氟化鈣催化的Biginelli反應(yīng)_一鍋法合成3_4_二氫嘧啶_2_酮

1、收稿日期:2009-11-26;*通訊聯(lián)系人.基金項(xiàng)目:國家自然科學(xué)基金(20562005和江西省自然科學(xué)基金(2008GZH0029資助項(xiàng)目.作者簡介:劉 園(1985-,女,江西南昌人,碩士研究生,主要從事有機(jī)合成研究.文章編號:1000-5862(201004-0374-06氟化鈣催化的Biginelli 反應(yīng)一鍋法合成3,4-二氫嘧啶-2-酮?jiǎng)?園1,2, 劉曉玲1*, 黃國文1, 王 清1(1.江西師范大學(xué)化學(xué)化工學(xué)院,江西南昌 330022;2.空軍總醫(yī)院藥學(xué)部,北京 100142摘要:在氟化鈣催化作用下,由醛、乙酰乙酸乙酯(或乙酰丙酮、脲(或硫脲3組份/一鍋法0合成了一系列3,4

2、-二氫嘧啶-2-酮衍生物.該法反應(yīng)條件溫和、反應(yīng)時(shí)間短、產(chǎn)率高,并且氟化鈣具有可重復(fù)使用的優(yōu)點(diǎn).關(guān)鍵詞:Biginelli 反應(yīng);3,4-二氫嘧啶-2-酮;氟化鈣;一鍋法中圖分類號:O 625.4 文獻(xiàn)標(biāo)識碼:A3,4-二氫嘧啶-2-酮及其衍生物由于具有抗病毒、抗腫瘤、抗菌、消炎等多種生理活性而成為生物活性有機(jī)雜環(huán)化合物研究的熱點(diǎn)之一1.Biginelli 反應(yīng)2是合成該類化合物常用、簡便的方法,但反應(yīng)時(shí)間長(18h、產(chǎn)率低(20%50%.近年來,人們對Biginelli 合成法進(jìn)行了廣泛的研究,如利用BF 3#Et 2O 3、H 2SO 4-SiO 24、LiBr 5、InX 3(X =Cl

3、,Br 6-7、FeCl 38、ZrCl 49、NH 4Cl 10、CdCl 211、Mg (ClO 4212、RuCl 313、NiCl 2#6H 2O 14、Cu(OTf315、Bi(OTf316-17、La(OTf318和離子液體19等為催化劑,或用微波促進(jìn)20等均能高產(chǎn)率地制得3,4-二氫嘧啶-2(1H -酮衍生物.但是,有的催化劑毒性較大、昂貴;有的催化劑需化學(xué)計(jì)量;有的反應(yīng)時(shí)間較長.因此,值得進(jìn)一步探索廉價(jià)易得、無毒、可循環(huán)使用的催化劑,能在溫和的反應(yīng)條件下促進(jìn)3,4-二氫嘧啶-2-酮衍生物合成的新方法.本文報(bào)道了氟化鈣催化醛、尿素(或硫脲和1,3-二羰基化合物3組份/一鍋法0合成

4、3,4-二氫嘧啶-2-酮衍生物的研究結(jié)果.合成路線如圖1所示.R 1C HO 1+H 2NXNH 22+O O R 23CaF 2EtO H,reflux,X=O,SN N H MeOR 2R 1H X4圖1 一鍋法合成3,4-二氫嘧啶-2-酮衍生物的路線圖1 實(shí)驗(yàn)部分1.1 主要試劑和測試儀器所有試劑均為市售A.R.或C.P.級試劑,乙酰乙酸乙酯、乙酰丙酮、脲、硫脲直接使用;液體醛在使用之前經(jīng)蒸餾提純;WC -1型顯微熔點(diǎn)儀(溫度未經(jīng)校正;Bruker Avance 400MHz 型核磁共振儀(CDCl 3為溶劑,TMS 為內(nèi)標(biāo);Perkin -Elmer SP One FT -IR 光譜儀

