一种噻苯唑的合成新方法
阅读说明:本技术 一种噻苯唑的合成新方法 (Novel synthesis method of thiabendazole ) 是由 汪清民 王兹稳 李刚 刘玉秀 宋红健 李永强 于 2018-07-26 设计创作,主要内容包括:本发明涉及通用名为噻苯唑的药物合成新路线,以噻唑-4-甲醛为原料,与盐酸羟胺缩合得到噻唑-4-甲醛肟,用NCS氯代后与苯胺反应的到N-苯基噻唑-4-甲胺肟,然后与对三氟甲基苯甲酰氯反应得到胺肟酯,最后采用可见光催化的自由基反应关环得到噻苯唑。本发明首次将可见光催化的自由基反应运到噻苯唑的合成中,避免了传统合成方法中高温、强酸的反应条件,反应更加绿色、温和。本方法具备广谱性,还可用于咪唑类化合物Ia-Ial的合成。<Image he="261" wi="700" file="DSA0000167897760000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a new synthesis route of a medicine with the general name of thiabendazole, which takes thiazole-4-formaldehyde as a raw material to be condensed with hydroxylamine hydrochloride to obtain thiazole-4-formaldehyde oxime, reacts with aniline after NCS chlorination to obtain N-phenylthiazole-4-methanamine oxime, and then reacts with p-trifluoromethyl benzoyl chlorideObtaining amidoxime ester through reaction, and finally obtaining thiabendazole through ring closing reaction by adopting free radical reaction catalyzed by visible light. The invention firstly transports the free radical reaction of visible light catalysis to the synthesis of thiabendazole, avoids the reaction conditions of high temperature and strong acid in the traditional synthesis method, and the reaction is more green and mild. The method has broad spectrum and can be used for synthesizing imidazole compounds Ia-Ial.)
技术领域
本发明涉及通用名为噻苯唑的药物合成新路线,以及该路线在咪唑杂环合成中的应用,属于有机化学技术领域。
背景技术
噻苯唑,化学名为2-(4-噻唑基)-1H-苯并咪唑,又被称为噻菌灵、涕必灵,起初该类化合物被发现具有很好的驱虫效果,作为广谱的驱虫药使用。后来,该类化合物因为能防治多种植物的真菌病害而被当做广谱的杀菌剂使用。近十几年,噻苯唑因具有水果蔬菜保鲜、食品防腐和生活用品防霉等作用,成为一种优异的防霉保鲜剂。
到目前为止,已有许多文献专利报道噻苯唑的合成方法。其传统方法包括三种:1)邻苯二胺和噻唑-4-羧酸及其衍生物在酸的作用下高温缩合;2)邻苯二胺和噻唑-4-甲腈在三氟甲烷磺酸酐的催化下缩合;3)邻苯二胺和噻唑-4-甲醛在氧化剂的作用下氧化缩合。早在1961年,Brown等(Brown,H.D.et al.J.Am.Chem.Soc.,1961,83,1764-1765)就报道了如反应式一所示的合成路线,即噻唑-4-甲酰胺、邻苯二胺和多聚磷酸在250℃的高温下反应3小时缩合得到噻苯唑。
1965年,Grenda等(Grenda,V.J.et al.J.Org.Chem.,1965,30,259-261)使用N-苯基噻唑-4-甲脒盐酸盐作为原料,在碱性条件下用次氯酸钠处理关苯并咪唑环就能以较高的收率得到噻苯唑,相比于Brown的方法要有明显的改进(如反应式二所示)。
1994年,杜邦公司申请发明专利(US5310923A、US5310924A)报道了由邻苯二胺和噻唑-4-甲腈和邻苯二胺反应制备噻苯唑的方法。专利中涉及了两种反应条件,一种是使用水,正丁醇加维生素C体系,用三氟甲烷磺酸酐催化;第二种则是使用水,甲醇加维生素C和EDTA体系,用盐酸维持体系酸度。两种条件都能以较高的收率实现噻苯唑的合成,但加热和酸的使用不可避免(如反应式三所示)。
2015年,孟祥豹等(Meng X.et al.Bioorg.Med.Chem.,2015,23,3774-3780)报道了由噻唑-4-甲醛和邻苯二胺在焦亚硫酸钠的作用下加热缩合氧化合成噻苯唑的方法。反应需要用到过量的氧化剂(如反应式四所示)。
2015年,毕海东等(CN104557902A)发明了一种制备噻苯唑的新方法。他们从基本化工原料丙酮出发,与氯气反应制备的到一氯丙酮,然后与硫脲关环得到2-氨基-4-甲基噻唑,通过重氮化反应去氨基,再氧化甲基得到噻唑-4-甲酸,然后与邻苯二胺和多聚磷酸在高温下缩合得到。该路线适合工业大规模生产,但产生大量废酸和高温能耗(如反应式五所示)。
尽管目前已经报道了多种合成噻苯唑的方法,但它们普遍存在需要酸性条件、加热高温或者过量氧化剂的特点,反应条件相对强烈,且产生了废酸污染,因此还需要发展新的合成方法还实现噻苯唑的绿色高效合成。
发明内容
本发明提供了一种噻苯唑(1)(Thiabendazole,化学名为2-(4-噻唑基)-1H-苯并咪唑)的合成新方法。
