Oxazoline Ligands Research Articles

Palladium‐Catalyzed Cascade sp2 C−H Functionalization/Intramolecular Asymmetric Allylation: From Aryl Ureas and 1,3‐Dienes to Chiral Indolines

AbstractA chiral PdII‐catalyzed cascade sp2 C−H functionalization/intramolecular asymmetric allylation reaction is reported. A new chiral sulfoxide–oxazoline (SOX) ligand bearing single chiral center on the sulfur was identified as the optimal ligand for the reaction, being efficient both in the C−H cleavage step and the stereocontrol of the allylation step. The broad scope of this method with respect to aryl ureas and 1,3‐dienes enables the rapid construction of valuable chiral indoline derivatives with high yields and enantioselectivities (up to 99 % yield, up to 95:5 e.r.).

Palladium-Catalyzed Enantioselective Redox-Relay Heck Alkynylation of Alkenols To Access Propargylic Stereocenters.

An enantioselective redox-relay Heck alkynylation of di- and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β-alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

Palladium‐Catalyzed Enantioselective Redox‐Relay Heck Alkynylation of Alkenols To Access Propargylic Stereocenters

AbstractAn enantioselective redox‐relay Heck alkynylation of di‐ and trisubstituted alkenols to construct propargylic stereocenters is disclosed using a new pyridine oxazoline ligand. This strategy allows direct access to chiral β‐alkynyl carbonyl compounds employing allylic alcohol substrates in contrast to more traditional conjugate addition methods.

Synthesis and characterization of yttrium, europium, terbium and dysprosium complexes containing a novel type of triazolyl–oxazoline ligand

We report the synthesis of a novel type of bidentate chiral ligand which structurally derives from the association of a 1,2,3-triazole ring with a chiral oxazoline. Yttrium and lanthanide nitrato-complexes of the new triazolyl–oxazoline ligand were prepared and characterized. The coordination mode of the ligand was ascertained by means of DFT calculations. Trivalent europium and terbium derivatives resulted appreciably photoluminescent upon excitation with UV light, showing the typical 5D0 → 7FJ and 5D4 → 7FJ emissions, respectively. These species were successfully used for the preparation of luminescent-doped polymeric materials.

Synthesis of chiral aza-bis(oxazolines) derived from (+)-camphor

Two novel chiral structurally azabis(oxazoline) ligands were synthesized using (+)-camphor as the starting material. Each of the ligands was prepared through the corresponding aminoalcohols. The structures of some crystalline derivatives were unambiguously established by X-ray analysis.

Enantioselective Palladium-Catalyzed Carbene Insertion into the N-H Bonds of Aromatic Heterocycles.

C3-substituted indoles and carbazoles react with α-aryl-α-diazoesters under palladium catalysis to form α-(N-indolyl)-α-arylesters and α-(N-carbazolyl)-α-arylesters. The products result from insertion of a palladium-carbene ligand into the N-H bond of the aromatic N-heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

Enantioselective Palladium‐Catalyzed Carbene Insertion into the N−H Bonds of Aromatic Heterocycles

AbstractC3‐substituted indoles and carbazoles react with α‐aryl‐α‐diazoesters under palladium catalysis to form α‐(N‐indolyl)‐α‐arylesters and α‐(N‐carbazolyl)‐α‐arylesters. The products result from insertion of a palladium‐carbene ligand into the N−H bond of the aromatic N‐heterocycles. Enantioselection was achieved using a chiral bis(oxazoline) ligand, in many cases with high enantioselectivity (up to 99 % ee). The method was applied to synthesize the core of a bioactive carbazole derivative in a concise manner.

Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation.

Pd(II)-catalyzed enantioselective borylation of C(sp3)-H bonds has been realized for the first time using chiral acetyl-protected aminomethyl oxazoline ligands. This reaction is compatible with carbocyclic amides containing α-tertiary as well as α-quaternary carbon centers. The chiral β-borylated amides are useful synthons for the synthesis of chiral β-hydroxylated, β-fluorinated, and β-arylated carboxylic acids.

Formation of α-chiral centers by asymmetric β-C(sp3)-H arylation, alkenylation, and alkynylation.

