CN110078605B - 有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法 - Google Patents

有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法 Download PDF

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CN110078605B
CN110078605B CN201910458237.7A CN201910458237A CN110078605B CN 110078605 B CN110078605 B CN 110078605B CN 201910458237 A CN201910458237 A CN 201910458237A CN 110078605 B CN110078605 B CN 110078605B
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柴国利
汪娟
郭蓉
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Abstract

有机硼酸与α,β‑不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，属于有机化学中的不对称合成技术领域，反应方程式如下：
Figure DEST_PATH_IMAGE002
具体步骤如下：以β‑CF3‑α,β‑不饱和酮1和有机硼酸2为原料，在手性四苯并环辛四烯类或手性联萘酚类催化剂，以及分子筛和叔丁醇镁添加剂存在下，经过不对称共轭加成反应，得到三氟甲基化合物，其中，R1=苯基，取代苯基、2‑萘基、1‑萘基、2‑噻吩基、3‑噻吩基、环己基，R2=苯乙烯基、2‑呋喃基、2‑苯并呋喃基。本发明反应原料易得，反应条件温和，后处理简单，催化剂可回收再利用，产物收率和对映选择性良好至优秀，产物含三氟甲基手性中心。

Description

有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活 性三氟甲基化合物的方法
技术领域
本发明属于有机化学中的不对称合成领域，具体涉及有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法。
背景技术
含三氟甲基的手性化合物广泛存在于生物活性分子和药物分子中，遗憾的是自然界中天然三氟甲基化合物非常少见，因此发展普适高效合成三氟甲基化合物，特别是含三氟甲基手性中心的化合物，在有机合成中至关重要(Chem.Rev.2011,111,455.)。采用不对称催化方法将潜手性的含三氟甲基底物转化为手性的含三氟甲基产物是获得此类化合物主要方法之一(Chin,J.Org.Chem.2019,39,1.)。亲核试剂与β-CF3-α,β-不饱和酮的对映选择性共轭加成可用于简单构筑光学活性三氟甲基化合物。
近年来，有机硼化物(烃基硼酸、有机硼酸酯和有机硼酸盐)以其低毒、廉价易得、稳定性好和良好的官能团耐受性等优点在现代有机合成中发挥重要作用，有机硼化物与α,β-不饱和羰基化合物的不对称共轭加成反应是构筑C-C键的重要合成方法之一(Molecules2018,23,2317.)。尽管过渡金属Rh(Ⅰ)、Ir(Ⅰ)、Pd(Ⅱ)和Cu(Ⅰ)催化的有机硼酸及其衍生物与α,β-不饱和羰基化合物中的不对称共轭加成反应取得了长足的进展，但是有机小分子催化不对称共轭加成反应由于催化剂低毒性、易于制备、价格便宜、稳定性好、操作简单和不存在反应后金属残留等优点，成为过渡金属催化的一种重要的补充方法((a)Org.Lett.2009,11,2425；(b)J.Am.Chem.Soc.2007,129,15438；(c)J.Am.Chem.Soc.2012,134,19965；(d)J.Am.Chem.Soc.2005,127,3244；(e)Angew.Chem.Int.Ed.2015,54,9931；(f)Chem.Commun.2010,46,7799.)。
