CN113501764B - 一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法 - Google Patents

一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法 Download PDF

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CN113501764B
CN113501764B CN202110770330.9A CN202110770330A CN113501764B CN 113501764 B CN113501764 B CN 113501764B CN 202110770330 A CN202110770330 A CN 202110770330A CN 113501764 B CN113501764 B CN 113501764B
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蔡云飞
徐磊
杨倩
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Chongqing University
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Abstract

本发明提供了一种不对称合成含三氟甲基的多官能化环戊烯酮衍生物的方法。采用一价铜、手性布朗斯特酸和非手性路易斯酸作为组合催化剂，以呋喃烯烃、Togni试剂和芳胺类化合物为原料进行不对称三组分氮杂‑Piancatelli重排反应，制得含三氟甲基的手性多官能化环戊烯酮衍生物。该方法反应条件温和，对映选择性和非对映选择性优良，化学收率高，具有潜在的实际应用价值。

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一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成 方法
技术领域
本发明属于有机化学中的不对称合成领域，具体涉及一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法。
背景技术
手性多官能化环戊烯酮是一类极其重要的有机小分子化合物，不仅可以用作医药关键中间体，同时具有广泛生理活性，也是许多天然产物的核心骨架。呋喃氧鎓离子导向的不对称重排反应是一种高效构建该类化合物的方法，然而目前局限在基于糠醇类底物的双组分重排反应，限制了该类反应官能团兼容性以及在不对称合成中的应用。在药物化学中，含三氟甲基的化合物具有显著的生理活性，在有机分子中引入三氟甲基是新药的开发中研究的重要内容。目前在环戊烯酮侧链引入三氟甲基的方法尚无相关文献报道。因此，开发一种简单、高效的方法实现含三氟甲基的手性多官能化环戊烯酮衍生物的不对称合成具有重要意义。
发明内容
本发明的目的在于提供一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法。
为实现上述目的，本发明采用的技术方案如下：
本发明以呋喃烯烃、Togni试剂和芳胺类化合物为底物，一价铜、手性布朗斯特酸(B*H)和非手性路易斯酸(LA)为组合催化剂，通过三氟甲基自由基介导的三组分氮杂-Piancatelli重排反应，制得含三氟甲基的多官能化环戊烯酮衍生物，对映异构体过量高达95％；其反应式如下：
Figure GDA0004174695530000011
其中
R为氢或者溴；
R1为苯基、2-萘基、2-噻吩基、连有吸电子或供电子的不同基团R’的苯环，所述R’为甲基、甲氧基、三氟甲基或卤素。
R2为H或者甲基；
Ar为连有吸电子的不同基团的苯环，所述不同基团为卤素、酯基、三氟甲基、苯甲酰基、乙酰基、三氟甲磺酸酯基或者2-(1H-吡咯-1-基)。
所述的一价铜为氯化亚铜；
所述的非手性路易斯酸为三氟甲磺酸镝；
所述的手性布朗斯特酸结构式如下：
Figure GDA0004174695530000021
所述的技术方案实施操作包括以下：将反应催化剂CuCl、Dy(OTf)3和布朗斯特酸A1置于反应管中，放入合适大小磁力搅拌子。抽真空干燥，用氩气置换三次，氩气保护下加入一定量的有机溶剂。然后将反应冷却至0℃，再依次加入Togni试剂、芳胺衍生物和呋喃烯烃。升温至一定温度下反应，TLC跟踪监测。待反应完成，经快速柱层析后，使用1,3,5-三甲氧基苯作为内标，进行1H NMR表征以确定产物的核磁产率和dr值。粗产物通过硅胶柱层析进一步纯化，得到产物的主要非对映异构体及其相应的分离产率。ee值通过液相色谱仪(HPLC)进行手性分析确定。
本发明所述的制备方法中，呋喃烯烃、Togni试剂和芳胺类化合物用量比为0.15mmol:0.15mmol:0.1mmol。
本发明所述的制备方法中，CuCl、Dy(OTf)3、手性布朗斯特酸A1摩尔用量分别为芳胺类化合物的5％、2％、6％。
本发明所述的制备方法中，有机溶剂为三氯甲烷，芳胺类化合物的物质的量与三氯甲烷的体积之比为0.1mmol:2–4mL。
本发明所述的制备方法中，反应在氩气氛围下进行，反应温度为45℃，反应时间为8–36h。
本发明提供的这种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法，其反应条件温和，对映选择性和非对映选择性优良，化学收率高，具有潜在的实际应用价值。
具体实施方式：
本发明的任一实施方案中的监控方法是：薄层层析法。
结构确证技术手段均为本领域技术人员知晓的通用技术手段：核磁共振技术，高分辨质谱。
下面结合实施例将对本发明作进一步的说明，但并不因此而限制本发明。
实施例1
本发明的(4R,5R)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮的合成路线：
Figure GDA0004174695530000031
将反应催化剂CuCl(0.5mg,0.005mmol)、Dy(OTf)3(1.2mg,0.002mmol)和布朗斯特酸A1(5.4mg,0.006mmol)置于反应管中，放入合适大小磁力搅拌子。抽真空干燥，用氩气置换三次，氩气保护下加入4mL三氯甲烷。然后将反应冷却至0℃，再依次加入Togni试剂3a(49.5mg，0.15mmol)、邻氯苯胺(0.10mmol,1.0eq)和2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)。升温至45℃并在此温度下搅拌，用TLC监测反应。待反应完成，经快速柱层析后，使用1,3,5-三甲氧基苯作为内标，进行1H NMR表征以确定产物的核磁产率和dr值。粗产物通过硅胶柱层析进一步纯化(石油醚/乙酸乙酯＝20/1–15/1)，得到(4R,5R)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮，分离收率88％。ee值通过HPLC进行分析确定。
所得结构式1的表征数据：
黄色固体,核磁收率94％,分离收率88％,>20/1dr。HPLC分析得94％ee(FLMChiral NS,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.2min,tr(minor)＝9.7min；[α]D 20＝–117.4(c＝0.83,in CHCl3)；mp＝66–68℃.1H NMR(500MHz,CDCl3)δ7.67–7.59(m,1H),7.31–7.26(m,3H),7.21–7.10(m,2H),7.05–6.99(m,2H),6.85(d,J＝7.3Hz,1H),6.70–6.58(m,2H),5.31(d,J＝10.7Hz,1H),3.85(d,J＝10.4Hz,1H),3.26–3.09(m,2H).13C NMR(126MHz,CDCl3)δ206.8,161.8,141.9,137.5,134.8,129.6,129.0,128.3,128.0,127.5,126.1(q,J＝279.0Hz),120.0,118.5,111.3,59.2(q,J＝2.7Hz),56.5,39.0(q,J＝27.6Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C19H15ClF3NNaO[M+Na]+388.0687,found 388.0681.
实施例2
(4R,5R)-4-((2-氯苯基)氨基)-5-(4-甲苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(2):
Figure GDA0004174695530000041
以2-(1-(对甲苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物2,核磁收率90％,分离收率83％,>20/1dr。HPLC分析得92％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝8.0min，tr(minor)＝6.2min；[α]D 20＝–112.5(c＝0.97,in CHCl3).1H NMR(500MHz,CDCl3)δ7.66–7.56(m,1H),7.20–7.12(m,2H),7.08(d,J＝7.8Hz,2H),6.90(d,J＝8.4Hz,2H),6.85(d,J＝8.2Hz,1H),6.65(t,J＝7.5Hz,1H),6.62–6.57(m,1H),5.27(d,J＝10.4Hz,1H),3.88(d,J＝10.4Hz,1H),3.24–3.05(m,2H),2.30(s,3H).13C NMR(126MHz,CDCl3)δ206.8,161.7,142.0,138.1,134.7,134.4,129.6,129.5,128.0,127.3,126.1(q,J＝278.9Hz),122.8,120.0,118.4,111.4,59.2(q,J＝2.6Hz),56.3,51.6,38.9(q,J＝27.6Hz),20.9.19F NMR(564MHz,CDCl3)δ-58.3(t,J＝10.9Hz).HRMS(ESI)m/z calcd.For C20H17ClF3NNaO[M+Na]+402.0843,found 402.0856.
实施例3
(4R,5R)-5-([1,1'-联苯基)-4-基)-4-((2-氯苯基)氨基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(3):
Figure GDA0004174695530000051
以2-(1-(对甲苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到白色固体的产物3,核磁收率87％,分离收率82％,>20/1dr。HPLC分析得93％ee(FLM Chiral INB,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝42.1min,tr(minor)＝9.9min；[α]D 20＝–29.2(c＝0.97,in CHCl3)；mp＝138–140℃.1H NMR(500MHz,CDCl3)δ7.68–7.62(m,1H),7.52(d,J＝7.5Hz,2H),7.47(d,J＝7.0Hz,2H),7.43(t,J＝7.5Hz,2H),7.35(t,J＝7.5Hz,1H),7.18(t,J＝8.0Hz,1H),7.13(d,J＝7.2Hz,1H),7.06(d,J＝7.1Hz,2H),6.88(d,J＝8.2Hz,1H),6.69–6.63(m,2H),5.35(d,J＝10.6Hz,1H),3.91(d,J＝10.6Hz,1H),3.29–3.11(m,2H).13CNMR(126MHz,CDCl3)δ206.8,161.9,141.9,141.2,140.2,136.5,134.8,129.7,129.4,128.9,128.0,127.9,127.7,127.6,127.2,126.1(q,J＝278.9Hz),120.1,118.6,111.5,59.4(q,J＝2.7Hz),56.5,39.0(q,J＝27.7Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝10.9Hz).HRMS(ESI)m/z calcd.For C25H19ClF3NNaO[M+Na]+464.0999,found 464.1015.
