Abstract The B 3 NO 2 six‐membered heterocycle (1,3‐dioxa‐5‐aza‐2,4,6‐triborinane=DATB), comprising three different non‐carbon period 2 elements, has been recently demonstrated to be a powerful ...catalyst for dehydrative condensation of carboxylic acids and amines. The tedious synthesis of DATB, however, has significantly diminished its utility as a catalyst, and thus the inherent chemical properties of the ring system have remained virtually unexplored. Here, a general and facile synthetic strategy that harnesses a pyrimidine‐containing scaffold for the reliable installation of boron atoms is disclosed, giving rise to a series of Pym‐DATBs from inexpensive materials in a modular fashion. The identification of a soluble Pym‐DATB derivative allowed for the investigation of the dynamic nature of the B 3 NO 2 ring system, revealing differential ring‐closing and ‐opening behaviors depending on the medium. Readily accessible Pym‐DATBs proved their utility as efficient catalysts for dehydrative amidation with broad substrate scope and functional‐group tolerance, offering a general and practical catalytic alternative to reagent‐driven amidation.
An efficient and external oxidant-free, Cp*Co(III) -catalyzed C(sp(3) )-H bond amidation of 8-methylquinoline, using oxazolone as an efficient amidating agent, is reported for the first time under ...mild conditions. The reaction is selective and tolerates a variety of functional groups. Based on previous reports and experimental results, the deprotonation pathway proceeds through an external base-assisted concerted metalation and deprotonation process.
The invention of a commercial route to the Bruton's tyrosine kinase inhibitor branebrutinib (BMS-986195) in four total chemical steps is described. The execution of high-throughput experimentation ...(HTE) coupled with a first-principles approach across the proposed synthetic route enabled the identification of a novel indolization reaction that rapidly generated high synthetic complexity, as the centerpiece of the synthesis. A parallel HTE strategy during route design enabled the efficient and rapid evaluation of multiple options within a short timeframe to complete rigorous process development while mitigating the risks associated with implementing new chemistry featuring an aggressive disconnection strategy.
An iridium‐catalyzed direct CH amidation of weakly coordinating substrates, in particular of those bearing ester and ketone groups, under very mild conditions has been developed. The observed high ...reaction efficiency was achieved by the combined use of acetic acid and lithium carbonate as additives.
Mild and direct: The iridium‐catalyzed direct CH amidation of weakly coordinating substrates, particularly of those with ester and ketone groups, under very mild conditions has been developed. With the aid of a combined use of acetic acid and lithium carbonate as additives, the reaction proceeded with high efficiency. Cp*=pentamethylcyclopentadienyl.
Deucravacitinib (BMS-986165) is a deuterated small-molecule TYK2 inhibitor developed for the treatment of numerous autoimmune disorders. While the first-generation discovery chemistry route to access ...deucravacitinib was concise and sufficient to access kilogram quantities of API, impurity control and cost-of-goods concerns necessitated the design of a new route. Once a new route was identified and demonstrated, each step was optimized for yield, purity, robustness, and sustainability. Key accomplishments include (1) the development of a novel cyclocondensation under mild conditions to afford a methylated 1,2,4-triazole with excellent regiocontrol, (2) the development of safe, homogeneous conditions to quench POCl3 following chlorination of a substrate that is sensitive to nucleophilic and basic conditions, (3) the discovery of a robust, scalable “dual-base” palladium-catalyzed C–N coupling reaction, and (4) mechanistic understanding to inform control strategies for a number of process-related impurities in an API step amidation mediated by EDC. Ultimately, the optimized commercial route was successfully scaled up to afford more than a metric ton of deucravacitinib for clinical and commercial use.
Transformations of aromatic compounds into the corresponding amines, amides, and imides through carbon–hydrogen (C–H) bond functionalization represent one of the most step- and atom-economical ...methods for the synthesis of arylamine compounds. Because arylamines are privileged structures in materials- and biology-oriented functional molecules, the development of novel and efficient synthetic methods for aromatic C–H amination has received significant attention from a wide range of research fields including materials and pharmaceuticals. This review covers recent advances in catalytic aromatic C–H amination reactions. An array of recently developed new reactions are categorized by the nature of aromatic substrates: (1) 5-membered heteroarenes, (2) arenes having a nitrogen moiety in the molecule (intramolecular C–H amination), (3) arenes having a directing group, (4) simple arenes with excess amounts, and (5) simple arenes as the limiting reagents.
The ionophore has been successfully synthesized from p-t-butyl(carboxymethoxy)calix4arene subtituted amide. The ionophore was obtained in two steps of the synthesis reaction. The first step is the ...chlorination reaction of p-t-butyl(carboxymethoxy)calix4arene with thionyl chloride in dry benzene solvent. The product of the chlorination reaction is p-t-butyl(chloroacetylmethoxy)calix4arene in the form of the light brown viscous liquid with the rendemen of 78.25% and TLC (SiO2, CH3OH : CH2Cl2 = 1 : 1 v/v, Rf = 0.65). The second step is the amidation reaction of p-t-butyl(chloroacetylmethoxy) calix4arene with dimethylamine in dry tetrahydrofuran solvent. The product of the amidation reaction is p-t-butyl(dimethylcarbamoylmethoxy)-calix4arene or the DIMECAC4ND3 ionophore in the form of white solid with the rendemen of 60.75%, a melting point of 277-279 °C, and TLC (SiO2, CH3OH : CH2Cl2 = 1 : 1 v/v, Rf = 0.82).
The emergence of colored crystals in a field of diamonds is illustrated in this cover picture. Whereas diamonds represent carbon, colored crystals represent boron (yellow), nitrogen (blue), and ...oxygen (red) and assemble to furnish B3NO2 exotic molecular entity. More information can be found in the Communication by M. Shibasaki, N. Kumagai et al. on page 4648.
This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically ...analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.
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