CN110294702B - 一种手性α-含氟高烯丙胺衍生物及其制备方法和应用 - Google Patents
一种手性α-含氟高烯丙胺衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种通过新型的铱催化的含氟靛红亚胺参与的偶极反转的烯丙基化/2‑氮杂‑Cope重排反应合成具有手性α‑含氟高烯丙胺衍生物,其合成方法为:在有机溶剂中,在惰性气体保护下,以烯丙基碳酸酯和含氟靛红亚胺作为原料,铱催化剂为催化剂,在25℃温度下反应12‑36小时,经柱层析得到目标化合物。
Description
技术领域
本发明属于化学医药领域,具体涉及手性α-含氟高烯丙胺衍生物及其制备方法和应用。
背景技术
手性α-含氟高烯丙胺结构单元广泛存在于具有重要生物活性的化合物(如上市药物)中。因此高效,普适,容易使用的手性α-含氟高烯丙胺合成方法一直是合成化学中的热点研究领域。含氟靛红亚胺,具有廉价易得等特点,该化合物作为合成子被广泛应用于含氟化合物的合成中。然而到目前为止,没有课题组报到使用不对称催化烯丙基化的方法利用含氟靛红亚胺合成手性α-含氟高烯丙胺。(a)Ojima,I.,Ed.;Wiley-Blackwell:New York,2009.(b)Bégué, J.-P.,Bonnet-Delpon,D.,Bioorganic and Medicinal Chemistry ofFluorine;John Wiley&Sons, Inc.:New York,2008.(c)Tressaud,A.;Haufe,G.Fluorineand Health-Molecular Imaging, Biomedical Materials and Pharmaceuticals;Elsevier:Amsterdam,2008(d)Y.Zhou,J.Wang,Z. Gu,S.Wang,W.Zhu,J.L.V.A.Soloshonok,K.Izawa,H.Liu,Chem.Rev.,2016,116,422; (e)J.Wang,M.Sánchez-Roselló,J.L.C.del Pozo,A.E.Sorochinsky,S.Fustero,V.A. Soloshonok,H.Liu,Chem.Rev.,2014,114,2432;(f)S.Purser,P.R.Moore,S.Swallow,V. Gouverneur,Chem.Soc.Rev.,2008,37,320;(g)T.Fujiwara,D.O'Hagan,J.Fluorine Chem.,2014, 167,16;(h)W.Zhang,Chem.Rev.,2009,109,749;(i)R.Berger,G.Resnati,P.Metrangolo,E.Weber,J.Hulliger,Chem.Soc.Rev.,2011,40,3496。
发明内容
为了解决上述技术问题,本发明提供了一种通过新型的铱催化的含氟靛红亚胺参与的偶极反转的烯丙基化/2-氮杂-Cope重排反应合成具有手性的α-含氟高烯丙胺衍生物的方法。
本发明提供的方案如下:
一方面,本发明提供一种手性α-含氟高烯丙胺衍生物I及其制备方法。该化合物结构如式I所示:
其中,R1、R2、R3、R4为氢、C1-24的烃基或卤素;所述的烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1- 萘基、2-萘基,甲氧基;
R5为氢或C1-24的烃基;所述的烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基或烯丙基;
R6为氢或C1-24的烃基;所述烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基或烯丙基;
R7为一氟甲基、二氟甲基、三氟甲基或C2-5的全氟烷基;
R8为H、取代或未取代的芳基、取代或不取代的不饱和杂环基、C1-C6链式或环状烷烃;所述取代或不取代的不饱和杂环基含有杂原子为N、O或S;所述取代芳基取代基为烷基、烷氧基、卤素或链烯基;
R9为H、烷烃、取代或未取代的芳基。
上述的手性α-含氟高烯丙胺衍生物I的制备方法,包括以下制备步骤:
在铱催化剂存在的条件下,底物-1与底物-2进行催化反应,制备得到式I所示的手性α- 含氟高烯丙胺衍生物I;
制备反应式如下:
其中,R1、R2、R3、R4为氢、C1-24的烃基或卤素;所述烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、 2-萘基,甲氧基;
R5为氢或C1-24的烃基;所述烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基或烯丙基;
R6为氢或C1-24的烃基;所述的烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基或烯丙基;
R7为一氟甲基、二氟甲基、三氟甲基或C2-5的全氟烷基;
R8为H、取代或未取代的芳基、取代或不取代的不饱和杂环基、C1-C6链式或环状烷烃;所述取代或不取代的不饱和杂环基含有杂原子为N、O或S;所述取代芳基取代基为烷基、烷氧基、卤素或链烯基;
R9为H、烷烃、取代或未取代的芳基。
上述制备方法,包括以下制备步骤:
将底物-1、底物-2、铱催化剂和1~10当量的有机碱溶于溶剂中,在0~100℃反应6~36 小时即得式I所述的手性α-含氟高烯丙胺衍生物I;优选的,反应温度为10~50℃;进一步优选,反应温度为25℃。
所述底物-1、底物-2的浓度分别为0.001~3.0M;所述底物-1与底物-2的摩尔比为1:0.1~10;所述铱催化剂的用量为底物-1或底物-2中浓度较低者的0.0001~10mol%。优选的,底物-1与底物-2的摩尔比为1.0:1.1。
上述铱催化剂选自[Ir(COD)Cl]2、[Ir(DBCOT)Cl]2或[Ir(COD)OMe]2。优选的,铱催化剂为[Ir(COD)Cl]2。
上述铱催化剂采用如下方法制备:50℃下,按金属铱盐和配体L1溶于有机溶剂中,加入有机碱经反应得到;
所述手性配体L1的结构式为:
上述溶剂选自甲醇、乙醇、异丙醇、叔丁醇、仲丁醇、乙酸乙酯、乙酸异丁酯、乙酸异丙酯、正己烷、环己烷、正庚烷、丙酮、丁酮、乙醚、甲基叔丁基醚、甲基环戊基醚、甲基四氢呋喃、四氢呋喃、乙氰、二氯甲烷、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯和二氧六环中的至少一种。优选的,溶剂为二氯甲烷。
上述反应温度为10~50℃。
第二方面,本发明提供一种手性α-含氟高烯丙胺衍生物II及其制备方法。该化合物结构如式II所示:
其中,R7为一氟甲基、二氟甲基、三氟甲基或C2-5的全氟烷基;
R8为H、取代或未取代的芳基、取代或不取代的不饱和杂环基、C1-C6链式或环状烷烃;所述取代或不取代的不饱和杂环基含有杂原子为N、O或S;所述取代芳基取代基为烷基、烷氧基、卤素或链烯基;
R9为H、烷烃、取代或未取代的芳基。
上述的手性α-含氟高烯丙胺衍生物II的制备方法,由式I所述的手性α-含氟高烯丙胺衍生物I在酸中水解得到。
上述水解温度为0~100℃,水解时间为0.5~24小时。
