CN111689887B - 铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应及其应用 - Google Patents
铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应及其应用 Download PDFInfo
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Abstract
本发明公开了一种通过新型的铜/铱协同催化的亚甲胺叶立德参与的烯丙基化/2‑氮杂‑Cope重排反应合成具有手性的多取代高烯丙胺衍生物,其合成方法为:在有机溶剂中,在惰性气体保护下,以烯丙基碳酸酯和氨基酸衍生的亚胺作为原料,以铜络合物和铱络合物为共催化剂,加入碳酸铯,在25℃温度下反应12‑24小时,加入高沸点溶剂25‑100℃温度下继续反应4‑24小时,经水解、保护等后处理通过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,具体涉及铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应合成端位取代高烯丙基胺衍生物及其制备方法和用途。
背景技术
手性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)以及过渡金属配体中。因此高效,普适,容易使用的手性胺合成方法一直是合成化学中的热点研究领域。亚甲胺叶立德作为一种常见的合成中间体,具有廉价易得等特点,被广泛应用于含氮杂环以及非天然氨基酸衍生物的合成中。然而到目前为止,没有课题组报到使用不对称催化的方法利用亚甲胺叶立德合成手性胺((a)Nugent,T.C.Chiral AmineSynthesis:Methods,Developments and Applications,Wiley-VCH,2010.(b)Puentes,C.O.Kouznetsov,V.J.Heterocycl.Chem.2002,39,595;(c)Przheval’skii,N.M.Grandberg,I.I.Usp.Khim.1987,56,814;(d)Kobayashi,S.;Mori,Y.;Fossey,J.S;Salter,M.M.Chem.Rev.2011,111,2626;(e)Yus,M.;González-Gómez,J.C.;Foubelo,F.Chem.Rev.2011,111,7774;(f)Yus,M.;González-Gómez,J.C.;Foubelo,F.Chem.Rev.2013,113,5595.)。
发明内容
为了解决上述技术问题,本发明提供一种端位取代高烯丙基胺衍生物、制备方法及其应用。
本发明提供了使用不对称催化的方法利用亚甲胺叶立德合成手性胺。该方法使用新型的铜/铱协同催化体系首次实现了利用简便易得的亚甲胺叶立德合成端位取代高烯丙胺类化合物。该方法具有原料简便易的,路径简单,所得目标化合物产率高,对映选择性好等优点。
本发明提供的方案如下:
一种铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应合成的端取代高烯丙基胺衍生物,其结构如通式(I)所示:
其中,
R1为H、苯基、对甲基苯基、间甲基苯基、邻甲基苯基、对甲氧基苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、3,5-二甲基苯基、1-萘基、2-萘基、2-呋喃基、2-噻吩基、3-吡啶基、6-甲氧基-3-吡啶基、6-喹啉基、氮-对甲苯磺酰基-3-吲哚基、苯乙烯基、苯乙基、甲基、异丙基或环己基;
R3为苯基、对甲基苯基、间甲基苯基、邻甲基苯基、对甲氧基苯基、对氯苯基、间氯苯基、邻氯苯基、3,4-二氯苯基、2,4-二氯苯基、对溴苯基、对氟苯基、2-萘基、2-呋喃基、2-噻吩基、3-吡啶基、6-甲氧基-3-吡啶基、5-甲氧基-3-吡啶基、6-喹啉基、甲基、正丙基或环己基;
R4为H、苯基、甲基。
本发明的另一目的在于提供上述端位取代高烯丙基胺衍生物的制备方法,合成路线如下:
其中,
R1为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;
R2为异丁基、苯基或1-萘取代基;
R3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;
R4为H、烷烃、取代或未取代的芳基;
L1、L2为配体;
反应在溶剂中进行;
水解在酸中进行。
具体的,上述制备方法包括以下步骤:
(1)在碱、铱催化剂及配体L1、铜催化剂及配体L2存在的条件下,将底物-1与底物-2溶于溶剂中进行催化反应,制备得到式II所示的高烯丙基胺衍生物中间体化合物;
(2)将式Ⅱ所示的高烯丙基胺衍生物中间体化合物在酸中水解,得到式I所示的高烯丙基胺衍生物。
上述碱为醇的碱金属盐、胺的碱金属盐、碱金属碳酸盐、碱金属氢氧化物或有机碱;
所述醇的碱金属盐为叔丁醇钾、叔丁醇钠、异丙醇钾或异丙醇钠;
所述胺的碱金属盐为二异丙基胺基锂、双三甲基硅基胺基锂、双三甲基硅基胺基钠或双三甲基硅基胺基钾;
所述碱金属碳酸盐为碳酸钾、碳酸钠或碳酸铯;
所述碱金属氢氧化物为氢氧化钾或氢氧化钠;
所述有机碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯、1,5-二氮杂二环[4.3.0]壬-5-烯、1,4-二氮杂二环[2.2.2]辛烷或三乙胺。
所述碱的用量为1~10个当量,优选的,碱用量为1.5当量。
上述铱催化剂选自[Ir(COD)Cl]2、[Ir(DBCOT)Cl]2和[Ir(COD)OMe]2中的任意一种,优选的,铱催化剂为[Ir(COD)Cl]2;
上述配体L1的结构式为
上述铜催化剂选自Cu(MeCN)4BF4、Cu(MeCN)4ClO4和Cu(MeCN)4PF6中的任意一种;优选的,铜催化剂为Cu(MeCN)4BF4;
上述手性配体L2的结构式为
上述底物-1和底物-2的浓度为0.001-3.0M,底物-1与底物-2的摩尔比为1:10~10:1,优选的,底物-1和底物-2的摩尔比为1.5:1;所述配体L1、配体L2用量均为底物-1或底物-2中浓度较低者的0.001~30mol%;所述反应温度为10-50℃,优选的反应温度为15~35℃。
上述溶剂为甲醇、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、甲苯或二氧六环中的至少一种。优选的,溶剂为二氯甲烷。
上述水解用酸为柠檬酸、盐酸、甲磺酸、对甲苯磺酸、乙酸、硫酸、盐酸羟胺或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,酸为盐酸,用量为5倍当量。;所述水解的时间为0.5~24小时,温度为0~100℃,优选的,水解时间为0.5小时,温度为室温。
本发明还提供了上述端取代高烯丙基胺衍生物在制备抗抑郁类药物、抗肿瘤类药物、天然产物和具有手性胺结构单元的化合物的应用。
本发明进一步提供了上述端取代高烯丙基胺衍生物制备具有手性四氢吡咯结构的化合物的方法:
其中,R1为H、苯基、对甲基苯基、间甲基苯基、邻甲基苯基、对甲氧基苯基、对氯苯基、间氯苯基、邻氯苯基、对溴苯基、3,5-二甲基苯基、1-萘基、2-萘基、2-呋喃基、2-噻吩基、3-吡啶基、6-甲氧基-3-吡啶基、6-喹啉基、氮-对甲苯磺酰基-3-吲哚基、苯乙烯基、苯乙基、甲基、异丙基或环己基;
R2为苯基、对甲基苯基、间甲基苯基、邻甲基苯基、对甲氧基苯基、对氯苯基、间氯苯基、邻氯苯基、3,4-二氯苯基、2,4-二氯苯基、对溴苯基、对氟苯基、2-萘基、2-呋喃基、2-噻吩基、3-吡啶基、6-甲氧基-3-吡啶基、5-甲氧基-3-吡啶基、6-喹啉基、甲基、正丙基或环己基。
本发明进一步提供了上述具有手性四氢吡咯结构的化合物作为有机催化剂的应用。
本发明的有益效果:
1)本发明提供的制备方法合成路径简单,成本低,产率高,所得反应目标化合物对映选择性好,产率42-94%,绝大多数对应选择性过量≥90%;
2)本发明方法采用铜络合物和铱络合物作为共催化剂,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)本发明提供的端位取代高烯丙基胺衍生物可应用于制备抗抑郁类药物、抗肿瘤类药物、天然产物和具有手性胺结构单元的化合物,极具药物合成价值及前景。
具体实施方式
下面结合具体实施例对本发明进一步说明,本发明的内容完全不限于此。
为避免重复,对部分原料的结构进行统一说明:
下述实施例中采用的配体(S,S,S)-L1的结构式为下述实施例中采用的配体(R,R,R)-L1的结构式为下述实施例中采用的配体(rac)-L1的结构式为所采用的配体(S,Sa)-L1的结构式为所采用的配体(S,Sp)-L2的结构式为所采用的配体(R,Rp)-L2的结构式为所采用的的配体DPEphos结构式为
实施例1
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2NNaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率94%,熔点118-120℃,产物的对映选择性过量96%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=6.69and 7.42min.);[α]30 D=-26.7(c 0.46,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.36–7.28(m,6H),7.25–7.20(m,3H),6.45(d,J=15.6Hz,1H),6.02(dt,J=15.6,7.2Hz,1H),4.90(s,1H),4.79(s,1H),2.65(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,136.9,133.5,132.8,128.7,128.6,127.6,127.5,126.2,124.8,79.8,53.8,40.3,28.3.HRMS(ESI+)计算值C21H24ClNO2Na([M+Na]+):380.1388,测量值:380.1397。
实施例2
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-对甲苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率86%,熔点142-144℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=7.65and 9.63);[α]30 D=-35.0(c 0.14,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.31(d,J=8.4Hz,2H),7.25–7.15(m,4H),7.10(d,J=8.0Hz,2H),6.42(d,J=16.0Hz,1H),5.99–5,91(m,1H),4.91(brs,1H),4.78(brs,1H),2.63-2.60(m,2H),2.33(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.0,137.3,134.1,133.4,132.7,129.22,128.6,127.5,126.0,123.7,79.8,53.8,40.3,28.3,21.2.HRMS(ESI+)计算值C22H26ClNO2Na([M+Na]+):394.1544,测量值:394.1548。