实施例4
(4R,5R)-4-((2-氯苯基)氨基)-5-(4-氟苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(4):
Figure GDA0004174695530000052
以2-(1-(4-氟苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物4,核磁收率84％,分离收率75％,16/1dr。HPLC分析得92％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝210nm),tr(major)＝15.4min,tr(minor)＝8.9min；[α]D 20＝–110.0(c＝0.91,in CHCl3).1H NMR(500MHz,CDCl3)δ7.68–7.61(m,1H),7.21–7.13(m,2H),7.01–6.93(m,4H),6.86(d,J＝8.1Hz,1H),6.68(t,J＝7.8Hz,1H),6.64–6,60(m,1H),5.32(d,J＝10.8Hz,1H),3.80(d,J＝10.7Hz,1H),3.33–2.98(m,2H).13C NMR(126MHz,CDCl3)δ206.5,162.2(d,J＝248.8Hz),161.9,141.7,134.7,133.4(d,J＝3.6Hz),129.7,129.4(d,J＝8.2Hz),128.1,125.9(q,J＝278.7Hz),120.0,118.7,115.8(d,J＝21.6Hz),111.4,59.3(q,J＝2.7Hz),56.1,39.4(q,J＝27.9Hz).19F NMR(564MHz,CDCl3)δ-58.3(t,J＝10.9Hz),-113.4–-114.5(m).HRMS(ESI)m/z calcd.For C19H13ClF4NO[M-H]-382.0627,found382.0625.
实施例5
(4R,5R)-5-(4-氯苯基)-4-((2-氯苯基)氨基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(5):
Figure GDA0004174695530000061
以2-(1-(4-氯苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物5,核磁收率79％,分离收率71％,14/1dr。HPLC分析得91％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝210nm),tr(major)＝13.6min,tr(minor)＝9.2min；[α]D 20＝–69.6(c＝0.81,in CHCl3).1H NMR(500MHz,CDCl3)δ7.68–7.61(m,1H),7.24(d,J＝8.7Hz,1H),7.21–7.14(m,2H),6.93(d,J＝8.8Hz,2H),6.86(d,J＝8.1Hz,1H),6.69(t,J＝7.7Hz,1H),6.64–6.59(m,1H),5.33(d,J＝10.8Hz,1H),3.81(d,J＝10.8Hz,1H),3.24–2.97(m,2H).13C NMR(126MHz,CDCl3)δ206.3,161.9,141.7,136.1,134.7,134.3,129.7,128.9,128.1,125.9(q,J＝279.0Hz),120.1,118.8,111.4,59.4(q,J＝2.7Hz),56.3,39.3(q,J＝28.0Hz).19F NMR(564MHz,CDCl3)δ-58.3(t,J＝10.8Hz).HRMS(ESI)m/z calcd.For C19H14Cl2F3NNaO[M+Na]+422.0297,found 422.0311.
实施例6
(4R,5R)-5-(4-溴苯基)-4-((2-氯苯基)氨基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(6):
Figure GDA0004174695530000071
以2-(1-(4-溴苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物6,核磁收率81％,分离收率70％,13/1dr。HPLC分析得92％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝210nm),tr(major)＝13.4min,tr(minor)＝9.5min；[α]D 20＝–57.3(c＝0.86,in CHCl3).1H NMR(500MHz,CDCl3)δ7.67–7.61(m,1H),7.39(d,J＝6.8Hz,2H),7.22–7.13(m,2H),6.91–6.83(m,3H),6.69(t,J＝7.6Hz,1H),6.64–6.58(m,1H),5.33(d,J＝10.9Hz,1H),3.81(d,J＝10.7Hz,1H),3.24–2.99(m,2H).13C NMR(126MHz,CDCl3)δ206.2,161.9,141.7,136.6,134.8,131.9,129.7,129.2,128.1,125.9(q,J＝278.9Hz),122.5,120.1,118.8,111.4,59.3(q,J＝2.9Hz),56.3,39.2(q,J＝28.1Hz).19F NMR(564MHz,CDCl3)δ-58.3(t,J＝10.8Hz).HRMS(ESI)m/z calcd.For C19H13BrClF3NO[M-H]-441.9827,found441.9806.
实施例7
(4R,5R)-4-((2-氯苯基)氨基)-5-(2,2,2-三氟乙基)-5-(4-(三氟甲基)苯基)环戊-2-烯-1-酮(7):
Figure GDA0004174695530000072
以2-(1-(4-(三氟甲基)苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,反应溶剂的体积由4mL改为2mL，其余操作同实施例1。反应36h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物7,核磁收率50％,分离收率37％,4.6/1dr。HPLC分析得91％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝14.4min,tr(minor)＝9.4min；[α]D 20＝–120.3(c＝0.96,in CHCl3).1H NMR(500MHz,CDCl3)δ7.71–7.66(m,1H),7.50(d,J＝8.0Hz,2H),7.19(t,J＝8.0Hz,1H),7.16–7,08(m,3H),6.87(d,J＝8.1Hz,1H),6.76–6.60(m,2H),5.40(d,J＝11.0Hz,1H),3.76(d,J＝11.0Hz,1H),3.29–2.97(m,2H).13C NMR(126MHz,CDCl3)δ206.1,162.0,141.6,134.9,130.4(q,J＝32.9Hz),129.7,128.0,128.0,126.9,125.6(q,J＝3.7Hz),123.7(q,J＝272.1Hz),123.6(q,J＝279.1Hz),120.1,119.0,111.5,59.6(q,J＝1.9Hz),56.6,39.3(q,J＝27.9Hz).19FNMR(564MHz,CDCl3)δ-58.2(t,J＝10.8Hz),-63.0(s).HRMS(ESI)m/z calcd.ForC20H13ClF6NO[M-H]-432.0595,found 432.0574.
实施例8
(4R,5R)-4-((2-氯苯基)氨基)-5-(3-甲苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(8):
Figure GDA0004174695530000081
以2-(1-(3-甲苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色固体的产物8,核磁收率88％,分离收率81％,>20/1dr。HPLC分析得92％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝9.4min,tr(minor)＝5.9min；[α]D 20＝–143.8(c＝0.87,in CHCl3)；mp＝86–88℃.1H NMR(500MHz,CDCl3)δ7.66–7.59(m,1H),7.20–7.13(m,3H),7.09(d,J＝7.7Hz,1H),6.86(d,J＝8.1Hz,1H),6.82–6.76(m,2H),6.66(t,J＝7.7Hz,1H),6.63–6.59(m,1H),5.30(d,J＝10.4Hz,1H),3.87(d,J＝10.5Hz,1H),3.28–3.04(m,2H),2.23(s,3H).13C NMR(126MHz,CDCl3)δ206.9,161.7,142.0,138.7,137.4,134.7,129.6,129.0,128.8,128.3,128.0,126.1(q,J＝279.0Hz),124.5,122.8,119.9,118.4,111.4,59.2(q,J＝2.6Hz),56.6,39.0(q,J＝27.7Hz),21.5.19F NMR(564MHz,CDCl3)δ-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C20H17ClF3NNaO[M+Na]+402.0843,found402.0840.
实施例9
(4R,5R)-4-((2-氯苯基)氨基)-5-(3-甲氧基苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(9):
Figure GDA0004174695530000091
以2-(1-(3-甲氧基苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝3/1–2/1),得到黄色油状的产物9,核磁收率85％,分离收率75％,13/1dr。HPLC分析得93％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flowrate＝1.0mL/min,l＝254nm),tr(major)＝13.5min,tr(minor)＝9.8min；[α]D 20＝–106.8(c＝0.94,in CHCl3).1H NMR(500MHz,CDCl3)δ7.65–7.60(m,1H),7.23–7.12(m,3H),6.86(d,J＝8.2Hz,1H),6.82(d,J＝8.1Hz,1H),6.66(t,J＝7.7Hz,1H),6.63–6.55(m,2H),6.51(s,1H),5.30(d,J＝10.7Hz,1H),3.94(d,J＝10.6Hz,1H),3.65(s,3H),3.27–3.04(m,2H).13CNMR(126MHz,CDCl3)δ206.4,161.7,159.8,142.1,138.9,134.7,129.9,129.6,128.0,126.1(q,J＝278.8Hz),120.0,119.7,118.4,113.8,113.5,111.3,59.3(q,J＝2.6Hz),56.5,55.2,39.0(q,J＝27.8Hz).19F NMR(564MHz,CDCl3)δ-58.2(s)HRMS(ESI)m/z calcd.ForC20H17ClF3NNaO2[M+Na]+418.0792,found 418.0781.
