楊雅琴,　葛松蘭,　馬　磊

(華東理工大學(xué)藥學(xué)院,上海市新藥設(shè)計(jì)重點(diǎn)實(shí)驗(yàn)室,上海 200237)

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鹽酸硫胺(VB1)催化合成四氫咔唑類(lèi)化合物

楊雅琴,葛松蘭,馬磊

(華東理工大學(xué)藥學(xué)院,上海市新藥設(shè)計(jì)重點(diǎn)實(shí)驗(yàn)室,上海 200237)

1,2,3,4-四氫咔唑類(lèi)衍生物廣泛應(yīng)用于醫(yī)藥領(lǐng)域。在鹽酸硫胺(VB1)催化作用下,苯肼鹽酸鹽和環(huán)己酮在乙醇中反應(yīng),可以簡(jiǎn)便、高產(chǎn)率地得到四氫咔唑類(lèi)化合物。將不同基團(tuán)取代的環(huán)己酮和含有吸電子或供電子基團(tuán)的苯肼用VB1進(jìn)行底物擴(kuò)展,大部分目標(biāo)產(chǎn)物的產(chǎn)率在90%以上,證實(shí)在合成四氫咔唑的反應(yīng)中,VB1是一種溫和、高效、環(huán)保型的催化劑。對(duì)VB1進(jìn)行回收再利用,催化效率沒(méi)有明顯降低。

鹽酸硫胺(VB1); 四氫咔唑; 苯肼; 環(huán)己酮

1,2,3,4-四氫咔唑類(lèi)衍生物具有多種生物活性,在醫(yī)藥領(lǐng)域被廣泛應(yīng)用。據(jù)報(bào)道,1,2,3,4-四氫咔唑類(lèi)衍生物可作為5-HT6受體拮抗劑[1],也被用作止吐藥物的分子骨架[2]。同時(shí),這類(lèi)化合物對(duì)人乳頭瘤病毒(HPVs)具有潛在的抵抗作用[3],也是很好的脂肪型脂肪酸結(jié)合蛋白(A-FABP)抑制劑[4]。有研究發(fā)現(xiàn),四氫咔唑骨架在抗氧化方面具有顯著效果[5]。當(dāng)骨架上有不飽和羰基取代時(shí),這類(lèi)化合物是一種新型的神經(jīng)肽Y-1(NPY-1)和G蛋白偶聯(lián)受體(GPCR)拮抗劑[6-7];當(dāng)骨架上被特定的烷基取代時(shí),此類(lèi)分子對(duì)某些癌細(xì)胞具有抑制作用[8]。

隨著有機(jī)合成方法學(xué)的發(fā)展,有多種方法合成四氫咔唑類(lèi)化合物。Siddalingamurthy等[9]以苯肼鹽酸鹽和環(huán)己酮為原料,通過(guò)三聚氯氰(TCT)催化,得到四氫咔唑。也可在超聲波輻射條件下,通過(guò)Fischer吲哚合成方法,得到目標(biāo)產(chǎn)物[10-11]。Yedukondalu等[12]發(fā)現(xiàn),苯肼鹽酸鹽和環(huán)己酮在聚乙二醇(PEG-400)中反應(yīng),生成四氫咔唑。這類(lèi)化合物也可通過(guò)還原[13]、交叉耦合[14]等其他反應(yīng)[15-16]得到。近年來(lái),酸性離子液體催化四氫咔唑類(lèi)化合物的合成也有相關(guān)報(bào)道[17-20]。傳統(tǒng)的合成方法,有反應(yīng)溫度高,時(shí)間過(guò)長(zhǎng),所用的催化劑缺乏經(jīng)濟(jì)性和環(huán)保性等缺點(diǎn)。因此,研究高效環(huán)保型的合成四氫咔唑類(lèi)化合物具有重要意義。

VB1無(wú)毒無(wú)公害,價(jià)格經(jīng)濟(jì),可以回收再利用,是一種環(huán)保型催化劑。VB1及其類(lèi)似物在許多碳-碳偶聯(lián)和碳-雜原子偶聯(lián)的反應(yīng)中,可以作為高效催化劑[21-23]。本文將鹽酸硫胺(VB1)作為催化劑,以取代的鹽酸苯肼和環(huán)己酮為底物,在非常溫和的條件下,合成了一系列四氫咔唑類(lèi)化合物,拓展了VB1在有機(jī)合成中的應(yīng)用。

1　實(shí)驗(yàn)部分

1.1儀器和試劑

1H-NMR,13C-NMR:以DMSO-d6,CDCl3或CD3OD 為溶劑,由Bruker AVANCE 400 核磁共振儀測(cè)得; 熔點(diǎn):SGWX4顯微熔點(diǎn)儀; ESI低分辨質(zhì)譜:Bruker Esquire 3000 plus spectrometer型質(zhì)譜儀; ESI高分辨質(zhì)譜:Bruker Atex III spectrometer型質(zhì)譜儀。所有試劑均為分析純,安耐吉化學(xué)公司。柱層析色譜使用200～300目(48～75 μm)的硅膠。

