Aryl Amino Research Articles

Remote sp3 C–H Amination of Alkenes with Nitroarenes

Summary Direct installation of a functional group at remote, unfunctionalized sites in an alkyl chain is a synthetically valuable but rarely reported process. The remote relay hydroarylamination of distal and proximal olefins, and of olefin isomeric mixtures, has been achieved through NiH-catalyzed alkene isomerization and sequential reductive hydroarylamination with nitroarenes. This provides an attractive approach to the direct installation of a distal arylamino group within alkyl chains. The single-step conversion of simple olefins and nitro(hetero)arenes to value-added arylamines is a practical strategy for amine synthesis as well as the remote activation of sp3 C–H bonds. The value of this transformation is further supported by the regioconvergent arylamination of isomeric mixtures of olefins.

Β-Arylamino Functionalized Porphyrins: Regioselective Synthesis, Structural, Photophysical and Electrochemical Properties

Among the different approaches for β-functionlization of poprhyrins, a limited number of β-arylamino functionalized poprhyirns were reported.1 Porhyrins and metallopoprhyrins that consist arylamino group have exhibited unique physiochemical and electrochemical redox properties and utilized for various applications such as dye-sensitized solar cells (DSSCs), catalysis, and nonlinear optics.2 In this regard, we report the regioselective synthesis of 2-arylamino-12,13-dibromo-5,10,15,20-tetraphenylporphyrins and their metal (Cu(II) and Zn(II)) complexes (Fig. 1a). The palladium catalyzed coupling reaction of tetrabromoporphyrin with substituted anilines yielded various mono-β-arylamino substituted poprhyrins. All β-arylamino porphyrins were characterized by UV-Vis, fluorescence, 1H NMR spectroscopic techniques and cyclic voltammetry studies. β-arylamino porphyrins exhibited broadened absorption spectra which consist one Soret and two Q bands as shown in Fig. 1b. Notably, β-arylamino porphyrins exhibited multiple oxidations and reductions due to 'push-pull' β-substituents which alters the energy levels of frontier molecular orbitals. DFT studies revealed that these porphyrins are having quasiplanar confirmation. In this presentation, we will discuss about the regioselective synthesis, spectral, electrochemical redox properties of β-arylamino functionalized porphyrins in detail. Figure 1

1,3-Diaza[3]ferrocenophanes functionalized with a nitronyl nitroxide group

An aza-Wittig reaction of 1,1′-bis(triphenylphosphoranylidenamino)-ferrocene with 4-iodo-, 2,5-difluoro-4-iodo-, pentafluoro-, or 4-methoxycarbonylphenylisocyanates is described here. Intermediate betaines, which are products of a nucleophilic attack of the nitrogen atom of the remaining iminophosphorane moiety on the carbon atom of the carbodiimide functional group, were isolated; their structures were proved by monocrystal X-ray diffraction. Hydrolysis of the betaines under mild conditions gave corresponding arylamino-1,3-diaza[3]ferrocenophanes. On the other hand, as demonstrated, under more rigid conditions, the betaines could be converted into ferrocenophanes with the 1,3-diazetidine-2,4-diimine coupler. The iodo- or diiodo-derivatives of 1,3-diaza[3]ferrocenophanes were cross-coupled with a nitronyl nitroxide-2-ide gold(I) complex to obtain corresponding metallocenophanes functionalized with the nitronyl nitroxide group(s). The molecular and crystal structures of the halogenated and spin-labeled ferrocenophanes were solved by X-ray analysis. In arylamino-1,3-diaza[3]ferrocenophanes, according to cyclic voltammetry, the position of the quasi-reversible oxidation peak associated with the Fe(II)/Fe(III) redox couple deviates within 0.09 V depending on substituents in the arylamino group.

An efficient and atom-economical route to N-aryl amino alcohols from primary amines.

In this paper we reported a novel method for generation of N-aryl amino alcohols from N,N-disubstituted picolinamides through reduction/ring-opening reaction with NaBH4. The N,N-disubstituted picolinamides can be easily obtained from primary amines after convenient condensation with picolinic acid and coupling with cyclic ethers. The whole route proceeded under simple and mild conditions with high efficiency. Picolinic acid can be recovered in the form of piconol after reaction. It indicated an efficient and atom-economical route for the preparation of N-aryl amino alcohols from primary amines.

