Amino Derivatives of 2,2-Diphenylcyclohexanone. I¹

Abstract

The purpose of this investigation was t u synthesize compounds in which the keto group of the potent analgetic drug methadon is incorporated in a saturated ring. As examples of this type of structure we have prepared a number of amino substituted 2,2-diphenylcyclohexanone derivatives of types I1 and V. In addition, the amino alcohols 111 and the amine VI1 have been prepared for general pharmacodynamic screening tests.Our starting material, 2,2-diphenylcyclohexanone (I), was prepared essentially according to the directions of M e e r~e i n .~ The @-amino ketones I1 were obtained smoothly by the Xannich reaction and could be hydrogenated uneventfully to the amino alcohols 111. The a-amino ketones V were synthesized by treating the readily available bromo ketone IV with secondary amines. When 2,2-diphenyl-fi-brornocyclohexarione (IV) was heated with collidine, hydrogen bromide was eliminated and 2,2-diphenylcyclohexen-~i-one-l (VI) was formed.Reduction of 2,2-diphenylcyclohexanone oxime with lithium aluminum hydride furnished 2,2diphenylcyclohexylamine (VII) in good yield. In view of the ease of this reduction, and of the hydrogenation of the &amino ketones I1 to the amino alcohols 111, we attempted to hydrogenate the a-amino ketones V to the corresponding amino alcohols. These experiments were unsuccessful, and we tried therefore to reduce the bromo ketone Ponndorff-Xeerweinthis step could not be I V to a bromohydrin by the Verley method. However, accomplished, either. 0 ii Vol. 7 2 cicntly stirred mixture of 1395 g. of cyclopentanone and a solution of 980 g. of sodium cyanide in 3750 cc. of water was added over a period of 40 minutes a solution of 2000 g. of sodium bisulfite in 2700 cc. of water. The temperature mas maintained below 30 a by periodical addition of ice.The solution was filtered, the layers were separated, the aqueous layer was extracted with ether, and the latter evaporated. The crude cyanohydrin was refluxed with 7.5 1. of 37% hydrochloric acid for one hour, and the solution evaporated. The yield of 1 -hydroxycyclopentanecarboxylic acid was 1306 g. (60Oj,).The ester, obtained from the acid and methanol in the presence of concentrated sulfuric acid in a yield of 77y0, reacted with a twofold excess of phenylmagnesium bromide to give yields of 80 to 91% of diphenyl-(1-hydroxy-1cyclopentyl) -carbinol. We were unable to get good yields of 2,2-diphenylcyclohexanone from the pinacol rearrangement with sulfuric acid as described by Meerwein, but found' that refluxing 50 g. of the pinacol in 350 cc. of glacial acetic acid containing 0.3 g. of iodine for thirty minutes, cooling, and pouring onto ice led to a yield of 98% of a product melting a t 96.599". Recrystallization from ethanol gave 39.5 g. (85%) of colorless prisms, m . p. 98.5-99.5".Preparation of 2,2-Diphenyl-6-diakylaminomethylcyclohexanones (11) .-These compounds were prepared by dissolving 0.12 mole of the secondary amine hydrochloride and 0.1 mole of 2,2-diphenylcyclohexanone in isoamyl alcohol, heating to reflux, adding a fivefold exces of par...

Polymer-Mediated Pinacol Rearrangements

“…In the final example, there was a literature report that heating of 22 with acetic acid gave an 85% yield of 23. 29 Likewise, heating of 22 with sulfuric acid afforded 23 in 99% yield. 27 When 22 was heated with 1 in toluene, we obtained a 93% yield of 23, and heating in hexane gave an 84% yield of 23.…”

Structure of the Cornubert ketone

“…The route selected for a confirming synthesis was initiated by preparation of l-carbomethoxycyclopentanol (8) by a method developed by Burger and Bennet (4). Cyclopentanone cyanohydrin, obtained by treating cyclopentanone bisulphite addition product with potassium cyanide, was hvdrolvzed with concentrated hvdrochloric acid to l~hydrbxycyclopentanoic acid.…”

MOLECULAR REARRANGEMENTS. VI.1 THE REARRANGEMENT OF OXIMES ON REDUCTION WITH LITHIUM ALUMINUM HYDRIDE

“…pected primary amines from the reduction of acetophenone and propiophenone oximes with lithium aluminum hydride (4a, b). This last rearrangement would appear to be related to the Beckmann rearrangement; however, it is not as general as the Beckmann rearrangement, for many oximes have been reduced without rearrangement with lithium aluminum hydride (5). Since only oximes of phenyl ketones had been found to undergo rearrangement, substituted acetophenone oximes seemed to be the most promising series of compounds to use for the study of this reaction.…”