Chiral Bis Oxazoline Research Articles

ChemInform Abstract: The First Examples of the Enantioselective Heck—Matsuda Reaction: Arylation of Unactivated Cyclic Olefins Using Chiral Bisoxazolines.

Abstract Successful enantioselective Heck–Matsuda arylations were accomplished for the first time using chiral bisoxazolines as ligands. Enantioselective Heck arylations were performed with several cyclic nonactivated olefins to provide the Heck products in 63–96% isolated yields and in enantiomeric excesses of 54% up to 84%.

ChemInform Abstract: Enantioselective Oxidative Cross‐Dehydrogenative Coupling of Tertiary Amines to Aldehydes.

The direct oxidative cross-dehydrogenative coupling (CDC) of two C H bonds can be an efficient and relatively clean strategy in organic synthesis. Various sp C Hbonds, such as benzylic and allylic C H bonds, the a-C H bonds of amines and ethers, and the C H bonds of alkanes can be oxidized for direct reaction with carbon nucleophiles. Among these reactions, the oxidation of tertiary amines to generate iminium intermediates, as pioneered by Murahashi et al., Li et al. and others, has received considerable attention. Carbonyl compounds, such as 1,3-dicarbonyls, 10b,g] a,bunsaturated ketones, and simple ketones have been successfully coupled with tertiary amines by using metal catalysis, acid catalysis, metal/organic cooperative catalysis, or photoredox catalysis. In all of these reactions, the development of enantioselective catalysis remains a challenge. Very recently, Wang and co-workers used metals together with chiral bisoxazoline ligands to realize enantioselective reactions of activated carbonyl nucleophiles (such as 1,3dicarbonyls and acetyl phosphates) to oxidatively generate iminiums or their analogues. However, this approach with chiral ligands was found to be unsuccessful for reactions starting with simple ketone nucleophiles, as reported by Klussmann and co-workers as well as Xie and Huang. Approaches that use asymmetric enamine catalysis for the activation of carbonyl compounds have led to disappointing results (for example, less than 20% ee) as well . As part of a larger program for developing sustainable oxidation chemistry, we herein report an enantioselective oxidative coupling reaction of aldehydes and tertiary amines under cooperative amine and metal catalysis. The racemic version of this reaction was also realized by using metal catalysts alone (without amine catalysts), on account of its potential utility and the very different optimized conditions, relative to the enantioselective reactions. We examined metal-catalyzed oxidative coupling reactions between N-phenyltetrahydroisoquinoline (1a) and propionaldehyde (2a) in the presence of tBuOOH without an amine catalyst. An initial survey of solvents and catalysts indicated that DMF is a good solvent and CuBr2 is an effective metal catalyst (Table 1, entries 1–3, see also the Supporting Information). The amino aldehyde product 3a is unstable and, thus, was isolated as the corresponding amino alcohol product 4a in 72% yield after reduction with NaBH4 in situ, albeit with no diastereoselectivity (Table 1, entry 3). Under these conditions, various amines, such as N-aryl tetrahydroisoquinolines 1 and N,N-dialkyl anilines, and aldehydes 2 were used to obtain the corresponding racemic amino alcohols 4 in acceptable yields. Aldehydes with longer carbon chains required elevated reaction temperatures. N,Ndialkyl anilines gave the corresponding products in lower yields (Table S6 and Scheme S3 in the Supporting Information).

Access to Both Enantiomers of α‐Chloro‐β‐keto Esters with a Single Chiral Ligand: Highly Efficient Enantioselective Chlorination of Cyclic β‐Keto Esters Catalyzed by Chiral Copper(II) and Zinc(II) Complexes of a Spiro‐2,2′‐bischroman‐Based Bisoxazoline Ligand

AbstractThe spiro‐2,2′‐bichroman‐based chiral bisoxazoline ligands (SPANbox) were found to be highly efficient in copper(II)‐ and zinc(II)‐catalyzed asymmetric chlorinations of cyclic β‐keto esters with N‐chlorosuccinimide (NCS) as the chlorination reagent, to give the corresponding α‐chloro‐β‐keto esters in excellent yields in 5–30 min with ee values up to 97%. The copper(II) triflate and zinc(II) triflate complexes of a single SPANbox ligand demonstrated complementary results to each other with respect to the enantioselection, affording both antipodes of the chlorinated product enantiomers with good to excellent optical purities.

