We report a novel synthesis of phenanthridinones from N-methoxybenzamides using an oxidative C–H amidation reaction at room temperature in open air with modest to excellent yields. This method demonstrated unprecedented substrate scope. In particular, it solved the long-standing challenge in the synthesis of phenanthridinones with sterically demanding substitutions.

The sequential use of a hypervalent iodine reagent leads to the one-pot synthesis of 2-bromo/chloro-phenanthridinones via an amidation of arenes followed by a regioselective halogenation reaction. These consecutive C–H functionalization reactions can be used efficiently to construct 2-substituted-phenanthridinones at room temperature with good to high yields. Application of the current method is highlighted by the concise synthesis of the natural product PJ34.

•A one-step transformation from free (NH) indoles to 2-arylindole derivatives.•Using norbornene as a transient directing group mediator.•This reaction is compatible with a wide range of functionalized aryl iodides and various substituents on indole.A palladium-catalyzed direct C2-arylation reaction of free (NH) indoles has been developed. This reaction relies on a norbornene-mediated CH activation process on the indole ring, which features high regioselectivity and excellent functional group tolerance.Download high-res image (58KB)Download full-size image

New therapeutic targets are required to combat multidrug resistant infections, such as the iron-regulated heme oxygenase (HemO) of Pseudomonas aeruginosa, due to links between iron and virulence and dependence on heme as an iron source during infection. Herein we report the synthesis and activity of a series of iminoguanidine-based inhibitors of HemO. Compound 23 showed a binding affinity of 5.7 μM and an MIC50 of 52.3 μg/mL against P. aeruginosa PAO1. An in cellulo activity assay was developed by coupling HemO activity to a biliverdin-IXα-dependent infrared fluorescent protein, in which compound 23 showed an EC50 of 11.3 μM. The compounds showed increased activity against clinical isolates of P. aeruginosa, further confirming the target pathway. This class of inhibitors acts by binding to an allosteric site; the novel binding site is proposed in silico and supported by saturation transfer difference (STD) NMR as well as by hydrogen exchange mass spectrometry (HXMS).

A method for Pd-catalyzed, aminoquinoline-directed arylation of vinylic C–H bonds with aryl iodides has been developed. This reaction represents a rare example of Pd-catalyzed vinylic C–H functionalization of unsubstituted acrylamide, allowing for the highly regio- and stereoselective preparation of Z-olefins. High tolerance to functional groups is observed with good yields and excellent selectivity. It offers a complementary synthetic method to traditional pathways for Z-olefins.

A facile synthesis of spirocyclic lactams starting from β-keto carboxylic acids via a one-pot cascade reaction involving a Curtius rearrangement and an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate is reported. The same conditions have also been used for the generation of fused cyclic lactams with similar good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and pentacyclic spirolactam 9.

We report a practical high-yield synthesis of 5,7-disubstituted-1,2,4-triazolo[1,5-a]pyrimidines using a base-assisted cyclocondensation of chalcone and 1,2,4-triazol-3-amine in an open reaction vessel. The same conditions can also be used for the preparation of novel imidazo[1,2-a]pyrimidine derivatives.

We report a ligand-free copper-catalyzed Goldberg coupling of a spirocyclic lactam with an aryl iodide or bromide to provide an N-aryl spirocyclic lactam in good to excellent yields. The protocol is applicable to a broad diversity of spirocyclic lactams. The corresponding products can be used for the preparation of tetra- and pent-cyclic compounds 4–7 as potential therapeutic agents in the treatment of diffuse large B-cell lymphoma (DLBCL) and triple negative breast cancer (TNBC).Figure optionsDownload full-size imageDownload as PowerPoint slide

Positive allosteric modulators (PAMs) binding to the transmembrane (TM) domain of metabotropic glutamate receptor 5 (mGluR5) are promising therapeutic agents for psychiatric disorders and traumatic brain injury (TBI). Novel PAMs based on a trans-2-phenylcyclopropane amide scaffold have been designed and synthesized. Facilitating ligand design and allowing estimation of binding affinities to the mGluR5 TM domain was the novel computational strategy, site identification by ligand competitive saturation (SILCS). The potential protective activity of the new compounds was evaluated using nitric oxide (NO) production in BV2 microglial cell cultures treated with lipopolysaccharide (LPS), and the toxicity of the new compounds tested using a cell viability assay. One of the new compounds, 3a, indicated promising activity with potency of 30 μM, which is 4.5-fold more potent than its lead compound 3,3′-difluorobenzaldazine (DFB), and showed no detectable toxicity with concentrations as high as 1000 μM. Thus this compound represents a new lead for possible development as treatment for TBI and related neurodegenerative disorders.

We report a facile synthesis of 1,2-dihydro-2-oxo-4-quinolinyl phosphates (1a–l) starting from 2-acyl-benzoic acids (2a–l) in the presence of phosphoryl azides via a one-pot cascade reaction involving a Curtius rearrangement, an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate, and an addition-elimination of the enol oxygen to the phosphoryl azide. During the reaction three new bonds are formed under mild conditions to yield 1,2-dihydro-2-oxo-4-quinolinyl phosphates in modest yields.

1-(3-Oxocyclobutyl) carboxylic acid (4a) was converted into N-Boc-protected 1-(3-oxocyclobutyl) urea (5a), a key intermediate for the preparation of agonists of metabotropic glutamate receptor 5, in one-step when treated with diphenyl phosphoryl azide and triethylamine in tert-butanol. The mechanism of the reaction involves a nucleophilic addition of the in situ generated tert-butyl carbamate to the isocyanate intermediate. This reaction is applicable to other 1-(3-oxocycloalkyl) carboxylic acids but not to linear γ-keto carboxylic acids.

We report a one-step protocol for the general synthesis of 2,5-diketopiperazines from an Fmoc-protected amino acid and an amino acid ester. The application of the method is highlighted by rapid and efficient preparation of various 2,5-diketopiperazines.

We report a highly efficient method for the synthesis of (Z)-3-ylidenephthalides via intramolecular cyclization of readily available 2-acyl-benzoic acids mediated by TSTU at room temperature. Using this method, diversely substituted (Z)-3-ylidenephthalides have been generated in good to excellent yields. The application of the method is highlighted by gram-scale preparation of the antiplatelet drug n-butylphthalide.

A catalyst-free Knoevenagel type synthesis of isatinylidenerhodanines is reported starting from substituted isatins and rhodanines. The reaction proceeds spontaneously at room temperature in dimethyl sulfoxide (DMSO), employing a unique macrocyclic intermediate formed through an intramolecular H-bonding. Various substituted isatinylidenerhodanines could be synthesized in good yields.

A method for Pd-catalyzed, aminoquinoline-directed arylation of vinylic C–H bonds with aryl iodides has been developed. This reaction represents a rare example of Pd-catalyzed vinylic C–H functionalization of unsubstituted acrylamide, allowing for the highly regio- and stereoselective preparation of Z-olefins. High tolerance to functional groups is observed with good yields and excellent selectivity. It offers a complementary synthetic method to traditional pathways for Z-olefins.

The sequential use of a hypervalent iodine reagent leads to the one-pot synthesis of 2-bromo/chloro-phenanthridinones via an amidation of arenes followed by a regioselective halogenation reaction. These consecutive C–H functionalization reactions can be used efficiently to construct 2-substituted-phenanthridinones at room temperature with good to high yields. Application of the current method is highlighted by the concise synthesis of the natural product PJ34.