Amine Coupling Partners Research Articles

Direct Aryl C−H Amination with Primary Amines Using Organic Photoredox Catalysis

AbstractThe direct catalytic C−H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C−H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C−N bonds, using primary amines, by direct C−H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron‐rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate.

Dehydrosulfurative C-N Cross-Coupling and Concomitant Oxidative Dehydrogenation for One-Step Synthesis of 2-Aryl(alkyl)aminopyrimidines from 3,4-Dihydropyrimidin-1H-2-thiones.

A method for the synthesis of 2-aryl(alkyl)aminopyrimidines from readily available 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative C-N cross-coupling and concomitant oxidative dehydrogenation under a Pd/Cu catalytic system is described. This reaction protocol provides unprecedented diversity of fully substituted 2-aryl(alkyl)aminopyrimidines in a single step from a wide range of DHPMs and amine coupling partners.

ChemInform Abstract: A General Method for Aminoquinoline‐Directed, Copper‐Catalyzed sp2 C—H Bond Amination.

AbstractPrimary, secondary, and aromatic amines, heterocycles as well as electron‐deficient aromatic and heteroaromatic are employed as amine coupling partners using Cu(OAc)2 or CuCO3·Cu(OH)2 as catalysts and oxygen from the air as the terminal oxidant.

Aryl fluorosulfonates set new electrophile standard

Palladium-catalyzed amination in which an aryl halide or aryl triflate electrophile is coupled with an aryl or alkyl amine is one of the most popular reactions in organic chemistry. Streamlining this fundamental chemistry is hard to do, yet Patrick S. Hanley and coworkers at Dow Chemical have reported a breakthrough by developing an in situ method for generating aryl fluorosulfonates as alternative electrophiles in aminations (ACS Catal. 2016, DOI: 10.1021/acscatal.6b00865). The Dow team and other research groups previously reported using premade aryl fluorosulfonates for Suzuki couplings with aryl boronates. But the team’s one-pot amination method goes further. The researchers treated phenols with sulfuryl fluoride and a base at room temperature followed by addition of an amine coupling partner to create amination products. They found that aryl fluorosulfonates outperform other common electrophiles. In addition, the phenols can be sourced from biobased materials that are less expensive and more sustainab...

Ligand-Controlled Synthesis of Azoles via Ir-Catalyzed Reactions of Sulfoxonium Ylides with 2-Amino Heterocycles.

An iridium-catalyzed method was developed for the synthesis of imidazo-fused pyrrolopyrazines. The presence or absence of a nitrogenated ligand controlled the outcome of the reaction, leading to simple β-keto amine products in the absence of added ligand and the cyclized 7- and 8-substituted-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine products in the presence of ligand. This catalyst control was conserved across a variety of ylide and amine coupling partners. The substrate was shown to act as a ligand for the iridium catalyst in the absence of other ligands via NMR spectroscopy. Kinetic studies indicated that formation of the Ir-carbene was reversible and the slow step of the reaction. These mechanistic investigations suggest that the β-keto amine products form via an intramolecular carbene N-H insertion, and the imidazopyrrolopyrazines form via an intermolecular carbene N-H insertion.

A General Method for Aminoquinoline-Directed, Copper-Catalyzed sp(2) C-H Bond Amination.

An operationally simple and general method for copper-catalyzed, aminoquinoline-assisted amination of β-C(sp(2))-H bonds of benzoic acid derivatives is reported. The reaction employs Cu(OAc)2 or (CuOH)2CO3 catalysts, an amine coupling partner, and oxygen from air as a terminal oxidant. Exceptionally high generality with respect to amine coupling partners is observed. Specifically, primary and secondary aliphatic and aromatic amines, heterocycles, such as indoles, pyrazole, and carbazole, sulfonamides, as well as electron-deficient aromatic and heteroaromatic amines are competent coupling components.

Investigation of Reactive Intermediates and Reaction Pathways in the Coupling Agent Mediated Phos­phonamidation Reaction

