CN116003445A

CN116003445A - 一类烷基锌试剂及其制备方法与应用

Info

Publication number: CN116003445A
Application number: CN202310058778.7A
Authority: CN
Inventors: 李�杰; 林杰; 陈开鑫
Original assignee: Suzhou University
Current assignee: Suzhou University
Priority date: 2023-01-17
Filing date: 2023-01-17
Publication date: 2023-04-25

Abstract

本发明公开了一类烷基锌试剂及其制备方法与应用，属于合成有机化学技术领域。本发明所述烷基锌试剂的结构通式：R‑znOPiv·Mg(OPiv)Br，其中，R选自链状烷基，环状烷基或取代烷基。本发明通过锂盐催化或者碘单质催化，完成格式试剂的制备，再通过转金属化和无机盐活化策略完成锌试剂的制备进而合成烷基取代的烷基二氟试剂，上述烷基取代的烷基二氟试剂的结构通式：

其中，R₁选自酯基、烷基、炔基、酰胺、苯并恶唑、磷酸二乙酯或全氟取代烷基；R选自链状烷基、环状烷基或含取代烷基；R₂，R₃独立选自有取代的烷基；R₄选自酯基。所述烷基锌试剂应用于烯烃的双官能团反应中，以及烷基取代的烷基二氟试剂在点击化学反应中得到应用。

Description

一类烷基锌试剂及其制备方法与应用

技术领域

本发明属于合成有机化学技术领域，尤其是一类烷基锌试剂及其制备方法与应用。

背景技术

选择性将氟原子或含氟基团安装到生物活性分子中，其作用为能够独特地调节溶解度、代谢稳定性和生物利用度。例如，CF₂基团是各种化合物的一个非常重要的结构基序，具有与农业化学和药物化学相关的活性。因此，现有技术对能够有效引入CF₂的方法的需求持续强烈。近年来，通过连续C–C键形成烯烃的选择性二碳官能化已经得到了广泛的关注。然而，迄今为止，在烯烃之间形成两个新的Csp₃部分的双重Csp₃–Csp₃交叉偶联是较难实现的，这可归因于(1)过渡金属物种被阻碍氧化添加到烷基–X键中；(2)新形成的Csp₃–[M]中间体的β-H容易消除的倾向；(3)区域选择性和位点选择性的控制。

本发明通过无机盐活化的策略，完成对烷基锌试剂的制备，因该类烷基锌试剂卓越的反应活性，将其应用于烯烃双官能团化反应，高效地实现对烷基取代的烷基二氟试剂的合成。

发明内容

为解决上述技术问题，本发明提供了一种烷基锌试剂及其制备方法与应用。本发明通过锂盐催化或者碘单质催化，完成格式试剂的制备，再通过转金属化和无机盐活化策略完成锌试剂的制备以及合成烷基取代的烷基二氟试剂。本发明通过阴离子调节策略设计新型烷基锌试剂，为新型有机锌试剂开辟了一个前景。

本发明通过以下技术方案实现：

本发明第一个目的是提供一类烷基锌试剂，所述烷基锌试剂的结构通式：R-ZnOPiv·Mg(OPiv)Br；其中，R选自链状烷基、环状烷基和取代烷基中的一种或多种。

在本发明的一个实施例中，所述烷基锌试剂选自以下化合物之一：

本发明第二个目的是提供所述的烷基锌试剂的制备方法，包括以下步骤：

(1)在有机溶剂中，将烷基溴代物、镁与催化剂混合反应，得到格式试剂；

(2)向步骤(1)所得格式试剂中加入特戊酸锌混合反应，得到所述的烷基锌试剂；其中，Zn(OPiv)₂的结构式为

在本发明的一个实施例中，所述烷基溴代物选自链状烷基溴代物、环状烷基溴代物和取代烷基溴代物中的一种或多种。

在本发明的一个实施例中，所述催化剂为碘和/或锂盐。

在本发明的一个实施例中，所述碘为碘粒；所述碘粒的个数为1-2粒。

在本发明的一个实施例中，所述有机溶剂选自乙腈、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环和N-甲基吡咯烷酮中的一种或多种。

在本发明的一个实施例中，所述格式试剂与特戊酸锌的摩尔比为1:1.2-1:1.5。

在本发明的一个实施例中，步骤(1)中，所述混合反应条件：反应时间0.5h-2h，反应温度为23℃-60℃。

在本发明的一个实施例中，步骤(2)中，所述混合反应条件：反应时间10min-30min，反应温度为0℃-40℃。

本发明第三个目的是提供所述的烷基锌试剂在烯烃双官能团化反应中的应用。

本发明第四个目的是提供所述的烷基锌试剂在制备烷基取代的烷基二氟试剂中的应用。

在本发明的一个实施例中，所述烷基取代的烷基二氟试剂的制备包括以下步骤：

在有机溶剂中，将

与R-ZnOPiv·Mg(OPiv)Br在催化剂作用下混合反应，得到所述烷基取代的烷基二氟试剂，其中X＝Br、I；

其中，R₁选自酯基、烷基、炔基、酰胺、苯并恶唑、磷酸二乙酯和全氟取代烷基中的一种或多种；R选自链状烷基、环状烷基和取代烷基中的一种或多种；R₂和R₃均独立的选自取代烷基；R₄选自酯基。

在本发明的一个实施例中，所述

与R-ZnOPiv·Mg(OPiv)Br的摩尔比为1:1:1.5-1:2:3，其中X＝Br、I。

在本发明的一个实施例中，所述催化剂选自Co、Fe、Cr、Ni和Cu中的一种或多种。

在本发明的一个实施例中，混合反应的条件：反应温度为0℃-23℃，反应时间为1h-16h。

在本发明的一个实施例中，所述烷基取代的烷基二氟试剂选自以下化合物之一：：

本发明的第五个目的是提供所述烷基取代的烷基二氟试剂在click反应中应用。

本发明的技术方案相比现有技术具有以下优点：

本发明所述的新型OPiv负载的烷基锌试剂的制备方法是首次报道，该试剂在无导向基团钴催化的二氟烷基化反应中显示出独特的反应性，从而通过级联Csp₃–Csp₃/Csp₃-Csp₃键在双键上实现CF₂和Csp₃基团的模块化安装，同时完成立体构型保持。特别值得注意的是对烷基锌试剂的显著OPiv调节效应，这导致在其他卤化物负载的有机锌中具有优异的反应性。本发明制备所得烷基锌试剂为固体试剂，与传统的液体试剂(不稳定)相比，本发明制备的烷基锌试剂具有更高的稳定性，且使用方便。此外，通过1,2-选择性二碳官能化的合成简单性和实用性完成对类药物分子和天然产物的简单修饰以及氟化产物的后期衍生得到了很好的说明。本发明通过阴离子调节策略设计新型烷基锌试剂，为新型有机锌试剂开辟了一个前景。

附图说明

为了使本发明的内容更容易被清楚的理解，下面根据本发明的具体实施例并结合附图，对本发明作进一步详细的说明，其中，

图1是本发明实施例1和实施例2中烷基取代的烷基二氟试剂的制备可行性说明；

图2是本发明实施例1中烷基锌试剂的外形图；

图3是本发明实施例1和实施例2中烷基锌试剂及烷基取代的烷基二氟试剂的制备方法；

图4是本发明烷基锌试剂及烷基取代的烷基二氟试剂的反应性；

图5是本发明烷基锌试剂及烷基取代的烷基二氟试剂的反应性；

图6是本发明在应用例中烷基取代的烷基二氟试剂在后续结构修饰及click反应中的合成应用实例。

具体实施方式

下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。

实施例1烷基锌试剂R-ZnOPiv·Mg(OPiv)Br的合成

本实施例提供了一种烷基锌试剂的合成方法，具体如下：

在25mL干燥和充满惰性气体(N₂)的反应管中加入Mg(182mg,1.5eq),一粒I₂和超干THF(5mL)，将(取代)烷基溴代物(5mmol,1.0eq)在微沸条件下逐滴加入，然后在油浴60℃下搅拌1h，得到相应的格式试剂，根据Kofron的方法，用碘滴定格式试剂并计算浓度，按照格式试剂浓度的1.2倍加入Zn(OPiv)₂，并将反应混合物在室温搅拌15min，即得到相应的烷基锌试剂，如图3所述3a-I。其中，烷基溴代物的结构式：

实施例2-14烷基锌试剂R-ZnOPiv·Mg(OPiv)Br的合成

本实施例提供了一种烷基锌试剂的合成方法，具体如下：

在25mL干燥和充满惰性气体(N₂)的反应管中加入Mg(182mg,1.5eq),一粒I₂和超干THF(5mL)，将(取代)烷基溴代物(5mmol,1.0eq)在微沸条件下逐滴加入，然后在油浴60℃下搅拌1h，得到相应的格式试剂，根据Kofron的方法，用碘滴定格式试剂并计算浓度，按照格式试剂浓度的1.2倍加入Zn(OPiv)₂，并将反应混合物在室温搅拌15min，即得到相应的烷基锌试剂。其中，烷基溴代物的结构式：

其中，由烷基溴代物

制备所得烷基锌试剂

(附图中缩写为

)如图2所示。由图2可以看出，本发明制备所得烷基锌试剂为固体。

实施例15烷基锌试剂R-ZnOPiv·Mg(OPiv)Br的合成

在25mL干燥和充满惰性气体(N₂)的反应管中加入Mg(2.4eq),干燥的LiCl(1.25eq)，Zn(OPiv)₂(1.1eq)超干THF(1mol/mL相当于所用溴代物)，将相应的溴代物(1.0eq)在0℃加入上述溶液，然后该反应液在室温下搅拌5h，即得到相应的烷基锌试剂。其中，烷基溴代物的结构式：

