陈永正，崔宝东，白 玫,，袁伟成

(1.遵义医学院 药学院,贵州 遵义 563000；2.中国科学院 成都有机化学研究所，四川 成都 610041；3.中国科学院大学，北京 100039)

·研究简报·

手性螺[(吡唑啉-5-酮)-4，4′-环己酮]的合成*

陈永正1，崔宝东2,3，白 玫1,2,3，袁伟成2

(1.遵义医学院 药学院,贵州 遵义 563000；2.中国科学院 成都有机化学研究所，四川 成都 610041；3.中国科学院大学，北京 100039)

以9-氨基-9-脱氧奎尼丁为催化剂，三氟乙酸为添加剂，乙腈为溶剂,吡唑啉-5-酮与1,5-二取代戊二烯-3-酮经不对称双Michael加成反应合成了一系列手性的螺[(吡唑啉-5-酮)-4，4′-环己酮]，收率42%～71%，72%ee～97%ee，其结构经1H NMR，13C NMR和HR-ESI-MS确证。

Michael加成；有机催化；螺[(吡唑啉-5-酮)-4,4′-环己酮]吡唑啉-5-酮；二烯酮；不对称合成

近年来，含杂环的螺环环己酮类化合物的合成倍受关注[1-2]。1-苯基-3-甲基-5-吡唑啉酮(2)是一类重要的杂环化合物，具有独特的生物与药理活性[3]，但用于催化不对称Michael加成反应较少[4-5,8]。二烯酮作为受体参与的不对称双Michael加成反应已有文献报道[6-8]。

我们预测2能够与二烯酮发生双Michael加成反应，得到同时含有环己酮与吡唑啉酮结构单元的螺环化合物。为此,本文以9-氨基-9-脱氧奎尼丁(Ⅰ，Chart 1)为催化剂，三氟乙酸(TFA)为添加剂，在乙腈中成功实现了2与1,5-二取代戊二烯-3-酮(1a～1j)的不对称双Michael加成反应，构建了一系列手性的螺[(吡唑啉-5-酮)-4，4′-环己酮]化合物(3a～3j，Scheme 1)，收率42%～71%，72%ee～97%ee，其结构经1H NMR，13C NMR和HR-ESI-MS确证。

表1 3a～3j的实验结果Table1 Experimental results of 3a～3j

1 实验部分

1．1 仪器与试剂

Bruker-300型核磁共振仪(CDCl3为溶剂，TMS为内标)；BioTOF Q型质谱分析仪；岛津高效液相色谱仪[HPLC:Chiralpak OD-H,V(异丙醇)∶V(正己烷)=30∶70,流速1.0mL·min-1,λ=254nm]。

所用试剂均为分析纯。

1.23a～3j的合成通法

向硬质反应管中加入10.18mmol(1.2eq.)，Ⅰ．20mol%(0.2eq.),TFA 50mol%(0.5eq.)及乙腈1mL[3b用THF(1mL)为溶剂，3j用1,2-二氯乙烷(1mL)作溶剂]，搅拌下于室温反应15min。加入226.1mg(0.15mmol)，于室温反应96h。真空蒸出溶剂后经硅胶柱层析[梯度洗脱剂：V(乙酸乙酯)∶V(石油醚)=1∶10～1∶5]纯化得棕红色油状物3a～3d,3f～3j和白色固体3e。

3a{4-甲基-2，6，10-三苯基-2，3-二氮杂螺[4．5]癸-3-烯-1，8-二酮}:1H NMRδ：1.67(s,3H),2.65(dd,J=2.7Hz,15.9Hz,1H),2.98(dd,J=9.6Hz,16.2Hz,1H),3.38(dd,J=5.1Hz,16.5Hz,1H),3.66(dd,J=3.0Hz,14.4Hz,1H),3.83～3.93(m,2H),7.13～7.20(m,8H),7.29～7.34(m,5H),7.47(d,J=8.1Hz,2H);13C NMR(75MHz，下同)δ：15.6,40.5,41.2,42.3,44.1,61.7,119.7,125.5,127.5,127.6,127.9,128.0,128.5,128.6,128.9,136.5,137.1,138.4,160.5,174.7,209.2;HR-ESI-MSm/z:Calcd for C27H24N2O2Na{[M+Na]+}431.1754,found 431.1736。

