CN112552215B - 一种合成烯丙基胺衍生物的方法 - Google Patents
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- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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Abstract
本发明公开一种合成烯丙基胺衍生物的方法，利用金属镍催化剂实现反应物胺中的氢转移，并且在同一催化体系下，实现其与炔烃的偶联反应构建烯丙基胺；该反应对于胺类化合物和炔烃都能很好的适用，并且能够实现手性烯丙胺的构建。本发明的方法无需添加额外还原剂作为氢源，也无需引入额外导向基，且规模放大到克级，产率依然可以保持。
Description
技术领域
本发明涉及脱氢还原偶联反应技术领域，具体涉及一类由普通非导向胺与炔烃出发，制备烯丙基胺衍生物的方法。
背景技术
烯丙胺结构广泛存在于功能材料、活性药物分子以及诸多手性配体中，是一类重要的有机结构骨架，因此如何高效地制备多样性结构的烯丙胺衍生物具有较高的研究和应用价值。
目前，烯丙胺衍生物主要通过以下方法进行合成：
(1)烯基硼试剂与亚胺过渡金属催化下，得到烯丙胺衍生物。该反应需要用到贵金属铑(Rh)作为催化剂，且反应底物亚胺不稳定容易分解，合成较为不便；烯基硼酸盐也需要预先制备。(Brak,K.；J.A.Ellman.J.Am.Chem.Soc.2009,131,3850)
(2)炔烃与亚胺通过还原偶联直接制备。然而已知报道的方法均需要额外添加当量的还原剂，比如Et3B、ZnEt2、异丙醇或者氢气等，产生当量的废弃物，不利于原子经济性和环境友好，反应成本较高，反应底物局限，而且较难实现反应的不对称。(Patel，S.J.；Jamison，T.F.Angew.Chem.，Int.Ed.2003，42，1364；Barchuk，A.；Krische，M.J.J.Am.Chem.Soc.2007，129，12644；Zhou，C.Y.；Zhu，S.F；Wang，L.X.；Zhou，Q.L.J.Am.Chem.Soc.2010，132，10955；Ngai，M.Y.；Yao,W.W.；Li,R.；Li,J.F.；Sun，J.；Ye,M.C.Green Chem.2019,21,2240.)
综上所述，虽然烯丙基胺衍生物在有机合成中具有重要意义，但现有的合成大多基于亚胺出发(预先合成，不易保存)，在当量还原剂的条件下才能发生偶联反应生成烯丙基胺，底物适用性窄，较难放大量操作，原子经济性差，不符合绿色化学的理念。
发明内容
针对现有的底物适用性窄，需要当量额外的还原剂，原子经济性差等不足之处，本发明提供一种在胺的α位直接实现炔基化反应，高效的构建具有多样性结构的烯丙基胺衍生物。
本发明的目的通过如下的技术方案来实现：
一种合成烯丙基胺衍生物的方法，在氮气氛围中，将原料一、原料二、无机碱(base)、金属催化剂(M)和配体(ligand)混合均匀，然后加入溶剂(solvent)，在80～140℃温度下搅拌使其反应完全，冷却至室温，浓缩，柱层析分离得到原料3，即烯丙基胺衍生物，具体的反应式如下：
其中，原料一为苄胺衍生物或烷基胺类衍生物，原料一中的R2基团为磺酰基，例如对甲基苯磺酰基(Ts)，对甲氧基苯磺酰基，对三氟甲基苯磺酰基，甲基磺酰基(Ms)以及均三甲基苯磺酰基(Mts)，其中Mts效果最优；
原料二中的R3和R4基团均选自芳基、烷基或硅基中的任意一种，例如对称的烷基炔烃，对称的芳基炔烃，R3和R4也可以不同，例如不对称的烷基芳基炔烃；另外，对于硅基(如三甲基硅基TMS)取代的炔烃，也可以取得很好的效果，以上均不局限于这些基团。
所述的金属催化剂为Ni(cod)2；
所述的配体为单膦配体或氮杂卡宾配体，单膦配体例如三环己基膦，二环己基苯基膦，三叔丁基膦，三(4-甲氧基苯基)膦以及Buchwald型配体(Sphos，Davephos以及Xphos)和Jamison教授采用的二茂铁型配体FcPPh3等；其中三环己基膦、二环己基苯基膦的催化效果最好；另外，常见的氮杂卡宾(NHC)，如IPr，IMes等也可以。当制备手性烯丙基胺时，所选用的配体为手性单膦配体，如下述的L1～L5，其中手性单膦配体L1具有最好的催化效果。
所述溶剂为醚类溶剂或非极性溶剂，如四氢呋喃(THF)、甲苯、1,4-二氧六环(Dioxane)、乙二醇二甲醚、正己烷等，其中1,4-二氧六环(Dioxane)效果最优，其次为四氢呋喃。
所述无机碱选自碳酸钾、碳酸铯、醋酸钾、醋酸钠、甲酸钠、叔丁醇钾以及叔丁醇钠等均可，其中磷酸钾最优。
本发明的有益效果如下：
(1)本发明用到的原料大多均为商业可得，配体价格亦非常低廉，操作处理方便，无需特别纯化处理。
(2)本发明采取的催化剂为常见镍络合物，避免了钌铑等贵金属的使用。
(3)本发明操作简便，仅仅需要将所有反应物混合加热即可一步高产率得到目标化合物，无需添加额外还原剂作为氢源，也无需引入额外导向基，避免了额外添加剂带来繁琐的后续处理，符合绿色化学理念。
(4)本发明中配体替换为手性磷配体，可进一步得到高光学纯的烯丙胺衍生物。
(5)本发明规模放大至克级，产率依然可以保持，即可容易产业化。
具体实施方式
下面根据优选实施例详细描述本发明，本发明的目的和效果将变得更加明白，应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
下面的实施示例中选取不同种类底物，且详细说明反应的具体操作、反应的具体条件，从不同结构范围更好的说明本发明。产物通过核磁和高分辨质谱鉴定，手性产物通过超临界液相色谱(SFC)检测。
实施例1
(E)-2,4,6-trimethyl-N-(1,2,3-triphenylallyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率92％,43.0mg。1H NMR(500MHz,CDCl3)δ7.24(m,5H),7.20-7.17(m,1H),7.13-7.10(m,2H),7.06-7.01(m,3H),6.85(s,2H),6.77-6.74(m,4H),6.52(s,1H),5.31(d,J＝6.5Hz,1H),4.94(d,J＝6.5Hz,1H),2.52(s,6H),2.23(s,3H)；13C NMR(126MHz,CDCl3)δ142.1,140.1,139.1,138.9,137.5,135.9,134.5,131.9,129.4,129.2,129.2,128.5,128.5,127.8,127.8,127.6,127.4,126.9,64.2,23.0,20.8；HRMS(ESI-TOF)m/zcalcd.for C30H29NO2SNa[M+Na]+:490.1817,found 490.1818.
