Biaryl Amines Research Articles

Biocatalytic Desymmetrization for the Atroposelective Synthesis of Axially Chiral Biaryls Using an Engineered Imine Reductase.

The enzymatic atroposelective synthesis of biaryl compounds is relatively rare, despite considerable attention received by biocatalysis in academic and industrial sectors. Imine reductases (IREDs) are an important class of enzymes that have been applied in the asymmetric synthesis of chiral amine building blocks. In this work, two IREDs (IR140 and IR189) were identified to catalyze the efficient desymmetrization of biaryls utilizing various amine donors. Further protein engineering enabled the identification of variants (IR189 M8-M9 and IR189 M13-M14) that are able to catalyze the formation of both (R) and (S) atropisomers in excellent yields and atroposelectivities for up to 24 examples (up to 99% ee and yield). The absolute configuration and rotational barriers were confirmed, and the reactions were readily enlarged to allow isolation of the atropisomeric products in 99% ee and 82% isolated yields. The optically pure biaryl amines were further derivatized into various synthetically useful atropisomers. To shed light on the molecular recognition mechanisms, molecular dynamics (MD) simulations were performed, offering plausible explanations for the improved atroposelectivities and enzymatic activities. The current strategy expands the scope of IRED-catalyzed synthesis of axially chiral biaryl amines, contributing significantly to the field of atroposelective biocatalysis.

Amide C–N bonds activation by A new variant of bifunctional N-heterocyclic carbene

We report an organocatalyst that combines a triazolium N-heterocyclic carbene (NHC) with a squaramide as a hydrogen-bonding donor (HBD), which can effectively catalyze the atroposelective ring-opening of biaryl lactams via a unique amide C–N bond cleavage mode. The free carbene species attacks the amide carbonyl, forming an axially chiral acyl-azolium intermediate. Various axially chiral biaryl amines can be accessed by this methodology with up to 99% ee and 99% yield. By using mercaptan as a catalyst turnover agent, the resulting thioester synthon can be transformed into several interesting atropisomers. Both control experiments and theoretical calculations reveal the crucial role of the hybrid NHC-HBD skeleton, which activates the amide via H-bonding and brings it spatially close to the carbene centre. This discovery illustrates the potential of the NHC-HBD chimera and demonstrates a complementary strategy for amide bond activation and manipulation.

Synthesis of Axially Chiral Biaryls through Cobalt(II)-Catalyzed Atroposelective C-H Arylation.

Highly efficient synthesis of axially chiral biaryl amines through cobalt-catalyzed atroposelective C-H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl-2-amines in good yields (up to 99%) with excellent enantioselectivities (up to 99% ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.

Synthesis of Axially Chiral Biaryls through Cobalt(II)‐Catalyzed Atroposelective C−H Arylation

AbstractHighly efficient synthesis of axially chiral biaryl amines through cobalt‐catalyzed atroposelective C−H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl‐2‐amines in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.

Palladium-catalyzed interannular C-H amination of biaryl amines.

A palladium-catalyzed interannular C-H amination of biaryl amines with O-benzoylhydroxylamines is reported. This reaction undergoes smoothly with operational practicality and good tolerance of functional groups, thereby providing a concise synthesis of 2,2'-diaminobiaryls. Moreover, the readily accessible scale-up synthesis and the ability to transform the products into structurally diverse N-containing heterocycles demonstrate the synthetic potential of this catalytic protocol.

Novel biaryl imines and amines as potential competitive inhibitors of dihydropteroate synthase

Antibiotic-resistant bacteria account for over 2.8 million infections and 35,000 deaths annually in the United States. The evolution of new resistant strains necessitates the continued development of new antimicrobial compounds. A target for further pharmaceutical development is the enzyme dihydropteroate synthase (DHPS), which plays a key role in prokaryotic biosynthesis of folic acid. A class of drugs called sulfonamides, including drugs sulfamethoxazole and sulfatrim, bind and act as competitive substrates to p-aminobenzoic acid (pABA), a substrate of DHPS, but are limited by their numerous side effects on the human body and bacterial resistance mutations that block larger molecules from entering the binding pocket. Here, we report the design, combinatorial synthesis, and antibacterial properties of a library of novel biaryl small molecules to target the binding pocket of DHPS. We hypothesize that the synthesized compounds in this study will have strong antibiotic efficacy because of their structural similarities to dihydropteroate, an intermediate in the biosynthesis of folate by the enzyme DHPS. Compounds were first screened in silico via docking to the binding pocket in DHPS. The antibiotic efficacy of these compounds was then tested on three species of bacteria related to human pathogens through a Kirby Bauer assay. Two hit compounds were discovered as having larger radii of inhibition compared to other compounds from the data of the assay. The larger radii of inhibition indicates that the bacteria tested against were susceptible to the use of the hit compounds. The results of the assay establish a definitive structure-activity relationship for the compounds studied and provide a basis for the future development of antibiotics targeting DHPS.

