Acid and the Synthesis of Dihydro-a-fencholenic Acid

Vic, R = CH,. VII. The bromination of fenchone has been carried out2·5 with bromine in sealed tubes. ..... P. Kohman and G. C. Harris, This Jour- nal...
2 downloads 0 Views 673KB Size
Download PDF
April 20, 1958

1963

REARRANGEMENT OF BROMOPENCHONE BY BASE

+

0.746 g. (96y0, VI1 epimer), m.p. 169-185' dec., were removed by filtration. A partial purification was accomplished by dissolving the solid in dilute bicarbonate (a minute amount of insoluble material was removed) followed by acidification with hydrochloric acid which gave a white solid, m.p. 173.5-185.5'. A n d . Calcd. for C17HlaO3: C, 76.67; H , 5.30. Found (S): C, 76.77; H , 5.41.

[CONTRIBUTION FROM

THE

Oxidation of the Hydroxyacid Mixture with Alkaline Potassium Permanganate.-A portion of the mixture (0.315 g., 0.00118 mole), was treated with 0.187 g. (0.00118 mole, 1.5 equivalents) of potassium permanganate by the method used in the oxidation of VI. T t i s resulted in 0.289 g. (92%) of VIIa, m.p. 209.0-210.5 , showing no depression with the characterized ANN ARBOR,MICH.

DEPARTMEXT OF CHEMISTRY OF THE UNIVERSITY

OF

ROCHESTER]

The Rearrangement of Bromofenchone by Base. The Structure of yFencholenic Acid and the Synthesis of Dihydro-a-fencholenic Acid BY D. S. TARBELL AND F. C , LOVELESS' RECEIVED NOVEMBER 14, 1957 Bromination of dl-fenchone yields the hitherto undescribed crystalline dl-bromofenchone. Treatment of this with alcoholic alkali yields a mixture of dl-yfencholenic acid and the corresponding ester. Catalytic reduction of both y- and cu-dl-fencholenic acids yields the same acid, dl-cu-(3-methylcyclopentyl)-isobutyric acid, the structure of which has been established by synthesis from 3-methylcyclopentanone by the Reformatsky reaction. y-Fencholenic acid has been shown not to possess an ethylidenec clobutane structure I11 as postulated by Semmler and Bartelt, but to be a methylenecyclopentane derivative VI; it yields Crmaldehyde and the expected cyclopentanone derivative on ozonization. The bromofenchone rearrangement is analogous t o other base-catalyzed rearrangements and, although the position of the bromine has not been established rigorously, it is probably on the 10-carbon.

I n connection with work on another problem in the fenchone field, we became interested in the report2 that bromination of fenchone (I) yielded 6bromofenchone (11), which was converted by base to y-fencholenic acid; to this acid was assigned2 structure 111. The assignment of structure I11

c 1-1

CH.:

.j

CHsCCHa I11 COOI-I

-------I

.I

O8

CHs

J.

The bromination of fenchone and some transformation products of bromofenchone recently have been s t ~ d i e dwithout ,~ establishing any of the structures involved. If structures 11-V are correct, the reactions involved are unusual; furthermore, the sequence might be useful for the preparation of cyclobutanone derivatives of an interesting type. We have, therefore, reinvestigated these compounds, have found that y-fencholenic acid has the structure VI, rather than 111, and have established the structures of y- and a-fencholenic acids (VI and V) by the synthesis of the dihydrofencholenic acid VI1 . The position of the double bond in a-fencholenic acid is not, of course, established by this synthesis. CH2

II

CHa

I

I

/'\

L/ I

CHiCCHa

I

0

-//

Ll

I CHaCCHi

I

IV COOH V COOH was based on ozonization to a keto acid, regarded as IV, which was characterized as the crystalline semicarbazone. The y-fencholenic acid was reported to isomerize very readily on standing to afencholenic acid. The structure of the latter compound does not seem to have been established; the nitrile corresponding to it is formed by the action of sulfuric acid on fenchone oxime, and the afencholenic acid is obtained by hydrolysis of the nitrile.3 The postulated2 structure V (or a double bond isomer) is a reasonable one for a-fencholenic acid; we have provided synthetic evidence for its correctness below. (1) Chas. Pfizer and Co. Fellow,1956-1957. (2) F. W .Semmler and K . Bartelt, Ber., 40, 432 (1907). (3) G. B. Cockburn, J. Ckem. Soc., 76, 501 (1899).

