Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

The “magic methyl” effect – a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group – provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)–H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthetic strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules

The “magic methyl” effect – a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group – provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)–H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthetic strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.

C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

The “magic methyl” effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)–H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light–initiated triplet energy transfer promotes homolysis of the O–O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C–H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.

Acceptor-donor-acceptor-linked triphenylamine and phenothiazine motifs as cousin molecules: Methyl-effect on stimuli-responsiveness, crystallochromism and dual-state emission

Stimuli-responsive materials are in high demand but are hard to achieve. Although many molecules with donor-acceptor-donor (D-A-D) have been investigated as stimuli-responsive materials, the relatively A-D-A system has not been...

Recent Progress in Methylation of (Hetero)Arenes by Cross-Coupling or C–H Activation

Owing to the ‘magic methyl effect’ on a compound’s physical and biological properties, methylation is a strategy frequently used by medicinal chemists in structure–activity relationship studies or in lead optimization. This article highlights the most recent reported methods for the direct methylation of (hetero)arenes, which mainly involve either C–H functionalization or cross-coupling of methylating reagents with (hetero)aryl halides. Methylation of C–H bonds of (hetero)-arenes, which is atom economical, has been explored by several research groups in recent years. Given the unmatchable availability of (hetero)aryl halides, we believe that Ni-catalyzed methylation using iodomethane or deuterated iodomethane as the methyl source is one of the most convenient methods.

Selectivity of Iodosulfuron-Methyl to Oat Cultivars

ABSTRACT Weeds are among the main constraints to high grain yield on hexaploid oat (Avena sativa), but there are few herbicides registered for weed control on this cereal crop. The objectives of this study were to evaluate the impact of the iodosulfuron-methyl on grain yield of elite oat cultivars and investigate the mechanism of oat tolerance to this herbicide. A field experiment conducted in 2012 demonstrated there was no difference on grain yield between cultivars URS Guará and URS Guria, when iodosulfuron-methyl was used up to 4.5 g ha-1. Likewise, experiments from 2013 have demonstrated that iodosulfuron-methyl, at 5 g ha-1, did not affect the oat grain yield of the genotype UFRGS 14, but affected it on the cultivars URS Guará and URS Guria. In 2014, the oat grain yield of five cultivars, including URS Guará, URS Guria and UFRGS 14 was reduced by iodosulfuron-methyl even at only 2.5 g ha-1. The activity of the ALS enzyme, extracted from oat plants, was sensitive to iodosulfuron-methyl. The increment of the iodosulfuron-methyl effect on oat plants treated with herbicide-detoxification inhibitors (malathion + chlorpyrifos), or the reduction of the herbicide efficacy in plants sprayed with the stimulator of detoxification (mefenpyr-diethyl), suggest that iodosulfuron-methyl degradation is the mechanism involved on its selectivity to oat plants.