CN113402351A - 一种配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法 - Google Patents

一种配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法 Download PDF

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CN113402351A
CN113402351A CN202110547388.7A CN202110547388A CN113402351A CN 113402351 A CN113402351 A CN 113402351A CN 202110547388 A CN202110547388 A CN 202110547388A CN 113402351 A CN113402351 A CN 113402351A
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韩维
程璐
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Abstract

本发明公开了一种配体促进铁催化氧化芳香族化合物碳‑氢键合成酚的方法,包括以下步骤:以铁为催化剂金属,含硫氨基酸或胱氨酸衍生的双肽为配体,在双氧水为氧化剂的共同作用下,氧化芳香族化合物合成制备酚。本发明使用含硫氨基酸或胱氨酸衍生的双肽配体与廉价环保的铁组成催化剂,在酸为促进剂和双氧水为氧化剂的作用下,氧化芳碳‑氢键直接羟基化形成酚类化合物,本发明催化氧化反应制备酚的方法具有诸多优势:催化剂、反应原料、氧化剂和促进剂来源广泛、廉价、环保和稳定性好;芳香族化合物碳‑氢键直接参与反应一步形成酚;反应条件温和、官能团相容性和适用范围广;反应选择性好,在优化的反应条件之下,目标产品分离收率可高达85%。

Description

一种配体促进铁催化氧化芳香族化合物碳-氢键合成酚的 方法
技术领域
本发明属于催化合成领域,涉及一种铁催化合成酚的方法,具体涉及配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法。
背景技术
酚是具有高附加价值的有机合成中间体,广泛应用于医药、农药、染料和香料等的合成。目前公认的合成酚最理想的方法是芳碳-氢的氧化羟基化法,因为该方法具有底物来源广泛、稳定和廉价;原子经济性和步骤经济性高的优势。然而该方法存在着一些挑战性问题:芳碳-氢键键能大,极性小,难于活化;芳碳-氢键的键能大于烷基碳-氢的键能,会导致烷基苯氧化参与反应时更易于发生烷基的氧化,而非芳环碳-氢的氧化;产物酚相对于原料芳香化合物更容易被氧化,通常导致过氧化的副反应的发生;取代芳环参与反应容易形成位置异构的混合物,而且难于分开。这些问题都严重的阻碍了芳碳-氢氧化合成酚方法的广泛应用(Ottenbacher,R.V.,Talsi,E.P.&Bryliakov,K.P.Appl.Organomet.Chem.2020,34,e5900)。为了提高反应的选择性和活性,发展了导向基策略,然而这些方法需要额外引入导向基,而且只能获得邻位羟基化的产物(Iqbal,Z.,Joshi,A.&Ranjan De,S.Adv.Synth.Catal.2020,362,5301–5351)。另一种常用的策略是多步法,通过引入更加稳定性的基团如硅基(Cheng,C.&Hartwig,J.F.Science 2014,343,853–857)、硼基(Lv,J.H.et al.Nature 2019,575,336–341)或酰氧基(Yuan,C.X.et al.Nature 2013,499,192–196),再进一步转化为酚,该策略虽然能避免直接反应导致的酚过氧化问题,但是反应步骤多,容易形成大量的废物。迄今为止,尚未有一种非导向的、通用的、高选择性的、一步法催化氧化芳碳-氢合成酚的方法。
