CN101402537B - 2-吡啶-β酮类化合物的应用 - Google Patents
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Abstract
本发明涉及用具有式I结构的2-吡啶-β酮类化合物作为添加剂在促进N-芳基化反应中的应用。本发明中因使用所述2-吡啶-β酮类化合物作为添加剂,能很好地促进所述N-芳基化反应,且该N-芳基化反应所使用的催化剂为CuI即可,该催化剂价格便宜,易得;所述添加剂2-吡啶-β酮类化合物新颖,在空气中稳定,与文献中报道的同类型反应相比,碘代化合物的乌尔曼反应在室温下就能进行,溴代化合物反应的温度平均可以降低约20℃反应条件非常的温和,有很好的应用前景。
Description
技术领域
本发明属于化学领域,具体是涉及2-吡啶-β酮类化合物的应用。
背景技术
乌尔曼偶联反应(Ullmann,F.ber Dtsch.Chem.Ges.1903,36,2382.)有很长时间的发展历史,在学术上广为人们所关注,且该反应已经实现了工业化生产(Lindley,J.Tetrahedron 1984,40,1433)。传统的乌尔曼偶联反应由于要求在高温,高极性溶剂条件下进行,而且需要大量的铜试剂,因而使此反应的应用受到了很大的限制(Lindley,J.Tetrahedron1984,40,1433)。近年来使用钯催化剂((a)Yang,B.H.;Buchwald,S.L J.Organomet.Chem.1999,576(1-2),125-146.(b)Hartwig,J.F.Angew.Chem.,Int.Ed.Engl.1998,37,2046-2067),使该反应进行的条件有了较大的改善。但是,使用钯催化剂仍然存在着很多限制,比如含有某些特定官能团的底物很难反应,同时钯试剂价格昂贵。因此,在过去几年中,以廉价的Cu为催化剂,通过添加配体来促使反应在比较温和的条件下进行的方法得到了很大的发展。各种促进乌尔曼反应的配体逐渐被发现,如N’N-二乙基水杨酰胺(Kwong,FY.;Buchwald,S.L Org Lett.2003,5,793),氨基酸(Ma,D.;Cai,Q.;Zhang,H.Org.Lett.2003,5,2453),膦酰胺(Zhang,Z.;Mao,J.;Zhu,D.;Wu,F.;Chen,H.;Wan,B.Tetrahedron 2006,62,443),β-环二酮(Shafir,A.;Buchwald,S.L.J.Am.Chem.Soc.2006,128,8742),连二萘酚(Jiang,D.,Fu,H.,Jiang,Y.,Zhao,Y.J.Org.Chem.2007,72,672),这些配体使N-芳基化反应的条件得到了较好的改善。
发明内容
本发明的目的是提供一类2-吡啶-β酮类化合物在N-芳基化反应中的应用,从而以Cul作为催化剂,使胺类化合物,与碘代芳香化合物的氮芳基化反应得以在室温下进行,溴代芳香化合物的氮芳基化反应在60℃进行,反应条件非常温和;同时,该2-吡啶-β酮类化合物(配体)可以促使许多含有各种官能团的化合物发生乌尔曼偶联反应,有很宽的底物适用范围。
实现上述目的的技术方案如下:
具有式I结构的2-吡啶-β酮类化合物作为添加剂在促进N-芳基化反应中的应用,
其中:
n=0~4;X=C或N;
R选自:
1)C1~C3烷基;
2)芳基;
3)C1~C3全氟烷基;
4)C1~C3芳烷基;
5)C3~C6环烷基;
6)杂环基。
优选地,本发明中所涉及到的N-芳基化反应在溶剂和碱的环境中,用2-吡啶-β酮类化合物作为配体,CuI为催化剂,其反应通式如下:
其中Y-是碘或者溴;
Ar代表2,3-或4-位的、或3-,5-位二取代的苯或者取代的含氮、氧或硫原子的芳香杂环,所述的取代基是H,NO2-,-COOH,-COOR′,卤素,C1-C6烷基,C1-C6烷氧基,或芳基,R’为C1-C6烷基,其中卤素例如为氟、氯、溴、碘,C1-C6烷基例如为CH3-,C1-C6烷氧基例如为Me0-、Et0-,芳基例如Ph-或苯并环等;
R1R2NH可以是含C1-C6直链或支链烷基,C3-C6的环烷基,苄基,取代苄基(取代基推荐为C1-C6烷基或C1-C6烷氧基等)等的脂肪族伯胺,仲胺,或者五~七元的环状仲胺;R1R2NH或者是含芳香取代基的伯胺,所述的芳香取代基推荐为Ph-,取代Ph-(取代基推荐为C1-C6烷基或烷氧基等),噻唑,苯并噻唑等;
R1R2NH也可以是含NH在环内的五到七元杂环类芳香化合物,推荐为咪唑,吡咯,吡唑等,环上可以无取代基或有其它取代基如CH3-,-COOR′,-CH2CH(NHCbz)CO2R′,C1-C6烷基例如甲基、乙基、丙基等,C1-C6烷氧基例如Me0-、Et0-等;
R1R2NH或者是含NH在环内的苯并五到七元杂环,二苯并五到七元杂环,带取代基的苯并五到七元杂环或二苯并五到七元杂环,推荐为吲哚,2-甲基吲哚,咔唑,苯并氮三唑等。环上可以无取代基或有其它取代基如-COOR′,-CH2CH(NHCbz)CO2R′,-CH2CH(NHCO2CH3)CO2R′,-CH2CH(NHBoc)CO2R′,C1-C6烷基例如甲基、乙基、丙基等,C1-C6烷氧基例如MeO-、EtO-等。
本发明的反应中,所述的催化剂CuI用量推荐为3%mol到20%mol(相对于Ar-Y),使用的配体与CuI的摩尔比推荐为1:1到5:1,所述的R1R2NH与Ar—Y的摩尔比推荐为1.2:1到2.0:1。
碘代芳香化合物的氮芳基化反应进行的温度推荐在室温(20~25℃)进行,溴代芳香化合物的氮芳基化反应进行的温度在60~90℃,尤其推荐在60~70℃之间。
