A Synthesis of Iridomyrmecin

sulfate, and concentrated using a rotary evaporator. Distilla- tion of the residue gave 2.8 g. of starting material, CUD +89.8", and 3.9 g. of acetate...
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NOVEMBER, 1964

SYNTHESIS OF IRIDOMYRMECIN

and filtered giving 5.5 g. (83%) of selenium. The filtrate was distilled a t reduced pressure to remove most of the solvent, and the residue was steam distilled. The distillate was extracted twice with ether. The combined ether solution was washed with water, dried over anhydrous sodium sulfate, and concentrated using a rotary evaporator. The residue was distilled giving 9.7 g. of crude product, b.p. 10C-140", a t 13 mm., and 1.0 g. of residue. The crude product was analyzed by gas chromatography and was found to contain 7.2 g. (75y0) of (+)-carvotanacetone (CUD +28.6'), 1.0 g. (10yc) of (+)-phellandral, (CUD +117.4"), and 1.3 g. (14%) of an unsaturated hydrocarbon. Reaction of Selenium Dioxide with Excess (+)-Carvomenthene in Acetic Acid.-To a solution of 8.0 g. (58 mmoles) of (+)-carvomenthene, C ~ D+89.4", in 30 ml. of glacial acetic acid and 10 ml. of acetic anhydride was added 1.97 g. (17.7 mmoles) of selenium dioxide. The mixture was heated with stirring on a steam bath for 8 hr. The precipitated selenium (0.9 g., 717,) was removed by filtration, and the filtrate was steam distilled. The distillate was extracted twice with ether. The ether solution was washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated using a rotary evaporator. Distillation of the residue gave 2.8 g. of starting material, CUD +89.8", and 3.9 g. of acetatea, b.p. 108-118" a t 10 mm. Analysis of the latter by gas chromatography indicated the presence of 53y0 (30% yield) of carvotanacetol acetates with an isomer ratio of 61% trans to 39% cis.

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Reaction of Cyclohexene-1-W with Selenium Dioxide in Acetic Acid.-To a solution of 4.05 g. (49 mmoles) of cyclohexene-l-C13 in 50 ml. of glacial acetic acid and 5 ml. of acetic anhydride was added 2.70 g. (24.5 mmoles) of selenium dioxide, and the mixture was heated on a steam bath with stirring overnight. The solution was filtered to remove selenium (0.24 g., 12%) and the filtrate was steam distilled. Essentially, no oxidized material was found in the distillate. The residue from the steam distillation was taken up in ether. The ether solution was dried over anhydrous sodium sulfate and concentrated using a rotary evaporator giving 2.2 g. of residue. Pyrolysis carried out in a distilling flask, gave 1.34 g. of essentially pure 3-acetoxycyclohexene. This was degraded in the manner described above. Chromic Acid Oxidation of Cyclohexene-l-C1~.-To a solution of 4.1 g. of cyclohexene in 10 ml. of acetic acid was added with stirring a t room temperature a solution of 7.5 g. of chromium trioxide in 4.5 ml. of water and 15 ml. of acetic acid over a period of 7 hr. After an additional hour, the solution was distilled giving 1.9 nil. of recovered cyclohexene. A solution of 12 g. of sodium hydroxide in 12 ml. of water was added to the remaining acetic acid solution with external cooling. The gelatinous mixture waa extracted with ether. The ether solution was dried over anhydrous sodium sulfate and distilled giving cyclohexenone, b.p. 69-71 O a t 20 mm. After hydrogenation, the cyclohexanone was degraded by the method of L0ftfie1d.l~

A Synthesis of Iridomyrmecin KEIITISISIDO,KIITIRGUTIMOTO, A N D T Y ~ISIDA z ~ Department of Industrial Chemistry, KyBto University, Kyoto, Japan Received April 16, 1964 Hydroboration of ethyl 2-(3-methyl-2-methylenecyclopentyl)propionate (V) followed by oxidation gave a mixture of dl-iridomyrmecin ( I X ) and dl-isoiridomyrmecin in satisfactory yield. The ester V was obtained from ethyl 2-(3-methyl-2-oxocyclopentyl)propionate( I V ) by the Wittig reaction with methylenetriphenylphosphorane. The Darzens-Claisen glycidic ester condensation of I V did not give 2-( 2-formyl-3-methylcyclopenty1)propionic acid. This formyl derivative was obtained by condensation of I V with methoxymethylenetriphenylphosphorane followed by hydrolysis. However, reduction of the carbonyl group gave the trans-lactone, an isomer of iridomyrmecin.

In continuation of the interest in preparative studies on natural cyclopentane derivatives, a synthesis of iridomyrmecin was effected. This bactericidal and insecticidal lactone of an Argentine ant, Iridomyrmex h ~ m i l i swas , ~ ~found ~ also to be a cat-attracting ingredient of a Japanese plant Actinidia polygama Miq.* The reported syntheses of iridomyrmecin and isoiridomyrmecin6 consisted in either an intramolecular cyclization of an acyclic Clocompound6 or an addition of a side chain to cyclopentene derivative^.^ The present investigation started from a cyclopentanone derivative, ethyl 2-(3-methyl-2-oxocyclopentyl)propionate (IV).*

An improved preparationgof 2-carbethoxy-5-methylcyclopentanone (I)lo from 2-carbethoxy-2-methylcyclopentanonelo-'* allowed the subsequent reactions without isolating the intermediates. Addition of ethyl 2bromopropionate to the reaction product followed by hydrolysis, decarboxylation, and esterification gave IV in 55% yield.

