- ZnMe2-Mediated, Direct Alkylation of Electron-Deficient N-Heteroarenes with 1,1-Diborylalkanes: Scope and Mechanism
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The regioselective, direct alkylation of electron-deficient N-heteroarenes is, in principle, a powerful and efficient way of accessing alkylated N-heteroarenes that are important core structures of many biologically active compounds and pharmaceutical agents. Herein, we report a ZnMe2-promoted, direct C2- or C4-selective primary and secondary alkylation of pyridines and quinolines using 1,1-diborylalkanes as alkylation sources. While substituted pyridines and quinolines exclusively afford C2-alkylated products, simple pyridine delivers C4-alkylated pyridine with excellent regioselectivity. The reaction scope is remarkably broad, and a range of C2- or C4-alkylated electron-deficient N-heteroarenes are obtained in good yields. Experimental and computational mechanistic studies imply that ZnMe2 serves not only as an activator of 1,1-diborylalkanes to generate (α-borylalkyl)methylalkoxy zincate, which acts as a Lewis acid to bind to the nitrogen atom of the heterocycles and controls the regioselectivity, but also as an oxidant for rearomatizing the dihydro-N-heteroarene intermediates to release the product.
- Jo, Woohyun,Baek, Seung-Yeol,Hwang, Chiwon,Heo, Joon,Baik, Mu-Hyun,Cho, Seung Hwan
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supporting information
p. 13235 - 13245
(2020/09/01)
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- Small organic molecules with tailored structures: Initiators in the transition-metal-free C-H arylation of unactivated arenes
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Simple, small organic molecules containing nitrogen and oxygen atoms in their structures have been disclosed to catalyze transition-metal-free C-H arylation of unactivated arenes with aryl iodides in the presence of tBuOK. In this article, an optimized catalytically active molecule, (2-(methylamino)phenyl)methanol, was designed. A broad range of aryl iodides could be converted into the corresponding arylated products at 100 °C over 24 h with good to excellent yields. Mechanistic experiments verified that radicals participated in this catalytic transformation and that the cleavage of the aromatic C-H bond was not the rate determining step. A K+ capture experiment by 18-crown-6 emphasized the significance of the cation species of the strong base. Fourier transform infrared spectroscopy proved that the catalytic system was activated by the hydrogen bonds between small organic molecules and tBuOK. Also, a clear mechanism was proposed. This transition-metal-free method affords a promising system for efficient and inexpensive synthesis of biaryls via a user-friendly approach, as confirmed by scale-up experiments.
- Chen, Suqing,Chen, Wenjun,Chen, Yu,Liu, Zhenghui,Mu, Tiancheng,Wang, Peng,Yan, Zhenzhong
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p. 14500 - 14509
(2020/04/27)
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- Visible Light-Mediated Decarboxylative Alkylation of Pharmaceutically Relevant Heterocycles
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A net redox-neutral method for the decarboxylative alkylation of heteroarenes using photoredox catalysis is reported. Additionally, this method features the use of simple, commercially available carboxylic acid derivatives as alkylating agents, enabling the facile alkylation of a variety of biologically relevant heterocyclic scaffolds under mild conditions.
- Sun, Alexandra C.,McClain, Edward J.,Beatty, Joel W.,Stephenson, Corey R. J.
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supporting information
p. 3487 - 3490
(2018/06/26)
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- Transition-Metal-Free Regioselective Alkylation of Pyridine N-Oxides Using 1,1-Diborylalkanes as Alkylating Reagents
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Reported herein is an unprecedented base-promoted deborylative alkylation of pyridine N-oxides using 1,1-diborylalkanes as alkyl sources. The reaction proceeds efficiently for a wide range of pyridine N-oxides and 1,1-diborylalkanes with excellent regioselectivity. The utility of the developed method is demonstrated by the sequential C?H arylation and methylation of pyridine N-oxides. The reaction also can be applied for the direct introduction of a methyl group to 9-O-methylquinine N-oxide, thus it can serve as a powerful method for late-stage functionalization.
