Differentiation between enamines and tautomerizable imines in the oxidation reaction with TEMPO

Xiaoming Jie,Yaping Shang,Xiaofeng Zhang,Weiping Su,Zhe-Ning Chen,Wei Zhuang

doi:10.1038/s41467-018-07534-x

Abstract

Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing α-hydrogen often exhibit the similar reactivity to enamines due to their rapid tautomerization to enamine tautomers. Herein, we report that the minor structural difference between the enamine and the enamine tautomer derived from imine tautomerization results in the different chemo- and regioselectivity in the reaction of cyclohexanones, amines and TEMPO: the reaction of primary amines furnishes the formal oxygen 1,2-migration product, α-amino-enones, while the reaction of secondary amines under similar conditions generates exclusively arylamines via consecutive dehydrogenation on the cyclohexyl rings. The 18O-labeling experiment for α-amino-enone formation revealed that TEMPO served as oxygen transfer reagent. Experimental and computational studies of reaction mechanisms revealed that the difference in chemo- and regioselectivity could be ascribed to the flexible imine-enamine tautomerization of the imine intermediate containing an α-hydrogen.

Highlights

Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing α-hydrogen often exhibit the similar reactivity to enamines due to their rapid tautomerization to enamine tautomers
We demonstrate the distinct difference between enamines and tautomerizable imines in the metal-free oxidation reactions with TEMPO as oxidant (Fig. 1c): the tautomerizable imines, which are generated in-situ from the condensation of cyclohexanones with primary amines, bring about oxygen transfer from TEMPO to α-carbon atom of imines and furnish αamino enone products, whereas enamines generated in situ from the condensation of cyclohexanones with secondary amines undergo dehydrogenative aromatization to produce aryl amines
We have demonstrated that the regio- and chemo-selectivity in the reaction of cyclohexanone with amine and TEMPO heavily depends on the nature of the amines used: the reactions of primary amines produced α-amino-enone products via αoxygenation of the imine intermediate while the reactions of secondary amines led to consecutive dehydrogenation on the six-membered rings of cyclohexanones to afford aryl amines

Summary

Introduction

Enamine and imine represent two of the most common reaction intermediates in syntheses, and the imine intermediates containing α-hydrogen often exhibit the similar reactivity to enamines due to their rapid tautomerization to enamine tautomers. A series of α-aminoxylation reactions of carbonyl compounds[14,15,23,24,25,26,27,28,29,30] using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) as oxidant has been established, some of which involved metal-promoted oxidation of the enamine intermediates generated in-situ from the condensation of aldehydes with secondary amines[14,15,23,24,25,26,27,28] These elegant studies provided a good starting point for our investigation of the structure-reactivity relationship of enamine and tautomerizable imine. We demonstrate the distinct difference between enamines and tautomerizable imines in the metal-free oxidation reactions with TEMPO as oxidant (Fig. 1c): the tautomerizable imines, which are generated in-situ from the condensation of cyclohexanones with primary amines, bring about oxygen transfer from TEMPO to α-carbon atom of imines and furnish αamino enone products, whereas enamines generated in situ from the condensation of cyclohexanones with secondary amines undergo dehydrogenative aromatization to produce aryl amines

Methods

Results

Conclusion