实施例3
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸甲酯、0.20mmol 3-间甲苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率79%,熔点123-125℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.62and 7.85min);[α]30 D=-28.1(c 0.31,CH2Cl2);1HNMR(400MHz,Chloroform-d)δ7.33–7.30(m,2H),7.25–7.20(m,3H),7.14–7.09(m,2H),7.04(d,J=7.6Hz,2H),6.42(d,J=16.0Hz,1H),6.04–5.96(m,1H),4.91(brs,1H),4.79(brs,1H),2.65–2,60(m,2H),2.33(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.0,138.1,136.8,133.6,132.8,128.6,128.4,128.3,127.5,126.9,124.6,123.3,79.8,53.7,40.3,28.3,21.4.HRMS(ESI+)计算值C22H26ClNO2Na([M+Na]+):394.1544,测量值:394.1551。
实施例4
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸甲酯、0.20mmol 3-对甲氧基苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率89%,熔点140-142℃,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=7.21and 8.95min);[α]30 D=-23.3(c 0.70,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.33–7.28(m,2H),7.26–7.20(m,4H),6.83(d,J=8.8Hz,2H),6.39(d,J=16.0Hz,1H),5.96–5.78(m,1H),4.94(s,1H),4.87–4.67(m,1H),3.84–3.76(m,3H),2.60(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ159.0,155.1,141.0,132.9,132.7,129.7,128.6,127.5,127.3,122.5,113.9,79.7,55.2,53.8,40.3,28.3.HRMS(ESI+)计算值C22H26ClNO3Na([M+Na]+):410.1493,测量值:410.1497。
实施例5
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol对氟苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率81%,熔点125-127℃,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;5.54and 6.33min);[α]30 D=-26.4(c 0.81,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.37–7.21(m,6H),7.00–6.95(m,2H),6.40(d,J=16.0Hz,1H),6.06–5.86(m,1H),4.92–4.90(m,1H),4.79(brs,1H),2.62(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ162.2(d,J=245Hz),155.1,140.8,133.1,132.8,132.2,128.7,127.6(d,J=8.0Hz),127.5,124.6,115.4(d,J=21.4Hz),79.8,53.8,40.3,28.3.HRMS(ESI+)计算值C21H23ClFNO2Na([M+Na]+):398.1299,测量值:398.1302。
实施例6
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸甲酯、0.20mmol对氯苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率81%,熔点128-130℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flowrate 1.0mL/min,λ=254nm;tr=5.75and 6.73min);[α]30 D=-19.5(c 1.10,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.35–7.20(m,8H),6.39(d,J=16.0Hz,1H),6.09–5.93(m,1H),4.94–4.92(m,1H),4.79(brs,1H),2.63(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.0,140.7,135.4,133.0,132.9,132.2,128.7,128.6,127.5,127.3,125.7,79.8,53.7,40.3,27.4.HRMS(ESI+)计算值C21H23Cl2NO2Na([M+Na]+):414.0998,测量:414.1004。
实施例7
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol间氯苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率78%,熔点118-120℃,产物的对映选择性过量96%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.69and 7.34min);[α]30 D=-21.7(c 0.94,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.34–7.26(m,3H),7.25–7.12(m,5H),6.37(d,J=16.0Hz,1H),6.14–5.95(m,1H),4.93(m,1H),4.79(brs,1H),2.63(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.0,140.6,138.8,134.4,132.9,132.1,129.7,128.7,127.5,127.3,126.6,126.0,124.3,79.8,53.7,40.2,28.2.HRMS(ESI+)计算值C21H23Cl2NO2Na([M+Na]+):414.0998,测量值:414.0999。
实施例8
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(3,4-二氯苯基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmolBoc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率79%,熔点85-87℃,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=6.49and 8.21min);[α]30 D=-24.4(c 0.35,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.39–7.30(m,4H),7.22(d,J=8.4Hz,2H),7.11(dd,J=8.5,2.0Hz,1H),6.34(d,J=16.0Hz,1H),6.12–5.98(m,1H),4.85–4.80(m,2H),2.64(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.0,140.5,137.0,133.1,132.6,131.1,131.0,130.4,128.8,127.8,127.6,127.3,125.3,79.9,53.7,40.3,28.3.HRMS(ESI+)计算值C21H23Cl3NO2Na([M+Na]+):448.0608,测量值:448.0621。
实施例9
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol对溴苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率90%,熔点148-150℃,产物的对映选择性过量94%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.29and 7.52min);[α]30 D=-19.7(c 1.10,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.40(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),7.15(d,J=8.4Hz,2H),6.37(d,J=16.0Hz,1H),6.18–5.92(m,1H),4.93–4.90(m,1H),4.78(brs,1H),2.62(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.0,140.7,135.8,132.9,132.2,131.6,128.7,127.6,127.5,125.9,121.1,79.8,53.7,40.3,28.3.HRMS(ESI+)计算值C21H23ClBrNO2Na([M+Na]+):458.0493,测量值:458.0501。
实施例10
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(S,Sa)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol邻甲苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率89%,熔点123-125℃,产物的对映选择性过量94%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.09and 6.91min);[α]30 D=25.9(c 0.84,CH2Cl2);1HNMR(400MHz,Chloroform-d)δ7.36–7.27(m,3H),7.24–7.21(m,2H),7.15–7.11(m,3H),6.62(d,J=15.6Hz,1H),5.92–5.84(m,1H),4.93(m,1H),4.79(brs,1H),2.68–2.63(m,2H),2.29(s,3H),1.40(s,3H).13CNMR(101MHz,CDCl3)δ155.0,140.9,136.1,135.1,132.8,131.5,130.2,128.6,127.6,127.4,126.2,126.0,125.6,79.7,53.7,40.5,28.3,19.8.HRMS(ESI+)计算值C22H26ClNO2Na([M+Na]+):394.1544,测量值:394.1551。
