CN114835655A - 一种合成光学活性三氟甲基丙烯酸酯类化合物的方法 - Google Patents
一种合成光学活性三氟甲基丙烯酸酯类化合物的方法 Download PDFInfo
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Abstract
本发明公开了一种合成光学活性三氟甲基丙烯酸酯类化合物的方法，属于有机化学中技术领域。以MBH碳酸酯和噁唑酮为起始原料，在L‑叔亮氨酸和环己基衍生手性双官能团叔胺脲‑膦酰胺/酯类催化剂存在下，经过烯丙基烷基化反应，得到高光学活性的三氟甲基丙烯酸酯类化合物。本发明反应过程对映选择性优异，无需使用过渡金属或化学计量氧化剂；反应原料易得，催化剂结构简单，催化效率高，反应条件温和，后处理简单。
Description
技术领域
本发明属于有机化学中的不对称合成技术领域，具体涉及合成三氟甲基丙烯酸酯类化合物的方法。
背景技术
作为合成含有手性三氟甲基丙烯酸酯类化合物的重要方法，在过去的几十年中进行了广泛研究。在母体分子中引入全氟烷基官能团会显著影响其化学、物理和生物性质，已知的许多含有三氟甲基的手性分子具有重要的要用价值。
许多药物分子的手性部位都含有立体三氟甲基基团，构建含有立体三氟甲基为中心的化合物仍然是目前的研究热点。因此开发经济有效合成光学活性三氟甲基丙烯酸酯类化合物的方法显得非常重要。
发明内容
为了克服上述技术缺陷，本发明提供了以简单的起始原料合成具有光学活性的三氟甲基丙烯酸酯类化合物的方法。以MBH碳酸酯为起始原料，接着在手性双官能团叔胺脲-膦酯类催化剂存在下，与噁唑酮经过不对烯丙基烷基化反应，合成光学活性三氟甲基丙烯酸酯类化合物。
基于上述目的，本发明采用以MBH碳酸酯1和噁唑酮2为起始原料，接着以手性双官能团叔胺脲-膦酯类化合物作为催化剂，经过不对称烯丙基烷基化反应，以高产率，高对映选择性合成光学活性三氟甲基丙烯酸酯类化合物。
一种光学活性三氟甲基丙烯酸酯类化合物的合成方法，包括如下步骤：以 MBH碳酸酯1和噁唑酮2为原料，在L-叔亮氨酸衍生手性双官能团叔胺脲-膦类催化剂存在下，经过不对称烯丙基烷基化反应，得到三氟甲基丙烯酸酯类化合物3。
反应方程式如下：
其中：R1选自卤素、C1-C4烷基、C1-C4烷氧基、噻吩基；R2选自C1-C4烷基。
进一步地，在上述技术方案中，R1选自2-F、3-Me、2-噻吩基、3-噻吩基； R2选自Me、Et。
进一步地，在上述技术方案中，催化剂选自C1-C8，具体结构式如下：
进一步地，在上述技术方案中，催化剂优选自C1或C6。
进一步地，在上述技术方案中，所述MBH碳酸酯1、噁唑酮2与催化剂摩尔比为1：1-1.5：0.05-0.10；优选摩尔比为1：1.5：0.10。
进一步地，在上述技术方案中，反应温度为0-30℃，优选25℃。
进一步地，在上述技术方案中，反应在空气氛围下进行。
进一步地，在上述技术方案中，反应在有机溶剂中进行，反应溶剂选自甲苯、二氯甲烷、四氢呋喃、均三甲苯、氯苯、五氟苯、间二甲苯、邻二甲苯或***；优选反应溶剂为甲苯。
发明有益效果：
本发明以MBH碳酸酯为起始原料与噁唑酮的不对称烯丙基烷基化反应一锅得到光学三氟甲基丙烯酸酯类化合物，原料简单易得，催化剂结构简单/催化效率高，反应条件温和，后处理简单，催化剂可回收再利用，产物收率、对映选择性良好至优秀。
具体实施方式
以下结合具体实施例对本发明的技术方案作进一步详细说明，但本发明的保护范围并不局限于此。
反应条件的考察
典型操作如下：将Morita-Baylis-Hillman碳酸酯1(0.1mmol,1.0eq和催化剂C1(0.76mg,0.01mmol,0.1eq)溶解在超干甲苯(1.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(0.15mmol,1.5eq)。将反应混合物在室温搅拌72h，并通过TLC监测。待原料完全反应后，将反应混合物直接在短硅胶柱上PE/EA＝50:1-20:1梯度洗脱得到产物。
