蒲 健,汪軍鑫,韋芳芳,劉雄利,譚 丹*

(1.貴州益佰制藥股份有限公司，貴州 貴陽 550025；2.貴州大學(xué) 貴州省藥食同源植物資源開發(fā)工程技術(shù)研究中心，貴州 貴陽 550025)

幾十年來，由于具有多種生物活性，色酮類化合物一直受到人們的關(guān)注[1-3]。因此，開發(fā)有效的方法來獲取結(jié)構(gòu)多樣的色酮衍生物無疑在有機合成中具有吸引力。另一方面，吡唑啉酮[4-6]和查爾酮衍生物[7-9]也是一類重要的具有多種生物活性的生物活性分子。因此，開發(fā)高效的含吡唑啉酮和查爾酮骨架的色酮類衍生物的方法也具有重要意義。

最近，色酮-吡唑啉酮合成子[10]為本課題組開發(fā)的新的高效的合成子，用于生物重要的吡唑啉酮色酮衍生物的多樣性導(dǎo)向合成[11-14]。鑒于色酮、吡唑啉酮和二氫查爾酮的相關(guān)性，預(yù)期將3個結(jié)構(gòu)基元結(jié)合到一個分子中可以得到新的具有潛在的生物學(xué)特性化合物[15-16]。本文以色酮-吡唑啉酮合成子1為原料,在三級胺DABCO催化下，第一次與查爾酮發(fā)生Michael加成反應(yīng),獲得了10個新型色酮吡唑啉酮骨架拼接二氫查爾酮類化合物3a～3j，產(chǎn)率79%～90%，dr值6/1～10/1,其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-MS(ESI-TOF)表征，化合物3b的相對構(gòu)型通過單晶進一步進行了確定。該類化合物含有連續(xù)兩個立體中心，包括一個季碳中心，可以為生物活性篩選提供物質(zhì)基礎(chǔ)。

Scheme 1

1 實驗部分

1.1 儀器與試劑

WRS-1B型數(shù)字熔點儀；Bruker-400 MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo));MicroTMQ-TOF型高分辨質(zhì)譜儀。

所用試劑均為分析純。

1.2 3a～3j的合成(以3a為例)

依次加入吡唑啉酮-色酮合成子1a(0.10 mmol)，查爾酮2a(0.12 mmol)，DABCO(10 mol%，0.01 mmol) 和2.0 mL氯仿，攪拌下反應(yīng)4 d(TLC檢測)。經(jīng)硅膠柱層析[洗脫劑：V(石油醚)/V(乙酸乙酯)=4/1]純化得化合物3a。

用類似的方法合成3b～3j。

3a:白色固體,產(chǎn)率87%,m.p.202.3～203.1 ℃;dr10/1;1H NMRδ:2.29～2.34(m,4H),2.93～2.98(m,1H),3.34(d,J=13.6 Hz,1H),3.65～3.72(m,1H),3.95～3.98(m,1H),7.07～7.10(m,1H),7.13～7.16(m,1H),7.21～7.32(m,8H),7.41～7.47(m,3H),7.57～7.59(m,2H),7.66～7.74(m,4H);13C NMRδ:14.1,27.0,38.3,43.6,61.8,109.7(d,JCF=24.3 Hz),116.6,118.3,119.2,119.3,120.9(d,JCF=25.1 Hz),123.5,124.5,126.7,127.0,127.2,127.6,127.8,129.0,132.3,135.6,136.2,136.6,151.3,154.3,158.6(d,JCF=247.2 Hz),161.9,173.2,175.0,195.7;HR-MS(ESI-TOF)m/z:Calcd for C35H27N2O4FNa{[M+Na]+}581.1847,found 581.1853。