本发明的噻苯唑具体合成路线如反应式六所示:
本发明包含以下步骤:
1、由商品化试剂噻唑-4-甲醛(1)经三步反应合成得到中间体4,中间体3与苯胺反应得到中间体4可用的碱包括:吡啶、三乙胺、二异丙基乙胺、N-乙基哌啶、三乙烯二胺,可用的溶剂包括:***、甲基叔丁基醚、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环。
2、中间体4与对三氟甲基苯甲酰氯反应制备得到中间体5,可用的碱包括:吡啶、三乙胺、二异丙基乙胺、N-乙基哌啶、N-甲基吗啉,可用的溶剂包括:四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、二氯甲烷、1,2-二氯乙烷。
3、中间体5在光催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6作用下经过可见光照射反应得到目标化合物I,可用的溶剂包括:N,N-二甲基甲酰胺、N,N-二乙基甲酰胺、N,N-二甲基乙酰胺、二甲基亚砜、乙腈、丙酮、二氯甲烷、1,2-二氯乙烷、甲基叔丁基醚、四氢呋喃、1,4-二氧六环,可用的光源包括:不同瓦数的白色LED灯、不同瓦数的蓝色LED灯、不同瓦数的白色CFL灯。
本发明首次将可见光催化的自由基反应运到噻苯唑的合成中,避免了传统合成方法中高温、强酸的反应条件,反应更加绿色、温和。
本方法具备广谱性,还可用于咪唑类化合物Ia-Ial的合成,如反应式七所示,前三步反应可以不用纯化,直接合成出4a-4al,然后引入导向基得5a-5al,再在光照条件下关环得Ia-Ial,R1和R2指代的基团见实施例二中具体化合物结构。
具体实施方式
:
下述的实施例可用来进一步说明本发明,但不意味着限制本发明。
实施例一:噻苯唑的合成
中间体2的合成:
在一个100mL的圆底烧瓶中加入噻唑-4-甲醛(1)(2.26g,20mmol),乙醇(40mL),室温搅拌下加入盐酸羟胺(1.47g,21mmol)和吡啶(1.67g,21mmol),加毕,反应16h,TLC检测。将反应液减压浓缩,加入50mL乙酸乙酯稀释,倒入分液漏斗中,加入30mL饱和碳酸钠溶液,萃取,分液,水相用乙酸乙酯萃取(50mL×2),合并有机相,饱和食盐水洗,无水硫酸钠干燥,减压脱溶得黄色固体2.60g,收率99%。E/Z=2∶1,E构型:1H NMR(400MHz,CDCl3)δ10.72(brs,1H),8.86(d,J=2.0Hz,1H),8.47(d,J=2.0Hz,1H),7.91(s,1H).Z构型:1H NMR(400MHz,CDCl3)δ8.90(d,J=2.0Hz,1H),8.37(s,1H),7.65(d,J=2.0Hz,1H).
中间体3的合成:
在一个25mL的圆底烧瓶中加入噻唑-4-甲醛肟(2)(0.52g,4.1mmol),DMF(4.1mL),冰浴冷却,加入1/5的NCS(0.116g,0.86mmol),保持0℃反应1h,然后再分批加入剩余的NCS(0.464g,3.5mmol),自然升温,反应2h,有大量固体析出。加入14mL水,将反应淬灭,抽滤,滤饼用5mL水洗涤,干燥,得白色固体0.55g,收率83%。1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),9.19(d,J=2.0Hz,1H),8.16(d,J=2.0Hz,1H).13C NMR(100MHz,DMSO-d6)δ155.4,148.3,130.9,121.0.
中间体4的合成:
在一个100mL的圆底烧瓶中加入氯代噻唑-4-甲醛肟(3)(0.54g,3.3mmol),Ar保护,注入THF(20mL)和苯胺(0.325g,3.3mmol),室温搅拌下注入三乙胺(0.68g,6.6mmol),然后升温至60℃反应过夜。将反应液冷却,抽滤,滤饼用10mL四氢呋喃洗涤,母液减压脱溶,粗品柱层析得黄色固体0.34g,收率47%。E/Z=7.6∶1,E构型:1H NMR(400MHz,CDCl3)δ8.75(s,1H),7.58(s,1H),7.14(t,J=7.6Hz,2H),6.97(t,J=7.2Hz,1H),6.72(d,J=8.0Hz,2H).13CNMR(100MHz,CDCl3)δ153.0,147.5,146.8,139.6,128.8,123.2,121.3,120.1.HR-MS(ESI):Calcd for C10H10N3Os[M+H]+220.0539,found 220.0542.
中间体5的合成:
在一个100mL的圆底烧瓶中加入中间体4(0.219g,1mmol)胺肟,用10mL重蒸的二氯甲烷溶解,加入1.2mmol三乙胺,冰浴冷却,然后缓慢滴加5mL溶有1.1mmol对三氟甲基苯甲酰氯的二氯甲烷溶液,滴加完毕,冰浴下反应1h,TLC监测。加入25mL饱和碳酸氢钠溶液,萃取,分液,水相再用二氯甲烷萃取(40mL×2),合并有机层,饱和食盐水洗,无水硫酸钠干燥,减压脱溶,经硅胶柱层析得到0.32g中间体5,白色固体,收率82%,熔点150-151℃。1H NMR(400MHz,CDCl3)δ8.80(d,J=2.0Hz,1H),8.19(d,J=2.0Hz,1H),7.84(s,1H),7.54(d,J=8.8Hz,2H),7.51(d,J=8.8Hz,2H),7.27(t,J=7.6Hz,2H),7.16-7.10(m,3H).13C NMR(100MHz,CDCl3)δ162.6,152.8,149.0,147.0,139.5,134.3(q,J=32.5Hz),132.2,129.8,128.9,125.2,125.1(q,J=3.5Hz),123.8,123.6(q,J=271.1Hz),120.9.HR-MS(ESI):Calcd for C18H13F3N3O2S[M+H]+392.0675,found 392.0677.
