CN107963996B - 一锅法制备3-三氟甲基异噁唑化合物的方法 - Google Patents
一锅法制备3-三氟甲基异噁唑化合物的方法 Download PDFInfo
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- -1 3-trifluoromethyl isoxazole compound Chemical class 0.000 title claims abstract description 56
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- 238000005580 one pot reaction Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims abstract description 9
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- 229940102001 zinc bromide Drugs 0.000 claims description 10
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种新型的一锅法制备3‑三氟甲基取代的异噁唑化合物的方法,该方法是利用市场中可购买到的三氟乙胺制备成氟代重氮甲烷,再与炔烃类化合物在廉价的铜催化下发生偶联反应得到;该方法操作简单、反应条件温和、成本低、副产物少、收率高、官能团耐受性高,并且可以放大反应。同时做了更深入的机理研究,并提出了该反应中会经过三氟甲基酮肟类化合物中间体的机理。
Description
技术领域
本发明涉及一种3-三氟甲基取代的异噁唑化合物的制备方法,特别涉及以三氟乙胺和末端炔烃为原料制备3-三氟甲基取代的异噁唑化合物的方法,属于有机氟化学和药物中间体合成技术领域。
背景技术
将三氟甲基基团引入到有机化合物中能使目标产物的极性、偶极矩、稳定性和亲脂性得到提高,因此含三氟甲基的化合物在医药、农药和新型功能材料等领域有重要意义。异噁唑杂环骨架不但广泛分布于诸多活性药物分子中,而且是有机合成化学中重要的中间体。而在异噁唑骨架中3号位尝试引入三氟甲基,可以通过影响化合物的脂溶性、稳定性以及渗透性等性能来改变其生物活性,这将使得原本的活性药物在性能上更具有用量少、毒性低、药效高、代谢能力强等特点。因而长久以来,如何高效地合成多样性的3-三氟甲基异噁唑一直是化学家们研究的热点问题。常见的合成方法包括:
(1)1989年,Linderman以三氟甲基取代的炔酮和盐酸羟胺为原料合成了3-三氟甲基异噁唑,但是炔基酮自身的合成条件就很苛刻,产率也不高。另外最为关键的是最后一步关环反应区域选择性差(可以是氮原子对羰基加成,也可以是氧原子对羰基加成),且底物局限性很大。(R.J.Linderman et al,Tetrahedron Letters 1989,30,2049-2052)
(2)2002年,J.C.Sloop使用三氟甲基取代的1,3-二酮作为关键中间体,并将其与盐酸羟胺缩合得到3-三氟甲基异噁唑。该方法用的1,3-二酮需要经过多步合成,步骤冗长,而且最为关键的是最后一步与羟胺关环反应同样存在区域选择性问题,大大降低了合成效率。(J.C.Sloop et al,Journal of Fluorine Chemistry 2002,118,135-147)
(3)2016年,Y.Wu和D.L.Browne分别都报道了使用原味制备的三氟甲基腈氧化合物与炔烃来合成三氟甲基异噁唑。使用三氟甲基取代的半缩醛为三氟甲基源,然后与盐酸羟胺缩合得到三氟甲基取代的肟。之后,在NCS或者NBS氧化条件下将肟转化成氯代或溴代肟,并在碱性条件下原味生成三氟甲基腈氧化物。最后原位生成的腈氧化物与炔烃发生[3+2]环加成反应得到三氟甲基异噁唑。同样,该合成方法存在步骤冗长,不经济,合成效率低等缺陷。(D.L.Browne et al,Org.Biomol.Chem.2016,5983-5991,Y.Wu et al,Synlett.2016,2259-2263)
尽管有这么多条合成路线来合成3-三氟甲基异噁唑,但是反应步骤普遍冗长,直接导致合成效率低下。到目前为止,还没有文献报道一类高效、快捷的合成方法。
发明内容
针对现有的3-三氟甲基异噁唑的合成过程中所用存在的一些问题,如反应步骤冗长、原料利用率低、反应条件苛刻等缺点,本发明的目的是在于提供一种高效的、原料易得、反应条件温和、产物收率高、副产物少的3-三氟甲基异噁唑类杂环化合物的合成方法,该方法设计合成具有全新结构的3-三氟甲基异噁唑,为药物筛选和新药合成提供原料来源。
本发明采用以下技术方案:
一种一锅法制备3-三氟甲基取代的异噁唑化合物的方法,将式I的末端炔烃类化合物溶于氯仿中,再加入2,2,2-三氟乙胺与亚硝酸叔丁酯和醋酸,加入碘化亚铜和溴化锌试剂,并在氮气保护下于室温下搅拌24小时。到了反应时间之后直接将溶剂通过减压蒸馏除去,利用快速柱层析法即可得到3-三氟甲基取代的异噁唑化合物。
