Bis Oxazoline Research Articles

Synthesis and cure kinetics of bisoxazoline monomers during cationic ring‐opening polymerization

AbstractIn this work, the synthesis and characterization of highly aromatic bisoxazoline (BOX) monomers containing diphenyl ether, furan, and thiophene backbones are presented. Preliminary investigations of the cure and reaction kinetics are performed to understand the impact of these moieties on polymerization and their glass transition temperatures. To do this, two catalysts are used, methyl triflate (MT) and dodecyl benzene sulfonic acid (DBS) to explore their role in controlling the cationic ring‐opening polymerization (CROP) mechanism. Polymerization was monitored using non‐isothermal differential scanning calorimetry and characterized according to the Kissinger and Ozawa models. Kinetic modeling using the Malek and Sestak‐Berggren methods showed excellent agreement with experimental values and was used to determine reaction rate constants. The polymerization of BOX monomers in the presence of both MT and DBS is shown to be highly latent, being stable until the melting point is reached, after which reaction occurs rapidly.

Copper(I)-BOX Catalyzed Asymmetric 3-Component Reaction for the Synthesis of Trifluoromethylated Propargylic Ethers and Anilines.

An asymmetric 3-component reaction between EthynylBenziodoXoles (EBXs), 2,2,2-trifluorodiazoethane and nucleophiles catalyzed by a Cu(I)-BOX (Bisoxazoline) catalyst is described. This protocol gives access to chiral trifluoromethylated propargyl ethers and anilines, which are valuable building blocks in synthetic and medicinal chemistry. The reaction proceeds with high enantioselectivity and yield with different nucleophiles such as primary, secondary and tertiary alcohols, as well as both electron-rich and electron-poor anilines. Aryl-, alkyl- and silyl-substituted alkynes can be successfully introduced as electrophiles. In case of chiral substrates, high catalyst control was observed, leading to good diastereoselectivity.

Divergent Access to Chiral C2- and C3-Alkylated Pyrrolidines by Catalyst-Tuned Regio- and Enantioselective C(sp3)-C(sp3) Coupling.

Novel-substituted pyrrolidine derivatives are widely used in drugs and bioactive molecules. The efficient synthesis of these valuable skeletons, especially enantiopure derivatives, is still recognized as a key bottleneck to overcome in chemical synthesis. Herein, we report a highly efficient catalyst-tuned regio- and enantioselective hydroalkylation reaction for the divergent synthesis of chiral C2- and C3-alkylated pyrrolidines through desymmetrization of the readily available 3-pyrrolines. The catalytic system consists of CoBr2 with a modified bisoxazoline (BOX) ligand, which can achieve the asymmetric C(sp3)-C(sp3) coupling via the distal stereocontrol, providing a series of C3-alkylated pyrrolidines in high efficiency. Moreover, the nickel catalytic system allows the enantioselective hydroalkylation to synthesize the C2-alkylated pyrrolidines through the tandem alkene isomerization/hydroalkylation reaction. This divergent method uses readily available catalysts, chiral BOX ligands, and reagents, delivering enantioenriched 2-/3-alkyl substituted pyrrolidines with excellent regio- and enantioselectivity (up to 97% ee). We also demonstrate the compatibility of this transformation with complex substrates derived from a series of drugs and bioactive molecules in good efficiency, which offers a distinct entry to more functionalized chiral N-heterocycles.

Exploration of varying coordination reactivity of Schiff base H3L toward CdII, ZnII and MgII: Hydroxido-bridged dimer, acetato-directed chain and live cell-imaging