Enantioselective Construction of Axially Chiral Amino Sulfide Vinyl Arenes by Chiral Sulfide‐Catalyzed Electrophilic Carbothiolation of Alkynes

AbstractThe enantioselective construction of axially chiral compounds by electrophilic carbothiolation of alkynes is disclosed for the first time. This enantioselective transformation is enabled by the use of a Ts‐protected bifunctional sulfide catalyst and Ms‐protected ortho‐alkynylaryl amines (Ts=tosyl; Ms=mesyl). Both electrophilic arylthiolating and electrophilic trifluoromethylthiolating reagents are suitable for this reaction. The obtained products of axially chiral vinyl–aryl amino sulfides can be easily converted into biaryl amino sulfides, biaryl amino sulfoxides, biaryl amines, vinyl–aryl amines, and other valuable difunctionalized compounds.

Enantioselective Construction of Axially Chiral Amino Sulfide Vinyl Arenes by Chiral Sulfide-Catalyzed Electrophilic Carbothiolation of Alkynes.

The enantioselective construction of axially chiral compounds by electrophilic carbothiolation of alkynes is disclosed for the first time. This enantioselective transformation is enabled by the use of a Ts-protected bifunctional sulfide catalyst and Ms-protected ortho-alkynylaryl amines (Ts=tosyl; Ms=mesyl). Both electrophilic arylthiolating and electrophilic trifluoromethylthiolating reagents are suitable for this reaction. The obtained products of axially chiral vinyl-aryl amino sulfides can be easily converted into biaryl amino sulfides, biaryl amino sulfoxides, biaryl amines, vinyl-aryl amines, and other valuable difunctionalized compounds.

Development of the Direct Transformations of Aromatic C-H Bonds Using a Heterogeneous Metal Catalyst

Heterogeneous metal catalysts constitute a very important tool for the synthesis of functional materials and fine chemicals owing to their high efficiency, robustness, and facile recyclability. Biaryls are privileged structural motifs in many natural products, chiral ligands, and catalysts. The oxidative biaryl coupling reaction is one of the most promising methods for biaryl synthesis in terms of atom and step economies. However, although oxidative biaryl coupling of naphthols has been studied thoroughly, the coupling of aryl amines providing biaryl amines like 2,2'-diamino-1,1'-binaphthyl (BINAM) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives remains elusive. Recently, we have found that aryl amines are efficiently dimerized with the use of a heterogeneous Rh/C catalyst under acidic conditions. This heterogeneously catalyzed method can be adapted to the highly selective cross-coupling reaction of aryl amines and the intramolecular biaryl coupling reaction. Furthermore, we developed an aerobic direct C-H oxidation of polycyclic aromatics catalyzed by a recyclable heterogeneous rhodium catalyst. These methodologies are advantageous compared with the existing reactions owing to the mild aerobic conditions employed and the facile recyclability of the heterogeneous catalysts used.

Synthesis of Dihydrophenanthridines by Dehydrogenative Coupling

Key words cross-dehydrogenative coupling - dihydro-phenanthridines - aminoalkyl radicals - biaryl amines

Pd(PPh3)4‐Catalyzed Buchwald–Hartwig Amination ofAryl Fluorosulfonates with Aryl Amines

AbstractNovel Buchwald–Hartwig aminations of aryl fluorosulfonates using a catalytic amount of Pd(PPh3)4 in the presence of Cs2CO3 are described. From these reactions, a variety of biaryl amines were obtained in moderate to good yields. This system allows for the efficient amination of aromatic groups containing electron‐rich as well as electron‐poor functional groups. Aryl fluorosulfonates could be applied as alternative cross‐coupling partners to aryl halides in palladium‐catalyzed aminations.

Heterogeneous Rhodium-Catalyzed Aerobic Oxidative Dehydrogenative Cross-Coupling: Nonsymmetrical Biaryl Amines.

The first heterogeneously catalyzed oxidative dehydrogenative cross-coupling of aryl amines is reported herein. 2-Naphthylamine analogues were reacted with various electron-rich arenes using a heterogeneous Rh/C catalyst under mild aerobic conditions, thus affording nonsymmetrical biaryl amines in excellent yields with high selectivities. This reaction provides a mild, operationally simple, and efficient approach for the synthesis of biaryls which are important to pharmaceutical and materials chemistry.

