D. K. BANERJEE AND T. R. KASTURI
92ti
Vol. 70
hexylamine and N-Bromocyclohexy1amine.-A 4.4-g. (0.02 mole) sample of the unsaturated ketone was dissolved in 10 ml. of benzene and 1.98 g. (0.02 mole) of cyclohexylamine. After standing for 30 minutes, 25 ml. of a benzene solution containing about 3.56 g. (0.02 mole) of N-bromocyclohexyltrans-l,2-Dimethyl-3-(p-phenylbenzoyl)-ethylenimine (Vb). was added rapidly. After standing a t room tem-An 8.0 g. (0.036 mole) sample of p-phenylcrotonophenone perature for 14 hr., the cyclohesylamine hydrobromide, in 40 ml. of benzene was treated with an ether solution of 3.4 g. (0.0189 mole), was removed and the filtrate worked methylamine (0.144 mole) using ice-bath cooling. T o this up to give 6.35 g. (99% yield) of solid material, m.p. 114solution was added 9.26 g. (0.036 mole) of iodine dissolved in 122". One recrystallization from petroleum ether (b.p. 60120 ml. of benzene. The iodine color disappeared com- 70") gave 6.3 g. of colorless crystalline solid, m.p. 120-128'. pletely in 1 hr. The benzene layer was separated from the A 1.0-g. sample of this material was chromatographed to oily methylamine hydroiodide, washed with water, dried give as a first eluate 0.25 g. of a mixed product, m.p. 109and evaporated to leave a red colored oil. This crude product 12O0,and in later eluates 0.74 g. of the pure cis isomer, n1.p. was crystallized from petroleum ether (b.p. 40-50') to give 128-129". 7.0 g. of a nearly colorless product, m.p. 65-67'. D. Reaction of P-Cyclohexylamino-p-phenylbutyrophenThe pcyclohexylAnal. Calcd. for CI.IHITNO: C, 81.24; H, 6.82; N, one with N-Bromocyclohexylamine. amino-p-phenylbutyrophenone was prepared from 2.2 g. of 5.57. Found: C,81.01; H , 6.93; N, 5.43. p-phenylcrotonophenone and 1.O g. of cyclohexylamine in This product decomposed in the air a t room temperature 8 ml. of abs. ethanol upon standing in the refrigerator fo to a red oil in a few hours. cis- and trans-l-Cyclohexyl-2-methyl-3-(p-phenylbenzoyl)- three days. The yield was 2.9 g., m.p. 84.5-85.5'. ethylenimines, VIa and VIb. A. Reaction of a-BromoAnal. Calcd. for C i ~ H ~ ~ NCO, : 82.20; €1, 8.47; N, p-phenylcrotonophenone with Cyclohexylamine .-To a solu- 4.36. Found: C,82.43; H,8.61; N , 4 . 3 4 . tion of 6 .O g. (0.020 mole) of u-bromo-p-phenyl-crotonoA 1.6-g. (0.005 mole) sample of the p-aminoketone was phenone(I1) in 50 ml. of dry benzene was added 4.5 g. dissolved without heating in 5 ml. of benzene and a solution (0.044 mole) of cyclohexylamine. The reaction mixture of 0.89 g. (0.005 mole) of N-bromocyclohexylamine13 in 15 was stirred for 3 hr. and allowed t o stand 12 hr. in the ice- ml. of benzene was added rapidly. After standing a t room chest. The reaction mixture was worked up and the crude temperature for 12 hr. the working up of the reaction mixproduct separated by a chromatographic method as pre- ture produced 0.87 g. (97% yield) of cyclohexylamine hydroviously described for the reaction using the analogous a,@- bromide and 1.33 g. (85% yield) of the pure cis isomer, dibromo-p-phenylbutyrophenone.] The yield of crude, m.p. 127-128". mixed product was 6.1 g. (95a/0),m.p. 110-118°. Thefirst