1.2VB1催化四氫咔唑類(lèi)化合物的合成

圖1所示為四氫咔唑類(lèi)化合物的合成路線。在25 mL雙口圓底燒瓶中,依次加入取代的苯肼鹽酸鹽1(2 mmol)、乙醇(15 mL)、環(huán)己酮類(lèi)化合物2(2 mmol)。攪拌均勻后,加入催化劑VB1(0.2 mmol),在50 ℃下反應(yīng)。薄層色譜(TLC)檢測(cè)至反應(yīng)完全。減壓蒸出溶劑,分別用二氯甲烷(2×20 mL)、飽和食鹽水(2×15 mL)萃取,無(wú)水硫酸鈉干燥后除去溶劑,得粗品。柱層析分離提純,得到產(chǎn)物3。

圖2所示為化合物3b的合成路線。在雙口燒瓶中分別加入對(duì)甲基苯肼鹽酸鹽(2 mmol)、溶劑(15 mL)、對(duì)甲基環(huán)己酮(2 mmol),攪拌10 min后,加入催化劑。分別在室溫、50 ℃、回流狀態(tài)下反應(yīng)。TLC檢測(cè)反應(yīng)情況。待完全反應(yīng)后,減壓蒸出溶劑,分別用二氯甲烷(2×20 mL)、飽和食鹽水(2×15 mL)萃取,無(wú)水硫酸鈉干燥后減壓蒸出溶劑,得粗品。柱層析分離提純(石油醚和乙酸乙酯的體積比為40∶1),得產(chǎn)物3b。

圖1　VB1催化下的苯肼鹽酸鹽和環(huán)己酮類(lèi)的反應(yīng)Fig.1　Reaction of phenylhydrazine with cyclohexanone in the presence of VB1

圖2　3,6-二甲基-1,2,3,4-四氫咔唑(3b)的合成Fig.2　Synthesis of 3,6- dimethyl-1,2,3,4- tetrahydrocarbazole (3b)

1.3催化劑的回收利用

反應(yīng)結(jié)束后,減壓蒸出溶劑,濃縮物用二氯甲烷(20 mL)和水(15 mL)萃取。將萃取液(水層)pH調(diào)至3,減壓濃縮萃取液。將濃縮物冷卻至室溫,加入乙醇(25 mL),攪拌30 min后放入冰箱過(guò)夜,析出結(jié)晶。過(guò)濾,真空干燥2 h,得到VB1。將回收的VB1重復(fù)使用,催化苯肼鹽酸鹽和環(huán)己酮類(lèi)化合物的反應(yīng)。重復(fù)4次,催化效果沒(méi)有明顯降低。

2　結(jié)果與討論

2.1反應(yīng)條件篩選

使用對(duì)甲基苯肼鹽酸鹽和對(duì)甲基環(huán)己酮為反應(yīng)底物進(jìn)行條件的優(yōu)化。優(yōu)化的條件包括反應(yīng)溫度、催化劑用量、溶劑種類(lèi),結(jié)果見(jiàn)表1。首先,討論溫度對(duì)反應(yīng)的影響。在室溫時(shí),反應(yīng)較慢(Entry 1),而回流狀態(tài)下,副產(chǎn)物多且不易分離(Entry 3),因此選用50 ℃作為反應(yīng)溫度。接下來(lái),研究催化劑摩爾分?jǐn)?shù)對(duì)反應(yīng)的影響。結(jié)果表明VB1摩爾分?jǐn)?shù)為10%是最佳催化劑用量(Entry 5)。增加VB1摩爾分?jǐn)?shù),反應(yīng)產(chǎn)率沒(méi)有明顯提升(Entry 2,4); 當(dāng)VB1摩爾分?jǐn)?shù)低于10%時(shí),產(chǎn)率降低(Entry 6,7); 當(dāng)用鹽酸的乙醇飽和溶液作催化劑時(shí),產(chǎn)率沒(méi)有明顯提升(Entry 8)。在探索溶劑對(duì)反應(yīng)的影響中發(fā)現(xiàn)(Entry 9～Entry 13),以水作為反應(yīng)溶劑時(shí),產(chǎn)率較低且反應(yīng)時(shí)間長(zhǎng); 以甲醇、DCM(二氯甲烷)作為反應(yīng)溶劑時(shí),反應(yīng)較慢; 以DMF(N,N-二甲基甲酰胺)和DMSO(二甲基亞砜)作反應(yīng)溶劑時(shí),雜點(diǎn)較多,后處理不易。因此,選用乙醇作為反應(yīng)溶劑。

綜上所述,在VB1(摩爾分?jǐn)?shù)10%)的催化下,等物質(zhì)的量的4-甲基苯肼鹽酸鹽和4-甲基環(huán)己酮在乙醇中、50 ℃下反應(yīng),能簡(jiǎn)單、高效地得到四氫咔唑類(lèi)化合物。