实施例11
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(S,Sa)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol邻氯苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率81%,熔点100-102℃,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);1HNMR(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0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(2,4-二氯苯基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmolBoc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率85%,熔点104-106℃,产物的对映选择性过量88%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=5.27and 6.04min);[α]30 D=16.1(c0.4,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.39–7.29(m,4H),7.23(d,J=8.4Hz,2H),7.16(dd,J=8.4,2.0Hz,1H),6.74(d,J=15.6Hz,1H),6.05–5.96(m,1H),4.89–4.81(m,2H),2.70–2.65(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,140.6,133.7,133.4,133.1,133.0,129.3,129.0,128.8,128.6,127.6,127.5,127.2,79.9,53.6,40.5,28.3.HRMS(ESI+)计算值C21H23Cl3NO2Na([M+Na]+):448.0608,测量值:448.0616。
实施例13
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(1-萘基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率77%,熔点145-147℃,产物的对映选择性过量96%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=12.99and 18.27min);[α]30 D=-24.3(c0.42,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.88–7.71(m,3H),7.65(s,1H),7.52–7.48(m,1H),7.46–7.42(m,2H),7.34–7.31(m,2H),7.26–7.24(m,2H),6.61(d,J=16.0Hz,1H),6.19–6.11(m,1H),4.94–4.83(m,2H),2.72–2.68(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,140.9,134.3,133.6,133.5,132.8,128.7,128.2,127.9,127.6,127.6,126.3,125.9,125.8,125.3,125.2,123.4,79.8,53.8,40.5,28.3.HRMS(ESI+)计算值C25H26ClNO2Na([M+Na]+):430.1544,测量值:430.1552.。
实施例14
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(2-呋喃基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率82%,熔点116-118℃,产物的对映选择性过量91%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.51and 7.07min);[α]30 D=-22.9(c 0.70,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.35–7.27(m,3H),7.22(d,J=8.4Hz,2H),6.34(dd,J=3.2,1.6Hz,1H),6.26(d,J=16.0Hz,1H),6.16(d,J=3.2Hz,1H),6.01–5.89(m,1H),4.91(m,1H),4.77(brs,1H),2.60(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.0,152.4,141.7,140.8,132.8,128.6,127.5,123.5,121.9,111.2,107.2,79.8,53.7,40.1,28.3.HRMS(ESI+)计算值C19H22ClNO3Na([M+Na]+):370.1180,测量值:370.1186。
实施例15
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(2-噻吩基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率79%,熔点136-138℃,产物的对映选择性过量96%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=6.51and 7.07min);[α]30 D=-18.3(c 0.58,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.31(d,J=8.5Hz,2H),7.21(d,J=8.4Hz,2H),7.11(d,J=5.1Hz,1H),6.94(dd,J=5.1,3.5Hz,1H),6.88(d,J=3.3Hz,1H),6.56(d,J=15.7Hz,1H),5.96–5.76(m,1H),4.91(s,1H),4.77(s,1H),2.59(s,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.0,142.0,140.8,132.8,128.7,127.5,127.3,126.6,125.2,124.6,123.9,79.8,53.7,40.1,28.3.HRMS(ESI+)计算值C19H22ClNO2SNa([M+Na]+):386.0952,测量值:386.0955。
实施例16
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(3-吡啶基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率64%,熔点115-117℃,产物的对映选择性过量90%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=11.97and 17.69min);[α]30 D=-22.2(c 0.36,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.48(d,J=26.0Hz,2H),7.61(d,J=8.0Hz,1H),7.32(d,J=8.4Hz,2H),7.25–7.22(m,3H),6.43(d,J=16.0Hz,1H),6.16–6.08(m,1H),4.98–4.96(m,1H),4.81(brs,1H),2.67(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.0,148.5,148.1,140.5,133.0,132.6,129.8,128.8,127.7,127.6,123.4,79.8,53.7,40.4,28.3.HRMS(ESI+)计算值C20H23ClN2O2Na([M+Na]+):381.1340,测量值:381.1345。
实施例17
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(6-甲氧基-3-吡啶基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率86%,熔点120-122℃,产物的对映选择性过量96%,HPLC(ChiralpakOD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=7.28and 8.66min);[α]30 D=-21.1(c0.90,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.02(d,J=2.4Hz,1H),7.56(dd,J=8.8,2.4Hz,1H),7.31(d,J=8.4Hz,2H),7.22(d,J=8.4Hz,2H),6.68(d,J=8.8Hz,1H),6.37(d,J=16.0Hz,1H),6.02–5.85(m,1H),4.99–6.97(m,1H),4.78(brs,1H),3.92(s,3H),2.62(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ163.4,155.1,145.1,140.8,135.3,132.8,129.4,128.6,127.5,126.1,124.3,110.8,79.7,53.8,53.4,40.3,28.2.HRMS(ESI+)计算值C21H25ClN2O2Na([M+Na]+):411.1446,测量值:411.1449。
实施例18