ChemInform Abstract: Highly Enantioselective Copper‐Catalyzed Alkylation of β‐Ketoesters and Subsequent Cyclization to Spirolactones/Bi‐spirolactones.

AbstractThe copper(II)‐complex derived from the chiral bisoxazoline ligand BOI efficiently catalyzes the alkylation reaction.

A Reusable TNF-Tagged Chiral Bis(oxazoline)-Copper Catalyst for Diels- Alder Transformations

A chiral bis(oxazoline) ligand, substituted on the methylene bridge by a covalent link to an electron-deficient moiety (2,4,7-trinitrofluoren-9-one, TNF), is a useful ligand associated to copper(II) salts to promote enantioselective Diels–Alder reactions between N-acyloxazolidinones and cyclopentadiene. Owing to different solubility properties, the corresponding catalyst was precipitated by pentane addition after reaction completion and was easily recovered by filtration. It was successfully reused in up to 20 successive catalytic cycles for the formation of the targeted products with no loss of either the activity or the enantioselectivity along with the recycling.

The first examples of the enantioselective Heck–Matsuda reaction: arylation of unactivated cyclic olefins using chiral bisoxazolines

Successful enantioselective Heck–Matsuda arylations were accomplished for the first time using chiral bisoxazolines as ligands. Enantioselective Heck arylations were performed with several cyclic nonactivated olefins to provide the Heck products in 63–96% isolated yields and in enantiomeric excesses of 54% up to 84%.

Enantioselective Oxidative Cross‐Dehydrogenative Coupling of Tertiary Amines to Aldehydes

The direct oxidative cross-dehydrogenative coupling (CDC) of two C H bonds can be an efficient and relatively clean strategy in organic synthesis. Various sp C Hbonds, such as benzylic and allylic C H bonds, the a-C H bonds of amines and ethers, and the C H bonds of alkanes can be oxidized for direct reaction with carbon nucleophiles. Among these reactions, the oxidation of tertiary amines to generate iminium intermediates, as pioneered by Murahashi et al., Li et al. and others, has received considerable attention. Carbonyl compounds, such as 1,3-dicarbonyls, 10b,g] a,bunsaturated ketones, and simple ketones have been successfully coupled with tertiary amines by using metal catalysis, acid catalysis, metal/organic cooperative catalysis, or photoredox catalysis. In all of these reactions, the development of enantioselective catalysis remains a challenge. Very recently, Wang and co-workers used metals together with chiral bisoxazoline ligands to realize enantioselective reactions of activated carbonyl nucleophiles (such as 1,3dicarbonyls and acetyl phosphates) to oxidatively generate iminiums or their analogues. However, this approach with chiral ligands was found to be unsuccessful for reactions starting with simple ketone nucleophiles, as reported by Klussmann and co-workers as well as Xie and Huang. Approaches that use asymmetric enamine catalysis for the activation of carbonyl compounds have led to disappointing results (for example, less than 20% ee) as well . As part of a larger program for developing sustainable oxidation chemistry, we herein report an enantioselective oxidative coupling reaction of aldehydes and tertiary amines under cooperative amine and metal catalysis. The racemic version of this reaction was also realized by using metal catalysts alone (without amine catalysts), on account of its potential utility and the very different optimized conditions, relative to the enantioselective reactions. We examined metal-catalyzed oxidative coupling reactions between N-phenyltetrahydroisoquinoline (1a) and propionaldehyde (2a) in the presence of tBuOOH without an amine catalyst. An initial survey of solvents and catalysts indicated that DMF is a good solvent and CuBr2 is an effective metal catalyst (Table 1, entries 1–3, see also the Supporting Information). The amino aldehyde product 3a is unstable and, thus, was isolated as the corresponding amino alcohol product 4a in 72% yield after reduction with NaBH4 in situ, albeit with no diastereoselectivity (Table 1, entry 3). Under these conditions, various amines, such as N-aryl tetrahydroisoquinolines 1 and N,N-dialkyl anilines, and aldehydes 2 were used to obtain the corresponding racemic amino alcohols 4 in acceptable yields. Aldehydes with longer carbon chains required elevated reaction temperatures. N,Ndialkyl anilines gave the corresponding products in lower yields (Table S6 and Scheme S3 in the Supporting Information).