3b:1H NMRδ：1.63(s,3H),2.20(s,3H),2.33(s,3H),2.62(dd,J=3.0Hz,15.9Hz,1H),2.91(dd,J=8.7Hz,16.2Hz,1H),3.40(dd,J=5.4Hz,16.2Hz,1H),3.64(dd,J=3.0Hz,14.1Hz,1H),3.80～3.90(m,2H),6.98～7.05(m,6H),7.11(d,J= 8.1Hz,2H),7.18(d,J=7.5Hz,1H),7.31～7.36(m,2H),7.51～7.54(m,2H);13C NMRδ：15.7,20.9,21.0,40.7,41.6,42.1,44.1,61.8,119.8,125.5,127.5,127.6,128.7,129.3,129.5,133.7,135.6,137.2,137.7,137.8,160.9,175.0,209.6;HR-ESI-MSm/z:Calcd for C29H28N2O2Na{[M+Na]+}459.2043,found 459.2051。

3c:1H NMRδ：1.67(s,3H),2.60(dd,J=3.0Hz,15.9Hz,1H),2.90(dd,J=9.0Hz,16.2Hz,1H),3.36(dd,J=5.1Hz,16.2Hz,1H),3.61(dd,J=3.0Hz,14.4Hz,1H),3.67(s,3H),3.78(s,3H),3.82～3.88(m,2H),6.71(d,J=8.7Hz,2H),6.82(d,J=8.7Hz,2H),7.02～7.07(m,4H),7.16～7.18(m,1H),7.30～7.35(m,2H),7.51～7.54(m,2H);13C NMRδ：15.7,40.8,41.6,41.7,43.6,55.1,55.2,62.0,113.9,114.2,119.7,125.5,128.6,128.7,130.6,137.2,159.1,159.2,160.9,175.0,209.5;HR-ESI-MSm/z:Calcd for C29H28N2O4Na{[M+Na]+}491.1941,found 491.1942。

3d:1H NMRδ：1.67(s,3H),2.64(dd,J=2.1Hz,15.9Hz,1H),2.93(dd,J=9.0Hz,16.2Hz,1H),3.38(dd,J=5.1Hz,16.2Hz,1H),3.62(m,3H),3.67(m,3H),3.77～3.89(m,3H),6.63(s,1H),6.68～6.73(m,4H),6.83(d,J=8.1Hz,1H),7.07～7.23(m,3H),7.30～7.35(m,2H),7.56(d,J=7.8Hz,2H);13C NMRδ：15.7,40.6,41.4,42.6,44.4,55.0,55.1,61.6,113.2,113.4,113.6,119.6,119.8,120.0,125.5,128.7,129.6,129.9,137.3,138.2,140.1,159.6,159.9,160.7,174.9,209.1；HR-ESI-MSm/z:Calcd for C29H28N2O4Na{[M+Na]+}491.1941,found 491.1936。

3e:1H NMRδ：1.39(s,3H),2.42～2.52(m,1H),3.03(dd,J=9.0Hz,15.3Hz,1H),3.30(dd,J=4.5Hz,15.6Hz,1H),3.52(s,3H),3.69(s,3H),3.75～3.85(m,1H),4.11～4.15(m,1H),4.48～4.56(m,1H),6.72(d,J=7.5Hz,2H),6.79(d,J=7.8Hz,1H),6.97～7.14(m,3H),7.21～7.33(m,5H),7.71(d,J=7.5Hz,2H);13C NMRδ：14.9,33.7,37.9,40.9,54.5,54.9,60.2,110.1,110.2,118.7,120.3,120.6,124.6,125.5,127.6,128.0,128.4,128.7,128.9,137.7,155.9,157.1,161.8,175.6;HR-ESI-MSm/z:Calcd for C29H28N2O4Na{[M+Na]+}491.1941,found 491.1942。

