CN109574867B - 一种钌催化芳基胺化合物的不对称氢化合成手性三级胺的方法 - Google Patents

一种钌催化芳基胺化合物的不对称氢化合成手性三级胺的方法 Download PDF

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CN109574867B
CN109574867B CN201710906866.2A CN201710906866A CN109574867B CN 109574867 B CN109574867 B CN 109574867B CN 201710906866 A CN201710906866 A CN 201710906866A CN 109574867 B CN109574867 B CN 109574867B
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严忠
谢焕平
孙蕾
周永贵
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Abstract

一种钌‑双膦配体催化9‑酰胺菲化合物的不对称氢化合成手性三级胺的方法。采用2‑5mol％钌催化剂，加入4‑10mol％氟硼酸，对9‑酰胺菲化合物进行不对称氢化，得到相应的手性三级胺化合物，其对映体过量可达到98％。本发明操作简便实用易行，收率高，环境友好，催化剂商业可得，反应条件温和，具有潜在的实际应用价值。

Description

一种钌催化芳基胺化合物的不对称氢化合成手性三级胺的 方法
技术领域
本发明涉及一种应用钌的均相体系高度对映选择性催化芳基胺化合物不对称氢化合成手性三级胺的方法。
背景技术
近年来，芳香杂环化合物的不对称氢化已经取得了很大的进展。多样的芳香杂环化合物，诸如：吲哚、吡啶、吡咯、喹啉等均能通过不对称催化实现高立体选择性的氢化反应得到相应的杂环化合物(参考文献一：(a)Wang,D.S.；Chen,Q.A.；Li,W.；Yu,C.-B.；Zhou,Y.-G.；Zhang,X.J.Am.Chem.Soc.2010,132,8909.(b)Ye,Z-S.；Chen,M.-W.；Chen,Q.-A.；Shi,L.；Duan,Y.；Zhou,Y.-G.Angew.Chem.Int.Ed.2012,51,10181.(c)Wang,D.-S,；Ye,Z.-S.；Chen,Q.-A.；Zhou,Y.-G.J.Am.Chem.Soc.2011,133,8866.(d)Wang,W.-B.；Lu,S-M.；Yang,P.-Y.；Han,X.-W.；Zhou,Y.-G.J.Am.Chem.Soc.2003,125,10536.)。但是相比于不含杂原子的芳香化合物而言，归因于其稳定的芳香性和缺少配位位点，其不对称氢化一直是一个充满挑战的课题。
2011年，Glorius小组发展了一种钌/N-杂环卡宾配合物催化喹喔啉底物的区域选择性氢化，最高能以88％ee实现5,6,7,8-四氢喹喔啉的合成(参考文献二：Urban,S.；Ortega,N.；Glorius,F.Angew.Chem.Int.Ed.2011,50,3803.)；
随后，Kuwano小组使用其发展的PhTrap配体成功实现了萘环和喹啉中全碳芳环的不对称氢化，能取得较好的结果，但是苛刻的温度条件是需要的(参考文献三：(a)Kuwano,R.；Morioka,R.；Kashiwabara,M.；Kameyama,N.Angew.Chem.Int.Ed.2012,51,4136.(b)Kuwano,R.；Ikeda,R.；Hirasada,K.Chem.Commun.2015,51,7558.)。
然而，相比于芳香杂环化合物，不含杂原子的芳香化合物及其官能化衍生物的不对称氢化始终是一个充满挑战的方向。
发明内容
本发明的目的是提供一种钌催化芳基胺化合物，尤其是9-酰胺菲化合物的不对称氢化合成手性三级胺的方法。为实现上述目的，本发明采用的技术方案如下：
本发明以钌的手性双膦P-P*配合物催化剂，实现芳基胺的不对称氢化，反应式和条件如下：
Figure BDA0001424137610000021
式中：
R为C1-C4的烷基或芳基；R’为甲基、乙基和甲氧基中的一种或两种以上；R1为甲基、甲氧基中的一种或两种以上；R2为甲基、甲氧基和F中的一种或两种以上。
所述氢化反应包括催化剂制备和底物氢化两个阶段：
(1)催化剂制备，将钌金属前体和手性双膦配体，氟硼酸加入有机溶剂后反应得到，反应条件如下：把钌的金属前体、手性双膦配体和氟硼酸加入到有机溶剂中，在室温搅拌下0.5小时，然后直接用于氢化反应。
(2)氢化反应，将上述催化剂和有机溶剂加入9-酰胺菲底物中，通入氢气反应得到产物，反应条件如下：氮气保护下，上述催化剂和有机溶剂加入9-酰胺菲底物中，移至反应釜中，通入氢气，一定温度下下反应24小时；释放氢气，除去溶剂后直接柱层析分离得到纯的产物。
所述催化剂制备中，钌的金属前体及双膦配体均为市售且无需任何处理。
所述催化剂制备和氢化反应中，有机溶剂均选自二氯甲烷、1,2-二氯乙烷、甲醇、异丙醇和四氢呋喃中的一种，其中二氯甲烷和四氢呋喃稍差，乙酸乙酯和异丙醇较好，甲醇、乙醇和1,2-二氯乙烷较优。
所述钌金属前体选自双-(2-甲基烯丙基)环辛-1,5-二烯钌。