3b:白色固體,產(chǎn)率83%,m.p.182.8～183.6 ℃;dr10/1;1H NMRδ:2.25(d,J=14.0 Hz,1H),2.32(s,3H),2.87～2.91(m,1H),3.32(d,J=13.6 Hz,1H),3.58～3.65(m,1H),3.90～3.94(m,1H),7.09～7.12(m,1H),7.18～7.39(m,10H),7.42～7.46(m,1H),7.49～7.54(m,1H),7.58～7.61(m,2H),7.65(s,1H),7.70～7.73(m,2H),8.06～8.08(m,1H);13C NMRδ:14.0,27.1,38.2,42.9,61.5,117.0,117.1,118.3,120.8,122.3,124.2,124.6,124.9,127.0,127.7,127.9,130.3,130.8,132.5,132.7,135.4,135.7,136.2,154.1,155.1,161.8,173.1,175.6,195.4;HR-MS(ESI-TOF)m/z:Calcd for C35H27N2O4BrNa{[M+Na]+}641.1046,found 641.1051。

3c:白色固體,產(chǎn)率90%,m.p.140.5～141.3 ℃;dr10/1;1H NMRδ:2.26(d,J=13.6 Hz,1H),2.32(s,3H),2.89～2.94(m,1H),3.33(d,J=14.0 Hz,1H),3.58～3.65(m,1H),3.90～3.94(m,1H),7.08～7.12(m,2H),7.19～7.33(m,7H),7.43～7.46(m,2H),7.49～7.54(m,1H),7.60(d,J=7.6 Hz,2H),7.67(d,J=7.6 Hz,2H),7.72～7.74(m,2H),8.06～8.08(m,1H);13C NMRδ:14.0,27.1,38.4,43.1,61.5,117.0,117.1,118.3,121.3,122.4,124.2,124.6,124.9,127.0,127.7,127.9,128.7,129.9,132.1,132.5,132.7,135.4,136.2,139.2,154.1,155.1,161.7,173.1,175.6,195.3;HR-MS(ESI-TOF)m/z:Calcd for C35H27N2O4BrNa{[M+Na]+}641.1046,found 641.1047。

3d:白色固體,產(chǎn)率87%,m.p.189.9～190.5 ℃;dr8/1;1H NMRδ:2.28(d,J=14.0 Hz,1H),2.32(s,3H),2.88～2.93(m,1H),3.30(d,J=14.0 Hz,1H),3.58～3.65(m,1H),3.90～3.93(m,1H),7.08～7.12(m,2H),7.19(s,1H),7.23～7.34(m,7H),7.42～7.46(m,2H),7.59～7.61(m,2H),7.67～7.74(m,4H);13C NMRδ:13.9,27.1,38.3,43.0,61.5,109.7(d,JCF=24.3 Hz),116.4,118.3,119.2(d,JCF=8.1 Hz),121.0(d,JCF=26.0 Hz),121.3,123.4,123.5,124.6,127.0,127.7,127.9,128.7,129.9,132.1,132.5,135.3,136.1,139.1,151.3,154.4,158.2(d,JCF=236.3 Hz),161.7,173.0,174.9,195.3;HR-MS(ESI-TOF)m/z:Calcd for C35H26N2O4FBrNa{[M+Na]+}659.0952,found 659.0957。

3e:白色固體,產(chǎn)率89%,m.p.98.4～99.2 ℃;dr9/1;1H NMRδ:2.30(d,J=14.0 Hz,1H),2.34(s,3H),2.90～2.95(m,1H),3.35(d,J=14.0 Hz,1H),3.60～3.67(m,1H),3.95～3.98(m,1H),6.83～6.87(m,1H),7.08～7.12(m,1H),7.18～7.21(m,2H),7.24～7.33(m,7H),7.43～7.46(m,1H),7.50～7.54(m,1H),7.58(s,1H),7.60(s,1H),7.67(s,1H),7.72～7.74(m,2H),8.06～8.09(m,1H);13C NMRδ:14.0,27.0,38.4,43.2,61.6,113.7(d,JCF=21.4 Hz),115.9(d,JCF=21.3 Hz),117.0,117.1,118.3,122.4,124.2,124.5,124.9,127.0,127.7,127.9,128.6,129.9,132.5,132.7,135.4,136.2,154.1,155.1,161.4(d,JCF=257.0 Hz),161.7,173.1,175.6,195.4;HR-MS(ESI-TOF)m/z:Calcd for C35H27N2O4FNa{[M+Na]+}581.1847,found 581.1848。

