Aniline Nucleophiles Research Articles

Synthesis of 1,2,5-substituted pyrrole derivatives by a modification of the Reisch-Schulte reaction

A synthesis method was developed for the formation of several 1,2,5-substituted pyrrole derivatives and were characterized by NMR, IR, UV–Vis spectroscopies and HRMS. This method involves adding aniline derivatives to a dialkyne, catalyzed by Cu(I) and is carried out under modified Reisch-Schulte protocol by adding N,N,N′,N′-tetramethylethylenediamine (TMEDA). Notably, the reaction does not proceed in absence of TMEDA. The yields of synthesized pyrroles ranged from quantitative to acceptable ones. Generally, the reaction yields correlated well with the Global nucleophilicities (GN) of the aniline reagents obtained from theoretical calculations; more nucleophilic anilines resulted in higher yields, except para-anisidine, the molecule with the biggest GN value. Mechanistic explications of the observed effects were proposed. Additionally, experimental studies and theoretical simulation showed that the novel pyrrole molecules had semiconducting properties since their band gap energy (Eg) lied within the range typical for organic semiconductors. It was observed that the presence of electron-withdrawing groups led to a significant decrease in the Eg value.

Synthesis of Anilides by Aminolysis of Unactivated Esters using MnCl2 in Combination with strong Bases as Catalyst

AbstractAnilides are often found in pharmaceuticals and active ingredients in crop protection. Although of great interest, the atom‐ and step economic formation of the amide bond between a less nucleophilic aniline with an acid or ester remains still a major challenge. Herein, we report an aminolysis of aromatic and alkyl esters with anilines catalyzed by a readily available catalytic system comprising of an earth‐abundant Mn‐salt in combination with an inexpensive base.

Total synthesis of (+)-asperazine A: A stereoselective domino dimerization

<h2>Summary</h2> The concise total synthesis of (+)-asperazine A, bearing unsymmetrical C3–N1′ linkage, was achieved stereoselectively via an unprecedented 4<i>N</i>-based cascade linkage. Umpolung from nucleophilic aniline (N¹) to electrophilic <i>N</i>-iodoaniline was implemented via oxidant iodine cation, released steadily by Ni-catalyzed keto/enol-tautomerism ring-opening of 1,3-dicarbonyl iodomethylcyclopropane. It triggered the condensation via <i>endo</i>-attack by enamine (N²) followed by the addition of aniline (N³) for the key quaternization at C3 position. The proton generated in the first cyclization initiates the isomerism from enamine (N⁴) to iminium, followed by the addition from aniline (N¹). The unsymmetrical dimer <b>4</b> was acquired via ring-reopening (N⁴) driven by the thermodynamic stability of indole aromatization. This domino process assembles four distinct "N"s in sequence to achieve the aniline-dihydro-pyrrole dimerization-isomerization, efficiently establishing a 22-membered library of asperazine A scaffolds. Control experiments and density functional theory calculations supported the electrophilic <i>N</i>-iodoaniline pathway and elucidated the highly <i>endo</i>-selective preference.

Rhodium-/Iridium-Catalyzed Hydroamination for the Synthesis of 1,2-, 1,3-, or 1,4-Diamines.

An Ir-catalyzed regioselective hydroamination of allyl amines using aryl amines and catalyst-controlled regiodivergent hydroamination of allylic and homoallylic amines with aniline nucleophiles are reported. The directed hydroamination reactions afford a variety of 1,2-, 1,3-, and 1,4-diamines in good to excellent yields and high regio- and chemoselectivities. Mechanistic investigations suggests that the reactions are proceeding through an oxidative addition into the ArHN-H bond and that the observed regioselectivity is due to the selective formation of a 5- or 6-membered metalacyclic intermediate, depending on the catalyst employed.

Photoinduced, Copper-Catalyzed Enantioconvergent Alkylations of Anilines by Racemic Tertiary Electrophiles: Synthesis and Mechanism.