发明内容
发明目的:针对现有技术通过氧化芳碳-氢键合成酚合成方法存在反应效率低、选择性差、官能团相容性差和适用范围窄等问题,本发明提供配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,实现了高效和高选择性的催化氧化芳碳-氢键合成酚,该方法具有较好的通用性,活性高和选择性好,甚至敏感官能团的兼容性好,而且能有效实现对复杂分子的后期氧化羟基化。
技术方案:为了实现上述目的,本发明所述一种配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,包括以下步骤:以铁为催化剂金属,含硫氨基酸或胱氨酸衍生的双肽为配体,在双氧水为氧化剂的共同作用下,氧化芳香族化合物合成酚;
反应通式表示如下:
Figure BDA0003074041720000021
本发明的方法所合成的酚产品的结构通式为:
Figure BDA0003074041720000022
式中:
Ar表示的芳基为取代或非取代的苯基、联苯基、萘基、蒽基、菲基、芘基、或吡啶基。
其中,所述含硫氨基酸为半胱氨酸、蛋氨酸、胱氨酸或者高胱氨酸。
其中,胱氨酸衍生的双肽是由氨基保护的胱氨酸与氨基酸酯或氨基酸酯的盐酸盐,在活化剂N,N'-二环己基碳二亚胺(DCC)作用下缩合形成双肽。
作为优选,所述双肽配体选自如下结构中任意一种:
Figure BDA0003074041720000023
Figure BDA0003074041720000031
其中,所述芳基上的取代基单取代或多取代芳环上的氢。
进一步地,所述取代基任意选自氢、C1~C20直链或支链的烃基、C3~C12的环烷基、烷氧基、芳基、羟基、羧基、-B(OH)2、氟、氯、溴、碘、酯基、酰胺基、磺酰胺基、醛基、硝基、氰基、烷酰氧基或芳酰氧基。
其中,所述铁催化剂选自三氟甲磺酸亚铁、三氟甲磺酸铁、氯化亚铁、乙酰丙酮亚铁、乙酰丙酮铁、2,2,6,6-四甲基-3,5-庚二酮亚铁、2,2,6,6-四甲基-3,5-庚二酮铁、1,3-二苯基丙二酮亚铁、1,3-二苯基丙二酮铁、苯甲酰丙酮亚铁、苯甲酰丙酮铁、铁氰化亚铁、铁氰化铁、醋酸亚铁、硫酸亚铁、硫酸亚铁铵、硫酸铁、高氯酸铁、硝酸铁、酞菁亚铁、二茂铁、溴化亚铁、溴化铁、碘化亚铁、碘化铁或三氯化铁。
其中,整个合成反应的介质为水、乙腈的水溶液或1,2-二氯乙烷的水溶液,其中有机溶剂与水的体积比为1:(0.5~100)。
作为优选,整个合成反应中还包括酸,所述酸为乙酸、氯乙酸、三氟乙酸、丙酸、丁酸、特戊酸、alpha-酮戊二酸、抗坏血酸、樟脑磺酸或苯甲酸,
反应通式表示如下:
Figure BDA0003074041720000032
其中,所述芳香族化合物、酸、双氧水、铁催化剂和配体的摩尔比为1:(0~10):(1~10):(0.005~0.5):(0.0025~2.5)。
其中,所述方法中反应温度为20~120℃,反应时间为0.5~60小时。
高效的催化剂,可以提高反应的活性和选择性,高效催化剂的根本是找到理想的配体。本发明发现了一系列配体,特别是胱氨酸衍生的双肽配体和铁作用,有效的实现了芳碳-氢直接氧化成酚类化合物。本发明发现了一类配体与铁一起作用,能解决芳碳-氢直接氧化成酚类化合物的挑战性问题。本发明中特定的配体与铁作用可以改善铁催化中心的电子云密度,从而影响反应活性;配体本身有空间位阻调控的作用,与铁作用即是改善了铁催化中心的空间位阻,从而影响铁催化中心反应的位点,进而影响反应的选择性。所以本发明特定的配体提高铁催化氧化芳碳-氢羟基化反应的活性和选择性,保证了反应的高效性。
本发明的反应不同官能团能兼容,且效果与现有方法比有优势,说明本发明的方法具有较好的通用性,活性高和选择性好,甚至敏感官能团的兼容性好,而且能有效实现对复杂分子的后期氧化羟基化。
有益效果:与现有技术相比,本发明具有如下优点:
(1)本发明提供了一种铁催化氧化芳香族化合物碳-氢键一步合成酚方法,具体是一种在水或有机溶剂的水溶液中含硫氨基酸或胱氨酸衍生的双肽为配体促进铁催化氧化芳碳-氢羟基化反应来制备酚的新方法,该方法具有活性高,选择性好,配体易于获得等优势;该方法需要的氧化剂为双氧水,来源广泛和环境友好;官能团相容性好,适用范围广;适用于复杂分子的后期氧化羟基化,这在医药和生物化学领域有重要的应用价值;
(2)本发明提供的酚合成方法中,底物来源广泛、稳定和廉价,方法操作简单,一步法直接得到酚,反应条件温和,在优化的反应条件之下,目标产品分离收率高达85%,是一种通用、高效、经济和环境友好的合成酚的方法;
(3)本发明的方法能取得理想催化效果的关键在于,发现了含硫氨基酸或胱氨酸衍生的双肽配体能显著提高铁催化氧化芳碳-氢羟基化反应的活性和选择性,保证了反应的高效性;在反应高效进行的同时,抑制了过氧化和过还原的难题,保证了反应的高选择性、官能团相容性好和适用范围广的优势。
具体实施方式
根据下述实施例,可以更好地理解本发明。然而,本领域的技术人员容易理解,实施例所描述的内容仅用于说明本发明,而不应当也不会限制权利要求书中所详细描述的本发明。
实施例中所述实验方法,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,均可从商业途径或通过现有技术简单制备获得。
其中,含硫氨基酸为半胱氨酸、蛋氨酸、胱氨酸、或者高胱氨酸等均市售可得。
实施例中的底物和产物的具体结构见表1。
本发明中L1-L10的具体合成过程如下:
配体合成通用反应步骤:在-5℃条件下,依次向圆底烧瓶中加入Boc-L-胱氨酸(N,N'-双(叔丁氧羰基)-L-胱氨酸)(1.0mmol)、氨基酸甲酯盐酸盐(2.0mmol)、N-甲基吗啉(2.4mmol)和二氯甲烷(6mL)。随后,滴加二环己基碳二亚胺(2.0mmol)的二氯甲烷溶液10mL。该反应液在-5℃条件下搅拌3小时,紧接着在室温下搅拌12小时。反应结束,过滤掉沉淀,溶液相依次用水(5mL)、饱和食盐水(5mL)、饱和碳酸氢钠(5mL)、水(5mL)洗涤,得到的有机相用无水Na2SO4干燥,最后浓缩,并通过柱层析分离得到配体L1-L2,L6-L10(60-90%收率)。
配体合成通用反应如下所示:
Figure BDA0003074041720000051
其中R基来自于配体L1-L10,L1-L10上是相对应的基团,已确定。
L1合成为例:在-5℃条件下,依次向圆底烧瓶中加入Boc-L-胱氨酸(N,N'-双(叔丁氧羰基)-L-胱氨酸)(1.0mmol)、L-脯氨酸甲酯盐酸盐(2.0mmol)、N-甲基吗啉(2.4mmol)和二氯甲烷(6mL)。随后,滴加二环己基碳二亚胺(2.0mmol)的二氯甲烷溶液10mL。该反应液在-5℃条件下搅拌3小时,紧接着在室温下搅拌12小时。反应结束,过滤掉沉淀,溶液相依次用水(5mL)、饱和食盐水(5mL)、饱和碳酸氢钠(5mL)、水(5mL)洗涤,得到的有机相用无水Na2SO4干燥,最后浓缩,并通过柱层析(洗脱剂为:乙酸乙酯:石油醚=10:2)分离得到配体L1(60%收率)。1H NMR(400MHz,CDCl3):δ5.41-5.25(m,2H),4.75-4.71(m,2H),4.47-4.44(m,2H),3.74-3.65(m,10H),3.07-2.99(m,2H),2.96-2.81(m,2H),2.17-2.11(m,2H),2.05-1.94(m,6H),1.36ppm(s,18H);13C NMR(100MHz,CDCl3):δ172.0,169.3,155.2,79.8,58.7,52.1,51.2,46.9,41.2,28.8,28.1,24.7ppm.HRMS(ESI)m/z calcd for C28H46N4O10S2Na+[M+Na]+685.2548,found 685.2550;IR(KBr,cm-1):νmax 3455,3049,2920,1629,1459,1366,1297,1253,767,741;Mp:332.6-333.0℃.
