CN108503574A - 一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法 - Google Patents
一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法 Download PDFInfo
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- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 17
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 12
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 11
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
- C07D207/48—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种合成3‑乙烯基‑4‑乙炔基‑2,3‑二氢吡咯衍生物的方法,属于联烯胺环化化学方法合成领域;其中,方法的主要特征在于:(1)采用过渡金属元素进行催化;(2)采用联烯作为合成的原材料;(3)反应温度温和;(4)反应步骤一步完成;(5)催化剂可以进行回收重新利用;(6)反应溶剂须严格去除掉水分子,达微量级别;(7)所生成产物物理、化学性质在常温及高温环境中不会产生变化:(9)所生成产物的产率≥85%wt(10)所生成的副产物易于采用常规方法去除。
Description
技术领域
一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,属于有机化合物工艺应用技术领域。
背景技术
多官能团化的吡咯类这类结构的化合物由于其在天然产物、生物活性分子、材料化学和精细化工中间体的广泛存在,一直引起人们的关注。就在近期,众多的生物制剂和生物活性分子相继报道,甚至某些物质已经应用在实际生活当中;例如,人类体内的胆红素,高效和选择性的FAP(成纤维细胞活化蛋白)抑制剂,肾上腺素能受体激动剂vibegron,口服有效的FTase(Farnesyltransferase)抑制剂LB-42708,以及强效的PKC(Protein KinaseC)抑制剂Go-6976,和能促进肝蛋白合成,抑制肝过氧化氢酶活性降低的锌原卟啉。
我们课题组一直致力钯催化下联烯胺环化生成杂环的研究,并且取得了一些较为满意的结果;随着我们对各种有机活性分子的深入探索,炔烃类的物质,尤其是端炔烃,由于其独特的结构和高活性引起了我们的注意。炔烃这类化合物,作为一种非常重要的结构基序,在有机合成领域结构的构建中扮演者非常重要的角色;采用新的方法合成炔烃类衍生化合物的发展也是研究中的热点问题。在这个邻域中,直接将炔烃引入形成碳碳新键,一直以来对于科学工作者来说是一个挑战;传统的有机合成制备炔烃类化合物的方法是采用碱金属炔基化合物通过发生亲核烷基化反应来制得;很明显,这类方法反应条件苛刻,产率也并不让人满意;除此之外,采用有机金属催化偶联反应合成炔烃类化合物也被广泛的报道;像末端炔烃与卤代芳烃、卤代烯烃的Sonogashira交叉偶联的反应,是当前非常有效构建碳碳键的方法;还有,通过有机金属化合物为媒介,发生偶联的炔烃烷基化;近年来发展起来的,一类通过铜卡宾迁移插入氮腙类化合物生成炔基化物质;以及端炔烃和吲哚类化合物发生Heck/sonogashira连锁偶联反应,得到炔烃衍生物的方法,等等。
在这些有机金属催化的例子中,我们可以看到,生成的金属炔基化物是整个反应进程过程中的一个关键所在;纵观我们课题组所做的工作中,在联烯胺合成杂环关键性问题上,π-烯丙基所引导的串联环化偶联过程中,可以生成联烯胺环化偶联中间体这样一类的活性物质;这样的中间体可以和具有活性的分子(亲核或者亲电)结合生成非常稳定的二氢吡咯类化合物或吡啶类化合物,并且有较高的收率;尽管在串联环化过程中有两种活性不同的中间体生成,我们可以通过对其他添加剂的调控,从而影响反应进程的方向,能够生成单一的五元杂环或者六元杂环;基于以上的例子带给我们新认识,我们设想把这样的中间体能够与由金属有机催化下生成的金属炔基化物生成新的碳碳键,从而生成一种具有炔基和烯基的吡咯类化合物;经过努力我们得到了具有1,6-炔烃结构的二氢吡咯类衍生物,这类物质在生物活性中间体和医药制药领域,广泛地存在和应用;具有非常好的实用价值和使用前景。
发明内容
本发明克服现有技术的缺陷,首次创新地提出了一种简单高效一步法制备3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,通过使用金属钯催化剂和金属铜催化剂,两者共催化可以高效地实现反应的转化。
图1;式(I);
如以上式(I)所示,本发明利用联烯胺衍生物(底物1)和端乙炔基衍生物(底物2)作为起始原料;在金属钯催化剂和铜催化剂的共同作用下,在反应溶剂中进行反应,合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物。
