CN109053754B - 基于生物质源2,5-二甲基呋喃去芳香化环加成策略构建多取代色满化合物的合成方法 - Google Patents
基于生物质源2,5-二甲基呋喃去芳香化环加成策略构建多取代色满化合物的合成方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明利用生物质平台分子2,5‑二甲基呋喃作为新的亲双烯体与邻亚甲基苯醌实现去芳香化环加成反应构建多取代色满化合物。本发明的技术方案克服2,5‑二甲基呋喃与醇直接取代的竞争反应,实现了2,5‑二甲基呋喃去芳香化的逆电子需求的D‑A环加成,并且首次实现了亚甲基苯醌与富电子芳香烃进行分子间去芳香化[4+2]环加成反应,为生物质平台分子呋喃的转化利用提供了实验依据,具有很好的实践意义和应用价值。
Description
技术领域
本发明属于化学合成技术领域,具体涉及基于生物质源2,5-二甲基呋喃去芳香化环加成策略构建多取代色满化合物的合成方法。
背景技术
生物质是地球上最广泛的资源之一,有一个很大的优点就是可再生,能不断地给我们提供生物燃料和生物基化学品,是代替有限化石资源的优良物质。其中,呋喃基化合物作为生物质基分子之一,逐渐引起了研究者广泛的关注,对它的研究也相对较多。2,5-二甲基呋喃,是一种重要的生物质平台分子,通常作为第二代燃料及重要的化学工业原料。它在有机合成上主要作为双烯体发生D-A反应,其中,最重要的应用是通过串联D-A反应、脱水反应制备甲苯。然而,其它的反应类型非常有限,尤其是作为亲双烯体去参与去芳香化环加成反应构建高附加值生物分子的例子还未见报道。
多取代色满类化合物广泛存在于天然产物及药物分子中,如今合成色满的策略之一是邻亚甲基苯醌参与的逆电子需求的杂Diels-Alder(IED-HDA)反应。
2015年,Magnus Rueping课题组发展了一种手性磷酸催化的邻亚甲基苯醌与苯乙烯的IED-HAD反应,以很好的收率和对映选择性构建了一系列色满骨架化合物(Angew.Chem.Int.Ed.2015,54,5762–5765)。
同年,石枫课题组发展了一种手性磷酸催化下,邻亚甲基苯醌与吲哚乙烯的IED-HAD反应构建多种含吲哚骨架的色满骨架化合物(Angew.Chem.Int.Ed.2015,54,5460–5464)。
但是,以上合成策略尽管成功合成色满骨架化合物,但是在邻亚甲基苯醌参与的IED-HAD反应中亲双烯体的种类基本局限于烯烃或者活化烯烃这个种类,这在很大程度上限制了该类反应方法学的发展。
目前,还没有利用邻亚甲基苯醌与富电子芳环的分子间去芳香化环加成反应,例如生物质平台分子2,5-二甲基呋喃作为新的亲双烯体与邻亚甲基苯醌实现去芳香化环加成反应构建多取代色满化合物。该反应在反应机理上存在一个重大的挑战,即邻亚甲基苯醌与2,5-二甲基呋喃的F-C烷基化反应。
因此,为了实现生物质平台分子到高附加值化学品的转化,解决有机合成方法学中存在的问题,构建具有生物活性的重要化合物,需要发展一种基于生物质平台分子2,5-二甲基呋喃与邻亚甲基苯醌的去芳香化环加成反应。
发明内容
本发明的目的在于提供基于生物质源2,5-二甲基呋喃去芳香化环加成策略构建多取代色满化合物的合成方法。本发明操作简单实用,产率好,且反应具有绿色经济性,对环境友好。
本发明所提供的合成方法,具体为:
邻羟基苄醇类化合物与2,5-二甲基呋喃,在催化剂作用下,反应生成所述多取代色满化合物。
上述多取代色满化合物为式Ⅰ、式Ⅱ所示化合物中至少一种:
其中
式Ⅰ、式Ⅱ中,
R1选自甲基、苯基、C1-C3烷基取代苯基、C1-C3烷氧基取代苯基、C1-C3卤代烷基取代苯基、噻吩基、萘基、卤化苯基、联二苯基中任意一种;并且
R2选自甲基、卤素、C1-C3烷氧基中任意一种。
上述邻羟基苄醇类化合物为式Ⅲ所示化合物:
式Ⅲ中,
R1选自甲基、苯基、C1-C3烷基取代苯基、C1-C3烷氧基取代苯基、C1-C3卤代烷基取代苯基、噻吩基、萘基、卤化苯基、联二苯基中任意一种;并且
R2选自甲基、卤素、C1-C3烷氧基中任意一种。
上述催化剂为布朗斯酸或路易斯酸,具体为甲磺酸、三氟甲磺酸、三氟甲磺酸锌、三氟甲磺酸钪、S-联萘酚磷酸酯、樟脑磺酸、乙酸、苯甲酸、溴化铟、四氟化钛、碘化亚铜、三氯化铈中任意一种。
上述反应在溶剂中进行,溶剂为甲苯、1,2-二氯乙烷、二氯甲烷、四氢呋喃中任意一种。
上述催化剂的用量为5mol%-20mol%。
上述邻羟基苄醇类化合物与2,5-二甲基呋喃的摩尔比为1:3;上述溶剂的用量为每摩尔邻羟基苄醇类化合物添加10L溶剂。
上述反应在25℃-40℃条件下进行。
本发明提供了式Ⅰ、式Ⅱ所示化合物的合成方法,具体包括以下步骤:
将邻羟基苄醇类化合物加入溶剂中,按比例向溶剂中加入2,5-二甲基呋喃,最后加入催化剂,搅拌反应,通过薄层色谱法检测反应情况,反应完毕纯化,制得多取代色满化合物;
本发明涉及的化合物可以以一种或者多种立体异构体的形式存在。各种异构体包括对映异构体、非对映异构体、几何异构体。这些异构体包括这些异构体的混合物均在本发明的保护范围内。
本发明的技术方案取得了如下有益效果:邻羟基苄醇在酸性条件下脱水生成中间产物o-QMs,o-QMs与2,5-二甲基呋喃发生逆电子需求的氧杂D-A反应,形成热力学稳定的呋喃并色满结构,在酸性条件下该结构质子化,水解开环生成色满骨架化合物。