I

COOR VIa, R = H VIb, R = CzHb VIC, R = CHj

I

COOH VI1

The bromination of ienchone has been carried o ~ twith ~ . bromine ~ in sealed tubes. This method proved unsatisfactory, and we tried several other brominating agents without much success. However, the treatment of dl-fenchone with bromine and copper powder4 on the steam-bath for many hours yielded, in addition to much unchanged fenchone, a crystalline monobromofenchone, m.p. 44.5', and oily material with the composition of a monobromofenchone. Previous worker^^.^^^ have not reported a crystalline bromofenchone. Bromination of d-fenchone by the same procedure yielded an oily nionobromo compound, [ a ] ~ 14.3',

+

(4) L. Y. Bryusova, J . Gen. Chcm. U S S R , 10, 14G2 (1940) ( 5 ) H. Czerny. Ber., 33, 2291 (1900).

11. S.TARBELL AND F. C. LOVELESS

196-1

which gave the same products as the crystalline bromo compound when treated with base. The fact that the formation of the crystalline bromo compound did not involve rearrangement of the carbon skeleton during bromination was established by reduction t o fcnchone with zinc and acetic acid; the fenchonc was identified by its infrared spectrum and by conversion to the oximes. The relationships are described in detail in the Experimental section. Treatment of the crystalline bromofenchone with ethanolic potassium hydroxide yieldkd a mixture of 7-fencholenic acid VIa and the corresponding ethyl ester VIb. Both of these showed an infrared band at S73 cm.-l, due to the exocyclic -CH2 group. ,Uthough this value does not correspond exactly to the one (890 cm-l) reported for this group6 in open-chain compounds, it agrees well with other compounds containing the exocyclic =CH% group.7 This band a t 873 cm.-l disappeared on catalytic reduction. The neutral product from the rearrangement in ethanol was considered to be the ester VIb because of the ester band in its infrared spectrum; hydrolysis converted it to an acid with the same infrared spectrum as the y-fencholenic acid produced directly in the rearrangement. Esterification of y-fencholenic acid with diazomethane gave thc methyl ester VIc, which had the same infrared spectrum as the neutral product obtained from bromofenchone and metizmzolic alkali. The correctness of structure VI for the y-fencholenic acid obtained from bromofenchone in our experiments, and the incorrectness of structure 111, was shown by ozonization to yield formaldehyde. This was identified in one run as the crystallinc methone derivative,ia and in another run as the cliriitrophenylhydrazone,8the purity of which was checked by running a paper chromatogram ; the formaldehyde dinitrophenylhydrazone was not cofitaminated by any other dinitrophenylhydra zone. The other product of ozonization, which on the basis of structure Irshould l be the cyclopentanone derivative VI11 instead of the cyclobuta0

CI-IaCCI-13 VI11 COOR

so

structure VI11 rather than with that of the lower homolog IV. Treatment of y-fencholenic acid with sulfuric acid gave a mixture of y- and tj-lactones, according to the infrared spectrum, from which a pure crystalline &lactone IX was isolated; this was identical with the lactone obtained from a-fencholenic acid (V) by sulfuric acid treatment. Because of thc possibility of rearrangement of one or both of the y-fencholenic and a-fencholenic acid pair under acidic conditions, the observations just described do not necessarily prove that the two acids have the same carbon skeleton. This was establishcd unequivocally, however, by catalytic reduction of both y- and a-fencholenic acids to the same saturated acid VII, which was characterized in each case by conversion to the same crystalliiie aiiiicle X. Since, as has been mentioned, the correctness oi' the proposed structure 171for a-fcncholenic acid does not seem to have been conclusively dcmonstrated, we synthesized the saturated acid VI1 by the Reformatsky reaction of ethyl a-bromoisobutyrate on 3-methylcyclopentanone, going through the usual stages. The synthetic product was shown to be identical with the product obtained by reduction of both thc a- and y-acids, by comparison of the crystalline amides X ; the mixed m.p. of the samples prepared by the various routes showed no depression, and the infrared spectra were identical. The synthetic ester YIIa and the material obtained by reduction of the y-fencliolenic ester were also compared through the crystalline dinitrobenzoate XIa, prepared froin the alcohol X I obtained b y lithium aluniinuin hydride rcduction of the two samples of the ester. There was no depression in the mixed m.p. CHJ I