表1　反應(yīng)條件的優(yōu)化

1)mol fraction of VB1

2.2底物擴(kuò)展

在獲得最佳反應(yīng)條件之后,用VB1催化不同的苯肼鹽酸鹽和環(huán)己酮類(lèi)化合物,得到一系列化合物(表2)。總體而言,用VB1催化合成四氫咔唑的方法具有較好的底物適應(yīng)性和官能團(tuán)耐受性。當(dāng)?shù)孜锃h(huán)己酮鄰位上含有較大基團(tuán),如環(huán)己烯基時(shí),反應(yīng)較慢,產(chǎn)率也相對(duì)降低(Entry 23); 當(dāng)?shù)孜锃h(huán)己酮鄰位上含有乙氧羰基時(shí),反應(yīng)產(chǎn)率低于其他反應(yīng)(Entry 24),這可能因?yàn)橐已豸驶?—CO2Et)中的—C=O和環(huán)己酮上的—C=O競(jìng)爭(zhēng)性和苯肼結(jié)合,影響反應(yīng)的進(jìn)行。底物苯肼上含有吸電子或供電子小基團(tuán)如羧基、三氟甲基、甲氧基、甲基等時(shí),反應(yīng)在較短的時(shí)間內(nèi)(0.8～2 h)具有很高的產(chǎn)率,說(shuō)明VB1催化合成四氫咔唑的方法具有較好的底物適用性和官能團(tuán)耐受性。

3-羧基-6,8-二氟-1,2,3,4-四氫咔唑(3a):黃色固體,產(chǎn)率92%,熔點(diǎn)183～184 ℃。1H-NMR(400 MHz,DMSO-d6,δ):11.28(s,1H),7.03(dd,J=9.4,1.6 Hz,1H),6.84(t,J=10.6 Hz,1H),2.88(q,J=9.6 Hz,1H),2.82～2.64(m,4H),2.18(d,J=14.1 Hz,1H),1.96～1.77(m,1H);13C-NMR(100 MHz,DMSO-d6,δ):176.2,156.7,154.2,137.2,119.9,108.5,98.7,95.4,94.8,38.8,25.2,23.4,21.8; ESI-MS[M+H]+m/z:252; HRMS(ESI)m/z:[M+H]+分子式為C13H12F2NO2,相對(duì)分子質(zhì)量計(jì)算值為252.083 1,測(cè)量值為252.083 5。

3,6-二甲基-1,2,3,4-四氫咔唑(3b):淺棕色固體,產(chǎn)率96%,熔點(diǎn)112～113 ℃(文獻(xiàn)值112～113 ℃[24])。1H-NMR(400 MHz,CDCl3,δ):7.57(s,1H),7.23(s,1H),7.15(d,J= 8.2 Hz,1H),6.92(d,J= 8.0 Hz,1H),2.85～2.68(m,3H),2.43(s,3H),2.25(dd,J=15.3,9.3 Hz,1H),1.99～1.88(m,2H),1.56～1.50(m,1H),1.13(d,J=6.5Hz,3H);13C-NMR(100 MHz,DMSO-d6,δ):134.2,134.1,127.4,126.1,121.4,116.8,110.2,107.4,31.1,29.2,29.2,22.4,21.7,21.2; ESI-MS[M+H]+m/z:200; HRMS(ESI)m/z:[M+H]+分子式為C14H18N,相對(duì)分子質(zhì)量計(jì)算值為200.143 4,測(cè)量值為200.143 0。

3-乙酰氨基-8-氟-1,2,3,4-四氫咔唑(3c):棕色固體,產(chǎn)率97%,熔點(diǎn)207～208 ℃。1H-NMR(400 MHz,CDCl3,δ):8.21(s,1H),7.18(d,J=7.8 Hz,1H),6.98(td,J=7.8,4.8 Hz,1H),6.85(dd,J=11.2,7.9 Hz,1H),5.69(d,J=7.0 Hz,1H),4.51～4.36(m,1H),3.07(dd,J=15.4,5.1 Hz,1H),2.93～2.73(m,2H),2.60(dd,J=15.5,6.4 Hz,1H),1.98(s,3H),1.79(d,J=17.7 Hz,2H);13C-NMR(100 MHz,CDCl3,δ):169.8,148.0,133.6,119.7,113.5,108.2,106.7,106.6,99.8,45.0,27.9,27.8,23.6,20.4; ESI-MS[M+H]+m/z:247; HRMS(ESI)m/z:[M+H]+的分子式為C14H16FN2O,相對(duì)分子質(zhì)量計(jì)算值為247.124 2,測(cè)量值為247.123 9。

