CN103402949A - 新型钯催化剂、其制备方法及其用途 - Google Patents

新型钯催化剂、其制备方法及其用途 Download PDF

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CN103402949A
CN103402949A CN2011800679604A CN201180067960A CN103402949A CN 103402949 A CN103402949 A CN 103402949A CN 2011800679604 A CN2011800679604 A CN 2011800679604A CN 201180067960 A CN201180067960 A CN 201180067960A CN 103402949 A CN103402949 A CN 103402949A
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palladium
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CN103402949B (zh
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Z·达利察克
T·索斯
Z·芬塔
G·蒂玛里
G·弗拉德
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Chinoin Private Co Ltd
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Chinoin Gyogyszer es Vegyeszeti Termekek Gyara Zrt
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Abstract

本发明涉及式(I)的钯(0)-四{三-[3,5-二(三氟甲基)-苯基]-膦}配合物，以及其制备和用途。该化合物非常稳定，可用作催化剂，具有优异的结果。

Description

新型钯催化剂、其制备方法及其用途
本发明涉及一种新型钯催化剂，更具体地涉及式(I)的钯(0)-四{三-[3,5-二(三氟甲基)-苯基]-膦}配合物：
Figure BDA0000367481410000011
[经验式：Pd{[3,5-(CF3)2-C6H3]3P}4]。
本发明进一步涉及制备所述新型催化剂的方法。本发明也涉及所述新型催化剂在需要这种催化剂的反应中的用途，更具体地在用于形成C-C键的反应(交叉偶联反应，例如Suzuki、Heck、Stille等偶联)中、在用于形成C-杂原子(C-N、C-O、C-S、C-P，主要是C-N)键的反应(例如Buchwald反应)中的用途以及用于加氢反应的用途。
因为当前由过渡金属配合物(最常见由Pd和Ni配合物)催化的交叉偶联反应在C-C键的形成中具有优异的作用，并且这种反应已经带来合成路径中的根本的改变，本发明将在下文主要关于交叉偶联反应进行讨论，然而并不将其范围限制到该用途模式。
交叉偶联反应的总流程可以描述为：
Figure BDA0000367481410000012
其中
R和R′表示将用C-C键偶联的有机基团，
M是催化剂配合物的金属组分，
L表示出现在催化剂配合物中的配体，
n是存在的配体数，
X是离去原子或基团(例如：Cl、Br、I、三氟甲磺酸根(triflate)、甲磺酸根、甲苯磺酸根)，并且M′是与关注的交叉偶联反应类型相对应的金属或含金属基团(例如：该金属组分是用于Suzuki-Miyaura偶联的硼、用于Sonogashira偶联的铜、用于Kharash偶联的镁、用于Hiyama偶联的硅、用于Stille偶联的锡、用于Negishi偶联的锌等)。
交叉偶联反应的一般性机理在图1中显示。
Figure BDA0000367481410000021
图1
然而，从实际应用方面，这些方法(特别地据称在制药产业的领域中)有一些缺点。其中之一是要求相当高的催化剂的量(相对基质的1-5摩尔%)，另外源自催化剂的金属杂质一般仅可以由繁琐及昂贵的操作从终产物中除去。对于钯催化剂后者尤其真实，另外所述钯催化剂高度易分解。作为实例，当式(II)的钯(0)-四(三-苯基-膦)
Figure BDA0000367481410000031
在室温下在空气中储存时，大量的钯黑在短时间内分离，因此建议将其储存在在氩气氛下的冷藏库中，其中所述式(II)依然是工业中常用的催化剂。尽管使用式(II)的催化剂的交叉偶联反应在惰性气氛下进行，但钯黑的分离依然常见，其不仅导致大量的催化剂的损失，而且还应该引入繁琐耗时并且昂贵的纯化步骤。
