CN114249641B - 一种钯催化酮羰基α位烷基化的方法 - Google Patents

一种钯催化酮羰基α位烷基化的方法 Download PDF

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CN114249641B
CN114249641B CN202011014880.XA CN202011014880A CN114249641B CN 114249641 B CN114249641 B CN 114249641B CN 202011014880 A CN202011014880 A CN 202011014880A CN 114249641 B CN114249641 B CN 114249641B
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陈庆安
赵朝阳
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Abstract

本发明涉及钯催化酮羰基α位的烷基化的反应。具体为，以1‑四氢萘酮，异戊烯醇为原料，在卡宾钯催化的条件下，实现酮羰基α位的烷基化。本发明有以下优点，异戊烯醇直接作为烷基化试剂，广泛的底物范围，很好的收率。

Description

一种钯催化酮羰基α位烷基化的方法
技术领域
本发明涉及钯催化酮羰基α位的烷基化的反应。具体为，以1-四氢萘酮，异戊烯醇为原料，在卡宾钯催化的条件下，实现酮羰基α位的烷基化。本发明有以下优点，异戊烯醇直接作为烷基化试剂，广泛的底物范围，很好的收率。
背景技术
羰基是天然产物中常见的官能团，也广泛存在于在前200种处方药物中。在过去的这些年中，已经报道了许多非常成功的Pd催化的Tsuji烯丙基化反应合成α-烯丙基酮产物(式1)。此类反应的特征之一是利用带有易于离去基团(X，NR2，OCO2R，OR等)的底物先形成π-烯丙基钯配合物，再进一步跟底物酮反应合成目标产物。
通过文献检索发现(式1)，张万斌小组分别在2011年和2014年独立地报道了通过烯丙基氯化钯催化合成α-烯丙基酮产物的方法(X.Zhao,D. Liu,H.Guo,Y.Liu,W.-B.Zhang*,J.Am.Chem.Soc,2011,133， 19354.；X.Huo,M.Quan,G.Yang,X.Zhao,D.Liu*,Y.Liu,and W.-B. Zhang*,Org.Lett.,2014,16,1570.)。上述方法的成功取决于π-烯丙基钯配合物的生成，属于Tsuji烯丙基化反应的一种，相比之下，利用简单的烷基化试剂醇，实现羰基α位的烷基化同样十分重要。
Figure BDA0002698718840000011
式1.文献中报道合成手性α-氨基酸的反应
发明内容
本发明目的在于以酮和异戊烯醇为原料，在钯卡宾催化的条件下，快速实现酮α位的烷基化，具有很好的收率。
本发明是通过以下技术方案实现的：
一种钯催化酮羰基α位烷基化的方法
以酮和异戊烯醇为原料，在钯卡宾催化的条件下，以很好的收率快速实现酮α位的烷基化。反应式如下所示：
Figure BDA0002698718840000021
具体操作步骤如下：
在氩气或氮气气氛下，于反应器中加入烯丙基氯化钯，卡宾盐，甲醇钠/乙醇钠，无水甲苯溶剂，室温下搅拌反应1h，随后加入酮与异戊烯醇，反应生成目标产物3。点板监测反应体系，反应结束后，旋干溶剂，柱层析流动相：石油醚/乙醚(体积比)
反应物酮上取代基R1可以是苯基、3-甲氧基苯基、4-甲氧基苯基、5- 甲氧基苯基、3-甲基苯基、以及3-氟苯基中的一种、二种、三种或四种；反应物酮亚氨基酸酯取代基R2可以是甲基、乙基、苯基以及苄基中的一种、二种、三种或四种。
所用金属铜盐为下述中的一种或二种以上：烯丙基氯化钯、氯化钯、醋酸钯、三氟乙酸钯、肉桂基氯化钯以及二(乙酰丙酮)钯。其中，钯盐与酮的摩尔比为0.001-1，优选范围为0.01-0.2。
所用卡宾盐试剂为下述中的一种或二种以上：L1、L2、L3、L4、L5、 L6，(结构式如下式)卡宾盐试剂与与酮的摩尔比为0.001-1，优选范围为 0.01-0.2。
Figure BDA0002698718840000022
