COBALT CATALYSED ALLYLIC OXIDATION OF
UNSATURATED STEROIDS
The invention described hereunder relates to the allylic oxidation of steroids using cobalt compounds.
Introduction and background
Allylic oxidation is a fundamental organic reaction of significant interest to organic chemists practising in a variety of fields ranging from agricultural products to pharmaceuticals. A variety of procedures are known for the allylic oxidation of 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. The allylic oxidation of steroids is a particularly important subject.
Allylic oxidation reactions of steroids have traditionally been performed with chromium reagents, such as CrO -pyridine complex, a mixture of chromium trioxide and 3,5- dimethylprazole, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), sodium chromate, sodium dichromate in acetic acid and pyridinium fluorochromate. However, the great excess of reagent and the large volume of solvent required in such procedures, in combination with the difficult work-up and the production of environmentally hazardous chromium residues, causes such procedures to be inconvenient for commercial production.
Of greater preparative interest has been the use of hydroperoxides with various catalysts to effect allylic oxidation. For example, the use of CrO3 as a catalyst in the allylic oxidation of Δ5-steroids yields Δ5-7-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 RuCl3 in the preparation of allylic oxidation products from Δ5-steroids, the toxicity of the chromium reagents and the high cost of the ruthenium catalyst renders commercialisation of the procedures inconvenient. More environmentally acceptable methods based on the use of copper salts and copper metal have been reported but a difficult separation step is needed to remove the spent copper salts which cannot easily be recovered and reused.
Hence, a continuing need exists for a simple, efficient, safe and cost effective procedure for selectivity effecting the allylic oxidation of Δ5-steroids, and especially where the separation stages of the reaction are simple, avoid toxic metallic waste, and enable catalyst recycling.
SUMMARY OF THE INVENTION
We have discovered a simple, efficient, safe, cost effective and ecologically friendly procedure for oxidizing steroids having allylic hydrogen atom(s). The procedure involves reactively contacting the organic compound with an alkyl hydroperoxide in the presence of a cobalt catalyst under conditions sufficient to effect oxidation of the
allylic hydrogen(s) on the organic compound. The cobalt catalyst may be immobilised on a support material facilitating separation, and enabling effective catalyst reuse.
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.
DESCRIPTION AND PREFERRED EMBODIMENTS
Definitions
As utilized herein, including the claims, the term "allylic compound" refers to 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 (steroid) substrates and alkyl hydroperoxide. Solvents, including both aqueous and organic solvents, and the cobalt 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 (steroid) compound with an alkyl hydroperoxide in the presence of a cobalt catalyst under conditions sufficient to effect allylic oxidation of the allylic hydrogen atom(s) on the organic compound.
Constituents
Substrates
Steroids include dehydroepiandrosterone and derivatives of dehydroepiandrosterone and include Δ5 and Δ4 steroids.
Oxidant (Alkyl Hydroperoxide)
An alkyl hydroperoxide is used to allylically oxidize steroid in the presence of a cobalt including supported cobalt catalysts. 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.
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 steroid. Concentrations of less than about 4 mole equivalents of the 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 characterisitic of the process or resultant product(s).
Organic Solvent(s)
The organic reactants (i.e. allylic compound and alkyl hydroperoxide) are preferably dissolved in a suitable organic solvent. Selection of an organic solvent depends upon the specific steroid and alkyl hydroperoxide 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 steroids is acetonitrile.
Cobalt Catalyst
Suitable cobalt catalysts effective for catalysing the alkylic oxidation in accordance with this invention include cobalt salts and supported cobalt materials. Examples of suitable catalysts include specifically but not exclusively cobalt (II) acetate, cobalt (II)
trifluoroacetate and supported cobalt catalysts including those based on chemically modified silica gels as described for example in the Journal of the Chemical Society, Dalton Transaction, 2000, pages 101-110.
PROCESSING PARAMETERS AND PROCEDURES
Reaction Time
While dependent upon a number of variables, including the specific steroid being oxidized, the specific alkyl hydroperoxide being used, the specific cobalt catalyst employed, and the concentration of reactants and catalyst within the reaction mixture, the reactions can typically be conducted in about 2 to about 48 hours.
Reaction Temperature
The reaction is preferably conducted at temperatures slightly above ambient (i.e., temperatures between about 50° to 70°C). Temperatures below about 50°C tend to slow the reaction rate without an observed increase in yield and/or quality of product, while temperatures above about 70°C tend to reduce the yield and or quality of desired oxidized product(s).
Mixing
The reaction mixture should be continuously and vigorously stirred in order to promote contact between the reactants and thereby speed-up the reaction time and
enhance the yield and/or quality of the desired allylically oxidized steroid. This is particularly important for reactions involving supported cobalt.
Separation and Purification Techniques
Upon completion of the oxidation reaction, the oxidized steroid can be first separated from the supported catalyst (when used) by filtration or decantation and then from the solvent system, as well as any unused reactants and any byproducts, by any of the variety of techniques known to those skilled in the art including (i) dilution, (ii) extraction, (iii) evaporation, (iv) distillation, (v) crystallization / recrystallization, and/or (vi) chromatography.
Any excess alkyl hydroperoxide present in the reaction mixture upon completion of the reaction can be decomposed, as desired, by those methods, known to those skilled in the art, such as (i) adding an aqueous solution of an alkali metal sulfite, (ii) adding a mixture of a mineral acid and acetic acid at a temperature of about 0° to 5°C, or (iii) adding a transition metal salt (e.g. ferrous ammonium sulfate) in water.
