- Green synthesis method of polyaryl substituted methanol
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The invention relates to a green synthesis method of polyaryl substituted methanol, in particular to a method for efficiently synthesizing polyaryl substituted methanol in a polar aprotic solvent under the condition of an oxidizing agent by taking polyaryl substituted methane as a raw material and alkali as an additive. The method provided by the invention is green and environment-friendly, avoids using expensive metal catalysts, and has the advantages of low cost, few reaction steps, short time, high yield and the like.
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Paragraph 0127-0131; 0147-0151
(2021/04/17)
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- Transition-Metal Free Chemoselective Hydroxylation and Hydroxylation-Deuteration of Heterobenzylic Methylenes
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We developed an approach for direct selective hydroxylation of heterobenzylic methylenes to secondary alcohols avoiding overoxidation to ketones by using a KOBu-t/DMSO/air system. Most reactions could reach completion in several minutes to give hydroxylated products in 41-76% yields. Using DMSO-d6, this protocol resulted in difunctionalization of heterobenzylic methylenes to afford α-deuterated secondary alcohols (>93% incorporation). By employing this method, active pharmaceutical ingredients carbinoxamine and doxylamine were synthesized in two steps in moderate yields.
- Fu, Yiwei,Li, Hao,Liu, Yonghai,Mang, Zhiguo,Shi, Lei,Sun, Chengyu,Yu, Yang
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supporting information
p. 8127 - 8131
(2020/11/03)
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- Targeting the aryl hydrocarbon receptor with a novel set of triarylmethanes
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The aryl hydrocarbon receptor (AhR) is a chemical sensor upregulating the transcription of responsive genes associated with endocrine homeostasis, oxidative balance and diverse metabolic, immunological and inflammatory processes, which have raised the pharmacological interest on its modulation. Herein, a novel set of 32 unsymmetrical triarylmethane (TAM) class of structures has been synthesized, characterized and their AhR transcriptional activity evaluated using a cell-based assay. Eight of the assayed TAM compounds (14, 15, 18, 19, 21, 22, 25, 28) exhibited AhR agonism but none of them showed antagonist effects. TAMs bearing benzotrifluoride, naphthol or heteroaromatic (indole, quinoline or thiophene) rings seem to be prone to AhR activation unlike phenyl substituted or benzotriazole derivatives. A molecular docking analysis with the AhR ligand binding domain (LBD) showed similarities in the binding mode and in the interactions of the most potent TAM identified 4-(pyridin-2-yl (thiophen-2-yl)methyl)phenol (22) compared to the endogenous AhR agonist 5,11-dihydroindolo[3,2-b]carbazole-12-carbaldehyde (FICZ). Finally, in silico predictions of physicochemical and biopharmaceutical properties for the most potent agonistic compounds were performed and these exhibited acceptable druglikeness and good ADME profiles. To our knowledge, this is the first study assessing the AhR modulatory effects of unsymmetrical TAM class of compounds.
- Barigye, Stephen J.,Carpio, Laureano E.,Ferroud, Clotilde,Giner, Rosa M.,Goya-Jorge, Elizabeth,Gozalbes, Rafael,Loones, Nicolas,Rampal, Celine,Sylla-Iyarreta Veitía, Maité
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supporting information
(2020/10/02)
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- Conformational Dynamics-Guided Loop Engineering of an Alcohol Dehydrogenase: Capture, Turnover and Enantioselective Transformation of Difficult-to-Reduce Ketones
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Directed evolution of enzymes for the asymmetric reduction of prochiral ketones to produce enantio-pure secondary alcohols is particularly attractive in organic synthesis. Loops located at the active pocket of enzymes often participate in conformational changes required to fine-tune residues for substrate binding and catalysis. It is therefore of great interest to control the substrate specificity and stereochemistry of enzymatic reactions by manipulating the conformational dynamics. Herein, a secondary alcohol dehydrogenase was chosen to enantioselectively catalyze the transformation of difficult-to-reduce bulky ketones, which are not accepted by the wildtype enzyme. Guided by previous work and particularly by structural analysis and molecular dynamics (MD) simulations, two key residues alanine 85 (A85) and isoleucine 86 (I86) situated at the binding pocket were thought to increase the fluctuation of a loop region, thereby yielding a larger volume of the binding pocket to accommodate bulky substrates. Subsequently, site-directed saturation mutagenesis was performed at the two sites. The best mutant, where residue alanine 85 was mutated to glycine and isoleucine 86 to leucine (A85G/I86L), can efficiently reduce bulky ketones to the corresponding pharmaceutically interesting alcohols with high enantioselectivities (~99% ee). Taken together, this study demonstrates that introducing appropriate mutations at key residues can induce a higher flexibility of the active site loop, resulting in the improvement of substrate specificity and enantioselectivity. (Figure presented.).
