CN109912418B - 一种反式-4-苯基-3-丁烯酸乙酯化合物的制备方法 - Google Patents
一种反式-4-苯基-3-丁烯酸乙酯化合物的制备方法 Download PDFInfo
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Abstract
本发明属于医药化工中间体及相关化学技术领域,涉及到一种反式‑4‑苯基‑3‑丁烯酸乙酯化合物的制备方法,以2‑苯基环丙烷‑1,1‑二羧酸二乙酯衍生物为原料,在Lewis酸作为促进剂作用下,发生异构化/消除反应,于有机溶剂中在130℃条件下,反应24小时,即到反式‑4‑苯基‑3‑丁烯酸乙酯化合物。本发明的有益效果是操作简便、起始原料廉价易得、无副产物生成,有实现工业化的可能性,并且以较高收率得到反式‑4‑苯基‑3‑丁烯酸乙酯化合物;利用该方法所合成的反式‑4‑苯基‑3‑丁烯酸乙酯化合物可以进一步官能化得到各类化合物,应用于天然产物、功能材料及精细化学品的开发与研究。
Description
技术领域
本发明属于医药化工中间体及相关化学技术领域,涉及到新颖的反式-4-苯基-3-丁烯酸乙酯化合物的制备方法。
背景技术
不饱和脂肪羧酸酯是一类极其重要的结构单元,其在医药、农药、染料、功能材料和香料等领域中都有着很重要的应用价值。其中,反式-4-苯基-2-丁烯酸乙酯可以用于合成医药化合物,[Alexey O.C.,Olga A.I.,Eduard R.R.,Ekaterina M.B.,Igor V.T.,Mikhail Y.M.,Adv.Synth.Catal.2010,352,3179–3184],鉴于反式-4-苯基-3-丁烯酸乙酯及其衍生化的化合物的重要性,如何高效地合成反式-4-苯基-3-丁烯酸乙酯化合物已引起人们的广泛关注。
由于较大的环张力,环丙烷化合物热力学不稳定。环丙烷化合物与丙烯化合物互为异构体,如果环丙烷底物易于得到,通过互变异构的策略,以环丙烷作为底物,则可实现烯烃衍生物的简便合成。热力学角度上,由环丙烷异构成丙烯化合物需要高的活化能,已报道光催化的策略可实现异构化反应[H.E.Zimmerman,A.P.Kamath,J.Am.Chem.Soc.1988,110,900–911],然而这类方法的选择性通常很低;最近,有报道在酸的作用下,三元环化合物通过异构化反应可实现2-苯乙烯基-丙二酸二乙酯的合成[Alexey O.C.,Olga A.I.,Eduard R.R.,Ekaterina M.B.,Igor V.T.,Mikhail Y.M.,Adv.Synth.Catal.2010,352,3179–3184],该方法得到的二酯需要进一步反应合成单酯,这些均为反式-4-苯基-3-丁烯酸乙酯的高效合成及工业化带来困难。随着人们对C-C键活化反应的认识不断加深,三元环开环异构化反应逐渐受到人们的广泛关注,与此同时,三元环衍生物作为重要的化工原料,可以合成很多有用的化合物,如果可以以三元环衍生物为初始原料,通过异构化/消除的方法实现反式-4-苯基-3-丁烯酸乙酯化合物的合成,则可以大大缩短合成步骤,节约合成成本,有利于反式-4-苯基-3-丁烯酸乙酯化合物的工业制备。
发明内容
本发明提供了一种反式-4-苯基-3-丁烯酸乙酯化合物的新颖制备方法,该方法的合成路线短、底物易得、操作简便,并且收率较高。
本发明的技术方案:
一种反式-4-苯基-3-丁烯酸乙酯化合物的制备方法,以2-苯基环丙烷-1,1-二羧酸二乙酯衍生物为原料,在Lewis酸作为促进剂作用下,发生异构化/消除反应,于有机溶剂中在130℃条件下,反应24小时,即到反式-4-苯基-3-丁烯酸乙酯化合物;
合成路线如下:
其中,R1选自氢、卤素、烷基、甲氧基、氰基、羟基和硝基;
R2选自氢、甲基和烷基;
2-苯基环丙烷-1,1-二羧酸二乙酯衍生物与Lewis酸的摩尔比为1:2~1:3;
2-苯基环丙烷-1,1-二羧酸二乙酯衍生物在反应体系中的摩尔浓度为0.1mmol/mL~0.2mmol/mL。
所述的有机溶剂为N,N-二甲基甲酰胺、1,4-二氧六环、甲苯、四氢呋喃、乙腈中的一种或两种以上混合,优选N,N-二甲基甲酰胺。
所述的Lewis酸为三氯化铝、氯化镁、三氟乙酸、三氟甲烷磺酸铜(II)、三氯化铁、氯化亚铜中的一种或两种以上混合,优选三氯化铝。
分离方法包括柱层析等。
用柱层析方法进行产物分离时,可以使用硅胶或氧化铝作为固定相,展开剂一般为极性与非极性的混合溶剂,如乙酸乙酯-石油醚、乙酸乙酯-正己烷、二氯甲烷-石油醚、甲醇-石油醚。
本发明的有益效果是操作简便、起始原料廉价易得、无副产物生成,三氯化铝酸为催化剂,有实现工业化的可能性,并且以较高收率得到反式-4-苯基-3-丁烯酸乙酯化合物;利用该方法所合成的反式-4-苯基-3-丁烯酸乙酯化合物可以进一步官能化得到各类化合物,应用于天然产物、功能材料及精细化学品的开发与研究。