L2:HRMS(ESI)m/z calcd for C22H34N4O8S2Na+[M+Na]+569.1710,found 569.1712。
L6:HRMS(ESI)m/z calcd for C30H50N4O10S2Na+[M+Na]+713.2861,found713.2863。
L7:HRMS(ESI)m/z calcd for C40H54N4O10S2Na+[M+Na]+837.3174,found837.3176。
L8:HRMS(ESI)m/z calcd for C30H54N4O10S2Na+[M+Na]+717.3174,found717.3178。
L9:HRMS(ESI)m/z calcd for C36H50N4O10S2Na+[M+Na]+785.2861,found785.2869。
L10:HRMS(ESI)m/z calcd for C24H42N4O12S2Na+[M+Na]+665.2133,found665.2137。
配体L3合成:L1(1mmol)溶于甲醇(0.2M),并在0℃滴加NaOH 1M(2.1mmol),反应室温下搅拌3h。反应结束,除掉甲醇,再加10mL水稀释,并用乙醚10mL和用柠檬酸10%调PH 3-4。随后用乙酸乙酯(3x 10mL)萃取,合并有机相,并用MgSO4干燥,最后除去溶剂和真空干燥得到L3(95%收率)。HRMS(ESI)m/z calcd for C26H42N4O10S2Na+[M+Na]+657.2235,found657.2239。
Figure BDA0003074041720000061
配体L5合成:在0℃下,L3(1mmol)溶于二氯甲烷,同时滴加三氟乙酸(1.5ml)。该反应室温搅拌1h,真空蒸出溶剂,紧接着加入饱和碳酸钠调PH3-4,同时析出沉淀。该沉淀依次用冷水、乙醇、乙醚洗涤,即可得到纯的L5(90%收率)。HRMS(ESI)m/z calcd forC16H26N4O6S2Na+[M+Na]+457.1186,found 457.1188。
配体L4合成:在0℃下,L1(1mmol)溶于二氯甲烷,同时滴加三氟乙酸(1.5ml)。该反应室温搅拌1h,真空蒸出溶剂,紧接着加入饱和碳酸钠溶解,同时用乙酸乙酯萃取三次。合并有机相,并用饱和食盐水洗涤,最后无水硫酸钠干燥和减压蒸除溶剂,即可得到纯的L4(92%收率)。HRMS(ESI)m/z calcd for C18H30N4O6S2Na+[M+Na]+485.1499,found 485.1495。
Figure BDA0003074041720000071
实施例1
化合物1:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L1(0.05mmol),1a(0.25mmol),乙酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物1,产率70%。1H NMR(400MHz,CDCl3):δ7.31(t,J=7.8Hz,2H),7.02(t,J=7.8Hz,1H),6.92(d,J=8.4Hz,2H),5.93ppm(bs,1H).13C NMR(100MHz,CDCl3):δ155.1,129.7,120.9,115.3ppm.
实施例2
化合物2:25mL反应瓶中依次加入乙酰丙酮铁(0.025mmol),L2(0.05mmol),1b(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物2,产率60%。
实施例3
化合物3:25mL反应瓶中依次加入三氟甲磺酸铁(0.025mmol),L3(0.025mmol),1c(0.25mmol),氯乙酸(0.125mmol),乙腈(0.5mL)和水(1.5mL)。随后,滴加双氧水(0.3mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物3,产率50%。
实施例4
化合物4:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L4(0.025mmol),1d(0.25mmol),乙酸(0.25mmol),水(2mL)。随后,滴加双氧水(0.3mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物4,产率80%。1H NMR(400MHz,CDCl3):δ6.44(d,1H),6.40(d,1H),5.72(bs,1H),4.71(s,2H),3.85(s,3H),3.76ppm(s,3H).13C NMR(100MHz,CDCl3):δ153.1,147.1,137.7,126.3,103.8,98.9,61.8,56.0,55.8ppm.
