A Cross‐Dehydrogenative Annulation Strategy towards Synthesis of Polyfluorinated Phenanthridinones with Copper

Abstract

The first cross-dehydrogenative annulation of (hetero)aromatic amides with polyfluoro(hetero)arenes is presented. This operationally simple oxidative annulation process is mediated by inexpensive copper salt, accommodates a wide range of substrates with exquisite chemo- and regioselectivity profile, and produces demanding polyfluorinated phenanthridinones in high yields (up to 92 %). Using alkenyl amides under identical conditions, the synthesis of polyfluorinated 2-quinolones has also been accomplished. Given the importance of fluorinated heterocycles in the pharmaceutical industry and drug discovery, this work is highly significant.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…Copper is an abundant, non-expensive, and relatively nontoxic transition metal, and therefore copper-mediated reactions for direct functionalization of C-H bonds have emerged as promising tools for development of more sustainable methods for the synthesis of fine chemicals. Reactions involving copper-medi-ated C-H activations allow for a direct insertion of functional groups in unreactive C-H bonds and the formation of carbon-carbon bonds without the requirement of prefunctionalized substrates, which allow for shorter synthetic routes or latestage modifications of structurally complex compounds [304][305][306][307][308][309][310][311][312]. However, the development of efficient methods can be challenging due to the requirement of directing groups and control of selectivity.…”

“…On the other hand, such heterocyclic moieties present in bioactive compounds, or their synthetic intermediates may eventually play the role of a directing group, thus providing an opportunity for convenient and straightforward transformations based on metal-mediated C-H activation [314]. Many methods potentially useful for the synthesis or modification of bioactive compounds based on copper-promoted activation of C-H bonds in (hetero)arenes have been reported in the last years, including methods for the formation of C-C [304][305][306][307][308][309][310][311][312], C-X [315][316][317][318][319], C-N [305,[320][321][322][323][324], C-O [325][326][327][328][329][330], and C-S [324,331,332] bonds. Some of these methods are highlighted herein.…”

2-Amino-5,6-difluorophenyl-1H-pyrazole-Directed PdII Catalysis: Arylation of Unactivated β-C(sp3)–H Bonds

“…Recently, Li’s and Baidya’s groups presented 2-aminophenyl-1 H -pyrazole as an effective N,N-bidentate auxiliary to realize various C­(sp 2 )–H functionalizations . Most recently, our groups reported ortho-arylation of aromatic amides directed by 2-amino-5-chlorophenyl-1 H -pyrazole with general work conditions, broader substrate scope, and wider functional group tolerance .…”

Copper-Catalyzed 8-Aminoquinoline-Directed Oxidative C–H/N–H Coupling for N-Arylation of Sulfoximines

“…Recently, Bolm et al also delineated a Cu­(II)-catalyzed direct amination of benzamide derivatives utilizing N -arylated dibenzothiophene sulfoximine as an intermediate, where pyridine was used as the solvent (Scheme b) . With our continuous interest in developing general protocols toward carbon–heteroatom bonds, we envisaged that the Cu­(II)-catalyzed bidentate auxiliary-directed ortho -C–H bond activation of benzamides and the concomitant C–N bond-forming reaction with readily available sulfoximines can provide an easy entry to N -arylated sulfoximines. However, the materialization of this concept in a catalytic fashion is increasingly challenging as the product formed in this process can act as a tridentate N , N , N -type pincer ligand, which can form a complex with the Cu­(II) catalyst and diminish the catalytic efficacy.…”