CN111646999A - 一种吲哚啉羧酸类化合物及其制备方法 - Google Patents
一种吲哚啉羧酸类化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种吲哚啉羧酸类化合物及其制备方法,制备方法包括以下步骤:在干燥环境中依次称取吲哚类化合物、碱和电解质并加入溶剂中,然后装入阴极材料和阳极材料,通入二氧化碳鼓泡,再在‑28~120℃和非过渡金属催化剂催化条件下,恒流电解1~48h,同时进行磁子搅拌,待底物完全消耗后,加入盐酸淬灭,最后依次经萃取和柱层析,得吲哚啉羧酸类化合物。本发明还包括采用上述方法制得的吲哚啉羧酸类化合物。本发明在电化学催化下,实现吲哚啉羧酸类化合物的高效合成,避免金属有机中间体与亲电试剂原位的双组分催化偶联、质子化、β‑H消除、异构化等副反应的发生,有效解决了副反应多、化学选择性差等问题。
Description
技术领域
本发明涉及吲哚啉羧酸类化合物合成技术领域,具体涉及一种吲哚啉羧酸类化合物及其制备方法。
背景技术
三维立体结构骨架广泛存在于多种药物分子以及具有生物活性的天然产物分子中,在有机化学、材料科学、生命科学等领域起着至关重要的作用,因此,该类结构的高效合成一直是一个很重要的领域。其中,去芳构化反应作为芳香族化合物的特有转化,能够直接将二维平面的、相对易得的芳香族化合物转化为高度官能团化的、且具有丰富三维立体结构的分子。通过去芳构化策略成功实现了季碳中心、桥环、并环以及螺环等结构的快速构筑;通过去芳构化策略带来许多全新的分子骨架,增强了产物结构的复杂性和适用性,极大地拓宽了产物的化学空间。如通过对吲哚的去芳构化,可以高效构建具有三维立体结构的吲哚啉并环类化合物。然而,现有方法均是基于过渡金属催化,不仅增加了反应的成本,也在一定程度上限制了这些方法的广泛应用。更重要的是,利用这些方法,不能一步合成吲哚啉羧酸类化合物。到目前为止,吲哚啉羧酸的合成仍没有高效的方法。
由此,如何开发一种可以高效、高选择性构建吲哚啉羧酸类化合物的合成方法是本领域所亟待解决的问题。
发明内容
针对现有技术中的上述不足,本发明提供了一种吲哚啉羧酸类化合物及其制备方法,在电化学催化下,实现吲哚啉羧酸类化合物的高效合成,避免金属有机中间体与亲电试剂原位的双组分催化偶联、质子化、β-H消除、异构化等副反应的发生,有效解决了副反应多、化学选择性差等问题。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:提供一种吲哚啉羧酸类化合物的制备方法,包括以下步骤:
在干燥环境中按照物质量比为1:0.5~1:4.5依次称取吲哚类化合物、碱和电解质并加入溶剂中,然后装入阴极材料和阳极材料,通入二氧化碳鼓泡10~20min,气流量为1~3mL/min,再在-28~120℃和非过渡金属催化剂催化条件下,恒流电解1~48h,同时进行磁子搅拌,待底物完全消耗后,加入盐酸淬灭,最后依次经萃取和柱层析,得吲哚啉羧酸类化合物。
进一步,吲哚类化合物结构式为:
其中,R为H、甲基、乙基、苯基、羧酸甲酯、乙酯、异丙酯、叔丁酯、酰胺或烷氧基;X为卤素或磺酸酯。
进一步,电解质浓度范围为0.05~0.5M。
进一步,电解质为碘化钠、溴化钠、氯化钠、碘化锂、碘化钠、碘化钾、碘化镁、溴化镁、氯化镁、四丁基碘化、四丁基溴化铵、四丁基氯化铵、四丁基六氟磷酸铵、四丁基四氟硼酸铵、四丁基三氟甲磺酸铵、四丁基对甲苯磺酸铵、四丁基高氯酸铵、高氯酸锂、高氯酸钠或高氯酸钾。
进一步,碱为无机碱或有机碱。
进一步,无机碱为碳酸钾、磷酸钾、碳酸铯、磷酸钾、特戊酸钾、叔丁醇钾、叔丁醇锂、叔丁醇钠、乙醇钠、甲醇钠、甲醇钾、三氟甲磺酸钠、醋酸钾、醋酸钠、三氟乙酸钠或三氟乙酸钾。