本发明的反应中,所使用的碱可以是K2CO3,Cs2CO3,K3PO4,NaOH或KOH等。
所使用的溶剂可以是有机溶剂,推荐为DMSO(二甲基亚砜),DMF(N,N-二甲基甲酰胺),DMA(N,N-二甲基乙酰胺),Dioxane(1,4-二氧六环),CH3CN等。
本发明的另一目的是提供一种能促进N-芳基化反应的2-吡啶-β酮类化合物。
本发明中因使用所述2-吡啶-β酮类化合物作为添加剂,能很好地促进所述N-芳基化反应,且该N-芳基化反应所使用的催化剂为CuI,该催化剂价格便宜,易得;所述添加剂2-吡啶-β-酮类化合物新颖,在空气中稳定,与文献中报道的同类型反应相比,碘代化合物的乌尔曼反应在室温下就能进行,溴代化合物反应的温度平均可以降低约20℃反应条件非常的温和,有很好的应用前景。
具体实施方式
通过下述具体实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1
配体2-丙酮基吡啶的合成
氩气保护下,0℃往溶解有32mmol nBuLi的60ml THF溶液中滴加2.96ml(32mmol)2-甲基吡啶,0℃搅拌反应45min,往反应混合液加入1.56ml(32mmol)乙腈,室温搅拌3h,往反应混合液加入30ml*3N硫酸,离子相用乙醚(2*25ml)萃取,然后用2N氢氧化钠溶液碱化(PH=11~12),用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压旋掉溶剂,剩余油状物再减压蒸馏得产物2.2g(产率:51%)。
1H NMR(CDCl3):δ=8.52(d,J=4.8Hz,1H;Phenyl),7.60(td,J=8.0,1.6Hz,1H;Phenyl),7.20-7.15(m,2H;Phenyl),3.89(s,2H;CH2),2.19ppm(s,3H;CH3);13C NMR(CDCl3):δ=205.3(-C=O),154.7,149.5,136.7,124.1,121.9(Phenyl),53.1(CH2),29.9ppm(CH3);MS(APCI):M/Z:136[M+].
实施例2
配体2-(异丁酰基甲基)吡啶的合成
合成方法如实施例1,产率:50%。
1H NMR(CDCl3):δ=8.52(d,J=4.8Hz,1H;Phenyl),7.60(td,J=7.6,1.6Hz,1H;Phenyl),7.21-7.13(m,2H;Phenyl),3.96(s,2H;CH2),2.80-2.74(m,1H;CH),1.11ppm(d,J=7.2Hz,6H;2CH3);13C NMR(CDCl3):δ=211.1(-C=O),155.1,149.4,136.5,124.2,121.9(Phenyl),49.9(CH2),40.8(CH),18.1ppm(CH3);GC/MS:rt=5.91min,M/Z=163.
实施例3
配体8-乙酰基-5,6,7,8-四氢喹啉的合成
氩气保护下,0℃往溶解有32mmol nBuLi的60ml THF溶液中滴加4.26g(32mmol)5,6,7,8-四氢喹啉,0℃搅拌反应45min,往反应混合液加入1.56ml(32mmol)乙腈,室温搅拌3h,往反应混合液加入30ml*3N硫酸,离子相用乙醚(2*25ml)萃取,然后用2N氢氧化钠溶液碱化(PH=11~12),用二氯甲烷萃取,有机相用无水硫酸钠干燥,减压旋掉溶剂,剩余油状物再减压蒸馏得产物2.3g,产率:46%。
1H NMR(CDCl3):δ=8.41(s,1H;Phenyl),7.42(d,J=7.6Hz,1H;Phenyl),7.09(t,J=7.2Hz,1H;Phenyl),4.01(t,J=6.4Hz,1H;CH),2.882-2.78(m,2H;CH2),2.25(s,3H;CH3),2.16-2.12(m,2H;CH2),1.81ppm(br,2H;CH2);13C NMR(CDCl3):δ=209.8(-C=O),162.6,154.6,147.2,137.1,132.8,121.9(Phenyl),55.5(CH),29.1,28.4,25.9,20.3ppm(CH2);GC/MS:rt=7.09min,M/Z=175;HRMS(EI):calcd for C11H13NO:175.0992[M+];found:175.0996.
实施例4
配体8-异丁酰基-5,6,7,8-四氢喹啉的合成
合成方法如实施例1,产率:42%,。
1H NMR(CDCl3):δ=8.36(d,J=4.4Hz,1H;Phenyl),7.39(d,J=8.0Hz,1H;Phenyl),7.06(dd,J=7.6,4.8Hz,1H;Phenyl),4.20(t,J=6.8Hz,1H;CH),3.07-3.00(m,1H;CH),2.79-2.73(m,2H;CH2),2.11-2.06(m,2H;CH2),1.85-1.80(m,2H;CH2),1.20-1.14ppm(m,6H;CH3);13CNMR(CDCl3):δ=215.8(-C=O),155.3,147.1,136.9,132.9,121.7(Phenyl),53.1(CH),40.3(CH),28.4(CH2),26.1(CH2),20.2(CH2),18.5ppm(CH3);GC/MS:rt=7.57min,M/Z=203;HRMS(EI):calcd for C13H17NO:203.1305[M+];found:203.1301.