In the present work, a discrete dinuclear cadmium(II) complex Cd2(μ−H2L)(μ−OH)Cl2⋅H2O (1) and a dinuclear zinc(II) based 1D chain complex ({Zn2(L')(O2CCH3)}ClO4⋅3H2O)n (2) (where H3L = 2,6-bis{2-(2-hydroxyethylamino)ethylimino}methyl-4-methylphenol and H2L′ = bis-oxazoline (BOX) ligand), have been synthesized and characterized by single-crystal X-ray crystallography. The Cd2+ ions in the first case showed straight cut incorporation of metal ions within the ligand pockets. In case of zinc(II), the coordination induced oxazolidine ring formation resulted in macrocyclic ligand formation having two adjacent coordination pockets. In complex 2, the acetate ion acts as an O,O linker and joins the Zn2 nodes bound within the newly formed macrocyclic ligand bearing bis-oxazolidine rings to form 1D polymeric chain at the end. The H3L was next screened for its efficacy as selective fluorescence sensor for Mg2+ ions in aqueous MeOH medium. Steady state absorption and emission behaviour of H3L, 1 and 2 have been investigated. Time resolved fluorescence properties of H3L and the complexes 1 and 2 have been examined, and their lifetimes have been determined in 0.038–0.257 ns range. The cell viability in presence of H3L makes it a suitable candidate for application in live cell imaging studies.

Enantioselective C-H Amination Catalyzed by Nickel Iminyl Complexes Supported by Anionic Bisoxazoline (BOX) Ligands.

The trityl-substituted bisoxazoline (TrHBOX) was prepared as a chiral analogue to a previously reported nickel dipyrrin system capable of ring-closing amination catalysis. Ligand metalation with divalent NiI2(py)4 followed by potassium graphite reduction afforded the monovalent (TrHBOX)Ni(py) (4). Slow addition of 1.4 equiv of a benzene solution of 1-adamantylazide to 4 generated the tetrazido (TrHBOX)Ni(κ2-N4Ad2) (5) and terminal iminyl adduct (TrHBOX)Ni(NAd) (6). Investigation of 6 via single-crystal X-ray crystallography, NMR and EPR spectroscopies, and computations revealed a Ni(II)-iminyl radical formulation, similar to its dipyrrinato congener. Complex 4 exhibits enantioselective intramolecular C-H bond amination to afford N-heterocyclic products from 4-aryl-2-methyl-2-azidopentanes. Catalytic C-H amination occurs under mild conditions (5 mol % catalyst, 60 °C) and provides pyrrolidine products in decent yield (29%-87%) with moderate ee (up to 73%). Substrates with a 3,5-dialkyl substitution on the 4-aryl position maximized the observed enantioselectivity. Kinetic studies to probe the reaction mechanism were conducted using 1H and 19F NMR spectroscopies. A small, intermolecular kinetic isotope effect (1.35 ± 0.03) suggests an H-atom abstraction step with an asymmetric transition state while the reaction rate is measured to be first order in catalyst and zeroth order in substrate concentrations. Enantiospecific deuterium labeling studies show that the enantioselectivity is dictated by both the H-atom abstraction and radical recombination steps due to the comparable rate between radical rotation and C-N bond formation. Furthermore, the competing elements of the two-step reaction where H-removal from the pro-R configuration is preferred while the preferential radical capture occurs with the Si face of the carboradical likely lead to the diminished ee observed, as corroborated by theoretical calculations. Based on these enantio-determining steps, catalytic enantioselective synthesis of 2,5-bis-tertiary pyrrolidines is demonstrated with good yield (50-78%) and moderate ee (up to 79%).

Studies on a catalytic version of the Matteson asymmetric homologation reaction.

Studies of a catalytic asymmetric version of the Matteson reaction between dichloromethylboronates and organolithium reagents have been undertaken. From several different chiral catalytic systems studied, only one based on a mannitol derivative has given substantial asymmetric induction close to that previously achieved with a bis(oxazoline) derivative and ytterbium triflate. More detailed study of the latter reaction revealed that fresh ytterbium triflate actually reduced the level of asymmetric induction, while "aged" ytterbium triflate, or a fresh sample that had been treated with water, brought about improved induction. The implications of these findings are discussed.

Planar Chiral [2.2]Paracyclophane-Based Bisoxazoline Ligands and Their Applications in Cu-Mediated N–H Insertion Reaction

New catalysts for important C–N bond formation are highly sought after. In this work, we demonstrate the synthesis and viability of a new class of planar chiral [2.2]paracyclophane-based bisoxazoline (BOX) ligands for the copper-catalyzed N–H insertion of α-diazocarbonyls into anilines. The reaction features a wide substrate scope and moderate to excellent yields, and delivers the valuable products at ambient conditions.

