Nickel-Catalyzed C(sp2)-H Trifluoromethylation and Nitration of 8-Aminoquinoline Derivatives

Joseph P. Lokant*, Mariah L. Murray* and Jessica M. Hoover, C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506

Field (Broad Category): Chemistry (Physical Sciences & Engineering)

Student’s Major: Biochemistry (ACS Track) 

The activation and functionalization of inert C(sp2)-H bonds continues to be a prominent area of research in organic chemistry. This field has the potential to significantly improve current synthetic routes to pharmaceuticals, materials, and natural products. Earth-abundant first-row transition metals, such as nickel, are often used as catalysts to mediate these difficult transformations. Much of the work in nickelcatalyzed C(sp2)-H activation involves the 8-aminoquinoline directing group, which has proven very versatile for enabling formation of new C-C or C-heteroatom bonds on a pendant amide. Functionalizations of the 8-aminoquinoline backbone are also highly targeted due to the motifs’ presence in a variety of biologically active compounds. We recently identified an unexpected nickel-mediated trifluoromethylation at the C5 position of the quinoline moiety. In this reaction, nickel (II) nitrate is used as the catalyst in the presence of sodium carbonate base, pivalic acid, and Umemoto’s Reagent I (a CF3+ source). Interestingly, removal of the sodium carbonate base resulted in C5 nitration, with the nitro group being generated from the nickel (II) nitrate catalyst. Using tert-butyl nitrite as the nitro source greatly improved the yield of this compound. Current work in our laboratory is devoted to optimizing these two functionalizations independently, and the progress is reported herein. 

Funding: NIH 

Program/mechanism supporting research/creative efforts: WVU 497-level course