示例1的放大量制备：
在氮气氛围中，依次向反应管中加入原料1a(5mmol,1.44g)，原料2a(10mmol,1.78g)，K3PO4(2mmol,0.42g)，Ni(cod)2(0.35mmol，0.095g),和PCy3(0.7mmol，0.196g)，最后加入Dioxane(15mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率85％,1.98g.
实施例2
(E)-N-(2,3-diphenyl-1-(o-tolyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1b(0.1mmol,30.3mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3b，收率87％,41.8mg。1H NMR(500MHz,CDCl3)δ7.32-7.27(m,1H),7.20-6.97(m,9H),6.87-6.84(m,2H),6.81(s,2H),6.70-6.66(m,2H),6.36(s,1H),5.52(d,J＝5.1Hz,1H),4.88(d,J＝5.1Hz,1H),2.52(s,6H),2.21(s,3H),2.14(s,3H)；13C NMR(126MHz,CDCl3)δ142.0,139.8,138.8,138.3,137.0,136.0,135.9,134.5,131.9,130.6,129.1,129.0,128.9,128.6,127.8,127.7,127.5,127.3,126.8,126.2,60.3,23.0,20.8,19.1；HRMS(ESI-TOF)m/z calcd.for C31H31NO2SNa[M+Na]+:504.1973,found 504.1975.
实施例3
(E)-N-(1-(2-fluorophenyl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1c(0.1mmol,30.7mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3c，收率73％,35.4mg。1H NMR(500MHz,CDCl3)δ7.22-7.11(m,5H),7.06-6.85(m,7H),6.77(s,2H),6.76-6.72(m,2H),6.41(s,1H),5.52(d,J＝6.8Hz,1H),5.10(d,J＝7.0Hz,1H),2.48(s,6H),2.22(s,3H)；13C NMR(126MHz,CDCl3)δ160.1(d,J＝247.0Hz),142.0,139.5,138.9,137.6,135.8,133.7,131.8,129.5,129.4(d,J＝8.5Hz),129.2,129.1(d,J＝3.8Hz),129.0,128.7,127.8,127.6,127.0,126.5(d,J＝12.7Hz),124.0(d,J＝3.5Hz),115.4(d,J＝21.6Hz),58.3(d,J＝2.5Hz),23.0,20.8；HRMS(ESI-TOF)m/zcalcd.for C30H28FNO2SNa[M+Na]+:508.1722,found 508.1718.
实施例4
(E)-N-(1-(3-methoxyphenyl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1d(0.1mmol,31.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3d，收率83％,41.2mg。1H NMR(500MHz,CDCl3)δ7.14-7.03(m,4H),6.99-6.93(m,3H),6.80-6.75(m,3H),6.74-6.65(m,6H),6.45(s,1H),5.20(d,J＝6.5Hz,1H),4.85(d,J＝6.5Hz,1H),3.62(s,3H),2.45(s,6H),2.16(s,3H)；13C NMR(126MHz,CDCl3)δ159.6,142.1,140.7,139.9,138.9,137.5,135.9,134.5,131.9,129.6,129.5,129.3,129.2,128.6,127.8,127.6,126.9,119.7,113.4,112.9,64.1,55.1,23.0,20.8；HRMS(ESI-TOF)m/z calcd.for C31H31NO3S[M+Na]+:520.1923,found 520.1928.
实施例5
(E)-N-(2,3-diphenyl-1-(3-(trifluoromethyl)phenyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1e(0.1mmol,31.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3e，收率84％,44.9mg。1H NMR(500MHz,CDCl3)δ7.40-7.36(m,2H),7.31-7.23(m,2H),7.18-7.13(m,1H),7.13-7.06(m,2H),7.02-6.94(m,3H),6.75(s,2H),6.73-6.66(m,4H),6.42(s,1H),5.31(d,J＝6.3Hz,1H),4.93(d,J＝6.3Hz,1H),2.41(s,6H),2.15(s,3H)；13C NMR(126MHz,CDCl3)δ142.4,140.1,139.6,138.8,136.8,135.5,134.0,132.0,130.8,130.4,129.22,129.19,128.9,128.8,128.0,127.9,127.3,124.6(q,J＝3.8Hz),124.1(q,J＝3.9Hz),123.8(q,J＝272.4Hz),63.9,23.0,20.8；HRMS(ESI-TOF)m/zcalcd.for C31H28F3NO2SNa[M+Na]+:558.1691,found 558.1691.
实施例6
Methyl-(Z)-3-(3-phenyl-1-((2,4,6-trimethylphenyl)sulfonamido)-2-(trimethylsilyl)allyl)benzoate的制备
在氮气氛围中，依次向反应瓶中加入原料1f(0.1mmol,34.7mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3f，收率94％,49.4mg。1H NMR(500MHz,CDCl3)δ7.92-7.88(m,1H),7.86-7.83(m,1H),7.44-7.40(m,1H),7.33-7.28(m,1H),7.24-7.10(m,3H),7.08-7.01(m,3H),6.81(s,2H),6.79-6.75(m,4H),6.48(s,1H),5.37(d,J＝6.4Hz,1H),5.02(d,J＝6.5Hz,1H),3.88(s,3H),2.49(s,6H),2.22(s,3H)；13C NMR(126MHz,CDCl3)δ166.6,142.2,139.8,139.5,138.9,137.1,135.7,134.2,132.0,131.9,130.3,130.1,129.21,129.20,129.0,128.7,128.5,128.4,127.8,127.1,63.9,52.1,23.0,20.8；HRMS(ESI-TOF)m/z calcd.forC32H31NO4SNa[M+Na]+:548.1871,found 548.1880.
