CN111116450B - 一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用 - Google Patents
一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用,利用手性磷酸催化的双氢键作用以及弱π‑π共轭作用高效构筑了具有高对映选择性以及较好的Z/E选择性的轴手性萘胺方酰胺类催化剂,制备获得的轴手性萘胺方酰胺类催化剂同时包含轴手性和中心手性,可以成功地用于催化控制Michael、Aldol等反应,从而可以更高效地催化、控制反应,具有较好的研究前景。
Description
技术领域
本发明属于有机化学技术领域,尤其是涉及一种轴手性萘胺方酰胺类有机催化剂及其制备方法和应用。
背景技术
小分子有机催化剂在近年来得到广泛的发展,方酰胺类催化剂作为其中一类典型的有机催化剂在Michael、Aldol及Morita-Baylis-Hillman等经典反应中均取得了较好的应用。然而,这些方酰胺类催化剂主要是通过中心手性诱导产物的手性生成,而通过轴手性诱导新手性生成的方酰胺类催化剂却未曾报道。王卫等报道了含轴手性的碱性硫脲催化剂的应用(Org.Lett.,2005,7,4713),但是对于同时具有轴手性以及中心手性双手性的方酰胺催化剂未曾报道。因此新型的同时具有含轴手性及中心手性的方酰胺类催化剂的开发具有较高的研究价值和实际意义。
联芳基轴手性化合物广泛存在于天然产物以及活性分子中,也是手性磷酸、联萘酚等催化剂以及配体的主要结构。近年来,许多化学工作者都在努力尝试寻找一种高效、简洁的方法构建此类联芳基轴手性化合物。其中,以萘酚为核心结构,通过碱性硫脲或者碱性方酰胺作为催化剂来构筑联萘酚苯乙烯结构的研究较多(Org.Lett.,2019,21,95;J.Am.Chem.S℃.2018,140,7056)。而利用手性磷酸来高效构筑联萘胺苯乙烯结构也未曾报道。
发明内容
本发明的目的就是为了克服上述现有技术存在的缺陷而提供一种利用手性磷酸催化的双氢键作用以及弱π-π共轭作用高效构筑具有高对映选择性以及较好的Z/E选择性的轴手性萘胺方酰胺类催化剂及其制备方法和应用。
本发明的目的可以通过以下技术方案来实现:
一种轴手性萘胺方酰胺类有机催化剂,化学结构式为:
其中,R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或萘环;R5选自N,N-二甲基乙胺基、奎宁基或苯基中的一种。
轴手性萘胺方酰胺类有机催化剂的制备方法,包括以下步骤:
(1)向结构式1所示的化合物中加入溶剂,结构式2所示的化合物,催化剂以及添加剂,室温条件下搅拌反应后,层析柱分离,获得结构式3所示的化合物,化学反应式如(I)所示:
其中,R1选自氢、甲基、甲氧基或氟中的至少一种,或者R1所在的芳环为苄基;R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或者萘环;
(2)将制备得到的结构式3所示的化合物溶于第一有机溶剂中,通入H2在5-8atm的压力下30-80℃还原,然后减压蒸馏除去溶剂、层析柱分离,得到脱除苄基的中间体化合物4,将其溶于第二有机溶剂中,再加入化合物5,有机碱N,N-二异丙基乙胺,在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂前体6;
反应式化学反应式如(II)所示:
(3)将纯产物催化剂前体6所示的化合物溶于溶剂中,加入有机碱N,N-二异丙基乙胺,然后加入胺类化合物7,在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂8,
其中R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或者萘环,R5选自N,N-二甲基乙胺基、奎宁基或苯基中的至少一种。
步骤(1)中:
结构式1所示的化合物、结构式2所示的化合物、催化剂摩尔比为1:(1-2):0.1。
所述溶剂为甲苯或二氯甲烷中的一种,浓度为0.05~0.5mmol/mL,
所述催化剂为:
步骤(2)中:
所述第一溶剂为甲醇或四氢呋喃,浓度为0.01-0.2mmol/mL,所述第二溶剂为甲醇,浓度为0.01-0.2mmol/mL。
结构式3所示的化合物与Pd(OH)2/C的质量比为100:5-20。
化合物5为二酮化合物,中间体化合物4与化合物5的摩尔比为1:(1-1.5)。
步骤(3)中:
所述溶剂为甲醇,浓度为0.01-0.2mmol/mL。
纯产物催化剂前体6与胺类化合物7的摩尔比为1:(1-1.5),所述胺类化合物7为N,N-二甲基乙二胺、奎宁胺或苯胺中的一种。
轴手性萘胺方酰胺类有机催化剂能够在不对称催化反应中应用,所述不对称催化反应包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应。
本发明所公开的技术方案提出了利用手性磷酸的双氢键以及弱π-π共轭作用高效、高选择性地构建轴手性杂环取代的苯乙烯联萘胺化合物的合成方法,并成功合成得到了轴手性萘胺方酰胺类有机催化剂。现有技术中,多采用动力学拆分法或者脯氨醇催化法,动力学拆分常需要冷却或者加热来实现,并提前构建好消旋的联萘杂环化合物,通过额外的反应物实现动力学拆分;而脯氨醇催化法反应历程较长,反应条件相对较复杂,对反应物的要求更为严格。由于手性磷酸可以提供氢键并有效控制手性,还具有一定的酸性,能够与邻炔萘胺结合,使炔被活化后形成具有手性的高活性连烯中间体;同时手性磷酸可以杂环化合物在氢键的作用下结合,利用手性磷酸的位阻以及π-π共轭作用,使得杂环化合物只能从位阻小的位置对连烯中间体进行亲核反应,实现轴手性,然后通过氢转移完成杂环对炔的加成过程。本方法可以有效地控制轴手性,反应体系简单,底物适用性广,不需要提前制备联萘杂环化合物,反应条件温和。
