Exploiting the Chiral Ligands of Bis(imidazolinyl)- and Bis(oxazolinyl)thiophenes-Synthesis and Application in Cu-Catalyzed Friedel-Crafts Asymmetric Alkylation.

Five new C2-symmetric chiral ligands of 2,5-bis(imidazolinyl)thiophene (L1-L3) and 2,5-bis(oxazolinyl)thiophene (L4 and L5) were synthesized from thiophene-2,5-dicarboxylic acid (1) with enantiopure amino alcohols (4a-c) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel-Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand L5 and Cu(OTf)2 catalyst (15 mol%) in toluene for 48 h promoted Friedel-Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ee). The bis(oxazolinyl)thiophene ligands were more potent than bis(imidazolinyl)thiophene analogues for the asymmetric induction of the Friedel-Crafts asymmetric alkylation.

Anionic Bisoxazoline Ligands Enable Copper-Catalyzed Asymmetric Radical Azidation of Acrylamides.

Asymmetric radical azidation for the synthesis of chiral alkylazides remains a tremendous challenge in organic synthesis. We report here an unprecedented highly enantioselective radical azidation of acrylamides catalyzed by 1 mol % of a copper catalyst. The substrates were converted to the corresponding alkylazides in high yield with good-to-excellent enantioselectivity. Notably, employing an anionic cyano-bisoxazoline (CN-Box) ligand is crucial to generate a monomeric CuII azide species, rather than a dimeric CuII azide intermediate, for this highly enantioselective radical azidation.

Catalytic Asymmetric Fluorination of Copper Carbene Complexes: Preparative Advances and a Mechanistic Rationale.

The Cu-catalyzed reaction of substituted α-diazoesters with fluoride gives α-fluoroesters with ee values of up to 95 %, provided that chiral indane-derived bis(oxazoline) ligands are used that carry bulky benzyl substituents at the bridge and moderately bulky isopropyl groups on their core. The apparently homogeneous solution of CsF in C6 F6 /hexafluoroisopropanol (HFIP) is the best reaction medium, but CsF in the biphasic mixture CH2 Cl2 /HFIP also provides good results. DFT studies suggest that fluoride initially attacks the Cu- rather than the C-atom of the transient donor/acceptor carbene intermediate. This unusual step is followed by 1,2-fluoride shift; for this migratory insertion to occur, the carbene must rotate about the Cu-C bond to ensure orbital overlap. The directionality of this rotatory movement within the C2 -symmetric binding site determines the sense of induction. This model is in excellent accord with the absolute configuration of the resulting product as determined by X-ray diffraction using single crystals of this a priori wax-like material grown by capillary crystallization.

Asymmetric Cyclizative Dimerization of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides with Palladium(II) Bisoxazoline Catalyst.

The first example of an asymmetric cyclization-dimerization of (ortho-alkynyl phenyl) (methoxymethyl) sulfides with a palladium(II) bisoxazoline (box) catalyst has been developed. The box ligand enhances the alkynophilicity of benzothienyl palladium(II) intermediate A and thus promotes coordination of the second alkyne substrate, leading to the dimerization. The characteristic properties of the box ligand were supported by density functional theory (DFT) calculations of the intermediate. Axially chiral bibenzothiophenes were obtained in good yields with good enantioselectivities.

Synthesis of alternating metallocopolymers by chiral recognition.

We report the synthesis of chiral enantiopure polytopic bridging ligands, which may lead to the formation of metallosupramolecular polymers with zinc (II) as metal linker. We show that chiral C2 -symmetric bisoxazoline ligands are useful moieties to efficiently generate heterochiral complexes and thus polymeric entities. The corresponding metallopolymers were further characterized by powder X-ray diffraction (PXRD) to obtain information on the level of crystallinity of our different metallopolymers.

Planar Chiral [2.2]Paracyclophane-Based Bisoxazoline Ligands: Design, Synthesis, and Use in Cu-Catalyzed Inter- and Intramolecular Asymmetric O-H Insertion Reactions.

Centrally chiral bisoxazolines connected directly to a planar chiral [2.2]paracyclophane backbone were synthesized and evaluated as asymmetric ligands in Cu-catalyzed intermolecular ethanolic O-H insertion reactions of α-diazo esters. The reactivities and enantioselectivities of Cu complexes of the synthesized bisoxazoline ligands were lower than those of ligands without central chirality. However, planar chiral [2.2]paracyclophane-based bisoxazoline ligands with an inserted benzene spacer that had a sterically demanding isopropyl substituent showed good enantioselectivities in inter- and intramolecular aromatic O-H insertion reactions, without the aid of central chirality.

Palladium(II) Catalyzed Cyclization-Carbonylation-Cyclization Coupling Reaction of (ortho-Alkynyl Phenyl) (Methoxymethyl) Sulfides Using Molecular Oxygen as the Terminal Oxidant.

