CN117756767A - 一种γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法 - Google Patents
一种γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法 Download PDFInfo
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Abstract
本发明涉及一种环保且简便的γ,γ‑二氟烯丙基醛类化合物及其衍生物的制备方法。与现有技术相比,本发明提供了一种有机光氧化还原的α‑三氟甲基烯烃掩蔽甲酰化反应方法,包括:将α‑三氟甲基烯烃、1,3‑二氧戊环、催化剂、HAT试剂、碱性化合物在有机溶剂中混合、反应,得到含有掩蔽甲酰基的γ,γ‑二氟烯丙基醛类化合物。本发明提供的制备方法操作步骤简单、反应条件温和、收率高、底物普适性好,同时产物具有较高的纯度。
Description
技术领域
本发明涉及一种环保且简便的γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法。
背景技术
脂肪族醛类不仅在生物活性分子中无处不在,而且是有机合成中最特殊和最重要的一类原料。在开发高效获取脂肪族醛的努力中,最初的工作主要集中在以合成气(CO/H2)为甲酰基金属前体的过渡金属催化加氢甲酰化反应上。使用昂贵的过渡金属(如钯、铱、铑)、高压、合成气的毒性以及不对称烯烃的化学选择性和区域化学性质等问题虽然有效,但需要新的合成范例。为此,自由基甲酰化方法为甲酰基金属中间体提供了一种极具吸引力的替代方法。其中,遮蔽的甲酰基等价物已成为一种极具吸引力的策略,能以优异的区域选择性实现烯烃的加氢甲酰化。当甲酰化作为合成复杂分子的中间步骤时,这种策略就显得极为有利,可以省去醛基的额外缩醛保护。
α-三氟甲基烯烃作为有机合成领域的多功能和强大的构建块,在通过C-F键激活构建各种含氟分子方面得到了广泛的应用,已经公开了大量的方法来通过向烯烃部分添加各种亲核试剂和自由基来官能化α-三氟甲基烯烃,从而裂解三氟甲基中的单个C-F键以得到偕-二氟烯烃。随着光氧化催化技术的发展,在温和的条件下,1,3-二氧戊环已经实现了多种掩蔽甲酰化反应。但是这些方法通常受到高能紫外线照射、昂贵的铱光催化剂和作为HAT试剂的外部牺牲氧化剂的影响。在此,我们以低价的1,3-二氧戊环为掩蔽甲酰基等效物,以奎宁环为HAT试剂,对α-三氟甲基烯烃进行有机光氧化还原掩蔽甲酰化反应的研究。
发明内容
发明目的:为了打破现有技术方法的局限性,作为对现有研究有机光氧化还原掩蔽甲酰化方法的补充,本发明提供了一种环保且简便的γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法。
技术方案:为实现上述目的,本发明提供了如下技术方案:
本发明的技术方案之一,一种γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法,其结构式为:
其中,R为苯基、苄氧基、酯基、氰基、羰基、卤素原子、多环芳基、杂环基等中的一种。
本发明的技术方案之二,提供上述γ,γ-二氟烯丙基醛类化合物的制备方法,包括步骤如下:
向装有搅拌子的施伦克管中加入α-三氟甲基烯烃、4CzIPN、奎宁环和碳酸氢钠,用氮气置换3次,在氮气氛围下加入溶剂(乙腈,2mL)和1,3-二氧戊环。将反应混合物密封,用波长为427nm的蓝光LED灯照射,室温下搅拌12小时。反应结束后减压蒸馏去除溶剂即得粗产品,再以石油醚∶乙酸乙酯为淋洗液进行柱层析,即得目标产物。
所述的催化剂为(Ir[dF(CF3)ppy]2(dtbpy))PF6、4CzlPN、4DPAIPN、Mes-Acr-Me+BF4 -、Eosin Y、4tBuCzBN。
所述的碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸铯、磷酸氢二钠、磷酸二氢钠、氢氧化钾、氟化钾、三乙胺。
所述的溶剂为乙腈、二甲基亚砜、N,N-二甲基乙酰胺。
所述的HAT试剂为四丁基溴化铵、奎宁环。
所述的如式1所示化合物和如式2所示化合物的摩尔比可为1∶4或1∶5或1∶10。
所述反应较佳地在惰性气氛下进行,所述的惰性气氛可为氮气。
所述的反应的进程可以采用本领域中的常规监测方法(例如TLC)进行监测。
所述的R基团为苯基、4-甲基苯基、4-甲氧基苯基、2-甲氧基苯基、4-叔丁基苯基、4-联苯基、4-氯苯基、3,4-二氯苯基、4-苄氧苯基、4-氰基苯基、4-乙酰基苯基、4-甲酯基苯基、4-氨基甲酰基苯基、4-乙酰胺基苯基、3,4,5-三甲氧基苯基、3-甲氧基苯基、3-三氟甲氧基苯基、3-硫甲基、3-苄氧苯基、3-氰基苯基、1-萘基、2-萘基、3-喹啉基、4-二苯并呋喃基、4-二苯并噻吩基、苯乙炔基等。
