無(wú)催化劑下2-氨基-3-氰基-5-氧代-5,6,7,8-四氫色烯衍生物的三組分合成

何心偉,陸 鵬,謝慧敏,查陶春,商永嘉

(安徽師范大學(xué) 化學(xué)與材料科學(xué)學(xué)院,安徽 蕪湖 241000)

0 引言

雜環(huán)化合物廣泛存在于自然界中,為有機(jī)化合物中數(shù)量最多的一類(lèi).其中吡喃或苯并吡喃(色烯)骨架廣泛存在于藥物和天然產(chǎn)物中[1-2],且具有良好的生物活性，如抗氧化、抗菌和抗癌等活性[3-5],因而在醫(yī)藥和農(nóng)藥等行業(yè)具有廣泛的應(yīng)用.同時(shí)吡喃類(lèi)化合物還具有較好的光響應(yīng)性能,較快的褪色速度以及較好的光穩(wěn)定性能,是一類(lèi)具有實(shí)際應(yīng)用價(jià)值的光致變色材料[6].近年來(lái)關(guān)于吡喃衍生物的合成方法不斷被發(fā)展,但是已報(bào)到的合成方法中往往具有較高的反應(yīng)溫度、使用有毒有害的有機(jī)溶劑或催化劑等缺點(diǎn),且產(chǎn)率不高[7-11].近年來(lái)，實(shí)現(xiàn)對(duì)環(huán)境友好的有機(jī)合成,已成為有機(jī)化學(xué)工作者迫切需要研究的課題.

多組分反應(yīng)由于采用一鍋煮的方法可以實(shí)現(xiàn)多種具有生物活性物質(zhì)的高效合成而成為有機(jī)化學(xué)、組合化學(xué)和藥物化學(xué)領(lǐng)域研究的熱點(diǎn)之一[12].多組分反應(yīng)不需經(jīng)過(guò)中間體的分離,可以直接獲得結(jié)構(gòu)復(fù)雜的分子,在終產(chǎn)物的結(jié)構(gòu)中含有所有原料的片斷,因而具有高效、高選擇性、反應(yīng)條件溫和,操作簡(jiǎn)潔方便等優(yōu)點(diǎn),能夠容易地合成常規(guī)方法難以合成的目標(biāo)分子[13].為發(fā)展吡喃衍生物的綠色合成方法,本文以乙醇為溶劑,室溫?zé)o催化劑下,實(shí)現(xiàn)了芳醛或靛紅、丙二腈、5,5-二甲基-1,3-環(huán)己二酮的三組分“一鍋”串聯(lián)反應(yīng)合成系列2-氨基-3-氰基環(huán)己酮并吡喃衍生物,并通過(guò)1H NMR和13CNMR對(duì)化合物結(jié)構(gòu)進(jìn)行了表征,合成路線設(shè)計(jì)如(1)所示.

1 實(shí)驗(yàn)部分

1.1 實(shí)驗(yàn)儀器及試劑

Bruker-AV-300核磁共振儀(300 MHz,CDCl3和DMSO-d6為溶劑,TMS為內(nèi)標(biāo)),Vario EL III 元素分析儀,所用試劑均為分析純(可直接使用).

1.2 2-氨基-3-氰基-4-芳基-5-氧代-5,6,7,8-四氫色烯衍生物的合成

50 mL的圓底燒瓶中加入1 mmol的取代芳香醛,1.2 mmol的丙二腈、1.0 mmol的雙甲酮,然后加入5 mL左右的乙醇作為溶劑,室溫下攪拌反應(yīng),待反應(yīng)溶液中出現(xiàn)大量沉淀即停止反應(yīng),過(guò)濾生成的沉淀物,固體用少量無(wú)水乙醇洗滌3次,干燥得目標(biāo)產(chǎn)物.

2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4a).白色固體,1H NMR (300 MHz,CDCl3):δ7.12-7.27 (m,5H,ArH),4.51 (s,2H,NH2),4.35 (s,1H,CH),2.18 (d,J=3.3 Hz,2H,CH2),1.06 (s,3H,CH3),0.99 (s,3H,CH3);13C NMR (75 MHz,CDCl3):δ195.9,161.5,143.1,128.5,127.5,118.6,114.0,104.4,50.6,40.6,35.4,32.1,28.8,27.6;Anal.calcd for C18H18N2O2:C 73.45,H 6.16,N 9.52; found C 73.42,H 6.32,N 9.54.