CII, I

CHI

I CH3

IX none derivative 111, had a carbonyl band a t 173G ciii. - l , in agreement with the cyclopentanone structure ; a cyclobutanone should absorbg a t about 1775 cm-'. Compound VI11 also was characterized by preparation of a crystalline semicarbazone, whose composition agreed with that of and l>.31.Simpson, Ozcavt. Rpas., 6 , 26 (19523. (7) 11. E. A p p l e q u i s t and J . D. Roberts, T H I S J O U R N A L , 78, 4012 (1QX);A. 'r. I%lomquist and I'.C. Meinwald, i b i J . , 79, 5:316 ( 1 9 3 7 ) . C:imphene slions a b a u d at 872 cni.-' (the present rese:irch). (7)a D. Vorlander, Z . a n a l . C h e m . , 77, 247 (1928). ( 8 ) W. R I . D . Bryant. THISJ O U R N A L , 64, 3780 (1932). (9) R. N. Jones, P. Humphries and R. Dobriner, i b i d . , 72, 956 (1950); D. 11. Whiffcn and €1. W. Thompson, J . C h e m Sor , 100.5 (194ti). (ti) N. Sheppard

Vol.

Structure VI1 can exist as a pair of racemates; the synthetic route obviously leads to the same raccmate as is obtained from the rcarrangemellt of the y- and a-fencholenic acids. This is not surprising, because catalytic hydrogenatio~~ is involved in all of the series, in the step in which the second asyinmetric carbon is formed. Although the configuration of the side chains in VI1 is not known, onc would expect the trtzns form to bc iiiore stable ther-

April 20, 1958

REARRANGEMENT OF BROMOFENCHONE BY BASE

modynamically. However, the cis form might be favored in a catalytic reduction, since the unsaturated compound would be adsorbed more readily on the catalyst surface with the alkyl side chain which is already attached to a saturated carbon "trans" to the catalyst surface. This would mean that the hydrogen added would be trans to this alkyl group, and hence that the two alkyl side chains would be cis. The facile isomerization2 of y-fencholenic acid to the a-isomer (VI + V) is in agreement with both old and new observations'o which show t h a t 1-alkylcyclopentenes are much more stable than the isomers with the exocyclic double bond. It should be noted t h a t the amide X , prepared from y-fencholenic acid derived from d-bromofenchone, melted only 4' higher than the dl-amide, obtained from the synthesis or from dl-bromofenchone, and showed no depression on mixed m.p. The position of the bromine atom in bromofenchone has not been established conclusively. The conversion of bromofenchone to y-fencholenic acid is best represented as a n example of the generalized &elimination reacti0n.l' On this basis, the reasonable position for the bromine atom is the 10-position (XII). If the bromine atom was in CH?

E1 r-- C H 1

BrClI

l i

I!

0-3

/\

XI I

YIa

COOH

the 6-position, as previously postulated,2one would expect that a-fencholenic acid, with the endocyclic double bond, would result directly from the action CHS

CH3

CHB

I CHsCCHi

XI11

I

COOH

of base. The formation of VIa from XI11 would require a shift of the double bond from the endocyclic to the exocyclic position, which is not favored. lo

Experimentall 2 Fenchone.-dl-Fenchone mas a technical grade. Attempts t o resolve dl-fenchone by reaction with I-menthyl Na m i n ~ c a r b a m a t e 'were ~ unsuccessful, due t o the very low reactivity of the carbonyl group in fenchone; no derivative was formed on refluxing in ethanol or in Cellosolve for 25 days. d-Fenchone was prepared by three distillations of 750 g. of fennel seed oil (from S. B. Poenick); 75 g. of d~ The fenchone was obtained, b.p. 170-180 , [ a ]61'. (10) 0. Wallach, A?in., 353, 308 (1907); R. B. Turner and G . H. Garner, THISJOERNAI., 79, 253 119.57); R . Fleck, J. Org. Chem., 22. 434 (1957). (11) A . Eschenmoser and A . Frey, H e h . Chiin. A c l n , 35, lG60 (1952); C. A. Grob and W. Baumann, i b i d . , 38, 594 (1066). (12) All m.p.'s are corrected; microanalyses are b y Miss Annette Smith and Micro-tech Laboratories. (13) R. B. Woodward, T. P. Kohman and G. C. Harris, THISJ O V R N A L , 63. 120 (1911).

