。
1H NMR(400MHz,CDCl3-d)δ9.45–9.36(m,1H),8.91(s,1H),7.94(dd,J＝8.1,1.4Hz,1H),7.85(d,J＝9.0Hz,1H),7.70–7.63(m,2H),7.56(ddd,J＝8.1,6.9,1.2Hz,1H),4.48(q,J＝7.1Hz,2H),1.48(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3-d)δ179.6,162.8,156.6,154.1,131.7,128.8(2C),128.2,127.5,127.0,125.7,121.4,119.0,112.0,62.9,14.2；HRMS(ESI)m/z calcd for C16H12O4Na+[M+Na]+291.0628,found 291.0653.
实施例15
化合物15：收率为65％。
1H NMR(400MHz,CDCl3-d)δ8.99(s,1H),8.35–8.27(m,2H),7.98(d,J＝8.1Hz,1H),7.82(d,J＝8.6Hz,1H),7.65(ddd,J＝8.3,7.0,1.2Hz,1H),7.57(ddd,J＝8.2,6.9,1.3Hz,1H),4.47(q,J＝7.2Hz,3H),1.47(t,J＝7.1Hz,4H)；13C NMR(100MHz,CDCl3-d)δ178.9,161.3,154.7,151.2,132.4,128.6,127.1,126.4,125.8,120.9,120.5,120.2,120.1,119.8,62.9,14.2；HRMS(ESI)m/z calcd for C16H12O4Na+[M+Na]+291.0628,found291.0654.
实施例16
化合物16：收率为54％。
1H NMR(400MHz,CDCl3-d)δ8.89(s,1H),8.31–8.22(m,1H),7.67(d,J＝8.1Hz,2H),7.62–7.55(m,3H),7.46–7.39(m,2H),5.44(s,2H)；19F{1H}NMR(376MHz,CDCl3-d)δ-62.69；19F NMR(376MHz,CDCl3-d)δ-62.69；13C NMR(100MHz,CDCl3-d)δ177.7,160.8,156.2,155.2,138.5,130.5(q,J＝32.5Hz),128.7(2C),126.5,125.91(q,J＝3.8Hz),125.4,124.2,124.1(q,J＝241.2Hz),122.7,118.8,111.8,67.2；HRMS(ESI)m/z calcd for C18H11F3O4Na+[M+Na]+371.0502,found371.0502.
实施例17
化合物17：收率为80％。
1H NMR(400MHz,CDCl3-d)δ8.83(s,1H),8.31–8.22(m,1H),7.62–7.51(m,1H),7.46–7.33(m,4H),7.21(d,J＝7.8Hz,2H),5.37(s,2H),2.37(s,3H)；13CNMR(100MHz,CDCl3-d)δ178.2,161.0,156.1,155.2,138.9,131.6,129.6(2C),129.0(2C),126.3,125.2,124.3,122.9,118.8,111.7,68.3,21.4；HRMS(ESI)m/zcalcd for C18H14O4Na+[M+Na]+317.0784,found 317.0785.
实施例18
化合物18：收率为72％。
1H NMR(400MHz,CDCl3-d)δ8.86(s,1H),8.36–8.18(m,1H),7.65–7.50(m,1H),7.41(dq,J＝10.3,6.2,4.7Hz,2H),7.28(d,J＝6.9Hz,3H),7.18(d,J＝7.0Hz,1H),5.37(s,2H),2.38(s,3H)；13C NMR(100MHz,CDCl3-d)δ178.2,161.0,156.2,155.2,138.7,134.5,129.7,129.5,128.8,126.4,125.9,125.2,124.3,122.9,118.8,111.7,68.4,21.5；HRMS(ESI)m/zcalcd for C18H14O4Na+[M+Na]+317.0784,found317.0785.
实施例19
化合物19：收率为77％。
1H NMR(400MHz,CDCl3-d)δ8.88(s,1H),8.32–8.24(m,1H),7.61–7.54(m,1H),7.46–7.37(m,2H),4.18(d,J＝6.3Hz,2H),1.89–1.74(m,5H),1.73–1.60(m,1H),1.25(ddtt,J＝24.5,12.3,6.3,3.1Hz,3H),1.13–0.98(m,2H)；13C NMR(100MHz,CDCl3-d)δ178.6,161.4,156.1,155.2,126.3,125.2,124.3,122.9,118.9,111.7,71.7,37.1,29.7(2C),26.3,25.7(2C)；HRMS(ESI)m/z calcd for C17H18O4Na+[M+Na]+309.1097,found309.1097.
