Disubstituted Pyridines Research Articles

Synthesis, Reactivity and Stability of Aryl Halide Protecting Groups towards Di-Substituted Pyridines

This paper reports the synthesis and reactivity of different Benzyl derivative protecting groups. The synthesis and stability of Benzyl halides, 4-methoxybenzyl halides, 3,5-dimethoxybenzyl halides, 3,4-dimethoxybenzyl halides, 3,4,5-trimethoxybenzyl halide protecting groups and their reactivity towards nitrogen atom of a di-substituted pyridine ring in formation of pyridinium salts is also reported.

On the nonadditivity of the substituent effect in homo-disubstituted pyridines

The substituent effect in mono- and disubstituted pyridines was studied by means of the sEDA and pEDA substituent effect descriptors expressing the substituent effect on the σ- and π-electron systems of the ring, respectively. The sEDA descriptors calculated for mono- or disubstituted pyridines can be presented as perfectly linear functions of either benzene or monosubstituted pyridine sEDA descriptors, respectively. For the pEDA descriptors, there are substantial deviations from linearity observed for both mono- and disubstituted systems. For the disubstituted systems, the nonadditivity of the pEDA descriptors is strongly pronounced for the substituents in the ortho- and para-positions to each other while it is only weak for the meta-located groups. For both mono- and disubstituted systems, there are correlations between charge at the nitrogen lone electron pair and the σ- and π-electron withdrawing and donating properties of the substituent. In general, the electron charge increases with the increase of the σ-electron donating ability but decreases with the increase of π-electron donating ability of substituents. Again, the effects are more significant for substituents in the ortho- and para-positions than in the meta-position. The influence of the π-electron properties of the substituent on the lone pair, belonging to σ-electron system of pyridines, shows the presence of hyperconjugation effects in the substituted pyridines. The hyperconjugation can be also clearly observed in cross-dependencies of the sEDA and pEDA descriptors.

Highly Regioselective Assembly of Di‐ or Trisubstituted Pyridines from Arynes, Isocyanides, and 3‐Bromo‐ or 3‐Acetoxypropynes

AbstractA facile synthetic method for the preparation of di‐ and trisubstituted pyridines with high regioselectivity through an intramolecular pericyclization strategy is disclosed. The multicomponent reaction of isocyanides, arynes, and 3‐bromopropyne affords disubstituted pyridines in good yields. In contrast, the use of 3‐acetoxypropyne results in the formation of trisubstituted pyridines through intramolecular pericyclization of an in situ formed azatriene. In this way, desirable pyridines can be constructed in a one‐pot manner.

Biological activity of Pd(II) complexes with mono- and disubstituted pyridines—Experimental and theoretical studies

Due to the similarity between Pd and Pt, the complexes of palladium(II) can be considered as potential anticancer agents. Activity of six PdCl2(X2Py)2 complexes (Py=pyridine, and X=CH3 or Cl) was measured by MTT test using MCF7, CCRF-SB, PC3 and human B-lymphoblastoid cell lines. We found that the effect of PdCl2(XnPy)2 was cell-specific and time-dependent. Obtained results were discussed and compared with the activation parameters calculated for the hydrolysis of PdCl2(XnPy)2, indicating a correlation between viability of MCF7 and CCRF-SB cells and rates of hydrolysis of the Pd(II) complexes.

Synthesis and antiproliferative evaluation of some new amidino-substituted bis-benzothiazolyl-pyridines and pyrazine

Novel diamidino substituted conformationally restricted derivatives of bis-benzothiazolyl-pyridines and pyrazine were synthesized and their antiproliferative activity against several human cancer cell lines were determinated. The synthetic approach used for preparation of isomeric amidinobenzotiazolyl disubstituted pyridines 3a–3k and pyrazine 3l was achieved by condenzation reaction of commercially available pyridine and pyrazine dicarboxylic acids with amidino- 2a and 2-imidazolinyl-substituted 2-aminothiophenol 2b in polyphosphoric acid in moderate to good yield. The condenzation reaction was greatly optimized. The targeted compounds were converted in the desired water soluble dihydrochloride salts by reaction of appropriate free base with concd HCl in ethanol or acetic acid. Antiproliferative assays revealed significant differences in antiproliferative activities of diamidino- and diimidazolinyl-derivatives, the latter exerting stronger concentration-dependent antiproliferative effects on tested tumor cell lines and thus being a prominent compound class for further chemical optimization and biological studies. Biological studies on SW620 cell line and BJ fibroblasts performed for the diimidazolinyl- derivative 3b revealed oxidative stress as a possible mechanism of antiproliferative action and predicted antineoplastic properties for this class of compounds.

Flow microreactor synthesis of disubstituted pyridines from dibromopyridines via Br/Li exchange without using cryogenic conditions

A flow microreactor method for the synthesis of disubstituted pyridines by generation of pyridyllithiums followed by reactions with electrophiles has been developed. By using a short residence time and efficient temperature control, the cryogenic conditions required for conventional batch macro processes can be avoided. Sequential introduction of two different electrophiles into dibromopyridines has been achieved using an integrated flow microreactor system composed of four micromixers and four microtube reactors, to obtain disubstituted pyridine compounds.