目标化合物I的合成:
在一个25mL的Schlenk管中加入0.2mmol的中间体5,1%的光催化剂Ir[dF(CF3)ppy]2(dtbbpy)PF6,密闭,插氩气球,置换气体三至四次,然后注入1mL甲基叔丁基醚,置于光反应器中光照室温反应36h。反应完毕,加入15mL乙酸乙酯将反应液稀释,倒入分液漏斗中,加入10mL饱和碳酸钠溶液,萃取,分液,水相再用乙酸乙酯萃取(20mL×2),合并有机层,饱和氯化钠洗,无水硫酸钠干燥,减压脱溶,粗品经柱层析分离得到16mg目标产物I,白色固体,收率40%,熔点297-298℃。1H NMR(400MHz,DMSO-d6)δ12.97(s,1H),9.34(d,J=1.8Hz,1H),8.45(d,J=1.8Hz,1H),7.66(d,J=7.2Hz,1H),7.52(d,J=7.2Hz,1H),7.27-7.16(m,2H).13C NMR(100MHz,DMSO-d6)δ156.1,147.6,147.5,144.2,134.8,123.1,122.2,119.9,119.2,112.2.HR-MS(ESI):Calcd for C10H8N3S[M+H]+202.0433,found 202.0434.
实施例二:合成方法拓展,Ia-Ial的合成
合成步骤同实施例一,化合物数据如下:
(E)-N′-hydroxy-N-phenylbenzimidamide(4a)
152.0,139.7,131.1,129.7,128.8,128.4,128.4,122.7,121.3.
(E)-N′-hydroxy-4-methyl-N-phenylbenzimidamide(4b)
128.3,128.0,122.7,121.4,21.4.HR-MS(ESI):Calcd for C14H15N2O[M+H]+227.1179,found227.1180.
(E)-N′-hydroxy-4-methoxy-N-phenylbenzimidamide(4c)
160.7,151.7,139.9,129.8,128.7,123.4,122.6,121.3,113.8,55.3.HR-MS(ESI):Calcdfor C14H15N2O2[M+H]+243.1128,found 234.1129.
(E)-4-cyano-N′-hydroxy-N-phenylbenzimidamide(4d)
150.7,139.0,135.7,132.2,129.1,128.9,123.6,121.7,118.3,113.3.HR-MS(ESI):Calcdfor C14H12N3O[M+H]+238.0975,found 238.0975.
(E)-N′-hydroxy-4-nitro-N-phenylbenzimidamide(4e)
(100MHz,CDCl3)δ150.5,148.4,138.9,137.5,129.2,129.2,123.7,123.7,121.8.HR-MS(ESI):Calcd for C13H12N3O3[M+H]+258.0873,found 258.0874.
(E)-4-fluoro-N′-hydroxy-N-phenylbenzimidamide(4f)
139.5,130.4(d,J=8.3Hz),128.9,127.1(d,J=3.0Hz),123.0,121.6,115.6(d,J=21.7Hz).HR-MS(ESI):Calcd for C13H12FN2O[M+H]+231.0928,found 231.0930.
(E)-4-chloro-N′-hydroxy-N-phenylbenzimidamide(4g)
129.7,129.6,128.9,128.8,123.1,121.6.HR-MS(ESI):Calcd for C13H12ClN2O[M+H]+247.0633,found 247.0635.
(E)-4-bromo-N′-hydroxy-N-phenylbenzimidamide(4h)
131.7,130.1,129.9,128.9,124.1,123.1,121.6.HR-MS(ESI):Calcd for C13H12BrN2O[M+H]+291.0128,found 291.0124.
(E)-N′-hydroxy-N-phenyl-4-(trifluoromethoxy)benzimidamide(4i)
150.2,139.3,130.0,129.6,128.9,123.2,121.6,120.7.HR-MS(ESI):Calcd forC14H12F3N2O2[M+H]+297.0845,found 297.0846.
(E)-3-chloro-N′-hydroxy-N-phenylbenzimidamide(4j)
(100 MHz,CDCl3)δ151.0,139.3,134.4,133.0,129.8,129.6,128.9,128.4,126.7,123.3,121.5.HR-MS(ESI):Calcd for C13H12ClN2O[M+H]+247.O633,found 247.0634.
(E)-2-chloro-N′-hydroxy-N-phenylbenzimidamide(4k)
131.8,131.0,130.5,130.0,128.8,126.9,123.1,120.8.HR-MS(ESI):Calcd forC13H12ClN2O[M+H]+247.0633,found 247.0634.
