PROCESS FOR MAKING NEO-ENRICHED p-MENTHANE COMPOUNDS
A process for making neo-enriched p-menthane intermediates is disclosed. Lewis acid-catalyzed rearrangement of an oxaspiro compound provides an aldehyde mixture comprising normal (II) and neo (III) p-menthane-3-aldehydes: with the neo aldehyde (III) as the major product. The aldehyde mixture is readily oxidized to provide the corresponding carboxylic acids, and the acids are easily converted to a host of neo-enriched p-menthane esters or amides. The esters and amides are valuable as physiological coolants.
1 . A process for making neo-enriched p-menthane intermediates, comprising reacting an oxaspiro compound of formula (I):
with a Lewis acid to produce an aldehyde mixture comprising normal (II) and neo (III) p-menthane-3-aldehydes:
wherein the neo aldehyde (III) is the major product.
2 . The process of claim 1 wherein the Lewis acid is selected from the group consisting of zinc chloride, zinc bromide, boron trifluoride, lithium perchlorate, iron trichloride, and tin tetrachloride.
3 . The process of claim 1 wherein the molar ratio of neo to normal p-menthane-3-aldehydes is greater than 2.
4 . The process of claim 1 wherein the aldehyde mixture is oxidized to give a mixture of the corresponding normal and neo p-menthane-3-carboxylic acids.
5 . The process of claim 4 wherein the oxidation is performed aerobically.
6 . The process of claim 4 wherein the mixture of p-menthane-3-carboxylic acids is converted to a mixture of esters or amides.
7 . The process of claim 6 wherein the ester or amide mixture comprises normal (IV) and neo (V) isomers:
wherein X is OR or NHR 1 ; R is alkyl, hydroxyalkyl, or alkoxyalkyl; and R 1 is alkyl, hydroxyalkyl, alkoxycarbonylalkyl, aryl, cyanomethylaryl, arylalkyl, or heteroaryl.
8 . The process of claim 7 wherein R is 2-hydroxyethyl or 2,3-dihydroxypropyl.
9 . The process of claim 7 wherein R 1 is ethyl, ethoxycarbonylmethyl, or 4-cyanomethylphenyl.
10 . The process of claim 1 wherein the reaction is performed in the presence of a solvent.
11 . An aldehyde mixture made by the process of claim 1 .
12 . A neo-enriched carboxylic acid mixture made by the process of claim 4 .
13 . A neo-enriched ester or amide mixture made by the process of claim 6 .
14 . The process of claim 1 wherein the oxaspiro compound (I) is prepared by reacting a sulfur ylide with (−)-menthone, (+)-isomenthone, or a mixture thereof.