27068-65-1Relevant academic research and scientific papers
Improved synthesis of 2,4,6-trialkylpyridines from 1,5-diketoalkanes: The total synthesis of Anibamine
Miyakoshi, Takeru,Konno, Hiroyuki
, p. 2896 - 2905 (2019)
Many pyridine syntheses have been developed to date. In this study, we focused on pyridine synthesis with 1,5-diketone derivatives and hydroxylamine. Treatment of simple 1,5-diketoalkanes and hydroxylamine in basic or acidic conditions gave aldol adducts without any pyridine compounds. However, by screening the reaction conditions, we found that acidic conditions produced via the formation of oxime intermediates derived from 1,5-diketoalkanes allowed the formation of the corresponding pyridine derivatives. This is the first example of 2,4,6-trialkylpyridine synthesis from quite simple 1,5-diketoalkanes. In order to demonstrate the utility of the reaction, we demonstrated the synthesis of pyridine derivatives and the total synthesis of a 6-substituted pyridyl-natural product, anibamine. This was achieved by following the above methodology using a reported compound as the starting material to give the product in 12% yield.
The one-pot synthesis of pyridine derivatives from the corresponding 1,5-dicarbonyl compounds
Mihara, Hiromichi,Miyakoshi, Takeru,Kikuchi, Yui,Konno, Hiroyuki
, p. 1375 - 1383 (2019/12/23)
The optimization of the one-pot, acid-promoted synthesis of pyridine and alkylpyridine derivatives from simple alkyl-1,5-dicarbonyl derivatives and via the corresponding oxime intermediate is described. Of all the combinations of and solvents tested, the use of HCl in refluxing dioxane was found to result in the highest chemical yields. Twelve pyridines were prepared using this method.
Simple and Clean Photo-induced Methylation of Heteroarenes with MeOH
Liu, Wenbo,Yang, Xiaobo,Zhou, Zhong-Zhen,Li, Chao-Jun
supporting information, p. 688 - 702 (2017/05/15)
Heteroarene methylation utilizing a cheap and safe methylation source without involving transition metals represents an important yet challenging objective. Here, a simple and clean catalyst-free protocol for the methylation of various heteroarenes (including six- and five-membered types) is described under light irradiation. This protocol employs cheap, readily available, and abundant MeOH as both the solvent and the methylation source. It was found that adding dichloromethane (DCM) as a co-solvent could significantly increase the yield of the methylation products. Heteroarenes bearing various functional groups could be methylated and tri-deuteromethylated successfully. Deuterium labeling studies suggested that the newly generated methyl group in the products consisted of two hydrogens from the methyl group and one hydrogen from the OH group in MeOH.
The photochemical alkylation and reduction of heteroarenes
McCallum,Pitre,Morin,Scaiano,Barriault
, p. 7412 - 7418 (2017/10/31)
The functionalization of heteroarenes has been integral to the structural diversification of medicinally active molecules such as quinolines, pyridines, and phenanthridines. Electron-deficient heteroarenes are electronically compatible to react with relatively nucleophilic free radicals such as hydroxyalkyl. However, the radical functionalization of such heteroarenes has been marked by the use of transition-metal catalyzed processes that require initiators and stoichiometric oxidants. Herein, we describe the photochemical alkylation of quinolines, pyridines and phenanthridines, where through direct excitation of the protonated heterocycle, alcohols and ethers, such as methanol and THF, can serve as alkylating agents. We also report the discovery of a photochemical reduction of these heteroarenes using only iPrOH and HCl. Mechanistic studies to elucidate the underlying mechanism of these transformations, and preliminary results on catalytic methylations are also reported.
Alcohols as alkylating agents in heteroarene C-H functionalization
Jin, Jian,MacMillan, David W. C.
, p. 87 - 90 (2015/09/15)
Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H2O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.
Three-component coupling sequence for the regiospecific synthesis of substituted pyridines
Chen, Ming Z.,Micalizio, Glenn C.
, p. 1352 - 1356 (2012/03/11)
A de novo synthesis of substituted pyridines is described that proceeds through nucleophilic addition of a dithiane anion to an α,β- unsaturated carbonyl followed by metallacycle-mediated union of the resulting allylic alcohol with preformed trimethylsilane-imines (generated in situ by the low-temperature reaction of lithium hexamethyldisilazide with an aldehyde) and Ag(I)- or Hg(II)-mediated ring closure. The process is useful for the convergent assembly of di- through penta-substituted pyridines with complete regiochemical control.
