| Research Abstract |
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.
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