THE SYNTHESIS OF CERTAIN SUBSTITUTED ALICYCLIC METHYL

J. Org. Chem. , 1939, 04 (3), pp 270–283. DOI: 10.1021/jo01215a009. Publication Date: July 1939. ACS Legacy Archive. Cite this:J. Org. Chem. 04, 3, ...
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[ CONTRIBUTION FROM THE FRICKCHEMICAL LABORATORY, PRINCETON UNIVERSITY,

PRINCETON, NEWJERSEYI

THE SYNTHESIS OF CERTAIN SUBSTITUTED ALICYCLIC METHYL KETONES. I WILLIS AARON YARNALL*

AND

EVERETT S. WALLIS

Received March 94, 19S8

It is well known that a condensation reaction' takes place between a ketone or an aldehyde, and an a-halogenated ester in the presence of sodium ethylate. The resulting glycidic ester on saponification yields an acid which, with the loss of a molecule of carbon dioxide, rearranges into a ketone or an aldehyde (R8=H), as the case may be. 0

R1

\ C=O /

// + Rs-CH-C-OGH6

NsOCzHs

I c1

R2

In search for a new and convenient method for the preparation of progesterone (11) from the more plentiful sterol cholesterol the authors of

CH3 I

Progesterone I1

Deh ydroandrosterone I

* Research Assistant on special funds from Merck and Co., Inc., Rahway, New Jersey. 1 DARZENS AND CO-WORKERS, Compt. rend., (a) 139,1214(1905); ( b ) 141,766 (1906); ( c ) 142, 714 (1906); ( d ) 144, 1123 (1907);( e ) 146, 1342 (1908); cf) 160, 1243 (1910); ( 8 ) 161, 758 (1911); ( h ) 162, 1105 (1911); ( i )164, 1812 (1912); 0') 196,884 (1932). 270

SYNTHESIS OF ALICYCLIC METHYL KETONES

271

the present paper investigated the applicability of the above reaction, known as the Darzens condensation, to the steroid ketone, dehydro androsterone (I). Some time ago the results2 of the preliminary qualitative studies of this problem were published. It was soon found however that the reaction itself needed a mwe detailed study, and in view of the costly materials involved when working with steroid compounds, experiments were first carried out on such model substances as cyclohexanone, cyclopentanone, etc. It should be noted in this connection that previous work by other investigators on compounds of this type had revealed certain facts which were pertinent to this problem. Darzens and his co-workers' have reported that while the reaction is fairly general for ketones it cannot be extended always to aldehydes. In their hands aliphatic and alicyclic ketones gave better yields of the glycidic ester than semi-aromatic ketones. They observed also that better yields of the glycidic ester can be obtained by substituting ethyl a-chloropropionate for ethyl chloroacetate. The a-methyl glycidic acids,

Ri

0

\/\ C-C-COOH, / I

Rz

Ra

so formed were observed also to decompose to the corresponding methyl ketones more readily. In some instances the sodium salts, which as a rule are more stable than the corresponding acids, decomposed at the temperatures of the boiling alkaline solutions. Although Darzens claimed good yields for the decomposition of these glyciclic acids to aldehydes and ketones, in no case did he give definite figures. This made it necessary for us to study the effect of various factors, such as temperature, solvent, excess of one or of the other reactants, etc., .which, we observed a t an early stage in our investigations, greatly influenced the yield of the desired products. It seems pertinent a t this time .to record some of our more important observations made during the course of these studies. During the addition of powdered sodium ethoxide, which brings about the condensation, it was noticed that by cooling to -80" the mixture so produced was practically devoid of the brown coloration always noticed when Darzens' procedure was followed. Yields of the glycidic acid ester (65-69 per cent.) were also increased when the mixture was allowed to stand several hours a t room temperature before heating on the water YARNALL AND

WALLIS,

J . Am. Chem. Soc., 69, 951 (1937).

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WILLIS AARON YARNALL AND EVERETT S. WALLIS