实施例10
(4R,5R)-4-((2-氯苯基)氨基)-5-(2-氟苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(10):
Figure GDA0004174695530000092
以2-(1-(3-氟苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应36h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物10,核磁收率63％,分离收率55％,13/1dr。HPLC分析得91％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝11.8min,tr(minor)＝8.6min；[α]D 20＝–107.7(c＝0.79,in CHCl3).1H NMR(500MHz,CDCl3)δ7.60–7.55(m,1H),7.23–7.17(m,1H),7.11–6.93(m,5H),6.71(d,J＝8.2Hz,1H),6.57(t,J＝7.7Hz,1H),6.54–6.50(m,1H),5.32(d,J＝10.5Hz,1H),4.15(d,J＝10.5Hz,1H),3.36–3.23(m,1H),3.17–3.04(m,1H).13C NMR(126MHz,CDCl3)δ206.4,160.9(d,J＝246.3Hz),159.3,141.9,134.1,130.1(d,J＝9.1Hz),129.4,128.6(d,J＝3.8Hz),127.6,125.8(q,J＝278.7Hz),124.9(d,J＝12.1Hz),124.2(d,J＝3.1Hz),119.4,118.3,116.7(d,J＝23.4Hz),111.2,60.2(q,J＝2.7Hz),54.0,39.2(q,J＝28.1Hz).19F NMR(564MHz,CDCl3)δ-58.7(t,J＝11.0Hz),-102.5(s).HRMS(ESI)m/zcalcd.For C19H14ClF4NNaO[M+Na]+406.0592,found 406.0586.
实施例11
(4R,5R)-4-((2-氯苯基)氨基)-5-(2-甲氧基苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(11):
Figure GDA0004174695530000101
以2-(1-(2-甲氧基苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝3/1–2/1),得到黄色油状的产物11,核磁收率62％,分离收率57％,>20/1dr。HPLC分析得92％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flowrate＝1.0mL/min,l＝254nm),tr(major)＝11.7min,tr(minor)＝7.4min；[α]D 20＝–29.1(c＝1.00,in CHCl3).1H NMR(500MHz,CDCl3)δ7.50–7.45(m,1H),7.17(t,J＝7.3Hz,1H),7.11–6.91(m,3H),6.80(d,J＝8.3Hz,1H),6.78–6.59(m,2H),6.57–6.43(m,2H),5.26(d,J＝10.8Hz,1H),4.46(br,1H),3.59(s,3H),3.30(br,1H),3.07–2.94(m,1H).13C NMR(126MHz,CDCl3)δ208.2,156.7,142.6,133.8,129.4,129.3,128.0,127.6,126.1(q,J＝278.7Hz),121.0,119.0,117.7,112.2,111.0,60.4,54.8,40.0.19F NMR(564MHz,CDCl3)δ-58.7(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C20H17ClF3NNaO[M+Na]+418.0792,found418.0784.
实施例12
(4R,5R)-4-((2-氯苯基)氨基)-5-(萘-2-基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(12):
Figure GDA0004174695530000111
以2-(1-(萘-2-基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色固体的产物12,核磁收率73％,分离收率68％,>20/1dr。HPLC分析得93％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝10.5min,tr(minor)＝9.3min；[α]D 20＝–74.0(c＝0.80,in CHCl3)；mp＝136–138℃.1H NMR(500MHz,CDCl3)δ7.79(d,J＝7.6Hz,1H),7.74(d,J＝8.4Hz,1H),7.70–7.64(m,2H),7.53–7.43(m,3H),7.09–7.00(m,1H),7.19(t,J＝7.9Hz,1H),7.12(d,J＝8.8Hz,1H),7.06(d,J＝7.4Hz,1H),6.91(d,J＝8.2Hz,1H),6.75–6.54(m,1H),5.40(d,J＝10.4Hz,1H),3.87(d,J＝10.5Hz,1H),3.27(q,J＝11.1Hz,2H).13C NMR(126MHz,CDCl3)δ206.6,161.8,141.9,134.7,134.7,133.0,132.6,129.6,128.6,128.2,128.0,127.5,127.2,126.8,126.7,126.1(q,J＝279.0Hz),124.9,120.1,118.5,111.4,59.4(q,J＝2.5Hz),56.8,39.3(q,J＝27.8Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C23H17ClF3NNaO[M+Na]+438.0843,found 438.0823.
实施例13
(4R,5R)-4-((2-氯苯基)氨基)-5-(噻吩-3-基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(13):
Figure GDA0004174695530000112
以2-(1-(噻吩-3-基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色油状的产物13,核磁收率57％,分离收率44％,5.1/1dr。HPLC分析得92％ee(FLM Chiral NS,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝8.6min,tr(minor)＝10.3min；[α]D 20＝–88.2(c＝0.86,in CHCl3).1H NMR(500MHz,CDCl3)δ7.65–7.59(m,1H),7.30–7.35(m,1H),7.21–7.15(m,2H),6.93(s,1H),6.85(d,J＝8.1Hz,1H),6.77–6.73(m,1H),6.67(t,J＝7.5Hz,1H),6.61–6.56(m,1H),5.26(d,J＝10.3Hz,1H),4.00(d,J＝10.1Hz,1H),3.29–3.12(m,1H),3.11–2.96(m,1H).13C NMR(126MHz,CDCl3)δ204.9,161.4,142.0,137.6,133.9,129.7,128.0,127.0,126.2,125.8(q,J＝278.8Hz),123.2,120.1,118.6,111.4,58.9(q,J＝2.5Hz),54.6,38.8(q,J＝28.1Hz).19F NMR(564MHz,CDCl3)δ-58.6(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C17H14ClF3NOS[M+H]+372.0431,found 372.0432.
实施例14
(4S,5R)-3-(溴)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(15):
Figure GDA0004174695530000121
以4-溴-2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应36h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝30/1–20/1),得到黄色固体的产物15,核磁收率52％,分离收率41％,4.4/1dr。HPLC分析得48％ee(FLM Chiral NS,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝5.4min,tr(minor)＝8.8min；[α]D 20＝–80.0(c＝0.72,in CHCl3)；mp＝160–162℃.1H NMR(500MHz,CDCl3)δ7.36–7.30(m,3H),7.21–7.14(m,2H),7.08–7.01(m,2H),6.91(d,J＝8.2Hz,1H),6.85(s,1H),6.68(t,J＝7.6Hz,1H),5.40(d,J＝10.8Hz,1H),3.93(d,J＝10.8Hz,1H),3.30–3.02(m,2H).13C NMR(126MHz,CDCl3)δ202.0,162.7,142.0,136.7,136.1,129.6,129.2,128.6,127.9,127.4,125.9(q,J＝279.0Hz),119.8,118.8,111.4,63.8(q,J＝2.7Hz),58.8,38.6(q,J＝28.1Hz).19F NMR(377MHz,CDCl3)δ-58.2(t,J＝10.9Hz).HRMS(ESI)m/z calcd.For C19H14BrClF3NNaO[M+Na]+465.9792,found 465.9792.
实施例15
(4R,5R)-2-(溴)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(15):
Figure GDA0004174695530000131
以3-溴-2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝30/1–20/1),得到黄色固体的产物15,核磁收率59％,分离收率36％,2.1/1dr。HPLC分析得50％ee(FLM Chiral NS,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝5.1min,tr(minor)＝5.7min；[α]D 20＝–76.9(c＝0.85,in CHCl3)；mp＝116–118℃.1H NMR(500MHz,CDCl3)δ7.72(s,1H),7.35–6.30(m,3H),7.20–6.13(m,2H),7.02–6.97(m,2H),6.82(d,J＝8.2Hz,1H),6.69(t,J＝7.7Hz,1H),5.23(d,J＝10.5Hz,1H),3.83(d,J＝10.6Hz,1H),3.31–3.12(m,2H).13C NMR(126MHz,CDCl3)δ199.6,158.8,141.4,136.8,129.7,129.2,128.7,128.1,127.4,125.8(q,J＝278.7Hz),120.2,118.9,111.4,58.5(q,J＝2.9Hz),56.2,39.1(q,J＝28.2Hz).19F NMR(377MHz,CDCl3)δ-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C19H14BrClF3NNaO[M+Na]+465.9792,found465.9795.
实施例16
(4R,5R)-4-((2-溴苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(16):
Figure GDA0004174695530000132
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-溴苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到白色固体的产物16,核磁收率87％,分离收率81％,>20/1dr。HPLC分析得94％ee(FLM Chiral INB,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝12.6min,tr(minor)＝8.0min；[α]D 20＝–169.1(c＝0.89,in CHCl3)；mp＝89–91℃.1H NMR(500MHz,CDCl3)δ7.66–7.61(m,1H),7.34–7.26(m,4H),7.21(t,J＝7.8Hz,1H),7.07–7.01(m,2H),6.82(d,J＝8.1Hz,1H),6.67–6.55(m,2H),5.29(d,J＝9.1Hz,1H),3.87(d,J＝10.3Hz,1H),3.26–3.09(m,2H).13C NMR(126MHz,CDCl3)δ206.7,161.7,142.8,137.5,134.8,132.9,129.1,128.7,128.3,127.5,126.1(q,J＝279.0Hz),119.0,111.3,110.5,59.3(q,J＝2.6Hz),56.4,38.9(q,J＝27.8Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝10.9Hz).HRMS(ESI)m/z calcd.For C19H15BrF3NNaO[M+Na]+432.0181,found 432.0195.