The isolated allylically oxidized steroid can be further purified by various known techniques such as (i) washing the isolated product with a solvent effective for selectively dissolving any remaining contaminants without dissolving appreciable quantities of the product, such as water or diethyl ether, and/or (ii) crystallizing the isolated product in a suitable solvent or cosolvent system.
EXAMPLES
Standard Protocol
The supported cobalt catalysts were prepared as described elsewhere (see P. M. Price, D. J. Macquarrie and J. H. Clark, J. Chem. Soc. Dalton, 2000, 101 and J. S. Rafelt and J. H. Clark, Catal. Today, 2000, 33 for reviews describing these and related supported cobalt catalysts). Steroid substrate (2 mmole) is dissolved in an organic solvent (12 ml) and purged with nitrogen. A cobalt catalyst and t-butyl hydroperoxide are added to the solution and heated under constant agitation with a magnetic stirrer for a specified time period. The resultant solution was first filtered (in the case of supported cobalt catalysts) and then poured into a sodium sulfite solution (10% aq.) and extracted with diethyl ether. The extract is washed with an aqueous saturated solution of NaHCO , water, dried over MgS0 and evaporated to dryness to yield an allylically oxidized product.
Examples 1-14
Various Δ5-steroids and a Δ4-steroid were allylically oxidized in accordance with the standard protocol set forth above utilizing the reagents, cobalt catalyst, solvent and processing parameters set forth in Table One below. Two of the examples illustrate the good activity on reuse of the supported cobalt catalysts.
GLOSSARY
(Chemical Structure and Formula of Substrates)
t-8uOOH/ catalyst
.R,;R2=0 8
.R1=H:R2=H 11
t-BuOOH/ catalyst
Solvent/N,
12 13
t-BuOOH/ catalyst
14 15
t-BuOOH/ catalyst
16 17
Table 1. Allylic oxidation of unsaturated steroids
Example Substrate/ t-BuOOH" Catalyst (mmoles Co) Solvent Time Temp. Prod. Isolated
(mmoles) (ml) (h) (°C) Yield
1 4/1 1.2 Co(OAc)2.4H2O/Q.0i2 CH3CN 20 50 8 84b
2 5/2 2.4 Co(OAc)2.4H.O/o.024 CHjCN 24 50 9 86
3 4/1 1.2 1/0.01 CH3CN 18 50 8 85
4 4/1 1.2 2/0.009 CH3CN 20 50 8 84
5 4/1 1.2 2 / (recycled) CH3CN 20 50 8 80
6 6/1 1.2 2 / 0.022 Benzene 48 70 10 70c
7 4/1 1.2 3/0.016 CH3CN 20 55 8 85
8 4/1 1.2 3 / (recycled) CH3CN 20 55 8 81b
9 4/2 2.4 3 / 0.0025 CH3CN 24 55 8 86
10 5/2 2.4 3 / 0.0025 CH3CN 20 50 9 82b
11 7/1 1.2 3/0.007 CH3CN 24 55 11 72
12 12/0.65 0.8 3/0.016 CH3CN 20 55 13 73c
13 14 / 0.63 0.8 3 / 0.006 CH3CN 3 55 15 70'
14 16/1 1.2 3/0.016 CH^CN 24 55 17 71d
' 50-6 Om solution in decane (Aldπch) b Traces of starting mateπal and a by product are visible by 11 c but not detectable in the ' H-NMR spectra (SOOMHz) of the crude product
L Recovered by flash chromatography (ethyl acetate.petroleum ether 40"-60l,C) α Calculated on the basis of the Η-NMR signal (6H) of the crude product.
GLOSSARY
(Chemical Structure and Formula of Catalysts Supported on silica)
Co(OAc)2/Si02 catalyst 1
catalyst 3
CONCLUSIONS AND OBSERVATIONS
Using Δ5-steriods 4, 5, 6, 7 and 12 as substrates allylic oxidations products 8, 9, 10, 11 and 13 were obtained in very high isolated yields, 70 to 86% (Table 1). Apart from the reaction with substrate 6 which required benzene as solvent and a temperature of 70°C all the reactions were performed in acetonitrile using a milder temperature of 50-55°C. The best results were obtained using the supported catalyst 3 which may be a result of its greater organophilic character. These reactions are very selective compared to those carried out using Fe(acac)3 as catalyst described in M. Kimura and T. Muto, Chem. Pharm. Bull., 1979, 27, 109 and Chem. Pharm. Bull., 1980, 28, 1836. Mo(CO)6 has been also described as catalyst for this reaction, but this led to epoxidation of the cholesteryl acetate under similar oxidative conditions as described in M. Kimura and T. Muto, Chem. Pharm. Bull, 1980, 28, 1836.
While the product yields of the allylic oxidations are very similar under homogeneous and heterogeneous conditions, the easier recovery of the catalyst in the heterogeneous reactions make these more environmentally friendly processes. Furthermore using the heterogeneous catalysts 2 and 3 it was possible to reuse the catalyst with only a small reduction in the product yields, under similar experimental conditions (80% for
recycled catalyst 2 and 81% for recycled catalyst 3, Table 1). Our catalytic method is also effective for other unsaturated steroids. Thus the Δ -steroid 14 gives the testosterone acetate 15, in a yields of 70%. Furthermore, the method is also effective in the presence of an oxidatively vulnerable secondary alcohol group. The steroid 16 is oxidised to the alcohol product 17 with impressive selectivity (71%).