in Pure Synthetics'
synthetic method for MCP

 This page was posted:
December 20, 1998, 8:00AM Pacific Time
       Latest update: Jan 11, 1999

Below are the three tautomers (A, B, and C) of the ring-closed starting material which we called A-1 (Es = carboalkoxy-). What actually exists in solution at pH 9 are the monosodium salts of these tautomers. Alkylation can proceed on either carbon or oxygen. Because multiple alkylations do occur and because some of the alkylating agent is lost through base hydroysis, we found that best results came from using about two moles of dimethyl sulfate for each mole of A-1.

A-1 Tautomers


|   NaOH
|   Water (pH 9)
|/ (CH3)2SO4 Two moles

Monomethylation products

The initial products are the two mono-methylation products shown here (I & II). Each of these in turn may form an enolic salt and can possibly undergo a second alkylation to the fully methylated derivatives (III, IV, or V). If not, product I will produce MCP in the subsequent acid hydroysis whereas II will not.


|   NaOH
|   Water (pH 9)
|/ (CH3)2SO4

Dimethylation products

The product of the reaction would then be a mixture of the two monomethyl derivatives together with the three dimethyl derivatives with undoubtedly some unreacted starting material. Compound III would not form to any great extent because the great dipolar repulsion of the coplanar unenolizable ketones would prevent this. And only V would ultimately yield MCP upon acid hydrolysis. The methyl ether linkages in these compounds are very labile and undergo hydrolysis comparable to ester groups.

We took representative residues from the toluene extracts of the methylation run in the plant and subjected them to a careful fractionation between toluene and water at varying pH. A typical result of these partitions between toluene and water at decreasing pH is outlined below:

1. At pH = 9, the toluene fraction was predominantly neutral material which we believe is mostly V with perhaps some III & IV. Upon paper chromatography (Whatman #1, ethyl acetate), this neutral mixture gave no spots on spray with 1% FeCl3 (negative test for enols and phenols). It did give one elongated spot with a dip in KMnO4 solution.
These neutrals were 42% of the starting mixture and were converted into MCP by dilute HCl in 69% yield based on structure V.

2. The aqueous from step 1 was taken (HCl) to pH = 6 and extracted using toluene. The toluene-soluble product was the "weak-acid" fraction which we believe is II. Paper chromatography (Whatman #1, ethyl acetate) gave, on spraying with 1% FeCl3, a blue spot at a distance 80% to the front. Upon acid hydrolysis, it produced no MCP. Presumably the product produced by hydrolysis is the very labile cyclopent-2-en-2-ol-1-one (1,2-cyclpentanedione). This product in contact with skin produces dark brown blotches very rapidly. As an aside, this is the reason that black-walnut fruits must be handled with rubber gloves if you want to avoid dark brown stains on the hands from this ever-present compound. Another aside is that one of our other marketed products was 3,4-dimethylcyclopent-2-en-2-ol-1-one which, we believe, is an important part of natural black-walnut flavoring.

3. The aqueous residue from step 2 was acidified with HCl to pH 2.5, and toluene extraction removed the "strong-acid" fraction which we believe is the mixture of tautomers of I. This extract upon paper chromatography (Whatman #1, ethyl acetate) gave a flesh-colored spot (1% FeCl3 spray) at a distance 75% to the front. This same flesh-colored spot was seen in papergrams of the products of our early experiments using MeI and NaOMe in methanol to alkylate A-1.
This monomethyl derivative was 22% of the mixture and was converted to MCP by dilute HCl in 32% yield based on structure I.

We surmise that compound I is much more acidic than compound II. The enol is the favored form to relieve dipolar repulsion of an alpha-diketone, and this enolic hydrogen is very acidic. To illustrate this, MCP produces a pH of about 5 in water solution. This difference in acidity explains why compound II appears in the pH 6 fraction and compound I is not extractable until the pH is much lower. Return to previous page.

Disclaimer: The procedures described on these web pages, while detailed in many ways, are still incomplete. I hope to give more details as time goes on until there will be detailed directions of these processes. However, be advised that I give this and subsequent information at no charge with no warranties expressed nor implied that this procedure will either work or be safe since I have no control over who might be trying to use the method nor over the quality of the chemicals that might be employed. The user is responsible for determining the fitness and safety of the method in his or her own particular case.

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