- A Journey through Hemetsberger–Knittel, Leimgruber–Batcho and Bartoli Reactions: Access to Several Hydroxy 5- and 6-Azaindoles
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The preparation of various 5- and 6-azaindoles, heterocyclic structures that are frequently part of molecules in clinical development, and their monohydroxy analogues were described. Different strategies, relying on the de novo pyrrole ring formation, were investigated and, thanks to Hemetsberger–Knittel, Bartoli and Leimgruber–Batcho approaches, 4- and 7-monohydroxy 5- and 6-azaindoles were obtained. The crucial introduction of the oxygen atom was carried out from halogen derivatives, using nucleophilic substitution reactions under basic conditions with or without a copper catalyst. Some preliminary oxidation reactions have shown that it was yet not possible to synthesize the azaquinone indole structure from monohydroxy azaindole, using molecular oxygen in the presence of salcomine as a catalyst.
- Radix, Sylvie,Hallé, Fran?ois,Mahiout, Zahia,Teissonnière, Amélie,Bouchez, Grégoire,Auberger, Ludovic,Barret, Roland,Lomberget, Thierry
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- Sequential Synthesis of Organosilicon-Linked 2-Methoxypyridines by Non-Cryogenic ortho-Metallation Using the nBu2TMPMg·Li Reagent and Hydrosilylation
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The non-cryogenic synthesis of 5/6- and/or 3-silyl-functionalised 2-methoxypyridines by a 5-Br/Mg exchange process using nBu2iPrMg Li and LiCl and involving C-3 metallation using a novel nBu2TMPMg Li reagent is described. Furthermore, the usefulness of nBu2TMPMg Li in the functionalisation of 2-methoxypyridine at the 3-position with a wide range of electrophiles was successfully tested. The above achievements have allowed the construction of organosilicon-linked 2-methoxypyridines composed of two, three and four rings by the hydrosilylation of 5- and/or 3-SiH(or alkenyl) derivatives using the hitherto rarely applied [Pt(cod)Me2] catalyst. Additionally, the synthesis of a one-chain oligomer consisting of eight 2-methoxypyridines obtained by the hydrosilylation/polymerisation approach, followed by protodesilylation of the SiHMe2 group was also achieved by manipulating the amount of catalyst in the reactions.
- Struk, ?ukasz,Sos?nicki, Jacek G.,Idzik, Tomasz J.,Maciejewska, Gabriela
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p. 1292 - 1304
(2016/03/19)
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- Synthesis and pharmacological evaluation of N-benzyl substituted 4-bromo-2,5-dimethoxyphenethylamines as 5-HT2A/2C partial agonists
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N-Benzyl substitution of phenethylamine 5-HT2A receptor agonists has dramatic effects on binding affinity, receptor selectivity and agonist activity. In this paper we examine how affinity for the 5-HT2A/2C receptors are influenced by N-benzyl substitution of 4-bromo-2,5-dimethoxyphenethylamine derivatives. Special attention is given to the 2′ and 3′-position of the N-benzyl as such compounds are known to be very potent. We found that substitutions in these positions are generally well tolerated. The 2′-position was further examined using a range of substituents to probe the hydrogen bonding requirements for optimal affinity and selectivity, and it was found that small changes in the ligands in this area had a profound effect on their affinities. Furthermore, two ligands that lack a 2′-benzyl substituent were also found to have high affinity contradicting previous held notions. Several high-affinity ligands were identified and assayed for functional activity at the 5-HT2A and 5-HT2C receptor, and they were generally found to be less efficacious agonists than previously reported N-benzyl phenethylamines.
- Hansen, Martin,Jacobsen, Stine Engesgaard,Plunkett, Shane,Liebscher, Gudrun Eckhard,McCorvy, John D.,Br?uner-Osborne, Hans,Kristensen, Jesper Langgaard
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supporting information
p. 3933 - 3937
(2015/01/30)
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- Noncryogenic synthesis of functionalized 2-methoxypyridines by halogen-magnesium exchange using lithium dibutyl(isopropyl)magnesate(1-) and lithium chloride
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2-Methoxypyridines functionalized in the 3-, 5-, or 6-position and 2,6-dimethoxypyridines functionalized in the 3-position were prepared from the corresponding bromo or iodo analogues by using lithium dibutyl(isopropyl) magnesate(1-) and lithium chloride
- Struk, Lukasz,Sosnicki, Jacek G.