Preparation of new chiral bisoxazoline ligands for the catalytic asymmetric intramolecular cyclopropanation of α-diazo-β-keto phenyl sulfone to afford a useful bicyclo[3.1.0]hexane derivative

Herein we describe the preparation of novel chiral bisoxazoline ligands with various substituents at the bisoxazoline linkage, for use in the catalytic asymmetric intramolecular cyclopropanation (CAIMCP) of α-diazo-β-keto phenyl-5-hexenyl sulfone to afford a simple, but useful, bicyclo[3.1.0]hexane derivative. The enantioselectivity of the CAIMCP of α-diazo-β-keto phenyl-5-hexenyl sulfone was improved and a product with 84% ee was obtained using 30mol% of the catalyst, which was prepared in situ by CuOTf and the new bisoxazoline ligand with two 3,5-di-tert-butylbenzyl groups at the bisoxazoline linkage. The product was obtained in enantiomerically pure form by a single crystallization, enabling its use as a chiral building block.

ChemInform Abstract: Enantioselective Michael Addition of Malonates to 2‐Enoylpyridine N‐Oxides Catalyzed by Chiral Bisoxazoline—Zn(II) Complex.

AbstractThe reaction is general for various N‐oxides tolerating aromatic, aliphatic and alkenic substituents and affords the products with enantioselectivities up to 96% e.e.

ChemInform Abstract: Catalytic Asymmetric Activation of a C(sp3)—H Bond Adjacent to a Nitrogen Atom: A Versatile Approach to Optically Active α‐Alkyl α‐Amino Acids and C1‐Alkylated Tetrahydroisoquinoline Derivatives.

AbstractThe DDQ‐mediated cross‐dehydrogenative coupling of a variety of oxocyclopentanecarboxylates or analogues with glycine esters is efficiently catalyzed by Cu(II)/chiral bisoxazoline.

Well-Defined Binuclear Chiral Spiro Copper Catalysts for Enantioselective N–H Insertion

An asymmetric N-H insertion of α-diazoesters with anilines catalyzed by well-defined copper complexes of chiral spiro bisoxazoline ligands was studied in detail. The copper-catalyzed asymmetric N-H insertion of a wide range of α-alkyl-α-diazoacetates with anilines was accomplished with excellent enantioselectivity (up to 98% ee) and provided an efficient method for the preparation of optically active α-amino acid derivatives. A correlation study of the electronic properties of the substrates with the enantioselectivity of the N-H insertion reaction supports a stepwise insertion mechanism, and the significant first-order kinetic isotope effect proves that the proton transfer is most likely the rate-limiting step. A binuclear chiral spiro copper catalyst having 14-electron copper centers, a trans coordination model, a perfect C(2)-symmetric chiral pocket, and significant Cu-Cu interaction was isolated and extensively studied. The novel structure of the binuclear chiral spiro copper catalyst leads to unique reactivity as well as enantioselectivity in the N-H insertion reaction.

Iron‐Catalyzed CH Fuctionalization of Indoles

AbstractAn easily available iron catalyst was developed to accomplish the CH functionalization of indoles with α‐aryl‐α‐diazoesters in high yields under mild conditions. The asymmetric CH functionalization of indoles was also realized by using iron complexes of chiral spiro bisoxazolines with up to 78% ee.

Identification and characterization of intermediates in the formation of the cyclobutadiene linked dimeric cobalt sandwich compound [( ${\eta ^{5}}$ -RCp)Co( ${\eta^{4}}$ -C 4 Ph 3 )] 2 [R ${=}$ H, CH 3 C(O)O

