CN116375603A - 一种合成苯丙环丁烯衍生物的方法 - Google Patents
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- UMIVXZPTRXBADB-UHFFFAOYSA-N benzocyclobutene Chemical class C1=CC=C2CCC2=C1 UMIVXZPTRXBADB-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 8
- 238000001308 synthesis method Methods 0.000 claims description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 239000011698 potassium fluoride Substances 0.000 claims description 3
- 235000003270 potassium fluoride Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 1
- 235000011181 potassium carbonates Nutrition 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 66
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 239000003208 petroleum Substances 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- -1 benzocyclobutene compound Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 2
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 description 2
- 229960003825 ivabradine Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000000178 monomer Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000007115 1,4-cycloaddition reaction Methods 0.000 description 1
- KIDDROYEHJYRSO-UHFFFAOYSA-N C(=C)C1(C(C=2C1=CC=CC=2)[SiH2]OC1(C(C=2C1=C(C=CC=2)C)(C)C)C)C=C Chemical compound C(=C)C1(C(C=2C1=CC=CC=2)[SiH2]OC1(C(C=2C1=C(C=CC=2)C)(C)C)C)C=C KIDDROYEHJYRSO-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 238000006012 Parham cyclization reaction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003935 benzaldehydes Chemical class 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 1
- 239000003989 dielectric material Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
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- 239000003480 eluent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000004377 microelectronic Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
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- 238000010898 silica gel chromatography Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/06—One of the condensed rings being a six-membered aromatic ring the other ring being four-membered
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明提供一种结构如式(Ⅲ)所示的苯并环丁烯衍生物的制备方法,所述方法是以结构如式(Ⅰ)所示的α‑亚甲基环丁酮类化合物和丙二腈(Ⅱ)在碱性条件下,有机溶剂中80~120℃下反应8~16小时,反应液经分离纯化制得结构如式(Ⅲ)所示的苯并环丁烯衍生物。本发明具有操作简便实用,原料廉价易得,无需金属催化剂,反应条件温和,环境友好等优点,具有良好的实际应用价值。
Description
技术领域
本发明涉及一种合成苯并环丁烯类衍生物的方法。
技术背景
苯并环丁烯(BCB)是一类非常重要的苯并碳环化合物。它在合成多环化合物、复杂的天然产物和药物以及在材料化学方面均有着广泛的应用[1]。其作为单体可以聚合成高TG树脂,用作材料的涂层具有良好的抗划伤性能。由二乙烯基四甲基硅氧烷双苯并环丁烯(DVS-bisBCB)作为单体形成的树脂因具有介电常数低、吸湿率低,粘度低等特点而作为优良的介电材料广泛应用于半导体芯片等微电子领域[2]。在药物化学方面,苯并环丁烯作为重要的结构单元,广泛存在于抗肿瘤,抗心血管疾病的药物分子结构中。例如,目前广泛用于临床的治疗心力衰竭的药物伊伐布雷定(Ivabradine)[3]。此外,苯并环丁烯类化合物也具有独特的反应性,兼具芳香体系的热力学稳定性和与四元张力环相关的动力学反应性,在热激发下发生四元环开环,再进行周环反应。因此合成苯并环丁烯类化合物具有重要意义。
传统的苯并环丁烯类化合物的合成方法有消除法(反应式一)、Parham环化(反应式二)、环加成(反应式三)法等,这些方法一般需要高温高压等苛刻的条件,收率也较低,普遍在30%~60%左右。在传统合成方法基础上苯并环丁烯衍生物的合成方法也在不断改进,2008年Baudoin课题组和2021年Sorensene课题组均报道了通过碳氢键活化来合成苯并环丁烯的方法[4](反应式四)。但两种方法均需要金属催化,原料昂贵,反应步骤复杂。所以寻找一种原料经济易得,条件绿色温和地合成苯并环丁烯衍生物的方法具有重要的意义。
参考文献:
[1](a)Segura,J.L.;Martin,N.Chem.Rev.1999,99,3199.(b)Sadana,A.K.Saini,R.K.Billups,E.E.Chem.Rev.2003,103,1539.
[2]Jiang,T.;Rigney,J.;Jones,M.-C.G.;Markoski,L.J.;Spilman,G.E.;Mielewski,D.F.;Martin,D.C.Macromolecules 1995,28,3301.
[3](a)Kirchhoff,R.A.;Bruza,K.J.Prog.Polym.Sci.1993,18,85.(b)Psotka,M.A.;Teerlink,J.R.Circution 2016,133,2066.
[4](a)Chaumontet,M.;Baudoin,O.J.Am.Chem.Soc.2008,130,15157(b)Provencher,P.A.;Sorensen,E.J.J.Am.Chem.Soc.2021,143,20035.
