Synthesis of 2,3‐Disubstituted Quinoline‐4‐carbonitriles through Truce–Smiles Rearrangement of Phenacyl‐4‐nitrobenzenesulfonamides

Abstract

2‐Aminobenzyl cyanide was sulfonylated with 4‐nitrobenzenesulfonyl chloride and reacted with 2‐haloketones and N,N‐diisopropylethylamine (DIPEA). 2,3‐Disubstituted quinoline‐4‐carbonitriles were obtained as the main products originating from subsequent N‐alkylation, base‐catalysed intramolecular C‐arylation, aldol condensation and aromatization. A single‐step protocol was successfully tested for various starting materials. Nevertheless, 3‐substituted quinoline‐4‐carbonitriles were received as the separable by‐products resulting from competitive denosylation. Some of the prepared compounds showed medium activity against E. coli.

Synthesis of 2‐Amino‐3‐arylindoles and their Fused Analogues via Intramolecular C‐Arylation

“…Interestingly, acidification of the reaction mixture with trifluoroacetic acid (TFA) led to conversion to a single product, which was isolated in a yield of 58% upon neutralization. The use of recently reported potassium trimethylsilanolate (TMSOK) as an alternative base for Truce-Smiles rearrangement [4,5,22] generated similar results; nevertheless, the reaction time was considerably longer. For this reason, DBU was used as the base of choice for further experiments.…”

“…To test the synthetic route, 2‐aminobenzyl cyanide 1 was reacted with 4‐nitrobenzenesulfonyl chloride (4‐NsCl) [22] followed by Mitsunobu alkylation with methanol, which smoothly yielded intermediate 3 a (Scheme 2).…”

“…In brief, Figure 2 summarizes the 1 HÀ 13 C { 1 H} and 1 HÀ 15 N long-range correlations within/ between the 2-aminoindole, 4-nitrophenyl and 4-methoxyphenylalkynyl moieties. In the case of the 2aminoindole moiety, the 1 HÀ 13 C HMBC spectrum provided key H 10 À C2, H 10 À C9, H 10 À C11, H 10 À C12, H 10 À C13, H 20 À C3 and H 22,26 À C3 correlations, and the 1 HÀ 15 N HMBC and 1 HÀ 15 N HMQC spectra provided H 10 À N 1 and H 20 À N 20 correlations. NOE correlations were observed between 2-aminoindole and protons H 10 , H 14 and H 22,26. (Figure 2).…”