与现有技术相比,本发明在手性磷酸催化剂的作用下,先形成萘胺连烯中间体,然后实现了连烯手性到轴手性的转换,高效地构筑了高对映选择性以及较好的Z/E选择性的轴手性吲哚取代的苯乙烯萘胺类化合物。此外,本发明主要发明了一种新型的轴手性方酰胺类催化剂,我们还将其成功地用于催化控制Michael、Aldol等反应,而且该类催化剂也可以同时包含轴手性和中心手性,从而可以更高效地催化、控制反应。
具体实施方式
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进。这些都属于本发明的保护范围。
轴手性萘胺方酰胺类有机催化剂的制备方法,包括以下步骤:
(1)向结构式1所示的化合物中加入浓度为0.05~0.5mmol/mL的甲苯或二氯甲烷作为溶剂,并加入结构式2所示的化合物,催化剂以及添加剂MS,结构式1所示的化合物、结构式2所示的化合物、催化剂摩尔比为1:(1-2):0.1,添加剂的加入量为每0.1 mmol结构式1所示的化合物,加入50mg-100mg的添加剂,室温条件下搅拌反应后,层析柱分离,获得结构式3所示的化合物,化学反应式如(I)所示:
加入的催化剂为:
上述结构式中的R1选自氢、甲基、甲氧基或氟中的至少一种,或者R1所在的芳环为苄基;R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或者萘环;
(2)将制备得到的结构式3所示的化合物溶于浓度为0.01-0.2mmol/mL的甲醇或四氢呋喃中,通入H2在5-8atm的压力下30-80℃,加入Pd(OH)2/C进行还原,结构式3所示的化合物与Pd(OH)2/C的质量比为100:5-20,然后减压蒸馏除去溶剂、层析柱分离,得到脱除苄基的中间体化合物4,将其溶于浓度为0.01-0.2mmol/mL的甲醇,再加入化合物5,有机碱N,N-二异丙基乙胺,在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂前体6,使用的化合物5为二酮化合物,中间体化合物4与化合物5的摩尔比为1:(1-1.5);
反应式化学反应式如(II)所示:
(3)将纯产物催化剂前体6所示的化合物溶于浓度为0.01-0.2mmol/mL的甲醇中,加入有机碱N,N-二异丙基乙胺,然后加入胺类化合物7,可以选用N,N-二甲基乙二胺、奎宁胺或苯胺中的一种,纯产物催化剂前体6与胺类化合物7的摩尔比为1:(1-1.5),在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂8,
其中R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或者萘环,R5选自N,N-二甲基乙胺基、奎宁基或苯基中的至少一种。
制备得到的轴手性萘胺方酰胺类有机催化剂,化学结构式为:
其中,R2选自氢、甲基、乙基、溴或苯乙炔基中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,或者R4所在的芳环为噻吩环或萘环;R5选自N,N-二甲基乙胺基、奎宁基或苯基中的一种,在步骤(1)中采用不同的催化剂,得到的不同化学结构式的催化剂产物。
制备得到的轴手性萘胺方酰胺类有机催化剂能够在不对称催化反应中,包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应中应用。
以下是更加详细的实施案例,通过以下实施案例进一步说明本发明的技术方案以及所能够获得的技术效果。
本实施方式中,化合物的氢核磁共振谱(1H NMR)由Bruker AVANCE III HD 400或Bruker AVANCE III HD 500测定;质谱(ESI-MS)由Waters ACQUITYTM UPLC&Q-TOF MSPremier测定;所用试剂均为市售试剂。
步骤1:吲哚取代的苯乙烯萘胺的合成
在室温下,将萘胺炔1(0.1mmol,1当量)加入到含有吲哚衍生物2(0.15mmol,1.5当量)、CPA1(0.01mmol,0.1当量)的甲苯(1mL)溶液中,然后加入100mg活化后的分子筛,反应在室温下搅拌,直至TLC表明萘胺炔接近消失,将反应液通过硅胶柱色谱纯化,用石油醚/乙酸乙酯体系洗脱,得到所需产物3。
实施例1
按照以上公开的方法,得到3a,收率为90%,94%ee。
1H NMR(400MHz,CDCl3)δ8.18(m,1H),7.93(s,1H),7.78-7.75(m,3H),7.68(dr,1H),7.55(dd,J=8.9,1.9Hz,1H),7.34–7.31(m,1H),7.27–7.22(m,5H),7.13(ddd,J=8.9,7.1,1.9Hz,2H),7.01-7.00(m,5H),6.87–6.83(m,3H),6.67(d,J=2.7Hz,1H),6.15(s,1H).13C NMR(101MHz,CDCl3)δ143.05,137.83,137.29,137.23,133.26,131.25,129.29,129.13,128.42,128.24,128.01,127.97,126.73,125.41,125.20,125.13,123.34,122.72,122.64,121.53,120.81,120.75,119.24,118.47,118.19,111.73.HRMS(ESI)calculatedfor[M+H]+C32H25N2 +,m/z:437.2018,found:437.2015.M.P.76.1℃.[α]20D=-39.6°(c=1,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=60/40,flow rate=1mL/min,λ=254nm),tR(major)=13.9min,tR(minor)=4.5min,ee=94%。
实施例2
按照以上公开的方法,得到3b,收率为92%,90%ee。