发明内容
本发明的目的是提供一种操作简便,不用金属催化,条件温和地合成苯并环丁烯衍生物的方法。
为实现上述目的,本发明所采用的技术方案如下:
一种结构如式(Ⅲ)所示的苯并环丁烯类化合物的制备方法,所述方法是以结构如式(Ⅰ)所示的α-亚甲基环丁酮类化合物和丙二腈(Ⅱ)为原料在碱性条件下有机溶剂中于80~120℃下反应8~16小时,反应液经分离纯化制得结构如式(Ⅲ)所示的苯并环丁烯类化合物。所述α-亚甲基环丁酮类化合物为双烯体,丙二腈为亲双烯体,二者经过形式[4+2]环加成反应得到苯并环丁烯类化合物。
反应式如下:
式中:
R取代基选自氢、烷基、烷氧基、苯基、杂芳基、卤素等,其中烷基和烷氧基优选空间位阻较小的取代基。
本发明所述的碱选自N-甲基哌嗪、哌啶、吡咯烷、二异丙胺、三乙胺、叔丁胺、三乙烯二胺、氟化钾、碳酸钠、碳酸钾、磷酸钾等,优选为N-甲基哌嗪。
本发明所述的α-亚甲基环丁酮类化合物和丙二腈摩尔用量比为1:2~1:5,优选为1:3。
本发明所述的α-亚甲基环丁酮类化合物和碱摩尔用量比为1:1~1:5,优选为1:3。
本发明所述的有机溶剂选自二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙醇、乙腈、吡啶其中的一种或两种的组合,优选为二甲基亚砜。
本发明所述反应温度优选为120℃,反应时间优选为13小时。
本发明所述的分离纯化可采用如下步骤:反应液经乙酸乙酯提取,乙酸乙酯层浓缩后经硅胶柱层析分离得最后产物。
本发明所述反应步骤具体为:
将α-亚甲基环丁酮类化合物溶于有机溶剂中,加入丙二腈和碱,在80~120℃下搅拌反应8~16小时后,柱层析得到相应的苯并环丁烯衍生物。
与现有技术相比本发明具有以下优点:(1)原料廉价易得、无需金属催化剂;(2)反应操作简便、分离方便;(3)反应条件温和,环境友好,具有良好的实际应用价值。
具体实施方式
下面通过实施例详述本发明,但本发明并不限于下述的实施例。
下述实施中原料α-亚甲基环丁酮类化合物为根据已知文献自制的,其详细制备方法如下:
将30mmol取代苯甲醛和环丁酮3.0eq溶于30毫升无水乙醇中得混合溶液,N2下将混合溶液加入装有Ca(OH)2 0.1eq的schlenk瓶中,在N2氛围下80℃反应24小时,减压蒸出溶剂后柱层析分离得产物。
实施例1
将0.2m molα-亚甲基环丁酮1a溶于2毫升乙醇中,依次加入丙二腈3.0eq、N-甲基哌嗪3.0eq,80℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率33%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率33%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例2
将0.2m molα-亚甲基环丁酮1a溶于2毫升乙醇中,依次加入丙二腈3.0eq、碳酸钠3.0eq,80℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率21%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率21%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例3
将0.2m molα-亚甲基环丁酮1a溶于2毫升N,N-二甲基乙酰胺中,依次加入丙二腈3.0eq、N-甲基哌嗪3.0eq,120℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯体积比为10:1)收率26%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率26%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例4
将0.2m molα-亚甲基环丁酮1a溶于2毫升二甲基亚砜中,依次加入丙二腈3.0eq、N-甲基哌嗪3.0eq,120℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率64%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率64%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例5
将0.2m molα-亚甲基环丁酮1a溶于2毫升二甲基亚砜中,依次加入丙二腈3.0eq、氟化钾3.0eq,120℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率36%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率36%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例6
将0.2m molα-亚甲基环丁酮1a溶于2毫升二甲基亚砜中,依次加入丙二腈3.0eq、三乙烯二胺3.0eq,120℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2a(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率40%。
反应式如下:
所得苯并环丁烯衍生物2a为黄色固体,收率40%,Rf=0.4(石油醚/乙酸乙酯=5/1)。1H NMR(400MHz,Chloroform-d)δ7.60(d,J=4.0Hz,2H),7.51(m,3H),5.19(s,2H),3.31(t,J=4.1Hz,2H),3.21(t,J=4.1Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.83,153.18,143.53,133.86,132.53,129.76,128.96,128.49,116.74,114.21,93.80,91.30,29.17,28.78。