进一步,有机碱为三乙胺、二异丙基乙基胺、1,5-二氮杂双环[4.3.0]壬-5-烯、1,8-二氮杂双环[5.4.0]十一碳-7-烯、四甲基胍、1,4-二氮双环[2.2.2]辛烷、1,5,7-三氮杂二环[4.4.0]癸-5-烯、四甲基哌啶或二甲氨基吡啶。
进一步,溶剂为乙醚、四氢呋喃、甲苯、三氟甲苯、丙酮、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮、1,4-二氧六环或二乙二醇二甲醚。
进一步,恒流电解时,电流强度为1~50mA。
进一步,盐酸浓度为2mol/L。
进一步,阴极材料为碳毡、铁、铜、钯、镍、钨、锰、钼、铌、钴、钛、铅、铝、铂、泡沫镍、泡沫铜、不锈钢、镀镍铁、玻璃碳或网状玻璃态碳,阳极材料为锌、铁、铝、镁、铂、石墨棒或石墨板。
进一步,吲哚啉羧酸类化合物的制备方法的化学反应式如下:
其中,R为H、甲基、乙基、苯基、羧酸甲酯、乙酯、异丙酯、叔丁酯、酰胺或烷氧基;X为卤素或磺酸酯。
上述的吲哚啉羧酸类化合物的制备方法制得的吲哚啉羧酸类化合物。
采用上述方法制得的吲哚啉羧酸类化合物,包括但不限于以下结构的物质:
综上所述,本发明具有以下优点:
1、本发明在电化学催化下,实现非过渡金属催化下吲哚啉羧酸类化合物的高效合成,发展和利用了“连续单电子还原策略”,利用碳负离子实现对软亲电试剂二氧化碳的活化,将其作为羧基源引入三维立体结构之中,避免金属有机中间体与亲电试剂原位的双组分催化偶联、质子化、β-H消除、异构化等副反应的发生,大部分反应均能以较高的立体选择性(d.r.>19:1)生成对应产物,且反应条件温和,底物适应性好,避免了过渡金属的使用,有效解决了副反应多、化学选择性差等问题。
2、选择性问题:本发明利用电化学合成手段,是芳基亲电试剂经历单电子还原的形式参与反应之中,利用自由基物种不与二氧化碳直接的反应的特性从而实现反应选择性的调控。
3、副反应抑制问题:本发明通过反应路线设计,利用自由基物种易与不饱和双键易发生加成的特性,实现自由基串联环化,同时利用2-位取代基的电子效应和位阻效应合理调控,有效抑制以上副反应。
4、体系兼容性问题:该反应设计通过碳负离子对二氧化碳的亲核进攻实现羧酸的合成,将电化学合成技术与还原性体系相结合,利用电化学手段构建强还原性体系,保证体系中的自由基能够顺利还原为亲核性的碳负离子,进而保证反应的顺利进行。
具体实施方式
实施例1
一种吲哚啉羧酸类化合物,其制备方法包括以下步骤:在手套箱中,向50mL的三口瓶中(碳毡电极与锌电极通过翻口塞固定在三口瓶两侧)依次加入吲哚类化合物(0.3mmol),无水叔丁醇钾(0.3mmol,纯度大于99.99%)以及无水碘化钠(0.012mol,纯度大于98%)。装置密封从手套箱中取出后,通过双排导气系统将反应瓶中的氮气抽置换成二氧化碳(反复五次,每次持续1分钟),接着在二氧化碳氛围下用注射器依次加入超干的N-甲基吡咯烷酮(NMP)6mL。开动搅拌器,直至所有的固体全部溶解后,将电极浸没到溶液中(碳毡电极有效的浸没体积大约为1×1×1cm3,锌电极有效的浸没面积大约1×1cm2)。在室温下设定恒定电流I=8mA并开始电解,通过TLC检测反应情况。反应结束后,加入约15mL的2N盐酸水溶液酸化1h左右,此时碳毡电极需要完全浸没到盐酸溶液中。酸化结束后,乙酸乙酯萃取反应液,有机层合并后用水(2×50mL)清洗有机层中的NMP。需要注意的是由于碳毡电极极容易吸收溶液,因此需要反复多次用乙酸乙酯冲洗直到检不出目标羧酸为止,并将清洗出的有机层合并。随后浓缩旋干反应液,通过柱层析的方式(干法上样,展开剂主要为石油醚:乙酸乙酯)分离得到目标羧酸。所得目标羧酸结构式为:
10b-(isopropoxycarbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(1)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.77–7.73(m,2H),7.52–7.46(m,3H),7.41–7.37(m,1H),7.27–7.25(m,2H),7.14–7.10(m,1H),4.98–4.88(m,1H),4.76(s,1H),1.09(dd,J=11.2,6.4Hz,6H);
13C NMR(101MHz,CDCl3)δ172.1,169.1,168.0,141.0,139.9,133.7,132.8,132.0,130.0,129.9,125.5,125.0,124.9,123.2,117.1,78.6,71.1,52.3,21.3,21.2;
HRMS calcd for C19H16NO3[M-COOH]-:306.1136,found for:306.1135.
实施例2
将铁阴极与铂阳极分别安插在50mL三口瓶的两侧。随后进入手套箱中依次称取吲哚类基化合物(0.3mmol),叔丁醇锂(0.3mmol,纯度大于99.99%)。称取结束后封好取出。随后将带有二氧化碳气囊的双排管出气管与电解池连接,并抽置换为二氧化碳氛围(抽置换5次,每次1min)。紧接着在二氧化碳氛围下通过注射器将6mL的N-甲基吡咯烷酮的四丁基碘化铵溶液注入装置中(电解液浓度0.1M)。采用恒定电流电解,电流强度为6mA,通过TLC检测反应情况。反应结束后后处理同实施例1,所得目标羧酸结构式为:
10b-(tert-butoxycarbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(2)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.78–7.74(m,2H),7.55–7.47(m,3H),7.39–7.38(m,1H),7.29–7.27(m,1H),7.14–7.10(m,1H),4.74(s,1H),1.32(s,9H);
13C NMR(101MHz,CDCl3)δ171.9,168.3,167.9,141.4,140.1,133.9,132.7,132.2,129.9,129.8,125.5,124.9,124.8,123.3,117.0,84.0,79.0,52.4,27.6;
HRMS calcd for C21H19NNaO5[M+Na]+:388.1155,found for:388.1162.
采用实施例1,2的制备方法还可得24种吲哚啉羧酸类化合物,其结构式和核磁共振结果如下:
6-oxo-10b-(pyrrolidine-1-carbonyl)-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(3)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.77–7.75(m,1H),7.68–7.67(m,1H),7.57–7.43(m,3H),7.39–7.35(m,1H),7.29–7.27(m,1H),7.17–7.13(m,1H),5.24(s,1H),3.48–3.42(m,1H),3.38–3.32(m,1H),3.29–3.23(m,1H),2.99–2.93(m,1H),1.82–1.75(m,1H),1.65–1.50(m,3H)ppm;
13C NMR(100MHz,CDCl3)δ172.4,169.1,166.8,141.6,139.7,133.7,133.5,133.2,129.9,129.4,125.9,125.4,124.3,123.9,116.9,80.4,53.6,49.4,46.7,26.9,22.6;
HRMS calcd for C21H18N2NaO4[M+Na]+:385.1159,found for:385.1160.