本发明的目标是提供新型钯(0)配合物催化剂，其与以前在交叉偶联反应中使用的钯(0)配合物催化剂相比稳定得多，并且也使技术人员能显著减少1摩尔基质所需的催化剂的量。在此领域中发明人的主要目标是消除钯黑的形成，因为从Pd(0)配合物中形成的钯黑是最后的状态，该催化剂的分解显著地降低总催化效率。另外，不受控的催化剂分解经常事实上导致不可容忍的量的P沥滤到产物中。
现在申请人已经发现式(I)的钯(0)配合物催化剂完全满足上述要求并且还具有进一步的优点。
因此，在一方面，本发明涉及式(I)的钯(0)配合物。
该化合物是亮柠檬黄色的固体，具有优异的稳定性：即使在储存于室温下的空气中大于20个月的样品中也不能观察到钯黑的形成。
式(I)的化合物在空气中在变化的T温度和湿度下储存。从储存的产物中定期地取出样品，并且基于31P、19F、13C和1H的NMR波谱检测产物的分解。结果总结在下表中。
Figure BDA0000367481410000041
当通过DSC检测式(I)的化合物时，在169.5℃下空气中在大气压下观察到分解。当在惰性气氛中进行测试时，发现所述化合物的熔点为220℃。仅用于比较，式(II)的未氟化的催化剂在98℃下开始分解。
当检测式(I)的化合物相比其接近的结构相似物式(II)的化合物的优异储存稳定性的可能原因时，进行DFT计算以测定金属-配体的结合能，其中所述式(II)的化合物在工业中广泛使用。在给出非常精确的结果的M05/sddp级别(Level)得到以下数据：
L=P(C6H5)3[式(II)] L=P[C6H3(CF3)2]3[式(I)]
PdL→Pd+L -33.8kcal/mol -33.6kcal/mol
PdL2→PdL+L -31.7kcal/mol -31.9kcal/mol
在该级别上，考虑仅包含一个或两个配体的催化剂而非具有四个配体的实际催化剂，式(I)和(II)化合物中存在的配体的金属-配体的结合能之间没有发现差别。
因实际结构的催化剂包含4个配体，由于催化剂的大尺寸，只有在B3LYP/lanl2dz级别上的DFT计算得到考虑。该方法比之前提到的方法给出较低精确的结合能值数据，然而其给出结合能比上的实际信息。在该后者的级别的计算的数据如下：
L=P(C6H5)3[式(II)] L=P[C6H3(CF3)2]3[式(I)]
PdL4→PdL3+L -6.2kcal/mol -23.5kcal/mol
根据该后者的对包含4个配体(即实际结构)的化合物的计算，在式(I)的化合物中的金属-配体结合能是为式(II)的化合物观察到的四倍。在此基础上，申请人假设式(I)的化合物的优异的储存稳定性不能归因于金属-配体相互作用，而是归因于特定的配体-配体的相互作用。
为了评估配体-配体的相互作用的特征，在Pd(0)-四[三-(取代苯基)-膦]配合物催化剂上进行稳定性测试，其中接合在配体中磷原子上的3个3,5-(三氟甲基)-苯基基团中的2个得到保留，但第三个被单、二或三甲氧基-苯基、三异丙基-苯基或2-吡啶基基团代替。这些化合物中甚至没有能在储存稳定性上接近式(I)的化合物的。因此式(I)的化合物的优异的储存稳定性是非常令人惊奇的特征，该特征甚至不出现在与其非常接近的结构相似物中。
当在交叉偶联反应条件中检测式(I)的催化剂的稳定性时，申请人已经发现催化剂对温度上升不敏感；其在任何低于其熔点的温度下保持其稳定性。相似地，压力的增加对催化剂的稳定性没有影响。
当检测式(I)的催化剂的稳定性时，已经发现以下：
催化剂在工业相关的温度下不溶于水；同时当在水中储存时，其保持不受限制的稳定。
在室温下催化剂在醇中的溶解度随着所述醇的碳原子数目的增加而增加；然而，在催化反应的测试的温度区间(110-130℃)，其在醇中的稳定性并行于所述醇的碳原子数目的增加而降低。然而，当向反应混合物中加水时，催化剂的稳定性可以增加甚至完全恢复。在含水醇中催化剂的溶解在约90℃下开始，取决于关注的醇，溶解在110-130℃下完成，在此催化活性达到其最大值。然而，即使在导致完全溶解的温度下也没有发现钯黑的分离。有时发生少量的可容忍的分解，这由反应混合物颜色的轻微变深显示(从柠檬黄到土黄)。特别值得注意的是即使在这种条件下也可以得到完全(100%)转化。作为对比：当式(II)的化合物在比以上讨论的条件(大气压力；反应混合物的沸点)温和得多的条件下用作催化剂时钯黑的形成不可避免，这清楚地表明催化剂的大量分解。
为了避免使用从工业方面不利的超大气压力，式(I)的催化剂的稳定性也在工业上重要的极性非质子和非极性非质子有机溶剂(例如：二甲基亚砜、二甲基甲酰胺、乙基-甲基-酮、甲基-异丁基-酮、N-甲基–吡咯啉酮和四氢呋喃)中测试，其中在较低温度下催化剂完全溶解。在这些溶剂中也没有发现钯黑形成，尽管有时在催化反应期间反应混合物的颜色在一定程度上变得更深(观察到从柠檬黄到粉色、橙色、红色或褐色的变色)。与以上讨论的醇相似，在这些溶剂中的一些中，可以通过向反应混合物中加入水很大地抑制催化剂的轻微的稳定性降低。