实施例5
化合物5:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L5(0.025mmol),1e(0.25mmol),三氟乙酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.75mmol)。反应混合物在25℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物5,产率46%。
实施例6
化合物6:25mL反应瓶中依次加入乙酰丙酮亚铁(0.025mmol),L6(0.025mmol),1f(0.25mmol),乙酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.75mmol)。反应混合物在80℃下反应6h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物6,产率58%。
实施例7
化合物7:25mL反应瓶中依次加入二茂铁(0.025mmol),酞菁亚铁(0.0025mmol),L7(0.025mmol),1g(0.25mmol),丙酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.25mmol)。反应混合物在25℃下反应1h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物7,产率52%。
实施例8
化合物8:25mL反应瓶中依次加入氯化铁(0.025mmol),L8(0.05mmol),1h(0.25mmol),丁酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应9h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物8,产率70%。1H NMR(400MHz,CDCl3):δ7.21(dd,J=8.4Hz,2.0Hz,1H),7.17(d,J=2.0Hz,1H),6.89(d,J=8.4Hz,1H),5.80(bs,1H),3.96ppm(s,3H).13C NMR(100MHz,CDCl3):δ150.2,145.8,125.6,119.0,117.6,110.7,104.5,56.1ppm.
实施例9
化合物9:25mL反应瓶中依次加入三氟甲磺酸亚铁(0.025mmol),L9(0.05mmol),1i(0.25mmol),特戊酸(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物9,产率75%。1H NMR(400MHz,CD3COCD3):δ7.36(s,1H),7.19(s,2H),6.99(s,2H),3.82ppm(s,6H).13C NMR(100MHz,CD3COCD3):δ148.3,139.3,112.3,56.5ppm.11B NMR(160MHz,CD3COCD3):δ28.8ppm.
实施例10
化合物10:25mL反应瓶中依次加入碘化铁(0.025mmol),L10(0.05mmol),alpha-酮戊二酸(0.125mmol),1j(0.25mmol),1,2-二氯乙烷(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在50℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物10,产率40%。
实施例11
化合物11:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L1(0.05mmol),抗坏血酸(0.125mmol),1k(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应3h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物11,产率65%。
实施例12
化合物12:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L-半胱氨酸(0.05mmol),樟脑磺酸(0.25mmol),1l(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在60℃下反应12h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物12,产率47%。
实施例13
化合物13:25mL反应瓶中依次加入二茂铁(0.025mmol),蛋氨酸(0.05mmol),苯甲酸(0.15mmol),1m(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在100℃下反应12h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物13,产率47%。
实施例14
化合物14:25mL反应瓶中依次加入1,3-二苯基丙二酮铁(0.025mmol),L-胱氨酸(0.025mmol),乙酸(0.15mmol),1n(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应15h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物14,产率65%。
实施例15
化合物15:25mL反应瓶中依次加入二茂铁(0.025mmol),L-高胱氨酸(0.025mmol),乙酸(0.25mmol),1o(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在50℃下反应1h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物15,产率65%。
实施例16
化合物16:25mL反应瓶中依次加入硫酸亚铁(0.025mmol),L1(0.05mmol),乙酸(0.15mmol),1p(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应9h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物16,产率50%。
实施例17
化合物17:25mL反应瓶中依次加入1,3-二苯基丙二酮亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1q(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在50℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物17,产率58%。
实施例18
化合物18:25mL反应瓶中依次加入酞菁亚铁(0.0025mmol),L1(0.05mmol),乙酸(0.25mmol),1r(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在20℃下反应1h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物18,产率50%。
实施例19
化合物19:25mL反应瓶中依次加入2,2,6,6-四甲基-3,5-庚二酮亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1s(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在20℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物19,产率48%。
实施例20
化合物20:25mL反应瓶中依次加入乙酰丙酮亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1t(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在20℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物20,产率61%。
实施例21
化合物21:25mL反应瓶中依次加入醋酸亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1u(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物21,产率70%。1H NMR(400MHz,CD3COCD3):δ8.09(s,1H),7.18(s,1H),6.83(d,J=2.8Hz,1H),6.64(d,J=2.8Hz,1H),2.20ppm(s,3H).13C NMR(100MHz,CD3COCD3):δ151.7,145.6,128.2,118.0,116.9,111.0,17.3ppm.