所述配体选自(1R,1’R,2S,2’S)-DuanPhos,(S,S)-MeDuPhos,(S,S)-iPrDuPhos,(S,S)-MeFerrocelane,(R,R)-iPrFerrocelane,(R)-(S)-Cy2PF-PtBu2,(R,R)-QuinoxP，优选双膦配体：(S,S)-iPrDuPhos和(R)-(S)-Cy2PF-PtBu2。
所述催化剂制备中：钌的金属前体、手性双膦配体、氟硼酸、底物摩尔比为：0.02-0.05：0.022-0.055：0.04-0.10：1。
所述不对称氢化反应时，反应压力为10-1000psi,优选600psi-1000psi，反应温度为0-80℃，优选30-60℃。
所述底物制备中，酰胺基团的引入对对映选择性的控制是必要的，其它取代基团如羟基、烷氧基、甲酸酯基不适用。
本发明有益效果：
1.反应活性和对映选择性高，反应完全，生成产物专一，核磁氢谱没有检测到副反应，使得能分离方便，能获得高的对映体过量纯品；
2.催化剂制备方便，反应操作简便实用；
3.氢化反应条件温和。
具体实施方式
下面通过实施例详述本发明，但本发明并不限于下述的实施例。
实施例1：单取代底物氢化反应条件的优化
在反应瓶中投入双-(2-甲基烯丙基)环辛-1,5-二烯钌(底物用量的2mol％-5mol％)和手性双膦配体(底物用量的2.2mol％-5.5mol％)，氮气置换后加入有机溶剂(1.0-2.0mL)和氟硼酸(底物用量的4mol％-10mol％)，室温搅拌0.5小时；然后用有机溶剂(1.0-2.0mL)将此溶液转到预先放有芳基胺底物1a(0.1mmol)的反应瓶中，移至反应釜中，通入氢气(600psi-1000psi)，0-50℃下反应24小时；释放氢气，除去溶剂后直接柱层析分离得到纯的产物，反应式和配体结构如下：
Figure BDA0001424137610000041
其产率为转化率，产物的对映体过量用手性液相色谱测定，详见表1。
表1.N-乙酰基-9-菲胺1a的不对称氢化条件优化a
Figure BDA0001424137610000042
Figure BDA0001424137610000051
实施例2：钌催化不对称氢化合成手性三级胺2
在反应瓶中投入双-(2-甲基烯丙基)环辛-1,5-二烯钌(底物用量的5mol％)和(S,S)-iPrDuPhos(底物用量的5.5mol％)，氮气置换后加入有机溶剂(1.0mL)和氟硼酸(底物用量的10mol％)，室温搅拌0.5小时；然后用有机溶剂(1.0mL)将此溶液转到预先放有芳基胺底物1(0.2mmol)的反应瓶中，移至反应釜中，通入氢气(1000psi)，30℃下反应24小时；释放氢气，除去溶剂后直接柱层析分离得到纯的产物，反应式如下：
Figure BDA0001424137610000052
产率为分离收率，产物的对映体过量用手性液相色谱测定，见表2。
表2.钌催化不对称氢化合成手性三级胺2a
Figure BDA0001424137610000053
Figure BDA0001424137610000061
实施例3：二取代底物氢化反应条件的优化
在反应瓶中投入双-(2-甲基烯丙基)环辛-1,5-二烯钌(底物用量的5mol％)和手性双膦配体(底物用量的5.5mol％)，氮气置换后加入有机溶剂(1.0mL)和氟硼酸(底物用量的10mol％)，室温搅拌0.5小时；然后用有机溶剂(1.0mL)将此溶液转到预先放有芳基胺底物3e(0.1mmol)的反应瓶中，移至反应釜中，通入氢气(1000psi)，30℃下反应24小时；释放氢气，除去溶剂后直接柱层析分离得到纯的产物，反应式如下：
Figure BDA0001424137610000062
产率为转化率，产物的对映体过量用手性液相色谱测定，见表3。
表3.N-乙酰基-10-甲基-9-菲胺3e的不对称氢化条件优化a
Figure BDA0001424137610000063
Figure BDA0001424137610000071
实施例4：钌催化不对称氢化合成手性三级胺4
在反应瓶中投入双-(2-甲基烯丙基)环辛-1,5-二烯钌(底物用量的5mol％)和L8(底物用量的5.5mol％)，氮气置换后加入异丙醇(2.0mL)和氟硼酸(底物用量的10mol％)，室温搅拌0.5小时；然后用异丙醇(2.0mL)将此溶液转到预先放有芳基胺底物3(0.2mmol)的反应瓶中，移至反应釜中，通入氢气(1000psi)，30℃下反应24小时；释放氢气，除去溶剂后直接柱层析分离得到纯的产物，反应式如下：
Figure BDA0001424137610000072
产率为分离收率，产物的对映体过量用手性液相色谱测定，见表4。
表4.钌催化不对称氢化合成手性三级胺4a
Figure BDA0001424137610000073
(S)-N-(9,10-Dihydrophenanthren-9-yl)acetamide(2a):45mg,95％yield,93％ee,[α]20 D＝-164.87(c 0.84,CHCl3),unknown compound,white solid,m.p.＝179-180℃,Rf＝0.50(diethyl ether).1H NMR(400MHz,
Figure BDA0001424137610000081
