A. M. Starosotnikov

3-R-4-Nitro-6,7-furoxanobenzo[ d ]isoxazoles – a new type of condensed nitroarenes capable of Diels–Alder reaction

Pericyclic [4+2] cycloaddition (Diels–Alder reaction) of nitrofuroxanobenzo[d]isoxazoles, capable of acting both as dienophiles (at the C=CNO2 bond) or heterodienes (at the C=C–N(O)=O fragment) was used to synthesize a new type of condensed polycyclic systems. The obtained compounds combining in one molecule two pharmacophore moieties, furoxan (nitric oxide donor) and substituted isoxazole, may be considered as a potential basis for the design of compounds with dual biological activity.

Regiospecificity of nucleophilic substitution in 4,6-dinitro-1-phenyl-1H-indazole

The reactions of 4,6-dinitro-1-phenyl-1H-indazole with anionic nucleophiles RS– and N3– lead to the regiospecific replacement of the nitro group at position 4. The reaction with N2H4·H2O + FeCl3 also results in reduction of only the 4-NO2 group. Based on this fact, a procedure was developed for the preparation of previously unknown 3-unsubstituted 4-X-6-nitro-1-phenyl-1H-indazoles (X is a residue of a nucleophile or NH2). Comparison of the data on the selective nucleophilic substitution (4-NO2 group) in 3-Z-1-aryl-4,6-dinitro-1H-indazoles shows that in the case of Z = H, the regiospecificity of substitution is determined by the electronic effect of the annelated pyrazole ring.

Pericyclic [4+2] and [3+2] Cycloaddition Reactions of Nitroarenes in Heterocyclic Synthesis

A summary is given of our results and literature data on the use of nitroarenes in pericyclic [4+2] and [3+2] cycloaddition reactions to give heterocycles fused with the original aromatic carbocycle. Highly electrophilic bicyclic nitroarenes, which are considered superelectrophiles, are capable of undergoing the Diels–Alder reaction with nucleophilic alkenes as C=C–N(O)=O heterodienes to give dihydro-1,2-oxazine N-oxides. Dinitrobenzenes, 1,3,5-trinitrobenzene, and their substituted derivatives and analogs as well as nitrobenzenes and 1,3-dinitrobenzenes fused with electron-withdrawing azoles and pyridine are capable of undergoing 1,3-dipolar cycloaddition as dipolarophiles at the C=C(NO2) bond with N-alkylazomethine ylides serving as 1,3-dipoles to give N-alkylpyrrolidines, pyrrolines, or pyrroles fused to an aromatic ring, depending on the structure of the nitro compound substrates. A relationship was found between the reactivity of the nitroarenes in pericyclic [4+2] and [3+2] cycloaddition reactions and the electrophilicity of these substrates.

Synthesis of 3-substituted 1-aryl-4,6-dinitro-1H-indazoles based on picrylacetaldehyde and their behavior in nucleophilic substitution reactions

A method for the synthesis of 1-aryl-3-formyl-4,6-dinitro-1H-indazoles by the reaction of picrylacetaldehyde with aryldiazonium salts followed by intramolecular cyclization of the resulting picrylglyoxal monoarylhydrazones was developed. Various 4,6-dinitro-1-phenyl-1H-indazoles substituted in position 3 were prepared via transformations involving the formyl group of 3-formyl-4,6-dinitro-1-phenyl-1H-indazole. 3-R-4,6-Dinitro-1-phenyl-1H-indazoles (R = CHO, CN, 1,3-dioxolan-2-yl) react regiospecifically with anionic O-, S-, and N-nucleophiles, in particular, with replacement of only the 4-NO2 group. Thus previously unknown 3-R-4-Nu-6-nitro-1-phenyl-1H-indazoles were synthesized (Nu is a nucleophile residue).

Synthesis of 4,6-dinitro-3-R-benzo[d]isoxazoles and their transformations under the action of nucleophiles

A new procedure was developed for the preparation of 4,6-dinitro-3-R-benzo[d]isoxazoles (R are derivatives of the aldehyde group) based on 2,4,6-trinitrophenylacetaldehyde. The resulting compounds are characterized by the regiospecific substitution of the nitro group at position 4 under the action of anionic nucleophiles RS–, RO–, F–, or N3–, which allowed the development of a new method for the preparation of previously unknown 4-Nu-6-nitro-3-R-benzo[d]isoxazoles (Nu is the residue of a nucleophile). At the same time, oxidative nucleophilic substitution under the action of anions of some β-dicarbonyl compounds leads to the replacement of the hydrogen atom at position 7 with the corresponding C-nucleophiles.

