CN104974121A - 一种3-芳甲酰基香豆素衍生物的合成方法 - Google Patents
一种3-芳甲酰基香豆素衍生物的合成方法 Download PDFInfo
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Abstract
本发明公开了一种3-芳甲酰基香豆素衍生物(I)和(II) 制备方法,属有机化学领域。该方法以取代香豆素衍生物和芳基醛为原料,在金属铁催化下,过氧叔丁醇为氧化剂,合成3-芳甲酰基香豆素衍生物。原料廉价易得、反应条件温和、操作简便、产率较高、有利于工业化生产。该类衍生物在材料、化工、医药等领域具有潜在的应用,本发明为3-芳甲酰基香豆素衍生物的合成提供了一条新的途径。
Description
技术领域
本发明涉及一种3-芳甲酰基香豆素衍生物的合成方法,属有机化学领域。
背景技术
香豆素是一类重要的天然产物,其衍生物具有广泛的生物活性,如抗菌抗炎、抗老年痴呆、抗HIV、抗胸腺癌、抗凝血和抗白血病等。3位含有羰基的香豆素衍生物通常可用来作为抗生素、抗凝血剂等药物使用,目前临床上正在使用的3位含羰基的香豆素衍生物有亮菌甲素、华法林和醋硝香豆素等。可见,3位含羰基的香豆素衍生物中可能会发现具有更好生物活性的化合物,开展此类结构香豆素衍生物的合成是极具研究价值的。
3-芳甲酰基香豆素衍生物作为3位含羰基的香豆素衍生物中的重要类别,其化学合成与生物活性研究近年来受到重视。目前,3-芳甲酰基香豆素衍生物的合成通常采用香豆素与苯甲酰氯在胺基锌和胺基镁碱条件下反应(Wunderlich S H,Rohbogner C J,Unsinn A,et al.Scaleable preparation of functionalizedorganometallics via directed ortho metalation using Mg-and Zn-amide bases[J].Org.Process Res Dev,2010,14(2):339-345.),或使用邻羟基苯甲醛与α-芳基烯酮二硫缩醛(AKDTAs)在催化量的哌啶作用下在THF中回流得到(Prakash Rao H S,Sivakumar S.Condensation ofα-aroylketene dithioacetals and 2-hydroxyarylakdehydes results in facile synthesis of a combinatorial library of 3-aroylcoumarins[J].J Org Chem,2006,71(23):8715-8723.),但是这些方法需要条件相对比较苛刻、原料复杂,缺乏经济性和实用性。文献“Wang H,Zhou S L,Guo L N,et al.Diacylation of coumarins by silver-catalyzed decarboxylative cross-coupling[J].Tetrahedron,2015,71(4):630-636.”以AgNO3为催化剂,K2S2O8为氧化剂,香豆素与羰基酸反应得到3-芳甲酰基香豆素衍生物和3,4-二芳甲酰基香豆素衍生物。文献“Yan K L,Yang D S,Wei W,et al.Silver-mediated radical cyclization ofalkynoates andα-keto acids leading to coumarins via cascade double C-C bondformation[J].J Org Chem,2015,80(3):1550-1556.”以Ag2CO3为催化剂,K2S2O8为氧化剂,以炔酯为原料,与羰基酸通过自由基反应得到3-芳甲酰基香豆素衍生物。但是这些合成方法以价格较贵的羰基酸为原料,或使用不易得到的反应前体。因此,急需探索一种步骤简单,条件温和,收率较高的3-芳甲酰基香豆素衍生物的合成方法。
发明内容
基于上述研究背景,本发明的目的在于提供一种原料廉价、条件温和、收率高,通过一步反应得到3-芳甲酰基香豆素衍生物的合成新方法。
为实现本发明目的,本发明以取代香豆素与芳香醛为原料,在催化剂铁盐和氧化剂过氧叔丁醇作用下合成3-芳甲酰基香豆素衍生物。本发明所述的3-芳甲酰基香豆素衍生物有如下通式I和II。
