2-(4-Carboxyphenyl)-3-(pyridin-2-yl)-4,5,6,7-tetrahydroindazole

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-(4-Carboxyphenyl)-3-(pyridin-2-yl)-4,5,6,7-tetrahydroindazole
• 英文别名: 4-(3-Pyridin-2-yl-4,5,6,7-tetrahydroindazol-2-yl)benzoic acid
• 化学式: C₁₉H₁₇N₃O₂
• 分子量: 319.363
• InChiKey: LZZKCKSIBFNLOW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-吡啶甲酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 2-(4-Carboxyphenyl)-3-(pyridin-2-yl)-4,5,6,7-tetrahydroindazole
  参考文献：
  名称：

  Chelation-Controlled Regioselectivity in the Synthesis of Substituted Pyrazolylpyridine Ligands. 1. Bidentates

  摘要：

  En route to novel C-linked pyrazole-pyridine bidentate ligands for transition metals, a new, higher-yielding synthesis of diketone 1 was found. It was quantitatively converted to the parent, C-linked 3-(pyridin-2-yl)pyrazole 2. Condensations of 1 with five aromatic hydrazines led to in-substituted derivatives of 2 (4i-8i). With CH3NHNH2, both in and out isomers formed, but 3o could be isolated pure. In the presence of ZnCl2, CH3NHNH2 and methyl 4-hydrazinobenzoate formed the isolable 1:1 complexes (3o)ZnCl2 and (6o)ZnCl2, respectively, which were characterized by NMR and elemental analysis. The bidentate, out-substituted 3o and 6o were freed from the complexes with NH4OH. Without isolation of complexes, PhNHNH(2) and 4-hydrazinobenzoic acid were similarly used to prepare the out-substituted derivatives 4o and 5o, respectively. Nucleophilic aromatic substitution by 2 of a-bromopyridine and ethyl 4-fluorobenzoate led to the out products 8o (a novel tridentate) and 9o, respectively. Both esters 6o and 9o could be hydrolyzed to the acid 5o in higher overall yield than the direct condensation of 4-hydrazinobenzoic acid. The regiochemistries were assigned by several arguments: Only bidentate out-substituted materials were expected to form stable ZnCl2 complexes. It was also shown that 4o reacted with TiCl4. The formation of out materials in the presence of ZnCl2 could be rationalized by a preferred attack of the metal-activated, inner carbonyl of 1 by the more nucleophilic NH2 ends of the aromatic hydrazines, whereas the outer carbonyl is more reactive in the absence of ZnCl2. The formation of out materials by nucleophilic aromatic substitutions of 2 could be rationalized as proceeding through a K+ chelate intermediate that disallows access to the inner pyrazole nitrogen. These two mechanistic arguments were tied through the conversion of a product of nucleophilic aromatic substitution (9o) into a product of ZnCl2-mediated condensation (5o). The aromatic H-1-NMR signals were also diagnostic of the regiochemistries: in all cases, the pyridine H-3 doublets lay upfield of the H-4 signals for in isomers and downfield for out isomers but, in the latter case, the H-3 signals shifted upfield in the Zn complexes (and in the TiCl4 adduct of 4o). This pattern was interpreted in conformational terms and the interpretation found support in MM2 calculations: The out products, like bipyridine, prefer anti orientations of the imino nitrogens due to electronic and steric effects (calculated Delta G(syn-anti) > 3.3 kcal/mol for 3o-7o). Complexation forces a syn orientation which produces a shielding of the pyridine H-3 by a nearby CH2 group. This same shielding effect is present in either conformation of the in isomers, which are much closer in energy (calculated /Delta G(syn-anti)/ < 0.5 kcal/mol for 3i-7i). Finally, the mass spectral fragmentations could be related to the regiochemistry.

  DOI：

  10.1021/jo00086a028

文献信息

• Chelation-Controlled Regioselectivity in the Synthesis of Substituted Pyrazolylpyridine Ligands. 1. Bidentates
  作者：Yue Luo、Pierre G. Potvin

  DOI：10.1021/jo00086a028

  日期：1994.4

  En route to novel C-linked pyrazole-pyridine bidentate ligands for transition metals, a new, higher-yielding synthesis of diketone 1 was found. It was quantitatively converted to the parent, C-linked 3-(pyridin-2-yl)pyrazole 2. Condensations of 1 with five aromatic hydrazines led to in-substituted derivatives of 2 (4i-8i). With CH3NHNH2, both in and out isomers formed, but 3o could be isolated pure. In the presence of ZnCl2, CH3NHNH2 and methyl 4-hydrazinobenzoate formed the isolable 1:1 complexes (3o)ZnCl2 and (6o)ZnCl2, respectively, which were characterized by NMR and elemental analysis. The bidentate, out-substituted 3o and 6o were freed from the complexes with NH4OH. Without isolation of complexes, PhNHNH(2) and 4-hydrazinobenzoic acid were similarly used to prepare the out-substituted derivatives 4o and 5o, respectively. Nucleophilic aromatic substitution by 2 of a-bromopyridine and ethyl 4-fluorobenzoate led to the out products 8o (a novel tridentate) and 9o, respectively. Both esters 6o and 9o could be hydrolyzed to the acid 5o in higher overall yield than the direct condensation of 4-hydrazinobenzoic acid. The regiochemistries were assigned by several arguments: Only bidentate out-substituted materials were expected to form stable ZnCl2 complexes. It was also shown that 4o reacted with TiCl4. The formation of out materials in the presence of ZnCl2 could be rationalized by a preferred attack of the metal-activated, inner carbonyl of 1 by the more nucleophilic NH2 ends of the aromatic hydrazines, whereas the outer carbonyl is more reactive in the absence of ZnCl2. The formation of out materials by nucleophilic aromatic substitutions of 2 could be rationalized as proceeding through a K+ chelate intermediate that disallows access to the inner pyrazole nitrogen. These two mechanistic arguments were tied through the conversion of a product of nucleophilic aromatic substitution (9o) into a product of ZnCl2-mediated condensation (5o). The aromatic H-1-NMR signals were also diagnostic of the regiochemistries: in all cases, the pyridine H-3 doublets lay upfield of the H-4 signals for in isomers and downfield for out isomers but, in the latter case, the H-3 signals shifted upfield in the Zn complexes (and in the TiCl4 adduct of 4o). This pattern was interpreted in conformational terms and the interpretation found support in MM2 calculations: The out products, like bipyridine, prefer anti orientations of the imino nitrogens due to electronic and steric effects (calculated Delta G(syn-anti) > 3.3 kcal/mol for 3o-7o). Complexation forces a syn orientation which produces a shielding of the pyridine H-3 by a nearby CH2 group. This same shielding effect is present in either conformation of the in isomers, which are much closer in energy (calculated /Delta G(syn-anti)/ < 0.5 kcal/mol for 3i-7i). Finally, the mass spectral fragmentations could be related to the regiochemistry.