1965

oxime,

[CY]D 116' (c 0.928, eJhanol), melted from 120 t o 165", and was apparently a mixture of d-fenchone p-oximel4 (m.p. 123", [m]D 129") and d-fenchone a-oxime16 (m.p. 165", [ a ] 47"), ~ with the former predominating. Bromination of Fenchone.-Bromination of fenchone in a sealed tube a t 100' appeared to yield mainly polymeric material. Bromination at 100" and atmospheric pressure yielded only starting material, as did also treatment with N-bromosuccinimide and with pyridine hydrobromide perbromide.10 T h e procedure of Bryusova4 was modified as follows: dl-Fenchone (Technical grade, 200 9.) and 4 g. of copper powder were heated t o 90' in a four-necked flask fitted with stirrer, condenser, thermometer and dropping funnel. Bromine (210 9.) was added slowly over a period of 10 hours t o the heated stirred solution, and the temperature was maintained a t 90" with stirring for a total of 3 days. The reaction mixture was then subjected to steam distillation from the reaction flask, and 110 g. of steam-volatile oil was obtained; 95 g. of non-volatile material remained, and n-as saved. Further purification was carried out on 294 g. of steamvolatile material and 241 g. of non-volatile product, isolated from three runs in which a total of 500 g. of fenchone and 525 g. of bromine was used. Distillation of the 294 g. of steam-volatile material gave 201 g. 0.P fenchone (b.p. 36" (3 mm.)), and the remainder was separated into three fractions, boiling in the range 73-85' (4 mm.). These fractions crystallized partially on standing, and the crystalline bromofenchone was obtained by dissolving the oil in petroleum ether and cooling t o -78". Repetition of this procedure yielded 31.5 g. of crystalline bromofenchone, m.p. 43-44', and 16 g. of oily bromofenchone, from which no more crystals could be obtained. Distillation of the 241 g. of nonsteam-volatile bromination product gave 46.4 g. of bromofenchone, from which 25 g. of crystalline and 17 g. of oily product was obtained. T h e total yield of bromofenchone from 500 g. of fenchone was thus 56.5 g. of crystalline material and 34 g. of oily pioduct. T h e solid product melted a t 44.5" after purification by sublimation, showed a carbonyl band a t 1740 cm.-l and was optically inactive. The oily product showed ~ W Din thc range of 1.5080, had a n infrared spectrum practically identical with that of the crystalline material. Anal. Calcd. for CIOH1SBrO: C, 51.96; H, 6.54. Found (crystalline product): C, 51.38; H, 6.54. Found (oil): C, 52.66; H, 6.74. T h e analysis was carried out on a sample of oily broniofenchone from which the crystalline product had not been removed. Bromination of d-Fenchone.-Bromination as above of dfenchone (34 g., [ a ]61') ~ yielded 6 g. of d-bromofemhone, [ a ] 14.3", ~ nZ6D 1.5068, w h p h did not crystallize a t -78'. Czernys reported [ a ] D 11.6 , nl% 1.5101. Anal. Calcd. for ClOHllBrO: C, 51.96; H , 6.54. Found: C, 51.58; H, 6.46. Reduction of Bromofenchone to Fenchone.-Crystalline bromofenchone (10.0 g.) dissolved in 75 ml. of acetic acid was refluxed with 7.5 g. of zinc dust for 7 hours, the mixture was diluted with water and was extracted with benzene. T h e benzene extract was washed with water, then with several portions of aqueous bicarbonate solution, was dried, and after the solvent was evaporated, it yielded 6.7 g. of oil. T h e oil was converted to the oxime by refluxing for 25 hours in 200 ml. of methanol with 6.7 g. of hydroxylamine hydrochloride and 23 g. of potassium hydroxide. After the refluxing, water was added to the solution until it became cloudy. Cooling the solution yielded 1.0 g. of fenchone oxime, which had the same infrared spectrum as an authentic sample of the oxime prepared i n the same way. The m.p. of the oxime (120') differed from that of an authentic sample of dl-fenchone oxime (m.p. 155'), but by heating the 120' oxime to 170" and allowing it to crystallize, the m.p. was raised to 155'. When a mixture of 120" oxime and authentic dl-fenchone oxime (ii1.p. 155") wcrc heated together t o 170", the resulting solid nieltcd a t 147--150°. Apparently here we were dealing with isomerizatioii o f the @-oximeto the a-oxime. _______ (1.1) M . Delepine, Conzpt. r e n d . , 178, 1721 (192i). (15) 0 . Wallach, A m . , 272, 104 (1802). ( I O ) C. Djerassi and C. K . Scholz, T I r I s JOTRSN., 7 0 , 417 \1!146),