实施例7
将0.2m molα-亚甲基环丁酮类化合物1b-1i溶于2毫升二甲基亚砜中,依次加入丙二腈3.0eq、N-甲基哌嗪3.0eq,120℃下搅拌反应13小时。用乙酸乙酯萃取,之后柱层析提纯得到目标产物2b-2i(淋洗剂石油醚和乙酸乙酯的体积比为10:1)收率31~48%。
7.32(d,J=7.9Hz,2H),5.17(s,2H),3.29(t,J=4.0Hz,2H),3.25(t,J=4.0Hz,2H),2.44(s,3H).13C NMR(100MHz,Chloroform-d)δ154.67,153.22,143.63,140.04,132.39,130.98,129.66,128.40,116.86,114.25,93.71,91.01,29.10,28.81,21.41。
=5.5Hz,1H),5.19(s,2H),3.25(dt,J=39.1,4.1Hz,4H),2.45(s,3H).13C NMR(100MHz,Chloroform-d)δ154.71,153.18,143.76,138.69,133.85,132.50,130.51,129.03,128.83,125.60,116.71,114.22,93.91,91.21,29.10,28.78,21.50。
MHz,DMSO-d6)δ7.71–7.49(m,4H),6.62(s,2H),3.22(t,J=4.1 Hz,2H),3.09(t,J=4.1 Hz,2H).13C NMR(100 MHz,DMSO-d6)δ156.00,154.47,142.20,134.88,133.16,131.22,130.80,129.35,117.01,114.66,92.94,91.30,29.02,28.26。
7.13(m,1H),7.14–7.09(m,1H),7.02(dd,J=8.3,2.6 Hz,1H),5.19(s,2H),3.88(s,3H),3.33–3.28(m,2H),3.24–3.19(m,2H).13C NMR(100 MHz,Chloroform-d)δ159.80,154.78,153.16,143.37,135.11,132.53,130.04,120.83,116.66,115.44,114.15,113.98,91.39,77.25,55.42,29.12,28.82。
J=8.2 Hz,2H),6.63(s,2H),3.23(t,J=4.1 Hz,2H),3.09(t,J=4.1 Hz,2H).13CNMR(100 MHz,DMSO-d6)δ156.05,154.49,142.29,133.54,132.30,131.19,131.03,123.62,117.01,114.68,92.89,91.31,29.03,28.25。
–7.63(m,4H),7.50(t,J=8.0Hz,2H),7.41(t,J=8.0Hz,1H),5.20(s,2H),3.33(t,J=4.2Hz,2H),3.26(t,J=4.0Hz,2H).13C NMR(100MHz,Chloroform-d)δ154.80,153.24,143.11,142.61,140.08,132.69,132.54,128.95,127.92,127.62,127.16,116.81,114.17,93.67,91.33,77.23,29.18,28.89。
1H),7.28(dd,J=5.1,3.8Hz,1H),5.75(s,2H),3.33(s,2H),3.21(s,2H).13C NMR(100MHz,DMSO-d6)δ155.88,154.78,136.08,135.48,130.69,130.07,129.54,128.84,117.65,114.75,90.46,90.28,29.83,28.84。
2H),5.16(s,2H),3.30(dd,J=5.2,3.6Hz,2H),3.22(dd,J=5.0,3.6Hz,2H),2.99(m,J=6.8Hz,1H),1.31(d,J=6.9Hz,6H).13C NMR(100MHz,Chloroform-d)δ154.66,153.21,150.80,132.46,131.28,128.49,127.06,116.92,114.25,93.65,91.00,77.22,34.05,29.09,28.90,23.79。
本发明提供了一种由α-苯亚甲基环丁酮类化合物和丙二腈为原料合成苯并环丁烯衍生物的方法,其产率可达64%。本发明操作简便实用,原料易得,无需金属催化剂,反应绿色友好,具有良好的实际应用价值。
Claims (6)
2.如权利要求1所述的合成方法,其特征在于:所述的碱选自N-甲基哌嗪、哌啶、吡咯烷、二异丙胺、三乙胺、叔丁胺、三乙烯二胺、氟化钾、碳酸钠、碳酸钾、磷酸钾。
3.如权利要求1所述的合成方法,其特征在于:所述的有机溶剂选自二甲基亚砜、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、乙醇、乙腈、吡啶中的一种或两种。
4.如权利要求1所述的合成方法,其特征在于:反应温度为80~120℃,反应时间为8~16小时。
5.如权利要求1所述的合成方法,其特征在于:α-亚甲基环丁酮类化合物和丙二腈的摩尔比为1:2~1:5,α-亚甲基环丁酮类化合物和碱的摩尔比为1:1~1:5。
6.如权利要求1所述的合成方法,其特征在于:反应步骤具体为:将α-亚甲基环丁酮类化合物溶于有机溶剂中,加入丙二腈和碱,在80~120℃下搅拌反应8~16小时后,柱层析得到相应的苯并环丁烯衍生物。
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