An attempt to add one molar equivalent of N-bromocycloeluates from the chromatographic separation of a 3.0-g. h e ~ y l a m i n e 'to ~ 2.22 g. of p-phenylcrotonophenone in bensample of the mixed product produced 0.98 g. (%yo of the zene solution produced only small amounts of cyclohexyltotal material recovered) of the trans isomer VIb, m.p. 141amine hydrobromide and 2 .O g. of unchanged unsaturated 142". The final eluates contained the low melting, cis ketone. isomer VIa, m.p. 127-128', wt. 1.8 g. (62a/, of the total Chromatographic Separation of cis- and trans-1-Cyclomaterial recovered). Both products were nearly colorless. hexyl-2 -phenyl - 3 - ( p - phenylbenzoyl) ethy1enimines.--A B. Reaction of p-Phenylcrotonophenone with Bromine 0.50-9. sample of a 50-50 mixture of the cis and trans isomers and Cyclohexylamine.-A 5-g. (0.0225 mole) sample of the which had been separated previously by fractional crystalliunsaturated ketone' was dissolved in 12 ml. of benzene and zation* was re-separated by the chromatographic method.' 9 g. (0.091 mole) of cyclohexylamine. The solution was The first eluates contained 0.24 g. (50% of the total material cooled and 3.6 g. (0.0225 mole) of bromine in 50 ml. of ben- recovered) of the low melting trans isomer, m.p. 118-119", zene was added over a period of 20 minutes with stirring. while the final eluates produced the same amount of the The nearly colorless reaction mixture, after standing a t room higher-melting cis form, m.p. 144-146'. Both of these temperature for 12 hr., was filtered to remove 8.1 g. (0.045 products were colorless. mole) of cyclohexylamine hydrobromide. The filtrate was washed with water, dried and concentrated under reduced (13) Using the procedureoutlined for X-bromomorpholine, see ref. ?a, pressure to give 6.25 g. (0.0195 mole) of a colorless crystal- benzene solutions of N-bromocyclohexylamine were freshly prepared line product, m.p. 112-124". A chromatographic separation from one equiv. of bromine and two equiv. of cyclohexylamine and used of 2 g. of this material produced 0.51 g. of a mixed product, immediately after removing the cyclohexylamine hydrobromide by m.p. 110-121°, in theofirst eluate and 1.47 g. of the pure cis filtration. isomer, m.p. 127-129 , in later eluates. C. Reaction of p-Phenylcrotonophenone with Cyclo- LINCOLN, NEBRASKA acid and 0.43 g. (0.004 mole) of phenylhydrazine. The pyrazole was isolated in the usual way,lSz m.p. 128-129", wt. 0.81 g. (67% yield). This product was identical with a n authentic sample of l-phenyl-3-(p-biphenylyl)-&methylpyrazole.'
-
[CONTRIBUTION FROM
THE
ORGANIC CHEMISTRY LABORATORY O F THE
INDIAS
INSTITUTE
OF
SCIENCE, BANGALORE]
Hydrolysis of Ethyl 4-(l-Carbethoxy-2-oxocyclopentyl)-2-pentenoate and Ethyl 4-( 1-Carbethoxy-2-oxocyclopentyl)-valerate BY D.K. BANERJEE AND T. R. KASTURI RECEIVED SEPTEMBER 5, 1956 Hydrolysis of ethyl 4-( l-carbethoxy-2-oxocyclopentyl)-2-pentenoate ( I a ) and ethyl 4-(1-carbethoxy-2-oxocyclopentyl)valerate ( I b ) with 10% sulfuric acid yielded the normal products ICand Id, respectively. Treatment of I a with hydrochloric acid yielded a mixture of 11, a rearrangement product, and IC.
