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

选择性含氟杂环在农化、医药和染料工业中被广泛用作重要成分。然而，目前报道的合成含氟杂环化合物的方法很少。我们开发了新的合成反应来构建这些环系，从官能化的GEM-二氟烯烃开始。它们通过加成-消除过程被亲核试剂取代。以2，2，2-三氟乙基对甲苯磺酸为原料，通过我们最近开发的一般合成方法，可以很容易地合成二氟烯烃的底物，并成功地用亲核的N-、0-、S-或C-官能团取代了GEM-二氟烯烃中的氟。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，分别得到3-氟异色烯、-硫代异辛烯和-异喹啉等六元环。Gern-二氟苯乙烯中的下列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、甲酰基和氨基被转化为相应的亲核试剂时，所需的环化反应很容易得到高产率的3-氟化异喹啉、喹啉、异喹啉N-氧化物和辛诺林。此外，这种方法甚至可以用于五元环的形成，这在鲍德温规则中是不受欢迎的。环的闭合顺利地得到了2-氟吲哚、-苯并呋喃和-苯并噻吩类化合物，这可能是由于(I)二氟烯烃的高度极化的双键和(Ii)氟离子的消除。这种方法中也使用了不带稠苯环的底物。

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.