Chiral Nickel Research Articles

An asymmetric approach to the synthesis of a carbon-11 labelled gliotransmitter d-serine

Endogenous d-serine, a co-transmitter of glutamate for synaptic N-methyl-d-aspartate receptors, is implicated in an array of health conditions. The feasibility of a rapid asymmetric preparation of carbon-11 labelled gliotransmitter d-serine is demonstrated via the hydroxy-methylation of a chiral nickel(II) complex. Using an automated radiochemistry synthesiser the key intermediate was obtained with 80 % diastereomeric excess in a 1 min reaction. Further optimisation of the starting glycine synthon is possible in order to achieve even higher stereoselectivity of synthesis, which can benefit subsequent separation–deprotection of the diastereomeric intermediate.

Chiral Palladium(II) and Nickel(II) Complexes with C2-Symmetrical Tridentate Bis(oxazoline) Ligands: Synthesis, Characterization, and Catalytic Norbornene Polymerization

A series of chiral palladium(II) and nickel(II) complexes bearing a C2-symmetric monoanionic tridentate bis(oxazoline) ligand, (R2-(S,S)-BOZ)M(X) (1–6: R = CH(CH3)2, M = Pd, X = OAc (1); R = CH(CH3)2, M = Pd, X = Cl (2); R = Ph, M = Pd, X = Cl (3); R = Ph, M = Ni, X = Cl (4); R = CH(CH3)2, M = Ni, X = Cl (5); R = CH(CH3)2, M = Pd, X = OTf (6)), have been synthesized and structurally characterized. The experimental results demonstrate that such chiral palladium(II) and nickel(II) complexes bearing C2-symmetric tridentate ligands in which the monoanionic group is located inside are effective for norbornene polymerization. In the presence of various cocatalysts such as MAO, MMAO, and activator/AlR3, these chiral palladium(II) complexes exhibit much higher activities of up to 4.8 × 108 g of PNB (mol of Pd)−1 h–1 for the vinylic polymerization of norbornene, affording insoluble polynorbornenes with high packing density. In contrast, the chiral nickel(II) complexes show relatively low activities of ca. 4.5 × 107 g of PNB (mol of Ni)−1 h–1 and produce both insoluble polynorbornenes and soluble high-molecular-weight polynorbornenes with moderate molecular weight distributions.

Stereoselective Hydrodehalogenation via a Radical‐Based Mechanism Involving T‐Shaped Chiral Nickel(I) Pincer Complexes

We herein report the catalytic enantioselective hydrodehalogenation based on the interplay of a chiral molecular nickel(I)/nickel(II)hydride system. Prochiral geminal dihalogenides are dehalogenated via a secondary configurationally unstable, potentially metal-stabilized radical intermediate. In a subsequent step, the liberated radical is then trapped by the nickel(II) hydrido complex, present in a large excess under the catalytic conditions, which in turn induces the enantioselectivity during the hydrogen atom transfer onto the radical intermediate. These new chiral nickel(I) complexes were found to catalyze the asymmetric hydrodehalogenation of geminal dihalogenides with moderate to good enantiomeric excess values using LiEt3 BH as reductant. The main side product generally observed is the dehalogenated alkene, whereas the hydrodehalogenation of the chiral monohalogen compound occurred much more slowly despite the large excess of reductant.

New nickel(II) diimine complexes bearing phenyl and sec‐phenethyl groups: synthesis, characterization and ethylene polymerization behaviour

A series of nickel(II) catalysts containing phenyl and chiral sec‐phenethyl groups, {[(4‐R1‐2‐R2C6H2NC)2Nap]NiBr2} (Nap: 1,8‐naphthdiyl, R1 = Me, R2 = Ph (3a); R1 = Me, R2 = sec‐phenethyl (3b); R1 = Cl, R2 = sec‐phenethyl (3c); R1 = Me, R2 = Me (3d) were synthesized and characterized. All organic compounds were fully characterized by FT‐IR and NMR spectroscopy and elemental analysis. The single crystal for X‐ray crystallography was isolated from 3a in CH2Cl2/n‐hexane under air; the crystal structure showed a binuclear complex 3a′, in which each nickel atom was six‐coordinate. The two nickel atoms together with two bromine atoms form a planar four‐membered ring, with a bromine and H2O axial ligands. These complexes, activated by diethylaluminum chloride and chiral nickel pre‐catalysts rac‐3c, exhibited good activities (up to 2.85 × 106 g PE (mol Ni h bar)−1) for ethylene polymerization, and produced polyethylene products with a high degree of branching (up to 117 branched per 1000 carbons) at high temperature. The type and amount of branches of the polyethylenes obtained were determined by 1H and 13C NMR spectroscopy. Copyright © 2014 John Wiley & Sons, Ltd.

