Ethylene glycol-p-Toluenesulfonic acid

Ketalization Adipic acid (catalyst). Butanone ethylene ketal. Dimethylformamide ethylene ketal. Ethylene glycol. Mesityl oxide ethylene ketal. p-Toluenesulfonic acid. 

Acetoxyandrost-5-en-17-one (59) is converted into the ethylene ketal (60) by treatment with ethylene glycol, triethylorthoformate and p-toluenesulfonic acid. The ketal is brominated with pyridinium bromide perbromide in THF and then treated with sodium iodide to remove bromine from the 5 and 6 positions. This gives the 16a-bromo compound (61) which is hydrolyzed in methanol to the free alcohol (62). Dehydrobromination is effected with potassium Fbutoxide in DMSO to give the -compound (63). Acid catalyzed hydrolysis of the ketal in aqueous acetone gives the title compound (64). ... 

A -3-Ketones react easily with ethylene glycol or other glycols in the presence of p-toluenesulfonic acid to give 3-ketals with migration of the 4,5-double bond to the 5,6-position. With 19-nor-A" -3-ketones a mixture of A -and... 

Bisethylenedioxypregn-5-ene. Method A. A mixture of progesterone (10 g), freshly distilled ethylene glycol (80 ml) and benzene (350 ml) is slowly distilled for 15 min to remove traces of water. p-Toluenesulfonic acid monohydrate (0.3 g) is added and the mixture is heated under reflux with stirring for 5 hr with a water separator. Saturated sodium bicarbonate solution is added to the cooled mixture and the benzene layer is separated. The organic layer is washed twice with water, dried and evaporated in vacuo. The residue is crystallized twice from acetone-methanol to give 4.15 g (32%) of bisketal, mp 178-181°. 

Preparation of 17a-Hydroxyprogesterone 3,20-Bis-(Ethylene Keta/J A solution was prepared containing 50.0 g of 17a-hydroxyprogesterone in 1,000 ml of ben2ene, 100 ml of ethylene glycol and 2.5 g of p-toluenesulfonic acid monohydrate. This mixture was re-... 

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. 

In a similar manner, coccinelline (99) and precoccinelline (100) have been synthesized from 2,6-lutidine (351) (336,450). Thus, treatment of the monolithium derivative (153) of 351 with P-bromopropionaldehyde dimethylacetal gave an acetal, which was converted to the keto acetal (412) by treatment with phenyllithium and acetonitrile. Reaction of 412 with ethylene glycol and p-toluenesulfonic acid followed by reduction with sodium-isoamyl alcohol gave the cw-piperidine (413). Hydrolysis of 413 with 5% HCl gave the tricyclic acetal (414) which was transformed to a separable 1 1 mixture of the ketones (415 and 416) by treatment with pyrrolidine-acetic acid. Reaction of ketone 416 with methyllithium followed by dehydration with thionyl chloride afforded the rather unstable olefin (417) which on catalytic hydrogenation over platinum oxide in methanol gave precoccinelline (100). Oxidation of 100 with m-chloroperbenzoic acid yielded coccinelline (99) (Scheme 52) (336,450). 

An improved yield of ketal is obtained by heating a solution of 2 g of progesterone in 16 ml of ethylene glycol and 70 ml of toluene containing 65 mg of p-toluenesulfonic acid monohydrate at reflux for 4 hr. The yield of bisethy-lene ketal is 1.34 g (67%), mp 178-182°. 

A4-3-Ketones react easily with ethylene glycol or other glycols in the presence of p-toluenesulfonic acid to give 3-ketals with migration of the 4,5-double bond to the 5,6-position.57 With 19-nor-A4-3-ketones a mixture of A5(6)-and A5(10)-enes is obtained.190 In this series selectivity is achieved only in the presence of the 17-ketone when exchange dioxolanation is used.32 Andros-tenedione has also been converted into the 3-monoketal by initial protection of the 17-ketone as the cyanohydrin.52 Similarly, the 3-monoketal (34) has... 