Transition-metal catalysis of substitution reactions of alkyl electrophiles by nitrogen nucleophiles is beginning to emerge as a powerful strategy for synthesizing higher-order amines, as well as controlling their stereochemistry. Herein, we report that a readily accessible chiral copper catalyst (commercially available components) can achieve the photoinduced, enantioconvergent coupling of a variety of racemic tertiary alkyl electrophiles with aniline nucleophiles to generate a new C-N bond with good ee at the fully substituted stereocenter of the product; whereas this photoinduced, copper-catalyzed coupling proceeds at -78 °C, in the absence of light and catalyst, virtually no C-N bond formation is observed even upon heating to 80 °C. The mechanism of this new catalytic enantioconvergent substitution process has been interrogated with the aid of a wide array of tools, including the independent synthesis of proposed intermediates and reactivity studies, spectroscopic investigations featuring photophysical and EPR data, and DFT calculations. These studies led to the identification of three copper-based intermediates in the proposed catalytic cycle, including a chiral three-coordinate formally copper(II)-anilido (DFT analysis points to its formulation as a copper(I)-anilidyl radical) complex that serves as a persistent radical that couples with a tertiary organic radical to generate the desired C-N bond with good enantioselectivity.

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Diarylation of N- and O-nucleophiles through a metal-free cascade reaction

Thermal grafting of aniline derivatives to silicon (1 1 1) hydride surfaces

Through a series of aniline derivatives with para-substituents possessing different electron donating/withdrawing characteristics, we examined the nature of thermal grafting of these nucleophilic anilines onto planar Silicon (111) surfaces via detailed XPS and AFM analysis. Based on our current results, para-positioned electron withdrawing group (4-Trifluoromethylaniline) would draw electron density away from the nucleophilic NH2 site which consequently reduces surface grafting. We also concluded that para-positioned halide (Cl and Br) may produce inductive effect that significantly reduces nucleophilic grafting of the NH2 to the silicon hydride while their bulky distal groups may further limited packing density on the surface. On the other hand, 1,3-diaminopropane (control) as well as Phenylenediamine were found to be highly reactive to the surface due to high electron density confinement at the NH2 groups. Furthermore, grafting of aromatic phenylenediamine was observed to have significantly lowered the underlying Si-Si back bonding lysis. Our results and proposed mechanisms were complemented by AFM surface interrogation, contact angle measurements, ATR-FTIR as well as DFT optimized electrostatic potential presentation. Herein, this study presents an in-depth view on molecular grafting through deliberate modulation of the electron density distribution around aromatic system and this may present an important insight towards producing useful bifunctional monolayers.

Preparation of 6-aminocyclohepta-2,4-dien-1-one Derivatives via Tricarbonyl(tropone)iron.

aza-Michael adducts of tricarbonyl(tropone)iron are synthesized by two different methods. Primary aliphatic amines and cyclic secondary amines participate in a direct aza-Michael reaction with tricarbonyl(tropone)iron under solvent-free conditions. Less nucleophilic aniline derivatives and more hindered secondary amines add efficiently to the cationic tropone complex formed by protonation of tricarbonyl(tropone)iron. While the protocol utilizing the cationic complex is less efficient overall for accessing the aza-Michael adducts than the direct, solvent-free addition to the neutral complex, it allows the use of a broader range of amine nucleophiles. Following protection of the amine of the aza-Michael adduct as a tert-butyl carbamate, the diene is decomplexed from the iron tricarbonyl fragment upon treatment with cerium(IV) ammonium nitrate to provide derivatives of 6-aminocyclohepta-2,4-dien-1-one. These products can serve as precursors to diverse compounds containing a seven-membered carbocyclic ring. Because the demetallation requires protection of the amine as a carbamate, the aza-Michael adducts of secondary amines cannot be decomplexed using the protocol described here.