其中,克量级的3-三氟甲基取代的异噁唑化合物的制备方法是将式I的末端炔烃类化合物溶于氯仿中,再加入2,2,2-三氟乙胺、醋酸,加入碘化亚铜和溴化锌试剂,并在氮气保护下先于冰水浴下搅拌十五分钟充分溶解。再在此条件下缓慢加入亚硝酸叔丁酯,此时可以看到溴化锌被溶解并且溶液变成亮绿色,然后将体系转移到室温下搅拌。反应24小时之后用硅藻土抽滤,并用二氯甲烷洗涤滤渣,滤液用硫代硫酸钠溶液洗涤,分液得到有机相,有机相用无水硫酸镁干燥,随后直接将溶剂通过减压蒸馏除去,利用快速柱层析法即可得到克量级3-三氟甲基取代的异噁唑化合物。
式I和式II中,R独立选自芳基或烷基。
优选的方案,式I和式II中R基为独立自选的苯基、联苯基、4-甲苯基、4-戊基苯基、4-甲氧基苯基、4-氯苯基、4-溴苯基、4-氟苯基、4-三氟甲基苯基、4-氰基苯基、4-硝基苯基、4-甲酸甲酯基、4-苯乙酮基、4-甲基苯硫醚基、4-甲基亚磺酰基苯基、4-甲基磺酰基苯基、2-甲氧基苯基、2-氯苯基、2-丙烯基甲酸酯基苯基、3-硝基苯基、3-氟苯基、3-羟基苯基、3-(叔丁基二苯基硅烷基)氧基苯基、3-氨基甲酸苄酯基苯基、3-氨基甲酸叔丁酯基苯基、3-氨基乙酰基苯基、3-氨基苯甲酰基苯基、3-氨基-(2,2-苄氧基)基苯基、2-氟-3-甲氧基苯基、2-甲氧基-3-氟苯基、β萘基、噻吩、呋喃、吡啶、1H-吲哚-1-甲酸乙酯基、苯乙烯基、乙基、乙基4-甲氧基苯甲酸酯基、4-硝基苯甲酸乙酯、甲酸乙酯基、N-苯基甲酰胺基。
优选的方案,式I末端炔烃类化合物与三氟乙胺的摩尔比为1:1~10;式I所示的末端炔烃类化合物与亚硝酸叔丁酯的摩尔比为1:1~10;式I末端炔烃类化合物与醋酸的摩尔比为1:0.2~5;式I末端炔烃类化合物与碘化亚铜的摩尔比为1:0.05~1;式I末端炔烃类化合物与溴化锌的摩尔比为1:1~10;反应时间为12-48小时;反应条件为室温。
相对现有技术,本发明的技术方案带来以下技术优势:
(1)本发明制备3-三氟甲基取代的异噁唑化合物的过程操作简单、条件温和,整个反应过程可以在常温及空气条件下进行。
(2)本发明制备3-三氟甲基取代的异噁唑化合物采用的已经商业化的原料三氟乙胺和末端炔烃,可以采用现有的成熟工艺简单合成,且安全性高,避免了复杂原料的制备过程。
(3)本发明制备3-三氟甲基取代的异噁唑化合物过程中无需采用昂贵的金属催化剂,降低了生产成本,有利于环保。
(4)本发明制备3-三氟甲基取代的异噁唑化合物的方法具有副反应少,收率高的特点,收率达到58~93%。
(5)本发明制备3-三氟甲基取代的异噁唑化合物的方法不受底物局限,以便建立芳香类3-三氟甲基取代的异噁唑库,为药物筛选和新药合成提供原料来源。
附图说明
图1为实施例3产物的单晶结构图。
具体实施方式
下列实施例旨在进一步说明本发明内容,而不是限制本发明权利要求的保护范围。
按照以下合成方法:
将末端炔烃类化合物底物(0.25mmol,1equiv)溶于氯仿中,再加入2,2,2-三氟乙胺(0.75mmol,3equiv)与亚硝酸叔丁酯(0.75mmol,3equiv)和醋酸(0.1mmol,0.4equiv),加入碘化亚铜(0.025mmol,0.1equiv)和溴化锌试剂(0.5mmol,2equiv),并在氮气保护下于室温下搅拌24小时。到了反应时间之后直接将溶剂通过减压蒸馏除去,利用快速柱层析法即可得到产物3-三氟甲基取代的异噁唑化合物。
实施例1~41根据以上方法,只需改变末端炔烃类化合物底物的种类,就可以制备如下式1~41所示的3-三氟甲基取代的异噁唑化合物:
实施例1:
底物:4-苯基苯乙炔
产物表征数据:pale yellow solid(60.7mg,84%yield);mp:128.5–129.5;1HNMR(400MHz,CDCl3)δ7.88(d,J=8.0Hz,2H),7.73(d,J=8.0Hz,2H),7.64(d,J=8.0Hz,2H),7.49(t,J=8.0Hz,2H),7.42(d,J=8.0Hz,1H),6.77(s,1H);13C NMR(100MHz,CDCl3)δ172.5,156.4(q,J=38.0Hz),144.4,140.0,129.4,128.6,128.2,127.4,126.8,125.2,120.1(q,J=270.0Hz),97.1;19F NMR(376MHz,CDCl3)δ-63.19(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.19(s,3F);HRMS(ESI)m/z calcd for C16H11ONF3 +[M+H]+290.0787,found290.0784.
实施例2:
底物:苯乙炔
产物表征数据:pale yellow solid(46.7mg,88%yield);mp:44.4–45.2;1H NMR(400MHz,CDCl3)δ7.83–7.78(m,2H),7.53–7.50(m,3H),6.74(s,1H);13C NMR(100MHz,CDCl3)δ172.8,156.4(q,J=38.0Hz),131.6,129.6,126.4,120.1(q,J=270Hz),97.1;19FNMR(376MHz,CDCl3)δ-63.27(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.27(s,3F);HRMS(ESI)m/zcalcd for C10H7ONF3 +[M+H]+214.0474,found 214.0471.
