Simple Synthesis of Substituted 3-Hydroxyfuran-2(5H)-ones

A convenient and facile approach to functionalized 4-substituted 3,5-dihydroxy-5-(trichloromethyl)furan-2(5H)-ones was developed. This method is based on regioselective synthesis of novel furan-2,3-diones containing the trichloromethyl group and subsequent hydrolysis. The structures of compounds were unambiguously confirmed by single-crystal X-ray diffraction.

Synthesis and Antiplasmodial Evaluation of 4-Carboxamido- and 4-Alkoxy-2-Trichloromethyl Quinazolines

From three previously identified antiplasmodial hit compounds (A–C) and inactive series (D), all based on a 2-trichloromethylquinazoline scaffold, we conducted a structure-activity relationship (SAR) study at position four of the quinazoline ring by synthesizing 42 novel derivatives bearing either a carboxamido- or an alkoxy-group, to identify antiplasmodial compounds and to enrich the knowledge about the 2-trichloromethylquinazoline antiplasmodial pharmacophore. All compounds were evaluated in vitro for their cytotoxicity towards the HepG2 cell line and their activity against the multiresistant K1 P. falciparum strain, using doxorubicin, chloroquine and doxycycline as reference drugs. Four hit-compounds (EC50 K1 P. falciparum ≤ 2 µM and SI ≥ 20) were identified among 4-carboxamido derivatives (2, 9, 16, and 24) and two among 4-alkoxy derivatives (41 and 44). Regarding the two most potent molecules (16 and 41), five derivatives without a 2-CCl3 group were prepared, evaluated, and appeared totally inactive (EC50 > 50 µM), showing that the 2-trichloromethyl group was mandatory for the antiplasmodial activity.

Preparation and Reactions of Trichloromethyl-Substituted Pyridine and Pyrimidine Derivatives

The three-component reaction of lithiated methoxyallene, nitriles and trichloroacetic acid gave three model β-keto enamides that were starting materials for the synthesis of trichloromethyl-substituted pyridine and pyrimidine N-oxide derivatives. Upon treatment with acetic anhydride, the methyl group of the prepared pyrimidine N-oxides was converted into an acetoxymethyl group by a Boekelheide rearrangement. A few typical experiments also revealed that the trichloromethyl group of the prepared pyrimidine N-oxides can be replaced by an alkoxy or a hydroxy group, or transformed into an arylthiomethyl group. An alternative approach to β-keto enamides via the corresponding β-keto enamines was also examined and provided the expected 4-hydroxy-6-(trichloromethyl)pyridine derivative in good yield.

Synthetic Versatility of β-Alkoxyvinyl Trichloromethyl Ketones for Obtaining [1,2,4]Triazolo[1,5-a]pyrimidines

The synthetic versatility of 4-alkoxy-4-alkyl/aryl-1,1,1-trichloroalk-3-en-2-ones (enones) for the synthesis of [1,2,4]triazolo[1,5-a]pyrimidines, in which the trichloromethyl group is either maintained or eliminated from the product by simply controlling the reaction medium, is reported. These enones react with 3-amino-1H-1,2,4-triazoles under acidic conditions to furnish exclusively 7-(trichloromethyl)-[1,2,4]triazolo[1,5-a]pyrimidines, whereas under basic conditions [1,2,4]triazolo[1,5-a]pyrimidin-5/7(1H)-ones are obtained with elimination of the trichloromethyl group. The regioselectivity of the reactions performed under basic conditions is highly influenced by the substituents present in the starting enones. Twenty-one examples are synthesized using these two methodologies, with yields of up to 86%.

Reactivity of electrophilic chlorine atoms due to σ-holes: a mechanistic assessment of the chemical reduction of a trichloromethyl group by sulfur nucleophiles

σ-Holes are shown to promote the electrophilic behavior of chlorine atoms in a trichloromethyl group when bound to an electron-withdrawing moiety.

Chlorido[N,N′-dibenzyl-N′′-(trichloroacetyl)phosphoramidato-κ2O,O′](1,10-phenanthroline-κ2N,N′)copper(II)

In the title complex, [Cu(C16H16Cl3N3O2P)Cl(C12H8N2)], the CuIIcation presents a square-pyramidal environment, where the CuO2N2base is formed by two O atoms from carbonyl and phosphoryl groups, and by two N atoms from a 1,10-phenanthroline molecule. A coordinated Cl atom occupies the apex. N—H...Cl hydrogen bonds link the molecules into one-dimensional chains. The trichloromethyl group is rotationally disordered over two positions, with occupancies of 0.747 (7) and 0.253 (7).