杜曼飛, 侯　丹, 惠文萍, 陳戰(zhàn)國(guó)

(陜西省大分子科學(xué)重點(diǎn)實(shí)驗(yàn)室, 陜西師范大學(xué)化學(xué)化工學(xué)院, 西安 710119)

?

β-硝基苯乙烯衍生物與丙烯酰胺及N-溴代丁二酰亞胺的區(qū)域?qū)Ｒ恍园变寮映煞磻?yīng)

杜曼飛, 侯丹, 惠文萍, 陳戰(zhàn)國(guó)

(陜西省大分子科學(xué)重點(diǎn)實(shí)驗(yàn)室, 陜西師范大學(xué)化學(xué)化工學(xué)院, 西安 710119)

摘要以β-硝基苯乙烯衍生物為底物, 丙烯酰胺和N-溴代丁二酰亞胺(NBS)為氮源和鹵素源, 建立了碳-碳雙鍵上的選擇性氨溴加成反應(yīng)新體系. 以二氯甲烷為溶劑, 在沒(méi)有惰性氣體保護(hù)及乙醇鈉促進(jìn)下, β-硝基苯乙烯衍生物與丙烯酰胺和NBS于室溫反應(yīng)即可高收率地獲得α-氨基-β,β-二溴加成產(chǎn)物, 最高收率達(dá)83%; 以甲醇為溶劑, 在無(wú)水碳酸鈉作用下, β-甲基-β-硝基苯乙烯衍生物也可高收率地獲得相應(yīng)的鄰位氨溴加成產(chǎn)物, 最高收率達(dá)97%. 共考察了25種不同結(jié)構(gòu)β-硝基苯乙烯衍生物的氨溴加成反應(yīng), 結(jié)果表明, 該反應(yīng)具有廣泛的適應(yīng)性. 采用核磁共振波譜及質(zhì)譜表征了產(chǎn)物的結(jié)構(gòu), 并提出了可能的反應(yīng)機(jī)理.

關(guān)鍵詞氨溴加成反應(yīng); β-硝基苯乙烯; 區(qū)域?qū)Ｒ恍? 丙烯酰胺; N-溴代丁二酰亞胺

烯烴的氨鹵加成反應(yīng)是一類(lèi)在碳-碳雙鍵上同時(shí)引入氨基和鹵原子而形成具有鄰位氨基鹵素雙官能團(tuán)的重要反應(yīng)[1]. 在一定條件下, 鄰位氨基鹵素可以發(fā)生分子內(nèi)親核取代反應(yīng)形成氮雜環(huán)丙烷, 再由氮雜環(huán)丙烷的開(kāi)環(huán)-閉環(huán)反應(yīng)構(gòu)建一系列的雜環(huán)化合物; 由于鹵素是一個(gè)容易離去的基團(tuán), 可與其它親核試劑發(fā)生分子間的親核取代反應(yīng), 形成新的雙官能化合物(如氨基醇、 內(nèi)酰胺及α,β-脫氫氨基酸衍生物[2]等); 鄰位氨基鹵素在一定條件下還可形成氨基烯, 進(jìn)而發(fā)生Diels-Alder反應(yīng). 因此, 烯烴的氨鹵化反應(yīng)在有機(jī)合成[3]、 藥物分子設(shè)計(jì)及天然產(chǎn)物結(jié)構(gòu)改造[4]等方面有重要的應(yīng)用.

β-硝基苯乙烯是進(jìn)行氨鹵加成反應(yīng)最有用的底物之一[5], 其加成產(chǎn)物中的硝基易被還原成氨基, 從而形成鄰位二氨基化合物[6], 該類(lèi)化合物在化學(xué)和生物學(xué)上有廣闊的應(yīng)用前景. 多數(shù)已報(bào)道的β-硝基苯乙烯的氨鹵化反應(yīng)均需在氮?dú)獗Ｗo(hù)下進(jìn)行[7], 且所用氮源/鹵素源(如N,N-二氯對(duì)甲苯磺酰胺[8])的獲取比較困難. 近年來(lái), 本課題組[9～14]對(duì)烯烴的氨鹵加成反應(yīng)進(jìn)行了深入研究, 發(fā)現(xiàn)多種新的氮源/鹵素源, 建立了多種氨鹵加成反應(yīng)新方法. 在此基礎(chǔ)上, 本文研究了β-硝基苯乙烯衍生物的氨鹵加成反應(yīng), 建立了乙醇鈉和碳酸鈉促進(jìn)下, 丙烯酰胺和NBS作為氮源和鹵素源的β-硝基苯乙烯衍生物的氨溴加成新方法. 以丙烯酰胺作為氮源, 可以在產(chǎn)物中引入一個(gè)丙烯酰氨基活性官能團(tuán). 由于丙烯酰氨基活性官能團(tuán)能參與多種反應(yīng), 如可與其它試劑形成具有生物活性的聚合物[15], 在過(guò)渡金屬催化下, 聚合物繼續(xù)與芳香族腈類(lèi)發(fā)生還原偶合反應(yīng), 形成吡咯烷酮衍生物[16]. 因此, 丙烯酰氨基的引入有望擴(kuò)大氨鹵加成反應(yīng)的應(yīng)用范圍.

1實(shí)驗(yàn)部分

1.1試劑與儀器

實(shí)驗(yàn)所用試劑均為分析純, 使用前未經(jīng)純化處理; 丙烯酰胺和N-溴代丁二酰亞胺(NBS)購(gòu)自國(guó)藥集團(tuán)化學(xué)試劑有限公司.

