Heteroaryl Amines Research Articles

Synthesis and Antimicrobial Efficacy of Some Novel Heterocyclic Acetyl Istain Derivatives

A series of novel heterocyclic compounds containing N-acetyl isatine moiety were synthesized. Herein, reaction of N-acetyl isatine with water in the presence of a catalytic amount of glacial acetic acid, via a ring opening route, yielded 2-(2-acetamidophenyl)-2-oxoaceticacid,which acts as an adjustable precursor with different heteroaryl amines such as aniline, 2-amino pyridine, 5-amino-1,3,4-thiadiazole-2-thiol,phenylhydrazeine, for the preparation of different schiff bases. Furthermore, acetamide derivatives were prepared via the ring opening path of N-acetyl isatin, by the interaction of it with 2-aminomethylpyridine, aniline, and hydrazine hydrate. All prepared samples were confirmed by their spectral data such as FTIR, 1H-NMR, 13C-NMR, Mass spectrometry, and elemental analysis. Furthermore, all the obtained compounds were evaluated as antibacterial agents and gave promising results.

A Bulky and Electron-Rich N-Heterocyclic Carbene–Palladium Complex (SIPr)Ph2Pd(cin)Cl: Highly Efficient and Versatile for the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides with (Hetero)aryl Amines at Room Temperature

A Bulky and Electron-Rich <i>N</i>-Heterocyclic Carbene–Palladium Complex (SIPr)^Ph₂Pd(cin)Cl: Highly Efficient and Versatile for the Buchwald–Hartwig Amination of (Hetero)aryl Chlorides with (Hetero)aryl Amines at Room Temperature

Convenient one-pot synthesis of some novel heteroaryl aminoindandione derivatives

An efficient, one-pot, three-component synthesis of some novel heteroaryl aminoindandione derivatives using ninhydrin, various heteroaryl amines, and barbituric/2-thiobarbituric acids catalyzed by p-toluenesulfonic acid as organocatalyst has been achieved within a short period of time. The present methodology offers several advantages including operational simplicity, clean reaction, high yield, short reaction times, high atom economy, easy workup procedure, and simple purification of products by nonchromatographic methods.

Nature-inspired remodeling of (aza)indoles to meta-aminoaryl nicotinates for late-stage conjugation of vitamin B3 to (hetero)arylamines

Despite the availability of numerous routes to substituted nicotinates based on the Bohlmann–Rahtz pyridine synthesis, the existing methods have several limitations, such as the inevitable ortho-substitutions and the inability to conjugate vitamin B3 to other pharmaceutical agents. Inspired by the biosynthesis of nicotinic acid (a form of vitamin B3) from tryptophan, we herein report the development of a strategy for the synthesis of meta-aminoaryl nicotinates from 3-formyl(aza)indoles. Our strategy is mechanistically different from the reported routes and involves the transformation of (aza)indole scaffolds into substituted meta-aminobiaryl scaffolds via Aldol-type addition and intramolecular cyclization followed by C–N bond cleavage and re-aromatization. Unlike previous synthetic routes, this biomimetic method utilizes propiolates as enamine precursors and thus allows access to ortho-unsubstituted nicotinates. In addition, the synthetic feasibility toward the halo-/boronic ester-substituted aminobiaryls clearly differentiates the present strategy from other cross-coupling strategies. Most importantly, our method enables the late-stage conjugation of bioactive (hetero)arylamines with nicotinates and nicotinamides and allows access to the previously unexplored chemical space for biomedical research.

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles.

N-(Hetero)aryl-4,5-unsubstituted pyrroles were synthesized from (hetero)arylamines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal by using aluminum(III) chloride as a Lewis acid catalyst through [1 + 2 + 2] annulation. This new versatile methodology provides a wide scope for the synthesis of different functional N-(hetero)aryl-4,5-unsubstituted pyrrole scaffolds, which can be further derived to access multisubstituted pyrrole-3-carboxamides. In the presence of 1.2 equiv of KI, a polysubstituted pyrazolo[3,4-b]pyridine derivative was also successfully synthesized.

Solvent and catalyst-free synthesis of some new aminonaphthoquinones from lawsone, ninhydrin and heteroaryl amines

An efficient and easy method has been developed for the preparation of some new aminonaphthoquinone derivatives from a one-pot three-component condensation of 2-hydroxy-1,4-naphthoquinone, ninhydrin and heteroaryl amines under catalyst and solvent-free conditions at 75 °C. The protocol describes in situ generated imine as intermediate from the condensation reaction of ninhydrin with heteroaryl amines followed by the addition of 2-hydroxynaphthalene-1,4-dione to the imine, afforded the desired products. The operational simplicity of the procedure, shorter reaction times, simple workup procedure, clean reaction, easy purification of products by nonchromatographic methods, environmentally friendly conditions and high yields make this method much attractive.

Synthesis of β-Diamine Building Blocks by Photocatalytic Hydroamination of Enecarbamates with Amines, Ammonia and N-H Heterocycles.

