鹽酸硫胺(VB1)催化合成四氫咔唑類化合物

楊雅琴,　葛松蘭,　馬　磊

(華東理工大學藥學院,上海市新藥設計重點實驗室,上海 200237)

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鹽酸硫胺(VB1)催化合成四氫咔唑類化合物

楊雅琴,葛松蘭,馬磊

(華東理工大學藥學院,上海市新藥設計重點實驗室,上海 200237)

1,2,3,4-四氫咔唑類衍生物廣泛應用于醫藥領域。在鹽酸硫胺(VB1)催化作用下,苯肼鹽酸鹽和環己酮在乙醇中反應,可以簡便、高產率地得到四氫咔唑類化合物。將不同基團取代的環己酮和含有吸電子或供電子基團的苯肼用VB1進行底物擴展,大部分目標產物的產率在90%以上,證實在合成四氫咔唑的反應中,VB1是一種溫和、高效、環保型的催化劑。對VB1進行回收再利用,催化效率沒有明顯降低。

鹽酸硫胺(VB1); 四氫咔唑; 苯肼; 環己酮

1,2,3,4-四氫咔唑類衍生物具有多種生物活性,在醫藥領域被廣泛應用。據報道,1,2,3,4-四氫咔唑類衍生物可作為5-HT6受體拮抗劑[1],也被用作止吐藥物的分子骨架[2]。同時,這類化合物對人乳頭瘤病毒(HPVs)具有潛在的抵抗作用[3],也是很好的脂肪型脂肪酸結合蛋白(A-FABP)抑制劑[4]。有研究發現,四氫咔唑骨架在抗氧化方面具有顯著效果[5]。當骨架上有不飽和羰基取代時,這類化合物是一種新型的神經肽Y-1(NPY-1)和G蛋白偶聯受體(GPCR)拮抗劑[6-7];當骨架上被特定的烷基取代時,此類分子對某些癌細胞具有抑制作用[8]。

隨著有機合成方法學的發展,有多種方法合成四氫咔唑類化合物。Siddalingamurthy等[9]以苯肼鹽酸鹽和環己酮為原料,通過三聚氯氰(TCT)催化,得到四氫咔唑。也可在超聲波輻射條件下,通過Fischer吲哚合成方法,得到目標產物[10-11]。Yedukondalu等[12]發現,苯肼鹽酸鹽和環己酮在聚乙二醇(PEG-400)中反應,生成四氫咔唑。這類化合物也可通過還原[13]、交叉耦合[14]等其他反應[15-16]得到。近年來,酸性離子液體催化四氫咔唑類化合物的合成也有相關報道[17-20]。傳統的合成方法,有反應溫度高,時間過長,所用的催化劑缺乏經濟性和環保性等缺點。因此,研究高效環保型的合成四氫咔唑類化合物具有重要意義。

VB1無毒無公害,價格經濟,可以回收再利用,是一種環保型催化劑。VB1及其類似物在許多碳-碳偶聯和碳-雜原子偶聯的反應中,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化合物,拓展了VB1在有機合成中的應用。

1　實驗部分

1.1儀器和試劑

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

1.2VB1催化四氫咔唑類化合物的合成

圖1所示為四氫咔唑類化合物的合成路線。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)、環己酮類化合物2(2 mmol)。攪拌均勻后,加入催化劑VB1(0.2 mmol),在50 ℃下反應。薄層色譜(TLC)檢測至反應完全。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,無水硫酸鈉干燥后除去溶劑,得粗品。柱層析分離提純,得到產物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甲基苯肼鹽酸鹽(2 mmol)、溶劑(15 mL)、對甲基環己酮(2 mmol),攪拌10 min后,加入催化劑。分別在室溫、50 ℃、回流狀態下反應。TLC檢測反應情況。待完全反應后,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),得產物3b。

