Trisubstituted Pyridines Research Articles

Tetrasubstituted pyridines as potent and selective AKT inhibitors: Reduced CYP450 and hERG inhibition of aminopyridines

The synthesis and evaluation of tetrasubstituted aminopyridines, bearing novel azaindazole hinge binders, as potent AKT inhibitors are described. Compound 14c was identified as a potent AKT inhibitor that demonstrated reduced CYP450 inhibition and an improved developability profile compared to those of previously described trisubstituted pyridines. It also displayed dose-dependent inhibition of both phosphorylation of GSK3β and tumor growth in a BT474 tumor xenograft model in mice.

Synthesis of Highly Substituted Pyridines Over Zeolite Molecular Sieves Under High Pressure

Simple and selective single step synthesis of highly substituted pyridines (trisubstituted pyridines) from aliphatic aldehydes and aqueous ammonia using zeolite as a catalyst under high pressure (autogenous pressure) conditions with high conversion and moderate selectivity is presented. The catalyst can be reused many times without significant loss of activity. An efficient novel protocol for the synthesis of 2,3,5-trisubstituted pyridines in single step is achieved using aliphatic aldehydes and aqueous ammonia over zeolites under high pressure (autogenous pressure) in batch process. The catalyst is inexpensive, reusable and the product isolation is simple and environmentally benign.

ChemInform Abstract: Microwave‐Assisted Regioselective One‐Pot Synthesis of Trisubstituted Pyridine Scaffolds Using K5CoW12O40×3H2O under Solvent‐Free Conditions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Diverse Reactions of 1,4‐Dilithio‐1,3‐dienes with Nitriles: Facile Access to Tricyclic Δ1‐Bipyrrolines, Multiply Substituted Pyridines, Siloles, and (Z,Z)‐Dienylsilanes by Tuning of Substituents on the Butadienyl Skeleton

Addition cyclization of 1,2,3,4-tetrasubstituted 1,4-dilithio-1,3-dienes (Type I) with four equivalents of various aromatic nitriles in the presence of hexamethylphosphoramide (HMPA) gives exclusively fully substituted pyridines in moderate to good yields. Similarly, trisubstituted pyridines can be prepared by the reaction of 2,3-dialkyl- or diaryl-substituted 1,4-dilithio-1,3-dienes (Type II) with nitriles. However, five- or six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-dienes (Type III) reacted with various aromatic and aliphatic nitriles without alpha-hydrogen atoms to afford tricyclic Delta1-bipyrrolines in high yields. The reaction of six-membered-ring fused 2,3-disubstituted 1,4-dilithio-1,3-diene (Type III) with 2-cyanopyridine afforded the corresponding pyridine, and no tricyclic Delta1-bipyrroline was observed. Seven-membered-ring fused dilithiodienes reacted with PhCN or trimethylacetonitrile to afford the corresponding pyridines in good yield. When 1,2,3,4-tetrasubstituted dilithio reagents (Type I) were treated with Me3SiCN, a tandem silylation/intramolecular substitution process readily occurred to yield siloles, whereas the reaction of 2,3-disubstituted dilithio reagents (Types II and III) with Me3SiCN gave rise to (Z,Z)-dienylsilanes with high stereoselectivity. These results revealed that the formation of tricyclic Delta1-bipyrrolines, pyridines, siloles, and (Z,Z)-dienylsilanes are strongly dependent on the substitution patterns of the dilithio butadienes and the nature of the nitriles employed.

Synthesis and reactions of 3-[3-(dimethylamino)propenoyl]-1,7-diphenyl [1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one

3-Acetyl-1,7-diphenyl[1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one (1) reacts with N,N-dimethylformamide dimethylacetal (DMFDMA) yielding the enaminone 2. The latter compound reacts with active methylene compounds, hydrazine hydrate, hydroxylamine and some heterocyclic amines to afford trisubstituted pyridine, substituted pyrazole, substituted isoxazole and azolopyrimidines. The antimicrobial activities of the compounds prepared were screened.

Multicomponent and one-pot synthesis of trisubstituted pyridines through a Pd-catalyzed cross-coupling/cross-coupling/cycloaddition sequence

Trisubstituted pyridines are regioselectively synthesized through multicomponent and one-pot processes promoted by a bifunctional Pd-catalyst. The process involves formation of an enamine by Pd-catalyzed amination of an alkenyl bromide, formation of a 2-aza-1,3-butadiene by Pd-catalyzed cross-coupling of a trimethylsilylimine with an alkenyl bromide, and Lewis acid catalyzed cycloaddition between the enamine and the azadiene.

The Synthesis of Trisubstituted Pyridines via Kröhnke Reaction

The Synthesis of Trisubstituted Pyridines via Kröhnke Reaction

Synthesis and Reactivity of Imide‐Derived Bisvinyl Phosphates. Reactivity of 2,6‐Disubstituted 1,4‐Dihydropyridines.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

An RNA polymerase inhibitor, cyclothiazomycin B1, and its isomer

Novel cyclic thiopeptides, cyclothiazomycins B1 ( 1) and B2 ( 2), were isolated from Streptomyces sp. A307 as potent hyphal swelling inducing substances. They are stable in the solid state but slowly isomerize with one another in solution. Degradation experiments and spectroscopic analyses disclosed that they comprise unique tricyclic structures each containing a dehydroalanine, and two dehydrohomoalanine residues, along with three thiazolines, three thiazoles, and a trisubstituted pyridine. Cyclothiazomycin B1 ( 1) is expected to be a powerful tool for DNA–RNA transcription studies, because this cyclopeptide inhibits DNA-dependent RNA synthesis by bacteriophage RNA polymerases.