5、.第34卷第4期2010年7月 江西師范大學(xué)學(xué)報(bào)(自然科學(xué)版J OURNAL OF JIANGXI NORMAL UNIVERSITY(NATURAL SCIE NCEVol.34No.4 Jul.20101.2 3,4-二氫嘧啶-2-酮合成的一般步驟以5-乙氧羰基-4-苯基-6-甲基-3,4-二氫嘧啶-2-酮(4a 的合成為例:在50mL 的圓底燒瓶中加入苯甲醛(1.06g,10.0mmol、乙酰乙酸乙酯(1.30g,10.0mmol、尿素(0.90g,15.0mmol、氟化鈣(78.0mg,1.0mmol,摩爾分?jǐn)?shù)為10%和乙醇(20mL.加熱回流2.0h(TC L 檢測.冷卻至室溫,抽濾

6、,乙醇重結(jié)晶得產(chǎn)物4a (2.6g,產(chǎn)率為98%.2 結(jié)果與討論首先,以氟化鈣為催化劑,用苯甲醛(1a 、尿素和乙酰乙酸乙酯為反應(yīng)底物,考察了Biginelli 反應(yīng)一鍋法合成5-乙氧羰基-4-苯基-6-甲基-3,4-二氫嘧啶-2-酮(4a 的溶劑體系、反應(yīng)溫度與時(shí)間、催化劑用量等條件(見表1.通過優(yōu)化反應(yīng)條件,當(dāng)使用催化量的氟化鈣(摩爾分?jǐn)?shù)為10%,上述3組份在乙醇中加熱回流2.0h,可以高產(chǎn)率(98%地得到產(chǎn)物4a .在此基礎(chǔ)上,本文對氟化鈣的重復(fù)使用性能進(jìn)行了進(jìn)一步探索.實(shí)驗(yàn)表明,當(dāng)反應(yīng)完全(TCL 檢測,冷卻至室溫,析出固體產(chǎn)物,抽濾得產(chǎn)物4a ;然后在濾液中直接加入反應(yīng)底物,可得97

7、%的產(chǎn)物;濾液再重復(fù)使用1次,可得到95%的產(chǎn)物;濾液重復(fù)使用第3次,仍可得到94%的產(chǎn)物.說明氟化鈣重復(fù)使用仍具有很好的催化活性.表1 不同反應(yīng)條件下氟化鈣催化苯甲醛、乙酰乙酸乙酯和尿素的縮合反應(yīng)a No.催化量(摩爾分?jǐn)?shù)/%溶劑反應(yīng)時(shí)間/h產(chǎn)率/%b15H 2O 2.02025C H 2Cl 2 2.05235THF 2.05745C H 3CN 2.08055MeOH 2.08565EtOH 2.09078EtOH 2.092810EtOH 2.098910EtOH 2.046c1010EtOH 1.5881110EtOH 2.097d 1210EtOH 2.095e 1310EtOH2

8、.094fa:反應(yīng)條件為苯甲醛10.0mmol 、脲15.0mmol 、乙酰乙酸乙酯10.0mmol 、回流溫度;b:結(jié)晶分離后的產(chǎn)率;c:反應(yīng)溫度為25e ;d:同一催化劑使用第2次的結(jié)果;e:同一催化劑使用第3次的結(jié)果;e:同一催化劑使用第4次的結(jié)果.此外,從實(shí)驗(yàn)結(jié)果(見表2可知,氟化鈣對不同的醛均具有很好的催化活性.對于芳香醛(無論含給電子基或吸電子基都能得到高產(chǎn)率產(chǎn)物;在一般Biginelli 合成法中,脂肪醛的產(chǎn)物的產(chǎn)率通常很低,但氟化鈣進(jìn)行催化反應(yīng),也能獲得較高產(chǎn)率(Entry 9;并且不管醛含有堿性基團(tuán)(Entry 5或?qū)λ嵝悦舾谢鶊F(tuán)(Entry 7和Entry 14,還是含有不

9、飽和鍵(Entry 8和Entry 15,在當(dāng)前的反應(yīng)體系中都能得到滿意的產(chǎn)率.化合物的IR 和1H NMR 表征如下:5-Ethoxycarbony-l 4-pheny-l 6-methy-l 3,4-dihydropyrimidin -2(1H -one (4a :1H NMR (D MSO -d 6,D :9.16(s,1H,7.71(s,1H,7.217.33(m,5H ,5.12(d,J =2.9Hz,1H,3.98(q,J =7.1Hz,2H,2.24(s,3H ,1.08(t,J =7.1Hz,3H;I R(KBr,M /cm -1:3415,3230,3110,2935,170