2-Amino-7,7-dimethyl-4-(4-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4b).白色固體,1H NMR (300 MHz,CDCl3):δ8.81(d,J=8.7 Hz,2H,ArH),7.39 (d,J=8.1 Hz,2H,ArH),4.63 (s,2H,NH2),4.47 (s,1H,CH),2.44 (s,2H,CH2),2.20 (s,2H,CH2),1.08 (s,3H,CH3),0.99 (s,3H,CH3);13C NMR (75 MHz,CDCl3):δ195.7,162.2,157.7,150.4,128.6,123.9,117.9,113.3,58.4,50.5,40.6,35.6,32.2,28.8,27.6;Anal.calcd for C18H17N3O4:C 63.71,H 5.05,N 12.38; found C 63.73,H 5.12,N 12.35.

2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4c).白色固體,1H NMR (300 MHz,CDCl3):δ7.23 (d,J=8.4 Hz,2H,ArH),7.14 (d,J=8.4 Hz,2H,ArH),4.54 (s,2H,NH2),4.34 (s,1H,CH),2.48 (s,2H,CH2),2.18 (d,J=5.2 Hz,2H,CH2),1.06 (s,3H,CH3),0.98 (s,3H,CH3);13C NMR (75 MHz,CDCl3):δ195.8,161.7,157.5,141.7,132.8,129.0,128.7,118.4,113.8,110.0,59.4,50.5,40.6,35.0,32.1,28.8,27.6;Anal.calcd for C18H17ClN2O2:C 65.75,H 5.21,Cl 10.78,N 8.52; found C 65.77,H 5.28,Cl 10.74,N 8.50.

2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4d).白色固體,1H NMR (300 MHz,CDCl3):δ7.12-7.08 (m,2H,ArH),6.79-6.76 (m,2H,ArH),4.47 (s,2H,NH2),4.31 (s,1H,CH),3.74 (t,J=5.4 Hz,3H,CH3),2.39 (s,2H,CH2),2.17 (d,J=2.7 Hz,2H,CH2),1.06 (d,3H,J=4.8 Hz,CH3),0.99 (d,J=5.1 Hz,3H,CH3);13C NMR (75 MHz,CDCl3):δ195.9,161.2,158.5,157.4,135.4,128.6,118.7,114.2,63.6,55.2,50.6,40.65,34.7,32.4,28.8,27.6;Anal.calcd for C19H20N2O3:C 70.35,H 6.21,N 8.64; found C 70.31,H 6.30,N 8.61.

2-Amino-7,7-dimethyl-5-oxo-4-(p-tolyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4e).白色固體,1H NMR (300MHz,CDCl3):δ7.12 (t,J=9.9 Hz,4H,ArH),4.54 (s,2H,NH2),4.35 (s,1H,CH),2.44 (s,2H,CH2),2.28 (s,3H,CH3),2.21 (d,J=3.3 Hz,2H,CH2),1.10 (s,3H,CH3),1.03 (s,3H,CH3);13C NMR (75 MHz,CDCl3):δ 195.9,161.3,157.3,140.2,136.6,129.3,127.3,118.6,114.1,50.6,40.6,35.1,32.1,28.8,27.7,21.0;Anal.calcd for C19H20N2O2:C 74.00,H 6.54,N 9.08; found C 74.04,H 6.61,N 9.02.

2-Amino-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4f).白色固體,1H NMR (300MHz,CDCl3):δ6.79-6.72 (m,3H,ArH),4.55 (s,2H,NH2),4.35 (s,1H,CH),3.86 (s,3H,CH3),3.82 (s,3H,CH3),2.44 (s,2H,CH2),2.23 (s,2H,CH2),1.11 (s,3H,CH3) 1.04 (s,3H,CH3);13C NMR (75 MHz,CDCl3):δ196.2,161.5,157.6,148.8,147.9,119.4,114.0,111.2,62.8,55.8,50.6,40.6,35.0,32.1,28.9,27.4;Anal.calcd for C20H22N2O4:C 67.78,H 6.26,N 7.90; found C 67.71,H 6.36,N 7.82.

1.3 2-氨基-3-氰基-5,6,7,8-四氫螺色烯-4,3′-二氫吲哚-2′,5-二酮衍生物的合成

50mL的圓底燒瓶中加入1 mmol的取代靛紅，1.2 mmol的丙二腈、1.0 mmol的雙甲酮，然后加入5 mL左右的乙醇作為溶劑，室溫下攪拌反應(yīng)，溶液由紅色變?yōu)闊o(wú)色，待反應(yīng)溶液中出現(xiàn)大量沉淀即可停止反應(yīng)，過(guò)濾反應(yīng)生成的固體沉淀物，固體用少量無(wú)水乙醇洗滌3次，干燥得目標(biāo)產(chǎn)物.

