CN112175004A - 一种通过自由基环化反应构建二苯并环庚酮骨架的方法 - Google Patents
一种通过自由基环化反应构建二苯并环庚酮骨架的方法 Download PDFInfo
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Abstract
本发明公开了一种经过自由基串联加成环化制备二苯并环庚酮骨架的方法，包括如下步骤：在催化量银盐存在条件下，亚磷酸二烷基酯转变为一个磷自由基，随后其与炔酮底物羰基α位炔碳发生加成反应得到一个烯基自由基，然后烯基自由基继续通过7‑endo‑trig环化加成到另一个芳环，最后脱氢芳构化为二苯并环庚酮类化合物。在一个反应中实现多个化学键的搭建。该制备方法反应物设计巧妙，操作简单、区域及化学选择性好。反应发生在十分绿色安全的的水相体系中，收率良好。
Description
技术领域
本发明属于有机合成领域，具体涉及一种通过自由基串联环化反应直接构建七元环的方法，得到秋水仙碱的类似物。
背景技术
秋水仙碱代表了一类十分重要的具有多种生理活性的生物碱，二苯并环庚烷是其核心骨架。该结构在有机合成和药物研发方面，是一种十分有利用价值的中间体。比如图6中的colchicine，N-acetylcoichine，ZD 6126和NSC51046。colchicine 从百合科植物秋水仙中发现的重要生物碱，能够与微管蛋白二聚体结合，阻止微管蛋白转换，使细胞停止于有丝分裂中期，从而导致细胞死亡，因此，可以用于地中海热综合征、急性通风等疾病的治疗；而且，它具有很好的抗肿瘤活性，在化疗中具有良好的效果。Allocolchicine是一种天然的微管蛋白抑制剂,能够有效地抑制肿瘤细胞的有丝分裂,进而使癌细胞产生凋亡。ZD 6126通过抑制微管蛋白聚合而表现出很强的抗癌作用。NSC 51046表现出了比秋水仙碱更强的微管蛋白结合活性和更小的毒副作用是一种更有前景的抗肿瘤候选药物之一。
因此，设计新的二苯并环庚烷衍生物的合成方法是一项十分有意义的工作。
发明内容
本发明提供了二苯并环庚酮类化合物的制备方法，该制备方法通过自由基 7-endo-trig环化实现。
一种自由基环化反应得到二苯并环庚酮的方法，包括如下步骤：
在催化量一价银盐的催化作用下，亚磷酸酯被氧化为磷自由基；该自由基进攻炔酮反应物羰基α位，得到一个烯基自由基，接着烯基自由基加成到另一个苯环处通过7-endo-trig环化实现七元环的构建，最后脱质子得到二苯并环庚酮类化合物；
所述的邻炔丙酰基联苯类化合物结构如式(I)所示：
所述的磷自由基前体亚磷酸酯的结构如式(II)所示：
式(I)～式(II)中，Ar代表芳环，可以是烷基、芳基、卤素、酯基取代的苯环；最优选择为烷基；
R1为H、烷基、卤素原子、酯基、硝基、氰基、烷氧基；最优选择为烷基或烷氧基；
R2为芳基、烷基或硅基；最优选择为芳基；
R及R'为相同或不相同的烷基；
本发明利用邻炔丙酰基联苯类化合物在乙腈溶剂中与磷自由基前体亚磷酸酯，在催化量的硝酸银催化下，生成分子内环化/去质子得到二苯并环庚酮骨架，所述的反应式具体如下式所示：
制备二苯并环庚酮类化合物反应
反应中，在催化量一价银盐的催化作用下，亚磷酸酯被氧化为磷自由基；该自由基去进攻炔酮1的羰基α位，得到一个烯基自由基A，接着烯基自由基A 加成到另一个苯环处经过7-endo-trig环化得到自由基B，自由基B进一步被氧化为碳正离子C，最后脱质子得到二苯并环庚酮类化合物，推测该反应机理如下式所示：
作为优选，两种反应物的摩尔比例为邻炔丙酰基联苯类化合物：亚磷酸酯＝ 1:2。
作为优选，使用的溶剂为乙腈和水的混合体系，二者体积比为1:1。
作为优选，反应的温度为60～100℃，反应温度过高，会使得副反应增多，反应温度过低，会降低反应物的转化率，作为进一步的优选，反应的温度为90℃。
作为优选，反应的氛围为氮气。
作为优选，所述的Ag(I)盐为硝酸银，用量为炔酮底物的0.2倍。
作为优选，所述的额外氧化剂为过二硫酸钾，用量为炔酮底物的2.5倍。
附图说明
图1为实施例1制得的产物的1H NMR谱图；
图2为实施例1制得的产物的13C NMR谱图；
图3为实施例2制得的产物的1H NMR谱图；
图4为实施例2制得的产物的13C NMR谱图；