I1 ( 1 ) K. Sisido, S. Torii, and M. Kawanisi, J . Ore. Chem., 29, 904 ( 1 9 6 4 ) ; 29, 2290 (1964). ( 2 ) M. Pavan, Proc. Intern. Congr. Entomol., 8th, Stockholm, 1948, 863 ( 1 9 5 0 ) ; Chem. A b s f r . , 46, 9809b ( 1 9 5 1 ) ; Ric. m i . , 19, 1011 ( 1 9 4 9 ) ; Chem. Abstr., 46, 7309a ( 1 9 5 1 ) ; Chim. ind. (Milan), 37, 714 ( 1 9 5 5 ) ; Chem. Abstr., 60, 13311c (1956). ( 3 ) R. Fusco, R. Trave, and A. Vercellone, Chim. ind. (Milan), 37, 251 ( 1 9 5 5 ) ; Chem. Absfr..6 0 , 8 4 5 1 / ( 1 9 5 6 ) . (4) (a) T. Sakan, A . Fujino, F. Murai, A: Suzui, and Y. Butsugan, Bull. Chem. Soc. Japan, 99, 1154 ( 1 9 5 9 ) ; Chem. Abstr., 64, 184926 ( 1 9 6 0 ) ; (b) T. Sakan, A . Fujino, and F. Murai. Nippon Kagaku Zasshi, 81, 1320, 1324 ( 1 9 6 0 ) ; Chem. Absfr.,6 6 , 11644b, 11644c ( 1 9 6 2 ) . ( 5 ) (a) G . W. K. Cavill, D. L. Ford, and H. D. Locksley, Chem. I n d . (London). 465 ( 1 9 5 6 ) ; Australian J . Chem., 9, 288 ( 1 9 5 6 ) ; (b) G . W. K. Cavill and H. D. Locksley, ibid., 10, 352 ( 1 9 5 7 ) . ( 6 ) K . J. Clark, G . I. Fray. R. H. Jaever, and R . Robinson, Tetrahedron, 6, 217 (1959). ( 7 ) (a) F. Korte. J. Falbe, and A. Zschocke, ibid.. 6 , 201 ( 1 9 5 9 ) ; (b) F. Korte, K. H. Biichel, and 4 . Zschocke, Chem. Ber., 94, 1952 ( 1 9 6 1 ) . (8) R. P. Linstead and R . L. Jones, J . Chem. Soc., 616 ( 1 9 3 6 ) .

bH3

The acetoacetic ester synthesis applied to I is believed to afford trans-2,5-disubstituted cyclopentanone 111. ( 9 ) K. Sisido, K. Utimoto, and T. Isida. J . O r g . Chem., 29, 2781 ( 1 9 6 4 ) . ( 1 0 ) I,. Bouveault and R. Locquin. Bull. soc. chim. France, [.&I 3 , 441 (1908). ( 1 1 ) F. H. Case and E. E. Reid, J . A m . Chem. Soc., 6 0 , 3026 ( 1 9 2 8 ) . ( 1 2 ) L. Kicole and L. Berlinguet, Can. J . Chem., 40, 353 ( 1 9 6 2 ) .

SISIDO, UTIMOTO, A N D ISIDA

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The keto-enol tautomerism (I1 e 111)13should favor the trans configuration of I11 to minimize the steric interaction of the two substituents in the cyclopentanone. This configuration seemed to be retained during the subsequent mild reactions. These assumptions were proved by the success of the present synthesis. The methyl group in the propionic acid residue, however, could not be sterically controlled. In order to introduce a hydroxymethyl group a t the carbonyl position of the cyclopentanone IV, hydroborationI4 of methylene derivative V was attempted. The Wittig reaction of methylenetriphenylphosphoranelb with IV gave ethyl 2-(3-methyl-2-methylenecyclopenty1)propionate (V) in 47% yield.

CH3

VI1 (dl)