Chiral nickel(II) and palladium(II) catalysts bearing strong electron‐withdrawing fluorine groups: synthesis, characterization and their application in catalytic polymerization for ethylene and styrene

A series of new chiral and achiral nickel(II) and palladium(II) complexes, {bis[N,N′‐(2,6‐diethyl‐4‐naphthylphenyl)imino]‐1,2‐dimethylethane}dibromonickel 3a, {bis[N,N′‐(4‐fluoro‐2‐methyl‐6‐sec‐phenethylphenyl)imino]‐1,2‐dimethylethane}dibromonickel rac‐(RS)‐3b, {bis[N,N′‐(4‐fluoro‐6‐sec‐phenethylphenyl)imino]‐1,2‐dimethylethane}dibromonickel rac‐(RR/SS)‐3c and {bis[N,N′‐(4‐fluoro‐6‐sec‐phenethylphenyl)imino]‐1,2‐dimethylethane}dichloropalladium rac‐(RR/SS)‐3d were successfully synthesized and characterized. The molecular structures of representative ligand rac‐(RS)‐2b, nickel complex 3a, rac‐(RR/SS)‐3c and palladium complex rac‐(RR/SS)‐3d were determined by X‐ray crystallography. The structures of complexes 3a and rac‐(RR/SS)‐3c have pseudo‐tetrahedral geometry about the nickel center, showing C2 molecular symmetry. However, the structure of palladium complex rac‐(RR/SS)‐3d has pseudo‐square planar geometry about the palladium center, showing C2 molecular symmetry. Complex 3e {bis[N,N′‐(2,6‐dimethylphenyl)imino]‐1,2‐dimethylethane}dibromonickel was also synthesized for comparison. Nickel complex rac‐(RS)‐3b bearing strong electron‐withdrawing fluorine group in the para‐aryl position and a chiral sec‐phenethyl group in the ortho‐aryl position of the ligand (one methyl group in the ortho‐aryl position) displays the highest catalytic activity for ethylene and styrene polymerization, and produced highly branched polyethylene and syndiotactic‐rich polystyrene. However, palladium complex rac‐(RR/SS)‐3d shows low catalytic activity for ethylene and styrene polymerization due to the poor leaving group, Cl, attached to palladium and the unfavorable molecular structure. Copyright © 2014 John Wiley & Sons, Ltd.

Electrochemically Deprotonated Chiral Nickel(II) Glycinate in Stereoselective Nucleophilic Addition to Michael Acceptors: Advantages and Limitations

A Ni(II) glycine/Schiff base complex containing (S)-o-[N-(N-benzylprolyl)amino]benzophenone as an auxiliary chiral moiety was deprotonated using electrochemically generated azobenzene radical anion and used in nucleophilic addition to Michael acceptors, terminal 2,2- and 1,2-disubstituted alkenes ((2E)-1,3-diphenylprop-2-en-1-one, (E)-2-nitroethenylbenzene, 2-methylprop-2-enenitrile, Ni(II) dehydroalanine complex), creating a preparatively convenient path for asymmetric functionalization of the α-glycine carbon in the Ni(II) coordination environment, yielding new chiral Ni(II) complexes. The main advantage of the application of electrochemical techniques is the possibility of precise control of the concentration of a base and its in situ reaction with the complex. This opens up the possibility to carry out further functionalization of the anionic adduct formed in Michael addition via a successive one-pot reaction with the other electrophile. A one-pot cascade reaction of electrochemically deprotonated Ni(II) glycinate with (E)-2-nitroethenylbenzene and the successive interaction with benzyl chloride or dimethyl sulfate allowed a new oxime-containing Ni(II) complex to be obtained, which might be considered as an important synthon. All complexes were reliably characterized using HRMS and 1H and 13C NMR (including 2D techniques); an adduct with (2E)-1,3-diphenylprop-2-en-1-one was also characterized by X-ray diffraction studies and CD spectrum. The manner of stereocontrol in the Michael addition of electrochemically deprotonated Ni(II) glycinate was shown to be different for terminal 2,2- and for 1,2-disubstituted alkenes. In the case of the 1,2-disubstituted alkene both stereocenters are already formed in the first reaction step, which is reversible and thermodynamically controlled. The second step (protonation of the anion) is fast and irreversible, and it does not influence the stereochemical result of the reaction. In contrast to the previous case, only one stereocenter is formed in the first thermodynamically controlled step for terminal alkenes, whereas the configuration of the second stereocenter is determined by a kinetically controlled protonation step.

