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CN114195611A - 一种二芳基甲烷类化合物的合成方法 - Google Patents

一种二芳基甲烷类化合物的合成方法 Download PDF

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CN114195611A
CN114195611A CN202111594298.XA CN202111594298A CN114195611A CN 114195611 A CN114195611 A CN 114195611A CN 202111594298 A CN202111594298 A CN 202111594298A CN 114195611 A CN114195611 A CN 114195611A
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许华建
畅维军
徐俊
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Abstract

本发明公开了一种二芳基甲烷类化合物的合成方法，是以苄位化合物为原料，在催化剂、溴源，硼试剂以及碱存在下，对苄位进行选择性的C‑H键芳基化，高效得到二芳基甲烷类化合物。本发明具有原料易得、工艺简单、操作方便、副产物较少等优点，并且适合于药物分子及天然产物的后期官能团化。

Description

一种二芳基甲烷类化合物的合成方法
技术领域
本发明涉及一种二芳基甲烷类化合物的合成方法，通过对苄位化合物进行选择性的C-H键的芳基化来合成二芳基甲烷类化合物，属于有机合成领域。
背景技术
1,1-二芳基烷烃骨架作为一种重要的药效团，广泛存在于药物和其它生物活性分子中[1]。因此，已经有很多工作发展了这些结构的有效合成方法[2]。其中，该骨架的经典合成方法主要是芳香族烃类物质与苯甲醇、苯甲基卤代烃作为反应物，在路易斯酸、非路易斯酸或过渡金属盐的催化作用下，通过芳香族化合物傅克苄基化反应而制得[2a-b]。此外，过渡金属催化的苄基亲电或亲核试剂和芳基试剂的交叉偶联已经被证明是构建1,1-二芳基烷烃最常用的一种方法[2c-i]。但是，烷基芳烃的选择性预官能团化制备苄基试剂是必不可少的，这会额外的增加反应步骤和成本，不符合绿色化学的理念。最后，还有以苯乙烯类似物为原料通过对双键的加成构建该结构也是很常用的一种方法[2j-n]。然而，这种方法的区域选择性是一个比较难解决的问题。
烷基芳烃的苄位C-H键直接芳基化是一个非常有吸引力的策略，因为它可以显著的缩短合成步骤以减少成本和浪费。近期，有几个小组报道了光氧化还原和Ni共同催化的亲电芳基卤代烃作为芳基试剂的直接sp3 C-H键芳基化[3]。然而，很多反应需要sp3 C-H键旁边有杂原子。更重要的是，需要大量过量的烷基芳烃作为sp3 C-H源，甚至作为溶剂。这些转化不适用于有价值和复杂底物的后期官能团化[4]。最近，Liu和Stahl团队同时报道了铜催化的苄基C-H键通过自由基接力过程的芳基化反应[5]。这两个反应存在着使用特殊的自由基试剂和烷基芳烃作为溶剂的弊端，不利于实际应用。因此，开发一种简单高效的苄位直接C-H键芳基化的方法是非常有价值的。
参考文献：
[1](a)Cheltsov,A.V.；Aoyagi,M.；Aleshin,A.；Yu,E.C.-W.；Gilliland,T.；Zhai,D.；Bobkov,A.A.；Reed,J.C.；Liddington,R.C.；Abagyan,R.J.Med.Chem.2010,53,3899.(b)Ameen,D.；Snape,T.J.Med.Chem.Commun.2013,4,893.(c)Vanjari,R.；Singh,K.N.Chem.Soc.Rev.2015,44,8062.