-+CH-COOH

I

In the hydroboration of this compound (V) it was hoped that the attack of the borohydride (VI) should occur from the back side of the side chain bearing the carbethoxyethyl group owing to the interaction of the two bulky groups."+'* The cis addition in the counter-Markovnikov sense14 of the borohydride (VI) shoulderesult in the attachment of hydrogen to the cyclopentane carbon on the side opposite the side chain bearing the carbethoxyethyl group giving VII. The same stereochemical arrangement of the side chain is realized in VIII. I n order to avoid the reduction of ester group and to effect the stereospecific addition of hydroborating agent, a monofunctional and bulky borohydride, diisopinocanipheylborane (VI),l 4 was employed. Use of ordinary diborane afforded less satisfactory results. Excess diborane gave the corresponding diol, reducing also the carboxylate group. When a solution of diisopinocampheylborane (VI) was added to V and the resulting organoboron compound (VII) was oxidized with hydrogen peroxide, the lactone (IX) of 2-(2-hydroxymethyl-3-methylcyclopenty1)propionic acid (VIII) was obtained in 44% yield (13) ( a ) W. von E. Doering and V. Z. Pasternak. J . Am. Chem. Soc.. 74, 143 (1950); (b) J. Hine, "Physical Organic Chemistry," 2nd Ed., McGraw-Hill Book Co., Inc., New York, N. Y., 1962, pp. 303-306. (14) H. C. Brown, "Hydroboration," W. A . Benjamin, h e . , New York. N . Y., 1962; G . Zaeifel and H . C. Brown, Org. Reactions. 18, 1 (1963). (15) G. Wittig and U. Schollkopf, Chem. Ber., 87, 1318 (1954). (16) H.C. Brown and G. Zw.eife1, J . A m . Chem. Soc.. 83, 2544 (1961). (17) H.C. Brown, G. Zweifel, and N. R. Ayyanger, i b i d . , 84,4341 (1962). (18) A . Hassner and C. Pillar, J . O T ~Chem., . 17,2914 (1962).

VOL. 29

together with l-methyl-2-hydroxymethyl-3-( l-hydroxy2-propy1)cyclopentane in 26% yield. The latter was considered to be produced by the reaction of the propionate (V) with diborane or monoisopinocampheylborane which might exist in diisopinocampheylborane solution. The infrared spectrum of the lactone (IX) had a carbonyl band at 1765 em.-', which is the same as that of iridomyrmecin and isoiridomyrmecin, showing the cis configuration of the lactone ring. The trans isomer, as described in a following paragraph, had a carbonyl band at 1730 em.-'. In order to confirm the structure of the product further, this lactone (IX) was oxidized with potassium permanganate to obtain nepetalinic acid, 2-(2-carboxy-3methylcyclopenty1)propionic acid (X). By fractional recrystallization, acid A, m.p. 124-125', and acid B, n1.p. 74-77', were separated. The infrared spectrum of acid A was identical with that of dl-nepetalinic acid of m.p. 124.5-126°,6119aderived from dl-isoiridomyrmecin or dl-nepetalactone, The acid B was considered to be the racemic form of l-nepetalinic acid, m.p. 117°,4,19b derived from natural Z-iridomyrniecin, since both infrared spectralga were identical. Thus the product proved to be a mixture of dl-iridomyrmecin and dl-isoiridomyrmecin. This synthesized mixture showed the characteristic activity in a bioassay on cats. An alternative route of introducing the hydroxymethyl group to the cyclopentanone (IV) involves the Darzens-Claisen glycidic ester condensation. Condensation of IV with ethyl chloroacetate gave the glycidic ester (XI) in 22% yield.

Hydrolysis of X I gave the glycidic acid as a viscous oil, but the attempted decarboxylation did not give the expected aldehyde acid, 2-(2-formyl-3-methylcyclopenty1)propionic acid. This heat treatment afforded crystals, CllH1404, which showed no infrared bands assignable to aldehyde and carboxyl groups, but to anhydride of glycidic acid (XII). Apparently the vicinally situated methyl and carboxyethyl groups in X I hindered the formation of an intermediary system necessary for the decarboxylation. According to the hitherto proposed mechanisms of the decarboxylation,*O a cyclic system21or at least an enolic system must be formed. An acid anhydride with a seven-membered ring with three- and six-membered rings attached is known in the (19) (a) By courtesy of Professor T. Sakan of Osaka City University. Cf. T. Sakan. A. Fujino, F. Murai, A. Sueui, and Y . Butsugan. BULL. Chem. Soc. Japan. 3 3 , 1737 (1960); Chem. 46st7., 66, 10493i (1961). (b) R. B. Bates, E . J. Eisenbraun, and S. M. &Elvain, J . A m . Chem. Soc.. 80, 3420 (1958). (20) V. J. Shiner, Jr. and B. Martin, i b i d , , 84,4842 (1962). (21) R.T.Arnold, Abstracts of Papers, 10th National Organic Symposium of the American Chemical Society. Boston, Mass., 1947, cited in "Steric Effects in Organic Chemistry," M . S. Newman, Ed., John Wiley and Sons, Inc., New York. N. Y.,1956,p. 361.

