CN1914218A - 制备不对称转化反应催化剂的方法 - Google Patents
制备不对称转化反应催化剂的方法 Download PDFInfo
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- CN1914218A CN1914218A CNA2005800037221A CN200580003722A CN1914218A CN 1914218 A CN1914218 A CN 1914218A CN A2005800037221 A CNA2005800037221 A CN A2005800037221A CN 200580003722 A CN200580003722 A CN 200580003722A CN 1914218 A CN1914218 A CN 1914218A
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- LVHBHZANLOWSRM-UHFFFAOYSA-N methylenebutanedioic acid Natural products OC(=O)CC(=C)C(O)=O LVHBHZANLOWSRM-UHFFFAOYSA-N 0.000 description 1
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
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Abstract
本发明涉及一种制备手性配位体的方法,包括提供通式(A)的初始材料:其中X*是手性或非手性的定向取代基,且○是任选取代的单环或多环芳基或环烷基;对底物进行邻位锂化;将邻位锂化的底物转化成具有通式-PR1R1”的膦基团,R1选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧,R1”和R1不同,选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将X*转化成不同的基团以制备手性配位体。
Description
技术领域
本发明涉及制备不对称转化反应催化剂的新方法,特别涉及制备在磷或砷上带有手性中心的膦和胂配位体,人们发现该配位体适用于各种不对称转化反应,包括氢化和形成碳氧和碳氮键的反应。本发明方法一般适用于制备含芳环体系的手性催化剂,特别适用于制备基于金属茂的手性膦或胂配位体。本发明还涉及用本发明方法制备的手性催化剂,以及该催化剂在不对称转化反应中的应用。
背景技术
二茂铁作为用于二膦配位体的骨架是由Kumada和Hayashi基于Ugi的开拓性工作而提出,该开拓性工作与对映体纯取代的金属茂的合成1有关。这些配位体显示如下:
Ppfa以及bppfa和bppfoh被证明是用于各种不对称转化的催化剂的有效配位体。以此为起点,近几年来,许多结构变化很大的、手性的基于二茂铁的二膦配位体已被开发出来。
已知配位体的某些种类在平面和碳上均显示手性:
Togni和Spindle2报道了一类非-C2-对称的基于二茂铁的二膦:Josiphos型配位体。Josiphos配位体具有广泛的商业用途,已经发现对α-乙酰氨基肉桂酸,衣康酸二甲酯,和β-酮酸酯的铑催化的氢化有效。因为二膦基团在连续步骤中被高产率地引入配位体,因此可获得具有不同空间排列和电子特性的各种配位体。该配位体已经应用于三种生产工艺3,若干中间工艺和许多其他的合成中。例如,PPF-tBu2,具有二(叔丁基)膦基的Josiphos型配位体,已经作为不对称氢化4中的配位体用于商业合成(+)生物素。另一个著名的例子是XyliPhos用于亚胺的铱催化氢化中,以合成除草剂(S)-异丙甲草胺5。
Bophoz6是膦和氨基膦的组合体,由Ppfa经三个步骤制备,具有高的总产量。该配位体在空气中稳定,对烯酰胺,衣康酸酯和α-酮酸衍生物的氢化有效。注意到若干配位体形成七元螯合物,可以达到高活性,并声称高达10,000TON。该组合配位体类的全部范围还没有确定。
非-C2-对称的、基于二茂铁的一类1,5-二膦配位体--Taniaphos,已经由Knochel7,8开发出来。与Josiphos配位体相比,Taniaphos在Ugi胺的侧链上插入了一个额外的苯环。Taniaphos在铑和钌催化的不对称氢化中表现出优异的效果。Taniaphos的α-位构型在对映选择性和活性中起重要的作用。在不对称转化的很宽的范围内,具有αS构型的Taniaphos 1b比具有αR构型的1a具有更高的对映选择性和活性。
Weissensteiner和Spindler9报道了一系列不同结构的基于二茂铁的1,5-二膦配位体Walphos。如同Josiphos,Walphos是定型的,其也由Ugi胺制备。其可望用于烯烃和酮的对映选择性氢化。
Mandyphos是C2对称的Ppfa的二配位基型,其中除了PPh2部分,R和R′能用于精调配位体10的功能。该配位体族的范围还没有完全地确定,但是初步结果显示出对烯酰胺,衣康酸酯和烯醇乙酸酯的铑催化氢化的高对映选择性。
由Ito11开发的TRAP配位体形成九元金属环。然而,还不清楚是少量存在的顺式异构体,还是主要的反式异构体导致催化活性。到目前为止,只测试了少数不同的PR2片段,但是很明显,R的选择强烈地影响催化性能。铑络合物适用于0.5±1巴的极低压力,有效地还原了吲哚衍生物,烯酰胺和衣康酸衍生物。
另一类已知的配位体仅显示平面手性:
Kang12报道了仅有平面手性的C2对称的FerroPHOS配位体。FerroPHOS配位体在空气中稳定,并且对各种脱氢氨基酸衍生物的不对称氢化非常有效(高达99%ee)。
Jendralla开发出了另一个C2对称平面手性二膦JAFAPhos,JAFAPhos在不对称氢化,烯丙基的烷基化,Grignard交叉耦合和醛醇缩合反应中有着优异的效果。
Kagan14报道了平面手性的基于二茂铁的二膦配位体2和3,用这些配位体作为催化剂,在衣康酸二甲酯的不对称氢化中得到了高达95%的ee。
另一类已知的二膦配位体仅在磷原子显示手性:
手性1,1′-二(磷杂环丁基)二茂铁(FerroTANE)的合成已经分别由Marinetti15和Burk16报道。FerroTANE已经成功地应用于衣康酸酯和(E)-β-(酰胺基)丙烯酸酯的铑催化氢化中。
Mezzetti18和van Leeuwen19分别报道了对-手性二茂铁基二膦4a和4b。这两种配位体在α-脱氢氨基酸衍生物的不对称氢化中显示了优异的对映选择性(高达99%ee)。
Zhang报道了在3位和4位有缩酮取代基的二(磷杂环戊基)二茂铁配位体5。20该配位体在β-脱氢氨基酸衍生物的氢化中显示优异的对映选择性。配位体的缩酮基对实现高对映选择性非常重要,因为无缩酮基的相应配位体仅提供中等的ee。此外,Zhang开发了1,1’-二(二萘并磷杂庚英基)二茂铁f-binaphane,它们已经成功地应用于非环芳基亚胺的铱催化氢化中。21
Reetz开发了一种衍生自联萘酚的基于二茂铁的亚膦酸酯配位体622,其在衣康酸酯和α-脱氢氨基酸衍生物的铑催化氢化中显示出优异的反应性和对映选择性。
另一类已知的配位体在平面和磷上均显示手性:
Van Leeuwen报道了基于二茂铁的二膦,其结合了平面和磷手性7a和7b23。这两种配位体在不对称烯丙基烷基化中显示优异的对映选择性(高达99%ee)。
因此,大部分已知的基于二茂铁的二膦具有平面和碳手性、仅平面手性或仅磷手性。近年来,Togni报道了第一个三配位基的基于二茂铁的膦配位体12,其结合了平面、磷和碳手性。24
在我们的申请中的专利申请GB0400720.9中,我们描述了具有通式(I),(II)或(III)的配位体:
其中定义了R1-5,W,Q,m,n和G,以及制备该配位体的方法。但我们发现其中描述的方法可更广泛地用于制备各种手性配位体。
发明内容
本发明提供了一种制备手性配位体的方法,包括提供通式(A)的初始材料:
其中X*是手性或非手性的定向取代基;且
○是任选取代的单环或多环芳基或环烷基;对底物进行邻位锂化;将邻位锂化的底物转化成具有通式-PR1R1“的膦基团,R1和R1“彼此不相同,独立选自取代和未取代支链和直链烷基、烷氧基、烷基氨基,取代和未取代的环烷基,取代和未取代的环烷氧基,取代和未取代的环烷基氨基,取代和未取代的碳环芳基,取代和未取代的碳环芳氧基,取代和未取代的杂芳基,取代和未取代的杂芳氧基,取代和未取代的碳环芳基氨基,和取代和未取代的杂芳基氨基,其中每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将X*转化成不同的基团以制备手性配位体。
○在本发明的方法中是金属茂化合物的一个芳环(任选地被进一步取代)。
本发明还提供了一种制备手性配位体的方法,包括提供通式(A)的初始材料:
其中X*是手性或非手性的定向取代基;且
○是任选取代的单环或多环芳基或环烷基;对底物进行邻位锂化;将邻位锂化的底物与R1取代的膦或胂反应,R1选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;然后和带有R1“的格氏试剂或有机锂化合物反应,R1“和R1不同,选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将X*转化成不同的基团以制备手性配位体。
例外的情况是手性配位体不是具有通式(I),(II)或(III)的配位体:
其中R1-5,W,Q,m,n和G如GB0400720.9中所定义。
○在本发明的方法中是金属茂化合物的一个芳环(任选地被进一步取代)。
本发明的方法适用于制备具有三种手性元素;平面手性,磷(或砷)手性,和任选碳手性的磷或胂配位体。
为方便起见,接下来的描述将会围绕制备膦配位体的方法。请注意,尽管制备膦配位体的方法是本发明优选的方法,制备胂配位体的相应方法也在本发明的范围之内。
同样,当通过本发明方法获得的手性配位体是金属茂配位体,优选用于制备基于二茂铁的配位体的方法,但其它合适的金属也可用于本发明方法制得的金属茂配位体,因此,本发明在述及二茂铁时也包括通常的金属茂。
本发明还提供通过本发明方法制得的手性配位体。该配位体的例子包括具有平面、磷和碳手性的基于金属茂的膦配位体。
本发明还提供利用本发明方法制得的手性配位体(不包括具有通式(I),(II)或(III)的那些)。该配位体的例子包括具有平面、磷和碳手性的基于金属茂的膦配位体。
本发明方法制得的配位体相对现有技术配位体具有特定的优势,因为其提供了可高达三或四种手性元素,这使得配位体的设计者为了特定用途所设计的配位体比迄今为止设计的配位体具有更大的选择范围。
当获得在平面、碳和磷手性中的匹配时,引入磷手性会强化催化剂产生的手性识别力。匹配的催化剂会具有高ee,不匹配的催化剂具有低ee。
本发明还提供过渡金属络合物,其中含有与本发明方法制备的配位体配合的过渡金属。金属优选是VIb族或VIII族金属。
优选X*是邻位定向取代基。
根据本发明,使用合适的手性邻位定向取代基,可以实现磷手性膦的合成,例如下列反应式所示:
其中○是任选取代的单环或多环芳基或环烷基,且其中R1“Z是有机碱类或格氏试剂。
合适的手性定向取代基的例子:
其中R,R2和R3独立选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧。
○在本发明的方法中是金属茂化合物的一个芳环(任选地被进一步取代)。
其中
例如,使用合适的手性邻位定向取代基,可以实现基于二茂铁的磷手性膦的合成,例如下列反应式所示:
合适的手性定向取代基的例子如上述。
其中,在反应式3中,L是一个连接物。例如,L可选自二茂铁,二苯醚,三环二苯并吡喃,2,3-苯并噻吩,1,2-苯,琥珀酰亚胺以及很多其它物质。这些双阴离子连接物可从相应的二卤前体方便地制备,例如:
某些合适的双阴离子连接物如下所示:
但是,根据本发明,二茂铁是优选的连接物。
(类似的路线可用于合成相应的胂,及其它金属茂,亦可用于其它的环体系。同样为了方便起见,这些路线用基于二茂铁的底物来描述,但是也适用于其它基于芳族的底物。)
相应地,本发明提供了一种制备具有磷手性的膦配位体的方法,包括提供任选取代的单环或多环芳基或环烷基底物,其在至少一个环上带有手性或非手性的定向取代基,将该底物进行进行邻位锂化;将邻位锂化的底物转化成具有通式-PR1R1“或PR1L的膦基团,其中L是如上所述的连接物,R1和R1“彼此不相同,独立选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中的每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将定向取代基转化成一个手性基团,或转化为不同的手性基团。
相应地,本发明提供了一种制备具有磷手性的膦配位体的方法,包括提供基于金属茂的底物,底物在至少一个环上带有手性或非手性的定向取代基,将该取代金属茂进行邻位锂化;将邻位锂化的底物转化成具有通式-PR1R1“或PR1L的膦基团,其中L是如上所述的连接物,R1和R1“彼此不相同,独立选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中的每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将定向取代基转化成一个手性基团,或不同的手性基团。