Effects of Chiral Ligands on the Asymmetric Carbonyl-Ene Reaction

The carbonyl-ene reaction is one of the most well-known reactions for C–C bond formation. Based on frontier molecular orbitals (FMO), carbonyl-ene reactions occur between the highest occupied molecular orbital (HOMO) of the ene compound bearing an active hydrogen atom at the allylic center and the lowest unoccupied molecular orbital (LUMO) of the electron-deficient enophile, which is a carbonyl compound. A high activation barrier enforces the concerted ene reaction rather than a Diels–Alder reaction at high temperature. Employing a catalytic system can eliminate defects in the ene reaction, and chiral catalysts promote the reaction under mild conditions to produce optically active compounds. In this account, we highlight investigations on the effects of various classes of chiral ligands on intermolecular and intramolecular carbonyl-ene reactions.1 Introduction2 Biaryl-Type Chiral Ligands3 C 1- and C 2-Symmetric Bis(oxazoline) Ligands4 Schiff Base Ligands5 N,N′-Dioxide Ligands6 Conclusions

Merrifield’s Resin-Supported Palladium–Bis(oxazoline) Complex-Catalyzed Cross-Coupling Reactions of Aryl Bromides and Aryl Chlorides

The catalytic activity and the recycling ability of palladium–bis(oxazoline) (Pd–BOX-M) complex supported on Merrifield’s resin have been investigated in Suzuki–Miyaura and Mizoroki–Heck cross-coupling reactions of aryl bromides and aryl chlorides. The supported palladium–bis(oxazoline) catalyst demonstrated exceptional catalytic activity and excellent recycling ability. The characterization of the recycled palladium catalyst reveals no significant change in its structure, oxidation state and the amount of loaded palladium. This confirms the excellent stability of the palladium-supported catalyst.

SaBOX/Copper Catalysts for Highly Syndio-Specific Atom Transfer Radical Polymerization of Methyl Methacrylate

SaBOX/copper catalysts have been developed, giving a highly syndio-specific (triad syndiotacticity rr over 90%) and well-controlled (molecular weight distribution Đ = 1.1–1.4) atom transfer radical polymerization (ATRP) of methyl methacrylate. The substituents on the bisoxazoline (BOX) scaffold significantly affect the polymerization rate, molecular weight, and stereoselectivity. The side arms installed on the bridge carbon of BOX have been proven to strongly influence both the activity of the catalyst and the tacticity of the resulting polymers, paving an alternative way for the control of stereoselectivity in ATRP. X-ray structural determination and the Eyring approach were employed to obtain insights into the scaffold and side arm effects on catalyst performance.

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.

New palladium-bis(oxazoline)-phosphine complexes: synthesis, characterization and catalytic application in alkoxycarbonylation of alkynes

New cationic palladium-bis(oxazoline)-phosphine (Pd-BOX-PR3) complexes (Pd-BOX-B and Pd-BOX-C) have been synthesized and characterized using 1H, 13C and 31P NMR, FTIR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). The new complexes were used as catalysts in the alkoxycarbonylation of alkynes with various alcohols as nucleophiles. The carbonylation has produced the gem-α,β-unsaturated ester isomer (3) in high regioselectivity and excellent yields. The catalyst systems have been optimized by screening the type of palladium complexes and also by varying the reaction parameters including the reaction time, solvent, and temperature. A mechanism of the catalytic cycle based on a N-protonated palladium bis(oxazoline) phosphine active species was proposed for the alkoxycarbonylation reaction.

ChemInform Abstract: Asymmetric Copper‐Catalyzed Vinylogous Mukaiyama Michael Addition of Cyclic Dienol Silanes to Unsaturated α‐Keto Phosphonates.

A highly stereoselective vinylogous Mukaiyama Michael reaction (VMMR) leading to α-keto phosphonate-containing γ-butenolides with two stereogenic centers is described. The presented transformation is catalyzed by a combination of a commercially available C2 -symmetric bisoxazoline (BOX) ligand and a copper salt and tolerates a variety of nucleophiles and electrophiles. The stereoselectivities of the reactions are good to excellent and the products are obtained in moderate to high yields.