SYNTHESIS OF IRIDOMYRMECIN

NOVEMBER, 1964

case of thujopsene.22a This has a cis ring fusion, whereas XI1 must have a trans fusion if addition follows the same course as in the hydroboration. Since, however, the difference in the stability of the trans and cis isomers is not so serious in the case of bicyclic compounds consisting of a seven-membered ringZ2bcontrary to the case of bicyclic compounds consisting of a six-membered ring, the ready formation of the novel anhydride (XII) can be understood. As the second alternative the reaction of IV with met hoxy met hy lenet r ipheny lphosphor ane2 was car ried out. This gave ethyl 2-(2-methoxymethylene-3methylcyclopenty1)propionate in 80% yield. Selective hydrolysis of the methoxymethylene group afforded ethyl 2-(2-formyl-3-methylcyclopentyl)propionate which on reduction with sodium borohydride followed by hydrolysis and lactonization gave the lactone of 2-(2-hydroxymethyl-3-methylcyclopentyl)propionic acid in 40YGyield. The structure was proved by the infrared spectrum and elementary analysis. The infrared spectrum of the lactone showed, however, a carbonyl band at 1730 cm.-l, while the corresponding band of iridomyrniecin5bj6 and isoiridomyrnieci1PbP6is 1757-1761 cm.-l. This fact may be explained by assuming that the synthesized lactone has a trans fusion of cyclopentane and lactone rings instead of the cis fusion of natural iridoinyrinecin and isoiridomymecin. Presumably upon hydrolysis of the enol ether the aldehyde group takes up the most stable position, i.e., cis to the methyl group. This isomer of iridoniyrniecin showed no catnip activity on cats. HUckelz5and SondheimerZ6showed that %hydroxycyclopentylacetic acid was obtained when the hydroxy and carboxymethyl group were situated trans, while the hydroxy acid was not obtained when the two groups were situated cis. In the latter case, the lactone was obtained. 2-(2-Hydroxy-3-niethylcyclopentyl)propionic acid was considered to show the same property. Reduction of I11 with sodium borohydride in an aqueous alkaline solution gave the lactone of 2-(2-hydroxy-3methylcyclopenty1)propionic acid, i.e., normethyleneiridomyrmecin, and 2-(2-hydroxy-3-methylcyclopentyl)propionic acid in 63 and 19% yield, respectively. By the above reason, the former is considered to have the cis configuration and the latter the trans configuration with respect to the hydroxy and carboxyethyl groups. When the hydroxy acid was heated with a catalytic amount of sulfuric acid a t diminished pressure, the acid was converted to the lactone in 96% yield. The configuration of this lactone and the above mentioned lactone were considered to be the same, because the infrared spectra of both lactones showed the same band a t 1762 cm.-l. This band corresponded to that of iridomyrmecin. The configuration of the inethyl group with respect to the hydroxy group was not studied. v2*

Experimental Ethyl 2-(l-Carbethoxy-3-methyl-2-oxocyclopentyl)propionate. -To a solution prepared from 170 ml. of absolute ethanol and 10 g . of sodium was added 64 g. of 2-carbethoxy-2-methylcyclo(22) (a) T. Norin, Acta Chem. Scand.. 15, 1676 (1961); (b) W. Herz and L. A. Glick, J . Org. Chem., 58, 2970 (1963); 59, 613 (1964); N . L. Allinger and V. B. Zalkow, J . A m . Chem. Soc., 83, 1144 (1961). (23) S.G.Levine, i b t d . , 80,6150 (1956). (24) G.Wittig and M. Schlosser, Chem. Ber., 94, 1373 (1961).