实施例17
(4R,5R)-4-((2-氟苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(17):
Figure GDA0004174695530000141
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-氟苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝3/1–2/1),得到白色固体的产物17,核磁收率87％,分离收率79％,17/1dr。HPLC分析得90％ee(Chiralcel AD-H,hexane/i-PrOH＝95/5,flow rate＝1.0mL/min,l＝254nm),tr(major)＝7.3min,tr(minor)＝9.6min；[α]D 20＝–8.3(c＝0.68,inCHCl3)；mp＝127–129℃.1H NMR(500MHz,CDCl3)δ7.64–7.60(m,1H),7.26(d,J＝7.1Hz,3H),7.05–6.96(m,3H),6.91–6.78(m,2H),6.69–6.63(m,1H),6.62–6.57(m,1H),5.29(d,J＝10.8Hz,1H),3.40(d,J＝11.0Hz,1H),3.25–3.04(m,2H).13C NMR(126MHz,CDCl3)δ207.0,162.2,151.8(d,J＝239.5Hz),137.8,134.9,134.7(d,J＝11.3Hz),128.9,128.3,127.6,126.3(q,J＝278.8Hz),124.9(d,J＝3.6Hz),118.4(d,J＝7.0Hz),115.2,115.1,112.8(d,J＝2.8Hz),59.8(q,J＝2.8Hz),56.9,39.3(q,J＝27.9Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝10.9Hz),-135.76–-153.9(m).HRMS(ESI)m/z calcd.For C19H15F4NNaO[M+Na]+372.0982,found 372.0995.
实施例18
(4R,5R)-5-苯基-5-(2,2,2-三氟乙基)-4-((2-(三氟甲基)苯基)氨基)环戊-2-烯-1-酮(18):
Figure GDA0004174695530000151
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-(三氟甲基)苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1–15/1),得到黄色固体的产物18,核磁收率81％,分离收率78％,>20/1dr。HPLC分析得95％ee(FLM Chiral NS,hexane/i-PrOH＝90/10,flowrate＝1.0mL/min,l＝254nm),tr(major)＝4.8min,tr(minor)＝7.1min；[α]D 20＝–101.8(c＝0.94,in CHCl3)；mp＝71–73℃.1H NMR(500MHz,CDCl3)δ7.70–7.62(m,1H),7.42(t,J＝8.0Hz,1H),7.36(d,J＝8.0Hz,1H),7.33–7.29(m,3H),7.13–7.01(m,2H),6.91(d,J＝8.4Hz,1H),6.77(t,J＝7.7Hz,1H),6.66–6.63(m,1H),5.30(d,J＝9.6Hz,1H),3.78(d,J＝9.6Hz,1H),3.21(q,J＝11.3,10.9Hz,2H).13C NMR(126MHz,CDCl3)δ206.5,161.2,143.4,137.2,134.9,133.4,129.0,128.4,127.3,127.2(q,J＝6.0Hz),126.5(q,J＝272.9Hz),126.1(q,J＝277.2Hz),117.3,114.3(q,J＝29.3Hz),111.6,59.0(q,J＝2.9Hz),56.2,38.6(q,J＝27.7Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝11.0Hz),-62.9(s).HRMS(ESI)m/zcalcd.For C20H14F6NO[M-H]-398.0985,found 398.0976.
实施例19
(4R,5R)-4-((2-乙酰基苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(19):
Figure GDA0004174695530000152
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、1-(2-氨基苯基)乙烷-1-酮(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1–8/1),得到黄色油状的产物19,核磁收率81％,分离收率76％,3.6/1dr。HPLC分析得94％ee(FLM Chiral NS,hexane/i-PrOH＝80/20,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.0min,tr(minor)＝10.3min；[α]D 20＝–409.6(c＝0.95,in CHCl3).1H NMR(500MHz,CDCl3)δ8.41(d,J＝9.3Hz,1H),7.67–7.57(m,2H),7.41–7.37(m,1H),7.21–7.16(m,3H),6.99–6.89(m,3H),6.69–6.58(m,2H),5.44(d,J＝10.1Hz,1H),3.25–3.12(m,2H),2.61(s,0.82H),2.34(s,3H).13C NMR(126MHz,CDCl3)δ207.0,200.2,161.8,149.2,137.9,135.1,134.8,132.9,128.5,127.7,127.5,126.2(q,J＝278.7Hz),118.8,115.6,111.7,59.4(q,J＝2.6Hz),56.7,39.3(q,J＝27.9Hz),27.8.19F NMR(377MHz,CDCl3)δ-58.2(t,J＝11.1Hz).HRMS(ESI)m/z calcd.ForC21H18F3NNaO2[M+Na]+396.1182,found 396.1164.
实施例20
(4R,5R)-4-((2-苯甲酰基苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(20):
Figure GDA0004174695530000161
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、(2-氨基苯基)(苯基)甲酮(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,反应条件的温度由45℃改为35℃，其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1–8/1),得到黄色油状的产物20,核磁收率95％,分离收率83％,10/1dr。HPLC分析得93％ee(Chiralcel AD-H,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝11.0min,tr(minor)＝6.7min；[α]D 20＝–444.9(c＝0.94,in CHCl3).1H NMR(500MHz,CDCl3)δ8.07(d,J＝10.1Hz,1H),7.72–7.67(m,1H),7.50–7.45(m,1H),7.44–7.36(m,5H),7.33(d,J＝8.0Hz,1H),7.12(t,J＝7.6Hz,2H),7.07(t,J＝7.6Hz,1H),7.02–6.94(m,3H),6.66–6.60(m,1H),6.57(t,J＝7.5Hz,1H),5.51(d,J＝10.1Hz,1H),3.22(q,J＝11.2Hz,2H).13C NMR(126MHz,CDCl3)δ207.4,198.8,162.1,150.0,140.1,138.1,135.9,135.3,135.2,131.2,129.3,128.7,128.2,128.1,127.7,126.5(q,J＝278.7Hz),118.6,115.5,111.8,59.6(q,J＝2.7Hz),57.0,39.6(q,J＝27.6Hz).19F NMR(564MHz,CDCl3)δ-58.3(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C26H20F3NNaO2[M+Na]+458.1338,found 458.1316.
实施例21
甲基2-(((1R,5R)-4-氧代-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-基)氨基)苯甲酸甲酯(21):
Figure GDA0004174695530000171
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-氨基苯甲酸甲酯(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝2/1–1/1),得到黄色油状的产物21,核磁收率92％,分离收率88％,6.2/1dr。HPLC分析得89％ee(FLM Chiral INB,hexane/i-PrOH＝90/10,flowrate＝1.0mL/min,l＝254nm),tr(major)＝9.8min,tr(minor)＝＝7.6min；[α]D 20＝–284.6(c＝0.95,in CHCl3).1H NMR(500MHz,CDCl3)δ7.76(d,J＝8.0Hz,1H),7.67–7.63(m,1H),7.39(t,J＝8.1Hz,1H),7.29–7.25(m,1H),7.19–7.13(m,3H),6.97–6.89(m,3H),6.67–6.58(m,2H),5.45(d,J＝8.0Hz,1H),3.88(s,0.48H),3.61(s,3H),3.27–3.08(m,2H).13C NMR(126MHz,CDCl3)δ207.8,168.6,162.7,149.9,138.7,135.4,135.3,132.6,129.7,129.1,128.2,126.8(q,J＝278.7Hz),116.8,112.1,67.0,60.2,57.5,52.0,40.1(q,J＝27.6Hz).19F NMR(377MHz,CDCl3)-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C21H18F3NNaO3[M+Na]+412.1131,found 412.1112.
实施例22
(4R,5R)-4-((3-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(22):
Figure GDA0004174695530000172
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、3-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1–8/1),得到白色固体的产物22,核磁收率85％,分离收率71％,6.7/1dr。HPLC分析得83％ee(Chiralcel AD-H,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.8min,tr(minor)＝18.6min；[α]D 20＝–20.8(c＝0.86,in CHCl3)；mp＝121–123℃.1H NMR(500MHz,CDCl3)δ7.60(dd,J＝5.8,2.5Hz,1H),7.32–7.28(m,3H),7.08–6.96(m,3H),6.71(d,J＝7.9Hz,1H),6.59(dd,J＝5.7,2.4Hz,1H),6.39(s,1H),6.32(d,J＝7.7Hz,1H),5.24(d,J＝10.4Hz,1H),3.31–3.00(m,3H).13C NMR(126MHz,CDCl3)δ206.6,161.9,147.1,137.6,135.3,134.7,130.5,128.8,128.2,127.7,126.0(q,J＝278.7Hz),118.8,113.6,111.5,59.9(q,J＝2.7Hz),56.6,39.1(q,J＝27.8Hz).19F NMR(564MHz,CDCl3)δ-58.2(t,J＝10.9Hz).HRMS(ESI)m/z calcd.ForC19H14ClF3NO[M-H]-364.0722,found 364.0714.
