Pybox Complex Research Articles

Catalytic asymmetric Friedel–Crafts alkylation of unprotected indoles with nitroalkenes using a novel chiral Yb(OTf)3–pybox complex

Chiral chloro-indeno pybox has served as a new ligand for the Yb(OTf)3-catalyzed asymmetric Friedel–Crafts alkylation reaction of indoles with nitroalkenes. The tunable nature of pybox ligands enables the rational design of catalysts for optimal performance in terms of both activity and stereoselectivity in a Friedel–Crafts-type reaction. Good to excellent yields and enantioselectivities were obtained for a relatively wide range of substrates, including sterically hindered compounds, under optimized reaction conditions.

Desymmetrization of a Propane-1,3-diol to Introduce the Quaternary Chiral Center of an AMG 176 Drug Substance Intermediate

AbstractA chiral Cu(II)-PyBOX complex was prepared and utilized to accomplish desymmetrization of a 1,3-diol en route to AMG 176. An expedient synthesis of the racemic 1,3-diol is described, in addition to efforts for rapid optimization and subsequent kilogram-scale execution of the desymmetrization process to generate material for pre-clinical activities. An overview of the kilogram-scale synthesis of the Cu(II)-PyBOX complex is provided.

Asymmetric Transfer Hydrogenation of Arylketones Catalyzed by Enantiopure Ruthenium(II)/Pybox Complexes Containing Achiral Phosphonite and Phosphinite Ligands.

A family of complexes of the formula trans-[RuCl2(L)(R-pybox)] (R-pybox = (S,S)-iPr-pybox, (R,R)-Ph-pybox, L = monodentate phosphonite, PPh(OR)2, and phosphinite, L = PPh2(OR), ligands) were screened in the catalytic asymmetric transfer hydrogenation of acetophenone, observing a strong influence of the nature of both the R-pybox substituents and the L ligand in the process. The best results were obtained with complex trans-[RuCl2{PPh2(OEt)}{(R,R)-Ph-pybox}] (2c), which provided high conversion and enantioselectivity (up to 96% enantiomeric excess, e.e.) for the reduction of a variety of aromatic ketones, affording the (S)-benzylalcohols.

Asymmetric diastereodivergent Michael addition of 2-chloromalonate esters to conjugated imines enabled by catalyst metal change

A change of the metal ion in pyBOX complex catalysts enables the asymetric diastereodivergent conjugate addition of 2-chloromalonate esters to β,γ-unsaturated α-ketiminoesters.

Highly Chemo- and Stereoselective Catalyst-Controlled Allylic C-H Insertion and Cyclopropanation Using Donor/Donor Carbenes.

The highly chemo-, enantio-, and diastereoselective catalyst-controlled intramolecular allylic C-H insertion and cyclopropanation of donor/donor carbenes are reported. The RuII /Pybox complex selectively catalyzed the intramolecular allylic C-H insertion, providing vinyl-substituted dihydroindoles with greater than 20:1 chemoselectivity and up to greater than 99 % ee. Chiral dirhodium(II) tetracarboxylates, however, selectively promoted the intramolecular cyclopropanation, giving rise to cyclopropane-fused tetrahydroquinoline derivatives in excellent yields with greater than 99:1 chemoselectivity and up to 97 % ee.

Applications of Pybox Complexes in Asymmetric Catalysis

AbstractPybox ligands have found widespread application in organic synthesis and catalysis ever since their discovery, and their involvement in various C−C and C–heteroatom bond‐forming reactions is rapidly increasing. In this Focus Review, we summarise the reactions involving various Pybox–metal combinations used for forming C−C bonds, such as cross‐coupling reactions, carbonyl–ene reactions, three‐component reactions, allylation reactions, Diels–Alder reactions and other C−C bond‐forming reactions. The literature from 2006 to 2017 is covered.

Metal-Controlled Switching of Enantioselectivity in the Mukaiyama-Michael Reaction of α,β-Unsaturated 2-Acyl Imidazoles Catalyzed by Chiral Metal-Pybox Complexes.

Metal-directed switching of enantioselectivity in the Mukaiyama-Michael reaction of silyl enol ethers to α,β-unsaturated 2-acyl imidazoles using the same chiral indapybox ligand has been reported. The utility of this approach has been portrayed in the synthesis of both enantiomers of optically active δ-keto acid and ester as well as 3,4-dihydropyran-2-one. Moreover, enantioswitching in the construction of the tertiary stereocenter adjacent to a gem-dimethyl group has been achieved.