bath. When, however, ethyl a-bromopropionate was substituted for ethyl a-chloropropionate in the condensation with cyclohexanone a lower yield (44 per cent.) of the glycidic ester was always obtained. Solvents appear to have some influence on the yield. The effect of benzene, of ether, and of a mixture of benzene and diisopropyl ether on the condensation was studied. Other important facts influencing the condensation were observed. An increase in the yield of the glycidic ester was always noted when a large excess of the a-halogen ester and of sodium ethoxide was used. In one experiment, in which a large excess of ethyl a-bromopropionate and of sodium ethoxide, with ether as the diluent, was used, a yield of 66 per cent. was obtained as compared with 44 per cent. when the bromo ester was used without any solvent. The order of the addition of the reactants appears to have an appreciable effect on the Condensation. In one experiment when ethyl a-chloropropionate was added to the mixture of the ketone and sodium ethoxide in ether a conversion of only 25 per cent. was observed. This result can be interpreted as supporting the view of Scheibler3 who believes that in this condensation the sodium ethoxide forms an enolate with the ester and not with the ketone. In our experiments it was also observed that lower yields of the glycidic ester were obtained when cyclopentanone was used in the condensation instead of cyclohexanone. We were unable to obtain yields greater than 35 per cent. Large amounts of high-boiling products were always formed, the exact nature of which waa not determined. The results of our experiments show that the yields of the ketones obtained from the corresponding glycidic esters by saponification and rearrangement are also sensitive to the conditions employed. Excellent yields of the corresponding glycidic acids 111 and IV were obtained from the glycidic esters when alcoholic sodium hydroxide was used. It was also

0

/cH2-cH2 CH2

\

CH2-CH2

\/\ C-C-COOH I /

CH3

I11

CH2-CH2

0

\/\

I /

C---C-COOH

I

CH2-CH2

cH3

IV

observed, that if the free glycidic acids were allowed to stand in weakly acidic solutions for certain periods of time before their isolation, decomposition took place and small amounts of ketones were produced. In certain experiments the sodium salts of tlhe glycidic acids were a

SCHEIBLER AND TUTUNDZITBCH, B e y . , 64B,2916 (1931).

SYNTHESIS OF ALICYCLIC METHYL KETONES

273

obtained in good yields by allowing them to crystallize from the cooled alcoholic solution in which the saponification process had taken place. In the present work on the decomposition and rearrangement of the glycidic acids it was found that the pyrolysis of the glycidic acids both at ordinary and at reduced pressures gave low yields of ketones. Thus, methyl cyclohexyl ketone was formed in 27-45 per cent. yield, and methyl cyclopentyl ketone in 10-16 per cent. yield. In all our pyrolysis experimentis appreciable amounts of resinous material always remained, and are probably formed as a result of secondary condensations of the carboxyl group with the oxide bridge of the glycidic acid. Because of these facts, a study was made of other possible ways of bringing about the rearrangement. As a result, two new methods were developed for the conversion of glycidic acids to ketones. It had previously been observed by Darzenslf that certain 8-chloro-ahydroxy esters on treatment with aqueous alkali rearrange to aldehydes or ketones. This reaction was therefore studied with ethyl a-(1-chloro1-cyclohexy1)-a-hydroxypropionate,a compound obtained by saturating a cold ether solution of the glycidic ester with dry hydrogen chloride. Results obtained by the treatment of this product with one equivalent of sodium hydroxide in either water or alcohol indicated that the reaction leading to the reformation of the glycidic ester is faster than the hydrolysis of the ester and its subsequent rearrangement. Thus, the main product of the reaction was the glycidic ester,

n&-cooCH6. I

Only traces of methylcyclohexanone were formed. Thus it became evident that better results should be obtained if hydrogen chloride were allowNed to react with the free glycidic acid. Consultation of the literature showed that glycidic acids add hydrogen chloride to give 8-chloro-a-hydroxy acids':

0

/ \

CH2-CH-COOH

CH2-CH-COOH

I

ACLC1

/

OH

Erlenmeyer4 had also observed that an aqueous solution of the sodium salt of such an acid on warming gave acetaldehyde, sodium chloride and carbon dioxide, It has also been reported by Melikow5that similar treatEFLLBNMEYER, ibid., 13, 307 (1880). MXILIKOW AND PETRENKO-KRITSCHENKO, J . Russ. Phys. Ges., 21, 396; see also BEILsmm, 4th Ed. 111, 305, 317. 4

5

274

WILLIS AARON YARNALL AND EVERETT S. WALLIS

ment of 8-chloro-a-hydroxybutyricand -isobutyric acids gives propionaldehyde and acetone respectively. With these facts in mind a study was made of the action of hydrogen chloride on the free glycidic acids obtained from cyclohexanone and cyclopentanone. The results so obtained are of interest. With a-l-oxido-acyclohexylpropionic acid (V) hydrogen chloride gave a halogen derivative which, when dissolved in a solution of sodium carbonate and steamdistilled, gave methyl cyclohexyl ketone (VI) in 29 per cent. yield and a mixture of acids.

i:8,,,,

HC?

(yf?