其中R代表氢基或如下基团的单取代或双取代:C1-2烷基、甲氧基、乙酰氨基、乙酰氧基、氟基、氯基和溴基,优选-CH3,-OCH3,-F,-Cl,-Br;R1代表如下基团之一:氢基、甲基、乙基、甲氧基和苯基,优选-H,-CH3、-OCH3;R2代表氢基或如下基团的单取代或双取代:甲基、乙基、甲氧基、乙氧基、硝基、氨基、羟基、乙酰氨基、乙酰氧基和卤基,优选单取代的-CH3,-C2H5,-OCH3,-OC2H5,-OH,-NHCOCH;X代表如下原子或基团:氧原子、硫原子或-NCH3,优选O或S。
具体技术方案通过如下步骤实现:首先将取代香豆素与芳香醛溶解在合适的有机溶剂中,然后加入催化剂铁盐和氧化剂,在80-120℃下反应。反应结束后,冷却至室温,减压蒸去溶剂,残液经洗涤,萃取,干燥,得通式(I)3-芳甲酰基香豆素衍生物粗品。
取代香豆素和芳香醛的摩尔比选1:2~1:4,优选1:3。
催化剂铁盐选择Fe(NO3)3,Fe2(SO4)3,FeCl3,FeCl2,FeSO4,优选FeCl2作为催化剂,加入的量为取代香豆素摩尔量的10%。
氧化剂选:过氧叔丁醇(t-BuOOH),加入的量为取代香豆素摩尔量的3倍。
有机溶剂选择DMF、氯苯、二氧六环、1,2-二氯乙烷、DMSO和乙腈中等中一种或多种作为溶剂,优选氯苯为溶剂。优选采用120℃为最佳的反应温度,最佳的反应时间为10h。
式中R、R1、R2和X表述同上。
分离和纯化3-芳甲酰基香豆素衍生物粗品,例如,将粗品通过硅胶柱层析进行分离得3-芳甲酰基香豆素衍生物(I)或(II),使其获得更好的应用。另外,可以通过在(I)或(II)的乙酸乙酯溶液中加入适量的石油醚,使(I)或(II)结晶析出。该类衍生物在材料、化工、医药等领域具有潜在的应用。
本发明所用试剂均市售可得。
本发明原理在于:过氧叔丁醇首先在Fe2+作用下产生叔丁氧基自由基,同时Fe2+转化为Fe3+,叔丁氧基自由基夺取芳香醛醛基中的H自由基,产生了芳甲酰基自由基;然后芳甲酰基自由基进攻香豆素的3位碳,就形成了碳(Csp2)自由基,Fe3+得到一个电子转变成Fe2+,就形成了3-芳甲酰基二氢香豆素碳正离子;最后脱去一个质子形成目标产物3-芳甲酰基香豆素衍生物。该反应的原理是在Fe2+催化下的自由基取代反应。
本发明有益效果在于:本发明3-芳甲酰基香豆素衍生物的合成方法原料廉价易得,通过一步反应得到目标物,反应条件温和、操作简便、合成产率高,达60%以上,非常有利于工业化生产,为制备具有抗菌抗炎、抗癌、抗凝血等活性的3-芳甲酰基香豆素衍生物提供了一条新的途径。
具体实施方式
下面通过实施例对本发明进行进一步的阐述,但并不意味着本发明的内容局限于实施例。
实施例1.R=-CH3,R1=R2=-H时,3-(4-甲基苯甲酰基)香豆素衍生物的制备
在25mL反应瓶中加入香豆素(0.5mmol,73mg)和对甲基苯甲醛(1.5mmol,180mg)溶解在5.0mL氯苯中,然后加入FeCl3·6H2O(0.05mmol,13.5mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为80℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/10),得到无色晶体0.079g,产率60.0%。
熔点:132-133℃.1H NMR(CDCl3)δ:8.05(s,1H),7.78(d,JH-H=8.2Hz,2H),7.63(td,JH-H=8.7Hz,JH-H=1.5Hz,1H),7.60(dd,JH-H=7.8Hz,JH-H=1.5Hz,1H),7.39(d,JH-H=8.2Hz,2H),7.32(td,JH-H=8.2Hz,JH-H=7.8Hz,1H),7.27(d,JH-H=8.0Hz,1H),2.42(s,JH-H=2.43,3H).13C NMR(CDCl3)δ:191.2(C=O),158.5(C=O),154.7,145.1(CH),144.9,133.6(CH),133.5,129.8(CH),129.4(CH),129.2(CH),127.2,124.9(CH),118.2,116.9(CH),21.8(CH3).IR(KBr)ν(cm-1):1720,1658(C=O),1608,1567,1455(Ar-).ESI MS m/z:265.1[M+H]+(calculated forC17H13O3 +m/z:265.0).
