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

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.


Naphtho[1,2,3-de][1]benzothieno[3,2-b]quinolin-5(3H)-one (4ma).
The following work-up procedure was conducted after stirring at 130 ºC for 24 h: a saturated NaHCO 3 aqueous solution (0.1 mL) was added at room temperature. The resulting mixture was stirred for 20 min and then dried over anhydrous sodium sulfate (Na 2 SO 4 ). The mixture was filtered and eluted with CHCl 3 (60 mL). (Note: due to the low solubility of the title compound in CHCl 3 , a larger amount of CHCl 3 should be required.) The solvent was evaporated, and recrystallization from CH 2 Cl 2 /EtOAc followed by washing with a small amount of EtOAc gave product 4ma. A

II. N-Methylation of Indolo[3,2-b]quinolines with MeOTf: A General Procedure for
The filtrate was concentrated, and the residue was filtered and then washed with Et 2 O (5 mL).
This concentration-filtration-washing sequence was repeated once again, and the combined solid was dried in vacuo to give analytically pure product 10. Compounds 10 synthesized here were fully characterized by 1 H, 13 C and 19 F NMR spectroscopy and HRMS.

1-[2-(Benzo[b]thien-3-ylamino)phenyl]-2-methyl-1-propanone (6ea
NMR spectra of substrates and products are collected in the following pages. Only 1 H NMR spectra are provided in the case of compounds for which 1 H NMR, 13 C NMR, and HRMS or elemental analysis data have been already reported in the literature. Both of 1 H and 13 C NMR spectra are provided in the case of compounds that have not been reported in the literature.
In the case of compounds with fluorine atoms that have not been reported in the literature, 19 F NMR spectra are also provided along with 1 H and 13 C NMR spectra.