1H NMR(400MHz,CDCl3)δ8.25–8.22(m,1H),7.98(s,1H),7.81–7.78(m,3H),7.73(s,1H),7.52(d,J=9.0Hz,1H),7.39–7.37(m,1H),7.32–7.29(m,2H),7.28–7.26(m,2H),7.07(s,5H),7.01–6.99(m,2H),6.82–6.79(m,2H),6.73(d,J=2.7Hz,1H),6.13(s,1H),2.28(s,3H).13C NMR(101MHz,CDCl3)δ140.33,138.68,137.29,133.25,131.54,131.29,129.67,128.97,128.41,128.26,128.21,127.97,127.94,126.67,125.44,125.16,125.04,123.02,122.60,121.67,120.83,120.71,120.45,118.48,117.63,111.70,20.71.HRMS(ESI)calculated for[M+H]+C33H27N2 +,m/z:451.2174,found:451.2171.M.P.85.9℃.[α]20 D=-52°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=60/40,flow rate=1mL/min,λ=254nm),tR(major)=44.8min,tR(minor)=7.8min,ee=90%。
实施例3
按照以上公开的方法,得到3c,收率为86%,92%ee。
1H NMR(400MHz,CDCl3)δ8.23–8.21(m,1H),8.02(s,1H),7.82–7.79(m,3H),7.73(s,1H),7.42–7.38(m,2H),7.32–7.28(m,4H),7.08–7.02(m,5H),6.89–6.84(m,2H),6.80–6.77(m,2H),6.73(d,J=2.7Hz,1H),6.07(s,1H).13CNMR(101MHz,CDCl3)δ159.67,157.28,139.08,139.05,138.63,137.30,137.24,133.32,131.22,129.08,128.59,128.24,128.21,127.99,127.95,126.79,126.74,125.38,125.14,125.11,123.24,122.69,122.17,122.10,121.88,120.82,120.78,118.47,117.47,115.80,115.58,111.74.HRMS(ESI)calculatedfor[M+H]+C32H24FN2 +,m/z:C32H24FN2,found:455.1920.M.P.90.1℃.[α]20 D=-11°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=60/40,flow rate=1mL/min,λ=365nm),tR(major)=25.7min,tR(minor)=7.2min,ee=92%.
实施例4
按照以上公开的方法,得到3d,收率为95%,93%ee。
1H NMR(400MHz,CDCl3)δ8.15(dd,J=6.1,3.1Hz,1H),7.93(s,1H),7.72–7.65(m,4H),7.36–7.33(m,1H),7.27–7.24(m,2H),7.21–7.14(m,2H),7.11–7.00(m,9H),6.87–6.85(m,2H),6.59(d,J=2.7Hz,1H),4.81(t,J=6.3Hz,1H),4.35–4.24(m,2H).13C NMR(101MHz,CDCl3)δ141.86,139.67,137.48,137.30,133.12,131.39,128.89,128.38,128.32,128.23,127.94,127.88,127.41,126.87,126.76,126.64,126.58,125.56,125.30,124.47,122.53,121.86,120.86,120.66,118.49,118.07,114.10,111.67,47.84.HRMS(ESI)calculatedfor[M+H]+C33H27N2 +,m/z:451.2174,found:451.2171.M.P.72.4℃.[α]20 D=169°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK IB,hexane/isopropyl alcohol=90/10,flow rate=0.5mL/min,λ=360nm),tR(major)=20.7min,tR(minor)=22.5min,ee=93%.
实施例5
按照以上公开的方法,得到3e,收率为91%,91%ee。
1H NMR(400MHz,CDCl3)δ8.19–8.17(m,1H),7.94(s,1H),7.71–7.65(m,3H),7.55–7.52(m,2H),7.35–7.32(m,1H),7.28–7.23(m,2H),7.13–7.06(m,3H),7.03–6.98(m,5H),6.85–6.81(m,3H),6.68(d,J=2.7Hz,1H),6.08(s,1H),2.42(s,3H).13C NMR(101MHz,CDCl3)δ143.35,137.28,137.26,136.95,132.84,131.39,131.36,129.61,129.08,128.94,128.24,128.22,127.87,127.72,127.06,126.67,125.38,125.13,123.09,122.61,121.17,120.83,120.71,118.80,118.60,118.57,111.69,21.40.HRMS(ESI)calculated for[M+H]+C33H27N2 +,m/z:451.2174,found:451.2171.M.P.75.1℃.[α]20 D=-22°(c=0.2,CHCl3).HPLCanalysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=9.5min,tR(minor)=5.8min,ee=91%.
