謝庭輝, 蔣筱瑩, 謝媛媛
(浙江工業(yè)大學(xué) 藥學(xué)院 綠色制藥技術(shù)與裝備教育部重點(diǎn)實(shí)驗(yàn)室,浙江 杭州 310014)
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·快遞論文·
相轉(zhuǎn)移催化合成2-苯基喹啉衍生物
謝庭輝, 蔣筱瑩, 謝媛媛*
(浙江工業(yè)大學(xué) 藥學(xué)院 綠色制藥技術(shù)與裝備教育部重點(diǎn)實(shí)驗(yàn)室,浙江 杭州310014)
以喹啉(1)和取代苯肼(2a~2d)為原料,K2S2O8為引發(fā)劑,TBAB為相轉(zhuǎn)移催化劑,乙腈為溶劑,經(jīng)自由基反應(yīng)合成了4個(gè)2-苯基喹啉化合物(3a~3d, 3d為新化合物),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-ESI-MS表征。以3a的合成為模板反應(yīng),研究了引發(fā)劑,溶劑和反應(yīng)溫度對3收率的影響。結(jié)果表明:在最佳反應(yīng)條件(1 1.0 mmol, 2 1.2 eq., K2S2O82.0 eq., TBAB 0.2 eq.,于室溫反應(yīng)4 h)下,3a~3d收率54%~72%。
2-苯基喹啉; 相轉(zhuǎn)移催化; 自由基反應(yīng); 合成; 工藝優(yōu)化
喹啉化合物是一類重要的雜環(huán)化合物,廣泛應(yīng)用于醫(yī)藥、染料和冶金等諸多領(lǐng)域[1-3]。尤其在醫(yī)藥領(lǐng)域,許多含喹啉骨架的化合物均表現(xiàn)出良好的抗瘧疾、抗腫瘤、抗炎和抗精神分裂等藥理活性[4-6]。此外,2-苯基喹啉衍生物還可與金屬配位形成配合物,顯示出良好的電化學(xué)性能[7]。
C—C偶聯(lián)反應(yīng)是有機(jī)合成反應(yīng)的研究熱點(diǎn)之一。該類反應(yīng)大多需使用毒性較大的過渡金屬作催化劑,反應(yīng)溫度較高。如采用格氏反應(yīng)[8],過渡金屬催化的Suzuki偶聯(lián)反應(yīng)[9]及鈷催化的交叉偶聯(lián)反應(yīng)[10]制備2-苯基喹啉類化合物。
為避免使用過渡金屬催化劑,降低反應(yīng)難度,本文以喹啉(1)和取代苯肼(2a~2d)為原料,K2S2O8為引發(fā)劑,TBAB為相轉(zhuǎn)移催化劑,乙腈為溶劑,經(jīng)自由基反應(yīng)合成了4個(gè)2-苯基喹啉化合物(3a~3d, 3d為新化合物,Scheme 1),其結(jié)構(gòu)經(jīng)1H NMR,13C NMR和HR-ESI-MS表征。以3a的合成為模板反應(yīng),研究了引發(fā)劑,溶劑和反應(yīng)溫度對3收率的影響。結(jié)果表明:在最佳反應(yīng)條件(1 1.0 mmol, 2 1.2 eq., K2S2O82.0 eq., TBAB 0.2 eq.,于室溫反應(yīng)4 h)下,3a~3d收率為54%~72%。
Scheme 1
1.1儀器與試劑
Varian Mercury Plus-400 MHz型核磁共振儀(CDCl3為溶劑,TMS為內(nèi)標(biāo));Trace DSQ FINNIGSH型和AGILENT 6210 TOF型質(zhì)譜儀。
1,上海贏瑞化學(xué)科技有限公司;過硫酸鉀、苯肼,阿拉丁公司;其余所用試劑均為分析純。
1.23a~3d的合成(以3a為例)
在單口燒瓶中加入1 129 mg(1 mmol), K2S2O8540 mg(2.0 eq.), TBAB 64 mg(0.2 eq.)和乙腈 5 mL,攪拌10 min;于室溫滴加苯肼(2a)130 mg(1.2 eq.)的乙腈(10 mL)溶液,滴畢,反應(yīng)4 h(TLC監(jiān)測)。過濾,濾餅用乙腈洗滌,合并濾液和洗液,濃縮后經(jīng)硅膠柱層析[洗脫劑:V(乙酸乙酯) ∶V(石油醚)=1 ∶20]純化得淡黃色固體3a。
用類似的方法合成淡黃色固體3b和黃色固體3c, 3d。
3a: 收率72%, m.p.84~85 ℃(85~86 ℃[11]);1H NMRδ: 8.24(d,J=8.4 Hz, 2H, ArH), 8.15(d,J=7.6 Hz, 2H, ArH), 7.87(d,J=8.8 Hz, 1H, ArH), 7.82(d,J=8.0 Hz, 1H, ArH), 7.73(t,J=7.6 Hz, 1H, ArH), 7.55~7.44(m, 4H, ArH);13C NMRδ: 157.1, 136.8, 129.6, 129.5, 129.3, 128.7(2C), 128.5, 127.5(2C), 127.3, 127.1, 126.2, 125.5, 118.9; ESI-MSm/z: 206{[M+H]+}。