对比例1

本对比例提供了一种烷基锌试剂的合成方法，具体方法如下：

在25mL干燥和充满惰性气体(N₂)的反应管中加入1.2eq的1M的ZnCl₂溶液，加入1mLTHF，然后加入实施例1中相同方法制备的1.0eq的格式试剂，搅拌15min后，即得到相应化合物，如图3所示3a-II。

对比例2

在25mL干燥和充满惰性气体(N₂)的反应管中加入1.2eq的干燥的ZnBr₂固体，加入1mL THF，然后加入实施例1中相同方法制备的1.0eq的格式试剂，搅拌15min后，得到相应化合物，如图2所示3a-III。

对比例3

在25mL干燥和充满惰性气体(N₂)的反应管中加入1.2eq的干燥的ZnI₂固体，加入1mL THF，然后加入实施例1中相同方法制备的1.0eq的格式试剂，搅拌15min后，得到相应化合物，如图3所示3a-IV。

对比例4

在25mL干燥和充满惰性气体(N₂)的反应管中加入0.5eq的Zn(OPiv)₂固体，加入1mLTHF，然后加入实施例1中相同方法制备的1.0eq格式试剂，搅拌15min后，得到相应化合物，如图3所示3a-V。

对比例5

在25mL干燥和充满惰性气体(N₂)的反应管中加入0.5eq的ZnCl₂固体，加入1mLTHF，然后加入实施例1中相同方法制备的1.0eq的格式试剂，搅拌15min后，即得到相应化合物，如图3所示3a-VI。

应用例烷基取代的烷基二氟试剂化合物的合成

将实施例1-15中所得R-ZnOPiv·Mg(OPiv)Br(附图中缩写为R-ZnOPiv)分别与

反应混合，得到

其中，X＝Br、I，具体反应条件见图3-5，R选自链状烷基、环状烷基或含取代烷基；R₁选自酯基、烷基、炔基、酰胺、苯并恶唑、磷酸二乙酯或全氟取代烷基；R选自链状烷基、环状烷基或含取代烷基；R₂，R₃独立选自有取代的烷基；R₄选自酯基。反应所得产物见图4和图5，由图4和图5可知，使用本发明所得烷基锌试剂在过渡金属钴催化烯烃的双官能团化反应中的应用，产物具有较高的收率。

测试例

将实施例1和对比例1-5制备的6中不同的烷基锌试剂在相同的条件下通过烯烃的双官能团化反应制备烷基取代的烷基二氟试剂。利用气相色谱内标法获得产物产率分别是78％、16％、11％、20％、37％和15％，即如图3所示。

由此可见，实施例1的效果最好，即该类烷基锌试剂反应性更优。对比例4，5加入的Zn盐与格式试剂摩尔比是1：2的关系，与实施例1和对比例1加入的摩尔比不同，生成化合物结构如3a-V，3a-VI所示，这类二倍体的结构反应性不如3a-I。

为了进一步测试上述烷基锌试剂的反应性，设计了本发明烷基锌试剂在过渡金属钴催化烯烃的双官能团化反应。通过对催化体系的反应条件筛选后进行系统的反应动力学监测，实验结果表明该类烷基锌试剂在反应性方面表现出了明显的优越性，以高转化率得到目标产物，具体如图3示，所得化合物4-化合物49核磁表征结果如下所示。

化合物4-化合物49的核磁表征数据：

Ethyl

2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclohex-1-ene-1-carboxylate(4)

¹H-NMR(400MHz,CDCl₃):δ＝4.30(q,J＝7.1,2H),4.17(qd,J＝7.1,2.0,2H),3.50–3.41(m,1H),2.32–2.24(m,2H),2.23–1.91(m,4H),1.64–1.56(m,4H),1.49(dt,J＝13.1,6.6,1H),1.44–1.37(m,2H),1.35(t,J＝7.2,3H),1.29(t,J＝7.1,3H),1.16(ddt,J＝12.4,10.6,6.3,1H),1.04(tdd,J＝13.2,8.7,6.0,1H),0.86(dd,J＝6.6,2.2,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.5,164.2(t,²J_C-F＝32.7),145.1,127.5,116.2(t,¹J_C-F＝251.0),62.8,60.1,37.6(t,²J_C-F＝22.1),36.2,35.5(t,³J_C-F＝3.2),31.1,28.0,27.2,23.9,22.7,22.4,22.2,22.0,14.2,13.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.22(d,J＝262.5),-104.09(d,J＝262.4).HR-MS(EI)m/z calcd for C₂₀H₃₂F₂O₄[M+H⁺]375.2341,found 375.2345.

Ethyl

8-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-car boxylate(5)

¹H-NMR(400MHz,CDCl₃):δ＝4.33–4.26(m,2H),4.17(tt,J＝7.2,3.6,2H),4.02–3.93(m,4H),3.76–3.68(m,1H),2.52(q,J＝17.7,2H),2.33–2.04(m,4H),1.72(t,J＝6.5,2H),1.57–1.37(m,3H),1.34(t,J＝7.2,3H),1.28(t,J＝7.1,3H),1.21–1.11(m,1H),1.11–1.00(m,1H),0.86(d,J＝6.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝168.0,164.3(t,²J_C-F＝32.8),146.7,124.9,116.2(t,¹J_C-F＝251.1),107.4,64.6,64.6,62.9,60.4,37.8(t,²J_C-F＝22.3),37.4,36.2,34.9(t,³J_C-F＝3.3),31.3,30.7,28.1,23.8,22.8,22.5,14.3,14.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.13(d,J＝262.6),-103.97(d,J＝263.0).HR-MS(EI)m/zcalcd for C₂₂H₃₄F₂O₆[M+H⁺]433.2396,found433.2399.

Ethyl

2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-5,5-difluorocyclohex-1-ene-1-carbo xylate(6)

¹H-NMR(400MHz,CDCl₃):δ＝4.30(qd,J＝7.1,1.6,2H),4.19(q,J＝7.1,2H),3.90–3.80(m,1H),2.89–2.72(m,2H),2.43–2.12(m,4H),2.10–1.90(m,2H),1.54–1.37(m,3H),1.34(t,J＝7.2,3H),1.30(t,J＝7.1,3H),1.22–1.12(m,1H),1.06–0.95(m,1H),0.86(dd,J＝6.6,1.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝167.0,164.1(t,²J_C-F＝32.7),147.1,123.1(dd,³J_C-F＝6.3,4.4),122.3(t,¹J_C-F＝238.9),116.0(t,¹J_C-F＝251.2),63.0,60.8,37.6(t,²J_C-F＝22.3),36.3(t,²J_C-F＝28.0),36.1,34.6,31.4,29.8(t,²J_C-F＝24.3),28.1,22.8,22.5,14.2,14.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-95.45(d,J＝235.9),-97.01(d,J＝235.9),-103.09(d,J＝264.7),-104.20(d,J＝264.6).HR-MS(EI)m/z calcd forC₂₀H₃₀F₄O₄[M+H⁺]411.2153,found411.2157.

Ethyl

2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-5,5-dimethylcyclohex-1-ene-1-carb oxylate(7)

¹H-NMR(400MHz,CDCl₃):δ＝4.30(qd,J＝7.1,1.2,2H),4.16(qd,J＝7.1,1.9,2H),3.53–3.44(m,1H),2.30–2.15(m,1H),2.15–1.96(m,5H),1.53–1.39(m,3H),1.38–1.32(m,5H),1.29(t,J＝7.1,3H),1.17(ddt,J＝12.3,10.5,6.2,1H),1.10–0.96(m,1H),0.92(d,J＝10.4,6H),0.85(dd,J＝6.6,2.2,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.7,164.4(t,²J_C-F＝32.7),143.7,126.9,116.3(t,¹J_C-F＝251.1),62.9,60.2,41.0,37.9(t,²J_C-F＝22.1),36.46,35.3(t,³J_C-F＝3.0),34.9,31.4,28.8,28.6,28.1,27.7,22.9,22.5,21.8,14.3,14.0.¹⁹F-NMR(376MHz,CDCl₃)δ＝-103.39(d,J＝262.6),-104.21(d,J＝262.6).HR-MS(EI)m/z calcd for C₂₂H₃₆F₂O₄[M+H⁺]403.2654,found 403.2657.

Ethyl

4-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)-4'-methoxy-1,2,5,6-tetrahydro-[1,1'-biphenyl]-3-carboxylate(8)

¹H-NMR(400MHz,CDCl₃):δ＝7.15(d,J＝8.6,2H),6.86(dd,J＝8.7,2.8,2H),4.32(q,J＝7.2,2H),4.17(qdd,J＝7.1,3.5,1.5,2H),3.79(d,J＝1.4,3H),3.62–3.49(m,1H),2.84–2.50(m,2H),2.42–2.04(m,5H),1.95(d,J＝12.6,1H),1.74–1.62(m,1H),1.57–1.39(m,3H),1.36(t,J＝7.1,3H),1.27(td,J＝7.1,2.9,3H),1.23–0.96(m,2H),0.91–0.82(m,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.2,169.2,164.4(t,²J_C-F＝32.8),164.3(t,²J_C-F＝32.7),158.2,158.1,145.6,145.0,138.4,138.2,127.9,127.8,127.6,127.3,116.3(t,¹J_C-F＝251.8),116.3(t,¹J_C-F＝250.8),114.0,62.9,60.4,55.4,39.2,38.6,38.0(t,²J_C-F＝22.2),37.5(t,²J_C-F＝22.2),36.4,36.4,35.8,35.5(t,³J_C-F＝3.3),35.3(t,³J_C-F＝3.2),35.1,31.8,30.9,29.4,29.2,28.2,28.2,25.0,24.3,22.9,22.9,22.6,14.4,14.3,14.1.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.10(d,J＝262.5),-103.65(s),-104.07(d,J＝262.7).HR-MS(EI)m/z calcd for C₂₇H₃₈F₂O₅[M+H⁺]481.2760,found 481.2764.