Molecular docking and glucosidase inhibition studies of novel N-arylthiazole-2-amines and Ethyl 2-[aryl(thiazol-2-yl)amino]acetates

This study describes an efficient synthesis of a series of novel ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a–l) from N-arylthiazole-2-amines (3a–l). The reaction conditions were optimized and the best results were obtained when ethyl chloroacetate was used as alkylating agent and NaH as base in THF. α-glucosidase and β-glucosidase inhibition activities of N-arylthiazole-2-amines (3a–l) and ethyl 2-[aryl(thiazol-2-yl)amino]acetates (4a–l) were determined, which revealed that most of the compounds showed high percentage inhibition towards the enzymes. Among the synthesized compounds, 4e appeared to have the highest inhibition towards α-glucosidase having IC50 value of 150.4 ± 1.9 μM which was almost two folds as compared to acarbose (336.9 ± 9.0 μM) taken as standard. Molecular docking of the compounds 3g, 3f, 4a, and 4e was also performed which showed their bonding modes to the enzyme’s active sites via amino and acetate groups, respectively.

Chiral phosphite-type ligands based on ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) ((R,R)-TADDOL) with peripheral arylamino groups

New phosphite and amidophosphite inductors of chirality were obtained based on ((4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol) ((R,R)-TADDOL) containing arylamino groups in the exocyclic substituents. Their use in the palladium-catalyzed enantioselective alkylation of (E)-1,3-diphenylallyl acetate with dimethyl malonate gave the ee value up to 98%.

Synthesis and biological evaluation of new C-12(α/β)-(N-) sulfamoyl-phenylamino-14-deoxy-andrographolide derivatives as potent anti-cancer agents

Andrographolide, the major diterpenoidal constituent of Andrographis paniculata (Acanthaceae) and its derivatives have been reported to possess plethora of biological properties including potent anti-cancer activity. In this work, synthesis and in-vitro anti-cancer evaluation of new C-12-substituted aryl amino 14-deoxy-andrographolide derivatives (III a–f) are reported. The substitutions include various sulfonamide moieties –SO2-NH-R1. The new derivatives (III a–e) exhibited improved cytotoxicity (GI50, TGI and LC50) compared to andrographolide (I) and the corresponding 3,14,19-O-triacetyl andrographolide (II) when evaluated against 60 NCI cell line panel. Compounds III c and III e are found to be non-toxic to normal human dermal fibroblasts (NHDF) cells compared to reference drug THZ-1.

Redox-active and electrochromic polymers from triarylamine end-capped, 2,7-bis(diphenylamino)naphthalene-cored dicarboxamides

Two N-phenylcarbazole and triphenylamine end-capped, 2,7-bis(diphenylamino)naphthalene-cored dicarboxamides were prepared by the condensation reactions from N,N′-bis(4-aminophenyl)-N,N′-bis(4-methoxyphenyl)-2,7-naphthalenediamine with two equivalent amount of N-(4-carboxyphenyl)carbazole and 4-carboxytriphenylamine, respectively. These two dicarboxamides can be electropolymerized into electroactive films on the electrode surface in an electrolyte solution via the oxidative coupling reactions between the terminal arylamino groups. The electro-generated polymer films exhibited reversible electrochemical oxidation processes and strong color changes upon electro-oxidation, which can be switched by potential modulation. The electrochromic films did not delaminate from the electrode surface upon cycling electrochemically between their neutral and oxidized states.

The role of 5-arylalkylamino- and 5-piperazino- moieties on the 7-aminopyrazolo[4,3-d]pyrimidine core in affecting adenosine A1 and A2A receptor affinity and selectivity profiles