2,5-二甲基呋喃作为一个稳定的芳香化合物,作为环加成反应中的亲双烯体较为少见,并且2,5-二甲基呋喃与醇通过傅-克反应进行简单取代是热力学上的优势反应;本发明的技术方案克服2,5-二甲基呋喃与醇直接取代的竞争反应,实现了2,5-二甲基呋喃去芳香化的逆电子需求的D-A环加成,并且首次实现了o-QMs与富电子芳香烃进行分子间去芳香化[4+2]环加成反应。
本发明发展了一种布朗斯特酸催化的2,5-二甲基呋喃的去芳香化[4+2]环加成反应,构建了多取代色满化合物。首次实现由呋喃去芳香化,与o-QMs通过分子间环加成反应合成色满骨架的环加成反应。该方法反应条件温和,通过一步反应合成多取代色满化合物,底物普适性好,底物取代基可以是吸电子基或供电子基,且取代基的位置对反应产率没有明显的影响。该方法可以通过简单调整添加物和催化剂种类而获得高产率的优势产物,便于制备两种类型的多取代色满化合物。本发明为生物质平台分子呋喃的转化利用提供了实验依据,具有很好的实践意义和应用价值。
具体实施方式
通过以下实施例提供的具体实施方案,对本发明的上述内容进行进一步详细说明,对于本研究领域的技术人员而言,不应将此理解为本发明上述主题的范围仅限于以下实例;凡基于本发明上述内容所实现的技术均属于本发明的范围。
下面实施例中所使用的实验方法如无特殊说明,均为常规方法;下述实施例中所用的试剂、材料、仪器等,如无特殊说明,均可从商业途径得到。
实施例1
取0.1mmol邻羟基苄醇于反应瓶中,依次加入1mL溶剂,加入0.3mmol 2,5-二甲基呋喃,最后再加入催化剂。控制体系温度,持续搅拌,通过薄层色谱板点样跟踪反应至原料反应完全。
待反应完成后,使用硅胶柱进行分离纯化,将纯化后的产品旋蒸得目标产物。
利用上述反应式,设立20组平行试验组,使用不同的催化剂、溶剂和反应时间。催化剂分别为甲磺酸MeSO3H、三氟甲磺酸TfOH、三氟甲磺酸锌Zn(OTf)2、三氟甲磺酸钪Sc(OTf)3、醋酸铜Cu(OAc)2、S-联萘酚磷酸酯PA、樟脑磺酸(-)-CSA、乙酸AcOH、苯甲酸Benzoicacid、溴化铟InBr3、四氟化钛TiF4、碘化亚铜CuI、三氯化铈CeCl3。溶剂分别为甲苯、1,2-二氯乙烷DCE、二氯甲烷DCM、四氢呋喃THF。试验组具体使用的催化剂、溶剂种类和浓度如表1所示:
表1.邻羟基苄醇与2,5-二甲基呋喃反应产率表
根据以上平行试验结果分析,第8组中2,5-二甲基呋喃3位与苄醇发生傅-克反应生成的副产物产率为52%,其他试验组中反应进行均会产生痕量该取代产物。布朗斯酸和路易斯酸做催化剂,反应可以进行,并生成目标产物。催化剂PA和分子筛可以有效提高呋喃并色满化产物的产率,以及其在产物中的占比。
下列实施例2-15中,按照实施例1的操作步骤,反应体系中,原料邻羟基苄醇与2,5-二甲基呋喃分别为0.1mmol、0.3mmol,在10mol%PA催化下,以1mL DCE作溶剂,70mg分子筛作添加物,在25℃温度下持续搅拌反应至原料反应完全。
实施例2
原料:2,5-二甲基呋喃,α-苯基邻羟基苄醇
产物:化学式:C19H18O2
分子量:278.1307
产率:81%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.53–7.47(m,2H),7.45–7.39(m,2H),7.39–7.34(m,1H),7.12(t,J=7.6Hz,1H),6.93–6.86(m,1H),6.84(td,J=7.5,1.1Hz,1H),6.69(d,J=7.6Hz,1H),5.18(dd,J=2.2,1.0Hz,1H),4.71(dd,J=2.2,1.0Hz,1H),3.98(s,1H),1.67(s,3H),1.30(s,3H).13C NMR(125MHz,CDCl3)δ161.00,154.61,136.50,131.36,129.84,128.35,127.39,127.34,127.01,121.73,118.26,96.00,90.03,89.71,49.69,23.81,13.98.HRMS(ESI):calcd for C19H18O2Na[M+Na]+:301.1199,found:301.1201.
实施例3
原料:2,5-二甲基呋喃,5-溴-2-羟基-α-苯基苄醇
产物:化学式:C19H17BrO2
分子量:356.0412
产率:67%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.42(ddd,J=23.0,14.0,7.1Hz,5H),7.22(d,J=8.3Hz,1H),6.83–6.73(m,2H),5.17(s,1H),4.70(s,1H),3.93(s,1H),1.69(s,3H),1.28(s,3H).13CNMR(125MHz,CDCl3)δ161.32,153.85,135.58,132.18,131.21,130.22,129.97,128.61,127.69,120.07,114.44,95.91,89.93,89.81,49.61,23.65,13.98.HRMS(ESI):calcd forC19H17BrO2Na[M+Na]+:379.0304,found:379.0305.