所用溶剂为，以甲醇、乙醇、异丙醇、叔丁醇、乙腈、甲苯、环己烷、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、1,4-二氧六环、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜中的一种或二种以上为溶剂，溶剂优选甲苯、四氢呋喃、1,4- 二氧六环、二氯乙烷中的一种或两种，1-四氢萘酮于溶剂中优选浓度范围0.01-1.5mol/L。
异戊烯醇用量是摩尔量的0.5-10倍之间，优选2-5倍之间；反应温度为70℃条件；反应时间在0.5-36h之间，优选反应时间16-24h。
本发明具有如下优点：
本发明有以下优点，金属钯盐和卡宾盐在碱条件下原位制备卡宾钯；异戊烯醇直接作为烷基化试剂，广泛的底物范围，很好的收率。
附图说明
图1为化合物3a的1H NMR和13C NMR图；
图2为化合物3b的1H NMR和13C NMR图；
图3为化合物3c的1H NMR和13C NMR图；
图4为化合物3d的1H NMR和13C NMR图；
图5为化合物3e的1H NMR和13C NMR图；
图6为化合物3f的1H NMR和13C NMR图；
图7为化合物3g的1H NMR，13C NMR和19F NMR图；
图8为化合物3h的1H NMR和13C NMR图；
图9为化合物3i的1H NMR和13C NMR图；
图10为化合物3j的1H NMR和13C NMR图；
图11为化合物3k的1H NMR和13C NMR图；
图12为化合物3l的1H NMR和13C NMR图；
具体实施方式
下面将以具体的实施例来对本发明加以说明，但本发明的保护范围不局限于这些实例。
1.钯卡宾催化酮α位烷基化的反应
在氮气气氛下，在2.0mL封管中，依次加入烯丙基氯化钯(相对于酮量的2.5mol％,1.8mg)，卡宾盐试剂L(相对于酮量的5mol％)，有机碱(相对于酮量的1.5equiv.)，溶剂1mL，室温下搅拌反应1h，随后加入1-四氢萘酮(0.20mmol,29.2mg)，苯胺(0.10mmol,9.3mg)、苯甲醇(0.30 mmol,32.4mg)和异戊烯醇(0.30mmol,25.8mg)，70℃反应16h，结束后加入均三甲基苯作为内标，GC-FID检测目标产物收率。
Figure BDA0002698718840000051
表1.催化剂、溶剂对反应的影响
Figure BDA0002698718840000052
Figure BDA0002698718840000061
2.底物类型
在2.0mL封管中，依次加入烯丙基氯化钯(2.5mol％,1.8mg)，卡宾盐(5mol％)，甲醇钠(1.5equiv.,16.2mg)，溶剂1mL，室温下搅拌反应 1h，随后加入1-四氢萘酮(0.20mmol,29.2mg)，苯胺(0.10mmol, 9.3mg)、苯甲醇(0.30mmol,32.4mg)和异戊烯醇(0.30mmol,25.8mg)，70℃反应16h，结束后旋干，柱层析分离，流动相为石油醚/乙酸乙酯(体积比30：1)可得到目标产物3a。
Figure BDA0002698718840000062
Figure BDA0002698718840000063
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Figure BDA0002698718840000071
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Figure BDA0002698718840000081
Figure BDA0002698718840000082
δ8.07–7.98(m,1H),7.44(td,J＝7.5,1.3Hz,1H),7.29(t, J＝7.5Hz,1H),7.22(d,J＝7.6Hz,1H),3.06–2.88(m,2H),2.51 –2.36(m,1H),2.31–2.15(m,1H),2.01–1.81(m,2H),1.63 –1.40(m,3H),1.34–1.20(m,3H),0.91(d,J＝6.6Hz,3H),0.90 (d,J＝6.6Hz,3H).13CNMR(101MHz,CDCl3)δ200.5,143.9,133.0, 132.6,128.6,127.4,126.5,47.7,36.2,28.3,28.3,28.2,27.2,22.8, 22.5.HRMS calculated for C15H20O[M+H]+217.1587,found217.1578.