Continuous Flow Hydrogenation of Functionalized Pyridines

AbstractThe heterogeneous hydrogenation of substituted pyridines has been accomplished by employing a continuous flow hydrogenation device that incorporates in situ hydrogen generation by electrolysis of H2O and pre‐packed catalyst cartridges. In general, the hydrogenation reactions proceeded smoothly regardless of the supported precious metal catalyst (Pd/C, Pt/C, or Rh/C). By using 30–80 bar of hydrogen pressure at 60–80 °C full conversion was typically achieved in all cases at a flow rate of 0.5 mL min–1, providing the corresponding piperidines in high yields. For disubstituted pyridines, variations in stereoselectivity were observed depending on both the metal catalyst and the temperature/pressure of the hydrogenation reaction. For ethyl nicotinate the selectivity between partial and full hydrogenation could be tuned depending on the hydrogen pressure, solvent, and the choice of supported metal catalyst. Changing the hydrogen source from H2O to D2O allowed the preparation of deuteriated derivatives. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

A significant substituent effect on the regioselectivity in addition of alkynes to 3-substituted pyridines

A substituent at the 3-position on a pyridine ring significantly affects the regioselectivity during the addition of alkynes to pyridinium salts. When the substituent is an electron-withdrawing group, 1,6-adducts are predominantly produced, whereas, 1,2-adducts become the major products when the substituent is an electron-donating group. The changes in the regioselectivity depending on the substituent can be explained by the difference in the product stabilities. The produced dihydropyridines are easily aromatized into disubstituted pyridines with chloranil in quantitative yields.

Triazolopyridines. Part 26: The preparation of novel [1,2,3]triazolo[1,5- a]pyridine sulfoxides

The regioselective synthesis of new triazolopyridine halides and sulfoxides with the substituent in all different ring positions of [1,2,3]triazolo[1,5- a]pyridines is presented. The triazolo ring opening reaction of some representative sulfoxides to obtain disubstituted pyridines is also studied.

One-Pot Double Suzuki Cross-Coupling: Synthesis of Diarylated Pyridines

A highly regioselective, one-pot, double Suzuki cross-coupling procedure for the construction of 2,5- and 2,3-diaryl pyridines is described. Starting from 2,3- and/or 2,5-dibromo­pyridines, sequential regioselective coupling with aryl- and alkenylboronic acids to give the disubstituted pyridines in reasonable to good yields was achieved. Interestingly, the modest isolated yields of many of the products increased (by approximately 20%) with purification on neutral alumina instead of silica gel flash chromatography.

Disubstituted Pyridines: The Double-Coupling Approach

A one-pot procedure leading to disubstituted pyridines from the starting dibromopyridines is described. Key features include the ability to couple a range of aryl and even alkenylboronic acids at the 2,3 and/or 2,5 positions with excellent regiocontrol under a standard set of conditions. Further, isolated yields are greatly improved by the use of neutral alumina in place of silica for product purification. Finally, the intrinsic electronic bias of the pyridine ring can be overcome by using a bromoiodopyridine.

Identification of Inhibitors of the Kinase Activity of Oncogenic V600EBRAF in an Enzyme Cascade High-Throughput Screen

The Cancer Genome Project has identified several oncogenic mutations in BRAF that represent important opportunities for cancer drug discovery. The V600E BRAF mutation accounts for approximately 90% of the mutations identified. A strong case has emerged from molecular, cellular, and structural studies for the identification and development of inhibitors of this mutated BRAF protein. The authors have developed and run a high-throughput screen to find inhibitors of V600E BRAF using an enzyme cascade assay in which oncogenic BRAF activates MEK1, which in turn activates ERK2, which then phosphorylates the transcription factor ELK1. A phosphospecific antibody, Europium-labeled secondary antibody, and a time-resolved fluorescent readout were used to measure phosphorylation of ELK1. Overall assay variation was 12.4%. The assay was used to screen 64,000 compounds with an overall Z' factor of 0.58 +/- 0.12. A series of 3,5, di-substituted pyridines were identified as inhibitors of the cascade assay. These compounds did not inhibit a shortened activated MEK1 to ELK1 cascade but were active (0.5-27.9 microM) in a V600E BRAF assay and represent a potential starting point for future drug discovery and development.

Bridged Azabicycles by Ring-Closing Metathesis

A diallylboration and Ru-catalyzed ring-closing metathesis route to bridged azabicycles is reported. It features a reductive trans-diallylation of mono- or disubstituted pyridines, isoquinoline and pyrrole followed by successive heating with triallylborane (1 equiv) under which conditions a deprotonation (isopropylene evoluation), deallylation and allylation sequence occurs to give the cis-isomer. Boc protection yields key heterocyclic precursors for the metathesis reactions. The Grubbs first and second generation catalysts I and II are employed in the ring-closing metathesis to give aza-bicyclo[4.3.1]deca-3,7-dienes and aza-bicyclo[4.2.1]nonene derivatives, respectively, in excellent yields (89-98%).

