Nitrogen heterocycles are ubiquitous in natural products and pharmaceuticals. Herein, we disclose a nitrogen complexation strategy that employs a strong Brønsted acid (HBF4) or an azaphilic Lewis acid (BF3) to enable remote, non-directed C(sp3)—H oxidations of tertiary (3°), secondary (2°), and primary (1°) amine- and pyridine- containing molecules with tunable iron catalysts. Imides resist oxidation and promote remote functionalization.

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance, remains a challenge for intermolecular C–H amination. Herein, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Brønsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed C–H aminations and provide new opportunities for tunable selectivities.

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Allylic amination enables late-stage functionalization of natural products where allylic C−H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [Mn III (ClPc)], achieves selective, preparative intermolecular allylic C−H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [Mn III (ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

We report a versatile and functional-group-tolerant method for the Pd-catalyzed C–N cross-coupling of five-membered heteroaryl halides with primary and secondary amines, an important but underexplored transformation. Coupling reactions of challenging, pharmaceutically relevant heteroarenes, such as 2-H-1,3-azoles, are reported in good-to-excellent yields. High-yielding coupling reactions of a wide set of five-membered heteroaryl halides with sterically demanding α-branched cyclic amines and acyclic secondary amines are reported for the first time. The key to the broad applicability of this method is the synergistic combination of (1) the moderate-strength base NaOTMS, which limits base-mediated decomposition of sensitive five-membered heteroarenes that ultimately leads to catalyst deactivation, and (2) the use of a GPhos-supported Pd catalyst, which effectively resists heteroarene-induced catalyst deactivation while promoting efficient coupling, even for challenging and sterically demanding amines. Cross-coupling reactions between a wide variety of five-membered heteroaryl halides and amines are demonstrated, including eight examples involving densely functionalized medicinal chemistry building blocks.

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Frequently referred to as the “magic methyl” effect, the introduction of a methyl group into a biologically active molecule has the potential to drastically alter its physical and biological properties and significantly increase potency. This effect is most pronounced when the methyl group is added at the α-position of an aliphatic heterocycle or ortho to a large rotatable group on an aromatic ring. Although seminal developments in C–H activation strategies offered solutions to the latter, until recent years there had been no selective and functional-group-tolerant method for C(sp3)–H methylation at late stages of synthesis. For many years, the lack of a generally applicable methylation strategy necessitated arduous de novo synthesis approaches to access methylated drug candidates, and discouraged further investigation and understandings of the magic methyl effect. This review will provide a summary of the most recent advances that enabled non-directed late-stage C(sp3)–H methylation, including through hydride transfer, chemical or anodic oxidation, and photocatalytic hydrogen atom transfer.

A nitrogen complexation strategy using a strong Broensted acid (HBF4) or an azaphilic Lewis acid (BF3, not shown) enables remote, non‐directed C(sp3)—H oxidations of tertiary, secondary, and primary amine‐ and pyridine‐containing molecules with tunable iron catalysts.