实施例7
(Z)-N-(1-(4-methoxyphenyl)-3-phenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1g(0.1mmol,31.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3g，收率87％,43.2mg。1H NMR(500MHz,CDCl3)δ7.13-7.01(m,5H),6.98-6.90(m,3H),6.77(s,2H),6.72-6.65(m,6H),6.43(s,1H),5.17(d,J＝6.2Hz,1H),4.81(d,J＝6.2Hz,1H),3.68(s,3H),2.45(s,6H),2.15(s,3H)；13C NMR(126MHz,CDCl3)δ159.2,142.0,140.2,138.9,137.7,136.0,134.5,131.9,131.1,129.2,129.1,129.0,128.6,128.5,127.7,127.5,126.9,113.8,63.7,55.2,23.0,20.8；HRMS(ESI-TOF)m/z calcd.forC31H31NO3SNa[M+Na]+:520.1923,found 520.1923.
实施例8
Tert-butyl-(E)-(4-(2,3-diphenyl-1-((2,4,6-trimethylphenyl)sulfonamido)allyl)benzyl)carbamate的制备
在氮气氛围中，依次向反应瓶中加入原料1h(0.1mmol,41.8mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3h，收率81％,48.2mg。1H NMR(500MHz,CDCl3)δ7.16-7.02(m,7H),7.00-6.93(m,3H),6.78(s,2H),6.70-6.63(m,4H),6.41(s,1H),5.22(d,J＝6.4Hz,1H),4.86(d,J＝6.4Hz,1H),4.74(s,1H),4.20(s,2H),2.44(s,6H),2.17(s,3H),1.39(s,9H)；13C NMR(126MHz,CDCl3)δ155.8,142.1,140.0,138.9,138.6,138.3,137.4,135.9,134.4,131.9,129.5,129.2,129.2,128.6,127.8,127.7,127.7,127.6,127.5,127.3,127.0,77.3,77.0,76.7,63.9,44.2,28.4,27.9,23.1,20.8；HRMS(ESI-TOF)m/z calcd.for C36H40N2O4SNa[M+Na]+:619.2606,found 619.2603.
实施例9
(E)-N-(1-(4-chlorophenyl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1i(0.1mmol,32.3mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3i，收率76％,38.1mg。1H NMR(500MHz,CDCl3)δ7.16-7.03(m,7H),7.01-6.93(m,3H),6.78(s,2H),6.71-6.65(m,4H),6.39(s,1H),5.21(d,J＝6.4Hz,1H),4.84(d,J＝6.4Hz,1H),2.43(s,6H),2.18(s,3H)；13C NMR(126MHz,CDCl3)δ142.3,139.7,138.9,137.7,137.1,135.7,134.2,133.6,131.9,129.9,129.19,129.18,128.8,128.7,128.6,127.9,127.2,63.7,23.1,20.8；HRMS(ESI-TOF)m/z calcd.for C30H28ClNO2SNa[M+Na]+:524.1427,found 524.1428.
实施例10
(E)-N-(2,3-diphenyl-1-(4-(trifluoromethyl)phenyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1j(0.1mmol,35.7mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3j，收率76％,43.8mg。1H NMR(500MHz,CDCl3)δ7.40(d,J＝8.2Hz,2H),7.29(d,J＝8.1Hz,2H),7.18-7.13(m,1H),7.11-7.06(m,2H),7.03-6.95(m,3H),6.75(s,2H),6.73-6.66(m,4H),6.38(s,1H),5.30(d,J＝6.4Hz,1H),4.91(d,J＝6.4Hz,1H),2.41(s,6H),2.17(s,3H)；13C NMR(126MHz,CDCl3)δ143.2,142.4,139.6,138.9,136.8,135.5,134.1,131.9,130.4,129.9(q,J＝32.5Hz),129.21,129.18,128.9,128.0,127.9,127.7,127.3,125.3(q,J＝3.8Hz),124.0(q,J＝272.1Hz),63.9,23.0,20.8；HRMS(ESI-TOF)m/zcalcd.for C31H28F3NO2SNa[M+Na]+:558.1691,found 558.1687.
实施例11
(E)-N-(1-(4-cyanophenyl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1k(0.1mmol,31.4mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3k，收率86％,42.3mg。1H NMR(500MHz,CDCl3)δ7.45(d,J＝8.3Hz,2H),7.30(d,J＝8.2Hz,2H),7.19-7.13(m,1H),7.08(m,2H),6.99(m,3H),6.77(s,2H),6.72-6.60(m,4H),6.35(s,1H),5.27(d,J＝6.6Hz,1H),5.04(d,J＝6.6Hz,1H),2.40(s,6H),2.19(s,3H)；13C NMR(126MHz,CDCl3)δ144.7,142.5,139.1,138.9,136.5,135.3,133.9,132.1,131.9,130.7,129.2,129.1,128.9,128.1,127.9,127.4,118.5,111.5,63.9,23.0,20.8；HRMS(ESI-TOF)m/z calcd.for C31H28N2O2SNa[M+Na]+:515.1769,found 515.1763.
实施例12
(E)-2,4,6-trimethyl-N-(1-(naphthalen-2-yl)-2,3-diphenylallyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1l(0.1mmol,33.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3l，收率85％,43.9mg。1H NMR(500MHz,CDCl3)δ7.74-7.57(m,3H),7.51(s,1H),7.41-7.29(m,3H),7.12-6.92(m,6H),6.76-6.66(m,6H),6.52(s,1H),5.39(d,J＝6.6Hz,1H),4.95(d,J＝6.6Hz,1H),2.43(s,6H),2.11(s,3H)；13C NMR(126MHz,CDCl3)δ142.1,140.0,138.9,137.5,136.3,135.9,134.4,133.1,132.8,131.9,129.8,129.3,129.2,128.6,128.4,128.1,127.8,127.7,127.5,127.0,126.5,126.16,126.15,125.1,64.3,23.1,20.8；HRMS(ESI-TOF)m/z calcd.for C34H31NO2SNa[M+Na]+:540.1973,found540.1982.
实施例13
(E)-N-(1-(furan-2-yl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1m(0.1mmol,27.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3m，收率65％,29.7mg。1H NMR(500MHz,CDCl3)δ7.23(s,1H),7.17-7.07(m,3H),6.98(d,J＝7.4Hz,3H),6.78(s,2H),6.77-6.69(m,4H),6.45(s,1H),6.16(dd,J＝3.3,1.8Hz,1H),6.01(d,J＝3.3Hz,1H),5.28(d,J＝7.8Hz,1H),4.96(d,J＝7.8Hz,1H),2.48(s,6H),2.16(s,3H)；13C NMR(126MHz,CDCl3)δ151.7,142.4,142.1,138.9,138.3,137.1,135.8,134.3,131.9,129.9,129.2,129.1,128.6,127.8,127.7,127.1,110.5,108.3,58.6,23.0,20.8；HRMS(ESI-TOF)m/z calcd.for C28H27NO3SNa[M+Na]+:480.1609,found 480.1614.
