On the Stereochemistry of Diaryl-Substituted Cyclohexanones Formed by Michael Reactions. Trans to Cis Isomerization of Their Ketals under Basic Conditions

Abstract

The stereochemistry of C-1-substituted 2,6-diphenylcyclohexan-4-ones 1-3 prepared by Michael reactions has been investigated. While preparations of these compounds have been reported over the past 70 years, in many instances the correct stereochemistry at C-2 (6) and, in some instances at C-1, was uncertain. We show here that in one case in which two identical substituents (CN) are present at C-1, it is possible to isomerize the initially formed trans isomer 1d to the cis isomer 3f. When a cyano group and a dissimilar substituent are present at C-1, the initially formed trans isomer may be isomerized to the cis compound. The stereochemistry is vertified by NMR spectroscopy and by X-ray analysis. Reaction of the ethylene ketals (4 and 5) of these ketones with KOH in DMSO at elevated temperatures gives rise to cis products, and deuterium-labeling studies demonstrated the acidity of the benzylic hydrogen at C-2 (6). Isomerization was evident since the trans ketal 4a and the cis ketal 4b gave the same amide 6a. 1 H and 13 C NMR spectra provided conclusive evidence for the cis f trans rearrangement.

4-Ethoxycarbonyl-3-hydroxy-3-phenylcyclohexanone

“…The molecule consists of a cyclohexanone ring, which displays the chair conformation, and hydroxy, phenyl and ethoxycarbonyl groups, which adopt -axial, -equatorial and -equatorial con®gurations, respectively. By comparing (I) with similar 4-substituted 3-phenylcyclohexanones described in the Cambridge Structural Database (CONQUEST, Version 1.0; Cambridge Structural Database, 2000), we found that 4-ethoxycarbonyl-3-ethoxypropanoyl-3phenylcyclohexanone, (III) (Brunner & Maas, 1995), showed a phenyl group in a -axial position and an ethoxycarbonyl group in an -axial position, but in 4-cyano-4-tert-butoxycarbonyl-3,5-diphenylcyclohexanone, (IV) (Rowland et al, 1998), and 5-hydroxy-5-methyl-2,4-bis(methylcarbamoyl)-3-(3-nitrophenyl)cyclohexanone, (V) (Ravikumar & Mehdi, 1993), the phenyl groups are disposed in -equatorial positions.…”

c-5-Hydroxy-r-2,c-4-bis(isopropoxycarbonyl)-t-5-methyl-t-3-phenylcyclohexanone

“…A comparison of the conformation of (I) with those in the related compounds 4-ethoxycarbonyl-3-hydroxy-3-phenylcyclohexanone, (II) (Herná ndez-Ortega et al, 2001), 4ethoxycarbonyl-3-ethoxypropanoyl-3-phenylcyclohexanone, (III) (Brunner & Maas, 1995), (4-cyano-4-tert-butoxycarbonyl-3,5-diphenylcyclohexanone, (IV) (Rowland et al, 1998), and 5hydroxy-5-methyl-2,4-bis(methylcarbonyl)-3-(3-nitrophenyl)cyclohexanone, (V) (Ravikumar & Mehdi, 1993), shows the following features. In (I), the two isopropoxycarbonyl groups at C2 and C4 are substituted in -equatorial positions ( Table 1).…”

Synthesis of 1,1-disubstituted-2,6-diarylcyclohexane-4-ones catalyzed by KF/basic Al2O3 under ultrasound

“…This proves that the effect of irradiation frequency did not influence the reaction. We also studied H 1 NMR spectra of the compounds and the results were identical to those reported in literatures [6,12]. The methylene (H A and H B ) and methine (H X ) protons constitute two identical ABX systems (Scheme 2).…”

“…The Michael reaction of 1,5-diaryl-1,4-pentadien-3-ones with active methylene compounds have been the subject of many investigations [1][2][3][4][5][6]. It is known that a weak base or acid such as piperidine [7] or phosphorus trichloride [8] often afforded open chain adducts, while cyclic products have been obtained in presence of sodium methoxide [2] or sodium hydroxide [9].…”