图5为实施例2制得的产物的31P NMR谱图；
图6为含有苯并环庚烷骨架的药物分子。
具体实施方式
实施例1
在反应管中，准确加入邻炔丙酰基联苯1a(135mg，0.4mmol,1.0equiv.)、亚磷酸二乙酯2a(110mg，0.8mmol,2.0equiv.)、AgNO3(14mg，0.08mmol,0.2 equiv.)和K2S2O8(270mg，1mmol,2.5equiv.)，抽真空，氮气置换，反复三次，于氮气氛围下加入混合溶剂MeCN/H2O(1:1,4mL)中。在90℃下进行反应14h。将所有溶剂转移到圆底烧瓶中。在烧瓶中加入二氧化硅，真空蒸发溶剂。以 n-hexane/EtOAc(v/v,1:1)为洗脱液，用硅胶柱柱层析法进行纯化处理，得到相应的产物3a，收率为60％。该反应式如下：
产物核磁共振数据：1H NMR(CDCl3,400MHz),δ:7.78(d,J＝7.6Hz,1H), 7.63-7.58(m,2H),7.52-7.36(m,7H),7.24(s,1H),6.95(d,J＝2.0Hz,1H),4.09-3.92 (m,2H),3.79-3.75(m,1H),3.60-3.56(m,1H),1.21(t,J＝6.8Hz,3H),1.09(s,9H), 0.98(t,J＝6.8Hz,3H)；13C NMR(CDCl3,100MHz),δ:197.5(d,J＝8.6Hz,Cq), 154.2(d,J＝5.4Hz,Cq),150.0(Cq),144.2(d,J＝4.9Hz,Cq),140.7(d,J＝8.1Hz, Cq),136.2(d,J＝20.0Hz,Cq),135.7(Cq),134.7(Cq),132.9(Cq),131.0(CH),130.6 (CH),130.0(CH),125.4(CH),125.1(CH),62.8(d,J＝5.4Hz,CH2),62.1(d,J＝5.9 Hz,CH2),34.5(Cq),30.0(CH3),16.3(d,J＝5.7Hz,CH3),16.0(d,J＝6.4Hz,CH3)；31P NMR(CDCl3,243MHz),δ:10.3.
图1为实施例1制得的产物的1H NMR谱图；
图2为实施例1制得的产物的13C NMR谱图。
实施例2
在反应管中，准确加入邻炔丙酰基联苯1b(136.8mg，0.4mmol,1.0equiv.)、亚磷酸二乙酯2a(110mg，0.8mmol,2.0equiv.)、AgNO3(14mg，0.08mmol,0.2 equiv.)和K2S2O8(270mg，1mmol,2.5equiv.)，抽真空，氮气置换，反复三次，于氮气氛围下加入混合溶剂MeCN/H2O(1:1,4mL)中。在90℃下进行反应14h。将所有溶剂转移到圆底烧瓶中。在烧瓶中加入二氧化硅，真空蒸发溶剂。以n-hexane/EtOAc(v/v,1:2)为洗脱液，用硅胶柱柱层析法进行纯化处理，得到相应的产物3b，收率为65％。该反应式如下：
产物核磁共振数据：1H NMR(CDCl3,600MHz),δ:7.87(d,J＝7.8Hz,1H), 7.62-7.59(m,1H),7.47-7.46(m,2H),7.37-7.27(m,6H),6.89(s,1H),4.12-4.05(m, 1H),3.97-3.90(m,1H),3.69-3.62(m,2H),2.36(s,3H),1.77(s,3H),1.20(t,J＝7.2 Hz,3H),0.95(t,J＝7.2Hz,3H)；13C NMR(CDCl3,150MHz),δ:197.9(d,J＝9.4 Hz,Cq),151.6,145.0,140.3(d,J＝7.6Hz),139.1,138.8,138.5,136.8,134.2(d,J＝ 170.4Hz),133.3,133.2,132.1,130.7,129.8,128.8,128.7,127.8(d,J＝7.2Hz), 127.5,124.8,62.7(d,J＝5.8Hz,CH2),62.2(d,J＝5.8Hz,CH2),23.1,21.2,16.1(d, J＝6.8Hz,CH3),15.8(d,J＝6.4Hz,CH3)；31PNMR(CDCl3,243MHz),δ:10.3.