a反应条件：1(0.1mmol),2(0.15mmol),催化剂(0.01mmol)，超干甲苯(1.0mL)，25℃。b通过快速柱层析得到产率。c通过高效液相测得ee，d通过1H NMR谱测到d.r.。
在反应条件筛选过程中，首先考察了不同催化剂对反应的影响(entries 1-8)，最终确定了催化剂C1为最佳催化剂，在C2催化剂作用下，得到是α-烯丙基烷基化产物，然后考察了溶剂对反应的影响(entries 9-12)，最终确定了无水甲苯为最佳溶剂，反应温度为25℃，催化剂用量为10mol％。
典型催化剂C1合成路线，采用反应方程式表示如下：
氮气保护下，在15mL圆底烧瓶中，将1.0g 2-氨基环己醇A加入20mL二氯甲烷溶解，然后滴加3,5-双三氟甲基异硫1.84mL，快速点板进行监测。反应完全后，旋干柱层析，采用二氯甲烷/甲醇＝60/1洗脱，得到中间体B，收率 81％。
氮气保护下，在15mL圆底烧瓶中，将2.0g中间体B加入30mL二氯甲烷溶解后，依次加入EDC 0.903mL和DMAP 315.2mg，再加入1.56g二苯基膦苯甲酸，室温反应8h，点板监测反应完毕。加水淬灭，二氯甲烷萃取，干燥旋干，柱层析得到白色固体催化剂C1，收率78％，熔点168.3-169.2℃。
1H NMR(400MHz,CDCl3)δ8.46(s,1H),8.17-8.08(m,1H),7.90(s,2H),7.59(s,1H),7.41(pd,J＝7.5,1.7Hz,2H),7.37-7.17(m,9H),7.12(t,J＝7.4Hz,2H),6.90 (td,J＝4.8,2.3Hz,1H),4.91(td,J＝9.9,4.2Hz,1H),2.30(s,1H),1.92-1.09(m, 8H).
13C NMR(100MHz,CDCl3)δ181.2,168.5,140.7,139.6(d,J＝21.3Hz),136.7(d, J＝4.6Hz),134.2,134.0,133.6(d,J＝16.6Hz),132.8,131.8(q,J＝33.5Hz), 131.3,129.3,129.1,128.9,128.8,128.7,123.2(q,J＝272.8Hz),118.4,76.0, 57.7,31.4,30.5,24.0.
19F NMR(376MHz,CDCl3)δ-62.90.31P NMR(162MHz,CDCl3)δ-4.24. HRMS(ESI)calcd.for C34H30F6O2N2PS([M+H]+):675.1664,found:675.1666.
实施例1
将Morita-Baylis-Hillman碳酸酯1(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol,1.5eq)。将反应混合物在室温搅拌72h，TLC监测原料完全反应后，减压除去溶剂后直接快速硅胶柱层析(石油醚/乙酸乙酯＝1/50- 1/20)分离纯化得到无色油状产物3aa，收率为82％；HPLC CHIRALPAK OD- H,n-Hexane/2-prop anol＝96/4,flow rate＝0.8mL/min,λ＝210nm,retention time: 9.166min(major),4.717min(minor)；97％ee,dr＝10:1；[α]30 D＝-25.8(c 1.5, CHCl3)；1H NMR(600MHz,CDCl3)δ7.34–7.08(m,5H),6.60(s,1H),6.48(s,1H), 5.11(s,1H),3.67(s,3H),1.13(s,9H)；13C NMR(100MHz,CDCl3)δ175.0,166.4, 161.4,135.3,132.9,130.9,130.7,128.5,128.4,121.8(q,J＝286.3Hz),100.9(q,J＝ 29.9Hz),52.7,47.4,35.0,26.3；19F NMR(565MHz,CDCl3)δ-75.08；HRMS(ESI)calcd.for C19H20F3O4N[M+H]+:384.14 17,found:384.1422.
