CN114875433A - 一种多氟芳基硒醚衍生物的制备方法 - Google Patents
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Abstract
本发明公开了一种多氟芳基硒醚衍生物的制备方法,涉及一种多氟芳烃和二芳基二硒醚衍生物在有机电化学促进下的芳香亲核取代反应方法。该方法通过向三口电解池中加入多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱和溶剂,在一定电流、温度和氮气气氛条件下搅拌反应,得到产物多氟芳基硒醚衍生物。本发明无需借助任何催化剂,便可以高选择性和较高产率制备获得目标产物。此外,该反应操作过程简单,同时避免了使用贵重金属催化剂,便于工业化应用生产;此方法还可以轻易的扩大至克级,为此类化合物的大规模合成应用提供了可能。
Description
技术领域
本发明属于有机合成领域,具体涉及利用有机电化学氧化还原条件,在碱促进下发生芳香亲核取代反应,从而实现多氟芳基硒醚衍生物的制备方法。
背景技术
多氟芳基硒醚衍生物在有机合成中是一种重要的含氟衍生物,在医药和功能材料方面有着广泛的应用,可以在有机合成中作为多功能的合成模块,尤其是在天然产物及有机光电材料的合成中。因此,多氟芳基硒醚衍生物的合成受到了有机合成工作者的广泛关注。然而从有机化学绿色及原子经济性角度考虑,目前的合成方法仍存在着较多不足之处。例如现有的合成方法要么需要用到昂贵的过渡金属Pd作为催化剂(Eur. J. Org. Chem.2019 , 1588-1593.),或者需要使用有毒的烷基锡试剂作为芳基硒前体化合物(Rus. J.Org. Chem. 2001, 37, 1463-1475.)。因此,如何利用廉价易得的试剂,发展绿色无毒,操作简单的方法,从而高转化率地获得多氟芳基硒醚衍生物是一项极具挑战性又亟待解决的问题。
发明内容
本发明目的在于克服现有技术的不足,提供一种绿色高效、无毒、低成本的多氟芳基硒醚化合物的合成方法,该方法无需借助任何催化剂,便可以高选择性和较高产率制备获得目标产物。此外,该反应操作过程简单,同时避免了使用贵重金属催化剂,便于工业化应用生产;此方法还可以轻易的扩大至克级,为此类化合物的大规模合成应用提供了可能。
本发明提供了电化学促进下的多氟芳基硒醚衍生物制备方法,该方法以多氟芳烃衍生物和二芳基二硒醚衍生物为原料,具体采用以下技术方案:
一种多氟芳基硒醚衍生物的制备方法,以多氟芳烃衍生物、二苯二硒醚衍生物为原料,在电解质、碱和溶剂存在下,通电反应,得到多氟芳基硒醚衍生物。
本发明中,通电反应在惰性气体气氛下进行,为1atm的氮气气氛,也可以替换为1atm的氩气气氛或其它惰性气体气氛,从经济成本等方面考虑,优选为氮气气氛;电流为5~20 mA,优选为10 mA。
本发明中,所述反应的时间为12~48小时,得到高产率,优选为24小时;所述反应的温度为0~50 ℃,优选为25 ℃。
本发明中,多氟芳基硒醚衍生物的制备在三口电解池中进行,具体三口电解池为现有装置,自带正负电极,本发明由电解质和溶剂组成导电体系。
本发明中,所述电解质为四丁基溴化铵、碘化钾、四丁基碘化铵、四丁基六氟磷酸铵、四丁基高氯酸胺等其中的任意一种,优选为四丁基碘化铵;所述碱为三乙胺、N,N-二异丙基乙基胺、二乙胺、碳酸钾、碳酸钠、氢氧化钠等其中的任意一种,优选为N,N-二异丙基乙基胺;所述有机溶剂为甲醇、乙腈、二氯甲烷、N,N-二甲基甲酰胺、三氯甲烷、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、乙腈等其中的任意一种或几种的混合物。
在本发明的反应中,所述的有机溶剂为甲醇、乙醇、二氯甲烷、三氯甲烷、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、乙腈等其中的任意一种或几种的混合物,作为优选,所述有机溶剂为乙腈,此时,各种原料都能以较高的转化率转化成产物。
本发明中,所述多氟芳烃衍生物的结构如式(I)所示:
所述二芳基二硒醚衍生物的结构如式(II)所示:
所述多氟芳基硒醚化合物结构如式(III)或(IV)所示:
在上述通式(I)、(II)、(III)和(IV)表示的化合物中:R1选自H、卤素、C1~C8烷基、C5~C13芳基、C2~C10酰基、C2~C10杂环基;R2选自氢、C1~C5烷基、C5~C12芳基;Fn为芳杂环上取代的多个氟原子,n = 1~6;优选地,R1选自H、卤素、C2~C10酰基、C5~C8杂环基;R2选自氢、C1~C5烷基;Fn中的n选自4~6。Ar代表芳香环,Het代表杂环,比如吡啶,为本领域常规表示。
本发明中,多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱的摩尔量比为1∶(1~4)∶(1~3)∶(1~3)。可通过控制二苯二硒醚衍生物的量来控制硒化产物的类型为(III)或(IV),当多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱的摩尔量比为1∶(1~2)∶(1~3)∶(1~3)时,产物为式(III);当多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱的摩尔量比为1∶(3~4)∶(1~3)∶(1~3)时,产物为式(IV)。