实施例23
(4R,5R)-4-((4-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(23):
Figure GDA0004174695530000181
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、4-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1–5/1),得到白色固体的产物23,核磁收率78％,分离收率59％,3.8/1dr。HPLC分析得83％ee(FLM Chiral INB,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝13.2min,tr(minor)＝15.5min；[α]D 20＝11.9(c＝0.71,in CHCl3)；mp＝149–151℃.1H NMR(500MHz,CDCl3)δ7.63–7.58(m,1H),7.28(s,3H),7.07(d,J＝8.9Hz,2H),7.02–6.96(m,2H),6.61–6.55(m,1H),6.34(d,J＝9.0Hz,2H),5.23(d,J＝11.1Hz,1H),3.23–3.01(m,3H).13C NMR(126MHz,CDCl3)δ206.9,162.4,144.8,138.0,135.0,129.6,129.0,128.4,127.9,126.3(q,J＝278.9Hz),123.7,115.0,60.5(q,J＝2.5Hz),57.0,39.4(q,J＝27.9Hz).19F NMR(377MHz,CDCl3)δ-58.2(t,J＝10.9Hz).HRMS(ESI)m/z calcd.For C19H14ClF3NO[M-H]-364.0722,found 364.0715.
实施例24
(4R,5R)-4-((4-溴苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(24):
Figure GDA0004174695530000182
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、4-溴苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应24h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1–5/1),得到白色固体的产物24,核磁收率80％,分离收率63％,5/1dr。HPLC分析得80％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝10.0min,tr(minor)＝13.7min；[α]D 20＝22.4(c＝0.75,inCHCl3)；mp＝130–132℃.1H NMR(500MHz,CDCl3)δ7.63–7.56(m,1H),7.30–7.25(m,3H),7.21(d,J＝6.7Hz,2H),7.08–6.97(m,2H),6.62–6.54(m,1H),6.30(d,J＝8.8Hz,2H),5.22(d,J＝10.9Hz,1H),3.27–2.97(m,3H).13C NMR(126MHz,CDCl3)δ206.6,162.1,145.0,137.7,134.7,132.3,128.8,128.2,127.7,126.0(q,J＝278.8Hz),115.2,110.5,60.1(d,J＝2.7Hz),56.7,39.1(q,J＝27.7Hz).19F NMR(377MHz,CDCl3)δ-58.2(t,J＝11.0Hz).HRMS(ESI)m/z calcd.For C19H15BrF3NNaO[M+Na]+432.0181,found 432.0195
实施例25
(4R,5R)-5-苯基-5-(2,2,2-三氟乙基)-4-((4-(三氟甲基)苯基)氨基)环戊-2-烯-1-酮(25):
Figure GDA0004174695530000191
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、4-(三氟甲基)苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1–5/1),得到白色固体的产物25,核磁收率79％,分离收率68％,13/1dr。HPLC分析得88％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flowrate＝1.0mL/min,l＝254nm),tr(major)＝9.1min,tr(minor)＝10.4min；[α]D 20＝–12.8(c＝0.92,in CHCl3)；mp＝111–113℃.1H NMR(500MHz,CDCl3)δ7.68–7.57(m,1H),7.37(d,J＝7.1Hz,2H),7.29(s,3H),7.06–6.93(m,2H),6.66–6.58(m,1H),6.46(d,J＝7.1Hz,2H),5.33(d,J＝10.9Hz,1H),3.37(d,J＝10.8Hz,1H),3.30–3.03(m,2H).13C NMR(126MHz,CDCl3)δ206.4,161.6,148.6,137.6,134.9,128.9,128.3,127.7,126.9(q,J＝3.8Hz),126.0(q,J＝279.7Hz),124.6(q,J＝271.0Hz),120.5(q,J＝32.9Hz),112.6,59.5(q,J＝2.3Hz),56.7,39.2(q,J＝28.0Hz).19F NMR(564MHz,CDCl3)δ-58.3(t,J＝10.8Hz),-61.4(s).HRMS(ESI)m/z calcd.For C20H14F6NO[M-H]-398.0985,found 398.0980.
实施例26
4-(((1R,5R)-4-氧代-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-基)氨基)苯基三氟甲基磺酸酯(26):
Figure GDA0004174695530000201
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、4-氨基苯基三氟甲磺酸盐(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应8h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝1/2–1/3),得到黄色油状的产物26,核磁收率66％,分离收率54％,6.7/1dr。HPLC分析得85％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝9.7min,tr(minor)＝10.8min；[α]D 20＝–5.6(c＝0.77,in CHCl3).1H NMR(500MHz,CDCl3)δ7.63–7.56(m,1H),7.29-7.27(m,3H),7.03(d,J＝9.1Hz,2H),6.99(d,J＝6.7Hz,2H),6.64–6.59(m,1H),6.40(d,J＝9.1Hz,2H),5.24(d,J＝10.8Hz,1H),3.25(d,J＝11.2Hz,1H),3.22–3.04(m,2H).13C NMR(126MHz,CDCl3)δ206.4,161.5,145.8,141.6,137.5,135.0,128.8,128.3,127.7,126.0(q,J＝278.7Hz),122.5,118.8(q,J＝322.7Hz),113.9,60.0(q,J＝1.9Hz),56.6,39.2(q,J＝27.9Hz).19F NMR(377MHz,CDCl3)δ-58.2(t,J＝10.9Hz),-72.8(s).HRMS(ESI)m/zcalcd.For C20H15F6NNaO4[M+Na]+502.0518,found 502.0528.
实施例27
(4R,5R)-4-((2-(1H-吡咯-1-基)苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(27):
Figure GDA0004174695530000202
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、2-(1H-吡咯-1-基)苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/三氯甲烷＝3/1–2/1),得到棕色油状的产物27,核磁收率34％,分离收率28％,>20/1dr。HPLC分析得93％ee(FLM Chiral NS,hexane/i-PrOH＝80/20,flowrate＝1.0mL/min,l＝254nm),tr(major)＝5.3min,tr(minor)＝10.2min；[α]D 20＝–108.7(c＝0.73,in CHCl3).1H NMR(500MHz,CDCl3)δ7.54–7.49(m,1H),7.28–7.22(m,2H),7.21–7.17(m,2H),7.01(d,J＝7.7Hz,1H),6.90(t,J＝7.3Hz,3H),6.75(t,J＝7.6Hz,1H),6.54–6.50(m,1H),6.13(s,2H),6.05(s,2H),5.27(d,J＝10.5Hz,1H),3.42(d,J＝10.4Hz,1H),3.23–3.11(m,2H).13C NMR(126MHz,CDCl3)δ206.8,161.7,141.4,137.8,134.7,129.0,128.9,128.0,127.7,127.7,127.2,126.1(q,J＝278.8Hz),121.3,117.7,110.8,109.4,59.1(q,J＝2.7Hz),56.4,39.1(q,J＝27.9Hz).19F NMR(377MHz,CDCl3)δ-58.1(t,J＝11.1Hz).HRMS(ESI)m/z calcd.For C23H19F3N2NaO[M+Na]+419.1342,found 419.1351.
实施例28
(4R,5R)-4-(甲基(4-(三氟甲基)苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(28):
Figure GDA0004174695530000211
以2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)、N-甲基-4-(三氟甲基)苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝15/1–10/1),得到黄色油状的产物28,核磁收率83％,分离收率76％,>20/1dr。HPLC分析得72％ee(Chiralcel OD,hexane/i-PrOH＝98/2,flow rate＝1.0mL/min,l＝254nm),tr(major)＝8.4min,tr(minor)＝10.5min；[α]D 20＝70.0(c＝0.86,in CHCl3).1H NMR(500MHz,CDCl3)δ7.57–7.50(m,3H),7.25–7.14(m,3H),6.94(d,J＝7.6Hz,2H),6.77(d,J＝8.3Hz,2H),6.68–6.63(m,1H),5.76(s,1H),3.23–3.05(m,2H),1.85(s,3H).13C NMR(126MHz,CDCl3)δ205.0,159.6,149.2,135.9,133.2,126.9,126.5,126.2,125.3(q,J＝3.7Hz),126.3(q,J＝279.7Hz),123.2(q,J＝270.9Hz),117.3(q,J＝32.7Hz),109.2,63.5(q,J＝1.9Hz),55.5,40.3(q,J＝27.5Hz),31.8.19F NMR(564MHz,CDCl3)δ-58.2(t,J＝11.0Hz),-61.1(s).HRMS(ESI)m/z calcd.For C21H16F6NO[M-H]-412.1142,found 412.1139.