实施例5
配体8-苯甲酰基-5,6,7,8-四氢喹啉的合成
合成方法如实施例1,产率:66%。
1H NMR(CDCl3):δ=8.37(d,J=4.0Hz,1H;Phenyl),8.07(d,J=8.0Hz,2H;Phenyl),7.60-7.36(m,4H;Phenyl),7.09(dd,J=7.6,4.8Hz,1H;Phenyl),5.02(t,J=6.4Hz,1H;CH),2.85-2.78(m,2H;CH2),2.26-2.21(m,2H;CH2),1.98-1.83(m,2H;CH2);13C NMR(CDCl3):δ=202.0(-C=O),155.7,147.3,136.9,133.3,132.9,128.9,128.6,127.9,121.8(Phenyl),49.6(CH),28.4,27.3,19.9ppm(CH2);GC/MS:rt=9.76min,M/Z=236.
实施例6
碘代化合物乌尔曼反应的典型制备方法(方法A)
N-苄基-4-甲氧基苯胺
在一个一端密封的反应管内,加入234mg对甲氧碘苯(MW=234,1.0mmol),然后加入161mg苄胺(MW=107,1.5mmol),650mg Cs2CO3(MW=325,2mmol),35mg 8-乙酰基-5,6,7,8-四氢喹啉(MW=175,0.2mmol),19mg CuI(MW=190,0.1mmol),0.5ml DMF作为溶剂,在氩气或氮气保护下,于室温(20~25℃)搅拌反应12h,用10毫升乙酸乙酯稀释反应混合液,过滤除掉无机盐,用10毫升乙酸乙酯淋洗两次滤渣,滤液减压蒸馏,过硅胶柱分离(淋洗液石油醚:乙酸乙酯=10:1),得到194mg产物N-苄基-对甲氧苯胺,产率91%。
1H NMR(CDCl3):δ=7.43-7.33(m,5H;Phenyl),6.84(d,J=8.8Hz,2H;Phenyl),6.65(d,J=8.8Hz,2H;Phenyl),4.33(s,2H;CH2),3.79ppm(s,3H;-OCH3);13C NMR(CDCl3):δ=152.3,142.5,139.8,128.7,127.7,127.3,115.0,114.3(Phenyl),55.7(CH2),49.3ppm(CH3);GC/MS:rt=8.92min,M/Z=213.
实施例7
N-正己基-4-甲氧基苯胺
采用41mg8-异丁酰基-5,6,7,8-四氢喹啉作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:87%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例8
采用47mg8-苯甲酰基-5,6,7,8-四氢喹啉作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:83%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例9
采用27mg 2-丙酮基吡啶作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:45%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例10
采用33mg 2-(异丁酰基甲基)吡啶作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:43%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例11
采用280mg K2CO3(MW=140,2mmol)作碱,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:46%;1HNMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例12
采用414mg K3PO4(MW=212,2mmol)作碱,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:86%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例13
采用0.5mL DMSO做溶剂,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:96%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例14
采用0.5mL CH3CN做溶剂,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:40%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例15
采用18mg 8-乙酰基-5,6,7,8-四氢喹啉(MW=175,0.1mmol)作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:77%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例16
采用88mg 8-乙酰基-5,6,7,8-四氢喹啉(MW=175,0.5mmol)作配体,按照如方法A所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌5h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:97%;1H NMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例17
按照如实施例6(方法A)所述,4-甲氧基碘苯(234mg,1.0mmol)与正己胺(203mg,2.0mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:98%;1HNMR(CDCl3):δ=6.82(d,J=8.8Hz,2H;Phenyl),6.62(d,J=8.8Hz,2H;Phenyl),3.79(s,3H;OCH3),3.34(s,1H;NH),3.08(t,J=7.2Hz,2H;-N-CH2-),1.63(m,2H;CH2),1.47-1.35(m,6H;CH2),0.94ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=152.1,142.8,114.9,114.1(Phenyl),55.8(-N-CH-),45.1,31.7,29.7,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.11min,M/Z=207.
实施例18
N-正己基-3,5-二甲基苯胺
按照方法A所述,采用DMA(0.5mL)做溶剂,3,5-二甲基碘苯(232mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌10h.粗产物经柱层析(20:1 石油醚:乙酸乙酯)提纯,产率:97%;1H NMR(CDCl3):δ=6.5(s,1H;Phenyl),6.38(s,2H;Phenyl),3.56(s,1H;NH),3.19(t,J=7.2,2H;-N-CH2),2.39(s,6H;CH3),1.77-1.69(m,2H;CH2),1.57-1.43(m,6H;CH2),1.04ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=148.8,138.9,119.3,110.9(Phenyl),44.2(-N-CH2-),31.8(Aryl-CH3),29.8,27.0,22.8,21.6(CH2),14.2ppm(CH3);GC/MS:rt=7.82min,M/Z=205.
实施例19
N-取代正己基苯胺
按照方法A所述,碘苯(204mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌10h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:97%;1H NMR(CDCl3):δ=7.21-7.17(m,2H;Phenyl),6.69(t,J=7.6Hz,1H;Phenyl),6.63(d,J=7.6Hz,2H;Phenyl),3.73(s,1H;NH),3.10(t,J=7.2,2H;-N-CH2-),1.67-1.60(m,2H;CH2),1.46-1.29(m,6H;CH2),0.91ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=148.3,129.2,117.3,112.9(Phenyl),44.2(-NH-CH2),31.7,29.5,26.9,22.7(CH2),14.1ppm(CH3);GC/MS:rt=7.06min,M/Z=177.
实施例20
N-正己基-4-腈基苯胺
按照方法A所述,4-腈基碘苯(229mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌10h.粗产物经柱层析(20:1 石油醚:乙酸乙酯)提纯,产率:95%;1H NMR(CDCl3):δ=7.39(d,J=8.8Hz,2H;Phenyl),6.55(d,J=8.4Hz,2H;Phenyl),4.51(s,1H;NH),3.11(t,J=8.8Hz,2H;-N-CH2-),1.66-1.59(m,2H;CH2),1.43-1.25(m,6H;CH2),0.88ppm(t,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=151.3,133.7,120.5,112.3(Phenyl),98.5(CN),43.5(-N-CH2),31.5,29.1,26.7,22.6(CH2),14.0ppm(CH3);GC/MS:rt=9.02min,M/Z=202.