实施例2
将Morita-Baylis-Hillman碳酸酯1b(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol,1.5eq)。将反应混合物在室温搅拌72h，TLC监测原料完全反应后，减压除去溶剂后直接快速硅胶柱层析(石油醚/乙酸乙酯＝1/50- 1/20)分离纯化得到无色油状产物3ab，收率为75％；HPLC CHIRALPAK OD- H+IG,n-Hexane/2-propanol＝96/4,flow rate＝0.8mL/min,λ＝210nm,retention time:16.448min(major),20.390min(minor)；91％ee,dr＝8:1；[α]30 D＝-88.1(c 1.5, CHCl3)；1H NMR(400MHz,CDCl3)δ7.37–7.19(m,2H),7.06(t,J＝7.8Hz,2H), 6.64(s,1H),6.46(s,1H),5.70(s,1H),3.75(s,3H),1.25(s,9H)；13C NMR(150 MHz,CDCl3)δ175.1,166.1,161.4,161.1(d,J＝249.9Hz),135.1,131.4,131.0,130.3(d,J＝7.9Hz),124.4(d,J＝31.0Hz),123.6(d,J＝4.2Hz),121.6(q,J＝286.1 Hz),121.0(d,J＝14.1Hz),116.1(d,J＝23.1Hz),100.8(q,J＝30.2Hz),52.7,38.8, 35.1,26.4；19F NMR(376MHz,CDCl3)δ–75.61,–114.70；HRMS(ESI)calcd.for C19H19F4O4N([M+H]+):402.1323,found:402.1318.
实施例3
将Morita-Baylis-Hillman碳酸酯1c(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol,1.5eq)。将反应混合物在室温搅拌72h，TLC监测原料完全反应后，减压除去溶剂后直接快速硅胶柱层析(石油醚/乙酸乙酯＝1/50- 1/20)分离纯化得到无色油状产物3ac，收率为91％；HPLC CHIRALPAK OD- H+IG,n-Hexane/2-propanol＝96/4,flow rate＝0.8mL/min,λ＝210nm,retention time:14.735min(major),17.525min(minor)；99％ee,dr＝12:1；[α]30 D＝-24.9(c 1.5,CHCl3)；1H NMR(400MHz,CDCl3)δ7.16(t,J＝7.6Hz,1H),7.09–6.98(m, 3H),6.66(s,1H),6.54(s,1H),5.14(s,1H),3.75(s,3H),2.30(s,3H),1.21(s,9H)；13C NMR(100MHz,CDCl3)δ174.9,166.5,161.4,137.9,135.3,132.8,131.4, 130.8,129.2,128.2,127.9,121.8(q,J＝286.0Hz),100.9(q,J＝29.8Hz),52.7,47.4, 35.0,26.3,21.5；19F NMR(376MHz,CDCl3)δ-75.10；HRMS(ESI)calcd.for C20H22F3O4N([M+H]+):398.1574,found:398.1578.
实施例4
将Morita-Baylis-Hillman碳酸酯1d(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol,1.5eq)。将反应混合物在室温搅拌72h，TLC监测原料完全反应，减压除去溶剂直接快速硅胶柱层析(石油醚/乙酸乙酯＝1/50-1/20)分离纯化得到无色油状产物3ad，收率为92％；HPLC CHIRALPAK OD-H+IG,n- Hexane/2-propa nol＝96/4,flow rate＝0.8mL/min,λ＝210nm,retention time: 15.550min(major),25.067min(minor)；98％ee,dr＝11:1；[α]30 D＝-35.9(c 1.5, CHCl3)；1H NMR(400MHz,CDCl3)δ7.24–7.17(m,1H),7.01–6.95(m,1H),6.97– 6.89(m,1H),6.69(s,1H),6.54(s,1H),5.49(s,1H),3.79(s,3H),1.21(s,9H)；13C NMR(100MHz,CDCl3)δ175.1,166.1,161.5,135.8,135.5,131.7,129.8,129.0, 127.2,126.6,121.6(q,J＝285.7Hz),100.4(q,J＝29.8Hz),52.8,42.6,35.0,26.2；19F NMR(376MHz,CDCl3)δ-75.10；HRMS(ESI)calcd.for C17H18F3O4NS ([M+H]+):390.0981,found:390.0988.