Methoxy-17,17-ethylenedioxy-1 S-methylestra-1,3,5(10)-/ne e.48b A solution of (+)3-methoxy-18-methylestra-l,3,5(10)-trien-17-one (5 g) dissolved in ethylene glycol (5 ml) and ethyl orthoformate (10 ml) containing p-toluenesulfonic acid (0.3 g) is heated under reflux for 2 hr in a nitrogen atmosphere. The resulting solution is diluted with methylene chloride and washed with dilute sodium bicarbonate and water. The organic phase is dried over sodium sulfate and evaporated to dryness in the presence of a trace of pyridine. Trituration of the residue with petroleum ether yields 4.7 g (82%) of the pure ketal. 

A useful method for the preparation of 3 (2i/)-dihydrofuranone ethylene acetals from readily available a -hydroxyenones has been developed (80H(14)1825). Treatment of a -hydroxyenones with ethylene glycol and p-toluenesulfonic acid produced the acetals in 65-100% yields. 

Reaction of 4-phenyl-6-chloro-2(lH)-pyridone and 3-aminopropanethiol on heating in ethylene glycol at 190-200°C afforded 8-phenyl 2,3, 4,6-tetrahydropyrido[2,l-6][l,3]thiazin-6-one (79CPB1207). 2,3,4,6,7,116-Hexahydro[l,3]thiazino[2,3-a]isoquinolin-4-ones (204) were obtained in the reactions of 3,4-dihydroisoquinolines and 3-mercaptopropionic acid in the presence of p-toluenesulfonic acid (69FRP155211 87MI1). 

B. 2-Bromocyclopentenone ethylene ketal. A solution of 22.00 g (136.7 mmol) of freshly distilled 2-bromo-2-cyclopentenone, 21.80 g (351.2 mmol) of ethylene glycol, 1.5 L of benzene (Note 4), and 60 mg of p-toluenesulfonic acid monohydrate is refluxed for 64 hr (Note 5), with azeotropic removal of water, in a 3-L, round-bottomed flask, equipped with a Dean-Stark trap, condenser, and Drierite drying tube. The solution is cooled to room temperature, dried with potassium carbonate, and filtered by vacuum through 15 g of Celite. The filter cake is washed with 150 mL of benzene. Removal of the solvent under reduced pressure yields a mobile yellow oil. Distillation (65-67°C, 0.7 mm) affords 22.4 g (109.0 mmol, 80%) (Note 6) of the ketal (Note 7). 

The michael addition of mercaptoacetaldehyde diethyl acetal 87 and 9-cyanononenal 86 in the presence of triethylamine gave the adduct 88 quantitatively. 1-Tributyl-phosphoranylidene-2-heptanone was reacted with the aldehyde and produced the conjugated enone 89, which ketalizated with four equivalents of ethylene glycol and catalytic amounts of p-toluenesulfonic acid in refluxing benzene to the bis-dioxolane 90. Surprisingly, the isomeric bisdioxolane with the double bond at positions C13 14 was not detected. 

The product from Step 2 (26.83 mmol), ethylene glycol (97.63 mmol) and p-toluenesulfonic acid monohydrate ( 0.5g) dissolved in 200 ml toluene were heated under reflux 3 days using a Dean-Stark trap to remove water. After cooling, the solid was washed, re-crystallized in DMF, and the product obtained in 90% yield, mp = 237 °C. H- and C-NMR data supplied. 

Aromatic and aliphatic carbonyl compounds condense with glycols, such as ethylene, propylene, and trimethylene glycols, to form cyclic acetals p-toluenesulfonic acid has proved to be an excellent catalyst. As before, the water formed in these reactions is conveniently removed by an azeotropic distillation with benzene. Representative aldehydes and ketones that undergo this acetalization include acetone, cyclohexanone, pinacolone, acetophenone, benzophenone, n-heptaldehyde. 

Hydrolysh-deearboxylation. The Organic Syntheses procedure for the conversion of diethyl 2,5-diketocyclohexane-l,4-dicarboxylate (I) to cyclohexane-1,4 iione (2) calls for treatment with water in a steel autoclave at 185 195° for 1015 min. (yield 72-80%). The reaction can be carried out more conveniently and in higher yield by refluxing in aqueous ethylene glycol containing some p-toluenesulfonic acid. ... 

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