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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.

Herein we describe a novel series of compounds from which varenicline (1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine) has been identified for smoking cessation. Neuronal nicotinic acetylcholine receptors (nAChRs) mediate the dependence-producing effects of nicotine. We have pursued alpha4beta2 nicotinic receptor partial agonists to inhibit dopaminergic activation produced by smoking while simultaneously providing relief from the craving and withdrawal syndrome that accompanies cessation attempts. Varenicline displays high alpha4beta2 nAChR affinity and the desired in vivo dopaminergic profile.

Preparations of 2,3,4,5-tetrahydro-1,5-methano-1H-3-benzazepine (5) from benzonorbornadiene (1) by oxidative cleavage and reductive amination sequences were investigated. Osmium-mediated dihydroxylation of 1 followed by NaIO 4 cleavage, reductive amination and debenzylation provides 5 in 64-73% yield overall in three operations. A tandem ozonolysis-reductive amination procedure gives 5 as the tosylate salt from benzonorbornadiene with no isolation of intermediates in 28% yield.

[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.

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.

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.

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.

In “greening up” the classical stoichiometry experiment where students determine the formula of copper(II) chloride dihydrate, it is critical that teachers and instructors use a 110°C oven rather t...

The chemical nomenclature of inorganic compounds is typically introduced early in many introductory chemistry courses at both the university and secondary school levels. From the perspective of the student, chemical nomenclature is a series of complex rules and situations involving unfamiliar concepts, such as, transition-metal oxidation states and polyatomic ions. Herein we present a method to teach chemical nomenclature to students in an introductory chemistry course that utilizes the discovery-learning model. Inorganic compounds are grouped into four categories: binary ionic compounds of the main-group elements, binary ionic compounds containing variably charged cations, ionic compounds containing polyatomic ions, and binary compounds of the nonmetals. The formal introduction of each category of compounds is handled as a separate activity and is interspersed throughout the first semester to provide context and to avoid confronting the student with all of the nomenclature rules at once. Through these di...