实施例3:
底物:4-甲基苯乙炔
产物表征数据:white solid(49.6mg,87%yield);mp:71.6–72.3;1H NMR(400MHz,CDCl3)δ7.69(d,J=8.0Hz,2H),7.30(d,J=8.0Hz,2H),6.68(s,1H),2.42(s,3H);13C NMR(100MHz,CDCl3)δ173.0,156.3(q,J=38.0Hz),142.2,130.3,126.3,123.8,120.1(q,J=270.0Hz),96.5,21.8;19F NMR(376MHz,CDCl3)δ-63.30(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.30(s,3F);HRMS(ESI)m/z calcd for C11H9ONF3 +[M+H]+228.0631,found228.0628.[13]
实施例4:
底物:4-正戊基苯乙炔
产物表征数据:colorless oil(61.2mg,86%yield);1H NMR(400MHz,CDCl3)δ7.71(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),6.68(s,1H),2.67(t,J=8.0Hz,2H),1.69–1.63(m,2H),1.36–1.33(m,4H),0.91(t,J=6.8Hz,3H);13C NMR(100MHz,CDCl3)δ173.0,156.3(q,J=38.0Hz),147.2,129.6,126.4,123.9,120.1(q,J=270.0Hz),96.5,36.2,31.8,31.2,22.8,14.3;19FNMR(376MHz,CDCl3)δ-63.29(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.29(s,3F);HRMS(ESI)m/z calcd for C15H17ONF3 +[M+H]+284.1257,found 284.1254.
实施例5:
底物:4-甲氧基苯乙炔
产物表征数据:yellow solid(49.4mg,81%yield);mp:82.5–83.3;1H NMR(400MHz,CDCl3)δ7.74(d,J=8.0Hz,2H),7.00(d,J=8.0Hz,2H),6.61(s,1H),3.88(s,3H);13C NMR(100MHz,CDCl3)δ172.8,162.3,156.3(q,J=38.0Hz),128.1,120.1(q,J=270.0Hz),119.2,115.0,95.7,55.8;19F NMR(376MHz,CDCl3)δ-63.30(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.30(s,3F);HRMS(ESI)m/z calcd for C11H9O2NF3 +[M+H]+244.0580,found 244.0579.
实施例6:
底物:4-氯苯乙炔
产物表征数据:white crystalline solid(56.2mg,91%yield);mp:97.4–97.7;1H NMR(400MHz,CDCl3)δ7.74(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),6.74(s,1H);13CNMR(100MHz,CDCl3)δ171.7,156.5(q,J=38.0Hz),137.9,130.0,127.6,124.9,120.0(q,J=270.0Hz),97.4;19F NMR(376MHz,CDCl3)δ-63.28(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.28(s,3F);HRMS(ESI)m/z calcd for C10H6ONClF3 +[M+H]+248.0085,found 248.0082.
实施例7:
底物:4-溴苯乙炔
产物表征数据:white crystalline solid(62.9mg,86%yield);mp:107.2–108.3;1H NMR(400MHz,CDCl3)δ7.68–7.63(m,4H),6.75(s,1H);13C NMR(100MHz,CDCl3)δ171.7,156.5(q,J=38.0Hz),132.9,127.8,126.2,125.3,119.9(q,J=270.0Hz),97.5;19FNMR(376MHz,CDCl3)δ-63.26(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.26(s,3F);HRMS(ESI)m/z calcd for C10H6ONBrF3 +[M+H]+291.9579,found 291.9576.
实施例8:
底物:4-氟苯乙炔
产物表征数据:white solid(53.6mg,93%yield);mp:59.4–60.4;1H NMR(400MHz,CDCl3)δ7.83–7.78(m,2H),7.23–7.18(m,2H),6.70(s,1H);13C NMR(100MHz,CDCl3)δ171.8,164.7(d,J=252Hz),156.5(q,J=38.0Hz),128.6(d,J=9.0Hz),122.9(d,J=4.0Hz),120.0(q,J=270.0Hz),117.0(d,J=22.0Hz),96.9;19F NMR(376MHz,CDCl3)δ-63.30(s,3F),-107.38–-107.46(m,1F);19F{1H}NMR(376MHz,CDCl3)δ-63.30(s,3F),-107.42(s,1F);HRMS(ESI)m/z calcd for C10H6ONF4 +[M+H]+232.0380,found 232.0378.
实施例9:
底物:4-三氟甲基苯乙炔
产物表征数据:white crystalline solid(58.4mg,83%yield);mp:94.8–95.3;1H NMR(400MHz,CDCl3)δ7.94(d,J=8.0Hz,2H),7.78(d,J=8.0Hz,2H),6.86(s,1H);13CNMR(100MHz,CDCl3)δ171.2,156.6(q,J=38.0Hz),133.3(q,J=33.0Hz),129.5,126.8,126.7(q,J=4.0Hz),123.9(q,J=270.0Hz),119.9(q,J=270.0Hz),98.6;19F NMR(376MHz,CDCl3)δ-63.19(s,3F),-63.31(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.19(s,3F),-63.31(s,3F);HRMS(ESI)m/z calcd for C11H6ONF6 +[M+H]+282.0348,found 282.0346.
实施例10:
底物:4-氰基苯乙炔
产物表征数据:white solid(42.1mg,71%yield);mp:120.0–120.8;1H NMR(400MHz,CDCl3)δ7.93(d,J=8.0Hz,2H),7.82(d,J=8.0Hz,2H),6.90(s,1H);13C NMR(100MHz,CDCl3)δ170.5,156.6(q,J=38.0Hz),133.4,130.0,126.9,119.7(q,J=270.0Hz),118.1,115.1,99.3;19F NMR(376MHz,CDCl3)δ-63.22(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.22(s,3F);HRMS(ESI)m/z calcd for C11H6ON2F3 +[M+H]+239.0427,found239.0425.
