CN115536505A - 铜催化末端炔烃的区域选择性碘化甲酰化生成(E)-β-碘代-α,β-不饱和醛 - Google Patents
铜催化末端炔烃的区域选择性碘化甲酰化生成(E)-β-碘代-α,β-不饱和醛 Download PDFInfo
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- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
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- 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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- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—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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- C07D223/22—Dibenz [b, f] azepines; Hydrogenated dibenz [b, f] azepines
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- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/20—[b, e]-condensed with two six-membered rings with hydrogen atoms directly attached to the ring nitrogen atom
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- 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
- C07D333/26—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D333/76—Dibenzothiophenes
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- C07C2603/58—Ring systems containing bridged rings containing three rings
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Abstract
本发明目的在于提供一种以廉价铜为催化剂制备(E)‑β‑碘代‑α,β‑不饱和醛骨架的高效、简便的方法。反应对各种末端炔烃表现出耐受性,相应产物具有较高的化学选择性和区域选择性,且反应条件温和。该催化方案具有原料广泛、无贵金属和有害副产品等优点。同时,成功的将这些产品进行了相关转化,展现了其实用价值。
Description
【技术领域】
本发明涉及一种通过铜催化的末端炔烃与TMSCF3和NaI的碘甲酰化反应,以及通过使用廉价的CuI催化剂,合成具有多反应位点的(E)-β-碘代-α,β-不饱和醛,其中包含α-E-烯醛和β-Z-乙烯基碘结构单元,该方案不仅不需要复杂的配体和敏感的有机金属试剂,还表现出令人印象深刻的官能团耐受性和底物范围:芳基和烷基炔,以及含有末端炔烃的各种生物活性分子,都能够顺利地以高产率高选择性提供所需的双亲电(E)-β-碘代-α,β-不饱和醛产物。同时实现了它的多种转化途径,实现了其应用价值。
【背景技术】
化学反应中具有亲电性的化学试剂在化学和生物学科中占据着核心的地位。因此,将廉价的化学原料直接转化为多功能的碳亲电试剂是十分可取的,特别是碘代不饱和醛。开发催化反应,将炔烃转化为(E)-β-碘代-α,β-不饱和醛,是制备农药、药物、生物活性分子和精细化学品的基础,具有重要意义。其次,(E)-β-碘代-α,β-不饱和醛具有多个反应位点,醛基可作为酯基、酰胺、酮、羧酸等基团的前体;碘可以轻易的发生交叉偶联、加成、还原等反应;烯烃同样可以轻易的发生转化。因此如何高效的合成此类化合物一直是科学家们努力的方向。据我们所知,目前仍然没有直接的简单的合成方法从炔烃中构建(E)-β-碘代-α,β-不饱和醛类化合物。在已开发出两条合成途径中需要多步反应来构建目标产物,比如:从丙二酸二乙酯开始,经过多达四个步骤,包括烷基化、Krapcho脱羧、还原和氧化等。通过这些方法获得的目标产物的官能团和结构多样性受到了严重的限制,底物的容忍性更不能保证。因此,开发末端炔烃的直接、区域选择性和立体选择性碘甲酰化以获得碘代不饱和醛是非常可取和迫切的。在此,我们展示了通过铜催化的末端炔烃与TMSCF3和NaI的碘甲酰化反应,本方案使用廉价的CuI催化剂,合成具有多反应位点的(E)-β-碘代-α,β-不饱和醛,其中包含α-E-烯醛和β-Z-乙烯基碘结构单元,该方案不仅不需要复杂的配体和敏感的贵金属试剂,还表现出令人印象深刻的官能团耐受性和底物范围:芳基和烷基炔,以及含有末端炔烃的各种生物活性分子,都能够顺利地以高产率高选择性提供所需的双亲电(E)-β-碘代-α,β-不饱和醛产物。同时实现了它的多种应用转化途径。目前,国内外还没有方法合成(E)-β-碘代-α,β-不饱和醛类化合物的公开文献和专利申请。
【发明内容】
本发明开发了一种以廉价铜为催化剂制备(E)-β-碘代-α,β-不饱和醛骨架的高效、简便的方法。反应对各种末端炔烃表现出耐受性,相应产物具有较高的化学选择性和区域选择性,且反应条件温和。该催化方案具有原料广泛、无贵金属和有害副产品等优点。并且,这些产品构成了多功能的亲电试剂,在有机合成和化学生物学中都有应用。
其中所述R1为芳香性基团(苯基等);烷烃基团(己基等)
【附图说明】
附图1所示是(E)-β-碘代-α,β-不饱和醛合成的路线图,附图2所示是(E)-β-碘代-α,β-不饱和醛合成转化的路线图,附图3所示是以(E)-2-苄基-3-碘丙烯醛作为反应底物合成消旋卡多曲药物的合成途径。
【具体实施方式】
其中所述R1为苯环取代基(甲基、甲氧基、氯等);烷烃基团(己基、戊等)
实例1:
向装有磁力搅拌的10mL Schlenk管中添加苯乙炔(0.30mmol,1.0当量)、CuI(0.03mmol, 0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