AVANCE600/300MHz超導(dǎo)傅里葉數(shù)字化核磁共振儀(瑞士Bruker公司);GCMS-Qp2010UItra型質(zhì)譜儀(日本島津公司);BS224S型電子天平(德國(guó)賽多利斯集團(tuán));RE-52AA型旋轉(zhuǎn)蒸發(fā)器(上海亞榮生化儀器廠);XT5A型顯微熔點(diǎn)測(cè)定儀(北京市科儀電光儀器廠).

1.2實(shí)驗(yàn)過(guò)程

1.2.1底物的合成參照文獻(xiàn)[17]方法合成β-硝基苯乙烯類(lèi)化合物(1a～25a, 見(jiàn)Scheme1), 產(chǎn)物的熔點(diǎn)列于表1.

1a: R1=H, R2=H; 2a: R1=4-CH3, R2=H; 3a: R1=4-OCH3, R2=H; 4a: R1=3,4-(OCH3)2, R2=H; 5a: R1=3,5-(OCH3)2, R2=H; 6a: R1=2-Br-4,5-(OCH3)2, R2=H; 7a: R1=4-F, R2=H; 8a: R1=4-Cl, R2=H; 9a: R1=4-Br, R2=H; 10a: R1=3,4-Cl2, R2=H; 11a: R1=4-NO2, R2=H; 12a: R1=2-NO2, R2=H; 13a: R1=3-CHCHCHCH-4, R2=H; 14a: R1=H, R2=CH3; 15a: R1=4-CH3, R2=CH3; 16a: R1=4-OCH3, R2=CH3; 17a: R1=3,4-(OCH3)2, R2=CH3; 18a: R1=3,5-(OCH3)2, R2=CH3; 19a: R1=3,4,5-(OCH3)3, R2=CH3; 20a: R1=2-Br-4,5-(OCH3)2, R2=CH3; 21a: R1=4-F, R2=CH3; 22a: R1=4-Cl, R2=CH3; 23a: R1=4-Br, R2=CH3; 24a: R1=4-NO2, R2=CH3; 25a: R1=2-NO2, R2=CH3. Scheme 1　Synthesis route of β-nitrostyrene derivativesTable 1　Melting points of β-nitrostyrene derivatives 1a—25a

Compd.m.p.(Ref.)/℃Compd.m.p.(Ref.)/℃1a57.1—58.5(58[18])14a65.7—66.8(65—66[28])2a100.1—102.1(102—102.5[19])15a54.0—54.4(55[29])3a84.4—86.0(85.5—87.5[20])16a47.6—49(48[30])4a143.6—144.217a71.5—72.05a133.6—135.1(133.5—134.5[21])18a87.0—87.4(87—88[31])6a98—99(98—99[22])19a94.0—94.8(95[32])7a101—103(101—102.5[23])20a96.4—97.3(96—97[22])8a114.3—115.4(113—114[24])21a64.0—65.1(66[33])9a149.3—150.6(151—153[25])22a86—89(86—87[34])10a56.2—57.823a92.6—93.8(93—95[33])11a123.1—124.3(124.5—126[20])24a113.8—114.1(114—115[35])12a105.4—105.8(106—107[26])25a73.5—74.8(74[36])13a120—122(121—122[27])

化合物4a, 10a和17a均未見(jiàn)文獻(xiàn)報(bào)道. 化合物4a,1HNMR(CDCl3, 600MHz), δ: 7.90(d, J=13.6Hz, 1H,CH), 7.47(d, J=13.6Hz, 1H,CH), 7.11(d, J=8.3Hz, 1H,ArH), 6.94(d, J=1.9Hz, 1H,ArH), 6.85(d, J=8.3Hz, 1H,ArH), 3.88(s, 3H,OCH3), 3.86(s, 3H,OCH3);13CNMR(CDCl3, 151MHz), δ: 152.8, 149.6, 139.3, 135.2, 124.6, 122.8, 111.4, 110.3, 56.11, 56.03, 14.20;HRMS(C10H11NNaO4計(jì)算值), m/z: 232.0582(232.0586)[M+Na]+. 化合物10a,1HNMR(CDCl3, 600MHz), δ: 7.91(d, J=13.7Hz, 1H,CH), 7.65(d, J=2.0Hz, 1H,CH), 7.56(d, J=10.3Hz, 1H,ArH), 7.54(d, J=4.9Hz, 1H,ArH), 7.39(dd, J=8.3, 2.0Hz, 1H,ArH);13CNMR(CDCl3, 151MHz), δ: 138.3, 136.4, 133.9, 131.5, 130.6, 130.0, 127.9;HRMS(C8H5Cl2NNaO4計(jì)算值), m/z: 239.9588(239.9595)[M+Na]+. 化合物17a,1HNMR(CDCl3, 600MHz), δ: 8.00(s, 1H,ArH), 7.02(d, J=8.3Hz, 1H,CH), 6.92～6.84(m, 2H,ArH), 3.87(s, 3H,OCH3), 3.85(s, 3H,OCH3), 2.43(s, 3H,CH3);13CNMR(CDCl3, 151MHz), δ: 171.1, 150.8, 149.1, 145.9, 133.8, 125.0, 124.0, 113.1, 111.3, 111.2, 77.24, 77.03, 76.82, 60.38, 56.00, 56.00, 21.03, 14.18;HRMS(C11H13NNaO4計(jì)算值), m/z: 246.0737(246.0742)[M+Na]+. 化合物4a, 10a和17a的磁共振譜圖見(jiàn)圖S1～圖S3(見(jiàn)本文支持信息), 質(zhì)譜圖見(jiàn)圖S4～圖S6(見(jiàn)本文支持信息).