相应地,本发明提供了一种制备具有砷手性的胂配位体的方法,包括提供任选取代的单环或多环芳基或环烷基底物,其在至少一个环上带有手性或非手性的定向取代基,将该底物进行邻位锂化;将邻位锂化的底物转化成具有通式-AsR1R1“或AsR1L的胂基团,其中L是如上所述的连接物,R1和R1“彼此不相同,独立选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中的每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将定向取代基转化成一个手性基团,或不同的手性基团。
相应地,本发明提供了一种制备具有砷手性的胂配位体的方法,包括提供基于金属茂的底物,底物在至少一个环上带有手性或非手性的定向取代基,将该取代金属茂进行邻位锂化;将邻位锂化的底物转化成具有通式-AsR1R1“或AsR1L的胂基团,其中L是如上所述的连接物,R1和R1“彼此不相同,独立选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中的每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将定向取代基转化成一个手性基团,或不同的手性基团。
接下来详细描述本发明的制备手性配位体的方法。
例如,一种该方法包括提供通式(A)的底物:
其中
○是任选取代的单环或多环芳基或环烷基;X*是手性定向取代基,优选自上述的基团;对底物进行进行邻位锂化;将邻位锂化的底物与R1取代的卤代膦或卤代胂反应,R1选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;然后和带有R1“的格氏试剂或有机碱(优选有机锂)化合物反应,R1“和R1不同,选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;选择性地,或若是必要的话,将X*转化成不同的基团以制备手性配位体。
○在本发明的方法中是金属茂化合物的一个芳环(任选地被进一步取代)。
另一种该方法包括提供通式(A)的化合物:
其中
○是任选取代的单环或多环芳基或环烷基;X*是手性定向取代基,优选自如上述限定的基团;对底物进行进行邻位锂化;将邻位锂化的底物与R1取代的卤代膦或卤代胂反应,R1选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;然后和带有R1“的格氏试剂或有机碱(优选有机锂)化合物反应,R1“选自取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;
任选地,或若是必要的话,将X*转化成不同的基团以制备手性配位体;
例外的情况是手性配位体不是具有通式(I),(II)或(III)的配位体:
其中R1-5,W,Q,m,n和G如在GB0400720.9中所定义。
○在本发明的方法中是金属茂化合物的一个芳环(任选地被进一步取代)。
上述每个方法中一个特别优选的X*基团是
邻位锂化步骤优选使用正丁锂,伯丁锂或叔丁锂的单-邻位-锂化。所得的单锂化合物优选与通式R1PCl2的二氯膦原位反应,然后与通式R1“Z的有机金属试剂反应,其中的R1和R1“如上所述;Z是Li或MgY,其中Y是卤离子。
实施这些步骤可以获得具有通式(C)的磷手性化合物(其中的芳环或脂肪环可被任选地取代):
优选在合成中将化合物(C)转化成化合物D,E或F:
其中Rd是酰基,Re选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧,R1“和R1如上所定义;
然后:
将化合物D与通式R6R7PH所示的仲膦反应,其中R6和R7相同或不同,并且独立选自取代和未取代的支链和直链烷基、烷氧基、烷基氨基,取代和未取代的环烷基,取代和未取代的环烷氧基,取代和未取代的环烷基氨基,取代和未取代的碳环芳基,取代和未取代的碳环芳氧基,取代和未取代的杂芳基,取代和未取代的杂芳氧基,取代和未取代的碳环芳基氨基和取代和未取代的杂芳基氨基,其中每个杂原子独立选自硫、氮和氧;R8选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧以获得综合平面、磷和碳手性的二膦,其具有通式G:
或者:
将化合物D与通式R8NH2所示的胺反应,其中R8选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧以获得化合物H:
或者:
将化合物D与通式J所示的胺反应:
其中R6和R7定义如上;R9选自氢,卤素,OR10,SR10,NR10R11,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;其中R10和R11是相同或不同的,独立选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;n’是0到4,Z是MgY(Y是卤离子)或Li,得到化合物K:
或;
将化合物D与通式H2N-R*-NH2或H2N-R**-NH2所示的胺反应,其中R*和R**选自下组:
其中R9定义如上;R12选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧;或(R12)2是-(CH2)m’-,n’为0到4;m’为1到8,得到化合物L和M:
或;
将化合物E与通式H2N-R*-NH2或H2N-R**-NH2所示的胺反应,其中R*和R**如上所示,得到化合物O和P:
化合物H可与通式R6R7PY所示的卤膦反应,其中R6和R7如上所述,Y是氯,溴或碘,得到化合物Q:
或者,化合物H可与通式R13COY所示的酸衍生物反应,其中R13选自氢,取代和未取代的支链和直链烷基,取代和未取代的环烷基,取代和未取代的碳环芳基,和取代和未取代的杂芳基,其中每个杂原子独立选自硫、氮和氧,Y是卤离子、硫酸根、咪唑、R13COO-或氢,得到化合物R:
或者,化合物H(其中R8是氢)可与通式OHC-R*-CHO或OHC-R**-CHO所示的醛反应,其中R*和R如上定义,得到通式为S和T的化合物:
或者,化合物H可与通式YOC-R*-COY和YOC-R**-COY所示的酸衍生物反应,其中R*,R**和Y如上定义,得到通式为U和V的化合物:
化合物K可被转化成化合物X:
其中R14选自OR10,SR10,NHR10和NR10R11,其中R10和R11如上定义。
化合物L,M,O,P,S,T,U,V可被还原得到相应的化合物L*,M*,O*,P*,S*,T*,U*,V*:
磷手性的基于金属茂的膦的合成还可以借助于对映选择性的邻位锂化来完成(下面列出的基于二茂铁的底物代表和本发明方法有关的一般芳族和脂环族的底物):
适当的非手性定向取代基的例子:
(其中R2和R3如上所述)
合适的手性二胺包括:
相应地,本发明提供了制备手性二膦配位体的方法,该配位体包括在一个或两个环上具有非手性的定向取代基的基于金属茂的底物,并对该取代金属茂实施对映选择性邻位锂化步骤,然后将邻位锂化底物转变为磷手性的膦。
在某些情况下,优选在邻位锂化步骤中使用辅助手性化合物(例如手性二胺),在这些情况下需要直接合成手性产物(在对映体过量中),也可以在没有该手性辅助物的情况下进行邻位锂化,然后在合成最后溶解光学异构的产物混合物。
(该方法也适用于胂。)
本发明提供了一种制备手性配位体的方法,包括提供通式A*的底物:
其中
○为任选取代的单环或多环芳基或环烷基;其中X**是手性定向取代基,优选如上文所定义;在纯手性叔胺存在的条件下,使用正丁锂或伯丁锂或叔丁锂,对化合物进行对映体选择性的单邻位锂化。所得的手性单锂化合物与通式R1PCl2的二氯膦原位反应,然后与通式R1“M的有机金属试剂反应,其中的R1和R1“如上所述;M是Li或MgY,其中X是卤素,得到具有通式C*的手性磷化合物:
任选或如果必要的话,进一步将化合物C*转化成所需的手性配位体。
本发明提供了一种制备基于二茂铁的手性配位体的方法,包括提供通式B*的化合物:
其中X*如上文所述;且使用正丁锂或仲丁锂或叔丁锂对化合物进行二邻位锂化,所得的二锂化合物与通式R1PCl2的二氯膦原位反应,然后与通式R1“Z的有机金属试剂反应,其中的R1和R1“如上所述;Z是Li或MgY,其中Y是卤离子,得到带有通式B***的磷手性化合物:
任选地或如果必要的话,进一步将化合物B***转化成所需的手性配位体。
现在参考以下实施例具体说明本发明。
具体实施方式
实施例1:
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(2-甲氧苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-2]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](3.86g,15mmol)的Et2O(50mL)溶液中加入1.7M t-BuLi的戊烷溶液(9.7mL,16.5mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(2.24mL,16.5mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入(2-甲氧基)苯基锂溶液[由2-溴甲氧基苯(3.32g,17.7mmol)和1.7M t-BuLi的戊烷(20.8mL,35.4mmol)溶液在Et2O(90mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(6.50g,92%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.29(d,3H,J=6.5Hz);1.80(s,6H);3.91(s,3H);3.97(s,6H,重叠);4.11(m,1H),4.25(t,1H,J=2.2Hz);4.37(br.s,1H);6.87(m,1H);6.94(dd,1H,J=8.3和6.7Hz);7.12-7.23(m,6H);7.31(m,1H);31P NMR(CDCl3,162MHz):δ-38.82。用单晶X射线衍射分析,确定其具有(Rc,SFe,Sp)-2的绝对构型。
实施例2
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-3]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](5.15g,20mmol)的Et2O(60mL)溶液中经10分钟加入1.7M t-BuLi的戊烷溶液(12.94mL,22mmol)。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(2.99mL,22mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入1-萘锂溶液[由1-溴萘(5.38g,26mmol)和1.7M t-BuLi的戊烷(30.6mL,52mmol)溶液在Et2O(120mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=90∶6∶4)将残留物提纯,得到的标题化合物(8.75g,89%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.33(d,3H,J=6.8Hz);1.91(s,6H);3.59(s,5H);4.00(m,1H);4.17(m,1H),4.26(t,1H,J=2.2Hz);4.38(m,1H);7.13-7.2(m,5H);7.39(t,1H,J=6.7Hz);7.43-7.54(m,2H);7.60-7.63(m,1H);7.87(dd,2H,J=9.7和9.2Hz),9.33(dd,1H,J=7.6和7.0Hz)。31P NMR(CDCl3,162MHz):δ-38.73。
实施例3
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-3]和(Rc,SFe,RP)-2-[(1-N,N-二甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Re,SFe,Rp)-4]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](1.29g,5mmol)的Et2O(15mL)溶液中经10分钟加入1.7M t-BuLi的戊烷溶液(3.2mL,5.5mmol)。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(0.75mL,5.5mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。接着在室温下用套管向混合物加入1-萘锂溶液[由1-溴萘(1.35g,6.5mmol)和1.7Mt-BuLi的戊烷(7.6mL,13mmol)溶液在Et2O(30mL)中,在-78℃制得]。将混合物在室温搅拌过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(2.21g,90%)是两种异构体的混合物。(Rc,SFe,Sp)-3与(Rc,SFe,Rp)-4的比例约为5∶1。由于(Rc,SFe,Rp)-4不溶于冷己烷,而(Rc,SFe,Sp)-3极易溶于冷己烷。可以用结晶法方便地将两种异构体从己烷中分离。(Rc,SFe,Rp)-4:1H NMR(CDCl3,400.13MHz):δ1.25(d,3H,J=6.8Hz);1.60(s,6H);3.88(br.s,1H);4.00(s,5H);4.16(m,1H),4.29(t,1H,J=2.2Hz);4.42(br.s,,1H);7.16-7.19(m,1H);7.28-7.29(m,5H),7.32-7.35(m,1H);7.59-7.63(m,2H);7.69(d,J=8.2Hz);7.76(d,J=7.6Hz);8.45(m,1H)。31P NMR(CDCl3,162MHz):δ-31.36。用单晶X射线衍射分析,确定其具有(Rc,SFe,Rp)-4的绝对构型。