10b-(morpholine-4-carbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(4)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.80–7.78(m,1H),7.66–7.64(m,1H),7.57–7.56(m,2H),7.52–7.48(m,1H),7.42–7.38(m,1H),7.30–7.28(m,1H),7.20–7.16(m,1H),5.39(s,1H),3.56–3.51(m,2H),3.33(br,6H);
13C NMR(101MHz,CDCl3)δ172.3,169.6,166.7,142.3,139.8,134.0,133.6,132.7,130.2,129.6,125.8,125.7,124.9,123.8,117.7,81.1,66.5,54.2,45.8;
HRMS calcd for C21H18N2NaO5[M+Na]+:401.1108,found for:401.1115.
6-oxo-10b-phenyl-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(5)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ7.79–7.74(m,2H),7.70–7.67(m,3H),7.64(td,J=7.2,1.2Hz,1H),7.51(td,J=7.2,0.8Hz,1H),7.42–7.33(m,4H),7.28–7.25(m,1H),7.14–7.10(m,1H),4.62(s,1H);
13C NMR(101MHz,DMSO-d6)δ170.5,167.6,147.2,142.3,139.9,134.7,133.1,132.0,129.1,129.0,128.1,126.0,125.0,124.9,124.2,124.1,116.8,78.8,57.2;
HRMS calcd for C22H15NNaO3[M+Na]+:364.0950,found for:364.0950.
10b-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(6)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.76–7.70(m,2H),7.52–7.49(m,1H),7.45–7.39(m,3H),7.29–7.26(m,1H),7.16–7.12(m,1H),3.96(s,1H),1.65(s,3H);
13C NMR(101MHz,CDCl3)δ172.9,168.1,147.4,139.7,133.3,133.0,132.7,129.7,129.0,125.9,124.8,124.7,122.4,117.7,73.9,55.7,27.8;
HRMS calcd for C16H12NO[M-COOH]-:234.0924,found for:234.0926.
6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(7)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ7.77–7.75(m,1H),7.72–7.64(m,2H),7.58–7.54(m,2H),7.41–7.36(m,2H),7.16–7.12(m,1H),5.91(d,J=8.0Hz,1H),4.43(d,J=8.0Hz,1H);
13C NMR(101MHz,DMSO-d6)δ170.6,167.6,143.4,140.6,135.5,134.0,132.6,128.9,128.8,125.9,124.5,124.1,123.8,116.0,66.8,48.8;
HRMS calcd for C16H12NO3[M+H]+:266.0817,found for:266.0820.
10b-(ethoxycarbonyl)-11-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(8)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ7.83–7.81(m,1H),7.76–7.71(m,2H),7.63–7.55(m,2H),7.40–7.29(m,2H),7.17–7.13(m,1H),4.12(q,J=7.2Hz,2H),1.73(s,3H),1.13(t,J=7.2Hz,3H);
13C NMR(101MHz,DMSO-d6)δ171.4,167.8,167.7,142.3,141.6,139.8,133.4,133.2,130.5,129.3,126.3,125.1,124.1,123.9,116.5,82.3,62.7,57.4,18.5,14.2;
HRMS calcd for C20H17NNaO5[M+Na]+:374.0999,found for:374.1008.
10b-(ethoxycarbonyl)-2-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(9)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.77–7.75(m,1H),7.63–7.61(m,1H),7.54–7.45(m,3H),7.20–7.18(m,1H),7.09–7.08(m,1H),4.75(s,1H),4.11(q,J=7.2Hz,2H),2.33(s,3H),1.12(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.2,169.9,168.0,140.9,137.6,134.9,133.9,132.7,132.1,130.4,130.0,126.2,124.9,123.2,116.8,78.8,63.1,52.4,21.1,13.8;
HRMS calcd for C20H17NNaO5[M+Na]+:374.0999,found for:374.0994.