Ethyl

2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclopent-1-ene-1-carboxylate(9)

¹H-NMR(400MHz,CDCl₃):δ＝4.27(q,J＝7.1,2H),4.18(q,J＝7.1,2H),3.92–3.83(m,1H),2.60(t,J＝7.3,2H),2.51–2.30(m,2H),2.29–2.11(m,2H),1.86–1.73(m,2H),1.56–1.36(m,3H),1.34(dd,J＝9.2,5.1,3H),1.29(t,J＝7.1,3H),1.15(ddd,J＝16.8,12.4,5.9,1H),1.05–0.95(m,1H),0.85(d,J＝6.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝166.0,164.2(t,²J_C-F＝32.7),158.6,129.9,116.1(t,¹J_C-F＝251.0),62.9,59.9,38.1(t,²J_C-F＝22.4),36.3,33.9,32.9,32.4(t,³J_C-F＝3.7),31.9,28.0,22.8,22.5,21.7,14.4,14.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.35(s),-103.38(s).HR-MS(EI)m/z calcd for C₁₉H₃₀F₂O₄[M+H⁺]361.2185,found361.2188.

Methyl

2-(1-ethoxy-2,2-difluoro-7-methyl-1-oxooctan-4-yl)cyclohept-1-ene-1-carboxylate(10)

¹H-NMR(400MHz,CDCl₃):δ＝4.34–4.26(m,2H),3.70(s,3H),3.36–3.27(m,1H),2.49–2.34(m,2H),2.22–2.03(m,4H),1.82–1.69(m,2H),1.61–1.38(m,7H),1.35(t,J＝7.1,3H),1.21–1.02(m,2H),0.86(dd,J＝6.6,2.5,6H).¹³C-NMR(100MHz,CDCl₃):δ＝170.7,164.3(t,²J_C-F＝32.9),151.3,133.2,116.3(t,¹J_C-F＝251.2),62.9,51.4,37.5(t,²J_C-F＝22.1),36.7(t,³J_C-F＝3.4),36.5,32.6,31.1,28.9,28.1,26.4,26.3,22.8,22.6,14.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-102.77(d,J＝262.6),-103.60(d,J＝262.8).HR-MS(EI)m/zcalcd for C₂₀H₃₂F₂O₄[M+H⁺]375.2341,found 375.2339.

Diethyl(Z)-2-butyl-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(11)

¹H-NMR(400MHz,CDCl₃):δ＝4.29(q,J＝7.1,2H),4.23–4.12(m,2H),3.25(tt,J＝8.5,5.7,1H),2.29–2.01(m,4H),1.62(s,3H),1.46(ddd,J＝17.4,12.1,6.1,2H),1.39–1.31(m,7H),1.29(t,J＝7.1,4H),1.15(ddd,J＝16.9,12.5,5.9,1H),1.01(tdd,J＝11.0,7.5,3.4,1H),0.89(t,J＝7.1,3H),0.85(dd,J＝6.6,2.4,6H).¹³C-NMR(100MHz,CDCl₃):δ＝170.0,164.3(t,²J_C-F＝32.7),141.5,131.5,116.2(t,¹J_C-F＝251.0),62.9,60.2,37.8(t,²J_C-F＝22.2),36.7(t,³J_C-F＝3.3),36.3,31.2,30.6,30.2,28.1,22.8,22.6,22.5,14.3,14.0,14.0,12.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.14(d,J＝263.5),-103.98(d,J＝263.1).HR-MS(EI)m/z calcd for C₂₁H₃₆F₂O₄[M+H⁺]391.2654,found 391.2650.

Diethyl

(Z)-2-((R)-3,7-dimethyloct-6-en-1-yl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(12)

¹H-NMR(400MHz,CDCl₃):δ＝5.09(t,J＝7.1,1H),4.29(q,J＝7.1,2H),4.22–4.12(m,2H),3.28(ddd,J＝14.1,8.4,5.7,1H),2.33–2.13(m,3H),2.13–1.88(m,3H),1.68(s,3H),1.63(s,3H),1.60(s,3H),1.52–1.37(m,4H),1.34(t,J＝7.2,4H),1.28(t,J＝7.1,4H),1.23–1.10(m,3H),1.06–0.96(m,1H),0.89(d,J＝6.4,3H),0.85(dd,J＝6.6,2.3,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.9,169.9,164.3(t,²J_C-F＝33.1),141.7,141.7,131.5,131.2,125.0,116.2(t,¹J_C-F＝251.2),62.9,60.2,37.8(t,²J_C-F＝22.3),37.0,37.0,36.6(t,³J_C-F＝2.8),36.3,35.4,35.4,32.6,31.2,28.1,28.1,25.9,25.7,22.9,22.5,19.6,19.6,17.8,14.4,14.0,12.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.14(d,J＝263.4),-103.15(d,J＝263.3),-103.89(d,J＝263.1),-103.91(d,J＝263.6).HR-MS(EI)m/z calcd forC₂₇H₄₆F₂O₄[M+H⁺]473.3437,found473.3440.

Diethyl

(Z)-6,6-difluoro-4-isopentyl-3-methyl-2-(2-(thiophen-3-yl)ethyl)hept-2-enedioate(13)

¹H-NMR(400MHz,CDCl₃):δ＝7.22(dd,J＝4.7,3.1,1H),6.97–6.90(m,2H),4.34–4.25(m,2H),4.22–4.13(m,2H),3.34(tt,J＝8.4,5.7,1H),2.76–2.68(m,2H),2.60–2.53(m,2H),2.24–2.03(m,2H),1.54(s,3H),1.47(dd,J＝13.2,6.5,1H),1.43–1.37(m,1H),1.34(dd,J＝8.7,5.6,4H),1.30(t,J＝7.1,3H),1.20–1.10(m,1H),1.03–0.94(m,1H),0.86(dd,J＝6.6,4.0,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.6,164.3(t,²J_C-F＝32.8),143.6,142.0,130.1,128.5,125.3,120.6,116.2(t,¹J_C-F＝251.1),62.9,60.4,37.7(t,²J_C-F＝22.2),36.2,36.6(t,³J_C-F＝3.2),31.7,31.2,29.0,28.1,22.8,22.5,14.3,14.0,13.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.58(s),-103.60(s).HR-MS(EI)m/z calcd for C₂₃H₃₄F₂O₄S[M+H⁺]445.2219,found445.2222.

Diethyl

(Z)-6,6-difluoro-4-isopentyl-2-(3-(4-methoxyphenoxy)propyl)-3-methylhept-2-enedioate(14)

¹H-NMR(400MHz,CDCl₃)：δ＝6.82(s,4H),4.33–4.23(m,2H),4.22–4.11(m,2H),3.94–3.84(m,2H),3.76(s,3H),3.31(tt,J＝8.7,5.7,1H),2.48(dd,J＝10.5,5.0,2H),2.25–2.00(m,2H),1.91–1.79(m,2H),1.64(s,3H),1.44(ddd,J＝17.6,12.2,6.1,2H),1.38–1.30(m,4H),1.28(t,J＝7.1,3H),1.20–1.09(m,1H),1.03–0.92(m,1H),0.83(t,J＝6.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.7,164.3(t,²J_C-F＝32.7),153.8,153.3,143.2,130.2,116.2(t,¹J_C-F＝251.1),115.4,114.7,67.4,62.9,60.4,55.9,37.8(t,²J_C-F＝22.1),36.3,31.2,28.1,28.1,26.7,22.8,22.4,14.3,14.0,13.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-102.67–-104.38(m,2F).HR-MS(EI)m/z calcd for C₂₇H₄₀F₂O₆[M+H⁺]499.2866,found499.2869.

Diethyl

(Z)-2-(4-(4-chloro-3-methylphenoxy)butyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioa te(15)

¹H-NMR(400MHz,CDCl₃):δ＝7.20(d,J＝8.7,1H),6.75(d,J＝2.9,1H),6.65(dd,J＝8.7,3.0,1H),4.34–4.25(m,2H),4.23–4.12(m,2H),3.90(t,J＝6.4,2H),3.29(tt,J＝8.6,5.7,1H),2.36–2.30(m,5H),2.27–2.02(m,2H),1.81–1.72(m,2H),1.64(s,3H),1.60–1.36(m,5H),1.34(t,J＝7.2,3H),1.28(t,J＝7.1,3H),1.20–1.10(m,1H),1.00(tdd,J＝11.8,8.5,4.9,1H),0.86(d,J＝2.0,3H),0.84(d,J＝1.9,3H).¹³C-NMR(100MHz,CDCl₃):δ＝-169.8,164.3(t,²J_C-F＝32.3),157.8,142.4,137.0,130.9,129.7,125.7,117.2,116.2(t,¹J_C-F＝251.3),113.2,68.0,62.9,60.3,37.7(t,²J_C-F＝22.2),36.7,36.3,31.2,30.1,29.0,28.1,24.9,22.8,22.5,20.4,14.3,14.0,13.1.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.59(d,J＝6.4).HR-MS(EI)m/z calcd for C₂₈H₄₁ClF₂O₅[M+H⁺]531.2683,found 531.2680.

