Aryl-substituted five-membered heteroaromatics have attracted great interest over the past years due to their presence in a large number of pharmaceuticals and natural products. Recently, an advance in the preparation of these scaffolds was achieved by employing a C-H functionalization strategy. This method allows easy access to these biaryl motifs by precluding the necessity of preparing specific coupling partners, although poor regioselectivity is sometimes observed when more than one reactive C-H is present on the substrate. In an effort to circumvent this liability, we envisioned the use of a carboxylic acid moiety as a blocking group that could be later functionalized or removed. Remarkably, the coupling was found to occur exclusively at the position previously occupied by the acid, even in the presence of a reactive C-H group. This selective transformation was also found to proceed with other heteroaromatic carboxylic acids, allowing for the preparation of a variety of aryl-substituted heteroaromatics that would be difficult to obtain via other methods.
A full overview of the decarboxylative cross-coupling reaction between heteroaromatic carboxylic acids and aryl halides is described. This transformation employs palladium catalysts with short reaction times providing facile synthesis of aryl-substituted heteroaromatics. The effect of each reaction parameter including solvent, base, and additive employed as well as the full substrate scope of this transformation are reported. Mechanistic evidence is also disclosed that sheds light on possible reaction pathways.
C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
A concise synthesis of heteroaryl dibenzopyranones 9a,b, 10a,b, 11a-c, and 12a-c has been achieved by the LDA-induced migration of heterobiaryl O-carbamates 18, 21, 25, and 30 which, in turn, were prepared in good yield using a combined directed ortho lithiation (DoM)-transition-metal-catalyzed Suzuki cross-coupling strategy. An efficient and general route to a wide variety of heterocycles including coumestans 19a,c and the previously unknown isothiocoumestan ring system 22b has been thereby achieved.
As carbon–carbon bonds are an essential bond type in Nature, reactions that form C–C bonds are of great interest in organic chemistry. Among the most popular C–C bond formation methods with aromatic systems are palladium‐catalyzed coupling reactions, such as the Heck, Suzuki, Negishi and Stille reactions. Even though these methods are efficient, they produce stoichiometric amounts of high molecular weight byproducts, placing them in conflict with the increasingly important ideas of sustainable reactions and green chemistry. In contrast, palladium‐catalyzed desulfinative coupling reactions produce minimal waste; in general, only hydrogen halides or alkali halides are formed as byproducts in addition to SO2 gas, which can potentially be recycled. This microreview provides a brief historic overview on palladium‐catalyzed coupling reactions with organosulfur compounds, with the main focus on the use of sulfinate salts as nucleophilic or electrophilic reaction partners. Various methods to access the sulfinate salts, and the coupling reactions of sulfonyl precursors that proceed through sulfinic acid/salt intermediates generated in situ are also discussed.
An anthranilic acid series of allosteric thumb pocket 2 HCV NS5B polymerase inhibitors exhibited hindered rotation along a covalent bond axis, and the existence of atropisomer chirality was confirmed by NMR, HPLC analysis on chiral supports, and computational studies. A thorough understanding of the concerted rotational properties and the influence exerted by substituents involved in this steric phenomenon was attained through biophysical studies on a series of truncated analogues. The racemization half-life of a compound within this series was determined to be 69 min, which was consistent with a class 2 atropisomer (intermediate conformational exchange). It was further found by X-ray crystallography that one enantiomer of a compound bound to the intended HCV NS5B polymerase target whereas the mirror image atropisomer was able to bind to an unrelated HIV matrix target. Analogues were then identified that selectively inhibited the former. These studies highlight that atropisomer chirality can lead to distinct entities with specific properties, and the phenomenon of atropisomerism in drug discovery should be evaluated and appropriately managed.
Bismuth
metallic nanoparticles have evoked considerable interest
in catalysis owing to their small size, high surface area-to-volume
ratio, and low toxicity. However, the need for toxic reductants and
organic solvents in their synthesis often limits their desirability
for application development. Here, we describe a green strategy to
synthesize bismuth nanodots via the redox reactions between bismuth
nitrate and d-glucose, in the presence of poly(vinylpyrrolidone)
in the basic aqueous phase. Both reagents play a crucial role in the
formation of monodisperse bismuth nanodots acting as mild reducing
and capping agents, respectively. We further demonstrate that the
catalytic activity of these dots via the successful reduction of the
environmental contaminant 4-nitrophenol to its useful 4-aminophenol
analogue requiring only 36 μg/mL nanocatalyst for 20 mM of the
substrate. Moreover, they can be recovered and recycled in multiple
reactions before the onset of an appreciable loss of catalytic activity.
The proposed facile synthetic route and inexpensive matrix materials
lead the way to access bismuth nanodots for both the fundamental study
of reactions and their industrial catalysis applications.
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