本发明中,X可以是OAc,OTf,I,Br,Cl,OSO2(CnF2n+1),n = 0,1,4。
优选地,X是OAc。
本发明中,X包括但不仅仅局限与上述基团,例如,X还可以是多氟磺酸衍生物基团等。
本发明中,PG可以是Ts,Ms,BoC,Bn,Ac,等。
本发明中,R可以是脂肪基,芳基,功能性基团。
本发明中,所述起始原料联烯胺衍生物(底物1)和端乙炔基衍生物(底物2)的用量比例是1equiv:2-4equiv。
优选地,两者用量比例为1equiv:2.2equiv。
本发明中,所述催化剂1是Pd2(dba)3、Pd(PPh3)4或PdCl2(PPh3)2。
优选地,所述催化剂1是PdCl2(PPh3)2或Pd(PPh3)4。
本发明中,所述钯催化剂1的用量为底物1的5-20mol%。
优选地,所述钯催化剂1的用量为底物1的10mol%。
本发明中,所述催化剂2是CuCl、CuBr或CuI。
优选地,所述催化剂2是CuCl。
本发明中,所述催化剂2的用量为底物1的1-10mol%。
优选地,所述催化剂2的用量为底物1的5mol%。
本发明中,所述配体是PCy3或PPh3。
优选地,所述配体是无或PPh3。
本发明中,所述配体的用量是10-40mol%。
优选地,所述配体的用量是20mol%。
本发明中,所述的碱性化合物是三乙胺(TEA),二异丙基乙基胺(DIEA),K2CO3,CsF,tBuONa,K3PO4或K3PO4·3H2O。
优选地,所述的碱性化合物是K3PO4·3H2O。
本发明中,所述碱性化合物的用量为2-4equiv。
优选地,所述碱性化合物的用量是2equiv。
本发明中,所述的溶剂是四氢呋喃(THF),2-甲基四氢呋喃,二氧六环(dioxane),N,N-二甲基甲酰胺(DMF)或乙醚(ether)。
优选地,所述的溶剂是二氧六环(dioxane)。
本发明中,所述的溶剂是四氢呋喃(THF),2-甲基四氢呋喃,二氧六环(dioxane),N,N-二甲基甲酰胺(DMF)或乙醚(ether)的的用量是1M-20M。
优选地,所述的溶剂的用量是10M。
本发明中,所述的反应温度是65~85℃。
优选地,所述反应温度是85℃。
本发明中,所述的反应时间是2-3小时。
优选地,所述反应时间是2.5小时。
具体地,本发明合成反应是:将催化剂1、催化剂2、配体(ligand)和碱性化合物混合搅匀放入适当封闭容器内,用惰性气体充分置换多次,使容器中呈现高纯单一的惰性气体气氛,将联烯胺按一当量溶于无水的溶剂(10M)当中,充分搅匀,一次性加入前文所述封闭容器中,而后,在确定的温度氛围中在确定的时间内将带有功能性官能团的端乙炔衍生物(两当量)等分逐一加入到前文所述的封闭容器当中,期间保持恒温,直到反应结束,而后,均速降至室温,加入弱酸性化合物,中和前文(1)中所述碱,搅拌2小时后,饱和食盐水洗涤一遍,用乙酸乙酯萃取,取有机相,过12cm层析柱,即得产物3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物,产率≥85%wt,回收过渡金属化合物;
本发明合成方法所使用的各原料非常简单,均为工业化商品,简单易得,来源广泛,并且性能非常稳定,不需要特殊保存条件。本发明所用的各种金属催化剂和添加剂也都是常用的商品化试剂,非常稳定,而且具有成本低、产率高、工艺简、污染少的特色,完全可适用于大规模生产。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例;在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围;实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
实施例1
图2;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuCl((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1a(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2a(0.4mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到黄褐色液体3aa(85%);1H NMR (400 MHz, CDCl3, δ ppm): 7.59 (d, J = 8.0 Hz,2H), 7.30–7.21 (m, 7H), 6.34 (s, 1H), 5.26–5.17 (m, 1H), 4.94–4.88 (m, 2H),3.66 (t, J = 10.0 Hz, 1H), 3.29–3.17 (m, 2H), 2.98 (d, J = 19.6 Hz, 1H), 2.85(d, J = 20.0 Hz, 1H), 2.32 (s, 3H);13C NMR (100 MHz, CDCl3, δ ppm): 144.0,137.2, 132.6, 131.6, 129.7, 128.4, 127.8, 127.0, 126.8, 123.7, 123.3, 117.4,85.5, 82.3, 53.7, 49.0, 21.7, 17.6;MS (EI) m/z 363 (M+); HRMS (ESI) Calcd forC22H21NO2S+H 364.1366, Found 364.1367。