New 7-amino-2-phenylpyrazolo[4,3-d]pyrimidine derivatives, substituted at the 5-position with aryl(alkyl)amino- and 4-substituted-piperazin-1-yl- moieties, were synthesized with the aim of targeting human (h) adenosine A1 and/or A2A receptor subtypes. On the whole, the novel derivatives 1–24 shared scarce or no affinities for the off-target hA2B and hA3 ARs. The 5-(4-hydroxyphenethylamino)- derivative 12 showed both good affinity (Ki = 150 nM) and the best selectivity for the hA2A AR while the 5-benzylamino-substituted 5 displayed the best combined hA2A (Ki = 123 nM) and A1 AR affinity (Ki = 25 nM). The 5-phenethylamino moiety (compound 6) achieved nanomolar affinity (Ki = 11 nM) and good selectivity for the hA1 AR. The 5-(N4-substituted-piperazin-1-yl) derivatives 15–24 bind the hA1 AR subtype with affinities falling in the high nanomolar range. A structure-based molecular modeling study was conducted to rationalize the experimental binding data from a molecular point of view using both molecular docking studies and Interaction Energy Fingerprints (IEFs) analysis.

Synthesis and structure of 3-{[aryl (hetaryl)amino]methylene}chromane-2,4-diones and their metal complexes

3-{[Aryl(hetaryl)amino]methylene}chromane-2,4-diones (HL) were synthesized and used for chemical and electrochemical synthesis of Cu(II), Ni(II), and Co(II) complexes of the general formula ML2, as well as the ZnLOOCCH3 complex. The structure of the complexes was studied by IR, 1Н NMR, and X-ray absorption spectroscopy. Density functional theory (DFT) calculations showed that the energetically most favored form of compounds HL is an aminoketone tautomeric form. The crystal structure of the solvate of bis-{3-[(4-methylanilinato)methylene]chromane-2,4-dionato}copper(II) with two DMF molecules was determined by X-ray diffraction analysis.

Substrate-Controlled Selectivity Switch in the Three-Component Coupling Involving Arynes, Aromatic Tertiary Amines, and CO2.

The transition-metal-free multicomponent coupling involving arynes, aromatic tertiary amines, and CO2 is reported. The reaction exhibits switchable selectivity depending on the electronic nature of the aromatic amines used. With amines bearing electron-releasing/neutral groups as the nucleophilic trigger, the reaction afforded 2-arylamino benzoates via a nitrogen to oxygen alkyl group migration. Employing electron-deficient amines in the reaction furnished 2-aminoaryl benzoates proceeding via the aryl to aryl amino group migration resembling a Smiles rearrangement.

Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new σ1 receptor (σ1R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based σ1 ligands, the three-dimensional homology model of the σ1R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the σ1R binding cavity was explored, and the effect on σ1R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward σ1 and σ2 receptors were tested. Finally, a representative series of best σ1R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as σ1R agents, as they were found endowed with the highest σ1R affinity (Kiσ1 values in the range 0.95–9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a σ1R agonist behavior.

Facile fabrication of redox‐active and electrochromic poly(amide‐amine) films through electrochemical oxidative coupling of arylamino groups

ABSTRACTTwo novel electropolymerizable monomers, namely 3,5‐bis(4‐diphenylaminobenzamido)‐N‐[4‐(carbazol‐9‐yl)phenyl]benzamide (5) and 3,5‐bis(4‐diphenylaminobenzamido)‐N‐[4‐(3,6‐dimethoxycarbazol‐9‐yl)phenyl]benzamide (5‐MeO), were synthesized, and their electrochemical properties were studied by cyclic voltammetry. The electron‐withdrawing amide groups efficiently blocked the radical cations delocalization between the two terminal TPA groups, rendering the electropolymerization of the TPA groups feasible. The polymer electrodeposited from monomer 5 could be further crosslinked through electro‐coupling of the carbazole groups, which showed both electrochromic and fluorescent properties (the emission of blue light (460 nm) in solid state). Both of the electro‐generated polymer films derived from 5 and 5‐MeO showed reversible electrochemical oxidation processes in the range of 0 − 1.4 V with strong color changes and high contrast ratios in the visible and NIR regions upon electro‐oxidation. © 2016 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. 2016, 54, 2476–2485

ChemInform Abstract: A New and Facile Synthesis of Novel Pyrazolothienopyrimidines and Imidazopyrazolothienopyrimidines.