当检测式(I)的化合物在交叉偶联反应中的催化活性时，申请人已经发现在相同基质及其它相同的反应条件下，所需的新型催化剂的量可以降低至相似的已知催化剂的量的小部分(从相对基质的1-5摩尔%到相对基质的0.1-0.3摩尔%)，而在相同反应时间下得到的收率和转化率没有任何显著的降低。尽管当催化剂的量进一步降低至该水平以下时，在相同反应条件下在给定的反应时间下得到的收率和转化率降低，但是该降低可以通过增加温度和/或反应时间良好地弥补。作为实例：在2-溴-吡啶与2-(4-乙氧基-3-甲基-苯基)-1,3,2-二氧杂环戊硼烷的Suzuki偶联中，当使用0.25摩尔%的式(I)的催化剂时，在1小时内得到100%的转化率，所述Suzuki偶联在10:1v/v的甲醇和水混合物中在K2CO3的存在下在110℃和压力下进行。当降低催化剂的量至0.05摩尔%(其为前者值的20%)时，在1小时内得到的转化率依然保持相当高(81%)，并且当使用仅0.005摩尔%的催化剂(其是前者值的2%并且是通常工业值的1-5‰)时，甚至可以在1小时内得到50%的转化率。
在多数实例中不要求从产物中除去钯，因为，归因于新型催化剂的低量和高稳定性，没有钯留在产物中，或残留的钯的量低于可接受的水平。如果依然除去残留的钯，则可以完全省略出于此目的常规使用的昂贵的清洁剂(scavenger)法(用于结合Pd(0)的特定操作)。依然配合钯的残留物可以通过在工业中常规使用的简单操作除去(层析法、通过廉价的碳过滤器过滤等)，并且通常需要不多于一个的纯化步骤。
本发明进一步涉及式(I)的化合物的制备方法。
式(I)的催化剂可以通过使钯(II)盐与摩尔数至少四倍超出的三-[3,5-二(三氟甲基)-苯基]-膦反应，并且在一锅(one-pot)反应中将在所得的配合物盐中的钯(II)还原到钯(0)而容易地制备。二氯化钯可以优选地用作钯(II)盐；优选的还原剂是水合肼。
用作配合试剂的三-[3,5-二(三氟甲基)-苯基]-膦是已知的物质(参见例如：H.G.Alt,R.Baumgaertner,H.A.Brune:Chemische Berichte119(5),1694-1703(1986))。
本发明也涉及式(I)的化合物在C-C和C-杂原子偶联反应中作为催化剂以及用于加氢的用途。申请人已经发现式(I)的化合物可以在任何类型的这些反应中使用。这种反应的条件可以与当使用其它Pd(0)配合物催化剂时所应用的相同，不同点是当使用式(I)的化合物作为催化剂时，通常更低，有时甚至低得多的催化剂的量依然足以进行反应。基于本领域技术人员的一般的知识和本说明书中出现的信息，本领域技术人员能容易地通过使用常规方法或有时使用简单测试并且考虑催化剂的溶解特征而确定使用式(I)的催化剂的反应中的优化参数。这里应该注意由于不受控的配合物的形成和导致低收率的钯黑的几乎立即的出现，使用原位制备的式(I)的催化剂(例如Pd2(dba)3和PPh3(CF3)6)的思想不是可行的。
以下实施例用于说明本发明的进一步的细节。
实施例1
制备式(I)的催化剂
在室温下将氩气鼓泡通过30ml二甲基亚砜，并且然后加入6.7g(0.01摩尔)的三-[3,5-二(三氟甲基)-苯基]-膦和0.355g(0.002摩尔)的氯化钯(II)。之后加热混合物至110-130℃。当得到表明配合物形成的完全透明的溶液时，加入0.5g(0.01摩尔)的水合肼到混合物中。之后烧瓶浸入冰水中。分离的产物过滤通过烧结玻璃过滤器并用氯仿洗涤三次。得到收率为90%的亮柠檬黄色的结晶固体。
NMR波谱的特征数据：1H-NMR(300MHz，THF-d8，δ=3.58ppm)，8.17(s，12H)，7.84(s，24H)；13C-NMR(75MHz，THF-d8，δ=67.3ppm)138.1(C)，133.7(q，J=38.7Hz，C)，133.4(CH)，126.3(CH)，123.4(q，J=271.57Hz，CF3)；31P-NMR(300MHz，THF-d8)28.77；19F-NMR(300MHz，THF-d8)-62.94。
实施例2
通过使用10/1v/v的甲醇和水的混合物作为溶剂并且使用式(I)的化合物作为催化剂的Suzuki偶联制备2-(4-乙氧基-3-甲基-苯基)-吡啶
一般性规则：
式(I)的催化剂的量将在以下给出，在烧瓶中称量618mg(3毫摩尔)的2-(4-乙氧基-3-甲基-苯基)-1,3,2-二氧杂环戊硼烷和553mg(4毫摩尔)的碳酸钾。之后将烧瓶放置在氩气氛下，并且加入10ml的甲醇和1ml的水。最后用自动移液管引入316mg(190μl，2毫摩尔)的2-溴-吡啶(基质)。封闭烧瓶，并且任选地在超大气压力下、在将在以下给出的温度和时间搅拌反应混合物。