到目前为止，无过渡金属参与的有机硼酸与β-CF3-α,β-不饱和酮类化合物不对称共轭加成反应合成光学活性三氟甲基化合物的方法还没有被报道。因此，发展高效的无过渡金属参与的催化体系实现有机硼酸与β-CF3-α,β-不饱和酮的不对称共轭加成反应，得到一系列光学活性的三氟甲基化合物，具有重要的研究意义。
发明内容
本发明的目的在于提供一种有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法。
基于上述目的，本发明采用有机硼酸与β-CF3-α,β-不饱和酮作为原料，在催化剂手性四苯并环辛四烯类或手性联萘酚类化合物、以及添加剂分子筛和叔丁醇镁下经过不对称共轭加成反应，以高收率和对映选择性一步合成三氟甲基化合物。
反应方程式如下：
Figure BDA0002077256750000021
其中：R1选自Ph、4-CH3C6H4、3-CH3C6H4、2-CH3C6H4、4-CH3OC6H4、3-CH3OC6H4、4-FC6H4、3-FC6H4、4-ClC6H4、4-BrC6H4、2-BrC6H4、4-NO2C6H4、4-CF3C6H4、3-CF3C6H4、2-萘基、1-萘基、2-噻吩基、3-噻吩基或环己基；R2选自
Figure BDA0002077256750000022
进一步地，在上述技术方案中，所述手性催化剂选自(S,S)-1,8,9,16-四羟基四苯并环辛四烯((S,S)-THTP)，(S)-1,16-二羟基四苯并环辛四烯((S)-DHTP)，(S)-2,15-二溴-1,16-二羟基四苯并环辛四烯((S)-2,15-Br2-DHTP)，(S)-2,15-二氯-1,16-二羟基四苯并环辛四烯((S)-2,15-Cl2-DHTP)，(S)-2,15-二苯基-1,16-二羟基四苯并环辛四烯((S)-2,15-Ph2-DHTP)和(S)-4,13-二溴-1,16-二羟基四苯并环辛四烯((S)-4,13-Br2-DHTP)中的一种。手性四苯并环辛四烯催化剂的合成依据参考文献(J.Org.Chem.2019,84,120.)合成。催化剂分别对应具体结构如下：
Figure BDA0002077256750000023
所述手性催化剂还可以为手性联萘酚类化合物，具体结构如下：
Figure BDA0002077256750000024
进一步地，在上述技术方案中，所述β-CF3-α,β-不饱和酮1、有机硼酸2、催化剂、叔丁醇镁的摩尔比为1:1.2:0.1:0.1，每0.1mmolβ-CF3-α,β-不饱和酮1中分子筛的用量为50mg。
进一步地，在上述技术方案中，所述反应溶剂为1,2-二氯乙烷、二氯甲烷、甲苯、三氟甲苯或甲基叔丁基醚。
进一步地，在上述技术方案中，反应温度为0至60℃。优选25℃。
进一步地，在上述技术方案中，整个反应过程需要在不活泼气体保护下操作，如氮气、氩气，优选氮气。
发明有益效果：
本发明反应原料易得，反应条件温和，后处理简单，催化剂可回收再利用，产物收率和对映选择性良好至优秀，产物具有含三氟甲基手性中心。
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。
实施例1：
Figure BDA0002077256750000031
Figure BDA0002077256750000032
Figure BDA0002077256750000041
[a]反应条件:β-CF3-α,β-不饱和酮1a(0.1mmol),反式-2-苯基乙烯基硼酸2a(0.12mmol),(S)-2,15-Br2-DHTP(0.01mmol),Mg(OtBu)2(0.01mmol),
Figure BDA0002077256750000042
分子筛(50mg),和1.0mL无水溶剂在N2气氛下搅拌.[b]分离产率.[c]ee值通过HPLC手性分析得到.[d]0.5mLDCE.