实施例6
按照以上公开的方法,得到3f,收率为52%,94%ee。
1H NMR(400MHz,CDCl3)δ8.14–8.12(m,1H),7.94(s,1H),7.90(d,J=1.9Hz,1H),7.70(d,J=8.2Hz,2H),7.59(d,J=8.7Hz,1H),7.52(d,J=9.0Hz,1H),7.33–7.22(m,4H),7.15–7.11(m,2H),7.06–6.97(m,5H),6.90–6.86(m,1H),6.85–6.83(m,2H),6.66(d,J=2.7Hz,1H),6.18(s,1H).13C NMR(101MHz,CDCl3)δ142.40,139.24,137.36,137.05,134.56,130.49,129.70,129.23,128.45,128.31,128.28,127.43,126.99,126.92,126.57,125.35,125.07,122.78,122.25,121.31,121.18,120.88,120.86,120.10,117.98,117.90,111.81.HRMS(ESI)calculated for[M+H]+C32H24BrN2 +,m/z:515.1123,found:515.1142.M.P.72.5℃.[α]20 D=33°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=6.5min,tR(minor)=4.8min,ee=94%.
实施例7
按照以上公开的方法,得到3g,收率为76%,92%ee。
1H NMR(500MHz,CDCl3)δ8.05(s,1H),7.92(br,1H),7.82–7.79(m,3H),7.71(s,1H),7.59(d,J=9.0Hz,1H),7.30–7.28(m,3H),7.19–7.16(m,2H),7.13(dd,J=8.3,1.6Hz,1H),7.07–7.03(m,5H),6.90–6.88(m,3H),6.67(d,J=2.7Hz,1H),6.20(s,1H),2.59(s,3H).13C NMR(126MHz,CDCl3)δ143.08,137.74,137.32,135.59,133.29,131.43,130.06,129.27,129.11,128.35,128.20,127.92,127.77,126.68,126.64,125.63,125.33,125.24,124.18,123.30,122.82,121.47,120.58,119.18,118.17,117.99,111.34,21.87.HRMS(ESI)calculated for[M+H]+C33H27N2 +,m/z:451.2174,found:451.2173.M.P.81.9℃.[α]20D=-27°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=80/20,flow rate=1mL/min,λ=254nm),tR(major)=16.6min,tR(minor)=5.9min,ee=92%.
实施例8
按照以上公开的方法,得到3h,收率为89%,91%ee。
1H NMR(500MHz,CDCl3)δ8.02(d,J=8.3Hz,1H),7.97(br,1H),7.75(t,J=7.9Hz,2H),7.59(d,J=8.8Hz,1H),7.32–7.29(m,2H),7.24–7.21(m,2H),7.16–7.10(m,4H),7.03(br,5H),6.91(d,J=8.2Hz,2H),6.85–6.82(m,1H),6.77(d,J=2.1Hz,1H),6.53(s,1H).13CNMR(126MHz,CDCl3)δ142.97,137.86,137.24,136.79,136.70,132.76,129.31,129.08,128.26,128.19,128.17,127.95,127.11,127.00,126.86,126.26,125.61,125.13,124.40,123.28,122.82,122.63,122.35,121.15,119.98,119.97,118.50,118.18,110.27.HRMS(ESI)calculated for[M+H]+C32H24ClN2 +,m/z:471.1628,found:471.1629.M.P.82.8℃.[α]20D=-183°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=90/10,flow rate=1mL/min,λ=254nm),tR(major)=32.6min,tR(minor)=16.8min,ee=91%.
实施例9
按照以上公开的方法,得到3i,收率为59%,92%ee。
1H NMR(600MHz,CDCl3)δ7.93(br,1H),7.78–7.75(m,3H),7.57(d,J=2.4Hz,1H),7.54(d,J=9.0Hz,1H),7.50(d,J=6.4Hz,3H),7.40(t,J=7.6Hz,2H),7.35–7.32(m,1H),7.27–7.24(m,4H),7.15–7.12(m,2H),7.03–6.96(m,6H),6.87–6.84(m,3H),6.74(d,J=2.7Hz,1H),6.14(s,1H),5.15–5.07(m,2H).13C NMR(151MHz,CDCl3)δ177.12,153.94,142.98,137.80,137.60,137.16,133.20,132.43,131.27,129.23,129.08,128.59,128.39,128.20,128.18,127.92,127.83,127.57,127.52,126.70,126.66,125.84,125.49,125.14,123.29,122.60,121.48,119.22,118.27,118.10,113.16,112.20,104.77,70.94.HRMS(ESI)calculated for[M+H]+C39H31N2O+,m/z:543.2436,found:543.2431.[α]20D=-30°(c=0.2,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropylalcohol=60/40,flow rate=1mL/min,λ=365nm),tR(major)=17.4min,tR(minor)=6.2min,ee=92%.