上述酸选自柠檬酸、盐酸、甲磺酸、对甲苯磺酸、乙酸、硫酸、盐酸羟胺和醋酸羟胺中的任意一种;所述酸的用量为底物-1或底物-2中浓度较低者的1~20倍。优选的,酸选用盐酸,浓度为1摩尔/升。
第三方面,本发明提供手性α-含氟高烯丙胺衍生物II在制备手性α-含氟高烯丙胺以及具有手性胺结构单元的抗抑郁类药物、抗肿瘤类药物和天然产物中的应用。
上述手性α-含氟高烯丙胺制备具有手性四氢吡咯结构的衍生物的方法,包括以下步骤:将手性α-含氟高烯丙胺溶于有机溶剂中,加入1到10个当量碳酸盐或碳酸氢盐、1到五个当量碘单质,在-40~0℃反应6~36小时;反应达到平衡后加入硫代硫酸钠饱和溶液淬灭,经柱层析得到目标产物:
其中,R7为一氟甲基、二氟甲基、三氟甲基或C2-5的全氟烷基;
R8为H、取代或未取代的芳基、取代或不取代的不饱和杂环基、C1-C6链式或环状烷烃;所述取代或不取代的不饱和杂环基含有杂原子为N、O或S;所述取代芳基取代基为烷基、烷氧基、卤素或链烯基。优选的,上述柱层析以硅胶为填充料,以石油醚和乙酸乙酯的混合溶剂为淋洗剂,并且石油醚和乙酸乙酯的体积比为3~20:1。
第四方面,本发明提供上述的手性四氢吡咯衍生物作为有机催化剂的应用。
本发明的有益效果:
1)本发明方法合成简单,成本低,产率高,所得反应目标化合物对应选择性好,产率 42-94%,绝大多数对应选择性过量≥90%;
2)本发明方法采用铱催化剂作为催化剂,在反应中表现出催化反应速度快和催化剂用量低的优点;
3)所制备的手性α-含氟高烯丙胺衍生物可以用于合成手性α-含氟高烯丙胺以及具有手性胺结构单元的抗抑郁类药物、抗肿瘤类药物和天然产物;
4)所制备的手性α-含氟高烯丙胺可用于合成可作为有机催化剂的具有手性四氢吡咯结构的衍生物;
5)为手性α-含氟高烯丙胺衍生物、手性α-含氟高烯丙胺及具有手性四氢吡咯结构的衍生物提供了一种极具前景的合成方法;对于含有手性α-含氟高烯丙胺结构单元的药物合成极具参考价值。
具体实施方式
为了更好的理解本发明,下面结合实施例对本发明做进一步的说明。本发明的内容完全不限于此。
实施例1
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体。产率99%,产物的对映选择性过量95%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm);tr=4.88and 5.29min);[α]25 D=-90.0(c 0.18,CH2Cl2);1H NMR (400MHz,CDCl3)δ7.70(d,J=7.6Hz,1H),7.41(t,J=7.6Hz,1H),7.26–7.14(m,5H),7.09(t, J=7.6Hz,1H),6.70(d,J=7.6Hz,1H),6.23(d,J=16.0Hz,1H),6.17–6.05(m,2H),3.04– 2.93(m,4H),2.64–2.53(m,1H).13C NMR(101MHz,CDCl3)δ159.0,155.9,145.8,135.5,133.8, 132.9,132.5,128.6,127.4,125.4(q,J=280.1Hz),125.6,123.4,123.0,120.7,108.7,59.9(q,J= 28.3Hz),34.0,25.6.19F NMR(376MHz,CDCl3)δ-74.47(d,J=7.3Hz)For C20H17F3N2ONa ([M+Na]+):381.1185,测量值:381.1185。
实施例2
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol对甲基苯烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,产率90%,熔点80-82℃,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=4.62and 4.83min.);[α]25 D= -124.6(c 0.13,CH2Cl2)1H NMR(400MHz,CDCl3)δ7.69(dd,J=7.6,0.8Hz,1H),7.41(td,J=7.9,1.2Hz,1H),7.13–6.98(m,5H),6.70(d,J=8.0Hz,1H),6.21(d,J=15.6Hz,1H),6.16– 5.98(m,2H),3.03(s,3H),3.01–2.92(m,1H),2.63–2.52(m,1H),2.30(s,3H).13CNMR(101 MHz,CDCl3)δ159.00,155.82,145.79,137.11,134.30,133.67,133.65,129.11,126.86,125.47(q, J=280.2Hz),123.73,123.34,122.92,120.80,108.60,59.98(q,J=28.1Hz),34.06,25.59,21.20. 19F NMR(376MHz,CDCl3)δ-74.44(d,J=7.3Hz).HRMS计算值For C21H19F3N2ONa ([M+Na]+):395.1342,测量值:395.1342。
实施例3
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol对甲氧基苯烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率92%,产物的对映选择性过量94%,Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm,tr=6.48and 6.78min.)[α]30 D=-81.0(c 0.20,CH2Cl2);1H NMR(400 MHz,CDCl3)δ7.69(d,J=7.2Hz,1H),7.41(td,J=8.0,1.2Hz,1H),7.15–7.05(m,3H),6.77(d, J=8.8Hz,2H),6.70(d,J=7.6Hz,1H),6.16(d,J=16.0Hz,1H),6.11–6.01(m,1H),6.01– 5.88(m,1H),3.77(s,3H),3.02(s,3H),2.99–2.89(m,1H),2.60–2.49(m,1H).13C NMR(101 MHz,CDCl3)δ158.99,158.96,155.74,145.73,133.59,133.18,129.88,127.25,125.44(d,J= 280.1Hz),123.30,122.88,122.56,120.78,113.76,108.54,60.02(q,J=28.1Hz),55.29,34.01, 25.58.19F NMR(376MHz,CDCl3)δ-74.46(d,J=7.3Hz).HRMS计算值C21H19F3N2O2Na ([M+Na]+):411.1292,测量值:411.1291。
实施例4
