Development of Novel Aromatic Nucleophilic Substitutions and Its Applicafion to the Highly Efficient Synthesis of Biologically Active Fluorine-Containing Heterocycles

新型芳香亲核取代基的发展及其在生物活性含氟杂环高效合成中的应用

• 批准号: 13650921
• 负责人: OKADA Etsuji
• 金额: $ 2.24万
• 依托单位: KOBE UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13650921/
• 关键词: Aromalic Nucleophilic Substitution; Heterocycle; Fluorine Atom; Trifluoroacetyl Group; Trifluoromethyl Group; Aminonaphthdene; Aminoquinoline; Biologicaliy Active Compound

Trifluoroacetylation of 4-dimethylaminoquinoline with N-trifluoroacetylpyridinium salts gave 3-trifluoroacetyl-4-dimethylaminoquinoline 1 in good yields. 5,7-Bis (trifluoroacetyl)-8-dimethylaminoquinoline 2 was easily prepared by the reaction of 8-dimethylaminoquinoline with trifluoroacetic anhydride. The combination of diacylation reaction and the following regioselective deacylation reaction of 1-dimethylaminonaphthalene provided new fluorine-containing building block, 2-trifluoroacetyl-1-dirnethyaminonaphthalene 3 in good yields. It was found that new substrates 1-3 underwent novel aromatic nucleophilic substitution reactions with N-, S-, O-nucleophiles to give the corresponding N-N, N-S and N-O exchanged products in high yields.New fluorine-containing heterocyclic compounds such as pyrazoles, isoxazoles, diazepines, dibenzonaphthyridines, benzothiopyranoquinolines and benzoquinolines were readily synthesized by the novel aromatic nucleophilic substitutions of 1 with bifunctional nucleophiles and the subsequent cyclization reactions. The three components cyclocondensation reactions of 3-trifluoroacetyl-4-aminoquinoline, ammonia water and aldehydes or ketones afforded the corresponding fluorine-containing pyrimidoquinolines and benzonaphthyridines in excellent yields. 3-Trifluoroacetyl-4-dialkylaminoquinoline underwent acid-catalyzed oxazine-ring formation reactions to give fluorine-containing oxazinoquinolines in good yields. Substrate 2 easily reacted with 1,2-diamines and hydroxylamines to afford the corresponding fluorine-containing 1,4-diazepinoquinolines and isoxazoloquinolines in high yields. Benzacridines, benzoquinolines and benzothioxanthenes having a trifluoromethyl group were highiy efficiently synthesized by the aromatic nucleophilic substitution reaction of 3 with bifunctional nucleophiles and the following intramolecular cyclizations.

用N-三氟乙酰基吡啶盐对4-二甲氨基喹啉进行三氟乙酰化，以高产率得到3-三氟乙酰基-4-二甲氨基喹啉1。5，7-双（三氟乙酰基）-8-二甲氨基喹啉2是通过8-二甲氨基喹啉与三氟乙酸酐反应而容易地制备的。将1-二甲氨基萘的双酰化反应与随后的区域选择性脱酰反应相结合，以良好的产率提供了新的含氟结构单元2-三氟乙酰基-1-二甲氨基萘3。发现新的底物1-3与N-、S-、O-亲核试剂发生了新型的芳香亲核取代反应，高产率地得到了相应的N-N、N-S和N-O交换产物，新的含氟杂环化合物如吡唑类、异恶唑类、二氮杂类、二苯并萘类、苯并噻喃并喹啉和苯并喹啉是通过用双官能亲核试剂对1进行新的芳族亲核取代而容易地合成的，随后的环化反应。以3-三氟乙酰基-4-氨基喹啉、氨水和醛或酮为原料，通过三组分环化缩合反应，以高产率合成了相应的含氟嘧啶并喹啉和苯并萘啶。3-三氟乙酰基-4-二烷基氨基喹啉经酸催化的恶嗪成环反应，以较好的产率合成了含氟恶嗪喹啉类化合物。底物2容易与1，2-二胺和羟胺反应，以高产率得到相应的含氟1，4-二氮杂喹啉和异恶唑并喹啉。通过3与双功能亲核试剂的芳香亲核取代反应和随后的分子内环化反应，高效地合成了含三氟甲基的苯并吖啶、苯并喹啉和苯并噻吨。

项目成果

Maurice Medebielle: "Indium-Mediated Reformatsky-Type Reaction of β -Amnovinyl Chlorodifluoromethyl Ketones with Heteroaryl Aldehydes"Synthesis. -・17. 2601-2608 (2002)

Maurice Medebielle：“β-氨乙烯基氯二氟甲基酮与杂芳基醛的铟介导的重整型反应”合成 -・17。

Maurice Medebielle: "Indium-Mediated Reformatsky-Type Reaction of β-Amnovinyl Chlorodifluoromethyl Ketones with Heteroaryl Aldehydes"Synthesis. 17. 2601-2608 (2002)

Maurice Medebielle：“β-氨乙烯基氯二氟甲基酮与杂芳基醛的铟介导的重整型反应”17. 2601-2608 (2002)。

Maurice Medebielle: "Ttrakis(dimethylamino)ethylene (TDAE) Mediated Addition of Heterocyclic Difluoromethylanions to Heteroaryl Aldehyde. A Facile Synthetic Method for New gem-Difluoronated Alcohols Derived from 4-Bromo-1-naphthylamine and 8-Quinolylamine

Maurice Medebielle：“Ttrakis（二甲基氨基）乙烯（TDAE）介导杂环二氟甲基阴离子与杂芳基醛的加成。一种从 4-溴-1-萘胺和 8-喹啉胺衍生的新型宝石二氟醇的简便合成方法

Etsuji Okada, Yoshihiro, Otsuki, Megumi Shinohara, Maurice Medebielle, Yuhei Shimizu, Hiroshi Takeuchi: "Synthesis and Aromatic Nucleophilic N-N, N-S and N-O Exchange Reactions of N,N-Dimethyl-2-trifluoroacetyl-1-naphthylamine"Tetrahedron Lett.. 44. 741-7

Etsuji Okada、Yoshihiro、Otsuki、Megumi Shinohara、Maurice Medebielle、Yuhei Shimizu、Hiroshi Takeuchi：“N,N-二甲基-2-三氟乙酰基-1-萘胺的合成和芳香亲核 N-N、N-S 和 N-O 交换反应”四面体 Lett..

Maurice Medebielle: "Electron Transfer Methodologies to the Synthesis of Organo Fluorine-Compounds (Electron Transfer Reactions in Organic Synthesis, 2002)"Research Signpost. 91-99 (2002)

Maurice Medebielle：“有机氟化合物合成的电子转移方法（有机合成中的电子转移反应，2002）”研究路标。