1,2,3,4-四氫咔唑(3d):米白色固體,產(chǎn)率93%,熔點(diǎn)118～120 ℃(文獻(xiàn)值118～120 ℃[25])。1H-NMR(400 MHz,CDCl3,δ):7.63(s,1H),7.45(d,J=7.5 Hz,1H),7.25(t,J= 5.4 Hz,1H),7.15～7.01(m,2H),2.71(dd,J=7.0,5.2 Hz,4H),1.97～1.81(m,4H);13C-NMR(100 MHz,CDCl3,δ):135.7,134.2,127.8,121.0,119.1,117.8,110.4,110.1,23.3,23.3,21.0; ESI-MS[M+H]+m/z:172; HRMS(ESI)m/z:[M+H]+分子式為C12H14N,相對(duì)分子質(zhì)量計(jì)算值為172.112 1,測(cè)量值為172.112 4。

3-乙酰氨基-6,8-二甲基-1,2,3,4-四氫咔唑(3e):棕色固體,產(chǎn)率93%,熔點(diǎn)78～79 ℃。1H-NMR(400 MHz,CDCl3,δ):7.67(s,1H),7.07(s,1H),6.80(s,1H),5.62(d,J=6.9 Hz,1H),4.45(m,1H),3.04(dd,J=15.5,5.0 Hz,1H),2.89～2.75(m,2H),2.60(dd,J=15.5,5.8 Hz,1H),2.42(d,J=6.9 Hz,6H),2.09～2.02(m,2H),1.96(s,3H);13C-NMR(100 MHz,CDCl3,δ):169.7,134.3,133.2,129.0,123.9,119.4,115.2,107.2,99.0,55.0,29.7,27.7,23.6,21.4,20.3,16.6; ESI-MS[M+H]+m/z:257; HRMS(ESI)m/z:[M+H]+分子式為C16H21N2O,相對(duì)分子質(zhì)量計(jì)算值為257.164 9,測(cè)量值為257.165 0。

3-苯基-1,2,3,4-四氫咔唑(3f):黃色固體,產(chǎn)率83%,熔點(diǎn)220～221 ℃(文獻(xiàn)值220～221 ℃[26])。1H-NMR(400 MHz,CDCl3,δ):7.76(s,1H),7.45(d,J=7.7 Hz,1H),7.36～7.29(m,5H),7.24(d,J= 5.6 Hz,1H),7.11(dt,J=14.8,7.1 Hz,2H),3.14～3.03(m,2H),2.98～2.77(m,3H),2.27～2.09(m,2H);13C-NMR(100 MHz,CDCl3,δ):146.7,136.0,133.6,128.5,127.5,127.1,126.2,121.2,119.3,117.8,110.4,110.2,41.2,30.3,29.3,23.4; ESI-MS[M+H]+m/z:248; HRMS(ESI)m/z:[M+H]+分子式C18H18N,相對(duì)分子質(zhì)量計(jì)算值為248.143 4,測(cè)量值為248.143 0。

3-苯基-6-羧基-1,2,3,4-四氫咔唑(3g):黃色固體,產(chǎn)率82%,熔點(diǎn)155～156 ℃。1H-NMR(400 MHz,DMSO-d6,δ):11.72(s,1H),8.11(dd,J= 7.6,5.8 Hz,2H),7.80(d,J= 8.5 Hz,1H),7.38～7.16(m,5H),2.65(td,J= 11.5,4.5 Hz,1H),2.08(dd,J= 26.8,7.4 Hz,2H),1.87～1.72(m,4H);13C-NMR(100 MHz,DMSO-d6,δ):210.2,145.3,132.7,130.5,129.2,128.5,128.4,126.7,126.6,126.2,123.9,122.1,122.0,41.6,40.7,33.3,30.4; ESI-MS[M+H]+m/z:292; HRMS(ESI)m/z:[M+H]+分子式為C19H18NO2,相對(duì)分子質(zhì)量計(jì)算值為292.133 3,測(cè)量值292.133 1。

3-乙酰氨基-7-甲基-1,2,3,4-四氫咔唑(3h):黃色固體,產(chǎn)率99%,熔點(diǎn)91～92 ℃。1H-NMR(400 MHz,CDCl3,δ):7.73(s,1H),7.31(d,J=8.0 Hz,1H),7.10(d,J=6.1 Hz,1H),6.92(d,J=8.0 Hz,1H),5.64(d,J=6.8 Hz,1H),4.43(m,1H),3.05(dd,J=15.5,5.1 Hz,1H),2.95～2.68(m,3H),2.65～2.55(m,2H),2.44(s,3H),1.96(s,3H);13C-NMR(100 MHz,DMSO-d6,δ):168.6,136.5,132.7,129.0,125.1,119.7,116.8,110.6,106.2,45.1,28.7,27.4,22.8,21.6,21.3; ESI-MS[M+H]+m/z:243; HRMS(ESI)m/z:[M+H]+分子式為C15H19N2O,相對(duì)分子質(zhì)量計(jì)算值為243.149 2,測(cè)量值為243.149 0。