The enzymatic β-C-H hydroxylation of the feedstock chemical isobutyric acid has enabled the asymmetric synthesis of a wide variety of polyketides. The analogous transition metal-catalyzed enantioselective β-C-H functionalization of isobutyric acid-derived substrates should provide a versatile method for constructing useful building blocks with enantioenriched α-chiral centers from this abundant C-4 skeleton. However, the desymmetrization of ubiquitous isopropyl moieties by organometallic catalysts has remained an unanswered challenge. Herein, we report the design of chiral mono-protected aminomethyl oxazoline ligands that enable desymmetrization of isopropyl groups via palladium insertion into the C(sp3)-H bonds of one of the prochiral methyl groups. We detail the enantioselective β-arylation, -alkenylation, and -alkynylation of isobutyric acid/2-aminoisobutyric acid derivatives, which may serve as a platform for the construction of α-chiral centers.

Catalytic Enantioselective Cyano‐Trifluoromethylation of Styrenes

AbstractReported herein is the catalytic enantioselective cyano‐trifluoromethylation of styrenes allowing a straightforward preparation of a new structural class of fluorine‐containing compounds. We demonstrate that the desired transformation can be successfully realized using catalytic system of Cu(II)/chiral bidentate bis(oxazoline) ligand, TMS‐CN and Togni reagents, as sources of the CN and CF3 groups, respectively. Preliminary results strongly suggest synthetic potential of this method as the target cyano‐trifluoromethylated products can be generally obtained with high chemical yields (59‐90 %) and excellent enantiomeric purity (91‐98 % ee).

Catalytic Asymmetric 1,3‐Dipolar Cycloaddition of β‐Fluoroalkylated α,β‐Unsaturated 2‐Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ‐Amino Alcohols

Abstract2‐Pyridylsulfone‐ and fluoroalkylated group‐activated olefins underwent highly efficient diastereo‐ and enantioselective 1,3‐dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral NiII/bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α‐trifluoromethylated γ‐amino alcohol in gram‐scale and a trifluoromethylated derivative of 1,3‐oxazinan‐2‐one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo‐ and enantioselectivity.

Catalytic Asymmetric 1,3-Dipolar Cycloaddition of β-Fluoroalkylated α,β-Unsaturated 2-Pyridylsulfones with Nitrones for Chiral Fluoroalkylated Isoxazolidines and γ-Amino Alcohols.

2-Pyridylsulfone- and fluoroalkylated group-activated olefins underwent highly efficient diastereo- and enantioselective 1,3-dipolar cycloadditions across various aromatic and aliphatic nitrones in the presence of a chiral NiII /bis(oxazoline) catalyst. The process was tuned by 4 Å molecular sieves, chiral bis(oxazoline) ligands, reaction solvents, and temperature. A wide array of optically pure fluoroalkylated isoxazolidines were obtained, thus facilitating the asymmetric synthesis of an enantioenriched α-trifluoromethylated γ-amino alcohol in gram-scale and a trifluoromethylated derivative of 1,3-oxazinan-2-one with potential pharmaceutical interest. A stereochemical model, based on the absolute configuration of one adduct and some control experiments, was postulated to account for the observed endo- and enantioselectivity.

Correction: Iridium catalysts with modular axial-unfixed biphenyl phosphine–oxazoline ligands: asymmetric hydrogenation of α,β-unsaturated carboxylic acids

Correction for ‘Iridium catalysts with modular axial-unfixed biphenyl phosphine–oxazoline ligands: asymmetric hydrogenation of α,β-unsaturated carboxylic acids’ by Qian Wang et al., Org. Chem. Front., 2017, DOI: 10.1039/c6qo00677a.

Identification of monodentate oxazoline as a ligand for copper-promoted ortho-C-H hydroxylation and amination.

The use of a weakly coordinating monodentate directing group for copper mediated ortho-hydroxylation and amination reactions allows for the identification of an external oxazoline ligand as a promoter.

Iridium catalysts with modular axial-unfixed biphenyl phosphine–oxazoline ligands: asymmetric hydrogenation of α,β-unsaturated carboxylic acids

Axial-unfixed biphenyl phosphine–oxazoline ligands were successfully applied to Ir-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids.

Sugar-Annulated Oxazoline Ligands: A Novel Pd(II) Complex and Its Application in Allylic Substitution.

