1996

In 1996 Zubkov F.I. graduated from the Peoples' Friendship University of Russia named after Patrice Lumumba, Chemistry department.

2000

In 2000 he defended his thesis for Ph.D. degree on "Synthesis of substituted and spiroannelated benz-2-azepines, 1,2,3-oxathiazine-2,2-dioxides, azetidines, 7-oxa-1-azabicyclo [2.2.1] heptanes and 6-phenylpiperidin-4-ol based on homoallylamines and their nitrones. Study of the [3 + 2] cycloaddition of alkenes to the N-oxide" and was awarded the Ph.D. degree in Chemistry.

2007

In 2007 he was awarded the academic title of Associate Professor in the Department of Organic Chemistry, the Faculty of Science, Peoples' Friendship University of Russia (RUDN University).

Lecturing experience

15-years of lecturing at the RUDN University.

Lecture courses in chemistry for 2-6th year students:

  • organic chemistry;
  • stereochemistry;
  • the strategy of organic synthesis;
  • the basis of nuclear magnetic resonance;
  • supervision of conducting scientific research practice with candidates for a master's  degree.

Research

New approaches to the construction of heterocyclic systems with an isoindole fragment based on IMDAF and IMDAV reactions were discovered. Original methods for the synthesis of partially hydrogenated quinolines, isoquinolines and benzazepines have been developed. Scientific works contributed to the understanding of the intramolecular [4 + 2] cycloaddition reaction mechanism and stereochemistry in the furan series.

Grant support of scientific research:

  • project manager of the Russian Foundation for Basic Research;
  • two-time holder of Potanin’s grants and the Moscow government's "Best Teacher" (2004, 2006);
  • author of more than 100 publications in international scientific journals;
  • Hirsch index 15 (Scopus).

Research interests

Various aspects of the chemistry of heterocyclic compounds: synthesis, stereochemistry, dynamics, reaction mechanisms. The greatest number of publications is devoted to the transformation of furan, isoindole and intramolecular Diels-Alder reaction.

NOVEL APPROACH TO ISOINDOLO[2,1-a]QUINOLINES: SYNTHESIS OF 1- AND 3-HALO-SUBSTITUTED 11-OXO-5,6,6A,11-TETRAHYDROISOINDOLO[2,1-a]QUINOLINE-10-CARBOXYLIC ACIDS

Boltukhina E.V., Zubkov F.I., Nikitina E.V., Varlamov A.V.

Synthesis. 2005. № 11. С. 1859-1875.

DOI: 10.1055/s-2005-869948

Abstract:

A series of 1- and 3-halo-substituted isoindolo[2,1-a]quinolines were obtained by means of electrophilic cyclization of methallyl- and allyl-substituted isoindolo-7-carboxylic acids. The influence of halogen atoms on the stereochemistry of the formation of key intermediates, 3a,6-epoxyisoindoles, was studied.

AN EFFICIENT SYNTHESIS OF ISOINDOLO[2,1-a]QUINOLINE DERIVATIVES VIA IMINO DIELS-ALDER AND INTRAMOLECULAR DIELS-ALDER REACTIONS WITH FURAN

Kouznetsov V.V., Cruz U.M., Zubkov F.I., Nikitina E.V.

Synthesis. 2007. № 3. С. 0375-0384.

DOI: 10.1055/s-2007-965875

Abstract:

The straightforward synthesis of new isoindolo[2,1-a]quinoline derivatives from 2,4-disubstituted 1,2,3,4-tetrahydroquinolines bearing a furan fragment via the intramolecular Diels-Alder reaction is reported. The synthesis of key precursors was realized with excellent levels of diastereoselectivity either by Povarov reaction or by a multicomponent condensation approach.

THERMAL AND CATALYTIC INTRAMOLECULAR [4 + 2]-CYCLOADDITION IN 2-ALKENYLFURANS

Zubkov F.I., Nikitina E.V., Varlamov A.V.

Russian Chemical Reviews. 2005. Т. 74. № 7. С. 639-669.

