Non-covalent interactions in the diastereoselective synthesis of cis-2,3-dihydrobenzofurans: experimental and computational studies.

The diastereoselective synthesis of 2,3-DHBs has been previously reported via an intramolecular Michael addition reaction using alkali bases such as Cs2CO3 and K2CO3. However, no systematic study has been performed to understand the possible role of bases in the mechanism of the reaction and factors behind the stereoselective outcome of the reaction. Herein, from experimental and theoretical points of view, we disclose the role of the cesium salt in the rate-determining step along the catalytic cycle and the key role of stabilizing non-covalent interactions in the stereoselective outcome of the reaction.

Mechanistic Insights into the DABCO-Catalyzed Cloke-Wilson Rearrangement: A DFT Perspective.

The mechanism and selectivity patterns of the DABCO-catalyzed Cloke-Wilson rearrangement were computationally studied in detail using density functional theory calculations. Our computations suggest that the process occurs stepwise involving the initial ring opening of the cyclopropane promoted by a DABCO molecule followed by a ring-closure reaction of the readily formed zwitterionic intermediate. The regioselectivity of the initial nucleophilic ring-opening step strongly depends on the nature of the substituent attached to the cyclopropane moiety. The physical factors governing the preference for the more sterically hindered C2 (tertiary) position have been quantitatively analyzed by applying the combined activation strain model-energy decomposition analysis method. In addition, our calculations revealed a new mechanism for the analogous transformation involving vinylcyclopropanes consisting of an initial SN2' ring-opening process followed by a 5-exo-trig cyclization step, which proceeds without facial selectivity.

Selective reduction of nitroarenes using Ru/C and CaH2.

Herein, we report an efficient and highly selective method for the reduction of aromatic, heteroaromatic and halonitro compounds using the readily available and cost-effective Ru/C as a catalyst along with unconventional CaH2 as a source of hydride. In most cases the corresponding anilines can be obtained by simple filtration without further purification. The use of 2-MeTHF and the simple operational work-up constitute a valid alternative to previous methodologies.

Phenoxy- and Phenylamino-Heterocyclic Quinones: Synthesis and Preliminary Anti-Pancreatic Cancer Activity.

The successful application of fragment-based drug discovery strategy for the efficient synthesis of phenoxy- or phenylamino-2-phenyl-benzofuran, -benzoxazole and -benzothiazole quinones is described. Interestingly, in the final step of the synthesis of the target compounds, unusual results were observed on the regiochemistry of the reaction of bromoquinones with phenol and aniline. A theoretical study was carried out for better understanding the factors that control the regiochemistry of these reactions. The substituted heterocyclic quinones were evaluated in vitro to determine their cytotoxicity by the MTT method in three pancreatic cancer cell lines (MIA-PaCa-2, BxPC-3, and AsPC-1). Phenoxy benzothiazole quinone 26a showed potent cytotoxic activity against BxPC-3 cell lines, while phenylamino benzoxazole quinone 20 was the most potent on MIA-PaCa-2 cells. Finally, electrochemical properties of these quinones were determined to correlate with a potential mechanism of action. All these results, indicate that the phenoxy quinone fragment led to compounds with increased activity against pancreatic cancer cells.

Reduction Over Condensation of Carbonyl Compounds Through a Transient Hemiaminal Intermediate Using Hydrazine.

Reduction of carbonyl moieties to the corresponding alcohol using simply hydrazine hydrate has been considerably unfeasible until now due to the well-known condensation reaction. However, herein, we report that using an excess of 20-fold equivalents, the reduction proceeds in excellent yields. 1H NMR study of the reaction and density functional theory (DFT) calculations indicate that the final fate of the hemiaminal intermediate is crucial to obtain the alcohol or the hydrazone.

Unraveling the Selectivity Patterns in Phosphine-Catalyzed Annulations of Azomethine Imines and Allenoates.

The mechanism and selectivity of phosphine-catalyzed [3 + 2] and [3 + 3] annulations of azomethine imines and allenoates have been computationally studied. Exploration of the potential energy surface reveals that the cyclization step is a key step controlling the selectivity of the process. This contrasts with previous studies on related transformations where the initial nucleophilic addition involving the activated allenoate was found to exclusively control the regioselectivity of the transformation. Among the possible reaction pathways, the energetically low-lying reaction channel involves an intramolecular Michael addition leading to the experimentally observed [3 + 2] product. The factors controlling the observed regioselectivity have been quantitatively rationalized by means of state-of-the-art computational methods, namely, the activation strain model of reactivity in combination with the energy decomposition analysis.

Meisenheimer complexes as hidden intermediates in the aza-SNAr mechanism.

In this work we report a computational study about the aza-SNAr mechanism in fluorine- and chlorine-containing azines with the aim to unravel the physical factors that determine the reactivity patterns in these heterocycles towards propylamine. The nature of the reaction intermediate was analyzed in terms of its electronic structure based on a topological analysis framework in some non-stationary points along the reaction coordinate. The mechanistic dichotomy of a concerted or a stepwise pathway is interpreted in terms of the qualitative Diabatic Model of Intermediate Stabilization (DMIS) approach, providing a general mechanistic picture for the SNAr process involving both activated benzenes and nitrogen-containing heterocycles. With the information collected, a unified vision of the Meisenheimer complexes as transition state, hidden intermediate or real intermediate was proposed.

Influence of Non-Covalent Interactions in the Exo- and Regioselectivity of Aza-Diels-Alder Reactions: Experimental and DFT Calculations.

A systematic experimental and theoretical study of the intermolecular Aza-Diels-Alder reaction using 5-aminopyrrole as a building block shows that the commonly accepted endo selectivity, ruled by controversial secondary orbital interactions, are overcome by non-covalent interactions affording to the unusual exo adduct. Additionally, the regioselectivity is also influenced for such interactions. The starting materials are easily prepared, and the use of water as the solvent is a great achievement for the development of cleaner synthetic methodologies.

Mechanistic insights into the ANRORC-like rearrangement between methylhydrazine and 1,2,4-oxadiazole derivatives.

We herein present the first in-depth theoretical study devoted to elucidate the mechanism of the reaction between 1,2,4-oxadiazole derivatives and methylhydrazine. For this purpose, the reaction between methylhydrazine and some polyfluoroaryl-1,2,4-oxadiazoles has been employed as a model reaction. The analysis of the potential energy surface (PES) indicates that the most favorable path involves an initial amine attack at the C(2') site of the aryl moiety to yield an aryl-hydrazine intermediate whose thermodynamic stability appears as the main determinant of the favored reaction path. Next, the cyclization step leading to a spiro intermediate through a favored 5-exo-trig process appears as the rate determining step. Additionally, this study highlights the relevance of the torsional strain effects on the favored ANRORC pathway. Finally, both the origins of the substituent effects on the regioselectivity patterns as well as the need of using a large excess of nucleophile to afford the favored ANRORC pathway are discussed.