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pentanone.10-12 The mixture was heated a t reflux for 7 hr., when 80 ml. of ethanol were then removed from the reaction mixture and 500 ml. of toluene was added. An azeotropic mixture of tolueneethanol was distilled until the boiling point of the distillate became 110", when 78 g. of ethyl 2-bromopropionate was added to the reaction mixture. After refluxing for 8 hr., the product was poured into 200 ml. of water. The toluene layer was separated and washed with water, 7Y0 sodium carbonate solution, and water. After removing toluene, distillation of the residue afforded 80 g. (797,) of ethyl 2-( l-carbethoxy-3-methyl-2-0~0cyclopentyl)propionate, b.p. 137-140" ( 5 mm.), n Z o 1.4615. ~ Analyses gave correct values. Ethyl 2-(3-Methyl-2-oxocyclopentyl)propionate (IV).-According to the procedure of Linstead and Jones,* from 76 g. of ethyl )propionate there was 2-( l-carbethoxy-3-methyl-2-oxocyclopentyl ~ obtained 39 g. (707,) of IV, b.p. 130-132" (14 mm.), n z O1.4470 ~ (lit.8 n Z 01.4468). Ethyl 2-(3-Methyl-2-methylenecyclopentyl~propionate(V).To a suspension of 0.91 g. of sodium hydride (1.7 g. of a 537, suspension in mineral oil), 50 ml. of 1,2-dimethoxyethane, and 1 drop of ethanol was added 12.1 g. of methyltriphenylphosphonium iodidez7; this was stirred for 1 hr. a t room temperature under an atmosphere of nitrogen. After an additional 2 hr. stirring a t 30-40", this solution was added to a solution of 5.9 g. of IV and 30 ml. of 1,2-dimethoxyethane in the course of 30 min. a t 18-23' under nitrogen. After stirring for 40 min. a t room temperature, the reaction mixture was refluxed for 3 hr. About 60 ml. of solvent was distilled and after addition of 80 ml. of water, the product was extracted with ether. Ether extract was washed with water, dried over anhydrous sodium sulfate, and evaporated. There was obtained 2.7 g. (4iYc) of V: b.p. 75-77' ( 5 mm.); n Z 01.4634; ~ infrared typical bands (liquid film), 3080, 1735,1653, and 883 em. -l. Anal. Calcd. for CI2H~0O2:C, 73.43; H, 10.27. Found: C, 73.52; H, 10.42. When the condensation of phosphorane and the ester (IF') was operated inversely, that is, the ester (IT)solution was added t o the phosphorane solution, the yield of the olefin ( V ) was decreased to 37%. dl-Iridomyrmecin and dl-1soiridomyrmecin.-To a solution of 16.0 g . of a-pinene (optical purity, 21%) and 1.8 g. of sodium borohydride in 80 ml. of diethyleneglycol dimethyl ether, 13.5 g. of boron trifluoride etherate was added a t G5"under an atmosphere of nitrogen in the course of 2 hr. After an additional 2 hr. of stirring, the solution mas added dropwise to a solution of 10.8 g. of V in 30 ml. of diethyleneglycol dimethyl ether at 0" in the course of 2 hr.; after 3 hr., the solvent was removed at reduced pressure. To the residue ether was added, the misture was washed with water, and ether was removed. ..1 mixture of the residue, 16 g. of sodium hydroxide, 40 ml. of water, 30 ml. of ethanol, and 45 ml. of 30% hydrogen peroxide solution was heated a t reflux temperature for 3 hr. The reaction misture was acidified with 55 ml. of concentrated hydrochloric acid and 20 ml. of water and refluxed for 1 hr. The ether extract of the mixture was added to a solution of 18 g. of sodium hydroxide, 20 ml. of ethanol, and 50 ml. of water. After refluxing for 3 hr. the reaction mixture was extracted with ether. This ether solution gave 2.5 g. of l-methyl-2hydroxymethyl-3-( l-hydrosy-2-propyl)cyclopentane, b .p. 130150" ( 5 mm.), nZ0D1.4908. The infrared spectrum was identical with that of analytically pure compound ( v i d e i q f r a ) . The aqueous layer was acidified to pH 3 with hydrochloric acid, refluxed for 30 min., and extracted with ether. Thisethereal solution was washed with water, 2:4 sodium carbonate solution, and then water, and dried over anhydrous sodium sulfate. When the ether was removed, the residue afforded on distillation 4.0 g. (44%) of cis-lactone of 2 4 2-hydrosymethyl-3-methylcyclopentyl Ipropionic acid (IX), i . ~ .a ,mixture of d2-iridomyrmecin and dl-isoiridomyrmecin: b.p. 104-120" ( 6 mm.); T L ~ O D 1.4660; no optical activity; infrared typival bands (liquid gave correct analyses for C10H1602; film), 1765 and 1240 em.-'. Hydroboration of V with Diborane.-To a solution of 2.1 g. of T and 0.22 g. of sodium borohydride in 36 ml. of diethyleneglycol dimethyl ether, a solution of 1.2 ml. of boron trifluoride etherate in 5 ml. of diethyleneglycol dimethyl ether was added at 10-20" in the course of 40 min. under nitrogen. The reaction ( 2 5 ) W. Hiickel and W . Gelmroth, Ann. C h e m . , 614, 233 (193.4). (26) F. Sondheimer, Y. Rlazur, and N. Danieli, J . A m . C h e m . Soc., sa, 5689 (1960). (27) (a) A. Michaelis and L. Gleichmann, Ber., 16, 801 (1882); (b) A , Michaelis and H.yon Soden. Ann. Chem., 559, 295 (1885).

