Preparation of ketals

CH(OMe>3, MeN02, CF3COOH, reflux, 4 h, 81-93% yield. This procedure was reported to be particularly effective for the preparation of ketals of diaiyl ketones. 

Preparation of ketals, 406 Preparation of 16/3-methyl-lla,17a,21-tri-hydroxypregna-1,4-diene-3,20-dione 21-acetate, 299... 

The preparation of ketals of monohydric alcohols is not as readily accomplished. 

The following catalysts may also be used for the preparation of ketals ... 

I60C-Hydroxy Derivatives of Gorticoids and their Acetonides. The preparation of 16a-hydroxy-9a-fluoroprednisolone (48) from the 3,20-bisethylene ketal of hydrocortisone acetate (49) has been reported (73). The latter was dehydrated with thionyl chloride in pyridine to yield the 4,9(11),16-triene (50). The 16,17-unsaturated linkage was selectively hydroxylated with OsO /pyridine to yield the 16a,17a-diol (51), which was converted... 

MeO)3CH, anhydrous MeOH, TsOH, reflux, 2 h. Diethyl ketals have been prepared under similar conditions (EtOH, TsOH, 0-23°, 15 min-6 h, 80-95% yield) in the presence of molecular sieves to shift the equilibrium by adsorbing water. Amberlyst-15 or graphite bisulfate and (EtO)3CH have been used to prepare diethyl ketals. 

Me3SiOCH2CH20SiMe3, Me3SiOTf, 15 kbar (1.5 GPa), 40°, 48 h. These conditions were used to prepare the ketal of fenchone, which cannot be done under normal acid-catalyzed conditions. 

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

Ethylene ketals can be readily prepared by the ethylene glycol technique. 6-Ethylene ketals can also be prepared by exchange dioxolanation and suitable conditions have been described for the preparation of either the 3-mono-ketal (78), the 3,6-diketal (79) or 3,6,17-triketal (80) from the triketone... 

Many functional groups are stable to alkaline hydrogen peroxide. Acetate esters are usually hydrolyzed under the reaction conditions although methods have been developed to prevent hydrolysis.For the preparation of the 4,5-oxiranes of desoxycorticosterone, hydrocortisone, and cortisone, the alkali-sensitive ketol side chains must be protected with a base-resistant group, e.g., the tetrahydropyranyl ether or the ethylene ketal derivative. Sodium carbonate has been used successfully as a base with unprotected ketol side chains, but it should be noted that some ketols are sensitive to sodium carbonate in the absence of hydrogen peroxide. The spiroketal side chain of the sapogenins is stable to the basic reaction conditions. 

During the preparation of the dihalo-(usually dibromo) 20-ketopregnanes, other reactive sites must be protected (e.g., addition of bromine to the A -double bond, ketal formation with a 3-ketone). An elegant method which avoids such problems has been devised by the Upjohn group in their studies on the conversion of 11-ketoprogesterone to hydrocortisone. The former is reacted with ethyl oxalate at C-2 and C-21, then addition of three moles of bromine gives a 2,21,21-tribromide. Alkaline rearrangement produces the side chain unsaturated acid, and the bromine at C-2 is subsequently removed with zinc. 

Preparation of l9-Norandrost-A-ene-3, l-dionef A solution of 1.1 g of 10y5-cyano-19-norandrost-5-ene-3,17-dione bis-ethylene ketal in a mixture of 15 ml of ethanol and 15 ml of toluene is carefully added to a vigorously stirred suspension of 10 g of sodium in 150 ml of boiling toluene. The addition is regulated to maintain the reaction mixture at the boiling point of the solvent. Another 40 ml of anhydrous ethanol is then added at the same rate. The solution is cooled and the excess of sodium is decomposed by addition of 95% ethanol. The reaction mixture is then diluted with water, the toluene layer separated and the aqueous phase extracted twice with ether. The organic solution is washed with water, dried and evaporated to yield 1 g of an amorphous mixture of the bis-ethylene ketals of 19- norahd-rost-5- and -5(10)-ene-3,17-dione (Note 1). 