DOI: https://doi.org/10.1070/RC2005v074n07ABEH001180

Abstract:

The published data on the intramolecular Diels–Alder reaction in compounds of the 2-alkenylfuran series are generalised. The methods and conditions for the preparation of tricyclic systems are considered. The effects of the substituents in the furan and the unsaturated fragments on the cycloaddition are discussed. The application of this reaction to the synthesis of alkaloids and terpenoids is exemplified.

EXPERIMENTAL EVIDENCE FOR INTRAMOLECULAR IPSO SUBSTITUTION OF ALKYL GROUPS

Zubkov F.I., Nikitina E.V., Kouznetsov V.V., Duarte L.D.A.

European Journal of Organic Chemistry. 2004. № 24. С. 5064-5074.

DOI: 10.1002/ejoc.200400356

Abstract:

An acid-mediated intramolecular Friedel−Crafts intramolecular alkene alkylation of the ortho-alkyl group in the N-arylamino moiety of various N-(1-allylcycloalkyl)-N-arylamines resulting in alkyl-substituted 3′,4′-dihydro-1′H-spiro[cycloalkane-1,2′-quinolines] is described. The mechanistic details of this intramolecular Friedel−Crafts alkylation by an alkene moiety can be explained by an intramolecular alkylation with ipso substitution of alkyl groups and their 1,2-rearrangement. The scope and limitations of this reaction were determined. As a conclusive proof of the proposed mechanism, previously unknown interesting by-products, dispiro[quino[6,7-f]quinoline-3,1′:9,1′′-bis(cycloalkanes), were isolated and characterized.

WAGNER-MEERWEIN SKELETAL REARRANGEMENT OF 3-SPIROANNULATED 6,8A-EPOXY- AND 6,8a;7,8-DIEPOXYISOQUINOLINES (3-AZA-11-OXATRICYCLO[6.2.1.01,6]UNDEC-9-ENES). ISOLATION AND IDENTIFICATION OF 5-AZA-2-OXATRICYCLO[6.2.1.03,9]UNDEC-3-ENES

Zubkov F.I., Nikitina E.V., Safronova A.A., Borisov R.S., Varlamov A.V., Turchin K.F., Aleksandrov G.G.

Journal of Organic Chemistry. 2004. Т. 69. № 2. С. 432-438.

DOI: 10.1021/jo0353684

Abstract:

The reactions of 3-acetyl-3-aza-11-oxatricyclo[6.2.1.01,6]undec-9-ene and its 9,10-epoxy derivative with bromine and Ac2O/BF3·OEt2 under different conditions were studied. Unusual products of Wagner−Meerwein rearrangement bearing the olefin fragment (5-aza-2-oxatricyclo[6.2.1.03,9]undecen-3-enes) were isolated and characterized by X-ray analysis.

AN IMPROVED AND STEREOSELECTIVE ROUTE TO ALL-CIS-2,6-DISUBSTITUTED 4-HYDROXYPIPERIDINES FROM ACCESSIBLE 4-SUBSTITUTED 4-N-BENZYLAMINOBUT-1-ENES

Varlamov A., Kouznetsov V., Zubkov F., Chernyshev A., Shurupova O., Vargas Méndez L.Y., Palma Rodríguez A., Rivero Castro J., Rosas-Romero A.J.

Synthesis. 2002. № 6. С. 771-783.

DOI: 10.1055/s-2002-25770

Abstract:

The reaction between allylmagnesium bromide and imin­es 5a-l leads to the corresponding 4-substituted 4-N-benzylaminobut-1-enes 6a-l, which were oxidized in a regioselective manner to the alkenylnitrones 7a-l. The intramolecular 1,3-dipolar cycloaddition of these nitrones gave 2-spiroannulated or 2-substituted 6-exo-phenyl-1-aza-7-oxabicyclo[2.2.1]heptanes 8a-j. Reductive cleavage of the N-O bond of the obtained bicycles afforded the diverse substituted 4-hydroxypiperidines 9a-h in good yields. This stereoselective approach allowed the preparation of all-cis-4-hydroxy-6-phenyl-2-nonylpiperidine (9i), a close analogue of dendrobatid frog alkaloid 241D.