通过柱色谱法分离纯化(石油醚/乙酸乙酯=250:1),得到标题化合物,为黄色固体。收率:65.2mg,84%。1H NMR(400MHz,CDCl3)δ9.70(s,1H),8.12(s,1H),7.46–7.41(m,3H), 7.27–7.24(m,2H).13C NMR(101MHz,CDCl3)δ188.5,153.8,134.1,129.0,128.9,128.4,109.6. HRMS(ESI)m/z:[M+H]+Calcd for C9H8IO+,258.9620,Found,258.9610.
实例2:
向装有磁力搅拌的10mL Schlenk管中添加4-卤素苯乙炔(卤素=氟、氯、溴)(0.30mmol, 1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例3:
向装有磁力搅拌的10mL Schlenk管中添加甲氧基苯乙炔(甲氧基位置=对位、间位、邻位) (0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例4:
向装有磁力搅拌的10mL Schlenk管中添加4-烷基苯乙炔(烷基=甲基、乙基、正丁基、正己基、正庚基)(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol, 2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β- 碘代-α,β-不饱和醛。
实例5:
向装有磁力搅拌的10mL Schlenk管中添加1-萘乙炔(卤素=氟、氯、溴)(0.30mmol,1.0 当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例6:
向装有磁力搅拌的10mL Schlenk管中添加4-卤素苯乙炔(卤素=氟、氯、溴)(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例7:
向装有磁力搅拌的10mL Schlenk管中添加3-苯-1-丙炔(0.30mmol,1.0当量)、CuI(0.03mmol, 0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例8:
向装有磁力搅拌的10mL Schlenk管中添加4-苯基-1-丁炔(0.30mmol,1.0当量)、CuI(0.03 mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol, 2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例9:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-二苯氨基甲酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例10:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-4-氰基苯甲酸庚酯(0.30mmol,1.0 当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例11:
向装有磁力搅拌的10mL Schlenk管中添加1-戊炔、1-庚炔、1-辛炔、1-葵炔(0.30mmol,1.0 当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例12:
向装有磁力搅拌的10mL Schlenk管中添加3-甲基-1-丁炔(0.30mmol,1.0当量)、CuI(0.03 mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol, 2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例13:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-1-金刚甲烷酯(0.30mmol,1.0当量)、 CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3, 0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时 (恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例14:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-1-金刚乙烷酯(0.30mmol,1.0当量)、 CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3, 0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时 (恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例15:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-4-氯丁酸庚酯、6-庚-1-炔基-5-氯戊酸庚酯、6-庚-1-炔基-6-氯己酸庚酯、6-庚-1-炔基-7-氯庚酸庚酯(0.30mmol,1.0当量)、CuI (0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3, 0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时 (恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例16:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-十一碳-10-烯酸酯(0.30mmol,1.0 当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例17:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-1-基油酸酯(0.30mmol,1.0当量)、 CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3, 0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时 (恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例18:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-呋喃-2-羧酸酯、6-庚-1-炔基-噻吩-2- 羧酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol, 2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β- 碘代-α,β-不饱和醛。