10b-(ethoxycarbonyl)-2-methoxy-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(10)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.68(d,J=6.8Hz,1H),7.61(d,J=8.6Hz,1H),7.52–7.41(m,3H),6.90–6.87(m,1H),6.83–6.82(m,1H),4.74(s,1H),4.11(q,J=7.2Hz,2H),3.76(s,3H),1.11(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.0,169.8,168.2,157.4,140.8,133.8,133.5,133.4,132.8,130.1,124.8,123.2,117.7,114.7,111.9,79.0,63.1,55.7,52.7,13.8;
HRMS calcd for C20H17NNaO6[M+Na]+:390.0948,found for:390.0953.
10b-(ethoxycarbonyl)-2-fluoro-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(11)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.72–7.70(m,1H),7.67–7.64(m,1H),7.53–7.44(m,3H),7.10–7.05(m,1H),7.00–6.98(m,1H),4.77(s,1H),4.12(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ171.3,169.6,168.1,160.1(d,J=244.7Hz),140.8,136.2(d,J=2.4Hz),133.8(d,J=8.8Hz),133.5,133.0,130.2,125.0,123.4,117.9(d,J=8.6Hz),116.5(d,J=23.5Hz),113.3(d,J=25.0Hz),78.9,63.2,52.5,13.8;
19F NMR(376MHz,CDCl3)δ-116.74,-117.09;
HRMS calcd for C19H14FNNaO5[M+Na]+:378.0748,found for:378.0745.
2-chloro-10b-(ethoxycarbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(12)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ7.84–7.82(m,1H),7.80–7.72(m,2H),7.68–7.64(m,1H),7.62–7.57(m,2H),7.49–7.46(m,1H),4.80(s,1H),4.15(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H);
13C NMR(101MHz,DMSO-d6)δ169.6,167.7,141.4,139.3,136.1,134.1,133.1,131.0,129.6,129.4,126.7,124.9,124.8,117.8,79.0,63.5,53.1,14.1;
HRMS calcd for C19H14ClNNaO5[M+Na]+:394.0453,found for:394.0466.
2-bromo-10b-(ethoxycarbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(13)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.78–7.76(m,1H),7.63–7.61(m,1H),7.55–7.49(m,4H),7.42–7.41(m,1H),4.78(s,1H),4.13(q,J=7.2Hz,2H),1.13(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ171.8,169.4,167.9,140.6,139.1,133.9,133.3,133.1,132.9,130.2,128.7,125.1,123.4,118.4,117.8,78.6,63.3,52.2,13.8;
HRMS calcd for C19H14BrNNaO5[M+Na]+:437.9948,found for:437.9953.
2,10b-bis(ethoxycarbonyl)-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(14)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.80–7.78(m,1H),7.59–7.46(m,4H),7.27–7.21(m,1H),6.85–6.80(m,1H),4.76(s,1H),4.13(q,J=7.2Hz,2H),3.63(q,J=6.8Hz,2H),1.79(t,J=6.8Hz,3H),1.14(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.1,169.4,167.7,165.9,143.7,140.9,133.3,133.2,132.3,132.2,130.2,127.2,127.0,125.2,123.5,116.4,78.7,63.3,61.2,52.2,14.3,13.8;
HRMS calcd for C22H20NO7[M+H]+:410.1234,found for:410.1240.
10b-(ethoxycarbonyl)-3-fluoro-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(15)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ7.84–7.82(m,1H),7.79–7.75(m,1H),7.72–7.71(m,1H),7.68–7.64(m,1H),7.48–7.44(m,1H),7.41–7.38(m,1H),7.03–6.98(m,1H),4.74(s,1H),4.15(q,J=7.2 Hz,2H),1.11(t,J=7.2 Hz,3H);
13C NMR(101 MHz,DMSO-d6)δ170.0,169.7,167.8,163.0(d,J=244.1 Hz),141.7,141.5,134.2,133.0,131.0,130.1,130.0(d,J=1.9 Hz),127.7(d,J=10.0 Hz),124.8(d,J=32.7 Hz),111.9(d,J=22.5 Hz),104.5(d,J=27.1 Hz),79.6,63.4,52.7,14.1;
19F NMR(376 MHz,DMSO-d6)δ-111.99;
HRMS calcd for C19H14FNNaO5[M+Na]+:378.0748,found for:378.0746.