Two novel carbohydrate-derived pyridyl (PYOX)- and cyclopropyl (CYBOX)-substituted oxazoline ligands were prepared from d-glucosamine hydrochloride and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-d-glucopyranose hydrochloride in two steps, respectively. The sugar-annulated PYOX ligand formed a stable metal complex with Pd(II), which was fully characterized by NMR spectroscopy and X-ray crystallography. NMR and X-ray analysis revealed a change of the conformation in the sugar moiety upon complexation with the palladium(II) species. Both glycosylated ligands resulted in high asymmetric induction (up to 98% ee) upon application as chiral ligands in the Pd-catalyzed allylic alkylation of rac-1,3-diphenylallyl acetate with dimethyl malonate (Tsuji-Trost reaction). Both ligands provided mainly the (R)-enantiomer of the alkylation product.

Coupling phenols and allylic alcohols

Although chemists have plenty of ways to add carbon atoms to alkenes—including the Nobel Prize-winning Heck reaction—they have fewer options when working with heteroatom nucleophiles, such as alcohols. Now, Matthew S. Sigman and his group at the University of Utah report an intermolecular oxa-Heck reaction that allows them to couple phenols with allylic alcohols in an enantioselective manner (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b11486). The reaction, which is catalyzed by palladium in the presence of a chiral pyridine oxazoline ligand, creates building blocks that would be tough to make using more common synthetic reactions, such as a Michael addition (example shown). Sigman’s team selected allylic alcohols as the alkene in the reaction in order to influence which hydrogen would be removed during the β-elimination to form the chiral product. The chemists show the reaction works with a broad scope of allylic alcohols and phenols, and even successfully swaps the

Polystyrene-supported cu(II)-R-Box as recyclable catalyst in asymmetric Friedel–Crafts reaction

The complex of copper(II) trifluoromethanesulfonate with chiral isopropyl bis(oxazoline) ligand (i-Pr-Box) was immobilized on accessible and inexpensive Merrifield resin according to a “click” procedure. The resulting catalyst showed high efficiency and recyclability in the asymmetric Friedel–Crafts alkylation of indole and its derivatives. The catalyst can be recycled five times without appreciable loss in activity and enantioselectivity.

A silica-supported palladium-bis(oxazoline) complex efficiently catalyzes the synthesis of cinnamic acid derivatives via Mizoroki–Heck coupling reactions

A palladium(II)-bis(oxazoline) complex supported on silica (Pd-BOX-Si) was prepared, characterized and applied as a catalyst in Mizoroki–Heck cross-coupling reactions. The bis(oxazoline) (BOX) ligand has a hydroxyl group that can be anchored to 4-benzyl chloride-functionalized silica gel, followed by the coordination of palladium(II) chloride. The catalytic activity and the recyclability of Pd-BOX-Si have been investigated in the production of cinnamic acid derivatives via Mizoroki–Heck coupling reactions of acrylates with aryl halides; The Pd-BOX-Si catalyst demonstrated excellent catalytic activity. Characterization of the recycled Pd-BOX-Si catalyst revealed its good stability under the reaction conditions employed.

Design, Synthesis, Fungicidal Activity, and Unexpected Docking Model of the First Chiral Boscalid Analogues Containing Oxazolines.

Chirality greatly influences the biological and pharmacological properties of a pesticide and will contribute to unnecessary environmental loading and undesired ecological impact. No structure and activity relationship (SAR) of enantiopure succinate dehydrogenase inhibitors (SDHIs) was documented during the structure optimization of boscalids. On the basis of commercial SDHIs, oxazoline natural products, and versatile oxazoline ligands in organic synthesis, the first effort was devoted to explore the chiral SDHIs and the preliminary mechanism thereof. Fine-tuning furnished chiral nicotinamides 4ag as a more promising fungicidal candidate against Rhizoctonia solani, Botrytis cinerea, and Sclerotinia sclerotiorum, with EC50 values of 0.58, 0.42, and 2.10 mg/L, respectively. In vivo bioassay and molecular docking were investigated to explore the potential in practical application and plausible novelty in action mechanism, respectively. The unexpected molecular docking model showed the different chiral effects on the binding site with the amino acid residues. This chiral nicotinamide also featured easy synthesis and cost-efficacy. It will provide a powerful complement to the commercial SDHI fungicides with the introduction of chirality.