AbstractThe preparation of carboxamides through the coupling agent mediated reaction of carboxylic acids and amines is one of the most frequently employed reaction types of modern organic synthesis and has largely replaced older methods of amide formation based on reactive acyl chloride intermediates. However, the preparations of analogous phosphonamidates still rely on the use of phosphonochloridate intermediates – a method that is incompatible with sensitive functional groups. Herein, we present a comprehensive study in which different coupling agents are tested in the phosphonamidation reaction. The procedures, parallel to those typically applied to the preparation of carboxamides, were generally unsuccessful with regard to the coupling reactions of monoesters of phosphonic acids and amines, with the exception of those mediated by (benzotriazol‐1‐yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP). The implementation of a preactivation period in the absence of the amine coupling partner allowed for efficient phosphonamidate formation with coupling agents such as (1‐cyano‐2‐ethyoxy‐2‐oxoethylideneaminooxy)dimethylamino‐morpholino‐carbenium hexafluorophosphate (COMU), [ethyl cyano(hydroxyimino)acetato‐O2]tri‐1‐pyrrolidinylphosphonium hexafluorophosphate (PyOxim), dicyclohexyl carbodiimide (DCC), N,N′‐diisopropylcarbodiimide (DIC), and N,N,N′,N′‐tetramethyl‐O‐(1H‐benzotriazol‐1‐yl)uronium hexafluorophosphate (HBTU). The reactive intermediates observed by 31P NMR analysis were individually synthesized and examined to understand their influence on the reaction.

Design of Modified Amine Transfer Reagents Allows the Synthesis of α-Chiral Secondary Amines via CuH-Catalyzed Hydroamination.

The CuH-catalyzed hydroamination of alkenes and alkynes using a silane and an amine transfer reagent represents a simple strategy to access chiral amine products. We have recently reported methods to prepare chiral amines with high efficiency and stereoselectivity using this approach. However, the current technology is limited to the synthesis of trialkylamines from dialkylamine transfer reagents (R2NOBz). When monoalkylamine transfer reagents [RN(H)OBz] were used for the synthesis of chiral secondary amines, competitive, nonproductive consumption of these reagents by the CuH species resulted in poor yields. In this paper, we report the design of a modified type of amine transfer reagent that addresses this limitation. This effort has enabled us to develop a CuH-catalyzed synthesis of chiral secondary amines using a variety of amine coupling partners, including those derived from amino acid esters, carbohydrates, and steroids. Mechanistic investigations indicated that the modified amine transfer reagents are less susceptible to direct reaction with CuH.

Removable bidentate directing group assisted-recyclable metal–organic frameworks-catalyzed direct oxidative amination of Sp2 C–H bonds

Several Cu-MOFs were showed to be efficient heterogeneous catalysts for ortho-amination of benzoic acid derivative C–H bonds by N–H amines using 8-aminoquinoline as bidentate directing group. The optimal reaction conditions involve the use of Cu-MOFs (25%), N-methylmorpholine oxide (NMO) as an oxidant, secondary or primary amine coupling partner, DMF, DMA, or NMP solvent at 90–100°C. Furthermore, the Cu-MOFs catalyst could be facilely isolated from the reaction mixture and reused several times without remarkable degradation in catalytic reactivity. Contribution from homogeneous leached active copper species, if any, is negligible. To the best of our knowledge, C–H activation reactions using bidentate directing groups, which are increasingly gaining importance, under heterogeneous catalytic systems were not previously mentioned in the literature.

Rational and Predictable Chemoselective Synthesis of Oligoamines via Buchwald–Hartwig Amination of (Hetero)Aryl Chlorides Employing Mor-DalPhos

We report a diverse demonstration of synthetically useful chemoselectivity in the synthesis of di-, tri-, and tetraamines (62 examples) by use of Buchwald-Hartwig amination employing a single catalyst system ([Pd(cinnamyl)Cl](2)/L1; L1 = N-(2-(di(1-adamantyl)phosphino)phenyl)morpholine, Mor-DalPhos). Competition reactions established the following relative preference of this catalyst system for amine coupling partners: linear primary alkylamines and imines > unhindered electron-rich primary anilines, primary hydrazones, N,N-dialkylhydrazines, and cyclic primary alkylamines > unhindered electron-deficient primary anilines, α-branched acyclic primary alkylamines, hindered electron-rich primary anilines ≫ cyclic and acyclic secondary dialkylamines, secondary alkyl/aryl and diarylamines, α,α-branched primary alkylamines, and primary amides. The new isomeric ligand N-(4-(di(1-adamantyl)phosphino)phenyl)morpholine (p-Mor-DalPhos, L2) was prepared in 63% yield and was crystallographically characterized; the [Pd(cinnamyl)Cl](2)/L2 catalyst system exhibited divergent reactivity. Application of the reactivity trends established for [Pd(cinnamyl)Cl](2)/L1 toward the chemoselective synthesis of di-, tri-, and tetraamines was achieved. Preferential arylation was observed at the primary alkylamine position within 2-(4-aminophenyl)ethylamine with [Pd(cinnamyl)Cl](2)/L1 and 4-chlorotoluene (affording 5a); the alternative regioisomer (5a') was obtained when using [Pd(cinnamyl)Cl](2)/L2. These observations are in keeping with coordination chemistry studies, whereby binding of 2-(4-aminophenyl)ethylamine to the in situ generated [(L1)Pd(p-tolyl)](+) fragment occurred via the primary amine moiety, affording the crystallographically characterized adduct [(L1)Pd(p-tolyl)(NH(2)CH(2)CH(2)(4-C(6)H(4)NH(2))](+)OTf(-) (7) in 72% yield.

