6943-00-6Relevant articles and documents
A one pot protocol to convert nitro-arenes into: N-aryl amides
Massolo, Elisabetta,Pirola, Margherita,Puglisi, Alessandra,Rossi, Sergio,Benaglia, Maurizio
, p. 4040 - 4044 (2020/02/04)
A two-step one pot, experimentally simple protocol, based on readily available and inexpensive reagents allowed the conversion of nitro-arenes directly to N-aryl amides. A metal-free reduction of the nitro group, mediated by trichlorosilane, followed by the addition of an anhydride afforded the corresponding N-aryl carboxyamide, that was isolated after a simple aqueous work up in good-excellent yields. When the methodology was applied to the reaction with γ-butyrolactone, the desired N-aryl butanamide derivative was obtained, featuring a chlorine atom at the γ-position, a functionalized handle that can be used for further synthetic manipulation of the reaction product. Such an intermediate has already been employed as a key advanced precursor of pharmaceutically active compounds.
Late-stage oxidative C(sp 3)–H methylation
Feng, Kaibo,Kohrt, Jeffrey T.,Oderinde, Martins S.,Quevedo, Raundi E.,Reilly, Usa,White, M. Christina
, p. 621 - 627 (2020/05/04)
Frequently referred to as the ‘magic methyl effect’, the installation of methyl groups—especially adjacent (α) to heteroatoms—has been shown to dramatically increase the potency of biologically active molecules1–3. However, existing methylation methods show limited scope and have not been demonstrated in complex settings1. Here we report a regioselective and chemoselective oxidative C(sp3)–H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C–H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF3PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C–H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp3)–H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites—including drugs (for example, tedizolid) and natural products—are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates—an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1—via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.
Synthesis of 3-(5-amino-1: H -1,2,4-triazol-3-yl)propanamides and their tautomerism
Lim, Felicia Phei Lin,Tan, Lin Yuing,Tiekink, Edward R. T.,Dolzhenko, Anton V.
, p. 22351 - 22360 (2018/07/03)
Two complementary pathways for the preparation of N-substituted 3-(5-amino-1H-1,2,4-triazol-3-yl)propanamides (5) were proposed and successfully realized in the synthesis of 20 representative examples. These methods use the same types of starting material
