Various 5,7-bis(trifluoroacetyl)-8-quinolylamines, sulfides and ethers were synthesized in excellent yields by aromatic nucleophilic N-N, N-S and N-O exchange reactions of N,N-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine with amines, thiols and alcohols. Base-catalyzed cyclization of the resulting benzyl 8-quinolyl sulfide and subsequent dehydration gave fluorine-containing thieno[3,2-h]quinolines in high yields. Activated aromatic compounds bearing good leaving groups such as halo-, alkoxy-, etc., are well known to undergo aromatic nucleophilic substitution with various nucleophiles. 1 However, amino groups attached to aromatic rings are seldom replaced by nucleophiles. Previously, we have found that N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine (1) reacts easily with various amines, thiols and alcohols under mild conditions to afford the corresponding N-N, N-S and N-O exchanged 2,4-bis(trifluoroacetyl)-1-naphthylamines, sulfides and ethers 2 in excellent yields, respectively (Scheme 1). 2 Up-to-lately we succeeded in extending the present S N Ar reaction to the less reactive N, N-dimethyl-2-trifluoroacetyl-4-halo-1-naphthylamines. 3 In recent years, considerable attention has been paid to the development of new methodologies for the syntheses of many kinds of fluorine-containing heterocycles, since these compounds are now widely recognized as important organic materials showing interesting biological activities for their potential use in medicinal and agricultural scientific fields. 4 Besides, quinolines are important heterocyclic systems, constituting the structure of many naturally occurring products and having interesting pharmacological properties as antimicrobial agents and antitumor drugs. 5
Scheme 1In this situation, we have very recently reported that N,Ndimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine (3) undergoes a novel aromatic nucleophilic substitution with amines to give the corresponding 5,7-bis(trifluoroacetyl)-8-quinolylamines. 6 Herein, we report a full account of our systematic studies on this type of aromatic nucleophilic substitution including the new finding of the reactions of 3 with various thiols and alcohols, which are considerably less reactive than amines. Furthermore, we also present its application to the synthesis of fluorine-containing 2,3-dihydrothieno[3,2-h]quinoline 7 and thieno[3,2-h]quinoline 8, which are greatly expected to show antibacterial, 7 antitumor 8 and antianaphylactic activities. 9Starting material 3 was very easily prepared in 95% yield through the reaction of N,N-dimethyl-8-quinolylamine with trifluoroacetic anhydride in the presence of pyridine at 50 ∞C for 24 hours according to our method (Scheme 2). 10
Scheme 2First, we examined the reaction of 3 with various amines (Scheme 3, Table 1). Reactions of 3 with ammonia and aliphatic primary amines such as methyl-, ethyl-, benzyland i-propylamines took place very easily at room temperature within 1 hour to afford the desired 8-quinolylamine derivatives 4a-e quantitatively (entries 1-5). Bulky t-buty...