实施例4
原料:2,5-二甲基呋喃,2-羟基-5-甲基-α-苯基苄醇
产物:化学式:C20H20O2
分子量:292.1463
产率:83%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.51–7.47(m,2H),7.45–7.40(m,2H),7.39–7.35(m,1H),6.91(ddd,J=8.0,1.3,0.7Hz,1H),6.78(d,J=8.0Hz,1H),6.49(s,1H),5.15(dd,J=2.4,1.1Hz,1H),4.69(dd,J=2.4,1.1Hz,1H),3.95(s,1H),2.15(s,3H),1.67(t,J=1.0Hz,3H),1.28(s,3H).13C NMR(125MHz,CDCl3)δ160.92,152.22,136.63,131.35,131.02,129.49,128.34,127.95,127.44,127.28,117.90,95.99,90.00,89.60,49.77,23.89,21.00,14.03.HRMS(ESI):calcd for C20H20O2Na[M+Na]+:315.1356,found:315.1357.
实施例5
原料:2,5-二甲基呋喃,2-羟基-4-甲基-α-苯基苄醇
产物:化学式:C20H20O2
分子量:292.1463
产率:74%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.48(d,J=7.2Hz,2H),7.41(t,J=7.3Hz,2H),7.38–7.33(m,1H),6.71(s,1H),6.64(d,J=7.6Hz,1H),6.56(d,J=7.7Hz,1H),5.16(s,1H),4.71(s,1H),3.93(s,1H),2.27(s,3H),1.68(s,3H),1.29(s,3H).13C NMR(125MHz,CDCl3)δ160.94,154.44,136.96,136.73,131.36,128.29,127.26,127.14,126.56,122.37,118.88,96.04,89.89,89.53,49.44,23.86,21.12,14.05.HRMS(ESI):calcd for C20H20O2Na[M+Na]+:315.1356,found:315.1358.
实施例6
原料:2,5-二甲基呋喃,2-羟基-5-甲氧基-α-苯基苄醇
产物:化学式:C20H20O3
分子量:308.1412
产率:80%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.48(d,J=7.5Hz,2H),7.40(t,J=7.4Hz,2H),7.35(t,J=7.2Hz,1H),6.82(d,J=8.6Hz,1H),6.64(dd,J=8.5,2.0Hz,1H),6.30(d,J=1.3Hz,1H),5.14(s,1H),4.68(s,1H),3.96(s,1H),3.62(s,3H),1.67(s,3H),1.28(s,3H).13C NMR(125MHz,CDCl3)δ160.98,154.55,148.16,136.31,131.27,131.19,128.40,127.40,118.55,114.16,111.05,95.82,89.89,89.79,55.49,49.99,23.80,14.00.HRMS(ESI):calcd for C20H20O3Na[M+Na]+:331.1305,found:331.1309.
实施例7
原料:2,5-二甲基呋喃,2-羟基-α-(2-甲基苯基)苄醇
产物:化学式:C20H20O2
分子量:292.1463
产率:75%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.76(d,J=7.3Hz,1H),7.33–7.22(m,3H),7.11(t,J=7.6Hz,1H),6.90(d,J=7.9Hz,1H),6.82(t,J=7.5Hz,1H),6.57(d,J=7.5Hz,1H),5.20(s,1H),4.72(s,1H),4.33(s,1H),2.31(s,3H),1.67(s,3H),1.35(s,3H).13C NMR(125MHz,CDCl3)δ161.02,154.98,138.00,134.95,130.79,130.39,129.68,127.22,127.05,126.92,126.06,121.82,118.25,95.85,90.49,90.19,43.74,23.35,20.38,14.02.HRMS(ESI):calcd for C20H20O2Na[M+Na]+:315.1356,found:315.1356.
实施例8
原料:2,5-二甲基呋喃,2-羟基-α-(2-甲氧基苯基)苄醇
产物:化学式:C20H20O3
分子量:308.1412
产率:70%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.68(d,J=7.6Hz,1H),7.33(t,J=7.8Hz,1H),7.10(t,J=7.6Hz,1H),7.05(t,J=7.5Hz,1H),6.97(d,J=8.2Hz,1H),6.89(d,J=7.9Hz,1H),6.83(t,J=7.5Hz,1H),6.71(d,J=7.5Hz,1H),5.19(s,1H),4.80(s,1H),4.70(s,1H),3.79(s,3H),1.66(s,3H),1.31(s,3H);13C NMR(125MHz,CDCl3)δ160.91,158.54,155.10,132.09,129.87,128.20,127.09,126.68,124.80,121.62,120.46,118.19,110.57,95.93,90.45,89.79,55.67,39.40,23.33,14.02.HRMS(ESI):calcd for C20H20O3Na[M+Na]+:331.1305,found:331.1307.
实施例9
原料:2,5-二甲基呋喃,2-羟基-α-(3-甲氧基苯基)苄醇
产物:化学式:C20H20O3
分子量:308.1412
产率:78%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.33(t,J=7.9Hz,1H),7.10(q,J=7.7Hz,3H),6.90(dd,J=14.3,8.3Hz,2H),6.84(t,J=7.5Hz,1H),6.73(d,J=7.5Hz,1H),5.17(s,1H),4.71(s,1H),3.95(s,1H),3.83(s,3H),1.66(s,3H),1.32(s,3H);13C NMR(125MHz,CDCl3)δ161.02,159.56,154.56,138.08,129.74,129.26,127.43,127.01,123.83,121.77,118.24,117.17,112.44,95.97,90.03,89.74,55.18,49.65,23.76,13.98.HRMS(ESI):calcd for C20H20O3Na[M+Na]+:331.1305,found:331.1304.