[2](a)Teruhisa T.；Kazuo T.；Tamejiro H.；Shin-ichi F.J.Org.Chem.1997,62,6997.(b)Grigoriy A.S.Tetrahedron Lett.2004,45,7265.(c)Nichele T Z,MonteiroA L.Tetrahedron Lett.2007,48,7472.(d)Taylor,B.L.H.；Swift,E.C.；Waetzig,J.D.；Jarvo,E.R.J.Am.Chem.Soc.2011,133,389.(e)Binder,J.T.；Cordier,C.J.；Fu,G.C.J.Am.Chem.Soc.2012,134,17003.(f)Choi,J.；Fu,G.C.J.Am.Chem.Soc.2012,134,9102.(g)Do,H.-Q.；Chandrashekar,E.R.R.；Fu,G.C.J.Am.Chem.Soc.2013,135,16288.(h)Zhou,Q.；Cobb,K.M.；Tan,T.；Watson,M.P.J.Am.Chem.Soc.2016,138,12057.(i)Poremba,K.E.；Kadunce,N.T.；Suzuki,N.；Cherney,A.H.；Reisman,S.E.J.Am.Chem.Soc.2017,139,5684.(j)Paquin,J.F.；Defieber,C.；Stephenson,C.R.J.；Carreira,E.M.J.Am.Chem.Soc.2005,127,10850.(k)Wang,Z.-Q.；Feng,C.-G.；Zhang,S.-S.；Xu,M.-H.；Lin,G.-Q.Angew.Chem.,Int.Ed.2010,49,5780.(l)Wang,Z.；Ai,F.；Wang,Z.；Zhao,W.；Zhu,G.；Lin,Z.；Sun,J.J.Am.Chem.Soc.2015,137,383.(m)Friis,S.D.；Pirnot,M.T.；Buchwald,S.L.J.Am.Chem.Soc.2016,138,8372.(n)Chen,Y.-G.；Shuai,B.；Xu,X.-T.；Li,Y.-Q.；Yang,Q.-L.；Qiu,H.；Zhang,K.；Fang,P.；Mei,T.-S.J.Am.Chem.Soc.2019,141,3395.
[3](a)Li,Y.；Li,B.-J.；Lu,X.-Y.；Lin,S.；Shi,Z.-J.Angew.Chem.,Int.Ed.2009,48,3817.(b)Liu,D.；Liu,C.；Li,H.；Lei,A.Angew.Chem.,Int.Ed.2013,52,4453.(c)Zuo,Z.；Ahneman,D.T.；Chu,L.；Terrett,J.A.；Doyle,A.G.；MacMillan,D.W.C.Science2014,345,437.(d)Liu,D.；Li,Y.；Qi,X.；Liu,C.；Lan,Y.；Lei,A.Org.Lett.2015,17,998.(e)Heitz,D.R.；Tellis,J.C.；Molander,G.A.J.Am.Chem.Soc.2016,138,12715.(f)Shields,B.J.；Doyle,A.G.J.Am.Chem.Soc.2016,138,12719.
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发明内容
本发明针对现有合成路线的不足，提供了一种二芳基甲烷类化合物的合成方法，具有原料易得、工艺简单、操作方便、底物范围广、副产物比较少等优点。
本发明二芳基甲烷类化合物的合成方法，是以苄位化合物为原料，在催化剂、碱、溴源以及硼试剂的存在下进行反应，分离提纯后得到二芳基甲烷类化合物。
具体是将苄位化合物在氩气保护条件下溶于溶剂中，在催化剂、碱、溴源以及硼试剂的存在下进行反应，反应结束后分离提纯得到目标产物。
所述苄位化合物的结构式为：
Figure BDA0003430594860000021
其中：R1为H、Ph、COOEt、卤素、或萘基团，R2为H、-Me或-Et。
所述催化剂为醋酸钯、溴化钯、氯化钯、四三苯基磷钯、三(二亚苄基丙酮)二钯、双三苯基磷二氯化钯、双(二亚苄基丙酮)钯、[1.3-双三苯基磷丙烷]氯化钯、氯化烯丙基钯二聚物、二(乙酰丙酮)钯、三氟乙酸钯中的至少一种，催化剂的添加量为0.01-0.05倍当量。
所述碱为碳酸钾、碳酸铯、甲醇锂、甲醇钠、叔丁基醇钾、叔丁基醇锂、叔丁基醇钠、氢氧化钾、氢氧化钠、1,8-二氮杂二环十一碳-7-烯、吡啶中的至少一种，添加量为1-3倍当量。
所述溴源为溴单质、溴化钠、溴化钾、溴化锂、次溴酸钠中的至少一种，溴源的添加量为1-3倍当量。
所述硼试剂为ArB(OH)2、ArBpin、ArBCat、ArBneop中的至少一种，硼试剂的添加量为1-4倍当量。
本发明合成方法的反应温度为60-150℃，反应时间为6-18h；优选为110℃。
所述溶剂为氯苯、苯、氟苯、三氟甲苯、硝基苯、四氯化碳、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二乙二醇二甲醚、或四氢呋喃。
所述分离提纯是向反应液中加入适量的水，用乙酸乙酯萃取，无水硫酸钠干燥，最后利用旋蒸除去溶剂，通过柱层析(石油醚：乙酸乙酯＝5:1～100:1，v/v)分离纯化，即可得到目标产物。
本发明反应路线如下所示：
Figure BDA0003430594860000031