出于处理的目的，冷却的反应混合物用每次5ml的氯仿萃取4次；用这种方法几乎所有的催化剂的量都从产物中除去。因为氯仿萃取物依然包含二氧杂环戊硼烷杂质，所以通过使用3/1v/v的己烷和乙酸乙酯的混合物作为洗提剂的硅胶柱层析法进一步纯化由此分离的物质。
测试系列(A)：
在该测试系列中在110℃的温度和超大气压力下进行反应1小时。改变式(I)的化合物的量，并且检测该改变如何影响得到的转化率。
在本说明书中出现的所有情况中，基于1HNMR波谱或通过气相色谱测定转化率的值。结果总结在表1中。尽管有这些相当小规模的测试反应的混合物的处理影响分离收率，这些数据也出于信息的目的给出。
表1
*催化剂作为与四氢呋喃形成的储备溶液加入混合物。
没有在任何情况中观察到钯黑的分离；在所有反应中反应混合物的颜色保持柠檬黄。特别值得注意的是当式(I)的催化剂的量低至0.005摩尔%时依然可以在1小时内得到50%的转化率。根据申请人在其它测试中收集到的经验，该转化率的降低可以通过增加反应的时间和/或温度弥补。
在出于检查目的进行的测试中重复以上反应，以使得没有催化剂加入反应混合物。申请人意图用这种方法确认产物的形成确实可以归因于以非常低的量施加的催化剂，并且不受任何可能存在于溶剂或烧瓶中的金属杂质的影响。在这些条件下，转化率为0，因此可以完全确定地声明即使是以0.005摩尔%的量式(I)的催化剂也是有活性的。
测试系列(B)：
在该测试系列中0.25摩尔%的式(I)的催化剂用于1摩尔的2-溴-吡啶基质，并且反应在表2列出的温度，(如果需要)超大气压力下进行1小时。检测温度的变化如何影响得到的转化率。结果列在表2中；分离收率也出于信息的目的给出。
表2
温度，℃ 1小时内得到的转化率，% 分离收率，%
25 0 0
50 5 未测定
70 25 16
90 60 47
110 100 88
观察到的结果显示当使用10/1v/v的甲醇和水混合物作为反应介质时，建议在90℃以上的温度和超大气压力下进行偶联反应，这使反应混合物能保持为液体。这可以通过催化剂在这种温度下出现显著的溶解的事实解释。在任何反应中都不可以观察到钯黑的形成或任何其它催化剂分解的迹象。作为对比：当在110℃下进行的反应中时，式(I)的催化剂被相同量的式(II)的催化剂替代，反应混合物在几分钟内变黑。终止反应后非常难以除去金属杂质。在该后者的反应中获得的产物即使在完全除去钯黑后依然保持橙黄色/深橙黄色，而当使用根据本发明的催化剂时得到雪白的产物。
在实施例2中获得的所有产物样品的物理常数，在测量精确度的限制内，与彼此和可信产物样品的相关参数有良好的一致性。出于信息的目的申请人在以下提供由申请人在10/1v/v的甲醇和水的混合物中在110℃下1小时使用0.25摩尔%的式(I)的催化剂制备的2-(4-乙氧基-3-甲氧基-苯基)-吡啶样品上测量的物理常数：
1H NMR(300MHz，CDCl3，δTMS=0ppm)：8.65(d，J=4.8Hz，1H)，7.75(m，4H)，7.16(m，1H)，6.90(d，J=8.4Hz，1H)，4.10(q，J=6.9Hz，2H)，2.31(s，3H)，1.45(t，J=7.2Hz)。
13C-NMR(75MHz，CDCl3，δCDCl3=77.00ppm)：158.2(C)，157.3(C)，149.3(CH)，136.7(CH)，131.1(C),129(CH)，127.1(C)，125.5(CH)，121.2(CH)，119.9(CH)，111.0(CH)，63.6(CH2)，16.4(CH3)，14.9(CH3)。
IR(KBr，νcm-1)：1604，1587，1561，1467，1433，1394，1309，1281，1247，1181，1151，1131，1109，1042，926，884，777，742，618。
实施例3
通过在除10/1v/v的甲醇和水的混合物外的反应介质中并且使用式(I)的化合物作为催化剂的Suzuki偶联制备2-(4-乙氧基-3-甲基-苯基)-吡啶
使用316mg(190μl，2毫摩尔)的2-溴-吡啶作为基质和总量为11ml的反应介质重复实施例2中描述的Suzuki偶联，然而，反应条件(反应混合物的组成；催化剂的量；二氧杂环戊硼烷试剂的量；反应时间；温度)如在表3中所示改变。如在实施例2中所述地测定转化率。结果列在表3中。
表3
Figure BDA0000367481410000111