Conversion of the oxime from fenchone, regenerated from analysis by repeated wnsliing with watcr, chloroform and bromofenchone, to the nitriles,* followed by hydrolysis to acetone; i t melted a t 198-200" with decomposition. dl-p-fencholenamidea yielded material of m.p. 81.5-82.5'; Anal. Calcd. for C,OHI&~O:;: C, 52.85; 1-1, 7.54. the amount was insufficient t o recrystallize. dl-P-FencholenFound: C, 52.71; H, 7.66. amide prepared from P-fencholenic acid melted at 87Semmler and Bartelt2 reported the semicarbazone of the 88", and gave a mixed m.p. with the amide above, from the supposed cyclobutanone acid I V to melt a t 182', and to have regenerated fenchone, of 81-86', dl-y-Fencholenic Acid (VIa) and its Ester by Action of the composition C, 51.06; H, 7.17. They did not identify acetaldehyde as a product of the ozonization. Their seiniBase on Crystalline dl-Bromofenchone.-dl-Bromofenchone (10 g., m.p. 43-44') was refluxed for 3 hours in 83 cc. of carbazone was recrystallized from methanol, which may have altered the compound. absolute ethanol containing 7.5 g. of potassium hydroxide. Ozonization of Methyl dl-y-Fencholenate (VIc).-This A precipitate of potassium bromide appeared after a short time. The reaction mixture was diluted with watcr, and compound (1.728 g.) was ozonized in 100 ml. of chloroform extracted with ether; the extract yielded 3.6 g. (477c) of for 120 minutes a t room temperature, the exhaust gases ethyl dl-7,-fencholenate (VIb): i t showed a n ester carbonyl being bubbled into tIvo wash bottles filled with water. The two water solutions were added to a hot solution of 600 band a t 1727, and the terminal methylene band a t 873 cin.-l. Acidification of the aqueous layer, followed by the usual mg. of methone in 75 ml. of water. T h e white precipitate extraction procedure, yielded 1.70 g. (2670) of dZ-yfencho- which formed was collected, and melted a t 189.5-192.5'; it shom-ed no depression on mixed m.p. with a n authentic lenic acid; this showed the expected infrared absorption for sample of the methone derivative of formaldehyde. a carboxylic acid. dl--a-( 3-M ethylcyclop entyl )-isobutyric Acid (VII). A. dl-r-Fencholenic Acid by Saponification of the Ester.T h e ethyl ester VIb (3.5 g.) obtained as above from dl- By Catalytic Reduction of dZ--+Fencholenic Acid.-?-Feuhromofenchone, was refluxed for 48 hours in a solution of cliolenic acid (1.0 g.) was reduced in ethanol with hydrogen and 100 mg. of 5Yc palladium-on-charcoal a t room tempera2 g. of potassium hydroxide in 80 ml. of dioxane and 20 ml. ture and atmospheric pressure. The product showed the of water. T h e solvent was removed in v u c z ~ o ,the residue same infrared spectrum as the product obtained by rcducwas added to excess water, 0.4 g. of unredcted ester was removed by ether extraction, and the aqueous laycr was tinn of dl--a-fencholenic acid. T h e amide melted a t 126.5128.5', and gave no depression with the sample prepared acidified with mineral acid. The resulting oil was isolated below from the dihydro-~-fencholenicacid. k y ether cxtraction, and yielded 1.80 g. of material whose B. By Catalytic Reduction of dl-a-Fencholenic Acid.infrared spectrum mas identical with that of the y-fcncholThe ru-acid3 (1.14 g.), was catalytically reduced as deenic acid obtained directly from the action of alkali on bromoscribed above, and the product was identical with the one fenchone. c!esrribed above. Methyl dl-y-Fencholenate (VIc). A. By Esterification The amide TWS prepared using tliionyl chloride ani1 of the Acid VIa.-The y-fencholenic acid (1.7 g . ) obtained ammonia, and melted, after crystallization from as above by action of base on dl-bromofenchone, was esteri- :iqiieous hcuane, a t 128-12Ra. fied with diazomethane prepared from 2 g. of nitrosomethyl,11tnZ. Calcd. for ClnHlqSO: C, 70.95; 11, 11.31; K, urea. T h e infrared spectrum was identical with that of the methyl ester obtained below, and was practically idcnt ical 8.28. Found: C , 70.83; H, 11.57; S,8.20. with that of the ethyl ester obtained above. T h s dl-Lactons I X . A. From dl-7-Fencholenic Acid.B. By Action of Methanolic Alkali on d!