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-(6-喹啉基)烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率65%,熔点170-172℃,产物的对映选择性过量90%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=17.67and 21.72min);[α]30 D=-10.0(c 0.90,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ8.85(s,1H),8.10(d,J=8.4Hz,1H),8.02(d,J=8.8Hz,1H),7.74(d,J=9.2Hz,1H),7.62(s,1H),7.43–7.36(m,2H),7.34(d,J=8.4Hz,2H),7.30–7.22(m,2H),6.62(d,J=16.0Hz,1H),6.24–6.17(m,1H),4.96–4.84(m,2H),2.74–2.68(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,150.1,147.9,140.7,135.9,135.1,132.9,132.7,129.6,128.7,128.4,127.6,127.1,126.7,125.3,121.4,79.8,53.8,40.4,28.3.HRMS(ESI+)计算值C24H25ClN2O2Na([M+Na]+):431.1497,测量值:431.1498。
实施例19
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(S,Sp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol巴豆基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入1mL甲苯在100℃下反应12h后冷却至室温,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2NNaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率75%,熔点82-84℃,产物的对映选择性过量91%,HPLC(ChiralpakOD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=4.97and5.42min);[α]30 D=-4.9(c 0.42,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.30–7.26(m,2H),7.19–7.17(m,2H),5.56–5.49(m,1H),5.29–5.23(m,1H),4.86(m,1H),4.63(brs,1H),2.39(m,2H),1.64(d,J=6.4Hz,3H),1.41(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.3,132.5,129.3,128.5,127.5,125.8,79.6,53.7,40.0,28.3,18.0.HRMS(ESI+)计算值C16H22ClNO2Na([M+Na]+):318.1231,测量值:318.1224。
实施例20
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(S,Sp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-丙基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入1mL甲苯在100℃下反应12h后冷却至室温,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率51%,熔点101-103℃,产物的对映选择性过量94%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=4.97and 5.42min);[α]30 D=-4.2(c 0.12,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.29(d,J=8.4Hz,2H),7.18(d,J=8.4Hz,2H),5.49(dt,J=13.8,6.8Hz,1H),5.31–5.15(m,1H),4.86(m,1H),4.63(brs,1H),2.40–2.38(m,2H),2.03–1.89(m,2H),1.48–1.32(m,11H),0.86(t,J=7.2Hz,3H).13C NMR(101MHz,CDCl3)δ155.1,138.0,134.8,132.6,128.5,127.6,124.8,79.6,53.8,40.0,34.6,28.3,22.4,13.6.HRMS(ESI+)计算值C18H26ClNO2Na([M+Na]+):346.1544,测量:346.1549。
实施例21
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(S,Sp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 3-环己基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入1mL甲苯在100℃下反应12h后冷却至室温,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率67%,熔点119-121℃,产物的对映选择性过量98%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate 1.0mL/min,λ=254nm;tr=5.04and 5.75min);[α]30 D=-8.1(c 0.42,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.32–7.25(m,2H),7.17(d,J=8.4Hz,2H),5.44(dd,J=15.2,6.8Hz,1H),5.29–5.09(m,1H),4.85(m,1H),4.62(brs,1H),2.38–2.36(m,2H),1.92–1.88(m,1H),1.72–1.63(m,4H),1.41(s,9H),1.25–1.21(m,4H),1.05–0.99m,2H).13C NMR(101MHz,CDCl3)δ155.1,141.4,141.0,132.5,128.5,127.6,121.0,79.6,53.8,40.6,40.0,32.9,28.3,26.1,25.9.HRMS(ESI+)计算值C21H30ClNO2Na([M+Na]+):386.1857,测量值:386.1549。
实施例22
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率82%,熔点100-102℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=7.97and 9.33min);[α]30 D=-17.7(c 0.43,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.37–7.26(m,9H),7.23–7.18mz,1H),6.45(d,J=16.0Hz,1H),6.06(dt,J=16.0,7.2Hz,1H),4.93–4.83(m,2H),2.68(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.2,142.2,137.1,133.1,128.5,128.5,127.3,127.2,126.2,126.1,125.5,79.5,54.3,40.5,28.3.HRMS(ESI+)计算值C21H25NO2Na([M+Na]+):346.1778,测量值:346.1778。
实施例23
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对甲苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率79%,熔点96-98℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=4.18and 8.49min);[α]30 D=-24.4(c 0.72,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.32–7.25(m,4H),7.22–7.12(m,5H),6.45(d,J=16.0Hz,1H),6.10–5.98(m,1H),4.90(m,1H),4.79(brs,1H),2.66(m,2H),2.33(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,139.2,137.2,136.7,132.9,129.2,128.4,127.2,126.10,126.07,125.6,79.4,54.0,40.5,28.3,21.0.HRMS(ESI+)计算值C22H27NO2Na([M+Na]+):360.1934,测量值:360.1934。
实施例24
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(间甲苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率81%,熔点86-88℃,产物的对映选择性过量98%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=6.51and 7.57min);[α]30 D=-18.7(c 0.31,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.32–7.26(m,4H),7.24–7.18(m,2H),7.12–7.05(m,3H),6.45(d,J=16.0Hz,1H),6.16–5.99(m,1H),4.92(m,1H),4.79(brs,1H),2.66(m,2H),2.35(s,3H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ174.01,155.38,155.15,142.16,138.11,137.15,132.96,128.45,128.41,127.92,127.23,126.99,126.10,125.65,123.13,79.44,54.28,40.53,28.26,21.47.HRMS(ESI+)计算值C22H27NO2Na([M+Na]+):360.1934,测量值:360.1939。
实施例25
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(邻甲苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率71%,熔点81-83℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=7.09and 9.71min);[α]30 D=-32.6(c 0.74,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.33–7.25(m,4H),7.24–7.18(m,3H),7.16–7.12(m,2H),6.46(d,J=16.0Hz,1H),6.12–6.01(m,1H),5.04(brs,1H),4.93–4.91(m,1H),2.63(m,2H),2.40(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,140.3,137.2,135.3,132.9,130.7,128.5,127.2,127.0,126.1,126.1,125.6,124.8,79.4,50.5,39.5,28.3,19.2.HRMS(ESI+)计算值C22H27NO2Na([M+Na]+):360.1934,测量值d:360.1938。