附图说明
图1是实施例1中反式-4-苯基-3-丁烯酸乙酯的1H核磁谱图。
图2是实施例2中反式-4-(4-氟苯基)-3-丁烯酸乙酯的1H核磁谱图。
图3是实施例3中反式-4-(4-甲基苯基)-3-丁烯酸乙酯的1H核磁谱图。
图4是实施例4中反式-4-(4-甲氧基苯基)-3-丁烯酸乙酯的1H核磁谱图。
图5是实施例5中反式-4-(4-氯苯基)-3-丁烯酸乙酯的1H核磁谱图。
图6是实施例6中反式-4-(4-溴苯基)-3-丁烯酸乙酯的1H核磁谱图。
图7是实施例7中反式-4-(4-叔丁基苯基)-3-丁烯酸乙酯的1H核磁谱图。
图8是实施例8中反式-4-(萘-2-基)-3-丁烯酸乙酯的1H核磁谱图。
具体实施方式
本发明所述的反式-4-苯基-3-丁烯酸乙酯化合物的制备方法,具有原料廉价易得、反应步骤少、无副产物生成、便于操作和反应收率高等优点。
下面结合具体实施例,进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。在本领域内的技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案之内。
实施例1:反式-4-苯基-3-丁烯酸乙酯的合成
在25mL反应器中,加入三氯化铝(0.13g,1mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(2mL),加入2-苯基环丙烷-1,1-二羧酸二乙酯(0.104g,0.4mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-苯基-3-丁烯酸乙酯0.053g,产率72%。
无色油状液体;1H NMR(400MHz,CDCl3):δ7.39–7.23(m,5H),6.48(d,J=15.0Hz,1H),6.33(dt,J=15.0,6.8Hz,1H),4.18(q,J=7.0Hz,1H),3.25(d,J=7.0Hz,2H),1.28(t,J=6.0Hz,3H).
实施例2:反式-4-(4-氟苯基)-3-丁烯酸乙酯的合成
在25mL反应器中,加入氯化镁(0.11g,1.2mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(2mL),加入2-(4-氟苯基)环丙烷-1,1-二羧酸二乙酯(0.112g,0.4mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-(4-氟苯基)-3-丁烯酸乙酯0.051g,产率62%。反式-4-(4-氟苯基)-3-丁烯酸乙酯
无色油状液体;1H NMR(400MHz,CDCl3):δ7.33–7.00(m,4H),6.46(d,J=15.0Hz,1H),6.22(dt,J=15.0,6.8Hz,1H),4.18(q,J=7.0Hz,1H),3.23(d,J=7.0Hz,2H),1.28(t,J=6.0Hz,3H).
实施例3:反式-4-(4-甲基苯基)-3-丁烯酸乙酯的合成
在25mL反应器中,加入三氯化铝(0.26g,2mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(4mL),加入2-(4-甲基苯基)环丙烷-1,1-二羧酸二乙酯(0.221g,0.8mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-(4-甲基苯基)-3-丁烯酸乙酯0.114g,产率70%。
无色油状液体;1H NMR(400MHz,CDCl3):δ7.25–7.10(m,4H),6.47(d,J=15.0Hz,1H),6.24(dt,J=15.0,6.8Hz,1H),4.18(q,J=7.0Hz,1H),3.23(d,J=7.0Hz,2H),2.33(s,3H),1.28(t,J=6.0Hz,3H).
实施例4:反式-4-(4-甲氧基苯基)-3-丁烯酸乙酯的合成
在25mL反应器中,加入三氟甲烷磺酸铜(II)(0.36g,1mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(2mL),加入2-(4-甲氧基苯基)环丙烷-1,1-二羧酸二乙酯(0.116g,0.4mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-(4-甲氧基苯基)-3-丁烯酸乙酯0.052g,产率60%。
无色油状液体;1H NMR(400MHz,CDCl3):δ7.31–6.85(m,4H),6.45(d,J=15.0Hz,1H),6.16(dt,J=15.0,6.8Hz,1H),4.18(q,J=7.0Hz,1H),3.80(s,3H),3.22(d,J=7.0Hz,2H),1.28(t,J=6.0Hz,3H).