(E)-N′-hydroxy-N-phenylbenzo[d][1,3]dioxole-5-carboximidamide(4l)
151.7,148.9,147.6,139.8,128.8,124.9,122.8,122.7,121.2,108.7,108.4,101.4.HR-MS(ESI):Calcd for C14H13N2O3[M+H]+257.0921,found 257.0923.
(E)-N′-hydroxy-N-phenyl-[1,1′-biphenyl]-4-carboximidamide(4m)
140.2,139.6,129.6,128.9,128.8,127.7,127.1,127.1,122.9,121.5.HR-MS(ESI):Calcdfor C19H17N2O[M+H]+289.1335,found 289.1335.
(E)-N′-hydroxy-N-phenyl-2-naphthimidamide(4n)
6.70(d,J=7.6Hz,2H).13C NMR(100 MHz,DMSO-d6)δ149.6,142.0,133.5,133.0,131.0,128.9,128.7,128.2,128.0,127.4,127.1,126.9,125.7,121.0,120.1.HR-MS(ESI):Calcdfor C17H15N2O[M+H]+263.1179,found 263.1183.
Methyl(E)-4-(N′-hydroxy-N-phenylcarbamimidoyl)benzoate(4o)
13C NMR(100 MHz,CDCl3)δ166.6,151.3,139.3,135.5,131.1,129.7,128.9,128.4,123.2,121.6,52.3.HR-MS(ESI):Calcd for C15H15N2O3[M+H]+271.1077,found 271.1079.
(E)-N-(4-(N′-hydroxy-N-phenylcarbamimidoyl)phenyl)acetamide(4p)
13C NMR(100 MHz,CDCl3)δ168.6,151.7,139.6,139.3,129.1,128.8,126.6,122.8,121.4,119.3,24.6.HR-MS(ESI):Calcd for C15H16N3O2[M+H]+270.1237,found 270.1238.
Ethyl(E)-2-(hydroxyimino)-2-(phenylamino)acetate(4q)
143.3,139.1,128.9,124.0,121.1,62.4,13.8.HR-MS(ESI):Calcd for C10H13N2O3[M+H]+209.0921,found 209.0922.
(E)-N′-hydroxy-N-phenylpivalimidamide(4r)
28.2.HR-MS(ESI):Calcd for C11H17N2O[M+H]+193.1335,found 193.1335.
(E)-N′-hydroxy-N-(p-tolyl)benzimidamide(4aa)
152.2,137.1,132.4,131.2,129.6,129.3,128.5,128.4,121.7,20.7.HR-MS(ESI):Calcdfor C14H15N2O[M+H]+227.1179,found 227.1181.
(E)-N′-hydroxy-N-(4-methoxyphenyl)benzimidamide(4ab)
128.3,123.9,114.0,55.4.HR-MS(ESI):Calcd for C14H15N2O2[M+H]+243.1128,found243.1128.(E)-N-(4-(tert-butyl)phenyl)-N′-hydroxybenzimidamide(4ac)
129.6,128.5,128.4,125.6,120.9,34.2,31.4.HR-MS(ESI):Calcd for C17H21N2O[M+H]+269.1648,found 269.1652.
(E)-N-(4-fluorophenyl)-N′-hydroxybenzimidamide(4ad)
130.8,129.8,128.5,123.4(d,J=8.0Hz),115.50(d,J=22.5Hz).HR-MS(ESI):Calcd forC13H12FN2O[M+H]+231.0928,found 231.0928.
(E)-N-(4-chlorophenyl)-N′-hydroxybenzimidamide(4ae)
122.4.HR-MS(ESI):Calcd for C13H12ClN2O[M+H]+247.0633,found 247.0633.
-7.36(m,3H),7.35-7.30(m,2H),7.20(d,J=8.8Hz,2H),6.52(d,J=8.8Hz,2H).13C NMR(100 MHz,CDCl3)δ151.5,138.8,131.8,130.6,130.0,128.6,128.3,122.7,115.5.HR-MS(ESI):Calcd for C13H12BrN2O[M+H]+291.0128,found 291.0119.
(E)-N′-hydroxy-N-(m-tolyl)benzimidamide(4ag)
(100 MHz,CDCl3)δ152.1,139.6,138.7,131.2,129.6,128.5,128.4,123.5,121.9,118.4,21.3.HR-MS(ESI):Calcd for C14H15N2O[M+H]+227.1179,found 227.1183.
(E)-N′-hydroxy-N-(o-tolyl)benzimidamide(4ah)
152.7,138.1,131.33,130.5,129.8,129.6,128.3,128.2,126.1,123.7,123.5,18.0.HR-MS(ESI):Calcd for C14H15N2O[M+H]+227.1179,found 227.1181.
(E)-N-(benzo[d][1,3]dioxol-5-yl)-N′-hydroxybenzimidamide(4ai)
DMSO-d6)δ150.2,147.4,142.2,136.4,133.3,129.3,128.6,128.3,113.9,108.1,103.3,101.2.HR-MS(ESI):Calcd for C14H13N2O3[M+H]+257.0921,found 257.0921.
(E)-N-(3,4-dichlorophenyl)-N′-hydroxybenzimidamide(4aj)
132.5,130.3,130.2,130.2,128.8,128.2,126.0,122.4,120.3.HR-MS(ESI):Calcd forC13H11C12N2O[M+H]+281.0243,found 281.0245.