实施例29
(4R,5R)-4-((2-氯苯基)氨基)-5-(4-(((3aR,5R,6S,6aR)-5-((R)-2,2-二甲基-1,3-二氧杂戊环-4-基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]二氧杂环戊烯-6-基)氧)苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(29):
Figure GDA0004174695530000221
以(3aR,5R,6S,6aR)-5-((R)-2,2-二甲基-1,3-二氧杂戊环-4-基)-6-(4-(1-(呋喃-2-基)乙烯基))苯氧基)-2,2-二甲基四氢呋喃并[2,3-d][1,3]二氧杂环戊烯(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1–5/1),得到白色固体的产物29,核磁收率72％,分离收率70％,>20/1syn:anti。HPLC分析得93％de(Chiralcel AD-H,hexane/i-PrOH＝80/20,flow rate＝1.0mL/min,l＝254nm),tr(major)＝7.5min,tr(minor)＝5.4min；[α]D 20＝–49.7(c＝0.99,in CHCl3)；mp＝67–69℃.1H NMR(500MHz,CDCl3)δ7.65–7.60(m,1H),7.20–7.11(m,2H),6.95(d,J＝9.0Hz,2H),6.91–6.82(m,3H),6.67(t,J＝7.7Hz,1H),6.63–6.58(m,1H),5.94–5.90(m,1H),5.28(d,J＝10.5Hz,1H),4.68(s,1H),4.52–4.48(m,1H),4.42(q,J＝7.0,6.4Hz,1H),4.33–4.27(m,1H),4.16–4.02(m,2H),3.86(d,J＝10.6Hz,1H),3.26–3.00(m,2H),1.54(s,3H),1.43(s,3H),1.31(s,6H).13C NMR(126MHz,CDCl3)δ206.7,161.7,156.6,141.9,134.7,130.7,129.6,128.9,128.1,126.0(q,J＝278.8Hz),119.9,118.6,115.9,112.2,111.5,109.2,105.3,82.2,80.4,80.2,72.3,67.1,59.4(q,J＝2.7Hz),56.0,39.2(q,J＝27.8Hz),26.9,26.7,26.2,25.3.19F NMR(377MHz,CDCl3)δ-58.3(t,J＝10.8Hz).HRMS(ESI)m/z calcd.ForC31H33ClF3NNaO7[M+Na]+646.1790,found 646.1791.
实施例30
(4R,5S)-4-(2-氯苯基)-5-(4-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)苯基)-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(30):
Figure GDA0004174695530000231
以2-(1-(4-(((1R,2S,5R)-2-异丙基-5-甲基环己基)氧基)苯基)乙烯基)呋喃(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝50/1–30/1),得到黄色油状的产物30,核磁收率71％,分离收率66％,>20/1syn:anti。HPLC分析得92％de(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.0min,tr(minor)＝5.2min；[α]D 20＝–101.9(c＝0.90,in CHCl3).1H NMR(500MHz,CDCl3)δ7.63–7.56(m,1H),7.19–7.11(m,2H),6.90(d,J＝9.2Hz,2H),6.84(d,J＝8.2Hz,1H),6.78(d,J＝8.9Hz,2H),6.65(t,J＝7.8Hz,1H),6.59(d,J＝5.8Hz,1H),5.25(d,J＝10.3Hz,1H),4.03–3.94(m,1H),3.88(d,J＝10.2Hz,1H),3.23–3.00(m,2H),2.18–2.11(m,1H),2.07(d,J＝12.7Hz,1H),1.71(d,J＝10.6Hz,2H),1.53–1.40(m,2H),1.14–0.94(m,3H),0.91(d,J＝6.7Hz,6H),0.75(d,J＝6.9Hz,3H).13C NMR(126MHz,CDCl3)δ206.9,161.6,158.1,142.0,134.7,129.6,129.0,128.7,128.0,126.1(q,J＝278.7Hz),120.0,118.4,116.0,111.4,59.2(q,J＝2.5Hz),56.0,48.0,40.1,39.1(q,J＝27.6Hz),34.5,31.4,29.7,26.3,23.9,22.1,20.6,16.7.19F NMR(377MHz,CDCl3)δ-58.3(t,J＝11.0Hz).HRMS(ESI)m/zcalcd.For C29H33ClF3NNaO2[M+Na]+542.2044,found 542.2037.
实施例31
4-((1R,2R)-2-((2-氯苯基)氨基)-5-氧代-1-(2,2,2-三氟乙基)环戊-3-烯-1-基)苄基(S)-2-(6-甲氧基萘-2-基)丙酸酯(31):
Figure GDA0004174695530000232
以4-(1-(呋喃-2-基)乙烯基)苄基(S)-2-(6-甲氧基萘-2-基)丙酸酯(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝7/1–5/1),得到白色固体的产物31,核磁收率83％,分离收率74％,15/1syn:anti。HPLC分析得93％de(ChiralcelAD-H,hexane/i-PrOH＝70/30,flow rate＝1.0mL/min,l＝254nm),tr(major)＝9.7min,tr(minor)＝7.8min；[α]D 20＝–52.2(c＝0.87,in CHCl3)；mp＝43–45℃.1H NMR(500MHz,CDCl3)δ7.69–7.61(m,3H),7.60–7.56(m,1H),7.38(d,J＝8.5Hz,1H),7.16–7.06(m,6H),6.88(d,J＝6.4Hz,2H),6.82(d,J＝8.2Hz,1H),6.63(t,J＝7.7Hz,1H),6.57(d,J＝5.8Hz,1H),5.27(d,J＝10.6Hz,1H),5.08–4.99(m,2H),3.91–3.86(m,4H),3.75(d,J＝10.5Hz,1H),3.22–2.98(m,2H),1.57(d,J＝7.3Hz,3H).13C NMR(126MHz,CDCl3)δ206.5,174.3,161.8,157.7,141.8,137.4,136.2,135.5,134.7,133.8,129.6,129.3,129.0,128.4,128.0,127.8,127.6,126.4,126.1(q,J＝278.9Hz),126.0,120.1,119.0,118.6,111.4,105.7,65.6,59.3(q,J＝2.6Hz),56.4,55.3,45.5,39.0(q,J＝28.0Hz),18.4.19F NMR(377MHz,CDCl3)δ-58.1(t,J＝10.8Hz).HRMS(ESI)m/z calcd.For C34H29ClF3NNaO4[M+Na]+630.1629,found 630.1625.
实施例32
4-((1R,2R)-2-((2-氯苯基)氨基)-5-氧代-1-(2,2,2-三氟乙基)环戊-3-烯-1-基)苄基2-(11-氧代-6,11-二氢二苯并[b,e]氧杂卓-2-基)乙酸酯(32):
Figure GDA0004174695530000241
以4-(1-(呋喃-2-基)乙烯基)苄基2-(11-氧代-6,11-二氢二苯并[b,e]氧杂卓-2-基)乙酸酯(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1–3/1),得到白色固体的产物32,核磁收率89％,分离收率81％,18/1dr。HPLC分析得92％ee(Chiralcel AD-H,hexane/i-PrOH＝70/30,flow rate＝1.0mL/min,l＝254nm),tr(major)＝23.1min,tr(minor)＝18.9min；[α]D 20＝–46.0(c＝0.95,in CHCl3)；mp＝57–59℃.1H NMR(500MHz,CDCl3)δ8.12(s,1H),7.87(d,J＝7.7Hz,1H),7.64–7.59(m,1H),7.54(t,J＝7.5Hz,1H),7.45(t,J＝7.7Hz,1H),7.40(d,J＝8.5Hz,1H),7.34(d,J＝7.5Hz,1H),7.23(d,J＝7.9Hz,2H),7.15(t,J＝7.9Hz,1H),7.11(d,J＝7.9Hz,1H),7.04–6.94(m,3H),6.84(d,J＝8.2Hz,1H),6.65(t,J＝7.7Hz,1H),6.62–6.57(m,1H),5.30(d,J＝10.5Hz,1H),5.16(s,2H),5.08(s,2H),3.80(d,J＝10.5Hz,1H),3.67(s,2H),3.25–3.03(m,2H).13C NMR(126MHz,CDCl3)δ206.5,190.8,171.1,161.8,160.5,141.8,140.5,137.6,136.4,135.9,135.6,134.8,132.8,132.5,129.6,129.5,129.3,128.7,128.0,127.9,127.7,127.6,126.1(q,J＝279.0Hz),125.2,121.1,120.1,118.6,111.4,73.7,65.9,59.4(q,J＝2.6Hz),56.5,40.2,39.0(q,J＝27.8Hz).19F NMR(377MHz,CDCl3)δ-58.1(t,J＝10.9Hz).HRMS(ESI)m/zcalcd.For C36H27ClF3NNaO5[M+Na]+668.1422,found 668.1414.
