Construction of Ring-Flourinated Heterocycles via Intramolecular Substitutions for Vinylic Flourines

通过乙烯基氟的分子内取代构建环状氟化杂环

基本信息

批准号：
09640641
负责人：
ICHIKAWA Junji
金额：
$ 2.43万
依托单位：
KYUSHU INSTITUTE OF TECHNOLOGY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

项目摘要

Selectively fluorinated heterocycles are widely used as important components in the agrochemical, pharmaceutical, and dyestuffs industries. Only a limited number of methods, however, have been reported for the synthesis of ring-fluorinated heterocyclic compounds. We have developed new synthetic reactions to construct these ring systems starting from functionalized gem-difluoroolefins. which are subject to replacement of the fluorines by nucleophiles via addition-elimination process. The employed substrates of difluoroolefins are easily prepared from 2,2,2-trifluoroethyl p-toluenesulfonate by the general synthetic method that we have recently developed.The replacement of fluorine is successfully effected in gem-difluoroolefins with a nucleophilic N-, 0-, S-, or C-functional group. gem-Difluorostyrenes, bearing HOCH_2, AcSCH_2, or TsNHCH_2 group at the ortho position, readily undergo intramolecular substitution, leading to six-membered rings such as 3-fluoroisochromene, -thioisochipmene, and -isoquinoline derivatives, respectively. The following in-situ generated nitrogen or carbon nucleophiles in gern-difluorostyrenes also effect this type of intramolecular substitution. When o-cyano, isocyano, formyl, and amino groups are transformed to the corresponding nucleophiles, the desired cyclizations readily proceed to afford 3-fluorinated isoquinolines, quinolines, isoquinoline N-oxides, and cinnolines in high yields.Furthermore, this methodology can be applied to the formation of five-membered rings even via 5-endo-trigonal cycization, which is disfavored in Baldwin's rules. The ring closure smoothly proceeds to give 2-fluoroindoles, -benzofurans, and -benzothiophenes, probably due to (i) the highly polarized double bond of difluoroolefins and (ii) the elimination of a fluoride ion.Substrates without a fused benzene ring are also emploed in this methodology.

选择性氟化杂环作为重要成分广泛应用于农化、医药和染料工业。然而，仅报道了有限数量的合成环氟化杂环化合物的方法。我们开发了新的合成反应，以功能化偕二氟烯烃为原料构建这些环系统。它们可以通过加成-消除过程被亲核试剂取代。二氟烯烃所用的底物很容易由对甲苯磺酸2,2,2-三氟乙酯通过我们最近开发的通用合成方法制备。用亲核的N-,0-,成功地取代了偕二氟烯烃中的氟。 S-或C-官能团。邻位带有HOCH_2、AcSCH_2或TsNHCH_2基团的偕二氟苯乙烯很容易发生分子内取代，分别形成六元环，例如3-氟异色烯、-硫代异色烯和-异喹啉衍生物。以下在二氟苯乙烯中原位生成的氮或碳亲核试剂也影响这种类型的分子内取代。当邻氰基、异氰基、甲酰基和氨基转化为相应的亲核试剂时，所需的环化很容易进行，以高产率提供3-氟化异喹啉、喹啉、异喹啉N-氧化物和肉啉。此外，该方法可以是甚至通过 5-内三角环化也适用于五元环的形成，这在鲍德温的规则。闭环过程顺利进行，得到 2-氟吲哚、-苯并呋喃和-苯并噻吩，这可能是由于 (i) 二氟烯烃的高度极化双键和 (ii) 氟离子的消除。没有稠合苯环的底物也是如此在此方法中采用。