10、2,1650,1599.375第4期劉 園,等:氟化鈣催化的Biginelli 反應(yīng)一鍋法合成3,4-二氫嘧啶-2-酮表2氟化鈣催化合成3,4-二氫嘧啶-2-酮衍生物Entry R1R2X反應(yīng)時(shí)間/h產(chǎn)物產(chǎn)率/%b熔點(diǎn)/e測得值文獻(xiàn)值1C6H5OEt O 2.04a98203204202206324-MeOC6H4OEt O 1.54b98200202201203334-ClC6H4OEt O 2.04c97212214213215344-NO2C6H4OEt O 3.04d95210212208211354-Me2NC6H4OEt O 1.54e922302312302321464-OHC6

11、H4OEt O 2.04f94227229226228872-Furyl OEt O 2.54g90205207204206128(E-C6H5C H CH OEt O 2.54h92229230229230129n-C3H7OEt O 2.54i85154156154410C6H5OEt S 2.04j9520520620620819114-MeOC6H4OEt S 2.04k9613613713613819124-ClC6H4OEt S 2.04l9418018218018219134-NO2C6H4OEt S 3.04m9321121221021319142-Furyl OEt S 2.

12、54n91184(dec185(dec1215(E-C6H5C H CH OEt S 2.54o902432452442461216C6H5Me O 2.04p9623423623223510174-MeOC6H4Me O 2.04q9417818017717910184-NO2C6H4Me O 3.04r92230(dec229(dec10194-MeOC6H4Me S 2.04s9617818017117912 a:產(chǎn)物的熔點(diǎn)、紅外光譜、核磁共振氫譜與已知的標(biāo)準(zhǔn)樣品一致;b:分離結(jié)晶后的產(chǎn)率.5-Ethoxycarbony-l4-(4-methoxyphenyl-6-methy-l3,4-

13、dihydropyrimidin-2(1H-one(4b:1H NMR(DMSO-d6,D: 9.15(s,1H,7.67(s,1H,7.14(d,J=8.4Hz,2H,6.87(d,J=8.4Hz,2H,5.08(d,J=2.7Hz,1H,3.97(q, J=7.2Hz,2H,3.71(s,3H,2.23(s,3H,1.09(t,J=7.1Hz,3H;IR(KBr,M/c m-1:3415,3240,3112, 2954,1706,1646,1512.5-Ethoxycarbony-l4-(4-chlorophenyl-6-methy-l3,4-dihydropyrimidin-2(1H-o

14、ne(4c:1H NMR(DMSO-d6,D: 9.22(s,1H,7.75(s,1H,7.37(d,J=8.8Hz,2H,7.24(d,J=8.8Hz,2H,5.14(d,J=2.8Hz,1H,3.97(q, J=7.2Hz,2H,2.23(s,3H,1.08(t,J=7.2Hz,3H;IR(KBr,M/c m-1:3418,3245,3112,2978,1708, 1646,1488.5-Ethoxycarbony-l4-(4-nitrophenyl-6-methy-l3,4-dihydropyrimidin-2(1H-one(4d:1H NMR(DMSO-d6,D: 9.33(s,1H,

15、8.27(d,J=8.4Hz,2H,7.88(s,1H,7.64(d,J=8.4Hz,2H,5.24(d,J=3.1Hz,1H,3.95(q, J=7.2Hz,2H,2.28(s,3H,1.07(t,J=7.2Hz,3H;IR(KBr,M/c m-1:3416,3238,3085,2940,1728, 1694,1588,1509.5-Ethoxycarbony-l4-(4-dimethyla minophenyl-6-methy-l3,4-dihydropyrimidin-2(1H-one(4e:1H NMR(DMSO-d6,D:9.05(s,1H,7.56(s,1H,7.02(d,J=8.