3b: 收率66%, m.p.94~95 ℃(94~95 ℃[12]);1H NMRδ: 8.46(d,J=8.8 Hz, 1H, ArH), 8.35~8.31(m, 2H, ArH), 8.14(d,J=8.8 Hz, 1H, ArH), 8.06(d,J=8.4 Hz, 1H, ArH), 8.00(d,J=8.0 Hz, 1H, ArH), 7.80~7.76(m, 1H, ArH), 7.60(t,J=7.6 Hz, 1H, ArH), 7.40~7.36(m, 2H, ArH);13C NMRδ: 162.9 (1JCF=244.9 Hz), 154.7, 147.0, 137.2, 134.7, 129.8, 129.2(3JCF=8.5 Hz, 2C), 128.6, 127.6, 126.6, 126.3, 118.4, 115.6(2JCF=21.3 Hz, 2C); ESI-MSm/z: 224{[M+H]+}。
3c: 收率63%, m.p.113~115 ℃(112~114 ℃[13]);1H NMRδ: 8.22(d,J=8.4 Hz, 1H, ArH), 8.17(d,J=8.4 Hz, 1H, ArH), 8.12~8.10(m, 2H, ArH), 7.84~7.81(m, 2H, ArH), 7.74~7.71(m, 1H, ArH), 7.54~7.51(m, 1H, ArH), 7.49~7.47(m, 2H, ArH);13C NMRδ: 155.1, 146.5, 137.4, 130.0, 129.0, 128.9(2C), 128.7(2C), 128.4, 128.2, 127.1, 126.5, 125.9, 118.4; ESI-MSm/z: 240, 242 {[M+H]+}。
3d: 收率54%, m.p.91~93 ℃;1H NMRδ: 8.22~8.17(m, 2H, ArH), 7.85(d,J=8.4 Hz, 1H, ArH), 7.73(t,J=7.2 Hz, 1H, ArH), 7.57~7.51(m, 2H, ArH), 7.43(d,J=7.6 Hz, 1H, ArH), 7.38~7.29(m, 3H, ArH), 2.76(q,J=7.6 Hz, 2H, CH2), 1.12(t,J=7.6 Hz, 3H, CH3);13C NMRδ: 159.3, 152.4, 141.7, 136.3, 129.5, 129.3, 128.7, 128.5, 128.4, 127.0, 126.3, 126.2, 126.1, 125.5, 122.1, 26.7, 16.1; HR-ESI-MSm/z: Calcd for C17H15N{[M+H]+}234.127 7, found 234.126 8。
2.1反應(yīng)條件優(yōu)化
以3a的合成為例,研究了引發(fā)劑,溶劑和反應(yīng)溫度對反應(yīng)收率的影響,結(jié)果見表1。由表1可見,No.1~No.3為引發(fā)劑對收率的影響,以K2S2O8為引發(fā)劑,收率最高(No.3, 52%)。
表1 3a的合成條件優(yōu)化*
*1 1 mmol,其余條件同1.2;a柱層析收率。
No.3~No.6為K2S2O8用量對收率的影響,當(dāng)K2S2O8用量為2.0 eq.時(shí),收率最高(No.5, 72%)。繼續(xù)增加K2S2O8用量會導(dǎo)致1產(chǎn)生苯基自由基的速率過快,不能及時(shí)與2反應(yīng),導(dǎo)致收率下降。
No.5, No.7~No.9為溶劑對收率的影響,以THF, DMF和DMSO為溶劑時(shí),反應(yīng)時(shí)間較長,收率較低。以CH3CN為溶劑,反應(yīng)時(shí)間較短(No.5, 4 h),收率較高(No.5, 72%)。
No.5, No.10和No.11為反應(yīng)溫度對收率的影響。當(dāng)反應(yīng)溫度為10 ℃時(shí),反應(yīng)7 h結(jié)束,3a收率僅49%(No.10);當(dāng)溫度升至室溫,3a收率提高至72%(No.5);繼續(xù)升高溫度至50 ℃,反應(yīng)2 h即結(jié)束,但收率僅60%(No.11),這可能是因?yàn)闇囟冗^高導(dǎo)致2a分解所致。
綜上,合成3a的最佳反應(yīng)條件為:1 1.0 mmol, 2a 1.2 eq., K2S2O82.0 eq., TBAB 0.2 eq.,乙腈為溶劑,于室溫反應(yīng)4 h,收率72%。
2.2底物擴(kuò)展
在最佳反應(yīng)條件下,對底物進(jìn)行了擴(kuò)展,合成了3b~3d,收率54%~72%(Scheme 1)。由此可見,該反應(yīng)有一定的適用性。
報(bào)道了一種合成2-苯基喹啉衍生物的方法。該方法操作簡便,成本低廉,不使用有毒有害的過渡金屬作催化劑,符合綠色化學(xué)理念。
[1]劉春玉,楊定喬,黃成華. 喹啉衍生物的合成[J].合成化學(xué),2001,9(6):567-569.