Lanthanum-pyBOX complexes as catalysts for the enantioselective conjugate addition of malonate esters to β,γ-unsaturated α-ketimino esters

In this paper, we report the application of chiral complexes of La(III) with pyBOX ligands as Lewis acid catalysts in the conjugate addition of malonic esters to N-tosyl imines derived from β,γ-unsaturated α-keto esters to give the corresponding chiral α,β-dehydroamino esters. pyBOX complexes with La(III), Yb(III), Sc(III), and In(III) triflates were assessed in this reaction but only La(III) showed good activity and enantioselectivity, while Yb(III) provided the expected product with low yield and stereoselectivity, and the Sc(III) and In(III) complexes were completely inactive. The complex of La(OTf)3 with the diphenyl-pyBOX ligand prepared in situ provided the best results and allowed obtaining chiral α,β-dehydroamino esters 3 with excellent yields, E:Z diastereomeric ratios (29:71–99:1) and high enantiomeric excesses (20–95%). The reaction could be applied to imines having a substituted aromatic ring or a heterocycle attached to the double bond, although the presence of electron-withdrawing groups on the aromatic ring was detrimental for stereoselectivity. The reaction products were obtained with the S configuration at the stereogenic center and the Z configuration at the enamine double bond as determined by NOESY experiments and X-ray analysis. Based on the experimental results a stereochemical model involving a nine-coordinate La(III) species has been proposed.

Synthesis of Silver(I) and Gold(I) Complexes Containing Enantiopure Pybox Ligands. First Assays on the Silver(I)-Catalyzed Asymmetric Addition of Alkynes to Imines.

Dinuclear complexes [Ag2(CF3SO3){(S,S)-(i)Pr-pybox}2][CF3SO3] (1), [Ag2(R-pybox)2][X]2 [R-pybox = 2,6-bis[4-(S)-isopropyloxazolin-2-yl]pyridine (S,S)-(i)Pr-pybox and X = PF6 (2) and BF4 (3); R-pybox = 2,6-bis[(3aS,8aR)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]pyridine (3aS,3a'S,8aR,8a'R)-indane-pybox and X = CF3SO3 (4)], [Ag2{(S,S)-(i)Pr-pybox}{(3aS,3a'S,8aR,8a'R)-indane-pybox}][CF3SO3]2 (5), and [Ag2(R-pybox)3][X]2 [R-pybox = (3aS,3a'S,8aR,8a'R)-indane-pybox and X = CF3SO3 (10), SF6 (11), and PF6 (12)] as well as mononuclear complexes [Ag(R-pybox)2][X] [R-pybox = (S,S)-(i)Pr-pybox and X = SbF6 (6), PF6 (7), and BF4 (8); R-pybox = (3aS,3a'S,8aR,8a'R)-indane-pybox) and X = BF4 (9)] have been prepared by the reaction of the corresponding silver salts and pybox ligands using the appropriate molar ratio conditions. The first gold(I)/pybox complex [Au6Cl4{(S,S)-(i)Pr-pybox}4][AuCl2]2 (13) has been synthesized by the reaction of [AuCl{S(CH3)2}] and (S,S)-(i)Pr-pybox (1:1 molar ratio) in acetonitrile. The structures of the dinuclear (1, 4, 5, 10, and 11) and mononuclear (6 and 9) silver complexes and the hexanuclear gold complex 13 have been determined by single-crystal X-ray diffraction analysis. These studies have been complemented with a solution-state study by NMR spectroscopy, which included structure elucidation, variable-temperature measurements, and diffusion studies using diffusion-ordered spectroscopy (DOSY; for complexes 1, 4, 10, and 12). Complexes 1, 2, 4, and 10 have been assayed as catalysts in the asymmetric addition of phenylacetylene to N-benzylideneaniline.

Catalytic Asymmetric Tandem Reaction of Tertiary Enamides: Expeditious Synthesis of Pyrrolo[2,1-a]isoquinoline Alkaloid Derivatives.

Reported is a new and efficient strategy for rapid construction of the chiral tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one structure from unique tertiary enamide synthons. A Cu(OTf)2 /chiral Pybox complex catalyzes the intramolecular enantioselective addition of tertiary enamides to ketonic carbonyls with subsequent diastereoselective interception of the resulting acyliminium by tethered electron-rich aryl moiety. The tandem reaction produces diverse tetrahydropyrrolo[2,1-a]isoquinolin-3(2H)-one derivatives as the sole diastereoisomers in good to excellent yields with up to 98.5 % ee. The transformations of the resulting heterocycles into various hexahydropyrrolo[2,1-a]isoquinoline derivatives were also demonstrated. The cyclization products, which are difficult to obtain by other synthetic means, are structural motifs found in many bioactive alkaloids.

Catalytic Asymmetric Tandem Reaction of Tertiary Enamides: Expeditious Synthesis of Pyrrolo[2,1‐a]isoquinoline Alkaloid Derivatives

AbstractReported is a new and efficient strategy for rapid construction of the chiral tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one structure from unique tertiary enamide synthons. A Cu(OTf)2/chiral Pybox complex catalyzes the intramolecular enantioselective addition of tertiary enamides to ketonic carbonyls with subsequent diastereoselective interception of the resulting acyliminium by tethered electron‐rich aryl moiety. The tandem reaction produces diverse tetrahydropyrrolo[2,1‐a]isoquinolin‐3(2H)‐one derivatives as the sole diastereoisomers in good to excellent yields with up to 98.5 % ee. The transformations of the resulting heterocycles into various hexahydropyrrolo[2,1‐a]isoquinoline derivatives were also demonstrated. The cyclization products, which are difficult to obtain by other synthetic means, are structural motifs found in many bioactive alkaloids.