实施例11:
底物:4-硝基苯乙炔
产物表征数据:white solid(49.2mg,76%yield);mp:126.5–127.3;1H NMR(400MHz,CDCl3)δ8.38(d,J=8.0Hz,2H),8.01(d,J=8.0Hz,2H),6.96(s,1H);13C NMR(100MHz,CDCl3)δ170.2,156.7(q,J=38.0Hz),149.5,131.7,127.3,125.0,119.7(q,J=270.0Hz),99.7;19F NMR(376MHz,CDCl3)δ-63.23(s,3F).19F{1H}NMR(376MHz,CDCl3)δ-63.23(s,3F);HRMS(ESI)m/z calcd for C16H6O3N2F3 +[M+H]+259.0325,found 259.0321.
实施例12:
底物:4-甲酸甲酯基苯乙炔
产物表征数据:white solid(57.5mg,85%yield);mp:125.6–126.8;1H NMR(400MHz,CDCl3)δ8.15(d,J=8.0Hz,2H),7.86(d,J=8.0Hz,2H),6.85(s,1H),3.95(s,3H);13C NMR(100MHz,CDCl3)δ171.6,166.3,156.5(q,J=38.0Hz),132.8,130.8,130.0,126.3,119.9(q,J=270.0Hz),98.5,52.8;19F NMR(376MHz,CDCl3)δ-63.28(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.28(s,3F);HRMS(ESI)m/z calcd for C12H9O3NF3 +[M+H]+272.0529,found272.0526.
实施例13:
底物:4-乙炔基苯乙酮
产物表征数据:white crystalline solid(48.4mg,76%yield);mp:168.1–169.3;1H NMR(400MHz,CDCl3)δ8.08(d,J=8.0Hz,2H),7.91(d,J=8.0Hz,2H),6.86(s,1H),2.65(s,3H);13C NMR(100MHz,CDCl3)δ197.3,171.5,156.5(q,J=38.0Hz),139.2,130.1,129.5,126.6,119.9(q,J=270.0Hz),98.6,27.0;19F NMR(376MHz,CDCl3)δ-63.24(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.24(s,3F);HRMS(ESI)m/z calcd for C12H9O2NF3 +[M+H]+256.0580,found 256.0577.
实施例14:
底物:4-甲基硫醚苯乙炔
产物表征数据:yellow solid(58.2mg,90%yield);mp:89.1–90.2;1H NMR(400MHz,CDCl3)δ7.68(d,J=8.0Hz,2H),7.31(d,J=8.0Hz,2H),6.68(s,1H),2.52(s,3H);13C NMR(100MHz,CDCl3)δ172.4,156.3(q,J=38.0Hz),143.9,126.6,126.3,122.6,120.0(q,J=270.0Hz),96.5,15.2;19F NMR(376MHz,CDCl3)δ-63.27(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.27(s,3F);HRMS(ESI)m/z calcd for C11H9ONF3S+[M+H]+260.0352,found260.0349.
实施例15:
底物:4-甲基亚磺酰基苯乙炔
产物表征数据:pale yellow solid(51.1mg,74%yield);mp:119.4–121.9;1HNMR(400MHz,CDCl3)δ7.96(d,J=8.0Hz,2H),7.82(d,J=8.0Hz,2H),6.87(s,1H),2.88(s,3H);13CNMR(100MHz,CDCl3)δ171.0,156.5(q,J=38.0Hz),147.2,129.1,127.3,125.3,119.8(q,J=270.0Hz),98.6,43.5;19F NMR(376MHz,CDCl3)δ-63.22(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.22(s,3F);HRMS(ESI)m/z calcd for C11H9O2NF3S+[M+H]+276.0301,found 276.0298.
实施例16:
底物:4-甲基磺酰基苯乙炔
产物表征数据:white crystalline solid(54.9mg,75%yield);mp:146.3–147.5;1H NMR(400MHz,CDCl3)δ8.09(d,J=8.0Hz,2H),8.01(d,J=8.0Hz,2H),6.93(s,1H),3.10(s,3H);13C NMR(100MHz,CDCl3)δ170.5,156.6(q,J=38.0Hz),143.1,131.0,128.8,127.2,119.8(q,J=270.0Hz),99.4,44.7;19F NMR(376MHz,CDCl3)δ-63.20(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.20(s,3F);HRMS(ESI)m/z calcd for C11H9O3NF3S+[M+H]+292.0250,found 292.0245.
实施例17:
底物:2-甲氧基苯乙炔
产物表征数据:pale yellow solid(55.8mg,92%yield);mp:41.8–43.0;1H NMR(400MHz,CDCl3)δ7.98(dd,J=1.6,8.0Hz,1H),7.49–7.44(m,1H),7.09(t,J=8.0Hz,1H),7.04(d,J=8.0Hz,1H),7.00(s,1H),3.98(s,3H);13C NMR(100MHz,CDCl3)δ168.8,156.8,156.4(q,J=38.0Hz),132.7,128.1,121.3,120.3(q,J=270.0Hz),115.5,111.7,101.0,55.9;19F NMR(376MHz,CDCl3)δ-63.25(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.25(s,3F);HRMS(ESI)m/z calcd for C11H9O2NF3 +[M+H]+244.0580,found 244.0577.