Ecq distill

CH3 (VI

(VI)

Pyrolysis of this mixture also yielded some of the ketone VI. Much better yields were obtained when the chlorohydroxy acid was dissolved in pyridine. With a-l-oxido-a-cyclohexylpropionicacid yields of 75 per cent. of the ketone were obtained. With a-l-oxido-a-cyclopentylpropionic acids the yield of ketone was somewhat low (25 per cent.), although much better than when the acid was pyrolyzed. Since it was observed that pyrolysis of the free glycidic acids led to the formation of much resinous material it seemed desirable to study the pyrolysis of their sodium salts. Theoretically, such a pyrolysis should lead to the desired ketones for it involves a reaction analogous to the preparation of hydrocarbons. Accordingly, the sodium salts VI1 and VI11 were prepared in a pure state and heated with equivalent quantities of sodium hydroxide.

VI1 I z > A y C O O N a

cH3 VI11

I - - C - C /O H8

+

Na&03

SYNTHESIS O F ALICYCLIC METHYL KETONES

275

Yields of 45-56 per cent. of the ketones were produced depending on the conditions of the experiment. Thus both of these new methods are improvements over the known method of production of methyl alicyclic ketones from glycidic acids by pyrolysis. The condensation with dehydroandroster0ne.-The information obtained \ from the above experiments was utilized in the condensation with dehydroandrosterone. The details of the work will be found in the experimental part of this paper. The results may be briefly summarized as follows. The condensations were carried out under various conditions of temperature, concentrations of reactants, solvent, stirring, etc. The products isolated were mainly unchanged dehydroandrosterone, the glycidic ester, androstenediol, and traces of the sodium glycidate. Twelve different condensations were run. The poorest yields (10 per cent.) were obtained by permitting the ether solution of equivalent amounts of the reactants to stand at room temperature. When an excess of the chloroester and of the condensing agent was employed (10-100 per cent.), and the ether solution was shaken a t room temperature, and then refluxed in an atmosphere of nitrogen for a period of two and a half to four days, the per cent. conversion was increased (23 to 40 per cent.). When large excesses of sodium ethoxide and the chloro ester dissolved in ether were employed, and the mixture was shaken and refluxed several days the conversion was practically complete (90-93 per cent.) Attempts to crystallize the glycidic ester were unsuccessful. I n all probability this is due to the fact that the ester is produced in more than one enantiomorphic form, made possible by the introduction into the molecule of new asymmetric carbon atoms. However, on saponification an acid melting a t 160-163' was isolated. Experiments showed that this acid was a mixture of several isomers.6 By crystallization methods one isomer which melted at 183-185' was obtained. The presence of a second acid of much higher melting point, 240-244", was also noted. Undoubtedly this compound is an isomer. Other isomers may be present in the mother liquors. Indications of the presence of a t least one such acid were observed. The isolation of androstenediol-3,17 and the isomeric pregnenolones was carried out in the following manner. The condensation mixture was usually diluted with ether and thoroughly washed to remove sodium salts. 6 Since this work was done a paper by MIESCRER AND KAQI[Helv. Chim. Acta, 22, 184 (1939) ] has appeared in which they have described the results of certain investiga-

tions 011 the condensation of dehydroandrosterone with a, a-dihdogenated esters in the pregence of magnesium amalgam along lines similar to those previously outlined by US [J.Am. Chem. SOC.,69, 951 (1937)l. Their results strongly show that all four possible isomers of this acid are present.

276

WILLIS AARON YARNALL AND EVERETT S. WALLIS

The residue obtained from the ether solution was heated at 50-70' in a high vacuum to remove any propionates. The unchanged dehydroandrosterone was then removed in the form of its semicarbazone. The residue, which contains the glycidic ester and androstenediol, was saponified with alcoholic alkali. The ether extract from the saponification mixture gave a residue which was treated with semicarbazide hydrochloride in the usual manner. Small amounts of the semicarbazones of A5-pregnenolone and A5-isopregnonolone were obtained. This semicarbazone mixture melted a t 215-223'. When the above saponification mixture was acetylated before the treatment with semicarbazide hydrochloride a mixture of semicarbazone acetate was obtained which melted a t 240-244' with decomposition. Hydrolysis of these semicarbazones gave a product, which, on purification by high vacuum distillation and recrystallization, melted a t 153-159" and gave a correct analysis for pregnenolone, C21H3202. The separation of the two isomers was accomplished by precipitating the normal pregnenolone with digitonin by a method essentially described by Butenandt and Fleischer'. The pregnenolone so obtained melted a t 189'. Small amounts of isopregnenolone were also isolated. From the ether extract of the semicarbazones of the pregnenolones, androstenediol was obtained in yields of 4-21 per cent. based on the amount of hormone which entered into the reaction. The isolation of this diol as a reduction product causes one to recall the ketyl theory of Rutovski and Daev* for aromatic ketones which undergo the Darzens condensation. Studies were made in an attempt to increase the yields of As-pregnenolone. In most instances they were unsuccessful because of the stability of the free gIycidic acid. When pyrolysis was conducted in a high vacuum only resinous material was obtained. The sodium salt in boiling alkali was also found to be too stable to give good yields of the rearranged products. Heating the free acid with pyridine or quinoline did give in each case small amounts of neutral products, which on purification were found to contain As-pregnenolone, and small amounts of another ketone whose structure is still somewhat uncertain. When the free glycidic acid in dry ether solution was treated with dry hydrogen chloride, a halogen derivative was obtained, which, when boiled with pyridine, was more easily decarboxylated. Much better yields of ketonic material were produced when this method of decarboxylation was used. The ketones were isolated in the form of their semicarbazones. Hydrolysis of these semicarbazones gave a crystalline product which melted at 110-114'. When an acetic acid solution of this mixture of ketones was brominated, oxidized with chromic acid, and debrominated 7