实施例33
(8R,9S,13S,14S)-3-((4-((1R,2R)-2-((2-氯苯基)氨基)-5-氧代-1-(2,2,2-三氟乙基)环戊-3-烯-1-基)苄基)氧基-13-甲基-6,7,8,9,11,12,13,14,15,16-十氢-17H-环戊二烯并[a]菲-17-酮(33):
Figure GDA0004174695530000251
以(8R,9S,13S,14S)-3-((4-(1-(呋喃-2-基)乙烯基)苯基)氧基)-13-甲基-6,7,8,9,11,12,13,14,15,16-十氢-17H-环戊二烯并[a]菲-17-酮(0.15mmol,1.5eq)、2-氯苯胺(0.1mmol,1.0eq)和Togni试剂3a(49.5mg,0.15mmol)为反应原料,其余操作同实施例1。反应12h后,经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1–3/1),得到白色固体的产物33,核磁收率95％,分离收率82％,8.4/1syn:anti。HPLC分析得93％de(Chiralcel AD-H,hexane/i-PrOH＝70/30,flow rate＝1.0mL/min,l＝254nm),tr(major)＝11.1min,tr(minor)＝8.8min；[α]D 20＝35.2(c＝0.87,in CHCl3)；mp＝87–89℃.1H NMR(500MHz,CDCl3)δ7.64–7.59(m,1H),7.32(d,J＝7.8Hz,2H),7.17(t,J＝8.1Hz,2H),7.12(d,J＝7.9Hz,1H),7.02(d,J＝8.5Hz,2H),6.85(d,J＝8.2Hz,1H),6.73(d,J＝8.7Hz,1H),6.68–6.63(m,2H),6.63–6.58(m,1H),5.30(d,J＝10.5Hz,1H),5.01(s,2H),3.83(d,J＝10.5Hz,1H),3.25–3.07(m,2H),2.91–2.84(m,2H),2.49(dd,J＝19.1,8.7Hz,1H),2.42–2.34(m,1H),2.28–2.21(m,1H),2.18–1.92(m,4H),1.67–1.36(m,6H),0.90(s,3H).13C NMR(126MHz,CDCl3)δ206.5,161.8,156.6,141.9,137.9,137.7,137.0,134.7,132.5,129.6,128.0,127.7,127.6,126.4,126.1(q,J＝278.8Hz),120.0,118.5,115.0,112.5,111.4,69.1,59.3(q,J＝2.1Hz),56.4,50.5,48.0,44.0,39.0(q,J＝27.8Hz),38.4,35.9,31.6,29.7,26.6,26.0,21.6,13.9.19F NMR(377MHz,CDCl3)δ-58.1(t,J＝11.0Hz).HRMS(ESI)m/z calcd.ForC38H37ClF3NNaO3[M+Na]+670.2306,found 670.2284.
本发明的扩大量实验
(4R,5R)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(1)的合成路线：
Figure GDA0004174695530000261
将反应催化剂CuCl(14.9mg,0.15mmol)、Dy(OTf)3(36.6mg,0.06mmol)和布朗斯特酸A1(160.6mg,0.18mmol)置于反应瓶中，放入合适大小磁力搅拌子。抽真空干燥，用氩气置换三次，氩气保护下加入120mL三氯甲烷并在室温下搅拌5min。然后将反应冷却至0℃，再依次加入Togni试剂3a(49.5mg，0.15mmol)、邻氯苯胺(0.10mmol,1.0eq)和2-(1-苯基乙烯基)呋喃(0.15mmol,1.5eq)。升温至45℃并在此温度下搅拌24h，用TLC监测反应。待反应完成后，浓缩反应液，通过硅胶柱层析分离(石油醚/乙酸乙酯＝20/1–15/1),得到1.02g的产物(4R,5R)-4-((2-氯苯基)氨基)-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-酮(>20/1dr,94％ee)，分离收率93％。
(2R,3R)-2-苯基-3-(苯氨基)-2-(2,2,2-三氟乙基)环戊-1-酮(34)的合成路线：
Figure GDA0004174695530000262
向反应管中加入4-(((1R,5R)-4-氧代-5-苯基-5-(2,2,2-三氟乙基)环戊-2-烯-1-基)氨基)苯基三氟甲基磺酸酯(47.9mg,0.10mmol,85％ee,1.0eq),镁粉(24mg,1.00mmol,10.0eq),10％ Pd/C(64mg),醋酸铵(240mg,3.2mmol,3.2eq)和甲醇(3mL)。在室温下搅拌5h后,反应混合物经硅藻土过滤,乙酸乙酯淋洗,滤液减压浓缩得到粗产品经柱层析(石油醚/乙酸乙酯＝15/1–10/1)分离得产物(2R,3R)-2-苯基-3-(苯氨基)-2-(2,2,2-三氟乙基)环戊-1-酮(34)。dr值通过1H NMR分析确定。ee值通过HPLC进行分析确定。
所得结构式34的表征数据：
黄色油状,产率88％,>20/1dr。HPLC分析得85％ee(Chiralcel AD-H,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.1min,tr(minor)＝5.1min；[α]D 20＝58.9(c＝0.70,in CHCl3).1H NMR(500MHz,CDCl3)δ7.43–7.34(m,3H),7.18(t,J＝7.5Hz,2H),7.13(d,J＝7.4Hz,2H),6.75(t,J＝7.4Hz,1H),6.63(d,J＝7.9Hz,2H),4.53–4.45(m,1H),3.05–2.90(m,3H),2.71–2.63(m,1H),2.58–2.48(m,1H),2.47–2.39(m,1H),1.55–1.45(m,1H).13C NMR(126MHz,CDCl3)δ217.1,146.5,136.2,129.7,129.1,128.4,128.2,126.0(q,J＝279.1Hz),118.8,114.1,57.2,56.7,38.7(q,J＝27.9Hz),37.7,26.6.19F NMR(377MHz,CDCl3)δ-57.7(t,J＝11.0Hz).HRMS(ESI)m/z calcd.ForC18H18F3NNaO[M+Na]+356.1233,found 356.1236.
(4aS,5R,7aR)-1-(苄氧基)-3,3-二甲基-5-苯基-5-(2,2,2-三氟乙基)-4-(4-(三氟甲基)苯基)六氢-1H-环戊二烯并[b]吡嗪-2,6-二酮(35)的合成路线：
Figure GDA0004174695530000271
向干燥的反应试管中依次加入(4R,5R)-5-苯基-5-(2,2,2-三氟乙基)-4-((4-(三氟甲基)苯基)氨基)环戊-2-烯-1-酮(25,39.9mg,0.1mmol,88％ee,1.0eq),N-(苄氧基)-2-溴-2-甲基丙酰胺(54mg,0.2mmol,2.0eq)和碳酸钠(32mg,0.3mmol,3.0eq)。抽真空干燥，用氩气置换三次，氩气保护下加入六氟异丙醇(1.0mL)并在室温下搅拌12h。反应混合物经硅藻土过滤,乙酸乙酯淋洗,滤液减压浓缩后经柱层析(石油醚/乙酸乙酯＝15/1–10/1)分离得产物(4aS,5R,7aR)-1-(苄氧基)-3,3-二甲基-5-苯基-5-(2,2,2-三氟乙基)-4-(4-(三氟甲基)苯基)六氢-1H-环戊二烯并[b]吡嗪-2,6-二酮(35)。dr值通过1H NMR分析确定。ee值通过HPLC进行分析确定。
所得结构式35的表征数据：
白色固体,产率91％,>20/1dr。HPLC分析得88％ee(Chiralcel AD-H,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝210nm),tr(major)＝7.3min,tr(minor)＝10.8min；[α]D 20＝7.3(c＝0.49,in CHCl3)；mp＝173–175℃.1H NMR(500MHz,CDCl3)δ7.50–7.45(m,4H),7.44–7.40(m,3H),7.30–7.27(m,3H),7.07–7.01(m,2H),6.99(d,J＝8.1Hz,2H),5.09(d,J＝10.6Hz,1H),4.99(d,J＝10.5Hz,1H),4.86(d,J＝6.9Hz,1H),4.47(d,J＝7.3Hz,1H),3.45(d,J＝20.0Hz,1H),2.97–2.84(m,1H),2.70(dd,J＝20.0,7.5Hz,1H),2.39–2.24(m,1H),1.20(s,3H),1.01(s,3H).13C NMR(126MHz,CDCl3)δ213.5,170.4,148.9,137.1,135.0,131.0,130.0,129.4,128.8,128.4,128.0,127.8,126.8(q,J＝252.5Hz),126.0(q,J＝272.3Hz),125.7(q,J＝279.6Hz),125.6(q,J＝4.0Hz),64.6,63.0,58.2,55.8,40.3(q,J＝28.0Hz),26.1,22.8.19F NMR(377MHz,CDCl3)δ-56.6(t,J＝10.9Hz),-62.4(s).HRMS(ESI)m/z calcd.For C31H28F6N2NaO3[M+Na]+613.1896,found 613.1920.