实施例10
原料:2,5-二甲基呋喃,2-羟基-α-(对甲基苯基)苄醇
产物:化学式:C20H20O2
分子量:292.1463
产率:73%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.37(d,J=7.6Hz,2H),7.22(d,J=7.6Hz,2H),7.11(t,J=7.6Hz,1H),6.88(d,J=7.9Hz,1H),6.83(t,J=7.5Hz,1H),6.72(d,J=7.5Hz,1H),5.17(s,1H),4.70(s,1H),3.94(s,1H),2.40(s,3H),1.66(s,3H),1.29(s,3H);13C NMR(125MHz,CDCl3)δ161.01,154.65,136.88,133.32,131.23,129.98,129.08,127.45,126.95,121.69,118.22,96.00,90.08,89.68,49.25,23.83,21.21,14.00.HRMS(ESI):calcd for C20H20O2Na[M+Na]+:315.1356,found:315.1357.
实施例11
原料:2,5-二甲基呋喃,2-羟基-α-联二苯基苄醇
产物:化学式:C25H22O2
分子量:354.1620
产率:56%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.66(dd,J=7.5,3.3Hz,4H),7.56(d,J=7.9Hz,2H),7.46(t,J=7.5Hz,2H),7.36(t,J=7.2Hz,1H),7.13(t,J=7.5Hz,1H),6.91(d,J=7.9Hz,1H),6.86(t,J=7.5Hz,1H),6.77(d,J=7.5Hz,1H),5.20(s,1H),4.73(s,1H),4.03(s,1H),1.69(s,3H),1.35(s,3H);13C NMR(125MHz,CDCl3)δ161.01,154.63,140.96,140.11,135.60,131.75,129.74,128.82,127.46,127.27,127.09,127.05,121.80,118.32,96.08,90.05,89.69,49.39,23.92,14.01.HRMS(ESI):calcd for C25H22O2Na[M+Na]+:377.1512,found:377.1516.
实施例12
原料:2,5-二甲基呋喃,2-羟基-α-(对氟苯基)苄醇
产物:化学式:C19H17FO2
分子量:296.1213
产率:80%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.46(dd,J=7.8,5.9Hz,2H),7.16–7.08(m,3H),6.90(d,J=7.9Hz,1H),6.85(t,J=7.5Hz,1H),6.66(d,J=7.5Hz,1H),5.17(s,1H),4.71(s,1H),3.97(s,1H),1.66(s,3H),1.29(s,3H);13C NMR(125MHz,CDCl3)δ162.30(d,J=244Hz),160.91,154.58,132.82(d,J=7.8Hz),132.21(d,J=3.3Hz),129.63,127.22,127.17,121.81,118.36,115.23(d,J=21Hz),96.10,89.89,89.61,48.96,23.79,13.95.HRMS(ESI):calcd for C19H17FO2Na[M+Na]+:319.1105,found:319.1106.
实施例13
原料:2,5-二甲基呋喃,2-羟基-α-(对氯苯基)苄醇
产物:化学式:C19H17ClO2
分子量:312.0917
产率:78%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.43(d,J=8.2Hz,2H),7.39(d,J=8.2Hz,2H),7.13(t,J=7.6Hz,1H),6.90(d,J=7.9Hz,1H),6.85(t,J=7.5Hz,1H),6.65(d,J=7.5Hz,1H),5.17(s,1H),4.71(s,1H),3.96(s,1H),1.66(s,3H),1.29(s,3H);13C NMR(125MHz,CDCl3)δ160.92,154.56,135.09,133.31,132.67,129.32,128.57,127.25,127.18,121.84,118.41,96.10,89.76,89.59,49.15,23.80,13.95.HRMS(ESI):calcd for C19H17ClO2Na[M+Na]+:335.0809,found:335.0811.
实施例14
原料:2,5-二甲基呋喃,2-羟基-α-萘基苄醇
产物:化学式:C23H20O2
分子量:328.1463
产率:68%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.96–7.83(m,4H),7.70(d,J=8.4Hz,1H),7.55–7.46(m,2H),7.12(t,J=7.5Hz,1H),6.92(d,J=7.8Hz,1H),6.82(t,J=7.3Hz,1H),6.69(d,J=7.5Hz,1H),5.22(s,1H),4.75(s,1H),4.16(s,1H),1.71(s,3H),1.33(s,3H);13C NMR(125MHz,CDCl3)δ161.08,154.61,134.26,133.52,132.87,130.50,129.82,129.08,127.96,127.81,127.68,127.52,127.11,125.93,125.88,121.78,118.31,96.08,90.12,89.76,49.83,23.93,14.05.HRMS(ESI):calcd for C23H20O2Na[M+Na]+:351.1356,found:351.1357.
实施例15
原料:2,5-二甲基呋喃,2-羟基-α-(2-噻吩基)苄醇
产物:化学式:C17H16O2S
分子量:284.0871
产率:71%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.35(d,J=5.0Hz,1H),7.10(dd,J=12.0,7.8Hz,3H),6.89–6.84(m,2H),6.74(d,J=7.6Hz,1H),5.20(s,1H),4.69(s,1H),4.36(s,1H),1.67(s,3H),1.40(s,3H);13C NMR(125MHz,CDCl3)δ161.10,154.19,138.13,129.87,128.83,127.36,127.31,126.57,125.82,122.02,118.22,96.19,89.64,89.61,45.31,23.68,13.91.HRMS(ESI):calcd for C17H16O2SNa[M+Na]+:307.0763,found:307.0769.