在反应条件的筛选过程中，首先考察了不同的溶剂对反应的影响(entries 1-6)，最终选用1,2-二氯乙烷(DCE)作溶剂，当反应浓度增大之后，产物收率和对映选择性都有所提高(entry 7)。随后，考察了不同的手性催化剂对反应的影响(entries 8-14)，最终确定了Cat 1为最佳催化剂。同时考察了温度、催化剂用量对反应的影响，最终选择反应温度为25℃，催化剂用量为化合物1a的10mol％。
反应条件的考察(以entry7为例)：
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000043
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1a(21.4mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌30h。TLC点板跟踪至原料1a消失，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3aa，收率为88％，95％ee。
3aa白色固体(28.2mg,产率88％)；mp 94-96℃；HPLC(Daicel Chiralcel OD-H手性柱,正己烷/异丙醇＝90:10,流速0.8mL/min,λ＝254nm)tR(minor)＝6.05min,tR(major)＝8.49min,ee＝94％；[α]D 20＝-11.6(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.86(d,J＝8.4Hz,2H),7.35-7.23(m,7H),6.68(d,J＝16.0Hz,1H),6.03(dd,J＝15.6,8.4Hz,1H),3.89-3.84(m,1H),3.36-3.34(m,2H),2.42(s,3H)；13C{1H}NMR(150MHz,CDCl3)δ195.2,144.6,136.3,136.2,134.1,129.6,128.7,128.3,128.2,127.1(q,J＝277.5Hz),126.7,121.8,42.7(q,J＝27.0Hz),37.4,21.8；19F{1H}NMR(376MHz,CDCl3)δ-70.68；HRMS(ESI)calcd.for C19H17OF3Na([M+Na]+):341.1124,found:341.1110.
实施例2：
Figure BDA0002077256750000051
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000053
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1b(20.0mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌48h。TLC点板跟踪至原料1b消失，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3ba，收率为93％，94％ee。
3ba白色固体(28.4mg,产率93％)；mp 41-43℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速0.8mL/min,λ＝254nm)tR(minor)＝6.68min,tR(major)＝8.09min,ee＝94％；[α]D 17＝-20.0(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.98-7.95(m,2H),7.61-7.57(m,1H),7.50-7.46(m,2H),7.36-7.21(m,5H),6.69(d,J＝16.0Hz,1H),6.04(dd,J＝16.0,8.8Hz,1H),3.92-3.82(m,1H),3.39-3.73(m,2H)；13C{1H}NMR(150MHz,CDCl3)δ195.6,136.6,136.4,136.2,133.7,128.9,128.7,128.3,128.2,126.7,121.7(q,J＝2.4Hz),127.1(q,J＝277.5Hz),42.7(q,J＝27.0Hz),37.5；19F{1H}NMR(376MHz,CDCl3)δ-70.71；HRMS(ESI)calcd.for C18H15OF3Na([M+Na]+):327.0967,found:327.0965.
实施例3：
Figure BDA0002077256750000052
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000054
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1c(23.0mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌48h。TLC点板跟踪至原料1c消失，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3ca，收率为98％，94％ee。
3ca白色固体(33.0mg,产率98％)；mp 82-84℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速0.8mL/min,λ＝254nm)tR(minor)＝9.61min,tR(major)＝21.21min,ee＝94％；[α]D 17＝-3.1(c2.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.94(d,J＝8.8Hz,2H),7.35-7.22(m,5H),6.94(d,J＝8.8Hz,2H),6.68(d,J＝16.0Hz,1H),6.03(dd,J＝16.0,8.8Hz,1H),3.91-3.81(m,1H),3.86(s,3H),3.32(d,J＝6.4Hz,2H)；13C{1H}NMR(100MHz,CDCl3)δ194.0,164.0,136.3,131.4,130.5,129.7,128.7,128.2,127.2(q,J＝277.5Hz),126.7,121.8(q,J＝3.0Hz),114.0,55.7,42.8(q,J＝27.1Hz),37.1；19F{1H}NMR(376MHz,CDCl3)δ-70.6；HRMS(ESI)calcd.forC19H17O2F3Na([M+Na]+):357.1073,found:357.1068.
