Synthesis of 1′‐methylspiro[3<i>H</i>‐indole‐3,n'‐piperidines] from 1‐methyl‐n‐piperidinecarbaldehydes

Benito, Y.; Canoira, Laureano; Martinez-Lopez, N.; Rodriguez, Jose Gonzalo Gonzalez; Temprano, F.

doi:10.1002/jhet.5570240315

Cited by 16 publications

(3 citation statements)

References 6 publications

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“…In our efforts to synthesize 3,3-disubstituted oxindoles from arylhydrazines ( 1 ) and α-branched aldehydes ( 2 ), we found the intermediate indolenines ( 3 ) rearrange to afford 2,3-disubstituted indoles ( 4 ) when heated to elevated reaction temperatures for prolonged periods (Scheme ). Although Rodriguez , reported many years ago that rearrangement of spiroindolenines of type 3 can occur with an acid catalyst to give cycloalkanoindoles, detailed studies on this rearrangement and examination of the acyclic variant have not been reported. Our initial results prompted us to investigate the rearrangement in greater detail in the hopes of expanding the scope.…”

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confidence: 99%

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Liu

Robichaud

et al. 2006

Org. Lett.

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confidence: 99%

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Liu

Robichaud

et al. 2006

Org. Lett.

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“…4 The most important features of our reaction sequence are its shortness and the fact that the intermediate product, 4-(methoxymethylene)-1-methylpiperidine (2), was sufficiently stable to be stored in a freezer over a longer period of time (whereas 1-methyl-4-piperidinecarboxaldehyde (3) shows significant instability upon isolation). Furthermore, 4-(methoxymethylene)-1-methylpiperidine (2) not only can be produced on a larger scale, but also allows smooth separation from the Wittig by-product, triphenylphosphine, through sophisticated workup.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of novel 3-heterospiro[5.5]undecanes

Fröhlich¹,

Sauter²,

Hametner³

et al. 2009

Arkivoc

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Synthetic strategies leading to novel 3-heterospiro[5.5]undecan-9-ones are described. Starting from aliphatic 4-substituted heterocyclic aldehydes (1-methyl-4-piperidine carboxaldehyde, 4-formyl-1-piperidinecarboxylic acid 1,1-dimethylethyl ester, 2H-tetrahydrothiopyran-4-carboxaldehyde, and 2H-tetrahydropyran-4-carboxaldehyde) 3-heterospiro[5.5]undec-7-en-9-ones were made by Robinson annelation and upon further hydrogenation gave the desired 3-heterospiro[5.5]undecan-9-ones.

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“…The synthetic sequence had to be modified slightly for the synthesis of the 6-pyrazol-1-yl-5-methyl-2-pyridinecarboxaldehyde 3e . Thus, the alcohol 17 was first oxidized and then the aldehyde function protected as the dioxolane 20 . Reaction of 20 with the sodium salt of pyrazole yielded the intermediate 21 , which upon removal of the protecting group, afforded the desired 6-pyrazolo-5-methyl-pyridine-2-carboxaldehyde derivative 3e .…”

Section: Chemistrymentioning

confidence: 99%

Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT_1A Receptors

et al. 1999

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The aim of this work was to improve the oral bioavailability of a recently discovered, novel structural class of 5-HT 1A receptor agonists: aryl-{[4-(6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone. Incorporation of a fluorine atom in the -position to the amino function in the side chain led to analogues that exhibited, in general, enhanced and longlasting 5-HT 1A agonist activity in rats after oral administration. Location of the fluorine atom at the C-4 position of the piperidine ring was the most favorable, and among the various substituents tested, the ability of the fluorine was unique in improving the oral activity of this family of ligands. Thus, the derivatives 39, 46, and 61 bound with higher affinity and selectivity to 5-HT 1A receptors (versus dopaminergic D 2 and adrenergic R 1 receptors) and displayed more potent 5-HT 1A agonist activity in vitro and in vivo than their C-4 desfluoro analogues. To examine the relationship between the conformation of the pharmacophore and the level of agonistic activity of this type of ligand, we synthesized a series of 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-(H or CH 3 )-6-R-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone derivatives and found that the combination of a 5-methyl and a 6-methylamino substituent on the pyridine ring synergistically affected their 5-HT 1A agonist properties. Thus, the 3-chloro-4-fluorophenyl-(4-fluoro-4{[(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl-methanone 40 behaved as a more potent 5-HT 1A receptor agonist in vitro and in vivo than its 5-unsubstituted analogue 38. The antidepressant potential of the lead compounds 40, 45, and 54 was examined by means of the forced swimming test (FST) in rats. The results indicated that, after a single oral administration, these compounds inhibited immobility in the FST more potently and more extensively than the clinically used antidepressant imipramine. Thus, 40, 45, and 54 are potent, orally active 5-HT 1A receptor agonists with marked antidepressant potential.

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Synthesis of 1′‐methylspiro[3H‐indole‐3,n'‐piperidines] from 1‐methyl‐n‐piperidinecarbaldehydes

Cited by 16 publications

References 6 publications

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Synthesis of novel 3-heterospiro[5.5]undecanes

Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT_1A Receptors

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Synthesis of 1′‐methylspiro[3H‐indole‐3,n'‐piperidines] from 1‐methyl‐n‐piperidinecarbaldehydes

Cited by 16 publications

References 6 publications

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Rearrangement of 3,3-Disubstituted Indolenines and Synthesis of 2,3-Substituted Indoles

Synthesis of novel 3-heterospiro[5.5]undecanes

Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT1A Receptors

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Product

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Novel Derivatives of 2-Pyridinemethylamine as Selective, Potent, and Orally Active Agonists at 5-HT_1A Receptors