实施例21
N-正己基-4-氯苯胺
按照方法A所述,4-氯碘苯(238mg,1.0mmol)与正己胺(152mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:91%;1H NMR(CDCl3):δ=7.11(dd,J=6.8,2.4Hz,2H;Phenyl),6.51(dd,J=6.8,2.0Hz,2H;Phenyl),3.59(s,1H;NH),3.06(t,J=7.2Hz,2H;-N-CH2-),1.65-1.58(m,2H;CH2),1.45-1.30(m,6H;CH2),0.92ppm(t,J=7.2Hz,3H;CH3);13C NMR(CDCl3):δ=147.1,129.0,121.6,113.8(Phenyl),44.2(-N-CH2),31.7,29.4,26.8,22.7(CH2),14.1ppm(CH3);GC/MS:rt=8.07min,M/Z=257.
实施例22
2-(4-甲氧基苄基氨基)苯甲酸
按照方法A所述,2-碘苯甲酸(248mg,1.0mmol)与对甲氧基苄胺(206mg,1.5mmol)在室温下搅拌10h.粗产物经柱层析(20:1 石油醚:乙酸乙酯)提纯,产率:92%;1HNMR(CDCl3):δ=7.79(d,J=7.6Hz,1H;Phenyl),7.33-7.27(m,3H;Phenyl),6.90(d,J=8.4Hz,2H;Phenyl),6.69(d,J=8.4,1H;Phenyl),6.54(t,J=7.2,1H;Phenyl),4.36(s,2H;CH2),3.73ppm(s,3H;-OCH3);13C NMR(CDCl3):δ=158.8,151.1,134.8,132.1,131.5,128.9,114.9,114.4,112.1,111.5,55.5,45.9ppm;MS(APCI):m/z:256[M-].
实施例23
(S)-N-苯基-α-甲基苄胺
按照方法A所述,碘苯(204mg,1.0mmol)与(S)-α-苯乙胺(181mg,1.5mmol)在室温下搅拌15h.粗产物经柱层析(20:1石油醚:乙酸乙酯)提纯,产率:85%;1H NMR(CDCl3):δ=7.49-7.41(m,4H;Phenyl),7.32(t,J=7.2Hz,1H;Phenyl),7.19(t,J=8.0Hz,2H;Phenyl)6.76(t,J=7.6Hz,1H;Phenyl),6.63(d,J=8.0Hz,2H;Phenyl),4.58(m,1H;CH),4.19(s,1H;NH),1.62ppm(d,J=6.8Hz,3H;CH3);13C NMR(CDCl3):δ=147.3,145.3,129.2,128.8,126.9,126.9,117.4,113.5(Phenyl),53.6(CH),25.1ppm(CH3);GC/MS:rt=7.85min,M/Z=197.
实施例24
N-烯丙基-p-对苯二胺
按照方法A所述,4-氨基碘苯(219mg,1.0mmol)与烯丙胺(115mg,1.5mmol)在室温下搅拌16h.粗产物经柱层析(10:1 石油醚:乙酸乙酯)提纯,产率:80%;1H NMR(CDCl3):δ=6.66-6.55(m,4H;Phenyl),6.01-5.92(m,1H;-CH2-CH=),5.24(m,1H;-CH=CHH),5.13(m,1H;-CH=CHH),3.72(br s,2H;CH2),4.58ppm(br s,3H;NH and NH2);13C NMR(CDCl3):δ=140.9,137.9,135.8,116.9(Phenyl),116.3(-CH=),115.1(=CH2),47.9ppm(-CH2-);GC/MS:rt=6.93min,M/Z=148.
实施例25
2-对甲基苯胺基乙醇
按照方法A所述,4-甲基碘苯(218mg,1.0mmol)与乙醇胺(92mg,1.5mmol)在室温下搅拌8h.粗产物经柱层析(5:1石油醚:乙酸乙酯)提纯,产率:98%;1H NMR(CDCl3):δ=7.03(d,J=8.0Hz,2H;Phenyl),6.60(d,J=8.4Hz,2H;Phenyl),3.78(t,J=5.2Hz,2H;-O-CH2-),3.43(br s,2H;NH and OH),3.24(t,J=5.2Hz,2H;-N-CH2),2.30ppm(s,3H;CH3);13CNMR(CDCl3):δ=145.8,129.8,127.3,113.7(Phenyl),61.1(-O-CH2-),46.7(-N-CH2-),20.4ppm(CH3);GC/MS:rt=6.82min,M/Z=151.
实施例26
5-[(4-甲氧基苯)氨基]-1-戊醇
按照方法A所述,4-甲基碘苯(218mg,1.0mmol)与5-氨基-1-戊醇(107mg,1.5mmol)在室温下搅拌12h.粗产物经柱层析(5:1 石油醚:乙酸乙酯)提纯,产率:93%;1HNMR(CDCl3):δ=7.01(d,J=8.0Hz,2H;Phenyl),6.56(d,J=8.0Hz,2H;Phenyl),3.61(t,J=6.8Hz,2H;-O-CH2-),3.09(t,J=6.8Hz,2H;-N-CH2),2.92(br s,2H;NH and OH),2.27(s,3H;CH3),1.68-1.57(m,4H;CH2),1.51-1.45ppm(m,2H;CH2);13C NMR(CDCl3):δ=146.2,129.8,126.6,113.2(Phenyl),62.6(-O-CH2-),44.4(-N-CH2-),32.5(CH3),29.4,23.4,20.4ppm(CH2);GC/MS:rt=8.31min,M/Z=193.