当使用含水乙醇、含水异丙醇和含水叔丁醇时，在1小时的反应时间期间内，反应混合物的颜色逐渐变深并且成为棕色；变深的顺序是乙醇-异丙醇-叔丁醇。然而，在任何实例中都没有分离出钯黑并且转化率都保持100%，反映催化剂保持其活性。当在己烷/水、二甲氧基乙烷/水和四氢呋喃/水混合物中进行反应时，申请人已经发现反应混合物的有机溶剂组分质量高度影响在给定的一段时间内得到的转化率。这是有交叉偶联反应时的通常现象。用这些溶剂时再一次不能观察到钯黑的形成，尽管有时反应混合物的颜色在反应期间变深。在四氢呋喃/水混合物中进行的测试的结果是特别值得关注的。测试也是用极低的量(0.002摩尔%；已知催化剂所需的量的约1‰)的催化剂完成的。与在实施例2中相似，此极低的量的催化剂作为在四氢呋喃中的储备溶液引入混合物。数据清楚地表明转化率的降低可以良好地通过增加反应时间和/或反应温度弥补：在提高温度到130℃并且提高反应时间到19小时时，即使用此极低的的量的催化剂也可以得到100%的转化率。当进行在实施例2中所述的检查测试时(没有催化剂的反应)，申请人已经再一次确认产物的形成可以仅归因于催化剂的存在，并且不受任何可以存在于溶剂或烧瓶中的可能的金属杂质的影响。通过以下事实良好地说明式(I)的催化剂的优异的稳定性：即使在130℃下进行19小时反应之后也没有催化剂分解的迹象可以被观察到，这是非常剧烈的条件。
实施例4
使用式(I)的催化剂通过Suzuki偶联制备吡啶衍生物
一般性规则：
在烧瓶中称量14mg(相对2-溴-吡啶基质的0.25摩尔%)的式(I)的催化剂、3毫摩尔的二氧杂环戊硼烷试剂和553mg(4毫摩尔)的碳酸钾。之后将烧瓶放置在氩气氛下，并且加入10ml的甲醇和1ml的水。最后用自动移液管引入316mg(190μl，2毫摩尔)的2-溴-吡啶(基质)。然后封闭烧瓶,并且在110℃和维持液体反应混合物所需的压力下搅拌反应混合物1小时。之后如实施例2中所述地处理反应混合物。
使用的反应物、获得的产物和它们的物理常数，以及分离收率(%)在表4中列出。
表4
Figure BDA0000367481410000121
*反应16小时后得到的收率
获得的所有产物的物理常数，在测量精确度的限制内，与可信产物样品的相关参数有良好的一致性。反应混合物总保持柠檬黄，甚至是在16小时的反应时间之后。没有涉及任选的催化剂的分解的迹象可以被检测到。
实施例5
使用式(I)的催化剂通过Suzuki偶联制备吲哚衍生物
一般性规则：
在烧瓶中称量14mg(相对5-溴-吲哚基质的0.25摩尔%)的式(I)的催化剂、3毫摩尔的二氧杂环戊硼烷试剂、553mg(4毫摩尔)的碳酸钾和390mg(2毫摩尔)的5-溴-吲哚。之后将烧瓶放置在氩气氛下，并且加入10ml的甲醇和1ml的水。然后封闭烧瓶,并且在110℃和维持液体反应混合物所需的压力下搅拌反应混合物1小时。
获得的终产物中只有5-(对甲苯基)-1H-吲哚可溶于水。当制备该化合物时，如实施例2中所述地处理反应混合物。
包含其它(不溶于水的)吲哚化合物的反应混合物如下处理：
加入9ml的水至反应混合物，并且使包含催化剂和产物的分离的固体过滤通过烧结玻璃过滤器。为了除去催化剂，在氯仿中溶解所得固体，过滤掉不溶于氯仿的催化剂，在硫酸钠上干燥滤液并且在真空中蒸发滤液。
使用的反应物、获得的产物和它们的物理常数，以及分离收率(%)列在表5中。
表5
Figure BDA0000367481410000131
Figure BDA0000367481410000141
获得的所有产物的物理常数，在测量精确度的限制内，与可信产物样品的相关参数有良好的一致性。在反应混合物中没有发现钯黑的出现；分离的催化剂总保持柠檬黄色。
实施例6
使用式(I)的催化剂通过Suzuki偶联制备异喹啉衍生物
一般性规则：
在烧瓶中称量14mg(相对5-溴-异喹啉基质的0.25摩尔%)的式(I)的催化剂、3毫摩尔的二氧杂环戊硼烷试剂、553mg(4毫摩尔)的碳酸钾和416mg(2毫摩尔)的5-溴-异喹啉。之后将烧瓶放置在氩气氛下，并且加入10ml的甲醇和1ml的水。然后封闭烧瓶,并且在110℃和维持液体反应混合物所需的压力下搅拌反应混合物1小时。如实施例2中所述地处理所得的反应混合物。
使用的反应物、获得的产物和它们的物理常数，以及分离收率(%)列在表6中。
表6
Figure BDA0000367481410000151
*反应3小时后得到的收率
获得的所有产物的物理常数，在测量精确度的限制内，与可信产物样品的相关参数有良好的一致性。反应混合物总保持柠檬黄，并且没有涉及任选的催化剂的分解的迹象可以被检测到。
实施例7
使用式(I)的催化剂通过Suzuki偶联制备联苯衍生物
一般性规则：
在烧瓶中称量14mg(相对对溴甲苯基质的0.25摩尔%)的式(I)的催化剂、3毫摩尔的二氧杂环戊硼烷试剂、553mg(4毫摩尔)的碳酸钾和342mg(2毫摩尔)的对溴甲苯。之后将烧瓶放置在氩气氛下，并且加入10ml的甲醇和1ml的水。然后封闭烧瓶,并且在110℃和维持液体反应混合物所需的压力下搅拌反应混合物1小时。如实施例5中所述地处理所得的反应混合物。