(4aS,5R,7aR)-1-(苄氧基)-3,3-二甲基-5-苯基-5-(2,2,2-三氟乙基)-4-(4-(三氟甲基)苯基)六氢-1H-环戊二烯并[b]吡嗪-2,6-二酮(36)的合成路线：
Figure GDA0004174695530000281
向反应管中加入(4R,5R)-5-苯基-5-(2,2,2-三氟乙基)-4-((2-(三氟甲基)苯基)氨基)环戊-2-烯-1-酮(18,39.9mg,0.1mmol,95％ee,1.0eq)和六水合氯化镱(38.7mg,0.1mmol,1.0eq)和甲醇(2mL)。在室温下搅拌2h后,反应液冷却至-78℃,一次加入硼氢化钠(22.7mg,0.6mmol,6eq)。在-78℃的温度下搅拌2h后,反应混合物经柱层析(石油醚/乙酸乙酯＝7/1–5/1)分离得产物(1S,2R,3R)-2-苯基-2-(2,2,2-三氟乙基)-3-((2-(三氟甲基)苯基)氨基)环戊-1-醇(18')。dr值通过1H NMR分析确定。ee值通过HPLC进行分析确定。
在氩气保护下,将化合物18'溶于四氢呋喃(0.5mL)中并加到60％氢化钠(6.0mg,0.15mmol,1.5eq)的四氢呋喃(1.5mL)溶液中,23℃下搅拌2h。然后,将3,5-双三氟甲基苄基溴(46.1mg，0.15mmol，1.5eq)加入到反应液中并将继续在23℃下搅拌12h。在0℃下加冷水淬灭反应,并用乙酸乙酯萃取三次,合并的有机相用无水硫酸镁干燥，过滤减压浓缩得粗产物,经柱层析(石油醚/乙酸乙酯＝15/1–10/1)分离得到产物N-((1R,2R,3S)-3-((3,5-双(三氟甲基)苄基)氧基)-2-苯基-2-(2,2,2-三氟乙基)环戊基)-2-(三氟甲基))苯胺(36)。dr值通过1H NMR分析确定,ee值通过HPLC进行分析确定。
所得结构式18'的表征数据：
产率87％,>20/1dr。HPLC分析得95％ee(FLM Chiral NS,hexane/i-PrOH＝80/20,flow rate＝1.0mL/min,l＝254nm),tr(major)＝6.2min,tr(minor)＝4.3min；[α]D 20＝–27.5(c＝0.83,in CHCl3).1H NMR(500MHz,CDCl3)δ7.42–7.37(m,2H),7.34–7.29(m,4H),7.25–7.22(m,1H),6.79(d,J＝8.3Hz,1H),6.70(t,J＝7.7Hz,1H),5.43(d,J＝7.6Hz,1H),4.68(s,1H),4.45–4.38(m,1H),2.45–2.22(m,5H),2.17–2.08(m,2H).13C NMR(126MHz,CDCl3)δ144.2,137.5,133.1,129.5,128.6,127.2,127.0(q,J＝5.6Hz),125.9(q,J＝278.2Hz),124.8(q,J＝273.7Hz),115.7,114.4(q,J＝29.2Hz),111.3,78.4,58.0,57.1,43.0(q,J＝26.7Hz),30.5,29.4.19F NMR(377MHz,CDCl3)δ-59.2(t,J＝10.8Hz),-63.2(s).HRMS(ESI)m/z calcd.For C20H18F6NO[M-H]-402.1298,found 402.1277.
所得结构式36的表征数据：
黄色油状,产率89％,>20/1dr。HPLC分析得95％ee(Chiralcel OD,hexane/i-PrOH＝90/10,flow rate＝1.0mL/min,l＝254nm),tr(major)＝5.5min,tr(minor)＝4.8min；[α]D 20＝–63.8(c＝0.93,in CHCl3).1H NMR(500MHz,CDCl3)δ7.75(s,1H),7.53(s,2H),7.36(t,J＝8.0Hz,1H),7.31–7.23(m,6H),6.71(d,J＝8.4Hz,1H),6.62(t,J＝7.6Hz,1H),5.28(d,J＝8.1Hz,1H),4.77(d,J＝11.9Hz,1H),4.55–4.48(m,2H),4.41(t,J＝6.9Hz,1H),2.45(q,J＝10.8Hz,2H),2.42–2.19(m,3H),2.16–2.09(m,1H).13C NMR(126MHz,CDCl3)δ143.9,139.7,137.4,133.0,131.5(q,J＝33.2Hz),129.7,127.7,127.4(q,J＝3.8Hz),126.9(q,J＝4.7Hz),126.6(q,J＝274.2Hz),125.8(q,J＝284.2Hz),123.3(q,J＝272.1Hz),121.6(q,J＝3.7Hz),115.0,113.5(q,J＝29.2Hz),110.6,86.2,70.3,58.4,57.3,43.5(q,J＝26.4Hz),29.5,27.0.19F NMR(377MHz,CDCl3)δ-59.2(t,J＝10.8Hz),-63.1(s),-63.7(s).HRMS(ESI)m/z calcd.For C29H22F12NO[M-H]-628.1515,found 628.1517.
附图说明
图1为本发明所采用的技术方案的化学式
图2为一系列含三氟甲基的手性多官能化环戊烯酮衍生物的结构式
图3为(2R,3R)-2-苯基-3-(苯氨基)-2-(2,2,2-三氟乙基)环戊-1-酮(34)的合成路线的反应式
图4为(4aS,5R,7aR)-1-(苄氧基)-3,3-二甲基-5-苯基-5-(2,2,2-三氟乙基)-4-(4-(三氟甲基)苯基)六氢-1H-环戊二烯并[b]吡嗪-2,6-二酮(35)的合成路线的反应式
图5为(4aS,5R,7aR)-1-(苄氧基)-3,3-二甲基-5-苯基-5-(2,2,2-三氟乙基)-4-(4-(三氟甲基)苯基)六氢-1H-环戊二烯并[b]吡嗪-2,6-二酮(36)的合成路线的反应式
以上各化合反应所用的原料来源列表如下：
试剂名称 CAS号 纯度 规格 厂家
氯化亚铜 7758-89-6 ≥98％ 100g 笛柏
三氟甲磺酸镝 139177-62-1 98％ 25g Adamas
三氯甲烷 67-66-3 AR 500mL 科隆
Togni试剂 887144-97-0 98％ 5g 毕得医药
镁条 7439-95-4 AR 25g 华夏试剂
醋酸铵 631-61-8 AR 500g 科隆
甲醇 67-56-1 AR 2.5L 科隆
10％Pd/C 7440-05-3 RG 25g Adamas
石油醚 8032-32-4 AR 15kg 科隆
乙酸乙酯 141-78-6 AR 20kg 科隆
碳酸钠 497-19-8 99％ 500g 毕得医药
六氟异丙醇 920-66-1 99％ 25g Adamas
六水合氯化镱 10035-01-5 99％ 25g Adamas
硼氢化钠 16940-66-2 AR 100g 科隆
60％氢化钠 7646-69-7 AR 250g Adamas
四氢呋喃 109-99-9 AR 500mL 科隆

Claims (5)

1.一种含三氟甲基的多官能化环戊烯酮衍生物的不对称合成方法，其特征在于：以呋喃烯烃、Togni试剂和芳胺类化合物为底物，一价铜、手性布朗斯特酸和非手性路易斯酸为组合催化剂，通过三氟甲基自由基介导的三组分氮杂-Piancatelli重排反应，制得含三氟甲基的多官能化环戊烯酮衍生物,对映异构体过量高达95％；其反应式如下：
Figure FDA0004174695520000011
其中
R为氢或者溴；
R1为苯基、2-萘基、2-噻吩基、连有吸电子或供电子的不同基团R’的苯环，所述R’为甲基、甲氧基、三氟甲基或卤素；
R2为H或者甲基；
Ar为连有吸电子的不同基团的苯环，所述不同基团为卤素、酯基、三氟甲基、苯甲酰基、乙酰基、三氟甲磺酸酯基或者2-(1H-吡咯-1-基)；
所述的一价铜为氯化亚铜；
所述的非手性路易斯酸为三氟甲磺酸镝；
所述的手性布朗斯特酸结构式如下：
Figure FDA0004174695520000012
2.如权利要求1所述的方法，其特征在于：反应中所用的呋喃烯烃、Togni试剂和芳胺类化合物用量比为0.15mmol:0.15mmol:0.1mmol。
3.如权利要求1所述的方法，其特征在于：反应中所用的CuCl、Dy(OTf)3、手性布朗斯特酸摩尔用量分别为芳胺类化合物的5％、2％、6％。
4.如权利要求1所述的方法，其特征在于：反应中所用的有机溶剂为三氯甲烷，芳胺类化合物的物质的量与三氯甲烷的体积之比为0.1mmol:2–4mL。
5.如权利要求1所述的方法，其特征在于：反应在氩气氛围下进行，反应温度为45℃，反应时间为8–36h。
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Guanglong Pan等.Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds.《Beilstein J. Org. Chem.》.2021,第17卷第1171-1180页. *
Huilin Li等.Catalytic Enantioselective Aza-Piancatelli Rearrangement.《Angew. Chem. Int. Ed.》.2016,第55卷第15125-15128页. *
Lei Xu等.Ln(III)/Chiral Brønsted Acid catalyzed Asymmetric Cascade Ring Opening/Aza-Piancatelli Rearrangement of D-A Cyclopropanes.《Org. Lett.》.2020,第22卷第9016-9021页. *
Yunfei Cai等.Catalytic Asymmetric Piancatelli Rearrangement: Brønsted Acid Catalyzed 4p Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones.《Angew. Chem. Int. Ed.》.2016,第55卷第14126-14130页. *

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