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol对氟苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,产率99%,熔点85-87℃,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.24and 5.54min.);[α]25 D= -134.2(c 0.12,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.69(d,J=7.2Hz,1H),7.42(t,J=7.6Hz, 1H),7.20–7.06(m,3H),6.92(t,J=8.4Hz,2H),6.71(d,J=8.0Hz,1H),6.19(d,J=16.0Hz, 1H),6.13–5.96(m,2H),3.03(s,3H),3.00–2.86(m,1H),2.62–2.50(m,1H).13CNMR(101 MHz,CDCl3)δ162.2(d,J=246.4Hz),159.0,155.8,145.8,133.7,133.2(d,J=3.3Hz),132.6, 127.6(d,J=7.9Hz),124.6(d,J=2.0Hz),124.0(d,J=280.1Hz),123.4,123.0,120.8,115.3(d,J =21.5Hz),108.62,59.9(q,J=28.3Hz),33.99,25.60.19F NMR(376MHz,CDCl3)δ-74.47(d,J =7.3Hz),-114.89(m)HRMS(ESI+)计算值C20H16F4N2ONa([M+Na]+):399.1091,测量值: 399.1091。
实施例5
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol对氯苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,产率93%,熔点88-90℃,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=6.74and 7.56min.);[α]25 D= -172.9(c 0.21,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.69(d,J=6.8Hz,1H),7.42(td,J=7.6, 1.2Hz,1H),7.24–7.17(m,2H),7.15–7.07(m,3H),6.72(d,J=7.6Hz,1H),6.19(d,J=16.0Hz, 1H),6.15–6.01(m,2H),3.04(s,3H),3.01–2.92(m,1H),2.62–2.51(m,1H).13CNMR(101 MHz,CDCl3)δ158.9,155.8,145.7,135.5,133.7,132.9,132.5,128.5,127.3,125.5,125.4(q,J= 280.8Hz),123.4,122.9,120.7,108.6,59.8(q,J=28.3Hz),34.0,25.6.19F NMR(376MHz,CDCl3) δ-74.48(d,J=7.3Hz).HRMS计算值For C20H16ClF3N2ONa([M+Na]+):415.0795,测量值: 415.0795。
实施例6
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol对溴苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,产率93%,熔点100-102℃,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm);tr=5.44and 5.86min);[α]25 D= -205.5(c 0.11,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.69(d,J=6.8Hz,1H),7.42(td,J=8.0, 1.2Hz,1H),7.38–7.28(m,2H),7.13–7.02(m,3H),6.73(d,J=7.6Hz,1H),6.21–6.01(m,3H), 3.04(s,3H),2.99–2.91(m,1H),2.62–2.51(m,1H).13C NMR(101MHz,CDCl3)δ159.0,155.9, 145.8,136.0,133.8,132.6,131.52,127.7,125.7,125.4(q,J=280.1Hz),123.4,123.0,121.1,120.7, 108.7,59.8(q,J=28.2Hz),34.0,25.7.19F NMR(376MHz,CDCl3)δ-74.50(d,J=7.2Hz). HRMS计算值C20H16BrF3N2ONa([M+Na]+):459.0290,测量值:459.0290。
实施例7
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol间甲基苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率99%,产物的对映选择性过量94%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=4.99and 5.26min.);[α]25 D=-67.9(c 0.29,CH2Cl2). 1H NMR(400MHz,CDCl3)δ7.70(d,J=6.8Hz,1H),7.45–7.38(m,1H),7.16–7.06(m,2H), 7.06–6.93(m,3H),6.70(d,J=8.0Hz,1H),6.27–6.01(m,3H),3.06–2.90(m,4H),2.62–2.52 (m,1H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ158.9,155.8,145.7,137.9,136.9,133.9, 133.6,128.2,128.0,126.8,125.4(q,J=280.1Hz),124.5,123.3,123.1,122.8,120.7,108.5,59.9 (q,J=28.1Hz).34.0,25.4,21.3.19F NMR(376MHz,CDCl3)δ-74.47(d,J=7.3Hz).HRMS计算值C21H19F3N2ONa([M+Na]+):395.1342,测量值:395.1342.HRMS(ESI+)。
实施例8
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol间甲氧基苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率94%,产物的对映选择性过量92%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=6.64and 7.18min.);[α]25 D=-107.2(c0.26,CH2Cl2). 1H NMR(400MHz,CDCl3)δ7.69(d,J=7.6Hz,1H),7.41(t,J=7.6Hz,1H),7.15(t,J=8.0Hz, 1H),7.09(t,J=7.6Hz,1H),6.80(d,J=7.6Hz,1H),6.77–6.66(m,3H),6.20(d,J=15.6Hz, 1H),6.16–6.05(m,2H),3.75(s,3H),3.06–2.91(m,4H),2.64–2.52(m,1H).13C NMR(100 MHz,CDCl3)δ159.7,159.0,155.9,145.8,138.5,133.8,133.7,129.4,125.4(q,J=280.8Hz), 125.2,123.4,122.9,120.8,118.7,113.1,111.4,108.6,59.9(q,J=28.2Hz),55.2,34.0,25.6.19F NMR(376MHz,CDCl3)δ-74.45(d,J=7.3Hz).HRMS计算值C21H19F3N2O2Na([M+Na]+): 411.1291,测量值:411.1296。