实施例2
图3;
在25 mL的反应试管中,将Pd(PPh3)4(0.02 mmol),CuCl((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1b(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2b(0.4mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到褐色液体3bb(82%);1H NMR (400 MHz, CDCl3, δ ppm): 7.68 (d, J = 7.6 Hz, 2H),7.34–7.28 (m, 4H), 7.12 (d, J = 7.6 Hz, 2H), 6.42 (s, 1H), 5.36–5.27 (m, 2H),5.03–4.98 (m, 2H), 3.76 (t, J =10.0 Hz, 1H), 3.39–3.26 (m, 2H), 3.07 (d, J =19.6 Hz, 1H), 2.94 (d, J = 20.0 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 3H);13C NMR(100 MHz, CDCl3, δ ppm): 143.9, 138.1, 137.1, 132.6, 131.4, 129.7, 129.0,127.8, 126.8, 123.8, 120.2, 117.4, 84.6, 82.3, 53.6, 49.0, 21.6, 21.4, 17.6;MS (EI) m/z 377 (M+); HRMS (ESI) Calcd for C23H23NO2S+H 378.1522, Found:378.1524。
实施例3
图4;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuCl((0.01 mmol)),K3PO4(0.4mmol)放入,密闭,用氮气置换3次;将联烯胺底物1c(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2c(0.4 mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到黄褐色液体3cc(77%);1H NMR (400 MHz, CDCl3, δ ppm): 7.68 (d, J = 7.6 Hz, 2H), 7.33(d, J = 8.0 Hz, 4H), 6.84 (d, J = 8.0 Hz, 2H), 6.42 (s, 1H), 5.35-5.27 (m,1H), 5.03-4.98 (m, 2H), 3.81 (s, 3H), 3.75 (t, J = 10 Hz, 1H), 3.38-3.26 (m,2H), 3.06 (d, J = 19.6 Hz, 1H), 2.92(d, J = 19.6 Hz, 1H), 2.43 (s, 3H);13C NMR(100 MHz, CDCl3, δ ppm): 159.4, 143.9, 137.1, 132.9, 132.7, 129.7, 127.8,126.8, 123.9, 117.3, 115.4, 113.9, 83.8, 82.1, 55.3, 53.6, 49.0, 21.6, 17.6;MS (EI) m/z 393 (M+); HRMS (ESI) Calcd for C21H23NO2S +H 394.1471, Found:394.1472。
实施例4
图5;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuBr((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1e(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2e(0.4mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到褐色膏状物3ee(77%);1H NMR (400 MHz, CDCl3, δ ppm): 7.68 (d, J = 8.0 Hz,2H), 7.39–7.32 (m, 5H), 7.02-6.99 (m, 2H), 6.42 (s, 1H), 5.35-5.27 (m, 1H),5.03–4.99 (m, 2H), 3.76 (t, J = 9.6 Hz, 1H), 3.39-3.26 (m, 2H), 3.06 (d, J =19.6 Hz, 1H), 2.93 (d, J = 19.6 Hz, 1H), 2.43 (s, 3H);13C NMR (100 MHz, CDCl3,δ ppm): 162.3(d, J = 247 Hz), 143.91, 137.05, 133.4(d, J = 8 Hz), 132.65,129.71, 127.78, 126.90, 123.45, 119.4(d, J = 3 Hz), 117.41, 115.5(d, J = 22Hz), 85.13, 81.22, 53.58, 48.98, 21.59, 17.54;19F{1H} NMR (376 MHz, CDCl3, δppm): -111.4 - -111.5(m);MS (EI) m/z 381 (M+); HRMS (ESI) Calcd for C22H20FNO2S+H 382.1271,Found: 382.1272。