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SISIDO, UTIMOTO,

mixture was stirred a t room temperature for 3 hr. and for an additional 40 min. at 3540'. The solvent was removed a t reduced pressure, and to the residue 20 ml. of water was added and it was extracted with ether. After removal of ether, 1.6 g. of sodium hydroxide, 1.6 ml. of water, and 24 ml. of ethanol were added to the residue. To this 4 ml. of 30% hydrogen peroxide solution was added during 20 min.; this was refluxed for 2 hr. After cooling, 80 ml. of water was added, the solution was acidified with hydrochloric acid, heated under reflux for 30 min., and extracted with eth3r. After removal of ether, the residue was hydrolyzed with alkali. The reaction mixture was acidified and heated under reflux for 1 hr. and was extracted with ether. The ethereal solution was washed with 570 sodium carbonate solution and water and dried over anhydrous sodium sulfate. Ether was removed and distillation of the residue gave 0.4 g. (9%) of cislactone (IX), b.p. 111-118" ( 5 mm.), and 0.2 g. of l-methyl-2hydroxymethyl-3-( l-hydroxy-2-propyl)cyclopentane, b .p . 120126" (5 mm.). These structure were established by comparison of infrared spect,ra with those of analytically pure compounds described in the following section. Using 4.7 g. of V, 0.9 g. of sodium borohydride, and 2.6 ml. of boron trifluoride etherate, the reaction was carried out as described above, when 3.0 g. of l-methyl-2-hydroxymethyl-3-( 1hydroxy-2-propyl)cyclopentane,b.p. 125140O (4.5 mni.), n Z o ~ 1.4906, was obtained; infrared typical bands (liquid film), 3330 __ and 1030 Anal. Calcd. for ClnHnoOB: _.__ - C., 69.72:, H.. 11.70. Found: C, 70.01; H , 11.73. dl-Nepetalinic Acids (X).-According to the procedure describ2d by Cavil1 and Locksley,jb oxidation of 1.0 g. of the synthesized cis-lactone ( I X ) with 2.5 g. of potassium permanganate gave 0.8 g. of crude acid mixture. Separative recrystallization gave 0.3 g. of acid A, m.p. 124-125", and 0.4 g. of acid B, m.p. 74-77'. Both acids gave correct analyses for C10H1604 and showed the identical infrared spectra (CSZ solution) with the respective authentic compounds. dl-Sepetalinic acid of m.p. 74-77" was not described in the literature. Anal. Calcd. for CioH1,Oa: C, 59.98; H , 8.05. Found: C, 60.42; H, 8.41. Glvcidic Ester IXI).-To a mixture of 45.5 e . of IT and 28.4 g. o f ethyl chloroacetate w-as added a solution of potassium tbutoxide, prepared from 9.0 g. of potassium and 230 ml. of anhydrous t-butyl alcohol. This mixture was stirred for 2 . 5 hr. at 10" and additional 30 min. at 25'. After removal of t-butyl alcohol at reduced pressure, ether was added to the residue and the ethereal solution was washed with water and dried over anhydrous sodium sulfate. After removal of ether, distillation of the residue recovered 18.3 g. of IV, b.p. 99-100" ( 5 mm.), and gave 14.5 g. (22.3qi) of glycidic ester ( X I ) , b.p. 135-140" (0.4-0.5 mm.), nz6~ 1.4630. The infrared spectrum (liquid film) showed typical bands a t 1732, 1728,865, and 765 cm.-'. Anal. Calcd. for C~SHUO~: C, 63.36; H, 8.51. Found: C, 63.04; H , 8.50. Hydrolysis of the Glycidic Ester (XI) and the Thermal Treatment.-To a solution of 85 ml. of absolute ethanol and 2.5 g. of sodium was added 14.5 g. of the glycidic ester ( X I ) . After addition of 1.8 g. of water, the solution was left standing. After 2 days, 200 ml. of water was added; this was acidified with hydrochloric acid and extracted with ether. The ethereal solution was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. When the solvent was removed at 40" under reduced pressure of 8 mm., 9.0 g. of viscous liquid was obt,ained. The infrared spectrum (liquid film) showed typical bands at 350&2600, 172G169.5, 840, and 750 cm.-'. This liquid was so hygroscopic that it could not be analyzed satisfactory. When the viscous liquid was added to 0.2 g. of copper powder and was heated at 14G190' (bath temperature) for 1 hr. under nitrogen, the reaction mixture afforded 4.0 g. of viscous liquid, b.p. 1 4 5 155" (0.8 mm.), which crystallized on standing. Recrystallization from petroleum ether (b.p. 30-70') gave the acid anhydride of m.p. 72-73'; infrared typical bands (Kujol mull), 1780, 1765,8,55, and 765 em.-'. Anal. Calcd. for CIIHMO~: C, 62.84; H, 6.71. Found: C, 62.82; H , 6.70. Ethyl 2-(2-Methoxymethylene-3-methylcyclopentyl)propionate. -To a mixture of 50 ml. of 1,2-dimethoxyethane, 1.2 g. of sodium hydride (2.3 g. of 53% suspension in mineral oil), and 1 drop of ethanol was added 17.1 g. of methoxpmethgltriphenglphosphonium c h l ~ r i d e . ~After ~ , ~ the ~ mixture was stirred for 1 hr. at 3233", 6.2 g. of IT' was added in the course of 30 min. and stirring