在本发明的某一方案中,所述的如式3所示的γ,γ-二氟烯丙基醛类化合物为如下任一结构:
本发明的有益效果为:本发明提供的γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法科学合理,拓宽了该方法的底物范围,其特点为溶剂使用单一,无金属催化剂;含有不同取代基的烯烃掩蔽甲酰化;反应条件温和,原子利用率高。
附图说明
为了更清楚地说明本发明实施例的技术方案,下面将对实施例描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其它的附图。其中:
图1为α-三氟甲基烯烃光氧化还原掩蔽甲酰化反应式;
图2-1为实施例制备的化合物3a的核磁共振氢谱图;
图2-2为实施例制备的化合物3a的核磁共振碳谱图;
图3为实施例制备的化合物4的核磁共振氢谱图;
图4-1为实施例制备的化合物3b的核磁共振氢谱图;
图4-2为实施例制备的化合物3b的核磁共振碳谱图;
图5-1为实施例制备的化合物3c的核磁共振氢谱图;
图5-2为实施例制备的化合物3c的核磁共振碳谱图;
图6-1为实施例制备的化合物3d的核磁共振氢谱图;
图6-2为实施例制备的化合物3d的核磁共振碳谱图;
图7-1为实施例制备的化合物3e的核磁共振氢谱图;
图7-2为实施例制备的化合物3e的核磁共振碳谱图;
图8-1为实施例制备的化合物3f的核磁共振氢谱图;
图8-2为实施例制备的化合物3f的核磁共振碳谱图;
图9-1为实施例制备的化合物3g的核磁共振氢谱图;
图9-2为实施例制备的化合物3g的核磁共振碳谱图;
图10-1为实施例制备的化合物3h的核磁共振氢谱图;
图10-2为实施例制备的化合物3h的核磁共振碳谱图;
图11-1为实施例制备的化合物3i的核磁共振氢谱图;
图11-2为实施例制备的化合物3i的核磁共振碳谱图。
具体实施方式
下面结合附图和具体的实施例对本发明进一步详细说明。
下述实施例中所述试验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。
实施例1:2-(2-([1,1′-联苯]-4-基)-3,3-二氟烯丙基)-1,3-二氧戊环3a的制备,方程式如下:
向装有搅拌子的施伦克管中加入4-苯基-α-三氟甲基烯(0.2mmol)、4CzIPN(1mol%)、奎宁环(20mol%)和碳酸氢钠(1.5equiv.),用氮气置换3次,在氮气氛围下加入乙腈(2mL)、1,3-二氧戊环(1mmol)。将反应混合物密封,用波长为427nm的40W蓝光LED灯照射,室温下搅拌12小时。12小时后反应结束后减压蒸馏去除溶剂即得粗产品,再以石油醚∶乙酸乙酯=20∶1为淋洗液进行柱层析纯化,得到产物45.5mg,产率75%。
核磁分析:1H NMR(600MHz,CDCl3):δ=7.61-7.58(m,4H),7.48-7.43(m,4H),7.38-7.34(m,1H),4.96(td,J=4.9,0.8Hz,1H),3.99-3.95(m,2H),3.86-3.82(m,2H),2.80-2.77(m,2H).13C NMR(150MHz,CDCl3):δ=154.7(dd,J=289.0,289.0Hz),140.5,140.1,132.5,128.8,128.7,127.4,127.1,127.0,102.6,87.8(dd,J=15.8,15.5Hz),65.0,33.0。
实施例2:3-([1,1′-联苯]-4-基)-4,4-二氟丁-3-烯醛4的制备,方程式如下:
向装有搅拌子的施伦克管中加入4-苯基-α-三氟甲基烯(0.2mmol)、4CzIPN(1mol%)、奎宁环(20mol%)和碳酸氢钠(1.5equiv.),用氮气置换3次,在氮气氛围下加入乙腈(2mL)、1,3-二氧戊环(1mmol)。将反应混合物密封,用波长为427nm的40W蓝光LED灯照射,室温下搅拌12小时。反应完成后,用6N HCl(2mL)处理并在室温下搅拌5小时。浓缩反应混合物,用水(10mL)稀释,并用乙酸乙酯(3×10mL)萃取。将合并的有机层用无水Na2SO4干燥,过滤并在减压下浓缩。用石油醚/乙酸乙酯作为洗脱剂通过柱色谱法纯化混合物,得到所需的醛,产率59%。
核磁分析:1H NMR(600MHz,CDCl3):δ=9.72(s,1H),7.59(t,J=7.5Hz,4H),7.45(t,J=7.7Hz,2H),7.39(d,J=7.7Hz,2H),7.36(t,J=7.5Hz,1H),3.51(d,J=2.0Hz,2H).