实施例5
图6;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuCl((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1f(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2f(0.4mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到深褐色膏状物3ff(79%);1H NMR (400 MHz, CDCl3, δ ppm): 7.67 (d, J = 8.4 Hz,2H), 7.33–7.26 (m, 6H), 6.41 (s, 1H), 5.34–5.26 (m, 1H), 5.02–4.98 (m, 2H),3.75 (t, J = 10.0 Hz, 1H), 3.38–3.25 (m, 2H), 3.06 (d, J = 19.6 Hz, 1H), 2.93(d, J = 20.0 Hz, 1H), 2.42 (s, 3H);13C NMR (100 MHz, CDCl3, δ ppm): 143.9,137.0, 134.0, 132.8, 132.6, 129.7, 128.6, 127.8, 126.9, 123.3, 121.8, 117.4,86.6, 81.2, 53.6, 49.0, 21.6, 17.6;MS (EI) m/z 397 (M+); HRMS (ESI) Calcd forC22H20ClNO2S+H 398.0976, Found: 398.0978。
实施例6
图7;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuCl((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1g(0.2 mmol)溶于除过水的THF溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2g(0.4 mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到褐色固体3gg(80%);1H NMR (400 MHz, CDCl3, δ ppm): 7.68 (d, J = 8.0 Hz, 2H), 7.57 (d,J = 7.6 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.6 Hz, 2H), 6.43 (s,1H), 5.36–5.27 (m, 1H), 5.04–4.99 (m, 2H), 3.77 (t, J = 10.0 Hz, 1H), 3.37(q, J = 8.0 Hz, 1H), 3.29 (t, J = 8.4 Hz, 1H), 3.10 (d, J = 19.6 Hz, 1H),2.97 (d, J = 19.6 Hz, 1H), 2.43 (s, 3H);13C NMR (100 MHz, CDCl3, δ ppm):144.0, 137.0, 132.7, 131.9, 129.8(q, J = 32 Hz), 129.7, 127.8, 127.1, 125.2(q, J = 4 Hz), 123.9(q, J = 271Hz), 122.9, 117.5, 88.3, 81.1, 53.6, 49.0,21.6, 17.6;19F{1H} NMR (376 MHz, CDCl3, δ ppm): -62.8(s);MS (EI) m/z 431 (M+);HRMS (ESI) Calcd for C23H20F3NO2S+H 432.1240, Found: 432.1241。
实施例7
图8;
