Super-Electron-Donor 2-Azaallyl Anions Enable Construction of Isoquinolines

Abstract

Herein is introduced the application of “super-electron-donor”(SED) 2-azaallyl anions in a tandem reduction/radical cyclization/radical coupling/aromatization protocol that enables the rapid construction of isoquinolines. The value of this transition-metal-free method is highlighted by the wide range of isoquinoline ethyl amines prepared with good functional group tolerance and yields. An operationally simple gram scale synthesis is also conducted, confirming the scalability.

Copper-Catalyzed Domino Three-Component Benzannulation: Access to Isoquinolines

“…Solvent screening showed the importance of the H 2 O, since, in toluene, THF, DMSO, and MeCN, no better results were observed (Table 1, entries 4−7). Several common copper catalysts, such as CuBr, CuCl, CuCl 2 , or Cu(OAC) 2 , were also examined, and CuI was proven to have high catalysis efficiency (Table 1, entries 8− 11). Moreover, we found that the isolated yields were decreased when NaOH was replaced by KOH or Na 2 CO 3 (Table 1, entries 12 and 13).…”

“…Particularly, isoquinoline motifs possess various bioactivities such as cardiovascular, antitumor, anti-inflammatory, or anti-malaria properties. In order to improve the chemical toolbox for the synthesis of biologically relevant molecules, great effort has been devoted to developing efficient methodologies for the preparation of isoquinolines, which include transition-metal-catalyzed annulation reactions of 2-alkynylbenzyl azides or 2-alkylnyl aromatic imines and oximes, C–H functionalization, dehydrogenation of N -heterocycles, the tandem reduction/radical cyclization protocol, and tandem reduction/rearrangement of cyclic imides . Most of these procedures require multistep synthesis or prefunctionalized substrates or give limited substrate scope.…”

Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives

“…We developed a series of radical–radical coupling approaches enabled by single electron transfer (SET) from 2-azaallyl anions (Scheme a). ,, Specifically, 2-azaallyl anions undergo SET with various aryl/alkyl halides or allyl ethers to generate 2-azaallyl radicals and aryl, alkyl, or allyl radicals followed by radical–radical coupling processes to form new C–C bonds. This strategy has proven useful in tandem reactions to prepare heterocycles of medicinal chemistry interest. − …”

Synthesis of Tryptamines from Radical Cyclization of 2-Iodoaryl Allenyl Amines and Coupling with 2-Azallyls

“…Panetti, Schelter, Walsh, and co-workers reported the solid-state structures and electrochemistry of the 2-azaallyl anions . Recently, Yang, Zhang, Walsh, and co-workers applied this unique radical generation and coupling strategy in the synthesis of benzofurylethylamines, isochromenylethylamines, and isoquinoline ethylamines using 2-iodo aryl allenyl ethers and amines as electron acceptors (Scheme c). − Cross-dehydrogenative coupling reactions were also introduced. , Additionally, Nishikata, Yazaki, Ohshima, and their co-workers used a copper-catalyzed generation of 2-azaallyl radicals to develop a synthesis of hindered α-amino acid derivatives. , …”