Six-membered Azaheterocycles Research Articles

Discovery of N-(4-((6-(3,5- Dimethoxyphenyl)-9H-purine derivatives as irreversible covalent FGFR inhibitors

Fibroblast growth factor receptor (FGFR) is an attractive target for cancer therapy, but existing FGFR inhibitors appear to hardly meet the demand for clinical application. Herein, a number of irreversible covalent FGFR inhibitors were designed and synthesized by selecting several five- and six-membered azaheterocycles as parent scaffold with different substituents to take over the hydrophobic region in the active pocket of FGFR proteins. Among the resulting target compounds, III-30 showed the most potent effect on enzyme activity inhibition and anti-proliferative activity against the tested cancer cell lines. Significantly, III-30 could inhibit the enzyme activity by achieving irreversible covalent binding with FGFR1 and FGFR4 proteins. It could also regulate FGFR-mediated signaling pathway and mitochondrial apoptotic pathway to promote cancer cell apoptosis and inhibit cancer cell invasion and metastasis. Moreover, III-30 had a good metabolic stability and showed relatively potent anti-tumor activity in the MDA-MB-231 xenograft tumor mice model.

Application of 2-Aminopyridines in the Synthesis of Five- and Six-Membered Azaheterocycles

Application of 2-Aminopyridines in the Synthesis of Five- and Six-Membered Azaheterocycles

Ruthenium-Catalyzed Tandem Carbene/Alkyne Metathesis/N-H Insertion: Synthesis of Benzofused Six-Membered Azaheterocycles.

The Cp*RuCl-based catalyst enables expedient access to a variety of benzofused six-membered azaheterocycles from unprotected o-alkynylanilines and trimethylsilyldiazomethane through an unprecedent tandem carbene/alkyne metathesis/N-H insertion reaction. The transformation takes place under mild reaction conditions (room temperature, <15 min) and with excellent functional group tolerance. The synthetic utility of the final products and a mechanistic rationale are also discussed.

Nature of the Nucleophilic Oxygenation Reagent Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and Internal Alkynes to 1,2-Dicarbonyls.

2,3-Dichloropyridine N-oxide, a novel oxygen transfer reagent, allows the conductance of the gold(I)-catalyzed oxidation of alkynes to 1,2-dicarbonyls in the absence of any acid additives and under mild conditions to furnish the target species, including those derivatized by highly acid-sensitive groups. The developed strategy is effective for a wide range of alkyne substrates such as terminal- and internal alkynes, ynamides, alkynyl ethers/thioethers, and even unsubstituted acetylene (40 examples; yields up to 99%). The oxidation was successfully integrated into the trapping of reactive dicarbonyls by one-pot heterocyclization and into the synthesis of six-membered azaheterocycles. This synthetic acid-free route was also successfully applied for the total synthesis of a natural 1,2-diketone.

Synthesis of Six-membered Azaheterocycles by Means of the β-lactam Synthon Method

Azaheterocycles comprise relevant target structures within organic chemistry due to the broad diversity of biological activities associated with these scaffolds. In this review, the most important recent procedures for the preparation of functionalized six-membered azaheterocyclic compounds by ring transformation of β-lactams are summarized and discussed.

Reactions of heterocumulenes with organometallic reagents: XVII. One-pot synthesis of alkoxy and (alkylsulfanyl)-substituted pyrroles and 2,3-dihydropyridines from aliphatic isothiocyanates and lithiated alkoxyallenes

A fundamentally new approach was developed to designing pyrrole and dihydropyridine rings from available allenes and isothiocyanates involving a single preparative stage. Applying the reaction of lithiated alkoxyallenes with aliphatic isothiocyanates we have synthesized previously unknown 1-alkyl(cycloalkyl) pyrroles and 2,3-dihydropyridines with rare alkoxy- and alkylsulfanyl substituents. It was proved that the five- and six-membered azaheterocycles formed as a result of competing reactions of direct intramolecular cyclization of S-alkylated adducts of lithiated alkoxyallenes with isothiocyanates (1-aza-1,3,4-trienes) into pyrroles and of [1,5]-sigmatropic rearrangement into conjugated 2-aza-1,3,5-trienes with subsequent closure into dihydropyridine ring (through 6π-electrocyclization).

Control of Relative Direction and Amplitude in Extension/Contraction Motions of Molecular Strands Induced by Ion Binding

The shape of ligand strands composed of six-membered aza-heterocycles (het) connected at the alpha and alpha' positions by hydrazone (hyz) units is determined in a predictable fashion by the nature of the heterocyclic groups (pyridine, pyrimidine, pyrazine etc.), and covers the range from extended linear to compact helical structures. The binding of metal ions to the coordination subunits, defined by the het-hyz sequences, leads to marked shape changes by inter-converting bent and linear conformations of the subunits, thus inducing relative motions of strand domains either in the same (con-sense, "twirling") or in opposite (dis-sense, "flapping") directions. The amplitude of the motion induced by metal-ion binding and release and the relative directions of the formal motions can be controlled by the nature of the heterocyclic units. Thus, motions around a central 4,6-disubstituted pyrimidine are dis-sense motions, whereas there are con-sense motions around a central 2,5-disubstituted pyrazine unit, as illustrated by model ligands 1 and 2, respectively. The more extended helical 3 and undulating (zigzag shape) 4 ligands undergo larger-amplitude motions combining the relative displacements displayed by 1 and 2. Ligands 3 and 4 form linear tetranuclear Pb(II) and Zn(II) complexes, thus producing an extension motion. The same holds for [Ru(4)(terpy)(4)](PF(6))(8) (terpy=terpyridine). Reversible acid-base-triggered molecular motions have been generated with [Zn(4)(4)(OTf)(8)] (TfOH=triflic acid).

Ring Transformation of 2-(Haloalkyl)azetidines into 3,4-Disubstituted Pyrrolidines and Piperidines

[reaction: see text] Reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane (AlH(2)Cl) afforded new 2-(haloalkyl)azetidines in high yields. The latter compounds proved to be very useful starting materials for rearrangements toward stereospecifically defined five- and six-membered azaheterocycles, such as 3,4-cis-disubstituted pyrrolidines and piperidines. During these reactions, bicyclic azetidinium intermediates were formed which were ring opened by a variety of nucleophiles. Hereby, reactions proceeding via 1-azoniabicyclo[2.2.0]hexanes are reported for the first time.

Fatigue resistance of photochromic 2,2-diaryl-[2H]-heteroannellated chromenes in solution

The photodegradation in toluene of photochromic compounds in the [2H]-chromenes series has been studied under continuous irradiation. It is shown that the resistance to fatigue depends on the nature of the heteroatoms, the size of the ring and the annellation position. Six-membered aza-heterocycles, as in the spiro[indoline-hetero-annellated benzoxazine] series, improve the fatigue resistance to UV-light; in contrast, the five-membered heteroannellated chromenes (containing benzimidazole, benzothiazole, benzofurane, indole or pyrrole moieties) show a significant increase in the photodegradation process, but a broadening of the visible spectra for the photomerocyanines.

Reductive amination in the synthesis of azaheterocycles (review)

Methods for obtaining saturated five- and six-membered azaheterocycles based on the use of catalytic intra- and intermolecular hydroamination of dicarbonyl compounds and ketones and amines of the furan series, hydride amination of aldehydes and ketones, and the Leuckart reaction are examined.