在25 mL的反应试管中,将Pd2(dba)3(0.02 mmol),PPh3(0.04 mmol),CuCl((0.01mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1a(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2k(0.4 mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到褐色膏状物3kk(80%);1H NMR (400 MHz, CDCl3, δ ppm): 7.68 (d, J= 8.0 Hz, 2H), 7.38 -7.26 (m, 4H), 7.08–7.07 (m, 1H), 6.42 (s, 1H), 5.35–5.26(m, 1H), 5.03–4.98 (m, 2H), 3.75 (t, J = 10.0 Hz, 1H), 3.38–3.26 (m, 2H),3.06 (d, J = 19.6 Hz, 1H), 2.92 (d, J = 20.0 Hz, 1H), 2.43 (s, 3H);13C NMR(100 MHz, CDCl3, δ ppm)(with coupling): 143.9, 137.1, 132.7, 130.0, 129.8,128.3, 127.8, 127.0, 126.8, 125.3, 123.5, 122.3, 117.4, 85.0, 53.5, 48.9,21.5, 17.6;MS (EI) m/z 369 (M+); HRMS (ESI) Calcd for C20H19NO2S2+H 370.0930,Found: 370.0932。
实施例8
图9;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuI((0.01 mmol)),CsF(0.4mmol)放入,密闭,用氮气置换3次;将联烯胺底物1b(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2m(0.4 mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到黄色液体3mm(56%);
1H NMR (400 MHz, CDCl3, δ ppm): 7.65 (d, J = 7.6 Hz, 2H), 7.32 (d, J =7.6 Hz, 2H), 6.34 (s, 1H), 5.29–5.21 (m, 1H), 4.98–4.94 (m, 2H), 3.73 (t, J =8.8 Hz, 1H), 3.31–3.22 (m, 2H), 2.87 (d, J = 20.0 Hz, 1H), 2.73 (d, J = 19.6Hz, 1H), 2.43 (s, 3H), 0.17 (s, 9H);13C NMR (100 MHz, CDCl3, δ ppm): 143.8,137.0, 132.5, 129.6, 127.7, 127.0, 126.8, 123.2, 117.3, 102.2, 86.7, 53.6,48.8, 21.6, 18.0, 0.00;MS (EI) m/z 359 (M+); HRMS (ESI) Calcd for C19H25NO2SSi+H 360.1448, Found: 360.1449。
实施例9
图10;
在25 mL的反应试管中,将Pd2(dba)3(0.02 mmol),PCy3(0.04 mmol),CuCl((0.01mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1h(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2b(0.4 mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到淡褐色液体3nn(67%);
1H NMR (400 MHz, CDCl3, δ ppm): 7.30 (d, J = 7.6 Hz, 2H), 7.10 (d, J =7.6 Hz, 2H), 6.34 (s, 1H), 5.76-5.67 (m, 1H), 5.22-5.16 (m, 2H), 3.95 (t, J =10.0 Hz, 1H), 3.61 (q, J = 8.0 Hz, 1H), 3.53–3.49 (m, 1H), 3.17 (d, J = 19.6Hz, 1H), 3.04 (d, J = 19.6 Hz, 1H), 2.87 (s, 3H), 2.34 (s, 3H);13C NMR (100MHz, CDCl3, δ ppm): 138.1, 136.9, 131.5, 129.0, 126.3, 123.5, 120.1, 117.8,84.4, 82.5, 54.1, 49.0, 35.1, 21.4, 17.7;MS (EI) m/z 301 (M+); HRMS (ESI)Calcd for C17H19NO2S+H 302.1209, Found: 302.1211。
实施例10
图11;
在25 mL的反应试管中,将PdCl2(PPh3)2(0.02 mmol),CuCl((0.01 mmol)),K3PO4·3H2O(0.4 mmol)放入,密闭,用氮气置换3次;将联烯胺底物1i(0.2 mmol)溶于除过水的二氧六环溶剂(2.0 mL)中,而后,将溶液打入密闭的反应试管中;称量好乙炔基衍生物2f(0.4mmol),在80oC温度下,缓慢的,逐滴的滴入密闭的反应试管中,历时2.5小时;TLC检测反应结束后,将体系冷却至室温;洗涤,萃取有机相,加粗硅胶旋干;快速柱层析过出目标产物,得到褐色膏状物3oo(75%);
