CN104230828B - 一锅法合成1,4-二取代三氮唑化合物的方法 - Google Patents
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明公开了一种分子碘促进的一锅法合成1,4‑二取代的三氮唑化合物的方法,包括如下步骤:将分子碘、芳香酮、芳香胺以及对甲基苯磺酰肼加入到有机溶剂中,加热至80~100℃进行反应,反应完全后,后处理得到所述的1,4‑二取代的三氮唑化合物。该制备方法步骤简单,原料容易得到,避免了重金属催化剂的使用,而且反应不需要在无水无氧条件下进行,更重要的是不需要用到有毒且易于爆炸的叠氮化物,反应可以轻易的扩大至克级,便于操作以及规模应用。
Description
技术领域
本发明属于有机合成领域,尤其涉及一种1,4-二取代的三氮唑化合物的制备方法。
背景技术
三氮唑化合物作为一种重要的五元含氮杂环,广泛存在于各种具有生物活性分子结构中(Chem.Rev.2013.113,4905-4979),许多药物分子都含有三氮唑结构的骨架,例如TSAO-T的三唑衍生物对诱导HIV-1病变的细胞产生了更好的抑制作用,药理活性能够提高1-2个数量级;1,2,3-三氮唑取代的苯磺酰胺类化合物是对人类β3肾上腺激素受体强有力且有选择性的收缩剂,以下是一些具有典型的三氮唑结构的活性化合物:
三氮唑类化合物在农药和功能材料方面的应用也相当广泛,可用作杀虫剂,除草剂,杀真菌增效剂和缓蚀剂,光稳定剂,紫外线吸收剂等。
文献报道中合成1,4-二取代三氮唑的主要方法是由Sharpless和Meldal发现的铜催化的叠氮-炔烃环加成反应(CuAAC)(V.V.Rostovtsev,L.G.Green,V.V.Fokin,K.B.Sharpless,Angew.Chem.2002,114,2708–2711;Angew.Chem.Int.Ed.2002,41,2596-2599)。鉴于1,2,3-三氮唑广泛的生物活性和在生命科学领域的广泛应用,为了避免重金属在样品中的残留,阻碍其进一步应用,发展非金属促进的合成三氮唑类化合物的方法具有重要意义。目前通过非金属促进的合成三氮唑方法包括有机催化的叠氮与烯胺或酮的选择性1,3-偶极环加成反应,碱促进的胺类与α,α-二氯代对甲苯磺酰腙的环化反应以及有机催化的有机叠氮,硝基化合物和醛类的多组分反应构建三氮唑等。
但是该方法具有一些共同的局限性,比如需要用到有毒且容易发生爆炸的叠氮化钠或有机叠氮化物或者原料制备困难等缺点。
发明内容
本发明提供了一种一锅法合成1,4-二取代三氮唑化合物的方法,该制备方法步骤简单,原料容易得到,避免了重金属催化剂的使用,而且反应不需要在无水无氧条件下进行,更重要的是不需要用到有毒且易于爆炸的叠氮化物,便于操作。
一种一锅法合成1,4-二取代三氮唑化合物的方法,包括如下步骤:将分子碘、芳香胺、芳香酮以及对甲基苯磺酰肼加入到有机溶剂中,加热至800~100℃进行反应,反应完全后,后处理得到所述的1,4-二取代的三氮唑化合物;
所述的芳香胺的结构如式(II)所示:
所述的芳香酮的结构如式(III)所示:
所述的对甲基苯磺酰肼的结构如式(Ⅳ)所示:
TsNHNH2 (IV)
所述的1,4-二取代的三氮唑化合物的结构如式(Ⅰ)所示:
式(Ⅰ)~(III)中,R1为氢、C1~C5烷基、C1~C5烷氧基、苯基或卤素;
R2为氢、C1~C5烷基、C1~C5烷氧基,三氟甲基或卤素;
所述的芳香胺、芳香酮,对甲苯磺酰肼和分子碘的摩尔比为1~1.2:1:1.2~1.5:1.0~2.0。
R1和R2的取代位置可以为邻位、对位或者间位。
反应式如下:
反应可能经由两条路径发生,其一,可能是芳香酮在分子碘在二甲亚砜的存在下加热发生Kornblum氧化生成苯甲酰甲醛或其水合物,然后与芳酰胺发生缩合反应生成碳酰基亚胺中间体,后者与对甲苯磺酰肼反应生成对甲苯磺酰腙,然后在分子碘的作用下发生环化生成氮氮键之后芳构化得到目标化合物。其二,可能是芳香酮与对甲苯磺酰肼先生成对甲苯磺酰腙,后者在分子碘作用下发生α位碘化,之后消除一分子碘化氢形成重氮二烯中间体,芳香胺进攻重氮二烯发生氮杂Michael加成之后再在分子碘的作用下发生环化和芳构化形成目标化合物。其中,分子碘作为反应的促进剂或氧化剂。
本发明中,可选用的后处理过程包括:萃取,洗涤,干燥,硅胶拌样,最后经过柱层析纯化得到相应的1,4-二取代的三氮唑化合物,采用柱层析纯化为本领域常用的技术手段。
作为优选,R1为氢、甲基、甲氧基、氟、氯,溴或苯基,此时,所述的芳香胺容易得到,并且反应的产率较高。
作为优选,R2为氢、甲基、甲氧基、氟、氯,溴、三氟甲基或正丁基,此时,所述的芳香酮容易得到,并且反应的产率较高。
作为优选,对甲苯磺酰肼廉价易得,且操作简便。
所述的芳香胺和对甲苯磺酰肼的价格较便宜,在自然界中广泛存在,相对于所述的对芳香酮的用量为过量,作为优选,以摩尔量计,芳香胺:芳香酮:对甲基苯磺酰肼:分子碘=1~1.2:1:1.2~1.5:1~1.5;作为进一步的优选,以摩尔量计,芳香胺:芳香酮:对甲苯磺酰腙:分子碘=1.2:1:1.5:1.5。