Diethyl(Z)-2-benzyl-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(16)

¹H-NMR(400MHz,CDCl₃):δ＝7.27–7.22(m,2H),7.19–7.13(m,3H),4.34–4.22(m,2H),4.14–4.04(m,2H),3.74–3.62(m,2H),3.55(tt,J＝8.8,5.6,1H),2.34–2.05(m,2H),1.68(s,3H),1.44(tdd,J＝14.4,11.0,5.2,3H),1.34(t,J＝7.2,3H),1.27–1.18(m,1H),1.16(t,J＝7.1,3H),1.05(tdd,J＝12.3,7.0,5.2,1H),0.86(dd,J＝6.6,4.9,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.1,164.3(t,²J_C-F＝32.7),145.7,139.5,129.5,128.4,128.3,126.1,116.2(t,¹J_C-F＝251.2),62.9,60.3,37.7(t,²J_C-F＝22.2),36.4,36.1,31.5,28.1,22.8,22.5,14.2,14.0,13.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-102.90(d,J＝263.6),-103.82(d,J＝263.7).HR-MS(EI)m/z calcd for C₂₄H₃₄F₂O₄[M+H⁺]425.2498,found425.2501.

Diethyl(Z)-2-(4-chlorobenzyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(17)

¹H-NMR(400MHz,CDCl₃):δ＝7.22(d,J＝8.4,2H),7.10(d,J＝8.5,2H),4.33–4.24(m,2H),4.13–4.05(m,2H),3.66(d,J＝17.0,2H),3.56(tt,J＝8.8,5.4,1H),2.31–2.04(m,2H),1.67(s,3H),1.45(qdd,J＝13.4,8.9,5.5,3H),1.34(t,J＝7.2,3H),1.23–1.13(m,4H),1.09–0.97(m,1H),0.86(dd,J＝6.6,4.1,6H).¹³C-NMR(100MHz,CDCl₃):δ＝168.9,164.2(t,²J_C-F＝32.7),146.3,138.0,131.8,129.7,129.1,128.5,116.2(t,¹J_C-F＝251.1),62.9,60.4,37.7(t,²J_C-F＝22.2),36.4,35.5,31.5,28.1,22.8,22.5,14.2,14.0,13.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-102.66(d,J＝264.5),-104.17(d,J＝263.7).HR-MS(EI)m/zcalcd for C₂₄H₃₃ClF₂O₄[M+H⁺]459.2108,found 459.2114.

Diethyl(Z)-2-(4-bromobenzyl)-6,6-difluoro-4-isopentyl-3-methylhept-2-enedioate(18)

¹H-NMR(400MHz,CDCl₃):δ＝7.37(d,J＝8.4,2H),7.05(d,J＝8.4,2H),4.33–4.24(m,2H),4.14–4.05(m,2H),3.71–3.51(m,3H),2.33–2.04(m,2H),1.67(d,J＝6.0,3H),1.54–1.36(m,3H),1.34(t,J＝7.2,3H),1.26–1.15(m,4H),1.09–0.97(m,1H),0.86(dd,J＝6.6,4.1,6H).¹³C-NMR(100MHz,CDCl₃):δ＝168.71,164.08(t,²J_C-F＝32.7),146.34,138.41,131.33,129.98,128.83,119.74,116.03(t,¹J_C-F＝251.1),62.81,60.32,37.55(t,²J_C-F＝22.2),36.24,35.46,31.39,27.94,22.69,22.41,14.09,13.90,13.83.¹⁹F-NMR(376MHz,CDCl₃):δ＝-102.64(d,J＝263.9),-104.17(d,J＝264.0).HR-MS(EI)m/z calcdfor C₂₄H₃₃BrF₂O₄[M+H⁺]503.1603,found 503.1598.

Ethyl

2-(5-ethoxy-4,4-difluoro-5-oxopentan-2-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(19)

¹H-NMR(400MHz,CDCl₃):δ＝4.31(q,J＝7.1,2H),4.22–4.12(m,2H),3.59(m,1H),2.34–2.18(m,1H),2.16–1.96(m,5H),1.38–1.32(m,5H),1.32–1.27(m,3H),1.11(d,J＝6.9,3H),0.91(d,J＝3.2,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.6,164.4(t,²J_C-F＝32.8),145.6,125.1,116.3(t,¹J_C-F＝251.3),62.9,60.3,40.7,38.8(t,²J_C-F＝22.2),34.9,30.4,28.5,28.1,21.9,19.7,14.3,14.0.¹⁹F-NMR(376MHz,CDCl₃)δ＝-104.03(d,J＝261.7),-104.80(d,J＝260.9).HR-MS(EI)m/z calcd for C₁₈H₂₈F₂O₄[M+H⁺]347.2028,found347.2023.

Ethyl 2-(6-ethoxy-5,5-difluoro-6-oxohexan-3-yl)cyclohex-1-ene-1-carboxylate(20)

¹H-NMR(400MHz,CDCl₃):δ＝4.33–4.26(m,2H),4.22–4.13(m,2H),3.40(tt,J＝8.8,5.7,1H),2.35–1.90(m,6H),1.65–1.56(m,4H),1.53–1.38(m,2H),1.35(t,J＝7.2,3H),1.29(t,J＝7.1,3H),0.84(t,J＝7.4,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.7,164.4(t,²J_C-F＝32.8),144.7,128.0,116.3(t,¹J_C-F＝251.0),62.9,60.2,37.5(t,²J_C-F＝22.2),37.0(t,³J_C-F＝3.3),27.3,26.4,23.9,22.4,22.2,14.3,14.0,11.8.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.22(d,J＝263.1),-104.23(d,J＝262.2).HR-MS(EI)m/z calcd forC₁₇H₂₆F₂O₄[M+H⁺]333.1872,found333.1877.

Ethyl 8-(9-cyano-5,5-difluorononan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(21)

¹H-NMR(400MHz,CDCl₃):δ＝4.22–4.13(m,2H),4.04–3.94(m,4H),3.60–3.51(m,1H),2.54(s,2H),2.37(t,J＝7.0,2H),2.25(qd,J＝17.7,8.8,2H),2.08–1.80(m,4H),1.72(dd,J＝13.4,6.7,4H),1.66–1.58(m,2H),1.55–1.37(m,2H),1.29(t,J＝7.1,3H),0.83(t,J＝7.4,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.5,146.7,125.0,124.8(t,¹J_C-F＝241.5),119.6,107.4,64.6,60.5,39.7(t,²J_C-F＝24.6),37.4,37.1(t,³J_C-F＝4.0),35.2(t,²J_C-F＝25.4),30.7,27.0,25.3,23.5,21.6(t,³J_C-F＝4.6),17.1,14.3,11.8.¹⁹F-NMR(376MHz,CDCl₃)δ＝-94.30(d,J＝242.7),-95.83(d,J＝242.7).HR-MS(EI)m/z calcd forC₂₁H₃₁F₂NO₄[M+H⁺]400.2294,found400.2297.

Ethyl

8-(1-cyano-5,5-difluoro-10,12,12-trimethyltridecan-7-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-car boxylate(22)

¹H-NMR(400MHz,CDCl₃):δ＝4.21–4.10(m,2H),4.02–3.91(m,4H),3.66–3.52(m,1H),2.57–2.45(m,2H),2.35(t,J＝7.1,2H),2.31–2.18(m,2H),2.07–1.77(m,4H),1.74–1.57(m,6H),1.48–1.30(m,3H),1.27(t,J＝7.1,3H),1.21–0.95(m,4H),0.86(t,J＝4.4,12H).¹³C-NMR(100MHz,CDCl₃):δ＝168.4,168.3,147.4,147.1,124.8(t,¹J_C-F＝241.6),124.7,124.6,119.6,107.4,107.4,64.6,64.6,60.4,51.5,51.2,40.1(t,²J_C-F＝24.4),39.9(t,²J_C-F＝24.6),37.4,36.9,36.7,35.7(t,³J_C-F＝3.8),35.3(t,²J_C-F＝25.5),35.2(t,²J_C-F＝25.5),31.8,31.6,31.2,31.2,30.8,30.1,29.5,29.3,25.3,23.7,22.8,22.5,21.6(t,³J_C-F＝4.6),17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-95.02(ddd,J＝284.4,242.6,27.5).HR-MS(EI)m/z calcd for C₂₈H₄₅F₂NO₄[M+H⁺]498.3389,found 498.3382.