下列实施例16-36中,按照实施例1的操作步骤,反应体系中,原料邻羟基苄醇与2,5-二甲基呋喃分别为0.1mmol、0.3mmol,在5mol%(-)-CSA催化下,以1mL DCE作溶剂,在25℃温度下持续搅拌反应至原料反应完全。实施例22中,产率为过滤后的分离产率。实施例35中,催化剂(-)-CSA用量为20mol%。
实施例16
原料:2,5-二甲基呋喃,α-苯基邻羟基苄醇
产物:化学式:C19H20O3
分子量:296.1412
产率:91%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.37–7.31(m,3H),7.20(d,J=6.3Hz,2H),7.12(dd,J=8.0,7.4Hz,1H),6.87(dd,J=8.2,0.9Hz,1H),6.82–6.77(m,1H),6.65(d,J=7.8Hz,1H),4.57(dd,J=8.0,4.1Hz,1H),4.11(s,1H),3.06(dd,J=16.4,8.0Hz,1H),2.89(dd,J=16.4,4.1Hz,1H),2.32(s,3H),1.98(s,1H),1.06(s,3H).13C NMR(125MHz,CDCl3)δ206.67,154.01,139.22,131.27,130.84,128.21,127.82,127.40,124.51,121.45,116.44,78.43,68.34,53.63,43.58,31.27,22.74.HRMS(ESI):calcd for C19H20O3Na[M+Na]+:319.1305,found:319.1306.
实施例17
原料:2,5-二甲基呋喃,5-溴-2-羟基-α-苯基苄醇
产物:化学式:C19H19BrO3
分子量:374.0518
产率:70%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.36(q,J=5.5Hz,3H),7.20(dd,J=14.8,5.6Hz,3H),6.75(d,J=9.3Hz,2H),4.54(dd,J=7.6,4.1Hz,1H),4.06(s,1H),3.05(dd,J=16.6,7.8Hz,1H),2.89(dd,J=16.6,3.9Hz,1H),2.30(s,3H),1.95–1.89(m,1H),1.04(s,3H).13CNMR(125MHz,CDCl3)δ206.38,153.24,138.33,133.14,131.14,130.79,128.50,127.76,126.81,118.33,113.51,78.47,68.02,53.43,43.46,31.27,22.93.HRMS(ESI):calcd forC19H19BrO3[M+Na]+:397.0410,found:397.0415.
实施例18
原料:2,5-二甲基呋喃,2-羟基-5-甲基-α-苯基苄醇
产物:化学式:C20H22O3
分子量:310.1569
产率:89%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.33(t,J=6.4Hz,3H),7.23–7.16(m,2H),6.91(dd,J=8.1,1.5Hz,1H),6.76(d,J=8.3Hz,1H),6.44(s,1H),4.51(dd,J=8.0,4.2Hz,1H),4.05(s,1H),3.02(dd,J=16.3,8.0Hz,1H),2.86(dd,J=16.3,4.2Hz,1H),2.30(s,3H),2.10(s,3H),2.05(s,1H),1.03(s,3H).13C NMR(125MHz,CDCl3)δ206.79,151.84,139.30,131.31,130.94,130.74,128.53,128.16,127.33,124.16,116.21,78.43,68.42,53.68,43.61,31.24,22.63,20.61.HRMS(ESI):calcd for C20H22O3Na[M+Na]+:333.1461,found:333.1468.
实施例19
原料:2,5-二甲基呋喃,2-羟基-5-甲氧基-α-苯基苄醇
产物:化学式:C20H22O4
分子量:326.1518
产率:85%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.36–7.29(m,3H),7.19(d,J=7.2Hz,2H),6.80(d,J=8.9Hz,1H),6.69(dd,J=8.9,2.9Hz,1H),6.17(d,J=2.9Hz,1H),4.50(dd,J=8.0,4.1Hz,1H),4.06(s,1H),3.56(s,3H),3.02(dd,J=16.3,8.0Hz,1H),2.85(dd,J=16.3,4.1Hz,1H),2.30(s,3H),2.05(d,J=7.6Hz,1H),1.04(s,3H).13C NMR(125MHz,CDCl3)δ206.79,154.08,148.10,139.00,131.27,128.19,127.42,125.36,117.10,115.50,113.76,78.42,68.41,55.63,53.92,43.57,31.26,22.64.HRMS(ESI):calcd for C20H22O4Na[M+Na]+:349.1410,found:349.1411.
实施例20
原料:2,5-二甲基呋喃,2-羟基-α-(对氟苯基)苄醇
产物:化学式:C19H19FO3
分子量:314.1318
产率:80%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.21–7.15(m,2H),7.12(t,J=7.6Hz,1H),7.03(t,J=8.5Hz,2H),6.86(d,J=8.1Hz,1H),6.81(t,J=7.5Hz,1H),6.62(d,J=7.7Hz,1H),4.56(dd,J=7.7,4.2Hz,1H),4.09(s,1H),3.03(dd,J=16.4,7.8Hz,1H),2.89(dd,J=16.5,4.2Hz,1H),2.31(s,3H),2.06(s,1H),1.04(s,3H).13C NMR(125MHz,CDCl3)δ206.47,163.22,161.26,153.90,134.95,134.93,132.68,130.69,127.96,124.42,121.61,116.50,115.12,114.95,78.44,77.28,77.03,76.77,68.34,52.94,43.52,31.21,22.50.HRMS(ESI):calcd for C19H19FO3Na[M+Na]+:337.1210,found:337.1215.
实施例21
原料:2,5-二甲基呋喃,2-羟基-α-(2-噻吩基)苄醇
产物:化学式:C17H18O3S
分子量:302.0977
产率:75%,dr 5:1
1H NMR(500MHz,CDCl3)δ7.30(d,J=4.7Hz,1H),7.12(t,J=7.6Hz,1H),7.06–7.01(m,2H),6.85–6.79(m,2H),6.75(d,J=7.7Hz,1H),4.58(dd,J=7.7,4.2Hz,1H),4.45(s,1H),3.04(dd,J=16.4,7.8Hz,1H),2.90(dd,J=16.5,4.2Hz,1H),2.31(s,3H),2.27(s,1H),1.13(s,4H).13C NMR(125MHz,CDCl3)δ206.48,153.02,140.78,130.53,129.09,128.23,126.04,126.02,123.89,121.57,116.34,78.21,68.17,49.29,43.59,31.24,22.38.HRMS(ESI):calcd for C17H18O3S Na[M+Na]+:325.0869,found:325.0873.