8-R-5,7-Dinitroquinolines in [3+2] cycloaddition reactions with N-methylazomethine ylide

Novel derivatives of isoindole and dihydroisoindole fused to the pyridine ring were obtained by 1,3-dipolar cycloaddition reactions of N-methylazomethine ylide with substituted 5,7-dinitroquinolines. The substituents in the benzene ring were found to affect the cycloaddition outcome.

Synthesis of novel polycyclic heterosystems from 5-nitro[1,2,5]selenadiazolo[3,4-e]benzofuroxans

A method for the preparation of 5-nitro[1,2,5]selenadiazolo[3,4-e]benzofuroxan has been developed. Employing the reactivity of this compound in pericyclic (4+2) and (3+2) cycloaddition reactions as a dienophile or dipolarophile (at the C=C–NO2 bond) with a heterodiene (fragment C=C–N(O)=O) representatives of novel types of fused polycyclic heterosystems were synthesized.

Quantum-chemical and NMR study of nitrofuroxanoquinoline cycloaddition

Using DFT/B3LYP and ab initio RHF quantum-chemical calculations in the triple-zeta basis set 6-31++G** the endo and exo cycloaddition mechanism for the interaction of ethyl vinyl ether, trimethylsilyloxybutadiene, or cyclopentadiene with 5-nitro-7,8-furoxanoquinolines was studied in details. Considering that both in solutions and crystals nitrofuroxanoquinoline exists as an inseparable mixture of two N-oxide tautomers, all cycloaddition processes were studied for both of them. The studied mechanisms practically do not depend on the location of the exocyclic oxygen atom in nitrofuroxanoquinoline molecule. At the first step of all reactions the conjugated nitroarene fragments C=C–N=O react with nucleophilic reagents following the mechanism of endo-[4+2] cycloaddition with inverse electronic demand. Further (in the cases of trimethylsilyloxybutadiene and cyclopentadiene) endo-[4+2] cycloadducts recyclize spontaneously according to the mechanism of [3,3] sigmatropic rearrangement into more thermodynamically stable, experimentally detected endo-[2+4] cycloadducts. Both endo-[4+2] and endo-[2+4] cycloadducts obtained from cyclopentadiene and nitrofuroxanoquinoline have been experimentally isolated and characterized. For this case, the kinetic and activation parameters of [4+2] → [2+4] transformation have been studied by 1H NMR method, which have shown an excellent agreement with quantum-chemical results. In all cases the exo processes are one-step reactions, less favorable kinetically than their endo competitors.

Synthesis of 3-R-2-aryl-4,6-dinitroindoles and specific features of their reactions with anionic nucleophiles

Reaction of different anionic S-nucleophiles with 3-R-2-aryl-4,6-dinitroindoles led to a regiospecific nucleophilic substitution of the nitro group in position 4 with 6-NO2 group remaining intact. The representatives of some peri-annulated polycyclic systems were synthesized on the basis of the substitution products.

Synthesis of mesoionic 3-aryl(hetaryl)-1,2,3,4-oxatriazol-5-ones b based on N-aryl-and N-hetarylhydrazones of bromonitroformaldehyde

Dehydrobromination of N-arylhydrazones of bromonitroformaldehyde (at 20°C) in the presence of alkali and ammonium salts of strong mineral acids, HNO3, silica gel, and Al2O3 forms mesoionic 3-aryl-1,2,3,4-oxatriazol-5-ones (3-arylazasydnones). The effect of the electronic properties of the aryl substituent on the course of the reaction is evaluated. This evaluation is used to develop a general method for preparing 3-arylazasydnones with various substituents including novel 3-hetarylazasydnone derivatives of pyrazole, 1,2,4-triazole and pyridine. Aromatic electronic effects (σI, σR, σm, σp) of the mesionic 1,2,3,4-oxatriazol-5-on-3-yl moiety are determined by19F NMR. A scheme is proposed for the dehydrobromination of the bromonitroformaldehyde N-arylhydrazones that includes the intermediate N-aryl-C-(nitro) nitrilimines, ArN−−N=C+NO2, with subsequent isomerization of the latter into 3-arylazasydnones.