10b-(ethoxycarbonyl)-3-methoxy-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(16)
其核磁共振结果如下:1H NMR(400 MHz,DMSO-d6)δ7.81–7.62(m,4H),7.32–7.30(m,1H),7.15–7.14(m,1H),6.73–6.71(m,1H),4.65(s,1H),4.14(q,J=7.2 Hz,2H),3.82(s,3H),1.11(t,J=7.2 Hz,3H);
13C NMR(101 MHz,DMSO-d6)δ169.9,169.5,167.2,160.3,141.2,140.9,133.4,133.0,130.3,126.4,125.2,124.3,123.8,110.3,102.4,79.1,62.8,55.8,52.1,13.7;
HRMS calcd for C20H17NNaO6[M+Na]+:390.0948,found for:390.0955.
10b-(ethoxycarbonyl)-1-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(17)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.80–7.78(m,1H),7.60–7.47(m,4H),7.31–7.28(m,1H),6.96–6.94(m,1H),4.79(s,1H),4.12(q,J=7.2Hz,2H),2.24(s,3H),1.11(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ171.4,170.0,168.0,140.9,139.9,135.6,133.9,132.8,130.9,130.1,129.8,126.3,124.9,123.3,114.6,78.5,63.1,51.5,18.3,13.8;
HRMS calcd for C20H18NO5[M+H]+:352.1179,found for:352.1191.
10b-(ethoxycarbonyl)-2,3-dimethoxy-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(18)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.78–7.76(m,1H),7.56–7.45(m,3H),7.36(s,1H),6.82(s,1H),4.73(s,1H),4.13(q,J=7.2Hz,2H),3.96(s,3H),3.83(s,3H),1.14(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ171.9,170.0,167.9,150.4,146.7,140.9,134.0,133.9,132.7,130.0,124.8,123.2,122.6,108.7,101.3,79.4,63.1,56.4,56.3,52.5,13.8;
HRMS calcd for C21H19NNaO7[M+Na]+:420.1054,found for:420.1062.
10b-(ethoxycarbonyl)-8-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(19)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.73–7.71(m,1H),7.59–7.58(m,1H),7.42–7.35(m,2H),7.32–7.30(m,1H),7.27–7.25(m,1H),7.13–7.09(m,1H),4.79(s,1H),4.09(q,J=7.2Hz,2H),2.39(s,3H),1.10(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.4,170.0,168.1,140.4,139.9,138.1,133.8,133.7,132.0,129.8,125.5,125.2,124.9,123.0,117.0,78.3,63.0,52.3,21.3,13.7;
HRMS calcd for C20H17NNaO5[M+Na]+:374.0999,found for:374.1000.
10b-(ethoxycarbonyl)-9-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(20)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.73–7.71(m,1H),7.63–7.61(m,1H),7.39–7.35(m,1H),7.32(s,1H),7.25–7.23(m,2H),7.13–7.09(m,1H),4.78(s,1H),4.09(q,J=7.2Hz,2H),2.36(s,3H),1.11(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.4,169.2,168.2,139.9,139.2,134.7,134.3,133.6,132.7,130.0,129.8,125.5,125.1,122.6,116.9,78.6,63.0,50.8,18.1,13.7;
HRMS calcd for C19H16NO3[M-COOH]-:306.1136,found for:306.1134.
10b-(ethoxycarbonyl)-10-methyl-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(21)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.74–7.72(m,1H),7.40–7.36(m,1H),7.33–7.31(m,2H),7.26–7.20(m,2H),7.13–7.09(m,1H),4.78(s,1H),4.10(q,J=7.2Hz,2H),2.66(s,3H),1.12(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.4,169.2,168.2,139.9,139.2,134.7,134.3,133.6,132.7,130.0,129.8,125.5,125.1,122.6,116.9,78.6,63.0,50.8,18.1,13.7;
HRMS calcd for C19H16NO3[M-COOH]-:306.1136,found for:306.1134.