使用的反应物、获得的产物和它们的物理常数，以及分离收率(%)列在表7中。
表7
Figure BDA0000367481410000161
获得的所有产物的物理常数，在测量精确度的限制内，与可信产物样品的相关参数有良好的一致性。反应混合物总保持柠檬黄，并且没有涉及任选的催化剂的分解的迹象可以被检测到。
实施例8
使用式(I)的催化剂通过Heck偶联制备均二苯代乙烯衍生物
通过使苯乙烯与多种芳基溴化物反应制备均二苯代乙烯衍生物，如以下反应机制所示：
Figure BDA0000367481410000162
一般性规则：
将552mg(4毫摩尔，2eq.)的K2CO3、14mg(为芳基溴化物基质计算的0.25摩尔%)的式(I)的催化剂、312mg(0.343ml，3毫摩尔，1.5eq)的苯乙烯、2毫摩尔(1eq.)的芳基溴化物基质和10ml的10:1的甲醇和水的混合物加料至烘干的Schlenk管(Schlenk tube)中。反应在110℃下进行3小时或20小时，如在表8中所示。通过使反应混合物经受GC测定转化率，并且之后分离产物。对于测试号1、2、3和5，在冷却时从混合物中沉淀产物，因此可以通过简单过滤分离它们；而对于测试号4、6和7通过急骤层析法分离产物。
结果总结在表8中。
表8
所得的均二苯代乙烯衍生物的NMR数据如下：
(E)-3-氟均二苯代乙烯：1H NMR(300MHz，CDCl3)δ7.53(d，J=7.5Hz，2H)，7.39(t，J=7.5Hz，2H)，7.41-7.22(m，4H)，7.11(s，1H)，7.10(s，1H)，6.99-6.94(m，1H)；13C NMR(ATP)(75MHz，CDCl3)δ163.5(C，d，J=244Hz)，139.9(C，d，J=7.65Hz)，137.1(C)，130.3(CH，d，J=8.18Hz)，129.0(CH)，128.2(CH)，127.7(CH，d，J=2.70Hz)，126.9(CH)，122.7(CH，d，J=2.78Hz)，114.62(CH，d，J=21.5Hz)，113.0(CH，d，J=21.5Hz)。
(E)-4硝基均二苯代乙烯：1H NMR(300MHz，CDCl3)δ8.23-8.21(m，2H)，7.63(d，J=8.7Hz，2H)，7.55(d，J=7.5Hz，2H)，7.43-7.25(m，4H)，7.14(d，J=16.5Hz，1H)；13C NMR(ATP)(75MHz，CDCl3)δ147.0(C)，136.4(C)，133.6(CH)，129.1(CH)，127.3(CH)，127.1(CH)，126.5(CH)，124.4(CH)。
(E)-4-甲基均二苯代乙烯：1H NMR(300MHz，CDCl3)δ7.54(d，J=7.8Hz，2H)，7.46(d，J=7.8Hz，2H)，7.41-7.36(m，2H)，7.31-7.26(m，1H)，7.21(d，J=7.8Hz，2H)，7.12)s，2H)，2.40(s，3H)；13C NMR(ATP)(75MHz，CDCl3)δ137.8(C)，137.8(C)，134.8(C)，129.7((CH)，128.9(CH)，128.0(CH)，127.7(CH)，126.7(CH)，21.5(CH3)。
(E)-2,4-二甲氧基均二苯代乙烯：1H NMR(300MHz，CDCl3)δ7.53(d，J=8.4Hz，3H)，7.42(d，J=16.5Hz，1H)，7.35(t，J=7.5Hz，2H)，7.24(dd，J=4.9Hz，12.1Hz，1H)，7.02(d，J=16.5Hz，1H)，6.53(dd，J=2.2Hz，9.9Hz，1H)，6.49(d，J=2.4Hz，1H)。3.88(s，1H)，3.84(s，1H)；13C NMR(ATP)(75MHz，CDCl3)δ160.5(C)，138.3(C)，128.5(CH)，127.2(CH)，127.0(CH)，126.9(CH)，126.3(CH)，123.3(CH)，119.5(C)，105.0(CH)，98.5(CH)，55.5(CH3)，55.4(CH3)。
(E)-3,5-二甲基均二苯代乙烯。1H NMR(300MHz，CDCl3)δ7.55-7.53(m，2H),7.41-7.36(m，2H)，7.31-7.26(m，1H)，7.18(s，2H)，7.11(d，J=2.4Hz，2H)，6.95(s，1H)，2.38(s，6H)；13C NMR(ATP)(75MHz，CDCl3)δ138.3(C)，137.5(C)，129.7(CH)，129.1(CH)，128.9(CH)，128.5(CH)，127.7(CH)，126.7(CH)，124.7(CH)，21.5(CH3)。
