Dmitrii S. Bolotin

Metal-Involving Synthesis and Reactions of Oximes

This review classifies and summarizes the past 10-15 years of advancements in the field of metal-involving (i.e., metal-mediated and metal-catalyzed) reactions of oximes. These reactions are diverse in nature and have been employed for syntheses of oxime-based metal complexes and cage-compounds, oxime functionalizations, and the preparation of new classes of organic species, in particular, a wide variety of heterocyclic systems spanning small 3-membered ring systems to macroheterocycles. This consideration gives a general outlook of reaction routes, mechanisms, and driving forces and underlines the potential of metal-involving conversions of oxime species for application in various fields of chemistry and draws attention to the emerging putative targets.

Trinuclear (aminonitrone)ZnII complexes as key intermediates in zinc(ii)-mediated generation of 1,2,4-oxadiazoles from amidoximes and nitriles

Aliphatic and aromatic amidoximes RC(NH2)NOH (R = Et, tBu, Ph, o-ClC6H4) react with Zn(OAc)2·2H2O in Me2CO giving [Zn(OAc)2{RC(NH2)NOH}2] complexes bearing N-bound amidoximes, which are involved in a moderate strength (7.3–11.9 kcal mol−1 by the DFT calculations) intramolecular resonance-assisted hydrogen bonding between the oxime HO group and the oxo group of the acetate ligand. The complexes [Zn(OAc)2{RC(NH2)NOH}2] react with excess Zn(OTf)2 in acetone accomplishing trinuclear species [Zn3(μ2-OAc)2{μ2-RC(NH2)N(H)O}4(H2O)6](OTf)4 featuring both O-ligated amidoximes—stabilized in the aminonitrone tautomeric form—and bridging acetate ligands. The aminonitrone trinuclear species were also prepared directly via the reaction of the amidoximes with Zn(OTf)2 in EtOAc; ethyl acetate in this reaction plays the role of the acetate donor and OAc− is generated in situ via ZnII-mediated hydrolysis of EtOAc. Although [Zn(OAc)2{RC(NH2)NOH}2] are inactive toward dimethylcyanamide, the [Zn3(μ2-OAc)2{μ2-RC(NH2)N(H)O}4(H2O)6](OTf)4 complexes readily react with Me2NCN giving, as a result of ZnII-mediated amidoxime–cyanamide coupling, the O-carbamidine amidoxime complexes [Zn(OTf)2{RC(NH2)NOC(NMe2)NH}2]. All synthesized compounds were characterized by HRESI-MS, FTIR, 1H-, CP-MAS TOSS 13C{1H}-, and 13C{1H} NMR, and additionally by single-crystal X-ray diffraction for eight species. Different types of non-covalent interactions in the obtained solid-state structures were studied by DFT calculations (M06-2X/6-311+G(d,p) level of theory) and topological analysis of the electron density distribution within the formalism of Baders theory (QTAIM method).

Nucleophilic addition of aromatic amide oximes to [2-B10H9NCC2H5]– anion

A series of closo-decaborate anions containing an O-iminoacylamide oxime fragment were synthesized by nucleophilic addition of aromatic amide oximes to 2-propionitrilium closo-decaborate anion. The isolated compounds were characterized by IR, 1H, 13C–{1H}, and 11B–{1H} NMR, and mass spectra. The structure of (Ph4P)[2-B10H9NH=C(Et)ON=C(NH2)C6H4Me-2] was determined by single-crystal X-ray analysis.

Amidoxime platinum(II) complexes: pH-dependent highly selective generation and cytotoxic activity

The reaction of cis-[PtCl2(Me2O)2] with 1 equiv. of each of the amidoximes RC(NH2)NOH in neutral media in MeOH results in the formation of complexes cis-[PtCl2{RC(NH2)OH}(Me2O)] (5 examples; 83–98% isolated yields). In the presence of 2 equiv. of NaOH in MeOH solution, the reaction of cis-[PtCl2(Me2O)2] with 1 equiv. of each of the amidoximes RC(NH2)NOH leads to [Pt{RC(H)N}(Me2O)2] (7 examples; 74–95% isolated yields). All new complexes were characterized by C, H, and N elemental analyses, HRESI+-MS, IR, 1H, 13C{1H}, and CP-MAS TOSS 13C{1H} NMR spectroscopies, and additionally by single-crystal XRD (for seven species). The cytotoxic potency of six compounds was determined in the human cancer cell lines CH1/PA-1, A549, SK-BR-3, and SW480. Generally, the second class of complexes containing chelating amidoximato ligands shows much higher cytotoxicity than the non-chelate amidoxime analogs, despite the lack of easily exchangeable chlorido ligands. Especially, the complex [Pt(p-CF3C6H4C(H)N)(Me2O)2] displays a remarkable activity in the inherently cisplatin resistant SW480 cell line (0.51 μM vs. 3.3 μM).

