Synthesis of 6-Trifluoromethyl-Phenanthridines from Diaryl Isonitriles

Key words

phenanthridines - Togni’s reagent - radical trifluoromethylation - isonitriles - Ruppert–Prakash reagent

Significance

Reported is the synthesis of 6-tri­fluoromethyl phenanthridines (3–5) from the reaction of readily available isonitriles 1 with the Togni reagent (2, n = 1) involving a radical trifluoromethylation reaction. Initially, transition metals (salts of copper, iron, nickel, and cobalt) were used to carry out this transformation, but later it was realized that Bu₄NI can be successfully used as a radical initiator. A range of 6-trifluoromethyl-phenanthridines were obtained in moderate to good yields. For meta-substituted ring-C derivatives of 1, cyclization preferably occurred at the position distal to the meta substituent, but regiocontrol was low (1:1 to 7.4:1). The method was also applied to the synthesis of 6-perfluoroalkylated phenanthridines (C_nF_2n+1, n = 2, 3). The reaction did not proceed in the presence of TEMPO, suggesting a radical mechanism involving the addition of CF₃ radical to the isonitrile group, followed by a cyclization event.

Reviews

X.-F. Wu, H. Neumann, M. Beller Chem. Asian J. 2012, 7, 1744–1754; H. Liu, Z. Gu, X. Jiang Adv. Synth. Catal. 2013, 355, 617–626; T. Besset, C. Schneider, D. Cahard ­Angew. Chem. Int. Ed. 2012, 51, 5048–5050.

Comment

Trifluoromethylated (hetero)arenes are important structural motifs for drug discovery programs. Classic methods for the synthesis of CF₃-substituted (hetero)arenes rely mostly on the commercial availability of CF₃-bearing starting materials usually obtained by industrially unviable Swarts-type reactions (G. K. S. Prakash, J. Hu, J. Simon, D. R. Bellew, G. A. Olah J. Fluorine Chem. 2004, 125, 595). In more recent developments, the CF₃ group has been introduced by transition-metal-mediated cross-coupling reactions or direct C–H trifluoromethylation (see Reviews below). Despite some modest improvement in this field, new routes for the high-yielding and site-selective introduction of CF₃ groups on (hetero)arenes are required. The present method utilizes readily prepared isonitriles and provides 6-perfluoroalkylated phenanthridines without transition-metal-based catalysis. However, the Togni reagent is potentially explosive and should be handled with care (N. Fiederling, J. Haller, H. Schramm Org. Process Res. Dev. 2013, 17, 318). Conceptually, this ­method is similar to Zhou’s approach (Q. Wang, X. Dong, T. Xiao, L. Zhou Org. Lett. 2013, 15, 4846) in which, instead of the Togni reagent, a combination of PhI(OAc)₂ and the Ruppert–Prakash reagent (TMSCF₃) was used at room temperature to obtain similar derivatives.