ChemInform Abstract: An Asymmetric Alkynylation/Hydrothiolation Cascade: An Enantioselective Synthesis of Thiazolidine‐2‐imines from Imines, Acetylenes and Isothiocyanates.

A multicomponent reaction between imines, terminal alkynes, and isothiocyanates in the presence of a catalytic chiral copper–pybox complex proceeds enantioselectively to give enantiopure thiazolidine-2-imines (60–99% ee) via a highly regioselective intramolecular 5-exo-dig hydrothiolation reaction.

ChemInform Abstract: Fast, Solvent‐Free, Highly Enantioselective Three‐Component Coupling of Aldehydes, Alkynes, and Amines Catalyzed by the Copper(II)pybox Complex under High‐Vibration Ball‐Milling.

AbstractThe employed copper(II) pybox catalyst system can be easily recovered and reused five times maintaining high performance without additional replenishment of ligands.

Direct asymmetric dearomatization of 2-naphthols by scandium-catalyzed electrophilic amination.

Catalytic asymmetric aminative dearomatization of 1-substituted 2-naphthols was successfully implemented with electrophilic azodicarboxylates under the catalysis of chiral Sc(III)/pybox complexes. This intermolecular reaction represents a hitherto unknown enantioselective C-N bond-forming process through direct dearomatization of phenolic compounds to generate chiral nitrogen-containing quaternary carbon stereocenters.

Fast, solvent-free, highly enantioselective three-component coupling of aldehydes, alkynes, and amines catalysed by the copper(ii)pybox complex under high-vibration ball-milling

Chiral propargylamines were prepared by a ball-milling promoted, fast, high yielding, and highly enantioselective solvent-free A3 reaction using a reusable catalyst.

ChemInform Abstract: Enantioselective Intramolecular Propargylic Amination Using Chiral Copper—Pybox Complexes as Catalysts.

Intramolecular propargylic amination of propargylic acetates bearing an amino group at the suitable position in the presence of chiral copper–pybox complexes proceeds enantioselectively to give optically active 1-ethynyl-isoindolines (up to 98% ee). The method described in this communication provides a useful synthetic approach to the enantioselective preparation of nitrogen containing heterocyclic compounds with an ethynyl group at the α-position.

Highly enantioselective hydrogenation of N-aryl imines derived from acetophenones by using Ru-pybox complexes under hydrogenation or transfer hydrogenation conditions in isopropanol.

The asymmetric reduction of N-aryl imines derived from acetophenones by using Ru complexes bearing both a pybox (2,6-bis(oxazoline)pyridine) and a monodentate phosphite ligand has been described. The catalysts show good activity with a diverse range of substrates, and deliver the amine products in very high levels of enantioselectivity (up to 99 %) under both hydrogenation and transfer hydrogenation conditions in isopropanol. From deuteration studies, a very different labeling is observed under hydrogenation and transfer hydrogenation conditions, which demonstrates the different nature of the hydrogen source in both reactions.

Asymmetric Mannich Reaction of Malonates with Aldimines Using YbIII‐Pybox Complexes Supported on Self‐Assembled Organic–Inorganic Hybrid Silica with an Imidazolium Framework

AbstractYb(OTf)3/iPr‐pybox (3b) immobilized on a self‐assembled organic–inorganic hybrid silica with ionic liquid phase (SAILP) (Catalyst A) behaves as an efficient and recyclable catalyst in the enantioselective Mannich reaction of malonate esters with N‐Boc aldimines to afford the corresponding products in good yields and enantioselectivities. In particular, it has been shown that the use of catalyst A resulted in much superior enantioselectivities in comparison with either 1:2 Yb(OTf)3/3b on a periodic mesoporous organosilica with 10 percent imidazolium framework (catalyst C) or a catalyst comprising 1:1 Yb(OTf)3/3b on SAILP under the same reaction conditions. Catalyst A could be recycled and reused at least four times with only a slight decrease in either catalytic activity or enantioselectivity.

Catalytically Active Cu(II)-Pybox Complexes: Insights by EPR Spectroscopy and DFT Computations

This paper addresses the geometry of the catalytic Cu(II) complexes formed in the course of stereoselective Diels–Alder reaction. The parent catalyst is [Cu(II)-isopropyl-pybox](OTf)2. Ethyl glyoxylate serves as dienophile and it reacts with 1,3-cyclohexadiene. The reaction is followed by CW EPR, HYSCORE, and (pulsed) ENDOR spectroscopy and the experimental results are supported by DFT computations. It is shown that during the catalytic process, the Cu(II) complex is pentacoordinated and one of the triflate counterions is coordinated to the Cu(II) center in axial position.

Enantioselective intramolecular propargylic amination using chiral copper-pybox complexes as catalysts.

Intramolecular propargylic amination of propargylic acetates bearing an amino group at the suitable position in the presence of chiral copper-pybox complexes proceeds enantioselectively to give optically active 1-ethynyl-isoindolines (up to 98% ee). The method described in this communication provides a useful synthetic approach to the enantioselective preparation of nitrogen containing heterocyclic compounds with an ethynyl group at the α-position.