10b-(ethoxycarbonyl)-9-fluoro-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(22)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.74–7.72(m,1H),7.51–7.46(m,1H),7.41–7.37(m,1H),7.32–7.27(m,2H),7.16–7.10(m,2H),4.80(s,1H),4.12(q,J=7.2Hz,2H),1.12(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.2,169.5,164.7(d,J=2.2Hz),159.0(d,J=263.1Hz),143.3(d,J=2.9Hz),139.7,135.0(d,J=7.8Hz),131.7,130.0,125.6,125.3,120.8(d,J=13.8Hz),119.3(d,J=4.0Hz),117.6(d,J=19.2Hz),117.2,78.2,63.3,52.4,13.8;
19F NMR(376MHz,CDCl3)δ-115.33,-116.00;
HRMS calcd for C19H13FNO5[M-H]-:354.0783,found for:354.0775.
10b-(ethoxycarbonyl)-10-fluoro-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(23)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.73–7.71(m,1H),7.64–7.62(m,1H),7.51–7.46(m,1H),7.41–7.35(m,2H),7.22–7.13(m,2H),5.03(s,1H),4.11(q,J=5.2Hz,2H),1.10(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.6,168.1,166.8(d,J=2.3Hz),157.2(d,J=253.7Hz),138.9,136.6(d,J=3.3Hz),132.3(d,J=6.6Hz),131.9,129.9,127.9(d,J=17.4Hz),125.9,125.4,121.0(d,J=3.7Hz),119.9(d,J=19.5Hz),116.8,76.5,63.3,50.8,13.7;
19F NMR(376MHz,CDCl3)δ-116.90;
HRMS calcd forC18H13FNO3[M-COOH]-:310.0885,found for:310.0886.
10b-(ethoxycarbonyl)-7,8-difluoro-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(24)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.72–7.70(m,1H),7.63–7.59(m,1H),7.43–7.38(m,2H),7.31–7.30(m,1H),7.17–7.13(m,1H),4.76(s,1H),4.14(q,J=7.2Hz,2H),1.15(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ172.2,169.1,165.9,154.1(dd,J=163.0,14.1Hz),151.6(dd,J=159.7,14.0Hz),139.5,137.4(dd,J=8.0,3.2Hz),131.4,130.3(dd,J=6.6,2.7Hz),130.1,125.6(d,J=23.8Hz),117.0,116.8,113.9(d,J=19.3Hz),112.9(d,J=20.6Hz),77.8,63.5,52.3,13.8;
19F NMR(376MHz,CDCl3)δ-127.25,-132.50;
HRMS calcd for C19H12F2NO5[M-H]-:372.0689,found for:372.0682.
10b-(ethoxycarbonyl)-7,8-dimethoxy-6-oxo-10b,11-dihydro-6H-isoindolo[2,1-a]indole-11-carboxylic acid(25)
其核磁共振结果如下:1H NMR(400MHz,CDCl3)δ7.72–7.70(m,1H),7.40–7.36(m,1H),7.28–7.25(m,2H),7.14–7.12(m,1H),7.00(s,1H),4.79(s,1H),4.18–4.08(m,2H),3.85(s,6H),1.13(t,J=7.2Hz,3H);
13C NMR(101MHz,CDCl3)δ170.9,170.4,168.6,153.3,150.8,140.3,135.2,132.5,129.5,126.1,125.5,124.7,116.7,106.0,105.7,78.2,62.9,56.2,52.7,39.9,13.8;
HRMS calcd for C21H18NO7[M-H]-:396.1089,found for:396.1086.
