One-pot synthesis of oxazolidinones and five-membered cyclic carbonates from epoxides and chlorosulfonyl isocyanate: theoretical evidence for an asynchronous concerted pathway.

The one-pot reaction of chlorosulfonyl isocyanate (CSI) with epoxides having phenyl, benzyl and fused cyclic alkyl groups in different solvents under mild reaction conditions without additives and catalysts was studied. Oxazolidinones and five-membered cyclic carbonates were obtained in ratios close to 1:1 in the cyclization reactions. The best yields of these compounds were obtained in dichloromethane (DCM). Together with 16 known compounds, two novel oxazolidinone derivatives and two novel cyclic carbonates were synthesized with an efficient and straightforward method. Compared to the existing methods, the synthetic approach presented here provides the following distinct advantageous: being a one-pot reaction with metal-free reagent, having shorter reaction times, good yields and a very simple purification method. Moreover, using the density functional theory (DFT) method at the M06-2X/6-31+G(d,p) level of theory the mechanism of the cycloaddition reactions has been elucidated. The further investigation of the potential energy surfaces associated with two possible channels leading to oxazolidinones and five-membered cyclic carbonates disclosed that the cycloaddition reaction proceeds via an asynchronous concerted mechanism in gas phase and in DCM.

Prognostic significance of NGAL in early stage chronic kidney disease.

BACKGROUND: Neutrophilgelatinase-associated lipocalin (NGAL) has been proven to be a useful biomarker for early detection of acute kidney injury, but it is not known whether adding NGAL measurements to conventional risk factors will improve the risk assessment in the setting of chronic kidney disease (CKD). The aim of the present study was to examine the correlation of NGAL with early stage renal impairment in CKD and to evaluate its prognostic value in these subjects. METHODS: This is a prospective observational cohort study of 54 patients with early stage (stage 1-2) CKD. Patients aged between 18 and 65 years with stable disease were enrolled in this study. Patients with a history of primary glomerulonephritis, diabetes mellitus, acute kidney injury, systemic diseases and stage 3-4-5 CKD were excluded from the study group. Estimated glomerular filtration (eGFR) rate was calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The patients were followed for two years to determine the ability of baseline NGAL for prediction of renal outcome. In our study disease progression was defined as changes in eGFR (ΔeGFR) and proteinuria (Δproteinuria). Patients divided into two groups according to NGAL cut-off value as group 1 (N.=23, NGAL ≤98.71 ng/mL) and group 2 (N.=31, NGAL >98.71 ng/mL). RESULTS: Out of 54 patients (mean age: 45.6±7.6 years, 64.8% female, baseline eGFR: 84.6±16.8 mL/min/1.73 m2, baseline NGAL level: 157.47±121.52 ng/mL); 18 patients were stage 1 and 36 patients were stage 2 CKD. In the ROC analysis, we found that the optimal cut-off value of NGAL for predicting stage 2 CKD was 98.71ng/mL (P=0.005) with the 72.2% sensitivity and 72.2% specificity. In correlation analysis, we evaluated significantly positive correlations between NGAL and CKD stage (r=0.389, P=0.004), baseline/last serum creatinine level (r=0.530, P<0.001 and r=0.439, P=0.003; respectively), last proteinuria level (r=0.359, P=0.043). There were significantly negative correlation between NGAL and baseline/last eGFR (r=-0.498, P<0.001 and r=-0.462, P=0.002; respectively). Compared to the group 1, we determined that group 2 patients had further deterioration in renal functions regarding ΔeGFR (-1.12±12.6 mL/min vs. -1.46±12.4 mL/min: respectively, P=0.930) and Δproteinuria (98.1±569.3 mg/day vs. 339±701.6 mg/day; respectively, P=0.305); however these differences were not statistically significant at the end of the two years follow-up period. CONCLUSIONS: Altough NGAL has a positive correlation with disease severity, it does not seem to be a marker of disease progression in patients with early stage CKD. But further studies stated in different patient groups may also explain the usability of NGAL in clinical practice.

Mechanisms of the reaction between polyhalogenated nitrobutadienes and electron-deficient anilines: computational modeling.

Nitro-substituted polyhalogenated butadienes are valuable synthetic precursors for polyfunctionalized bioactive heterocyclic compounds. Recently, a new reaction between 2-nitroperchloro-1,3-butadiene and electron-deficient anilines producing the Z stereoisomers of a variety of allylidene arylhydrazines has been reported. Although the formation of a chlorinated nitrile oxide intermediate was proved by trapping it with appropriate alkenes via 1,3-dipolar cycloaddition, the details of the overall mechanism remained unclear. The elucidation of the mechanism is important for a better understanding of polyhalogenated nitrobutadiene chemistry. We proposed six reaction paths for the formation of allylidene arylhydrazine, starting from 2-nitroperchloro-1,3-butadiene and para-nitro aniline, and generated the potential energy profiles with the DFT/B3LYP/6-31+G(d,p) method. To include the solvent effect, single-point energy calculations were carried out at the B3LYP/6-31+G(d,p) level by the polarizable continuum model with tetrahydrofuran, as used in the experimental study. The Gibbs activation energies of the rate-determining steps of each mechanism were defined. Taking into account the downhill nature of the overall potential energy profile, Paths 5 and 6 which proceed via extrusion of p-nitrophenylisocyanate and the formation of chlorinated nitrile oxide were chosen as plausible mechanisms. Results also provide insights into the chemistry of nitrile oxides, oximes, oxazete, and nitroso compounds as well as S(N)Vin reactions.

Design and synthesis of pyrrolotriazepine derivatives: an experimental and computational study.

The pyrrole derivatives having carbonyl groups at the C-2 position were converted to N-propargyl pyrroles. The reaction of those compounds with hydrazine monohydrate resulted in the formation of 5H-pyrrolo[2,1-d][1,2,5]triazepine derivatives. The synthesis of these compounds was accomplished in three steps starting from pyrrole. On the other hand, attempted cyclization of a pyrrole ester substituted with a propargyl group at the nitrogen atom gave, unexpectedly, the six-membered cyclization product, 2-amino-3-methylpyrrolo[1,2-a]pyrazin-1(2H)-one as the major product. The expected cyclization product with a seven-membered ring, 4-methyl-2,3-dihydro-1H-pyrrolo[2,1-d][1,2,5]triazepin-1-one was formed as the minor product and was converted quantitatively to the major product. The formation mechanism of the products was investigated, and the results obtained were also supported by theoretical calculations.