实施例18:
底物:2-氯苯乙炔
产物表征数据:colorless oil(52.8mg,85%yield);1H NMR(400MHz,CDCl3)δ7.98–7.96(m,1H),7.55–7.53(m,1H),7.45–7.42(m,2H),7.18(s,1H);13C NMR(100MHz,CDCl3)δ169.1,156.3(q,J=38.0Hz),132.4,132.2,131.4,129.8,127.8,125.3,120.0(q,J=270.0Hz),101.9;19F NMR(376MHz,CDCl3)δ-63.21(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.21(s,3F);HRMS(ESI)m/z calcd for C10H6ONClF3 +[M+H]+248.0085,found 248.0082.
实施例19:
底物:2-乙炔基-苯丙炔酸甲酯
产物表征数据:white solid(61.9mg,83%yield);mp:64.5–65.7;1H NMR(400MHz,CDCl3)δ7.92(d,J=16.0Hz,1H),7.76–7.74(m,1H),7.69–7.67(m,1H),7.56–7.50(m,2H),6.62(s,1H),6.44(d,J=16.0Hz,1H),3.81(s,3H);13C NMR(100MHz,CDCl3)δ171.2,166.8,156.1(q,J=38.0Hz),141.8,134.0,131.7,130.5,129.6,128.2,126.1,122.5,119.9(q,J=270.0Hz),101.7,52.3;19F NMR(376MHz,CDCl3)δ-63.09(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.09(s,3F);HRMS(ESI)m/z calcd for C14H11O3NF3 +[M+H]+298.0686,found 298.0684.
实施例20:
底物:3-硝基苯乙炔
产物表征数据:white solid(54.7mg,85%yield);mp:98.7–99.2;1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.37(d,J=8.0Hz,1H),8.16(d,J=8.0Hz,1H),7.76(t,J=8.0Hz,1H),6.95(s,1H);13C NMR(100MHz,CDCl3)δ170.1,156.7(q,J=38.0Hz),149.1,131.8,131.0,127.8,126.0,121.4,119.7(q,J=270.0Hz),99.0;19F NMR(376MHz,CDCl3)δ-63.26(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.26(s,3F);HRMS(ESI)m/z calcd forC16H6O3N2F3 +[M+H]+259.0325,found 259.0322.
实施例21:
底物:3-氟苯乙炔
产物表征数据:white solid(48.5mg,84%yield);mp:47.2–47.7;1H NMR(400MHz,CDCl3)δ7.60–7.58(m,1H),7.52–7.47(m,2H),7.24–7.19(m,1H),6.77(s,1H);13CNMR(100MHz,CDCl3)δ171.4(d,J=3.0Hz),163.3(d,J=247.0Hz),156.5(q,J=38.0Hz),131.5(d,J=8.0Hz),128.2(d,J=9.0Hz),122.2(d,J=4.0Hz),119.9(q,J=270.0Hz),118.6(d,J=21.0Hz),113.4(d,J=24.0Hz),97.9;19F NMR(376MHz,CDCl3)δ-63.31(s,3F),-110.81–-110.87(m,1F);19F{1H}NMR(376MHz,CDCl3)δ-63.31(s,3F),-110.84(s,1F);HRMS(ESI)m/zcalcd for C10H6ONF4 +[M+H]+232.0380,found 232.0378.
实施例22:
底物:3-羟基苯乙炔
产物表征数据:white solid(42.8mg,75%yield);mp:115.4–116.5;1H NMR(400MHz,CDCl3)δ7.48(t,J=2.0Hz,1H),7.40–7.32(m,2H),7.04–7.01(m,1H),6.75(s,1H),6.31(s,1H);13C NMR(100MHz,CDCl3)δ172.7,157.0,156.4(q,J=38.0Hz),131.1,127.4,119.9(q,J=270.0Hz),119.2,118.8,113.0,97.5;19F NMR(376MHz,CDCl3)δ-63.31(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.31(s,3F);HRMS(ESI)m/z calcd for C10H7O2NF3 +[M+H]+230.0423,found 230.0423.
实施例23:
底物:3-(叔丁基二苯基硅烷基)氧基苯乙炔
产物表征数据:bright yellow oil(112.0mg,96%yield);1H NMR(400MHz,CDCl3)δ7.64–7.62(m,4H),7.33–7.31(m,2H),7.29–7.26(m,4H),7.19–7.17(m,1H),7.09–7.04(m,2H),6.76–6.73(m,1H),6.37(s,1H),1.04(s,9H);13C NMR(100MHz,CDCl3)δ172.5,156.6,156.2(q,J=38.0Hz),135.9,132.7,130.5,130.5,128.3,127.4,123.0,120.0(q,J=270.0Hz),119.1,117.7,97.2(q,J=1.0Hz),26.9,19.8;19F NMR(376MHz,CDCl3)δ-63.24(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.24(s,3F);HRMS(ESI)m/z calcd forC26H25O2NF3Si+[M+H]+468.1601,found 468.1597.
实施例24:
底物:3-氨基甲酸苄酯基苯乙炔
产物表征数据:white solid(83.2mg,92%yield);mp:137.3–137.9;1H NMR(400MHz,CDCl3)δ7.94(s,1H),7.49–7.47(m,2H),7.45–7.35(m,6H),7.05(s,1H),6.71(s,1H),5.23(s,2H);13C NMR(100MHz,CDCl3)δ172.3,156.3(q,J=38.0Hz),153.6,139.2,136.1,130.3,129.0,128.8,128.7,127.1,121.5,121.2,120.0(q,J=270.0Hz),116.3,97.5,67.7;19F NMR(376MHz,CDCl3)δ-63.22(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.22(s,3F);HRMS(ESI)m/z calcd for C18H14O3N2F3 +[M+H]+363.0951,found 363.0947.