实施例2.R=-OCH3,R1=R2=-H时,3-(3,4-二甲氧基苯甲酰基)香豆素衍生物的制备
在25mL反应瓶中加入香豆素(0.5mmol,73mg)和3,4-二甲氧基苯甲醛(1.5mmol,249mg)溶解在5.0mL乙腈中,然后加入FeCl2·4H2O(0.05mmol,9.9mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为120℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/8),得到白色固体0.106g,产率69.0%。
熔点:190-195℃.1H NMR(CDCl3)δ:8.02(s,1H),7.66-7.55(m,3H),7.42(td,JH-H=8.8Hz,JH-H=1.7Hz,2H),7.36(t,JH-H=7.5Hz,1H),6.88(d,JH-H=8.4Hz,1H),3.96(s,3H),3.95(s,3H).13C NMR(CDCl3)δ:190.0(C=O),158.6(C=O),154.6,154.2,149.3,144.4(CH),133.3(CH),129.1,128.9(CH),127.5,125.5(CH),124.9(CH),118.2,116.9(CH),110.9(CH),109.9(CH),56.2(OCH3),56.1(OCH3).IR(KBr)ν(cm-1):1708,1654(C=O),1592,1581,1515,1454(Ar-).ESI MS m/z:311.1[M+H]+(calculated for C18H15O5 +m/z:311.0).
实施例3.X=S,R1=R2=-H时,3-(5-甲基噻吩-2-甲酰基)香豆素衍生物的制备
在25mL反应瓶中加入香豆素(0.5mmol,73mg)和5-甲基噻吩-2-甲醛(1.5mmol,189mg)溶解在5.0mL DMF中,然后加入FeCl3·6H2O(0.05mmol,13.5mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为90℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/8),得到白色固体0.092g,产率68.0%。
熔点:153-154℃.1H NMR(CDCl3)δ:8.06(s,1H),7.65(td,JH-H=7.3Hz,JH-H=1.2Hz,1H),7.58(d,JH-H=7.7Hz,1H),7.54(d,JH-H=3.8Hz,1H),7.40(d,JH-H=8.3Hz,1H),7.34(t,JH-H=7.5Hz,1H),2.57(s,3H).13C NMR(CDCl3)δ:182.4(C=O),158.3(C=O),154.6,152.4,144.3(CH),140.6,136.0(CH),133.5(CH),129.1(CH),127.2(CH),126.9,124.9(CH),118.1,116.9(CH),16.3(CH3).IR(KBr)ν(cm-1):2981,2935(-CH3),1706,1657(C=O),1614,1566(Ar-).ESI MS m/z:271.2[M+H]+(calculated for C15H11O3S+m/z:271.0).