EFFICIENT SYNTHESIS AND SPECTROSCOPIC ANALYSIS OF 8-NITRO SPIRO C-3-ANNULATED 2-BENZAZEPINES AND THEIR N-OXIDES

Varlamov A., Zubkov F., Chernyshev A., Alexandrov G., Kouznetsov V., Palma A., Vargas L., Salas S.

Synthesis. 2001. № 6. С. 849-854.

DOI: 10.1055/s-2002-25770

Abstract:

The reaction between allylmagnesium bromide and imin­es 5a-l leads to the corresponding 4-substituted 4-N-benzylaminobut-1-enes 6a-l, which were oxidized in a regioselective manner to the alkenylnitrones 7a-l. The intramolecular 1,3-dipolar cycloaddition of these nitrones gave 2-spiroannulated or 2-substituted 6-exo-phenyl-1-aza-7-oxabicyclo[2.2.1]heptanes 8a-j. Reductive cleavage of the N-O bond of the obtained bicycles afforded the diverse substituted 4-hydroxypiperidines 9a-h in good yields. This stereoselective approach allowed the preparation of all-cis-4-hydroxy-6-phenyl-2-nonylpiperidine (9i), a close analogue of dendrobatid frog alkaloid 241D.

COPPER(II) ARYLHYDRAZONE COMPLEXES AS CATALYSTS FOR C[SBND]H ACTIVATION IN THE HENRY REACTION IN WATER

Ma Z., Gurbanov A.V., Kopylovich M.N., Mahmudov K.T., Pombeiro A.J.L., Maharramov A.M., Guseinov F.I., Zubkov F.I.

Journal of Molecular Catalysis A: Chemical. 2017. Т. 426. С. 526-533.

DOI: 10.1016/j.molcata.2016.05.030

Abstract:

Three new water-soluble copper(II) complexes [Cu(HL)(H2O){(CH3)2NCHO}] (1), [Cu(H2L)2(im)4]·CH3OH (2) and [Cu(HL)(CH3OH)]2(μ2-py) (3) were synthesized from copper(II) nitrate and sodium (Z)-2-(2-(1,3-dioxo-1-(phenylamino)butan-2-ylidene)hydrazinyl)benzene-sulfonate (NaH2L), in the absence (for 1) and presence of imidazole (im) (for 2) or pyrazine (py) (for 3), and fully characterized. The complexes 1–3 have been tested as stereoselective CH activating catalysts for the model nitroaldol (Henry) condensation of nitroethane with various aldehydes in water. 1 was the most active catalyst affording 64−87% yields with syn/anti diasteroselectivities up to 77:23.

A TWO-STAGE SYNTHESIS OF 8,10a-EPOXYPYRIDO[2,1-a]ISOINDOLES: STEREOCHEMISTRY OF THE [4+2] CYCLOADDITION OF MALEIC ANHYDRIDE WITH 2,6-DIFURYLPIPERIDIN-4-ONES

Zubkov F.I., Airiyan I.K., Zaytsev V.P., Nikitina E.V., Varlamova A.V., Turchin K.F., Gurbanov A.V., Maharramov A.M., Khrustalev V.N., Peregudov A.S.

Synthesis. 2009. № 24. С. 4235-4255.

DOI: 10.1055/s-0029-1217033

Abstract:

A new straightforward synthesis of 8,10a-epoxypyrido[2,1-a]isoindoles and their 7-carboxylic acids from 2,6-difuryl-substituted piperidin-4-ones and maleic anhydride or acryloyl chloride via the intramolecular Diels-Alder reaction has been demonstrated. It has been shown that a one-stage synthesis of the title compounds can be performed under mild conditions and with high levels of regio- and stereoselectivity from easily accessible 2-furylpiperidines.

AROMATIZATION OF IMDAF ADDUCTS IN AQUEOUS ALKALINE MEDIA

Zubkov F.I., Airiyan I.K., Ershova J.D., Galeev T.R., Zaytsev V.P., Nikitina E.V., Varlamov A.V.