(E)-N-(3,5-dimethylphenyl)-N′-hydroxybenzimidamide(4ak)
128.3,124.4,119.1,21.2.HR-MS(ESI):Calcd for C15H17N2O[M+H]+241.1335,found241.1333.
(E)-N-(2,4-dimethoxyphenyl)-N′-hydroxybenzimidamide(4al)
J=8.8Hz,1H),6.13(dd,J=8.8,2.4Hz,1H),3.80(s,3H),3.70(s,3H).13C NMR(100 MHz,CDCl3)δ156.2,152.4,151.7,131.6,129.4,128.4,128.2,122.9,122.4,103.3,99.0,55.6,55.4.HR-MS(ESI):Calcd for C15H17N2O3[M+H]+273.1234,found 273.1233.
(E)-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5a)
138.7,134.5(q,J=32.7Hz),132.7,130.8,130.0,129.6,129.4,129.0,128.5,125.5(J=3.2Hz),124.5,123.6(q,J=270.9Hz),123.1.HR-MS(ESI):Calcd for C21H16F3N2O2[M+H]+385.1158,found 385.1159.
(E)-4-methyl-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5b)
(ESI):Calcd for C22H18F3N2O2[M+H]+399.1315,found 399.1318.
(E)-4-methoxy-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5c)
130.9,129.9,129.0,125.5(q,J=3.7Hz),124.3,123.6(q,J=271.0Hz),122.9,121.6,113.9,55.3.HR-MS(ESI):Calcd for C22H18F3N2O3[M+H]+415.1264,found 415.1263.
(E)-4-cyano-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5d)
136.0,133.1,133.0(q,J=31.8Hz),132.8,130.93,130.6,129.2,126.0(q,J=3.7Hz),124.6,124.2,124.2(q,J=271.7Hz),118.7,113.4.HR-MS(ESI):Calcd for C22H15F3N3O2[M+H]+410.1111,found 410.1113.
J=8.4Hz,2H),8.16(d,J=8.8Hz,2H),7.75(d,J=8.4Hz,2H),7.71(d,J=8.8Hz,2H),7.33(s,1H),7.22(t,J=7.6Hz,2H),7.11(t,J=7.2Hz,1H),6.84(d,J=7.6Hz,2H).13C NMR(100MHz,CDCl3)δ162.6,155.3,149.0,137.7,136.0,134.9(q,J=32.7Hz),132.2,130.5,130.0,129.4,125.7(q,J=3.5Hz),125.5,123.6,123.6,123.5(q,J=271.1Hz).HR-MS(ESI):Calcd for C21H15F3N3O4[M+H]+430.1009,found 430.1013.
(E)-4-fluoro-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5f)
Hz),130.0,129.1,125.6(q,J=3.5Hz),124.8,123.5(q,J=271.2Hz),123.2,115.7(d,J=21.9Hz).HR-MS(ESI):Calcd for C21H15F4N2O2[M+H]+403.1064,found 403.1068.
(E)-4-chloro-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5g)
135.2,132.8(q,J=31.8Hz),132.8,131.0,130.37,129.6,128.6,128.5,125.5(q,J=3.6Hz),123.8,123.7(q,J=271.3Hz),123.4.HR-MS(ESI):Calcd for C21H15ClF3N2O2[M+H]+419.0769,found 419.0771.
(E)-4-bromo-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5h)
125.4,124.9,123.5(q,J=271.0Hz),123.2.HR-MS(ESI):Calcd for C21H15BrF3N2O2[M+H]+463.0264,found 463.0262.
(E)-N-phenyl-4-(trifluoromethoxy)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5i)
125.6(q,J=3.7Hz),125.0,123.5(q,J=271.0Hz),123.3,120.7,120.3(q,J=256.8Hz).HR-MS(ESI):Calcd for C22H15F6N2O3[M+H]+469.0981,found 469.0984.
(E)-3-chloro-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5j)
129.7,129.4,129.2,127.6,125.6(q,J=3.6Hz),125.0,123.5(q,J=271.2Hz),123.2.HR-MS(ESI):Calcd for C21H15ClF3N2O2[M+H]+419.0769,found 419.0771.
(E)/(Z)-2-chloro-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5k)
32.8Hz),133.8,132.4,131.8,130.1,130.0,130.90,129.6,128.9,127.0,125.6(q,J=3.7Hz),125.3,123.6(q,J=271.4Hz),123.2.HR-MS(ESI):Calcd for C21H15ClF3N2O2[M+H]+419.0769,found 419.0773.
(E)-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)benzo[d][1,3]dioxole-5-carboximidamide(5l)
271.0Hz),123.1,122.8,109.5,108.4,101.6.HR-MS(ESI):Calcd for C22H16F3N2O4[M+H]+429.1057,found 429.1060.
(E)-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)-[1,1′-biphenyl]-4-carboximidamide(5m)
123.0.HR-MS(ESI):Calcd for C27H20F3N2O2[M+H]+461.1471,found 461.1472.
(E)-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)-2-naphthimidamide(5n)
125.6(q,J=3.5Hz),125.6,124.5,123.6(q,J=271.1Hz),123.0.HR-MS(ESI):Calcd forC25H18F3N2O2[M+H]+435.1315,found 435.1312.