实施例9
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol间氯苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点78-80℃,产率97%,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.50and 6.00min.);[α]25 D= -175.8(c 0.12,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.66(d,J=7.6Hz,1H),7.58–7.35(m, 1H),7.17–7.02(m,5H),6.73(d,J=7.8Hz,1H),6.25–5.93(m,3H),3.05(s,3H),3.02–2.91(m, 1H),2.66–2.44(m,1H).13C NMR(101MHz,CDCl3)δ159.0,156.0,145.8,139.0,134.4,133.8, 132.5,129.7,127.3,126.6,126.1,125.4(q,J=280.8Hz),124.4,123.5,123.0,120.7,108.7,59.8 (q,J=28.4Hz),33.97,25.65.19F NMR(376MHz,CDCl3)δ-74.53(d,J=7.2Hz).HRMS计算值C20H16ClF3N2ONa([M+Na]+):415.0795,测量值:415.0796。
实施例10
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol邻甲基苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率82%,产物的对映选择性过量95%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.13and 5.53min);[α]25 D=-109.4(c 0.18,CH2Cl2). 1H NMR(400MHz,CDCl3)δ7.70(d,J=6.8Hz,1H),7.42(t,J=7.6,1H),7.16–7.06(m,2H), 7.05–6.94(m,3H),6.70(d,J=8.0Hz,1H),6.19(d,J=16.0Hz,1H),6.15–5.98(m,2H),3.05– 2.87(m,4H),2.62–2.52(m,1H),2.28(s,3H).13C NMR(101MHz,CDCl3).159.0,155.9,145.8, 138.0,137.0,134.0,133.7,128.3,128.1,126.9,125.4(q,J=280.1Hz),124.6,123.4,123.2,122.9, 120.8,108.6,59.95(q,J=28.1Hz)34.1,25.5,21.4.19F NMR(376MHz,CDCl3)δ-74.47(d,J= 7.3Hz).HRMS计算值C21H19F3N2ONa([M+Na]+):395.1342,测量值:395.1342
实施例11
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol胡椒苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点80-82℃,产率91%,产物的对映选择性过量95%,HPLC(Chiralpak IE-H,i-propanol /hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=7.85and 8.34min);[α]30 D=31.2(c 0.24, CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.46–7.37(m,1H),7.37–7.29(m,3H),7.25– 7.20(m,2H),7.19-7.14(m,2H),6.82(d,J=16.0Hz,1H),6.05–5.96(m,1H),4.92(m,1H), 4.82(brs,1H),2.70–2.86(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.1,140.7, 135.1,132.9,132.7,129.7,129.6,128.7,128.5,128.0,127.8,127.6,126.8,79.8,53.6,40.4,28.3. HRMS(ESI+)计算值C21H23Cl2NO2Na([M+Na]+):414.0998,测量值:414.1003。
实施例12
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3,4 二氯苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点90-92℃,产率83%,产物的对映选择性过量90%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.78and 6.35min);[α]25 D=-228.8(c 0.16,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.69(d,J=7.2Hz,1H),7.52–7.38(m,1H),7.29(d,J=8.4,1H),7.25(d,J=2.0Hz,1H),7.14–7.08(m,1H),7.08–6.99(m,1H),6.75 (d,J=8.0Hz,1H),6.17–6.01(m,3H),3.08(s,3H),3.02–2.88(m,1H),2.67–2.30(m,1H).13C NMR(101MHz,CDCl3)δ159.0,155.9,145.8,137.2,133.9,132.5,131.4,131.0,130.3,127.8, 127.1,125.5(q,J=280.1Hz),125.4,123.5,123.0,120.7,108.7,59.8(q,J=28.3Hz),34.0,25.7. 19F NMR(376MHz,CDCl3)δ-74.54(d,J=7.2Hz).HRMS计算值C20H15Cl2F3N2ONa ([M+Na]+):449.0406,计算值449.0415.