实施例27
1-[N-(哌啶)]-2-乙酰氨基苯
按照方法A所述,2-碘乙酰苯胺(261mg,1.0mmol)与哌啶(128mg,1.5mmol)在室温下搅拌15h.粗产物经柱层析(8:1石油醚:乙酸乙酯)提纯,产率:83%;1H NMR(CDCl3):δ=8.54(br s,1H;NH),8.33(d,J=7.6Hz,1H;Phenyl),7.14-7.02(m,3H;Phenyl),2.79(br s,4H;-N-CH2-),2.21(s,3H;CH3),1.74(br s,4H;CH2),1.62ppm(br s,2H;CH2);13C NMR(CDCl3):δ=168.0(-C=O),142.4,133.5,124.9,123.5,120.3,119.3(Phenyl),53.7(-N-CH2-),26.9,24.9,24.0ppm(CH2);GC/MS:rt=8.67min,M/Z=218.
实施例28
4-[N-(吡硌)]硝基苯
按照方法A所述,4-硝基碘苯(249mg,1.0mmol)与吡硌(107mg,1.5mmol)在室温下搅拌24h.粗产物经柱层析(8:1石油醚:乙酸乙酯)提纯,产率:95%;1H NMR(d-DMSO):δ=8.02(d,J=9.6Hz,2H;Phenyl),6.56(d,J=9.2Hz,2H;Phenyl),3.34(t,J=5.6Hz,4H;-N-CH2-),1.96ppm(t,J=6.8Hz,4H;CH2);13C NMR(d-DMSO):δ=152.3,135.7,126.4,111.3(Phenyl),48.2(-N-CH2-),25.4ppm(CH2);GC/MS:rt=9.56min,M/Z=192.
实施例29
N-环己基-4-氯苯胺
按照方法A所述,4-氯碘苯(238mg,1.0mmol)与吡硌(149mg,1.5mmol)在室温下搅拌19h.粗产物经柱层析(25:1 石油醚:乙酸乙酯)提纯,产率:86%;1H NMR(CDCl3):δ=7.28-7.10(m,2H;Phenyl),6.53(m,2H;Phenyl),3.61(br s,1H;NH),3.27-3.19(m,1H;-N-CH-),2.08-2.05(m,2H;CH2),1.82-1.77(m,2H;CH2),1.71-1.66(m,1H;CH2),1.45-1.24ppm(m,5H;CH2);13C NMR(CDCl3):δ=145.9,129.1,121.4,114.3(Phenyl),51.9(-N-CH-),33.3,25.9,24.9ppm(CH2);GC/MS:rt=8.31min,M/Z=209.
实施例30
4-吗啡啉基苯
按照方法A所述,碘苯(204mg,1.0mmol)与吗啡啉(131mg,1.5mmol)在室温下搅拌24h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:90%;1H NMR(CDCl3):δ=7.34-7.29(m,2H;Phenyl),6.97-6.91(m,3H;Phenyl),3.89(t,J=4.8Hz,4H;-O-CH2-),3.18ppm(t,J=4.8Hz,4H;-N-CH2-);13C NMR(CDCl3):δ=151.2,129.2,120.2,115.8(Phenyl),66.9(-O-CH2-),49.5ppm(-N-CH2-);GC/MS:rt=6.59min,M/Z=163.
实施例31
(S)-2-(4-氯苯氨基)丙酸
按照方法A所述,4-氯碘苯(238mg,1.0mmol)与L-丙氨酸(134mg,1.5mmol)在室温下搅拌11h。加入5%NaOH溶液(10mL)及乙醚(10mL),有机相用5%NaOH溶液萃取(3×5mL),水相合并后用盐酸中和至PH=4,析出的沉淀经过滤,干燥即得目标产物。产率:89%;1HNMR(d-DMSO):δ=7.08(dd,J=6.8,2.0Hz,2H;Phenyl),6.55(dd,J=6.8,2.0Hz,2H;Phenyl),3.92(m,1H;CH),1.36ppm(d,J=7.2Hz,3H;CH3);13C NMR(d-DMSO):δ=176.0(COOH),147.2,128.9,119.9,114.2(Phenyl),51.5(CH),18.5ppm(CH3);MS(APCI):M/Z:198[M-]。
实施例32
(S)-2-N-对甲苯基苯丙氨酸
按照方法A所述,4-甲基碘苯(218mg,1.0mmol)与L-苯丙氨酸(248mg,1.5mmol)在室温下搅拌12h。加入5%NaOH溶液(10mL)及乙醚(10mL),有机相用5%NaOH溶液萃取(3×5mL),水相合并后用盐酸中和至PH=4,析出的沉淀经过滤,干燥即得目标产物。产率:85%;1H NMR(d-DMSO):δ=7.29-7.20(m,5H;Phenyl),6.87(d,J=7.6Hz,2H;Phenyl),6.49(d,J=7.6Hz,2H;Phenyl),4.09(br s,1H;NH),3.35(br s,1H;CH),3.08-2.94(m,2H;CH2),2.13ppm(s,3H;CH3);13C NMR(d-DMSO):δ=175.2(COOH),145.9,138.4,129.8,129.6,128.6,126.8,125.3,113.2(Phenyl),58.2(CH),38.3(CH2),20.5ppm(CH3);ES(APCI):m/z:254[M-];
实施例33
2-对甲氧基苄胺基吡啶
按照方法A所述,2-碘吡啶(205mg,1.0mmol)与对甲氧基苄胺(206mg,1.5mmol)在室温下搅拌17h.粗产物经柱层析(6:1石油醚:乙酸乙酯)提纯,产率:96%;1H NMR(CDCl3):δ=8.09(d,J=5.2Hz,1H;Phenyl),7.39(td,J=6.8,2.0Hz,2H;Phenyl),7.29(d,J=8.8Hz,2H;Phenyl),6.88(d,J=8.4Hz,2H;Phenyl),6.57(m,1H;Phenyl),6.37(d,J=8.4Hz,1H;Phenyl),5.06(br s,1H;NH),4.43(d,J=5.6Hz,2H;CH2),3.81ppm(s,3H;CH3);13C NMR(CDCl3):δ=158.9,158.7,148.1,137.5,131.2,128.7,114.1,113.0,106.8(Phenyl),55.3(CH2),45.8ppm(CH3);GC/MS:rt=9.06min,M/Z=214.
