Despite attracting tremendous interest over the last few decades, the field of electrophilic cyclizations is still continuously and rapidly developing. Particularly, metal-free reactions that involve the activation of an alkyne using electrophilic halogen sources are powerful tools in the repertoire of synthetic chemists. This brief overview highlights recent progress in C-C bond-forming halocyclizations allowing for the reaction of alkynes with carbon-nucleophiles. Primarily guided by the type of carbon nucleophile, methods are categorized as the addition of arene, malonate, and olefin nucleophiles.
Two cats, two paths: two novel domino reactions starting from 6-hydroxy-2-alkyl-2-alkynylcyclohexanones have been discovered. While redox-neutral platinum catalysis gives rise to furans through a sequence of cyclization, 1,2-shift, and Grob fragmentation, oxidative copper catalysis provides an entry to bicyclic 2,3-dihydrofurans. Upon cyclization and oxidation, an unusual benzilic acid rearrangement can take place in this case.
Mounting evidence from the literature
suggests that blocking S1P2
receptor (S1PR2) signaling could be effective for the treatment of
idiopathic pulmonary fibrosis (IPF). However, only a few antagonists
have been so far disclosed. A chemical enablement strategy led to
the discovery of a pyridine series with good antagonist activity.
A pyridazine series with improved lipophilic efficiency and with no
CYP inhibition liability was identified by scaffold hopping. Further
optimization led to the discovery of 40 (GLPG2938), a
compound with exquisite potency on a phenotypic IL8 release assay,
good pharmacokinetics, and good activity in a bleomycin-induced model
of pulmonary fibrosis.
The generation of highly substituted furans from propargyl vinyl ethers bearing a free hydroxy group was investigated. In the presence of catalytic amounts of AgBF4, a formal [3,3] sigmatropic rearrangement takes place in the first stage of the sequence. The resulting allenyl carbonyl intermediates then undergo cyclocondensation, which upon double‐bond isomerization leads directly to the five‐membered heterocyclic products. This domino reaction allows the synthesis of various tri‐ and tetrasubstituted furan products; an example leading to pyrroles in an analogous way is also described.
Oxidieren oder nicht oxidieren, das ist hier die Frage: Zwei neue Dominoreaktionen mit 6‐Hydroxy‐2‐alkyl‐2‐alkinylcyclohexanonen wurden gefunden. Während die redoxneutrale Platinkatalyse durch eine Sequenz aus Cyclisierung, 1,2‐Verschiebung und Grob‐Fragmentierung Furane erzeugt, bietet die oxidative Kupferkatalyse einen Zugang zu bicyclischen 2,3‐Dihydrofuranen. Nach Cyclisierung und Oxidation läuft hier eine ungewöhnliche Benzilsäure‐Umlagerung ab.
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