实施例26
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对甲氧基苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率78%,熔点118-120℃,产物的对映选择性过量97%,HPLC(Chiralpak AD-H,i-propanol/hexane=10/90,flowrate 1.0mL/min,λ=254nm;tr=9.53and 11.56min);[α]30 D=-30.8(c 0.43,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.31–7.26(m,4H),7.24–7.18(m,3H),6.87(d,J=8.87Hz,2H),6.44(d,J=16.0Hz,1H),6.10–5.97(m,1H),4.88–4.76(m,2H),3.80(s,3H),2.66(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ158.6,155.1,137.2,134.3,133.0,128.5,127.3,127.2,126.1,125.7,113.9,79.4,55.2,53.8,40.4,28.3.HRMS(ESI+)计算值C22H27NO3Na([M+Na]+):376.1883,测量值:376.1884。
实施例27
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(邻氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率73%,熔点100-102℃,产物的对映选择性过量95%,HPLC(Chiralpak OJ-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=6.61and 13.64min);[α]30 D=-15.0(c 0.27,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.40–7.30(m,6H),7.24–7.17(m,3H),6.47(d,J=16.0Hz,1H),6.10–6.01(m,1H),5.22–5.10(m,2H),2.72–2.64(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ154.9,139.7,137.0,133.4,132.5,130.0,128.5,128.3,127.4,127.1,126.9,126.2,125.1,79.7,51.8,38.6,28.3.HRMS(ESI+)计算值C21H24ClNO2Na([M+Na]+):380.1388,测量值:380.139。
实施例28
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(间氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率83%,熔点99-101℃,产物的对映选择性过量96%,HPLC(Chiralpak OJ-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=7.84and 9.94min);[α]30 D=-18.2(c 0.85,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.34–7.28(m,5H),7.26–7.19(m,3H),7.17(d,J=7.2Hz,1H),6.46(d,J=16.0Hz,1H),6.06–5.94(m,1H),4.95(m,1H),4.80(brs,1H),2.65–2.62(m,2H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.1,144.6,136.9,134.4,133.5,129.8,128.5,127.4,127.3,126.3,126.2,124.8,124.4,79.8,53.8,40.3,28.3.HRMS(ESI+)计算值C21H24ClNO2Na([M+Na]+):380.1388,测量:380.1389。
实施例29
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对溴苯亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率88%,熔点110-112℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=7.51and 8.25min);[α]30 D=-18.9(c 0.71,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.46(d,J=8.4Hz,2H),7.30–7.29(m4H),7.25–7.20(m,1H),7.17(d,J=8.4Hz,2H),6.45(d,J=16.0Hz,1H),6.09–5.95(m,1H),4.92(m,1H),4.77(brs,1H),2.63(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.5,136.9,133.5,131.6,128.6,127.9,127.5,126.2,124.8,120.9,79.8,53.8,40.3,28.3.HRMS(ESI+)计算值C21H24BrNO2Na([M+Na]+):424.0883,测量:424.0883。
实施例30
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(1-萘亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率88%,熔点104-106℃,产物的对映选择性过量95%,HPLC(Chiralpak AD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=8.51and 12.48min);[α]30 D=-49.0(c 0.52,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ8.16(d,J=8.4Hz,1H),7.88(d,J=8.4Hz,1H),7.82–7.75(m,1H),7.61–7.42(m,4H),7.35–7.23(m,4H),7.22–7.18(m,1H),6.51(d,J=16.0Hz,1H),6.15–6.08(m,1H),5.73–5.63(m,1H),5.08–4.99(m,1H),2.96–2.70(m,2H),1.41(s,9H).13CNMR(101MHz,CDCl3)δ155.1,137.7,137.1,134.0,133.0,130.8,128.9,128.5,128.0,127.3,126.3,126.1,125.7,125.7,125.2,123.1,122.6,79.6,50.1,39.4,28.3.HRMS(ESI+)计算值C25H27NO2Na([M+Na]+):396.1934,测量值:396.1938。
实施例31
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(2-萘亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率89%,熔点120-122℃,产物的对映选择性过量96%,HPLC(Chiralpak AD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=9.47and 10.13min);[α]30 D=-38.1(c 0.57,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.89–7.78(m,3H),7.73(s,1H),7.52–7.39(m,3H),7.32–7.24(m,4H),7.22–7.19(m,1H),6.48(d,J=16.0Hz,1H),6.11–6.03(m,1H),5.04–5.00(m,2H),2.76(m,2H),1.41(s,9H).13C NMR(101MHz,CDCl3)δ155.2,139.7,137.0,133.3,133.2,132.7,128.5,128.4,127.9,127.6,127.3,126.1,126.1,125.7,125.4,124.8,124.5,79.6,54.4,40.4,28.3.HRMS(ESI+)计算值for C25H27NO2Na([M+Na]+):396.1934,测量值:396.1929。
实施例32
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(2-呋喃亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率63%,熔点87-89℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=5.18and 5.81min);[α]30 D=-40.4(c 0.67,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.36–7.18(m,6H),6.45(d,J=16.0Hz,1H),6.31–6.29(m,1H),6.18(d,J=3.2Hz,1H),6.12–6.04(m,1H),5.02–4.93(dm,2H),2.74–2.70(m,2H),1.42(s,9H).13CNMR(101MHz,CDCl3)δ155.1,154.3,141.7,137.1,133.1,128.4,127.2,126.1,125.1,110.1,105.9,79.7,48.4,37.8,28.2..HRMS(ESI+)计算值for C19H23NO3Na([M+Na]+):336.1570,测量值:336.1575。
实施例33