＝0.7 mL/min,retention time 18.0 min and 22.2 min(maj).HRMS Calculated forC16H16NO[M+H]+238.1226,found 238.1229.
(S)-N-(9,10-Dihydrophenanthren-9-yl)propionamide(2b):48 mg,95％yield,90％ee,[α]20 D＝-150.10
Figure BDA0001424137610000082
133.8,133.6,133.6,129.8,128.9,128.4,128.4,128.2,127.8,124.3,124.0,47.2,35.2,29.9,9.9.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 10.7 min and 13.6 min(maj).HRMS Calculatedfor C17H18NO[M+H]+252.1383,found 252.1381.
(S)-N-(9,10-Dihydrophenanthren-9-yl)pentanamide(2c):50 mg,89％yield,88％ee,[α]20 D＝-116.87(c0.80,CHCl3),unknown compound,white solid,m.p.＝105-106℃,Rf＝0.40(petroleum ether/diethyl
Figure BDA0001424137610000083
124.0,47.3,36.8,35.2,27.9,22.5,13.9.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 11.1 min and 16.6min(maj).HRMS Calculated for C19H22NO[M+H]+280.1696,found 280.1696.
(S)-N-(9,10-Dihydrophenanthren-9-yl)pivalamide(2d):23 mg,41％yield,75％ee,[α]20 D＝-59.11(c0.34,CHCl3),unknown compound,colorless oil,Rf＝0.50(petroleum ether/dichloromethane 1/1).1H NMR(400
Figure BDA0001424137610000084
n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 5.6 min and 6.1min(maj).HRMS Calculated for C19H22NO[M+H]+280.1696,found 280.1697.
(S)-N-(9,10-Dihydrophenanthren-9-yl)benzamide(2e):58 mg,97％yield,79％ee,[α]20 D＝-92.55(c0.94,CHCl3),unknown compound,white solid,m.p.＝194-195℃,Rf＝0.50(petroleum ether/dichloromethane
Figure BDA0001424137610000085
35.3.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 13.5 min and 16.9 min(maj).HRMS Calculated forC21H18NO[M+H]+300.1383,found 300.1384.
(S)-N-(9,10-Dihydrophenanthren-9-yl)-4-methylbenzamide(2f):53 mg,85％yield,82％ee,[α]20 D＝-95.81(c0.86,CHCl3),unknown compound,white solid,m.p.＝212-213℃,Rf＝0.50(petroleumether/dichloromethane 1/1).1H NMR(400 MHz,CDCl3)δ7.83(t,J＝6.8 Hz,2H),7.57-7.47(m,3H),
Figure BDA0001424137610000091
n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 19.7 min and 25.5min(maj).HRMS Calculated for C22H20NO[M+H]+314.1539,found 314.1535.
(S)-N-(7-Methyl-9,10-dihydrophenanthren-9-yl)acetamide(2g):48 mg,95％yield,94％ee,[α]20 D＝-143.85(c 0.88,CHCl3),unknown compound,white solid,m.p.＝201-202℃,Rf＝0.20(petroleum
Figure BDA0001424137610000092
124.2,123.7,47.4,35.2,23.7,21.4.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 14.8 min and 19.5min(maj).HRMS Calculated for C17H18NO[M+H]+252.1383,found 252.1383.