1.2.2氨溴加成反應(yīng)氨溴加成反應(yīng)路線如Scheme2所示.

1b, 14b: R1=H; 2b, 15b: R1=4-CH3; 3b, 16b: R1=4-OCH3; 4b, 17b: R1=3,4-(OCH3)2; 5b, 18b: R1=3,5-(OCH3)2; 6b, 20b: R1=2-Br-4,5-(OCH3)2; 7b, 21b: R1=4-F; 8b, 22b: R1=4-Cl; 9b, 23b: R1=4-Br; 10b: R1=3,4-Cl2; 11b, 24b: R1=4-NO2; 12b, 25b: R1=2-NO2; 13b: R1=3-CHCHCHCH-4; 19b: R1=3,4,5-(OCH3)3. Scheme 2　Aminobromination of β-nitrostyrene derivatives with acrylamide and NBS

化合物1b～13b的合成: 以化合物1b的合成為例, 向25mL燒瓶中依次加入化合物1a(1.0mmol)、 丙烯酰胺(2.0mmol)、NBS(2.0mmol)、 乙醇鈉(1.1mmol)和10mL二氯甲烷, 室溫下攪拌, 用薄層色譜(TLC)跟蹤反應(yīng). 反應(yīng)完成后, 向反應(yīng)液中加入25mL乙酸乙酯稀釋, 稀釋液依次用飽和食鹽水(10mL×3)和蒸餾水(10mL×3)洗滌, 有機(jī)相用無(wú)水硫酸鈉干燥, 過(guò)濾除去干燥劑, 減壓濃縮. 粗產(chǎn)物經(jīng)柱色譜[V(石油醚)∶V(乙酸乙酯)=2∶1]分離純化后真空干燥. 化合物2b～13b的合成方法與化合物1b相同.

化合物14b～25b的合成與化合物1b～13b的合成類(lèi)似, 使用14a～25a各1.0mmol, 丙烯酰胺2.0mmol,NBS2.0mmol, 促進(jìn)劑為Na2CO3(1.1mmol), 溶劑為甲醇(10mL).

化合物1b～25b的表征結(jié)果見(jiàn)表2和表3, 核磁共振譜圖見(jiàn)圖S7～圖S31(見(jiàn)本文支持信息), 質(zhì)譜圖見(jiàn)圖S32～圖S56(見(jiàn)本文支持信息).

Table 2　Appearance, yields, melting points and HRMS data for compounds 1b—25b

*Yieldafterpurificationbycolumnchromatography.