BUTENANDT AND FLEISCHER, Ber., 70, 96 (1937). 04B,693 (1931).

* RUTOVBKI AND DAEV,ibid.,

SYNTHESIS O F ALICYCLIC METHYL KETONES

277

according to the usual methods, a crystalline product WM isolated, which, upon purification by crystallization, was found to be identical with a sample of progesterone prepared from stigmasterol. Since the glycidic acid from dehydroandrosterone can also add hydrogen chloride a t the double bond as well as a t the oxide bridge, it seemed wise to determine if in the subsequent treatment with pyridine the double bond is shifted to the 4-5 position, thereby producing an allo type of compound. Because of this possibility, the effect of heating cholesterol hydrochloride with moist pyridine was studied. Results were obtained which showed conclusively that on treatment with pyridine, cholesterol hydrochloride yields both cholesterol and allocholesterol. Thus, reasoning by analogy, one of the pregnenolones which we would expect to be present in the ketone mixtures described above would be A4-pregnenolone. At the present writing this particular ketone has not been isolated in a pure state from the neutral ketone fraction. It should be noted however that its presence is not bothersome since in this case also, bromination, oxidation, and debromination would yield the desired progesterone. EXPERIMENTAL

Preparation of sodium ethoxide.-The dry, powdered sodium ethoxide used in the condensation experiments was always freshly prepared. A weighed amount of sodiuin was dissolved in 20-25 times its weight of absolute alcohol. After solution the excess alcohol was rapidly distilled. The solid sodium ethoxide was baked at 160-180° and 15 mm. for fifteen minutes. On cooling to room temperature i t was carefully powdered, and used immediately. The condensation of cyclohexanone with ethgl a-ch1oropropionate.-A. The method of Daraens. To a mixture of 5.0 g. (5.26 cc.) of pure cyclohexanone and 6.97 g. (6.4 cc.) of ethyl a-chloropropionate there was added the powdered sodium ethoxide made from 1.2 g. of sodium. Yield of glycidic ester 5.5 g. (54% of the calculated amount); b.p. 126-128/19 mm. Anal. Calc'd for CllHlsOa:C, 66.64; H , 9.15. Found: C, 66.5; H, 9.26. B. Modifications of the above method showing effect of temperature, concentration, nolvent, etc. 1. A mixture of 10.5 cc. of cyclohexanone and 12.8 cc. of ethyl a-chloropropionate was cooled to -80" in a glass-stoppered flask, and t o this was added in 0.1-mole portions ,with shaking, powdered sodium ethoxide made from 2.35 g. of sodium. The mixture was allowed to stand for ten minutes and then was brought to room temperature and left overnight. After warming on a steam bath for two and a half hours (moisture excluded) the mixture was poured into ice water and ether, and was thoroughly shaken. The ether layer was washed with a 5% solution of sodium carbonate, and dried over sodium sulfate. Evaporation of the ether solution left a residue which on distillation gave 13.6 g. of the glycidic ester; b.p. 126-127"/20 mm.; yield, 68% of the calculated amount. 2. The above experiment was repeated with 50 cc. of dry ether as the solvent. The reaction mixture was shaken 24 hours at room temperature and then refluxed for another 24 hours; yield of glycidic ester, 34% of the theoretical.

