Sequential Modification of Pyrrole Ring with up to Three Different Nucleophiles.

An umpolung strategy was used for the preparation of highly functionalized 3-pyrrolin-2-ones. This approach involves dearomative double chlorination of 1H-pyrroles to form highly reactive dichloro-substituted 2H-pyrroles. The resulting intermediate reacts selectively with wet alcohols to form the corresponding alkoxy-substituted 3-pyrrolin-2-ones via double nucleophilic substitution in up to 99% yield. The subsequent reaction with different N-, O-, and S-nucleophiles opens access to highly functionalized pyrrolinones bearing additional functionality. The overall outcome of the reported sequence is step-by-step nucleophilic modification of pyrroles with three different nucleophiles. All steps were found to be highly efficient and 100% regioselective. This transformation proceeds under mild conditions and does not require any catalyst to give final products in very high yields. The obtained experimental results are in perfect agreement with the data obtained by theoretical investigation of these reactions.

Regioselective Synthesis of Highly Functionalized 2H-Pyrroles via Dearomative Chlorination of 1H-Pyrroles.

An efficient protocol was developed for the synthesis of highly functionalized 2H-pyrroles. This synthetic approach involves the in situ generation of highly reactive 2,5-dichloro-substituted 2H-pyrroles through dearomative chlorination of the corresponding 1H-pyrroles. The resulting reaction mixture is then treated with various amines, leading to the formation of 2,5-diaminated 2H-pyrroles. Subsequent nucleophilic substitution of fluorine with different N-, O-, and S-nucleophiles allows us to introduce additional functionality into a 2H-pyrrole core. The overall outcome of this reaction sequence is the triple nucleophilic modification of pyrroles. All steps of the sequence were found to be highly efficient, regioselective in the preparation of desired di- and trisubstituted derivatives in up to 96% overall yield. In addition, the computational study of this reaction sequence was carried out using density functional theory (DFT). The results of calculations are in perfect agreement with experimental observations.

Barton-Zard Reaction of ß-Fluoro-ß-nitrostyrenes─a Selective Route to Functionalized 4-Fluoropyrroles.

The Barton-Zard reaction of ß-fluoro-ß-nitrostyrenes with ethyl α-isocyanoacetate was studied. The reaction was found to proceed in a highly chemoselective manner to form preferably 4-fluoropyrroles in up to 77% yield. The corresponding 4-nitrosubstituted pyrroles are formed as minor products of the reaction. The broad scope of ß-fluoro-ß-nitrostyrenes was demonstrated in the preparation of a variety of fluorinated pyrroles. The obtained experimental results are in perfect agreement with the data obtained by theoretical investigation of this reaction. The subsequent study of synthetic utility of monofluorinated pyrroles was performed to open a way for the development of a variety of functionalized pyrrole derivatives.

First Trifluoromethylated Phenanthrolinediamides: Synthesis, Structure, Stereodynamics and Complexation with Ln(III).

The first examples of 1,10-phenanthroline-2,9-diamides bearing CF3-groups on the side amide substituents were synthesized. Due to stereoisomerism and amide rotation, such complexes have complicated behavior in solutions. Using advanced NMR techniques and X-ray analysis, their structures were completely elucidated. The possibility of the formation of complex compounds with lanthanoids nitrates was shown, and the constants of their stability are quantified. The results obtained are explained in terms of quantum-chemical calculations.

An Easy Synthesis of Monofluorinated Derivatives of Pyrroles from ß-Fluoro-ß-Nitrostyrenes.

The catalyst-free conjugate addition of pyrroles to ß-Fluoro-ß-nitrostyrenes was investigated. The reaction was found to proceed under solvent-free conditions to form 2-(2-Fluoro-2-nitro-1-arylethyl)-1H-pyrroles. The effectiveness of this approach was demonstrated through the preparation of a series of the target products in a quantitative yield. The kinetics of a conjugate addition of pyrrole was studied in detail to reveal the substituent effect and activation parameters of the reaction. The subsequent base-induced elimination of nitrous acid afforded a series of novel 2-(2-Fluoro-1-arylvinyl)-1H-pyrroles prepared in up to an 85% isolated yield. The two-step sequence herein proposed is an indispensable alternative to a direct reaction with elusive and unstable 1-Fluoroacetylenes.

Diels-Alder reaction of ß-fluoro-ß-nitrostyrenes with cyclic dienes.

The Diels-Alder reaction of ß-fluoro-ß-nitrostyrenes with cyclic 1,3-dienes was investigated. A series of novel monofluorinated norbornenes was prepared in up to 97% yield. The reaction with 1,3-cyclohexadiene permits the preparation of monofluorinated bicyclo[2.2.2]oct-2-enes. The kinetic data of the reactions with 1,3-cyclopentadiene and 1,3-cyclohexadiene were used to calculate activation parameters. Furthermore, the synthetic utility of the cycloadducts obtained was demonstrated.

ß-Aminocarbonates in Regioselective and Ring Expansion Reactions.

The reactivity of ß-aminocarbonates as anisotropic electrophiles has been investigated with several phenols. Products distribution shows that the regioselectivity of the anchimerically driven alkylation reaction depends on the nucleophiles. The results suggest that in the presence of nucleophiles that are also good leaving groups, the reaction takes place under thermodynamic control favoring the attack on the most sterically hindered carbon of the cyclic aziridinium intermediate. Furthermore, when an enantiomerically pure pyrrolidine-based carbonate was used, the reaction with phenols proceeds via a bicyclic aziridinium intermediate leading to the stereoselective synthesis of optically active 3-substituted piperidines via ring expansion reaction. These results were confirmed both by NMR spectroscopy and X-ray diffraction analysis.