Description
Main areas of research
Fundamental studies of the reactions of diazoalkanes and diazoesters as precursors of carbenes and reagents for 1,3-dipolar addition to multiple bonds; development of safe and technologically advanced methods for introducing cyclopropane fragments into various classes of organic compounds.
Priority research in the field of chemistry of diazocyclopropanes and cyclopropyl diazonium ions as promising high-reactive intermediates; development of new methods for the synthesis of cyclopropane-containing heterocycles and cyclopropyl hydrazones.
New electron-deficient cycloheptatrienes and their stable antiaromatic anions: theoretical aspects, structure, properties and use in the synthesis of polyfunctional carboxy- and heterocyclic compounds and metal complexes.
Development of new methods for the synthesis of polyfunctional condensed and frame azaheterocycles based on cyclopropylimine rearrangement, chemical transformations of donor-acceptor cyclopropanes and pyrazolines in the interests of medical chemistry.
Conducted research and scientific support of chemical processes involving their practical implementation; creation of a cyclopropanation technology for strained unsaturated hydrocarbons with diazomethane under the conditions of its simultaneous generation and catalytic decomposition at the enterprise of JSC Redkinsky Experimental Plant.
Main achievements
The possibility of accelerating the reactions of 1,3-dipolar addition of diazoesters to electron-deficient alkenes catalyzed by Lewis acids has been shown, which in some cases allows them to be carried out at 20 ° C for several minutes. GaCl3 (acceleration ~ 300 times), Yb (OTf) 3 and Sc (OTf) 3 (50-100 times) are acceptable catalysts, and with the use of GaCl3 another process actively takes place, namely the introduction of an electrophilic fragment of the diazoether into the NH bond 2-pyrazolines. The course of the target reaction of a 1,3-dipolar cycloaddition substantially depends not only on the Lewis acid used, but also on the nature of the diazo compound and the unsaturated substrate (Dr. Yu. V. Tomilov, asp. R. Novikov).
Diagram 0
New transformations of 2-aryl-cyclopropane-1,1-dicarboxylates (donor-acceptor cyclopropanes) with 1- and 2-pyrazolines, catalyzed by scandium or ytterbium triflates with the formation of N-substituted 2-pyrazolines or 1,2-diazabicyclo [3.3. 0] octanes, as well as dimerization and cascade oligomerization of these cyclopropanes in the presence of Ga and Sn compounds with the formation of polysubstituted cyclopentanes and tetralins. Probable mechanisms of occurring transformations are proposed and studied, including using low-temperature NMR spectroscopy on 71Ga and 35Cl nuclei for fixing intermediate intermediates. A new dimerization pathway for diesters of 2-arylcyclopropane-1,1-dicarboxylic acids was discovered for the first time, which, under the action of 20 mol% GaCl3 and dimethyl-3,5-dimethyl-1-pyrazoline-3,5-dicarboxylate, transform into trimethyl-1- methoxy-3,6-diaryl-2-oxabicyclo [3.3.0] octane-5,8,8-tricarboxylates. The compounds obtained are analogues of natural substances exhibiting various types of biological activity. (Doctor of chemical sciences Yu.V. Tomilov, asp. R.A. Novikov) ..
Scheme 1
On the basis of the thermal iminocyclopropane-pyrroline rearrangement of 2-cyclopropylbenzimidazoles, thiazoles, and benzothiazoles, convenient methods have been developed for the synthesis of condensed heterocyclic compounds containing a pyrrolidine moiety. 2-spiropentylbenzimidazoles enter into a similar rearrangement, and the reaction proceeds exclusively with the cleavage of the CH = CH2 bond of the first cyclopropane ring. The influence of the nature of the substituents in the benzene and cyclopropane ring on the rate and selectivity of the rearrangement was studied, and an environmentally friendly method for carrying out the process without solvents was proposed by fusing the starting compounds with ammonium hydrohalides. The proposed methodology for the preparation of pyrrolo [1,2-a] benzimidazoles is used to synthesize the precursor of the anticancer drug Yujungamycin, as well as its closest analogue, the corresponding trifluoromethyl derivative. For the first time, using the example of 2-cyclobutyl-substituted benzothiazole and N-benzylbenzimidazole hydrohalides, the possibility of a cyclobutylylimine rearrangement with the formation of a condensed 6-membered cycle was shown (Dr. Yu. V. Tomilov, Dr. N. N. Platonov, asp. R . F. Salikov).