实施例4：
Figure BDA0002077256750000061
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000063
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1d(21.8mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌48h。搅拌72h之后，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3da，收率为72％，94％ee。
3da白色固体(23.1mg,产率72％)；mp 43-44℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速0.8mL/min,λ＝254nm)tR(minor)＝6.44min,tR(major)＝10.74min,ee＝94％；[α]D 19＝-18.9(c1.0,CH2Cl2)；1H NMR(600MHz,CDCl3)δ8.00-7.98(m,2H),7.36-7.24(m,4H),7.16-7.13(m,3H),6.69(d,J＝15.6Hz,1H),6.02(dd,J＝15.6,8.4Hz,1H),3.88-3.83(m,1H),3.39-3.31(m,2H)；13C{1H}NMR(150MHz,CDCl3)δ193.9,166.1(d,J＝253.6Hz),136.5,136.1,132.9,130.9(d,J＝9.0Hz),128.7,128.3,127.0(q,J＝277.8Hz),126.7,121.5,116.1(d,J＝21.9Hz),42.7(q,J＝27.5Hz),37.4；19F{1H}NMR(564MHz,CDCl3)δ-70.7,-104.1；HRMS(ESI)calcd.for C18H14OF4Na([M+Na]+):345.0873,found:345.0869.
实施例5：
Figure BDA0002077256750000062
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000064
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1e(24.5mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌72h。TLC点板跟踪至原料1b消失，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/2)分离纯化得到目标产物3ea，收率为63％，90％ee。
3ea白色固体(22.2mg,产率63％)；mp 96-98℃；HPLC(Daicel Chiralpak AD-H,正己烷/异丙醇＝80:20,流速0.8mL/min,λ＝254nm)tR(minor)＝11.08min,tR(major)＝13.16min,ee＝90％；[α]D 19＝-4.5(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ8.34-8.31(m,2H),8.13-8.09(m,2H),7.37-7.23(m,5H),6.71(d,J＝15.6Hz,1H),6.02(dd,J＝15.6,8.8Hz,1H),3.90-3.82(m,1H),3.48-3.35(m,2H)；13C{1H}NMR(100MHz,CDCl3)δ194.2,150.7,140.8,137.0,135.9,129.3,128.8,128.5,126.8(q,J＝277.8Hz),126.7,124.2,121.0(q,J＝2.3Hz),42.7(q,J＝27.6Hz),38.2；19F{1H}NMR(376MHz,CDCl3)δ-70.7；HRMS(ESI)calcd.for C18H14O3NF3Na([M+Na]+):372.0818,found:372.0815.
实施例6：
Figure BDA0002077256750000071
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000072
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1f(20.0mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌72h。TLC点板跟踪至原料1f有较少剩余，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3fa，收率为74％，93％ee。
3fa白色固体(23.1mg,产率74％)；mp61-64℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝80:20,流速0.8mL/min,λ＝254nm)tR(minor)＝7.31min,tR(major)＝10.52min,ee＝94％；[α]D 19＝-27.9(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.75(dd,J＝4.0,1.2Hz,1H),7.66(dd,J＝5.2,1.2Hz,1H),7.35-7.23(m,5H),7.16-7.13(m,1H),6.68(d,J＝16.0Hz,1H),6.03(dd,J＝15.6,8.4Hz,1H),3.86-3.79(m,1H),3.34-3.24(m,2H)；13C{1H}NMR(100MHz,CDCl3)δ188.4,143.8,136.6,136.1,134.5,132.4,128.7,128.4,128.3,126.7,125.5,121.3(q,J＝2.9Hz),42.9(q,J＝27.5Hz),38.2；19F{1H}NMR(376MHz,CDCl3)δ-70.8；HRMS(ESI)calcd.for C16H13OSF3Na([M+Na]+):333.0531,found:333.0517.
