Selective Synthesis of Dihydrophenanthridine and Phenanthridine Derivatives from the Cascade Reactions of o-Arylanilines with Alkynoates through C–H/N–H/C–C Bond Cleavage

Abstract

In this paper, an unprecedented selective synthesis of dihydrophenanthridine and phenanthridine derivatives through the cascade reactions of 2-arylanilines with alkynoates is presented. Mechanistic studies showed that the formation of the dihydrophenanthridine scaffold involves an initial C­(sp2)–H alkenylation of 2-arylaniline with alkynoate followed by an intramolecular aza-Michael addition. When this reaction is carried out at elevated temperature, the in situ formed substituted dihydrophenanthridine readily undergoes a retro-Mannich-type reaction to give the corresponding phenanthridine through C–C bond cleavage. Compared with literature methods, this novel protocol has advantages such as easily obtainable substrates with a free amino group, pharmaceutically privileged products, cheap catalysts, and conveniently controllable selectivity.

Transition Metal Catalyzed Free‐Amine (−NH2) Directed C−H Bond Activation and Functionalization for Biaryl Frameworks

“…Zhang and colleagues unveiled an elegant example of Ru(II)catalyzed cascade 6-membered annulation of o-arylanilines with diverse alkynoates, where ubiquitous dihydrophenanthridine and phenanthridine skeletons can be directly accessed (Scheme 7). [14] Authors recognized the substantial effects of 4 Å molecular sieve, silver salt (AgOTf), and the reaction…”

Free Amine, Hydroxyl and Sulfhydryl Directed C−H Functionalization and Annulation: Application to Heterocycle Synthesis

“…Fan and co‐workers reported the selective synthesis of dihydrophenanthridines 11 and phenanthridines 12 via C(sp 2 )−H bond activation and functionalization of 2‐arylanilines with alkynoates 10 (Scheme 5). [16] [Ru( p ‐cymene)Cl 2 ] 2 catalyzed the transformation in the presence of AgOTf additive at 60 °C to provide dihydrophenanthridines 11 in moderate to good yields, whereas increasing the temperature to 120 °C resulted into phenanthridine derivatives 12 under similar catalytic conditions. In general, electron‐donating substituents on aniline ring of 2‐arylanilines gave corresponding adducts in higher yields than the electron‐withdrawing groups on aniline ring.…”

Synthesis of 5,6-Dihydrophenanthridines via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds

“…In view of the structural feature of 5,6-dihydrophenanthridines, the formation of their aryl−aryl bond is undoubtedly the key step. To date, there are three main strategies to forge the aryl−aryl bond of 5,6-dihydrophenanthridines ( Scheme 1 ): (1) transition-metal-catalyzed cross-couplings of organometallic aryls with aryl halides (path A) [ 24 , 25 , 26 , 27 , 28 , 29 , 30 ]; (2) annulation via benzyne intermediates (path B) [ 31 , 32 , 33 ]; and (3) the direct arylation of nonactivated aryl C−H bonds with aryl halides (path C) [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Compared to paths A and B, the biggest advantage of path C is that the more expensive and difficult-to-prepare organometallic coupling partner is replaced in this transformation.…”