实施例3:2-(3,3-二氟-2-苯基烯丙基)-1,3-二氧戊环3b的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成同摩尔量的α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物31.1mg,产率69%。1H NMR(600MHz,CDCl3):δ=7.39-7.34(m,4H),7.29-7.27(m,1H),4.67(td,J=4.9,0.8Hz,1H),3.98-3.93(m,2H),3.84-3.79(m,2H),2.76-2.73(m,2H);13C NMR(150MHz,CDCl3):δ=154.6(dd,J=291.0,288.6Hz),133.5(t,J=3.7Hz),128.4,128.3(t,J=3.3Hz),127.4,102.6(t,J=3.2Hz),88.1(dd,J=21.4,16.2Hz),65.0,33.0。
实施例4:2-(3,3-二氟-2-(对甲苯基)烯丙基)-1,3-二氧戊环3c的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成同摩尔量的4-甲基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物32.4mg,产率62%。1H NMR(600MHz,CDCl3):δ=7.27-7.26(m,2H),7.16(d,J=8.0Hz,2H),4.91(td,J=4.9,0.5Hz,1H),3.97-3.94(m,2H),3.83-3.80(m,2H),2.73-2.71(m,2H),2.34(s,3H);13C NMR(150MHz,CDCl3):δ=154.5(dd,J=290.3,288.4Hz),137.1,130.4(t,J=3.4Hz),129.2,128.2(t,J=3.2Hz),102.6(t,J=3.3Hz),87.9(dd,J=21.0,16.5Hz),65.0,33.1,22.1。
实施例5:2-(2-(4-(叔丁基)苯基)-3,3-二氟烯丙基)-1,3-二氧戊环3d的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成同摩尔量的4-叔丁基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物33.9mg,产率60%。1H NMR(600MHz,CDCl3):δ=7.37(d,J=7.8Hz,2H),7.331(d,J=7.8Hz,2H),4.92(t,J=4.9Hz,1H),3.98-3.95(m,2H),3.84-3.81(m,2H),2.74-2.72(m,2H),1.32(s,9H);13C NMR(150MHz,CDCl3):δ=159.5,154.6(dd,J=290.8,289.1Hz),134.8(t,J=2.7Hz),129.4,120.7(t,J=3.3Hz),114.3(t,J=3.3Hz),112.8,102.6(t,J=3.3Hz),88.1(dd,J=20.7,16.8Hz),65.0,55.2,33.1。
实施例6:2-(3,3-二氟-2-(4-甲氧基苯基)烯丙基)-1,3-二氧戊环3e的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成2毫摩尔量的4-甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物33.9mg,产率60%。1H NMR(600MHz,CDCl3):δ=7.37(d,J=7.8Hz,2H),7.331(d,J=7.8Hz,2H),4.92(t,J=4.9Hz,1H),3.98-3.95(m,2H),3.84-3.81(m,2H),2.74-2.72(m,2H),1.32(s,9H);13C NMR(150MHz,CDCl3):δ=158.7,154.5(dd,J=289.4,288.5Hz),129.5(t,J=3.2Hz),125.6(t,J=3.6Hz),113.9,102.7(t,J=3.3Hz),87.6(dd,J=21.3,16.5Hz),64.9,55.2,33.2。
实施例7:2-(3,3-二氟-2-(2-甲氧基苯基)烯丙基)-1,3-二氧戊环3f的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成2毫摩尔量的2-甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物21.0mg,产率41%。1H NMR(600MHz,CDCl3):δ=7.31-7.27(m,2H),7.21(d,J=7.4Hz,2H),6.96-6.92(m,2H),6.90(d,J=8.3Hz,2H),4.90(t,J=4.9Hz,1H),3.97-3.92(m,2H),3.83-3.80(m,5H),2.72-2.70(m,2H);13C NMR(150MHz,CDCl3):δ=157.3(d,J=2.4Hz),154.1(dd,J=288.3,286.8Hz),131.4(d,J=2.0Hz),129.3,122.1(d,J=4.3Hz),120.4,110.9,102.8(d,J=3.8Hz),94.8,85.5(dd,J=23.1,19.7Hz),64.9,55.4,32.6。
实施例8:2-(3,3-二氟-2-(3,4,5-三甲氧基苯基)烯丙基)-1,3-二氧戊环3g的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成2毫摩尔量的3,4,5-三甲氧基-α-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物40.6mg,产率62%。1H NMR(600MHz,CDCl3):δ=7.59(s,2H),4.92-4.89(m,1H),3.98-3.95(m,2H),3.86-3.82(m,11H),2.70-2.68(m,2H)。13C NMR(150MHz,CDCl3):δ=157.3(t,J=290.5Hz),153.1,137.3,130.0(t,J=3.6Hz),105.7(t,J=3.2Hz),102.5(t,J=3.2Hz),88.2(dd,J=21.7,16.1Hz),65.0,60.8,56.1,33.3.