实施例10
按照以上公开的方法,得到3j,收率为90%,90%ee。
1H NMR(500MHz,CDCl3)δ8.18–8.16(m,1H),8.07(s,1H),7.81–7.78(m,2H),7.73(d,J=8.5Hz,2H),7.61(s,1H),7.56(d,J=9.0Hz,1H),7.38–7.36(m,1H),7.29–7.27(m,4H),7.17(t,J=7.9Hz,2H),7.13(d,J=8.6Hz,2H),6.90(t,J=7.4Hz,2H),6.87–6.84(m,4H),6.72–6.70(m,1H),6.09(s,1H).13C NMR(126MHz,CDCl3)δ142.87,137.79,137.28,136.17,133.05,132.14,131.21,129.66,129.22,129.12,128.57,127.99,126.81,126.38,125.66,124.93,124.91,123.41,122.71,122.15,121.62,120.81,120.69,120.34,119.08,118.25,118.08,111.77.HRMS(ESI)calculated for[M+H]+C32H24BrN2 +,m/z:515.1123,found:515.1100.M.P.88.1℃.[α]20 D=-23°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=365nm),tR(major)=8.9min,tR(minor)=5.2min,ee=90%.
实施例11
按照以上公开的方法,得到3k,收率为62%,90%ee。
1H NMR(400MHz,CDCl3)δ8.22–8.20(m,1H),7.98(s,1H),7.83–7.80(m,3H),7.67(s,1H),7.62(d,J=8.9Hz,1H),7.39–7.37(m,1H),7.32–7.28(m,4H),7.20–7.16(m,2H),6.98–6.95(m,2H),6.93–6.88(m,3H),6.71(d,J=2.7Hz,1H),6.62–6.60(m,2H),6.23(s,1H),3.70(s,3H).13C NMR(101MHz,CDCl3)δ158.39,143.12,137.77,137.25,133.24,130.00,129.50,129.33,129.10,129.00,128.30,127.94,127.60,126.70,125.23,125.15,124.89,123.33,122.94,122.53,121.42,120.80,120.58,119.09,118.66,118.21,113.73,111.65,55.12.HRMS(ESI)calculated for[M+H]+C33H27N2O+,m/z:467.2123,found:467.2119.M.P.87.1℃.[α]20 D=-70°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=14.8min,tR(minor)=6.6min,ee=90%.
实施例12
按照以上公开的方法,得到3l,收率为70%,91%ee。
1H NMR(400MHz,CDCl3)δ8.23–8.21(m,1H),8.09(s,1H),7.85–7.82(m,2H),7.77–7.75(m,1H),7.73(s,1H),7.58(d,J=9.0Hz,1H),7.44–7.41(m,1H),7.35–7.26(m,6H),7.19–7.15(m,2H),7.08(d,J=8.2Hz,2H),6.93–6.898(m,1H),6.85–6.83(m,2H),6.78(d,J=2.8Hz,1H),6.07(s,1H).
13C NMR(126MHz,CDCl3)δ142.86,140.81,137.91,137.37,133.93,133.14,129.28,129.17,128.78,128.23,128.10,127.97,126.95,126.19,126.07,125.08,125.05,125.02,124.99,124.93,124.88,123.55,122.91,121.98,121.75,121.05,120.76,119.09,118.42,117.99,117.87,111.87.HRMS(ESI)calculated for[M+H]+C33H24F3N2 +,m/z:505.1892,found:505.1890.M.P.82.4℃.[α]20 D=-1.2°(c=0.5,CHCl3).HPLC analysis:HPLC DAICEL CHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=6.2min,tR(minor)=4.4min,ee=91%.
实施例13
按照以上公开的方法,得到3m,收率为73%,93%ee。
1H NMR(500MHz,CDCl3)δ8.23–8.20(m,2H),7.87–7.83(m,4H),7.75(s,1H),7.73–7.71(m,1H),7.60(d,J=9.0Hz,1H),7.44–7.42(m,1H),7.36–7.30(m,4H),7.17(dd,J=8.5,7.3Hz,2H),7.10(d,J=8.9Hz,2H),6.93–6.90(m,1H),6.89–6.85(m,2H),6.81(d,J=2.7Hz,1H),6.03(s,1H).13C NMR(126MHz,CDCl3)δ145.62,144.18,142.62,137.99,137.46,136.24,132.95,129.28,129.23,129.10,128.50,128.20,127.12,126.98,125.02,124.80,124.64,123.70,123.54,123.14,121.93,121.45,121.31,120.77,119.07,118.38,117.80,112.03.HRMS(ESI)calculated for[M+H]+C32H24N3O2 +,m/z:482.1869,found:482.1867.M.P.114.5℃.[α]20 D=-77°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=365nm),tR(major)=9.9min,tR(minor)=8.1min,ee=93%.
