Aromatic Nucleophilic N-N, N-S and N-O Exchange Reactions: Efficient Synthesis of 5,7-Bis(trifluoroacetyl)-8-quinolylamines, Sulfides and Ethers

Abstract

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...

Copper catalyzed 1,3-dipolar cycloaddition reaction of azides with N-(2-trifluoroacetylaryl)propargylamines

“…[10] and was obtained in a 96% isolated yield in acetonitrile under refluxing conditions for 4 h. The 4-bromo derivative 13 was prepared from N,N-dimethyl-2-trifluoroacetyl-4-bromo-1-naphthylamine [8] and needed as substrate 11, a large excess of the amine (10 equivalent) in acetonitrile under refluxing conditions for 18 h. 8-Amino quinoline derived substrate 14 was prepared as described in Ref. [9] and was obtained in a quantitative yield; a temperature of 0 8C in acetonitrile for 2 h was crucial to get such high yield. N,Ndimethylamino precursors 5 and 9 were found to be the most reactive substrates, while 7 being the less reactive in this series.…”

“…Compounds 10 and 14 were already described in Refs. [12,9]. Benzo [b]thiophene-3-carbonitrile was prepared as described in Ref.…”

“…For some years we have been interested to develop new synthetic approaches to prepare fluorinated organic molecules. Among the recent studies developed in our laboratories, we have launched a program directed to the synthesis of novel trifluoromethylated heterocycles using aromatic nucleophilic substitution reactions of N,N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine [7], N,Ndimethyl-2-trifluoroacetyl-4-halo-1-naphthyl-amines [8], N,Ndimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine [9], with amines, thiols and alcohols and we have shown that the corresponding exchanged products could be easily converted to various fluorinated fused-heterocycles of potential biological importance. Recently these aromatic nucleophilic substitution reactions were extended to 3-trifluoroacetyl-4-dimethylaminoquinoline [10] and N,N-dimethyl-2-trifluoroacetyl-1-naphthylamine [11].…”

A Facile Synthetic Method for Fluorine-Containing 1,7-Phenanthrolines: Pyridine-Ring Formation Reaction of N-Propargyl-6,8-bis(trifluoroacetyl)quinolin-5-amine with Various Nucleophiles

“…So far, we have found that N, N-dimethyl-2,4-bis(trifluoroacetyl)naphthalen-1-amine (1) 9 and N, N-dimethyl-5,7-bis(trifluoroacetyl)quinolin-8-amine (2) 10 react easily with various amines, thiols, and alcohols under mild conditions to afford the corresponding N-N-, N-S-, and N-O-exchanged products 3 and 4, respectively, in excellent yields (Scheme 1). Moreover, we succeeded in extending this type of aromatic nucleophilic substitution to the simple syntheses of various trifluoromethyl-containing heterocycles with naphthalene 11 and quinoline 12 skeletons. During the course of our studies, we have recently revealed that propargylamino derivatives 5 and 6, which were readily prepared through a dimethylamino-propargylamino exchange reaction, undergo the pyridine-ring formation reaction with N-, S-, and O-nucleophiles to give the corresponding novel fluorine-containing benzo[h]quinolines 7 13 and 1,10-phenanthrolines 8 14 (Scheme 2).…”

Tetrakis(dimethylamino)ethylene (TDAE) Mediated Addition of Heterocyclic Difluoromethyl Anions to Heteroaryl Aldehydes. A Facile Synthetic Method for New gem-Difluorinated Alcohols Derived from 4-Bromo-1-naphthylamine and 8-Quinolylamine

“…3 In particular quinolylamine derivatives have been used as the basis in the molecular design for synthetic antimalarial compounds, 4 anti-HIV agents, 5 and for the treatment of the Alzheimer disease. 6 Recently we have been interested in the aromatic nucleophilic substitution reactions of N, N-dimethyl-2,4-bis(trifluoroacetyl)-1-naphthylamine, 7 N, N-dimethyl-2-trifluoroacetyl-4-halo-1-naphthylamine, 8 and N, N-dimethyl-5,7-bis-trifluoroacetyl-8-quinolylamine, 9 with amines, thiols and alcohols and we have shown that the corresponding exchanged products could be easily converted in various fluorinated fused-heterocycles of potential biological importance. As part of our ongoing efforts in the search of new methodologies to the synthesis of fluorinated compounds with potential biological and synthetic applications, 10 we wish to present a synthetic method to prepare, under very mild conditions, new -CF 2 CHOH-de-rivatives that incorporate quinoline as well as naphthalene units.…”