Synthesis of 4‐Substituted Pyrrolo[2, 3‐c]quinolines via Microwave‐Assisted C‐N Bond Formation

Abstract

A metal‐free approach for the synthesis of 4‐substituted pyrolo[2, 3‐c]quinoline is reported in this paper. Synthesis of the target molecule started from easily available quinoline and was carried out in five steps. The fused pyrrolo‐quinoline unit was assembled using Bartoli indolization and the crucial final step involving microwave assisted C−N bond formation was carried out by reaction of 4‐chloro‐3H‐pyrrolo[2, 3‐c]quinolines and diverse aliphatic amines, in the presence of N, N’‐diisopropylethylamine (DIPEA). Final molecules were obtained in good yields even in the presence of additional bromine functionality on the quinolines, thus demonstrating the selectivity of the developed coupling procedure and possibility of increasing the product diversity.

The Chemistry and Biological Applications of 3H‐Pyrrolo[2,3‐c]quinolines and Marinoquinolines

“…This method was applicable to both primary and secondary amines, generating the amino‐MQs ( 112 a – m , Scheme 22b) in yields between 70% and 85%. No C−N coupling was observed using aromatic amines, probably due to their lower nucleophilicity [45] …”

“… (a) Synthesis of 4‐substituted pyrrolo[2,3‐ c ]quinolines, (b) structure of 4‐substituted pyrrolo[2,3‐ c ]quinolines 112 a – m as reported by Penjarla and co‐workers, and (c) structures of 4‐substituted pyrrolo[2,3‐ c ]quinolines 112 n – t containing a bromine atom or substituents at pyrrole/quinoline rings [45] …”

“…Also in 2018, Penjarla and co-workers reported a microwave-assisted CÀ N coupling to synthesize 4-substituted pyrrolo [2,3-c]quinolines in five steps. [45] The synthesis initiated with the quantitative conversion of quinoline 109 to the corresponding N-oxide 110 using m-CPBA as oxidant. The quinoline-N-oxide…”

“…(a) Synthesis of 4-substituted pyrrolo[2,3-c]quinolines, (b) structure of 4-substituted pyrrolo[2,3-c]quinolines 112 a-m as reported by Penjarla and co-workers, and (c) structures of 4-substituted pyrrolo[2,3-c]quinolines 112 n-t containing a bromine atom or substituents at pyrrole/quinoline rings. [45] Scheme 23. (a) General procedure used for the synthesis of natural and unnatural marinoquinoline analogues and selected examples synthesized by Aguiar and co-workers.…”

“…No CÀ N coupling was observed using aromatic amines, probably due to their lower nucleophilicity. [45] The authors further explored the scope of their protocol to obtain brominated analogues (compounds 112 n, 112 r and 112 s, Scheme 22c) and analogues with other N-heterocycles attached to the quinoline ring (compounds 112 o-t, Scheme 22c). In all cases (112 n-t), the products were obtained in good yields (72-88%), [45] showing that this is a good strategy to create a library of marinoquinolines from the quinoline moiety.…”