2-Amino-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (6a).白色固體,1H NMR (300 MHz,DMSO-d6):δ10.38 (s,1H,NH),7.21 (s,2H,NH2),7.12 (t,J=7.2 Hz,1H,ArH),6.97 (d,J=6.6 Hz,1H,ArH),6.89 (t,J=7.2 Hz,1H,ArH),6.77 (d,J=7.8 Hz,1H,ArH),2.54 (s,1H,CH2),2.48 (s,1H,CH2),2.18,2.13 (d,d,J=43.5 Hz,J=17.1 Hz,2H,CH2),1.01 (s,3H,CH3),0.98 (s,3H,CH3);13C NMR (75 MHz,DMSO-d6):δ195.3,182.6,178.4,164.6,159.2,142.5,134.8,128.6,123.4,122.1,117.8,111.2,109.6,95.9,57.8,50.4,47.2,32.4,28.0,27.4;Anal.calcd for C19H17N3O3:C 68.05,H 5.11,N 12.53; found C 68.02,H 5.23,N 12.55.

2-Amino-5′-fluoro-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (6b).白色固體,1H NMR (300 MHz,DMSO-d6):δ10.42 (s,1H,NH),7.28 (s,2H,NH2),6.92-6.98 (m,2H,ArH),6.74-6.78 (m,1H,ArH),2.53 (s,2H,CH2),2.13 (s,2H,CH2),0.99 (s,6H,CH3),;13C NMR (75 MHz,DMSO-d6):δ195.4,178.5,164.9,160.2,159.3,157.0,138.7,136.5,136.4,117.7,114.9,111.5,57.3,50.4,47.7, 32.3,27.8;Anal.calcd for C19H16FN3O3:C 64.58,H 4.56,F 5.38,N 11.89; found C 64.53,H 4.65,F 5.32,N 11.83.

2-Amino-5′,7,7-trimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (6c).白色固體,1H NMR (300 MHz,DMSO-d6):δ10.28 (s,1H,NH),7.19 (s,2H,NH2),6.94 (d,J=7.5 Hz,1H,ArH),6.77 (s,1H,ArH),6.68 (d,J=7.5 Hz,1H,ArH),2.53 (s,1H,CH2),2.18(s,3H,CH3),2.12 (s,2H,CH2),2.06 (s,3H,CH3),1.01 (s,3H,CH3),0.99(s,3H,CH3) .13C NMR (75 MHz,DMSO-d6):δ195.3,178.4,164.5,159.1,140.0,134.9,130.9,128.9,124.0,117.8,111.2,109.4,58.1,50.4,47.3,32.4,27.9,21.1;Anal.calcd for C20H19N3O3:C 68.75,H 5.48,N 12.03; found C 68.71,H 5.51,N 12.01.

2-Amino-5′-chloro-7,7-dimethyl-2′,5-dioxo-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-3-carbonitrile (6d).白色固體,1H NMR (300 MHz,DMSO-d6):δ10.52 (s,1H,NH),7.29 (s,2H,NH2),7.18 (d,J=8.1 Hz,1H,ArH),7.07 (s,1H,ArH),6.79 (d,J=8.4 Hz,1H,ArH),2.48 (s,2H,CH2),2.13 (s,2H,CH2),0.99 (s,3H,CH3) ;13C NMR (75 MHz,DMSO-d6):δ196.0,178.5,165.4,159.3,141.0,136.6,128.6,126.3,123.6,117.5,111.2,110.4,50.3,57.0,47.4,32.3,27.8,27.5;Anal.calcd for C19H16ClN3O3:C 61.71,H 4.36,Cl 9.59,N 11.36; found C 61.65,H 4.42,Cl 9.51,N 11.31.

2 結(jié)果與討論

在實(shí)驗(yàn)條件下,首先考察了芳香醛中取代基對(duì)該反應(yīng)的影響，具體結(jié)果見(jiàn)表1.實(shí)驗(yàn)結(jié)果表明,當(dāng)芳香醛中苯環(huán)上連有吸電子基(如-Cl,-NO2)時(shí),芳醛活性較高,有利于反應(yīng)的進(jìn)行,反應(yīng)產(chǎn)率較高(表1,Entries 2,3).當(dāng)芳香醛中苯環(huán)上連有供電子基(如-CH3,-OCH3)時(shí),芳醛活性降低,不有利于反應(yīng)的進(jìn)行,反應(yīng)產(chǎn)率較低(表1,Entries 4-6).