RSC Advances. 2012. Т. 2. № 10. С. 4103-4109.

DOI: 10.1039/C2RA20295F

Abstract:

In this paper, we propose a simple synthesis of isoindoline-4-carboxylic acids by means of the aromatization of 3a,6-epoxyisoindoles in alkaline media. The method is facile from an experimental point of view: a short-term (0.5–2h) reflux of epoxyisoindoles in 5% aqueous solutions of alkali leads to the target products in 40–90% yields. The absence of by-products, ease of isolation of the target products and applicability to acidophobic group bearing substrates favorably distinguishes the proposed procedure from previously utilized acid-catalyzed methods. The proposed strategy has been successfully utilized for isoindole containing compounds and nuevamine-type alkaloids.

EASY CONSTRUCTION OF FURO[2,3-F]ISOINDOLE CORE BY THE IMDAV REACTION BETWEEN 3-(FURYL)ALLYLAMINES AND α,β-UNSATURATED ACID ANHYDRIDES

Zubkov F.I., Zaytsev V.P., Mertsalov D.F., Nikitina E.V., Varlamov A.V., Horak Y.I., Lytvyn R.Z., Homza Y.V., Obushak M.D., Dorovatovskii P.V., Khrustalev V.N.

Tetrahedron. 2016. Т. 72. № 18. С. 2239-2253.

https://doi.org/10.1016/j.tet.2016.03.023

Abstract:

The vinylogues of furfurylamines, easily available in two steps from furylacroleins (3-(furyl)allylamines), were studied in a tandem N-acylation/intramolecular [4+2] cycloaddition with maleic, pyrocinchonic, and citraconic anhydrides, as well as furylacryloyl and cinnamoyl chlorides. By using a domino reaction of 3-(furyl)allylamines and α,β-unsaturated acid anhydrides under mild conditions, various hexahydro-4H-furo[2,3-f]isoindoles and their carboxyl derivatives were synthesized efficiently. The domino sequence includes three steps: acylation of the nitrogen atom in 3-(furyl)allylamines, intramolecular Diels–Alder cycloaddition in the resulting N-acyl vinylfurans (IMDAV reaction), and prototropic shift of the adducts followed by recovery of aromaticity of the furan nucleus. The key step, IMDAV reaction, leads to the target products, furo[2,3-f]isoindoles, diastereoselectively and with relatively high yields.