实施例13
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3,5 二甲基苯基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点110-112℃,产率98%,产物的对映选择性过量95%,HPLC(Chiralcel OD-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.59and 6.29min);[α]25 D=-45.0 (c 0.47,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.70(d,J=7.6Hz,1H),7.42(td,J=8.0,1.2Hz, 1H),7.10(td,J=7.6,0.8Hz,1H),6.85–6.78(m,3H),6.70(d,J=8.0Hz,1H),6.21–6.02(m, 3H),3.05–2.92(m,4H),2.62–2.51(m,1H),2.25(s,6H).13C NMR(101MHz,CDCl3)δ159.0, 155.9,145.8,137.9,137.0,134.2,133.62,129.0,125.5(q,J=280.1Hz),124.4,124.0,123.3,122.9, 120.8,108.6,60.0(q,J=28.3Hz),34.1,25.5,21.3.19F NMR(376MHz,CDCl3)δ-74.42(d,J= 7.3Hz).HRMS计算值C22H21F3N2ONa([M+Na]+):409.1498,测量值409.1501。
实施例14
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3,5 二萘基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率87%,产物的对映选择性过量99%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.65and 5.98min);[α]25 D=-79.2(c 0.37,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.8--7.68(m,4H),7.50–7.33(m,5H),7.10(t,J=7.2Hz,1H),6.61 (d,J=8.0Hz,1H),6.37(d,J=16.0Hz,1H),6.32–6.07(m,2H),3.09–3.00(m,1H),2.92(s, 3H),2.69–2.59(m,1H).13C NMR(101MHz,CDCl3)δ159.0,155.9,145.7,134.5,134.0,133.7, 133.5,132.8,128.0,127.9,127.6,126.2,125.8,125.5(q,J=280.0Hz).125.3,123.5,123.4,122.9, 120.8,108.6,60.0(q,J=28.2Hz),34.2,25.5.19F NMR(376MHz,CDCl3)δ-74.48(d,J=7.2Hz). HRMS计算值C24H19F3N2ONa([M+Na]+):431.1342,测量值431.1342。
实施例15
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 2-甲氧基4-吡啶基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点80-82℃,产率92%,产物的对映选择性过量90%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=8.65and 9.71min);[α]25 D=-93.2 (c 0.19,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.90(d,J=2.4Hz,1H),7.76–7.64(m,1H),7.52 (dd,J=8.4,2.4Hz,1H),7.42(t,J=7.6,1H),7.08(t,J=7.6Hz,1H),6.73(d,J=8.0Hz,1H), 6.64(d,J=8.4Hz,1H),6.19(d,J=16.0Hz,1H),6.11–5.91(m,2H),3.89(s,3H),3.07(s,3H), 3.02–2.87(m,1H),2.64–2.52(m,1H).13C NMR(101MHz,CDCl3)δ163.5,159.0,155.8,145.8, 145.1,135.5,133.8,129.8,128.0,125.4(q,J=282.0Hz),123.5,123.0,120.7,110.8,108.7,59.8(q, J=28.2Hz),53.5,34.1,25.7.19F NMR(376MHz,CDCl3)δ-74.45(d,J=7.3Hz).HRMS计算值 C20H18F3N3O2Na([M+Na]+):412.1243,测量值:412.1243。
实施例16
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3,5 二噻吩基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率84%,产物的对映选择性过量94%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=6.33and 6.72min);[α]25 D=-108.52(c0.27, CH2Cl2).1H NMR(400MHz,CDCl3)δ7.69(d,J=7.9,1H),7.42(t,J=7.6,1H),7.16–7.04(m, 2H),6.92–6.83(m,1H),6.78–6.69(m,2H),6.37(d,J=15.6Hz,1H),6.13–6.02(m,1H),6.00 –5.87(m,1H),3.07(s,3H),2.97-2.87(m,1H),2.63–2.43(m,1H).13C NMR(101MHz,CDCl3) δ158.9,156.0,145.9,142.1,133.7,127.2,127.0,125.5(q,J=282.0Hz),125.0,124.5,124.0, 123.4,123.0,120.8,108.6,60.0(q,J=28.2Hz),33.9,25.7.19F NMR(376MHz,CDCl3)δ-74.48 (d,J=7.2Hz).HRMS计算值C18H15F3N2OSNa([M+Na]+):387.0749,测量值:387.0727。
实施例17
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3,5 二呋喃基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率94%,产物的对映选择性过量88%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=6.84and 7.50min);[α]25 D=-136.8(c0.44,CH2Cl2). 1H NMR(400MHz,CDCl3)δ7.69(d,J=6.8Hz,1H),7.43(t,J=8.0,1H),7.28(d,J=1.2Hz, 1H),7.10(t,J=7.6Hz,1H),6.76(d,J=8.0Hz,1H),6.29(dd,J=3.2,1.8Hz,1H),6.21–5.98(m, 4H),3.13(s,3H),2.97–2.88(m,1H),2.65–2.54(m,1H).13C NMR(101MHz,CDCl3)δ158.9, 156.0,152.6,145.9,141.8,133.8,125.4(q,J=282.0Hz),123.4,123.3,123.0,122.2,120.8,111.1, 108.6,107.1,60.0(q,J=28.0Hz),34.0,25.8.19F NMR(376MHz,CDCl3)δ-74.30(d,J=7.3Hz). HRMS计算值C18H15F3N2O2Na([M+Na]+):371.0978,测量值:371.0978。
实施例18
