CN105801625B - 双齿亚磷酸酯配体的制备方法及其在Buchwald‑Hartwig反应中的应用 - Google Patents

双齿亚磷酸酯配体的制备方法及其在Buchwald‑Hartwig反应中的应用 Download PDF

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CN105801625B
CN105801625B CN201610366862.5A CN201610366862A CN105801625B CN 105801625 B CN105801625 B CN 105801625B CN 201610366862 A CN201610366862 A CN 201610366862A CN 105801625 B CN105801625 B CN 105801625B
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phosphite ester
bidentate phosphite
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张攀科
李青青
李恒
杨贯羽
郭涛
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Xintiandi Pharmaceutical Technology Research Institute Zhengzhou Co ltd
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Abstract

本发明公开了一种新型双齿亚磷酸酯配体的制备方法及其在Buchwald‑Hartwig反应中的应用，属有机合成化学领域。本发明由3,3’,5,5’‑四叔丁基‑2,2’‑二羟基联苯和具有不同结构二醇为原料经两步反应“一锅法“合成得到一系列新型双齿亚磷酸酯配体化合物，该类配体是一种应用非常广泛的化合物，其具有如下结构。本发明的优点：配体结构稳定，合成简便，产率高易大量制备。本发明的配体在Pd催化的Buchwald‑Hartwig反应中具有较高的反应活性和底物普适性。

Description

双齿亚磷酸酯配体的制备方法及其在Buchwald-Hartwig反应 中的应用
技术领域
本发明属于有机合成技术领域，具体涉及一种新型双齿亚磷酸酯配体的制备方法和在有机合成催化方面的应用。
背景技术
胺类化合物及其衍生物是一类重要的天然产物，并广泛存在于自然界中。因其常具有独特的生理活性，故在医药、精细化工和染料等领域中得到广泛的应用。虽然，胺类化合物的合成方法有很多种，但其中许多是多步反应，并且存在诸多问题，如反应条件苛刻、需强酸强碱等对环境不友好试剂以及副反应多等。在100多年前，Ullman首次利用化学计量的铜试剂作为催化剂用于催化碳-氮交叉偶联反应，并成功构建了C-N键(And S Guram,Roger A Rennels,Stephen L Buchwald.A Simple Catalytic Method for theConversion of Aryl Bromides to Arylamines.Angew.Chem.Int.Ed.,1995,34,12)，但该方法并不能够取得良好的化学选择性以及较高的化学产率。在上世纪九十年代,Buchwald和Hartwig课题组分别独立的报道了以钯为催化剂，采用合适的二级胺或者膦配体实现的N-芳基化反应(John P Wolfe,Stephen L Buchwald.Palladium-Catalyzed Amination ofAryl Iodides.J.Org.Chem.,1996,61:1133～1135)，并对催化剂体系不断完善，逐步发展成为构建碳-氮的一种切实有效的方法(Buchwald-Hartwig，偶联反应)。
通过胺(氨)对卤代芳烃加成反应来合成相应的胺类化合物的方法有巨大优势。Buchwald-Hartwig偶联反应具有芳烃底物简单易得、无需其它转化，一步合成目标分子、原子利用率高等优点，无疑是构建碳-氮键最简洁高效的方法(化学式1)。
化学式1钯催化的卤代烃与胺类化合物的Buchwald-Hartwig反应
到目前为止，在催化应用方面，双齿亚磷酸酯配体主要应用于催化氢化、氢甲酰化等领域中，有关Buchwald-Hartwig反应研究进展文献综述中尚未见此类配体的相关报道。
围绕这一目的进行相关研究和探索，设计并成功合成出三种双齿亚磷酸酯配体，与钯盐催化Buchwald-Hartwig反应，期望能够获得高反应活性以及较广的底物普适性。
发明内容
本发明的目的提供一种新型双齿亚磷酸酯配体的制备方法及应用，其合成条件温和、反应时间短，并且此类配体稳定易大量制备，与钯催化的Buchwald-Hartwig反应，构建新型碳-氮键，合成不同胺类化合物。
为实现上述目的，本发明采用以下技术方案：