An Aldol-Based Build/Couple/Pair Strategy for the Synthesis of Medium- and Large-Sized Rings: Discovery of Macrocyclic Histone Deacetylase Inhibitors

An aldol-based build/couple/pair (B/C/P) strategy was applied to generate a collection of stereochemically and skeletally diverse small molecules. In the build phase, a series of asymmetric syn- and anti-aldol reactions were performed to produce four stereoisomers of a Boc-protected γ-amino acid. In addition, both stereoisomers of O-PMB-protected alaninol were generated to provide a chiral amine coupling partner. In the couple step, eight stereoisomeric amides were synthesized by coupling the chiral acid and amine building blocks. The amides were subsequently reduced to generate the corresponding secondary amines. In the pair phase, three different reactions were employed to enable intramolecular ring-forming processes: nucleophilic aromatic substitution (S(N)Ar), Huisgen [3+2] cycloaddition, and ring-closing metathesis (RCM). Despite some stereochemical dependencies, the ring-forming reactions were optimized to proceed with good to excellent yields, providing a variety of skeletons ranging in size from 8- to 14-membered rings. Scaffolds resulting from the RCM pairing reaction were diversified on the solid phase to yield a 14 400-membered library of macrolactams. Screening of this library led to the discovery of a novel class of histone deacetylase inhibitors, which display mixed enzyme inhibition, and led to increased levels of acetylation in a primary mouse neuron culture. The development of stereo-structure/activity relationships was made possible by screening all 16 stereoisomers of the macrolactams produced through the aldol-based B/C/P strategy.

Development of a Scalable Synthesis of Dipeptidyl Peptidase-4 Inhibitor ABT-279

A convergent, scalable synthesis of dipeptidyl peptidase-4 inhibitor, ABT-279, has been developed and demonstrated on multikilogram scale. The cis-2,5-disubstituted pyrrolidine is generated by cyclization of a Boc-amine onto an alkynyl ketone followed by stereospecific reduction of the resulting acyliminium intermediate. The amine coupling partner was prepared by a novel Hofmann rearrangement promoted by 1,3-dibromo-5,5-dimethylhydantoin. The final product was isolated as the l-malic acid salt. The scale-up campaign consisted of 15 steps and delivered 42 kg of ABT-279 in 14% overall yield. A second-generation synthesis that addresses some of the issues encountered during scale-up was developed and demonstrated on kilogram scale.

An Air‐Stable Palladium/N‐Heterocyclic Carbene Complex and Its Reactivity in Aryl Amination.

AbstractFor Abstract see ChemInform Abstract in Full Text.

An Air-Stable Palladium/N-Heterocyclic Carbene Complex and Its Reactivity in Aryl Amination

[reaction: see text] The synthesis and characterization of [Pd(IPr)Cl(2)](2) (1), an air- and moisture-stable complex, is reported. The utilization of 1 as a catalyst for amination of aryl chlorides and bromides with a variety of amine coupling partners under mild conditions is described. The amination reactions with 1 show a remarkable insensitivity to oxygen and water, and thus the amination reactions could be performed in air on the benchtop with undried reagent grade solvents and substrates with small effects on reaction times and conversions.

Catalysis of carbamate hydrolysis by vancomycin and semisynthetic derivatives

The semisynthesis of vancomycin (1a) derivatives bearing propyl (1b), histaminyl (1c), and 3-aminopropyl (1c) groups attached to the C-terminus is reported. This work was undertaken as part of a program to create new biomimetic catalysts and to ulimately test the relative potencies of antibiotics that act stoichiometrically versus catalytically against a common target. 1b-d were prepared by dicyclohexylcarbodiimide-mediated condensations between vancomycin's carboxyl group and amine coupling partners and were found to bind to N α ,N ω -diacetyl-L-Lys-D-Ala-D-Ala (2a, a tripeptide analogue of the C-terminus of the Staphyloccus aureus cell wall precursor) with affinities similar to that observed with 1a