4-Amino-3-methyl-1-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxamide (5), which was synthesized by an innovative method, was used as a versatile precursor for synthesizing pyrazolothienopyrimidines and imidazopyrazolothienopyrimidines compounds. Reaction of amino thienopyrazole carboxamide 5 with triethyl orthoformate afforded thienopyrazolopyrimidine 6. Chlorination of the latter compound, using phosphorus oxychloride afforded the chloro pyrazolothienopyrimidine 7, which underwent nucleophilic substitution reactions with various primary and secondary amines to give the alkyl (aryl) amino pyrimidine compounds 8a–d. On the other hand, the reaction of chloropyrimidine 7 with thiourea afforded the pyrimidine thione compound 9, which was alkylated with α-halogentaed compounds to afford the S-alkylated derivatives 10a–c. Also, chloroacetylation of the amino carboxamide 5 using chloroacetyl chloride yielded the chloromethyl pyrazolothienopyrimidine 12, which underwent nucleophilic substitu- tion reactions with various primary and secondary amines to afford the alkyl (aryl) aminomethyl compounds 13a–f. The latter Compounds underwent Mannich reaction to give imidazopyrimidothieno- pyrazoles 14a–c. The newly synthesized compounds and their derivatives were fully characterized by elemental and spectral analysis.

ChemInform Abstract: Three‐Component Coupling Involving Arynes, Aromatic Tertiary Amines, and Aldehydes via Aryl—Aryl Amino Group Migration.

Abstract2‐Functionalized tertiary amines are rapidly synthesized.

Synthesis, Characterization and Antimicrobial Evaluation of Schiff’s Base and Aryl Aminomethyl Derivatives

Schiff’s bases are obtained on heating an aldehydes with aromatic amine in presence of glacial acetic acid. These are the compounds containing characteristic –HC=N– group. Aryl amino methyl derivatives of heterocyclic compounds to synthesize by selective reduction of schiff’s bases (imine group) with sodiumborohydride in controlled experimental condition. Schiff’s base of N-Aryl-1-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methanimines & Aryl amines of N-Aryl-1-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methanamines were prepared. Their chemical structures were confirmed by means of IR, NMR, Mass data and by elemental analysis. All of the synthesized compounds were tested for their antibacterial and antifungal activity.

Synthesis, Characterization and Antimicrobial Evaluation of Schiff’s Base and Aryl Aminomethyl Derivatives

Schiff’s bases are obtained on heating an aldehydes with aromatic amine in presence of glacial acetic acid. These are the compounds containing characteristic –HC=N– group. Aryl amino methyl derivatives of heterocyclic compounds to synthesize by selective reduction of schiff’s bases (imine group) with sodiumborohydride in controlled experimental condition. Schiff’s base of N-Aryl-1-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methanimines & Aryl amines of N-Aryl-1-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]methanamines were prepared. Their chemical structures were confirmed by means of IR, NMR, Mass data and by elemental analysis. All of the synthesized compounds were tested for their antibacterial and antifungal activity.

Discovery of spirocyclic proline tryptophan hydroxylase-1 inhibitors

The central role of the biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) as a neurotransmitter with important cognitive and behavioral functions is well known. However, 5-HT produced in the brain only accounts for approximately 5% of the total amount of 5-HT generated in the body. At the onset of our work, it appeared that substituted phenylalanine derivatives or related aryl amino acids were required to produce potent inhibitors of TPH1, as significant losses of inhibitory activity were noted in the absence of this structural element. We disclose herein the discovery of a new class of TPH1 inhibitors that significantly lower peripherally 5-HT.

Isocyanide-based three component reaction for synthesis of highly cyano substituted furan derivatives

A rapid and efficient solvent-free one-pot synthesis of novel alkyl amino aryl furan tricarbonitrile derivatives is described under catalyst-free conditions.

Three-Component Coupling Involving Arynes, Aromatic Tertiary Amines, and Aldehydes via Aryl-Aryl Amino Group Migration.

The transition-metal-free multicomponent coupling of arynes, aromatic tertiary amines, and aldehydes proceeding via the aryl to aryl amino group migration has been demonstrated. This protocol allows rapid access to ortho-functionalized tertiary amines in moderate to good yields. Moreover, activated ketones can also be used as the aldehyde component in the present reaction. The similarity of the aryl-aryl tertiary amino group migration with the Smiles rearrangement is striking.