一种新型双齿亚磷酸酯配体化合物，其特征在于：所述的双齿亚磷酸酯配体化合物具有不同连接结构的双齿亚磷酸酯配体，并且能够与钯催化Buchwald-Hartwig反应，构建碳-氮键，所述的双齿亚磷酸酯配体具有以下通式：
通式中Linker为1,2-丙二醇、顺丁烯-1,4-二醇或新戊二醇或1,4-丁二醇中的一种，其中所述的Linker为相应的二醇脱去羟基上的H之后与P连接。
所述的新型双齿亚磷酸酯配体化合物的制备方法，步骤如下：
(1)3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：以2,4-二叔丁基苯酚为起始原料，甲醇为溶剂，在氧气存在下，加入铜盐和碱作为催化剂，在10-25℃的条件下反应10-72小时，停止搅拌，过滤得到白色固体，并用少量甲醇洗涤3次，干燥后得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯；
(2)双齿亚磷酸酯配体化合物的制备：氮气保护下，将3,3',5,5'-四叔丁基-2,2'-二羟基联苯溶解在有机溶剂中，滴加三氯化磷和NEt3，滴加完毕后，在室温条件下反应2小时，再加热回流4小时，停止加热，反应体系冷却至室温后，在氮气保护下加入不同结构的二醇和NEt3，在25-140℃的条件下反应1-22小时，浓缩液体除去大部分溶剂，用甲苯和乙腈重结晶得到白色固体双齿亚磷酸酯配体。
所述步骤(1)中的2,4-二叔丁基苯酚与铜盐的摩尔比为5-50:1；其中铜盐为氯化铜、碘化铜、氧化铜或氧化亚铜。
所述步骤(1)中的2,4-二叔丁基苯酚与碱盐的摩尔比为2-25:1；其中碱为碳酸钾、碳酸钠或四甲基乙二胺。
所述步骤(2)中的3,3',5,5'-四叔丁基-2,2'-二羟基联苯、三氯化磷与二醇的摩尔比为1:1-4:0.5-1，其中，二醇为1,2-丙二醇、顺丁烯-1,4-二醇或新戊二醇或1,4-丁二醇。
所述步骤(2)中以3,3',5,5'-四叔丁基-2,2'-二羟基联苯为基准，第一次加入的NEt3与3,3',5,5'-四叔丁基-2,2'-二羟基联苯的摩尔比为3-1:1，第二次加入的NEt3与3,3',5,5'-四叔丁基-2,2'-二羟基联苯的摩尔比为3-1:1。
所述步骤(2)中的3,3',5,5'-四叔丁基-2,2'-二羟基联苯与有机溶剂的摩尔比为1:30-80，其中有机溶剂为苯、甲苯、乙苯、二氯甲烷、四氢呋喃、氯仿、吡啶、DMF或DMSO。
所述的新型双齿亚磷酸酯配体化合物在Buchwald-Hartwig反应中的应用，在惰性气体保护下，甲苯为溶剂，双齿亚磷酸酯配体化合物/Pd为催化剂，叔丁醇钠为碱剂，100℃条件下反应，TLC监测，待反应完全后，淬灭、柱层析分离得到产物。
所述的卤代烃为溴苯、邻溴甲苯、间溴甲苯、对溴甲苯、对甲氧基溴苯、对硝基溴苯、对氰基溴苯、6-甲氧基-2-溴萘、4-甲基-1-溴萘、2-溴吡啶、3-溴吡啶、5-氰基-2溴吡啶或4-三氟甲基-2溴吡啶。
所述的胺类化合物为哌啶、3-甲基哌啶、4-甲基哌啶、硫代吗啡、四氢吡咯、环己基胺、苯胺、甲基苄胺、二丁基胺或四氢异喹啉。
本发明的有益效果：新型的亚磷酸酯配体以3,3',5,5'-四叔丁基-2,2'-二羟基联苯为骨架，通过不同结构的连接单元来调节和稳定配体空间结构，能够与钯催化Buchwald-Hartwig反应，催化体系不仅反应活性高，而且底物普适性广。此催化体系构建碳-氮键合成不同胺类化合物，反应催化剂用量小。
具体实施方式
下面结合具体实施例，对本发明做进一步说明。应理解，以下实施例仅用于说明本发明而非用于限制本发明的范围，该领域的技术熟练人员可以根据上述发明的内容作出一些非本质的改进和调整。
实施例1
本实施例的新型双齿亚磷酸酯配体化合物的制备方法，步骤如下：
(1)3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：向干燥、洁净的250mL三口烧瓶中加入2,4-二叔丁基苯酚(20g，97.10mmol)，带结晶水的氯化铜(0.34g，1.99mmol)，四甲基乙二胺(0.45g，3.88mmol)，并加入100mL工业甲醇作为溶剂，在10℃条件下搅拌72h，采用TLC法监测反应，待原料反应完全，将反应液抽滤，所得白色固体用甲醇(10mL)洗涤3次，干燥，得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯白色固体18.80g(94％)。Mp:196-197℃；1HNMR(400MHz,CDCl3,TMS)δ1.37(s,18H,2×C4H9),1.50(s,18H,2×C4H9),5.26(s,2H,2×OH),7.16(d,J＝2.4Hz，4H,2×Ar-H),7.44(d,J＝2.4Hz，2H,2×Ar-H)ppm；13C NMR(100MHz,CDCl3,TMS)δ29.7,31.7,34.5,35.2,122.3,124.9,125.3,136.3,143.0,149.8.