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(2-噻吩亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率76%,熔点90-92℃,产物的对映选择性过量95%,HPLC(Chiralpak AD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=8.55and 10.31min);[α]30 D=-28.3(c 0.29,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.36–7.28(m,4H),7.23–7.19(m,2H),6.98–6.95(m,2H),6.49(d,J=16.0Hz,1H),6.19–6.10(m,1H),5.12(m,1H),4.88(brs,1H),2.80–2.75(m,2H),1.42(s,9H).13C NMR(101MHz,CDCl3)δ155.0,146.2,137.1,133.5,128.5,127.4,126.8,126.2,125.0,124.1,124.0,79.8,50.2,40.6,28.3.HRMS(ESI+)计算值for C19H23NO2SNa([M+Na]+):352.1342,测量值:352.1344。
实施例34
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(3-吡啶亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率74%,熔点117-119℃,产物的对映选择性过量97%,HPLC(Chiralpak AD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=9.88and 11.98min);[α]30 D=-19.2(c 0.91,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.67–8.47(m,2H),7.62–7.59(m,1H),7.33–7.22(m,6H),6.46(d,J=16.0Hz,1H),6.09–5.99(m,1H),5.12–5.09(m,1H),4.86(brs,1H),2.68(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.02,148.56,148.06,137.77,136.70,133.83,128.51,127.51,126.16,126.12,124.34,123.34,79.88,53.39,40.06,28.22.HRMS(ESI+)计算值For C20H25N2O2([M+Na]+):325.1911,测量值:325.1910。
实施例35
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(6-甲氧基-3-吡啶亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率76%,熔点120-122℃,产物的对映选择性过量95%,HPLC(Chiralpak IA-H,i-propanol/hexane=20/80,flowrate 1.0mL/min,λ=254nm;tr=7.82and 18.67min);[α]30 D=-22.9(c 0.35,CH2Cl2);1HNMR(400MHz,Chloroform-d)δ8.11(s,1H),7.51(dd,J=8.8,2.4Hz,1H),7.31–7.29(m,4H),7.24–7.19(m,1H),6.73(d,J=8.8Hz,1H),6.46(d,J=16.0Hz,1H),6.09–6.01(m,1H),4.88-4.78(m,2H),3.93(s,3H),2.68–2.64(m,2H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ163.4,155.0,144.8,137.0,136.9,133.6,130.5,128.5,127.4,126.1,124.8,110.7,53.5,51.8,40.1,28.3.HRMS(ESI+)计算值For C21H26N2O3Na([M+Na]+):377.1836,测量值:377.1840。
实施例36
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(6-喹啉亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率88%,熔点138-140℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=25/75,flow rate1.0mL/min,λ=254nm;tr=7.38and 9.62min);[α]30 D=-39.4(c 0.82,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.90–8.88(m,1H),8.13–8.09(m,2H),7.75–7.64(m,2H),7.40–7.36(m,1H),7.30–7.24(m,4H),7.23–7.20(m,1H),6.48(d,J=16.0Hz,1H),6.10–5.98(m,1H),5.19(m,1H),5.02(brs,1H),2.76(m,2H),1.41(s,9H).13C NMR(101MHz,CDCl3)δ155.2,150.2,147.6,140.6,136.9,136.0,133.5,129.8,128.5,128.1,128.0,127.4,126.1,124.9,124.7,121.3,79.8,54.2,40.3,28.3.HRMS(ESI+)计算值For C24H26N2O2Na([M+Na]+):397.1886,测量值:397.1895。
实施例37
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(N-Ts-3吲哚亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯5:1),得到白固体,产率72%,熔点132-134℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=25/75,flowrate 1.0mL/min,λ=254nm;tr=6.89and 8.13min);[α]30 D=-26.5(c 0.54,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.97(d,J=8.2Hz,1H),7.66(d,J=8.2Hz,2H),7.59(d,J=7.6Hz,1H),7.47(s,1H),7.32–7.22(m,7H),7.03(d,J=7.6Hz,2H),6.49(d,J=16.0Hz,1H),6.13–6.05(m,1H),5.12(m,1H),4.80(brs,1H),2.84(m,2H),2.28(s,3H),1.42(s,9H).13C NMR(101MHz,CDCl3)δ155.1,144.9,137.1,135.4,134.9,133.2,129.8,129.3,128.5,127.4,126.7,126.2,125.4,125.0,123.5,123.3,123.2,120.0,113.4,79.8,46.8,38.2,29.7,21.5.HRMS(ESI+)计算值.For C30H32N2O4SNa([M+Na]+):539.1975,测量值:539.1977。
实施例38
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(苯乙烯基亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2NNaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率88%,熔点102-104℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flowrate 1.0mL/min,λ=254nm;tr=10.21and 15.55min);[α]30 D=1.7(c 0.24,CH2Cl2);1HNMR(400MHz,CDCl3)δ7.40–7.27(m,8H),7.25–7.19(m,2H),6.56–6.46(m,2H),6.23–6.15(m,2H),4.66(brs,1H),4.48(brs,1H),2.56–2.53(m,2H),1.44(s,9H).13C NMR(101MHz,CDCl3)δ155.2,137.1,136.7,133.2,130.1,129.8,128.51,128.5,127.5,127.3,126.4,126.1,125.3,79.5,51.9,39.1,28.4.HRMS(ESI+)计算值ForC23H25NO2Na([M+Na]+):372.1934,测量值:372.1936。
实施例39
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(苯乙基亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率72%,熔点82-84℃,产物的对映选择性过量98%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=7.27and 8.25min);[α]30 D=-17.0(c 0.63,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.34–7.26(m,6H),7.20–7.17(m,4H),6.41(d,J=16.0Hz,1H),6.24–6.12(m,1H),4.46–4.43(m,1H),3.80(m,1H),2.79–2.61(m,2H),2.51–2.29(m,2H),1.94–1.77(m,1H),1.73–1.67(m,1H),1.43(s,9H).13C NMR(101MHz,CDCl3)δ155.5,141.8,137.2,132.8,128.4,128.4,128.3,127.1,126.2,126.0,125.8,79.1,50.2,45.2,40.0,36.7,28.3.HRMS(ESI+)计算值For C23H29NO2Na([M+Na]+):374.2091,测量值:374.2091。
实施例40
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(异丙基亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率78%,熔点88-90℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=3.94and 4.37min);[α]30 D=5.2(c 0.60,CH2Cl2);1H NMR(400MHz,Chloroform-d)δ7.37–7.32(m,2H),7.31–7.27(m,1H),7.23–7.17(m,1H),6.42(d,J=16.0Hz,1H),6.18–6.13(m,1H),4.40–4.37(m,1H),3.61–3.58(m,1H),2.42–2.28(m,2H),1.82–1.73(m,1H),1.40(s,9H),0.96(d,J=6.8Hz,3H),0.92(d,J=6.8Hz,3H).13C NMR(101MHz,CDCl3)δ155.8,137.4,132.2,128.4,127.0,126.8,126.0,79.0,55.3,36.2,31.4,28.4,19.4,17.8.HRMS(ESI+)计算值For C18H27NO2Na([M+Na]+):312.1934,测量值:312.1939。