-Brornofendl-;~-I;encliolenic acid (1.83 g . ) w a s nddcd to 10 nil. of conchone.-dl-Broinofenchone (5.0 g., m.p. 4 - 4 4 ' ) is rccentrated sulfuric acid and allov-et1 to stand a t room temfluxed for 24 hours in 10 cc. of methnni~lccmt perature for 30 niin. T h e solution vas poured into iceof potassium hydroxide. The reaction TWS Iwter, the mixture was extracted with ether, and the ether the procedure described above, and :3.0 g . of tlie iiietliyl solution was washed with sodium bicarbonate solution. ester was obtained. The ether layer was dried, and the 0.90 g. of partly crystalOzonization of dZ--pFencholenic Acid (VIa) .--.I solution line residue was dissolved in petroleum ether, decolorized of 1.00 g. of yfencholenic acid in 50 ml. of chloroform was with charcoal and cooled to -78"; the white crystals (0.3 ozonized a t -78" for about 45 minutes. The mixture \vas 9.) ,melted a t 72-74' and showed carbonyl absorption indithen reduced catalytically with hydrogen and palladiuni-oncating some y-lactone (1731 cni.-l) as well as some Maccharcoal at -78' until no more hydrogen was absorbed. tone (1709 cm.?). -4fter three sublimations, the lactone The mixture was then filtered and was extracted with water nielted a t 71.2-79.8", and shoived only the &lactone peak. rapidly t o avoid loss of low-boiling carbonyl compounds. The optically active lactone I S is reportcdl8 to melt a t 77Addition of purified solution of 2,4-dinitrophen~-lhydrazine~~ 78". gave a precipitate of the dinitrophenylhydrazone of formalAmi. Calcd. for CIIHleO:: C , 71.39; 13, 0.59. Found: dehyde. Paper chromatography of this material C , 71.32:. H ., 9.70. that no other dinitrophenylhydrazone was present, in addiB. From dZ--a-Fcncholsnic Acid.--a-Fencholenic acid3 tion t o t h a t of formaldehyde. Recrystallization of the (0.5 g.) was swirled for 2 min. n i t h 5 ml. of concentrated sample gave a product melting at 162-165", which gave no sulfuric acid and was poured onto ice. The mixture was depression when mixed with an authentic sample. T h e chloroform layer from reduction of the ozonide 11 as extracted with ether and the ether layer was washed several dried, and yielded a thick oil on evaporation of the solvent. times with bicarbonate solution. Concentration of the dried ether solution yielded an oil, which gavc a white solid This showed infrared bands among others, at 1736 em.-' I t gave no depression (corresponding t o a cyclopentanorie derivative ( V I I I ) and on sublimation, m.p. 68.5-71.5'. ruling out the cyclobutanone structure (11')) and at 1698 tin mixed m.p. with the lactone obtained from the yacid above, and had the same infrared spectrum. cm.-l (carboxylic acid). 3-Methylcyclopentanone was prepared in 51 'A yield b y The keto acid VIII, obtained by ozonization of another distillation of 6-methyladipic acid with manganous earbonbatch of dl-y-fencholenic acid (0.5 g.) was allowed to stand ate.%? in 5 ml. of ethanol and a few drops of water for 5 days a t Ethyl -a-(3-Methyl-l-hydroxycyclopentyl)-isobutyrate.*I-room temperature, along with 0.5 g . of seniicarbazirie hy- Ethyl -a-bromoisobutyrate (40 g.) in 150 inl. of anhydrous c!rochloride and 0.75 g. of sodium acetate. The white ether was added dropwise to 4.5 g. of dry magnesium turncrystals of the semicarbazone of VI11 which formed (0..5 2 . ) ings. .\fter about 50 ml. of this solution had been added, were collected. They could be recrystallized in poor yield the reaction was proceeding very vigorously, and 16.0 g. of from methanol; the analytical sample was prepared for 3-methylcyclopentanone was mixed with the remaining 150 ml. of ether solution, which as added a t a rate sufficient (17) T h e solution mas freshly prepared by dissolving 1 s. o f 2.4to maintain gentle reflux. After t h e addition was complete, dinitrophenylhydrazine in 35 ml. of concentrated liydrochloric acid, the mixture was ri4used with stirring for 2 hours, at xvhich 17