(2)新型双齿亚磷酸酯配体L1的制备：
向干燥，洁净的50mL三口烧瓶中加入3,3',5,5'-四叔丁基-2,2'-二羟基联苯(1.50g，3.66mmol)，用油泵抽真空并置换N2三次，在N2保护下加入干燥甲苯(25mL,235.33mmol)，PCl3(0.32mL，3.67mmol)，NEt3(1.10mL，7.89mmol)，在室温条件下搅拌2h，再回流4h，停止加热，待反应液冷却至室温于N2保护下加入1,2-丙二醇(0.14mL，1.90mmol)，NEt3(0.55mL，3.95mmol)，25℃下，反应22小时后，过滤，滤液旋干得出产品，采用快速柱层析法得0.98g白色泡沫状固体L1，产率65％。Mp:85-87℃；31P NM R(162MHz,CD2Cl2,H3PO4)δ145.9,136.6ppm；1H NMR(400MHz,CD2Cl2,TMS)δ1.08-1.09(d,3H,CH3),1.23(s,18H,2×C4H9),1.26(s,18H,2×C4H9),1.33(s,9H,C4H9),1.36(s,27H,3×C4H9),3.57-3.63(m,1H,CH),3.75-4.45(m,2H,CH2),7.00(d,2H,2×Ar-H),7.06-7.08(m,3H,3×Ar-H),7.31(d,1H,Ar-H),7.34-7.35(m,2H,2×Ar-H)ppm；13C NMR(100MHz,CD2Cl2,TMS)δ18.9,29.5,30.8,30.9,31.0,31.1,31.3,31.4,34.3,34.6,35.1,35.3,67.8,71.5,71.6,122.6,124.3,124.4,124.8,125.3,126.3,126.4,132.6,132.9,136.2,140.0,140.1,140.2,143.1,145.9,146.6,146.7,146.8,149.8ppm.
实施例2
(1)3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：向干燥、洁净的250mL三口烧瓶中加入2,4-二叔丁基苯酚(20g，97.10mmol)，氧化亚铜(2.754g，19.42mmol)，碳酸钾(6.695g，48.55mmol)，并加入100mL工业甲醇作为溶剂，在20℃条件下搅拌48h。采用TLC法监测反应，待原料反应完全，将反应液抽滤，所得白色固体用甲醇(10mL)洗涤3次，干燥，得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯白色固体17.37g(85％)。
(2)新型双齿亚磷酸酯配体L2的制备：
向干燥，洁净的250mL三口烧瓶中加入3,3',5,5'-四叔丁基-2,2'-二羟基联苯(1.50g，3.66mmol)，用油泵抽真空并置换N2三次，在N2保护下加入干燥二氯甲烷(70mL,109.8mmol)，PCl3(0.64mL，7.32mmol)，NEt3(1.02mL，7.32mmol)，在室温条件下搅拌2h，再回流4h，停止加热，待反应液冷却至室温于N2保护下加入顺丁烯-1,4-二醇(129mg，2.15mmol)，NEt3(1.02mL，7.32mmol)，50℃下，反应11小时后，过滤，滤液旋干得出产品，采用快速柱层析法得0.98g白色泡沫状固体L2，产率79％。Mp:92-94℃；31P NM R(162MHz,CDCl3,H3PO4)δ135.5ppm；1H NMR(400MHz,CDCl3,TMS)δ1.37(s,36H,4×C4H9),1.46(s,36H,4×C4H9),4.21-4.30(m,4H,2×CH2),5.53-5.60(m,2H,CH＝CH),7.18(d,4H,4×Ar-H),7.43(d,4H,4×Ar-H)ppm；13C NMR(100MHz,CDCl3,TMS)δ30.0,30.5,33.6,34.3,59.1,125.5,127.8,131.5,138.8,145.0,145.4ppm.
