Ethanolysis of N-substituted norbornane epoxyimides: Discovery of diverse pathways depending on substituent's character

Abstract

Combined experimental and theoretical studies have been carried out to investigate the transformations of the epoxyimides of norbornane into heterocyclic compounds. We established that interaction of the aryl-substituted epoxyimides of norbornane with sodium ethoxide results in the formation of new heterocyclic compounds in preparatively useful yields and with complete regioselectivity. The reactions of epoxyimides, containing aryl electron-donor substituents, result in the formation of endo-9-carbamoyl-exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0(3,7)]nonanes, while in the case of the absence of an aryl electron-donor group or the presence of aryl electron-withdrawing group in the epoxyimide, exo-2-hydroxy-5-oxo-4-azatricyclo[4.2.1.0(3,7)]nonan-endo-9-carboxylic acids were obtained as products of the ethanolysis reaction. Unexpectedly, the ethanolysis of alkyl-substituted epoxyimides leads to dihydroxyimide formation as the major product. In order to understand the vital role of the imide substituent, a systematic theoretical DFT study at the PCM/B3LYP/6-31+G(d) level was carried out. We found that substituents at the nitrogen atom of epoxyimides exerted remarkable effects on the regioselectivity in the ethanolysis reaction, based on the solvent effects and intramolecular electronic interactions. Particularly, the preference for the formation of dihydroxyimides over heterocyclic systems for alkyl derivatives might be explained by kinetic stability of the formed acetal intermediate over the competitive epoxyamido acid intermediate. The above results provide a convenient and efficient method for predicting the structures of heterocyclic systems formed under basic ethanol conditions depending on the substituent on the nitrogen atom of the norbornane epoxyimides.

Grignard Reagents and Their N‐analogues in the Synthesis of Tricyclic and Tetracyclic Cage‐like Lactams

“…We started this work investigating the reaction between epoxyimides 10a – i and preformed Grignard reagents [ethylmagnesium bromide, i ‐propylmagnesium bromide, phenylmagnesium bromide, and (phenylethynyl)magnesium bromide] in tetrahydrofuran (THF) at 0°C and found that in all cases desired C 5 ‐substituted 6‐aza‐4‐oxatetracyclo[5.2.1.1 3,5 0 8,9 ]undecan‐7‐ones 11a – s were obtained in good to excellent yields independently from the nature of substituent at the nitrogen atom (Scheme ). Surprisingly, however, all attempts to react epoxyimides 10a – h with equimolar amount of ethylmagnesium bromide proved unsuccessful.…”

Reaction of N-substituted exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.03,7]nonane-endo-9-carboxamides with acetic acid

“…We also isolated a fraction (21%) containing amido lactone IV and intermediate V. The latter was not detected in the reaction mixture by NMR spectroscopy; presumably, it was formed as a result of unexpected isomerization of compound IV during chromatography. By special experiments we showed that pure acetoxy lactone IV is converted into final product IIIa in 91% yield on heating in boiling acetic acid over a period of 26 h. Diacetates IIIa, VI, and VII were also synthesized by independent method, by reaction of trans-dihydroxy imides VIIIa-VIIIc [8] with acetic acid (Scheme 4).…”

“…The present work was aimed at developing a new procedure for the synthesis of potentially biologically active N-aryl-exo-2,endo-3-diacetoxybicyclo[2.2.1]-heptane-endo-5,endo-6-dicarboximides by acylation of the corresponding N-aryl-exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0 3,7 ]nonane-endo-9-carboxamides IIaIIf and studying the effect of the reaction time on the product composition. Initial N-aryl-exo-2-hydroxy-5-oxo-4-oxatricyclo[4.2.1.0 3,7 ]nonane-endo-9-carboxamides IIa-IIf were prepared according to the procedures reported in [8]. By heating amides IIa-IIf in boiling glacial acetic acid over a period of 32-48 h we obtained compounds IIIa-IIIf (Scheme 2).…”

Azacycloalkanes from epoxides and aziridines

“…The related systems 122 [R = Ph, 3-NO 2 C 6 H 4 , 4-NO 2 C 6 H 4 , 4-EtOC(O)C 6 H 4 ] were obtained by ethanolysis of epoxyimides 121 [124]. The results of quantumchemical investigations of the formation mechanisms of azabrendane systems are reported in [117,118,125] (Scheme 42).…”