_ _ _ _ I _

with enough added water t o produce a clear solutio= when cooled. T h e solution was then extracted with six 50-ml. portions (of reagent grade benzene. (18) T h e methanol-heptane system ( F . E. Huelin iinr! I3 IT. Kennett, Chemrslvy ?f I n d n s l v y , 715 (19SO)) was used. \Ye arc indebted to Dr. Alexander D. Cross of this 1-aboratory for the paper chromatogram.

(19) F.n'. Semmler, Bcr., 39, 2854 (19Oti). ( 2 0 ) 11, 1,uc:is and r). Pressman, "PrincipIcP and Practices in Organic Chemistry." John Wiley and Sons, Inc., New York, N . Y.,1950, p ?8l. (21) i3 Sl!ivc, \V. W. Crouch a n d €1. Id, I.ocltte, Tms J O I J K N A I . , 63, 2079 (1911).

point most of the magnesium had reacted. Sulfuric acid (100 ml., 1 M )was added cautiously with stirring, the ether layer was separated and dried, and the solution was distilled until the b.p. reached 100". A t this point dehydration appeared to be starting. T h e residue in the distilling flask (24 g.) was chromatographed on 300 g. of alumina. T h e column was eluted with the following solvents in succession: petroleum ether, petroleum ether-ether (6: l ) , pure ether, ether-methanol (6: 1, then 1 : l ) , and pure methanol. Ten fractions were collected, most of the product coming off with petroleum ether (10.0 g.), and ethermethanol (6.0 g. and 4.5 g.). T h e last two fractions were apparently identical, shoxing similar infrared spectra with strong hydroxyl bands; they represented a combined yield of 32%. The first fraction of 10.0 g. showed no hydroxyl band. T h e analytical saniple was prepared from fraction 10 (4.5 g.) by chromatographing twice more in the system above. Anal. Calcd. for C12H2~01:C, 67.25; H, 10.35. Found: C,66.56; H,10.39. Ethyl dZ-a-(3-Methylcyclopentyl)-isobutyrate (VIIa).The hydroxyester above (6.0 g.) was dehydrated by heating t o 125' for 15 hours with 10.0 g. of anhydrous magnesium sulfate; the mixture was thoroughly extracted with ether, which yielded, after evaporation, 5.05 g. of unsaturated ester showing no hydroxyl absorption in the infrared. This unsaturated ester (5.0 g . ) was hydrogenated in ethanol with palladium-on-charcoal catalyst, with the absorption of the theoretical amount of hydrogen. The analytical sample was prepared by distillation (b.p. 84' ( 5 m m . ) ) of a sample from a n earlier run which had not been chromatographed. Purification by chromatography is preferable, however. A n d . Calcd. for C12H2202: C, 72.68; H, 11.18. Found: C, 73.19;H, 10.78. dl-(3-Methylcyclopentyl)-isobutyric Acid (VII).-The ester VIIa (3.0 g.) was refluxed for 72 hours with 2.0g. of potassium hydroxide in 70 ml. of dioxane and 15 ml. of water. T h e mixture was worked up in the conventional way, and yielded 1.70 g. of unchanged ester and 600 mg. of the acid VII.

The amide of the synthetic acid was prepared with thionyl chloride and ammonia, and melted a t 124-125'; its infrared spectrum was identical with t h a t of the samples of amide prepared from samples VI1 obtained by catalytic reduction of both a- and r-dl-fencholenic acids; further, a mixed m.p. with amide derived from the reduced a-acid showed no depression. dl-2,2-Dimethyl-2-(3-methylcyclopentyl)-ethanol(XI).Ethyl a-(3-methylcyclopentyl)-isobutyrate (1.70 g., prepared by the Reformatsky reaction) dissolved in 2,j ml. of anhydrous ether, was added dropwise to 0.65 g. of lithium aluminum hydride in 25 ml. of ether. T h e mixture was refluxed with stirring for 4 hours. Ethyl acetate (2 ml.) was added carefully, followed by 3 . 5 ml. of saturated sodium sulfate solution. T h e mixture was stirred for 15 minutes to coagulate the salts, which were then removed by filtration. The ethereal filtrate was dried and the solvent was removed, leaving 1.0 g. of 2,2-dimethy1-2-(3-methylcyclopentyl)ethanol ( X I ) . This was characterized by preparation of the 3,5.-dinitrobenzoate XIa; the alcohol X I (1.0 g.) and freshly prepared 3,5-dinitrobenzoyl chloride (1.25 g . ) in 5 nil. of anhydrous pyridine was heated on the steam-bath for 1.5 hours. T h e mixture was then poured into 10 ml. of saturated bicarbonate solution, and the resulting cloudy suspension was extracted with ether. The ether solution was washed with water and concentrated. T h e resulting oil was dissolved in ethanol, made turbid with water, and cooled. T h e crystals which formed melted, after recrystallization from ethanolmater, at 58.5-59.5'. Anal. Calcd. for CliHazNzOs: C, 58.27; Found: C, 58.13; H, 6.64.

