A novel one-pot, three-component reaction employing variously substituted benzimidazole-linked amino pyridines, aldehydes, and isonitriles catalyzed by scandium(III) triflate under solvent-free conditions were accomplished. This new synthetic methodology facilitates the rapid generation of intricate molecular frameworks in three-dimensional fashion leading to benzimidazole-imidazo[1,2-a] pyridines. This approach is envisioned as an environmentally benign process and a simple operation to the biological interesting compounds. The present synthetic sequence permits the introduction of three points of structural diversity to expand chemical space with high purity and excellent yields.
Transition metal-catalyzed C–H functionalization and decarboxylative coupling are two of the most notable synthetic strategies developed in the last 30 years. Herein, we connect these two reaction pathways using bases and a simple Pd-based catalyst system to promote a
para
-selective C–H functionalization reaction from benzylic electrophiles. Experimental and computational mechanistic studies suggest a pathway involving an uncommon Pd-catalyzed dearomatization of the benzyl moiety followed by a base-enabled rearomatization through a formal 1,5-hydrogen migration. This reaction complements “C–H activation” strategies that convert inert C–H bonds into C–metal bonds prior to C–C bond formation. Instead, this reaction exploits an inverted sequence and promotes C–C bond formation prior to deprotonation. These studies provide an opportunity to develop general
para
-selective C–H functionalization reactions from benzylic electrophiles and show how new reactive modalities may be accessed with careful control of reaction conditions.
Small-molecule drug
target identification is an essential and often
rate-limiting step in phenotypic drug discovery and remains a major
challenge. Here, we report a novel platform for target identification
of activators of signaling pathways by leveraging the power of a clustered
regularly interspaced short palindromic repeats (CRISPR) knockout
library. This platform links the expression of a suicide gene to the
small-molecule-activated signaling pathway to create a selection system.
With this system, loss-of-function screening using a CRISPR single-guide
(sg) RNA library positively enriches cells in which the target has
been knocked out. The identities of the drug targets and other essential
genes required for the activity of small molecules of interest are
then uncovered by sequencing. We tested this platform on BDW568, a
newly discovered type-I interferon signaling activator, and identified
stimulator of interferon genes (STING) as its target and carboxylesterase
1 (CES1) to be a key metabolizing enzyme required to activate BDW568
for target engagement. The platform we present here can be a general
method applicable for target identification for a wide range of small
molecules that activate different signaling pathways.
A highly efficient synthesis of benzoimidazo[1,2-a]imidazolone through a novel oxidative 5-exo-dig cyclization-ketonization cascade of 2-aminobenzimidazole, aldehyde and terminal alkyne has been explored under aerobic conditions. The reaction proceeds through copper-catalyzed addition of terminal alkynes to imines derived from 2-aminobenzimidazole with aldehyde followed by intramolecular cyclization. The atmospheric molecular oxygen acts as an oxygen source for the newly formed carbonyl group in the final product.
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