- Practical and Regioselective Synthesis of C-4-Alkylated Pyridines
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The direct position-selective C-4 alkylation of pyridines has been a long-standing challenge in heterocyclic chemistry, particularly from pyridine itself. Historically this has been addressed using prefunctionalized materials to avoid overalkylation and mixtures of regioisomers. This study reports the invention of a simple maleate-derived blocking group for pyridines that enables exquisite control for Minisci-type decarboxylative alkylation at C-4 that allows for inexpensive access to these valuable building blocks. The method is employed on a variety of different pyridines and carboxylic acid alkyl donors, is operationally simple and scalable, and is applied to access known structures in a rapid and inexpensive fashion. Finally, this work points to an interesting strategic departure for the use of Minisci chemistry at the earliest possible stage (native pyridine) rather than current dogma that almost exclusively employs Minisci chemistry as a late-stage functionalization technique.
- Baran, Phil S.,Choi, Jin,Godineau, Edouard,Laudadio, Gabriele
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p. 11927 - 11933
(2021/08/20)
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- Site-selective direct C-H pyridylation of unactivated alkanes by triplet excited anthraquinone
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Site-selective C-H functionalization in chemical feedstocks is a challenging and useful reaction in the broad field of chemical research. Here, we report a modular photochemical platform for the site-selective C-H pyridylation of unactivated hydrocarbons via the unique synergistic effects of triplet excited anthraquinone and an amidyl radical-based reverse hydrogen atom transfer (RHAT) agent. The selective pyridylation of tertiary and secondary C(sp3)-H bonds in abundant chemical feedstocks was achieved by employing various N-aminopyridinium salts in a highly selective fashion, thus providing a new catalytic system for the direct construction of high-value-added compounds under ambient reaction conditions. Moreover, this operationally simple protocol is applicable to a variety of linear-, branched-, and cyclo-alkanes and more complex molecules with high degrees of site selectivity under visible-light conditions, which provides rapid and straightforward access to versatile synthons for upgrading feedstocks under mild, metal-free reaction conditions.
- Lee, Wooseok,Jung, Sungwoo,Kim, Minseok,Hong, Sungwoo
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supporting information
p. 3003 - 3012
(2021/03/01)
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- Visible-Light-Driven C4-Selective Alkylation of Pyridinium Derivatives with Alkyl Bromides
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Reported herein is a general strategy for the photochemical cross-coupling between N-amidopyridinium salts and various alkyl bromides under photocatalyst-free conditions, granting facile access to various C4-alkylated pyridines. This approach exploits the intriguing photochemical activity of electron donor-acceptor (EDA) complexes between N-amidopyridinium salts and bromide, which provides a photoactive handle capable of generating silyl radicals and driving the alkylation process. The robustness of this protocol was further demonstrated by the late-stage functionalization of complex compounds under mild and metal-free conditions.
- Hong, Sungwoo,Jung, Sungwoo,Park, Seongjin,Shin, Sanghoon
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supporting information
p. 11370 - 11375
(2020/07/21)
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- A Practical Method for Continuous Production of sp3-Rich Compounds from (Hetero)Aryl Halides and Redox-Active Esters
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A practically useful coupling reaction between aromatic halides and redox-active esters was realized by nickel catalysis through the use of a packed zinc bed column in continuous flow. Multiple reuse of the column showed a negligible decrease in efficiency, affording high space/time yields. A wide range of substrates, including a number of heteroaryl halides and polyfunctional materials were coupled in generally good yields. Longer-time and larger-scale experiments further demonstrates the robustness of the system.
- Watanabe, Eiichi,Chen, Yiding,May, Oliver,Ley, Steven V.
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supporting information
p. 186 - 191
(2019/12/24)
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- Efficient Diastereoselective Three-Component Synthesis of Pipecolic Amides
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An efficient Ugi-type three-component reaction (U-3CR) for the synthesis of pipecolic amides is reported. The U-3CR between electronically diverse isocyanides, carboxylic acids and 4-substituted Δ1-piperideines proceeds in a highly diastereoselective fashion. The Δ1-piperideines are obtained by NCS-mediated oxidation of the corresponding 4-substituted piperidines, which in turn are generated by an efficient two-step procedure involving the alkylation of 4-picoline and subsequent catalytic hydrogenation of the pyridine ring. We demonstrate the utility of this U-3CR, in combination with the convertible isocyanide 2-bromo-6-isocyanopyridine, in the synthesis of the anticoagulant argatroban.