Table 3　1H NMR and 13C NMR data for compounds 1b—25b*

Continued

Compd.1HNMR(CDCl3),δ13CNMR(CDCl3),δ16b7.19(d,J=8.7Hz,2H,ArH),6.84(d,J=8.8Hz,2H,ArH),6.36(dd,J=17.0,1.2Hz,1H,CH),6.23(dd,J=17.0,10.3Hz,1H,CH),5.80(d,J=9.7Hz,1H,CH),5.74(dd,J=10.3,1.2Hz,1H,CH),3.78(s,3H,CH3),2.24(s,3H,CH3)164.6,160.2,130.2,129.8,129.4,128.1,126.0,114.4,114.1,96.7,60.11,55.29,29.417b7.74(d,J=9.4Hz,1H,NH),6.88(d,J=8.0Hz,1H,ArH),6.83(s,1H,ArH),6.76(d,J=8.2Hz,1H,ArH),6.31(d,J=17.1Hz,1H,CH),6.25(t,J=13.4Hz,1H,CH),5.89(d,J=9.5Hz,1H,CH),5.66(d,J=8.7Hz,1H,CH),3.80(s,3H,OCH3),3.77(s,3H,OCH3),2.25(s,3H,CH3)165.0,149.7,149.0,130.1,128.2,126.5,121.0,111.8,111.2,96.9,60.40,55.98,55.81,28.8718b7.51(d,J=8.7Hz,1H,ArH),6.72(dd,J=7.5,5.8Hz,1H,ArH),6.51(dd,J=5.8,3.0Hz,1H,ArH),6.45(d,J=2.6Hz,1H,CH),6.38(dt,J=17.1,3.7Hz,1H,CH),6.26(t,J=6.5Hz,1H,CH),5.75(dd,J=10.1,1.4Hz,1H,CH),3.86(s,3H,OCH3),3.74(s,3H,OCH3),2.27(s,3H,CH3)164.5,160.4,157.2,136.1,129.9,128.3,105.8,103.8,100.2,93.82,59.33,56.43,55.58,28.2419b6.46(s,2H,ArH),6.39(dd,J=17.0,1.1Hz,1H,CH),6.26(dd,J=17.0,10.3Hz,1H,CH),5.78(dd,J=10.3,1.1Hz,1H,CH),5.72(d,J=9.6Hz,1H,CH),3.82(s,9H,3OCH3),2.25(s,3H,CH3)164.6,153.5,138.9,130.1,129.4,128.3,105.4,95.68,60.93,60.82,56.28,29.7120b7.04(t,J=17.9Hz,2H,ArH),6.56(s,1H,CH),6.43—6.38(m,1H,CH),6.29—6.26(m,1H,CH),5.77(d,J=10.3Hz,1H,CH),3.86(s,3H,OCH3),3.78(s,3H,OCH3),2.27(s,3H,CH3)164.5,150.1,149.3,129.9,128.4,125.8,116.2,116.0,115.7,109.6,94.06,60.40,59.44,21.0421b7.27(dd,J=6.0,2.7Hz,2H,ArH),7.02(t,J=8.6Hz,2H,ArH),6.37(dd,J=17.0,1.1Hz,1H,CH),6.23(dd,J=17.0,10.3Hz,1H,CH),5.85(d,J=9.6Hz,1H,CH),5.76(dd,J=10.3,1.1Hz,1H,CH),2.25(s,3H,CH3)164.7,163.9,130.5,130.1,130.1,129.9,128.5,116.1,116.0,96.41,59.98,29.4122b7.31(d,J=8.5Hz,2H,ArH),7.22(d,J=8.5Hz,2H,ArH),6.37(dd,J=17.0,1.1Hz,1H,CH),6.23(dd,J=17.0,10.3Hz,1H,CH),5.83(d,J=9.6Hz,1H,CH),5.76(dd,J=10.3,1.1Hz,1H,CH),2.25(s,3H,CH3)164.7,135.5,132.7,130.0,129.9,129.6,129.2,128.9,128.5,96.17,60.06,29.3923b7.47(d,J=8.5Hz,2H,ArH),7.16(d,J=8.5Hz,2H,ArH),6.37(dd,J=17.0,1.0Hz,1H,CH),6.23(dd,J=17.0,10.3Hz,1H,CH),5.81(d,J=9.6Hz,1H,CH),5.77(dd,J=10.3,1.0Hz,1H,CH),2.25(s,3H,CH3)164.7,133.2,132.2,131.9,130.2,129.9,129.9,128.5,123.7,96.03,60.13,29.4424b8.21(d,J=7.0Hz,3H,ArH,NH),7.49(d,J=8.7Hz,2H,ArH),6.39(d,J=16.3Hz,1H,CH),6.2(dd,J=17.0,10.3Hz,1H,CH),5.92(d,J=9.3Hz,1H,CH),5.82(d,J=10.4Hz,1H,CH),2.30(s,3H,CH3)171.6,165.3,148.2,141.7,130.0,129.9,129.5,129.0,123.7,96.59,59.95,21.0425b7.99(dd,J=20.3,8.1Hz,1H,ArH),7.72(d,J=53.7Hz,1H,ArH),7.63—7.50(m,2H,ArH),7.01(dd,J=31.6,8.0Hz,1H,CH),6.79—6.66(m,1H,CH),6.34(dd,J=27.1,16.6Hz,1H,CH),5.75(dd,J=17.5,9.7Hz,1H,CH),2.27(d,J=6.2Hz,3H,CH3)164.7,149.9,133.9,133.4,130.2,129.6,128.0,125.6,125.4,102.3,54.90,29.98

*Compounds1b, 8b, 9b, 11band18b:1HNMR(300MHz),13CNMR(75MHz);compounds2b—7b, 10b, 12b—17band19b—25b:1HNMR(600MHz),13CNMR(151MHz).

2結(jié)果與討論

2.1促進(jìn)劑、 溶劑和反應(yīng)溫度的影響

β-硝基苯乙烯屬于缺電子烯烴, 在加成反應(yīng)中應(yīng)該表現(xiàn)出Michael反應(yīng)的特征, 堿是必要的促進(jìn)劑. 首先選用β-硝基苯乙烯1a作為反應(yīng)模板, 以丙烯酰胺和NBS作為氮源和溴源, 二氯甲烷作為溶劑, 室溫下對(duì)常見(jiàn)堿的促進(jìn)作用進(jìn)行了考察, 結(jié)果見(jiàn)表4. 由表4可知, 當(dāng)促進(jìn)劑用量為硝基苯乙烯的110%(摩爾分?jǐn)?shù))時(shí)(表4中Entries1～10),CH3CH2ONa對(duì)該反應(yīng)有較好的促進(jìn)作用(表4中Entry10, 收率為83%);K3PO4,K2CO3,Na2CO3,NaOH和KOH也有一定的促進(jìn)作用, 但都不及CH3CH2ONa； 乙二胺和三乙胺等有機(jī)堿(表4中Entries8和9)不是該反應(yīng)的有效促進(jìn)劑. 進(jìn)一步篩選CH3CH2ONa的用量(表4中Entries11～14)發(fā)現(xiàn), 其用量為110%(摩爾分?jǐn)?shù))時(shí)收率最高, 增加或減少堿的用量, 收率都會(huì)下降. 對(duì)比實(shí)驗(yàn)結(jié)果表明, 不加堿(表4中Entry15), 該反應(yīng)只能得到痕量產(chǎn)物, 說(shuō)明堿在反應(yīng)中具有重要的作用. 加熱回流時(shí)(表4中Entry23), 反應(yīng)的收率未明顯提高. 通過(guò)對(duì)常用溶劑的篩選發(fā)現(xiàn), 二氯甲烷是該反應(yīng)的有效溶劑(表4中Entries16～22). 以中等活性β-甲基-β-硝基苯乙烯(14b)為底物模板, 丙烯酰胺和NBS作為氮源和溴源, 在CH2Cl2溶劑中反應(yīng)24h的結(jié)果列于表4. 可見(jiàn), 當(dāng)促進(jìn)劑用量為硝基苯乙烯的110%(摩爾分?jǐn)?shù))時(shí)(表4中Entries24～33),Na2CO3對(duì)該反應(yīng)有較好的促進(jìn)作用(表4中Entry26, 收率24%);K3PO4,NaOH,KOH,CH3ONa和CH3CH2ONa等無(wú)機(jī)堿也具有一定的促進(jìn)作用, 但效果都不及Na2CO3; 乙二胺和三乙胺等有機(jī)堿(表4