实施例41
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(环己基亚甲基氨基)异戊酸酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌24h后,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率72%,熔点110-112℃,产物的对映选择性过量97%,HPLC(Chiralpak OD-H,i-propanol/hexane=10/90,flow rate1.0mL/min,λ=254nm;tr=4.11and 4.87min);[α]30 D=15.4(c 0.74,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.37–7.17(m,5H),6.41(d,J=16.0Hz,1H),6.17(dt,J=16.0,7.2Hz,1H),4.31–4.38(m,1H),3.58(brs,1H),2.43–2.40(m,1H),2.32–2.24(m,1H),1.78–1.65(m,5H),1.39(s,9H),1.29–0.94(m,6H).13CNMR(101MHz,CDCl3)δ155.8,146.7,137.5,132.2,128.4,127.0,126.0,78.9,54.8,41.4,36.0,29.8,27.4,26.4,26.2.HRMS(ESI+)计算值ForC21H31NO2Na([M+Na]+):352.2247,测量值:352.2250。
实施例42
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 2-甲基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率88%,熔点82-84℃,产物的对映选择性过量93%,HPLC(Chiralpak AS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=5.40and 6.64min);[α]30 D=11.4(c 0.78,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.29(d,J=8.4Hz,2H),7.21(d,J=8.4Hz,2H),4.83-4.73(m,4H),2.38-2.34(m,2H),1.72(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.2,141.7,141.4,132.6,128.6,127.4,114.1,79.6,52.2,45.7,28.3,21.9.HRMS(ESI+)计算值For C16H22ClNO2Na([M+Na]+):318.1231,测量值:318.1228。
实施例43
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 2-甲基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率91%,熔点78-80℃,产物的对映选择性过量95%,HPLC(Chiralpak AS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=5.05and 5.83min);[α]30 D=10.1(c 0.80,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.39–7.18(m,5H),4.82-4.73(m,4H),2.42-2.39(m,2H),1.73(s,3H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.2,143.0,141.9,128.4,127.0,126.0,113.8,79.4,52.8,45.8,28.3,21.9.HRMS(ESI+)计算值ForC16H23NO2Na([M+Na]+):284.1629,测量值:284.1621。
实施例44
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对甲苯亚甲基氨基)异戊酸酸甲酯、0.20mmol 2-甲基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率84%,熔点77-79℃,产物的对映选择性过量91%,HPLC(Chiralpak AS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=5.08and 6.43min);[α]30 D=12.2(c 0.48,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.17(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),4.81-4.72(d,J=32.5Hz,4H),2.41–2.37(m,2H),2.32(s,3H),1.72(s,3H),1.39(s,9H).13C NMR(101MHz,CDCl3)δ155.2,142.0,140.1,136.6,129.1,126.0,113.6,79.4,52.4,45.8,28.3,22.0,21.0.HRMS(ESI+)计算值For C17H28NO2Na([M+Na]+):298.1777,测量值:298.1778。
实施例45
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(3,5-二甲苯亚甲基氨基)苯甘氨酸甲酯、0.20mmol 2-甲基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2NNaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率74%,熔点81-83℃,产物的对映选择性过量83%,HPLC(ChiralpakAS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;3.90and 4.87min);[α]30 D=12.8(c 0.65,CH2Cl2);1H NMR(400MHz,CDCl3)δ6.88(s,3H),4.82-4.74(m,4H),2.45–2.35(m,2H),2.30(s,6H),1.74(s,3H),1.40(s,9H).13C NMR(101MHz,CDCl3)δ155.3,142.1,137.9,128.7,123.8,113.5,79.3,52.7,46.0,28.3,21.9,21.3.HRMS(ESI+)计算值For C18H27NO2Na([M+Na]+):312.1954,测量值:312.1946。
实施例46
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(6-甲氧基-3-吡啶基亚甲基氨基)苯甘氨酸甲酯、0.20mmol2-甲基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率92%,熔点90-92℃,产物的对映选择性过量91%,HPLC(ChiralpakAS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=7.14and7.99min);[α]30 D=15.1(c 0.66,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.09(s,1H),7.50(dd,J=8.4,2.4Hz,1H),6.71(d,J=8.4Hz,1H),4.72–4.69(m,4H),3.92(s,3H),2.41(d,J=7.2Hz,2H),1.73(s,3H),1.39(s,9H).13CNMR(101MHz,CDCl3)δ163.4,155.1,144.8,141.3,136.7,131.1,114.2,110.7,79.6,53.4,50.2,45.3,28.3,21.9.HRMS(ESI+)计算值ForC16H25NO2([M+H]+):293.1861,测量值:293.1860。
实施例47
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4PF6与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)苯甘氨酸甲酯、0.20mmol 2-苯基烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率85%,熔点94-96℃,产物的对映选择性过量84%,HPLC(Chiralpak AS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=8.96and 11.14min);[α]30 D=9.8(c 0.34,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.37–7.23(m,7H),7.12(d,J=8.4Hz,2H),5.28(s,1H),5.00(s,1H),4.84-4.82(m,1H),4.63(brs,1H),2.88(d,J=6.0Hz,2H),1.37(s,9H).13C NMR(101MHz,CDCl3)δ155.0,144.5,141.3,140.1,132.7,128.5,128.5,127.8,127.6,126.2,115.9,79.6,53.0,43.2,28.2.HRMS(ESI+)计算值For C21H24ClNO2Na([M+Na]+):380.1388,测量值:380.1389。
实施例48
