Isomer Distribution of Succinylcyclohexenyl, Acetylcyclohexenyl and Acetylcyclopentenyl Enamines

Abstract

The isomeric distributions of some cyclohexenyl enamines substituted by succinyl or acetyl groups at either the 2-or 6-positions are reported as are the isomeric distributions of similarly substituted cyclopentenyl enamines. Correlation between the 13 C NMR chemical shifts in these enamines and isomer distribution is shown. Density functional molecular modeling is used to demonstrate resonance and electrostatic effects on isomeric distributions.One of the most common methods of synthesizing cyclohexenyl and cyclopentenyl enamines is to allow a cyclohexanone or a cyclopentanone compound to react with a secondary amine [1,2]. If the enamine is unsymmetrically substituted at the 2,6-positions (cyclohexenyl) or at the 2,5-positions (cyclopentenyl), two different isomers may be produced, namely tet and tri (Eq. 1) with the latter present as two different conformers in the cyclohexenyl case, tri ax (substituted X is pseudoaxial) and tri eq (substituted X is pseudoequatorial).We produced cyclohexenyl enamines with acetyl substituents in the 2-and 6-positions and cyclopentenyl enamines with acetyl substituents in the 2-and 5-positions in two different ways. They were synthesized by direct carbon acylation of the enamine [3,4] and by reaction of an acetylcycloalkanone with a secondary amine [5,6] (Scheme 1). We have found that the isomeric distributions of enaminoketones 1 and 2 are essentially the same for each of the two alternative methods of synthesis. We have further discovered that the second method (acetylcycloalkane with a secondary amine) also produces an amide. For example amide 5 is produced along with acylated cyclic enamines 1 and 2 when this method is used. Production of amides from enamines by the reaction of acyl halides with enamines has been reported before [7], but this reaction involves different reagents and so follows a different mechanistic pathway. These amides are probably produced by way of initial formation of pseudobase 3 or 4 followed by elimination of amide 5 in a retro condensation reaction. Further proof for this mechanism is shown by the appearance of significant amounts of simple cyclic ketones and simple enamines in the crude reaction products as determined by GC-MS. A similar reaction has been reported with the reaction of pyrrolidine with acetylacetone under microwave conditions [8]. The yields of amides represent the amount of alternate enaminoketone (with an exocyclic double bond due to attack of the acetyl carbonyl by the amine) which would have formed if the retro reaction to form amide 5 did not take place. + + 1 tet, n=1 1 tri, n=1 2 tet, n=0 2 tri, n=0 + + 3, n=1 4, n=0 5 + Scheme 1.The isomeric distributions of products for these reactions are given in Tables 1 and 2 along with the isomeric distribution of some previously unreported or erroneously reported enamines of 2-methyl-and 3-phenylcyclohexanones.The relative amounts of the isomers were determined by using 13 C NMR in CDCl 3 solvent with a long relaxation delay. The pseudo-equatorial and pseudo-axial configurational iden...

N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines with Enamines Promoted by the Lewis Acid ZnCl2

“…Unsymmetrical cyclohexanones that contain β-substituents ( 3o – 3ab ) typically form two enamine regioisomers with the selectivity highly dependent on the substitution pattern that could lead to two regioisomeric cycloaddition products. As shown in Figure A, conventional TiCl 4 -mediated enamine preparation from a series of ketones results in various Δ 1,6 /Δ 1,2 ratios for the morpholine enamines 2o (1:1), 2q (1:1), 2r (1:0.4), 2x (1:1.2), and 2ab (only Δ 1,6 ).…”