同现有技术相比,本发明的有益效果体现在:该反应克服现有技术的不足,提供一种绿色高效、低成本的多氟芳基硒醚衍生物化合物的合成方法,从而避免了有毒烷基试剂和昂贵的过渡金属盐的使用,最大化降低了产物中杂质的残留。此外,该反应无需借助任何催化剂,操作过程简单,在室温条件下便可以较高产率制备获得目标产物。此方法还可以轻易的扩大至克级,为此类化合物的工业化合成应用提供了可能。
附图说明
图1为本发明多氟芳基硒醚衍生物的制备方法示意图;
图2为实施例1得到的产物的核磁共振氢谱;
图3为实施例1得到的产物的核磁共振碳谱;
图4为实施例1得到的产物的核磁共振氟谱。
具体实施方式
本发明公开的多氟芳基硒醚衍生物的制备方法具体为,向三口电解池中加入多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱和溶剂,在一定电流、温度、氮气气氛条件下搅拌反应,经后处理得到多氟芳基硒醚衍生物(III)或(IV)。反应示意图参见图1。本发明中,反应完成后进行后处理,可选用的后处理过程包括:过滤,硅胶拌样,最后经过柱层析纯化得到相应的多氟芳基硒醚衍生物,采用柱层析纯化为本领域常用的技术手段。示例后处理操作如下:将反应完成后的反应液用乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到目标产物多氟芳基硒醚衍生物。
以下结合具体实施例,对本发明进行进一步详细的描述,但本发明并不局限于此。
下述实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和原料,如无特殊说明,均可以从商业途径获得和/或根据已知的方法制备获得。
实施例1
向三口电解池中加入式2所示的五氟吡啶I-1(0.4 mmol)、二苯二硒醚II-1(0.8mmol)、四丁基碘化铵(TBAI)(0.8 mmol)、N,N-二异丙基乙基胺(0.8 mmol)、乙腈(5 mL)。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应,20小时后反应结束,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到无色油状产物III-1(87%的产率)。产物谱图见图2至图4。
1H NMR (400 MHz, Chloroform-d) δ 7.66 (d, J = 7.4 Hz, 2H), 7.42 (t, J= 7.3 Hz, 1H), 7.35 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 143.39(dm, J = 247.5 Hz), 141.79 (dm, J = 256.0 Hz), 135.30, 129.89, 129.78,125.39. 19F NMR (377 MHz, Chloroform-d) δ 90.81 (d, J = 6.7 Hz), -123.91 – -142.54 (m)。
实施例2
溶剂用N,N-二甲基甲酰胺(5 mL)代替乙腈,其余条件同实施例1,得到目标产物III-1的收率为72%。
实施例3
溶剂用DMSO(5 mL)代替乙腈,其余条件同实施例1,得到目标产物III-1的收率为76%。
实施例4
碱用三乙胺代替N,N-二异丙基乙基胺,其余条件同实施例1,得到目标产物III-1的收率为82%。
实施例5
电解质用碘化钾代替四丁基碘化铵,其余条件同实施例1,得到目标产物III-1的收率为33%。
实施例6
将反应温度升高至50oC,其余条件同实施例1,得到目标产物III-1的收率为68%。
实施例7
将反应温度降为0 oC,其余条件同实施例1,得到目标产物III-1的收率为63%。
实施例8
将二苯二硒醚用量改为1当量,其余条件同实施例1,得到目标产物III-1的收率为59%。
实施例9
将电流改为20mA,其余条件同实施例1,得到目标产物III-1的收率为60%。
实施例10
向三口电解池中加入式3所示的多氟芳烃衍生物I-2(0.4 mmol)和二苯二硒醚II-1(0.8 mmol),四丁基碘化铵(TBAI)(0.8 mmol)和N,N-二异丙基乙基胺(0.8 mmol)溶于乙腈(5 mL)溶剂中。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应,15小时后反应结束,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到白色固体产物III-2(89%的产率)。