16、4Hz,2H,6.64(d,J=8.4Hz,2H,5.01(d,J=3.2Hz,1H, 3.96(q,J=7.2Hz,2H,2.83(s,6H,2.22(s,3H,1.09(t,J=7.2Hz,3H;IR(KBr,M/c m-1:3420,3244,376江西師范大學(xué)學(xué)報(bào)(自然科學(xué)版2010年3116,2975,1700,1648,1525.5-Ethoxycarbony-l 4-(4-hydroxyphenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -one(4f :1H NMR(DMSO -d 6,D :9.32(s,1H,9.10(s,1H,7.60(

17、s,1H,7.02(d,J =8.4Hz,2H,6.68(d,J =8.4Hz,2H,5.04(d,J =3.2Hz,1H,3.97(q,J =7.2Hz,2H ,2.24(s,3H,1.08(t,J =7.2Hz,3H;IR(KBr,M /cm -1:3417,3240,3085,3120,2985,1687,1650,1510.5-Ethoxycarbony-l 4-(2-furyl-6-methy-l 3,4-dihydropyrimidin -2(1H -one(4g :1H NMR(D MSO -d 6,D :9.21(s,1H,7.75(s,1H,7.53(s,1H,6.33(d,

18、J =2.8Hz,1H,6.08(d,J =2.8Hz,1H,5.20(d,J =3.7Hz,1H ,3.99(q,J =7.2Hz,2H,2.22(s,3H ,1.11(t,J =7.2Hz,3H ;I R(KBr,M /cm -1:3414,3240,3119,2984,1702,1645,1458.5-Ethoxycarbony-l 4-(E -2-phenylethenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -one (4h :1H NMR (DMSO -d 6,D :9.15(s,1H,7.56(s,1H,7.39(d,J =7.2Hz,2H,

19、7.33(d,J =7.2Hz,2H,7.23(t,J =7.2Hz,1H ,6.38(d,J =15.6Hz,1H ,6.22(d,J =15.6,6.0Hz,1H,4.73(d,J =3.6Hz,1H,4.09(q,J =7.2Hz,2H ,2.20(s,3H,1.20(t,J =7.2Hz,3H;I R(KBr,M /cm -1:3354,3262,2984,1696,1655,1495,1372,1224.5-E thoxycarbony-l 4-(n -propyl-6-methy-l 3,4-dihydropyrimidin -2(1H -one(4i :1H NMR(DMSO -

20、d 6,D :8.54(s,1H,6.31(s,1H,4.31(s,1H,4.15(q,J =7.2Hz,2H,2.29(s,3H,1.591.40(m,4H ,1.28(t,J =7.2Hz,3H,0.91(t,J =7.2Hz,3H;IR(KBr,M /cm -1:3414,3246,3119,1708,1675,1645.5-Ethoxycarbony-l 6-methy-l 4-pheny-l 3,4-dihydropyrimidin -2(1H -thione(4j :1H NMR(D MSO -d 6,D :10.20(s,1H,9.58(s,1H,7.377.21(m,5H ,5

21、.17(d,J =3.1Hz,1H,4.00(q,J =7.1Hz,2H,2.28(s,3H ,1.06(t,J =7.1Hz,3H;I R(KBr,M /cm -1:3242,3115,2976,1722,1700,1648,1220.5-Ethoxycarbony-l 4-(4-methoxyphenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -thione(4k :1H NMR(DMSO -d 6,D :10.18(s,1H,9.55(s,1H,7.14(d,J =8.6Hz,2H,6.88(d,J =8.6Hz,2H,5.10(d,J =3.3Hz,

22、1H ,3.91(q,J =7.1Hz,2H,3.72(s,3H,2.27(s,3H,1.09(t,J =7.1Hz,3H;IR(KBr,M /cm -1:3305,3178,3102,2962,1706,1652,1568,1504.5-Ethoxycarbony-l 4-(4-chlorophenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -thione(4l :1H NMR(DMSO -d 6,D :10.28(s,1H,9.60(s,1H,7.42(d,J =8.5Hz,2H,7.21(d,J =8.5Hz,2H,5.15(d,J =3.3Hz,1H

23、,3.99(q,J =7.1Hz,2H,2.29(s,3H,1.12(t,J =7.1Hz,3H;I R(KBr,M /c m -1:3326,3175,2982,1670,1575,1465.5-Ethoxycarbony-l 4-(4-nitrophenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -thione(4m :1H NMR(DMSO -d 6,D :10.38(s,1H,9.68(s,1H,8.25(d,J =8.6Hz,2H,7.49(d,J =8.6Hz,2H,5.25(d,J =3.4Hz,1H,4.01(q,J =7.1Hz,2H,2.