was continued for 1 hr. The mixture was then heated a t reflux temperature for 3 hr. During these procedures the characteristic coloration of phosphorane was observed. After removing most of the solvent, 5 ml. of ethanol and successively 50 ml. of water were added, and the resulting solution was extracted with ether. The ether extract was washed with water and after drying over anhydrous sodium sulfate ether was removed. Distillation of the residue afforded 5.5 g. (80%) of ethyl 2-(2-methoxymethylene-3methylcyclopenty1)propionate: b.p. 104-1 10" ( 5 mm.); ~ Z O D 1.4650; infrared typical bands (liquid film), 1735 and 1680 em.-'. Anal. Calcd. for C13H2203: C, 68.97; H , 9.80. Found: C , 68.99; H, 9.97. Ethyl 2-(2-Formyl-3-methylcyclopentyl)propionate .-According of methoxymethylene group was acto L e ~ i n e ,hydrolysis ~~ complished by adding 6.7 g. of ethyl 2-(2-methoxymethylene-3methylcyclopenty1)propionate to 50 ml. of ether saturated with 707, perchloric acid. After 8 min., 100 ml. of water was added, a n j the ether layer was separated and washed with saturated sodium sulfate. After removal of ether, distillation afforded 5.1 g. of ethyl 2-(2-formyl-3-methylcyclopentyl)propionate: b.p. ~ infrared typical bands (liquid 95-97' (4 mm.); l t Z o 1.4590; film), 2700, 1740, and 1735 em.-' Because of experimental difficulties, this aldehyde could not be purified, but the infrared spectrum as well as the following derivative were in accord with the proposed structure. Anal. Calcd. for C12H2003: C, 67.89; H, 9.50. Found: C, 67.19; H, 9.74. 2,4-Dinitrophenylhydrazoneof Ethyl 2-(2-Formyl-3-methylcyclopenty1)propionate.-Ethyl 2-(2-methoxymethylene-3-methyl cyclopenty1)propionate and ethyl 2-(2-formyl-3-methylcyclopenty1)propionate gave, by the ordinary procedure, the same 2,4dinitrophenylhydrazone, m.p. 155156', in an analytically pure state. Anal. Calcd. for CI7Hz4N4O6:C, 55.09; H , 6.17. Found: C, 55.10; H , 6.26. Lactone of 2-(2-Hydroxymethyl-J-rnethylcyclopentyl)propionic Acid. Procedure A,-A solution of 5.1 g. of ethyl 2-(2-formyl-3niethylcyclopentyl)propionate, 0.6 g. of sodium borohydride, and 50 ml. of ethanol was heated at reflux temperature for 40 rnin. To the reaction mixture 0.5 g. of sodium hydroxide and 20 ml. of water were added and, after heating at the reflux temperature for 2 hr., the reaction mixture was acidified with hydrochloric acid and refluxed for an additional 30 min. The cold reaction mixture vias extracted with ether and the ether extract was washed with water and dried over anhydrous sodium sulfate. On removal of ether, 1.5 g. (407,) of trans-lactone of 2-(2-hydroxymethyl-3-methylcyclopenty1)propionicacid, b .p. 94-95' ( 5 mm.), n% 1.4649, was obtained; infrared typical bands (liquid film), 1730 and 1170 em.-' -Anal. Calcd. for C10H1602:C, 71.39; H , 9.59. Found: C, 70.89; H , 9.60. Procedure B.-A mixture of 3.2 g. of ethyl 2-(2-methoxymethylene-3-methylcyclopenty1)propionate and 25 ml. of concentrated hydrochloric acid was heated at refluxed temperature for 13 hr. under an atmosphere of nitrogen. When hydrochloric acid was removed a t reduced pressure, a brown viscous oil was obtained. An infrared spectrum showed typical bands at 350C2800, 2700, 1720, and 1700. A solution of this oil, 0.5 g. of SOdium borohydride, and 10 ml. of water was left standing for 1 day and after acidification with hydrochloric acid was heated for 20 rnin. on a steam bath and extracted with ether. The ether extract was washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and evaporated. A 0.7-g. (30cI,) sample of trans-lactone of 2-( 2-hydroxymethyl-3-methylcyclopenty1)propionic acid, b.p. 98-102" (6 mm.), was obtained. The infrared spectrum was identical with that of the product of procedure A. Reduction of 2-(3-Methyl-2-oxocyclopentyl)propionicAcid with Sodium Borohydride.-A solution of 53 .0 g. of 2-(3-methyl-2oxocyclopenty1)propionic acid, 14.4 g. of sodium hydroxide, and 322 ml. of water was added to a solution of 7.8 g. of sodium borohydride and 125 ml. of water in the course of 1 hr. The solution was stirred for 5 hr. a t room temperature and was left standing for 2 days. Concentrated hydrochloric acid (150 ml.) was added to the reaction mixture with cooling under 10" in an ice bath. After heating at reflux for 15 min., the reaction mixture was extracted with three 250-ml. portions of benzene and with four 200-ml. portions of ether. Distillation of the benzene extract afforded 30.0 g. (62.5YG)of the lactone of cis-2-(2-hydroxy-

INTRAMOLECULAR NUCLEOPHILIC PARTICIPATIOK. IV

KOVEMBER, 1964

3-methylcyclopentyl)propionic acid: b.p. 86-88' ( 5 mm.); n a o D 1.4638; infrared typical bands (liquid film), 1762 and 1160 em.-' Anal. Calcd. for CgHi402: C , 70.10; H, 9.15. Found: C , 69.74; H, 9.20. The residue of the distillation and the ether extracts gave 10.4 g. ( 19.4'3 ) of trans-2-(2-hydroxy-3-methylcyclopentyl)propionic acid: m.p. 111-112°; infrared typical bands (Nujol mull), 3300 and 1705 em. -l Anal. Calcd. for C9H1603:C , 62.76; H, 9.36. Found: C, 62.84; H, 9.38. Lactonization of trans-2-(2-Hydroxy-3-methylcyclopentyl)propionic Acid.-When 3.0 g. of trans-2-(2-hydroxy-3-methylcyclo-

3365

penty1)propionic acid were heated with 1 drop of concentrated sulfuric acid a t 30 mm. in an oil bath a t 180-190", most of the material was distilled. The distillate was dried and 2.5 g. (96%) of the lactone of the cis acid, b.p. 92-93" (4 mm.), n Z o D 1.4641, was obtained; infrared typical bands (liquid film), 1762 and 1160 cm

-1

Anal. Calcd. for COHidO~:C, 70.10; H, 9.15. Found: C, 70.04; H, 9.35.