The synthesis of novel cyclobutadiene linked dimers of [η 5-RCp]Co(η 4-C4Ph4) was reported recently from a three-component reaction of 1,4-diphenylbutadiyne, diphenylacetylene and [η 5-RCp]Co(PPh3)2 [R = H or MeOC(O)]. The chiral bis oxazoline derivative of this dimer was found to form cobalt oxazolinyl palladacycles which were excellent chiral catalysts for the Overman–Claisen rearrangement of trichloroacetimidates, similar to the well-known COP catalysts. In this paper, we report reactions carried out for identifying the intermediates in the formation of the dimeric sandwich compound {[η 5-MeOC(O)Cp]Co(η 4-C4Ph3)}2 (1). On varying the stoichiometric ratio of the reactants of the three component reaction, two new cobalt sandwich compounds [η 5-MeOC(O)Cp]Co[η 4-C4Ph3(C≡CPh)] (2) and [η 5-MeOC(O)Cp]Co[η 4-C4-Ph2(C≡CPh)2] (3) were found to form as viscous oily liquids. The identity of 2 was ascertained by oxidizing its alkyne moiety to yield crystalline [η 5-MeOC(O)Cp]Co{η 4-C4Ph3[C(O)-C(O)Ph]} (4) which was structurally characterized. Further, the role of phenylethynyl derived monomeric sandwich compound 2 as a precursor to the dimeric compound 1 was established by reacting 2 with diphenylacetylene and CpCo(COD) which yielded the first example of an unsymmetrical cyclobutadiene linked dimeric cobalt sandwich compound {η 5-[MeOC(O)Cp]Co(η 4-C4Ph3)}[(η 5-Cp)Co(η 4-C4Ph3)] (5) which was also structurally characterized. The mechanism of the formation of cyclobutadiene linked dimers of the cobalt sandwich compound (η5-Cp)Co(η4-C4Ph4) has been studied. Two intermediates [η5-MeOC(O)Cp]Co[η4-C4Ph3(C≡CPh)] and [η5-MeOC(O)Cp]Co[η4-C4Ph2(C≡CPh)2] were isolated. The identity of the former was proved by oxidizing its alkyne moiety. Further, this compound was converted to a novel unsymmetrical cyclobutadiene linked dimer {η5-[MeOC(O)Cp]Co(η4-C4Ph3)} [(η5-Cp)Co(η4-C4Ph3)].

Recycling Chiral Copper Bis(oxazoline) Complexes in an Original Multireaction Procedure

Recycling Chiral Copper Bis(oxazoline) Complexes in an Original Multireaction Procedure

Asymmetric NH Insertion Reaction Cooperatively Catalyzed by Rhodium and Chiral Spiro Phosphoric Acids

Nitrogen-containing organic compounds, such as a-amino acids and alkaloids, are important biologically active compounds, thus the development of efficient and enantioselective methods for the construction of carbon–nitrogen bonds is a fundamental goal in modern organic synthesis. Transitionmetal-catalyzed carbene insertion into N H bonds is one of the most efficient methods to construct carbon–nitrogen bonds and the development of asymmetric versions of the N H insertion reaction has attracted considerable attention. In initial studies, chiral dirhodium catalysts were tested in intramolecular and intermolecular N H insertion reactions, however, only low to modest enantioselectivities (< 50% ee) were achieved. Since these reports, other transition metals including copper and silver have been used as catalysts, and gave enantioselectivities up to 48% ee. Recently, we reported a highly enantioselective N H insertion reaction (up to 98% ee) using a copper complex with chiral spiro bisoxazoline ligands. Subsequently, two other types of chiral copper catalysts have been developed, one with a planar chiral bipyridine ligand and the other with a binolderivative ligand, and both of these catalysts give high enantioselectivities in N H insertion reactions. Although progress on copper-catalyzed asymmetric N H insertion reactions has been substantial, they still have serious limitations. For instance, all the copper-catalyzed N H insertion reactions require high catalyst loading (5– 10 mol%) for satisfactory yields and enantioselectivities, thus more-efficient chiral catalysts are highly desirable. Because the activity of dirhodium(II) catalysts is usually superior to that of copper catalysts in nonenantioselective N H insertion reactions, the possibility of using dirhodium catalysts to achieve highly enantioselective N H insertion reactions is an intriguing one. Recently, Saito et al. reported that dirhodium(II) carboxylates and cinchona alkaloids cooperatively catalyze the asymmetric N H insertion reactions of a-diazo-a-arylacetates with anilines. The combined catalysts exhibit excellent reactivity but only modest enantioselectivity (up to 71% ee). It is generally accepted that the rhodium-catalyzed N H insertion most likely proceeds via an ylide intermediate (Scheme 1A). We speculated that the subsequent protontransfer step could be facilitated by a chiral phosphoric acid species via a seven-membered-ring transition state, and that, consequently, chiral induction could be accomplished in this step (Scheme 1B). The groups of Yu and Platz have reported that either water or alcohols can assist proton transfer in O H insertion reactions, as indicated by density functional theory calculations and ultrafast time-resolved IR spectroscopy studies. These studies stimulated our interest in exploring asymmetric N H insertion in the presence of a proton-transfer catalyst. As part of our ongoing work on the development of asymmetric carbene insertion reactions, we report herein the asymmetric N H insertion reaction cooperatively catalyzed by dirhodium(II) carboxylates and chiral spiro phosphoric acids (SPAs). Excellent reactivity and high enantioselectivity (up to 95% ee) were achieved in the presence of as little as 0.1 mol% of catalyst. In our initial study, we carried out the insertion of methyl a-diazo-a-phenylacetate (3a) into the N H bond of tert-butyl carbamate (BocNH2) in CHCl3 at 25 8C using 1 mol% of [Rh2(OAc)4] and 10 mol% of chiral SPAs 1 as the catalysts (Table 1). SPAs 1 were prepared by a simple condensation of P(O)Cl3 with 6,6’-disubstituted-1,1’-spirobiindane-7,7’-diols 2, followed by hydrolysis (Scheme 2). Diols 2 were synthesized from spinol (1,1’-spirobiindane-7,7’-diol), as described previously. In the presence of (R)-1a, the N H insertion reaction proceeded within 5 minutes to afford the insertion product in excellent yield with 11% ee (Table 1, entry 2). Control experiments showed that the SPAs alone did not promote the insertion reaction. A range of SPAs with various substituents at the 6 and 6’ positions were evaluated (Table 1, entries 3–9). All the tested SPAs afforded high yields in the N H insertion reaction. SPA (R)-1h, which bears a 6,6’-di(naphth-2-yl) group, afforded the Scheme 1. Proposed mechanism for chiral phosphoric acid induced asymmetric N H insertion.

