Synthesis of Quinazolinone-Fused Tetrahydroisoquinolines and Related Polycyclic Scaffolds by Iodine-Mediated sp³ C–H Amination

Abstract

An iodine-mediated intramolecular sp 3 C−H amination reaction producing quinazolinone-fused polycyclic skeletons from 2-aminobenzamide precursors is reported. This reaction does not use transition metals, has a broad substrate scope, and can be used on a gram scale. Under the optimal reaction conditions, a variety of quinazolinone-fused tetrahydroisoquinolines and derivatives of Rutaecarpine were synthesized from readily accessible compounds. The reaction proceeds well with crude 2aminobenzamide derivatives, allowing for the synthesis of the products from simple 2-aminobenzoic acids and tetrahydroisoquinolines without purification of the 2-aminobenzamide intermediates. Preliminary biological experiments have identified Cereblon (CRBN) inhibitory activity and relevant anti-myeloma medicinal properties in some of these polycyclic products.

Synthesis of bioactive evodiamine and rutaecarpine analogues under ball milling conditions

“…28 mp: 259–260 °C; lit. 37 mp: 257–259 °C;). 1 H NMR (400 MHz, CDCl 3 ) δ 9.17 (br s, 1H), 8.32 (dd, J = 8.1, 1.6 Hz, 1H), 7.73–7.69 (m, 1H), 7.68–7.61 (m, 2H), 7.45–7.39 (m, 2H), 7.34 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 4.59 (t, J = 6.9 Hz, 2H), 3.24 (t, J = 6.9 Hz, 2H).…”

“…13 C NMR (100 MHz, CDCl 3 ): δ 164.5, 150.7, 137.1, 133.2, 132.6, 128.9, 128.8, 128.5, 127.9, 127.0, 122.1, 121.9, 119.7, 72.0, 39.4, 36.4, 28.6; the spectral data are in accordance with the literature data. 37…”

“…13 C NMR (100 MHz, CDCl 3 ): δ 164.5, 150.7, 137.1, 133.2, 132.6, 128.9, 128.8, 128.5, 127.9, 127.0, 122.1, 121.9, 119.7, 72.0, 39.4, 36.4, 28.6; the spectral data are in accordance with the literature data. 37 Cell lines and cell viability assay ATCC cell lines (Manassas, VA, USA) including oral cancer (CAL 27, OC-2, and SCC9) and normal (HGF-1) cell lines, as well as the RIKEN BioResource Research Center cell lines (Tsukuba, Ibaraki, Japan) including oral cancer cells (HSC-3 and Ca9-22) were used. All detailed culture conditions have been previously described.…”