实施例25:
底物:3-氨基甲酸叔丁酯基苯乙炔
产物表征数据:white crystalline solid(67.2mg,82%yield);mp:153.8–154.6;1H NMR(400MHz,CDCl3)δ7.97(s,1H),7.47–7.45(m,1H),7.40–7.39(m,2H),6.77(s,1H),6.75(s,1H),1.53(s,9H);13C NMR(100MHz,CDCl3)δ172.6,156.3(q,J=38.0Hz),152.9,139.8,130.2,127.1,121.3,120.8,120.0(q,J=270.0Hz),116.0,97.5,81.5,28.6;19F NMR(376MHz,CDCl3)δ-63.27(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.27(s,3F);HRMS(ESI)m/z calcd for C15H16O3N2F3 +[M+H]+329.1108,found 329.1103.
实施例26:
底物:3-氨基乙酰基苯乙炔
产物表征数据:white crystalline solid(54.3mg,80%yield);mp:174.4–175.8;1H NMR(400MHz,acetone-d6)δ9.47(s,1H),8.34(s,1H),7.78–7.76(m,1H),7.65–7.63(m,1H),7.50(t,J=8.0Hz,1H),7.33(s,1H),2.14(s,3H);13C NMR(100MHz,acetone-d6)δ173.6,169.4,156.7(q,J=38.0Hz),141.4,130.7,127.3,122.6,121.7,120.9(q,J=269.0Hz),117.1,98.4,24.3;19F NMR(376MHz,acetone-d6)δ-64.06(s,3F);19F{1H}NMR(376MHz,acetone-d6)δ-64.06(s,3F);HRMS(ESI)m/z calcd for C12H10O2N2F3 +[M+H]+271.0689,found 271.0687.
实施例27:
底物:3-氨基苯甲酰基苯乙炔
产物表征数据:white crystalline solid(64.9mg,78%yield);mp:195.6–196.3;1H NMR(400MHz,acetone-d6)δ9.78(s,1H),8.52(s,1H),8.05–8.02(m,3H),8.71–7.69(m,1H),7.61–7.50(m,4H),7.35(s,1H);13C NMR(100MHz,acetone-d6)δ173.6,166.7,156.8(q,J=38.0Hz),141.4,135.9,132.7,130.8,129.4,128.5,127.4,123.8,123.7,122.3,121.0(q,J=270.0Hz),118.3,118.2,98.5;19F NMR(376MHz,acetone-d6)δ-64.00(s,3F);19F{1H}NMR(376MHz,acetone-d6)δ-64.00(s,3F);HRMS(ESI)m/z calcd forC17H12O2N2F3 +[M+H]+333.0845,found 333.0844.
实施例28:
底物:3-氨基-(2,2-苄氧基)基苯乙炔
产物表征数据:yellow solid(78.4mg,77%yield);mp:104.8–106.8;1H NMR(400MHz,CDCl3)δ7.25–7.21(m,4H),7.17–7.11(m,8H),7.06–7.05(m,1H),6.97(d,J=8.0Hz,1H),6.74(dd,J=2.4,8.4Hz,1H),6.44(s,1H),4.60(s,4H);13C NMR(100MHz,CDCl3)δ173.5,156.1(q,J=38.0Hz),149.9,138.1,130.5,129.2,127.5,127.2,126.9,120.1(q,J=270.0Hz),115.6,114.8,109.7,97.0,54.7;19F NMR(376MHz,CDCl3)δ-63.15(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.15(s,3F);HRMS(ESI)m/z calcd for C24H20ON2F3 +[M+H]+409.1522,found 409.1520.
实施例29:
底物:2-氟-3-甲氧基苯乙炔
产物表征数据:pale yellow solid(56.7mg,87%yield);mp:116.5–117.1;1HNMR(400MHz,CDCl3)δ7.55(dd,J=3.2,8.8Hz,1H),7.50(dd,J=2.0,11.2Hz,1H),7.18(t,J=8.8Hz,1H),6.63(s,1H),3.95(s,3H);13C NMR(100MHz,CDCl3)δ171.6(d,J=2.5Hz),156.4(q,J=38.0Hz),152.7(d,J=247.0Hz),150.6(d,J=11.0Hz),123.0(d,J=3.0Hz),120.0(q,J=269.0Hz),119.3(d,J=7.0Hz),114.2(d,J=21.0Hz),114.0(d,J=3.0Hz),96.5(d,J=1.0Hz),56.6;19F NMR(376MHz,CDCl3)δ-63.36(s,3F),-133.09–-133.14(m,1F);19F{1H}NMR(376MHz,CDCl3)δ-63.36(s,3F),-133.12(s,1F);HRMS(ESI)m/z calcd forC11H8O2NF4 +[M+H]+262.0486,found 262.0482.
实施例30:
底物:2-甲氧基-3-氟基苯乙炔
产物表征数据:white solid(59.3mg,91%yield);mp:95.9–97.0;1H NMR(400MHz,CDCl3)δ7.39(dd,J=2.0,7.6Hz,1H),7.33(dq,J=2.0,8.4Hz,1H),7.18(dd,J=8.4,10.8Hz,1H),6.69(s,1H),3.96(s,3H);13C NMR(100MHz,CDCl3)δ171.9(d,J=1.4Hz),156.4(q,J=38.0Hz),154.5(d,J=251Hz),148.8(d,J=11Hz),123.0(d,J=4.0Hz),120.0(q,J=270.0Hz),119.6(d,J=7.0Hz),117.3(d,J=19.0Hz),111.3(d,J=19.0Hz),97.1,56.7;19F NMR(376MHz,CDCl3)δ-63.34(s,3F),-129.35–-129.41(m,1F);19F{1H}NMR(376MHz,CDCl3)δ-63.34(s,3F),-129.38(s,1F);HRMS(ESI)m/z calcd for C11H8O2NF4 +[M+H]+262.0486,found 262.0482.
