CN108997089B - 一种催化苄醇类化合物芳基化的方法 - Google Patents

一种催化苄醇类化合物芳基化的方法 Download PDF

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CN108997089B
CN108997089B CN201810806066.8A CN201810806066A CN108997089B CN 108997089 B CN108997089 B CN 108997089B CN 201810806066 A CN201810806066 A CN 201810806066A CN 108997089 B CN108997089 B CN 108997089B
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陈新滋
孟山水
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Sun Yat Sen University
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Abstract

本发明属于有机合成领域，公开了一种催化苄醇类化合物芳基化的方法,将苄醇类化合物与芳基类化合物混合，加入溶剂与催化剂三五氟苯基硼烷，60‑120℃下反应4‑8小时即得到苄醇芳基化产物。该反应利用三五氟苯基硼烷作为催化剂对于一系列苄醇实现脱水芳基化反应，反应可以快速构建在药物分子中具有重要意义的三芳基甲烷类型化合物及含多个杂环的有机小分子。本发明操作简单，反应高效并且具有多样性。

Description

一种催化苄醇类化合物芳基化的方法
技术领域
本发明是一种有机化合物合成新方法，具体涉及的是利用非金属路易斯酸催化剂催化醇类化合物芳基化反应，并将其利用到一系列不同类型三芳基甲烷类化合物及含多个杂环分子的合成。
背景技术
三芳基甲烷类型结构在药物及具有重要生物活性分子具有广泛的分布，这一类型化合物多具有抗癌，抗艾滋，抗抑郁等特性，因此针对该类型结构发展一种稳定快速的合成方法在生物医药中具有重要的意义。
日本Hikawa课题组在2013年报道了使用金催化剂对于苄醇的芳基化反应，该反应使用NaAuCl4作为催化剂实现了对于不同取代基苄醇的吲哚化反应，反应所使用的芳基化试剂较为单一(式1)。
Figure BDA0001738193640000011
2007年Kobayashi课题组通过使用有机酸催化剂也实现了醇的脱水芳基化反应，该反应同样采用了吲哚作为芳基试剂(式2)。
Figure BDA0001738193640000012
由上述可以看出目前采用醇芳基化反应实现对于三芳基甲烷结构的合成目前还比较单一，所使用的芳基亲核试剂大多为吲哚，因此发展一种多样性的醇芳基化反应是非常有必要的。
发明内容
本发明的目的在于提供一种使用三五氟苯基硼烷催化苄醇类化合物直接芳基化的方法。
本发明的目的通过以下技术方案实现：
一种催化苄醇类化合物芳基化的方法,将苄醇类化合物与芳基类化合物混合，加入溶剂与催化剂三五氟苯基硼烷，60-120℃下反应4-8小时即得到苄醇芳基化产物。
该方法具体如下：
Figure BDA0001738193640000021
优选地，所述苄醇类化合物为
Figure BDA0001738193640000022
其中R1基团为氢原子，烷基，芳基，酯基，卤素；R2基团为烷基，芳基，或氰基。
优选地，所述苄醇类化合物为二苯甲醇及其类似物，苯乙醇及其类似物或扁桃腈。
优选地，所述芳基类化合物为苯酚类化合物或吲哚类化合物。
优选地，所述芳基类化合物为
Figure BDA0001738193640000023
R为氢原子，芳基或烷基。
优选地，所述芳基类化合物为2,6-二叔丁基苯酚或吲哚。
优选地，所述苄醇类化合物与芳基类化合物的摩尔比为1:2。
优选地，所述催化剂的添加量摩尔百分比为1％-20％。
优选地，所述苄醇类化合物与催化剂的摩尔比为1:0.1。
优选地，所述溶剂为硝基甲烷，甲苯，1，2-二氯乙烷，四氢呋喃或氯仿。
与现有技术相比，本发明具有如下优点：
(1)本发明利用三五氟苯基硼烷催化对于苄醇类型底物芳基化反应。该反应利用商业可得的三五氟苯基硼烷作为催化剂对于一系列苄醇类化合物实现脱水芳基化，反应无需对醇进行预活化或保护，该方法可以高效的构建一系列三芳基甲烷类型化合物及含多个杂环分子化合物。
(2)本发明操作简单，反应高效并且具有多样性。
附图说明
图1为实施例1制得产物的核磁共振图，(a)为氢谱图，(b)为碳谱图。
图2为实施例2制得产物的核磁共振图，(a)为氢谱图，(b)为碳谱图。
图3为实施例3制得产物的核磁共振图，(a)为氢谱图，(b)为碳谱图。
图4为实施例4制得产物的核磁共振图，(a)为氢谱图，(b)为碳谱图。
具体实施方式
下面结合具体实施例对本发明作进一步说明。
实施例1
Figure BDA0001738193640000031
将二苯甲醇(36.8mg)置于10毫升反应管中，加入1毫升1，2-二氯乙烷作为溶剂，随后加入11mg三五氟苯基硼烷及2,6-二叔丁基苯酚(82.4mg)，反应温度升高至60摄氏度，反应8小时后将反应冷却至室温随后将溶剂去除后通过柱层析对于产物进行分离：4-二苯甲基-2,6-二叔丁基苯酚(67mg，产率98％)。无色液体，分析数据:1H NMR(400MHz,CDCl3)δ7.31–7.22(m,4H),7.18(t,J＝7.3Hz,2H),7.11(d,J＝7.3Hz,4H),6.90(s,2H),5.44(s,1H),5.07(s,1H),1.35(s,18H).13C NMR(100MHz,CDCl3)δ152.09,144.84,135.42,134.12,129.43,128.14,126.07,126.02,56.83,34.35,30.33.HRMS(ESI)m/z[M-H]-:CalcdforC27H31O:371.2375.Found:371.2374.
实施例2
Figure BDA0001738193640000041
将1-苯基乙醇(24.4mg)置于10毫升反应管中，加入1毫升1，2-二氯乙烷作为溶剂，随后加入11mg三五氟苯基硼烷及2,6-二叔丁基苯酚(82.4mg)，反应温度升高至60摄氏度，反应8小时后将反应冷却至室温随后将溶剂去除后通过柱层析对于产物进行分离：1-苯基乙基-2,6-二叔丁基苯酚(55mg，产率89％)无色液体，分析数据:1H NMR(500MHz,CDCl3)δ7.30(dd,J＝20.3,12.9Hz,4H),7.20(t,J＝7.1Hz,1H),7.06(s,2H),5.06(s,1H),4.10(q,J＝7.2Hz,1H),1.66(d,J＝7.3Hz,3H),1.45(s,18H).13C NMR(125MHz,CDCl3)δ151.91,147.10,136.78,135.57,128.24,127.58,125.77,124.11,44.83,34.39,30.37,22.40.HRMS(ESI)m/z[M-H]-:Calcd for C22H29O:309.2218.Found:309.2218.
实施例3
Figure BDA0001738193640000042
将2-苯基苯并噻吩乙醇(48.0mg)置于10毫升反应管中，加入1毫升1，2-二氯乙烷作为溶剂，随后加入11mg三五氟苯基硼烷及2,6-二叔丁基苯酚(82.4mg)，反应温度升高至60摄氏度，反应8小时后将反应冷却至室温随后将溶剂去除后通过柱层析对于产物进行分离(67mg，产率98％)。无色液体，分析数据:1H NMR(400MHz,CDCl3)δ7.83(d,J＝7.9Hz,1H),7.49(d,J＝7.8Hz,1H),7.35–7.11(m,7H),6.96(s,2H),6.74(s,1H),5.65(s,1H),5.09(s,1H),1.35(s,18H).13C NMR(100MHz,CDCl3)δ152.30,143.22,140.68,140.10,138.68,135.61,133.23,128.99,128.34,126.34,125.69,124.70,124.11,123.81,122.86,122.71,51.35,34.35,30.34.HRMS(ESI)m/z[M-H]-:Calcd for C29H31OS:427.2096.Found:427.2094.
实施例4
Figure BDA0001738193640000051
将二苯甲醇(36.8mg)置于10毫升反应管中，加入1毫升1，2-二氯乙烷作为溶剂，随后加入11mg三五氟苯基硼烷及吲哚(46.8mg)，反应温度升高至60摄氏度，反应8小时后将反应冷却至室温随后将溶剂去除后通过柱层析对于产物进行分离：3-二苯甲基吲哚(50mg，产率89％)无色液体，分析数据:1H NMR(400MHz,CDCl3)δ7.83(br,1H),7.30–7.04(m,13H),6.91(t,J＝7.5Hz,1H),6.47(d,J＝1.4Hz,1H),5.59(s,1H).13C NMR(100MHz,CDCl3)δ142.88,135.65,127.96,127.23,125.94,125.18,123.01,121.06,118.88,118.35,109.99,98.93,47.76.HRMS(ESI)m/z[M+H]+:Calcd for C21H18N:284.1439.Found:284.1445.
以上所述，仅是本发明的较佳实施例，并非对本发明作任何形式上的限制，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，依据本发明的技术实质，对以上实施例所作的任何简单的修改、等同替换与改进等，均仍属于本发明技术方案的保护范围之内。

