From N–H Nitration to Controllable Aromatic Mononitration and Dinitration─The Discovery of a Versatile and Powerful N-Nitropyrazole Nitrating Reagent

Abstract

Nitroaromatics are tremendously valuable organic compounds with a long history of being used as pharmaceuticals, agrochemicals, and explosives as well as vital intermediates to a wide variety of chemicals. Consequently, the exploration of aromatic nitration has become an important endeavor in both academia and industry. Herein, we report the identification of a powerful nitrating reagent, 5-methyl-1,3-dinitro-1 H -pyrazole, from the N -nitro-type reagent library constructed using a practical N–H nitration method. This nitrating reagent behaves as a controllable source of the nitronium ion, enabling mild and scalable nitration of a broad range of (hetero)arenes with good functional group tolerance. Of note, our nitration method could be controlled by manipulating the reaction conditions to furnish mononitrated or dinitrated product selectively. The value of this method in medicinal chemistry has been well established by its efficient late-stage C–H nitration of complex biorelevant molecules. Density functional theory (DFT) calculations and preliminary mechanistic studies reveal that the powerfulness and versatility of this nitrating reagent are due to the synergistic “nitro effect” and “methyl effect”.

Photochemical Nitration of Protected Anilines by 5‐Methyl‐1,4‐dinitroimidazole

“…[9] Very recently, Zhuang and co-workers reported N-nitropyrazoles as versatile nitrating reagents that efficiently introduce nitro groups in (hetero)arenes, including protected anilines, under heat conditions. [10] Despite the abovementioned progress, nitration protocols that proceed under room temperature and work for a variety of anilines without the use of transition metals or acids are still highly desired. Recently, we reported that 5-methyl-dinitroimidazole (DNIm) is a photoreactive reagent that converts phenol derivatives to corresponding ortho-nitrophenol products under 390 nm light irradiation in aqueous solutions.…”

“…[ 9 ] Very recently, Zhuang and co‐workers reported N ‐nitropyrazoles as versatile nitrating reagents that efficiently introduce nitro groups in (hetero)arenes, including protected anilines, under heat conditions. [ 10 ]…”

Dinitro-5,5-Dimethylhydantoin: An Arene Nitration Reagent

“…13 Zhuang, Zhou, Shi, and coworkers succeeded in the development of 10 as a facile Nnitropyrazole reagent for controllable aromatic mononitration and dinitration. 21 The advantages of N-nitro-type reagents include mild reaction conditions, good functional group tolerance, and arene substrates without the requirement of being prefunctionalized. It is noteworthy that the nitration capability is closely related to the host-structure of the N-nitro type reagent.…”

“…9 had been developed as a light-controlled nitration reagent of proteins by Wang, Tian, and co-workers . Zhuang, Zhou, Shi, and co-workers succeeded in the development of 10 as a facile N -nitropyrazole reagent for controllable aromatic mononitration and dinitration . The advantages of N -nitro-type reagents include mild reaction conditions, good functional group tolerance, and arene substrates without the requirement of being prefunctionalized.…”

Trifluoromethanesulfonic Acid Promoted Controllable Electrophilic Aromatic Nitration

“…This method demonstrated exceptional functional group tolerance and was used for the late-stage functionalization of complex molecules. In 2022, Zhuang and co-workers reported a controllable aromatic mononitration and dinitration method with N -nitropyrazole as the nitrating reagent and Lewis acid as the catalyst (Scheme c) …”