Design and Scalable Synthesis of N‐Alkylhydroxylamine Reagents for the Direct Iron‐Catalyzed Installation of Medicinally Relevant Amines**

Abstract

Secondary and tertiary alkylamines are privileged substance classes that are often found in pharmaceuticals and other biologically active small molecules. Herein, we report their direct synthesis from alkenes through an aminative difunctionalization reaction enabled by iron catalysis. A family of ten novel hydroxylamine‐derived aminating reagents were designed for the installation of several medicinally relevant amine groups, such as methylamine, morpholine and piperazine, through the aminochlorination of alkenes. The method has excellent functional group tolerance and a broad scope of alkenes was converted to the corresponding products, including several drug‐like molecules. Besides aminochlorination, the installation of other functionalities through aminoazidation, aminohydroxylation and even intramolecular carboamination reactions, was demonstrated, further highlighting the broad potential of these new reagents for the discovery of novel amination reactions.

A Combined Spectroscopic and Computational Study on the Mechanism of Iron-Catalyzed Aminofunctionalization of Olefins Using Hydroxylamine Derived N–O Reagent as the “Amino” Source and “Oxidant”

“…The unusual electronic structure of Int II , with an elongated Fe–N bond, makes it highly efficient for participating in the N -transfer reaction to styrenyl olefins (Scheme , Figure ), and in the presence of nucleophilic solvent, regioselectively forms aminoethers, which are versatile intermediates for the synthesis of bioactive compounds. Besides unravelling the mechanism for the aminomethoxylation reaction, the mechanistic cycle proposed above, and the electronic structure of the two new iron–nitrogen intermediates reported in this study, should also provide key reference points for understanding the mechanism of other iron catalyzed aminofunctionalization reactions of organic molecules by the hydroxyl amine derived reagent (PivONH 3 OTf) reported in literature. − Int I , a high spin Fe­(III)- N -acyloxy species, has a resemblance to high spin Fe­(III)-alkyl/acyl peroxo intermediates known in the literature, formed during the reaction of an Fe­(II) catalyst and alkyl/aryl peroxides. Though Fe­(NH) complexes as isoelectronic surrogates to Fe­(O) functionalities are reported in literature, , to the best of our knowledge this is the first report of a high-spin Fe­(III)- N -acyloxy intermediate as a synthetic analogue of the Fe­(III)-alkyl/acyl peroxo intermediate.…”

“…In order to address these issues, and inspired by the seminal work from Minisci, Morandi and co-workers have developed a research program focused on iron-catalyzed direct synthesis of unprotected amines (aminofunctionalization of alkenes) using hydroxylamine derived reagents (Scheme , left panel). − The versatile reactivity of the iron-catalyzed aminofunctionalization was also successfully exploited for heteroatom amination (Scheme , left panel). , Subsequently, Arnold and co-workers broadened the utility of these hydroxylamine-derived reagents to mimic the non-natural nitrene transfer reaction for enantioselective amination of styrenyl olefins, as well as −C–H bonds of alkanes, catalyzed by engineered hemoproteins (Scheme , right panel). , However, despite the successful utilization of the iron-catalyzed amination reaction on various organic substrates, the mechanistic pathway and nature of the active species responsible for the aminofunctionalization reaction, whether a free aminium organic radical (NH 3 +• ) − or any iron-based aminating species is involved ,,− remains unknown. To date there has been no spectroscopic or theoretical report on the mechanistic details of the iron-catalyzed reaction by these novel hydroxyl-amine derived reagents.…”

“…To date there has been no spectroscopic or theoretical report on the mechanistic details of the iron-catalyzed reaction by these novel hydroxyl-amine derived reagents. However, control studies have strongly implicated the key role of iron in the amination reaction. − …”

Electrophilic Aminating Agents in Total Synthesis

“…[251,252] Related radical-based processes that use electrophilic nitrogen sources enable,f or example,a lkene aminochlorination reactions. [253,254] Less commonly,e lectrophilic nitrogen radicals are employed in hydrogen-atom-transfer reactions and fragmentations related to the classical Norrish Ia nd II reactions. [255,256] It is important to note that, due to differences in philicity,n ot all electrophilic nitrogen radicals are amenable to all types of transformations.Adistinct highlight is that electrophilic nitrogen radicals can engage in the functionalization of typically unreactive bonds,a nd this feature can be harnessed for the synthesis of complex N-heterocycles.…”