Table 4　Effects of catalyst and temperature as well as solvent to the aninobronation of β-nitrostyrenea

a.Reactionconditionforformula(1)inScheme2: β-nitrostyrene(1.0mmol),acrylamide(2.0mmol),NBS(2.0mmol),catalyst,solvent(10mL), 25 ℃;forformula(2)inScheme2: β-methyl-β-nitrostyrene(1.0mmol),acrylamide(2.0mmol),NBS(2.0mmol),catalyst,solvent(10mL), 25 ℃; b.isolatedyieldaftercolumnchromatographicpurification; c.NR:noreaction.

中Entries32和33)不是該反應(yīng)的有效促進(jìn)劑. 在此基礎(chǔ)上對(duì)常用的溶劑也進(jìn)行了篩選(表4中Entries34～40), 發(fā)現(xiàn)甲醇是該反應(yīng)的最有效溶劑(表4中Entry40, 產(chǎn)率93%). 在確定甲醇為溶劑后, 進(jìn)一步篩選Na2CO3的用量(表4中Entries40～43)發(fā)現(xiàn),Na2CO3用量為110%(摩爾分?jǐn)?shù))時(shí)收率最高. 對(duì)比實(shí)驗(yàn)結(jié)果表明, 不加堿(表4中Entry44), 該反應(yīng)僅能得到痕量產(chǎn)物, 說(shuō)明堿在反應(yīng)中起到重要作用. 當(dāng)加熱回流24h后, 反應(yīng)變得相當(dāng)復(fù)雜. 控制回流時(shí)間為2h, 僅得到了27%的目標(biāo)產(chǎn)物(表4中Entry45), 說(shuō)明提高反應(yīng)溫度不利于該反應(yīng)的進(jìn)行.

上述實(shí)驗(yàn)結(jié)果表明, 反應(yīng)的優(yōu)化條件為: (1)CH3CH2ONa(摩爾分?jǐn)?shù)110%), n[β-硝基苯乙烯衍生物(1a～13a)]∶n(丙烯酰胺)∶n(NBS)=1∶2∶2, 溶劑為CH2Cl2, 室溫下攪拌反應(yīng); (2)Na2CO3(摩爾分?jǐn)?shù)110%), n[β-甲基-β-硝基苯乙烯衍生物(14a～25a)]∶n(丙烯酰胺)∶n(NBS)=1∶2∶2, 溶劑CH3OH, 室溫下攪拌反應(yīng).

2.2底物結(jié)構(gòu)對(duì)反應(yīng)的影響

為了探索該反應(yīng)的普適性, 在優(yōu)化條件下對(duì)各種β-硝基苯乙烯衍生物的氨溴加成反應(yīng)進(jìn)行了考察, 結(jié)果列于表5. 可見(jiàn), 各種硝基苯乙烯衍生物均能順利地進(jìn)行氨溴加成反應(yīng), 但因結(jié)構(gòu)不同而表現(xiàn)出不同的反應(yīng)活性.

Table 5　Aminobromination of β-nitrostyren derivatives with acrylamide and NBS promoted by basea

a.RractionequationsarethesameasScheme2.Reactionconditionsforthesynthesesofcompounds1b—13b: β-nitrostyrenderivation(1.0mmol),acrylamide(2.0mmol),NBS(2.0mmol),CH3CH2ONa(110%,molarfraction),CH2Cl2(10mL), 24h, 25 ℃;reactionconditionsforthesynthesesofcompounds14b—25b: β-methyl-β-nitrostyrenederivation(1.0mmol),acrylamide(2.0mmol),NBS(2.0mmol),Na2CO3(110%,molarfraction),CH3OH(10mL), 24h, 25 ℃; b.isolatedyieldaftercolumnchromatographicpurification.

2.2.1反應(yīng)活性與苯環(huán)上取代基的關(guān)系從反應(yīng)收率看, 苯環(huán)上有供電子基團(tuán)的β-硝基苯乙烯衍生物的反應(yīng)收率相對(duì)較低(表5中Entries2～6, 40%～52%)； 而對(duì)于苯環(huán)上有吸電子基的β-硝基苯乙烯衍生物, 其反應(yīng)收率相對(duì)較高(表5中Entries7～12, 收率56%～81%)； 1-萘型的硝基烯得到中等收率(表5中Entry13, 收率58%). 以上結(jié)果表明, 對(duì)于β-硝基苯乙烯衍生物, 碳-碳雙鍵上電子密度越小, 反應(yīng)的活性越高; 同時(shí)底物的空間位阻越大, 反應(yīng)的活性越低. 對(duì)于β-甲基-β-硝基苯乙烯衍生物(14a～25a), 在優(yōu)化條件下, 反應(yīng)活性的規(guī)律與β-硝基苯乙烯衍生物活性的規(guī)律相似. 當(dāng)苯環(huán)上有給電子基團(tuán)時(shí), 其氨溴加成反應(yīng)活性降低, 相應(yīng)的收率也隨之降低(表5中Entries15～20, 收率19%～45%). 當(dāng)苯環(huán)上有吸電子基團(tuán)時(shí), 其反應(yīng)活性增強(qiáng), 反應(yīng)收率也相應(yīng)提高(表5中Entries21～25, 收率52%～97%). 當(dāng)苯環(huán)上有多個(gè)取代基時(shí), 特別是在苯環(huán)的3,5-位有強(qiáng)的給電子基時(shí), 電子效應(yīng)和位阻效應(yīng)的疊加導(dǎo)致反應(yīng)收率進(jìn)一步下降(表5中Entries18和19). 以上結(jié)果表明, 無(wú)論是β-硝基苯乙烯衍生物還是β-甲基-β-硝基苯乙烯衍生物, 其氨溴加成反應(yīng)的活性不僅取決于底物的空間位阻效應(yīng), 還取決于底物雙鍵上的電子效應(yīng). 雙鍵上的電子密度越低, 其反應(yīng)活性越高; 反之, 雙鍵上的電子密度越高, 其反應(yīng)活性越低. 此結(jié)果表明, 該氨溴加成反應(yīng)可能是一個(gè)親核加成反應(yīng).