24、30(s,3H,1.10(t,J =7.1Hz,3H;I R(KBr,M /c m -1:3325,3170,2985,1677,1515,1522,1466,1200.5-Ethoxycarbony-l 4-(2-furyl-6-methy-l 3,4-dihydropyrimidin -2(1H -thione(4n :1H NMR(DMSO -d 6,D :10.45(s,1H,9.75(s,1H,7.737.67(m,1H,6.49(s,1H,6.24(d,J =3.1Hz,1H,5.33(d,J =3.9Hz,1H ,4.11(q,J =6.9Hz,2H,2.39(s,3H,1.14

25、(t,J =6.9Hz,3H;IR(KB r,M /c m -1:3315,2983,1665,1576.5-E thoxycarbony-l 4-(E -2-phenylethenyl-6-methy-l 3,4-dihydropyrimidin -2(1H -thione(4o :1H NMR(DMSO -d 6,D :8.75(s,1H,7.90(s,1H,7.447.38(m,5H,6.66(d,J =14.6Hz,1H ,6.39(d,J =14.6Hz,1H ,4.73(d,J =5.0Hz,1H,4.12(q,J =7.0Hz,2H,2.12(s,3H,1.18(t,J =7.0

26、Hz,3H;IR(KBr,M /cm -1:3340,3265,2967,1620,1543,1225.5-Aceto -4-pheny-l 6-methy-l 3,4-dihydropyrimidin -2(1H -one(4p :1H NMR(DMSO -d 6,D :8.21(s,1H,8.10(s,1H,7.507.07(m,5H,5.75(d,J =3.6Hz,1H,3.32(s,3H,2.29(s,3H;IR(KBr,M /c m -1:3308,377第4期劉 園,等:氟化鈣催化的Biginelli 反應(yīng)一鍋法合成3,4-二氫嘧啶-2-酮378江西師范大學(xué)學(xué)報(bào)(自然科學(xué)版2010

27、年3204,2958,1663,1606,1466.5-Aceto-6-methy-l4-(4-methoxyphenyl-3,4-dihydropyrimidin-2(1H-one(4q:1H NMR(DMSO-d6,D:8.26(s, 1H,8.15(s,1H,7.15(d,J=8.4Hz,2H,6.93(d,J=8.4Hz,2H,5.78(d,J=4.1Hz,1H,3.71(s,3H, 3.34(s,3H,2.32(s,3H;IR(KB r,M/c m-1:3307,3199,2963,1666,1604,1463.5-Aceto-6-methy-l4-(4-nitrophenyl-3,

28、4-dihydropyrimidin-2(1H-one(4r:1H NMR(DMSO-d6,D:8.76(s, 1H,8.15(s,1H,7.65(d,J=8.4Hz,2H,6.70(d,J=8.4Hz,2H,5.75(d,J=3.9Hz,1H,3.32(s,3H, 2.52(s,3H;IR(KBr,M/cm-1:3303,3204,2958,1664,1608,1520,1465.5-Aceto-6-methy-l4-(4-methoxyphenyl-3,4-dihydropyrimidin-2(1H-thione-(4s:1H NMR(DMSO-d6,D:10.21 (s,1H,9.68(

29、s,1H,7.15(d,J=8.8Hz,2H,6.92(d,J=8.4Hz,2H,5.25(d,J=3.6Hz,1H,3.74(s,3H, 2.33(s,3H,2.11(s,3H;IR(KB r,M/c m-1:3311,3230,2965,1623,1545,1225.3結(jié)論氟化鈣可有效促進(jìn)醛、尿素(硫脲和1,3-二羰基化合物發(fā)生Biginelli反應(yīng)合成3,4-二氫嘧啶-2-酮衍生物.該法反應(yīng)條件溫和,操作簡單,產(chǎn)物純化方便,催化劑可以重復(fù)使用,符合綠色化學(xué)的要求.參考文獻(xiàn):1Oliver Kappe C O,Ku mar D,Varma R S.M icrowave-assisted h

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