Ade NovoDesign Probe of a Dopamine Receptor Ligand Based on a Theoretical Approach

Bagiński, Maciej; Claudi, Francesco; Giorgioni, Gianfabio; Fontenla, J. A.; Rosa, Elizabeth De La; Cardellini, Mario

doi:10.1006/bioo.1996.0031

Cited by 2 publications

(2 citation statements)

References 14 publications

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“…The structure of bromide 43 has been confirmed by acid hydrolysis of the dihydro-1,3-oxazine moiety to provide 5-amino-2-bromocyclohexanol ( 44 ) as the corresponding trifluoroacetate, which on acetylation gave derivative 45 in 99% yield. t -BuOK/THF-promoted hydrogen bromide elimination on compound 45 provided ketone 46 in low yield. The formation of ketone 46 is probably the result of the preferred capture of the hydrogen bonded to the carbon bearing the acetoxy group, located in a favorable trans -diaxial arrangement referring to the leaving group followed by bromide elimination, and aqueous hydrolysis of the intermediate enol ester during the workup.…”

Section: Resultsmentioning

confidence: 99%

“…N -(3-Oxocyclohexyl)acetamide (46). To a solution of compound 45 (157 mg, 0.56 mmol) in dry THF (7.5 mL, 0.075 M), t -BuOK (73 mg, 0.64 mmol, 1.13 equiv) was added at rt, under argon. The mixture was refluxed for 23 h. Then, more t -BuOK (36 mg, 0.31 mmol, 0.56 equiv) was added; after 5 h, a similar aliquot of t -BuOK (36 mg, 0.31 mmol, 0.56 equiv) was added again.…”

Section: Methodsmentioning

confidence: 99%

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Synthesis of 7-Azabicyclo[2.2.1]heptane and 2-Oxa-4-azabicyclo[3.3.1]non-3-ene Derivatives by Base-Promoted Heterocyclization of Alkyl N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-Dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides

Gómez-Sánchez¹,

Soriano²,

Marco‐Contelles³

2007

J. Org. Chem.

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We have studied the base-promoted heterocyclization of alkyl N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)carbamates and N-(cis(trans)-3,trans(cis)-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamides, investigating the effect of the nitrogen protecting group and the relative configuration of the leaving group at C3 and C4 on the outcome of this reaction. We have observed that the sodium hydride-promoted heterocyclization of alkyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamates (10, 12, 14, 16, 18) is a convenient method for the synthesis of 7-azabicyclo[2.2.1]heptane derivatives. For instance, the reaction of tert-butyl N-(cis-3,trans-4-dibromocyclohex-1-yl)carbamate (10) with sodium hydride in DMF at room temperature provides 2-bromo-7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]heptane (2) (52% yield), whose t-BuOK-promoted hydrogen bromide elimination affords 7-[(tert-butoxy)carbonyl]-7-azabicyclo[2.2.1]hept-2-ene (31) in 78% yield, an intermediate in the total synthesis of epibatidine (1). However, the NaH/DMF-mediated heterocyclization of alkyl N-(trans-3,cis-4-dibromocyclohex-1-yl)carbamates (11, 13) is a more structure dependent reaction, where the nucleophilic attack of the oxygen atom of the protecting group controls the outcome of the reaction, giving rise to benzooxazolone and 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, from low to moderate yields, in complex reaction mixtures. Conversely, the NaH/DMF heterocyclizations of N-(cis-3,trans-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (40) or N-(trans-3,cis-4-dibromocyclohex-1-yl)-2,2,2-trifluoroacetamide (42) are very clean reactions giving 7-azabicyclo[2.2.1]heptane or 2-oxa-4-azabicyclo[3.3.1]non-3-ene derivatives, respectively, in good yields. Finally, a mechanistic investigation, based on DFT calculations, has been carried out to rationalize the formation of the different adducts.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%