本发明的有益效果体现在：
1、本发明的合成方法原料易得，工艺简单，操作简便安全。
2、本发明的合成方法底物适用性广，产率比较高，副产物比较少，能兼容多种官能团，适用于多种取代基的苄位化合物。
具体实施方式
为进一步阐述本发明的特征和优点，下面结合具体的实施例对本发明的技术方案进行描述。但下列实施例仅为了进一步说明本发明，而不是限制本发明。
实施例1：
Figure BDA0003430594860000032
向装有磁力搅拌子的25mL氮保管中，加入原料1-乙基萘(0.2mmol)、溴化钯(0.01mmol)、碳酸钾(0.6mmol)、4-联苯硼酸(0.3mmol)、Br2(0.4mmol)，在氩气保护下加入1.5mL氯苯；将反应管固定于磁力搅拌器上，混合物110℃反应9h后，反应结束；向反应液中加入适量的水，用乙酸乙酯萃取，无水硫酸钠干燥，最后利用旋蒸除去溶剂，粗产品经柱层析(石油醚：乙酸乙酯＝100:1)分离提纯得到目标产物(3a)，收率60％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.07(dd,J＝6.4,3.4Hz,1H),7.85(dd,J＝6.3,3.3Hz,1H),7.75(dd,J＝6.4Hz,1H),7.61–7.34(m,10H),7.35–7.26(m,3H),4.96(q,J＝7.2Hz,1H),1.79(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ145.73,141.46,138.82,133.99,128.79,128.66,128.00,127.13,127.02,127.00,126.95,125.89,125.46,125.34,124.33,123.94,40.21,22.52.
实施例2：
Figure BDA0003430594860000041
用4-甲氧基苯硼酸(2b)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝50:1)得到目标产物(3b)，收率69％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.16–8.01(m,1H),7.94–7.83(m,1H),7.76(d,J＝7.9Hz,1H),7.53–7.39(m,4H),7.17(d,J＝8.5Hz,2H),6.83(d,J＝8.6Hz,2H),4.91(q,J＝7.1Hz,1H),3.77(s,3H),1.77(d,J＝7.1Hz,3H).13C NMR(101MHz,CDCl3)δ157.73,141.90,131.65,128.74,128.50,126.86,125.79,125.41,125.26,124.16,123.96,113.77,55.16,39.68,22.64.
实施例3：
Figure BDA0003430594860000042
用4-甲氧羰基苯硼酸(2c)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝30:1)得到目标产物(3c)，收率78％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.00–7.92(m,3H),7.88–7.84(m,1H),7.78(d,J＝8.4Hz,1H),7.50(t,J＝7.6Hz,1H),7.45–7.39(m,3H),7.32(d,J＝8.4Hz,2H),4.98(q,J＝7.2Hz,1H),3.88(s,3H),1.80(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ167.0,152.1,140.5,134.0,131.5,129.8,128.8,127.9,127.6,127.3,126.0,125.41,125.38,124.4,123.7,51.9,40.7,22.2.
实施例4：
Figure BDA0003430594860000051
用3-氟-4-甲基苯硼酸(2d)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝40:1)得到目标产物(3d)，收率77％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.04-8.01(m,1H),7.92–7.5(m,1H),7.77(d,J＝8.0Hz,1H),7.54–7.43(m,4H),7.08(t,J＝8.0Hz,1H),6.93(dd,J＝8.0,1.6Hz,1H),6.89(dd,J＝10.8,1.6Hz,1H),4.90(q,J＝7.2Hz,1H),2.22(d,J＝1.6Hz,3H),1.75(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ161.3(d,J＝242.9Hz),146.5(d,J＝6.1Hz),141.0,134.0,131.6,131.2(d,J＝6.0Hz),128.8,127.1,125.9,125.41,125.36,124.2,123.8,122.9(d,J＝3.0Hz),122.1(d,J＝17.4Hz),114.1(d,J＝22.0Hz),40.0(d,J＝1.6Hz),22.4,14.1(d,J＝3.8Hz).19F NMR(376MHz,CDCl3)δ-117.59(t,J＝7.9Hz).