278

WILLIS AARON YARNALL AND EVERETT S. WALLIS

3. The experiment was similar to No. 1 except that 25 CC. of anhydrous benzene was used as the solvent. The mixture was allowed to stand overnight, and was then refluxed for eight hours. Yield of glycidic ester, 47%. 4. Same as in No. 3, with benzene-petroleum ether ( 1 : l ) instead of ether as the solvent. Yield of glycidic ester, 54%. 6. Same as in No. 2 with the use of a 10% excess of both ethyl a-chloropropionate and sodium ethoxide. Shaken for four days at room temperature. Yield of glycidio ester 37% of the calculated amount. 6. Same as No. 1, with 0.1 mole of ethyl a-bromopropionate instead of ethyl achloropropionate. Yield of glycidic ester, 44%. 7. In this experiment a reversal was made in the order of mixing the reagents. Sodium ethoxide (0.1 mole) was added to 0.1 mole of cyclohexanone dissolved in 20 cc. of dry ether. The mixture was cooled to 0", and 0.1 mole of ethyl a-chloropropionate was slowly added. A rise in temperature was noted. The contents of the flask were shaken for 24 hours and worked up in the usual manner. Yield of glycidic ester, 25%. Condensation of cyclopentanone with ethyl a-ch1oropropionate.-The condensation was carried out by the method No. 1 for cyclohexanone described above. Yield of glycidic ester, b.p. 128'/25 mm., 35%. A n a l . Calc'd for CloHleOa: C, 65.2; H, 8.7. Found: C, 65.0; H, 8.9. A higher-boiling material was also obtained, but was not further investigated. Experiments o n the hydrolysis of the glycidic esters.-i. Preparation of sodium a-1-oxido-a-cyclohexylpropionate. Ten grams of the corresponding glycidic ester described in the above experiments was dissolved in 50 cc. of an alcoholic solution of sodium hydroxide which contained 6 g. of sodium hydroxide. The solution was refluxed for two hours and allowed to cool. On standing overnight, crystals separated in plates. Recrystallization from 95% alcohol gave 6.5 g. of the pure sodium salt; yield, 63%. Neutralization equivalent.-A 0.741-g. sample of the sodium salt required 38.9 cc. of 0.6969 N hydrochloric acid. Equiv. wt. for CoHlrNaOs: calc'd, 192.2; found, 196. 2. Preparation of sodium a-1-oxido-a-cyclopentyl propionate. The method used was essentially the same as that described above. Essentially the same yields were obtained. Neutralization equivalent.-A 0.804-g. sample of the sodium salt required 47.2 cc. of 0.969 N hydrochloric acid. Equiv. wt. for CsH11NaOa: calc'd, 178.2; found, 176. 8. Preparation of a-1-oxido-a-cyclohexylpropionicacid. Twelve grams of the corresponding glycidic ester were hydrolyzed in the manner already described. The alcoholic solution was diluted with water and extracted with ether. The aqueous layer was acidified with 10% hydrochloric acid to Congo red, and then 2 cc. of 10% hydrochloric acid was added. The oil so produced was worked up in the usual way; yield of acid, 9.1 g.; 88% of the theoretical. 4. Preparation of a-1-oxido-a-cyclopentylpropionicacid. The preparation was carried out as described in No. 3. Yield of acid, b.p. 128"/25 mm.; 91% of the theoretical. Preparation of the alicyclic methyl ketones.-i . Preparation of methyl cyclohexyl ketone by pyrolysis of a-I-oxido-a-cyclohexylpropionicacid under reduced pressure. Four and four-tenths grams of the glycidic acid was used in this experiment. At 120" and 15 mm. carbon dioxide evolution began. Pyrolysis was continued for fifteen minutes a t 130". The temperature of the bath was then raised to 160" for the distillation of the ketone. Yield 0.88 g.; 27% of the calculated amount. The