实施例7：
Figure BDA0002077256750000081
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000083
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1g(20.6mg，0.1mmol)和有机硼酸2a(17.7mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌72h。TLC点板跟踪至原料1g有较少量剩余，加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3ga，收率为68％，97％ee。
3ga白色固体(21.2mg,产率68％)；mp 31-37℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝90:10,流速0.8mL/min,λ＝254nm)tR(minor)＝4.64min,tR(major)＝6.10min,ee＝97％；[α]D 17＝-39.3(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.36-7.23(m,5H),6.61(d,J＝16.0Hz,1H),5.96(dd,J＝16.0,8.8Hz,1H),3.70-3.63(m,1H),2.88-2.75(m,2H),2.36-2.30(m,1H),1.87-1.64(m,5H),1.37-1.16(m,5H)；13C{1H}NMR(100MHz,CDCl3)δ209.2,136.3,136.2,128.7,128.3,127.0(q,J＝277.8Hz),126.6,121.7(q,J＝2.6Hz),51.4,42.4(q,J＝27.5Hz),39.4,28.30,28.27,25.9,25.67,25.64；19F{1H}NMR(376MHz,CDCl3)δ-70.8；HRMS(ESI)calcd.for C18H21OF3Na([M+Na]+):333.1437,found:333.1432.
实施例8：
Figure BDA0002077256750000082
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000084
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1a(21.4mg，0.1mmol)和有机硼酸2b(13.4mg，0.12mmol，1.2equiv)，抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌72h。加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3ab，收率为58％，77％ee。
3ab白色固体(28.2mg,产率58％)；mp 65-68℃；HPLC(Daicel Chiralcel OD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝5.75min,tR(major)＝6.76min,ee＝77％；[α]D 15＝25.8(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.87-7.85(m,2H),7.35-7.34(m,1H),7.28-7.25(m,2H),6.34-6.31(m,2H),4.44-4.38(m,1H),3.78-3.41(m,2H),2.42(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ194.7,147.7,144.7,142.8,133.8,129.6,128.4,126.0(q,J＝277.9Hz),110.7,109.5,39.2(q,J＝29.1Hz),35.9,21.8；19F{1H}NMR(376MHz,CDCl3)δ-70.2；HRMS(ESI)calcd.for C15H13O2F3Na([M+Na]+):305.0760,found:305.0759.
实施例9：
Figure BDA0002077256750000091
在氮气保护下，向经过无水无氧处理的25mL Schlenk管中加入50mg
Figure BDA0002077256750000092
分子筛、手性催化剂Cat1(4.9mg，0.01mmol，10mol％)、叔丁醇镁(1.7mg，0.01mmol，10mol％)、β-CF3-α,β-不饱和酮1a(21.4mg，0.1mmol)和有机硼酸2c(19.4mg，0.12mmol，1.2equiv)，再抽换气3次，再加入干燥的1,2-二氯乙烷(0.5mL)，25℃搅拌72h。加0.1mL水淬灭反应，减压除去溶剂后直接快速硅胶柱层析(洗脱剂为二氯甲烷/石油醚体积比1/5)分离纯化得到目标产物3ac，收率为82％，70％ee。
3ac白色固体(27.2mg,产率82％)；mp 72-73℃；HPLC(Daicel Chiralpak AD-H,正己烷/异丙醇＝95:5,流速0.8mL/min,λ＝254nm)tR(minor)＝11.00min,tR(major)＝12.57min,ee＝70％；[α]D 17＝25.1(c1.0,CH2Cl2)；1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.4Hz,2H),7.51(d,J＝8.0Hz,1H),7.43(d,J＝8.8Hz,1H),7.24-7.17(m,4H),6.75(s,1H),4.59-4.53(m,1H),3.91-3.51(m,2H),2.41(s,3H)；13C{1H}NMR(100MHz,CDCl3)δ194.4,155.0,150.5,144.9,133.7,129.6,128.4,128.1,124.6,123.1,121.2,111.4,106.7,39.7(q,J＝29.3Hz),35.9,21.8；19F{1H}NMR(376MHz,CDCl3)δ-69.5；HRMS(ESI)calcd.forC19H15O2F3Na([M+Na]+):355.0916,found:355.0914.