3f:白色固體,產(chǎn)率83%,m.p.136.2～137.1 ℃;dr6/1;1H NMRδ:2.28(d,J=13.6 Hz,1H),2.34(s,3H),2.87～2.92(m,1H),3.48(d,J= 13.6 Hz,1H),3.64～3.71(m,1H),4.40～4.43(m,1H),6.98～7.12(m,3H),7.13～7.21(m,2H),7.25～7.33(m,5H),7.41～7.45(m,1H),7.48～7.52(m,1H),7.54～7.58(m,1H),7.62～7.65(m,3H),7.71～7.73(m,2H),8.05～8.08(m,1H);13C NMRδ:13.7,26.1,28.7,37.6,61.2,114.4(d,JCF=23.1 Hz),117.0,118.2,122.4,123.0,123.7,124.2,124.4,124.9,127.0,127.6,127.9,128.2,128.3,129.8(d,JCF=19.7 Hz),132.6,135.4,136.3,154.1,155.1,160.5(d,JCF=244.2 Hz),162.4,173.0,175.6,195.3;HR-MS(ESI-TOF)m/z:Calcd for C35H27N2O4FNa{[M+Na]+}581.1847,found 581.1850。

3g:白色固體,產(chǎn)率79%,m.p.210.3～211.2 ℃;dr9/1;1H NMRδ:2.26(d,J=13.6 Hz,1H),2.33(s,3H),2.88～2.93(m,1H),3.31(d,J=14.0 Hz,1H),3.59～3.66(m,1H),3.93～3.96(m,1H),6.89～6.94(m,2H),7.09～7.12(m,1H),7.18～7.20(m,2H),7.25～7.33(m,4H),7.43～7.47(m,3H),7.59(d,J=7.6 Hz,2H),7.65(s,1H),7.71～7.73(m,2H),8.03(d,J=2.8 Hz,1H);13C NMRδ:14.0,27.1,38.4,42.9,61.7,114.1(d,JCF=19.5 Hz),117.2,118.2,118.9,123.2,124.5(d,JCF=24.1 Hz),127.0,127.6,127.9,130.2,130.6,132.3,132.5,132.9,135.4,136.2,153.4,154.3,161.2(d,JCF=246.1 Hz),161.8,173.1,174.6,195.6;HR-MS(ESI-TOF)m/z:Calcd for C35H26N2O4ClFNa{[M+Na]+}615.1457,found 615.1453。

3h:白色固體,產(chǎn)率88%,m.p.78.4～79.2 ℃;dr7/1;1H NMRδ:2.11(s,3H),2.33(s,3H),2.87(d,J=14.0 Hz,1H),3.48(d,J=13.6 Hz,1H),3.92(d.J=6.8 Hz,2H),4.45～4.49(m,1H),6.75～6.78(m,1H),6.87～6.92(m,1H),6.98～7.04(m,1H),7.06～7.15(m,3H),7.23～7.27(m,2H),7.31～7.38(m,3H),7.45～7.51(m,3H),7.62～7.67(m,1H),7.77(s,1H),7.90～7.92(m,2H);13C NMRδ:13.1,18.2,19.9,26.5,36.7,61.4,114.7(d,JCF=24.3 Hz),116.8,116.9,118.7,122.1,123.3,124.3,124.6,127.1,127.6,127.8,128.1,129.9,132.3,133.9,134.3,135.7,136.2,153.4,153.7,159.5(d,JCF=237.1 Hz),162.0,173.8,175.5,196.4;HR-MS(ESI-TOF)m/z:Calcd for C36H29N2O4FNa{[M+Na]+}595.2004,found 595.2001。