实施例14
(E)-N-(2,3-diphenyl-1-(thiophen-2-yl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1n(0.1mmol,29.5mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3n，收率91％,43.0mg。1H NMR(500MHz,CDCl3)δ7.16-7.12(m,2H),7.10-7.04(m,2H),7.01-6.96(m,3H),6.85-6.83(m,2H),6.80(s,2H),6.77-6.72(m,4H),6.51(s,1H),5.48(d,J＝7.5Hz,1H),4.95(d,J＝7.4Hz,1H),2.47(s,6H),2.16(s,3H)；13C NMR(126MHz,CDCl3)δ144.3,142.2,139.9,139.0,136.8,135.8,134.4,131.9,129.4,129.35,129.3,128.6,127.8,127.2,127.1,125.9,125.8,60.3,23.1,20.9；HRMS(ESI-TOF)m/zcalcd.for C28H27NO2S2Na[M+Na]+:496.1381,found 496.1381.
实施例15
(E)-2,4,6-trimethyl-N-(4-methyl-1,2-diphenylpent-1-en-3-yl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1o(0.1mmol,25.5mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.01mmol，2.8mg),和PhPCy2(0.02mmol，5.5mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3o，收率95％,41.1mg。1H NMR(500MHz,CDCl3)δ7.25-7.20(m,3H),7.05-6.98(m,3H),6.96-6.90(m,2H),6.86(s,2H),6.72-6.65(m,2H),6.25(s,1H),4.59(d,J＝8.6Hz,1H),3.97-3.89(m,1H),2.63(s,6H),2.18(s,3H),1.85-1.72(m,1H),0.96(d,J＝6.7Hz,3H),0.94(d,J＝6.7Hz,3H)；13C NMR(126MHz,CDCl3)δ141.9,140.2,138.5,138.1,136.2,135.2,131.9,129.3,129.2,129.1,128.7,127.7,127.5,126.6,67.0,30.7,23.4,20.8,20.3,18.0；HRMS(ESI-TOF)m/z calcd.For C27H31NO2SNa[M+Na]+:456.1973,found456.1978.
实施例16
(E)-N-(5-((tert-butyldimethylsilyl)oxy)-4,4-dimethyl-1,2-diphenylpent-1-en-3-yl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1p(0.1mmol,39.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.01mmol，2.8mg),和PhPCy2(0.02mmol，5.5mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3p，收率96％,55.4mg。1H NMR(500MHz,CDCl3)δ7.25-7.14(m,5H),7.03-6.94(m,3H),6.89(d,J＝5.9Hz,1H),6.67-6.64(m,2H),6.63–6.54(m,0H),6.27(s,1H),4.36(d,J＝5.9Hz,1H),3.67(d,J＝10.2Hz,1H),3.30(d,J＝10.2Hz,1H),2.65(s,6H),2.00(s,3H),0.96(s,9H),0.94(s,3H),0.70(s,3H),0.12(s,3H),0.10(s,3H)；13C NMR(126MHz,CDCl3)δ141.1,140.4,139.2,138.1,136.6,136.1,131.6,131.2,129.8,128.9,128.3,127.4,127.1,126.3,71.2,68.3,39.5,26.0,24.8,23.1,22.6,20.6,18.4,1.0,-5.5,-5.6；HRMS(ESI)m/z calcd.For C34H47NO3SSiNa[M+Na]+:600.2944,found 600.2947.
实施例17
(E)-N-(1-cyclobutyl-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1q(0.1mmol,26.7mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.01mmol，2.8mg),和PhPCy2(0.02mmol，5.5mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3q，收率99％,44.0mg。1H NMR(500MHz,CDCl3)δ7.22-7.15(m,3H),6.97-6.91(m,3H),6.87-6.84(m,2H),6.82(s,2H),6.68-6.61(m,2H),6.27(s,1H),4.31(d,J＝7.7Hz,1H),3.91(dd,J＝10.1,7.7Hz,1H),2.55(s,6H),2.31-2.17(m,1H),2.16(s,3H),1.92-1.82(m,2H),1.78-1.62(m,3H),1.61-1.53(m,1H)；13C NMR(126MHz,CDCl3)δ142.0,139.5,138.9,137.4,136.1,134.8,131.9,129.7,129.5,129.1,128.6,127.7,127.4,126.8,67.3,38.5,25.7,25.6,23.2,20.9,16.9；HRMS(ESI)m/z calcd.For C28H31NO2SNa[M+Na]+:468.1973,found 468.1971.
实施例18
(E)-N-(1-(4,4-difluorocyclohexyl)-2,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1r(0.1mmol,33.1mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.01mmol，2.8mg),和PhPCy2(0.02mmol，5.5mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3r，收率89％,45.3mg。1H NMR(500MHz,CDCl3)δ7.31-7.21(m,3H),7.08-6.96(m,3H),6.88(s,2H),6.86-6.80(m,2H),6.71-6.66(m,2H),6.26(s,1H),4.71-4.66(m,1H),4.02-3.95(m,1H),2.60(s,6H),2.20(s,3H),2.15-2.02(m,3H),1.88-1.82(m,1H),1.75-1.62(m,1H),1.57-1.41(m,2H),1.40–1.16(m,2H)；13C NMR(126MHz,CDCl3)δ142.1,139.1,138.5,137.2,135.7,135.0,132.0,130.0,129.2,129.1,128.9,127.8,127.8,127.0,123.2(dd,J＝242.3,239.7Hz),65.1(d,J＝2.3Hz),38.8,33.2(d,J＝23.0Hz),33.0(d,J＝23.0Hz),26.6(d,J＝9.4Hz),25.2(d,J＝9.4Hz),23.4,20.8；HRMS(ESI)m/zcalcd.For C30H33F2NO2SNa[M+Na]+:532.2098,found 532.2095.
