Expeditious Synthesis of 6-Fluoroalkyl-Phenanthridines via Palladium-Catalyzed Norbornene-Mediated Dehydrogenative Annulation

Abstract

A novel palladium-catalyzed, norbornene-mediated intermolecular dehydrogenative annulation approach for the synthesis of 6-fluoroalkyl-phenanthridines from aryl iodides and fluorinated imidoyl chlorides, which are important structural motifs for bioactive molecules, is reported. Fluorinated imidoyl chlorides served as a new type of electrophilic reagent in the Catellani-type reaction, which, in turn, could be readily prepared from various anilines and fluorinated carboxylic acids. Control experiments were carried out to study the mechanism of the reaction. This transformation is scalable and tolerates a broad range of functional groups.

Trifluoroacetimidoyl halides: a potent synthetic origin

“…Oxidative addition of the Pd 0 catalyst into the C-Cl bond of the imidoyl chloride gave palladium complex 79-A, which under- Chen, Zhu and co-workers developed a palladium-catalyzed, Catellani-type dehydrogenation annulation reaction from fluorinated imidoyl chlorides and aryl iodines for the synthesis of biologically relevant 6-fluoroalkyl phenanthridines (Scheme 84). 101 The norbornene (NBE) was utilized to mediate the reaction. The transformation showed broad substrate scope with respect to fluorinated imidoyl chlorides and aryl iodines.…”

Metal‐Free Synthesis of 5‐Trifluoromethyl‐1,2,4‐Triazoles from Iodine‐Mediated Annulation of Trifluoroacetimidoyl Chlorides and Hydrazones

“…Additionally, transition‐metal‐catalyzed transformations of trifluoroacetimidoyl halides with alkynes for the construction of 2‐trifluoromethyl quinolones have also been extensively investigated (Scheme e) . The 2‐trifluoromethyl quinolone could also be obtained through palladium‐catalyzed tandem Suzuki/C−H arylation reaction of trifluoroacetimidoyl chlorides with arylboronic acids– or norbornene‐mediated intermolecular dehydrogenative annulation with aryl iodides (Scheme f). Recently, a Pd(0)‐catalyzed C( sp 3 )−H functionalization of trifluoroacetimidoyl chlorides to lead to 2‐(trifluoromethyl)indoles was reported by Cramer and co‐workers.…”

“…[2] In general, there are two mainstream pathways to access to versatile trifluoromethyl-substituted N-heterocycles: 1 st ) trifluoromethylation of pre-synthesized N-heterocycles by the employment of diverse trifluoromethyl reagents; [3] 2 ed ) direct construction of trifluoromethyl-substituted N-heterocycles through the reaction of different trifluoromethyl-containing synthons with suitable coupling substrates. [6][7][8][9][10][11][12] Trifluoroacetimidoyl halides were usually applied as useful building blocks for the assembly of trifluoromethyl-substituted N-heterocycles in synthetic organofluorine chemistry. [6][7][8][9][10][11][12] Trifluoroacetimidoyl halides were usually applied as useful building blocks for the assembly of trifluoromethyl-substituted N-heterocycles in synthetic organofluorine chemistry.…”

“…[4] In this context, in contrast to the frequent application of 2,2,2trifluorodiazoethane (CF 3 CHN 2 ) as an appealing trifluoromethyl-containing 1,3-dipole to build numer-ous trifluoromethyl-substituted N-heterocycles, [5] the using of trifluoroacetimidoyl halide as trifluoromethyl synthon is proven to be exceptional in many cases. [6][7][8][9][10][11][12] Trifluoroacetimidoyl halides were usually applied as useful building blocks for the assembly of trifluoromethyl-substituted N-heterocycles in synthetic organofluorine chemistry. In 2010, the research groups of Wu [6a] and Zhang [6b] reported palladium-or coppercatalyzed cyclization of trifluoroacetimidoyl chlorides with sodium hydrosulfide hydrate to synthesize 2trifluoromethylbenzothiazoles, respectively (Scheme 1a).…”

Recent Developments in the Palladium‐Catalyzed/Norbornene‐Mediated Synthesis of Carbo‐ and Heterocycles

“…The synthetic In 2018, Zhu and coworkers demonstrated palladium catalyzed/norbornene mediated dehydrogenative annulation strategy for the synthesis of 6-fluoroalkyl-phenanthridines 66 from aryl iodides 1 and fluorinated imidoyl chlorides 65 (Scheme 11). [19] Optimized reaction condition was realized with Pd(OAc) 2 (10 mol %) as the catalyst, P(4-F-C 6 H 4 ) 3 (20 mol %) as the ligand, norbornene (1 equiv) as the co-catalyst and K 3 PO 4 (4 equiv) as a base in toluene at 100°C for 12 h. Notably, P(4-F-C 6 H 4 ) 3 ligand and K 3 PO 4 base were essential for this transformation to achieve better yields of the required products. Substrate scope studies revealed that various functional groups such as isopropyl, methoxyl, fluoro, chloro, trifluoromethyl, trifluoromethoxyl and phenyl present at ortho position of aryl iodides were well tolerated provided the corresponding annulated products in moderate to excellent yields.…”