表1無(wú)催化劑下的多組分反應(yīng)合成2-氨基-3-氰基5-氧代-5,6,7,8-四氫色烯衍生物
Tab. 1Synthesisof2-amino-3-cyano-5-oxo-5,6,7,8-tetrahydro-4H-chromenederivativesviacatalyst-freemulticomponentreactions

EntryR1Time/hProduct 4Yield/%1H (1a)124a8524-NO2 (1b)84b9234-Cl (1c)84c8844-OCH3 (1d)154d8354-CH3 (1e)124e8463,4-OCH3 (1f)184f78

隨后,在同樣實(shí)驗(yàn)條件下,將芳香醛換成靛紅衍生物與丙二腈、雙甲酮進(jìn)行三組分反應(yīng),結(jié)果顯示該三組分反應(yīng)同樣可以順利進(jìn)行,且反應(yīng)在較短時(shí)間內(nèi)即可完成,并得到一種2-氨基-3-氰基-5,6,7,8-四氫螺色烯-4,3′-二氫吲哚-2′,5-二酮衍生物.隨后考察了靛紅苯環(huán)上不同取代基對(duì)該反應(yīng)的影響,具體結(jié)果見(jiàn)表2.

表2無(wú)催化劑下的多組分反應(yīng)合成2-氨基-3-氰基-5,6,7,8-四氫螺色烯-4,3′-二氫吲哚-2′,5-二酮衍生物
Tab. 2Synthesisof2-amino-3-cyano-5,6,7,8-tetrahydrospiro[chromene-4,3′-indoline]-2,5′-dionederivativesviacatalyst-freemulticomponentreactions

EntryR2Time/hProduct 6Yield/%1H (5a)86a8625-F (5b)46b8135-Cl (5d)66c8245-CH3 (5c)86d89

結(jié)果表明,當(dāng)?shù)寮t苯環(huán)上連有吸電子基(如-F,-Cl)時(shí),靛紅羰基活性降低,不利于反應(yīng)的進(jìn)行,反應(yīng)產(chǎn)率偏低(表2,Entries 2,3).當(dāng)?shù)寮t苯環(huán)上連有供電子基(如-CH3)時(shí),靛紅羰基活性增強(qiáng),有利于反應(yīng)的進(jìn)行,反應(yīng)產(chǎn)率較高(表2,Entry 4).反應(yīng)后得到的系列環(huán)己酮并吡喃衍生物的結(jié)構(gòu)均經(jīng)1H NMR,13C NMR表征.

根據(jù)文獻(xiàn)報(bào)道、反應(yīng)底物及產(chǎn)物的結(jié)構(gòu)等,對(duì)該反應(yīng)提出一種可能的反應(yīng)機(jī)理(2).首先,芳醛1中醛基或靛紅5中3位羰基與丙二腈2發(fā)生Knoevenagel縮合得到芐叉基化合物A,進(jìn)而與雙甲酮的烯醇式中間體B發(fā)生Michael加成反應(yīng)得到中間體C,中間體C中羥基親核進(jìn)攻氰基得到中間體D,中間體D發(fā)生異構(gòu)化反應(yīng)得到目標(biāo)化合物4.用靛紅作反應(yīng)底物與丙二腈和5,5-二甲基-1,3-環(huán)己二酮反應(yīng)合成2-氨基-3-氰基-5,6,7,8-四氫螺色烯-4,3′-二氫吲哚-2′,5-二酮衍生物時(shí),反應(yīng)機(jī)理與此類(lèi)似.

3 結(jié)論

本文發(fā)展了一種乙醇中無(wú)催化劑下的芳醛或靛紅與丙二腈、5,5-二甲基-1,3-環(huán)己二酮的三組分反應(yīng)合成環(huán)己酮并吡喃和螺吲哚-3,4′-吡喃-2-酮衍生物的新方法.該反應(yīng)沒(méi)有使用催化劑和有毒有害的有機(jī)溶劑,室溫下三組分一步即可得到目標(biāo)產(chǎn)物,具有實(shí)驗(yàn)操作簡(jiǎn)單,反應(yīng)條件溫和,產(chǎn)率高等優(yōu)點(diǎn),原子經(jīng)濟(jì)性高,符合綠色化學(xué)的要求.