1H NMR (400 MHz, Chloroform-d) δ 7.47 (d, J = 7.3 Hz, 2H), 7.21 (q, J= 7.1, 6.1 Hz, 3H), 3.50 (q, J = 7.1 Hz, 2H), 3.14 (q, J = 7.1 Hz, 2H), 1.17(t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H);13C NMR (101 MHz, CDCl3) δ158.5, 146.7 (ddt, J = 246.5, 13.9, 3.8 Hz), 142.1 (dm, J = 251.6 Hz), 133.7,129.6,128.7, 127.8, 117.7, 110.1, 43.3, 39.7, 14.1, 12.8.19F NMR (377 MHz,Chloroform-d) δ -121.62 – -131.89 (m), -135.24 – -145.89 (m)。
实施例11
向三口电解池中加入式4所示的多氟芳烃衍生物I-3(0.4 mmol)和二苯二硒醚II-1(0.8 mmol),四丁基碘化铵(TBAI)(0.8 mmol)和N,N-二异丙基乙基胺(0.8 mmol)溶于乙腈(5 mL)溶剂中。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应15小时,反应结束后,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到白色固体产物III-3(82%的产率)。
1H NMR (400 MHz, Chloroform-d) δ 7.66 – 7.45 (m, 2H), 7.38 – 7.20 (m,3H), 2.87 (s, 3H), 1.53 (s, 9H).13C NMR (101 MHz, CDCl3) δ 159.6, 146.8 (dd, J= 246.6, 13.9 Hz), 142.1 (d, J = 268.6 Hz), 133.7, 129.7, 128.7, 128.0, 119.7(t, J = 22.2 Hz), 109.6 (t, J = 24.6 Hz). 58.4, 33.6, 28.0.19F NMR (377 MHz,Chloroform-d) δ -124.80 – -128.88 (m), -139.04 – -144.95 (m)。
实施例12
向三口电解池中加入式5所示的多氟芳烃衍生物I-4(0.4 mmol)和二苯二硒醚II-1(0.8 mmol),四丁基碘化铵(TBAI)(0.8 mmol)和N,N-二异丙基乙基胺(0.8 mmol)溶于乙腈(5 mL)溶剂中。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应15小时,反应结束后,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到白色固体产物III-4(76%的产率)。
1H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 7.0 Hz, 2H), 7.30 (q, J= 7.4, 6.6 Hz, 3H), 3.69 (m, J = 6.6 Hz, 1H), 3.56 (m, J = 13.5, 6.8 Hz, 1H),1.55 (s, 3H), 1.53 (s, 3H), 1.19 (s, 3H), 1.18 (s, 3H).13C NMR (101 MHz,CDCl3) δ 157.98, 146.78 (d, J = 260.4 Hz), 145.16 – 140.27 (dm, J = 251.1Hz), 133.91, 129.69, 128.74, 128.03, 119.05 (t, J = 23.0 Hz), 109.44 (t, J =24.5 Hz), 51.96, 46.95, 20.98, 20.38.19F NMR (377 MHz, Chloroform-d) δ -113.56– -130.14 (m), -136.99 – -146.19 (m)。
实施例13
向三口电解池中加入式6所示的多氟芳烃衍生物I-5(0.4 mmol)和二苯二硒醚II-1(0.8 mmol),四丁基碘化铵(TBAI)(0.8 mmol)和N,N-二异丙基乙基胺(0.8 mmol)溶于乙腈(5 mL)溶剂中。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应36小时,反应结束后,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到白色固体产物III-5(66%的产率)。