3-乙酰氨基-6-甲基-1,2,3,4-四氫咔唑(3i):淺黃色固體,產(chǎn)率99%,熔點(diǎn)182～183 ℃。1H-NMR(400 MHz,DMSO-d6,δ):10.54(s,1H),7.94(d,J=7.6 Hz,1H),7.20～7.03(m,2H),6.81(d,J=8.1 Hz,1H),4.03(d,J=6.8 Hz,1H),2.90～2.69(m,3H),2.44(dd,J=15.1,8.6 Hz,1H),2.34(s,3H),2.01～1.91(m,1H),1.83(s,3H),1.78～1.67(m,1H);13C-NMR(100 MHz,DMSO-d6,δ):168.6,134.4,133.5,127.3,126.4,121.7,116.9,110.3,105.9,45.2,28.7,27.3,22.7,21.2,21.2;ESI-MS[M+H]+m/z:243; HRMS(ESI)m/z:[M+H]+分子式為C15H19N2O,相對(duì)分子質(zhì)量計(jì)算值為243.149 2,測(cè)量值為243.149 0。

(1)確保PCL控制系統(tǒng)運(yùn)用環(huán)境干燥。雖然PCL控制系統(tǒng)的環(huán)境適應(yīng)能力較強(qiáng)，但是由于其為電氣設(shè)備，因此應(yīng)當(dāng)保證應(yīng)用PCL控制系統(tǒng)的環(huán)境的干燥，確保PCL控制技術(shù)在金礦山電氣設(shè)備中的安全穩(wěn)定性。

3-乙酰氨基-1,2,3,4-四氫咔唑(3j):黃色固體,產(chǎn)率91%,熔點(diǎn)123～125 ℃(文獻(xiàn)值123～125 ℃[27])。1H-NMR(400 MHz,CDCl3,δ):7.83(s,1H),7.44(d,J=7.7 Hz,1H),7.31(d,J=7.9 Hz,1H),7.12(dt,J=23.0,7.2 Hz,2H),5.62(d,J=7.3 Hz,1H),4.53～4.39(m,1H),3.09(dd,J=15.5,5.1 Hz,1H),2.94～2.73(m,2H),2.63(dd,J=15.5,6.1 Hz,1H),2.20～2.00(m,2H),1.97(s,3H);13C-NMR(100 MHz,CDCl3,δ):169.8,136.2,132.9,127.6,121.5,119.4,117.7,110.6,107.2,58.4,27.9,27.7,23.6,20.4; ESI-MS[M+H]+m/z:229; HRMS(ESI)m/z:[M+H]+分子式為C14H17N2O,相對(duì)分子質(zhì)量計(jì)算值為229.133 6,測(cè)量值為229.133 2。

3-乙酰氨基-6-甲氧基-1,2,3,4-四氫咔唑(3k):淺棕色固體,產(chǎn)率95%,熔點(diǎn)93～94 ℃(文獻(xiàn)值93～94 ℃[27])。1H-NMR(400 MHz,CDCl3,δ):7.73(s,1H),7.18(t,J=12.9 Hz,1H),6.89(s,1H),6.79(t,J=9.1 Hz,1H),5.65(d,J=7.0 Hz,1H),4.45(m,1H),3.85(s,3H),3.06(dd,J=15.3,4.8 Hz,1H),2.80(qd,J=16.7,8.4 Hz,2H),2.60(dd,J=15.4,5.9 Hz,1H),2.03(dd,J=12.3,5.7 Hz,2H),1.98(s,3H);13C-NMR(100 MHz,DMSO-d6,δ):168.6,152.9,134.2,131.1,127.5,111.1,109.7,106.3,99.6,55.3,45.1,28.6,27.4,22.8,21.2; ESI-MS[M+H]+m/z:259; HRMS(ESI)m/z:[M+H]+分子式為C15H19N2O2,相對(duì)分子質(zhì)量計(jì)算值為259.144 2,測(cè)量值為259.144 5。

3-乙酰氨基-8-三氟甲基-1,2,3,4-四氫咔唑(3l):黃色固體,產(chǎn)率93%,熔點(diǎn)129～130 ℃。1H-NMR(400 MHz,CDCl3,δ):7.66(d,J=8.4 Hz,1H),7.58(s,1H),7.44(t,J=9.5 Hz,2H),6.85(t,J=7.4 Hz,1H),4.09(d,J=8.0 Hz,1H),2.70(d,J=15.1 Hz,1H),2.60(d,J=15.2 Hz,1H),2.46～2.35(m,1H),2.24～2.05(m,3H),2.00(s,3H);13C-NMR(100 MHz,CD3OD,δ):172.9,136.7,134.3,130.7,126.8,122.4,119.6,118.9,115.7,108.5,47.3,31.7,29.7,24.2,22.7; ESI-MS[M+H]+m/z:297; HRMS(ESI)m/z:[M+H]+分子式為C15H16F3N2O,相對(duì)分子質(zhì)量計(jì)算值為297.121 0,測(cè)量值為297.121 3。

