Regioselective Synthesis of Benzimidazolones via Cascade C–N Coupling of Monosubstituted Ureas

A direct method for the regioselective construction of benzimidazolones is reported wherein a single palladium catalyst is employed to couple monosubstituted urea substrates with differentially substituted 1,2-dihaloaromatic systems. In this method, the catalyst is able to promote a cascade of two discrete chemoselective C–N bond-forming processes that allows the highly selective and predictable formation of complex heterocycles from simple, readily available starting materials.National Institutes of Health (U.S.) (Award GM58160)National Institutes of Health (U.S.) (Award GM099817)Lanxess CorporationMassachusetts Institute of Technology. Undergraduate Research Opportunities Progra

Synthesis of air‐stable, odorless thiophenol surrogates via Ni‐Catalyzed C−S cross‐coupling

Thiophenols are versatile synthetic intermediates whose practical appeal is marred by their air sensitivity, toxicity and extreme malodor. Herein we report an efficient catalytic method for the preparation of S-aryl isothiouronium salts, and demonstrate that these air-stable, odorless solids serve as user-friendly sources of thiophenols in synthesis. Diverse isothiouronium salts featuring synthetically useful functionality are readily accessible via nickelcatalyzed C-S cross-coupling of (hetero)aryl iodides and thiourea. Convenient, chromatography-free isolation of these salts is achieved via precipitation, allowing the methodology to be translated directly to large scales. Thiophenols are liberated from the corresponding isothiouronium salts upon treatment with a weak base, enabling an in situ release / S-functionalization strategy that entirely negates the need to isolate, purify or manipulate these noxious reagent

Mild Pd-Catalyzed Aminocarbonylation of (Hetero)Aryl Bromides with a Palladacycle Precatalyst

A palladacyclic precatalyst is employed to cleanly generate a highly active XantPhos-ligated Pd-catalyst. Its use in low temperature aminocarbonylations of (hetero)aryl bromides provides access to a range of challenging products in good to excellent yields with low catalyst loading and only a slight excess of CO. Some products are unattainable by traditional carbonylative coupling.National Institutes of Health (U.S.) (Award GM46059)Danish National Research Foundation (Grant DNRF59)Villum FoundationDanish Council for Independent Researc

Suzuki-Miyaura Cross-Coupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation

The Suzuki-Miyaura cross-coupling of unprotected, nitrogen-rich heterocycles using precatalysts P1 or P2 is reported. The procedure allows for the reaction of variously substituted indazole, benzimidazole, pyrazole, indole, oxindole, and azaindole halides under mild conditions in good to excellent yields. Additionally, the mechanism behind the inhibitory effect of unprotected azoles on Pd-catalyzed cross-coupling reactions is described based on evidence gained through experimental, crystallographic, and theoretical investigations.National Institutes of Health (U.S.) (Award GM46059)German Science Foundation (Postdoctoral Fellowship

Discovery, optimization, and biological evaluation of 5-(2- (trifluoromethyl)phenyl)indazoles as a novel class of transient receptor potential A1 (TRPA1) antagonists

A high throughput screening campaign identified 5-(2-chlorophenyl)indazole compound 4 as an antagonist of the transient receptor potential A1 (TRPA1) ion channel with IC50 = 1.23 μM. Hit to lead medicinal chemistry optimization established the SAR around the indazole ring system, demonstrating that a trifluoromethyl group at the 2-position of the phenyl ring in combination with various substituents at the 6-position of the indazole ring greatly contributed to improvements in vitro activity. Further lead optimization resulted in the identification of compound 31, a potent and selective antagonist of TRPA1 in vitro (IC50 = 0.015 μM), which has moderate oral bioavailability in rodents and demonstrates robust activity in vivo in several rodent models of inflammatory pain. © 2014 American Chemical Society