Asymmetric Copper-Catalyzed Vinylogous Mukaiyama Michael Addition of Cyclic Dienol Silanes to Unsaturated α-Keto Phosphonates.

A highly stereoselective vinylogous Mukaiyama Michael reaction (VMMR) leading to α-keto phosphonate-containing γ-butenolides with two stereogenic centers is described. The presented transformation is catalyzed by a combination of a commercially available C2 -symmetric bisoxazoline (BOX) ligand and a copper salt and tolerates a variety of nucleophiles and electrophiles. The stereoselectivities of the reactions are good to excellent and the products are obtained in moderate to high yields.

Effective palladium(II)-bis(oxazoline) catalysts: synthesis, crystal structure, and catalytic coupling reactions

New bis(oxazoline) ligands and their palladium complexes were synthesized and characterized. X-ray crystal structures of the two new complexes showed distorted square planar geometry with the palladium ion bonded to nitrogens of two bidentate heterocycles in addition to two bromides and two acetate ions for Pd-BOX-1 and Pd-BOX-2, respectively. The complexes adopt a chair structure with a rigid curvature inducing an inherent chirality. The complexes were effective catalysts for Suzuki–Miyaura, Mizoroki–Heck, and copper-free Sonogashira coupling reactions in aqueous dimethylformamide and under aerobic conditions. The reaction conditions were optimized for best solvent, base, and temperature. The substrate scope of the new catalytic system was evaluated for coupling reactions of a variety of aryl halides with aryl boronic acids, alkenes, and alkynes.

Bisoxazoline-Catalyzed Asymmetric Nucleophilic Addition of Diethyl Zinc to Fluorinated Alkyl Ketones: Enantiofacial Control by Changing the Bisoxazoline Substituent

Abstract Bisoxazoline (BOX)-catalyzed asymmetric nucleophilic addition of diethyl zinc to fluorinated alkyl ketones successfully afforded enantioenriched fluorinated alkyl tertiary alcohols. The effect of the size of the substituent on the oxazoline ring on the stereoselectivity of the reaction was investigated. Furthermore, the enantioselectivity could be reversed by altering the BOX bridge structure while retaining the C-4 substituent on the oxazoline ring.

ChemInform Abstract: Highly Enantioselective Alkylation of Allyl Acetates Using Tartrate‐Derived Bioxazoline Ligands.

AbstractThe bisoxazoline (BOX) is found to be an efficient ligand in Pd‐catalyzed asymmetric allylic alkylation.

Chiral Bis(Oxazolinyl)thiophenes for Enantioselective Cu(II)-Catalyzed Friedel–Crafts Alkylation of Indole Derivatives with Nitroalkenes

A series of chiral bis(oxazoline)thiophenes were used as chiral ligands in the Cu(II)-catalyzed asymmetric Friedel–Crafts alkylation of indole derivatives with nitroalkenes, and the effects of reaction conditions on the yield and enantioselectivity were investigated. The ligand 1c was identified as the best ligand of this family in the same reaction.

Bis(oxazoline)-copper catalyzed enantioselective hydrophosphonylation of aldehydes

A highly enantioselective copper-catalyzed hydrophosphonylation of aldehydes in the presence of bis(oxazoline) ligand is presented.

Chiral Bis(oxazoline)palladium(II) Complexes With 2,2′-methylenebis(4S,5R)-4,5-diphenyl-2-oxazoline as Ligand

Chiral bis(oxazoline)palladium(II) complexes Pd[(4S,5R)-mbd poxo]Cl2·2MeCN (1) and Pd[(4S, 5R)-mbdpoxo](MeCN)2(SbF6)2 (2) were synthesized ((4S,5R)-mbdpoxo = 2,2′-methylenebis (4S,5R)-4,5-diphenyl-2-oxazoline) and characterized by elemental analysis, IR, 1H, and 13C NMR spectra. The structure of complex 1 was determined by X-ray diffraction and the results show that it crystallizes in monoclinic space group P21 with a = 11.6278(16) Å, b = 8.2371(7) Å, c = 17.825(2) Å, β = 99.037(14)°, V = 1686.1(4) Å3 and Z = 2.