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

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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.