In the course of a synthetic project currently in progress in our laboratory, the introduction of the bile acid side chain was contemplated by the condensation of a cyclopentanone-2-carboxylic ester derivative with ethyl 4-bromo-2-pentenoate followed by hydrolysis and reduction. Recently Herzl has shown that such condensation products, after reduction, on hydrolysis with hydrochloric (1) (a) W. Herz. THIS JOURNAL, 78, 1485 (1956); (1956).
(b) 78, 2529
acid yield rearranged products. We have now reinvestigated this step and it has been possible to obtain the desired normal hydrolysis product in good yield by using 10% sulfuric acid. At first the hydrolysis of ethyl 4-(l-carbethoxy2 - oxocyclopentyl) - 2 - pentenoate(1a) la under the condition of Herz2 was studied, as in this case (2) These experiments were completed before the appearance of the second paperlb of Herz, where he has expressed the intention of studying the hydrolysis of Ia.
Feb. 20, 1857
HYDROLYSIS OF ETHYL4-(1-CARBETHOXY-2-OXOCYCLOPENTYL)-2-PENTENOATE
927
a similar rearrangement should lead to the forma- /3-diketone IVla is formed through a transition tion of a cyclopentenone derivative easily detect- state VI and elimination of proton, which may be able by the ultraviolet absorption spectrum. How- visualized through an electrophilic attack of the ever, the treatment of I a with hydrochloric acid dioxycarbonium ion V, formed from the carboxylic yielded a mixture which could be resolved by group of the keto acid Id in the presence of hydrochromatography on an acid-washed alumina column gen ion, on the ketomethine carbon atom. Preinto two components. One of these has been as- sumably a lower hydrogen ion concentration leads signed the structure of 4-(5-methyl-2-oxocyclo- to the formation of mainly the normal product. pent-3-enyl)-butyric acid (11), a rearrangement product, for the following reasons: (1) its ultraviolet spectrum had absorption maximum charac-+teristic of a,/?-unsaturated ketone, (2) i t yielded a semicarbazone and a red 2,4-dinitrophenylhydrazone which also had absorption maxima typical of a,P-unsaturated ketonic derivatives, (3) on catalytic hydrogenation it yielded a product identical with 4-(5-methyl-2-oxocyclopentyl)-butyric acid (111) previously obtained by H e n l a as a rearrangeId IV He ment product by the hydrolysis of ethyl 4-(1Experimental4 carbethoxy-2-oxocyclopentyl)-valerate (Ib) . The Ethyl 4-( 1-Carbethoxy-2-oxocyclopentyl)-2-pentenoate~~ second product yielded a semicarbazone and a yelour hands alkylation of Z-carbethoxycyclopentanlow 2,4-dinitrophenylhydrazonewhich showed ab- (Ia).-In one with ethyl 4-bromo-2-pentenoate (nz2D 1.4850) gave a sorption maxima characteristic of those of a sat- higher yield (7770, reported1' 60%) of the condensation urated ketone, and on ozonolysis furnished 2- product Ia, b.p. 155-156' (1 mm.), n% 1.4780. Hydrolysis of 1a.-(a) A mixture of 10 g. of Ia and 40 (2-oxocyclopentyl)-propionicacid (Ie), This has ml. of concentrated hydrochloric acid was refluxed for 15 hr. been assigned the structure of 4-(2-oxocyclopen- and 5.5 g. of a product, b.p. 160-165' ( 1 mm.), n l 4 1.4994, ~ tyl)-2-pentenoic acid (IC), the normal product of was isolated through its sodium salt as described by Herz hydrolysis. When I a was hydrolyzed with 10% for the hydrolysis of Ib.'B The semicarbazone, m.p. 184-185', ultraviolet spectrum sulfuric acid, only ICcould be isolated in 93% yield. A$$"' 230 mfi (log E 4.01), 261 mp (log E 4.02), prepared by Hydrolysis of the hydrogenated keto ester I b the sodium acetate method, is obviously a mixture of the with 10% sulfuric acid also gave the corresponding semicarbazones of I1 and IC, as evident from ultraviolet normal product Id, as proved by its identity with data. 4-(2-oxocyclopentyl)-valeric acid obtained by the Anal. Calcd. for CIOHITN~O~: N, 17.57. Found: N, hydrogenation of IC, and was found to be different 17.4. The crude 2,4-dmitrophenylhydrazoneprepared by usual from the rearranged keto acid 111.