Acknowledgment.-We thank Miss Kenko Ogawa of this laboratory for the elemental analyses reported here.

Intramolecular Nucleophilic Participation. IV. The Hydrolysis Rates of Various ortho- and para- Substituted 1,l-Diphenylethyl Chlorides and Benzhydryl Chlorides and Bromides in Aqueous Acetone E. h.JEFFERY, R.B. BASSAL,L. J. ANDREWS, A N D R.-11. KEEFER Department o j Chemzstry, L'naversaty of Calafornaa, Davas, Calafornza Receaved J u n e 3, 1964 The relative reactivities of the ortho and para isomers of l-carbophenoxyphenyl-l-phenylethyl chloride with respect to hydrolysis in aqueous acetone have been compared with those of the corresponding l-phenyl-l-tolylethyl chlorides and with those of the o- and p-carbophenoxybenzhydryl bromides and chlorides. It appears that the -COOC& group contributes much less extensively as a participating nucleophile in the reaction of 1o-carbophenoxyphenyl-l-phenylethylchloride than in the reactions of the o-carbophenoxybenzhydryl halides. The capacity of this group to promote the hydrolysis of o-carbophenoxybenzhydryl bromide seems to diminish as the water content of the medium is increased. The mechanistic implications of these results are discussed. Evidence is also presented that the ?JOz group does not participate extensively, if a t all, in the hydrolysis of o-nitrobenzhydryl bromide.

It has been demonstrated that o-carbophenoxybenzhydryl broiiiide is hydrolyzed in aqueous acetone much more rapidly than is its para isomer. The high reactivity of the ortho isomer is ascribed to its capacity to promote polarization of the carbon-halogen bond by releasing electrons to the p-orbital being vacated a t the site of the displacement reaction (eq. 1). The evidence

Y

cd-IH,c-o

C&,CHBr &cmc6H5

Br-

+

&y0c6H5

I

(1)

for similar participation by the -COOCH, group in the hydrolyses of o-carboethoxybenzyl and o-carbomethoxycumyl halides is negative.'!* It has been suggested, by way of explanation, that it is energetically critical for positive polarization of carbon a t the reaction center of the benzyl and' cumyl halides that the electron deficient p-orbital overlap the n-orbital of the ring. This constitutes an unfavorable geometric situation for partici2ation by an o-COOCH, group. The hydrolyses of benzhydryl halides in aqueous acetone are frequently discussed as examples of Sxl-type solvolyses. Clearly the carbon-halogen bonds must be substantially polarized, with solvent assistance, in the slow stages of these reactions. The slow step in the hydrolysis of o-carbophenoxybenzhydryl bromide is very likely a concerted process in which the exocyclic ( 1 ) A. Singh, L. J. Andrewa, and R. .M.Keefer, J . Am. Chem. Soc., 84, 1179 (1962). (2) J. L. Cotter, L. J. A n d r e w . and R. M. Keefer, J . Org. Chem., 88, 1917 (1963). (3) See for example J. Hine. "Phyaical Organic Chemistry," 2nd Ed., McGraw-Hill Book Co., Inc.. h'ew York, N. Y.. 1962.

carbon loses bromide ion and siniultaneously coordinates with the -COOCsHS group; that is, hydrolysis with ortho-substituent participation has some of the characteristics of an Sx2-type reaction. I n this connection it has seemed of interest to determine whether changes in reactant structure and in medium polarity, which may be conducive to Sx-2 as opposed to S N displacement, ~ have a favorable or unfavorable influence on the capacity of the o-carbophenoxy group to participate in benzhydryl halide hydrolysis. A comparison of the rates of solvolysis in aqukous acetone of the ortho and para isomers of l-phenyl-ltolylethyl chloride and also of the o- and p-carbophenoxybenzhydryl chlorides has been made. An investigation of the effect of changes in the water content of aqueous acetone solvent mixtures on the oTtho-para reactivity ratio for hydrolysis of the isomeric carbophenoxybenzhydryl bromides has also been conducted. As an incidental matter the hydrolysis rates of the oand p-nitrobenzhydryl bromides have been investigated to provide information concerning the nucleophilic character of the o-SOz group. Experimental 1-p-Carbophenoxyphenyl-1-pheny1ethane.-The procedure of Szmant and Yoncoskie4 mas used in the preparation of 1,l-diphenylethane, b.p. 123-125' (6 mm.). This hydrocarbon was converted to l-p-iodophenyl-l-phenylethane, b.p. 168-175' (0.5 mm.); the iodo compound was converted to l-p-cyanophenyl-l-phenylethane, m.p. XI", and the nitrile was hydrolyzed to provide a sample of p-l-phenethylbenzoic acid, m.p. 123", by methods all of which have been described p r e ~ i o u s l y . ~A 20-g. (0.088-mole) sample of the arid was heated with 10.5 g. (0.0% mole) of thionyl chloride for 1 hr., and 8.3 g. (0.088 mole) (4)

H. H. Szmant and R. Yoncoskie, J . Org. Chem.. 81, 78 (1956)