SYNTHESIS OF ALICYCLIC METHYL KETONES

279

ketone was converted into its semicarbazone in the usual manner. Recrystallization from dilute alcohol gave a product which melted at 177". (Beilstein records m.p. 175"; Darzens, m.p. 177".) 2. Pyrolysis a t atmospheric pressure. Four and seven-tenths grams of the glycidic acid gave 1.4 g. of methyl cyclohexyl ketone. Yield, 41% of the theoretical. S. Pyrolysis of the sodium salt of the glycidic acid. The sodium salt (1.6 9.) prepared as described above was heated with 0.35 g. of sodium hydroxide. An intimate mixture was made by the addition of 1 cc. of alcohol, which was subsequently removed. After removal of the solvent the bath temperature was raised to 300" and kept a t that temperature for 45 minutes. Most of the material distilled a t this temperature. Decomposition was completed a t 400'. Yield of ketone in form of ~ t semicarbazone, s m.p. 176O, 45% of the theoretical. 4. Rearrangement of a-(1-chloro-1-cyclohexy1)-a-hydroxypropionicacid. Eleven grams of an impure a-(1-chloro-1-cyclohexy1)-a-hydroxypropionicacid, prepared from the above glycidic acid by saturation with dry hydrogen chloride, was dissolved in 35 cc of pyridine, to which had been added 5 g. of semicarbazide hydrochloride dissolved in the minimum amount of water. The solution was refluxed for 30 minutes. On working up the product, 5 g. of a semicarbazone was obtained. Recrystallization gave 3.8 g., which melted at 175-176". This is equivalent to 2.5 g. of inethyl cyclohexyl ketone. Yield, 75% of the calculated amount. 6. Preparation of methyl cyclopentyl ketone. Pyrolysis of the corresponding glycidic acid gave the ketone, whose semicarbazone melted at 141'. Yield, 16% of the theoretical. When the sodium salt of the glycidic acid was pyrolyzed as described above for the corresponding cyclohexyl derivative the yield was increased i,o 56 per cent. Rearrangement of an impure a-( 1-chloro-1-cyclopenty1)-a-hydroxypropionic acid gave a semicarbazone, m.p. 141, in a yield of 25%. Condensattons of dehydroandrosterone with ethyl a-ch1oropropionate.-The dehydroandrosterone used in these experiments was prepared from cholesterol by welllcnown methods. Many condensations were carried out. However, only four typical experiments will be given in detail. Experiment 1. In this experiment a 10% excess of the chloro ester, and of sodium ethoxicle was used. The dehydroandrosterone (0.401 9.) was dissolved in 30 cc. of dry ether in a 50-cc. glass-stoppered Erlenmeyer flask. After cooling to -SOo, 0.19 cc. of ethyl a-chloropropionate and 0.10 g. of powdered sodium ethoxide were added. The mixture was then allowed to come to room temperature, and shaken for four days in a shaking machine. It was finally refluxed for one day in an atmosphere of dry nitrogen. The product was diluted with ether and extracted with a 5% solution of sodium bicarbonate. The water extract gave but a slight cloudiness on acidification. The ether layer was worked up in the usual manner, and the residue was subjected to a high vacuum (0.02 mm.) for one-half hour to remove any a-chloro-, or a-ethoxypropionic acid esters which might have been present. The residue was treated in the usual manner with semicarbazide hydrochloride (0.7 g.) and sodium acetate (2 9 . ) dissolved in 50 cc. of alcohol. The mixture was refluxed for two hours and then worked up. After i t had stood overnight a semicarbazone separated between the water-ether layers. This product was separated by filtration and dried i n vacuo, m.p. 247-250". The weight of product was 0.34 g., corresponding to 0.12 g. of dehydroandrosterone; amount of dehydroandrosterone which mtered into reaction, 70%. The semicarbazone was hydrolyzed in the usual manner, and the dehydroandronterone obtained from i t was recovered.

280

Wfeft,fd AARON YARNALL AND EVERETT 8. WALLIS

Experiment 2. In this experiment a 65% excess of ethyl a-chloropropionate was used. The amount of sodium ethoxide employed was three and one-half times the theoretical quantity. A solution of 1.60 g. of dehydroandrosterone and 1.18 cc. of ethyl a-chloropropionate in 150 cc. of dry ether was cooled to -80" and to i t was added the powdered sodium ethoxide from 0.584 g. of sodium. After the mixture had come to room temperature, i t was refluxed for 60 hours in an atmosphere of nitrogen. The ether was then evaporated, and the residue was refluxed for two hours with a solution of 120 cc. of 90% alcohol which contained 4 g. of sodium hydroxide. The cold solution was diluted with water and extracted with ether. The alkaline water layer was acidified with dilute acid and again extracted with ether. This latter ether extract was worked up in the usual manner and gave 0.91 g. of a glycidic acid. Melting point 160-163". This corresponds to a 46% conversion of the dehydroandrosterone. Anal. Calc'd for C Z ~ H ~ C, ~O 73.30; ~ : H, 8.96. Found: C, 73.20; H, 9.10. Crystallization of this crude acid from a variety of solvents finally gave a product which melted a t 183-185". Another acid was isolated from the mother liquors which me1t ed a t 240-244". The first ether extract which contained the unchanged dehydroandrosterone was worked up, and the dehydroandrosterone was recovered as the semicarbazone. It also contained some androstenediol. A description of the recovery of this substance will be given later. Experiment 3. In this experiment, twenty times the equivalent amounts of ethyl a-chloropropionate were used. One gram of the hormone and 8.7 cc. of the a-chloro ester was dissolved in 10 cc. of ether. The solution was cooled to -80°, and finely powdered sodium ethoxide from 1.60 g. of sodium was added. The resulting mixture was allowed to stand one day a t room temperature and then shaken for one day. It was then worked up essentially as described in Experiment 1. The amount of the semicarbazone of dehydroandrosterone recovered was 0.11 g. The amount of ketone therefore which reacted was 91%. Experiment 4. In this experiment a mixture of benzene and diisopropyl ether was used as the solvent. Therefore, a higher temperature of refluxing was obtained. Three grams of dehydroandrosterone and 1.31 cc. (1 mole) of ethyl a-chloropropionate were dissolved in a mixture of 20 cc. of dry benzene and 20 cc. of diisopropyl ether, The solution was cooled to -80" and one mole of powdered sodium ethoxide was added (from 0.27 g. of sodium). The mixture was allowed to stand overnight a t room temperature and then refluxed for four hours. Another equivalent of the CYchloro ester and of sodium ethoxide was then added, and heating under reflux was continued for an additional four hours. The product was then worked u p as described in Experiment 2. The amount of free glycidic acid obtained indicated a 58% conveysion. The ether layer, containing the unchanged dehydroandrosterone, neutral products of rearrangement, and androstenediol, gave a residue which weighed 1.55 g. Recovery of unchanged dehydroandrosterone.-In all experiments the unchanged dehydroandrosterone was recovered as the semicarbazone during some stage of the procedure. Thus, in Experiment 4 above, the excess hormone was separated from androstenediol in this way. The crude semicarbazone was hydrolyzed in the usual manner. The ketone was sublimed in a high vacuum and recrystallized; m.p. 146148". Isolation of androstenedio1.-In the earlier stages of this research attempts t o purify the excess dehydroandrosterone by simple recrystallization failed. In this

