Copper-catalysed allylic oxidation using alkyl hydroperoxide

Details Copper-catalysed allylic oxidation using alkyl hydroperoxide Copper-catalysed allylic oxidation using alkyl hydroperoxide

1997-07-28

2001-06-26

Mullis, Jeffrey (Department: 1711)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S349000, C568S954000, C568S955000, C568S956000

Reexamination Certificate

active

06252119

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 ranging from agricultural products to pharmaceuticals. A variety of procedures are known for allylically oxidizing various organic compounds. Unfortunately, such procedures typically suffer from unsatisfactory yields, tedious workups and/or require the use of expensive and/or ecologically and physiologically undesirable reagents.
Allylic oxidation reactions have traditionally been performed with chromium reagents, such as a CrO
3
-pyridine complex, a mixture of chromium trioxide and 3,5-dimethylprazole, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium chromate, or sodium dichromate in acetic acid. However, the great excess of reagent and the large volume of solvent required in such procedures, in combination with the difficult work-up required of the environmentally hazardous chromium residues, causes such procedures to be inconvenient for large scale production.
Of greater preparative interest has been the use of hydroperoxides with various catalysts to effect allylic oxidation. For example, the use of Cro
3
as a catalyst in the allylic oxidation of &Dgr;5 steroids yields &Dgr;5-7-ketones as the allylic oxidation product, along with minor quantities of a reaction product in which the double-bond is epoxidized. While good yields have been reported with hexacarbonyl chromium, Cr(CO)
6
pyridinium dichromate and RuCl
3
in the preparation of allylic oxidation products from &Dgr;5-steroids, the toxicity of the chromium reagents and the high cost of the ruthenium catalyst renders commercialization of the procedures inconvenient.
Hence, a continuing need exists for a simple, efficient, safe and cost effective procedure for selectively effecting the allylic oxidation of organic compounds, particularly &Dgr;5-steroids.
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 an alkyl hydroperoxide in the presence of a copper catalyst under conditions sufficient to effect oxidation of the allylic hydrogen(s) on the organic compound.
The reaction can conveniently be conducted at ambient pressure and elevated temperatures of approximately 50° to 70° C., and is conveniently conducted in a suitable organic solvent.
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 substrates and alkyl hydroperoxide. Solvents, including both aqueous and organic solvents, and the copper catalyst are specifically excluded from the definition of reactants.
As utilized herein, including the claims, the term “wt %” means grams per 100 milliliters.
Process
The process involves reactively contacting an allylic compound with an alkyl hydroperoxide in the presence of a copper catalyst under conditions sufficient to effect allylic oxidation of the allylic hydrogen atom(s) on the organic compound.
CONSTITUENTS
Allylic Compounds
Allylic compounds include any organic compound incorporating the structure —RC
1
═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, particularly &Dgr;5 steroids such as dehydroepiandrosterone and derivatives of dehydroepiandrosterone, because such steroids possess pharmacological activity and can be allylically oxidized by the process of this invention without the use of physiologically or ecologically hazardous materials, such as the transition metals.
Oxidant (Alkyl Hydroperoxide)
An alkyl hydroperoxide is used to allylically oxidize an allylic compound in the presence of a copper catalyst. Experimentation has shown that butyl hydroperoxide, specifically t-butyl hydroperoxide, can generally provide a superior yield and/or superior quality of allylically oxidized product in accordance with the process of this invention. An additional benefit provided by the use of t-butyl hydroperoxide is that t-butyl hydroperoxide is a liquid under ambient conditions and can facilitate dissolution of the allylic compound in the organic solvent.
Alkyl hydroperoxide is available from a number of chemical suppliers. We have found anhydrous alkyl hydroperoxide to produce superior yields relative to aqueous solutions.
Generally, a concentration of about 4 to about 9 mole equivalents, preferably about 6 to about 7 mole equivalents, of alkyl hydroperoxide are effective for allylically oxidizing an allylic compound. Concentrations of less than about 4 mole equivalents of alkyl hydroperoxide significantly slows the reaction, while greater than about 9 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) and the copper catalyst are preferably dissolved in a suitable organic solvent. Selection of an organic solvent depends upon the specific allylic compound, alkyl hydroperoxide and copper catalyst used. A partial listing of suitable organic solvents includes specifically, but not exclusively; (i) water miscible solvents such as acetone, acetonitrile, and t-butanol, (ii) water immiscible solvents such as petroleum ether, n-hexane, n-heptane, iso-octane, benzene and cyclohexane, and (iii) organic bases such as pyridine. A preferred solvent for use in connection with most &Dgr;5-Androstenes, such as dehydroepiandrosterone, is acetonitrile.
Copper Catalyst
Suitable copper catalysts effective for catalyzing the allylic oxidation in accordance with this invention include cuprous and cupric salts, and copper metal. Examples of suitable cuprous salts include specifically, but not exclusively, copper (I) oxide, copper (I) hydroxide, copper (I) chloride, copper (I) bromide, copper (I) iodide. Examples of suitable cupric salts include specifically, but not exclusively, copper (II) oxide, copper (II) sulfates, copper (II) chloride, copper (II) bromide, copper (II) iodide, copper (II) sulfide, copper (II) triflate. A particularly suitable copper metal is copper powder, such as available from Aldrich Chemicals. It is believed that the copper powder is transformed in situ into soluble copper compounds effective for catalyzing the allylic oxidation reaction.
P
ROCESSING
P
ARAMETERS AND
P
ROCEDURES
Reaction Time
While dependent upon a number of variables, including the specific allylic compound being oxidized, the specific alkyl hydroperoxide being used, the specific copper catalyst employed, and the concentration of reactants and catalyst within the reaction mixture, the reactions can typically be conducted in abou

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