2-Azabicyclo[2.1.1]hexanes. 2. Substituent Effects on the Bromine-Mediated Rearrangement of 2-Azabicyclo[2.2.0]hex-5-enes

Abstract

Methyl -and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 have been prepared by photoirradiation of appropriately substituted 1,2-dihydropyridines. Torquoselectivity is observed in the synthesis of the 3-endo-methyl-and 3-endo-phenyl-2-azabicyclo[2.2.0]hexenes 6c-e from 2-methyl-and 2-phenyl-1,2-dihydropyridines 5c-e. Products formed upon addition of bromine to 3-endo-, 4-, and 5-methyl-and 3-endo-phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6a-f were substituent dependent. For 6a,b, which lack substituents at C 3 or C 5 , mixtures of unrearranged dibromides 8a,b and rearranged dibromides 9a,b were obtained. With the 3-endo-substituents in 6c-e, only rearranged dibromides 9c-e were formed; 5-methyl substitution afforded mainly unrearranged dibromide 8f and some allylic bromide 10. Both unrearranged 5-endo,6-exo-dibromo-2-azabicyclo[2.2.0]hexanes 8 and rearranged 5-anti-6-anti-dibromo-2-azabicyclo[2.

Synthesis of Three‐Membered and Four‐Membered Heterocycles with the Assistance of Photochemical Reactions

“…The constrained 2-azabicyclo[2.2.0]hex-5-ene was produced from dihydropyridine derivative (Scheme 34) [124][125][126][127][128][129][130][131][132]. The reaction occurred at the singlet state, and theoretical treatment revealed two conical intersections [133,134].…”

Cyclobutane-Containing Alkaloids: Origin, Synthesis, and Biological Activities

“…Also analogues containing the 2-azabicyclo[2.1.1]hexane skeleton are often synthesized by the light-induced [2+2] cyclization [14-17]. The rearrangement of an appropriate bromohydrine to synthesize 5-hydroxy-2-azabicyclo[2.1.1]-hexanes has also been described [18,19]. A two-step synthetic approach toward 3-(chloromethyl)cyclobutanone was described and used in the synthesis of 2,4-methanoproline analogues [20].…”

The Rearrangement Route to 3-CH2X-2-azabicyclo[2.1.1]hexanes. Substituent Control of Neighboring Group Participation

“…Of several synthetic routes to 2-azabicyclo[2.1.1]hexanes, , only the rearrangement approach 7 has been reported for the formation of 3-substituted structures. 7b,c The success of the rearrangement route for 3-methyl and 3-phenyl derivatives has relied upon the steric effect associated with these groups. However, with the 3- endo -hydroxymethyl precursor 2 , the steric effect cannot be relied upon.…”

“…The synthesis of the desired 3- endo -hydroxymethyl precursor 2a from pyridine has been described . According to a published protocol (Table ), 7b, addition of NBS to a solution of the alcohol in 2:1 DMSO/water (entry 1) resulted in isolation of the azatricycle 4 in 54% yield; no other product was isolated. The 4- exo -bromo stereochemistry was assigned on the basis of J 3,4 = 0 Hz, indicative of a trans relationship of H 3 and H 4 .…”

“…We were unable to find precedent for neighboring group nucleophilic participation by the carbon-bonded oxygen atom of a tosylate group, and it was expected that the oxonium ion intermediate 7 would be inductively destabilized. Reaction of nosylate 2d according to the general procedure (entry 4) was sluggish but did result in a low conversion (16%) to the desired rearranged bicycle 6 , which had the characteristic J 1,4 = 7.5 Hz of this ring system . To overcome the slow reactivity problem, the solvent was changed to 2:1 THF:water (entry 5).…”