1H NMR (400 MHz, Chloroform-d) δ 8.76 (d, J = 4.1 Hz, 1H), 7.83 (t, J= 7.3 Hz, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.49 (d, J = 7.7 Hz, 1H), 7.40 –7.32 (m, 1H), 7.30 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 150.25, 147.74, 147.05(ddt, J = 244.8, 14.4, 4.4 Hz), 144.22 (ddt, J = 252.7, 16.8, 4.6 Hz),136.79,133.49, 129.65, 128.53, 128.44, 126.01, 123.93, 120.97 (t, J = 16.3 Hz),109.46 (t, J = 24.6 Hz). 19F NMR (377 MHz, Chloroform-d) δ -127.39 (dd, J =24.9, 12.6 Hz), -142.53 (dd, J = 24.9, 12.6 Hz)。
实施例14
向三口电解池中加入式7所示的多氟芳烃衍生物I-6(0.4 mmol)和二苯二硒醚II-1(1.2 mmol),四丁基碘化铵(TBAI)(0.8 mmol)和N,N-二异丙基乙基胺(0.8 mmol)溶于乙腈(5 mL)溶剂中。在10 mA恒定电流作用下和25℃氮气气氛下搅拌反应30小时,反应结束后,向反应体系中加入15 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到白色固体产物IV-1(75%的产率)。
1H NMR (400 MHz, Chloroform-d) δ 7.72-7.40 (m, 4H), 7.37-7.17 (m,6H).13C NMR (101 MHz, Chloroform-d) δ 147.99 (m), 145.34 (m), 133.82, 129.64,128.66, 128.12.19F NMR (377 MHz, Chloroform-d) δ -126.30。
实施例15
向三口电解池中加入式2所示的五氟吡啶I-1(5 mmol)、二苯二硒醚II-1(10mmol)、四丁基碘化铵(TBAI)(10 mmol)、N,N-二异丙基乙基胺(10 mmol)、乙腈(30 mL)。在30 mA恒定电流作用下和25℃氮气气氛下搅拌反应,20小时后反应结束,向反应体系中加入40 mL乙酸乙酯萃取,有机相用饱和氯化钠溶液洗涤后,用无水硫酸钠干燥,过滤并减压浓缩除去溶剂,将残余物经柱层析分离,洗脱溶剂为:乙酸乙酯/正己烷,得到无色油状产物III-1(83%的产率)。
由上述实例的顺利实施可知,该反应转化率较高且易于操作。有望为工业化合成多氟芳基硒醚衍生物提供技术支撑。发明人首次公开了有机电化学促进下的多氟芳烃衍生物和二芳基二硒醚衍生物间的芳香亲核取代反应,提出了一种通过利用电化学氧化还原条件,实现二芳基硒醚的还原,并在碱性条件下和多氟芳烃衍生物发生芳香亲核取代反应,最终生成相应的多氟芳基硒醚衍生物。该方法无需使用催化剂和有毒的锡试剂,反应条件温和绿色且可放大至克级规模,符合绿色化学生产要求。
以上所述实施例仅为本发明的优选实施例,而并非本发明可行实施的穷举。对于本领域技术人员而言,在不背离本发明原理和精神的前提下,对其所作出的任何显而易见的改动,都应当被认为包含在本发明的权利要求保护范围之内。
Claims (10)
1.一种多氟芳基硒醚衍生物的制备方法,其特征在于,以多氟芳烃衍生物、二苯二硒醚衍生物为原料,在电解质、碱和溶剂存在下,通电反应,得到多氟芳基硒醚衍生物。
2.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,通电反应在惰性气体气氛下进行;电流为5~20 mA。
3.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,所述反应的时间为12~48小时;所述反应的温度为0~50 ℃。
4.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,多氟芳基硒醚衍生物的制备在三口电解池中进行。
5.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,所述电解质为四丁基溴化铵、碘化钾、四丁基碘化铵、四丁基六氟磷酸铵、四丁基高氯酸胺等其中的任意一种;所述碱为三乙胺、N,N-二异丙基乙基胺、二乙胺、碳酸钾、碳酸钠、氢氧化钠等其中的任意一种;所述有机溶剂为甲醇、乙腈、二氯甲烷、N,N-二甲基甲酰胺、三氯甲烷、1,2-二氯乙烷、甲苯、N,N-二甲基甲酰胺、二甲基亚砜、四氢呋喃、二氧六环、乙腈等其中的任意一种或几种的混合物。
7.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,多氟芳烃衍生物、二苯二硒醚衍生物、电解质、碱的摩尔量比为1∶(1~4)∶(1~3)∶(1~3)。
8.根据权利要求1所述多氟芳基硒醚衍生物的制备方法,其特征在于,所述无需借助催化剂。
9.多氟芳烃衍生物、二苯二硒醚衍生物为原料在通电反应制备多氟芳基硒醚衍生物中的应用。
10.根据权利要求1所述多氟芳基硒醚衍生物的制备方法制备的多氟芳基硒醚衍生物。
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