3f:1H NMRδ：1.76(s,3H),2.63(dd,J=2.7Hz,16.2Hz,1H),2.96(dd,J=10.2Hz,16.5Hz,1H),3.28(dd,J=4.8Hz,16.5Hz,1H),3.59(dd,J=2.7Hz,14.4Hz,1H),3.77～3.87(m,1H),3.89～3.94(m,1H),6.98～7.04(m,2H),7.12～7.15(m,5H),7.19(d,J=7.5Hz,2H),7.24～7.36(m,2H),7.46(d,J=7.5Hz,2H);13C NMRδ：15.7,40.1,40.7,42.0,43.4,61.5,119.9,125.6,125.8,125.9,127.6,128.0,128.3,128.4,128.8,129.9,130.2,134.4,134.9,136.7,138.2,140.1,159.7,174.3,207.9;HR-ESI-MSm/z:Calcd for C27H22N2O2Cl2Na{[M+Na]+}499.0951,found 499.0938。

3g:1H NMRδ：1.75(s,3H),2.63(dd,J=2.4Hz,16.2Hz,1H),2.96(dd,J=10.2Hz,16.5Hz,1H),3.29(dd,J=4.8Hz,16.5Hz,1H),3.57(dd,J=2.7Hz,14.4Hz,1H),3.76～3.86(m,1H),3.87～3.92(m,1H),7.02～7.08(m,3H),7.16～7.21(m,2H),7.31～7.37(m,5H),7.43～7.48(m,3H);13C NMRδ：15.7,40.1,40.7,42.0,43.4,61.5,120.0,122.6,123.1,125.9,126.0,126.3,128.8,130.2,130.5,130.6,130.9,131.3,131.4,136.7,138.4,140.4,159.7,174.3,207.8;HR-ESI-MSm/z:Calcd for C27H22N2O2Br2Na{[M+Na]+}586.9940,found 586.9946。

3h:1H NMRδ：1.77(s,3H),2.64(dd,J=2.7HZ,16.2Hz,1H),2.98(dd,J=10.2Hz,16.5Hz,1H),3.29(dd,J=4.8Hz,16.5Hz,1H),3.63(dd,J=2.7Hz,14.4Hz,1H),3.78～3.88(m,1H),3.91～3.96(m,1H),6.83～6.94(m,5H),6.97～7.03(m,1H),7.17～7.21(m,2H),7.24～7.35(m,3H),7.47(d,J=7.8Hz,2H);13C NMRδ：15.6,40.2,40.8,42.0,43.5,61.6,114.4,114.7,115.0，115.1(d,J=4.3Hz,1C),115.3(d,J=4.7Hz,1C),119.7,123.3(d,J=2.9Hz,1C),123.4(d,J=2.9Hz,1C),125.8,128.8,130.2(d,J=8.3Hz,1C),130.6(d,J=8.3Hz,1C),136.8,138.7(d,J=6.8Hz,1C),140.6(d,J=6.8Hz,1C),159.8,162.5(d,J=245.8Hz,1C),162.8(d,J=246.5Hz,1C),174.3,208.0;HR-ESI-MSm/z:Calcd for C27H22N2O2F2Na{[M+Na]+}467.1542,found 467.1540。

3i:1H NMRδ：1.76(s,3H),2.62(dd,J=2.7Hz,16.2Hz,1H),2.98(dd,J=10.5Hz,16.5Hz,1H),3.28(dd,J=4.8Hz,16.5Hz,1H),3.61(dd,J=2.7Hz,14.4Hz,1H),3.77～3.88(m,1H),3.90～3.95(m,1H),6.87～6.90(m,2H),6.97～7.03(m,2H),7.07～7.17(m,5H),7.30～7.35(m,2H),7.46(d,J=8.4Hz,2H);13C NMRδ：15.7,40.5,41.1,41.6,43.2,62.0,115.5(d,J=21.4Hz,1C),115.9(d,J=21.3Hz,1C),125.8,128.8,129.1(d,J=8.0Hz,1C),129.4(d,J=8.1Hz,1C),132.1(d,J=3.3Hz,1C),134.0(d,J=3.4,Hz,1C),136.9,162.0(d,J=293.2Hz,1C),162.3(d,J=246.4Hz,1C),174.6,208.4;HR-ESI-MSm/z:Calcd for C27H22N2O2F2Na{[M+Na]+}467.1542,found 467.1549。