实例19:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-苯并噻吩-2-羧酸酯(0.30mmol,1.0 当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例20:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-10H-吩噻嗪-10-羧酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例21:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-吡啶-2-羧酸酯(0.30mmol,1.0当量)、 CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3, 0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时 (恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例22:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-10,11-二氢-5H-二苯并[b,f]氮平-5-羧酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0 当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β- 不饱和醛。
实例23:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-5H-二苯并[b,f]氮杂-5-羧酸酯(0.30 mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例24:
向装有磁力搅拌的10mL Schlenk管中添加庚烷-1-羧酸6-庚基-1-炔基(1S,4R)-7,7-二甲基 -3-氧代-2-氧杂环[2.2.1]庚烷(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠 (NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0 mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水 (0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例25:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-2-(10-氧代-10,11-二氢二苯并[b,f] 噻吩-2-基)丙酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI, 0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例26:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-2-(11-氧基-6,11-二氢二苯并[b,e]奥克平-3-基)乙酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI, 0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例27:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-4-(N,N-二丙基氨磺酰)苯甲酸酯 (0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例28:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-((1S,2R,5S)-2-异丙基-5-甲基环己基)羧酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol, 1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β- 碘代-α,β-不饱和醛。
实例29:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-(R)-2-(4-异丁基苯基)丙酸酯(0.30 mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例30:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-3-(4,5-二苯基恶唑-2-基)丙酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β- 不饱和醛。
实例31:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-基)乙酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例32:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-6-(3-(3r,5r,7r)-金刚烷-1- 基)-4-甲氧基苯基)-2-萘酚(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠 (NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0 mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例33:
向装有磁力搅拌的10mL Schlenk管中添加6-庚-1-炔基-((3S,8R,9S,10R,13R,14S,17R)-10,13,14-三甲基-17-((R)-6-甲基庚烷-2-基)-2,3,4,7,8,9,10,11,12,13,14,15,16,17- 十四氢-1H-环戊基菲-3-基)羧酸酯(0.30mmol,1.0当量)、CuI(0.03mmol,0.1当量)和碘化钠(NaI,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,三氟甲基三甲基硅烷(TMSCF3,0.75mmol,2.5当量),去离子水(0.45mmol,1.5当量)。该混合物在50℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛。
实例34:
向装有磁力搅拌的10mL Schlenk管中添加(E)-3-碘-2-(4-甲氧基苯基)丙烯醛(0.30mmol, 1.0当量)、苯硼酸(0.45mmol,1.5当量)、四三苯基膦钯(0.06mmol)和碳酸钠(Na2CO3, 0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂甲苯和乙醇。该混合物在70℃下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-α,β-不饱和醛。
实例35:
向装有磁力搅拌的10mL Schlenk管中添加(E)-2-苄基-3-碘丙烯醛(0.30mmol,1.0当量)、叠碳化钠(0.45mmol,1.5当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂DMF。该混合物在室温下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-叠氮-α,β-不饱和醛。
实例36:
向装有磁力搅拌的10mL Schlenk管中添加(E)-3-碘-2-(4-甲氧基苯基)丙烯醛(0.30mmol, 1.0当量)、苯乙炔(0.45mmol,1.5当量)、二三苯基膦氯化钯(0.06mmol)、CuI(0.03mmol, 0.1当量)和碳酸钠(Na2CO3,0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂三乙胺。该混合物在室温下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的β-炔-α,β-不饱和醛。
实例37:
向装有磁力搅拌的10mL Schlenk管中添加(E)-3-碘-2-(4-甲氧基苯基)丙烯醛(0.30mmol, 1.0当量)、甲醇或者苄醇(0.45mmol,1.5当量)、季铵盐(0.06mmol)、酮衍生物(0.03 mmol,0.1当量)和DBU(0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃。该混合物在室温下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的β-炔-α,β-不饱和酯类衍生物。
实例38:
向装有磁力搅拌的10mL Schlenk管中添加(E)-3-碘-2-(4-甲氧基苯基)丙烯醛(0.30mmol, 1.0当量)、酯苄胺(0.45mmol,1.5当量)、季铵盐(0.06mmol)、酮衍生物(0.03mmol, 0.1当量)和DBU(0.60mmol,2.0当量)。用泵抽真空后填充氮气,三次。然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃。该混合物在室温下搅拌12小时(恒温油浴锅)。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。随后,加入乙酸硫酸钾和乙腈在80℃反应4小时后。冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩。粗产物在硅胶上通过柱色谱分离方法,得到纯化的消旋卡多曲。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对本发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (1)
1.一种通过铜催化的末端炔烃与TMSCF3和NaI的碘甲酰化反应,其特征在于,此反应通过使用廉价的CuI催化剂,合成具有多反应位点的(E)-β-碘代-α,β-不饱和醛,其中包含α-E-烯醛和β-Z-乙烯基碘结构单元,该方案不仅不需要复杂的配体和敏感的有机金属试剂,还表现出令人印象深刻的官能团耐受性和底物范围:芳基和烷基炔,以及含有末端炔烃的各种生物活性分子,都能够顺利地以高产率高选择性提供所需的双亲电(E)-β-碘代-α,β-不饱和醛产物;合成方法如下:向装有磁力搅拌的10mL Schlenk管中添加1a 0.30mmol,1.0当量、CuI 0.03mmol,0.1当量和2b NaI,0.60mmol,2.0当量;用泵抽真空后填充氮气,三次;然后,在N2气氛下添加1.0mL超干溶剂四氢呋喃,2a TMSCF3,0.75mmol,2.5当量,去离子水0.45mmol,1.5当量;该混合物在50℃下搅拌12小时;冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩;粗产物在硅胶上通过柱色谱分离方法,得到纯化的(E)-β-碘代-α,β-不饱和醛;
其中所述R1为芳香性基团或烷烃基团;
由于双亲电(E)-β-碘代-α,β-不饱和醛是多用途的合成中间体,具有多个不同的亲电位点用于下游合成应用,开发了产品的多种合成转化,需要保护这些合成应用方案;将从烯基碘的转化、烯醛的酯、烯醛的酯化及还原和合成药物分子几个方面进行;合成方案如下:向装有磁力搅拌的10mL Schlenk管中添加30.30mmol,1.0当量、Pd(PPh3)40.006mmol、碳酸钠NaCO3,0.60mmol,2.0当量和芳基苯硼酸0.45mmol,1.5当量;用泵抽真空后填充氮气,三次;然后,在N2气氛下添加1.0mL超干溶剂甲苯和乙醇V:V=3:1;该混合物在70℃下搅拌12小时;冷却至室温后,该混合物用乙酸乙酯稀释后,加入适量水,再用乙酸乙酯萃取三次,收集有机相,并加入适量的无水Na2SO4脱水合并的有机层,在减压下浓缩,粗产物在硅胶上通过柱色谱分离方法,得到纯化的产物4;
最后,选择(E)-2-苄基-3-碘丙烯醛作为反应底物,它是合成消旋卡多曲药物的关键中间体;在此之前,构建消旋卡多曲需要多步合成;而在我们的方案中可以两步一锅法获得最终产物;合成方案如下:在氩气气氛下,向配备磁力搅拌棒的10mL Schlenk管中依次加入DBU(1.0mmol,2.0equiv.)、1,1,1,3,3,3-六氟异丙醇(HFIP,(0.75mmol,1.5equiv.)加入到1,3-二甲基***碘化物(L1,0.1mmol,20mol%)在THF(2.0mL,c=0.25M)中的溶液中;将混合物搅拌1小时,然后加入醛(0.5mmol,1.0equiv.)和3,3',5,5'-四叔丁基二苯醌(L2,0.45mmol,1.5equiv.).反应混合物在室温下搅拌6h;将2.5当量)加入反应容器中并将反应混合物在65℃搅拌12小时;减压除去溶剂;所得产物无需额外纯化即可使用;并且然后向管中加入硫代乙酸钾(AcSK,1.0mmol)、3.0mLMeCN,继续在80℃反应4h,反应完成后中和反应液通过5%HCl水溶液,然后分离水相并进一步用EtOAc萃取;合并的有机层用盐水洗涤并经Na2SO4干燥;并减压浓缩;使用石油醚和乙酸乙酯的混合溶剂***在硅胶上通过快速色谱法纯化粗产物,得到所需产物
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