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

Abstract

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.

Bismuth Triflate‐Catalyzed Addition of Allylsilanes to N‐Alkoxycarbonylamino Sulfones: Convenient Access to 3‐Cbz‐Protected Cyclohexenylamines

“…The crude product was purified by column chromatography (eluent hexanes/EtOAc 92:8 to 85:15, or toluene). Spectral data for 1a ,20f 1l ,20h 2a ,20a 2c ,20a 2e ,20a 2g ,12 2i ,20b 2l ,20i 2m ,20c 2n ,20a 2o ,20c 2p ,20j 3a ,20d 4a ,20a 4a′ ,20l 5 ,20e 7 ,20g 14 ,20j 15 ,20k 18a ,20m and 19 20n agree with those previously reported in the literature.…”

Practical Synthetic Procedures for the Iron-Catalyzed Intermolecular Olefin Aminohydroxylation Using Functionalized Hydroxylamines

“…By following the general procedure under the conditions described in Scheme 7, 10 was isolated through a silica gel flash column (hexanes/EtOAc: from 4:1 to 1:1) as a white solid, which is a known compound; 15 yield: 34.5 mg (62%); mp 86–88 °C.…”

Why trans- or cis-Dimethyl Fumarate Addition to 2,5-Dimethylpyrrole Gives Exclusively trans-7-Azanorbornane

“…5 7-Azanorbornane can be synthesized by sodium hydride-promoted heterocyclization of alkyl N-(cis-3, trans-4-dibromocyclohex-1-yl)carbamates. 6 N-Methylpyrrole and acetylenedicarboxylic acid go through Diels−Alder addition to give 7-azanorbornane derivatives. 7 1,3-Dipolar cycloaddition of azomethine ylide with 6-cholro-3-vinylpyridine can generate the 7-azanorbornane skeleton.…”

“…Under base conditions, N -acylcyclohex-3-en-1-amines undergo intramolecular bromo-amidation and dibromination-cyclization to give 7-azanorbornane derivatives with 60–80% yield . 7-Azanorbornane can be synthesized by sodium hydride-promoted heterocyclization of alkyl N -( cis -3, trans -4-dibromocyclohex-1-yl)­carbamates .…”