实施例19
(E)-N-(2,3-diphenyl-1-(tetrahydro-2H-thiopyran-4-yl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1s(0.1mmol,31.3mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.01mmol，2.8mg),和PhPCy2(0.02mmol，5.5mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3s，收率46％,22.6mg。1H NMR(500MHz,CDCl3)δ7.31-7.20(m,3H),7.07-6.98(m,3H),6.88-6.83(m,4H),6.72-6.64(m,2H),6.22(s,1H),4.62(d,J＝8.9Hz,1H),3.99(m,1H),2.68-2.50(m,9H),2.31-2.25(m,1H),2.19(s,3H),2.13-2.06(m,1H),1.57-1.42(m,2H),1.41-1.30(m,2H)；13C NMR(126MHz,CDCl3)δ142.1,138.7,138.5,137.5,135.8,135.1,132.0,130.0,129.2,129.0,128.9,127.8,127.8,126.9,66.0,40.0,32.0,29.9,28.6,28.4,23.4,20.8；HRMS(ESI)m/z calcd.For C29H33NO2S2Na[M+Na]+:514.1851,found 514.1849.
实施例20
(E)-N-(2,3-bis(4-methoxyphenyl)-1-phenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2b(0.2mmol,47.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4b，收率90％,47.4mg。1H NMR(500MHz,CDCl3)δ7.26-7.19(m,5H),6.85(s,2H),6.74-6.68(m,2H),6.67(s,4H),6.62-6.57(m,2H),6.37(s,1H),5.26(d,J＝6.6Hz,1H),4.90(d,J＝6.6Hz,1H),3.75(s,3H),3.71(s,3H),2.51(s,6H),2.25(s,3H)；13C NMR(126MHz,CDCl3)δ158.9,158.4,142.0,139.5,138.9,137.6,134.6,131.8,130.5,130.4,129.6,128.8,128.7,128.4,127.6,127.3,114.0,113.3,64.4,55.1,23.1,20.8；HRMS(ESI)m/z calcd.For C32H33NO4SNa[M+Na]+:550.2028,found 550.2025.
实施例21
(E)-2,4,6-trimethyl-N-(1-phenyl-2,3-bis(4-(trifluoromethyl)phenyl)allyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2c(0.2mmol,62.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4c，收率71％,42.3mg。1H NMR(600MHz,CDCl3)δ7.40(d,J＝7.8Hz,2H),7.32(d,J＝8.2Hz,2H),7.29-7.25(m,3H),7.21-7.13(m,2H),6.92(d,J＝7.9Hz,2H),6.86(s,2H),6.83(d,J＝8.1Hz,2H),6.70(s,1H),5.29(d,J＝5.9Hz,1H),4.93(d,J＝5.9Hz,1H),2.54(s,6H),2.23(s,3H)；13C NMR(151MHz,CDCl3)δ142.5,141.5,141.4,139.0,138.9,138.0,134.3,132.0,130.0(q,J＝32.6Hz),129.5,129.3,129.1(q,J＝31.7Hz),129.0,128.8,128.5,127.4,125.65(q,J＝3.7Hz),124.92(q,J＝3.8Hz),123.9(q,J＝3.8Hz),123.8(q,J＝3.8Hz),64.0,23.0,20.8；HRMS(ESI)m/z calcd.For C32H27F6NO2SNa[M+Na]+:626.1564,found 626.1561.
实施例22
(E)-N-(3-(4-fluorophenyl)-2-(4-methoxyphenyl)-1-phenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2d(0.2mmol,45.2mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4d，收率92％,47.4mg。Re 1 1H NMR(600MHz,CDCl3)δ7.26-7.17(m,5H),6.87-6.78(m,3H),6.76-6.71(m,3H),6.70-6.65(m,3H),6.63-6.57(m,1H),6.42(s,1H),5.28(d,J＝6.4Hz,1H),4.90-4.85(m,1H),3.75(s,3H),2.52(s,6H),2.24(s,3H)；13C NMR(151MHz,CDCl3)δ161.5(d,J＝247.6Hz),159.1,142.1,139.5(d,J＝1.5Hz),139.1,138.9,134.6,132.3(d,J＝4.5Hz),131.9,130.7(d,J＝7.6Hz),130.5,129.2,128.6,128.0,127.8,127.3,114.7(d,J＝21.1Hz),114.1,64.2,55.1,23.1,20.8；HRMS(ESI)m/zcalcd.For C31H30FNO3SNa[M+Na]+:538.1828,found 538.1825.
Re 2 1H NMR(600MHz,CDCl3)δ7.26-7.17(m,5H),6.87-6.78(m,3H),6.76-6.71(m,3H),6.70-6.65(m,3H),6.63-6.57(m,1H),6.47(s,1H),5.25(d,J＝6.5Hz,1H),4.90-4.85(m,1H),3.75(s,3H),2.52(s,6H),2.25(s,3H)；13C NMR(151MHz,CDCl3)δ162.1(d,J＝247.6Hz),159.7,142.2,139.1,138.9,137.1,134.5,133.7(d,J＝7.6Hz),131.9,131.1(d,J＝4.5Hz),130.4,129.4,128.6,128.3,127.9,127.3,115.6(d,J＝21.1Hz),113.4,64.3,55.1,23.0,20.9；HRMS(ESI)m/z calcd.For C31H30FNO3SNa[M+Na]+:538.1828,found538.1825.
实施例23
(E)-N-(2-benzylidene-3-methyl-1-phenylbutyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2e(0.2mmol,28.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4e，收率99％,42.9mg(re＝6.7:1)。1H NMR(600MHz,CDCl3)δ7.30-7.26(m,2H),7.24-7.11(m,6H),7.01(d,J＝7.4Hz,2H),6.87(s,2H),6.53(s,1H),5.23(d,J＝5.4Hz,1H),4.77(d,J＝5.4Hz,1H),3.05-2.95(m,1H),2.57(s,6H),2.27(s,3H),1.03(d,J＝7.0Hz,3H),0.71(d,J＝7.0Hz,3H)；13C NMR(151MHz,CDCl3)δ146.3,142.0,140.7,138.8,137.3,134.9,131.8,128.6,128.5,128.1,127.7,127.6,127.5,126.6,57.6,29.0,22.9,22.0,21.4,20.8；HRMS(ESI)m/z calcd.For C27H31NO2SNa[M+Na]+:456.1973,found456.1976.
