RESUMO
The key elimination step for the formation of 3-substituted and 3,6-disubstituted benzynes from 2-haloaryllithiums displays a pronounced solvent-dependent regioselectivity. All 2-haloaryllithiums with electron withdrawing groups in the 6 position are shown by 6Li and 13C NMR spectroscopic studies to be monomers in THF. DFT computational studies implicate trisolvates. Rate studies reveal that LiF eliminates via monomer-based pathways requiring THF dissociation whereas LiCl eliminates via nondissociative pathways. Elimination to form 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity that is traced to competing solvent-dissociative and nondissociative dissociative pathways for the elimination of LiCl and LiF, respectively.
Assuntos
Derivados de Benzeno/química , Derivados de Benzeno/síntese química , Simulação por Computador , Hidrocarbonetos Halogenados/química , Cinética , Lítio/química , Espectroscopia de Ressonância Magnética/métodos , Modelos Químicos , Estrutura Molecular , Compostos Organometálicos/química , Solventes/químicaRESUMO
[Structure: see text] The development of a concise enantioselective synthesis of nicotinic alkaloid 1 is presented. The route features the synthesis and use of a "stable" aliphatic triflate 21 in an alkylation step to generate Heck precursor 24 and an enantioselective cyclization to establish a compound with the key [3.2.1]-bicyclic core, 29.
Assuntos
Sondas Moleculares , Nicotina/análogos & derivados , Receptores Nicotínicos/química , Cristalografia por Raios X , Modelos Moleculares , Nicotina/síntese química , EstereoisomerismoRESUMO
3,5-Bicyclic aryl piperidines are a new class of high-affinity alpha4beta2 nicotinic receptor agents. We have sought nicotinic receptor partial agonists of the alpha4beta2 nicotinic acetylcholine receptor for smoking cessation, and a number of compounds fulfill potency, selectivity, and efficacy requirements in vitro. In vivo, selected agents demonstrate potent partial agonist efficacy on the mesolimbic dopamine system, a key measure of therapeutic potential for smoking cessation.
Assuntos
Piperidinas/química , Piperidinas/farmacologia , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar/métodos , Animais , Ciclização , Estrutura Molecular , Piperidinas/classificação , Ratos , Relação Estrutura-AtividadeRESUMO
The preparation and biological activity of analogs of (-)-cytisine, an alpha4beta2 nicotinic receptor partial agonist, are discussed. All-carbon-containing phenyl ring replacements of the pyridone ring system, generated via Heck cyclization protocols, exhibited weaker affinity and lower efficacy partial agonist profiles relative to (-)-cytisine. In vivo, selected compounds exhibit lower efficacy partial agonist profiles than that of (-)-cytisine.
Assuntos
Alcaloides/farmacologia , Carbono/química , Dopamina/metabolismo , Agonistas Nicotínicos/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Receptores Nicotínicos/química , Alcaloides/química , Animais , Azocinas/química , Azocinas/farmacologia , Agonistas Nicotínicos/química , Quinolizinas/química , Quinolizinas/farmacologia , Ratos , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar , Relação Estrutura-AtividadeRESUMO
The key elimination step for the formation of 3-chloro- and 3-fluorobenzyne from 2-chloro-6-fluorophenyllithium displays a pronounced solvent-dependent regioselectivity. 6Li and 13C NMR spectroscopic studies on 2-chloro-6-fluorophenyllithium reveal a single monomeric aryllithium, suggested by DFT computational studies to be a trisolvate. Rate studies indicate that the elimination of LiCl and LiF proceeds via trisolvated and disolvated monomers, respectively.
Assuntos
Derivados de Benzeno/síntese química , Compostos Bicíclicos com Pontes/síntese química , Lítio/química , Derivados de Benzeno/química , Cinética , Espectroscopia de Ressonância Magnética/métodos , Compostos Organometálicos/químicaRESUMO
Noncoordinating solvents permit the halogen-metal exchange-induced formation of benzyne (aryne) from di- and trihalobenzene precursors in the presence of cyclopentadiene to give 1,4-dihydro-1,4-methano-naphthalenes. Studies with mixed halide precursors and nonacidic Diels-Alder diene traps reveal that ethereal and hydrocarbon solvents influence the halide leaving group facility, resulting in a reversal of 3-halobenzyne regioselectivity.
RESUMO
A synthesis of 4,5-benzo-1-aza-tricyclo[4.3.1.1(3,8)]undecane (1), a benzo-1-aza-adamantane derivative, is described and features a previously unknown application of the Wolff-Kishner reduction of a nonresonance stabilized or "twisted" amide. An intermediate amino ester is converted to a severely "twisted amide", which, when exposed to hydrazine in alcohol, provides the corresponding "twisted" amino hydrazone. Wolff-Kishner conditions (KOH/ethylene glycol, 200 degrees C) provide the reduced target 1 without hydrolysis to amino acid derivatives. These operations are conveniently performed in a single flask in high yield.