3‐Amino‐substituted saturated nitrogen heterocycles are an important subclass of β‐diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox‐mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.

Palladium-Catalyzed O - and N -Glycosylation with Glycosyl Chlorides

Despite the significant progress in carbohydrate chemistry, there remains a pressing need for efficient and practical glycosylation methods using simple glycosyl donors and with high atom economy. ...

Synthesis of Amido Sulfonamido Heteroaromatics Under Ultrasonication and Their Antimicrobial Activity.

A convenient and facile methodology for N-sulfonylation of heteroaryl amines with ethyl chlorosulfonylacetate in the presence of dispersed sodium in THF under ultrasonication is reported. The corresponding heteroaryl sulfonamido esters are directly condensed with heteroaryl amines to get amido sulfonamido heteroaromatics in the presence of a mild base in THF under ultrasonication. Utilization of easy reaction conditions, shorter reaction times, and isolation of products in high yields under ultrasonication make this process as economically viable. The compounds 12c, 12d, 12f and 13f are potential antibacterial agents against B. subtilis and the compounds 12f, 13c and 13f are potential antifungal agents against A. niger.

Synthesis, Characterization, and Properties of N- Heteroaryl Formamide Derivatives in the Presence of the Al-MCM-41-Nanocatalyst

This study aims to find out an efficient and simple method for N-formylation of different kinds of heteroaryl amines. The method is based on presence of formic acid and use of aluminum nanoparticles, loaded on a regular porous silica MCM-41 (Al-MCM-41), as the catalyst (at 60 °C in a solvent-free condition). The synthesized Al-MCM-41 nanocatalyst with average size 25–35 nm was characterized by FT-IR, SEM and TEM. The results show that the Al-MCM-41 nanocatalyst can provide yields of up 91% between 15 and 30 min for the N-formylation of different aromatic amines. The use of Al-MCM-41 nanocatalysts for the synthesis of N-heteroaryl formamide is reported for the first time in this article.

One-pot α-ferrocenylalkylation of amines and alcohols with α-ferrocenyl substituted alcohols under acid-free conditions

One-pot reaction of FcCH(R)OH with equimolar quantities of BunLi and EtOCOCl followed by an excess of amine produces N-(α-ferrocenylalkyl)amines in up to 98% yields. Nitrogen heteroaryl amines undergo the α-ferrocenylalkylation at the amino group. The α-ferrocenylalkylation of alcohols and phenols (R’OH) leads to a formation of ethers FcCH(R)OR′ in lower yields. The reactions proceed via an intermediate formation of α-ferrocenylalkyl carbonates FcCH(R)OCOOEt. The side reactions associated with this protocol are discussed.

Synthesis and antiviral study of novel 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives

A series of ten new compounds (7a–j) has been synthesized by absolutely replacing the glutamic acid part of Pemetrexed drug, chemically known as N-{4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-l-glutamic acid, with primary, secondary, and aryl amines in high yields using diethylphosphorocyanidate (DEPC) as a peptide coupling agent. All the synthesized compounds are characterized by 1H and 13C NMR, LCMS, and FT-IR spectral techniques. All the synthesized novel non-glutamate 4-(2-(6-amino-4-oxo-4,5-dihydro-1H-pyrrolo[2,3-d]pyrimidin-3-yl)ethyl)benzamide derivatives showed 4- to 7-folds higher antiviral activity than its structurally similar commercial drug Pemetrexed against Newcastle disease virus, an avian paramyxovirus. Among the lot, compounds possessing carboxamide synthesized using five-membered heteroaryl amines (7i and 7j) exhibited the highest antiviral activity.

Green Synthesis and Z/E-Isomerization of Novel Coumarin Enamines Induced by Organic Solvents

An efficient and straightforward synthesis of novel (Z/E)-3-[(heteroarylamino)methylidene]chromane-2,4-dione derivatives via a one-pot three-component condensation of 4-hydroxycoumarin, triethyl orthoformate, and heteroaryl amines in the presence of guanidinium chloride as organocatalyst under solvent-free conditions is described. Investigation of spectroscopy data indicated that coumarin enamines exist in the ketoenamine tautomeric form and undergo Z/E-isomerization in respect to the C=C bond in CDCl3 and DMSO-d6 at room temperature. Furthermore, intramolecular hydrogen bonds have been observed in the synthesized compounds. Also, 1H NMR spectra indicated that E-ketoenamines are the major isomers. High to excellent yields, short reaction times, simple workup, and very easy purification of products by non-chromatographic methods are advantages of this synthetic procedure.

Synthesis and biological evaluation of 1-amino isochromans from 2-bromoethyl benzaldehyde and amines in acid medium

We have developed a facile and efficient synthetic route to substituted isochromans for the first time by reacting 2-(2-bromoethyl)benzaldehyde with a variety of aryl, heteroaryl amines in AcOH. The reaction is catalyst/additive free and takes place at reflux conditions with short reaction time to furnish products in good to excellent yields. All the compounds have been characterized by spectral techniques such as IR, 1H NMR and Mass etc. Synthesized compounds were evaluated for antimicrobial activity against specific bacterial like 1) Staphylococcus strains aureus 2) Bacillus subtilis 3) Escherichia coli 4) Pseudomonas aeruginosa. Compounds 3e, 3n, 3 m, 3 l, 3 k, 3j and 3b showed most potent in vitro activity against bacterial strains.