Claims (6)

1.一种催化苄醇类化合物芳基化的方法,其特征在于，将苄醇类化合物与芳基类化合物混合，加入溶剂与催化剂三五氟苯基硼烷，60℃下反应4-8小时即得到苄醇芳基化产物；
所述苄醇类化合物为二苯甲醇及其类似物，苯乙醇及其类似物或扁桃腈；
所述芳基类化合物为苯酚类化合物或吲哚类化合物，所述溶剂为硝基甲烷，甲苯，1，2-二氯乙烷，四氢呋喃或氯仿。
2.根据权利要求1所述的方法，其特征在于，所述芳基类化合物为
Figure FDA0003380439980000011
R为氢原子，芳基或烷基。
3.根据权利要求2所述的方法，其特征在于，所述芳基类化合物为2,6-二叔丁基苯酚。
4.根据权利要求1～3任意一项所述的方法，其特征在于，所述苄醇类化合物与芳基类化合物的摩尔比为1:2。
5.根据权利要求4所述的方法，其特征在于，所述催化剂的添加量摩尔百分比为1％-20％。
6.根据权利要求5所述的方法，其特征在于，所述苄醇类化合物与催化剂的摩尔比为1:0.1。
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* Cited by examiner, † Cited by third party
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B(C6F5)3-Catalyzed Allylation of Secondary Benzyl Acetates with Allylsilanes;Michael Rubin等;《Org. Lett.》;20010721;第17卷(第3期);第2705-2707页 *
Breaking the dichotomy of reactivity vs. chemoselectivity in catalytic SN1 reactions of alcohols;Malik Hellal等;《Organic & Biomolecular Chemistry》;20140624;第12卷(第31期);第5990-5994页 *
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