(S)-N-(7-Methoxy-9,10-dihydrophenanthren-9-yl)acetamide(2h):52 mg,97％yield,97％ee,[α]20 D＝-144.89(c 0.98,CHCl3),unknown compound,white solid,m.p.＝179-180℃,Rf＝0.20(petroleum
Figure BDA0001424137610000093
35.3,23.7.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 19.7 min and 35.1 min(maj).HRMS Calculatedfor C17H18NO2[M+H]+268.1332,found 268.1336.
(S)-N-(7-Fluoro-9,10-dihydrophenanthren-9-yl)acetamide(2i):46 mg,90％yield,94％ee,[α]20 D＝-145.10(c 0.92,CHCl3),unknown compound,white solid,m.p.＝225-226 ℃,Rf＝0.30(petroleum ether/diethyl
Figure BDA0001424137610000094
(d,J＝8.1 Hz),123.8,115.7(d,J＝21.5 Hz),114.9(d,J＝22.0 Hz),47.3,35.1,23.6；19FNMR(376 MHz,CDCl3)δ-113.4.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7mL/min,retention time 14.5 min and 18.0 min(maj).HRMS Calculated for C16H15FNO[M+H]+256.1132,found 256.1130.
(S)-N-(1-Methyl-9,10-dihydrophenanthren-9-yl)acetamide(2j):48 mg,95％yield,85％ee,[α]20 D＝-134.68(c 0.96,CHCl3),unknown compound,white solid,m.p.＝192-193 ℃,Rf＝0.20(petroleum ether/diethyl
Figure BDA0001424137610000095
132.0,130.2,128.9,128.2,128.0,127.1,124.6,121.9,47.2,31.2,23.7,20.1.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 9.4 min and 14.5 min(maj).HRMS Calculated for C17H18NO[M+H]+252.1383,found252.138.
(S)-N-(2-Methyl-9,10-dihydrophenanthren-9-yl)acetamide(2k):45 mg,89％yield,
Figure BDA0001424137610000101
1H),3.15-2.95(m,2H),2.37(s,3H),1.87(s,3H)；13C NMR(100 MHz,CDCl3)δ169.5,138.2,135.7,133.8,133.4,130.8,130.6,128.9,128.5,128.5,127.9,123.9,123.9,47.4,35.1,23.7,21.4.HPLC:Chiralcel AS-Hcolumn,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 13.9 min and 21.5min(maj).HRMS Calculated forC17H18NO[M+H]+252.1383,found 252.1383.
(S)-N-(3-Methyl-9,10-dihydrophenanthren-9-yl)acetamide(2l):47 mg,93％yield,93％ee,[α]20 D＝-154.56(c 0.94,CHCl3),unknown compound,white solid,m.p.＝165-166 ℃,Rf＝0.20
Figure BDA0001424137610000102
128.9,128.8,128.4,128.2,124.6,124.1,47.5,34.7,23.6,21.6.HPLC:Chiralcel AS-Hcolumn,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retentiontime 18.2 min and 22.2 min(maj).HRMS Calculated for C17H18NO[M+H]+252.1383,found 252.1386.
N-((9S,10R)-10-Methoxy-9,10-dihydrophenanthren-9-yl)acetamide(4a):53mg,99％yield,93％ee,d.r.>20:1,[α]20 D＝-91.03(c1.06,CHCl3),unknown compound,white solid,m.p.＝171-172℃,Rf＝0.50(diethyl
Figure BDA0001424137610000103
50.7,23.7.HPLC:Chiralcel IC-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 11.8 min(maj)and 27.1 min.HRMS Calculated forC17H18NO2[M+H]+268.1332,found 268.1331.
N-((9S,10R)-10-Methoxy-7-methyl-9,10-dihydrophenanthren-9-yl)acetamide(4b):52 mg,92％yield,93％ee,d.r.>20:1,[α]20 D＝-64.03(c1.04,CHCl3),unknown compound,white solid,m.p.＝147-148 ℃,Rf＝0.50
Figure BDA0001424137610000104
30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 10.5 min(maj)and 26.7 min.HRMS Calculated for C18H20NO2[M+H]+282.1489,found 282.1490.
N-((9S,10R)-7,10-Dimethoxy-9,10-dihydrophenanthren-9-yl)acetamide(4c):59 mg,99％yield,94％ee,
Figure BDA0001424137610000105
133.6,131.4,129.8,129.5,126.6,125.8,125.4,123.8,113.1,112.5,79.5,56.5,55.5,50.8,23.6.HPLC:Chiralcel IC-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 17.9 min(maj)and 30.8 min.HRMS Calculated forC18H20NO3[M+H]+298.1438,found 298.1436.
