2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal | 1351469-60-7

• 分子结构分类: 有机化合物 - 有机卤素化合物 - 芳基卤化物
• 英文名称: 2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal
• 英文别名: 3-Bromo-4-(2,2-dimethoxyethyl)thiophene
• CAS: 1351469-60-7
• 化学式: C₈H₁₁BrO₂S
• 分子量: 251.144
• InChiKey: AKCVEJMCCMHSHU-UHFFFAOYSA-N

物化性质

• 沸点：
  251.1±35.0 °C(Predicted)
• 密度：
  1.443±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  12
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.7
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal 在 2,2'-联吡啶 、 正丁基锂 、 对甲苯磺酸 、 silver carbonate 、 palladium dichloride 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 间二甲苯 为溶剂， 反应 39.75h， 生成 1-[4-(1-benzyl-5'-methoxy-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-yl)phenyl]ethanone
  参考文献：
  名称：

  Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor

  摘要：

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.

  DOI：

  10.1021/jm300894h
• 作为产物：
  描述：

  甲醇 、 3-bromo-4-(2-methoxyvinyl)thiophene 在 对甲苯磺酸 作用下， 反应 18.0h， 以90%的产率得到2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal
  参考文献：
  名称：

  σ的附加的疏水口袋的剥削1个受体：由C-H键的官能化的螺环的噻吩的后期多样的修改

  摘要：

  该σ假说1受体会容忍在螺环系统的1位附加的芳基部分是基于螺环的吡唑衍生物，的σ药效模型1受体配体和DFT计算。在合成的最后步骤中引入所述芳基残基的策略允许一大组不同的配体的为σ的疏水口袋的开发制备1受体蛋白。催化剂体系PdCl 2 /2,2'-联吡啶/ Ag 2 CO 3能够将各种芳基引入螺环噻吩衍生物5和6的α位置上，从而提供目标芳基附加的螺环噻吩3和4。虽然σ 1 1-苯基取代的螺环的噻吩的亲和力3A和4A与σ相比稍微降低1所述非芳基化化合物的亲和力5和6，这两个化合物代表非常有效的σ 1受体配体（3A：ķ我= 4.5 nM；4a：K i＝ 1.0nM）。该结果表明，σ1受体蛋白对1位的芳基部分具有良好的耐受性。附加苯基部分的取代图案具有仅在σ作用较弱1的亲和力。甚至配体3F和4H具有扩展萘基残基显示出高σ 1倍的亲和力。然而，σ的减少1倍通过扩展的π系统的一种联苯基取代基的亲和性（4J：ķ我=

  DOI：

  10.1039/c1ob06149f

文献信息

• Improvement of σ1 receptor affinity by late-stage C–H-bond arylation of spirocyclic lactones
  作者：Christina Meyer、Benedikt Neue、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Ernst-Ulrich Würthwein、Kenichiro Itami、Bernhard Wünsch

  DOI：10.1016/j.bmc.2013.01.038

  日期：2013.4

  of the synthesis. A selective α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag2CO3, whereas the β-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both α-positions providing 4′-mono-, 6′-mono-

  复杂的螺环的直接C-H键的芳基化内酯13，14，和18允许在合成的最后步骤中，引入不同的芳基部分的。使用催化体系PdCl 2 / 2,2'-联吡啶/ Ag 2 CO 3对噻吩部分进行选择性α-芳基化，而噻吩环的β位则通过使用另一种催化体系PdCl 2 / P [OCH（CF 3）2 ] 3 / Ag 2 CO 3。由于电子和空间原因，五元内酯18芳基化发生在两个提供4'-单-，6'-单和4'，6'-二芳基噻吩的α位中22 – 26a – c。在“上左（上）”的位置与另外的芳基部分的化合物（1'-位置13，3'-位的14，4'-位置的18）显示增加的σ 1倍的亲和力相比，所述非芳基化亲本化合物。在“左”的位置（在2'-位置A苯基部分20A）也增加了σ 1亲和力，但到较低的程度。显着降低的σ 1倍中的6'-位上引入的芳基部分后观察到的亲和力18，这可能导致从屏蔽叔胺，这是用于与σ相互作用至关重
• Exploitation of an additional hydrophobic pocket of σ1 receptors: Late-stage diverse modifications of spirocyclic thiophenes by C–H bond functionalization
  作者：Christina Meyer、Benedikt Neue、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Ernst-Ulrich Würthwein、Kenichiro Itami、Bernhard Wünsch

  DOI：10.1039/c1ob06149f

  日期：——

  nM; 4a: Ki = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the σ1receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ1 affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ1 affinity. However, decrease of σ1 affinity by extension of the π-system to a biphenylyl substituent (4j: Ki = 30

  该σ假说1受体会容忍在螺环系统的1位附加的芳基部分是基于螺环的吡唑衍生物，的σ药效模型1受体配体和DFT计算。在合成的最后步骤中引入所述芳基残基的策略允许一大组不同的配体的为σ的疏水口袋的开发制备1受体蛋白。催化剂体系PdCl 2 /2,2'-联吡啶/ Ag 2 CO 3能够将各种芳基引入螺环噻吩衍生物5和6的α位置上，从而提供目标芳基附加的螺环噻吩3和4。虽然σ 1 1-苯基取代的螺环的噻吩的亲和力3A和4A与σ相比稍微降低1所述非芳基化化合物的亲和力5和6，这两个化合物代表非常有效的σ 1受体配体（3A：ķ我= 4.5 nM；4a：K i＝ 1.0nM）。该结果表明，σ1受体蛋白对1位的芳基部分具有良好的耐受性。附加苯基部分的取代图案具有仅在σ作用较弱1的亲和力。甚至配体3F和4H具有扩展萘基残基显示出高σ 1倍的亲和力。然而，σ的减少1倍通过扩展的π系统的一种联苯基取代基的亲和性（4J：ķ我=
• Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor
  作者：Christina Meyer、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Valentina Dal Col、Erik Laurini、Kenichiro Itami、Sabrina Pricl、Bernhard Wünsch

  DOI：10.1021/jm300894h

  日期：2012.9.27

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.