Viktor O. Iaroshenko

Regioselective and Guided C–H Activation of 4-Nitropyrazoles

A divergent and regioselective approach to 5-aryl-4-nitro-1H-pyrazoles was developed by guided transition-metal-catalyzed arylation of 4-nitro-1H-pyrazoles. This method provides a convenient tool for the functionalization of the pharmacologically relevant pyrazole scaffold. The scope and limitations of the methodology were studied.

Synthesis of Fluorinated Purine and 1-Deazapurine Glycosides as Potential Inhibitors of Adenosine Deaminase

The synthesis of 2- and 6-trifluoromethylated purines and 1-deazapurines was performed by formal [3 + 3]-cyclization reactions of 5-aminoimidazoles with a set of trifluoromethyl-substituted 1,3-CCC- and 1,3-CNC-dielectrophiles. The corresponding fluorinated nucleosides were synthesized by glycosylation of 9-unsubstituted purines and 1-deazapurines with peracetylated β-ribose, β-glucose, and rhamnose and subsequent deprotection. These scaffolds can be considered as potential inhibitors of adenosine deaminase (ADA) and inosine monophosphate dehydrogenase (IMPDH) enzymes.

One-Pot, Three-Component Synthesis of 7-Azaindole Derivatives from N-Substituted 2-Amino-4-cyanopyrroles, Various Aldehydes, and Active Methylene Compounds

An efficient and practical route to 7-azaindole framework has been developed by one-pot, three-component cyclocondensation of N-substituted 2-amino-4-cyanopyrroles, various aldehydes, and active methylene compounds in ethanol or acetic acid at reflux. Reactions involving tetronic acid, indane-1,3-dione, dimedone, and 5-phenylcyclohexane-1,3-dione gave carbocyclic fused 7-azaindoles, whereas Meldrums acid, benzoylacetonitrile, and malononitrile resulted in the highly substituted 7-azaindole derivatives, making this strategy very useful in diversity-oriented synthesis (DOS).

Reactions of 3-acylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone: one-pot synthesis of functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins

Reactions of 3-methoxalyl-, 3-polyfluoroacyl- and 3-aroylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone in the presence of DBU proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent formal [3 + 3] cyclocondensation to functionalized 2-hydroxybenzophenones, 6H-benzo[c]chromenes and benzo[c]coumarins, depending on the substituent at the 3-position. An NMR study and X-ray crystallographic analysis are reported. The compounds synthesized can be considered as promising scaffolds for the design of the novel UV-A/B and UV-B filters.

Copper-Catalyzed O-Difluoromethylation of Functionalized Aliphatic Alcohols: Access to Complex Organic Molecules with an OCF2H Group.

A two-step synthetic strategy toward difluoromethyl ethers via a CuI-catalyzed reaction of the alcohols, bearing additional protected functionalities, with FSO2CF2CO2H has been developed. The high potential of the developed protocol has been shown by preparing novel OCF2H-analogues of GABA and l-proline. The described transformation has good functional group compatibility and can serve as a powerful synthetic tool for late-stage preparation of complex OCF2H-containing organic compounds as well as building blocks for drug discovery.

Pyrrole versus quinoline formation in the palladium catalyzed reaction of 2-alkynyl-3-bromothiophenes and 2-alkynyl-3-bromofurans with anilines. A combined experimental and computational study

Benzofuroquinolines were prepared by a new type of Pd catalyzed annulation reaction. In the first step, 2-alkynyl-3-bromobenzofurans were prepared by Sonogashira reactions of 2,3-dibromobenzofuran. Their Pd catalyzed reaction with electron-rich anilines afforded benzofuroquinolines by a domino C-N coupling/annulation process. This reaction proceeds as a C,N-cyclization via the nitrogen atom and the ortho-carbon of the aniline. Similarly, furoquinolines were prepared from 2,3-dibromofuran. In contrast, benzofuropyrroles and furopyrroles were formed by N,N-cyclization when electron-poor anilines were used. Earlier, we reported results related to the thiophene and benzothiophene series. Quinolines were formed from 2,3-dibromobenzothiophene when electron rich anilines were used. In contrast, pyrroles were obtained in the case of electron-poor anilines. On the other hand, pyrroles were generally obtained, not depending on the type of aniline, when 2,3-dibromothiophene was employed as the starting material. In the present article, a detailed DFT study related to the mechanism (quinoline versus pyrrole formation) is reported which provides a rationalization of the selectivities observed for the furan, benzofuran, thiophene and benzothiophene series and for the different selectivities observed for electron-rich and -poor anilines.