实施例4
(Rc,SFe,RP)-2-[(1-N,N-二甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Re,SFe,Rp)-4]:
(Rc,SFe,Sp)-3(491mg,1.0mmol)的己烷(5mL)溶液回流过夜。冷却到室温后,将沉淀物过滤,并用冷己烷洗,得到纯(Re,SFe,Rp)-4。
实施例5
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-5]和(Rc,SFe,RP)-2-[(1-N,N-二甲氨基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-6]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](2.57g,5mmol)的Et2O(15mL)溶液中加入1.7M t-BuLi的戊烷溶液(6.4mL,11mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.5mL,11mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。然后将混合物再冷却至-78℃,接着在-78℃下用套管缓慢向混合物加入2-萘锂的悬浮液[由2-溴萘(2.69g,13mmol)和1.7M t-BuLi的戊烷溶液(15.2mL,26mmol)在Et2O(60mL)中,在-78℃反应制得]。将混合物加热到室温,过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(4.42g,90%)是两种异构体的混合物。(Rc,SFe,Sp)-5与(Rc,SFe,Rp)-6的比例约为5∶1。从己烷中分步结晶得到(Rc,SFe,Sp)-5(3.10g,63%),(Rc,SFe,Rp)-6(687mg,14%)。(Rc,SFe,Sp)-5:1H NMR(CDCl3,400.13MHz):δ1.28(d,3H,J=6.2Hz);1.80(s,6H);3.90(br.s,1H);3.92(s,5H);4.20(m,1H),4.22(t,1H,J=2.2Hz);4.38(br.s,,1H);7.18-7.26(m,5H);7.48(m,2H),7.58(ddd,1H,J=8.4,5.6和1.6Hz);7.79(d,1H,J=8.4Hz);7.83(m,2H);8.18(d,1H,J=9.5Hz);。31P NMR(CDCl3,162MHz):δ-20.88。(Rc,SFe,Rp)-6:1H NMR(CDCl3,400.13MHz):δ1.27(d,3H,J=5.7Hz);1.76(s,6H);3.90(br.s,1H);3.96(s,5H);4.18(m,1H),4.29(t,1H,J=2.2Hz);4.41(br.s,,1H);7.29(ddd,1H,J=8.3,7.0和1.6Hz);7.34(m,3H);7.39(m,2H);7.59-7.67(m,5H),7.74(m,1H);。31P NMR(CDCl3,162MHz):δ-20.57。
实施例6
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-5]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](2.06g,8mmol)的Et2O(15mL)溶液中加入1.5M t-BuLi的戊烷溶液(6.0mL,9mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.22mL,9mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。然后将混合物再冷却至-78℃,接着在-78℃下用套管缓慢加入2-溴化萘镁溶液[由2-溴萘(2.20g,10.6mmol)和镁(258mg,10.6mmol)在Et2O(20mL)中反应制得]。将混合物加热到室温,过夜,然后用饱和的NH4Cl溶液(20mL)抑制反应。分离有机层,用Et2O(20mL)提取水层。合并的有机层用盐水(20mL)洗涤,干燥(MgSO4)并浓缩。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(3.42g,87%)是单一的非对映异构体。1H NMR(CDCl3,400.13MHz):δ1.28(d,3H,J=6.2Hz);1.80(s,6H);3.90(br.s,1H);3.92(s,5H);4.20(m,1H),4.22(t,1H,J=2.2Hz);4.38(br.s,,1H);7.18-7.26(m,5H);7.48(m,2H),7.58(ddd,1H,J=8.4,5.6和1.6Hz);7.79(d,1H,J=8.4Hz);7.83(m,2H);8.18(d,1H,J=9.5Hz);。31P NMR(CDCl3,162MHz):δ-20.88。
实施例7
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[(2-联苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-7]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](2.57g,10mmol)的Et2O(20mL)溶液中加入1.5M t-BuLi的戊烷溶液(7.33mL,11mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.50mL,11mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入2-联苯基锂悬浮液[由2-溴联苯(2.24mL,13mmol)和1.5M t-BuLi的戊烷溶液(17.3mL,26mmol)在Et2O(30mL)中,在-78℃反应制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(4.87g,94%)是单一的非对应异构体。1H NMR(CDCl3,400.13MHz):δ1.25(d,3H,J=6.7Hz);1.85(s,6H);3.69(s,5H);3.76(m,1H),4.17(m,1H),4.29(t,1H,J=2.4Hz);4.32(m,1H);7.10-7.19(m,5H);7.31(m,1H),7.37-7.48(m,5H),7.64(m,1H);7.69(m,1H);7.71(m,1H).31P NMR(CDCl3,162MHz):δ-32.96
实施例8
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-(1-甲基苯基膦基)二茂铁[(Re,SFe,Rp)-8]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](2.57g,10mmol)的Et2O(20mL)溶液中加入1.5M t-BuLi的戊烷溶液(7.33mL,11mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.50mL,11mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着在-78℃用注射器加入3.0M的MeMgBr的Et2O溶液(4.0mL,12mmol)。将混合物加热到室温过夜,然后用饱和的NH4Cl溶液(20mL)抑制反应。分离有机层,用Et2O(20mL)提取水层。合并的有机层用盐水(20mL)洗涤,干燥(MgSO4)并浓缩。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将残留物提纯,得到的标题化合物(3.36g,89%)是红色油。1H NMR(CDCl3,400.13MHz):δ1.24(d,3H,J=6.7Hz);1.56(d,3H,J=4.4Hz);1.72(s,6H);4.07(m,1H),4.13(s,5H);4.30(m,1H),4.34(m,2H);7.14-7.20(m,3H);7.30-7.37(m,2H)。31P NMR(CDCl3,162MHz):δ-43.47
实施例9
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-(环己基苯基膦基)二茂铁[(Rc,SFe,Rp)-9]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](2.57g,10mmol)的Et2O(20mL)溶液中加入1.5M t-BuLi的戊烷溶液(7.35mL,11mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.50mL,11mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着在-78℃,用注射器加入2.0M的氯化环己镁的Et2O溶液(6.0mL,12mmol)。将混合物加热到室温过夜,然后用饱和的NH4Cl溶液(20mL)抑制反应。分离有机层,用Et2O(20mL)提取水层。合并的有机层用盐水(20mL)洗涤,干燥(MgSO4)并浓缩。用色谱分离法(SiO2,己烷-EtOAc-Et3N=90∶5∶5)将残留物提纯,得到的标题化合物(4.09g,92%)是红色油。1H NMR(CDCl3,400.13MHz):δ1.16(d,3H,J=6.7Hz);1.19-2.03(m,11H);1.50(s,6H);3.99(m,1H),4.11(s,5H);4.30(m,1H),4.32(t,1H,J=2.5Hz);4.37(m,1H),7.12-7.150(m,3H);7.18-7.23(m,2H)。31PNMR(CDCl3,162MHz):δ-14.86
实施例10
(Rc,SFe,SP)-2-[(1-N,N-二甲氨基)乙基]-1-[甲基(叔丁基)苯基膦基]二茂铁[(Rc,SFe,Rp)-10]:
用注射器在-78℃向(R)-N,N-二甲基-1-二茂铁乙胺[(R)-Ugi胺,(R)-1](1.29g,5mmol)的Et2O(15mL)溶液中加入1.5M t-BuLi的戊烷溶液(3.7mL,5.5mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入叔丁基二氯膦(875mg,5.5mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。接着在-78℃用注射器向混合物加入1.6M甲基锂的Et2O溶液(3.75mL,6.0mmol)。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤出液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=90∶5∶5)将残留物提纯,得到的标题化合物(1.54g,86%)是红色油。1H NMR(CDCl3,250.13MHz):δ1.09(d,9H,J=12.0Hz);1.27(d,3H,J=6.7Hz);1.45(d,3H,J=3.3Hz);2.08(s,6H);3.92(m,1H),4.10(s,5H);,4.28(m,3H)。31P NMR(CDCl3,101MHz):δ-6.47。
实施例11:
(Rc,SFe,SP)-2-(1-乙酰氧基乙基)-1-[(2-甲氧苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-11]:
在室温搅拌(Rc,SFe,SP)-2(1.18g,2.5mmol)的乙酸酐(10mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐,得到的标题化合物(1.21g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ1.19(s,3H);1.64(d,3H,J=6.5Hz);3.90(s,3H);3.92(m,1H);4.07(s,5H);4.34(t,1H,J=2.6Hz);5.55(m,1H);6.15(m,1H);6.87(td,1H,J=7.4和0.9Hz);6.95(q,1H,J=4.8Hz);7.08-7.21(m,6H);7.35(m,1H);31P NMR(CDCl3,162MHz):δ-39.30。
