王蘇惠, 查云赟, 榮良策

(江蘇師范大學(xué) 化學(xué)化工學(xué)院,江蘇 徐州 221116)

無溶劑反應(yīng)是指反應(yīng)過程中不使用溶劑,可大大減少溶劑對(duì)環(huán)境的危害,逐漸成為綠色有機(jī)合成的重要途徑之一[1-2].在無溶劑反應(yīng)體系中,反應(yīng)物分子之間可以直接接觸,造成局部高濃度,從而使反應(yīng)的選擇性和轉(zhuǎn)化率提高,加快了反應(yīng)的周期.這類反應(yīng)操作簡單,實(shí)施起來較為方便,通常經(jīng)過固相研磨、加熱或微波輔助以及振蕩等合成方法來實(shí)現(xiàn),因此已被廣泛應(yīng)用于各類化合物的合成中,成為開發(fā)制備綠色材料和產(chǎn)品的重要手段．嘧啶酮衍生物是一類重要的含氮雜環(huán)化合物,具有良好的生物活性和廣闊的應(yīng)用前景,如用做抗病毒、抗高血壓、抗腫瘤、抗菌和抗HIV等藥物[3-5].此外,還具有調(diào)節(jié)鈣離子通道、降血壓的作用,在除草劑、染料、殺蟲劑方面也有著悠久的應(yīng)用歷史[6-7].因此,合成嘧啶酮衍生物成為人們研究的熱點(diǎn)之一．很多文獻(xiàn)報(bào)道了嘧啶酮衍生物的合成[8-10],但多數(shù)反應(yīng)在有機(jī)溶劑中進(jìn)行,如Hamper等[8]報(bào)道了在DMF，CH2Cl2，TFA中合成1,2,4-三取代嘧啶-6-酮-5-羧酸衍生物,使用了復(fù)雜的催化劑硝酸鈰銨(CAN),Wu等[10]報(bào)道合成此類化合物需要5步．所以選擇更簡單、容易操作的途徑合成此類化合物是十分必要的．本文報(bào)道在無溶劑條件下,以芳醛(1),氰乙酸乙酯(2)和氰基胍(3)為底物,一步法合成嘧啶-6-酮衍生物(4).在反應(yīng)過程中使用實(shí)驗(yàn)室常見的低值試劑,因此具有環(huán)境友好、成本低廉、操作簡單等優(yōu)點(diǎn).反應(yīng)方程式如下:

1234

1 實(shí)驗(yàn)部分

1.1 儀器和試劑

儀器:瑪瑙研缽;熔點(diǎn)在TX5型顯微熔點(diǎn)儀上測(cè)定(溫度未經(jīng)校正);紅外光譜使用FT/IR-8101型紅外光譜儀測(cè)定(KBr壓片);核磁共振氫譜在Bruker-400 MHZ型核磁共振儀上測(cè)定,DMSO-d6為溶劑,TMS為內(nèi)標(biāo);高分辨率質(zhì)譜數(shù)據(jù)在Bruker-micrOTOF-Q-II高分辨質(zhì)譜儀上測(cè)定.

試劑:所用試劑均為分析純或化學(xué)純,使用前未經(jīng)純化.

表1 產(chǎn)物的合成結(jié)果

1.2 標(biāo)題化合物的合成

1，2，3各1 mmol，NaOH 0.05 g置于瑪瑙研缽中混合均勻,轉(zhuǎn)至50 ml圓底燒瓶中,在70 ℃條件下加熱30 min,得到淡黃色固體,用水充分洗至中性,抽濾,固體產(chǎn)物用95%乙醇重結(jié)晶,得目標(biāo)化合物4.反應(yīng)結(jié)果見表1.產(chǎn)物的結(jié)構(gòu)表征如下：

4a mp:262～264 ℃.IRν: 3229,3135,3030,2936,2220,1707,1605,1501,1384,1341,1258,1247,1165,854,835,805,775,760,647,584 cm-1.1HNMRδ:7.40(2H,m,ArH),7.85(2H,m,ArH),11.57(1H,s,NH).HRMSm/z：C12H6FN5O[M+H]+，計(jì)算值,256.0635;實(shí)測(cè)值,256.0636.