- van der Heijden, Gydo,van Schaik, Timo B.,Mouarrawis, Valentinos,de Wit, Martin J. M.,Velde, Christophe M. L. Vande,Ruijter, Eelco,Orru, Romano V. A.
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supporting information
p. 5313 - 5325
(2019/06/10)
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- Direct arylation of strong aliphatic C–H bonds
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Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3–5, the direct functionalization of carbon–hydrogen (C–H) bonds—the most abundant moiety in organic molecules—represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)–heteroatom bonds from strong C–H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon–carbon bonds from the corresponding C(sp3)–H bonds via substrate-directed transition-metal C–H insertion8, undirected C–H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C–H bonds by electrophilic open-shell species10–14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)–H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C–H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C–H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)–C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.
- Perry, Ian B.,Brewer, Thomas F.,Sarver, Patrick J.,Schultz, Danielle M.,DiRocco, Daniel A.,MacMillan, David W. C.
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- Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation
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We developed a strategy to harness alkyl amines as alkylating agents via C-N bond activation. This Suzuki-Miyaura cross coupling of alkylpyridinium salts, readily formed from primary amines, is the first example of a metal-catalyzed cross coupling via C-N bond activation of an amine with an unactivated alkyl group. This reaction enjoys broad scope and functional group tolerance. Primary and secondary alkyl groups can be installed. Preliminary studies suggest a NiI/NiIII catalytic cycle.
- Basch, Corey H.,Liao, Jennie,Xu, Jianyu,Piane, Jacob J.,Watson, Mary P.
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supporting information
p. 5313 - 5316
(2017/04/27)
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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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- Transition-metal-free BF3-mediated oxidative and non-oxidative cross-coupling of pyridines
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We report a BF3-mediated direct alkynylation of pyridines at C(2) by using a variety of alkynyllithium reagents (oxidative cross-coupling). Moreover, we have developed a novel transition-metal-free cross-coupling method between alkylmagnesium reagents and 4-substituted pyridines, such as isonicotinonitrile and 4-chloropyridine, by employing BF3· OEt2 as a promoter. The combination of these methods enabled us to efficiently prepare a range of di-, tri-, and tetrasubstituted pyridines. Oxidative or non-oxidative - That is the question! Pyridines bearing a substituent at position 4 readily undergo a BF3-mediated oxidative coupling at position 2 with a wide range of alkynyllithium compounds. In contrast, 4-cyano- or 4-chloropyridines undergo a novel BF3-mediated cross-coupling at position 4 with alkylmagnesium reagents. The combination of the two transition-metal-free procedures allows the preparation of a broad range of pyridines.
- Chen, Quan,Leon, Thierry,Knochel, Paul
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supporting information
p. 8746 - 8750
(2014/08/18)
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- Homodimeric bis-quaternary heterocyclic ammonium salts as potent acetyl- and butyrylcholinesterase inhibitors: A systematic investigation of the influence of linker and cationic heads over affinity and selectivity
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A molecular library of quaternary ammonium salts (QASs), mainly composed of symmetrical bis-quaternary heterocyclic bromides exhibiting choline kinase (ChoK) inhibitory activity, were evaluated for their ability to inhibit acetyl- and butyrylcholinesterase (AChE and BChE, respectively). The molecular framework of QASs consisted of two positively charged heteroaromatic (pyridinium or quinolinium) or sterically hindered aliphatic (quinuclidinium) nitrogen rings kept at an appropriate distance by lipophilic rigid or semirigid linkers. Many homodimeric QASs showed AChE and BChE inhibitory potency in the nanomolar range along with a low enzymatic selectivity. Computational studies on AChE, BChE, and ChoK allowed identification of the key molecular determinants for high affinity and selectivity over either one of the three enzymes and guided the design of a hybrid bis-QAS (56) exhibiting the highest AChE affinity (IC50 = 15 nM) and selectivity over BChE and ChoK (SI = 50 and 562, respectively) and a promising pharmacological potential in myasthenia gravis and neuromuscular blockade.
- Conejo-García, Ana,Pisani, Leonardo,Del Carmen Nú?ez, Maria,Catto, Marco,Nicolotti, Orazio,Leonetti, Francesco,Campos, Joaquín M.,Gallo, Miguel A.,Espinosa, Antonio,Carotti, Angelo
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experimental part
p. 2627 - 2645
(2011/06/21)
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- Nickel-catalyzed cross-coupling of potassium aryl- and heteroaryltrifluoroborates with unactivated alkyl halides
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A method for the cross-coupling of alkyl electrophiles with various potassium aryl- and heteroaryltrifluoroborates has been developed. Nearly stoichiometric amounts of organoboron species could be employed to cross-couple a large variety of challenging heteroaryl nucleophiles. Several functional groups were tolerated on both the electrophilic and the nucleophilic partners. Chemoselective reactivity of C(sp3) - Br bonds in the presence of C(sp2) - Br bonds was achieved.