Scheme 2
A unique cascade reaction of dimethyl bromo maleate with alkyldiazoacetate in pyridine was discovered, as a result of which cyclohepta-1,3,5-triene-1,2,3,4,5,6 was obtained from one bromide molecule and one diazo compound in one experimental stage, 7-heptacarboxylic acid with high C-H acidity (pKa ~ 7.7). For the first time, structural studies of heptamethoxycarbonylcycloheptatrienyl potassium (HMCH-K) obtained from it by X-ray diffraction and 1H and 13C NMR spectroscopy were performed, showing that the seven-membered cycle in the solid state is not flat and the conjugationonly between five carbon atoms, which is consistent with the antiaromatic character of this anion. The reactions of HMCH-K with electrophilic reagents, in particular with allyl bromide and aryl- and cyclopropyl-diazonium salts, that are able to easily transform into polyfunctional frame compounds or 3a, 7a-dihydroindazoles (d.kh.n. Yu.V. Tomilov), were studied. , N.S. DN Platonov).
Scheme 3
A new strategy has been developed for the selective synthesis of polyfunctional compounds of the northropene and 3-vinylpyridin-2-one series based on the interaction of cycloheptatrieneheptacarboxylate with primary amines. The key role in these transformations is played by the basicity of the medium, the increase of which leads first to the exceptional formation of 3-vinylpyridinones, and then as a result of cyclocondensation of the active methylene fragment along one of the ester groups to 5-hydroxy-1-oxo-1,2-dihydroisoquinoline derivatives. The use of ethanolamine or ethylene diamine makes it possible to obtain substituted 1,3,4,6-tetrahydro [1,4] oxazino [4,3b] - or 2H-pyrazino [1,2b] isoquinolines in one experimental stage - new structural blocks of analogues of biologically active compounds (Doctor of chemical sciences Yu.V. Tomilov, researcher, DN D. Platonov, researcher, GP GP Okonishnikova).
Scheme 4
It is shown for the first time that the thermolysis of 1-aryl-3,3a, 4,5,6,7,7a-hepta (methoxycarbonyl) -3a, 7a-dihydroindazoles in the presence of sterically uncomplicated unsaturated substrates is accompanied by the elimination of hex (methoxycarbonyl) benzene and the generation of 1- aryl-3-methoxycarbonylnitrilemines that join multiple bonds as 1,3-dipoles to form pyrazolines or pyrazoles. Thermolysis of 3a, 7a-dihydroindazoles in the presence of acetylacetone, azines, and aldehyde hydrazones also proceeds by interception of the nitrilemino fragment, however, due to partial fragmentation of cycloadducts, the separated products are pyrazoles or triazoles. At the same time, the reaction with 4-methyl-1,1-dichloropenta-1,3-diene gives a new type of transformation; instead of attaching a nitrilemin fragment to the diene, formal dechlorination of the initial substrate is observed with the formation of hydrazonoyl chloride, on the one hand, and 4-methyl-1,1,3-trichloropent-1-ene-4-ol, on the other hand, which can be explained only by a peculiar electrophilic transfer of a chlorine atom to the initial substrate molecule.
Scheme 5
Selective methods have been developed for the synthesis of a number of 6,8-dioxabicyclo [3.2.1] octane derivatives with condensed cyclopropane and pyrazoline, as well as spiro-linked oxaspiropentane and cyclobutanone fragments in the molecule. The cycloaddition reactions of diazo compounds via C = C or C = O bonds of levoglucosenone and some of its derivatives, occurring with high regio and stereoselectivity, are implemented. The interaction of diazocyclopropane with levoglucosenone and its analogs, as well as alantho-isoalantholactones, was studied for the first time. It is shown that at low temperature in methanol, the interaction of diazocyclopropane with levoglucosenone through the carbonyl group with the elimination of nitrogen mainly occurs, while at 0 ° C in dichloromethane it is mainly attached via the C = C bond to form pyrazolines. Studied the stereochemistry of the resulting compounds. The ways of chemical transformation of the obtained compounds with small cycles in the molecule (dediazotization, hydrolysis, oxidation) are shown in order to synthesize optically active synthons, including substituted cyclopropanes and γ-lactones, which are promising for obtaining new physiologically active substances.