实施例24
(E)-N-(2,3-dicyclohexyl-1-phenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2f(0.2mmol,38.0mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4f，收率97％,46.3mg。1H NMR(500MHz,CDCl3)δ7.10-7.03(m,5H),6.79(s,2H),5.04(d,J＝9.6Hz,1H),4.88(d,J＝5.8Hz,1H),4.57(d,J＝5.8Hz,1H),2.47(s,6H),2.19(s,3H),2.15-2.09(m,2H),1.61-1.42(m,8H),1.29-1.01(m,9H),0.96-0.85(m,3H)；13C NMR(126MHz,CDCl3)δ141.8,141.0,140.9,138.7,134.9,134.5,131.7,128.1,127.4,127.3,59.3,40.4,36.5,33.4,33.0,32.2,31.8,26.8,26.8,25.93,25.89,25.84,25.83,23.0,20.8；HRMS(ESI-TOF)m/z calcd.for C30H41NO2SNa[M+Na]+:502.2756,found502.2752.
实施例25
(Z)-N-(1,3-diphenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2g(0.2mmol,34.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.9mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4g，收率96％,44.4mg。1H NMR(500MHz,CDCl3)δ7.66(s,1H),7.55-7.52(m,6H),7.44-7.39(m,2H),7.27-7.24(m,2H),7.22(s,2H),5.59(d,J＝6.7Hz,1H),5.05(d,J＝6.7Hz,1H),2.87(s,6H),2.61(s,3H),0.01(s,9H)；13C NMR(126MHz,CDCl3)δ142.2,142.0,141.5,140.0,139.5,138.8,135.0,131.9,128.6,128.4,128.1,128.0,127.7,127.1,61.9,23.1,20.9,0.3；HRMS(ESI-TOF)m/z calcd.for C27H33NO2SSiNa[M+Na]+:486.1899,found 486.1903.
实施例25的放大量制备：
在氮气氛围中，依次向反应管中加入原料1a(10mmol,2.89g)，原料2g(15mmol,2.6g)，K3PO4(4mmol,0.84g)，Ni(cod)2(0.7mmol，0.19g),和PCy3(1.4mmol，0.392g)，最后加入Dioxane(30mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4m，收率89％,4.12g.
实施例26
(Z)-N-(3-(2-methoxyphenyl)-1-phenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2h(0.2mmol,40.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4h，收率89％,43.8mg。1H NMR(500MHz,CDCl3)δ7.21-7.11(m,7H),6.80(s,2H),6.78-6.71(m,3H),5.18(d,J＝7.0Hz,1H),4.78(d,J＝7.0Hz,1H),3.72(s,3H),2.50(s,6H),2.20(s,3H),-0.39(s,9H)；13C NMR(126MHz,CDCl3)δ157.0,141.8,141.7,140.2,139.2,138.8,134.9,131.8,130.2,128.8,128.6,128.3,128.2,127.6,119.6,109.9,61.5,55.2,23.0,20.8,0.0；HRMS(ESI-TOF)m/z calcd.for C28H35NO3SSiNa[M+Na]+:516.2004,found 516.2004.
实施例27
(Z)-N-(3-(2-fluorophenyl)-1-phenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2i(0.2mmol,38.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4i，收率94％,45.2mg。1H NMR(500MHz,CDCl3)δ7.18-7.13(m,5H),7.08-7.04(m,2H),6.97-6.89(m,2H),6.83(s,2H),6.81-6.79(m,1H),5.20(d,J＝6.8Hz,1H),4.70(d,J＝6.6Hz,1H),2.51(s,6H),2.22(s,3H),-0.37(s,9H)；13C NMR(126MHz,CDCl3)δ159.8(d,J＝245.6Hz),144.6,142.0,139.7,138.8,135.2,134.8,131.9,130.9(d,J＝3.4Hz),129.1(d,J＝7.9Hz),128.6,128.1,128.0,127.2(d,J＝16.5Hz),123.3(d,J＝3.6Hz),115.1(d,J＝21.9Hz),61.8,23.0,20.8,-0.2；HRMS(ESI-TOF)m/z calcd.forC27H32FNO2SSiNa[M+Na]+:504.1805,found 504.1803.
实施例28
(Z)-N-(3-(3-methoxyphenyl)-1-phenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2j(0.2mmol,40.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4j，收率91％,44.9mg。1H NMR(500MHz,CDCl3)δ7.26(s,1H),7.19-7.15(m,3H),7.11-7.03(m,3H),6.86(s,2H),6.70(m,1H),6.51(d,J＝7.5Hz,1H),6.40(s,1H),5.21(d,J＝6.7Hz,1H),4.68(d,J＝6.7Hz,1H),3.70(s,3H),2.50(s,6H),2.24(s,3H),-0.33(s,9H)；13C NMR(126MHz,CDCl3)δ159.1,142.0,141.9,141.5,140.9,139.9,138.8,135.1,131.9,128.7,128.6,128.1,128.0,121.0,114.1,112.6,77.3,77.0,76.7,61.9,55.2,23.1,20.9,0.3；HRMS(ESI-TOF)m/z calcd.for C28H35NO3SSiNa[M+Na]+:516.2004,found 516.2013.
实施例29
(Z)-2,4,6-trimethyl-N-(1-phenyl-3-(3-(trifluoromethyl)phenyl)-2-(trimethylsilyl)allyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2k(0.2mmol,48.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4k，收率92％,48.9mg。1H NMR(500MHz,CDCl3)δ7.41(d,J＝7.8Hz,1H),7.32-7.28(m,2H),7.22-7.18(m,3H),7.10(d,J＝7.7Hz,1H),7.08-7.04(m,3H),6.87(s,2H),5.26(d,J＝6.3Hz,1H),4.70(d,J＝6.3Hz,1H),2.51(s,6H),2.24(s,3H),-0.36(s,9H)；13C NMR(126MHz,CDCl3)δ143.5,142.3,140.28,140.27,139.5,138.8,135.0,131.9,131.7,130.2(q,J＝32.2Hz),128.8,128.3,128.23,128.2,125.3(q,J＝3.7Hz),124.04(q,J＝272.4Hz),123.8(q,J＝3.8Hz),62.0,23.1,20.8,0.2；HRMS(ESI-TOF)m/z calcd.forC28H32F3NO2SSiNa[M+Na]+:554.1773,found 554.1771.