- Molander, Gary A.,Argintaru, O. Andreea,Aron, Ioana,Dreher, Spencer D.
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supporting information; experimental part
p. 5783 - 5785
(2011/03/18)
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- Bis(trimethylsilyl)ketene acetals as C,O-dinucleophiles: One-pot formation of polycyclic γ- and δ-lactones from pyridines and pyrazines
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Bis(trimethylsilyl)ketene acetals react with pyridines, quinoline and isoquinoline in the presence of stoichiometric amounts of methyl chloroformate to give the corresponding dihydropyridine-, dihydroquinoline- and dihydroisoquinoline-substituted carboxylic acids in satisfactory yields. The regio- and diastereoselectivities of the addition reactions, together with the presence or absence of rotamers, have been established. The isolated acids react with peracids to give β-hydroxy-δ-lactones through an intramolecular reaction. Similar lactonizations could also be brought about directly from the azaaromatic compounds in one-pot reactions with silica gel, iodine or bromine. In these cases δ-lactones or β-halo-δ-lactones were produced. The behaviour of pyrazines in these transformations is peculiar, since methyl chloroformate on its own induces the formation, through interaction with both nitrogen atoms, of polycyclic γ-lactones, a reaction formally reminiscent of the double nucleophilic addition of the same ketene acetals to (arene)tricarbonylchromium complexes. Most of the new structures were assigned through X-ray crystal structure determinations. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.
- Rudler, Henri,Denise, Bernard,Xu, Yiming,Parlier, Andree,Vaissermann, Jacqueline
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p. 3724 - 3744
(2007/10/03)
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- The functionalization of saturated hydrocarbons. Part 39. Further evidence for the role of the iron-carbon bond in Gif chemistry
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The functionalization of saturated hydrocarbons utilizing the Gif oxidation system is considered to occur via an intermediate containing an Fe-C bond. Iodine and iodide ion have been found to capture efficiently the Fe-C bond to give the corresponding alkyl iodide in both the Fe(II)-Fe(IV) and Fe(III)-Fe(V) manifolds. This trapping of the Fe-C bond in both manifolds is shown to be non-radical in nature.
- Barton, Derek H.R.,Costas Salgueiro, Miquel,MacKinnon, John
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p. 7417 - 7428
(2007/10/03)
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- The conversion of saturated hydrocarbons into carboxylic acids using Fe(CO)5-H2O2 oxidation
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Saturated hydrocarbons are transformed into their corresponding homologous carboxylic acids by treatment with iron pentacarbonyl and hydrogen peroxide in pyridine-acetic acid. A mechanism for this reaction is proposed. Attention is also directed to a new and convenient procedure for the determination of carbon monoxide.
- Barton, Derek H. R.,Delanghe, Nathalie C.
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p. 8137 - 8140
(2007/10/03)
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- The carboxylation of saturated hydrocarbons by Gif systems. (FeIII trispicolinate/P(OMe)3/CO/H2O2 in pyridine-acetic acid)
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Saturated hydrocarbons are transformed into the corresponding homologous carboxylic acids by treatment with Fe(Pa)3/P(OMe)3/CO/H2O2 in pyridine-acetic acid. Optimisation of the reaction conditions and mechanistics studies are reported.
- Barton, Derek H. R.,Beck, Albert H.,Delanghe, Nathalie C.
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p. 1555 - 1558
(2007/10/03)
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- Mechanism of the Gif-Barton type alkane functionalization by halide and pseudohalide ions.
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The functionalization of alkanes by halide ions under the conditions of a Gif system can be explained by free-radical redox processes.The evidence is provided by trapping the intermediate alkyl radical by protonated heteroaromatic bases.
- Minisci, Francesco,Fontana, Francesca
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p. 1427 - 1430
(2007/10/02)
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- On the Mechanism of Carbon-Hydrogen Activation in Gif-type Reactions. Kinetic Isotopic Effects in Pyridine Solution.
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Kinetic isotopic effects (KIE) were measured for oxidation, bromination and selenylation of c-C6H12/c-C6D12 in pyridine solution for different Gif-type, Fenton and other systems.The comparison of KIE and relative reactivity data for the pair c-C5H10/c-C6H12 proved that the mechanism of activation in Gif-type reactions is different from a hydrogen atom abstraction.