Chiral Nickel(II) Binuclear Complexes: Targeted Diastereoselective Electrosynthesis

Ni(II) complexes containing (S)-o-[N-(N-benzylprolyl)amino]benzophenone as an auxiliary chiral moiety in the form of a Schiff base with α-amino acids (α-amino acid = glycine, alanine, dehydroalanine; Gly-Ni, Ala-Ni, and Δ-Ala-Ni) were subjected to various types of electrochemical activation (oxidation, reduction, and a treatment with electrogenerated base), affording regio- and diastereoselective synthesis of novel types of binuclear Ni(II) complexes via C–C coupling. New compounds were fully characterized by HRMS, MALDI-TOF, CD, and 1H and 13C NMR (including two-dimensional techniques) spectroscopy; two complexes were characterized by X-ray diffraction analysis. The structures of the novel complexes obtained via electrosynthesis completely match the predictions (made from preliminary voltammetric investigations of the starting complexes as well as from DFT estimations of the energy and symmetry of their frontier molecular orbitals) about the nature of chemical transformations which may follow the electron transfer steps. Electrochemical oxidation of Gly-Ni and Ala-Ni allows access to new dimeric complexes linked via benzophenone moieties in the Ni(II) coordination environment. These new binuclear Ni(II) complexes are of interest as chiral redox mediators for both oxidative and reductive transformations, since they exhibit quasi-reversible electrochemical behavior (their reduced and oxidized forms are stable, at least on the time scale of cyclic voltammetry). Three other binuclear Ni(II) complexes which were obtained via reductive dimerization of the Δ-Ala-Ni complex, via nucleophilic addition of electrochemically deprotonated Gly-Ni to Δ-Ala-Ni, and via oxidative electrochemical dimerization of deprotonated Gly-Ni are of interest as convenient precursors for the stereoselective preparation of diamino dicarboxylic acids HO(O)CCH(NH2)(CH2)n(NH2)CHC(O)OH (n = 2–0), since the obtained binuclear Ni(II)–Schiff base complexes can be easily disassembled using aqueous HCl in methanol.

An approach to the asymmetric synthesis of 18F-labeled analog of l-threo-3,4-dihydroxyphenylserine (6-l-threo-[18F]FDOPS) — a new radiotracer for visualization of norepinephrine transporters by positron emission tomography

An asymmetric synthesis method has been suggested as a feasible approach for the preparation of fluorine-18-labeled (T1/2 110 min) analog of l-threo-3,4-dihydroxyphenylserine, i.e., 6-l-threo-[18F]FDOPS ((2S,3R)-2-amino-3-(2-[18F]fluoro-4,5-dihydroxyphenyl)-3-hydroxypropionic acid), a new radiotracer for the evluation of norepinephrine transporters by positron emission tomography (PET). The approach is based on the condensation reaction of 2-[18F]fluoro-4,5-bis(methoxymethoxy)benzaldehyde with a chiral nickel(II) complex and glycine (Ni-(R)-BPB-Gly) with subsequent removal of protection from hydroxy groups by acid hydrolysis. The radiochemical synthesis includes three steps and can be easily implemented into modern automated modules for the synthesis of radiopharmaceutical agents for PET.

ChemInform Abstract: Enantioselective Synthesis of 2‐Substituted‐tetrahydroisoquinolin‐1‐yl Glycine Derivatives via Oxidative Cross‐Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate.