N-((9S,10R)-7-Fluoro-10-methoxy-9,10-dihydrophenanthren-9-yl)acetamide(4d):55 mg,96％yield,92％ee,d.r.>20:1,[α]20 D＝-109.27(c1.10,CHCl3),unknown compound,white solid,m.p.＝196-197 ℃,Rf＝
Figure BDA0001424137610000111
131.6,130.1,129.9,129.2,127.4,125.9(d,J＝8.2 Hz),124.4,114.9(d,J＝21.6 Hz),113.6(d,J＝23.3 Hz),79.3,56.4,51.0,23.6；19F NMR(376 MHz,CDCl3)δ-113.1.HPLC:Chiralcel IC-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 10.5 min(maj)and 13.1 min.HRMS Calculated for C17H17FNO2[M+H]+286.1238,found 286.1239.
N-((9R,10R)-10-Methyl-9,10-dihydrophenanthren-9-yl)acetamide(4e):48mg,95％yield,83％ee,d.r.>20:1,[α]20 D＝+122.93(c 0.92,CHCl3),unknown compound,white solid,m.p.＝180-181 ℃,Rf＝0.60
Figure BDA0001424137610000112
254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 10.0min(maj)and 21.7min.HRMS Calculated for C17H18NO[M+H]+252.1383,found 252.1382.
N-((9R,10R)-10-Ethyl-9,10-dihydrophenanthren-9-yl)acetamide(4f):50mg,94％yield,82％ee,d.r.>20:1,[α]20 D＝+43.00(c 1.00,CHCl3),unknown compound,white solid,m.p.＝180-181 ℃,Rf＝0.50(diethyl
Figure BDA0001424137610000113
20.7,12.1.HPLC:Chiralcel AS-H column,254 nm,30 ℃,n-hexane/i-propanol＝70/30,flow＝0.7 mL/min,retention time 9.7 min(maj)and 23.7 min.HRMS Calculated forC18H20NO[M+H]+266.1539,found 266.1539.

Claims (10)

1.一种钌催化9-酰胺菲化合物的不对称氢化合成手性三级胺的方法，催化体系为钌的手性双膦P-P*配合物，其特征在于：
Figure 68280DEST_PATH_IMAGE001
式中：
R为C1-C4的烷基或芳基；R’为甲基、乙基和甲氧基中的一种或两种以上；R1为甲基、甲氧基中的一种或两种以上；R2为甲基、甲氧基和F中的一种或两种以上；
反应所用的有机溶剂选自二氯甲烷、1,2-二氯乙烷、甲醇、乙醇、异丙醇、乙酸乙酯和四氢呋喃中的一种；
所述双膦配体选自下列化合物中的一种：
Figure 554756DEST_PATH_IMAGE002
Figure 268896DEST_PATH_IMAGE003
Figure 191721DEST_PATH_IMAGE004
；
反应压力为10-1000 psi，反应温度为0 - 80 oC。
2.如权利要求1所述的方法，其特征在于：氢化反应包括催化剂制备和底物氢化两个阶段：（1）催化剂制备，将钌金属前体和手性双膦配体，氟硼酸加入有机溶剂后反应得到；（2）氢化反应，将催化剂和有机溶剂加入9-酰胺菲底物中，通入氢气反应得到产物。
3.如权利要求1或2所述的方法，其特征在于：所述催化剂为钌的金属前体和双膦配体的配合物，钌的金属前体及双膦配体均为市售且无需任何处理。
4.如权利要求2所述的合成方法，其特征在于：反应所用的有机溶剂为乙酸乙酯或异丙醇中的一种。
5.如权利要求4所述的合成方法，其特征在于：反应所用的有机溶剂为甲醇、乙醇或1,2-二氯乙烷中的一种。
6.如权利要求1或2所述的方法，其特征在于：所述钌金属前体选自双-（2-甲基烯丙基）环辛-1,5-二烯钌。
7.如权利要求1或2所述的方法，其特征在于：所述双膦配体选自
Figure 804669DEST_PATH_IMAGE005
或
Figure 598181DEST_PATH_IMAGE003
。
8.如权利要求1或2所述的方法，其特征在于：催化剂的制备过程物料配比为：钌的金属前体、手性双膦配体、氟硼酸、底物摩尔比为：0.02-0.05：0.022-0.055：0.04-0.10：1。
9.如权利要求1或2所述的方法，其特征在于：反应压力为600 psi - 1000 psi，反应温度为30 -60 oC。
10.如权利要求1或2所述的方法，其特征在于：底物摩尔浓度0.025-0.1。
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