Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N-Acylguanidines.

A convenient synthetic strategy toward N-acylguanidines via a sequential one-pot multicomponent carbonylation/amination reaction has been developed. The compounds were readily obtained via an N-cyanobenzamide intermediate formed from the Pd(0)-catalyzed carbonylative coupling of cyanamide and aryl iodides or bromides. Subsequent amination with a large variety of amines provided the final N-acylguanidines, with the overall formation of one C-C and two C-N bonds, in moderate to excellent yields. The substrate scope was found to be wide and the methodology was used to produce over 50 compounds, including 29 novel molecules. Furthermore, three separate nitrogen-containing heterocycles were prepared from the N-acylguanidines synthesized using the developed multicomponent, carbonylative method.

Mild and Low-Pressure fac-Ir(ppy)3 -Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible-Light Photoredox Catalysis.

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac-Ir(ppy)3 -catalyzed radical aminocarbonylation protocol has been developed. Using a two-chambered system, alkyl iodides, fac-Ir(ppy)3 , amines, reductants, and CO gas (released ex situ from Mo(CO)6 ), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.

Synthesis of 2-Aminoquinazolinones via Carbonylative Coupling of ortho-Iodoanilines and Cyanamide.

Herein, we describe a convenient and efficient synthesis of 2-aminoquinazolin-4(3H)-ones and N1-substituted 2-aminoquinazolin-4(1H)-ones by a domino carbonylation/cyclization process. The reaction proceeds via carbonylative coupling of readily available ortho-iodoanilines with cyanamide followed by in situ ring closure of an N-cyanobenzamide intermediate. The products were easily isolated by precipitation in moderate to excellent yields for a wide range of substrates, making this a highly attractive method for the synthesis of 2-aminoquinazolinones.

Synthesis of 4-quinolones via a carbonylative Sonogashira cross-coupling using molybdenum hexacarbonyl as a CO source.

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 °C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO.

Synthesis and In Vitro Biological Evaluation of Quinolinyl Pyrimidines Targeting Type II NADH-Dehydrogenase (NDH-2).

Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736-740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-µM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 µg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.

Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide.

Invited for this month's cover are researchers from the Division of Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University (Sweden). The research interests in the group span areas such as enzyme inhibitors, new antibiotics, angiotensin II AT2R ligands, PET tracers, palladium catalysis, heterocycle synthesis, and the development of novel multicomponent reactions. In particular, sequential carbonylation and cyclization appeal to us as a convenient and straightforward synthetic route for the synthesis of heterocycles. The cover picture shows how carbon monoxide gas is diffused over a bridge, in the two-chamber system set-up used in this work, to take part in the catalytic cycle, and be incorporated into the heterocyclic core by a carbonylation/cyclization domino reaction to yield4H -benzo[e][1,3]oxazin-4-ones. For more details, see the full text of the Full Paper at 10.1002/open.201700130.

Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation-Cyclization Domino Reaction of ortho-Halophenols and Cyanamide.

A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation-cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)6 and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is extended to include challenging ortho-bromophenols. Finally, to highlight the versatility of the developed method, Mo(CO)6 is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.

Optimization and Evaluation of 5-Styryl-Oxathiazol-2-one Mycobacterium tuberculosis Proteasome Inhibitors as Potential Antitubercular Agents.

This is the first report of 5-styryl-oxathiazol-2-ones as inhibitors of the Mycobacterium tuberculosis (Mtb) proteasome. As part of the study, the structure-activity relationship of oxathiazolones as Mtb proteasome inhibitors has been investigated. Furthermore, the prepared compounds displayed a good selectivity profile for Mtb compared to the human proteasome. The 5-styryl-oxathiazol-2-one inhibitors identified showed little activity against replicating Mtb, but were rapidly bactericidal against nonreplicating bacteria. (E)-5-(4-Chlorostyryl)-1,3,4-oxathiazol-2-one) was most effective, reducing the colony-forming units (CFU)/mL below the detection limit in only seven days at all concentrations tested. The results suggest that this new class of Mtb proteasome inhibitors has the potential to be further developed into novel antitubercular agents for synergistic combination therapies with existing drugs.