Methyl(E)-4-(N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)carbamimidoyl)benzoate(5o)
162.7,156.3,138.2,134.7(q,J=32.5Hz),134.0,132.4,132.0,130.0,129.7,129.5,129.2,125.6(q,J=3.5Hz),125.0,123.5(q,J=271.0Hz),123.3,52.4.HR-MS(ESI):Calcdfor C23H18F3N2O4[M+H]+443.1213,found 443.1217.
(E)-N-(4-(N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)carbamimidoyl)phenyl)acetamide(5p)
130.8,130.3,129.0,126.0(q,J=3.7Hz),125.2,124.2(q,J=271.2Hz),123.8,123.4,118.8,24.6.HR-MS(ESI):Calcd for C23H19F3N3O3[M+H]+442.1373,found 442.1368.
Ethyl(E)-2-(phenylamino)-2-(((4-(trifluoromethyl)benzoyl)oxy)imino)acetate(5q)
145.1,138.3,134.6(q,J=32.7Hz),131.6,129.9,129.1,126.0,125.2(q,J=3.7Hz),124.0,123.5(q,J=272.8Hz),63.9,14.0.HR-MS(ESI):Calcd for C18H16F3N2O4[M+H]+381.1057,found 381.1056.
(E)-N-phenyl-N′-((4-(trifluoromethyl)benzoyl)oxy)pivalimidamide(5r)
27.6.HR-MS(ESI):Calcd for C19H20F3N2O2[M+H]+365.1471,found 365.1472.
MHz,DMSO-d6)δ163.1,157.3,137.6,133.4,133.3,132.8(q,J=31.3Hz),131.3,130.9,130.8,129.7,129.5,128.8,125.9(q,J=3.6Hz),124.2(q,J=270.9Hz),124.1,20.7.HR-MS(ESI):Calcd for C22H18F3N2O2[M+H]+399.1315,found 399.1319.
(E)-N-(4-methoxyphenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ab)
131.3,130.9,130.6,129.7,128.7,126.3,125.9(q,J=3.8Hz),124.3(q,J=270.9Hz),114.2,55.6.HR-MS(ESI):Calcd for C22H18F3N2O3[M+H]+415.1264,found 415.1267.
(E)-N-(4-(tert-butyl)phenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ac)
131.0,130.6,130.2,129.1,128.4,125.4(q,J=3.6Hz),125.2,123.7(q,J=271.1Hz),122.6,33.9,31.0.HR-MS(ESI):Calcd for C25H24F3N2O2[M+H]+441.1784,found 441.1789.
(E)-N-(4-fluorophenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ad)
=8.3Hz),123.5(q,J=271.2Hz),115.8(d,J=23.0Hz).HR-MS(ESI):Calcd forC21H15F4N2O2[M+H]+403.1064,found 403.1070.
(E)-N-(4-chlorophenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ae)
=3.4Hz),124.2,123.5(q,J=271.0Hz).HR-MS(ESI):Calcd for C21H15ClF3N2O2[M+H]+419.0769,found 419.0768.
2H),7.11(s,1H),6.70(d,J=8.8Hz,2H).13C NMR(100 MHz,CDCl3)δ162.8,156.7,137.7,134.6(q,J=32.6Hz),132.4,132.0,131.0,130.0,129.3,129.1,128.7,125.6(q,J=3.8Hz),124.5,123.5(q,J=271.4Hz),117.5.HR-MS(ESI):Calcd for C21H15BrF3N2O2[M+H]+463.0264,found 463.0267.
(E)-N-(m-tolyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ag)
MHz,CDCl3)δ162.8,157.1,139.0,138.5,134.5(q,J=32.9Hz),132.7,130.7,130.0,129.7,129.4,128.7,128.5,125.5(q,J=3.5Hz),125.3,123.6,123.6(q,J=271.3Hz),120.2,21.2.HR-MS(ESI):Calcd for C22H18F3N2O2[M+H]+399.1315,found 399.1320.
(E)-N-(o-tolyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ah)
130.8,130.8,129.9,129.1,128.4,127.6,126.5,125.6,125.6,125.5(q,J=3.7Hz),123.6(q,J=271.1Hz),18.1.HR-MS(ESI):Calcd for C22H18F3N2O2[M+H]+399.1315,found399.1316.
(E)-N-(benzo[d][1,3]dioxol-5-yl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ai)
132.7,132.6,130.6,130.0,129.5,129.4,128.4,125.5(q,J=3.6Hz),123.6(q,J=271.0Hz),117.5,108.0,106.0,101.5.HR-MS(ESI):Calcd for C22H18F3N2O2[M+H]+429.1057,found 429.1060.
(E)-N-(3,4-dichlorophenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5aj)
130.4,130.0,129.2,128.8,128.0,125.6(q,J=3.6Hz),124.2,123.5(q,J=270.9Hz),122.1.HR-MS(ESI):Calcd for C21H14C12F3N2O2[M+H]+453.0379,found 453.0377.
(E)-N-(3,5-dimethylphenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5ak)
Hz),132.8,130.7,129.9,129.8,129.3,128.4,126.2,125.5(q,J=3.6Hz),123.6(q,J=271.1Hz),120.8,21.1.HR-MS(ESI):Calcd for C23H20F3N2O2[M+H]+413.1471,found413.1475.
