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The first site-selective methodology for the construction of fused [1,2-a]indolone derivativesviaan unexpected anti-Nenitzescu strategy has been developed.

A three-component catalyst-free protocol for the regioselective synthesis of dual highly functionalized fused pyrroles has been developed from a cascade [3 + 2] cyclization of heterocyclic ketene aminals (HKAs) 1 with arylglyoxal monohydrates 2 and cyclohexane-1,3-diones 3 in water–ethanol media. The kinetically controlled products 4 could be synthesized within 1 h but would irreversibly transform to thermodynamically controlled products 5 over an additional 5 h. At the same time, the transformative synthesis of 5a from 4a by controlling the oxygen or nitrogen proved the proposed mechanism. Furthermore, the DFT calculation also corroborated that the stability of products 5 are a 100,000 times more thermodynamically stable than products 4. Finally, the origin of the greater stability of 5 could be explained by the reduced density gradient (RDG) analysis, which hinted that the crucial factors are the formation of a new intramolecular hydrogen bond and the release of the steric effect of the crowded rings. In conclusion, this novel synthetic strategy offers an alternative method using thermodynamic or kinetic control for regioselective construction of biologically meaningful fused pyrrole architectures from a concise, rapid, and environmentally friendly vision.

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A three-component strategy for the efficient and diastereoselective synthesis of unprecedented polycyclic pyrroles (4) bearing four consecutive quaternary stereocenters has been developed. The reaction was performed with three readily available starting materials: heterocyclic ketene aminals (HKAs) (1), acenaphthylene-1,2-dione (2), and ethyl trifluoroacetylacetate (3). In the one-step cascade reaction, two C–C bonds, two C–Hetero bonds, four consecutive quaternary stereocenters, and two heterocycles were constructed. The established protocol presented outstanding diastereoselectivity (up to 99:1) and provided a valuable route to access highly functionalized polycyclic pyrroles with conciseness, rapidness, and practicability. The reaction is particularly attractive due to the following advantages: atom economy, optimum convergence, high bond-forming efficiency, and operational simplicity.

Vascular endothelial growth factor receptor-2 (VEGFR-2) kinase inhibition is a well-established strategy to promptly tackle tumor growth by suppression of angiogenesis. We report herein a series of 5-anilinoquinazoline derivatives substituted by 1,3-disubstituted urea. All the newly synthesized compounds described were evaluated for VEGFR-2 kinase inhibition and antiproliferative activity against various cancer cells. The novel 1-aryl, 3-aryl-disubstituted urea quinazolines were effective VEGFR-2 kinase inhibitors with in vitro IC50 values in the submicromolar range (compound 6f, IC50 12.0 nM), but showed a weak to moderate inhibitory activity on cancer cells. Molecular interactions of the compounds were studied using molecular docking studies.

A one-step, transition-metal-free protocol, involving facile post-treatment, for the regioselective synthesis of 1,3-diazaheterocycle fused [1,2-a][1,8]naphthyridine derivatives (3) from 2-chloroquinoline-3-carbaldehydes (ClQuAlds) (1) and heterocyclic ketene aminals (HKAs) (2) was developed via a joint experimental-computational approach. The computational prediction of the reactivity of two series of synthons was applied in the process of optimizing the reaction conditions, which relied on density functional theory (DFT) calculations together with concepts of frontier molecular orbital (FMO) theory and quantitative structure-reactivity relationship (QSRR) presumptions. The combined results enabled the proposal of a pre-synthetic prediction of global reactivity. The fully consistent results of the synthetic experiments with the in silico evaluation confirmed the rationality, effectiveness, and practicability of the new strategy. Notably, the joint method is not limited to the laboratory, but has applications ranging from routine to industry. This approach is likely to yield numerous insights to accelerate HKA-related synthetic chemistry that can be extended to numerous heterocycles. It thus opens up a novel entry towards rapidly investigating the reactivity of novel synthons with unique properties, a further step towards exploiting cascade reactions by avoiding the futile waste of time and resources.

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