Figure BDA0002698718840000091
Chloroform-d)δ8.08–7.95(m,2H),7.55–7.43(m,2H),7.39 (d,J＝7.8Hz,1H),7.35–7.23(m,3H),3.18(dtd,J＝12.2,7.1, 5.0Hz,1H),3.08(ddd,J＝11.7,7.0,5.1Hz,1H),2.65(ddt,J＝ 10.1,7.8,5.1Hz,1H),2.46(ddt,J＝13.7,7.3,4.4Hz,1H),2.19 (dt,J＝13.1,4.3Hz,1H),2.15–1.86(m,4H),1.64–1.51(m, 3H),1.52–1.36(m,7H),1.34–1.21(m,4H),0.97–0.85(m, 12H).13C NMR(101MHz,CDCl3)δ200.6,200.5,148.5,148.0,133.3, 133.2,132.6,131.6,127.9,127.5,127.4,126.5,126.4,126.3,48.1, 43.2,38.0,36.2,36.1,35.1,33.1,31.1,28.4,28.2,27.5,27.4, 22.8,22.8,22.5,22.5,21.5,20.3.HRMScalculated for C16H22O[M+H]+ 231.1743,found 231.1748./>
Figure BDA0002698718840000092
Chloroform-d)δ7.63(d,J＝7.8Hz,1H),7.25(t,J＝8.0Hz,1H), 6.99(d,J＝8.1Hz,1H),3.85(s,3H),3.03(dt,J＝17.8,5.1Hz, 1H),2.74(ddd,J＝17.8,9.7,4.9Hz,1H),2.47–2.34(m,1H), 2.22(dq,J＝14.3,4.9Hz,1H),1.97–1.77(m,2H),1.62–1.40 (m,2H),1.28(dq,J＝10.7,6.9Hz,2H),0.91(d,J＝6.6Hz,3H), 0.90(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ200.7,156.7, 133.6,132.9,126.7,119.0,113.9,55.6,47.2,36.3,28.3,27.4,27.1, 22.8,22.5,21.7.HRMS calculated for C16H22O2[M+H]+247.1693,found 247.1695.
Figure BDA0002698718840000101
Chloroform-d)δ8.00(d,J＝8.7Hz,1H),6.81(dd,J＝8.8,2.6 Hz,1H),6.67(d,J＝2.5Hz,1H),3.84(s,3H),3.01–2.82(m, 2H),2.45–2.31(m,1H),2.25–2.14(m,1H),2.01–1.80(m,2H),1.62–1.40(m,2H),1.34–1.19(m,2H),0.91(d,J＝6.6 Hz,3H),0.90(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ199.3, 163.3,146.4,129.9,126.2,113.0,112.4,55.4,47.4,36.3,28.7, 28.3,28.2,27.3,22.8,22.5.HRMS calculated for C16H22O2[M+H]+247.1693,found 247.1703.
Figure BDA0002698718840000102
Chloroform-d)δ7.51(d,J＝2.8Hz,1H),7.13(d,J＝8.4Hz,1H), 7.03(dd,J＝8.4,2.9Hz,1H),3.83(s,3H),2.99–2.81(m,2H), 2.47–2.36(m,1H),2.26–2.14(m,1H),1.99–1.81(m,2H), 1.62–1.42(m,2H),1.33–1.21(m,2H),0.91(d,J＝6.6Hz,3H), 0.90(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ200.4,158.3, 136.5,133.3,129.8,121.4,109.4,55.4,47.6,36.2,28.4,28.3,27.5, 27.3,22.8,22.4.HRMS calculated for C16H22O2[M+H]+247.1693,found 247.1703.
Figure BDA0002698718840000111
Chloroform-d)δ7.83(d,J＝1.9Hz,1H),7.26(dd,J＝7.5,2.0 Hz,1H),7.11(d,J＝7.8Hz,1H),3.00–2.82(m,2H),2.48–2.36 (m,1H),2.35(s,3H),2.26–2.15(m,1H),2.00–1.79(m,2H), 1.62–1.41(m,2H),1.34–1.20(m,2H),0.91(d,J＝6.6Hz,3H), 0.90(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ200.7,141.1,136.1, 134.0,132.3,128.6,127.5,47.7,36.2,28.3,28.3,27.9,27.3,22.8, 22.5,21.0.HRMS calculated for C16H22O[M+H]+231.1743,found 231.1748.
Figure BDA0002698718840000112
Chloroform-d)δ7.67(dd,J＝9.2,2.8Hz,1H),7.21(dd,J＝8.5, 5.2Hz,1H),7.15(td,J＝8.2,2.8Hz,1H),3.03–2.86(m,2H), 2.48–2.37(m,1H),2.27–2.16(m,1H),2.00–1.81(m,2H), 1.61–1.42(m,2H),1.33–1.20(m,2H),0.91(d,J＝6.6Hz,3H), 0.90(d,J＝6.6Hz,3H).13C NMR(101MHz,CDCl3)δ199.4,161.5(d, J＝245.8Hz),139.6(d,J＝3.2Hz),134.1(d,J＝6.1Hz),130.4 (d,J＝7.0Hz),120.4(d,J＝22.2Hz),113.3(d,J＝21.7Hz),47.4,36.2,28.2,28.2,27.6,27.1,22.7,22.4.19F NMR(376MHz,CDCl3)δ -115.4.HRMScalculated for C15H19FO[M+H]+235.1493,found 235.1494.
