Fischer indolisation of N-(α-ketoacyl)anthranilic acids into 2-(indol-2-carboxamido)benzoic acids and 2-indolyl-3,1-benzoxazin-4-ones and their NMR study

N-(α-ketoacyl)anthranilic acids reacted with phenylhydrazinium chloride in boiling acetic acid to afford 2-(indol-2-carboxamido)benzoic acids in good to excellent yields and 2-indolyl-3,1-benzoxazin-4-ones as by-products. The formation of the latter products could easily be suppressed by a hydrolytic workup. Alternatively, by increasing the reaction temperature and/or time, 2-indolyl-3,1-benzoxazin-4-ones can be obtained exclusively. Optimisations of the reaction conditions as well as the scope and the course of the transformations were investigated. The products were characterized by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H-1H gs-COSY, 1H-13C gs-HSQC, 1H-13C gs-HMBC) with 1H-15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.TBU in Zlin [IGA/FT/2014/010]; Ministry of Education, Science and Sport, Republic of Slovenia; Slovenian Research Agency [P1-0230, 430-168/2013/114]; EN-FIST Centre of Excellence, Ljubljan

Diaryltriazenes as antibacterial agents against methicillin resistant Staphylococcus aureus (MRSA) and Mycobacterium smegmatis

Diaryltriazene derivatives were synthesized and evaluated for their antimicrobial properties. Initial experiments showed some of these compounds to have activity against both methicillin-resistant strains of Staphylococus aureus (MRSA) and Mycobacterium smegmatis, with MICs of 0.02 and 0.03 μg/mL respectively. Those compounds with potent anti-staphylococcal and anti-mycobacterial activity were not found to act as growth inhibitors of mammalian cell lines or yeast. Furthermore, we demonstrated that one of the most active anti-MRSA diaryltriazene derivatives was subject to very low frequencies of resistance at <10−9. Whole genome sequencing of resistant isolates identified mutations in the enzyme that lysylates phospholipids. This could result in the modification of phospholipid metabolism and consequently the characteristics of the staphylococcal cell membrane, ultimately modifying the sensitivity of these pathogens to triazene challenge. Our work has therefore extended the potential range of triazenes, which could yield novel antimicrobials with low levels of resistance

Synthesis of bis(1,2,3-triazole) functionalized quinoline-2,4-diones

Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope. © 2018 b the authors.Slovenian Research Agency [P1-0230, J1-8147, J1-9166]; [IGA/FT/2018/007

Designing homogeneous copper-free Sonogashira reaction through a prism of Pd-Pd transmetalation

Simultaneous introduction of two different palladium (pre)catalysts, one tuned to promote oxidative addition to (hetero)aryl bromide and another to activate terminal alkyne substrate, leads to productive Pd−Pd transmetalation, subsequent reductive elimination, and formation of disubstituted alkyne. This conceptually novel rational design of copper-free Sonogashira reaction enabled facile identification of the reaction conditions, suitable for the synthesis of alkyl, aryl, and heteroaryl substituted alkynes at room temperature with as low as 0.125 mol % total Pd loading

Copper-catalyzed azide–alkyne cycloaddition of hydrazoic acid formed in situ from sodium azide affords 4-monosubstituted-1,2,3-triazoles

We report a copper-catalyzed cycloaddition of hydrogen azide (hydrazoic acid, HN3) with terminal alkynes to form 4-substituted-1H-1,2,3-triazoles in a sustainable manner. Hydrazoic acid was formed in situ from sodium azide under acidic conditions to react with terminal alkynes in a copper-catalyzed reaction. Using polydentate N-donor chelating ligands and mild organic acids, the reactions were realized to proceed at room temperature under aerobic conditions in a methanol–water mixture and with 5 mol % catalyst loadings to afford 4-substituted-1,2,3-triazoles in high yields. This method is amenable on a wide range of alkyne substrates, including unprotected peptides, showing diverse functional group tolerance. It is applicable for late-stage functionalization synthetic strategies, as demonstrated in the synthesis of the triazole analogue of losartan. The preparation of orthogonally protected azahistidine from Fmoc-l-propargylglycine was realized on a gram scale. The hazardous nature of hydrazoic acid has been diminished as it forms in situ in <6% concentrations at which it is safe to handle. Reactions of distilled solutions of hydrazoic acid indicated its role as a reactive species in the copper-catalyzed reaction

Pyridine wingtip in ▫[Pd(Py−tzNHC)2]2+[Pd(Py-tzNHC)_2]^{2+}▫ complex is a proton shuttle in the catalytic hydroamination of alkynes

The cationic palladium(II) complex 1 of pyridylmesoionic carbene ligand catalyzes Markovnikov-selective intermolecular hydroamination between anilines and terminal alkynes into the corresponding imines. The reaction proceeds at room temperature, in the absence of additives, with exquisite selectivity and diverse functional group tolerance. The key intrinsic feature of the catalyst is the pyridine wingtip confined to the proximity of the alkynophilic metal active site, which mimics the function of enzyme-like architectures by assisting entropically favored proton transfers

Database independent automated structure elucidation of organic molecules based on IR, 1^1H NMR, 13^{13}C NMR, and MS data

Herein, we report a computational algorithm that follows a spectroscopist-driven elucidation process of the structure of an organic molecule based on IR, $^1$H and $^{13}$C NMR, and MS tabular data. The algorithm is independent from database searching and is based on a bottom-up approach, building the molecular structure from small structural fragments visible in spectra. It employs an analytical combinatorial approach with a graph search technique to determine the connectivity of structural fragments that is based on the analysis of the NMR spectra, to connect the identified structural fragments into a molecular structure. After the process is completed, the interface lists the compound candidates, which are visualized by the WolframAlpha computational knowledge engine within the interface. The candidates are ranked according to the predefined rules for analyzing the spectral data. The developed elucidator has a user-friendly web interface and is publicly available (http://schmarnica. si)

Mechanistically guided development of homogenous nickel catalysis through rapid computational catalyst screening

Advances in understanding the mechanisms of homogeneous nickel catalysis has led to a remarkable progress in this field. However, the discovery of active catalysts is still largely based on trial and error, and the catalysts are mostly based on chelating (nitrogen) ligands. We report a combined theoretical and experimental study of nickel-catalyzed hydroarylation of vinylarenes, where experimental advances were complemented with a rapid computation catalyst screening. Once the mechanism is known and preliminary experimental data is available, the screening approach can predict other suitable ligands by assessing the electronic structure of the catalyst complex without the computationally intensive determination of the transition states. Using the approach described, we developed the reaction that proceeds under unusually mild conditions and is broadly applicable on a range of vinylarenes and (het)aryl halides, including previously inaccessible chlorides. The reaction was found to be highly dependent on the choice of ligand, with monodentate $PPh_3$ proving optimal. Extensive quantum chemical simulations elucidated the reaction mechanism and identified $Ni(PPh_3)_xCl_yH$ as the crucial active species