4b mp：244～246 ℃.IRν：2934,2802,2204,1518,1494,1344,1275,1250,1221,1135,1112,1092,1012,842,774,729,718,686,667,628,561 cm-1.1HNMRδ：7.65(2H,d,J=8.4 Hz,ArH),7.73(2H,d,J=8.8 Hz,ArH),11.65(1H,s,NH).HRMSm/z:C12H6ClN5O[M+H]+,計(jì)算值,272.0339;實(shí)測(cè)值,272.0339.

4c mp:>280 ℃; IRν：3087,2952,2806,2203,1552,1473,1353,1268,1221,1142,1032,919,891,843,772,744,720,633,573,547 cm-1.1HNMRδ：7.54(1H,d,J=8.4 Hz,ArH),7.60(1H,d,J=8.4 Hz,ArH),7.82(1H,d,J=1.6 Hz,ArH),11.77(1H,s,NH).HRMSm/z:C12H5Cl2N5O[M+H]+,計(jì)算值,305.9949;實(shí)測(cè)值,305.9954.

4d mp:246～247 ℃.IRν：3087,2952,2806,2203,1654,1552,1473,1353,1268,1221,1142,1032,919,891,843,772,744,720,633,573,547 cm-1.1HNMRδ：7.74(1H,d,J=8.0 Hz,ArH),7.86(1H,t,J=6.4 Hz,ArH),7.98(1H,d,J=2.0 Hz,ArH),11.59(1H,s,NH).HRMSm/z:C12H5Cl2N5O[M+H]+,計(jì)算值,305.9949;實(shí)測(cè)值,305.9954.

4e mp：274～276 ℃.IRν：3142,3086,2960,2806,2205,1512,1489,1466,1431,1352,1274,1252,1222,1072,1024,1010,837,774,727,627,564 cm-1.1HNMRδ：7.66(2H,d,J=8.4 Hz,ArH),7.78(2H,d,J=8.8 Hz,ArH),11.68(1H,s,NH).HRMSm/z:C12H6BrN5O[M+H]+,計(jì)算值,315.9834;實(shí)測(cè)值,315.9836.

4f mp：275～277 ℃.IRν:3240,3135,2933,2194,1709,1494,1380,1337,1292,1190,1118,1032,1019,828,807,698,627,583,546 cm-1.1HNMRδ：2.40(3H,s,CH3),7.39(2H,d,J=8.0 Hz,ArH),7.60(2H,d,J=8.0 Hz,ArH),11.75(1H,s,NH).HRMSm/z:C13H9N5O[M+H]+,計(jì)算值,252.0885;實(shí)測(cè)值,252.0876.

4g mp：252～254 ℃.IRν：2804,2199,1647,1465,1357,1287,1234,1122,1036,999,840，774,724 cm-1.1HNMRδ：2.32(3H,s,CH3),2.30(3H,s,CH3),7.33(1H,d,J=4.8 Hz,ArH),7.45(2H,t,J=8.0 Hz,ArH),11.67(1H,s,NH).HRMSm/z:C14H11N5O[M+H]+,計(jì)算值,266.1042;實(shí)測(cè)值,266.1037.

4h mp：266～268 ℃.IRν：3171,3092,3043,2957,2804,2212,1717,1670,1584,1502,1449,1342,1284,1223,1183,1131,1015,841,765,747,582 cm-1.1HNMRδ：3.85(3H,s,OCH3),7.11(2H,d,J=8.8 Hz,ArH),7.72(2H,d,J=8.8 Hz,ArH),11.64(1H,s,NH).HRMSm/z:C13H9N5O2[M+H]+,計(jì)算值,268.0834;實(shí)測(cè)值,268.0839.

4i mp：234～236 ℃.IRν：2978,2813,2209,1714,1663,1597,1568,1524,1462,1352,1330,1275,1213,1177,1154,1103,1016,945,866,813,764,646,556 cm-1.1HNMRδ：3.82(3H,s,OCH3),3.85(3H,s,OCH3),7.15(1H,d,J=8.4 Hz,ArH),7.35(1H,d,J=2.0 Hz,ArH),7.38(1H,d,J=8.0 Hz,ArH),11.82(1H,s,NH).HRMSm/z:C14H11N5O3[M+H]+,計(jì)算值,298.0940;實(shí)測(cè)值,298.0944.