An Efficient and Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with Alcohols

Herein, we developed an efficient and selective nickel-catalyzed monoalkylation of various primary alcohols with aryl and heteroaryl amines together with diols and amino alcohol derivatives. Notably, the catalytic protocol consisting of an earth-abundant and non-precious NiBr2/L1 system enables the transformations in the presence of hydroxyl, alkene, nitrile, and nitro functionalities. As a highlight, we have demonstrated the alkylation of diamine, intramolecular cyclization to N-heterocycles, and functionalization of complex vitamin E, an (±)-α-tocopherol derivative. Preliminary mechanistic studies revealed the participation of a benzylic C–H bond in the rate-determining step.

Regioselective Metal‐Free C2−H Arylation of Quinoline N‐Oxides with Aryldiazonium Salts/Anilines under Ambient Conditions

AbstractHerein, a base‐promoted direct C2−H arylation of quinoline N‐oxides with aryldiazonium salts under metal‐free conditions is reported. This reaction avoids the need for an oxidant, metal catalyst, or inert atmosphere and proceeds through a highly regioselective C−H bond functionalization to provide a series of C2‐arylated quinoline N‐oxides. Abundantly available amines (anilines and heteroaryl amines) can also be employed as arylating agents through an in situ diazotization process, thereby affording a library of diverse 2‐arylquinoline N‐oxides in moderate‐to‐good yields. The synthesized 2‐arylated quinoline N‐oxides were further converted into C8‐substituted quinolines to demonstrate the applicability of this catalytic approach. A radical pathway is proposed for the C2 arylation, based on a preliminary mechanistic study.

Nickel-Catalyzed Synthesis of Primary Aryl and Heteroaryl Amines via C–O Bond Cleavage

A nickel-catalyzed protocol for the conversion of aryl and heteroaryl alcohol derivatives to primary and secondary aromatic amines via C(sp2)-O bond cleavage is described. The new amination protocol can be applied to a range of substrates bearing diverse functional groups and uses readily available benzophenone imines as an effective nitrogen source.

An Efficient Synthetic Strategy for sp3(C)‐N Amination on 4‐thiazolidinone with Primary Heteroaryl Amines

AbstractAn efficient sp3(C)‐N amination reaction between 4‐thiazolidinone and primary heteroaryl amine has been developed under C−H functionalization. Cross‐coupling reaction between non‐prefunctionalized slightly more acidic sp3 C−H bond of 4‐thiazolidinone and different heteroaryl amines involving one‐pot synthetic strategy, single step reaction as well as aerial oxidation make this amination more effective than existing methods for the construction of sp3(C)‐N bond.

Attaching ‘unlinkable’ drugs to antibodies

Attaching a small-molecule drug to a targeting agent such as an antibody can improve the delivery of the drug. A common way to achieve that with antibodies is using a linker that connects to the drug through an amide or carbamate functional group. But tertiary and heteroaryl amines common to many drug molecules lack a place for such a connection, leading researchers to deem them “unlinkable.” A team led by Thomas H. Pillow of Genentech has now devised a strategy to attach and release such drugs through a p-aminobenzyl quaternary ammonium salt (Nat. Chem. 2016, DOI: 10.1038/nchem.2635). The team treated an alcohol-containing linker with methanesulfonyl chloride or thionyl chloride to yield a benzyl chloride that can form quaternary ammonium salts with a variety of tertiary amines. The quaternary ammonium connection was applied to dipeptide linkers, which permits enzymatic cleavage by proteases, and to disulfide-containing linkers, which allows drugs to be

Targeted drug delivery through the traceless release of tertiary and heteroaryl amines from antibody-drug conjugates.

The reversible attachment of a small-molecule drug to a carrier for targeted delivery can improve pharmacokinetics and the therapeutic index. Previous studies have reported the delivery of molecules that contain primary and secondary amines via an amide or carbamate bond; however, the ability to employ tertiary-amine-containing bioactive molecules has been elusive. Here we describe a bioreversible linkage based on a quaternary ammonium that can be used to connect a broad array of tertiary and heteroaryl amines to a carrier protein. Using a concise, protecting-group-free synthesis we demonstrate the chemoselective modification of 12 complex molecules that contain a range of reactive functional groups. We also show the utility of this connection with both protease-cleavable and reductively cleavable antibody-drug conjugates that were effective and stable in vitro and in vivo. Studies with a tertiary-amine-containing antibiotic show that the resulting antibody-antibiotic conjugate provided appropriate stability and release characteristics and led to an unexpected improvement in activity over the conjugates previously connected via a carbamate.