Mechanism of generation of closo-decaborato amidrazones. Intramolecular non-covalent B–H⋯π(Ph) interaction determines stabilization of the configuration around the amidrazone CN bond

Three types of N(H)-nucleophiles, viz. hydrazine, acetyl hydrazide, and a set of hydrazones, were used to study the nucleophilic addition to the CN group of the 2-propanenitrilium closo-decaborate cluster (Ph3PCH2Ph)[B10H9NCEt], giving N-closo-decaborato amidrazones. A systematic mechanistic study of the nucleophilic addition is provided and included detailed synthetic, crystallographic, computational and kinetic work. As a result, two possible mechanisms have been proposed, which consist of firstly a consecutive incorporation of two Nu(H) nucleophiles, with the second responsible for a subsequent rapid proton exchange. The second possible mechanism assumes a pre-formation of a dinuclear [Nu(H)]2 species which subsequently proceeds with the nucleophilic attack on the boron cluster. The activation parameters for hydrazones indicate a small dependence on bond formation [ΔH‡ = 6.8–15 kJ mol−1], but significantly negative entropies of activation [ΔS‡ ranges from −139 to −164 J K−1 mol−1] with the latter contributing some 70–80% of the total Gibbs free energy of activation, ΔG‡. In the X-ray structure of (Z)-(Ph3PCH2Ph)[B10H9N(H)C(Et)NHNCPh2], very rare intramolecular non-covalent B–H⋯π(Ph) interactions were detected and studied by DFT calculations (M06-2x/6-311++G** level of theory) and topological analysis of the electron density distribution within the framework of Baders theory (QTAIM method). The estimated strength of these non-covalent interactions is 0.8–1.4 kcal mol−1.

Structure of aminonitrones and electronic effect of substituents on their acid-base properties

A series of para-substituted aromatic aminonitrones p-RC6H4C(NH2)=N+(Me)O– (R = NMe2, H, Br, Cl, CF3) have been prepared. Acidity constants of the conjugate acids RC6H4C(NH2)N+(Me)OH at 25°C in a EtOH–H2O mixture (5: 95) have been determined by potentiometric titration. A linear correlation between log (kR/kH) and σpara values has been revealed, and a ρ298(σpara) parameter has been determined as of 0.635.

Facile selective synthesis of 2-methyl-5-amino-1,2,4-oxadiazolium bromides as further targets for nucleophilic additions

The reaction of aminonitrones R1C(NH2) = N+(Me)O− (R1 = Alk, Ar) with isocyanides R2NC (R2 = Alk, Ar; 1.2 equiv.) and Br2 (1 equiv.) conducted in CHCl3 (RT, 5 min) gives 2-methyl-5-amino-1,2,4-oxadiazolium bromides in good to excellent yields (65–95%; 16 examples). These species are highly electrophilically activated and 5-cyclohexylamino-2-methyl-3-phenyl-1,2,4-oxadiazolium bromide, taken as a model compound for the reactivity study, reacts rapidly under mild conditions with hydroxylamine, hydrazine, or benzamidine, to give 5-cyclohexylamino-3-phenyl-1,2,4-oxadiazole (88%), 5-cyclohexylamino-3-phenyl-1,2,4-triazole (95%), and 2-cyclohexylamino-4,6-diphenyl-1,3,5-triazine (64%), respectively. Treatment of the oxadiazolium salt with excess water provides N-benzoyl-N′-cyclohexylurea (95%).

3-Dialkylamino-1,2,4-triazoles via ZnII-Catalyzed Acyl Hydrazide–Dialkylcyanamide Coupling

Zinc(II)-catalyzed (10 mol % ZnCl2) coupling of acyl hydrazides and dialkylcyanamides in ethanol leads to 3-dialkylamino-1,2,4-triazoles (76–99%; 17 examples). This reaction represents a novel, straightforward, and high-yielding approach to practically important 3-NR2-1,2,4-triazoles, which utilizes commercially available and/or easily generated substrates. Seventeen new 3-NR2-1,2,4-triazoles were characterized by HRESI+-MS and IR, 1H, and 13C{1H} NMR spectroscopies and five species additionally by single-crystal X-ray diffraction (XRD). The ZnII-catalyzed reaction proceeds via initial generation of the [Zn{RC(=O)NHNH2}3](ZnCl4) complexes (exemplified by isolation of the complex with R = Ph, 76%; characterized by HRESI+-MS, IR, CP-MAS TOSS 13C{1H} NMR, and XRD). Electronic effects of substituents at the acyl hydrazide moiety do not significantly affect the reaction rate and the yield of the target triazoles, whereas the steric hindrances reduce the reaction rate without affecting the yield of the heterocycles.

Di-chlorido-[N-(N,N-di-methyl-carbamimido-yl)-N',N',4-tri-methyl-benzohydrazonamide]-platinum(II) nitro-methane hemisolvate.

In the title compound, [PtCl2(C13H21N5)]·0.5CH3NO2, the PtII atom is coordinated in a slightly distorted square-planar geometry by two Cl atoms and two N atoms of the bidentate ligand. The (1,3,5-triazapentadiene)PtII metalla ring is slightly bent and does not conjugate with the aromatic ring. In the crystal, N—H⋯Cl hydrogen bonds link the complex molecules, forming chains along [001]. The nitromethane solvent molecule shows half-occupancy and is disordered over two sets of sites about an inversion centre.