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 (6)

1.有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，反应方程式如下：
Figure DEST_PATH_IMAGE001
具体步骤如下：以β-CF3-α,β-不饱和酮1和有机硼酸2为原料，在催化剂手性四苯并环辛四烯类，以及分子筛和叔丁醇镁添加剂存在下，经过不对称共轭加成反应，得到三氟甲基化合物，其中，R1 = 苯基，取代苯基、2- 萘基、1- 萘基、2-噻吩基、3-噻吩基、环己基，R2 = 苯乙烯基、2-呋喃基、2-苯并呋喃基；手性四苯并环辛四烯类催化剂选自Cat 1至Cat 5中的一种， Cat 1至Cat 5的结构式如下：
Figure 576885DEST_PATH_IMAGE002
。
2.根据权利要求1所述有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，R1选自Ph、4-CH3C6H4、3-CH3C6H4、2-CH3C6H4、4-CH3OC6H4、3-CH3OC6H4、4-FC6H4、3-FC6H4、4-ClC6H4、4-BrC6H4、2-BrC6H4、4-NO2C6H4、4-CF3C6H4、3-CF3C6H4、2- 萘基、1- 萘基、2-噻吩基、3-噻吩基或环己基；R2选自
Figure 680977DEST_PATH_IMAGE004
、
Figure DEST_PATH_IMAGE006
或
Figure DEST_PATH_IMAGE008
。
3.根据权利要求1所述有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，所述β-CF3-α,β-不饱和酮1、有机硼酸2、催化剂、叔丁醇镁的摩尔比为1:1.2:0.1:0.1，每0.1mmol β-CF3-α,β-不饱和酮1分子筛的用量为50mg。
4.根据权利要求1所述有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，反应溶剂选自1,2-二氯乙烷、二氯甲烷、甲苯、三氟甲苯和甲基叔丁基醚中的一种。
5.根据权利要求1所述有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，反应温度为0至60℃。
6.根据权利要求1所述有机硼酸与α,β-不饱和酮的不对称共轭加成反应合成光学活性三氟甲基化合物的方法，其特征在于，整个反应过程需要在氮气或氩气气氛下进行。
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106631726A (zh) * 2015-11-04 2017-05-10 香港中文大学深圳研究院 光学纯的双螺旋寡聚四苯并环辛四烯类物质的合成方法
CN109748841A (zh) * 2019-01-08 2019-05-14 浙江工业大学 一种催化不对称合成手性β-氨基酮衍生物的方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106631726A (zh) * 2015-11-04 2017-05-10 香港中文大学深圳研究院 光学纯的双螺旋寡聚四苯并环辛四烯类物质的合成方法
CN109748841A (zh) * 2019-01-08 2019-05-14 浙江工业大学 一种催化不对称合成手性β-氨基酮衍生物的方法

Non-Patent Citations (24)

* Cited by examiner, † Cited by third party
Title
A first high enantiocontrol of an asymmetric tertiary carbon center attached with a fluoroalkyl group via Rh(I)-catalyzed conjugate addition reaction;Tsutomu Konno;《Tetrahedron Letters》;20081231;第49卷;2106-2110 *
A General Method for the Enantioselective Synthesis of α-Chiral Heterocycles;Le, P.Q.;《Org. Lett.》;20121231;第14卷;6104-6107 *
A Theoretical Study On Rh(I) Catalyzed Enantioselective Conjugate Addition Reactions of Fluoroalkylated Olefins;Esra Boz;《Organometallics》;20140828;第33卷;5111-5119 *
Asymmetric Conjugate Addition of Alkynylboronates to Enones Rationale for the Intriguing Catalysis Exerted by Binaphthols;Pellegrinet, S. C.;《J. Am. Chem. Soc.》;20061231;第128卷;3116-3117 *
Asymmetric Conjugate Alkenylation of Enones Catalyzed by Chiral Diols;T. Robert Wu;《J. Am. CHEM. SOC.》;20070403;第129卷;4908-4909 *
Asymmetric Construction of Stereogenic Carbon Centers Featuring a Trifluoromethyl Group from Prochiral Trifluoromethylated Substrates;Jing Nie;《Chem. Rev.》;20111231;第111卷;455-529 *
Binaphthol-Catalyzed Asymmetric Conjugate Arylboration of Enones;Turner. H.M.;《Org. Lett.》;20111231;第13卷;5796-5799 *