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基靛红亚胺、0.22mmol 3-吡啶基烯丙基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点95-97℃,产率99%,产物的对映选择性过量90%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=26.12and 28.65min);[α]25 D= -91.0(c 0.31,CH2Cl2).1H NMR(400MHz,CDCl3)δ8.44–8.34(m,2H),7.69(d,J=7.6Hz,1H), 7.56(d,J=8.0Hz,1H),7.43(t,J=7.2Hz,1H),7.18(dd,J=7.6,4.8Hz,1H),7.10(t,J=7.6Hz, 1H),6.74(d,J=7.8Hz,1H),6.28–6.16(m,2H),6.14–6.02(m,1H),3.06(s,3H),3.02–2.94(m, 1H),2.71–2.51(m,1H).13C NMR(101MHz,CDCl3)δ159.0,156.0,148.4,148.0,145.9,134.0, 132.9,132.8,130.2,127.5,125.4(q,J=282.0Hz),123.6,123.5,123.1,120.7,108.8,59.8(q,J= 28.4Hz),34.1,25.8.19F NMR(376MHz,CDCl3)δ-74.48(d,J=7.3Hz).HRMS计算值 C19H16F3N3ONa([M+Na]+):382.1138,测量值:382.1138。
实施例19
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基5-甲基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率90%,产物的对映选择性过量93%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=4.69and 5.02min);[α]25 D=-126.9(c 0.16,CH2Cl2).1H NMR (400MHz,CDCl3)δ7.54–7.50(m,1H),7.25–7.14(m,6H),6.59(d,J=8.0Hz,1H),6.24(d,J= 16.0Hz,1H),6.18–6.05(m,2H),3.02–2.92(m,4H),2.64–2.50(m,1H),2.34(s,3H).13C NMR (101MHz,CDCl3)δ159.1,156.2,143.6,137.1,134.0,133.8,133.1,128.4,127.3,126.2,125.5(q, J=282.0Hz),124.9,123.48,120.7,108.4,59.8(q,J=28.2Hz),34.1,25.6,20.9.19F NMR(376 MHz,CDCl3)δ-74.49(d,J=7.3Hz).HRMS计算值C21H19F3N2ONa([M+Na]+):395.1342,测量值:395.1342。
实施例20
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基7-甲基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率99%,产物的对映选择性过量90%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.02and 5.44min);[α]25 D=-83.6(c 0.11,CH2Cl2).1H NMR (400MHz,CDCl3)δ7.57(d,J=7.6Hz,1H),7.28–7.13(m,5H),6.89(d,J=7.6Hz,1H),6.52(s, 1H),6.24(d,J=16.0Hz,1H),6.19–6.03(m,2H),3.03–2.91(m,4H),2.64–2.52(m,1H),2.39 (s,3H).13C NMR(101MHz,CDCl3)δ159.4,155.7,146.0,144.9,137.1,133.7,128.4,127.3, 126.2,125.5(q,J=282.0Hz),124.9,123.9,122.9,118.3,59.7(q,J=28.2Hz),34.1,25.5,22.5. 19F NMR(376MHz,CDCl3)δ-74.47(d,J=7.3Hz).HRMS计算值C21H19F3N2ONa([M+Na]+): 395.1342,测量值:395.1342。
实施例21
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基8-甲基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率88%,产物的对映选择性过量94%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=4.75and 5.00min);[α]25 D=-111.3(c 0.68,CH2Cl2).1H NMR (400MHz,CDCl3)δ7.56(d,J=7.6Hz,1H),7.26–7.10(m,6H),6.96(t,J=7.6Hz,1H),6.19(d, J=16.0Hz,1H),6.15–6.02(m,2H),3.25(s,3H),3.00–2.90(m,1H),2.61–2.51(m,1H),2.44 (s,3H).13C NMR(101MHz,CDCl3)δ159.7,156.0,143.4,137.5,137.1,133.9,128.4,127.3, 126.2,125.5(q,J=282.0Hz),125.0,123.3,121.6,121.0,120.3,60.0(q,J=28.2Hz),34.0,28.9, 18.8.19F NMR(376MHz,CDCl3)δ-74.52(d,J=7.3Hz).HRMS计算值C21H19F3N2ONa ([M+Na]+):395.1342,测量值:395.1342。
实施例22
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基7-甲氧基靛红亚胺、0.22mmol 肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点81-85℃,产率92%,产物的对映选择性过量92%,HPLC(Chiralpak AS-H,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=7.05and 7.63min);[α]25 D= -101.0(c 0.21,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.26–7.13(m,7H),6.96(dd,J=8.4,2.8 Hz,1H),6.61(d,J=8.4Hz,1H),6.23(d,J=16.0Hz,1H),6.16–6.06(m,1H),3.83(s,3H),3.05 –2.88(m,4H),2.63–2.52(m,1H).13C NMR(101MHz,CDCl3)δ159.1,156.5,156.3,139.6, 137.1,133.9,128.4,127.4,126.2,125.5(q,J=282.0Hz),124.8,121.5,112.0,109.5,107.9,59.9(q, J=28.2Hz),56.1,34.0,25.6.19F NMR(376MHz,CDCl3)δ-74.45(d,J=7.3Hz).HRMS计算值C21H19F3N2O2Na([M+Na]+):411.1291,测量值:411.1291。
实施例23