(E)-N-(2,4-dimethoxyphenyl)-N′-((4-(trifluoromethyl)benzoyl)oxy)benzimidamide(5al)
134.5(q,J=32.6Hz),132.9,130.5,130.0,129.8,129.2,128.3,125.5(q,J=3.6Hz),125.1,123.6(q,J=270.8Hz),120.7,103.7,99.0,55.6,55.5.HR-MS(ESI):Calcd forC23H20F3N2O4[M+H]+445.1370,found 445.1371.
2-phenyl-1H-benzo[d]imidazole(Ia)
126.4,122.5,121.6,118.8,111.3.HR-MS(ESI):Calcd for C13H11N2[M+H]+195.0917,found194.0919.
2-(p-tolyl)-1H-benzo[d]imidazole(Ib)
139.5,129.5,127.4,126.4,121.9,20.9.HR-MS(ESI):Calcd for C14H13N2[M+H]+209.1073,found 209.1076.
2-(4-methoxyphenyl)-1H-benzo[d]imidazole(Ic)
151.8,128.4,123.1,118.9,114.8,111.5,55.8.HR-MS(ESI):Calcd for C14H13N2O[M+H]+225.1022,found 225.1025.
4-(1H-benzo[d]imidazol-2-yl)benzonitrile(Id)
Hz,1H),7.59(d,J=7.6Hz,1H),7.36-7.14(m,2H).13C NMR(100 MHz,DMSO-d6)δ149.3,143.7,135.1,134.2,133.0,126.9,123.4,122.2,119.3,118.6,111.8,111.7.HR-MS(ESI):Calcd for C14H10N3[M+H]+220.0869,found 220.0871.
2-(4-nitrophenyl)-1H-benzo[d]imidazole(Ie)
MHz,DMSO-d6)δ149.0,147.7,143.8,136.0,135.2,127.3,124.2,123.5,122.3,119.4,111.8.HR-MS(ESI):Calcd for C13H10N3O2[M+H]+240.0768,found 240.0769.
2-(4-fluorophenyl)-1H-benzo[d]imidazole(If)
(100 MHz,MeOD-d4)δ164.0(d,J=249.5Hz),151.1,128.7(d,J=8.6Hz),126.1(d,J=3.1Hz),122.6,115.7(d,J=22.3Hz),114.5.HR-MS(ESI):Calcd for C13H10FN2[M+H]+213.0823,found 213.0826.
2-(4-chlorophenyl)-1H-benzo[d]imidazole(Ig)
2H),7.55(d,J=7.2Hz,1H),7.23(t,J=7.6Hz,2H).13C NMR(100 MHz,DMSO-d6)δ150.1,143.7,135.0,134.5,129.0,128.1,122.8,121.8,118.9,111.4.HR-MS(ESI):Calcd forC13H10ClN2[M+H]+229.0527,found 229.0528.
2-(4-bromophenyl)-1H-benzo[d]imidazole(Ih)
Hz,1H),7.54(d,J=7.6Hz,1H),7.30-7.12(m,2H).13C NMR(100 MHz,DMSO-d6)δ150.2,143.8,135.1,132.0,129.4,128.3,123.2,122.7,122.0,118.9,111.4.HR-MS(ESI):Calcdfor C13H10BrN2[M+H]+273.0022,found 273.0023.
2-(4-(trifluoromethoxy)phenyl)-1H-benzo[d]imidazole(Ii)
149.2,129.4,128.4,122.3,121.4,120.0(q,J=256.8Hz),111.5.HR-MS(ESI):Calcd forC14H10F3N2O[M+H]+279.0740,found 279.0742.
2-(3-chlorophenyl)-1H-benzo[d]imidazole(Ij)
135.4,134.2,132.6,131.4,130.0,126.5,125.5,123.4,122.4,119.6,112.0.HR-MS(ESI):Calcd for C13H10ClN2[M+H]+229.0527,found 229.0527.
2-(2-chlorophenyl)-1H-benzo[d]imidazole(Ik)
134.6,132.1,131.6,131.2,130.3,129.9,127.4,122.7,121.7,119.1,111.7.HR-MS(ESI):Calcd for C13H10ClN2[M+H]+229.0527,found 229.0529.
2-(benzo[d][1,3]dioxol-5-yl)-1H-benzo[d]imidazole(Il)
149.2,148.3,124.7,122.4,121.3,109.2,106.9,102.0.HR-MS(ESI):Calcd for C14H11N2O2[M+H]+239.0815,found 239.0814.
2-([1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazole(Im)
2H),7.74-7.36(m,5H),7.24(s,2H).13C NMR(100 MHz,DMSO-d6)δ150.9,144.0,141.3,139.2,135.0,129.1,129.0,127.9,127.1,127.0,126.7,122.6,121.8,118.9,111.3.HR-MS(ESI):Calcd for C19H15N2[M+H]+271.1230,found 271.1228.
2-(naphthalen-2-yl)-1H-benzo[d]imidazole(In)
13C NMR(100 MHz,DMSO-d6)δ151.2,133.4,132.8,128.5,128.4,127.8,127.6,127.1,126.9,125.8,123.9,122.1.HR-MS(ESI):Calcd for C17H13N2[M+H]+245.1073,found245.1075.