Ethyl

8-(9-cyano-1-cyclohexyl-5,5-difluorononan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(23)

¹H-NMR(400MHz,CDCl₃):δ＝4.21–4.12(m,2H),4.03–3.93(m,4H),3.63–3.54(m,1H),2.59–2.45(m,2H),2.41–2.33(m,2H),2.32–2.17(m,2H),2.06–1.80(m,4H),1.74–1.58(m,11H),1.49–1.33(m,2H),1.28(t,J＝7.1,3H),1.22–1.00(m,6H),0.90–0.80(m,2H).¹³C-NMR(100MHz,CDCl₃):δ＝168.4,147.3,124.9(t,¹J_C-F＝241.6),124.5,119.6,107.4,64.6,64.6,60.5,39.9(t,²J_C-F＝24.6),37.8,37.4,35.8(t,³J_C-F＝3.9),35.2(t,²J_C-F＝25.5),34.9,33.6,33.3,31.4,30.8,26.8,26.5,26.5,25.3,23.7,21.6(t,³J_C-F＝4.6),17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.18(d,J＝242.6),-95.76(d,J＝242.4).HR-MS(EI)m/z calcd for C₂₇H₄₁F₂NO₄[M+H⁺]482.3076,found482.3080.

Ethyl

8-(9-cyano-5,5-difluoro-1-(4-fluorophenyl)nonan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carbo xylate(24)

¹H-NMR(400MHz,):δ＝7.13–7.06(m,2H),6.97–6.89(m,2H),4.15(q,J＝7.1,2H),4.04–3.94(m,4H),3.78–3.68(m,1H),2.60–2.43(m,4H),2.39–2.27(m,4H),2.11–1.81(m,4H),1.80–1.61(m,8H),1.28(t,J＝7.1,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.3,162.6,160.1,146.6,137.8,129.8,129.7,125.3,124.7(t,¹J_C-F＝241.8),119.6,115.2,115.0,107.3,64.7,64.6,60.6,39.9(t,²J_C-F＝24.6),37.4,35.8,35.4(t,²J_C-F＝25.4),32.8,30.7,27.2,25.3,23.8,21.6(t,³J_C-F＝4.6),17.1,14.3.¹⁹F-NMR(376MHz,CDCl₃):δ＝-95.21(dd,J＝662.5,243.0),-117.83(s).HR-MS(EI)m/z calcd for C₂₇H₃₄F₃NO₄[M+H⁺]494.2513,found494.2517.

Ethyl

2-(1-((5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)-6-ethoxy-5,5-difluoro-6-oxohexan-3-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(25)

¹H-NMR(400MHz,CDCl₃):δ＝5.15(s,1H),4.30(dd,J＝14.2,7.1,2H),4.22–4.12(m,2H),3.51(s,1H),2.43–1.66(m,16H),1.56–1.41(m,2H),1.37–1.27(m,9H),0.92(d,J＝8.9,6H),0.80(s,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.5,169.4,164.2(t,²J_C-F＝32.7),148.1,148.0,143.4,143.2,127.1,127.1,116.1(t,¹J_C-F＝251.1),115.9,115.8,62.8,60.2,45.9,45.8,40.9,37.9,37.8(t,²J_C-F＝22.2),35.1,34.7,31.7,31.6,31.2,31.1,28.7,28.6,28.4,27.7,27.6,26.3,21.2,14.2,13.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-96.91–-109.40(m,).HR-MS(EI)m/z calcd for C₂₈H₄₂F₂O₄[M+H⁺]481.3124,found481.3128.

Ethyl

8-(12-cyano-8,8-difluorododec-1-en-6-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(26)

¹H-NMR(400MHz,CDCl₃):δ＝5.77(ddt,J＝16.9,10.2,6.7,1H),5.04–4.90(m,2H),4.23–4.12(m,2H),4.04–3.92(m,4H),3.71–3.61(m,1H),2.59–2.47(m,2H),2.36(t,J＝7.1,2H),2.24(ddt,J＝17.7,12.8,6.6,2H),2.08–1.80(m,6H),1.75–1.67(m,4H),1.62(dt,J＝8.8,2.8,2H),1.50–1.31(m,3H),1.31–1.26(m,4H).¹³C-NMR(100MHz,CDCl₃):δ＝168.4,147.0,138.8,124.8(t,¹J_C-F＝241.6),124.8,119.6,114.8,107.4,64.6,60.5,39.9(t,²J_C-F＝24.6),37.4,35.4(t,³J_C-F＝3.9),35.3(t,²J_C-F＝25.4),33.8,33.4,30.7,26.5,25.3,23.7,21.6(t,³J_C-F＝4.6),17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.33(d,J＝242.8),-95.85(d,J＝242.7).HR-MS(EI)m/z calcd for C₂₄H₃₅F₂NO₄[M+H⁺]440.2607,found 440.2611.

Ethyl

8-(8-chloro-1-ethoxy-2,2-difluoro-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxyl ate(27)

¹H-NMR(400MHz,CDCl₃):δ＝4.34–4.25(m,2H),4.20–4.13(m,2H),4.02–3.93(m,4H),3.79(dd,J＝13.3,7.1,1H),3.51(t,J＝6.8,2H),2.52(q,J＝17.8,2H),2.33–2.08(m,4H),1.82–1.69(m,4H),1.52–1.37(m,3H),1.34(t,J＝7.2,4H),1.29(t,J＝7.1,3H).¹³C-NMR(100MHz,CDCl₃):δ＝167.9,164.2(t,²J_C-F＝32.7),146.2,125.4,116.1(t,¹J_C-F＝251.2),107.3,64.6,64.6,63.0,60.5,44.9,37.8(t,²J_C-F＝22.4),37.4,34.4(t,³J_C-F＝3.2),32.7,32.5,30.7,24.3,23.8,14.3,14.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-103.08(d,J＝263.3),-104.15(d,J＝263.0).HR-MS(EI)m/z calcd for C₂₁H₃₁ClF₂O₆[M+H⁺]453.1850,found453.1855.

Ethyl

2-(9-cyano-1-(1,3-dioxan-2-yl)-5,5-difluorononan-3-yl)cyclohex-1-ene-1-carboxylate(28)

¹H-NMR(400MHz,CDCl₃):δ＝4.49(t,J＝4.6,1H),4.16(qd,J＝7.1,1.2,2H),4.08(dd,J＝11.5,4.0,2H),3.80–3.68(m,2H),3.43(dd,J＝8.1,5.2,1H),2.36(t,J＝7.0,2H),2.27(s,2H),2.12–1.94(m,4H),1.94–1.78(m,3H),1.70(dd,J＝14.6,7.4,2H),1.66–1.56(m,7H),1.56–1.42(m,4H),1.28(t,J＝7.1,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.8,145.3,127.6,124.9(t,¹J_C-F＝241.6),119.6,102.2,67.0,60.3,39.9(t,²J_C-F＝24.4),35.9(t,³J_C-F＝3.8),35.3(t,²J_C-F＝25.5),32.9,27.8,27.3,25.9,25.3,23.8,22.3,22.1,21.6(t,³J_C-F＝4.6),17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.67(d,J＝242.7),-95.40(d,J＝242.6).HR-MS(EI)m/z calcd for C₂₃H₃₅F₂NO₄[M+H⁺]428.2607,found 428.2612.

Ethyl

2-(9-cyano-1-(1,3-dioxan-2-yl)-5,5-difluorononan-3-yl)-5,5-dimethylcyclohex-1-ene-1-carbo xylate(29)

¹H-NMR(400MHz,CDCl₃)：δ＝4.49(t,J＝4.7,1H),4.20–4.12(m,2H),4.11–4.04(m,2H),3.79–3.68(m,2H),3.44(dd,J＝8.7,5.0,1H),2.36(t,J＝7.0,2H),2.11–1.98(m,6H),1.95–1.79(m,3H),1.75–1.66(m,2H),1.60(ddd,J＝11.2,10.1,6.1,3H),1.56–1.42(m,4H),1.34(dd,J＝7.4,5.2,2H),1.28(t,J＝7.1,3H),0.91(d,J＝9.5,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.8,143.9,126.9,124.9(t,¹J_C-F＝241.6),119.6,102.2,67.0,60.3,41.0,40.0(t,²J_C-F＝24.5),35.7(t,³J_C-F＝3.9),35.3(t,²J_C-F＝25.5),34.9,33.0,28.8,28.6,28.2,27.8,25.9,25.3,21.6,17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-95.14(d,J＝3.8).HR-MS(EI)m/z calcd for C₂₅H₃₉F₂NO₄[M+H⁺]456.2920,found 456.2926.

Ethyl 8-[1-(4-chlorophenoxy)-11-cyano-7,7-difluoroundecan-5-yl]-1,4-dioxaspiro[4.5]d ec-7-ene-7-carboxylate(30)

¹H-NMR(400MHz,CDCl₃):δ＝7.24–7.18(m,2H),6.82–6.76(m,2H),4.16(q,J＝7.1Hz,2H),4.02–3.93(m,4H),3.90(t,J＝6.5Hz,2H),3.79–3.61(m,1H),2.53(s,2H),2.36(t,J＝7.0Hz,2H),2.33–2.16(m,2H),2.09–1.81(m,4H),1.78–1.66(m,6H),1.66–1.59(m,2H),1.49(dt,J＝16.6,7.4Hz,2H),1.43–1.33(m,2H),1.26(d,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.4,157.8,147.0,129.4,127.2,125.4,124.8(t,¹J_C-F＝241.6Hz),119.6,115.9,107.4,68.1,64.7,64.6,60.6,39.9(t,²J_C-F＝24.7Hz),37.4,35.4(t,²J_C-F＝25.5Hz),33.7,30.7,29.2,25.3,23.7,23.6,21.6(t,³J_C-F＝4.6Hz),17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.47(d,J＝242.8Hz),-96.07(d,J＝242.9Hz).HR-MS(EI)m/zcalcd for C₂₉H₃₈ClF₂NO₅,[M+H⁺]554.2479 found 554.2476.