实施例31:
底物:β-萘苯乙炔
产物表征数据:white solid(53.5mg,81%yield);mp:96.9–97.5;1H NMR(400MHz,CDCl3)δ8.31(s,1H),7.95–7.91(m,2H),7.89-7.86(m,1H),7.79(dd,J=2.0,8.4Hz,1H),7.59–7.57(m,2H),6.83(s,1H);13C NMR(100MHz,CDCl3)δ172.8,156.4(q,J=38.0Hz),134.7,133.2,129.6,129.1,128.3,128.3,127.6,126.6,123.6,122.8,120.1(q,J=270.0Hz),97.4;19F NMR(376MHz,CDCl3)δ-63.19(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.19(s,3F);HRMS(ESI)m/z calcd for C14H9ONF3 +[M+H]+264.0631,found 264.0629.
实施例32:
底物:2-噻吩苯乙炔
产物表征数据:brown oil(38.2mg,70%yield);1H NMR(400MHz,CDCl3)δ7.60(dd,J=1.2,3.6Hz,1H),7.54(dd,J=1.2,4.2Hz,1H),7.17(dd,J=3.6,4.8Hz,1H),6.60(s,1H);13CNMR(100MHz,CDCl3)δ167.7,156.3(q,J=38.0Hz),129.8,128.7,128.7,128.0,119.9(q,J=270.0Hz),96.7;19F NMR(376MHz,CDCl3)δ-63.27(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.27(s,3F);HRMS(ESI)m/z calcd for C8H5ONSF3 +[M+H]+220.0039,found220.0040.
实施例33:
底物:2-呋喃苯乙炔
产物表征数据:pale brown oil(38.4mg,76%yield);1H NMR(400MHz,CDCl3)δ7.60–7.59(m,1H),7.02(d,J=4.0Hz,1H),6.65(s,1H),6.58(dd,J=1.6,3.6Hz,1H);13CNMR(100MHz,CDCl3)δ164.2,156.1(q,J=38.0Hz),145.5,142.3,119.9(q,J=270.0Hz),112.6,112.4,96.6;19F NMR(376MHz,CDCl3)δ-63.23(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.23(s,3F);HRMS(ESI)m/z calcd for C8H5NO2F3 +[M+H]+204.0267,found 204.0261.
实施例34:
底物:3-吡啶苯乙炔
产物表征数据:yellow solid(33.5mg,63%yield);mp:64.1–65.9;1H NMR(400MHz,CDCl3)δ9.06(s,1H),8.76(d,J=4.0Hz,1H),8.13(dt,J=2.0,8.0Hz,1H),7.48(dd,J=4.8,8.0Hz,1H),6.86(s,1H);13C NMR(100MHz,CDCl3)δ170.1,156.6(q,J=38.0Hz),152.4,147.5,133.5,124.3,122.8,119.9(q,J=269.0Hz),98.2;19F NMR(376MHz,CDCl3)δ-63.20(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.20(s,3F);HRMS(ESI)m/z calcdfor C9H6ON2F3 +[M+H]+215.0427,found 215.0426.
实施例35:
底物:3-乙烯基-1H-吲哚-1-甲酸乙酯
产物表征数据:yellow solid(68.3mg,84%yield);mp:126.1–127.2;1H NMR(400MHz,CDCl3)δ8.23(d,J=8.0Hz,1H),8.13(s,1H),7.86(t,J=8.0Hz,1H),7.45–7.36(m,2H),6.73(s,1H),4.55(q,J=8.0Hz,2H),1.52(t,J=8.0Hz,3H);13C NMR(100MHz,CDCl3)δ167.7,154.1(q,J=38Hz),150.6,135.8,126.2,126.0,124.6,120.4,120.1(q,J=270Hz),115.9,108.7,97.2,64.5,14.6;19F NMR(376MHz,CDCl3)δ-63.13(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.13(s,3F);HRMS(ESI)m/z calcd for C15H12O3N2F3 +[M+H]+325.0795,found 325.0794.
实施例36:
底物:苯乙烯基乙炔
产物表征数据:yellow solid(43.5mg,73%yield);mp:80.8–82.0;1H NMR(400MHz,CDCl3)δ7.55–7.53(m,2H),7.46–7.38(m,4H),6.98(d,J=16Hz,1H),6.49(s,1H);13CNMR(100MHz,CDCl3)δ171.3,156.1(q,J=38.0Hz),137.5,135.2,130.2,129.4,127.7,120.0(q,J=270.0Hz),112.1,98.6;19F NMR(376MHz,CDCl3)δ-63.28(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.28(s,3F);HRMS(ESI)m/z calcd for C12H9ONF3 +[M+H]+240.0631,found 240.0628.
实施例37:
底物:正戊基-1-炔
产物表征数据:colorless oil(30.4mg,55%yield);1H NMR(400MHz,CDCl3)δ6.23(s,1H),2.81(t,J=7.8Hz,2H),1.76–1.68(m,2H),1.38–1.30(m,6H),0.89(t,J=6.8Hz,3H);13C NMR(100MHz,CDCl3)δ176.9,155.7(q,J=38Hz),120.2(t,J=270Hz),98.7,31.7,29.0,27.6,27.1,22.8,14.3;19F NMR(376MHz,CDCl3)δ-63.31(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.31(s,3F);HRMS(ESI)m/z calcd for C10H15ONF3 +[M+H]+222.1100,found222.1101.
