The Asymmetric Buchwald–Hartwig Amination Reaction

Lu, Chuan‐Jun; Xu, Qi; Feng, Jiu‐Ju; Liu, Renrong

doi:10.1002/anie.202216863

Cited by 49 publications

(38 citation statements)

References 93 publications

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“…Next, we explored desymmetrizing Buchwald-Hartwig amination (Scheme B) . Our initial attempts using KO t Bu as base led to the formation of coupling product 63 in low enantiopurity (20% yield, 65.5:34.5 er with Pd– L8 ; 15% yield, 65:35 er with Pd– L11 ).…”

Section: Resultsmentioning

confidence: 99%

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

2023

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Synthetic application of asymmetric catalysis relies on strategic alignment of bond construction to creation of chirality of a target molecule. Remote desymmetrization offers distinctive advantages of spatial decoupling of catalytic transformation and generation of a stereogenic element. However, such spatial separation presents substantial difficulties for the chiral catalyst to discriminate distant enantiotopic sites through a reaction three or more bonds away from a prochirality center. Here, we report a strategy that establishes acyclic quaternary carbon stereocenters through cross-coupling reactions at distal positions of aryl substituents. The new class of amino acid-derived ionic chiral catalysts enables desymmetrizing (enantiotopic-group-selective) Suzuki–Miyaura reaction, Sonogashira reaction, and Buchwald–Hartwig amination between diverse diarylmethane scaffolds and aryl, alkynyl, and amino coupling partners, providing rapid access to enantioenriched molecules that project substituents to widely spaced positions in the three-dimensional space. Experimental and computational investigations reveal electrostatic steering of substrates by the C-terminus of chiral ligands through ionic interactions. Cooperative ion-dipole interactions between the catalyst’s amide group and potassium cation aid in the preorganization that transmits asymmetry to the product. This study demonstrates that it is practical to achieve precise long-range stereocontrol through engineering the spatial arrangements of the ionic catalysts’ substrate-recognizing groups and metal centers.

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Section: Resultsmentioning

confidence: 99%

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

2023

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“…Despite these achievements, efficient and divergent N–C atropisomer synthesis remains highly desirable. Along with the great success of Buchwald–Hartwig amination in atropisomeric synthesis, we completed the intramolecular C–N coupling of amidines to provide N–C atropisomers with excellent yield and enantioselectivity (Scheme b). , To achieve cyclic amination, we had to address certain challenges. First, amidines coordinated with the transition metal to deactivate the catalyst.…”

Section: Asymmetric Synthesis Of N–c Atropisomersmentioning

confidence: 99%

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Feng,

Lu,

Liu

2023

Acc. Chem. Res.

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Metrics & More Article Recommendations CONSPECTUS: Atropisomers bearing a rotation-restricted axis are common structural units in natural products, chiral ligands, and drugs; thus, the prevalence of asymmetric synthesis has increased in recent decades. Research into atropisomers featuring an N-containing axis (N−X atropisomers) remains in its infancy compared with the well-developed C−C atropisomer analogue. Notably, N−X atropisomers could offer divergent scaffolds, which are extremely important in bioactive molecules. The asymmetric synthesis of N−X atropisomers is recognized as both appealing and challenging. Recently, we devoted our efforts to the catalytic asymmetric synthesis of N−X atropisomers, benzimidazole−aryl N−C atropisomers, indole−aryl N−C atropisomers, hydrogen-bond-assisted N−C atropisomers, pyrrole−pyrrole N−N atropisomers, pyrrole−indole N−N atropisomers, and indole−indole N−N atropisomers. To obtain the N−C atropisomers, an asymmetric Buchwald−Hartwig reaction of amidines or enamines was employed. Using a Pd(OAc) 2 /(S)-BINAP or Pd(OAc) 2 /(S)-Xyl-BINAP catalyst system, benzimidazole−aryl N−C atropisomers and indole−aryl N−C atropisomers were readily obtained. To address the issue of the reduced stability of the diarylamine axis, a six-membered intramolecular N−H−O hydrogen bond was introduced into the N−C atropisomer scaffold. A tandem N-arylation/oxidation process was used for the chiral phosphoric acid (CPA)-catalyzed asymmetric synthesis of N-aryl quinone atropisomers. For N−N atropisomers, a copper-mediated asymmetric Friedel−Crafts alkylation/arylation reaction was developed. The desymmetrization process was completed successfully via a Cu(OTf) 2 /chiral bisoxazoline or (CuOTf)•Tol/bis(phosphine) dioxide system, thereby achieving the first catalytic asymmetric synthesis of N/N bipyrrole atropisomers. Asymmetric Buchwald−Hartwig amination of enamines was utilized to provide N−N bisindole atropisomers with excellent stereogenic control. This was the first asymmetric synthesis of N−N atropisomers featuring a bisindole structural scaffold using the de novo indole construction strategy. The asymmetric N−N heterobiaryl atropisomer synthesis was substantially facilitated using palladium-catalyzed transient directing group (TDG)-mediated C−H functionalization. Atropisomeric alkenylation, allylation, or alkynylation was accomplished using the Pd(OAc) 2 /L-tert-leucine system. Herein, we summarize our work on the palladium-, copper-, and CPA-catalyzed asymmetric syntheses of N−C and N−N atropisomers. Furthermore, the application of our work in the synthesis of bioactive molecule analogues and axially chiral ligands is demonstrated. Subsequently, the stability of the chiral N-containing axis is briefly discussed in terms of single crystals and obtained rotational barriers. Finally, an outlook on the asymmetric N−X atropisomer synthesis is provided.