实施例5:
将Morita-Baylis-Hillman碳酸酯1e(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol,1.5eq)。将反应混合物在室温搅拌72h，TLC监测原料完全反应，减压除去溶剂直接快速硅胶柱层析(石油醚/乙酸乙酯＝1/50-1/20) 分离纯化得到无色油状产物3ae，收率为92％；HPLC CHIRALPAK OD-H+IG, n-Hexane/2-prop anol＝96/4,flow rate＝0.8mL/min,λ＝210nm,retention time: 14.127min(major),16.605min(minor)；99％ee,dr＝10:1；[α]30 D＝-26.4(c 1.5, CHCl3)；1H NMR(400MHz,CDCl3)δ7.26(s,5H),6.65(s,1H),6.50(s,1H),5.18 (s,1H),4.18(tt,J＝7.3,3.5Hz,2H),1.26(t,J＝7.1Hz,3H),1.21(s,9H)；13CNMR (150MHz,CDCl3)δ174.9,165.9,161.4,135.6,133.1,130.7,130.5,128.6,128.4,121.8(q,J＝286.2Hz),100.9(q,J＝29.9Hz),61.7,47.3,35.0,26.3,14.2；19F NMR(376MHz,CDCl3)δ-75.14；HRMS(ESI)calcd.for C20H22F3O4N([M+H]+): 398.1574,found:398.1577.
实施例6:
将Morita-Baylis-Hillman碳酸酯1f(1mmol,1.0eq)和催化剂C1(7.6mg,0.01mmol,0.1eq)溶解在超干甲苯(5.0mL)中，然后将4-叔丁基-2-三氟甲基噁唑-5(2H)-酮2(1.5mmol，1.5equiv)。将反应混合物在室温搅拌72h，TLC监测原料完全反应后，减压除去溶剂直接快速硅胶柱层析(洗脱剂石油醚/乙酸乙酯＝1/50-1/20)分离纯化得到无色油状产物3af，收率为92％；99％ee,dr＝12:1； HPLC CHIRAL PAK OD-H+IG,n-Hexane/2-propanol＝96/4,flow rate＝0.8 mL/min,λ＝210nm,retention time:16.695min(major),21.775min(minor)；[α]30 D＝-32.4(c 1.5,CHCl3)；1H NMR(600MHz,CDCl3)δ7.24(dd,J＝5.1,3.0Hz, 1H),7.18(d,J＝3.0Hz,1H),7.03–6.96(m,1H),6.62(s,1H),6.37(s,1H),5.34(s, 1H),3.78(s,3H),1.22(s,9H).13C NMR(100MHz,CDCl3)δ175.1,166.1,161.5,135.8,135.5,131.7,129.8,129.0,127.2,126.6,121.6(q,J＝285.7Hz),100.4(q,J＝29.8Hz),52.8,42.6,35.0,26.2.19F NMR(565MHz,CDCl3)δ-75.35；HRMS(ESI) calcd.forC17H18F3O4NS([M+H]+):390.0981,found:390.0984.
以上实施例描述了本发明的基本原理、主要特征及优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明原理的范围下，本发明还会有各种变化和改进，这些变化和改进均落入本发明保护的范围内。
Claims (8)
1.一种合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于，包括如下步骤：以MBH碳酸酯1和噁唑酮2为原料，在L-叔亮氨酸衍生手性双官能团叔胺脲-膦类催化剂存在下，经过不对称烯丙基烷基化反应，得到三氟甲基丙烯酸酯类化合物3；反应方程式如下：
其中：R1选自卤素、C1-C4烷基、C1-C4烷氧基、噻吩基；R2选自C1-C4烷基。
2.根据权利要求1所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：R1选自2-F、3-Me、2-噻吩基、3-噻吩基；R2选自Me、Et。
3.根据权利要求1所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：催化剂选自C1-C8，具体结构式如下：
4.根据权利要求3所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：催化剂选自C1或C6。
5.根据权利要求1所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：所述MBH碳酸酯1、噁唑酮2与催化剂摩尔比为1：1-1.5：0.05-0.10。
6.根据权利要求1所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：反应温度为0-30℃。
7.根据权利要求1所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：反应在空气氛围下进行。
8.根据权利要求1-7任意一项所述合成光学活性三氟甲基丙烯酸酯类化合物的方法，其特征在于：反应在有机溶剂中进行，反应溶剂选自甲苯、二氯甲烷、四氢呋喃、均三甲苯、氯苯、五氟苯、间二甲苯、邻二甲苯或***。
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