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way i t was found that the products of the reaction were contaminated with another material, androstenediol. It was isolated in the following manner. The residue (containing the neutral products) from the ether extract of the alkaline solution from the saponification of the products of condensation, Experiment 2, was refluxed for two hours with an alcoholic solution of semicarbazide acetate. After separation OP the semicarbazone of dehydroandrosterone and other ketones, the ether extract was dried and evaporated, and the residue was sublimed in a high vacuum at 140-150'. The sublimate, wt. 35 mg., was crystallized from acetone. Crystals were obtained which melted a t 170-173". The melting point of a mixture with an authentic specimen of androstenediol (m.p. 172") was not depressed. The semicarbazone fraction (wt. 0.51 9.) was hydrolyzed as usual, and the product was recrystallized from benzene and petroleum ether three times without obtaining a pure compound. Other ketones (pregnenolones) besides dehydroandrosterone vere found to be present. The following experiments show how they were isolated. Zsola!ion of the pregnenolones.-(A) A solution of 0.71 g. of dehydroandrosterone in dry ether was boiled under reflux with 0.57 g. (1.75 mole) of ethyl a-chloropropionate and the sodium ethoxide from 0.11 g. (1.9 mole) of sodium for 56 hours. Water and ether were then added, and after the ether layer was washed free of alkali, i t was dried over sodium sulfate and evaporated. The excess dehydroandrosterone was then removed as the semicarbazone as in Experiment 1. In this manner 0.05 g. of the semicarbazone was obtained, showing the conversion to have been practically complete. The ether extract from the semicarbazone was dried and evaporated, and the residue was taken up in acetone. As crystals did not form quickly, the acetone was evaporated, and the residue was taken up in alcohol and boiled under reflux with an excess of 2 N sodium hydroxide for two hours. The solution was then diluted, and extracted with ether. The aqueous layer was acidified, and the free unrearranged glycidic acid was recovered. The amorphous residue from the dried ether extract was partially crystallized. It was taken up in alcohol and treated with sodium acetate and semicarbazide hydrochloride as usual. A semicarbazone was obtained Tyhich melted at 215-223'; yield, 50 mg. This semicarbazone was hydrolyzed in the usual manner. The mixture of ketones so obtained melted a t 120-124". Distillation in a high vacuum (115-125') gave a product which on recrystallization from acebone melted a t 153-159" (uncorr.) ; yield, 12 mg. Anal. Calc'd for C~H9202:C, 79.73; H, 10.18. Found, C, 79.69; H, 10.60; 10.4. ( B ) The ether solution containing the materials from which the dehydroandrosterone semicarbazone had been removed (Experiment 1) was evaporated and warmed for 20 minutes with about 15 cc. of alcohol containing 0.5 g. of sodium. The solution was diluted, and extracted with ether. The ether solution was dried and evaporated. A residue was obtained which was acetylated. The acetic anhydride solution was then poured into water and ether. The ether solution was extracted with a 10% solution of sodium carbonate and then worked u p in the usual manner. The residue was dissolved in alcohol and treated with semicarbazide hydrochloride and sodium acetate. On working up the products, 40 mg. of a semicarbazone acetate, m.p. 241-243", was obtained. This semicarbazone was hydrolyzed in the usual way and gave a ketonic material which was sublimed in a high vacuum. The product 80 obtained was recrystallized from dilute alcohol (70%). Crystals were obtained which melted at 124-130"; yield, 15 mg.