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基7-溴靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点120-1225℃,产率91%,产物的对映选择性过量92%,HPLC Chiralcel OD-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=9.81and 10.26min);[α]25 D= -70.7(c 0.15,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.69(d,J=7.2Hz,1H),7.42(t,J=7.6Hz, 1H),7.24–7.16(m,2H),7.15–7.06(m,3H),6.72(d,J=7.6Hz,1H),6.19(d,J=16.0Hz,1H), 6.14–5.99(m,2H),3.04(s,3H),3.00–2.91(m,1H),2.63–2.52(m,1H).13C NMR(101MHz, CDCl3)δ159.0,155.9,145.8,135.6,133.8,133.0,132.6,128.6,127.4,125.6,125.5(q,J=282.0 Hz),123.5,123.0,120.8,108.7,59.9(q,J=28.2Hz),34.1,25.7.19FNMR(376MHz,CDCl3)δ -74.54(d,J=7.1Hz).HRMS计算值C20H16BrF3N2ONa([M+Na]+):459.0290,测量值: 459.0290。
实施例24
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟乙基7-氯靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点87-89℃,产率81%,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol /hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.51and 7.57min);[α]25 D=-264.4(c 0.18, CH2Cl2).1H NMR(400MHz,CDCl3)δ7.67(d,J=1.2Hz,1H),7.42–7.31(m,1H),7.27–7.14 (m,5H),6.62(d,J=8.4Hz,1H),6.18(d,J=16.0Hz,1H),6.14–5.97(m,2H),3.04-2.92(m, 4H),2.60–2.48(m,1H).13C NMR(101MHz,CDCl3)δ158.6,155.0,144.1,136.9,134.1,133.2, 129.1,128.5,127.5,126.1,125.3(q,J=282.0Hz),124.7,123.1,121.9,109.7,60.0(q,J=28.2 Hz),34.0,25.7.19F NMR(376MHz,CDCl3)δ-74.54(d,J=7.2Hz).HRMS计算值 C20H16ClF3N2ONa([M+Na]+):415.0795,测量值:415.0795。
实施例25
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol N-丁基三氟乙基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点75-77℃,产率99%,产物的对映选择性过量93%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.33and 5.64min);[α]25 D=-90.0 (c 0.13,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.70(d,J=7.6Hz,1H),7.40(t,J=7.6Hz,1H), 7.25–7.13(m,5H),7.08(t,J=7.6Hz,1H),6.73(d,J=7.6Hz,1H),6.25(d,J=16.0Hz,1H), 6.18–6.07(m,2H),3.56–3.42(m,2H),3.00–2.92(m,1H),2.66–2.52(m,1H),1.53–1.39(m, 2H),1.35–1.22(m,2H),0.89(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ158.8,155.9, 145.4,137.1,133.8,133.6,128.5,127.3,126.1,125.5(q,J=282.0Hz),124.7,123.1,123.1,120.9, 108.9,59.8(q,J=28.2Hz),39.5,34.0,29.2,20.2,13.8.19FNMR(376MHz,CDCl3)δ-74.54(d,J =7.2Hz).HRMS计算值C23H23F3N2ONa([M+Na]+):423.1655,测量值:423.1655。
实施例26
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol N-烯丙基三氟乙基靛红亚胺、0.22mmol 肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点107-109℃,产率84%,产物的对映选择性过量93%,HPLC(Chiralpak IE,i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=4.93and 5.15min);[α]25 D=-91.4 (c 0.14,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.71(d,J=7.6,1H),7.37(t,J=7.6,1H),7.25– 7.12(m,5H),7.08(t,J=7.6,1H),6.70(d,J=8.0Hz,1H),6.23(d,J=16.0Hz,1H),6.16–6.02 (m,2H),5.62–5.50(m,1H),5.11–5.01(m,2H),4.24–4.04(m,2H),3.08–2.89(m,1H),2.64– 2.53(m,1H).13C NMR(101MHz,CDCl3)δ158.6,155.6,145.1,137.0,133.9,133.6,130.5,128.5, 127.5,126.2,125.5(q,J=282.0Hz),124.7,123.3,123.0,120.8,118.0,109.5,60.0(q,J=28.2Hz), 41.9,34.0.19F NMR(376MHz,CDCl3)δ-74.61(d,J=7.2Hz).HRMS计算值C22H19F3N2ONa+: 407.1342,测量值:407.1342.。
实施例27
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol N-苄基三氟乙基靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点97-99℃,产率99%,产物的对映选择性过量91%,HPLC(Chiralpak AS-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=5.01and 5.42min);[α]25 D= -112.9(c 0.34,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.70(d,J=7.2Hz,1H),7.32–7.15(m,9H),7.13–7.07(m,2H),7.04(t,J=7.6Hz,1H),6.56(d,J=8.0Hz,1H),6.29(d,J=16.0Hz,1H),6.23–6.11(m,2H),4.77(d,J=16.0Hz,1H),4.67(d,J=16.0Hz,1H),3.05–2.95(m,1H), 2.70–2.57(m,1H).13C NMR(101MHz,CDCl3)δ158.9,155.6,145.0,137.0,134.8,133.8,133.6, 129.0,128.6,127.8,127.4,127.1,126.2,125.5(q,J=282.0Hz),124.6,123.4,123.0,120.9,109.7, 60.0(q,J=28.2Hz),43.5,34.0.19F NMR(376MHz,CDCl3)δ-74.60(d,J=7.3Hz).HRMS计算值C26H21F3N2ONa([M+Na]+):457.1498,测量值:457.1498。
实施例28