Figure BDA0002698718840000121
(d,J＝7.6Hz,1H),7.58(td,J＝7.5,1.3Hz,1H),7.46(d,J＝7.8Hz,1H),7.40–7.33(m,1H),3.32(dd,J＝17.2,7.9Hz,1H), 2.81(dd,J＝17.2,3.9Hz,1H),2.68–2.57(m,1H),2.04–1.90 (m,1H),1.58(dt,J＝13.2,6.6Hz,1H),1.45(dtd,J＝13.0,9.7, 6.2Hz,1H),1.36–1.24(m,2H),0.91(d,J＝6.2Hz,3H),0.89 (d,J＝6.2Hz,3H).13C NMR(101MHz,CDCl3)δ209.1,153.8,136.9, 134.6,127.3,126.5,123.9,47.6,36.6,32.9,29.4,28.2,22.7,22.5. HRMS calculated for C14H18O[M+H]+203.1430,found 203.1440.
Figure BDA0002698718840000122
δ7.62(dd,J＝7.6,1.4Hz,1H),7.36(td,J＝7.4,1.5Hz,1H), 7.26(t,J＝7.5Hz,1H),7.20(d,J＝7.5Hz,1H),3.06–2.89(m, 2H),2.85–2.71(m,1H),2.12–2.00(m,1H),2.01–1.84(m,2H),1.74–1.39(m,4H),1.15(dq,J＝10.8,6.8Hz,2H),0.88(d, J＝6.5Hz,3H),0.87(d,J＝6.6Hz,3H).13C NMR(100MHz,CDCl3) δ207.9,141.8,140.5,131.0,129.8,128.0,126.3,50.2,36.7,33.8, 30.5,29.0,28.3,25.5,22.6,22.5.HRMS calculated for C16H22O[M+H]+231.1743,found 231.1750.
Figure BDA0002698718840000131
7.5Hz,2H),7.55(t,J＝7.4Hz,1H),7.46(t,J＝7.6Hz,2H),2.95 (t,J＝7.4Hz,2H),1.74(p,J＝7.6Hz,2H),1.63–1.51(m,1H), 1.33–1.20(m,2H),0.90(d,J＝6.6Hz,6H).13C NMR(101MHz,CDCl3) δ200.6,137.1,132.9,128.5,128.0,38.9,38.6,27.9,22.5,22.2. HRMScalculated for C16H22O[M+H]+231.1743,found 231.1748 HRMS calculated for C13H18O[M+H]+191.1430,found 191.1434.
Figure BDA0002698718840000132
(m,2H),7.59–7.52(m,1H),7.47(dd,J＝8.3,6.8Hz,2H),3.52 –3.35(m,1H),1.87–1.74(m,1H),1.57–1.38(m,2H),1.20 (t,J＝7.0Hz,5H),0.86(d,J＝6.7Hz,3H),0.85(d,J＝6.7Hz,3H).13C NMR(101MHz,CDCl3)δ204.6,136.8,132.8,128.6,128.2, 40.8,36.6,31.6,28.2,22.6,22.4,17.3.HRMS calculated for C14H20O [M+H]+205.1587,found 205.1590.
Figure BDA0002698718840000141
(m,2H),7.50–7.44(m,1H),7.42–7.35(m,2H),7.33 –7.24(m,4H),7.22–7.16(m,1H),4.50(t,J＝7.3Hz,1H),2.25 –2.12(m,1H),1.88–1.77(m,1H),1.60–1.49(m,1H),1.27 –1.04(m,2H),0.87(d,J＝6.6Hz,3H),0.85(d,J＝6.6Hz,3H). 13C NMR(101MHz,CDCl3)δ200.2,139.9,137.0,132.8,128.9,128.6, 128.5,128.2,126.9,54.0,36.9,32.0,28.1,22.6,22.5.HRMS calculated for C19H22O[M+H]+267.1743,found 267.1746.