3i:白色固體,產(chǎn)率84%,m.p.213.8～214.2 ℃;dr7/1;1H NMRδ:2.26(d,J=14.0 Hz,1H),2.32(s,3H),2.86～2.91(m,1H),3.30(d,J=14.0 Hz,1H),3.58～3.65(m,1H),3.92～3.95(m,1H),7.09～7.13(m,1H),7.19～7.34(m,8H),7.42～7.47(m,4H),7.59～7.61(m,2H),7.66(s,1H),7.69～7.73(m,2H);13C NMRδ:14.0,27.1,38.3,42.9,61.5,109.6(d,JCF=25.0 Hz),116.4,118.2,119.3,121.1(d,JCF=24.5 Hz),124.6,127.0,127.4,127.7,127.9,130.4,132.5,132.7,135.1,135.4,136.2,154.3,158.4(d,JCF=253.2 Hz),161.8,172.2,173.1,174.7,195.4;HR-MS(ESI-TOF)m/z:Calcd for C35H26N2O4ClFNa{[M+Na]+}615.1457,found 615.1458。

3j:白色固體,產(chǎn)率87%,m.p.200.4～201.2 ℃;dr8/1;1H NMRδ:2.25(d,J=14.0 Hz,1H),2.33(s,3H),2.34(s,3H),2.87～2.92(m,1H),3.34(d,J=14.0 Hz,1H),3.59～3.66(m,1H),3.91～3.95(m,1H),7.09～7.13(m,2H),7.19(s,1H),7.21(s,1H),7.25～7.33(m,5H),7.43(d,J=8.4 Hz,3H),7.58～7.63(m,3H),7.71～7.73(m,2H),7.85(s,1H);13C NMRδ:14.0,19.9,27.2,38.3,42.9,61.6,116.7,116.9,118.3,122.0,124.2,124.6,127.0,127.4,127.6,127.9,130.4,132.5,132.6,133.9,134.3,135.2,135.4,136.2,153.4,154.0,161.9,173.2,175.7,195.5;HR-MS(ESI-TOF)m/z:Calcd for C36H29N2O4ClNa{[M+Na]+}611.1708,found 611.1714。

2 結(jié)果與討論

2.1 合成

在該Michael加成環(huán)化反應(yīng)中,對反應(yīng)溶劑和催化劑進行了篩選，發(fā)現(xiàn)氯仿作溶劑，DABCO為堿，反應(yīng)4 d，產(chǎn)率能達到87%，dr值達到10/1。

對底物通過擴展，發(fā)現(xiàn)該反應(yīng)產(chǎn)率普遍較高，在溶劑氯仿中反應(yīng)4 d,TLC檢測基本反應(yīng)完全,目標(biāo)化合物3產(chǎn)率為79%～90%，dr值為6/1～10/1。

表1 反應(yīng)條件的優(yōu)化Table 1 Optimization of reaction conditions

2.2 化合物3b的單晶制備

在無水乙醇溶劑中對化合物3b進行了單晶培養(yǎng)，分析確證白色晶體3b(CCDC:1941654)的結(jié)構(gòu)。圖1 為化合物3b的單晶結(jié)構(gòu)圖。由圖1分析可知，化合物3b屬monoclinic晶系，P21/n空間群，晶胞參數(shù)a=10.0962(8) ?，b=25.9866(16) ?，c=11.1225(7) ?，α=90°，β=104.840(7)°，γ=90°。

Scheme 2

圖1化合物3b的單晶結(jié)構(gòu)Figure 1Single crystal structure of compound 3b

2.3 反應(yīng)機理

該反應(yīng)可能機理如Schem 2所示:色酮-吡唑啉酮合成子1在DABCO催化活化下，合成子1的3-位進攻發(fā)生查爾酮2的β-位，發(fā)生Michael加成反應(yīng),得目標(biāo)產(chǎn)物色酮吡唑啉酮骨架拼接二氫查爾酮類化合物3。

合成了10個新型色酮吡唑啉酮骨架拼接二氫查爾酮類化合物3a～3j，產(chǎn)率79%～90%，dr值為6/1～10/1。該類化合物包含色酮吡唑啉酮骨架和二氫查爾酮骨架，且含有連續(xù)兩個立體中心，包括一個季碳中心，可以為生物活性篩選提供物質(zhì)基礎(chǔ)。