圖1　VB1催化下的苯肼鹽酸鹽和環己酮類的反應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

反應結束后,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后放入冰箱過夜,析出結晶。過濾,真空干燥2 h,得到VB1。將回收的VB1重復使用,催化苯肼鹽酸鹽和環己酮類化合物的反應。重復4次,催化效果沒有明顯降低。

2　結果與討論

2.1反應條件篩選

使用對甲基苯肼鹽酸鹽和對甲基環己酮為反應底物進行條件的優化。優化的條件包括反應溫度、催化劑用量、溶劑種類,結果見表1。首先,討論溫度對反應的影響。在室溫時,反應較慢(Entry 1),而回流狀態下,副產物多且不易分離(Entry 3),因此選用50 ℃作為反應溫度。接下來,研究催化劑摩爾分數對反應的影響。結果表明VB1摩爾分數為10%是最佳催化劑用量(Entry 5)。增加VB1摩爾分數,反應產率沒有明顯提升(Entry 2,4); 當VB1摩爾分數低于10%時,產率降低(Entry 6,7); 當用鹽酸的乙醇飽和溶液作催化劑時,產率沒有明顯提升(Entry 8)。在探索溶劑對反應的影響中發現(Entry 9～Entry 13),以水作為反應溶劑時,產率較低且反應時間長; 以甲醇、DCM(二氯甲烷)作為反應溶劑時,反應較慢; 以DMF(N,N-二甲基甲酰胺)和DMSO(二甲基亞砜)作反應溶劑時,雜點較多,后處理不易。因此,選用乙醇作為反應溶劑。

綜上所述,在VB1(摩爾分數10%)的催化下,等物質的量的4-甲基苯肼鹽酸鹽和4-甲基環己酮在乙醇中、50 ℃下反應,能簡單、高效地得到四氫咔唑類化合物。

表1　反應條件的優化

1)mol fraction of VB1

2.2底物擴展

在獲得最佳反應條件之后,用VB1催化不同的苯肼鹽酸鹽和環己酮類化合物,得到一系列化合物(表2)?？傮w而言,用VB1催化合成四氫咔唑的方法具有較好的底物適應性和官能團耐受性。當底物環己酮鄰位上含有較大基團,如環己烯基時,反應較慢,產率也相對降低(Entry 23); 當底物環己酮鄰位上含有乙氧羰基時,反應產率低于其他反應(Entry 24),這可能因為乙氧羰基(—CO2Et)中的—C=O和環己酮上的—C=O競爭性和苯肼結合,影響反應的進行。底物苯肼上含有吸電子或供電子小基團如羧基、三氟甲基、甲氧基、甲基等時,反應在較短的時間內(0.8～2 h)具有很高的產率,說明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耐受性。

3-羧基-6,8-二氟-1,2,3,4-四氫咔唑(3a):黃色固體,產率92%,熔點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,相對分子質量計算值為252.083 1,測量值為252.083 5。

3,6-二甲基-1,2,3,4-四氫咔唑(3b):淺棕色固體,產率96%,熔點112～113 ℃(文獻值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,相對分子質量計算值為200.143 4,測量值為200.143 0。

3-乙酰氨基-8-氟-1,2,3,4-四氫咔唑(3c):棕色固體,產率97%,熔點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,相對分子質量計算值為247.124 2,測量值為247.123 9。

1,2,3,4-四氫咔唑(3d):米白色固體,產率93%,熔點118～120 ℃(文獻值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,相對分子質量計算值為172.112 1,測量值為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,產率93%,熔點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,相對分子質量計算值為257.164 9,測量值為257.165 0。

3-苯基-1,2,3,4-四氫咔唑(3f):黃色固體,產率83%,熔點220～221 ℃(文獻值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,相對分子質量計算值為248.143 4,測量值為248.143 0。

3-苯基-6-羧基-1,2,3,4-四氫咔唑(3g):黃色固體,產率82%,熔點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,相對分子質量計算值為292.133 3,測量值292.133 1。