3j:1H NMRδ：1.67(s,3H),2.73～2.80(m,2H),3.65(dd,J=5.7Hz,15.6Hz,1H),3.76～3.86(m,1H ),4.07～4.17(m,2H),6.83～6.89(m,3H),6.97～6.99(m,1H),7.08(d,J=5.1Hz,1H),7.19～7.25(m,2H),7.34～7.39(m,2H),7.69(d,J=7.8Hz,2H);13C NMRδ：15.3,38.4,40.8,41.9,43.2,61.2,119.6,124.7,125.1,125.5,125.6,126.0,126.9,127.2,128.8,137.3,139.6,141.4,160.7,173.8,207.1;HR-ESI-MSm/z:Calcd for C23H20N2O2S2Na{[M+Na]+}443.0858,found 443.0870。

2 结果与讨论

2．1 底物的适用性

从Scheme 1可见，该反应体系适用于芳香环上含有各种取代基团的二烯酮底物。无论是给电子基团还是吸电子基团取代以及不同位置取代的底物都能很好的与2反应，得到较好收率与高选择性的产物3。此外,当二烯酮的芳香环由苯基取代换为2-噻吩基团取代(2j)时，反应也能很好的进行，得到中等收率以及高达82%ee值的螺环化合物3j。

2．2 反应机理

[6]，本文提出了合成3的分步反应机理(Scheme 2)。首先，在酸性条件下，1a～1j与Ⅰ形成亚胺正离子中间体A，从而增加了1a～1j的亲电活性。2在催化剂叔胺部分的作用下失去质子并以烯醇负离子的形式与催化剂的叔胺部分形成氢键，从而得到中间体B；此时，被活化了的2与1的一个双键发生第一次Michael加成反应生成中间体C；紧接着，在催化剂的促进下，吡唑啉-5-酮负离子与2的另一个双键发生第二次Michael加成反应生成3a～3j。

Scheme 2

3 结论

以9-氨基-9-脱氧奎尼丁为催化剂，三氟乙酸为添加剂，实现了吡唑啉-5-酮与二烯酮的不对称双Michael加成反应。该方法适用于含不同取代基团的二烯酮底物，以较好收率、高非对映选择性以及高对映选择性的得到螺环产物，为手性螺[(吡唑啉-5-酮)-4，4′-环己酮]化合物的合成提供了一种新的方法。

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SynthesisofChiralSpiro[(pyrazolin-5-one)-4,4′-cyclohexanones]

CHEN Yong-zheng1, CUI Bao-dong2,3, BAI Mei1,2,3, YUAN Wei-cheng2

(1.School of Pharmacy,Zunyi Medical University,Zunyi 563000,China;2.Chengdu Institute of Organic Chemistry,Chinese Academy of Sciences,Chengdu 610041,China;3.University of Chinese Academy of Sciences,Beijing 100039,China)

A series of chiral spiro[(pyrazolin-5-one)-4,4′-cyclohexanones] in yield of 42%～71% with 72%ee～97%eewere synthesized by an asymmetric double Michael addition of pyrazolin-5-one with 1,5-disubstituted-pentylene-3-one using 9-amino-9-deoxyepiquinidine as the catalyst,trifluoroacetic acid as the additive and acetonitrile as the solvent.The structures were confirmed by1H NMR，13C NMR and HR-ESI-MS.

Michael addition;organocatalysis;spiro[(pyrazolin-5-one)-4,4′-cyclohexanone];dienone;asymmetric synthesis

2014-01-06；

2014-04-16

国家自然科学基金资助项目(21372217)；贵州省科学技术基金资助项目{黔科合J字LKZ[2013]27号}；遵义医学院博士启动基金资助项目(F-563)

陈永正(1982-)，男，汉族，贵州遵义人，博士，副教授，硕士生导师，主要从事不对称合成的研究。E-mail:yzchen@zmc.edu.cn

袁伟成，研究员，博士生导师，E-mail:yuanwc@cioc.ac.cn

O626．21；O643．36

A

1005-1511(2014)04-0544-04