Catalytic Enantioselective Conjugate Alkynylation of β‑Aryl-β-trifluoromethyl Enones Constructing Propargylic All-Carbon Quaternary Stereogenic Centers;Amparo Sanz-Marco;《Org. Lett.》;20160715;第18卷;3538-3541 *
Chiral Diol-Based Organocatalysts in Enantioselective Reactions;Nguyen, T.N.;《molecules》;20181231;第23卷;2317-2353 *
Enantioselective Addition of Boronates to o-Quinone Methides Catalyzed by Chiral Biphenols;Luan, Y;《J. Am. Chem.Soc.》;20120816;第134卷;19965-19968 *
Enantioselective Conjugate Addition of Alkenylboronic Acids to Indole-Appended Enones;Lundy, B.J.;《Org. Lett.》;20110816;第13卷;4958-4961 *
Experimental Mechanistic Insight into the BINOL-Catalyzed Enantioselective Conjugate Addition of Boronates to Enones;Nguyen, T.S.;《Tetrahedron Lett.》;20151231;第56卷;3337-3341 *
Hydroxytetraphenylenes as Chiral Ligands Application to Asymmetric Darzens Reaction of Diazoacetamide with Aldehydes;Guo-Li Chai;《Synthesis》;20161231;第48卷;2188-2198 *
Ligand-Catalyzed Asymmetric Alkynylboration of Enones A New Paradigm for Asymmetric Synthesis Using Organoboranes;Wu. T.R.;《J. Am. Chem. Soc.》;20051231;第127卷;3244-3245 *
Lundy, B.J..Enantioselective Conjugate Addition of Alkenylboronic Acids to Indole-Appended Enones.《Org. Lett.》.2011,第13卷4958-4961. *
Organocatalyzed Asymmetric Conjugate Addition of Heteroaryl and Aryl Trifluoroborates A Synthetic Strategy for Discoipyrrole D;Shi, J. L.;《Angew. Chem., Int. Ed.》;20151231;第54卷;9931-9935 *
Our expedition in eight-membered ring compounds from planar dehydrocyclooctenes to tub-shaped chiral tetraphenylenes;Jian-Wei Han;《Chem. Rec.》;20151231;第15卷;8918-8931 *
Recent Developments and Applications of Chiral Tetraphenylenes;J. -W. Han;《Synlett》;20131231;第24卷;107-131 *
Rhodium(I)-catalyzed 1,4-conjugate arylation toward β-fluoroalkylated electron-deficient alkenes: a new entry to a construction of a tertiary carbon center possessing a fluoroalkyl group;Atsunori Morigaki;《 Org. Biomol. Chem.》;20131231;第11卷;586-595 *
Synthesis and Application of Substituted 1,16-Dihydroxytetraphenylenes in Catalytic Asymmetric Allylboration of Ketones;Guo-Li Chai;《J. Org. Chem.》;20181210;第84卷;120-127 *
Synthesis, resolution, and applications of 1,16-dihydroxytetraphenylene as a novel building block in molecular recognition and assembly;Jian-Feng Wen;《J. Org. Chem.》;20031231;第68卷;A-G *
Theoretical Study of the Asymmetric Conjugate Alkenylation of Enones Catalyzed by Binaphthols;Paton, R.S.;《J. Org. Chem.》;20081231;第73卷;5078-5089 *
Transition-metal-free C–C Bond Forming Reactions of Aryl, Alkenyl and Alkynylboronic Acids and Their Derivatives;Roscales, S.;《chem. soc. rev.》;20141231;第43卷;8215-8225 *
以四苯并环辛四烯为骨架并包含手性分子结的大环化合物的合成;喻峰;《中国优秀博硕士学位论文全文数据库(硕士)工程科技Ⅰ辑》;20180815(第8期);B014-18 *

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