Sodium 2-(2-(1-cyano-2-oxopropylidene)hydrazinyl)benzenesulfonate (NaHL) was synthesized by azocoupling of diazonium salt of 2-aminobenzenesulfonic acid with 3-oxobutanenitrile and characterized by IR, 1H and 13C NMR spectroscopies and ESI-MS analysis. In dimethylsulfoxide-d6 solution NaHL exists as a mixture of Z- and E-hydrazone forms in the amounts of 96 and 4%, respectively. Treatment of this isomeric mixture with copper(II) nitrate hydrate in the presence of ethylenediamine (en) provides unusual (E,Z) → E switching of NaHL to give [Cu(H2O)2(en)2](HL)2 (1). The process is interpreted on the basis of cooperative ionic interactions and resonance assisted hydrogen bonding (RAHB) → charge assisted hydrogen bonding (CAHB) transition.
The new copper(II) complexes [Cu(HL1)(H2O)(CH3OH)] (1, H3L1 = (Z)-2-(2-(1,3-dioxo-1-(phenylamino)butan-2-ylidene)hydrazinyl)benzoic acid) and [Cu(HL2)(H2O)(CH3OH)] (2, NaH2L2 = sodium (Z)-2-(2-(1,3-dioxo-1-(phenylamino)butan-2-ylidene) hydrazinyl) benzenesulfonate) were synthesized and characterized by IR and ESI-MS spectroscopies, elemental and X-ray crystal structural analyses. The coordination environment of the central copper(II) has a square pyramidal geometry, three sites being occupied by (HL1,2)2−, which chelates in the O,N,O fashion, while the two other sites are filled with the water and methanol ligands. Multiple intra- and intermolecular non-covalent interactions between the (HL1,2)2−, water and methanol ligands lead to supramolecular network. Both compounds 1 and 2 act as homogenous catalysts for the cyanosilylation reaction of a variety of both aromatic and aliphatic aldehydes with trimethylsilyl cyanide affording the corresponding cyanohydrin trimethylsilyl ethers in high yields (up to 90%) and at room temperature.
Sodium 2-(2-(1-cyano-2-oxopropylidene)hydrazinyl)benzenesulfonate (NaHL) was synthesized by azocoupling of diazonium salt of 2-aminobenzenesulfonic acid with 3-oxobutanenitrile and characterized by IR, 1H and 13C NMR spectroscopies and ESI-MS analysis. In dimethylsulfoxide-d6 solution NaHL exists as a mixture of Z- and E-hydrazone forms in the amounts of 96 and 4%, respectively. Treatment of this isomeric mixture with copper(II) nitrate hydrate in the presence of ethylenediamine (en) provides unusual (E,Z) → E switching of NaHL to give [Cu(H2O)2(en)2](HL)2 (1). The process is interpreted on the basis of cooperative ionic interactions and resonance assisted hydrogen bonding (RAHB) → charge assisted hydrogen bonding (CAHB) transition.
The vinylogues of furfurylamines, easily available in two steps from furylacroleins (3-(furyl)allylamines), were studied in a tandem N-acylation/intramolecular [4+2] cycloaddition with maleic, pyrocinchonic, and citraconic anhydrides, as well as furylacryloyl and cinnamoyl chlorides. By using a domino reaction of 3-(furyl)allylamines and α,β-unsaturated acid anhydrides under mild conditions, various hexahydro-4H-furo[2,3-f]isoindoles and their carboxyl derivatives were synthesized efficiently. The domino sequence includes three steps: acylation of the nitrogen atom in 3-(furyl)allylamines, intramolecular Diels–Alder cycloaddition in the resulting N-acyl vinylfurans (IMDAV reaction), and prototropic shift of the adducts followed by recovery of aromaticity of the furan nucleus. The key step, IMDAV reaction, leads to the target products, furo[2,3-f]isoindoles, diastereoselectively and with relatively high yields.
An investigation of a skeletal Wagner–Meerwein rearrangement of variously substituted or quinoline-annulated 3a,6;4,5-diepoxyisoindol-1-ones is reported. Optimum reaction conditions (Ac2O, BF3·OEt2, rt) were discovered for the formation of the target 4,6-epoxycyclopenta[c]pyridines in 40–80% yields. It was shown that the direction of the sigmatropic rearrangement of 3a,6;4,5-diepoxyisoindol-1-ones depended dramatically on the carboxyl group position (exo-/endo-) in the oxabicyclo[2.2.1]heptane moiety. The spatial structure of previously unknown 7,9-epoxycyclopenta[4,5]pyrido[1,2-a]quinolines derived from Wagner–Meerwein rearrangement of 2,11b-epoxyoxireno[6,7]isoindolo[2,1-a]quinolines was established based on the X-ray analysis data. The skeletal rearrangement proceeded regio- and stereospecifically in all the cases examined due to the absence of the epimerization of the carbon atoms adjacent to the carbocation centres.