TBAB‐Catalyzed Csp3–N Bond Formation by Coupling Pyridotriazoles with Anilines: A New Route to (2‐Pyridyl)alkylamines

A new metal‐free procedure allowing Csp3–N bond formation through coupling of pyridotriazoles and weakly nucleophilic anilines has been developed. This sustainable reaction shows high tolerance towards functional groups (ketones, free alcohols) leading to 2‐picolylamine derivatives. The key to our success is the use of a catalytic amount of TBAB and water as a co‐solvent leading to the formation of pyridylalkylamine derivatives. As this coupling tolerates the presence of Csp2–Br bond on both partners of the reaction, we performed a sequential one‐pot reaction between functionalized triazolopyridines and anilines followed by a second coupling with N‐tosylhydrazones leading to the formation of Csp3–N and Csp2–Csp2 bonds.

Catalytic direct amidations in tert-butyl acetate using B(OCH2CF3)3.

Catalytic direct amidation reactions have been the focus of considerable recent research effort, due to the widespread use of amide formation processes in pharmaceutical synthesis. However, the vast majority of catalytic amidations are performed in non-polar solvents (aromatic hydrocarbons, ethers) which are typically undesirable from a sustainability perspective, and are often poor at solubilising polar carboxylic acid and amine substrates. As a consequence, most catalytic amidation protocols are unsuccessful when applied to polar and/or functionalised substrates of the kind commonly used in medicinal chemistry. In this paper we report a practical and useful catalytic direct amidation reaction using tert-butyl acetate as the reaction solvent. The use of an ester solvent offers improvements in terms of safety and sustainability, but also leads to an improved reaction scope with regard to polar substrates and less nucleophilic anilines, both of which are important components of amides used in medicinal chemistry. An amidation reaction was scaled up to 100 mmol and proceeded with excellent yield and efficiency, with a measured process mass intensity of 8.

Synthesis of Mono‐substituted Anthraquinone Derivatives to be Used in the Purification of Lactate Dehydrogenase

Cibacron Blue 3G‐A has been previously used in biochemical laboratories for purification of enzymes containing the dinucleotide fold. Lactate dehydrogenase is one such enzyme that can be purified using Cibacron Blue 3G‐A in affinity chromatography. Rising costs and inaccessibility to Cibacron Blue 3G‐A have created a demand to find a more cost effective replacement. Electron withdrawing and donating properties of the anthraquinone core substituent groups are believed to affect the affinity of the core for various enzymes. A range of anthraquinone dyes were synthesized to determine the importance of the substituents' electronic properties with the coupling of ortho substituted aniline nucleophiles to the anthraquinone core via a diazonium salt link. The aniline substituents include: methyl, methoxy, chloro, and sulfonyl groups. For each anthraquinone dye synthesized, the λmax value was determined to effectively monitor the kinetics of the dyes. Spectrometric assays measured the oxidation of NADH to NAD+ determining the dye's affinity for enzymes containing the dinucleotide fold.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Diastereoselective Synthesis and Diversification of Highly Functionalized Cyclopentanones

An efficient entry into highly substituted cyclopentanones is presented based on functionalizing cyclopentenones by means of an aza-Michael reaction with different aniline nucleophiles. The excellent diastereoselectivity of this process is ascribed to H-bonding between a tertiary alcohol and the incoming nucleophiles. Additionally, the functionalization of the parent cyclopentenones via the Baylis–Hillman reaction is demonstrated. Together, these transformations showcase the elaboration of a simple precursor by installation of versatile functionalities at either the α- or β-position of the embedded enone and thus represent valuable methods for the construction of diversely functionalized cyclopentanones.

Catalytic, Enantioselective, Intramolecular Sulfenoamination of Alkenes with Anilines.

A method for the catalytic, enantioselective, intramolecular sulfenoamination of alkenes with aniline nucleophiles has been developed. The method employs a chiral, Lewis basic selenophosphoramide catalyst and a Brønsted acid co-catalyst to promote stereocontrolled C–N and C–S bond formation by activation of an achiral sulfenylating agent. Benzoannulated nitrogen-containing heterocycles such as indolines, tetrahydroquinolines, and tetrahydrobenzazepines were prepared with high to excellent enantioselectivities. The impact of tether length and electron density of both the nucleophile and olefin on the reactivity, site selectivity, and enantioselectivity were investigated and interpreted in terms of substrate-dependent stereodetermining thiiranium ion formation or capture.