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(rac)-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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4ClO4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)-1-萘乙酸甲酯、0.20mmol烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯和0.02mmol左旋樟脑磺酸在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率42%,熔点94-96℃,产物的对映选择性过量80%,HPLC(Chiralpak AD-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=7.64and 8.81min);[α]30 D=9.8(c 0.34,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.29(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,2H),5.70–5.59(m,1H),5.13–5.08(m,2H),4.87(m,1H),4.70(brs,1H),2.47(m,2H),1.41(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.0,133.5,132.7,128.6,127.5,118.6,79.7,53.4,41.1,28.3.HRMS(ESI+)计算值For C15H20ClNO2Na([M+Na]+):304.1081,测量值:304.1075。
实施例49
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol(R,Rp)-L2,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(对氯苯亚甲基氨基)-1-萘乙酸甲酯、0.20mmol烯丙基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌36h后,加入1mL甲苯在100℃反应12h,加入0.5mL 2N盐酸反应0.5h,加入1.0mL 2N NaoH水溶液和0.4mmol Boc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到白固体,产率79%,熔点103-105℃,产物的对映选择性过量82%,HPLC(Chiralpak AS-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=5.59and 6.90min);[α]30 D=15.6(c 0.34,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.29(d,J=8.4Hz,2H),7.20(d,J=8.4Hz,2H),5.62–5.54(m,1H),5.30–5.23(m,1H),4.86(m,1H),4.67(brs,1H),2.48–2.47(m,2H),1.57–1.55(m,3H),1.41(s,9H).13C NMR(101MHz,CDCl3)δ155.1,141.2,132.7,128.5,127.6,125.8,124.9,79.6,53.9,34.0,28.3,12.9.HRMS(ESI+)计算值ForC16H22ClNO2Na([M+Na]+):318.1231,测量值:318.1227。
实施例50
在25mL反应管中加入0.003mmol[Ir(COD)Cl]2、0.006mmol(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络合物。在另外一个25mL反应管中加入0.01mmol Cu(CH3CN)4BF4与0.011mmol DPEphos,在氮气保护下,加入1mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入0.30mmol 2-(苯亚甲基氨基)异戊酸甲酯、0.20mmol肉桂基碳酸甲酯、0.3mmol碳酸铯和铱络合物,搅拌12h后,加入0.5mL 2N盐酸反应0.5h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯3:1),得到白固体,产率88%,熔点94-96℃,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=40/60,flow rate 1.0mL/min,λ=254nm;tr=7.05and 9.39min);[α]30 D=-25.2(c 0.98,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.39–7.15(m,10H),6.48(d,J=16.0Hz,1H),6.24–6.08(m,1H),4.07(dd,J=8.0,5.2Hz,1H),2.61–2.44(m,2H),1.65(brs,2H).13CNMR(101MHz,CDCl3)δ145.7,137.3,132.8,128.5,128.4,127.2,127.0,126.9,126.3,126.0,55.7,43.4.HRMS(ESI+)计算值For C16H17NNa([M+Na]+):246.1253,测量值:246.1254。
实施例51
在25mL反应管中加入0.03mmol[Ir(COD)Cl]2、0.06mmol(R,R,R)-L1、3mL除氧THF和3mL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络合物。在另外一个25mL反应管中加入0.1mmol Cu(CH3CN)4BF4与0.11mmol DPEphos,在氮气保护下,加入3mL二氯甲烷,室温下搅拌半小时。然后在25℃下,依次加入3mmol 2-(对氯苯亚甲基氨基)-1-萘乙酸甲酯、2mmol烯丙基碳酸甲酯、3mmol碳酸铯和铱络合物,搅拌18h后,加入8mL 2N盐酸反应0.5h,加入10mL 2N NaoH水溶液和4mmolBoc2O反应3h,蒸去溶剂,产物经硅胶柱层析(石油醚/乙酸乙酯10:1),得到无色液体,产率79%,产物的对映选择性过量>99%,HPLC(Chiralpak OD-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=4.31and 4.71min);[α]30 D=5.2(c 0.60,CH2Cl2);1H NMR(400MHz,CDCl3)δ8.16(s,2H),7.17(s,1H),6.40(d,J=16.0Hz,1H),6.30–6.21(m,1H),4.47(brs,1H),3.87–3.78(m,4H),2.40–2.36(m,2H),1.42(s,9H),1.18(d,J=6.7Hz,3H).13C NMR(101MHz,CDCl3)δ155.6,155.2,140.6,136.2,133.5,129.2,128.8,116.6,79.2,55.5,46.1,40.8,28.3,20.7.HRMS(ESI+)计算值For C16H24N2O3Na([M+Na]+):315.1679,测量值:315.1675。
应用实施例1
在25mL反应管中加入0.5mmol化合物49、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20:1),得到无色液体,产率82%,产物的对映选择性过量95%,HPLC(Chiralpak OD-H,i-propanol/hexane=3/97,flow rate 1.0mL/min,λ=254nm;tr=12.14and 17.17min);[α]30 D=-65.2(c 0.48,CH2Cl2);1H NMR(400MHz,CDCl3)δ7.54–7.42(m,2H),7.42–7.21(m,8H),4.59–4.55(mz,2H),4.14–4.07(m,1H),3.04–2.98(m,1H),2.38–2.30(m,1H),2.08(brs,1H).13C NMR(101MHz,CDCl3)δ142.9,140.4,132.7,128.8,128.6,128.2,127.5,126.8,72.8,61.1,48.4,28.3.HRMS(ESI+)计算值For C16H16INNa([M+Na]+):372.0220,测量值:372.0227。
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 (7)
1.铜/铱协同催化不对称烯丙基化/2-氮杂-Cope重排反应合成的端位取代高烯丙基胺衍生物的制备方法,其特征在于,合成路线如下:
其中,
R1为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;
R2为异丁基、苯基或1-萘取代基;
R3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;
R4为H、烷烃、取代或未取代的芳基;
X为碳酸甲酯基;
L1、L2为配体;
反应在溶剂中进行;
水解在酸中进行;
所述铜催化剂选自Cu(MeCN)4BF4、Cu(MeCN)4ClO4和Cu(MeCN)4PF6中的任意一种;所述手性配体L2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,包括以下步骤:
(1)在碱、铱催化剂及配体L1、铜催化剂及配体L2存在的条件下,将底物-1与底物-2溶于溶剂中进行催化反应,制备得到式II所示的端位取代高烯丙基胺衍生物中间体化合物;
(2)将式Ⅱ所示的高烯丙基胺衍生物中间体化合物在酸中水解,得到式I所示的高烯丙基胺衍生物。
3.根据权利要求2所述的制备方法,其特征在于:所述的碱为醇的碱金属盐、胺的碱金属盐、碱金属碳酸盐、碱金属氢氧化物或有机碱;
所述醇的碱金属盐为叔丁醇钾、叔丁醇钠、异丙醇钾或异丙醇钠;
所述胺的碱金属盐为二异丙基胺基锂、双三甲基硅基胺基锂、双三甲基硅基胺基钠或双三甲基硅基胺基钾;
所述碱金属碳酸盐为碳酸钾、碳酸钠或碳酸铯;
所述碱金属氢氧化物为氢氧化钾或氢氧化钠;
所述有机碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯、1,5-二氮杂二环[4.3.0]壬-5-烯、1,4-二氮杂二环[2.2.2]辛烷或三乙胺;
所述碱的用量为1~10个当量。
5.根据权利要求1或2所述的制备方法,其特征在于:所述底物-1和底物-2的浓度为0.001-3.0M,底物-1与底物-2的摩尔比为1:10~10:1;所述配体L1、配体L2用量均为底物-1或底物-2中浓度较低者的0.001~30mol%;所述反应温度为10-50℃。
6.根据权利要求1或2所述的制备方法,其特征在于:所述溶剂为甲醇、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、乙腈、二氯甲烷、二甲亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、甲苯或二氧六环中的至少一种。
7.根据权利要求1或2所述的制备方法,其特征在于:所述水解用酸为柠檬酸、盐酸、甲磺酸、对甲苯磺酸、乙酸、硫酸、盐酸羟胺或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;所述水解的时间为0.5~24小时,温度为0~100℃。
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