H , 6.33.

A sample of this same derivative was prepared by lithium aluminum hydride reduction of ethyl dihydro-y-fencholenate, followed by acylation with dinitrobenzoyl chloride. T h e two crystalline samples showed no depression on mixed m.p. ROCHESTER, SEW YORK

[CONTRIBUTION FROM THE DASIEL SIEFF RESEARCHIXSTITUTE,

THE U'EIZRIASN ISSTITUTE O F S C I E S C E ]

Syntheses in the Terpene Series. V.I A Synthesis of D~-1,1,6a,lOfl-Tetramethyltrans-decal-Zfl-ol-5-one, the Racemate of a Degradation Product of a-Amyrin BY FRANZ SONDHEIMER AND Dov ELAD RECEIVEDXOVEMBER 15, 1957 The previously described 1,1,10~-trimethyl-A8-octal-5/3-ol-2-one benzoate (IIa) has beeii converted bj- a seven-step sequence t o 1,1,10/3-trimethyl-trans-decal-2p-ol-d-one benzoate ( XrIIb) The latter substance has becn found to differ from the compound of King, et el., t o which structure S'IIb had been ascribed, but the corresponding keto-acetate 1 . 1 1 ~was identical with the substance prepared independently by Halsall, et al. Methylation of the keto-benzoate VIIb gave l , l , 6a,1O~-tetramethyl-trens-decal-2~-ol-5-one (Xa), which was shown to be the racemate of an optically active degradation product of a-amyrin and of ursolic acid. Condensation of the tetraniethyl keto-benzoate X b with sodium acetylidc yielded the acetylenic carbinol X I , which appears to be a useful intermediate for syntheses in the triterpene field.

I n Part I11 of this series2 the conversion of the and pentacyclic triterpene group of substances, it readily available 10-methyl-A1(9)-octalin-2,5-dione was necessary to keep intact the C-2 oxygen func(Ia) via l,1,10~-trimethyl-As-octal-jp-ol-2-one ben- tion of IIa instead of removing it as had been done zoate (IIa) to 1,1,1O-trimethyl-trans-decal-S-onep r e ~ i o u s l y . ~I n~ ~this paper we describe the con(VIId) was reported. The last-mentioned sub- version of the keto1 benzoate I I a to l,l,I.Op-tristance, which was prepared independently by methyl-trans-decal-2,B-ol-5-one (VIIa) and thence Cocker and Halsal13 b y a similar route, appears to to 1,1,6a,1O~-tetra1nethyl-trans-decal-2~-ol-5-one be a useful intermediate for the synthesis of some of (Xa).5 The latter was shown to be the racemate the diterpene alcohols and acids. However for of the optically active substance X a which had the synthesis of members belonging to the onocerin4 been obtained previously by the degradation of aamyrin'ja and of ursolic acid.6b (1) For P a r t IV, see F. Sondheimer and D. Elad, Proc. Chem. Soc., 320 (1957). The majority of the diterpenes, the tetracyclic ( 2 ) F. Sondheimer and D. Elad, THIS JOURNAL, 79, 5542 (1967). triterpenes and the pentacyclic triterpenes have all

(3) J. D. Cocker and T. G. Halsall, J . Chem. Soc., 3441 (1957). (4) D. H. R. Barton and K. H. Overton, ibid., 2639 (1955); K. Schaffner, R. Viterbo, D. Arigoni and 0. Jeger, Hela. Chim. Acta, 39, 174 (1956); J. D. Cocker and T. G. Halsall, J . Chem. SOL., 4262 (1956).

(5) For a preliminary communication, see footnote 1. (6) (a) R . Ruegg, J. Dreiding, 0. Jeger and L. Ruzicka, R s l v . Chim. Acta, 33, 889 (1950); (b) D. Arigoni, H. Bosshard, J. Dreiding and 0. Jeger, ibid., 37, 2173 (1954).