实施例22
原料:2,5-二甲基呋喃,2-羟基-α-萘基苄醇
产物:化学式:C23H22O3
分子量:346.1569
产率:78%,dr 14:1
1H NMR(500MHz,CDCl3)δ7.87–7.78(m,3H),7.72(s,1H),7.49(dd,J=6.0,2.9Hz,2H),7.29(d,J=7.9Hz,1H),7.14(t,J=7.5Hz,1H),6.90(d,J=8.1Hz,1H),6.78(t,J=7.5Hz,1H),6.65(d,J=7.7Hz,1H),4.62(dd,J=7.8,4.1Hz,1H),4.28(s,1H),3.08(dd,J=16.4,7.9Hz,1H),2.91(dd,J=16.4,4.0Hz,1H),2.33(s,3H),2.07(s,1H),1.11(s,3H).13CNMR(125MHz,CDCl3)δ206.70,154.02,136.80,133.15,132.80,130.91,127.92,127.78,127.67,126.15,125.99,124.45,121.54,116.50,78.49,68.67,53.75,43.56,31.30,22.85.HRMS(ESI):calcd for C23H22O3Na[M+Na]+:369.1461,found:369.1464.
实施例23
原料:2,5-二甲基呋喃,2-羟基-α-甲基苄醇
产物:化学式:C14H18O3
分子量:234.1256
产率:72%,dr 2:1
1H NMR(500MHz,CDCl3)7.11(m,2H),6.91(t,J=7.4Hz,1H),6.80(d,J=8.3Hz,1H),4.49(dd,J=8.1,3.9Hz,1H),3.01–2.74(m,3H),2.28(s,3H),2.11(s,1H),1.29(d,J=7.3Hz,3H),1.23(s,3H).13C NMR(125MHz,CDCl3)δ207.15,152.07,130.01,127.71,125.62,121.38,116.67,73.78,70.08,43.06,42.01,31.30,21.97,20.36.HRMS(ESI):calcd forC14H18O3Na[M+Na]+:257.1148,found:257.1152.
实施例24
原料:2,5-二甲基呋喃,2-羟基-3-甲氧基-α-苯基苄醇
产物:化学式:C20H22O4
分子量:326.1518
产率:71%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.35–7.29(m,3H),7.22–7.15(m,2H),6.73(dd,J=6.6,2.5Hz,2H),6.28–6.22(m,1H),4.60–4.55(m,1H),4.12(s,1H),3.85(s,3H),3.10(dd,J=16.7,6.7Hz,1H),3.01(dd,J=16.7,5.1Hz,1H),2.33(s,3H),2.05(s,1H),1.04(s,3H);13CNMR(125MHz,CDCl3)δ206.74,148.01,143.88,139.26,131.27,128.08,127.31,125.52,122.59,120.98,110.03,78.62,68.29,56.11,53.65,43.77,31.14,22.56.HRMS(ESI):calcd for C20H22O4Na[M+Na]+:349.1410,found:349.1410.
实施例25
原料:2,5-二甲基呋喃,2-羟基-4-甲基-α-苯基苄醇
产物:化学式:C20H22O3
分子量:310.1569
产率:92%,dr>20:1
1HNMR(500MHz,CDCl3)δ7.36–7.30(m,3H),7.19(d,J=6.5Hz,2H),6.70(s,1H),6.62(d,J=7.9Hz,1H),6.53(d,J=7.9Hz,1H),4.54(dd,J=8.1,4.1Hz,1H),4.06(s,1H),3.04(dd,J=16.3,8.1Hz,1H),2.86(dd,J=16.3,4.1Hz,1H),2.32(s,3H),2.26(s,3H),1.98(s,1H),1.05(s,3H);13C NMR(125MHz,CDCl3)δ206.75,153.77,139.37,137.92,131.22,130.60,128.15,127.33,122.47,121.41,116.77,78.45,68.38,53.39,43.57,31.27,22.63,20.98.HRMS(ESI):calcd for C20H22O3Na[M+Na]+:333.1461,found:333.1461.
实施例26
原料:2,5-二甲基呋喃,2-羟基-3-叔丁基-α-苯基苄醇
产物:化学式:C23H28O3
分子量:352.2038
产率:78%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.36–7.29(m,3H),7.19(d,J=6.9Hz,2H),7.14(d,J=7.6Hz,1H),6.73(t,J=7.7Hz,1H),6.51(d,J=7.7Hz,1H),4.66(dd,J=8.1,3.7Hz,1H),4.13(s,1H),3.11(dd,J=16.6,8.1Hz,1H),2.90(dd,J=16.7,3.7Hz,1H),2.33(s,3H),2.04(s,1H),1.37(s,9H),1.06(s,3H);13C NMR(125MHz,CDCl3)δ206.64,152.78,139.73,137.16,131.30,129.15,128.08,127.23,125.16,124.87,120.81,78.49,67.94,54.12,43.40,34.70,31.55,29.82,22.51.HRMS(ESI):calcd for C23H28O3Na[M+Na]+:375.1931,found:375.1936.