实施例30
(Z)-N-(3-(4-methoxyphenyl)-1-phenyl-2-(trimethylsilyl)allyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2l(0.2mmol,40.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4l，收率78％,38.5mg。1H NMR(600MHz,CDCl3)δ7.28(s,1H),7.26(s,1H),7.24-7.20(m,3H),7.14-7.08(m,2H),6.92(s,2H),6.91-6.87(m,2H),6.81-6.76(m,2H),5.28(dd,J＝6.8,1.6Hz,1H),4.72(d,J＝6.7Hz,1H),3.80(s,3H),2.57(s,6H),2.32(s,3H),-0.25(s,9H)；13C NMR(151MHz,CDCl3)δ158.9,142.0,142.0,140.4,140.1,138.8,135.1,131.9,129.7,128.6,128.1,127.9,113.1,62.0,55.2,23.1,20.9,0.4；HRMS(ESI)m/z calcd.For C28H35NO3SSiNa[M+Na]+:516.2004,found 516.2011.
实施例31
(Z)-2,4,6-trimethyl-N-(1-phenyl-3-(4-(trifluoromethyl)phenyl)-2-(trimethylsilyl)allyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2m(0.2mmol,48.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4m，收率94％,49.9mg。1H NMR(500MHz,CDCl3)δ7.44(d,J＝7.9Hz,2H),7.33(m,1H),7.19(m,3H),7.03(m,2H),7.02(d,J＝7.9Hz,2H),6.87(s,2H),5.21(d,J＝6.4Hz,1H),4.66(d,J＝6.4Hz,1H),2.50(s,6H),2.26(s,3H),-0.36(s,9H)；13C NMR(126MHz,CDCl3)δ143.6,143.3,142.2,140.4,139.5,138.9,134.9,131.9,129.3(q,J＝32.5Hz),128.8,128.7,128.3,128.1,124.7(q,J＝3.8Hz),124.1(q,J＝271.9Hz),61.9,23.1,20.9,0.3；HRMS(ESI-TOF)m/z calcd.for C28H32F3NO2SSiNa[M+Na]+:554.1773,found554.1766.
实施例32
(Z)-2,4,6-trimethyl-N-(1-phenyl-3-(thiophen-2-yl)-2-(trimethylsilyl)allyl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2n(0.2mmol,36.0mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4n，收率90％,42.2mg。1H NMR(600MHz,CDCl3)δ7.26-7.19(m,4H),7.17-7.14(m,1H),7.14-7.07(m,2H),6.92(s,2H),6.88-6.85(m,1H),6.71(dd,J＝5.0,1.2Hz,1H),5.28(dd,J＝6.6,1.6Hz,1H),4.72(d,J＝6.6Hz,1H),2.57(s,6H),2.31(s,3H),-0.21(s,9H)；13C NMR(151MHz,CDCl3)δ142.0,141.8,140.1,139.9,138.8,136.3,135.1,131.9,128.6,128.5,128.1,128.0,124.9,122.9,62.0,23.1,20.9,0.1；HRMS(ESI)m/z calcd.ForC25H31NO2S2SiNa[M+Na]+:492.1463,found 492.1459.
实施例33
(Z)-2,4,6-trimethyl-N-(1-phenyl-2-(trimethylsilyl)but-2-en-1-yl)benzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2o(0.2mmol,22.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4o，收率91％,36.5mg(re＝12:1)。1H NMR(600MHz,CDCl3)δ7.20-7.16(m,3H),7.07-7.01(m,2H),6.89(s,2H),6.15(m,1H),5.03(d,J＝7.0Hz,1H),4.64(d,J＝6.9Hz,1H),2.54(s,6H),2.29(s,3H),1.68(d,J＝7.1Hz,3H),-0.04(s,9H)；13C NMR(151MHz,CDCl3)δ141.9,140.6,138.9,138.7,137.9,134.9,131.7,128.3,127.7,127.5,62.0,23.1,20.8,17.4,-0.03；HRMS(ESI)m/z calcd.For C22H31NO2SSiNa[M+H]+:424.1743,found 424.1736.
实施例34
(Z)-N-(2-(dimethyl(phenyl)silyl)-1,3-diphenylallyl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2p(0.2mmol,47.2mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4p，收率92％,48.3mg。1H NMR(600MHz,CDCl3)δ7.55(s,1H),7.25-7.20(m,2H),7.20-7.12(m,7H),7.04-7.00(m,2H),6.98-6.92(m,2H),6.90-6.86(m,4H),5.14(dd,J＝6.9,1.6Hz,1H),4.71(d,J＝6.9Hz,1H),2.51(s,6H),2.30(s,3H),-0.05(s,3H),-0.07(s,3H)；13C NMR(151MHz,CDCl3)δ143.4,142.0,140.4,139.7,139.2,138.8,138.0,134.9,134.0,131.8,128.8,128.6,128.5,128.2,127.9,127.7,127.5,127.2,62.1,23.0,20.9,-0.9,-1.2；HRMS(ESI)m/z calcd.For C32H35NO2SSiNa[M+Na]+:548.2056,found548.2059.
实施例35
(Z)-N-(2-(dimethyl(phenyl)silyl)-1-phenylbut-2-en-1-yl)-2,4,6-trimethylbenzenesulfonamide的制备
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2q(0.2mmol,34.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PhPCy2(0.014mmol，3.8mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物4q，收率85％,39.4mg。1H NMR(600MHz,CDCl3)δ7.33-7.27(m,1H),7.27-7.20(m,4H),7.20-7.11(m,3H),6.91-6.84(m,4H),6.40(m,1H),5.03(d,J＝6.9Hz,1H),4.64(d,J＝6.9Hz,1H),2.52(s,6H),2.29(s,3H),1.61(dd,J＝7.1,1.2Hz,3H),0.24(s,3H),0.20(s,3H)；13C NMR(151MHz,CDCl3)δ141.9,140.2,140.0,138.8,138.2,136.6,134.8,133.8,131.8,128.8,128.3,127.8,127.7,127.5,62.0,23.0,20.9,17.9,-1.2,-1.3；HRMS(ESI)m/z calcd.For C27H33NO2SSiNa[M+Na]+:486.1899,found 486.1893.