实施例20
化合物20：收率为66％。
1H NMR(400MHz,CDCl3-d)δ8.89(s,1H),8.31–8.25(m,1H),7.66–7.53(m,7H),7.49–7.40(m,4H),7.39–7.34(m,1H),5.45(s,2H)；13C NMR(101MHz,CDCl3-d)δ178.1,161.0,156.2,155.2,141.9,140.6,133.5,129.3(2C),129.0(2C),127.7,127.6(2C),127.3(2C),126.4,125.2,124.2,122.9,118.8,111.7,68.1；HRMS(ESI)m/z calcd for C23H16O4Na+[M+Na]+379.0941,found 379.0942.
实施例21
化合物21：收率为58％。
1H NMR(400MHz,CDCl3-d)δ8.75(s,1H),8.04(s,1H),7.48(dd,J＝7.8,1.8Hz,2H),7.44–7.34(m,4H),5.40(s,2H),3.00(t,J＝7.4Hz,4H),2.15(p,J＝7.4Hz,2H)；13C NMR(100MHz,CDCl3-d)δ178.3,161.1,155.9,154.9,143.7,141.9,134.7,129.0,128.9,128.8,122.6,118.8,117.7,107.4,68.2,33.1,32.6,26.5；HRMS(ESI)m/z calcd for C20H16O4Na+[M+Na]+343.0941,found 343.0942.
实施例22
化合物22：收率为52％。
1H NMR(400MHz,CDCl3-d)δ8.78(s,1H),8.04(s,1H),7.67(d,J＝8.1Hz,2H),7.59(d,J＝8.1Hz,2H),7.38(s,1H),5.43(s,2H),3.00(t,J＝7.4Hz,4H),2.15(p,J＝7.4Hz,2H)；19F{1H}NMR(376MHz,CDCl3-d)δ-62.68；19F NMR(376MHz,CDCl3-d)δ-62.68；13C NMR(100MHz,CDCl3-d)δ177.8,160.9,156.0,154.9,143.9,142.0,138.6,131.2(q,J＝32.3Hz),130.9,128.7(2C),125.9(q,J＝3.8Hz),124.0(q,J＝272.3Hz),122.6,118.8,117.7,67.1,33.1,32.6,26.6；HRMS(ESI)m/zcalcd for C21H15F3O4Na+[M+Na]+411.0815,found 411.0817.
实施例23(放大反应)
将共轭烯基脒类化合物(0.624g,1.0equiv)和对甲苯磺酸一水合物(0.912g,2.0equiv.)加入Schlenck管，加入25mL乙腈溶剂，在100℃搅拌8h，直接减压浓缩得到粗产物，以PE：EA＝100：1的混合溶液为洗脱剂经SiO2柱色谱分离，得到苯并呋喃-3-乙酸乙酯产物，收率为78％。
Claims (5)
1.一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，其特征在于：共轭烯基脒类化合物在
酸作用下进行重排-环化串联反应，即得；
所述共轭烯基脒类化合物具有式1所示结构：
所述苯并呋喃-3-氧代羧酸酯类化合物具有式2所示结构：
其中，
R0和R1为非邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基；
R0和R1为邻位取代基时，R0和R1独立选自氢、碳原子数为1～10的烷基、碳原子数为1～10的烷氧基、苄氧基、烯丙氧基或卤素取代基，或者，R0和R1构成闭合环状结构，环状结构由碳原子数为3～7的烷链构成，或由碳原子数为4～7的单烯烃链或共轭烯烃链构成，或由碳原子数为3～7的烷氧醚链构成；
R2为碳原子数为1～10的烷基、芳基甲基或对甲苯磺酰基；
所述芳基甲基具有式3所示结构：
其中，Ar选自苯基、萘基、取代苯基或联苯基，所述取代苯基为含有碳原子数为1～5的烷基、碳原子数为1～5的烷氧基、三氟甲基和卤素取代基中至少一种取代基的苯基。
2.根据权利要求1所述的一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，其特征在于：所述
酸选自甲磺酸、樟脑磺酸、对甲苯磺酸和对甲苯磺酸一水合物中至少一种。
3.根据权利要求1或2所述的一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，其特征在于：所述
酸与共轭烯基脒类化合物的摩尔比为1.5～2.5:1。
4.根据权利要求1所述的一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，其特征在于：所述重排-环化串联反应采用乙腈、四氢呋喃、DCM、丙酮中至少一种作为反应溶剂。
5.根据权利要求1所述的一种苯并呋喃-3-氧代羧酸酯类化合物的合成方法，其特征在于：所述重排-环化串联反应的条件为：温度为80～110℃，时间为6～12h。
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