2-甲基-6-羧基-1,2,3,4-四氫咔唑(3m):黃色固體,產(chǎn)率94%,熔點(diǎn)96～97 ℃。1H-NMR(400 MHz,DMSO-d6,δ):8.00～7.92(m,1H),7.64(dd,J=13.3,5.9 Hz,1H),7.51(t,J=7.7 Hz,1H),2.35～2.10(m,3H),1.97～1.87(m,1H),1.86～1.72(m,2H),1.57(tdd,J=16.7,8.3,4.7 Hz,1H),0.95(d,J=6.5 Hz,3H);13C-NMR(100 MHz,DMSO-d6,δ):167.4,150.2,130.9,130.4,122.0,120.7,119.1,118.0,111.0,34.4,32.2,25.6,24.4,21.9; ESI-MS[M+H]+m/z:230; HRMS(ESI)m/z:[M+H]+分子式為C14H16NO2,相對(duì)分子質(zhì)量計(jì)算值為230.117 6,測(cè)量值為230.118 0。

3-羧基-8-氟-1,2,3,4-四氫咔唑(3n):棕色固體,產(chǎn)率96%,熔點(diǎn)141～142 ℃。1H-NMR(400 MHz,DMSO-d6,δ):12.31(s,1H),11.15(s,1H),7.19(d,J=7.7 Hz,1H),6.94～6.75(m,2H),2.91(dd,J=19.3,9.1 Hz,1H),2.81～2.67(m,4H),2.19(d,J=13.8 Hz,1H),1.85(dd,J=20.8,9.1 Hz,1H);13C-NMR(100 MHz,DMSO-d6,δ):176.3,147.5,135.2,131.0,123.7,118.5,113.5,107.9,105.3,38.9,25.3,23.5,21.7; ESI-MS[M+H]+m/z:234; HRMS(ESI)m/z:[M+H]+分子式為C13H13FNO2,相對(duì)分子質(zhì)量計(jì)算值為234.092 5,測(cè)量值為234.092 5。

3-乙酰氨基-6-三氟甲基-1,2,3,4-四氫咔唑(3o):棕色固體,產(chǎn)率95%,熔點(diǎn)76～77 ℃。1H-NMR(400 MHz,CDCl3,δ):7.86(d,J=8.3 Hz,1H),7.76(d,J=8.4 Hz,1H),7.56～7.45(m,1H),5.66(s,1H),4.26(ddt,J=11.1,7.7,5.2 Hz,1H),2.53～2.35(m,3H),2.30～2.20(m,2H),2.02(t,J=3.3 Hz,3H),1.75～1.68(m,1H);13C-NMR(100 MHz,CD3OD,δ):172.6,135.0,132.3,129.9,127.4,123.9,118.1,116.2,112.6,100.4,46.9,31.7,29.7,28.3,23.6; ESI-MS[M+H]+m/z:297; HRMS(ESI)m/z:[M+H]+分子式為C15H16F3N2O,相對(duì)分子質(zhì)量計(jì)算值為297.121 0,測(cè)量值為297.121 3。

3-羧基-6-甲氧基-1,2,3,4-四氫咔唑(3p):淺黃色固體,產(chǎn)率97%,熔點(diǎn)205～206 ℃。1H-NMR(400 MHz,CD3OD,δ):7.14(d,J=8.7 Hz,1H),6.90(d,J=2.4 Hz,1H),6.69(dd,J=8.7,2.4 Hz,1H),3.82(s,3H),2.98(t,J=9.7 Hz,1H),2.92～2.70(m,4H),2.40～2.18(m,1H),2.14～1.84(m,1H);13C-NMR(100 MHz,DMSO-d6,δ):176.5,152.9,134.5,130.9,127.4,111.1,109.7,106.7,99.6,55.3,38.8,25.5,23.7,21.9; ESI-MS[M+H]+m/z:246; HRMS(ESI)m/z:[M+H]+分子式為C14H16NO3,相對(duì)分子質(zhì)量計(jì)算值為246.112 5,測(cè)量值為246.112 3。

3-羧基-1,2,3,4-四氫咔唑(3q):白色固體,產(chǎn)率95%,熔點(diǎn)199～200 ℃(文獻(xiàn)值199～200 ℃[28])。1H-NMR(400 MHz,CD3OD,δ):7.37(d,J=7.6 Hz,1H),7.26(d,J=7.9 Hz,1H),7.00(dt,J=25.8,7.2 Hz,2H),3.00(d,J=11.2 Hz,1H),2.92～2.72(m,4H),2.28(d,J=12.5 Hz,1H),2.12～1.89(m,1H);13C-NMR(100 MHz,DMSO-d6,δ):176.5,135.9,133.7,127.0,120.2,118.1,117.1,110.5,106.7,38.8,25.5,23.5,21.8; ESI-MS[M+H]+m/z:216; HRMS(ESI)m/z:[M+H]+分子式為C13H14NO2,相對(duì)分子質(zhì)量計(jì)算值為216.102 0,測(cè)量值為216.101 5。