- Barton, Derek H. R.,Doller, Dario,Geletii, Yurii V.
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p. 3811 - 3814
(2007/10/02)
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- Functionalization of Saturated Hydrocarbons. 14. Further Studies on the Mechanism of Gif-Type Systems
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The photolysis (W light) of acyl derivatives of N-hydroxy-2-thiopyridone in pyridine-acetic acid permits a study of the partioning of secondary radicals between oxygen, pyridine, and the thione function.Comparison with the GifIV oxidation system for saturated hydrocarbons confirms that radicals are not involved in oxidation at secondary positions.On the contrary, radical behavior at the tertiary position in adamantane is again established.The two recently introduced Gif-type systems, GoAggI and GoAggII, have been shown to give the same overall selectivity in attack on adamantane with the usual coupling of the tertiary radical with pyridine.
- Barton, Derek H. R.,Halley, Frank,Ozbalik, Nubar,Schmitt, Martine,Young, Esme,Balavoine, Gilbert
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p. 7144 - 7149
(2007/10/02)
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- PHOTOCHEMICAL GENERATION OF ALIPHATIC RADICALS FROM BENZOPHENONE OXIME ESTERS: SIMPLE SYNTHESIS OF ALKYLBENZENES AND ALKYLPYRIDINES
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Photolysis of benzophenone oxime esters, prepared with aliphatic carboxylic acids and benzophenone oxime, in benzene and pyridine generates various primary, secondary and tertiary aliphatic radicals selectively, and corresponding alkylbenzenes and alkylpyridines are produced in good yields, respectively.
- Hasebe, Masato,Tsuchiya, Takashi
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p. 3239 - 3242
(2007/10/02)
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- Alkylation of Pyridine in Free Radical Chain Reactions Utilizing Alkylmercurials
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Pyridines or N,N,N',N'-tetramethyl-p-phenylenediamine will undergo a photostimulated free radical chain reaction with alkylmercury halides or carboxylates, yielding ring alkylated substitution products.Alkene mercuration products (R1CH(Y)CH(R2)HgX with Y=HO, RO, CH3CONH; X=Cl, CH3CO2, CF3CO2) can be used without isolation for the alkylation reaction
- Russell, Glen A.,Guo, Deliang,Khanna, Rajive K.
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p. 3423 - 3425
(2007/10/02)
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- ON THE MECHANISM OF THE GIF SYSTEM FOR THE OXIDATION OF SATURATED HYDROCARBONS
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The high selectivity of the Gif system for hydrocarbon oxidation is shown to depend upon the capture of tert. radicals by pyridine; the mechanism for the secondary oxidation products has only a minor radical component as judged by competitive trapping.
- Barton, Derek H. R.,Boivin, Jean,Ozbalik, Nubar,Schwartzentruber, Kathy M.,Jankowski, Krzysztof
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p. 447 - 450
(2007/10/02)
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- SELECTIVE SUBSTITUTION OF UNPROTONATED PYRIDINES BY ALKYL RADICALS
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The reactions of dioxanyl and cyclohexyl radicals with 2- and 3-X-pyridines (X=CN, COMe, CO2Me) give a single substitution product deriving by addition at the 5- and 6-position respectively; with 4-X-pyridines substitution occurs preferentially at the 3-position.If the reactions are carried out with protonated pyridines other positional isomers are obtained.From the synthetic point of view the two procedures are therefore complementary.The change in positional selectivity on passing from unprotonated to protonated aromatic substrates is discussed and interpreted on the basis of the different nature of the transition state of the addition step.
- Chianelli, D.,Testaferri, L.,Tiecco, M.,Tingoli, M.
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p. 657 - 663
(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 13. N-(2,5-Dimethylpyrrol-1-yl)pyridinium Salts in the Synthesis of 4-Alkyl and 4-Aryl-pyridines via Regiospecific Attack of Grignard Reagents and Organolithium Compounds.
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The reaction between N-(2,5-dimethylpyrrol-1-yl)pyridinium salts and alkyl- or aryl-Grignard reagents, or organolithium compounds, gives regiospecifically 1,4-dihydro-intermediates.These may be isolated and decomposed under free-radical conditions to give moderate to good yields of 4-alkyl- and 4-aryl-pyridines.Results are compared with those obtained from a related reaction sequence involving N-(2,6-dimethyl-4-oxopyridin-1-yl)pyridinium salts.
- Katritzky, Alan R.,Beltrami, Hector,Sammes, Michael P.
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p. 1684 - 1696
(2007/10/02)
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