实施例14
按照以上公开的方法,得到3n,收率为64%,93%ee。
1H NMR(600MHz,CDCl3)δ8.17(s,1H),7.86(s,1H),7.77–7.74(m,3H),7.64(s,1H),7.55(d,J=8.9Hz,1H),7.29–7.21(m,5H),7.13–7.10(m,2H),6.87–6.83(m,5H),6.81(d,J=7.4Hz,1H),6.73(d,J=7.6Hz,1H),6.61(d,J=2.7Hz,1H),6.14(s,1H),2.07(s,3H).13CNMR(151MHz,CDCl3)δ143.09,137.70,137.48,137.20,137.06,133.17,130.94,129.44,129.25,129.05,128.26,128.06,128.03,127.86,127.45,126.64,125.32,125.16,125.03,124.88,123.28,123.01,122.54,121.35,120.75,120.64,118.95,118.37,118.24,111.67,21.28.HRMS(ESI)calculated for[M+H]+C33H27N2 +,m/z:451.2174,found:451.2171.M.P.70.8℃.[α]20 D=-80°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=365nm),tR(major)=16.4min,tR(minor)=4.4min,ee=93%.
实施例15
按照以上公开的方法,得到3o,收率为74%,92%ee。
1H NMR(400MHz,CDCl3)δ8.24–8.22(m,1H),7.99(s,1H),7.87–7.82(m,2H),7.79–7.77(m,2H),7.66(d,J=9.0Hz,1H),7.41–7.37(m,1H),7.34–7.29(m,4H),7.22–7.18(m,2H),7.00(dd,J=5.1,3.0Hz,1H),6.97–6.90(m,3H),6.76–6.74(m,2H),6.57(dd,J=5.0,1.3Hz,1H),6.20(s,1H).13C NMR(126MHz,CDCl3)δ143.04,138.68,137.98,137.32,133.01,129.88,129.29,129.17,128.51,128.23,127.93,127.82,126.80,125.40,125.03,124.84,123.43,123.00,122.80,122.61,121.91,121.58,120.80,120.70,119.29,118.19,117.88,111.74.HRMS(ESI)calculated for[M+H]+C30H23N2S+,m/z:443.1582,found:443.1579.M.P.78.5℃.[α]20 D=-53°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=365nm),tR(major)=15.6min,tR(minor)=6.0min,ee=92%.
步骤2、3:轴手性萘胺吲哚方酰胺类化合物的合成
实施例16
将化合物3d溶于含有15mL干燥甲醇的高压反应釜中,加入60mg Pd(OH)2/C,往反应釜中充入H2,在50℃下,反应过夜,经过滤、浓缩,硅胶柱分离,制得化合物4,产率为95%,ee值为93%。
1H NMR(400MHz,CDCl3)δ8.11(d,J=6.9Hz,1H),7.77(s,1H),7.72–7.69(m,1H),7.68(s,1H),7.66–7.63(m,2H),7.56(s,1H),7.23–7.15(m,5H),6.99–6.98(m,5H),6.91(d,J=8.7Hz,1H),6.42(d,J=2.6Hz,1H),3.80(s,2H).13C NMR(101MHz,CDCl3)δ140.57,137.49,137.30,133.15,131.35,128.86,128.27,128.24,128.12,127.92,127.45,126.68,126.54,125.46,125.23,124.59,122.51,122.38,120.79,120.62,118.48,118.36,118.32,111.70.HRMS(ESI)calculated for[M+H]+C26H21N2 +,m/z:361.1705,found:361.1702.M.P.62.5℃.[α]20 D=166°(c=0.2,CHCl3).HPLC analysis:HPLC DAICELCHIRALPAK IF,hexane/isopropyl alcohol=90/10,flow rate=0.5mL/min,λ=360nm),tR(major)=20.7min,tR(minor)=20.1min,ee=93%.
实施例17
将化合物4溶于10mL干燥的甲醇中,依次0.55mmol 3,4-二甲氧基-3-环丁烯-1,2-二酮、0.25mmol N,N-二甲基异丙基胺,于50℃下反应24h,过滤干燥,制得化合物6,产率为90%,ee值为93%。
1H NMR(400MHz,DMSO-d6)δ11.18(d,J=2.7Hz,1H),10.40(s,1H),8.02(d,J=8.8Hz,1H),8.00–7.96(m,1H),7.79(dd,J=8.4,1.1Hz,1H),7.74(d,J=8.1Hz,1H),7.54(s,1H),7.49–7.43(m,2H),7.42–7.40(m,1H),7.35(ddd,J=8.3,6.8,1.3Hz,1H),7.16–7.04(m,3H),6.99–6.97(m,2H),6.82–6.80(m,2H),6.74(d,J=2.7Hz,1H),4.10(d,J=4.4Hz,3H).13C NMR(101MHz,DMSO)δ188.45,184.31,178.20,170.82,137.90,137.54,132.96,132.25,132.09,130.98,130.58,128.74,128.64,128.32,128.28,127.31,126.88,126.58,126.52,126.13,126.11,125.17,124.31,122.03,120.58,120.23,117.85,112.49,60.39.HRMS(ESI)calculated for[M+H]+C31H23N2O3 +,m/z:471.1709,found:471.1705M.P.248.2℃.[α]20 D=37°(c=0.2,THF).HPLC analysis:HPLC DAICELCHIRALPAK AD-H,hexane/isopropyl alcohol=60/40,flow rate=1mL/min,λ=360nm),tR(major)=6.9min,tR(minor)=5.6min,ee=93%.
