Rafał Loska

Synthesis of α-Trifluoromethyl-β-lactams and Esters of β-Amino Acids via 1,3-Dipolar Cycloaddition of Nitrones to Fluoroalkenes†

Nitrones derived from aromatic or aliphatic aldehydes or ketones react with hexafluoropropene (HFP) or 2H-pentafluoropropene (PFP) to give the respective fluorinated isoxazolidine derivatives in good yields with complete regioselectivity and moderate diastereoselectivity. Catalytic hydrogenolysis of the N-O bond under ambient pressure and temperature leads to fluorides of beta-amino acids that undergo cyclization to alpha-trifluoromethylated beta-lactams or, under acidic conditions, form esters of alpha-trifluoromethylated beta-amino acids.

New synthesis of 2-heteroarylperfluoropropionic acids derivatives by reaction of azine N-oxides with hexafluoropropene.

Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the N--O bond in the isoxazolidine ring and elimination of HF. When the reaction is carried out in the presence of alcohols or N-alkyl anilines, the in situ formed acyl fluorides give the corresponding esters and amides. They can be also treated separately with nucleophiles to produce the respective acylation products, whereas their hydrolysis leads to unstable carboxylic acids that undergo spontaneous decarboxylation to 1-aryl-1,2,2,2-tetrafluoroethanes. This new reaction provides a simple and general method of synthesizing 2-heteroarylperfluoropropionic acid derivatives that were previously unknown and unavailable.

Synthesis and catalytic activity of ruthenium indenylidene complexes bearing unsymmetrical NHC containing a heteroaromatic moiety

New robust and air stable ruthenium(II) indenylidene second generation olefin metathesis catalysts with unsymmetrical N-heterocyclic carbene (NHC) ligands were synthesized. Model metathesis reactions were performed in the presence of newly-developed complexes in commercial grade toluene under air, leading to high conversions and good selectivities.

Design and synthesis of protoporphyrin IX/vitamin B12 molecular hybrids viaCuAAC reaction

The design and synthesis of new molecular hybrids composed of protoporphyrin IX (PPIX) and vitamin B12 via copper catalyzed alkyne azide cycloaddition reaction is described. New, clickable aminoazide and aminoalkyne linkers were prepared and subsequently attached to PPIX (via vinyl group) and to vitamin B12 giving desired building blocks. Preliminary results showed that respective water soluble hybrids were formed under CuAAC reaction. Gratifyingly, Cu incorporation into the PPIX core was avoided, which was important for further biological studies.

Selective modifications of hydrophobic vitamin B12 derivatives at c-and d-positions.

The acid-sensitivity of vitamin B(12) derived mono- and diamides was studied. It was found that the use of reductive ring-opening of the lactone moiety deactivated undesired decomposition of c-mono- and c,d-diamides under acidic conditions. As a result, reactions gave respectively c- or d-acids which were further functionalized via coupling with amino acids. Though mono- and diamides exhibited acid sensitivity, they were used for the preparation of several highly functionalized molecules showing their stability under various reaction conditions.

Introduction of Perfluoroalkyl Substituents into Heteroarenes via Nucleophilic Substitution of Hydrogen

Abstract A summary of research in the area of fluoroalkylation of electron-deficient aromatic compounds is presented. The reaction of dinitro- and cyanonitroarenes with trifluoromethyl-trimethylsilane (Me3SiCF3) and tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) and subsequently with DMD provides trifluoromethylated cyano- and nitrophenols via oxidative nucleophilic substitution of hydrogen. Addition of fluorinated carbanions, generated either by addition of F− anions to hexafluoropropene or by activation of Me3SiCF3, to N-alkylazinium salts leads to dihydropyridines, dihydroquinolines etc., oxidation of which affords the respective fluoroalkylated heterocycles. 1,3-Dipolar cycloaddition of azine N-oxides to hexafluoropropene gives 2-heteroaryl-2,3,3,3-tetrafluoropropionic acid fluorides, which react with various protic nucleophiles to give esters and amides of 2-heteroarylperfluoropropionic acids, whereas reaction with water and decarboxylation of the free acids gives azines with a 1,2,2,2-tetrafluoroethyl group at C-2.

α-Chlorobenzylation of Nitroarenes via Vicarious Nucleophilic Substitution with Benzylidene Dichloride: Umpolung of the Friedel–Crafts Reaction

Readily available α,α-dichlorotoluenes enter a vicarious nucleophilic substitution (VNS) reaction with electron-deficient arenes to give α-chlorobenzylated nitrobenzenes, as well as six- and five-membered heterocycles. Oxidation of the initially formed α-chlorobenzylic carbanions instead of protonation results in formation of diaryl ketones, providing a means for overall nucleophilic C-H benzoylation of electron-deficient aromatic rings. Alternatively, benzoylated nitroarenes can be obtained via the reaction of isolated α-chlorodiarylmethanes with sodium azide.

Recent Advances in Cycloaddition Reactions of Heterocyclic N-Oxides

1,3-Dipolar cycloaddition of N-oxides of azines and azoles has become a reliable and versatile synthetic method of preparation of highly functionalized nitrogen heterocycles. Mechanisms of cycloaddition of N-oxides are outlined, including various reaction pathways available for the initial five-membered cycloadducts. Cycloaddition to multiple carbon–carbon, carbon–nitrogen, and carbon–sulfur bonds is discussed, with particular emphasis on modern methods of selective C-2-functionalization of the heteroaromatic ring.

Application of the Radical Cascade of Acyclic Peptide-Based Precursors into Analogues of Type I β-Turn

Radical cyclizations of di-, tri- and tetrapeptides containing N-2-bromobenzyl,N-methyl-substituted alanine or aspartic acid lead in good yields to α,β-unsaturated γ-lactams. The overall cascade, relying on a hydrogen atom transfer-elimination strategy could serve as a way to incorporate a flat and rigid five-membered ring into the peptide framework.