Ethyl

8-(1-(4-chloro-3-methylphenoxy)-11-cyano-7,7-difluoroundecan-5-yl)-1,4-dioxaspiro[4.5]de c-7-ene-7-carboxylate(31)

¹H-NMR(400MHz,CDCl₃):δ＝7.20(dd,J＝8.7,5.0,1H),6.76(dd,J＝8.1,2.9,1H),6.65(td,J＝8.3,3.0,1H),4.21–4.11(m,2H),4.04–3.93(m,4H),3.92–3.84(m,2H),3.76–3.65(m,1H),2.53(s,2H),2.36(t,J＝7.0,2H),2.33(s,3H),2.27(dd,J＝15.0,6.7,2H),2.08–1.31(m,16H),1.28(td,J＝7.1,4.6,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.3,157.7,147.0,137.0,129.6,125.7,124.9,124.8(t,²J_C-F＝241.6),119.6,117.2,113.2,107.4,68.0,64.6,64.6,60.5,39.9(t,²J_C-F＝24.6),37.4,35.4(t,²J_C-F＝25.5),33.7,30.7,29.6,29.3,25.9,25.3,23.7,21.6(t,³J_C-F＝4.7),20.4,17.1,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.45(d,J＝242.8),-96.05(d,J＝242.9).HR-MS(EI)m/z calcd for C₃₀H₄₀ClF₂NO₅[M+H⁺]568.2636,found568.2640.

Ethyl 8-[1-(2-chloro-4-methoxyphenoxy)-11-cyano-7,7-difluoroundecan-5-yl]-1,4-diox aspiro[4.5]dec-7-ene-7-carboxylate(32)

¹H-NMR(400MHz,CDCl₃):δ＝6.93(d,J＝3.0Hz,1H),6.85(d,J＝9.0Hz,1H),6.73(dd,J＝9.0,3.0Hz,1H),4.17(q,J＝7.1Hz,2H),4.01–3.92(m,6H),3.75(s,3H),3.71(dd,J＝10.2,4.3Hz,1H),2.53(s,2H),2.36(t,J＝7.0Hz,2H),2.31–2.20(m,2H),2.00–1.89(m,2H),1.86–1.68(m,8H),1.65–1.60(m,2H),1.56–1.46(m,2H),1.42(dd,J＝14.2,6.9Hz,2H),1.26(d,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.3,153.8,148.9,146.9,124.7,124.7(t,¹J_C-F＝241.7Hz),123.7,119.5,115.9,115.0,112.9,107.3,69.8,64.5,60.4,55.9,39.8(t,²J_C-F＝24.6Hz),37.3,35.3(t,⁴J_C-F＝3.8Hz),35.2(t,²J_C-F＝25.4Hz),33.6,30.6,29.2,27.0,25.2,23.6,21.5(t,³J_C-F＝4.6Hz),17.0,14.2.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.62(d,J＝243.7Hz),-96.13(d,J＝241.8Hz).HR-MS(EI)m/z calcd forC₃₀H₄₀ClF₂NO₆[M+H⁺]584.2585,found 584.2588.

Ethyl

8-(7-cyano-1-cyclopropyl-3,3-difluoroheptyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(33)

¹H-NMR(400MHz,CDCl₃):δ＝4.18–4.09(m,2H),3.99(pd,J＝7.8,4.3,4H),2.90(td,J＝9.2,5.3,1H),2.54(s,2H),2.51–2.40(m,2H),2.36(t,J＝7.0,2H),2.23–2.02(m,2H),1.96–1.80(m,2H),1.76(t,J＝6.5,2H),1.73–1.67(m,2H),1.66–1.59(m,2H),1.26(t,J＝7.1,3H),0.85–0.74(m,1H),0.65–0.51(m,1H),0.44–0.34(m,1H),0.32–0.15(m,2H).¹³C-NMR(100MHz,CDCl₃):δ＝168.2,148.1,124.5(t,¹J_C-F＝241.1),123.2,119.6,107.4,64.6,64.6,60.4,40.8,39.7(t,²J_C-F＝24.9),37.3,35.3(t,²J_C-F＝25.6),30.8,25.2,24.7,21.6,17.0,15.7,14.3,6.4,3.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.67(d,J＝242.8),-96.03(d,J＝242.7).HR-MS(EI)m/z calcd for C₂₂H₃₁F₂NO₄[M+H⁺]412.2294,found 412.2299.

Ethyl

8-(7-cyano-1-cyclobutyl-3,3-difluoroheptyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(34)

¹H-NMR(400MHz,CDCl₃):δ＝4.26–4.17(m,2H),4.05–3.91(m,4H),3.63(t,J＝9.1,1H),2.53(s,2H),2.37(t,J＝7.1,2H),2.33–2.02(m,4H),1.94–1.57(m,15H),1.31(t,J＝7.1,3H).¹³C-NMR(100MHz,CDCl₃):δ＝168.6,145.7,125.0,124.7(t,¹J_C-F＝241.3),119.6,107.4,64.6,64.6,60.5,39.1,37.4,36.5(t,²J_C-F＝25.0),34.9(t,²J_C-F＝25.4),30.7,28.0,27.1,25.7,25.3,21.5(t,³J_C-F＝4.7),17.3,17.0,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-94.38(d,J＝242.6),-95.37(d,J＝242.6).HR-MS(EI)m/z calcd for C₂₃H₃₃F₂NO₄[M+H⁺]426.2450,found426.2448.

Ethyl

8-(1-cyclopropyl-4-(diethylamino)-3,3-difluoro-4-oxobutyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-c arboxylate(35)

¹H-NMR(400MHz,CDCl₃):δ＝4.11(q,J＝7.1,2H),4.01–3.91(m,4H),3.60–3.21(m,4H),3.03(dd,J＝15.4,8.4,1H),2.56–2.35(m,6H),1.74(t,J＝6.9,2H),1.23(t,J＝7.1,3H),1.14(dt,J＝14.0,7.0,6H),0.87–0.78(m,1H),0.56–0.47(m,1H),0.42–0.32(m,1H),0.31–0.22(m,2H).¹³C-NMR(100MHz,CDCl₃):δ＝168.2,163.0(t,²J_C-F＝29.3),148.4,122.8,119.4(t,¹J_C-F＝255.5),107.5,64.6,64.5,60.2,41.9(t,³J_C-F＝6.3),41.6,40.2,37.7(t,²J_C-F＝22.6),37.3,30.8,24.9,15.2,14.3,14.2,12.4,6.3,3.8.¹⁹F-NMR(376MHz,CDCl₃):δ＝-98.26(d,J＝280.2),-99.70(d,J＝280.2).HR-MS(EI)m/z calcd forC₂₂H₃₃F₂NO₅[M+H⁺]430.2400,found430.2405.

Ethyl

8-(1-cyclopropyl-3,3-difluoro-4-morpholino-4-oxobutyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-car boxylate(36)

¹H-NMR(400MHz,CDCl₃):δ＝4.17–4.07(m,2H),4.03–3.94(m,4H),3.76–3.59(m,8H),3.05(dd,J＝16.6,7.1,1H),2.59–2.37(m,6H),1.82–1.69(m,2H),1.27–1.23(t,J＝7.06,3H),0.92–0.74(m,1H),0.60–0.36(m,2H),0.32–0.21(m,2H).¹³C-NMR(100MHz,CDCl₃):δ＝168.1,162.3(t,²J_C-F＝29.5),148.2,122.9,119.2(t,¹J_C-F＝255.4),107.5,66.9,66.8,64.6,64.6,60.3,46.6(t,³J_C-F＝6.4),43.5,40.1,37.5(t,²J_C-F＝22),37.3,30.8,24.9,15.3,14.3,6.3,3.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-97.89(d,J＝282.0),-98.74(d,J＝282.0).HR-MS(EI)m/z calcd for C₂₂H₃₀F₂NO₆[M+H⁺]444.2192,found 444.2199.

Ethyl

2-(1-cyclopropyl-3,3-difluoro-4-oxo-4-(pyrrolidin-1-yl)butyl)cyclohept-1-ene-1-carboxylate(37)

¹H-NMR(400MHz,CDCl₃):δ＝3.63(d,J＝9.3,5H),3.48(t,J＝6.9,2H),2.56(td,J＝9.1,5.2,1H),2.48–2.23(m,6H),1.96–1.88(m,2H),1.87–1.77(m,3H),1.74–1.37(m,5H),1.22(s,2H),0.85–0.74(m,1H),0.55–0.32(m,2H),0.31–0.22(m,2H).¹³C-NMR(100MHz,CDCl₃):δ＝170.9,162.5(t,²J_C-F＝30.1),152.8,131.3,118.9(t,¹J_C-F＝252.1),51.3,47.6,46.8(t,³J_C-F＝6.8),42.1(t,⁴J_C-F＝3.3),37.0(t,²J_C-F＝22.4),32.6,30.9,29.8,27.2,26.7,26.6,26.2,23.4,14.8,6.1,4.3.¹⁹F-NMR(376MHz,CDCl₃):δ＝-100.18(d,J＝277.2),-101.98(d,J＝277.3).HR-MS(EI)m/z calcd for C₂₁H₃₁F₂NO₃[M+H⁺]384.2345,found 384.2347.