Fig.1　Crystal structure of 1-acrylamido-2,2-dibromo-1-(4-methylphenyl) nitroethane(2b)

2.2.2反映的區(qū)域選擇性從2類(lèi)反應(yīng)的結(jié)果看, 所有產(chǎn)物中氨基均加在與苯環(huán)相連的碳原子上, 而溴原子則加在與硝基相連的碳原子上, 表現(xiàn)出區(qū)域?qū)Ｒ恍? 為了進(jìn)一步確證反應(yīng)的區(qū)域選擇性, 對(duì)其中1個(gè)加成產(chǎn)物進(jìn)行了單晶結(jié)構(gòu)分析. 1-(4-甲苯基)-1-丙烯酰胺-2,2-二溴-2-硝基乙烷(2b,CCDCNo.1432487)的單晶結(jié)構(gòu)分析結(jié)果表明, 氨基加在與苯環(huán)相連的碳原子上, 而溴原子加在與硝基相連的碳原子上, 而且該碳原子完全溴化(見(jiàn)圖1). 其它產(chǎn)物的結(jié)構(gòu)以1HNMR和13CNMR波譜中的化學(xué)位移和氫的偶合常數(shù)得以確證, 說(shuō)明堿催化能高度控制該反應(yīng)的區(qū)域選擇性.

2.2.3鹵素源的普適性為了考察該反應(yīng)對(duì)鹵素源的普適性, 將實(shí)驗(yàn)所用鹵素源NBS換為N-氯代丁二酰亞胺(NCS), 以丙烯酰胺為氮源, β-硝基苯乙烯為底物, 在相同的實(shí)驗(yàn)條件下制得1-苯基-1-丙烯酰氨基-2,2-二氯-2-硝基乙烷白色固體作為對(duì)照,m.p. 168.5～168.7 ℃,HRMS(C11H10Cl2NaN2O3計(jì)算值), m/z: 310.9955(310.9966)[M+Na]+, 質(zhì)譜圖見(jiàn)圖S57(見(jiàn)本文支持信息), 說(shuō)明鹵素源NBS和NCS均適合該反應(yīng)(見(jiàn)Scheme3).

Scheme 3　Aminochlorination of β-nitrostyrene with acryl amide and NCS

Scheme 4　Possible mechanism of the aminobromination reaction

2.3反應(yīng)機(jī)理

根據(jù)實(shí)驗(yàn)結(jié)果提出了與文獻(xiàn)[37]相似的反應(yīng)機(jī)理, 如Scheme4所示. 首先, 丙烯酰胺和N-溴代丁二酰亞胺之間發(fā)生質(zhì)子和溴的交換反應(yīng), 建立一個(gè)4組分共存的平衡體系(混合物的1HNMR圖譜見(jiàn)圖S58, 見(jiàn)本文支持信息), 生成重要的中間體N-溴代丙烯酰胺(A), 在堿(B=CH3CH2O-或NaOCOO-)的作用下, 中間體A失去質(zhì)子, 產(chǎn)生一個(gè)氮負(fù)離子B,B作為親核試劑與β-硝基苯乙烯發(fā)生加成反應(yīng), 生成中間體C, 接著發(fā)生分子內(nèi)溴正離子的遷移, 得到中間體D. 當(dāng)β-硝基苯乙烯結(jié)構(gòu)中R=H時(shí), 中間體D發(fā)生氫遷移得到中間體E,E與A作用得到產(chǎn)物P1(即產(chǎn)物1b～13b), 同時(shí)A被轉(zhuǎn)變成氮負(fù)離子F,F再與另一分子A作用得到氮負(fù)離子B,B參加下一次循環(huán). 當(dāng)β-硝基苯乙烯衍生物結(jié)構(gòu)中R為甲基時(shí), 中間體D與A作用生成產(chǎn)物P2(即產(chǎn)物14b～25b)和中間體B,B再參與下一次循環(huán).