+
methods melted at 100-110' and was a mixture of yellow and red crystals. The yellow solid (0.1 9.) was separated from 0.25 g. of this mixture by trituration with dry benzene. After repeated crystallization from ethanol it was obtained as clusters of needles, m.p. 194-196'; ultraviolet spectrum U Xzgho'229 mp (log e4.11), 364 mfi (log E 4.31). RI Anal. Calcd. for C 1 ~ H 1 ~ N ~ O N,~ :15.47. Found: N, RI 15.19. Ia, -COOCZHS 4 H ( CHs)CH=CHCOOCzHa Ib, --COOCzHs -CH( C H ~ ) C H ~ C H ~ C O O C Z H ~ The aforementioned benzene filtrate was passed through -CH( CHs)CH=CH-COOH IC, -H a column of 10 g. of acid-washed alumina,s which on evapo-CH( CHa)CHzCH2COOH Id,-H ration yielded 0.11 g. of the red 2,4-dinitrophenylhydrazone Ie,-H -CH( CH8)COOH which crystallized in red silky needles from ethanol, m.p. If, -COOH -CH( CH~)CH~CHZ-COOH 256 mfi (log E 4.23), 131-132'; ultraviolet spectrum 387 mfi (log E 4.4). 0 0 0 0 Anal. Calcd. for C I ~ H ~ ~ NN, ~ O15.47. ~: Found: N, 15.38. The column was further eluted with ethyl acetate when a small quantity of the yellow 2,4-dinitrophenylhydrazone, m.p. 194-196", was obtained. A solution of 1 g. of the aforementioned acid mixture, obTo explain the rearrangement, Herzla assumed tained by hydrolysis of Ia, in 10 ml. of benzene was chromathe formation of a diketone IV via the normal keto tographed over a column of 30 g. of acid-washed alumina. acid Id. We considered that IV might have been Elution with benzene gave 0.5 g. of 4-(2-oxocyclopentyl)-penformed via the keto diacid If. The normal keto tenoic acid (IC), which showed no absorption maximum of conjugated ketones and gave only the aforeacid Id, however, on treatment with hydrochloric characteristic mentioned yellow 2,4-dinitrophenylhydrazone,m.p. 194acid yielded the rearranged product 111, thus prov- 196'. ing the correctness of Herz's suggestion regarding Anal. Calcd. for C10H1.103: C, 65.93; H , 7.69. Found: the intermediate product. C, 65.42; H, 7.89. For this rearrangement,3 we suggest that the Further elution with ether yielded, after initial separation of a small quantity of the acid mixture, 0.4 g. of 4-(5(3) An alternative mechanism for this type of rearrangement was methyl-2-oxocyclopent-3-enyl)-butyricacid (11)whose ultrapreviously suggested by F. Ramirez and A. P . Paul, THIS JOURNAL, I T , 235 mp, and gave the aforeviolet spectrum had 1035 (1965), on the basis of the mechanism proposed by M. J . S.
Xe;ho'
Dewar ("The Electronic Theory of Organic Chemistry," Oxford University Press, London, 1949, p . 126) for acid-catalyzed Claisen condensation proceeding through the enol. The present mechanism may also be extended to explain the acid-catalyzed Claisen condensation tbrough an oxycarbonium ion.
(4) All melting points and boiling points are uncorrected and ranges of temperature less than one degree have not been recorded. (5) We are indebted to Merck and Co. Inc., Rahway, N. J., for a gift of acid-washed alumina, QR8094.