作为优选,所述的反应的时间为4~12小时,反应时间过长增加反应成本,相反则难以保证反应的完全。
本发明中,能将原料充分溶解的有机溶剂都能使反应发生,但反应效率差别较大,优选为非质子性溶剂,非质子性溶剂能够有效地促进反应的进行;作为优选,所述的有机溶剂为二甲基亚砜,DMF或者1,4-二氧六环;作为进一步的优选,所述的有机溶剂为二甲基亚砜,此时,各种原料都能以较高的转化率转化成产物。
所述的有机溶剂的用量能将原料较好的溶解即可,1mmol的芳香酮使用的有机溶剂的量约为3~5mL。
作为优选,所述的分子碘为碘单质,碘单质价格较便宜,而且使用碘单质时反应效率较高。
作为进一步的优选,所述的1,4-二取代的三氮唑化合物为式(I-1)-式(I-5)所示化合物中的一种:
如式(I-1)-(I-5)所示的化合物都为已知的化合物。
上述制备方法中,所述的芳香胺,芳香酮,对甲苯磺酰肼以及分子碘一般采用市售产品,都能从市场上方便地得到。
同现有技术相比,本发明的有益效果体现在:该制备方法无需无水无氧条件,易于操作,后处理简便;反应原料容易得到,且避免了重金属催化剂和有毒易爆的叠氮化物的使用,底物可设计性强,可根据实际需要设计合成出所需结构的化合物,并且可以轻易扩大至克级,实用性较强。
具体实施方式
下面结合具体实施例对本发明做进一步的描述。
按照表1的原料配比在35ml的Schlenk管中加入分子碘、芳香胺(II)、芳香酮(III)、对甲基苯磺酰肼(Ⅳ)(0.75mmol)和有机溶剂2ml,混合搅拌均匀,按照表2的反应条件反应完成后,萃取,洗涤,干燥,硅胶拌样,经过柱层析纯化得到相应的1,4-二取代的三氮唑化合物(Ⅰ),反应过程如下式所示:
表1
表2
表1和表2中,T为反应温度,t为反应时间,Me为甲基,OMe为甲氧基,CF3为三氟甲基,Ph为苯基,DMF为N,N-二甲基甲酰胺。
实施例1~8制备得到化合物的结构确认数据:
由实施例1制备得到的1,4-二取代的三氮唑化合物(I-1,CAS号:13148-78-2)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ8.21(s,1H),7.92(d,2H,J=7.2Hz),7.80(d,2H,J=7.6Hz),7.55(t,2H,J=7.8Hz),7.45-7.48(m,3H),7.38(t,1H,J=7.4Hz).13C NMR(CDCl3,100MHz)δ148.4,137.0,130.2,129.8,128.9,128.8,128.4,125.8,120.5,117.6.MS(EI):m/z(%):221(M+,3),193(100),165(66),116(45),89(53),77(71)。
由实施例2制备得到的1,4-二取代的三氮唑化合物(I-2,CAS号:634604-04-9)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ8.16(s,1H),7.91(d,2H,J=7.2Hz),7.67(d,2H,J=8.4Hz),7.55(t,2H,J=7.6Hz),7.33-7.39(m,3H),2.44(s,3H).13C NMR(CDCl3,100MHz)δ148.3,138.9,134.8,130.3,130.2,128.9,128.3,125.8,120.4,117.6,21.1.MS(EI):m/z(%):235(M+,2),207(100),192(11),179(8),116(10),89(18)。
由实施例3制备得到的1,4-二取代的三氮唑化合物(I-3,CAS号:116373-83-2)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(DMSO-d6,400MHz)δ9.35(s,1H),7.94(d,4H,J=8.4Hz),7.85(d,2H,J=8.8Hz),7.51(t,2H,J=7.6Hz),7.40(t,1H,J=7.2Hz).13CNMR(DMSO-d6,100MHz)δ147.5,135.8,132.8,130.1,129.0,128.3,125.3,121.9,121.3,119.6.MS(EI):m/z(%):301(M+,Br81,50),299(M+,Br79,50),271(100),192(100),165(99),116(100),102(29),90(98),77(19)。
由实施例4制备得到的1,4-二取代的三氮唑化合物(I-4,CAS号:68809-41-6)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ8.11(s,1H),7.84(d,2H,J=8.8Hz),7.79(d,2H,J=7.6Hz),7.54(t,2H,J=7.8Hz),7.45(t,1H,J=7.4Hz),6.99(t,2H,J=6.8Hz),3.86(s,3H).13C NMR(CDCl3,100MHz)δ159.8,148.2,137.1,129.7,128.6,127.2,122.9,120.5,116.8,114.3,55.3.MS(EI):m/z(%):251(M+,40),223(100),208(100),180(89),152(45),103(22),77(98)。