4j mp：272～274 ℃.IRν：3233,2921,2795,2220,1705,1578,1491,1445,1331,1271,1215,1125,1097,1041,922,872,808,773,763,734,700,670,643,581,569,552 cm-1.1HNMRδ：6.16(2H,s,OCH2O),7.11(1H,d,J=8.0 Hz,ArH),7.27(2H,d,J=5.6 Hz,ArH),11.79(1H,s,NH).HRMSm/z:C13H7N5O3[M+H]+,計(jì)算值,282.0627;實(shí)測(cè)值,282.0626.

2 結(jié)果與討論

從表1中可以看到,不同取代基的芳醛在反應(yīng)中都具有較好的反應(yīng)結(jié)果,雖然芳環(huán)上的取代基的化學(xué)性質(zhì)不同,但無論是帶有吸電子基(如鹵原子),還是帶有給電子基(如甲基和甲氧基),反應(yīng)都沒有受到明顯的影響,說明本反應(yīng)對(duì)不同電子性質(zhì)的芳醛都具有良好的適應(yīng)性．

本文報(bào)道了一種高效合成嘧啶-6-酮衍生物的方法,與傳統(tǒng)的合成法相比,具有環(huán)境友好、操作簡單、產(chǎn)物的收率較高的優(yōu)點(diǎn),是合成此類結(jié)構(gòu)化合物的一條綠色途徑．

參考文獻(xiàn):

[1] Tanaka K,Toda F.Solvent-free organic synthesis[J].Chem Rev,2000,100(3):1025.

[2] 榮良策,李小躍,王海營.固相合成α,β-不飽和酮[J].徐州師范大學(xué)學(xué)報(bào):自然科學(xué)版,2006,24(2):61.

[3] George T,Kaul C L,Grewal R S,et al.Antihypertensive and monoamine oxidase inhibitory activity of some derivatives of 3-formyl-4-oxo-4H-pyrido[1,2-a]pyrimidine[J].J Med Chem,1971,14(10):913.

[4] Bergstorm D E,Brattesani A J,Ogawa M K,et al.Antiviral activity of C-5 substituted tubercidin analogued[J].J Med Chem,1984,27(3):285.

[5] Sanghvi Y S,Larson S B,Matsumoto S S,et al.Antitumor and antiviral activity of syntheticα- andβ-ribonucleosides of certain substituted pyrimido[5,4-d]pyrimidines:a new synthetic strategy for exocyclic aminonucleosides[J].J Med Chem,1989,32(3):629.

[6] Hinks D，F(xiàn)reeman H S,Arai Y,et al.Synthesis and evaluation of organic pigments:studies of bisazomethine pigments based on planar nonmutagenic benzidine analogs[J].Dyes Pigm,2001,48(1):7.

[7] Kappe C O,Fabian M F.Conformational analysis of 4-aryl-dihydropyrimidine calcium channelmodulators:a comparison of abinitio,semiemp irical and X-ray crystal-lographic studies[J].Tetrahedron,1997,53(8):2803.

[8] Hamper B C,Kesselring A S,Chott R C,et al.Parallel solid-phase synthesis and high-throughput1HNMR evaluation of 96-member 1,2,4-trisubstituted-pyrimidin-6-ones-5-carboxylic acid library[J].J Comb Chem,2009,11(3):469.

[9] Ramanjulu J M,DeMartino M P,Lan Y F,et al.Titanium(Ⅳ) isopropoxide mediated synthesis of pyrimidin-4-ones[J].Org Lett,2010,12(10):2270.

[10] Wu Minghu,Hu Jihuan,Shen Dongsheng,et al.Regiospecific synthesis of 6-aryl-3-cyano-5-alkylamino/arylamino-1-p-tolyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-ones via iminophosphorane-mediated annulation[J].Tetrahedron,2010,66(27/28):5112.

[11] 劉麗華,殷姍,夏盛,等.無溶劑條件下簡單、有效地合成1,6-二氫嘧啶-6-酮衍生物[J].有機(jī)化學(xué)，2010,32(3):612.