An efficient Pd(II)/Pd°-p-benzoquinone/hydroquinone-CuCl2/CuCl catalyst system was developed that uses environmentally friendly molecular oxygen as the terminal oxidant to catalyze the cyclization-carbonylation-cyclization coupling reaction (CCC-coupling reaction) of (o-alkynyl phenyl) (methoxymethyl) sulfides.

Copper-catalyzed asymmetric synthesis of tertiary α-hydroxy phosphonic acid derivatives with in situ generated nitrosocarbonyl compounds as the oxygen source.

α-Hydroxy phosphonic acids and their derivatives are highly bioactive structural motifs. It is now reported that these compounds can be accessed through the copper-catalyzed direct α-oxidation of ß-ketophosphonates using in situ generated nitrosocarbonyl compounds as an electrophilic oxygen source. These reactions proceeded in high yields (up to 95 %) and enantioselectivities (up to >99 % ee) for both cyclic as well as acyclic substrates. This method was also applied for the synthesis of α,ß-dihydroxy phosphonates and ß-amino-α-hydroxy phosphonates.

Enantioselective palladium-catalyzed insertion of α-aryl-α-diazoacetates into the O-H bonds of phenols.

A palladium-catalyzed asymmetric O-H insertion reaction was developed. Palladium complexes with chiral spiro bisoxazoline ligands promoted the insertion of α-aryl-α-diazoacetates into the O-H bond of phenols with high yield and excellent enantioselectivity under mild reaction conditions. This palladium-catalyzed asymmetric O-H insertion reaction provided an efficient and highly enantioselective method for the preparation of synthetically useful optically active α-aryl-α-aryloxyacetates.

Catalytic asymmetric tandem Friedel-Crafts alkylation/Michael addition reaction for the synthesis of highly functionalized chromans.

The enantioselective tandem Friedel-Crafts alkylation/Michael addition reaction of indoles with nitroolefin enoates catalyzed by a diphenylamine-linked bis(oxazoline)-Zn(OTf)2 complex was investigated. This tandem reaction afforded functionalized chiral chromans in good yields with moderate to high stereoselectivities (up to 95:5 dr, up to 99% ee).

Synthesis and Characterization of Photoswitchable Dithienylethene-Based Chiral Bisoxazoline Compounds with Bidirectional Visible-Light Control.

In this paper, we have successfully synthesized dithienylethene-based chiral bisoxazoline ligands with bidirectional photoswitching capabilities under visible light irradiation and proposed a strategy for adjusting the conjugation system length in sensitizer groups. The detailed experimental procedures and the characterization data are presented in the main text and the Supporting Information. Despite their moderate photoswitching rates, these ligands provide a promising approach towards developing fully visible light-responsive chiral catalysts.

Linear Regression Model Development for Analysis of Asymmetric Copper-Bisoxazoline Catalysis.

Multivariate linear regression analysis (MLR) is used to unify and correlate different categories of asymmetric Cu-bisoxazoline (BOX) catalysis. The versatility of Cu-BOX complexes has been leveraged for several types of enantioselective transformations including cyclopropanation, Diels-Alder cycloadditions and difunctionalization of alkenes. Statistical tools and extensive molecular featurization has guided the development of an inclusive linear regression model, providing a predictive platform and readily interpretable descriptors. Mechanism-specific categorization of curated datasets and parameterization of reaction components allows for simultaneous analysis of disparate organometallic intermediates such as carbenes and Lewis acid adducts, all unified by a common ligand scaffold and metal ion. Additionally, this workflow permitted the development of a complementary linear regression model correlating analogous BOX-catalyzed reactions employing Ni, Fe, Mg, and Pd complexes. Comparison of ligand parameters in each model reveals the relevant structural requirements necessary for high selectivity. Overall, this strategy highlights the utility of MLR analysis in exploring mechanistically driven correlations across a diverse chemical space in organometallic chemistry and presents an applicable workflow for related ligand classes.

A mass spectrometric method for rapidly assaying the chiral selectivities of the copper(I) complexes of C2-symmetric ligands.

A gas-phase method for rapidly assaying the enantioselectivity of metal-centered catalysts is presented. It relies on gas-phase equilibrium measurements in a quadrupole ion trap mass spectrometer. A group of well-established C2-symmetric bis-oxazoline copper(I) complexes was used to identify chiral probe reagents that are capable of profiling the quality of the asymmetric environment provided by the metal complex. The chiral probes were then applied to a wide variety of copper(I) bis-di-imine complexes. Complexes based on a BINAM backbone exhibited selectivities that were comparable to the bis-oxazolines. Taking advantage of the mass selectivity capabilities of the ion trap mass spectrometer, the method was also applied to an un-purified mix of copper(I) complexes derived from a combinatorial synthesis of bis-di-imine ligands. This approach holds promise as a rapid screening tool for potential chiral catalysts.