Direct, One-Pot Reductive Alkylation of Anilines with Functionalized Acetals Mediated by Triethylsilane and TFA. Straightforward Route for Unsymmetrically Substituted Ethylenediamine

Righi, Marika; Bedini, Annalida; Piersanti, Giovanni; Romagnoli, Federica; Spadoni, Gilberto

doi:10.1021/jo102109f

Cited by 22 publications

(23 citation statements)

References 26 publications

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“…[39] General procedure for reductive N-alkylation of anilines. TFA (1 mL) and TES (0.4 mL, 2.5 mmol) were added to a solution of the opportune aniline (1 mmol) and N-(2,2-dimethoxyethyl) acetamide [40] (206 mg, 1.4 mmol) in DCM (2 mL), and the resulting mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. After cooling to 0°C, the reaction mixture was carefully neutralized with NaHCO 3 aqueous saturated solution of and diluted with DCM.…”

Section: -Methoxy-[11'-biphenyl]-2-amine (4 H)mentioning

confidence: 99%

N‐(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

et al. 2021

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The MT 2 -selective melatonin receptor ligand UCM765 (N-(2-((3methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT 1 and MT 2 binding affinities. Introduction of a m-hydroxymethyl substitu-ent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a Nmethyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.

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Section: -Methoxy-[11'-biphenyl]-2-amine (4 H)mentioning

confidence: 99%

N‐(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

et al. 2021

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“…To overcome this challenge, we turned our attention to a one-pot reductive N-alkylation procedure previously reported by Righi. 29 It was extended to the direct N-alkylation of a-f with acetals 7 and 8, in the presence of triethylsilane (TES), as nontoxic and stable reducing agent (Scheme 2). To obtain acetamide 7 from nitrile 5, we slightly modified a procedure involving the use of a large excess of NaBH 4 (7 eq.…”

Section: Chemistrymentioning

confidence: 99%

“…1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 148. 29 Chloro-10H-phenothiazin-10-yl)-N-methylpropan-1-amine (2Ab).…”

Section: -(1011-dihydro-5h-dibenzo[bf]azepin-5-yl)-n-methylpropan-mentioning

confidence: 99%

A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential

Uliassi

Peña-Altamira

Morales

et al. 2018

ACS Chem. Neurosci.

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Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a purposely developed phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bcshowed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases.

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“…[11][12][13][14] These polycyclic compounds are also identified as vital structural constituents useful intermediates in organic synthesis. [15][16][17] Moreover, they exhibit diverse medical functions as antidepressant, antiviral, antiepileptic, antiseizure, anticonvulsant, antimicrobial, antimalarial, anticancer, antioxidant antitumor, antibiotics and sirtuin-2 inhibitory activities. [18][19][20] Full literature survey for the applied methodologies in the synthesis of 5H-dibenz[b,f]azepine, dihydrodibenzazepine and tetrahydro-5H-dibenz[b,f]azocine systems revealed that synthesis of such heterocycles has been a prominent research objective for over a century and a variety of well established methods have been developed to access 5H-dibenzo[b,f]azepine derivatives.…”

Section: Introductionmentioning

confidence: 99%

Friedel-Crafts chemistry. Part 40. An expedient novel synthesis of some dibenz-azepines, -azocines, 11H-benzo[f]pyrido[2,3-b]azepines and 6H-benzo[g]pyrido[2,3-c]azocines

El-Aal¹,

Khalaf²

2013

Arkivoc

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A new synthetic approach for the synthesis of novel 5H-dibenz [2,3-c]azocine derivatives is reported. The key step of this methodology is based on Friedel-Crafts ring closure of nitrogen containing carboxylic acids and alkanols in the presence of AlCl 3 , P 2 O 5 or PPA catalysts in overall high yields. The starting carboxylic acids were prepared via an unequivocal synthetic pathway by the basic hydrolysis of trimethyloxindole followed by N-arylation reactions.

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Direct, One-Pot Reductive Alkylation of Anilines with Functionalized Acetals Mediated by Triethylsilane and TFA. Straightforward Route for Unsymmetrically Substituted Ethylenediamine

Cited by 22 publications

References 26 publications

N‐(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

N‐(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

A Focused Library of Psychotropic Analogues with Neuroprotective and Neuroregenerative Potential

Friedel-Crafts chemistry. Part 40. An expedient novel synthesis of some dibenz-azepines, -azocines, 11H-benzo[f]pyrido[2,3-b]azepines and 6H-benzo[g]pyrido[2,3-c]azocines

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