实施例22
化合物22:25mL反应瓶中依次加入硫酸亚铁铵(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1v(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应3h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物22,产率72%。1H NMR(400MHz,CD3COCD3):δ8.41(bs,1H),8.07(bs,1H),7.22(d,J=2.8Hz,1H),6.79(d,J=8.8Hz,1H),6.71ppm(dd,J=8.8,2.8Hz,1H);13C NMR(100MHz,CD3COCD3):δ152.0,150.6,125.9,117.2,116.1,84.1ppm.
实施例23
化合物23:25mL反应瓶中依次加入苯甲酰丙酮亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1w(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物23,产率85%。1H NMR(400MHz,CDCl3):δ10.65(s,1H),6.82(d,J=2.4Hz,1H),6.67(d,J=2.8Hz,1H),3.94(s,3H),3.86(s,3H),3.77ppm(s,3H).13C NMR(100MHz,CDCl3):δ170.6,151.7,149.2,147.0,111.3,106.6,101.0,56.1,55.6,52.4ppm.
实施例24
化合物24:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1x(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物24,产率65%。
实施例25
化合物25:25mL反应瓶中依次加入2,2,6,6-四甲基-3,5-庚二酮亚铁(0.0025mmol),L1(0.05mmol),乙酸(0.25mmol),1y(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在60℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物25,产率60%。
实施例26
化合物26:25mL反应瓶中依次加入铁氰化铁(0.05mmol),L1(0.05mmol),乙酸(0.25mmol),1z(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物26,产率55%。
实施例27
化合物27:25mL反应瓶中依次加入硫酸铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1aa(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应6h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物27,产率60%。
实施例28
化合物28:25mL反应瓶中依次加入乙酰丙酮亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1ab(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物28,产率40%。
实施例29
化合物29:25mL反应瓶中依次加入溴化铁(0.025mmol),L1(0.05mmol),乙酸(0.5mmol),1ac(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应12h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物29,产率60%。
实施例30
化合物30:25mL反应瓶中依次加入铁氰化亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1ad(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应6h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物30,产率75%。1H NMR(400MHz,CD3COCD3):δ7.74(bs,1H),7.70(bs,1H),7.67(t,J=4.2Hz,1H),7.31(d,J=4.4Hz,2H),3.40(m,2H),2.35(s,3H),1.17ppm(t,J=7.2Hz,3H).13C NMR(100MHz,CD3COCD3):δ167.1,138.6,136.1,132.3,128.9,128.5,125.0,35.1,21.3,15.2ppm.
实施例31
化合物31:25mL反应瓶中依次加入溴化亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1ae(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应6h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物31,产率70%。1H NMR(400MHz,CD3COCD3):δ10.19(bs,1H),8.75(bs,1H),7.11(s,1H),6.94ppm(s,1H).13C NMR(100MHz,CD3COCD3):δ155.2,149.4,144.2,124.5,122.9,111.2,100.2ppm.
实施例32
化合物32:25mL反应瓶中依次加入苯甲酰丙酮铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1af(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物32,产率70%。1H NMR(400MHz,CD3COCD3):δ6.60(s,4H),4.96-4.92(m,1H),4.18-4.10(m,2H),3.77-3.73(m,1H),3.54-3.50(m,1H),2.25ppm(s,6H).13CNMR(100MHz,CD3COCD3):δ159.6,159.5,139.8,123.6,113.2,74.9,69.3,42.8,21.4ppm.