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experimental part
p. 735 - 746
(2012/04/04)
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- SUBSTITUTED 4-AMINO-1-(PYRIDYLMETHYL)PIPERIDINE AND RELATED COMPOUNDS
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This invention provides 4-amino-1-(pyridylmethyl)piperidine and related compounds and pharmaceutically acceptable salts thereof which are useful as muscarinic receptor antagonists. This invention also provides pharmaceutical compositions containing such compounds; processes and intermediates useful for preparing such compounds; and methods for treating disease conditions mediated by muscarinic receptors, such as overactive bladder, irritable bowel syndrome and chronic obstructive pulmonary disease, using such compounds.
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- Piperidine derivatives
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This invention relates to piperidine derivatives having antitumor activity and useful as pharmaceuticals such as an antitumor agent.
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- Le phenyl-lithium: nouvel agent de metallation du cycle pyridinique
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Nucleophilic addition was the sole reaction of phenyl-lithium with a pyridinic ring; now the novel catalysed metallation, with phenyl-lithium, of many substituted pyridine compounds giving various derivatives in high yields with many different reagents, has been achieved.
- Mallet, Marc
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- Improved Synthesis of 2,3-Disubstituted Pyridines by Metallation of 2-Chloropyridine: a Convenient Route to Fused Polyheterocycles
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Chemoselective directed metallation of 2-chloropyridine allows the synthesis of 2-substituted 3-carbonylated pyridines, advantage being taken of the metallation ortho-directing effect of the halogen, as well as its reactivity towards nucleophiles.Thus (2-chloro-, 2-methoxy-, and 2-amino-3-pyridyl)-ethanones and -arylmethanones as well as carbaldehydes have been prepared.Some of these ortho-disubstituted intermediates have been readily cyclized to fused polyheterocycles such as naphthiridines and aza-analoges of coumarins, xanthones, and acridones.
- Trecourt, Francois,Marsais, Francis,Guengoer, Timur,Queguiner, Guy
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p. 2409 - 2415
(2007/10/02)
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- Lithiation of Methoxypyridines Directed by α-Amino Alkoxides
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The addition of methoxypyridinecarboxaldehydes to certain lithium dialkylamides gave α-amino alkoxides in situ that were ring-lithiated with alkyllithium bases.Alkylation and hydrolysis on workup provided ring-substituted methoxypyridinecarboxaldehydes via a one-pot reaction.The one-pot methylation of isomeric methoxypyridinecarboxaldehydes was examined.The regioselectivity of the lithiation-methylation was dependent on the aldehyde, the amine component of the α-amino alkoxide, and the metalation conditions.When lithiated N,N,N'-trimethylethylenediamine was used as the amine component of the α-amino alkoxide, methylation generally occured ortho to the aldehyde function.The analogous reactions using lithium N-methylpiperazide as the amine component gave substitution next to the methoxy group.Several new methylated methoxypyridinecarboxaldehydes were prepared in a regioselective manner by using this one-pot procedure.
- Comins, Daniel L.,Killpack, Michael O.
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- Catalyzed Metalation Applied to 2-Methoxypyridine
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Directed ortho lithiation of 2-methoxypyridine (1) has been regioselectively achieved at position 3 by using methyllithium catalyzed by a small amount of diisopropylamine.This metalation methodology, called "catalyzed metalation", gave good results whereas other metalation routes failed.This allowed the convenient synthesis of various 3-substituted 2-methoxypyridines of general interest.
- Trecourt, F.,Mallet, M.,Marsais, F.,Queguiner, G.
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p. 1367 - 1371
(2007/10/02)
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- ORTHO LITHIATION OF 2-, 3-, AND 4-METHOXYPYRIDINES
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The ortho lithiation of 2-, 3-, and 4-methoxypyridine was effected using mesityllithium as the metalating base.
- Comins, Daniel L.,LaMunyon, Donald H.
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p. 773 - 776
(2007/10/02)
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