Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-08-14
2004-02-03
Pryor, Alton N (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S542000, C504S145000, C568S054000, C568S326000, C560S129000
Reexamination Certificate
active
06686486
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the allylic oxidation of organic compounds.
BACKGROUND
Allylic oxidation is a fundamental organic reaction of significant interest to organic chemists practicing in a variety of fields from agricultural products to pharmaceuticals. A variety of procedures are known for oxidizing various organic compounds that possess allylically activated hydrogen, but such procedures typically suffer from unsatisfactory yields, tedious workups and/or require the use of expensive and/or ecologically and physiologically undesirable reagents, such as chromium.
Hence, a continuing need exists for a simple, efficient, safe and cost-effective procedure for selectively effecting allylic oxidation of organic compounds.
SUMMARY OF THE INVENTION
We have discovered a simple, efficient, safe, cost-effective and ecologically friendly procedure for oxidizing organic compounds having allylic hydrogen atom(s). The procedure involves reactively contacting the organic compound with a combination of periodic acid or metal periodate and an alkyl hydroperoxide under conditions sufficient to effect oxidation of the allylic hydrogen(s) on the organic compound.
The reaction is conveniently conducted in a cosolvent system of water and organic solvent(s), and is usually conducted at ambient temperature and normal pressure conditions. However, the yield of the desired product can generally be further improved and/or the reaction process facilitated by conducting the reaction under increased pressure and/or above ambient temperature.
DETAILED DESCRIPTION OF THE INVENTION INCLUDING A BEST MODE
Definitions
As utilized herein, including the claims, the term “allylic compound” references an organic compound having at least one allylic hydrogen atom.
As utilized herein, including the claims, the term “allylic oxidation” means oxidation of an allylic compound by replacing the allylic hydrogen(s) with oxygen or an oxygen containing group.
As utilized herein, including the claims, the term “reactants” collectively references allylic compound, periodic acid or metal periodate and alkyl hydroperoxide. Solvents, including both organic solvent(s) and water, are specifically excluded from the definition of reactants.
As utilized herein, including the claims, “(v/v)” refers to the volumetric percentage of water to total water miscible solvent(s).
Process
The process involves reactively contacting an allylic compound with a metal periodate or periodic acid and an alkyl hydroperoxide under conditions of normal to increased pressure of air or nitrogen and/or zero to above ambient temperature to effect allylic oxidation of the allylic hydrogen atom(s) on the organic compound. For example, the allylic compound can be allylically oxidized by (i) dissolving the allylic compound in a suitable mixture of a water miscible organic solvent, a water immiscible organic solvent and the alkyl hydroperoxide, (ii) incorporating the periodic acid or metal periodate and a suitable amount of water into the reaction mixture, and then (iii) optionally pressurizing the reaction vessel with air or nitrogen. In the case of metal periodates, water gradually dissolves the periodate during the course of the reaction and thereby provides the necessary reactive contact between the reactants. As an added feature, the limited solubility of metal periodate in water permits the pH of the reaction mixture to be controlled to some extent should such pH control be desired.
CONSTITUENTS
Allylic Compounds
Allylic compounds include any organic compound incorporating the structure —C
1
R≡C
2
H—C
3
H
n
— within the molecule, wherein n is 1, 2 or 3. Hydrogen atoms attached to the C
1
and C
2
carbon atoms are referenced as vinylic hydrogen. Hydrogen atoms attached to the C
3
carbon atom are referenced as allylic hydrogen. The process of this invention selectively oxidizes allylic hydrogen atoms over vinylic hydrogen atoms. Exemplary allylic compounds include specifically, but not exclusively, (i) aliphatic vinylic compound such as methyl oleate, (ii) aromatic benzylic compounds such as fluorene and diphenyl methane, (iii) isoprenoids, such as carotenoids, terpenes, sesquiterpenes and vitamins, and (iv) steroids and sterols, such as androstenes, cholesterol, estraenes, pregnenes and derivatives thereof such as esters, ethers and ketals of these compounds.
Of particular commercial interest is the allylic oxidation of steroids, such as dehydroepiandrosterone and various derivatives of dehydroepiandrosterone, because the steroid can be allylically oxidized without the use of physiologically or ecologically hazardous materials, such as the transition metals. The invention does not contaminate the allylically oxidized product with a toxic metal.
Cooxidants
(Periodic Acid, Metal Periodate and Alkyl Hydroperoxide)
A cooxidant system of a metal periodate or a periodic acid and an alkyl hydroperoxide is used to allylically oxidize the allylic compound. The term metal periodates references salts of periodic acid with monovalent alkali metals such as sodium, divalent metals such as zinc or transition metals like iron. The required salts may be generated in the reaction in-situ, if required, by the addition of commonly available salts of the metals such as zinc acetate, ferric chloride, etc. Experimentation has shown that the specific combination of sodium periodate and butyl hydroperoxide can generally provide a superior yield and/or superior quality of allylically oxidized product under ambient reaction conditions, which can further be improved by conducting the reaction under slightly increased pressure of air or nitrogen and slightly above ambient temperature. An additional benefit provided by the use of butyl hydroperoxide is that butyl hydroperoxide is a liquid under ambient conditions and can also facilitate dissolution of the allylic compound in the organic solvent(s).
The metal periodate, periodic acid and alkyl hydroperoxide reactants are available from a number of chemical suppliers. The alkyl hydroperoxide can be conveniently utilized as an aqueous solution or even in its anhydrous form. Since the reaction mixture preferably includes water for the purpose of gradually dissolving the metal periodate during the course of the reaction, the alkyl hydroperoxide is most conveniently utilized as a 70-90 wt % aqueous solution.
Generally, a concentration of about 0.5 to about 5 mole equivalents of periodic acid or metal periodate, preferably about 1.0 to about 3 mole equivalents of periodic acid or metal periodate, and about 10 to about 15 mole equivalents of alkyl hydroperoxide are effective for allylically oxidizing an allylic compound. Concentrations of less than about 0.5 mole equivalent of periodic acid or metal periodate and less than about 10 mole equivalents of alkyl hydroperoxide significantly slows the reaction, while greater than about 3 mole equivalents of periodic acid or metal periodate and greater than about 15 mole equivalents of alkyl hydroperoxide increases the cost of the process without producing a corresponding increase in any beneficial property or characteristic of the process or resultant product(s).
Organic Solvent(s)
The organic reactants (i.e., allylic compound and alkyl hydroperoxide) can be conveniently dissolved in suitable organic solvent(s). Depending upon the specific allylic compound and alkyl hydroperoxide used, the organic compounds may be suitably dissolved in a water miscible organic solvent(s), or may require the use of a biphasic organic solvent system which includes at least one water miscible organic solvent and at least one water immiscible organic solvent.
The water miscible solvent, when utilized, is selected primarily for its ability to dissolve the organic reactants and in a biphasic system, to facilitate reactive contact between the water soluble periodic acid or metal periodate and the organic reactants solubilized in the water immiscible organic solvent. Suitable water miscible organic solvents include specifically, but not exclusively, acetone, acetonitrile, t-butanol and organic
Lardy Henry A.
Marwah Padma
Callahan Heather L.
Pryor Alton N
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