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WILLIS AARON YARNALL AND EVERETT 8. WALLIS

This material was united with that obtained in A and the same material from two other experiments. Since i t was regarded as a mixture of isomeric pregnenolones, i t was treated according to the method of Butenandt and Fleischer' for the separation of these isomers. The pregnenolone so obtained melted a t 189", and gave no melting point depression with an authentic specimen. Small amounts of A6-isopregnenolone were also isolated. Other ketonic material also seemed to be present. Action of hydrogen chloride on the glycidic acid.-As stated in the general discussion, many attempts were made to increase the yields of the pregnenolones formed by the rearrangement. They were generally unsuccessful. The action of hydrogen chloride on the acid, however, is of interest, and the details of the experiments follow. Experiment A . A solution of one gram of the glycidic acid in 25 cc. of anhydrous ether was saturated with dry hydrogen chloride a t 0" and allowed to stand overnight a t room temperature. The ether was partially evaporated to remove the major portion of the excess hydrogen chloride. The solution was then diluted with ether and washed repeatedly with distilled water until the washings were free of chloride ion. The dried ether solution yielded, on evaporation, a non-crystalline residue which gave a strong Beilstein test for halogen. This crude chloro acid was heated on the steam bath for one hour with 15 cc. of pyridine which contained two grams of semicarbazide hydrochloride dissolved in 5 cc. of water. Addition of ether and water gave an insoluble material. The water solution was made acid to extract the pyridine, and the precipitate was filtered and dried. Recrystallization from alcohol gave crystals melting at 227" (uncorr.) ; weight of crude semicarbazone, 420 mg. The semicarbazone was dissolved in 10 cc. of alcohol which contained 5 cc. of 5 N sulfuric acid, and boiled under reflux for three hours. From an ether extract of the resulting mixture, 300 mg. of neutral non-crystalline material was obtained. This was sublimed in a high vacuum, giving a t 110-130" about 150 mg. of a mixture of crystals and oil. The crystals, on treatment with petroleum ether and drying, melted at 110-114". Experiment B. In this experiment, performed for us by Dr. E . Gilmore Ford, the crude chlorohydroxy acid obtained as in A was dissolved in pyridine and refluxed for approximately two hours. The pyridine was removed by vacuum distillation, and the residue was treated with semicarbazide hydrochloride in the usual manner. A semicarbazone was obtained which melted at 226-235'. The ether solution from the semicarbazone was evaporated and found to contain free glycidic acid. Thus, the velocity of reformation of the glycidic acid is comparable to the velocity of decarboxylation and rearrangement. Preparation of progesterone.-The mixture of ketones obtained by hydrolysis from 0.5 g. of the semicarbazone described above was dissolved in 20 cc. of glacial acetic acid, treated with bromine in the usual manner and oxidized a t room temperature for seventeen hours with chromic acid (one gram of chromic oxide in 1 cc. of water and 5 cc. of glacial acetic acid.) The organic material was precipitated with water, an! after solution in acetic acid, was debrominated with zinc. Recrystallization of the crude ketone so produced gave a product which melted a t 126-128'. !Action! of pyridine on cholesterol hydrochloride.-(This experiment was performed by Dr. E. Gilmore Ford.) A solution of 6 g. of cholesterol hydrochloride (m.p. 164") in 30 cc. of pyridine and 6 cc. of water was refluxed for one hour. The solution was then worked up in the usual manner, and the product so obtained was systematically recrystallized from alcohol. After many recrystallizations three crops of crystals were obtained which were identified as (I) cholesterol, ( 9 ) the molecular compound of cholesterol and allocholesterol, and (3) allocholesterol.

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We wish to take this opportunity to express our thanks to Merck and Company, Inc., Rahway, New Jersey, for certain analyses and for a grant-in-aid for this work, and to Dr. E. Gilmore Ford of this laboratory for certain experiments herein described. SUMMARY

A study has been made of the Darzens condensation of ethyl a-chloropropionate with cyclohexanone, cyclopentanone, and dehydroandrosterone. Yields of the corresponding glycidic ester produced in this condensation are increased by using an excess of the a-halogenated ester and of the condensing agent; ethyl a-chloropropionate is more efficient than the a-bromo ester in this condensation. A modified procedure, giving good yields in the Daraens condensation in a shorter time than previously used has been developed. Two new methods for the rearrangement of glycidic acids have been developed. The Darzens condensation has been applied for the first time to cyclopentanone and to dehydroandrosterone. A part of the latter ketone is reduced to androstenediol by the action of the condensing agent. Rearrangement of the condensation product under suitable conditions gives low ,yields of pregnenolone and other isomeric ketones. Dehydroandrosterone behaves like an aromatic aldehyde in respect to the stability of its glycidic acid, and like an aromatic ketone in that it is partially reduced to androstenediol.