A Heteroarylamine Library: Indium‐Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines

Abstract

Under indium Lewis acid catalysis, electron-rich five-membered heteroaryl electrophiles fused with/without a benzene ring were found to couple with amines to produce heteroarylamines with broad structural diversity. The heteroarylamine formation proceeds through the cleavage of a heteroarylÀOMe bond by the nucleophilic attack of the amine based on the nucleophilic aromatic substitution (S N Ar) reaction. In contrast to the corresponding traditional S N Ar amination, the present S N Ar-based heteroaryl amination can be performed without relying on both heteroaryl electrophiles with electron-withdrawing groups and nucleophilicity-enhanced metal amides. High compatibility towards the functional groups such as NO 2 , Br, I, CF 3 , CN, CO 2 Et, pyridyl, thiazolyl, C=C, and OH groups was observed, thus showing the practicality and reliability of this method. Mechanistic studies indicated that a carbonÀindium bond is likely to be formed on the heteroaryl ring during the process. Scheme 3. Indium-catalyzed S N Ar amination of 3,4-dimethoxythiophene with aniline.Scheme 4. Indium-catalyzed S N Ar amination of 3-bromo-4methoxythiophene with aniline.Scheme 5. Indium-catalyzed tandem S N Ar reaction of 2methoxythiophene with N-methyl-p-toluidine.

Indium-Catalyzed Annulation of o-Acylanilines with Alkoxyheteroarenes: Synthesis of Heteroaryl[b]quinolines and Subsequent Transformation to Cryptolepine Derivatives

“…This result is likely to be related, at least in part, to the relatively low reaction rate of the desired S N Ar process between 2h and 3e , and, in fact, 70% of 3e loaded for the reaction remained unconsumed. In this context, we have previously confirmed that the S N Ar amination reaction of 3-methoxythiophene ( 3e ) requires a higher loading of an indium catalyst as well as higher temperature compared to those for the reaction of 2-methoxythiophene ( 3c ) [ 54 ]. In addition to the sulfur-containing HA[ b ]Qs, the tetracyclic and tricyclic oxygen-containing analogues can be addressed by our method in moderate to good yields ( 4af , 4hf , and 4ag ).…”

“…As collected separately in Table 5 , we successively present the result of constructing the framework of the indolo[3,2- b ]quinoline, which is alternatively named quindoline, having been known to show cytotoxic activity against human cancer cell lines [ 81 ]. As in our preceding S N Ar amination [ 54 ], commercially unavailable 3-methoxyindole was not required, but rather commercially available 3-acetyloxyindole ( 3i ) can be used here again as a substrate. Thus, mixing 2a , 3i , and InBr 3 (5 mol %) in PhCl, and then heating the mixture at 110 °C for 24 h gave 4ai in 55% yield.…”

“…On the basis of the above experimental results as well as the previous ones, a proposed reaction mechanism is illustrated in Scheme 4 that exemplifies the reaction of 2e with 3a . First up is the S N Ar-based intermolecular amination of 3a by the nucleophilic attack of the nitrogen atom of 2e via previously proposed transition state A [ 54 ], followed by the release of the indium catalyst ( In ) and MeOH to give intermediate 6ea . Next is the nucleophilic attack of the thienyl ring to the carbonyl moiety activated by In as shown in transition state B , hereby providing 8ea , and then desired structure 4ea after aromatizing dehydration.…”

“…MeOH was stored over molecular sieves 3Å (MS 3Å) under argon. The following indium salts and substrates were synthesized according to the respective literature methods: In(NTf 2 ) 3 [ 83 , 84 ], In(ONf) 3 [ 56 , 85 ], 1-(2-aminophenyl)-2-methyl-1-propanone ( 2e ) [ 86 ], 1-(2-aminophenyl)-2,2,2-trifluoroethanone ( 2f ) [ 87 ], (2-aminophenyl)(4-methoxyphenyl)methanone ( 2j ) [ 88 ], (2-aminophenyl)(2-methylphenyl)methanone ( 2l ) [ 88 ], 3-methoxybenzo[ b ]thiophene ( 3a ) [ 89 ], 2-methoxybenzo[ b ]thiophene ( 3b ) [ 54 ], 2-methoxy-5-methylthiophene ( 3d ) [ 54 ], 2-methoxybenzo[ b ]furan ( 3f ) [ 54 ], 2-methoxy-5-phenylfuran ( 3g ) [ 54 ], 2-methoxy-1-phenyl-1 H -pyrrole ( 3h ) [ 54 ]. Unless otherwise noted, other substrates and reagents were commercially available, and used as received without further purification.…”

“…On the other hand, we have recently reported a new C(heteroaryl)–N bond-forming reaction by reacting electron-rich methoxyheteroarenes with amines via a nucleophilic aromatic substitution (S N Ar) reaction [ 54 ]. In addition to this, we have also developed several new C(heteroaryl)–C bond-forming reactions by reacting alkynes [ 55 , 56 , 57 ] or carbonyl compounds [ 58 , 59 , 60 ] with heteroarenes.…”