Methyl 4-(1H-benzo[d]imidazol-2-yl)benzoate(Io)
NMR(100 MHz,DMSO-d6)δ165.8,150.0,143.8,135.1,134.3,130.3,129.8,126.6,123.1,122.0,119.2,111.6,52.3.HR-MS(ESI):Calcd for C15H13N2O2[M+H]+253.0972,found253.0973.
N-(4-(1H-benzo[d]imidazol-2-yl)phenyl)acetamide(Ip)
(100 MHz,DMSO-d6)δ168.6,151.2,140.8,127.1,124.6,121.9,118.9,24.1.HR-MS(ESI):Calcd for C15H14N3O[M+H]+252.1131,found 252.1131.
Ethyl 1H-benzo[d]imidazole-2-carboxylate(Iq)
for C10H11N2O2[M+H]+191.0815,found 191.0809.
5-methyl-2-phenyl-1H-benzo[d]imidazole(Iaa)
=6.0Hz,2H),7.65-7.27(m,5H),7.04(s,1H),2.45(s,3H).13C NMR(100MHz,DMSO-d6)δ151.6,151.2,144.6,142.4,135.7,133.5,132.3,130.8,130.1,129.4,126.7,124.4,123.7,119.1,118.9,111.5,111.3,21.8,21.8.HR-MS(ESI):Calcd for C14H13N2[M+H]+209.1073,found 209.1075.
5-methoxy-2-phenyl-1H-benzo[d]imidazole(Iab)
CDCl3)δ156.7,151.5,130.0,129.9,129.1,126.4,112.6,55.8.HR-MS(ESI):Calcd forC14H13N2O[M+H]+225.1022,found 225.1026.
(tert-butyl)-2-phenyl-1H-benzo[d]imidazole(Iac)
138.8,137.4,130.0,130.0,129.1,127.1,121.0,114.8,111.2,34.8,31.8.HR-MS(ESI):Calcd for C17H19N2[M+H]+251.1543,found 251.1545.
5-fluoro-2-phenyl-1H-benzo[d]imidazole(Iad)
DMSO-d6)δ153.4,152.7,144.6,140.9,132.1,130.6,130.4,130.4,130.3,129.5,126.9,126.8,120.3,120.2,112.4,112.4,111.2,110.9,110.4,110.2,104.9,104.7,98.3,98.0.HR-MS(ESI):Calcd for C13H10FN2[M+H]+213.0823,found 213.0824.
5-chloro-2-phenyl-1H-benzo[d]imidazole(Iae)
8.19(d,J=7.2Hz,2H),7.74(s,0.5H),7.69(d,d=8.4Hz,0.5H),7.64-7.47(m,4H),7.29-7.18(m,1H).13C NMR(100 MHz,DMSO-d6)δ152.8,152.4,144.7,142.6,135.7,133.8,130.2,130.2,129.7,129.0,126.8,126.6,126.0,122.6,122.0,120.1,118.2,112.6,111.0.HR-MS(ESI):Calcd for C13H10ClN2[M+H]+229.0527,found 229.0528.
5-bromo-2-phenyl-1H-benzo[d]imidazole(Iaf)
(ESI):Calcd for C13H10BrN2[M+H]+273.0022,found 273.0020.
4-methyl-2-phenyl-1H-benzo[d]imidazole(Iag’)
131.3,131.2,130.1,128.0,124.4,123.9,17.2.HR-MS(ESI):Calcd for C14H13N2[M+H]+209.1073,found 209.1074.
6-methyl-2-phenyl-1H-benzo[d]imidazole(Iag”)
2.46(s,3H).13C NMR(100MHz,MeOD-d4)δ153.1,134.0,131.2,131.2,130.1,127.7,125.5,115.5,21.8.HR-MS(ESI):Calcd for C14H13N2[M+H]+209.1073,found 209.1075.7-methyl-2-phenyl-1H-benzo[d]imidazole(Iah)
131.3,131.2,130.1,128.0,124.5,123.9,17.2.HR-MS(ESI):Calcd for C14H13N2[M+H]+209.1073,found 209.1074.
4,5-dichloro-2-phenyl-1H-benzo[d]imidazole(Iaj’)and5,6-dichloro-2-phenyl-1H-benzo[d]imidazole(Iaj”)
NMR(400 MHz,MeOD-d4)δ8.05(dd,d=6.4,2.8Hz,2H),7.60-7.52(m,3H),7.74(s,2H).Iaj’+Iaj”:13C NMR(100 MHz,MeOD-d4)δ155.5,155.4,139.8,138.8,138.2,132.5,132.2,130.4,130.2,129.9,129.4,128.4,128.2,127.6,125.8,120.2,117.1,114.4.HR-MS(ESI):Calcd for C13H9Cl2N2[M+H]+263.0137,found 263.0140.
4,6-dimethyl-2-phenyl-1H-benzo[d]imidazole(Iak)
126.5,124.7,20.3,15.7.HR-MS(ESI):Calcd for C15H15N2[M+H]+223.1230,found223.1233.
5,7-dimethoxy-2-phenyl-1H-benzo[d]imidazole(Ial)
136.6,130.4,129.2,128.8,125.9,94.1,86.6,55.5,55.4.HR-MS(ESI):Calcd forC15H15N2O2[M+H]+255.1128,found 255.1133。