(E)-2,6-二甲基均二苯代乙烯：1H NMR(300MHz，CDCl3)δ7.54-7.52(m，2H),7.42-7.37(m，2H)，7.32-7.26(m，1H)，7.13(d，J=16.8Hz，1H)，7.1(m，3H)，(m，3H)，6.63(d，J=16.8Hz，1H)，2.39(s，6H)；13C NMR(ATP)(75MHz，CDCl3)δ137.6(C)，137.0(C)，136.2(C)，134.0(CH)，128.7(CH)，127.9(CH)，127.6(CH)，126.9(CH)，126.7(CH)，126.3(CH)，21.0(CH3)。
(E)-2,4,6-三异丙基均二苯代乙烯：1H NMR(300MHz，CDCl3)δ7.54-7.52(m，2H),7.43-7.38(m，2H)，7.33-7.26(m，1H)，7.22(d，J=16.5Hz，1H)，7.07(s，2H)，6.52(d，J=16.8Hz，1H)，3.31(h，J=6.9Hz，2H)，2.94(h，J=6.9Hz，1H)，1.33-1.23(m，18H)；13C NMR(ATP)(75MHz，CDCl3)δ142.4(C)，141.4(C)，132.3(C)，128.6(CH)，127.7(C)，123.4(CH)，122.1(CH)，121.7(CH)，121.0(CH)，115.3(CH)，29.0(CH)，24.9(CH)，18.7(CH3)，18.5(CH3)。
实施例9
使用式(I)的催化剂通过Sonogishara偶联制备苯乙炔衍生物
通过使苯乙炔与多种芳基溴化物反应制备苯乙炔衍生物，如以下反应机制所示：
Figure BDA0000367481410000191
一般性规则：
将276mg(2毫摩尔，1eq.)的K2CO3、7mg(为芳基溴化物基质计算的0.25摩尔%)的式(I)的催化剂、0.165ml(1.5毫摩尔，1.5eq.)的苯乙炔、1毫摩尔(1eq.)的芳基溴化物基质和5ml的溶剂(溶剂(a)：5:1的甲醇和水的混合物；溶剂(b)：正丁醇；溶剂(c)：环亚甲基甘油醚)加料至烘干的Schlenk管中。反应在110℃下进行3小时或24小时，如在表9中所示。通过使反应混合物经受GC测定产物的量。
结果总结在表9中。
表9
Figure BDA0000367481410000192
所得的苯乙炔衍生物的NMR数据如下：
1-甲基-4-(苯基乙炔基)-苯：1H NMR(300MHz，CDCl3)δ7.43(d，J=8.0Hz，2H)，7.26-7.22(m，5H)，6.70(d，J=8.3Hz，1H)，3.75(s，3H)，2.13(s，3H)；13C NMR(ATP)(75MHz，CDCl3)δ158.2(C)，133.9(CH)，131.5(CH)，130.6(CH),128.5(CH)，128.3(CH)，127.9(CH)，123.8(C)，109.9(CH)，89.9(C)，55.4(CH)，16.1(CH)。
1-硝基-4-(苯基乙炔基)-苯：1H NMR(300MHz，CDCl3)δ8.17(d，J=9.0Hz，2H)，7.62(d，J=9.0Hz，2H)，7.58-7.55(m，2H)，7.41-7.38(m，3H)；13C NMR(ATP)(75MHz，CDCl3)δ147.0(C)，132.3(CH)，131.9(CH)，130.3(C)，129.4(CH)，129.0(CH)，123.7(CH)，122.2(C)，94.8(C)，87.7(C)。
1-甲基-4-(苯基乙炔基)-苯：1H NMR(300MHz，CDCl3)δ7.60-7.57(m，2H)，7.49(d，J=8.1Hz，2H)，7.40-7.35(m，3H)，7.20(d，J=7.9Hz，2H)，2.41(s，3H)；13C NMR(ATP)(75MHz，CDCl3)δ138.6(C)，131.8(CH)，131.7(CH)，129.3(CH)，128.5(CH)，128.3(CH)，123.7(C)，120.4(C)，89.8(C)，89.0(CH)，21.7(CH3)。
苯基-(2,4,6-三异丙基-苯基)-乙炔：1H NMR(300MHz，CDCl3)δ7.58(dd，J=8.0Hz，1.4Hz，2H)，7.43-7.35(m，3H)，7.07(s，2H)，3.65(sept，J=6.9Hz，2H)，2.96(sept，J=6.9Hz，1H)，1.36(d，J=6.9Hz，12H)，1.32(d，J=6.9Hz，6H)；
13C NMR(ATP)(75MHz，CDCl3)δ150.9(C)，149.5(C)，131.5(CH)，128.6(CH)，128.1(CH)，124.6(CH)，120.7(CH)，118.7(C)，97.0(C)，87.3(C)，4.9(CH3)，32.2(CH3)，24.2(CH3)，23.6(CH3)。