实施例9:2-(2-(4-(苄氧基)苯基)-3,3-二氟烯丙基)-1,3-二氧戊环3h的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成2毫摩尔量的4-苄甲氧基-α.-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物39.2mg,产率59%。1H NMR(600MHz,CDCl3):δ=7.44(d,J=7.4Hz,2H),7.40(t,J=7.4Hz,2H),7.35-7.32(m,1H),7.31(d,J=8.4Hz,2H),6.98-6.96(m,2H),5.07(s,2H),4.91(t,J=4.9Hz,1H),3.98-3.95(m,2H),3.84-3.81(m,2H),2.72-2.70(m,2H);13C NMR(150MHz,CDCl3):δ=158.0,155.9(t,J=289.4Hz),136.9,129.5,128.6,128.0,127.5,125.9(t,J=4.1Hz),114.8,102.7,94.8,87.6(dd,J=21.7,116.0Hz),70.3,65.0,33.1。
实施例10:N-(4-(3-(1,3-二氧戊环-2-基)二氟丙基-1-烯-2-基)苯基)乙酰胺3i的制备,除了将实施例1中的4-苯基-α-三氟甲基烯换成2毫摩尔量的4-乙酰胺基-d-三氟甲基苯乙烯外,按与实施例1同样的方法进行,获得目标化合物30.9mg,产率55%。1H NMR(600MHz,CDCl3):δ=7.78(s,1H),7.49(d,J=7.9Hz,2H),7.30(d,J=7.7Hz,2H),4.88(s,1H),3.98-3.90(m,2H),3.85-3.75(m,2H),2.70(s,2H),2.15(s,3H);13C NMR(150MHz,CDCl3):δ=169.0,154.6(t,J=289.9Hz),137.2,128.8,119.9,102.6,87.6(dd,J=21.6,16.1Hz),64.9,32.9,24.4。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (9)
1.一种γ,γ-二氟烯丙基醛类化合物及其衍生物的制备方法,其结构式为:
其中,R为苯基、苄氧基、酯基、氰基、羰基、卤素原子、多环芳基、杂环基等多种中的一种。
2.如权利要求1所述γ,γ-二氟烯丙基醛类化合物制备方法,其特征在于,所述的催化剂为(Ir[dF(CF3)ppy]2(dtbpy))PF6、4CzIPN、4DPAIPN、Mes-Acr-Me+BF4 -、Eosin Y、4tBuCzBN。
3.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的碱为碳酸氢钠、碳酸氢钾、碳酸钠、碳酸铯、磷酸氢二钠、磷酸二氢钠、氢氧化钾、氟化钾、三乙胺。
4.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的溶剂为乙腈、二甲基亚砜、N,N-二甲基乙酰胺。
5.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的HAT试剂为四丁基溴化铵、奎宁环。
6.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的如式1所示化合物和如式2所示化合物的摩尔比可为1∶4或1∶5或1∶10。
7.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述反应较佳地在惰性气氛下进行,所述的惰性气氛可为氮气。
8.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的反应的进程可以采用本领域中的常规监测方法(例如TLC)进行监测。
9.如权利要求1所述γ,γ-二氟烯丙基醛类化合物的制备方法,其特征在于,所述的R基团为苯基、4-甲基苯基、4-甲氧基苯基、2-甲氧基苯基、4-叔丁基苯基、4-联苯基、4-氯苯基、3,4-二氯苯基、4-苄氧苯基、4-氰基苯基、4-乙酰基苯基、4-甲酯基苯基、4-氨基甲酰基苯基、4-乙酰胺基苯基、3,4,5-三甲氧基苯基、3-甲氧基苯基、3-三氟甲氧基苯基、3-硫甲基、3-苄氧苯基、3-氰基苯基、1-萘基、2-萘基、3-喹啉基、4-二苯并呋喃基、4-二苯并噻吩基、苯乙炔基等。
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