Synthesis and Reactivity of Imide-Derived Bisvinyl Phosphates. Reactivity of 2,6-Disubstituted 1,4-Dihydropyridines

Symmetrical and unsymmetrical 2,6-disubstituted dihydropyridines were prepared in high yields under mild conditions using the Suzuki and Stille Pd-catalyzed coupling reactions of imide-derived bisvinyl phosphates with a range of aryl, heteroaryl, and alkenyl moieties. The alkylation reaction at C-4 easily afforded original tri- and tetrasubstituted dihydropyridines. Hydrolysis of the latter under acidic condition provided efficiently either open-chain 1,5-diketones or di- or trisubstituted pyridines.

Regioselective Functionalization of Trisubstituted Pyridines Using a Bromine—Magnesium Exchange.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Regioselective functionalization of trisubstituted pyridines using a bromine–magnesium exchange

A tosyloxy substituent in position 2 allows a highly regioselective Br/Mg exchange reaction on 3,5-dibromopyridine derivatives using iso-PrMgCl.LiCl. The resulting functionalized pyridylmagnesium reagents react with various electrophiles in position 3. Acylated pyridines of this type can be readily converted into pyrazolo [3,4-b] pyridines.

Total Synthesis of the Naphthyridine Alkaloid Jasminine.

Abstract The synthesis of (±)-jasminine ( 1 ), a member of a small group of naphthyridine alkaloids, has been achieved. The synthetic route takes advantage of the reactivity of dihydropyridine intermediates for the preparation of trisubstituted pyridine 4 , which gives access to the alkaloid by a reductive amination-lactamization tandem reaction.

Total synthesis of the naphthyridine alkaloid jasminine

The synthesis of (±)-jasminine ( 1 ), a member of a small group of naphthyridine alkaloids, has been achieved. The synthetic route takes advantage of the reactivity of dihydropyridine intermediates for the preparation of trisubstituted pyridine 4 , which gives access to the alkaloid by a reductive amination-lactamization tandem reaction.

Synthesis of (+/‐) Mappicine and Mappicine Ketone.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of (+/‐) mappicine and mappicine ketone

AbstractMappicine and mappicine ketone are camptothecin analogs of interest as antiviral agents. A novel synthesis of these compounds is described using a Friedlander condensation. The requisite ketone is prepared via a regioselective ortho‐directed metallation/alkylation of a trisubstituted pyridine. This is condensed with N‐t‐butyloxycarbonyl‐o‐aminobenzaldehyde as a convenient, stable o‐aminobenzaldehyde equivalent in the Friedlander condensation.

ChemInform Abstract: Annulation of Ketones with Vinamidinium Hexafluorophosphate Salts: An Efficient Preparation of Trisubstituted Pyridines.

α-Aryl ketones react with vinamidinium hexafluorophosphate salts to give access to the corresponding 3-arylpyridines. The annulation reactions proceed in good to excellent yields with vinamidinium salts containing electron-withdrawing groups at the β-position (R2). The reaction was applied to the preparation of the COX-2 specific inhibitor 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (1), as well as a series of analogues.

Annulation of ketones with vinamidinium hexafluorophosphate salts: an efficient preparation of trisubstituted pyridines.

alpha-Aryl ketones react with vinamidinium hexafluorophosphate salts to give access to the corresponding 3-arylpyridines. The annulation reactions proceed in good to excellent yields with vinamidinium salts containing electron-withdrawing groups at the beta-position (R(2)). The reaction was applied to the preparation of the COX-2 specific inhibitor 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine (1), as well as a series of analogues.

A Study of Acid-Base Equilibria in Acetonitrile Systems of 2-Halo(Cl,Br,I)-4-nitropicoline(3,5,6) N-oxides

An attempt has been made to determine potentiometrically (1) acid dissociation constants of cations obtained by protonation of nine trisubstituted pyridine N-oxides, namely 2-halo(Cl, Br and I)-4-nitropicoline N-oxides with the methyl group at positions 3, 5, and 6, as well as (2) the cationic homoconjugation constants of these cationic acids with conjugated N-oxides in acetonitrile. On the basis of the substitution effect, variations of the acid dissociation constants of the trisubstituted pyridine N-oxide cations are discussed. The determined pKa values of the protonated 2-halo-4-nitropicoline N-oxides are compared with the previously determined equilibrium constants of the cationic acids conjugated with the mono- and disubstituted pyridine N-oxides in acetonitrile. Further, based on the pKa values of the protonated 2-halo-4-nitropicoline N-oxides in acetonitrile, supplemented with correlations between pKa’s of the protonated mono- and disubstituted pyridine N-oxides in acetonitrile and water, the pKa's of the acids conjugated with the trisubstituted N-oxides studied in aqueous solutions have been estimated. Moreover, it has been concluded that the cationic homoconjugation constants cannot be determined by potentiometric titration in acetonitrile solutions of the 2-halo-4-nitropicoline N-oxide systems.

Experimental Studies on the UV-Spectra of Several Substituted Pyridine N-Oxides and Conjugated Cationic Acids in Acetonitrile

The ultraviolet spectra of heterocyclic N-oxides of pyridine N-oxide series and the conjugated cationic acids (simple cations of protonated N-oxides) in acetonitrile as the representative of polar aprotic solvents, were determined. The obtained spectra of N-oxides studied (mainly tri-substituted pyridine N-oxides) and their cations obtained by the protonation of free N-oxides by the excess of perchloric acid, have been collected and discussed. Taking into account the spectroscopic results, a scheme of acid-base equilibria in polar aprotic solvents has been discussed. The influence of the traces of water on acid-base equilibria in nonaqueous media has been stressed.