实施例12:
(Rc,SFe,SP)-2-(1-乙酰氧基乙基)-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-12]:
在室温搅拌(Rc,SFe,SP)-3(1.47g,3.0mmol)的乙酸酐(20mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐得到的标题化合物(1.52g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ1.29(s,3H);1.67(d,3H,J=6.5Hz);3.72(s,5H);3.94(m,1H);4.35(t,1H,J=2.6Hz);4.57(m,1H);6.28(m,1H);7.13-7.22(m,5H);7.38-7.43(m,2H),7.53(ddd,1H,J=8.0,6.7和1.1Hz),7.64(ddd,1H,J=8.4,6.8和1.4Hz),7.89(t,2H,J=7.0Hz);9.28(t,1H,J=7.0Hz);31P NMR(CDCl3,162MHz):δ-39.81。
实施例13:
(Rc,S Fe,RP)-2-(1-乙酰氧基乙基)-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-13]:
在室温搅拌(Rc,SFe,RP)-4(1.47g,3.0mmol)的乙酸酐(20mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐,得到的标题化合物(1.52g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ0.83(s,3H);1.62(d,3H,J=6.5Hz);3.83(m,1H);4.10(s,5H);4.40(t,1H,J=2.6Hz);5.61(m,1H);6.21(m,1H);7.11(ddd,1H,J=7.0,4.6和1.1Hz),7.28-7.41(m,6H);7.55-7.43(m,2H),7.75(m,2H),8.29(m,1H);31P NMR(CDCl3,162MHz):δ-31.33。
实施例14:
(Rc,SFe,SP)-2-(1-乙酰氧基乙基)-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-14]:
在室温搅拌(Rc,SFe,SP)-5(1.47g,3.0mmol)的乙酸酐(20mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐,得到的标题化合物(1.52g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ1.21(s,3H);1.65(d,3H,J=6.5Hz);3.83(m,1H);4.03(s,5H);4.33(t,1H,J=2.6Hz);4.57(m,1H);6.24(m,1H);7.19-7.27(m,5H);7.46-7.51(m,3H),7.81(m,3H),8.11(d,1H,J=10.4Hz);31P NMR(CDCl3,162MHz):δ-22.89。
实施例15:
(Rc,SFe,RP)-2-(1-乙酰氧基乙基)-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-15]:
在室温搅拌(Rc,SFe,RP)-6(1.47g,3.0mmol)的乙酸酐(20mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐,得到的标题化合物(1.52g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ0.92(s,3H);1.64(d,3H,J=6.4Hz);3.87(m,1H);4.07(s,5H);4.40(t,1H,J=2.6Hz);5.61(m,1H);6.23(m,1H);7.27(ddd,1H,J=8.2,6.8和1.4Hz),7.32~7.38(m,3H);7.39~7.44(m,2H),7.53~7.57(m,2H),7.60(d,1H,J=8.0Hz),7.69(m,2H),7.74(m,1H);31P NMR(CDCl3,162MHz):δ-22.58。
实施例16:
(Rc,SFe,SP)-2-(1-乙酰氧基乙基)-1-[(2-联苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-16]:
在室温搅拌(Rc,SFe,SP)-7(1.47g,3.0mmol)的乙酸酐(20mL)溶液60小时。减压(<1Torr,<30℃)除去多余的乙酸酐,得到的标题化合物(1.52g,100%)是黄色固体,其纯度足以用于下一反应。1H NMR(CDCl3,400.13MHz):δ1.25(s,3H);1.52(d,3H,J=6.5Hz);3.73(s,5H);3.96(m,1H);4.33(t,1H,J=2.6Hz);4.48(m,1H);5.81(m,1H);7.16~7.27(m,6H);7.38~7.51(m,6H),7.70-7.73(m,2H)。31P NMR(CDCl3,162MHz):δ-35.03。
实施例17:
(Rc,SFe,SP)-2-[(1-N-甲氨基)乙基]-1-[(2-甲氧基苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-17]:
在40℃搅拌(Rc,SFe,SP)-11(1.21g,2.5mmol)和40%甲胺水溶液(6.0mL)在THF(20mL)和MeOH(5mL)中的溶液3天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc-Et3N=80∶15∶5)将粗产物提纯,得到的标题化合物(1.07g,94%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ1.44(d,3H,J=6.5Hz);1.94(s,3H);3.91(m,2H);3.95(s,3H);4.05(s,5H);4.29(t,1H,J=2.5Hz);4.46(m,1H);7.90(dt,1H,J=7.3和1.0Hz),6.97(ddd,1H,J=8.3,5.0和1.0Hz),7.15(ddd,1H,J=7.3,5.5和1.8Hz),7.23(m,5H);7.36(ddd,1H,J=8.3,7.3和1.8Hz)。31P NMR(CDCl3,101MHz):δ-41.43。
实施例18:
(Rc,SFe,SP)-2-[(1-N-甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-18]:
在40℃搅拌(Rc,SFe,SP)-12(633mg,1.25mmol)和40%甲胺水溶液(3.0mL)在THF(10mL)和MeOH(2.5mL)中的溶液3天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将粗产物提纯,得到的标题化合物(549mg,92%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.49(d,3H,J=6.6Hz);2.07(s,3H);3.69(s,5H);3.95(m,1H);4.01(m,1H);4.31(t,1H,J=2.5Hz);4.48(m,1H);7.23(m,5H);7.39~7.47(m,2H);7.54(m,1H);7.66(m,1H);7.90(t,2H,J=7.9Hz),9.25(dd,1H,J=7.9和6.7Hz)。31P NMR(CDCl3,162MHz):δ-39.91。
实施例19:
(Rc,SFe,RP)-2-[(1-N-甲氨基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-19]:
在40℃搅拌(Rc,SFe,RP)-7(633mg,1.25mmol)和40%甲胺水溶液(3.0mL)在THF(10mL)和MeOH(2.5mL)中的溶液3天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将粗产物提纯,得到的标题化合物(537mg,90%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.45(d,3H,J=6.5Hz);1.83(s,3H);3.82(m,1H);3.97(m,1H);4.07(s,5H);34.35(t,1H,J=2.5Hz);4.53(m,lH);7.20(m,1H);7.30~7.36(m,5H);7.40(m,1H);7.56~7.61(m,2H);7.78(t,2H,J=8.2Hz),8.38(m,1H)。31P NMR(CDCl3,162MHz):δ-32.25。
实施例20:
(Rc,SFe,SP)-2-[(1-N-甲氨基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-20]:
在40℃搅拌(Rc,SFe,SP)-14(633mg,1.25mmol)和40%甲胺水溶液(3.0mL)在THF(10mL)和MeOH(2.5mL)中的溶液3天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将粗产物提纯,得到的标题化合物(513mg,86%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.47(d,3H,J=6.7Hz);1.98(s,3H);3.82(m,1H);3.98(m,1H);4.02(s,5H);4.27(t,1H,J=2.5Hz);4.47(m,1H);7.27~7.34(m,5H);7.50(m,2H);7.55(m,1H);7.83(m,3H);8.12(d,1H,J=10.0Hz)。31P NMR(CDCl3,162MHz):δ-22.68
实施例21:
(Rc,SFe,RP)-2-[(1-N-甲氨基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Re,SFe,Rp)-21]:
在室温搅拌(Rc,SFe,RP)-15(633mg,1.25mmol)和40%甲胺水溶液(3.0mL)在THF(10mL)和MeOH(2.5mL)中的溶液3天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc-Et3N=85∶10∶5)将粗产物提纯,得到的标题化合物(537mg,90%)是橙色晶体。
实施例22:
(Rc,SFe,SP)-2-[(1-N-甲氨基)乙基]-1-[(2-联苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-22]:
在40℃搅拌(Rc,SFe,SP)-16(1.063g,2mmol)和40%甲胺水溶液(5.0mL)在THF(10mL)和MeOH(2.5mL)中的溶液2天并浓缩该溶液。残留物溶于Et2O(20mL),用盐水(10mL)洗,干燥(Na2SO4),并减压蒸发。残留物从己烷中重结晶得到的标题化合物(621mg,62%)是橙色晶体。1HNMR(CDCl3,400.13MHz):δ1.34(d,3H,J=6.6Hz);1.93(s,3H);3.60(m,1H);3.74(s,5H);4.08(m,1H);4.30(t,1H,J=2.5Hz);4.39(m,1H);7.19~7.24(m,5H);7.31(m,1H);7.38~7.50(m,5H),7.59(ddt,1H,J=7.6,3.5和1.0Hz);7.67(m,2H)。31P NMR(CDCl3,162MHz):δ-34.29
实施例23:
(Rc,SFe,SP)-2-[1-[(N-甲基-N-二苯膦基)氨基]乙基]-1-[(2-甲氧基苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-23]:
在0℃向(Rc,SFe,SP)-17(457mg,1.0mmol)和Et3N(0.28mL,2.0mmol)的甲苯(2.5mL)溶液中滴加氯二苯膦(188μL,1.05mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(570mg,89%)是橙色泡沫。1H NMR(CDCl3,400.13MHz):δ1.55(d,3H,J=6.9Hz);2.17(d,3H,J=3.4Hz);3.87(s,8H,重叠);4.24(m,1H);4.38(t,1H,J=2.4Hz);4.53(m,1H);4.88(m,1H);6.88-6.96(m,6H);7.03~7.14(m,6H);7.20~7.37(m,7H)。31P NMR(CDCl3,162MHz):δ56.93,-38.64
实施例24:
(Rc,SFe,SP)-2-[1-[(N-甲基-N-二苯膦基)氨基]乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-24]:
在0℃向(Rc,SFe,SP)-18(477mg,1.0mmol)和Et3N(0.28mL,2.0mmol)的甲苯(2.5mL)溶液中滴加氯二苯膦(188μL,1.05mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(595mg,90%)是橙色泡沫。1H NMR(CDCl3,400.13MHz):δ1.53(d,3H,J=6.8Hz);2.22(d,3H,J=3.3Hz);3.44(s,5H);4.26(m,1H);4.39(t,1H,J=2.4Hz);4.50(m,1H);5.03(m,1H);6.85~6.94(m,4H);7.04(tt,1H,J=7.2和1.4Hz);7.09~7.19(m,4H);7.27~7.31(m,4H);7.37~7.43(m,3H);7.48~7.56(m,2H);7.68(m,1H);7.89(dd,2H,J=8.1和4.8Hz);9.44(t,1H,J=7.6Hz)。31P NMR(CDCl3,162MHz):δ59.59,-41.03
实施例25:
(Rc,SFe,RP)-2-[1-[(N-甲基-N-二苯膦基)氨基]乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-25]:
在0℃向(Rc,SFe,RP)-19(239mg,0.5mmol)和Et3N(0.14mL,1.0mmol)的甲苯(2.0mL)溶液中滴加氯二苯膦(89μL,0.50mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(304mg,92%)是橙色泡沫。1H NMR(CDCl3,400.13MHz):δ1.51(d,3H,J=6.8Hz);2.08(d,3H,J=3.5Hz);3.90(s,5H);4.15(m,1H);4.44(t,1H,J=2.4Hz);4.58(m,1H);5.02(m,1H);6.44(td,2H,J=8.0和1.8Hz);6.62(td,2H,J=8.0和1.2Hz);6.80(tt,1H,J=7.4和1.2Hz);7.20(m,1H);7.15~7.30(m,H);7.58~7.64(m,H);7.70(dd,1H,J=6.8~1.8Hz);7.79(d,1H,J=8.0Hz);8.20(dd,1H,J=8.2和2.4Hz)。31P NMR(CDCl3,162MHz):δ-58.81,-31.16
实施例26:
(Rc,SFe,SP)-2-[1-[(N-甲基-N-二苯膦基)氨基]乙基]-1-[(2-联苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-26]:
在0℃向(Rc,SFe,SP)-22(XXmg,1.0mmol)和Et3N(0.28mL,2.0mmol)的甲苯(2.5mL)溶液滴加氯二苯膦(188μL,1.05mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(XXmg,X%)是橙色泡沫。1HNMR(CDCl3,250MHz):δ1.50(d,3H,J=6.6Hz);2.16(d,3H,J=3.0Hz);3.68(s,5H);4.08(m,1H);4.33(m,1H);4.42(m,2H);4.56(m,1H);6.98-7.75(m,24H)。31P NMR(CDCl3,101MHz):δ50.70,-35.51
实施例27:
(Rc,SFe,SP,Ra)-27:
在0℃向(Rc,SFe,SP)-17(229mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(R)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(359mg,93%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ1.73(d,3H,J=3.5Hz);1.79(d,3H,J=7.0Hz);3.71(s,3H),3.80(m,1H);4.00(s,5H);4.31(t,1H,J=2.3Hz);4.46(m,1H);5.34(m,1H);6.60(ddd,1H,J=7.5,4.5和1.8Hz),6.72(t,1H,J=7.5Hz),6.82(dd,1H,J=8.8和0.8Hz),6.91(ddd,1H,J=8.8,4.5和0.8Hz),7.15~7.38(m,11H),7.58(m,2H),7.77~7.87(m,4H)。31P NMR(CDCl3,101MHz):δ148.51(d,J=53.4Hz);-35.37(d,J=53.4Hz)。
实施例28:
(Rc,SFe,SP,Ra)-28:
在0℃向(Rc,SFe,SP)-18(239mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(R)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(376mg,95%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ0.87(d,3H,J=7.0Hz);1.82(d,3H,J=3.5Hz);3.62(s,5H),4.06(m,1H);4.33(t,1H,J=2.3Hz);4.46(m,1H);5.43(m,1H);6.69(dd,1H,J=8.8和0.8Hz),7.07~7.93(m,22H),9.39(m,1H)。31P NMR(CDCl3,101MHz):δ148.37(d,J=61.8Hz);-41.59(d,J=61.8Hz)。
实施例29:
(Rc,SFe,SP,Ra)-29:
在0℃向(Rc,SFe ,SP)-18(239mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(S)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(373mg,95%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ1.71(d,3H,J=7.0Hz);1.99(d,3H,J=3.3Hz);3.51(s,5H),4.27(m,1H);4.42(t,1H,J=2.3Hz);4.51(m,1H);5.28(m,1H);5.98(d,1H,J=8.5Hz),7.10~7.95(m,22H),9.42(m,1H)。31P NMR(CDCl3,101MHz):δ150.23(d,J=34.3Hz);-44.84(d,J=34.3Hz)。
实施例30:
(Rc,SFe,RP,Ra)-30:
在0℃向(Rc,SFe,RP)-19(239mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(R)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(371mg,95%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ1.64(d,3H,J=3.5Hz);1.79(d,3H,J=7.0Hz);4.88(m,1H),4.07(s,5H);4.38(t,1H,J=2.3Hz);4.52(m,1H);4.91(dd,1H,J=8.5和0.8Hz),5.37(m,1H),6.91(m,1H),7.10~7.90(m,21H),8.44(m,1H)。31P NMR(CDCl3,101MHz):δ148.18(d,J=54.5Hz);-32.43(d,J=54.5Hz)。
实施例31:
(Rc,SFe,RP,Ra)-31:
在0℃向(Rc,SFe,RP)-19(239mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(S)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(377mg,95%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ1.69(d,3H,J=6.8Hz);1.86(d,3H,J=3.5Hz);3.97(s,5H),4.07(m,1H);4.43(t,1H,J=2.3Hz);4.58(m,1H);5.15(m,1H);5.58(dd,1H,J=8.5和0.8Hz),6.91(m,1H),7.10~7.92(m,22H),8.31(m,1H)。31P NMR(CDCl3,101MHz):δ150.64(d,J=21.8Hz);-33.31(d,J=21.8Hz)。
实施例32:
(Rc,SFe,SP,Ra)-32:
在0℃向(Rc,SFe,SP)-22(252mg,0.5mmol)和Et3N(209μL,1.5mmol)的甲苯(4mL)溶液添加(R)-4-氯-3,5-二氧杂-4-磷杂庚英并[2,1-a:3,4-a′]二萘(175mg,0.5mmol)。然后将混合物加热到室温,室温搅拌过夜(16小时),通过中性氧化铝垫过滤,并用己烷-EtOAc(9∶1)洗脱,得到的标题化合物(392mg,96%)是橙色泡沫。1H NMR(CDCl3,250MHz):δ1.63(d,3H,J=7.0Hz);1.76(d,3H,J=3.5Hz);3.69(s,5H),4.09(m,1H);4.30(t,1H,J=2.3Hz);4.34(m,1H);4.89(m,1H);6.71(dd,1H,J=8.5和0.8Hz),7.07~7.84(m,25H)。31P NMR(CDCl3,101MHz):δ149.07(d,J=60.5Hz);-36.59(d,J=60.5Hz)。
实施例33:
(Rc,SFe,SP)-2-(1-二环己基膦基)乙基]-1-[(2-甲氧苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-33]:
在室温搅拌(Rc,SFe,SP)-11(486mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(601mg,96%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ1.08~1.68(m,25H);3.12(m,1H),3.91(s,5H),4.07(m,1H),4.29(t,1H,J=2.3Hz);4.38(m,1H),6.87-6.98(m,2H),7.15-7.25(m,6H),7.35(t,1H,J=7.3Hz);31P NMR(CDCl3,101.25MHz):δ-15.58(d,J=23.2Hz);-42.23(d,J=23.2Hz)。
实施例34:
(Rc,SFe,SP)-2-(1-二环己基膦基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-34]:
在室温搅拌(Rc,SFe,SP)-12(506mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-Et0Ac=9∶1)将残留物提纯,得到的标题化合物(613mg,95%)是橙色晶体。1H NMR(CDCl3,400.13MHz):δ1.14~1.57(m,25H);3.22(m,1H),3.40(s,5H),4.08(m,1H),4.23(t,1H,J=2.4Hz);4.31(m,1H),7.16-7.22(m,5H),7.36(dd,1H,J=8.0和7.2Hz);7.45-7.49(m,2H),7.60(ddd,1H,J=8.5,5.8和1.4Hz);7.82(t,2H,J=8.1Hz);9.28(dd,1H,J=7.6和6.8Hz);31P NMR(CDCl3,162MHz):δ17.46(d,J=27.7Hz):-42.43(d,J=27.7Hz)。
实施例35:
(Rc,SFe,RP)-2-(1-二环己基膦基)乙基]-1-[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-35]:
在室温搅拌(Rc,SFe,RP)-13(506mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(618mg,95%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ0.84~1.85(m,25H),3.16(m,1H),3.96(s,5H),4.00(m,1H),4.35(t,1H,J=2.3Hz);4.41(m,1H),7.29-7.40(m,7H),7.62-7.79(m,4H),8.33(m,1H);31P NMR(CDCl3,101.25MHz):δ14.93(d,J=22.8Hz);-34.80(d,J=22.8Hz)。
实施例36:
(Rc,SFe,SP)-2-(1-二环己基膦基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-36]:
在室温搅拌(Rc,SFe,SP)-14(506mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(599mg,93%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ1.15~1.71(m,25H),3.26(m,1H),3.79(s,5H),4.10(m,1H),4.29(t,1H,J=2.3Hz);4.37(m,1H),7.17-7.24(m,5H),7.34(m,1H),7.50(d,1H,J=9.5Hz);7.50(dd,1H,J=3.0和1.5Hz);7.57(ddd;1H;J=8.3,5.0和1.5Hz);7.81(d,1H,J=8.5Hz);7.87(m,1H),8.31(d,1H,J=9.5Hz);31P NMR(CDCl3,101.25MHz):δ15.67(d,J=30.9Hz);-34.20(d,J=30.9Hz)。
实施例37:
(Rc,SFe,RP)-2-(1-二环己基膦基)乙基]-1-[(2-萘基)苯基膦基]二茂铁[(Rc,SFe,Rp)-37]:
在室温搅拌(Rc,SFe,SP)-15(506mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(608mg,94%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ1.07~1.68(m,25H),3.26(m,1H),3.85(s,5H),4.07(m,1H),4.34(t,1H,J=2.3Hz);4.40(m,1H),7.30-7.77(m,12H);31P NMR(CDCl3,101.25MHz):δ15.56(d,J=33.1Hz):-25.12(d,J=33.1Hz)。
实施例38:
(Rc,SFe,SP)-2-(1-二环己基膦基)乙基]-1-[(2-联苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-38]:
在室温搅拌(Rc,SFe,SP)-16(531mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液过夜。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(650mg,97%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ1.02~1.72(m,25H),2.93(m,1H),3.66(s,5H),3.76(m,1H),4.29(t,1H,J=2.3Hz);4.32(m,1H),7.14~7.69(m,14H);31P NMR(CDCl3,101.25MHz):δ18.44(d,J=36.7Hz);-37.67(d,J=36.7Hz)。
实施例39:
(Rc,SFe,SP)-2,2’-二[(1-N,N-二甲基氨基)乙基]-1,1’-二[(2-甲氧苯基)苯基膦基]二茂铁[(Rc,SFe,Sp)-40]:
用注射器在-78℃向(R,R)-1,1’-二(1-N,N-二甲氨基乙基)二茂铁[(R,R)-20](986mg,3.0mmol)的Et2O(30mL)溶液中加入1.5M t-BuLi的戊烷溶液(6.0mL,9mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.12mL,9.0mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入(2-甲氧基)苯基锂溶液[由2-溴甲氧基苯(1.87g,10mmol)和1.5M t-BuLi的戊烷溶液(13.3mL,20mmol)在Et2O(50mL)中,在-78℃反应制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=80∶15∶5)将残留物提纯,得到的标题化合物(1.10g,48%)是黄色泡沫。1H NMR(CDCl3,400.13MHz):δ1.28(d,6H,J=6.7Hz);1.71(s,12H);3.16(m,2H);3.84(s,6H);4.05(m,2H),4.16(m,2H);4.53(t,2H,J=2.3Hz);6.62(t,2H,J=7.4Hz);6.73(dd,2H,J=8.1和4.6Hz);6.85(ddd,2H,J=7.4,5.3和1.8Hz);7.03~7.11(m,10H);7.17(td,2H,J=8.5和1.6Hz);31P NMR(CDCl3,162MHz):δ-39.53(s)。
实施例40:
(Rc,SFe,SP)-2,2’-二[(1-N,N-二甲氨基)乙基]-1,1’-二[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-41]:
用注射器在-78℃向(R,R)-1,1’-二(1-N,N-二甲氨基乙基)二茂铁[(R,R)-20](986mg,3.0mmol)的Et2O(30mL)溶液中加入1.5M t-BuLi的戊烷溶液(6.0mL,9mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(1.22mL,9.0mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入1-萘锂溶液[由1-溴萘(2.07g,10mmol)和1.5M t-BuLi的戊烷溶液(13.3mL,20mmol)在Et2O(50mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc-Et3N=80∶15∶5)将残留物提纯,得到的标题化合物(827mg,35%)是黄色晶体。1H NMR(CDCl3,400.13MHz):δ1.28(d,6H,J=6.8Hz);1.74(s,12H);2.49(m,2H);4.01(t,2H,J=2.3Hz);4.06(m,2H);4.08(m,2H);6.87~6.93(m,4H);6.99~7.09(m,10H);7.50(td,2H,J=8.1和1.1Hz);7.53(td,2H,J=6.8和1.3Hz);7.70(d,2H,J=8.1Hz);7.83(d,2H,J=8.1Hz);9.16(t,2H,J=7.1Hz);31P NMR(CDCl3,162MHz):δ-39.47(s)。
实施例41:
(Rc,SFe,SP)-2,2’-二[(α-N,N-二甲氨基)苯甲基]-1,1’-二[(1-萘基)苯基膦基]二茂铁[(Rc,SFe,Sp)-43]:
用注射器在-78℃向(R,R)-1,1’-二[((α-N,N-二甲氨基)苯甲基]二茂铁[(R,R)-23](903mg,2.0mmol)的Et2O(20mL)溶液中加入1.5M t-BuLi的戊烷溶液(4.0mL,6mmol),添加时间为10分钟。完成添加后,将混合物加热到室温,在室温搅拌1.5小时。将所得的红色溶液再冷却至-78℃,接着一次性加入二氯苯膦(814μL,6.0mmol)。在-78℃搅拌10分钟后,将混合物缓慢加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入1-萘锂溶液[由1-溴萘(1.45g,7mmol)和1.5M t-BuLi的戊烷溶液(9.3mL,14mmol)在Et2O(40mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤出液,并用色谱分离法(SiO2,己烷-EtOAc=3∶1)将残留物提纯,得到的标题化合物(369mg,20%)是黄色晶体。1H NMR(CDCl3,250.13MHz):δ1.54(s,12H);2.46(m,2H);3.01(m,2H);3.96(t,2H,J=2.5Hz);4.42(d,2H,J=5.3Hz);6.69(ddd,2H,J=7.3,4.3和1.0Hz);6.96~7.34(m,22H);7.55(d,2H,J=8.3Hz);7.66(d,4H,J=8.3Hz);7.81(d,2H,J=7.8Hz);9.20(t,2H,J=7.8Hz);31P NMR(CDCl3,162MHz):δ-41.73(s)。
实施例42:
(2’S,4’S,S Fe,RP)-2-[4’-(甲氧甲基-1,3-二噁烷-2’-基)-1-[(2-甲氧苯基)苯基膦基]二茂铁[(2’S,4’S,SFe,Rp)-46]:
在-40℃向(2S,4S)-4-(甲氧甲基)-2-二茂铁基-1,3-二噁烷[(2S,4S)-45]二茂铁(1.58g,5mmol)的Et2O(20mL)溶液中加入1.7M t-BuLi的戊烷溶液(3.23mL,5.5mmol)。搅拌10分钟后,移去冷却浴,将混合物加热到室温,在室温搅拌1.5小时。将所得的橙色悬浮液冷却至-78℃,接着一次性加入二氯苯膦(750μL,5.5mmol)。搅拌10分钟后,移去冷却浴,将混合物加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入2-甲氧基苯基锂溶液[由2-溴甲氧基苯(1.22mL,6.5mmol)和1.7M t-BuLi的戊烷溶液(7.6mL,13mmol)在Et2O(40mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc=6∶1)将残留物提纯,得到的标题化合物(2.41g,91%)是两种非对映异构体的混合物(比例约为3.3∶1)。从己烷中重结晶后,得到主要产物[(2’S,4’S,SFe,Rp)-46](1.41g,53%)。用单晶X射线衍射分析,确定其具有(2’S,4’S,SFe,Rp)-46的绝对构型。1H NMR(CDCl3,400.13MHz):δ1.42(dm,1H,J=13.3Hz);1.74(m,1H);2.89(d,2H,J=5.1Hz);3.03(s,3H);3.59(m,1H);3.60(s,3H);3.74(m,1H);3.91(td,1H,J=12.2和2.5Hz);4.08(s,5H);4.24~4.27(m,2H);4.70(m,1H);5.71(d,1H,J=2.5Hz);6.74(dd,1H,J=7.9和4.6Hz);6.80~6.86(m,2H);7.22(m,1H);7.22(m,1H);7.31~7.35(m,3H);7.51~7.56(m,2H);31P NMR(CDCl3,162MHz):δ31.46(s)。
实施例43:
(2’S,4’S,SFe,RP)-2-[4’-(甲氧甲基-1,3-二噁烷-2’-基)-1-[(1-萘基)苯基膦基]二茂铁[(2’S,4’S,SFe,Rp)-47]:
在-40℃向(2S,4S)-4-(甲氧甲基)-2-二茂铁基-1,3-二噁烷[(2S,4S)-45](3.16g,10mmol)的Et2O(40mL)溶液中加入1.5M t-BuLi的戊烷溶液(7.4mL,11mmol)。搅拌10分钟后,移去冷却浴,将混合物加热到室温,在室温搅拌1.5小时。将所得的橙色悬浮液冷却至-78℃,接着一次性加入二氯苯膦(1.49mL,11mmol)。搅拌10分钟后,移去冷却浴,将混合物加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管缓慢加入1-萘锂溶液[由1-溴萘(1.67mL,12mmol)和1.5M t-BuLi的戊烷溶液(16mL,24mmol)在Et2O(60mL)中,在-78℃制得]。将混合物加热到室温过夜,然后用Celite垫过滤。浓缩滤液,并用色谱分离法(SiO2,己烷-EtOAc=6∶1)将残留物提纯,得到的标题化合物(4.95g,90%)是两种非对映异构体的混合物(比例约为3.4∶1)。从己烷中重结晶后,得到纯净的主要产物[(2’S,4’S,SFe,Rp)-47](2.53g,51%)是黄色针状结晶。用单晶X射线衍射分析,确定其具有(2’S,4’S,SFe,Rp)-47的绝对构型。1H NMR(CDCl3,400.13MHz):δ1.33(dm,1H,J=13.3Hz);1.63(m,1H);2.56(dd,1H,J=10.3和4.8Hz);2.67(dd,1H,J=10.3和5.6Hz);2.76(s,3H);3.58(m,1H);3.67(m,1H);3.86(td,1H,J=12.2和2.5Hz);4.15(s,5H);3.74(m,1H);4.21(ddd,1H,J=11.4,5.1和1.0Hz);4.31(t,1H,J=2.5Hz);4.74(m,1H);5.69(d,1H,J=2.5Hz);7.16(ddd,1H,J=7.1,5.1和1.2Hz);7.29~7.40(m,6H);7.54~7.58(m,2H);7.74(d,1H,J=8.3Hz);7.78(d,1H,J=8.0Hz);8.25-8.28(m,1H);31P NMR(CDCl3,162MHz):δ-28.03(s)。
实施例44:
(SFe,RP)-2-[(2-甲氧苯基)苯基膦基]二茂铁甲醛[(SFe,Rp)-48]:
在室温搅拌缩醛[(2’S,4’S,SFe,Rp)-46](4.0g,7.5mmol),p-TsOH.H2O(2.0g),CH2Cl2(50mL)和H2O(30mL)的混合物24小时。分离有机层,用饱和NaHCO3溶液(20mL)洗,干燥(MgSO4)并减压蒸发得到粗产物(3.20g,100%),为红色晶体,可以直接在下一步中使用。1HNMR(CDCl3,250.13MHz):δ3.66(s,3H);3.96(m,1H);4.22(s,5H);4.71(t,1H,J=2.3Hz);5.13(m,1H);6.72(m,1H);6.78-6.87(m,2H);7.29(m,1H);7.41(m,3H);7.54(m,2H);10.24(d,1H,J=3.3Hz);31PNMR(CDCl3,101MHz):δ-34.66(s)。
实施例45:
(SFe,RP)-2-[(1-萘基)苯基膦基]二茂铁甲醛[(SFe,Rp)-49]:
在室温搅拌缩醛[(2’S,4’S,SFe,Rp)-46](4.73g,7.5mmol),p-TsOH.H2O(2.0g),CH2Cl2(50mL)和H2O(30mL)的混合物24小时。分离有机层,用饱和NaHCO3溶液(20mL)洗,干燥(MgSO4)并减压蒸发得到粗产物(3.36g,100%),为红色晶体,可以直接在下一步中使用。1HNMR(CDCl3,250.13MHz):δ4.04(m,1H);4.28(s,5H);4.76(t,1H,J=2.3Hz);5.17(m,1H);7.02(m,1H);7.29~7.48(m,6H);7.52~7.59(m,2H);7.80(t,2H,J=7.5Hz);8.26(m,1H);10.20(d,1H,J=3.0Hz);31P NMR(CDCl3,101MHz):δ-30.50(s)。
实施例46:
(SFe,RP,αS)-2-[(2-甲氧苯基)苯基膦基]-1-[(二苯膦基苯基)二茂铁甲醇[(Sp,αS)-51]:
将镁屑(63mg,2.6mmol)和2-溴苯)二苯膦50(887mg,2.6mmol)的THF(10mL)悬浮液回流,直至镁被溶解(约30分钟)。将所得的Gragnard试剂溶液冷却至-78℃,接着用注射器缓慢加入(SFe,RP)-2-[(2-甲氧苯基)苯基膦基]二茂铁甲醛[(SFe,RP)-48](856mg,2.0mmol)的THF(10mL)溶液。在-78℃搅拌5小时后,将混合物加热到室温,在室温搅拌过夜。然后用饱和的NH4Cl溶液(20mL)抑制反应,并用CH2Cl2(2×20mL)萃取。合并的萃取物用盐水(20mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=6∶1)将残留物提纯,得到的黄色晶体(1.297g,96%)是两种非对映异构体(~9∶1)的混合物。主要产物1HNMR(CDCl3,250MHz):δ2.91(br.s,1H);3.57(m,1H),3.59(s,3H),4.05(m,1H),4.14(t,1H,J=2.4Hz),4.18(s,5H),4.22(m,1H),6.48~4.56(m,2H),6.68~6.80(m,2H),7.02~7.37(m,13H);7.49~7.58(m,2H),7.67(m,1H)。31P NMR(CDCl3,101MHz):δ-18.69(d,J=14.6Hz),-32.85(d,J=14.6Hz)。
实施例47:
(SFe,RP,αS)-2-[(1-萘基)苯基膦基]-1-[α-(二苯膦基苯基)]二茂铁甲醇[(SFe,RP,αS)-52]:
回流镁屑(63mg,2.6mmol)和2-溴苯)二苯膦50(887mg,2.6mmol)的THF(10mL)悬浮液,直至镁被溶解(约30分钟)。将所得的Gragnard试剂溶液冷却至-78℃,接着用注射器缓慢加入(SFe,RP)-2-[(1-萘基)苯基膦基]二茂铁甲醛[(SFe,RP)-49](897mg,2.0mmol)的THF(10mL)溶液。在-78℃搅拌5小时后,将混合物加热到室温,在室温搅拌过夜。然后用饱和的NH4Cl溶液(20mL)抑制反应,并用CH2Cl2(2×20mL)萃取。合并的萃取物用盐水(20mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=6∶1)将残留物提纯,得到的黄色晶体(1.322g,93%)是两种非对映异构体(~9∶1)的混合物。主要产物1HNMR(CDCl3,250MHz):δ2.39(br.s,1H);3.66(m,1H),4.24(s,5H),4.29(t,1H,J=2.4Hz),4.57(m,1H),4.22(m,2H),6.40~4.49(m,3H),6.61~6.67(m,2H),6.83~7.01(m,4H);7.10~7.59(m,H),7.75(br.D,1H,J=7.8Hz),8.28(m,1H)。31P NMR(CDCl3,101MHz):δ-18.54(d,J=21.0Hz),-29.56(d,J=21.0Hz)。
实施例48:
(SFe,RP,αS)-2-[(2-甲氧苯基)苯基膦基]-1-[α-甲氧基-(2-二苯膦基苯甲基)]二茂铁[(SFe,RP,αS)-53]:
在0℃向KH(30%,174mg,1.3mmol,经过己烷清洗)的THF(10mL)的悬浮液中加入醇[(SP,αS)-51](690g,1.0mmol)。在0℃搅拌2小时后,用注射器添加甲基碘(68μL,1.1mmol)。在0℃搅拌该混合物2小时后,用MeOH(0.5mL)抑制反应,然后减压除去溶剂。残留物溶解在CH2Cl2(20mL)中,用水(10mL)和盐水(10mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=10∶1)将残留物提纯,得到黄色晶体(463mg,66%)。1H NMR(CDCl3,250MHz):δ2.82(s,3H);3.50(m,1H),3.57(s,3H),4.11(t,1H,J=2.3Hz),4.17(s,5H),4.19(m,1H),5.79(d,1H,J=6.8Hz),6.54~6.64(m,2H),6.69(m,1H),6.84(ddd,1H,J=7.8,4.3和1.5Hz),7.02~7.37(m,12H),7.52(m,2H),7.66(m,1H)。31P NMR(CDCl3,101MHz):δ-18.44(d,J=18.7Hz),-31.19(d,J=18.7Hz)。
实施例49:
(SFe,αS)-2-溴-1-[α-(2-二苯膦基苯)]二茂铁甲醇[(SFe,αS)-55]:
在约50℃向Mg(729mg,30mmol)的THF(10mL)的悬浮液中逐滴加入2-溴苯二苯膦(50)(9.42g,27.6mmol)的THF(30mL)的溶液。添加完毕后,将混合物回流1小时,冷却到室温,在加入到-78℃的(SFe)-2-溴二茂铁甲醛[(SFe)-54](6.74g,23mmol)的Et2O(20mL)溶液。在-78℃搅拌6小时后,将混合物加热至室温,在室温搅拌过夜。用饱和NH4Cl溶液(50mL)抑制反应,然后用EtOAc稀释(100mL)。有机层被分离,用盐水(50mL)洗涤,干燥(Na2SO4)并减压蒸发。用色谱分离法(SiO2,己烷-EtOAc=5∶1)将残留物提纯,得到的黄色晶体(12.51g,98%)是单一的非对映异构体。1H NMR(CDCl3,250MHz):δ2.67(dd,1H,J=3.5和2.0Hz),4.04(t,1H,J=2.5Hz),4.18(m,1H),4.27(s,5H),4.40(m,1H),6.47(dd,1H,J=6.5和3.5Hz),7.00(m,1H),7.18(m,1H),7.15~7.37(m,12H);31P NMR(CDCl3,101MHz):δ-17.30。
实施例50:
(SFe,αS)-2-溴-1-[α-甲氧基-(2-二苯膦基苯甲基)]二茂铁[(SFe,αS)-56]:
在0℃向KH(30%,3.75g,28.1mmol,经过己烷清洗)的THF(20mL)的悬浮液中加入(SP,αS)-2-溴-1-[α-(2-二苯膦基苯基)]二茂铁甲醇[(SFe,αS)-55](12.00g,21.6mmol)的THF(180mL)溶液。在0℃搅拌2小时后,用注射器添加甲基碘(1.48mL,23.8mmol)。在0℃搅拌混合物1小时后,用MeOH(5mL)抑制反应,然后减压除去溶剂。残留物溶解在EtOAc(150mL)中,用水(100mL)和盐水(100mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=5∶1)将残留物提纯,得到黄色晶体(12.10g,98%)。1H NMR(CDCl3,250MHz):δ3.29(s,3H),3.96(t,1H,J=2.5Hz),4.01(m,1H),4.27(s,5H),4.33(m,1H),6.09(d,1H,J=7.8Hz),7.04(m,1H),7.15~7.37(m,12H),7.44(m,1H)。31P NMR(CDCl3,101MHz):δ-18.46。
实施例51:
(SFe,SP,αS)-2-[(2-甲氧苯基)苯基膦基]-1-[α-甲氧基-(2-二苯膦基苯甲基)]二茂铁[(SFe,SP,αS)-57]:
在-78℃用注射器向溴化物[(SFe,αS)-56](2.85mg,5mmol)的THF(30mL)的溶液中缓慢添加1.7M t-BuLi(6.5mL,11mmol)。在-78℃搅拌10分钟后,用注射器添加PhPCl2(746μL,5.5mmol)。在-78℃搅拌30分钟后,将混合物加热到室温,在室温搅拌1小时。然后再将混合物冷却到-78℃,用套管加入o-AnLi的悬浮液[由2-溴甲氧基苯(805μL,6.5mmol)和1.7M t-BuLi(7.6mL,13mmol)在Et2O(30mL)中,在-78℃制得]。然后将混合物在-78℃到室温搅拌过夜。用水(20mL)抑制反应,分离有机层,用盐水(30mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=10∶1)将残留物提纯,得到的黄色晶体(3.21g,91%)是单一的非对映异构体。1H NMR(CDCl3,250MHz):δ2.71(s,3H);3.67(m,1H),3.90(m,1H),3.96(s,3H),4.06(t,1H,J=2.3Hz),4.22(s,5H),5.52(d,1H,J=6.5Hz),6.80~6.98(m,4H),7.08~7.36(m,14H),7.76(m,1H);31P NMR(CDCl3,101MHz):δ-17.98(d,J=10.0Hz),-33.15(d,J=10.0Hz)。
实施例52:
(SFe,SP,αS)-2-[(1-萘基)苯基膦基]-1-[α-甲氧基-(2-二苯膦基苯甲基)]二茂铁[(SFe,SP,αS)-58]和(SFe,RP,αS)-2-[(1-萘基)苯基膦基]-1-[α-甲氧基-(2-二苯膦基苯甲基)]二茂铁[(SFe,RP,αS)-59]:
在-78℃用注射器向溴化物[(SFe,αS)-56](2.85mg,5mmol)的THF(30mL)的溶液中缓慢1.7M t-BuLi(6.5mL,11mmol)。在-78℃搅拌10分钟后,用注射器添加PhPCl2(746μL,5.5mmol)。在-78℃搅拌30分钟后,将混合物加热到室温,在室温搅拌1小时。然后再将混合物冷却到-78℃,用套管加入o-AnLi的悬浮液[由1-溴萘(900μL,6.5mmol)和1.7Mt-BuLi(7.6mL,13mmol)在Et2O(30mL)中,在-78℃制得],然后将混合物在-78℃到室温搅拌过夜。用水(20mL)抑制反应,分离有机层,用盐水(30mL)洗涤,干燥(MgSO4)并减压蒸发。用快速色谱分离法(SiO2,己烷-EtOAc=10∶1)将残留物提纯,得到的黄色晶体(3.30g,91%)是两种非对映异构体的混合物(比例~9∶1),混合物从己烷中重结晶,得到纯净的主产物[(SFe,SP,αS)-58](2.83g,78%)是黄色晶体。母液被浓缩,残留物从MeOH中重结晶,得到纯净的次产物[(SFe,RP,αS)-59](217mg,6%)是黄色晶体。主产物[(SFe,SP,αS)-58]:1H NMR(CDCl3,250MHz):δ2.96(s,3H);3.74(m,1H),3.84(s,5H),4.13(t,1H,J=2.5Hz),4.20(m,1H),6.04(d,1H,J=7.3Hz),6.89~7.41(m,20H),7.55(ddd,1H,J=8.0,6.8和1.3Hz),7.64(dd,1H,J=6.8和1.5Hz),7.69(ddd,1H,J=5.3,3.5和1.7Hz),7.89(t,2H,J=8.0Hz),9.32(dd,1H,J=7.5和6.8Hz).31PNMR(CDCl3,101MHz):δ-18.83(d,J=21.3Hz),-35.08(d,J=21.3Hz)。次产物[(SFe,RP,αS)-59]:1H NMR(CDCl3,250MHz):δ2.73(s,3H),3.61(m,1H),4.21(t,1H,J=2.5Hz),4.22(s,5H),4.28(m,1H),5.86(d,1H,J=7.3Hz),6.67(ddd,1H,J=7.8,4.3和1.3Hz),6.79~7.61(m,23H),7.75(br.d,1H,J=8.0Hz),8.29(m,1H)。31P NMR(CDCl3,101MHz):δ-18.52(d,J=18.4Hz),-27.69(d,J=18.4Hz)。
实施例53:
(SFe,RP)-2-[(2-甲氧苯基)苯基膦基]二茂铁甲醇[(SFe,RP)-60]:
在0℃向醛[(SFe,RP)-48](856mg,2.0mmol)的THF(10mL)的溶液中添加NaBH4(38mg,1.0mmol),然后加入MeOH(2mL)。在0℃搅拌2小时后,将混合物加热到室温,在室温搅拌过夜。用饱和NH4Cl溶液(5mL)抑制反应,用EtOAc(10mL)稀释。分离有机层,用盐水(10mL)洗涤,干燥(MgSO4)并减压蒸发,得到的粗产物(857mg,100%)是黄色晶体,可直接用于接下来的步骤。1H NMR(CDCl3,250MHz):δ3.63(m,1H),3.66(s,3H),4.10(s,5H),4.29(t,1H,J=2.0Hz),4.41(d,1H,J=12.5Hz),4.53(m,1H),4.58(dd,1H,J=12.5和2.0Hz),6.77~6.90(m,3H),7.28(m,1H),7.34~7.41(m,3H),7.48~7.55(m,2H)。31P NMR(CDCl3,101MHz):δ-35.05。
实施例54:
(SFe,RP)-2-[(1-萘基)苯基膦基]二茂铁甲醇[(SFe,RP)-61]:
在0℃向醛[(SFe,RP)-49](897mg,2.0mmol)的THF(10mL)的溶液中添加NaBH4(38mg,1.0mmol),然后加入MeOH(2mL)。在0℃搅拌2小时后,将混合物加热到室温,在室温搅拌过夜。用饱和NH4Cl溶液(5mL)抑制反应,用EtOAc(10mL)稀释。分离有机层,用盐水(10mL)洗涤,干燥(MgSO4)并减压蒸发,得到的粗产物(900mg,100%)是黄色晶体,可直接用于接下来的步骤。1H NMR(CDCl3,250MHz):δ3.71(m,1H),4.16(s,5H),4.36(t,1H,J=2.5Hz),4.41(d,1H,J=12.5Hz),4.54(dd,1H,J=12.5和1.3Hz),4.58(m,1H),7.11(ddd,1H,J=7.0,4.5和1.3Hz),7.30~7.57(m,8H),7.80(m,2H),8.26(m,1H)。31P NMR(CDCl3,101MHz):δ-31.14。
实施例55:
(SFe,RP)-2-[(2-甲氧苯基)苯基膦基]二茂铁甲醇乙酸酯[(SFe,RP)-62]:
在室温搅拌醇[(SFe,RP)-60](857mg,2.0mmol),Ac2O(2mL)和吡啶(2mL)的CH2Cl2(10mL)溶液过夜。在35℃以下,减压除去挥发性物质,得到的粗产物(880mg,100%)是黄色晶体,可直接用于接下来的步骤。1H NMR(CDCl3,250MHz):δ1.62(s,3H),3.64(s,4H,重叠),4.10(s,5H),4.30(t,1H,J=2.5Hz),4.54(m,1H),5.01(d,1H,J=12.0Hz),5.12(dd,1H,J=12.0和2.3Hz),6.77(m,2H),6.83(t,1H,J=7.5Hz),7.25(m,1H),7.37(m,3H),7.51(m,2H)。31P NMR(CDCl3,101MHz):δ-34.60。
实施例56:
(SFe,RP)-2-[(2-萘基)苯基膦基]二茂铁甲醇乙酸酯[(SFe,RP)-63]:
在室温搅拌醇[(SFe,RP)-61](900mg,2.0mmol),Ac2O(2mL)和吡啶(2mL)的CH2Cl2(10mL)溶液过夜。在35℃以下,减压除去挥发性物质,得到的粗产物(983mg,100%)是黄色晶体,可直接用于接下来的步骤。1H NMR(CDCl3,250MHz):δ1.46(s,3H),3.74(m,1H),4.15(s,5H),4.38(t,1H,J=2.5Hz),4.59(m,1H),5.00(d,1H,J 1.3.5Hz),7.28~7.45(m,5H),7.54(m,1H),7.69(tt,1H,J=7.8和1.8Hz),7.78(m,2H),8.23(m,1H),8.64(m,2H)。31P NMR(CDCl3,101MHz):δ-30.85。
实施例57:
(SFe,RP)-1-[(二环己基膦基)甲基]-2-[(2-甲氧苯基)苯基膦基]二茂铁[(SFe,Rp)-64]:
在室温搅拌(SFe,RP)-62(472mg,1.0mmol)和二环己基膦(243μL,1.2mmol)的乙酸(3mL)溶液7天。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(573mg,94%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ0.99~1.79(m,22H);2.56(br.d,1H,J=12.5Hz),2.73(br.d,1H,J=12.5Hz),3.58(m,1H),4.00(s,5H),4.20(m,1H),4.57(m,1H);4.32(m,1H),6.74~7.58(m,9H);31P NMR(CDCl3,101.25MHz):δ-2.93;-35.19。
实施例58:
(SFe,RP)-1-[(二环己基膦基)甲基]-2-[(1-萘基)苯基膦基]二茂铁[(SFe,Rp)-65]:
在室温搅拌(SFe,RP)-63(492mg,1.0mmol)和二环己膦(243μL,1.2mmol)的乙酸(3mL)溶液7天。然后搅拌下将溶液倒入10%K2CO3水溶液(60mL),用Et2O(2×25mL)萃取。干燥(MgSO4)并浓缩合并的醚层。用色谱分离法(SiO2,己烷-EtOAc=9∶1)将残留物提纯,得到的标题化合物(599mg,95%)是橙色晶体。1H NMR(CDCl3,250.13MHz):δ0.83~1.76(m,22H);2.57(dm,1H,J=12.5Hz),2.70(dm,1H,J=12.5Hz),3.67(m,1H),4.06(s,5H),4.27(t,1H,J=2.5Hz),4.60(m,1H);7.12(m,1H),7.31~7.82(m,10H);8.28(m,1H)。31P NMR(CDCl3,101.25MHz):δ-2.19;-31.85。
实施例59:
(Sc,RFe,RP)-67:
在-78℃向(S)-66(1.56g,5mmol)和TMEDA(1.0mL,6.5mmol)的Et2O(50mL)溶液中加入2.5M n-BuLi(2.6mL,6.5mmol),在-78℃搅拌3小时后,加入PhPCl(0.95mL,7.0mmol)。-78℃搅拌20分钟后,将混合物加热至室温,在室温搅拌1.5小时。将混合物再冷却至-78℃,接着用套管添加入1-NpLi悬浮液[由1-溴萘(1.39mL,10mmol)和1.7Mt-BuLi(11.8mL,20mmol),在Et2O(40mL)中,在-78℃制得]。将混合物搅拌,加热到室温过夜,然后用水(40mL)抑制反应。分离有机层,用盐水(40mL)洗涤,干燥(MgSO4)并浓缩。用色谱分离法(SiO2,EtOAc-己烷=1∶5~1∶3)将残留物提纯,得到的产物(2.25g,85%)是橙色晶体。1H NMR和31P NMR分析显示de为约9∶1。主产物:(CDCl3,400.13MHz):δ0.58(d,3H,J=6.7Hz);0.73(d,3H,J=6.7Hz);1.58(m,1H),3.453.52(m,2H),3.61(m,1H),3.78(m,1H),4.29(s,5H);4.44(t,1H,J=2.6Hz);5.05(m,1H);7.08(dd,1H,J=7.0和4.4Hz);7.24~7.48(m,8H);7.74(d,1H,J=8.0Hz);7.80(d,1H,J=8.0Hz);8.37(dd,1H,J=8.3和4.3Hz)。31P NMR(CDCl3,162MHz):δ-23.52(s)
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Claims (13)
1.一种制备手性配位体的方法,包括提供通式(A)的初始材料:
其中X*是手性或非手性的定向取代基;且
○是任选取代的单环或多环芳基或环烷基;对底物进行邻位锂化;将邻位锂化的底物转化成具有通式-PR1R1”的膦基团,R1和R1”彼此不相同,独立选自取代和未取代的支链和直链烷基、烷氧基、烷基氨基,取代和未取代的环烷基,取代和未取代的环烷氧基,取代和未取代的环烷基氨基,取代和未取代的碳环芳基,取代和未取代的碳环芳氧基,取代和未取代的杂芳基,取代和未取代的杂芳氧基,取代和未取代的碳环芳基氨基,和取代和未取代的杂芳基氨基,其中每个杂原子独立选自硫、氮和氧;任选地,或若是必要的话,将X*转化成不同的基团以制备手性配位体。
2.按照权利要求1所述的方法,其中X*是手性的定向取代基,邻位锂化是对映体选择性的。
4.按照权利要求1到3中任一项所述的方法,其中X*是手性的定向取代基,邻位锂化在手性辅助物的存在下进行,且是对映体选择性的。
6.按照权利要求1到5中任一项所述的方法,其中
是任选地被进一步取代的金属茂化合物的芳环。
7.按照权利要求1到6中任一项所述的方法,其中X*是邻位定向取代基。
8.按照权利要求1到7中任一项所述的方法,其中将邻位锂化的底物与R1取代的膦或胂反应形成中间化合物。
9.按照权利要求8所述的方法,其中将中间化合物和带有R1“的格氏试剂或有机锂化合物反应。
10.可按照权利要求1到9中任一项所述的方法所制备的配位体。
11.按照权利要求10的配位体,它是根据权利要求1到9中任一项所述的方法所制备的。
12.含有权利要求10或11中至少一种配位体的过渡金属络合物催化剂。
13.权利要求12所述的过渡金属络合物催化剂在不对称催化中的用途。
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GB0400720D0 (en) * | 2004-01-14 | 2004-02-18 | Stylacats Ltd | Novel ferrocene-based phosphorus chiral phosphines |
ES2293596T3 (es) * | 2004-07-05 | 2008-03-16 | Solvias Ag | 1,1'-difosfinoferrocenos con restos quirales o aquirales enlazados en la posicion 2,2'. |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102775418A (zh) * | 2012-06-11 | 2012-11-14 | 中国人民解放军第四军医大学 | 新型手性季铵盐相转移催化剂的合成及应用 |
Also Published As
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ATE424404T1 (de) | 2009-03-15 |
ES2313282T3 (es) | 2009-03-01 |
EP1725570A1 (en) | 2006-11-29 |
GB2410951B (en) | 2009-07-22 |
ATE404573T1 (de) | 2008-08-15 |
DE602005013062D1 (de) | 2009-04-16 |
AU2005205224A1 (en) | 2005-07-28 |
EP1709054A1 (en) | 2006-10-11 |
WO2005068478A1 (en) | 2005-07-28 |
ES2323717T3 (es) | 2009-07-23 |
US20070161762A1 (en) | 2007-07-12 |
CA2553608A1 (en) | 2005-07-28 |
US20080281106A1 (en) | 2008-11-13 |
GB0400720D0 (en) | 2004-02-18 |
GB2410950B (en) | 2009-05-20 |
CN1914217A (zh) | 2007-02-14 |
WO2005068477A1 (en) | 2005-07-28 |
AU2005205229A1 (en) | 2005-07-28 |
GB0500704D0 (en) | 2005-02-23 |
AU2005205224B2 (en) | 2009-04-23 |
US7994355B2 (en) | 2011-08-09 |
GB2410951A (en) | 2005-08-17 |
GB0905212D0 (en) | 2009-05-13 |
JP2007517850A (ja) | 2007-07-05 |
AU2005205229B2 (en) | 2010-03-04 |
CA2553607A1 (en) | 2005-07-28 |
JP2007517849A (ja) | 2007-07-05 |
EP1709054B1 (en) | 2009-03-04 |
DE602005008917D1 (de) | 2008-09-25 |
EP1725570B1 (en) | 2008-08-13 |
GB2410950A (en) | 2005-08-17 |
GB0500701D0 (en) | 2005-02-23 |
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