Transition-Metal-Catalyzed Arylation of Nitroimidazoles and Further Transformations of Manipulable Nitro Group

Pd- or Ni-catalyzed C-H arylation of 4-nitroimidazole derivatives directed by a manipulable nitro group was developed. The reaction tolerates a wide range of substituted aryl halides and 4-nitroimidazoles. The experiments indicated that the nitro group has influence on regioselectivity of the reaction. In addition, we have shown that the efficiency of the Suzuki-Miyaura cross-coupling reaction of nitroimidazoles is slightly lower in comparison to the direct C-H arylation. The exploration of the chemical potential of the nitro group and a putative reaction mechanism are discussed.

Reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine: planning and serendipity.

Inverse electron-demand Diels–Alder (IEDDA) reactions have gained a wide popularity as synthetic tool for the assembly of complex carbocyclic and heterocyclic products, as well as natural products, and drug-like scaffolds. Electron-deficient heterocyclic azadienes have proven to be useful reagents for IEDDA reactions with electron-rich dienophiles, providing a rapid access to a wide range of highly substituted heterocyclic systems. Reactions of azadienes with classical enamines, enol esters, and thioenol esters, as well as with amidines and guanidines have been reported. 1,2-Diazines, 1,2,4-triazines, and 1,2,4,5-triazines can be regarded as masked azadienes. Their reactions with dienophiles generally involve the formation of a bridged intermediate and subsequent extrusion of nitrogen (N2). In case of 1,3,5-triazines, elimination of a nitrile is observed. For example, CF3-containing electronpoor heterocyclic azadienes, such as 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine and 3,6-bis(trifluoromethyl)-1,2,4-triazine, were recently explored for the assembly of heterocyclic and carbocyclic frameworks. We have reported the synthesis of annulated 2,6-bis(trifluoromethyl)pyrimidines and the corresponding nucleosides of purine isosteres by the IEDDA reaction of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine with electron-excessive heteroaromatic amines, anilines, and enamines. Based on these results, and on our experience related to the chemistry of 1,3-bis(trimethylsilyloxy)-1,3-butadienes, we decided to study the reaction of the latter with 2,4,6-tris(trifluoromethyl)-1,3,5-triazine (2). We considered that this reaction may produce a novel synthetic access to 2(2,6-bis(trifluoromethyl)pyrimidin-4-yl)acetate derivatives 3, which to date have only scarcely been reported in the literature. In analogy to the known transformations of enol esters and silyl enol ethers, it was expected that the reaction of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine (2) with 1,3-bis(trimethylsilyloxy)-1,3-butadiene 1a would deliver pyrimidine 3. To our surprise, the reaction followed an unusual pathway and led to the formation of g-pyridone 4a as the major product in 78% yield (Table 1). The reaction was carried

Regioselective Direct Arylation of Fused 3-Nitropyridines and Other Nitro-Substituted Heteroarenes: The Multipurpose Nature of the Nitro Group as a Directing Group

We report Pd‐ and Ni‐catalysed, guided and regioselective CH arylations of a series of fused 3‐nitropyridines. The method described here is a facile tool for the chemical functionalisation of drug‐like fused pyridines. The scope and limitations of the reaction, the chemical potential of the nitro group and a putative reaction mechanism are discussed.

Diversity oriented synthesis of 6-nitro- and 6- aminoquinolones and their activity as alkaline phosphatase inhibitors†

The novel quinolone derivatives synthesized by cyclization of α,β-ynones with primary amines were shown to be promising TNAP and IAP inhibitors. The mechanism of their formation was studied by the isolation of intermediates.