- Jo, Woohyun,Kim, Junghoon,Choi, Seoyoung,Cho, Seung Hwan
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supporting information
p. 9690 - 9694
(2016/08/10)
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- Route to Highly Substituted Pyridines
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Pyridine rings are common structural motifs found in a number of biologically active compounds, including some top-selling pharmaceuticals. We have developed a new approach to access substituted pyridines. The method aims to provide a reliable synthesis of a diverse range of substituted pyridines through a three-step procedure. Readily available enones are first converted into 1,5-dicarbonyls through a two-step Hosomi-Sakurai allylation/oxidative cleavage sequence, which is followed by subsequent cyclization to the corresponding pyridine using hydroxylamine hydrochloride. A variety of substituted pyridines have been synthesized using this method.
- Hilf, Justin A.,Holzwarth, Michael S.,Rychnovsky, Scott D.
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p. 10376 - 10382
(2016/11/17)
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- Synthesis and utility of dihydropyridine boronic esters
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When activated by an acylating agent, pyridine boronic esters react with organometallic reagents to form a dihydropyridine boronic ester. This intermediate allows access to a number of valuable substituted pyridine, dihydropyridine, and piperidine products.
- Panda, Santanu,Coffin, Aaron,Nguyen, Q. Nhu,Tantillo, Dean J.,Ready, Joseph M.
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supporting information
p. 2205 - 2209
(2016/02/18)
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- Flow synthesis of 2-methylpyridines via α-methylation
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A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch reaction protocols. Eight 2-methylated pyridines were produced by progressing starting material through a column packed with Raney nickel using a low boiling point alcohol (1-propanol) at high temperature. Simple collection and removal of the solvent gave products in very good yields that were suitable for further use without additional work-up or purification. Overall, this continuous flow method represents a synthetically useful protocol that is superior to batch processes in terms of shorter reaction times, increased safety, avoidance of work-up procedures, and reduced waste. A brief discussion of the possible mechanism(s) of the reaction is also presented which involves heterogeneous catalysis and/or a Ladenberg rearrangement, with the proposed methyl source as C1 of the primary alcohol.
- Manansala, Camille,Tranmer, Geoffrey K.
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p. 15797 - 15806
(2015/12/01)
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- Alcohols as alkylating agents in heteroarene C-H functionalization
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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.
- Jin, Jian,MacMillan, David W. C.
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- Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates to access isoquinolines
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The concise synthesis of 3-substituted or non-C3-substituted isoquinolines through Rh-catalyzed sequential oxidative C-H activation/annulation with geminal-substituted vinyl acetates was developed with good functional group tolerance. The protocol was successfully applied to the total synthesis of the natural product papaverine.
- Chu, Haoke,Sun, Song,Yu, Jin-Tao,Cheng, Jiang
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supporting information
p. 13327 - 13329
(2015/08/24)
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- Iridium-catalyzed C-H borylation of pyridines
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The iridium-catalysed C-H borylation is a valuable and attractive method for the preparation of aryl and heteroaryl boronates. However, application of this methodology for the preparation of pyridyl and related azinyl boronates can be challenged by low reactivity and propensity for rapid protodeborylation, particularly for a boronate ester ortho to the azinyl nitrogen. Competition experiments have revealed that the low reactivity is due to inhibition of the active catalyst through coordination of the azinyl nitrogen lone pair at the vacant site on the iridium. This effect can be overcome through the incorporation of a substituent at C-2. Moreover, when this is sufficiently electron-withdrawing protodeborylation is sufficiently slowed to permit isolation and purification of the C-6 boronate ester. Following functionalization, reduction of the directing C-2 substituent provides the product arising from formal ortho borylation of an unhindered pyridine ring. This journal is the Partner Organisations 2014.
- Sadler, Scott A.,Tajuddin, Hazmi,Mkhalid, Ibraheem A. I.,Batsanov, Andrei S.,Albesa-Jove, David,Cheung, Man Sing,Maxwell, Aoife C.,Shukla, Lena,Roberts, Bryan,Blakemore, David C.,Lin, Zhenyang,Marder, Todd B.,Steel, Patrick G.