AbstractIt provides a new, easy, and highly stereoselective approach to a number of tetrahydroisoquinolinyl glycine derivatives.

Diastereoselective three-component reactions of chiral nickel(II) glycinate for convenient synthesis of novel α-amino-β-substituted-γ,γ-disubstituted butyric acids.

The convenient, high yielding and diastereoselective synthesis of α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives was carried out by a three-component tandem reaction of a chiral equivalent of nucleophilic glycine. The reaction was performed smoothly under mild conditions and enabled the construction of two or three adjacent chiral centers in one step, thus affording a novel and convenient route to α-amino-β-substituted-γ,γ-disubstituted butyric acid derivatives.

Disproportionation of Achiral Nickel(II) Centers into Two Kinds of Chiral Nickel(II) Centers Caused by an Achiral Diimine Ligand

Disproportionation of Achiral Nickel(II) Centers into Two Kinds of Chiral Nickel(II) Centers Caused by an Achiral Diimine Ligand

Enantioselective Synthesis of 2-Substitued-Tetrahydroisoquinolin-1-yl Glycine Derivatives via Oxidative Cross-Dehydrogenative Coupling of Tertiary Amines and Chiral Nickel(II) Glycinate

The asymmetric synthesis of 2-substituted-tetrahydroisoquinolin-1-yl glycines was achieved by an oxidative cross-dehydrogenative coupling (CDC) reaction. This method for activation of the α-C-H bonds of amines with chiral nickel(II) glycinate using o-chloranil as the sole oxidant afforded highly diastereoselective coupling adducts. The decomposition of coupling adducts readily afforded 2-substituted-tetrahydroisoquinolin-1-yl glycine derivatives.

Synthesis and characterization of chiral trinuclear cobalt and nickel complexes supported by binaphthol-derived bis(salicylaldimine) ligands

Chiral bis(salicylaldimine) ligands derived from binaphthol (LH2) were synthesized by condensation of (R/S) 2,2′-dihydroxy-1,1′-binaphthyl-3,3′-dicarbaldehyde with 2-anisidine. Cobalt and nickel complexes (CoL)2(OAc)2Co (1) and (NiL)2(OAc)2Ni (2) were synthesized via reactions of the ligand with the corresponding metal acetate salt. Both complexes were characterized by elemental analysis, IR, MS, and single-crystal X-ray diffraction analysis. The X-ray analysis reveals linear trinuclear for 1 and 2 and the metal ions in both complexes are octahedral coordination. The two acetates separately bridge the center metal with one of the terminal metals in M–O–C–O–M manner. The magnetic susceptibility of 1 below 150 K suggests the existence of a weak ferromagnetic exchange at low temperatures, while antiferromagnetic interactions among Co(II) cores were observed above 150 K. Complex 2 shows similar magnetic behavior to that of 1.

ChemInform Abstract: Reaction of ω‐Nitrostyrene with Diethyl Malonate in the Presence of Chiral Nickel(II) Complexes.

AbstractChiral Ni‐complexes (I)—(III) are prepared from the known ligands and nickel(II)chloride hexahydrate in boiling MeCN.

Highly Thermal‐Stable Supramolecular Assembly of a Hydrogen‐Bonded Mononuclear Nickel(II) Histidine Compound

AbstractA chiral nickel histidine compound, [Ni(L‐his)2]×H2O (1, L‐his = anion of L‐histidine), was synthesized in high yield from the reaction of Ni(OAc)2×4H2O and L‐histidine in the presence of 4,4′‐bipyridine under mild reaction conditions. A single‐crystal X‐ray diffraction analysis showed that compound 1 crystallizes in the monoclinic system, space group C2, with a chemical formula of C12H18N6NiO5, cell parameters: a = 29.416(2) Å, b = 8.2667(7) Å, c = 6.3137(5) Å, β = 90.066(2)°, V = 1535.3(2) Å3 and Z = 4. Each nickel(II) ion in 1 is six coordinated, bonded to two oxygen donors and four nitrogen donors from two crystallographically independent L‐his− ligands with a tridentate coordination mode to form a monomeric species. Monomeric forms of 1 undergo self‐assembly to form a three‐dimensional (3D) supramolecular architecture via subtle combinations of N‐H···O type hydrogen bonding interactions among the adjacent L‐his−ligands and π‐π stacking interactions among the imidazole rings of the L‐his− ligands. The supramolecular entity exhibits an unusually high thermal stability, at temperatures of up to 360 °C and shows reversible de‐/re‐hydration properties.