3結(jié)論

以丙烯酰胺和N-溴代丁二酰亞胺為氮源/溴源, 分別以二氯甲烷和甲醇作溶劑, 在不同促進(jìn)劑CH3CH2ONa和Na2CO3的存在下, 建立了2類(lèi)不同的β-硝基苯乙烯衍生物的氨溴加成反應(yīng)新體系. 該反應(yīng)具有條件溫和、 操作簡(jiǎn)單、 可接受的收率及區(qū)域選擇性高等特點(diǎn). 該反應(yīng)以不飽和酰胺作為氮源, 在產(chǎn)物中引入了1個(gè)丙烯酰氨基活性官能團(tuán). 由于該活性官能團(tuán)能參與多種反應(yīng), 如可與其它試劑形成具有生物活性的聚合物, 在過(guò)渡金屬催化下, 聚合物繼續(xù)與芳香族腈類(lèi)發(fā)生還原偶合反應(yīng), 形成吡咯烷酮衍生物. 因此, 丙烯酰氨基的引入有望擴(kuò)大氨鹵加成反應(yīng)的應(yīng)用范圍. 通過(guò)大量不同結(jié)構(gòu)的氨溴加成反應(yīng)活性的比較, 證明該類(lèi)缺電子烯烴的氨溴加成反應(yīng)是一個(gè)親核加成反應(yīng). 在實(shí)驗(yàn)基礎(chǔ)上, 提出了可能的反應(yīng)機(jī)理.

支持信息見(jiàn)http://www.cjcu.jlu.edu.cn/CN/10.7503/cjcu20150883.

參考文獻(xiàn)

[1]KempJ.E.G.,FlemingM.I., Comprehensive Organic Synthesis,Pergamon,Oxford, 1991, 471—513

[2]ChenD.J.,GuoL.,LiuJ.Y.,KirtaneS.,CannonJ.F.,LiG., Org. Lett., 2005, 7(5), 921—924

[3]YeungY.Y.,GaoX.R.,CoreyE.J., J. Am. Chem. Soc., 2006, 128(30), 9644—9645

[4]BaerH.H.,RankW., Can. J. Chem., 1974, 52(12), 2257—2267

[5]LiuY.L.,LiuD.E.,DuM.F.,CaoC.X.,ChenZ.G., Chem. J. Chinese Universities, 2015, 36(6), 1117—1125(劉亞麗, 劉德娥, 杜曼飛, 曹晨茜, 陳戰(zhàn)國(guó). 高等學(xué)?；瘜W(xué)學(xué)報(bào), 2015, 36(6), 1117—1125)

[6]NishimuraT., Bull. Chem. Soc. Jpn., 1954, 27, 617—619

[7]ZhiS.J.,SunH.,LinC.,ZhangG.Q.,LiG.,PanY., Science China: Chemistry, 2010, 53(1), 140—146

[8]LucetD.,ToupetL.,LeG.T.,MioskowskiC., J. Org. Chem., 1997, 62(9), 2682—2683

[9]ChenZ.G.,ZhaoP.F.,WangY., Eur. J. Org. Chem., 2011, 5887—5893

[10]ChenZ.G.,HuJ.L.,XiaW.,WangD.,LiY.N., Chem. J. Chinese Universities, 2013, 34(5), 1151—1159(陳戰(zhàn)國(guó), 胡均利, 夏偉, 王丹, 李亞男. 高等學(xué)?；瘜W(xué)學(xué)報(bào), 2013, 34(5), 1151—1159)

[11]ChenZ.G.,XiaW.,WenH.,WangD.,LiY.N.,HuJ.L., Chem. Res. Chinese Universities, 2013, 24(9), 699—705

[12]ChenZ.G.,LiY.N.,ZhouJ.M.,WangD.,GeM., Chem. Res. Chinese Universities, 2014, 30(2), 266—271

[13]ChenZ.G.,LiuD.E.,LiW.L.,LiuY.L., Chem. J. Chinese Universities, 2014, 35(11), 2360—2365(陳戰(zhàn)國(guó), 劉德娥, 李文麗, 劉亞麗. 高等學(xué)?；瘜W(xué)學(xué)報(bào), 2014, 35(11), 2360—2365)

[14]ChenZ.G.,LiuY.L.,HuJ.L.,LiuD.E., Chem. Res. Chinese Universities, 2015, 3(11), 65—70

[15]BauerJ.,RappA.,StanislawskiB.,CapitoF., Copolymers for Protein Precipitation,MerckPatentGmbH,Germany,PCTInt.Appl.,WO2014094957A1, 2014-06-26

[16]WongY.C.,ParthasarathyK.,ChengC.H., J. Am. Chem. Soc., 2009, 131(51), 18252—18253

[17]FryszkowskaA.,FisherK.,GardinerJ.M.,StephensG.M., J. Org. Chem., 2008, 73(11), 4295—4298

[18]MilhazesN.,CalheirosR.,MarquesM.P.M.,GarridoJ.,CordeiroM.N.D.S.,RodriguesC.,QuinteiraS.,NovaisC.,PeixeL.B.F., Bioorg. Med. Chem., 2006, 14(12), 4078—4088

[19]WangW.,WangJ.,LiH., Angew. Chem. Int. Ed., 2005, 44(9), 1369—1371

[20]OheT.,UemuraS., Bull. Chem. Soc. Jpn., 2003, 76(7), 1423—1431

[21]LloydH.A.,KielarE.A.,HighetR.J.,UyeoS.,FalesH.M.,WildmanW.C., J. Org. Chem., 1962, 27, 373—377

[22]WangY., Study on the Aminobromination of β-Nitrostyrene Derivatives with Acetamide and NBS,ShaanxiNormalUniversity,Xi’an, 2010(王蕓. β-硝基苯乙烯與乙酰胺/N-溴代丁二酰亞胺的氨溴加成反應(yīng)研究, 西安: 陜西師范大學(xué), 2010)