Ethyl(Z)-4-cyclopropyl-6,6-difluoro-3-methyl-7-oxo-7-(piperidin-1-yl)-2-(2-(thiophen-2-yl)ethyl)hept-2-enoate(38)

¹H-NMR(400MHz,CDCl₃):δ＝7.22(dd,J＝4.8,3.0Hz,1H),6.96(d,J＝4.9Hz,2H),4.17–4.09(m,2H),3.61(dd,J＝10.6,5.0Hz,2H),3.54(dd,J＝10.6,5.0Hz,2H),2.73(t,J＝7.7Hz,2H),2.68–2.62(m,1H),2.61–2.51(m,2H),2.41(ddd,J＝22.7,13.8,6.9Hz,2H),1.68(s,3H),1.65(dd,J＝6.6,3.2Hz,2H),1.61–1.56(m,4H),1.27(d,J＝7.1Hz,3H),0.83–0.76(m,1H),0.58–0.50(m,1H),0.40–0.29(m,2H),0.26(dt,J＝8.9,4.3Hz,1H).¹³C-NMR(100MHz,CDCl₃):δ＝169.9,162.1(t,²J_C-F＝29.0Hz),145.0,142.1,128.5,128.1,125.2,120.6,119.4(t,¹J_C-F＝255.5Hz),60.2,47.0(t,³J_C-F＝6.7Hz),44.6,41.8(t,⁴J_C-F＝2.7Hz),37.7(t,²J_C-F＝22.4Hz),31.6,29.1,26.7,25.7,24.7,15.4,14.3,14.1,6.2,3.9.¹⁹F-NMR(376MHz,CDCl₃):δ＝-97.83(d,J＝280.1Hz),-99.13(d,J＝280.1Hz).HR-MS(EI)m/z calcd for C₂₄H₃₃F₂NO₃S[M+H⁺]454.2222,found 454.2227.

Ethyl 8-(2,2-difluoro-1-(indolin-1-yl)-7-methyl-1-oxooctan-4-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(39)

¹H-NMR(400MHz,CDCl₃):δ＝8.19(d,J＝8.3,1H),7.21(t,J＝6.9,2H),7.08(t,J＝7.1,1H),4.38–4.24(m,2H),4.10(qq,J＝10.8,7.1,2H),4.00–3.90(m,4H),3.83–3.74(m,1H),3.17(t,J＝8.3,2H),2.58–2.23(m,6H),1.78–1.69(m,2H),1.56–1.40(m,3H),1.26–1.19(m,4H),1.14–1.04(m,1H),0.87(d,J＝6.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝168.4,161.6(t,²J_C-F＝30.3),147.2,142.9,131.8,127.6,125.1,124.7,124.4,119.3(t,¹J_C-F＝255.4),118.0,107.5,64.6,64.6,60.3,48.1(t,³J_C-F＝8.0),37.4,37.3(t,²J_C-F＝22.0),36.3,35.0,31.7,30.8,28.8,28.2,23.9,22.8,22.6,14.3.¹⁹F-NMR(376MHz,CDCl₃):δ＝-101.27(d,J＝281.1),-102.05(d,J＝280.9).HR-MS(EI)m/z calcd for C₂₈H₃₇F₂NO₅[M+H⁺]506.2713,found506.2717.

Ethyl 2-{1-[3,4-dihydroquinolin-1(2H)-yl]-1,1-difluoro-6-methylheptan-3-yl}-5,5-dimethylcyclohex-1-ene-1-carboxylate(40)

¹H-NMR(400MHz,CDCl₃):δ＝6.93(d,J＝3.0Hz,1H),6.85(d,J＝9.0Hz,1H),6.73(dd,J＝9.0,3.0Hz,1H),4.17(q,J＝7.1Hz,2H),4.01–3.92(m,6H),3.75(s,3H),3.71(dd,J＝10.2,4.3Hz,1H),2.53(s,2H),2.36(t,J＝7.0Hz,2H),2.31–2.20(m,2H),2.00–1.89(m,2H),1.86–1.68(m,8H),1.65–1.60(m,2H),1.56–1.46(m,2H),1.42(dd,J＝14.2,6.9Hz,2H),1.26(d,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):δ＝184.5,170.1,162.9(t,²J_C-F＝29.7Hz),144.3,134.5,134.2,132.9,132.5,128.8,128.7,127.1,126.8,126.7,126.7,126.6,126.3,126.2,119.6(t,¹J_C-F＝255.2Hz),60.2,47.3(t,³J_C-F＝7.5Hz),45.7,43.5(t,³J_C-F＝7.0Hz),41.8,41.0,38.6,37.7(td,³J_C-F＝21.9,7.2Hz),36.6,35.2,35.0,31.9,29.6,28.6,28.4,28.2,28.1,28.0,22.9,22.6,21.8,14.4,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-99.04(dd,J＝279.3,11.9Hz),-100.02(dd,J＝279.3,120.4Hz).HR-MS(EI)m/z calcdfor C₂₈H₄₁F₂NO₂[M+H⁺]462.3178,found 462.3175.

Ethyl 2-(3,3-difluoro-8-methyl-1-(triisopropylsilyl)non-1-yn-5-yl)cyclohex-1-ene-1-carboxylate(41)

¹H-NMR(400MHz,CDCl₃):δ＝4.16(qd,J＝7.1,0.9,2H),3.50–3.30(m,1H),2.32–1.93(m,5H),1.66–1.32(m,8H),1.28(t,J＝7.1,3H),1.08(d,J＝2.1,23H),0.85(dd,J＝6.6,2.5,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.9,145.0,127.4,113.8(t,¹J_C-F＝233.6),99.8(t,²J_C-F＝38.8),89.5(t,³J_C-F＝5.4),60.2,42.8(t,²J_C-F＝25.4),37.0,36.6,30.7,28.3,27.3,24.5,23.0,22.5,22.4,22.3,18.6,14.4,11.1.¹⁹F-NMR(376MHz,CDCl₃):δ＝-78.99(d,J＝272.0),-82.30(d,J＝272.0).HR-MS(EI)m/z calcd for C₂₈H₄₈F₂O₂Si[M+H⁺]483.3464,found483.3461.

Ethyl 2-(3,3-difluoro-8-methylnon-1-yn-5-yl)-5,5-dimethylcyclohex-1-ene-1-carboxylate(42)

¹H-NMR(400MHz,CDCl₃):δ＝4.22–4.10(m,2H),3.60–3.43(m,1H),2.73(t,J＝5.0,1H),2.31–1.95(m,6H),1.53–1.40(m,2H),1.35(t,J＝6.5,2H),1.29(t,J＝7.1,3H),1.25–0.98(m,3H),0.92(d,J＝5.8,6H),0.86(dd,J＝6.6,2.6,6H).¹³C-NMR(100MHz,CDCl₃):δ＝169.9,143.3,127.0,114.1(t,¹J_C-F＝233.9),76.9(t,²J_C-F＝40.5),75.3(t,³J_C-F＝6.8),60.2,42.5(t,²J_C-F＝24.7),41.0,36.5,34.9,31.3,28.7,28.6,28.2,27.8,22.9,22.6,21.8,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-80.89(d,J＝275.6),-82.17(d,J＝275.0).HR-MS(EI)m/z calcd for C₂₁H₃₂F₂O₂[M+H⁺]355.2443,found 355.2447.

Ethyl 2-(1-(1,3-dioxan-2-yl)-5,5-difluoro-7-(triisopropylsilyl)hept-6-yn-3-yl)cyclohex-1-ene-1-carb oxylate(43)

¹H-NMR(400MHz,CDCl₃):δ＝4.48(t,J＝4.9,1H),4.18–4.11(m,2H),4.10–4.01(m,2H),3.72(td,J＝12.2,2.5,2H),3.57–3.46(m,1H),2.35–1.96(m,7H),1.70–1.42(m,9H),1.26(t,J＝7.1,3H),1.10–1.05(m,21H).¹³C-NMR(100MHz,CDCl₃):δ＝169.6,144.7,127.7,113.5(t,¹J_C-F＝233.7),102.3,99.8(t,²J_C-F＝38.8),89.5(t,³J_C-F＝5.5),67.0,60.2,42.8(t,²J_C-F＝25.6),36.2,33.1,27.2,27.1,26.0,24.3,22.3,22.2,18.6,14.4,11.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-79.98(d,J＝272.1),-82.83(d,J＝272.1).HR-MS(EI)m/z calcdfor C₂₉H₄₈F₂O₄Si[M+H⁺]527.3363,found 527.3366.

tert-Butyl 4-(benzyloxy)-4-(5-(2-(ethoxycarbonyl)-4,4-dimethylcyclohex-1-en-1-yl)-3,3-difluorohept-1-yn-1-yl)piperidine-1-carboxylate(44)

¹H-NMR(400MHz,CDCl₃):δ＝7.37–7.29(m,5H),4.64(s,2H),4.13(dtt,J＝10.8,7.3,3.7,2H),3.47(dddd,J＝24.9,12.6,10.5,3.5,5H),2.29–1.96(m,9H),1.92–1.81(m,2H),1.56(dd,J＝14.0,6.5,1H),1.46(s,9H),1.36(t,J＝5.6,2H),1.25(t,J＝7.1,3H),0.92(s,6H),0.83(t,J＝7.4,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.6,154.7,143.8,138.3,128.5,127.8,127.8,126.9,114.5(t,¹J_C-F＝234.1),86.9(t,³J_C-F＝6.5),80.7(t,²J_C-F＝40.7),79.9,72.1,66.3,60.2,42.5(t,²J_C-F＝25.1),40.9,37.9,34.9,28.6,28.4,28.1,26.3,22.1,14.4,12.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-79.06(d,J＝272.8),-81.94(d,J＝272.8).HR-MS(EI)m/z calcd for C₃₅H₄₉F₂NO₅[M+H⁺]602.3652,found 602.3657.