Heterogeneous Rhodium‐Catalyzed Aerobic Oxidative Dehydrogenative Cross‐Coupling: Nonsymmetrical Biaryl Amines

AbstractThe first heterogeneously catalyzed oxidative dehydrogenative cross‐coupling of aryl amines is reported herein. 2‐Naphthylamine analogues were reacted with various electron‐rich arenes using a heterogeneous Rh/C catalyst under mild aerobic conditions, thus affording nonsymmetrical biaryl amines in excellent yields with high selectivities. This reaction provides a mild, operationally simple, and efficient approach for the synthesis of biaryls which are important to pharmaceutical and materials chemistry.

Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce–Smiles Rearrangement

AbstractA new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.

Metal Free Bi(hetero)aryl Synthesis: A Benzyne Truce-Smiles Rearrangement.

A new benzyne transformation is described that affords versatile biaryl structures without recourse to transition‐metal catalysis or stoichiometric amounts of organometallic building blocks. Aryl sulfonamides add to benzyne upon fluoride activation, and then undergo an aryl Truce–Smiles rearrangement to afford biaryls with sulfur dioxide extrusion. The reaction proceeds under simple reaction conditions and has excellent scope for the synthesis of sterically hindered atropisomeric biaryl amines.

ChemInform Abstract: Synthesis of Biaryl Tertiary Amines Through Pd/Norbornene Joint Catalysis in a Remote C—H Amination/Suzuki Coupling Reaction.

Here, we report on an efficient palladium/norbornene-catalyzed domino reaction of aryl halide, O-acyl hydroxylamine (R1R2N-OBz), and aromatic pinacol boronate (R-Bpin), selectively affording a series of biaryl tertiary amines in good to high yields with excellent functional group tolerance. This catalytic reaction provides a new opportunity for the convergent synthesis of biaryl amines from easily accessible starting materials.

Synthesis of biaryl tertiary amines through Pd/norbornene joint catalysis in a remote C-H amination/Suzuki coupling reaction.

Here, we report on an efficient palladium/norbornene-catalyzed domino reaction of aryl halide, O-acyl hydroxylamine (R1R2N-OBz), and aromatic pinacol boronate (R-Bpin), selectively affording a series of biaryl tertiary amines in good to high yields with excellent functional group tolerance. This catalytic reaction provides a new opportunity for the convergent synthesis of biaryl amines from easily accessible starting materials.

Room-Temperature Palladium-Catalyzed Coupling of Heteroaryl Amines with Aryl or Heteroaryl Bromides

Heteroaryl amines readily undergo Buchwald-Hartwig amination reactions with a range of aryl and heteroaryl bromides at room temperature using t-BuXPhos Pd-precatalyst and NaOt-Bu. The pharmaceutically attractive biaryl amines are generally formed in short reaction times (0.5-16 h) and in good to excellent yields.

Insights into the Origins of Configurational Stability of Axially Chiral Biaryl Amines with an Intramolecular N−H−N Hydrogen Bond

Configurationally stable chiral biaryl amines with an intramolecular N-H-N hydrogen bond have been developed. The barriers for racemization are in the range of 19.3-28.2 kcal/mol, which corresponds to the half-lives of racemization of the enantiomers in the range of 7 s to 2 years at 20 degrees C. Enantiomers of some of these compounds were separable by HPLC with chiral stationary phases. The biaryl amines are supposed to have a conformation similar to that of a binaphthyl skeleton, which was indicated by an X-ray crystal analysis of a biaryl amine. The N-H appears at 11.1-13.3 ppm in their (1)H NMR spectrum in CDCl(3), indicating strong hydrogen bonding. Biaryl amines with an extremely strong intramolecular N-H-N hydrogen bond (delta(NH) approximately 13 ppm) were assumed to undergo racemization without cleavage of an N-H-N hydrogen bond, while those with a mediumly strong N-H-N hydrogen bond (delta(NH) approximately 11 ppm) are assumed to undergo racemization via cleavage of an N-H-N hydrogen bond. Hydrogen/deuterium exchange of a chiral biaryl amine was found to proceed without any trace of racemization.

M 3 muscarinic acetylcholine receptor antagonists: SAR and optimization of bi-aryl amines

Exploration of multiple regions of a bi-aryl amine template led to the identification of highly potent M 3 muscarinic acetylcholine receptor antagonists such as 14 (pA 2 = 11.0) possessing good sub-type selectivity for M 3 over M 2. The structure–activity relationships (SAR) and optimization of the bi-aryl amine series are described.