Enantioselective Michael Addition of Malonates to 2-Enoylpyridine N-Oxides Catalyzed by Chiral Bisoxazoline–Zn(II) Complex

An enantioselective Michael addition of malonates to 2-enoylpyridine N-oxides catalyzed by a chiral bisoxazoline-Zn(II) complex has been developed. The corresponding Michael adducts have been obtained in high yields with up to 96% ee. A plausible transition-state model has been proposed to explain the stereochemical outcome of the reaction.

ChemInform Abstract: Enantioselective Copper‐Catalyzed Propargylic Substitution: Synthetic Scope Study and Application in Formal Total Syntheses of (+)‐Anisomycin and (‐)‐Cytoxazone.

AbstractA variety of propargylic esters is converted into the amine counterparts by reaction with primary or secondary amines in the presence of a Cu(I)/chiral pyridine bisoxazoline catalyst.

Catalytic Enantioselective Aziridoarylation of Aryl Cinnamyl Ethers toward Synthesis of trans-3-Amino-4-arylchromans

Catalytic enantioselective one-pot aziridoarylation reaction of aryl cinnamyl ethers has been demonstrated in detail. Combination of suitable copper catalyst and chiral bis-oxazoline ligand was found to be very efficient for asymmetric aziridination followed by intramolecular arylation (Friedel-Crafts) reaction to provide a general and direct method for the synthesis of trans-3-amino-4-arylchromans with high regio-, diastereo- (dr > 99:1), and enantioselectivity (up to 95% ee) with moderate yield. trans-3-Amino-4-arylchroman is an advanced intermediate for the synthesis of chromenoisoquinoline compounds such as doxanthrine, a potent and selective full agonist for the dopamine-D(1) receptor.

ChemInform Abstract: Enantioselective Copper‐Catalyzed O—H Insertion of α‐Diazo Phosphonates.

AbstractThe asymmetric O—H insertion of α‐diazo phosphonates with alcohols in the presence of a catalyst, generated in situ from a Cu(I) precursor, a chiral spiro bisoxazoline ligand and a sodium borate, provides good yields of α‐alkoxy phosphonates with high enantioselectivities.

ChemInform Abstract: Asymmetric 1,3‐Dipolar Cycloaddition Reactions Catalyzed by Heterocycle‐Based Metal Complexes

AbstractReview: 116 refs.