实施例5：
Figure BDA0003430594860000052
用5-乙酰基-2-噻吩硼酸(2e)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝20:1)得到目标产物(3e)，收率62％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.08–8.02(m,1H),7.93–7.85(m,1H),7.89(dd,J＝7.6,2.4Hz,1H),7.52–7.44(m,5H),6.81(dd,J＝4.0,0.8Hz,1H),5.17(q,J＝7.2Hz,1H),2.49(s,3H),1.87(d,J＝7.2Hz,3H).13C NMR(101MHz,CDCl3)δ190.6,160.7,142.2,140.1,133.9,132.6,131.1,129.0,127.7,126.2,125.6,125.5,125.4,124.1,123.2,36.7,26.4,22.9.
实施例6：
Figure BDA0003430594860000061
用1-正丙基萘(1b)代替1-乙基萘(1a)，用3-氰基苯硼酸(2f)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝40:1)得到目标产物(3f)，收率69％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.03–7.98(m,1H),7.90–7.83(m,1H),7.76(d,J＝7.2Hz,1H),7.58(s,1H),7.56–7.42(m,6H),7.36(t,J＝7.6Hz,1H),4.63(t,J＝7.6Hz,1H),2.35–2.24(m,1H),2.20–2.09(m,1H),1.02(t,J＝7.2Hz,3H).13CNMR(101MHz,CDCl3)δ146.6,138.7,134.0,132.6,131.7,131.5,129.8,129.1,129.0,127.5,126.1,125.5,125.4,124.3,123.2,119.0,112.3,47.7,29.0,12.8.
实施例7：
Figure BDA0003430594860000062
用1-(2-甲氧基乙基)萘(1c)代替1-乙基萘(1a)，用3-甲氧基羰基苯硼酸(2g)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝15:1)得到目标产物(3g)，收率72％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ8.08–8.04(m,2H),7.86(d,J＝8.0Hz,1H),7.85–7.81(m,1H),7.76(d,J＝8.4Hz,1H),7.50–7.42(m,4H),7.41(d,J＝7.2Hz,1H),7.32(t,J＝7.6Hz,1H),5.15(t,J＝7.2Hz,1H),4.12–4.03(m,2H),3.88(s,3H),3.43(s,3H).13C NMR(101MHz,CDCl3)δ167.1,142.6,136.7,134.0,133.1,131.7,130.3,129.4,128.9,128.5,127.8,127.6,126.2,125.4,125.3,125.1,123.4,75.6,58.9,52.0,46.2.
实施例8：
Figure BDA0003430594860000071
用苊(1d)代替1-乙基萘(1a)，用4-(甲磺酰基)苯硼酸(2h)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝5:1)得到目标产物(3h)，收率55％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ7.88(d,J＝8.4Hz,2H),7.70(d,J＝8.0Hz,2H),7.54(t,J＝7.6Hz,1H),7.45(t,J＝7.6Hz,1H),7.36(d,J＝8.4Hz,2H),7.34(d,J＝7.2Hz,1H),7.07(d,J＝6.8Hz,1H),4.97(dd,J＝8.8,4.0Hz,1H),4.01(dd,J＝17.6,8.8Hz,1H),3.38(dd,J＝17.6,4.0Hz,1H),3.03(s,3H).13C NMR(101MHz,CDCl3)δ152.3,147.3,143.1,138.6,138.5,131.5,128.7,128.3,128.1,127.8,123.5,122.8,120.2,119.6,49.3,44.5,41.4.
实施例9：
Figure BDA0003430594860000072
用2-乙基-9H-芴(1e)代替1-乙基萘(1a)，用3-三氟甲基苯硼酸(2i)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝100:1)得到目标产物(3i)，收率75％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ7.78(d,J＝7.2Hz,1H),7.73(d,J＝8.0Hz,1H),7.56(s,1H),7.55(d,J＝7.6Hz,1H),7.54–7.37(m,5H),7.31(t,J＝7.6Hz,1H),7.27(d,J＝7.6Hz,1H),4.31(q,J＝7.2Hz,1H),3.87(s,2H),1.74(d,J＝7.2Hz,3H).13CNMR(101MHz,CDCl3)δ147.5,144.1,143.7,143.2,141.4,140.1,131.1,130.6(q,J＝31.9Hz),128.8,126.7,126.5,126.2,125.0,124.25(q,J＝271.8Hz),124.19(q,J＝3.0Hz),124.18,122.9(q,J＝3.8Hz),119.8,119.7,44.7,36.8,21.9.19F NMR(376MHz,CDCl3)δ-62.38(s).