实施例3
(1)3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：向干燥、洁净的250mL三口烧瓶中加入2,4-二叔丁基苯酚(20g，97.10mmol)，氧化铜(766.31mg，9.71mmol)，碳酸钠(1.029g，9.71mmol)，并加入100mL工业甲醇作为溶剂，在25℃条件下搅拌10h。采用TLC法监测反应，待原料反应完全，将反应液抽滤，所得白色固体用甲醇(10mL)洗涤3次，干燥，得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯白色固体18.00g(90％)。
(2)新型双齿亚磷酸酯配体L3的制备：
向干燥，洁净的250mL三口烧瓶中加入3,3',5,5'-四叔丁基-2,2'-二羟基联苯(1.50g，3.66mmol)，用油泵抽真空并置换N2三次，在N2保护下加入干燥DMF(141mL,183.00mmol)，PCl3(0.96mL，11.01mmol)，NEt3(1.53mL，10.98mmol)，在室温条件下搅拌2h，再回流4h，停止加热，待反应液冷却至室温于N2保护下加入新戊醇(292mg，2.82mmol)，NEt3(1.53mL，10.98mmol)，80℃下，反应5小时后，过滤，滤液旋干得出产品，采用快速柱层析法得0.98g白色泡沫状固体L2，产率76％。Mp:81-82℃；31P NM R(162MHz,CDCl3,H3PO4)δ136.8ppm；1H NMR(400MHz,CDCl3,TMS)δ0.82(s,6H,2×CH3),1.46(s,36H,4×C4H9),1.57(s,36H,4×C4H9),3.58(d,4H,2×CH2),7.28(d,4H,4×Ar-H),7.53(d,4H,4×Ar-H)ppm；13C NMR(100MHz,CDCl3,TMS)δ31.1,31.6,34.7,35.4,36.4,68.7,124.2,126.5,132.7,139.9,146.3,146.4ppm.
实施例4
(1)3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：向干燥、洁净的250mL三口烧瓶中加入2,4-二叔丁基苯酚(20g，97.10mmol)，碘化铜(1.537g，4.86mmol)，碳酸钠(1.029g，9.71mmol)，并加入100mL工业甲醇作为溶剂，在25℃条件下搅拌10h。采用TLC法监测反应，待原料反应完全，将反应液抽滤，所得白色固体用甲醇(10mL)洗涤3次，干燥，得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯白色固体18.00g(90％)。
(2)新型双齿亚磷酸酯配体L4的制备：
向干燥，洁净的500mL三口烧瓶中加入3,3',5,5'-四叔丁基-2,2'-二羟基联苯(1.50g，3.66mmol)，用油泵抽真空并置换N2三次，在N2保护下加入干燥四氢呋喃(236mL,292mmol)，PCl3(1.28mL,14.64mmol)，NEt3(1.28mL，9.15mmol)，在室温条件下搅拌2h，再回流4h，停止加热，待反应液冷却至室温于N2保护下加入1,4-丁二醇(329mg，3.66mmol)，NEt3(1.28mL，9.15mmol)，140℃下，反应1小时后，过滤，滤液旋干得出产品，采用快速柱层析法得0.98g白色泡沫状固体L2，产率79％。Mp:118-120℃；31P NM R(600MHz,CDCl3,H3PO4)δ136.1ppm；1H NMR(600MHz,CDCl3,TMS)δ1.33(s,36H,4×C4H9),1.45(s,36H,4×C4H9),1.54(br,4H,2×CH2),3.72(br,4H,4×CH2),7.15(d,4H,4×Ar-H),7.40(d,4H,4×Ar-H),ppm；13C NMR(600MHz,CDCl3,TMS)δ27.2,31.0,31.5,34.6,35.3,64.1,124.1,126.5,132.6,139.8,146.2,146.3ppm.