B. The preparation of enamines by heating seeondary amines and ketals was originated by Hoch (118) and has been extended by Bianchetti and eo-workers (119-121). 

This is one of the few methods available for the direct and efficient conversion of an acid, via the acid chloride, to an ortho ester. The preparation of the oxetane is straightforward, and a large number of oxetanes have been prepared [triol, (EtO)2CO, KOH]." In addition, the -butyl analogue has been used for the protection of acids. During the course of a borane reduction, the ortho ester was reduced to form a ketal. This was attributed to an intramolecular delivery of the hydride. ... 

Conversion of a ketone into a ketal is frequently employed where protection of the group is required (77). An example of the use of the process is the preparation of 4-ketocyclohexanol. The example presented in the procedure is typical. The product of... 

Preparation of 5a,6a-0xido-17a-Hydroxya//opregnane-3,20-dione 3,20-Bis-(Ethy ene Ketal) A solution was prepared by heating 19.96 g (0.0477 mol) of 17a-hydroxyprogesterone 3,20-bis-(ethylene ketal) and 500 ml of benzene. After the solution was effected the flask was cooled to 5°C and a mixture of 3.68 g (0.0449 mol) of sodium acetate and 174 ml of 40% peracetic acid was added with stirring. The reaction mixture was stirred in the ice bath for 3 hours. The lower peracid layer was separated, diluted with water and extracted twice with benzene. 

Preparation of 5a,17a-Dihydroxy-6 -Methylallopregnane-3,20-dione 3,20-Bis-fEthylene Ketal) To a solution of 91.6 g of 5a,6a-oxido-17a-hydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 3,500 ml of freshly distilled tetrahydrofuran was added 1,170 ml of commercial 3 molar methyl magnesium bromide in ether solution. The reaction mixture was boiled to remove 1,800 ml of solvent by distillation and thereafter 1,000 ml of freshly distilled tetrahydrofuran was added. 

Preparation of 5a,17a-Dihydroxy-6 -Methylallopregnane-3,20-dione A solution was prepared containing 38.9 g of 5a,17a-dihydroxy-6/3-methylallopregnane-3,20-dione 3,20-bis-(ethylane ketal) in 389 ml of boiling acetone. Thereto was added 39 ml of 1 N sulfuric acid in portions under swirling and seeding with product. 8oiling was continued for a pariod of 2 minutes and the mixture was allowed to stand at room temperature. Thereafter the mixture was diluted with 1,500 ml of water, chilled and filtered. 

Preparation of 11-Keto-6 -Methy progesterone 3,20-Bis-(Ethylene Ketal) A mixture of 5 g of 11-keto-6(3-methylprogesterone (Spero et al, 7. Am. them. Soc., 78, 6213 (1956)], 503 ml of benzene, 26 ml of ethylene glycol, and 0.152 g of p-toluenesulfonic acid monohydrate was stirred and heated under reflux for 22 hours while water was removed by means of a water trap. The reaction mixture was then cooled to 30°C, 0.4 ml of pyridine was added, and stirring was continued for 10 minutes. 

Preparation of 11 -Hydroxy-6a-Methylprogesterone A mixture of 2.68 g of 11-keto-6(3-methylprogesterone 3,20-bis-(ethylene ketal), 161 ml of tetrahydrofuran (previously distilled from lithium aluminum hydride), 1.34 g of lithium aluminum hydride and 14.5 ml of absolute ether was stirred and refluxed under nitrogen for 1.5 hours, then 27 ml of water was added cautiously, to decompose excess hydride. The resulting mixture was filtered and the filter cake was washed with 135 ml of ether. The combined filtrate and wash was shaken with 135 ml of water and separated. The aqueous layer was washed with four 55-ml portions of ether, then the organic layer and the washes were combined, washed once with water, and evaporated to dryness under diminished pressure leaving a tan residue. 

M. A. Brook and T. H. Chan, Synthesis 201 (1983) fora similar use ofTMSCl in the facile preparation of ethylene ketals and other acetals, sec T. H. Chan, M. A. Brook and T. Chaly, Synthesis 203 (1983). 

---