实施例18
将0.25mmol化合物6溶于干燥的5mL甲醇中,加入0.275mmol N,N’-二甲基乙二胺,于50℃下反应24h,过滤干燥,制得化合物8a,产率为95%。
1H NMR(400MHz,DMSO-d6)δ11.23(d,J=2.7Hz,1H),9.13(s,1H),8.08(t,J=6.0Hz,1H),8.00(d,J=9.0Hz,1H),7.93(d,J=7.9Hz,1H),7.85(d,J=8.0Hz,1H),7.76(d,J=8.9Hz,1H),7.72(d,J=8.5Hz,1H),7.63(s,1H),7.43–7.40(m,1H),7.38–7.35(m,1H),7.29(ddd,J=8.3,6.8,1.4Hz,1H),7.12(dddd,J=27.6,8.2,7.0,1.2Hz,2H),7.00–6.98(m,2H),6.94–6.92(m,2H),6.82(d,J=2.7Hz,1H),3.61(p,J=6.2Hz,2H),2.37(t,J=5.9Hz,2H),2.13(s,6H).13CNMR(101MHz,DMSO)δ185.26,180.64,169.38,164.59,137.74,137.72,134.11,131.87,131.04,130.80,128.63,128.52,128.47,128.24,127.18,127.04,126.85,126.64,126.23,125.41,125.31,125.18,122.88,122.18,120.64,120.39,117.52,112.64,59.74,45.48,41.49.HRMS(ESI)calculated for[M+H]+C34H31N4O2 +,m/z:527.2447,found:527.2445.M.P.271.2℃.[α]20 D=-204°(c=0.2,THF).
实施例19
将0.25mmol化合物6溶于干燥的5mL甲醇中,加入0.275mmol奎宁胺,于50℃下反应24h,过滤干燥,制得化合物8b,产率为95%。
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),8.94(s,1H),8.72(d,J=4.6Hz,1H),8.46(d,J=9.0Hz,1H),7.95–7.89(m,3H),7.75(d,J=8.0Hz,1H),7.70(d,J=8.5Hz,1H),7.63–7.55(m,2H),7.46(d,J=4.7Hz,1H),7.42(dd,J=9.2,2.5Hz,1H),7.35(d,J=8.2Hz,2H),7.30–7.26(m,1H),7.09(t,J=8.0Hz,2H),6.98–6.95(m,2H),6.90-6.88(m,2H),6.78(d,J=2.6Hz,1H),6.65(s,1H),5.99–5.90(m,2H),5.04–4.95(m,2H),3.91(s,3H),3.28–3.18(m,2H),2.72–2.64(m,2H),2.34–2.16(m,3H),1.57–1.46(m,4H),0.61–0.57(m,1H).13CNMR(176MHz,DMSO)δ185.08,179.99,168.24,164.75,158.26,151.94,148.21,144.67,142.66,139.67,137.68,137.57,133.73,131.98,131.91,131.10,130.76,128.73,128.56,128.51,128.47,128.24,127.48,127.18,126.85,126.83,126.07,125.51,125.39,125.17,122.13,120.48,120.30,117.51,114.80,112.56,107.46,102.04,97.63,67.08,66.17,59.34,56.13,34.86,30.88,27.79,26.64,21.51.HRMS(ESI)calculated for[M+H]+C50H44N5O3 +,m/z:762.3444,found:762.3445.M.P.113.2℃.[α]20 D=-36°(c=0.1,CHCl3).
轴手性萘胺吲哚方酰胺类化合物的应用
实施例20
在0℃条件下,将化合物9(0.1mmol,1当量)溶于2mL重蒸三氯甲烷中,加入化合物8a(0.01mmol,0.1当量)、化合物10(0.2mmol,2当量)和10mg硫酸镁,在0℃条件下搅拌反应35h后,反应液通过硅胶柱色谱纯化,用石油醚/乙酸乙酯体系洗脱,得到所需产物11,产率为60%,50%ee。
1H NMR(400MHz,CDCl3)δ11.66(s,1H),8.75–8.71(m,2H),8.19(dd,J=8.3,1.7Hz,1H),7.60–7.57(m,4H),7.47(dd,J=8.3,4.2Hz,1H),7.22(d,J=7.7Hz,2H),5.25(s,0H),4.86(d,J=2.9Hz,1H),3.77(d,J=10.2Hz,1H),3.56–3.52(m,1H),3.33(d,J=10.2Hz,1H),3.11(dd,J=11.2,1.2Hz,1H),2.41(s,3H).13C NMR(101MHz,CDCl3)δ169.57,148.51,139.23,138.91,136.37,133.54,131.88,129.10,127.98,127.22,122.86,121.85,118.83,117.04,89.37,85.26,80.78,56.61,39.06,38.87,21.58.HRMS(ESI)calculated for[M+H]+C23H21N2O2S+,m/z:389.1324,found:389.1323.M.P.121.4℃.HPLC analysis:HPLC DAICELCHIRALPAK IC,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=19.2min,tR(minor)=12.4min,ee=50%.[α]20 D=25°(c=0.2,CHCl3).