一、双齿亚磷酸酯配体/钯催化的Buchwald-Hartwig反应应用
1)最佳反应条件筛选：
以溴苯和吗啡啉作为模板反应，对反应钯源、碱、溶剂、温度等条件进行了筛选。
化学式Buchwald-Hartwig模板反应
表1 L/Pd催化溴苯和吗啡啉反应的条件筛选[a]
[a]反应条件：溴苯(0.5mmol)，吗啡啉(1.0mmol)，Pd/L＝1:1，碱(0.7mmol)，溶剂(2.0mL)，反应时间1h，收率为分离收率。[b]24h.[c]48h.
首先选用溴苯和吗啡啉作为模板反应，以Pd2(dab)3为钯源，选用1.4当量的叔丁醇钠为碱，对配体进行了筛选，从表1中，可以发现，反应4小时，配体L3的收率最高为98％(编号3)。当选用PdCl2、Pd(PPh3)2Cl2、Pd(OAc)2、PdCl2dppf等代替Pd2(dab)3时(编号5-7)，收率都有所降低。对常用溶剂的考察(编号8-15)，发现甲苯是最优溶剂。接下来对碱进行了筛选(编号16-21)，当改用K2CO3、KHCO3、HCOONa、CF3COONa和NEt3时，反应不能够发生，当碱为Cs2CO3反应的收率为80％。温度对反应影响很大(编号22-26)，反应在100℃以下时，催化效果很差。最后，在以甲苯为溶剂、NaOtBu为碱、100℃，催化剂为Pd2(dab)3/L3条件下，延长反应时间对催化剂的用量进行了筛选(编号27-29)，发现及时催化剂用量降低到0.1％时，催化剂仍然表现出较高的催化活性。
通过对溴苯和吗啡啉反应条件的筛选，选用最佳反应条件即：100℃、以Pd2(dab)3(2.5mol％)/L3(5mol％)作为催化剂，1.4当量NaOtBu为碱，在甲苯溶剂中催化Buchwald-Hartwig反应，对不同结构的溴代烃和胺分别做了研究和探索(表2)。
化学式Pd2(dab)3/L3催化不同底物的Buchwald-Hartwig反应
表2 Pd2(dab)3/L3催化不同底物Buchwald-Hartwig的反应结果
[a]反应条件：溴代烃(0.5mmol)，胺(1.0mmol)，以Pd2(dab)3(2.5mol％)/L3(5mol％)作为催化剂，NaOtBu(0.7mmol)，甲苯(2.0mL)，反应温度100℃，收率为分离收率。
从反应结构来看，选用的催化体系用于Buchwald-Hartwig反应时，整体催化效果都很好，收率>80％。对于溴苯衍生物为底物时，具有不同空间位阻(编号1-4)和不同电子效应(编号5-7)的结构时对反应影响不大，都能够以较高产率(85-98％)得到目标产物。当溴代芳烃含有萘环时，催化效果较差，特别是当溴在β位时，延长反应时间为30小时，反应收率仅为32％(编号8)。为了进一步验证该催化体系的催化活性，尝试了底物为溴代吡啶衍生物(编号10-13)与吗啡啉的偶联反应，得到了满意的结果，反应对不同位置溴代的吡啶、含有不同取代基的溴代吡啶都表现出了较高的催化活性。催化剂还能够很好地催化溴苯与哌啶及其衍生物的偶联反应，能以83-90％的收率得到相应产物(编号14-17)。最后还考察了芳香胺、脂肪胺(伯胺和仲胺)与溴苯的反应(编号18-23)，反应都能够顺利进行，同时发现，芳香胺与溴苯的反应活性稍低于其它胺类化合物(编号20)。
Pd2(dab)3/L3催化体系不仅对溴代苯衍生物与吗啡啉反应活性高，而且对溴代吡啶衍生物与吗啡啉反应活性也很高；不同结构的脂肪胺和苯胺都能够与溴苯发生Buchwald-Hartwig反应，其中脂肪胺的活性要高于苯胺。Pd2(dab)3/L3催化体系构建碳-氮键合成不同结构胺类化合物，反应时间短，产率高，底物普适性强。
以上显示和描述了本发明的基本原理和主要特征以及本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。

Claims (9)