实施例34
3-N-环己基吡啶
按照方法A所述,3-碘吡啶(205mg,1.0mmol)与环己胺(149mg,1.5mmol)在室温下搅拌24h.粗产物经柱层析(6:1 石油醚:乙酸乙酯)提纯,产率:88%;1H NMR(CDCl3):δ=8.01(br s,1H;Phenyl),7.91(br s,1H;Phenyl),7.05(br s,1H;Phenyl),6.84(d,J=7.6Hz,1H;Phenyl),3.70(br s,1H;NH),3.28-3.21(m,1H;-N-CH-),2.05-2.02(m,2H;CH2),1.68-1.63(m,1H;CH2),1.43-1.26ppm(m,5H;CH2);13C NMR(CDCl3):δ=143.5,137.9,136.1,123.8,118.8(Phenyl),51.4(-N-CH-),33.2,25.8,24.9ppm(CH2);GC/MS:rt=7.85min,M/Z=176.
实施例35
6-N-烯丙基-喹啉胺
按照方法A所述,6-碘喹啉(255mg,1.0mmol)与烯丙胺(115mg,2mmol)在室温下搅拌19h.粗产物经柱层析(6:1石油醚:乙酸乙酯)提纯,产率:87%;1HNMR(CDCl3):δ=8.61(d,J=4.0Hz,1H;Phenyl),7.91(m,2H;Phenyl),7.29-7.26(m,1H;Phenyl),7.12(m,1H;Phenyl),6.72(d,J=2.0Hz,1H;Phenyl),6.05-5.98(m,1H;-CH2-CH=),5.33(m,1H;-CH=CHH),5.22(m,1H;-CH=CHH),4.22(br s,1H;NH),3.89ppm(d,J=4.4Hz,2H;CH2);13CNMR(CDCl3):δ=167.5,146.1,145.8,134.6,134.2,130.2,129.9,121.6,121.3(Phenyl),116.7(-CH=),103.3(-CH=CHH),46.4ppm(CH2);GC/MS:rt=8.54min,M/Z=184.
实施例36
4-(N-苄基)-1-甲基-1H-吡唑胺
按照方法A所述,4-碘-1-甲基-1H-吡唑(208mg,1.0mmol)与苄胺(161mg,1.5mmol)在室温下搅拌24h.粗产物经柱层析(4:1石油醚:乙酸乙酯)提纯,产率:83%;1H NMR(CDCl3):δ=7.39-7.28(m,5H;Phenyl),7.14(s,1H;Phenyl),6.86(s,1H;Phenyl),4.16(s,2H;CH2),3.78ppm(s,3H;CH3);13C NMR(CDCl3):δ=139.6,134.1,128.7,128.5,127.7,127.2,116.7(Phenyl),52.2(CH2),39.1ppm(CH3);GC/MS:rt=8.08min,M/Z=187.
实施例37
2-(N-甲基哌嗪)-5-硝基吡啶
按照方法A所述,2-碘-5-硝基吡啶(250mg,1.0mmol)与N-甲基哌嗪(150mg,1.5mmol)在室温下搅拌11h.粗产物经柱层析(1:2 石油醚:乙酸乙酯)提纯,产率:82%;1HNMR(CDCl3):δ=9.03(t,J=2.4Hz,1H;Phenyl),8.19(m,1H;Phenyl),6.57(dd,J=9.60.8Hz,1H;Phenyl),3.83(d,J=4.4Hz,4H;Aryl-N-CH2-),2.57(d,J=4.0Hz,4H;CH3-N-CH2-),2.39ppm(s,3H;CH3);13C NMR(CDCl3):δ=160.3,146.4,135.1,133.0,104.6(Phenyl),54.5(Aryl-N-CH2-),45.9(CH3-N-CH2-),44.7ppm(CH3);GC/MS:rt=9.63min,M/Z=222.
实施例38
3-[N-(2-甲硫醚基乙烷基)]-吡啶胺
按照方法A所述,3-碘吡啶(205mg,1.0mmol)与2-甲硫醚基乙胺(138mg,1.5mmol)在室温下搅拌20h.粗产物经柱层析(5:1 石油醚:乙酸乙酯)提纯,产率:95%;1HNMR(CDCl3):δ=8.04(s,1H;Phenyl),7.94(d,J=3.6Hz,1H;Phenyl),7.08-7.05(m,1H;Phenyl),6.87(d,J=8.0Hz,1H;Phenyl),4.28(br s,1H;NH),3.29(t,J=6.4Hz,2H;-N-CH2-),2.73(t,J=6.4Hz,2H;-S-CH2-),2.09ppm(s,3H;CH3);13C NMR(CDCl3):δ=143.9,138.8,135.9,123.8,118.9(Phenyl),41.5(-N-CH2-),33.4(-S-CH2-),15.0ppm(CH3);GC/MS:rt=7.72min,M/Z=168;HRMS(EI):calcd for C8H12N2S:168.0716[M+];found:168.0719.