由实施例5制备得到的1,4-二取代的三氮唑化合物(I-5,CAS号:13178-00-2)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(DMSO-d6,400MHz)δ9.36(s,1H),7.90-7.96(m,4H),7.72(d,2H,J=8.8Hz),7.65(t,2H,J=8.0Hz),7.53(t,1H,J=7.6Hz).13C NMR(DMSO-d6,100MHz)δ146.3,136.6,132.0,130.0,129.5,128.8,127.3,121.2,120.0.MS(EI):m/z(%):301(M+,Br81,7),299(M+,Br79,7),273(100),194(26),165(70),115(19),77(47)。
由实施例6制备得到的1,4-二取代的三氮唑化合物(I-6,CAS号:116557-89-2)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ8.11(s,1H),7.90(d,2H,J=7.6Hz),7.68(d,2H,J=8.8Hz),7.45(t,2H,J=7.4Hz),7.36(t,1H,J=7.2Hz),6.03(d,2H,J=8.8Hz),3.87(s,3H).13C NMR(CDCl3,100MHz)δ159.8,148.2,130.5,130.3,128.8,128.3,125.8,122.1,117.8,114.7,55.6.MS(EI):m/z(%):251(M+,14),223(100),208(100),180(100),152(65),116(52),92(46),77(60)。
由实施例7制备得到的1,4-二取代的三氮唑化合物(I-7,CAS号:875312-72-4)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ9.51(s,1H),7.18(d,2H,J=6.0Hz),7.98(d,2H,J=6.8Hz),7.90(d,2H,J=6.8Hz),7.66(t,2H,J=7.2Hz),7.55(br s,1H).13C NMR(CDCl3,100MHz)δ147.0,145.9,145.4,136.5,130.0,128.6(q,JC-CF3=246.8Hz),128.3(q,JC-CF3=31.6Hz),126.0(q,JC-CF3=3.6Hz),125.8,121.0,120.1.MS(EI):m/z(%):290(M+,5),261(100),209(100),165(35),91(14),77(92).
由实施例8制备得到的1,4-二取代的三氮唑化合物(I-8,CAS号:1534356-78-9)的核磁共振(1H NMR和13C NMR)检测数据为:
1H NMR(CDCl3,400MHz)δ8.11(s,1H),7.90(d,2H,J=7.6Hz),7.68(d,2H,J=8.8Hz),7.45(t,2H,J=7.4Hz),7.36(t,1H,J=7.2Hz),6.03(d,2H,J=8.8Hz),3.87(s,3H).13CNMR(CDCl3,100MHz)δ159.8,148.2,130.5,130.3,128.8,128.3,125.8,122.1,117.8,114.7,55.6.MS(EI):m/z(%):251(M+,14),223(100),208(100),180(100),152(65),116(52),92(46),77(60)。
Claims (4)
1.一种一锅法合成1,4-二取代三氮唑化合物的方法,其特征在于,包括如下步骤:将分子碘、芳香胺、芳香酮以及对甲基苯磺酰肼加入到有机溶剂中,加热至80~100℃进行反应,反应完全后,后处理得到所述的1,4-二取代的三氮唑化合物;
所述的芳香胺的结构如式(II)所示:
所述的芳香酮的结构如式(III)所示:
所述的1,4-二取代的三氮唑化合物的结构如式(Ⅰ)所示:
式(Ⅰ)~(III)中,R1为氢、C1~C5烷基、C1~C5烷氧基、苯基或卤素;
R2为氢、C1~C5烷基、C1~C5烷氧基、三氟甲基或卤素;
以摩尔量计,芳香胺:芳香酮:对甲基苯磺酰肼:分子碘=1~1.2:1:1.2~1.5:1~1.5;
反应的时间为4~12小时;
所述的有机溶剂为二甲基亚砜、DMF或者1,4-二氧六环。
2.根据权利要求1所述的一锅法合成1,4-二取代三氮唑化合物的方法,其特征在于,R1为氢、甲基、甲氧基、氟、氯、溴或苯基。
3.根据权利要求1或2所述的1,4-二取代的三氮唑化合物的制备方法,其特征在于,R2为氢、甲基、甲氧基、氟、氯、溴、三氟甲基或正丁基。
4.根据权利要求1所述的一锅法合成1,4-二取代三氮唑化合物的方法,其特征在于,所述的1,4-二取代的三氮唑化合物为式(I-1)-式(I-5)所示化合物中的一种:
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