实施例4.X=O,R1=R2=-H时,3-(5-甲基呋喃-2-甲酰基)香豆素衍生物的制备
在25mL反应瓶中加入香豆素(0.5mmol,73mg)和5-甲基呋喃-2-甲醛(1.5mmol,165mg)溶解在5.0mL氯苯中,然后加入FeCl2·4H2O(0.05mmol,9.9mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为120℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/8),得到无色晶体0.092g,产率73.0%。
熔点:158-159℃.1H NMR(CDCl3)δ:8.12(s,1H),7.64(t,JH-H=7.5Hz,2H),7.60(d,JH-H=7.8Hz,1H),7.39(d,JH-H=8.3Hz,1H),7.33(t,JH-H=7.6Hz,1H),7.25(d,JH-H=3.5Hz,1H),6.24(d,JH-H=3.4Hz,1H),2.43(s,3H).13C NMR(CDCl3)δ:177.1(C=O),159.7(C=O),158.2,154.6,150.5,145.0(CH),133.6(CH),129.2(CH),126.5,124.9(CH),123.3(CH),118.2,116.8(CH),109.7(CH),14.2(CH3).IR(KBr)ν(cm-1):1720,1644(C=O),1606,1567,1508(Ar-).ESI MS m/z:255.2[M+H]+(calculated for C15H11O4 +m/z:255.0).
实施例5.R=-OCH3,R1=-H,R2=-NO2时,3-(4-甲氧基苯甲酰基)-6-硝基香豆素衍生物的制备
在25mL反应瓶中加入6-硝基香豆素(0.5mmol,95.5mg)和对甲氧基苯甲醛(1.5mmol,204mg)溶解在5.0mL 1,2-二氯乙烷中,然后加入Fe(NO3)3(0.05mmol,12.1mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为100℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/6),得到白色固体0.085g,产率52.0%。
熔点:153-154℃.1H NMR(DMSO)δ:8.82(d,JH-H=2.7Hz,1H),8.51(dd,JH-H=9.1Hz,JH-H=2.7Hz,1H),8.49(s,1H),7.98(dd,JH-H=7.0Hz,JH-H=2.0Hz,2H),7.72(d,JH-H=9.1Hz,1H),7.08(dd,JH-H=7.0Hz,JH-H=2.0Hz,2H),3.88(s,3H).13C NMR(DMSO)δ:189.8(C=O),164.6,158.1(C=O),157.7,144.1,143.5,132.8,129.0,128.8,128.0,125.7,119.2,118.3,114.6,56.2.IR(KBr)ν(cm-1):1716,1650(C=O),1618,1556,1449(Ar-).ESI MS m/z:326.1[M+H]+(calculated forC17H12O6 +m/z:326.0).
实施例6.R=-OCH3,R1=-H,R2=-OH时,3-(4-甲氧基苯甲酰基)-7-羟基香豆素衍生物的制备
在25mL反应瓶中加入7-羟基香豆素(0.5mmol,81mg)和对甲氧基苯甲醛(1.5mmol,204mg)溶解在5.0mL 1,2-二氯乙烷中,然后加入FeSO4(0.05mmol,7.6mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为100℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/4),得到白色固体0.089g,产率60.0%。
熔点134-135℃.1H NMR(DMSO)δ:10.94(s,1H),8.27(s,1H),7.86(dd,JH-H=6.8Hz,JH-H=2.0Hz,2H),7.68(d,JH-H=8.5Hz,1H),7.05(dd,JH-H=6.8Hz,JH-H=2.0Hz,2H),6.85(dd,JH-H=8.5Hz,JH-H=2.2Hz,1H),6.79(d,JH-H=2.2Hz,1H),3.86(s,3H).13C NMR(DMSO)δ:190.7(C=O),164.0,163.4,158.9(C=O),156.8,146.2(CH),132.4(CH),131.7(CH),129.7,122.2,114.3(CH),114.2(CH),111.2,102.5(CH),56.0(CH3).IR(KBr)ν(cm-1):1714,1654(C=O),1608,1565,1448(Ar-).ESI MS m/z:297.3[M+H]+(calculated for C17H13O5 +m/z:297.1).