Diels–Alder reactions in the 2,3,4,4a-tetrahydroquinolines series were studied for the first time. It was shown that these dienes demonstrate only moderate reactivity. [4+2] Cycloaddition occurs stereo- and regioselectively only for alkenes bearing an electron-withdrawing group (acrylonitrile, maleic anhydride, dimethyl acetylene dicarboxylate, methyl propiolate). In this case, endo-Diels–Alder adducts, spiroannelated 5,8-ethanoquinolines, are formed in a high yield. Cyclopentadiene, being a highly reactive diene component, reacts with 2,3,4,4a-tetrahydroquinolines as the dienophile. Electron-rich unsaturated compounds (N-vinylpyrrolidone, vinylethyl ether, phenylacetylene) are inert to this cycloaddition reaction.
The interaction between 1-furyl-1,2,3,4-tetrahydroisoquinolines and unsaturated acids derivatives (acryloyl, methacryloyl, and crotonoyl chloride, maleic and citraconic anhydride) was studied. It was shown that the reaction proceeds via amide formation and subsequent intramolecular Diels–Alder reaction of the furan (IMDAF). The [4+2] cycloaddition proceeded under mild reaction conditions (25–80 °C) and afforded only the exo-adduct in a high yield. With this method, a new approach to the isoindolo[1,2-a]isoquinoline system, the basic structural element of alkaloids Jamtine, Hirsutine, and Nuevamine, is proposed.
A number of new analogs of 3,3-dimethyl-4,5-dihydro-3H-2-benzazepine 2-oxide, structurally related to the nitrone spin trap α-phenyl-N-tert-butylnitrone (PBN), were synthesized and evaluated for their activity in vitro as protectants against oxidative stress induced in rat brain mitochondria by 6-hydroxydopamine (6-OHDA), a neurotoxin producing experimental model of Parkinson's disease (PD). As assessed by a fluorimetric assay, all 2-benzazepine-based nitrones were shown to decrease hydroxyl radicals ( OH) generated during 6-OHDA autoxidation. The inhibition effects on the OH formation shown by the 5-gem-dimethyl derivatives, 2–4 times higher than those of the corresponding 5-methyl derivatives, were attributed to the flattening effect of the 5-gem-dimethyl group on the azepine ring, which should enhance nitrone reactivity and/or increase stability of the radical adducts. In contrast, owing to steric hindrance, a methyl group to C-1 diminishes the OH-scavenging activity of the nitrone group. All the assayed compounds were more potent than PBN as inhibitors of 6-OHDA-induced lipid peroxidation (LPO) and protein carbonylation (PCO), taken as an indicator of mitochondrial protein oxidative damage. The most promising antioxidant (compound 11), bearing 5-gem-dimethyl and spiro C-3 cyclohexyl groups, highlighted in this study as the best features, inhibited LPO and PCO with IC50 values of 20 and 48 μM, respectively, showing a potency improvement over PBN of two order magnitude. Both LPO and PCO inhibition potency data were found primarily related to the OH-scavenging activities, whereas lipophilicity plays a role in improving the LPO (but not PCO) inhibition, as a statistically valuable two-parameter equation proved.
Acylation of substituted 4-(furyl-2)-4-arylaminobut-1-enes with maleic anhydride provided 2-allyl-6-carboxy-4-oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-enes in high yield under mild reaction conditions. The Diels–Alder adducts are formed via an initial amide formation followed by a stereoselective intramolecular [4+2] exo-cycloaddition reaction. Treatment of the tricyclic compounds with phosphoric acid at high temperatures (70–120 °C) promoted cyclic ether opening, intramolecular cyclization and aromatization to give the corresponding tetracyclic compounds, 5,6,6a,11-tetrahydro-10-carboxyisoindolo[2,1-a]quinolines, in moderate yields. The influence of the acid and the reaction temperature on the cyclization reactions are also discussed.
Acylation of 4-α-furyl-4-N-benzylaminobut-1-enes with maleic anhydride gave 4-oxo-3-aza-10-oxatricyclo[5.2.1.01,5]dec-8-ene-6-carboxylic acid via amide formation followed by intramolecular Diels–Alder reaction of furan (IMDAF). The cycloaddition proceeded under mild reaction conditions (25 °C) and provided only the exo-adduct in quantitative yield. Treatment of this compound with PPA gave isoindolo[2,1-b][2]benzazepine derivatives via ring opening, aromatization and intramolecular electrophilic alkylation. In order to extend the scope of the reaction sequence, 7-oxo-5,11b,12,13-tetrahydro-7H-isoindolo[2,1-b][2]benzazepine-8-carboxylic acids were further transformed into useful synthetic intermediates.