[23]SandharR.K.,SharmaJ.R.,ManraoM.R., J. Ind. Chem. Soc., 2006, 83(3), 263—265

[24]CampbellN.,AndersonW.,GilmoreJ., J. Chem. Soc., 1940, 446—451

[25]OheT.,UemuraS., Bull. Chem. Soc. Jpn., 2003, 76(7), 1423—1431

[26]CorbettJ.F.,HoltP.F.,HughesA.N., J. Chem. Soc., 1960, 3643—3645

[27]KoremuraM.,OkuH.,ShonoT.,NakanishiT., Takamine Kenkyusho Nenpo, 1961, 13, 216—221

[28]MilhazesN.,CalheirosR.,MarquesM.P.M.,GarridoJ.,CordeiroM.N.D.S.,RodriguesC.,QuinteiraS.,NovaisC.,PeixeL.,BorgesF., Bioorg. Med. Chem., 2006, 14(12), 4078—4088

[29]WorrallD.E., J. Am. Chem. Soc., 1938, 60, 2841—2844

[30]MilhazesN.,BorgesF.,CalheirosR.,MarquesM.P.M., Analyst, 2004, 129(11), 1106—1117

[31]MathisC.A.,ShulginA.T.,SargentT. Ⅲ., Journal of Labelled Compounds and Radiopharmaceuticals, 1986, 23(2), 115—125

[32]PradhanP.K.,DeyS.,JaisankarP.,GiriV.S., Syn. Comm., 2005, 35(7), 913—922

[33]AgafonovN.E.,SedishevI.P.,DudinA.V.,KutinA.A.,StashinaG.A.,ZhulinV.M., Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, 1991, (2), 426—433

[34]NguyenB.,ChernousK.,EndlarD.,OdellB.,PiacentiM.,BrownJ.M.,DorofeevA.S.,BurasovA.V., Angew. Chem. Int. Ed., 2007, 46(40), 7655—7658

[35]YangJ.K.,ZhengM.,LuoS.P.,LiZ.B., Acta Crystallographica, Section E: Structure Reports Online, 2010, 66(7),o1781

[36]NiwasS.,KumarS.,BhaduriA.P., Synthesis, 1983, (12), 1027—1028

[37]ChenZ.G.,ZhouJ.M.,WangY.,LiW.L., Acta Chim Sinica, 2011, 69(23), 2851—2858(陳戰(zhàn)國(guó), 周繼梅, 王蕓, 李文麗. 化學(xué)學(xué)報(bào), 2011, 69(23), 2851—2858)

(Ed.:P,H,W,K)

?SupportedbytheNationalNaturalScienceFoundationofChina(No.20572066),theNaturalScienceFoundationofShaanxiProvince,China(No.2009JM2001)andtheInnovationFoundationofPostgraduateCultivationofShaanxiNormalUniversity,China(No.2008CXB009).

doi:10.7503/cjcu20150883

收稿日期:2015-11-19. 網(wǎng)絡(luò)出版日期: 2016-04-20.

基金項(xiàng)目:國(guó)家自然科學(xué)基金(批準(zhǔn)號(hào): 20572066)、 陜西省自然科學(xué)基金(批準(zhǔn)號(hào): 2009JM2011)和陜西師范大學(xué)研究生創(chuàng)新基金(批準(zhǔn)號(hào): 2008CXB009)資助.

中圖分類(lèi)號(hào)O626.3

文獻(xiàn)標(biāo)志碼A

RegiospecificAminobrominationofβ-NitrostyreneDerivativeswithAcrylamideandN-Bromobutanimide?

DUManfei,HOUDan,HUIWenping,CHENZhanguo*

(Key Laboratory for Macromolecular Science of Shaanxi Province, School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi’an 710119, China)

AbstractA new protocol for the high regioselective aminobromination of β-nitrostyrene derivatives with acrylamide and N-Bromobutanimide(NBS) as nitrogen/bromine sources was developed. β-Nitrostyrene derivatives reacted with acrylamide and NBS promoted by CH3CH2ONa at room temperature(without the protection of an inert gaseous atmosphere) in CH2Cl2, offered vicinal haloamine products in good yields(up to 83%). For the β-methyl-β-nitrostyrene, the good yields(up to 98%) were also achieved in CH3OH promoted by Na2CO3. Although the strong electron-donating substituents(e.g., OCH3) on the 4-position of benzene ring could deactivated the reaction activity of β-nitrostyrenederi-vetives, the vicinal haloamines were also afforded as the sole addition product. Whereas strong electron-withdrawing substituents(e.g., NO2) could activated reaction activity remarkably and the vicinal haloamines were afforded as the sole addition product, too. The result revealed that the addition reaction has a nucleophilic addition feature. The aminobromination of 25 examples of β-nitrostyrenes were investigated and the structure of all products were confirmed by the corresponding nuclear magnetic resonance(NMR) spectra and high resolution mass spectrometer(HRMS). A possible mechanism involving a nucleophilic conjugate addition was proposed．

KeywordsAminobromination; β-Nitrostyrene; Regiospecific; Acrylamide; N-Bromobutanimide

聯(lián)系人簡(jiǎn)介: 陳戰(zhàn)國(guó), 男, 博士, 副教授, 主要從事有機(jī)合成及天然產(chǎn)物結(jié)構(gòu)改造方面的研究.E-mail:chzhg@snnu.edu.cn