实施例27
原料:2,5-二甲基呋喃,5-氯-2-羟基-α-苯基苄醇
产物:化学式:C19H19ClO3
分子量:330.1023
产率:74%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.36(q,J=5.0Hz,3H),7.18(d,J=6.9Hz,2H),7.06(dd,J=8.7,2.2Hz,1H),6.80(d,J=8.7Hz,1H),6.63–6.59(m,1H),4.54(dd,J=7.7,4.1Hz,1H),4.05(s,1H),3.04(dd,J=16.6,7.8Hz,1H),2.88(dd,J=16.6,4.0Hz,1H),2.30(s,3H),1.94(d,J=9.5Hz,1H),1.04(s,3H);13C NMR(125MHz,CDCl3)δ206.45,152.70,138.36,131.12,130.23,128.49,127.90,127.75,126.26,126.15,117.88,78.48,68.04,53.48,43.46,31.30,22.92.HRMS(ESI):calcd for C19H19ClO3Na[M+Na]+:353.0915,found:353.0923.
实施例28
原料:2,5-二甲基呋喃,5-溴-2-羟基-α-苯基苄醇
产物:化学式:C19H19BrO3
分子量:374.0518
产率:70%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.36(q,J=5.5Hz,3H),7.20(dd,J=14.8,5.6Hz,3H),6.75(d,J=9.3Hz,2H),4.54(dd,J=7.6,4.1Hz,1H),4.06(s,1H),3.05(dd,J=16.6,7.8Hz,1H),2.89(dd,J=16.6,3.9Hz,1H),2.30(s,3H),1.95–1.89(m,1H),1.04(s,3H);13CNMR(125MHz,CDCl3)δ206.38,153.24,138.33,133.14,131.14,130.79,128.50,127.76,126.81,118.33,113.51,78.47,68.02,53.43,43.46,31.27,22.93.HRMS(ESI):calcd forC19H19BrO3Na[M+Na]+:397.0410,found:397.0415.
实施例29
原料:2,5-二甲基呋喃,2-羟基-α-(2-甲氧基苯基)苄醇
产物:化学式:C20H22O4
分子量:326.1518
产率:89%,dr 2:1
1HNMR(500MHz,CDCl3)δ7.30(t,J=7.5Hz,1H),7.12–7.02(m,2H),6.91(m,2H),6.85(t,J=8.1Hz,1H),6.75(t,J=7.5Hz,1H),6.61(t,J=7.0Hz,1H),4.90(s,1H),4.62(dd,J=8.0,4.1Hz,1H),3.85(s,3H),3.03(dd,J=16.2,8.1Hz,1H),2.87(dd,J=16.4,4.1Hz,1H),2.31(s,3H),2.02(s,1H),1.02(s,3H);13C NMR(125MHz,CDCl3)δ206.90,158.77,154.34,131.45,130.70,128.29,127.77,127.38,125.14,121.30,120.63,116.32,110.35,78.67,68.88,55.55,43.68,43.63,31.24,22.52.HRMS(ESI):calcd for C20H22O4Na[M+Na]+:349.1410,found:349.1423.
实施例30
原料:2,5-二甲基呋喃,2-羟基-α-(3-甲氧基苯基)苄醇
产物:化学式:C20H22O4
分子量:326.1518
产率:82%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.26(t,J=7.9Hz,1H),7.11(t,J=7.7Hz,1H),6.89–6.84(m,2H),6.79(t,J=7.4Hz,2H),6.75(s,1H),6.67(d,J=7.7Hz,1H),4.55(dd,J=8.0,4.1Hz,1H),4.08(s,1H),3.76(s,3H),3.05(dd,J=16.3,8.0Hz,1H),2.88(dd,J=16.3,4.1Hz,1H),2.32(s,3H),1.99(s,1H),1.08(s,3H);13C NMR(125MHz,CDCl3)δ206.69,159.49,153.94,140.78,130.84,129.14,127.82,124.29,121.42,116.41,112.64,78.41,68.31,55.23,53.60,43.58,31.27,22.87.HRMS(ESI):calcd for C20H22O4Na[M+Na]+:349.1410,found:349.1413.
实施例31
原料:2,5-二甲基呋喃,2-羟基-α-(4-甲氧基苯基)苄醇
产物:化学式:C20H22O4
分子量:326.1518
产率:84%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.11(t,J=6.8Hz,3H),6.87(dd,J=14.2,8.4Hz,3H),6.79(t,J=7.5Hz,1H),6.68(d,J=7.7Hz,1H),4.55(dd,J=7.9,4.1Hz,1H),4.05(s,1H),3.82(s,3H),3.05(dd,J=16.3,8.0Hz,1H),2.88(dd,J=16.3,4.1Hz,1H),2.31(s,3H),1.95(d,J=5.9Hz,1H),1.05(s,3H);13C NMR(125MHz,CDCl3)δ206.71,158.95,153.99,132.19,131.10,130.82,127.75,124.77,121.41,116.40,113.66,78.42,68.40,55.26,52.77,43.62,31.26,22.74.HRMS(ESI):calcd for C20H22O4Na[M+Na]+:349.1410,found:349.1414.
实施例32
原料:2,5-二甲基呋喃,2-羟基-α-(2-甲基苯基)苄醇
产物:化学式:C20H22O3
分子量:310.1569
产率:87%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.25(d,J=6.0Hz,1H),7.20(td,J=7.3,1.7Hz,1H),7.17–7.07(m,3H),6.85(d,J=8.1Hz,1H),6.77(t,J=7.5Hz,1H),6.52(d,J=7.7Hz,1H),4.64(dd,J=7.8,4.2Hz,1H),4.49(s,1H),3.05(dd,J=16.4,7.9Hz,1H),2.89(dd,J=16.4,4.2Hz,1H),2.42(s,3H),2.32(s,3H),2.08(s,1H),1.04(s,3H);13C NMR(125MHz,CDCl3)δ206.70,154.01,138.16,137.84,130.64,130.39,130.25,127.62,127.10,126.15,125.22,121.43,116.30,78.77,69.00,47.44,43.59,31.26,22.38,20.64.HRMS(ESI):calcd for C20H22O3Na[M+Na]+:333.1461,found:333.1462.