实施例33
化合物33:25mL反应瓶中依次加入碘化亚铁(0.025mmol),L2(0.05mmol),乙酸(0.25mmol),1ag(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应1h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物33,产率40%。
实施例34
化合物34:25mL反应瓶中依次加入硝酸铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1ah(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在80℃下反应3h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物34,产率45%。1H NMR(400MHz,CD3COCD3):δ8.87(bs,2H),8.00(dd,J=8.0Hz,1H);7.83(d,1H),7.50(d,1H),7.10(dd,J=8.0,4.0Hz,1H),6.89(bs,1H),2.69-2.63(m,1H),1.28-1.24(m,2H),1.09-1.04ppm(m,2H).13C NMR(100MHz,CDCl3):δ201.8,156.5,139.2,129.8,120.6,120.5,114.6,17.5,12.3ppm.HRMS(ESI)calcd forC13H12N2O6SNa+[M+Na]+m/z 347.0308,found 347.0311.
实施例35
化合物35:25mL反应瓶中依次加入硝酸铁(0.025mmol),氯化亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1ai(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.75mmol)。反应混合物在80℃下反应9h。反应液用乙酸乙酯萃取(10mL×3),合并有机相,减压蒸除溶剂后柱层析分离得到产物化合物35,产率46%。1H NMR(400MHz,CDCl3):δ8.01(s,1H),7.73(d,J=8.8Hz,2H),7.44(d,J=8.4Hz,2H),7.38(d,J=2Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),6.93(d,J=8.4Hz,1H),5.17-5.08(m,1H),1.60(s,6H),1.28ppm(d,J=6.4Hz,6H).13C NMR(100MHz,CDCl3):δ194.5,175.3,149.8,145.9,138.6,136.0,133.6,131.3,128.5,121.8,121.5,118.0,81.6,70.5,25.5,21.5ppm.HRMS(ESI)calcd forC20H22ClO5 +[M+H]+m/z 377.1150,found 377.1151.
实施例36
化合物36:25mL反应瓶中依次加入氯化亚铁(0.025mmol),L1(0.05mmol),乙酸(0.25mmol),1aj(0.25mmol),乙腈(1mL)和水(1mL)。随后,滴加双氧水(0.5mmol)。反应混合物在25℃下反应1h。反应液旋干,并用乙酸乙酯萃取(10mL×3),减压蒸除溶剂后柱层析分离得到产物化合物36,产率50%。1H NMR(400MHz,CDCl3):δ7.49(d,J=2.4Hz,1H),7.23(dd,J=8.4,2.4Hz,1H),7.03(s,1H),6.99(d,J=8.8Hz,1H),6.40ppm(s,1H).13C NMR(100MHz,CDCl3):δ150.0,145.0,143.1,140.5,130.7,128.3,126.5,123.8,121.5,116.1,114.5,104.9ppm.