Ethyl

2-(2,2-difluoro-7-methyl-1-(tosyloxy)octan-4-yl)cyclopent-1-ene-1-carboxylate(45)

¹H-NMR(400MHz,CDCl₃):δ＝7.79(d,J＝8.3,2H),7.35(d,J＝8.1,2H),4.23–4.09(m,4H),3.85–3.69(m,1H),2.64–2.53(m,2H),2.45(s,3H),2.43–2.27(m,2H),2.13–1.92(m,2H),1.82–1.73(m,2H),1.51–1.31(m,3H),1.27(t,J＝7.1,3H),1.13–0.90(m,2H),0.83(dd,J＝6.6,0.8,6H).¹³C-NMR(100MHz,CDCl₃):δ＝166.2,159.1,145.4,132.4,130.1,129.7,128.2,120.8(t,¹J_C-F＝244.1),68.1(t,²J_C-F＝35.1),59.9,37.2(t,²J_C-F＝22.5),36.3,33.8,32.7,32.5(t,³J_C-F＝3.7),32.3,27.9,22.8,22.4,21.8,21.7,14.4.¹⁹F-NMR(376MHz,CDCl₃):δ＝-101.96(d,J＝257.8),-103.27(d,J＝257.8).HR-MS(EI)m/z calcdfor C₂₄H₃₄F₂O₅S[M+H⁺]473.2168,found 473.2172.

Ethyl 8-(1-cyclopropyl-3-(diethoxyphosphoryl)-3,3-difluoropropyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(46)

¹H-NMR(400MHz,CDCl₃):δ＝4.30–4.19(m,4H),4.12(q,J＝7.1,2H),4.03–3.92(m,4H),3.10(dd,J＝16.5,7.2,1H),2.62–2.14(m,6H),1.79–1.68(m,2H),1.36(t,J＝7.1,6H),1.26–1.22(m,3H),0.89–0.74(m,1H),0.62–0.34(m,2H),0.28(pd,J＝9.2,5.0,2H).

¹³C-NMR(100MHz,CDCl₃):δ＝168.1,147.9,123.1,119.6(t,¹J_C-F＝261.1),107.5,64.6,64.6,60.4,39.5,39.4,37.3,36.6(t,²J_C-F＝20.0),36.4(t,²J_C-F＝20.1),30.9,27.2,24.9,16.6,16.5,15.2,14.3,6.6,4.0.¹⁹F-NMR(376MHz,CDCl₃):δ＝-112.54(qd,J＝296.5,108.5,2F).HR-MS(EI)m/z calcd for C₂₁H₃₃F₂O₇P[M+H⁺]467.2005,found 467.2008.

Ethyl

8-(1-(benzo[d]oxazol-2-yl)-1,1-difluoro-6-methylheptan-3-yl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carboxylate(47)

¹H-NMR(400MHz,CDCl₃):δ＝7.79(d,J＝7.4,1H),7.59(d,J＝7.6,1H),7.47–7.37(m,2H),4.03–3.83(m,7H),2.73–2.43(m,2H),2.42–2.20(m,4H),1.72–1.63(m,2H),1.55–1.40(m,3H),1.22–1.15(m,4H),1.07(ddd,J＝18.2,12.5,6.0,1H),0.85(dd,J＝6.6,0.7,6H).¹³C-NMR(100MHz,CDCl₃):δ＝168.0,158.3(t,²J_C-F＝33.6),150.7,146.5,140.2,126.8,125.3,124.9,121.3,116.8(t,¹J_C-F＝242.7),111.5,107.3,64.6,64.5,60.3,39.3(t,²J_C-F＝22.8),37.3,36.2,35.1,31.6,30.7,28.2,23.9,22.8,22.6,14.2.¹⁹F-NMR(376MHz,CDCl₃):δ＝-96.70(d,J＝275.2),-98.46(d,J＝275.2).HR-MS(EI)m/z calcdfor C₂₆H₃₃F₂NO₅[M+H⁺]478.2400,found478.2404.

Ethyl 2-[1-(1,3-dioxan-2-yl)-5,5,6,6,7,7,8,8,8-nonafluorooctan-3-yl]-5,5-dimethylcycloh ex-1-ene-1-carboxylate(48)

¹H-NMR(400MHz,CDCl₃):δ＝4.51(t,J＝3.4Hz,1H),4.17(q,J＝7.1Hz,2H),4.08(dd,J＝11.3,3.8Hz,2H),3.74(td,J＝12.1,2.3Hz,2H),3.69–3.60(m,1H),2.33–2.16(m,1H),2.16–1.96(m,6H),1.68–1.47(m,4H),1.40–1.33(m,2H),1.32–1.29(m,1H),1.27(t,J＝7.1Hz,3H),0.92(s,3H),0.91(s,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.5,142.2,127.8,102.0,67.0,67.0,60.4,40.9,34.9,34.0,33.6(t,²J_C-F＝21.2Hz),32.8,28.5,28.4,28.1,27.8,25.9,21.6,14.3.¹⁹F-NMR(376MHz,CDCl₃):δ＝-81.06(ddd,J＝13.6,6.8,3.5Hz),-111.18–-118.07(m),-124.59(dd,J＝20.2,10.0Hz),-125.88(ddd,J＝24.5,15.3,6.5Hz).HR-MS(EI)m/z calcd for C₂₃H₃₁F₉O₄[M+H⁺]543.2151,found 543.2148.

Ethyl(Z)-4-[2-(1,3-dioxan-2-yl)ethyl]-6,6,7,7,8,8,9,9,9-nonafluoro-3-methyl-2-[2-(thiop hen-2-yl)ethyl]non-2-enoate(49)

¹H-NMR(400MHz,CDCl₃):δ＝7.25–7.16(m,1H),6.94(d,J＝4.1Hz,2H),4.51(t,J＝4.6Hz,1H),4.18(q,J＝7.1Hz,2H),4.08(dd,J＝11.2,4.5Hz,2H),3.74(td,J＝12.2,2.3Hz,2H),3.64–3.44(m,1H),2.78–2.68(m,2H),2.62–2.53(m,2H),2.24–1.89(m,3H),1.64–1.57(m,2H),1.55(s,3H),1.53–1.32(m,3H),1.28(t,J＝7.1Hz,3H).¹³C-NMR(100MHz,CDCl₃):δ＝169.5,142.0,141.9,131.0,128.5,125.4,120.7,102.0,67.0,67.0,60.5,35.3,33.7(t,²J_C-F＝21.2Hz),32.7,31.7,29.0,27.4,25.9,14.3,12.7.¹⁹F-NMR(376MHz,CDCl₃):δ＝-81.06(ddd,J＝9.9,8.7,3.0Hz),-107.27–-117.07(m),-124.60(dd,J＝20.4,10.0Hz),-125.88(ddd,J＝20.9,9.5,5.0Hz).HR-MS(EI)m/z calcd for C₂₄H₂₉F₉O₄S[M+H⁺]585.1716,found585.1708.

本发明研究了一种新型烷基锌试剂在烯烃双官能团化反应中的底物适用性和官能团兼容性等方面的考察，在该反应体系中表现出广泛的底物适用性和优秀的官能团兼容性，并且可以顺利的进行反应放大至克级规模，反应效率基本保持不变。该烷基锌试剂通过无机盐活化策略拥有良好化学反应活性，该试剂可以进一步应用于具有药理学活性的天然产物以及药物分子的结构修饰，从而也进一步说明了该类烷基锌试剂，以及该合成方法学在有机化学，生物化学，药物化学领域具有潜在的应用价值。具体反应成果如图4-6所示。

显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。

Claims

1.一类烷基锌试剂，其特征在于，所述烷基锌试剂的结构通式：R-ZnOPiv·Mg(OPiv)Br；其中，R选自链状烷基、环状烷基和取代烷基中的一种或多种。

2.权利要求1所述的烷基锌试剂的制备方法，其特征在于，包括以下步骤：

(2)向步骤(1)所得格式试剂中加入特戊酸锌混合反应，得到所述的烷基锌试剂。

3.根据权利要求2所述的制备方法，其特征在于，步骤(1)中，所述烷基溴代物选自链状烷基溴代物、环状烷基溴代物和取代烷基溴代物中的一种或多种。

4.根据权利要求2所述的制备方法，其特征在于，步骤(1)中，所述催化剂为碘和/或锂盐。

5.根据权利要求2所述的制备方法，其特征在于，步骤(2)中，所述格式试剂与特戊酸锌的摩尔比为1:1.2-1:1.5。

6.权利要求1所述的烷基锌试剂在烯烃双官能团化反应中的应用。

7.权利要求1所述的烷基锌试剂在制备烷基取代的烷基二氟试剂中的应用。

8.根据权利要求7所述的应用，其特征在于，所述烷基取代的烷基二氟试剂的制备包括以下步骤：

在有机溶剂中，将

9.根据权利要求8所述的应用，其特征在于，所述

与R-ZnOPiv·Mg(OPiv)Br的摩尔比为1:1:1.5-1:2:3，其中X＝Br、I。

10.根据权利要求8所述的应用，其特征在于，所述催化剂选自Co、Fe、Cr、Ni和Cu中的一种或多种。