68965-77-5Relevant academic research and scientific papers
Site-Selective C–H Functionalization of (Hetero)Arenes via Transient, Non-symmetric Iodanes
Fosu, Stacy C.,Hambira, Chido M.,Chen, Andrew D.,Fuchs, James R.,Nagib, David A.
, p. 417 - 428 (2019/02/14)
Fosu, Hambira, and colleagues describe the direct C–H functionalization of medicinally relevant arenes or heteroarenes. This strategy is enabled by transient generation of reactive, non-symmetric iodanes from anions and PhI(OAc)2. The site-selective incorporation of Cl, Br, OMs, OTs, and OTf to complex molecules, including within medicines and natural products, can be conducted by the operationally simple procedure included herein. A computational model for predicting site selectivity is also included. The discovery of new medicines is a time- and labor-intensive process that frequently requires over a decade to complete. A major bottleneck is the synthesis of drug candidates, wherein each complex molecule must be prepared individually via a multi-step synthesis, frequently requiring a week of effort per molecule for thousands of candidates. As an alternate strategy, direct, post-synthetic functionalization of a lead candidate could enable this diversification in a single operation. In this article, we describe a new method for direct manipulation of drug-like molecules by incorporation of motifs with either known pharmaceutical value (halides) or that permit subsequent conversion (pseudo-halides) to medicinally relevant analogs. This user-friendly strategy is enabled by combining commercial iodine reagents with salts and acids. We expect this simple method for selective, post-synthetic incorporation of molecular diversity will streamline the discovery of new medicines. A strategy for C–H functionalization of arenes and heteroarenes has been developed to allow site-selective incorporation of various anions, including Cl, Br, OMs, OTs, and OTf. This approach is enabled by in situ generation of reactive, non-symmetric iodanes by combining anions and bench-stable PhI(OAc)2. The utility of this mechanism is demonstrated via para-selective chlorination of medicinally relevant arenes, as well as site-selective C–H chlorination of heteroarenes. Spectroscopic, computational, and competition experiments describe the unique nature, reactivity, and selectivity of these transient, unsymmetrical iodanes.
Pd-catalyzed intermolecular ortho-C-H amidation of anilides by N-nosyloxycarbamate
Ng, Ka-Ho,Chan, Albert S. C.,Yu, Wing-Yiu
supporting information; body text, p. 12862 - 12864 (2010/11/03)
A palladium-catalyzed ortho-C-H amidation of anilides by N-nosyloxycarbamates was developed for the synthesis of 2-aminoanilines. This reaction can be carried out under relatively mild conditions and exhibits excellent regioselectivity and functional group tolerance. The amidation reaction is probably initiated by rate-limiting C-H cyclopalladation (k H/kD = 3.7) to form an arylpalladium complex, followed by nitrene functionalization.
Substituted 2-anilines as Potential Inhibitors of H+/K+ ATPase
Adelstein, Gilbert W.,Yen, Chung H.,Haack, Richard A.,Yu, Stella,Gullikson, Gary,et al.
, p. 1215 - 1220 (2007/10/02)
A series of substituted 2-anilines were synthesized as potential inhibitors of the acid secretory enzyme H+/K+ ATPase.Substitutions on the aniline nitrogen atom resulted in potent enzyme inhibition in vitro but weak activity in gastric fistula dogs.Electron-donating substituents on the aniline ring enhanced in vitro and in vivo potency relative to the unubstituted analogue.The potency showed a correlation to the calculated pKa of the aniline nitrogen atom.Substitutions on the aniline and benzimidazole rings did not further enhance potency.Di- and trisubstituted aniline derivatives were potent inhibitors of the enzyme system.The preferred combination of substituents were a methoxy group on the benzimidazole ring and a single alkyl group on the aniline ring.One such compound, 76, was an effective inhibitor of acid secretion in the dog and was selected for further pharmacological study.