ChemInform Abstract: Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)—H and C(sp2)—H under Rhodium(III) Catalysis.

AbstractAnthranil is designed as novel bifunctional aminating reagent for both C(sp2)—H and C(sp3)—H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl.

Phenyl (2‐quinolyl) methanol: A Valuable Reagent for Metal‐Free Reduction of Aromatic Nitro Compounds and Imines

AbstractPhenyl (2‐quinolyl) methanol (PQM) behaves as a new efficient reagent for metal‐free reduction of nitro aromatic and heteroaromatic compounds. The reduction proceeds in mild reaction conditions affording anilines in good yields. Phenyl (2‐quinolyl) ketone (PQK), the oxidation product of PQM, can be quantitatively recovered and reused after reduction making sustainable the overall process. The reduction outcome changes with electron‐deficient nitroarenes that afford the expected anilines and electron‐rich nitro compounds that give reductive amination products via reduction of imines formed by condensation of nucleophilic anilines with PQK. These multicomponent reactions were observed also with activated aldehydes and in the presence of acrylates for the synthesis of β‐anilino esters. The synthetic value of the new metal‐free reducing agent, unmatched by the well‐known Hantzsch ester, has been exploited in metal‐free Reissert indole and Friedländer quinoline syntheses.

ChemInform Abstract: Microwaves and Aqueous Solvents Promote the Reaction of Poorly Nucleophilic Anilines with a Zincke Salt.

AbstractThe reaction tolerates a wide range of functional groups and delivers the arylpyridinium chloride products in generally high yields.

ChemInform Abstract: Rhodium‐Catalyzed Oxidative Amidation of Allylic Alcohols and Aldehydes: Effective Conversion of Amines and Anilines into Amides.

The rhodium-catalyzed oxidative amidation of allylic alcohols and aldehydes is reported. In situ generated [(BINAP)Rh]BF4 catalyzes the one-pot isomerization/oxidative amidation of allylic alcohols or direct amidation of aldehydes using acetone or styrene as the hydrogen acceptor. The conditions are general, affording good to excellent yields with a wide array of amine and aniline nucleophiles, and chemoselective, other alcohols do not participate in the oxidation reaction. Utilization of biphasic conditions is critical, as they promote an equilibrium between the imine/enamine byproducts and the hemiaminal, which can undergo oxidation to the amide.

Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp(3) )-H and C(sp(2) )-H under Rhodium(III) Catalysis.

Previous direct C-H nitrogenation suffered from simple amidation/amination with limited atom-economy and is mostly limited to C(sp(2) )-H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp(2) )-H and C(sp(3) )-H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.

Anthranil: An Aminating Reagent Leading to Bifunctionality for Both C(sp3)−H and C(sp2)−H under Rhodium(III) Catalysis

AbstractPrevious direct C−H nitrogenation suffered from simple amidation/amination with limited atom‐economy and is mostly limited to C(sp2)−H substrates. In this work, anthranil was designed as a novel bifunctional aminating reagent for both C(sp2)−H and C(sp3)−H bonds under rhodium(III) catalysis, thus affording a nucleophilic aniline tethered to an electrophilic carbonyl. A tridendate rhodium(III) complex has been isolated as the resting state of the catalyst, and DFT studies established the intermediacy of a nitrene species.

Microwaves and Aqueous Solvents Promote the Reaction of Poorly Nucleophilic Anilines with a Zincke Salt.

The Zincke reaction allows the transformation of primary amines into their respective N-alkylated or N-arylated pyridinium salts. While nucleophilic primary amines (typically, aliphatic primary amines) often lead to quantitative reactions and has been documented profusely, the use of poorly nucleophilic amines still requires an in depth account. To date, the lack of nucleophilicity of the amines is redhibitory. The subject addressed in this article is a series of primary amines deriving from aniline having been engaged in Zincke reactions. Efficient transformations were obtained, even when conducted on electronically deactivated, eventually also sterically hindered, substrates. This was achieved by the combined use of microwave activation and aqueous solvents. Under our conditions, the role of water revealed indeed crucial to avoid the self-degradation of the Zincke salt, the reagent of the reaction.