Synthesis and structure-activity relationships of phenylenebis(methylene)-linked bis-tetraazamacrocycles that inhibit human immunodeficiency virus replication. 2. Effect of heteroaromatic linkers on the activity of bicyclams
Bridger, Gary J.,Skerlj, Renato T.,Padmanabhan, Sreenivasan,Martellucci, Stephen A.,Henson, Geoffrey W.,Abrams, Michael J.,Joao, Heidi C.,Witvrouw, Myriam,De Vreese, Karen,Pauwels, Rudi,De Clercq, Erik
, p. 109 - 119 (2007/10/03)
A series of bicyclam analogs connected through a heteroaromatic linker have been synthesized and evaluated for their inhibitory effects on HIV-1 (IIIB) and HIV-2 (ROD) replication in MT-4 cells. The activity of pyridine- and pyrazine-linked bicyclams was found to be highly dependent upon the substitution of the heteroaromatic linker connecting the cyclam rings. For example, 2,6- and 3,5-pyridine-linked bicyclams were potent inhibitors of HIV-1 and HIV-2 replication, whereas the 2,5- and 2,4-substituted pyridine-linked compounds exhibited substantially reduced activity and, in addition, were found to be highly toxic to MT-4 cells. We have subsequently discovered that these effects are not unique; amino-substituted linkers also have the potential to deactivate phenylenebis(methylene)-linked bicyclams. A model is proposed to explain the deactivating effects of the pyridine group in certain substitution patterns based on the ability of the pyridine nitrogen to participate in pendant conformations (complexation) with the adjacent azamacrocyclic ring, which may involve hydrogen bonding or coordination to a transition metal. The introduction of a sterically hindering group such as phenyl at the 6-position of the 2,4-substituted pyridine-linked bicyclam appears to prevent pendant conformations, providing an analog with comparable anti-HIV-1 and anti-HIV-2 activities to the parent m-phenylenebis(methylene)-linked bicyclam. The results of this study have been used to develop a quantitative structure-activity relationship model with improved predictive capability in order to aid the design of antiviral bis-azamacrocyclic analogs.
THERMOLYSIS OF 1,2,3-TRIAZINES
Itoh, Takashi,Okada, Mamiko,Nagata, Kazuhiro,Ohsawa, Akio
, p. 1183 - 1190 (2007/10/02)
Thermal reactions of 1,2,3-triazines were investigated using neat thermolysis and flash vacuum thermolysis (FVT).Neat thermolysis afforded the products which were derived from intermolecular reaction, whereas unimolecular degradation occurred by FVT to give alkyne, nitrile and nitrogen.The selectivity of the reaction was considered using molecular orbital calculation.
The Reactions of N-Vinyliminophosphoranes. Part 14. A Short New Synthesis of (2,4)Pyridinophane Ring System (n=9-6): Static and Dynamic Structural Studies of - and (2,4)Pyridinophanes
Kanomata, Nobuhiro,Nitta, Makoto
, p. 1119 - 1126 (2007/10/02)
A short new synthesis of the (2,4)pyridinophane ring system (n=9-6) consists of allowing N-vinyl- and N-(1-phenylvinyl)iminophosphoranes to react with cyclic α,β-unsaturated ketones.Structural studies of the compounds prepared were based on spectroscopic measurements and MNDO calculations.The 1H and 13C NMR spectra at various temperatures showed dynamic behaviour for the oligomethylene chains of - and -(2,4)pyridinophane derivatives (8c,d).The energy barriers ΔG*c of the bridge flipping are 12-13 kcal mol-1 (Tc, 20 deg C) for (8c) and 21-22 kcal mol-1 (Tc, 150 deg C) for (8d).The lower-energy process of the oligomethylene chain in (8d) is the pseudorotation with Ea=10.3 +/- 0.2 kcal mol-1, ΔH*=9.8 +/- 0.2 kcal mol-1, and ΔS*=-4.8 cal mol-1 deg-1.Two stable conformations of the hexamethylene bridge of (8d) were unambiguously determined by low-temperature NMR.The strain of the (2,4)pyridinophane ring system was found to increase as the chain length becomes shorter.Remarkable deformation of the pyridine rings of (8c,d) was suggested by the geometrical optimization by MNDO calculation and the red shift of the UV spectrum.