1.一种双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述的双齿亚磷酸酯配体化合物具有不同连接结构，并且能够与钯催化Buchwald-Hartwig反应，构建碳-氮键，在惰性气体保护下，甲苯为溶剂，双齿亚磷酸酯配体化合物/Pd为催化剂，叔丁醇钠为碱剂，100℃条件下反应，TLC监测，待反应完全后，淬灭、柱层析分离得到产物，所述的双齿亚磷酸酯配体的结构式如下：
。
2.根据权利要求1所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述Buchwald–Hartwig反应的卤代烃为溴苯、邻溴甲苯、间溴甲苯、对溴甲苯、对甲氧基溴苯、对硝基溴苯、对氰基溴苯、6-甲氧基-2-溴萘、4-甲基-1-溴萘、2-溴吡啶、3-溴吡啶、5-氰基-2溴吡啶或4-三氟甲基-2溴吡啶。
3.根据权利要求1所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述Buchwald–Hartwig反应中的胺类化合物为哌啶、3-甲基哌啶、4-甲基哌啶、硫代吗啡、四氢吡咯、环己基胺、苯胺、甲基苄胺、二丁基胺或四氢异喹啉。
4.根据权利要求1所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于所述双齿亚磷酸酯配体化合物的制备方法如下：
（1） 3,3',5,5'-四叔丁基-2,2'-二羟基联苯的制备：以2,4-二叔丁基苯酚为起始原料，甲醇为溶剂，在氧气存在下，加入铜盐和碱作为催化剂或氧化铜和碱作为催化剂或氧化亚铜和碱作为催化剂，在10-25℃的条件下反应10-72小时，停止搅拌，过滤、洗涤、干燥后得到3,3',5,5'-四叔丁基-2,2'-二羟基联苯；
（2）双齿亚磷酸酯配体化合物的制备：氮气保护下，将3,3',5,5'-四叔丁基-2,2'-二羟基联苯溶解在有机溶剂中，滴加三氯化磷和NEt3，滴加完毕后，在室温条件下反应2小时，再加热回流4小时，停止加热，反应体系冷却至室温后，在氮气保护下加入二醇和NEt3，在25-140 ℃的条件下反应1-22小时，浓缩后，用甲苯和乙腈重结晶得到双齿亚磷酸酯配体。
5.根据权利要求4所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述步骤（1）中的2,4-二叔丁基苯酚与铜盐的摩尔比为5-50:1；其中铜盐为氯化铜或碘化铜。
6.根据权利要求4所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述步骤（1）中的2,4-二叔丁基苯酚与碱盐的摩尔比为2-25:1；其中碱为碳酸钾、碳酸钠或四甲基乙二胺。
7.根据权利要求4所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述步骤（2）中的3,3',5,5'-四叔丁基-2,2'-二羟基联苯、三氯化磷与二醇的摩尔比为1:1-4:0.5-1，其中，二醇为1,2-丙二醇、顺丁烯-1,4-二醇或新戊二醇或1,4-丁二醇。
8.根据权利要求4所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述步骤（2）中以3,3',5,5'-四叔丁基-2,2'-二羟基联苯为基准，第一次加入的NEt3与3,3',5,5'-四叔丁基-2,2'-二羟基联苯的摩尔比为3-1:1，第二次加入的NEt3与3,3',5,5'-四叔丁基-2,2'-二羟基联苯的摩尔比为3-1:1。
9.根据权利要求4所述的双齿亚磷酸酯配体化合物在Buchwald–Hartwig反应中的应用，其特征在于：所述步骤（2）中的3,3',5,5'-四叔丁基-2,2'-二羟基联苯与有机溶剂的摩尔比为1:30-80，其中有机溶剂为苯、甲苯、乙苯、二氯甲烷、四氢呋喃、氯仿、吡啶、DMF或DMSO。
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