实施例1~36涉及具体酚的合成方法对应的实验结果列于表1:
表1铁催化氧化芳碳-氢键合成酚[a]
Figure BDA0003074041720000141
Figure BDA0003074041720000151
Figure BDA0003074041720000161
Figure BDA0003074041720000171
Figure BDA0003074041720000181
[a]反应条件见实施例;[b]柱分离收率。
对比例1
对比例1与实施例1的方法相同,不同之处在于,不使用配体L1,产率为4%。
对比例2
对比例1与实施例1的方法相同,不同之处在于,不使用氯化亚铁,反应不发生。
对比例3
对比例3与实施例23的方法相同,不同之处在于,不使用配体L1,产率为10%。
对比例4
对比例4与实施例23的方法相同,不同之处在于,不使用苯甲酰丙酮亚铁,反应不发生。
由对比例可以看出,本发明中配体在反应中的重要性。
实施例37
实施例37与实施例1的方法相同,不同之处在于:芳香族化合物、酸(不加酸)、双氧水、铁催化剂和配体的摩尔比为1:0:1~:0.005:0.0025。
实施例38
实施例38与实施例1的方法相同,不同之处在于:芳香族化合物、酸、双氧水、铁催化剂和配体的摩尔比为1:10:10:0.5:2.5。
实施例39
实施例39与实施例1的方法相同,不同之处在于:溶剂全部为水,总体积保持不变。
实施例40
实施例40与实施例1的方法相同,不同之处在于:溶剂为乙腈的水溶液,有机溶剂与水的体积比为1:0.5。
实施例41
实施例41与实施例1的方法相同,不同之处在于:溶剂为乙腈的水溶液,有机溶剂与水的体积比为1:100。
实施例42
实施例42与实施例35的方法相同,不同之处在于:反应的温度为20℃、时间为15小时。
实施例43
实施例43与实施例34的方法相同,不同之处在于:反应的温度为80℃、时间为0.5小时。

Claims (10)

1.一种配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,包括以下步骤:以铁为催化剂金属,含硫氨基酸或胱氨酸衍生的双肽为配体,在双氧水为氧化剂的共同作用下,氧化芳香族化合物合成酚;
反应通式表示如下:
Figure FDA0003074041710000011
式中:
Ar表示的芳基为取代或非取代的苯基、联苯基、萘基、蒽基、菲基、芘基、或吡啶基。
2.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述含硫氨基酸为半胱氨酸、蛋氨酸、胱氨酸或者高胱氨酸。
3.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,胱氨酸衍生的双肽是由氨基保护的胱氨酸与氨基酸酯或氨基酸酯的盐酸盐,在活化剂N,N'-二环己基碳二亚胺(DCC)作用下缩合形成。
4.根据权利要求1-3任一所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述胱氨酸衍生的双肽配体优选选自如下结构中任意一种:
Figure FDA0003074041710000012
Figure FDA0003074041710000021
5.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述芳基上的取代基单取代或多取代芳环上的氢,所述取代基任意选自氢、C1~C20直链或支链的烃基、C3~C12的环烷基、烷氧基、芳基、羟基、羧基、-B(OH)2、氟、氯、溴、碘、酯基、酰胺基、磺酰胺基、醛基、硝基、氰基、烷酰氧基或芳酰氧基。
6.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述铁催化剂选自三氟甲磺酸亚铁、三氟甲磺酸铁、氯化亚铁、乙酰丙酮亚铁、乙酰丙酮铁、2,2,6,6-四甲基-3,5-庚二酮亚铁、2,2,6,6-四甲基-3,5-庚二酮铁、1,3-二苯基丙二酮亚铁、1,3-二苯基丙二酮铁、苯甲酰丙酮亚铁、苯甲酰丙酮铁、铁氰化亚铁、铁氰化铁、醋酸亚铁、硫酸亚铁、硫酸亚铁铵、硫酸铁、高氯酸铁、硝酸铁、酞菁亚铁、二茂铁、溴化亚铁、溴化铁、碘化亚铁、碘化铁或三氯化铁。
7.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,整个合成反应的介质为水、乙腈的水溶液或1,2-二氯乙烷的水溶液,其中有机溶剂与水的体积比为1:(0.5~100)。
8.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,整个合成反应中还包括酸,所述酸为乙酸、氯乙酸、三氟乙酸、丙酸、丁酸、特戊酸、alpha-酮戊二酸、抗坏血酸、樟脑磺酸或苯甲酸,
反应通式表示如下:
Figure FDA0003074041710000031
9.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述芳香族化合物、酸、双氧水、铁催化剂和配体的摩尔比为1:(0~10):(1~10):(0.005~0.5):(0.0025~2.5)。
10.根据权利要求1所述的配体促进铁催化氧化芳香族化合物碳-氢键合成酚的方法,其特征在于,所述方法中反应温度为20~80℃,反应时间为0.5~15小时。
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