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

Abstract

We disclose herein the first synthetic method that is capable of offering heteroaryl[b]quinolines (HA[b]Qs) with structural diversity, which include tricyclic and tetracyclic structures with (benzo)thienyl, (benzo)furanyl, and indolyl rings. The target HA[b]Q is addressed by the annulation of o-acylanilines and MeO–heteroarenes with the aid of an indium Lewis acid that effectively works to make two different types of the N–C and C–C bonds in one batch. A series of indolo[3,2-b]quinolines prepared here can be subsequently transformed to structurally unprecedented cryptolepine derivatives. Mechanistic studies showed that the N–C bond formation is followed by the C–C bond formation. The indium-catalyzed annulation reaction thus starts with the nucleophilic attack of the NH2 group of o-acylanilines to the MeO-connected carbon atom of the heteroaryl ring in an SNAr fashion, and thereby the N–C bond is formed. The resulting intermediate then cyclizes to make the C–C bond through the nucleophilic attack of the heteroaryl-ring-based carbon atom to the carbonyl carbon atom, providing the HA[b]Q after aromatizing dehydration.

Iodothiophenes and Related Compounds as Coupling Partners in Copper-Mediated N-Arylation of Anilines

“…Tsuchimoto and co-workers reported in 2018 an efficient approach to access such compounds in a similar scope by indiumcatalyzed annulation of 2-acylanilines with suitably methoxy-substituted (benzo)furans or (benzo)thiophenes. 28 In the same paper, they also highlighted the similarity between 11-methylbenzothieno[3,2-b]quinoline (8f) and 11methylcryptolepine (Figure 4, bottom), which is a submicromolar cytotoxic agent against KB cancer cells. 36 Furthermore, Bonjean, Bailly, and co-workers showed in 1998 that cryptolepine selectively binds to DNA and acts both as a potent topoisomerase II inhibitor and a promising antitumor agent in melanoma cells.…”

“…The analyses are as described previously. 28 Also isolated with eluent: heptane/EtOAc 90:10 (R f = 0.62) was 2-(5-methyl-2-thienylamino)acetophenone (8c′) (30 mg, 13%) as an orange oil. 594, 612, 750, 796, 955, 1019, 1038, 1092, 1151, 1242, 1311, 1357, 1398, 1419, 1450, 1504, 1572, 1604, 1638, 1678, 2914, 2965, 3236 cm -1 .…”

Recent Advances in the Synthesis of Thienoquinolines (Quinoline‐fused heterocycle)

“…[36] (Scheme 13) Here, 2-aminoketones were efficiently reacted with 2-iodobenzo In 2018, Tsuchimoto and co-workers explored an indiumcatalyzed synthesis of benzo[4,5]thieno[3,2-b]quinolines 48 from o-acylanilines 46 with alkoxyheteroarenes 47. [37] (Scheme 14) The exemplary reaction of o-acetylaniline with 3methoxybenzothiophene (1.2 equiv.) in the presence of indium (III)bromide as a Lewis-acid catalyst under chlorobenzene to obtain corresponding benzo[4,5]thieno [3,2-b]quinolines via intermolecular annulation.…”

Recent progress on the chemistry of thieno[3,2‐b]quinoline derivatives (part III)

“…Thieno[3,2‐ b ]quinoline 63a‐m were obtained in high yields by the mixing of o ‐acylanilines 62a‐m with 2‐methoxythiophenes 49 in the presence of a catalytic InBr 3 Lewis acid (Scheme 11). [ 21 ]…”

“…Finally, dehydration of the intermediate 56 afforded the desired benzothieno[3,2‐ b ]quinoline derivatives 63 (Scheme 12). [ 21 ]…”