Studies in the synthesis of bridged nitrogen heterocycles. I. Regioselectivity and stereoselectivity of Diels-Alder cycloadditions of 1,2-dihydropyridines with styrene and methyl vinyl ketone. II. A rapid and efficient synthetic route toward 5-substituted-2-azabicyclo[2.1.1]hexanes .

摘要

The neutral cycloaddition reactions of substituted 1,2-dihydropyridines (1,2-DHPs) with styrene and its derivatives can occur at high temperatures. All cycloadditions gave exclusively 7-phenyl-2-azabicyclo[2.2.2]oct-5-ene regioisomers with the exception of the cycloadditions with 3-methyl-1,2-DHP and 3,5-dimethyl-1,2-DHP, which afforded additional 8-endo-phenyl regioisomers. Substitutions in the 1,2-DHP ring lead to variations of the endo/exo product ratios, but the endo stereoselectivity is preferred for all cycloadditions. The endo/exo product ratios range from 54:46 to 96:4, and are kinetically controlled. Theoretical calculations of the energies of the endo and exo transitions states at the RHF/3-21G//6-31G* level are consistent with the experimental results and the dominant endo stereoselectivity. The Diels-Alder reactions of substituted 1,2-DHPs with methyl vinyl ketone are regiospecific and afford only kinetically controlled 7-acetyl products. The 7-endoacetyl products are favored over the 7- exo-acetyl products. Solvents do not affect the stereoselectivity of the cycloadditions. Calculations of the energies of the endo and exo transition states using a RIF/3-21G//6-31G* model produced mixed results. The discrepancies can be reconciled when zero-point vibration energies and thermal corrections are added to the total energy calculations. When beta-trans-acetylstyrene with both acetyl and phenyl function groups was used as the dienophile, the cycloaddition regiospecifically afforded the 7-exo-acetyl-8-endo-phenyl and 7-endo-acetyl-8-exo-phenyl products in a ratio of 55:45.; The compounds of 5-carboxylic-2-azabicyclo[2.1.1]hexanes 19a and 19b were prepared in large scale and high yield from 5-acetyl-2-azabicyclo[2.1.1]hexanes. The 5-carboxylic acids 19a and 19b have served as versatile starting materials for the syntheses of a variety of 5-substituted 2-azabicyclo[2.1.1]hexanes. The functionalities include halogen, amino, thio, and carbon. Decarboxylation of 19a and 19b afforded the parent 2-azabicyclo[2.1.1]hexane 25 in high yields. The parent compound 25 is a useful synthon for preparation of other derivatives. The reaction mechanisms for preparing 5-substitutions involve the generation of a free radical at C5. Attempts to oxidize the C5 radical to a cation and reaction with a nucleophile were unsuccessful due to the highly strained nature of the bridge carbon.