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

选择性氟化杂环化合物在农化、医药、染料等工业中被广泛用作重要成分。然而，仅报道了几种合成环氟化杂环化合物的方法。我们开发了新的合成反应，从功能化宝石二氟烯烃开始构建这些环体系。它们会通过加成-消去过程被亲核试剂取代。所使用的二氟烯烃底物很容易由2,2,2-三氟乙基对甲苯磺酸通过我们最近开发的一般合成方法制备。在宝石-二氟烯烃中，氟被亲核的N-、0-、S-或c -官能团成功取代。在邻位上含有HOCH_2、AcSCH_2或TsNHCH_2基团的gem-二氟苯乙烯很容易发生分子内取代，分别形成6元环，如3-氟异铬烯、-硫代异晶片烯和-异喹啉衍生物。在根二氟苯乙烯中，以下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，所需的环化反应很容易进行，以高产出3氟化异喹啉、喹啉、异喹啉n -氧化物和喹啉。此外，该方法还可以应用于五元环的形成，即使是通过5-内三角环化，这在Baldwin规则中是不利的。环闭合顺利地得到2-氟吲哚、-苯并呋喃和-苯并噻吩，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。在本方法中也采用不含苯环的底物。

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.