3-羧基-6-三氟甲基-1,2,3,4-四氫咔唑(3r):淺黃色固體,產(chǎn)率96%,熔點(diǎn)298～299 ℃。1H-NMR(400 MHz,CD3OD,δ):7.14(d,J=8.7 Hz,1H),6.90(d,J= 2.4 Hz,1H),6.69(dd,J=8.7,2.4 Hz,1H),2.98(t,J=9.7 Hz,1H),2.92～2.70(m,4H),2.40～2.18(m,1H),2.14～1.84(m,1H);13C-NMR(100 MHz,CD3OD,δ):171.8,140.7,136.6,128.1,125.5,123.5,121.4,119.9,111.1,109.8,41.4,27.0,24.8,23.0; ESI-MS[M+H]+m/z:284; HRMS(ESI)m/z:[M+H]+分子式為C14H13F3NO2,相對(duì)分子質(zhì)量計(jì)算值為284.089 3,測(cè)量值為284.089 0。

3,6-二羧基-1,2,3,4-四氫咔唑(3s):淺黃色固體,產(chǎn)率97%,熔點(diǎn)291～293 ℃。1H-NMR(400 MHz,CD3OD,δ):7.14(d,J=8.7 Hz,1H),6.90(d,J=2.4 Hz,1H),6.69(dd,J=8.7,2.4 Hz,1H),2.98(t,J=9.7 Hz,1H),2.92～2.70(m,4H),2.40～2.18(m,1H),2.14～1.84(m,1H);13C-NMR(100 MHz,DMSO-d6,δ):176.3,168.5,138.4,135.6,126.6,121.8,120.6,119.7,110.2,108.2,38.9,25.3,23.2,21.7; ESI-MS[M+H]+m/z:260; HRMS(ESI)m/z:[M+H]+分子式為C14H14NO4,相對(duì)分子質(zhì)量計(jì)算值為260.091 8,測(cè)量值為260.091 5。

6-三氟甲基-1,2,3,4-四氫咔唑(3t):黃色固體,產(chǎn)率94%,熔點(diǎn)83～84 ℃(文獻(xiàn)值83～84 ℃[29])。1H-NMR(400 MHz,CDCl3,δ):7.84(s,1H),7.73(s,1H),7.34(dd,J=8.5,1.5 Hz,2H),2.81～2.63(m,4H),2.01～1.80(m,4H);13C-NMR(100 MHz,CDCl3,δ):140.5,129.6,124.6,121.3,119.9,117.6,112.2,108.4,106.1,25.0,24.4,22.7; ESI-MS[M+H]+m/z:240; HRMS(ESI)m/z:[M+H]+分子式為C13H13F3N,相對(duì)分子質(zhì)量計(jì)算值為240.099 5,測(cè)量值為240.099 2。

3-甲基-6-甲氧基-1,2,3,4-四氫咔唑(3u):棕色固體,產(chǎn)率94%,熔點(diǎn)112～113 ℃(文獻(xiàn)值112 ℃[30])。1H-NMR(400 MHz,CDCl3,δ):7.36(d,J=8.3 Hz,1H),6.94(s,1H),6.84(d,J=8.4 Hz,1H),3.79(d,J=1.4 Hz,3H),2.78(ddd,J=15.0,10.9,6.2 Hz,4H),2.41(dt,J=14.6,3.0 Hz,1H),1.64～1.55(m,2H),0.93(d,J=6.6 Hz,3H);13C-NMR(100 MHz,CDCl3,δ):153.8,134.9,131.1,128.1,111.0,110.5,110.0,100.3,56.0,31.4,29.7,29.5,23.0,21.8; ESI-MS[M+H]+m/z:216; HRMS(ESI)m/z:[M+H]+分子式為C14H18NO,相對(duì)分子質(zhì)量計(jì)算值為216.138 3,測(cè)量值為216.138 0。

3-乙酰氨基-7-氟-1,2,3,4-四氫咔唑(3v):棕色固體,產(chǎn)率98%,熔點(diǎn)188～189 ℃。1H-NMR(400 MHz,CDCl3,δ):7.38～7.27(m,1H),7.17～7.01(m,2H),6.30(s,1H),4.29～4.18(m,1H),2.48～2.38(m,4H),2.22(dt,J=20.8,7.2 Hz,2H),2.02(s,3H);13C-NMR(100 MHz,CDCl3,δ):169.9,138.8,133.0,130.5,124.2,121.8,118.2,107.9,107.0,45.2,29.7,27.7,23.6,20.5; ESI-MS[M+H]+m/z:247; HRMS(ESI)m/z:[M+H]+分子式為C14H16FN2O,相對(duì)分子質(zhì)量計(jì)算值為247.124 2,測(cè)量值為247.124 5。