- Liu, Beibei,Qu, Ge,Li, Jun-Kuan,Fan, Wenchao,Ma, Jun-An,Xu, Yan,Nie, Yao,Sun, Zhoutong
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supporting information
p. 3182 - 3190
(2019/05/15)
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- Ligand-Free Iridium-Catalyzed Dehydrogenative ortho C?H Borylation of Benzyl-2-Pyridines at Room Temperature
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A convenient and ligand-free iridium-catalyzed dehydrogenative ortho C?H borylation of benzyl-2-pyridines has been developed. The reaction proceeds smoothly at room temperature using pinacolborane as a borylating reagent in the presence of catalytic amount of [IrOMe(COD)]2. The reaction is compatible with many functional groups, providing a vast array of ortho borylated products in moderate to excellent yields with excellent selectivities. (Figure presented.).
- Yang, Yuhuan,Gao, Qian,Xu, Senmiao
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supporting information
p. 858 - 862
(2019/01/04)
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- Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of Aryl N-Heteroaryl Ketones with N-Oxide as a Removable ortho-Substituent
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A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric synthesis of bepotastine besilate in 51% total yield and 99.9% ee.
- Liu, Qixing,Wang, Chunqin,Zhou, Haifeng,Wang, Baigui,Lv, Jinliang,Cao, Lu,Fu, Yigang
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supporting information
p. 971 - 974
(2018/02/23)
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- Rhodium Catalyzed Asymmetric Hydrogenation of 2-Pyridine Ketones
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Catalyzed by [Rh(COD)Binapine]BF4, the asymmetric hydrogenation of 2-pyridine ketones has been achieved with excellent enantioselectivities (enantiomeric excesses up to 99%) under mild conditions. This method is suitable for various kinds of 2-pyridine ketones and their derivatives. A number of enantiomerically pure chiral 2-pyridine-aryl/alkyl alcohols were prepared through hydrogenation, which can be used directly in organic synthesis.
- Yang, Hailong,Huo, Ningning,Yang, Ping,Pei, Hao,Lv, Hui,Zhang, Xumu
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supporting information
p. 4144 - 4147
(2015/09/15)
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- Facile one-pot synthesis of [1,2,3]triazolo[1,5-a]pyridines from 2-acylpyridines by copper(II)-catalyzed oxidative N-N bond formation
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An efficient and simple method for the synthesis of various [1,2,3]triazolo[1,5-a]pyridines has been established. The method involves a copper(II)-catalyzed oxidative N-N bond formation that uses atmospheric oxygen as the terminal oxidant following hydrazonation in one pot. The use of ethyl acetate as the solvent dramatically promotes the oxidative N-N bond-formation reaction and enables the application of oxidative cyclization in the efficient one-pot reaction. A mechanism for the reaction was proposed on the basis of the results of a spectroscopic study. In the same pot: [1,2,3]Triazolo[1,5-a] pyridines are synthesized from the corresponding 2-acylpyridines by a one-pot method, consisting of hydrazonation followed by oxidative cyclization through copper(II)-catalyzed N-N bond formation (see scheme).
- Hirayama, Tasuku,Ueda, Satoshi,Okada, Takahiro,Tsurue, Norihiko,Okuda, Kensuke,Nagasawa, Hideko
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supporting information
p. 4156 - 4162
(2014/04/17)
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- Effective dehydrogenation of 2-pyridylmethanol derivatives catalyzed by an iron complex
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An unprecedented iron complex-catalyzed dehydrogenation of alcohols was achieved using CpFe(CO)2Cl with a base or CpFe(CO)(Py)(Ph) as a catalyst without sacrificing the hydrogen acceptors. This reaction effectively (up to TON 67000) converted 2-pyridylmethanol derivatives to the corresponding ketones or aldehydes. The mechanistic study is also discussed. the Partner Organisations 2014.
- Kamitani, Masahiro,Ito, Masaki,Itazaki, Masumi,Nakazawa, Hiroshi
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supporting information
p. 7941 - 7944
(2014/07/08)
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- Iron-catalyzed C-H bond functionalization for the exclusive synthesis of pyrido[1,2-a]indoles or triarylmethanols
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The efficient and selective iron-catalyzed C-H activation of 2-benzhydrylpyridine derivatives was employed for the preparation of pyrido[1,2-a]indoles through an intramolecular C-H amination reaction. In the presence of molecular oxygen as the sole oxidant, the same 2-benzhydrylpyridines were also used for the synthesis of the corresponding tertiary alcohols. In these approaches, the iron catalyst was used to selectively activate the C(sp2)-H bond of 2-benzhydrylpyridine, in the case of the intramolecular ring-closing C-H amination reaction in which the pyridine nitrogen atom was a directing group as well as a nucleophile, and the C(sp3)-H bond of the same compound, in the case of the oxidation reaction to give the corresponding triaryl carbinol.