实施例36
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,14.5mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3a*，收率74％,17.3mg。SFC conditions:AS-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝5.34min,tminor＝6.65min,er＝94.1:5.9。
实施例37
在氮气氛围中，依次向反应瓶中加入原料1d(0.05mmol,15.9mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3d*，收率54％,13.4mg。SFC conditions:AD-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝4.31min,tminor＝5.69min,er＝95.2:4.8。
实施例38
在氮气氛围中，依次向反应瓶中加入原料1f(0.05mmol,17.4mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3f*，收率89％,23.4mg。SFC conditions:AD-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝4.97min,tminor＝6.12min,er＝95.4:4.6。
实施例39
在氮气氛围中，依次向反应瓶中加入原料1g(0.05mmol,15.9mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3g*，收率71％,17.6mg。SFC conditions:AD-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝5.90min,tminor＝7.42min,er＝92.2:7.8。
实施例40
在氮气氛围中，依次向反应瓶中加入原料1k(0.05mmol,15.7mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3k*，收率73％,17.9mg。SFC conditions:OD-3column,MeOH/CO2＝15:85,1.0mL/min,254nm,tmajor＝6.93min,tminor＝5.70min,er＝93.3:6.7。
实施例41
在氮气氛围中，依次向反应瓶中加入原料1n(0.05mmol,14.8mg)，原料2a(0.1mmol,17.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3n*，收率73％,17.3mg。SFC conditions:OJ-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝6.04min,tminor＝5.34min,er＝96.3:3.7。
实施例42
在氮气氛围中，依次向反应瓶中加入原料1o(0.05mmol,12.8mg)，原料2a(0.1mmol,17.8mg)，NaOAc(0.04mmol,3.3mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.013mmol，4.4mg)，最后加入Dioxane(0.25mL)，在140℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3o*，收率47％,10.2mg。SFC conditions:OD-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝3.72min,tminor＝4.19min,er＝91.1:8.9。
实施例43
在氮气氛围中，依次向反应瓶中加入原料1r(0.05mmol,16.7mg)，原料2a(0.1mmol,17.8mg)，NaOAc(0.04mmol,3.3mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.013mmol，4.4mg)，最后加入Dioxane(0.25mL)，在140℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性3r*，收率70％,17.9mg。SFC conditions:AS-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝4.17min,tminor＝2.64min,er＝91.4:8.6。
实施例44
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,11.9mg)，原料2b(0.1mmol,23.8mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性4b*，收率74％,19.5mg。SFC conditions:AS-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝7.14min,tminor＝8.73min,er＝95.4:4.6。
实施例45
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,11.9mg)，原料2e(0.1mmol,14.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性4e*，收率81％,17.5mg(re＝9:1)。SFC conditions:IA-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝3.92min,tminor＝4.45min,er＝93.8:6.2。
实施例46
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,11.9mg)，原料2g(0.1mmol,17.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性4g*，收率81％,18.8mg。SFC conditions:IA-3column,MeOH/CO2＝7:93,1.0mL/min,202nm,tmajor＝5.14min,tminor＝6.50min,er＝95.5:4.5。
实施例47
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,11.9mg)，原料2i(0.1mmol,20.4mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性4i*，收率80％,19.8mg。SFC conditions:AS-3column,MeOH/CO2＝10:90,1.0mL/min,254nm,tmajor＝2.94min,tminor＝4.28min,er＝97.2:2.8。
实施例48
在氮气氛围中，依次向反应瓶中加入原料1a(0.05mmol,11.9mg)，原料2m(0.1mmol,24.2mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.005mmol，1.4mg),和L1(0.01mmol，3.5mg)，最后加入THF(0.25mL)，在80℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物手性4m*，收率79％,21.1mg。SFC conditions:IA-3column,MeOH/CO2＝5:95,1.0mL/min,210nm,tmajor＝4.49min,tminor＝6.27min,er＝97.9:2.1。
实施例49
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，K3CO3(0.04mmol,5.5mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率78％,36.4mg。
实施例50
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，NaOOCH(0.04mmol,2.7mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率83％,38.8mg。
实施例51
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入THF(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率90％,42.0mg。
实施例52
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Toluene(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率80％,37.4mg。
实施例53
在氮气氛围中，依次向反应瓶中加入原料1a(0.1mmol,28.9mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和(4-OMePh)3P(0.014mmol，4.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3a，收率72％,33.6mg。
实施例54
在氮气氛围中，依次向反应瓶中加入原料1L(0.1mmol,31.1mg)，原料2a(0.2mmol,35.6mg)，K3PO4(0.04mmol,8.4mg)，Ni(cod)2(0.007mmol，1.9mg),和PCy3(0.014mmol，3.92mg)，最后加入Dioxane(0.5mL)，在120℃下搅拌24小时，冷却至室温，浓缩，直接柱层析分离得到目标产物3L，收率79％,38.7mg。1H NMR(500MHz,CDCl3)δ7.85-7.64(m,6H),7.59-7.35(m,3H),7.32-7.03(m,8H),6.92-6.68(m,4H),6.59(s,1H),5.54(d,J＝8.0Hz,1H),5.14(d,J＝8.1Hz,1H),2.30(s,3H)；13C NMR(126MHz,CDCl3)δ143.3,139.6,137.5,137.1,136.3,135.8,133.1,132.7,130.2,129.4,129.3,129.2,128.7,128.4,128.1,127.8,127.7,127.5,127.3,127.1,126.3,126.2,126.1,125.1,64.4,21.4.
各实施例的制备工艺参数如下表1和2所示。
表1实施例1～18的制备工艺参数表
表2为实施例27～54的制备工艺参数表
从表1和表2中可以进一步验证，本发明用到的原料大多均为商业可得，操作处理方便，无需特别纯化处理；且规模放大至克级，产率依然可以保持，即可容易产业化。且当配体替换为手性磷配体，可进一步得到高光学纯的烯丙胺衍生物。
本领域普通技术人员可以理解，以上所述仅为发明的优选实例而已，并不用于限制发明，尽管参照前述实例对发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实例记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在发明的精神和原则之内，所做的修改、等同替换等均应包含在发明的保护范围之内。
Claims (2)
1.一种合成手性烯丙基胺衍生物的方法，其特征在于，在氮气氛围中，将原料1、原料2、无机碱、金属催化剂和配体混合均匀，然后加入溶剂，在一定温度下搅拌使其反应完全，冷却至室温，浓缩，柱层析分离得到式3化合物，即手性烯丙基胺衍生物，具体的反应式如下：
其中，原料1为苄胺衍生物或烷基胺类衍生物，R2基团为均三甲基苯磺酰基；
原料2中的R3和R4基团均选自芳基、烷基或硅基中的任意一种，但R3和R4不能同时选自硅基；
所述的金属催化剂为Ni(cod)2，所述的配体为手性单膦配体，配体的结构式如下：
所述溶剂为1,4-二氧六环或四氢呋喃；所述无机碱为磷酸钾。
2.根据权利要求1所述的合成手性烯丙基胺衍生物的方法，其特征在于，反应温度为80~140℃。
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