1-環(huán)己烯基-6-甲基-1,2,3,4-四氫咔唑(3w):黃色固體,產(chǎn)率83%,熔點(diǎn)102～104 ℃。1H-NMR(400 MHz,CDCl3,δ):7.45(d,J=7.8 Hz,1H),7.10(d,J=7.8 Hz,1H),7.01(s,1H),5.79(t,J=3.7 Hz,1H),2.90～2.79(m,1H),2.77～2.68(m,1H),2.54～2.41(m,1H),2.36(s,3H),2.18～2.01(m,4H),1.84～1.67(m,2H),1.46(m,6H);13C-NMR(100 MHz,CDCl3,δ):146.1,134.6,134.0,130.0,128.1,122.9,122.4,119.5,115.3,108.4,35.2,30.9,29.1,25.6,24.7,22.8,22.3,21.8,21.5; ESI-MS[M+H]+m/z:266; HRMS(ESI)m/z:[M+H]+分子式為C19H24N,相對(duì)分子質(zhì)量計(jì)算值為266.190 4,測(cè)量值為266.190 8。

1-乙氧羰基-1,2,3,4-四氫咔唑(3x):米白色固體,產(chǎn)率66%,熔點(diǎn)81～82 ℃。1H-NMR(400 MHz,CDCl3,δ):7.67(d,J=8.1 Hz,2H),7.39(t,J=7.8 Hz,2H),4.17(q,J=7.0 Hz,2H),3.48(m,1H),2.68(t,J=6.0 Hz,2H),2.60(t,J=5.9 Hz,2H),1.85～1.78(m,2H),1.32(t,J= 7.0 Hz,3H);13C-NMR(100 MHz,DMSO-d6,δ):164.8,148.8,138.8,128.8,125.6,121.4,118.4,113.6,99.6,68.1,40.1,23.7,22.7,20.0,15.1; ESI-MS[M+H]+m/z:244;HRMS(ESI)m/z:[M+H]+分子式為C15H18NO2,相對(duì)分子質(zhì)量計(jì)算值為244.133 3,測(cè)量值為244.133 7。

表2　VB1催化合成化合物31)

1)Reaction conditions:phenylhydrazine hydrochloride 1 (2 mmol),cyclohexanone 2 (2 mmol) and VB1(0.2 mmol) were mixed in 15 mL of EtOH at 50 ℃;2) Isolated yields

2.3催化劑的回收再利用

考察催化劑的回收利用情況。將萃取液(水層)pH調(diào)至3,減壓濃縮后,將濃縮物冷卻至室溫,加入乙醇,攪拌并放至冰箱過(guò)夜,析出結(jié)晶。VB1重復(fù)使用4次,產(chǎn)率沒(méi)有明顯下降(表3)。因此,用VB1催化合成四氫咔唑類(lèi)化合物的方法在工業(yè)生產(chǎn)上具有潛在的應(yīng)用價(jià)值。

表3　VB1 的循環(huán)使用1)

1) Reaction conditions:p-tolylhydrazine hydrochloride (2 mmol),4-methylcyclohexanone (2 mmol) and VB1(0.2 mmol) were mixed in 15 mL of EtOH at 50 ℃;2)Recrystallized in ethanol

3　結(jié)　論

本文以VB1為催化劑,以取代的苯肼鹽酸鹽和環(huán)己酮為底物,在非常溫和的條件下,簡(jiǎn)單、高效地得到一系列四氫咔唑類(lèi)化合物,拓展了VB1在有機(jī)合成中的應(yīng)用。VB1無(wú)毒無(wú)公害,價(jià)格經(jīng)濟(jì),可以回收再利用,同時(shí)具有較好的底物適用性。用VB1催化合成四氫咔唑類(lèi)化合物,在綠色制藥工藝領(lǐng)域具有潛在的應(yīng)用價(jià)值。

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Synthesis of Tetrahydrocarbazole Derivatives Using Thiamine Hydrochloride (VB1) as Efficient Catalyst

YANG Ya-qin,GE Song-lan,MA Lei

(Shanghai Key Laboratory of New Drug Design,School of Pharmacy,East China University of Science and Technology,Shanghai 200237,China)

The tetrahydrocarbazole derivatives are widely used in pharmaceutical chemistry.A simple and highly efficient method was developed for the construction of tetrahydrocarbazole derivatives from phenylhydrazine hydrochloride and cyclohexanone in the presence of thiamine hydrochloride (VB1) in ethanol.This protocol relies on the use of various cyclohexanone and phenylhydrazine hydrochloride with electron-donating and electron-withdrawing groups to access tetrahydrocarbazole scaffolds with a wide scope.Most of the target products catalyzed by VB1were obtained in good to excellent yields (> 90%).VB1acted as an efficient,mild and non-toxic catalyst in the reaction,and it could be reused without reducing the catalytic efficiency.

thiamine hydrochloride (VB1); tetrahydrocarbazole; phenylhydrazine; cyclohexanone

1006-3080(2016)04-0499-09

10.14135/j.cnki.1006-3080.2016.04.010

2015-11-27

上海自然科學(xué)基金(15ZR1408800);上海浦江人才計(jì)劃(15PJD0122015)

楊雅琴(1991-),女,江西人,碩士生,研究方向?yàn)楹铣伤幬锘瘜W(xué)。E-mail:yangyaqin09@126.com

通信聯(lián)系人：馬磊,E-mail:malei@ecust.edu.cn

O621.3

A