实施例5:反式-4-(4-氯苯基)-3-丁烯酸乙酯的合成的合成
在25mL反应器中,加入三氯化铝(0.07g,0.5mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(2mL),加入2-(4-氯苯基)环丙烷-1,1-二羧酸二乙酯(0.059g,0.2mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-(4-氯苯基)-3-丁烯酸乙酯0.03g,产率67%。
淡黄色油状液体;1H NMR(400MHz,CDCl3):δ7.27–7.18(m,4H),6.42(d,J=15.0Hz,1H),6.19(dt,J=15.0,6.8Hz,1H),4.10(q,J=7.0Hz,1H),3.16(d,J=7.0Hz,2H),1.22(t,J=6.0Hz,3H).
实施例6:反式-4-(4-溴苯基)-3-丁烯酸乙酯合成
在25mL反应器中,加入三氯化铝(0.13g,1mmol),氮气置换3次后,加入N,N-二甲基甲酰胺(4mL),加入2-(4-溴苯基)环丙烷-1,1-二羧酸二乙酯(0.136g,0.4mmol),130℃条件下搅拌24小时。柱层析分离(硅胶,200-300目;展开剂,石油醚/乙酸乙酯=10/1)得到反式-4-(4-溴苯基)-3-丁烯酸乙酯0.067g,产率63%。
淡黄色油状液体;1H NMR(400MHz,CDCl3):δ7.36–7.19(m,4H),6.37(d,J=15.0Hz,1H),6.24(dt,J=15.0,6.8Hz,1H),4.11(q,J=7.0Hz,1H),3.16(d,J=7.0Hz,2H),1.21(t,J=6.0Hz,3H).
实施例7:反式-4-(4-叔丁基苯基)-3-丁烯酸乙酯的合成
操作同实施例1,由2-(4-叔丁基苯基)环丙烷-1,1-二羧酸二乙酯异构/消除反应得到反式-4-(4-叔丁基苯基)-3-丁烯酸乙酯0.069g,产率70%。
淡黄色油状液体;1H NMR(400MHz,CDCl3):δ7.34(m,4H),6.46(d,J=15.0Hz,1H),6.27(dt,J=15.0,6.8Hz,1H),4.17(q,J=7.0Hz,1H),3.22(d,J=7.0Hz,2H),1.30(s,9H),1.26(t,J=6.0Hz,3H).
实施例8:反式-4-(萘-2-基)-3-丁烯酸乙酯的合成
操作同实施例1,由2-4-(萘-2-基)环丙烷-1,1-二羧酸二乙酯异构/消除反应得到反式-4-(萘-2-基)-3-丁烯酸乙酯0.072g,产率75%。
无色油状液体;1H NMR(400MHz,CDCl3):δ7.81-7.47(m,7H),6.70(d,J=15.0Hz,1H),6.48(dt,J=15.0,6.8Hz,1H),4.23(q,J=7.0Hz,1H),3.33(d,J=7.0Hz,2H),1.32(t,J=6.0Hz,3H).
Claims (1)
1.一种反式-4-苯基-3-丁烯酸乙酯化合物的制备方法,其特征在于,该制备方法以2-苯基环丙烷-1,1-二羧酸二乙酯衍生物为原料,在Lewis酸作为促进剂作用下,发生异构化/消除反应,于有机溶剂中在130℃条件下,反应24小时,即到反式-4-苯基-3-丁烯酸乙酯化合物;
合成路线如下:
其中,R1选自氢、卤素、烷基、甲氧基、氰基、羟基和硝基;
R2选自氢、甲基和烷基;
2-苯基环丙烷-1,1-二羧酸二乙酯衍生物与Lewis酸的摩尔比为1:2~1:3;
2-苯基环丙烷-1,1-二羧酸二乙酯衍生物在反应体系中的摩尔浓度为0.1mmol/mL~0.2mmol/mL;
所述的有机溶剂为N,N-二甲基甲酰胺;
所述的Lewis酸为三氯化铝、氯化镁、三氟甲烷磺酸铜(II)中的一种或两种以上混合。
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Iridium complex-catalyzed carbonylation of allylic phosphates;Ryo Takeuchi 等;《Journal of Organometallic Chemistry》;20021231;137-145 * |
Protolysis of cyclopropanes with geminal electronegative substituents;Kolsaker, Per 等;《Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry》;19881231;第B42卷(第6期);345-353 * |
Ring Expansion of Epoxides under Bronsted Base Catalysis: Formal[3+2] Cycloaddition of b,g-Epoxy Esters with Imines Providing 2,4,5-Trisubstituted 1,3-Oxazolidines;Azusa Kondoh 等;《Angew. Chem. Int. Ed.》;20150812(第54期);第 11240-11244页 * |
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