Preparation and antioxidant activity of α-pyridoin and its derivatives

Focusing on α-pyridoin ( 1, 1,2-di(2-pyridyl)-1,2-ethenediol) as the lead compound of the novel antioxidative enediol, we synthesized 5,5′- or 6,6′-bis-substituted derivatives of 1 from disubstituted pyridines. The antioxidant activity of 1 and its synthetic derivatives 2- 7 was evaluated by DPPH (1,1-diphenyl-2-picrylhydrazyl radical) scavenging assay and inhibition of lipid peroxidation. In the DPPH assay, 1 exhibited an activity stronger than that of ascorbic acid, and 5,5′-dimethyl-( 5) or 5,5′-dimethoxy-substituted derivatives ( 6) exhibited more potent activity than 1. The DPPH scavenging activities of α-pyridoins were correlated with their oxidation potential and thus the electron density of enediol. 5 and 6 effectively inhibited lipid peroxidation in the rat liver microsome/ tert-butyl hydroperoxide system. Therefore, 5 and 6 serve as good candidates for a pharmacologically useful enediol antioxidant.

Synthesis and characterization of mixed ligand complexes of manganese-, iron-, cobalt- and nickel(II) with some disubstituted pyridines and catechol

Mixed ligand complexes of the type (NH 4 ) 2 [M(L 1 ) 2 L 2 ]; M = Mn I I , Fell, Co I I or Ni I I , HL 1 = 2,3-dihydroxypyridine or 2-amino-3-hydroxypyridine; H 2 L 2 = catechol, have been synthesized. All the complexes have octahedral geometry. Thermal stability, order of reaction, apparent activation energy and heat of reaction have been determined. The thermal stability order with respect to metal is, Mn < Fe < Co < Ni.

Partial reduction of electron-deficient pyridines

The partial reduction of electron-deficient pyridines is described herein. Mono- and disubstituted pyridines can be transformed into functionalized dihydropyridines using either Birch reduction conditions or sodium/naphthalene in THF. The compounds formed by these high-yielding reductive alkylation protocols have potential as synthetic intermediates, and we have shown that bicyclo compounds containing 6,5, 6,6, and 6,7 ring systems can be prepared in one step via a base-promoted cylization.

Structural effects in the electron absorptio and luminescence spectra of decaborane(14) derivatives B10H12L2

The electron absorption and luminescence spectra of some adducts B10H12L2 with L-alkylsubstituted pyridines are compared. In each subgroup with mono- and disubstituted pyridines, the largest hypsochromic shift of the long-wave edge of the charge transfer band (CTB) and the increased fluorescence yield correspond to the maximum basicity of L. Steric strains between the ortho methyl group of L and |B10H12| result in an insignificant bathochromic shift of the CTB and decrease the fluorescence yield. The optimal interactions |B10H12|→L, which are responsible for the absorption and emission properties of the adducts, should correspond to conformations where the planes of the heterocyclic system of L make an angle of 30° and are symmetric relative to the |B10H12| plane.

Protonation constants of some pyridine derivatives in ethanol-water mixtures

Protonation constants of a number of mono- and disubstituted pyridines were determined potentiometrically in 0, 10, 20, 30, 40, 50, 60, 70, 80% (v/v) ethanol-water mixtures at 25°C with an ionic strength of 0.1 M. Data were calculated by a computer programme. The logarithm of the protonation constants of pyridines linearly decreased with increasde of ethanol contents but the values determined in water and 80% ethanol did not follow this linear trend. Furthermore, the effects of the substituents on the basicity of pyridine, the additives of these effects and the applicability of the Hammett equation to the behaviour of substituents are discussed.

Correlation of 2-, 3-, 4- and disubstituted pyridine gas-phase proton affinities with ab initio calculated energies at the sto-3g basis set level

Total energies of 2-, 3-, 4- and disubstituted pyridines were calculated for the salt and the free base using ab initio molecular orbital calculations at the STO-3G basis set level [2]. In each set, the difference in energy, ΔEH, between the salt and the free base was calculated and plotted against experimentally derived gas-phase proton affinities. The correlation was very good for each of the substituent categories listed. All of the energies and proton affinities were then plotted together on the same graph. The result was an excellent correlation with r = 0.97. The linear equation for gas phase proton affinity, PAB = 28.51 + 435.45ΔEH kcal/mole, was derived from this plot and was used to calculate proton affinities for all of the thirty-one compounds used in this study as well as for a series of dicyanopyridines for which values of proton affinity are not available at this time.

ChemInform Abstract: Reaction of Ylide Salts Containing Ph3P and Py Groups in the Positions 1 and 3 with Benzylidenecyclopentanone.

AbstractThe reaction between pyridinium ylides and α,β‐unsaturated ketone is known to afford disubstituted pyridines.