实施例39
2-[N-(2-甲基噻吩)]-吡啶胺
按照方法A所述,2-碘吡啶(205mg,1.0mmol)与2-甲胺基噻吩(170mg,1.5mmol)在室温下搅拌14h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:97%;1H NMR(CDCl3):δ=8.13(m,1H;Phenyl),7.46-7.41(m,1H;Phenyl),7.21(dd,J=5.21.2Hz,1H;Phenyl),7.02(m,1H;Phenyl),6.96(m,1H;Phenyl),6.61(td,J=6.0,0.4Hz,1H;Phenyl),6.44(d,J=8.0Hz,1H;Phenyl),5.08(br s,1H;NH),4.71ppm(d,J=6.0Hz,2H;CH2);13C NMR(CDCl3):δ=158.1,147.9,142.6,137.5,126.8,125.2,124.6,113.5,107.4(Phenyl),41.3ppm(CH2);GC/MS:rt=8.01min,M/Z=190.
实施例40
3-[N-(3-吗啡啉基丙烷基)]噻吩胺
按照方法A所述,3-碘噻吩(210mg,1.0mmol)与2-甲胺基噻吩(170mg,1.5mmol)在室温下搅拌14h.粗产物经柱层析(40:1 二氯甲烷:甲醇)提纯,产率:90%;1H NMR(CDCl3):δ=7.15(dd,J=4.82.8Hz,1H;Phenyl),6.62(dd,J=5.21.6Hz,1H;Phenyl),5.95(m,1H;Phenyl),3.73(m,4H;-O-CH2-),3.16(t,J=6.4Hz,2H;-NH-CH2-),2.51(m,6H;-N-CH2-),1.87-1.81ppm(m,2H;CH2);13C NMR(CDCl3):δ=148.9,125.1,119.9,95.2(Phenyl),66.9(-O-CH2-),57.6(-NH-CH2-),53.7(-N-CH2-),45.5(-N-CH2-),25.5ppm(CH2);GC/MS:rt=8.79min,M/Z=226;HRMS(EI):calcd for C11H18ON2S:226.1134[M+];found:226.1133.
实施例41
N-(4-甲氧基苯基)-4-甲氧基苄胺
溴代化合物乌尔曼反应的典型制备方法(方法B)
在一个反应管内,加入234mg对甲氧溴苯(MW=187,1.0mmol),然后加入206mg对甲氧基苄胺(MW=137,1.5mmol),650mg Cs2CO3(MW=325,2mmol),35mg8-乙酰基-5,6,7,8-四氢喹啉(MW=175,0.2mmol),19mg CuI(MW=190,0.1mmol),0.5ml DMF作为溶剂,在氩气或氮气保护下,于60~70℃搅拌反应14h,用10毫升乙酸乙酯稀释反应混合液,过滤除掉无机盐,用10毫升乙酸乙脂淋洗两次滤渣,滤液减压蒸馏,过硅胶柱分离(淋洗液石油醚:乙酸乙脂=10:1),得到206mg产物N-对甲氧基苄基-对甲氧苯胺,产率85%。
1H NMR(CDCl3):δ=7.31(d,J=8.4Hz,2H;Phenyl),6.89(d,J=8.4Hz,2H;Phenyl),6.79(d,J=9.2Hz,2H;Phenyl),6.65(d,J=9.2Hz,2H;Phenyl),4.24(s,2H;CH2),3.83(s,3H;CH3),3.77ppm(s,3H;CH3);13C NMR(CDCl3):δ=158.9,152.5,142.0,131.4,128.9,114.9,114.5,114.0(Phenyl),55.8(CH2),55.3(CH3),48.9,ppm(CH3);GC/MS:rt=10.01min,M/Z=243.
实施例42
N-正己基-4-乙酰基苯胺
按照实施例41(方法B)所述,4-乙酰基溴苯(199mg,1.0mmol)与1-正己胺(152mg,1.5mmol)在60~70℃搅拌8h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:95%;1HNMR(CDCl3):δ=7.81(d,J=8.8Hz,2H;Phenyl),6.55(d,J=8.8Hz,2H;Phenyl),4.47(br s,1H;NH),3.15(t,J=7.6Hz,2H;-NH-CH2),2.49(s,3H;CH3),1.67-1.59(m,2H;CH2),1.42-1.27(m,6H;CH2),0.91ppm(m,3H;CH3);13C NMR(CDCl3):δ=196.3(-C=O),152.4,130.8,126.4,111.3(Phenyl),43.4(-NH-CH2),31.6(CH3),29.2,26.7,25.9,22.6(CH2),14.0ppm(CH3);GC/MS:rt=9.27min,M/Z=219.
实施例43
1-(N-环己基)-萘胺
按照方法B所述,1-溴代萘(207mg,1.0mmol)与环己胺(149mg,1.5mmol)在90~100℃搅拌18h.粗产物经柱层析(100:1石油醚:乙酸乙酯)提纯,产率:83%;1H NMR(CDCl3):δ=7.87-7.83(m,2H;Phenyl),7.52-7.45(m,2H;Phenyl),7.38(t,J=8.0Hz,1H;Phenyl),7.25(d,J=8.0Hz,1H;Phenyl),6.71(d,J=7.6Hz,1H;Phenyl),4.38(br s,1H;NH),3.57-3.49(m,1H;-NH-CH-),2.22(m,2H;CH2),2.19-1.85(m,2H;CH2),1.78-1.73(m,1H;CH2),1.56-1.41ppm(m,5H;CH2);13C NMR(CDCl3):δ=142.3,134.6,128.7,126.7,125.6,124.5,123.5,119.9,116.8,104.9(Phenyl),51.9(-NH-CH-),33.3,26.1,25.1ppm(CH2);GC/MS:rt=9.66min,M/Z=225.