3-乙酰氨基-7-甲基-1,2,3,4-四氫咔唑(3h):黃色固體,產率99%,熔點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,相對分子質量計算值為243.149 2,測量值為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,產率99%,熔點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,相對分子質量計算值為243.149 2,測量值為243.149 0。

(1)確保PCL控制系統運用環境干燥。雖然PCL控制系統的環境適應能力較強，但是由于其為電氣設備，因此應當保證應用PCL控制系統的環境的干燥，確保PCL控制技術在金礦山電氣設備中的安全穩定性。

3-乙酰氨基-1,2,3,4-四氫咔唑(3j):黃色固體,產率91%,熔點123～125 ℃(文獻值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,相對分子質量計算值為229.133 6,測量值為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,產率95%,熔點93～94 ℃(文獻值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,相對分子質量計算值為259.144 2,測量值為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,產率93%,熔點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,相對分子質量計算值為297.121 0,測量值為297.121 3。

2-甲基-6-羧基-1,2,3,4-四氫咔唑(3m):黃色固體,產率94%,熔點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,相對分子質量計算值為230.117 6,測量值為230.118 0。

3-羧基-8-氟-1,2,3,4-四氫咔唑(3n):棕色固體,產率96%,熔點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,相對分子質量計算值為234.092 5,測量值為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,產率95%,熔點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,相對分子質量計算值為297.121 0,測量值為297.121 3。

3-羧基-6-甲氧基-1,2,3,4-四氫咔唑(3p):淺黃色固體,產率97%,熔點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,相對分子質量計算值為246.112 5,測量值為246.112 3。

3-羧基-1,2,3,4-四氫咔唑(3q):白色固體,產率95%,熔點199～200 ℃(文獻值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,相對分子質量計算值為216.102 0,測量值為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,產率96%,熔點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,相對分子質量計算值為284.089 3,測量值為284.089 0。

3,6-二羧基-1,2,3,4-四氫咔唑(3s):淺黃色固體,產率97%,熔點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,相對分子質量計算值為260.091 8,測量值為260.091 5。

6-三氟甲基-1,2,3,4-四氫咔唑(3t):黃色固體,產率94%,熔點83～84 ℃(文獻值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,相對分子質量計算值為240.099 5,測量值為240.099 2。

3-甲基-6-甲氧基-1,2,3,4-四氫咔唑(3u):棕色固體,產率94%,熔點112～113 ℃(文獻值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,相對分子質量計算值為216.138 3,測量值為216.138 0。

3-乙酰氨基-7-氟-1,2,3,4-四氫咔唑(3v):棕色固體,產率98%,熔點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,相對分子質量計算值為247.124 2,測量值為247.124 5。

1-環己烯基-6-甲基-1,2,3,4-四氫咔唑(3w):黃色固體,產率83%,熔點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,相對分子質量計算值為266.190 4,測量值為266.190 8。

1-乙氧羰基-1,2,3,4-四氫咔唑(3x):米白色固體,產率66%,熔點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,相對分子質量計算值為244.133 3,測量值為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,攪拌并放至冰箱過夜,析出結晶。VB1重復使用4次,產率沒有明顯下降(表3)。因此,用VB1催化合成四氫咔唑類化合物的方法在工業生產上具有潛在的應用價值。

表3　VB1 的循環使用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　論

本文以VB1為催化劑,以取代的苯肼鹽酸鹽和環己酮為底物,在非常溫和的條件下,簡單、高效地得到一系列四氫咔唑類化合物,拓展了VB1在有機合成中的應用。VB1無毒無公害,價格經濟,可以回收再利用,同時具有較好的底物適用性。用VB1催化合成四氫咔唑類化合物,在綠色制藥工藝領域具有潛在的應用價值。

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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

上海自然科學基金(15ZR1408800);上海浦江人才計劃(15PJD0122015)

楊雅琴(1991-),女,江西人,碩士生,研究方向為合成藥物化學。E-mail:yangyaqin09@126.com

通信聯系人：馬磊,E-mail:malei@ecust.edu.cn

O621.3

A