图3为实施例2制得的产物的1H NMR谱图；
图4为实施例2制得的产物的13C NMR谱图；
图5为实施例2制得的产物的31P NMR谱图。
Claims (6)
1.一种利用自由基环化构建二苯并环庚酮骨架的方法，其特征在于，包括如下步骤：使用邻炔丙酰基联苯类化合物作为反应物，在催化量的硝酸银催化下生成的磷自由基进攻炔酮反应物的羰基α位，后经过自由基分子内环化/去质子得到二苯并环庚酮骨架；
所述的邻炔丙酰基联苯类化合物结构如式(I)所示：
所述的磷自由基前体亚磷酸酯的结构如式(II)所示：
式(I)～式(II)中，Ar代表芳环，可以是烷基、芳基、卤素、酯基取代的苯环；
R1为H、烷基、卤素原子、酯基、硝基、氰基、烷氧基；
R2为芳基、烷基或硅基；
R及R'为相同或不相同的烷基。
2.根据权利要求1所述的自由基环化制备二苯并环庚酮的方法，其特征在于，反应中加入催化量的Ag(I)盐，并且需要加入当量的额外氧化剂保证Ag(I)的再生。
3.根据权利要求1或2所述的自由基环化制备二苯并环庚酮的方法，其特征在于，所述的Ag(I)盐为碳酸银、醋酸银、三氟乙酸银、氧化银和硝酸银中的一种，用量为炔酮底物的0.1～1.0倍。
4.根据权利要求1所述的自由基环化制备二苯并环庚酮的方法，其特征在于，所述的溶剂为乙腈、水、甲醇、乙醇、1,4-二氧六环、二甲基亚砜和四氢呋喃中的至少一种。
5.根据权利要求1所述的自由基环化制备二苯并环庚酮的方法，其特征在于，反应的温度为60～100℃。
6.根据权利要求1所述的自由基环化制备二苯并环庚酮的方法，其特征在于，反应的氛围为空气、氮气中的一种；额外氧化剂为过二硫酸钾(过硫酸钾)或过二硫酸钠(过硫酸钠)中的一种。
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| CN113957463A (zh) * | 2021-11-26 | 2022-01-21 | 浙江师范大学 | 一种电氧化条件下自由基串联环化合成二苯并环庚酮衍生物的方法 |
| CN113957463B (zh) * | 2021-11-26 | 2022-07-29 | 浙江师范大学 | 一种电氧化条件下自由基串联环化合成二苯并环庚酮衍生物的方法 |
| US11834400B2 (en) | 2021-11-26 | 2023-12-05 | Zhejiang Normal University | Method for synthesizing dibenzocycloheptane derivatives by series cyclization of free radicals under electrooxidation conditions |
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Application publication date: 20210105 Assignee: ZHEJIANG YUEXU MATERIAL TECHNOLOGY CO.,LTD. Assignor: ZHEJIANG NORMAL University Contract record no.: X2022980008290 Denomination of invention: A method of constructing dibenzocycloheptone skeleton by free radical cyclization reaction Granted publication date: 20210903 License type: Common License Record date: 20220627 |