Figure BDA0002698718840000142
在2.0mL封管中，依次加入醋酸钯(5mol％,2.2mg)，BINAP(1,1'- 联萘-2,2'-双二苯膦)(5mol％,6.2mg)，溶剂四氢呋喃1mL，室温下搅拌反应1h，随后加入3a(0.20mmol,43.2mg)，溴苯(0.30mmol,47.1 mg)，70℃反应16h，结束后旋干，柱层析分离，流动相为石油醚/乙酸乙酯(体积比30：1)可得到目标产物4，产率为86％，50.3mg。

Claims (11)

1.酮羰基α位的烷基化的反应方法，其特征在于：
酮和异戊烯醇在钯卡宾试剂的作用下，实现酮羰基α位的烷基化；
具体操作步骤如下：
在氩气和/或氮气气氛下，于反应器中加入金属钯盐、卡宾盐试剂、有机碱、溶剂，室温下搅拌反应1h以上，随后加入有机胺、有机醇、酮与异戊烯醇，反应生成目标产物；
所述的酮具有如式1所示的结构；
Figure 515896DEST_PATH_IMAGE001
式1上取代基R1是苯基、3-甲氧基苯基、4-甲氧基苯基、5-甲氧基苯基、3-甲基苯基、以及3-氟苯基中的一种；取代基R2是甲基、乙基、苯基以及苄基中的一种；
所用金属钯盐为烯丙基氯化钯、氯化钯、醋酸钯、三氟乙酸钯、肉桂基氯化钯、或二(乙酰丙酮)钯中的一种或二种以上；
所用卡宾盐试剂为下述式L1、L2、L3、L4、L5、L6中的一种或二种以上：
Figure 777244DEST_PATH_IMAGE002
所述有机碱为叔丁醇钠、叔丁醇钾、甲醇钠和/或乙醇钠，有机胺为苯胺、哌啶和/或四氢吡咯，有机醇为甲醇、异丙醇、乙醇、苯甲醇。
2.根据权利要求1所述的方法，其特征在于：
点板监测反应体系，反应结束后，旋干溶剂，柱层析流动相：石油醚/乙醚体积比50:1-10:1。
3.根据权利要求1所述的方法，其特征在于：
反应式如下所示：
Figure 760244DEST_PATH_IMAGE004
其中R1是苯基、3-甲氧基苯基、4-甲氧基苯基、5-甲氧基苯基、3-甲基苯基、以及3-氟苯基中的一种R2是甲基、乙基、苯基以及苄基中的一种。
4.根据权利要求1所述的方法，其特征在于：
钯盐与酮的摩尔比为0.001-1。
5.根据权利要求1所述的方法，其特征在于：
卡宾盐试剂与酮的摩尔比为0.001-1。
6.根据权利要求1-5任一所述的方法，其特征在于：
所用溶剂为甲醇、乙醇、异丙醇、叔丁醇、乙腈、甲苯、环己烷、四氢呋喃、2-甲基四氢呋喃、乙二醇二甲醚、甲基叔丁基醚、二氯甲烷、二氯乙烷、1,4-二氧六环、乙酸乙酯、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲亚砜中的一种或二种以上，酮于溶剂中浓度范围0.01-1.5mol/L。
7.根据权利要求1所述的方法，其特征在于：
异戊烯醇用量是酮摩尔量的0.5-10倍之间；反应生成目标物的反应温度为50-100 oC；反应时间在0.5-36 h之间。
8.根据权利要求1所述的方法，其特征在于：
有机碱与酮的摩尔比为0.1-6.0。
9.根据权利要求1所述的方法，其特征在于：
有机胺与酮的摩尔比为0.1-3.0。
10.根据权利要求1所述的方法，其特征在于：
有机醇与酮的摩尔比为0.1-3.0。
11.根据权利要求1所述的方法，其特征在于：在氩气和/或氮气气氛下，于反应器中加入金属钯盐、卡宾盐试剂、有机碱、溶剂，室温下搅拌反应1-3h；溶剂选自甲苯、四氢呋喃、1,4-二氧六环、二氯乙烷中的一种或两种，
钯盐与酮的摩尔比为0.01-0.2；卡宾盐试剂与酮的摩尔比为0.01-0.2；酮于溶剂中浓度范围为0.05-1 mol/L；
异戊烯醇用量是酮摩尔量的2-5倍之间；反应生成目标物的反应温度为50-100 oC；反应时间为16-24h；
有机碱与酮的摩尔比为0.5-3.0；有机胺与酮的摩尔比为0.2-1.0；有机醇与酮的摩尔比为0.2-2.0。
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