C−H Cyanation of 6‐Ring N‐Containing Heteroaromatics

Abstract

Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far‐reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C−H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one‐pot protocol is simple to perform, is applicable to a broad range of decorated 6‐ring N‐containing heterocycles, and has been shown to be suitable for late‐stage functionalization of complex drug‐like architectures.

New trends and applications in cyanation isotope chemistry

“…It is also worth mentioning that there are C―H cyanation reactions described wherein no leaving group‐containing precursor needs to be synthesized. The 1‐pot protocol reported by Dixon et al activates N‐heterocycles by triflic anhydride (Tf 2 O) and adds cyanide from TMSCN to the reaction mixture . Unfortunately, an excess of 5 eq.…”

Regioselective Cyanation of Six‐Membered N‐Heteroaromatic Compounds Under Metal‐, Activator‐, Base‐ and Solvent‐Free Conditions

“…Two encouraging reports appeared in the recent literature one each by the groups of Fier [15] and Paton [16] describing the transition metalfree direct cyanation approach. Two encouraging reports appeared in the recent literature one each by the groups of Fier [15] and Paton [16] describing the transition metalfree direct cyanation approach.…”

“…Various reagents like dimethyl sulphate, [17] N,N-dimethylcarbamoyl chloride, [18] ethyl chloroformate, [19] benzoyl halides, [20] acetic anhydrides, [21] and MsCl, [22] have been used as activators for this purpose [more recently, Sun and coworkers used hypervalent iodine (III) [23] as an activating agent]. [15,16,25] Therefore, it is apparent that these particular method- ologies need not only high cost but have environmental issues. In addition, these reagents are often hazardous, toxic, and sensitive towards air and moisture, which stiffen easy handling.…”

“…In general, the transition metal‐free approach for the cyanation of N ‐heteroarenes (or N ‐oxides) often involves two steps: (1) activation of the heteroaromatic ring by a suitable electrophilic activator and (2) the nucleophilic addition of the cyanide ion immediately followed by the associated base mediated elimination and rearomatization to generate the cyanated heteroaromatic compounds. Two encouraging reports appeared in the recent literature one each by the groups of Fier and Paton describing the transition metal‐free direct cyanation approach. However, both methodologies have limitations.…”

Hypervalent Iodine(III)‐Mediated Regioselective Cyanation of Quinoline N‐Oxides with Trimethylsilyl Cyanide

“…Nonetheless, the reaction had other isomers with poor regioselectivity (Scheme 1d). [12] In 2017, P. S. Fier reported that cyanation of pyridine used NaCN as an cyanation reagent with a-chloro O-methanesulfonyl aldoximes as an activator under mild conditions (Scheme 1e). [13] However, NaCN as a toxic cyanation reagent was required.…”