928
REYNOLD C. FUSON, W. C. HARZMANN AND PAUL R. JONES
mentioned red 2,4-dinitrophenylhydrazone,m.p. 130-132'. Anal. Calcd. for C I O H J ~ OC,~ :65.03; H, 7.60. Found: C, 65.52; H , 7.86. The semicarbazone crystallized in shiny needles from ethanol, m.p. 208-210", ultraviolet spectrum X$;:""' 266 tnp (log B 4.17). Anal. Calcd. for C11HnN~03: X, 17.57. Found: X, 17.32. (b) A mixture of 10 g. of Ia and 150 ml. of 10% sulfuric acid was refluxed for 36 hr. On working u p in the usual 1.4985, way, 6 g. (93y0) of IC,b.p. 158-160' (1 mm.), TPD was isolated. The yellow 2,4-dinitrophenylhydrazonemelted at 194196' and remained undemessed on admixture with the Dreviously described yellow- 2,4-dinitrophenylhydrazone. The semicarbazone crystallized in plates from ethanol, 1n.p. 185-186", ultraviolet spectrum hzgho'227 m p (log e 4.3). Anal. Calcd. for C11H17NsOa: N, 17.57. Found: X, 17.31. 4-( 5-Methyl-2-oxocyclopentyl)-butyric Acid (111).-A solution of 80 mg. of 4-(5-methyl-2-oxocyclopent-3-enyl)butyric acid (11) in 10 ml. of ethanol was hydrogenated in the presence of 15 mg. of platinum oxide catalyst. The theoretical amount of hydrogen was absorbed in 3 hr. The product was worked up in the usual manner t o yield 70 mg. of 111, b.p. 110-115° (bath temperature) (1 mrn.). Anal. Calcd. for CIOH&: C, 65.22; H, 8.70. Found: C, 64.76; H , 8.70. The semicarbazone, m.p. 195-196', did not depress the melting point (195-196") of the semicarbazone of I11 prepared according t o Herz.la I n this connection i t may be mentioned that the crude semicarbazone of Herz's hydrolysis product melted a t 160-170". 4-( 2-Oxocyclopentyl)-valeric Acid (Id).--A solution of 2 g. of 4-(2-oxocyclopentyl)-2-pentenoicacid (IC) in 40 ml. of ethanol was hydrogenated in the presence of 0.2 g. of 10Y0 palladium-charcoal catalyst. The theoretical amount of hydrogen was absorbed in 4 hr. The product was worked up in the usual manner t o yield 1.7 g. of Id, b.p. 110-115" (bath temperature) (1 mm.), n Z 3 D 1.4740. Anal. Calcd. for C10H1603: C, 65.22; H , 8.70. Found: C, 64.85; H , 8.98. A
[CONTRIBUTION FROM
THE
Vol. i 9
The semicarbazoae crystallized in thin plates from etlim o l , m.p. 184-185 . .4nnl. Calcd. for Cl11i,9N~30:~: 5 , I;. I:{. 1 ~ ~ ) u i i dS: , 17.W. Hydrolysis of 1b.--Hydrolysis of 2 g. of ethyl 4-( l-carbethoxy-3-oxocyclopentyl)-valerate,b .p. 146-148' (1 m m . ), n Z 3 D 1.4640, prepared by the method of HerzlS from Ia in almost quantitative yield ( reportedla SO%), was carried out with lOyo sulfuric acid as before t o yield 1.1 g. of 4-(2oxocyclopenty1)-valeric acid (Id), b.p. 110-115O (bath teinperature) (1 mm.), 132333 1.4738. The semicarbazone, m.p. 1 8 - 4 - 1 8 5 O , did not depress t h e melting point of the semicarbazone of Id prepared by hydrogenation of IC, but depressed that of the semicarbazone of I11 by 24'. Ozonolysis of Ic.