Ru(II)‐Catalyzed Difluoromethylations of 7‐Azaindoles: Access to Novel Fluoro‐7‐Azaindole Derivatives

Abstract

Fluorinated compounds are prevalence in agrochemicals, pharmaceuticals, and biochemical sciences. Herein, we develop an efficient Ru(II)-catalyzed site-selective CÀ H functionalization/difluoromethylated reaction to separately construct 3-difluoromethylated and remote meta-difluoromethylated 7-azaindole derivatives.Methods installing functional groups after activation of inert CÀ H bonds have granted powerful and atom-economical techniques in molecular syntheses and derivatization. [1] In recent years, transition-metal-catalyzed remote meta-CÀ H fluoromethylations to construct fluorinated molecules have received certain efforts. [3] Nevertheless, site-selective CÀ H functionalization/(di)fluoromethylated reaction is still a big challenge because most molecules possess multiple complex and similarity CÀ H bonds. [2] Therefore, the popularity of the elegant protocols is attributed to the use of the heteroatomassisted chelation and ingenious design of substrates. However, most directing groups need to be removed in the end because of lacking bioactivity and potential for further functionalization besides the chelation assistance.In drug design, the most well-established methods are to selective fluorination of the existing bioactive compounds. [4] 7azaindoles with the unique structure have provoked great interest, thus widely applied to drug discovery, such as the anticancer drug vemurafenib, hNM1 receptor, and ATP-competitive inhibitors. [5] Furthermore, 7-azaindole itself could also be used as a directing group. [6] Therefore, we hope to induce fluorine into 7-azaindoles to synthesize various fluorinated-7azaindole derivatives, which might have potential biological activity to become drug candidates. Herein, we report regiodivergent CÀ H functionalization/difluoromethylated reaction of 7-azaindoles with bromo difluoroesters to separately generate 3-difluoromethylated and remote meta-difluoromethylated 7-azaindole derivatives, that the former involves radical mechanism while the latter might proceed cyclometalation/remote σactivation pathway (Figure 1).

Laser spectroscopic characterization of supersonic jet cooled 2,7-diazaindole

“…[10][11][12] Because of their donor and acceptor properties, azaindoles have been extensively investigated by synthetic and medicinal chemists for developing novel biological targets. [13][14][15][16] 7-Azaindole (1H-pyrrolo [2,3-b]pyridine) in particular has actively attracted interest since its dimer has been identified as a simple model system for DNA base pairs, to study the photochemical processes and its role in mutations. [17][18][19][20][21] Most of the 7-azaindole derivatives are synthetic molecules, however, some of them do exist in nature.…”

Difluoromethylation of heterocyclesviaa radical process

“…In order to achieve this purpose, Dong and coworkers developed an efficient remote regioselective C–H difluoromethylation reaction of 7-azaindole derivatives under Ru catalysis (Scheme 12). 52 Various para -substituted substrates were fully examined, affording the corresponding remote meta -functionalization products 95–98 in good to excellent yields. Moreover, the substituents on the azaindole ring were also well tolerated.…”

Laser Spectroscopic Characterization of Supersonic Jet Cooled 2,7-Diazaindole (27DAI)

“…[10][11][12] Because of their donor and acceptor properties, they have been extensively investigated by synthetic and medicinal chemists for developing novel biological targets. [13][14][15][16] 7-azaindole (1H-pyrrolo [2,3-b]pyridine) in particular has actively gained interest since its dimer been identified as a simple model system for DNA base pairs, to study the photochemical processes and their role in mutations. [17][18][19][20][21] Most of the 7-azaindole derivatives are synthetic molecules, however some of them do exist in nature.…”