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“…Amines are valuable synthons and play a vital role in the synthesis of pharmaceutical reagents and preclinical candidates . They are also widely utilized in the manufacturing of agrochemicals, personal care products, organic electronics, and so forth. – The conventional methodologies for the preparation of amines include transition-metal-catalyzed coupling reactions, such as catalytic Ullmann-type reactions, – Buchwald–Hartwig amination, – hydroamination of alkenes and alkynes, ,– and others. , In recent years, the nucleophilic addition of organolithium reagents to imines has emerged as an efficient approach to amines, giving secondary amines and chiral nonracemic amines in a controllable manner. – Particularly, compounds bearing both an amine group and other chemical moieties, such as phenol and pyrrolyl scaffolds, could be produced, directly affording aminophenols and 1-(2-pyrrolyl)alkylamines in a very simple fashion.…”

Section: Introductionmentioning

confidence: 99%

Octalithium, Tetrasodium, and Decalithium Compounds Based on Pyrrolyl Ligands: Synthesis, Structures, and Activation of the C–H Bonds of Pyrrolyl Rings and C═N Bonds of a Series of Ligands by Organolithium Reagents

Jia

She

et al. 2023

Inorg. Chem.

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The organometallic compounds of lithium ions have garnered continuous interest as indispensable precursors for the syntheses of organometallic complexes of main-group metals, transition metals, lanthanide metals, and actinide metals. In this work, we present a strategy for the preparation of a series of polynuclear lithium complexes. This methodology features the utilization of organolithium reagents both as metal sources to coordinate with the ligands and as nucleophilic reagents to undergo nucleophilic addition to the C�N bonds of the ligands. Reaction of a ligand HL1amino)phenol]. One prominent feature regarding the formation of 1•1.5Tol is the occurrence of nucleophilic addition of n-BuLi to the C�N bond of HL1, leading to the generation of a new [L1a] 2− ligand that contains both aminophenol and 1-(2-pyrrolyl)alkylamine scaffolds. The developed protocol can be adapted to a series of organolithium reagents. Compounds [Li 8 (L1b) 4 ] (2) and [Li 8 (L1c) 4 ] (3) were afforded by treatment of HL1 with sec-BuLi and LiCH 2 SiMe 3 , respectively. Reaction of an analogous ligand HL2 [HL2 = 2-(((1-(2-(dimethylamino)ethyl)-1H-pyrrol-2yl)methylene)amino)-4-methylphenol] with n-BuLi generated compound [Li 8 (L2a) 4 ] ( 4). C�N bond activation was not observed in the reaction of HL1 with NaO t Bu, and the complex [Na 4 (L1) 4 ]•Tol (5•Tol) was obtained. A decanuclear complex [Li 10 (L3a) 2 (L3b) 2 ] (6) was also prepared via the reaction of HL3 [HL3 = 2-(2-((((1H-pyrrol-2-yl)methylene)amino)methyl)-1Hpyrrol-1-yl)-N,N-dimethylethan-1-amine] with t-BuLi. A remarkable feature in terms of the synthesis of 6 is the simultaneous occurrence of hydrogen atom abstraction from the C−H bond of the pyrrolyl ring and nucleophilic addition to the C�N bond of the HL3 ligand by t-BuLi. A series of amines containing biologically and physiologically important moieties were achieved by hydrolysis of the crude products from the reactions of the HL1−HL3 ligands and organolithium reagents. This work provides an efficient approach to high-nuclearity lithium compounds as well as a series of amines.

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The Asymmetric Buchwald–Hartwig Amination Reaction

Cited by 49 publications

References 93 publications

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters

Catalytic Asymmetric Synthesis of Atropisomers Featuring an Aza Axis

Octalithium, Tetrasodium, and Decalithium Compounds Based on Pyrrolyl Ligands: Synthesis, Structures, and Activation of the C–H Bonds of Pyrrolyl Rings and C═N Bonds of a Series of Ligands by Organolithium Reagents

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