使用2-溴-3-甲基-2-丁烯作为基质重复以上反应。获得的结果列在表10中。
表10
所得产物的NMR数据如下：1H NMR(300MHz，CDCl3)δ7.45-7.39(m，2H)，7.34-7.22(m，3H)，2.02(s，3H)，1.89(s，3H)，1.79(s，3H)。
实施例10
使用式(I)的化合物作为催化剂通过Buchwald反应制备N-苯基-哌啶
将224mg(2毫摩尔)的叔丁醇钾、70mg(为溴苯基质计算的2.5摩尔%)的式(I)的催化剂、105μl(1毫摩尔)的溴苯、198μl(2毫摩尔)的哌啶和5ml的溶剂加料至烘干的Schlenk管中。反应混合物在油浴中在110℃下加热24小时，然后允许冷却至室温，并且在降低的压力下蒸发。残留物通过在硅胶上的柱层析法(洗提液：己烷/乙酸乙酯)纯化，以便给出希望的产物；1H NMR(300MHz，CDCl3)δ7.31-7.26(m，2H)，7.00-6.97(m，2H)，6.89-6.84(m，1H)，3.19(t，J=5.6Hz，4H)，1.79-1.72(m，4H)，1.64-1.59(m,2H)。
在不同溶剂中进行的测试的结果总结在表11中。
表11
Figure BDA0000367481410000211

Claims (11)

1.式(I)的钯(0)-四{三-[3,5-二(三氟甲基)-苯基]-膦}配合物：
Figure FDA0000367481400000011
2.根据权利要求1的式(I)的化合物，其为固体形式。
3.根据权利要求1的式(I)的化合物的制备方法，特征在于使钯(II)盐与摩尔数至少四倍超出的三-[3,5-二(三氟甲基)-苯基]-膦反应，并且在一锅反应中将在所得的配合物盐中的钯(II)还原到钯(0)。
4.如权利要求3中要求保护的方法，特征在于使用二氯化钯作为钯(II)盐。
5.如权利要求3或4中要求保护的方法，特征在于利用水合肼进行还原。
6.根据权利要求1的式(I)的化合物在C-C和C-杂原子偶联反应中作为催化剂以及用于加氢的用途。
7.根据权利要求6的用途，其中反应是C-C交叉偶联反应。
8.根据权利要求7的用途，其中交叉偶联反应是Suzuki偶联、Heck偶联或Sonogashira偶联。
9.根据权利要求6至8任一项的用途，其中在反应中为1摩尔基质使用的式(I)的催化剂的量为0.25摩尔%或更少。
10.根据权利要求6的用途，其中所述反应是C-N偶联反应。
11.根据权利要求10的用途，其中所述反应是Buchwald偶联。
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MATTHEW L. CLARKE ET AL.: "The electron-poor phosphines P{C6H3(CF3)2-3,5}3 and P(C6F5)3 do not mimic phosphites as ligands for hydroformylation. A comparison of the coordination chemistry of P{C6H3(CF3)2-3,5}3 and P(C6F5)3 and the unexpectedly low hydroformylation activity of their", 《DALTON TRANS.》, 28 February 2005 (2005-02-28), pages 1294 - 1300 *

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WO2012093271A1 (en) 2012-07-12
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US9056314B2 (en) 2015-06-16
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HU1000668D0 (en) 2011-02-28
EP2651856A1 (en) 2013-10-23
US20130281700A1 (en) 2013-10-24
US20140012004A1 (en) 2014-01-09
HU230438B1 (hu) 2016-06-28
BR112013015220A2 (pt) 2016-09-13
JP6113076B2 (ja) 2017-04-12
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