实施例38:
底物:丁-3-炔-1-基4-甲氧基苯甲酸甲酯
产物表征数据:colorless oli(78.9mg,63%yield);1H NMR(400MHz,CDCl3)δ7.96–7.93(m,2H),6.93–6.90(m,2H),6.39(s,1H),4.60(t,J=6.3Hz,2H),3.85(s,3H),3.31(t,J=6.3Hz,2H);13C NMR(100MHz,CDCl3)δ172.9,166.2,164.1,155.9(q,J=38.0Hz),132.0,122.1,120.0(t,J=271.0Hz),114.1,100.1,61.2,55.8,27.1;19F NMR(376MHz,CDCl3)δ-63.26(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.26(s,3F);HRMS(ESI)m/zcalcd for C14H13O4NF3 +[M+H]+316.0791,found 316.0793.
实施例39:
底物:丁-3-炔-1-基4-硝基苯甲酸甲酯
产物表征数据:pale yellow solid(54.4mg,66%yield);mp:55.2–56.9;1H NMR(400MHz,CDCl3)δ8.29–8.26(m,2H),8.18–8.15(m,2H),6.42(s,1H),4.70(t,J=6.3Hz,2H),3.37(t,J=6.3Hz,2H);13C NMR(100MHz,CDCl3)δ172.3,164.6,155.9(q,J=38.0Hz),151.1,135.1,131.1,124.0,119.9(q,J=270.0Hz),100.2,62.4,27.0;19F NMR(376MHz,CDCl3)δ-63.27(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.27(s,3F);HRMS(ESI)m/z calcdfor C13H13O5N3F3 +[M+NH4]+348.0802,found 348.0796.
实施例40:
底物:丙炔酸乙酯
产物表征数据:colorless oil(27.8mg,53%yield);1H NMR(400MHz,CDCl3)δ7.15(s,1H),4.47(q,J=7.2Hz,2H),1.43(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ163.0,156.3(q,J=39.0Hz),155.9,119.4(q,J=271.0Hz),106.9,63.4,14.4;19F NMR(376MHz,CDCl3)δ-63.12(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.12(s,3F);HRMS(ESI)m/z calcdfor C7H7O3NF3 +[M+H]+210.0373,found 210.0372.
实施例41:
底物:N-苯基丙炔酰胺
产物表征数据:white crystalline solid(36.6mg,57%yield);mp:115.0–156.0;1H NMR(400MHz,CDCl3)δ8.32(br s,1H),7.66–7.64(m,2H),7.43–7.39(m,2H),7.26–7.21(m,2H);13C NMR(100MHz,CDCl3)δ165.9,157.0(q,J=39.0Hz),152.5,136.3,129.7,126.3,120.8,119.4(q,J=272.0Hz),105.6;19F NMR(376MHz,CDCl3)δ-63.06(s,3F);19F{1H}NMR(376MHz,CDCl3)δ-63.06(s,3F);HRMS(ESI)m/z calcd for C11H8O2N2F3 +[M+H]+257.0532,found 257.0532.
此外,我们还尝试使用了别的金属试剂体系:
对比实施例1:
将实施例1中的碘化亚铜移除,反应24小时,直接将溶剂通过减压蒸馏除去,无法得到3-三氟甲基取代的异噁唑的目标产物。
对比实施例2:
将实施例1中的溴化锌移除,反应24小时,直接将溶剂通过减压蒸馏除去,无法得到3-三氟甲基取代的异噁唑的目标产物。
对比实施例3:
将实施例1中的溴化锌试剂换成氯化铁试剂(0.5mmol,2equiv),反应24小时,无法得到3-三氟甲基取代的异噁唑的目标产物。
对比实施例4:
将实施例1中的溴化锌试剂换成氯化锌试剂(0.5mmol,2equiv),反应24小时,直接将溶剂通过减压蒸馏除去,利用快速柱层析法即可得到产物化合物1(19mg,0.07mmol,产率为28%)。
对比实施例5:
将实施例1中碘化亚铜换成醋酸铜试剂(0.1mmol,0.1equiv),反应24小时,直接将溶剂通过减压蒸馏除去,利用快速柱层析法即可得到产物化合物1(19mg,0.07mmol,产率为28%)。
Claims (9)
2.根据权利要求1所述的方法,其特征在于:如式I所示的末端炔烃类化合物与2,2,2-三氟乙胺的摩尔比为1:1~10。
3.根据权利要求1所述的方法,其特征在于:如式I所示的末端炔烃类化合物与亚硝酸叔丁酯的摩尔比为1:1~10。
4.根据权利要求1所述的方法,其特征在于:如式I所示的末端炔烃类化合物与醋酸的摩尔比为1:0.2~5。
5.根据权利要求1所述的方法,其特征在于:如式I所示的末端炔烃类化合物与碘化亚铜的摩尔比为1:0.05~1。
6.根据权利要求1所述的方法,其特征在于:如式I所示的末端炔烃类化合物与溴化锌的摩尔比为1:1~10。
7.根据权利要求1所述的方法,其特征在于:反应时间为12~48小时。
8.根据权利要求1所述的方法,其特征在于:反应温度为室温。
9.根据权利要求1所述的方法,其特征在于:有机溶剂为氯仿。
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