实施例7.R=-H,R1=-CH3,R2=-OCOCH3时,3-(苯甲酰基)-4-甲基-7-乙酰氧基香豆素衍生物的制备
在25mL反应瓶中加入4-甲基-7-乙酰氧基香豆素(0.5mmol,109mg)和苯甲醛(1.5mmol,159mg)溶解在5.0mL DMSO中,然后加入FeCl2·4H2O(0.05mmol,9.9mg)和t-BuOOH(1.5mmol,195mg)。在油浴中加热搅拌下反应,反应温度为120℃。通过TLC跟踪反应过程,反应时间为10h,反应结束后,减压蒸除溶剂,残液中加入10mL乙酸乙酯,用20mL饱和的NaHCO3洗涤二次,再用10mL饱和的食盐水洗涤一次,有机相用无水Na2SO4干燥,溶液浓缩后用硅胶柱层析提纯(洗脱剂:乙酸乙酯/石油醚=1/5),得到白色固体0.098g,产率61.0%。
熔点:114-115℃.1H NMR(CDCl3)δ:7.91(dd,JH-H=8.0Hz,JH-H=0.8Hz,2H),7.71(d,JH-H=8.7Hz,1H),7.61(td,JH-H=7.4Hz,JH-H=1.2Hz,1H),7.47(t,JH-H=8.0Hz,2H),7.18(d,JH-H=2.2Hz,1H),7.14(dd,JH-H=8.7Hz,JH-H=2.2Hz,1H),2.35(s,3H),2.33(s,3H).13C NMR(CDCl3)δ:192.9(C=O),168.6,158.4(C=O),153.7,153.6,149.7,136.0,134.3(CH),129.3(CH),129.0(CH),126.2(CH),125.3,118.7(CH),117.4,110.5(CH),21.1(CH3),16.0(CH3).IR(KBr)ν(cm-1):1716,1655(C=O),1612,1569,1452(Ar-).ESI MS m/z:323.1[M+H]+(calculatedfor C19H15O5 +m/z:323.0).。
Claims (4)
1. 一种如式 (I) 和(II)所示3-芳甲酰基香豆素衍生物的制备方法,其特征在于,通过如下步骤合成:首先将取代香豆素衍生物A与芳香醛B1或B2溶解在有机溶剂中,然后加入铁催化剂和氧化剂,在80-120℃下反应;反应结束后,冷却至室温,减压蒸去溶剂,残液经萃取,干燥,得通式 (I) 或 (II) 3-芳甲酰基香豆素衍生物粗品;所述的催化剂为Fe(NO3)3,Fe2(SO4)3,FeCl3,FeCl2,FeSO4;所述的氧化剂选:过氧叔丁醇;所述的有机溶剂为DMF、氯苯、二氧六环、1,2-二氯乙烷、DMSO、乙腈中的一种或多种;
其中R代表氢基或如下基团的单取代或双取代:C1-3的烷基、甲氧基、乙酰氨基、乙酰氧基、氟基、氯基或溴基;R1代表如下基团:氢基、甲基、乙基、甲氧基或苯基;R2代表氢基或如下基团的单取代或双取代:甲基、乙基、甲氧基、乙氧基、硝基、氨基、羟基、乙酰氨基、乙酰氧基或卤基;X代表如下原子或基团:氧原子、硫原子或-NCH3;
。
2. 根据权利要求1所述的3-芳甲酰基香豆素衍生物制备方法,其特征在于,R选单取代的-CH3,-OCH3,-F,-Cl,-Br;R1选-H,-CH3,-OCH3;R2选单取代的-CH3,-C2H5,-OCH3,-OC2H5,-OH,-NHCOCH3;X选O或S。
3. 根据权利要求 1或2 所述的3-芳甲酰基香豆素衍生物的制备方法,其特征在于,所述的取代香豆素与芳香醛的摩尔比为1 : 2-1 : 4。
4. 如权利要求 1或2所述3-芳甲酰基香豆素衍生物的制备方法,其特征在于,反应温度选120℃。
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