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supporting information
p. 7318 - 7327
(2014/11/07)
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- Modular pyridine synthesis from oximes and enals through synergistic copper/iminium catalysis
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We describe here a [3+3]-type condensation reaction of O-acetyl ketoximes and α,β-unsaturated aldehydes that is synergistically catalyzed by a copper(I) salt and a secondary ammonium salt (or amine). This redox-neutral reaction allows modular synthesis of a variety of substituted pyridines under mild conditions with tolerance of a broad range of functional groups. The reaction is driven by a merger of iminium catalysis and redox activity of the copper catalyst, which would initially reduce the oxime N-O bond to generate a nucleophilic copper(II) enamide and later oxidize a dihydropyridine intermediate to the pyridine product.
- Wei, Ye,Yoshikai, Naohiko
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supporting information
p. 3756 - 3759
(2013/04/23)
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- Direct synthesis of 4,4-disubstituted N-silyl-1,4-dihydropyridines
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An unprecedented method for the preparation of 4,4-disubstituted 1,4-dihydropyridines is presented. It is based on the trapping reaction of 4-substitued N-silylpyridinium ions. When performed with dialkylmagnesium reagents, such as iPr2Mg, silyl protected 4,4-disubstituted 1,4-dihydropyridines were obtained in up to quantitative yields. High 1,4-selectivity was found for sterically demanding nucleophiles, whereas small nucleophiles (Me2Mg) tend to yield 1,2-addition-products. Grignard, dialkylzinc and organocopper reagents were found to give either no addition products or less favorable results. Reduction of the obtained 1,4-dihydropyridine with NaCNBH3 in the presence of HCl, followed by treatment with tert-butyl dicarbonate provided the corresponding N-Boc protected piperidines with high yields.
- Br?ckow, Jan,Wanner, Klaus T.
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p. 2395 - 2404
(2007/10/03)
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- PYRIDINE SYNTHESIS VIA ANODIC OXIDATION OF 1-ACYLDIHYDROPYRIDINES
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The preparation of several substituted pyridines via anodic oxidation of 1-acyldihydropyridines is reported
- Comins, Daniel L.,Killpack, Michael O.
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p. 2025 - 2028
(2007/10/02)
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- α-METALATION OF 1-(TERT-BUTOXYCARBONYL)-1,4-DIHYDROPYRIDINES
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The α-metalation-alkylation of 4-substituted 1-(tert-butoxycarbonyl)-1,4-dihydropyridines is described.Subsequent aromatization provides a new route to 2,4-disubstituted pyridines.
- Comins, Daniel L.
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p. 2807 - 2810
(2007/10/02)
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- Regioselective Addition of Grignard Reagents to 1-Acylpyridinium Salts. A Convenient Method for the Synthesis of 4-Alkyl(aryl)pyridines
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The addition of Grignard reagents to 1-acylpyridinium salts afforded 1-acyl-2-alkyl(aryl)-1,2-dihydropyridines and 1-acyl-4-alkyl(aryl)-1,4-dihydropyridines.The regioselectivity of this reaction, 1,2- vs. 1,4-addition, was examined and found to be dependent upon the structures of the Grignard reagent and the 1-acyl group.Pyridine, 2-picoline, and 3-picoline were studied, and in most cases, significant amounts of 1,4-addition occurred.When a catalytic amount of cuprous iodide was present, nearly exclusive 1,4-addition resulted.The crude 1,4-dihydropyridines were aromatized by heating with sulfur to provide 4-substituted pyridines and picolines in good yield and high isomeric purity.
- Comins, Daniel L.,Abdullah, Abdul H.
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p. 4315 - 4319
(2007/10/02)
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- Synthetic Applications of N-N Linked Heterocycles. Part 7. The Preparation of 4-Alkyl- and 4-Aryl-pyridines by Regiospecific Attack of Grignard Reagents γ to Quaternary Nitrogen in N-(2,6-Dimethyl-4-oxopyridin-1-yl)pyridinium Salts
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N-(2,6-Dimethyl-4-oxopyridin-1-yl)pyridinium salts (4), new reagents for the regiospecific synthesis of 4-substituted pyridines, give moderate to high yields of 4-alkyl- and 4-aryl-pyridines (8) - (10) on reaction with Grignard reagents.The scope and limitations on the reaction, which proceeds via 1,4-dihydro-intermediates (5) - (7), are explored.No 2-substituted pyridines were detected.Some reactions with organolithium compounds are also described.
- Katritzky, Alan R.,Beltrami, Hector,Sammes, Michael P.
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p. 2480 - 2484
(2007/10/02)
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