Alkene and Olefin Functionalization by Organoaluminum Compounds, Catalyzed with Zirconocenes: Mechanisms and Prospects

Alkene and olefin functionalization via addition of electro‐ or nucleophilic reagents is one of the convenient synthetic methods for the insertion of heteroatoms into organic molecules. The use of organometallic reagents in these reactions in combination with the specific catalysts provides high substrate conversion and process selectivity. The introduction of this approach into the chemistry of organoaluminum compounds leads to the development of chemo‐, regio‐ and stereoselective catalytic methods of alkene and olefin functionalization. The chapter focuses on the modern concepts of the alkene hydro‐, carbo‐ and cycloalumination mechanisms, that is, the experimental and theoretical data on the intermediate structures involved in the product formation, the effects of the catalyst and organoaluminum compound structure, reaction conditions on the activity and selectivity of the bimetallic systems. The prospects of the development of enantioselective methods using these catalytic systems for the alkene and olefin transformations are considered

Current Trends in the Synthesis of Practically Important Five-Membered Boracarbocycles by Transmetalation of Aluminacarbocycles with Boron Halides

The data obtained by the authors in the field of chemistry of substituted borolanes and 2,3-dihydro-1H-boroles are summarized. The authors developed a selective method for the synthesis of five-membered boracarbocycles via transmetalation of aluminacarbocycles, obtained by the catalytic cycloalumination of unsaturated compounds (terminal olefins or acetylenes) with AlEt3 in the presence of Cp2ZrCl2 as a catalyst by boron halides (BF3·Et2O, BCl3, and BBr3). Some examples of the use of this approach to modify steroid compounds (in particular, to introduce a borolan fragment into them) are described in this review

Approach to the Synthesis of Five-Membered Organophosphorus Compounds via Alumoles and Alumolanes

This work summarizes the results of a new approach to the synthesis of previously undescribed, hard-to-obtain five-membered cyclic organophosphorus compounds: 3-alkyl(aryl)-substituted phospholanes, α,ω-bisphospholanes, polycyclic phospholanes, 4,5-dialkyl(diaryl)-disubstituted 2,3-dihydrophospholes, as well as their oxides and sulfides. Alumoles and alumolanes synthesized by the reaction of cycloalumination of available unsaturated compounds (terminal alkenes, α,ω-alkadienes, norbornene derivatives, symmetrical internal alkynes) with Et3Al in the presence of a Cp2ZrCl2 catalyst were used as precursors. The substitution of aluminum atoms in cyclic organoaluminum compounds for phosphorus atoms takes place using alkyl(aryl)phosphorus (III) dichlorides. The developed one-pot method gives high yields of products under mild conditions

Phosphorylation of Hyaluronic Acid

Chemical phosphorylation of hyaluronic acid (HA) remains an unresolved problem for the chemistry of this unique polysaccharide, since convenient phosphorylating reagents are not reactive enough to obtain HA phosphates (HA-P) with a satisfactory degree of esterification of hydroxyl groups. The synthesis of phosphates of low-molecular-weight (43 kDa) and high-molecular-weight (0.5–0.7 MDa) HA was undertaken using such reagents as sodium trimetaphosphate Na3P3O9, H3PO4, NaH2PO4/Na2HPO4, and anhydride P2O5. Solid-phase HA esterification with P2O5 was found to be the most convenient and efficient method. The HA-P samples were characterized by XRF and NMR spectroscopy (31P and 1H-31P) and contained, depending on the HA/P2O5 ratio, 0.30–6.25% P wt., in the form of disubstituted mono-, di-, and polyphosphates

Cyclic 1H-Phospolane Oxides as a Potential Candidate for Cancer Therapy

Organophosphorus compounds have been investigated for agricultural and medicinal applications for decades, and a considerable number of phosphorus-containing drugs have achieved commercial success. A recent review by P. Finkbeiner et al. has shown that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist’s toolbox. A new approach to the synthesis of previously hard-to-obtain 3-alkyl-1H-phospholanes oxides was developed by us. In order to assess the potential of five-membered cyclic organophosphorus compounds in cancer therapy, we carried out docking 3-buthyl-1H-phospholanes oxide and 2,3-dihydrophosphole in the binding site of 24 human proteins involved in oncogenesis processes. Proteins were selected using the PharmMapper in-house pharmacophore model database. The results are presented in the article

Cyclic 1H-Phospolane Oxides as a Potential Candidate for Cancer Therapy

Organophosphorus compounds have been investigated for agricultural and medicinal applications for decades, and a considerable number of phosphorus-containing drugs have achieved commercial success. A recent review by P. Finkbeiner et al. has shown that phosphine oxides and related phosphorus-containing functional groups are valuable polar structural elements and that they deserve to be considered as a routine part of every medicinal chemist’s toolbox. A new approach to the synthesis of previously hard-to-obtain 3-alkyl-1H-phospholanes oxides was developed by us. In order to assess the potential of five-membered cyclic organophosphorus compounds in cancer therapy, we carried out docking 3-buthyl-1H-phospholanes oxide and 2,3-dihydrophosphole in the binding site of 24 human proteins involved in oncogenesis processes. Proteins were selected using the PharmMapper in-house pharmacophore model database. The results are presented in the article

Enantioselectivity of chiral zirconocenes as catalysts in alkene hydro-, carbo- and cycloalumination reactions