1H NMR (400 MHz, CDCl3, δ ppm): 7.33 (d, J = 8.0 Hz, 2H), 7.27 (d, J =8.0 Hz, 2H), 6.33 (s, 1H), 5.75–5.66 (m, 1H), 5.22–5.16 (m, 2H), 3.95 (t, J =10.0 Hz, 1H), 3.60 (q, J = 8.4 Hz, 1H), 3.53–3.49 (m, 1H), 3.17 (d, J = 19.6Hz, 1H), 3.04 (d, J = 19.6 Hz, 1H), 2.88 (s, 3H);13C NMR (100 MHz, CDCl3, δppm): 136.8, 134.0, 132.9, 128.6, 126.4, 122.9, 121.7, 117.9, 86.3, 81.4,54.1, 49.1, 35.3, 17.7;MS (EI) m/z 321 (M+); HRMS (ESI) Calcd for C22H21NO3S+H322.0663, Found: 322.0664。
Claims (9)
1.一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于,采用如下步骤:
(1)将催化剂1、催化剂2、配体(ligand)和碱性化合物混合搅匀放入适当封闭容器内,用惰性气体充分置换多次,使容器中呈现高纯单一的惰性气体气氛,将联烯胺(图示1所示化合物1结构)按一当量溶于无水的溶剂(10M)当中,充分搅匀,一次性加入前文所述封闭容器中,而后,在确定的温度中,在确定的时间内将带有功能性官能团的端乙炔衍生物(两当量)平均等分量逐一加入到前文所述的封闭容器当中,期间保持恒温,直到反应结束,反应方程式(I)所示:
式(I);
其中:
(2)均速降至室温,加入弱酸性化合物,中和(1)中所述碱性化合物,搅拌2小时后,饱和食盐水洗涤一遍,用乙酸乙酯萃取,取有机相,过12cm层析柱,即得产物3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物,产率≥85%wt,回收过渡金属化合物,回收率≥90%wt。
2.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的催化剂1是Pd2(dba)3、Pd(PPh3)4或PdCl2(PPh3)2,所述催化剂1的用量为5-20%mol。
3.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的催化剂2是CuCl、CuBr或CuI,所述催化剂2的用量为1-10%mol。
4.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的配体为PCy3或PPh3,所述配体的用量为10-40%mol。
5.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的碱性化合物为三乙胺(TEA),二异丙基乙基胺(DIEA),K2CO3,CsF,tBuONa,K3PO4或K3PO4·3H2O。
6.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的溶剂为四氢呋喃(THF),2-甲基四氢呋喃,二氧六环(dioxane),N,N-二甲基甲酰胺(DMF)或乙醚(ether)。
7.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的温度为65oC-85oC。
8.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:所述的时间为2 hours≤T≤3 hours。
9.根据权利要求1所述的一种合成3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物的方法,其特征在于:一步生成物为3-乙烯基-4-乙炔基-2,3-二氢吡咯衍生物。
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CN109180566A (zh) * | 2018-10-09 | 2019-01-11 | 山东理工大学 | 一种制备2-氨基-3-亚甲基-1,2,3,6-四氢吡啶衍生物的方法 |
CN109336792A (zh) * | 2018-11-28 | 2019-02-15 | 山东理工大学 | 一种4-甲基-n-苯基-n-(2-苯基烯丙基)苯磺酰胺类化合物的合成方法 |
CN109553555A (zh) * | 2018-11-28 | 2019-04-02 | 山东理工大学 | 一种4-甲基-n-苯基-n-(2-苯基丙-1-烯基)苯磺酰胺类化合物的合成方法 |
CN109553555B (zh) * | 2018-11-28 | 2021-01-08 | 山东理工大学 | 一种4-甲基-n-苯基-n-(2-苯基丙-1-烯基)苯磺酰胺类化合物的合成方法 |
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