实施例10：
Figure BDA0003430594860000081
用1-(4-乙基苯基)-1H-吡唑(1f)代替1-乙基萘(1a)，用5-氯-2-氟苯硼酸(2j)代替4-联苯硼酸(2a)，其他同实施例1。柱层析(石油醚：乙酸乙酯＝30:1)得到目标产物(3j)，收率75％。该化合物的核磁数据为：1H NMR(400MHz,CDCl3)δ7.88(d,J＝2.4Hz,1H),7.73(d,J＝1.6Hz,1H),7.62–7.57(m,2H),7.31–7.27(m,2H),7.16–7.02(m,3H),6.46(t,J＝2.0Hz,1H),4.44(q,J＝7.2Hz,1H),1.62(d,J＝7.2Hz,3H).13C NMR(100MHz,CDCl3)δ160.2(d,J＝247.5Hz),142.7,140.9,138.6,132.6(d,J＝9.9Hz),131.6(d,J＝14.5Hz),129.1(d,J＝4.5Hz),128.3,126.6,124.4(d,J＝3.8Hz),119.2,116.2(d,J＝25.8Hz),107.4,36.8,20.5.19F NMR(376MHz,CDCl3)δ-115.04(t,J＝8.6Hz)。

Claims (10)

1.一种二芳基甲烷类化合物的合成方法，其特征在于：
以苄位化合物为原料，在催化剂、碱、溴源以及硼试剂的存在下进行反应，分离提纯后得到二芳基甲烷类化合物；
所述苄位化合物的结构式为：
Figure FDA0003430594850000011
其中：R1为H、Ph、COOEt、卤素、或萘基团，R2为H、-Me或-Et。
2.根据权利要求1所述的合成方法，其特征在于：
将苄位化合物在氩气保护条件下溶于溶剂中，在催化剂、碱、溴源以及硼试剂的存在下进行反应，反应结束后分离提纯得到目标产物。
3.根据权利要求2所述的合成方法，其特征在于：
所述催化剂为醋酸钯、溴化钯、氯化钯、四三苯基磷钯、三(二亚苄基丙酮)二钯、双三苯基磷二氯化钯、双(二亚苄基丙酮)钯、[1.3-双三苯基磷丙烷]氯化钯、氯化烯丙基钯二聚物、二(乙酰丙酮)钯、三氟乙酸钯中的至少一种，催化剂的添加量为0.01-0.05倍当量。
4.根据权利要求2所述的合成方法，其特征在于：
所述碱为碳酸钾、碳酸铯、甲醇锂、甲醇钠、叔丁基醇钾、叔丁基醇锂、叔丁基醇钠、氢氧化钾、氢氧化钠、1,8-二氮杂二环十一碳-7-烯、吡啶中的至少一种，添加量为1-3倍当量。
5.根据权利要求2所述的合成方法，其特征在于：
所述溴源为溴单质、溴化钠、溴化钾、溴化锂、次溴酸钠中的至少一种，溴源的添加量为1-3倍当量。
6.根据权利要求2所述的合成方法，其特征在于：
所述硼试剂为ArB(OH)2、ArBpin、ArBCat、ArBneop中的至少一种，硼试剂的添加量为1-4倍当量。
7.根据权利要求2所述的合成方法，其特征在于：
反应温度为60-150℃，反应时间为6-18h。
8.根据权利要求2所述的合成方法，其特征在于：
所述溶剂为氯苯、苯、氟苯、三氟甲苯、硝基苯、四氯化碳、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、二乙二醇二甲醚或四氢呋喃。
9.根据权利要求2所述的合成方法，其特征在于：
所述分离提纯是向反应液中加入适量的水，用乙酸乙酯萃取，无水硫酸钠干燥，最后利用旋蒸除去溶剂，通过柱层析分离纯化，即可得到目标产物。
10.根据权利要求9所述的合成方法，其特征在于：
柱层析分离纯化时的洗脱液为石油醚：乙酸乙酯＝5:1～100:1，v/v。
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