实施例33
原料:2,5-二甲基呋喃,2-羟基-α-(3-甲基苯基)苄醇
产物:化学式:C20H22O3
分子量:310.1569
产率:89%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.23(t,J=7.6Hz,1H),7.12(dd,J=13.3,7.2Hz,2H),6.99(d,J=7.6Hz,2H),6.86(d,J=8.0Hz,1H),6.79(t,J=7.5Hz,1H),6.66(d,J=7.7Hz,1H),4.55(dd,J=8.0,4.1Hz,1H),4.06(s,1H),3.06(dd,J=16.3,8.1Hz,1H),2.87(dd,J=16.3,4.1Hz,1H),2.33(s,3H),2.32(s,3H),1.06(s,3H);13C NMR(125MHz,CDCl3)δ206.76,154.02,139.12,137.81,130.88,128.18,128.09,127.74,124.58,121.39,116.41,78.44,68.29,53.51,43.60,31.28,22.87,21.51.HRMS(ESI):calcd for C20H22O3Na[M+Na]+:333.1461,found:333.1465.
实施例34
原料:2,5-二甲基呋喃,2-羟基-α-(4-甲基苯基)苄醇
产物:化学式:C20H22O3
分子量:310.1569
产率:84%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.15(d,J=7.9Hz,2H),7.09(dd,J=18.6,7.5Hz,3H),6.88–6.83(m,1H),6.79(t,J=7.5Hz,1H),6.67(d,J=7.7Hz,1H),4.55(dd,J=8.0,4.1Hz,1H),4.07(s,1H),3.05(dd,J=16.3,8.0Hz,1H),2.87(dd,J=16.3,4.1Hz,1H),2.36(s,3H),2.31(s,3H),1.94(s,1H),1.05(s,3H);13C NMR(125MHz,CDCl3)δ206.73,154.05,137.04,136.08,131.10,130.85,128.96,127.73,124.65,121.38,116.41,78.42,68.33,53.18,43.61,31.26,22.80,21.11.HRMS(ESI):calcd for C20H22O3Na[M+Na]+:333.1461,found:333.1460.
实施例35
原料:2,5-二甲基呋喃,2-羟基-α-(4-三氟甲基苯基)苄醇
产物:化学式:C20H19F3O3
分子量:364.1286
产率:80%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.59(d,J=7.9Hz,2H),7.33(d,J=7.8Hz,2H),7.14(t,J=7.6Hz,1H),6.88(d,J=8.2Hz,1H),6.81(t,J=7.5Hz,1H),6.57(d,J=7.7Hz,1H),4.58(dd,J=7.6,4.3Hz,1H),4.17(s,1H),3.03(dd,J=16.6,7.6Hz,1H),2.90(dd,J=16.6,4.2Hz,1H),2.31(s,3H),2.23–2.17(m,1H),1.05(s,3H);13C NMR(125MHz,CDCl3)δ206.34,153.89,143.58,131.68,130.66,129.63(q,J=32.4Hz),128.20,124.97(q,J=3.8Hz),124.22(q,J=270.5Hz),123.86,121.81,116.65,78.40,68.37,53.62,43.41,31.23,22.41.HRMS(ESI):calcd for C20H19F3O3Na[M+Na]+:387.1179,found:387.1178.
实施例36
原料:2,5-二甲基呋喃,2-羟基-α-(对氯苯基)苄醇
产物:化学式:C19H19ClO3
分子量:330.1023
产率:87%,dr>20:1
1H NMR(500MHz,CDCl3)δ7.31(d,J=8.3Hz,2H),7.13(dd,J=13.0,7.8Hz,3H),6.86(d,J=8.2Hz,1H),6.81(t,J=7.5Hz,1H),6.61(d,J=7.7Hz,1H),4.56(dd,J=7.7,4.3Hz,1H),4.08(s,1H),3.03(dd,J=16.5,7.8Hz,1H),2.89(dd,J=16.5,4.2Hz,1H),2.31(s,3H),2.08(s,1H),1.04(s,3H);13C NMR(125MHz,CDCl3)δ206.47,153.90,137.81,133.32,132.59,130.69,128.32,128.05,124.16,121.67,116.55,78.40,68.31,53.11,43.48,31.24,22.48.HRMS(ESI):calcd for C19H19ClO3Na[M+Na]+:353.0915,found:353.0921.
以上所述,仅是本发明的较佳实施例而已,并非是对本发明作其它形式的限制,任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。但是凡是未脱离本发明技术方案内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型,仍属于本发明技术方案的保护范围。
Claims (3)
1.一种式Ⅱ所述化合物的合成方法,其特征在于,包括以下步骤:
将邻羟基苄醇类化合物加入溶剂中,按比例向溶剂中加入2,5-二甲基呋喃,最后加入催化剂,搅拌反应,通过薄层色谱法检测反应情况,反应完毕进行纯化,制得式Ⅱ所述化合物;
所述式Ⅱ化合物为:
所述邻羟基苄醇类化合物为式Ⅲ所示化合物:
所述式Ⅱ和式Ⅲ中,
R1选自甲基、苯基、C1-C3烷基取代苯基、C1-C3烷氧基取代苯基、C1-C3卤代烷基取代苯基、噻吩基、萘基、卤化苯基、联二苯基中任意一种;并且
R2选自甲基、卤素、C1-C3烷氧基中任意一种;
所述溶剂为1,2-二氯乙烷;
所述催化剂为S-联萘酚磷酸酯;
所述反应在25℃-40℃条件下进行。
2.根据权利要求1所述的合成方法,其特征在于:所述催化剂的用量为5mol%-20mol%。
3.根据权利要求1所述的合成方法,其特征在于:所述邻羟基苄醇类化合物与2,5-二甲基呋喃的摩尔比为1:3;所述溶剂的用量为每摩尔邻羟基苄醇类化合物添加10L溶剂。
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