实施例21
在0℃条件下,将化合物9(0.1mmol,1当量)溶于2mL重蒸三氯甲烷中,加入化合物8b(0.01mmol,0.1当量)、化合物10(0.2mmol,2当量)和10mg硫酸镁,在0℃条件下搅拌反应35h后,反应液通过硅胶柱色谱纯化,用石油醚/乙酸乙酯体系洗脱,得到所需产物11,产率为97%,88%ee。
结构表征数据同实施例20。
实施例22
在0℃条件下,将化合物12(0.1mmol,1当量)溶于2mL重蒸三氯甲烷中,加入化合物8a(0.01mmol,0.1当量)、化合物10(0.2mmol,2当量)和10mg硫酸镁,在0℃条件下搅拌反应35h后,反应液通过硅胶柱色谱纯化,用石油醚/乙酸乙酯体系洗脱,得到所需产物13,产率为59%,49%ee。
1H NMR(400MHz,CDCl3)δ11.65(s,1H),8.75–8.71(m,2H),8.19(dd,J=8.3,1.7Hz,1H),7.61–7.55(m,2H),7.52–7.50(m,2H),7.47(dd,J=8.3,4.2Hz,1H),7.30(t,J=7.8Hz,1H),7.25–7.21(m,1H),5.24(s,1H),4.86(dd,J=3.4,1.2Hz,1H),3.78(d,J=10.2Hz,1H),3.54(dd,J=11.2,3.4Hz,1H),3.34(d,J=10.2Hz,1H),3.11(dd,J=11.2,1.2Hz,1H),2.40(s,3H).13C NMR(101MHz,CDCl3)δ169.47,148.45,138.91,138.03,136.38,133.51,132.52,129.90,129.06,128.25,127.98,127.22,122.87,121.86,121.69,117.05,89.37,85.57,80.76,56.59,39.03,38.84,21.26.HRMS(ESI)calculated for[M+H]+C23H21N2O2S+,m/z:389.1324,found:389.1323.M.P.108.4℃.HPLC analysis:HPLC DAICEL CHIRALPAK IC,hexane/isopropyl alcohol=70/30,flow rate=1mL/min,λ=254nm),tR(major)=18.8min,tR(minor)=12.1min,ee=49%.[α]20 D=24°(c=0.2,CHCl3).
实施例23
在0℃条件下,将化合物12(0.1mmol,1当量)溶于2mL重蒸三氯甲烷中,加入化合物8b(0.01mmol,0.1当量)、化合物10(0.2mmol,2当量)和10mg硫酸镁,在0℃条件下搅拌反应35h后,反应液通过硅胶柱色谱纯化,用石油醚/乙酸乙酯体系洗脱,得到所需产物13,产率为93%,90%ee。
结构表征数据同实施例22。
在本说明书的描述中,参考术语“一个实施例”、“示例”、“具体示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不一定指的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。
上述对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (8)
1.一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,轴手性萘胺方酰胺类有机催化剂化学结构式为:
制备方法包括以下步骤:
(1)向结构式1所示的化合物中加入溶剂,结构式2所示的化合物,催化剂以及添加剂,室温条件下搅拌反应后,层析柱分离,获得结构式3所示的化合物,化学反应式如(I)所示:
(2)将制备得到的结构式3所示的化合物溶于甲醇中,催化剂为Pd(OH)2/C,通入H2在5-8atm的压力下30-80℃还原,然后减压蒸馏除去溶剂、层析柱分离,得到脱除苄基的中间体化合物4,将其溶于甲醇中,再加入化合物5,有机碱N,N-二异丙基乙胺,在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂前体6;
反应式化学反应式如(II)所示:
(3)将纯产物催化剂前体6所示的化合物溶于甲醇中,加入有机碱N,N-二异丙基乙胺,然后加入胺类化合物7,在30-80℃下反应,然后过滤,用少量甲醇洗涤固体,得到纯产物催化剂8,
其中R2选自氢、甲基、乙基或溴中的至少一种;R3选自氢、氟、氯、甲基、甲氧基甲酸甲酯基或苄氧基中的至少一种;R4选自氢、氟、氯、溴、甲基、三氟甲基、甲氧基、氰基或硝基中的至少一种,R5选自N,N-二甲基乙胺基、奎宁基或苯基中的至少一种。
2.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(1)中结构式1所示的化合物、结构式2所示的化合物、催化剂摩尔比为1:(1-2):0.1。
3.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(1)中
所述溶剂为甲苯或二氯甲烷中的一种,浓度为0.05~0.5mmol/mL,
所述添加剂的加入量为每0.1mmol结构式1所示的化合物,加入50mg-100mg的添加剂。
4.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(2)中所述甲醇的浓度为0.01-0.2mmol/mL。
5.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(2)中结构式3所示的化合物与Pd(OH)2/C的质量比为100:5-20。
6.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(2)中化合物5为二酮化合物,中间体化合物4与化合物5的摩尔比为1:(1-1.5)。
7.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(3)中所述甲醇的浓度为0.01-0.2mmol/mL。
8.根据权利要求1所述的一种轴手性萘胺方酰胺类有机催化剂的制备方法,其特征在于,步骤(3)中纯产物催化剂前体6与胺类化合物7的摩尔比为1:(1-1.5),所述胺类化合物7为N,N-二甲基乙二胺、奎宁胺或苯胺中的一种。
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