Regioselective and Direct Azidation of Anilines via Cu(II)-Catalyzed C–H Functionalization in Water

Abstract

We report herein the first example of Cu(II)-catalyzed site selective azidation of aromatic amines via C-H functionalization in aqueous media. In our strategy, a mild reagent was utilized. HO served as the oxidant, and sodium azide was used as the azidation reagent. This method could also be applied to late-stage functionalization of drugs that possess an aromatic amine moiety. In addition, we found that bromination or iodination on the ortho-position of aromatic amines could occur efficiently using this catalytic system.

Transition Metal Catalyzed Azidation Reactions

“…Reasonably, the diazidation compound 14 arises from 13 through an analogous reaction path, which involves the unoccupied o-position of the amino group. Some years later, the same approach was exploited for a direct and regioselective azidation of anilines by use of a Cu(OAc) 2 catalyst, NaN 3 , and H 2 O 2 as the oxidant (Scheme 16) [66]. The reaction runs in mild conditions in water as solvent through a mechanism analogous to that previously reported in Scheme 15.…”

Chemical versatility of azide radical: journey from a transient species to synthetic accessibility in organic transformations

“…In 2017, the Zheng and Zhu group also reported the environmentally-benign direct azidation of anilines via Cu(II)catalyzed C-H functionalization in water using NaN as a mild oxidant (Scheme 63). 191 This reaction features broad substrates scope, high site-selectivity, applicability in late-stage functionalization of aniline-based drugs (such as procaine, benzocaine, and aminoglutethimide), and showing biocompatibility in water or even in the presence of cell lysate medium. The authors proposed a free-radical cross-coupling reaction mechanism based on radical trapping and radical inhibition experiments using 1,1-diphenylethylene and TEMPO, respectively, and XPS study for citing the role of Cu(II).…”

Methods for direct C(sp2)–H bonds azidation

“…Based on a series of other control experiments, the authors suggested that the reaction starts with the generation of an aryl-Cu II complex A through the coordination of Cu(OAc) 2 to the nitrogen atoms of 8-aminoquinoline 11, which is followed by reaction with the azide radical, which is generated in situ from the NaN 3 and K 2 S 2 O 8 Recently, the same group developed an interesting Cucatalyzed free amino group-directed C-H bond azidation of aromatic amines with NaN 3 . 21 Thus, various electron-rich and electron-poor anilines 13 in the presence of 25 mol% of Cu(OAc) 2 and 2 equiv. of H 2 O 2 in neat water underwent orthoselective azidation and afforded the target aryl azides 14 in moderate to high yields (Scheme 8).…”

“…Recently, the same group developed an interesting Cu-catalyzed free amino group-directed C–H bond azidation of aromatic amines with NaN 3 . 21 Thus, various electron-rich and electron-poor anilines 13 in the presence of 25 mol% of Cu(OAc) 2 and 2 equiv. of H 2 O 2 in neat water underwent ortho -selective azidation and afforded the target aryl azides 14 in moderate to high yields ( Scheme 8 ).…”