实施例44
1-(N-哌啶)-3,4,5-三甲氧基苯胺
按照方法B所述,5-溴-1,2,3-三甲氧基苯(247mg,1.0mmol)与哌啶(128mg,1.5mmol)在90~100℃搅拌20h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:80%;1HNMR(CDCl3):δ=6.22(s,2H;Phenyl),3.86(s,6H;CH3),3.80(s,3H;CH3),3.09(t,J=5.6Hz,4H;-N-CH2),1.78-1.72(m,4H;CH2),1.61-1.58ppm(m,2H;CH2);13C NMR(CDCl3):δ=153.5,149.6,132.1,95.3(Phenyl),60.9(CH3),56.1(CH3),51.8(-N-CH2-),25.9,24.2ppm(CH2);GC/MS:rt=9.01min,M/Z=251.
实施例45
(S)-4-甲基-2-(苯基氨基)丁酸
按照方法B所述,溴苯(157mg,1.0mmol)与L-异亮氨酸(197mg,1.5mmol)在60~70℃搅拌12h。加入5% NaOH溶液(10mL)及乙醚(10mL),有机相用5%NaOH溶液萃取(3×5mL),水相合并后用盐酸中和至PH=4,析出的沉淀经过滤,干燥即得目标产物。产率:93%;1H NMR(d-DMSO):δ=7.05(t,J=8.0Hz,2H;Phenyl),6.53(m,3H;Phenyl),3.83(m,1H;-N-CH-),1.78(m,1H;-CH-CH3),1.64-1.57(m,2H;CH2),0.94(d,J=6.8Hz,3H;CH3),0.88ppm(d,J=6.4Hz,3H;CH3);13C NMR(d-DMSO):δ=176.3,148.5,129.3,116.6,112.8(Phenyl),54.7(-N-CH-),41.6(-CH-CH3),24.9(CH2),23.2(CH3),22.2ppm(CH3);MS(APCI):M/Z:206[M-].
实施例46
5-(4-氯苯氨基)-1-戊醇
按照方法B所述,4-溴-氯苯(191mg,1.0mmol)与5-氨基-1-戊醇(155mg,1.5mmol)在60~70℃搅拌17h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:87%;1H NMR(CDCl3):δ=7.11(m,2H;Phenyl),6.54(m,2H;Phenyl),3.66(t,J=6.4Hz,2H;-O-CH2-),3.09(t,J=7.2Hz,2H;-N-CH2-),2.58(br s,2H;NH and OH),1.70-1.59(m,4H;CH2),1.53-1.47ppm(m,2H;CH2);13C NMR(CDCl3):δ=146.7,129.1,122.0,114.0(Phenyl),62.7(-O-CH2-),44.2(-N-CH2-),32.4,29.1,23.3ppm(CH2);GC/MS:rt=8.94min,M/Z=213.
实施例47
3-[N-(2-甲基噻吩)]-6-甲氧基吡啶胺
按照方法B所述,5-溴-2-甲氧基吡啶(188mg,1.0mmol)与2-甲氨基噻吩(170mg,1.5mmol)在60~70℃搅拌18h.粗产物经柱层析(10:1石油醚:乙酸乙酯)提纯,产率:92%;1HNMR(CDCl3):δ=7.66(s,1H;Phenyl),7.22(d,J=5.2Hz,1H;Phenyl),7.06-6.96(m,3H;Phenyl),6.63(d,J=8.8Hz,1H;Phenyl),4.48(s,2H;CH2),3.88(s,3H;CH3),3.74ppm(br s,1H;NH);13C NMR(CDCl3):δ=157.8,142.5,138.4,130.9,126.9,126.3,125.2,124.8,110.8(Phenyl),53.4(CH2),44.4ppm(CH3);GC/MS:rt=8.84min,M/Z=220.
实施例48
4-(3-吗啡啉丙氨基)-苄醇
按照方法B所述,4-溴-苄醇(187mg,1.0mmol)与1-(3-吗啡啉)丙胺(216mg,1.5mmol)在60~70℃搅拌17h.粗产物经柱层析(30:1CH2Cl2:MeOH)提纯,产率:90%;1HNMR(d-DMSO):δ=7.00(d,J=8.0Hz,2H;Phenyl),6.49(d,J=8.4Hz,2H;Phenyl),5.5(br s,1H;NH),4.77(t,J=5.2Hz,1H;OH),4.29(d,J=5.2Hz,2H;-CH2-OH),3.58(s,4H;-O-CH2-),3.03(br s,2H;-NH-CH2-),2.36(s,6H;-N-CH2-),1.66ppm(t,J=6.8Hz,2H;CH2);13CNMR(d-DMSO):δ=148.5,129.8,128.4,112.1(Phenyl),66.7(-CH2-OH),63.6(-O-CH2-),56.7(-NH-CH2-),53.9(-N-CH2-),41.8(-N-CH2-),26.1ppm(CH2);MS(EI):m/z:250[M+],162,132,100;HRMS(EI):calcd for C14H22O2N2:250.1676[M+];found:250.1674.
Claims (8)
2.根据权利要求1所述的应用,其特征是:所述X=C,R为C1~C3烷基,n=2~4。
3.根据权利要求2所述的应用,其特征是:所述具有式I结构的2-吡啶-β-酮类化合物为
5.根据权利要求4所述的应用,其特征是,所述催化剂CuI相对于Ar-Y的用量的摩尔百分比为3%到20%;所述2-吡啶-β酮类化合物与CuI的摩尔比为1∶1到5∶1;所述R1R2NH与Ar-Y的摩尔比为1.2∶1到2∶1。
6.根据权利要求4或5所述的应用,其特征是,所述N-芳基化反应的进行温度在20~90℃之间。
7.根据权利要求4或5所述的应用,其特征是,所述的碱是K2CO3、Cs2CO3、K3PO4、NaOH或KOH;所述的溶剂是DMF、DMSO、DMA、1,4-二氧六环、CH3CN。
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