Enantioselectivity of chiral Zr catalysts L1L2ZrCl2 (L1 = L2 = 1-neomenthylindenyl (Ind*), (1); L1 = Cp, L2 = Ind* (2); L1 = Cp, L2 = 1-neomenthylindenyl-4,5,6,7-tetrahydroindenyl (Cp*) (3)) in the hydro-, carbo- and cyclo-alumination of alkenes by organoaluminium compounds (OAC) (AlMe3, AlEt3, HAlBui2) has been studied. It was found that OAC type exhibits the most effect on the reactions chemo- and enantioselectivity. The reaction chemo- and enantio-selectivity depend on the catalyst structure and reaction conditions (solvent type, catalyst concentration, temperature) as well. It is shown that lack of asymmetric induction in the reaction of ?-methylstyrene hydroalumination by HAlBui2, catalyzed with complexes 1 or 3, is the result of the formation of Zr hydride complexes of different structure as reaction intermediates. MTPA was used as derivatization reagent for enantiomeric excess estimation and absolute configuration assignment of ?-chiral alcohols obtained after the oxidation and hydrolysis of reaction products. The applicability of MTPA for the assignment of chiral center absolute configuration in ?–ethyl substituted primary alcohols and ?–alkyl-1,4-butanediols was shown

Ti Group Metallocene-Catalyzed Synthesis of 1-Hexene Dimers and Tetramers

1-Hexene transformations in the catalytic systems L2MCl2–XAlBui2 (L = Cp, M = Ti, Zr, Hf; L = Ind, rac-H4C2[THInd]2, M = Zr; X = H, Bu i) and [Cp2ZrH2]2-ClAlR2 activated by MMAO-12, B(C6F5)3, or (Ph3C)[B(C6F5)4] in chlorinated solvents (CH2Cl2, CHCl3, o-Cl2C6H4, ClCH2CH2Cl) were studied. The systems [Cp2ZrH2]2-MMAO-12, [Cp2ZrH2]2-ClAlBui2-MMAO-12, or Cp2ZrCl2-HAlBui2-MMAO-12 (B(C6F5)3) in CH2Cl2 showed the highest activity and selectivity towards the formation of vinylidene head-to-tail alkene dimers. The use of chloroform as a solvent provides further in situ dimer dimerization to give a tetramer yield of up to 89%. A study of the reaction of [Cp2ZrH2]2 or Cp2ZrCl2 with organoaluminum compounds and MMAO-12 by NMR spectroscopy confirmed the formation of Zr,Zr-hydride clusters as key intermediates of the alkene dimerization. The probable structure of the Zr,Zr-hydride clusters and ways of their generation in the catalytic systems were analyzed using a quantum chemical approach (DFT)

Mechanistic aspects of chemo- and regioselectivity in Cp2ZrCl2 – catalyzed alkene cycloalumination by AlEt3

The reactions of styrene and 1-hexene with zirconacyclopropane and the bimetallic five-membered Zr,Al-complex [Cp2Zr(m-Cl)CH2CH2AlEt2] as catalytically active sites in Cp2ZrCl2-catalyzed cyclo- alumination of a-olefins with AlEt3 have been studied by DFT quantum chemical methods (PBE/3z, B3LYP/VDZ, B3LYP(GD3)/VDZ, M06-2X/VDZ, M06-2X/VTZ//VDZ). It was shown that key intermediates can exist in dynamic equilibrium with each other, and with ClAlEt2 adducts. Comparative analysis was carried out for the energy characteristics of alternative pathways in the reaction of styrene or 1-hexene with the intermediates, implying different orientations of the substrates towards the Zr-C bond. The obtained data were used to elucidate the reasons for the observed dependence of the reaction regio- selectivity on the substrate structure and the minor by-products formation. The applicability of M06-2X/ cc-pVTZ-PP//M06-2X/cc-pVDZ-PP and PBE/3z methods for the description of the available experimental data was shown

Mechanism of Cp₂ZrCl₂‑Catalyzed Olefin Cycloalumination with AlEt₃: Quantum Chemical Approach

A mechanism of α-olefin cycloalumination by AlEt₃ in the presence of Cp₂ZrCl₂ catalyst was proposed, based on theoretical estimation of the thermodynamic and activation parameters of the possible reaction pathways calculated at the DFT level using the PBE/3ζ and M06-2X/cc-pVDZ quantum chemical methods. The reaction steps to bimetallic Zr,Al- and Zr,Zr-complexes, [Cp₂Zr­(μ-Cl)­CH₂CH₂­AlEt₂], [Cp₂Zr­(μ-H)­CH₂CH₂­AlEt₂], and [Cp₂Zr­(Cl)­CH₂CH₂­Zr­(Cl)­Cp₂], observable on the NMR time scale were considered. Among the possible intermediates, zirconacyclopropane was proposed as the catalyst species most active toward the alkenes, whose formation goes via two-step ligand exchange between Cp₂ZrCl₂ and AlEt₃, and subsequent ethane elimination from the Cp₂ZrEt₂. The reaction of zirconacyclopropane with the alkene gives the zirconacyclopentane intermediate, in which transmetalation by ClAlEt₂ and AlEt₃ gives 1-ethyl-3-alkyl­alumolanes via 2-substituted dialuminobutane