-.A current of ozonized oxygen was bubbled through a solution of 2, g. of ICin 30 nil. of purified ethyl acetate and cooled to 0 . Ozonization was over in about 2 hr. Ethyl acetate was removed in V Q C U O at room temperature, when 2.5 g. of a sirupy liquid was obtained. The ozonide was decomposed with 20 ml. of distilled mater, by heating for 4 hr. on a steam-bath. The cooled solution was thrice extracted with ether. Oxalic acid could be detected in the aqueous solution. The ether extract was separated into 0.5 g. of an acidic product, b.p. 85-90" (bath temp.) (1 mtn.), and 0.8 g. of a neutral fraction. The semicarbazone of the acidic fraction crystallized in small fragile needles from hot water and melted a t 185-1863", which remained undepressed on admixture with an autheutic sample of the semicarbazone of 2-(2-oxocyclopentyl)-propionic acid (Ie).6 Rearrangement of Id to 111.--A mixture of 0.5 g . of I d and 5 ml. of concentrated hvdrochloric acid was refluxed for 7 hr. Excess of hydrochloric acid was removed in vacuo to yield 0.4 g. of a product, b.p. 110-115' (bath temp.) ( 1 mm.), n% 1.4758. The semicarbazone, m.p. 195-196", did not depress t h e melting point of the semicarbazone of 111, but depresstxl that of the semicarbazone of Id by 12". ( 6 ) F, Sorm, 2. Sormova and L . Sedivy Collection Czechoslou. Chein. Commzrns., 12, 554 (1947); C. A , . 42, 7742" (1948).
BANGALORE 3, INDIA
KOYES LABORATORY, UNIVERSITY O F
ILLINOIS]
Selective Side Chain Metalation of Duryl o-Tolyl Ketone1 B Y REYNOLD c. FUSON, W I L L I A M c. HAMM.4NN2 A N D PACLR.J O N E S 3 RECEIVED SEPTEMBER 24, 1956 Trcatrnent of duryl o-tolyl ketone with n-butyllithiuni, followed by carbonation, gave o-duroylphenylacetic acid. \Then oxygen was passed through the reaction mixture, the product was 2,2'-diduroylbibenzyl. The structures o f theqe compounds were established by independent syntheses.
The facility of the displacement of substituents such as methoxyl from an o-position in highly hindered diary1 ketones4 by the action of Grignard reagents is ascribed to electron withdrawal from the ring by the carbonyl group. The electron deficit a t the o-position must be greatly enhanced by the polarization of the ketone function through its coordination with the magnesium atom of the reagent. The same influence would be expected to confer increased mobility on the hydrogen atoms of a methyl group in an o-position. T o test this idea we have studied the metalation of duryl o-tolyl ketone with n-butyllithium. (1) T h i s investigation was supported in p a r t by a grant from the Office of Ordnance Research U S Army (Contract I i o DA11-022-ORD-874). (2) Rohm a n d H a a s Fellow, 195G-1951 (3) Allied Chemical and Dye Corporation Fellow, 1954-1955 ( 4 ) R C h s o n a n d S B Speck, THIS JOURNAL, 64, 244fi (1942)
This ketone offers special interest since it possesses three methyl radicals in positions ortho to the carbonyl group. From the work of Kadesch and Weller5 i t seems safe to assume that resonance interaction of the carbonyl group with the durene ring cannot be important and hence that the methyl groups of this ring would show an activity not greatly different from that of those in durene itself. Moreover, in the infrared spectrum of acetodurene,6 the band assigned to the carbonyl function is a t a considerably higher frequency than a similar band in the spectrum of acetophenone. Similarly, the band attributable to the ketone group in duryl o-tolyl ketone is much higher (1672 cm.-l) than that of benzophenone (1655 cm. -l) ,' ( 5 ) R. G. Kadesch a n d S. W. Welter, ibid., 63, 1310 (1941). (0) H . S. Killam, private communication. (7) H . W. Thompson and P. Torkington, J . Chem. Sot., 640 (1945)