[2]Teguh S C, Klonis N, Duffy S,etal. Novel conjugated quinoline-indoles compromise plasmodium falciparum mitochondrial function and show promising antimalarial activity[J].J Med Chem,2013,56(15):6200-6215.
[3]張志文,潘瑞龍,吳杰穎. 新型喹啉類衍生物的合成及其光學(xué)性質(zhì)[J].合成化學(xué),2013,21(6):692-694.
[4]Yu Z Y, Shi G Y, Sun Q,etal. Design, synthesis andinvitroantibacterial/antifungal evaluation of novel 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7 (1-piperazinyl) quinoline-3-carboxylic acid derivatives[J].Eur J M Chem,2009,44(11):4726-4733.
[5]馬俊雨,郭娜,成明,等. 溴化金催化醛及芳香胺串聯(lián)反應(yīng)合成2,3-二取代喹啉[J].華西藥學(xué)雜志,2015,30(5):525-527.
[6]Candéa A L P, Ferreira M L, Pais K C,etal. Synthesis and antitubercular activity of 7-chloro-4-quinolinylhydrazones derivatives[J].Bioorg Med Chem Lett,2009,19(22):6272-6274.
[7]童碧海,梅群波,李志文,等. 系列2-苯基喹啉類銥配合物的合成及電化學(xué)發(fā)光性能研究[J].化學(xué)學(xué)報(bào),2012,70(23):2451-2456.
[8]Iglesias M J, Prieto A, Nicasi M C. Kumada-tamao-corriu coupling of heteroaromatic chlorides and aryl ethers catalyzed by (IPr)Ni(allyl)Cl[J].Org Lett,2012,14(17):4318-4321.
[9]Yang J F, Liu S J, Zheng J F,etal. Room-temperature Suzuki-Miyaura coupling of heteroaryl chlorides and tosylates[J].Eur J Org Chem,2012,2012(31):6248-6259.
[10]Kuzmina O M, Steib A K, Markiewicz J T,etal. Ligand-accelerated iron- and cobalt-catalyzed cross-coupling reactions betweenN-heteroaryl halides and aryl magnesium reagents[J].Angew Che Int Edit,2013,18(52):54312-54315.
[11]Lutz A, Harish K P, Andreas A,etal. Tetra-ortho-substituted biaryls through palladium-catalyzed Suzuki-Miyaura couplings with a diaminochlorophosphine ligand[J].Org Lett,2010,12(5):1004-1007.
[12]Ashley M B, Lewis J C, Robert G B,etal. Rh(I)-catalyzed direct arylation of pyridines and quinolines[J].J Am Chem Soc,2008,130(45):14926-14927.
[13]Su W K, Yu J B, Li Z H,etal. Unexpected and divergent reactions ofN-formyl-1,2-dihydroquinolines with sodium azide:Highly chemoselective formation of 2-substituted quinolines and isoxazolo[4,3-c]quinolines[J].Synlett,2008,(8):1281-1284.
Phase-transfer Catalytic Synthesis of 2-Phenylquinoline Derivatives
XIE Ting-hui,JIANG Xiao-ying,XIE Yuan-yuan*
(Key Laboratory for Green Pharmaceutical Technologies and Related Equipment of Ministry of Education,College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, China)
Four 2-phenylquinolines(3a~3d, 3d was new compound) were synthesized by radical reaction of quinoline(1) with phenylhydrazines(2a~2d), using K2S2O8as initiator, TBAB as phase-transfer catalyst and MeCN as solvent. The structures were characterized by1H NMR,13C NMR and HR-ESI-MS. Effects of initiators, solvents and reaction temperature on yield of 3 were investigated, using synthesizing 3a as the template reaction. The yields of 3a~3d were 54%~72% under the optimum reaction conditions(1 1.0 mmol, 2 1.2 eq., K2S2O82.0 eq., TBAB 0.2 eq., reaction at rt for 4 h).
2-phenylquinoline; phase-transfer catalysis; radical reaction; synthesis; process improvement
2016-01-28;
2016-06-14
國家自然科學(xué)基金資助項(xiàng)目(21576239)
謝庭輝(1991-),男,漢族,浙江臺州人,碩士研究生,主要從事藥物中間體綠色合成的研究。
通信聯(lián)系人: 謝媛媛,教授, E-mail: xyycz@zjut.edu.cn
O625.6; O626.32
A
10.15952/j.cnki.cjsc.1005-1511.2016.08.16030