3b-(ethoxycarbonyl)-10-oxo-4,10-dihydro-3bH-thieno[3',2':3,4]pyrrolo[1,2-a]indole-4-carboxylic acid(26)
其核磁共振结果如下:1H NMR(400MHz,DMSO-d6)δ8.19–8.18(m,1H),7.52–7.50(m,1H),7.41–7.36(m,2H),7.30–7.29(m,1H),7.17–7.15(m,1H),4.68(s,1H),4.16(q,J=7.2Hz,2H),1.14(t,J=7.2Hz,3H);
13C NMR(101MHz,DMSO-d6)δ170.2,168.8,164.0,152.8,140.8,139.5,136.4,133.5,129.6,126.6,125.2,123.1,116.3,77.4,63.3,52.9,14.2;
HRMS calcd for C17H13NNaO5S[M+Na]+:366.0407,found for:366.0403.
本发明的制备方法是在电化学催化下,实现26种吲哚啉羧酸类化合物的高效合成,避免金属有机中间体与亲电试剂原位的双组分催化偶联、质子化、β-H消除、异构化等副反应的发生,有效解决了副反应多、化学选择性差等问题。
虽然本发明的具体实施方式对本发明进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (10)
1.一种吲哚啉羧酸类化合物的制备方法,其特征在于,包括以下步骤:
在干燥环境中按照物质量比为1:0.5~1:4.5依次称取吲哚类化合物、碱和电解质并加入溶剂中,然后装入阴极材料和阳极材料,通入二氧化碳鼓泡10~20min,气流量为1~3mL/min,再在-28~120℃和非过渡金属催化剂催化条件下,恒流电解1~48h,同时进行磁子搅拌,待底物完全消耗后,加入盐酸淬灭,最后依次经萃取和柱层析,得吲哚啉羧酸类化合物。
3.如权利要求1所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述电解质为碘化钠、溴化钠、氯化钠、碘化锂、碘化钠、碘化钾、碘化镁、溴化镁、氯化镁、四丁基碘化、四丁基溴化铵、四丁基氯化铵、四丁基六氟磷酸铵、四丁基四氟硼酸铵、四丁基三氟甲磺酸铵、四丁基对甲苯磺酸铵、四丁基高氯酸铵、高氯酸锂、高氯酸钠或高氯酸钾。
4.如权利要求1所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述碱为无机碱或有机碱。
5.如权利要求4所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述无机碱为碳酸钾、磷酸钾、碳酸铯、磷酸钾、特戊酸钾、叔丁醇钾、叔丁醇锂、叔丁醇钠、乙醇钠、甲醇钠、甲醇钾、三氟甲磺酸钠、醋酸钾、醋酸钠、三氟乙酸钠或三氟乙酸钾。
6.如权利要求4所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述有机碱为三乙胺、二异丙基乙基胺、1,5-二氮杂双环[4.3.0]壬-5-烯、1,8-二氮杂双环[5.4.0]十一碳-7-烯、四甲基胍、1,4-二氮双环[2.2.2]辛烷、1,5,7-三氮杂二环[4.4.0]癸-5-烯、四甲基哌啶或二甲氨基吡啶。
7.如权利要求1所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述溶剂为乙醚、四氢呋喃、甲苯、三氟甲苯、丙酮、二氯甲烷、二氯乙烷、乙酸乙酯、乙腈、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二甲亚砜、N-甲基吡咯烷酮、1,4-二氧六环或二乙二醇二甲醚。
8.如权利要求1所述的吲哚啉羧酸类化合物的制备方法,其特征在于,恒流电解时,电流强度为1~50mA。
9.如权利要求1所述的吲哚啉羧酸类化合物的制备方法,其特征在于,所述阴极材料为碳毡、铁、铜、钯、镍、钨、锰、钼、铌、钴、钛、铅、铝、铂、泡沫镍、泡沫铜、不锈钢、镀镍铁、玻璃碳或网状玻璃态碳,所述阳极材料为锌、铁、铝、镁、铂、石墨棒或石墨板。
10.权利要求1~9任一项所述的吲哚啉羧酸类化合物的制备方法制得的吲哚啉羧酸类化合物。
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