- Karthikeyan, Iyyanar,Sekar, Govindasamy
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supporting information
p. 8055 - 8063
(2015/01/09)
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- Friedel-Crafts hydroxyalkylation through activation of a carbonyl group using AlBr3: An easy access to pyridyl aryl/heteroaryl carbinols
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Aromatic electrophilic substitution of aromatic/electron rich heteroaromatic compounds with AlBr3 activated aldehydes/ketone to afford pyridyl aryl/heteroaryl or diaryl carbinols is described. The strong electron donating group dictates the regiochemical outcome of the product.
- Harikrishnan, Adhikesavan,Selvakumar, Jayaraman,Gnanamani, Elumalai,Bhattacharya, Suman,Ramanathan, Chinnasamy Ramaraj
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supporting information
p. 563 - 567
(2013/04/10)
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- Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring
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A newly developed microscale ReactIR flow cell was used as a convenient and versatile inline analytical tool for Grignard formation in continuous flow chemical processing. The LiCl-mediated halogen/Mg exchange reaction was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides. Furthermore, inline IR monitoring was used for the analysis of conversion and possible byproduct formation, as well as a potential tool for elucidation of mechanistic details. The results described herein indicate that the continuous flow systems are effective for highly exothermic reactions such as the Grignard exchange reaction due to fast mixing and efficient heat transfer.
- Brodmann, Tobias,Koos, Peter,Metzger, Albrecht,Knochel, Paul,Ley, Steven V.
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experimental part
p. 1102 - 1113
(2012/08/27)
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- Indolizinones as synthetic scaffolds: Fundamental reactivity and the relay of stereochemical information
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Indolizinones are under-explored N-heterocycles that react with exquisite chemo- and stereoselectivity. An exploration of the fundamental reactivity of these azabicycles demonstrates the potential to relay stereochemical information from the ring-fusion to newly formed stereocenters on the bicyclic core. The indolizinone diene undergoes selective hydrogenation and readily participates in Diels-Alder cycloadditions as well as ene reactions. The vinylogous amide embedded in the five-membered ring is resistant to reaction when the diene is in place. However, removal of the diene allows for diastereoselective hydrogenation of, and 1,4-additions to, the vinylogous amide. These fundamental reactions with indolizinones have provided a structurally diverse array of products that hold promise in the context of natural product synthesis.
- Hardin Narayan, Alison R.,Sarpong, Richmond
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supporting information; experimental part
p. 70 - 78
(2012/01/04)
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- Synthesis of fluorescent 1,3-diarylated imidazo[1,5-α]pyridines: Oxidative condensation-cyclization of aryl-2-pyridylmethylamines and aldehydes with elemental sulfur as an oxidant
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Oxidative condensation - cyclization of aldehydes and aryl-2- pyridylmethylamines proceeded in the presence of a stoichiometric amount of elemental sulfur as an oxidant in the absence of catalyst. The reaction gave a variety of 1,3-diarylated imidazo[l,5-a]pyridines in good to high yields. The products showed fluorescence emission in a wavelength range of 454-524 nm. The quantum yields of 1,3-diarylated imidazopyridines were greatly improved compared to those of the parent 3-monosubstituted compounds.
- Shibahara, Fumitoshi,Sugiura, Rie,Yamaguchi, Eiji,Kitagawa, Asumi,Murai, Toshiaki
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supporting information; experimental part
p. 3566 - 3568
(2009/09/05)
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- Convenient, benign and scalable synthesis of 2- and 4-substituted benzylpiperidines
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A short, scalable and environmentally benign synthesis of 2- and 4-substituted benzylpiperidines has been developed. The method is based on the temperature-programmed consecutive deoxygenation and heteroaromatic ring saturation of aryl(pyridin-2-yl)- and aryl(pyridin-4-yl)methanols and aryl(pyridin-4-yl)methanones in the presence of Pd/C catalyst. The crucial roles of the temperature, the acidity and the substrate structure in the change of selectivity have been demonstrated by isolation of several substituted aryl(piperidine)methanols. The carbinols and ketones were prepared from commercially available pyridinecarbaldehydes or 4-cyanopyridine and substituted bromobenzenes via organometallic intermediates. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Agai, Bela,Proszenyak, Agnes,Tarkanyi, Gabor,Vida, Laszlo,Faigl, Ferenc
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p. 3623 - 3632
(2007/10/03)
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