Highly diastereoselective synthesis of 3-indolylglycines via an asymmetric oxidative heterocoupling reaction of a chiral nickel(ii) complex and indoles

The asymmetric synthesis of 3-indolylglycine derivatives was achieved by an oxidative heterocoupling reaction. This method for the selective C-3 functionalization of unprotected indoles with the chiral equivalent of a nucleophilic glycine nickel(II) complex afforded adducts with high diastereoselectivities. The decomposition of adducts readily afforded 3-indolylglycine derivatives in high yields.

Reaction of ω-nitrostyrene with diethyl malonate in the presence of chiral nickel(II) complexes

Single-ligand complexes of nickel(II) with chiral diamines based on L-proline and (S)-camphor efficiently catalyze addition of diethyl malonate to ω-nitrostyrene in the presence of 1 equiv of triethylamine as co-catalyst. The reaction enantioselectivity depends on the chiral ligand structure.

Alkylations of Chiral Nickel(II) Complexes of Glycine under Phase‐Transfer Conditions

AbstractAlkylation reactions of nickel(II) complex 6 derived from glycine and 2‐[(1‐benzyl‐L‐prolyl)amino]benzophenone (BPBP) were studied under phase‐transfer‐catalysis (PTC) conditions. The goal of this work was to find an alternative suitable solvent for these reactions to replace the commonly used CH2Cl2 which leads to the formation of several by‐products, thus lowering the yield of target compounds. We demonstrate that 1,2‐dichloroethane is a markedly better solvent providing higher yields (75–99%) of the desired products 10 with 36–88% diastereoisomer purity (Scheme 3 and Table). Furthermore, we show that the stereochemical outcome of these PTC reactions (kinetic control) can be easily improved to >95% de by treatment of the PTC products with MeONa/MeOH. The scope of these reactions includes alkylations with methyl iodide as well as activated halides such as benzyl, allyl or propargyl, bromides and most notably ethyl 2‐bromoacetate (Table).

Mutually Complementary Metal‐ and Organocatalysis with Collective Synthesis: Asymmetric Conjugate Addition of 1,3‐Carbonyl Compounds to Nitroenynes and Further Reactions of the Products

AbstractThe first metal‐catalyzed 1,4‐selective asymmetric addition of malonates to nitroenynes promoted by a simple chiral nickel(II)‐diamine catalyst, was developed, facilitating a mild synthesis of a novel type of multifunctional chiral β‐alkynyl acids bearing a nitro group. Based on this protocol, we have developed a practical and collective synthesis of a series of diverse functional molecules and building blocks including new types of chiral β‐alkynyl‐γ‐amino acids, β‐functionalized chiral δ‐keto‐γ‐lactones, chiral γ‐alkylidenelactones, alkynyl‐substituted pyrrole‐3‐carboxylic acid derivatives, tetrasubstituted furans and chiral β‐alkynyl‐γ‐lactams. Notably, we discovered two unusual tandem reactions leading to functionalized chiral 1,5‐dicarbonyl compounds. In addition, by employing simple bifunctional organocatalysts, we have developed the first regio‐, diastereo‐ and enantioselective conjugate addition of α‐substituted β‐keto esters to nitroenynes, which is poorly diastereoselective with chiral nickel(II)‐diamine catalysts, providing a new entry to adjacent quaternary and tertiary stereocenters in one step. Based on this protocol, we have developed a concise asymmetric synthesis of conformationally constrained bicyclic γ2‐amino acids featuring an alkynyl side chain with an adjacent quaternary carbon stereocenter. The study described here demonstrates that the mutually complementary strategy of transition metal catalysis and organocatalysis is a powerful and promising tool in catalytic asymmetric synthesis.

ChemInform Abstract: Enantioselective Synthesis of Nitrocyclopropanes via Conjugate Addition of Bromomalonate to Nitroalkenes Catalyzed by Ni(II) Complexes.

AbstractThe air‐ and moisture‐stable chiral nickel complex (I) is successfully applied to the title reactions.