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟丙酮靛红亚胺、0.22mmol肉桂基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色液体,产率93%,产物的对映选择性过量91%,HPLC(Chiralpak IA,i-propanol/hexane=10/90,flowrate 1.0mL/min,λ=254nm);tr=5.27and 5.71min;[α]25 D=-145.9(c 0.12,CH2Cl2).1HNMR(400 MHz,CDCl3)δ7.63(d,J=7.3Hz,1H),7.41(t,J=7.6Hz,1H),7.34–7.23(m,4H),7.18(t,J= 7.1Hz,1H),7.09(t,J=7.6Hz,1H),6.78(d,J=7.8Hz,1H),6.44(d,J=15.6Hz,1H),6.23– 6.10(m,1H),3.34–3.23(m,1H),3.23(s,3H),3.15–3.03(m,1H),1.73(s,3H).13C NMR(101 MHz,CDCl3)δ157.4,153.5,145.7,137.5,133.6,133.2,128.5,127.8(q,J=284.8Hz),127.2, 126.3,124.8,123.5,123.0,122.3,108.4,67.1(q,J=25.3Hz),36.6,26.2,17.2.19F NMR(376 MHz,C6D5CD3)δ-78.95.HRMS计算值C21H19F3N2ONa([M+Na]+):395.1342,测量值: 395.1347。
实施例29
在25mL反应管中加入0.005mmol[Ir(COD)Cl]2、0.010mmol(S,S,S)-L1、0.5mL除氧THF 和0.5mL除氧正丙胺,50℃下反应30分钟后在减压条件下蒸去溶剂得到铱催化剂。在25℃氮气保护下,加入1mL二氯甲烷,依次加入0.20mmol三氟丙酮靛红亚胺、0.22mmol对甲氧基苯基碳酸甲酯。搅拌24h后,产物经硅胶柱层析(石油醚/乙酸乙酯20:1),得到黄色固体,熔点110-112℃,产率95%,产物的对映选择性过量95%,HPLC(Chiralpak AD-H, i-propanol/hexane=5/95,flow rate 1.0mL/min,λ=254nm;tr=8.33and 9.84min);[α]25 D=-95.9 (c 0.22,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.63(d,J=7.6Hz,1H),7.40(td,J=8.0,1.2Hz, 1H),7.26–7.20(m,2H),7.08(t,J=7.6Hz,1H),6.83-6.75(m,3H),6.38(d,J=15.6Hz,1H), 6.09–5.86(m,1H),3.78(s,3H),3.33–3.17(m,4H),3.10–3.01(m,1H),1.72(s,3H).13C NMR (101MHz,CDCl3)δ159.0,157.4,153.4,145.7,133.2,133.0,130.3,127.9(q,J=284.8Hz),127.4, 123.4,122.9,122.5,122.4,113.9,108.4,67.1(q,J=24.8Hz),55.3,36.6,26.2,17.2.19F NMR(376 MHz,CDCl3)δ-79.23(s).HRMS计算值C22H21F3N2O2Na([M+Na]+):425.1447,测量值: 425.1451。
实施例30
在25mL反应管中加入0.5mmol实施例1所制备的化合物、5mL THF和1mL 2N盐酸,25℃反应2h后在减压条件下蒸去溶剂,再加入2mL三乙胺,旋干得到的产物直接柱层析,产物经硅胶柱层析(石油醚/乙酸乙酯3:1),得到黄色固体,熔点92-93℃,产率97%,产物的对映选择性95%,HPLC(Chiralpak IA,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ= 254nm;tr=7.52and 8.18min);[α]25 D=-101.4(c 0.23,CH2Cl2).1H NMR(400MHz,CDCl3)δ 7.39–7.27(m,4H),7.26–7.20(m,1H),6.53(d,J=15.6Hz,1H),6.26–6.08(m,1H),3.37–3.35(m,1H),2.68–2.60(m,1H),2.45–2.27(m,1H),1.40(s,2H).13C NMR(101MHz,CDCl3) δ136.8,134.0,128.6,127.6,126.2(q,J=282.0Hz),126.3,124.2,53.5(q,J=28.5Hz),33.7.19F NMR(376MHz,CDCl3)δ-78.18(d,J=7.3Hz).HRMS计算值C11H13F3N+:215.0922,测量值: 215.0924.。
实施例31
在25mL反应管中加入0.5mmol实施例30所制备的化合物、1mmol NaHCO3和3mL 乙腈并将反应管置于-20摄氏度低温,加入1mmol I2反应12h后加入5mL二氯甲烷和2mL 饱和硫代硫酸钠溶液淬灭反应。分液,水相使用二氯甲烷萃取后合并,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到无色液体,产率92%,产物的对映选择性过量94%, HPLC(Chiralcel OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.02 and 7.00min);[α]25 D=-137.1(c 0.1.2,CH2Cl2).1H NMR(400MHz,CDCl3)δ7.44–7.30(m,5H), 4.34(d,J=10.0Hz,1H),3.99–3.79(m,2H),2.95–2.82(m,1H),2.48–2.36(m,1H),2.24(s, 1H).13C NMR(100MHz,CDCl3)δ138.0,128.9,128.8,127.2,126.1(q,J=282.0Hz),58.6(q,J= 30.9Hz),71.9,38.6,38.6,25.1.19F NMR(376MHz,CDCl3)δ-77.17(d,J=7.8Hz).HRMS计算值C11H12F3IN+:341.9957,测量值:341.9961。
以上所述,仅为本发明较佳的具体实施方式,但本发明保护的范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改,等同替换和改进等,均应包含在发明的保护范围之内。
Claims (3)
1.一种手性α-含氟高烯丙胺衍生物I的制备方法,包括以下步骤:
将底物-1、底物-2、铱催化剂和1~10当量的有机碱溶于溶剂中,在0~100℃反应6~36小时即得式I所述的手性α-含氟高烯丙胺衍生物I;
制备反应式如下:
其中,X为碳酸甲酯基;
所述底物-1、 底物-2的浓度分别为0.001~3.0M;所述底物-1与底物-2的摩尔比为1:0.1~10;所述铱催化剂的用量为底物-1或底物-2中浓度较低者的0.0001~10mol %;
其中, R1、R2、R3、R4选自氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基、甲氧基或卤素;
R5为氢或C1-24 的烃基;所述的烃基选自甲基、乙基、正丙基、异丙基、正丁基、叔丁基、环戊基、环己基、环庚基、苯基、苄基、(1-苯基)乙基、1-萘基、2-萘基或烯丙基;
R6为氢或甲基;
R7为三氟甲基;
R8为H、取代或未取代的芳基、取代或不取代的不饱和杂环基、C1-C6链式或环状烷烃;所述取代或不取代的不饱和杂环基含有杂原子为N、O或S;所述取代芳基的取代基为烷基、烷氧基、卤素或链烯基;
R9为H、烷烃、取代或未取代的芳基;
所述铱催化剂采用如下方法制备:50℃下,按金属铱盐和配体L1溶于有机溶剂中,加入有机碱经反应得到;
所述金属铱盐选自[Ir(COD)Cl]2、[Ir(DBCOT)Cl]2或 [Ir(COD)OMe]2;
所述手性配体L1的结构式为:
2.根据权利要求1所述的制备方法,其特征在于:所述溶剂选自甲醇、乙醇、异丙醇、叔丁醇、仲丁醇、乙酸乙酯、乙酸异丁酯、乙酸异丙酯、正己烷、环 己烷、正庚烷、丙酮、丁酮、乙醚、甲基叔丁基醚、甲基环戊基醚、甲基四氢呋喃、四氢呋喃、乙氰、二氯甲烷、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯和二氧六环中的至少一种。
3.根据权利要求1所述的制备方法,其特征在于:所述反应温度为10~50℃。
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